WO2020260857A1 - Hydroxamate compounds as antagonists of the adenosine a2a receptor - Google Patents

Hydroxamate compounds as antagonists of the adenosine a2a receptor Download PDF

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WO2020260857A1
WO2020260857A1 PCT/GB2020/051432 GB2020051432W WO2020260857A1 WO 2020260857 A1 WO2020260857 A1 WO 2020260857A1 GB 2020051432 W GB2020051432 W GB 2020051432W WO 2020260857 A1 WO2020260857 A1 WO 2020260857A1
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amino
pyrimidine
cyanophenyl
carboxamide
methyl
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PCT/GB2020/051432
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French (fr)
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Clive Mccarthy
Edward Richard WALKER
Pearl Siobhan MCMAHON
Frédéric Jacques MARLIN
Ben MOULTON
Joseph Rogers
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AdoRx Therapeutics Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
    • 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
    • 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
    • C07D403/12—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 linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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

Definitions

  • the present invention relates to certain hydroxamate compounds that function as antagonists of the adenosine A2a receptor.
  • 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 adenosine A2a receptor activity is implicated, such as, for example, cancer.
  • a number of immunosuppressive pathways are active in the tumour microenvironment which enable tumour cells to evade elimination by cytotoxic T cells and can diminish the clinical response of patients to immunotherapy with anti-checkpoint antibodies.
  • the anti-PD- 1 antibodies pembrolizumab and nivolumab and anti-PD-L1 antibodies durvalumab, avelumab and atezolizumab are approved for the treatment of number of solid tumours including non- small cell lung cancer, head and neck squamous cancer and urothelial cancer.
  • only 20-30% of patients respond to checkpoint blockade and the side effects of such treatments are significant (Sukari et al, 2016). Consequently, other approaches to enhance the cytotoxic potential of the tumour microenvironment are actively being investigated. This includes agents that could be used as monotherapies or, more likely, used in combination with checkpoint inhibitors and cytotoxic agents to enhance their efficacy.
  • Adenosine has immunosuppressive properties and is present in the tumour microenvironment at high concentrations. Recent studies estimate the concentration of adenosine to be about 10 ⁇ M in human tumours compared to ⁇ 1 ⁇ M in normal tissue (Houthuys et al 2017). Adenosine is formed at both intracellular and extracellular sites by two distinct pathways that involve two different substrates.
  • Intracellular adenosine is derived from AMP and S-adenosyl homocysteine whilst the high extracellular adenosine concentrations observed during metabolic stress are associated with the release and degradation of precursor adenine nucleotides (ATP, ADP and AMP) by the concerted action of CD39 and CD73 (Vijayan et al, 2017).
  • CD39 and CD73 are upregulated in the tumour microenvironment in response to hypoxia.
  • CD73 represents a putative patient stratification method for adenosine antagonists as its expression on tumour cells is also associated with poor overall prognosis in many different cancer types suggesting that adenosine production contributes to the undesirable immunosuppressive phenotype of the tumour microenvironment (Gao et al 2014; Loi et al, 2013;).
  • CD73 expression by tumour-infiltrating immune cells is also important in promoting tumour immune suppression as CD73 negative Treg cells fail to suppress effector T cell functions (Deaglio et al, 2007; Reinhardt et al, (2017).
  • patients resistant to anti- PD1 treatment have elevated levels of CD73 (Reinhardt et al, 2017).
  • Adenosine regulates cell function via occupancy of specific GPCRs on the cell surface of the P1 purinoceptor subtypes.
  • the P1 receptor family is further subdivided into A1, A2a, A2b and A3.
  • A2 receptors are subdivided into A2a and A2b, based on high and low affinity for adenosine, respectively.
  • A2a is expressed by lymphocytes and activation of A2a leads to suppression of cytokine production and other effector functions. Tumour growth is inhibited by genetic ablation of A2a in syngeneic mouse models and this effect has been demonstrated to be due to enhanced lymphocyte activation and cytotoxic function (Ohta et al, 2006; Waickman et al 2012; Beavis et al, 2013; Mittal et al, 2014; Cekic et al, 2014).
  • A2a-/- mice show an increased response to inhibition of checkpoint pathways such as PD-1, with an improvement in both tumour free survival and overall survival.
  • Adenosine-mediated A2a activation also limits the efficacy of ant-CTLA4 treatment (Iannone et al, 2014).
  • A2a antagonists have been shown to enhance the cytotoxic CD8+T cells and to enhance the ability of NK cells prevent metastasis of CD73-expressing tumours (Beavis et al, 2013). Importantly, A2a antagonists enhance the efficacy of anti-PD1 antibodies (Beavis et al, 2015).
  • 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 antagonising adenosine A2a receptors 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 antagonising adenosine A2a receptors 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 with adenosine A2a receptor 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).
  • 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 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).
  • a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein for use as an adenosine A2a antagonist for use as an adenosine A2a antagonist.
  • the compounds of the invention are selective adenosine A2a antagonists.
  • certain compounds of the invention are selective adenosine A2a and adenosine A2b antagonists.
  • 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).
  • 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.
  • references to“treating” or“treatment” include prophylaxis as well as the alleviation of established symptoms of a condition.“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.
  • a similar convention applies to other radicals, for example“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.
  • An“alkylene,”“alkenylene,” or“alkynylene” group 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 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.
  • heterocycles containing sulfur 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.
  • a heterocyclyl group may bear one or more oxo or thioxo groups.
  • 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 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
  • 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:
  • thiazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms
  • 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.
  • 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 term“wherein a/any CH, CH 2 , CH 3 group or heteroatom (i.e. NH) within a R 1 group is optionally substituted” suitably means that (any) one of the hydrogen radicals of the R 1 group is substituted by a relevant stipulated group.
  • the present invention relates to compounds, or pharmaceutically acceptable salts, hydrates or solvates thereof, having the structural formula I shown below:
  • R 1 is selected from aryl or heteroaryl, each of which is optionally substituted with one or more substituents independently selected from halo, OH, cyano, R 5 , OR 5 , S(O)0-2R 5 and NR 5 R 6 , wherein each R 5 and R 6 is independently H, (1-6C)alkyl or (3-7C)cycloalkyl, either of which is optionally substituted with one or more substituents selected from halo, OH, aryl and heteroaryl, wherein aryl and heteroaryl groups are optionally substituted with one or more substituents selected from halo, OH, (1-6C)alkyl and (1-6C)haloalkyl;
  • R 2 is selected from:
  • R 2a and R 2b are each independently selected from hydrogen, fluoro or (1-2C)alkyl;
  • L 1a is absent or selected from C(O), C(O)O, C(O)N(R a1 ) or C(S)N(R a1 ), wherein R a1 is selected from hydrogen or (1-2C)alkyl;
  • L 1b is absent or selected from O, S, SO, SO 2 , N(R a ), C(O), C(O)O, OC(O), C(O)N(R a ), N(R a )C(O), N(R a )C(O)N(R b ), C(S)N(R a ), N(R a )C(S), N(R a )C(S)N(R b ), S(O) 2 N(R a ), or N(R a )SO 2 , wherein R a and R b are each independently selected from hydrogen or (1- 2C)alkyl; and
  • Z 1 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl or heteroaryl; and wherein Z 1 is optionally substituted by one or more substituents selected from (1-6C)- alkyl, halo, (1-6C)haloalkyl, (1-6C)haloalkoxy, cyano, aryl, heteroaryl, heterocyclyl, nitro, NR c R d , OR c , C(O)R c , C(O)OR c , OC(O)R c , C(O)N(R c )R d , N(R c )C(O)R d , S(O) y R c (where y is 0, 1 or 2), SO 2 N(R c )R d , N(R c )SO 2 R d , (CH 2 ) z NR c R d (where z is 1, 2 or 3) or
  • R 3 is selected from:
  • R3a and R3b are each independently selected from hydrogen or (1-2C)alkyl
  • L2a is absent or selected from C(O), C(O)O, C(O)N(Rj) or C(S)N(Rj), wherein Rj is selected from hydrogen or (1-2C)alkyl;
  • Z2 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl or heteroaryl; and wherein Z2 is optionally substituted by one or more substituents selected from (1-6C)- alkyl, halo, (1-6C)haloalkyl, (1-6C)haloalkoxy, cyano, aryl, heteroaryl, heterocyclyl, nitro, NR h R i , OR h , C(O)R h , C(O)OR h , OC(O)R h , C(O)N(R h )R i , N(R h )C(O)R i , N(R h )C(O)N(R i )R k , N(R h )C(O)OR i , OC(O)N(R h )R i , S(O) y R h (where y is 0, 1
  • R 1 is selected from aryl or heteroaryl, each of which is optionally substituted with one or more substituents independently selected from halo, OH, cyano, R 5 , OR 5 , S(O) 0-2 R 5 and NR 5 R 6 , wherein each R 5 and R 6 is independently H, (1-6C)alkyl or (3-7C)cycloalkyl, either of which is optionally substituted with one or more substituents selected from halo, OH, aryl and heteroaryl, wherein aryl and heteroaryl groups are optionally substituted with one or more substituents selected from halo, OH, (1-6C)alkyl and (1-6C)haloalkyl;
  • R 2 is selected from:
  • R2a and R2b are each independently selected from hydrogen, fluoro or (1-2C)alkyl;
  • L1a is absent or selected from C(O), C(O)O, C(O)N(Ra1) or C(S)N(Ra1), wherein Ra1 is selected from hydrogen or (1-2C)alkyl;
  • L 1b is absent or selected from O, S, SO, SO 2 , N(R a ), C(O), C(O)O, OC(O), C(O)N(R a ), N(R a )C(O), N(R a )C(O)N(R b ), C(S)N(R a ), N(R a )C(S), N(R a )C(S)N(R b ), S(O) 2 N(R a ), or N(R a )SO 2 , wherein R a and R b are each independently selected from hydrogen or (1- 2C)alkyl; and
  • Z 1 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl or heteroaryl; and wherein Z 1 is optionally substituted by one or more substituents selected from (1-6C)- alkyl, halo, (1-6C)haloalkyl, (1-6C)haloalkoxy, cyano, aryl, heteroaryl, heterocyclyl, nitro, NR c R d , OR c , C(O)R c , C(O)OR c , OC(O)R c , C(O)N(R c )R d , N(R c )C(O)R d , S(O) y R c (where y is 0, 1 or 2), SO 2 N(R c )R d , N(R c )SO 2 R d or (CH 2 ) z NR c R d (where z is 1, 2 or 3), wherein
  • R 3 is selected from:
  • R3a and R3b are each independently selected from hydrogen or (1-2C)alkyl
  • L2a is absent or selected from C(O), C(O)O, C(O)N(Rj) or C(S)N(Rj), wherein Rj is selected from hydrogen or (1-2C)alkyl
  • Z2 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl or heteroaryl; and wherein Z2 is optionally substituted by one or more substituents selected from (1-6C)- alkyl, halo, (1-6C)haloalkyl, (1-6C)haloalkoxy, cyano, aryl, heteroaryl, heterocyclyl, nitro, NRhRi, ORh, C(O)Rh, C(O)ORh, OC(O)Rh, C(O)N(Rh)Ri, N(Rh)C(O)Ri, S(O)yRh (where y is 0, 1 or 2), SO2N(Rh)Ri, N(Rh)SO2Ri or (CH2)zNRhRi (where z is 1, 2 or 3), wherein any alkyl, aryl, heteroaryl or heterocyclyl moiety in a substituent group on Z z is optionally further substitute
  • Particular compounds of the invention include, for example, compounds of the formula I, or pharmaceutically acceptable salts, hydrates and/or solvates thereof, wherein, unless otherwise stated, each of R 1 , R 2 and R 3 have any of the meanings defined hereinbefore or in any of paragraphs (1) to (50) hereinafter:- (1) R 1 is phenyl or a 5- or 6-membered heteroaryl optionally substituted with one or more substituents independently selected from halo, OH, cyano, R 5 , OR 5 , S(O) 0-2 R 5 and NR 5 R 6 ,
  • each R 5 and R 6 is independently H, (1-6C)alkyl or (3-7C)cycloalkyl, either of which is optionally substituted with one or more substituents selected from halo, OH, aryl and heteroaryl, wherein aryl and heteroaryl groups are optionally substituted with one or more substituents selected from halo, OH, (1-4C)alkyl and (1-4C)haloalkyl;
  • R 1 is phenyl or 5- or 6-membered heteroaryl optionally substituted with with one or more substituents independently selected from halo, OH, cyano, R 5 or OR 5 , wherein each R 5 is independently H, (1-6C)alkyl or (3-7C)cycloalkyl, either of which is optionally substituted with one or more substituents selected from halo, OH, aryl and heteroaryl, wherein aryl and heteroaryl groups are optionally substituted with one or more substituents selected from halo, OH, (1-4C
  • R 1 is phenyl or 5- or 6-membered heteroaryl optionally substituted with with one or more substituents independently selected from halo, OH, cyano, R 5 or OR 5 , wherein each R 5 is independently H or (1-4C)alkyl;
  • R 1 is phenyl or 5-membered heteroaryl optionally substituted with with one or more substituents independently selected from halo, OH, cyano, R 5 or OR 5 , wherein each R 5 is independently H or (1-4C)alkyl;
  • R 1 is phenyl, furanyl, pyridyl, oxazolyl or pyrazolyl, optionally substituted with with one or more substituents independently selected from halo, OH, cyano, R 5 or OR 5 , wherein each R 5 is independently H or (1-4C)alkyl;
  • R 1 is phenyl, furan-2-yl, oxazol-2-yl, pyrazol-1-yl, m-cyanophenyl or thiazolyl, optionally substituted with with one or more substituents independently selected from halo, OH, cyano, R 5 or OR 5 , wherein each R 5 is independently H or (1-4C)alkyl;
  • R 1 is phenyl, furyl, pyridyl or oxazolyl, optionally substituted by halo or cyano;
  • R 1 is phenyl, optionally substituted with with one or more substituents independently selected from halo, OH, cyano, R 5 or OR 5 , wherein each R 5 is independently H or (1- 4C)alkyl;
  • R 1 is 3-halophenyl, for example 3-fluorophenyl and 3-chlorophenyl, 2-halophenyl, for example 2-fluorophenyl, and 2-chlorophenyl, 4-halophenyl, for example 4- fluorophenyl and 4-chlorophenyl, 3-cyanophenyl, 2-cyanophenyl or 4-cyanophenyl (10) R 1 is 3-fluorophenyl, 2-fluorophenyl, 4-fluorophenyl or 3-cyanophenyl, especially 3- fluorophenyl and 3-cyanophenyl;
  • R 1 is 3-cyanophenyl.
  • R 2 is selected from:
  • R 2a and R 2b are each independently selected from hydrogen, fluoro or (1-2C)alkyl;
  • L 1a is absent or selected from C(O), C(O)O or C(O)N(R a1 ), wherein R a1 is selected from hydrogen or (1-2C)alkyl;
  • L1b is absent or selected from O, S, SO, SO2, N(Ra), C(O), C(O)O, OC(O), C(O)N(Ra), N(Ra)C(O), N(Ra)C(O)N(Rb), S(O)2N(Ra), or N(Ra)SO2, wherein Ra and Rb are each independently selected from hydrogen or (1-2C)alkyl; and
  • Z1 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl or heteroaryl; and wherein Z1 is optionally substituted by one or more substituents selected from (1-6C)- alkyl, halo, (1-6C)haloalkyl, (1-6C)haloalkoxy, cyano, aryl, heteroaryl, heterocyclyl, nitro, NRcRd, ORc, C(O)Rc, C(O)ORc, OC(O)Rc, C(O)N(Rc)Rd, N(Rc)C(O)Rd, S(O)yRc (where y is 0, 1 or 2), SO2N(Rc)Rd, N(Rc)SO2Rd or (CH2)zNRcRd (where z is 1, 2 or 3), wherein any alkyl, aryl, heteroaryl or heterocyclyl moiety in a substituent group on Z1 is optionally further substituted
  • R 2 is selected from:
  • R 2a and R 2b are each independently selected from hydrogen, fluoro or (1-2C)alkyl;
  • L 1a is absent or selected from C(O), C(O)O or C(O)N(R a1 ), wherein R a1 is selected from hydrogen or (1-2C)alkyl;
  • L 1b is absent or selected from O, S, SO, SO 2 , N(R a ), C(O), C(O)O, OC(O), C(O)N(R a ), N(R a )C(O), N(R a )C(O)N(R b ), S(O) 2 N(R a ), or N(R a )SO 2 , wherein R a and R b are each independently selected from hydrogen or (1-2C)alkyl; and
  • Z 1 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl or heteroaryl; and wherein Z 1 is optionally substituted by one or more substituents selected from (1- 6C)alkyl, halo, (1-6C)haloalkyl, (1-6C)haloalkoxy, cyano, phenyl, a 5- or 6-membered heteroaryl, a 4- to 7-membered heterocyclyl, NR c R d , OR c , C(O)R c , C(O)OR c , OC(O)R c , C(O)N(R c )R d , N(R c )C(O)R d , S(O) y R c (where y is 0, 1 or 2), SO 2 N(R c )R d , N(R c )SO 2 R d or (CH 2 ) z NR c
  • R 2 is selected from:
  • R2a and R2b are each independently selected from hydrogen, fluoro or methyl;
  • L1a is absent or selected from C(O), C(O)O or C(O)N(Ra1), wherein Ra1 is selected from hydrogen or (1-2C)alkyl;
  • L1b is absent or selected from O, S, SO, SO2, N(Ra), C(O), C(O)O, OC(O), C(O)N(Ra), N(Ra)C(O), N(Ra)C(O)N(Rb), S(O)2N(Ra), or N(Ra)SO2, wherein Ra and Rb are each independently selected from hydrogen or (1-2C)alkyl; and
  • Z1 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl or heteroaryl; and wherein Z1 is optionally substituted by one or more substituents selected from (1- 6C)alkyl, halo, (1-6C)haloalkyl, (1-6C)haloalkoxy, cyano, phenyl, a 5- or 6-membered heteroaryl, a 4- to 7-membered heterocyclyl, NRcRd, ORc, C(O)Rc, C(O)ORc, OC(O)Rc, C(O)N(R c )R d , N(R c )C(O)R d , S(O) y R c (where y is 0, 1 or 2), SO 2 N(R c )R d , N(R c )SO 2 R d or (CH 2 ) z NR c R d (where z is 1, 2 or
  • R 2 is selected from:
  • R 2a and R 2b are each independently selected from hydrogen, fluoro or methyl
  • L 1a is absent
  • L 1b is absent or selected from O, S, SO, SO 2 , N(R a ), C(O), C(O)O, OC(O), C(O)N(R a ), N(R a )C(O), N(R a )C(O)N(R b ), S(O) 2 N(R a ), or N(R a )SO 2 , wherein R a and R b are each independently selected from hydrogen or (1-2C)alkyl; and
  • Z 1 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl or heteroaryl; and wherein Z 1 is optionally substituted by one or more substituents selected from (1- 6C)alkyl, halo, (1-6C)haloalkyl, (1-6C)haloalkoxy, cyano, phenyl, a 5- or 6-membered heteroaryl, a 4- to 7-membered heterocyclyl, NRcRd, ORc, C(O)Rc, C(O)ORc, OC(O)Rc, C(O)N(Rc)Rd, N(Rc)C(O)Rd, S(O)yRc (where y is 0, 1 or 2), SO2N(Rc)Rd, N(Rc)SO2Rd or (CH2)zNRcRd (where z is 1, 2 or 3), wherein any alkyl, aryl, heteroaryl or heterocyclyl moiety
  • R2a and R2b are each independently selected from hydrogen, fluoro or methyl
  • L1a is absent
  • L1b is absent or selected from O, S, SO, SO2, N(Ra), C(O), C(O)O, OC(O), C(O)N(Ra), or N(Ra)C(O), wherein Ra and Rb are each independently selected from hydrogen or (1-2C)alkyl; and
  • Z 1 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl or heteroaryl; and wherein Z 1 is optionally substituted by one or more substituents selected from (1- 6C)alkyl, halo, (1-6C)haloalkyl, (1-6C)haloalkoxy, cyano, phenyl, a 5- or 6-membered heteroaryl, a 4- to 7-membered heterocyclyl, NR c R d , OR c , C(O)R c , C(O)OR c , OC(O)R c , C(O)N(R c )R d , N(R c )C(O)R d , S(O) y R c (where y is 0, 1 or 2), SO 2 N(R c )R d , N(R c )SO 2 R d or (CH 2 ) z NR c
  • R 2 is selected from:
  • R 2a and R 2b are each independently selected from hydrogen, fluoro or methyl
  • L 1a is absent
  • L1b is absent
  • Z1 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl or heteroaryl; and wherein Z1 is optionally substituted by one or more substituents selected from (1- 6C)alkyl, halo, (1-6C)haloalkyl, (1-6C)haloalkoxy, cyano, phenyl, a 5- or 6-membered heteroaryl, a 4- to 7-membered heterocyclyl, NRcRd, ORc, C(O)Rc, C(O)ORc, OC(O)Rc, C(O)N(Rc)Rd, N(Rc)C(O)Rd, S(O)yRc (where y is 0, 1 or 2), SO2N(Rc)Rd, N(Rc)SO2Rd or (CH2)zNRcRd (where z is 1, 2 or 3), wherein any alkyl, aryl, heteroaryl or heterocyclyl moiety
  • R 2 is selected from:
  • R 2a and R 2b are each independently selected from hydrogen, fluoro or methyl
  • L 1a is absent
  • L 1b is absent
  • Z 1 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl or heteroaryl; and wherein Z 1 is optionally substituted by one or more substituents selected from (1- 6C)alkyl, halo, (1-6C)haloalkyl, (1-6C)haloalkoxy, cyano, phenyl, NR c R d , OR c , C(O)R c , C(O)OR c , OC(O)R c , C(O)N(R c )R d , N(R c )C(O)R d , S(O) y R c (where y is 0, 1 or 2), SO 2 N(R c )R d , N(R c )SO 2 R d or (CH 2 ) z NR c R d (where z is 1, 2 or 3), wherein any alkyl or phenyl moiety
  • R 2 is selected from:
  • R2a and R2b are each independently selected from hydrogen, fluoro or methyl
  • L1a is absent
  • L1b is absent
  • Z1 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl or heteroaryl; and wherein Z1 is optionally substituted by one or more substituents selected from (1- 6C)alkyl, halo, (1-6C)haloalkyl, (1-6C)haloalkoxy, cyano, phenyl, NRcRd, ORc, C(O)Rc, C(O)ORc, OC(O)Rc, C(O)N(Rc)Rd, N(Rc)C(O)Rd, S(O)yRc (where y is 0, 1 or 2), SO2N(Rc)Rd, N(Rc)SO2Rd or (CH2)zNRcRd (where z is 1, 2 or 3), wherein any alkyl or phenyl moiety in a substituent group on Z1 is optionally further substituted by cyano, halo, hydroxy, amino, (1-2C)al
  • R 2 is selected from:
  • R 2a and R 2b are hydrogen
  • L 1a is absent
  • L 1b is absent
  • Z 1 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl or heteroaryl; and wherein Z 1 is optionally substituted by one or more substituents selected from (1- 6C)alkyl, halo, (1-6C)haloalkyl, (1-6C)haloalkoxy, cyano, phenyl, NR c R d , OR c , C(O)R c , C(O)OR c , OC(O)R c , C(O)N(R c )R d , N(R c )C(O)R d , S(O) y R c (where y is 0, 1 or 2), SO 2 N(R c )R d , N(R c )SO 2 R d or (CH 2 ) z NR c R d (where z is 1, 2 or 3), wherein R c and R d are each independently selected
  • R 2 is selected from:
  • Z1 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl or heteroaryl; and wherein Z1 is optionally substituted by one or more substituents selected from (1- 6C)alkyl, halo, (1-6C)haloalkyl, (1-6C)haloalkoxy, cyano, NRcRd, ORc, C(O)Rc, C(O)ORc, OC(O)Rc, C(O)N(Rc)Rd, N(Rc)C(O)Rd, S(O)yRc (where y is 0, 1 or 2), SO2N(Rc)Rd, N(Rc)SO2Rd or (CH2)zNRcRd (where z is 1, 2 or 3), wherein Rc and Rd are each independently selected from hydrogen, (1-4C)alkyl, (1-4C)haloalkyl or (3- 6C)cycloalkyl;
  • R 2 is selected from:
  • Z1 is selected from (1-6C)alkyl, (3-6C)cycloalkyl or heterocyclyl; and wherein Z1 is optionally substituted by one or more substituents selected from (1-6C)alkyl, halo, (1- 6C)haloalkyl, (1-6C)haloalkoxy, cyano, NR c R d , OR c , C(O)R c , C(O)OR c , OC(O)R c , C(O)N(R c )R d , N(R c )C(O)R d , S(O) y R c (where y is 0, 1 or 2), SO 2 N(R c )R d , N(R c )SO 2 R d or (CH 2 ) z NR c R d (where z is 1, 2 or 3), wherein R c and R d are each independently selected from hydrogen, or (1-4C)alkyl;
  • R 2 is selected from:
  • Z 1 is selected from (1-6C)alkyl or (3-6C)cycloalkyl or heterocyclyl; and wherein Z 1 is optionally substituted by one or more substituents selected from (1-6C)alkyl, halo, cyano, NR c R d , OR c , C(O)R c , C(O)OR c , OC(O)R c , C(O)N(R c )R d , N(R c )C(O)R d , or S(O) y R c (where y is 0, 1 or 2), wherein R c and R d are each independently selected from hydrogen, or (1-4C)alkyl;
  • R 2 is selected from:
  • Z1 is selected from (1-6C)alkyl or (3-6C)cycloalkyl optionally substituted by one or more substituents selected from methoxy and OH;
  • R 3 is selected from: (i) –Z2;
  • R3a and R3b are each independently selected from hydrogen or (1-2C)alkyl
  • L2a is absent or selected from C(O), C(O)O or C(O)N(Rj), wherein Rj is selected from hydrogen or (1-2C)alkyl
  • R 3 is selected from:
  • R 3a and R 3b are each independently selected from hydrogen or (1-2C)alkyl
  • L 2a is absent or selected from C(O)O or C(O)N(R j ), wherein R j is selected from hydrogen or (1-2C)alkyl
  • L2b is absent or selected from O, S, SO, SO2, N(Re), C(O), C(O)O, OC(O), C(O)N(Re), N(Re)C(O), S(O)2N(Re), or N(Re)SO2, wherein Re is selected from hydrogen or (1- 2C)alkyl; and
  • Z2 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl or heteroaryl; and wherein Z2 is optionally substituted by one or more substituents selected from (1-6C)- alkyl, halo, (1-6C)haloalkyl, (1-6C)haloalkoxy, cyano, aryl, heteroaryl, heterocyclyl, nitro, NRhRi, ORh, C(O)Rh, C(O)ORh, OC(O)Rh, C(O)N(Rh)Ri, N(Rh)C(O)Ri, S(O)yRh (where y is 0, 1 or 2), SO2N(Rh)Ri, N(Rh)SO2Ri or (CH2)zNRhRi (where z is 1, 2 or 3), wherein any alkyl, aryl, heteroaryl or heterocyclyl moiety in a substituent group on Zz is optionally further substituted
  • R 3 is selected from:
  • R 3a and R 3b are each independently selected from hydrogen or methyl
  • L 2a is absent or selected from C(O)O or C(O)N(R j ), wherein R j is selected from hydrogen or (1-2C)alkyl
  • L 2b is absent or selected from O, S, SO, SO 2 , N(R e ), C(O), C(O)O, OC(O), C(O)N(R e ), or N(R e )C(O), wherein R e is selected from hydrogen or (1-2C)alkyl;
  • Z 2 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl or heteroaryl; and wherein Z 2 is optionally substituted by one or more substituents selected from (1-6C)- alkyl, halo, (1-6C)haloalkyl, (1-6C)haloalkoxy, cyano, aryl, heteroaryl, heterocyclyl, nitro, NR h R i , OR h , C(O)R h , C(O)OR h , OC(O)R h , C(O)N(R h )R i , N(R h )C(O)R i , S(O) y R h (where y is 0, 1 or 2), SO 2 N(R h )R i , N(R h )SO 2 R i or (CH 2 ) z NR h R i (where z is 1, 2 or 3), wherein
  • R 3 is selected from:
  • R3a and R3b are each independently selected from hydrogen or methyl
  • L2a is absent
  • L2b is absent or selected from O, S, SO, SO2, N(Re), C(O), C(O)O, OC(O), C(O)N(Re), or N(Re)C(O), wherein Re is selected from hydrogen or (1-2C)alkyl;
  • Z2 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl or heteroaryl; and wherein Z2 is optionally substituted by one or more substituents selected from (1-6C)- alkyl, halo, (1-6C)haloalkyl, (1-6C)haloalkoxy, cyano, phenyl, 5- or 6-membered heteroaryl, 4- to 7-membered heterocyclyl, NRhRi, ORh, C(O)Rh, C(O)ORh, OC(O)Rh, C(O)N(Rh)Ri, N(Rh)C(O)Ri, S(O)yRh (where y is 0, 1 or 2), SO2N(Rh)Ri, N(Rh)SO2Ri or (CH 2 ) z NR h R i (where z is 1, 2 or 3), wherein any alkyl, aryl, heteroaryl or heterocyclyl
  • R 3 is selected from:
  • R 3a and R 3b are each independently selected from hydrogen or methyl
  • L 2a is absent
  • L 2b is absent or selected from O, S, SO, SO 2 , N(R e ), C(O), C(O)O, OC(O), C(O)N(R e ), or N(R e )C(O), wherein R e is selected from hydrogen or (1-2C)alkyl;
  • Z 2 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl or heteroaryl; and wherein Z 2 is optionally substituted by one or more substituents selected from (1-6C)- alkyl, halo, (1-6C)haloalkyl, (1-6C)haloalkoxy, cyano, phenyl, 5- or 6-membered heteroaryl, 4- to 7-membered heterocyclyl, NR h R i , OR h , C(O)R h , C(O)OR h , OC(O)R h , C(O)N(Rh)Ri, N(Rh)C(O)Ri, S(O)yRh (where y is 0, 1 or 2), SO2N(Rh)Ri, N(Rh)SO2Ri or (CH2)zNRhRi (where z is 1, 2 or 3), wherein Rh and Ri are each independently selected from hydrogen, (1-6
  • R 3 is selected from:
  • R3a and R3b are hydrogen
  • L2a is absent
  • L2b is absent
  • Z2 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl or heteroaryl; and wherein Z2 is optionally substituted by one or more substituents selected from (1-6C)- alkyl, halo, (1-6C)haloalkyl, (1-6C)haloalkoxy, cyano, phenyl, 5- or 6-membered heteroaryl, 4- to 7-membered heterocyclyl, NRhRi, ORh, C(O)Rh, C(O)ORh, OC(O)Rh, C(O)N(R h )R i , N(R h )C(O)R i , S(O) y R h (where y is 0, 1 or 2), SO 2 N(R h )R i , N(R h )SO 2 R i or (CH 2 ) z NR h R i (where z is 1, 2 or 3), wherein
  • R 3 is selected from:
  • Z 2 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, phenyl, heterocyclyl or heteroaryl; and wherein Z 2 is optionally substituted by one or more substituents selected from (1- 6C)alkyl, halo, (1-6C)haloalkyl, (1-6C)haloalkoxy, cyano, phenyl, 5- or 6-membered heteroaryl, 4- to 7-membered heterocyclyl, NR h R i , OR h , C(O)R h , C(O)OR h , OC(O)R h , C(O)N(R h )R i , N(R h )C(O)R i , S(O) y R h (where y is 0, 1 or 2), SO 2 N(R h )R i , N(R h )SO 2 R i or (CH 2 ) z NR h R i
  • R 3 is selected from:
  • Z2 is selected from (1-6C)alkyl, (3-6C)cycloalkyl or heterocyclyl; and wherein Z2 is optionally substituted by one or more substituents selected from (1-6C)alkyl, halo, (1- 6C)haloalkyl, (1-6C)haloalkoxy, cyano, phenyl, 5- or 6-membered heteroaryl, 4- to 7- membered heterocyclyl, NRhRi, ORh, C(O)Rh, C(O)ORh, OC(O)Rh, C(O)N(Rh)Ri, N(Rh)C(O)Ri, S(O)yRh (where y is 0, 1 or 2), SO2N(Rh)Ri, N(Rh)SO2Ri or (CH2)zNRhRi (where z is 1, 2 or 3), wherein Rh and Ri are each independently selected from hydrogen or (1-4C)alkyl.
  • R 3 is selected from:
  • Z 2 is selected from 4, 5 or 6-membered heterocyclyl; and wherein Z 2 is optionally substituted by one or more substituents selected from (1-6C)alkyl, halo, (1- 6C)haloalkyl, (1-6C)haloalkoxy, cyano, phenyl, 5- or 6-membered heteroaryl, 4- to 7- membered heterocyclyl, NR h R i , OR h , C(O)R h , C(O)OR h , OC(O)R h , C(O)N(R h )R i , N(R h )C(O)R i , S(O) y R h (where y is 0, 1 or 2), SO 2 N(R h )R i , N(R h )SO 2 R i or (CH 2 ) z NR h R i (where z is 1, 2 or 3), wherein R h and R i are
  • Z 2 is a (1-4C)alkyl optionally substituted with one substituents selected from halo (e.g. fluoro), hydroxy, (1-2C)alkoxy and (1-2C)alkyl;
  • R 3 is selected from:
  • Z 2 is a 4, 5 or 6-membered heterocyclyl comprising 1 or 2 hetereoatoms selected from N, O or S which is optionally substituted by one or more substituents selected from (1- 4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, cyano, aryl, NR h R i , OR h , C(O)R h , C(O)ORh, OC(O)Rh, C(O)N(Rh)Ri, N(Rh)C(O)Ri, S(O)yRh (where y is 0, 1 or 2), SO2N(Rh)Ri, N(Rh)SO2Ri or (CH2)zNRhRi (where z is 1, 2 or 3), wherein Rh and Ri are each independently selected from hydrogen or (1-4C)alkyl;
  • R 3 is selected from:
  • Z2 is a 4, 5 or 6-membered heterocyclyl comprising 1 or 2 O atoms which is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo, (1- 4C)haloalkyl, (1-4C)haloalkoxy, cyano, aryl, NRhRi, ORh, C(O)Rh, C(O)ORh, OC(O)Rh, C(O)N(Rh)Ri, N(Rh)C(O)Ri, S(O)yRh (where y is 0, 1 or 2), SO2N(Rh)Ri, N(Rh)SO2Ri or (CH2)zNRhRi (where z is 1, 2 or 3), wherein Rh and Ri are each independently selected from hydrogen or (1-4C)alkyl;
  • R 3 is tetrahydrofuranyl or a (1-4C)alkyl optionally substituted with one or more of a halo (e.g. fluoro), hydroxy, (1-2C)alkoxy and (1-2C)alkyl;
  • a halo e.g. fluoro
  • R 3 is tetrahydrofuranyl.
  • R 3 is selected from:
  • R 3a and R 3b are each independently selected from hydrogen or (1-2C)alkyl
  • L 2a is absent or selected from C(O), C(O)O or C(O)N(R j ), wherein R j is selected from hydrogen or (1-2C)alkyl
  • Z 2 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl or heteroaryl; and wherein Z 2 is optionally substituted by one or more substituents selected from (1-6C)- alkyl, halo, (1-6C)haloalkyl, (1-6C)haloalkoxy, cyano, aryl, heteroaryl, heterocyclyl, nitro, NR h R i , OR h , C(O)R h , C(O)OR h , OC(O)R h , C(O)N(R h )R i , N(R h )C(O)R i , N(Rh)C(O)N(Ri)Rk, N(Rh)C(O)ORi, OC(O)N(Rh)Ri, S(O)yRh (where y is 0, 1 or 2), SO2N(Rh)Ri, N(R
  • R3a and R3b are each independently selected from hydrogen or (1-2C)alkyl
  • L2a is absent or selected from C(O)O or C(O)N(Rj), wherein Rj is selected from hydrogen or (1-2C)alkyl
  • L2b is absent or selected from O, S, SO, SO2, N(Re), C(O), C(O)O, OC(O), C(O)N(Re), N(R e )C(O), S(O) 2 N(R e ), N(R e )SO 2 , N(R e )C(O)N(R f ), N(R e )C(O)O, OC(O)N(R e ) wherein R e is selected from hydrogen or (1-2C)alkyl; and
  • Z 2 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl or heteroaryl; and wherein Z 2 is optionally substituted by one or more substituents selected from (1-6C)- alkyl, halo, (1-6C)haloalkyl, (1-6C)haloalkoxy, cyano, aryl, heteroaryl, heterocyclyl, nitro, NR h R i , OR h , C(O)R h , C(O)OR h , OC(O)R h , C(O)N(R h )R i , N(R h )C(O)R i , N(R h )C(O)N(R i )R k , N(R h )C(O)OR i , OC(O)N(R h )R i , S(O) y R h (where y is 0, 1
  • R 3 is selected from:
  • R3a and R3b are each independently selected from hydrogen or methyl
  • L2a is absent or selected from C(O)O or C(O)N(Rj), wherein Rj is selected from hydrogen or (1-2C)alkyl
  • L2b is absent or selected from O, S, SO, SO2, N(Re), C(O), C(O)O, OC(O), C(O)N(Re), N(Re)C(O), N(Re)C(O)N(Rf), N(Re)C(O)O, OC(O)N(Re) wherein Re is selected from hydrogen or (1-2C)alkyl; and
  • Z2 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl or heteroaryl; and wherein Z2 is optionally substituted by one or more substituents selected from (1-6C)- alkyl, halo, (1-6C)haloalkyl, (1-6C)haloalkoxy, cyano, aryl, heteroaryl, heterocyclyl, nitro, NRhRi, ORh, C(O)Rh, C(O)ORh, OC(O)Rh, C(O)N(Rh)Ri, N(Rh)C(O)Ri, N(Rh)C(O)N(Ri)Rk, N(Rh)C(O)ORi, OC(O)N(Rh)Ri, S(O)yRh (where y is 0, 1 or 2), SO2N(Rh)Ri, N(Rh)SO2Ri (CH2)zNRhRi (where z is
  • R 3 is selected from:
  • R 3a and R 3b are each independently selected from hydrogen or methyl
  • L 2a is absent
  • L 2b is absent or selected from O, S, SO, SO 2 , N(R e ), C(O), C(O)O, OC(O), C(O)N(R e ), N(R e )C(O), N(R e )C(O)N(R f ), N(R e )C(O)O, OC(O)N(R e ), wherein R e is selected from hydrogen or (1-2C)alkyl; and
  • Z 2 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl or heteroaryl; and wherein Z 2 is optionally substituted by one or more substituents selected from (1-6C)- alkyl, halo, (1-6C)haloalkyl, (1-6C)haloalkoxy, cyano, phenyl, 5- or 6-membered heteroaryl, 4- to 7-membered heterocyclyl, NRhRi, ORh, C(O)Rh, C(O)ORh, OC(O)Rh, C(O)N(Rh)Ri, N(Rh)C(O)Ri, N(Rh)C(O)N(Ri)Rk, N(Rh)C(O)ORi, OC(O)N(Rh)Ri, S(O)yRh (where y is 0, 1 or 2), SO2N(Rh)Ri, N(Rh)SO2Ri, (
  • R3a and R3b are each independently selected from hydrogen or methyl
  • L2a is absent
  • L2b is absent or selected from O, S, SO, SO2, N(Re), C(O), C(O)O, OC(O), C(O)N(Re), N(Re)C(O), N(Re)C(O)N(Rf), N(Re)C(O)O, OC(O)N(Re), wherein Re is selected from hydrogen or (1-2C)alkyl; and
  • Z 2 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl or heteroaryl; and wherein Z 2 is optionally substituted by one or more substituents selected from (1-6C)- alkyl, halo, (1-6C)haloalkyl, (1-6C)haloalkoxy, cyano, phenyl, 5- or 6-membered heteroaryl, 4- to 7-membered heterocyclyl, NR h R i , OR h , C(O)R h , C(O)OR h , OC(O)R h , C(O)N(R h )R i , N(R h )C(O)R i , N(R h )C(O)N(R i )R k , N(R h )C(O)OR i , OC(O)N(R h )R i , S(O)
  • R 3 is selected from:
  • R 3a and R 3b are hydrogen
  • L 2a is absent
  • L 2b is absent
  • Z2 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl or heteroaryl; and wherein Z2 is optionally substituted by one or more substituents selected from (1-6C)- alkyl, halo, (1-6C)haloalkyl, (1-6C)haloalkoxy, cyano, phenyl, 5- or 6-membered heteroaryl, 4- to 7-membered heterocyclyl, NRhRi, ORh, C(O)Rh, C(O)ORh, OC(O)Rh, C(O)N(Rh)Ri, N(Rh)C(O)Ri, N(Rh)C(O)N(Ri)Rk, N(Rh)C(O)ORi, OC(O)N(Rh)Ri, S(O)yRh (where y is 0, 1 or 2), SO2N(Rh)Ri, N(Rh)SO2Ri, (
  • R 3 is selected from:
  • Z2 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, phenyl, heterocyclyl or heteroaryl; and wherein Z 2 is optionally substituted by one or more substituents selected from (1- 6C)alkyl, halo, (1-6C)haloalkyl, (1-6C)haloalkoxy, cyano, phenyl, 5- or 6-membered heteroaryl, 4- to 7-membered heterocyclyl, NR h R i , OR h , C(O)R h , C(O)OR h , OC(O)R h , C(O)N(R h )R i , N(R h )C(O)R i , N(R h )C(O)N(R i )R k , N(R h )C(O)OR i , OC(O)N(R h )R i , S(O)
  • R 3 is selected from:
  • Z 2 is selected from (1-6C)alkyl, (3-6C)cycloalkyl or heterocyclyl; and wherein Z 2 is optionally substituted by one or more substituents selected from (1-6C)alkyl, halo, (1- 6C)haloalkyl, (1-6C)haloalkoxy, cyano, phenyl, 5- or 6-membered heteroaryl, 4- to 7- membered heterocyclyl, NR h R i , OR h , C(O)R h , C(O)OR h , OC(O)R h , C(O)N(R h )R i , N(R h )C(O)R i , N(R h )C(O)N(R i )R k , N(R h )C(O)OR i , OC(O)N(R h )R i , S(O) y R h (where y
  • R 3 is selected from:
  • Z2 is selected from 4, 5 or 6-membered heterocyclyl; and wherein Z2 is optionally substituted by one or more substituents selected from (1-6C)alkyl, halo, (1- 6C)haloalkyl, (1-6C)haloalkoxy, cyano, phenyl, 5- or 6-membered heteroaryl, 4- to 7- membered heterocyclyl, NRhRi, ORh, C(O)Rh, C(O)ORh, OC(O)Rh, C(O)N(Rh)Ri, N(Rh)C(O)Ri, N(Rh)C(O)N(Ri)Rk, N(Rh)C(O)ORi, OC(O)N(Rh)Ri, S(O)yRh (where y is 0, 1 or 2), SO2N(Rh)Ri, N(Rh)SO2Ri, (CH2)zNRhRi (where z is 1, 2 or 3) or
  • Z 2 is a (1-4C)alkyl optionally substituted with one substituents selected from halo (e.g. fluoro), hydroxy, (1-2C)alkoxy and (1-2C)alkyl;
  • R 3 is selected from:
  • Z 2 is a 4, 5 or 6-membered heterocyclyl comprising 1 or 2 hetereoatoms selected from N, O or S which is optionally substituted by one or more substituents selected from (1- 4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, cyano, aryl, NR h R i , OR h , C(O)R h , C(O)OR h , OC(O)R h , C(O)N(R h )R i , N(R h )C(O)R i , N(R h )C(O)N(R i )R k , N(R h )C(O)OR i , OC(O)N(R h )R i , S(O) y R h (where y is 0, 1 or 2), SO 2 N(R h )R i ,
  • R 3 is selected from:
  • Z2 is a 4, 5 or 6-membered heterocyclyl comprising 1 or 2 O atoms which is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo, (1- 4C)haloalkyl, (1-4C)haloalkoxy, cyano, aryl, NRhRi, ORh, C(O)Rh, C(O)ORh, OC(O)Rh, C(O)N(Rh)Ri, N(Rh)C(O)Ri, N(Rh)C(O)N(Ri)Rk, N(Rh)C(O)ORi, OC(O)N(Rh)Ri, S(O)yRh (where y is 0, 1 or 2), SO2N(Rh)Ri, N(Rh)SO2Ri, (CH2)zNRhRi (where z is 1, 2 or 3) or oxo, wherein Rh, Ri and Rk are each independently selected from hydrogen or
  • R 3 is tetrahydrofuranyl, oxetanyl or a (1-4C)alkyl optionally substituted with one or more of a halo (e.g. fluoro), hydroxy, (1-2C)alkoxy and (1-2C)alkyl;
  • a halo e.g. fluoro
  • R 3 is tetrahydrofuranyl or oxetanyl.
  • a heteroaryl or heterocyclyl group as defined herein is a monocyclic heteroaryl or 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- or 6-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 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 (11). More suitably, R 1 is as defined in any one of paragraphs (6) to (11). Most suitably, R 1 is as defined in paragraph (11).
  • R 2 is as defined in any one of paragraphs (12) to (24). More suitably, R 2 is as defined in any one of paragraphs (20) to (24). Most suitably, R 2 is as defined in paragraph (24).
  • R 3 is as defined in any one of paragraphs (25) to (37) or (38) to (50). More suitably, R 3 is as defined in any one of paragraphs (33) to (37) or (46) to (50). Most suitably, R 3 is as defined in paragraph (37) or (50).
  • 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:
  • R2 and R3 are each as defined hereinbefore.
  • R2 is as defined in any one of paragraphs (12) to (24) above;
  • R3 is as defined in any one of paragraphs (25) to (37) above.
  • R2 is as defined in any one of paragraphs (20) to (24) above;
  • R3 is as defined in any one of paragraphs (33) to (37) above.
  • R2 is as defined in any one of paragraphs (12) to (24) above;
  • R3 is as defined in any one of paragraphs (38) to (50) above.
  • R2 is as defined in any one of paragraphs (20) to (24) above;
  • R 3 is as defined in any one of paragraphs (46) to (50) above.
  • R 2 is as defined in paragraph (24) above;
  • R 3 is as defined in paragraph (37) 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:
  • R 1 , R 2 and R 3 are each as defined hereinbefore.
  • R1 is as defined in any one of paragraphs (1) to (11) above;
  • R3 is as defined in any one of paragraphs (25) to (37) above.
  • R1 is as defined in any one of paragraphs (8) to (11) above;
  • R3 is as defined in any one of paragraphs (33) to (37) above.
  • R1 is as defined in any one of paragraphs (1) to (11) above;
  • R3 is as defined in any one of paragraphs (38) to (50) above.
  • R1 is as defined in any one of paragraphs (8) to (11) above;
  • R3 is as defined in any one of paragraphs (46) to (50) above.
  • R1 is as defined in paragraph (7) above;
  • R 3 is as defined in paragraphs (34), (35), (36) or (37) above.
  • R 1 is as defined in paragraph (11) above;
  • R3 is as defined in paragraph (37) above.
  • the compounds have the structural formula I defined hereinbefore, wherein R1 and R2 are each as defined hereinbefore and R3 is as defined in any one of paragraphs (25) to (37) above.
  • the compounds have the structural formula I defined hereinbefore, wherein R1 and R2 are each as defined hereinbefore and R3 is as defined in paragraph (34) above.
  • the compounds have the structural formula I defined hereinbefore, wherein R1 and R2 are each as defined hereinbefore and R3 is as defined in paragraph (35) above.
  • the compounds have the structural formula I defined hereinbefore, wherein R1 and R2 are each as defined hereinbefore and R3 is as defined in paragraph (36) above.
  • the compounds have the structural formula I defined hereinbefore, wherein R 1 and R 2 are each as defined hereinbefore and R 3 is as defined in paragraph (37) above.
  • R 1 is as defined in any one of paragraphs (1) to (11) above;
  • R 2 is as defined in any one of paragraphs (12) to (24) above;
  • R 3 is as defined in paragraph (34) above.
  • R 1 is as defined in any one of paragraphs (1) to (11) above;
  • R 2 is as defined in any one of paragraphs (12) to (24) above;
  • R 3 is as defined in paragraph (35) above.
  • R 1 is as defined in any one of paragraphs (1) to (11) above;
  • R 2 is as defined in any one of paragraphs (12) to (24) above;
  • R3 is as defined in paragraph (36) above.
  • R1 is as defined in any one of paragraphs (1) to (11) above;
  • R2 is as defined in any one of paragraphs (12) to (24) above; and R3 is as defined in paragraph (37) above.
  • R1 is as defined in paragraph (7) above;
  • R2 is as defined in any one of paragraphs (12) to (24) above;
  • R3 is as defined in paragraph (34) above.
  • R1 is as defined in paragraph (7) above;
  • R 2 is as defined in any one of paragraphs (12) to (24) above;
  • R 3 is as defined in paragraph (35) above.
  • R 1 is as defined in paragraph (7) above;
  • R 2 is as defined in any one of paragraphs (12) to (24) above;
  • R 3 is as defined in paragraph (36) above.
  • R 1 is as defined in paragraph (7) above;
  • R 2 is as defined in any one of paragraphs (12) to (24) above;
  • R 3 is as defined in paragraph (37) above.
  • R 1 is as defined in paragraph (11) above;
  • R 2 is as defined in any one of paragraphs (12) to (24) above;
  • R 3 is as defined in paragraph (34) above.
  • R1 is as defined in paragraph (11) above;
  • R2 is as defined in any one of paragraphs (12) to (24) above; and
  • R3 is as defined in paragraph (35) above.
  • R1 is as defined in paragraph (11) above;
  • R2 is as defined in any one of paragraphs (12) to (24) above;
  • R3 is as defined in paragraph (36) above.
  • R 1 is as defined in paragraph (11) above;
  • R 2 is as defined in any one of paragraphs (12) to (24) above;
  • R 3 is as defined in paragraph (37) 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:
  • R1 and R2 are each as defined hereinbefore.
  • R1 is as defined in any one of paragraphs (1) to (11) above;
  • R2 is as defined in any one of paragraphs (12) to (24) above.
  • R1 is as defined in any one of paragraphs (8) to (11) above;
  • R2 is as defined in any one of paragraphs (20) to (24) above.
  • R1 is as defined in paragraph (7) above;
  • R2 is as defined in paragraph (24) above.
  • R1 is as defined in paragraph (11) above;
  • R2 is as defined in paragraph (24) above.
  • 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:
  • 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.
  • 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.
  • An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R and Ssequencing 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. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof.
  • the methods for the determination of stereochemistry and the separation of stereoisomers are wellknown in the art (see discussion in Chapter 4 of “Advanced Organic Chemistry”, 4th edition J. March, John Wiley and Sons, New York, 2001), for example by synthesis from optically active starting materials or by resolution of a racemic form.
  • Some of the compounds of the invention may have geometric isomeric centres (E and Z isomers). It is to be understood that the present invention encompasses all optical, diastereoisomers and geometric isomers and mixtures thereof that possess antiproliferative activity.
  • 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.
  • tautomeric forms 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.
  • N-oxides 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.
  • one or more than one nitrogen atom may be oxidised to form an N-oxide.
  • Particular Examples of 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.
  • 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. Accordingly, 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.
  • pro-drug 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. Widder, et al. (Academic Press, 1985);
  • 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.
  • Figures 1 and 2 show a general reaction schemes for the preparation of compounds of Formula (I).
  • Figure 3 shows a general reaction scheme for the preparation of various hydroxylamines.
  • 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.
  • 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.
  • a base such as sodium hydroxide
  • 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.
  • the compounds of the invention demonstrate an IC50 of 1 ⁇ M or less in the assay described in Biological Example 1, with preferred compounds of the invention demonstrating an IC50 of 200 nM or less and the most preferred compounds of the invention demonstrating an IC50 of 50 nM or less.
  • the IC50 at the adenosine A1, A2b or A3 receptors of the compounds of the invention in the assay described in Biological Example 1 is at least two-fold higher than the IC 50 at the adenosine A2a receptor, and more suitably it is at least 5-fold higher, and even more suitably it is at least 10-fold higher.
  • a pharmaceutical composition 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.
  • 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.
  • 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.
  • the present invention provides compounds that function as antagonists of adenosine A2 receptors, especially adenosine A2a receptors.
  • a method of antagonising adenosine A2a receptors 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 antagonising adenosine A2a receptros 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 in which adenosine A2a receptor activity is implicated 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).
  • a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein for use in therapy 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 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).
  • a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein for use as an adenosine A2a antagonist.
  • the compounds of the invention are selective adenosine A2a antagonists.
  • certain compounds of the invention are selective adenosine A2a and adenosine A2b antagonists.
  • 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).
  • 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).
  • 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 (by virtue of their adenosine A2a antagonist activity).
  • 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.
  • a compound of general formula (I) in the manufacture of a medicament for the treatment of cancer, particularly solid tumours, for example non-small cell lung cancer, head and neck squamous cancer and urothelial cancer.
  • 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).
  • cancer particularly solid tumours, for example non-small cell lung cancer, head and neck squamous cancer and urothelial cancer
  • the patient to be treated is suitably a mammal and more suitably a human.
  • Routes of Administration are suitably a mammal and more suitably a human.
  • 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, subcut
  • 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:
  • anti-PD-1 and PDL-1 antibodies including, but not limited to, pembrolizumab, nivolumab, durvalumab, avelumab and atezolizumab; and
  • 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.
  • A2a antagonists 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.
  • 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
  • MEK inhibitors e.g. XL518, CI-1040
  • 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 sulfonates (e.g., busulfan
  • cisplatin oxaloplatin, arboplatin
  • anthracenedione e.g., mitoxantrone
  • substituted urea e.g., hydroxyurea
  • methyl hydrazine derivative e.g., procarbazine
  • adrenocortical suppressant e.g., mitotane, aminoglutethimide
  • epipodophyllotoxins e.g., etoposide
  • antibiotics e.g., daunorubicin, doxorubicin, bleomycin
  • enzymes e.g., L-asparaginase
  • inhibitors of mitogen-activated protein kinase signaling e.g.
  • adecypenol adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine;
  • amidox amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti- dorsalizing morphogenetic protein- 1; antiandrogen, prostatic carcinoma; antiestrogen;
  • antineoplaston antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene
  • apoptosis regulators apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol; batimastat; BCR/ABL antagonists; benzochlorins; benzoylstaurosporine; beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistratene A; bizelesin; breflate; bropirimine; budotitane; buthionine sulfoximine; calcipotriol; calphost
  • carzelesin casein kinase inhibitors (ICOS); castanospermine; cecropin B; cetrorelix;
  • chlorins chloroquinoxaline sulfonamide; cicaprost; cisporphyrin; cladribine; clomifene analogues; clotrimazole; collismycin A; collismycin B; combretastatin A4; combretastatin analogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A; cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone; didemnin B; didox; diethyln
  • estramustine analogue estramustine analogue
  • estrogen agonists include estrogen agonists; estrogen antagonists; etanidazole; etoposide phosphate; exemestane; fadrozole; trasrabine; fenretinide; filgrastim; finasteride;
  • flavopiridol flezelastine; fluasterone; fiudarabine; fluorodaunorunicin hydrochloride;
  • galocitabine ganirelix; gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam; heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene; idramantone; ilmofosine; ilomastat; imidazoacridones; imiquimod; immunostimulant peptides; insulin-like growth factor-1 receptor inhibitor; interferon agonists; interferons;
  • lanreotide leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia inhibiting factor; leukocyte alpha interferon; leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole; linear polyamine analogue; lipophilic disaccharide peptide; lipophilic platinum compounds; lissoclinamide 7; lobaplatin; lombricine; lometrexol; lonidamine;
  • losoxantrone lovastatin; loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides; maitansine; mannostatinA; marimastat; masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone; meterelin; methioninase;
  • metoclopramide MIF inhibitor; mifepristone;miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone; mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonal antibody, human chorionic gonadotrophin; monophosphoryl lipid A+myobacterium cell wall sk; mopidamol; multiple drug resistance gene inhibitor; multiple tumor suppressor 1-based therapy; mustard anticancer agent; mycaperoxide B; mycobacterial cell wall extract;
  • myriaporone N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip;
  • naloxone+pentazocine napavin; naphterpin; nartograstim; nedaplatin; nemorubicin;
  • neridronic acid neutral endopeptidase; nilutamide; nisamycin; nitric oxide modulators;
  • nitroxide antioxidant nitrullyn; 06-benzyl guanine; octreotide; okicenone; oligonucleotides; onapristone; ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin; palauamine; palmitoylrhizoxin; pamidronic acid; panaxytriol;
  • pyrazoloacridine pyridoxylated hemoglobin polyoxyethylerie conjugate; raf antagonists; raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors; ras inhibitors; ras- GAPinhibitor; retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin; ribozymes; RII retinamide; rogletimide; rohitukine; romurtide; roquinimex; rubiginone B1; ruboxyl; safingol; saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics; semustine; senescence derived inhibitor 1; sense oligonucleotides; signal transduction inhibitors; signal transduction modulators; single chain antigen-binding protein; sizofur
  • borocaptate sodium phenylacetate; solverol; somatomedin binding protein; sonermin;
  • sparfosic acid spicamycin D; spiromustine; splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stemcell division inhibitors; stipiamide; stromelysin inhibitors; sulfinosine;
  • triciribine trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors;
  • tyrphostins UBC inhibitors; ubenimex; urogenital sinus-derived growth inhibitory factor; urokinase receptor antagonists; vapreotide; variolin B; vector system, erythrocyte gene therapy; velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; zinostatin stimalamer, Adriamycin, Dactinomycin,
  • azotomycin batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan;
  • cactinomycin calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelesin; cedefingol; chlorambucil; cirolemycin; cladribine; crisnatol mesylate; cyclophosphamide; cytarabine; dacarbazine; daunorubicin hydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate; diaziquone; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin; edatrexate; eflornithine hydrochloride; elsamitrucin; enloplatin; enpromate; epipropidine; epirubicin hydrochloride; erbulozole;
  • fluorouracil fluorocitabine
  • fosquidone fostriecin sodium
  • gemcitabine gemcitabine hydrochloride
  • hydroxyurea idarubicin hydrochloride
  • ifosfamide iimofosine
  • interleukin 2 including recombinant interleukin 2, or rlL.sub.2
  • interferon alfa-2a interferon alfa-2b;
  • interferon alfa-nl interferon alfa-n3; interferon beta- la; interferon gamma-lb; iproplatin;
  • irinotecan hydrochloride lanreotide acetate; letrozole; leuprolide acetate; liarozole hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol;
  • mitosper mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazoie;
  • nogalamycin nogalamycin; ormaplatin; oxisuran; pegaspargase; peliomycin; pentamustine; peplomycin sulfate; perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride; plicamycin;
  • paclitaxel 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 Epothilone B
  • 21-aminoepothilone B i.e. BMS-310705
  • 21- hydroxyepothilone D i.e.
  • Diazonamide A Taccalonolide A, Diozostatin, (-)-Phenylahistin (i.e. NSCL-96F037),
  • 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-2, alpha-interferon, etc.
  • monoclonal antibodies e.g., anti-CD20, anti-F£ER2, anti-CD52, anti- ULA-DR, and anti- VEGF monoclonal antibodies
  • immunotoxins e.g., anti-CD33 monoclonal antibody- calicheamicin conjugate, anti-CD22 monoclonal antibody-pseudomonas exotoxin conjugate, etc.
  • radioimmunotherapy e.g., anti-CD20 monoclonal antibody conjugated to ln, 0Y, or
  • gefitinib IressaTM
  • erlotinib TarcevaTM
  • 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, dasat
  • 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 pharmaceutically acceptable salt, hydrate or solvate thereof, and one or more additional antiproliferative/anticancer agents selected from those listed 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.
  • Immune checkpoint proteins present on immune cells and/or cancer cells [e.g.
  • CTLA4 also known as cytotoxic T-lymphocyte-associated protein 4 and CD152
  • LAG3 also known as lymphocyte-activation gene 3 and CD223
  • PD1 also known as programmed cell death protein 1 and CD279
  • PD-L1 also known as programmed death-ligand 1 and CD274
  • TIM-3 also known as T-cell immunoglobulin mucin-3
  • TIGIT also known as T-cell Immunoreceptor with Ig and ITIM domains
  • CTLA4, LAG3, PD1, PD-L1, TIM-3 and/or TIGIT inhibitors promote an anti-tumour immune response that can be utilised to effectively treat certain forms of cancer.
  • the present invention relates to a combination comprising a compound of formula I as defined herein, or a pharmaceutically acceptable salt thereof, and an immune checkpoint inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of a proliferative disorder.
  • the present invention relates to a use of a combination comprising a compound of formula I as defined herein, or a pharmaceutically acceptable salt thereof, and an immune checkpoint inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating of a proliferative disorder.
  • the present invention relates to a method of treating of a proliferative disorder in a subject in need thereof comprising administering to said subject a combination comprising a compound of formula I as defined herein, or a pharmaceutically acceptable salt thereof, and an immune checkpoint inhibitor, or a pharmaceutically acceptable salt thereof, as defined herein.
  • the present invention relates to a compound of formula I as defined herein, or a pharmaceutically acceptable salt thereof, as defined herein for use in the treatment of a proliferative disorder, wherein the compound of formula I, or a
  • pharmaceutically acceptable salt thereof is for simultaneous, separate or sequential administeration with an immune checkpoint inhibitor, or a pharmaceutically acceptable salt thereof.
  • the present invention relates to an immune checkpoint inhibitor, or a pharmaceutically acceptable salt thereof, for use in the treatment of a proliferative disorder, wherein the immune checkpoint inhibitor is for simultaneous, separate or sequential administeration with a compound of formula I as defined herein, or a
  • the present invention relates to a use of a compound of formula I as defined herein, or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for treating a proliferative disorder, wherein the medicament is for simultaneous, separate or sequential administeration with an immune checkpoint inhibitor, or a pharmaceutically acceptable salt thereof.
  • the present invention relates to a use of an immune checkpoint inhibitor, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a proliferative disorder, wherein the medicament is for simultaneous, separate or sequential administeration with a compound of formula I as defined herein, or a
  • the present invention relates to a method of treating a proliferative disorder comprising adminstering to a subject in need thereof a therapetuically effective amount of a compound of formula I as defined herein, or a pharmaceutically acceptable salt thereof, as defined herein and an immune checkpoint inhibitor, or a pharmaceutically acceptable salt thereof, either sequentially, separately or simultaneously
  • Any immune checkpoint inhibitor may be used in the combination therapy defined herein.
  • the immune checkpoint inhibitor is selected from a PD1, a PD- L1 inhibitor, a LAG3 inhibitor, aCTLA-4 inhibitor, a TIM-3 inhibitor and/or a TIGIT inhibitor.
  • the immune checkpoint inhibitor is a PD1 or PD-L1 inhibitor.
  • PD-1 is a cell surface receptor protein present on T cells. PD-1 plays an important role in down-regulating the immune system and promoting self-tolerance by suppressing T cell inflammatory activity.
  • the PD-1 protein is an immune checkpoint that guards against autoimmunity through a dual mechanism of promoting apoptosis (programmed cell death) in antigen specific T cells in lymph nodes, while simultaneously reducing apoptosis in regulatory T cells (anti-inflammatory suppressive T cells).
  • PD-1 therefore inhibits the immune system. This prevents autoimmune diseases, but it can also prevent the immune system from killing cancer cells.
  • PD1 binds two ligands, PD-L1 and PD-L2.
  • PD-L1 is of particular interest as it is highly expressed in several cancers and hence the role of PD1 in cancer immune evasion is well established.
  • Monoclonal antibodies targeting PD-1 that boost the immune system are being developed for the treatment of cancer.
  • Many tumour cells express PD-L1, an immunosuppressive PD-1 ligand; inhibition of the interaction between PD-1 and PD-L1 can enhance T-cell responses in vitro and mediate preclinical antitumour activity. This is known as immune checkpoint blockade.
  • Examples of drugs that target PD-1 include pembrolizumab (Keytruda) and nivolumab (Opdivo). These drugs have been shown to be effective in treating several types of cancer, including melanoma of the skin, non-small cell lung cancer, kidney cancer, bladder cancer, head and neck cancers, and Hodgkin lymphoma. They are also being studied for use against many other types of cancer. Examples of drugs in development include BMS-936559 (Bristol Myers Squibb), MGA012 (MacroGenics) and MEDI-0680 (MedImmune).
  • Examples of drugs that inhibit PD-L1 include atezolizumab (Tecentriq), avelumab (Bavencio) and durvalumab (Imfinzi). These drugs have also been shown to be helpful in treating different types of cancer, including bladder cancer, non-small cell lung cancer, and Merkel cell skin cancer (Merkel cell carcinoma). They are also being studied for use against other types of cancer.
  • LAG3 inhibitors examples include BMS-986016/Relatlimab, TSR-033,
  • CTLA-4 inhibitors examples include MDX-010/Ipilimumab, AGEN1884, and CP- 675,206/Tremelimumab.
  • TIM-3 inhibitors examples include MBG453 (Novartis), TSR-022 (Tesaro), and LY3321367 (Lilly).
  • TIGIT inhibitors examples include Tiragolumab (MTIG7192A; RG6058;
  • the immune checkpoint inhibitor is selected from BMS- 986016/Relatlimab, TSR-033, REGN3767, MGD013 (bispecific DART binding PD-1 and LAG-3), GSK2831781, LAG525, MDX-010/Ipilimumab, AGEN1884, and CP- 675,206/Tremelimumab, pembrolizumab, nivolumab, atezolizumab, avelumab, durvalumab, MBG453, TSR-022, LY3321367, Tiragolumab (MTIG7192A; RG6058), AB154, MK-7684, BMS-986207, and/or ASP8374 or a pharmaceutically acceptable salt or solvate thereof.
  • BMS- 986016/Relatlimab TSR-033, REGN3767
  • MGD013 bispecific DART binding PD-1 and LAG-3
  • Mass spectra were run on LC-MS systems using electrospray ionization. These were run using either a Waters Acquity H-Class UPLC with PDA and QDa mass detection, an Acquity UPLC (binary pump/PDA detector) + ZQ Mass Spectrometer or Acquity i-Class (quaternary pump/PDA detector) + Quattro Micro Mass Spectrometer, a Waters Acquity uPLC system with Waters PDA and ELS detectors or a Shimadzu LCMS-2010EV system. [M+H]+ refers to mono-isotopic molecular weights.
  • NMR spectra were run on either a Bruker Ultrashield 500 MHz NMR spectrometer, a Bruker Avance III HD 400 MHz NMR spectrometer, a Bruker Avance DPX 300 MHz NMR spectrometer a Bruker Avance III HD 500 MHz or a Bruker Avance III HD 250 MHz. Spectra were recorded at 298K and were referenced using the solvent peak.

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Abstract

The present invention relates to compounds of formula I shown below: (I) wherein R1, R2 and R3 are each as defined in the application. 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 adenosine A2a receptor activity is implicated, such as, for example, cancer.

Description

HYDROXAMATE COMPOUNDS
INTRODUCTION
[0001] The present invention relates to certain hydroxamate compounds that function as antagonists of the adenosine A2a receptor. 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 adenosine A2a receptor activity is implicated, such as, for example, cancer. BACKGROUND OF THE INVENTION
[0002] A number of immunosuppressive pathways are active in the tumour microenvironment which enable tumour cells to evade elimination by cytotoxic T cells and can diminish the clinical response of patients to immunotherapy with anti-checkpoint antibodies. The anti-PD- 1 antibodies pembrolizumab and nivolumab and anti-PD-L1 antibodies durvalumab, avelumab and atezolizumab are approved for the treatment of number of solid tumours including non- small cell lung cancer, head and neck squamous cancer and urothelial cancer. However, only 20-30% of patients respond to checkpoint blockade and the side effects of such treatments are significant (Sukari et al, 2016). Consequently, other approaches to enhance the cytotoxic potential of the tumour microenvironment are actively being investigated. This includes agents that could be used as monotherapies or, more likely, used in combination with checkpoint inhibitors and cytotoxic agents to enhance their efficacy.
[0003] One approach that has attracted attention is to interfere with the production and/or action of adenosine in the tumour microenvironment (Vijayan et al, 2017). Adenosine has immunosuppressive properties and is present in the tumour microenvironment at high concentrations. Recent studies estimate the concentration of adenosine to be about 10µM in human tumours compared to <1 µM in normal tissue (Houthuys et al 2017). Adenosine is formed at both intracellular and extracellular sites by two distinct pathways that involve two different substrates. Intracellular adenosine is derived from AMP and S-adenosyl homocysteine whilst the high extracellular adenosine concentrations observed during metabolic stress are associated with the release and degradation of precursor adenine nucleotides (ATP, ADP and AMP) by the concerted action of CD39 and CD73 (Vijayan et al, 2017).
[0004] CD39 and CD73 are upregulated in the tumour microenvironment in response to hypoxia. CD73 represents a putative patient stratification method for adenosine antagonists as its expression on tumour cells is also associated with poor overall prognosis in many different cancer types suggesting that adenosine production contributes to the undesirable immunosuppressive phenotype of the tumour microenvironment (Gao et al 2014; Loi et al, 2013;). CD73 expression by tumour-infiltrating immune cells is also important in promoting tumour immune suppression as CD73 negative Treg cells fail to suppress effector T cell functions (Deaglio et al, 2007; Reinhardt et al, (2017). Furthermore, patients resistant to anti- PD1 treatment have elevated levels of CD73 (Reinhardt et al, 2017).
[0005] Adenosine regulates cell function via occupancy of specific GPCRs on the cell surface of the P1 purinoceptor subtypes. The P1 receptor family is further subdivided into A1, A2a, A2b and A3.
[0006] A2 receptors are subdivided into A2a and A2b, based on high and low affinity for adenosine, respectively. A2a is expressed by lymphocytes and activation of A2a leads to suppression of cytokine production and other effector functions. Tumour growth is inhibited by genetic ablation of A2a in syngeneic mouse models and this effect has been demonstrated to be due to enhanced lymphocyte activation and cytotoxic function (Ohta et al, 2006; Waickman et al 2012; Beavis et al, 2013; Mittal et al, 2014; Cekic et al, 2014). A2a-/- mice show an increased response to inhibition of checkpoint pathways such as PD-1, with an improvement in both tumour free survival and overall survival. Adenosine-mediated A2a activation also limits the efficacy of ant-CTLA4 treatment (Iannone et al, 2014).
[0007] The effects of genetic deficiency of A2a in mouse models is mimicked by pharmacological blockade of A2a. A2a antagonists have been shown to enhance the cytotoxic CD8+T cells and to enhance the ability of NK cells prevent metastasis of CD73-expressing tumours (Beavis et al, 2013). Importantly, A2a antagonists enhance the efficacy of anti-PD1 antibodies (Beavis et al, 2015).
[0008] These findings have prompted the development of selective A2a antagonists for use in cancer immunotherapy and clinical trials are ongoing with CPI-444, the first selective A2a antagonist to be evaluated in cancer, being used as both as a monotherapy and in combination with the anti-PDL1 antibody atezolizumab. The preliminary data indicated that the compound was well tolerated and showed early indications of reducing tumour size and enhancing CD8+T infiltration into tumour tissue.
[0009] However, there remains a need for second generation compounds that are potent adenosine A2a antagonists. In particular, there is a need for compounds that are potent and selective adenosine A2a antagonists and, in some cases, potent and selective adenosine A2a and A2b antagonists. There is also a need for compounds that are potent adenosine A2a antagonists or adenosine A2a and A2b antagonists that retain activity in the presence of the high concentrations of adenosine that are present in the tumour microenvironment. SUMMARY OF THE INVENTION
[0010] According to a first aspect of the present invention, there is provided a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein. [0011] According to a further aspect of the present invention, there is provided 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.
[0012] According to a further aspect of the present invention, there is provided a method of antagonising adenosine A2a receptors in vitro or in vivo, said method comprising contacting a cell with an effective amount of a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein.
[0013] According to a further aspect of the present invention, there is provided a method of selectively antagonising adenosine A2a receptors in vitro or in vivo, said method comprising contacting a cell with an effective amount of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein.
[0014] According to a further aspect of the present invention, there is provided a method of inhibiting cell proliferation, in vitro or in vivo, said method 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. Suitably, the compound or pharmaceutical composition is administered in combination with one or more additional antiproliferative agents (e.g. checkpoint inhibitors and/or cytotoxic agents).
[0015] According to a further aspect of the present invention, there is provided a method of treating a disease or disorder associated with adenosine A2a receptor activity in a patient in need of such treatment, said method 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.
[0016] According to a further aspect of the present invention, there is provided a method of treating a proliferative disorder in a patient in need of such treatment, said method 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. Suitably, the compound or pharmaceutical composition is administered in combination with one or more additional antiproliferative agents (e.g. checkpoint inhibitors and/or cytotoxic agents).
[0017] According to a further aspect of the present invention, there is provided a method of treating cancer in a patient in need of such treatment, said method 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. Suitably, the compound or pharmaceutical composition is administered in combination with one or more additional anticancer agents (e.g. checkpoint inhibitors and/or cytotoxic agents). [0018] According to a further aspect of the present invention, there is provided a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein for use in therapy.
[0019] According to a further aspect of the present invention, there is provided 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. Suitably, the compound or pharmaceutical composition is administered in combination with one or more additional antiproliferative agents (e.g. checkpoint inhibitors and/or cytotoxic agents).
[0020] According to a further aspect of the present invention, there is provided 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. Suitably, the compound or pharmaceutical composition is administered in combination with one or more additional anticancer agents (e.g. checkpoint inhibitors and/or cytotoxic agents).
[0021] According to a further aspect of the present invention, there is provided a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein for use as an adenosine A2a antagonist. In an embodiment, the compounds of the invention are selective adenosine A2a antagonists. In an alternative embodiment, certain compounds of the invention are selective adenosine A2a and adenosine A2b antagonists.
[0022] According to a further aspect of the present invention, there is provided 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 adenosine A2a is implicated.
[0023] According to a further aspect of the present invention, there is provided the use of 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. Suitably, the compound or pharmaceutical composition is administered in combination with one or more additional antiproliferative agents (e.g. checkpoint inhibitors and/or cytotoxic agents).
[0024] According to a further aspect of the present invention, there is provide the use of 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. Suitably, the cancer is a human cancer. Suitably, the compound or pharmaceutical composition is administered in combination with one or more additional anticancer agents (e.g. checkpoint inhibitors and/or cytotoxic agents).
[0025] According to a further aspect of the present invention, there is provided a use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein in the manufacture of a medicament for use as an adenosine A2a antagonist. [0026] According to a further aspect of the present invention, there is provided a use of 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 disease or disorder in which adenosine A2a is implicated.
[0027] According to a further aspect of the present invention, there is provided a process for preparing a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein.
[0028] According to a further aspect of the present invention, 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.
[0029] According to a further aspect of the present invention, there are provided novel intermediates as defined herein which are suitable for use in any one of the synthetic methods set out herein.
[0030] Features, including optional, suitable, and preferred features in relation to one aspect of the invention may also be features, including optional, suitable and preferred features in relation to any other aspect of the invention. DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0031] Unless otherwise stated, the following terms used in the specification and claims have the following meanings set out below.
[0032] It is to be appreciated that references to“treating” or“treatment” include prophylaxis as well as the alleviation of established symptoms of a condition.“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.
[0033] 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. [0034] In this specification the term 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. For Example,“(1-6C)alkyl” includes (1- 4C)alkyl, (1-3C)alkyl, propyl, isopropyl and t-butyl. A similar convention applies to other radicals, for example“phenyl(1-6C)alkyl” includes phenyl(1-4C)alkyl, benzyl, 1-phenylethyl and 2-phenylethyl.
[0035] The term "(m-nC)" or "(m-nC) group" used alone or as a prefix, refers to any group having m to n carbon atoms.
[0036] An“alkylene,”“alkenylene,” or“alkynylene” group is an alkyl, alkenyl, or alkynyl group that is positioned between and serves to connect two other chemical groups. Thus,“(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.
[0037]“(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.
[0038]“(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.
[0039]“(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.
[0040]“(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.
[0041]“(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.
[0042] The term“halo” or“halogeno” refers to fluoro, chloro, bromo and iodo.
[0043] The term “heterocyclyl”, “heterocyclic” 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. Examples of 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. Other heterocycles include dihydrooxathiolyl, tetrahydrooxazolyl, tetrahydro-oxadiazolyl, tetrahydrodioxazolyl, tetrahydrooxathiazolyl, hexahydrotriazinyl, tetrahydrooxazinyl, morpholinyl, thiomorpholinyl, tetrahydropyrimidinyl, dioxolinyl, octahydrobenzofuranyl, octahydrobenzimidazolyl, and octahydrobenzothiazolyl. For heterocycles containing sulfur, the oxidized sulfur heterocycles containing SO or SO2 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. A heterocyclyl group may bear one or more oxo or thioxo groups. A suitable example of a heterocyclyl group which bears 1 or 2 oxo (=O) or thioxo (=S) substituents is, for example, 2-oxopyrrolidinyl, 2-thioxopyrrolidinyl, 2-oxoimidazolidinyl, 2-thioxoimidazolidinyl, 2-oxopiperidinyl, 2,5-dioxopyrrolidinyl, 2,5- dioxoimidazolidinyl or 2,6-dioxopiperidinyl. Particular 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. As the skilled person would appreciate, any heterocycle may be linked to another group via any suitable atom, such as via a carbon or nitrogen atom. However, reference herein to piperidino or morpholino refers to a piperidin-1-yl or morpholin-4-yl ring that is linked via the ring nitrogen.
[0044] By“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, 4th Edition, Wiley Interscience, pages 131-133, 1992. Examples of bridged heterocyclyl ring systems 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.
[0045] By“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. Examples of spiro ring systems 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.
[0046]“Heterocyclyl(1-6C)alkyl” means a heterocyclyl group covalently attached to a (1- 6C)alkylene group, both of which are defined herein. [0047] The term 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. The term 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. Typically the heteroaryl ring will contain up to 3 heteroatoms, more usually up to 2, for example a single heteroatom. In one embodiment, 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. In general the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents of the ring, will be less than five.
[0048] Examples of heteroaryl 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, naphthyridinyl, carbazolyl, phenazinyl, benzisoquinolinyl, pyridopyrazinyl, thieno[2,3b]-furanyl-, 2H-furo[3,2b]-pyranyl-, 5H-pyrido[2,3-d]-ooxazinyl-, 1H-pyrazolo[4,3-d]-oxazolyl, 4H-imidazo[4,5d]thiazolyl, pyrazino[2,3d]pyridazinyl, -imidazo[2,1b]thiazolyl, -imidazo[1,2b][1,2,4]-triazinyl.“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-. Examples of 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]triazolo[4,3-a]pyrazinyl.
[0049] 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. [0050] Examples of six membered heteroaryl groups include but are not limited to pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl and triazinyl.
[0051] 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 oxazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;
an isoxazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;
a thiazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;
an isothiazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; a thiophene ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; a furan ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms;
a cyclohexyl ring fused to a 5- or 6-membered heteroaromatic ring containing 1, 2 or 3 ring heteroatoms; and
a cyclopentyl ring fused to a 5- or 6-membered heteroaromatic ring containing 1, 2 or 3 ring heteroatoms.
[0052] Particular Examples of 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.
[0053] Particular Examples of 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.
[0054]“Heteroaryl(1-6C)alkyl” means a heteroaryl group covalently attached to a (1- 6C)alkylene group, both of which are defined herein. Examples of heteroaralkyl groups include pyridin-3-ylmethyl, 3-(benzofuran-2-yl)propyl, and the like. [0055] The term aryl means a cyclic or polycyclic aromatic ring having from 5 to 12 carbon atoms. The term 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.
[0056] The term“aryl(1-6C)alkyl” means an aryl group covalently attached to a (1-6C)alkylene group, both of which are defined herein. Examples of aryl-(1-6C)alkyl groups include benzyl, phenylethyl, and the like.
[0057] 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. For Example heterocyclyl(m-nC)alkyl comprises (m-nC)alkyl substituted by heterocyclyl.
[0058] The term "optionally substituted" refers to either groups, structures, or molecules that are substituted and those that are not substituted. The term“wherein a/any CH, CH2, CH3 group or heteroatom (i.e. NH) within a R1 group is optionally substituted” suitably means that (any) one of the hydrogen radicals of the R1 group is substituted by a relevant stipulated group.
[0059] Where optional substituents are chosen from“one or more” groups it is to be understood that this definition includes all substituents being chosen from one of the specified groups or the substituents being chosen from two or more of the specified groups.
[0060] The phrase“compound of the invention” means those compounds which are disclosed herein, both generically and specifically. Compounds of the invention
[0061] In one aspect, the present invention relates to compounds, or pharmaceutically acceptable salts, hydrates or solvates thereof, having the structural formula I shown below:
2
Figure imgf000011_0001
(I)
wherein R1 is selected from aryl or heteroaryl, each of which is optionally substituted with one or more substituents independently selected from halo, OH, cyano, R5, OR5, S(O)0-2R5 and NR5R6, wherein each R5 and R6 is independently H, (1-6C)alkyl or (3-7C)cycloalkyl, either of which is optionally substituted with one or more substituents selected from halo, OH, aryl and heteroaryl, wherein aryl and heteroaryl groups are optionally substituted with one or more substituents selected from halo, OH, (1-6C)alkyl and (1-6C)haloalkyl; R2 is selected from:
(i) –Z1;
(ii) –CR2aR2b–L1a–Z1; or
(iii) –[CR2aR2b]2-6–L1b–Z1;
wherein
R2a and R2b are each independently selected from hydrogen, fluoro or (1-2C)alkyl; L1a is absent or selected from C(O), C(O)O, C(O)N(Ra1) or C(S)N(Ra1), wherein Ra1 is selected from hydrogen or (1-2C)alkyl;
L1b is absent or selected from O, S, SO, SO2, N(Ra), C(O), C(O)O, OC(O), C(O)N(Ra), N(Ra)C(O), N(Ra)C(O)N(Rb), C(S)N(Ra), N(Ra)C(S), N(Ra)C(S)N(Rb), S(O)2N(Ra), or N(Ra)SO2, wherein Ra and Rb are each independently selected from hydrogen or (1- 2C)alkyl; and
Z1 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl or heteroaryl; and wherein Z1 is optionally substituted by one or more substituents selected from (1-6C)- alkyl, halo, (1-6C)haloalkyl, (1-6C)haloalkoxy, cyano, aryl, heteroaryl, heterocyclyl, nitro, NRcRd, ORc, C(O)Rc, C(O)ORc, OC(O)Rc, C(O)N(Rc)Rd, N(Rc)C(O)Rd, S(O)yRc (where y is 0, 1 or 2), SO2N(Rc)Rd, N(Rc)SO2Rd, (CH2)zNRcRd (where z is 1, 2 or 3) or oxo, wherein any alkyl, aryl, heteroaryl or heterocyclyl moiety in a substituent group on Z1 is optionally further substituted by cyano, halo, hydroxy, amino, oxo, (1-2C)alkyl or (1-2C)alkoxy and Rc and Rd are each independently selected from hydrogen, (1- 6C)alkyl, (1-6C)haloalkyl or (3-6C)cycloalkyl;
R3 is selected from:
(i) –Z2;
(ii) –CR3aR3b–L2a–Z2; or
(iii) –[CR3aR3b]2-6–L2b–Z2;
wherein R3a and R3b are each independently selected from hydrogen or (1-2C)alkyl;
L2a is absent or selected from C(O), C(O)O, C(O)N(Rj) or C(S)N(Rj), wherein Rj is selected from hydrogen or (1-2C)alkyl;
L2b is absent or selected from O, S, SO, SO2, N(Re), C(O), C(O)O, OC(O), C(O)N(Re), N(Re)C(O), C(S)N(Re), N(Re)C(S), N(Re)C(O)N(Rf), N(Re)C(=NRg)N(Rf), S(O)2N(Re) N(Re)SO2, N(Re)C(O)N(Rf) or N(Re)C(O)O, wherein Re, Rf and Rg are each independently selected from hydrogen or (1-2C)alkyl; and
Z2 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl or heteroaryl; and wherein Z2 is optionally substituted by one or more substituents selected from (1-6C)- alkyl, halo, (1-6C)haloalkyl, (1-6C)haloalkoxy, cyano, aryl, heteroaryl, heterocyclyl, nitro, NRhRi, ORh, C(O)Rh, C(O)ORh, OC(O)Rh, C(O)N(Rh)Ri, N(Rh)C(O)Ri, N(Rh)C(O)N(Ri)Rk, N(Rh)C(O)ORi, OC(O)N(Rh)Ri, S(O)yRh (where y is 0, 1 or 2), SO2N(Rh)Ri, N(Rh)SO2Ri, (CH2)zNRhRi (where z is 1, 2 or 3) or oxo, wherein any alkyl, aryl, heteroaryl or heterocyclyl moiety in a substituent group on Zz is optionally further substituted by cyano, halo, hydroxy, amino, oxo, (1-2C)alkyl or (1-2C)alkoxy and Rh, Ri and Rk are each independently selected from hydrogen, (1-6C)alkyl, (1-6C)haloalkyl or (3-6C)cycloalkyl. [0062] In an embodiment, the present invention relates to compounds, or pharmaceutically acceptable salts, hydrates or solvates thereof, having the structural formula I shown below:
2
Figure imgf000013_0001
(I)
wherein
R1 is selected from aryl or heteroaryl, each of which is optionally substituted with one or more substituents independently selected from halo, OH, cyano, R5, OR5, S(O)0-2R5 and NR5R6, wherein each R5 and R6 is independently H, (1-6C)alkyl or (3-7C)cycloalkyl, either of which is optionally substituted with one or more substituents selected from halo, OH, aryl and heteroaryl, wherein aryl and heteroaryl groups are optionally substituted with one or more substituents selected from halo, OH, (1-6C)alkyl and (1-6C)haloalkyl; R2 is selected from:
(i) –Z1;
(ii) –CR2aR2b–L1a–Z1; or
(iii) –[CR2aR2b]2-6–L1b–Z1;
wherein
R2a and R2b are each independently selected from hydrogen, fluoro or (1-2C)alkyl; L1a is absent or selected from C(O), C(O)O, C(O)N(Ra1) or C(S)N(Ra1), wherein Ra1 is selected from hydrogen or (1-2C)alkyl;
L1b is absent or selected from O, S, SO, SO2, N(Ra), C(O), C(O)O, OC(O), C(O)N(Ra), N(Ra)C(O), N(Ra)C(O)N(Rb), C(S)N(Ra), N(Ra)C(S), N(Ra)C(S)N(Rb), S(O)2N(Ra), or N(Ra)SO2, wherein Ra and Rb are each independently selected from hydrogen or (1- 2C)alkyl; and
Z1 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl or heteroaryl; and wherein Z1 is optionally substituted by one or more substituents selected from (1-6C)- alkyl, halo, (1-6C)haloalkyl, (1-6C)haloalkoxy, cyano, aryl, heteroaryl, heterocyclyl, nitro, NRcRd, ORc, C(O)Rc, C(O)ORc, OC(O)Rc, C(O)N(Rc)Rd, N(Rc)C(O)Rd, S(O)yRc (where y is 0, 1 or 2), SO2N(Rc)Rd, N(Rc)SO2Rd or (CH2)zNRcRd (where z is 1, 2 or 3), wherein any alkyl, aryl, heteroaryl or heterocyclyl moiety in a substituent group on Z1 is optionally further substituted by cyano, halo, hydroxy, amino, (1-2C)alkyl or (1- 2C)alkoxy and Rc and Rd are each independently selected from hydrogen, (1-6C)alkyl, (1-6C)haloalkyl or (3-6C)cycloalkyl;
R3 is selected from:
(i) –Z2;
(ii) –CR3aR3b–L2a–Z2; or
(iii) –[CR3aR3b]2-6–L2b–Z2;
wherein
R3a and R3b are each independently selected from hydrogen or (1-2C)alkyl;
L2a is absent or selected from C(O), C(O)O, C(O)N(Rj) or C(S)N(Rj), wherein Rj is selected from hydrogen or (1-2C)alkyl; L2b is absent or selected from O, S, SO, SO2, N(Re), C(O), C(O)O, OC(O), C(O)N(Re), N(Re)C(O), C(S)N(Re), N(Re)C(S), N(Re)C(O)N(Rf), N(Re)C(=NRg)N(Rf), S(O)2N(Re), or N(Re)SO2, wherein Re, Rf and Rg are each independently selected from hydrogen or (1-2C)alkyl; and
Z2 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl or heteroaryl; and wherein Z2 is optionally substituted by one or more substituents selected from (1-6C)- alkyl, halo, (1-6C)haloalkyl, (1-6C)haloalkoxy, cyano, aryl, heteroaryl, heterocyclyl, nitro, NRhRi, ORh, C(O)Rh, C(O)ORh, OC(O)Rh, C(O)N(Rh)Ri, N(Rh)C(O)Ri, S(O)yRh (where y is 0, 1 or 2), SO2N(Rh)Ri, N(Rh)SO2Ri or (CH2)zNRhRi (where z is 1, 2 or 3), wherein any alkyl, aryl, heteroaryl or heterocyclyl moiety in a substituent group on Zz is optionally further substituted by cyano, halo, hydroxy, amino, (1-2C)alkyl or (1- 2C)alkoxy and Rh and Ri are each independently selected from hydrogen, (1-6C)alkyl, (1-6C)haloalkyl or (3-6C)cycloalkyl. [0063] Particular compounds of the invention include, for example, compounds of the formula I, or pharmaceutically acceptable salts, hydrates and/or solvates thereof, wherein, unless otherwise stated, each of R1, R2 and R3 have any of the meanings defined hereinbefore or in any of paragraphs (1) to (50) hereinafter:- (1) R1 is phenyl or a 5- or 6-membered heteroaryl optionally substituted with one or more substituents independently selected from halo, OH, cyano, R5, OR5, S(O)0-2R5 and NR5R6,
wherein each R5 and R6 is independently H, (1-6C)alkyl or (3-7C)cycloalkyl, either of which is optionally substituted with one or more substituents selected from halo, OH, aryl and heteroaryl, wherein aryl and heteroaryl groups are optionally substituted with one or more substituents selected from halo, OH, (1-4C)alkyl and (1-4C)haloalkyl; (2) R1 is phenyl or 5- or 6-membered heteroaryl optionally substituted with with one or more substituents independently selected from halo, OH, cyano, R5 or OR5, wherein each R5 is independently H, (1-6C)alkyl or (3-7C)cycloalkyl, either of which is optionally substituted with one or more substituents selected from halo, OH, aryl and heteroaryl, wherein aryl and heteroaryl groups are optionally substituted with one or more substituents selected from halo, OH, (1-4C)alkyl and (1-4C)haloalkyl;
(3) R1 is phenyl or 5- or 6-membered heteroaryl optionally substituted with with one or more substituents independently selected from halo, OH, cyano, R5 or OR5, wherein each R5 is independently H or (1-4C)alkyl;
(4) R1 is phenyl or 5-membered heteroaryl optionally substituted with with one or more substituents independently selected from halo, OH, cyano, R5 or OR5, wherein each R5 is independently H or (1-4C)alkyl;
(5) R1 is phenyl, furanyl, pyridyl, oxazolyl or pyrazolyl, optionally substituted with with one or more substituents independently selected from halo, OH, cyano, R5 or OR5, wherein each R5 is independently H or (1-4C)alkyl;
(6) R1 is phenyl, furan-2-yl, oxazol-2-yl, pyrazol-1-yl, m-cyanophenyl or thiazolyl, optionally substituted with with one or more substituents independently selected from halo, OH, cyano, R5 or OR5, wherein each R5 is independently H or (1-4C)alkyl;
(7) R1 is phenyl, furyl, pyridyl or oxazolyl, optionally substituted by halo or cyano;
(8) R1 is phenyl, optionally substituted with with one or more substituents independently selected from halo, OH, cyano, R5 or OR5, wherein each R5 is independently H or (1- 4C)alkyl;
(9) R1 is 3-halophenyl, for example 3-fluorophenyl and 3-chlorophenyl, 2-halophenyl, for example 2-fluorophenyl, and 2-chlorophenyl, 4-halophenyl, for example 4- fluorophenyl and 4-chlorophenyl, 3-cyanophenyl, 2-cyanophenyl or 4-cyanophenyl (10) R1 is 3-fluorophenyl, 2-fluorophenyl, 4-fluorophenyl or 3-cyanophenyl, especially 3- fluorophenyl and 3-cyanophenyl;
(11) R1 is 3-cyanophenyl.
(12) R2 is selected from:
(i) –Z1
(ii) –CR2aR2b–L1a–Z1; or
(iii) –[CR2aR2b]2-6–L1b–Z1;
wherein
R2a and R2b are each independently selected from hydrogen, fluoro or (1-2C)alkyl; L1a is absent or selected from C(O), C(O)O or C(O)N(Ra1), wherein Ra1 is selected from hydrogen or (1-2C)alkyl;
L1b is absent or selected from O, S, SO, SO2, N(Ra), C(O), C(O)O, OC(O), C(O)N(Ra), N(Ra)C(O), N(Ra)C(O)N(Rb), S(O)2N(Ra), or N(Ra)SO2, wherein Ra and Rb are each independently selected from hydrogen or (1-2C)alkyl; and
Z1 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl or heteroaryl; and wherein Z1 is optionally substituted by one or more substituents selected from (1-6C)- alkyl, halo, (1-6C)haloalkyl, (1-6C)haloalkoxy, cyano, aryl, heteroaryl, heterocyclyl, nitro, NRcRd, ORc, C(O)Rc, C(O)ORc, OC(O)Rc, C(O)N(Rc)Rd, N(Rc)C(O)Rd, S(O)yRc (where y is 0, 1 or 2), SO2N(Rc)Rd, N(Rc)SO2Rd or (CH2)zNRcRd (where z is 1, 2 or 3), wherein any alkyl, aryl, heteroaryl or heterocyclyl moiety in a substituent group on Z1 is optionally further substituted by cyano, halo, hydroxy, amino, (1-2C)alkyl or (1- 2C)alkoxy and Rc and Rd are each independently selected from hydrogen, (1-6C)alkyl, (1-6C)haloalkyl or (3-6C)cycloalkyl;
(13) R2 is selected from:
(i) –Z1
(ii) –CR2aR2b–L1a–Z1; or
(iii) –[CR2aR2b]2-6–L1b–Z1;
wherein
R2a and R2b are each independently selected from hydrogen, fluoro or (1-2C)alkyl; L1a is absent or selected from C(O), C(O)O or C(O)N(Ra1), wherein Ra1 is selected from hydrogen or (1-2C)alkyl;
L1b is absent or selected from O, S, SO, SO2, N(Ra), C(O), C(O)O, OC(O), C(O)N(Ra), N(Ra)C(O), N(Ra)C(O)N(Rb), S(O)2N(Ra), or N(Ra)SO2, wherein Ra and Rb are each independently selected from hydrogen or (1-2C)alkyl; and
Z1 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl or heteroaryl; and wherein Z1 is optionally substituted by one or more substituents selected from (1- 6C)alkyl, halo, (1-6C)haloalkyl, (1-6C)haloalkoxy, cyano, phenyl, a 5- or 6-membered heteroaryl, a 4- to 7-membered heterocyclyl, NRcRd, ORc, C(O)Rc, C(O)ORc, OC(O)Rc, C(O)N(Rc)Rd, N(Rc)C(O)Rd, S(O)yRc (where y is 0, 1 or 2), SO2N(Rc)Rd, N(Rc)SO2Rd or (CH2)zNRcRd (where z is 1, 2 or 3), wherein any alkyl, aryl, heteroaryl or heterocyclyl moiety in a substituent group on Z1 is optionally further substituted by cyano, halo, hydroxy, amino, (1-2C)alkyl or (1-2C)alkoxy and Rc and Rd are each independently selected from hydrogen, (1-6C)alkyl, (1-6C)haloalkyl or (3-6C)cycloalkyl;
(14) R2 is selected from:
(i) –Z1
(ii) –CR2aR2b–L1a–Z1; or
(iii) –[CR2aR2b]2-4–L1b–Z1;
wherein
R2a and R2b are each independently selected from hydrogen, fluoro or methyl; L1a is absent or selected from C(O), C(O)O or C(O)N(Ra1), wherein Ra1 is selected from hydrogen or (1-2C)alkyl;
L1b is absent or selected from O, S, SO, SO2, N(Ra), C(O), C(O)O, OC(O), C(O)N(Ra), N(Ra)C(O), N(Ra)C(O)N(Rb), S(O)2N(Ra), or N(Ra)SO2, wherein Ra and Rb are each independently selected from hydrogen or (1-2C)alkyl; and
Z1 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl or heteroaryl; and wherein Z1 is optionally substituted by one or more substituents selected from (1- 6C)alkyl, halo, (1-6C)haloalkyl, (1-6C)haloalkoxy, cyano, phenyl, a 5- or 6-membered heteroaryl, a 4- to 7-membered heterocyclyl, NRcRd, ORc, C(O)Rc, C(O)ORc, OC(O)Rc, C(O)N(Rc)Rd, N(Rc)C(O)Rd, S(O)yRc (where y is 0, 1 or 2), SO2N(Rc)Rd, N(Rc)SO2Rd or (CH2)zNRcRd (where z is 1, 2 or 3), wherein any alkyl, aryl, heteroaryl or heterocyclyl moiety in a substituent group on Z1 is optionally further substituted by cyano, halo, hydroxy, amino, (1-2C)alkyl or (1-2C)alkoxy and Rc and Rd are each independently selected from hydrogen, (1-6C)alkyl, (1-6C)haloalkyl or (3-6C)cycloalkyl;
(15) R2 is selected from:
(i) –Z1
(ii) –CR2aR2b–L1a–Z1; or
(iii) –[CR2aR2b]2-4–L1b–Z1;
wherein
R2a and R2b are each independently selected from hydrogen, fluoro or methyl;
L1a is absent;
L1b is absent or selected from O, S, SO, SO2, N(Ra), C(O), C(O)O, OC(O), C(O)N(Ra), N(Ra)C(O), N(Ra)C(O)N(Rb), S(O)2N(Ra), or N(Ra)SO2, wherein Ra and Rb are each independently selected from hydrogen or (1-2C)alkyl; and
Z1 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl or heteroaryl; and wherein Z1 is optionally substituted by one or more substituents selected from (1- 6C)alkyl, halo, (1-6C)haloalkyl, (1-6C)haloalkoxy, cyano, phenyl, a 5- or 6-membered heteroaryl, a 4- to 7-membered heterocyclyl, NRcRd, ORc, C(O)Rc, C(O)ORc, OC(O)Rc, C(O)N(Rc)Rd, N(Rc)C(O)Rd, S(O)yRc (where y is 0, 1 or 2), SO2N(Rc)Rd, N(Rc)SO2Rd or (CH2)zNRcRd (where z is 1, 2 or 3), wherein any alkyl, aryl, heteroaryl or heterocyclyl moiety in a substituent group on Z1 is optionally further substituted by cyano, halo, hydroxy, amino, (1-2C)alkyl or (1-2C)alkoxy and Rc and Rd are each independently selected from hydrogen, (1-6C)alkyl, (1-6C)haloalkyl or (3-6C)cycloalkyl; (16) R2 is selected from:
(i) –Z1
(ii) –CR2aR2b–L1a–Z1; or
(iii) –[CR2aR2b]2-4–L1b–Z1;
wherein
R2a and R2b are each independently selected from hydrogen, fluoro or methyl;
L1a is absent;
L1b is absent or selected from O, S, SO, SO2, N(Ra), C(O), C(O)O, OC(O), C(O)N(Ra), or N(Ra)C(O), wherein Ra and Rb are each independently selected from hydrogen or (1-2C)alkyl; and
Z1 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl or heteroaryl; and wherein Z1 is optionally substituted by one or more substituents selected from (1- 6C)alkyl, halo, (1-6C)haloalkyl, (1-6C)haloalkoxy, cyano, phenyl, a 5- or 6-membered heteroaryl, a 4- to 7-membered heterocyclyl, NRcRd, ORc, C(O)Rc, C(O)ORc, OC(O)Rc, C(O)N(Rc)Rd, N(Rc)C(O)Rd, S(O)yRc (where y is 0, 1 or 2), SO2N(Rc)Rd, N(Rc)SO2Rd or (CH2)zNRcRd (where z is 1, 2 or 3), wherein any alkyl, aryl, heteroaryl or heterocyclyl moiety in a substituent group on Z1 is optionally further substituted by cyano, halo, hydroxy, amino, (1-2C)alkyl or (1-2C)alkoxy and Rc and Rd are each independently selected from hydrogen, (1-6C)alkyl, (1-6C)haloalkyl or (3-6C)cycloalkyl;
(17) R2 is selected from:
(i) –Z1
(ii) –CR2aR2b–L1a–Z1; or
(iii) –[CR2aR2b]2-4–L1b–Z1;
wherein
R2a and R2b are each independently selected from hydrogen, fluoro or methyl;
L1a is absent;
L1b is absent; and
Z1 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl or heteroaryl; and wherein Z1 is optionally substituted by one or more substituents selected from (1- 6C)alkyl, halo, (1-6C)haloalkyl, (1-6C)haloalkoxy, cyano, phenyl, a 5- or 6-membered heteroaryl, a 4- to 7-membered heterocyclyl, NRcRd, ORc, C(O)Rc, C(O)ORc, OC(O)Rc, C(O)N(Rc)Rd, N(Rc)C(O)Rd, S(O)yRc (where y is 0, 1 or 2), SO2N(Rc)Rd, N(Rc)SO2Rd or (CH2)zNRcRd (where z is 1, 2 or 3), wherein any alkyl, aryl, heteroaryl or heterocyclyl moiety in a substituent group on Z1 is optionally further substituted by cyano, halo, hydroxy, amino, (1-2C)alkyl or (1-2C)alkoxy and Rc and Rd are each independently selected from hydrogen, (1-6C)alkyl, (1-6C)haloalkyl or (3-6C)cycloalkyl;
(18) R2 is selected from:
(i) –Z1
(ii) –CR2aR2b–L1a–Z1; or
(iii) –[CR2aR2b]2-4–L1b–Z1;
wherein
R2a and R2b are each independently selected from hydrogen, fluoro or methyl;
L1a is absent;
L1b is absent; and
Z1 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl or heteroaryl; and wherein Z1 is optionally substituted by one or more substituents selected from (1- 6C)alkyl, halo, (1-6C)haloalkyl, (1-6C)haloalkoxy, cyano, phenyl, NRcRd, ORc, C(O)Rc, C(O)ORc, OC(O)Rc, C(O)N(Rc)Rd, N(Rc)C(O)Rd, S(O)yRc (where y is 0, 1 or 2), SO2N(Rc)Rd, N(Rc)SO2Rd or (CH2)zNRcRd (where z is 1, 2 or 3), wherein any alkyl or phenyl moiety in a substituent group on Z1 is optionally further substituted by cyano, halo, hydroxy, amino, (1-2C)alkyl or (1-2C)alkoxy and Rc and Rd are each independently selected from hydrogen, (1-6C)alkyl, (1-6C)haloalkyl or (3- 6C)cycloalkyl;
(19) R2 is selected from:
(i) –Z1
(ii) –CR2aR2b–L1a–Z1; or
(iii) –[CR2aR2b]2-4–L1b–Z1;
wherein
R2a and R2b are each independently selected from hydrogen, fluoro or methyl;
L1a is absent;
L1b is absent; and
Z1 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl or heteroaryl; and wherein Z1 is optionally substituted by one or more substituents selected from (1- 6C)alkyl, halo, (1-6C)haloalkyl, (1-6C)haloalkoxy, cyano, phenyl, NRcRd, ORc, C(O)Rc, C(O)ORc, OC(O)Rc, C(O)N(Rc)Rd, N(Rc)C(O)Rd, S(O)yRc (where y is 0, 1 or 2), SO2N(Rc)Rd, N(Rc)SO2Rd or (CH2)zNRcRd (where z is 1, 2 or 3), wherein any alkyl or phenyl moiety in a substituent group on Z1 is optionally further substituted by cyano, halo, hydroxy, amino, (1-2C)alkyl or (1-2C)alkoxy and Rc and Rd are each independently selected from hydrogen, (1-4C)alkyl, (1-4C)haloalkyl or (3- 6C)cycloalkyl;
(20) R2 is selected from:
(i) –Z1
(ii) –CR2aR2b–L1a–Z1; or
(iii) –[CR2aR2b]2-4–L1b–Z1;
wherein
R2a and R2b are hydrogen;
L1a is absent;
L1b is absent; and
Z1 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl or heteroaryl; and wherein Z1 is optionally substituted by one or more substituents selected from (1- 6C)alkyl, halo, (1-6C)haloalkyl, (1-6C)haloalkoxy, cyano, phenyl, NRcRd, ORc, C(O)Rc, C(O)ORc, OC(O)Rc, C(O)N(Rc)Rd, N(Rc)C(O)Rd, S(O)yRc (where y is 0, 1 or 2), SO2N(Rc)Rd, N(Rc)SO2Rd or (CH2)zNRcRd (where z is 1, 2 or 3), wherein Rc and Rd are each independently selected from hydrogen, (1-4C)alkyl, (1-4C)haloalkyl or (3- 6C)cycloalkyl;
(21) R2 is selected from:
(i) –Z1
(ii) –CH2–Z1; or
(iii) –[CH2]2-4–Z1;
wherein
Z1 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl or heteroaryl; and wherein Z1 is optionally substituted by one or more substituents selected from (1- 6C)alkyl, halo, (1-6C)haloalkyl, (1-6C)haloalkoxy, cyano, NRcRd, ORc, C(O)Rc, C(O)ORc, OC(O)Rc, C(O)N(Rc)Rd, N(Rc)C(O)Rd, S(O)yRc (where y is 0, 1 or 2), SO2N(Rc)Rd, N(Rc)SO2Rd or (CH2)zNRcRd (where z is 1, 2 or 3), wherein Rc and Rd are each independently selected from hydrogen, (1-4C)alkyl, (1-4C)haloalkyl or (3- 6C)cycloalkyl;
(22) R2 is selected from:
(i) –Z1
(ii) –CH2–Z1; or
(iii) –[CH2]2-4–Z1;
wherein
Z1 is selected from (1-6C)alkyl, (3-6C)cycloalkyl or heterocyclyl; and wherein Z1 is optionally substituted by one or more substituents selected from (1-6C)alkyl, halo, (1- 6C)haloalkyl, (1-6C)haloalkoxy, cyano, NRcRd, ORc, C(O)Rc, C(O)ORc, OC(O)Rc, C(O)N(Rc)Rd, N(Rc)C(O)Rd, S(O)yRc (where y is 0, 1 or 2), SO2N(Rc)Rd, N(Rc)SO2Rd or (CH2)zNRcRd (where z is 1, 2 or 3), wherein Rc and Rd are each independently selected from hydrogen, or (1-4C)alkyl;
(23) R2 is selected from:
(i) –Z1
(ii) –CH2–Z1; or
(iii) –[CH2]2-4–Z1;
wherein
Z1 is selected from (1-6C)alkyl or (3-6C)cycloalkyl or heterocyclyl; and wherein Z1 is optionally substituted by one or more substituents selected from (1-6C)alkyl, halo, cyano, NRcRd, ORc, C(O)Rc, C(O)ORc, OC(O)Rc, C(O)N(Rc)Rd, N(Rc)C(O)Rd, or S(O)yRc (where y is 0, 1 or 2), wherein Rc and Rd are each independently selected from hydrogen, or (1-4C)alkyl;
(24) R2 is selected from:
(i) –Z1: or
(ii) –CH2–Z1;
wherein
Z1 is selected from (1-6C)alkyl or (3-6C)cycloalkyl optionally substituted by one or more substituents selected from methoxy and OH;
(25) R3 is selected from: (i) –Z2;
(ii) –CR3aR3b–L2a–Z2; or
(iii) –[CR3aR3b]2-6–L2b–Z2;
wherein
R3a and R3b are each independently selected from hydrogen or (1-2C)alkyl;
L2a is absent or selected from C(O), C(O)O or C(O)N(Rj), wherein Rj is selected from hydrogen or (1-2C)alkyl
L2b is absent or selected from O, S, SO, SO2, N(Re), C(O), C(O)O, OC(O), C(O)N(Re), N(Re)C(O), N(Re)C(O)N(Rf), N(Re)C(=NRg)N(Rf), S(O)2N(Re), or N(Re)SO2, wherein Re, Rf and Rg are each independently selected from hydrogen or (1-2C)alkyl; and Z2 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl or heteroaryl; and wherein Z2 is optionally substituted by one or more substituents selected from (1-6C)- alkyl, halo, (1-6C)haloalkyl, (1-6C)haloalkoxy, cyano, aryl, heteroaryl, heterocyclyl, nitro, NRhRi, ORh, C(O)Rh, C(O)ORh, OC(O)Rh, C(O)N(Rh)Ri, N(Rh)C(O)Ri, S(O)yRh (where y is 0, 1 or 2), SO2N(Rh)Ri, N(Rh)SO2Ri or (CH2)zNRhRi (where z is 1, 2 or 3), wherein any alkyl, aryl, heteroaryl or heterocyclyl moiety in a substituent group on Zz is optionally further substituted by cyano, halo, hydroxy, amino, (1-2C)alkyl or (1- 2C)alkoxy and Rh and Ri are each independently selected from hydrogen, (1-6C)alkyl, (1-6C)haloalkyl or (3-6C)cycloalkyl.
(26) R3 is selected from:
(i) –Z2;
(ii) –CR3aR3b–L2a–Z2; or
(iii) –[CR3aR3b]2-6–L2b–Z2;
wherein
R3a and R3b are each independently selected from hydrogen or (1-2C)alkyl;
L2a is absent or selected from C(O)O or C(O)N(Rj), wherein Rj is selected from hydrogen or (1-2C)alkyl
L2b is absent or selected from O, S, SO, SO2, N(Re), C(O), C(O)O, OC(O), C(O)N(Re), N(Re)C(O), S(O)2N(Re), or N(Re)SO2, wherein Re is selected from hydrogen or (1- 2C)alkyl; and
Z2 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl or heteroaryl; and wherein Z2 is optionally substituted by one or more substituents selected from (1-6C)- alkyl, halo, (1-6C)haloalkyl, (1-6C)haloalkoxy, cyano, aryl, heteroaryl, heterocyclyl, nitro, NRhRi, ORh, C(O)Rh, C(O)ORh, OC(O)Rh, C(O)N(Rh)Ri, N(Rh)C(O)Ri, S(O)yRh (where y is 0, 1 or 2), SO2N(Rh)Ri, N(Rh)SO2Ri or (CH2)zNRhRi (where z is 1, 2 or 3), wherein any alkyl, aryl, heteroaryl or heterocyclyl moiety in a substituent group on Zz is optionally further substituted by cyano, halo, hydroxy, amino, (1-2C)alkyl or (1- 2C)alkoxy and Rh and Ri are each independently selected from hydrogen, (1-6C)alkyl, (1-6C)haloalkyl or (3-6C)cycloalkyl.
(27) R3 is selected from:
(i) –Z2;
(ii) –CR3aR3b–L2a–Z2; or
(iii) –[CR3aR3b]2-6–L2b–Z2;
wherein
R3a and R3b are each independently selected from hydrogen or methyl;
L2a is absent or selected from C(O)O or C(O)N(Rj), wherein Rj is selected from hydrogen or (1-2C)alkyl
L2b is absent or selected from O, S, SO, SO2, N(Re), C(O), C(O)O, OC(O), C(O)N(Re), or N(Re)C(O), wherein Re is selected from hydrogen or (1-2C)alkyl; and
Z2 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl or heteroaryl; and wherein Z2 is optionally substituted by one or more substituents selected from (1-6C)- alkyl, halo, (1-6C)haloalkyl, (1-6C)haloalkoxy, cyano, aryl, heteroaryl, heterocyclyl, nitro, NRhRi, ORh, C(O)Rh, C(O)ORh, OC(O)Rh, C(O)N(Rh)Ri, N(Rh)C(O)Ri, S(O)yRh (where y is 0, 1 or 2), SO2N(Rh)Ri, N(Rh)SO2Ri or (CH2)zNRhRi (where z is 1, 2 or 3), wherein any alkyl, aryl, heteroaryl or heterocyclyl moiety in a substituent group on Zz is optionally further substituted by cyano, halo, hydroxy, amino, (1-2C)alkyl or (1- 2C)alkoxy and Rh and Ri are each independently selected from hydrogen, (1-6C)alkyl, (1-6C)haloalkyl or (3-6C)cycloalkyl.
(28) R3 is selected from:
(i) –Z2;
(ii) –CR3aR3b–L2a–Z2; or
(iii) –[CR3aR3b]2-4–L2b–Z2;
wherein R3a and R3b are each independently selected from hydrogen or methyl;
L2a is absent;
L2b is absent or selected from O, S, SO, SO2, N(Re), C(O), C(O)O, OC(O), C(O)N(Re), or N(Re)C(O), wherein Re is selected from hydrogen or (1-2C)alkyl; and
Z2 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl or heteroaryl; and wherein Z2 is optionally substituted by one or more substituents selected from (1-6C)- alkyl, halo, (1-6C)haloalkyl, (1-6C)haloalkoxy, cyano, phenyl, 5- or 6-membered heteroaryl, 4- to 7-membered heterocyclyl, NRhRi, ORh, C(O)Rh, C(O)ORh, OC(O)Rh, C(O)N(Rh)Ri, N(Rh)C(O)Ri, S(O)yRh (where y is 0, 1 or 2), SO2N(Rh)Ri, N(Rh)SO2Ri or (CH2)zNRhRi (where z is 1, 2 or 3), wherein any alkyl, aryl, heteroaryl or heterocyclyl moiety in a substituent group on Zz is optionally further substituted by cyano, halo, hydroxy, amino, (1-2C)alkyl or (1-2C)alkoxy and Rh and Ri are each independently selected from hydrogen, (1-6C)alkyl, (1-6C)haloalkyl or (3-6C)cycloalkyl.
(29) R3 is selected from:
(i) –Z2;
(ii) –CR3aR3b–L2a–Z2; or
(iii) –[CR3aR3b]2-4–L2b–Z2;
wherein
R3a and R3b are each independently selected from hydrogen or methyl;
L2a is absent;
L2b is absent or selected from O, S, SO, SO2, N(Re), C(O), C(O)O, OC(O), C(O)N(Re), or N(Re)C(O), wherein Re is selected from hydrogen or (1-2C)alkyl; and
Z2 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl or heteroaryl; and wherein Z2 is optionally substituted by one or more substituents selected from (1-6C)- alkyl, halo, (1-6C)haloalkyl, (1-6C)haloalkoxy, cyano, phenyl, 5- or 6-membered heteroaryl, 4- to 7-membered heterocyclyl, NRhRi, ORh, C(O)Rh, C(O)ORh, OC(O)Rh, C(O)N(Rh)Ri, N(Rh)C(O)Ri, S(O)yRh (where y is 0, 1 or 2), SO2N(Rh)Ri, N(Rh)SO2Ri or (CH2)zNRhRi (where z is 1, 2 or 3), wherein Rh and Ri are each independently selected from hydrogen, (1-6C)alkyl or (3-6C)cycloalkyl.
(30) R3 is selected from:
(i) –Z2;
(ii) –CR3aR3b–L2a–Z2; or (iii) –[CR3aR3b]2-4–L2b–Z2;
wherein
R3a and R3b are hydrogen;
L2a is absent;
L2b is absent; and
Z2 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl or heteroaryl; and wherein Z2 is optionally substituted by one or more substituents selected from (1-6C)- alkyl, halo, (1-6C)haloalkyl, (1-6C)haloalkoxy, cyano, phenyl, 5- or 6-membered heteroaryl, 4- to 7-membered heterocyclyl, NRhRi, ORh, C(O)Rh, C(O)ORh, OC(O)Rh, C(O)N(Rh)Ri, N(Rh)C(O)Ri, S(O)yRh (where y is 0, 1 or 2), SO2N(Rh)Ri, N(Rh)SO2Ri or (CH2)zNRhRi (where z is 1, 2 or 3), wherein Rh and Ri are each independently selected from hydrogen, (1-6C)alkyl or (3-6C)cycloalkyl.
(31) R3 is selected from:
(i) –Z2;
(ii) –CH2–Z2; or
(iii) –[CH2]2-4–Z2;
wherein
Z2 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, phenyl, heterocyclyl or heteroaryl; and wherein Z2 is optionally substituted by one or more substituents selected from (1- 6C)alkyl, halo, (1-6C)haloalkyl, (1-6C)haloalkoxy, cyano, phenyl, 5- or 6-membered heteroaryl, 4- to 7-membered heterocyclyl, NRhRi, ORh, C(O)Rh, C(O)ORh, OC(O)Rh, C(O)N(Rh)Ri, N(Rh)C(O)Ri, S(O)yRh (where y is 0, 1 or 2), SO2N(Rh)Ri, N(Rh)SO2Ri or (CH2)zNRhRi (where z is 1, 2 or 3), wherein Rh and Ri are each independently selected from hydrogen or (1-4C)alkyl.
(32) R3 is selected from:
(i) –Z2;
(ii) –CH2–Z2; or
(iii) –[CH2]2-4–Z2;
wherein
Z2 is selected from (1-6C)alkyl, (3-6C)cycloalkyl or heterocyclyl; and wherein Z2 is optionally substituted by one or more substituents selected from (1-6C)alkyl, halo, (1- 6C)haloalkyl, (1-6C)haloalkoxy, cyano, phenyl, 5- or 6-membered heteroaryl, 4- to 7- membered heterocyclyl, NRhRi, ORh, C(O)Rh, C(O)ORh, OC(O)Rh, C(O)N(Rh)Ri, N(Rh)C(O)Ri, S(O)yRh (where y is 0, 1 or 2), SO2N(Rh)Ri, N(Rh)SO2Ri or (CH2)zNRhRi (where z is 1, 2 or 3), wherein Rh and Ri are each independently selected from hydrogen or (1-4C)alkyl.
(33) R3 is selected from:
(i) –Z2;
(ii) –CH2–Z2; or
(iii) –[CH2]2-4–Z2;
wherein
Z2 is selected from 4, 5 or 6-membered heterocyclyl; and wherein Z2 is optionally substituted by one or more substituents selected from (1-6C)alkyl, halo, (1- 6C)haloalkyl, (1-6C)haloalkoxy, cyano, phenyl, 5- or 6-membered heteroaryl, 4- to 7- membered heterocyclyl, NRhRi, ORh, C(O)Rh, C(O)ORh, OC(O)Rh, C(O)N(Rh)Ri, N(Rh)C(O)Ri, S(O)yRh (where y is 0, 1 or 2), SO2N(Rh)Ri, N(Rh)SO2Ri or (CH2)zNRhRi (where z is 1, 2 or 3), wherein Rh and Ri are each independently selected from hydrogen or (1-4C)alkyl;
or Z2 is a (1-4C)alkyl optionally substituted with one substituents selected from halo (e.g. fluoro), hydroxy, (1-2C)alkoxy and (1-2C)alkyl;
(34) R3 is selected from:
(i) –Z2; or
(ii) –CH2–Z2;
wherein
Z2 is a 4, 5 or 6-membered heterocyclyl comprising 1 or 2 hetereoatoms selected from N, O or S which is optionally substituted by one or more substituents selected from (1- 4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, cyano, aryl, NRhRi, ORh, C(O)Rh, C(O)ORh, OC(O)Rh, C(O)N(Rh)Ri, N(Rh)C(O)Ri, S(O)yRh (where y is 0, 1 or 2), SO2N(Rh)Ri, N(Rh)SO2Ri or (CH2)zNRhRi (where z is 1, 2 or 3), wherein Rh and Ri are each independently selected from hydrogen or (1-4C)alkyl;
(35) R3 is selected from:
(i) –Z2; or
(ii) –CH2–Z2; wherein
Z2 is a 4, 5 or 6-membered heterocyclyl comprising 1 or 2 O atoms which is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo, (1- 4C)haloalkyl, (1-4C)haloalkoxy, cyano, aryl, NRhRi, ORh, C(O)Rh, C(O)ORh, OC(O)Rh, C(O)N(Rh)Ri, N(Rh)C(O)Ri, S(O)yRh (where y is 0, 1 or 2), SO2N(Rh)Ri, N(Rh)SO2Ri or (CH2)zNRhRi (where z is 1, 2 or 3), wherein Rh and Ri are each independently selected from hydrogen or (1-4C)alkyl;
(36) R3 is tetrahydrofuranyl or a (1-4C)alkyl optionally substituted with one or more of a halo (e.g. fluoro), hydroxy, (1-2C)alkoxy and (1-2C)alkyl;
(37) R3 is tetrahydrofuranyl.
(38) R3 is selected from:
(i) –Z2;
(ii) –CR3aR3b–L2a–Z2; or
(iii) –[CR3aR3b]2-6–L2b–Z2;
wherein
R3a and R3b are each independently selected from hydrogen or (1-2C)alkyl;
L2a is absent or selected from C(O), C(O)O or C(O)N(Rj), wherein Rj is selected from hydrogen or (1-2C)alkyl
L2b is absent or selected from O, S, SO, SO2, N(Re), C(O), C(O)O, OC(O), C(O)N(Re), N(Re)C(O), N(Re)C(O)N(Rf), N(Re)C(=NRg)N(Rf), S(O)2N(Re), N(Re)SO2, N(Re)C(O)N(Rf), N(Re)C(O)O, OC(O)N(Re) wherein Re, Rf and Rg are each independently selected from hydrogen or (1-2C)alkyl; and
Z2 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl or heteroaryl; and wherein Z2 is optionally substituted by one or more substituents selected from (1-6C)- alkyl, halo, (1-6C)haloalkyl, (1-6C)haloalkoxy, cyano, aryl, heteroaryl, heterocyclyl, nitro, NRhRi, ORh, C(O)Rh, C(O)ORh, OC(O)Rh, C(O)N(Rh)Ri, N(Rh)C(O)Ri, N(Rh)C(O)N(Ri)Rk, N(Rh)C(O)ORi, OC(O)N(Rh)Ri, S(O)yRh (where y is 0, 1 or 2), SO2N(Rh)Ri, N(Rh)SO2Ri, (CH2)zNRhRi (where z is 1, 2 or 3) or oxo wherein any alkyl, aryl, heteroaryl or heterocyclyl moiety in a substituent group on Zz is optionally further substituted by cyano, halo, hydroxy, amino, oxo, (1-2C)alkyl or (1-2C)alkoxy and Rh, Ri and Rk are each independently selected from hydrogen, (1-6C)alkyl, (1-6C)haloalkyl or (3-6C)cycloalkyl. (39) R3 is selected from:
(i) –Z2;
(ii) –CR3aR3b–L2a–Z2; or
(iii) –[CR3aR3b]2-6–L2b–Z2;
wherein
R3a and R3b are each independently selected from hydrogen or (1-2C)alkyl;
L2a is absent or selected from C(O)O or C(O)N(Rj), wherein Rj is selected from hydrogen or (1-2C)alkyl
L2b is absent or selected from O, S, SO, SO2, N(Re), C(O), C(O)O, OC(O), C(O)N(Re), N(Re)C(O), S(O)2N(Re), N(Re)SO2, N(Re)C(O)N(Rf), N(Re)C(O)O, OC(O)N(Re) wherein Re is selected from hydrogen or (1-2C)alkyl; and
Z2 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl or heteroaryl; and wherein Z2 is optionally substituted by one or more substituents selected from (1-6C)- alkyl, halo, (1-6C)haloalkyl, (1-6C)haloalkoxy, cyano, aryl, heteroaryl, heterocyclyl, nitro, NRhRi, ORh, C(O)Rh, C(O)ORh, OC(O)Rh, C(O)N(Rh)Ri, N(Rh)C(O)Ri, N(Rh)C(O)N(Ri)Rk, N(Rh)C(O)ORi, OC(O)N(Rh)Ri, S(O)yRh (where y is 0, 1 or 2), SO2N(Rh)Ri, N(Rh)SO2Ri, (CH2)zNRhRi (where z is 1, 2 or 3) or oxo, wherein any alkyl, aryl, heteroaryl or heterocyclyl moiety in a substituent group on Zz is optionally further substituted by cyano, halo, hydroxy, amino, oxo, (1-2C)alkyl or (1-2C)alkoxy and Rh, Ri and Rk are each independently selected from hydrogen, (1-6C)alkyl, (1-6C)haloalkyl or (3-6C)cycloalkyl.
(40) R3 is selected from:
(i) –Z2;
(ii) –CR3aR3b–L2a–Z2; or
(iii) –[CR3aR3b]2-6–L2b–Z2;
wherein
R3a and R3b are each independently selected from hydrogen or methyl;
L2a is absent or selected from C(O)O or C(O)N(Rj), wherein Rj is selected from hydrogen or (1-2C)alkyl L2b is absent or selected from O, S, SO, SO2, N(Re), C(O), C(O)O, OC(O), C(O)N(Re), N(Re)C(O), N(Re)C(O)N(Rf), N(Re)C(O)O, OC(O)N(Re) wherein Re is selected from hydrogen or (1-2C)alkyl; and
Z2 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl or heteroaryl; and wherein Z2 is optionally substituted by one or more substituents selected from (1-6C)- alkyl, halo, (1-6C)haloalkyl, (1-6C)haloalkoxy, cyano, aryl, heteroaryl, heterocyclyl, nitro, NRhRi, ORh, C(O)Rh, C(O)ORh, OC(O)Rh, C(O)N(Rh)Ri, N(Rh)C(O)Ri, N(Rh)C(O)N(Ri)Rk, N(Rh)C(O)ORi, OC(O)N(Rh)Ri, S(O)yRh (where y is 0, 1 or 2), SO2N(Rh)Ri, N(Rh)SO2Ri (CH2)zNRhRi (where z is 1, 2 or 3) or oxo, wherein any alkyl, aryl, heteroaryl or heterocyclyl moiety in a substituent group on Zz is optionally further substituted by cyano, halo, hydroxy, amino, oxo, (1-2C)alkyl or (1-2C)alkoxy and Rh, Ri and Rkare each independently selected from hydrogen, (1-6C)alkyl, (1-6C)haloalkyl or (3-6C)cycloalkyl.
(41) R3 is selected from:
(i) –Z2;
(ii) –CR3aR3b–L2a–Z2; or
(iii) –[CR3aR3b]2-4–L2b–Z2;
wherein
R3a and R3b are each independently selected from hydrogen or methyl;
L2a is absent;
L2b is absent or selected from O, S, SO, SO2, N(Re), C(O), C(O)O, OC(O), C(O)N(Re), N(Re)C(O), N(Re)C(O)N(Rf), N(Re)C(O)O, OC(O)N(Re), wherein Re is selected from hydrogen or (1-2C)alkyl; and
Z2 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl or heteroaryl; and wherein Z2 is optionally substituted by one or more substituents selected from (1-6C)- alkyl, halo, (1-6C)haloalkyl, (1-6C)haloalkoxy, cyano, phenyl, 5- or 6-membered heteroaryl, 4- to 7-membered heterocyclyl, NRhRi, ORh, C(O)Rh, C(O)ORh, OC(O)Rh, C(O)N(Rh)Ri, N(Rh)C(O)Ri, N(Rh)C(O)N(Ri)Rk, N(Rh)C(O)ORi, OC(O)N(Rh)Ri, S(O)yRh (where y is 0, 1 or 2), SO2N(Rh)Ri, N(Rh)SO2Ri, (CH2)zNRhRi (where z is 1, 2 or 3) or oxo, wherein any alkyl, aryl, heteroaryl or heterocyclyl moiety in a substituent group on Zz is optionally further substituted by cyano, halo, hydroxy, amino, oxo, (1-2C)alkyl or (1-2C)alkoxy and Rh, Ri and Rk are each independently selected from hydrogen, (1- 6C)alkyl, (1-6C)haloalkyl or (3-6C)cycloalkyl. (42) R3 is selected from:
(i) –Z2;
(ii) –CR3aR3b–L2a–Z2; or
(iii) –[CR3aR3b]2-4–L2b–Z2;
wherein
R3a and R3b are each independently selected from hydrogen or methyl;
L2a is absent;
L2b is absent or selected from O, S, SO, SO2, N(Re), C(O), C(O)O, OC(O), C(O)N(Re), N(Re)C(O), N(Re)C(O)N(Rf), N(Re)C(O)O, OC(O)N(Re), wherein Re is selected from hydrogen or (1-2C)alkyl; and
Z2 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl or heteroaryl; and wherein Z2 is optionally substituted by one or more substituents selected from (1-6C)- alkyl, halo, (1-6C)haloalkyl, (1-6C)haloalkoxy, cyano, phenyl, 5- or 6-membered heteroaryl, 4- to 7-membered heterocyclyl, NRhRi, ORh, C(O)Rh, C(O)ORh, OC(O)Rh, C(O)N(Rh)Ri, N(Rh)C(O)Ri, N(Rh)C(O)N(Ri)Rk, N(Rh)C(O)ORi, OC(O)N(Rh)Ri, S(O)yRh (where y is 0, 1 or 2), SO2N(Rh)Ri, N(Rh)SO2Ri, (CH2)zNRhRi (where z is 1, 2 or 3) or oxo, wherein Rh, Ri and Rk are each independently selected from hydrogen, (1-6C)alkyl or (3-6C)cycloalkyl.
(43) R3 is selected from:
(i) –Z2;
(ii) –CR3aR3b–L2a–Z2; or
(iii) –[CR3aR3b]2-4–L2b–Z2;
wherein
R3a and R3b are hydrogen;
L2a is absent;
L2b is absent; and
Z2 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl or heteroaryl; and wherein Z2 is optionally substituted by one or more substituents selected from (1-6C)- alkyl, halo, (1-6C)haloalkyl, (1-6C)haloalkoxy, cyano, phenyl, 5- or 6-membered heteroaryl, 4- to 7-membered heterocyclyl, NRhRi, ORh, C(O)Rh, C(O)ORh, OC(O)Rh, C(O)N(Rh)Ri, N(Rh)C(O)Ri, N(Rh)C(O)N(Ri)Rk, N(Rh)C(O)ORi, OC(O)N(Rh)Ri, S(O)yRh (where y is 0, 1 or 2), SO2N(Rh)Ri, N(Rh)SO2Ri, (CH2)zNRhRi (where z is 1, 2 or 3) or oxo, wherein Rh, Ri and Rk are each independently selected from hydrogen, (1- 6C)alkyl or (3-6C)cycloalkyl.
(44) R3 is selected from:
(i) –Z2;
(ii) –CH2–Z2; or
(iii) –[CH2]2-4–Z2;
wherein
Z2 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, phenyl, heterocyclyl or heteroaryl; and wherein Z2 is optionally substituted by one or more substituents selected from (1- 6C)alkyl, halo, (1-6C)haloalkyl, (1-6C)haloalkoxy, cyano, phenyl, 5- or 6-membered heteroaryl, 4- to 7-membered heterocyclyl, NRhRi, ORh, C(O)Rh, C(O)ORh, OC(O)Rh, C(O)N(Rh)Ri, N(Rh)C(O)Ri, N(Rh)C(O)N(Ri)Rk, N(Rh)C(O)ORi, OC(O)N(Rh)Ri, S(O)yRh (where y is 0, 1 or 2), SO2N(Rh)Ri, N(Rh)SO2Ri, (CH2)zNRhRi (where z is 1, 2 or 3) or oxo, wherein Rh, Ri and Rk are each independently selected from hydrogen or (1- 4C)alkyl.
(45) R3 is selected from:
(i) –Z2;
(ii) –CH2–Z2; or
(iii) –[CH2]2-4–Z2;
wherein
Z2 is selected from (1-6C)alkyl, (3-6C)cycloalkyl or heterocyclyl; and wherein Z2 is optionally substituted by one or more substituents selected from (1-6C)alkyl, halo, (1- 6C)haloalkyl, (1-6C)haloalkoxy, cyano, phenyl, 5- or 6-membered heteroaryl, 4- to 7- membered heterocyclyl, NRhRi, ORh, C(O)Rh, C(O)ORh, OC(O)Rh, C(O)N(Rh)Ri, N(Rh)C(O)Ri, N(Rh)C(O)N(Ri)Rk, N(Rh)C(O)ORi, OC(O)N(Rh)Ri, S(O)yRh (where y is 0, 1 or 2), SO2N(Rh)Ri, N(Rh)SO2Ri, (CH2)zNRhRi (where z is 1, 2 or 3) or oxo, wherein Rh, Ri and Rk are each independently selected from hydrogen or (1-4C)alkyl.
(46) R3 is selected from:
(i) –Z2;
(ii) –CH2–Z2; or (iii) –[CH2]2-4–Z2;
wherein
Z2 is selected from 4, 5 or 6-membered heterocyclyl; and wherein Z2 is optionally substituted by one or more substituents selected from (1-6C)alkyl, halo, (1- 6C)haloalkyl, (1-6C)haloalkoxy, cyano, phenyl, 5- or 6-membered heteroaryl, 4- to 7- membered heterocyclyl, NRhRi, ORh, C(O)Rh, C(O)ORh, OC(O)Rh, C(O)N(Rh)Ri, N(Rh)C(O)Ri, N(Rh)C(O)N(Ri)Rk, N(Rh)C(O)ORi, OC(O)N(Rh)Ri, S(O)yRh (where y is 0, 1 or 2), SO2N(Rh)Ri, N(Rh)SO2Ri, (CH2)zNRhRi (where z is 1, 2 or 3) or oxo, wherein Rh, Ri and Rk are each independently selected from hydrogen or (1-4C)alkyl;
or Z2 is a (1-4C)alkyl optionally substituted with one substituents selected from halo (e.g. fluoro), hydroxy, (1-2C)alkoxy and (1-2C)alkyl;
(47) R3 is selected from:
(i) –Z2; or
(ii) –CH2–Z2;
wherein
Z2 is a 4, 5 or 6-membered heterocyclyl comprising 1 or 2 hetereoatoms selected from N, O or S which is optionally substituted by one or more substituents selected from (1- 4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, cyano, aryl, NRhRi, ORh, C(O)Rh, C(O)ORh, OC(O)Rh, C(O)N(Rh)Ri, N(Rh)C(O)Ri, N(Rh)C(O)N(Ri)Rk, N(Rh)C(O)ORi, OC(O)N(Rh)Ri, S(O)yRh (where y is 0, 1 or 2), SO2N(Rh)Ri, N(Rh)SO2Ri, (CH2)zNRhRi (where z is 1, 2 or 3) or oxo, wherein Rh, Ri and Rk are each independently selected from hydrogen or (1-4C)alkyl;
(48) R3 is selected from:
(i) –Z2; or
(ii) –CH2–Z2;
wherein
Z2 is a 4, 5 or 6-membered heterocyclyl comprising 1 or 2 O atoms which is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo, (1- 4C)haloalkyl, (1-4C)haloalkoxy, cyano, aryl, NRhRi, ORh, C(O)Rh, C(O)ORh, OC(O)Rh, C(O)N(Rh)Ri, N(Rh)C(O)Ri, N(Rh)C(O)N(Ri)Rk, N(Rh)C(O)ORi, OC(O)N(Rh)Ri, S(O)yRh (where y is 0, 1 or 2), SO2N(Rh)Ri, N(Rh)SO2Ri, (CH2)zNRhRi (where z is 1, 2 or 3) or oxo, wherein Rh, Ri and Rk are each independently selected from hydrogen or (1- 4C)alkyl;
(49) R3 is tetrahydrofuranyl, oxetanyl or a (1-4C)alkyl optionally substituted with one or more of a halo (e.g. fluoro), hydroxy, (1-2C)alkoxy and (1-2C)alkyl;
(50) R3 is tetrahydrofuranyl or oxetanyl. [0064] Suitably, a heteroaryl or heterocyclyl group as defined herein is a monocyclic heteroaryl or heterocyclyl group comprising one, two or three heteroatoms selected from N, O or S.
[0065] Suitably, a heteroaryl is a 5- or 6-membered heteroaryl ring comprising one, two or three heteroatoms selected from N, O or S.
[0066] Suitably, a heterocyclyl group is a 4-, 5- or 6-membered heterocyclyl ring comprising one, two or three heteroatoms selected from N, O or S. Most suitably, a heterocyclyl group is a 5-, 6- or 7-membered 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].
[0067] Suitably an aryl group is phenyl.
[0068] Suitably, R1 is as defined in any one of paragraphs (1) to (11). More suitably, R1 is as defined in any one of paragraphs (6) to (11). Most suitably, R1 is as defined in paragraph (11).
[0069] Suitably, R2 is as defined in any one of paragraphs (12) to (24). More suitably, R2 is as defined in any one of paragraphs (20) to (24). Most suitably, R2 is as defined in paragraph (24).
[0070] Suitably R3 is as defined in any one of paragraphs (25) to (37) or (38) to (50). More suitably, R3 is as defined in any one of paragraphs (33) to (37) or (46) to (50). Most suitably, R3 is as defined in paragraph (37) or (50).
[0071] In a particular group of compounds of the invention, 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 R2 and R3 are each as defined hereinbefore.
[0072] In an embodiment of the compounds of formula Ia:
R2 is as defined in any one of paragraphs (12) to (24) above; and
R3 is as defined in any one of paragraphs (25) to (37) above.
[0073] In another embodiment of the compounds of formula Ia:
R2 is as defined in any one of paragraphs (20) to (24) above; and
R3 is as defined in any one of paragraphs (33) to (37) above.
[0074] In an embodiment of the compounds of formula Ia:
R2 is as defined in any one of paragraphs (12) to (24) above; and
R3 is as defined in any one of paragraphs (38) to (50) above.
[0075] In another embodiment of the compounds of formula Ia:
R2 is as defined in any one of paragraphs (20) to (24) above; and
R3 is as defined in any one of paragraphs (46) to (50) above.
[0076] In another embodiment of the compounds of formula Ia:
R2 is as defined in paragraph (24) above;
R3 is as defined in paragraph (37) above.
[0077] In a particular group of compounds of the invention, 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:
Figure imgf000036_0001
wherein R1, R2 and R3 are each as defined hereinbefore.
[0078] In an embodiment of the compounds of formula Ib:
R1 is as defined in any one of paragraphs (1) to (11) above; and
R3 is as defined in any one of paragraphs (25) to (37) above.
[0079] In another embodiment of the compounds of formula Ib:
R1 is as defined in any one of paragraphs (8) to (11) above;
R3 is as defined in any one of paragraphs (33) to (37) above.
[0080] In an embodiment of the compounds of formula Ib:
R1 is as defined in any one of paragraphs (1) to (11) above; and
R3 is as defined in any one of paragraphs (38) to (50) above.
[0081] In another embodiment of the compounds of formula Ib:
R1 is as defined in any one of paragraphs (8) to (11) above;
R3 is as defined in any one of paragraphs (46) to (50) above.
[0082] In another embodiment of the compounds of formula Ib:
R1 is as defined in paragraph (7) above; and
R3 is as defined in paragraphs (34), (35), (36) or (37) above.
[0083] In another embodiment of the compounds of formula Ib:
R1 is as defined in paragraph (11) above; and
R3 is as defined in paragraph (37) above.
[0084] In a particular group of compounds of the invention, the compounds have the structural formula I defined hereinbefore, wherein R1 and R2 are each as defined hereinbefore and R3 is as defined in any one of paragraphs (25) to (37) above. [0085] In a particular group of compounds of the invention, the compounds have the structural formula I defined hereinbefore, wherein R1 and R2 are each as defined hereinbefore and R3 is as defined in paragraph (34) above.
[0086] In a particular group of compounds of the invention, the compounds have the structural formula I defined hereinbefore, wherein R1 and R2 are each as defined hereinbefore and R3 is as defined in paragraph (35) above.
[0087] In a particular group of compounds of the invention, the compounds have the structural formula I defined hereinbefore, wherein R1 and R2 are each as defined hereinbefore and R3 is as defined in paragraph (36) above.
[0088] In a particular group of compounds of the invention, the compounds have the structural formula I defined hereinbefore, wherein R1 and R2 are each as defined hereinbefore and R3 is as defined in paragraph (37) above.
[0089] In a particular group of compounds of the invention, the compounds have the structural formula I defined hereinbefore, wherein:
R1 is as defined in any one of paragraphs (1) to (11) above;
R2 is as defined in any one of paragraphs (12) to (24) above; and
R3 is as defined in paragraph (34) above.
[0090] In a particular group of compounds of the invention, the compounds have the structural formula I defined hereinbefore, wherein:
R1 is as defined in any one of paragraphs (1) to (11) above;
R2 is as defined in any one of paragraphs (12) to (24) above; and
R3 is as defined in paragraph (35) above.
[0091] In a particular group of compounds of the invention, the compounds have the structural formula I defined hereinbefore, wherein:
R1 is as defined in any one of paragraphs (1) to (11) above;
R2 is as defined in any one of paragraphs (12) to (24) above; and
R3 is as defined in paragraph (36) above.
[0092] In a particular group of compounds of the invention, the compounds have the structural formula I defined hereinbefore, wherein:
R1 is as defined in any one of paragraphs (1) to (11) above;
R2 is as defined in any one of paragraphs (12) to (24) above; and R3 is as defined in paragraph (37) above.
[0093] In a particular group of compounds of the invention, the compounds have the structural formula I defined hereinbefore, wherein:
R1 is as defined in paragraph (7) above;
R2 is as defined in any one of paragraphs (12) to (24) above; and
R3 is as defined in paragraph (34) above.
[0094] In a particular group of compounds of the invention, the compounds have the structural formula I defined hereinbefore, wherein:
R1 is as defined in paragraph (7) above;
R2 is as defined in any one of paragraphs (12) to (24) above; and
R3 is as defined in paragraph (35) above.
[0095] In a particular group of compounds of the invention, the compounds have the structural formula I defined hereinbefore, wherein:
R1 is as defined in paragraph (7) above;
R2 is as defined in any one of paragraphs (12) to (24) above; and
R3 is as defined in paragraph (36) above.
[0096] In a particular group of compounds of the invention, the compounds have the structural formula I defined hereinbefore, wherein:
R1 is as defined in paragraph (7) above;
R2 is as defined in any one of paragraphs (12) to (24) above; and
R3 is as defined in paragraph (37) above.
[0097] In a particular group of compounds of the invention, the compounds have the structural formula I defined hereinbefore, wherein:
R1 is as defined in paragraph (11) above;
R2 is as defined in any one of paragraphs (12) to (24) above; and
R3 is as defined in paragraph (34) above.
[0098] In a particular group of compounds of the invention, the compounds have the structural formula I defined hereinbefore, wherein:
R1 is as defined in paragraph (11) above; R2 is as defined in any one of paragraphs (12) to (24) above; and
R3 is as defined in paragraph (35) above.
[0099] In a particular group of compounds of the invention, the compounds have the structural formula I defined hereinbefore, wherein:
R1 is as defined in paragraph (11) above;
R2 is as defined in any one of paragraphs (12) to (24) above; and
R3 is as defined in paragraph (36) above.
[00100] In a particular group of compounds of the invention, the compounds have the structural formula I defined hereinbefore, wherein:
R1 is as defined in paragraph (11) above;
R2 is as defined in any one of paragraphs (12) to (24) above; and
R3 is as defined in paragraph (37) above.
[00101] In a particular group of compounds of the invention, 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:
Figure imgf000039_0001
Ic
wherein R1 and R2 are each as defined hereinbefore.
[00102] In an embodiment of the compounds of formula Ic:
R1 is as defined in any one of paragraphs (1) to (11) above; and
R2 is as defined in any one of paragraphs (12) to (24) above.
[00103] In another embodiment of the compounds of formula Ic:
R1 is as defined in any one of paragraphs (8) to (11) above; R2 is as defined in any one of paragraphs (20) to (24) above.
[00104] In another embodiment of the compounds of formula Ic:
R1 is as defined in paragraph (7) above; and
R2 is as defined in paragraph (24) above.
[00105] In another embodiment of the compounds of formula Ic:
R1 is as defined in paragraph (11) above; and
R2 is as defined in paragraph (24) above.
[00106] 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:
4-Amino-2-(3-cyanophenyl)-N-ethoxy-6-(2-fluoroethoxy)pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-6-(2-fluoroethoxy)-N-(2-hydroxyethoxy) pyrimidine-5- carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(cyclopropylmethoxy)-6-(2-fluoroethoxy)pyrimidine-5- carboxamide;
4-Amino-2-(3-cyanophenyl)-6-(2-fluoroethoxy)-N-(2-methoxyethoxy) pyrimidine-5- carboxamide;
4-Amino-2-(3-cyanophenyl)-6-(2-fluoroethoxy)-N-(2-morpholinoethoxy) pyrimidine-5- carboxamide;
4-Amino-2-(3-cyanophenyl)-6-(2-fluoroethoxy)-N-(2-hydroxy-2-methyl-propoxy)pyrimidine-5- carboxamide;
4-Amino-2-(3-cyanophenyl)-6-(2-fluoroethoxy)-N-(2-hydroxypropoxy) pyrimidine-5- carboxamide;
4-Amino-2-(3-cyanophenyl)-6-(2-fluoroethoxy)-N-(2-hydroxy-1-methyl-ethoxy)pyrimidine-5- carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2,3-dihydroxypropoxy)-6-(2-fluoroethoxy)pyrimidine-5- carboxamide;
4-Amino-2-(3-cyanophenyl)-6-(2-fluoroethoxy)-N-(morpholin-2-ylmethoxy)pyrimidine-5- carboxamide;
4-Amino-2-(3-cyanophenyl)-6-(2-fluoroethoxy)-N-[(4-methylmorpholin-2- yl)methoxy]pyrimidine-5-carboxamide;
4-Amino-N-(2-hydroxy-2-methyl-propoxy)-2-oxazol-5-yl-6-(oxetan-3-yloxy)pyrimidine-5- carboxamide; 4-Amino-2-(3-cyanophenyl)-6-(2-hydroxyethoxy)-N-(2-hydroxy-2-methyl-propoxy) pyrimidine- 5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methylpropoxy)-6-[(1r,3r)-3- aminocyclobutoxy]pyrimidine-5-carboxamide;
4-(2-Acetamidoethoxy)-6-amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy) pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-methoxy-pyrimidine-5- carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-(oxetan-3-yloxy) pyrimidine- 5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[[(4R)-2,2-dimethyl-1,3- dioxolan-4-yl]methoxy] pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-6-(2,2-difluoroethoxy)-N-(2-hydroxy-2-methyl- propoxy)pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[[rac-(4S)-2,2-dimethyl-1,3- dioxolan-4-yl]methoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-6-(2-fluoro-1-methyl-ethoxy)-N-(2-hydroxy-2-methyl- propoxy)pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methylpropoxy)-6-[(1r,3r)-3- fluorocyclobutoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(3S)-tetrahydrofuran-3- yl]oxy-pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(3S)-tetrahydropyran-3- yl]oxy-pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[rac-(3R)-tetrahydrofuran-3- yl]oxy-pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-tetrahydropyran-4-yloxy- pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[rac-(3R)-tetrahydropyran-3- yl]oxy-pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1R)-2-fluoro-1-methyl- ethoxy]pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1S)-2-fluoro-1-methyl- ethoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1R)-2-fluoro-1-methyl- ethoxy]pyrimidine-5-carboxamide; 4-amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1S)-2-fluoro-1-methyl- ethoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-[(1-hydroxycyclopropyl)methoxy]-6-(oxetan-3-yloxy) pyrimidine-5-carboxamide;
Ethyl (2S)-2-[[4-amino-2-(3-cyanophenyl)-6-(oxetan-3-yloxy) pyrimidine-5-carbonyl]amino] oxypropanoate;
4-Amino-6-(azetidin-3-yloxy)-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy) pyrimidine- 5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-(2-methoxyethoxy) pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1S)-2-methoxy-1-methyl- ethoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N,6-bis(2-hydroxy-2-methyl-propoxy)pyrimidine-5-carboxamide; 4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1R)-2-methoxy-1-methyl- ethoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-6-(2-fluoropropoxy)-N-(2-hydroxy-2-methyl-propoxy)pyrimidine- 5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(2-phenyl-1,3-dioxan-5- yl)oxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-(oxetan-2- ylmethoxy)pyrimidine-5-carboxamide;
4-Amino-6-(3-cyanocyclobutoxy)-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl- propoxy)pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(2S)-2- fluoropropoxy]pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(2R)-2- fluoropropoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(2S)-2- fluoropropoxy]pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(2R)-2- fluoropropoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(2S)-2-hydroxypropoxy] pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1S)-2-hydroxy-1-methyl- ethoxy] pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(2R)-2- hydroxypropoxy]pyrimidine-5-carboxamide; 4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1R)-2-hydroxy-1-methyl- ethoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(2S)-2,3-dihydroxy propoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[rac-(2R)-2,3-dihydroxy propoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-6-(oxetan-3-yloxy)-N-[(1S)-2-hydroxy-1,2-dimethyl- propoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-6-(3-hydroxycyclobutoxy)-N-(2-hydroxy-2-methyl- propoxy)pyrimidine-5-carboxamide. [00107] Further compounds of the invention include any of the following compounds, or a pharmaceutically acceptable salt or solvate thereof:
4-amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1R)-1- hydroxymethyl)propoxy]pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1S)-1- (hydroxymethyl)propoxy]pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-[(1-hydroxycyclobutyl)methoxy]-6-[(1R)-1- (hydroxymethyl)propoxy]pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-[(1-hydroxycyclobutyl)methoxy]-6-[(1S)-1- (hydroxymethyl)propoxy]pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1r, 3r)-3- methoxycyclobutoxy]pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1s, 3s)-3- methoxycyclobutoxy]pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-[(1-hydroxycyclobutyl)methoxy]-6-[(1r, 3r)-3- methoxycyclobutoxy]pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-[(1-hydroxycyclobutyl)methoxy]-6-[(1r, 3r)-3- methoxycyclobutoxy]pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1S,3R)-3- hydroxycyclopentoxy]pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1S,3S)-3- hydroxycyclopentoxy]pyrimidine-5-carboxamide; 4-amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1R,3R)-3- hydroxycyclopentoxy]pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1R,3S)-3- hydroxycyclopentoxy]pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-[(1-hydroxycyclobutyl)methoxy]-6-[(1S,3R)-3- hydroxycyclopentoxy]pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-[(1-hydroxycyclobutyl)methoxy]-6-[(1S,3S)-3- hydroxycyclopentoxy]pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-[(1-hydroxycyclobutyl)methoxy]-6-[(1R,3R)-3- hydroxycyclopentoxy]pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-[(1-hydroxycyclobutyl)methoxy]-6-[(1S,3S)-3- hydroxycyclopentoxy]pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1S,3R)-3- acetamidocyclopentoxy]pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1S,3S)-3- acetamidocyclopentoxy]pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1R,3R)-3- acetamidocyclopentoxy]pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1R,3S)-3- acetamidocyclopentoxy]pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-[(1-hydroxycyclobutyl)methoxy]-6-[(1S,3R)-3- acetamidocyclopentoxy]pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-[(1-hydroxycyclobutyl)methoxy]-6-[ 1S,3S)-3- acetamidocyclopentoxy]pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-[(1-hydroxycyclobutyl)methoxy]-6-[(1R,3R)-3- acetamidocyclopentoxy]pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-[(1-hydroxycyclobutyl)methoxy]-6-[(1R,3S)-3- acetamidocyclopentoxy]pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1S)-1-[(3R)-5-oxopyrrolidin- 3-yl]ethoxy]pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1S)-1-[(3S)-5-oxopyrrolidin- 3-yl]ethoxy]pyrimidine-5-carboxamide; 4-amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1R)-1-[(3R)-5-oxopyrrolidin- 3-yl]ethoxy]pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1R)-1-[(3S)-5-oxopyrrolidin- 3-yl]ethoxy]pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-[(1-hydroxycyclobutyl)methoxy]-6-[(1S)-1-[(3R)-5- oxopyrrolidin-3-yl]ethoxy]pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-[(1-hydroxycyclobutyl)methoxy]-6-[(1S)-1-[(3S)-5- oxopyrrolidin-3-yl]ethoxy]pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-[(1-hydroxycyclobutyl)methoxy]-6-[(1R)-1-[(3R)-5- oxopyrrolidin-3-yl]ethoxy]pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-[(1-hydroxycyclobutyl)methoxy]-6-[(1R)-1-[(3S)-5- oxopyrrolidin-3-yl]ethoxy]pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-6-[(1s, 3s)-3-(difluoromethyl)cyclobutoxy]-N-(2-hydroxy-2- methyl-propoxy)pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-6-[(1r, 3r)-3-(difluoromethyl)cyclobutoxy]-N-(2-hydroxy-2-methyl- propoxy)pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-6-[(1s, 3s)-3-(difluoromethyl)cyclobutoxy]-N-[(1- hydroxycyclobutyl)methoxy]pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-6-[(1r, 3r)-3-(difluoromethyl)cyclobutoxy]-N-[(1- hydroxycyclobutyl)methoxy]pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-phenoxy-pyrimidine-5- carboxamide;
4-amino-2-(3-cyanophenyl)-N-[(1-hydroxycyclobutyl)methoxy]-6-phenoxy-pyrimidine-5- carboxamide;
4-amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-(3-pyridyloxy)pyrimidine-5- carboxamide;
4-amino-2-(3-cyanophenyl)-N-[(1-hydroxycyclobutyl)methoxy]-6-(3-pyridyloxy)pyrimidine-5- carboxamide;
4-amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-(1-oxothian-4-yl)oxy- pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-[(1-hydroxycyclobutyl)methoxy]-6-(1-oxothian-4-yl)oxy- pyrimidine-5-carboxamide; 4-amino-2-(3-cyanophenyl)-6-(1,1-dioxothian-4-yl)oxy-N-(2-hydroxy-2-methyl- propoxy)pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-6-(1,1-dioxothian-4-yl)oxy-N-[(1- hydroxycyclobutyl)methoxy]pyrimidine-5-carboxamide;
4-amino-2-(3-cyano-2-methyl-phenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(3S)- tetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxamide;
4-amino-2-(3-cyano-2-methyl-phenyl)-N-[(1-hydroxycyclobutyl)methoxy]-6-[(3S)- tetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxamide;
4-amino-6-[(1r, 3r)-3-cyanocyclobutoxy]-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl- propoxy)pyrimidine-5-carboxamide;
4-amino-6-[(1s, 3s)-3-cyanocyclobutoxy]-2-(3-cyanophenyl)-N-[(1- hydroxycyclobutyl)methoxy]pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(2S,3R)-2- (hydroxymethyl)tetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(2S,3S)-2- (hydroxymethyl)tetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(2R,3R)-2- (hydroxymethyl)tetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(2R,3S)-2- (hydroxymethyl)tetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-[(1-hydroxycyclobutyl)methoxy]-6-[(2S,3R)-2- (hydroxymethyl)tetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-[(1-hydroxycyclobutyl)methoxy]-6-[(2S,3S)-2- (hydroxymethyl)tetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-[(1-hydroxycyclobutyl)methoxy]-6-[(2R,3R)-2- (hydroxymethyl)tetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-[(1-hydroxycyclobutyl)methoxy]-6-[(2R,3S)-2- (hydroxymethyl)tetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(3S,5R)-5- (hydroxymethyl)tetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(3S,5S)-5- (hydroxymethyl)tetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxamide; 4-amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(3R,5R)-5- (hydroxymethyl)tetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(3R,5S)-5- (hydroxymethyl)tetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-[(1-hydroxycyclobutyl)methoxy]-6-[(3S,5R)-5- (hydroxymethyl)tetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-[(1-hydroxycyclobutyl)methoxy]-6-[(3S,5S)-5- (hydroxymethyl)tetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-[(1-hydroxycyclobutyl)methoxy]-6-[(3R,5R)-5- (hydroxymethyl)tetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-[(1-hydroxycyclobutyl)methoxy]-6-[(3R,5S)-5- (hydroxymethyl)tetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1S,2R)-2,3-dihydroxy-1- methyl-propoxy]pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1S,2S)-2,3-dihydroxy-1- methyl-propoxy]pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1R,2R)-2,3-dihydroxy-1- methyl-propoxy]pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1R,2S)-2,3-dihydroxy-1- methyl-propoxy]pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-[(1-hydroxycyclobutyl)methoxy]-6-[(1S,2R)-2,3-dihydroxy-1- methyl-propoxy]pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-[(1-hydroxycyclobutyl)methoxy]-6-[(1S,2S)-2,3-dihydroxy-1- methyl-propoxy]pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-[(1-hydroxycyclobutyl)methoxy]-6-[(1R,2R)-2,3-dihydroxy-1- methyl-propoxy]pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-[(1-hydroxycyclobutyl)methoxy]-6-[(1R,2S)-2,3-dihydroxy-1- methyl-propoxy]pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-[(1S)-2-hydroxy-1,2-dimethyl-propoxy]-6-[(3S)- tetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-[(1R)-2-hydroxy-1,2-dimethyl-propoxy]-6-[(3S)- tetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxamide; 4-amino-2-(3-cyanophenyl)-N-[(1-hydroxycyclobutyl)methoxy]-6-[(3S)-tetrahydrofuran-3- yl]oxy-pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-[(1-hydroxycyclopentyl)methoxy]-6-[(3S)-tetrahydrofuran-3- yl]oxy-pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-[(1-hydroxycyclohexyl)methoxy]-6-[(3S)-tetrahydrofuran-3- yl]oxy-pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-[(3-hydroxyazetidin-3-yl)methoxy]-6-[(3S)-tetrahydrofuran-3- yl]oxy-pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-[[(3R)-3-hydroxytetrahydrofuran-3-yl]methoxy]-6-[(3S)- tetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-[[(3S)-3-hydroxytetrahydrofuran-3-yl]methoxy]-6-[(3S)- tetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-(oxazol-2-ylmethoxy)-6-[(3S)-tetrahydrofuran-3-yl]oxy- pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-[(1R)-1-oxazol-2-ylethoxy]-6-[(3S)-tetrahydrofuran-3-yl]oxy- pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-[(1S)-1-oxazol-2-ylethoxy]-6-[(3S)-tetrahydrofuran-3-yl]oxy- pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-6-[(3S)-tetrahydrofuran-3-yl]oxy-N-(1H-1,2,4-triazol-5- ylmethoxy)pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-6-[(3S)-tetrahydrofuran-3-yl]oxy-N-[(1R)-1-(1H-1,2,4-triazol-5- yl)ethoxy]pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-6-[(3S)-tetrahydrofuran-3-yl]oxy-N-[(1S)-1-(1H-1,2,4-triazol-5- yl)ethoxy]pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-(1,2,4-oxadiazol-5-ylmethoxy)-6-[(3S)-tetrahydrofuran-3- yl]oxy-pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-[(1R)-1-(1,2,4-oxadiazol-5-yl)ethoxy]-6-[(3S)-tetrahydrofuran- 3-yl]oxy-pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-[(1S)-1-(1,2,4-oxadiazol-5-yl)ethoxy]-6-[(3S)-tetrahydrofuran- 3-yl]oxy-pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-(1H-imidazol-2-ylmethoxy)-6-[(3S)-tetrahydrofuran-3-yl]oxy- pyrimidine-5-carboxamide; 4-amino-2-(3-cyanophenyl)-N-[(1R)-1-(1H-imidazol-2-yl)ethoxy]-6-[(3S)-tetrahydrofuran-3- yl]oxy-pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-[(1S)-1-(1H-imidazol-2-yl)ethoxy]-6-[(3S)-tetrahydrofuran-3- yl]oxy-pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-[(1-methylimidazol-2-yl)methoxy]-6-[(3S)-tetrahydrofuran-3- yl]oxy-pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-[(1R)-1-(1-methylimidazol-2-yl)ethoxy]-6-[(3S)-tetrahydrofuran- 3-yl]oxy-pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-[(1S)-1-(1-methylimidazol-2-yl)ethoxy]-6-[(3S)-tetrahydrofuran- 3-yl]oxy-pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-(1H-imidazol-5-ylmethoxy)-6-[(3S)-tetrahydrofuran-3-yl]oxy- pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-[(1R)-1-(1H-imidazol-5-yl)ethoxy]-6-[(3S)-tetrahydrofuran-3- yl]oxy-pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-[(1S)-1-(1H-imidazol-5-yl)ethoxy]-6-[(3S)-tetrahydrofuran-3- yl]oxy-pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-[(3-methylimidazol-4-yl)methoxy]-6-[(3S)-tetrahydrofuran-3- yl]oxy-pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-[(1R)-1-(3-methylimidazol-4-yl)ethoxy]-6-[(3S)-tetrahydrofuran- 3-yl]oxy-pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-[(1S)-1-(3-methylimidazol-4-yl)ethoxy]-6-[(3S)-tetrahydrofuran- 3-yl]oxy-pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-(1H-pyrazol-5-ylmethoxy)-6-[(3S)-tetrahydrofuran-3-yl]oxy- pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-[(1R)-1-(1H-pyrazol-5-yl)ethoxy]-6-[(3S)-tetrahydrofuran-3- yl]oxy-pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-[(1S)-1-(1H-pyrazol-5-yl)ethoxy]-6-[(3S)-tetrahydrofuran-3- yl]oxy-pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-(1H-pyrazol-4-ylmethoxy)-6-[(3S)-tetrahydrofuran-3-yl]oxy- pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-[(1R)-1-(1H-pyrazol-4-yl)ethoxy]-6-[(3S)-tetrahydrofuran-3- yl]oxy-pyrimidine-5-carboxamide; 4-amino-2-(3-cyanophenyl)-N-[(1S)-1-(1H-pyrazol-4-yl)ethoxy]-6-[(3S)-tetrahydrofuran-3- yl]oxy-pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-[2-(methylamino)-2-oxo-ethoxy]-6-[(3S)-tetrahydrofuran-3- yl]oxy-pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-[(1R)-1-methyl-2-(methylamino)-2-oxo-ethoxy]-6-[(3S)- tetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-[(1S)-1-methyl-2-(methylamino)-2-oxo-ethoxy]-6-[(3S)- tetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxamide;
4-amino-N-(2-amino-2-oxo-ethoxy)-2-(3-cyanophenyl)-6-[(3S)-tetrahydrofuran-3-yl]oxy- pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-[(1R)-2-amino-1-methyl-2-oxo-ethoxy]-6-[(3S)-tetrahydrofuran- 3-yl]oxy-pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-[(1S)-2-amino-1-methyl-2-oxo-ethoxy]-6-[(3S)-tetrahydrofuran- 3-yl]oxy-pyrimidine-5-carboxamide.
The above compounds may be prepared according to the general reaction schemes disclosed herein.
[00108] Further compounds of the invention include any of the following compounds, or a pharmaceutically acceptable salt or solvate thereof:
4-Amino-2-(3-cyanophenyl)-N-ethoxy-6-(2-fluoroethoxy)pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-6-(2-fluoroethoxy)-N-(2-hydroxyethoxy) pyrimidine-5- carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(cyclopropylmethoxy)-6-(2-fluoroethoxy)pyrimidine-5- carboxamide;
4-Amino-2-(3-cyanophenyl)-6-(2-fluoroethoxy)-N-(2-methoxyethoxy) pyrimidine-5- carboxamide;
4-Amino-2-(3-cyanophenyl)-6-(2-fluoroethoxy)-N-(2-morpholinoethoxy) pyrimidine-5- carboxamide;
4-Amino-2-(3-cyanophenyl)-6-(2-fluoroethoxy)-N-(2-hydroxy-2-methyl-propoxy)pyrimidine-5- carboxamide;
4-Amino-2-(3-cyanophenyl)-6-(2-fluoroethoxy)-N-(2-hydroxypropoxy) pyrimidine-5- carboxamide;
4-Amino-2-(3-cyanophenyl)-6-(2-fluoroethoxy)-N-(2-hydroxy-1-methyl-ethoxy)pyrimidine-5- carboxamide;
4-Amino-2-(3-cyanophenyl)-6-(2-fluoroethoxy)-N-(1H-pyrazol-3-ylmethoxy)pyrimidine-5- carboxamide; 4-Amino-2-(3-cyanophenyl)-N-(2,3-dihydroxypropoxy)-6-(2-fluoroethoxy)pyrimidine-5- carboxamide;
4-Amino-2-(3-cyanophenyl)-6-(2-fluoroethoxy)-N-(morpholin-2-ylmethoxy)pyrimidine-5- carboxamide;
4-Amino-2-(3-cyanophenyl)-6-(2-fluoroethoxy)-N-[(4-methylmorpholin-2- yl)methoxy]pyrimidine-5-carboxamide;
4-Amino-N-(2-hydroxy-2-methyl-propoxy)-2-oxazol-5-yl-6-(oxetan-3-yloxy)pyrimidine-5- carboxamide;
4-Amino-2-(3-cyanophenyl)-6-(2-hydroxyethoxy)-N-(2-hydroxy-2-methyl-propoxy) pyrimidine- 5-carboxamide;
4-Amino-2-(2;-furyl)-N-(2-hydroxy-2-methyl-propoxy)-6-(oxetan-3-yloxy)pyrimidine-5- carboxamide
4-Amino-2-(3-fluorophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-(oxetan-3-yloxy) pyrimidine-5- carboxamide;
4-Amino-2-(3-cyano-2-methyl-phenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-(oxetan-3- yloxy)pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[rac-(1R,2R)-2- hydroxycyclopentoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1R,2R)-2- hydroxycyclopentoxy]pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1S,2S)-2- hydroxycyclopentoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1R,2R)-2- hydroxycyclopentoxy]pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1S,2S)-2- hydroxycyclopentoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[rac-(1R,2S)-2- hydroxycyclopentoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1R,2S)-2- hydroxycyclopentoxy]pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1S,2R)-2- hydroxycyclopentoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1R,2S)-2- hydroxycyclopentoxy]pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1S,2R)-2- hydroxycyclopentoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(3R)-2-oxopyrrolidin-3- yl]oxy-pyrimidine-5-carboxamide; 4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(3S)-2-oxopyrrolidin-3-yl]oxy- pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[rac-(3R,4R)-4- hydroxytetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(3R,4R)-4- hydroxytetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy;)-6-[(3S,4S)-4- hydroxytetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxamide
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(3R,4R)-4- hydroxytetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(3S,4S)-4- hydroxytetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[rac-(3R,4S)-4- hydroxytetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1-methyl-6-oxo-3- piperidyl)oxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methylpropoxy)-6-[(1r,3r)-3- aminocyclobutoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methylpropoxy)-6-[(1s,3s)-3-aminocyclo butoxy]pyrimidine-5-carboxamide;hydrochloride;
4-(2-Acetamidoethoxy)-6-amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy) pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-methoxy-pyrimidine-5- carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-(oxetan-3-yloxy) pyrimidine- 5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[[(4R)-2,2-dimethyl-1,3- dioxolan-4-yl]methoxy] pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-6-(2,2-difluoroethoxy)-N-(2-hydroxy-2-methyl- propoxy)pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[[(4S)-2,2-dimethyl-1,3- dioxolan-4-yl]methoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-6-(2-fluoro-1-methyl-ethoxy)-N-(2-hydroxy-2-methyl- propoxy)pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methylpropoxy)-6-[(1r,3r)-3- fluorocyclobutoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(3R)-tetrahydropyran-3- yl]oxy-pyrimidine-5-carboxamide; 4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(3S)-tetrahydropyran-3- yl]oxy-pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(3R)-tetrahydrofuran-3- yl]oxy-pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-tetrahydropyran-4-yloxy- pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1R)-2-fluoro-1-methyl- ethoxy]pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1S)-2-fluoro-1-methyl- ethoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1R)-2-fluoro-1-methyl- ethoxy]pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1S)-2-fluoro-1-methyl- ethoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(3S)-tetrahydrofuran-3- yl]oxy-pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-[(1-hydroxycyclopropyl)methoxy]-6-(oxetan-3-yloxy) pyrimidine-5-carboxamide;
Ethyl (2S)-2-[[4-amino-2-(3-cyanophenyl)-6-(oxetan-3-yloxy) pyrimidine-5-carbonyl]amino] oxypropanoate;
4-Amino-2-(3-cyanophenyl)-N-[(1-hydroxycyclobutyl)methoxy]-6-(oxetan-3-yloxy) pyrimidine- 5-carboxamide;
4-Amino-6-(azetidin-3-yloxy)-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy) pyrimidine- 5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-(2-methoxyethoxy) pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1S)-2-methoxy-1-methyl- ethoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N,6-bis(2-hydroxy-2-methyl-propoxy)pyrimidine-5-carboxamide; 4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1R)-2-methoxy-1-methyl- ethoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-6-(2-fluoropropoxy)-N-(2-hydroxy-2-methyl-propoxy)pyrimidine- 5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(2-phenyl-1,3-dioxan-5- yl)oxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-(oxetan-2- ylmethoxy)pyrimidine-5-carboxamide;
4-Amino-6-(3-cyanocyclobutoxy)-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl- propoxy)pyrimidine-5-carboxamide; 4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(2S)-2- fluoropropoxy]pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(2R)-2- fluoropropoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(2S)-2-hydroxypropoxy] pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1S)-2-hydroxy-1-methyl- ethoxy] pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(2R)-2- hydroxypropoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1R)-2-hydroxy-1-methyl- ethoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(2S)-2,3-dihydroxy propoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(2R)-2,3-dihydroxy propoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-6-(oxetan-3-yloxy)-N-[(1S)-2-hydroxy-1,2-dimethyl- propoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methylpropoxy)-6-[(1r,3r)-3- Hydroxycyclobutoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-(oxetan-3-ylmethoxy) pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-methoxy-2-methyl-propoxy)-6-(oxetan-3-yloxy) pyrimidine- 5-carboxamide;
Ethyl 2-[[4-amino-2-(3-cyanophenyl)-6-(oxetan-3-yloxy)pyrimidine-5- carbonyl]amino]oxyacetate;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methylpropoxy)-6-[(1s,3s)-3- hydroxycyclobutoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-tetrahydrothiophen-3-yloxy- pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-(1-oxothiolan-3-yl)oxy- pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-6-(1,1-dioxothiolan-3-yl)oxy-N-(2-hydroxy-2-methyl- propoxy)pyrimidine-5-carboxamide;
4-Amino-6-(1-cyanoethoxy)-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy) pyrimidine- 5-carboxamide;
4-Amino-2-(3-cyanophenyl)-6-[2-hydroxy-1-(hydroxymethyl)ethoxy]-N-(2-hydroxy-2-methyl- propoxy)pyrimidine-5-carboxamide; 4-Amino-2-(3-cyanophenyl)-N-[(1-hydroxycyclobutyl)methoxy]-6-[(3S)-tetrahydrofuran-3- yl]oxy-pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-[(1-hydroxycyclopentyl)methoxy]-6-[(3S)-tetrahydrofuran-3- yl]oxy-pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-[(3-hydroxytetrahydrofuran-3-yl)methoxy]-6-[(3S)- tetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-[(1R)-1-oxazol-2-ylethoxy]-6-[(3S)-tetrahydrofuran-3-yl]oxy- pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-[(1S)-1-oxazol-2-ylethoxy]-6-[(3S)-tetrahydrofuran-3-yl]oxy- pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(1H-pyrazol-3-ylmethoxy)-6-[(3S)-tetrahydrofuran-3-yl]oxy- pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-1,2-dimethyl-propoxy)-6-[(3S)-tetrahydrofuran-3- yl]oxy-pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-6-[(3S)-tetrahydrofuran-3-yl]oxy-N-(1H-1,2,4-triazol-3- ylmethoxy)pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-[(1-methylimidazol-2-yl)methoxy]-6-[(3S)-tetrahydrofuran-3- yl]oxy-pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-[(3-methylimidazol-4-yl)methoxy]-6-[(3S)-tetrahydrofuran-3- yl]oxy-pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-[2-(ethylamino)-2-oxo-ethoxy]-6-[(3S)-tetrahydrofuran-3- yl]oxy-pyrimidine-5-carboxamide;
4-Amino-N-(2-amino-2-oxo-ethoxy)-2-(3-cyanophenyl)-6-[(3S)-tetrahydrofuran-3-yl]oxy- pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-6-[(3S)-tetrahydrofuran-3-yl]oxy-N-(1H-triazol-5- ylmethoxy)pyrimidine-5-carboxamide;
4-Amino-N-(2-amino-2-methyl-propoxy)-2-(3-cyanophenyl)-6-[3S)-tetrahydrofuran-3-yl]oxy- pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-phenoxy-6-[(3S)-tetrahydrofuran-3-yl]oxy-pyrimidine-5- carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(1H-pyrazol-4-ylmethoxy)-6-[(3S)-tetrahydrofuran-3-yl]oxy- pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-6-[(3S)-tetrahydrofuran-3-yl]oxy-N-[(1S)-1-(4H-1,2,4-triazol-3- yl)ethoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-6-[(3S)-tetrahydrofuran-3-yl]oxy-N-[(1R)-1-(4H-1,2,4-triazol-3- yl)ethoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-[(1R)-2-hydroxy-1,2-dimethyl-propoxy]-6-[(3S)- tetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxamide; 4-amino-2-(3-cyanophenyl)-N-[(1S)-2-hydroxy-1,2-dimethyl-propoxy]-6-[(3S)- tetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-[(1R)-2-hydroxy-1,2-dimethyl-propoxy]-6-[(3S)- tetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-[(1S)-2-hydroxy-1,2-dimethyl-propoxy]-6-[(3S)- tetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-[(5-isopropyl-4H-1,2,4-triazol-3-yl)methoxy]-6-[(3S)- tetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-6-[(3S)-tetrahydrofuran-3-yl]oxy-N-(2H-tetrazol-5- ylmethoxy)pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(1H-imidazol-2-ylmethoxy)-6-[(3S)-tetrahydrofuran-3-yl]oxy- pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1R)-1- (hydroxymethyl)propoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(2R)-2- hydroxybutoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[rac-(1R,3R)-3- hydroxycyclopentoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[rac-(1S,3S)-3- hydroxycyclopentoxy]pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1R,3R)-3- hydroxycyclopentoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1S,3S)-3- hydroxycyclopentoxy]pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1R,3R)-3- hydroxycyclopentoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(oxazol-2-ylmethoxy)-6-[(3S)-tetrahydrofuran-3-yl]oxy- pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-[(3-hydroxyazetidin-3-yl)methoxy]-6-[(3S)-tetrahydrofuran-3- yl]oxy-pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(2R,3S)-2- (hydroxymethyl)tetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(3S,5S)-5- (hydroxymethyl)tetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1R,3S)-3- acetamidocyclopentoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1S,3R)-3- acetamidocyclopentoxy]pyrimidine-5-carboxamide; 4-Amino-2-(3-cyano-2-methyl-phenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(3S)- tetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-6-[(1r,3r)-3-(difluoromethyl)cyclobutoxy]-N-(2-hydroxy-2-methyl- propoxy)pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-6-[(1s,3s)-3-(difluoromethyl)cyclobutoxy]-N-(2-hydroxy-2-methyl- propoxy)pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-6-[(1r,3r)-3-(difluoromethyl)cyclobutoxy]-N-(2-hydroxy-2-methyl- propoxy)pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-6-[(1s,3s)-3-(difluoromethyl)cyclobutoxy]-N-(2-hydroxy-2-methyl- propoxy)pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-6-[(1r, 3r)-3-(difluoromethyl)cyclobutoxy]-N-(2-hydroxy-2-methyl- propoxy)pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-6-[(1s, 3s)-3-(difluoromethyl)cyclobutoxy]-N-(2-hydroxy-2- methyl-propoxy)pyrimidine-5-carboxamide;
4-Amino-6-((1r, 3r)-3-cyanocyclobutoxy)-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl- propoxy)pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-6-((1s,3s)-3-fluorocyclobutoxy)-N-(2-hydroxy-2-methyl- propoxy)pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-(3-pyridyloxy)pyrimidine-5- carboxamide;
4-amino-2-(3-cyanophenyl)-6-(3,3-difluorocyclobutoxy)-N-(2-hydroxy-2-methyl- propoxy)pyrimidine-5-carboxamide;
4-Amino-N-(2-hydroxy-2-methyl-propoxy)-2-(1H-indol-7-yl)-6-[(3S)-tetrahydrofuran-3-yl]oxy- pyrimidine-5-carboxamide;
4-Amino-N-(2-hydroxy-2-methyl-propoxy)-2-(1H-indol-4-yl)-6-tetrahydrofuran-3-yloxy- pyrimidine-5-carboxamide;
4-Amino-2-(3-cyano-2-methoxy-phenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(3S)- tetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1S)-1-methyl-2- (propanoylamino)ethoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(2S)-2- hydroxybutoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[[(2S)-5-oxopyrrolidin-2- yl]methoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1S)-1-methyl-2-ureido- ethoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[rac-(1S,3R)-3- hydroxycyclopentoxy]pyrimidine-5-carboxamide; 4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1R,3S)-3- hydroxycyclopentoxy]pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1S,3R)-3- hydroxycyclopentoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1R,3S)-3- hydroxycyclopentoxy]pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1S,3R)-3- hydroxycyclopentoxy]pyrimidine-5-carboxamide;
Methyl N-[2S)-2-[6-amino-2-(3-cyanophenyl)-5-[(2-hydroxy-2-methyl- propoxy)carbamoyl]pyrimidin-4-yl]oxypropyl]carbamate;
4-Amino-2-(3-cyanophenyl)-6-(1,1-dioxothian-4-yl)oxy-N-(2-hydroxy-2-methyl- propoxy)pyrimidine-5-carboxamide;
(1s,4s)-4-{[6-amino-2-(3-cyanophenyl)-5-[(2-hydroxy-2-methylpropoxy)carbamoyl] pyrimidin- 4-yl]oxy}thian-1-ium-1-olate;
(1r,4r)-4-{[6-amino-2-(3-cyanophenyl)-5-[(2-hydroxy-2-methylpropoxy)carbamoyl]pyrimidin-4- yl]oxy}thian-1-ium-1-olate;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1R)-2-acetamido-1-methyl- ethoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1S)-2-acetamido-1-methyl- ethoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-6-(2-fluoroethoxy)-N-(1H-1,2,4-triazol-3-ylmethoxy)pyrimidine-5- carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1s,3s)-3- methoxycyclobutoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1r,3r)-3- methoxycyclobutoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-6-(3-hydroxy-3-methyl-cyclobutoxy)-N-(2-hydroxy-2-methyl- propoxy)pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(5-oxopyrrolidin-3- yl)methoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-phenoxy-pyrimidine-5- carboxamide.
[00109] The above compounds may be prepared according to the general reaction schemes disclosed herein.
[00110] 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.
[00111] 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. In addition, 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.
[00112] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers”. Isomers 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”. 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 Ssequencing 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”.
[00113] 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. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are wellknown in the art (see discussion in Chapter 4 of “Advanced Organic Chemistry”, 4th edition J. March, John Wiley and Sons, New York, 2001), for example by synthesis from optically active starting materials or by resolution of a racemic form. Some of the compounds of the invention may have geometric isomeric centres (E and Z isomers). It is to be understood that the present invention encompasses all optical, diastereoisomers and geometric isomers and mixtures thereof that possess antiproliferative activity.
[00114] The present invention also encompasses compounds of the invention as defined herein which comprise one or more isotopic substitutions. For Example, 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.
[00115] It is also to be understood that 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.
[00116] It is also to be understood that certain compounds of the formula I may exhibit polymorphism, and that the invention encompasses all such forms that possess antiproliferative activity.
[00117] Compounds of the formula I may exist in a number of different tautomeric forms and references to compounds of the formula I include all such forms. For the avoidance of doubt, where a compound can exist in one of several tautomeric forms, and only one is specifically described or shown, all others are nevertheless embraced by formula I. Examples of tautomeric forms 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.
Figure imgf000060_0001
[00118] 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. Particular Examples of 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. Comm.1977, 7, 509-514) in which the amine compound is reacted with m-chloroperoxybenzoic acid (mCPBA), for example, in an inert solvent such as dichloromethane. [00119] 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. Examples of 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).
[00120] Accordingly, 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. Accordingly, 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.
[00121] 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.
[00122] 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. Widder, et al. (Academic Press, 1985);
b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985);
c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5“Design and Application of Pro-drugs”, by H. Bundgaard p. 113-191 (1991);
d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992);
e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988);
f) N. Kakeya, et al., Chem. Pharm. Bull., 32, 692 (1984);
g) T. Higuchi and V. Stella,“Pro-Drugs as Novel Delivery Systems”, A.C.S. Symposium Series, Volume 14; and h) E. Roche (editor), Bioreversible Carriers in Drug Design , Pergamon Press, 1987.
[00123] 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.
[00124] 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). Further suitable pharmaceutically acceptable 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. Examples of 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. Suitable pharmaceutically acceptable ether forming groups for a hydroxy group include ^-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.
[00125] 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. [00126] 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. Examples of 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.
[00127] 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).
[00128] Though 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.
[00129] Suitably, the present invention excludes any individual compounds not possessing the biological activity defined herein.
Synthesis
[00130] Figures 1 and 2 show a general reaction schemes for the preparation of compounds of Formula (I).
[00131] Figure 3 shows a general reaction scheme for the preparation of various hydroxylamines.
[00132] 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.
[00133] In the description of the synthetic methods described herein and in any referenced synthetic methods that are used to prepare the starting materials, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, can be selected by a person skilled in the art. [00134] It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reaction conditions utilised.
[00135] It will be appreciated that during the synthesis of the compounds of the invention in the processes defined herein, or during the synthesis of certain starting materials, it may be desirable to protect certain substituent groups to prevent their undesired reaction. The skilled chemist will appreciate when such protection is required, and how such protecting groups may be put in place, and later removed.
[00136] For Examples of 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.
[00137] Thus, if 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.
[00138] By way of Example, 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. Thus, for example, 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. Alternatively 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.
[00139] 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. Thus, for example, 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. Alternatively, an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladiumoncarbon.
[00140] 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.
[00141] Resins may also be used as a protecting group.
[00142] The methodology employed to synthesise a compound of formula (I) will vary depending on the nature of A, R1, R2 and R3 and any substituent groups associated therewith. Suitable processes for their preparation are described further in the accompanying Examples.
[00143] Once a compound of formula (I) has been synthesised by any one of the processes defined herein, the processes may then further comprise one or more of the additional steps of:
(i) removing any protecting groups present;
(ii) converting the compound formula (I) into another compound of formula (I);
(iii) forming a pharmaceutically acceptable salt, hydrate or solvate of the compound of formula I; and/or
(iv) forming a prodrug of the compound of formula I.
[00144] An Example of (ii) above is when a compound of formula (I) is synthesised and then one or more of the groups of A, R1, R2 or R3, may be further reacted to change the nature of the group and provide an alternative compound of formula (I).
[00145] The resultant compounds of formula (I) can be isolated and purified using techniques well known in the art.
Biological Activity
[00146] The biological assays described in the Biological Examples section (Biological Examples 1, 2 and 3) may be used to measure the pharmacological effects of the compounds of the present invention. [00147] Although the pharmacological properties of the compounds of formula I vary with structural change, as expected, the compounds of the invention were found to be active in the assays described in the Biological Examples 1, 2 and 3.
[00148] In general, in terms of adenosine A2a antagonism, the compounds of the invention demonstrate an IC50 of 1 µM or less in the assay described in Biological Example 1, with preferred compounds of the invention demonstrating an IC50 of 200 nM or less and the most preferred compounds of the invention demonstrating an IC50 of 50 nM or less.
[00149] Suitably the IC50 at the adenosine A1, A2b or A3 receptors of the compounds of the invention in the assay described in Biological Example 1is at least two-fold higher than the IC50 at the adenosine A2a receptor, and more suitably it is at least 5-fold higher, and even more suitably it is at least 10-fold higher. Pharmaceutical Compositions
[00150] According to a further aspect of the invention there is provided a pharmaceutical composition 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.
[00151] The 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).
[00152] The compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents.
[00153] 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.
[00154] 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. For Example, 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.
[00155] 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.
[00156] In using a compound of the invention for therapeutic or prophylactic purposes it will generally be administered so that 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. In general lower doses will be administered when a parenteral route is employed. Thus, for example, for intravenous or intraperitoneal administration, a dose in the range, for example, 0.1 mg/kg to 30 mg/kg body weight will generally be used. Similarly, for administration by inhalation, 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. Typically, unit dosage forms will contain about 0.5 mg to 0.5 g of a compound of this invention. Therapeutic Uses and Applications
[00157] The present invention provides compounds that function as antagonists of adenosine A2 receptors, especially adenosine A2a receptors.
[00158] According to a further aspect of the present invention, there is provided a method of antagonising adenosine A2a receptors in vitro or in vivo, said method comprising contacting a cell with an effective amount of a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein.
[00159] According to a further aspect of the present invention, there is provided a method of selectively antagonising adenosine A2a receptros in vitro or in vivo, said method comprising contacting a cell with an effective amount of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein.
[00160] According to a further aspect of the present invention, there is provided a method of inhibiting cell proliferation, in vitro or in vivo, said method 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. Suitably, the compound or pharmaceutical composition is administered in combination with one or more additional antiproliferative agents (e.g. checkpoint inhibitors and/or cytotoxic agents).
[00161] According to a further aspect of the present invention, there is provided a method of treating a disease or disorder in which adenosine A2a receptor activity is implicated in a patient in need of such treatment, said method 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.
[00162] According to a further aspect of the present invention, there is provided a method of treating a proliferative disorder in a patient in need of such treatment, said method 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. Suitably, the compound or pharmaceutical composition is administered in combination with one or more additional antiproliferative agents (e.g. checkpoint inhibitors and/or cytotoxic agents).
[00163] According to a further aspect of the present invention, there is provided a method of treating cancer in a patient in need of such treatment, said method 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. Suitably, the compound or pharmaceutical composition is administered in combination with one or more additional anticancer agents (e.g. checkpoint inhibitors and/or cytotoxic agents).
[00164] According to a further aspect of the present invention, there is provided a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein for use in therapy.
[00165] According to a further aspect of the present invention, there is provided 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. Suitably, the compound or pharmaceutical composition is administered in combination with one or more additional antiproliferative agents (e.g. checkpoint inhibitors and/or cytotoxic agents).
[00166] According to a further aspect of the present invention, there is provided 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. Suitably, the compound or pharmaceutical composition is administered in combination with one or more additional anticancer agents (e.g. checkpoint inhibitors and/or cytotoxic agents).
[00167] According to a further aspect of the present invention, there is provided a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein for use as an adenosine A2a antagonist. In an embodiment, the compounds of the invention are selective adenosine A2a antagonists. In an alternative embodiment, certain compounds of the invention are selective adenosine A2a and adenosine A2b antagonists. [00168] According to a further aspect of the present invention, there is provided 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 adenosine A2a is implicated.
[00169] According to a further aspect of the present invention, there is provided the use of 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. Suitably, the compound or pharmaceutical composition is administered in combination with one or more additional antiproliferative agents (e.g. checkpoint inhibitors and/or cytotoxic agents).
[00170] According to a further aspect of the present invention, there is provide the use of 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. Suitably, the cancer is a human cancer. Suitably, the compound or pharmaceutical composition is administered in combination with one or more additional anticancer agents (e.g. checkpoint inhibitors and/or cytotoxic agents).
[00171] According to a further aspect of the present invention, there is provided a use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein in the manufacture of a medicament for use as an adenosine A2a antagonist.
[00172] According to a further aspect of the present invention, there is provided a use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein in the manufacture of a medicament for use as an adenosine A2a antagonist.
[00173] According to a further aspect of the present invention, there is provided a use of 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 disease or disorder in which adenosine A2a receptor activity is implicated.
[00174] The term "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. Examples of 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.
[00175] The anti-proliferative effects of the compounds of the present invention have particular application in the treatment of human cancers (by virtue of their adenosine A2a antagonist activity). [00176] More specifically, there is provided 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.
[00177] There is also provided the use of a compound of general formula (I) in the manufacture of a medicament for the treatment of cancer, particularly solid tumours, for example non-small cell lung cancer, head and neck squamous cancer and urothelial cancer.
[00178] 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).
[00179] The patient to be treated is suitably a mammal and more suitably a human. Routes of Administration
[00180] 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).
[00181] 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, subcuticular, intraarticular, subarachnoid, and intrasternal; by implant of a depot or reservoir, for example, subcutaneously or intramuscularly. Combination Therapies
[00182] 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.
[00183] 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. [00184] Therefore, in a further aspect of the present invention there is provided 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.
[00185] 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.
[00186] In particular, 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.
[00187] 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:
(i) other forms of cancer immunotherapy and anti-cancer chemotherapeutic agents;
(ii) A2b antagonists;
(iii) anti-PD-1 and PDL-1 antibodies including, but not limited to, pembrolizumab, nivolumab, durvalumab, avelumab and atezolizumab; and
(iv) anti-CTLA4 antibodies including, but not limited to, ipilimumab.
[00188] 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.
[00189] The A2a antagonists 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.
[00190] 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. XL518, CI-1040,
PD035901,selumetinib/ AZD6244, GSK1120212/ trametinib, GDC-0973, ARRY-162, ARRY- 300, AZD8330, PD0325901, U0126, PD98059, TAK-733, PD318088, AS703026, BAY 869766), 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 sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomusitne, semustine, streptozocin), triazenes (decarbazine)), anti-metabolites (e.g., 5-azathioprine, leucovorin, capecitabine, fludarabine, gemcitabine, pemetrexed, raltitrexed, folic acid analog (e.g., methotrexate), or pyrimidine analogs (e.g., fluorouracil, floxouridine, Cytarabine), purine analogs (e.g., mercaptopurine, thioguanine, pentostatin), etc.), plant alkaloids (e.g., vincristine, vinblastine, vinorelbine, vindesine, podophyllotoxin, paclitaxel, docetaxel, etc.), topoisomerase inhibitors (e.g., irinotecan, topotecan, amsacrine, etoposide (VP16), etoposide phosphate, teniposide, etc.), antitumor antibiotics (e.g., doxorubicin, adriamycin, daunorubicin, epirubicin, actinomycin, bleomycin, mitomycin, mitoxantrone, plicamycin, etc.), platinum-based compounds or platinum containing agents (e.g. cisplatin, oxaloplatin, arboplatin), anthracenedione (e.g., mitoxantrone), substituted urea (e.g., hydroxyurea), methyl hydrazine derivative (e.g., procarbazine), adrenocortical suppressant (e.g., mitotane, aminoglutethimide),
epipodophyllotoxins (e.g., etoposide), antibiotics (e.g., daunorubicin, doxorubicin, bleomycin), enzymes (e.g., L-asparaginase), inhibitors of mitogen-activated protein kinase signaling (e.g. U0126, PD98059, PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY 43-9006, wortmannin, or LY294002, Syk inhibitors, mTOR inhibitors, antibodies (e.g., rituxan), gossyphol, genasense, polyphenol E, Chlorofusin, all trans-retinoic acid (ATRA), bryostatin, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), 5- aza-2'-deoxycytidine, all trans retinoic acid, doxorubicin, vincristine, etoposide, gemcitabine, imatinib (Gleevec.RTM.), geldanamycin, 17-N-Allylamino-17-Demethoxygeldanamycin (17- AAG), flavopiridol, LY294002, bortezomib, trastuzumab, BAY 11-7082, PKC412, PD184352, 20-epi-l, 25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene;
adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine;
amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti- dorsalizing morphogenetic protein- 1; antiandrogen, prostatic carcinoma; antiestrogen;
antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene
modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol; batimastat; BCR/ABL antagonists; benzochlorins; benzoylstaurosporine; beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistratene A; bizelesin; breflate; bropirimine; budotitane; buthionine sulfoximine; calcipotriol; calphostin C; camptothecin derivatives; canarypox IL-2; capecitabine; carboxamide-amino- triazole; carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor;
carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropin B; cetrorelix;
chlorins; chloroquinoxaline sulfonamide; cicaprost; cisporphyrin; cladribine; clomifene analogues; clotrimazole; collismycin A; collismycin B; combretastatin A4; combretastatin analogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A; cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone; didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine; 9-dioxamycin; diphenyl spiromustine; docosanol; dolasetron; doxifluridine; droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab; eflornithine; elemene; emitefur; epirubicin; epristeride;
estramustine analogue; estrogen agonists; estrogen antagonists; etanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine; fenretinide; filgrastim; finasteride;
flavopiridol; flezelastine; fluasterone; fiudarabine; fluorodaunorunicin hydrochloride;
forfenimex; formestane; fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate;
galocitabine; ganirelix; gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam; heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene; idramantone; ilmofosine; ilomastat; imidazoacridones; imiquimod; immunostimulant peptides; insulin-like growth factor-1 receptor inhibitor; interferon agonists; interferons;
interleukins; iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact; irsogladine; isobengazole; isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F; lamellarin-N triacetate;
lanreotide; leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia inhibiting factor; leukocyte alpha interferon; leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole; linear polyamine analogue; lipophilic disaccharide peptide; lipophilic platinum compounds; lissoclinamide 7; lobaplatin; lombricine; lometrexol; lonidamine;
losoxantrone; lovastatin; loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides; maitansine; mannostatinA; marimastat; masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone; meterelin; methioninase;
metoclopramide; MIF inhibitor; mifepristone;miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone; mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonal antibody, human chorionic gonadotrophin; monophosphoryl lipid A+myobacterium cell wall sk; mopidamol; multiple drug resistance gene inhibitor; multiple tumor suppressor 1-based therapy; mustard anticancer agent; mycaperoxide B; mycobacterial cell wall extract;
myriaporone; N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip;
naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin; nemorubicin;
neridronic acid; neutral endopeptidase; nilutamide; nisamycin; nitric oxide modulators;
nitroxide antioxidant; nitrullyn; 06-benzyl guanine; octreotide; okicenone; oligonucleotides; onapristone; ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin; palauamine; palmitoylrhizoxin; pamidronic acid; panaxytriol;
panomifene; parabactin; pazelliptine; pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin; pentrozole; perflubron; perfosfamide; perillyl alcohol; phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A; placetin B; plasminogen activator inhibitor; platinum complex; platinum compounds; platinum-triamine complex; porfimer sodium; porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2; proteasome inhibitors; protein A-basedimmune modulator; protein kinase C inhibitor; protein kinase C inhibitors, microalgal; proteintyrosine
phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurins;
pyrazoloacridine; pyridoxylated hemoglobin polyoxyethylerie conjugate; raf antagonists; raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors; ras inhibitors; ras- GAPinhibitor; retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin; ribozymes; RII retinamide; rogletimide; rohitukine; romurtide; roquinimex; rubiginone B1; ruboxyl; safingol; saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics; semustine; senescence derived inhibitor 1; sense oligonucleotides; signal transduction inhibitors; signal transduction modulators; single chain antigen-binding protein; sizofuran; sobuzoxane; sodium
borocaptate; sodium phenylacetate; solverol; somatomedin binding protein; sonermin;
sparfosic acid; spicamycin D; spiromustine; splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stemcell division inhibitors; stipiamide; stromelysin inhibitors; sulfinosine;
superactive vasoactive intestinal peptide antagonist; suradista; suramin; swainsonine;
synthetic glycosaminoglycans; tallimustine; tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium; tegafur; tellurapyrylium; telomerase inhibitors; temoporfin; temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocene bichloride; topsentin; toremifene; totipotent stem cell factor; translation inhibitors; tretinoin; triacetyluridine;
triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors;
tyrphostins; UBC inhibitors; ubenimex; urogenital sinus-derived growth inhibitory factor; urokinase receptor antagonists; vapreotide; variolin B; vector system, erythrocyte gene therapy; velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; zinostatin stimalamer, Adriamycin, Dactinomycin,
Bleomycin, Vinblastine, Cisplatin, acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantrone acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa;
azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan;
cactinomycin; calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelesin; cedefingol; chlorambucil; cirolemycin; cladribine; crisnatol mesylate; cyclophosphamide; cytarabine; dacarbazine; daunorubicin hydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate; diaziquone; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin; edatrexate; eflornithine hydrochloride; elsamitrucin; enloplatin; enpromate; epipropidine; epirubicin hydrochloride; erbulozole; esorubicin hydrochloride; estramustine; estramustine phosphate sodium; etanidazole; etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride; fazarabine; fenretinide; floxuridine; fludarabine phosphate;
fluorouracil; fluorocitabine; fosquidone; fostriecin sodium; gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; iimofosine; interleukin 2 (including recombinant interleukin 2, or rlL.sub.2), interferon alfa-2a; interferon alfa-2b;
interferon alfa-nl; interferon alfa-n3; interferon beta- la; interferon gamma-lb; iproplatin;
irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liarozole hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol;
maytansine; mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate; melphalan; menogaril; mercaptopurine; methotrexate; methotrexate sodium; metoprine; meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin; mitomycin;
mitosper; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazoie;
nogalamycin; ormaplatin; oxisuran; pegaspargase; peliomycin; pentamustine; peplomycin sulfate; perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride; plicamycin;
plomestane; porfimer sodium; porfiromycin; prednimustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin; riboprine; rogletimide; safingol; safingol hydrochloride; semustine; simtrazene; sparfosate sodium; sparsomycin; spirogermanium hydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin; tecogalan sodium; tegafur; teloxantrone hydrochloride; temoporfin; teniposide; teroxirone; testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin; tirapazamine; toremifene citrate; trestolone acetate; triciribine phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; tubulozole hydrochloride; uracil mustard; uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfate; vorozole; zeniplatin; zinostatin; zorubicin hydrochloride, agents that arrest cells in the G2-M phases and/or modulate the formation or stability of microtubules, (e.g. 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. Spongistatin 1, Spongistatin 2, Spongistatin 3, Spongistatin 4, Spongistatin 5, Spongistatin 6, Spongistatin 7, Spongistatin 8, and Spongistatin 9), Cemadotin hydrochloride (i.e. LU-103793 and NSC- D-669356), Epothilones (e.g. Epothilone A, Epothilone B, Epothilone C (i.e. desoxyepothilone A or dEpoA), Epothilone D (i.e. KOS-862, dEpoB, and desoxyepothilone B), 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, Auristatin PE (i.e. NSC-654663), Soblidotin (i.e. TZT-1027), , Vincristine sulfate, Cryptophycin 52 (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. NSC- 698666), Eleutherobins (such as Desmethyleleutherobin, Desaetyleleutherobin,
lsoeleutherobin A, and ZEleutherobin), Caribaeoside, Caribaeolin, Halichondrin B,
Diazonamide A, Taccalonolide A, Diozostatin, (-)-Phenylahistin (i.e. NSCL-96F037),
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-2, alpha-interferon, etc.), monoclonal antibodies (e.g., anti-CD20, anti-F£ER2, anti-CD52, anti- ULA-DR, and anti- VEGF monoclonal antibodies), immunotoxins (e.g., anti-CD33 monoclonal antibody- calicheamicin conjugate, anti-CD22 monoclonal antibody-pseudomonas exotoxin conjugate, etc.), radioimmunotherapy (e.g., anti-CD20 monoclonal antibody conjugated to ln, 0Y, or I, etc.), triptolide, homoharringtonine, dactinomycin, doxorubicin, epirubicin, topotecan, itraconazole, vindesine, cerivastatin, vincristine, deoxyadenosine, sertraline, pitavastatin, irinotecan, clofazimine, 5-nonyloxytryptamine, vemurafenib, dabrafenib, erlotinib, gefitinib, EGFR inhibitors, epidermal growth factor receptor (EGFR)-targeted therapy or therapeutic (e.g. gefitinib (Iressa™), erlotinib (Tarceva™), cetuximab (Erbitux™), lapatinib (Tykerb™), panitumumab (Vectibix™), vandetanib (Caprelsa™), 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, dasatinib, hormonal therapies, or the like.
[00191] As indicated above, 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. [00192] According to this aspect of the invention there is provided a combination for use in the treatment of a 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.
[00193] According to this aspect of the invention there is also provided 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.
[00194] In a further aspect of the invention there is provided 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.
[00195] Herein, where the term“combination” is used it is to be understood that this refers to simultaneous, separate or sequential administration. In one aspect of the invention “combination” refers to simultaneous administration. In another aspect of the invention “combination” refers to separate administration. In a further aspect of the invention “combination” refers to sequential administration. Where the administration is sequential or separate, the delay in administering the second component should not be such as to lose the beneficial effect of the combination.
[00196] According to a further aspect of the invention there is provided 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.
Combination therapy with Immune Checkpoint Inhibitors
[001] Immune checkpoint proteins present on immune cells and/or cancer cells [e.g.
CTLA4 (also known as cytotoxic T-lymphocyte-associated protein 4 and CD152), LAG3 (also known as lymphocyte-activation gene 3 and CD223), PD1 (also known as programmed cell death protein 1 and CD279) PD-L1 (also known as programmed death-ligand 1 and CD274), TIM-3 (also known as T-cell immunoglobulin mucin-3) and TIGIT (also known as T-cell Immunoreceptor with Ig and ITIM domains) are molecular targets that have been found to play an important role in regulating anti-tumour immune responses. Inhibitors of these immune checkpoint proteins (e.g. CTLA4, LAG3, PD1, PD-L1, TIM-3 and/or TIGIT inhibitors) promote an anti-tumour immune response that can be utilised to effectively treat certain forms of cancer. [002] In one aspect, the present invention relates to a combination comprising a compound of formula I as defined herein, or a pharmaceutically acceptable salt thereof, and an immune checkpoint inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of a proliferative disorder.
[003] In another aspect, the present invention relates to a use of a combination comprising a compound of formula I as defined herein, or a pharmaceutically acceptable salt thereof, and an immune checkpoint inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating of a proliferative disorder.
[004] In another aspect, the present invention relates to a method of treating of a proliferative disorder in a subject in need thereof comprising administering to said subject a combination comprising a compound of formula I as defined herein, or a pharmaceutically acceptable salt thereof, and an immune checkpoint inhibitor, or a pharmaceutically acceptable salt thereof, as defined herein.
[005] In another aspect, the present invention relates to a compound of formula I as defined herein, or a pharmaceutically acceptable salt thereof, as defined herein for use in the treatment of a proliferative disorder, wherein the compound of formula I, or a
pharmaceutically acceptable salt thereof, is for simultaneous, separate or sequential administeration with an immune checkpoint inhibitor, or a pharmaceutically acceptable salt thereof.
[006] In another aspect, the present invention relates to an immune checkpoint inhibitor, or a pharmaceutically acceptable salt thereof, for use in the treatment of a proliferative disorder, wherein the immune checkpoint inhibitor is for simultaneous, separate or sequential administeration with a compound of formula I as defined herein, or a
pharmaceutically acceptable salt thereof, as defined herein.
[007] In another aspect, the present invention relates to a use of a compound of formula I as defined herein, or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for treating a proliferative disorder, wherein the medicament is for simultaneous, separate or sequential administeration with an immune checkpoint inhibitor, or a pharmaceutically acceptable salt thereof.
[008] In another aspect, the present invention relates to a use of an immune checkpoint inhibitor, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a proliferative disorder, wherein the medicament is for simultaneous, separate or sequential administeration with a compound of formula I as defined herein, or a
pharmaceutically accpetable salt thereof. [009] In another aspect, the present invention relates to a method of treating a proliferative disorder comprising adminstering to a subject in need thereof a therapetuically effective amount of a compound of formula I as defined herein, or a pharmaceutically acceptable salt thereof, as defined herein and an immune checkpoint inhibitor, or a pharmaceutically acceptable salt thereof, either sequentially, separately or simultaneously
[0010] Any immune checkpoint inhibitor may be used in the combination therapy defined herein.
[0011] In one embodiment, the immune checkpoint inhibitor is selected from a PD1, a PD- L1 inhibitor, a LAG3 inhibitor, aCTLA-4 inhibitor, a TIM-3 inhibitor and/or a TIGIT inhibitor. In a particular embodiment, the immune checkpoint inhibitor is a PD1 or PD-L1 inhibitor.
[0012] PD-1 is a cell surface receptor protein present on T cells. PD-1 plays an important role in down-regulating the immune system and promoting self-tolerance by suppressing T cell inflammatory activity. The PD-1 protein is an immune checkpoint that guards against autoimmunity through a dual mechanism of promoting apoptosis (programmed cell death) in antigen specific T cells in lymph nodes, while simultaneously reducing apoptosis in regulatory T cells (anti-inflammatory suppressive T cells).
[0013] PD-1 therefore inhibits the immune system. This prevents autoimmune diseases, but it can also prevent the immune system from killing cancer cells.
[0014] PD1 binds two ligands, PD-L1 and PD-L2. PD-L1 is of particular interest as it is highly expressed in several cancers and hence the role of PD1 in cancer immune evasion is well established. Monoclonal antibodies targeting PD-1 that boost the immune system are being developed for the treatment of cancer. Many tumour cells express PD-L1, an immunosuppressive PD-1 ligand; inhibition of the interaction between PD-1 and PD-L1 can enhance T-cell responses in vitro and mediate preclinical antitumour activity. This is known as immune checkpoint blockade.
[0015] Examples of drugs that target PD-1 include pembrolizumab (Keytruda) and nivolumab (Opdivo). These drugs have been shown to be effective in treating several types of cancer, including melanoma of the skin, non-small cell lung cancer, kidney cancer, bladder cancer, head and neck cancers, and Hodgkin lymphoma. They are also being studied for use against many other types of cancer. Examples of drugs in development include BMS-936559 (Bristol Myers Squibb), MGA012 (MacroGenics) and MEDI-0680 (MedImmune).
[0016] Examples of drugs that inhibit PD-L1 include atezolizumab (Tecentriq), avelumab (Bavencio) and durvalumab (Imfinzi). These drugs have also been shown to be helpful in treating different types of cancer, including bladder cancer, non-small cell lung cancer, and Merkel cell skin cancer (Merkel cell carcinoma). They are also being studied for use against other types of cancer.
[0017] Examples of LAG3 inhibitors include BMS-986016/Relatlimab, TSR-033,
REGN3767, MGD013 (bispecific DART binding PD-1 and LAG-3), GSK2831781 and LAG525.
[0018] Examples of CTLA-4 inhibitors include MDX-010/Ipilimumab, AGEN1884, and CP- 675,206/Tremelimumab.
[0019] Examples of TIM-3 inhibitors include MBG453 (Novartis), TSR-022 (Tesaro), and LY3321367 (Lilly).
[0020] Examples of TIGIT inhibitors include Tiragolumab (MTIG7192A; RG6058;
Genentech/Roche), AB154 (Arcus Bioscience), MK-7684 (Merck), BMS-986207 (Bristol- Myers Squibb), ASP8374 (Astellas Pharma; Potenza Therapeutics).
[0021] In one embodiment, the immune checkpoint inhibitor is selected from BMS- 986016/Relatlimab, TSR-033, REGN3767, MGD013 (bispecific DART binding PD-1 and LAG-3), GSK2831781, LAG525, MDX-010/Ipilimumab, AGEN1884, and CP- 675,206/Tremelimumab, pembrolizumab, nivolumab, atezolizumab, avelumab, durvalumab, MBG453, TSR-022, LY3321367, Tiragolumab (MTIG7192A; RG6058), AB154, MK-7684, BMS-986207, and/or ASP8374 or a pharmaceutically acceptable salt or solvate thereof. EXAMPLES
General Conditions:
[00197] Mass spectra were run on LC-MS systems using electrospray ionization. These were run using either a Waters Acquity H-Class UPLC with PDA and QDa mass detection, an Acquity UPLC (binary pump/PDA detector) + ZQ Mass Spectrometer or Acquity i-Class (quaternary pump/PDA detector) + Quattro Micro Mass Spectrometer, a Waters Acquity uPLC system with Waters PDA and ELS detectors or a Shimadzu LCMS-2010EV system. [M+H]+ refers to mono-isotopic molecular weights.
[00198] NMR spectra were run on either a Bruker Ultrashield 500 MHz NMR spectrometer, a Bruker Avance III HD 400 MHz NMR spectrometer, a Bruker Avance DPX 300 MHz NMR spectrometer a Bruker Avance III HD 500 MHz or a Bruker Avance III HD 250 MHz. Spectra were recorded at 298K and were referenced using the solvent peak.
[00199] The following examples are intended to illustrate the invention and are not to be construed as being limitations thereon. Temperatures are given in degrees centigrade. If not mentioned otherwise, all evaporations are performed in vacuo, preferably between about 15 mm Hg and 100 mm Hg (= 20-133 mbar). The structure of final products, intermediates and starting materials is confirmed by standard analytical methods, e.g., microanalysis and spectroscopic characteristics, e.g., MS, IR, and NMR. Abbreviations used are those conventional in the art. If not defined, the terms have their generally accepted meanings. Abbreviations
app apparent
br broad
d doublet
dd doublet of doublets
DCM dichloromethane
DIAD diisopropyl azodicarboxylate
DIBAL diisobutylaluminum hydride
DIEA diethylisopropylamine
DIPEA diisopropylethylamine
DMF N,N-dimethylformamide
EtOAc ethyl acetate
HATU hexafluorophosphate azabenzotriazole tetramethyl uronium
HPLC high pressure liquid chromatography
LC-MS liquid chromatography and mass spectrometry
MeOH MeOH
MeCN acetonitrile
MS mass spectrometry
m multiplet
mins minute(s)
mL milliliter(s)
m/z mass to charge ratio
NMR nuclear magnetic resonance
ppm parts per million
rac- racemate
Rt retention time
s singlet
t triplet
TFA trifluoroacetic acid
THF tetrahydrofuran [00200] Referring to the examples that follow, compounds of the preferred embodiments were synthesized using the methods described herein, or other methods, which are known in the art.
[00201] The various starting materials, intermediates, and compounds of the preferred embodiments may be isolated and purified, where appropriate, using conventional techniques such as precipitation, filtration, crystallization, evaporation, distillation, and chromatography. Unless otherwise stated, all starting materials are obtained from commercial suppliers and used without further purification. Salts may be prepared from compounds by known salt-forming procedures.
[00202] If not indicated otherwise, the analytical HPLC conditions are as follows:
Method 2A
Column: Kinetex Core-Shell C182.1 x 50 mm 5 µm
Column Temp 40 ˚C
Eluents: A: H20+0.1% formic acid, B: MeCN+ 0.1% formic acid
Flow Rate: 1.2 mL/min
Gradient: 0-1.83 min 5-100 B, 1.83- 2.25 min 100% B, 2.25-2.26 min
100-5% B
Method 2.5B
Column: Phenomenex Gemini-NX C182 x 50 mm 3 µm
Column Temp: 40 ˚C
Eluents: A: 2 mM ammonium bicarbonate, buffered to pH10, B: MeCN Flow Rate: 1 mL/min
Gradient: 0-1.80 min 1-100% B, 1.80-2.10 min 100% B, 2.10-2.30 min 100- 1% B
Method 3A
Column: Acquity UPLC CSH C182.1 x 50 mm, 1.7 µm
Column Temp: 50 ˚C
Eluents: A: H2O, B: MeCN, 0.1% formic acid
Flow Rate: 1 mL/min Gradient: 0.2-2.5 min 2-98% B, 2.5-3.0 min 98% B
Method 3B
Column: Acquity UPLC BEH C182.1 x 50 mm, 1.7 µm
Column Temp: 50 ˚C
Eluents: A: H2O, B: MeCN, 0.1% ammonia
Flow Rate: 1 mL/min
Gradient: 0.2-2.5 min 2-98% B, 2.5-3.0 min 98% B
Method 5A
Column: YMC-Triart C182 x 50 mm, 5 mm.
Flow rate: 0.8 mL/min.
Eluents: A: H2O, B: MeCN, C: 50% H2O / 50% MeCN + 1.0% formic acid Gradient: 0.0-4.0 min 0-95% B, 5% C; 4.0-4.4 min 95% B, 5%C; 4.4-4.5 min
95% A, 5% B
Method 5B
Column: YMC-Triart C182 x 50 mm, 5 mm.
Flow rate: 0.8 mL/min.
Eluents: A: H2O, B: MeCN, C: 50% H2O / 50% MeCN + 1.0% ammonia (aq.) Gradient: 0.0-4.0 min 0-95% B, 5% C; 4.0-4.4 min 95%B, 5% C; 4.4-4.5 min 95%
A, 5% B
Method 7A
Column: Phenomenex Kinetix-XB C182.1 x 100 mm, 1.7 µm
Column Temp: 40 ˚C
Eluents: A: H2O 0.1% formic acid, B: MeCN, 0.1% formic acid
Flow Rate: 0.6 mL/min
Gradient: 0-5.3.0 min 5-100% B, 5.3-5.8 min 100% B, 5.8-5.82 min 100-5% B,
5.82-7.00 min 5% B
Method 7B
Column: Waters UPLC® BEHTM C18, 2.1 mm x 100 mm, 1.7 mm
Column Temp: 40 °C Eluents: A: 2 mM ammonium bicarbonate buffered to pH10, B: MeCN
Flow Rate: 0.6 mL/min
Gradient: 0-5.3.0 min 5-100% B, 5.3-5.8 min 100% B, 5.8-5.82 min 100-5% B, 5.82- 7.00 min 5% B
Method 7B2
Column: Phenomenex Gemini C18, 2.0 x 100 mm, 3 µm
Column Temp 40 ˚C
Eluents: A: 2 mM ammonium bicarbonate, buffered to pH10 with ammonium hydroxide, B: acetonitrile
Flow Rate: 0.5 mL/min
Gradient: 0-5.5 min 5-100% B, 5.5-5.9 min 100% B, 5.9-5.92 min 100-5% B
Method 8A
Column: Acquity UPLC CSH C182.1 x 100 mm, 1.7 µm
Column Temp: 50 ˚C
Eluents: A: H2O, B: MeCN, 0.1% formic acid
Flow Rate: 0.6 mL/min
Gradient: 0.5-6.5 min 2-98% B 6.5-7.5 min 98% B
Preparative HPLC using acidic pH, early elution method
[00203] Purifications by were performed on a Gilson LC system using Waters Sunfire C18 columns (30 mm x 100 mm, 10 µM; temperature: room temperature) and a gradient of 10-95% B (A= 0.1% formic acid in water; B= 0.1% formic acid in MeCN) over 14.44 min then 95% B for 2.11 min, with an injection volume of 1500 µL and a flow rate of 40 mL/min. UV spectra were recorded at 215 nm using a Gilson detector.
Preparative HPLC using acidic pH, standard elution method
[00204] Purifications by preparative HPLC (acidic pH, standard elution method) were performed on a Gilson LC system using Waters Sunfire C18 columns (30 mm x 100 mm, 10 µM; temperature: room temperature) and a gradient of 30-95% B (A= 0.1% formic acid in water; B= 0.1% formic acid in MeCN) over 11 min then 95% B for 2.11 min, with an injection volume of 1500 µL and a flow rate of 40 mL/min. UV spectra were recorded at 215 nm using a Gilson detector.
Preparative HPLC using basic pH, early elution method [00205] Purifications by preparative HPLC (basic pH, early elution method) were performed on a Gilson LC system using Waters Xbridge C18 columns (30 mm x 100 mm, 10 µM; temperature: room temperature) and a gradient of 10-95% (A= 0.2% ammonium hydroxide in water; B= 0.2% ammonium hydroxide in MeCN) over 14.44 min then 95% B for 2.11 min, with an injection volume of 1500 µL and a flow rate of 40 mL/min. UV spectra were recorded at 215 nm using a Gilson detector.
Preparative HPLC using basic pH, standard elution method
[00206] Purifications by preparative HPLC (basic pH, standard elution method) were performed on a Gilson LC system using Waters Xbridge C18 columns (30 mm x 100 mm, 10 µM; temperature: room temperature) and a gradient of 30-95% (A= 0.2% ammonium hydroxide in water; B= 0.2% ammonium hydroxide in MeCN) over 11 min then 95% B for 2.11 min, with an injection volume of 1500 µL and a flow rate of 40 mL/min. UV spectra were recorded at 215 nm using a Gilson detector.
Chiral Purity Analysis Conditions
Method CP1
Column Details Amy-C (4.6 mm x 250 mm, 5 mm)
Column Temperature 40 ˚C
Flow Rate 4 mL/min
Detector Wavelength 210-400 nm
Injection Volume 1.0 mL
BPR 125 BarG
Isocratic Conditions 30:70 EtOH:CO2 (0.2% v/v NH3)
Method CP2
Column Details Lux iC5 (4.6 mm x 250 mm, 5 mm)
Column Temperature 40 ˚C
Flow Rate 4 mL/min
Detector Wavelength 210-400 nm
Injection Volume 1.0 mL
BPR 125 BarG
Isocratic Conditions 50:50 MeOH:CO2 (0.2% v/v NH3) Method CP3
Column Details Lux C3 (4.6 mm x 250 mm, 5 mm) Column Temperature 40 ˚C
Flow Rate 4 mL/min
Detector Wavelength 210-400 nm
Injection Volume 1.0 uL
BPR 125 BarG
Isocratic Conditions 30:70 MeOH:CO2 (0.2% v/v NH3)
Method CP4
Column Details Chiralpak IG (4.6 mm x 250 mm, 5 mm) Column Temperature 40 ˚C
Flow Rate 4 mL/min
Detector Wavelength 210-400 nm
Injection Volume 1.0 mL
BPR 125 BarG
Isocratic Conditions 40:60 MeOH:CO2 (0.2% v/v NH3)
Method CP5
Column Details Lux A2 (4.6 mm x 250 mm, 5 mm) Column Temperature Ambient
Flow Rate 1 mL/min
Detector Wavelength 254 nm
Injection Volume 1.0 mL
Isocratic Conditions 50:50 HEPT:EtOH (0.2% v/v NH3) Example 1
4-Amino-2-(3-cyanophenyl)-N-ethoxy-6-(2-fluoroethoxy)pyrimidine-5-carboxamide
Figure imgf000087_0001
Step 1: Ethyl 4,6-dichloro-2-methylsulfanyl-pyrimidine-5-carboxylate
Figure imgf000087_0002
[00207] This compound was prepared according to the method described in U.S. Pat. Appl. Publ., 20100249110, page 36, 30 Sep 2010).
[00208] LDA (2M in THF/n-heptane/ethylbenzene) (41.56 mL, 83.12 mmol) was added dropwise over 20 mins to a solution of 4,6-dichloro-2-methylsulfanyl-pyrimidine (10.81 g, 55.42 mmol) in anhydrous THF (60 mL) at -78 ºC under nitrogen and the resulting mixture stirred for 1 h. To this mixture was added dropwise ethyl chloroformate (7.95 mL, 83.12 mmol) over 10 mins and stirring continued at -78 ºC for 1 h. The reaction was quenched by addition of saturated aqueous ammonium chloride (100 mL) and the resulting mixture was diluted with water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were washed with brine (50 mL), dried over MgSO4 and concentrated in vacuo to afford the title compound as a dark orange oil.
LC-MS (Method 5B): Rt 3.51 mins; MS m/z 267.0 = [M+H]+
1H NMR (500 MHz, Chloroform-d) d 4.45 (q, J = 7.1 Hz, 2H), 2.58 (s, 3H), 1.41 (t, J = 7.1 Hz, 3H)
[00209] This compound may also be prepared as follows:
[00210] n-BuLi (1.6M in hexanes) (224.28 mL, 358.85 mmol) was added dropwise over 50 mins to a stirred solution of 4,6-dichloro-2-methylsulfanyl-pyrimidine (50.0 g, 256.32 mmol) in anhydrous THF (300 mL) at -78 ºC under nitrogen and the reaction mixture stirred at -78 ºC for 1 h. Ethyl chloroformate (33.08 mL, 346.03 mmol) was then added dropwise over 5 mins and the mixture stirred at -78 ºC for a further 45 mins. The mixture was allowed to warm to room temperature, then quenched by addition of saturated aqueous ammonium chloride (300 mL) and water (300 mL). The mixture was extracted with EtOAc (2 x 600 mL) and the combined organic extracts were washed with water (600 mL), brine (600 mL), dried over MgSO4 and concentrated in vacuo. The resulting oil crystallized overnight to yield a crystalline solid. The solid was sonicated in heptane (200 mL), filtered, washed with heptane (100 mL) and dried to afford the title compound as an off-white solid.
LC-MS (Method 5B): Rt 3.57 mins; MS m/z 267.0 / 269.0 = [M+H]+
1H NMR (500 MHz, Chloroform-d) d 4.45 (q, J = 7.1 Hz, 2H), 2.59 (s, 3H), 1.41 (t, J = 7.1 Hz, 3H).
Step 2: Ethyl 4-amino-6-chloro-2-methylsulfanyl-pyrimidine-5-carboxylate
Figure imgf000088_0001
[00211] To a solution of ethyl 4,6-dichloro-2-methylsulfanyl-pyrimidine-5-carboxylate (step 1) (133.0 g, 497.88 mmol) in THF (2 L) at 0 ˚C was added NH4OH (35% in water) (566.1 mL, 4978.9 mmol) portion wise. The resulting mixture was stirred vigorously at room temperature for 45 mins. The mixture was diluted with EtOAc (1.5 L) and washed with 20% brine (2 x 2.5 L), dried over MgSO4 and concentrated in vacuo. Petroleum ether (800 mL) was added to the crude product causing precipitation of a solid. The solid was collected by filtration, washed with petroleum ether (2 x 500 mL) and dried under vacuum to afford the title compound as a pale yellow solid.
LC-MS (Method 3B): Rt 1.68 mins; MS m/z 248.0 / 250.0 = [M+H]+
1H NMR (500 MHz, Chloroform-d) d 7.84 (br s, 1H), 5.73 (br s, 1H), 4.38 (q, J = 7.1 Hz, 2H), 2.50 (s, 3H), 1.40 (t, J = 7.1 Hz, 3H).
Step 3: Ethyl 4-amino-6-(2-fluoroethoxy)-2-methylsulfanyl-pyrimidine-5-carboxylate
Figure imgf000088_0002
[00212] 2-Fluoroethanol (0.73 mL, 12.43 mmol) was added dropwise to a stirred suspension of sodium hydride (60% in oil) (678 mg, 16.96 mmol) in anhydrous THF (20 mL) under nitrogen and stirring continued for 15 mins. The resulting suspension was treated with a solution of ethyl 4-amino-6-chloro-2-methylsulfanyl-pyrimidine-5-carboxylate (step 2) (2.8 g, 11.3 mmol) in anhydrous THF (50 mL) via cannula and the mixture stirred at room temperature for 2 h. The reaction was quenched with water (60 mL) and brine (20 mL) was added. The mixture was extracted with EtOAc (150 mL) and the organic portion was dried over MgSO4 and concentrated in vacuo. Purification by chromatography on silica eluting with a gradient of 10-30% EtOAc in petrol afforded the title compound as a pale yellow solid. LC-MS (Method 3B): Rt 1.70 mins; MS m/z 276.1 = [M+H]+
1H NMR (500 MHz, Chloroform-d) d 8.18 (s, 1H), 5.57 (s, 1H), 4.81– 4.76 (m, 1H), 4.71– 4.67 (m, 1H), 4.67– 4.63 (m, 1H), 4.63– 4.57 (m, 1H), 4.30 (q, J = 7.1 Hz, 2H), 2.49 (s, 3H), 1.38 (t, J = 7.1 Hz, 3H).
Step 4: Ethyl 4-amino-2-(3-cyanophenyl)-6-(2-fluoroethoxy)pyrimidine-5-carboxylate
Figure imgf000089_0001
[00213] A mixture of ethyl 4-amino-6-(2-fluoroethoxy)-2-methylsulfanyl-pyrimidine-5- carboxylate (step 3) (1.53 g, 5.17 mmol), (3-cyanophenyl)boronic acid (1.22 g, 8.27 mmol), copper(I) thiophene-2-carboxylate (1.97 g, 10.34 mmol) and Pd(PPh3)4 (597 mg, 0.52 mmol) under nitrogen was treated with anhydrous THF (40 mL) and stirred at 55 °C overnight. Further Pd(PPh3)4 (299 mg, 0.26 mmol), (3-cyanophenyl)boronic acid (380 mg, 2.58 mmol) and copper(I) thiophene-2-carboxylate (493 mg, 2.58 mmol) were added and the reaction was stirred at 55 °C for 4 h. After cooling to room temperature, the mixture was washed with 15% NH3 solution (5 x 150 mL), brine (50 mL), dried over MgSO4 and concentrated in vacuo. Purification by chromatography on silica eluting with a gradient of 20-100% EtOAc in petrol afforded a yellow solid. Trituration of the solid from EtOAc/petrol 1:1 afforded the title compound as a pale green solid.
LC-MS (Method 3B): Rt 1.93 mins; MS m/z 331.1 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 8.66 (dd, J = 1.3, 1.3 Hz, 1H), 8.60 (ddd, J = 8.0, 1.4, 1.3 Hz, 1H), 8.02 (ddd, J = 7.7, 1.4, 1.3 Hz, 1H), 7.86 (s, 2H), 7.74 (dd, J = 8.0, 7.7 Hz, 1H), 4.86– 4.80 (m, 1H), 4.80– 4.75 (m, 1H), 4.75– 4.68 (m, 2H), 4.26 (q, J = 7.1 Hz, 2H), 1.30 (t, J = 7.1 Hz, 3H).
Step 5: 4-Amino-2-(3-cyanophenyl)-6-(2-fluoroethoxy)pyrimidine-5-carboxylic acid
Figure imgf000089_0002
[00214] A solution of lithium hydroxide (139 mg, 5.78 mmol) in water (7.5 mL) was added to a solution of ethyl 4-amino-2-(3-cyanophenyl)-6-(2-fluoroethoxy)pyrimidine-5- carboxylate (step 4) (955 mg, 2.89 mmol) in THF (12.5 mL) and the resulting mixture stirred vigorously at room temperature for 67.5 h. The mixture was filtered through a plug of cotton wool and the filtrate was diluted with water (12.5 mL) and extracted with Et2O (2 x 20 mL). The aqueous phase was acidified to pH 1 by dropwise addition of concentrated HCl. The resulting precipitate was collected by filtration, washed with water (3 x 5 mL) and vacuum dried to afford the title compound as a cream solid.
LC-MS (Method 3A): Rt 1.63 mins; MS m/z 303.0 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 12.82 (br s, 1H), 8.67– 8.64 (m, 1H), 8.62– 8.58 (m, 1H), 8.04– 8.00 (m, 1H), 7.95 (br s, 2H), 7.77– 7.72 (m, 1H), 4.84– 4.78 (m, 2H), 4.73 (s, 2H). Step 6: 4-Amino-2-(3-cyanophenyl)-N-ethoxy-6-(2-fluoroethoxy)pyrimidine-5-carboxamide
[00215] O-Ethylhydroxylamine hydrochloride (24 mg, 0.25 mmol), HATU (126 mg, 0.33 mmol) and DIPEA (173 µL, 0.99 mmol) were added in quick succession to a solution of 4- amino-2-(3-cyanophenyl)-6-(2-fluoroethoxy)pyrimidine-5-carboxylic acid (step 5) (50 mg, 0.17 mmol) in DMF (1 mL) and the mixture stirred at room temperature for 90 mins. The resulting mixture was diluted with EtOAc (20 mL) and washed with 50% brine (20 mL). The aqueous portion was re-extracted with EtOAc (2 x 20 mL) and the organic extracts were combined, washed with brine (4 x 20 mL), dried over MgSO4 and concentrated in vacuo. Purification by chromatography on silica eluting with a gradient of 40-50% EtOAc in petrol afforded a colourless gum. The gum was triturated with diethyl ether (5 mL) and collected by suction filtration to afford the title compound as a colourless solid.
LC-MS (Method 8A): Rt 4.61 mins; MS m/z 346.1 = [M+H]+
1H NMR (500 MHz, Chloroform-d) d 10.09 (s, 1H), 9.15 (s, 1H), 8.64 (t, J = 1.5 Hz, 1H), 8.57 (dt, J = 7.8, 1.5 Hz, 1H), 7.76 (dt, J = 7.8, 1.5 Hz, 1H), 7.57 (t, J = 7.8 Hz, 1H), 5.75 (s, 1H), 4.94– 4.87 (m, 2H), 4.85 (ddd, J = 4.9, 2.6, 1.0 Hz, 1H), 4.83– 4.78 (m, 1H), 4.07 (q, J = 7.1 Hz, 2H), 1.35 (t, J = 7.1 Hz, 3H).
[00216] The compounds of the following tabulated Examples (Table Ex1) were prepared analogously to Example 1 step 6 from 4-amino-2-(3-cyanophenyl)-6-(2- fluoroethoxy)pyrimidine-5-carboxylic acid (step 5) and the appropriate amine.
Table Ex1 Ex. Structure and Name Retention Time, [M+H]+, 1H NMR 1 z
+ , = , , = 1 z
, = , 5 = 7 - 1 z
, , , 0 , 1 z
, = , 6 7 J
, 1 S , = 1 8 1 S
, = , 1 5
Figure imgf000091_0001
pyrimidine-5-carboxamide Ex. Structure and Name Retention Time, [M+H]+, 1H NMR
1 z
, , , , = 1 z
r 0 , 9 5
Figure imgf000092_0003
Example 2
4-Amino-2-(3-cyanophenyl)-N-(2,3-dihydroxypropoxy)-6-(2-fluoroethoxy)pyrimidine-5- carboxamide
Figure imgf000092_0001
Step 1: 4-Amino-2-(3-cyanophenyl)-N-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]-6-(2- fluoroethoxy)pyrimidine-5-carboxamide
Figure imgf000092_0002
[00217] The title compound was prepared from 4-amino-2-(3-cyanophenyl)-6-(2- fluoroethoxy)pyrimidine-5-carboxylic acid (Example 1 step 5) and O-[(2,2-dimethyl-1,3- dioxolan-4-yl)methyl]hydroxylamine (Intermediate E) analogously to Example 1 step 6.
LC-MS (Method 7A): Rt 3.24 min; MS m/z 432.2 [M+H]+
1H NMR (500 MHz, DMSO-d6) d 11.16 (s, 1H), 8.64 (t, J = 1.5 Hz, 1H), 8.61– 8.53 (m, 1H), 8.00 (dt, J = 7.7, 1.5 Hz, 1H), 7.79– 7.62 (m, 3H), 4.91– 4.85 (m, 1H), 4.84– 4.77 (m, 2H), 4.77– 4.71 (m, 1H), 4.41– 4.31 (m, 1H), 4.12– 4.02 (m, 1H), 3.93 (d, J = 5.4 Hz, 2H), 3.80– 3.71 (m, 1H), 1.34 (s, 3H), 1.29 (s, 3H). Step 2: 4-Amino-2-(3-cyanophenyl)-N-(2,3-dihydroxypropoxy)-6-(2-fluoroethoxy)pyrimidine- 5-carboxamide
[00218] 4M HCl in 1,4-dioxane (0.5 mL, 2 mmol) was added to a suspension of 4- amino-2-(3-cyanophenyl)-N-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]-6-(2- fluoroethoxy)pyrimidine-5-carboxamide (step 1) (75 mg, 0.15 mmol) in 1,4-dioxane (5 mL) and the reaction mixture was stirred for 1 h. The resulting mixture was concentrated in vacuo and purification of the residue by preparative HPLC (acidic pH, early elution method) afforded the title compound as a colourless solid.
LCMS (Method 7B): Rt ~ 1.84 min, MS m/z 392.3 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 11.11 (br. s, 1H), 8.64 (t, J = 1.4 Hz, 1H), 8.59 (dt, J = 7.8, 1.4 Hz, 1H), 8.01 (dt, J = 7.8, 1.4 Hz, 1H), 7.92– 7.69 (m, 3H), 4.96 (br. s, 1H), 4.89– 4.86 (m, 1H), 4.84– 4.73 (m, 3H), 4.63 (br. s, 1H), 3.97 (dd, J = 10.0, 3.3 Hz, 1H), 3.86– 3.70 (m, 2H), 3.41 (s, 2H).
Example 2.1
4-Amino-2-(3-cyanophenyl)-6-(2-fluoroethoxy)-N-(morpholin-2-ylmethoxy)pyrimidine- 5-carboxamide
Figure imgf000093_0001
Step 1: tert-Butyl 2-[[[4-amino-2-(3-cyanophenyl)-6-(2-fluoroethoxy)pyrimidine-5- carbonyl]amino]oxymethyl]morpholine-4-carboxylate
Figure imgf000093_0002
[00219] The title compound was prepared from 4-amino-2-(3-cyanophenyl)-6-(2- fluoroethoxy)pyrimidine-5-carboxylic acid (Example 1 step 5) and tert-butyl 2- (aminooxymethyl)morpholine-4-carboxylate (Intermediate A) analogously to Example 1 step 6.
LC-MS (Method 7B): Rt 3.54 mins; MS m/z 517.3 = [M+H]+ 1H NMR(500 MHz, DMSO-d6) d 11.12 (s, 1H), 8.64 (t, J = 1.4 Hz, 1H), 8.58 (dt, J = 7.8, 1.4 Hz, 1H), 8.03– 7.97 (m, 1H), 7.74 (t, J = 7.8 Hz, 3H), 4.93– 4.66 (m, 4H), 3.97– 3.80 (m, 4H), 3.78– 3.60 (m, 2H), 3.44– 3.39 (m, 1H), 2.97– 2.66 (m, 2H), 1.41 (s, 9H).
Step 2: 4-Amino-2-(3-cyanophenyl)-6-(2-fluoroethoxy)-N-(morpholin-2-ylmethoxy)pyrimidine- 5-carboxamide
[00220] The title compound was prepared from tert-butyl 2-[[[4-amino-2-(3- cyanophenyl)-6-(2-fluoroethoxy)pyrimidine-5-carbonyl]amino]oxymethyl]morpholine-4- carboxylate (step 1) and 4M HCl in 1,4-dioxane analogously to Example 2 step 2. The reaction was carried out in MeOH and DCM.
LC-MS (Method 7A): Rt 1.77 mins; MS m/z 417.2 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 11.07 (s, 1H), 8.64 (t, J = 1.5 Hz, 1H), 8.59 (dt, J = 7.8, 1.5 Hz, 1H), 8.04– 7.98 (m, 1H), 7.74 (t, J = 7.8 Hz, 3H), 4.94– 4.71 (m, 4H), 3.86– 3.82 (m, 2H), 3.77– 3.71 (m, 1H), 3.66 (s, 1H), 3.45 (td J = 10.9, 3.1 hZ, 1H), 2.86– 2.80 (m, 1H), 2.70 – 2.64 (m, 2H), 2.48– 2.40 (m, 1H).
Example 3
4-Amino-2-(3-cyanophenyl)-6-(2-fluoroethoxy)-N-[(4-methylmorpholin-2- yl)methoxy]pyrimidine-5-carboxamide
Figure imgf000094_0001
[00221] To a solution of 4-amino-2-(3-cyanophenyl)-6-(2-fluoroethoxy)-N-(morpholin-2- ylmethoxy)pyrimidine-5-carboxamide (Example 2.1) (105 mg, 0.25 mmol) , AcOH (0.04 mL, 0.76 mmol) and formaldehyde (37 wt% in water) (0.02 mL, 0.76 mmol) in MeOH (5 mL) was added sodium triacetoxyborohydride (107 mg, 0.50 mmol) and stirring continued at room temperature for 20 h. The resulting mixture was treated with aqueous NaHCO3 (5 mL) and extracted with DCM (3 x 5 mL). The combined organic extracts were concentrated in vacuo and purification of the crude residue by preparative HPLC (basic pH, early elution method) afforded the title compound as a colourless solid.
LC-MS (Method 7B2): Rt 3.41 mins; MS m/z 431.2 = [M+H]+ 1H NMR (500 MHz, DMSO-d6) d 11.09 (s, 1H), 8.64 (t, J = 1.5 Hz, 1H), 8.59 (dt, J = 7.9, 1.5 Hz, 1H), 8.01 (dt, J = 7.9, 1.5 Hz, 1H), 7.74 (t, J = 7.9 Hz, 3H), 4.92– 4.69 (m, 4H), 3.89 (m, 2H), 3.80 (m, 2H), 3.52 (td, J = 11.3, 2.1 Hz, 1H), 2.77– 2.72 (m, 1H), 2.61– 2.57 (m, 1H), 2.19 (s, 3H), 1.98 (td, J = 11.3, 3.3 Hz, 1H), 1.81 (t, J = 10.7 Hz, 1H).
Example 4
4-Amino-N-(2-hydroxy-2-methyl-propoxy)-2-oxazol-5-yl-6-(oxetan-3-yloxy)pyrimidine- 5-carboxamide
Figure imgf000095_0001
Step 1: Ethyl 4-amino-6-chloro-2-oxazol-5-yl-pyrimidine-5-carboxylate
Figure imgf000095_0002
[00222] A pressure tube equipped with a magnet stirrer was charged with ethyl 4- amino-6-chloro-2-methylsulfanyl-pyrimidine-5-carboxylate (Example 1 step 2) (350 mg, 1.41 mmol), copper (I) thiophene-2-carboxylate (674 mg, 3.53 mmol) and THF (10 mL). Tetrakis(triphenylphosphine)palladium(0) (163 mg, 0.14 mmol) was added followed by triisopropyl-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazol-2-yl]silane (745 mg, 2.12 mmol). The mixture was purged with nitrogen sealed and heated at 55 °C for 1 h. Further portions triisopropyl-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazol-2-yl]silane (4 x 745 mg) were added at 1 hour intervals and heated continued at 55 °C for a total of 5 h. After cooling to room temperature, the mixture was diluted with EtOAc, filtered through Celite® (filter material) and washed through with EtOAc.14% Aqueous ammonia (12.5 mL) was added and the mixture was left to stand at room temperature overnight. A further portion of 14% aqueous ammonia (12.5 mL) was added the phases were separated. The organic portion was washed again with 14% aqueous ammonia (25 mL) and the combined aqueous washes were extracted with EtOAc (12.5 mL). The organic extracts were combined, washed with brine (12.5 mL), dried over MgSO4 and concentrated in vacuo. The residue was diluted with THF (12.5 mL) and 1N aqueous HCl (10 mL) was added. After stirring at room temperature for 30 mins the mixture was diluted with water (12.5 mL), extracted with EtOAc (2 x 25 mL). The combined organic extracts were washed with brine (12.5 mL), dried over MgSO4 and concentrated in vacuo. The residue was triturated with EtOH (12.5 mL), sonicated, filtered and dried under vacuum to afford the title compound as a beige solid.
LC-MS (Method 2A): Rt 1.01 mins; MS m/z 268.9, 270.9 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 8.62 (s, 1H), 8.12 (br. s, 1H), 7.88 (s, 1H), 7.65 (br. s, 1H), 4.34 (q, J = 7.1 Hz, 2H), 1.31 (t, J = 7.1 Hz, 3H).
Step 2: Ethyl 4-amino-2-oxazol-5-yl-6-(oxetan-3-yloxy)pyrimidine-5-carboxylate
Figure imgf000096_0001
[00223] A solution of oxetan-3-ol (165 mg, 2.23 mmol) in THF (2 mL) was added dropwise to an ice cooled, stirred suspension of sodium hydride (60% in oil) (71 mg, 1.79 mmol) in THF (8 mL) under nitrogen. The mixture was stirred at 0 °C for 5 mins and then at room temperature for 10 mins before cooling again to 0 °C. The resulting mixture was treated dropwise with a solution of ethyl 4-amino-6-chloro-2-oxazol-5-yl-pyrimidine-5-carboxylate (step 1) ( (400 mg, 1.49 mmol) in THF (5 mL) and stirring continued at 0 °C for 45 mins. The reaction was quenched with water (3 mL) and EtOAc (15 mL) was added. The suspension was concentrated in vacuo and the residue triturated with EtOH (15 mL). The resulting solid was isolated by filtration, rinsed with EtOH (15 mL) and dried in a vacuum oven to afford the title compound as a beige solid.
LC-MS (Method 2A): Rt 1.00 mins; MS m/z 307.1 = [M+H]+
1H NMR (400 MHz, Chloroform-d) d 8.29 (br s, 1H), 8.01 (s, 1H), 7.77 (s, 1H), 5.87 (br. s, 1H), 5.72 (apr p, J = 5.9 Hz, 1H), 5.04– 4.98 (m, 2H), 4.82– 4.74 (m, 2H), 4.36 (q, J = 7.1 Hz, 2H), 1.41 (t, J = 7.1 Hz, 3H).
Step 3: 4-Amino-2-oxazol-5-yl-6-(oxetan-3-yloxy)pyrimidine-5-carboxylic acid
Figure imgf000096_0002
[00224] The title compound was prepared from ethyl 4-amino-2-oxazol-5-yl-6-(oxetan- 3-yloxy)pyrimidine-5-carboxylate (step 2) and lithium hydroxide monohydrate analogously to Example 1 step 5.
LC-MS (Method 2A): Rt 0.81 mins; MS m/z 278.9 = [M+H]+ 1H NMR (400 MHz, DMSO-d6) d 13.77– 11.60 (v. br. s, 1H), 8.58 (s, 1H), 8.04 (s, 2H), 7.89 (s, 1H), 5.61 (p, J = 5.8 Hz, 1H), 4.92 (apr t, J = 7.1 Hz, 2H), 4.57 (dd, J = 7.4, 5.8 Hz, 2H).
Step 4: 4-Amino-N-(2-hydroxy-2-methyl-propoxy)-2-oxazol-5-yl-6-(oxetan-3-yloxy)pyrimidine- 5-carboxamide
[00225] The title compound was prepared from 4-amino-2-oxazol-5-yl-6-(oxetan-3- yloxy)pyrimidine-5-carboxylic acid (step 3) and 1-aminooxy-2-methyl-propan-2-ol (Intermediate C) analogously to Example 1 step 6.
LC-MS (Method 7A): Rt 1.71 mins; MS m/z 366.2 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 11.23 (s, 1H), 8.56 (s, 1H), 7.87 (d, J = 11.0 Hz, 3H), 5.61 (p, J = 5.9 Hz, 1H), 4.90 (t, J = 7.2 Hz, 2H), 4.74 (s, 1H), 4.71– 4.62 (m, 2H), 3.72 (s, 2H), 1.18 (s, 6H).
Example 5
4-Amino-2-(3-cyanophenyl)-6-(2-hydroxyethoxy)-N-(2-hydroxy-2-methyl-propoxy) pyrimidine-5-carboxamide
Figure imgf000097_0001
Step 1: Ethyl 4-amino-6-chloro-2-(3-cyanophenyl)pyrimidine-5-carboxylate
Figure imgf000097_0002
[00226] Pd(PPh3)4 (9.33 g, 8.07 mmol) was added in one portion to a stirred, degassed suspension of ethyl 4-amino-6-chloro-2-methylsulfanyl-pyrimidine-5-carboxylate (Example 1, step 2) (20.0 g, 80.74 mmol), (cyanophenyl)boronic acid (1.8 g, 12.2 mmol) and Copper(I) thiophene-2-carboxylate (30.8 g, 161.49 mmol) in anhydrous THF (400 mL) at room temperature under nitrogen. The mixture was stirred at 55 °C under nitrogen and treated with seven further portions of (cyanophenyl)boronic acid at 30 minute intervals until a total of 14.24 g (96.89 mmol) had been added. The resulting mixture was stirred at 55 °C for 2 h and then allowed to cool to room temperature. The mixture was diluted with EtOAc (250 mL) and filtered through a pad of Celite® (filter material), eluting with EtOAc (500 mL). The filtrate was washed with 5% aqueous ammonia solution (~5 x 500 mL), dried over MgSO4 and then concentrated in vacuo. The crude product was suspended in petroleum ether (250 mL) and the solvent decanted before EtOH (200 mL) was added at which point a solid formed which was collected by filtration, washed with EtOH (100 mL), Et2O (2 x 100 mL) and dried to afford the title compound as a beige solid.
LC-MS (Method 5B): Rt 3.43 mins; MS m/z 303.1 and 305.0 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 8.55 (t, J= 1.6 Hz, 1H), 8.52 (dt, J= 7.8, 1.6 Hz, 1H), 8.24– 7.49 (br. S, 2H), 8.03 (dt, J = 7.8, 1.6 Hz, 1H), 7.75 (t, J= 7.8 Hz, 1H), 4.35 (q, J= 7.1 Hz, 2H), 1.32 (t, J= 7.1 Hz, 3H).
Step 2: 4-Amino-2-(3-cyanophenyl)-6-(2-hydroxyethoxy)pyrimidine-5-carboxylic acid
Figure imgf000098_0001
[00227] Sodium hydride (60% in oil) (119 mg, 2.97 mmol) was added portionwise to an ice cooled solution of ethylene glycol (0.17 mL, 2.97 mmol) in THF (5 mL). The mixture was allowed to warm to room temperature and stirred for 10 mins before re-cooling in the ice bath and treating with a suspension of ethyl 4-amino-6-chloro-2-(3-cyanophenyl)pyrimidine-5- carboxylate (step 1) (300 mg, 0.99 mmol) in THF (10 mL). The resulting mixture was allowed to warm to room temperature and stirred overnight. The reaction was quenched with water and further diluted with water (20 mL). The resulting precipitate was removed by vacuum filtration and the filtrate was washed with EtOAc (2 x 20 mL). The aqueous portion was acidified to pH 2 by dropwise addition of 2M HCl to yield a precipitate. The suspension was cooled in an ice bath, allowed to stand for 20 mins and filtered under vacuum to afford the title compound as a colourless solid.
LCMS: LC-MS (Method 2A): Rt 1.00 mins; MS m/z 301.0 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 8.62 (t, J = 1.4 Hz, 1H), 8.59 (dt, J = 7.8, 1.4 Hz, 1H), 8.00 (dt, J = 7.8, 1.4 Hz, 1H), 7.85 (br. s, 2H), 7.73 (t, J = 7.8 Hz, 1H), 4.52 (t, J = 5.2 Hz, 2H), 3.71 (t, J = 5.2 Hz, 2H). Step 3: 4-Amino-2-(3-cyanophenyl)-6-(2-hydroxyethoxy)-N-(2-hydroxy-2-methyl-propoxy) pyrimidine-5-carboxamide
[00228] The title compound was prepared from 4-amino-2-(3-cyanophenyl)-6-(2- hydroxyethoxy)pyrimidine-5-carboxylic acid (step 2) and 1-aminooxy-2-methyl-propan-2-ol (Intermediate C) analogously to Example 1 step 6.
LC-MS (Method 7A): Rt 2.44 mins; MS m/z 388.2 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 11.07 (s, 1H), 8.65– 8.54 (m, 2H), 8.16– 7.63 (m, 4H), 5.01 (s, 1H), 4.73 (s, 1H), 4.58 (t, J = 5.1 Hz, 2H), 3.86– 3.73 (m, 2H), 3.74– 3.65 (m, 2H), 1.17 (s, 6H).
Example 5.1
4-Amino-2-(2-furyl)-N-(2-hydroxy-2-methyl-propoxy)-6-(oxetan-3-yloxy)pyrimidine-5- carboxamide
Figure imgf000099_0001
Step 1: Ethyl 4-amino-6-chloro-2-(2-furyl)pyrimidine-5-carboxylate
Figure imgf000099_0002
[00229] The title compound was prepared from ethyl 4-amino-6-chloro-2- methylsulfanyl-pyrimidine-5-carboxylate (Example 1 step 2) and 2-furylboronic acid analogously to Example 5 step 1.
LC-MS (Method 5B): Rt 2.78 mins; MS m/z 268.1 and 270.0 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 7.93 (br. s, 1H), 7.73 (br. s, 2H), 7.26 (d, J = 3.4 Hz, 1H), 6.70 (dd, J = 3.4, 1.7 Hz, 1H), 4.33 (q, J = 7.1 Hz, 2H), 1.31 (t, J = 7.1 Hz, 3H).
Step 2: 4-Amino-2-(2-furyl)-6-(oxetan-3-yloxy)pyrimidine-5-carboxylic acid [00230] Sodium hydride (60% in oil) (90 mg, 2.24 mmol) was suspended in anhydrous DMF (2 mL) under nitrogen and the mixture cooled to 0 ºC. To this mixture was added dropwise a solution of oxetan-3-ol (180 mg, 2.43 mmol) in anhydrous DMF (2 mL) and the mixture stirred at 0 ºC for 30 mins. A solution of ethyl 4-amino-6-chloro-2-(2-furyl)pyrimidine- 5-carboxylate (step 1) (500 mg, 1.87 mmol) in anhydrous DMF (10 mL) was added and the mixture was stirred at room temperature for 18 h. The resulting mixture was diluted with EtOAc (60 mL) and washed with 50% brine (4 x 30 mL). The organic portion was dried over Na2SO4 and concentrated in vacuo to afford as a yellow residue. This material was re-dissolved in THF (10 mL) and treated with a solution of lithium hydroxide (134 mg, 5.6 mmol) in water (5 mL). The resulting mixture was stirred vigorously at room temperature for 66 h after which time the mixture was diluted with water (50 mL) and extracted with Et2O (3 x 30 mL). The aqueous portion was acidified to pH 2 with 2M HCl and the resulting cream suspension filtered. The solids were washed with water (3 x 5 mL) and re-dissolved in MeCN/MeOH. The resulting solution was concentrated in vacuo and the residues azeotroped from MeCN (2 x 20 mL) to afford the title compound as a cream solid.
LC-MS (Method 5A): Rt 1.70 mins; MS m/z 278.1 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 12.78 (br s, 1H), 7.98 (br s, 2H), 7.90 (s, 1H), 7.25 (d, J = 3.5 Hz, 1H), 6.70– 6.66 (m, 1H), 5.62 (apr p, J = 5.9 Hz, 1H), 4.91 (apr t, J = 6.9 Hz, 2H), 4.58 (apr t, J = 6.4 Hz, 2H).
Step 3: 4-Amino-2-(2-furyl)-N-(2-hydroxy-2-methyl-propoxy)-6-(oxetan-3-yloxy)pyrimidine-5- carboxamide
[00231] The title compound was prepared from 4-amino-2-(2-furyl)-6-(oxetan-3- yloxy)pyrimidine-5-carboxylic acid (step 2) and 1-aminooxy-2-methyl-propan-2-ol (Intermediate C) analogously to Example 1 step 6.
LC-MS (Method 8B): Rt 3.01 mins; MS m/z 365.2 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 11.19 (br s, 1H), 7.88 (s, 1H), 7.84 (br s, 2H), 7.21 (d, J = 3.4 Hz, 1H), 6.66 (dd, J = 3.4, 1.8 Hz, 1H), 5.61 (apr p, J = 5.9 Hz, 1H), 4.88 (apr t, J = 7.0 Hz, 2H), 4.79 (br s, 1H), 4.69 (apr t, J = 6.6 Hz, 2H), 3.71 (s, 2H), 1.17 (s, 6H). Example 5.2
4-Amino-2-(3-fluorophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-(oxetan-3-yloxy) pyrimidine-5-carboxamide
Figure imgf000101_0001
Step 1: Ethyl 4-amino-6-chloro-2-(3-fluorophenyl)pyrimidine-5-carboxylate
Figure imgf000101_0002
[00232] The title compound was prepared from ethyl 4-amino-6-chloro-2- methylsulfanyl-pyrimidine-5-carboxylate (Example 1, step 2) and (3-fluorophenyl)boronic acid analogously to Example 5 step 1.
LC-MS (Method 5B): Rt 3.60 mins; MS m/z 296.1 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 8.25 - 7.38 (v br s, 2H), 8.10 (apr d, J = 7.9 Hz, 1H), 7.95 (ddd, J = 10.2, 2.6, 1.6 Hz, 1H), 7.58 (dt, J = 7.9, 5.9 Hz, 1H), 7.42 (td, J = 8.4, 2.6 Hz, 1H), 4.35 (q, J = 7.2 Hz, 2H), 1.32 (t, J = 7.2 Hz, 3H).
Step 2: Ethyl 4-amino-2-(3-fluorophenyl)-6-(oxetan-3-yloxy)pyrimidine-5-carboxylate
Figure imgf000101_0003
[00233] The title compound was prepared from ethyl 4-amino-6-chloro-2-(3- fluorophenyl)pyrimidine-5-carboxylate (step 1) and oxetan-3-ol analogously to Example 5 step 2.
LC-MS (Method 5B): Rt 3.33 mins; MS m/z 334.1 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 8.11 (br dt, J = 7.9, 1.2 Hz, 1H), 7.96 (ddd, J = 10.5, 2.8, 1.5 Hz, 1H), 7.90 (br s, 2H), 7.56 (td, J = 7.9, 5.9 Hz, 1H), 7.39 (td, J = 8.6, 2.8 Hz, 1H), 5.81– 5.72 (m, 1H), 4.97 (apr t, J = 7.0 Hz, 2H), 4.62 (dd, J = 7.6, 5.2 Hz, 2H), 4.29 (q, J = 7.1 Hz, 2H), 1.33 (t, J = 7.1 Hz, 3H). Step 3: 4-Amino-2-(3-fluorophenyl)-6-(oxetan-3-yloxy)pyrimidine-5-carboxylic acid
Figure imgf000102_0001
[00234] A solution of lithium hydroxide (18 mg, 0.76 mmol) in water (1 mL) was added to a solution of ethyl 4-amino-2-(3-fluorophenyl)-6-(oxetan-3-yloxy)pyrimidine-5-carboxylate (step 2) (90 mg, 0.27 mmol) in THF (2 mL) and the mixture was stirred vigorously at room temperature for 67 h. The reaction was quenched by addition of 2M aqueous HCl (0.5 mL) and the mixture was concentrated in vacuo to afford the title compound as a cream solid. LC-MS (Method 3A): Rt 1.60 mins; MS m/z 306.1 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 12.91 (br s, 1H), 8.11 (d, J = 7.9 Hz, 1H), 8.00 (br s, 2H), 7.99– 7.92 (m, 1H), 7.56 (td, J = 7.9, 5.8 Hz, 1H), 7.39 (td, J = 8.4, 2.8 Hz, 1H), 5.75 (p, J = 5.6 Hz, 1H), 4.95 (t, J = 6.9 Hz, 2H), 4.61 (dd, J = 7.5, 5.6 Hz, 2H)
Step 4: 4-Amino-2-(3-fluorophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-(oxetan-3-yloxy) pyrimidine-5-carboxamide
[00235] The title compound was prepared from 4-amino-2-(3-fluorophenyl)-6-(oxetan- 3-yloxy)pyrimidine-5-carboxylic acid (step 3) and 1-aminooxy-2-methyl-propan-2-ol (Intermediate C) analogously to Example 1 step 6.
LC-MS (Method 8B): Rt 3.63 mins; MS m/z 393.2 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 11.26 (br s, 1H), 8.12– 8.06 (m, 1H), 7.97– 7.92 (m, 1H), 7.81 (br s, 2H), 7.55 (td, J = 8.0, 5.9 Hz, 1H), 7.37 (td, J = 8.6, 2.7 Hz, 1H), 5.73 (apr p, J = 5.9 Hz, 1H), 4.93 (apr t, J = 7.0 Hz, 2H), 4.81 (br s, 1H), 4.72 (apr t, J = 6.5 Hz, 2H), 3.72 (s, 2H), 1.18 (s, 6H).
Example 5.3
4-Amino-2-(3-cyano-2-methyl-phenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-(oxetan-3- yloxy)pyrimidine-5-carboxamide Step 1: Ethyl 4-amino-6-c
Figure imgf000103_0003
hloro 2 (3 cyano 2 methyl phenyl)pyrimidine-5-carboxylate
Figure imgf000103_0001
[00236] The title compound was prepared from ethyl 4-amino-6-chloro-2- methylsulfanyl-pyrimidine-5-carboxylate (Example 1, step 2) and (3-cyano-2-methyl- phenyl)boronic acid analogously to Example 5 step 1.
LC-MS (Method 5B): Rt 3.24 mins; MS m/z 317.0 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 7.97 (dd, J = 7.8, 1.4 Hz, 1H), 7.92 (dd, J = 7.8, 1.4 Hz, 1H), 7.69 (br s, 2H), 7.51 (t, J = 7.8 Hz, 1H), 4.36 (q, J = 7.1 Hz, 2H), 2.65 (s, 3H), 1.32 (t, J = 7.1 Hz, 3H).
Step 2: Ethyl 4-amino-2-(3-cyano-2-methyl-phenyl)-6-(oxetan-3-yloxy)pyrimidine-5- carboxylate
Figure imgf000103_0002
[00237] The title compound was prepared from ethyl 4-amino-6-chloro-2-(3-cyano-2- methyl-phenyl)pyrimidine-5-carboxylate (step 1) and oxetan-3-ol analogously to Example 5 step 2.
LC-MS (Method 5B): Rt 3.05 mins; MS m/z 355.1 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 7.98 (dd, J = 7.9, 1.5 Hz, 1H), 7.93– 7.84 (m, 3H), 7.50 (t, J = 7.9 Hz, 1H), 5.62 (p, J = 5.5 Hz, 1H), 4.88 (t, J = 7.0 Hz, 2H), 4.59 (t, J = 7.0, 5.5 Hz, 2H), 4.30 (q, J = 7.1 Hz, 2H), 2.66 (s, 3H), 1.33 (t, J = 7.1 Hz, 3H).
Step 3: 4-Amino-2-(3-cyano-2-methyl-phenyl)-6-(oxetan-3-yloxy)pyrimidine-5-carboxylic acid
Figure imgf000104_0002
[00238] The title compound was prepared from ethyl 4-amino-2-(3-cyano-2-methyl- phenyl)-6-(oxetan-3-yloxy)pyrimidine-5-carboxylate (step 2) and lithium hydroxide analogously to Example 5.2 step 3.
LC-MS (Method 5A): Rt 2.12 mins; MS m/z 327.0 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 12.96 (br s, 1H), 7.98 (dd, J = 7.8, 1.4 Hz, 1H), 7.96 (br s, 2H), 7.89 (dd, J = 7.8, 1.4 Hz, 1H), 7.49 (t, J = 7.8 Hz, 1H), 5.61 (p, J = 5.6 Hz, 1H), 4.86 (d, J = 7.5 Hz, 2H), 4.58 (t, J = 7.5, 5.6 Hz, 2H), 2.66 (s, 3H).
Step 4: 4-Amino-2-(3-cyano-2-methyl-phenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-(oxetan-3- yloxy)pyrimidine-5-carboxamide
[00239] The title compound was prepared from 4-amino-2-(3-cyano-2-methyl-phenyl)- 6-(oxetan-3-yloxy)pyrimidine-5-carboxylic acid (step 3) and 1-aminooxy-2-methyl-propan-2-ol (Intermediate C) analogously to Example 1 step 6.
LC-MS (Method 8B): Rt 3.65 mins; MS m/z 414.3 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 11.30 (s, 1H), 7.96 (d, J = 7.8 Hz, 1H), 7.89 (dd, J = 7.8, 1.5 Hz, 1H), 7.78 (br s, 2H), 7.49 (t, J = 7.8 Hz, 1H), 5.60 (p, J = 5.7 Hz, 1H), 4.84 (t, J = 7.2 Hz, 2H), 4.76 (s, 1H), 4.68 (dd, J = 7.2, 5.7 Hz, 2H), 3.73 (s, 2H), 2.65 (s, 3H), 1.18 (s, 6H).
Example 5.4
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[rac-(1R,2R)-2- hydroxycyclopentoxy]pyrimidine-5-carboxamide
Figure imgf000104_0001
Step 1: 4-Amino-6-chloro-2-(3-cyanophenyl)pyrimidine-5-carboxylic acid [00240] To a stirred solu
Figure imgf000105_0002
y o-2-(3-cyanophenyl)pyrimidine-5- carboxylate (Example 5 step 1) (1 g, 3.3 mmol) in THF (24 mL) was added a solution of lithium hydroxide (158 mg, 6.61 mmol) in water (8 mL) dropwise and the mixture was stirred at room temperature for 16 h. The resulting mixture was concentrated in vacuo and the crude solid was partitioned between Et2O (30 mL) and water (20 mL). The layers were separated and the aqueous portion was acidified with 2M HCl. The resulting solid was collected by filtration and the solid was azeotroped from MeOH to afford the title compound as an off-white solid.
LC-MS (Method 3A): Rt 1.58 mins; MS m/z 275.0 / 277.0 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 13.93 (br s, 1H), 8.55 (d, J = 1.7 Hz, 1H), 8.53 (dt, J = 7.9, 1.7 Hz, 1H), 8.29 - 7.61 (br s, 2H), 8.03 (dt, J = 7.9, 1.7 Hz, 1H), 7.75 (t, J = 7.9 Hz, 1H).
Step 2: 4-Amino-2-(3-cyanophenyl)-6-[rac-(1R,2R)-2-hydroxycyclopentoxy]pyrimidine-5- carboxylic acid
Figure imgf000105_0001
[00241] The title compound was prepared from 4-amino-6-chloro-2-(3- cyanophenyl)pyrimidine-5-carboxylic acid (step 1) and trans-cyclopentane-1,2-diol analogously to Example 5 step 2.
LC-MS (Method 3A): Rt 1.63 mins; MS m/z 341.1 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 12.67 (br s, 1H), 8.66 (t, J = 1.6 Hz, 1H), 8.63 (dt, J = 7.9, 1.6 Hz, 1H), 8.02 (dt, J = 7.7, 1.6 Hz, 1H), 7.88 (br s, 2H), 7.75 (apr t, J = 7.8 Hz, 1H), 5.40 (dt, J = 5.2, 2.4 Hz, 1H), 4.94 (br s, 1H), 4.12 (dt, J = 5.8, 2.9 Hz, 1H), 2.23– 2.14 (m, 1H), 1.94– 1.85 (m, 1H), 1.80– 1.62 (m, 3H), 1.59– 1.52 (m, 1H)
Step 3: 4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[rac-(1R,2R)-2- hydroxycyclopentoxy]pyrimidine-5-carboxamide [00242] A solution of 1-aminooxy-2-methyl-propan-2-ol (Intermediate C) (55 mg, 0.52 mmol) in anhydrous DMF (0.5 mL) was added to a solution of 4-amino-2-(3-cyanophenyl)-6- [rac-(1R,2R)-2-hydroxycyclopentoxy]pyrimidine-5-carboxylic acid (step 2) (119 mg, 0.35 mmol) in anhydrous DMF (2.5 mL) under nitrogen followed by DIPEA (0.3 mL, 1.75 mmol). T3P® (50% in DMF) (0.49 mL, 0.70 mmol) was then added, and the reaction mixture stirred at room temperature for 2.5 h.
[00243] The resulting mixture was diluted with EtOAc (30 mL) and washed with 90% brine (30 mL) followed by 50% brine (3 x 30 mL). The organic portion was dried over Na2SO4 and concentrated in vacuo. Purification of the crude material by chromatography on silica eluting with 0 to 5% MeOH in DCM yielded a clear oil which was azeotroped from Et2O to afford the title compound as a colourless solid.
LC-MS (Method 8B): Rt 3.91 mins; MS m/z 428.3 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 10.96 (br s, 1H), 8.64 (t, J = 1.5 Hz, 1H), 8.61 (dt, J = 8.0, 1.5 Hz, 1H), 8.01 (dt, J = 7.8, 1.5 Hz, 1H), 7.74 (apr t, J = 7.9 Hz, 1H), 7.72 (br s, 2H), 5.38– 5.34 (m, 1H), 5.00 (br s, 1H), 4.77 (br s, 1H), 4.24– 4.18 (m, 1H), 3.69 (s, 2H), 2.27– 2.15 (m, 1H), 1.97– 1.86 (m, 1H), 1.80– 1.68 (m, 3H), 1.61– 1.51 (m, 1H), 1.16 (s, 6H)
Example 5.4a and 5.4b
[00244] Chiral separation of racemic 4-amino-2-(3-cyanophenyl)-N-(2-hydroxy-2- methyl-propoxy)-6-[rac-(1R,2R)-2-hydroxycyclopentoxy]pyrimidine-5-carboxamide (Example 5.4) using Supercritical Fluid Chromatography under the following conditions afforded the individual enantiomers:
Column: AmyC (20 mm x 250 mm, 5 µm)
Column Temperature: 40 ˚C
Flow Rate: 50 mL/min
BPR: 100 BarG
Detector Wavelength: 294 nm
Injection Volume: 500 µL (12.5 mg)
Isocratic Conditions: 30:70 EtOH:CO2 Example 5.4a: 4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1R,2R)- 2-hydroxycyclopentoxy]pyrimidine-5-carboxamide or 4-amino-2-(3-cyanophenyl)-N-(2- hydroxy-2-methyl-propoxy)-6-[(1S,2S)-2-hydroxycyclopentoxy]pyrimidine-5- carboxamide
Figure imgf000107_0001
Chiral SFC (Method CP1): First Eluted Peak Rt = 1.61 mins
LC-MS (Method 8B): Rt 3.79 mins; MS m/z 428.3 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 10.95 (br s, 1H), 8.64 (br t, J = 1.5 Hz, 1H), 8.61 (br dt, J = 8.0, 1.5 Hz, 1H), 8.01 (br dt, J = 7.7, 1.5 Hz, 1H), 7.74 (apr t, J = 7.8 Hz, 1H), 7.72 (br s, 2H), 5.39– 5.34 (m, 1H), 4.99 (br s, 1H), 4.76 (br s, 1H), 4.24– 4.17 (m, 1H), 3.69 (s, 2H), 2.25– 2.16 (m, 1H), 1.97– 1.86 (m, 1H), 1.79– 1.68 (m, 3H), 1.60– 1.53 (m, 1H), 1.16 (s, 6H)
Example 5.4b: 4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1R,2R)- 2-hydroxycyclopentoxy]pyrimidine-5-carboxamide or 4-amino-2-(3-cyanophenyl)-N-(2- hydroxy-2-methyl-propoxy)-6-[(1S,2S)-2-hydroxycyclopentoxy]pyrimidine-5- carboxamide
Figure imgf000107_0002
Chiral SFC (Method CP1): Second Eluted Peak Rt = 2.41 mins
LC-MS (Method 3B): Rt 3.71 mins; MS m/z 428.3 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 10.95 (br s, 1H), 8.64 (br t, J = 1.5 Hz, 1H), 8.61 (br dt, J = 8.0, 1.5 Hz, 1H), 8.01 (br dt, J = 7.7, 1.5 Hz, 1H), 7.74 (apr t, J = 7.8 Hz, 1H), 7.72 (br s, 2H), 5.39– 5.33 (m, 1H), 5.00 (br s, 1H), 4.76 (br s, 1H), 4.24– 4.17 (m, 1H), 3.69 (s, 2H), 2.24– 2.17 (m, 1H), 1.97– 1.86 (m, 1H), 1.79– 1.69 (m, 3H), 1.60– 1.53 (m, 1H), 1.16 (s, 6H) Example 5.5
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[rac-(1R,2S)-2- hydroxycyclopentoxy]pyrimidine-5-carboxamide
Figure imgf000108_0001
Step 1: 4-Amino-2-(3-cyanophenyl)-6-[rac-(1R,2S)-2-hydroxycyclopentoxy]pyrimidine-5- carboxylic acid
Figure imgf000108_0002
[00245] The title compound was prepared from 4-amino-6-chloro-2-(3- cyanophenyl)pyrimidine-5-carboxylic acid (Example 5.4 step 1) and cis-1,2-cyclopentanediol analogously to Example 5 step 2.
LC-MS (Method 3B): Rt 1.17 mins; MS m/z 341.1 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 12.35 (br s, 1H), 8.65– 8.61 (m, 1H), 8.59 (dt, J = 7.9, 1.5 Hz, 1H), 8.02 (dt, J = 7.7, 1.5 Hz, 1H), 7.97 (br s, 2H), 7.75 (apr t, J = 7.8 Hz, 1H), 5.49 (apr dt, J = 6.7, 4.6 Hz, 1H), 4.69 (br s, 1H), 4.21 (apr q, J = 5.9 Hz, 1H), 2.12– 2.04 (m, 1H), 1.91 – 1.75 (m, 3H), 1.70– 1.62 (m, 1H), 1.59– 1.50 (m, 1H).
Step 2: 4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[rac-(1R,2S)-2- hydroxycyclopentoxy]pyrimidine-5-carboxamide
[00246] The title compound was prepared from 4-amino-2-(3-cyanophenyl)-6-[rac- (1R,2S)-2-hydroxycyclopentoxy]pyrimidine-5-carboxylic acid (step 1) and 1-aminooxy-2- methyl-propan-2-ol (Intermediate C) analogously to Example 5.4 step 3.
LC-MS (Method 8B): Rt 3.94 mins; MS m/z 428.3 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 11.33 (br s, 1H), 8.61 (t, J = 1.6 Hz, 1H), 8.58 (dt, J = 7.9, 1.6 Hz, 1H), 8.01 (dt, J = 7.7, 1.6 Hz, 1H), 7.91 (br s, 2H), 7.74 (apr t, J = 7.8 Hz, 1H), 5.45 (br s, 1H), 5.43 (dt, J = 6.8, 4.8 Hz, 1H), 4.67 (s, 1H), 4.23 (apr q, J = 5.7 Hz, 1H), 3.69 (s, 2H), 2.20 – 2.13 (m, 1H), 1.96– 1.77 (m, 3H), 1.68 (ddt, J = 12.7, 8.8, 6.5 Hz, 1H), 1.60– 1.51 (m, 1H), 1.17 (s, 3H), 1.16 (s, 3H).
Example 5.5a and 5.5b
[00247] Chiral separation of racemic 4-amino-2-(3-cyanophenyl)-N-(2-hydroxy-2- methyl-propoxy)-6-[rac-(1R,2S)-2-hydroxycyclopentoxy]pyrimidine-5-carboxamide (Example 5.5) using Supercritical Fluid Chromatography under the following conditions afforded the individual enantiomers:
Column: Lux iC5 (21.2 mm x 250 mm, 5 µm)
Column Temperature: 40 ˚C
Flow Rate: 50 mL/min
BPR: 125 BarG
Detector Wavelength: 210 nm
Injection Volume: 1000 µL (20 mg)
Isocratic Conditions: 50:50 MeOH:CO2
Example 5.5a: 4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1R,2S)- 2-hydroxycyclopentoxy]pyrimidine-5-carboxamide or 4-amino-2-(3-cyanophenyl)-N-(2- hydroxy-2-methyl-propoxy)-6-[(1S,2R)-2-hydroxycyclopentoxy]pyrimidine-5- carboxamide
Figure imgf000109_0001
Chiral SFC (Method CP2): First Eluted Peak Rt = 1.53 mins
LC-MS (Method 8B): Rt 4.35 mins; MS m/z 428.3 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 11.33 (br s, 1H), 8.61 (br t, J = 1.5 Hz, 1H), 8.58 (br dt, J = 7.9, 1.5 Hz, 1H), 8.01 (br dt, J = 7.7, 1.5 Hz, 1H), 7.89 (br s, 2H), 7.74 (apr t, J = 7.8 Hz, 1H), 5.46 (br s, 1H), 5.43 (dt, J = 6.8, 4.8 Hz, 1H), 4.67 (s, 1H), 4.23 (apr q, J = 5.7 Hz, 1H), 3.69 (s, 2H), 2.20– 2.13 (m, 1H), 1.96– 1.77 (m, 3H), 1.72– 1.64 (m, 1H), 1.60– 1.51 (m, 1H), 1.17 (s, 3H), 1.16 (s, 3H)
Example 5.5b: 4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1R,2S)- 2-hydroxycyclopentoxy]pyrimidine-5-carboxamide or 4-amino-2-(3-cyanophenyl)-N-(2- hydroxy-2-methyl-propoxy)-6-[(1S,2R)-2-hydroxycyclopentoxy]pyrimidine-5- carboxamide
Figure imgf000110_0001
Chiral SFC (Method CP2): Second Eluted Peak Rt = 2.28 mins
LC-MS (Method 8B): Rt 4.28 mins; MS m/z 428.3 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 11.33 (br s, 1H), 8.61 (br t, J = 1.5 Hz, 1H), 8.58 (br dt, J = 8.0, 1.5 Hz, 1H), 8.01 (br dt, J = 7.7, 1.5 Hz, 1H), 7.88 (br s, 2H), 7.74 (apr t, J = 7.8 Hz, 1H), 5.46 (br s, 1H), 5.43 (dt, J = 6.8, 4.8 Hz, 1H), 4.67 (s, 1H), 4.23 (apr q, J = 5.8 Hz, 1H), 3.69 (s, 2H), 2.20– 2.13 (m, 1H), 1.96– 1.77 (m, 3H), 1.72– 1.64 (m, 1H), 1.60– 1.52 (m, 1H), 1.17 (s, 3H), 1.16 (s, 3H)
Example 5.6
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(3R)-2-oxopyrrolidin-3- yl]oxy-pyrimidine-5-carboxamide
Figure imgf000110_0002
Step 1: 4-Amino-2-(3-cyanophenyl)-6-[(3R)-2-oxopyrrolidin-3-yl]oxy-pyrimidine-5-carboxylic acid [00248] The title compound was prepared from 4-amino-6-chloro-2-(3- cyanophenyl)pyrimidine-5-carboxylic acid (Example 5.4 step 1) and (3R)-3-hydroxypyrrolidin- 2-one analogously to Example 5 step 2.
LC-MS (Method 3A): Rt 1.37 / 1.38 mins; MS m/z 340.1 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 12.80 (br s, 1H), 8.68– 8.63 (m, 1H), 8.61 (dt, J = 8.0, 1.1 Hz, 1H), 8.08 (s, 1H), 8.02 (dt, J = 7.7, 1.1 Hz, 1H), 7.95 (br s, 2H), 7.74 (apr t, J = 7.8 Hz, 1H), 5.92 (t, J = 8.3 Hz, 1H), 3.33– 3.27 (m, 2H), 2.63 (ddt, J = 12.9, 8.8, 4.8 Hz, 1H), 2.08 (dq, J = 13.0, 8.4 Hz, 1H).
Step 2: 4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(3R)-2-oxopyrrolidin- 3-yl]oxy-pyrimidine-5-carboxamide
[00249] The title compound was prepared from 4-amino-2-(3-cyanophenyl)-6-[(3R)-2- oxopyrrolidin-3-yl]oxy-pyrimidine-5-carboxylic acid (step 1) and 1-aminooxy-2-methyl-propan- 2-ol (Intermediate C) analogously to Example 5.4 step 3.
LC-MS (Method 8B): Rt 2.92 mins; MS m/z 427.3 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 11.16 (br s, 1H), 8.64 (br t, J = 1.5 Hz, 1H), 8.59 (br dt, J = 8.1, 1.5 Hz, 1H), 8.24 (s, 1H), 8.02 (br dt, J = 7.8, 1.5 Hz, 1H), 7.93 (br s, 2H), 7.74 (apr t, J = 7.8 Hz, 1H), 5.79 (t, J = 8.7 Hz, 1H), 4.68 (br s, 1H), 3.70 (s, 2H), 3.38– 3.32 (m, 2H), 2.72 (ddt, J = 12.5, 8.2, 3.8 Hz, 1H), 2.20 (dq, J = 12.5, 9.0 Hz, 1H), 1.16 (s, 6H).
Example 5.7
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(3S)-2-oxopyrrolidin-3- yl]oxy-pyrimidine-5-carboxamide
Figure imgf000111_0001
Step 1: 4-Amino-2-(3-cyanophenyl)-6-[(3S)-2-oxopyrrolidin-3-yl]oxy-pyrimidine-5-carboxylic acid
Figure imgf000112_0001
[00250] The title compound was prepared from 4-amino-6-chloro-2-(3- cyanophenyl)pyrimidine-5-carboxylic acid (Example 5.4 step 1) and (3S)-3-hydroxypyrrolidin- 2-one analogously to Example 5 step 2.
LC-MS (Method 3A): Rt 1.36 / 1.39 mins; MS m/z 340.1 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 12.79 (br s, 1H), 8.66 (t, J = 1.5 Hz, 1H), 8.61 (dt, J = 8.0, 1.5 Hz, 1H), 8.08 (s, 1H), 8.02 (dt, J = 7.7, 1.5 Hz, 1H), 7.95 (br s, 2H), 7.74 (apr t, J = 7.8 Hz, 1H), 5.92 (t, J = 8.3 Hz, 1H), 3.32– 3.29 (m, 2H), 2.63 (ddt, J = 12.7, 9.2, 4.6 Hz, 1H), 2.08 (dq, J = 12.9, 8.4 Hz, 1H).
Step 2: 4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(3S)-2-oxopyrrolidin- 3-yl]oxy-pyrimidine-5-carboxamide
[00251] The title compound was prepared from 4-amino-2-(3-cyanophenyl)-6-[(3S)-2- oxopyrrolidin-3-yl]oxy-pyrimidine-5-carboxylic acid (step 1) and 1-aminooxy-2-methyl-propan- 2-ol (Intermediate C) analogously to Example 5.4 step 3.
LC-MS (Method 8B): Rt 3.37 mins; MS m/z 427.3 = [M+H]+ 1H NMR (500 MHz, DMSO-d6) d 11.14 (br s, 1H), 8.64 (t, J = 1.5 Hz, 1H), 8.59 (dt, J = 8.0, 1.5 Hz, 1H), 8.24 (s, 1H), 8.02 (dt, J = 7.8, 1.5 Hz, 1H), 7.93 (br s, 2H), 7.74 (apr t, J = 7.8 Hz, 1H), 5.79 (t, J = 8.7 Hz, 1H), 4.68 (br s, 1H), 3.70 (s, 2H), 3.38– 3.32 (m, 2H), 2.72 (ddd, J = 16.8, 8.4, 4.2 Hz, 1H), 2.20 (dq, J = 12.5, 8.9 Hz, 1H), 1.16 (s, 6H).
Example 5.8
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[rac-(3R,4R)-4- hydroxytetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxamide
Figure imgf000113_0002
Step 1: 4-Amino-2-(3-cyanophenyl)-6-[rac-(3R,4R)-4-hydroxytetrahydrofuran-3-yl]oxy- pyrimidine-5-carboxylic acid
Figure imgf000113_0001
[00252] The title compound was prepared from 4-amino-6-chloro-2-(3- cyanophenyl)pyrimidine-5-carboxylic acid (Example 5.4 step 1) and trans-tetrahydrofuran-3,4- diol analogously to Example 5 step 2.
LC-MS (Method 5A): Rt 1.95 mins; MS m/z 343.2 = [M+H]+
1H NMR (500 MHz, Methanol-d4) d 8.75 (s, 1H), 8.72 (d, J = 8.0 Hz, 1H), 7.88 (d, J = 7.7 Hz, 1H), 7.68 (t, J = 7.8 Hz, 1H), 5.70– 5.62 (m, 1H), 4.49 (dd, J = 3.7, 1.8 Hz, 1H), 4.35 (dd, J = 10.4, 4.5 Hz, 1H), 4.08 (dd, J = 9.5, 4.5 Hz, 1H), 3.96 (dd, J = 10.4, 1.6 Hz, 1H), 3.83 (dd, J = 9.5, 1.6 Hz, 1H).4 x exchangeable protons not observed.
Step 2: 4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[rac-(3R,4R)-4- hydroxytetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxamide
[00253] The title compound was prepared from 4-amino-2-(3-cyanophenyl)-6-[rac- (3R,4R)-4-hydroxytetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxylic acid (step 1) and 1- aminooxy-2-methyl-propan-2-ol (Intermediate C) analogously to Example 5.4 step 3.
LC-MS (Method 8B): Rt 2.76 mins; MS m/z 430.3 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 11.03 (s, 1H), 8.66 (s, 1H), 8.62 (d, J = 8.1 Hz, 1H), 8.02 (d, J = 7.6 Hz, 1H), 7.75 (t, J = 7.9 Hz, 1H), 7.68 (s, 2H), 5.50 (d, J = 4.2 Hz, 1H), 5.48 (d, J = 3.9 Hz, 1H), 4.73 (s, 1H), 4.41 (s, 1H), 4.19 (dd, J = 10.5, 4.5 Hz, 1H), 3.94 (dd, J = 9.4, 4.3 Hz, 1H), 3.86 (d, J = 10.5 Hz, 1H), 3.70 (s, 2H), 3.65 (dd, J = 9.4, 2.0 Hz, 1H), 1.17 (s, 6H).
Example 5.8a and 5.8b [00254] Chiral separation of racemic 4-amino-2-(3-cyanophenyl)-N-(2-hydroxy-2- methyl-propoxy)-6-[rac-(3R,4R)-4-hydroxytetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxamide (Example 5.8) using Supercritical Fluid Chromatography under the following conditions afforded the individual enantiomers:
Column: Lux C3 (21.2 mm x 250 mm, 5 µm)
Column Temperature: 40 ˚C
Flow Rate: 50 mL/min
BPR: 125 BarG
Detector Wavelength: 221 nm
Injection Volume: 1000 µL (10 mg)
Isocratic Conditions: 30:70 MeOH:CO2
Example 5.8a: 4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(3R,4R)- 4-hydroxytetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxamide or 4-amino-2-(3- cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(3S,4S)-4-hydroxytetrahydrofuran-3- yl]oxy-pyrimidine-5-carboxamide
Figure imgf000114_0001
Chiral SFC (Method CP3): First Eluted Peak Rt = 1.13 mins
LC-MS (Method 8B): Rt 2.83 mins; MS m/z 430.3 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 11.02 (s, 1H), 8.65 (t, J = 1.7 Hz, 1H), 8.61 (dt, J = 7.8, 1.7 Hz, 1H), 8.01 (dt, J = 7.8, 1.7 Hz, 1H), 7.74 (t, J = 7.8 Hz, 1H), 7.67 (s, 2H), 5.49 (d, J = 4.4 Hz, 1H), 5.47 (s, 1H), 4.75 (s, 1H), 4.40 (s, 1H), 4.18 (dd, J = 10.5, 4.4 Hz, 1H), 3.94 (dd, J = 9.5, 4.4 Hz, 1H), 3.85 (d, J = 9.5 Hz, 1H), 3.69 (s, 2H), 3.64 (dd, J = 9.5, 2.0 Hz, 1H), 1.16 (s, 6H). Example 5.8b: 4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(3R,4R)- 4-hydroxytetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxamide or 4-amino-2-(3- cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(3S,4S)-4-hydroxytetrahydrofuran-3- yl]oxy-pyrimidine-5-carboxamide
Figure imgf000115_0001
Chiral SFC (Method CP3): Second Eluted Peak Rt = 1.60 mins
LC-MS (Method 8B): Rt 2.61 mins; MS m/z 430.3 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 11.02 (s, 1H), 8.65 (t,J= 1.5 Hz, 1H), 8.61 (dt,J= 7.8, 1.5 Hz, 1H), 8.01 (dt,J= 7.8, 1.5 Hz, 1H), 7.74 (t,J= 7.8 Hz, 1H), 7.67 (s, 2H), 5.50– 5.48 (m, 1H), 5.48 – 5.45 (m, 1H), 4.76 (s, 1H), 4.40 (s, 1H), 4.18 (dd,J= 10.4, 4.4 Hz, 1H), 3.94 (dd,J= 9.4, 4.4 Hz, 1H), 3.88– 3.82 (m, 1H), 3.69 (s, 2H), 3.64 (dd,J= 9.4, 2.0 Hz, 1H), 1.16 (s, 6H).
Example 5.9
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[rac-(3R,4S)-4- hydroxytetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxamide
Figure imgf000115_0002
Step 1: 4-Amino-2-(3-cyanophenyl)-6-[rac-(3R,4S)-4-hydroxytetrahydrofuran-3-yl]oxy- pyrimidine-5-carboxylic acid
Figure imgf000115_0003
[00255] The title compound was prepared from 4-amino-6-chloro-2-(3- cyanophenyl)pyrimidine-5-carboxylic acid (Example 5.4 step 1) and cis-tetrahydrofuran-3,4- diol analogously to Example 5 step 2.
LC-MS (Method 5A): Rt 1.98 mins; MS m/z 343.2 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 12.61 (br s, 1H), 8.66 (d, J = 1.8 Hz, 1H), 8.61 (dt, J = 7.8, 1.6 Hz, 1H), 8.03 (dt, J = 7.8, 1.5 Hz, 1H), 8.01 (br s, 2H), 7.75 (t, J = 7.8 Hz, 1H), 5.70 (q, J = 5.2 Hz, 1H), 5.07 (br s, 1H), 4.48 (q, J = 5.6 Hz, 1H), 4.16 (dd, J = 9.8, 5.8 Hz, 1H), 3.94 (dd, J = 8.8, 5.8 Hz, 1H), 3.84 (dd, J = 9.8, 4.3 Hz, 1H), 3.59 (dd, J = 8.8, 5.6 Hz, 1H).
Step 2: 4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[rac-(3R,4S)-4- hydroxytetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxamide
[00256] The title compound was prepared from 4-amino-2-(3-cyanophenyl)-6-[rac- (3R,4S)-4-hydroxytetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxylic acid (step 1) and 1- aminooxy-2-methyl-propan-2-ol (Intermediate C) analogously to Example 5.4 step 3.
LC-MS (Method 8B): Rt 3.61 mins; MS m/z 430.3 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 11.25 (br s, 1H), 8.63 (t, J = 1.6 Hz, 1H), 8.58 (dt, J = 7.8, 1.6 Hz, 1H), 8.40 (s, 1H), 8.01 (dt, J = 7.8, 1.6 Hz, 1H), 7.90 (s, 1H), 7.74 (t, J = 7.8 Hz, 1H), 5.90 (s, 1H), 5.61 (dt, J = 5.8, 3.9 Hz, 1H), 4.68 (s, 1H), 4.48 (q, J = 5.8 Hz, 1H), 4.22 (dd, J = 10.2, 5.8 Hz, 1H), 3.96 (dd, J = 9.0, 5.8 Hz, 1H), 3.88 (dd, J = 10.2, 3.9 Hz, 1H), 3.69 (s, 2H), 3.61 (dd, J = 9.0, 5.8 Hz, 1H), 1.16 (d, J = 2.9 Hz, 6H).
Example 5.10
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1-methyl-6-oxo-3- piperidyl)oxy]pyrimidine-5-carboxamide
Figure imgf000116_0001
Step 1: 4-Amino-2-(3-cyanophenyl)-6-[(1-methyl-6-oxo-3-piperidyl)oxy]pyrimidine-5- carboxylic acid [00257] The title
Figure imgf000117_0001
compound was prepared from 4-amino-6-chloro-2-(3- cyanophenyl)pyrimidine-5-carboxylic acid (Example 5.4 step 1) and 5-hydroxy-1-methyl- piperidin-2-one analogously to Example 5 step 2.
LC-MS (Method 5A): Rt 2.08 mins; MS m/z 368.2 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 12.81 (s, 1H), 8.66 (t, J = 1.7 Hz, 1H), 8.61 (d, J = 7.8 Hz, 1H), 8.02 (dd, J = 7.8, 1.6 Hz, 1H), 7.93 (s, 2H), 7.75 (t, J = 7.8 Hz, 1H), 5.85– 5.79 (m, 1H), 3.74 (dd, J = 13.5, 3.9 Hz, 1H), 3.53– 3.46 (m, 1H), 2.81 (s, 3H), 2.53 (s, 1H), 2.26 (dt, J = 16.6, 4.7 Hz, 1H), 2.13– 2.07 (m, 2H).
Step 2: 4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1-methyl-6-oxo-3- piperidyl)oxy]pyrimidine-5-carboxamide
[00258] The title compound was prepared from 4-amino-2-(3-cyanophenyl)-6-[(1- methyl-6-oxo-3-piperidyl)oxy]pyrimidine-5-carboxylic acid (step 1) and 1-aminooxy-2-methyl- propan-2-ol (Intermediate C) analogously to Example 5.4 step 3.
LC-MS (Method 15B): Rt 5.27 mins; MS m/z 455.2 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 11.04 (br s, 1H), 8.63 (t, J = 1.7 Hz, 1H), 8.59 (dt, J = 7.9, 1.4 Hz, 1H), 8.01 (dt, J = 7.9, 1.4 Hz, 1H), 7.74 (t, J = 7.9 Hz, 1H), 7.65 (br s, 2H), 5.76 (dt, J = 7.1, 3.4 Hz, 1H), 4.70 (br s, 1H), 3.74 (dd, J = 13.3, 4.1 Hz, 1H), 3.65 (s, 2H), 3.54 (ddd, J = 13.6, 3.8, 1.6 Hz, 1H), 2.83 (s, 3H), 2.45– 2.37 (m, 1H), 2.30 (dt, J = 17.3, 5.4 Hz, 1H), 2.23 – 2.08 (m, 2H), 1.15 (s, 6H).
Example 6
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methylpropoxy)-6-[(1r,3r)-3- aminocyclobutoxy]pyrimidine-5-carboxamide
Figure imgf000118_0001
Step 1: Ethyl 4-amino-2-(3-cyanophenyl)-6-[(1r,3r)-3-{[(tert- butoxy)carbonyl]amino}cyclobutoxy] pyrimidine-5-carboxylate
Figure imgf000118_0002
[00259] To a cooled (0 °C ) solution of sodium hydride (60% in oil) (111 mg, 2.76 mmol) in THF (5 mL) under nitrogen was added tert-butyl N-[(1r,3r)-3-hydroxycyclobutyl]carbamate (518 mg, 2.76 mmol) and the mixture was allowed to warm to room temperature and stirred for 10 mins. The resulting solution was cooled to 0 °C and treated slowly with a solution of ethyl 4-amino-6-chloro-2-(3-cyanophenyl)pyrimidine-5-carboxylate (Example 5 step 1) (300 mg, 0.92 mmol) in THF (10 mL). After warming to room temperature, the mixture was stirred for 1 h and diluted further with THF (10 mL). Stirring continued for 2 h and the reaction was quenched by slow addition of water until effervescence was no longer observed. The mixture was diluted with water (30 mL) and the resulting precipitate was collected under vacuum filtration. Purification by chromatography on silica eluting with 0-100% EtOAc in heptane afforded the title compound as a colourless powder.
LC-MS (Method 2A): Rt 1.31 mins; MS m/z 454.2 = [M+H]+
1H NMR (400 MHz, Chloroform-d) d 8.63 (s, 1H), 8.56 (d, J = 7.8 Hz, 1H), 7.75 (ddd, J = 7.8, 1.4 Hz, 1H), 7.56 (t, J = 7.8 Hz, 1H), 5.58– 5.47 (m, 1H), 4.83 (br. s, 2H), 4.45– 4.29 (m, 3H), 2.55– 2.36 (m, 4H), 1.54 (s, 9H), 1.43 (t, J = 7.1 Hz, 3H).
Step 2: 4-Amino-2-(3-cyanophenyl)-6-[(1r,3r)-3-{[(tert-butoxy)carbonyl]amino}cyclobutoxy] pyrimidine-5-carboxylic acid [00260] The title compoun
Figure imgf000119_0002
d was prepared from ethyl 4-amino-2-(3-cyanophenyl)-6- [(1r,3r)-3-{[(tert-butoxy)carbonyl]amino}cyclobutoxy]pyrimidine-5-carboxylate (step 1) and lithium hydroxide monohydate analogously to Example 1 step 5.
LC-MS (Method 2A): Rt 1.17 mins; MS m/z 426.3 = [M+H]+, 448.2 = [M+Na]+
1H NMR (400 MHz, DMSO-d6) d 8.60– 8.54 (m, 2H), 8.05 (br. s, 2H), 7.97 (dt, J = 7.7, 1.3 Hz, 1H), 7.76– 7.67 (m, 1H), 7.41– 7.34 (m, 1H), 5.48– 5.37 (m, 1H), 4.11– 4.02 (m, 1H), 2.44 – 2.35 (m, 4H), 1.40 (s, 9H).
Step 3: tert-Butyl N-[(1r,3r)-3-{[6-amino-2-(3-cyanophenyl)-5-[(2-hydroxy-2-methylpropoxy) carbamoyl]pyrimidin-4-yl]oxy}cyclobutyl]carbamate
Figure imgf000119_0001
[00261] The title compound was prepared from 4-Amino-2-(3-cyanophenyl)-6-[(1r,3r)- 3-{[(tert-butoxy)carbonyl]amino}cyclobutoxy] pyrimidine-5-carboxylic acid (step 2) and 1- aminooxy-2-methyl-propan-2-ol (Intermediate C) analogously to Example 1 step 6.
LC-MS (Method 2A): Rt 1.17 mins; MS m/z 513.4 = [M+H]+, 535.4 = [M+Na]+
1H NMR (400 MHz, Chloroform-d) d 10.77 (s, 1H), 9.11 (s, 1H), 8.60 (t, J = 1.4 Hz, 1H), 8.55 (dd, J = 7.9, 1.4 Hz, 1H), 7.78– 7.71 (dd, J = 7.9, 1.4 Hz, 1H), 7.55 (t, J = 7.9 Hz, 1H), 5.63 - 5.56 (m, 1H), 4.87 (s, 1H), 4.55 (s, 1H), 3.71 (s, 2H), 2.72– 2.65 (m, 2H), 2.46 (s, 2H), 1.47 (s, 6H), 1.31 (s, 3H), 1.22 (s, 6H).
Step 4: 4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methylpropoxy)-6-[(1r,3r)-3-aminocyclo butoxy]pyrimidine-5-carboxamide [00262] To a solution of tert-butyl N-[(1r,3r)-3-{[6-amino-2-(3-cyanophenyl)-5-[(2- hydroxy-2-methylpropoxy)carbamoyl]pyrimidin-4-yl]oxy}cyclobutyl]carbamate (step 3) (83 mg, 0.11 mmol) in DCM (2 mL) was added 4M HCl in 1,4-dioxane (0.28 mL, 1.13 mmol) and the mixture was stirred at room temperature for 40 h. The resulting mixture was concentrated in vacuo and purification by C18 reverse phase chromatography eluting with 0.1% formic acid in MeCN/water followed by purification by C18 reverse phase chromatography eluting 0.1% NH3 in MeCN/water afforded the title compound as an off-white powder.
LC-MS (Method 7B): Rt 2.15 mins; MS m/z 413.3 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 8.60– 8.54 (m, 2H), 8.01 (dt, J = 7.7, 1.3 Hz, 1H), 7.77 (br. s, 2H), 7.75 (t, J = 7.9 Hz, 1H), 5.55 (p, J = 6.2 Hz, 1H), 4.76 (s, 1H), 3.71 (s, 2H), 3.68– 3.59 (m, 1H), 2.46– 2.40 (m, 2H), 2.27– 2.17 (m, 2H),1.18 (s, 6H).
Example 6.1
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methylpropoxy)-6-[(1s,3s)-3-aminocyclo butoxy]pyrimidine-5-carboxamide;hydrochloride
Figure imgf000120_0001
[00263] The title compound was prepared from ethyl 4-amino-6-chloro-2-(3- cyanophenyl)pyrimidine-5-carboxylate (Example 5 step 1) and tert-butyl N-[(1s,3s)-3- hydroxycyclobutyl]carbamate analogously to Example 6 steps 1-4. Purification in step 4 was carried out by trituration of the crude material with DCM to afford the title compound as a hydrochloride salt.
LC-MS (Method 7B): Rt 2.21 mins; MS m/z 413.3 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 11.18 (s, 1H), 8.60 (d, J = 1.3 Hz, 1H), 8.60– 8.55 (m, 1H), 8.21 (s, 3H), 8.03 (d, J = 7.8 Hz, 1H), 7.76 (t, J = 7.8 Hz, 3H), 5.20 (p, J = 7.4 Hz, 1H), 3.74 (s, 2H), 3.54 (s, 1H), 2.95– 2.80 (m, 2H), 2.44 (s, 2H), 1.20 (s, 6H). Example 6.2
4-(2-Acetamidoethoxy)-6-amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy) pyrimidine-5-carboxamide
Figure imgf000121_0001
Step 1: Ethyl 4-(2-acetamidoethoxy)-6-amino-2-(3-cyanophenyl)pyrimidine-5-carboxylate
Figure imgf000121_0002
[00264] The title compound was prepared from ethyl 4-amino-6-chloro-2-(3- cyanophenyl)pyrimidine-5-carboxylate (Example 5 step 1) and N-(2-hydroxyethyl)acetamide analogously to Example 6 step 1.
LC-MS (Method 2B): Rt 1.09 mins; MS m/z 370.1 = [M+H]+
1H NMR (400 MHz, Chloroform-d) d 8.61 (t, J = 1.5 Hz, 1H), 8.53 (dt, J = 8.0, 1.4 Hz, 1H), 7.69 (dt, J = 7.7, 1.4 Hz, 1H), 7.50 (t, J = 7.8 Hz, 1H), 5.97 (s, 1H), 4.60– 4.42 (m, 2H), 4.32 (q, J = 7.1 Hz, 2H), 3.67 (q, J = 5.5 Hz, 2H),, 1.94 (s, 3H), 1.36 (t, J = 7.1 Hz, 3H).
Step 2: 4-(2-Acetamidoethoxy)-6-amino-2-(3-cyanophenyl)pyrimidine-5-carboxylic acid
Figure imgf000121_0003
[00265] The title compound was prepared from ethyl 4-(2-acetamidoethoxy)-6-amino- 2-(3-cyanophenyl)pyrimidine-5-carboxylate (step 1) and lithium hydroxide monohydrate analogously to Example 1 step 5.
LC-MS (Method 2B) Rt 0.93 mins; MS m/z 363.9 = [M+Na]+
1H NMR (500 MHz, DMSO-d6) d 12.70 (s, 1H), 8.66 (t, J = 1.4 Hz, 1H), 8.62 (dt, J = 7.8, 1.4 Hz, 1H), 8.02 (dt, J = 7.8, 1.4 Hz, 1H), 7.99 (t, J = 5.8 Hz, 1H), 7.92 (br. s, 2H), 7.74 (t, J = 7.8 Hz, 1H), 4.52 (t, J = 6.0 Hz, 2H), 3.45 (apr q, J = 6.0 Hz, 2H), 1.79 (s, 3H).
Step 3: 4-(2-Acetamidoethoxy)-6-amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy) pyrimidine-5-carboxamide
[00266] The title compound was prepared from 4-(2-acetamidoethoxy)-6-amino-2-(3- cyanophenyl)pyrimidine-5-carboxylic acid and 1-aminooxy-2-methyl-propan-2-ol (Intermediate C) analogously to Example 6 step 3.
LC-MS (Method 7A): Rt = 2.39 min; m/z = 429.3 [M+H]+
1H NMR (400 MHz, DMSO-d6) d 11.07 (s, 1H), 8.65 (t, J = 1.4 Hz, 1H), 8.61 (dt, J = 7.7, 1.4 Hz, 1H), 8.15 (t, J = 5.7 Hz, 1H), 8.05 (br. s, 1H), 8.02 (dt, J = 7.7, 1.4 Hz, 2H), 7.74 (t, J = 7.7 Hz, 1H), 4.78 (s, 1H), 4.56 (t, J = 5.4 Hz, 2H), 3.74 (s, 2H), 3.53 (apr q, J = 5.6 Hz, 2H), 1.84 (s, 3H), 1.18 (s, 6H).
Example 7
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-methoxy-pyrimidine-5- carboxamide
Figure imgf000122_0001
[00267] Step 1: 4-Amino-2-(3-cyanophenyl)-6-methoxy-pyrimidine-5-carboxylic acid
Figure imgf000122_0002
[00268] To a stirred solution of sodium hydride (60% in oil) (15.86 mg, 0.40 mmol) in MeOH (0.01 mL, 0.36 mmol) under nitrogen was added ethyl 4-amino-6-chloro-2-(3- cyanophenyl)pyrimidine-5-carboxylate (Example 5 step 1) (100 mg, 0.33 mmol) in THF (2 mL) and the mixture was stirred at room temperature. After 30 mins, the mixture was treated with 2M lithium hydroxide (0.33 mL, 0.66 mmol) and stirring continued for 17 h. Additional 2M lithium hydroxide (0.33 mL, 0.66 mmol) was added and stirring continued for a total of 66 h. The resulting mixture was diluted with EtOAc (3 mL) and extracted with water (3 x 2 mL). The aqueous layer was neutralised with 1M HCl and the resulting precipitate was collected by filtration to afford the title compound as a colourless solid.
LC-MS (Method 7A): Rt 2.61 mins; MS m/z 271.1 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 12.80 (s, 1H), 8.66 (s, 1H), 8.63 (d, J = 7.8 Hz, 1H), 8.02 (d, J = 7.8 Hz, 1H), 7.91 (s, 2H), 7.75 (t, J = 7.8 Hz, 1H), 4.05 (s, 3H).
Step 2: 4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-methoxy-pyrimidine- 5-carboxamide
[00269] The title compound was prepared from 4-amino-2-(3-cyanophenyl)-6-methoxy- pyrimidine-5-carboxylic acid (step 1) and 1-aminooxy-2-methyl-propan-2-ol (Intermediate C) analogously to Example 1 step 6.
LC-MS (Method 7B): Rt 2.60 mins; MS m/z 358.2 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 11.27 (s, 1H), 8.64 (d, J = 1.6 Hz, 1H), 8.60 (dt, J = 8.0, 1.3 Hz, 1H), 8.04– 7.99 (m, 1H), 7.92 (s, 2H), 7.74 (t, J = 7.8 Hz, 1H), 4.78 (s, 1H), 4.07 (s, 3H), 3.70 (s, 2H), 1.17 (s, 6H).
Example 8
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-(oxetan-3-yloxy) pyrimidine-5-carboxamide
Figure imgf000123_0001
Step 1: Ethyl 4-amino-2-(3-cyanophenyl)-6-(oxetan-3-yloxy)pyrimidine-5-carboxylate
Figure imgf000124_0002
[00270] A solution of ethyl 4-amino-6-chloro-2-(3-cyanophenyl)pyrimidine-5- carboxylate (Example 5 step 1) (200 mg, 0.65 mmol), oxetan-3-ol (72 mg, 0.97 mmol) and 1M potassium t-butoxide in THF (0.65 mL, 0.65 mmol) in 1,4-dioxane (2.5 mL) was stirred at room temperature for 18 h. Further portions of oxetan-3-ol (72 mg, 0.97 mmol) and 1M potassium t-butoxide in THF (0.65 mL, 0.65 mmol) were added and stirring continued for 2 h. The resulting mixture was diluted with water (5 mL) and the precipitate collected under vacuum filtration to afford the title compound.
LC-MS (Method 2A): Rt 1.14 mins; MS m/z 340.9 = [M+H]+
1H NMR (400 MHz, DMSO-d6) d 8.59 (t, J = 1.4 Hz, 1H), 8.54 (dt, J = 7.8, 1.4 Hz, 1H), 8.02 (dt, J = 7.8, 1.4 Hz, 1H), 7.92 (s, 2H), 7.74 (t, J = 7.8 Hz, 1H), 5.80 (q, J = 6.2 Hz, 1H), 5.02– 4.95 (m, 2H), 4.62 (dd, J = 8.0, 5.3 Hz, 2H), 4.30 (q, J = 7.1 Hz, 2H), 1.33 (t, J = 7.1 Hz, 3H).
Step 2: 4-Amino-2-(3-cyanophenyl)-6-(oxetan-3-yloxy)pyrimidine-5-carboxylic acid
Figure imgf000124_0001
[00271] A solution of ethyl 4-amino-2-(3-cyanophenyl)-6-(oxetan-3-yloxy)pyrimidine-5- carboxylate (step 1) (207 mg, 0.55 mmol) and lithium hydroxide monohydrate (46 mg, 1.09 mmol) in THF (5 mL) and water (2 mL) was stirred vigorously at room temperature for 48 h. The resulting mixture was diluted with water (10 mL) and washed with diethyl ether (2 x 10 mL). The aqueous portion was acidified using 1M HCl and the give a precipitate which was collected under vacuum filtration to afford the title compound.
LC-MS (Method 2A): Rt 1.03 mins; MS m/z 312.9 = [M+H]+
1H NMR (400 MHz, DMSO-d6) d 12.95 (s, 1H), 8.58 (t, J = 1.4 Hz, 1H), 8.54 (dt, J = 7.8, 1.4 Hz, 1H), 8.01 (dt, J = 7.8, 1.4 Hz, 3H), 7.73 (t, J = 7.8 Hz, 1H), 5.79 (p, J = 5.8 Hz, 1H), 4.97 (t, J = 7.1 Hz, 2H), 4.66-4.58 (dd, J = 7.8, 5.4 Hz, 2H). Step 3: 4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-(oxetan-3- yloxy)pyrimidine-5-carboxamide
[00272] To a solution of 4-amino-2-(3-cyanophenyl)-6-(oxetan-3-yloxy)pyrimidine-5- carboxylic acid (step 2) (58 mg, 0.17 mmol), 1-aminooxy-2-methyl-propan-2-ol (Intermediate C) (22 mg, 0.21 mmol) and DIPEA (0.09 mL, 0.51 mmol) in DMF (2 mL) was added HATU (98 mg, 0.26 mmol) and the mixture was stirred at room temperature for 1 h. The mixture was diluted with water (10 mL) and the resulting precipitate was removed by vacuum filtration. The filtrate was extracted with EtOAc (3 x 10 mL) and the combined organic extracts were filtered through a phase separating cartridge and concentrated in vacuo. Purification of the crude product by preparative HPLC (basic pH, early elution method) afforded the title compound as a colourless powder
LC-MS (Method 7B): Rt 2.15 mins; MS m/z 400.3 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 11.27 (s, 1H), 8.57 (t, J = 1.4 Hz, 1H), 8.53 (dt, J = 7.8, 1.4 Hz, 1H), 8.00 (dt, J = 7.8, 1.4 Hz, 1H), 7.84 (s, 2H), 7.73 (t, J = 7.8 Hz, 1H), 5.78 (p, J = 5.9 Hz, 1H), 4.96– 4.93 (m, 2H), 4.77 (s, 1H), 4.74– 4.69 (m, 2H), 3.73 (s, 2H), 1.18 (s, 6H).
[00273] The compounds of the following tabulated Examples (Table Ex8) were prepared analogously to Example 8 step 1-3 by replacing oxetan-3-ol (step 1) with the appropriate commercially available alcohol
Table x8
E
8 z
, = , , – , ,
Figure imgf000125_0001
Ex. Structure and Name Retention Time, [M+H]+, 1H NMR
8 z
, = , , = ,
8 S
, = 5 , 3 5 0
8 z
, = , 4 , =
8 z
, , , 7 , 1
Figure imgf000126_0001
carboxamide Ex. Structure and Name Retention Time, [M+H]+, 1H NMR 8 z
, 2 J
, 8 = , ,
8 z
, , 5 , 2 J
, , 8 z
, , , , 5 1
8 z
, , , , 9 ,
Figure imgf000127_0001
carboxamide
Example 8.5a and 8.5b
[00274] Chiral separation of racemic 4-amino-2-(3-cyanophenyl)-6-(2-fluoro-1-methyl- ethoxy)-N-(2-hydroxy-2-methyl-propoxy)pyrimidine-5-carboxamide (Example 8.5) using Supercritical Fluid Chromatography (90:10 heptane: EtOH with CHIRALPAK AD-H @ 18 mL/min) afforded the individual enantiomers: Example 8.5a: 4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1R)-2- fluoro-1-methyl-ethoxy]pyrimidine-5-carboxamide or 4-amino-2-(3-cyanophenyl)-N-(2- hydroxy-2-methyl-propoxy)-6-[(1S)-2-fluoro-1-methyl-ethoxy]pyrimidine-5- carboxamide
Figure imgf000128_0001
First Eluted Peak: SFC Retention time = 38.58 mins
LC-MS (Method 7A): Rt 3.10 mins; MS m/z 404.2 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 11.04 (s, 1H), 8.62 (s, 1H), 8.60– 8.55 (m, 1H), 8.01 (d, J = 7.8 Hz, 1H), 7.83 (s, 2H), 7.74 (t, J = 7.8 Hz, 1H), 5.81– 5.70 (m, 1H), 4.77 (s, 1H), 4.68 (dd, J = 47.5, 4.1 Hz, 2H), 3.70 (s, 2H), 1.39 (d, J = 6.4 Hz, 3H), 1.17 (d, J = 3.1 Hz, 6H).
Example 8.5b: 4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1R)-2- fluoro-1-methyl-ethoxy]pyrimidine-5-carboxamide or 4-amino-2-(3-cyanophenyl)-N-(2- hydroxy-2-methyl-propoxy)-6-[(1S)-2-fluoro-1-methyl-ethoxy]pyrimidine-5- carboxamide
Figure imgf000128_0002
Second Eluted Peak: SFC Retention time = 60.43 mins
LC-MS (Method 7A): Rt 3.09 mins; MS m/z 404.2 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 11.03 (s, 1H), 8.62 (d, J = 1.5 Hz, 1H), 8.60– 8.55 (m, 1H), 8.01 (d, J = 7.7 Hz, 1H), 7.83 (s, 2H), 7.74 (t, J = 7.8 Hz, 1H), 5.82– 5.71 (m, 1H), 4.77 (s, 1H), 4.68 (dd, J = 47.5, 4.2 Hz, 2H), 3.70 (s, 2H), 1.39 (d, J = 6.6 Hz, 3H), 1.17 (d, J = 2.8 Hz, 6H).
Example 8.11
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(3S)-tetrahydrofuran-3- yl]oxy-pyrimidine-5-carboxamide
Figure imgf000129_0001
[00275] Oxalyl chloride (12.75 mL, 150.68 mmol) was added dropwise over 1 h to a stirred suspension of 4-amino-2-(3-cyanophenyl)-6-[(3S)-tetrahydrofuran-3-yl]oxy-pyrimidine- 5-carboxylic acid (Intermediate K) (44.7 g, 136.99 mmol) in DCM (800 mL) and DMF (5 mL) at room temperature under nitrogen. After stirring at room temperature for 2 h, the acid chloride mixture was added dropwise over 1 h to a stirred solution of 1-aminooxy-2-methyl-propan-2- ol (Intermediate C) (21.6 g, 205.48 mmol) and DIPEA (71.58 mL, 410.96 mmol) in DCM (600 mL) at 0 °C under nitrogen. The mixture was stirred at 0 °C for 1 h and allowed to warm to room temperature overnight. EtOAc (3.0 L), brine (1.0 L) and 2M aqueous hydrochloric acid (400 mL) were added to the mixture. The organic phase was separated and washed with 1M HCl (2 x 0.5 L), brine (0.5 L) and saturated aqueous sodium hydrogen carbonate solution (0.5 L). The organic phase was filtered, the residual water was separated and the organic phase was dried over MgSO4 and concentrated in vacuo to leave a light yellow solid. The solid was recrystallised from IPA (0.5 L) with a hot decantation. The crystallised solid was collected by filtration, washed with IPA (2 x 50 mL), hexanes (3 x 75 mL), and dried under high vacuum to afford the title compound as a light yellow crystalline solid.
LC-MS (Method 8B): Rt 3.80 mins; MS m/z 414.3 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 11.04 (s, 1H), 8.62 (t, J = 1.5 Hz, 1H), 8.58 (dt, J = 7.8, 1.5 Hz, 1H), 8.01 (dt, J = 7.8, 1.5 Hz, 1H), 7.74 (t, J = 7.8 Hz, 1H), 7.71 (br. s, 2H), 5.81– 5.76 (m, 1H), 4.73 (s, 1H), 4.04 (dd, J = 10.4, 4.9 Hz, 1H), 3.91– 3.85 (m, 2H), 3.82– 3.78 (m, 1H), 3.70 (s, 2H), 2.33– 2.26 (m, 1H), 2.20– 2.14 (m, 1H), 1.17 (s, 6H).
Example 9 4-Amino-2-(3-cyanophenyl)-N-[(1-hydroxycyclopropyl)methoxy]-6-(oxetan-3-yloxy) pyrimidine-5-carboxamide
Figure imgf000130_0001
[00276] The title compound was prepared from 4-amino-2-(3-cyanophenyl)-6-(oxetan- 3-yloxy)pyrimidine-5-carboxylic acid (Example 8 step 2) and 1- (aminooxymethyl)cyclopropanol (Intermediate F) analogously to Example 8 step 3.
LC-MS (Method 7B): Rt 2.25 mins; MS m/z 398.2 = [M+H]+
1H NMR (400 MHz, DMSO-d6) d 11.17 (s, 1H), 8.57 (t, J = 1.4 Hz, 1H), 8.53 (dt, J = 7.8, 1.4 Hz, 1H), 8.00 (dt, J = 7.8, 1.4 Hz, 1H), 7.81 (s, 2H), 7.73 (t, J = 7.8 Hz, 1H), 5.79 (p, J = 5.9 Hz, 1H), 5.63 (s, 1H), 4.95 (t, J = 7.1 Hz, 2H), 4.76– 4.70 (m, 2H), 3.90 (s, 2H), 0.69– 0.62 (m, 2H), 0.59 (d, J = 4.0 Hz, 2H).
Example 9.1
Ethyl (2S)-2-[[4-amino-2-(3-cyanophenyl)-6-(oxetan-3-yloxy) pyrimidine-5- carbonyl]amino] oxypropanoate
Figure imgf000130_0002
[00277] The title compound was prepared from 4-amino-2-(3-cyanophenyl)-6-(oxetan- 3-yloxy)pyrimidine-5-carboxylic acid (Example 8 step 2) and ethyl (2S)-2-aminooxypropanoate (Intermediate G) analogously to Example 8 step 3.
LC-MS (Method 7A): Rt 3.23 mins; MS m/z 428.2 = [M+H]+
1H NMR (400 MHz, DMSO-d6) d 11.18 (s, 1H), 8.57 (t, J = 1.4 Hz, 1H), 8.52 (dt, J = 7.8, 1.4 Hz, 1H), 8.00 (dt, J = 7.8, 1.4 Hz, 1H), 7.82 (s, 2H), 7.73 (t, J = 7.8 Hz, 1H), 5.84– 5.74 (m, 1H), 4.98– 4.92 (m, 2H), 4.70 (dt, J = 12.9, 7.2 Hz, 2H), 4.63 (q, J = 6.9 Hz, 1H), 4.19 (q, J = 7.1 Hz, 2H), 1.42 (d, J = 6.9 Hz, 3H), 1.24 (t, J = 7.1 Hz, 3H). Example 9.2
4-Amino-2-(3-cyanophenyl)-N-[(1-hydroxycyclobutyl)methoxy]-6-(oxetan-3-yloxy) pyrimidine-5-carboxamide
Figure imgf000131_0001
[00278] The title compound was prepared from 4-amino-2-(3-cyanophenyl)-6-(oxetan- 3-yloxy)pyrimidine-5-carboxylic acid (Example 8 step 2) and 1-(aminooxymethyl)cyclobutanol (Intermediate J) analogously to Example 8 step 3.
LC-MS (Method 7A): Rt 2.79 mins; MS m/z 412.3 = [M+H]+
1H NMR (400 MHz, DMSO-d6) d 8.57 (t, J = 1.5 Hz, 1H), 8.53 (dt, J = 8.0, 1.3 Hz, 1H), 8.03 – 7.97 (m, 1H), 7.86 (s, 2H), 7.73 (t, J = 7.8 Hz, 1H), 5.50 (br. s, 2H), 5.77 (q, J = 6.0 Hz, 1H), 4.94 (t, J = 7.2 Hz, 2H), 4.75– 4.68 (m, 2H), 3.91 (s, 2H), 2.12 (d, J = 9.1 Hz, 2H), 2.03– 1.91 (m, 2H), 1.67 (d, J = 11.1 Hz, 1H), 1.58– 1.46 (m, 1H).
Example 10
4-Amino-6-(azetidin-3-yloxy)-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy) pyrimidine-5-carboxamide
Figure imgf000131_0002
Step 1: Ethyl 4-amino-6-(1-tert-butoxycarbonylazetidin-3-yl)oxy-2-(3-cyanophenyl)pyrimidine- 5-carboxylate
Figure imgf000131_0003
[00279] The title compound was prepared from ethyl 4-amino-6-chloro-2-(3- cyanophenyl)pyrimidine-5-carboxylate (Example 5 step 1) and tert-butyl 3-hydroxyazetidine- 1-carboxylate analogously to Example 8 step 1.
LCMS (Method 2A): Rt ~ 1.41 min, MS m/z 440.1 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 8.62 (s, 1H), 8.58 (dt, J = 7.8, 1.4 Hz, 1H), 8.02 (dt, J = 7.8, 1.4 Hz, 1H), 7.97– 7.86 (m, 2H), 7.75 (t, J = 7.8 Hz, 1H), 5.59– 5.50 (m, 1H), 4.43– 4.34 (m, 2H), 4.28 (q, J = 7.1 Hz, 2H), 3.88 (dd, J = 9.6, 3.3 Hz, 2H), 1.40 (s, 9H), 1.32 (t, J = 7.1 Hz, 3H).
Step 2: 4-Amino-6-(1-tert-butoxycarbonylazetidin-3-yl)oxy-2-(3-cyanophenyl)pyrimidine-5- carboxylic acid
Figure imgf000132_0001
[00280] The title compound was prepared from ethyl 4-amino-6-(1-tert- butoxycarbonylazetidin-3-yl)oxy-2-(3-cyanophenyl)pyrimidine-5-carboxylate (step 1) and 1M lithium hydroxide analogously to Example 8 step 2.
LCMS (Method 2A): Rt= 1.22 min, MS m/z 412.1 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 12.92 (s, 1H), 8.61 (t, J = 1.5 Hz, 1H), 8.57 (dt, J = 7.9, 1.5 Hz, 1H), 8.13– 7.85 (m, 3H), 7.74 (t, J = 7.9 Hz, 1H), 5.58– 5.48 (m, 1H), 4.42– 4.29 (m, 2H), 3.93– 3.82 (m, 2H), 1.39 (s, 9H).
Step 3: tert-Butyl 3-[6-amino-2-(3-cyanophenyl)-5-[(2-hydroxy-2-methyl- propoxy)carbamoyl]pyrimidin-4-yl]oxyazetidine-1-carboxylate
Figure imgf000132_0002
[00281] The title compound was prepared from 4-amino-6-(1-tert- butoxycarbonylazetidin-3-yl)oxy-2-(3-cyanophenyl)pyrimidine-5-carboxylic acid (step 2) and 1-aminooxy-2-methyl-propan-2-ol (Intermediate C) analogously to Example 8 step 3.
LCMS (Method 2A): Rt = 1.25 min, MS m/z 499.2 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 11.25 (s, 1H), 8.60 (t, J = 1.4 Hz, 1H), 8.56 (dt, J = 7.8, 1.5 Hz, 1H), 8.01 (dt, J = 7.8, 1.4 Hz, 1H), 7.88– 7.68 (m, 3H), 5.52 (ddd, J = 11.3, 6.8, 4.4 Hz, 1H), 4.73 (s, 1H), 4.38– 4.28 (m, 2H), 4.08– 3.93 (m, 2H), 3.73 (s, 2H), 2.54 (s, 6H), 1.40 (s, 9H).
Step 4: 4-Amino-6-(azetidin-3-yloxy)-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl- propoxy)pyrimidine-5-carboxamide
Figure imgf000133_0001
[00282] A mixture of tert-butyl 3-[6-amino-2-(3-cyanophenyl)-5-[(2-hydroxy-2-methyl- propoxy)carbamoyl]pyrimidin-4-yl]oxyazetidine-1-carboxylate (step 3) (15 mg, 0.03 mmol) and TFA (0.21 mL, 2.76 mmol) in DCM (2 mL) was stirred at room temperature for 4 h. The resulting mixture was loaded onto a 1 g Isolute® SCX cartridge. The column was washed with MeOH and the product was eluted with 7M NH3 in MeOH. The methanolic ammonia eluent was concentrated in vacuo and the resulting solid was purified by C18 reverse phase column chromatography (acidic pH) to afford the title compound as a yellow solid.
LCMS (Method 7B): Rt = 1.76 min, MS m/z 399.3 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 8.57 (s, 1H), 8.54 (d, J = 7.8 Hz, 1H), 8.28 (s, 1H), 8.01 (d, J = 7.8 Hz, 1H), 7.82 (s, 2H), 7.74 (t, J = 7.8 Hz, 1H), 5.61– 5.53 (m, 1H), 3.99 (s, 2H), 3.83 (s, 2H), 3.73 (s, 2H), 1.18 (s, 6H).
Example 11
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-(2-methoxyethoxy) pyrimidine-5-carboxamide
Figure imgf000134_0002
Step 1: 4-Amino-2-(3-cyanophenyl)-6-(2-methoxyethoxy)pyrimidine-5-carboxylic acid
Figure imgf000134_0001
[00283] 1M Potassium t-butoxide in THF (0.79 mL, 0.79 mmol) was added to a solution of 2-methoxyethanol (521 µL, 6.61 mmol) in 1,4-dioxane (5 mL) followed by ethyl 4-amino-6- chloro-2-(3-cyanophenyl)pyrimidine-5-carboxylate (Example 5 step 1) (200 mg, 0.66 mmol) and the reaction mixture was stirred at room temperature for 3 h. Water (3 mL) was added and the mixture was stirred for a total of 24 h and then partitioned between water (10 mL) and DCM (10 mL). The phases were separated and the aqueous portion was acidified to pH 2 with 2M HCl and extracted with DCM (3 x 10 mL). The combined organic extracts were passed through a hydrophobic frit and concentrated in vacuo to afford the title compound as a yellow solid.
LCMS (Method 2A): Rt ~ 1.11 min, MS m/z 315.0 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 12.73 (s, 1H), 8.64 (t, J = 1.4 Hz, 1H), 8.60 (dt, J = 7.8, 1.4 Hz, 1H), 8.01 (dt, J = 7.8, 1.4 Hz, 1H), 7.90 (s, 2H), 7.74 (t, J = 7.8 Hz, 1H), 4.67– 4.61 (m, 2H), 3.71 (dd, J = 3.7, 2.3 Hz, 2H), 3.32 (s, 3H).
Step 2: 4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-(2- methoxyethoxy)pyrimidine-5-carboxamide
[00284] A solution of 4-amino-2-(3-cyanophenyl)-6-(2-methoxyethoxy)pyrimidine-5- carboxylic acid (step 1) (85 mg, 0.27 mmol) and 1-aminooxy-2-methyl-propan-2-ol (34 mg, 0.32 mmol) in DMF (2 mL) was treated with HATU (113 mg, 0.30 mmol) and DIPEA (0.12 mL, 0.68 mmol) and the mixture was stirred for 72 h. Additional DIPEA (0.12 mL, 0.68 mmol), HATU (113 mg, 0.30 mmol) and 1-aminooxy-2-methyl-propan-2-ol (34 mg, 0.32 mmol) were added and the reaction mixture was stirred for a further hour. The resulting mixture was partitioned between EtOAc (15 mL) and water (15 mL). The organic layer was washed with water (15 mL) and brine (2 x 10 mL) and the combined organic extracts were dried over MgSO4 and were concentrated in vacuo to afford a yellow oil. The oil was purified by preparative HPLC (acidic pH, early elution method) to afford the title compound as a yellow solid.
LCMS (Method 7A): Rt ~ 2.92 min, MS m/z 402.2 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 11.05 (s, 1H), 8.63 (t, J = 1.4 Hz, 1H), 8.58 (dt, J = 7.8, 1.4 Hz, 1H), 8.01 (dt, J = 7.8, 1.4 Hz, 1H), 7.90 (s, 2H), 7.74 (t, J = 7.8 Hz, 1H), 4.70 (s, 1H), 4.68 – 4.63 (m, 2H), 3.75 (d, J = 4.8 Hz, 2H), 3.70 (s, 2H), 3.34 (s, 3H), 1.17 (s, 6H).
[00285] The compounds of the following tabulated Examples (Table Ex11) were prepared analogously to Example 11 (steps 1 and 2) by replacing 2-methoxyethanol (step 1) with the appropriate alcohol.
Table Ex11
E
1 z
, = , , , 7 , 1
1 z
, = , , 2
Figure imgf000135_0001
5-carboxamide Ex. Structure and Name Retention Time, [M+H]+, 1H NMR 1 z
, = 4 , = 8 ,
1 z
, = , = , , 1 z
, , , – , 9
1 S
, = , 3 , 5
1 z
, , 8 , 6 9
Figure imgf000136_0001
cya op e y)- -( - y oy- - e y- propoxy)pyrimidine-5-carboxamide Example 11.4a and 11.4b
[00286] Chiral separation of racemic 4-amino-2-(3-cyanophenyl)-6-(2-fluoropropoxy)- N-(2-hydroxy-2-methyl-propoxy)pyrimidine-5-carboxamide (Example 11.4) using Supercritical Fluid Chromatography (EtOH +0.2% DEA with CHIRALPAK AD-H 25cm column @ 6 mL/min) afforded the individual enantiomers:
Example 11.4a: 4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(2S)-2- fluoropropoxy]pyrimidine-5-carboxamide or 4-amino-2-(3-cyanophenyl)-N-(2-hydroxy- 2-methyl-propoxy)-6-[(2R)-2-fluoropropoxy]pyrimidine-5-carboxamide
Figure imgf000137_0001
First Eluted Peak: SFC Retention time = 18.37 mins
LC-MS (Method 7A): Rt 3.08 mins; MS m/z 404.2 = [M+H]+
1H NMR (400 MHz, DMSO-d6) d 11.11 (s, 1H), 8.63 (s, 1H), 8.59 (d, J = 7.8 Hz, 1H), 8.00 (d, J = 7.8 Hz, 1H), 7.73 (t, J = 7.8 Hz, 3H), 5.29– 4.99 (m, 1H), 4.87 (br. s, 1H), 4.72– 4.52 (m, 2H), 3.69 (s, 2H), 1.41 (dd, J = 23.8, 6.4 Hz, 3H), 1.16 (s, 6H).
Example 11.4b: 4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(2S)-2- fluoropropoxy]pyrimidine-5-carboxamide or 4-amino-2-(3-cyanophenyl)-N-(2-hydroxy- 2-methyl-propoxy)-6-[(2R)-2-fluoropropoxy]pyrimidine-5-carboxamide
Figure imgf000137_0002
Second Eluted Peak: SFC Retention time = 24.20 mins LC-MS (Method 7A): Rt 3.08 mins; MS m/z 404.3 = [M+H]+
1H NMR (400 MHz, DMSO-d6) d 11.09 (s, 1H), 8.63 (s, 1H), 8.59 (d, J = 7.8 Hz, 1H), 8.00 (d, J = 7.8 Hz, 1H), 7.74 (t, J = 7.8 Hz, 3H), 5.27– 4.99 (m, 1H), 4.87 (br. s, 1H), 4.73– 4.51 (m, 2H), 3.69 (s, 2H), 1.41 (dd, J = 23.8, 6.4 Hz, 3H), 1.16 (s, 6H).
Example 12: 4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(2S)-2- hydroxypropoxy] pyrimidine-5-carboxamide and
Example 12.1: 4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1S)-2- hydroxy-1-methyl-ethoxy]pyrimidine-5-carboxamide
Figure imgf000138_0001
Step 1: Ethyl 4-amino-2-(3-cyanophenyl)-6-[(2S)-2-[tert-butyl(dimethyl)silyl]oxypropoxy] pyrimidine-5-carboxylate
Figure imgf000138_0002
[00287] To a stirred solution of (2S)-2-[tert-butyl(dimethyl)silyl]oxypropan-1-ol (Intermediate HA) (377 mg, 1.98 mmol) and 1M potassium t-butoxide in THF (2.97 mL, 2.97 mmol) in 1,4-dioxane (5 mL) under nitrogen was added ethyl 4-amino-6-chloro-2-(3- cyanophenyl)pyrimidine-5-carboxylate (Example 5 step 1) (300 mg, 0.99 mmol) and the mixture was stirred at room temperature for 17 h. The resulting mixture was treated with aqueous NaHCO3 (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic extracts were passed through a phase separator and concentrated in vacuo. The crude product was purified by chromatography on silica eluting with 0-100% EtOAc in heptane to afford the title compound as a colourless solid.
LC-MS (Method 2A new): Rt 2.04 mins; MS m/z 457.2 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 8.63– 8.54 (m, 2H), 8.01 (ddd, J = 7.7, 3.2, 2.0 Hz, 1H), 7.83– 7.68 (m, 3H), 4.53 (dd, J = 10.9, 5.8 Hz, 1H), 4.36– 4.13 (m, 3H), 3.84– 3.67 (m, 1H), 1.67– 1.54 (m, 1H), 1.32– 1.28 (m, 3H), 1.25– 1.22 (m, 3H), 0.84– 0.78 (m, 9H), 0.06– - 0.02 (m, 6H).
Step 2: Ethyl 4-amino-2-(3-cyanophenyl)-6-[(2S)-2-hydroxypropoxy]pyrimidine-5-carboxylate
Figure imgf000139_0001
[00288] 4M HCl in 1,4-dioxane (0.2 mL, 0.79 mmol) was added to ethyl 4-amino-2-(3- cyanophenyl)-6-[(2S)-2-[tert-butyl(dimethyl)silyl]oxypropoxy]pyrimidine-5-carboxylate (90 mg, 0.20 mmol) in 1,4-dioxane (1 mL) and the mixture was stirred at room temperature for 17 h. The resulting mixture was filtered and washed with water (3 x 2 mL) to afford the title compound as a colourless solid.
LC-MS (Method 2A): Rt 1.37 mins; MS m/z 343.1 = [M+H]+
1H NMR (400 MHz, DMSO-d6) d 8.62– 8.51 (m, 2H), 7.97 (dq, J = 7.7, 1.5 Hz, 1H), 7.77 (s, 2H), 7.70 (d, J = 7.9 Hz, 1H), 4.39 (dd, J = 10.6, 5.2 Hz, 1H), 4.28– 4.13 (m, 3H), 4.00– 3.86 (m, 1H), 1.29– 1.22 (m, 4H), 1.17 (d, J = 6.3 Hz, 2H).
Step 3: 4-Amino-2-(3-cyanophenyl)-6-[(2S)-2-hydroxypropoxy]pyrimidine-5-carboxylic acid
Figure imgf000139_0002
[00289] The title compound was prepared from ethyl 4-amino-2-(3-cyanophenyl)-6- [(2S)-2-hydroxypropoxy]pyrimidine-5-carboxylate (step 2) and 2M lithium hydroxide analogously to Example 1 step 5.
LC-MS (Method 2A): Rt 1.20 mins; MS m/z 315.0 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 8.65– 8.56 (m, 2H), 8.01 (dd, J = 7.7, 1.4 Hz, 1H), 7.89 (s, 1H), 7.74 (t, J = 7.8 Hz, 1H), 4.42 (dd, J = 10.6, 5.7 Hz, 1H), 4.28 (dd, J = 10.6, 5.7 Hz, 1H), 4.01– 3.95 (m, 1H), 3.64– 3.52 (m, 1H), 1.18 (d, J = 6.3 Hz, 3H). Step 4: Example 12: 4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(2S)-2- hydroxypropoxy] pyrimidine-5-carboxamide and
Example 12.1: 4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1S)-2- hydroxy-1-methyl-ethoxy] pyrimidine-5-carboxamide
[00290] To a stirred solution of 4-amino-2-(3-cyanophenyl)-6-[(2S)-2- hydroxypropoxy]pyrimidine-5-carboxylic acid (step 3) (45 mg, 0.14 mmol) in DMF (1 mL) was added HATU (65 mg, 0.17 mmol), 1-aminooxy-2-methyl-propan-2-ol (Intermediate C) (17 mg, 0.16 mmol) followed by DIPEA (0.07 mL, 0.43 mmol) and the mixture was stirred at room temperature for 20 h. The resulting mixture was diluted with water (3 mL) and extracted with EtOAc (3 x 3 mL). The organic phase was passed through a phase separator and concentrated in vacuo. The crude product was purified by preparative HPLC (acidic pH, early elution method)followed by preparative HPLC (basic pH, early elution method)to afford the title compounds as colourless solids:
Example 12: 4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(2S)-2- hydroxypropoxy] pyrimidine-5-carboxamide
LC-MS (Method 7B): Rt 2.18 mins; MS m/z 402.3 = [M+H]+
1H NMR (500 MHz, Methanol-d4) d 8.66 (t, J = 1.3 Hz, 1H), 8.63(dt, J = 7.8, 1.3 Hz, 1H), 7.83 (dt, J = 7.8, 1.3 Hz, 1H), 7.64 (t, J = 7.8 Hz, 1H), 4.61 (dd, J = 11.0, 3.6 Hz, 1H), 4.41 (dd, J = 11.0, 7.3 Hz, 1H), 4.27 - 4.21 (m, 1H), 3.85 (s, 2H), 1.31 (d, J = 6.4 Hz, 3H), 1.28 (s, 6H). Example 12.1: 4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1S)-2- hydroxy-1-methyl-ethoxy] pyrimidine-5-carboxamide
LC-MS (Method 7B): Rt 2.27 mins; MS m/z 402.3 = [M+H]+
1H NMR (500 MHz, Methanol-d4) d 8.67 (t, J = 1.4 Hz, 1H), 8.65 (dt, J = 7.8, 1.4 Hz, 1H), 7.84 (dt, J = 7.8, 1.4 Hz, 1H), 7.65 (t, J = 7.8 Hz, 1H), 5.65 - 5.60 (m, 1H), 3.90– 3.74 (m, 4H), 1.47 (d, J = 6.4 Hz, 3H), 1.28 (s, 6H). Example 12.2: 4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(2R)-2- hydroxypropoxy]pyrimidine-5-carboxamide and
Example 12.3: 4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1R)-2- hydroxy-1-methyl-ethoxy]pyrimidine-5-carboxamide
Figure imgf000141_0001
[00291] The title compounds were prepared analogously to Examples 12 and 12.1 by replacing (2S)-2-[tert-butyl(dimethyl)silyl]oxypropan-1-ol (Intermediate HA) (step 1) with (2R)- 2-[tert-butyl(dimethyl)silyl]oxypropan-1-ol (Intermediate HB).
Example 12.2: 4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(2R)-2- hydroxypropoxy]pyrimidine-5-carboxamide
LC-MS (Method 7B): Rt 2.20 mins; MS m/z 402.2 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 11.09 (br s, 1H), 8.62 (t, J = 1.4 Hz, 1H), 8.58 (dt, J = 7.8, 1.3 Hz, 1H), 8.01 (dt, J = 7.8, 1.3 Hz, 1H), 7.91 (br s, 2H), 7.74 (t, J = 7.8 Hz, 1H), 5.11 (br s, 1H), 4.75 (br s, 1H), 4.43 (dd, J = 10.6, 4.4 Hz, 1H), 4.36 (dd, J = 10.6, 6.6 Hz, 1H), 4.14– 4.01 (m, 1H), 3.70 (s, 2H), 1.18 (d, J = 6.6 Hz, 3H), 1.17 (s, 6H).
Example 12.3: 4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1R)-2- hydroxy-1-methyl-ethoxy]pyrimidine-5-carboxamide
LC-MS (Method 7B): Rt 2.29 mins; MS m/z 402.3 = [M+H]+
1H NMR (400 MHz, DMSO-d6) d 11.02 (br s, 1H), 8.60 (t, J = 1.4 Hz, 1H), 8.57 (dt, J = 7.8, 1.4 Hz, 1H), 8.01 (dt, J = 7.8, 1.4 Hz, 1H), 7.91 (br s, 2H), 7.74 (t, J = 7.8 Hz, 1H), 5.53 - 5.42 (m, 1H), 5.09 (br s, 1H), 4.76 (br s, 1H), 3.69 (s, 2H), 3.67– 3.62 (m, 2H), 1.35 (d, J = 6.3 Hz, 3H), 1.17 (s, 6H). Example 13
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(2S)-2,3-dihydroxy propoxy]pyrimidine-5-carboxamide
Figure imgf000142_0001
[00292] A solution of 4-amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6- [[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy]pyrimidine-5-carboxamide (Example 8.2) (90 mg, 0.16 mmol) and 1M HCl (787 µL, 0.79 mmol) in THF (5 mL) was stirred at room temperature. After 24 h, the mixture was diluted with water (2 mL) and extracted with DCM (3 x 5 mL). The combined organic extracts were filtered through a phase separating cartridge and concentrated in vacuo. Purification of the crude product by preparative HPLC (basic pH, early elution method) afforded the title compound as a colourless powder.
LC-MS (Method 7A): Rt 2.17 mins; MS m/z 418.2 = [M+H]+
1H NMR (400 MHz, DMSO-d6) d 11.16 (s, 1H), 8.63 (t, J = 1.4 Hz, 1H), 8.59 (dt, J = 7.9, 1.4 Hz, 1H), 8.01 (dt, J = 7.9, 1.4 Hz, 3H), 7.74 (t, J = 7.9 Hz, 1H), 5.17 (s, 1H), 4.87 (s, 1H), 4.71 (s, 1H), 4.59 (dd, J = 10.9, 4.5 Hz, 1H), 4.47 (dd, J = 10.8, 6.0 Hz, 1H), 3.94– 3.84 (m, 1H), 3.71 (s, 2H), 3.56– 3.45 (m, 2H), 1.17 (s, 6H).
Example 13.1
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(2R)-2,3-dihydroxy propoxy]pyrimidine-5-carboxamide
Figure imgf000142_0002
[00293] The title compound was prepared from 4-amino-2-(3-cyanophenyl)-N-(2- hydroxy-2-methyl-propoxy)-6-[[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy]pyrimidine-5- carboxamide (Example 8.4) and 1M HCl analogously to Example 13.
LC-MS (Method 7A): Rt 2.17 mins; MS m/z 418.2 = [M+H]+
1H NMR (400 MHz, DMSO-d6) d 11.16 (s, 1H), 8.73– 8.52 (m, 2H), 8.02 (dt, J = 7.8, 1.3 Hz, 2H), 7.75 (t, J = 7.8 Hz, 1H), 5.76 (s, 1H), 5.17 (s, 1H), 4.80 (d, J = 66.6 Hz, 2H), 4.54 (ddd, J = 48.6, 10.9, 5.3 Hz, 2H), 3.96– 3.85 (m, 1H), 3.71 (s, 2H), 3.60– 3.44 (m, 2H), 1.18 (s, 6H).
Example 14
4-Amino-2-(3-cyanophenyl)-6-(oxetan-3-yloxy)-N-[(1S)-2-hydroxy-1,2-dimethyl- propoxy]pyrimidine-5-carboxamide
Figure imgf000143_0001
[00294] To a cooled (0 °C) solution of ethyl (2S)-2-[[4-amino-2-(3-cyanophenyl)-6- (oxetan-3-yloxy)pyrimidine-5-carbonyl]amino]oxypropanoate (Example 9.1) (32 mg, 0.07 mmol) in THF (1 mL) under nitrogen was added methylmagnesium bromide solution (3M in Et2O) (0.05 mL, 0.14 mmol) and the mixture was stirred at 0 °C for 30 mins. Further methylmagnesium bromide solution (3M in Et2O) (2 mL were added and stirring continued at 0 °C for 15 mins. The reaction was quenched by addition of water (1 mL) and the resulting mixture was poured into water (10 mL).The mixture was extracted with EtOAc (3 x 10 mL) and the combined organic extracts were washed with brine (10 mL), dried over MgSO4 and concentrated in vacuo. Purification of the crude product by preparative HPLC (basic pH, early elution method) afforded the title compound as a colourless solid.
LC-MS (Method 7A): Rt 2.85 mins; MS m/z 414.2 = [M+H]+
1H NMR (500 MHz, MeOH -d4) d 8.63 (s, 1H), 8.60 (dt, J = 7.8, 1.4 Hz, 1H), 7.85 (dt, J = 7.8, 1.4 Hz, 1H), 7.66 (t, J = 7.8 Hz, 1H), 5.87 (p, J = 5.8 Hz, 1H), 5.11– 5.07 (m, 2H), 4.90– 4.86 (m, 2H), 3.86 (q, J = 6.6 Hz, 1H), 1.33 (d, J = 6.6 Hz, 3H), 1.27 (s, 3H), 1.24 (s, 3H). Example 15
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methylpropoxy)-6-[(1r,3r)-3- Hydroxycyclobutoxy]pyrimidine-5-carboxamide
Figure imgf000144_0001
Step 1: 4-Amino-2-(3-cyanophenyl)-6-[(1r,3r)-3-hydroxycyclobutoxy]pyrimidine-5-carboxylic acid
Figure imgf000144_0002
[00295] To a stirred solution of (1r,3r)-3-[tert-butyl(dimethyl)silyl]oxycyclobutanol (100 mg, 0.49 mmol) and 1M potassium t-butoxide in THF (0.36 mL, 0.36 mmol) in THF (2 mL) was added ethyl 4-amino-6-chloro-2-(3-cyanophenyl)pyrimidine-5-carboxylate (Example 5 step 1) (100 mg, 0.33 mmol) and the mixture was stirred at room temperature. After 17 h 4M HCl in 1,4-dioxane (0.83 mL, 3.3 mmol) was added and stirring continued for 13 h. The resulting mixture was basified with 1M NaOH (1 mL) and washed with EtOAc (3 x 3 mL). The aqueous phase was acidified with 2M HCl (1 mL) and extracted with DCM (3 x 3 mL). The combined organic extracts were passed through a phase separator and concentrated to in vacuo to afford the title compound as a brown solid.
LC-MS (Method 2A): Rt 1.00 mins; MS m/z 327.0 = [M+H]+
Step 2: 4-Amino-2-(3-cyanophenyl)-6-[(1r,3r)-(3-hydroxycyclobutoxy]-N-(2-hydroxy-2- methyl-propoxy)pyrimidine-5-carboxamide
[00296] The title compound was prepared from 4-amino-2-(3-cyanophenyl)-6-[(1r,3r)3- hydroxycyclobutoxy]pyrimidine-5-carboxylic acid (step 1) and 1-aminooxy-2-methyl-propan-2- ol (Intermediate C) analogously to Example 1 step 6.
LC-MS (Method 7B): Rt 2.14 mins; MS m/z 414.2 = [M+H]+ 1H NMR (500 MHz, MeOH -d4) d 8.66 - 8.61 (m, 2H), 7.83 (dt, J = 7.8, 1.3 Hz, 1H), 7.64 (t, J = 7.8 Hz, 1H), 5.75– 5.61 (m, 1H), 4.56 (tt, J = 7.2, 3.9 Hz, 1H), 3.84 (s, 2H), 2.65 (ddd, J = 15.5, 7.2 , 5.1 Hz, 2H), 2.52 (ddd, J = 14.0, 7.2, 3.9 Hz, 2H), 1.28 (s, 6H).
Example 16
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-(oxetan-3-ylmethoxy) pyrimidine-5-carboxamide
Figure imgf000145_0001
Step 1: Ethyl 4-amino-2-(3-cyanophenyl)-6-(oxetan-3-ylmethoxy)pyrimidine-5-carboxylate
Figure imgf000145_0002
[00297] A mixture of ethyl 4-amino-6-chloro-2-(3-cyanophenyl)pyrimidine-5- carboxylate (Example 5 step 1) (200 mg, 0.66 mmol), oxetan-3-ylmethanol (116 mg, 1.32 mmol), cesium carbonate (538 mg, 1.65 mmol), Pd(OAc)2 (15 mg, 0.07 mmol) and X-Phos (22 mg, 0.05 mmol) in toluene (2 mL) was heated using microwave radiation at 100 °C for 2 h. The resulting mixture was filtered through Celite® (filter material) and concentrated in vacuo. Purification by chromatography on silica eluting with 0-100% EtOAc in DCM yielded a product that was further purified by chromatography on silica eluting with 0-100% EtOAc in heptane to afford the title compound as an off-white solid.
LC-MS (Method 2A): Rt 1.17 mins; MS m/z 355.0 = [M+H]+
1H NMR (400 MHz, Chloroform-d) d 8.69 (t, J = 1.5 Hz, 1H), 8.61 (dt, J = 7.8, 1.5 Hz, 1H), 7.76 (dt, J = 7.8, 1.5 Hz, 1H), 7.57 (t, J = 7.8 Hz, 1H), 4.88 (dd, J = 8.0, 6.2 Hz, 2H), 4.75– 4.68 (m, 4H), 4.35 (q, J = 7.1 Hz, 2H), 3.53 (ddd, J = 14.3, 8.0, 6.2 Hz, 1H), 1.38 (t, J = 7.1 Hz, 3H). Step 2: 4-Amino-2-(3-cyanophenyl)-6-(oxetan-3-ylmethoxy)pyrimidine-5-carboxylic acid
Figure imgf000146_0001
[00298] The title compound was prepared from ethyl 4-amino-2-(3-cyanophenyl)-6- (oxetan-3-ylmethoxy)pyrimidine-5-carboxylate (step 1) and lithium hydroxide monohydrate analogously to Example 1 step 5.
LC-MS (Method 2A): Rt 1.06 mins; MS m/z 327.0 = [M+H]+
1H NMR (500 MHz, Methanol-d4) d 8.71 (t, J = 1.4 Hz, 1H), 8.69 (dt, J = 7.8, 1.4 Hz, 1H), 7.85 (dt, J = 7.8, 1.4 Hz, 1H), 7.66 (t, J = 7.8 Hz, 1H), 4.88 (s, 2H), 4.79 (d, J = 6.2 Hz, 2H), 4.70 (t, J = 6.2 Hz, 2H), 3.59– 3.53 (m, 1H).
Step 3: 4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-(oxetan-3-ylmethoxy) pyrimidine-5-carboxamide
[00299] The title compound was prepared from 4-amino-2-(3-cyanophenyl)-6-(oxetan- 3-ylmethoxy)pyrimidine-5-carboxylic acid (step 2) and 1-aminooxy-2-methyl-propan-2-ol (Intermediate C) analogously to Example 1 step 6.
LC-MS (Method 7B): Rt 2.44 mins; MS m/z 414.2 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 11.16 (s, 1H), 8.64 (s, 1H), 8.62– 8.59 (m, 1H), 8.01 (d, J = 7.7 Hz, 1H), 7.88 (br.s, 2H), 7.74 (t, J = 7.8 Hz, 1H), 4.79– 4.70 (m, 5H), 4.50 (t, J = 5.9 Hz, 2H), 3.67 (s, 2H), 3.43 (dt, J = 13.7, 7.6 Hz, 1H), 1.16 (s, 6H).
Example 17
4-Amino-2-(3-cyanophenyl)-N-(2-methoxy-2-methyl-propoxy)-6-(oxetan-3-yloxy) pyrimidine-5-carboxamide
Figure imgf000146_0002
[00300] To a solution of 4-amino-2-(3-cyanophenyl)-6-(oxetan-3-yloxy)pyrimidine-5- carboxylic acid (Example 8 step 2) (100 mg, 0.32 mmol) and O-(2-methoxy-2-methyl- propyl)hydroxylamine (Intermediate I) (67 mg, 0.56 mmol) in DMF (5 mL) was added T3P® (50% solution in EtOAc, 1.14 mL, 1.6 mmol) followed by DIPEA (837 µL, 4.8 mmol) in quick succession and the mixture was stirred for 90 mins. The resulting mixture was partitioned between water (20 mL) and EtOAc (30 mL). The organic layer was separated and the aqueous portion was further extracted with EtOAc (2 x 30 mL). The organic extracts were combined, washed with brine (4 x 20 mL), dried over MgSO4 and concentrated in vacuo to afford a yellow oil. Purification by chromatography on silica eluting with a 7:3 mixture of EtOAc/hexane afforded a colourless solid which was suspended in hexane, filtered and dried to afford the title compound as a colourless solid.
LC-MS (Method 8B): Rt 4.24 mins; MS m/z 414.3 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 11.21 (s, 1H), 8.57 (t, J = 1.5 Hz, 1H), 8.52 (dt, J = 7.9, 1.5 Hz, 1H), 8.00 (dt, J = 7.9, 1.5 Hz, 1H), 7.79 - 7.72 (br s, 2H), 7.73 (t, J = 7.9 Hz, 1H), 5.77 (p, J = 5.9 Hz, 1H), 4.95 (apr t, J = 7.0 Hz, 2H), 4.70 (dd, J = 7.5, 5.9 Hz, 2H), 3.84 (s, 2H), 3.20 (s, 3H), 1.19 (s, 6H).
Example 17.1
Ethyl 2-[[4-amino-2-(3-cyanophenyl)-6-(oxetan-3-yloxy)pyrimidine-5- carbonyl]amino]oxyacetate
Figure imgf000147_0001
[00301] The title compound was prepared from 4-amino-2-(3-cyanophenyl)-6-(oxetan- 3-yloxy)pyrimidine-5-carboxylic acid (Example 8 step 2) and ethyl 2-aminooxyacetate (Intermediate Y) analogously to Example 17.
LC-MS (Method 8B): Rt 3.33 mins; MS m/z 414 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 11.31 (s, 1H), 8.57 (t, J = 1.8 Hz, 1H), 8.52 (dt, J = 8.1, 1.5 Hz, 1H), 8.01 (dt, J = 7.7, 1.4 Hz, 1H), 7.94– 7.80 (m, 2H), 7.73 (t, J = 7.8 Hz, 1H), 5.78 (p, J = 5.9 Hz, 1H), 4.95 (t, J = 7.0 Hz, 2H), 4.71 (dd, J = 7.5, 5.3 Hz, 2H), 4.61 (s, 2H), 4.20 (q, J = 7.1 Hz, 2H), 1.24 (t, J = 7.1 Hz, 3H). Example 18
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methylpropoxy)-6-[(1s,3s)-3- hydroxycyclobutoxy]pyrimidine-5-carboxamide
Figure imgf000148_0001
Step 1: Ethyl-4-amino-2-(3-cyanophenyl)-6-[(1s,3s)-3-[(tert- butyldimethylsilyl)oxy]cyclobutoxy] pyrimidine-5-carboxylate
Figure imgf000148_0002
[00302] A solution of ethyl 4-amino-6-chloro-2-(3-cyanophenyl)pyrimidine-5- carboxylate (Example 5 step 1) (500 mg, 1.65 mmol), (1s,3s)-3-[(tert- butyldimethylsilyl)oxy]cyclobutan-1-ol (501 mg, 2.48 mmol) and 1M potassium t-butoxide in THF (1.82 mL, 1.82 mmol) in THF (10 mL) was stirred at room temperature for 2 h. The resulting mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were filtered through a phase separating cartridge and concentrated in vacuo. The resulting orange gum was triturated in ether (20 mL), the solid removed by filtration, and the filtrate concentrated in vacuo. The resulting yellow gum was purified by chromatography on silica eluting with 0-100% EtOAc in heptane to afford a mixture of to afford a mixture of the title compound and [(1s, 3s)-3-[tert-butyl(dimethyl)silyl]oxycyclobutyl] 4- amino-6-[(1s, 3s)-3-[tert-butyl(dimethyl)silyl]oxycyclobutoxy]-2-(3-cyanophenyl)pyrimidine-5- carboxylate as a yellow oil.
LC-MS (Method 2A): Rt 2.08 mins; MS m/z 469.3 = [M+H]+ ethyl ester (53%) and Rt 2.39 min, MS m/z 625.4 = [M+H]+ trans esterified product (31%)
1H NMR (500 MHz, Chloroform-d) d 8.65 (s, 1H), 8.58 (dd, J = 7.8, 1.3 Hz, 1H), 7.74 (dt, J = 7.8, 1.3 Hz, 1H), 7.56 (t, J = 7.8 Hz, 1H), 4.98 (p, J = 7.3 Hz, 1H), 4.73 (p, J = 7.3 Hz, 0.3H), 4.58 (q, J = 6.5, 6.0 Hz, 0.2H), 4.35 (q, J = 7.1 Hz, 2H), 4.03 (q, J = 7.1 Hz, 0.3H), 3.83 (p, J = 7.2 Hz, 1H), 2.98– 2.91 (m, 2H), 2.87 (dtd, J = 9.5, 6.7, 3.0 Hz, 0.7H), 2.71 (dddd, J = 12.1, 9.4, 6.0, 2.8 Hz, 2H), 2.27– 2.16 (m, 3H), 1.93– 1.85 (m, 2H), 1.42 (t, J = 7.1 Hz, 2H), 0.90 (d, J = 3.1 Hz, 11H), 0.88 (s, 8H), 0.08 (s, 6H), 0.07 (s, 2H), 0.03 (s, 4H).
Step 2: Ethyl 4-amino-2-(3-cyanophenyl)-6-[(1s,3s)-3-hydroxycyclobutoxy]pyrimidine-5- carboxylate
Figure imgf000149_0001
[00303] To a stirred solution of a mixture of step 1 (896 mg, 1.01 mmol) in THF (10 mL) was added 4M HCl in 1,4-dioxane (1.82 mL, 7.29 mmol) and the mixture was stirred at room temperature for 1 h.
[00304] Additional 4M HCl in 1,4-dioxane (1.82 mL, 7.29 mmol) was added and stirring continued for 2 h. The resulting mixture was concentrated in vacuo and the residue was partitioned between DCM (50 mL) and sat. aq. sodium bicarbonate solution (50 mL). The organic portion was separated, washed with water (50 mL), sat. brine (50 mL), dried over Na2SO4 and concentrated in vacuo. The crude material was purified by chromatography on silica eluting with 0-100% EtOAc in heptane followed by 0-5% MeOH in EtOAc) to afford a mixture of the title compound and [(1s, 3s)-3-[tert-butyl(dimethyl)silyl]oxycyclobutyl] 4-amino- 6-[(1s, 3s)-3-[tert-butyl(dimethyl)silyl]oxycyclobutoxy]-2-(3-cyanophenyl)pyrimidine-5- carboxylate.
LC-MS (Method 2A): Rt 1.13 min; MS m/z 354.9 = [M+H]+
1H NMR (400MHz, DMSO-d6) d 8.63– 8.54 (m, 2H), 8.06– 7.98 (m, 1H), 7.90– 7.77 (m, 2H), 7.77– 7.71 (m, 1H), 5.20 (br. s, 1H), 4.99– 4.87 (m, 1H), 4.27 (q, J = 7.1 Hz, 2H), 3.98 – 3.86 (m, 1H), 2.94– 2.81 (m, 2H), 2.16– 1.73 (m, 2H), 1.32 (t, J = 7.1 Hz, 3H).
Step 3: 4-Amino-2-(3-cyanophenyl)-6-[(1s,3s)-3-hydroxycyclobutoxy]pyrimidine-5-carboxylic acid [00305] A solution of the mixture from step 2 (445 mg, 0.88 mmol) and lithium hydroxide monohydrate (148 mg, 3.52 mmol) in THF (6 mL) and water (2 mL) was stirred at room temperature for 2 h. The resulting mixture was diluted with water (5 mL) and washed with diethyl ether (10 mL). The aqueous layer was acidified to pH~1 using 1M HCl and the resulting precipitate was collected by vacuum filtration to afford the title compound as a mixture of 4- amino-2-(3-cyanophenyl)-6-[(1s,3s)-3-hydroxycyclobutoxy]pyrimidine-5-carboxylic acid and 4-amino-2-(3-carbamoylphenyl)-6-[(1s,3s)-3-hydroxycyclobutoxy]pyrimidine-5-carboxylic acid.
LC-MS (Method 2A): Rt 1.02 mins; MS m/z 327.1 = [M+H]+ 74% desired product
1H NMR (400 MHz, DMSO-d6) d 12.75 (s, 1H), 8.63– 8.56 (m, 2H), 8.01 (d, J = 7.8 Hz, 1H), 7.88 (s, 2H), 7.75 (t, J = 7.8 Hz, 1H), 5.18 (d, J = 6.7 Hz, 1H), 4.94 (p, J = 7.2 Hz, 1H), 3.92 (q, J = 6.9 Hz, 1H), 2.86 (ddt, J = 13.0, 9.5, 4.9 Hz, 2H), 2.06– 1.95 (m, 2H).
Step 4: 4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methylpropoxy)-6-[(1s,3s)-3- hydroxycyclobutoxy]pyrimidine-5-carboxamide
[00306] The title compound was prepared from a mixture of 4-amino-2-(3- cyanophenyl)-6-[(1s,3s)-3-hydroxycyclobutoxy]pyrimidine-5-carboxylic acid and 4-amino-2- (3-carbamoylphenyl)-6-[(1s,3s)-3-hydroxycyclobutoxy]pyrimidine-5-carboxylic acid (step 3) and 1-aminooxy-2-methyl-propan-2-ol (Intermediate C) analogously to Example 17.
LC-MS (Method 7A): Rt 2.52 mins; MS m/z 414.3 = [M+H]+
1H NMR(400MHz, DMSO-d6) d 11.13 (s, 1H), 8.73– 8.41 (m, 2H), 8.00 (dt, J = 7.7, 1.4Hz, 1H), 7.92– 7.42 (m, 3H), 5.20 (br s, 1H), 5.07– 4.85 (m, 1H), 4.75 (br s, 1H), 3.96– 3.88 (m, 1H), 3.72 (s, 2H), 2.95– 2.76 (m, 2H), 2.21– 1.97 (m, 2H), 1.18 (s, 6H). Example 19
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-tetrahydrothiophen-3- yloxy-pyrimidine-5-carboxamide
Figure imgf000151_0001
Step 1: 4-Amino-2-(3-cyanophenyl)-6-tetrahydrothiophen-3-yloxy-pyrimidine-5-carboxylic acid
Figure imgf000151_0002
[00307] Potassium t-butoxide (1M in THF) (1.17 mL, 1.17 mmol) was added to a solution of tetrahydrothiophen-3-ol (144 mg, 1.38 mmol) in THF (10 mL) at 0 ºC and the mixture stirred for 1 h. To this mixture was added ethyl 4-amino-6-chloro-2-(3- cyanophenyl)pyrimidine-5-carboxylate (Example 5 step 1) (350 mg, 1.06 mmol) and the resulting mixture was allowed to warm to room temperature and stirred for 18 h. Separately, tetrahydrothiophen-3-ol (55 mg, 0.53 mmol) was dissolved in THF (5 mL) and the mixture was cooled to 0 ºC and treated with potassium t-butoxide (1M in THF) (0.43 mL, 0.43 mmol). The mixture was stirred at 0 ºC for 1 h before being added to the reaction mixture. The resulting mixture was stirred at room temperature for a further 3.5 h before being diluted with water (30 mL) and saturated brine (20 mL) and extracted with EtOAc (3 x 40 mL). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo. The crude material was re- dissolved in THF (10 mL) and treated with a solution of lithium hydroxide (76 mg, 3.19 mmol) in water (5 mL). The resulting mixture was stirred vigorously at room temperature for 21 h. More lithium hydroxide (51 mg, 2.13 mmol) was added and the mixture stirred at room temperature for a further 72 h. The resulting mixture was concentrated in vacuo and the solid was re-dissolved in water and acidified to pH 2 by the dropwise addition of 2M HCl. A colourless solid formed which was filtered and washed with MeCN and Et2O to afford the title compound.
LC-MS (Method 5A): Rt 2.90 mins; MS m/z 343.1 = [M+H]+ 1H NMR (500 MHz, DMSO-d6) d 12.72 (s, 1H), 8.64 (s, 1H), 8.61 (d, J = 7.8 Hz, 1H), 8.02 (d, J = 7.8 Hz, 1H), 7.92 (s, 2H), 7.75 (t, J = 7.8 Hz, 1H), 6.11– 6.04 (m, 1H), 3.30– 3.24 (m, 1H), 3.04– 2.89 (m, 3H), 2.38– 2.29 (m, 1H), 2.11– 2.00 (m, 1H).
Step 2: 4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-tetrahydrothiophen-3- yloxy-pyrimidine-5-carboxamide
[00308] The title compound was prepared from 4-amino-2-(3-cyanophenyl)-6- tetrahydrothiophen-3-yloxy-pyrimidine-5-carboxylic acid (step 1) and 1-aminooxy-2-methyl- propan-2-ol (Intermediate C) analogously to Example 17.
LC-MS (Method 8B): Rt 4.65 mins; MS m/z 430.3 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 10.94 (s, 1H), 8.63 (t, J = 1.7 Hz, 1H), 8.59 (dt, J = 7.8, 1.4 Hz, 1H), 8.01 (dt, J = 7.8, 1.4 Hz, 1H), 7.79 (s, 2H), 7.74 (t, J = 7.8 Hz, 1H), 6.10 (s, 1H), 4.70 (s, 1H), 3.71 (s, 2H), 3.25 (dd, J = 12.0, 4.5 Hz, 1H), 3.09 (d, J = 12.0 Hz, 1H), 3.01– 2.92 (m, 2H), 2.48– 2.40 (m, 1H), 2.11 (dtd, J = 13.2, 9.0, 4.0 Hz, 1H), 1.17 (s, 6H).
Example 20a
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-(1-oxothiolan-3-yl)oxy- pyrimidine-5-carboxamide
Figure imgf000152_0001
[00309] mCPBA (41 mg, 0.24 mmol) was added to a suspension of 4-amino-2-(3- cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-tetrahydrothiophen-3-yloxy-pyrimidine-5- carboxamide (Example 19) (95 mg, 0.21 mmol) in chloroform (2 mL) and the mixture was stirred at room temperature for 20 h. Additional mCPBA (7 mg, 0.04 mmol) was added and the mixture was stirred for a further 30 mins. The resulting mixture was dry loaded onto silica and purified by chromatography eluting with 0-10% MeOH in DCM to afford the title compound as a colourless solid.
LC-MS (Method 8B): Rt 3.70 mins; MS m/z 446.2 = [M+H]+ 1H NMR (500 MHz, DMSO-d6) d 11.57 (s, 1H), 8.67 (t, J = 1.5 Hz, 1H), 8.62 (dt, J = 7.8, 1.5 Hz, 1H), 8.56 (br s, 1H), 8.02 (dt, J = 7.8, 1.5 Hz, 1H), 7.89 (br s, 1H), 7.75 (t, J = 7.8 Hz, 1H), 6.50– 6.42 (m, 1H), 4.58 (s, 1H), 3.64 (s, 2H), 3.55 (ddd, J = 14.2, 9.9, 4.4 Hz, 1H), 3.43 (d, J = 14.9 Hz, 1H), 3.13 (dd, J = 14.9, 4.4 Hz, 1H), 3.03– 2.93 (m, 1H), 2.75– 2.66 (m, 1H), 2.46– 2.38 (m, 1H), 1.13 (s, 6H).
Example 20b: 4-Amino-2-(3-cyanophenyl)-6-(1,1-dioxothiolan-3-yl)oxy-N-(2-hydroxy-2- methyl-propoxy)pyrimidine-5-carboxamide
Figure imgf000153_0001
[00310] A second compound was isolated from the reaction mixture obtained in Example 20a. Purification by chromatography eluting with 0-10% MeOH in DCM afforded a solid which was triturated from MeOH to afford the title compound as a colourless solid. LC-MS (Method 8B): Rt 3.85 mins; MS m/z 462.2 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 11.01 (s, 1H), 8.64 (d, J = 1.8 Hz, 1H), 8.59 (dt, J = 7.8, 1.5 Hz, 1H), 8.02 (dt, J = 7.8, 1.5 Hz, 1H), 7.87 (br s, 2H), 7.74 (t, J = 7.8 Hz, 1H), 6.14– 6.07 (m, 1H), 4.69 (s, 1H), 3.72 (s, 2H), 3.69 (dd, J = 14.4, 6.3 Hz, 1H), 3.51 (d, J = 14.4 Hz, 1H), 3.38 – 3.33 (m, 1H), 2.67– 2.59 (m, 1H), 2.59– 2.52 (m, 2H), 1.17 (s, 6H).
Example 21
4-Amino-6-(1-cyanoethoxy)-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy) pyrimidine-5-carboxamide
Figure imgf000153_0002
Step 1: Ethyl 4-amino-6-(1-cyanoethoxy)-2-(3-cyanophenyl)pyrimidine-5-carboxylate
Figure imgf000154_0001
[00311] To a suspension of ethyl 4-amino-6-chloro-2-(3-cyanophenyl)pyrimidine-5- carboxylate (Example 5 step 1) (500 mg, 1.65 mmol) in MeCN (40 mL) was added Cs2CO3 (1076 mg, 3.3 mmol) and 2-hydroxypropanenitrile (118 µL, 1.65 mmol) and the mixture was stirred at room temperature for 16 h. The temperature was increased to 40 °C and after stirring for a further 20 h, additional Cs2CO3 (1076 mg, 3.3 mmol) and 2-hydroxypropanenitrile (237 µL, 3.3 mmol) were added. The mixture was heated at 40 °C for a further 16 h and then diluted with water (15 mL). The mixture was extracted with EtOAc (3 x 50 mL) and the combined organic extracts were dried over MgSO4 and concentrated in vacuo. Purification by chromatography on silica eluting with 1% EtOAc in DCM afforded a colourless solid. The solid was suspended in Et2O (5 mL) and then filtered, washed with Et2O (5 mL) and dried to afford the title compound as a colourless solid.
LC-MS (Method 5B): Rt 3.36 mins; MS m/z 338.0 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 8.72 (t, J = 1.7 Hz, 1H), 8.64 (dt, J = 7.8, 1.7 Hz, 1H), 8.11 - 7.89 (br s, 2H), 8.06 (dt, J = 7.8, 1.7 Hz, 1H), 7.78 (t, J = 7.8 Hz, 1H), 6.04 (q, J = 6.8 Hz, 1H), 4.28 (q, J = 7.1 Hz, 2H), 1.72 (d, J = 6.8 Hz, 3H), 1.31 (t, J = 7.1 Hz, 3H).
Step 2: 4-Amino-6-(1-cyanoethoxy)-2-(3-cyanophenyl)pyrimidine-5-carboxylic acid
Figure imgf000154_0002
[00312] To a solution of ethyl 4-amino-6-(1-cyanoethoxy)-2-(3- cyanophenyl)pyrimidine-5-carboxylate (step 2) (38 mg, 0.11 mmol) in THF (1 mL) was added a solution of lithium hydroxide (5 mg, 0.23 mmol) in water (0.5 mL) and the mixture was stirred at room temperature for 16 h. The resulting mixture was partitioned between water (5 mL) and EtOAc (10 mL) and the organic portion was separated. The aqueous layer was further washed with EtOAc (10 mL) and the combined organic portions discarded. The aqueous portion was acidified with 2M HCl to pH ~ 2 and the resulting solid was collected by filtration and dried to afford the title compound as a mixture with 4-amino-6-(2-amino-1-methyl-2-oxo-ethoxy)-2-(3- cyanophenyl)pyrimidine-5-carboxylic acid.
LC-MS (Method 5A): Rt 2.44 mins; MS m/z 310.1 = [M+H]+
N71-35-1: 1H NMR (500 MHz, DMSO-d6) d 13.06 (s, 1H), 8.73 (s, 1H), 8.65 (d, J = 8.2 Hz, 1H), 8.06 (d, J = 7.7 Hz, 1H), 7.97 (s, 1H), 7.79 (t, J = 7.8 Hz, 1H), 7.56 (s, 1H), 6.07 (q, J = 6.8 Hz, 1H), 1.72 (d, J = 6.8 Hz, 3H).
Step 3: 4-Amino-6-(1-cyanoethoxy)-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy) pyrimidine-5-carboxamide
[00313] The title compound was prepared from 4-amino-6-(2-amino-1-methyl-2-oxo- ethoxy)-2-(3-cyanophenyl)pyrimidine-5-carboxylic acid (a mixture with 4-amino-6-(2-amino-1- methyl-2-oxo-ethoxy)-2-(3-cyanophenyl)pyrimidine-5-carboxylic acid) (step 2) and 1- aminooxy-2-methyl-propan-2-ol (Intermediate C) analogously to Example 17.
LC-MS (Method 8B): Rt 3.77 mins; MS m/z 397.3 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 11.28 (br s, 1H), 8.70 (s, 1H), 8.62 (d, J = 7.9 Hz, 1H), 8.04 (d, J = 7.9 Hz, 1H), 7.82– 7.70 (m, 3H), 5.97 (q, J = 6.9 Hz, 1H), 4.72 (br s, 1H), 3.72 (s, 2H), 1.75 (d, J = 6.9 Hz, 3H), 1.18 (s, 6H).
Example 22
4-Amino-2-(3-cyanophenyl)-6-[2-hydroxy-1-(hydroxymethyl)ethoxy]-N-(2-hydroxy-2- methyl-propoxy)pyrimidine-5-carboxamide
Figure imgf000155_0001
[00314] 1M aqueous HCl (0.59 mL, 0.59 mmol) was added to a solution of 4-amino-2- (3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(2-phenyl-1,3-dioxan-5- yl)oxy]pyrimidine-5-carboxamide (Example 11.5) (60 mg, 0.12 mmol) in THF (5 mL) and the reaction mixture was stirred at room temperature for 60 h.1M aqueous HCl (0.59 mL, 0.59 mmol) was added and stirring continued for 10 h after which time a further portion of 1M aqueous HCl (0.59 mL, 0.59 mmol) was added.
[00315] After a total of 88 h, the mixture was diluted with water (2 mL) and extracted with DCM (3 x 5 mL). The combined organic extracts were filtered through a phase separating cartridge and concentrated in vacuo. Purification of the crude material by preparative HPLC eluting with 0.1% NH3 in water and acetonitrile afforded the title compound as a colourless solid.
MSQ2 - LC-MS (Method 7A): Rt 2.07 mins; MS m/z 418.3 = [M+H]+
1H NMR (400 MHz, Methanol-d4) d 8.73– 8.63 (m, 2H), 7.89– 7.81 (m, 1H), 7.65 (t, J = 7.8 Hz, 1H), 5.59 (p, J = 5.1 Hz, 1H), 4.00– 3.88 (m, 4H), 3.85 (s, 2H), 1.28 (s, 6H).
Example 23
4-Amino-2-(3-cyanophenyl)-N-[(1-hydroxycyclobutyl)methoxy]-6-[(3S)-tetrahydrofuran- 3-yl]oxy-pyrimidine-5-carboxamide
Figure imgf000156_0001
[00316] T3P® (50% in DMF) (0.43 mL, 0.61 mmol) was added to a stirred mixture of 4- amino-2-(3-cyanophenyl)-6-[(3S)-tetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxylic acid (Intermediate K) (100 mg, 0.31 mmol), 1-(aminooxymethyl)cyclobutanol (Intermediate J) (53.85 mg, 0.46 mmol) and DIPEA (0.27 mL, 1.53 mmol) in anhydrous DMF (3 mL) under nitrogen. The mixture was stirred at room temperature overnight and then heated to 50 ºC for 2 h. The resulting mixture was diluted with EtOAc (20 mL) and washed with 90% brine (20 mL) and 50% brine (3 x 20 mL). The organic portion was dried over MgSO4 and concentrated in vacuo. The crude product was purified by C18 reverse phase chromatography eluting with 10 to 100% MeCN in water (+0.1% NH4OH) followed by re-purification by chromatography on silica eluting with 0 to 10% MeOH in DCM and then C18 reverse phase chromatography eluting with 10 to 100% MeCN in water (+0.1% formic acid) to afford the title compound as an off-white solid.
LC-MS (Method 8B): Rt 3.76 mins; MS m/z 426.3 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 11.04 (s, 1H), 8.63 (s, 1H), 8.59 (d, J = 8.0 Hz, 1H), 8.02 (d, J = 7.7 Hz, 1H), 7.83– 7.67 (m, 3H), 5.80 (s, 1H), 5.41 (s, 1H), 4.05 (dd, J = 10.4, 4.9 Hz, 1H), 3.92– 3.85 (m, 4H), 3.83– 3.77 (m, 1H), 2.34– 2.24 (m, 1H), 2.23– 2.08 (m, 3H), 2.03– 1.92 (m, 2H), 1.72– 1.61 (m, 1H), 1.57– 1.46 (m, 1H).
[00317] The compounds of the following tabulated Examples (Table Ex23) were prepared analogously to Example 23 from 4-amino-2-(3-cyanophenyl)-6-[rac-(3S)- tetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxylic acid (Intermediate K) and the appropriate alcohol. Preparations of non-commercial hydroxylamines are described hereinafter. Table Ex23
E
2 S
6 1 5 4 , , 7 – 2 2 S
0 0 5 0 = – , – 2 2
2
Figure imgf000157_0001
. p
after this table. Ex. Structure and Name Retention Time, [M+H]+, 1H NMR 2 S
6 8 2 , 2 , 9
2 S
8 , , , 6 , , – 1 0
2 S
7 1 , , 8 , , 0
2 S
0 8 = , , , – 5
Figure imgf000158_0001
py .
(Prepared using Intermediate LB) Ex. Structure and Name Retention Time, [M+H]+, 1H NMR 2 S
4 8 = , , , – 1 2 S
7 0 8 8 , , , 0 2 ;
6 9 = 4 , , – 0 2 ;
8 8 , , , , – 6
Figure imgf000159_0001
(Prepared using Intermediate LD) Ex. Structure and Name Retention Time, [M+H]+, 1H NMR 2 S
1 7 , , , 9 , , e 2 ;
6 J
5 2 J
1 8 , ,
2 ;
6 = , , , – = , ,
Figure imgf000160_0001
(Prepared using Intermediate LE) . Ex. Structure and Name Retention Time, [M+H]+, 1H NMR
2 S
6 = , 5 , , , 8 ,
2 S
1 = , , r , , – , 1
Figure imgf000161_0002
Examples 23.3 and 23.4
4-Amino-2-(3-cyanophenyl)-N-[(1R)-1-oxazol-2-ylethoxy]-6-[(3S)-tetrahydrofuran-3- yl]oxy-pyrimidine-5-carboxamide and 4-amino-2-(3-cyanophenyl)-N-[(1S)-1-oxazol-2- ylethoxy]-6-[(3S)-tetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxamide
Figure imgf000161_0001
and
[00318] A diastereomeric mixture of 4-amino-2-(3-cyanophenyl)-N-[(1R)-1-oxazol-2- ylethoxy]-6-[(3S)-tetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxamide and 4-amino-2-(3- cyanophenyl)-N-[(1S)-1-oxazol-2-ylethoxy]-6-[(3S)-tetrahydrofuran-3-yl]oxy-pyrimidine-5- carboxamide was prepared from 4-amino-2-(3-cyanophenyl)-6-[rac-(3S)-tetrahydrofuran-3- yl]oxy-pyrimidine-5-carboxylic acid (Intermediate K) and O-(1-oxazol-2-ylethyl)hydroxylamine (Intermediate AA). The mixture was separated using Supercritical Fluid Chromatography under the following conditions:
Column: Lux A2 (21.2 mm x 250 mm, 5 µm)
Column Temperature: Ambient
Flow Rate: 21 mL/min
Detector Wavelength: 220 nm
Injection Volume: 1000 µL (3 mg)
Isocratic Conditions: 60:40 Heptane:EtOH (0.2% v/v NH3)
Examples 23.3: 4-Amino-2-(3-cyanophenyl)-N-[(1R)-1-oxazol-2-ylethoxy]-6-[(3S)- tetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxamide or 4-amino-2-(3-cyanophenyl)-N- [(1S)-1-oxazol-2-ylethoxy]-6-[(3S)-tetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxamide
Figure imgf000162_0001
Chiral SFC (Method CP5): First Eluted Peak Rt = 8.83 mins
LC-MS (Method 8B): Rt 4.39 mins; MS m/z 437.3 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 10.99 (s, 1H), 8.62 (t, J = 1.8 Hz, 1H), 8.58 (dt, J = 7.8, 1.5 Hz, 1H), 8.17 (s, 1H), 8.01 (dt, J = 7.8, 1.5 Hz, 1H), 7.74 (t, J = 7.8 Hz, 1H), 7.64 (s, 2H), 7.25 (s, 1H), 5.76– 5.71 (m, 1H), 5.20 (q, J = 6.6 Hz, 1H), 4.03 (dd, J = 10.4, 5.0 Hz, 1H), 3.86– 3.75 (m, 3H), 2.30– 2.20 (m, 1H), 2.13– 2.04 (m, 1H), 1.61 (d, J = 6.6 Hz, 3H).
Examples 23.4: 4-Amino-2-(3-cyanophenyl)-N-[(1R)-1-oxazol-2-ylethoxy]-6-[(3S)- tetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxamide or 4-amino-2-(3-cyanophenyl)-N- [(1S)-1-oxazol-2-ylethoxy]-6-[(3S)-tetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxamide
Figure imgf000163_0001
Chiral SFC (Method CP5): First Eluted Peak Rt = 10.48 mins
LC-MS (Method 8B): Rt 4.29 mins; MS m/z 437.2 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 10.97 (s, 1H), 8.61 (d, J = 1.8 Hz, 1H), 8.57 (dt, J = 7.8, 1.5 Hz, 1H), 8.16 (s, 1H), 8.00 (dt, J = 7.8, 1.5 Hz, 1H), 7.73 (t, J = 7.8 Hz, 1H), 7.64 (s, 2H), 7.24 (s, 1H), 5.75– 5.70 (m, 1H), 5.19 (q, J = 6.6 Hz, 1H), 4.02 (dd, J = 10.4, 5.0 Hz, 1H), 3.85– 3.74 (m, 3H), 2.31– 2.20 (m, 1H), 2.11– 2.02 (m, 1H), 1.60 (d, J = 6.6 Hz, 3H).
Examples 23.6a and 23.6b
[00319] Chiral separation of racemic 4-amino-2-(3-cyanophenyl)-N-(2-hydroxy-1,2- dimethyl-propoxy)-6-[(3S)-tetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxamide (Example 23.6) using Supercritical Fluid Chromatography under the following conditions afforded the individual enantiomers:
Column: Lux iC5 (21.2 mm x 250 mm, 5 µm)
Column Temperature: 40 ˚C
Flow Rate: 50 mL/min
BPR: 125 BarG
Detector Wavelength: 218 nm
Injection Volume: 200 µL (7.5 mg)
Isocratic Conditions: 45:55 EtOH:CO2 (0.2% v/v NH3)
Example 23.6a: 4-Amino-2-(3-cyanophenyl)-N-[(1R)-2-hydroxy-1,2-dimethyl-propoxy]- 6-[(3S)-tetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxamide or 4-amino-2-(3- cyanophenyl)-N-[(1S)-2-hydroxy-1,2-dimethyl-propoxy]-6-[(3S)-tetrahydrofuran-3- yl]oxy-pyrimidine-5-carboxamide
Figure imgf000164_0002
Chiral SFC (Method CP2): First Eluted Peak Rt 2.44 mins
LC-MS (Method 8B): Rt 4.59 mins; MS m/z 428.3 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 10.97 (s, 1H), 8.62 (t, J = 1.5 Hz, 1H), 8.59 (dt, J = 7.8, 1.5 Hz, 1H), 8.01 (dt, J = 7.8, 1.5 Hz, 1H), 7.74 (t, J = 7.8 Hz, 1H), 7.69 (br s, 2H), 5.82– 5.76 (m, 1H), 4.73 (s, 1H), 4.04 (dd, J = 10.4, 5.0 Hz, 1H), 3.93– 3.84 (m, 2H), 3.80 (td, J = 8.2, 4.6 Hz, 1H), 3.72 (q, J = 6.4 Hz, 1H), 2.35– 2.25 (m, 1H), 2.17– 2.09 (m, 1H), 1.21 (d, J = 6.4 Hz, 3H), 1.18 (s, 3H), 1.10 (s, 3H).
Example 23.6b: 4-Amino-2-(3-cyanophenyl)-N-[(1R)-2-hydroxy-1,2-dimethyl-propoxy]- 6-[(3S)-tetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxamide or 4-amino-2-(3- cyanophenyl)-N-[(1S)-2-hydroxy-1,2-dimethyl-propoxy]-6-[(3S)-tetrahydrofuran-3- yl]oxy-pyrimidine-5-carboxamide
Figure imgf000164_0001
Chiral SFC (Method CP2): Second Eluted Peak Rt = 2.81 mins
LC-MS (Method 8B): Rt 4.47 mins; MS m/z 428.3 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 10.98 (s, 1H), 8.62 (t, J = 1.5 Hz, 1H), 8.59 (dt, J = 7.9, 1.4 Hz, 1H), 8.01 (dt, J = 7.9, 1.4 Hz, 1H), 7.74 (t, J = 7.9 Hz, 1H), 7.69 (br s, 2H), 5.83– 5.77 (m, 1H), 4.75 (s, 1H), 4.04 (dd, J = 10.4, 4.9 Hz, 1H), 3.92– 3.78 (m, 3H), 3.72 (q, J = 6.4 Hz, 1H), 2.33– 2.24 (m, 1H), 2.24– 2.15 (m, 1H), 1.20 (d, J = 6.4 Hz, 3H), 1.18 (s, 3H), 1.10 (s, 3H).
Example 24 4-Amino-2-(3-cyanophenyl)-N-[(5-isopropyl-4H-1,2,4-triazol-3-yl)methoxy]-6-[(3S)- tetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxamide
Figure imgf000165_0001
Step 1: tert-Butyl 3-[[[4-amino-2-(3-cyanophenyl)-6-[(3S)-tetrahydrofuran-3-yl]oxy-pyrimidine- 5-carbonyl]amino]oxymethyl]-5-isopropyl-1,2,4-triazole-4-carboxylate
Figure imgf000165_0002
[00320] The title compound was prepared from 4-amino-2-(3-cyanophenyl)-6-[(3S)- tetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxylic acid (Intermediate K) and tert-butyl 3- (aminooxymethyl)-5-isopropyl-1,2,4-triazole-4-carboxylate (Intermediate L) analogously to Example 23.
N85-69-2 LC-MS (Method 5A): Rt 3.21 mins; MS m/z 565.3 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 10.95 (s, 1H), 8.62 (t, J = 1.6 Hz, 1H), 8.58 (dt, J = 7.8, 1.6 Hz, 1H), 8.00 (dt, J = 7.8, 1.6 Hz, 1H), 7.73 (t, J = 7.8 Hz, 3H), 5.76– 5.71 (m, 1H), 4.91 (s, 2H), 3.98 (dd, J = 10.3, 4.9 Hz, 1H), 3.78– 3.63 (m, 4H), 2.27– 2.19 (m, 1H), 2.08– 2.02 (m, 1H), 1.60 (s, 9H), 1.29 (d, J = 6.8 Hz, 6H).
Step 2: 4-Amino-2-(3-cyanophenyl)-N-[(5-isopropyl-4H-1,2,4-triazol-3-yl)methoxy]-6-[(3S)- tetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxamide
[00321] 4M HCl in 1,4-dioxane (1.2 mL, 4.78 mmol) was added to tert-butyl 3-[[[4- amino-2-(3-cyanophenyl)-6-[(3S)-tetrahydrofuran-3-yl]oxy-pyrimidine-5- carbonyl]amino]oxymethyl]-5-isopropyl-1,2,4-triazole-4-carboxylate (step 1) (30 mg, 0.05 mmol) and the mixture stirred at room temperature for 3 h. The resulting mixture was concentrated in vacuo and purification of the crude material by C18 reverse phase chromatography eluting with 10 to 40% MeCN in water (+0.1% formic acid) afforded the title compound.
LC-MS (Method 8B): Rt 3.59 mins; MS m/z 465.3 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 13.68 (br s, 1H), 10.96 (br s, 1H), 8.62 (t, J = 1.5 Hz, 1H), 8.58 (dt, J = 7.8, 1.5 Hz, 1H), 8.01 (dt, J = 7.8, 1.5 Hz, 1H), 7.80 - 7.71 (m, 2H), 7.74 (t, J = 7.8 Hz, 1H), 5.77– 5.72 (m, 1H), 4.90 (s, 2H), 4.01 (dd, J = 10.4, 4.9 Hz, 1H), 3.82– 3.75 (m, 3H), 3.11– 2.97 (m, 1H), 2.31– 2.21 (m, 1H), 2.11– 2.02 (m, 1H), 1.26 (d, J = 7.0 Hz, 6H).
Example 25
4-Amino-2-(3-cyanophenyl)-6-[(3S)-tetrahydrofuran-3-yl]oxy-N-(2H-tetrazol-5- ylmethoxy)pyrimidine-5-carboxamide
Figure imgf000166_0001
Step 1: 4-Amino-2-(3-cyanophenyl)-6-[(3S)-tetrahydrofuran-3-yl]oxy-N-[(2-trityltetrazol-5- yl)methoxy]pyrimidine-5-carboxamide
Figure imgf000166_0002
[00322] The title compound was prepared from 4-amino-2-(3-cyanophenyl)-6-[(3S)- tetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxylic acid (Intermediate K) and O-[(2-trityltetrazol- 5-yl)methyl]hydroxylamine (Intermediate M) analogously to Example 23.
LC-MS (Method 5B): Rt 3.92 mins; MS m/z 664.3 = [M-H]- 1H NMR (500 MHz, DMSO-d6) d 11.09 (br s, 1H), 8.62 (br t, J = 1.5 Hz, 1H), 8.59 (br dt, J = 8.0, 1.5 Hz, 1H), 8.01 (br dt, J = 7.7, 1.5 Hz, 1H), 7.74 (apr t, J = 7.8 Hz, 1H), 7.65 (br s, 2H), 7.45– 7.29 (m, 9H), 7.08– 6.96 (m, 6H), 5.74– 5.68 (m, 1H), 5.26– 5.16 (m, 2H), 3.98 (dd, J = 10.4, 5.0 Hz, 1H), 3.82– 3.74 (m, 2H), 3.69 (td, J = 8.2, 4.6 Hz, 1H), 2.23– 2.15 (m, 1H), 2.11– 2.02 (m, 1H)
Step 2: 4-Amino-2-(3-cyanophenyl)-6-[(3S)-tetrahydrofuran-3-yl]oxy-N-(2H-tetrazol-5- ylmethoxy)pyrimidine-5-carboxamide
[00323] 4-Amino-2-(3-cyanophenyl)-6-[(3S)-tetrahydrofuran-3-yl]oxy-N-[(2- trityltetrazol-5-yl)methoxy] pyrimidine-5-carboxamide (step 1) (170 mg, 0.26 mmol) was dissolved in a mixture of DCM (0.5 mL) and MeOH (0.5mL) and treated dropwise with TFA (1 mL, 13.06 mmol). After stirring for 1 h, the resulting suspension was diluted with DCM (2 mL), filtered and the solid was washed with Et2O (5 mL) and dried to afford the title compound as a colourless solid.
LC-MS (Method 8A): Rt 3.97 mins; MS m/z 424.2 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 11.14 (s, 1H), 8.61 (t, J = 1.8 Hz, 1H), 8.58 (dt, J = 8.0, 1.5 Hz, 1H), 8.01 (dt, J = 7.7, 1.5 Hz, 1H), 7.73 (t, J = 7.8 Hz, 1H), 7.65 (s, 2H), 5.72 (apr ddt, J = 7.1, 4.7, 2.3 Hz, 1H), 5.29 (s, 2H), 4.02 (dd, J = 10.4, 5.0 Hz, 1H), 3.83– 3.73 (m, 3H), 2.29– 2.19 (m, 1H), 2.10– 2.02 (m, 1H).1 x exchangeable proton not observed.
Example 25.1
4-Amino-2-(3-cyanophenyl)-N-(1H-imidazol-2-ylmethoxy)-6-[(3S)-tetrahydrofuran-3- yl]oxy-pyrimidine-5-carboxamide
Figure imgf000167_0001
Step 1: 4-Amino-2-(3-cyanophenyl)-6-[(3S)-tetrahydrofuran-3-yl]oxy-N-[(1-tritylimidazol-2- yl)methoxy]pyrimidine-5-carboxamide
Figure imgf000168_0001
[00324] The title compound was prepared from 4-amino-2-(3-cyanophenyl)-6-[(3S)- tetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxylic acid (Intermediate K) and O-[(1-tritylimidazol- 2-yl)methyl]hydroxylamine (Intermediate N) analogously to Example 23.
LC-MS (Method 5B): Rt 3.88 mins; MS m/z 664.4 = [M+H
1H NMR (500 MHz, DMSO-d6) d 11.00 (s, 1H), 8.63 (d, J = 1.8 Hz, 1H), 8.59 (dt, J = 7.8, 1.5 Hz, 1H), 8.35 (br s, 2H), 8.02 (dt, J = 7.8, 1.5 Hz, 1H), 7.74 (t, J = 7.8 Hz, 1H), 7.41– 7.37 (m, 9H), 7.09– 7.04 (m, 6H), 7.03 (d, J = 1.5 Hz, 1H), 6.77 (d, J = 1.5 Hz, 1H), 5.83– 5.77 (m, 1H), 4.07 (dd, J = 10.6, 5.1 Hz, 1H), 3.95 (s, 2H), 3.88– 3.76 (m, 3H), 2.33– 2.24 (m, 1H), 2.19– 2.11 (m, 1H).
Step 2: 4-Amino-2-(3-cyanophenyl)-N-(1H-imidazol-2-ylmethoxy)-6-[(3S)-tetrahydrofuran-3- yl]oxy-pyrimidine-5-carboxamide
[00325] The title compound was prepared from 4-amino-2-(3-cyanophenyl)-6-[(3S)- tetrahydrofuran-3-yl]oxy-N-[(1-tritylimidazol-2-yl)methoxy]pyrimidine-5-carboxamide (step 1) and TFA analogously Example 25 step 2.
LC-MS (Method 8B): Rt 3.44 mins; MS m/z 422.3 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 12.29 (br s, 1H), 11.02 (br s, 1H), 8.62 (d,J= 1.8 Hz, 1H), 8.59 (dt,J= 7.8, 1.5 Hz, 1H), 8.01 (dt,J= 7.8, 1.6 Hz, 1H), 7.77 (br s, 2H), 7.74 (t,J= 7.8 Hz, 1H), 7.04 (s, 2H), 5.79– 5.71 (m, 1H), 4.91 (s, 2H), 4.02 (dd,J= 10.4, 5.0 Hz, 1H), 3.84– 3.73 (m, 3H), 2.31– 2.20 (m, 1H), 2.11– 2.02 (m, 1H). Example 26a: 4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1R)-1- (hydroxymethyl)propoxy]pyrimidine-5-carboxamide and
CH3
3
Figure imgf000169_0001
Example 26b: 4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(2R)-2- hydroxybutoxy]pyrimidine-5-carboxamide
Figure imgf000169_0002
Step 1: Ethyl 4-amino-2-(3-cyanophenyl)-6-[(1R)-1-[[tert-butyl(dimethyl)silyl] oxymethyl]propoxy]pyrimidine-5-carboxylate and ethyl 4-amino-2-(3-cyanophenyl)-6-[(2R)-1- [[tert-butyl(dimethyl)silyl] oxymethyl]propoxy]pyrimidine-5-carboxylate
Figure imgf000169_0003
[00326] To a mixture of ethyl 4-amino-6-chloro-2-(3-cyanophenyl)pyrimidine-5- carboxylate (Example 5 step 1) (500 mg, 1.65 mmol) and (2R)-1-[tert- butyl(dimethyl)silyl]oxybutan-2-ol (Intermediate S) (709 mg, 3.47 mmol) in dry THF (20 mL) under nitrogen at 0 ˚C was added LiHMDS (1M in THF) (3.3 mL, 3.3 mmol) and the mixture was stirred at 50 °C overnight. After cooling to room temperature, the mixture was poured into sat. NaHCO3 (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo. Purification by chromatography on silica eluting with 10% EtOAc in petrol afforded a mixture of the title compounds as a pale yellow oil.
LC-MS (Method 3B): Rt 2.73 mins; MS m/z 471.3 = [M+H]+ Step 2: 4-Amino-2-(3-cyanophenyl)-6-[(1R)-1-(hydroxymethyl)propoxy]pyrimidine-5- carboxylic acid and 4-amino-2-(3-cyanophenyl)-6-[(1R)-1- (hydroxymethyl)propoxy]pyrimidine-5-carboxylic acid
Figure imgf000170_0001
[00327] A mixture of ethyl 4-amino-2-(3-cyanophenyl)-6-[(1R)-1-[[tert- butyl(dimethyl)silyl]oxymethyl]propoxy]pyrimidine-5-carboxylate (step 1) (287 mg, 0.52 mmol) and lithium hydroxide (44 mg, 1.84 mmol) in THF (9 mL) and water (3 mL) were stirred at room temperature for 4 days. The resulting mixture was diluted with water (50 mL) and washed with Et2O (2 x 50 mL). The layers were separated and the aqueous portion was acidified with 2M HCl and extracted with EtOAc (3 x 50 mL). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo to afford a mixture of the title compounds as a clear colourless oil.
LC-MS (Method 5A): Rt 2.31 mins; MS m/z 329.2 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 12.70 (br. s, 1H), 8.67 (dt, J = 6.6, 1.9 Hz, 1H), 8.66– 8.61 (m, 1H), 8.06 (ddd, J = 7.7, 3.0, 1.3 Hz, 1H), 7.94 (br. s, 2H), 7.79 (t, J = 7.8 Hz, 1H), 5.50– 5.40 (m, 0.5H), 4.48 (dd, J = 10.8, 5.7 Hz, 0.5H), 4.40 (dd, J = 10.8, 5.7 Hz, 0.5H), 3.80 (m, 0.5H), 3.69 (dd, J = 11.3, 5.5 Hz, 0.5H), 3.62 (dd, J = 11.3, 5.5 Hz, 0.5H), 1.87– 1.77 (m, 0.5H), 1.77– 1.70 (m, 0.5H), 1.70– 1.63 (m, 0.5H), 1.52– 1.44 (m, 0.5H), 0.98 (dt, J = 9.9, 7.4 Hz, 3H).1 x exchangeable proton not observed. Step 3: Example 26a: 4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1R)- 1-(hydroxymethyl)propoxy]pyrimidine-5-carboxamide and
Example 26b:4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(2R)-2- hydroxybutoxy]pyrimidine-5-carboxamide
[00328] To a solution of 4-amino-2-(3-cyanophenyl)-6-[(1R)-1- (hydroxymethyl)propoxy]pyrimidine-5-carboxylic acid (74 mg, 0.23 mmol), 1-aminooxy-2- methyl-propan-2-ol (Intermediate C) (36 mg, 0.34 mmol) and DIPEA (196 µL, 1.13 mmol) in DMF (2 mL) was added T3P® (50% in DMF) (317 µL, 0.45 mmol) and the mixture was stirred at room temperature for 4 h. The resulting mixture was partitioned between EtOAc (20 mL) and water (20 mL). The layers were separated and the aqueous portion was extracted with EtOAc (2 x 20 mL). The combined organic extracts were washed with 50% brine (4 x 20 mL), dried over MgSO4 and concentrated in vacuo. Purification by chromatography on silica eluting with 50 to 70% EtOAc in petrol afforded of a colourless oil. The oil was further purified by chromatography on silica eluting with a gradient of 0 to 4% MeOH in DCM to yield a brown solid. Purification of the mixture using preparative HPLC under the following conditions afforded the 2 regioisomers:
Column: Lux A1 (21.2 mm x 250 mm, 5 µm)
Column Temperature: Ambient
Flow Rate: 21 mL/min
Detector Wavelength: 221 nm
Injection Volume: 1000 µL (5 mg)
Isocratic Conditions: 60:40 Heptane:EtOH (0.2% v/v NH3)
Example 26a: 4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1R)-1- (hydroxymethyl)propoxy]pyrimidine-5-carboxamide
Chiral SFC (Method CP1): First Eluted Peak Rt = 1.31 mins
LC-MS (Method 8B): Rt 4.14 mins; MS m/z 416.3 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 11.02 (br. s, 1H), 8.60 (dd, J = 1.6, 1.6 Hz, 1H), 8.57 (ddd, J = 7.9, 1.6, 1.4 Hz, 1H), 8.01 (ddd, J = 7.7, 1.6, 1.4 Hz, 1H), 7.91 (br. s, 2H), 7.74 (dd, J = 7.9, 7.7 Hz, 1H), 5.45– 5.35 (m, 1H), 5.04 (br. s, 1H), 4.74 (s, 1H), 3.70 (s, 2H), 3.68– 3.64 (m, 2H), 1.83– 1.72 (m, 2H), 1.17 (s, 6H), 0.95 (t, J = 7.5 Hz, 3H).
Example 26b: 4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(2R)-2- hydroxybutoxy]pyrimidine-5-carboxamide
Chiral SFC (Method CP1): Second Eluted Peak Rt = 2.01 mins
LC-MS (Method 8B): Rt 3.85 mins; MS m/z 416.3 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 11.11 (br. s, 1H), 8.62 (dd, J = 1.7, 1.7 Hz, 1H), 8.58 (ddd, J = 8.0, 1.7, 1.4 Hz, 1H), 8.01 (ddd, J = 7.9, 1.7, 1.4 Hz, 1H), 7.93 (br. s, 2H), 7.74 (dd, J = 8.0, 7.9 Hz, 1H), 5.06 (br. s, 1H), 4.73 (br. s, 1H), 4.49 (dd, J = 10.9, 4.3 Hz, 1H), 4.40 (dd, J = 10.9, 6.4 Hz, 1H), 3.85– 3.76 (m, 1H), 3.71 (s, 2H), 1.63– 1.52 (m, 1H), 1.51– 1.40 (m, 1H), 1.17 (s, 6H), 0.95 (t, J = 7.4 Hz, 3H). Example 27
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[rac-(1R,3R)-3- hydroxycyclopentoxy]pyrimidine-5-carboxamide
Figure imgf000172_0001
Step 1: [rac-(1R,3R)-3-[tert-Butyl(dimethyl)silyl]oxycyclopentyl] 4-amino-2-(3-cyanophenyl)-6- [rac-(1R,3R)-3-[tert-butyl(dimethyl)silyl]oxycyclopentoxy]pyrimidine-5-carboxylate
Figure imgf000172_0002
[00329] The title compound was prepared analogously from ethyl 4-amino-6-chloro-2- (3-cyanophenyl)pyrimidine-5-carboxylate (Example 5 step 1) and rac-(1R,3R)-3-[tert- butyl(dimethyl)silyl]oxycyclopentanol (Intermediate SA) analogously to Example 26 step 1. LC-MS (Method 3B): Rt 3.36 mins; MS m/z 653.4 = [M+H]+
1H NMR (500 MHz, Chloroform-d) d 8.67 (t, J = 1.5 Hz, 1H), 8.61 (dt, J = 7.8, 1.5 Hz, 1H), 7.75 (dt, J = 7.8, 1.5 Hz, 1H), 7.56 (t, J = 7.8 Hz, 1H), 5.81– 5.73 (m, 1H), 5.50– 5.41 (m, 1H), 4.51– 4.40 (m, 2H), 2.38– 2.22 (m, 2H), 2.19– 2.11 (m, 1H), 2.10– 1.92 (m, 5H), 1.88 – 1.74 (m, 2H), 1.73– 1.62 (m, 2H), 0.91 (s, 9H), 0.89 (s, 9H), 0.11– 0.03 (m, 12H).
2 x exchangeable protons not observed.
Step 2: [rac-(1R,3R)-3-Hydroxycyclopentyl] 4-amino-2-(3-cyanophenyl)-6-[rac-(1R,3R)-3- hydroxycyclopentoxy]pyrimidine-5-carboxylate [00330] To a solu
Figure imgf000173_0002
tion of [rac-(1R,3R)-3-[tert-butyl(dimethyl)silyl]oxycyclopentyl] 4- amino-2-(3-cyanophenyl)-6-[rac-(1R,3R)-3-[tert- butyl(dimethyl)silyl]oxycyclopentoxy]pyrimidine-5-carboxylate (step 1) (218 mg, 0.33 mmol) in 1,4-dioxane (5 mL) was added 4M HCl in 1,4-dioxane (835 µL, 3.34 mmol) dropwise and the mixture stirred for 16 h. Additional 4M HCl in 1,4-dioxane (835 µL, 3.34 mmol) was added and the mixture stirred for 80 h. The resulting precipitate was collected by filtration, washed with 1,4-dioxane (5 mL), Et2O (5 mL) and dried to afford the title compound as a colourless solid.
LC-MS (Method 5B): Rt 2.63 mins; MS m/z 425.2 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 8.62 (s, 1H), 8.59 (d, J = 7.8 Hz, 1H), 8.02 (d, J = 7.8 Hz, 1H), 7.83 (br s, 2H), 7.75 (t, J = 7.8 Hz, 1H), 5.74– 5.67 (m, 1H), 5.36– 5.30 (m, 1H), 4.32– 4.25 (m, 2H), 2.30– 2.20 (m, 1H), 2.18– 2.09 (m, 1H), 2.08– 2.01 (m, 1H), 1.97– 1.83 (m, 5H), 1.77– 1.63 (m, 2H), 1.61– 1.50 (m, 2H).1 x exchangeable proton not observed.
Step 3: 4-Amino-2-(3-cyanophenyl)-6-[rac-(1R,3R)-3-hydroxycyclopentoxy]pyrimidine-5- carboxylic acid
Figure imgf000173_0001
[00331] The title compound was prepared from [rac-(1S,3S)-3-hydroxycyclopentyl] 4- amino-2-(3-cyanophenyl)-6-[rac-(1R,3R)-3-hydroxycyclopentoxy]pyrimidine-5-carboxylate (step 2) and lithium hydroxide analogously to Example 26 step 2.
LC-MS (Method 5B): Rt 1.45 mins; MS m/z 341.2 = [M+H]+ 1H NMR (500 MHz, DMSO-d6) d 12.64 (s, 1H), 8.62 (t, J = 1.8 Hz, 1H), 8.60 (d, J = 7.9 Hz, 1H), 8.02 (d, J = 7.9 Hz, 1H), 7.87 (s, 2H), 7.75 (t, J = 7.9 Hz, 1H), 5.75– 5.68 (m, 1H), 4.64 (d, J = 3.8 Hz, 1H), 4.32– 4.25 (m, 1H), 2.30– 2.20 (m, 1H), 2.07– 2.00 (m, 1H), 1.98– 1.86 (m, 2H), 1.77– 1.69 (m, 1H), 1.59– 1.51 (m, 1H).
Step 4: 4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[rac-(1R,3R)-3- hydroxycyclopentoxy]pyrimidine-5-carboxamide
[00332] The title compound was prepared from 4-amino-2-(3-cyanophenyl)-6-[(1R,3R)- 3-hydroxycyclopentoxy]pyrimidine-5-carboxylic acid (step 3) and 1-aminooxy-2-methyl- propan-2-ol (Intermediate C) analogously to Example 26 step 3.
LC-MS (Method 8B): Rt 3.63 mins; MS m/z 428.3 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 11.00 (s, 1H), 8.61 (t, J = 1.6 Hz, 1H), 8.59 (dt, J = 7.8, 1.6 Hz, 1H), 8.01 (dt, J = 7.8, 1.6 Hz, 1H), 7.76 (t, J = 7.8 Hz, 1H), 7.73 (br s, 2H), 5.75– 5.69 (m, 1H), 4.76 (s, 1H), 4.64 (d, J = 3.9 Hz, 1H), 4.34– 4.28 (m, 1H), 3.69 (s, 2H), 2.30– 2.22 (m, 1H), 2.11– 2.00 (m, 2H), 1.99– 1.91 (m, 1H), 1.86– 1.78 (m, 1H), 1.61– 1.53 (m, 1H), 1.17 (s, 6H).
Example 27a and 27b
[00333] Chiral separation of racemic 4-amino-2-(3-cyanophenyl)-N-(2-hydroxy-2- methyl-propoxy)-6-[rac-(1R,3R)-3-hydroxycyclopentoxy]pyrimidine-5-carboxamide (Example 27) using Supercritical Fluid Chromatography under the following conditions afforded the individual enantiomers:
Column: Lux C3 (20 mm x 250 mm, 5 µm)
Column Temperature: 40 ˚C
Flow Rate: 50 mL/min
BPR: 125 BarG
Detector Wavelength: 220 nm
Injection Volume: 1000 µL (33 mg)
Isocratic Conditions: 20:80 MeOH:CO2 (0.2% v/v NH3) Example 27a: 4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1S,3S)- 3-hydroxycyclopentoxy]pyrimidine-5-carboxamide or 4-amino-2-(3-cyanophenyl)-N-(2- hydroxy-2-methyl-propoxy)-6-[(1R,3R)-3-hydroxycyclopentoxy]pyrimidine-5- carboxamide
Figure imgf000175_0001
Chiral SFC (Method CP3): First Eluted Peak: Rt = 1.90 mins
LC-MS (Method 8B): Rt 3.75 mins; MS m/z 428.3 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 11.00 (s, 1H), 8.61 (s, 1H), 8.59 (d, J = 8.0 Hz, 2H), 8.02 (d, J = 7.7 Hz, 1H), 7.83– 7.62 (m, 3H), 5.80– 5.66 (m, 1H), 4.75 (s, 1H), 4.64 (d, J = 3.8 Hz, 1H), 4.36– 4.26 (m, 1H), 3.69 (s, 2H), 2.31– 2.20 (m, 1H), 2.12– 2.00 (m, 2H), 2.00– 1.91 (m, 1H), 1.89– 1.77 (m, 1H), 1.62– 1.51 (m, 1H), 1.17 (s, 6H).
Example 27b: 4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1S,3S)- 3-hydroxycyclopentoxy]pyrimidine-5-carboxamide or 4-amino-2-(3-cyanophenyl)-N-(2- hydroxy-2-methyl-propoxy)-6-[(1R,3R)-3-hydroxycyclopentoxy]pyrimidine-5- carboxamide
Figure imgf000175_0002
Chiral SFC (Method CP3): Second Eluted Peak Rt = 2.57 mins
LC-MS (Method 8B): Rt 3.68 mins; MS m/z 428.3 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 11.00 (s, 1H), 8.61 (s, 1H), 8.59 (d, J = 8.0 Hz, 2H), 8.02 (d, J = 7.7 Hz, 1H), 7.83– 7.57 (m, 3H), 5.79– 5.60 (m, 1H), 4.74 (s, 1H), 4.64 (d, J = 3.7 Hz, 1H), 4.37– 4.24 (m, 1H), 3.69 (s, 2H), 2.32– 2.21 (m, 1H), 2.14– 2.00 (m, 2H), 1.99– 1.90 (m, 1H), 1.87– 1.76 (m, 1H), 1.62– 1.48 (m, 1H), 1.17 (s, 6H).
Example 28
4-Amino-2-(3-cyanophenyl)-N-(oxazol-2-ylmethoxy)-6-[(3S)-tetrahydrofuran-3-yl]oxy- pyrimidine-5-carboxamide
Figure imgf000176_0001
[00334] The title compound was prepared from 4-amino-2-(3-cyanophenyl)-6-[ (3S)- tetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxylic acid (Intermediate K) and O-(oxazol-2- ylmethyl)hydroxylamine (Intermediate T) analogously to Example 26a/b step 3.
LC-MS (Method 8B): Rt 3.64 mins; MS m/z 423.3 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 11.11 (s, 1H), 8.61 (dd, J = 1.7, 1.7 Hz, 1H), 8.58 (ddd, J = 7.9, 1.7, 1.4 Hz, 1H), 8.19 (s, 1H), 8.01 (ddd, J = 7.6, 1.7, 1.4 Hz, 1H), 7.73 (dd, J = 7.9, 7.6 Hz, 1H), 7.66 (s, 2H), 7.27 (s, 1H), 5.78– 5.68 (m, 1H), 5.02 (s, 2H), 4.03 (dd, J = 10.4, 5.0 Hz, 1H), 3.86– 3.74 (m, 3H), 2.31– 2.19 (m, 1H), 2.15– 2.04 (m, 1H).
Example 29
4-Amino-2-(3-cyanophenyl)-N-[(3-hydroxyazetidin-3-yl)methoxy]-6-[(3S)- tetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxamide
Figure imgf000176_0002
Step 1: tert-Butyl 3-[[[4-amino-2-(3-cyanophenyl)-6-[(3S)-tetrahydrofuran-3-yl]oxy-pyrimidine- 5-carbonyl]amino]oxymethyl]-3-[tert-butyl(dimethyl)silyl]oxy-azetidine-1-carboxylate [00335] The title
Figure imgf000177_0002
compound was prepared from 4-amino-2-(3-cyanophenyl)-6-[(3S)- tetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxylic acid (Intermediate K) and tert-butyl 3- (aminooxymethyl)-3-[tert-butyl(dimethyl)silyl]oxy-azetidine-1-carboxylate (Intermediate JC) analogously to Example 23.
LC-MS (Method 3A): Rt 2.65 mins; MS m/z 639.4 = [M-H]- 1H NMR (500 MHz, Chloroform-d) d 10.07 (s, 1H), 9.16 (br s, 1H), 8.67– 8.59 (m, 2H), 7.79 (dt, J = 7.7, 1.4 Hz, 1H), 7.60 (t, J = 7.8 Hz, 1H), 6.07 (br s, 1H), 6.00– 5.93 (m, 1H), 4.18– 4.03 (m, 7H), 3.97 (td, J = 8.6, 4.9 Hz, 1H), 3.88 (d, J = 9.2 Hz, 2H), 2.50– 2.42 (m, 1H), 2.27 – 2.20 (m, 1H), 1.45 (s, 9H), 0.91 (s, 9H), 0.16 (s, 6H).
Step 2: tert-Butyl 3-[[[4-amino-2-(3-cyanophenyl)-6-[(3S)-tetrahydrofuran-3-yl]oxy-pyrimidine- 5-carbonyl]amino]oxymethyl]-3-hydroxy-azetidine-1-carboxylate
Figure imgf000177_0001
[00336] The title compound was prepared from tert-butyl 3-[[[4-amino-2-(3- cyanophenyl)-6-[(3S)-tetrahydrofuran-3-yl]oxy-pyrimidine-5-carbonyl]amino]oxymethyl]-3- [tert-butyl(dimethyl)silyl]oxy-azetidine-1-carboxylate (step 1) and 1M TBAF in THF analogously to Intermediate JB step 4.
LC-MS (Method 3B): Rt 1.93 mins; MS m/z 525.3 = [M-H]- 1H NMR (500 MHz, Chloroform-d) d 10.29 (s, 1H), 8.91 (br s, 1H), 8.64 (br t, J = 1.5 Hz, 1H), 8.59 (br dt, J = 8.2, 1.5 Hz, 1H), 7.79 (br dt, J = 7.7, 1.5 Hz, 1H), 7.59 (apr t, J = 7.8 Hz, 1H), 6.03– 5.98 (m, 1H), 5.90 (br s, 1H), 5.76 (br s, 1H), 4.22– 4.13 (m, 2H), 4.13– 4.08 (m, 2H), 4.06 (dd, J = 11.0, 4.1 Hz, 1H), 3.97 (td, J = 8.7, 5.0 Hz, 1H), 3.93 (d, J = 9.5 Hz, 2H), 3.87 (dd, J = 9.5, 2.5 Hz, 2H), 2.52– 2.44 (m, 1H), 2.27– 2.21 (m, 1H), 1.44 (s, 9H).
Step 3: 4-Amino-2-(3-cyanophenyl)-N-[(3-hydroxyazetidin-3-yl)methoxy]-6-[(3S)- tetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxamide [00337] tert-Butyl 3-[[[4-amino-2-(3-cyanophenyl)-6-[(3S)-tetrahydrofuran-3-yl]oxy- pyrimidine-5-carbonyl]amino]oxymethyl]-3-hydroxy-azetidine-1-carboxylate (step 2) (154 mg, 0.29 mmol) was dissolved in a mixture of DCM (2 mL) and TFA (1 mL, 13.06 mmol) and the resulting solution was stirred at room temperature for 45 mins. The reaction was quenched with saturated aqueous NaHCO3 (20 mL) and extracted with DCM (3 x 20 mL). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo to afford a cream solid. The aqueous phase was further extracted with EtOAc (5 x 25 mL) and the combined organic portions dried over Na2SO4 and concentrated in vacuo to afford a clear gummy film. The combined crude solids were purified by C18 reverse phase chromatography eluting with 5 to 25% MeCN in 0.1% aqueous ammonia to afford the title as a colourless solid.
LC-MS (Method 8B): Rt 3.08 mins; MS m/z 427.3 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 8.61 (s, 1H), 8.58 (d, J = 8.1 Hz, 1H), 8.00 (d, J = 7.7 Hz, 1H), 7.73 (apr t, J = 7.8 Hz, 1H), 7.63 (s, 2H), 5.91 (br s, 1H), 5.80– 5.74 (m, 1H), 4.03 (dd, J = 10.4, 5.0 Hz, 1H), 4.01 (s, 2H), 3.90– 3.84 (m, 2H), 3.79 (td, J = 8.2, 4.7 Hz, 1H), 3.50 (s, 4H), 2.33– 2.25 (m, 1H), 2.19– 2.12 (m, 1H).2 x exchangeable protons not observed.
Example 30
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(2R,3S)-2- (hydroxymethyl)tetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxamide
Figure imgf000178_0001
Step 1: Ethyl 4-amino-2-(3-cyanophenyl)-6-[(2R,3S)-2-[[tert- butyl(dimethyl)silyl]oxymethyl]tetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxylate
[00338] The title compou
Figure imgf000179_0002
nd was prepared analogously from ethyl 4-amino-6-chloro-2- (3-cyanophenyl)pyrimidine-5-carboxylate (Example 5 step 1) and (2R,3S)-2-[[tert- butyl(dimethyl)silyl]oxymethyl]tetrahydrofuran-3-ol (Intermediate U) analogously to Example 26 step 1.
LC-MS (Method 8B): Rt 6.66 mins; MS m/z 499.3 = [M+H]+
Step2: 4-amino-2-(3-cyanophenyl)-6-[(2R,3S)-2-[[tert- butyl(dimethyl)silyl]oxymethyl]tetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxylate lithium salt
Figure imgf000179_0001
[00339] The title compound was prepared from ethyl 4-amino-2-(3-cyanophenyl)-6- [(2R,3S)-2-[[tert-butyl(dimethyl)silyl]oxymethyl]tetrahydrofuran-3-yl]oxy-pyrimidine-5- carboxylate (step 1) and lithium hydroxide analogously to Example 26 step 2.
LC-MS (Method 8A): Rt 6.12 mins; MS m/z 471.3 = [M+H]+
Step 3: 4-Amino-2-(3-cyanophenyl)-6-[(2R,3S)-2-(hydroxymethyl)tetrahydrofuran-3-yl]oxy- pyrimidine-5-carboxylic acid
[00340] The title comp
Figure imgf000180_0002
ound was prepared from 4-amino-2-(3-cyanophenyl)-6-[(2R,3S)- 2-[[tert-butyl(dimethyl)silyl]oxymethyl]tetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxylic acid lithium salt (step 2) and 4M HCl in 1,4-dioxane analogously to Example 27 step 2.
LC-MS (Method 8A): Rt 3.80 mins; MS m/z 357.1 = [M+H]+
Step 4: 4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(2R,3S)-2- (hydroxymethyl)tetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxamide
[00341] The title compound was prepared from 4-amino-2-(3-cyanophenyl)-6-[(2R,3S)- 2-(hydroxymethyl)tetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxylic acid (step 3) and 1- aminooxy-2-methyl-propan-2-ol (Intermediate C) analogously to Example 26 step 3.
LC-MS (Method 8B): Rt 3.36 mins; MS m/z 444.3 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 11.06 (s, 1H), 8.65 (s, 1H), 8.60 (d, J = 7.9 Hz, 1H), 8.01 (d, J = 7.9 Hz, 1H), 7.75 (t, J = 7.9 Hz, 1H), 7.67 (s, 2H), 5.73– 5.64 (m, 1H), 4.90 (t, J = 5.8 Hz, 1H), 4.73 (s, 1H), 4.04– 3.95 (m, 2H), 3.90– 3.83 (m, 1H), 3.70 (s, 2H), 3.61– 3.55 (m, 1H), 3.55– 3.49 (m, 1H), 2.34– 2.24 (m, 1H), 2.19– 2.11 (m, 1H), 1.17 (s, 6H).
Example 30.1
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(3S,5S)-5- (hydroxymethyl)tetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxamide
Figure imgf000180_0001
Step 1: Ethyl 4-amino-2-(3-cyanophenyl)-6-[(3S,5S)-5-[[tert- butyl(dimethyl)silyl]oxymethyl]tetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxylate
Figure imgf000181_0003
[00342] The title compound was prepared analogously from ethyl 4-amino-6-chloro-2- (3-cyanophenyl)pyrimidine-5-carboxylate (Example 5 step 1) and (3S,5S)-5-[[tert- butyl(dimethyl)silyl]oxymethyl]tetrahydrofuran-3-ol (Intermediate UA) analogously to Example 26 step 1.
LC-MS (Method 5A): Rt 4.39 mins; MS m/z 499.2 = [M+H]+
Step2: 4-Amino-2-(3-cyanophenyl)-6-[(3S,5S)-5-[[tert- butyl(dimethyl)silyl]oxymethyl]tetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxylic acid
Figure imgf000181_0001
[00343] The title compound was prepared from ethyl 4-amino-2-(3-cyanophenyl)-6- [(2R,3S)-2-[[tert-butyl(dimethyl)silyl]oxymethyl]tetrahydrofuran-3-yl]oxy-pyrimidine-5- carboxylate (step 1) and lithium hydroxide analogously to Example 26 step 2.
LC-MS (Method 3A): Rt 2.37 mins; MS m/z 471.3 = [M+H]+
Step 3: 4-Amino-2-(3-cyanophenyl)-6-[(3S,5S)-5-(hydroxymethyl)tetrahydrofuran-3-yl]oxy- pyrimidine-5-carboxylic acid
Figure imgf000181_0002
[00344] The title compound was prepared from 4-amino-2-(3-cyanophenyl)-6-[(3S,5S)- 5-[[tert-butyl(dimethyl)silyl]oxymethyl]tetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxylic acid (step 2) and 4M HCl in 1,4-dioxane analogously to Example 27 step 2. LC-MS (Method 3A): Rt 1.48 mins; MS m/z 357.2 = [M+H]+
Step 4: 4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(3S,5S)-5- (hydroxymethyl)tetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxamide
[00345] The title compound was prepared from 4-amino-2-(3-cyanophenyl)-6-[(3S,5S)- 5-(hydroxymethyl)tetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxylic acid (step 3) and 1- aminooxy-2-methyl-propan-2-ol (Intermediate C) analogously to Example 26 step 3.
LC-MS (Method 8B): Rt 3.66 mins; MS m/z 444.3 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 11.07 (br s, 1H), 8.62 (br t, J = 1.5 Hz, 1H), 8.58 (br dt, J = 8.1, 1.5 Hz, 1H), 8.01 (br dt, J = 7.8, 1.5 Hz, 1H), 7.83 br (s, 2H), 7.74 (apr t, J = 7.8 Hz, 1H), 5.82– 5.76 (m, 1H), 4.89 (t, J = 5.5 Hz, 1H), 4.73 (s, 1H), 4.03 (d, J = 10.4 Hz, 1H), 4.00– 3.95 (m, 1H), 3.94 (dd, J = 10.4, 4.5 Hz, 1H), 3.71 (s, 2H), 3.58– 3.46 (m, 2H), 2.46 (dd, J = 14.4, 7.3 Hz, 1H), 2.01– 1.95 (m, 1H), 1.17 (s, 6H).
Example 31
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1R,3S)-3- acetamidocyclopentoxy]pyrimidine-5-carboxamide
Figure imgf000182_0001
Step 1: A mixture of ethyl 4-amino-2-(3-cyanophenyl)-6-[(1R,3S)-3-(tert- butoxycarbonylamino)cyclopentoxy]pyrimidine-5-carboxylate and [(1R,3S)-3-(tert- butoxycarbonylamino)cyclopentyl] 4-amino-2-(3-cyanophenyl)-6-[(1R,3S)-3-(tert- butoxycarbonylamino)cyclopentoxy]pyrimidine-5-carboxylate
Figure imgf000182_0002
[00346] LiHMDS (1M in THF) (3.3 mL, 3.3 mmol) was added dropwise over 2 mins to a stirred solution of tert-butyl N-[(1S,3R)-3-hydroxycyclopentyl]carbamate (698 mg, 3.47 mmol) and ethyl 4-amino-6-chloro-2-(3-cyanophenyl)pyrimidine-5-carboxylate (Example 5 step 1) (500 mg, 1.65 mmol) in THF (10 mL) at 0 °C under nitrogen. The reaction mixture was stirred at 0 °C under nitrogen for 10 mins and then allowed to warm to room temperature stirring for 40 h. The resulting mixture was partitioned between EtOAc (100 mL) and water (50 mL). The layers were separated and the aqueous phase was further extracted with EtOAc (3 x 50 mL). The combined organic extracts were then dried over MgSO4 and concentrated in vacuo to afford a mixture of the title compounds.
[00347] Major component (ethyl 4-amino-2-(3-cyanophenyl)-6-[(1R,3S)-3-(tert- butoxycarbonylamino)cyclopentoxy]pyrimidine-5-carboxylate):
LC-MS (Method 3B): Rt 2.28 mins; MS m/z 466.2 = [M-H]- 1H NMR (500 MHz, Chloroform-d) d 8.70– 8.65 (m, 1H), 8.63– 8.57 (m, 1H), 7.76 (d,J= 7.8 Hz, 1H), 7.57 (td,J= 7.8, 2.2 Hz, 1H), 5.84– 5.68 (m, 1H), 5.07 (br s, 2H), 4.48– 4.21 (m, 3H), 4.04 (br s, 1H), 2.14– 2.05 (m, 3H), 2.03– 1.95 (m, 3H), 1.44 (s, 9H), 1.26 (t,J= 7.2 Hz, 3H).
[00348] Minor component [(1R,3S)-3-(tert-butoxycarbonylamino)cyclopentyl] 4-amino- 2-(3-cyanophenyl)-6-[(1R,3S)-3-(tert-butoxycarbonylamino)cyclopentoxy]pyrimidine-5- carboxylate:
LC-MS (Method 3B): Rt 2.37 mins; MS m/z 621.4 = [M-H]-
Step 2: A mixture of ethyl 4-amino-2-(3-cyanophenyl)-6-[(1R,3S)-3- acetamidocyclopentoxy]pyrimidine-5-carboxylate and [(1R,3S)-3-acetamidocyclopentyl] 4- amino-2-(3-cyanophenyl)-6-[(1R,3S)-3-acetamidocyclopentoxy]pyrimidine-5-carboxylate
Figure imgf000183_0001
[00349] A solution of ethyl 4-amino-2-(3-cyanophenyl)-6-[(1R,3S)-3-(tert- butoxycarbonylamino)cyclopentoxy]pyrimidine-5-carboxylate (350 mg, 0.75 mmol) and [(1R,3S)-3-(tert-butoxycarbonylamino)cyclopentyl] 4-amino-2-(3-cyanophenyl)-6-[(1R,3S)-3- (tert-butoxycarbonylamino)cyclopentoxy]pyrimidine-5-carboxylate (200 mg, 0.32 mmol) in TFA (0.82 mL, 10.7 mmol) and DCM (10 mL) was stirred at room temperature under nitrogen for 2 h. Additional TFA (0.82 mL, 10.7 mmol) was added dropwise over 2 mins and the mixture was stirred at room temperature under nitrogen overnight. The resulting mixture was concentrated in vacuo and the residue was dissolved in DCM (15 mL) and cooled to 0 °C under nitrogen. DIPEA (2.8 mL, 16.05 mmol) was added dropwise over 5 mins, followed by dropwise addition of acetic anhydride (0.26 mL, 2.67 mmol) and the mixture was stirred at 0 °C for 30 mins. The mixture was warmed to room temperature and then stirred for 2 h. The resulting mixture was partitioned between EtOAc (100 mL) and water (50 mL). The separated organic phase was washed with 1M aqueous HCl (2 x 50 mL), water (50 mL), saturated aqueous sodium hydrogen carbonate (50 mL), brine (50 mL), dried over MgSO4 and then concentrated in vacuo to afford a mixture of the title compounds.
[00350] Major component ethyl 4-amino-2-(3-cyanophenyl)-6-[(1R,3S)-3- acetamidocyclopentoxy]pyrimidine-5-carboxylate:
LC-MS (Method 3B): Rt 1.77 mins; MS m/z 410.3 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 8.65– 8.62 (m, 1H), 8.02 (dt,J= 7.6, 1.4 Hz, 1H), 7.88 (d,J= 7.5 Hz, 1H), 7.84– 7.77 (m, 2H), 7.75 (td,J= 7.8, 2.5 Hz, 1H), 5.18 (s, 1H), 4.53 (q,J= 7.0 Hz, 2H), 4.03 (q,J= 7.1 Hz, 2H), 1.94– 1.87 (m, 3H), 1.78– 1.76 (m, 3H), 1.64– 1.54 (m, 3H), 1.43– 1.34 (m, 3H).
[00351] Minor component [(1R,3S)-3-acetamidocyclopentyl] 4-amino-2-(3- cyanophenyl)-6-[(1R,3S)-3-acetamidocyclopentoxy]pyrimidine-5-carboxylate:
LC-MS (Method 3B): Rt 1.60 mins; MS m/z 507.4 = [M+H]+
Step 3: 4-Amino-2-(3-cyanophenyl)-6-[(1R,3S)-3-acetamidocyclopentoxy]pyrimidine-5- carboxylic acid
Figure imgf000184_0001
[00352] Lithium hydroxide (82 mg, 3.42 mmol) was added to a mixture [(1R,3S)-3- acetamidocyclopentyl] 4-amino-2-(3-cyanophenyl)-6-[(1R,3S)-3- acetamidocyclopentoxy]pyrimidine-5-carboxylate and ethyl 4-amino-2-(3-cyanophenyl)-6- [(1R,3S)-3-acetamidocyclopentoxy]pyrimidine-5-carboxylate (400 mg, 0.98 mmol) in THF (4 mL) and water (2 mL) and stirred at room temperature for 3 days. The resulting mixture was concentrated in vacuo and the residue was dissolved in water. The mixture was acidified to ~pH 2 by the dropwise addition of 2M HCl to afford a brown solid which was collected by filtration. The solid was azeotroped with MeCN (3 x 5 mL) and triturated from Et2O to afford the title compound as a beige solid.
LC-MS (Method 5A): Rt 2.27 mins; MS m/z 382.2 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 12.92 (br s, 1H), 8.63 (s, 1H), 8.02 (d, J = 7.9 Hz, 1H), 7.89 (br s, 3H), 7.81– 7.72 (m, 2H), 5.65 (dd, J = 6.4, 3.4 Hz, 1H), 4.23– 4.13 (m, 1H), 2.41– 2.32 (m, 1H), 2.08– 1.98 (m, 1H), 1.97– 1.85 (m, 2H), 1.79 (s, 3H), 1.70– 1.55 (m, 2H).
Step 4: 4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1R,3S)-3- acetamidocyclopentoxy]pyrimidine-5-carboxamide
[00353] The title compound was prepared from 4-amino-2-(3-cyanophenyl)-6-[(1R,3S)- 3-acetamidocyclopentoxy]pyrimidine-5-carboxylic acid (step 3) and 1-aminooxy-2-methyl- propan-2-ol (Intermediate C) analogously to Example 23.
LC-MS (Method 8B): Rt 3.88 mins; MS m/z 469.3 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 11.02 (s, 1H), 8.62 (d, J = 1.7 Hz, 1H), 8.60 (d, J = 7.7 Hz, 1H), 8.02 (d, J = 7.7 Hz, 1H), 7.87 (d, J = 7.2 Hz, 1H), 7.83– 7.66 (br m, 3H), 5.64– 5.53 (m, 1H), 4.77 (s, 1H), 4.09 (apr h, J = 7.3 Hz, 1H), 3.73 (s, 2H), 2.10– 1.99 (m, 2H), 1.99– 1.88 (m, 2H), 1.80 (s, 3H), 1.74– 1.59 (m, 2H), 1.18 (s, 6H).
Example 31.1
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1S,3R)-3- acetamidocyclopentoxy]pyrimidine-5-carboxamide
Figure imgf000185_0001
Step 1: A mixture of ethyl 4-amino-2-(3-cyanophenyl)-6-[(1S,3R)-3-(tert- butoxycarbonylamino)cyclopentoxy]pyrimidine-5-carboxylate and [(1S,3R)-3-(tert- butoxycarbonylamino)cyclopentyl] 4-amino-2-(3-cyanophenyl)-6-[(1S,3R)-3-(tert- butoxycarbonylamino)cyclopentoxy]pyrimidine-5-carboxylate
Figure imgf000186_0001
[00354] The title compounds were prepared from ethyl 4-amino-6-chloro-2-(3- cyanophenyl)pyrimidine-5-carboxylate (Example 5 step 1) and tert-butyl N-[(1R,3S)-3- hydroxycyclopentyl]carbamate analogously to Example 31 step 1.
[00355] Major component ethyl 4-amino-2-(3-cyanophenyl)-6-[(1S,3R)-3-(tert- butoxycarbonylamino)cyclopentoxy]pyrimidine-5-carboxylate:
LC-MS (Method 5B): Rt 3.98 mins; MS m/z 468.2 = [M+H]+
1H NMR (500 MHz, Chloroform-d) d 8.70– 8.64 (m, 1H), 8.64– 8.56 (m, 1H), 7.78– 7.73 (m, 1H), 7.57 (td, J = 7.8, 2.2 Hz, 1H), 5.72 (br. s, 1H), 5.08 (br. s, 2H), 4.51– 4.18 (m, 3H), 4.04 (br. s, 1H), 2.21– 2.08 (m, 3H), 2.01– 1.91 (m, 3H), 1.43 (s, 9H), 1.26– 1.22 (m, 3H).
[00356] Minor component [(1S,3R)-3-(tert-butoxycarbonylamino)cyclopentyl] 4-amino- 2-(3-cyanophenyl)-6-[(1S,3R)-3-(tert-butoxycarbonylamino)cyclopentoxy]pyrimidine-5- carboxylate:
LC-MS (Method 5B): Rt 4.12 mins; MS m/z 623.4 = [M+H]+
Step 2: A mixture of ethyl 4-amino-2-(3-cyanophenyl)-6-[(1S,3R)-3- acetamidocyclopentoxy]pyrimidine-5-carboxylate and [(1S,3R)-3-acetamidocyclopentyl] 4- amino-2-(3-cyanophenyl)-6-[(1S,3R)-3-acetamidocyclopentoxy]pyrimidine-5-carboxylate
Figure imgf000186_0002
[00357] The title compound was prepared from a mixture of ethyl 4-amino-2-(3- cyanophenyl)-6-[(1S,3R)-3-(tert-butoxycarbonylamino)cyclopentoxy]pyrimidine-5-carboxylate and [(1S,3R)-3-(tert-butoxycarbonylamino)cyclopentyl] 4-amino-2-(3-cyanophenyl)-6- [(1S,3R)-3-(tert-butoxycarbonylamino)cyclopentoxy]pyrimidine-5-carboxylate (step 2) and trifluoroacetic acid analogously to Example 31 step 2.
[00358] Major component Ethyl 4-amino-2-(3-cyanophenyl)-6-[(1S,3R)-3- acetamidocyclopentoxy]pyrimidine-5-carboxylate:
LC-MS (Method 5B): Rt 3.00 mins; MS m/z 410.2 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 8.63 (br. s, 1H), 8.02 (d, J = 7.8 Hz, 1H), 7.90– 7.87 (m, 1H), 7.81 (br. s, 2H), 7.75 (td, J = 7.8, 2.4 Hz, 1H), 5.18 (br. s, 1H), 4.53 (q, J = 7.0 Hz, 2H), 4.09– 3.97 (m, 2H), 1.94– 1.89 (m, 3H), 1.77 (s, 3H), 1.62– 1.56 (m, 3H), 1.43– 1.33 (m, 3H).
[00359] Minor component [(1S,3R)-3-acetamidocyclopentyl] 4-amino-2-(3- cyanophenyl)-6-[(1S,3R)-3-acetamidocyclopentoxy]pyrimidine-5-carboxylate
LC-MS (Method 5B): Rt 2.55 mins; MS m/z 507.2 = [M+H]+
Step 3: 4-Amino-2-(3-cyanophenyl)-6-[(1S,3R)-3-acetamidocyclopentoxy]pyrimidine-5- carboxylic acid
Figure imgf000187_0001
[00360] The title compound was prepared from ethyl 4-amino-2-(3-cyanophenyl)-6- [(1S,3R)-3-acetamidocyclopentoxy]pyrimidine-5-carboxylate (step 2) and lithium hydroxide analogously to Example 30 step 2.
LC-MS (Method 3.5A): Rt 1.62 mins; MS m/z 382.2 = [M+H]+
Step 4: 4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1S,3R)-3- acetamidocyclopentoxy]pyrimidine-5-carboxamide
[00361] The title compound was prepared from 4-amino-2-(3-cyanophenyl)-6-[(1S,3R)- 3-acetamidocyclopentoxy]pyrimidine-5-carboxylic acid (step 3) and 1-aminooxy-2-methyl- propan-2-ol (Intermediate C) analogously to Example 23.
LC-MS (Method 8B): Rt 3.42 mins; MS m/z 469.3 = [M+H]+ 1H NMR (500 MHz, DMSO-d6) d 11.01 (s, 1H), 8.61 (br t, J = 1.6 Hz, 1H), 8.59 (br dt, J = 8.0, 1.6 Hz, 1H), 8.01 (br dt, J = 7.7, 1.6 Hz, 1H), 7.86 (br d, J = 7.3 Hz, 1H), 7.74 (t, J = 7.8 Hz, 1H), 7.73 (br s, 2H), 5.61– 5.53 (m, 1H), 4.76 (s, 1H), 4.08 (apr h, J = 7.3 Hz, 1H), 3.72 (s, 2H), 2.09– 1.87 (m, 4H), 1.79 (s, 3H), 1.72– 1.61 (m, 2H), 1.17 (s, 6H).
Example 32
4-Amino-2-(3-cyano-2-methyl-phenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(3S)- tetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxamide
Figure imgf000188_0001
Step 1: Ethyl 4-amino-2-(3-cyano-2-methyl-phenyl)-6-[(3S)-tetrahydrofuran-3-yl]oxy- pyrimidine-5-carboxylate
Figure imgf000188_0002
[00362] To a stirring solution of ethyl 4-amino-6-chloro-2-(3-cyano-2-methyl- phenyl)pyrimidine-5-carboxylate (Example 5.3 step 1) (400 mg, 1.26 mmol) and (3S)- tetrahydrofuran-3-ol (0.41 mL, 5.18 mmol) in anhydrous THF (10 mL) under nitrogen was added LiHMDS (1M in THF) (5.05 mL, 5.05 mmol) dropwise. The reaction mixture was stirred for 10 mins then heated to 50 °C. After cooling to room temperature, the resulting mixture was added to saturated aqueous NaHCO3 (25 mL) and EtOAc (25 mL). The layers were separated and the aqueous layer was further extracted with EtOAc (2 x 25 mL). The combined organic extracts were dried over MgSO4 and concentrated in vacuo to afford the title compound as a brown oil.
LC-MS (Method 8B): Rt 4.53 mins; MS m/z 369.3 = [M+H]+ Step 2: 4-Amino-2-(3-cyano-2-methyl-phenyl)-6-[(3S)-tetrahydrofuran-3-yl]oxy-pyrimidine-5- carboxylic acid
Figure imgf000189_0001
[00363] To a stirring solution of ethyl 4-amino-2-(3-cyano-2-methyl-phenyl)-6-[(3S)- tetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxylate (step 1) (465 mg, 1.26 mmol) in THF (8 mL) was added a solution of lithium hydroxide (91 mg, 3.79 mmol) in water (4 mL). The reaction mixture was stirred at room temperature for 42 h. The resulting mixture was concentrated in vacuo and then diluted with water (40 mL) and diethyl ether (40 mL). The layers were separated and the aqueous layer was acidified to pH 2 with 2M aqueous HCl. The precipitated solid was collected by filtration and azeotroped from MeOH (2 x 20 mL) to afford the title compound as a colourless solid.
LC-MS (Method 5A): Rt 2.32 mins; MS m/z 341.2 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 12.77 (s, 1H), 8.03 (dd, J = 7.9, 1.0 Hz, 1H), 7.93– 7.81 (m, 3H), 7.50 (t, J = 7.9 Hz, 1H), 5.64– 5.57 (m, 1H), 3.93– 3.72 (m, 4H), 2.69 (s, 3H), 2.25– 2.15 (m, 1H), 2.08– 1.99 (m, 1H).
Step 3: 4-Amino-2-(3-cyano-2-methyl-phenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(3S)- tetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxamide
[00364] To a stirring solution of 4-amino-2-(3-cyano-2-methyl-phenyl)-6-[(3S)- tetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxylic acid (step 2) (150 mg, 0.44 mmol) and 1- aminooxy-2-methyl-propan-2-ol (Intermediate C) (70 mg, 0.66 mmol) in anhydrous DMF (4 mL) was added DIPEA (0.38 mL, 2.2 mmol) followed by T3P® (50% in DMF) (0.31 mL, 0.44 mmol) dropwise. The reaction mixture was stirred at room temperature for 45 mins and then added to EtOAc (50 mL) and water (50 mL). The layers were separated and the aqueous layer was further extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with 50% brine solution (4 x 50 mL), dried over MgSO4 and concentrated in vacuo to give a yellow/brown oil. Purification by chromatography on silica eluting with a gradient of 30 to 70% EtOAc in petroleum ether afforded a white oily solid. The solid was azeotroped from diethyl ether (10 mL) to afford the title compound as a colourless solid. LC-MS (Method 8B): Rt 3.95 mins; MS m/z 428.3 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 11.05 (s, 1H), 8.00 (d, J = 7.8 Hz, 1H), 7.89 (d, J = 7.8, 1.4 Hz, 1H), 7.64 (s, 2H), 7.50 (t, J = 7.8 Hz, 1H), 5.63– 5.54 (m, 1H), 4.74 (s, 1H), 3.93– 3.82 (m, 3H), 3.77 (td, J = 8.2, 4.7 Hz, 1H), 3.70 (s, 2H), 2.68 (s, 3H), 2.25– 2.10 (m, 2H), 1.16 (s, 6H).
Example 32.1a and 32.1b
4-Amino-2-(3-cyanophenyl)-6-[(1r, 3r)-3-(difluoromethyl)cyclobutoxy]-N-(2-hydroxy-2- methyl-propoxy)pyrimidine-5-carboxamide and 4-amino-2-(3-cyanophenyl)-6-[(1s, 3s)- 3-(difluoromethyl)cyclobutoxy]-N-(2-hydroxy-2-methyl-propoxy)pyrimidine-5- carboxamide
Figure imgf000190_0001
Step 1: Ethyl 4-amino-2-(3-cyanophenyl)-6-[3-(difluoromethyl)cyclobutoxy]pyrimidine-5- carboxylate
Figure imgf000190_0002
[00365] The title compound was prepared from ethyl 4-amino-6-chloro-2-(3- cyanophenyl)pyrimidine-5-carboxylate (Example 5 step 1) and 3-(difluoromethyl)cyclobutanol analogously to Example 32 step 1.
LC-MS (Method 5B): Rt 3.74 mins; MS m/z 389.1 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 8.61 (d, J = 1.7 Hz, 1H), 8.59 (dt, J = 7.8, 1.5 Hz, 1H), 8.02 (dt, J = 7.8, 1.5 Hz, 1H), 7.84 (s, 2H), 7.75 (t, J = 7.8 Hz, 1H), 5.35 (p, J = 7.4 Hz, 1H), 4.26 (q, J = 7.2 Hz, 2H), 4.06– 4.00 (m, 1H), 2.66– 2.58 (m, 2H), 2.15– 2.08 (m, 2H), 1.77– 1.69 (m, 1H), 1.31 (t, J = 7.2 Hz, 3H).
Step 2: 4-Amino-2-(3-cyanophenyl)-6-[3-(difluoromethyl)cyclobutoxy]pyrimidine-5-carboxylic acid
Figure imgf000191_0001
[00366] The title compound was prepared from ethyl 4-amino-2-(3-cyanophenyl)-6-[3- (difluoromethyl)cyclobutoxy]pyrimidine-5-carboxylate (step 1) and lithium hydroxide analogously to Example 32 step 2.
LC-MS (Method 5B): Rt 2.89 mins; MS m/z 361.1 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 12.79 (br s, 1H), 8.61 (s, 1H), 8.60– 8.57 (m, 1H), 8.02 (d, J = 7.7 Hz, 1H), 7.91 (br s, 2H), 7.75 (t, J = 7.8 Hz, 1H), 6.13 (td, J = 57.2, 3.5 Hz, 1H), 5.32 (p, J = 7.5 Hz, 1H), 2.65– 2.58 (m, 2H), 2.56– 2.51 (m, 2H), 2.15– 2.09 (m, 1H).
Step 3: 4-Amino-2-(3-cyanophenyl)-6-[3-(difluoromethyl)cyclobutoxy]-N-(2-hydroxy-2-methyl- propoxy)pyrimidine-5-carboxamide
Figure imgf000191_0002
[00367] The title compound was prepared from 4-amino-2-(3-cyanophenyl)-6-[3- (difluoromethyl)cyclobutoxy]pyrimidine-5-carboxylic acid (step 2) and 1-aminooxy-2-methyl- propan-2-ol (Intermediate C) analogously to Example 32 step 3.
LC-MS (Method 8B): Rt 4.69 mins; MS m/z 448.3 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 11.16 (s, 1H), 8.59 (d, J = 1.7 Hz, 1H), 8.59– 8.55 (m, 1H), 8.01 (dd, J = 7.8, 1.6 Hz, 1H), 7.86– 7.65 (m, 3H), 6.24– 6.00 (m, 1H), 5.37– 5.29 (m, 1H), 4.77 (s, 1H), 3.72 (s, 2H), 2.65– 2.53 (m, 3H), 2.24 (t, J = 9.3 Hz, 2H), 1.18 (s, 6H). [00368] Chiral separation of racemic 4-amino-2-(3-cyanophenyl)-6-[3- (difluoromethyl)cyclobutoxy]-N-(2-hydroxy-2-methyl-propoxy)pyrimidine-5-carboxamide using Supercritical Fluid Chromatography under the following conditions afforded the individual enantiomers:
Column: AmyC (20 mm x 250 mm, 5 µm)
Column Temperature: Ambient
Flow Rate: 21 mL/min
Detector Wavelength: 218 nm
Injection Volume: 500 µL (7.5 mg)
Isocratic Conditions: 50:50 Heptane:EtOH (0.2% v/v NH3)
Example 32.1a: 4-Amino-2-(3-cyanophenyl)-6-[(1r, 3r)-3-(difluoromethyl)cyclobutoxy]- N-(2-hydroxy-2-methyl-propoxy)pyrimidine-5-carboxamide or 4-amino-2-(3- cyanophenyl)-6-[(1s, 3s)-3-(difluoromethyl)cyclobutoxy]-N-(2-hydroxy-2-methyl- propoxy)pyrimidine-5-carboxamide
Figure imgf000192_0001
Chiral SFC (Method CP1): First Eluted Peak Rt = 1.97 mins
LC-MS (Method 8B): Rt 4.63 mins; MS m/z 448.3 = [M+H]+
1H NMR (500 MHz, Chloroform-d) d 10.42 (s, 1H), 9.02 (br. s, 1H), 8.61 (t, J = 1.5 Hz, 1H), 8.54 (dt, J = 7.8, 1.5 Hz, 1H), 7.76 (dt, J = 7.8, 1.5 Hz, 1H), 7.58 (t, J = 7.8 Hz, 1H), 6.00 (td, J = 57.0, 3.1 Hz, 1H), 5.80 (s, 1H), 5.56 (p, J = 7.1 Hz, 1H), 3.93 (s, 2H), 2.93– 2.80 (m, 1H), 2.80– 2.73 (m, 2H), 2.54– 2.45 (m, 2H), 1.30 (s, 6H).1 x exchangeable proton not observed. Example 32.1b: 4-Amino-2-(3-cyanophenyl)-6-[(1r, 3r)-3-(difluoromethyl)cyclobutoxy]- N-(2-hydroxy-2-methyl-propoxy)pyrimidine-5-carboxamide or 4-amino-2-(3- cyanophenyl)-6-[(1s, 3s)-3-(difluoromethyl)cyclobutoxy]-N-(2-hydroxy-2-methyl- propoxy)pyrimidine-5-carboxamide
Figure imgf000193_0001
Chiral SFC (Method CP1): Second Eluted Peak Rt = 2.63 mins
LC-MS (Method 8B): Rt 4.56 mins; MS m/z 448.3 = [M+H]+
1H NMR (500 MHz, Chloroform-d) d 10.46 (s, 1H), 9.08 (s, 1H), 8.62 (t, J = 1.5 Hz, 1H), 8.59 (d, J = 7.8 Hz, 1H), 7.77 (dt, J = 7.8, 1.4 Hz, 1H), 7.58 (t, J = 7.8 Hz, 1H), 5.93 (br. s, 1H), 5.88 (td, J = 57.0, 3.2 Hz, 1H), 5.49 (p, J = 7.5 Hz, 1H), 3.93 (s, 2H), 2.81– 2.72 (m, 2H), 2.68– 2.54 (m, 1H), 2.41– 2.30 (m, 2H), 1.31 (s, 6H).1 x exchangeable proton not observed.
Example 32.2
4-Amino-6-((1r,3r)-3-cyanocyclobutoxy)-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl- propoxy)pyrimidine-5-carboxamide
Figure imgf000193_0002
Step 1: Ethyl 4-amino-6-((1r,3r)-3-cyanocyclobutoxy)-2-(3-cyanophenyl)pyrimidine-5- carboxylate [00369] The title compound was prepared from ethyl 4-amino-6-chloro-2-(3- cyanophenyl)pyrimidine-5-carboxylate (Example 5 step 1) and (1r,3r)-3- hydroxycyclobutanecarbonitrile analogously to Example 32 step 1.
LC-MS (Method 5B): Rt 3.42 mins; MS m/z 364.2 = [M+H]+
Step 2: 4-Amino-6-((1r,3r)-3-cyanocyclobutoxy)-2-(3-cyanophenyl)pyrimidine-5-carboxylic acid
Figure imgf000194_0001
[00370] The title compound was prepared from ethyl 4-amino-6-((1r,3r)-3- cyanocyclobutoxy)-2-(3-cyanophenyl)pyrimidine-5-carboxylate (step 1) and lithium hydroxide analogously to Example 32 step 2.
LC-MS (Method 5A): Rt 2.53 mins; MS m/z 336.2 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 12.87 (br. s, 1H), 8.60 (dd, J = 1.5, 1.5 Hz, 1H), 8.58 (ddd, J = 7.8, 1.5, 1.4 Hz, 1H), 8.02 (ddd, J = 7.8, 1.5, 1.4 Hz, 1H), 7.95 (br. s, 2H), 7.77 (dd, J = 7.8, 7.8 Hz, 1H), 5.58 (tt, J = 7.1, 7.1 Hz, 1H), 3.47 (tt, J = 10.1, 4.7 Hz, 1H), 2.91– 2.81 (m, 2H), 2.66– 2.57 (m, 2H).
Step 3: 4-Amino-6-((1r,3r)-3-cyanocyclobutoxy)-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl- propoxy)pyrimidine-5-carboxamide
[00371] The title compound was prepared from 4-amino-6-((1r,3r)-3- cyanocyclobutoxy)-2-(3-cyanophenyl)pyrimidine-5-carboxylic acid (step 2) and 1-aminooxy-2- methyl-propan-2-ol (Intermediate C) analogously to Example 32 step 3.
LC-MS (Method 8B): Rt 4.11 mins; MS m/z 423.3 = [M+H]+ 1H NMR (500 MHz, DMSO-d6) d 11.18 (br. s, 1H), 8.59 (dd, J = 1.7, 1.7 Hz, 1H), 8.56 (ddd, J = 8.0, 1.7, 1.5 Hz, 1H), 8.01 (ddd, J = 7.7, 1.7, 1.5 Hz, 1H), 7.82 (s, 2H), 7.76 (dd, J = 8.0, 7.7 Hz, 1H), 5.63– 5.55 (m, 1H), 4.79 (br. s, 1H), 3.71 (s, 2H), 3.54– 3.44 (m, 1H), 2.89– 2.80 (m, 2H), 2.78– 2.68 (m, 2H), 1.18 (s, 6H).
Example 32.3
4-Amino-2-(3-cyanophenyl)-6-((1s,3s)-3-fluorocyclobutoxy)-N-(2-hydroxy-2-methyl- propoxy)pyrimidine-5-carboxamide
Figure imgf000195_0001
Step 1: Ethyl 4-amino-2-(3-cyanophenyl)-6-((1s,3s)-3-fluorocyclobutoxy)pyrimidine-5- carboxylate
Figure imgf000195_0002
[00372] The title compound was prepared from ethyl 4-amino-6-chloro-2-(3- cyanophenyl)pyrimidine-5-carboxylate (Example 5 step 1) and (1s,3s)-3-fluorocyclobutanol analogously to Example 32 step 1.
LC-MS (Method 5B): Rt 3.72 mins; MS m/z 357.2 = [M+H]+
1H NMR (500 MHz, Chloroform-d) d 8.64 (d, J = 1.6 Hz, 1H), 8.58 (dd, J = 7.8, 1.8 Hz, 1H), 7.75 (d, J = 7.8 Hz, 1H), 7.56 (t, J = 7.8 Hz, 1H), 5.07– 4.95 (m, 2H), 4.36 (q, J = 7.1 Hz, 2H), 3.16– 3.06 (m, 2H), 2.57– 2.45 (m, 2H), 1.42 (t, J = 7.1 Hz, 3H).2 x exchangeable protons not observed.
Step 2: 4-Amino-2-(3-cyanophenyl)-6-((1s,3s)-3-fluorocyclobutoxy)pyrimidine-5-carboxylic acid [00373] The title com
Figure imgf000196_0001
pound was prepared from ethyl 4-amino-2-(3-cyanophenyl)-6- ((1s,3s)-3-fluorocyclobutoxy)pyrimidine-5-carboxylate (step 1) and lithium hydroxide analogously to Example 32 step 2.
LC-MS (Method 5A): Rt 2.79 mins; MS m/z 329.1 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 12.83 (s, 1H), 8.62 (d, J = 1.8 Hz, 1H), 8.60 (dt, J = 8.0, 1.5 Hz, 1H), 8.03 (dt, J = 7.8, 1.6 Hz, 1H), 7.94 (s, 2H), 7.75 (t, J = 7.8 Hz, 1H), 5.01 (ddd, J = 13.1, 11.5, 6.4 Hz, 2H), 3.08 (ddp, J = 10.3, 6.8, 3.1 Hz, 2H), 2.32 (dddd, J = 26.6, 13.5, 7.0, 3.5 Hz, 2H).
Step 3: 4-Amino-2-(3-cyanophenyl)-6-((1s,3s)-3-fluorocyclobutoxy)-N-(2-hydroxy-2-methyl- propoxy)pyrimidine-5-carboxamide
The title compound was prepared from 4-amino-2-(3-cyanophenyl)-6-((1s,3s)-3- fluorocyclobutoxy)pyrimidine-5-carboxylic acid (step 2) and 1-aminooxy-2-methyl-propan-2-ol (Intermediate C) analogously to Example 32 step 3.
LC-MS (Method 8B): Rt 4.64 mins; MS m/z 416.3 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 11.20 (s, 1H), 8.59 (d, J = 1.7 Hz, 1H), 8.57 (dt, J = 7.8, 1.4 Hz, 1H), 8.01 (dt, J = 7.8, 1.4 Hz, 1H), 7.77 (s, 2H), 7.74 (t, J = 7.8 Hz, 1H), 5.05– 4.86 (m, 2H), 4.77 (s, 1H), 3.72 (s, 2H), 3.03 (dqd, J = 10.1, 6.7, 3.1 Hz, 2H), 2.56– 2.52 (m, 1H), 2.48 – 2.44 (m, 1H), 1.18 (s, 6H).
Example 32.4
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-(3- pyridyloxy)pyrimidine-5-carboxamide Step 1: Ethyl 4-amino-2-(3-cya
Figure imgf000197_0003
nophenyl)-6-(3-pyridyloxy)pyrimidine-5-carboxylate
3
Figure imgf000197_0001
[00374] The title compound was prepared from ethyl 4-amino-6-chloro-2-(3- cyanophenyl)pyrimidine-5-carboxylate (Example 5 step 1) and pyridin-3-ol analogously to Example 32 step 1.
LC-MS (Method 5B): Rt 3.14 mins; MS m/z 362.1 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 8.55 (d, J = 2.7 Hz, 1H), 8.52 (dd, J = 4.7, 1.0 Hz, 1H), 8.30 (t, J = 1.7 Hz, 1H), 8.22 (dt, J = 8.1, 1.4 Hz, 1H), 8.18– 7.91 (m, 3H), 7.76 (ddd, J = 8.3, 2.7, 1.4 Hz, 1H), 7.67 (t, J = 7.9 Hz, 1H), 7.54 (dd, J = 8.3, 4.7 Hz, 1H), 4.33 (q, J = 7.1 Hz, 2H), 1.30 (t, J = 7.1 Hz, 3H).
Step 2: 4-Amino-2-(3-cyanophenyl)-6-(3-pyridyloxy)pyrimidine-5-carboxylic acid
Figure imgf000197_0002
[00375] The title compound was prepared from ethyl 4-amino-2-(3-cyanophenyl)-6-(3- pyridyloxy)pyrimidine-5-carboxylate (step 1) and lithium hydroxide analogously to Example 32 step 2. LC-MS (Method 3A): Rt 1.45 mins; MS m/z 334.1 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 13.28 (s, 1H), 8.55 (d, J = 2.7 Hz, 1H), 8.52 (d, J = 4.7 Hz, 1H), 8.28 (t, J = 1.9 Hz, 1H), 8.20 (d, J = 7.9 Hz, 1H), 8.15 (s, 2H), 7.96 (d, J = 7.9 Hz, 1H), 7.77 (dd, J = 8.5, 2.7 Hz, 1H), 7.66 (t, J = 7.9 Hz, 1H), 7.55 (dd, J = 8.5, 4.7 Hz, 1H).
Step 3: 4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-(3- pyridyloxy)pyrimidine-5-carboxamide
[00376] The title compound was prepared from 4-amino-2-(3-cyanophenyl)-6-(3- pyridyloxy)pyrimidine-5-carboxylic acid (step 2) and 1-aminooxy-2-methyl-propan-2-ol (Intermediate C) analogously to Example 32 step 3.
LC-MS (Method 8B): Rt 3.47 mins; MS m/z 421.2 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 11.56 (s, 1H), 8.58 (d, J = 2.7 Hz, 1H), 8.52 (d, J = 4.6 Hz, 1H), 8.27 (s, 1H), 8.20 (d, J = 7.9 Hz, 1H), 7.95 (d, J = 7.9 Hz, 1H), 7.82 (s, 2H), 7.78 (d, J = 8.4 Hz, 1H), 7.65 (t, J = 7.9 Hz, 1H), 7.55 (dd, J = 8.4, 4.6 Hz, 1H), 4.71 (s, 1H), 3.75 (s, 2H), 1.17 (s, 6H).
Example 32.5
4-amino-2-(3-cyanophenyl)-6-(3,3-difluorocyclobutoxy)-N-(2-hydroxy-2-methyl- propoxy)pyrimidine-5-carboxamide
Figure imgf000198_0001
Step 1: Ethyl 4-amino-2-(3-cyanophenyl)-6-(3,3-difluorocyclobutoxy)pyrimidine-5-carboxylate
Figure imgf000198_0002
[00377] The title compound was prepared from ethyl 4-amino-6-chloro-2-(3- cyanophenyl)pyrimidine-5-carboxylate (Example 5 step 1) and 3,3-difluorocyclobutanol analogously to Example 32 step 1. LC-MS (Method 5B): Rt 3.73 mins; MS m/z 375.1 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 8.63 (d, J = 1.7 Hz, 1H), 8.60 (dt, J = 7.8, 1.4 Hz, 1H), 8.02 (dt, J = 7.8, 1.4 Hz, 1H), 7.90 (s, 2H), 7.75 (t, J = 7.8 Hz, 1H), 5.44– 5.34 (m, 1H), 4.27 (q, J = 7.1 Hz, 2H), 3.31– 3.22 (m, 2H), 2.77 (qd, J = 14.1, 4.7 Hz, 2H), 1.31 (t, J = 7.1 Hz, 3H).
Step 2: 4-Amino-2-(3-cyanophenyl)-6-(3,3-difluorocyclobutoxy)pyrimidine-5-carboxylic acid
Figure imgf000199_0001
[00378] The title compound was prepared from ethyl 4-amino-2-(3-cyanophenyl)-6- (3,3-difluorocyclobutoxy)pyrimidine-5-carboxylate (step 1) and lithium hydroxide analogously to Example 32 step 2.
LC-MS (Method 5A): Rt 2.81 mins; MS m/z 347.1 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 12.90 (br s, 1H), 8.62 (d, J = 1.9 Hz, 1H), 8.61– 8.56 (m, 1H), 8.02 (dd, J = 7.7, 1.6 Hz, 1H), 7.97 (br s, 2H), 7.75 (t, J = 7.7 Hz, 1H), 5.42– 5.29 (m, 1H), 3.30– 3.21 (m, 2H), 2.78 (qd, J = 14.5, 5.1 Hz, 2H).
Step 3: 4-Amino-2-(3-cyanophenyl)-6-(3,3-difluorocyclobutoxy)-N-(2-hydroxy-2-methyl- propoxy)pyrimidine-5-carboxamide
[00379] The title compound was prepared from 4-amino-2-(3-cyanophenyl)-6-(3,3- difluorocyclobutoxy)pyrimidine-5-carboxylic acid (step 2) and 1-aminooxy-2-methyl-propan-2- ol (Intermediate C) analogously to Example 32 step 3.
LC-MS (Method 8B): Rt 3.96 mins; MS m/z 434.3 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 11.21 (s, 1H), 8.61 (d, J = 1.7 Hz, 1H), 8.58 (dt, J = 7.8, 1.5 Hz, 1H), 8.01 (dt, J = 7.8, 1.5 Hz, 1H), 7.80 (br s, 2H), 7.73 (t, J = 7.8 Hz, 1H), 5.39– 5.30 (m, 1H), 4.75 (s, 1H), 3.72 (s, 2H), 3.27– 3.15 (m, 2H), 2.97 (qd, J = 15.1, 5.2 Hz, 2H), 1.18 (s, 6H).
Example 33
4-Amino-N-(2-hydroxy-2-methyl-propoxy)-2-(1H-indol-7-yl)-6-[(3S)-tetrahydrofuran-3- yl]oxy-pyrimidine-5-carboxamide Step 1: Ethyl 4-
Figure imgf000200_0002
amino-2-methylsulfanyl-6-[(3S)-tetrahydrofuran-3-yl]oxy-pyrimidine-5- carboxylate
Figure imgf000200_0001
[00380] Ethyl 4,6-dichloro-2-methylsulfanyl-pyrimidine-5-carboxylate (Example 1 step 1) (13.26 g, 49.64 mmol) and (3S)-tetrahydrofuran-3-ol (7.95 mL, 99.28 mmol) were dissolved in anhydrous THF (125 mL) under nitrogen and the resulting solution was cooled to 0 ºC in an ice bath. Under a continuous flow of nitrogen, solid NaH (2.08 g, 52.12 mmol) was added in portions over 15 mins whilst maintaining the internal temperature of the mixture below 10 ºC. The resulting brown mixture was stirred at ~ 5 ºC under nitrogen for 1 h, then at room temperature under nitrogen for a further 1.25 h. NH4OH (35% in water) (112.94 mL, 992.78 mmol) was added and the resulting bi-phasic mixture stirred vigorously under nitrogen for 42h before being partitioned between
water (100 mL) and EtOAc (150 mL). The layers were separated and the aqueous phase further extracted with EtOAc (2 x 150 mL). The combined organic portions were washed with brine (50 mL), dried over Na2SO4 and concentrated in vacuo to afford the crude material as an orange solid. This material was suspended in 10% Et2O in petrol (60 mL) and the resulting slurry filtered. The solids were washed with 10% Et2O in petrol (60 mL), 20% Et2O in petrol (2 x 20 mL), 50% Et2O in petrol (3 x 20 mL) and vacuum dried to afford the title compound as an orange solid.
LC-MS (Method 3B): Rt 1.83 mins; MS m/z 300.1 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 7.78 (s, 2H), 5.55 (ddt, J = 6.7, 4.4, 1.9 Hz, 1H), 4.19 (q, J = 7.1 Hz, 2H), 3.92 (dd, J = 10.4, 4.8 Hz, 1H), 3.85– 3.76 (m, 2H), 3.76– 3.72 (m, 1H), 2.44 (s, 3H), 2.23– 2.14 (m, 1H), 2.04– 1.97 (m, 1H), 1.26 (t, J = 7.1 Hz, 3H). Step 2: Ethyl 4-amino-2-(1H-indol-7-yl)-6-[(3S)-tetrahydrofuran-3-yl]oxy-pyrimidine-5- carboxylate
Figure imgf000201_0001
[00381] The title compound was prepared from ethyl 4-amino-2-methylsulfanyl-6-[(3S)- tetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxylate (step 1) and 1H-indol-7-ylboronic acid analogously to Example 1 step 4.
1H NMR (500 MHz, Chloroform-d) d 10.84 (s, 1H), 8.33 (d, J = 7.5 Hz, 1H), 7.82 (d, J = 7.7 Hz, 1H), 7.37– 7.33 (m, 1H), 7.21 (t, J = 7.7 Hz, 1H), 6.65– 6.60 (m, 1H), 5.89– 5.80 (m, 1H), 4.34 (q, J = 7.1 Hz, 2H), 4.24 (dd, J = 10.5, 5.0 Hz, 1H), 4.09– 3.95 (m, 3H), 2.39– 2.31 (m, 1H), 2.31– 2.24 (m, 1H), 1.41 (t, J = 7.1 Hz, 3H).2 x exchangeable protons not observed. LC-MS (Method 5A): Rt 3.48 mins; MS m/z 369.3 = [M+H]+
Step 3: 4-Amino-2-(1H-indol-7-yl)-6-[(3S)-tetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxylic acid
Figure imgf000201_0002
[00382] The title compound was prepared from ethyl 4-amino-2-(1H-indol-7-yl)-6-(3S)- tetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxylate (step 2) and lithium hydroxide analogously to Example 1 step 5.
LC-MS (Method 5A): Rt 2.83 mins; MS m/z 341.2 = [M+H]+
1H NMR (500 MHz, Chloroform-d) d 10.77 (s, 1H), 8.32 (d, J = 7.6 Hz, 1H), 7.86 (d, J = 7.7 Hz, 1H), 7.38– 7.33 (m, 1H), 7.22 (t, J = 7.7 Hz, 1H), 6.66– 6.60 (m, 1H), 6.08– 6.03 (m, 1H), 4.19 (dd, J = 11.2, 4.5 Hz, 1H), 4.15– 4.04 (m, 2H), 4.03– 3.95 (m, 1H), 2.54– 2.45 (m, 1H), 2.36– 2.29 (m, 1H).3 x exchangeable protons not observed. Step 4: 4-Amino-N-(2-hydroxy-2-methyl-propoxy)-2-(1H-indol-7-yl)-6-[(3S)-tetrahydrofuran-3- yl]oxy-pyrimidine-5-carboxamide
[00383] The title compound was prepared from amino-2-(1H-indol-7-yl)-6-[(3S)- tetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxylic acid (step 3) and 1-aminooxy-2-methyl- propan-2-ol (Intermediate C) analogously to Example 23.
LC-MS (Method 8B): Rt 4.73 mins; MS m/z 428.3 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 11.71 (s, 1H), 10.95 (s, 1H), 8.24 (d, J = 7.5 Hz, 1H), 7.97 (br s, 2H), 7.78 (d, J = 7.6 Hz, 1H), 7.49– 7.44 (m, 1H), 7.16 (t, J = 7.7 Hz, 1H), 6.59– 6.56 (m, 1H), 5.83– 5.77 (m, 1H), 4.77 (s, 1H), 4.08 (dd, J = 10.4, 5.0 Hz, 1H), 3.95– 3.88 (m, 2H), 3.84– 3.79 (m, 1H), 3.72 (s, 2H), 2.36– 2.27 (m, 1H), 2.26– 2.17 (m, 1H), 1.18 (s, 6H).
Example 33.1
4-Amino-N-(2-hydroxy-2-methyl-propoxy)-2-(1H-indol-4-yl)-6-tetrahydrofuran-3-yloxy- pyrimidine-5-carboxamide
Figure imgf000202_0001
Step 1: Ethyl 4-amino-2-(1H-indol-4-yl)-6-[(3S)-tetrahydrofuran-3-yl]oxy-pyrimidine-5- carboxylate
Figure imgf000202_0002
[00384] The title compound was prepared from ethyl 4-amino-2-methylsulfanyl-6-[(3S)- tetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxylate (Example 33 step 1) and 1H-indol-4- ylboronic acid analogously to Example 1 step 4.
LC-MS (Method 5B): Rt 3.14 mins; MS m/z 369.2 = [M+H]+ 1H NMR (500 MHz, DMSO-d6) d 11.30 (s, 1H), 8.15 (d, J = 7.5 Hz, 1H), 7.79 (s, 2H), 7.58 (d, J = 8.0 Hz, 1H), 7.55– 7.50 (m, 1H), 7.50– 7.45 (m, 1H), 7.20 (t, J = 7.8 Hz, 1H), 5.81– 5.75 (m, 1H), 4.25 (q, J = 7.1 Hz, 2H), 4.07 (dd, J = 10.3, 4.8 Hz, 1H), 3.92– 3.80 (m, 3H), 2.35– 2.25 (m, 1H), 2.15– 2.08 (m, 1H), 1.31 (t, J = 7.2 Hz, 3H).
Step 2: 4-Amino-2-(1H-indol-4-yl)-6-[(3S)-tetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxylic acid
Figure imgf000203_0001
[00385] The title compound was prepared from ethyl 4-amino-2-(1H-indol-4-yl)-6-[(3S)- tetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxylate (step 1) and lithium hydroxide analogously to Example 1 step 5.
LC-MS (Method 5A): Rt 2.25 mins; MS m/z 341.2 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 11.35 (s, 1H), 8.15 (d, J = 7.8 Hz, 1H), 7.94 (s, 2H), 7.60 (d, J = 7.8 Hz, 1H), 7.54– 7.47 (m, 2H), 7.21 (t, J = 7.8 Hz, 1H), 5.80 (t, J = 5.7 Hz, 1H), 4.05 (dd, J = 10.3, 4.8 Hz, 1H), 3.91– 3.86 (m, 1H), 3.81– 3.78 (m, 2H), 2.31 (dt, J = 14.6, 7.2 Hz, 1H), 2.11 (dt, J = 12.7, 5.8 Hz, 1H).1 x exchangeable proton not observed.
Step 3: 4-Amino-N-(2-hydroxy-2-methyl-propoxy)-2-(1H-indol-4-yl)-6-tetrahydrofuran-3-yloxy- pyrimidine-5-carboxamide
[00386] The title compound was prepared from 4-amino-2-(1H-indol-4-yl)-6- tetrahydrofuran-3-yloxy-pyrimidine-5-carboxylic acid (step 2) and 1-aminooxy-2-methyl- propan-2-ol (Intermediate C) analogously to Example 23.
LC-MS (Method 8B): Rt 3.30 mins; MS m/z 428.3 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 11.29 (br s, 1H), 10.95 (br s, 1H), 8.12 (d, J = 7.5 Hz, 1H), 7.84– 7.63 (br m, 2H), 7.57 (d, J = 8.0 Hz, 1H), 7.52– 7.44 (m, 2H), 7.19 (t, J = 7.5 Hz, 1H), 5.79 (s, 1H), 4.77 (s, 1H), 4.05 (dd, J = 10.4, 4.9 Hz, 1H), 3.99– 3.87 (m, 2H), 3.86– 3.78 (m, 1H), 3.71 (s, 2H), 2.31 (p, J = 7.1 Hz, 1H), 2.27– 2.18 (m, 1H), 1.17 (s, 6H). Example 33.2
4-Amino-2-(3-cyano-2-methoxy-phenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(3S)- tetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxamide
Figure imgf000204_0001
Step 1: Ethyl 4-amino-2-(3-cyano-2-methoxy-phenyl)-6-[(3S)-tetrahydrofuran-3-yl]oxy- pyrimidine-5-carboxylate
Figure imgf000204_0002
[00387] The title compound was prepared from ethyl 4-amino-2-methylsulfanyl-6-[(3S)- tetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxylate (Example 33 step 1) and (3-cyano-2- methoxy-phenyl)boronic acid analogously to Example 1 step 4.
LC-MS (Method 3A): Rt 1.94 mins; MS m/z 385.2 = [M+H]+
1H NMR (500 MHz, Chloroform-d) d 8.16 (br s, 1H), 7.98 (dd, J = 7.8, 1.8 Hz, 1H), 7.68 (dd, J = 7.8, 1.8 Hz, 1H), 7.28– 7.21 (m, 1H), 5.93 (br s, 1H), 5.72 (ddt, J = 6.8, 4.6, 2.0 Hz, 1H), 4.34 (q, J = 7.1 Hz, 2H), 4.09 (dd, J = 10.5, 4.9 Hz, 1H), 3.97 (s, 3H), 4.02– 3.92 (m, 3H), 2.29– 2.16 (m, 2H), 1.39 (t, J = 7.1 Hz, 3H).
Step 2: 4-Amino-2-(3-cyano-2-methoxy-phenyl)-6-[(3S)-tetrahydrofuran-3-yl]oxy-pyrimidine- 5-carboxylic acid
Figure imgf000204_0003
[00388] The title compound was prepared from ethyl 4-amino-2-(3-cyano-2-methoxy- phenyl)-6-[(3S)-tetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxylate (step 1) and lithium hydroxide analogously to Example 1 step 5.
LC-MS (Method 5A): Rt 2.20 mins; MS m/z 357.2 = [M+H]+ 1H NMR (500 MHz, DMSO-d6) d 12.77 (br s, 1H), 8.01 (dd, J = 7.8, 1.8 Hz, 1H), 7.91 (dd, J = 7.8, 1.8 Hz, 1H), 7.88 (br s, 2H), 7.38 (t, J = 7.8 Hz, 1H), 5.61 (ddt, J = 6.7, 4.6, 2.1 Hz, 1H), 3.90 (s, 3H), 3.94– 3.71 (m, 4H), 2.20 (dtd, J = 14.4, 8.1, 6.3 Hz, 1H), 2.07– 2.00 (m, 1H).
Step 3: 4-Amino-2-(3-cyano-2-methoxy-phenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(3S)- tetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxamide
[00389] The title compound was prepared from 4-amino-2-(3-cyano-2-methoxy- phenyl)-6-[(3S)-tetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxylic acid (step 2) and 1- aminooxy-2-methyl-propan-2-ol (Intermediate C) analogously to Example 23
LC-MS (Method 8B): Rt 3.01 mins; MS m/z 444.4 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 11.05 (br s, 1H), 7.98 (dd, J = 7.8, 1.8 Hz, 1H), 7.91 (dd, J = 7.8, 1.8 Hz, 1H), 7.62 (s, 2H), 7.38 (t, J = 7.8 Hz, 1H), 5.63– 5.57 (m, 1H), 4.73 (s, 1H), 3.90 (s, 3H), 3.95– 3.80 (m, 3H), 3.77 (td, J = 8.2, 4.7 Hz, 1H), 3.70 (s, 2H), 2.24– 2.11 (m, 2H), 1.17 (s, 6H).
Example 34
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1S)-1-methyl-2- (propanoylamino)ethoxy]pyrimidine-5-carboxamide
Figure imgf000205_0001
Step 1: Ethyl 4-Amino-2-(3-cyanophenyl)-6-[(1S)-2-(tert-butoxycarbonylamino)-1-methyl- ethoxy]pyrimidine-5-carboxylate
Figure imgf000205_0002
[00390] The title compound was prepared from ethyl 4-amino-6-chloro-2-(3- cyanophenyl)pyrimidine-5-carboxylate (Example 5 step 1) and (S)-1-(Boc-amino)-2-propanol analogously to Example 32 step 1. LC-MS (Method 5B): Rt 3.79 mins; MS m/z 442.2 = [M+H]+; 464.2 = [M+Na]+ 1H NMR (500 MHz, Chloroform-d) d 8.66 (t, J = 1.8 Hz, 1H), 8.59 (dt, J = 8.0, 1.5 Hz, 1H), 8.02 (br s, 1H), 7.75 (dt, J = 7.7, 1.5 Hz, 1H), 7.56 (t, J = 7.8 Hz, 1H), 5.74 (br s, 1H), 5.57– 5.49 (m, 1H), 5.14 (t, J = 6.0 Hz, 1H), 4.42– 4.33 (m, 2H), 3.56 (ddd, J = 14.0, 6.0, 3.6 Hz, 1H), 3.43– 3.34 (m, 1H), 1.49– 1.37 (m, 15H).
Step 2: 4-Amino-2-(3-cyanophenyl)-6-[(1S)-2-(tert-butoxycarbonylamino)-1-methyl- ethoxy]pyrimidine-5-carboxylic acid
Figure imgf000206_0001
[00391] The title compound was prepared from ethyl 4-amino-2-(3-cyanophenyl)-6- [(1S)-2-(tert-butoxycarbonylamino)-1-methyl-ethoxy]pyrimidine-5-carboxylate (step 1) and lithium hydroxide analogously to Example 32 step 2.
LC-MS (Method 5A): Rt 2.98 mins; MS m/z 414.3 = [M+H]+
1H NMR (500 MHz, Methanol-d4) d 8.64 (t, J = 1.7 Hz, 1H), 8.62 (dt, J = 7.8, 1.7 Hz, 1H), 7.78 (dt, J = 7.8, 1.7 Hz, 1H), 7.62 (t, J = 7.8 Hz, 1H), 5.65– 5.58 (m, 1H), 3.45 (dd, J = 14.1, 3.3 Hz, 1H), 3.26 (dd, J = 14.1, 7.6 Hz, 1H), 1.39– 1.32 (m, 12H).4 x exchangeable protons not observed.
Step 3: tert-Butyl N-[(2S)-2-[6-amino-2-(3-cyanophenyl)-5-[(2-hydroxy-2-methyl- propoxy)carbamoyl]pyrimidin-4-yl]oxypropyl]carbamate
Figure imgf000206_0002
[00392] The title compound was prepared from 4-amino-2-(3-cyanophenyl)-6-[(1S)-2- (tert-butoxycarbonylamino)-1-methyl-ethoxy]pyrimidine-5-carboxylic acid (step 2) and 1- aminooxy-2-methyl-propan-2-ol (Intermediate C) analogously to Example 32 step 3.
LC-MS (Method 5B): Rt 3.13 mins; MS m/z 501.3 = [M+H]+ 1H NMR (500 MHz, DMSO-d6) d 10.96 (s, 1H), 8.64 (t, J = 1.8 Hz, 1H), 8.59 (d, J = 8.0 Hz, 1H), 8.01 (dt, J = 7.6, 1.5 Hz, 1H), 7.95 (br s, 2H), 7.73 (t, J = 7.8 Hz, 1H), 7.16 (t, J = 6.1 Hz, 1H), 5.65 - 5.54 (m, 1H), 4.72 (s, 1H), 3.73 (s, 2H), 3.43– 3.34 (m, 1H), 3.25– 3.18 (m, 1H), 1.33 (s, 9H), 1.30 (d, J = 6.3 Hz, 3H), 1.21– 1.17 (m, 6H).
Step 4: 4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1S)-2-amino-1- methyl-ethoxy]pyrimidine-5-carboxamide 2,2,2-trifluoroacetic acid salt
Figure imgf000207_0001
[00393] The title compound was prepared from tert-butyl N-[(2S)-2-[6-amino-2-(3- cyanophenyl)-5-[(2-hydroxy-2-methyl-propoxy)carbamoyl]pyrimidin-4-yl]oxypropyl]carbamate (step 3) and TFA analogously to Example 10 step 4.
LC-MS (Method 5B): Rt 2.12 mins; MS m/z 401.3 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 11.01 (s, 1H), 8.63 (t, J = 1.9 Hz, 1H), 8.59 (dt, J = 8.0, 1.5 Hz, 1H), 8.03 (dt, J = 7.8, 1.6 Hz, 1H), 8.00– 7.79 (br m, 5H), 7.76 (t, J = 7.8 Hz, 1H), 5.81– 5.74 (m, 1H), 4.80 (s, 1H), 3.74 (s, 2H), 3.29– 3.19 (m, 2H), 1.40 (d, J = 6.3 Hz, 3H), 1.19 (s, 6H). CH2 next to NH2 partially obscured by water signal in spectra.
1H NMR (500 MHz, Methanol-d4) d 8.72 (t, J = 1.6 Hz, 1H), 8.69 (dt, J = 7.8, 1.6 Hz, 1H), 7.89 (dt, J = 7.8, 1.6 Hz, 1H), 7.69 (t, J = 7.8 Hz, 1H), 6.01– 5.92 (m, 1H), 3.92– 3.86 (m, 2H), 3.54– 3.44 (m, 1H), 3.41– 3.36 (m, 1H), 1.55 (d, J = 6.4 Hz, 3H), 1.35– 1.28 (m, 6H).6 x exchangeable protons not observed.
Step 5: 4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1S)-1-methyl-2- (propanoylamino)ethoxy]pyrimidine-5-carboxamide
[00394] To a solution of 4-amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)- 6-[(1S)-2-amino-1-methyl-ethoxy]pyrimidine-5-carboxamide 2,2,2-trifluoroacetic acid salt (40 mg, 0.08 mmol) in chloroform (2 mL) at 0 °C was added triethylamine (54 µL, 0.39 mmol) followed by propanoyl chloride (8 µL, 0.09 mmol). The ice bath was removed and the mixture stirred for 30 mins. The resulting mixture was partitioned between DCM (5 mL) and water (5 mL). The organic portion was separated and the aqueous layer was further extracted with DCM (2 x 5 mL). The combined organic extracts were dried over MgSO4 and the solvent removed in vacuo. Purification by chromatography on silica eluting with 80% EtOAc in hexanes followed by chromatography on silica eluting with a gradient of 2 to 4% MeOH in DCM afforded a viscous oil. The oil was further purified by C18 reverse phase chromatography eluting with 10 to 35% MeCN in water (+0.1% formic acid) to afford the title compound as a colourless solid.
LC-MS (Method 8B): Rt 4.09 mins; MS m/z 457.3 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 10.96 (s, 1H), 8.63 (t, J = 1.8 Hz, 1H), 8.58 (d, J = 7.8 Hz, 1H), 8.07 (s, 1H), 8.01 (d, J = 7.8 Hz, 1H), 7.91 (br s, 2H), 7.73 (t, J = 7.8 Hz, 1H), 5.66– 5.58 (m, 1H), 4.78 (br s, 1H), 3.73 (s, 2H), 3.54– 3.45 (m, 1H), 3.40– 3.34 (m, 1H), 2.04 (qd, J = 7.6, 2.9 Hz, 2H), 1.33 (d, J = 6.3 Hz, 3H), 1.18 (s, 6H), 0.92 (t, J = 7.6 Hz, 3H).
Example 35
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(2S)-2- hydroxybutoxy]pyrimidine-5-carboxamide
Figure imgf000208_0001
Step 1: Ethyl 4-amino-2-methylsulfanyl-6-[(1S)-1-(benzyloxymethyl)propoxy]pyrimidine-5- carboxylate
Figure imgf000208_0002
[00395] The title compound was prepared from ethyl 4,6-dichloro-2-methylsulfanyl- pyrimidine-5-carboxylate (Example 1 step 1) and (2S)-1-benzyloxybutan-2-ol (Intermediate W) analogously to Example 33 step 1.
LC-MS (Method 5B): Rt 4.02 mins; MS m/z 392.3 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 7.72 (s, 2H), 7.36– 7.21 (m, 5H), 5.34 (dt, J = 11.1, 5.5 Hz, 1H), 4.57– 4.46 (m, 2H), 4.18 (qd, J = 7.1, 2.5 Hz, 2H), 3.64 (dd, J = 10.6, 5.7 Hz, 1H), 3.59 (dd, J = 10.6, 4.3 Hz, 1H), 2.42 (s, 3H), 1.80– 1.62 (m, 2H), 1.22 (t, J = 7.1 Hz, 3H), 0.90 (t, J = 7.4 Hz, 3H). Step 2: Ethyl 4-amino-2-(3-cyanophenyl)-6-[(1S)-1-(benzyloxymethyl)propoxy]pyrimidine-5- carboxylate
Figure imgf000209_0001
[00396] The title compound was prepared from ethyl 4-amino-2-methylsulfanyl-6-[(1S)- 1-(benzyloxymethyl)propoxy]pyrimidine-5-carboxylate (step 1) and (3-cyanophenyl)boronic acid analogously to Example 1 step 4.
LC-MS (Method 5B): Rt 4.24 mins; MS m/z 447.3 = [M+H]+
1H NMR (500 MHz, Chloroform-d) d 8.65 (t, J = 1.7 Hz, 1H), 8.60 (d, J = 7.8 Hz, 1H), 7.75 (dd, J = 7.8, 1.6 Hz, 1H), 7.55 (t, J = 7.8 Hz, 1H), 7.30 (d, J = 4.4 Hz, 3H), 7.26– 7.22 (m, 2H), 5.63 (p, J = 5.4 Hz, 1H), 4.59 (q, J = 12.2 Hz, 2H), 4.39– 4.25 (m, 2H), 3.78 (dd, J = 10.4, 5.7 Hz, 1H), 3.69 (dd, J = 10.5, 4.6 Hz, 1H), 1.95– 1.79 (m, 2H), 1.35 (t, J = 7.1 Hz, 3H), 1.02 (t, J = 7.5 Hz, 3H).2 x exchangeable protons not observed
Step 3: Ethyl 4-amino-2-(3-cyanophenyl)-6-[(1S)-1-(hydroxymethyl)propoxy]pyrimidine-5- carboxylate
Figure imgf000209_0002
[00397] BCl3 (1M in DCM) (1.59 mL, 1.59 mmol) was added to ethyl 4-amino-2-(3- cyanophenyl)-6-[(1S)-1-(benzyloxymethyl)propoxy]pyrimidine-5-carboxylate (step 2) (163 mg, 0.32 mmol) in DCM (3 mL) and the reaction mixture was stirred at room temperature for 1 h. The reaction was quenched into water (5 mL) and extracted with DCM (3 x 5 mL). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo. Purification of the crude material by chromatography on silica eluting with a gradient of 0 to 100% EtOAc in petrol afforded the title compound as a colourless solid.
LC-MS (Method 5B): Rt 3.20 mins; MS m/z 357.2 = [M+H]+
1H NMR (500 MHz, Chloroform-d) d 8.65 (d, J = 1.7 Hz, 1H), 8.61 (d, J = 7.8 Hz, 1H), 8.06 (s, 1H), 7.77 (dt, J = 7.8, 1.5 Hz, 1H), 7.59 (t, J = 7.8 Hz, 1H), 5.96 (s, 1H), 5.44 (qd, J = 6.4, 3.1 Hz, 1H), 4.43– 4.31 (m, 2H), 3.89 (dd, J = 12.0, 3.1 Hz, 1H), 3.82 (dd, J = 12.0, 6.6 Hz, 1H), 2.72 (s, 1H), 1.95– 1.77 (m, 2H), 1.41 (t, J = 7.1 Hz, 3H), 1.06 (t, J = 7.5 Hz, 3H).
Step 4: 4-Amino-2-(3-cyanophenyl)-6-[(2S)-2-hydroxybutoxy]pyrimidine-5-carboxylic acid
Figure imgf000210_0001
[00398] The title compound was prepared from ethyl 4-amino-2-(3-cyanophenyl)-6- [(1S)-1-(hydroxymethyl)propoxy]pyrimidine-5-carboxylate (step 3) and lithium hydroxide analogously to Example 32 step 2.
LC-MS (Method 5B): Rt 2.42 mins; MS m/z 329.2 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 12.71 (s, 1H), 8.64 (d, J = 1.9 Hz, 1H), 8.61 (dt, J = 7.8, 1.5, 1.5 Hz, 1H), 8.03 (dt, J = 7.8, 1.5 Hz, 1H), 7.93 (s, 2H), 7.76 (t, J = 7.8 Hz, 1H), 4.45 (dd, J = 10.8, 5.7 Hz, 1H), 4.37 (dd, J = 10.8, 5.5 Hz, 1H), 3.79– 3.73 (m, 1H), 1.70– 1.59 (m, 1H), 1.50– 1.39 (m, 1H), 0.94 (t, J = 7.4 Hz, 3H).1 x exchangeable proton not observed
Step 5: 4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(2S)-2- hydroxybutoxy]pyrimidine-5-carboxamide
[00399] The title compound was prepared from 4-amino-2-(3-cyanophenyl)-6-[(2S)-2- hydroxybutoxy]pyrimidine-5-carboxylic acid (step 4) and 1-aminooxy-2-methyl-propan-2-ol (Intermediate C) analogously to Example 32 step 3.
LC-MS (Method 8B): Rt 3.92 mins; MS m/z 416.3 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 11.10 (s, 1H), 8.62 (t, J = 1.8 Hz, 1H), 8.58 (dt, J = 7.8, 1.5 Hz, 1H), 8.01 (dt, J = 7.8, 1.5 Hz, 1H), 7.92 (s, 2H), 7.74 (t, J = 7.8 Hz, 1H), 5.05 (s, 1H), 4.73 (s, 1H), 4.49 (dd, J = 10.8, 4.3 Hz, 1H), 4.40 (dd, J = 10.8, 6.5 Hz, 1H), 3.80 (s, 1H), 3.71 (s, 2H), 1.62– 1.52 (m, 1H), 1.51– 1.40 (m, 1H), 1.17 (s, 6H), 0.95 (t, J = 7.4 Hz, 3H).
Example 36
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[[(2S)-5-oxopyrrolidin- 2-yl]methoxy]pyrimidine-5-carboxamide
Step 1: Ethyl 4-amino-2-m
Figure imgf000211_0002
ethylsulfanyl-6-[[(2S)-1-[(2,4-dimethoxyphenyl)methyl]-5-oxo- pyrrolidin-2-yl]methoxy]pyrimidine-5-carboxylate
Figure imgf000211_0001
[00400] The title compound was prepared from ethyl 4,6-dichloro-2-methylsulfanyl- pyrimidine-5-carboxylate (Example 1 step 1) and (5S)-1-[(2,4-dimethoxyphenyl)methyl]-5- (hydroxymethyl)pyrrolidin-2-one (Intermediate X) analogously to Example 33 step 1.
LC-MS (Method 5B): Rt 2.99 mins; MS m/z 477.3 = [M+H]+
1H NMR (500 MHz, Chloroform-d) d 7.16 (d, J = 8.1 Hz, 1H), 6.41– 6.35 (m, 2H), 4.69 (d, J = 15.1 Hz, 1H), 4.55 (dd, J = 11.7, 4.0 Hz, 1H), 4.38 (dd, J = 11.7, 3.2 Hz, 1H), 4.35– 4.24 (m, 3H), 3.85– 3.68 (m, 7H), 2.62– 2.53 (m, 1H), 2.47 (s, 3H), 2.44– 2.34 (m, 1H), 2.18– 2.06 (m, 2H), 1.33 (t, J = 7.1 Hz, 3H).2 x exchangeable protons not observed.
Step 2: Ethyl 4-amino-2-(3-cyanophenyl)-6-[[(2S)-1-[(2,4-dimethoxyphenyl)methyl]-5-oxo- pyrrolidin-2-yl]methoxy]pyrimidine-5-carboxylate
Figure imgf000212_0002
[00401] The title compound was prepared from ethyl 4-amino-2-methylsulfanyl-6-[[(2S)- 1-[(2,4-dimethoxyphenyl)methyl]-5-oxo-pyrrolidin-2-yl]methoxy]pyrimidine-5-carboxylate (step 1) and (3-cyanophenyl)boronic acid analogously to Example 1 step 4.
LC-MS (Method 5B): Rt 3.35 mins; MS m/z 532.4 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 8.59 (t, J = 1.5 Hz, 1H), 8.54 (dt, J = 7.8, 1.5 Hz, 1H), 8.03 (dt, J = 7.8, 1.5 Hz, 1H), 7.87 (s, 2H), 7.74 (t, J = 7.8 Hz, 1H), 6.99 (d, J = 8.4 Hz, 1H), 6.35 (d, J = 2.4 Hz, 1H), 6.29 (dd, J = 8.4, 2.4 Hz, 1H), 4.69 (dd, J = 11.7, 3.3 Hz, 1H), 4.45– 4.37 (m, 2H), 4.32– 4.20 (m, 3H), 3.90– 3.85 (m, 1H), 3.68 (s, 3H), 3.60 (s, 3H), 2.32– 2.25 (m, 1H), 2.21– 2.10 (m, 2H), 2.07– 2.00 (m, 1H), 1.28 (t, J = 7.1 Hz, 3H).
Step 3: Ethyl 4-amino-2-(3-cyanophenyl)-6-[[(2S)-5-oxopyrrolidin-2-yl]methoxy]pyrimidine-5- carboxylate
Figure imgf000212_0001
[00402] The title compound was prepared from ethyl 4-amino-2-(3-cyanophenyl)-6- [[(2S)-1-[(2,4-dimethoxyphenyl)methyl]-5-oxo-pyrrolidin-2-yl]methoxy]pyrimidine-5- carboxylate (step 2) and TFA analogously to Example 10 step 4.
LC-MS (Method 5A): Rt 2.48 mins; MS m/z 382.2. = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 8.65 (t, J = 1.5 Hz, 1H), 8.61 (dt, J = 7.9, 1.5 Hz, 1H), 8.03 (dt, J = 7.9, 1.5 Hz, 1H), 7.86 (s, 2H), 7.75 (t, J = 7.9 Hz, 1H), 7.70 (s, 1H), 4.52– 4.43 (m, 2H), 4.27 (q, J = 7.1 Hz, 2H), 3.97– 3.91 (m, 1H), 2.32– 2.24 (m, 1H), 2.21– 2.10 (m, 2H), 2.02– 1.95 (m, 1H), 1.29 (t, J = 7.1 Hz, 3H).
Step 4: 4-Amino-2-(3-cyanophenyl)-6-[[(2S)-5-oxopyrrolidin-2-yl]methoxy]pyrimidine-5- carboxylic acid
Figure imgf000213_0001
[00403] The title compound was prepared from ethyl 4-amino-2-(3-cyanophenyl)-6- [[(2S)-5-oxopyrrolidin-2-yl]methoxy]pyrimidine-5-carboxylate (step 3) and lithium hydroxide analogously to Example 1 step 5.
LC-MS (Method 5A): Rt 2.02 mins; MS m/z 354.1 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 8.66 (t, J = 1.5 Hz, 1H), 8.62 (dt, J = 7.9, 1.5 Hz, 1H), 8.03 (dt, J = 7.9, 1.5 Hz, 1H), 7.93 (s, 2H), 7.75 (t, J = 7.9 Hz, 1H), 7.64 (s, 1H), 4.51 (dd, J = 11.1, 4.7 Hz, 1H), 4.45 (dd, J = 11.1, 4.4 Hz, 1H), 3.98– 3.92 (m, 1H), 2.41– 2.34 (m, 1H), 2.21– 2.14 (m, 1H), 2.13– 2.06 (m, 1H), 2.03– 1.96 (m, 1H).1 x exchangeable proton not observed.
Step 5: 4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[[(2S)-5-oxopyrrolidin- 2-yl]methoxy]pyrimidine-5-carboxamide
[00404] The title compound was prepared from 4-amino-2-(3-cyanophenyl)-6-[[(2S)-5- oxopyrrolidin-2-yl]methoxy]pyrimidine-5-carboxylic acid (step 4) and 1-aminooxy-2-methyl- propan-2-ol (Intermediate C) analogously to Example 23.
LC-MS (Method 8A): Rt 4.11 mins; MS m/z 441.3 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 11.09 (s, 1H), 8.63 (t, J = 1.8 Hz, 1H), 8.59 (dt, J = 7.9, 1.5 Hz, 1H), 8.01 (dt, J = 7.9, 1.5 Hz, 1H), 7.96 (s, 1H), 7.88– 7.64 (m, 3H), 4.75 (s, 1H), 4.51 (dd, J = 10.9, 6.4 Hz, 1H), 4.43 (dd, J = 10.8, 4.8 Hz, 1H), 4.04– 3.96 (m, 1H), 3.72 (s, 2H), 2.31– 2.12 (m, 3H), 1.96– 1.85 (m, 1H), 1.18 (s, 6H). Example 37
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1S)-1-methyl-2-ureido- ethoxy]pyrimidine-5-carboxamide
Figure imgf000214_0001
Step 1: Ethyl 4-amino-2-methylsulfanyl-6-[1S)-2-(tert-butoxycarbonylamino)-1-methyl- ethoxy]pyrimidine-5-carboxylate
Figure imgf000214_0002
[00405] The title compound was prepared from ethyl 4,6-dichloro-2-methylsulfanyl- pyrimidine-5-carboxylate (Example 1 step 1) and tert-butyl N-[(2S)-2- hydroxypropyl]carbamate analogously to Example 33 step 1.
LC-MS (Method 5B): Rt 3.47 mins; MS m/z 387.2 = [M+H]+, 409.3 = [M+Na]+
1H NMR (500 MHz, Chloroform-d) d 8.09 (br s, 1H), 5.51 (br s, 1H), 5.38– 5.31 (m, 1H), 5.16 – 5.07 (m, 1H), 4.35– 4.29 (m, 2H), 3.54– 3.47 (m, 1H), 3.33– 3.26 (m, 1H), 2.48 (s, 3H), 1.44– 1.34 (m, 15H).
Step 2: Ethyl 4-amino-2-(3-cyanophenyl)-6-[1S)-2-(tert-butoxycarbonylamino)-1-methyl- ethoxy]pyrimidine-5-carboxylate
Figure imgf000214_0003
[00406] The title compound was prepared from ethyl 4-amino-2-methylsulfanyl-6-[(1S)- 2-(tert-butoxycarbonylamino)-1-methyl-ethoxy]pyrimidine-5-carboxylate (step 1) and (3- cyanophenyl)boronic acid analogously to Example 1 step 4. LC-MS (Method 5B): Rt 3.81 mins; MS m/z 442.3 = [M+H]+, 464.3 = [M+Na]+ 1H NMR (500 MHz, Chloroform-d) d 8.67 (s, 1H), 8.61 (d, J = 7.8 Hz, 1H), 8.12 (v br s, 1H), 7.76 (dt, J = 7.8, 1.5 Hz, 1H), 7.57 (t, J = 7.8 Hz, 1H),5.79 (v br s, 1H), 5.57– 5.49 (m, 1H), 5.15– 5.09 (m, 1H), 4.42– 4.35 (m, 2H), 3.56 (ddd, J = 14.0, 6.2, 3.6 Hz, 1H), 3.43– 3.34 (m, 1H), 1.47– 1.41 (m, 15H).
Step 3: Ethyl 4-amino-2-(3-cyanophenyl)-6-[(1S)-2-amino-1-methyl-ethoxy]pyrimidine-5- carboxylate 2,2,2-trifluoroacetic acid salt
Figure imgf000215_0001
[00407] The title compound was prepared from ethyl 4-amino-2-(3-cyanophenyl)-6- [(1S)-2-(tert-butoxycarbonylamino)-1-methyl-ethoxy]pyrimidine-5-carboxylate (step 2) and TFA analogously to Example 10 step 4.
LC-MS (Method 5B): Rt 3.12 mins; MS m/z 342.3 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 8.65 (t, J = 1.7 Hz, 1H), 8.61 (dt, J = 7.8, 1.7 Hz, 1H), 8.04 (dt, J = 7.8, 1.7 Hz, 1H), 8.01– 7.79 (m, 5H), 7.76 (t, J = 7.8 Hz, 1H), 5.71– 5.64 (m, 1H), 4.30– 4.21 (m, 2H), 3.25– 3.16 (m, 1H), 3.15– 3.05 (m, 1H), 1.41 (d, J = 6.4 Hz, 3H), 1.32 (t, J = 7.1 Hz, 3H).
Step 4: Ethyl 4-amino-2-(3-cyanophenyl)-6-[(1S)-1-methyl-2-ureido-ethoxy]pyrimidine-5- carboxylate
Figure imgf000215_0002
[00408] Triethylamine (156 µL, 1.12 mmol) was added to ethyl 4-amino-2-(3- cyanophenyl)-6-[(1S)-2-amino-1-methyl-ethoxy]pyrimidine-5-carboxylate 2,2,2-trifluoroacetic acid salt (step 3) (185 mg, 0.22 mmol) in chloroform (5 mL) and the mixture stirred until a homogeneous solution was obtained. The solution was cooled to 0 C, isocyanato(trimethyl)silane (32 µL, 0.23 mmol) was added and the mixture warmed to room temperature. After stirring for 5 h, additional isocyanato(trimethyl)silane (3 µL, 0.02 mmol) was added and stirring continued for 16 h. MeOH (5 mL) was added and the mixture stirred for 1 h and then concentrated in vacuo. Water (10 mL) was added resulting in a precipitated which was collected by filtration, washed with water (10 mL), washed with Et2O (2 x 10 mL) and dried to afford the title compound as a colourless solid.
LC-MS (Method 5B): Rt 2.64 mins; MS m/z 385.2 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 8.64 (s, 1H), 8.62 (d, J = 7.8 Hz, 1H), 8.02 (d, J = 7.8 Hz, 1H), 7.82 (br s, 2H), 7.75 (t, J = 7.8 Hz, 1H), 5.97 (t, J = 5.8 Hz, 1H), 5.51 (s, 2H), 5.47– 5.41 (m, 1H), 4.32– 4.22 (m, 2H), 3.28– 3.20 (m, 1H), 1.37– 1.26 (m, 6H). 1 x exchangeable proton not observed.
Step 5: 4-Amino-2-(3-cyanophenyl)-6-[(1S)-1-methyl-2-ureido-ethoxy]pyrimidine-5-carboxylic acid
Figure imgf000216_0001
[00409] The title compound was prepared from ethyl 4-amino-2-(3-cyanophenyl)-6- [(1S)-1-methyl-2-ureido-ethoxy]pyrimidine-5-carboxylate (step 4) and lithium hydroxide analogously to Example 1 step 5.
LC-MS (Method 5A): Rt 2.00 mins; MS m/z 357.2 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 12.59 (br s, 1H), 8.63 (s, 1H), 8.61 (d, J = 7.8 Hz, 1H), 8.01 (d, J = 7.8 Hz, 1H), 7.90 (br s, 2H), 7.73 (t, J = 7.8 Hz, 1H), 6.12– 6.03 (m, 1H), 5.58– 5.44 (m, 3H), 3.27– 3.18 (m, 2H), 1.30 (d, J = 6.3 Hz, 3H).
Step 6: 4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1S)-1-methyl-2- ureido-ethoxy]pyrimidine-5-carboxamide
[00410] The title compound was prepared from 4-amino-2-(3-cyanophenyl)-6-[(1S)-1- methyl-2-ureido-ethoxy]pyrimidine-5-carboxylic (step 5) and 1-aminooxy-2-methyl-propan-2- ol (Intermediate C) analogously to Example 23. LC-MS (Method 8B): Rt 3.34 mins; MS m/z 444.3 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 11.20 (s, 1H), 8.61 (t, J = 1.5 Hz, 1H), 8.58 (dt, J = 8.0, 1.5 Hz, 1H), 8.01 (dt, J = 8.0, 1.5 Hz, 1H), 7.95 (br s, 2H), 7.73 (t, J = 8.0 Hz, 1H), 6.28 (s, 1H), 5.60– 5.50 (m, 3H), 4.82 (s, 1H), 3.76– 3.69 (m, 2H), 3.49– 3.40 (m, 1H), 3.28– 3.23 (m, 1H), 1.29 (d, J = 6.3 Hz, 3H), 1.18 (s, 3H), 1.17 (s, 3H).
Example 38
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[rac-(1S,3R)-3- hydroxycyclopentoxy]pyrimidine-5-carboxamide
Figure imgf000217_0001
Step 1: 4-Chloro-2-methylsulfanyl-6-[rac-(1S,3R)-3-[tert- butyl(dimethyl)silyl]oxycyclopentoxy]pyrimidine-5-carboxylic acid
Figure imgf000217_0002
[00411] Anhydrous DMF (10 mL) and anhydrous THF (2 mL) were added to a mixture of 4,6-dichloro-2-methylsulfanyl-pyrimidine-5-carboxylic acid (0.4 g, 1.67 mmol) and sodium hydride (60% in oil) (0.13 g, 3.35 mmol) at 0 ºC under nitrogen and the resulting cloudy mixture stirred at 0 ºC for 20 mins. rac-(1S,3R)-3-[tert-Butyl(dimethyl)silyl]oxycyclopentanol (0.45 g, 2.09 mmol) in THF (5 mL) was added dropwise over 5 mins and stirring continued at 0 ºC for 3.5 h. The reaction was quenched by addition of 10% aqueous citric acid (30 mL) and stirred until a clear solution was obtained. The resulting mixture was extracted with EtOAc (3 x 30 mL) and the combined organic extracts were washed with 90% brine (20 mL), 50% brine (3 x 20 mL), dried over Na2SO4 and concentrated in vacuo to afford the afford the title compound as a pale yellow oil.
LC-MS (Method 3A): Rt 2.64 mins; MS m/z 419.2 / 421.2 = [M+H]+ 1H NMR (500 MHz, Chloroform-d) d 5.57– 5.50 (m, 1H), 4.40– 4.34 (m, 1H), 2.56 (s, 3H), 2.18– 2.09 (m, 2H), 2.01– 1.92 (m, 4H), 0.86 (s, 9H), 0.06 (s, 3H), 0.02 (s, 3H). 1 x exchangeable proton not observed.
Step 2: Methyl 4-chloro-2-methylsulfanyl-6-[rac-(1S,3R)-3-[tert- butyl(dimethyl)silyl]oxycyclopentoxy]pyrimidine-5-carboxylate
Figure imgf000218_0001
[00412] Iodomethane (114 µL, 1.84 mmol) was added to a mixture of 4-chloro-2- methylsulfanyl-6-[rac-(1S,3R)-3-[tert-butyl(dimethyl)silyl]oxycyclopentoxy]pyrimidine-5- carboxylic acid (0.7 g, 1.67 mmol) and K2CO3 (231 mg, 1.67 mmol) in DMF (5 mL) at 0 ºC. The ice bath was then removed and the mixture stirred at room temperature for 2 h. The resulting mixture was diluted with EtOAc (50 mL) and washed with 90% brine (50 mL), 50% brine (3 x 50 mL), dried over Na2SO4 and concentrated in vacuo to afford the title compound as a yellow oil.
LC-MS (Method 3A): Rt 2.80 mins; MS m/z 433.3 / 435.3 = [M+H]+
1H NMR (500 MHz, Chloroform-d) d 5.35 (app tt, J = 7.1, 4.5 Hz, 1H), 4.20 (app p, J = 5.6 Hz, 1H), 3.86 (s, 3H), 2.50 (s, 3H), 2.35– 2.28 (m, 1H), 2.11– 2.02 (m, 1H), 1.99– 1.92 (m, 2H), 1.75– 1.71 (m, 2H), 0.84 (s, 9H), 0.01 (s, 3H), 0.00 (s, 3H).
Step 3: Methyl 4-chloro-2-methylsulfanyl-6-[rac-(1S,3R)-3-hydroxycyclopentoxy]pyrimidine-5- carboxylate
Figure imgf000218_0002
[00413] The title compound was prepared from methyl 4-chloro-2-methylsulfanyl-6- [rac-(1S,3R)-3-[tert-butyl(dimethyl)silyl]oxycyclopentoxy]pyrimidine-5-carboxylate (step 2) and 4M HCl in 1,4-dioxane analogously to Example 18 step 2.
LC-MS (Method 3A): Rt 1.87 mins; MS m/z 299.1 = [M-H2O]- 1H NMR (500 MHz, Chloroform-d) d 5.63 (app tt, J = 4.8, 2.1 Hz, 1H), 4.37 (app tt, J = 5.7, 2.7 Hz, 1H), 3.91 (s, 3H), 2.55 (s, 3H), 2.11– 2.03 (m, 4H), 2.00– 1.94 (m, 1H), 1.90– 1.84 (m, 1H).
1 x exchangeable proton not observed.
Step 4: Methyl 4-amino-2-methylsulfanyl-6-[rac-(1S,3R)-3-hydroxycyclopentoxy]pyrimidine-5- carboxylate
Figure imgf000219_0001
[00414] The title compound was prepared from methyl 4-chloro-2-methylsulfanyl-6- [rac-(1S,3R)-3-hydroxycyclopentoxy]pyrimidine-5-carboxylate (step 3) and NH4OH (35% in water) analogously to Example 1 step 2.
LC-MS (Method 3A): Rt 1.68 mins; MS m/z 300.1 = [M+H]+
1H NMR (500 MHz, Chloroform-d) d 8.13 (br s, 1H), 5.84– 5.78 (m, 1H), 5.49 (br s, 1H), 4.44 – 4.33 (m, 1H), 3.83 (s, 3H), 3.52 (d, J = 11.3 Hz, 1H), 2.49 (s, 3H), 2.18– 2.06 (m, 3H), 1.97 – 1.84 (m, 3H).
Step 5: Methyl 4-amino-2-(3-cyanophenyl)-6-[rac-(1S,3R)-3-hydroxycyclopentoxy]pyrimidine- 5-carboxylate 3
N
Figure imgf000219_0002
[00415] The title compound was prepared from 4-amino-2-methylsulfanyl-6-[rac- (1S,3R)-3-hydroxycyclopentoxy]pyrimidine-5-carboxylate (step 4) and (3- cyanophenyl)boronic acid analogously to Example 1 step 4. LC-MS (Method 5A): Rt 2.77 mins; MS m/z 355.3 = [M+H]+
1H NMR (500 MHz, Chloroform-d) d 8.68 (s, 1H), 8.61 (d, J = 7.9 Hz, 1H), 8.18 (br s, 1H), 7.76 (d, J = 7.9 Hz, 1H), 7.57 (app t, J = 7.9 Hz, 1H), 6.02– 5.95 (m, 1H), 5.73 (br s, 1H), 4.48– 4.38 (m, 1H), 3.89 (s, 3H), 3.51 (d, J = 11.1 Hz, 1H), 2.22– 2.12 (m, 3H), 2.11– 2.02 (m, 1H), 2.01– 1.88 (m, 2H).
Step 6: 4-Amino-2-(3-cyanophenyl)-6-[rac-(1S,3R)-3-hydroxycyclopentoxy]pyrimidine-5- carboxylic acid
Figure imgf000220_0001
[00416] The title compound was prepared from methyl 4-amino-2-(3-cyanophenyl)-6- [rac-(1S,3R)-3-hydroxycyclopentoxy]pyrimidine-5-carboxylate (step 5) and lithium hydroxide analogously to Example 1 step 5.
LC-MS (Method 5A): Rt 2.49 mins; MS m/z 341.2 = [M+H]+
1H NMR (500 MHz, Chloroform-d) d 8.68 (s, 1H), 8.61 (d, J = 7.6 Hz, 1H), 7.78 (d, J = 7.7 Hz, 1H), 7.58 (t, J = 7.8 Hz, 1H), 6.11– 6.04 (m, 1H), 4.67– 4.59 (m, 1H), 2.26– 2.17 (m, 3H), 2.11– 2.02 (m, 2H), 1.99– 1.93 (m, 1H).4 x exchangeable protons not observed.
Step 7: 4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[rac-(1S,3R)-3- hydroxycyclopentoxy]pyrimidine-5-carboxamide
[00417] The title compound was prepared from 4-amino-2-(3-cyanophenyl)-6-[rac- (1S,3R)-3-hydroxycyclopentoxy]pyrimidine-5-carboxylic acid (step 6) and 1-aminooxy-2- methyl-propan-2-ol (Intermediate C) analogously to Example 17.
LC-MS (Method 8A): Rt 4.77 mins; MS m/z 428.3 = [M+H]+)
1H NMR (500 MHz, DMSO-d6) d 11.52 (s, 1H), 8.64 (s, 1H), 8.60 (d, J = 7.9 Hz, 1H), 8.02 (d, J = 7.7 Hz, 1H), 7.75 (t, J = 7.8 Hz, 1H), 5.94– 5.81 (m, 1H), 5.33 (s, 1H), 4.66 (s, 1H), 4.37 (s, 1H), 3.68 (s, 2H), 2.06– 1.90 (m, 5H), 1.83– 1.71 (m, 1H), 1.16 (s, 6H).2 x exchangeable protons not clearly observed. Example 38a and 38b
Chiral separation of racemic 4-amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6- [rac-(1S,3R)-3-hydroxycyclopentoxy]pyrimidine-5-carboxamide (Example 38) using Supercritical Fluid Chromatography under the following conditions afforded the individual enantiomers:
Column: Chiralpak AD-H, 10 x 250 mm, 5 µm
Flow rate (min/mL): 15
Sample Diluent: MeOH, MeCN
Example 38a: 4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1R,3S)- 3-hydroxycyclopentoxy]pyrimidine-5-carboxamide or 4-amino-2-(3-cyanophenyl)-N-(2- hydroxy-2-methyl-propoxy)-6-[(1S,3R)-3-hydroxycyclopentoxy]pyrimidine-5- carboxamide
Figure imgf000221_0001
First Eluted Peak: SFC Retention time = 6.63 mins
MSQ1 - LC-MS (Method 7A): Rt 2.98 mins; MS m/z 428.3 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 11.52 (br.s, 1H), 8.62 (t, J = 1.4 Hz, 1H), 8.59 (dt, J = 8.0, 1.4 Hz, 1H), 8.01 (dt, J = 7.7, 1.4 Hz, 1H), 7.74 (t, J = 7.9 Hz, 1H), 5.88– 5.82 (m, 1H), 5.33 (br.s, 1H), 4.69 (br.s, 1H), 4.36 (s, 1H), 3.67 (s, 2H), 2.09– 1.88 (m, 5H), 1.81– 1.71 (m, 1H), 1.15 (s, 6H).2 x exchangeable protons not observed.
Example 38b: 4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1R,3S)- 3-hydroxycyclopentoxy]pyrimidine-5-carboxamide or 4-amino-2-(3-cyanophenyl)-N-(2- hydroxy-2-methyl-propoxy)-6-[(1S,3R)-3-hydroxycyclopentoxy]pyrimidine-5- carboxamide
Figure imgf000222_0003
Second Eluted Peak: SFC Retention time = 8.07 mins
MSQ1 - LC-MS (Method 7A): Rt 2.98 mins; MS m/z 428.3 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 11.52 (s, 1H), 8.62 (t, J = 1.4 Hz, 1H), 8.59 (dt, J = 8.0, 1.4 Hz, 1H), 8.01 (dt, J = 7.7, 1.4 Hz, 1H), 7.74 (t, J = 7.8 Hz, 1H), 5.86 (t, J = 4.9 Hz, 1H), 5.33 (s, 1H), 4.68 (s, 1H), 4.40– 4.33 (m, 1H), 3.67 (s, 2H), 2.08– 1.89 (m, 5H), 1.81– 1.71 (m, 1H), 1.15 (s, 6H).2 x exchangeable protons not observed.
Example 39
Methyl N-[2S)-2-[6-amino-2-(3-cyanophenyl)-5-[(2-hydroxy-2-methyl- propoxy)carbamoyl]pyrimidin-4-yl]oxypropyl]carbamate
Figure imgf000222_0001
Step 1: Ethyl 4-amino-2-(3-cyanophenyl)-6-[1S)-2-(methoxycarbonylamino)-1-methyl- ethoxy]pyrimidine-5-carboxylate
Figure imgf000222_0002
[00418] Triethylamine (189 µL, 1.36 mmol) was added to ethyl 4-amino-2-(3- cyanophenyl)-6-[(1S)-2-amino-1-methyl-ethoxy]pyrimidine-5-carboxylate 2,2,2-trifluoroacetic acid salt (Example 37 step 3) (225 mg, 0.27 mmol) in chloroform (4 mL) and the mixture stirred until a homogeneous solution was obtained. The solution was cooled to 0 °C and a solution of methyl carbonochloridate (21 µL, 0.27 mmol) in chloroform (100 µL) was added dropwise. The reaction mixture was warmed to room temperature and stirred for 90 mins. Additional methyl carbonochloridate (1 µL, 0.01 mmol) was added and the mixture stirred for a further 90 mins. The resulting mixture was diluted with DCM (100 mL) and water (10 mL) and the layers were separated. The aqueous portion was extracted with DCM (2 x 10 mL) and the combined organic extracts were dried over MgSO4 and the solvent removed in vacuo. Purification by chromatography on silica eluting with 25% EtOAc in petrol afforded the title compound as an off-white solid.
LC-MS (Method 5B): Rt 3.28 mins; MS m/z 400.2 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 8.68 (s, 1H), 8.60 (dt, J = 7.8, 1.5 Hz, 1H), 8.01 (dt, J = 7.8, 1.5 Hz, 1H), 7.78 (s, 2H), 7.74 (t, J = 7.8 Hz, 1H), 7.23 (t, J = 6.0 Hz, 1H), 5.57– 5.48 (m, 1H), 4.30– 4.17 (m, 2H), 3.48 (s, 3H), 3.27– 3.20 (m, 1H), 1.34– 1.27 (m, 6H). 1 proton signal obscured by water signal.
Step 2: 4-Amino-2-(3-cyanophenyl)-6-[(1S)-2-(methoxycarbonylamino)-1-methyl- ethoxy]pyrimidine-5-carboxylic acid
Figure imgf000223_0001
[00419] The title compound was prepared from ethyl 4-amino-2-(3-cyanophenyl)-6- [1S)-2-(methoxycarbonylamino)-1-methyl-ethoxy]pyrimidine-5-carboxylate (step 1) and lithium hydroxide analogously to Example 1 step 5.
LC-MS (Method 5A): Rt 2.46 mins; MS m/z 372.2 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 12.59 (br s, 1H), 8.68 (s, 1H), 8.60 (d, J = 7.8 Hz, 1H), 8.01 (d, J = 7.8 Hz, 1H), 7.88 (br s, 2H), 7.73 (t, J = 7.8 Hz, 1H), 7.32 - 7.23 (m, 1H), 5.59– 5.52 (m, 1H), 3.47 (s, 3H), 3.31 - 3.22 (m, 2H), 1.31 (d, J = 6.3 Hz, 3H).
Step 3: Methyl N-[2S)-2-[6-amino-2-(3-cyanophenyl)-5-[(2-hydroxy-2-methyl- propoxy)carbamoyl]pyrimidin-4-yl]oxypropyl]carbamate
[00420] The title compound was prepared from 4-amino-2-(3-cyanophenyl)-6-[(1S)-2- (methoxycarbonylamino)-1-methyl-ethoxy]pyrimidine-5-carboxylic acid (step 2) and 1- aminooxy-2-methyl-propan-2-ol (Intermediate C) analogously to Example 17.
LC-MS (Method 8B): Rt 3.65 mins; MS m/z 459.3 = [M+H]+ 1H NMR (500 MHz, DMSO-d6) d 10.94 (s, 1H), 8.66 (s, 1H), 8.59 (d, J = 7.8 Hz, 1H), 8.01 (dt, J = 7.8, 1.4 Hz, 1H), 7.91 (br s, 2H), 7.74 (t, J = 7.8 Hz, 1H), 7.49– 7.40 (m, 1H), 5.66– 5.57 (m, 1H), 4.75 (s, 1H), 3.73 (s, 2H), 3.50 (s, 3H), 3.44– 3.35 (m, 1H), 1.33 (d, J = 6.3 Hz, 3H), 1.19 (s, 3H), 1.19 (s, 3H).1 x exchangeable proton not observed.
Example 40
4-Amino-2-(3-cyanophenyl)-6-(1,1-dioxothian-4-yl)oxy-N-(2-hydroxy-2-methyl- propoxy)pyrimidine-5-carboxamide
Figure imgf000224_0001
Step 1: Ethyl 4-amino-2-(3-cyanophenyl)-6-(1,1-dioxothian-4-yl)oxy-pyrimidine-5-carboxylate
Figure imgf000224_0002
[00421] The title compound was prepared from ethyl 4-amino-6-chloro-2-(3- cyanophenyl)pyrimidine-5-carboxylate (Example 5 step 1) and 1,1-dioxothian-4-ol analogously to Example 32 step 1.
LC-MS (Method 3B): Rt 1.79 mins; MS m/z 417.2 = [M+H]+
1H NMR (500 MHz, Chloroform-d) d 8.63 (s, 1H), 8.56 (d, J = 7.9 Hz, 1H), 8.26 (br s, 1H), 7.77 (d, J = 7.6 Hz, 1H), 7.58 (t, J = 7.8 Hz, 1H), 5.88 (s, 1H), 5.75 (br s, 1H), 4.43 (q, J = 7.2 Hz, 2H), 3.50 (td, J = 13.3, 4.5 Hz, 2H), 3.04– 2.98 (m, 2H), 2.60– 2.42 (m, 4H), 1.45 (t, J = 7.2 Hz, 3H).
Step 2: 4-Amino-2-(3-cyanophenyl)-6-(1,1-dioxothian-4-yl)oxy-pyrimidine-5-carboxylic acid [00422] The titl
Figure imgf000225_0002
e compound was prepared from ethyl 4-amino-2-(3-cyanophenyl)-6- (1,1-dioxothian-4-yl)oxy-pyrimidine-5-carboxylate (step 1) and lithium hydroxide analogously to Example 32 step 2.
LCMS (Method 5A): Rt 2.28 min, m/z 389.1 [M+H]+
1H NMR (500 MHz, DMSO-d6) d 13.03 (s, 1H), 8.65 (s, 1H), 8.61 (d, J = 8.0 Hz, 1H), 8.03 (d, J = 7.7 Hz, 1H), 7.93 (br s, 2H), 7.75 (t, J = 7.8 Hz, 1H), 5.75 (s, 1H), 3.34– 3.25 (m, 2H), 3.19 – 3.09 (m, 2H), 2.43– 2.34 (m, 2H), 2.34– 2.23 (m, 2H).
Step 3: 4-Amino-2-(3-cyanophenyl)-6-(1,1-dioxothian-4-yl)oxy-N-(2-hydroxy-2-methyl- propoxy)pyrimidine-5-carboxamide
[00423] The title compound was prepared from 4-amino-2-(3-cyanophenyl)-6-(1,1- dioxothian-4-yl)oxy-pyrimidine-5-carboxylic acid (step 2) and 1-aminooxy-2-methyl-propan-2- ol (Intermediate C) analogously to Example 32 step 3.
LC-MS (Method 8B): Rt 3.47 mins; MS m/z 476.2 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 11.22 (br s, 1H), 8.64 (s, 1H), 8.61 (d, J = 8.0 Hz, 1H), 8.02 (d, J = 7.7 Hz, 1H), 7.74 (t, J = 7.8 Hz, 1H), 7.61 (br s, 2H), 5.62 (s, 1H), 4.73 (s, 1H), 3.73 (s, 2H), 3.30– 3.23 (m, 4H), 2.44– 2.27 (m, 4H), 1.19 (s, 6H)
Examples 41a and 41b
(1s,4s)-4-{[6-amino-2-(3-cyanophenyl)-5-[(2-hydroxy-2-methylpropoxy)carbamoyl] pyrimidin-4-yl]oxy}thian-1-ium-1-olate and (1r,4r)-4-{[6-amino-2-(3-cyanophenyl)-5-[(2- hydroxy-2-methylpropoxy)carbamoyl]pyrimidin-4-yl]oxy}thian-1-ium-1-olate
Figure imgf000225_0001
Step 1: 4-Amino-2-(3-cyanophenyl)-6-(1-oxothian-4-yl)oxy-pyrimidine-5-carboxylic acid [00424] The tit
Figure imgf000226_0001
le compound was prepared from ethyl 4-amino-6-chloro-2-(3- cyanophenyl)pyrimidine-5-carboxylate (Example 5 step 1) and 1-oxothian-4-ol analogously to Example 32 step 1 and 2.
LC-MS (Method 3A): Rt 1.45 + 1.49 mins; MS m/z 373.2 = [M+H]+
Step 2: (1s,4s)-4-{[6-Amino-2-(3-cyanophenyl)-5-[(2-hydroxy-2-methylpropoxy)carbamoyl] pyrimidin-4-yl]oxy}thian-1-ium-1-olate and (1r,4r)-4-{[6-amino-2-(3-cyanophenyl)-5-[(2- hydroxy-2-methylpropoxy)carbamoyl]pyrimidin-4-yl]oxy}thian-1-ium-1-olate
[00425] The title compounds were prepared from 4-amino-2-(3-cyanophenyl)-6-(1- oxothian-4-yl)oxy-pyrimidine-5-carboxylic acid (step 1) and 1-aminooxy-2-methyl-propan-2-ol (Intermediate C) analogously to Example 32 step 3. Stereochemistry for the 2 products was nominally assigned.
LC-MS (Method 8A): Rt 3.70 mins; MS m/z 458.3 = [M-H]- 1H NMR (500 MHz, DMSO-d6) d 11.13 (s, 1H), 8.63 (s, 1H), 8.59 (d, J = 8.0 Hz, 1H), 8.01 (d, J = 7.7 Hz, 1H), 7.75 (t, J = 7.9 Hz, 1H), 7.61 (br s, 2H), 5.58 (s, 1H), 4.75 (s, 1H), 3.71 (s, 2H), 3.04– 2.92 (m, 2H), 2.89– 2.80 (m, 2H), 2.49– 2.43 (m, 2H), 2.15– 2.01 (m, 2H), 1.17 (s, 6H).
LC-MS (Method 8A): Rt 3.43 mins; MS m/z 460.3 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 11.14 (s, 1H), 8.62 (s, 1H), 8.60 (d,J= 8.0 Hz, 1H), 8.02 (d,J= 7.7 Hz, 1H), 7.74 (t,J= 7.8 Hz, 1H), 7.69 (br s, 2H), 5.45– 5.38 (m, 1H), 4.74 (s, 1H), 3.74 (s, 2H), 3.05– 2.94 (m, 4H), 2.42– 2.33 (m, 2H), 2.16– 2.10 (m, 2H), 1.19 (s, 6H). Example 42
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1R)-2-acetamido-1- methyl-ethoxy]pyrimidine-5-carboxamide
Figure imgf000227_0001
Step 1: Ethyl 4-amino-2-(3-cyanophenyl)-6-[ (1R)-2-(tert-butoxycarbonylamino)-1-methyl- ethoxy]pyrimidine-5-carboxylate
Figure imgf000227_0002
[00426] The title compound was prepared from ethyl 4-amino-6-chloro-2-(3- cyanophenyl)pyrimidine-5-carboxylate (Example 5 step 1) and (R)-1-(Boc-amino)-2-propanol analogously to Example 32 step 1.
LC-MS (Method 5B): Rt 3.79 mins; MS m/z 442.1 = [M+H]+
1H NMR (500 MHz, Chloroform-d) d 8.67 (t, J = 1.3, 1.3 Hz, 1H), 8.61 (ddd, J = 7.9, 1.3, 1.2 Hz, 1H), 8.12 (br. s, 1H), 7.77 (ddd, J = 7.8, 1.3, 1.2 Hz, 1H), 7.58 (dd, J = 7.9, 7.8 Hz, 1H), 5.80 (br. s, 1H), 5.59– 5.49 (m, 1H), 5.14 (t, J = 5.3 Hz, 1H), 4.43– 4.34 (m, 2H), 3.57 (ddd, J = 14.1, 6.0, 3.6 Hz, 1H), 3.39 (ddd, J = 13.3, 6.0, 6.0 Hz, 1H), 1.51– 1.38 (m, 15H).
Step 2: Ethyl 4-amino-2-(3-cyanophenyl)-6-[ (1R)-2-amino-1-methyl-ethoxy]pyrimidine-5- carboxylate 2,2,2-trifluoroacetic acid salt
Figure imgf000227_0003
[00427] To a solution of ethyl 4-amino-2-(3-cyanophenyl)-6-[ (1R)-2-(tert- butoxycarbonylamino)-1-methyl-ethoxy]pyrimidine-5-carboxylate (step 1) (184 mg, 0.40 mmol) in DCM (5 mL) was added TFA (0.49 mL, 6.4 mmol) and the reaction was stirred at room temperature for 2 h. The resulting mixture was concentrated in vacuo and then azeotroped three times from DCM to afford the title compound as a pale yellow gum.
LC-MS (Method 5B): Rt 3.08 mins; MS m/z 342.2 = [M+H]+
Step 3: Ethyl 4-amino-2-(3-cyanophenyl)-6-[(1R)-2-acetamido-1-methyl-ethoxy]pyrimidine-5- carboxylate
Figure imgf000228_0001
[00428] To a solution of ethyl 4-amino-2-(3-cyanophenyl)-6-[(1R)-2-amino-1-methyl- ethoxy]pyrimidine-5-carboxylate 2,2,2-trifluoroacetic acid salt (step 2) (277 mg, 0.40 mmol) and triethylamine (0.56 mL, 4 mmol) in DCM (5 mL) was added acetic anhydride (75 µL, 0.80 mmol) and the reaction mixture was stirred at room temperature overnight. The resulting mixture was partitioned between sat. NaHCO3 (20 mL) and DCM (20 mL). The aqueous layer was extracted with DCM (2 x 20 mL) and the combined organic extracts were dried over Na2SO4 and concentrated in vacuo. The residue was azeotroped three times from DCM to afford the title compound as a yellow solid.
LC-MS (Method 5B): Rt 2.83 mins; MS m/z 384.1 = [M+H]+
1H NMR (500 MHz, Chloroform-d) d 8.67 (dd, J = 1.7, 1.7 Hz, 1H), 8.60 (ddd, J = 8.0, 1.7, 1.4 Hz, 1H), 8.00 (br. s, 1H), 7.77 (ddd, J = 7.7, 1.7, 1.5 Hz, 1H), 7.58 (dd, J = 8.0, 7.7 Hz, 1H), 6.22 (t, J = 6.7, 4.8 Hz, 1H), 5.88 (br. s, 1H), 5.56– 5.47 (m, 1H), 4.40 (q, J = 7.1 Hz, 2H), 3.82 (ddd, J = 14.1, 6.7, 3.4 Hz, 1H), 3.41 (ddd, J = 14.1, 7.8, 4.8 Hz, 1H), 1.98 (s, 3H), 1.47 (d, J = 6.2 Hz, 3H), 1.43 (t, J = 7.1 Hz, 3H).
Step 4: 4-Amino-2-(3-cyanophenyl)-6-[ (1R)-2-acetamido-1-methyl-ethoxy]pyrimidine-5- carboxylic acid
Figure imgf000228_0002
[00429] The title compound was prepared from ethyl 4-amino-2-(3-cyanophenyl)-6- [(1R)-2-acetamido-1-methyl-ethoxy]pyrimidine-5-carboxylate (step 3) and lithium hydroxide analogously to Example 32 step 2.
LC-MS (Method 3B): Rt 1.52 mins; MS m/z 356.1 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 12.60 (br. s, 1H), 8.64 (dd, J = 1.7, 1.7 Hz, 1H), 8.61 (ddd, J = 8.0, 1.7, 1.6 Hz, 1H), 8.01 (ddd, J = 7.7, 1.7, 1.6 Hz, 1H), 7.94 (t, J = 5.9 Hz, 1H), 7.89 (br. s, 2H), 7.74 (dd, J = 7.9 Hz, 1H), 5.59– 5.50 (m, 1H), 1.76 (s, 3H), 1.32 (d, J = 6.2 Hz, 3H). CH2 signal obscured by water peak.
Step 5: 4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1R)-2-acetamido-1- methyl-ethoxy]pyrimidine-5-carboxamide
[00430] The title compound was prepared from 4-amino-2-(3-cyanophenyl)-6-[(1R)-2- acetamido-1-methyl-ethoxy]pyrimidine-5-carboxylic acid (step 4) and 1-aminooxy-2-methyl- propan-2-ol (Intermediate C) analogously to Example 32 step 3.
LC-MS (Method 8B): Rt 3.72 mins; MS m/z 443.3 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 10.96 (s, 1H), 8.62 (dd, J = 1.7, 1.7 Hz, 1H), 8.58 (ddd, J = 7.9, 1.7, 1.4 Hz, 1H), 8.15 (s, 1H), 8.01 (ddd, J = 7.7, 1.7, 1.4 Hz, 1H), 7.93 (br. s, 2H), 7.74 (dd, J = 7.9, 7.7 Hz, 1H), 5.62– 5.53 (m, 1H), 4.79 (s, 1H), 3.72 (s, 2H), 3.52– 3.43 (m, 1H), 3.43– 3.33 (m, 1H), 1.80 (s, 3H), 1.33 (d, J = 6.3 Hz, 3H), 1.18 (s, 6H).
Example 42.1
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1S)-2-acetamido-1- methyl-ethoxy]pyrimidine-5-carboxamide
Figure imgf000229_0001
Step 1: Ethyl 4-amino-2-(3-cyanophenyl)-6-[(1S)-2-acetamido-1-methyl-ethoxy]pyrimidine-5- carboxylate [00431] The title com
Figure imgf000230_0002
pound was prepared from ethyl 4-amino-2-(3-cyanophenyl)-6- [(1S)-2-amino-1-methyl-ethoxy]pyrimidine-5-carboxylate;2,2,2-trifluoroacetic acid (Example 37 step 3) and acetic anhydride analogously to Example 42 step 3.
LC-MS (Method 3B): Rt 1.71 mins; MS m/z 384.2 = [M+H]+
1H NMR (500 MHz, Chloroform-d) d 8.66 (s, 1H), 8.59 (d, J = 8.0 Hz, 1H), 7.93 (br s, 1H), 7.76 (d, J = 7.6 Hz, 1H), 7.58 (t, J = 7.8 Hz, 1H), 6.21 (br s, 1H), 5.76 (br s, 1H), 5.56– 5.46 (m, 1H), 4.39 (q, J = 7.1 Hz, 2H), 3.81 (ddd, J = 13.8, 6.7, 3.4 Hz, 1H), 3.40 (ddd, J = 13.8, 7.8, 4.8 Hz, 1H), 1.97 (s, 3H), 1.46 (d, J = 6.3 Hz, 3H), 1.42– 1.37 (m, 3H).
Step 2: 4-Amino-2-(3-cyanophenyl)-6-[(1S)-2-acetamido-1-methyl-ethoxy]pyrimidine-5- carboxylic acid
Figure imgf000230_0001
[00432] The title compound was prepared from ethyl 4-amino-2-(3-cyanophenyl)-6- [(1S)-2-acetamido-1-methyl-ethoxy]pyrimidine-5-carboxylate (step 1) and lithium hydroxide analogously to Example 32 step 2.
LC-MS (Method 3A): Rt 1.53 mins; MS m/z 356.2 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 12.62 (br s, 1H), 8.64 (s, 1H), 8.61 (d, J = 8.0 Hz, 1H), 8.01 (d, J = 7.7 Hz, 1H), 7.99– 7.93 (m, 1H), 7.89 (br s, 2H), 7.74 (t, J = 7.8 Hz, 1H), 5.58– 5.50 (m, 1H), 1.76 (s, 3H), 1.32 (d, J = 6.3 Hz, 3H). CH2 signal obscured by water peak.
1H NMR (500 MHz, Methanol-d4) d 8.71– 8.70 (m, 1H), 8.68 (br dt, J = 8.0, 1.4 Hz, 2H), 7.85 (dt, J = 7.6, 1.4 Hz, 1H), 7.66 (t, J = 7.8 Hz, 1H), 5.76– 5.69 (m, 1H), 3.60 (dd, J = 14.0, 4.1 Hz, 1H), 3.45 (dd, J = 14.0, 7.2 Hz, 1H), 1.90 (s, 3H), 1.43 (d, J = 6.4 Hz, 3H).3 x exchangeable protons not observed. Step 3: 4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1S)-2-acetamido-1- methyl-ethoxy]pyrimidine-5-carboxamide
[00433] The title compound was prepared from 4-amino-2-(3-cyanophenyl)-6-[(1S)-2- acetamido-1-methyl-ethoxy]pyrimidine-5-carboxylic acid (step 2) and 1-aminooxy-2-methyl- propan-2-ol (Intermediate C) analogously to Example 32 step 3.
LC-MS (Method 8A): Rt 4.00 mins; MS m/z 443.3 = [M+H]+ 1H NMR (500 MHz, DMSO-d6) d 10.96 (s, 1H), 8.62 (s, 1H), 8.58 (d, J = 8.2 Hz, 1H), 8.15 (br s, 1H), 8.01 (d, J = 7.7 Hz, 1H), 7.93 (br s, 2H), 7.74 (t, J = 7.8 Hz, 1H), 5.61– 5.53 (m, 1H), 4.80 (br s, 1H), 3.72 (s, 2H), 3.52– 3.43 (m, 1H), 3.43– 3.34 (m, 1H), 1.80 (s, 3H), 1.33 (d, J = 6.3 Hz, 3H), 1.18 (s, 6H).
Example 43
4-Amino-2-(3-cyanophenyl)-6-(2-fluoroethoxy)-N-(1H-1,2,4-triazol-3- ylmethoxy)pyrimidine-5-carboxamide
Figure imgf000231_0001
[00434] 4-Amino-2-(3-cyanophenyl)-6-(2-fluoroethoxy)pyrimidine-5-carboxylic acid (Example 1 step 5) (100 mg, 0.33 mmol) was dissolved in thionyl chloride (2.0 mL, 27.57 mmol) and the mixture was stirred at room temperature under nitrogen for 1 h. The resulting mixture was concentrated in vacuo, azeotroping with toluene (3 x 2 mL).The residue was dissolved in DCM (1 mL) and added dropwise to a stirred solution of N,N- diisopropylethylamine (0.23 mL, 1.32 mmol) and O-(1H-1,2,4-triazol-3- ylmethyl)hydroxylamine (intermediate LA) (113 mg, 0.99 mmol) in DCM (3 mL) at 0 °C under nitrogen. The mixture was stirred at 0 °C under nitrogen for 30 mins, warmed to room temperature and then stirred at this temperature for 16 h. The resulting mixture was diluted with DCM (10 mL), brine (10 mL) was added and the layers were separated. The aqueous portion was further extracted with DCM (2 x 10 mL) and the combined organic extracts were dried over MgSO4 and concentrated in vacuo. The crude product was purified by C18 reverse phase chromatography eluting with 10 to 50% MeCN in water (+0.1% formic acid) to afford the title compound as a colourless solid.
LC-MS (Method 8B): Rt 3.14 mins; MS m/z 399.2 = [M+H]+ 1H NMR (500 MHz, DMSO-d6) d 8.64 (s, 1H), 8.59 (d, J = 8.1 Hz, 1H), 8.38 (br s, 1H), 8.01 (d, J = 7.8 Hz, 1H), 7.89– 7.59 (m, 3H), 4.99 (s, 2H), 4.82 (ddd, J = 27.1, 6.3, 3.5 Hz, 2H), 4.77– 4.68 (m, 2H).2 x exchangeable protons not observed.
Example 44a and Example 44b
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1s,3s)-3- methoxycyclobutoxy]pyrimidine-5-carboxamide and
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1r,3r)-3- methoxycyclobutoxy]pyrimidine-5-carboxamide
Figure imgf000232_0001
Step 1: 4-Amino-2-(3-cyanophenyl)-6-(3-methoxycyclobutoxy)pyrimidine-5-carboxylic acid
Figure imgf000232_0002
[00435] The title compound was prepared from ethyl 4-amino-6-chloro-2-(3- cyanophenyl)pyrimidine-5-carboxylate (Example 5 step 1) and 3-methoxycyclobutanol analogously to Example 19 step 1.
LC-MS (Method 5A): Rt 2.63 mins; MS m/z 341.2 = [M+H]+
Step 2: Racemic 4-amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-(3- methoxycyclobutoxy)pyrimidine-5-carboxamide
[00436] The title compound was prepared from 4-amino-2-(3-cyanophenyl)-6-(3- methoxycyclobutoxy)pyrimidine-5-carboxylic acid (step 1) and 1-aminooxy-2-methyl-propan- 2-ol (Intermediate C) analogously to Example 32 step 3. [00437] Chiral separation of racemic 4-amino-2-(3-cyanophenyl)-N-(2-hydroxy-2- methyl-propoxy)-6-(3-methoxycyclobutoxy)pyrimidine-5-carboxamide using Supercritical Fluid Chromatography under the following conditions afforded the individual enantiomers:
Column: Chiralpak IG (20 mm x 250 mm, 5 µm)
Column Temperature: 40 ˚C
Flow Rate: 50 mL/min
BPR: 100 BarG
Detector Wavelength: 219 nm
Injection Volume: 700 µL (10.5 mg)
Isocratic Conditions: 40:60 MeOH:CO2 (0.2% v/v NH3)
Example 44a: 4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1r,3r)-3- methoxycyclobutoxy]pyrimidine-5-carboxamide or 4-amino-2-(3-cyanophenyl)-N-(2- hydroxy-2-methyl-propoxy)-6-[(1s,3s)-3-methoxycyclobutoxy]pyrimidine-5- carboxamide
Figure imgf000233_0001
Chiral SFC (Method CP4): First Eluted Peak Rt = 1.66 mins
LC-MS (Method 8B): Rt 4.25 mins; MS m/z 428.4 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 11.14 (s, 1H), 8.57 (t, J = 1.5 Hz, 1H), 8.54 (dt, J = 7.8, 1.5 Hz, 1H), 8.00 (dt, J = 7.8, 1.5 Hz, 1H), 7.78 (br s, 2H), 7.75 (t, J = 7.8 Hz, 1H), 5.49 (p, J = 6.2 Hz, 1H), 4.78 (s, 1H), 4.10 (p, J = 5.3 Hz, 1H), 3.72 (s, 2H), 3.20 (s, 3H), 2.47 (apr t, J = 5.8 Hz, 4H), 1.18 (s, 6H).
Example 44b: 4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1r, 3r)-3- methoxycyclobutoxy]pyrimidine-5-carboxamide or 4-mino-2-(3-cyanophenyl)-N-(2- hydroxy-2-methyl-propoxy)-6-[(1s, 3s)-3-methoxycyclobutoxy]pyrimidine-5- carboxamide
Figure imgf000234_0001
Chiral SFC (Method CP4): Second Eluted Peak: Rt = 2.10 mins
LC-MS (Method 8B): Rt 4.20 mins; MS m/z 428.4 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 11.15 (s, 1H), 8.59 (t, J = 1.5 Hz, 1H), 8.57 (dt, J = 7.8, 1.5 Hz, 1H), 8.01 (dt, J = 7.8, 1.5 Hz, 1H), 7.74 (t, J = 7.8 Hz, 3H), 5.03 (p, J = 7.3 Hz, 1H), 4.75 (s, 1H), 3.75 - 3.66 (m, 3H), 3.18 (s, 3H), 2.92– 2.82 (m, 2H), 2.19– 2.10 (m, 2H), 1.18 (s, 6H).
Example 45
4-Amino-2-(3-cyanophenyl)-6-(3-hydroxy-3-methyl-cyclobutoxy)-N-(2-hydroxy-2- methyl-propoxy)pyrimidine-5-carboxamide
Figure imgf000234_0002
Step 1: Ethyl 4-amino-6-[3-[tert-butyl(dimethyl)silyl]oxy-3-methyl-cyclobutoxy]-2-(3- cyanophenyl)pyrimidine-5-carboxylate
Figure imgf000234_0003
[00438] [00439] The title compound was prepared from ethyl 4-amino-6-chloro-2-(3- cyanophenyl)pyrimidine-5-carboxylate (Example 5 step 1) and 3-[tert-butyl(dimethyl)silyl]oxy- 3-methyl-cyclobutanol (Intermediate Z) analogously to Example 18 step 1.
LC-MS (Method 2A): Rt 2.13 mins; MS m/z 483.3 = [M+H]+
Step 2: 4-amino-6-[3-[tert-butyl(dimethyl)silyl]oxy-3-methyl-cyclobutoxy]-2-(3- cyanophenyl)pyrimidine-5-carboxylic acid
Figure imgf000235_0001
[00440] The title compound was prepared from ethyl 4-amino-6-[3-[tert- butyl(dimethyl)silyl]oxy-3-methyl-cyclobutoxy]-2-(3-cyanophenyl)pyrimidine-5-carboxylate and lithium hydroxide monohydrate analogously to Example 18 step 3.
LC-MS (Method 2A): Rt 1.84 mins; MS m/z 455.1 = [M+H]+;
Step 3: 4-Amino-6-[3-[tert-butyl(dimethyl)silyl]oxy-3-methyl-cyclobutoxy]-2-(3-cyanophenyl)- N-(2-hydroxy-2-methyl-propoxy)pyrimidine-5-carboxamide
Figure imgf000235_0002
[00441] The title compound was prepared from 4-amino-6-[3-[tert- butyl(dimethyl)silyl]oxy-3-methyl-cyclobutoxy]-2-(3-cyanophenyl)pyrimidine-5-carboxylic acid (step 2) and 1-aminooxy-2-methyl-propan-2-ol (Intermediate C) analogously to Example 17. LC-MS (Method 2A): Rt 1.60 and 1.63 mins; MS m/z 542.3 = [M+H]+
1H NMR (400 MHz, DMSO-d6) d 11.14 (s, 1H), 8.61– 8.50 (m, 2H), 8.00 (dt, J = 7.7, 1.3 Hz, 1H), 7.81– 7.61 (m, 3H), 5.14– 4.99 (m, 1H), 4.73 (s, 1H), 3.70 (s, 2H), 2.70– 2.55 (m, 2H), 2.38– 2.26 (m, 2H), 1.44 (m, 3H), 1.17 (s, 6H), 0.94– 0.80 (m, 9H), 0.15– 0.03 (m, 6H). NMR suggests ~3:1 mixture of stereoisomers. Step 4: 4-Amino-2-(3-cyanophenyl)-6-(3-hydroxy-3-methyl-cyclobutoxy)-N-(2-hydroxy-2- methyl-propoxy)pyrimidine-5-carboxamide
[00442] The title compound was prepared from 4-amino-6-[3-[tert- butyl(dimethyl)silyl]oxy-3-methyl-cyclobutoxy]-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl- propoxy)pyrimidine-5-carboxamide (step 3) and 4M HCl in 1,4-dioxane analogously to Example 18 step 2.
LC-MS (Method 7A): Rt 2.61 and 2.76 mins; MS m/z 428.2 = [M+H]+.
1H NMR (400 MHz, DMSO-d6) d 11.12 (s, 1H), 8.61– 8.50 (m, 2H), 8.00 (dt, J = 7.7, 1.4 Hz, 1H), 7.75 (t, J = 8.0 Hz, 3H), 5.46 (m, 0.3H), 5.09– 4.98 (m, 0.7H), 3.71 (d, J = 4.4 Hz, 2H), 2.61– 2.52 (m, 3H), 2.32– 2.20 (m, 2H), 1.33 (d, J = 8.7 Hz, 3H), 1.18 (s, 6H). 1 x exchangeable proton not observed. NMR suggests ~2.4:1 mixture of cis/trans isomers.
Example 46
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(5-oxopyrrolidin-3- yl)methoxy]pyrimidine-5-carboxamide
Figure imgf000236_0001
Step 1: Ethyl 4-amino-2-(3-cyanophenyl)-6-[[1-[(2,4-dimethoxyphenyl)methyl]-5-oxo- pyrrolidin-3-yl]methoxy]pyrimidine-5-carboxylate
Figure imgf000236_0002
[00443] The title compound was prepared from ethyl 4-amino-6-chloro-2-(3- cyanophenyl)pyrimidine-5-carboxylate (Example 5 step 1) and 1-[(2,4- dimethoxyphenyl)methyl]-4-(hydroxymethyl)pyrrolidin-2-one analogously to Example 18 step 1.
LC-MS (Method 5B): Rt 3.37 mins; MS m/z 532.2 = [M+H]+
1H NMR (500 MHz, Chloroform-d) d 8.72– 8.62 (m, 2H), 7.79 (d, J = 7.6 Hz, 1H), 7.60 (t, J = 7.8 Hz, 1H), 7.18– 7.13 (m, 1H), 6.47– 6.39 (m, 2H), 4.54– 4.49 (m, 1H), 4.49– 4.38 (m, 3H), 4.34– 4.26 (m, 2H), 3.78 (s, 6H), 3.48 (dd, J = 10.2, 8.1 Hz, 1H), 3.25 (dd, J = 10.2, 5.7 Hz, 1H), 2.90– 2.81 (m, 1H), 2.65 (dd, J = 16.9, 9.0 Hz, 1H), 2.48 (dd, J = 16.9, 6.7 Hz, 1H), 1.31 (t, J = 7.2 Hz, 3H).2 x exchangeable protons not observed.
Step 2: 4-Amino-2-(3-cyanophenyl)-6-[[1-[(2,4-dimethoxyphenyl)methyl]-5-oxo-pyrrolidin-3- yl]methoxy]pyrimidine-5-carboxylic acid
Figure imgf000237_0001
[00444] The title compound was prepared from ethyl 4-amino-2-(3-cyanophenyl)-6-[[1- [(2,4-dimethoxyphenyl)methyl]-5-oxo-pyrrolidin-3-yl]methoxy]pyrimidine-5-carboxylate and lithium hydroxide analogously to Example 18 step 3.
LC-MS (Method 5A): Rt 2.61 mins; MS m/z 504.1 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 12.79 (s, 1H), 8.63 (d, J = 1.8 Hz, 1H), 8.60 (d, J = 8.0 Hz, 1H), 8.02 (d, J = 7.8 Hz, 1H), 7.93 (s, 2H), 7.74 (t, J = 7.8 Hz, 1H), 7.00 (d, J = 8.4, 2.8 Hz, 1H), 6.52 (d, J = 2.4 Hz, 1H), 6.44 (dd, J = 8.4, 2.5 Hz, 1H), 4.51 (dd, J = 10.8, 6.0 Hz, 1H), 4.43 (dd, J = 10.8, 7.4 Hz, 1H), 4.27 (s, 2H), 3.75 (s, 3H), 3.72 (s, 3H), 3.16 (dd, J = 10.0, 5.6 Hz, 1H), 2.82– 2.77 (m, 1H), 2.66– 2.63 (m, 1H), 2.47– 2.43 (m, 1H), 2.32 (dd, J = 16.8, 6.6 Hz, 1H).
Step 3: 4-Amino-2-(3-cyanophenyl)-6-[[1-[(2,4-dimethoxyphenyl)methyl]-5-oxo-pyrrolidin-3- yl]methoxy]-N-(2-hydroxy-2-methyl-propoxy)pyrimidine-5-carboxamide [00445] The title com
Figure imgf000238_0001
pound was prepared from 4-amino-2-(3-cyanophenyl)-6-[[1-[(2,4- dimethoxyphenyl)methyl]-5-oxo-pyrrolidin-3-yl]methoxy]pyrimidine-5-carboxylic acid (step 3) and 1-aminooxy-2-methyl-propan-2-ol (Intermediate C) analogously to Example 23.
LC-MS (Method 5B): Rt 2.78 mins; MS m/z 591.2 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 11.12 (s, 1H), 8.61 (t, J = 1.8 Hz, 1H), 8.57 (dt, J = 8.1, 1.5 Hz, 1H), 8.00 (dt, J = 7.8, 1.5 Hz, 1H), 7.86– 7.67 (m, 3H), 7.00 (d, J = 8.3 Hz, 1H), 6.51 (d, J = 2.4 Hz, 1H), 6.43 (dd, J = 8.4, 2.4 Hz, 1H), 4.77 (s, 1H), 4.53– 4.45 (m, 2H), 4.27 (q, J = 14.9 Hz, 4H), 3.74 (s, 3H), 3.71 (s, 3H), 3.67 (s, 2H), 2.93– 2.81 (m, 2H), 2.32 (dd, J = 16.8, 6.4 Hz, 1H), 1.15 (d, J = 3.1 Hz, 6H)
Step 4: 4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(5-oxopyrrolidin-3- yl)methoxy]pyrimidine-5-carboxamide
[00446] The title compound was prepared from 4-amino-2-(3-cyanophenyl)-6-[[1-[(2,4- dimethoxyphenyl)methyl]-5-oxo-pyrrolidin-3-yl]methoxy]-N-(2-hydroxy-2-methyl- propoxy)pyrimidine-5-carboxamide (step 3) and TFA analogously to Example 10 step 4. LC-MS (Method 8A): Rt 3.68 mins; MS m/z 441.3 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 11.14 (br s, 1H), 8.63 (br t, J = 1.5 Hz, 1H), 8.59 (br dt, J = 7.8, 1.5 Hz, 1H), 8.01 (br dt, J = 7.8, 1.5 Hz, 1H), 7.76 (br s, 2H), 7.74 (t, J = 7.8 Hz, 1H), 7.58 (s, 1H), 4.77 (br s, 1H), 4.51 (d, J = 7.1 Hz, 2H), 3.70 (s, 2H), 3.41 (apr t, J = 8.9 Hz, 1H), 3.18 (dd, J = 9.8, 5.6 Hz, 1H), 2.94 (apr hept, J = 7.3 Hz, 1H), 2.33 (dd, J = 16.7, 9.1 Hz, 1H), 2.15 (dd, J = 16.7, 6.8 Hz, 1H), 1.17 (s, 6H). Example 47
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-phenoxy-pyrimidine-5- carboxamide
Figure imgf000239_0001
Step 1: Ethyl 4-amino-2-(3-cyanophenyl)-6-phenoxy-pyrimidine-5-carboxylate
Figure imgf000239_0002
[00447] A mixture of ethyl 4-amino-6-chloro-2-(3-cyanophenyl)pyrimidine-5- carboxylate (Example 5 step 1) (500 mg, 1.65 mmol), phenol (311 mg, 3.3 mmol) and K2CO3 (457 mg, 3.3 mmol) in dry DMF (10 mL) was stirred at 50 °C overnight. The reaction mixture was allowed to cool to room temperature then partitioned between EtOAc (50 mL) and water (50 mL). The aqueous layer was extracted with EtOAc (2 x 50 mL) and the combined organic extracts were washed with 50% brine (4 x 50 mL), dried over Na2SO4 and concentrated in vacuo. Purification by chromatography on silica eluting with 10 to 20% EtOAc in petrol afforded the title compound as a colourless solid.
LC-MS (Method 3B): Rt 2.18 mins; MS m/z 361.2 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 8.30 (dd, J = 1.6, 1.6 Hz, 1H), 8.23 (ddd, J = 8.1, 1.6, 1.3 Hz, 1H), 8.06– 7.87 (m, 3H), 7.65 (dd, J = 8.1, 7.8 Hz, 1H), 7.51– 7.44 (m, 2H), 7.33– 7.27 (m, 1H), 7.27– 7.20 (m, 2H), 4.32 (q, J = 7.1 Hz, 2H), 1.29 (t, J = 7.1 Hz, 3H).
Step 2: 4-Amino-2-(3-cyanophenyl)-6-phenoxy-pyrimidine-5-carboxylic acid
Figure imgf000239_0003
[00448] The title compound was prepared from ethyl 4-amino-2-(3-cyanophenyl)-6- phenoxy-pyrimidine-5-carboxylate (step 1) and lithium hydroxide analogously to Example 18 step 3.
LC-MS (Method 3A): Rt 2.81 mins; MS m/z 333.1 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 13.18 (br. s, 1H), 8.28 (dd, J = 1.8, 1.8 Hz, 1H), 8.22 (ddd, J = 7.9, 1.8, 1.2 Hz, 1H), 8.07 (br. s, 2H), 7.95 (ddd, J = 7.8, 1.8, 1.2 Hz, 1H), 7.64 (dd, J = 7.9, 7.8 Hz, 1H), 7.52– 7.42 (m, 2H), 7.33– 7.26 (m, 1H), 7.26– 7.18 (m, 2H).
Step 3: 4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-phenoxy-pyrimidine- 5-carboxamide
[00449] The title compound was prepared from 4-amino-2-(3-cyanophenyl)-6-phenoxy- pyrimidine-5-carboxylic acid (step 2) and 1-aminooxy-2-methyl-propan-2-ol (Intermediate C) analogously to Example 23.
LC-MS (Method 8B): Rt 4.52 mins; MS m/z 420.3 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 11.51 (s, 1H), 8.27 (dd, J = 1.7, 1.7 Hz, 1H), 8.21 (ddd, J = 7.9, 1.7, 1.4 Hz, 1H), 7.94 (ddd, J = 7.7, 1.7, 1.4 Hz, 1H), 7.75 (s, 2H), 7.64 (dd, J = 7.9, 7.7 Hz, 1H), 7.52– 7.46 (m, 2H), 7.34– 7.26 (m, 3H), 4.69 (s, 1H), 3.75 (s, 2H), 1.16 (s, 6H).
Preparation of Intermediates
Intermediate A
tert-Butyl 2-(aminooxymethyl)morpholine-4-carboxylate
Figure imgf000240_0001
Step 1: tert-Butyl 2-[(1,3-dioxoisoindolin-2-yl)oxymethyl]morpholine-4-carboxylate
Figure imgf000240_0002
[00450] To a cooled (0 °C) mixture of 2-hydroxyisoindoline-1,3-dione (372 mg, 2.28 mmol), tert-butyl 2-(hydroxymethyl)morpholine-4-carboxylate (500 mg, 2.3 mmol) and triphenylphosphine (658 mg, 2.51 mmol) in THF (20 mL) was added DIAD (0.49 mL, 2.51 mmol) and the mixture was stirred for 1 h. Additional triphenylphosphine (658 mg, 2.51 mmol) and DIAD (0.49 mL, 2.51 mmol) were added and stirring continued for 3 h. The resulting mixture was concentrated in vacuo and purification by chromatography on silica eluting with 0-100% EtOAc in heptane afforded the title compound as a yellow oil.
LC-MS (Method 2A): Rt 1.19 mins; MS m/z 385.1 = [M+Na]+
1H NMR (500 MHz, DMSO-d6) d 7.86 (s, 4H), 4.17 (d, J = 5.1 Hz, 2H), 3.91 (d, J = 12.9 Hz, 1H), 3.83– 3.74 (m, 1H), 3.74– 3.64 (m, 2H), 3.37 (td, J = 11.6, 2.8 Hz, 1H), 2.84 (s, 2H), 1.41 (s, 9H).
Step 2: tert-Butyl 2-(aminooxymethyl)morpholine-4-carboxylate
[00451] To a mixture of tert-butyl 2-[(1,3-dioxoisoindolin-2-yl)oxymethyl]morpholine-4- carboxylate (step 1) (1443 mg, 2.27 mmol) in DCM (15 mL) was added hydrazine hydrate (0.33 mL, 6.81 mmol) and the mixture was stirred at room temperature for 1.5 h. The resulting mixture was filtered, and the filtrate was concentrated in vacuo. The crude product was loaded onto an Isolute® SCX-2 cartridge that had been pre-wetted with MeOH. The cartridge was washed with MeOH (3 x 5 mL) and eluted with 7 M ammonia in MeOH solution (3 x 5 mL). The methanolic ammonia elutant was concentrated in vacuo to afford the title compound as a yellow oil.
LC-MS (Method 2.5B): Rt 1.26 mins; MS m/z 233.2 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 3.78 (d, J = 9.5 Hz, 2H), 3.69 (d, J = 13.3 Hz, 1H), 3.59– 3.42 (m, 3H), 3.37 (dd, J = 11.6, 2.8 Hz, 2H), 3.17 (d, J = 5.1 Hz, 1H), 2.83 (s, 1H), 1.40 (s, 9H).
Intermediate AA
O-(1-Oxazol-2-ylethyl)hydroxylamine
Figure imgf000241_0001
Step 1: 1-Oxazol-2-ylethanol
Figure imgf000241_0002
[00452] A mixture of 1-oxazol-2-ylethanone (1 g, 9 mmol) and MeOH (20 mL) was cooled to 0 °C and treated portion wise with sodium borohydride (443 mg, 11.7 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The resulting mixture was diluted with water (20 mL) then the MeOH was removed under vacuum. The remaining aqueous layer was extracted with EtOAc (7 x 30 mL) and the combined organic extracts were dried over MgSO4 and concentrated in vacuo to afford the title compound as a clear colourless oil.
1H NMR (500 MHz, Chloroform-d) d 7.62 (s, 1H), 7.07 (s, 1H), 4.98 (q, J = 6.7 Hz, 1H), 3.47 (br. s, 1H), 1.61 (d, J = 6.7 Hz, 3H).
Step 2: 2-(1-Oxazol-2-ylethoxy)isoindoline-1,3-dione
Figure imgf000242_0001
[00453] A solution of 1-oxazol-2-ylethanol (step 1) (0.5 g, 4.42 mmol), 2- hydroxyisoindoline-1,3-dione (0.72 g, 4.42 mmol) and triphenylphosphine (1.28 g, 4.86 mmol) in THF (20 mL) was cooled to 0 ºC and DIAD (0.96 mL, 4.86 mmol) was added dropwise. The mixture was stirred overnight, slowly warming to room temperature. The resulting mixture was poured onto water and extracted with EtOAc (3 x 20 mL). The combined organic fractions were dried over MgSO4 and concentrated in vacuo. The crude product was purified by chromatography on silica eluting with 0 to 100% EtOAc in petrol to afford the title compound as a colourless solid.
LC-MS (Method 3A): Rt 1.50 mins; MS m/z 259.1 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 8.18 (s, 1H), 7.89– 7.83 (m, 4H), 7.20 (s, 1H), 5.40 (q, J = 6.7 Hz, 1H), 1.73 (d, J = 6.7 Hz, 3H).
Step 3: O-(1-Oxazol-2-ylethyl)hydroxylamine
[00454] To a solution of 2-(1-oxazol-2-ylethoxy)isoindoline-1,3-dione (step 2) (838 mg, 3.25 mmol) in DCM (5 mL) was added hydrazine hydrate (0.32 mL, 6.49 mmol) and the reaction mixture was stirred at room temperature for 2 h. The resulting suspension was filtered and the solid washed with DCM (2 x 40 mL). The filtrate was dried over Na2SO4 and concentrated in vacuo to afford the title compound as a colourless oil. 1H NMR (500 MHz, Chloroform-d) d 7.64 (s, 1H), 7.11 (s, 1H), 4.87 (qd, J = 6.8, 1.4 Hz, 1H), 4.24 (s, 2H), 1.54 (d, J = 6.8 Hz, 3H). Intermediate B
O-(2-Morpholinoethyl)hydroxylamine;dihydrochloride
Figure imgf000243_0001
Step 1: 2-(2-Morpholinoethoxy)isoindoline-1,3-dione
Figure imgf000243_0002
[00455] The title compound was prepared from 2-hydroxyisoindoline-1,3-dione and 2- morpholinoethanol analogously to Intermediate A step 1.
LC-MS (Method 2A): Rt 0.60 mins; MS m/z 277.0 = [M+H]+
1H NMR (250 MHz, Chloroform-d) d 7.84 (dd, J = 5.6, 3.1 Hz, 2H), 7.79– 7.71 (m, 2H), 4.35 (t, J = 5.1 Hz, 2H), 3.62– 3.54 (m, 4H), 2.81 (t, J = 5.1 Hz, 2H), 2.56– 2.48 (m, 4H). Step 2: O-(2-Morpholinoethyl)hydroxylamine;dihydrochloride
[00456] The title compound was prepared from 2-(2-morpholinoethoxy)isoindoline-1,3- dione (step 1) and hydrazine hydrate analogously to Intermediate A step 2:
LC-MS (Method 2A): Rt 0.72 mins; MS m/z 147.2 = [M+H]+
1H NMR (250 MHz, MeOH -d4) d 4.44– 4.36 (m, 2H), 4.01– 3.94 (m, 4H), 3.60– 3.52 (m, 2H), 3.46– 3.36 (m, 4H). Intermediate C
1-Aminooxy-2-methyl-propan-2-ol Step 1: 2-(2-Hydroxy-2-methyl-
Figure imgf000244_0004
propoxy)isoindoline-1,3-dione
Figure imgf000244_0001
[00457] A mixture of 2-hydroxyisoindoline-1,3-dione (2.49 g, 15.25 mmol) and 2,2- dimethyloxirane (1 g, 13.87 mmol) in DMF (25 mL) was treated with triethylamine (2.32 mL, 16.64 mmol) and stirred at 85 °C for 24 h. The resulting mixture was concentrated in vacuo and the crude product was dissolved in EtOAc (20 mL). The mixture was washed with water (3 x 20 mL), brine (20 mL), passed through a phase separator and concentrated in vacuo. The crude product was purified by chromatography on silica eluting with 0-10% MeOH in DCM to afford the title compound as a colourless solid.
LC-MS (Method 2.5B): Rt 3.15 mins; MS m/z 236.2 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 7.85 (s, 4H), 4.65 (s, 1H), 3.94 (s, 2H), 1.23 (s, 6H).
Step 2: 1-Aminooxy-2-methyl-propan-2-ol
[00458] The title compound was prepared from 2-(2-hydroxy-2-methyl- propoxy)isoindoline-1,3-dione (step 1) and hydrazine hydrate analogously to Intermediate A. 1H NMR (500 MHz, DMSO-d6) d 3.74 (s, 2H), 1.13 (s, 6H).
Intermediate D
2-Aminooxypropan-1-ol;hydrochloride
Figure imgf000244_0002
Step 1: Ethyl 2-(tert-butoxycarbonylamino)oxypropanoate
Figure imgf000244_0003
[00459] A mixture of tert-butyl N-hydroxycarbamate (883 mg, 6.63 mmol) and potassium hydroxide (372 mg, 6.63 mmol) in EtOH (18 mL) was treated with ethyl 2-bromopropanoate (0.71 mL, 5.52 mmol) and the mixture was heated to reflux for 3 h. After cooling to room temperature, the mixture was filtered and the filtrate concentrated in vacuo. The resulting residue was dissolved in ether and washed with water, brine and passed through a phase separator. The solvent was removed in vacuo to afford the title compound as a colourless oil.
1HNMR(500 MHz, DMSO-d6) d 10.04 (s, 1H), 4.30 (q,J = 6.9 Hz, 1H), 4.13 (q,J = 7.1 Hz, 2H), 1.40 (s, 9H), 1.28 (d,J = 6.9 Hz, 3H), 1.22 (t,J = 7.1 Hz, 3H).
Step 2: tert-Butyl N-(2-hydroxy-1-methyl-ethoxy)carbamate
Figure imgf000245_0001
[00460] To a solution of 2.4M lithium aluminium hydride in THF (3.11 mL, 7.46 mmol) at 0 °C under nitrogen was added dropwise a solution of ethyl 2-(tert- butoxycarbonylamino)oxypropanoate (step 1) (1145 mg, 4.66 mmol) in THF (20 mL). The mixture was allowed to warm to room temperature and stirred for 23 h. The reaction was quenched carefully with water (1 mL), diluted with EtOAc (30 mL), dried over MgSO4 and concentrated in vacuo to afford the title compound as a colourless oil.
LC-MS (Method 2.5B): Rt 2.80 mins; MS m/z 192.3 = [M+H]+
1H NMR (500 MHz, Chloroform-d) d 7.10 (s, 1H), 3.94 (pd, J = 6.6, 2.7 Hz, 1H), 3.68 (dd, J = 12.9, 3.9 Hz, 1H), 3.46 (dt, J = 12.0, 5.4 Hz, 1H), 1.65– 1.55 (m, 1H), 1.49 (d, J = 2.7 Hz, 9H), 1.20 (d, J = 6.6 Hz, 3H).
Step 3: 2-Aminooxypropan-1-ol;hydrochloride
[00461] tert-Butyl N-(2-hydroxy-1-methyl-ethoxy)carbamate (150 mg, 0.78 mmol) in DCM (2.5 mL) and MeOH (0.5 mL) was treated with 4M HCl in 1,4-dioxane (0.54 mL, 15.69 mmol) and stirred at room temperature for 5 h. The resulting mixture was concentrated in vacuo to afford the title compound as a colourless oil.
1H NMR (500 MHz, DMSO-d6) d 4.18 (pd, J = 6.5, 3.4 Hz, 1H), 3.57 (dd, J = 12.1, 3.4 Hz, 1H), 3.48 (dd, J = 12.1, 6.5 Hz, 1H), 1.13 (d, J = 6.5 Hz, 3H). Intermediate E
O-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]hydroxylamine
Figure imgf000246_0001
Step 1: 2-[(2,2-Dimethyl-1,3-dioxolan-4-yl)methoxy]isoindoline-1,3-dione
Figure imgf000246_0002
[00462] The title compound was prepared from (2,2-dimethyl-1,3-dioxolan-4- yl)methanol and 2-hydroxyisoindoline-1,3-dione analogously to Intermediate A step 1 LC-MS (Method 2A): Rt 0.76 mins; MS m/z 278.1 = [M+H]+
1H NMR (500 MHz, Chloroform-d) d 7.84 (dd, J = 5.5, 3.1 Hz, 2H), 7.76 (dd, J = 5.5, 3.1 Hz, 2H), 4.50 (p, J = 5.8 Hz, 1H), 4.31 (dd, J = 10.2, 5.8 Hz, 1H), 4.18 (dd, J = 8.7, 6.3 Hz, 1H), 4.14 (dd, J = 10.2, 6.3 Hz, 1H), 3.97 (dd, J = 8.7, 5.5 Hz, 1H), 1.40 (s, 3H), 1.34 (s, 3H).
Step 2: O-[(2,2-Dimethyl-1,3-dixolan-4-yl)methyl]hydroxylamine
[00463] Methylhydrazine (79 µL, 1.51 mmol) was added to an ice-cooled solution of 2- [(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]isoindoline-1,3-dione (step 1) (400 mg, 1.37 mmol) in DCM (5 mL). The reaction mixture was allowed to warm to room temperature and was stirred for 1 h. The resulting mixture was concentrated in vacuo and the residue was triturated with diethyl ether (5 mL). The solid was removed by filtration and the filtrate concentrated in vacuo to afford the title compound as a colourless liquid.
1H NMR (500 MHz, Chloroform-d) d 5.56 (s, 2H), 4.34 (qd, J = 6.5, 4.6 Hz, 1H), 4.06 (dd, J = 8.3, 6.5 Hz, 1H), 3.81– 3.65 (m, 3H), 1.43 (s, 3H), 1.38– 1.31 (m, 3H).
Intermediate F
1-(Aminooxymethyl)cyclopropanol
Figure imgf000246_0003
Step 1: Methyl 1-[tert-butyl(dimethyl)silyl]oxycyclopropanecarboxylate
Figure imgf000247_0003
[00464] This compound was prepared according to the literature procedure described in US2015/225381; page 30.
1H NMR (500 MHz, Chloroform-d) d 3.71 (s, 3H), 1.35– 1.29 (m, 2H), 1.10– 1.04 (m, 2H), 0.87 (s, 9H), 0.14 (s, 6H).
Step 2: [1-[tert-Butyl(dimethyl)silyl]oxycyclopropyl]MeOH
Figure imgf000247_0001
[00465] This compound was prepared according to the literature procedure described in WO2018/71447; page 347
1H NMR (500 MHz, Chloroform-d) d 3.58– 3.50 (m, 2H), 0.87 (s, 9H), 0.82– 0.72 (m, 2H), 0.63– 0.52 (m, 2H), 0.12 (s, 6H).
Step 3: 2-[[1-[tert-Butyl(dimethyl)silyl]oxycyclopropyl]methoxy]isoindoline-1,3-dione
Figure imgf000247_0002
[00466] The title compound was prepared from [1-[tert- butyl(dimethyl)silyl]oxycyclopropyl]methanol (step 3) and 2-hydroxyisoindoline-1,3-dione analogously to Intermediate A step 1.
LCMS (Method 2.5B); Rt 2.11 mins; MS m/z 348 = [M+H]+, 370 = = [M+Na]+
Step 4: 2-[(1-Hydroxycyclopropyl)methoxy]isoindoline-1,3-dione [00467] A suspe
Figure imgf000248_0003
nsion of 2-[[1-[tert- butyl(dimethyl)silyl]oxycyclopropyl]methoxy]isoindoline-1,3-dione (step 3) (1 g, 2.88 mmol) in 1,4-dioxane (5 mL) was treated with 4M HCl in 1,4-dioxane (2.88 mL, 11.51 mmol) and the mixture was stirred at room temperature overnight. The resulting mixture was concentrated in vacuo and the crude residue was triturated with DCM. The solid was removed by filtration and the filtrate was concentrated in vacuo to afford the title compound as an off-white solid.
LC-MS (Method 2A): Rt 0.90 mins; MS m/z 234 = [M+H]+, 256 = [M+Na]+
1H NMR (500 MHz, DMSO-d6) d 7.94– 7.78 (m, 4H), 5.47 (s, 1H), 4.19– 4.06 (m, 2H), 0.74 – 0.56 (m, 4H).
Step 5: 1-(Aminooxymethyl)cyclopropanol
[00468] A solution of 2-[(1-hydroxycyclopropyl)methoxy]isoindoline-1,3-dione (step 4) (422 mg, 1.81 mmol) in DCM (15 mL) was treated with hydrazine hydrate (0.35 mL, 3.62 mmol) and the mixture was stirred at room temperature for 1h 15 mins. The resulting mixture was filtered under vacuum, washing with DCM (5 mL), and the filtrate was concentrated in vacuo to afford the title compound as a pale orange oil.
1H NMR (400 MHz, DMSO-d6) d 6.11– 5.79 (m, 2H), 5.54– 5.05 (m, 1H), 3.53 (s, 2H), 0.59 – 0.41 (m, 4H).
Intermediate G
Ethyl (2S)-2-aminooxypropanoate
Figure imgf000248_0001
Step 1: Ethyl (2S)-2-(1,3-dioxoisoindolin-2-yl)oxypropanoate
Figure imgf000248_0002
[00469] The title compound was prepared from ethyl (2R)-2-hydroxypropanoate and 2- hydroxyisoindoline-1,3-dione analogously to Intermediate A step 1.
(Method 2A): Rt 1.07 mins; MS m/z 264.0 = [M+H]+
1H NMR (500 MHz, Chloroform-d) d 7.84 (dd, J = 5.3, 3.1 Hz, 2H), 7.76 (td, J = 5.3, 2.0 Hz, 2H), 4.87 (q, J = 6.9 Hz, 1H), 4.30– 4.18 (m, 2H), 1.65 (d, J = 6.9 Hz, 3H), 1.29 (t, J = 7.2 Hz, 3H).
Step 2: Ethyl (2S)-2-aminooxypropanoate
[00470] The title compound was prepared from ethyl (2S)-2-(1,3-dioxoisoindolin-2- yl)oxypropanoate (step 1) and hydrazine hydrate analogously to Intermediate A step 2.
1H NMR (400 MHz, DMSO-d6) d 6.15 (s, 1H), 4.17– 4.05 (m, 2H), 1.30– 1.05 (m, 6H).
Intermediate HA
(2S)-2-[tert-Butyl(dimethyl)silyl]oxypropan-1-ol
Figure imgf000249_0001
Step 1: Methyl (2S)-2-[tert-butyl(dimethyl)silyl]oxypropanoate
Figure imgf000249_0002
[00471] Methyl (2S)-2-hydroxypropanoate (1 g, 9.61 mmol) in DCM (10 mL) under nitrogen was treated with imidazole (981 mg, 14.41 mmol) and tert-butyl-chloro-dimethyl- silane (1593 mg, 10.57 mmol) and the mixture was stirred at room temperature for 4 h. The reaction was quenched with water (10 mL) and the phases were separated. The organic portion was passed through a phase separator and concentrated in vacuo to afford the title compound as a colourless liquid.
1H NMR (400 MHz, DMSO-d6) d 4.36 (q, J = 6.7 Hz, 1H), 3.64 (s, 3H), 1.29 (d, J = 6.7 Hz, 3H), 0.86 (s, 9H), 0.04 (d, J = 2.1 Hz, 6H). Step 2: (2S)-2-[tert-Butyl(dimethyl)silyl]oxypropan-1-ol
[00472] To a cooled (0 °C) solution of methyl (2S)-2-[tert- butyl(dimethyl)silyl]oxypropanoate (step 1) (1.86 g, 8.49 mmol) in THF (20 mL) under nitrogen was added dropwise 1M DIBAL in hexane (21.24 mL, 21.24 mmol). The reaction mixture was allowed to warm to room temperature and stirred at room temperature. After 1 h, the reaction was re-cooled to 0 °C and treated dropwise with 0.5 M Rochelle's salt (10 mL). The mixture was diluted with diethyl ether (20 mL) and stirred at room temperature for 15 mins. The resulting gel was filtered under vacuum and washed with diethyl ether (20 mL). The organic layer was washed with water (10 mL), brine (10 mL), passed through a phase separator and concentrated in vacuo to the title compound as a colourless liquid.
1H NMR (500 MHz, DMSO-d6) d 4.53 (t, J = 5.6 Hz, 1H), 3.73 (h, J = 6.1 Hz, 1H), 3.28 (dd, J = 10.7, 5.4 Hz, 1H), 3.14 (dt, J = 10.7, 5.8 Hz, 1H), 1.04 (d, J = 6.1 Hz, 3H), 0.85 (s, 9H), 0.04 (d, J = 1.3 Hz, 6H).
Intermediate HB
(2R)-2-[tert-butyl(dimethyl)silyl]oxypropan-1-ol
Figure imgf000250_0001
[00473] The title compound was prepared from methyl (2R)-2-hydroxypropanoate, imidazole and tert-butyl-chloro-dimethyl-silane analogously to Intermediate HA steps 1 and 2. 1H NMR (500 MHz, DMSO-d6) d 4.53 (t, J = 5.6 Hz, 1H), 3.73 (h, J = 6.1 Hz, 1H), 3.29 (dt, J = 10.8, 5.6 Hz, 1H), 3.14 (dt, J = 10.8, 5.9 Hz, 1H), 1.04 (d, J = 6.1 Hz, 3H), 0.85 (s, 9H), 0.03 (d, J = 1.3 Hz, 6H).
Intermediate I
O-(2-methoxy-2-methyl-propyl)hydroxylamine Step 1: 2-(2-Methoxy-2-methyl-pr
Figure imgf000251_0002
Figure imgf000251_0001
[00474] To a mixture of 2-hydroxyisoindoline-1,3-dione (1635 mg, 10.02 mmol) and 2- methoxy-2-methyl-propan-1-ol (1044 mg, 10.02 mmol) in THF (25 mL) was added triphenylphosphine (2629 mg, 10.02 mmol) and the mixture was sonicated for 20 mins. DIAD (1.97 mL, 10.02 mmol) was added and the mixture was stirred at room temperature for 24 h. The solvent was removed in vacuo and purification by chromatography on silica eluting with 20% EtOAc in iso-hexane afforded the title compound as a viscous clear oil.
1H NMR (500 MHz, Chloroform-d) d 7.86– 7.82 (m, 2H), 7.77– 7.72 (m, 2H), 4.12 (s, 2H), 3.35 (s, 3H), 1.36 (s, 6H).
Step 2: O-(2-Methoxy-2-methyl-propyl)hydroxylamine
[00475] To a mixture of 2-(2-methoxy-2-methyl-propoxy)isoindoline-1,3-dione (step 1) (860 mg, 3.45 mmol) in EtOH (30 mL) was added hydrazine hydrate (0.34 mL, 6.9 mmol) and the mixture was heated to 70 °C, forming a thick suspension. EtOH (20 mL) was added and the mixture was stirred at 70 °C for 2.5 h and then concentrated in vacuo. The residue was triturated with CHCl3 (20 mL), washing with CHCl3 (10 mL), filtering and the filtrate was concentrated in vacuo. The residue was subsequently triturated with EtOAc (10 mL), filtered, washing with EtOAc (5 mL) and the filtrate was concentrated in vacuo. The residue was further triturated with CHCl3 (2 mL), filtered, washing with CHCl3 (2 x 1 mL) and the filtrate was concentrated in vacuo to afford the title compound as a colourless solid.
1H NMR (500 MHz, Chloroform-d) d 5.59 (s, 2H), 3.62 (s, 2H), 3.26 (s, 3H), 1.18 (s, 6H).
Intermediate J
1-(Aminooxymethyl)cyclobutanol Step 1: Methyl 1-[tert-butyl(dim
Figure imgf000252_0003
ethyl)silyl]oxycyclobutanecarboxylate
Figure imgf000252_0001
[00476] A solution of methyl 1-hydroxycyclobutanecarboxylate (500 mg, 3.84 mmol) in DCM (20 mL) was treated with imidazole (392 mg, 5.76 mmol) and tert-butyl-chloro-dimethyl- silane (695 mg, 4.61 mmol) and the mixture was stirred at room temperature overnight. The reaction was quenched with water (30 mL) and the mixture was extracted with DCM (3 x 25 mL). The organic extracts were combined, dried over MgSO4 and concentrated in vacuo to afford the title compound as a pale yellow oil.
1H NMR (400 MHz, Chloroform-d) d 3.84 (s, 1H), 3.75 (s, 3H), 2.57– 2.50 (m, 2H), 2.28– 2.17 (m, 2H), 1.87– 1.77 (m, 2H), 0.91 (s, 9H), 0.07 (s, 6H).
Step 2: [1-[tert-Butyl(dimethyl)silyl]oxycyclobutyl]methanol
Figure imgf000252_0002
[00477] A cooled (-5 °C) solution of methyl 1-[tert- butyl(dimethyl)silyl]oxycyclobutanecarboxylate (step 1) (878 mg, 3.59 mmol) in THF (15 mL) was treated dropwise with 1.2M DIBAL in toluene (7.48 mL, 8.98 mmol) over 5 mins. The resulting mixture was stirred at -5 °C for 30 min and at room temperature for 1 h. The mixture was re-cooled to -5 °C and treated with Rochelle's salt (30 mL). The resulting mixture was diluted with Et2O (30 mL) and stirred at room temperature for a further 30 min. The organic portion of the resulting thick gel was separated and the aqueous phase was back-extracted with Et2O (3 x 30 mL). The combined organic extracts were washed with brine (30 mL), dried over MgSO4 and concentrated in vacuo to afford the title compound as a pale yellow oil. 1H NMR (500 MHz, Chloroform-d) d 3.53 (d, J = 6.3 Hz, 2H), 2.15– 2.00 (m, 5H), 1.87 (t, J = 6.3 Hz, 1H), 1.77– 1.68 (m, 1H), 1.52– 1.44 (m, 1H), 0.89 (s, 9H), 0.12 (s, 6H).
Step 3: 2-[[1-[tert-Butyl(dimethyl)silyl]oxycyclobutyl]methoxy]isoindoline-1,3-dione
Figure imgf000253_0002
[00478] The title compound was prepared from [1-[tert- butyl(dimethyl)silyl]oxycyclobutyl]methanol (step 2)) and 2-hydroxyisoindoline-1,3-dione analogously to Intermediate A step1.
LC-MS (Method 2A new): Rt 1.95 mins; MS m/z 362 = [M+H]+
1H NMR (400 MHz, Chloroform-d) d 7.85 - 7.78 (m, 2H), 7.76 - 7.70 (m, 2H), 4.21 (s, 2H), 2.44 - 2.34 (m, 2H), 2.24 - 2.13 (m, 2H), 1.86– 1.72 (m, 1H), 1.67– 1.56 (m, 1H), 0.92– 0.85 (m, 9H), 0.14 (s, 6H).
Step 4: O-[[1-[tert-Butyl(dimethyl)silyl]oxycyclobutyl]methyl]hydroxylamine
Figure imgf000253_0001
[00479] The title compound was prepared from 2-[[1-[tert- butyl(dimethyl)silyl]oxycyclobutyl] methoxy]isoindoline-1,3-dione (step 3) and hydrazine hydrate analogously to Intermediate A step 2.
LC-MS (Method 2A): Rt 1.15 mins; MS m/z 232 = [M+H]+
1H NMR (400 MHz, Chloroform-d) d 5.50 (s, 2H), 3.72 (s, 2H), 2.18– 1.99 (m, 4H), 1.78– 1.65 (m, 1H), 1.55– 1.42 (m, 1H), 0.89 (s, 9H), 0.08 (s, 6H)
Step 5: 1-(Aminooxymethyl)cyclobutanol
[00480] A suspension of O-[[1-[tert-butyl(dimethyl)silyl]oxycyclobutyl]methyl] hydroxylamine (step 4) (450 mg, 1.56 mmol) in 1,4-dioxane (7 mL) was treated with 4M HCl in 1,4-dioxane (1.56 mL, 6.22 mmol) and stirred for 2 h at room temperature. The resulting suspension was diluted with DCM (30 mL) and washed with aqueous sat. NaHCO3 (20 mL). The organic portion was separated and the aqueous extracted with DCM (30 mL). The combined organic extracts were washed with brine (20 mL), dried over MgSO4 and concentrated in vacuo. The crude residue was dissolved in DCM/MeOH, loaded onto an Isolute ®SCX (2 g) column pre-wetted with DCM eluting with DCM (10 mL), MeOH (10 mL) and 2N NH3 in MeOH (10 mL) to afford the title compound as a pale yellow oil. 1H NMR (500 MHz, DMSO-d6) d 6.04 (s, 2H), 5.13 (s, 1H), 3.51 (s, 2H), 2.03 -1.96 (m, 2H), 1.90 - 1.82 (m, 2H), 1.66– 1.54 (m, 1H), 1.48 - 1.37 (m, 1H).
Intermediate JA
1-(Aminooxymethyl)cyclopentanol
Figure imgf000254_0001
Step 1: Ethyl 1-[tert-butyl(dimethyl)silyl]oxycyclopentanecarboxylate
Figure imgf000254_0002
[00481] Ethyl 1-hydroxycyclopentanecarboxylate (1097 mg, 6.94 mmol), imidazole (708 mg, 10.4 mmol) and [tert-butyl(dimethyl)silyl] trifluoromethanesulfonate (1.79 mL, 8.32 mmol) were dissolved in chloroform (50 mL) and stirred at 60 ºC for 2 days. Another equivalent of [tert-butyl(dimethyl)silyl] trifluoromethanesulfonate and imidazole was added and the mixture was stirred at 60 ºC for a further 3 days. The reaction was quenched by pouring onto water, the organic layer was separated and the aqueous layer further extracted with DCM (3 x 25 mL). The organic extracts were combined, dried over MgSO4 and concentrated in vacuo. The crude product was filtered through a silica plug eluting with 0 to 5% EtOAc in petrol to afford the title compound as a colourless oil.
1H NMR (500 MHz, Chloroform-d) d 4.17 (qd, J = 7.1, 4.7 Hz, 2H), 2.11– 2.00 (m, 2H), 1.86 – 1.77 (m, 4H), 1.76– 1.68 (m, 2H), 1.29 (td, J = 7.1, 4.6 Hz, 3H), 0.88 (s, 9H), 0.13 (s, 6H).
Step 2: [1-[tert-Butyl(dimethyl)silyl]oxycyclopentyl]methanol
Figure imgf000254_0003
[00482] The title compound was prepared from methyl 1-[tert- butyl(dimethyl)silyl]oxycyclopentanecarboxylate and DIBAL (1.0 M in toluene) analogously to Intermediate J step 2. 1H NMR (500 MHz, Chloroform-d) d 3.42 (s, 2H), 2.05 (s, 1H), 1.78– 1.71 (m, 2H), 1.72– 1.65 (m, 4H), 1.57– 1.51 (m, 2H), 0.88 (s, 9H), 0.12 (s, 6H).
Step 3: 2-[[1-[tert-Butyl(dimethyl)silyl]oxycyclopentyl]methoxy]isoindoline-1,3-dione
Figure imgf000255_0001
[00483] The title compound was prepared from [1-[tert- butyl(dimethyl)silyl]oxycyclopentyl]methanol (step 2) and 2-hydroxyisoindoline-1,3-dione analogously to Intermediate A step1.
LC-MS (Method 5A): Rt 4.52 mins; MS m/z 398.3 = [M+Na]+
1H NMR (500 MHz, Chloroform-d) d 7.83 (dd, J = 5.5, 3.1 Hz, 2H), 7.74 (dd, J = 5.5, 3.1 Hz, 2H), 4.14 (s, 2H), 2.01– 1.91 (m, 2H), 1.84– 1.76 (m, 4H), 1.68– 1.61 (m, 2H), 0.87 (s, 9H), 0.15 (s, 6H).
Step 4: 2-[(1-Hydroxycyclopentyl)methoxy]isoindoline-1,3-dione
Figure imgf000255_0002
[00484] To a solution of 2-[[1-[tert-butyl(dimethyl)silyl]oxycyclopentyl]methoxy] isoindoline-1,3-dione (step 3) (436 mg, 1.16 mmol) in 1,4-dioxane (5 mL) was added 4M HCl in 1,4-dioxane (1.16 mL, 4.64 mmol) dropwise and the solution was stirred at room temperature for 60 h. Additional 4M HCl in 1,4-dioxane (2 mL) was added and stirring continued for 24 h. The reaction was quenched by addition of saturated aqueous Na2CO3 (30 mL). EtOAc (30 mL) was added and the layers were separated. The aqueous layer was extracted with EtOAc (3 x 20 mL) and the combined organic extracts were dried over MgSO4 and concentrated in vacuo. The crude product was purified by chromatography on silica eluting with 0 to 60% EtOAc in petrol to afford the title compound as a colourless oil.
LC-MS (Method 3A): Rt 2.31 mins; MS m/z 284.1 = [M+Na]+ 1H NMR (500 MHz, Chloroform-d) d 7.85 (dd, J = 5.4, 3.1 Hz, 2H), 7.76 (dd, J = 5.5, 3.1 Hz, 2H), 4.24 (s, 2H), 1.95– 1.85 (m, 2H), 1.83– 1.76 (m, 2H), 1.73– 1.60 (m, 4H). 1 x exchangeable proton not observed.
Step 5: 1-(Aminooxymethyl)cyclopentanol
[00485] Hydrazine hydrate (0.13 mL, 2.61 mmol) was added dropwise to a solution of 2-[(1-hydroxycyclopentyl)methoxy]isoindoline-1,3-dione (step 4) (196 mg, 0.75 mmol) in DCM (7.5 mL) at 0 °C and the resulting thick suspension stirred at room temperature for 1 h. The suspension was filtered and the solids washed with DCM (2 x 50 mL). The filtrate was dried over MgSO4 and concentrated in vacuo to yield a yellow oil. The oil was azeotroped from chloroform (3 x 50 mL) to afford the title compound as a yellow oil.
1H NMR (500 MHz, Chloroform-d) d 3.67 (s, 2H), 1.87– 1.75 (m, 2H), 1.70– 1.61 (m, 4H), 1.62– 1.52 (m, 2H).3 x exchangeable protons not observed.
Intermediate JB
3-(Aminooxymethyl)tetrahydrofuran-3-ol
Figure imgf000256_0001
Step 1: Methyl 3-[tert-butyl(dimethyl)silyl]oxytetrahydrofuran-3-carboxylate
Figure imgf000256_0002
[00486] tert-Butyl-chloro-dimethyl-silane (1.24 g, 8.21 mmol) was added in one portion to a stirred solution of methyl 3-hydroxytetrahydrofuran-3-carboxylate (1.0 g, 6.84 mmol) and imidazole (699 mg, 10.26 mmol) in DCM (20 mL) and the mixture was stirred at room temperature under nitrogen overnight. A further portion of imidazole (699 mg, 10.26 mmol) was added in one portion, followed by tert-butyldimethylsilyl trifluoromethanesulfonate (1.89 mL, 8.21 mmol) added dropwise over 10 mins. The mixture was stirred at 50 °C under nitrogen overnight. The resulting mixture was partitioned between DCM (50 mL) and water (50 mL) and the layers were separated. The separated aqueous phase was extracted with DCM (50 mL) and the combined organic extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified by chromatography on silica eluting with 5% EtOAc in petroleum ether to afford the title compound as a colourless oil.
LC-MS (Method 5B): Rt 3.76 mins; MS m/z 261.2 = [M+H]+
1H NMR (500 MHz, Chloroform-d) d 4.05 (d, J = 9.2 Hz, 1H), 4.03– 3.95 (m, 2H), 3.80 (d, J = 9.2 Hz, 1H), 3.76 (s, 3H), 2.43 (dt, J = 12.8, 8.5 Hz, 1H), 2.07 (dt, J = 12.8, 5.5 Hz, 1H), 0.89 (s, 9H), 0.10 (s, 6H).
Step 2: [3-[tert-Butyl(dimethyl)silyl]oxytetrahydrofuran-3-yl]methanol
Figure imgf000257_0001
[00487] The title compound was prepared from methyl 3-[tert- butyl(dimethyl)silyl]oxytetrahydrofuran-3-carboxylate (step 1) and DIBAL (1.0M in toluene) analogously to Intermediate J step 2.
LC-MS (Method 5B): Rt 3.10 mins; MS m/z 233.2 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 4.96 (t, J = 5.3 Hz, 1H), 3.80 (app. q, J = 8.2 Hz, 1H), 3.73 (td, J = 8.2, 4.6 Hz, 1H), 3.67 (d, J = 9.0 Hz, 1H), 3.46– 3.41 (m, 3H), 1.98 (dt, J = 12.4, 8.2 Hz, 1H), 1.70 (ddd, J = 12.4, 7.2, 4.6 Hz, 1H), 0.83 (s, 9H), 0.08 (s, 3H), 0.08 (s, 3H).
Step 3: 2-[[3-[tert-Butyl(dimethyl)silyl]oxytetrahydrofuran-3-yl]methoxy]isoindoline-1,3-dione
Figure imgf000257_0002
[00488] The title compound was prepared from [3-[tert- butyl(dimethyl)silyl]oxytetrahydrofuran-3-yl]methanol (step 2)) and 2-hydroxyisoindoline-1,3- dione analogously to Intermediate A step1.
LC-MS (Method 5A): Rt 3.88 mins; MS m/z 378.2 = [M+H]+
1H NMR (500 MHz, Chloroform-d) d 7.86– 7.80 (m, 2H), 7.78– 7.72 (m, 2H), 4.27– 4.21 (m, 2H), 4.02 (t, J = 8.4 Hz, 2H), 3.96– 3.92 (m, 1H), 3.78 (d, J = 9.6 Hz, 1H), 2.35 (dt, J = 13.0, 8.1 Hz, 1H), 1.97 (t, J = 7.2 Hz, 1H), 0.88 (s, 9H), 0.18 (d, J = 1.8 Hz, 6H). Step 4: 2-[(3-Hydroxytetrahydrofuran-3-yl)methoxy]isoindoline-1,3-dione
Figure imgf000258_0001
[00489] The title compound was prepared from 2-[[3-[tert- butyl(dimethyl)silyl]oxytetrahydrofuran-3-yl]methoxy]isoindoline-1,3-dione (step 3) and 4M HCl in 1,4-dioxane analogously to Intermediate JA step 4.
LC-MS (Method 5B): Rt 1.88 mins; MS m/z 264.1 = [M+H]+
1H NMR (500 MHz, Chloroform-d) d 7.91– 7.83 (m, 2H), 7.82– 7.75 (m, 2H), 4.38– 4.31 (m, 2H), 4.08– 4.00 (m, 1H), 3.94 (td, J = 8.4, 3.9 Hz, 1H), 3.87– 3.79 (m, 2H), 2.13– 1.94 (m, 2H).1 x exchangeable proton not observed.
Step 5: 3-(Aminooxymethyl)tetrahydrofuran-3-ol
[00490] Hydrazine hydrate (0.15 mL, 3.18 mmol) was added dropwise to a solution of 2-[(3-hydroxytetrahydrofuran-3-yl)methoxy]isoindoline-1,3-dione (step 4) (239 mg, 0.91 mmol) in DCM (7.5 mL) 0 °C and the resulting thick suspension stirred at room temperature for 1 h. The suspension was filtered and the solids washed with DCM (2 x 50 mL). The filtrate was dried over MgSO4 and concentrated in vacuo to yield an oil. The oil was azeotroped from chloroform (3 x 50 mL) to afford the title compound as a colourless oil.
1H NMR (500 MHz, Chloroform-d) d 5.52 (br s, 2H), 3.99 (app q, J = 8.0 Hz, 1H), 3.89 (dt, J = 8.5, 6.3 Hz, 1H), 3.81– 3.74 (m, 3H), 3.68 (d, J = 9.5 Hz, 1H), 1.95 (app dd, J = 7.8, 6.3 Hz, 2H).1 x exchangeable proton not observed.
Intermediate JC
tert-Butyl 3-(aminooxymethyl)-3-[tert-butyl(dimethyl)silyl]oxy-azetidine-1-carboxylate
Figure imgf000258_0002
Step 1: O1-tert-Butyl O3-methyl 3-[tert-butyl(dimethyl)silyl]oxyazetidine-1,3-dicarboxylate [00491] The title compound was prepared from O3-methyl 3-hydroxyazetidine-1,3- dicarboxylate and tert-butyl-chloro-dimethyl-silane analogously to Intermediate JB step 1. 1H NMR (500 MHz, Chloroform-d) d 4.28 (d, J = 9.5 Hz, 2H), 3.92 (d, J = 9.1 Hz, 2H), 3.80 (s, 3H), 1.45 (s, 9H), 0.92 (s, 9H), 0.10 (s, 6H).
Step 2: tert-Butyl 3-[tert-butyl(dimethyl)silyl]oxy-3-(hydroxymethyl)azetidine-1-carboxylate
Figure imgf000259_0001
[00492] The title compound was prepared from O1-tert-butyl O3-methyl 3-[tert- butyl(dimethyl)silyl]oxyazetidine-1,3-dicarboxylate (step 1) and DIBAL (1M in toluene) analogously to Intermediate J step 2.
1H NMR (500 MHz, Chloroform-d) d 3.88– 3.82 (m, 4H), 3.65 (s, 2H), 1.79 (br s, 1H), 1.44 (s, 9H), 0.90 (s, 9H), 0.15 (s, 6H).
Step 3: tert-Butyl 3-[tert-butyl(dimethyl)silyl]oxy-3-[(1,3-dioxoisoindolin-2- yl)oxymethyl]azetidine-1-carboxylate
Figure imgf000259_0002
[00493] The title compound was prepared from tert-butyl 3-[tert-butyl(dimethyl)silyl]oxy- 3-(hydroxymethyl)azetidine-1-carboxylate (step 2) and 2-hydroxyisoindoline-1,3-dione analogously to Intermediate A step1.
LC-MS (Method 3A): Rt 2.57 mins; MS m/z 363.2 = [M-Boc+H]+
1H NMR (500 MHz, Chloroform-d) d 7.86– 7.81 (m, 2H), 7.77– 7.73 (m, 2H), 4.29 (s, 2H), 4.19 (br d, J = 9.3 Hz, 2H), 3.91 (d, J = 9.3 Hz, 2H), 1.46 (s, 9H), 0.87 (s, 9H), 0.16 (s, 6H). Step 4: tert-Butyl 3-(aminooxymethyl)-3-[tert-butyl(dimethyl)silyl]oxy-azetidine-1-carboxylate
[00494] The title compound was prepared from tert-butyl 3-[tert-butyl(dimethyl)silyl]oxy- 3-[(1,3-dioxoisoindolin-2-yl)oxymethyl]azetidine-1-carboxylate (step 3) and hydrazine hydrate analogously to Intermediate A step 2.
1H NMR (500 MHz, Chloroform-d) d 5.79 (br s, 2H), 3.95 (d, J = 9.1 Hz, 2H), 3.81 (s, 2H), 3.79 (d, J = 9.1 Hz, 2H), 1.44 (s, 9H), 0.89 (s, 9H), 0.10 (s, 6H).
Intermediate K
4-Amino-2-(3-cyanophenyl)-6-[(3S)-tetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxylic acid
Figure imgf000260_0001
Step 1: Ethyl 4-amino-2-methylsulfanyl-6-[(3S)-tetrahydrofuran-3-yl]oxy-pyrimidine-5- carboxylate
Figure imgf000260_0002
[00495] Sodium hydride (21.35 g, 533.82 mmol) was added in eleven portions over 3 h to a stirred solution of ethyl 4,6-dichloro-2-methylsulfanyl-pyrimidine-5-carboxylate (Example 1 step 1) (142.6 g, 533.82 mmol) and (3S)-tetrahydrofuran-3-ol (85.29 mL, 1.07 mol) in THF (4 L) at 0 °C under nitrogen. The mixture was stirred at 0 °C under nitrogen for 1 h. Ammonia solution (1.04 L, 13.35 mol) was added and the mixture was stirred at 0 °C under nitrogen for 30 mins and then warmed to room temperature overnight. Additional ammonia solution (1.04 L, 13.35 mmol) was added and stirring continued at room temperature for 8 h. A further portion of ammonia solution (1.04 L, 13.35 mol) was added and the mixture was stirred at room temperature under nitrogen for 2 days. EtOAc (1.0 L) and water (1.0 L) were added to the mixture and the layers were separated. The aqueous phase was extracted with EtOAc (2 x 1.0 L) and the combined organic fractions were dried over MgSO4 and concentrated in vacuo to leave an orange solid. Petroleum ether (200 mL) was added and the solid was collected by filtration, washed with petroleum ether (2 x 200 mL), a mixture of 20% diethyl ether in petroleum ether (2 x 200 mL) and a mixture of 50% diethyl ether in petroleum ether (4 x 200 mL) and dried under vacuum to afford the title compound as a light orange solid. LC-MS (Method 5B): Rt 2.90 mins; MS m/z 300.2 = [M+H]+ 1H NMR (500 MHz, DMSO-d6) d 7.78 (br. s, 2H), 5.56 (ddt, J = 6.6, 4.5, 1.9 Hz, 1H), 4.19 (q, J = 7.1 Hz, 2H), 3.93 (dd, J = 10.4, 4.5 Hz, 1H), 3.87– 3.70 (m, 3H), 2.45 (s, 3H), 2.23– 2.15 (m, 1H), 2.04– 1.97 (m, 1H), 1.26 (t, J = 7.1 Hz, 3H).
Step 2: Ethyl 4-amino-2-(3-cyanophenyl)-6-[(3S)-tetrahydrofuran-3-yl]oxy-pyrimidine-5- carboxylate
Figure imgf000261_0001
[00496] Pd(PPh3)4 (45.74 g, 39.59 mmol) was added in five portions over 5 mins to a stirred, degassed suspension of 3-cyanophenylboronic acid (69.8 g, 475.03 mmol), ethyl 4- amino-2-methylsulfanyl-6-[(3S)-tetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxylate (step 1) (118.5 g, 395.86 mmol) and copper(I) thiophene-2-carboxylate (188.72 g, 989.64 mmol) in THF (3 L) at room temperature under nitrogen. The mixture was stirred at 60 °C under nitrogen overnight. EtOAc (1.50 L) was added and the mixture was filtered through Celite® (filter material), eluting with EtOAc (4 x 300 mL). The organic filtrate was washed with 10% aqueous ammonia solution (4 x 2.0 L) and brine (4 x 2.0 L). The combined aqueous fractions were extracted with EtOAc (2.0 L) and the combined organic fractions were dried over MgSO4 and concentrated in vacuo to yield a red solid. Petroleum ether (300 mL) was added and the solid was collected by filtration, washed with petroleum ether (3 x 300 mL), IMS (3 x 150 mL), diethyl ether (150 mL) and dried under vacuum to afford the title compound as a light orange solid.
LC-MS (Method 5B): Rt 3.34 mins; MS m/z 355.2 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 8.63 (t, J = 1.5 Hz, 1H), 8.60 (dt, J = 7.9, 1.5 Hz, 1H), 8.02 (dt, J = 7.9, 1.5 Hz, 1H), 7.86 (br. s, 2H), 7.74 (t, J = 7.9 Hz, 1H), 5.79 (ddt, J = 6.7, 4.6, 2.0 Hz, 1H), 4.25 (q, J = 7.1 Hz, 2H), 4.06 (dd, J = 10.4, 4.6 Hz, 1H), 3.89– 3.80 (m, 3H), 2.32– 2.25 (m, 1H), 2.10– 2.04 (m, 1H), 1.30 (t, J = 7.1 Hz, 3H). Step 3: 4-Amino-2-(3-cyanophenyl)-6-[(3S)-tetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxylic acid
[00497] A solution of ethyl 4-amino-2-(3-cyanophenyl)-6-[(3S)-tetrahydrofuran-3- yl]oxy-pyrimidine-5-carboxylate (step 2) (117.1 g, 330.45 mmol) and lithium hydroxide (15.83 g, 660.91 mmol) in THF (2 L) and water (1 L) was stirred at room temperature under nitrogen for 2 days. Diethyl ether (5.0 L) and water (3.0 L) were added and the layers were separated. The organic phase was extracted with water (2 x 1.0 L) and the combined aqueous fractions were washed with diethyl ether (2.0 L). The pH of the aqueous phase was adjusted to pH 2 by dropwise addition of 2M aqueous HCl (~350 mL). The precipitated solid was collected by filtration, washed with water (3 x 200 mL), IPA (2 x 100 mL), petroleum ether (3 x 150 mL) dried under vacuum to afford the title compound as a light orange solid.
LC-MS (Method 5A): Rt 2.39 mins; MS m/z 327.2 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 12.76 (br. s, 1H), 8.63 (t, J = 1.5 Hz, 1H), 8.60 (dt, J = 7.8, 1.5 Hz, 1H), 8.02 (dt, J = 7.8, 1.5 Hz, 1H), 7.92 (br. s, 2H), 7.74 (t, J = 7.8 Hz, 1H), 5.79 (ddt, J = 6.9, 4.8, 2.2 Hz, 1H), 4.03 (dd, J = 10.4, 4.8 Hz, 1H), 3.88– 3.77 (m, 3H), 2.33– 2.25 (m, 1H), 2.09– 2.02 (m, 1H).
Intermediate L
tert-Butyl 3-(aminooxymethyl)-5-isopropyl-1,2,4-triazole-4-carboxylate
Figure imgf000262_0001
Step 1: 2-[(5-Isopropyl-1H-1,2,4-triazol-3-yl)methoxy]isoindoline-1,3-dione
Figure imgf000262_0002
[00498] To a solution of 2-hydroxyisoindoline-1,3-dione (416 mg, 2.55 mmol) and 3- (chloromethyl)-5-isopropyl-1H-1,2,4-triazole hydrochloride (500 mg, 2.55 mmol) in MeCN (6 mL) was added DIPEA (1.11 mL, 6.37 mmol) and the mixture stirred at room temperature for 40 h. The resulting mixture was partitioned between EtOAc (15 mL) and water (15 mL) and the layers were separated. The aqueous portion was further extracted with EtOAc (2 x 15 mL) and the combined organic extracts were washed with brine (4 x 20 mL), dried over MgSO4 and the solvent removed in vacuo. The resulting solid was suspended in EtOAc (3 mL), filtered and dried to afford the title compound as a colourless solid.
LC-MS (Method 5A): Rt 1.73 mins; MS m/z 287.2 = [M+H]+
1H NMR (500 MHz, Chloroform-d) d 7.84– 7.79 (m, 2H), 7.77– 7.72 (m, 2H), 5.35 (s, 2H), 3.16 (hept, J = 7.0 Hz, 1H), 1.34 (d, J = 7.0 Hz, 6H).1 x exchangeable proton not observed.
Step 2: tert-Butyl 3-[(1,3-dioxoisoindolin-2-yl)oxymethyl]-5-isopropyl-1,2,4-triazole-4- carboxylate
Figure imgf000263_0001
[00499] To a solution of 2-[(5-isopropyl-4H-1,2,4-triazol-3-yl)methoxy]isoindoline-1,3- dione (step 1) (225 mg, 0.79 mmol) and Boc anhydride (0.2 mL, 0.86 mmol) in DCM (8 mL) was added triethylamine (219 µL, 1.57 mmol) and the mixture was stirred at room temperature for 16 h. The resulting mixture was partitioned between DCM (10 mL) and water (15 mL) and the layers were separated. The aqueous portion was further extracted with DCM (2 x 25 mL) and the combined organic extracts were dried over MgSO4. Purification of the crude material by chromatography on silica eluting with 50% EtOAc in petrol afforded the title compound as an inseparable ~ 2.8 : 1 mixture of regioisomers as a clear viscous oil.
LC-MS (Method 5A): Rt 2.98 mins; MS m/z 409.1 = [M+H]+, 287.2 [M-Boc]+
Major Isomer: 1H NMR (500 MHz, Chloroform-d) d 7.83– 7.72 (m, 4H), 5.24 (s, 2H), 3.68 (hept, J = 6.8 Hz, 1H), 1.61 (s, 9H), 1.28 (d, J = 6.8 Hz, 6H).
Minor Isomer: 1H NMR (500 MHz, Chloroform-d) d 7.79– 7.70 (m, 4H), 5.51 (s, 2H), 3.02 (hept, J = 6.8 Hz, 1H), 1.69 (s, 9H), 1.19 (d, J = 6.8 Hz, 6H).
Step 3: tert-Butyl 3-(aminooxymethyl)-5-isopropyl-1,2,4-triazole-4-carboxylate
[00500] Hydrazine hydrate (0.03 mL, 0.58 mmol) was added dropwise to a solution of tert-butyl 3-[(1,3-dioxoisoindolin-2-yl)oxymethyl]-5-isopropyl-1,2,4-triazole-4-carboxylate (step 2) (150 mg, 0.39 mmol) in DCM (4 mL) and the reaction mixture was stirred at room temperature for 2 h. The solvent was removed in vacuo and the resulting solid was suspended in Et2O (4 mL), collected by filtration, washed with Et2O (4 mL) and the filtrate concentrated in vacuo to afford the title compound as a clear oil.
1H NMR (500 MHz, Chloroform-d) d 4.79 (s, 2H), 3.75– 3.69 (sept, J = 6.8 Hz, 1H), 1.66 (s, 9H), 1.37 (d, J = 6.8 Hz, 6H).2 x exchangeable protons not observed.
Intermediate LA
O-(1H-1,2,4-triazol-3-ylmethyl)hydroxylamine ammonium salt
Figure imgf000264_0001
Step 1: 2-(1H-1,2,4-Triazol-3-ylmethoxy)isoindoline-1,3-dione
Figure imgf000264_0002
[00501] The title compound was prepared from 3-(chloromethyl)-1H-1,2,4-triazole hydrochloride and 2-hydroxyisoindoline-1,3-dione analogously to Intermediate L step 1. LC-MS (Method 5A): Rt 1.39 mins; MS m/z 245.1 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 14.16 (br s, 1H), 8.53 (br s, 1H), 7.86 (s, 4H), 5.18 (s, 2H)
Step 2: O-(1H-1,2,4-triazol-3-ylmethyl)hydroxylamine ammonium salt
[00502] The title compound was prepared from 2-(1H-1,2,4-triazol-3- ylmethoxy)isoindoline-1,3-dione and hydrazine hydrate analogously to Intermediate L step 2. LC-MS (Method 5A): Rt 0.40 mins; MS m/z 115.0 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 8.19 (s, 1H), 6.19 (br s, 2H), 4.63 (s, 2H).1 x exchangeable proton not observed.
Intermediate LB
O-[(1-Methylimidazol-2-yl)methyl]hydroxylamine Step 1: 2-(Chloromethyl)-1-methyl-imidazole hydrochloride salt
Figure imgf000265_0001
[00503] Following the procedure detailed by Robinson C. et al. in WO2011089396, pg 194.
[00504] To a solution of (1-methylimidazol-2-yl)methanol (2.0 g, 17.84 mmol) in DCM (80 mL) at 0 °C was added thionyl chloride (18.21 mL, 249.71 mmol). The reaction mixture was allowed to warm to room temperature and stirred overnight. The resulting mixture was concentrated in vacuo and the residue was washed with DCM (2 x 50 mL) and Et2O (2 x 20 mL) to afford the title compound as a colourless solid.
1H NMR (500 MHz, DMSO-d6) d 7.76– 7.72 (m, 1H), 7.69– 7.65 (m, 1H), 5.18– 5.13 (m, 2H), 3.86 (s, 3H).
Step 2: 2-[(1-Methylimidazol-2-yl)methoxy]isoindoline-1,3-dione
Figure imgf000265_0002
[00505] The title compound was prepared from 2-(chloromethyl)-1-methyl-imidazole hydrochloride (step 1) and 2-hydroxyisoindoline-1,3-dione analogously to Intermediate L step 1.
LC-MS (Method 5B): Rt 2.04 mins; MS m/z 258.2 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 7.88– 7.81 (m, 4H), 7.24 (d, J = 1.0 Hz, 1H), 6.78 (d, J = 1.0 Hz, 1H), 5.21 (s, 2H), 3.85 (s, 3H).
Step 3: O-[(1-Methylimidazol-2-yl)methyl]hydroxylamine [00506] The title compound was prepared from hydrazine hydrate and 2-[(1- methylimidazol-2-yl)methoxy]isoindoline-1,3-dione (step 2) analogously to Intermediate L step 3.
1H NMR (500 MHz, DMSO-d6) d 7.10 (d, J = 1.2 Hz, 1H), 6.79 (d, J = 1.2 Hz, 1H), 6.11 (s, 2H), 4.57 (s, 2H), 3.65 (s, 3H).
Intermediate LC
O-[(3-Methylimidazol-4-yl)methyl]hydroxylamine
Figure imgf000266_0001
Step 1: 5-(Chloromethyl)-1-methyl-imidazole hydrochloride salt
Figure imgf000266_0002
[00507] Following the procedure of Butler, T. W. detailed in WO2007034277, pg 58.
[00508] A solution of (3-methylimidazol-4-yl)methanol (1.0 g, 8.92 mmol) in thionyl chloride (32.53 mL, 445.91 mmol) was heated at reflux for 3 h. The resulting mixture was concentrated in vacuo and the crude material was dissolved in a minimal volume of IMS (2 mL). Et2O (2 mL) was added and a white precipitate formed. The mixture was sonicated and left to stand at room temperature overnight. The resulting solid was filtered, washed with Et2O (2 x 5 mL) and dried under vacuum to afford the title compound as an off-white solid.
1H NMR (500 MHz, DMSO-d6) d 14.88 (s, 1H), 9.24– 9.15 (m, 1H), 7.79 (d, J = 1.7 Hz, 1H), 5.03 (s, 2H), 3.89 (s, 3H).
Step 2: 2-[(3-Methylimidazol-4-yl)methoxy]isoindoline-1,3-dione
Figure imgf000266_0003
[00509] The title compound was prepared from 5-(chloromethyl)-1-methyl-imidazole hydrochloride (step 1) and 2-hydroxyisoindoline-1,3-dione analogously to Intermediate L step 1.
LC-MS (Method 5B): Rt 2.03 mins; MS m/z 258.2 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 7.89– 7.81 (m, 4H), 7.70 (s, 1H), 6.98 (s, 1H), 5.19 (s, 2H), 3.82 (s, 3H).
Step 3: O-[(3-Methylimidazol-4-yl)methyl]hydroxylamine
[00510] The title compound was prepared from 2-[(3-methylimidazol-4- yl)methoxy]isoindoline-1,3-dione (step 2) and hydrazine hydrate analogously to Intermediate L step 3.
1H NMR (500 MHz, Chloroform-d) d 7.46 (s, 1H), 7.07 (s, 1H), 4.96 (s, 2H), 4.64 (s, 2H), 3.66 (s, 3H).
Intermediate LD
Figure imgf000267_0001
Step 1: 2-(1H-Triazol-5-ylmethoxy)isoindoline-1,3-dione
Figure imgf000267_0002
[00511] The title compound was prepared from 5-(chloromethyl)-1H-triazole hydrochloride and 2-hydroxyisoindoline-1,3-dione analogously to Intermediate L step 1. LC-MS (Method 5A): Rt 1.59 mins; MS m/z 245.1 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 15.12 (br s, 1H), 8.08 (br s, 1H), 7.89– 7.81 (m, 4H), 5.27 (s, 2H).
Step 2: O-(1H-Triazol-5-ylmethyl)hydroxylamine
[00512] The title compound was prepared from 2-(1H-triazol-5-ylmethoxy)isoindoline- 1,3-dione (step 1) and hydrazine hydrate analogously to Intermediate L step 3.
1H NMR (500 MHz, DMSO-d6) d 13.97 (br s, 1H), 7.81 (s, 1H), 6.11 (br s, 2H), 4.64 (s, 2H). Intermediate LE
O-(1H-Pyrazol-4-ylmethyl)hydroxylamine
Figure imgf000268_0001
Step 1: 4-(Chloromethyl)-1H-pyrazole hydrochloride salt
Figure imgf000268_0002
[00513] Following the procedure of Kawabata K. et al. detailed in WO9507283, pg 46.
[00514] To a suspension of 1H-pyrazol-4-ylmethanol (500 mg, 5.1 mmol) in chloroform (12 mL) was added thionyl chloride (0.85 mL, 11.72 mmol) dropwise and the mixture stirred at room temperature for 2 h. The solvent was removed in vacuo to give a colourless solid which was suspended in Et2O (10 mL), filtered and dried to afford the title compound as a colourless solid.
1H NMR (500 MHz, DMSO-d6) d 7.73 (s, 2H), 4.72 (s, 2H). 1 x exchangeable proton not observed.
Step 2: 2-(1H-Pyrazol-4-ylmethoxy)isoindoline-1,3-dione
Figure imgf000268_0003
[00515] The title compound was prepared from 4-(chloromethyl)-1H-pyrazole hydrochloride (step 1) and 2-hydroxyisoindoline-1,3-dione analogously to Intermediate L step 1.
LC-MS (Method 5A): Rt 1.77 mins; MS m/z 244.1 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 12.89 (s, 1H), 7.89 (s, 1H), 7.87– 7.80 (m, 4H), 7.56 (s, 1H), 5.08 (s, 2H).
Step 3: O-(1H-Pyrazol-4-ylmethyl)hydroxylamine [00516] The title compound was prepared from 2-(1H-pyrazol-4-ylmethoxy)isoindoline- 1,3-dione (step 1) and hydrazine hydrate analogously to Intermediate L step 3.
1H NMR (500 MHz, DMSO-d6) d 12.72 (br s, 1H), 7.56 (br s, 2H), 5.87 (br s, 2H), 4.45 (br s, 2H). Intermediate M
O-[(2-Trityltetrazol-5-yl)methyl]hydroxylamine
Figure imgf000269_0001
Step 1: 2-(2H-Tetrazol-5-ylmethoxy)isoindoline-1,3-dione
Figure imgf000269_0002
[00517] The title compound was prepared from 2-hydroxyisoindoline-1,3-dione and 5- (chloromethyl)-2H-tetrazole analogously to Intermediate L step 1.
LC-MS (Method 5A): Rt 1.48 mins; MS m/z 246.1 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 7.87 (s, 4H), 5.49 (s, 2H). 1 x exchangeable proton not observed. Step 2: 2-[(2-Trityltetrazol-5-yl)methoxy]isoindoline-1,3-dione
Figure imgf000269_0003
[00518] To a solution of 2-(2H-tetrazol-5-ylmethoxy)isoindoline-1,3-dione (step 1) (376 mg, 1.53 mmol) and trityl chloride (513 mg, 1.84 mmol) in DMF (5 mL) was added triethylamine (321 µL, 2.3 mmol) and the mixture was stirred at room temperature for 40 h. The resulting mixture was partitioned between water (15 mL) and EtOAc (20 mL) and the layers were separated. The aqueous portion was further extracted with EtOAc (2 x 25 mL) and the combined organic extracts were washed with brine (4 x 20 mL), dried over MgSO4 and the solvent removed in vacuo. The crude material was suspended in Et2O and the solid collected by filtration to afford the title compound as a colourless solid.
LC-MS (Method 5B): Rt 3.82 mins; MS m/z = 510.2 [M+Na]+
1H NMR (500 MHz, DMSO-d6) d 7.90– 7.79 (m, 4H), 7.40– 7.31 (m, 9H), 6.97– 6.91 (m, 6H), 5.47 (s, 2H).
Step 3: O-[(2-Trityltetrazol-5-yl)methyl]hydroxylamine
[00519] The title compound was prepared from 2-[(2-trityltetrazol-5- yl)methoxy]isoindoline-1,3-dione (step 2) and hydrazine hydrate analogously to Intermediate L step 3.
LC-MS (Method 5B): Rt 3.32 mins; no ionisation observed.
1H NMR (500 MHz, DMSO-d6) d 7.42– 7.38 (m, 9H), 7.04– 6.99 (m, 6H), 6.23 (s, 2H), 4.82 (s, 2H)
Intermediate N
O-[(1-Tritylimidazol-2-yl)methyl]hydroxylamine
Figure imgf000270_0001
Step 1: (1-Tritylimidazol-2-yl)methanol [00520] Following the procedure of Aissaoui, H. et al detailed in WO2008078291 page 68.
[00521] A suspension of 1-tritylimidazole-2-carbaldehyde (1.5 g, 4.43 mmol) in anhydrous MeOH (30 mL) was heated to 45 °C and treated portion wise with NaBH4 (503 mg, 13.3 mmol). After stirring at 45 °C for 3 h, the resulting mixture was allowed to cool to room temperature and was concentrated in vacuo. The crude material was suspended in CHCl3 (50 mL), the solid collected by filtration and washed with further CHCl3 (2 x 50 mL). The filtrate was concentrated in vacuo to afford the title compound as a cream solid.
LC-MS (Method 5B): Rt 3.12 mins; MS m/z 363.2 = [M+Na]+
1H NMR (500 MHz, Chloroform-d) d 7.37– 7.33 (m, 9H), 7.13– 7.09 (m, 6H), 7.03 (d, J = 1.6 Hz, 1H), 6.81 (d, J = 1.6 Hz, 1H), 3.68 (s, 2H), 3.28 (br s, 1H).
Step 2: 2-[(1-Tritylimidazol-2-yl)methoxy]isoindoline-1,3-dione
Figure imgf000271_0001
[00522] A solution of (1-tritylimidazol-2-yl)methanol (step 1) (500 mg, 1.47 mmol), 2- hydroxyisoindoline-1,3-dione (240 mg, 1.47 mmol) and triphenylphosphine (424 mg, 1.62 mmol) in THF (10 mL) was cooled to 0 ºC and DIAD (318 µL, 1.62 mmol) was added dropwise. The mixture was warmed to room temperature and stirred for 18 h. The resulting mixture was poured onto water (20 mL) and extracted with DCM (3 x 20 mL). The combined organic fractions were dried over Na2SO4 and silica was added. The material was dry loaded onto silica and purification by chromatography on silica eluting with 0 to 100% EtOAc in petrol afforded the title compound as a white foam. LC-MS (Method 5B): Rt 3.74 mins; MS m/z 486.2 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 7.88– 7.79 (m, 4H), 7.45– 7.38 (m, 9H), 7.19– 7.15 (m, 6H), 6.84 (d, J = 1.4 Hz, 1H), 6.72 (d, J = 1.5 Hz, 1H), 4.33 (s, 2H).
Step 3: O-[(1-Tritylimidazol-2-yl)methyl]hydroxylamine
[00523] Hydrazine hydrate (0.05 mL, 0.95 mmol) was added to a solution of 2-[(1- tritylimidazol-2-yl)methoxy]isoindoline-1,3-dione (step 2) (418 mg, 0.86 mmol) in DCM (8 mL) and stirred at room temperature for 90 mins. The resulting mixture was filtered and the solid was washed with DCM (3 x 10 mL). The filtrate was concentrated in vacuo to afford to leave a yellow oil, which on standing at room temperature overnight, yielded a pale yellow solid. The material was dried under high vacuum to afford the title compound as a pale yellow foam. LC-MS (Method 5B): Rt 3.09 mins; MS m/z 356.2 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 7.42– 7.38 (m, 9H), 7.07– 7.03 (m, 6H), 6.94 (d, J = 1.4 Hz, 1H), 6.65 (d, J = 1.4 Hz, 1H), 5.88 (s, 2H), 3.66 (s, 2H).
Intermediate O
O-(1H-Pyrazol-3-ylmethyl)hydroxylamine
Figure imgf000272_0001
Step 1: 2-(1H-Pyrazol-3-ylmethoxy)isoindoline-1,3-dione
Figure imgf000272_0002
[00524] A solution of 3-(chloromethyl)-1H-pyrazole hydrochloride (250 mg, 1.63 mmol), 2-hydroxyisoindoline-1,3-dione (267 mg, 1.63 mmol) and potassium carbonate (565 mg, 4.08 mmol) in MeCN (10 mL) was stirred at 60 ºC for 4 h. The mixture was cooled to room temperature and partitioned between EtOAc (20 mL) and brine (30 mL). The layers were separated and the aqueous layer was further extracted with EtOAc (3 x 20 mL). The combined organic extracts were dried and concentrated in vacuo to afford the title compound as a colourless solid.
LC-MS (Method 5A): Rt 1.79 mins; MS m/z 244.2 = [M+H]+ 1H NMR (500 MHz, Chloroform-d) d 7.80 (dd, J = 5.4, 3.1 Hz, 2H), 7.73 (dd, J = 5.5, 3.1 Hz, 2H), 7.57 (d, J = 2.2 Hz, 1H), 6.53 (d, J = 2.2 Hz, 1H), 5.30 (s, 2H).1 x exchangeable proton not observed.
Step 2: O-(1H-Pyrazol-3-ylmethyl)hydroxylamine
[00525] Hydrazine hydrate (0.24 mL, 4.98 mmol) was added dropwise to a solution of 2-(1H-pyrazol-3-ylmethoxy)isoindoline-1,3-dione (step 1) (346 mg, 1.42 mmol) in DCM (9 mL):THF (1 mL) at 0 ˚C and the suspension was stirred at room temperature for 1 h. The resulting mixture was filtered and the solids washed with DCM (2 x 50 mL). The filtrate was dried over MgSO4 and concentrated in vacuo to afford the title compound as a colourless oil. 1H NMR (500 MHz, Chloroform-d) d 7.56 (d, J = 2.1 Hz, 1H), 6.33 (d, J = 2.1 Hz, 1H), 4.75 (s, 2H).3 x exchangeable protons not observed.
Intermediate P
3-Aminooxy-2-methyl-butan-2-ol 2,2,2-trifluoroacetic acid salt
Figure imgf000273_0001
Step 1: Ethyl 2-(tert-butoxycarbonylamino)oxypropanoate
Figure imgf000273_0002
[00526] Following the procedure of Dai, M. et al detailed in WO2011020861 page 68.
[00527] To a mixture of KOH (0.74 g, 13.26 mmol) in EtOH (30 mL) was added tert- butyl N-hydroxycarbamate (1.77 g, 13.26 mmol) and the mixture stirred at room temperature until a clear solution was obtained at which point ethyl 2-bromopropanoate (1.33 mL, 11.05 mmol) was added dropwise. The reaction mixture was heated to 80 °C for 18 h and then allowed to cool to room temperature, the formed solid was removed by filtration and the filtrate concentrated in vacuo to afford a clear oil. This material was partitioned between Et2O (50 mL) and water (50 mL), the organic portion was separated and the aqueous further extracted with Et2O (2x50 mL). The combined organic extracts were dried over MgSO4 and concentrated in vacuo. Purification of the crude material by chromatography on silica eluting with 15% EtOAc in petrol afforded the title compound as a clear oil.
1H NMR (500 MHz, Chloroform-d) d 7.56 (s, 1H), 4.47 (q, J = 7.0 Hz, 1H), 4.26– 4.19 (m, 2H), 1.47 (s, 9H), 1.45 (d, J = 7.0 Hz, 3H), 1.30 (t, J = 7.1 Hz, 3H).
Step 2: Tert-butyl N-(2-hydroxy-1,2-dimethyl-propoxy)carbamate
Figure imgf000274_0001
[00528] To a solution of ethyl 2-(tert-butoxycarbonylamino)oxypropanoate (step 1) (2.0 g, 8.57 mmol) in THF (15 mL) at 0 °C was added methylmagnesium bromide (3.4 M in 2- methyltetrahydrofuran) (10.09 mL, 34.3 mmol) dropwise and the mixture stirred for 1 h. The reaction was quenched by dropwise addition of NH4Cl (5 mL) and then diluted with water (50 mL). The mixture was extracted with EtOAc (3 x 100 mL) and the combined organic extracts were dried over MgSO4 and concentrated in vacuo. Purification of the crude material by chromatography on silica eluting with 15 to 25% EtOAc in petrol afforded the title compound as a colourless solid.
1H NMR (500 MHz, Chloroform-d) d 7.28 (s, 1H), 3.73 (q, J = 6.6 Hz, 1H), 1.48 (s, 9H), 1.19 (d, J = 6.6 Hz, 3H), 1.17 (s, 3H), 1.16 (s, 3H).1 x exchangeable proton not observed.
Step 3: 3-Aminooxy-2-methyl-butan-2-ol 2,2,2-trifluoroacetic acid salt
[00529] To a solution of tert-butyl N-(2-hydroxy-1,2-dimethyl-propoxy)carbamate (step 2) (250 mg, 1.14 mmol) in DCM (5 mL) was added TFA (1.05 mL, 13.68 mmol) and the mixture was stirred at room temperature for 90 mins. The solvent was removed in vacuo azeotroping with CHCl3 (3 x 10 mL) to yield a yellow oil which solidified on standing. Et2O (10 mL) was added and the mixture sonicated. The resulting solid collected was collected by filtration and dried to afford the title compound as a crystalline colourless solid.
1H NMR (500 MHz, DMSO-d6) d 10.23 (br s, 3H), 3.87 (q, J = 6.5 Hz, 1H), 1.15– 1.10 (m, 6H), 1.09 (s, 3H).1 x exchangeable proton not observed. Intermediate Q
2-Aminooxy-N-ethyl-acetamide;hydrochloride
Figure imgf000275_0001
Step 1 tert-Butyl N-[2-(ethylamino)-2-oxo-ethoxy]carbamate
Figure imgf000275_0002
[00530] 2-(tert-Butoxycarbonylamino)oxyacetic acid (100 mg, 0.52 mmol), DIPEA (0.18 mL, 1.05 mmol) and ethylamine (2M in THF) (0.39 mL, 0.78 mmol) were dissolved in DMF (5 mL) and HATU (298 mg, 0.78 mmol) was added. After stirring at room temperature for 18 h the resulting mixture was diluted with EtOAc (25 mL) and washed with 90% brine (25 mL), 50% brine (4 x 25 mL), dried over MgSO4 and concentrated in vacuo to afford the title compound as a colourless oil.
1H NMR (500 MHz, Chloroform-d) d 8.07 (s, 1H), 7.57 (s, 1H), 4.30 (s, 2H), 3.34 (qd, J = 7.3, 5.5 Hz, 2H), 1.48 (s, 9H), 1.17 (t, J = 7.3 Hz, 3H).
Step 2: 2-Aminooxy-N-ethyl-acetamide hydrochloride
[00531] tert-Butyl N-[2-(ethylamino)-2-oxo-ethoxy]carbamate (step 1) (114 mg, 0.52 mmol) was dissolved in HCl (1M in MeOH) (4 mL, 4 mmol) and the mixture was stirred at room temperature for 18 h. The resulting mixture was concentrated in vacuo, co-evaporating with toluene (5 mL) to afford the title compound as a pale yellow viscous oil.
1H NMR (500 MHz, Methanol-d4) d 4.52 (s, 2H), 3.27 (q, J = 7.3 Hz, 2H), 1.15 (t, J = 7.3 Hz, 3H).3 x exchangeable protons not observed.
Intermediate R
2-aminooxyacetamide
Figure imgf000275_0003
Step 1: 2-(1,3-Dioxoisoindolin-2-yl)oxyacetamide [00532] To a solution of 2-hydroxyisoindoline-1,3-dione (1.0 g, 6.13 mmol) and potassium carbonate (890 mg, 6.44 mmol) in DMF (10 mL) was added 2- bromoacetamide (930 mg, 6.74 mmol) and the mixture stirred at room temperature for 64 h. The mixture was poured into water and the resulting solid was collected by filtration and dried to afford the title compound as a colourless solid.
LC-MS (Method 5B): Rt 1.73 mins; MS m/z 221.1 = [M+H]+
1H NMR (500 MHz, DMSO-d6) d 7.91– 7.85 (m, 4H), 7.60 (apr br d, J = 11.8 Hz, 2H), 4.59 (s, 2H).
Step 2: 2-Aminooxyacetamide
[00533] To a solution 2-(1,3-dioxoisoindolin-2-yl)oxyacetamide (step 1) (500 mg, 2.27 mmol) in DCM (20 mL) and MeOH (4 mL) was added hydrazine hydrate (0.44 mL, 9.08 mmol) and the mixture stirred at room temperature for 3 h. The resulting solid was removed by filtration and the filtrate was concentrated in vacuo. The crude product was suspended in DCM (10 mL) and the solid again removed by filtration. The filtrate was concentrated in vacuo to afford the title compound as a pale yellow oil.
1H NMR (500 MHz, DMSO-d6) d 7.22 (apr br d, J = 13.9 Hz, 2H), 6.33 (br s, 2H), 3.87 (s, 2H).
Intermediate S
(2R)-1-[tert-Butyl(dimethyl)silyl]oxybutan-2-ol
Figure imgf000276_0001
[00534] To a solution of (2R)-butane-1,2-diol (1.0 g, 11.1 mmol) and imidazole (0.76 g, 11.1 mmol) in dry DCM (5 mL) at 0 °C was added a solution of tert-butyl-chloro-dimethyl-silane (1.67 g, 11.1 mmol) in DCM (5 mL) and the suspension was stirred under nitrogen at 0 °C for 2 h and then at room temperature overnight. The precipitate was removed by filtration and the filtrate was concentrated in vacuo. Purification of the crude material by chromatography on silica eluting with 20% EtOAc in petrol afforded the title compound as a clear colourless oil. 1H NMR (500 MHz, Chloroform-d) d 3.56 (dd, J = 9.8, 3.3 Hz, 1H), 3.52– 3.45 (m, 1H), 3.33 (dd, J = 9.8, 7.4 Hz, 1H), 2.34 (s, 1H), 1.42– 1.34 (m, 2H), 0.89 (t, J = 7.5 Hz, 3H), 0.83 (s, 9H), 0.00 (s, 6H).
Intermediate SA
rac-(1S,3S)-3-[tert-Butyl(dimethyl)silyl]oxycyclopentanol
Figure imgf000277_0001
and Intermediate SA1
rac-(1R,3S)-3-[tert-butyl(dimethyl)silyl]oxycyclopentanol
Figure imgf000277_0002
[00535] Following the procedure of Chen, Y. et al detailed in US2004/0204427 page 16.
[00536] To a solution of imidazole (6.67 g, 97.91 mmol) and cyclopentane-1,3-diol (10 g, 97.91 mmol) in THF (200 mL) cooled in an ice bath was added tert-butyl-chloro-dimethyl- silane (10.33 g, 68.54 mmol) portionwise over 25 mins. The reaction mixture was warmed to room temperature and stirred for 20 h. The resulting mixture was diluted in water (200 mL) and extracted with EtOAc (2 x 200 mL). The combined organic extracts were dried over MgSO4 and concentrated in vacuo. Purification of the crude material by chromatography on silica eluting with 5 to 20% EtOAc in iso-hexane to afford rac-(1S,3S)-3-[tert- butyl(dimethyl)silyl]oxycyclopentanol and rac-(1R,3S)-3-[tert- butyl(dimethyl)silyl]oxycyclopentanol as clear oils.
[00537] Intermediate SA: rac-(1S,3S)-3-[tert-Butyl(dimethyl)silyl]oxycyclopentanol 1H NMR (500 MHz, Chloroform-d) d 4.52– 4.38 (m, 2H), 2.19– 1.95 (m, 2H), 1.88– 1.75 (m, 2H), 1.60– 1.30 (m, 3H), 0.88 (s, 9H), 0.05 (s, 6H).
[00538] Intermediate SA1: rac-(1R,3S)-3-[tert-butyl(dimethyl)silyl]oxycyclopentanol N74-61-2 rheap 1H NMR (500 MHz, Chloroform-d) d 4.40 (t, J = 4.3 Hz, 1H), 4.30– 4.23 (m, 1H), 2.61 (s, 1H), 1.98– 1.63 (m, 6H), 0.89 (s, 9H), 0.09 (s, 6H).
Intermediate T
O-(Oxazol-2-ylmethyl)hydroxylamine
Figure imgf000278_0001
Step 1: 2-(Oxazol-2-ylmethoxy)isoindoline-1,3-dione
Figure imgf000278_0002
[00539] The title compound was prepared from 2-(chloromethyl)oxazole, 2- hydroxyisoindoline-1,3-dione and triethylamine analogously to Intermediate C step 1.
LC-MS (Method 3A): Rt 1.38 mins; MS m/z 245.1 = [M+H]+
1H NMR (500 MHz, Chloroform-d) d 7.84– 7.79 (m, 2H), 7.79 (s, 1H), 7.77– 7.73 (m, 2H), 7.13 (s, 1H), 5.24 (s, 2H).
Step 2: O-(Oxazol-2-ylmethyl)hydroxylamine
[00540] To a suspension of 2-(oxazol-2-ylmethoxy)isoindoline-1,3-dione (step 1) (845 mg, 3.29 mmol) in MeOH (10 mL) was added hydrazine hydrate (0.18 mL, 3.62 mmol) and the reaction mixture was stirred at room temperature for 4 h. The resulting mixture was concentrated in vacuo and the crude material was suspended in Et2O (10 mL) and the solid was removed by filtration washing with further Et2O (2 x 20 mL). The filtrate was concentrated in vacuo and azeotroped from CHCl3 (3 x 20 mL) to afford the title compound as a pale yellow solid.
1H NMR (500 MHz, DMSO-d6) d 8.09 (s, 1H), 7.20 (s, 1H), 6.26 (s, 2H), 4.61 (s, 2H).
Intermediate U
(2R,3S)-2-[[tert-Butyl(dimethyl)silyl]oxymethyl]tetrahydrofuran-3-ol [00541] To a stirring solution of 1,2-dideoxy-D-ribofuranose (500 mg, 4.23 mmol) in pyridine (20 mL) at 0 °C under nitrogen was added tert-butyl-chloro-dimethyl-silane (702 mg, 4.66 mmol) and the reaction mixture was stirred at 0 °C for 2 h. The resulting mixture partitioned between EtOAc (50 mL) and 10% aq. Cu(II)SO4 (20 mL) and the layers were separated. The organic layer was further washed with 10% aq. Cu(II)SO4 (3 x 20 mL), brine (30 mL), dried over MgSO4 and concentrated in vacuo. The crude material was purified by chromatography on silica eluting with 50% EtOAc in petroleum ether to afford the title compound as a colourless oil.
1H NMR (500 MHz, Chloroform-d) d 4.32 (d, J = 3.2 Hz, 1H), 3.96 (dd, J = 8.3, 5.6 Hz, 2H), 3.81– 3.71 (m, 2H), 3.57– 3.48 (m, 1H), 2.21– 2.09 (m, 1H), 1.93– 1.84 (m, 1H), 0.90 (s, 9H), 0.07 (s, 6H).1 x exchangeable proton not observed.
Intermediate UA
(3S,5S)-5-[[tert-butyl(dimethyl)silyl]oxymethyl]tetrahydrofuran-3-ol
Figure imgf000279_0001
[00542] The title compound was prepared from (3S,5S)-5- (hydroxymethyl)tetrahydrofuran-3-ol and tert-butyl-chloro-dimethyl-silane analogously to Intermediate U.
1H NMR (500 MHz, Chloroform-d) d 4.24 (br dd, J = 5.5, 3.0 Hz, 1H), 4.20 (dq, J = 10.1, 2.2 Hz, 1H), 4.15 (br s, 1H), 3.91 (dd, J = 9.3, 1.9 Hz, 1H), 3.88 (dd, J = 10.9, 2.3 Hz, 1H), 3.66 (dd, J = 9.3, 2.3 Hz, 1H), 3.56 (dd, J = 10.9, 1.9 Hz, 1H), 2.26 (ddd, J = 13.8, 10.1, 5.0 Hz, 1H), 1.93– 1.87 (m, 1H), 0.93 (s, 9H), 0.12 (s, 6H). Intermediate V
(3-Cyano-2-methoxy-phenyl)boronic acid
Figure imgf000280_0001
[00543] 3-Bromo-2-methoxy-benzonitrile (1.0 g, 4.72 mmol) was dissolved in anhydrous THF (5 mL) under nitrogen and the solution cooled to -10 ºC in a salt-ice bath. Isopropylmagnesium chloride lithium chloride complex (1.3M in THF) (4.53 mL, 5.9 mmol) was added dropwise over 5 mins and the resulting yellow solution stirred at -10 ºC for 1 h. To this mixture was added trimethyl borate (0.66 mL, 5.9 mmol) dropwise via syringe and stirring continued whilst allowing the mixture to warm to 0 ºC over 1 h. The THF was removed in vacuo at 35 ºC and the residue was partitioned between EtOAc (20 mL) and 5% aqueous citric acid (20 mL). The biphasic mixture was stirred vigorously overnight and the layers separated. The organic portion was washed with water (20 mL), brine (20 mL), dried over Na2SO4 and concentrated in vacuo. The crude material was triturated and sonicated with n-hexane/Et2O and the resulting suspension filtered. The solids were washed with n-hexane (3 x 2 mL) and vacuum dried to afford the title compound as a pale cream solid.
LC-MS (Method 3B): Rt 0.22 / 0.31 mins; MS m/z 176.1 = [M-H]- 1H NMR (500 MHz, DMSO-d6) d 8.47– 8.36 (m, 2H), 7.73 (dd, J = 7.6, 1.8 Hz, 1H), 7.67 (dd, J = 7.3, 1.8 Hz, 1H), 7.18 (apr t, J = 7.5 Hz, 1H), 3.94 (s, 3H).
Intermediate W
(2S)-1-Benzyloxybutan-2-ol
Figure imgf000280_0002
[00544] (2S)-Butane-1,2-diol (1.01 g, 11.23 mmol) was added to a suspension of sodium hydride (60% in mineral oil) (156 mg, 3.89 mmol) in anhydrous THF (20 mL) over 30 min at 0 °C. The reaction mixture was heated to reflux and treated dropwise with bromomethylbenzene (0.45 mL, 3.74 mmol). The resulting suspension was heated to reflux for 36 h. After cooling to room temperature, the mixture was diluted with Et2O (50 mL) and water (50 mL). The layers were separated and the aqueous portion was further extracted with Et2O (2 x 50 mL). The combined organic extracts were dried over MgSO4 and concentrated in vacuo. Purification of the crude material by chromatography on silica eluting with 0-50 % EtOAc in petrol afforded the title compound as a colourless oil.
LC-MS (Method 5B): Rt 2.52 mins; MS m/z 181.2 = [M+H]+
1H NMR (500 MHz, Chloroform-d) d 7.39– 7.28 (m, 5H), 4.56 (s, 2H), 3.78– 3.71 (m, 1H), 3.52 (dd, J = 9.4, 3.0 Hz, 1H), 3.34 (dd, J = 9.4, 7.9 Hz, 1H), 2.17 (br s, 1H), 1.55– 1.44 (m, 2H), 0.96 (t, J = 7.5 Hz, 3H).
Intermediate X
(5S)-1-[(2,4-Dimethoxyphenyl)methyl]-5-(hydroxymethyl)pyrrolidin-2-one
Figure imgf000281_0001
Step 1: Ethyl (2S)-1-[(2,4-dimethoxyphenyl)methyl]-5-oxo-pyrrolidine-2-carboxylate
Figure imgf000281_0002
[00545] Following the procedure of Stevenson, P. J. and McAlonan, H. detailed in Tetrahedron Asymmetry, 6, 1, pg 239-244, 1995.
[00546] To a solution of 2,4-dimethoxybenzaldehyde (0.9 g, 5.42 mmol) in DCM (10 mL) under nitrogen was added triethylamine (0.58 mL, 4.17 mmol). The reaction mixture was stirred at room temperature for 10 mins then MgSO4 (1.56 g, 12.94 mmol) and diethyl (2S)-2- aminopentanedioate hydrochloride (1.0 g, 4.17 mmol) were added. The reaction mixture was stirred overnight at room temperature. The resulting mixture was filtered and the filtrate concentrated in vacuo. The residue was diluted in THF (10 mL), cooled to 0 °C and acetic acid (2 mL) was added, followed by NaBH3CN (393 mg, 6.25 mmol). The reaction mixture was stirred at 0 °C for 1 h. The resulting mixture was concentrated in vacuo and diluted with EtOAc (30 mL) and NaHCO3 (30 mL). The layers were separated and the aqueous layer was further extracted with EtOAc (2 x 30 mL). The combined organic extracts were dried over MgSO4 and concentrated in vacuo. The residue was heated at 140 °C in xylenes (15 mL) for 50 mins and cooled to room temperature. The mixture was concentrated in vacuo and purification by chromatography on silica eluting with 25 to 100% EtOAc in petroleum ether afforded the title compound as a clear oil.
LC-MS (Method 5B): Rt 2.58 mins; MS m/z 308.2 = [M+H]+
1H NMR (500 MHz, Chloroform-d) d 7.16 (d, J = 8.0 Hz, 1H), 6.47– 6.39 (m, 2H), 4.82 (d, J = 14.4 Hz, 1H), 4.17 (q, J = 7.2 Hz, 2H), 4.14– 4.09 (m, 1H), 4.01 (dd, J = 9.3, 3.4 Hz, 1H), 3.79 (s, 3H), 3.76 (s, 3H), 2.56– 2.45 (m, 1H), 2.40– 2.29 (m, 1H), 2.28– 2.16 (m, 1H), 2.01– 1.93 (m, 1H), 1.29– 1.24 (m, 3H).
Step 2: (5S)-1-[(2,4-Dimethoxyphenyl)methyl]-5-(hydroxymethyl)pyrrolidin-2-one
[00547] To a stirring solution of ethyl (2S)-1-[(2,4-dimethoxyphenyl)methyl]-5-oxo- pyrrolidine-2-carboxylate (851 mg, 2.77 mmol) in EtOH (15 mL) at 0 °C was added sodium borohydride (105 mg, 2.77 mmol) portionwise over 10 mins. The mixture was warmed to room temperature and stirred overnight. The reaction mixture was cooled to 0 °C and additional sodium borohydride (31.42 mg, 0.83 mmol) was added. The mixture was warmed to room temperature and stirred for 48 h. A further portion of sodium borohydride (105 mg, 2.77 mmol) was added and the reaction mixture was stirred for 3 days. The resulting mixture was concentrated in vacuo and the residue was treated with 2M HCl (3 mL). The mixture was extracted with DCM (3 x 15 mL) and the combined organic extracts were dried over MgSO4 and concentrated in vacuo. Purification by chromatography on silica eluting with EtOAc afforded the title compound as a viscous colourless oil.
LC-MS (Method 5B): Rt 1.94 mins; MS m/z 266.2 = [M+H]+
1H NMR (500 MHz, Chloroform-d) d 7.21 (d, J = 8.1 Hz, 1H), 6.51– 6.42 (m, 2H), 4.68 (d, J = 14.9 Hz, 1H), 4.30 (d, J = 14.9 Hz, 1H), 3.81 (s, 3H), 3.80– 3.75 (m, 4H), 3.58– 3.53 (m, 1H), 3.51 (dd, J = 11.7, 2.9 Hz, 1H), 2.62– 2.51 (m, 1H), 2.42– 2.32 (m, 1H), 2.07– 2.01 (m, 1H), 2.01– 1.92 (m, 1H).1 x exchangeable proton not observed.
Intermediate Y
Ethyl 2-aminooxyacetate
Figure imgf000282_0001
Step 1: Ethyl 2-(1,3-dioxoisoindolin-2-yl)oxyacetate [00548] To a suspension of 2-hydroxyisoindoline-1,3-dione (2.93 g, 17.96 mmol) in THF (50 mL) was added triethylamine (3.76 mL, 26.95 mmol) and ethyl 2-bromoacetate (1.99 mL, 17.96 mmol) and the mixture was stirred at room temperature for 2 h 20 min. Additional ethyl bromoacetate (0.1 mL, 0.90 mmol) was added and stirring continued for 40 mins. The resulting mixture was concentrated in vacuo and the residue was partitioned between EtOAc (50 mL) and saturated aqueous NaHCO3 (50 mL). The layers were separated and the aqueous layer was further extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with brine (50 mL), dried over MgSO4 and concentrated in vacuo to afford the title compound as a colourless solid.
LC-MS (Method 5A): Rt 2.28 mins; MS m/z 250.1 = [M+H]+
1H NMR (500 MHz, Chloroform-d) d 7.90– 7.81 (m, 2H), 7.80– 7.72 (m, 2H), 4.81 (s, 2H), 4.27 (q, J = 7.2 Hz, 2H), 1.31 (t, J = 7.2 Hz, 3H).
Step 2: Ethyl 2-aminooxyacetate
[00549] The title compound was prepared from ethyl 2-(1,3-dioxoisoindolin-2- yl)oxyacetate (step 1) and hydrazine hydrate analogously to Intermediate L step 3.
1H NMR (500 MHz, Chloroform-d) d 5.87– 4.59 (m, 2H), 4.32– 4.16 (m, 4H), 1.30 (t, J = 7.1 Hz, 3H).
Intermediate Z
3-[tert-Butyl(dimethyl)silyl]oxy-3-methyl-cyclobutanol
Figure imgf000283_0001
Step 1: 3-Benzyloxy-1-methyl-cyclobutanol [00550] A solution of methylmagnesium bromide (3M in Et2O) (4.54 mL, 13.62 mmol) was diluted with ether (40 mL) and cooled to -25 °C. To this mixture was added slowly a solution of 3-benzyloxycyclobutanone (2.0 g, 11.35 mmol) in ether (10 mL) and the mixture was warmed to room temperature over 1 h and stirred for a further hour. The mixture was cooled to 0°C and quenched by pouring onto aqueous saturated NH4Cl (50 mL). The resulting mixture was extracted with Et2O (3 x 50 mL) and the combined organic extracts were washed with brine (50 mL), dried over MgSO4 and concentrated in vacuo to afford the title compound as a ~3:1 mixture of stereoisomers.
LC-MS (Method 2A): Rt 1.00 mins; no ionisation observed.
1H NMR (400 MHz, Chloroform-d) d 7.35– 7.31 (m, 5H), 4.41 (d, J = 4.4 Hz, 2H), 3.79– 3.66 (m, 1H), 2.50– 2.39 (m, 2H), 2.13– 2.06 (m, 2H), 1.33– 1.29 (m, 3H). 1 x exchangeable proton not observed.
Step 2: (3-Benzyloxy-1-methyl-cyclobutoxy)-tert-butyl-dimethyl-silane
Figure imgf000284_0001
[00551] To a solution of 3-benzyloxy-1-methyl-cyclobutanol (step 1) (2.15 g, 11.18 mmol) in DMF (20 mL) at room temperature was added imidazole (3.81 g, 55.92 mmol) followed by tert-butyl-chloro-dimethyl-silane (5.06 g, 33.55 mmol) and the mixture was stirred at room temperature for 6 h. The reaction was quenched by pouring onto water (50 mL) and the mixture was extracted with Et2O (3 x 50 mL). The combined organic extracts were washed with brine (50 mL), dried over MgSO4 and concentrated in vacuo. Purification of the crude material by chromatography on silica eluting with 0 to 4% EtOAc in heptane afforded the title compound as a ~3:1 mixture of stereoisomers.and as a colourless oil.
LC-MS (Method 2A): Rt 2.10 and 2.13 mins; MS m/z 305 = [M-H]+
1H NMR (400 MHz, Chloroform-d) d 7.37– 7.27 (m, 5H), 4.40 (m, 2H), 3.71– 3.62 (m, 1H), 2.38 (ddd, J = 11.6, 5.9, 2.6 Hz, 2H), 2.18– 2.03 (m, 2H), 1.28 (m, 3H), 0.87 (m, 9H), 0.07 (s, 6H). Step 3: 3-[tert-Butyl(dimethyl)silyl]oxy-3-methyl-cyclobutanol
[00552] To a solution of (3-benzyloxy-1-methyl-cyclobutoxy)-tert-butyl-dimethyl-silane (step 2) (2.45 g, 7.99 mmol) in EtOH (30 mL) was added 10% Pd on carbon (160 mg, 1.5 mmol) and the mixture was purged with nitrogen then stirred under hydrogen for 20 h. The resulting mixture was filtered through Celite® (filter material) eluting with EtOH. The filtrate was concentrated in vacuo to afford the title compound as a ~3:1 mixture of stereoisomers and as a colourless oil.
1H NMR (400 MHz, Chloroform-d) d 3.93 (q, J = 6.8 Hz, 1H), 2.46 (m, 2H), 2.00 (m, 2H), 1.64 (d, J = 6.1 Hz, 1H), 1.44 (s, 1H), 1.28 (s, 2H), 0.87 (m, 9H), 0.07 (s, 6H).
BIOLOGICAL EXAMPLES
Biological Example 1 - Adenosine receptor time-resolved fluorescence resonance energy transfer (TRFRET) binding assay
[00553] All FRET binding experiments were conducted at room temperature in white 384-well plates, in assay binding buffer containing 1x LabMed (Cisbio, France), 100µg/mL saponin, 1% DMSO and 0.02% pluronic acid. Binding of the fluorescently labelled Adenosine receptor antagonist XAC (CA200645, FRET acceptor) to terbium-labelled A1, A2a, A2b and A3 adenosine receptors (FRET donors) was detected by time-resolved FRET due to the close proximity of the donor and acceptor in a binding event. To investigate the ability of unlabelled test compounds to bind to Adenosine A1, A2a, A2b and A3 receptors, dose response curves were constructed that determined the ability of a range of concentrations to inhibit the binding of 30nM CA200645 to the A2b receptor and 100nM CA200645 to the A1, A2a, and A3 receptor.
[00554] Serial dilution (1:3 dilutions) of test compounds in neat DMSO and transfer of a 400nL sample of test compound into the assay plate was carried out using the Mosquito (TTP Labtech, UK). The compound samples were incubated for 2 hours at room temperature with a fixed concentration of CA200645 defined for each receptor (see above) and CHO cell membranes containing the human Adenosine A1 (0.5µg/well), A2a (0.3µg/well), A2b (1µg/well) or A3 (1 µg/well) receptor in 40 mL of assay buffer. Total and non-specific binding of CA200645 was determined in the absence and presence of 10µM XAC, respectively. Following 2 hours incubation, the level of CA200645 binding was detected on a Pherastar FSX (BMG Labtech, Germany) using standard TR-FRET settings. The terbium donor was excited with three laser flashes at a wavelength of 337 nm, and donor and acceptor emission was detected at 620 nm and 665 nm wavelengths, respectively. FRET ratios were obtained by multiplying the acceptor/donor ratio value by 10,000. Specific binding was determined by subtracting the non-specific binding FRET ratio from the total binding FRET ratio. Compound IC50 curves were analysed using GraphPad Prism 7.0 (GraphPad, USA) and Ki affinity values were determined from the obtained IC50 values using the method of Cheng and Prusoff. The results are presented in Table 1.
Table 1 E
N
1
1
1
1
1
1
1
1
1
2
2
3
4
5
5
5
5
5
Figure imgf000286_0001
. . 5.4a 2.0 174 24 96 5
5
5
5
5
5
5
5
5
5
5
6
6
7
8
8
8
8
8
8
8
8
8
8
Figure imgf000287_0001
. 8.9 2 376 1930 8
8
9
9
9
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
Figure imgf000288_0001
16 6.5 229 1
1
1
1
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
Figure imgf000289_0001
. . 23.14 2.5 608 61 749 2
2
2
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
3
Figure imgf000290_0001
. . 33 631.1 2550 2733
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
4
Figure imgf000291_0001
Biological Example– CD3/CD28 stimulated IL-2 release NECA reversal assay in human PBMCs
[00555] Blood is drawn from healthy volunteers using sodium citrate as the anticoagulant (0.3% final concentration). After centrifugation of the blood over Histopaque-1077, PBMCs are collected from the Histopaque/plasma interface and washed twice in PBS (300g for 10 mins at room temp). Cells are plated at 50,000 cells/well in 150ml RPMI/10% FCS in 96-well cell culture plates that have been precoated with 1ug/ml CD3 antibody.50ml diluted compound mix is added to the cells, to obtain final concentrations of 1ug/ml CD28 antibody, 1uM NECA and 0.003-10µM adenosine receptor antagonist. Assay plates are incubated for 24 hours at 37ºC in a humidified incubator. Culture supernatant is tested for IL-2 levels using the human IL- 2 Tissue Culture Kit (Meso Scale Discovery). Data for dose-response curves is calculated as % inhibition with 100% inhibition defined from no agonist control wells (+CD3/28 NECA).
Table 2
Figure imgf000292_0001
5.9 0.03 8 0.17
Figure imgf000293_0001
23.6 0.03 23.6a 0.01
Figure imgf000294_0001
43 0.15 44a 0.02
Figure imgf000295_0001
Biological Example– Measurement of pCREB in CD8+T cells in human whole blood
[00556] Heparinised human whole blood was pre-incubated at 37°C with serial dilutions of A2a antagonists for 20 min. and the phosphodiesterase inhibitor rolipram to amplify the pCREB response. The adenosine receptor agonist NECA is then added at a final concentration of 3µM and following a 60 min incubation the blood is fixed and red blood cells lysed. White blood cells are isolated, permeabilized and stained with directly conjugated fluorescent antibodies to phospho-CREB (Alexa Fluor 488) and CD8 (Alexa Fluor 647) and the level of phospho-CREB in CD8+ T cells is measured by FACS using a BD Accuri C6 Flow Cytometer.
Table 3
Figure imgf000295_0002
5.8b 0.29 5.8 1.1
Figure imgf000296_0001
23.2 2.1 23.3 0.05
Figure imgf000297_0001
38a 0.30 38b 0.65
Figure imgf000298_0002
Numbered Paragraphs
[00557] The following numbered paragraphs serve to define particular aspects and embodiments of the invention.
Paragraph 1. A compound of general formula (I), or a pharmaceutically acceptable salt thereof:
wh
Figure imgf000298_0001
erein
R1 is selected from aryl or heteroaryl, each of which is optionally substituted with one or more substituents independently selected from halo, OH, cyano, R5, OR5, S(O)0-2R5 and NR5R6, wherein each R5 and R6 is independently H, (1-6C)alkyl or (3-7C)cycloalkyl, either of which is optionally substituted with one or more substituents selected from halo, OH, aryl and heteroaryl, wherein aryl and heteroaryl groups are optionally substituted with one or more substituents selected from halo, OH, (1-6C)alkyl and (1-6C)haloalkyl; R2 is selected from:
(i) –Z1;
(ii) –CR2aR2b–L1a–Z1; or
(iii) –[CR2aR2b]2-6–L1b–Z1; wherein
R2a and R2b are each independently selected from hydrogen, fluoro or (1-2C)alkyl; L1a is absent or selected from C(O), C(O)O, C(O)N(Ra1) or C(S)N(Ra1), wherein Ra1 is selected from hydrogen or (1-2C)alkyl;
L1b is absent or selected from O, S, SO, SO2, N(Ra), C(O), C(O)O, OC(O), C(O)N(Ra), N(Ra)C(O), N(Ra)C(O)N(Rb), C(S)N(Ra), N(Ra)C(S), N(Ra)C(S)N(Rb), S(O)2N(Ra), or N(Ra)SO2, wherein Ra and Rb are each independently selected from hydrogen or (1- 2C)alkyl; and
Z1 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl or heteroaryl; and wherein Z1 is optionally substituted by one or more substituents selected from (1-6C)- alkyl, halo, (1-6C)haloalkyl, (1-6C)haloalkoxy, cyano, aryl, heteroaryl, heterocyclyl, nitro, NRcRd, ORc, C(O)Rc, C(O)ORc, OC(O)Rc, C(O)N(Rc)Rd, N(Rc)C(O)Rd, S(O)yRc (where y is 0, 1 or 2), SO2N(Rc)Rd, N(Rc)SO2Rd or (CH2)zNRcRd (where z is 1, 2 or 3), wherein any alkyl, aryl, heteroaryl or heterocyclyl moiety in a substituent group on Z1 is optionally further substituted by cyano, halo, hydroxy, amino, (1-2C)alkyl or (1- 2C)alkoxy and Rcand Rd are each independently selected from hydrogen, (1-6C)alkyl, (1-6C)haloalkyl or (3-6C)cycloalkyl;
R3 is selected from:
(i) –Z2;
(ii) –CR3aR3b–L2a–Z2; or
(iii) –[CR3aR3b]2-6–L2b–Z2;
wherein
R3a and R3b are each independently selected from hydrogen, fluoro or (1-2C)alkyl; L2a is absent or selected from C(O), C(O)O, C(O)N(Rj) or C(S)N(Rj), wherein Rj is selected from hydrogen or (1-2C)alkyl;
L2b is absent or selected from O, S, SO, SO2, N(Re), C(O), C(O)O, OC(O), C(O)N(Re), N(Re)C(O), C(S)N(Re), N(Re)C(S), N(Re)C(O)N(Rf), N(Re)C(=NRg)N(Rf), S(O)2N(Re), or N(Re)SO2, wherein Re, Rf and Rg are each independently selected from hydrogen or (1-2C)alkyl; and
Z2 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl or heteroaryl; and wherein Z2 is optionally substituted by one or more substituents selected from (1-6C)- alkyl, halo, (1-6C)haloalkyl, (1-6C)haloalkoxy, cyano, aryl, heteroaryl, heterocyclyl, nitro, NRhRi, ORh, C(O)Rh, C(O)ORh, OC(O)Rh, C(O)N(Rh)Ri, N(Rh)C(O)Ri, S(O)yRh (where y is 0, 1 or 2), SO2N(Rh)Ri, N(Rh)SO2Ri or (CH2)zNRhRi (where z is 1, 2 or 3), wherein any alkyl, aryl, heteroaryl or heterocyclyl moiety in a substituent group on Zz is optionally further substituted by cyano, halo, hydroxy, amino, (1-2C)alkyl or (1- 2C)alkoxy and Rh and Ri are each independently selected from hydrogen, (1-6C)alkyl, (1-6C)haloalkyl or (3-6C)cycloalkyl. Paragraph 2. The compound according to paragraph 1, wherein R1 is phenyl or 5- or 6- membered heteroaryl, optionally substituted with with one or more substituents independently selected from halo, OH, cyano , R5, OR5, S(O)0-2R5 and NR5R6,
wherein each R5 and R6 is independently H, (1-6C)alkyl or (3-7C)cycloalkyl, either of which is optionally substituted with one or more substituents selected from halo, OH, aryl and heteroaryl, wherein the aryl and heteroaryl groups are optionally substituted with one or more substituents selected from halo, OH, (1-6C)alkyl and (1-6C)haloalkyl.
Paragraph 3. The compound according to paragraph 1 or paragraph 2, wherein R1 is selected from phenyl, furyl, pyridyl, or oxazolyl, wherein a phenyl, furyl, pyridyl or oxazolyl ring is optionally substituted by halo or cyano.
Paragraph 4. The compound according to any preceding paragraph, wherein R1 is 3- cyanophenyl.
Paragraph 5. The compound according to any preceding paragraph, wherein R2 is selected from:
(i) –Z1
(ii) –CR2aR2b–L1a–Z1; or
(iii) –[CR2aR2b]2-6–L1b–Z1;
wherein
R2a and R2b are each independently selected from hydrogen, fluoro or (1-2C)alkyl; L1a is absent or selected from C(O), C(O)O or C(O)N(Ra1), wherein Ra1 is selected from hydrogen or (1-2C)alkyl; L1b is absent or selected from O, S, SO, SO2, N(Ra), C(O), C(O)O, OC(O), C(O)N(Ra), N(Ra)C(O), N(Ra)C(O)N(Rb), S(O)2N(Ra), or N(Ra)SO2, wherein Ra and Rb are each independently selected from hydrogen or (1-2C)alkyl; and
Z1 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl or heteroaryl; and wherein Z1 is optionally substituted by one or more substituents selected from (1-6C)- alkyl, halo, (1-6C)haloalkyl, (1-6C)haloalkoxy, cyano, aryl, heteroaryl, heterocyclyl, nitro, NRcRd, ORc, C(O)Rc, C(O)ORc, OC(O)Rc, C(O)N(Rc)Rd, N(Rc)C(O)Rd, S(O)yRc (where y is 0, 1 or 2), SO2N(Rc)Rd, N(Rc)SO2Rd or (CH2)zNRcRd (where z is 1, 2 or 3), wherein any alkyl, aryl, heteroaryl or heterocyclyl moiety in a substituent group on Z1 is optionally further substituted by cyano, halo, hydroxy, amino, (1-2C)alkyl or (1- 2C)alkoxy and Rc and Rd are each independently selected from hydrogen, (1-6C)alkyl, (1-6C)haloalkyl or (3-6C)cycloalkyl. Paragraph 6. The compound according to any preceding paragraph, wherein R2 is selected from:
(i) –Z1
(ii) –CR2aR2b–L1a–Z1; or
(iii) –[CR2aR2b]2-4–L1b–Z1;
wherein
R2a and R2b are each independently selected from hydrogen, fluoro or methyl;
L1a is absent;
L1b is absent or selected from O, S, SO, SO2, N(Ra), C(O), C(O)O, OC(O), C(O)N(Ra), N(Ra)C(O), N(Ra)C(O)N(Rb), S(O)2N(Ra), or N(Ra)SO2, wherein Ra and Rb are each independently selected from hydrogen or (1-2C)alkyl; and
Z1 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl or heteroaryl; and wherein Z1 is optionally substituted by one or more substituents selected from (1- 6C)alkyl, halo, (1-6C)haloalkyl, (1-6C)haloalkoxy, cyano, phenyl, a 5- or 6-membered heteroaryl, a 4- to 7-membered heterocyclyl, NRcRd, ORc, C(O)Rc, C(O)ORc,
OC(O)Rc, C(O)N(Rc)Rd, N(Rc)C(O)Rd, S(O)yRc (where y is 0, 1 or 2), SO2N(Rc)Rd, N(Rc)SO2Rd or (CH2)zNRcRd (where z is 1, 2 or 3), wherein any alkyl, aryl, heteroaryl or heterocyclyl moiety in a substituent group on Z1 is optionally further substituted by cyano, halo, hydroxy, amino, (1-2C)alkyl or (1-2C)alkoxy and Rc and Rd are each independently selected from hydrogen, (1-6C)alkyl, (1-6C)haloalkyl or (3- 6C)cycloalkyl.
Paragraph 7. The compound according to any preceding paragraph, wherein R2 is selected from:
(i) –Z1
(ii) –CH2–Z1; or
(iii) –[CH2]2-4–Z1;
wherein
Z1 is selected from (1-6C)alkyl, (3-6C)cycloalkyl or heterocyclyl; and wherein Z1 is optionally substituted by one or more substituents selected from (1-6C)alkyl, halo, (1- 6C)haloalkyl, (1-6C)haloalkoxy, cyano, NRcRd, ORc, C(O)Rc, C(O)ORc, OC(O)Rc, C(O)N(Rc)Rd, N(Rc)C(O)Rd, S(O)yRc (where y is 0, 1 or 2), SO2N(Rc)Rd, N(Rc)SO2Rd or (CH2)zNRcRd (where z is 1, 2 or 3), wherein Rc and Rd are each independently selected from hydrogen, or (1-4C)alkyl.
Paragraph 8. The compound according to any preceding paragraph, wherein R2 is selected from:
(i) –Z1: or
(ii) –CH2–Z1;
wherein
Z1 is selected from (1-6C)alkyl or (3-6C)cycloalkyl optionally substituted by one or more substituents selected from methoxy and OH;
Paragraph 9. The compound according to any preceding paragraph, wherein R3 is selected from:
(i) –Z2;
(ii) –CR3aR3b–L2a–Z2; or
(iii) –[CR3aR3b]2-6–L2b–Z2;
wherein R3a and R3b are each independently selected from hydrogen or (1-2C)alkyl;
L2a is absent or selected from C(O), C(O)O or C(O)N(Rj), wherein Rj is selected from hydrogen or (1-2C)alkyl
L2b is absent or selected from O, S, SO, SO2, N(Re), C(O), C(O)O, OC(O), C(O)N(Re), N(Re)C(O), N(Re)C(O)N(Rf), N(Re)C(=NRg)N(Rf), S(O)2N(Re), or N(Re)SO2, wherein Re, Rf and Rg are each independently selected from hydrogen or (1-2C)alkyl; and Z2 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl or heteroaryl; and wherein Z2 is optionally substituted by one or more substituents selected from (1-6C)- alkyl, halo, (1-6C)haloalkyl, (1-6C)haloalkoxy, cyano, aryl, heteroaryl, heterocyclyl, nitro, NRhRi, ORh, C(O)Rh, C(O)ORh, OC(O)Rh, C(O)N(Rh)Ri, N(Rh)C(O)Ri, S(O)yRh (where y is 0, 1 or 2), SO2N(Rh)Ri, N(Rh)SO2Ri or (CH2)zNRhRi (where z is 1, 2 or 3), wherein any alkyl, aryl, heteroaryl or heterocyclyl moiety in a substituent group on Zz is optionally further substituted by cyano, halo, hydroxy, amino, (1-2C)alkyl or (1- 2C)alkoxy and Rh and Ri are each independently selected from hydrogen, (1-6C)alkyl, (1-6C)haloalkyl or (3-6C)cycloalkyl.
Paragraph 10. The compound according to any preceding paragraph, wherein R3 is selected from:
(i) –Z2;
(ii) –CR3aR3b–L2a–Z2; or
(iii) –[CR3aR3b]2-4–L2b–Z2;
wherein
R3a and R3b are each independently selected from hydrogen or methyl;
L2a is absent;
L2b is absent or selected from O, S, SO, SO2, N(Re), C(O), C(O)O, OC(O), C(O)N(Re), or N(Re)C(O), wherein Re is selected from hydrogen or (1-2C)alkyl; and
Z2 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl or heteroaryl; and wherein Z2 is optionally substituted by one or more substituents selected from (1-6C)- alkyl, halo, (1-6C)haloalkyl, (1-6C)haloalkoxy, cyano, phenyl, 5- or 6-membered heteroaryl, 4- to 7-membered heterocyclyl, NRhRi, ORh, C(O)Rh, C(O)ORh, OC(O)Rh, C(O)N(Rh)Ri, N(Rh)C(O)Ri, S(O)yRh (where y is 0, 1 or 2), SO2N(Rh)Ri, N(Rh)SO2Ri or (CH2)zNRhRi (where z is 1, 2 or 3), wherein any alkyl, aryl, heteroaryl or heterocyclyl moiety in a substituent group on Zz is optionally further substituted by cyano, halo, hydroxy, amino, (1-2C)alkyl or (1-2C)alkoxy and Rh and Ri are each independently selected from hydrogen, (1-6C)alkyl, (1-6C)haloalkyl or (3-6C)cycloalkyl. Paragraph 11. The compound according to any any preceding paragraph, wherein R3 is selected from:
(i) –Z2;
(ii) –CH2–Z2; or
(iii) –[CH2]2-4–Z2;
wherein
Z2 is selected from 4, 5 or 6-membered heterocyclyl; and wherein Z2 is optionally substituted by one or more substituents selected from (1-6C)alkyl, halo, (1- 6C)haloalkyl, (1-6C)haloalkoxy, cyano, phenyl, 5- or 6-membered heteroaryl, 4- to 7- membered heterocyclyl, NRhRi, ORh, C(O)Rh, C(O)ORh, OC(O)Rh, C(O)N(Rh)Ri, N(Rh)C(O)Ri, S(O)yRh (where y is 0, 1 or 2), SO2N(Rh)Ri, N(Rh)SO2Ri or (CH2)zNRhRi (where z is 1, 2 or 3), wherein Rh and Ri are each independently selected from hydrogen or (1-4C)alkyl;
or Z2 is a (1-4C)alkyl optionally substituted with one substituents selected from halo (e.g. fluoro), hydroxy, (1-2C)alkoxy and (1-2C)alkyl; Paragraph 12. A compound of the formula Ia or Ib:
Figure imgf000304_0001
Ia
Figure imgf000305_0001
wherein R1, R2 and R3 are each as defined in any one of paragraphs 1 to 11.
Paragraph 13. A compound selected from any one of the following:
4-Amino-2-(3-cyanophenyl)-N-ethoxy-6-(2-fluoroethoxy)pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-6-(2-fluoroethoxy)-N-(2-hydroxyethoxy) pyrimidine-5- carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(cyclopropylmethoxy)-6-(2-fluoroethoxy)pyrimidine-5- carboxamide;
4-Amino-2-(3-cyanophenyl)-6-(2-fluoroethoxy)-N-(2-methoxyethoxy) pyrimidine-5- carboxamide;
4-Amino-2-(3-cyanophenyl)-6-(2-fluoroethoxy)-N-(2-morpholinoethoxy) pyrimidine-5- carboxamide;
4-Amino-2-(3-cyanophenyl)-6-(2-fluoroethoxy)-N-(2-hydroxy-2-methyl-propoxy)pyrimidine-5- carboxamide;
4-Amino-2-(3-cyanophenyl)-6-(2-fluoroethoxy)-N-(2-hydroxypropoxy) pyrimidine-5- carboxamide;
4-Amino-2-(3-cyanophenyl)-6-(2-fluoroethoxy)-N-(2-hydroxy-1-methyl-ethoxy)pyrimidine-5- carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2,3-dihydroxypropoxy)-6-(2-fluoroethoxy)pyrimidine-5- carboxamide;
4-Amino-2-(3-cyanophenyl)-6-(2-fluoroethoxy)-N-(morpholin-2-ylmethoxy)pyrimidine-5- carboxamide;
4-Amino-2-(3-cyanophenyl)-6-(2-fluoroethoxy)-N-[(4-methylmorpholin-2- yl)methoxy]pyrimidine-5-carboxamide; 4-Amino-N-(2-hydroxy-2-methyl-propoxy)-2-oxazol-5-yl-6-(oxetan-3-yloxy)pyrimidine-5- carboxamide;
4-Amino-2-(3-cyanophenyl)-6-(2-hydroxyethoxy)-N-(2-hydroxy-2-methyl-propoxy) pyrimidine- 5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methylpropoxy)-6-[(1r,3r)-3- aminocyclobutoxy]pyrimidine-5-carboxamide;
4-(2-Acetamidoethoxy)-6-amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy) pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-methoxy-pyrimidine-5- carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-(oxetan-3-yloxy) pyrimidine- 5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[[(4R)-2,2-dimethyl-1,3- dioxolan-4-yl]methoxy] pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-6-(2,2-difluoroethoxy)-N-(2-hydroxy-2-methyl- propoxy)pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[[rac-(4S)-2,2-dimethyl-1,3- dioxolan-4-yl]methoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-6-(2-fluoro-1-methyl-ethoxy)-N-(2-hydroxy-2-methyl- propoxy)pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methylpropoxy)-6-[(1r,3r)-3- fluorocyclobutoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(3S)-tetrahydrofuran-3- yl]oxy-pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(3S)-tetrahydropyran-3- yl]oxy-pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[rac-(3R)-tetrahydrofuran-3- yl]oxy-pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-tetrahydropyran-4-yloxy- pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[rac-(3R)-tetrahydropyran-3- yl]oxy-pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1R)-2-fluoro-1-methyl- ethoxy]pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1S)-2-fluoro-1-methyl- ethoxy]pyrimidine-5-carboxamide; 4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1R)-2-fluoro-1-methyl- ethoxy]pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1S)-2-fluoro-1-methyl- ethoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-[(1-hydroxycyclopropyl)methoxy]-6-(oxetan-3-yloxy) pyrimidine-5-carboxamide;
Ethyl (2S)-2-[[4-amino-2-(3-cyanophenyl)-6-(oxetan-3-yloxy) pyrimidine-5-carbonyl]amino] oxypropanoate;
4-Amino-6-(azetidin-3-yloxy)-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy) pyrimidine- 5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-(2-methoxyethoxy) pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1S)-2-methoxy-1-methyl- ethoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N,6-bis(2-hydroxy-2-methyl-propoxy)pyrimidine-5-carboxamide; 4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1R)-2-methoxy-1-methyl- ethoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-6-(2-fluoropropoxy)-N-(2-hydroxy-2-methyl-propoxy)pyrimidine- 5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(2-phenyl-1,3-dioxan-5- yl)oxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-(oxetan-2- ylmethoxy)pyrimidine-5-carboxamide;
4-Amino-6-(3-cyanocyclobutoxy)-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl- propoxy)pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(2S)-2- fluoropropoxy]pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(2R)-2- fluoropropoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(2S)-2- fluoropropoxy]pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(2R)-2- fluoropropoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(2S)-2-hydroxypropoxy] pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1S)-2-hydroxy-1-methyl- ethoxy] pyrimidine-5-carboxamide; 4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(2R)-2- hydroxypropoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1R)-2-hydroxy-1-methyl- ethoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(2S)-2,3-dihydroxy propoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[rac-(2R)-2,3-dihydroxy propoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-6-(oxetan-3-yloxy)-N-[(1S)-2-hydroxy-1,2-dimethyl- propoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-6-(3-hydroxycyclobutoxy)-N-(2-hydroxy-2-methyl- propoxy)pyrimidine-5-carboxamide;
or a pharmaceutically acceptable salt or solvate thereof. Paragraph 14. A pharmaceutical composition comprising a compound according to any one of paragraphs 1 to 13, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable diluent or carrier.
Paragraph 15. A compound according to any one of paragraphs 1 to 13, or a
pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to paragraph 14, for use in therapy.
Paragraph 16. A compound according to any one of paragraphs 1 to 13, or a
pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to paragraph 14, for use in the treatment of a proliferative condition.
Paragraph 17. A compound according to any one of paragraphs 1 to 13, or a
pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to paragraph 14, for use in the treatment of cancer.
Paragraph 18. A compound according to any one of paragraphs 1 to 13, or a
pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to paragraph 14, for use in the treatment of cancer, wherein the compound or pharmaceutical composition is administered in combination with one or more additional anticancer agents. Paragraph 19. A compound according to any one of paragraphs 1 to 13, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to paragraph 14, for use in the treatment of cancer, wherein the compound or pharmaceutical composition is administered in combination with one or more additional anticancer agents selected from the group consisting of:
(i) other forms of cancer immunotherapy and anti-cancer chemotherapeutic
agents;
(ii) A2b antagonists;
(iii) anti-PD-1 and PDL-1 antibodies (e.g. pembrolizumab, nivolumab,
durvalumab, avelumab and atezolizumab); and
(iv) anti-CTLA4 antibodies (e.g ipilimumab).
Paragraph 20. A method of treating a proliferative disorder in a patient in need of such treatment, the method comprising administering a therapeutically effective amount of a compound according to any one of paragraphs 1 to 13, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to paragraph 14.
Paragraph 21. A method of treating cancer in a patient in need of such treatment, the method comprising administering a therapeutically effective amount of a compound according to any one of paragraphs 1 to 13, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to paragraph 14.
Paragraph 22. A method of treating a proliferative disorder in a patient in need of such treatment, the method comprising administering a therapeutically effective amount of a compound according to any one of paragraphs 1 to 20, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to paragraph 21 in combination with one or more additional anticancer agents.
Paragraph 23. A method according to paragraph 22, wherein the one or more additional anticancer agents is selected from: (i) other forms of cancer immunotherapy and anti-cancer chemotherapeutic agents;
(ii) A2b antagonists;
(iii) anti-PD-1 and PDL-1 antibodies (e.g. pembrolizumab, nivolumab,
durvalumab, avelumab and atezolizumab); and
(iv) anti-CTLA4 antibodies (e.g ipilimumab).

Claims

Claims
1. A compound of general formula (I), or a pharmaceutically acceptable salt thereof:
Figure imgf000311_0001
wherein
R1 is selected from aryl or heteroaryl, each of which is optionally substituted with one or more substituents independently selected from halo, OH, cyano, R5, OR5, S(O)0-2R5 and NR5R6, wherein each R5 and R6 is independently H, (1-6C)alkyl or (3-7C)cycloalkyl, either of which is optionally substituted with one or more substituents selected from halo, OH, aryl and heteroaryl, wherein aryl and heteroaryl groups are optionally substituted with one or more substituents selected from halo, OH, (1-6C)alkyl and (1-6C)haloalkyl; R2 is selected from:
(i) –Z1;
(ii) –CR2aR2b–L1a–Z1; or
(iii) –[CR2aR2b]2-6–L1b–Z1;
wherein
R2a and R2b are each independently selected from hydrogen, fluoro or (1-2C)alkyl; L1a is absent or selected from C(O), C(O)O, C(O)N(Ra1) or C(S)N(Ra1), wherein Ra1 is selected from hydrogen or (1-2C)alkyl;
L1b is absent or selected from O, S, SO, SO2, N(Ra), C(O), C(O)O, OC(O), C(O)N(Ra), N(Ra)C(O), N(Ra)C(O)N(Rb), C(S)N(Ra), N(Ra)C(S), N(Ra)C(S)N(Rb), S(O)2N(Ra), or N(Ra)SO2, wherein Ra and Rb are each independently selected from hydrogen or (1- 2C)alkyl; and Z1 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl or heteroaryl; and wherein Z1 is optionally substituted by one or more substituents selected from (1-6C)- alkyl, halo, (1-6C)haloalkyl, (1-6C)haloalkoxy, cyano, aryl, heteroaryl, heterocyclyl, nitro, NRcRd, ORc, C(O)Rc, C(O)ORc, OC(O)Rc, C(O)N(Rc)Rd, N(Rc)C(O)Rd, S(O)yRc (where y is 0, 1 or 2), SO2N(Rc)Rd, N(Rc)SO2Rd, (CH2)zNRcRd (where z is 1, 2 or 3) or oxo, wherein any alkyl, aryl, heteroaryl or heterocyclyl moiety in a substituent group on Z1 is optionally further substituted by cyano, halo, hydroxy, amino, oxo, (1-2C)alkyl or (1-2C)alkoxy and Rc and Rd1 are each independently selected from hydrogen, (1- 6C)alkyl, (1-6C)haloalkyl or (3-6C)cycloalkyl;
R3 is selected from:
(i) –Z2;
(ii) –CR3aR3b–L2a–Z2; or
(iii) –[CR3aR3b]2-6–L2b–Z2;
wherein
R3a and R3b are each independently selected from hydrogen, fluoro or (1-2C)alkyl; L2a is absent or selected from C(O), C(O)O, C(O)N(Rj) or C(S)N(Rj), wherein Rj is selected from hydrogen or (1-2C)alkyl;
L2b is absent or selected from O, S, SO, SO2, N(Re), C(O), C(O)O, OC(O), C(O)N(Re), N(Re)C(O), C(S)N(Re), N(Re)C(S), N(Re)C(O)N(Rf), N(Re)C(=NRg)N(Rf), S(O)2N(Re), N(Re)SO2, N(Re)C(O)N(Rf), N(Re)C(O)O, OC(O)N(Re) wherein Re, Rf and Rg are each independently selected from hydrogen or (1-2C)alkyl; and
Z2 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl or heteroaryl; and wherein Z2 is optionally substituted by one or more substituents selected from (1-6C)- alkyl, halo, (1-6C)haloalkyl, (1-6C)haloalkoxy, cyano, aryl, heteroaryl, heterocyclyl, nitro, NRhRi, ORh, C(O)Rh, C(O)ORh, OC(O)Rh, C(O)N(Rh)Ri, N(Rh)C(O)Ri, N(Rh)C(O)N(Ri)Rk, N(Rh)C(O)ORi, OC(O)N(Rh)Ri, S(O)yRh (where y is 0, 1 or 2), SO2N(Rh)Ri, N(Rh)SO2Ri, (CH2)zNRhRi (where z is 1, 2 or 3) or oxo, wherein any alkyl, aryl, heteroaryl or heterocyclyl moiety in a substituent group on Zz is optionally further substituted by cyano, halo, hydroxy, amino, oxo, (1-2C)alkyl or (1-2C)alkoxy and Rh, Ri and Rk are each independently selected from hydrogen, (1-6C)alkyl, (1-6C)haloalkyl or (3-6C)cycloalkyl.
2. The compound according to claim 1, wherein R1 is phenyl or 5- or 6-membered heteroaryl, optionally substituted with with one or more substituents independently selected from halo, OH, cyano , R5, OR5, S(O)0-2R5 and NR5R6,
wherein each R5 and R6 is independently H, (1-6C)alkyl or (3-7C)cycloalkyl, either of which is optionally substituted with one or more substituents selected from halo, OH, aryl and heteroaryl, wherein the aryl and heteroaryl groups are optionally substituted with one or more substituents selected from halo, OH, (1-6C)alkyl and (1- 6C)haloalkyl.
3. The compound according to claim 1 or claim 2, wherein R1 is selected from phenyl, furyl, pyridyl, or oxazolyl, wherein a phenyl, furyl, pyridyl or oxazolyl ring is optionally substituted by halo or cyano.
4. The compound according to any preceding claim, wherein R1 is 3-cyanophenyl.
5. The compound according to any preceding claim, wherein R2 is selected from:
(i) –Z1
(ii) –CR2aR2b–L1a–Z1; or
(iii) –[CR2aR2b]2-6–L1b–Z1;
wherein
R2a and R2b are each independently selected from hydrogen, fluoro or (1-2C)alkyl; L1a is absent or selected from C(O), C(O)O or C(O)N(Ra1), wherein Ra1 is selected from hydrogen or (1-2C)alkyl;
L1b is absent or selected from O, S, SO, SO2, N(Ra), C(O), C(O)O, OC(O), C(O)N(Ra), N(Ra)C(O), N(Ra)C(O)N(Rb), S(O)2N(Ra), or N(Ra)SO2, wherein Ra and Rb are each independently selected from hydrogen or (1-2C)alkyl; and
Z1 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl or heteroaryl; and wherein Z1 is optionally substituted by one or more substituents selected from (1-6C)- alkyl, halo, (1-6C)haloalkyl, (1-6C)haloalkoxy, cyano, aryl, heteroaryl, heterocyclyl, nitro, NRcRd, ORc, C(O)Rc, C(O)ORc, OC(O)Rc, C(O)N(Rc)Rd, N(Rc)C(O)Rd, S(O)yRc (where y is 0, 1 or 2), SO2N(Rc)Rd, N(Rc)SO2Rd, (CH2)zNRcRd (where z is 1, 2 or 3) or oxo wherein any alkyl, aryl, heteroaryl or heterocyclyl moiety in a substituent group on Z1 is optionally further substituted by cyano, halo, hydroxy, amino, oxo, (1-2C)alkyl or (1-2C)alkoxy and Rc and Rd are each independently selected from hydrogen, (1- 6C)alkyl, (1-6C)haloalkyl or (3-6C)cycloalkyl.
6. The compound according to any preceding claim, wherein R2 is selected from:
(i) –Z1
(ii) –CR2aR2b–L1a–Z1; or
(iii) –[CR2aR2b]2-4–L1b–Z1;
wherein
R2a and R2b are each independently selected from hydrogen, fluoro or methyl;
L1a is absent;
L1b is absent or selected from O, S, SO, SO2, N(Ra), C(O), C(O)O, OC(O), C(O)N(Ra), N(Ra)C(O), N(Ra)C(O)N(Rb), S(O)2N(Ra), or N(Ra)SO2, wherein Ra and Rb are each independently selected from hydrogen or (1-2C)alkyl; and
Z1 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl or heteroaryl; and wherein Z1 is optionally substituted by one or more substituents selected from (1- 6C)alkyl, halo, (1-6C)haloalkyl, (1-6C)haloalkoxy, cyano, phenyl, a 5- or 6-membered heteroaryl, a 4- to 7-membered heterocyclyl, NRcRd, ORc, C(O)Rc, C(O)ORc,
OC(O)Rc, C(O)N(Rc)Rd, N(Rc)C(O)Rd, S(O)yRc (where y is 0, 1 or 2), SO2N(Rc)Rd, N(Rc)SO2Rd or (CH2)zNRcRd (where z is 1, 2 or 3) or oxo, wherein any alkyl, aryl, heteroaryl or heterocyclyl moiety in a substituent group on Z1 is optionally further substituted by cyano, halo, hydroxy, amino, oxo, (1-2Calkyl)(1-2C)alkyl or (1- 2C)alkoxy and Rc and Rd are each independently selected from hydrogen, (1- 6C)alkyl, (1-6C)haloalkyl or (3-6C)cycloalkyl.
7. The compound according to any preceding claim, wherein R2 is selected from:
(i) –Z1
(ii) –CH2–Z1; or
(iii) –[CH2]2-4–Z1;
wherein
Z1 is selected from (1-6C)alkyl, (3-6C)cycloalkyl or heterocyclyl; and wherein Z1 is optionally substituted by one or more substituents selected from (1-6C)alkyl, halo, (1- 6C)haloalkyl, (1-6C)haloalkoxy, cyano, NRcRd, ORc, C(O)Rc, C(O)ORc, OC(O)Rc, C(O)N(Rc)Rd, N(Rc)C(O)Rd, S(O)yRc (where y is 0, 1 or 2), SO2N(Rc)Rd, N(Rc)SO2Rd or (CH2)zNRcRd (where z is 1, 2 or 3) or oxo, wherein Rc and Rd are each
independently selected from hydrogen, or (1-4C)alkyl.
8. The compound according to any preceding claim, wherein R2 is selected from:
(i) –Z1: or
(ii) –CH2–Z1;
wherein
Z1 is selected from (1-6C)alkyl or (3-6C)cycloalkyl optionally substituted by one or more substituents selected from methoxy and OH;
9. The compound according to any preceding claim, wherein R3 is selected from:
(i) –Z2;
(ii) –CR3aR3b–L2a–Z2; or
(iii) –[CR3aR3b]2-6–L2b–Z2;
wherein
R3a and R3b are each independently selected from hydrogen or (1-2C)alkyl;
L2a is absent or selected from C(O), C(O)O or C(O)N(Rj), wherein Rj is selected from hydrogen or (1-2C)alkyl
L2b is absent or selected from e), N(R
Figure imgf000315_0001
e)C(O), N(Re)C(O)N(Rf), N(Re)C(=NRg)N(Rf), S(O)2N(Re), N(Re)C(O)N(Rf), N(Re)C(O)O, OC(O)N(Re) or N(Re)SO2, wherein Re, Rf and Rg are each independently selected from hydrogen or (1-2C)alkyl; and
Z2 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl or heteroaryl; and wherein Z2 is optionally substituted by one or more substituents selected from (1-6C)- alkyl, halo, (1-6C)haloalkyl, (1-6C)haloalkoxy, cyano, aryl, heteroaryl, heterocyclyl, nitro, NRhRi, ORh, C(O)Rh, C(O)ORh, OC(O)Rh, C(O)N(Rh)Ri, N(Rh)C(O)Ri, N(Rh)C(O)N(Ri)Rk, N(Rh)C(O)ORi, OC(O)N(Rh)Ri, S(O)yRh (where y is 0, 1 or 2), SO2N(Rh)Ri, N(Rh)SO2Ri or (CH2)zNRhRi (where z is 1, 2 or 3) or oxo, wherein any alkyl, aryl, heteroaryl or heterocyclyl moiety in a substituent group on Zz is optionally further substituted by cyano, halo, hydroxy, amino, oxo, (1-2C)alkyl or (1-2C)alkoxy and Rh, Ri and Rk are each independently selected from hydrogen, (1-6C)alkyl, (1- 6C)haloalkyl or (3-6C)cycloalkyl.
10. The compound according to any preceding claim, wherein R3 is selected from:
(i) –Z2;
(ii) –CR3aR3b–L2a–Z2; or
(iii) –[CR3aR3b]2-4–L2b–Z2;
wherein
R3a and R3b are each independently selected from hydrogen or methyl;
L2a is absent;
L2b is absent or selected from O, S, SO, SO2, N(Re), C(O), C(O)O, OC(O), C(O)N(Re), N(Re)C(O), N(Re)C(O)N(Rf), N(Re)C(O)O or OC(O)N(Re) wherein Re is selected from hydrogen or (1-2C)alkyl; and
Z2 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl or heteroaryl; and wherein Z2 is optionally substituted by one or more substituents selected from (1-6C)- alkyl, halo, (1-6C)haloalkyl, (1-6C)haloalkoxy, cyano, phenyl, 5- or 6-membered heteroaryl, 4- to 7-membered heterocyclyl, NRhRi, ORh, C(O)Rh, C(O)ORh, OC(O)Rh, C(O)N(Rh)Ri, N(Rh)C(O)Ri, N(Rh)C(O)N(Ri)Rk, N(Rh)C(O)ORi, OC(O)N(Rh)Ri, S(O)yRh (where y is 0, 1 or 2), SO2N(Rh)Ri, N(Rh)SO2Ri, (CH2)zNRhRi (where z is 1, 2 or 3) or oxo, wherein any alkyl, aryl, heteroaryl or heterocyclyl moiety in a substituent group on Zz is optionally further substituted by cyano, halo, hydroxy, amino, oxo, (1-2C)alkyl or (1-2C)alkoxy and Rh, Ri and Rk are each independently selected from hydrogen, (1- 6C)alkyl, (1-6C)haloalkyl or (3-6C)cycloalkyl.
11. The compound according to any any preceding claim, wherein R3 is selected from:
(i) –Z2;
(ii) –CH2–Z2; or
(iii) –[CH2]2-4–Z2;
wherein
Z2 is selected from 4, 5 or 6-membered heterocyclyl; and wherein Z2 is optionally substituted by one or more substituents selected from (1-6C)alkyl, halo, (1- 6C)haloalkyl, (1-6C)haloalkoxy, cyano, phenyl, 5- or 6-membered heteroaryl, 4- to 7- membered heterocyclyl, NRhRi, ORh, C(O)Rh, C(O)ORh, OC(O)Rh, C(O)N(Rh)Ri, N(Rh)C(O)Ri, N(Rh)C(O)N(Ri)Rk, N(Rh)C(O)ORi, OC(O)N(Rh)Ri, S(O)yRh (where y is 0, 1 or 2), SO2N(Rh)Ri, N(Rh)SO2Ri, (CH2)zNRhRi (where z is 1, 2 or 3) or oxo, wherein Rh,Ri and Rk are each independently selected from hydrogen or (1-4C)alkyl;
or Z2 is a (1-4C)alkyl optionally substituted with one substituents selected from halo (e.g. fluoro), hydroxy, (1-2C)alkoxy and (1-2C)alkyl;
12. A compound of the formula Ia, Ib or Ic:
Figure imgf000317_0001
Ib
Ic
wherein R1, R2 and R3 are each as defined in any one of claims 1 to 11.
13. A compound selected from any one of the following:
4-Amino-2-(3-cyanophenyl)-N-ethoxy-6-(2-fluoroethoxy)pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-6-(2-fluoroethoxy)-N-(2-hydroxyethoxy) pyrimidine-5- carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(cyclopropylmethoxy)-6-(2-fluoroethoxy)pyrimidine-5- carboxamide;
4-Amino-2-(3-cyanophenyl)-6-(2-fluoroethoxy)-N-(2-methoxyethoxy) pyrimidine-5- carboxamide;
4-Amino-2-(3-cyanophenyl)-6-(2-fluoroethoxy)-N-(2-morpholinoethoxy) pyrimidine-5- carboxamide;
4-Amino-2-(3-cyanophenyl)-6-(2-fluoroethoxy)-N-(2-hydroxy-2-methyl-propoxy)pyrimidine-5- carboxamide;
4-Amino-2-(3-cyanophenyl)-6-(2-fluoroethoxy)-N-(2-hydroxypropoxy) pyrimidine-5- carboxamide;
4-Amino-2-(3-cyanophenyl)-6-(2-fluoroethoxy)-N-(2-hydroxy-1-methyl-ethoxy)pyrimidine-5- carboxamide;
4-Amino-2-(3-cyanophenyl)-6-(2-fluoroethoxy)-N-(1H-pyrazol-3-ylmethoxy)pyrimidine-5- carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2,3-dihydroxypropoxy)-6-(2-fluoroethoxy)pyrimidine-5- carboxamide;
4-Amino-2-(3-cyanophenyl)-6-(2-fluoroethoxy)-N-(morpholin-2-ylmethoxy)pyrimidine-5- carboxamide;
4-Amino-2-(3-cyanophenyl)-6-(2-fluoroethoxy)-N-[(4-methylmorpholin-2- yl)methoxy]pyrimidine-5-carboxamide; 4-Amino-N-(2-hydroxy-2-methyl-propoxy)-2-oxazol-5-yl-6-(oxetan-3-yloxy)pyrimidine-5- carboxamide;
4-Amino-2-(3-cyanophenyl)-6-(2-hydroxyethoxy)-N-(2-hydroxy-2-methyl-propoxy) pyrimidine- 5-carboxamide;
4-Amino-2-(2;-furyl)-N-(2-hydroxy-2-methyl-propoxy)-6-(oxetan-3-yloxy)pyrimidine-5- carboxamide
4-Amino-2-(3-fluorophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-(oxetan-3-yloxy) pyrimidine-5- carboxamide;
4-Amino-2-(3-cyano-2-methyl-phenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-(oxetan-3- yloxy)pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[rac-(1R,2R)-2- hydroxycyclopentoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1R,2R)-2- hydroxycyclopentoxy]pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1S,2S)-2- hydroxycyclopentoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1R,2R)-2- hydroxycyclopentoxy]pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1S,2S)-2- hydroxycyclopentoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[rac-(1R,2S)-2- hydroxycyclopentoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1R,2S)-2- hydroxycyclopentoxy]pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1S,2R)-2- hydroxycyclopentoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1R,2S)-2- hydroxycyclopentoxy]pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1S,2R)-2- hydroxycyclopentoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(3R)-2-oxopyrrolidin-3- yl]oxy-pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(3S)-2-oxopyrrolidin-3-yl]oxy- pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[rac-(3R,4R)-4- hydroxytetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxamide; 4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(3R,4R)-4- hydroxytetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy;)-6-[(3S,4S)-4- hydroxytetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxamide
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(3R,4R)-4- hydroxytetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(3S,4S)-4- hydroxytetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[rac-(3R,4S)-4- hydroxytetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1-methyl-6-oxo-3- piperidyl)oxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methylpropoxy)-6-[(1r,3r)-3- aminocyclobutoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methylpropoxy)-6-[(1s,3s)-3-aminocyclo butoxy]pyrimidine-5-carboxamide;hydrochloride;
4-(2-Acetamidoethoxy)-6-amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy) pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-methoxy-pyrimidine-5- carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-(oxetan-3-yloxy) pyrimidine- 5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[[(4R)-2,2-dimethyl-1,3- dioxolan-4-yl]methoxy] pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-6-(2,2-difluoroethoxy)-N-(2-hydroxy-2-methyl- propoxy)pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[[(4S)-2,2-dimethyl-1,3- dioxolan-4-yl]methoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-6-(2-fluoro-1-methyl-ethoxy)-N-(2-hydroxy-2-methyl- propoxy)pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methylpropoxy)-6-[(1r,3r)-3- fluorocyclobutoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(3R)-tetrahydropyran-3- yl]oxy-pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(3S)-tetrahydropyran-3- yl]oxy-pyrimidine-5-carboxamide; 4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(3R)-tetrahydrofuran-3- yl]oxy-pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-tetrahydropyran-4-yloxy- pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1R)-2-fluoro-1-methyl- ethoxy]pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1S)-2-fluoro-1-methyl- ethoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1R)-2-fluoro-1-methyl- ethoxy]pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1S)-2-fluoro-1-methyl- ethoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(3S)-tetrahydrofuran-3- yl]oxy-pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-[(1-hydroxycyclopropyl)methoxy]-6-(oxetan-3-yloxy) pyrimidine-5-carboxamide;
Ethyl (2S)-2-[[4-amino-2-(3-cyanophenyl)-6-(oxetan-3-yloxy) pyrimidine-5-carbonyl]amino] oxypropanoate;
4-Amino-2-(3-cyanophenyl)-N-[(1-hydroxycyclobutyl)methoxy]-6-(oxetan-3-yloxy) pyrimidine- 5-carboxamide;
4-Amino-6-(azetidin-3-yloxy)-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy) pyrimidine- 5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-(2-methoxyethoxy) pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1S)-2-methoxy-1-methyl- ethoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N,6-bis(2-hydroxy-2-methyl-propoxy)pyrimidine-5-carboxamide; 4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1R)-2-methoxy-1-methyl- ethoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-6-(2-fluoropropoxy)-N-(2-hydroxy-2-methyl-propoxy)pyrimidine- 5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(2-phenyl-1,3-dioxan-5- yl)oxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-(oxetan-2- ylmethoxy)pyrimidine-5-carboxamide;
4-Amino-6-(3-cyanocyclobutoxy)-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl- propoxy)pyrimidine-5-carboxamide; 4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(2S)-2- fluoropropoxy]pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(2R)-2- fluoropropoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(2S)-2-hydroxypropoxy] pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1S)-2-hydroxy-1-methyl- ethoxy] pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(2R)-2- hydroxypropoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1R)-2-hydroxy-1-methyl- ethoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(2S)-2,3-dihydroxy propoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(2R)-2,3-dihydroxy propoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-6-(oxetan-3-yloxy)-N-[(1S)-2-hydroxy-1,2-dimethyl- propoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methylpropoxy)-6-[(1r,3r)-3- Hydroxycyclobutoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-(oxetan-3-ylmethoxy) pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-methoxy-2-methyl-propoxy)-6-(oxetan-3-yloxy) pyrimidine- 5-carboxamide;
Ethyl 2-[[4-amino-2-(3-cyanophenyl)-6-(oxetan-3-yloxy)pyrimidine-5- carbonyl]amino]oxyacetate;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methylpropoxy)-6-[(1s,3s)-3- hydroxycyclobutoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-tetrahydrothiophen-3-yloxy- pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-(1-oxothiolan-3-yl)oxy- pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-6-(1,1-dioxothiolan-3-yl)oxy-N-(2-hydroxy-2-methyl- propoxy)pyrimidine-5-carboxamide;
4-Amino-6-(1-cyanoethoxy)-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy) pyrimidine- 5-carboxamide; 4-Amino-2-(3-cyanophenyl)-6-[2-hydroxy-1-(hydroxymethyl)ethoxy]-N-(2-hydroxy-2-methyl- propoxy)pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-[(1-hydroxycyclobutyl)methoxy]-6-[(3S)-tetrahydrofuran-3- yl]oxy-pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-[(1-hydroxycyclopentyl)methoxy]-6-[(3S)-tetrahydrofuran-3- yl]oxy-pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-[(3-hydroxytetrahydrofuran-3-yl)methoxy]-6-[(3S)- tetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-[(1R)-1-oxazol-2-ylethoxy]-6-[(3S)-tetrahydrofuran-3-yl]oxy- pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-[(1S)-1-oxazol-2-ylethoxy]-6-[(3S)-tetrahydrofuran-3-yl]oxy- pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(1H-pyrazol-3-ylmethoxy)-6-[(3S)-tetrahydrofuran-3-yl]oxy- pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-1,2-dimethyl-propoxy)-6-[(3S)-tetrahydrofuran-3- yl]oxy-pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-6-[(3S)-tetrahydrofuran-3-yl]oxy-N-(1H-1,2,4-triazol-3- ylmethoxy)pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-[(1-methylimidazol-2-yl)methoxy]-6-[(3S)-tetrahydrofuran-3- yl]oxy-pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-[(3-methylimidazol-4-yl)methoxy]-6-[(3S)-tetrahydrofuran-3- yl]oxy-pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-[2-(ethylamino)-2-oxo-ethoxy]-6-[(3S)-tetrahydrofuran-3- yl]oxy-pyrimidine-5-carboxamide;
4-Amino-N-(2-amino-2-oxo-ethoxy)-2-(3-cyanophenyl)-6-[(3S)-tetrahydrofuran-3-yl]oxy- pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-6-[(3S)-tetrahydrofuran-3-yl]oxy-N-(1H-triazol-5- ylmethoxy)pyrimidine-5-carboxamide;
4-Amino-N-(2-amino-2-methyl-propoxy)-2-(3-cyanophenyl)-6-[3S)-tetrahydrofuran-3-yl]oxy- pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-phenoxy-6-[(3S)-tetrahydrofuran-3-yl]oxy-pyrimidine-5- carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(1H-pyrazol-4-ylmethoxy)-6-[(3S)-tetrahydrofuran-3-yl]oxy- pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-6-[(3S)-tetrahydrofuran-3-yl]oxy-N-[(1S)-1-(4H-1,2,4-triazol-3- yl)ethoxy]pyrimidine-5-carboxamide; 4-Amino-2-(3-cyanophenyl)-6-[(3S)-tetrahydrofuran-3-yl]oxy-N-[(1R)-1-(4H-1,2,4-triazol-3- yl)ethoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-[(1R)-2-hydroxy-1,2-dimethyl-propoxy]-6-[(3S)- tetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-[(1S)-2-hydroxy-1,2-dimethyl-propoxy]-6-[(3S)- tetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-[(1R)-2-hydroxy-1,2-dimethyl-propoxy]-6-[(3S)- tetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-[(1S)-2-hydroxy-1,2-dimethyl-propoxy]-6-[(3S)- tetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-[(5-isopropyl-4H-1,2,4-triazol-3-yl)methoxy]-6-[(3S)- tetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-6-[(3S)-tetrahydrofuran-3-yl]oxy-N-(2H-tetrazol-5- ylmethoxy)pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(1H-imidazol-2-ylmethoxy)-6-[(3S)-tetrahydrofuran-3-yl]oxy- pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1R)-1- (hydroxymethyl)propoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(2R)-2- hydroxybutoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[rac-(1R,3R)-3- hydroxycyclopentoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[rac-(1S,3S)-3- hydroxycyclopentoxy]pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1R,3R)-3- hydroxycyclopentoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1S,3S)-3- hydroxycyclopentoxy]pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1R,3R)-3- hydroxycyclopentoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(oxazol-2-ylmethoxy)-6-[(3S)-tetrahydrofuran-3-yl]oxy- pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-[(3-hydroxyazetidin-3-yl)methoxy]-6-[(3S)-tetrahydrofuran-3- yl]oxy-pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(2R,3S)-2- (hydroxymethyl)tetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxamide; 4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(3S,5S)-5- (hydroxymethyl)tetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1R,3S)-3- acetamidocyclopentoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1S,3R)-3- acetamidocyclopentoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyano-2-methyl-phenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(3S)- tetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-6-[(1r,3r)-3-(difluoromethyl)cyclobutoxy]-N-(2-hydroxy-2-methyl- propoxy)pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-6-[(1s,3s)-3-(difluoromethyl)cyclobutoxy]-N-(2-hydroxy-2-methyl- propoxy)pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-6-[(1r,3r)-3-(difluoromethyl)cyclobutoxy]-N-(2-hydroxy-2-methyl- propoxy)pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-6-[(1s,3s)-3-(difluoromethyl)cyclobutoxy]-N-(2-hydroxy-2-methyl- propoxy)pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-6-[(1r, 3r)-3-(difluoromethyl)cyclobutoxy]-N-(2-hydroxy-2-methyl- propoxy)pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-6-[(1s, 3s)-3-(difluoromethyl)cyclobutoxy]-N-(2-hydroxy-2- methyl-propoxy)pyrimidine-5-carboxamide;
4-Amino-6-((1r, 3r)-3-cyanocyclobutoxy)-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl- propoxy)pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-6-((1s,3s)-3-fluorocyclobutoxy)-N-(2-hydroxy-2-methyl- propoxy)pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-(3-pyridyloxy)pyrimidine-5- carboxamide;
4-amino-2-(3-cyanophenyl)-6-(3,3-difluorocyclobutoxy)-N-(2-hydroxy-2-methyl- propoxy)pyrimidine-5-carboxamide;
4-Amino-N-(2-hydroxy-2-methyl-propoxy)-2-(1H-indol-7-yl)-6-[(3S)-tetrahydrofuran-3-yl]oxy- pyrimidine-5-carboxamide;
4-Amino-N-(2-hydroxy-2-methyl-propoxy)-2-(1H-indol-4-yl)-6-tetrahydrofuran-3-yloxy- pyrimidine-5-carboxamide;
4-Amino-2-(3-cyano-2-methoxy-phenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(3S)- tetrahydrofuran-3-yl]oxy-pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1S)-1-methyl-2- (propanoylamino)ethoxy]pyrimidine-5-carboxamide; 4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(2S)-2- hydroxybutoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[[(2S)-5-oxopyrrolidin-2- yl]methoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1S)-1-methyl-2-ureido- ethoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[rac-(1S,3R)-3- hydroxycyclopentoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1R,3S)-3- hydroxycyclopentoxy]pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1S,3R)-3- hydroxycyclopentoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1R,3S)-3- hydroxycyclopentoxy]pyrimidine-5-carboxamide;
4-amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1S,3R)-3- hydroxycyclopentoxy]pyrimidine-5-carboxamide;
Methyl N-[2S)-2-[6-amino-2-(3-cyanophenyl)-5-[(2-hydroxy-2-methyl- propoxy)carbamoyl]pyrimidin-4-yl]oxypropyl]carbamate;
4-Amino-2-(3-cyanophenyl)-6-(1,1-dioxothian-4-yl)oxy-N-(2-hydroxy-2-methyl- propoxy)pyrimidine-5-carboxamide;
(1s,4s)-4-{[6-amino-2-(3-cyanophenyl)-5-[(2-hydroxy-2-methylpropoxy)carbamoyl] pyrimidin- 4-yl]oxy}thian-1-ium-1-olate;
(1r,4r)-4-{[6-amino-2-(3-cyanophenyl)-5-[(2-hydroxy-2-methylpropoxy)carbamoyl]pyrimidin-4- yl]oxy}thian-1-ium-1-olate;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1R)-2-acetamido-1-methyl- ethoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1S)-2-acetamido-1-methyl- ethoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-6-(2-fluoroethoxy)-N-(1H-1,2,4-triazol-3-ylmethoxy)pyrimidine-5- carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1s,3s)-3- methoxycyclobutoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(1r,3r)-3- methoxycyclobutoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-6-(3-hydroxy-3-methyl-cyclobutoxy)-N-(2-hydroxy-2-methyl- propoxy)pyrimidine-5-carboxamide; 4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-[(5-oxopyrrolidin-3- yl)methoxy]pyrimidine-5-carboxamide;
4-Amino-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propoxy)-6-phenoxy-pyrimidine-5- carboxamide;
or a pharmaceutically acceptable salt or solvate thereof.
14. A pharmaceutical composition comprising a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, in admixture with a
pharmaceutically acceptable diluent or carrier.
15. A compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 14, for use in therapy.
16. A compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 14, for use in the treatment of a proliferative condition.
17. A compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 14, for use in the treatment of cancer.
18. A compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 14, for use in the treatment of cancer, wherein the compound or pharmaceutical composition is administered in combination with one or more additional anticancer agents.
19. A compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 14, for use in the treatment of cancer, wherein the compound or pharmaceutical composition is administered in combination with one or more additional anticancer agents selected from the group consisting of:
(i) other forms of cancer immunotherapy and anti-cancer chemotherapeutic agents; (ii) A2b antagonists;
(iii) anti-PD-1 and PDL-1 antibodies (e.g. pembrolizumab, nivolumab, durvalumab,
avelumab and atezolizumab); and
(iv) anti-CTLA4 antibodies (e.g ipilimumab).
20. A method of treating a proliferative disorder in a patient in need of such treatment, the method comprising administering a therapeutically effective amount of a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 14.
21. A method of treating cancer in a patient in need of such treatment, the method comprising administering a therapeutically effective amount of a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 14.
22. A method of treating a proliferative disorder in a patient in need of such treatment, the method comprising administering a therapeutically effective amount of a compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 21 in combination with one or more additional anticancer agents.
23. A method according to claim 22, wherein the one or more additional anticancer agents is selected from:
(i) other forms of cancer immunotherapy and anti-cancer chemotherapeutic agents; (ii) A2b antagonists;
(iii) anti-PD-1 and PDL-1 antibodies (e.g. pembrolizumab, nivolumab, durvalumab,
avelumab and atezolizumab); and
(iv) anti-CTLA4 antibodies (e.g ipilimumab).
PCT/GB2020/051432 2019-06-13 2020-06-12 Hydroxamate compounds as antagonists of the adenosine a2a receptor WO2020260857A1 (en)

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