WO2017178844A1 - Heterocyclic compounds as ret kinase inhibitors - Google Patents

Heterocyclic compounds as ret kinase inhibitors Download PDF

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Publication number
WO2017178844A1
WO2017178844A1 PCT/GB2017/051076 GB2017051076W WO2017178844A1 WO 2017178844 A1 WO2017178844 A1 WO 2017178844A1 GB 2017051076 W GB2017051076 W GB 2017051076W WO 2017178844 A1 WO2017178844 A1 WO 2017178844A1
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Prior art keywords
amino
alkyl
pyrazolo
pyrimidin
indole
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PCT/GB2017/051076
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French (fr)
Inventor
Allan Jordan
Rebecca NEWTON
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Cancer Research Technology Limited
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Priority to IL297192A priority Critical patent/IL297192A/en
Priority to CA3020778A priority patent/CA3020778A1/en
Priority to ES17719687T priority patent/ES2886587T3/en
Priority to JP2018554114A priority patent/JP6943876B2/en
Priority to RS20211115A priority patent/RS62322B1/en
Priority to KR1020187032842A priority patent/KR102390578B1/en
Application filed by Cancer Research Technology Limited filed Critical Cancer Research Technology Limited
Priority to CN202211269931.2A priority patent/CN115650985A/en
Priority to AU2017250448A priority patent/AU2017250448C1/en
Priority to PL17719687T priority patent/PL3442980T3/en
Priority to SG11201808878UA priority patent/SG11201808878UA/en
Priority to LTEPPCT/GB2017/051076T priority patent/LT3442980T/en
Priority to RU2018138471A priority patent/RU2742115C2/en
Priority to BR112018071097-0A priority patent/BR112018071097B1/en
Priority to EP21172597.3A priority patent/EP3960180A1/en
Priority to IL289793A priority patent/IL289793B2/en
Priority to SI201730892T priority patent/SI3442980T1/en
Priority to US16/093,854 priority patent/US10954241B2/en
Priority to EP17719687.0A priority patent/EP3442980B1/en
Priority to CN201780031509.4A priority patent/CN109195972B/en
Priority to KR1020227013172A priority patent/KR20220054894A/en
Priority to BR122023026297-2A priority patent/BR122023026297A2/en
Priority to DK17719687.0T priority patent/DK3442980T3/en
Priority to MX2018012609A priority patent/MX2018012609A/en
Publication of WO2017178844A1 publication Critical patent/WO2017178844A1/en
Priority to IL262185A priority patent/IL262185B/en
Priority to AU2020220079A priority patent/AU2020220079B2/en
Priority to US17/165,151 priority patent/US11548896B2/en
Priority to HRP20211362TT priority patent/HRP20211362T1/en
Priority to CY20211100784T priority patent/CY1124478T1/en
Priority to AU2022203916A priority patent/AU2022203916A1/en
Priority to US17/992,049 priority patent/US20230339954A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • 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
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention relates to certain compounds that function as inhibitors of RET (rearranged during transfection) kinase enzyme activity.
  • 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 proliferative disorders, such as cancer, as well as other diseases or conditions in which RET kinase activity is implicated.
  • Cancer is caused by uncontrolled and unregulated cellular proliferation. Precisely what causes a cell to become malignant and proliferate in an uncontrolled and unregulated manner has been the focus of intense research over recent decades. This research has led to the identification of a number of molecular targets associated with key metabolic pathways that are known to be associated with malignancy.
  • RET REarranged during Transfection
  • RTK receptor tyrosine kinase
  • GDNF glial derived neurtrophic factor
  • GFRa glycosyl phosphatidylinositol
  • Ligand binding to the corresponding GFRa co-receptor triggers RET dimerization followed by trans-phosphorylation of intracellular signalling cascades.
  • MTC medullary thyroid carcinomas
  • RET inhibition is a secondary pharmacology of this agent, which also targets VEGFR2 (Vascular endothelial growth factor receptor, also known as KDR - kinase insert domain receptor) and EGFR (epidermal growth factor receptor).
  • VEGFR2 Vascular endothelial growth factor receptor
  • EGFR epidermal growth factor receptor
  • the clinical benefit in MTC is considered to be due to RET inhibition but is unfortunately accompanied by significant side effects (rash, hypertension, diarrhoea) due to inhibition of EGFR and/or VEGFR.
  • vandetanib also exhibits off-target activity versus hERG. Collectively all of these unwanted pharmacological activities may compromise its use in advanced MTC and also its extrapolation into earlier clinical settings (e.g. adjuvant).
  • RET V804M RET V804M
  • inhibitors that show less inhibition of KDR. It is anticipated that these more selective inhibitors will produce the desired therapeutic benefits associated with RET inhibition without the side effects associated with significant KDR inhibition.
  • Such inhibitors will offer the potential of better therapy for cancers such as MTC and NSCLC and will widen the scope for the clinical use of RET inhibitors in earlier disease settings.
  • Another object of the present invention is to provide inhibitors of RET kinase enzyme activity that show a greater selectivity for the inhibition of RET kinase relative to the inhibition of KDR.
  • 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.
  • RET kinase enzyme activity or mutant forms thereof (e.g. RET V804M ), 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.
  • RET kinase enzyme activity or mutant forms thereof (e.g. RET V804M ), over KDR enzyme activity 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.
  • a method of inhibiting cell proliferation, in vitro or in vivo comprising contacting a cell with an effective amount of a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.
  • a method of treating a disease or disorder in which RET kinase 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.
  • 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.
  • a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein for use in therapy 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 is human cancer.
  • a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein for use in the inhibition of mutant forms of RET kinase enzyme activity e.g. RET V804M kinase enzyme activity.
  • the proliferative disorder is cancer, suitably a human cancer (for example medullary thyroid cancer (MTC) or non-small cell lung cancer).
  • MTC medullary thyroid cancer
  • non-small cell lung cancer for example medullary thyroid cancer (MTC) or non-small cell lung cancer.
  • RET kinase enzyme activity or mutant forms thereof (e.g. RET V804M ).
  • RET kinase enzyme activity or mutant forms thereof (e.g. RET V804M ), relative to KDR enzyme activity.
  • 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 RET kinase activity is implicated.
  • 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 f-butyl.
  • phenyl(1-6C)alkyl includes phenyl(1-4C)alkyl, benzyl, 1-phenylethyl and 2-phenylethyl.
  • (m-nC) or "(m-nC) group” used alone or as a prefix, refers to any group having m to n carbon atoms.
  • alkylene is an alkyl, alkenyl, or alkynyl group that is positioned between and serves to connect two other chemical groups.
  • (1- 6C)alkylene means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms, for example, methylene, ethylene, propylene, 2-methylpropylene, pentylene, and the like.
  • (2-6C)alkenylene means a linear divalent hydrocarbon radical of two to six carbon atoms or a branched divalent hydrocarbon radical of three to six carbon atoms, containing at least one double bond, for example, as in ethenylene, 2,4-pentadienylene, and the like.
  • (2-6C)alkynylene means a linear divalent hydrocarbon radical of two to six carbon atoms or a branched divalent hydrocarbon radical of three to six carbon atoms, containing at least one triple bond, for example, as in ethynylene, propynylene, and butynylene and the like.
  • (3-8C)cycloalkyl means a hydrocarbon ring containing from 3 to 8 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or bicyclo[2.2.1]heptyl.
  • (3-8C)cycloalkenyl means a hydrocarbon ring containing from 3 to 8 carbon atoms and 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-2/-/-thiopyran, and hexahydrothiepine.
  • heterocycles include dihydro-oxathiolyl, tetrahydro-oxazolyl, tetrahydro-oxadiazolyl, tetrahydrodioxazolyl, tetrahydro-oxathiazolyl, hexahydrotriazinyl, tetrahydro-oxazinyl, morpholinyl, thiomorpholinyl, tetrahydropyrimidinyl, dioxolinyl, octahydrobenzofuranyl, octahydrobenzimidazolyl, and octahydrobenzothiazolyl.
  • 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.
  • 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 1-4, 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. 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.
  • 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, naphthy
  • 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 non-aromatic, saturated or partially saturated ring, provided at least one ring contains one or more heteroatoms selected from nitrogen, oxygen or sulfur.
  • partially aromatic heteroaryl groups include for example, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 2-oxo- 1 ,2,3,4-tetrahydroquinolinyl, dihydrobenzthienyl, dihydrobenzfuranyl, 2,3-dihydro- benzo[1 ,4]dioxinyl, benzo[1 ,3]dioxolyl, 2,2-dioxo-1 ,3-dihydro-2-benzothienyl, 4,5,6,7- tetrahydrobenzofuranyl, indolinyl, 1 ,2,3,4-tetrahydro-1 ,8-naphthyridinyl,
  • heteroaryl groups examples include but are not limited to pyrrolyl, furanyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl and tetrazolyl groups.
  • heteroaryl groups examples 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.
  • heteroaralkyi 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.
  • wherein a/any CH, CH2, CH3 group or heteroatom (i.e. N H) 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:
  • HET is selected from one of the following:
  • Ri is selected from hydrogen, (1-4C)haloalkyl, (1-4C)haloalkoxy or a group of the formula:
  • L is absent or (1-5C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkyl or oxo;
  • Y is absent or O, S, SO, S0 2 , N(R a ), C(O), C(0)0, OC(O), C(0)N(R a ), N(R a )C(0), N(Ra)C(0)N(R b ), N(R a )C(0)0, OC(0)N(R a ), S(0) 2 N(R a ), or N(R a )S02, wherein R a and Rb are each independently selected from hydrogen or (1-4C)alkyl; and
  • Q is hydrogen, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, aryl, (3- 10C)cycloalkyl, (3-10C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Q is optionally further substituted by one or more substituent groups independently selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, amino, (1-4C)aminoalkyl, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, mercapto, ureido, NR c Rd, OR c , C(0)R c , C(0)ORc, OC(0)Rc, C(0)N(Rd)Rc, N(R d )C(0)R c , S(0) y R c (where y is 0, 1 or 2), S0 2 N(Rd)Rc, N(R d )
  • Q is optionally substituted by a group of the formula:
  • Li is absent or (1-3C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkyl or oxo;
  • L Q i is absent or selected from or O, S, SO, S0 2 , N(R f ), C(O), C(0)0, OC(O), C(0)N(R f ), N(R f )C(0), N(R g )C(0)N(R f ), N(R f )C(0)0, OC(0)N(R f ), S(0) 2 N(R f ), or N(R f )S0 2 , wherein R f and R g are each independently selected from hydrogen or (1- 2C)alkyl; and
  • Zi is hydrogen, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, (3- 8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Zi is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, mercapto, ureido, aryl, heteroaryl, heterocycyl, (3-6C)cycloalkyl, NRhRi, ORh, C(0)R h , C(0)OR h , OC(0)R h , C(0)N(Ri)R h , N(Ri)C(0)R h , S(0) ya Rh (where y
  • W is selected from O, S or NRj, wherein Rj is selected from hydrogen or (1- 2C)alkyl;
  • bonds a, b, c and d are independently selected from a single or double bond
  • Xi and X2 are each independently selected from N or CRkWhen bond a is a double bond, or NRi or CRkRi when bond a is a single bond;
  • Rk is selected from hydrogen, halo, (1-4C)alkyl, (1-4C)alkoxy, amino, (1-4C)alkylamino, (1-4C)dialkylamino, cyano, (2C)alkynyl, C(0)R k i, C(0)ORki, OC(0)Rki, C(0)N(R k2 )Rki, N(R k2 )C(0)R k i, S(0) yb R k i (where y b is 0, 1 or 2), S0 2 N(R k2 )Rki, N(R k2 )S0 2 R k i or (CH 2 ) zb NRkiRk 2 (where z b is 1 , 2 or 3); wherein said (1-4C)alkyl is optionally substituted by one or more substituents selected from amino, hydroxy, (1-2C)alkoxy or halo;
  • Ri is selected from hydrogen or (1-4C)alkyl
  • Rki and Rk 2 are each independently selected from hydrogen or (1- 4C)alkyl
  • Rm is selected from hydrogen, halo, (1-4C)alkyl, (1-4C)alkoxy, amino, (1-4C)alkylamino, (1-4C)dialkylamino, cyano, (2C)alkynyl, C(0)R m i, C(0)ORmi, OC(0)Rmi, C(0)N(R m2 )R m1 , N(R m2 )C(0)R m i, S(0) yc Rmi (where y c is 0, 1 or 2), S0 2 N(R m2 )R m i, N(R m2 )S0 2 R m i or
  • R n is selected from hydrogen or (1-4C)alkyl
  • Rmi and R m2 are each independently selected from hydrogen or (1- 4C)alkyl;
  • X 4 is selected from N or CR 0 when bond d is a double bond, or NR X or CR 0 R X when bond d is a single bond;
  • Ro is selected from hydrogen, halo, (1-4C)alkyl, (1-4C)alkoxy, amino, (1-4C)alkylamino, (1-4C)dialkylamino, cyano, (2C)alkynyl, C(0)R 0 i, C(0)ORoi, OC(0)Roi, C(0)N(R o2 )Roi, N(R o2 )C(0)R 0 i, S(0) yd R 0 i (where y d is 0, 1 or 2), S0 2 N(Ro 2 )Roi, N(R o2 )S0 2 R 0 i or (CH 2 ) Z dNR 0 iR o2 (where z d is 1 , 2 or 3); wherein said (1-4C)alkyl is optionally substituted by one or more substituents selected from amino, hydroxy, (1-2C)alkoxy or halo;
  • Rx is selected from hydrogen or (1-4C)alkyl
  • R01 and R o2 are each independently selected from hydrogen or (1- 4C)alkyl
  • R 2 is selected from hydrogen, (1-4C)alkyl or a group of the formula:
  • L 2 is absent or (1-3C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkyl or oxo;
  • Y 2 is absent or C(O), C(0)0, C(0)N(R p ), wherein R p is selected from hydrogen or (1-4C)alkyl;
  • Q 2 is hydrogen, (1-6C)alkyl, aryl, (3-8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Q 2 is optionally further substituted by one or more substituent groups independently selected from (1- 4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, NR q R r , OR q , wherein R q and R r are each independently selected from hydrogen, (1-4C)alkyl or (3- 6C)cycloalkyl;
  • R3 is selected from a group of the formula:
  • Y 3 is C(O), C(0)N(R y ), C(0)N(R y )0, N(R y )(0)C, C(0)0, OC(O), N(R y )C(0)N(Ryi), S0 2 N(R y ), N(R y )S0 2 , oxazolyl, triazolyl, oxadiazolyl, thiazolyl, imidazolyl, thiadiazolyl, pyridinyl, pyrazolyl, pyrrolyl or tetrazolyl, wherein R y and R y i are independently selected from hydrogen or (1-2C)alkyl; and
  • Q 3 is hydrogen, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, (3-8C)cycloalkyl, (3- 8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Q3 is optionally further substituted by one or more substituent groups independently selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, NR z R aa , OR z , wherein R z and R aa are each independently selected from hydrogen, (1- 4C)alkyl or (3-6C)cycloalkyl; or Q3 is optionally substituted by a group of the formula:
  • l_4 is absent or (1-3C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkyl or oxo;
  • L Q4 is absent or selected from or O, S, SO, S0 2 , N(R ab ), C(O), C(0)0, OC(O), C(0)N(R ab ), N(R ab )C(0), N(R ac )C(0)N(R ab ), N(R ab )C(0)0, OC(0)N(R ab ), S(0) 2 N(R ab ), or N(R ab )S0 2 , wherein R ab and R ac are each independently selected from hydrogen or (1-2C)alkyl; and
  • Z 4 is hydrogen, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, (3- 8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Z4 is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, mercapto, ureido, aryl, heteroaryl, heterocycyl, (3-6C)cycloalkyl, NR a dR ae , OR ad , C(0)R ad , C(0)OR ad , OC(0)R ad , C(0)N(R ae )R ad , N(R a
  • Q3 and R y are linked such that, together with the nitrogen atom to which they are attached, they form a 4-7 membered heterocyclic ring which is optionally substituted by one or more substituents selected from (1- 4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1- 4C)alkylamino, amino, cyano or hydroxyl;
  • Particular compounds of the invention include, for example, compounds of the Formula I, or pharmaceutically acceptable salts and/or solvates thereof, wherein, unless otherwise stated, each of HET, Ri , Ri a , Rib, W, bonds a, b, c and d, Xi , X2, X3, X 4 , 2 and R3 and any associated substituent groups has any of the meanings defined hereinbefore or in any of paragraphs (1) to (68) hereinafter: -
  • HET is selected from one of the following:
  • HET is selected from one of the following:
  • Ri is selected from hydrogen, (1-4C)haloalkyl, (1-4C)haloalkoxy or a group of the formula:
  • L is absent or (1-5C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkyl or oxo;
  • Y is absent or O, S, SO, S0 2 , N(R a ), C(O), C(0)0, OC(O), C(0)N(R a ), N(R a )C(0), S(0) 2 N(R a ), or N(R a )S0 2 , wherein R a is selected from hydrogen or (1-4C)alkyl; and
  • Q is hydrogen, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, aryl, (3- 10C)cycloalkyl, (3-10C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Q is optionally further substituted by one or more substituent groups independently selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, amino, (1-4C)aminoalkyl, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, mercapto, ureido, NR c Rd, OR c , C(0)R c , C(0)ORc, OC(0)Rc, C(0)N(Rd)Rc, N(R d )C(0)R c , S(0) y R c (where y is 0, 1 or 2), S0 2 N(Rd)Rc, N(R d )
  • Q is optionally substituted by a group of the formula:
  • Li is absent or (1-3C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkyl;
  • L Q i is absent or selected from or O, S, SO, S0 2 , N(R f ), C(O), C(0)0, OC(O), C(0)N(R f ), N(R f )C(0), N(R f )C(0)0, S(0) 2 N(R f ), or N(Rf)S02, wherein Rf is selected from hydrogen or (1- 2C)alkyl; and
  • Zi is hydrogen, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, (3- 8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Zi is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, mercapto, ureido, aryl, heteroaryl, heterocycyl, (3-6C)cycloalkyl, NRhR, or ORh, wherein Rh and R, are each independently selected from hydrogen, (1-4C)alkyl or (3-6C)cycloalkyl;
  • Ri is selected from hydrogen, (1-4C)haloalkyl, (1-4C)haloalkoxy or a group of the formula:
  • L is absent or (1-3C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkyl or oxo;
  • Y is absent or O, N(R a ), C(O), C(0)0, OC(O), C(0)N(R a ), N(R a )C(0), S(0)2N(R a ), or N(R a )S02, wherein R a is selected from hydrogen or (1- 4C)alkyl;
  • Q is hydrogen, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, aryl, (3- 10C)cycloalkyl, (3-10C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Q is optionally further substituted by one or more substituent groups independently selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, amino, (1-4C)aminoalkyl, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, mercapto, ureido, NR c Rd, OR c , C(0)R c , C(0)ORc, OC(0)Rc, C(0)N(Rd)Rc, N(R d )C(0)R c , S(0) y R c (where y is 0, 1 or 2), S0 2 N(Rd)Rc, N(R d )
  • Q is optionally substituted by a group of the formula:
  • Li is absent or (1-3C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkyl;
  • L Q i is absent or selected from or C(O), C(0)0, OC(O), C(0)N(R f ), N(R f )C(0) or N(R f )C(0)0, wherein R f is selected from hydrogen or (1-2C)alkyl;
  • Zi is hydrogen, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, (3- 8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Zi is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano, hydroxy, NRhR, or ORh, wherein Rh and R, are each independently selected from hydrogen, (1-4C)alkyl or cyclopropyl; (10) Ri is selected from hydrogen, (1-4C)haloalkyl, (1-4C)haloalkoxy or a group of the formula:
  • L is absent or (1-3C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkyl or oxo;
  • Y is absent or O, N(R a ), C(O), C(0)0, OC(O), C(0)N(R a ), N(R a )C(0), S(0)2N(R a ), or N(R a )S02, wherein R a is selected from hydrogen or (1- 4C)alkyl;
  • Q is hydrogen, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, aryl, (3- 10C)cycloalkyl, (3-10C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Q is optionally further substituted by one or more substituent groups independently selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, amino, (1-4C)aminoalkyl, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, mercapto, ureido, NR c Rd, OR c , C(0)R c , C(0)ORc, OC(0)Rc, C(0)N(Rd)Rc, N(R d )C(0)R c , S(0) y R c (where y is 0, 1 or 2), S0 2 N(Rd)Rc, N(R d )
  • Ri is selected from hydrogen, (1-4C)haloalkyl, (1-4C)haloalkoxy or a group of the formula:
  • L is absent or (1-3C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkyl or oxo;
  • Y is absent or C(O), C(0)0, OC(O), C(0)N(R a ) or N(R a )C(0), wherein R a is selected from hydrogen or (1-4C)alkyl; and Q is hydrogen, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, aryl, (3- 10C)cycloalkyl, (3-10C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Q is optionally further substituted by one or more substituent groups independently selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, amino, (1-4C)aminoalkyl, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, mercapto, ureido, NR c Rd, OR c , C(0)R c , C(0)ORc, OC(0)Rc, C(0)
  • Ri is selected from hydrogen, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-6C)alkyl, (2- 6C)alkenyl, (2-6C)alkynyl, aryl, (3-10C)cycloalkyl, (3-10C)cycloalkenyl, heteroaryl or heterocyclyl; wherein each of said substituents is optionally further substituted by one or more substituent groups independently selected from (1-4C)alkyl, halo, (1- 4C)haloalkyl, (1-4C)haloalkoxy, amino, (1-4C)aminoalkyl, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, mercapto, ureido, NR c R d , OR c , C(0)R c , C(0)OR c , OC(0)R c , C(0)N(R d )Rc, N(R d )C(0)Rc,
  • Ri is selected from hydrogen, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-6C)alkyl, (3- 10C)cycloalkyl or heterocyclyl; wherein each of said substituents is optionally further substituted by one or more substituent groups independently selected from (1- 4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, amino, (1-4C)aminoalkyl, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, mercapto, ureido, NR c R d , OR c or
  • Ri is selected from hydrogen, (1-6C)alkyl, 4-7 membered heterocyclyl or (3- 10C)cycloalkyl; wherein each of said substituents is optionally further substituted by one or more substituent groups independently selected from (1-4C)alkyl, halo, amino, (1-4C)aminoalkyl, cyano, hydroxy, carboxy, NR c R d , OR c , S(0) 2 R c or Si(R d )(R c )R e ; wherein R c , R d and R e are each independently selected from hydrogen or (1-4C)alkyl;
  • Ri is selected from hydrogen, (4-6C)alkyl or 4-7 membered heterocyclyl; wherein each of said substituents is optionally further substituted by one or more substituent groups independently selected from (1-4C)alkyl, halo, amino, (1-4C)aminoalkyl, cyano, hydroxy, carboxy, NR c Rd, OR c orS(0)2R c ; wherein R c , and Rd are each independently selected from hydrogen or (1-4C)alkyl;
  • Ri is selected from hydrogen, (1-6C)alkyl or (3-10C)cycloalkyl; wherein each of said substituents is optionally further substituted by one or more substituent groups independently selected from (1-4C)alkyl, halo, amino, (1-4C)aminoalkyl, cyano, hydroxy, carboxy, NR c Rd, OR c or Si(Rd)(R c )R e ; wherein R c , Rd and R e are each independently selected from hydrogen or (1-4C)alkyl;
  • Ri is selected from hydrogen, (1-6C)alkyl or (3-6C)cycloalkyl; wherein each of said substituents is optionally further substituted by one or more substituent groups independently selected from (1-4C)alkyl, OR c or Si(Rd)(R c )R e ; wherein R c , Rd and R e are each independently selected from hydrogen or (1-2C)alkyl;
  • Ri is a (1-6C)alkyl or (4-6C)cycloalkyl
  • Ri is a (4-6C)alkyl
  • Ri is terf-butyl
  • Ria and Rib are each independently selected from hydrogen, (1-4C)alkyl, halo, (1- 4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano or hydroxy;
  • Ria and Rib are each independently selected from hydrogen, (1-4C)alkyl, halo, (1- 4C)haloalkyl, (1-4C)alkoxy, amino, cyano or hydroxy;
  • Ria and Rib are each independently selected from hydrogen or (1-4C)alkyl
  • Ria and Rib are each hydrogen
  • W is selected from O or S;
  • bonds a, b, c and d are all double bonds
  • bonds a, b, c and d are all single bonds
  • Xi and X2 are each independently selected from N or CRkWhen bond a is a double bond, or NRi or CRkRi when bond a is a single bond;
  • Rk is selected from hydrogen, halo, (1-4C)alkyl, (1-4C)alkoxy, amino, (1-4C)alkylamino, (1-4C)dialkylamino, cyano, (2C)alkynyl, wherein said (1-4C)alkyl is optionally substituted by one or more substituents selected from amino, hydroxy, (1-2C)alkoxy or halo; and Ri is selected from hydrogen or (1-4C)alkyl;
  • Xi and X2 are each independently selected from N or CRkWhen bond a is a double bond, or NRi or CR k Ri when bond a is a single bond;
  • R k is selected from hydrogen, halo, (1-4C)alkyl, (1-4C)alkoxy, amino, (1-4C)alkylamino, (1-4C)dialkylamino, cyano, (2C)alkynyl; and
  • Ri is selected from hydrogen or (1-4C)alkyl
  • Xi and X2 are each independently selected from N or CRk and bond a is a double bond, wherein Rk is selected from hydrogen, halo, (1-4C)alkyl or amino;
  • Xi and X2 are CRk and bond a is a double bond, wherein Rk is selected from hydrogen, halo or (1-4C)alkyl;
  • Xi and X2 are each independently selected from N or CH and bond a is a double bond;
  • Xi and X2 are CH and bond a is a double bond
  • X3 is selected from N or CRi when bond b is a double bond, or NR n or CR m Rn when bond b is a single bond;
  • Rm is selected from hydrogen, halo, (1-4C)alkyl, (1-4C)alkoxy, amino, (1- 4C)alkylamino, (1-4C)dialkylamino, cyano, (2C)alkynyl, wherein said (1- 4C)alkyl is optionally substituted by one or more substituents selected from amino, hydroxy, (1-2C)alkoxy or halo; and
  • R n is selected from hydrogen or (1-4C)alkyl
  • X3 is selected from N or CR m when bond b is a double bond, or NR n or CR m Rn when bond b is a single bond;
  • Rm is selected from hydrogen, halo, (1-4C)alkyl, (1-4C)alkoxy, amino, (1- 4C)alkylamino, (1-4C)dialkylamino, cyano, (2C)alkynyl; and
  • R n is selected from hydrogen or (1-4C)alkyl
  • X3 is selected from N or CR m and bond b is a double bond, wherein R m is selected from hydrogen, halo, (1-4C)alkyl or amino;
  • X3 IS CR m and bond b is a double bond, wherein R m is selected from hydrogen, halo, (1-4C)alkyl or amino;
  • X3 is selected from N or CH and bond b is a double bond
  • X3 is CH and bond b is a double bond
  • X 4 is selected from N or CR 0 when bond d is a double bond, or NR X or CR 0 R X when bond d is a single bond;
  • Ro is selected from hydrogen, halo, (1-4C)alkyl, (1-4C)alkoxy, amino, (1-4C)alkylamino, (1-4C)dialkylamino, cyano, (2C)alkynyl, wherein said (1-4C)alkyl is optionally substituted by one or more substituents selected from amino, hydroxy, (1-2C)alkoxy or halo; and
  • Rx is selected from hydrogen or (1-4C)alkyl
  • X 4 is selected from N or CR 0 when bond d is a double bond, or NR X or CR 0 R X when bond d is a single bond;
  • Ro is selected from hydrogen, halo, (1-4C)alkyl, (1-4C)alkoxy, amino, (1-4C)alkylamino, (1-4C)dialkylamino, cyano or (2C)alkynyl; and
  • Rx is selected from hydrogen or (1-4C)alkyl
  • X 4 is selected from N or CR 0 and bond d is a double bond, wherein R 0 is selected from halo, (1-4C)alkyl, (1-4C)alkoxy, amino, (1-4C)alkylamino, (1-4C)dialkylamino, cyano, (2C)alkynyl, C(0)R 0 i, C(0)OR 0 i, OC(0)R 0 i, C(0)N(R o2 )Roi, N(R o2 )C(0)R 0 i, S(0)y d Roi (where y d is 0, 1 or 2), S0 2 N(Ro 2 )Roi, N(Ro 2 )S0 2 Roi or (CH 2 ) Z dNR 0 iR o2 (where z d is 1 , 2 or 3); wherein said (1-4C)alkyl is optionally substituted by one or more substituents selected from amino, hydroxy, (1-2C)alkoxy or
  • X4 is selected from N or CR 0 and bond d is a double bond, wherein R 0 is selected from hydrogen, halo, (1-4C)alkyl, (1-4C)alkoxy, amino, (1-4C)alkylamino, (1- 4C)dialkylamino, cyano or (2C)alkynyl;
  • X4 is CR 0 and bond d is a double bond, wherein R 0 is selected from halo, (1-4C)alkyl, (1-4C)alkoxy, amino, (1-4C)alkylamino, (1-4C)dialkylamino, cyano or (2C)alkynyl;
  • X4 is CR 0 and bond d is a double bond, wherein R 0 is selected from hydrogen, halo, (1-4C)alkyl or amino; (47) X 4 is CR 0 and bond d is a double bond, wherein R 0 is selected from halo or (1- 4C)alkyl;
  • X 4 is CR 0 and bond d is a double bond, wherein R 0 is a halogen (e.g. chloro, bromo or fluoro, particularly chloro);
  • R2 is selected from hydrogen, (1-4C)alkyl or a group of the formula:
  • l_2 is absent or (1-3C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkyl or oxo;
  • Y2 is absent or C(O), C(0)0, C(0)N(R p ), wherein R p is selected from hydrogen or (1-4C)alkyl;
  • Q2 is hydrogen, (1-6C)alkyl, aryl, (3-8C)cycloalkyl, heteroaryl or heterocyclyl; wherein Q2 is optionally further substituted by one or more substituent groups independently selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)haloalkoxy, amino, cyano, hydroxy, NR q R r , OR q , wherein R q and R r are each independently selected from hydrogen or (1-4C)alkyl;
  • R2 is selected from hydrogen, (1-4C)alkyl or a group of the formula:
  • Y2 is absent or C(O), C(0)0, C(0)N(R p ), wherein R p is selected from hydrogen or (1-4C)alkyl;
  • Q2 is hydrogen, (1-6C)alkyl, aryl, (3-8C)cycloalkyl, heteroaryl or heterocyclyl; wherein Q2 is optionally further substituted by one or more substituent groups independently selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)haloalkoxy, amino, cyano, hydroxy, NR q R r , OR q , wherein R q and R r are each independently selected from hydrogen or (1-4C)alkyl;
  • R2 is selected from hydrogen, (1-4C)alkyl or a group of the formula:
  • Y2 is C(0)N(R p ), wherein R p is selected from hydrogen or (1-4C)alkyl; and Q2 is (1-6C)alkyl, aryl, (3-8C)cycloalkyl, heteroaryl or heterocyclyl; wherein Q2 is optionally further substituted by one or more substituent groups independently selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)haloalkoxy, amino, cyano or hydroxy;
  • R2 is selected from hydrogen or (1-4C)alkyl
  • R2 is hydrogen
  • R3 is selected from a group of the formula:
  • Y 3 is C(O), C(0)N(R y ), C(0)N(R y )0, N(R y )(0)C, C(0)0, OC(O), N(R y )C(0)N(Ryi), S0 2 N(R y ), N(R y )S0 2 , oxazolyl, triazolyl, oxadiazolyl, thiazolyl, imidazolyl, pyrazolyl or tetrazolyl, wherein R y and R y i are independently selected from hydrogen or (1-2C)alkyl; and
  • Q 3 is hydrogen, (1-6C)alkyl, (1-6C)alkoxy, aryl, aryl(1-2C)alkyl, (3- 8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Q3 is optionally further substituted by one or more substituent groups independently selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)haloalkoxy, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, NR z R aa , OR z , wherein R z and R aa are each independently selected from hydrogen, (1-4C)alkyl or (3-6C)cycloalkyl; or Q3 is optionally substituted by a group of the formula:
  • l_4 is absent or (1-3C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkyl or oxo;
  • L Q4 is absent or selected from or O, N(R ab ), C(O), C(0)0, OC(O), C(0)N(R ab ), N(R ab )C(0), S(0) 2 N(R ab ), or N(R ab )S0 2 , wherein R ab is selected from hydrogen or (1-2C)alkyl;
  • Z 4 is hydrogen, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, (3- 8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Z4 is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, mercapto, ureido, aryl, heteroaryl, heterocycyl, (3-6C)cycloalkyl, NRadRae, ORad,
  • Qz and R y are linked such that, together with the nitrogen atom to which they are attached, they form a 4-7 membered heterocyclic ring which is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano or hydroxyl;
  • Y 3 is C(O), C(0)N(R y ), N(Ry)(0)C, C(0)0, OC(O), triazolyl, oxadiazolyl or tetrazolyl, wherein R y is selected from hydrogen or (1-2C)alkyl;
  • Q 3 is hydrogen, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, (3-8C)cycloalkyl, (3- 8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Q3 is optionally further substituted by one or more substituent groups independently selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, NR z R aa , OR z , wherein R z and R aa are each independently selected from hydrogen, (1- 4C)alkyl or (3-6C)cycloalkyl; or Q3 is optionally substituted by a group of the formula:
  • l_4 is absent or (1-3C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkyl or oxo;
  • L Q4 is absent or selected from or O, S, SO, S0 2 , N(R ab ), C(O), 0(0)0, 00(0), C(0)N(Rab), N(Rab)C(0), N(R ac )C(0)N(Rab), N(Rab)C(0)0, OC(0)N(Rab), S(0) 2 N(R ab ), or N(R ab )S0 2 , wherein R a b and R ac are each independently selected from hydrogen or (1-2C)alkyl; and
  • Z 4 is hydrogen, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, (3- 8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Z 4 is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, mercapto, ureido, aryl, heteroaryl, heterocycyl, (3-6C)cycloalkyl, NRadRae, ORad,
  • R3 is selected from a group of the formula:
  • Y 3 is C(O), C(0)N(R y ), C(0)N(R y )0, N(R y )(0)C, C(0)0, OC(O), N(R y )C(0)N(Ryi), N(R y )S0 2 , oxazoyl, triazolyl, oxadiazolyl, thiadiazolyl or tetrazolyl, wherein R y and R y i are independently selected from hydrogen or (1-2C)alkyl; and
  • Q 3 is hydrogen, (1-6C)alkyl, (1-6C)alkoxy, aryl, aryl(1-2C)alkyl, (3- 8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Q3 is optionally further substituted by one or more substituent groups independently selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)haloalkoxy, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, NR z R aa , OR z , wherein R z and R aa are each independently selected from hydrogen, (1-4C)alkyl or (3-6C)cycloalkyl; or Q3 is optionally substituted by a group of the formula:
  • L 4 is absent or (1-3C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkyl or oxo;
  • LQ 4 is absent or selected from or O, N(R ab ), C(O), C(0)0,
  • R a b is selected from hydrogen or (1-2C)alkyl
  • Z 4 is hydrogen, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, (3- 8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Z 4 is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, mercapto, ureido, aryl, heteroaryl, heterocycyl, (3-6C)cycloalkyl, NRadRae, ORad,
  • Qz and R y are linked such that, together with the nitrogen atom to which they are attached, they form a 4-7 membered heterocyclic ring which is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano or hydroxyl;
  • R3 is selected from a group of the formula:
  • Y 3 is C(O), C(0)N(R y ), C(0)N(R y )0, N(R y )(0)C, C(0)0, OC(O), wherein R y is selected from hydrogen or (1-2C)alkyl;
  • Qs is hydrogen, (1-6C)alkyl, (1-6C)alkoxy, aryl, aryl(1-2C)alkyl, (3- 8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Q3 is optionally further substituted by one or more substituent groups independently selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)haloalkoxy, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, NR z R aa , OR z , wherein R z and R aa are each independently selected from hydrogen, (1-4C)alkyl or (3-6C)cycloalkyl; or Q3 is optionally substituted by a group of the formula: wherein:
  • l_4 is absent or (1-3C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkyl or oxo;
  • L Q4 is absent or selected from or O, N(R ab ), C(O), C(0)0, OC(O), C(0)N(R a ), N(R a )C(0), S(0) 2 N(R a ), or N(R a )S0 2 , wherein R a b is selected from hydrogen or (1-2C)alkyl; and
  • Z 4 is hydrogen, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, (3- 8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Z4 is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, mercapto, ureido, aryl, heteroaryl, heterocycyl, (3-6C)cycloalkyl, NRadRae, ORad,
  • Q3 and R y are linked such that, , together with the nitrogen atom to which they are attached, they form a 4-7 membered heterocyclic ring which is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano or hydroxyl;
  • R3 is selected from a group of the formula:
  • Y 3 is C(O), C(0)N(R y ), C(0)N(R y )0, N(R y )(0)C, C(0)0, OC(O), wherein R y is selected from hydrogen or (1-2C)alkyl;
  • Q 3 is hydrogen, (1-6C)alkyl, (1-6C)alkoxy, aryl, aryl(1-2C)alkyl, (3- 8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Q3 is optionally further substituted by one or more substituent groups independently selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)haloalkoxy, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, NR z R aa , OR z , wherein R z and R aa are each independently selected from hydrogen, (1-4C)alkyl or (3-6C)cycloalkyl; or Q3 is optionally substituted by a group of the formula:
  • l_4 is absent or (1-3C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkyl or oxo;
  • L Q4 is absent or selected from or O, N(R ab ), C(O), C(0)0, OC(O), C(0)N(R ab ), N(R ab )C(0), S(0) 2 N(R ab ), or N(R ab )S0 2 , wherein R ab is selected from hydrogen or (1-2C)alkyl;
  • Z 4 is hydrogen, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, (3- 8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Z4 is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, mercapto, ureido, aryl, heteroaryl, heterocycyl, (3-6C)cycloalkyl, NR a dR ae , OR ad , C(0)R ad , C(0)OR ad , OC(0)R ad , C(0)N(R ae )R ad , N(R a
  • Q3 and R y are linked such that, together with the nitrogen atom to which they are attached, they form a 4-7 membered heterocyclic ring which is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano or hydroxyl;
  • R3 is selected from a group of the formula:
  • Y 3 is C(O), C(0)N(R y ), N(Ry)(0)C, C(0)N(R y )0, C(0)0, OC(O), wherein R y is selected from hydrogen or (1-2C)alkyl;
  • Qs is hydrogen, (1-6C)alkyl, (1-6C)alkoxy, aryl, aryl(1-2C)alkyl, (3- 8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Qz is optionally further substituted by one or more substituent groups independently selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)haloalkoxy, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, NR z R aa , OR z , wherein R z and R aa are each independently selected from hydrogen, (1-4C)alkyl or (3-6C)cycloalkyl; or Q3 is optionally substituted by a group of the formula:
  • l_4 is absent or (1-3C)alkylene
  • L Q4 is absent or selected from or O, N(R ab ), C(O), C(0)0, OC(O), C(0)N(R ab ), N(R ab )C(0), S(0) 2 N(R ab ), or N(R ab )S0 2 , wherein R ab is selected from hydrogen or (1-2C)alkyl;
  • Z 4 is hydrogen, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, (3- 8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Z4 is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, mercapto, ureido, aryl, heteroaryl, heterocycyl, (3-6C)cycloalkyl, NR a dR ae , OR ad , C(0)R ad , C(0)OR ad , OC(0)R ad , C(0)N(R ae )R ad , N(R a
  • R3 is selected from a group of the formula:
  • Y3 is C(0)N(R y ), wherein R y is selected from hydrogen or (1-2C)alkyl; and Q 3 is hydrogen, (1-6C)alkyl, (1-6C)alkoxy, aryl, aryl(1-2C)alkyl, (3- 8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Qz is optionally further substituted by one or more substituent groups independently selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)haloalkoxy, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, NR z R aa , OR z , wherein R z and R aa are each independently selected from hydrogen, (1-4C)alkyl or (3-6C)cycloalkyl; or Q3 is optionally substituted by a group of the formula:
  • l_4 is absent or (1-3C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkyl or oxo;
  • L Q4 is absent or selected from or O, S, SO, S0 2 , N(R ab ), C(O), C(0)0, OC(O), C(0)N(R ab ), N(R ab )C(0), N(R ac )C(0)N(R ab ), N(R ab )C(0)0, OC(0)N(R ab ), S(0) 2 N(R ab ), or N(R ab )S0 2 , wherein R ab and R ac are each independently selected from hydrogen or (1-2C)alkyl; and
  • Z 4 is hydrogen, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, (3- 8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Z4 is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, mercapto, ureido, aryl, heteroaryl, heterocycyl, (3-6C)cycloalkyl, NR a dR ae , OR ad , C(0)R ad , C(0)OR ad , OC(0)R ad , C(0)N(R ae )R ad , N(R a
  • Q3 and R y are linked such that, together with the nitrogen atom to which they are attached, they form a 4-6 membered heterocyclic ring which is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano or hydroxyl; elected from a group of the formula:
  • Y3 is C(0)N(R y ), wherein R y is selected from hydrogen or (1-2C)alkyl;
  • Q 3 is hydrogen, (1-6C)alkyl, (1-6C)alkoxy, aryl, aryl(1-2C)alkyl, (3- 8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Q3 is optionally further substituted by one or more substituent groups independently selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)haloalkoxy, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, NR z R aa , OR z , wherein R z and R aa are each independently selected from hydrogen, (1-4C)alkyl or (3-6C)cycloalkyl; or Q3 is optionally substituted by a group of the formula:
  • l_4 is absent or (1-3C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkyl or oxo;
  • L Q4 is absent or selected from or O, S, SO, S0 2 , N(R ab ), C(O), C(0)0, OC(O), C(0)N(R ab ), N(R ab )C(0), N(R ac )C(0)N(R ab ), N(R ab )C(0)0, OC(0)N(R ab ), S(0) 2 N(R ab ), or N(R ab )S0 2 , wherein R ab and R ac are each independently selected from hydrogen or (1-2C)alkyl; and
  • Z 4 is hydrogen, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, (3- 8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Z4 is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, mercapto, ureido, aryl, heteroaryl, heterocycyl, (3-6C)cycloalkyl, NR a dR ae , OR ad , C(0)R ad , C(0)OR ad , OC(0)R ad , C(0)N(R ae )R ad , N(R a
  • Y 3 is C(0)NH
  • Qs is hydrogen, (1-6C)alkyl, (1-6C)alkoxy, aryl, aryl(1-2C)alkyl, (3- 8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Q3 is optionally further substituted by one or more substituent groups independently selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)haloalkoxy, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, NR z R aa , OR z , wherein R z and R aa are each independently selected from hydrogen, (1-4C)alkyl or (3-6C)cycloalkyl; or Q3 is optionally substituted by a group of the formula:
  • l_4 is absent or (1-3C)alkylene
  • LQ4 is absent or selected from or O, N(R a b), C(O), C(0)0, or C(0)N(Rab), wherein R a b is selected from hydrogen or (1- 2C)alkyl;
  • Z 4 is hydrogen, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, (3- 8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Z4 is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano or hydroxy;
  • R3 is selected from a group of the formula:
  • Y 3 is C(O), C(0)N(R y ), N(R y )(0)C or C(0)0, wherein R y is selected from hydrogen or (1-2C)alkyl;
  • Qs is hydrogen, (1-6C)alkyl, (1-6C)alkoxy, aryl, aryl(1-2C)alkyl, (3- 8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Q3 is optionally further substituted by one or more substituent groups independently selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)haloalkoxy, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, NR z R aa , OR z , wherein R z and R aa are each independently selected from hydrogen, (1-4C)alkyl or (3-6C)cycloalkyl; or Q3 is optionally substituted by a group of the formula:
  • l_4 is absent or (1-3C)alkylene
  • LQ4 is absent or selected from or O, N(R a b), C(O), C(0)0, or C(0)N(R a b), wherein R a b is selected from hydrogen or (1- 2C)alkyl;
  • Z 4 is hydrogen, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, (3- 8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Z4 is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano or hydroxy;
  • R3 is selected from a group of the formula:
  • Y 3 is C(0)NH
  • Q 3 is hydrogen, (1-6C)alkyl, (1-6C)alkoxy, aryl, aryl(1-2C)alkyl, (3- 8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Q3 is optionally further substituted by one or more substituent groups independently selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)haloalkoxy, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, NR z R aa , OR z , wherein R z and R aa are each independently selected from hydrogen or (1-4C)alkyl; or Q3 is optionally substituted by a group of the formula:
  • LQ4 is absent or selected from or O, N(R a b), C(O), C(0)0, or
  • R ab is selected from hydrogen or (1- 2C)alkyl
  • Z 4 is hydrogen, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, (3- 8C)cycloalkyl, heteroaryl or heterocyclyl; wherein Z 4 is optionally substituted by one or more substituents selected from (1- 4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano or hydroxy;
  • R3 is selected from a group of the formula:
  • Y 3 is C(0)NH
  • Q 3 is (1-6C)alkyl, (1-6C)alkoxy, aryl, aryl(1-2C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Q3 is optionally further substituted by one or more substituent groups independently selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, NR z R aa , OR z , wherein R z and R aa are each independently selected from hydrogen or (1-4C)alkyl; or Q3 is optionally substituted by a group of the formula:
  • LQ 4 is absent or selected from or O, N(R a b), C(O), C(0)0, or C(0)N(R a b), wherein R a b is selected from hydrogen or (1- 2C)alkyl;
  • Z 4 is hydrogen, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, (3- 8C)cycloalkyl, heteroaryl or heterocyclyl; wherein Z 4 is optionally substituted by one or more substituents selected from (1- 4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano or hydroxy;
  • R3 is selected from a group of the formula:
  • Y 3 is C(O), C(0)0 or C(0)NH
  • Q 3 is hydrogen, (1-6C)alkyl, (1-6C)alkoxy, aryl, aryl(1-2C)alkyl, (3- 8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Qz is optionally further substituted by one or more substituent groups independently selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)haloalkoxy, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, NR z R aa , OR z , wherein R z and R aa are each independently selected from hydrogen or (1-4C)alkyl;
  • R3 is selected from a group of the formula:
  • Y 3 is C(0)NH
  • Q 3 is hydrogen, (1-6C)alkyl, (1-6C)alkoxy, aryl, aryl(1-2C)alkyl, (3- 8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Q3 is optionally further substituted by one or more substituent groups independently selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)haloalkoxy, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, NR z R aa , OR z , wherein R z and R aa are each independently selected from hydrogen or (1-4C)alkyl;
  • R3 is selected from a group of the formula:
  • Y 3 is C(0)NH
  • Q3 is (1-6C)alkyl, phenyl, (3-6C)cycloalkyl or 5- or 6-membered heteroaryl; wherein Q3 is optionally further substituted by one or more substituent groups independently selected from (1-4C)alkyl, halo, (1- 4C)haloalkyl, (1-4C)haloalkoxy, amino, cyano, hydroxy, NR z R aa or OR z , wherein R z and R aa are each independently selected from hydrogen or (1-2C)alkyl.
  • 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
  • HET is as defined in any one of paragraphs (1) to (7). Most suitably, HET is as defined in paragraph (7).
  • Ri is as defined in any one of paragraphs (8) to (20). More suitably, Ri is as defined in any one of paragraphs (12) to (20). Most suitably, Ri is as defined in paragraph (20).
  • Ri a and Rib are as defined in any one of paragraphs (21) to (24). Most suitably, Ri a and Rib are as defined in paragraph (24).
  • W is as defined in any one of paragraphs (25) to (26). Most suitably, W is as defined in paragraph (26).
  • bonds a, b, c and d are as defined in any one of paragraphs (27) to (28).
  • bonds a, b, c and d are as defined in paragraph (28).
  • Xi and X2 are as defined in any one of paragraphs (29) to (34). Most suitably, Xi and X2 are as defined in paragraph (34).
  • X3 is as defined in any one of paragraphs (35) to (40). Most suitably, X3 is as defined in paragraph (40).
  • X 4 is as defined in any one of paragraphs (41) to (48). Most suitably, X 4 is as defined in paragraph (48).
  • R2 is as defined in any one of paragraphs (49) to (53). More suitably, R2 is as defined in any one of paragraphs (51) to (53). Most suitably, R2 is as defined in paragraph (53).
  • R3 is as defined in any one of paragraphs (54) to (68). Most suitably, R3 is as defined in paragraph (68).
  • the compounds have the structural Formula la (a sub-definition of formula (I)) shown below, or a pharmaceutically acceptable salt, hydrate and/or solvate thereof:
  • HET bonds a, b, c and d, Xi , X2, X3, X 4 , R2, Q3 and R y each have any one of the meanings defined herein.
  • HET is as defined in any one of paragraphs (1) to (7) above;
  • Ri is as defined in any one of paragraphs (8) to (20) above;
  • Ria and Rib are as defined in any one of paragraphs (21) to (24) above;
  • bonds a, b, c and d are as defined in any one of paragraphs (27) to (28) above;
  • Xi and X2 are as defined in any one of paragraphs (29) to (34) above;
  • X3 is as defined in any one of paragraphs (35) to (40) above;
  • X 4 is as defined in any one of paragraphs (41) to (48) above;
  • R2 is as defined in any one of paragraphs (49) to (53) above;
  • R y is as defined in any one of paragraphs (54) to (63) above;
  • Q3 is as defined in any one of paragraphs (54) to (68).
  • HET is as defined in paragraph (7) above;
  • Ri is as defined in paragraph (20) above;
  • Ria and Rib are as defined in paragraph (24) above;
  • bonds a, b, c and d are as defined in paragraph (28) above;
  • Xi and X2 are as defined in paragraph (34) above;
  • X3 is as defined in paragraph (40) above;
  • X 4 is as defined in paragraph (47) or (48) above;
  • R2 is as defined in paragraph (53) above;
  • R y is hydrogen
  • Ri is as defined in any one of paragraphs (8) to (20) above;
  • bonds a, b, c and d are as defined in any one of paragraphs (27) to (28) above;
  • Xi and X2 are as defined in any one of paragraphs (29) to (34) above;
  • X3 is as defined in any one of paragraphs (35) to (40) above;
  • X 4 is as defined in any one of paragraphs (41) to (48) above;
  • R2 is as defined in any one of paragraphs (49) to (53) above;
  • R y is as defined in any one of paragraphs (54) to (63) above;
  • Q3 is as defined in any one of paragraphs (54) to (68).
  • Ri is as defined in paragraph (20) above;
  • bonds a, b, c and d are as defined in paragraph (28) above;
  • Xi and X2 are as defined in paragraph (34) above;
  • X3 is as defined in paragraph (40) above;
  • X 4 is as defined in paragraph (47) or (48) above;
  • R2 is as defined in paragraph (53) above;
  • R y is hydrogen
  • Ri , Xi , X2, X3, X 4 , R2, Q3 and R y each have any one of the meanings defined herein.
  • Ri is as defined in any one of paragraphs (8) to (20) above;
  • Xi and X2 are as defined in any one of paragraphs (29) to (34) above;
  • X3 is as defined in any one of paragraphs (35) to (40) above;
  • X 4 is as defined in any one of paragraphs (41) to (48) above;
  • R2 is as defined in any one of paragraphs (49) to (53) above;
  • R y is as defined in any one of paragraphs (54) to (63) above;
  • Q3 is as defined in any one of paragraphs (54) to (68).
  • Ri is as defined in any one of paragraphs (8) to (20) above;
  • Xi and X2 are as defined in any one of paragraphs (29) to (34) above;
  • X3 is as defined in any one of paragraphs (35) to (40) above;
  • X 4 is CH
  • R2 is as defined in any one of paragraphs (49) to (53) above;
  • R y is as defined in any one of paragraphs (54) to (63) above;
  • Q3 is as defined in any one of paragraphs (54) to (68).
  • Ri is as defined in paragraph (20) above;
  • Xi and X2 are as defined in paragraph (34) above;
  • X3 is as defined in paragraph (40) above;
  • X 4 is as defined in paragraph (48) above;
  • R2 is as defined in paragraph (53) above;
  • R y is hydrogen
  • Ri is as defined in paragraph (20) above;
  • Xi and X2 are as defined in paragraph (34) above;
  • X3 is as defined in paragraph (40) above;
  • X 4 is CH
  • R2 is as defined in paragraph (53) above;
  • R y is hydrogen
  • the compounds have the structural Formula Id (a sub-definition of formula (I)) shown below, or a pharmaceutically acceptable salt, hydrate and/or solvate thereof:
  • Ri , X 4 , R2 and Q3 each have any one of the meanings defined herein.
  • Ri is as defined in any one of paragraphs (8) to (20) above;
  • X 4 is as defined in any one of paragraphs (41) to (48) above;
  • R2 is as defined in any one of paragraphs (49) to (53) above; and Q3 is as defined in any one of paragraphs (54) to (68) above.
  • Ri is as defined in paragraph (20) above;
  • X 4 is as defined in paragraph (48) above;
  • R2 is as defined in paragraph (53) above;
  • Ri is as defined in paragraph (20) above;
  • X 4 is CH
  • R2 is as defined in paragraph (53) above;
  • the compounds have the structural Formula le (a sub-definition of formula (I)) shown below, or a pharmaceutically acceptable salt, hydrate and/or solvate thereof:
  • HET, Xi , X2, X3, R2, R3 and R 0 each have any one of the meanings defined herein.
  • HET is as defined in any one of paragraphs (1) to (7) above;
  • Ri is as defined in any one of paragraphs (8) to (20) above;
  • Ria and Ri b are as defined in any one of paragraphs (21) to (24) above;
  • Xi and X2 are as defined in any one of paragraphs (29) to (34) above;
  • X3 is as defined in any one of paragraphs (35) to (40) above;
  • R2 is as defined in any one of paragraphs (49) to (53) above; and R3 is as defined in any one of paragraphs (54) to (68).
  • HET is as defined in paragraph (7) above;
  • Ri is as defined in paragraph (20) above;
  • Ria and Rib are as defined in paragraph (24) above;
  • Xi and X2 are as defined in paragraph (34) above;
  • X3 is as defined in paragraph (40) above;
  • Ro is halo, especially chloro
  • R2 is as defined in paragraph (53) above;
  • R3 is as defined in paragraph (68).
  • the compounds have the structural Formula If (a sub-definition of formula (I)) shown below, or a pharmaceutically acceptable salt, hydrate and/or solvate thereof:
  • HET, Xi , X2, X3, R2, Ro, Q3 and R y each have any one of the meanings defined herein.
  • HET is as defined in any one of paragraphs (1) to (7) above;
  • Ri is as defined in any one of paragraphs (8) to (20) above;
  • Ria and Rib are as defined in any one of paragraphs (21) to (24) above;
  • Xi and X2 are as defined in any one of paragraphs (29) to (34) above;
  • X3 is as defined in any one of paragraphs (35) to (40) above;
  • R2 is as defined in any one of paragraphs (49) to (53) above;
  • R y is as defined in any one of paragraphs (54) to (63) above;
  • HET is as defined in paragraph (7) above;
  • Ri is as defined in paragraph (20) above;
  • Ria and Rib are as defined in paragraph (24) above;
  • Xi and X2 are as defined in paragraph (34) above;
  • X3 is as defined in paragraph (40) above;
  • Ro is halo, especially chloro
  • R2 is as defined in paragraph (53) above;
  • R y is hydrogen
  • the compounds have the structural Formula Ig (a sub-definition of formula (I)) shown below, or a pharmaceutically acceptable salt, hydrate and/or solvate thereof:
  • Ri is as defined in any one of paragraphs (8) to (20) above;
  • Xi and X2 are as defined in any one of paragraphs (29) to (34) above;
  • X3 is as defined in any one of paragraphs (35) to (40) above;
  • Ro is as defined in any one of paragraphs (41) to (48) above;
  • R2 is as defined in any one of paragraphs (49) to (53) above;
  • R y is as defined in any one of paragraphs (54) to (63) above;
  • Q3 is as defined in any one of paragraphs (54) to (68).
  • Ri is as defined in paragraph (20) above;
  • Xi and X2 are as defined in paragraph (34) above;
  • X3 is as defined in paragraph (40) above;
  • Ro is halo, especially chloro
  • R2 is as defined in paragraph (53) above;
  • R y is hydrogen
  • Particular compounds of the present invention include any of the compounds exemplified in 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), and sub-formulae la to Ig, 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 acid-addition salt of a compound of the invention which is sufficiently basic, for example, an acid-addition 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 S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively).
  • a chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a "racemic mixture".
  • the compounds of this invention may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (S)-stereoisomers or as mixtures thereof. 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 well-known 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 1 H, 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 160 and180; 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, and sub-formulae la to Ig, containing an amine function may also form N-oxides.
  • a reference herein to a compound of the Formula I, or sub-formulae la to Ig, 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.
  • N-oxides are the N-oxides of a te/fiary 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.
  • 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.
  • mCPBA m-chloroperoxybenzoic acid
  • the compounds of Formula (I), and sub-formulae la to Ig may be administered in the form of a pro-drug 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 examples 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), or sub-formulae la to Ig, 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), or sub- formulae la to Ig.
  • the present invention includes those compounds of the Formula (I), and sub-formulae la to Ig, 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, and sub-formulae la to Ig, 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) or sub-formulae la to Ig, may be a synthetically-produced compound or a metabolically-produced compound.
  • a suitable pharmaceutically acceptable pro-drug of a compound of the Formula (I), or sub-formulae la to Ig 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, or sub-formulae la to Ig, 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, or sub-formulae la to Ig, 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 te/f-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,
  • 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.
  • a suitable pharmaceutically acceptable pro-drug of a compound of the Formula (I), or sub-formulae la to Ig, 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, or sub-formulae la to Ig, 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 a-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.
  • a suitable pharmaceutically acceptable pro-drug of a compound of the Formula (I), or sub-formulae la to Ig, 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 suitable pharmaceutically acceptable pro-drug of a compound of the Formula I, or sub-formulae la to Ig, 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
  • the in vivo effects of a compound of the Formula (I), or sub-formulae la to Ig 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), or sub-formulae la to Ig.
  • the in vivo effects of a compound of the Formula (I), or sub-formulae la to Ig may also be exerted by way of metabolism of a precursor compound (a pro-drug).
  • the present invention may relate to any compound or particular group of compounds defined herein by way of optional, preferred or suitable features or otherwise in terms of particular embodiments, the present invention may also relate to any compound or particular group of compounds that specifically excludes said optional, preferred or suitable features or particular embodiments.
  • the present invention excludes any individual compounds not possessing the biological activity defined herein. Synthesis
  • the compounds of the present invention can be prepared by any suitable technique known in the art. Particular processes for the preparation of these compounds are described further in the accompanying examples.
  • 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 t-butoxycarbonyl 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 te/f-butoxycarbonyl 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 palladium-on-carbon, 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 palladium-on-carbon.
  • 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 t-butyl 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 palladium-on-carbon.
  • a base such as sodium hydroxide
  • a t-butyl 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 palladium-on-carbon.
  • Resins may also be used as a protecting group.
  • the compounds of the invention demonstrate an IC50 of 1 ⁇ or less in the RET assay described in the Examples section, 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 ratio of RET activity to KDR activity measured in the RET and KDR assays set out in the Examples section herein is greater than 5, more suitably greater than 10, yet more suitably greater than 25, and most suitably greater than 100.
  • the compounds of Formula I suitably possess an activity of less than 1 ⁇ , with the preferred compounds demonstrating an activity of 100 nM or less and the most preferred compounds of the invention demonstrating an IC50 of 50 nM or less.
  • the compounds of Formula I suitably possess an activity of less than 1 ⁇ , with the preferred compounds demonstrating an activity of 250 nM or less and the most preferred compounds of the invention demonstrating an IC50 of 100 nM or less.
  • the compounds of Formula I suitably possess an activity of less than 1 ⁇ , with the preferred compounds demonstrating an activity of 500 nM or less, and more preferred compounds demonstrating an activity of 100 nM or less, and the most preferred compounds of the invention demonstrating an IC50 of 50 nM or less.
  • 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.
  • the amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the individual treated and the particular route of administration.
  • a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 0.5 g of active agent (more suitably from 0.5 to 100 mg, for example from 1 to 30 mg) compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition.
  • 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.
  • lower doses will be administered when 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 inhibitors of RET or mutant forms thereof (e.g. RET V804M ). Furthermore, the compounds of the present invention demonstrate an improved selectivity for RET, or mutant forms thereof (e.g. RET V804M ), relative to KDR (i.e. they are potent inhibitors of RET and poor inhibitors of KDR).
  • the present invention therefore provides a method of inhibiting RET kinase enzyme activity, or mutant forms thereof (e.g. RET V804M ), 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.
  • the present invention also provides a method of selectively inhibiting RET kinase enzyme activity, or mutant forms thereof (e.g. RET V804M ), over KDR enzyme activity 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.
  • the present invention also provides a method of treating a disease or disorder in which RET kinase 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, or a pharmaceutical composition as defined herein.
  • the present invention provides 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.
  • the present invention provides 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, or a pharmaceutical composition as defined herein.
  • the present invention provides 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, or a pharmaceutical composition as defined herein.
  • the present invention provides a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein for use in therapy.
  • the present invention provides a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein for use in the treatment of a proliferative condition.
  • the present invention provides 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.
  • the cancer is human cancer.
  • the present invention provides a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein for use in the inhibition of RET kinase enzyme activity or mutant forms thereof (e.g. RET V804M ).
  • the present invention provides a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein for use in the selective inhibition of RET kinase enzyme activity, or mutant forms thereof (e.g. RET V804M ), over KDR enzyme activity.
  • the present invention provides 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 RET kinase activity is implicated.
  • the present invention provides 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 proliferative condition.
  • the present invention provides 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 cancer.
  • the medicament is for use in the treatment of human cancers.
  • the present invention provides 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 inhibition of RET kinase enzyme activity, or mutant forms thereof (e.g.
  • the present invention provides 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 selective inhibition of RET kinase enzyme activity, or mutant forms thereof (e.g. RET V804M ), over KDR enzyme activity.
  • the present invention provides 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 RET kinase activity is implicated.
  • 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 inhibition of RET kinase enzyme activity, and/or the selective inhibition of RET kinase enzyme activity over KDR enzyme activity).
  • the anti-cancer effect may arise through one or more mechanisms, including but not limited to, the regulation of cell proliferation, the inhibition of angiogenesis (the formation of new blood vessels), the inhibition of metastasis (the spread of a tumour from its origin), the inhibition of invasion (the spread of tumour cells into neighbouring normal structures), or the promotion of apoptosis (programmed cell death).
  • the proliferative condition to be treated is cancer, for example medullary thyroid cancer (MTC) or non-small cell lung cancer (NSCLC).
  • MTC medullary thyroid cancer
  • NSCLC non-small cell lung cancer
  • 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 antiproliferative treatment defined hereinbefore may be applied as a sole therapy or may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy.
  • Such chemotherapy may include one or more of the following categories of anti-tumour agents:-
  • antiproliferative/antineoplastic drugs and combinations thereof as used in medical oncology, such as alkylating agents (for example cis-platin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan, temozolamide and nitrosoureas); antimetabolites (for example gemcitabine and antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, and hydroxyurea); antitumour antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids like vincristine, vinblast
  • cytostatic agents such as antioestrogens (for example tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5a-reductase such as finasteride;
  • antioestrogens for example tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene
  • antiandrogens for example
  • anti-invasion agents for example c-Src kinase family inhibitors like 4-(6-chloro-2,3- methylenedioxyanilino)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-tetrahydropyran-4- yloxyquinazoline (AZD0530; International Patent Application WO 01/94341), A/-(2-chloro-6- methylphenyl)-2- ⁇ 6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-ylamino ⁇ thiazole- 5-carboxamide (dasatinib, BMS-354825; J. Med.
  • anti-invasion agents for example c-Src kinase family inhibitors like 4-(6-chloro-2,3- methylenedioxyanilino)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-tetrahydropyran
  • inhibitors of growth factor function include growth factor antibodies and growth factor receptor antibodies (for example the anti-erbB2 antibody trastuzumab [HerceptinTM], the anti-EGFR antibody panitumumab, the anti-erbB1 antibody cetuximab [Erbitux, C225] and any growth factor or growth factor receptor antibodies disclosed by Stern et al. (Critical reviews in oncology/haematology, 2005, Vol.
  • inhibitors also include tyrosine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as A/-(3-chloro-4- fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (gefitinib, ZD1839), N- (3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) and 6- aci lamido-A/-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-quinazolin-4-amine (CI 1033), erbB2 tyrosine kinase inhibitors such as lapatinib); inhibitors of the hepatocyte growth factor family; inhibitors of the insulin growth factor family; inhibitors of the insulin
  • antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, [for example the anti-vascular endothelial cell growth factor antibody bevacizumab (AvastinTM) and for example, a VEGF receptor tyrosine kinase inhibitor such as vandetanib (ZD6474), vatalanib (PTK787), sunitinib (SU11248), axitinib (AG-013736), pazopanib (GW 786034) and 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidin-1- ylpropoxy)quinazoline (AZD2171 ; Example 240 within WO 00/47212), compounds such as those disclosed in International Patent Applications W097/22596, WO 97/30035, WO 97/32856 and WO 98/13354 and compounds that work by other mechanisms (for example linomide
  • vascular damaging agents such as Combretastatin A4 and compounds disclosed in International Patent Applications WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213;
  • an endothelin receptor antagonist for example zibotentan (ZD4054) or atrasentan;
  • antisense therapies for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense;
  • (ix) gene therapy approaches including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; and
  • GDEPT gene-directed enzyme pro-drug therapy
  • (x) immunotherapy approaches including for example ex-vivo and in-vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches using anti-idiotypic antibodies.
  • cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor
  • the antiproliferative treatment defined hereinbefore may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy, wherein the chemotherapy may include one or more anti-tumour agents selected from procarbazine, carmustine, lomustine, irinotecan, temozolomide, cisplatin, carboplatin, methotrexate, etoposide, cyclophosphamide, ifosfamide, and vincristine.
  • the chemotherapy may include one or more anti-tumour agents selected from procarbazine, carmustine, lomustine, irinotecan, temozolomide, cisplatin, carboplatin, methotrexate, etoposide, cyclophosphamide, ifosfamide, and vincristine.
  • Such conjoint treatment 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 another anti-tumour agent.
  • 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 any one of the anti-tumour agents listed herein above.
  • a compound of the invention or a pharmaceutically acceptable salt, hydrate or solvate thereof for use in the treatment of cancer in combination with another anti-tumour agent, optionally selected from one listed herein above.
  • a pharmaceutical composition which comprises a compound of the invention, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in combination with an anti-tumour agent (optionally selected from one listed herein above), in association with a pharmaceutically acceptable diluent or carrier.
  • DIPEA ⁇ /, ⁇ /,-di-isopropyethylamine, Hunig's base
  • Flash column chromatography refers to automated chromatography using prepacked silica cartridges.
  • LC-MS analyses may be performed on, for example, a Waters Acquity UPLC system fitted with BEH C18 1.7 ⁇ columns (2.1 ⁇ 50 mm or 2.1 ⁇ 100 mm), with UV diode array detection (210-400 nm). Positive and negative mass ion detection may also be performed using, for example, a Waters SQD detector. Analyses may then be performed with either buffered acidic or basic solvents, using gradients such as those detailed below.
  • Solvent A Water + 10mM ammonium hydrogen carbonate + 0.1 % ammonia solution
  • Solvent B Acetonitrile + 0.1 % ammonia solution
  • Preparative HPLC refers to mass-directed reverse-phase chromatography using various water: MeCN eluent gradients. It will be appreciated that various preparative HPLC machines and/or conditions may be used to purify the compounds of the present invention, and the person skilled in the art will be well versed in selecting appropriate conditions for each respective compound. Nonetheless, details of some non-limiting examples of suitable HPLC conditions are provided below.
  • Compounds may be purified by preparative HPLC on, for example, a Waters FractionLynx MS autopurification system, with a column such as a Waters XBridge 5 ⁇ C18, 100 mm x 19 mm i.d. column, running at a typical flow rate of 20 mL/min with UV diode array detection (210-400 nm) and mass-directed collection using both positive and negative mass ion detection.
  • a Waters FractionLynx MS autopurification system with a column such as a Waters XBridge 5 ⁇ C18, 100 mm x 19 mm i.d. column, running at a typical flow rate of 20 mL/min with UV diode array detection (210-400 nm) and mass-directed collection using both positive and negative mass ion detection.
  • Purifications may also be performed using buffered acidic or basic solvent systems, as appropriate. Compound retention times on such systems may then be assessed using a 30-50 test injection and a standard gradient, and then purified using an appropriately chosen focussed gradient as detailed below, based upon observed retention time.
  • suitable solvent gradients include: Low pH:
  • Substituted pyrazolopyrimidines C were prepared either via the known 3-step procedure from an appropriately substituted hydrazine A (General Method 1) or via elaboration of the unsubstituted pyrazolopyrimidine B (General Method 2).
  • X is usually Br or I.
  • Suzuki coupling of intermediate C with either 2-halo indole derivatives (General Method 3) or indolyl boronic acid derivatives (General Method 4) returned product D. Where necessary, further elaboration was conducted.
  • the alkylating agent employed was the corresponding halide or mesylate, depending on commercial availability or synthetic accessibility.
  • reaction mixture was heated at reflux for 2 hours then cooled to room temperature, diluted with EtOAc (50 mL) and washed with water (2 ⁇ 25 mL). The combined aqueous phases were back-extracted with EtOAc (50 mL). The combined organics were washed with brine (50 mL) then concentrated in vacuo and purified by fee (0-100% EtOAc in isohexane) to return the title compound (438 mg, 80%) as a yellow solid.
  • the reaction was cooled to 0 °C and quenched by the dropwise addition of a 20% (w/v) solution of Rochelle's salt in water (30 mL). The mixture was stirred for 30 mins and extracted with EtOAc (2 ⁇ 30 mL). The combined extracts were washed sequentially with water (30 mL) and brine (30 mL), and concentrated in vacuo. The crude product was purified by fee (0 to 10% MeOH in DCM) to return the title compound (170 mg, 45%) as a white solid.

Abstract

The present invention relates to compounds of Formula I that function as inhibitors of RET (rearranged during transfection) kinase enzyme activity: wherein HET, bonds a, b, c and d, X1, X2, X3, X4, R2, and R3 are each as defined herein. 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 proliferative disorders, such as cancer, as well as other diseases or conditions in which RET kinase activity is implicated.

Description

HETEROCYCLIC COMPOUNDS AS RET KINASE INHIBITORS
INTRODUCTION
[0001] The present invention relates to certain compounds that function as inhibitors of RET (rearranged during transfection) kinase enzyme activity. 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 proliferative disorders, such as cancer, as well as other diseases or conditions in which RET kinase activity is implicated.
BACKGROUND OF THE INVENTION
[0002] Cancer is caused by uncontrolled and unregulated cellular proliferation. Precisely what causes a cell to become malignant and proliferate in an uncontrolled and unregulated manner has been the focus of intense research over recent decades. This research has led to the identification of a number of molecular targets associated with key metabolic pathways that are known to be associated with malignancy.
[0003] RET (REarranged during Transfection) is a receptor tyrosine kinase (RTK) that forms part of a macromolecular receptor complex containing dimerized RET receptor, two co- receptors and a bound ligand. The glial derived neurtrophic factor (GDNF) family of ligands bind RET in association with one of four glycosyl phosphatidylinositol (GPI) anchored GDNF family a-receptors (GFRa). Ligand binding to the corresponding GFRa co-receptor triggers RET dimerization followed by trans-phosphorylation of intracellular signalling cascades. These downstream signalling networks play a key role in regulating cell survival, differentiation, proliferation, migration and chemotaxis.
[0004] Activating mutations in RET have been identified in familial and sporadic forms of medullary thyroid carcinomas (MTC) (Santoro & Carlomagno 2006; Schulmberger ef a/. 2008; Wells & Santoro 2009) and these correlate with aggressive disease progression (Elisei ef a/. 2008). Clinical benefit has been observed in MTC patients using the small molecule VEGFR2/EGFR inhibitor vandetanib (Wells et al. 2011) which has recently been approved by the FDA & EMEA. RET inhibition is a secondary pharmacology of this agent, which also targets VEGFR2 (Vascular endothelial growth factor receptor, also known as KDR - kinase insert domain receptor) and EGFR (epidermal growth factor receptor). The clinical benefit in MTC is considered to be due to RET inhibition but is unfortunately accompanied by significant side effects (rash, hypertension, diarrhoea) due to inhibition of EGFR and/or VEGFR. Furthermore, vandetanib also exhibits off-target activity versus hERG. Collectively all of these unwanted pharmacological activities may compromise its use in advanced MTC and also its extrapolation into earlier clinical settings (e.g. adjuvant).
[0005] Furthermore, several recent publications (Ju et al., 2012; Lipson et al., 2012; Kohno ef al., 2012; Wang et al., 2012; Chao et al., 2012) describe various RET fusion translocations {e.g. KIF5B-RET and CCDC6-RET) present in approximately 1 % of NSCLC (non-small cell lung carcinoma) patient samples, which may offer an important alternative disease segment in which a specific RET inhibitor would offer clinical benefit.
[0006] Mutation at the RET gatekeeper residue (V804) is predicted to confer resistance to first line therapies such as vandetanib and cabozantinib. Although not yet confirmed in this patient population, -5% of familial MTC patients do harbour the RETV804M mutation rendering them intrinsically resistant to the current therapies
[0007] Therefore, there is a requirement for the development of more selective inhibitors of RET and mutant forms thereof (e.g. RETV804M), in particular inhibitors that show less inhibition of KDR. It is anticipated that these more selective inhibitors will produce the desired therapeutic benefits associated with RET inhibition without the side effects associated with significant KDR inhibition. Such inhibitors will offer the potential of better therapy for cancers such as MTC and NSCLC and will widen the scope for the clinical use of RET inhibitors in earlier disease settings.
[0008] It is therefore an object of the present invention to provide further inhibitors of RET kinase enzyme activity and mutants thereof (e.g. RETV804M).
[0009] Another object of the present invention is to provide inhibitors of RET kinase enzyme activity that show a greater selectivity for the inhibition of RET kinase relative to the inhibition of KDR.
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 inhibiting RET kinase enzyme activity, or mutant forms thereof (e.g. RETV804M), 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 inhibiting RET kinase enzyme activity, or mutant forms thereof (e.g. RETV804M), over KDR enzyme activity 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.
[0015] According to a further aspect of the present invention, there is provided a method of treating a disease or disorder in which RET kinase 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.
[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.
[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.
[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.
[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.
[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 in the inhibition of RET kinase enzyme activity, or mutant forms thereof (e.g. RETV804M).
[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 inhibition of mutant forms of RET kinase enzyme activity (e.g. RETV804M kinase enzyme activity).
[0023] 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 selective inhibition of RET kinase enzyme activity, or mutant forms thereof (e.g. RETV804M), relative to KDR enzyme activity.
[0024] 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 RET kinase activity is implicated.
[0025] 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.
[0026] Suitably, the proliferative disorder is cancer, suitably a human cancer (for example medullary thyroid cancer (MTC) or non-small cell lung cancer).
[0027] 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.
[0028] 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 inhibition of RET kinase enzyme activity, or mutant forms thereof (e.g. RETV804M).
[0029] 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 selective inhibition of RET kinase enzyme activity, or mutant forms thereof (e.g. RETV804M), relative to KDR enzyme activity.
[0030] 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 RET kinase activity is implicated.
[0031] 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.
[0032] 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.
[0033] 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. [0034] 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
[0035] Unless otherwise stated, the following terms used in the specification and claims have the following meanings set out below.
[0036] 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.
[0037] 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.
[0038] 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 f-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.
[0039] The term "(m-nC)" or "(m-nC) group" used alone or as a prefix, refers to any group having m to n carbon atoms.
[0040] 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.
[0041] "(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.
[0042] "(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.
[0043] "(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.
[0044] "(3-8C)cycloalkenyl" means a hydrocarbon ring containing from 3 to 8 carbon atoms and at least one double bond, for example, cyclobutenyl, cyclopentenyl, cyclohexenyl or cycloheptenyl, such as 3-cyclohexen-1-yl, or cyclooctenyl.
[0045] "(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.
[0046] The term "halo" or "halogeno" refers to fluoro, chloro, bromo and iodo.
[0047] 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-2/-/-thiopyran, and hexahydrothiepine. Other heterocycles include dihydro-oxathiolyl, tetrahydro-oxazolyl, tetrahydro-oxadiazolyl, tetrahydrodioxazolyl, tetrahydro-oxathiazolyl, hexahydrotriazinyl, tetrahydro-oxazinyl, 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 suitable value for a heterocyclyl group which bears 1 or 2 oxo (=0) 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.
[0048] 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.
[0049] 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.
[0050] "Heterocyclyl(1-6C)alkyl" means a heterocyclyl group covalently attached to a (1- 6C)alkylene group, both of which are defined herein.
[0051] The term "heteroaryl" or "heteroaromatic" means an aromatic mono-, bi-, or polycyclic ring incorporating one or more (for example 1-4, 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.
[0052] 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[2,3-b]furanyl, 2H-furo[3,2-b]-pyranyl, 5H-pyrido[2,3-d]-o-oxazinyl, 1 /-/-pyrazolo[4,3-d]-oxazolyl,
4H-imidazo[4,5-d]thiazolyl, pyrazino[2,3-d]pyridazinyl, imidazo[2, 1-b]thiazolyl, imidazo[1 ,2-b][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 non-aromatic, 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- 5]pyrazinyl and 3,4-dihydro-2/-/-pyrido[3,2-£>][1 ,4]oxazinyl.
[0053] 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.
[0054] Examples of six membered heteroaryl groups include but are not limited to pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl and triazinyl.
[0055] 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.
[0056] 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.
[0057] 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.
[0058] "Heteroaryl(1-6C)alkyl" means a heteroaryl group covalently attached to a (1- 6C)alkylene group, both of which are defined herein. Examples of heteroaralkyi groups include pyridin-3-ylmethyl, 3-(benzofuran-2-yl)propyl, and the like.
[0059] 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.
[0060] 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.
[0061] 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. [0062] 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. N H) 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.
[0063] 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.
[0064] The phrase "compound of the invention" means those compounds which are disclosed herein, both generically and specifically.
Compounds of the invention
[0065] In one aspect, the present invention relates to compounds, or pharmaceutically acceptable salts, hydrates or solvates thereof, having the structural formula (I) shown below:
Figure imgf000012_0001
(I)
wherein:
HET is selected from one of the following:
Figure imgf000013_0001
wherein -^1 denotes the point of attachment;
Ri is selected from hydrogen, (1-4C)haloalkyl, (1-4C)haloalkoxy or a group of the formula:
-L-Y-Q
wherein:
L is absent or (1-5C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkyl or oxo;
Y is absent or O, S, SO, S02, N(Ra), C(O), C(0)0, OC(O), C(0)N(Ra), N(Ra)C(0), N(Ra)C(0)N(Rb), N(Ra)C(0)0, OC(0)N(Ra), S(0)2N(Ra), or N(Ra)S02, wherein Ra and Rb are each independently selected from hydrogen or (1-4C)alkyl; and
Q is hydrogen, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, aryl, (3- 10C)cycloalkyl, (3-10C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Q is optionally further substituted by one or more substituent groups independently selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, amino, (1-4C)aminoalkyl, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, mercapto, ureido, NRcRd, ORc, C(0)Rc, C(0)ORc, OC(0)Rc, C(0)N(Rd)Rc, N(Rd)C(0)Rc, S(0)yRc (where y is 0, 1 or 2), S02N(Rd)Rc, N(Rd)S02Rc, Si(Rd)(Rc)Re or (CH2)zNRcRd (where z is 1 , 2 or 3); wherein Rc, Rd and Re are each independently selected from hydrogen, (1-6C)alkyl or (3-6C)cycloalkyl; or Rc and Rd can be linked such that, together with the nitrogen atom to which they are attached, they form a 4-7 membered heterocyclic ring which is optionally substituted by one or more substituents selected from (1- 4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1- 4C)alkylamino, amino, cyano or hydroxyl; or
Q is optionally substituted by a group of the formula:
Figure imgf000014_0001
wherein:
Li is absent or (1-3C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkyl or oxo;
LQi is absent or selected from or O, S, SO, S02, N(Rf), C(O), C(0)0, OC(O), C(0)N(Rf), N(Rf)C(0), N(Rg)C(0)N(Rf), N(Rf)C(0)0, OC(0)N(Rf), S(0)2N(Rf), or N(Rf)S02, wherein Rf and Rg are each independently selected from hydrogen or (1- 2C)alkyl; and
Zi is hydrogen, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, (3- 8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Zi is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, mercapto, ureido, aryl, heteroaryl, heterocycyl, (3-6C)cycloalkyl, NRhRi, ORh, C(0)Rh, C(0)ORh, OC(0)Rh, C(0)N(Ri)Rh, N(Ri)C(0)Rh, S(0)yaRh (where ya is 0, 1 or 2), S02N(Ri)Rh, N(Ri)S02Rh or (CH2)zaNRiRh (where za is 1 , 2 or 3); wherein Rh and R, are each independently selected from hydrogen, (1-4C)alkyl or (3- 6C)cycloalkyl; Ria and Rib are each independently selected from hydrogen, (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl or mercapto;
W is selected from O, S or NRj, wherein Rj is selected from hydrogen or (1- 2C)alkyl;
bonds a, b, c and d are independently selected from a single or double bond;
Xi and X2 are each independently selected from N or CRkWhen bond a is a double bond, or NRi or CRkRi when bond a is a single bond;
wherein
Rk is selected from hydrogen, halo, (1-4C)alkyl, (1-4C)alkoxy, amino, (1-4C)alkylamino, (1-4C)dialkylamino, cyano, (2C)alkynyl, C(0)R ki, C(0)ORki, OC(0)Rki, C(0)N(Rk2)Rki, N(Rk2)C(0)Rki, S(0)ybRki (where yb is 0, 1 or 2), S02N(Rk2)Rki, N(Rk2)S02Rki or (CH2)zbNRkiRk2 (where zb is 1 , 2 or 3); wherein said (1-4C)alkyl is optionally substituted by one or more substituents selected from amino, hydroxy, (1-2C)alkoxy or halo;
Ri is selected from hydrogen or (1-4C)alkyl; and
Rki and Rk2 are each independently selected from hydrogen or (1- 4C)alkyl;
X3 IS selected from N or CRmwhen bond b is a double bond, or NRn or CRmRn when bond b is a single bond;
wherein
Rm is selected from hydrogen, halo, (1-4C)alkyl, (1-4C)alkoxy, amino, (1-4C)alkylamino, (1-4C)dialkylamino, cyano, (2C)alkynyl, C(0)Rmi, C(0)ORmi, OC(0)Rmi, C(0)N(Rm2)Rm1 , N(Rm2)C(0)Rmi, S(0)ycRmi (where yc is 0, 1 or 2), S02N(Rm2)Rmi, N(Rm2)S02Rmi or
(CH2)zcNRmiRm2 (where zc is 1 , 2 or 3); wherein said (1-4C)alkyl is optionally substituted by one or more substituents selected from amino, hydroxy, (1-2C)alkoxy or halo;
Rn is selected from hydrogen or (1-4C)alkyl; and
Rmi and Rm2 are each independently selected from hydrogen or (1- 4C)alkyl; X4 is selected from N or CR0when bond d is a double bond, or NRX or CR0RX when bond d is a single bond;
wherein
Ro is selected from hydrogen, halo, (1-4C)alkyl, (1-4C)alkoxy, amino, (1-4C)alkylamino, (1-4C)dialkylamino, cyano, (2C)alkynyl, C(0)R0i, C(0)ORoi, OC(0)Roi, C(0)N(Ro2)Roi, N(Ro2)C(0)R0i, S(0)ydR0i (where yd is 0, 1 or 2), S02N(Ro2)Roi, N(Ro2)S02R0i or (CH2)ZdNR0iRo2 (where zd is 1 , 2 or 3); wherein said (1-4C)alkyl is optionally substituted by one or more substituents selected from amino, hydroxy, (1-2C)alkoxy or halo;
Rx is selected from hydrogen or (1-4C)alkyl; and
R01 and Ro2 are each independently selected from hydrogen or (1- 4C)alkyl;
R2 is selected from hydrogen, (1-4C)alkyl or a group of the formula:
-L2-Y2-Q2
wherein:
L2 is absent or (1-3C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkyl or oxo;
Y2 is absent or C(O), C(0)0, C(0)N(Rp), wherein Rp is selected from hydrogen or (1-4C)alkyl; and
Q2 is hydrogen, (1-6C)alkyl, aryl, (3-8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Q2 is optionally further substituted by one or more substituent groups independently selected from (1- 4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, NRqRr, ORq, wherein Rq and Rr are each independently selected from hydrogen, (1-4C)alkyl or (3- 6C)cycloalkyl;
R3 is selected from a group of the formula:
Figure imgf000016_0001
wherein:
Y3 is C(O), C(0)N(Ry), C(0)N(Ry)0, N(Ry)(0)C, C(0)0, OC(O), N(Ry)C(0)N(Ryi), S02N(Ry), N(Ry)S02, oxazolyl, triazolyl, oxadiazolyl, thiazolyl, imidazolyl, thiadiazolyl, pyridinyl, pyrazolyl, pyrrolyl or tetrazolyl, wherein Ry and Ryi are independently selected from hydrogen or (1-2C)alkyl; and
Q3 is hydrogen, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, (3-8C)cycloalkyl, (3- 8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Q3 is optionally further substituted by one or more substituent groups independently selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, NRzRaa, ORz, wherein Rz and Raa are each independently selected from hydrogen, (1- 4C)alkyl or (3-6C)cycloalkyl; or Q3 is optionally substituted by a group of the formula:
Figure imgf000017_0001
wherein:
l_4 is absent or (1-3C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkyl or oxo;
LQ4 is absent or selected from or O, S, SO, S02, N(Rab), C(O), C(0)0, OC(O), C(0)N(Rab), N(Rab)C(0), N(Rac)C(0)N(Rab), N(Rab)C(0)0, OC(0)N(Rab), S(0)2N(Rab), or N(Rab)S02, wherein Rab and Rac are each independently selected from hydrogen or (1-2C)alkyl; and
Z4 is hydrogen, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, (3- 8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Z4 is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, mercapto, ureido, aryl, heteroaryl, heterocycyl, (3-6C)cycloalkyl, NRadRae, ORad, C(0)Rad, C(0)ORad, OC(0)Rad, C(0)N(Rae)Rad, N(Rae)C(0)Rad, S(0)yeRad (where ye is 0, 1 or 2), S02N(Rae)Rad, N(Rae)S02Rad or (CH2)zeNRadRae (where ze is 1 , 2 or 3); wherein Rad and Rae are each independently selected from hydrogen, (1-4C)alkyl or (3- 6C)cycloalkyl; or
Q3 and Ryare linked such that, together with the nitrogen atom to which they are attached, they form a 4-7 membered heterocyclic ring which is optionally substituted by one or more substituents selected from (1- 4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1- 4C)alkylamino, amino, cyano or hydroxyl;
with the proviso that only one or two of Xi , X2, X3 or X4 can be N.
[0066] Particular compounds of the invention include, for example, compounds of the Formula I, or pharmaceutically acceptable salts and/or solvates thereof, wherein, unless otherwise stated, each of HET, Ri , Ria, Rib, W, bonds a, b, c and d, Xi , X2, X3, X4, 2 and R3 and any associated substituent groups has any of the meanings defined hereinbefore or in any of paragraphs (1) to (68) hereinafter: -
(1) HET is selected from one of the following:
Figure imgf000018_0001
Figure imgf000019_0001
Figure imgf000020_0001
(6) HET is selected from one of the following:
Figure imgf000021_0001
Ri is selected from hydrogen, (1-4C)haloalkyl, (1-4C)haloalkoxy or a group of the formula:
-L-Y-Q
wherein:
L is absent or (1-5C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkyl or oxo;
Y is absent or O, S, SO, S02, N(Ra), C(O), C(0)0, OC(O), C(0)N(Ra), N(Ra)C(0), S(0)2N(Ra), or N(Ra)S02, wherein Ra is selected from hydrogen or (1-4C)alkyl; and
Q is hydrogen, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, aryl, (3- 10C)cycloalkyl, (3-10C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Q is optionally further substituted by one or more substituent groups independently selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, amino, (1-4C)aminoalkyl, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, mercapto, ureido, NRcRd, ORc, C(0)Rc, C(0)ORc, OC(0)Rc, C(0)N(Rd)Rc, N(Rd)C(0)Rc, S(0)yRc (where y is 0, 1 or 2), S02N(Rd)Rc, N(Rd)S02Rc, Si(Rd)(Rc)Re or (CH2)zNRdRc (where z is 1 , 2 or 3); wherein Rc, Rd and Re are each independently selected from hydrogen, (1-6C)alkyl or (3-6C)cycloalkyl; or Rc and Rd can be linked such that, together with the nitrogen atom to which they are attached, they form a 4-7 membered heterocyclic ring which is optionally substituted by one or more substituents selected from (1- 4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1- 4C)alkylamino, amino, cyano or hydroxy; or
Q is optionally substituted by a group of the formula:
Figure imgf000022_0001
wherein:
Li is absent or (1-3C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkyl;
LQi is absent or selected from or O, S, SO, S02, N(Rf), C(O), C(0)0, OC(O), C(0)N(Rf), N(Rf)C(0), N(Rf)C(0)0, S(0)2N(Rf), or N(Rf)S02, wherein Rf is selected from hydrogen or (1- 2C)alkyl; and
Zi is hydrogen, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, (3- 8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Zi is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, mercapto, ureido, aryl, heteroaryl, heterocycyl, (3-6C)cycloalkyl, NRhR, or ORh, wherein Rh and R, are each independently selected from hydrogen, (1-4C)alkyl or (3-6C)cycloalkyl;
(9) Ri is selected from hydrogen, (1-4C)haloalkyl, (1-4C)haloalkoxy or a group of the formula:
-L-Y-Q
wherein:
L is absent or (1-3C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkyl or oxo; Y is absent or O, N(Ra), C(O), C(0)0, OC(O), C(0)N(Ra), N(Ra)C(0), S(0)2N(Ra), or N(Ra)S02, wherein Ra is selected from hydrogen or (1- 4C)alkyl; and
Q is hydrogen, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, aryl, (3- 10C)cycloalkyl, (3-10C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Q is optionally further substituted by one or more substituent groups independently selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, amino, (1-4C)aminoalkyl, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, mercapto, ureido, NRcRd, ORc, C(0)Rc, C(0)ORc, OC(0)Rc, C(0)N(Rd)Rc, N(Rd)C(0)Rc, S(0)yRc (where y is 0, 1 or 2), S02N(Rd)Rc, N(Rd)S02Rc, Si(Rd)(Rc)Re or (CH2)zNRdRc (where z is 1 , 2 or 3); wherein Rc, Rd and Re are each independently selected from hydrogen, (1-6C)alkyl or (3-6C)cycloalkyl; or Rc and Rd can be linked such that, together with the nitrogen atom to which they are attached, they form a 4-7 membered heterocyclic ring which is optionally substituted by one or more substituents selected from (1- 4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1- 4C)alkylamino, amino, cyano or hydroxy; or
Q is optionally substituted by a group of the formula:
Figure imgf000023_0001
wherein:
Li is absent or (1-3C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkyl;
LQi is absent or selected from or C(O), C(0)0, OC(O), C(0)N(Rf), N(Rf)C(0) or N(Rf)C(0)0, wherein Rf is selected from hydrogen or (1-2C)alkyl; and
Zi is hydrogen, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, (3- 8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Zi is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano, hydroxy, NRhR, or ORh, wherein Rh and R, are each independently selected from hydrogen, (1-4C)alkyl or cyclopropyl; (10) Ri is selected from hydrogen, (1-4C)haloalkyl, (1-4C)haloalkoxy or a group of the formula:
-L-Y-Q
wherein:
L is absent or (1-3C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkyl or oxo;
Y is absent or O, N(Ra), C(O), C(0)0, OC(O), C(0)N(Ra), N(Ra)C(0), S(0)2N(Ra), or N(Ra)S02, wherein Ra is selected from hydrogen or (1- 4C)alkyl; and
Q is hydrogen, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, aryl, (3- 10C)cycloalkyl, (3-10C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Q is optionally further substituted by one or more substituent groups independently selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, amino, (1-4C)aminoalkyl, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, mercapto, ureido, NRcRd, ORc, C(0)Rc, C(0)ORc, OC(0)Rc, C(0)N(Rd)Rc, N(Rd)C(0)Rc, S(0)yRc (where y is 0, 1 or 2), S02N(Rd)Rc, N(Rd)S02Rc, Si(Rd)(Rc)Re or (CH2)zNRdRc (where z is 1 , 2 or 3); wherein Rc, Rd and Re are each independently selected from hydrogen, (1-6C)alkyl or (3-6C)cycloalkyl; or Rc and Rd can be linked such that, together with the nitrogen atom to which they are attached, they form a 4-7 membered heterocyclic ring which is optionally substituted by one or more substituents selected from (1- 4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1- 4C)alkylamino, amino, cyano or hydroxy;
(11) Ri is selected from hydrogen, (1-4C)haloalkyl, (1-4C)haloalkoxy or a group of the formula:
-L-Y-Q
wherein:
L is absent or (1-3C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkyl or oxo;
Y is absent or C(O), C(0)0, OC(O), C(0)N(Ra) or N(Ra)C(0), wherein Ra is selected from hydrogen or (1-4C)alkyl; and Q is hydrogen, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, aryl, (3- 10C)cycloalkyl, (3-10C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Q is optionally further substituted by one or more substituent groups independently selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, amino, (1-4C)aminoalkyl, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, mercapto, ureido, NRcRd, ORc, C(0)Rc, C(0)ORc, OC(0)Rc, C(0)N(Rd)Rc, N(Rd)C(0)Rc, S(0)yRc (where y is 0, 1 or 2), S02N(Rd)Rc, N(Rd)S02Rc, Si(Rd)(Rc)Re or (CH2)zNRdRc (where z is 1 , 2 or 3); wherein Rc, Rd and Re are each independently selected from hydrogen, (1-6C)alkyl or (3-6C)cycloalkyl;
(12) Ri is selected from hydrogen, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-6C)alkyl, (2- 6C)alkenyl, (2-6C)alkynyl, aryl, (3-10C)cycloalkyl, (3-10C)cycloalkenyl, heteroaryl or heterocyclyl; wherein each of said substituents is optionally further substituted by one or more substituent groups independently selected from (1-4C)alkyl, halo, (1- 4C)haloalkyl, (1-4C)haloalkoxy, amino, (1-4C)aminoalkyl, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, mercapto, ureido, NRcRd, ORc, C(0)Rc, C(0)ORc, OC(0)Rc, C(0)N(Rd)Rc, N(Rd)C(0)Rc, S(0)yRc (where y is 0, 1 or 2), S02N(Rd)Rc, N(Rd)S02Rc, Si(Rd)(Rc)Re or (CH2)zNRdRc (where z is 1 , 2 or 3); wherein Rc, Rd and Re are each independently selected from hydrogen, (1-6C)alkyl or (3-6C)cycloalkyl;
(13) Ri is selected from hydrogen, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-6C)alkyl, (3- 10C)cycloalkyl or heterocyclyl; wherein each of said substituents is optionally further substituted by one or more substituent groups independently selected from (1- 4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, amino, (1-4C)aminoalkyl, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, mercapto, ureido, NRcRd, ORc or
Si(Rd)(Rc)Re; wherein Rc, Rd and Re are each independently selected from hydrogen or (1-6C)alkyl;
(14) Ri is selected from hydrogen, (1-6C)alkyl, 4-7 membered heterocyclyl or (3- 10C)cycloalkyl; wherein each of said substituents is optionally further substituted by one or more substituent groups independently selected from (1-4C)alkyl, halo, amino, (1-4C)aminoalkyl, cyano, hydroxy, carboxy, NRcRd, ORc, S(0)2Rc or Si(Rd)(Rc)Re; wherein Rc, Rd and Re are each independently selected from hydrogen or (1-4C)alkyl;
(15) Ri is selected from hydrogen, (4-6C)alkyl or 4-7 membered heterocyclyl; wherein each of said substituents is optionally further substituted by one or more substituent groups independently selected from (1-4C)alkyl, halo, amino, (1-4C)aminoalkyl, cyano, hydroxy, carboxy, NRcRd, ORc orS(0)2Rc; wherein Rc, and Rd are each independently selected from hydrogen or (1-4C)alkyl;
(16) Ri is selected from hydrogen, (1-6C)alkyl or (3-10C)cycloalkyl; wherein each of said substituents is optionally further substituted by one or more substituent groups independently selected from (1-4C)alkyl, halo, amino, (1-4C)aminoalkyl, cyano, hydroxy, carboxy, NRcRd, ORcor Si(Rd)(Rc)Re; wherein Rc, Rd and Re are each independently selected from hydrogen or (1-4C)alkyl;
(157) Ri is selected from hydrogen, (1-6C)alkyl or (3-6C)cycloalkyl; wherein each of said substituents is optionally further substituted by one or more substituent groups independently selected from (1-4C)alkyl, ORc or Si(Rd)(Rc)Re; wherein Rc, Rd and Re are each independently selected from hydrogen or (1-2C)alkyl;
(18) Ri is a (1-6C)alkyl or (4-6C)cycloalkyl;
(19) Ri is a (4-6C)alkyl;
(20) Ri is terf-butyl;
(21) Ria and Rib are each independently selected from hydrogen, (1-4C)alkyl, halo, (1- 4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano or hydroxy;
(22) Ria and Rib are each independently selected from hydrogen, (1-4C)alkyl, halo, (1- 4C)haloalkyl, (1-4C)alkoxy, amino, cyano or hydroxy;
(23) Ria and Rib are each independently selected from hydrogen or (1-4C)alkyl;
(24) Ria and Rib are each hydrogen;
(25) W is selected from O or S;
(26) W is O;
(27) bonds a, b, c and d are all double bonds;
(28) bonds a, b, c and d are all single bonds;
(29) Xi and X2 are each independently selected from N or CRkWhen bond a is a double bond, or NRi or CRkRi when bond a is a single bond;
wherein
Rk is selected from hydrogen, halo, (1-4C)alkyl, (1-4C)alkoxy, amino, (1-4C)alkylamino, (1-4C)dialkylamino, cyano, (2C)alkynyl, wherein said (1-4C)alkyl is optionally substituted by one or more substituents selected from amino, hydroxy, (1-2C)alkoxy or halo; and Ri is selected from hydrogen or (1-4C)alkyl;
Xi and X2 are each independently selected from N or CRkWhen bond a is a double bond, or NRi or CRkRi when bond a is a single bond;
wherein
Rk is selected from hydrogen, halo, (1-4C)alkyl, (1-4C)alkoxy, amino, (1-4C)alkylamino, (1-4C)dialkylamino, cyano, (2C)alkynyl; and
Ri is selected from hydrogen or (1-4C)alkyl;
Xi and X2 are each independently selected from N or CRk and bond a is a double bond, wherein Rk is selected from hydrogen, halo, (1-4C)alkyl or amino;
Xi and X2 are CRk and bond a is a double bond, wherein Rk is selected from hydrogen, halo or (1-4C)alkyl;
Xi and X2 are each independently selected from N or CH and bond a is a double bond;
Xi and X2 are CH and bond a is a double bond;
X3 is selected from N or CRi when bond b is a double bond, or NRn or CRmRn when bond b is a single bond;
wherein
Rm is selected from hydrogen, halo, (1-4C)alkyl, (1-4C)alkoxy, amino, (1- 4C)alkylamino, (1-4C)dialkylamino, cyano, (2C)alkynyl, wherein said (1- 4C)alkyl is optionally substituted by one or more substituents selected from amino, hydroxy, (1-2C)alkoxy or halo; and
Rn is selected from hydrogen or (1-4C)alkyl;
X3 is selected from N or CRm when bond b is a double bond, or NRn or CRmRn when bond b is a single bond;
wherein
Rm is selected from hydrogen, halo, (1-4C)alkyl, (1-4C)alkoxy, amino, (1- 4C)alkylamino, (1-4C)dialkylamino, cyano, (2C)alkynyl; and
Rn is selected from hydrogen or (1-4C)alkyl;
X3 is selected from N or CRm and bond b is a double bond, wherein Rm is selected from hydrogen, halo, (1-4C)alkyl or amino; X3 IS CRm and bond b is a double bond, wherein Rm is selected from hydrogen, halo, (1-4C)alkyl or amino;
X3 is selected from N or CH and bond b is a double bond;
X3 is CH and bond b is a double bond;
X4 is selected from N or CR0when bond d is a double bond, or NRX or CR0RX when bond d is a single bond;
wherein
Ro is selected from hydrogen, halo, (1-4C)alkyl, (1-4C)alkoxy, amino, (1-4C)alkylamino, (1-4C)dialkylamino, cyano, (2C)alkynyl, wherein said (1-4C)alkyl is optionally substituted by one or more substituents selected from amino, hydroxy, (1-2C)alkoxy or halo; and
Rx is selected from hydrogen or (1-4C)alkyl;
X4 is selected from N or CR0when bond d is a double bond, or NRX or CR0RX when bond d is a single bond;
wherein
Ro is selected from hydrogen, halo, (1-4C)alkyl, (1-4C)alkoxy, amino, (1-4C)alkylamino, (1-4C)dialkylamino, cyano or (2C)alkynyl; and
Rx is selected from hydrogen or (1-4C)alkyl;
X4 is selected from N or CR0 and bond d is a double bond, wherein R0 is selected from halo, (1-4C)alkyl, (1-4C)alkoxy, amino, (1-4C)alkylamino, (1-4C)dialkylamino, cyano, (2C)alkynyl, C(0)R0i, C(0)OR0i, OC(0)R0i, C(0)N(Ro2)Roi, N(Ro2)C(0)R0i, S(0)ydRoi (where yd is 0, 1 or 2), S02N(Ro2)Roi, N(Ro2)S02Roi or (CH2)ZdNR0iRo2 (where zd is 1 , 2 or 3); wherein said (1-4C)alkyl is optionally substituted by one or more substituents selected from amino, hydroxy, (1-2C)alkoxy or halo; and wherein R01 and Ro2 are each independently selected from hydrogen or (1-4C)alkyl;
X4 is selected from N or CR0 and bond d is a double bond, wherein R0 is selected from hydrogen, halo, (1-4C)alkyl, (1-4C)alkoxy, amino, (1-4C)alkylamino, (1- 4C)dialkylamino, cyano or (2C)alkynyl;
X4 is CR0 and bond d is a double bond, wherein R0 is selected from halo, (1-4C)alkyl, (1-4C)alkoxy, amino, (1-4C)alkylamino, (1-4C)dialkylamino, cyano or (2C)alkynyl;
X4 is CR0 and bond d is a double bond, wherein R0 is selected from hydrogen, halo, (1-4C)alkyl or amino; (47) X4 is CR0 and bond d is a double bond, wherein R0 is selected from halo or (1- 4C)alkyl;
(48) X4 is CR0 and bond d is a double bond, wherein R0 is a halogen (e.g. chloro, bromo or fluoro, particularly chloro);
(49) R2 is selected from hydrogen, (1-4C)alkyl or a group of the formula:
Figure imgf000029_0001
wherein:
l_2 is absent or (1-3C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkyl or oxo;
Y2 is absent or C(O), C(0)0, C(0)N(Rp), wherein Rp is selected from hydrogen or (1-4C)alkyl; and
Q2 is hydrogen, (1-6C)alkyl, aryl, (3-8C)cycloalkyl, heteroaryl or heterocyclyl; wherein Q2 is optionally further substituted by one or more substituent groups independently selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)haloalkoxy, amino, cyano, hydroxy, NRqRr, ORq, wherein Rq and Rr are each independently selected from hydrogen or (1-4C)alkyl;
(50) R2 is selected from hydrogen, (1-4C)alkyl or a group of the formula:
Figure imgf000029_0002
wherein:
Y2 is absent or C(O), C(0)0, C(0)N(Rp), wherein Rp is selected from hydrogen or (1-4C)alkyl; and
Q2 is hydrogen, (1-6C)alkyl, aryl, (3-8C)cycloalkyl, heteroaryl or heterocyclyl; wherein Q2 is optionally further substituted by one or more substituent groups independently selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)haloalkoxy, amino, cyano, hydroxy, NRqRr, ORq, wherein Rq and Rr are each independently selected from hydrogen or (1-4C)alkyl;
(51) R2 is selected from hydrogen, (1-4C)alkyl or a group of the formula:
Figure imgf000029_0003
wherein:
Y2 is C(0)N(Rp), wherein Rp is selected from hydrogen or (1-4C)alkyl; and Q2 is (1-6C)alkyl, aryl, (3-8C)cycloalkyl, heteroaryl or heterocyclyl; wherein Q2 is optionally further substituted by one or more substituent groups independently selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)haloalkoxy, amino, cyano or hydroxy;
(52) R2 is selected from hydrogen or (1-4C)alkyl;
(53) R2 is hydrogen;
(54) R3 is selected from a group of the formula:
Figure imgf000030_0001
wherein:
Y3 is C(O), C(0)N(Ry), C(0)N(Ry)0, N(Ry)(0)C, C(0)0, OC(O), N(Ry)C(0)N(Ryi), S02N(Ry), N(Ry)S02, oxazolyl, triazolyl, oxadiazolyl, thiazolyl, imidazolyl, pyrazolyl or tetrazolyl, wherein Ry and Ryi are independently selected from hydrogen or (1-2C)alkyl; and
Q3 is hydrogen, (1-6C)alkyl, (1-6C)alkoxy, aryl, aryl(1-2C)alkyl, (3- 8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Q3 is optionally further substituted by one or more substituent groups independently selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)haloalkoxy, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, NRzRaa, ORz, wherein Rz and Raa are each independently selected from hydrogen, (1-4C)alkyl or (3-6C)cycloalkyl; or Q3 is optionally substituted by a group of the formula:
Figure imgf000030_0002
wherein:
l_4 is absent or (1-3C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkyl or oxo;
LQ4 is absent or selected from or O, N(Rab), C(O), C(0)0, OC(O), C(0)N(Rab), N(Rab)C(0), S(0)2N(Rab), or N(Rab)S02, wherein Rab is selected from hydrogen or (1-2C)alkyl; and
Z4 is hydrogen, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, (3- 8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Z4 is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, mercapto, ureido, aryl, heteroaryl, heterocycyl, (3-6C)cycloalkyl, NRadRae, ORad,
C(0)Rad, C(0)ORad, OC(0)Rad, C(0)N(Rae)Rad, N(Rae)C(0)Rad,
S(0)yeRad (where ye is 0, 1 or 2), S02N(Rae)Rad, N(Rae)S02Rad Or (CH2)zeNRadRae (where ze is 1 , 2 or 3); wherein Rad and Rae are each independently selected from hydrogen, (1-4C)alkyl or (3- 6C)cycloalkyl; or
Qz and Ry are linked such that, together with the nitrogen atom to which they are attached, they form a 4-7 membered heterocyclic ring which is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano or hydroxyl;
elected from a group of the formula:
Figure imgf000031_0001
wherein:
Y3 is C(O), C(0)N(Ry), N(Ry)(0)C, C(0)0, OC(O), triazolyl, oxadiazolyl or tetrazolyl, wherein Ry is selected from hydrogen or (1-2C)alkyl; and
Q3 is hydrogen, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, (3-8C)cycloalkyl, (3- 8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Q3 is optionally further substituted by one or more substituent groups independently selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, NRzRaa, ORz, wherein Rz and Raa are each independently selected from hydrogen, (1- 4C)alkyl or (3-6C)cycloalkyl; or Q3 is optionally substituted by a group of the formula:
Figure imgf000031_0002
wherein:
l_4 is absent or (1-3C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkyl or oxo;
LQ4 is absent or selected from or O, S, SO, S02, N(Rab), C(O), 0(0)0, 00(0), C(0)N(Rab), N(Rab)C(0), N(Rac)C(0)N(Rab), N(Rab)C(0)0, OC(0)N(Rab), S(0)2N(Rab), or N(Rab)S02, wherein Rab and Rac are each independently selected from hydrogen or (1-2C)alkyl; and
Z4 is hydrogen, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, (3- 8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Z4 is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, mercapto, ureido, aryl, heteroaryl, heterocycyl, (3-6C)cycloalkyl, NRadRae, ORad,
C(0)Rad, C(0)ORad, OC(0)Rad, C(0)N(Rae)Rad, N(Rae)C(0)Rad,
S(0)yeRad (where ye is 0, 1 or 2), S02N(Rae)Rad, N(Rae)S02Rad Or (CH2)zeNRadRae (where ze is 1 , 2 or 3); wherein Rad and Rae are each independently selected from hydrogen, (1-4C)alkyl or (3- 6C)cycloalkyl;
(56) R3 is selected from a group of the formula:
Figure imgf000032_0001
wherein:
Y3 is C(O), C(0)N(Ry), C(0)N(Ry)0, N(Ry)(0)C, C(0)0, OC(O), N(Ry)C(0)N(Ryi), N(Ry)S02, oxazoyl, triazolyl, oxadiazolyl, thiadiazolyl or tetrazolyl, wherein Ry and Ryi are independently selected from hydrogen or (1-2C)alkyl; and
Q3 is hydrogen, (1-6C)alkyl, (1-6C)alkoxy, aryl, aryl(1-2C)alkyl, (3- 8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Q3 is optionally further substituted by one or more substituent groups independently selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)haloalkoxy, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, NRzRaa, ORz, wherein Rz and Raa are each independently selected from hydrogen, (1-4C)alkyl or (3-6C)cycloalkyl; or Q3 is optionally substituted by a group of the formula:
Figure imgf000032_0002
wherein:
L4 is absent or (1-3C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkyl or oxo; LQ4 is absent or selected from or O, N(Rab), C(O), C(0)0,
OC(O), C(0)N(Ra ), N(Ra )C(0), S(0)2N(Ra ), or N(Ra )S02, wherein Rab is selected from hydrogen or (1-2C)alkyl; and
Z4 is hydrogen, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, (3- 8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Z4 is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, mercapto, ureido, aryl, heteroaryl, heterocycyl, (3-6C)cycloalkyl, NRadRae, ORad,
C(0)Rad, C(0)ORad, OC(0)Rad, C(0)N(Rae)Rad, N(Rae)C(0)Rad,
S(0)yeRad (where ye is 0, 1 or 2), S02N(Rae)Rad, N(Rae)S02Rad Or (CH2)zeNRadRae (where ze is 1 , 2 or 3); wherein Rad and Rae are each independently selected from hydrogen, (1-4C)alkyl or (3- 6C)cycloalkyl; or
Qz and Ry are linked such that, together with the nitrogen atom to which they are attached, they form a 4-7 membered heterocyclic ring which is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano or hydroxyl;
(57) R3 is selected from a group of the formula:
Figure imgf000033_0001
wherein:
Y3 is C(O), C(0)N(Ry), C(0)N(Ry)0, N(Ry)(0)C, C(0)0, OC(O), wherein Ry is selected from hydrogen or (1-2C)alkyl; and
Qs is hydrogen, (1-6C)alkyl, (1-6C)alkoxy, aryl, aryl(1-2C)alkyl, (3- 8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Q3 is optionally further substituted by one or more substituent groups independently selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)haloalkoxy, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, NRzRaa, ORz, wherein Rz and Raa are each independently selected from hydrogen, (1-4C)alkyl or (3-6C)cycloalkyl; or Q3 is optionally substituted by a group of the formula: wherein:
l_4 is absent or (1-3C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkyl or oxo;
LQ4 is absent or selected from or O, N(Rab), C(O), C(0)0, OC(O), C(0)N(Ra ), N(Ra )C(0), S(0)2N(Ra ), or N(Ra )S02, wherein Rab is selected from hydrogen or (1-2C)alkyl; and
Z4 is hydrogen, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, (3- 8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Z4 is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, mercapto, ureido, aryl, heteroaryl, heterocycyl, (3-6C)cycloalkyl, NRadRae, ORad,
C(0)Rad, C(0)ORad, OC(0)Rad, C(0)N(Rae)Rad, N(Rae)C(0)Rad,
S(0)yeRad (where ye is 0, 1 or 2), S02N(Rae)Rad, N(Rae)S02Rad Or (CH2)zeNRadRae (where ze is 1 , 2 or 3); wherein Rad and Rae are each independently selected from hydrogen, (1-4C)alkyl or (3- 6C)cycloalkyl; or
Q3 and Ryare linked such that, , together with the nitrogen atom to which they are attached, they form a 4-7 membered heterocyclic ring which is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano or hydroxyl;
(58) R3 is selected from a group of the formula:
Figure imgf000034_0001
wherein:
Y3 is C(O), C(0)N(Ry), C(0)N(Ry)0, N(Ry)(0)C, C(0)0, OC(O), wherein Ry is selected from hydrogen or (1-2C)alkyl; and
Q3 is hydrogen, (1-6C)alkyl, (1-6C)alkoxy, aryl, aryl(1-2C)alkyl, (3- 8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Q3 is optionally further substituted by one or more substituent groups independently selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)haloalkoxy, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, NRzRaa, ORz, wherein Rz and Raa are each independently selected from hydrogen, (1-4C)alkyl or (3-6C)cycloalkyl; or Q3 is optionally substituted by a group of the formula:
Figure imgf000035_0001
wherein:
l_4 is absent or (1-3C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkyl or oxo;
LQ4 is absent or selected from or O, N(Rab), C(O), C(0)0, OC(O), C(0)N(Rab), N(Rab)C(0), S(0)2N(Rab), or N(Rab)S02, wherein Rab is selected from hydrogen or (1-2C)alkyl; and
Z4 is hydrogen, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, (3- 8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Z4 is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, mercapto, ureido, aryl, heteroaryl, heterocycyl, (3-6C)cycloalkyl, NRadRae, ORad, C(0)Rad, C(0)ORad, OC(0)Rad, C(0)N(Rae)Rad, N(Rae)C(0)Rad, S(0)yeRad (where ye is 0, 1 or 2), S02N(Rae)Rad, N(Rae)S02Rad or (CH2)zeNRadRae (where ze is 1 , 2 or 3); wherein Rad and Rae are each independently selected from hydrogen, (1-4C)alkyl or (3- 6C)cycloalkyl; or
Q3 and Ry are linked such that, together with the nitrogen atom to which they are attached, they form a 4-7 membered heterocyclic ring which is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano or hydroxyl;
(59) R3 is selected from a group of the formula:
wherein: Y3 is C(O), C(0)N(Ry), N(Ry)(0)C, C(0)N(Ry)0, C(0)0, OC(O), wherein Ry is selected from hydrogen or (1-2C)alkyl; and
Qs is hydrogen, (1-6C)alkyl, (1-6C)alkoxy, aryl, aryl(1-2C)alkyl, (3- 8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Qz is optionally further substituted by one or more substituent groups independently selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)haloalkoxy, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, NRzRaa, ORz, wherein Rz and Raa are each independently selected from hydrogen, (1-4C)alkyl or (3-6C)cycloalkyl; or Q3 is optionally substituted by a group of the formula:
Figure imgf000036_0001
wherein:
l_4 is absent or (1-3C)alkylene;
LQ4 is absent or selected from or O, N(Rab), C(O), C(0)0, OC(O), C(0)N(Rab), N(Rab)C(0), S(0)2N(Rab), or N(Rab)S02, wherein Rab is selected from hydrogen or (1-2C)alkyl; and
Z4 is hydrogen, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, (3- 8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Z4 is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, mercapto, ureido, aryl, heteroaryl, heterocycyl, (3-6C)cycloalkyl, NRadRae, ORad, C(0)Rad, C(0)ORad, OC(0)Rad, C(0)N(Rae)Rad, N(Rae)C(0)Rad, S(0)yeRad (where ye is 0, 1 or 2), S02N(Rae)Rad, N(Rae)S02Rad or (CH2)zeNRadRae (where ze is 1 , 2 or 3); wherein Rad and Rae are each independently selected from hydrogen, (1-4C)alkyl or (3- 6C)cycloalkyl;
(60) R3 is selected from a group of the formula:
Figure imgf000036_0002
wherein:
Y3 is C(0)N(Ry), wherein Ry is selected from hydrogen or (1-2C)alkyl; and Q3 is hydrogen, (1-6C)alkyl, (1-6C)alkoxy, aryl, aryl(1-2C)alkyl, (3- 8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Qz is optionally further substituted by one or more substituent groups independently selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)haloalkoxy, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, NRzRaa, ORz, wherein Rz and Raa are each independently selected from hydrogen, (1-4C)alkyl or (3-6C)cycloalkyl; or Q3 is optionally substituted by a group of the formula:
Figure imgf000037_0001
wherein:
l_4 is absent or (1-3C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkyl or oxo;
LQ4 is absent or selected from or O, S, SO, S02, N(Rab), C(O), C(0)0, OC(O), C(0)N(Rab), N(Rab)C(0), N(Rac)C(0)N(Rab), N(Rab)C(0)0, OC(0)N(Rab), S(0)2N(Rab), or N(Rab)S02, wherein Rab and Rac are each independently selected from hydrogen or (1-2C)alkyl; and
Z4 is hydrogen, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, (3- 8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Z4 is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, mercapto, ureido, aryl, heteroaryl, heterocycyl, (3-6C)cycloalkyl, NRadRae, ORad, C(0)Rad, C(0)ORad, OC(0)Rad, C(0)N(Rae)Rad, N(Rae)C(0)Rad, S(0)yeRad (where ye is 0, 1 or 2), S02N(Rae)Rad, N(Rae)S02Rad or (CH2)zeNRadRae (where ze is 1 , 2 or 3); wherein Rad and Rae are each independently selected from hydrogen, (1-4C)alkyl or (3- 6C)cycloalkyl; or
Q3 and Ry are linked such that, together with the nitrogen atom to which they are attached, they form a 4-6 membered heterocyclic ring which is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano or hydroxyl; elected from a group of the formula:
wherein:
Y3 is C(0)N(Ry), wherein Ry is selected from hydrogen or (1-2C)alkyl; and
Q3 is hydrogen, (1-6C)alkyl, (1-6C)alkoxy, aryl, aryl(1-2C)alkyl, (3- 8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Q3 is optionally further substituted by one or more substituent groups independently selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)haloalkoxy, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, NRzRaa, ORz, wherein Rz and Raa are each independently selected from hydrogen, (1-4C)alkyl or (3-6C)cycloalkyl; or Q3 is optionally substituted by a group of the formula:
Figure imgf000038_0001
wherein:
l_4 is absent or (1-3C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkyl or oxo;
LQ4 is absent or selected from or O, S, SO, S02, N(Rab), C(O), C(0)0, OC(O), C(0)N(Rab), N(Rab)C(0), N(Rac)C(0)N(Rab), N(Rab)C(0)0, OC(0)N(Rab), S(0)2N(Rab), or N(Rab)S02, wherein Rab and Rac are each independently selected from hydrogen or (1-2C)alkyl; and
Z4 is hydrogen, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, (3- 8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Z4 is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, mercapto, ureido, aryl, heteroaryl, heterocycyl, (3-6C)cycloalkyl, NRadRae, ORad, C(0)Rad, C(0)ORad, OC(0)Rad, C(0)N(Rae)Rad, N(Rae)C(0)Rad, S(0)yeRad (where ye is 0, 1 or 2), S02N(Rae)Rad, N(Rae)S02Rad or (CH2)zeNRadRae (where ze is 1 , 2 or 3); wherein Rad and Rae are each independently selected from hydrogen, (1-4C)alkyl or (3- 6C)cycloalkyl; (62) R3 is selected from a group of the formula:
wherein:
Y3 is C(0)NH; and
Qs is hydrogen, (1-6C)alkyl, (1-6C)alkoxy, aryl, aryl(1-2C)alkyl, (3- 8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Q3 is optionally further substituted by one or more substituent groups independently selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)haloalkoxy, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, NRzRaa, ORz, wherein Rz and Raa are each independently selected from hydrogen, (1-4C)alkyl or (3-6C)cycloalkyl; or Q3 is optionally substituted by a group of the formula:
Figure imgf000039_0001
wherein:
l_4 is absent or (1-3C)alkylene;
LQ4 is absent or selected from or O, N(Rab), C(O), C(0)0, or C(0)N(Rab), wherein Rab is selected from hydrogen or (1- 2C)alkyl; and
Z4 is hydrogen, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, (3- 8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Z4 is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano or hydroxy;
(63) R3 is selected from a group of the formula:
Figure imgf000039_0002
wherein:
Y3 is C(O), C(0)N(Ry), N(Ry)(0)C or C(0)0, wherein Ry is selected from hydrogen or (1-2C)alkyl; and
Qs is hydrogen, (1-6C)alkyl, (1-6C)alkoxy, aryl, aryl(1-2C)alkyl, (3- 8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Q3 is optionally further substituted by one or more substituent groups independently selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)haloalkoxy, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, NRzRaa, ORz, wherein Rz and Raa are each independently selected from hydrogen, (1-4C)alkyl or (3-6C)cycloalkyl; or Q3 is optionally substituted by a group of the formula:
Figure imgf000040_0001
wherein:
l_4 is absent or (1-3C)alkylene;
LQ4 is absent or selected from or O, N(Rab), C(O), C(0)0, or C(0)N(Rab), wherein Rab is selected from hydrogen or (1- 2C)alkyl; and
Z4 is hydrogen, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, (3- 8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Z4 is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano or hydroxy;
R3 is selected from a group of the formula:
Figure imgf000040_0002
wherein:
Y3 is C(0)NH; and
Q3 is hydrogen, (1-6C)alkyl, (1-6C)alkoxy, aryl, aryl(1-2C)alkyl, (3- 8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Q3 is optionally further substituted by one or more substituent groups independently selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)haloalkoxy, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, NRzRaa, ORz, wherein Rz and Raa are each independently selected from hydrogen or (1-4C)alkyl; or Q3 is optionally substituted by a group of the formula:
Figure imgf000040_0003
wherein: LQ4 is absent or selected from or O, N(Rab), C(O), C(0)0, or
C(0)N(Rab), wherein Rab is selected from hydrogen or (1- 2C)alkyl; and
Z4 is hydrogen, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, (3- 8C)cycloalkyl, heteroaryl or heterocyclyl; wherein Z4 is optionally substituted by one or more substituents selected from (1- 4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano or hydroxy;
(65) R3 is selected from a group of the formula:
Figure imgf000041_0001
wherein:
Y3 is C(0)NH; and
Q3 is (1-6C)alkyl, (1-6C)alkoxy, aryl, aryl(1-2C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Q3 is optionally further substituted by one or more substituent groups independently selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, NRzRaa, ORz, wherein Rz and Raa are each independently selected from hydrogen or (1-4C)alkyl; or Q3 is optionally substituted by a group of the formula:
Figure imgf000041_0002
wherein:
LQ4 is absent or selected from or O, N(Rab), C(O), C(0)0, or C(0)N(Rab), wherein Rab is selected from hydrogen or (1- 2C)alkyl; and
Z4 is hydrogen, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, (3- 8C)cycloalkyl, heteroaryl or heterocyclyl; wherein Z4 is optionally substituted by one or more substituents selected from (1- 4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano or hydroxy;
(66) R3 is selected from a group of the formula:
wherein: Y3 is C(O), C(0)0 or C(0)NH; and
Q3 is hydrogen, (1-6C)alkyl, (1-6C)alkoxy, aryl, aryl(1-2C)alkyl, (3- 8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Qz is optionally further substituted by one or more substituent groups independently selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)haloalkoxy, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, NRzRaa, ORz, wherein Rz and Raa are each independently selected from hydrogen or (1-4C)alkyl;
(67) R3 is selected from a group of the formula:
Figure imgf000042_0001
wherein:
Y3 is C(0)NH; and
Q3 is hydrogen, (1-6C)alkyl, (1-6C)alkoxy, aryl, aryl(1-2C)alkyl, (3- 8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Q3 is optionally further substituted by one or more substituent groups independently selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)haloalkoxy, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, NRzRaa, ORz, wherein Rz and Raa are each independently selected from hydrogen or (1-4C)alkyl;
(68) R3 is selected from a group of the formula:
Figure imgf000042_0002
wherein:
Y3 is C(0)NH; and
Q3 is (1-6C)alkyl, phenyl, (3-6C)cycloalkyl or 5- or 6-membered heteroaryl; wherein Q3 is optionally further substituted by one or more substituent groups independently selected from (1-4C)alkyl, halo, (1- 4C)haloalkyl, (1-4C)haloalkoxy, amino, cyano, hydroxy, NRzRaa or ORz, wherein Rz and Raa are each independently selected from hydrogen or (1-2C)alkyl.
[0067] 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. [0068] Suitably, a heteroaryl is a 5- or 6-membered heteroaryl ring comprising one, two or three heteroatoms selected from N, O or S.
[0069] 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].
[0070] Suitably an aryl group is phenyl.
[0071] Suitably, HET is as defined in any one of paragraphs (1) to (7). Most suitably, HET is as defined in paragraph (7).
[0072] Suitably, Ri is as defined in any one of paragraphs (8) to (20). More suitably, Ri is as defined in any one of paragraphs (12) to (20). Most suitably, Ri is as defined in paragraph (20).
[0073] Suitably Ria and Rib are as defined in any one of paragraphs (21) to (24). Most suitably, Ria and Rib are as defined in paragraph (24).
[0074] Suitably, W is as defined in any one of paragraphs (25) to (26). Most suitably, W is as defined in paragraph (26).
[0075] Suitably, bonds a, b, c and d are as defined in any one of paragraphs (27) to (28). Suitably, bonds a, b, c and d are as defined in paragraph (28).
[0076] Suitably, Xi and X2 are as defined in any one of paragraphs (29) to (34). Most suitably, Xi and X2 are as defined in paragraph (34).
[0077] Suitably, X3 is as defined in any one of paragraphs (35) to (40). Most suitably, X3 is as defined in paragraph (40).
[0078] Suitably, X4 is as defined in any one of paragraphs (41) to (48). Most suitably, X4 is as defined in paragraph (48).
[0079] Suitably, R2 is as defined in any one of paragraphs (49) to (53). More suitably, R2 is as defined in any one of paragraphs (51) to (53). Most suitably, R2 is as defined in paragraph (53).
[0080] Suitably, R3 is as defined in any one of paragraphs (54) to (68). Most suitably, R3 is as defined in paragraph (68).
[0081] In a particular group of compounds of the invention, the compounds have the structural Formula la (a sub-definition of formula (I)) shown below, or a pharmaceutically acceptable salt, hydrate and/or solvate thereof:
Figure imgf000044_0001
la
wherein HET, bonds a, b, c and d, Xi , X2, X3, X4, R2, Q3 and Ry each have any one of the meanings defined herein.
[0082] In an embodiment of the compounds of Formula la:
HET is as defined in any one of paragraphs (1) to (7) above;
Ri is as defined in any one of paragraphs (8) to (20) above;
Ria and Rib are as defined in any one of paragraphs (21) to (24) above;
bonds a, b, c and d are as defined in any one of paragraphs (27) to (28) above;
Xi and X2 are as defined in any one of paragraphs (29) to (34) above;
X3 is as defined in any one of paragraphs (35) to (40) above;
X4 is as defined in any one of paragraphs (41) to (48) above;
R2 is as defined in any one of paragraphs (49) to (53) above;
Ry is as defined in any one of paragraphs (54) to (63) above; and
Q3 is as defined in any one of paragraphs (54) to (68).
[0083] In another embodiment of the compounds of Formula la:
HET is as defined in paragraph (7) above;
Ri is as defined in paragraph (20) above;
Ria and Rib are as defined in paragraph (24) above;
bonds a, b, c and d are as defined in paragraph (28) above;
Xi and X2 are as defined in paragraph (34) above;
X3 is as defined in paragraph (40) above;
X4 is as defined in paragraph (47) or (48) above;
R2 is as defined in paragraph (53) above;
Ry is hydrogen; and
Q3 is as defined in paragraph (68). [0084] In a particular group of compounds of the invention, the compounds have the structural Formula lb (a sub-definition of formula (I)) shown below, or a pharmaceutically acceptable salt, hydrate and/or solvate thereof:
Figure imgf000045_0001
lb
wherein Ri , bonds a, b, c and d, Xi , X2, X3, X4, R2, Q3 and Ry each have any one of the meanings defined herein.
[0085] In an embodiment of the compounds of Formula lb:
Ri is as defined in any one of paragraphs (8) to (20) above;
bonds a, b, c and d are as defined in any one of paragraphs (27) to (28) above;
Xi and X2 are as defined in any one of paragraphs (29) to (34) above;
X3 is as defined in any one of paragraphs (35) to (40) above;
X4 is as defined in any one of paragraphs (41) to (48) above;
R2 is as defined in any one of paragraphs (49) to (53) above; and
Ry is as defined in any one of paragraphs (54) to (63) above;
Q3 is as defined in any one of paragraphs (54) to (68).
[0086] In another embodiment of the compounds of Formula lb:
Ri is as defined in paragraph (20) above;
bonds a, b, c and d are as defined in paragraph (28) above;
Xi and X2 are as defined in paragraph (34) above;
X3 is as defined in paragraph (40) above;
X4 is as defined in paragraph (47) or (48) above;
R2 is as defined in paragraph (53) above;
Ry is hydrogen; and
Q3 is as defined in paragraph (68) above. [0087] 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 imgf000046_0001
Ic
wherein Ri , Xi , X2, X3, X4, R2, Q3 and Ry each have any one of the meanings defined herein.
[0088] In an embodiment of the compounds of Formula Ic:
Ri is as defined in any one of paragraphs (8) to (20) above;
Xi and X2 are as defined in any one of paragraphs (29) to (34) above;
X3 is as defined in any one of paragraphs (35) to (40) above;
X4 is as defined in any one of paragraphs (41) to (48) above;
R2 is as defined in any one of paragraphs (49) to (53) above;
Ry is as defined in any one of paragraphs (54) to (63) above; and
Q3 is as defined in any one of paragraphs (54) to (68).
[0089] In another embodiment of the compounds of Formula Ic:
Ri is as defined in any one of paragraphs (8) to (20) above;
Xi and X2 are as defined in any one of paragraphs (29) to (34) above;
X3 is as defined in any one of paragraphs (35) to (40) above;
X4 is CH;
R2 is as defined in any one of paragraphs (49) to (53) above;
Ry is as defined in any one of paragraphs (54) to (63) above; and
Q3 is as defined in any one of paragraphs (54) to (68).
[0090] In yet another embodiment of the compounds of Formula Ic:
Ri is as defined in paragraph (20) above; Xi and X2 are as defined in paragraph (34) above;
X3 is as defined in paragraph (40) above;
X4 is as defined in paragraph (48) above;
R2 is as defined in paragraph (53) above;
Ry is hydrogen; and
Q3 is as defined in paragraph (68) above.
[0091] In an alternative embodiment of the compounds of Formula Ic:
Ri is as defined in paragraph (20) above;
Xi and X2 are as defined in paragraph (34) above;
X3 is as defined in paragraph (40) above;
X4 is CH;
R2 is as defined in paragraph (53) above;
Ry is hydrogen; and
Q3 is as defined in paragraph (68) above
[0092] In a particular group of compounds of the invention, the compounds have the structural Formula Id (a sub-definition of formula (I)) shown below, or a pharmaceutically acceptable salt, hydrate and/or solvate thereof:
Figure imgf000047_0001
Id
wherein Ri , X4, R2 and Q3 each have any one of the meanings defined herein.
[0093] In an embodiment of the compounds of Formula Id:
Ri is as defined in any one of paragraphs (8) to (20) above;
X4 is as defined in any one of paragraphs (41) to (48) above;
R2 is as defined in any one of paragraphs (49) to (53) above; and Q3 is as defined in any one of paragraphs (54) to (68) above.
[0094] In another embodiment of the compounds of Formula Id:
Ri is as defined in paragraph (20) above;
X4 is as defined in paragraph (48) above;
R2 is as defined in paragraph (53) above; and
Q3 is as defined in paragraph (68) above.
[0095] In an alternative embodiment of the compounds of Formula Id:
Ri is as defined in paragraph (20) above;
X4 is CH;
R2 is as defined in paragraph (53) above; and
Q3 is as defined in paragraph (68) above.
[0096] In a particular group of compounds of the invention, the compounds have the structural Formula le (a sub-definition of formula (I)) shown below, or a pharmaceutically acceptable salt, hydrate and/or solvate thereof:
Figure imgf000048_0001
le
wherein HET, Xi , X2, X3, R2, R3 and R0 each have any one of the meanings defined herein.
[0097] In an embodiment of the compounds of Formula le:
HET is as defined in any one of paragraphs (1) to (7) above;
Ri is as defined in any one of paragraphs (8) to (20) above;
Ria and Ri b are as defined in any one of paragraphs (21) to (24) above;
Xi and X2 are as defined in any one of paragraphs (29) to (34) above;
X3 is as defined in any one of paragraphs (35) to (40) above;
Ro is as defined in any one of paragraphs (41) to (48) above;
R2 is as defined in any one of paragraphs (49) to (53) above; and R3 is as defined in any one of paragraphs (54) to (68).
[0098] In another embodiment of the compounds of Formula le:
HET is as defined in paragraph (7) above;
Ri is as defined in paragraph (20) above;
Ria and Rib are as defined in paragraph (24) above;
Xi and X2 are as defined in paragraph (34) above;
X3 is as defined in paragraph (40) above;
Ro is halo, especially chloro;
R2 is as defined in paragraph (53) above; and
R3 is as defined in paragraph (68).
[0099] In a particular group of compounds of the invention, the compounds have the structural Formula If (a sub-definition of formula (I)) shown below, or a pharmaceutically acceptable salt, hydrate and/or solvate thereof:
Figure imgf000049_0001
If
wherein HET, Xi , X2, X3, R2, Ro, Q3 and Ry each have any one of the meanings defined herein.
[00100] In an embodiment of the compounds of Formula If:
HET is as defined in any one of paragraphs (1) to (7) above;
Ri is as defined in any one of paragraphs (8) to (20) above;
Ria and Rib are as defined in any one of paragraphs (21) to (24) above;
Xi and X2 are as defined in any one of paragraphs (29) to (34) above;
X3 is as defined in any one of paragraphs (35) to (40) above;
Ro is as defined in any one of paragraphs (41) to (48) above;
R2 is as defined in any one of paragraphs (49) to (53) above; Ry is as defined in any one of paragraphs (54) to (63) above; and
Qz is as defined in any one of paragraphs (54) to (68).
[00101] In another embodiment of the compounds of Formula If:
HET is as defined in paragraph (7) above;
Ri is as defined in paragraph (20) above;
Ria and Rib are as defined in paragraph (24) above;
Xi and X2 are as defined in paragraph (34) above;
X3 is as defined in paragraph (40) above;
Ro is halo, especially chloro;
R2 is as defined in paragraph (53) above;
Ry is hydrogen; and
Q3 is as defined in paragraph (68).
[00102] In a particular group of compounds of the invention, the compounds have the structural Formula Ig (a sub-definition of formula (I)) shown below, or a pharmaceutically acceptable salt, hydrate and/or solvate thereof:
Figure imgf000050_0001
ig
wherein Xi , X2, X3, Ri , R2, Ro, Q3 and Ry each have any one of the meanings defined herein.
[00103] In an embodiment of the compounds of Formula Ig:
Ri is as defined in any one of paragraphs (8) to (20) above;
Xi and X2 are as defined in any one of paragraphs (29) to (34) above;
X3 is as defined in any one of paragraphs (35) to (40) above; Ro is as defined in any one of paragraphs (41) to (48) above;
R2 is as defined in any one of paragraphs (49) to (53) above;
Ry is as defined in any one of paragraphs (54) to (63) above; and
Q3 is as defined in any one of paragraphs (54) to (68).
[00104] In another embodiment of the compounds of Formula Ig:
Ri is as defined in paragraph (20) above;
Xi and X2 are as defined in paragraph (34) above;
X3 is as defined in paragraph (40) above;
Ro is halo, especially chloro;
R2 is as defined in paragraph (53) above;
Ry is hydrogen; and
Q3 is as defined in paragraph (68).
[00105] Particular compounds of the present invention include any of the compounds exemplified in the present application, or a pharmaceutically acceptable salt or solvate thereof, and, in particular, any of the following:
2-(4-Amino-1-(tert-butyl)-1 /-/-pyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-N-methyl-1 /-/- indole-6-carboxamide;
2-(4-Amino-1-isopropyl-1 /-/-pyrazolo[3,4-d]pyrimidin-3-yl)-N-methyl-1 /-/-indole-6- carboxamide;
2-(4-Amino-1-(tert-butyl)-1 /-/-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(1-methyl-1 /-/-pyrazol-3- yl)-1 /-/-indole-6-carboxamide; or
2-(4-Amino-1-(tert-butyl)-1 /-/-pyrazolo[3,4-d]pyrimidin-3-yl)-N-methyl-1 /-/-indole-6- carboxamide.
[00106] Further particular compounds of the present invention include any of the compounds exemplified in the present application, or a pharmaceutically acceptable salt or solvate thereof, and, in particular, any of the following:
2-(4-Amino-1-(tert-butyl)-1 /-/-pyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-N-methyl-1 /-/- indole-6-carboxamide;
2-(4-Amino-1-isopropyl-1 /-/-pyrazolo[3,4-d]pyrimidin-3-yl)-N-methyl-1 /-/-indole-6- carboxamide;
2-(4-Amino-1-(tert-butyl)-1 /-/-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(1-methyl-1 /-/-pyrazol-3- yl)-1 /-/-indole-6-carboxamide; 2-(4-Amino-1-(tert-butyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-methyl-1 H-in
carboxamide;
2-(4-Amino-1-isopropyl-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-N-methyl-1 /-/- indole-6-carboxamide;
2-(4-Amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-N-methyl-1 /-/-indole-6- carboxamide;
2-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-chloro-N-methyl-1 H-indole- 6-carboxamide;
2-(4-amino-1-(tert-butyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-3-bromo-N-methyl-1 /-/- indole-6-carboxamide; or
2-(8-amino-3-isopropylimidazo[1 ,5-a]pyrazin-1-yl)-3-chloro-N-methyl-1 /-/-indole-6- carboxamide.
[00107] Further particular compounds of the present invention include any of the compounds exemplified in the present application, or a pharmaceutically acceptable salt or solvate thereof, and, in particular, any of the following:
2-(4-Amino-1-isopropyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-methyl-1 /-/-indole-6- carboxamide;
2-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-methyl-1 /-/-indole-6- carboxamide;
2-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(1-methylpyrazol-3-yl)-1 /-/- indole-6-carboxamide;
2-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-1 /-/-indole-6-carboxamide;
2-(4-Amino-1-isopropyl-pyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-N-methyl-1 /-/-indole-6- carboxamide;
2-(4-Amino-1-(tert-butyl)-1 /-/-pyrazolo[3,4-d]pyrimidin-3-yl)-3-bromo-N-methyl-1 /-/- indole-6-carboxamide;
2-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-N-(2-methoxyethyl)- 1 /-/-indole-6-carboxamide;
2-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-N-[2- (dimethylamino)ethyl]-1 /-/-indole-6-carboxamide;
2-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-N-(2-morpholinoethyl)- 1 /-/-indole-6-carboxamide; 2-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-N-(3- morpholinopropyl)-1 /-/-indole-6-carboxamide;
2-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-N-methoxy-1 /-/-indole- 6-carboxamide;
[2-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-1 /-/-indol-6-yl]- pyrrolidin-1-yl-methanone;
2-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-N,N-dimethyl-1 /-/- indole-6-carboxamide;
2-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-N-[2-(2- methoxyethoxy)ethyl]-1 /-/-indole-6-carboxamide;
2-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-N-(3-methoxypropyl)- 1 /-/-indole-6-carboxamide;
2-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-N-(2-hydroxyethyl)-1 /-/- indole-6-carboxamide;
2-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-N-[2-(2- morpholinoethoxy)ethyl]-1 /-/-indole-6-carboxamide;
2-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-N-[2-[2- (dimethylamino)ethoxy]ethyl]-1 /-/-indole-6-carboxamide;
2-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-N-[3- (dimethylamino)propyl]-1 /-/-indole-6-carboxamide;
2-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-N-[3-(1- piperidyl)propyl]-1 /-/-indole-6-carboxamide;
2-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-N-(3- isopropoxypropyl)-1 /-/-indole-6-carboxamide;
2-[4-Amino-1-(2-hydroxyethyl)pyrazolo[3,4-d]pyrimidin-3-yl]-3-chloro-N-methyl-1 /-/- indole-6-carboxamide;
2-[4-Amino-1-(3-methoxypropyl)pyrazolo[3,4-d]pyrimidin-3-yl]-3-chloro-N-methyl-1 /-/- indole-6-carboxamide;
2-[4-Amino-1-(1-methylsulfonyl-4-piperidyl)pyrazolo[3,4-d]pyrimidin-3-yl]-3-chloro-N- methyl-1 /-/-indole-6-carboxamide;
2-(4-Amino-1-methyl-pyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-N-methyl-1 /-/-indole-6- carboxamide; 2-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-N-[1-(2- methoxyethyl)pyrazol-3-yl]-1 /-/-indole-6-carboxamide;
2-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-N-[1-(2- morpholinoethyl)pyrazol-3-yl]-1 /-/-indole-6-carboxamide;
2-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-N-[1-[2- (dimethylamino)ethyl]pyrazol-3-yl]-1 /-/-indole-6-carboxamide;
2-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-N-[1-[2-(4- methylpiperazin-1-yl)ethyl]pyrazol-3-yl]-1 /-/-indole-6-carboxamide;
2-[4-Amino-1-(2-aminoethyl)pyrazolo[3,4-d]pyrimidin-3-yl]-3-chloro-N-methyl-1 /-/- indole-6-carboxamide;
2-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-N-[1-(2- hydroxyethyl)pyrazol-3-yl]-1 /-/-indole-6-carboxamide;
2-{4-Amino-1-cyclobutyl-1 H-pyrazolo[3,4-d]pyrimidin-3-yl}-3-chloro-N-methyl-1 /-/- indole-6-carboxamide;
2-{4-Amino-1-cyclohexyl-1 H-pyrazolo[3,4-d]pyrimidin-3-yl}-N-methyl-1 /-/-indole-6- carboxamide;
2-{4-Amino-1-cyclopentyl-1 H-pyrazolo[3,4-d]pyrimidin-3-yl}-N-methyl-1 /-/-indole-6- carboxamide;
2-(4-Amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-N-methyl-1 /-/-indole-6- carboxamide;
2-(8-Amino-3-isopropylimidazo[1 ,5-a]pyrazin-1-yl)-3-chloro-N-methyl-1 /-/-indole-6- carboxamide;
2-(8-Amino-3-isopropyl-imidazo[1 ,5-a]pyrazin-1-yl)-N-methyl-1 /-/-indole-6- carboxamide;
2-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-methyl-3H-benzimidazole-5- carboxamide;
2-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-3-fluoro-N-methyl-1 /-/-indole-6- carboxamide;
2-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-N-methyl-1 /-/-indole-6- carboxamide;
2-(4-Amino-1-cyclohexyl-1 /-/-pyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-N-methyl-1 /-/- indole-6-carboxamide; 2-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-chloro-N-methyl-1 H-indole- 6-carboxamide;
2-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-1 /-/-indole-6-carboxylic acid;
2-{4-Amino-1-tert-butyl-1 H-pyrazolo[3,4-d]pyrimidin-3-yl}-3-chloro-N-(oxan-4-yl)-1 /-/- indole-6-carboxamide;
2-{4-Amino-1-tert-butyl-1 /-/-pyrazolo[3,4-d]pyrimidin-3-yl}-3-chloro-N-(propan-2-yl)- 1 /-/-indole-6-carboxamide;
2-{4-Amino-1-tert-butyl-1 H-pyrazolo[3,4-d]pyrimidin-3-yl}-3-chloro-N-ethyl-1 /-/-indole- 6-carboxamide;
2-{4-Amino-1-tert-butyl-1 H-pyrazolo[3,4-d]pyrimidin-3-yl}-3-chloro-N-cyclopropyl-1 /-/- indole-6-carboxamide;
2-{4-Amino-1-tert-butyl-1 H-pyrazolo[3,4-d]pyrimidin-3-yl}-3-chloro-N-phenyl-1 /-/- indole-6-carboxamide;
2-[4-Amino-1-(propan-2-yl)-1 /-/-pyrazolo[4,3-c]pyridin-3-yl]-N-methyl-1 /-/-indole-6- carboxamide;
2-[4-Amino-1-(propan-2-yl)-1 /-/-pyrazolo[4,3-c]pyridin-3-yl]-3-chloro-N-methyl-1 /-/- indole-6-carboxamide;
2-[4-Amino-1-(propan-2-yl)-1 /-/-pyrazolo[4,3-c]pyridin-3-yl]-3-bromo-N-methyl-1 /-/- indole-6-carboxamide;
2-{4-Aminothieno[2,3-d]pyrimidin-5-yl}-3-chloro-N-methyl-1 H-indole-6-carboxamide;
2-{4-Aminothieno[2,3-d]pyrimidin-5-yl}-N-methyl-1/-/-indole-6-carboxamide;
2-[4-Amino-7-(propan-2-yl)pyrrolo[2, 1-f][1 ,2,4]triazin-5-yl]-N-methyl-1 /-/-indole-6- carboxamide;
2-[4-Amino-7-(propan-2-yl)pyrrolo[2, 1-f][1 ,2,4]triazin-5-yl]-3-chloro-N-methyl-1 /-/- indole-6-carboxamide;
2-[4-Amino-7-(propan-2-yl)imidazo[4,3-f][1 ,2,4]triazin-5-yl]-3-chloro-N-methyl-1 /-/- indole-6-carboxamide;
2-[4-Amino-7-chloro-1-(propan-2-yl)-1 /-/-pyrazolo[4,3-c]pyridin-3-yl]-N-methyl-1 /-/- indole-6-carboxamide;
2-{4-Amino-1-tert-butyl-1 H-pyrazolo[3,4-d]pyrimidin-3-yl}-3-chloro-N-methyl-1 /-/- pyrrolo[2,3-b]pyridine-6-carboxamide; 2-{4-Amino-1-tert-butyl-1 H-pyrazolo[3,^
b]pyridine-6-carboxamide;
2-(4-Amino-1-(tert-butyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-1-methyl-1 H-indole-6- carboxylic acid;
2-(4-Amino-1-(tert-butyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-chloro-N-methyl-1 /-/- indole-6-carboxamide;
N-(2-{4-Amino-1-tert-butyl-1 H-pyrazolo[3,4-d]pyrimidin-3-yl}-1 H-indol-6-yl)acetamide
1- (2-{4-Amino-1-tert-butyl-1 H-pyrazolo[3,4-d]pyrimidin-3-yl}-3-chloro-1 H-indol-6- yl)propan-1-one;
2- {4-Amino-1-tert-butyl-1 H-pyrazolo[3,4-d]pyrimidin-3-yl}-N, 1-dimethyl-1 H-indo carboxamide;
2- (4-Amino-1-(1-methylpiperidin-4-yl)-1 H- cyclopropyl-1 /-/-indole-6-carboxamide;
3- [3-Chloro-6-(1 ,3,4-thiadiazol-2-yl)-1 /-/-indol-2-yl]-1-isopropyl-pyrazolo[3,4- d]pyrimidin-4-amine;
3-(3-Chloro-6-oxazol-2-yl-1 /-/-indol-2-yl)-1-isopropyl-pyrazolo[3,4-d]pyrimidin-4- amine;
1-lsopropyl-3-[6-(1 ,3,4-thiadiazol-2-yl)-1 H-indol-2-yl]pyrazolo[3,4-d]pyrimidin-4- amine; or
1- lsopropyl-3-(6-oxazol-2-yl-1 H-indol-2-yl)pyrazolo[3,4-d]pyrirnidin-4-arnine.
[00108] Further particular compounds of the present invention include any of the compounds exemplified in the present application, or a pharmaceutically acceptable salt or solvate thereof, and, in particular, any of the following:
2- (4-Amino-1-isopropyl-pyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-N-methyl-1 /-/-indole-6- carboxamide;
2-(4-Amino-1-(tert-butyl)-1 /-/-pyrazolo[3,4-d]pyrimidin-3-yl)-3-bromo-N-methyl-1 /-/- indole-6-carboxamide;
2-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-N-(2-methoxyethyl)- 1 /-/-indole-6-carboxamide;
2-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-N-[2- (dimethylamino)ethyl]-1 /-/-indole-6-carboxamide; 2-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-N-(2-morpholinoethyl)- 1 /-/-indole-6-carboxamide;
2-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-N-(3- morpholinopropyl)-1 /-/-indole-6-carboxamide;
2-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-N-methoxy-1 /-/-indole- 6-carboxamide;
[2-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-1 /-/-indol-6-yl]- pyrrolidin-1-yl-methanone;
2-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-N,N-dimethyl-1 /-/- indole-6-carboxamide;
2-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-N-[2-(2- methoxyethoxy)ethyl]-1 /-/-indole-6-carboxamide;
2-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-N-(3-methoxypropyl)- 1 /-/-indole-6-carboxamide;
2-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-N-(2-hydroxyethyl)-1 /-/- indole-6-carboxamide;
2-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-N-[2-(2- morpholinoethoxy)ethyl]-1 /-/-indole-6-carboxamide;
2-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-N-[2-[2- (dimethylamino)ethoxy]ethyl]-1 /-/-indole-6-carboxamide;
2-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-N-[3- (dimethylamino)propyl]-1 /-/-indole-6-carboxamide;
2-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-N-[3-(1- piperidyl)propyl]-1 /-/-indole-6-carboxamide;
2-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-N-(3- isopropoxypropyl)-1 /-/-indole-6-carboxamide;
2-[4-Amino-1-(2-hydroxyethyl)pyrazolo[3,4-d]pyrimidin-3-yl]-3-chloro-N-methyl-1 /-/- indole-6-carboxamide;
2-[4-Amino-1-(3-methoxypropyl)pyrazolo[3,4-d]pyrimidin-3-yl]-3-chloro-N-methyl-1 /-/- indole-6-carboxamide;
2-[4-Amino-1-(1-methylsulfonyl-4-piperidyl)pyrazolo[3,4-d]pyrimidin-3-yl]-3-chloro-N- methyl-1 /-/-indole-6-carboxamid; 2-(4-Amino-1-methyl-pyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-N-methyl-1 H-indole-6- carboxamide;
2-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-N-[1-(2- methoxyethyl)pyrazol-3-yl]-1 /-/-indole-6-carboxamide;
2-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-N-[1-(2- morpholinoethyl)pyrazol-3-yl]-1 /-/-indole-6-carboxamide;
2-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-N-[1-[2- (dimethylamino)ethyl]pyrazol-3-yl]-1 /-/-indole-6-carboxamide;
2-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-N-[1-[2-(4- methylpiperazin-1-yl)ethyl]pyrazol-3-yl]-1 /-/-indole-6-carboxamide;
2-[4-Amino-1-(2-aminoethyl)pyrazolo[3,4-d]pyrimidin-3-yl]-3-chloro-N-methyl-1 /-/- indole-6-carboxamide;
2-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-N-[1-(2- hydroxyethyl)pyrazol-3-yl]-1 /-/-indole-6-carboxamide;
2-{4-Amino-1-cyclobutyl-1 H-pyrazolo[3,4-d]pyrimidin-3-yl}-3-chloro-N-methyl-1 /-/- indole-6-carboxamide;
2-(8-Amino-3-isopropylimidazo[1 ,5-a]pyrazin-1-yl)-3-chloro-N-methyl-1 /-/-indole-6- carboxamide;
2-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-3-fluoro-N-methyl-1 /-/-indole-6- carboxamide;
2-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-N-methyl-1 /-/-indole-6- carboxamide;
2-(4-Amino-1-cyclohexyl-1 /-/-pyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-N-methyl-1 /-/- indole-6-carboxamide;
2-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-chloro-N-methyl-1 /-/-indole- 6-carboxamide;
2-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-1 /-/-indole-6-carboxylic acid;
2-{4-Amino-1-tert-butyl-1 H-pyrazolo[3,4-d]pyrimidin-3-yl}-3-chloro-N-(oxan-4-yl)-1 /-/- indole-6-carboxamide;
2-{4-Amino-1-tert-butyl-1 /-/-pyrazolo[3,4-d]pyrimidin-3-yl}-3-chloro-N-(propan-2-yl)- 1 /-/-indole-6-carboxamide; 2-{4-Amino-1-tert-butyl-1 H-pyrazolo[3,4-d]pyrimidin-3-yl}-3-chloro-N-ethyl-1 Hn 6-carboxamide;
2-{4-Amino-1-tert-butyl-1 H-pyrazolo[3,4-d]pyrimidin-3-yl}-3-chloro-N-cyclopropyl-1 /-/- indole-6-carboxamide;
2-{4-Amino-1-tert-butyl-1 H-pyrazolo[3,4-d]pyrimidin-3-yl}-3-chloro-N-phenyl-1 /-/- indole-6-carboxamide;
2-[4-Amino-1-(propan-2-yl)-1 /-/-pyrazolo[4,3-c]pyridin-3-yl]-3-chloro-N-methyl-1 /-/- indole-6-carboxamide;
2-[4-Amino-1-(propan-2-yl)-1 /-/-pyrazolo[4,3-c]pyridin-3-yl]-3-bromo-N-methyl-1 /-/- indole-6-carboxamide;
2-{4-Aminothieno[2,3-d]pyrimidin-5-yl}-3-chloro-N-me
2-[4-Amino-7-(propan-2-yl)pyrrolo[2, 1-f][1 ,2,4]triazin-5-yl]-3-chloro-N-methyl-1 /-/- indole-6-carboxamide;
2-[4-Amino-7-(propan-2-yl)imidazo[4,3-f][1 ,2,4]triazin-5-yl]-3-chloro-N-methyl-1 H- indole-6-carboxamide;
2-{4-Amino-1-tert-butyl-1 H-pyrazolo[3,4-d]pyrimidin-3-yl}-3-chloro-N-methyl-1 /-/- pyrrolo[2,3-b]pyridine-6-carboxamide;
1- (2-{4-Amino-1-tert-butyl-1 H-pyrazolo[3,4-d]pyrimidin-3-yl}-3-chloro-1 H-indol-6- yl)propan-1-one;
2- (4-Amino-1-(1-methylpiperidin-4-yl)-1 H-pyrazolo[3,4-<^py
cyclopropyl-1 /-/-indole-6-carboxamide;
3- [3-Chloro-6-(1 ,3,4-thiadiazol-2-yl)-1 /-/-indol-2-yl]-1-isopropyl-pyrazolo[3,4- d]pyrimidin-4-amine; or
3-(3-Chloro-6-oxazol-2-yl-1 /-/-indol-2-yl)-1-isopropyl-pyrazolo[3,4-d]pyrimidin-4- amine.
[00109] Further particular compounds of the present invention include any of the compounds exemplified in the present application, or a pharmaceutically acceptable salt or solvate thereof, and, in particular, any of the following:
2-(4-Amino-1-isopropyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-methyl-1 /-/-indole-6- carboxamide;
2-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-methyl-1 /-/-indole-6- carboxamide; 2-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(1-methylpyrazol-3-yl)-1 /-/- indole-6-carboxamide;
2-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-1 /-/-indole-6-carboxarriide;
2-{4-Amino-1-cyclohexyl-1 H-pyrazolo[3,4-d]pyrimidin-3-yl}-N-methyl-1 /-/-indole-6- carboxamide;
2-{4-Amino-1-cyclopentyl-1 H-pyrazolo[3,4-d]pyrimidin-3-yl}-N-methyl-1 /-/-indole-6- carboxamide;
2-(4-Amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-N-methyl-1 /-/-indole-6- carboxamide;
2-(8-Amino-3-isopropyl-imidazo[1 ,5-a]pyrazin-1-yl)-N-methyl-1 /-/-indole-6- carboxamide;
2-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-methyl-3H-benzimidazole-5- carboxamide;
2-[4-Amino-1-(propan-2-yl)-1 /-/-pyrazolo[4,3-c]pyridin-3-yl]-N-methyl-1 /-/-indole-6- carboxamide;
2-{4-Aminothieno[2,3-d]pyrimidin-5-yl}-N-methyl-1/-/-indole-6-carboxamide;
2-[4-Amino-7-(propan-2-yl)pyrrolo[2, 1-f][1 ,2,4]triazin-5-yl]-N-methyl-1 /-/-indole-6- carboxamide;
2-[4-Amino-7-chloro-1-(propan-2-yl)-1 /-/-pyrazolo[4,3-c]pyridin-3-yl]-N-methyl-1 /-/- indole-6-carboxamide;
2-{4-Amino-1-tert-butyl-1 H-pyrazolo[3,4-d]pyrimidin-3-yl}-N-methyl-1 /-/-pyrrolo[2,3- b]pyridine-6-carboxamide;
2-(4-Amino-1-(tert-butyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-1-methyl-1 /-/-indole-6- carboxylic acid;
2-(4-Amino-1-(tert-butyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-chloro-N-methyl-1 /-/- indole-6-carboxamide;
N-(2-{4-Amino-1-tert-butyl-1 H-pyrazolo[3,4-d]pyrimidin-3-yl}-1 H-indol-6-yl)acetamide;
2-{4-Amino-1-tert-butyl-1 /-/-pyrazolo[3,4-d]pyrimidin-3-yl}-N , 1-dimethyl-1 /-/-indole-6- carboxamide;
1-lsopropyl-3-[6-(1 ,3,4-thiadiazol-2-yl)-1 /-/-indol-2-yl]pyrazolo[3,4-d]pyrimidin-4- amine; or 1-lsopropyl-3-(6-oxazol-2-yl-1 H-indol-2-yl)pyrazolo[3,4-d]pyrimidin-4-amine.
[00110] The various functional groups and substituents making up the compounds of the Formula (I), and sub-formulae la to Ig, 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 acid-addition salt of a compound of the invention which is sufficiently basic, for example, an acid-addition 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 non-superimposable 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 S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a "racemic mixture".
[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 well-known 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 1 H, 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 160 and180; and the like.
[00115] It is also to be understood that certain compounds of the Formula (I), or sub-formulae la to Ig, 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, or sub-formulae la to Ig, may exhibit polymorphism, and that the invention encompasses all such forms that possess antiproliferative activity.
[00117] Compounds of the Formula I, and sub-formulae la to Ig, may exist in a number of different tautomeric forms and references to compounds of the Formula I, and sub-formulae la to Ig, 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, and sub-formulae la to Ig. 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.
— c-c c=c ^ c=c
I \ / \ H+ / \
keto enol enolate
[00118] Compounds of the Formula I, and sub-formulae la to Ig, containing an amine function may also form N-oxides. A reference herein to a compound of the Formula I, or sub-formulae la to Ig, 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 te/fiary 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), and sub-formulae la to Ig, may be administered in the form of a pro-drug 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), or sub-formulae la to Ig, 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), or sub- formulae la to Ig.
[00120] Accordingly, the present invention includes those compounds of the Formula (I), and sub-formulae la to Ig, 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, and sub-formulae la to Ig, 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) or sub-formulae la to Ig, 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), or sub-formulae la to Ig, 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. 1 13-191 (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, or sub-formulae la to Ig, 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, or sub-formulae la to Ig, 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 te/f-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), or sub-formulae la to Ig, 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, or sub-formulae la to Ig, 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, Ν,Ν-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and 4- (C1-4alkyl)piperazin-1-ylmethyl. Suitable pharmaceutically acceptable ether forming groups for a hydroxy group include a-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.
[00125] A suitable pharmaceutically acceptable pro-drug of a compound of the Formula (I), or sub-formulae la to Ig, 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, or sub-formulae la to Ig, 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), or sub-formulae la to Ig, 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), or sub-formulae la to Ig. As stated hereinbefore, the in vivo effects of a compound of the Formula (I), or sub-formulae la to Ig, 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] The compounds of the present invention can be prepared by any suitable technique known in the art. Particular processes for the preparation of these compounds are described further in the accompanying examples.
[00131] 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.
[00132] 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.
[00133] 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.
[00134] 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.
[00135] 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.
[00136] 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 t-butoxycarbonyl 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 te/f-butoxycarbonyl 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 palladium-on-carbon, 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.
[00137] 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 palladium-on-carbon.
[00138] 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 t-butyl 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 palladium-on-carbon.
[00139] Resins may also be used as a protecting group.
[00140] The methodology employed to synthesise a compound of Formula (I) will vary depending on the nature of HET, Ri , Ria, Rib, W, Xi , X2, X3, X4, R2 and R3 and any substituent groups associated therewith. Suitable processes for their preparation are described further in the accompanying Examples.
[00141] Once a compound of Formula (I) has been synthesised by any one of the processes defined herein, the processes may then further comprise 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 thereof; and/or
(iv) forming a prodrug thereof.
[00142] An example of (ii) above is when a compound of formula (I) is synthesised and then one or more of the groups of HET, Ri , Ria, Rib, W, Xi , X2, X3, X4, R2 and R3, may be further reacted to change the nature of the group and provide an alternative compound of formula (I). For example, the compound can be reacted to convert any R group into a substituent group other than hydrogen.
[00143] The resultant compounds of formula (I) can be isolated and purified using techniques well known in the art.
Biological Activity
[00144] The biological assays described in the Examples section herein may be used to measure the pharmacological effects of the compounds of the present invention.
[00145] 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 RET assays described in the Examples section.
[00146] In general, the compounds of the invention demonstrate an IC50 of 1 μΜ or less in the RET assay described in the Examples section, 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.
[00147] Suitably the ratio of RET activity to KDR activity measured in the RET and KDR assays set out in the Examples section herein is greater than 5, more suitably greater than 10, yet more suitably greater than 25, and most suitably greater than 100.
[00148] In the RETV804M enzyme assay described herein in the Examples section, the compounds of Formula I suitably possess an activity of less than 1 μΜ, with the preferred compounds demonstrating an activity of 100 nM or less and the most preferred compounds of the invention demonstrating an IC50 of 50 nM or less.
[00149] In the RET cell assay described herein in the Examples section, the compounds of Formula I suitably possess an activity of less than 1 μΜ, with the preferred compounds demonstrating an activity of 250 nM or less and the most preferred compounds of the invention demonstrating an IC50 of 100 nM or less.
[00150] In the RETV804M cell assay described herein in the Examples section, the compounds of Formula I suitably possess an activity of less than 1 μΜ, with the preferred compounds demonstrating an activity of 500 nM or less, and more preferred compounds demonstrating an activity of 100 nM or less, and the most preferred compounds of the invention demonstrating an IC50 of 50 nM or less.
[00151] The following compounds were tested but did not exhibit the desired activity in the assays described in the Examples section hereinbelow:
2-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-methyl-1/-/-indole-5-carboxamide; 2-{4-amino-1-tert-butyl-1 H-pyrazolo[3,4-d]pyrimidin-3-yl}-3-chloro-N-cyclohexyl-1 H carboxamide;
2-{4-amino-1-tert-butyl-1 H-pyrazolo[3,4-d]pyrimidin-3-yl}-3-chloro-N-(1-methylpiperi
1 H-indole-6-carboxamide.
Pharmaceutical Compositions
[00152] 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.
[00153] 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).
[00154] 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.
[00155] 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.
[00156] 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.
[00157] 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. [00158] 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
[00159] The present invention provides compounds that function as inhibitors of RET or mutant forms thereof (e.g. RETV804M). Furthermore, the compounds of the present invention demonstrate an improved selectivity for RET, or mutant forms thereof (e.g. RETV804M), relative to KDR (i.e. they are potent inhibitors of RET and poor inhibitors of KDR).
[00160] The present invention therefore provides a method of inhibiting RET kinase enzyme activity, or mutant forms thereof (e.g. RETV804M), 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.
[00161] The present invention also provides a method of selectively inhibiting RET kinase enzyme activity, or mutant forms thereof (e.g. RETV804M), over KDR enzyme activity 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.
[00162] The present invention also provides a method of treating a disease or disorder in which RET kinase 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, or a pharmaceutical composition as defined herein.
[00163] The present invention provides 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.
[00164] The present invention provides 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, or a pharmaceutical composition as defined herein.
[00165] The present invention provides 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, or a pharmaceutical composition as defined herein.
[00166] The present invention provides a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein for use in therapy.
[00167] The present invention provides a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein for use in the treatment of a proliferative condition.
[00168] The present invention provides 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.
[00169] The present invention provides a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein for use in the inhibition of RET kinase enzyme activity or mutant forms thereof (e.g. RETV804M).
[00170] The present invention provides a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein for use in the selective inhibition of RET kinase enzyme activity, or mutant forms thereof (e.g. RETV804M), over KDR enzyme activity.
[00171] The present invention provides 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 RET kinase activity is implicated.
[00172] The present invention provides 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 proliferative condition.
[00173] The present invention provides 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 cancer. Suitably, the medicament is for use in the treatment of human cancers.
[00174] The present invention provides 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 inhibition of RET kinase enzyme activity, or mutant forms thereof (e.g.
[00175] The present invention provides 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 selective inhibition of RET kinase enzyme activity, or mutant forms thereof (e.g. RETV804M), over KDR enzyme activity.
[00176] The present invention provides 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 RET kinase activity is implicated.
[00177] 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.
[00178] The anti-proliferative effects of the compounds of the present invention have particular application in the treatment of human cancers (by virtue of their inhibition of RET kinase enzyme activity, and/or the selective inhibition of RET kinase enzyme activity over KDR enzyme activity).
[00179] The anti-cancer effect may arise through one or more mechanisms, including but not limited to, the regulation of cell proliferation, the inhibition of angiogenesis (the formation of new blood vessels), the inhibition of metastasis (the spread of a tumour from its origin), the inhibition of invasion (the spread of tumour cells into neighbouring normal structures), or the promotion of apoptosis (programmed cell death).
[00180] In a particular embodiment of the invention, the proliferative condition to be treated is cancer, for example medullary thyroid cancer (MTC) or non-small cell lung cancer (NSCLC).
Routes of Administration
[00181] 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).
[00182] 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
[00183] The antiproliferative treatment defined hereinbefore may be applied as a sole therapy or may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy. Such chemotherapy may include one or more of the following categories of anti-tumour agents:-
(i) other antiproliferative/antineoplastic drugs and combinations thereof, as used in medical oncology, such as alkylating agents (for example cis-platin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan, temozolamide and nitrosoureas); antimetabolites (for example gemcitabine and antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, and hydroxyurea); antitumour antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine and taxoids like taxol and taxotere and polokinase inhibitors); and topoisomerase inhibitors (for example epipodophyllotoxins like etoposide and teniposide, amsacrine, topotecan and camptothecin);
(ii) cytostatic agents such as antioestrogens (for example tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5a-reductase such as finasteride;
(iii) anti-invasion agents [for example c-Src kinase family inhibitors like 4-(6-chloro-2,3- methylenedioxyanilino)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-tetrahydropyran-4- yloxyquinazoline (AZD0530; International Patent Application WO 01/94341), A/-(2-chloro-6- methylphenyl)-2-{6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-ylamino}thiazole- 5-carboxamide (dasatinib, BMS-354825; J. Med. Chem., 2004, 47, 6658-6661) and bosutinib (SKI-606), and metalloproteinase inhibitors like marimastat, inhibitors of urokinase plasminogen activator receptor function or antibodies to Heparanase];
(iv) inhibitors of growth factor function: for example such inhibitors include growth factor antibodies and growth factor receptor antibodies (for example the anti-erbB2 antibody trastuzumab [Herceptin™], the anti-EGFR antibody panitumumab, the anti-erbB1 antibody cetuximab [Erbitux, C225] and any growth factor or growth factor receptor antibodies disclosed by Stern et al. (Critical reviews in oncology/haematology, 2005, Vol. 54, pp11-29); such inhibitors also include tyrosine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as A/-(3-chloro-4- fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (gefitinib, ZD1839), N- (3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) and 6- aci lamido-A/-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-quinazolin-4-amine (CI 1033), erbB2 tyrosine kinase inhibitors such as lapatinib); inhibitors of the hepatocyte growth factor family; inhibitors of the insulin growth factor family; inhibitors of the platelet-derived growth factor family such as imatinib and/or nilotinib (AMN 107); inhibitors of serine/threonine kinases (for example Ras/Raf signalling inhibitors such as farnesyl transferase inhibitors, for example sorafenib (BAY 43-9006), tipifarnib (R1 15777) and lonafarnib (SCH66336)), inhibitors of cell signalling through MEK and/or AKT kinases, c-kit inhibitors, abl kinase inhibitors, PI3 kinase inhibitors, Plt3 kinase inhibitors, CSF-1 R kinase inhibitors, IGF receptor (insulin-like growth factor) kinase inhibitors; aurora kinase inhibitors (for example AZD1152, PH739358, VX-680, MLN8054, R763, MP235, MP529, VX-528 AND AX39459) and cyclin dependent kinase inhibitors such as CDK2 and/or CDK4 inhibitors;
(v) antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, [for example the anti-vascular endothelial cell growth factor antibody bevacizumab (Avastin™) and for example, a VEGF receptor tyrosine kinase inhibitor such as vandetanib (ZD6474), vatalanib (PTK787), sunitinib (SU11248), axitinib (AG-013736), pazopanib (GW 786034) and 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidin-1- ylpropoxy)quinazoline (AZD2171 ; Example 240 within WO 00/47212), compounds such as those disclosed in International Patent Applications W097/22596, WO 97/30035, WO 97/32856 and WO 98/13354 and compounds that work by other mechanisms (for example linomide, inhibitors of integrin ανβ3 function and angiostatin)];
(vi) vascular damaging agents such as Combretastatin A4 and compounds disclosed in International Patent Applications WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213;
(vii) an endothelin receptor antagonist, for example zibotentan (ZD4054) or atrasentan;
(viii) antisense therapies, for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense;
(ix) gene therapy approaches, including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; and
(x) immunotherapy approaches, including for example ex-vivo and in-vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches using anti-idiotypic antibodies.
[00184] In a particular embodiment, the antiproliferative treatment defined hereinbefore may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy, wherein the chemotherapy may include one or more anti-tumour agents selected from procarbazine, carmustine, lomustine, irinotecan, temozolomide, cisplatin, carboplatin, methotrexate, etoposide, cyclophosphamide, ifosfamide, and vincristine.
[00185] Such conjoint treatment 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.
[00186] 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 another anti-tumour agent.
[00187] According to this aspect of the invention there is 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 any one of the anti-tumour agents listed herein above.
[00188] 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.
[00189] 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.
[00190] 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. EXAMPLES
ABBREVIATIONS
B2(OH)4 Tetrahydroxyborate
br s broad singlet
d doublet
dd doublet of doublets
CDC Chloroform
DMAP 4-(dimethylamino) pyridine
DCM Dichloromethane (methylene chloride)
DIPEA Λ/,Λ/,-di-isopropyethylamine, Hunig's base
DMF A/,A/-dimethylformamide
DMSO Dimethylsulfoxide.
EDCI.HCI 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride
EtBr Ethylbromide (bromoethane)
EtOAc Ethyl acetate
EtOH Ethanol (ethyl alcohol)
Fee Flash column chromatography
HATU 1-[Bis(dimethylamino)methylene]-1 /-/-1 ,2,3-triazolo[4,5-b]pyridinium 3- oxid hexafluorophosphate)
HCI Hydrochloric acid
HPLC High Pressure Liquid Chromatography
Hz Hertz
J Coupling constant
K2CO3 Potassium carbonate
KOAc Potassium acetate
LCMS Liquid Chromatography-Mass Spectrometry
UOH. H2O Lithium hydroxide monohydrate
m multiplet
MeOH Methanol (methyl alcohol)
MgS04 Magnesium sulphate
MHz Mega hertz N2 Nitrogen
NaHCC>3 Sodium Bicarbonate
Na2S04 Sodium sulphate
NH4CI Ammonium chloride
NMR Nuclear Magnetic Resonance
POC Phosphorus oxychloride
q quartet
s singlet
t triplet
THF Tetrahydrofuran
XPhos 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl
XPhos-Pd-G2 Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1 , 1 '-biphenyl)[2-
(2'-amino-1 , 1 '-biphenyl)]palladium(ll)
METHODS
General Experimental
[00191] Flash column chromatography refers to automated chromatography using prepacked silica cartridges.
[00192] Generally, in the experimental procedures described hereinbelow, flash chromatography was performed using pre-packed silica gel cartridge and thin layer chromatography was conducted with 5 χ 10 cm plates coated with Merck Type 60 F254 silica gel to a thickness of 0.25 mm. Typically, reagents obtained from commercial sources were used without further purification unless stated otherwise. Anhydrous solvents were commonly obtained from the Sigma-Aldrich Chemical Company Ltd. or Fisher Chemicals Ltd., and used without further drying. HPLC grade solvents were predominately obtained from Fisher Chemicals Ltd.
[00193] 1 H NMR spectroscopy was carried out using various spectrometers in the stated solvent at room temperature unless stated otherwise. In all cases, NMR data were consistent with the proposed structure. Characteristic chemical shifts (δ) are given in parts-per-million using conventional abbreviations for designation of major peaks e.g. s, singlet; d, doublet; t, triplet; q, quartet; dd, doublet of doublets; br, broad. LCMS was run using various spectrometers to generate low resolution mass spectra under electron spray ionisation (ESI) conditions. [00194] Generally, in the experimental procedures described hereinbelow, proton (1 H) NMR spectra were recorded on a 300 MHz or 400 MHz Bruker spectrometer. Solutions were typically prepared in either deuterochloroform (CDC ) or deuterated dimethylsulfoxide (DMSO-d6) with chemical shifts referenced to tetramethylsilane (TMS) or deuterated solvent as an internal standard. Furthermore, deuterated solvents were typically obtained from the Sigma-Aldrich Chemical Company, Goss or Fluorochem.
LCMS Methods
Analytical LC-MS
[00195] It will be appreciated that various LC-MS conditions may be used in the analysis of the compounds of the present invention. Examples of some non-limiting LC-MS conditions are provided below.
Illustrative LC-MS conditions
[00196] LC-MS analyses may be performed on, for example, a Waters Acquity UPLC system fitted with BEH C18 1.7 μΜ columns (2.1 χ 50 mm or 2.1 χ 100 mm), with UV diode array detection (210-400 nm). Positive and negative mass ion detection may also be performed using, for example, a Waters SQD detector. Analyses may then be performed with either buffered acidic or basic solvents, using gradients such as those detailed below.
Examples of suitable solvent gradients
Low pH:
Solvent A - Water + 10mM ammonium formate + 0.1 % formic acid
Solvent B - Acetonitrile + 5% water + 0.1 % formic acid
High pH:
Solvent A - Water + 10mM ammonium hydrogen carbonate + 0.1 % ammonia solution Solvent B - Acetonitrile + 0.1 % ammonia solution
An Example of a Standard LC-MS Solvent Gradient:
Time Flow rate (mL/min) % Solvent A % Solvent B
0 0.6 95 5
1.2 0.6 5 95
1.7 0.6 5 95
1.8 0.6 95 5 Preparative HPLC
[00197] Preparative HPLC refers to mass-directed reverse-phase chromatography using various water: MeCN eluent gradients. It will be appreciated that various preparative HPLC machines and/or conditions may be used to purify the compounds of the present invention, and the person skilled in the art will be well versed in selecting appropriate conditions for each respective compound. Nonetheless, details of some non-limiting examples of suitable HPLC conditions are provided below.
Illustrative preparative HPLC conditions
[00198] Compounds may be purified by preparative HPLC on, for example, a Waters FractionLynx MS autopurification system, with a column such as a Waters XBridge 5 μηι C18, 100 mm x 19 mm i.d. column, running at a typical flow rate of 20 mL/min with UV diode array detection (210-400 nm) and mass-directed collection using both positive and negative mass ion detection.
[00199] Purifications may also be performed using buffered acidic or basic solvent systems, as appropriate. Compound retention times on such systems may then be assessed using a 30-50 test injection and a standard gradient, and then purified using an appropriately chosen focussed gradient as detailed below, based upon observed retention time.
[00200] Some typically examples of suitable solvent gradients include: Low pH:
Solvent A - Water + 10mM ammonium formate + 0.1 % formic acid
Solvent B - Acetonitrile + 5% water +0.1 % formic acid
High pH:
Solvent A - Water + 10mM ammonium formate + 0.1 % ammonia solution
Solvent B - Acetonitrile + 5% water + 0.1 % ammonia solution
An Example of a Standard HPLC Gradient:
Time Flow rate % Solvent % Solvent
(mL/min) A B
0 20 90 10
0.3 20 90 10
8.5 20 2 98
12 20 2 98
12.5 0 2 98 Examples of Some Focussed HPLC Gradients:
Figure imgf000080_0001
Synthetic methods
[00201] Several methods for the chemical synthesis of the compounds of the present invention are described herein. These and/or other well-known methods may be modified and/or adapted in known ways in order to facilitate the synthesis of additional compounds within the scope of the present invention.
[00202] Where the preparation of starting materials is not described, these are commercially available, known in the literature, or readily obtained by those skilled in the art using standard procedures. Where it is stated that compounds were prepared analogously to earlier examples or intermediates, using General Methods, it will be appreciated by the skilled person that the reaction time, number of equivalents of reagents and temperature can be modified for each specific reaction and that it may be desirable or necessary to employ different reagents, catalysts, work-up or purification techniques.
General Synthetic Schemes
Scheme 1 - Preparation of Indolyl Pyrazolopyrimidines D
Figure imgf000081_0001
B
[00203] Substituted pyrazolopyrimidines C were prepared either via the known 3-step procedure from an appropriately substituted hydrazine A (General Method 1) or via elaboration of the unsubstituted pyrazolopyrimidine B (General Method 2). X is usually Br or I. Suzuki coupling of intermediate C with either 2-halo indole derivatives (General Method 3) or indolyl boronic acid derivatives (General Method 4) returned product D. Where necessary, further elaboration was conducted.
Scheme 2 - Elaboration of Indolyl Pyrazolopyrimidines
Figure imgf000081_0002
E F G
[00204] Elaboration of esters E to amides F (where X = H, CI, Br etc) was achieved by a number of routes. These include hydrolysis (General Method 5), amide formation (General Method 6), direct amidation (General Method 7) and, in cases where X = CI, by halogenation with NCS (General Method 8). The order of these transformations varied. Alternatively, ester G could be alkylated, deprotected and converted to the amide (General Method 9).
General Methods for Intermediates and Examples
[00205] Representative procedures are provided to all General Methods although it will be appreciated that modifications to the procedures, work-up and isolation will be employed in individual preparations. In particular, in cases where Boc-protected intermediates are employed in Suzuki couplings, an additional treatment with HCI or TFA was included if deprotection did not occur thermally under the reaction conditions.
General Method 1 - representative procedure
3-Bromo-1 -cyclohexyl- 1 H-pyrazolo[3, 4-d]pyrimidin-4-amine
Figure imgf000082_0001
Step 1
[00206] To a mixture of ΕίβΝ (1.39 ml_, 10 mmol) and cyclohexylhydrazine hydrochloride (1.51 g, 10 mmol) in EtOH (35 ml_) was added ethoxymethylenemalononitrile (1.22 g, 10 mmol) portion wise. The reaction mixture was heated at reflux for 5 hours, then cooled to room temperature and concentrated in vacuo. The residue was taken up in EtOAc (50 ml_) and washed with water (2 χ 25 ml_). The organic phase was dried over MgSCU, filtered and concentrated in vacuo to return 5-amino-1-cyclohexyl-pyrazole-4-carbonitrile (1.95 g, 103%) as an orange solid which was used without further purification. 1 H NMR (300 MHz, CDC ) δ 7.49 (s, 1 H), 4.45 (s, 2H), 3.77 (tt, J = 1 1.2, 4.2 Hz, 1 H), 1.88 (ddt, J = 17.4, 1 1.4, 5.4 Hz, 6H), 1.83-1.65 (m, 1 H), 1.49-1.32 (m, 1 H), 1.38-1.15 (m, 2H).
Step 2
[00207] A suspension of 5-amino-1-cyclohexyl-pyrazole-4-carbonitrile (1.95 g, 10 mmol) in formamide (15 ml_) was heated at 180 °C for 1 hour in the MW. The reaction was cooled to room temperature then diluted with water (50 ml_) and extracted with EtOAc (3 χ 50 ml_). The combined organics were washed with brine (50 ml_), dried over MgSCU, filtered and concentrated in vacuo to return 1-cyclohexylpyrazolo[3,4-d]pyrimidin-4-amine (2.01 g, 90%) as a light brown solid which was used without further purification. 1 H NMR (300 MHz, DMSO- de) 6 8.15 (s, 1 H), 8.06 (s, 1 H), 7.64 (br s, 1 H), 4.57 (tt, J = 9.5, 4.9 Hz, 1 H), 2.0-1.78 (m, 6H), 1.69 (d, J = 13.0 Hz, 1 H), 1.48-1.13 (m, 3H).
Step 3
[00208] To a suspension of 1-cyclohexylpyrazolo[3,4-d]pyrimidin-4-amine (2.01 g, 9.3 mmol) in water (50 mL) was added bromine (0.95 mL, 18.5 mmol). The reaction was heated at reflux for 4 hours then cooled to room temperature and extracted with EtOAc (3 χ 50 mL). The combined organics were washed sequentially with with 5% aq. sodium bisulfite (25 mL), sat. aq. NaHCC (25 mL) and brine (25 mL), dried over MgSCU, filtered and concentrated in vacuo to return the title compound (1.58 g, 58%) as an orange solid which was used without further purification. LCMS [M+H]+ 296 and 298; 1 H NMR (300 MHz, DMSO-d6) δ 8.19 (s, 1 H), 7.92 (s, 2H), 4.57 (dt, J = 9.5, 5.2 Hz, 1 H), 1.92-1.72 (m, 5H), 1.67 (d, J = 12.9 Hz, 1 H), 1.52- 1.31 (m, 2H), 1.31-1.12 (m, 1 H).
[00209] Other intermediates prepared by this method include: 3-Bromo-1 -ethyl- 1H-pyrazolo[3, 4-d]pyrimidin-4-amine
N
Figure imgf000083_0001
Step 1
[00210] 1.8 g (16%) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 7.52 (s, 1 H), 6.54 (s, 2H), 3.89 (q, J = 7.2 Hz, 2H), 1.20 (t, J = 7.2 Hz, 3H).
Step 2
[00211] 850 mg (39%) as a yellow solid. LCMS [M-H]" 162.0; 1 H NMR (300 MHz, DMSO-de) δ 8.16 (s, 1 H), 8.07 (s, 1 H), 7.70 (s, 2H), 4.30 (q, J = 7.2 Hz, 2H), 1.36 (t, J = 7.2 Hz, 3H). Step 3
[00212] 870 mg (62%) as a solid. LCMS [M+H]+ 242.0 and 244.0; 1 H NMR (300 MHz, DMSO-de) δ 8.21 (s, 1 H), 7.88 (s, 1 H), 6.99 (s, 1 H), 4.28 (q, J = 7.2 Hz, 2H), 1.36 (t, J = 7.2 Hz, 3H).
General Method 2 - representative procedure
2-(4-Amino-3-bromo-pyrazolo[3,4-d]pyrimidin-1-yl)ethanol (Intermediate 1)
[00213] To a solution of 3-bromo-1 H-pyrazolo[3,4-d]pyrimidin-4-amine (250 mg, 1.2 mmol) and K2C03 (323 mg, 2.3 mmol) in DMF (2 mL) was added 2-bromoethanol (91 uL, 1.3 mmol). The mixture was heated to 100 °C under nitrogen for 17 hours. Water (5 mL) was added, the mixture stirred for 0.25 h, filtered, washed with water (2 χ 20 mL) and dried in vacuo at 50 °C to return the title compound (209 mg, 69%) as a beige powder which was used without further purification. LCMS [M+H]+ 258.0 and 261.0; 1 H NMR (300 MHz, DMSO-d6) δ 8.21 (s, 1 H), 4.87 (s, 1 H), 4.29 (t, J = 5.7 Hz, 2H), 3.78 (t, J = 5.7 Hz, 2H).
[00214] Typically, the alkylating agent employed was the corresponding halide or mesylate, depending on commercial availability or synthetic accessibility.
General Method 3 - representative procedure
Methyl 2-(4-amino- l-(tert-butyl)- 1H-pyrazolo[3, 4-d]pyrimidin-3-yl)- 1 H-indole-6-carboxylate (Intermediate 23)
A mixture of methyl 2-bromo-1 /-/-indole-6-carboxylate (254 mg, 1.0 mmol), XPhos Pd G2 (79 mg, 0.1 mmol), XPhos (95 mg, 0.2 mmol), B2(OH)4 (269 mg, 3.0 mmol) and KOAc (294 mg, 3.0 mmol) in EtOH (10 mL) was sonicated and degassed with argon for 5 mins, then heated at 80 ° for 2 hours. To this was added a degassed solution of aq K2CO3 (1.8M, 1.7 mL, 3.0 mmol) and a degassed solution of 3-bromo-1-(fe/f-butyl)-1 /-/-pyrazolo[3,4-d]pyrimidin-4- amine (270 mg, 1 mmol) in THF (2 mL) and heating continued for 18 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc (3*). The combined extracts were dried over Na2S04, filtered and concentrated in vacuo. The residue was purified by fee (0-100% EtOAc in pentane) to return the title compound (228 mg, 31 %) as a yellow solid LCMS [M+H]+ 365.1 ; 1 H NMR (400 MHz, CDC ) δ 9.09 (br s, 1 H), 8.40 (s, 1 H), 8.22 (s, 1 H), 7.86 (dd, J = 1.40, 8.36 Hz, 1 H), 7.69 (d, J = 8.36 Hz, 1 H), 6.93 (dd, J = 0.85, 2.08 Hz, 1 H), 5.78 (s, 2H), 3.96 (s, 3H), 1.86 (s, 9H). General Method 4 - representative procedure
Methyl 2-(4-amino- 1-isopropyl- 1H-pyrazolo[3, 4-d]pyrimidin-3-yl)- 1 H-indole-6-carboxylate (Intermediate 27)
[00215] A mixture of 3-bromo-1-isopropyl-1 /-/-pyrazolo[3,4-d]pyrimidin-4-amine (0.4 g, 1.56 mmol) and methyl 2-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 /-/-indole-6- carboxylate (0.47 g, 1.56 mmol) in 1 ,4-dioxane (10 mL) was degassed with nitrogen. Pd(dppf)CI2 DCM (32 mg, 0.04 mmol) was added followed by 1.8 M K2C03 (1.74 mL, 3.12 mmol). The reaction mixture was heated at reflux for 2 hours then cooled to room temperature, diluted with EtOAc (50 mL) and washed with water (2 χ 25 mL). The combined aqueous phases were back-extracted with EtOAc (50 mL). The combined organics were washed with brine (50 mL) then concentrated in vacuo and purified by fee (0-100% EtOAc in isohexane) to return the title compound (438 mg, 80%) as a yellow solid. LCMS [M+H]+ 351.2; 1 H NMR (300 MHz, DMSO-de) δ 1 1.98 (br s, 1 H), 8.28 (s, 1 H), 8.15 (s, 1 H), 7.65-7.74 (m, 2H), 7.16 (br s, 1 H), 6.96 (s, 1 H), 5.12 (quin, J = 6.64 Hz, 1 H), 3.88 (s, 3H), 1.55 (d, J = 6.78 Hz, 6H).
[00216] On occasion, the corresponding 3-iodo-1-isopropyl-1 /-/-pyrazolo[3,4- d]pyrimidin-4-amine was used as one of the coupling partners e.g. in the synthesis of Intermediate 81. Additionally, other heteroaryls rather than the pyrazolpyrimidine could be employed in the Suzuki coupling e.g. in the synthesis of Examples 6, 12, 37, 45, 47 and 49.
General Method 5 - representative procedure
2-(4-Amino-1-(tert-butyl)- 1H-pyrazolo[3, 4-d]pyrimidin-3-yl)- 1 H-indole-6-carboxylic acid (Intermediate 26)
[00217] To a solution of methyl 2-(4-amino-1-te/f-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-1 /-/- indole-6-carboxylate (228 mg, 0.63 mmol) in THF (1.5 mL), MeOH (1.5 mL) and water (1.5 mL) was added L1OH.H2O (106 mg, 2.52 mmol). The reaction was stirred at room temperature for 1 hour then at reflux for 2.5 hours. The reaction was cooled to room temperature and concentrated in vacuo. The residue was acidified with 1 M HCI and extracted with EtOAc (3*). The combined organics extracts were dried over Na2S04, filtered and concentrated in vacuo to return the title compound (200 mg, 91 %) as a yellow solid. LCMS [M+H]+ 351.1. General Method 6 - representative procedure
2-Bromo-N-methyl-1H-indole-6-carboxamide (Intermediate 34)
[00218] To a mixture of 2-bromo-1 /-/-indole-6-carboxylic acid (31 1 mg, 1.3 mmol) and HATU (593 mg, 1.56 mmol) in DMF (13 mL) was added DIPEA (0.68 mL, 3.9 mmol). The mixture was stirred for 5 mins before adding methylamine (2M in THF, 0.8 ml, 1.56 mmol). The mixture was stirred at room temperature for 18 hours then diluted with water and extracted with EtOAc (3x). The combined extracts were dried over Na2S04, filtered and concentrated under reduced pressure. The residue was triturated with DCM to return the title compound (204 mg, 64%) as an off-white solid. LCMS [M+H]+ 253.0 and 255.0; 1 H NMR (300 MHz, DMSO-d6) δ 12.13 (s, 1 H), 8.36 (br d, J = 4.14 Hz, 1 H), 7.83 (s, 1 H), 7.49-7.53 (m, 2H), 6.59 (s, 1 H), 2.79 (d, J = 4.52 Hz, 3H).
General Method 7 - representative procedure
Example 5 - 2-(4- Amino- 1-isopropyl- 1 H-pyrazolo[3, 4-d]pyrimidin-3-yl)-3-chloro-N-methyl- 1H- indole-6-carboxamide
[00219] To a suspension of methyl 2-(4-amino-1-isopropyl-pyrazolo[3,4-d]pyrimidin-3- yl)-3-chloro-1 /-/-indole-6-carboxylate (380 mg, 1.0 mmol) in THF (4 mL) was added methylamine (2.0 M in THF, 3.95 mL, 7.9 mmol) followed by AIMe3 (1.0 M solution in heptane, 3.95 mL, 3.95 mmol) dropwise. The resulting suspension was stirred at room temperature for 1 h then heated at 60 °C for 1 h whereby a solution formed. The reaction was cooled to 0 °C and quenched by the dropwise addition of a 20% (w/v) solution of Rochelle's salt in water (30 mL). The mixture was stirred for 30 mins and extracted with EtOAc (2 χ 30 mL). The combined extracts were washed sequentially with water (30 mL) and brine (30 mL), and concentrated in vacuo. The crude product was purified by fee (0 to 10% MeOH in DCM) to return the title compound (170 mg, 45%) as a white solid. LCMS [M+H]+ 384.2; 1 H NMR (300 MHz, DMSO- de) δ 12.16 (s, 1 H), 8.45-8.52 (m, 1 H), 8.27 (s, 1 H), 8.00 (s, 1 H), 7.69 (dd, J = 2.35, 8.57 Hz, 1 H), 7.61 (d, J = 8.57 Hz, 1 H), 5.12 (sept, J = 6.64 Hz, 1 H), 2.82 (d, J = 4.52 Hz, 3H), 1.53 (d, J = 6.69 Hz, 6H). NH2 not observed. General Method 8 - representative procedure
Methyl 2-(4-amino- 1-isopropyl- 1H-pyrazolo[3, 4-d]pyrimidin-3-yl)-3-chloro-1H-indole-6- carboxylate (Intermediate 28)
[00220] To a solution of methyl 2-(4-amino-1-isopropyl-pyrazolo[3,4-d]pyrimidin-3-yl)-1 /-/- indole-6-carboxylate (0.4 g, 1.14 mmol) in DMF (10 mL) was added NCS (0.15 g, 1.14 mmol) at room temperature. The orange solution was stirred at room temperature for 1 hour whereupon a suspension formed. The reaction mixture was diluted with water (150 mL) and stirred at room temperature for 30 mins. The solid was isolated by filtration, washed with water and dried in vacuo at 50 °C to return the title compound (3.8 g, 86%) as a sandy coloured solid. LCMS [M+H]+ 385.2; 1 H NMR (300 MHz, DMSO-d6) δ 12.29 (s, 1 H), 8.27 (s, 1 H), 8.12 (s, 1 H), 7.79 (dd, J = 1.79, 8.58 Hz, 1 H), 7.68 (d, J = 8.16 Hz, 1 H), 5.12 (quin, J = 6.73 Hz, 1 H), 3.89 (s, 3H), 1.53 (d, J = 6.69 Hz, 6H).
[00221] Typically, treatment of substrates with 1 eq NCS resulted in varying proportions of unreacted starting material, desired product and a bischlorinated impurity. A variety of purifications techniques were employed, dependent on the ratio of product. Precipitation and/or fee and/or preparative HPLC were variously used. On occasion, DIPEA was added to the reaction mixture and heated or the crude product was treated with NaBH4 in MeOH as this was sometimes beneficial in removing the bischlorinated impurity.
General Method 9 - representative procedure
Example 100 - 2-[4-Amino-1-(2, 2, 2-trifluo ethyl)- 1 H-pyrazolo[3, 4-d]pyrimidin-3-yl]-3-chloro- N -methyl- 1 H-indol -6-carboxamide
2
Figure imgf000087_0001
Figure imgf000087_0002
Step 1
[00222] A mixture of methyl 2-(4-amino-1/-/-pyrazolo[3,4-c]pyrimidin-3-yl)-3-chloro-1-((2- (trimethylsilyl)ethoxy)methyl)-1/-/-indole-6-carboxylate (308 mg, 0.651 mmol), 1 ,1 ,1 -trifluoro- 2-iodoethane (70.6 μΙ_, 0.716 mmol) and K2C03 (360 mg, 2.60 mmol) in DMF (10 mL) was heated at 80 °C for 20 h. The crude mixture was then cooled to room temperature and diluted with water (10 mL) and extracted with EtOAc (3 χ 10 mL). The combined organic extracts were washed with water (2 x 10 mL), brine (2 x 10 mL), dried and concentrated in vacuo to return methyl 2-(4-amino-1-(2,2,2-trifluoroethyl)-1/-/-pyrazolo[3,4-c]pyrimidin-3-yl)-3-chloro-1- ((2-(trimethylsilyl) ethoxy)methyl)-1/-/-indole-6-carboxylate (389 mg, 78% pure by HPLC) as a yellow solid. LCMS [M+H]+ 555. This material was used in the subsequent step without additional purification.
Step 2
[00223] Methyl 2-(4-amino-1-(2,2,2-trifluoroethyl)-1/-/-pyrazolo[3,4-c]pyrimidin-3-yl)-3-chloro- 1-((2-(trimethylsilyl)ethoxy)methyl)-1/-/-indole-6-carboxylate (389 mg, 0.701 mmol) and cone. HCI (0.43 mL) were dissolved in EtOH (5 mL) and heated at 50 °C for 20 h. The solvent was concentrated in vacuo and the residue taken up into 1 ,4-dioxane (5 mL) and treated with further cone. HCI (0.43 mL). This mixture was heated at 90 °C for 1 h, then concentrated in vacuo and partitioned between EtOAc (5 mL) and sat aq NaHCC>3 (5 mL). The organic layer was separated and retained and the aq phase was extracted with further EtOAc (2 x 5 mL). The combined organic extracts were washed with water (10 mL), brine (10 mL), dried and concentrated in vacuo to return the title compound, together with the corresponding methyl ester (2:1 mixture) (165 mg, 77% pure by HPLC, 56%). LCMS [M+H]+ 439 (Et) and 424 (Me). Major impurity present was hydrolysed ester, 2-(4-amino-1-(2,2,2-trifluoroethyl)-1/-/- pyrazolo[3,4-c]pyrimidin-3-yl)-3-chloro-1/-/-indole-6-carboxylic acid. LCMS [M+H]+ 410. This material was used in the subsequent step without additional purification.
Step 3
[00224] A mixture of ethyl 2-(4-amino-1-(2,2,2-trifluoroethyl)-1 H-pyrazolo[3,4-d]pyrimidin-3- yl)-3-chloro-1 H-indole-6-carboxylate and methyl 2-(4-amino-1-(2,2,2-trifluoroethyl)-1 H- pyrazolo [3,4-d]pyrimidin-3-yl)-3-chloro-1 H-indole-6-carboxylate (55 mg, 0.13 mmol [based on ethyl ester]) and methylamine (2.0 M in THF, 0.52 mL) in THF (4 mL) at 0 °C was added AIMe3 solution (2.0 M in heptane, 0.26 mL) dropwise over 5 min. The resulting mixture was maintained at this temperature for 30 min then heated at 60 °C for 3 h. After cooling back to 0 °C, Rochelle's salt (20% w/v, 5 mL) was added and the mixture warmed to room temperature and stirred for 30 min. EtOAc (10 mL) was added and the biphasic mixture separated. The aq layer was extracted with further EtOAc (2 x 10 mL) and the combined organic extracts washed with water (2 χ 10 mL), brine (10 mL), dried and evaporated in vacuo. The crude product was purified by fee (0-15% MeOH in DCM) to return the title compound (22 mg, 40% yield) as a white solid. LCMS [M+H]+ 424; 1 H N MR (400 MHz, DMSO-d6) δ 12.23 (s, 1 H), 8.49 (br q, 1 H), 8.35 (s, 1 H), 8.01 (app s, 1 H), 7.70 (br dd, 1 H), 7.62 (br d, 1 H), 5.35 (q, J = 9.0 Hz, 2H), 2.82 (d, J = 4.5 Hz, 3H). NH2 signals not observed.
Synthesis of Intermediates
Table A - List of Intermediates and their method of s nthesis
Figure imgf000089_0001
Figure imgf000090_0001
Figure imgf000091_0001
Figure imgf000092_0001
Figure imgf000093_0001
Figure imgf000094_0001
Figure imgf000095_0001
Figure imgf000096_0001
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0001
Ta£)/e B - List of intermediates Prepared Using General Methods
Yield
Intermediate Adduct m/z 1H NMR (300 or 400MHz, DMSO-cfe) δ
(%)
12.09 (s, 1 H), 8.29 (s, 1 H), 8.13 (s, 1 H), 7.72 (d, J = 8.4 Hz, 1 H), 7.67 (d, J = 8.4 Hz, 1 H), 7.20 (s, 2H),
2 76 [M-H]- 351
6.98 (s, 1 H), 4.95 (t, J = 5.7 Hz, 1 H), 4.44 (t, J = 5.8 Hz, 2H), 3.95-3.82 (m, 5H).
385
3 92* [M-H]- and ND
387
286 8.21 (s, 1 H), 7.97 (s, 1 H), 6.92 (s, 1 H), 4.30 (t, J =
4 74 [M+H]+ and 7.0 Hz, 2H), 3.29 (t, J = 6.1 Hz, 2H), 3.19 (s, 3H),
288 2.00 (p, J = 6.5 Hz, 2H).
12.08 (s, 1 H), 8.29 (s, 1 H), 8.13 (s, 1 H), 7.76 - 7.64
5 86 [M-H]- 379
(m, 2H), 7.19 (s, 2H), 6.98 (s, 1 H), 4.45 (t, J = 7.0 Hz, 2H), 3.87 (s, 3H), 3.42-3.30 (m, 2H, obscured by HOD), 3.23 (s, 3H), 2.13 (q, J = 6.5 Hz, 2H).
413
99* [M-H]- and ND
415
17 [M+H]+ 376 ND
12.00 (s, 1 H), 8.29 (s, 1 H), 8.14 (s, 1 H), 7.76-7.63 (m, 2H), 7.23 (s, 2H), 6.99 (s, 1 H), 4.99-4.84 (m,
73 [M-H]- 468 1 H), 3.88 (s, 3H), 3.83-3.69 (m, 2H), 3.11-2.99 (m,
2H), 2.96 (s, 3H), 2.36-2.21 (m, 2H), 2.16-2.02 (m, 2H).
12.30 (s, 1 H), 8.29 (s, 1 H), 8.12 (s, 1 H), 7.79 (d, J =
502
8.7 Hz, 1 H), 7.67 (d, J = 8.3 Hz, 1 H), 5.00-4.85 (m,
45 [M-H]- and
1 H), 3.89 (s, 3H), 3.80-3.67 (m, 2H), 3.12-2.99 (m, 504
2H), 2.95 (s, 3H), 2.34-2.03 (m, 4H).
8.19 (s, 1 H), 6.89 (t, J = 6.0 Hz, 1 H), 4.28 (t, J = 5.9
68 [M-H]- 355
Hz, 2H), 3.34-3.24 (m, 2H), 1.30 (s, 9H).
12.11 (s, 1 H), 8.28 (s, 1 H), 8.13 (s, 1 H), 7.78-7.58 (m, 2H), 7.19 (s, 2H), 6.97 (s, 1 H), 4.42 (t, J = 6.3
86 [M-H]- 450
Hz, 2H), 3.87 (s, 3H), 3.50-3.34 (m, 2H partially obscured by HOD peak), 1 .31 (s, 9H).
484
78* [M-H]- and ND
486
266 8.20 (s, 1 H), 7.87 (s, 1 H), 6.97 (s, 1 H), 5.24 (p, J =
48 [M-H]- and 8.5 Hz, 1 H), 2.60 (m, 2H), 2.47-2.28 (m, 2H), 1.85
268 (td, J = 10.1 , 5.6 Hz, 2H).
12.06 (s, 1 H), 8.28 (s, 1 H), 8.16 (s, 1 H), 7.78-7.63 (m, 2H), 7.20 (s, 2H), 6.98 (s, 1 H), 5.39 (p, J = 8.6
98 [M-H]- 361 Hz, 1 H), 3.88 (s, 3H), 2.79 (dq, J = 12.3, 9.8 Hz,
2H), 2.55-2.37 (m, 2H obscured by DMSO peak), 2.02-1.80 (m, 2H).
396
34* [M-H]- and ND 280
8.21 (s, 1H), 7.96 (s, 1H), 6.99 (s, 1H), 5.15 (tt, J =
32 [M-H]- and
8.1, 6.3 Hz, 1H), 2.16-1.57 (m, 8H).
282
11.96 (s, 1H), 8.28 (s, 1H), 8.15 (app t, J= 0.9 Hz, 1H), 7.77-7.62 (m, 2H), 7.16 (s, 2H), 6.96 (s, 1H),
60 [M+H]+ 377
5.28 (p, J= 7.4 Hz, 1H), 3.88 (s, 3H), 2.16-2.07 (m, 1 H), 2.03-1.87 (m, 2H), 1.82-1.68 (m, 2H).
12.11 (d, J= 10.1 Hz, 1H), 8.30 (s, 1H), 8.15-8.03
70 [M-H]- 321 (m, 1H), 7.77-7.61 (m, 2H), 7.21 (s, 2H), 6.98 (d, J
= 0.9 Hz, 1 H), 4.01 (s, 3H), 3.87 (d, J = 1.0 Hz, 3H).
355
91* [M-H]- and ND
357
11.99 (s, 1H), 8.27 (s, 1H), 8.14 (d, J= 1.3 Hz, 1H), 7.77-7.62 (m, 2H), 7.17 (s, 2H), 6.95 (d, J= 1.5 Hz,
56 [M+H]+ 391
1H), 4.72 (td, J= 10.8, 4.8 Hz, 1H), 3.88 (s, 3H), 2.12-1.84 (m, 7H), 1.82-1.19 (m, 3H).
12.09 (s, 1H), 8.30 (s, 1H), 8.13 (s, 1H), 7.77-7.62
56 [M+H]+ 337 (m, 2H), 7.19 (s, 2H), 6.98 (s, 1H), 4.44 (q, J= 7.2
Hz, 2H), 3.88 (s, 3H), 1.46 (t, J = 7.2 Hz, 3H).
12.04 (s, 1H), 8.30 (s, 1H), 8.13 (s, 1H), 7.76-7.62 (m, 2H), 7.18 (s, 2H), 6.96 (s, 1H), 3.97-3.83 (m,
49 [M+H]+ 349
1H), 3.88 (s, 3H), 1.34-1.19 (m, 2H), 1.25-1.07 (m, 2H).
11.74 (s, 1H), 8.19 (s, 1H), 8.01-8.04 (m, 1H), 7.71 (s, 1H), 7.64 (m, 2H), 6.63 (m, 1H), 6.44 (s, 2H),
72 [M+H]+ ND
5.01 (sept, J = 6.8 Hz, 1 H), 3.33 (s, 3H), 1.50 (d, J = 6.8 Hz, 6H).
95 [M+H]+ 241 ND
12.23 (s, 1H), 8.10 (dd, J= 0.67, 1.49 Hz, 1H), 7.78 (dd, J= 1.43, 8.40 Hz, 1H), 7.67 (d, J= 5.02 Hz,
70 [M+H]+ 384 1H), 7.64 (d, J= 8.41 Hz, 1H), 7.12 (d, J= 4.97 Hz,
1H), 6.20 (brs, 2H), 3.89 (s, 3H), 3.50 (p, J= 6.76 Hz, 1H), 1.36 (d, J = 6.81 Hz, 6H).
54 [M+H]+ ND ND 11.97 (s, 1H), 8.29 (s, 1H), 8.14 (s, 1H), 7.72 (d, J =
8.38 Hz, 1H), 7.67 (d, J= 8.52 Hz, 1H), 7.21 (brs,
75 [M-H]- ND 2H), 6.98 (s, 1H), 5.00-4.88 (m, 1 H), 4.13 (d, J =
11.37 Hz, 1H), 3.88 (s, 3H), 3.04 (brs, 3H), 2.18- 1.92 (m, 4H), 1.44 (s, 9H).
12.27 (s, 1H), 8.28 (s, 1H), 8.12 (dd, J= 0.70, 1.47
Hz, 1H), 7.79 (dd, J= 1.44, 8.43 Hz, 1H), 7.67 (dd,
J = 0.73, 8.48 Hz, 1H), 7.14 (brs, 2H), 4.98 (tt, J =
61 [M-H]- 525
4.96, 10.53 Hz, 1H), 4.10 (d, J= 13.24 Hz, 2H), 3.90 (s, 3H), 3.04 (brs, 2H), 2.15-1.88 (m, 4H), 1.43 (s, 9H).
12.01 (s, 1H), 8.28 (s, 1H), 8.16 (dd, J= 0.80, 1.56
Hz, 1H), 7.73 (dd, J= 0.79, 8.36 Hz, 1H), 7.68 (dd,
J = 1.45, 8.37 Hz, 1 H), 7.18 (br s, 2H), 6.97 (s, 1 H),
48 [M-H]- 391
5.21 (p, J = 8.27 Hz, 1 H), 4.96 (d, J = 4.89 Hz, 1 H), 4.25 (h, J = 6.06 Hz, 1H), 3.88 (s, 3H), 2.51-1.70 (m, 6H).
12.31 (s, 1H), 8.28 (d, J= 1.74 Hz, 1H), 8.12 (dd, J
= 0.68, 1.48 Hz, 1H), 7.80 (dd, J= 1.44, 8.42 Hz,
1H), 7.68 (d, J= 8.87 Hz, 1H), 7.15 (brs, 2H), 5.23
64 [M-H]- 425
(p, J= 8.18 Hz, 1H), 4.94 (d, J= 5.14 Hz, 1H), 4.24 (h, J= 5.88 Hz, 1H), 3.90 (s, 3H), 2.50-2.37 (m, 1H), 2.32-1.99 (m, 3H), 1.99-1.70 (m, 2H).
11.96 (s, 1H), 8.15 (d, J = 1.4 Hz, 1H), 7.79 (d, J =
6.1 Hz, 1H), 7.72 (d, J= 8.3 Hz, 1H), 7.68 (dd, J =
77 [M+H]+ 350 8.3, 1.4 Hz, 1 H), 6.98 - 6.93 (over-lapping m, 2H),
6.16 (bs, 2H), 4.94 (hept, J= 6.6 Hz, 1H), 3.88 (s, 3H), 1.54 (d, J = 6.6 Hz, 6H).
95* [M+H]+ 358 ND
31* [M+H]+ 325 ND
64* [M+H]+ 350 ND
11.93 (s, 1H), 8.13 (s, 1H), 7.98 (s, 1H), 7.68-7.63
(over-lapping m, 2H), 6.80 (s, 1H), 3.86 (s, 3H),
28 ND
3.57 (hept, J= 6.9 Hz, 1H), 1.40 (d, J= 6.9 Hz, 6H). NH2 signals not present.
12.24 (s, 1H), 8.34 (brs, 1H), 8.09 (brdd, 1H), 7.97
54 [M+H]+ 385
(s, 1H), 7.77 (dd, J= 8.4, 1.4 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1 H), 6.77 (br s, 1 H), 3.88 (s, 3H), 3.57
(hept, J = 7.0 Hz, 1 H), 1.38 (d, J = 7.0 Hz, 6H).
12.02 (s, 1 H), 8.27 (s, 1 H), 8.00 (s, 1 H), 7.80 (s,
62 23 [M+H]+ 399 1 H), 7.11 (br, 2H), 6.89 (s, 1 H), 3.87 (s, 3H), 1.79
(s, 9H).
10.90 (s, 1 H), 8.23 (s, 1 H), 7.26 (d, J = 8.4 Hz, 1 H), 6.95 (br 2H), 6.64-6.63 (m, 1 H), 6.59-6.58 (m, 1 H),
65 72 [M+H]+ 322
6.44 (dd, J = 8.4, 2.0 Hz, 1 H), 4.88 (s, 2H), 1.77 (9H, s).
69 71* [M+H]+ 365 ND
71 41 [M+H]+ 384 ND
12.30 (s, 1 H), 8.28 (s, 1 H), 8.10 (app t, J = 1.1 Hz,
74 36 [M+H]+ 399 1 H), 7.67 (d, J = 1.2 Hz, 1 H), 7.1 1 (br s, 2H), 6.90
(s, 1 H), 3.89 (s, 3H), 1.80 (s, 9H).
77 35 [M+H]+ 379 ND
79 34 [M+H]+ 439 ND
80 56 [M+H]+ 473 ND
11.71 (s, 1 H), 8.27 (s, 1 H), 7.63 (d, J = 1.76 Hz, 1 H), 7.59 (d, J = 8.43 Hz, 1 H), 7.18 (dd, J = 1.82,
81 38 [M+H]+ 373 8.41 Hz, 1 H), 7.11 (br s, 2H), 6.88 (s, 1 H), 5.10 (p,
J = 6.72 Hz, 1 H), 1.54 (d, J = 6.74 Hz, 6H).
ND = no data
* indicates material was impure but used without further purification.
Synthesis of Other Intermediates
3-Bromo- 1 -methyl- 1 H-pyrazolo[ 3, 4-d]pyrimidin-4-amine ( Intermediate 18)
[00225] To a suspension of 3-bromo-1 /-/-pyrazolo[3,4-c]pyrimidin-4-amine (1.75 g, 8.18 mmol), triphenylphosphine (4.29 g, 16.35 mmol) and MeOH (1 mL) in THF (50 mL) at O °C was added DIAD (3.22 mL, 16.35 mmol) dropwise at room temperature. The reaction was stirred for 5 days (for convenience) then concentrated in vacuo. The residue was dissolved in aq. HCI (1 M, 50 mL) and washed with EtOAc (2 χ 50 mL). The aqueous phase was basified with aq. NaOH (1 M, 50 mL) then extracted with 20 % MeOH:DCM (3 χ 50 mL). The combined organics were filtered through a hydrophobic frit and then concentrated in vacuo to return the title compound (1.16 g, 62%) as a yellow powder which was used without further purification. LCMS [M+H]+ 228.0 and 230.0; 1 H NMR (300 MHz, DMSO-cfe) δ 8.22 (s, 1 H), 3.86 (s, 3H).
Methyl 2-(4-aminoA -(tert-butyl)A H-pyrazolo[3,4-d]pyrimidin-3-yl)-3-bromoA H-indole-6- carboxylate (Intermediate 24)
[00226] To a solution of methyl 2-(4-amino-1-te/f-butyl-pyrazolo[3,4-c(]pyrimidin-3-yl)- 1 /-/-indole-6-carboxylate (399 mg, 1.1 mmol) in DMF (5 mL) was added NBS (195 mg, 1.1 mmol) at room temperature and the reaction stirred for 5 h. The mixture was left standing for 4 days (for convenience) then diluted with brine (30 mL), stirred for 30 mins, filtered, washed with water (2 χ 20 mL) and dried in vacuo at 50 °C. The crude product was purified by fee (0- 100 % EtOAc in isohexane) to return a dark red oil. The oil was triturated with Et20, filtered, washed with a minimum amount of Et20 and dried in vacuo at 50 °C to return the title compound (189 mg, 39%) as a beige solid. LCMS [M-H]" 441.2 and 443.2; 1 H NMR (300 MHz, DMSO-cfe) δ 12.38 (s, 1 H), 8.27 (s, 1 H), 8.11 (s, 1 H), 7.80 (dd, J = 1.32, 8.38 Hz, 1 H), 7.60 (d, J = 8.38 Hz, 1 H), 3.89 (s, 3H), 1.79 (s, 9H).
Methyl 2-(4-aminoA -(tert-butyl)A H-pyrazolo[3,4-d]pyrimidin-3-yl)-3-fluoroA H-indole-6- carboxylate (Intermediate 25)
[00227] To a suspension of methyl 2-(4-amino-1-te/f-butyl-pyrazolo[3,4-c]pyrimidin-3- yl)-1 /-/-indole-6-carboxylate (250 mg, 0.69 mmol) in acetonitrile (5 mL) was added Selectfluor (243 mg, 0.69 mmol) and the mixture heated to reflux for 4 h. The mixture was cooled, partitioned between EtOAc (20 mL) and sat. aq. NaHCC (20 mL) and the phases separated. The organic phase was washed with brine (20 mL), filtered through a hydrophobic frit and the solvent removed in vacuo. The crude product was purified by fee (0-100 % EtOAc in isohexane) to return the title compound (1 16 mg, 44%, 43% pure by HPLC) as orange powder. LCMS [M-H]" 381.2. Used directly in the next step.
tert-Butyl N-(3-bromoA H-pyrazolo[3, 4-d]pyrimidin-4-yl)-N-tert-butoxycarbonyl-carbamate (Intermediate 29)
[00228] A suspension of 3-bromo-1 /-/-pyrazolo[3,4-c]pyrimidin-4-amine (1.0 g, 4.7 mmol), Boc20 (4.08 g, 18.7 mmol) and DMAP (57 mg, 0.47 mmol) in THF (20 mL) was stirred at room temperature for 24 h. The solvent was concentrated in vacuo then the crude mixture was dissolved in methanol (20 mL). Aq. sat. NaHCO3(10 mL) was added and the reaction mixture stirred at room temperature for 30 mins then water (20 mL) was added and the reaction mixture was extracted with DCM (2 χ 50 mL). The combined organics were passed through a hydrophobic frit and concentrated in vacuo. The crude product was purified by fee (0-10% MeOH:DCM) to return the title compound (1.55 g, 80%) as a pale yellow solid. LCMS [M-H]- 414.1 and 412.2.
tert-Butyl N-(3-bromoA -cyclopropyl-pyrazolo[3, 4-d]pyrimidin-4-yl)-N-tert-butoxycarbonyl- carbamate (Intermediate 30)
[00229] To a solution of te/f-butyl A/-(3-bromo-1 /-/-pyrazolo[3,4-c]pyrimidin-4-yl)-/\/-fe/f- butoxycarbonyl-carbamate (1.0 g, 2.41 mmol) and cyclopropylboronic acid (415 mg, 4.83 mmol) in DCM (10 mL) was added Et3N (0.67 mL, 4.83 mmol) and copper(ll) acetate (877 mg, 4.83 mmol). The reaction mixture was stirred under an atmosphere of air at room temperature for 24 h then concentrated in vacuo. The crude product was purified by fee (0-30% EtOAc in isohexane) to return the title compound (285 mg, 26%). 1 H NMR (300 MHz, DMSO-d6) δ 9.06 (s, 1 H), 3.94 (tt, J = 7.3, 3.6 Hz, 1 H), 1.39 (s, 18H), 1.30-1.23 (m, 2H), 1.23-1.10 (m, 2H).
Methyl 2-(4-aminoA -(1 -methylpiperidin-4-yl)A H-pyrazolo[3,4-d]pyrimidin-3-yl)-3-chloroA H- indole-6-carboxylate (Intermediate 35)
Step 1
[00230] To methyl 2-[4-amino-1-(1-tert-butoxycarbonyl-4-piperidyl)pyrazolo[3,4- d]pyrimidin-3-yl]-3-chloro-1 /-/-indole-6-carboxylate (250 mg, 0.48 mmol) in 1 ,4-dioxane (10 mL) was added HCI solution (4M in 1 ,4-dioxane, 1.19 mL, 4.75 mmol). The reaction mixture was stirred at room temperature for 48 hours, concentrated and dried in vacuo at 50 °C to return methyl 2-[4-amino-1-(4-piperidyl)pyrazolo[3,4-d]pyrimidin-3-yl]-3-chloro-1 /-/-indole-6- carboxylate hydrochloride (188 mg, 86%) as an off white powder. LCMS [M-H]" 424.7.
Step 2
[00231] To a suspension of methyl 2-[4-amino-1-(4-piperidyl)pyrazolo[3,4-d]pyrimidin- 3-yl]-3-chloro-1 /-/-indole-6-carboxylate hydrochloride (133 mg, 0.29 mmol) in methanol (10 mL) was added formaldehyde (37% wt. % in H20, 5.0 mL, 180 mmol), aq. HCI (2M, to pH 1- 2) and Pd/C (10 wt. %, 15 mg). The mixture was heated to 70 °C for 5 h under an atmosphere of H2 (50 psi). The cooled mixture was filtered through a pad of celite which was washed with MeOH (2 x 20 mL). The combined filtrate was concentrated in vacuo, then the resulting residue was suspended in sat. aq. NaHC03 (20 mL) and extracted with DCM (3 χ 20 mL). The combined organic extracts were washed with brine (20 mL), filtered through a hydrophobic frit and concentrated in vacuo to return the title compound (115 mg, impure by HPLC) as an off white powder. Taken directly onto the next step without any further purification. LCMS [M-H]" 438.7.
3-(4-Amino-3-bromoA -pyrazolo[3,4-d]pyrimidinA -yl)cyclopentanA -ol (Intermediate 40) Step 1
[00232] To a solution of 3-bromo-1 H-pyrazolo[3,4-<^pyrimidin-4-amine (2.00 g, 9.34 mmol) and 2-cyclopenten-1-one (1.53 g, 18.69 mmol) in THF (20 ml_) was added HfCU (11 1 mg, 0.3 mmol). The reaction was heated at reflux for 15 h, then cooled to room temperature and concentrated in vacuo. The residue was treated with water and extracted with EtOAc. The combined organic extracts were dried over Na2S04, filtered and concentrated in vacuo to return the crude product which was purified by fee to return 3-(4-amino-3-bromo-1 /-/- pyrazolo[3,4-c]pyrimidin-1-yl)cyclopentan-1-one (750 mg, 27%) which was used without further purification.
Step 2
[00233] To a solution of 3-(4-amino-3-bromo-1 H-pyrazolo[3,4-<^pyrimidin-1- yl)cyclopentan-1-one (750 mg, 2.5 mmol) in MeOH (30 ml_) was added NaBH4 (105 mg, 2.8 mmol). The reaction was stirred at room temperature for 2 h then concentrated in vacuo. The residue was treated with water and extracted with EtOAc. The combined organic extracts were dried over Na2S04, filtered and concentrated in vacuo to return the title compound (750 mg, 100%). LCMS [M-H]" 298.6; 1 H NMR (300 MHz, DMSO-cfe) δ 8.19 (s, 1 H), 8.00 (s, 1 H), 6.87 (s, 1 H), 5.07 (p, J = 8.2 Hz, 1 H), 4.86 (d, J = 4.8 Hz, 1 H), 4.17 (h, J = 6.0 Hz, 1 H), 2.36 (ddd, J = 13.0, 8.4, 6.5 Hz, 1 H), 2.19-1.63 (m, 5H). Approx 9:1 ratio of isomers but unassigned whether cis or trans is the major isomer.
Methyl 2-(4-aminoA -(tert-butyl)A H-pyrazolo[3,4-d]pyrimidin-3-yl)A H-benzo[d]imidazole-6- carboxylate (Intermediate 43)
[00234] A solution of 4-amino-1-fe/f-butyl-pyrazolo[3,4-c]pyrimidine-3-carbaldehyde (60 mg, 0.27 mmol) and methyl 3,4-diaminobenzoate (45 mg, 0.27 mmol) in DMF (4.0 mL) was treated with OXONE® (42 mg, 0.27 mmol) and the resulting mixture was stirred at room temperature for 90 mins before adding further OXONE® (42 mg, 0.27 mmol). The reaction was stirred for 17 h at room temperature before adding further OXONE® (42 mg, 0.27 mmol) and stirred for another 16 h. The reaction mixture was diluted with aq. K2CO3 (0.5M, 10 mL) and extracted with EtOAc (2 x 15 mL). The combined organics were washed with water, filtered through a hydrophobic frit and concentrated in vacuo to return a crude product which was purified by fee (0-100% EtOAc in isohexane) to return methyl 2-(4-amino-1-te/f-butyl- pyrazolo[3,4-c]pyrimidin-3-yl)-3H-benzimidazole-5-carboxylate (39 mg, 31 %) as an orange solid. LCMS [M-H]" 364.2. Material was impure (80% by HPLC) but used without any further purification.
4-Chloro-3-iodoA -isopropylA H-pyrazolo[4,3-c]pyridine (Intermediate 44)
[00235] To a suspension of 4-chloro-3-iodo-1 /-/-pyrazolo[4,3-c]pyridine (859 mg, 2.92 mmol) and K2CO3 (605 mg, 4.38 mmol) in acetonitrile (45 mL) was added 2-iodopropane (0.292 mL, 2.92 mmol) and the resulting mixture heated at 60 °C for 18h. After cooling to room temperature, the mixture was partitioned between sat aq NH4CI (20 mL) and EtOAc (20 mL). The organic layer was separated and retained and the aq phase was extracted with further EtOAc (2 x 20 mL). The combined organic extracts were washed with brine (50 mL), dried and concentrated in vacuo. The residue obtained was purified by fee (0-100% EtOAc in isohexane) to return the title compound (478 mg, 51 %) as an off-white solid. LCMS [M+H]+ 322; 1 H NMR (400 MHz, CDC ) δ 8.15 (d, J = 6.0 Hz, 1 H), 7.31 (d, J = 6.0 Hz, 1 H), 4.78 (hept, J = 6.7 Hz, 1 H), 1.60 (d, J = 6.7 Hz, 6H).
3-lodoA -isopropylA H-pyrazolo[4,3-c]pyridin-4-amine (Intermediate 45)
[00236] To a solution of 4-chloro-3-iodo-1-isopropyl-1 /-/-pyrazolo[4,3-c]pyridine (4.56 g, 13.9 mmol) in 1 ,4-dioxane (30 mL) was added NH4OH (28% NH3, 205 mL) and the resulting suspension was heated in a sealed 500 mL pressure vessel at 140 °C for 19 h. Further NH4OH (28% NH3, 100 mL) was added and the mixture heated at 120 °C for 18 h. After cooling to room temperature the solvent was concentrated in vacuo and the resulting solid was slurried with EtOAc, filtered, washed with further EtOAc (20 mL) and dried to return the title compound (4.10 g, 98%) as an yellow solid. LCMS [M+H]+ 302; 1 H NMR (400MHz, DMSO-d6) δ 7.71 (d, J = 6.3 Hz, 1 H), 7.35 (br, 2H), 6.99 (d, J = 6.3 Hz, 1 H), 4.84 (hept, J = 6.6 Hz, 1 H), 1.42 (d, J = 6.6 Hz, 6H).
N-((3-Amino-5-oxo-4,5-dihydroA,2,4-triazin-6-yl)methyl)isobutyramide (Intermediate 50)
[00237] To a suspension 3-amino-6-(aminomethyl)-4/-/-1 ,2,4-triazin-5-one dihydrochloride (1.20 g, 5.61 mmol) in water (30 mL) at 0 °C was added aq. NaHCOs (1.0 M, 12.5 mL), the resulting mixture was warmed to room temperature and then a solution of (2,5- dioxopyrrolidin-1-yl) 2-methylpropanoate (1.47 g, 7.14 mmol) in THF:acetonitrile (1 : 1 , 20 mL) was added. This mixture was stirred at room temperature for 67 h and then further NaHCC>3 (1.0 M, 6.0 mL) and (2,5-dioxopyrrolidin-1-yl) 2-methylpropanoate (1.80 g, 9.72 mmol) in THF:acetonitrile (1 : 1 , 20 mL) were added. After a further 23 h the precipitate that had formed was filtered and washed with TBME (2 χ 20 mL) to return the title compound (0.53 g, 92% pure by HPLC, 45%) as an off-white solid. LCMS [M+H]+ 212. This material was used in the subsequent step without additional purification.
2-Amino-7-isopropylimidazo[5, 1 ,2,4]triazin-4(3H)-one (Intermediate 51 )
[00238] To a suspension A/-((3-amino-5-oxo-4,5-dihydro-1 ,2,4-triazin-6- yl)methyl)isobutyramide (530 mg, 2.26 mmol) in DCE (30 mL) at reflux was added phosphorus oxychloride (1.50 mL, 16.1 mmol). The resulting mixture was maintained at reflux for 2.5 h, then cooled to room temperature and concentrated in vacuo. The crude product was taken up in MeOH:water (2:1 , 15 mL), loaded onto SCX (ca. 5 g) and washed with MeOH (3 χ 50 mL). The resin was then washed with 1 % NH3 in MeOH (3 χ 50 mL) and the solution obtained concentrated in vacuo to return the title compound (430 mg, 89% pure by HPLC, 99%) as a tan brown solid. LCMS [M+H]+ 194. This material was used in the subsequent step without additional purification.
2-Amino-5-iodo-7-isopropylimidazo[5, 1 ,2,4]triazin-4(3H)-one (Intermediate 52)
[00239] To a solution of 2-amino-7-isopropylimidazo[5, 1-/][1 ,2,4]triazin-4(3/-/)-one (710 mg, 3.31 mmol) in DMF (17 mL) was added NIS (1.10 g, 4.89 mmol) and the resulting mixture was stirred at room temperature for 18 h. EtOAc (50 mL) and water (50 mL) were added and the layers separated. The aq layer was further extracted with EtOAc (50 mL) and the combined organic extracts washed sequentially with aq. Na2S203 solution (1.0 M, 2 χ 20 mL) and brine (3 x 20 mL), then dried and concentrated in vacuo to return the title compound (700 mg, 66%) as a yellow solid. LCMS [M+H]+ 320 ; 1 H NMR (400MHz, DMSO-d6) δ 10.79 (s, 1 H), 6.14 (s, 2H), 3.27 (hept, J = 6.9 Hz, 1 H), 1.23 (d, J = 6.9 Hz, 6H).
5-lodo-7-isopropylimidazo[5, 1 -f][\,2,4]triazin-4(3 )-one (Intermediate 53)
[00240] To a solution of 2-amino-5-iodo-7-isopropylimidazo[5, 1-/][1 ,2,4]triazin-4(3/-/)- one (690 mg, 2.12 mmol) in THF:DMF (6: 1 , 70 mL) was added t-butyl nitrite (1.20 mL, 10.1 mmoL) dropwise. The resulting mixture was stirred at room temperature for 3.5 h and then concentrated in vacuo. The crude product was purified by fee (0-100% EtOAc in isohexane) to return the title compound (600 mg, 85% pure by HPLC, 93%) as a dark yellow solid. LCMS [M+H]+ 305. This material was used in the subsequent step without additional purification.
5-lodo-7-isopropylimidazo[5, 1 ,2,4]triazin-4-amine (Intermediate 54)
[00241] Phosphorus oxychloride (0.500 mL, 5.36 mmol) was added to a solution of Λ - 1 ,2,4-triazole (1.04 g, 15.1 mmol) in pyridine (10 mL) and then stirred at room temperature for 15 min. A solution of 5-iodo-7-isopropylimidazo[5, 1-/][1 ,2,4]triazin-4(3/-/)-one (600 mg, 1.68 mmol) in pyridine (20 mL) was then added. The resulting mixture was maintained at room temperature for 3.5 h, then cooled to 0 °C and NH3 in IPA (2 M, 42 mL) was added dropwise over 10 min. After stirring at 0 °C for 30 min, the mixture was warmed to room temperature, maintained at this temperature for 75 mins and then concentrated in vacuo. The crude product was partitioned between EtOAc (75 mL) and sat. aq NaHCC>3 (75 mL) and the layers separated. The aq layer was further extracted with EtOAc (3 χ 50 mL) and the combined organic extracts washed with brine (50 mL), dried and concentrated in vacuo. The resulting dark red oil was purified by fee (0-2% MeOH:DCM) to return the title compound (390 mg, 77%) as a dark yellow solid. LCMS [M+H]+ 304; 1 H NMR (400MHz, DMSO-cfe) δ 8.43 (br s, 1 H), 7.86 (s, 1 H), 6.76 (br s, 1 H), 3.43 (hept, J = 7.0 Hz, 1 H), 1.27 (d, J = 7.0 Hz, 6H).
^ -(teιi-Butyl)-3-((trimethylsilyl)ethynyl)-^ H yrazolo[3,4-d] yrimidin-4-ami (Intermediate 57)
[00242] A mixture of 3-bromo-1-(fe/f-butyl)-1 /-/-pyrazolo[3,4-c]pyrimidin-4-amine (2.50 g, 9.25 mmol), ethynyl(trimethyl)silane (0.77 mL, 5.55 mmol) and diisopropylamine (2.60 mL, 18.5 mmol) in THF (25 mL) was degassed with nitrogen for 15 mins. PdCl2(PPh3)2 (650 mg, 0.930 mmol) and Cul (353 mg, 1.85 mmol) were added and the resulting mixture heated at 50 °C for 5 h. Further ethynyl(trimethyl)silane (0.77 mL, 5.55 mmol), PdCI2(PPh3)2 (195 mg, 0.290 mmol) and Cul (106 mg, 0.550 mmol) were added and the mixture heated at 70 °C for 20 h. EtOAc (20 mL) and water (30 mL) were added and the resulting biphasic mixture passed through a pad of Celite™ (ca. 20 g). The layers were then separated and the aq phase extracted with further EtOAc (2 χ 30 mL). The organic extracts were combined, washed with water (3 χ 60 mL), brine (30 mL), then dried and concentrated in vacuo. The crude product was purified by fee (0-2% MeOH (+ 1 % NH3) in DCM) to return the title compound (1.32 g, 87% pure by HPLC, 50%) as a light brown foam. LCMS [M+H]+ 288. This material was used in the subsequent step without additional purification. 1 -(ted-Butyl)-3-ethynylA H-pyrazolo[3,4-d]pyrimidin-4-amine (Intermediate 58)
[00243] A mixture of 1-(fe/f-butyl)-3-((trimethylsilyl)ethynyl)-1 /-/-pyrazolo[3,4- <^pyrimidin-4-amine (1.32 g, 4.13 mmol) and K2C03 (0.857 g, 6.20 mmol) in MeOH (30 mL) was stirred at room temperature for 2 h. The solvent was concentrated in vacuo and the resulting residue partitioned between EtOAc (50 mL) and water (30 mL). The organic layer was separated and retained and the aq phase was extracted with further EtOAc (2 χ 30 mL). The combined organic extracts were washed with water (20 mL), brine (20 mL), dried and concentrated in vacuo. The crude product was purified by fee (0-2% MeOH (+ 1 % NH3) in DCM). The crude product was then slurried with TBME: isohexane (1 :4, 10 mL), filtered and washed with further isohexane (10 mL) to return the title compound (0.78 g, 88%) as a pale yellow solid. LCMS [M+H]+ 216; 1 H NMR (400MHz, DMSO-cfe) δ 8.21 (s, 1 H), 8.12-7.40 (br, 1 H), 6.94-6.01 (br, 1 H), 4.60 (s, 1 H), 1.69 (s, 9H).
6-Amino-5-((4-aminoA -(tert-butyl)A H-pyrazolo[3,4-d]pyrimidin-3-yl)ethynyl)-N- methylpicolinamide (Intermediate 59)
[00244] A mixture of 1-(fe/f-butyl)-3-ethynyl-1 /-/-pyrazolo[3,4-c]pyrimidin-4-amine (200 mg, 0.930 mmol) and 6-amino-5-bromo-/V-methyl-pyridine-2-carboxamide (214 mg, 0.930 mmol) in Et3N:THF (17:3, 10 mL) was degassed with nitrogen. Pd(PPh3)4 (107 mg, 0.0930 mmol) and Cul (26.0 mg, 0.140 mmol) were added and the resulting mixture heated in the microwave at 80 °C for 1 h. The solvent was concentrated in vacuo and the resulting residue partitioned between EtOAc (50 mL) and water (30 mL). The organic layer was separated and retained and the aq phase was extracted with further EtOAc (2 χ 20 mL). The combined organic extracts were washed with water (3 x 10 mL), brine (10 mL), dried and concentrated in vacuo. The crude product was purified by fee (0-5% MeOH (+ 1 % N H3) in DCM) to return the title compound (138 mg, 41 %) as a pale yellow solid. LCMS [M+H]+ 365; 1 H NMR (400MHz, DMSO-cfe) δ 8.27-8.22 (over-lapping m, 2H), 7.92 (d, J = 7.7 Hz, 1 H), 7.24 (d, J = 7.7 Hz, 1 H), 6.49 (s, 2H), 2.82 (d, J = 5.0 Hz, 3H), 1.73 (s, 9H). NH2 signals not present.
^ -tert-Butyl 6-methyl 5-chloro-M-l-indoleA ,6-dicarboxylate (Intermediate 60)
[00245] A mixture of methyl 5-chloro-1 /-/-indole-6-carboxylate (500 mg, 2.39 mmol), B0C2O (781 mg, 3.58 mmol) and DMAP (58.3 mg, 0.477 mmol) in MeCN (8 mL) was stirred at room temperature for 16 h then concentrated in vacuo. The crude product was purified by fee (24 g, 0-50% EtOAc in isohexane) to return the title compound (737 mg, quant) as a colourless oil, which solidified on standing. LCMS [M+H]+ 310; 1 H NMR (400MHz, DMSO-d6) δ 8.59 (s, 1 H), 7.91 (d, J = 3.1 Hz, 1 H), 7.86 (s, 1 H), 6.77 (dd, J = 3.7, 0.7 Hz, 1 H), 3.88 (s, 3H), 1.63 (s, 9H).
(Ί -(tert-Butoxycarbonyl)-5-chloro-6-(methoxycarbonyl)- 1 H-indol-2-yl)boronic acid
(Intermediate 61)
[00246] To a mixture of 1-te/f-butyl 6-methyl 5-chloro-1 /-/-indole-1 ,6-dicarboxylate (500 mg, 1.61 mmol) and triisopropyl borate (0.641 ml_, 2.42 mmol) in THF (5 ml_) at 0 °C was added LDA (1.0 M, 2.4 ml_) dropwise over 10 min. The resulting solution was maintained at 0 °C for 2 h then quenched through the addition of AcOH:water (1 :5, 12 ml_) and allowed to warm to room temperature over 30 min. The mixture was neutralised through the addition of sat. aq NaHCC and diluted with EtOAc (50 ml_). The organic layer was separated and retained and the aq phase was extracted with further EtOAc (2 χ 50 ml_). The combined organic extracts were washed with brine (50 ml_), water (50 ml_), dried and concentrated in vacuo to return the title compound (556 mg, 90% pure by HPLC, 98%) as an orange solid. LCMS [M+H]+ 354. This material was used in the subsequent step without additional purification.
tert-Butyl 6-[bis(tert-butoxycarbonyl)amino]indoleA -carboxylate (Intermediate 63)
[00247] To a solution of te/f-butyl A/-(1 /-/-indol-6-yl)carbamate (760 mg, 3.17 mmol) in DCM (15 ml_) was added Boc20 (1.70 g, 7.79 mmol), Et3N (1.20 ml_, 8.61 mmol) and DMAP (35.0 mg, 0.290 mmol) and the resulting mixture stirred at room temperature for 71 h. Further B0C2O (850 mg, 3.90 mmol) and EtzN (600 μΙ_, 4.31 mmol) was added and the mixture stirred for a further 24 h. The solvent was concentrated in vacuo and the crude product purified by fee (0-20% EtOAc in isohexane) to return the title compound (1.35 g, 98%) as a colourless gum. LCMS [M+Na]+ 455; 1 H NMR (400MHz, DMSO-cfe) δ 7.81 (s, 1 H), 7.72 (d, J = 3.7 Hz, 1 H), 7.61 (d, J = 8.3 Hz, 1 H), 7.05 (dd, J = 8.3, 2.0 Hz, 1 H), 6.74 (d, J = 4.5 Hz, 1 H), 1.62 (s, 9H), 1.41 (s, 18H).
[6-[Bis(tert-butoxycarbonyl)amino]^ -tert-butoxycarbonyl-indol-2-yl]boronic acid (Intermediate 64)
[00248] To a solution of te/f-butyl 6-[bis(te/f-butoxycarbonyl)amino]indole-1- carboxylate (910 mg, 2.06 mmol) and triisopropyl borate (1.00 ml_, 4.33 mmol) in THF (15 ml_) at 0 °C was added LDA (1.0 M, 4.0 mL) dropwise over 10 min. The resulting mixture was maintained at 0 °C for 2 h then quenched through the addition of AcOH:water (1 :5, 12 mL) and allowed to warm to room temperature over 30 min. Water (10 mL) and EtOAc (20 mL) were added and the biphasic mixture separated. The aq layer was extracted with further EtOAc (2 x 20 mL) and the combined organic extracts dried and concentrated in vacuo to return the title compound (545 mg) as a dark orange solid. Spectroscopic analysis was difficult and therefore this material was taken forward into the next step.
(2-(4-AminoA -(tert-butyl)- -pyrazolo[3,4-d]pyrimidin-3-yl)-3-chloroA H-indol-6-yl) methanol (Intermediate 66)
[00249] To a solution of methyl 2-(4-amino-1-(fe/f-butyl)-1 /-/-pyrazolo[3,4-c]pyrimidin-3- yl)-3-chloro-1 /-/-indole-6-carboxylate (500 mg, 1.25 mmol) in THF (12 mL) at 0 °C was added L1AIH4 (2.0 M in THF, 2.19 mL). The resulting mixture was warmed to room temperature, maintained at this temperature for 45 min, then recooled to 0 °C. NaOH (2.0 M, 20 mL) and water (20 mL) were added, the mixture was warmed to room temperature and stirred for 15 min. EtOAc (20 mL) was added and the biphasic mixture separated. The aq layer was extracted with further EtOAc (2 χ 20 mL) and the combined organic extracts dried and concentrated in vacuo. The crude product was purified by fee (0-5% MeOH in DCM) to return the title compound (346 mg, 75%) as an off-white solid. LCMS [M+H]+ 371 ; 1 H NMR (400MHz, DMSO-cfe) δ 1 1.79 (s, 1 H), 8.26 (s, 1 H), 7.50 (d, J = 8.0 Hz, 1 H), 7.44 (dd, = 1.4, 0.8 Hz, 1 H), 7.14 (dd, J = 8.0, 1.4 Hz, 1 H), 7.00-6.61 (br, 2H), 5.21 (t, J = 5.8 Hz, 1 H), 4.63 (d, J = 5.8 Hz, 2H), 1.78 (s, 9H).
2-(4-Amino -(tert-butyl)- -pyrazolo[3,4-d]pyrimidin-3-yl)-3-chloroA H-indole-6- carbaldehyde (Intermediate 67)
[00250] To a solution of (2-(4-amino-1-(fe/f-butyl)-1 /-/-pyrazolo[3,4-c]pyrimidin-3-yl)-3- chloro-1 /-/-indol-6-yl)methanol (200 mg, 0.539 mmoL) in DCM (3 mL) was added a suspension of DMP (274 mg, 0.647 mmol) in DCM (3 mL) dropwise. The resulting mixture was stirred at room temperature for 45 min, then diluted with aq NaOH (1.0 M, 30 mL) and stirred for a further 15 min. EtOAc (30 mL) was added and the biphasic mixture separated. The organic layer was washed with water (30 mL), brine (30 mL), then dried and concentrated in vacuo to return the title compound (146 mg, 80% pure by HPLC, 74%) as a brown solid. LCMS [M+H]+ 369. This material was used in the subsequent step without additional purification.
1 -(2-(4-AminoA -(tert-butyl)A H-pyrazolo[3,4-d]pyrimidin-3-yl)-3-chloroA H-indol-6-yl)propan- 1 -0/ (Intermediate 68) [00251] To a solution of 2-(4-amino-1-(te f-butyl)-1 H-pyrazolo[3,4-c ]pyrimidin-3-yl)-3- chloro-1 /-/-indole-6-carbaldehyde (87 mg, 0.24 mmol) in THF (2.5 mL) at 0 °C was added bromo(ethyl)magnesium (1.0 M in THF, 0.71 mL) slowly. The resulting mixture was stirred at room temperature for 1 h then partitioned between EtOAc (10 mL) and sat aq NH4CI (10 mL). The layers were separated and the organic extracts washed with further brine (10 mL), dried and concentrated in vacuo. The crude product was purified by fee (0-5% MeOH in DCM) to return the title compound (32 mg, 34%) as a pale brown oil. LCMS [M+H]+ 399. This material was used in the subsequent step without additional purification.
7-Chloro-3-iodoA -isopropylA H-pyrazolo[4,3-c]pyridin-4-amine (Intermediate 70)
[00252] To 3-iodo-1-isopropyl-pyrazolo[4,3-c]pyridin-4-amine (200 mg, 0.66 mmol) in MeCN (5 mL) was added NCS (89 mg, 0.66 mmol) and the resulting solution was stirred at 70 °C for 3 h. The solvent was concentrated in vacuo and the residue obtained purified by fee (0- 20% MeOH in DCM) to return the title compound (80 mg, 36%) as a brown solid. LCMS [M+H]+ 336; 1 H NMR (400MHz, DMSO-cfe) δ 7.72 (s, 1 H), 6.53 (br, 2H), 5.46 (hept, J = 6.5 Hz, 1 H), 1.46 (d, J = 6.5 Hz, 6H).
^ -tert-Butyl 6-methyl 4-chloro-1H-indoleA ,6-dicarboxylate (Intermediate 72)
[00253] Prepared according to a similar procedure to that used for 1 -te/f-butyl 6-methyl 5-chloro-1 /-/-indole-1 ,6-dicarboxylate from methyl 4-chloro-1 /-/-indole-6-carboxylate (250 mg, 1.19 mmol) for a reaction time of 3 h and purified by fee (10-20% EtOAc in isohexane) to return the title compound (327 mg, 89%) as white solid. LCMS [M+H]+ 310; 1 H NMR (400MHz, DMSO-cfe) δ 8.69 (app t, 1 H), 7.99 (d, J = 3.7 Hz, 1 H), 7.82 (d, J = 1.3 Hz, 1 H), 6.83 (dd, J = 3.7, 0.9 Hz, 1 H), 3.90 (s, 3H), 1.65 (s, 9H).
(1 -(tert-Butoxycarbonyl)-4-chloro-6-(methoxycarbonyl)A H-indol-2-yl)boronic acid
(Intermediate 73)
[00254] Prepared according to a similar procedure to that used for (1-(te/f-butoxy carbonyl)-5-chloro-6-(methoxycarbonyl)-1 /-/-indol-2-yl) boronic acid from 1-te/f-butyl 6-methyl 4-chloro-1 /-/-indole-1 ,6-dicarboxylate (320 mg, 1.03 mmol) for a reaction time of 1 h to return the title compound (315 mg, 58% pure by HPLC, 86%) as an orange solid. This material was used in the subsequent step without additional purification. Methyl 2-bromo-3-methylA H-indole-6-carboxylate (Intermediate 75)
[00255] To a solution of methyl 3-methyl-1 /-/-indole-6-carboxylate (240 mg, 1.14 mmol) in AcOH (2.5 mL) was added NBS (207 mg, 1.14 mmol) and the resulting mixture stirred at room temperature for 1 h. Water (5 mL) was added and the resulting mixture neutralised through the dropwise addition of aq NaOH (1.0 M). The precipitate that formed was filtered and dried to return the title compound (214 mg, 70% pure by HPLC, 69%) as a brick red solid. LCMS [M+H]+ 267 and 269. This material was used in the subsequent step without additional purification.
Methyl 3-methyl-2-(4, 4, 5, 5-tetramethylA , 3, 2-dioxaborolan-2-yl)A H-indole-6-carboxylate (Intermediate 76)
[00256] A mixture of methyl 2-bromo-3-methyl-1 /-/-indole-6-carboxylate (210 mg, 0.548 mmol), KOAc (163 mg, 1.64 mmol) and bis(pinacolato)diboron (431 mg, 1.64 mmol) in 1 ,4- dioxane (5 mL) was degassed with nitrogen. Pd(PP i3)2Cl2 (24.0 mg, 0.0330 mmol) was added and the resulting mixture heated at 90 °C for 18 h. After being cooled to room temperature, a second portion of bis(pinacolato)diboron (72.0 mg, 0.274 mmol) and Pd(PP i3)Cl2 (12.0 mg, 0.0160 mmol) were added and the mixture heated at 90 °C for a further h. The crude mixture was cooled to room temperature, diluted with EtOAc (10 mL) and passed through a pad of Celite™ (ca. 2 g), washing with further EtOAc (2 χ 10 mL). The volatile solvents were concentrated in vacuo and the crude product partitioned between EtOAc (50 mL) and water (10 mL). The organic layer was separated, washed with further water (10 mL), brine (10 mL), dried and concentrated in vacuo to return the title compound (281 mg, 50% pure by HPLC) as a brown solid. LCMS [M+H]+ 316. This material was used in the subsequent step without additional purification.
(6-(Methoxycarbonyl)A -((2-(trimethylsilyl)ethoxy) methyl) -1 H-indol-2-yl)boronic acid
(Intermediate 78)
[00257] To a solution of methyl 1-(2-trimethylsilylethoxymethyl)indole-6-carboxylate (2.30 g, 7.38 mmol) and triisopropyl borate (2.61 mL, 11.1 mmol) in THF (35 mL) at O °C was added LDA (1.0 M, 10.3 mL). The resulting mixture was maintained at 0 °C for 2 h then quenched through the addition of water (5 mL) and sat aq NaHC03 (x mL). After stirring for 5 min the volatile solvents were concentrated in vacuo and the mixture obtained diluted with EtOAc (50 mL). The organic layer was separated and retained and the aq phase was extracted with further EtOAc (2 χ 50 mL). The combined organic extracts were washed with water (2 χ 20 mL), brine (2 χ 20 mL), dried and concentrated in vacuo to return the title compound (2.61 g, 60% pure by HPLC) as a brown solid. This material was used in the subsequent step without additional purification.
Phenyl (2-(4-Amino- l-(tert-butyl)- 1H-pyrazolo[3, 4-d]pyrimidin-3-yl)- 1H-indol-6-yl) carbamate (Intermediate 82)
[00258] To a solution of 3-(6-amino-1/-/-indol-2-yl)-1-(fe/f-butyl)-1/-/-pyrazolo[3,4- <^pyrimidin-4-amine (39 mg, 0.11 mmol) and DMAP (2.0 mg, 0.020 mmol) in DMF (1 mL) was added phenyl chloroformate (20 μί, 0.16 mmol). The resulting mixture was stirred at room temperature for 3.5 h, then partitioned between EtOAc (20 mL) and water (10 mL) and separated. The aq layer was extracted with further EtOAc (2 χ 20 mL) and the combined organic extracts washed with brine (4 x 10 mL), dried and concentrated in vacuo to return the title compound (57 mg, 85% pure by HPLC) as a yellow gum. LCMS [M+H]+ 442. This material was used in the subsequent step without additional purification.
Final Compounds
Table C- List of Examples and their method of synthesis
Figure imgf000115_0001
Figure imgf000116_0001
Figure imgf000117_0001
Figure imgf000118_0001
Figure imgf000119_0001
Figure imgf000120_0001
Figure imgf000121_0001
Figure imgf000122_0001
Figure imgf000123_0001
Figure imgf000124_0001
Figure imgf000125_0001
Figure imgf000126_0001
Figure imgf000127_0001
Figure imgf000128_0001
Figure imgf000129_0001
Figure imgf000130_0001
Figure imgf000131_0001
Table D - Examples Prepared Using General Methods
General Yield (%)
EXAMPLE FORMULA MW ADDUCT m/z
Method
1 C19H21 N7O 363.42 [M+H]+ 364.2 6 32
2 C22H23N9O 429.48 [M+H]+ 430.4 6 47
3 C18H19N7O 349.39 [M+H]+ 350.4 3 24
4 C19H20CIN7O 397.86 [M-H]- 396.3 8 40
5 CISHISCINTO 383.83 [M+H]+ 384.2 7 45
6 C19H20N6O 348.4 [M+H]+ 349.2 7 78
7 CigHigCINeO 382.85 [M+H]+ 383.2 8 28
8 Ci9H2oBrN70 442.31 [M-H]- 440.2 7 47 CigHigCINeO 382.85 [M+H]+ 383.3 8 67
Ci8H2oN80 364.4 [M-H]- 363.3 4 31
C18H19N7O 349.39 [M+H]+ 350.2 6 20
C19H19N5O2 349.39 [M+H]+ 350.2 4 85
C19H20N6O 348.4 [M+H]+ 349.2 7 48
C21 H24CIN7O2 441 .91 [M-H]- 440.3 7 99
C22H27CIN8O 454.96 [M-H]- 453.3 7 97
C24H29CIN8O2 496.99 [M-H]- 495.4 7 88
C25H31CIN8O2 51 1 .02 [M-H]- 509.4 7 90
C19H20CIN7O2 413.86 [M-H]- 412.2 7 43
C22H24CIN7O 437.93 [M-H]- 436.4 7 64
C20H22CIN7O 41 1 .89 [M-H]- 410.3 7 65
C23H28CIN7O3 485.97 [M-H]- 484.4 7 68
C22H26CIN7O2 455.94 [M-H]- 454.4 7 58
C20H22CIN7O2 427.89 [M-H]- 426.4 7 1 1
C26H33CIN8O3 541 .05 [M-H]- 539.5 7 9
C24H31CIN8O2 499.01 [M-H]- 497.4 7 59
C23H29CIN8O 468.98 [M-H]- 467.4 7 55
C26H33CIN8O 509.05 [M-H]- 507.5 7 57
C24H30CIN7O2 483.99 [M-H]- 482.5 7 53
C19H20FN7O 381 .41 [M-H]- 380.3 7 20
C17H16CIN7O2 385.81 [M-H]- 384.2 7 13
C19H20CIN7O2 413.86 [M-H]- 412.2 7 16
C21 H23CIN8O3S 502.98 [M-H]- 501 .3 7 26
C23H26CIN7O2 467.95 [M+H]+ 468.5 7 6
C16H14CIN7O 355.78 [M-H]- 354.1 7 18
C24H26CIN9O2 507.98 [M+H]+ 508.3 7 65
C27H31CIN10O2 563.05 [M+H]+ 563.3 7 5
C19H20N6O 348.4 [M+H]+ 349.0 7 52 CigHigCINeO 382.85 [M+H]+ 383.0 8 19
CigHigBrNeO 427.3 [M+H]+ 428.0 See Below 25
C25H2gCINioO 521 .02 [M+H]+ 521 .3 7 31
C28H34CIN11O 576.1 [M+H]+ 576.4 7 1
C17H17CIN8O 384.82 [M-H]- 383.2 7 34
C23H24CINg02 493.95 [M+H]+ 494.3 7 28
C16H12CIN5OS 357.82 [M+H]+ 358.3 8 18
C16H13N5OS 323.37 [M+H]+ 324.3 7 52
C18H17CIN6O2 384.82 [M+H]+ 385.2 5 36
CigH2oNeO 348.4 [M+H]+ 349.4 7 51
CigHigCINeO 382.85 [M+H]+ 383.4 8 39
C18H18CIN7O 383.83 [M+H]+ 384.3 7 68
CisHigCINsO 398.85 [M+H]+ 399.4 8 40
Ci8H2oN80 364.4 [M+H]+ 365.4 See Below 16
CigHigCINe02 398.85 [M-H]- 397.1 8 24
CigH2oCIN70 397.86 [M+H]+ 398.5 7 30
CigH2i N70 363.42 [M+H]+ 364.4 See Below 53
C20H21CIN6O 396.87 [M+H]+ 397.1 See Below 29
C21 H24CIN7O 425.91 [M+H]+ 426.4 7 33
C20H22CIN7O 41 1 .89 [M+H]+ 412.4 7 65
C21 H22CIN7O 423.9 [M+H]+ 424.4 7 50
C24H22CIN7O 459.93 [M+H]+ 460.4 7 6
C20H23N7O 377.44 [M+H]+ 378.3 6 39
CigHigCINeO 382.85 [M+H]+ 383.4 7 46
CigHi8CIN70 395.85 [M+H]+ 396.2 7 1 1
C21 H23N7O 389.45 [M+H]+ 390.3 7 50
C20H21 N7O 375.43 [M+H]+ 376.3 7 54
C21 H22CIN7O 423.9 [M+H]+ 424.2 8 17
C17H17N7O 335.36 [M+H]+ 336.2 7 61 C18H17N7O 347.37 [M+H]+ 348.1 7 16
CISHISCINTO 383.83 [M+H]+ 384.3 7 43
C19H19CI2N7O 432.31 [M+H]+ 432.3 8 20
C18H21 N7O2S 399.47 [M+H]+ 400 See Below 20
C19H22N8O 378.43 [M+H]+ 379.5 See Below 1 0
C21 H24CIN7O3S 489.98 [M+H]+ 490.4 7 56
C23H21CIN8O 460.92 [M+H]+ 461 .5 7 49
C19H20CIN7O 397.86 [M+H]+ 398.4 4 80
C25H24CIN7O 473.96 [M+H]+ 474.4 7 70
C26H26CIN7O 487.98 [M+H]+ 488.5 7 55
C21 H21CIF3N7O 479.89 [M+H]+ 480.4 7 56
C21 H21CIF3N7O2 495.89 [M+H]+ 496.4 7 27
C22H21CIN8OS 480.97 [M+H]+ 481 .4 7 42
C24H28CIN7O2 481 .98 [M+H]+ 482.4 7 55
C20H23N7O 377.44 [M+H]+ 378.4 7 39
C19H20CIN7O 397.86 [M+H]+ 398.4 8 52
C20H22CIN7O 41 1 .89 [M+H]+ 412.2 8 99
C17H16CIN7O 369.81 [M+H]+ 370.6 8 37
C18H16CIN7O 381 .82 [M+H]+ 382.7 8 57
C20H20CIN7O 409.87 [M+H]+ 41 0.7 8 23
C19H19CI2N7O 432.31 [M+H]+ 432.7 8 45
C21 H19CIN8OS 466.95 [M+H]+ 467.4 7 21
C23H25CIN8O3S 529.01 [M+H]+ 529.7 7 29
C27H31CIN8O3 551 .04 [M+H]+ 551 .7 7 43
C21 H24CIN7O 425.91 [M+H]+ 426.5 8 4
CigHisC NeO 41 7.29 [M+H]+ 41 7.4 8 90
C22H23CIN8O 450.92 [M+H]+ 451 .7 See Below
C21 H22CIN7O2 439.9 [M+H]+ 440.5 9 87
C22H24CIN7O2 453.92 [M+H]+ 454.3 9 2 96 C23H24CIN7O2 465.94 [M+H]+ 466.2 9 21
97 C20H20CIF2N7O 447.87 [M+H]+ 448.2 See Below 10
98 C21H22CIN7O2 439.9 [M+H]+ 440.5 9 27
99 C18H15CIF3N7O 437.81 [M+H]+ 438.7 9 28
100
C17H13CIF3N7O 423.78 [M+H]+ 424.4 9 40
101 C21H20CIN7O2 437.88 [M+H]+ 438.4 9 31
102 C19H15CIF3N7O 449.82 [M+H]+ 450.4 9 26
103 C22H22CIN7O2 451.91 [M+H]+ 452.4 9 20
104 C22H22CIN7O2 451.91 [M+H]+ 452.7 9 10
105 C23H25CIN8O 464.95 [M-H]- 463.7 7 7
106 ΟιβΗΐδΝδβ 376.44 [M-H]- 375.2 3 2
107 CisHisCINsS 410.88 [M+H]+ 411.1 8 30
108 C19H17N7O 359.38 [M+H]+ 360.2 3 14
109 C19H16CIN7O 393.83 [M+H]+ 394.2 8 21
Table E - Η NMR data for Examples
EXAMPLE 1H NMR (300 or 400 MHz, DMSO-cfe) δ
11.81 (s, 1H), 8.31-8.41 (m, 1H), 8.27 (s, 1H), 8.00 (s, 1H), 7.65 (d, J= 8.31 Hz,
1
1 H), 7.56 (d, J = 8.61 Hz, 1 H), 7.04 (br s, 2H), 6.86 (s, 1 H), 2.81 (d, J = 4.46 Hz, 3H), 1.80 (s, 9H).
11.87 (br s, 1 H), 8.37 (q, J = 4.22 Hz, 1 H), 8.27 (s, 1 H), 8.00 (s, 1 H), 7.65 (d, J =
3
8.31 Hz, 1H), 7.56 (dd, J= 1.50, 8.34 Hz, 1H), 7.10 (brs, 2H), 6.89 (s, 1H), 5.11 (spt, J = 6.66 Hz, 1 H), 2.82 (d, J = 4.46 Hz, 3H), 1.54 (d, J = 6.66 Hz, 6H).
11.88 (brs, 1H), 10.71 (s, 1H), 8.28 (s, 1H), 8.14 (s, 1H), 7.70-7.77 (m, 1H), 7.63-
2
7.70 (m, 1H), 7.61 (d, J= 2.20 Hz, 1H), 7.08 (brd, J= 19.01 Hz, 2H), 6.89 (s, 1H), 6.62 (d, J = 2.20 Hz, 1 H), 3.97 (br s, 1 H), 3.62 (br s, 2H), 1.76-1.84 (m, 9H).
12.15 (s, 1H), 8.41-8.57 (m, 1H), 8.28 (s, 1H), 8.00 (s, 1H), 7.70 (dd, J= 1.41, 8.57
4
Hz, 1H), 7.59 (d, J= 8.19 Hz, 1H), 6.98 (brs, 2H), 2.82 (d, J= 4.52 Hz, 3H), 1.79 (s, 9H).
10 13.26 (d, J = 15.66 Hz, 1H), 10.07 (d, J= 3.79 Hz, 1H), 8.49 (dd, J= 4.69, 8.45 Hz, 1H), 8.26 (brs, 1.5H), 8.14 (dd, J= 3.53, 16.45 Hz, 1H), 8.07 (s, 0.5H), 7.85 (dd, J = 1.60, 8.44 Hz, 0.5H), 7.77 (s, 1 H), 7.62 (d, J = 8.42 Hz, 0.5H), 2.83 (dd, J = 2.61 , 4.50 Hz, 3H), 1.83 (d, J = 1.83 Hz, 9H). Presumed 1:1 mixture of benzimidazole isomers.
11.82 (s, 1H), 8.27 (s, 1H), 8.03 (s, 1H), 7.92 (s, 1H), 7.64 (d, J= 8.24 Hz, 1H), 7.60 (dd, J = 1.29, 8.22 Hz, 1 H), 7.20 (s, 1 H), 7.04 (s, 1 H), 6.87 (d, J = 1.32 Hz, 1 H), 1.80 (s, 9H).
11.60 (s, 1H), 8.31-8.39 (m, 1H), 8.18 (s, 1H), 7.91 (s, 1H), 7.67 (s, 1H), 7.51-7.59 (m, 2H), 6.56 (s, 1 H), 6.43 (br s, 2H), 5.00 (sept, J = 6.64 Hz, 1 H), 2.81 (d, J = 4.43 Hz, 3H), 1.50 (d, J = 6.78 Hz, 6H).
11.90 (brs, 1H), 8.41-8.50 (m, J = 4.60 Hz, 1H), 8.19 (s, 1H), 7.94 (s, 1H), 7.64- 7.74 (m, 2H), 7.50-7.57 (m, 1H), 6.26 (brs, 2H), 5.02 (quin, J = 6.66 Hz, 1H), 2.81 (d, J = 4.43 Hz, 3H), 1.50 (d, J = 6.78 Hz, 6H).
12.26 (s, 1H), 8.49 (brd, J= 4.43 Hz, 1H), 8.28 (s, 1H), 8.01 (s, 1H), 7.62-7.80 (m, 1 H), 7.54 (d, J = 8.38 Hz, 1 H), 6.92 (br s, 2H), 2.83 (d, J = 4.43 Hz, 3H), 1.79 (s, 9H).
12.10 (brs, 1H), 8.46 (brd, J = 4.52 Hz, 1H), 7.98 (s, 1H), 7.63-7.71 (m, 2H), 7.57 (d, J= 7.16 Hz, 1H), 7.10 (d, J= 4.90 Hz, 1H), 6.15 (brs, 2H), 3.49 (quin, J= 6.80 Hz, 1 H), 2.82 (d, J = 4.43 Hz, 3H), 1.36 (d, J = 6.78 Hz, 6H).
11.85 (brs, 1H), 8.13 (s, 1H), 7.57-7.70 (m, 3H), 7.11 (brd, J = 4.99 Hz, 1H),6.77 (s, 1H), 6.47 (brs, 2H), 3.87 (s, 3H), 3.49 (sept, J= 6.8 Hz, 1H), 1.38 (d, J= 6.8 Hz, 6H).
11.74 (s, 1 H), 8.33 (q, J = 4.32 Hz, 1 H), 7.98 (d, J = 1.33 Hz, 1 H), 7.64 (d, J = 4.97 Hz, 1 H), 7.60 (d, J = 8.34 Hz, 1 H), 7.53 (dd, J = 1.52, 8.33 Hz, 1 H), 7.09 (d, J = 4.93 Hz, 1 H), 6.70 (s, 1 H), 6.45 (s, 2H), 3.48 (p, J = 6.83 Hz, 1 H), 2.81 (d, J = 4.48 Hz, 3H), 1.39 (s, 3H), 1.37 (s, 3H).
12.14 (s, 1H), 8.62-8.52 (m, 1H), 8.27 (s, 1H), 8.01 (s, 1H), 7.71 (d, J= 8.63 Hz, 1H), 7.60 (d, J= 8.39 Hz, 1H), 6.95 (brs, 2H), 3.54-3.42 (m, 4H), 3.29 (s, 3H), 1.79 (s, 9H).
12.13 (s, 1H), 8.47-8.37 (m, 1H), 8.27 (s, 1H), 7.99 (s, 1H), 7.69 (d, J= 8.58 Hz, 1 H), 7.59 (d, J = 8.42 Hz, 1 H), 6.95 (br s, 2H), 3.39 (q, J = 6.51 Hz, 2H), 2.45 (t, J = 6.80 Hz, 2H), 2.21 (s, 6H), 1.79 (s, 9H).
12.14 (s, 1H), 8.45 (t, J= 5.66 Hz, 1H), 8.27 (s, 1H), 7.99 (s, 1H), 7.69 (dd, J= 1.41, 8.44 Hz, 1H), 7.60 (d, J= 8.44 Hz, 1H), 6.95 (brs, 2H), 3.63-3.53 (m, 4H), 3.42 (q, J = 6.57 Hz, 2H), 2.46-2.41 (m, 4H), 1.78 (s, 9H).1 x CH2 under solvent peak. 12.13 (s, 1H), 8.54 (t, J= 5.53 Hz, 1H), 8.27 (s, 1H), 7.99 (s, 1H), 7.69 (dd, J = 1.38, 8.28 Hz, 1H), 7.60 (d, J= 8.43 Hz, 1H), 6.96 (s, 2H), 3.58 (t, J= 4.63 Hz, 4H), 2.41- 2.30 (m, 6H), 1.79 (s, 9H), 1.72 (p, J = 7.35 Hz, 2H).1 x CH2 under solvent peak.
12.19 (s, 1H), 11.78 (s, 1H), 8.27 (s, 1H), 7.92 (s, 1H), 7.67-7.54 (m, 2H), 6.96 (brs, 2H), 3.74 (s, 3H), 1.79 (s, 9H).
12.06 (s, 1H), 8.26 (s, 1 H), 7.65-7.61 (m, 1 H), 7.59 (d, J = 8.24 Hz, 1 H), 7.35 (dd, J = 1.39, 8.27 Hz, 1 H), 6.98 (br s, 2H), 3.56-3.42 (m, 4H), 1.89-1.79 (m, 4H), 1.79 (s, 9H).
12.05 (s, 1H), 8.27 (s, 1H), 7.60 (dd, J= 0.71, 8.21 Hz, 1H), 7.50 (d, J= 0.67 Hz, 1H), 7.22 (dd, J= 1.39, 8.21 Hz, 1H), 6.97 (brs, 2H), 3.00 (s, 6H), 1.79 (s, 9H).
12.15 (s, 1H), 8.56 (t, J= 5.34 Hz, 1H), 8.27 (s, 1H), 8.01 (s, 1H), 7.71 (dd, J= 1.42, 8.41 Hz, 1H), 7.60 (d, J= 8.42 Hz, 1H), 6.95 (brs, 2H), 3.62-3.49 (m, 4H), 3.52- 3.41 (m, 4H), 3.25 (s, 3H), 1.79 (s, 9H).
12.12 (s, 1H), 8.51 (t, J= 5.64 Hz, 1H), 8.27 (s, 1H), 8.00 (s, 2H), 7.69 (d, J= 8.18 Hz, 1 H), 7.59 (d, J = 8.41 Hz, 1 H), 6.96 (br s, 2H), 3.40 (t, J = 6.33 Hz, 2H), 3.26 (s, 3H), 1.79 (s, 9H).1 χ CH2 under 'Bu peak at 1.79 ppm.1 χ CH2 under solvent peak.
11.94 (s, 1 H), 8.28 (t, J = 5.50 Hz, 1 H), 8.07 (s, 1 H), 7.81 (s, 1 H), 7.52 (dd, J = 1.43, 8.38 Hz, 1H), 7.40 (d, J= 8.41 Hz, 1H), 6.78 (brs, 2H), 4.55 (t, J= 5.55 Hz, 1H), 3.34 (q, J = 6.10 Hz, 2H), 3.23-3.12 (m, 2H), 1.59 (s, 9H).
12.00 (s, 1H), 8.54 (t, J= 5.43 Hz, 1H), 8.27 (s, 1H), 8.00 (s, 1H), 7.69 (dd, J= 1.41, 8.45 Hz, 1H), 7.59 (d, J= 8.38 Hz, 1H), 7.04 (brs, 2H), 3.58-3.39 (m, 8H), 2.50- 2.42 (m, 2H), 2.44-2.34 (m, 4H), 1.79 (s, 9H).1 x CH2 under solvent peak.
12.15 (s, 1H), 8.55 (t, J= 5.40 Hz, 1H), 8.27 (s, 1H), 8.00 (s, 1H), 7.69 (dd, J= 1.42, 8.46 Hz, 1H), 7.60 (d, J= 8.36 Hz, 1H), 6.99 (brs, 2H), 3.68-3.41 (m, 6H), 2.46 (t, J = 5.83 Hz, 2H), 2.18 (s, 6H), 1.79 (s, 9H).
12.13 (s, 1H), 8.58 (s, 1H), 8.26 (s, 1H), 7.98 (s, 1H), 7.67 (d, J= 7.91 Hz, 1H), 7.58 (d, J= 8.17 Hz, 1H), 6.99 (brs, 2H), 2.31 (t, J= 7.13 Hz, 2H), 2.17 (s, 6H), 1.79 (s, 9H), 1.69 (t, J= 7.02 Hz, 2H).1 x CH2 under solvent peak.
12.14 (s, 1H), 8.56 (s, 1H), 8.26 (s, 1H), 7.98 (s, 1H), 7.67 (d, J= 8.85 Hz, 1H), 7.58 (d, J= 8.02 Hz, 1H), 6.98 (brs, 2H), 2.39-2.28 (m, 7H), 1.79 (s, 9H), 1.76-1.65 (m, 2H), 1.54-1.46 (m, 5H), 1.42-1.36 (m, 2H).
12.13 (s, 1H), 8.52-8.43 (m, 1H), 8.27 (s, 1H), 7.99 (s, 1H), 7.69 (d, J= 8.47 Hz, 1 H), 7.59 (d, J = 8.38 Hz, 1 H), 6.93 (br s, 2H), 3.54 (p, J = 6.08 Hz, 1 H), 3.44 (t, J = 6.26 Hz, 2H), 3.41-3.32 (m, 2H), 1.79 (s, 9H), 1.80-1.68 (m, 2H), 1.11 (s, 3H), 1.08 (s, 3H). 11.66 (s, 1 H), 8.46 (q, J = 4.05 Hz, 1 H), 8.26 (s, 1 H), 8.00-7.92 (m, 1 H), 7.65-7.61 (m, 2H), 7.03 (brs, 2H), 2.82 (d, J= 4.41 Hz, 3H), 1.79 (s, 9H)
12.21 (s, 1H), 8.48 (s, 1H), 8.27 (s, 1H), 7.99 (s, 1H), 7.68 (d, J= 8.39 Hz, 1H), 7.60 (d, J = 8.38 Hz, 1 H), 7.08 (br s, 2H), 4.96 (t, J = 5.60 Hz, 1 H), 4.45 (t, J = 5.90 Hz, 2H), 3.89 (q, J = 5.82 Hz, 2H), 2.82 (d, J = 4.42 Hz, 3H).
12.19 (s, 1H), 8.49 (d, J= 5.00 Hz, 1H), 8.28 (s, 1H), 8.00 (s, 1H), 7.69 (d, J= 8.38 Hz, 1 H), 7.60 (d, J = 8.36 Hz, 1 H), 7.09 (br s, 2H), 4.45 (t, J = 6.99 Hz, 2H), 3.38 (t, J = 6.15 Hz, 2H), 3.23 (s, 3H), 2.82 (d, J = 4.42 Hz, 3H), 2.10 (p, J = 6.57 Hz, 2H).
12.16 (s, 1H), 8.49 (d, J = 4.99 Hz, 1H), 8.29 (s, 1H), 8.00 (s, 1H), 7.69 (dd, J = 1.40, 8.47 Hz, 1H), 7.60 (d, J= 8.43 Hz, 1H), 7.18 (brs, 2H), 5.01-4.85 (m, 1H), 3.74 (d, J = 11.97 Hz, 2H), 3.06 (t, J = 12.60 Hz, 2H), 2.95 (s, 3H), 2.82 (d, J = 4.35 Hz, 3H), 2.34-2.16 (m, 2H), 2.17-2.06 (m, 2H).
12.10 (s, 1H), 8.37 (d, J= 7.7 Hz, 1H), 8.27 (s, 1H), 8.01 (app s, 1H), 7.72 (dd, J = 8.4, 1.5 Hz, 1H), 7.60 (d, J= 8.4 Hz, 1H), 6.92 (br, 2H), 4.08-4.00 (m, 1H), 3.92- 3.88 (m, 2H), 3.40 (td, J = 11.8, 2.0 Hz, 2H), 1.79 (s, 9H), 1.68-1.58 (m, 2H), 1.27- 1.23 (m, 2H).
12.22 (s, 1H), 8.48 (d, J= 5.07 Hz, 1H), 8.29 (s, 1H), 7.99 (s, 1H), 7.68 (dd, J = 1.44, 8.39 Hz, 1H), 7.59 (d, J= 8.41 Hz, 1H), 7.12 (brs, 2H), 4.02 (s, 3H), 2.82 (d, J = 4.41 Hz, 3H).
12.22 (s, 1H), 10.88 (s, 1H), 8.28 (s, 1H), 8.17 (s, 1H), 7.87 (d, J= 8.30 Hz, 1H), 7.64 (d, J = 2.30 Hz, 1 H), 7.62 (d, J = 8.47 Hz, 1 H), 6.97 (br s, 2H), 6.63 (d, J = 2.32 Hz, 1 H), 4.21 (t, J = 5.27 Hz, 2H), 3.70 (t, J = 5.29 Hz, 2H), 3.25 (s, 3H), 1.80 (s, 9H).
12.21 (s, 1H), 10.88 (s, 1H), 8.28 (s, 1H), 8.17 (s, 1H), 7.87 (dd, J = 1.31 , 8.46 Hz, 1 H), 7.68 (d, J = 2.20 Hz, 1 H), 7.62 (d, J = 8.51 Hz, 1 H), 6.96 (br s, 2H), 6.63 (d, J = 2.25 Hz, 1H), 4.18 (t, J= 6.68 Hz, 2H), 3.60-3.54 (m, 4H), 2.77-2.68 (m, 2H), 2.42 (s, 4H), 1.80 (s, 9H).
11.85 (br, 1 H), 8.37 (q, J = 4.7 Hz, 1 H), 8.00 (s, 1 H), 7.79 (d, J = 6.1 Hz, 1 H), 7.65 (d, J = 8.3 Hz, 1 H), 7.56 (dd, J = 8.3, 1.6 Hz, 1 H), 6.95 (d, J = 6.1 Hz, 1 H), 6.88 (br, 1 H), 6.14 (br, 2H), 4.94 (hept, J = 6.6 Hz, 1 H), 2.82 (d, J = 4.4 Hz, 3H), 1.53 (d, J = 6.6 Hz, 6H).
12.25 (s, 1 H), 8.53 (q, J = 4.3 Hz, 1 H), 8.04-7.97 (m, 1 H), 7.79 (d, J = 6.2 Hz, 1 H), 7.70 (dd, J = 8.4, 1.4 Hz, 1 H), 7.61 (d, J = 8.4 Hz, 1 H), 6.99 (d, J = 6.2 Hz, 1 H), 5.98 (s, 2H), 4.97 (hept, J = 6.7 Hz, 1 H), 2.82 (d, J = 4.5 Hz, 3H), 1.52 (d, J = 6.7 Hz, 6H). 12.35 (s, 1 H), 8.53 (q, J = 4.3 Hz, 1 H), 8.02-7.98 (m, 1 H), 7.79 (d, J = 6.2 Hz, 1 H), 7.71 (dd, J = 8.4, 1.4 Hz, 1 H), 7.54 (d, J = 8.4 Hz, 1 H), 6.99 (d, J = 6.2 Hz, 1 H), 5.95 (s, 2H), 4.97 (hept, J = 6.7 Hz, 1 H), 2.82 (d, J = 4.3 Hz, 3H), 1.52 (d, J = 6.7 Hz, 6H).
12.22 (s, 1H), 10.87 (s, 1H), 8.27 (s, 1H), 8.17 (s, 1H), 7.87 (dd, J= 1.36, 8.46 Hz, 1 H), 7.67 (d, J = 2.32 Hz, 1 H), 7.61 (d, J = 8.48 Hz, 1 H), 6.97 (br s, 2H), 6.62 (d, J = 2.26 Hz, 1H), 4.14 (t, J= 6.56 Hz, 2H), 2.66 (t, J = 6.54 Hz, 2H), 2.19 (s, 6H), 1.80 (s, 9H).
12.22 (s, 1H), 10.87 (s, 1H), 8.27 (s, 1H), 8.18-8.14 (m, 1H), 7.87 (dd, J= 1.48, 8.44 Hz, 1 H), 7.66 (d, J = 2.26 Hz, 1 H), 7.61 (d, J = 8.45 Hz, 1 H), 6.98 (br s, 2H), 6.63 (d, J = 2.26 Hz, 1 H), 4.16 (t, J = 6.61 Hz, 2H), 2.71 (t, J = 6.62 Hz, 2H), 2.44 (br s, 4H), 2.34 (brs, 4H), 2.17 (s, 3H), 1.79 (s, 9H).
8.42 (d, J= 5.20 Hz, 1H), 8.25 (s, 1H), 7.98 (s, 1H), 7.67-7.50 (m, 4H), 4.42 (t, J = 6.44 Hz, 2H), 3.12 (t, J = 6.42 Hz, 2H), 2.81 (d, J = 4.41 Hz, 3H). NH2 and indole NH not visible.
12.21 (s, 1H), 10.88 (s, 1H), 8.28 (s, 1H), 8.17 (s, 1H), 7.87 (dd, J= 1.24, 8.53 Hz, 1 H), 7.67-7.57 (m, 2H), 6.95 (br s, 2H), 6.63 (d, J = 2.27 Hz, 1 H), 4.90 (t, J = 5.30 Hz, 1 H), 4.09 (t, J = 5.65 Hz, 2H), 3.75 (q, J = 5.57 Hz, 2H), 1.80 (s, 9H).
12.21 (brs, 1H), 8.51 (appq, 1H), 8.38 (s, 1H), 7.98 (s, 1H), 7.88 (s, 1H), 7.71 (dd, J = 8.4, 1.4 Hz, 1 H), 7.59 (d, J = 8.4 Hz, 1 H), 2.81 (d, J = 4.4 Hz, 3H). NH2 signals not present.
11.92 (s, 1H), 8.42-8.36 (over-lapping m, 2H), 7.96 (s, 1H), 7.76 (s, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.59 (dd, J= 8.4, 1.5 Hz, 1H), 6.70 (s, 1H), 2.81 (d, J= 4.4 Hz, 3H). NH2 signals not present.
8.88 (s, 1H), 8.31 (s, 1H), 8.27 (app s, 1H), 8.13-8.09 (over-lapping m, 2H), 8.01 (d, J = 7.0 Hz, 1 H), 1.82 (s, 9H). NH2 signals not present.
11.71 (s, 1 H), 8.37 (q, J = 4.5 Hz, 1 H), 7.96 (s, 1 H), 7.92 (s, 1 H), 7.59-7.53 (overlapping m, 2H), 7.43-6.82 (brs, 2H), 6.76 (s, 1H), 6.57 (d, J= 1.1 Hz, 1H), 3.45 (hept, J = 6.9 Hz, 1 H), 2.81 (d, J = 4.5 Hz, 3H), 1.34 (d, J = 6.9 Hz, 6H).
11.94 (s, 1 H), 8.47 (q, J = 4.3 Hz, 1 H), 7.98 (s, 1 H), 7.93 (d, J = 1.5 Hz, 1 H), 7.67 (dd, J = 8.4, 1.5 Hz, 1 H), 7.53 (d, J = 8.4 Hz, 1 H), 6.74 (s, 1 H), 3.46 (hept, J = 7.0 Hz, 1 H), 2.81 (d, J = 4.3 Hz, 3H), 1.34 (d, J = 7.0 Hz, 6H). NH2 signals not present.
12.10 (s, 1H), 8.48 (appq, 1H), 8.34 (brs, 1H), 7.98-7.97 (m, 1H), 7.97 (s, 1H), 7.67 (dd, J = 8.4, 1.5 Hz, 1 H), 7.56 (d, J = 8.4 Hz, 1 H), 6.65 (br s, 1 H), 3.56 (hept, J = 7.0 Hz, 1 H), 2.82 (d, J = 4.4 Hz, 3H), 1.38 (d, J = 7.0 Hz, 6H). 12.50 (s, 1H), 8.46 (q, J = 4.7 Hz, 1H), 8.26 (s, 1H), 8.12 (d, J= 8.4 Hz, 1H), 7.93 (d, J= 8.4 Hz, 1H), 7.07 (brs, 2H), 2.88 (d, J= 4.8 Hz, 3H), 1.78 (s, 9H).
ND
12.28 (s, 1H), 8.27 (s, 1H), 8.11 (dd, J= 1.5, 0.7 Hz, 1H), 7.84-7.74 (m, 1H), 7.67 (d, J = 8.4 Hz, 1 H), 7.01 (s, 2H), 3.89 (s, 3H), 1.79 (s, 9H).
11.83 (s, 1 H), 8.27 (s, 1 H), 8.24 (d, J = 4.6 Hz, 1 H), 7.70 (s, 1 H), 7.49 (s, 1 H), 7.04 (br, 2H), 6.84 (s, 1 H), 2.79 (d, J = 4.6 Hz, 3H), 1.79 (s, 9H).
11.44 (s, 1 H), 9.89 (s, 1 H), 8.25 (s, 1 H), 8.06 (app s, 1 H), 7.50 (d, J = 8.5 Hz 1 H), 7.09 (dd, J= 8.5, 1.9 Hz, 1H), 6.99 (br, 2H), 6.77-6.75 (brdd, 1H), 2.06 (s, 3H), 1.78 (s, 9H).
12.24 (s, 1H), 8.27 (s, 1H), 8.09 (brdd, 1H), 7.81 (dd, J= 8.5, 1.5 Hz, 1H), 7.65 (d, J = 8.5 Hz, 1H), 7.14-6.80 (br, 2H), 3.12 (q, J= 7.1 Hz, 2H), 1.79 (s, 9H), 1.14 (t, J = 7.1 Hz, 3H).
12.09 (s, 1H), 8.27 (s, 1H), 8.25 (brs, 1H), 8.00 (app s, 1H), 7.72 (dd, J= 8.4, 1.5 Hz, 1H), 7.59 (d, J= 8.4 Hz, 1H), 7.15-6.65 (br, 2H), 4.19-4.10 (m, 1H), 1.79 (s, 9H), 1.20 (d, J = 6.6 Hz, 6H).
12.11 (s, 1H), 8.51 (brt, 1H), 8.27 (s, 1H), 8.00 (app s, 1H), 7.70 (dd, J = 8.4, 1.5 Hz, 1 H), 7.59 (d, J = 8.4 Hz, 1 H), 7.20-6.60 (br, 2H), 3.36-3.29 (assume q, 2H, obscured by solvent), 1.79 (s, 9H), 1.15 (t, J = 7.2 Hz, 3H).
12.11 (s, 1H), 8.48 (brd, J= 4.3 Hz, 1H), 8.27 (s, 1H), 7.98 (app s, 1H), 7.68 (dd, J = 8.4, 1.4 Hz, 1H), 7.58 (d, J= 8.4 Hz, 1H), 7.15-6.65 (br, 2H), 2.92-2.86 (m, 1H), 1.78 (s, 9H), 0.73-0.68 (m, 2H), 0.63-0.58 (m, 2H).
12.22 (br, 1H), 10.30 (s, 1H), 8.27 (s, 1H), 8.13 (s, 1H), 7.82 (appd, 3H), 7.67 (d, J = 8.5 Hz, 1H), 7.36 (app t, 2H), 7.10 (app t, 1H), 6.95 (br, 2H), 1.79 (s, 9H).
8.42 (br q, J = 4.6 Hz, 1 H), 8.28 (s, 1 H), 8.11 (app s, 1 H), 7.68 (app d,J= 8.3 Hz, 1H), 7.63 (dd, J= 8.3, 1.4 Hz, 1H), 6.84 (d, J= 0.8 Hz, 1H), 3.91 (s, 3H), 2.84 (d, J = 4.6 Hz, 3H), 1.79 (s, 9H). NH2 signals not present.
11.90 (s, 1 H), 8.38 (br q, J = 4.6 Hz, 1 H), 8.01 (app s, 1 H), 7.79 (s, 1 H), 7.67 (d, J = 8.3 Hz, 1H), 7.57 (dd, J= 8.3, 1.6 Hz, 1H), 6.88 (s, 1H), 6.31 (s, 2H), 5.59 (hept, J = 6.6 Hz, 1 H), 2.82 (d, J = 4.6 Hz, 3H), 1.58 (d, J = 6.6 Hz, 6H).
12.20 (s, 1H), 8.50 (d, J= 5.15 Hz, 1H), 8.27 (s, 1H), 8.01 (d, J= 1.24 Hz, 1H), 7.70 (dd, J= 1.36, 8.38 Hz, 1H), 7.61 (d, J= 8.38 Hz, 1H), 7.07 (brs, 2H), 5.39 (p, J = 8.46 Hz, 1 H), 2.82 (d, J = 4.39 Hz, 3H), 2.79-2.64 (m, 2H), 2.49-2.39 (m, 2H), 1.98- 1.81 (m, 2H).
11.88 (s, 1 H), 8.39 (d, J = 4.21 Hz, 1 H), 8.27 (s, 1 H), 8.00 (s, 1 H), 7.65 (d, J = 8.34 Hz, 1H), 7.56 (dd, J= 1.54,8.41 Hz, 1 H), 7.14 (br s, 2H), 6.89 (s, 1H), 4.72 (tt, J = 4.41, 10.77 Hz, 1H), 2.82 (d, J= 4.36 Hz, 3H), 2.07-1.67 (m, 6H), 1.58-1.18 (m, 4H).
11.84 (s, 1 H), 8.37 (d, J = 4.99 Hz, 1 H), 8.27 (s, 1 H), 8.00 (s, 1 H), 7.65 (d, J = 8.35 Hz, 1H), 7.55 (dd, J= 1.25, 8.45 Hz, 1H), 7.11 (brs, 2H), 6.89 (s, 1H), 5.33-5.21 (m, 1H), 2.82 (d, J = 4.43 Hz, 3H), 2.19-2.06 (m, 4H), 2.01-1.88 (m, 2H), 1.79-1.67 (m, 2H).
12.14 (s, 1H), 8.48 (s, 1H), 8.26 (s, 1H), 8.00 (s, 1H), 7.69 (d, J= 8.50 Hz, 1H), 7.60 (d, J= 8.38 Hz, 1H), 7.02 (brs, 2H), 4.82-4.65 (m, 1H), 2.82 (d, J= 4.42 Hz, 3H), 2.04-1.93 (m, 6H), 1.93-1.66 (m, 4H).
11.96 (s, 1 H), 8.37 (d, J = 4.70 Hz, 1 H), 8.29 (s, 1 H), 7.99 (s, 1 H), 7.65 (d, J = 8.43 Hz, 1H), 7.55 (dd, J= 1.54,8.37 Hz, 1H), 7.15 (brs, 2H), 6.91 (s, 1H), 4.43 (q, J = 7.21 Hz, 2H), 2.81 (d, J = 4.42 Hz, 3H), 1.46 (t, J = 7.20 Hz, 3H).
11.92 (s, 1H), 8.37 (d, J = 4.95 Hz, 1H), 8.30 (s, 1H), 7.98 (s, 1H), 7.65 (d, J= 8.31 Hz, 1H), 7.55 (dd, J= 1.50,8.28 Hz, 1 H), 7.14 (br s, 2H), 6.89 (s, 1H), 3.89 (tt, J = 3.81,7.40 Hz, 1H),2.81 (d, J = 4.39 Hz, 3H), 1.34-1.18 (m, 2H), 1.23-1.07 (m, 2H).
12.14 (s, 1H), 8.27 (s, 1H), 8.05-7.99 (over-lapping m, 2H), 7.73 (dd, J = 8.4, 1.4 Hz, 1H), 7.58 (d, J= 8.4 Hz, 1H), 7.28 (br, 1H), 7.05-6.80 (br, 2H), 1.79 (s, 9H).
12.20 (s, 1H), 8.31 (brq, J= 4.6 Hz, 1H), 8.27 (s, 1H), 7.60 (s, 1H), 7.50 (s, 1H), 6.94 (br, 2H), 2.80 (d, J = 4.6 Hz, 3H), 1.78 (s, 9H).
11.52 (br s, 1 H), 9.51 (br s, 1 H), 8.25 (s, 1 H), 7.56 (d, J = 8.5 Hz 1 H), 7.44-7.40 (m, 1H), 7.01 (br, 2H), 6.97 (dd, J= 8.5, 1.9 Hz, 1H), 6.79 (brd, 1H), 2.92 (s, 3H), 1.78 (s, 9H).
11.31 (s, 1 H), 8.43 (s, 1 H), 8.24 (s, 1 H), 7.82 (app s, 1 H), 7.43 (d, J = 8.5 Hz, 1 H), 6.99 (br, 2H), 6.89 (dd, J = 8.5, 1.9 Hz, 1 H), 6.70- 6.69 (m, 1 H), 5.92 (q, J = 4.6 Hz, 1 H), 2.66 (d, J = 4.6 Hz, 3H), 1.78 (s, 9H).
12.17 (s, 1H), 8.76 (t, J= 5.6 Hz, 1H), 8.27 (s, 1H), 8.01 (app s, 1H), 7.70 (dd, J = 8.5, 1.5 Hz, 1 H), 7.62 (d, J = 8.5 Hz, 1 H), 6.94 (br, 2H), 3.72 (app q, 2H), 3.42 (t, J = 6.9 Hz, 2H), 3.05 (s, 3H), 1.79 (s, 9H).
12.25 (s, 1H), 10.80 (s, 1H), 8.40 (ddd, J = 4.8, 2.0, 0.9 Hz, 1H), 8.27 (s, 1H), 8.23 (dt, J= 8.4, 0.9 Hz, 1H), 8.20 (app s, 1H), 7.90-7.83 (over-lapping m, 2H), 7.65 (d, J = 8.4 Hz, 1H), 7.17 (ddd, J = 7.3, 4.8, 1.0 Hz, 1H), 6.97 (br, 2H), 1.79 (s, 9H). 74 12.18 (s, 1H), 8.50 (brq, J= 4.5 Hz, 1H), 8.28 (s, 1H), 7.98 (app s, 1H), 7.65 (d, J = 1.1 Hz, 1H), 7.07 (br, 2H), 6.83 (s, 1H), 2.82 (d, J= 4.5 Hz, 3H), 1.80 (s, 9H).
12.14 (br, 1H), 9.09 (t, J= 6.0 Hz, 1H), 8.27 (s, 1H), 8.06 (app s, 1H), 7.76 (dd, J =
75
8.5, 1.4 Hz, 1 H), 7.62 (d, J = 8.5 Hz, 1 H), 7.36-7.21 (over-lapping m, assume 5H), 6.94 (br, 2H), 4.52 (d, J = 6.0 Hz, 2H), 1.79 (s, 9H)
12.13 (s, 1H), 8.61 (t, J= 5.6 Hz, 1H), 8.27 (s, 1H), 7.99 (app s, 1H), 7.69 (dd, J =
76
8.4, 1.4 Hz, 1H), 7.60 (d, J= 8.4 Hz, 1H), 7.33-7.25 (over-lapping m, 4H), 7.23-7.18 (m, 1H), 6.93 (br, 2H), 3.55-3.49 (m, 2H), 2.89 (appt, 2H), 1.79 (s, 9H).
12.16 (s, 1H), 8.72 (t, J= 5.6 Hz, 1H), 8.27 (s, 1H), 8.00 (app s, 1H), 7.70 (dd, J =
77
8.4, 1.5 Hz, 1 H), 7.62 (d, J = 8.4 Hz, 1 H), 6.93 (br, 2H), 3.54 (app q, 2H), 2.65-2.51 (m, 2H), 1.79 (s, 9H).
12.16 (s, 1H), 8.77 (t, J= 5.6 Hz, 1H), 8.27 (s, 1H), 8.02 (app s, 1H), 7.71 (dd, J =
78
8.4, 1.5 Hz, 1H), 7.62 (d, J= 8.4 Hz, 1H), 6.93 (br, 2H), 4.23 (t, J= 5.5 Hz, 2H), 3.61 (q, J = 5.5 Hz, 2H), 1.79 (s, 9H).
12.20 (s, 1H), 9.44 (t, J= 6.0 Hz, 1H), 8.27 (s, 1H), 8.08 (app s, 1H), 7.77-7. '4
79
(over-lapping m, 2H), 7.65-7.62 (over-lapping m, 2H), 4.79 (d, J= 6.0 Hz, 2H),1.79 (s, 9H). NH2 signals not present.
12.11 (s, 1H), 8.53 (brt, J = 6.0 Hz, 1H), 8.27 (s, 1H), 8.00 (app s, 1H), 7.71 (dd, J
80 = 8.4, 1.5 Hz, 1 H), 7.59 (d, J = 8.4 Hz, 1 H), 6.92 (br, 2H), 3.87-3.84 (m, 2H), 3.28 (td, obscured by solvent assume 2H), 3.19 (app t, J = 6.3 Hz, 2H), 1.88-1.74 (m, 1H), 1.78 (s, 9H), 1.65-1.58 (m, 2H), 1.27-1.16 (m, 2H).
81 11.50 (s, 1 H), 8.38 (br q, 1 H), 8.26 (s, 1 H), 7.93 (app s, 1 H), 7.60 (app s, 2H), 6.80 (br, 2H), 2.81 (d, J = 4.4 Hz, 3H), 2.33 (s, 3H), 1.78 (s, 9H)
82 11.70 (s, 1H), 10.00 (s, 1H), 8.25 (s, 1H), 8.08 (app s, 1H), 7.46 (d, J= 8.6 Hz, 1H), 7.21 (brdd, 1H), 6.84 (br, 2H), 2.07 (s, 3H), 1.77 (s, 9H).
8.49 (q, J = 4.4 Hz, 1 H), 8.27 (s, 1 H), 8.17 (br, 1 H), 7.74 (dd, J = 8.4, 1.4 Hz, 1 H),
83
7.63 (app d, J = 8.4 Hz, 1 H), 3.74 (s, 3H), 2.85 (d, J = 4.4 Hz, 3H), 1.79 (s, 9H). NH2 signals not present.
11.97 (s, 1 H), 8.25 (d, J = 4.67 Hz, 1 H), 8.05 (s, 1 H), 7.77 (d, J = 1.23 Hz, 1 H), 7.46
84
(dd, J= 1.42, 8.45 Hz, 1H), 7.37 (d, J= 8.44 Hz, 1H), 6.86 (brs, 2H), 4.21 (q, J = 7.23 Hz, 2H), 2.59 (d, J = 4.43 Hz, 3H), 1.23 (t, J = 7.20 Hz, 3H).
12.19 (s, 1H), 8.48 (d, J = 4.55 Hz, 1H), 8.29 (s, 1H), 7.98 (d, J= 1.28 Hz, 1H), 7.68
85
(d, J= 8.55 Hz, 1H), 7.59 (d, J= 8.38 Hz, 1H), 7.07 (brs, 2H), 3.94 (tt, J= 3.86, 7.38 Hz, 1H), 2.82 (d, J = 4.44 Hz, 3H), 1.31-1.06 (m, 4H). 12.15 (s, 1H), 8.49 (q, J = 4.22 Hz, 1H), 8.27 (s, 1H), 8.04-7.97 (m, 1H), 7.70 (dd, J = 1.45, 8.42 Hz, 1H), 7.60 (d, J= 8.41 Hz, 1H), 7.05 (brs, 2H), 5.29 (p, J= 7.19 Hz, 1 H), 2.82 (d, J = 4.42 Hz, 3H), 2.23-1.98 (m, 4H), 1.98-1.82 (m, 2H), 1.81-1.67 (m, 2H).
12.49 (s, 1H), 8.57 (brq, J= 4.4 Hz, 1H), 8.26 (s, 1H), 7.94 (d, J= 1.2 Hz, 1H), 7.66 (s, 1 H), 7.01 (br, 2H), 2.81 (d, J = 4.5 Hz, 3H), 1.78 (s, 9H).
12.67 (s, 1H), 12.33 (s, 1H), 8.29 (app s, 1H), 8.28 (s, 1H), 7.96 (dd, J= 8.4, 1.5 Hz, 1H), 7.68 (d, J= 8.4 Hz, 1H), 7.58 (d, J= 3.4 Hz, 1H), 7.29 (d, J= 3.4 Hz, 1H), 6.98 (br, 2H), 1.79 (s, 9H).
12.15 (s, 1H), 8.51 (d, J = 4.25 Hz, 1H), 8.29 (s, 1H), 7.99 (dd, J= 0.70, 1.44 Hz, 1H), 7.69 (dd, J= 1.41, 8.47 Hz, 1H), 7.60 (d, J= 8.42 Hz, 1H), 7.10 (brs, 2H), 5.02-4.85 (m, 1H), 3.74 (d, J= 12.03 Hz, 2H), 3.12-3.00 (m, 2H), 2.95 (s, 3H), 2.96- 2.82 (m, 1H), 2.35-2.07 (m, 2H), 0.78-0.62 (m, 2H), 0.67-0.55 (m, 2H).1 x CH2 not visible.
12.13 (s, 1H), 8.50 (d, J = 4.27 Hz, 1H), 8.28 (s, 1H), 7.99 (s, 1H), 8.02-7.95 (m, 1H), 7.69 (d, J= 8.40 Hz, 1H), 7.59 (d, J= 8.45 Hz, 1H), 7.06 (brs, 2H), 5.06-4.89 (m, 1H), 4.10 (d, J= 13.01 Hz, 2H), 3.03 (brs, 2H), 2.97-2.82 (m, 1H), 2.13-1.95 (m, 4H), 1.43 (s, 9H), 0.78-0.55 (m, 4H).
12.11 (s, 1H), 8.50 (brt, J= 5.6 Hz, 1H), 8.27 (s, 1H), 8.00 (app s, 1H), 7.71 (dd, J = 8.4, 1.5 Hz, 1 H), 7.60 (d, J = 8.4 Hz, 1 H), 6.93 (br, 2H), 3.29-3.23 (m, 2H), 1.79 (s, 9H), 1.57 (sext, J = 7.3 Hz, 2H), 0.91 (t, J = 7.3 Hz, 3H).
12.27 (s, 1H), 8.49 (brq, J= 4.5 Hz, 1H), 8.01 (app s, 1H), 7.80 (s, 1H), 7.71 (dd, J = 8.4, 1.5 Hz, 1 H), 7.62 (d, J = 8.4 Hz, 1 H), 6.06 (s, 2H), 5.60 (hept, J = 6.6 Hz, 1 H), 2.82 (d, J = 4.5 Hz, 3H), 1.56 (d, J = 6.6 Hz, 6H).
12.33 (s, 1H), 9.27 (d, J= 10.86 Hz, 1H), 8.94 (d, J= 10.35 Hz, 1H), 8.54 (d, J = 4.33 Hz, 1 H), 8.52 (s, 1 H), 8.03 (s, 1 H), 7.71 (dd, J = 1.42, 8.46 Hz, 1 H), 7.61 (d, J = 8.46 Hz, 1H), 5.26-5.12 (m, 1H), 3.77-3.58 (m, 1H), 3.55-3.42 (m, 1H), 3.30-3.13 (m, 2H), 2.90 (dq, J = 4.05, 7.25 Hz, 1 H), 2.40 (q, J = 11.18, 11.95 Hz, 2H), 2.20 (d, J = 13.07 Hz, 2H), 0.78-0.56 (m, 4H).
12.17 (s, 1H), 8.48 (brq, 1H), 8.28 (s, 1H), 8.00 (s, 1H), 7.70 (brd, 1H), 7.60 (brd, 1H), 7.04 (br, 2H), 4.31 (d, J= 7.0 Hz, 2H), 3.85-3.81 (m, 2H), 3.26 (brt, 2H), 2.82 (d, J = 4.4 Hz, 3H), 2.28-2.15 (m, 1H), 1.51-1.40 (m, 2H), 1.37-1.23 (m, 2H).
ND 12.14 (br, 1H), 8.49 (d, J = 4.2 Hz, 1H), 8.28 (s, 1H), 7.99 (app s, 1H), 7.68 (dd, J =
96 8.4, 1.4 Hz, 1H), 7.58 (d, J= 8.4 Hz, 1H), 7.06 (br, 2H), 4.31 (d, J= 7.1 Hz, 2H), 3.85-3.81 (m, 2H), 3.29-3.22 (m, 2H), 2.92-2.86 (m, 1H), 2.28-2.17 (m, 1H), 1.50- 1.42 (m, 2H), 1.38-1.26 (m, 2H), 0.73-0.68 (m, 2H), 0.63-0.59 (m, 2H).
8.66 (br q, J = 4.4 Hz, 1 H), 8.32 (br s, 1 H), 8.27 (s, 1 H), 7.90 (dd, J = 8.4, 1.4 Hz,
97
1 H), 7.76 (t, J = 57.3 Hz, 1 H), 7.74 (app d, J = 8.4 Hz, 1 H), 7.21 (br, 2H), 2.85 (d, J = 4.4 Hz, 3H), 1.77 (s, 9H).
12.14 (s, 1H), 8.50 (brt, 1H), 8.29 (s, 1H), 8.01 (app s, 1H), 7.71 (brdd, 1H), 7.60 (brd, 1H), 5.58-5.52 (m, 1H), 4.17-4.07 (over-lapping m, 1H), 4.14-4.07 (m, 1H),
98
3.99 (dd, J= 9.2, 4.4 Hz, 1H), 3.94-3.89 (m, 1H), 3.29-3.23 (m, 2H), 2.48-2.43 (m, 2H), 1.57 (app sext, 2H), 0.91 (t, J = 7.4 Hz, 3H). NH2 signals not observed.
12.22 (s, 1H), 8.52 (brt, 1H), 8.35 (s, 1H), 8.01 (app s, 1H), 7.71 (brd, 1H), 7.61 (br
99
d, 1 H), 5.35 (q, J = 8.9 Hz, 2H), 3.33 (assume 2H, obscured by solvent), 1.15 (t, J = 7.2 Hz, 3H). NH2 signals not observed.
12.23 (s, 1H), 8.49 (brq, 1H), 8.35 (s, 1H), 8.01 (app s, 1H), 7.70 (brdd, 1H), 7.6200
(br d, 1 H), 5.35 (q, J = 9.0 Hz, 2H), 2.82 (d, J = 4.5 Hz, 3H). NH2 signals not observed.
12.14 (s, 1H), 8.49 (brd,J = 4.2 Hz, 1H), 8.29 (s, 1H), 7.99 (app s, 1H), 7.68 (dd, J = 8.4, 1.3 Hz, 1H), 7.59 (d, J= 8.4 Hz, 1H), 7.09 (br, 2H), 5.58-5.52 (m, 1H),4.1501
(dd, J= 9.2, 6.9 Hz, 1H), 4.09 (q, J= 7.5 Hz, 1H), 3.99 (dd, J= 9.2, 4.3 Hz, 1H), 3.94-3.89 (m, 1H), 2.92-2.86 (m, 1H), 2.47-2.42 (m, 2H), 0.73-0.68 (m, 2H), 0.63- 0.59 (m, 2H).
12.21 (s, 1H), 8.50 (brd, 1H), 8.35 (s, 1H), 7.99 (app s, 1H), 7.69 (brd, 1H), 7.6002
(brd, 1H), 5.35 (q, J= 9.0 Hz, 2H), 2.91-2.87 (m, 1H), 0.73-0.68 (m, 2H), 0.63-0.59 (m, 2H). NH2 signals not observed.
12.13 (s, 1H), 8.49 (d, J = 4.2 Hz, 1H), 8.28 (s, 1H), 7.99 (app s, 1H), 7.68 (dd, J =03 8.4, 1.5 Hz, 1H), 7.59 (d, J= 8.4 Hz, 1H), 5.03-4.97 (m, 1H), 4.04-4.00 (m, 2H), 3.57 (appt, 2H), 2.91-2.87 (m, 1H), 2.28-2.18 (m, 2H), 1.97-1.91 (m, 2H), 0.73-0.68 (m, 2H), 0.63-0.59 (m, 2H). NH2 signals not observed.
8.49 (d, J = 4.27 Hz, 1 H), 8.27 (s, 1 H), 7.99 (s, 1 H), 7.68 (dd, J = 1.44, 8.45 Hz, 1H), 7.58 (d, J= 8.39 Hz, 1H), 7.16 (brs, 2H), 5.23 (p, J = 8.14 Hz, 1H), 4.95 (s,04
1H), 4.24 (dt, J = 6.04, 11.97 Hz, 1H), 2.90 (tt, J= 4.07, 7.12 Hz, 1H), 2.50-2.36 (m, 1H), 2.29-2.00 (m, 3H), 1.90 (dq, J = 7.16, 13.75 Hz, 1H), 1.80 (dt, J = 6.47, 12.64 Hz, 1H), 0.78-0.66 (m, 2H), 0.66-0.55 (m, 2H). Indole NH not visible.
ND
05 11.70 (s, 1H), 9.34 (s, 1H), 8.04 (s, 1H), 7.91 (d, J= 1.2 Hz, 1H), 7.54 (d, J= 8.3
106 Hz, 1H), 7.44 (dd, J= 8.3, 1.6 Hz, 1H), 6.92 (s, 2H), 6.72 (s, 1H), 4.88 (p, J= 6.7
Hz, 1 H), 2.30-2.21 (m, 18H), 1.31 (d, J = 6.7 Hz, 6H).
12.25 (s, 1H), 9.62 (s, 1H), 8.27 (s, 1H), 8.13 (d, J= 1.4 Hz, 1H), 7.81 (d, J= 8.2
107 Hz, 1H), 7.72 (d, J= 8.4 Hz, 1H), 7.10 (s, 2H), 5.13 (p, J = 6.6 Hz, 1H), 1.54 (d, J =
6.6 Hz, 6H).
11.90 (s, 1H), 8.28 (s, 1H), 8.23-8.09 (m, 2H), 7.81-7.67 (m, 2H), 7.37 (d, J= 0.8
108
Hz, 1H), 7.15 (s, 2H), 6.94 (s, 1H), 5.12 (p, J= 6.7 Hz, 1H), 1.55 (d, J = 6.7 Hz, 6H).
12.00 (s, 1H), 8.05 (d, J= 14.3 Hz, 2H), 7.89 (s, 1H), 7.64 (d, J= 8.5 Hz, 1H), 7.51
109 (d, J = 8.5 Hz, 1 H), 7.20 (d, J = 0.8 Hz, 1 H), 4.93 (p, J = 6.7 Hz, 1 H), 1.34 (d, J =
6.7 Hz, 6H). NH2 signals not observed.
Synthesis of Other Examples
Example 39 - 2-[4-A \noA-(propan-2-y\)A -pyrazo\o[4,3-c]pyr\d\n-3-y\]-3-bro o-N-^ 1 H-indole-6-carboxamide
[00259] Prepared according to a similar procedure to that used in General Method 8 from 2- (4-amino-1-isopropyl-1/-/-pyrazolo [4,3-c]pyridin-3-yl)-/V-methyl-1/-/-indole-6-carboxamide (100 mg, 0.287 mmol) and NBS (56 mg, 0.32 mmol) for a reaction time of 1 h (7:3 mixture of mono- and dibrominated products observed by HPLC) and purified by fee (0-5% MeOH:DCM) to return the title compound (31 mg, 25%) as a brown solid.
Example 51 - 2-{4-AminoA-tert-butylAH^yrazolo[3,4-d]pyrimidin-3-yl}-N-methylAH- pyrrolo[2,3-b]pyridine-6-carboxamide
[00260] A mixture of 6-amino-5-((4-amino-1-(fe/f-butyl)-1/-/-pyrazolo[3,4-c]pyrimidin-3- yl)ethynyl)-/V-methylpicolinamide (138 mg, 0.38 mmol) and potassium te/f-butoxide (1.0 M in THF, 1.89 mL) in DMF (7 mL) was stirred at room temperature for 20 h and then at 90 °C for 16 h. The solvent was concentrated in vacuo and the resulting residue taken up in MeOH (10 mL) and azetroped with heptane (20 mL). The solid that formed was dissolved in MeOH (10 mL) and purified by capture/release with MP-TsOH resin, washing with MeOH (50 mL) and eluting with NH3/MeOH (1%, 30 mL). The crude product was purified by fee (0-5% MeOH (+ 1% NH3) in DCM) to return the title compound (22 mg, 91% pure by HPLC, 16%) as a yellow solid. Example 54 - N-(2-{4-AminoA -tert-butylA H-pyrazolo[3^]pynmidin-3-yl}-^
yl)acetamide
[00261] To a solution of 3-(6-amino-1H-indol-2-yl)-1-(fe/f-butyl)-1H-pyrazolo[3,4-<^pyrirnidin- 4-amine (51 mg, 0.15 mmol) in DCM (2 mL) was added pyridine (20 μΙ_, 0.25 mmol) then acetic anhydride (20 μΙ_, 0.15 mmol) and the resulting mixture stirred at room temperature for 70 mins. EtOAc (20 mL) and water (10 mL) were added and the biphasic mixture separated. The organic layer was washed with sat aq NH4CI (10 mL), sat aq NaHCC>3 (10 mL) and brine (2 x 10 mL), then dried and concentrated in vacuo. The crude product was purified by fee (0- 10% MeOH in DCM) to return the title compound (29 mg, 53%) as an off-white solid.
Example 55 - 1 -(2-{4-A inoA -tert-butylA H-pyrazolo[3,4-d]pyrimidin-3-yl}-3-chloroA H-indol- 6-yi)propanA -one
[00262] To a solution of 1-(2-(4-amino-1-(fe/f-butyl)-1/-/-pyrazolo[3,4-c]pyrimidin-3-yl)-3- chloro-1/-/-indol-6-yl)propan-1-ol (32 mg, 0.079 mmol) in DCM (3 mL) was added a suspension of DMP (40 mg, 0.095 mmol) in DCM (3 mL) dropwise. The resulting mixture was stirred at room temperature for 45 mins, then diluted with aq NaOH (1.0 M, 30 mL) and stirred for a further 15 mins. EtOAc (30 mL) was added and the biphasic mixture separated. The organic layer was washed with water (30 mL), brine (30 mL), then dried and concentrated in vacuo. The crude product was purified by fee (0-5% MeOH in DCM) to return the title compound (9 mg, 91% pure by HPLC, 29%) as a brown solid.
Example 70 -N-(2-(4-Amino-1-(tert-butyl)- 1 H-pyrazolo[3, 4-d]pyrimidin-3-yl)- 1 H-indol-6-yl) methanesulfonamide
[00263] To a mixture of 3-(6-amino-1/-/-indol-2-yl)-1-(fe/f-butyl)-1/-/-pyrazolo[3,4- <^pyrimidin-4-amine (40 mg, 0.12 mmol) and pyridine (20 μί, 0.25 mmol) in DCM (1 mL) at 0 °C was added methanesulfonyl chloride (15 μί, 0.19 mmol). The resulting mixture was maintained at 0 °C for 1 h then partitioned between MeOH in DCM (1 :9, 10 mL) and water (10 mL). The pH was adjusted to between 7 and 8 through the addition of HCI (1.0 M) and sat aq NaHCOs and the layer separated. The aq layer was extracted with further DCM (2 χ 10 mL) and the combined organic extracts washed with brine (2 x 10 mL), passed through a phase separator and concentrated in vacuo. The result thus obtained was purified by fee (0-100% EtOAc in isohexane then 0-10% MeOH in DCM). The orange solid isolated was further purified by preparative HPLC to return the title compound (9 mg, 20% yield) as a pale yellow solid. Example 71 - 1-(2-(4-Amino- l-(tert-butyl)- 1H-pyrazolo[3, 4-d]pyrimidin-3-yl)- 1 H-indol-6-yl)-3- methylurea
[00264] To a solution of phenyl (2-(4-arnino-1-(fe/f-butyl)-1 /-/-pyrazolo[3,4-c]pyrirTiiclin- 3-yl)-1 /-/-indol-6-yl)carbamate (57 mg, 0.11 mmol) in THF (1 mL) was added methylamine (2.0 M in THF, 0.10 mL) and the resulting mixture stirred at room temperature for 23 h. THF (1 mL) was added, the mixture was stirred at room temperature for 30 min and then further methylamine (2.0 M in THF, 0.10 mL) was added. The resulting mixture was stirred for 24 h then additional methylamine (2.0 M in THF, 0.10 mL) and THF (1 mL) were added. After a further 7.5 h methylamine (2.0 M in THF, 0.10 mL) was added and the mixture stirred for 60 h. The resulting mixture was partitioned between EtOAc (20 mL) and sat aq NaHCC (20 mL) and the biphasic mixture separated. The aq layer was extracted with further EtOAc (20 mL) and the combined organic extracts washed with brine (2 χ 20 mL), dried and concentrated in vacuo. The crude product was purified by fee (0-10% MeOH in DCM) to return the title compound (4 mg, 10% yield) as a pale yellow solid.
Example 93 - 2-[4-amino^ -(piperidin-4-yl)^ H-pyrazolo[3,4-d]pyrimidin-3-yl]-3-chloro-N- cyclopropyl- 1 H-indole-6-carboxamide hydrochloride
[00265] To a solution of te/f-butyl 4-[4-amino-3-[3-chloro-6-(cyclopropylcarbamoyl)-1 /-/-indol- 2-yl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate (30 mg, 0.05 mmol) in 1 ,4-dioxane (4 mL) at room temperature was added HCI (4M in 1 ,4-dioxane, 0.14 mL, 0.54 mmol) and the resulting mixture was stirred at room temperature for 20 h. The solvent was concentrated in vacuo to return return the tile compound (24 mg, 90%) as a yellow solid.
Example 97 - 2-{4-aminoA -tert-butylA H^yrazolo[3,4-d]pyrimidin-3-yl}-3-chloroA - (difluoromethyl)-N-methyl-M-l-indole-6-carboxamide
[00266] To a mixture of 2-(4-amino-1-fe/f-butyl-pyrazolo[3,4-c]pyrimidin-3-yl)-3-chloro-/\/- methyl-1 /-/-indole-6-carboxamide (32 mg, 0.08 mmol) and NaOH (64 mg, 1.6 mmol) in MeCN:water (15:1 , 3.2 mL) at -5 °C was added diethyl(bromodifluoromethyl)phosphonate (43 mg, 0.16 mmol). The resulting mixture was stirred at 0 °C for 15 mins, then warmed to room temperature and maintained at this temperature for a further 2 h. A 2: 1 mixture of unreacted starting material and product was observed by HPLC. The solvent was concentrated in vacuo and the resulting residue partitioned between EtOAc (50 mL) and water (15 mL). The organic layer was separated and retained and the aq phase was extracted with further EtOAc (2 χ 50 mL). The combined organic extracts were washed with brine (50 mL), dried and concentrated in vacuo. The crude product was purified by fee (0-100% EtOAc in isohexane) to return the title compound (3.7 mg, 10%) as a white solid.
Biological data
RET, E7 804M and KDR Enzyme Assays
[00267] Kinase activity was detected using CisBio HTRF kinEASE kit based on time-resolved fluorescence transfer (FRET). The assay was performed in 384-well white plates (Corning #3574) in a reaction volume of 10 μΙ_ containing 1X CisBio enzymatic buffer supplemented with a final concentration of 5 mM MgCI2, 1 mM DTT, 10 nM SEB and 0.01 % Triton X100 for RET. The same buffer conditions were used for KDR with the addition of 2 mM MnC . RETV804M buffer used 1X CisBio enzymatic buffer supplemented with a final concentration of 2 mM MgCI2, 1 mM DTT, 20 nM SEB and 0.01 % Triton X100.
[00268] Inhibitors were pre-incubated in the plate for 15 mins with 5 μΙ_ kinase and assay buffer at the following concentrations; 13 pM RET (Carna Biosciences; 08-159), 30 pM R ETv804M (MiHipore; 14-760) and 150 pM KDR (Millipore; 14-630). The reaction was initiated by the addition of 5 μΙ_ ATP and substrate at 2X final reaction concentrations. For RET, this was 18 μΜ and 2 μΜ; for RETV804M, this was 4 μΜ and 1 .5 μΜ and for KDR, this was 16 μΜ and 1 μΜ, respectively. Reactions were performed at ATP Km for each target. The assay was allowed to proceed at room temperature for 30 mins before terminating with the addition of 10 μΙ_ HTRF detection buffer containing EDTA supplemented with TK-antibody labelled with Eu3+- Cryptate (1 :100 dilution) and streptavidin-XL665 (128 nM). Following incubation at room temperature for 1 hour, FRET signal was measured using the Pherastar FS Microplate Reader.
[00269] Activity data (IC50) for the compounds of the present invention against RET, KDR and RETV804M enzymes is shown in Table 1 below.
Table 1 - RET, RETV804M and KDR enzyme activity data
RET Enzyme KDR Enzyme RETV804ME nzyme
EXAMPLE IC50 (μΜ) IC50 (μΜ) IC50 (μΜ)
1 0.0172 5.98 0.7
2 0.0186 2.02 0.838
3 0.0232 1 1 .1 >1
4 0.0177 5.35 0.019
5 0.00315 1 .88 0.0165
6 0.00457 1 0.214
7 0.00803 1 .57 0.013
8 0.0147 9.01 0.0407 9 0.00453 1 .18 0.0148
10 8.14 »30 >30
1 1 0.0551 26.6 4.25
12 0.0457 2.91 3.94
13 0.0132 3.22 0.697
14 0.0402 26.9 0.138
15 0.463 >30 1 .16
16 0.804 >30 3.67
17 0.0821 >30 0.199
18 0.00873 0.345 0.00766
19 0.355 >30 2.59
20 0.212 >30 1 .35
21 0.139 >30 0.237
22 0.125 >30 0.0867
23 0.0143 1 .51 0.0239
24 0.0575 5.45 0.07
25 0.0298 10.5 0.0321
26 0.0492 >30 0.0549
27 0.0544 26.8 0.058
28 0.0681 >30 0.0153
29 0.00578 4.02 0.15
30 0.0804 >30 0.324
31 0.0543 >30 0.169
32 0.00793 4.58 0.0456
33 0.097 >30 0.0819
34 0.0739 >30 0.209
35 0.0171 1 0.0198
36 0.0652 0.234 0.0206
37 0.0324 9.42 1 .38
38 0.00524 3.47 0.0258
39 0.0231 1 1 .2 0.0434
40 0.00736 0.0667 0.00555
41 0.0212 0.142
42 0.607 >30 2.95
43 0.00566 0.566 0.00583
44 0.153 >30 2.6
45 0.1 14 >30 >30
46 0.194 >30 1 .96
47 0.00484 2.56 0.494
48 0.00831 8.53 0.0277
49 0.00541 4.2 0.0162
50 0.0507 >30 0.165
51 0.126 >30 5.01
52 0.0373 >30 0.147
53 0.0224 4.5 7.56
54 0.0022 1 .06 0.205
55 0.191 >30 >30
56 0.0355 >30 0.0579
57 0.0106 6.1 1
58 0.024 0.933 0.0176
59 0.328 >30 0.769
60 0.0647 8.59 6.12 61 0.00715 5.13 0.415
62 0.00578 3 0.0537
63 0.0357 >30 2.6
64 0.00635 4.31 0.827
65 0.01 9.49 0.0532
66 0.0393 >30 2.9
67 0.0421 >30
68 0.0142 0.0351
69 0.0168 1 .48 0.131
70 0.0299 4.68 3.4
71 0.00102 0.598 0.173
72 0.0509 18 0.101
73 0.0513 0.0856
74 0.0374 18.1 28.2
75 0.109 >30 0.204
76 0.227 >30
77 0.501 26.1 0.249
78 0.0704 10.6 0.205
79 0.188 >30 0.435
80 0.626 >30 1 .45
81 0.0188 7.42 0.213
82 0.01 1 1 1 .05
83 0.0536 1 1 .4 0.225
84 0.0215 >30 0.0648
85 0.0322 1 1 .3 0.135
86 0.00523 5.42 0.0445
87 0.0356 5.53 3.26
88 0.00949 1 .35 0.0278
89 0.00473 0.646 0.00872
90 0.0865 20 0.0796
91 0.0493 12.5 0.0203
92 0.0524 5.2 0.0901
93 0.0327 7.73 0.0998
94 0.0138 7.67 0.0395
95 0.031 1 8.37 0.0951
96 0.013 1 .08 0.0207
97 1 1 .2 >30 >30
98 0.0331 6.09 0.0843
99 0.0365 14 0.0787
100 0.0341 14.2 0.134
101 0.00988 0.652 0.0222
102 0.0354 4.65 0.0685
103 0.00866 0.924 0.0222
104 0.00425 0.245 0.00848
105 0.0318 5.31 0.1 14
106 0.00795 3 3
107 0.00415 0.712 0.0329
108 0.00419 1 .71 8
109 0.00629 0.894 0.0473 BaF3 Cell Assay
[00270] The system originally developed by Daley and Baltimore16 was used, whereby I Independent BaF3 cells are modified to express an activated recombinant kinase. Following removal of IL3, the modified cells are dependent on the activity of the recombinant kinase for survival and proliferation. The BaF3 cell lines, expressing KIF5B-RET (gift from Pasi Janne7), KDR and RETV804M (Advanced Cellular Dynamics, San Diego) were maintained in RPMI-1640 media containing 10% FBS and appropriate antibiotics. Non-modified BaF3 cells (WT) were maintained in RPMI-1640 media containing 10% FBS and supplemented with 10 ng/mL recombinant mouse IL3 (R&D systems). For assessment of compound IC50, cells were plated into 384-well plates at 1500 or 3000 cells per well in 30 μΙ_ culture medium and compounds dispensed using an acoustic liquid handling platform (LABCYTE). Following incubation of the cells for 48 hours at 37 °C in a humidified 5% CO2 atmosphere, viability was determined by addition of 10 μΙ_ CellTiter-Glo reagent (Promega) and measurement of luminescence.
[00271] Cell activity data is presented in Table 2 below.
Table 2 - BaF3 Cell activity data
KIF5B-RET KDR IC50 BCR-RET(V804M IC50 BaF3 IC50
EXAMPLE IC50(MM) (μΜ) (μΜ) (μΜ)
1 0.0691 1.93 0.64 2.53
2 0.0348 4.1 0.202 >10
3 0.0928 3.65 1.5 3.82
4 0.0125 1.92 0.0272 2.54
5 0.038 3.16 0.0848 4.64
6 0.0435 2.42 1.07 3.27
7 0.0346 2.74 0.0859 4.64
8 0.0468 6.89 0.0975 6.89
9 0.0608 4.42 0.0836 >10
10 0.539 2.39 1.15 4.53
11 0.164 6.05 2.71 8.92
12 0.119 7.39 1.73 >10
13 0.107 >10 1.56 >10
14 0.166 >10 0.142 >10
15 1.62 4.91 1.32 4.92
16 5.02 >10 1.98 >10
17 0.508 >10 0.429 >10
18 0.0111 0.554 0.0143 >10
19 0.664 5.49 0.615 >10
20 0.472 >10 0.711 >10
21 0.411 >10 0.41 >10
22 0.138 >10 0.114 >10
23 0.265 >10 0.362 >10
24 0.38 >10 0.692 >10
25 0.21 >10 1.35 >10
26 0.46 >10 0.538 6
27 0.475 4.91 0.556 4.88 0.0896 4.24 0.0678 6.4
0.0191 4.64 0.151 9.73
>10 >10 >10 >10
1 .19 >10 4.29 >10
5.91 >10 >10 >10
0.555 >10 0.308 >10
1 .51 >10 3.87 >10
0.0199 2.07 0.0264 >10
0.0164 1 .01 0.0338 6.56
0.17 >10 2.55 >10
0.101 8.24 0.235 >10
0.185 >10 0.602 >10
0.0159 0.905 0.0779 4.29
0.05 3.56 0.129 6.85
>10 >10 >10 >10
0.0537 5.03 0.083 >10
3.15 >10 6.94 >10
3.43 >10 >10 >10
>10 >10 >10 >10
0.0417 1 .39 0.445 4.6
0.0685 6.38 0.1 17 >10
0.0502 5.88 0.0985 >10
0.192 9.09 0.361 >10
0.71 4.02 1 .2 >10
0.0576 6.1 1 0.243 >10
0.0863 >10 2.58 >10
0.0137 1 .54 0.195 1 .75
0.308 >10 0.525 >10
0.101 6.83 0.1 16 >10
0.0245 3.55 0.0345 >10
0.0137 0.754 0.0137 >10
0.0804 3.62 0.12 >10
0.252 7.42 1 .32 9.1 1
0.0383 5.1 1 0.469 >10
0.0716 9.44 0.1 12 >10
0.091 4.53 0.565 4.37
0.0689 3.23 0.55 2.94
0.0235 5.4 0.0587 >10
0.488 >10 3.1 1 >10
0.467 >10 3.02 >10
0.0407 >10 0.0758 >10
0.0303 4.63 0.161 >10
0.1 1 .79 1 .77 >10
0.00825 0.051 0.0244 0.0539
1 .75 >10 2.07 >10
0.0661 2.23 0.0588 >10
0.0724 3.95 0.509 3.42
0.106 5.7 0.143 >10
0.28 6.78 0.239 7.45
0.153 5.7 0.125 8.44
0.0926 4.53 0.147 >10
0.223 >10 0.208 >10 80 1 .49 >10 0.561 >10
81 0.1 1 1 >10 0.34 >10
82 0.0072 0.871 0.01 12 1 .8
83 0.0966 3.43 0.214 >10
84 0.157 >10 0.427 >10
85 0.402 >10 1 .4 >10
86 0.0348 1 .42 0.0833 2.24
87 0.0229 0.831 0.578 2.24
88 0.0137 0.458 0.0137 >10
89 1 .82 >10 4.85 >10
90 0.173 4.77 0.242 >10
91 0.0481 3.41 0.048 >10
92 0.0646 5.73 0.12 >10
93 3.95 >10 5.38 >10
94 1 .23 >10 2.37 >10
95 0.331 >10 0.55 >10
96 0.629 >10 1 .1 >10
97 0.657 5.44 1 .39 8.4
98 0.455 >10 0.639 >10
99 0.215 8.9 0.417 8.15
100 0.222 >10 0.705 6.73
101 0.349 >10 0.761 >10
102 0.236 >10 0.458 >10
103 0.15 8.42 0.456 >10
104 0.544 >10 1 .66 >10
105 4.04 >10 >10 >10
106 0.0581 2.17 0.355 >10
107 0.0192 1 .99 0.0752 >10
108 0.0424 0.948 0.31 >10
109 0.0193 1 .12 0.109 >10
[00272] While specific embodiments of the invention have been described herein for the purpose of reference and illustration, various modifications will be apparent to a person skilled in the art without departing from the scope of the invention as defined by the appended claims.
REFERENCES
[I] Carlomagno, F., Guida, T., Anagantil, S., Vecchio, G., Fusco, A., Ryan, A., Billaud, M., Santoro, M. (2004). Disease associated mutations at valine 804 in the RET receptor tyrosine kinase confer resistance to selective kinase inhibitors. Oncogene 23, 6056-6063
[2] Chao, B., Briesewitz, R., Villalona-Calero, M. (2012) RET fusion genes in Non-Small-Cell Lung Cancer. JCO 30, 4439-4441.
[3] Diner, P., Alao, J., Soderland, J., Sunnerhagen, P. Grotli, M. (2012) J Med Chem 2012 55 (10) 4872-6
[4] Elisei, R., Cosci, B., Romei, C, Bottici, V., Renzini, G., Molinaro, E., Agate, L, Vivaldi, A., Faviana, P., Basolo, F., Miccoli, P., Berti, P., Pacini, F., Pinchera, A. (2008) RET genetic screening in patients with medullary thyroid cancer and their relatives: experience with 807 individuals at one center. Journal of Clinical Endocrinology and Metabolism 93, 682-687.
[5] Ju, Y., Lee, W., Shin, J., Lee, S., Bleazard, T., Won, J., Kim, Y., Kim, J., Kang, J., Seo, J. (201 1). A transforming KIF5B and RET gene fusion in lung adenocarcinoma revealed from whole- genome and transcriptome sequencing. Genome Res. 3, 436-445.
[6] Kohno, T., Ichikawa, H., Totoki, Y., Yasuda, K., Hiramoto, M., Nammo, T., Sakamoto, H., Tsuta, K., Furuta, K., Shimada, Y., Iwakawa, R., Ogiwara, H., Oike, T., Enari, M., Schetter, A., Okayama, H., Haugen, A., Skaug, V. Chiku, S., Yamanaka, I., Arai, Y., Watanabe, S., Sekine, I., Ogawa, S., Harris, C, Tsuda, H., Yoshida, T., Yokota, J., Shibata, T. (2012) KIF5B-RET fusions in lung adenocarcinoma. Nat Med. 12, 375-377.
[7] Lipson, D., Capelletti, M., Yelensky, R., Otto, G., Parker, A., Jaroszi, M., Curran, J., Balasubramanian, S., Bloom, T., Brennan, K., Donahue, A., Downing, S., Frampton, G., Garcia, L., Juhn, F., Mitchell, K., White, E., White, J., Zwirko, Z., Peretz, T., Nechushtan, H., Soussan- Gutman, L., Kim, J., Sasaki, H., Kim, H., Park, S., Ercan, D., Sheehan, C, Ross, J. Cronin, M., Janne, P., Stephens, P. (2012) Identification of new ALK and RET gene fusions from colorectal and lung cancer biopsies. Nat Med. 12, 382-384.
[8] Matsubara, D., Kanai, Y., Ishikawa, S., Ohara, S., Yoshimoto, T., Sakatani, T., Oguni, S., Tamura, T., Kataoka, H., Endo, S., Murakami, Y., Aburatani, H., Fukayama, M., Niki, T. (2012). Identification of CCDC6-RET fusion in the human lung adenocarcinoma cell line, LC-2/ad. J Thorac Oncol. 12, 1872-6.
[9] Nagilla, M., Brown, R., Cohen, E. (2012). Cabozantinib for the treatment of Advanced Medullary Thyroid Cancer. Adv Ther 1 1 , 925-934.
[10] Santoro, M. and Carlomagno, F. (2006). Drug insight: Small-molecule inhibitors of protein kinases in the treatment of thyroid cancer.Nature Clinical Practice: Endocrinology and Metabolism 2, 42-52.
[II] Verbeek. H.H., Alves, M.M., de Groot, J.W., Osinga J, Plukker, J.T., Links, T.P., Hofstra, R.M. (201 1). The effects of four different tyrosine kinase inhibitors on medullary and papillary thyroid cancer cells. J Clin Endocrinol Metab. 96, 2010-2381.
[12] Vitagliano, D., De Falco, V., Tamburrino, A., Coluzzi, S., Troncone, G., Chiappetta, G., Ciardiello, F., Tortora, G., Fagin, J., Ryan, A., Carlomagno, F., Santoro, (201 1). The tyrosine inhibitor ZD6474 blocks proliferation of RET mutant medullary thyroid carcinoma cells. Endocrine- related Cancer 18, 1-1 1 .
[13] Wang, R., Hu, H., Pan, Y., Li, Y., Ye, T., Li, C, Luo, X., Wang, L, Li, H., Zhang, Y., Li, F., Lu, Y., Lu, Q., Xu, J., Garfield, D., Shen, L, Ji, H., Pao, W., Sun, Y., Chen, H. (2012). RET fusions define a unique molecular and clinicopathologic subtype of non-small-cell lung cancer. JCO 30, 4352-4359.
[14] Wells, S. and Santoro, M. (2009) Targeting the RET pathway in thyroid cancer. Clin Can Res. 15, 71 19-7123.
[15] Wells, S., Gosnell, J., Gagel, R., Moley, J., Pfister, D., Sosa, J., Skinner, M., Krebs, A., Vasselli, J., Schlumberger, M. (2012). Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial. JCO 10, 134-141.
[16] Daley, G. Q.; Baltimore, D. Transformation of an interleukin 3-dependent hematopoietic cell line by the chronic myelogenous leukemia-specific P210bcr/abl protein. Proc. Natl. Acad. Sci. U. S. A. 1988, 85, 9312-16.

Claims

1. A compound, or compounds, or pharmaceutically acceptable salt, hydrate or solvate thereof, having the structural formula (Id) shown below:
Figure imgf000155_0001
(Id)
wherein:
HET is selected from one of the following:
Figure imgf000155_0002
wherein denotes the point of attachment;
Ri is selected from hydrogen, (1-4C)haloalkyl, (1-4C)haloalkoxy or a group of the formula:
-L-Y-Q
wherein:
L is absent or (1-5C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkyl or oxo;
Y is absent or O, S, SO, S02, N(Ra), C(O), C(0)0, OC(O), C(0)N(Ra), N(Ra)C(0), N(Ra)C(0)N(Rb), N(Ra)C(0)0, OC(0)N(Ra), S(0)2N(Ra), or N(Ra)S02, wherein Ra and Rb are each independently selected from hydrogen or (1-4C)alkyl; and
Q is hydrogen, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, aryl, (3- 10C)cycloalkyl, (3-10C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Q is optionally further substituted by one or more substituent groups independently selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, amino, (1-4C)aminoalkyl, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, mercapto, ureido, NRcRd, ORc, C(0)Rc, C(0)ORc, OC(0)Rc, C(0)N(Rd)Rc, N(Rd)C(0)Rc, S(0)yRc (where y is 0, 1 or 2), S02N(Rd)Rc, N(Rd)S02Rc, Si(Rd)(Rc)Re or (CH2)zNRcRd (where z is 1 , 2 or 3); wherein Rc, Rd and Re are each independently selected from hydrogen, (1-6C)alkyl or (3-6C)cycloalkyl; or Rc and Rd can be linked such that, together with the nitrogen atom to which they are attached, they form a 4-7 membered heterocyclic ring which is optionally substituted by one or more substituents selected from (1- 4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1- 4C)alkylamino, amino, cyano or hydroxyl; or
Q is optionally substituted by a group of the formula:
Figure imgf000156_0001
wherein:
Li is absent or (1-3C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkyl or oxo;
LQi is absent or selected from or O, S, SO, S02, N(Rf), C(O), C(0)0, OC(O), C(0)N(Rf), N(Rf)C(0), N(Rg)C(0)N(Rf), N(Rf)C(0)0, OC(0)N(Rf), S(0)2N(Rf), or N(Rf)S02, wherein Rf and Rg are each independently selected from hydrogen or (1- 2C)alkyl; and
Zi is hydrogen, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, (3- 8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Zi is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, mercapto, ureido, aryl, heteroaryl, heterocycyl, (3-6C)cycloalkyl, NRhRi, ORh, C(0)Rh, C(0)ORh, OC(0)Rh, C(0)N(Ri)Rh, N(Ri)C(0)Rh, S(0)yaRh (where ya is 0, 1 or 2), S02N(Ri)Rh, N(Ri)S02Rh or (CH2)zaNRiRh (where za is 1 , 2 or 3); wherein Rh and R, are each independently selected from hydrogen, (1-4C)alkyl or (3- 6C)cycloalkyl;
Ria and Rib are each selected from hydrogen, (1-4C)alkyl, halo, (1- 4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl or mercapto;
W is selected from O, S or NRj, wherein Rj is selected from H or (1-2C)alkyl;
Xi and X2 are each independently selected from N or CRk;
wherein
Rk is selected from hydrogen, halo, (1-4C)alkyl, (1-4C)alkoxy, amino, (1-4C)alkylamino, (1-4C)dialkylamino, cyano, (2C)alkynyl, C(0)Rki, C(0)ORk1, OC(0)Rk1, C(0)N(Rk2)Rc, N(Rk2)C(0)Rk1, S(0)ybRk1 (where yb is 0, 1 or 2), S02N(Rk2)Rki, N(Rk2)S02Rki or (CH2)zbNRkiRk2 (where zb is 1 , 2 or 3); wherein said (1-4C)alkyl is optionally substituted by one or more substituents selected from amino, hydroxy, (1-2C)alkoxy or halo; and
Rki and Rk2 are each independently selected from hydrogen or (1- 4C)alkyl;
X3 is selected from N or CRm;
wherein Rm is selected from hydrogen, halo, (1-4C)alkyl, (1-4C)alkoxy, amino, (1-4C)alkylamino, (1-4C)dialkylamino, cyano, (2C)alkynyl, C(0)Rmi ,
C(0)ORm1 , OC(0)Rm1 , C(0) N(Rm2)Rm1 , N(Rm2)C(0)Rm1 , S(0)ycRm1
(where yc is 0, 1 or 2), S02N(Rm2)Rmi , N(Rm2)S02Rmi or
(CH2)zcN Rmi Rm2 (where zc is 1 , 2 or 3); wherein said (1-4C)alkyl is optionally substituted by one or more substituents selected from amino, hydroxy, (1-2C)alkoxy or halo; and
Rmi and Rm2 are each independently selected from hydrogen or (1- 4C)alkyl;
Ro is selected from halo, (1-4C)alkyl, (1-4C)alkoxy, amino, (1-4C)alkylamino, (1-4C)dialkylamino, cyano, (2C)alkynyl, C(0)R0i , C(0)OR0i , OC(0)R0i , C(0)N(Ro2) Roi , N(Ro2)C(0)Roi , S(0)ydR0i (where yd is 0, 1 or 2),
S02N(Ro2)Roi , N(Ro2)S02Roi or (CH2)zdN R0i Ro2 (where zd is 1 , 2 or 3); wherein said (1-4C)alkyl is optionally substituted by one or more substituents selected from amino, hydroxy, (1-2C)alkoxy or halo; and
Roi and Ro2 are each independently selected from hydrogen or (1-4C)alkyl; R2 is selected from hydrogen, (1-4C)alkyl or a group of the formula:
-L2-Y2-Q2
wherein:
L2 is absent or (1-3C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkyl or oxo;
Y2 is absent or C(O), C(0)0, C(0)N(Rp), wherein Rp is selected from hydrogen or (1-4C)alkyl; and
Q2 is hydrogen, (1-6C)alkyl, aryl, (3-8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Q2 is optionally further substituted by one or more substituent groups independently selected from (1- 4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, N RqRr, ORq, wherein Rq and Rr are each independently selected from hydrogen, (1-4C)alkyl or (3- 6C)cycloalkyl;
R3 is selected from a group of the formula:
wherein: Y3 is C(O), C(0)N(Ry), C(0)N(Ry)0, N(Ry)(0)C, C(0)0, OC(O), N(Ry)C(0)N(Ryi), S02N(Ry), N(Ry)S02, oxazolyl, triazolyl, oxadiazolyl, thiazolyl, imidazolyl, thiadiazolyl, pyridinyl, pyrazolyl, pyrrolyl or tetrazolyl, wherein Ry and Ryi are independently selected from hydrogen or (1-2C)alkyl; and
Q3 is hydrogen, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, (3-8C)cycloalkyl, (3- 8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Q3 is optionally further substituted by one or more substituent groups independently selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, NRzRaa, ORz, wherein Rz and Raa are each independently selected from hydrogen, (1- 4C)alkyl or (3-6C)cycloalkyl; or Q3 is optionally substituted by a group of the formula:
Figure imgf000159_0001
wherein:
l_4 is absent or (1-3C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkyl or oxo;
LQ4 is absent or selected from or O, S, SO, S02, N(Rab), C(O), C(0)0, OC(O), C(0)N(Rab), N(Rab)C(0), N(Rac)C(0)N(Rab), N(Rab)C(0)0, OC(0)N(Rab), S(0)2N(Rab), or N(Rab)S02, wherein Rab and Rac are each independently selected from hydrogen or (1-2C)alkyl; and
Z4 is hydrogen, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, (3- 8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Z4 is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, mercapto, ureido, aryl, heteroaryl, heterocycyl, (3-6C)cycloalkyl, NRadRae, ORad, C(0)Rad, C(0)ORad, OC(0)Rad, C(0)N(Rae)Rad, N(Rae)C(0)Rad, S(0)yeRad (where ye is 0, 1 or 2), S02N(Rae)Rad, N(Rae)S02Rad or (CH2)zeNRadRae (where ze is 1 , 2 or 3); wherein Rad and Rae are each independently selected from hydrogen, (1-4C)alkyl or (3- 6C)cycloalkyl; or Q3 and Ry are linked such that, together with the nitrogen atom to which they are attached, they form a 4-7 membered heterocyclic ring which is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano or hydroxyl;
with the proviso that only one or two of Χι , X2 or X3 can be N.
Figure imgf000160_0001
wherein Ri , Ria and Rib are each as defined in claim 1 ;
armaceutically acceptable salt, hydrate or solvate thereof. A compound, or pharmaceutically acceptable salt, hydrate or solvate thereof, according to claims 1 or 2, wherein HET is selected from one of the following:
Figure imgf000161_0001
wherein Ri , Ria and Rib are each as defined in claim 1 ;
or a pharmaceutically acceptable salt, hydrate or solvate thereof.
A compound, or pharmaceutically acceptable salt, hydrate or solvate thereof, according to any one of claims 1 to 3, wherein the compound has the structural Formula If shown below:
Figure imgf000161_0002
If
wherein HET, Xi , X2, X3, R0, R2, Q3 and Ry are each as defined in claim 1.
A compound, or pharmaceutically acceptable salt, hydrate or solvate thereof, according to any one of claims 1 to 4, wherein Xi and X2 are each independently selected from N or CRk and bond a is a double bond, wherein Rk is selected from hydrogen, halo, (1-4C)alkyl or amino.
6. A compound, or pharmaceutically acceptable salt, hydrate or solvate thereof,
according to any one of claims 1 to 5, wherein X3 is selected from N or CRm and bond b is a double bond, wherein Rm is selected from hydrogen, halo, (1-4C)alkyl or amino.
7. A compound, or pharmaceutically acceptable salt, hydrate or solvate thereof,
according to any one of claims 1 to 6, wherein R0 is selected from halo, (1-4C)alkyl, (1-4C)alkoxy, amino, (1-4C)alkylamino, (1-4C)dialkylamino, cyano or (2C)alkynyl.
8. A compound, or pharmaceutically acceptable salt, hydrate or solvate thereof, according to claims 1 to 3, wherein R3 is selected from a group of the formula:
Figure imgf000162_0001
wherein:
Y3 is C(O), C(0)N(Ry), C(0)N(Ry)0, N(Ry)(0)C, C(0)0, OC(O), wherein Ry is selected from hydrogen or (1-2C)alkyl; and
Q3 is hydrogen, (1-6C)alkyl, (1-6C)alkoxy, aryl, aryl(1-2C)alkyl, (3- 8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Q3 is optionally further substituted by one or more substituent groups independently selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)haloalkoxy, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, NRzRaa, ORz, wherein Rz and Raa are each independently selected from hydrogen, (1-4C)alkyl or (3-6C)cycloalkyl; or Q3 is optionally substituted by a group of the formula:
Figure imgf000162_0002
wherein:
l_4 is absent or (1-3C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkyl or oxo; LQ4 is absent or selected from or O, N(Rab), C(O), C(0)0,
OC(O), C(0)N(Ra ), N(Ra )C(0), S(0)2N(Ra ), or N(Ra )S02, wherein Rab is selected from hydrogen or (1-2C)alkyl; and
Z4 is hydrogen, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, (3- 8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Z4 is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, mercapto, ureido, aryl, heteroaryl, heterocycyl, (3-6C)cycloalkyl, NRadRae, ORad,
C(0)Rad, C(0)ORad, OC(0)Rad, C(0)N(Rae)Rad, N(Rae)C(0)Rad,
S(0)yeRad (where ye is 0, 1 or 2), S02N(Rae)Rad, N(Rae)S02Rad Or (CH2)zeNRadRae (where ze is 1 , 2 or 3); wherein Rad and Rae are each independently selected from hydrogen, (1-4C)alkyl or (3- 6C)cycloalkyl; or
Qz and Ryare linked such that they form a 4-7 membered heterocyclic ring which is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano or hydroxyl.
9. A compound, or pharmaceutically acceptable salt, hydrate or solvate thereof, according to any preceding claim, wherein the compound has the structural Formula Ig shown below:
Figure imgf000164_0001
ig
wherein Ri , R0, R2, Ry and Q3 are each as defined in any one of claims 1 to 8.
A compound, or pharmaceutically acceptable salt, hydrate or solvate thereof, according to any preceding claim, wherein R0 is selected from halo, (1-4C)alkyl amino.
1 1. A compound, or pharmaceutically acceptable salt, hydrate or solvate thereof,
according to any preceding claim, wherein R0 is a halogen.
12. A compound, or pharmaceutically acceptable salt, hydrate or solvate thereof,
according to any preceding claim, wherein Ri is selected from hydrogen, (1- 4C)haloalkyl, (1-4C)haloalkoxy or a group of the formula:
-L-Y-Q
wherein:
L is absent or (1-3C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkyl or oxo; Y is absent or C(O), C(0)0, OC(O), C(0)N(Ra) or N(Ra)C(0), wherein Ra and Rb are each independently selected from hydrogen or (1- 4C)alkyl; and
Q is hydrogen, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, aryl, (3- 10C)cycloalkyl, (3-10C)cycloalkenyl, heteroaryl or heterocyclyl;
wherein Q is optionally further substituted by one or more substituent groups independently selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, amino, (1-4C)aminoalkyl, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, mercapto, ureido, NRcRd, ORc, C(0)Rc, C(0)ORc, OC(0)Rc, C(0)N(Rd)Rc, N(Rd)C(0)Rc, S(0)yRc (where y is 0, 1 or 2), S02N(Rd)Rc, N(Rd)S02Rc, Si(Rd)(Rc)Re or (CH2)zNRdRc (where z is 1 , 2 or 3); wherein Rc, Rd and Re are each independently selected from hydrogen, (1-6C)alkyl or (3-6C)cycloalkyl.
13. A compound, or pharmaceutically acceptable salt, hydrate or solvate thereof,
according to any preceding claim, wherein Ri is selected from hydrogen, (1- 4C)haloalkyl, (1-4C)haloalkoxy, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, aryl, (3- 10C)cycloalkyl, (3-10C)cycloalkenyl, heteroaryl or heterocyclyl; wherein each of said substituents is optionally further substituted by one or more substituent groups independently selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, amino, (1-4C)aminoalkyl, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, mercapto, ureido, NRcRd, ORc, C(0)Rc, C(0)ORc, OC(0)Rc, C(0)N(Rd)Rc,
N(Rd)C(0)Rc, S(0)yRc (where y is 0, 1 or 2), S02N(Rd)Rc, N(Rd)S02Rc, Si(Rd)(Rc)Re or (CH2)zNRdRc (where z is 1 , 2 or 3); wherein Rc, Rd and Re are each independently selected from hydrogen, (1-6C)alkyl or (3-6C)cycloalkyl.
14. A compound, or pharmaceutically acceptable salt, hydrate or solvate thereof,
according to any preceding claim, wherein Ri is selected from hydrogen, (1-6C)alkyl or (3-10C)cycloalkyl; wherein each of said substituents is optionally further substituted by one or more substituent groups independently selected from (1- 4C)alkyl, halo, amino, (1-4C)aminoalkyl, cyano, hydroxy, carboxy, NRcRd, ORc or Si(Rd)(Rc)Re; wherein Rc, Rd and Re are each independently selected from hydrogen or (1-4C)alkyl. A compound, or pharmaceutically acceptable salt, hydrate or solvate thereof, according to any preceding claim, wherein R2 is selected from hydrogen, (1-4C)alkyl or a group of the formula:
Figure imgf000166_0001
wherein:
Y2 is C(0)N(Rp), wherein Rp is selected from hydrogen or (1-4C)alkyl; and
Q2 is (1-6C)alkyl, aryl, (3-8C)cycloalkyl, heteroaryl or heterocyclyl; wherein Q2 is optionally further substituted by one or more substituent groups independently selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, amino, cyano or hydroxy.
A compound, or pharmaceutically acceptable salt, hydrate or solvate thereof, according to any preceding claim, wherein R2 is hydrogen.
A compound, or pharmaceutically acceptable salt, hydrate or solvate thereof, according to claims 9 to 16, wherein Q3 is hydrogen, (1-6C)alkyl, (1-6C)alkoxy, aryl, aryl(1-2C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Q3 is optionally further substituted by one or more substituent groups independently selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, NRaRaa, ORz, wherein Rzand Raa are each independently selected from hydrogen, (1-4C)alkyl or (3-6C)cycloalkyl; or Q3 is optionally substituted by a group of the formula:
Figure imgf000166_0002
wherein:
l_4 is absent or (1-3C)alkylene;
LQ4 is absent or selected from or O, N(Rab), C(O), C(0)0, or C(0)N(Rab), wherein Rab is selected from hydrogen or (1-2C)alkyl; and
Z4 is hydrogen, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, (3-8C)cycloalkyl, (3- 8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Z4 is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1- 4C)alkylamino, amino, cyano or hydroxy.
18. A compound, or pharmaceutically acceptable salt, hydrate or solvate thereof, according to claims 9 to 17, wherein Q3 is hydrogen, (1-6C)alkyl, (1-6C)alkoxy, aryl, aryl(1-2C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Q3 is optionally further substituted by one or more substituent groups independently selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, NRzRaa, ORz, wherein Rz and Raa are each independently selected from hydrogen or (1-4C)alkyl; or Q3 is optionally substituted by a group of the formula:
Figure imgf000167_0001
wherein:
LQ4 is absent or selected from or O, N(Rab), C(O), C(0)0, or C(0)N(Rab), wherein Rab is selected from hydrogen or (1-2C)alkyl; and
Z4 is hydrogen, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, (3-8C)cycloalkyl, heteroaryl or heterocyclyl; wherein Z4 is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano or hydroxy.
19. A compound, or pharmaceutically acceptable salt, hydrate or solvate thereof, which is selected from any one of the following:
2-(4-Amino-1-isopropyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-methyl-1 /-/-indole-6- carboxamide;
2-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-methyl-1 /-/-indole-6- carboxamide;
2-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(1-methylpyrazol-3-yl)-1 /-/- indole-6-carboxamide;
2-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-1 /-/-indole-6-carboxamide;
2-(4-Amino-1-isopropyl-pyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-N-methyl-1 /-/-indole-6- carboxamide;
2-(4-Amino-1-(tert-butyl)-1 /-/-pyrazolo[3,4-d]pyrimidin-3-yl)-3-bromo-N-methyl-1 /-/- indole-6-carboxamide; 2-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-N-(2-methoxyethyl)- 1 /-/-indole-6-carboxamide;
2-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-N-[2- (dimethylamino)ethyl]-1 /-/-indole-6-carboxamide;
2-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-N-(2-morpholinoethyl)- 1 /-/-indole-6-carboxamide;
2-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-N-(3- morpholinopropyl)-1 /-/-indole-6-carboxamide;
2-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-N-methoxy-1 /-/-indole- 6-carboxamide;
[2-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-1 /-/-indol-6-yl]- pyrrolidin-1-yl-methanone;
2-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-N,N-dimethyl-1 /-/- indole-6-carboxamide;
2-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-N-[2-(2- methoxyethoxy)ethyl]-1 /-/-indole-6-carboxamide;
2-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-N-(3-methoxypropyl)- 1 /-/-indole-6-carboxamide;
2-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-N-(2-hydroxyethyl)-1 /-/- indole-6-carboxamide;
2-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-N-[2-(2- morpholinoethoxy)ethyl]-1 /-/-indole-6-carboxamide;
2-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-N-[2-[2- (dimethylamino)ethoxy]ethyl]-1 /-/-indole-6-carboxamide;
2-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-N-[3- (dimethylamino)propyl]-1 /-/-indole-6-carboxamide;
2-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-N-[3-(1- piperidyl)propyl]-1 /-/-indole-6-carboxamide;
2-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-N-(3- isopropoxypropyl)-1 /-/-indole-6-carboxamide;
2-[4-Amino-1-(2-hydroxyethyl)pyrazolo[3,4-d]pyrimidin-3-yl]-3-chloro-N-methyl-1 /-/- indole-6-carboxamide; 2-[4-Amino-1-(3-methoxypropyl)pyrazolo[3,4-d]pyrimidin-3-yl]-3-chloro-N-methyl-1 /-/- indole-6-carboxamide;
2-[4-Amino-1-(1-methylsulfonyl-4-piperidyl)pyrazolo[3,4-d]pyrimidin-3-yl]-3-chloro-N- methyl-1 /-/-indole-6-carboxamide;
2-(4-Amino-1-methyl-pyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-N-methyl-1 /-/-indole-6- carboxamide;
2-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-N-[1-(2- methoxyethyl)pyrazol-3-yl]-1 /-/-indole-6-carboxamide;
2-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-N-[1-(2- morpholinoethyl)pyrazol-3-yl]-1 /-/-indole-6-carboxamide;
2-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-N-[1-[2- (dimethylamino)ethyl]pyrazol-3-yl]-1 /-/-indole-6-carboxamide;
2-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-N-[1-[2-(4- methylpiperazin-1-yl)ethyl]pyrazol-3-yl]-1 /-/-indole-6-carboxamide;
2-[4-Amino-1-(2-aminoethyl)pyrazolo[3,4-d]pyrimidin-3-yl]-3-chloro-N-methyl-1 /-/- indole-6-carboxamide;
2-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-N-[1-(2- hydroxyethyl)pyrazol-3-yl]-1 /-/-indole-6-carboxamide;
2-{4-Amino-1-cyclobutyl-1 H-pyrazolo[3,4-d]pyrimidin-3-yl}-3-chloro-N-methyl-1 /-/- indole-6-carboxamide;
2-{4-Amino-1-cyclohexyl-1 H-pyrazolo[3,4-d]pyrimidin-3-yl}-N-methyl-1 /-/-indole-6- carboxamide;
2-{4-Amino-1-cyclopentyl-1 H-pyrazolo[3,4-d]pyrimidin-3-yl}-N-methyl-1 /-/-indole-6- carboxamide;
2-(4-Amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-N-methyl-1 /-/-indole-6- carboxamide;
2-(8-Amino-3-isopropylimidazo[1 ,5-a]pyrazin-1-yl)-3-chloro-N-methyl-1 /-/-indole-6- carboxamide;
2-(8-Amino-3-isopropyl-imidazo[1 ,5-a]pyrazin-1-yl)-N-methyl-1 /-/-indole-6- carboxamide;
2-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-methyl-3H-benzimidazole-5- carboxamide; 2-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimi
carboxamide;
2-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-N-methyl-1 /-/-indole-6- carboxamide;
2-(4-Amino-1-cyclohexyl-1 /-/-pyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-N-methyl-1 /-/- indole-6-carboxamide;
2-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-chloro-N-methyl-1 /-/-indole- 6-carboxamide;
2-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-1 /-/-indole-6-carboxylic acid;
2-{4-Amino-1-tert-butyl-1 H-pyrazolo[3,4-d]pyrimidin-3-yl}-3-chloro-N-(oxan-4-yl)-1 /-/- indole-6-carboxamide;
2-{4-Amino-1-tert-butyl-1 /-/-pyrazolo[3,4-d]pyrimidin-3-yl}-3-chloro-N-(propan-2-yl)- 1 /-/-indole-6-carboxamide;
2-{4-Amino-1-tert-butyl-1 H-pyrazolo[3,4-d]pyrimidin-3-yl}-3-chloro-N-ethyl-1 /-/-indole- 6-carboxamide;
2-{4-Amino-1-tert-butyl-1 H-pyrazolo[3,4-d]pyrimidin-3-yl}-3-chloro-N-cyclopropyl-1 /-/- indole-6-carboxamide;
2-{4-Amino-1-tert-butyl-1 H-pyrazolo[3,4-d]pyrimidin-3-yl}-3-chloro-N-phenyl-1 /-/- indole-6-carboxamide;
2-[4-Amino-1-(propan-2-yl)-1 /-/-pyrazolo[4,3-c]pyridin-3-yl]-N-methyl-1 /-/-indole-6- carboxamide;
2-[4-Amino-1-(propan-2-yl)-1 /-/-pyrazolo[4,3-c]pyridin-3-yl]-3-chloro-N-methyl-1 /-/- indole-6-carboxamide;
2-[4-Amino-1-(propan-2-yl)-1 /-/-pyrazolo[4,3-c]pyridin-3-yl]-3-bromo-N-methyl-1 /-/- indole-6-carboxamide;
2-{4-Aminothieno[2,3-d]pyrimidin-5-yl}-3-chloro-N-methyl-1 H-indole-6-carboxamide;
2-{4-Aminothieno[2,3-d]pyrimidin-5-yl}-N-methyl-1/-/-indole-6-carboxamide;
2-[4-Amino-7-(propan-2-yl)pyrrolo[2, 1-f][1 ,2,4]triazin-5-yl]-N-methyl-1 /-/-indole-6- carboxamide;
2-[4-Amino-7-(propan-2-yl)pyrrolo[2, 1-f][1 ,2,4]triazin-5-yl]-3-chloro-N-methyl-1 /-/- indole-6-carboxamide; WO 2017/178844 l oa PCT/GB2017/051076
2-[4-Amino-7-(propan-2-yl)imidazo[4,3-f][1 ,2,4]triazin-5-yl]-3-chloro-N-methyl-1 ^ indole-6-carboxamide;
2-[4-Amino-7-chloro-1-(propan-2-yl)-1 /-/-pyrazolo[4,3-c]pyridin-3-yl]-N-methyl-1 /-/- indole-6-carboxamide;
2-{4-Amino-1-tert-butyl-1 H-pyrazolo[3,4-d]pyrimidin-3-yl}-3-chloro-N-methyl-1 /-/- pyrrolo[2,3-b]pyridine-6-carboxamide;
2-{4-Amino-1-tert-butyl-1 H-pyrazolo[3,4-d]pyrim^
b]pyridine-6-carboxamide;
2-(4-Amino-1-(tert-butyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-1-methyl-1 H-indole-6- carboxylic acid;
2-(4-Amino-1-(tert-butyl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-chloro-N-methyl-1 /-/- indole-6-carboxamide;
N-(2-{4-Amino-1-tert-butyl-1 H-pyrazolo[3,4-d]pyrimidin-3-yl}-1 H-indol-6-yl)acetamide
1- (2-{4-Amino-1-tert-butyl-1 H-pyrazolo[3,4-d]pyrimidin-3-yl}-3-chloro-1 H-indol-6- yl)propan-1-one;
2- {4-Amino-1-tert-butyl-1 H-pyrazolo[3,4-d]pyrimidin-3-yl}-N, 1-dimethyl-1 H-indol^ carboxamide;
2- (4-Amino-1-(1-methylpiperidin-4-yl)-1 H- cyclopropyl-1 /-/-indole-6-carboxamide;
3- [3-Chloro-6-(1 ,3,4-thiadiazol-2-yl)-1 /-/-indol-2-yl]-1-isopropyl-pyrazolo[3,4- d]pyrimidin-4-amine;
3-(3-Chloro-6-oxazol-2-yl-1 /-/-indol-2-yl)-1-isopropyl-pyrazolo[3,4-d]pyrimidin-4- amine;
1-lsopropyl-3-[6-(1 ,3,4-thiadiazol-2-yl)-1 H-indol-2-yl]pyrazolo[3,4-d]pyrimidin-4- amine; or
1-lsopropyl-3-(6-oxazol-2-yl-1 H-indol-2-yl)pyrazolo[3,4-d]pyrirnidin-4-arnine.
20. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt or hydrate thereof, for use in therapy.
21 A pharmaceutical composition comprising a compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt or hydrate thereof and a pharmaceutically acceptable carrier or excipient.
22. A compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition according to claim 21 , for use in the treatment of cancer.
23. A compound or a pharmaceutical composition according to claim 22, wherein said cancer is medullary thyroid cancer or non-small cell lung cancer.
24. A method for the treatment of cancer in a subject in need of such treatment, said method comprising administering a therapeutically effective amount of a compound according to any of claims 1 to 19, or a pharmaceutically acceptable salt or hydrate thereof, or a pharmaceutical composition according to claim 21.
25. A method according to claim 24, wherein said cancer is medullary thyroid cancer or non-small cell lung cancer.
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Cited By (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10023570B2 (en) 2015-07-16 2018-07-17 Array Biopharma Inc. Substituted pyrazolo[1,5-A]pyridine compounds as RET kinase inhibitors
WO2018136661A1 (en) 2017-01-18 2018-07-26 Andrews Steven W SUBSTITUTED PYRAZOLO[1,5-a]PYRAZINE COMPOUNDS AS RET KINASE INHIBITORS
WO2018136663A1 (en) 2017-01-18 2018-07-26 Array Biopharma, Inc. Ret inhibitors
US10112942B2 (en) 2016-10-10 2018-10-30 Array Biopharma Inc. Substituted pyrazolo[1,5-A]pyridine compounds as RET kinase inhibitors
US10144734B2 (en) 2016-10-10 2018-12-04 Array Biopharma Inc. Substituted pyrazolo[1,5-A]pyridine compounds as RET kinase inhibitors
WO2019075114A1 (en) 2017-10-10 2019-04-18 Mark Reynolds Formulations comprising 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazab icyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile
WO2019075108A1 (en) 2017-10-10 2019-04-18 Metcalf Andrew T Crystalline forms
WO2019143994A1 (en) 2018-01-18 2019-07-25 Array Biopharma Inc. Substituted pyrazolyl[4,3-c]pyridinecompounds as ret kinase inhibitors
WO2019143977A1 (en) 2018-01-18 2019-07-25 Array Biopharma Inc. Substituted pyrrolo[2,3-d]pyrimidines compounds as ret kinase inhibitors
WO2019192962A1 (en) * 2018-04-05 2019-10-10 Merck Patent Gmbh Heteroaryl compounds as type ii irak inhibitors and uses hereof
WO2020055672A1 (en) 2018-09-10 2020-03-19 Array Biopharma Inc. Fused heterocyclic compounds as ret kinase inhibitors
US10647730B2 (en) 2010-05-20 2020-05-12 Array Biopharma Inc. Macrocyclic compounds as TRK kinase inhibitors
CN111630054A (en) * 2018-01-18 2020-09-04 奥瑞生物药品公司 Substituted pyrazolo [3,4-d ] pyrimidine compounds as RET kinase inhibitors
US10844067B2 (en) 2016-04-15 2020-11-24 Cancer Research Technology Limited Heterocyclic compounds as RET kinase inhibitors
US10954241B2 (en) 2016-04-15 2021-03-23 Cancer Research Technology Limited Heterocyclic compounds as ret kinase inhibitors
US10966985B2 (en) 2017-03-16 2021-04-06 Array Biopharma Inc. Macrocyclic compounds as ROS1 kinase inhibitors
US11273160B2 (en) 2018-04-03 2022-03-15 Blueprint Medicines Corporation RET inhibitor for use in treating cancer having a RET alteration
US11279688B2 (en) 2015-11-02 2022-03-22 Blueprint Medicines Corporation Inhibitors of RET
US11352361B2 (en) 2017-04-13 2022-06-07 Cancer Research Technology Limited Compounds useful as RET inhibitors
WO2022140325A1 (en) * 2020-12-22 2022-06-30 Gilead Sciences, Inc. 6-substituted indole compounds
WO2022140326A1 (en) * 2020-12-22 2022-06-30 Gilead Sciences, Inc. Substituted indole compounds
US11471455B2 (en) 2018-10-05 2022-10-18 Annapurna Bio, Inc. Compounds and compositions for treating conditions associated with APJ receptor activity
WO2023064843A1 (en) 2021-10-15 2023-04-20 Stemline Therapeutics, Inc. Inhibitors of mutant ret kinases for use in treating cancer
US11661431B2 (en) 2021-04-16 2023-05-30 Gilead Sciences, Inc. Thienopyrrole compounds
US11767321B2 (en) 2020-10-05 2023-09-26 Enliven Inc. 5- and 6-azaindole compounds for inhibition of BCR-ABL tyrosine kinases
RU2810338C2 (en) * 2018-04-05 2023-12-27 Мерк Патент Гмбх Heteroaryl compounds as irak type ii inhibitors and their use

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JOP20180094A1 (en) 2017-10-18 2019-04-18 Hk Inno N Corp Heterocyclic compound as a protein kinase inhibito
JP7291243B2 (en) * 2019-04-03 2023-06-14 広州白雲山医薬集団股分有限公司白雲山制薬総廠 Pyrazolopyridine compounds as RET inhibitors and their use
CN117903123A (en) * 2020-02-20 2024-04-19 广州白云山医药集团股份有限公司白云山制药总厂 Quinoline compounds
CN113214294A (en) * 2020-06-10 2021-08-06 深圳铂立健医药有限公司 Tricyclic compound, pharmaceutical composition and application thereof
CN113248518B (en) * 2021-06-21 2022-03-25 山东大学 Pyrimidine piperazine derivative and preparation method and application thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010064875A2 (en) * 2008-12-05 2010-06-10 Korea Institute Of Science And Technology Novel indazole derivatives or pharmaceutically acceptable salts thereof as protein kinase inhibitors for proliferative diseases treatment, and a pharmaceutical composition containing the same as an active ingredient
WO2013077921A2 (en) * 2011-09-02 2013-05-30 The Regents Of The University Of California Substituted pyrazolo[3,4-d]pyrimidines and uses thereof
WO2015079251A1 (en) * 2013-11-29 2015-06-04 Cancer Research Technology Limited Quinazoline compounds

Family Cites Families (44)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0322779A3 (en) 1987-12-29 1991-05-08 Yoshitomi Pharmaceutical Industries, Ltd. Benzolactam compounds and pharmaceutical uses thereof
US5480883A (en) 1991-05-10 1996-01-02 Rhone-Poulenc Rorer Pharmaceuticals Inc. Bis mono- and bicyclic aryl and heteroaryl compounds which inhibit EGF and/or PDGF receptor tyrosine kinase
ATE248170T1 (en) * 1999-01-11 2003-09-15 Univ Princeton HIGH AFFINITY KINASE INHIBITORS FOR TARGET DETECTION AND THEIR USE
US7119200B2 (en) 2002-09-04 2006-10-10 Schering Corporation Pyrazolopyrimidines as cyclin dependent kinase inhibitors
US7429596B2 (en) 2003-06-20 2008-09-30 The Regents Of The University Of California 1H-pyrrolo [2,3-D] pyrimidine derivatives and methods of use thereof
US9512125B2 (en) 2004-11-19 2016-12-06 The Regents Of The University Of California Substituted pyrazolo[3.4-D] pyrimidines as anti-inflammatory agents
US9271963B2 (en) 2005-03-03 2016-03-01 Universitat Des Saarlandes Selective inhibitors of human corticosteroid synthases
CN102936250B (en) 2005-11-17 2014-07-09 Osi医药有限责任公司 Fused bicyclic mtor inhibitors
AR057960A1 (en) 2005-12-02 2007-12-26 Osi Pharm Inc BICYCLE PROTEIN QUINASE INHIBITORS
TW201307354A (en) 2005-12-29 2013-02-16 Abbott Lab Protein kinase inhibitors
GB0610242D0 (en) 2006-05-23 2006-07-05 Novartis Ag Organic compounds
JP2008063278A (en) 2006-09-07 2008-03-21 Fujifilm Finechemicals Co Ltd Method for producing 1-pyridin-4-yl-indole
US7514444B2 (en) 2006-09-22 2009-04-07 Pharmacyclics, Inc. Inhibitors of bruton's tyrosine kinase
US20090274698A1 (en) * 2007-07-06 2009-11-05 Shripad Bhagwat Combination anti-cancer therapy
US8193182B2 (en) 2008-01-04 2012-06-05 Intellikine, Inc. Substituted isoquinolin-1(2H)-ones, and methods of use thereof
MX2010007419A (en) 2008-01-04 2010-11-12 Intellikine Inc Certain chemical entities, compositions and methods.
CN102124009B (en) * 2008-07-08 2014-07-23 因特利凯公司 Kinase inhibitors and methods of use
WO2010006072A2 (en) 2008-07-08 2010-01-14 The Regents Of The University Of California Mtor modulators and uses thereof
US8703778B2 (en) 2008-09-26 2014-04-22 Intellikine Llc Heterocyclic kinase inhibitors
US20110269779A1 (en) 2008-11-18 2011-11-03 Intellikine, Inc. Methods and compositions for treatment of ophthalmic conditions
MY173795A (en) 2009-11-05 2020-02-24 Incozen Therapeutics Pvt Ltd Novel benzopyran kinase modulators
WO2011094628A1 (en) 2010-01-28 2011-08-04 University Of Washington Compositions and methods for treating toxoplasmosis. cryptosporidiosis and other apicomplexan protozoan related diseases
US9765037B2 (en) 2010-01-28 2017-09-19 University Of Washington Through Its Center For Commercialization Compositions and methods for treating toxoplasmosis, cryptosporidiosis, and other apicomplexan protozoan related diseases
WO2011153553A2 (en) 2010-06-04 2011-12-08 The Regents Of The University Of California Methods and compositions for kinase inhibition
US20130296316A1 (en) 2010-07-09 2013-11-07 Michael P. Pollastri Antiparasitic Agents Based On mTOR Inhibitors
TWI592411B (en) * 2011-02-23 2017-07-21 英特爾立秦有限責任公司 Combination of kinase inhibitors and uses thereof
CN103703174B (en) 2011-05-04 2017-05-10 因特利凯有限责任公司 Combination pharmaceutical compositions and uses thereof
WO2013023119A1 (en) 2011-08-10 2013-02-14 Novartis Pharma Ag JAK P13K/mTOR COMBINATION THERAPY
US20140377285A1 (en) 2011-11-08 2014-12-25 Intellikine, Llc Treatment regimens using multiple pharmaceutical agents
JP6130391B2 (en) 2011-11-23 2017-05-17 インテリカイン， エルエルシー Enhanced treatment regimen using MTOR inhibitors
US8501724B1 (en) 2012-01-31 2013-08-06 Pharmacyclics, Inc. Purinone compounds as kinase inhibitors
US8889730B2 (en) 2012-04-10 2014-11-18 Pfizer Inc. Indole and indazole compounds that activate AMPK
WO2014047662A2 (en) 2012-09-24 2014-03-27 Whitehead Institute For Biomedical Research Indazole derivatives and uses thereof
GB201217285D0 (en) 2012-09-27 2012-11-14 Univ Central Lancashire Indole derivatives
EP2968340A4 (en) 2013-03-15 2016-08-10 Intellikine Llc Combination of kinase inhibitors and uses thereof
JP6360881B2 (en) 2013-03-22 2018-07-18 ミレニアム ファーマシューティカルズ， インコーポレイテッドＭｉｌｌｅｎｎｉｕｍ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ， Ｉｎｃ． Combination of catalytic MTORC1 / 2 inhibitor and selective inhibitor of Aurora A kinase
US20210317140A1 (en) 2013-10-18 2021-10-14 Medivation Technologies, Inc. Heterocyclic Compounds and Methods of Use
US20160272645A1 (en) 2013-10-18 2016-09-22 Medivation Technologies, Inc. Heterocyclic Compounds and Methods of Use
WO2016075224A1 (en) * 2014-11-14 2016-05-19 Nerviano Medical Sciences S.R.L. 6-amino-7-bicyclo-7-deaza-purine derivatives as protein kinase inhibitors
EP3250290A4 (en) 2015-01-26 2018-07-11 University of Washington Compositions and methods for treating toxoplasmosis, cryptosporidiosis and other apicomplexan protozoan related diseases
EP3334430A4 (en) 2015-08-13 2019-02-06 San Diego State University Foundation Atropisomerism for increased kinase inhibitor selectivity
US20190077856A1 (en) 2016-03-15 2019-03-14 Memorial Sloan Kettering Cancer Center Method of treating diseases using kinase modulators
WO2017178844A1 (en) 2016-04-15 2017-10-19 Cancer Research Technology Limited Heterocyclic compounds as ret kinase inhibitors
RS63609B1 (en) * 2016-04-15 2022-10-31 Cancer Research Tech Ltd Heterocyclic compounds as ret kinase inhibitors

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010064875A2 (en) * 2008-12-05 2010-06-10 Korea Institute Of Science And Technology Novel indazole derivatives or pharmaceutically acceptable salts thereof as protein kinase inhibitors for proliferative diseases treatment, and a pharmaceutical composition containing the same as an active ingredient
WO2013077921A2 (en) * 2011-09-02 2013-05-30 The Regents Of The University Of California Substituted pyrazolo[3,4-d]pyrimidines and uses thereof
WO2015079251A1 (en) * 2013-11-29 2015-06-04 Cancer Research Technology Limited Quinazoline compounds

Cited By (55)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10647730B2 (en) 2010-05-20 2020-05-12 Array Biopharma Inc. Macrocyclic compounds as TRK kinase inhibitors
US10174027B2 (en) 2015-07-16 2019-01-08 Array Biopharma Inc. Substituted pyrazolo[1,5-a]pyridine compounds as RET kinase inhibitors
US10023570B2 (en) 2015-07-16 2018-07-17 Array Biopharma Inc. Substituted pyrazolo[1,5-A]pyridine compounds as RET kinase inhibitors
US10174028B2 (en) 2015-07-16 2019-01-08 Array Biopharma Inc. Substituted pyrazolo[1,5-A]pyridine compounds as RET kinase inhibitors
US10138243B2 (en) 2015-07-16 2018-11-27 Array Biopharma Inc. Substituted pyrazolo[1,5-a]pyridine compounds as RET kinase inhibitors
US11279688B2 (en) 2015-11-02 2022-03-22 Blueprint Medicines Corporation Inhibitors of RET
US10844067B2 (en) 2016-04-15 2020-11-24 Cancer Research Technology Limited Heterocyclic compounds as RET kinase inhibitors
US11661423B2 (en) 2016-04-15 2023-05-30 Cancer Research Technology Limited Heterocyclic compounds as RET kinase inhibitors
US10954241B2 (en) 2016-04-15 2021-03-23 Cancer Research Technology Limited Heterocyclic compounds as ret kinase inhibitors
US11548896B2 (en) 2016-04-15 2023-01-10 Cancer Research Technology Limited Heterocyclic compounds as RET kinase inhibitors
US10881652B2 (en) 2016-10-10 2021-01-05 Array Biopharma Inc. Substituted pyrazolo[1,5-A]pyridine compounds as RET kinase inhibitors
US11648243B2 (en) 2016-10-10 2023-05-16 Array Biopharma Inc. Substituted pyrazolo[1,5-A]pyridine compounds as RET kinase inhibitors
US10953005B1 (en) 2016-10-10 2021-03-23 Array Biopharma Inc. Substituted pyrazolo[1,5-a]pyridine compounds as RET kinase inhibitors
US10112942B2 (en) 2016-10-10 2018-10-30 Array Biopharma Inc. Substituted pyrazolo[1,5-A]pyridine compounds as RET kinase inhibitors
US10172851B2 (en) 2016-10-10 2019-01-08 Array Biopharma Inc. Substituted pyrazolo[1,5-A]pyridine compounds as RET kinase inhibitors
US10137124B2 (en) 2016-10-10 2018-11-27 Array Biopharma Inc. Substituted pyrazolo[1,5-a]pyridine compounds as RET kinase inhibitors
US10441581B2 (en) 2016-10-10 2019-10-15 Array Biopharma Inc. Substituted pyrazolo[1,5-A]pyridine compounds as RET kinase inhibitors
US10555944B2 (en) 2016-10-10 2020-02-11 Eli Lilly And Company Substituted pyrazolo[1,5-A]pyridine compounds as RET kinase inhibitors
US10172845B2 (en) 2016-10-10 2019-01-08 Array Biopharma Inc. Substituted pyrazolo[1,5-A]pyridine compounds as RET kinase inhibitors
US10144734B2 (en) 2016-10-10 2018-12-04 Array Biopharma Inc. Substituted pyrazolo[1,5-A]pyridine compounds as RET kinase inhibitors
WO2018136663A1 (en) 2017-01-18 2018-07-26 Array Biopharma, Inc. Ret inhibitors
WO2018136661A1 (en) 2017-01-18 2018-07-26 Andrews Steven W SUBSTITUTED PYRAZOLO[1,5-a]PYRAZINE COMPOUNDS AS RET KINASE INHIBITORS
US11851434B2 (en) 2017-01-18 2023-12-26 Array Biopharma Inc. Substituted pyrazolo[1,5-A]pyrazine compounds as ret kinase inhibitors
US11168090B2 (en) 2017-01-18 2021-11-09 Array Biopharma Inc. Substituted pyrazolo[1,5-a]pyrazines as RET kinase inhibitors
US10966985B2 (en) 2017-03-16 2021-04-06 Array Biopharma Inc. Macrocyclic compounds as ROS1 kinase inhibitors
US11680068B2 (en) 2017-04-13 2023-06-20 Cancer Research Technology Limited Compounds useful as RET inhibitors
US11352361B2 (en) 2017-04-13 2022-06-07 Cancer Research Technology Limited Compounds useful as RET inhibitors
WO2019075114A1 (en) 2017-10-10 2019-04-18 Mark Reynolds Formulations comprising 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazab icyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile
WO2019075108A1 (en) 2017-10-10 2019-04-18 Metcalf Andrew T Crystalline forms
WO2019143994A1 (en) 2018-01-18 2019-07-25 Array Biopharma Inc. Substituted pyrazolyl[4,3-c]pyridinecompounds as ret kinase inhibitors
WO2019143977A1 (en) 2018-01-18 2019-07-25 Array Biopharma Inc. Substituted pyrrolo[2,3-d]pyrimidines compounds as ret kinase inhibitors
CN111630054A (en) * 2018-01-18 2020-09-04 奥瑞生物药品公司 Substituted pyrazolo [3,4-d ] pyrimidine compounds as RET kinase inhibitors
US11603374B2 (en) 2018-01-18 2023-03-14 Array Biopharma Inc. Substituted pyrrolo[2,3-d]pyrimidines compounds as ret kinase inhibitors
US11524963B2 (en) 2018-01-18 2022-12-13 Array Biopharma Inc. Substituted pyrazolo[3,4-d]pyrimidines as RET kinase inhibitors
US11472802B2 (en) 2018-01-18 2022-10-18 Array Biopharma Inc. Substituted pyrazolyl[4,3-c]pyridine compounds as RET kinase inhibitors
US11273160B2 (en) 2018-04-03 2022-03-15 Blueprint Medicines Corporation RET inhibitor for use in treating cancer having a RET alteration
US11963958B2 (en) 2018-04-03 2024-04-23 Rigel Pharmaceuticals, Inc. RET inhibitor for use in treating cancer having a RET alteration
US11872192B2 (en) 2018-04-03 2024-01-16 Blueprint Medicines Corporation RET inhibitor for use in treating cancer having a RET alteration
US11873303B2 (en) 2018-04-05 2024-01-16 Merck Patent Gmbh Substituted pyrazoles as type II IRAK inhibitors
CN112236429A (en) * 2018-04-05 2021-01-15 默克专利有限公司 Heteroaryl compounds as type II IRAK inhibitors and uses thereof
JP2021520356A (en) * 2018-04-05 2021-08-19 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツングＭｅｒｃｋ Ｐａｔｅｎｔ Ｇｅｓｅｌｌｓｃｈａｆｔ ｍｉｔ ｂｅｓｃｈｒａｅｎｋｔｅｒ Ｈａｆｔｕｎｇ Heteroaryl compounds as type II IRAK inhibitors and their use
RU2810338C2 (en) * 2018-04-05 2023-12-27 Мерк Патент Гмбх Heteroaryl compounds as irak type ii inhibitors and their use
JP7328987B6 (en) 2018-04-05 2023-10-25 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツング Heteroaryl compounds and their use as type II IRAK inhibitors
WO2019192962A1 (en) * 2018-04-05 2019-10-10 Merck Patent Gmbh Heteroaryl compounds as type ii irak inhibitors and uses hereof
JP7328987B2 (en) 2018-04-05 2023-08-17 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツング Heteroaryl compounds and their use as type II IRAK inhibitors
WO2020055672A1 (en) 2018-09-10 2020-03-19 Array Biopharma Inc. Fused heterocyclic compounds as ret kinase inhibitors
US11964988B2 (en) 2018-09-10 2024-04-23 Array Biopharma Inc. Fused heterocyclic compounds as RET kinase inhibitors
US11471455B2 (en) 2018-10-05 2022-10-18 Annapurna Bio, Inc. Compounds and compositions for treating conditions associated with APJ receptor activity
US11944622B2 (en) 2018-10-05 2024-04-02 Annapurna Bio, Inc. Compounds and compositions for treating conditions associated with APJ receptor activity
US11767321B2 (en) 2020-10-05 2023-09-26 Enliven Inc. 5- and 6-azaindole compounds for inhibition of BCR-ABL tyrosine kinases
US11807638B2 (en) 2020-10-05 2023-11-07 Enliven Inc. 5- and 6-azaindole compounds for inhibition of Bcr-Abl tyrosine kinases
WO2022140325A1 (en) * 2020-12-22 2022-06-30 Gilead Sciences, Inc. 6-substituted indole compounds
WO2022140326A1 (en) * 2020-12-22 2022-06-30 Gilead Sciences, Inc. Substituted indole compounds
US11661431B2 (en) 2021-04-16 2023-05-30 Gilead Sciences, Inc. Thienopyrrole compounds
WO2023064843A1 (en) 2021-10-15 2023-04-20 Stemline Therapeutics, Inc. Inhibitors of mutant ret kinases for use in treating cancer

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