NZ787350A - Heterocyclic compounds as ret kinase inhibitors - Google Patents

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 R3are 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 This application is a divisional of New Zealand patent application 747678, which is the national phase entry in New Zealand of PCT international ation (published as reference.

INTRODUCTION 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 nds, 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 Cancer is caused by uncontrolled and unregulated cellular proliferation. Precisely what causes a cell to become malignant and proliferate in an rolled and unregulated manner has been the focus of intense research over recent decades. This research has led to the identification of a number of lar targets ated with key metabolic pathways that are known to be associated with malignancy.

RET anged during Transfection) is a receptor tyrosine kinase (RTK) that forms part of a macromolecular receptor complex containing dimerized RET receptor, two coreceptors 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 α-receptors (GFRα). Ligand binding to the corresponding GFRα 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, entiation, proliferation, migration and chemotaxis. ting mutations in RET have been identified in familial and sporadic forms of ary thyroid carcinomas (MTC) (Santoro & agno 2006; Schulmberger et al. 2008; Wells & Santoro 2009) and these correlate with aggressive disease progression (Elisei et al. 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 tion is a secondary cology 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 ty versus hERG. tively all of these unwanted pharmacological activities may compromise its use in advanced MTC and also its extrapolation into r clinical settings (e.g. adjuvant).

Furthermore, several recent publications (Ju et al., 2012; Lipson et al., 2012; Kohno et 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) t samples, which may offer an ant alternative disease segment in which a specific RET inhibitor would offer clinical t.

Mutation at the RET gatekeeper residue (V804) is ted 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 ing them intrinsically resistant to the current therapies 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 ts 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 e settings.

It is therefore an object of the present invention to provide further tors of RET kinase enzyme activity and mutants thereof (e.g. RETV804M).

Another object of the t invention is to provide inhibitors of RET kinase enzyme activity that show a greater selectivity for the inhibition of RET kinase ve to the inhibition of KDR.

SUMMARY OF THE INVENTION 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.

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, e or solvate thereof, in admixture with a pharmaceutically acceptable diluent or carrier.

According to a further aspect of the t 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 nd or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein. ing 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 able salt, hydrate or solvate thereof, as defined herein.

According to a further aspect of the present invention, there is provided a method of inhibiting cell eration, 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 ceutical composition as d herein.

According to a further aspect of the present invention, there is provided a method of treating a e or disorder in which RET kinase ty is implicated in a patient in need of such treatment, said method comprising administering to said patient a eutically effective amount of a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.

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 ive amount of a nd or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.

According to a further aspect of the present invention, there is provided a method of ng 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.

According to a further aspect of the t 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. ing to a further aspect of the present invention, there is provided a compound or a pharmaceutically able salt, hydrate or e thereof as defined , or a pharmaceutical composition as defined herein, for use in the treatment of a proliferative 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 d herein for use in the treatment of cancer. In a particular embodiment, the cancer is human cancer. ing 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).

According to a further aspect of the present invention, there is provided a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as d herein for use in the inhibition of mutant forms of RET kinase enzyme activity (e.g. RET V804M kinase enzyme activity).

According to a further aspect of the present invention, there is provided a compound, or a pharmaceutically acceptable salt, hydrate or solvate f, 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.

According to a further aspect of the present invention, there is provided a compound, or a pharmaceutically able salt, hydrate or solvate thereof, as defined herein for use in the treatment of a e or disorder in which RET kinase activity is implicated. ing to a further aspect of the t invention, there is provided the use of a compound, or a pharmaceutically able salt, hydrate or solvate thereof, as defined herein in the manufacture of a medicament for the treatment of a proliferative condition.

Suitably, the erative disorder is cancer, suitably a human cancer (for example medullary thyroid cancer (MTC) or all cell lung cancer).

According to a further aspect of the t invention, there is provide the use of a nd, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein in the cture of a medicament for the treatment of cancer.

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).

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 ive inhibition of RET kinase enzyme activity, or mutant forms thereof (e.g. RETV804M), relative to KDR enzyme activity.

According to a further aspect of the present invention, there is provided a use of a compound, or a pharmaceutically acceptable salt, e 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.

According to a further aspect of the present invention, there is provided a s for preparing a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein.

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 ly obtained by a process of preparing a compound as defined herein.

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 s set out herein.

Features, including optional, suitable, and preferred features in relation to one aspect of the invention may also be es, ing optional, suitable and preferred features in relation to any other aspect of the invention.

DETAILED DESCRIPTION OF THE INVENTION Definitions Unless otherwise stated, the following terms used in the specification and claims have the following meanings set out below.

It is to be appreciated that references to "treating" or "treatment" include prophylaxis as well as the alleviation of ished 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 ion 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 ion, (2) inhibiting the state, er 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 e, i.e., causing regression of the state, disorder or condition or at least one of its al 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.

In this specification the term "alkyl" es both straight and branched chain alkyl groups. References to individual alkyl groups such as "propyl" are specific for the ht chain version only and references to individual branched chain alkyl groups such as "isopropyl" are ic for the branched chain version only. For example, "(1-6C)alkyl" includes (1- 4C)alkyl, (1-3C)alkyl, propyl, isopropyl and l. A similar convention applies to other ls, for example "phenyl(1-6C)alkyl" includes (1-4C)alkyl, benzyl, 1-phenylethyl and 2-phenylethyl.

The term "(m-nC)" or "(m-nC) group" used alone or as a prefix, refers to any group having m to n carbon atoms.

An "alkylene," "alkenylene," or "alkynylene" group is an alkyl, l, or alkynyl group that is positioned between and serves to connect two other chemical groups. Thus, "(1- 6C)alkylene" means a linear ted divalent hydrocarbon l 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 l 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, ning at least one triple bond, for example, as in ethynylene, ylene, 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. )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-cyclohexenyl, 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 .

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

The term "heterocyclyl", "heterocyclic" or "heterocycle" means a non-aromatic saturated or partially saturated monocyclic, fused, bridged, or spiro bicyclic heterocyclic ring system(s). clic 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 . Heterocycles ning nitrogen include, for example, inyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrotriazinyl, tetrahydropyrazolyl, and the like. Typical sulfur containing heterocycles include tetrahydrothienyl, dihydro-1,3-dithiol, tetrahydro-2H-thiopyran, and drothiepine. Other heterocycles include dihydro-oxathiolyl, ydro-oxazolyl, tetrahydro-oxadiazolyl, tetrahydrodioxazolyl, tetrahydro-oxathiazolyl, hexahydrotriazinyl, tetrahydro-oxazinyl, morpholinyl, thiomorpholinyl, tetrahydropyrimidinyl, dioxolinyl, octahydrobenzofuranyl, drobenzimidazolyl, and octahydrobenzothiazolyl. For heterocycles containing , the oxidized sulfur heterocycles containing SO or SO2 groups are also included. Examples include the ide and sulfone forms of tetrahydrothienyl and thiomorpholinyl such as tetrahydrothiene oxide and thiomorpholinyl 1,1-dioxide. A suitable value for a heterocyclyl group which bears 1 or 2 oxo (=O) or thioxo (=S) substituents is, for example, 2-oxopyrrolidinyl, 2-thioxopyrrolidinyl, 2-oxoimidazolidinyl, 2-thioxoimidazolidinyl, iperidinyl, 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 atoms selected from nitrogen, oxygen or sulfur, for example azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, linyl, tetrahydrothienyl, tetrahydrothienyl 1,1-dioxide, thiomorpholinyl, thiomorpholinyl oxide, 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 yl or morpholinyl ring that is linked via the ring nitrogen.

By "bridged ring systems" is meant ring systems in which two rings share more than two atoms, see for e 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-oxaazabicyclo[2.2.1]heptane, aza-bicyclo[2.2.2]octane, azabicyclo [3.2.1]octane and quinuclidine.

By "spiro lic ring systems" we mean that the two ring s 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-oxaazaspiro[3.4]octane, 2-azaspiro[3.3]heptanes, 6- azaspiro[3.3]heptanes, 7-oxaazaspiro[3.5]nonane, 2-azaspiro[3.4]octane, 2-oxa azaspiro[3.5]nonane and 2-oxaazaspiro[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.

The term "heteroaryl" or "heteroaromatic" means an aromatic mono-, bi-, or polycyclic ring orating 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 e 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 ns 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 sic as in the case of an indole or pyrrole nitrogen. In general the number of basic en atoms present in the heteroaryl group, including any amino group substituents of the ring, will be less than five.

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, l, isoindolyl, benzothienyl, azolyl, benzimidazolyl, benzothiazolyl, benzothiazolyl, indazolyl, l, benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, cinnolinyl, pteridinyl, naphthyridinyl, carbazolyl, phenazinyl, benzisoquinolinyl, pyridopyrazinyl, thieno[2,3-b]furanyl, o[3,2-b]-pyranyl, 5H-pyrido[2,3-d]-o-oxazinyl, 1H-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, ydroquinolinyl, 2-oxo- 1,2,3,4-tetrahydroquinolinyl, dihydrobenzthienyl, obenzfuranyl, 2,3-dihydrobenzo [1,4]dioxinyl, benzo[1,3]dioxolyl, 2,2-dioxo-1,3-dihydrobenzothienyl, 4,5,6,7- tetrahydrobenzofuranyl, indolinyl, 1,2,3,4-tetrahydro-1,8-naphthyridinyl, 4-tetrahydropyrido[2,3-b]pyrazinyl and 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl.

Examples of five membered heteroaryl groups include but are not limited to pyrrolyl, furanyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl and tetrazolyl groups.

Examples of six ed heteroaryl groups include but are not limited to pyridyl, nyl, pyridazinyl, pyrimidinyl and triazinyl.

A bicyclic heteroaryl group may be, for example, a group selected from: a benzene ring fused to a 5- or ered 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 le 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 atoms; 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.

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, oxazolyl, benzthiazolyl, benzisothiazolyl, zofuranyl, indolyl, isoindolyl, indolizinyl, nyl, isoindolinyl, purinyl (e.g., adeninyl, guaninyl), indazolyl, benzodioxolyl and pyrazolopyridinyl groups.

Particular examples of bicyclic heteroaryl groups containing two fused six ed rings include but are not limited to quinolinyl, nolinyl, chromanyl, romanyl, chromenyl, isochromenyl, chromanyl, omanyl, benzodioxanyl, quinolizinyl, benzoxazinyl, benzodiazinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl and pteridinyl .

"Heteroaryl(1-6C)alkyl" means a heteroaryl group covalently attached to a (1- 6C)alkylene group, both of which are defined herein. Examples of aralkyl groups include pyridinylmethyl, 3-(benzofuranyl)propyl, and the like.

The term "aryl" means a cyclic or polycyclic aromatic ring having from 5 to 12 carbon atoms. The term aryl es both monovalent s 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.

The term "aryl(1-6C)alkyl" means an aryl group covalently attached to a (1-6C)alkylene group, both of which are defined . Examples of aryl-(1-6C)alkyl groups include benzyl, phenylethyl, and the like.

This specification also makes use of several composite terms to describe groups comprising more than one functionality. Such terms will be understood by a person skilled in the art. For example heterocyclyl(m-nC)alkyl comprises (m-nC)alkyl substituted by cyclyl.

The term "optionally substituted" refers to either groups, structures, or molecules that are substituted and those that are not substituted. The term "wherein a/any CH, CH2, CH3 group or heteroatom (i.e. NH) within a R1 group is optionally substituted" suitably means that (any) one of the hydrogen radicals of the R1 group is substituted by a relevant stipulated group.

Where al tuents are chosen from "one or more" groups it is to be tood that this definition includes all substituents being chosen from one of the specified groups or the tuents being chosen from two or more of the specified groups.

The phrase "compound of the invention" means those compounds which are disclosed herein, both generically and specifically.

Compounds of the ion In one aspect, the present invention relates to compounds, or pharmaceutically acceptable salts, hydrates or solvates thereof, having the structural formula (I) shown below: wherein: HET is selected from one of the following: wherein denotes the point of attachment; R1 is selected from hydrogen, (1-4C)haloalkyl, 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, SO2, N(Ra), C(O), C(O)O, OC(O), C(O)N(Ra), N(Ra)C(O), N(Ra)C(O)N(Rb), (O)O, OC(O)N(Ra), S(O)2N(Ra), or N(Ra)SO2, wherein Ra and Rb are each independently selected from hydrogen or (1-4C)alkyl; and Q is en, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, aryl, (3- 10C)cycloalkyl, (3-10C)cycloalkenyl, heteroaryl or heterocyclyl; n 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, moyl, mercapto, ureido, NRcRd, ORc, C(O)Rc, C(O)ORc, OC(O)Rc, C(O)N(Rd)Rc, N(Rd)C(O)Rc, S(O)yRc (where y is 0, 1 or 2), SO2N(Rd)Rc, N(Rd)SO2Rc, 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 ed 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 tuted by a group of the formula: -L1-LQ1-Z1 wherein: L1 is absent or alkylene optionally substituted by one or more substituents ed from (1-2C)alkyl or oxo; LQ1 is absent or selected from or O, S, SO, SO2, N(Rf), C(O), C(O)O, OC(O), C(O)N(Rf), N(Rf)C(O), N(Rg)C(O)N(Rf), N(Rf)C(O)O, OC(O)N(Rf), S(O)2N(Rf), or N(Rf)SO2, wherein Rf and Rg are each independently selected from hydrogen or (1- 2C)alkyl; and Z1 is en, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, (3- 8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Z1 is ally substituted by one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)haloalkoxy, alkoxy, (1-4C)alkylamino, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, mercapto, ureido, aryl, heteroaryl, heterocycyl, cycloalkyl, NRhRi, ORh, C(O)Rh, C(O)ORh, OC(O)Rh, C(O)N(Ri)Rh, N(Ri)C(O)Rh, S(O)yaRh (where ya is 0, 1 or 2), SO2N(Ri)Rh, N(Ri)SO2Rh or (CH2)zaNRiRh (where za is 1, 2 or 3); wherein Rh and Ri are each independently selected from hydrogen, (1-4C)alkyl or (3- 6C)cycloalkyl; R1a and R1b are each independently selected from hydrogen, (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, 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 en or (1- 2C)alkyl; bonds a, b, c and d are independently selected from a single or double bond; X1 and X2 are each independently selected from N or CRk when bond a is a double bond, or NRl or CRkRl when bond a is a single bond; wherein Rk is selected from hydrogen, halo, (1-4C)alkyl, alkoxy, amino, (1-4C)alkylamino, (1-4C)dialkylamino, cyano, (2C)alkynyl, C(O)R k1, C(O)ORk1, OC(O)Rk1, C(O)N(Rk2)Rk1, N(Rk2)C(O)Rk1, S(O)ybRk1 (where yb is 0, 1 or 2), SO2N(Rk2)Rk1, N(Rk2)SO2Rk1 or (CH2)zbNRk1Rk2 (where zb is 1, 2 or 3); wherein said alkyl is optionally substituted by one or more tuents selected from amino, hydroxy, (1-2C)alkoxy or halo; Rl is selected from hydrogen or (1-4C)alkyl; and Rk1 and Rk2 are each independently selected from hydrogen or (1- 4C)alkyl; X3 is ed 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 ed from hydrogen, halo, (1-4C)alkyl, (1-4C)alkoxy, amino, (1-4C)alkylamino, (1-4C)dialkylamino, cyano, (2C)alkynyl, C(O)Rm1, C(O)ORm1, OC(O)Rm1, C(O)N(Rm2)Rm1, N(Rm2)C(O)Rm1, S(O)ycRm1 (where yc is 0, 1 or 2), SO2N(Rm2)Rm1, N(Rm2)SO2Rm1 or (CH2)zcNRm1Rm2 (where zc is 1, 2 or 3); wherein said (1-4C)alkyl is optionally substituted by one or more substituents selected from amino, y, (1-2C)alkoxy or halo; Rn is selected from hydrogen or (1-4C)alkyl; and Rm1 and Rm2 are each independently selected from hydrogen or (1- 4C)alkyl; X4 is selected from N or CRo when bond d is a double bond, or NRx or CRoRx when bond d is a single bond; wherein Ro is selected from hydrogen, halo, (1-4C)alkyl, (1-4C)alkoxy, amino, (1-4C)alkylamino, dialkylamino, cyano, (2C)alkynyl, C(O)Ro1, C(O)ORo1, OC(O)Ro1, C(O)N(Ro2)Ro1, N(Ro2)C(O)Ro1, S(O)ydRo1 (where yd is 0, 1 or 2), SO2N(Ro2)Ro1, N(Ro2)SO2Ro1 or (CH2)zdNRo1Ro2 (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 en or (1-4C)alkyl; and Ro1 and Ro2 are each independently selected from hydrogen or (1- 4C)alkyl; R2 is ed 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(O)O, C(O)N(Rp), wherein Rp is ed from hydrogen or (1-4C)alkyl; and Q2 is hydrogen, (1-6C)alkyl, aryl, cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; n Q2 is optionally further substituted by one or more substituent groups independently selected from (1- 4C)alkyl, halo, (1-4C)haloalkyl, haloalkoxy, amino, cyano, hydroxy, y, 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: -Y3-Q3 wherein: Y3 is C(O), C(O)N(Ry), C(O)N(Ry)O, N(Ry)(O)C, C(O)O, OC(O), N(Ry)C(O)N(Ry1), SO2N(Ry), N(Ry)SO2, oxazolyl, triazolyl, oxadiazolyl, thiazolyl, imidazolyl, thiadiazolyl, pyridinyl, pyrazolyl, pyrrolyl or tetrazolyl, n Ry and Ry1 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, aryl 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 ally substituted by a group of the formula: -L4-LQ4-Z4 wherein: L4 is absent or (1-3C)alkylene optionally tuted by one or more substituents selected from alkyl or oxo; LQ4 is absent or selected from or O, S, SO, SO2, N(Rab), C(O), C(O)O, OC(O), C(O)N(Rab), N(Rab)C(O), C(O)N(Rab), N(Rab)C(O)O, OC(O)N(Rab), S(O)2N(Rab), or N(Rab)SO2, wherein Rab and Rac are each independently selected from hydrogen or (1-2C)alkyl; and Z4 is hydrogen, (1-6C)alkyl, aryl, -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, y, carbamoyl, sulphamoyl, mercapto, ureido, aryl, heteroaryl, heterocycyl, (3-6C)cycloalkyl, NRadRae, ORad, C(O)Rad, ad, OC(O)Rad, C(O)N(Rae)Rad, N(Rae)C(O)Rad, S(O)yeRad (where ye is 0, 1 or 2), SO2N(Rae)Rad, N(Rae)SO2Rad 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 ed 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 o that only one or two of X1, X2, X3 or X4 can be N.

Particular compounds of the invention include, for example, compounds of the a I, or pharmaceutically acceptable salts and/or solvates thereof, wherein, unless otherwise stated, each of HET, R1, R1a, R1b, W, bonds a, b, c and d, X1, X2, X3, X4, R2 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 ed from one of the following: (2) HET is ed from one of the following: (3) HET is selected from one of the following: (4) HET is ed from one of the following: (5) HET is selected from one of the following: (6) HET is selected from one of the following: (7) HET is: (8) R1 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, SO2, N(Ra), C(O), C(O)O, OC(O), C(O)N(Ra), N(Ra)C(O), S(O)2N(Ra), or N(Ra)SO2, 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 tuent groups independently selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, haloalkoxy, amino, (1-4C)aminoalkyl, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, to, ureido, NRcRd, ORc, C(O)Rc, C(O)ORc, OC(O)Rc, C(O)N(Rd)Rc, N(Rd)C(O)Rc, S(O)yRc (where y is 0, 1 or 2), d)Rc, N(Rd)SO2Rc, 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 en 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 tuted by a group of the formula: -L1-LQ1-Z1 wherein: L1 is absent or (1-3C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkyl; LQ1 is absent or selected from or O, S, SO, SO2, N(Rf), C(O), C(O)O, OC(O), C(O)N(Rf), N(Rf)C(O), N(Rf)C(O)O, S(O)2N(Rf), or N(Rf)SO2, wherein Rf is ed from hydrogen or (1- 2C)alkyl; and Z1 is hydrogen, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, (3- loalkyl, (3-8C)cycloalkenyl, aryl or heterocyclyl; wherein Z1 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 or ORh, wherein Rh and Ri are each independently selected from hydrogen, (1-4C)alkyl or (3-6C)cycloalkyl; (9) R1 is selected from hydrogen, (1-4C)haloalkyl, (1-4C)haloalkoxy or a group of the -L-Y-Q L is absent or (1-3C)alkylene optionally substituted by one or more substituents ed from (1-2C)alkyl or oxo; Y is absent or O, N(Ra), C(O), C(O)O, OC(O), C(O)N(Ra), N(Ra)C(O), S(O)2N(Ra), or N(Ra)SO2, wherein Ra is ed 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 tuted 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(O)Rc, C(O)ORc, OC(O)Rc, C(O)N(Rd)Rc, N(Rd)C(O)Rc, c (where y is 0, 1 or 2), d)Rc, N(Rd)SO2Rc, 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 ed cyclic ring which is optionally substituted by one or more substituents ed 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 tuted by a group of the formula: -L1-LQ1-Z1 wherein: L1 is absent or (1-3C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkyl; LQ1 is absent or selected from or C(O), C(O)O, OC(O), C(O)N(Rf), N(Rf)C(O) or N(Rf)C(O)O, wherein Rf is selected from en or (1-2C)alkyl; and Z1 is hydrogen, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, (3- 8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Z1 is ally 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, NRhRi or ORh, wherein Rh and Ri are each independently selected from hydrogen, (1-4C)alkyl or cyclopropyl; (10) R1 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(O)O, OC(O), C(O)N(Ra), N(Ra)C(O), S(O)2N(Ra), or O2, 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 cyclyl; 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, oyl, sulphamoyl, mercapto, ureido, NRcRd, ORc, C(O)Rc, C(O)ORc, c, C(O)N(Rd)Rc, N(Rd)C(O)Rc, S(O)yRc (where y is 0, 1 or 2), d)Rc, N(Rd)SO2Rc, 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 tuents ed from (1- 4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, alkoxy, (1- 4C)alkylamino, amino, cyano or hydroxy; (11) R1 is selected from hydrogen, (1-4C)haloalkyl, (1-4C)haloalkoxy or a group of the formula: -L-Y-Q wherein: L is absent or alkylene optionally substituted by one or more substituents selected from (1-2C)alkyl or oxo; Y is absent or C(O), C(O)O, OC(O), C(O)N(Ra) or N(Ra)C(O), wherein Ra is selected from hydrogen or (1-4C)alkyl; and Q is hydrogen, 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, haloalkyl, (1-4C)haloalkoxy, amino, (1-4C)aminoalkyl, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, mercapto, ureido, NRcRd, ORc, , C(O)ORc, OC(O)Rc, C(O)N(Rd)Rc, N(Rd)C(O)Rc, S(O)yRc (where y is 0, 1 or 2), SO2N(Rd)Rc, N(Rd)SO2Rc, 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) R1 is selected from en, (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 alkyl, halo, (1- 4C)haloalkyl, (1-4C)haloalkoxy, amino, (1-4C)aminoalkyl, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, mercapto, ureido, NRcRd, ORc, C(O)Rc, C(O)ORc, OC(O)Rc, C(O)N(Rd)Rc, N(Rd)C(O)Rc, S(O)yRc (where y is 0, 1 or 2), SO2N(Rd)Rc, N(Rd)SO2Rc, 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) R1 is selected from hydrogen, (1-4C)haloalkyl, 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 (Rc)Re; wherein Rc, Rd and Re are each independently selected from hydrogen or (1-6C)alkyl; (14) R1 is selected from hydrogen, (1-6C)alkyl, 4-7 ed cyclyl or (3- cloalkyl; 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(O)2Rc or Si(Rd)(Rc)Re; wherein Rc, Rd and Re are each independently selected from hydrogen or (1-4C)alkyl; (15) R1 is selected from hydrogen, (4-6C)alkyl or 4-7 ed cyclyl; wherein each of said substituents is ally further substituted by one or more substituent groups independently selected from alkyl, halo, amino, (1-4C)aminoalkyl, cyano, hydroxy, carboxy, NRcRd, ORc or S(O)2Rc; wherein Rc, and Rd are each independently selected from hydrogen or (1-4C)alkyl; (16) R1 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 ed 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 en or (1-4C)alkyl; (157) R1 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 ndently selected from (1-4C)alkyl, ORc or Si(Rd)(Rc)Re; n Rc, Rd and Re are each independently selected from hydrogen or (1-2C)alkyl; (18) R1 is a (1-6C)alkyl or (4-6C)cycloalkyl; (19) R1 is a alkyl; (20) R1 is tert-butyl; (21) R1a and R1b are each independently selected from hydrogen, (1-4C)alkyl, halo, (1- 4C)haloalkyl, (1-4C)haloalkoxy, alkoxy, (1-4C)alkylamino, amino, cyano or (22) R1a and R1b are each independently selected from hydrogen, (1-4C)alkyl, halo, (1- 4C)haloalkyl, (1-4C)alkoxy, amino, cyano or hydroxy; (23) R1a and R1b are each independently ed from hydrogen or (1-4C)alkyl; (24) R1a and R1b are each hydrogen; (25) W is ed 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) X1 and X2 are each independently selected from N or CRk when bond a is a double bond, or NRl or CRkRl 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 Rl is selected from hydrogen or (1-4C)alkyl; (30) X1 and X2 are each independently ed from N or CRk when bond a is a double bond, or NRl or CRkRl 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 Rl is selected from hydrogen or (1-4C)alkyl; (31) X1 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; (32) X1 and X2 are CRk and bond a is a double bond, wherein Rk is selected from hydrogen, halo or (1-4C)alkyl; (33) X1 and X2 are each independently selected from N or CH and bond a is a double bond; (34) X1 and X2 are CH and bond a is a double bond; (35) X3 is selected from N or CRl when bond b is a double bond, or NRn or CRmRn when bond b is a single bond; wherein Rm is ed 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 tuted by one or more substituents selected from amino, y, (1-2C)alkoxy or halo; and Rn is ed from hydrogen or (1-4C)alkyl; (36) 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, kynyl; and Rn is selected from hydrogen or (1-4C)alkyl; (37) 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; (38) X3 is CRm and bond b is a double bond, wherein Rm is ed from hydrogen, halo, (1-4C)alkyl or amino; (39) X3 is ed from N or CH and bond b is a double bond; (40) X3 is CH and bond b is a double bond; (41) X4 is selected from N or CRo when bond d is a double bond, or NRx or CRoRx 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; (42) X4 is selected from N or CRo when bond d is a double bond, or NRx or CRoRx 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 en or (1-4C)alkyl; (43) X4 is selected from N or CRo and bond d is a double bond, wherein Ro is selected from halo, (1-4C)alkyl, (1-4C)alkoxy, amino, (1-4C)alkylamino, (1-4C)dialkylamino, cyano, (2C)alkynyl, C(O)Ro1, C(O)ORo1, OC(O)Ro1, C(O)N(Ro2)Ro1, N(Ro2)C(O)Ro1, S(O)ydRo1 (where yd is 0, 1 or 2), SO2N(Ro2)Ro1, N(Ro2)SO2Ro1 or (CH2)zdNRo1Ro2 (where zd is 1, 2 or 3); wherein said (1-4C)alkyl is optionally substituted by one or more substituents selected from amino, y, (1-2C)alkoxy or halo; and wherein Ro1 and Ro2 are each independently ed from hydrogen or (1-4C)alkyl; (44) X4 is selected from N or CRo and bond d is a double 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; (45) X4 is CRo and bond d is a double bond, wherein Ro is selected from halo, (1-4C)alkyl, (1-4C)alkoxy, amino, (1-4C)alkylamino, (1-4C)dialkylamino, cyano or (2C)alkynyl; (46) X4 is CRo and bond d is a double bond, wherein Ro is selected from hydrogen, halo, (1-4C)alkyl or amino; (47) X4 is CRo and bond d is a double bond, wherein Ro is selected from halo or (1- 4C)alkyl; (48) X4 is CRo and bond d is a double bond, wherein Ro 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: -L2-Y2-Q2 wherein: L2 is absent or (1-3C)alkylene optionally substituted by one or more substituents selected from alkyl or oxo; Y2 is absent or C(O), C(O)O, C(O)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, n 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 a: -Y2-Q2 wherein: Y2 is absent or C(O), C(O)O, C(O)N(Rp), wherein Rp is selected from hydrogen or (1-4C)alkyl; and Q2 is hydrogen, (1-6C)alkyl, aryl, (3-8C)cycloalkyl, aryl 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, y, NRqRr, ORq, wherein Rq and Rr are each independently selected from hydrogen or alkyl; (51) R2 is selected from hydrogen, (1-4C)alkyl or a group of the a: -Y2-Q2 wherein: Y2 is C(O)N(Rp), wherein Rp is ed 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 ndently selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- oalkoxy, 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 a: -Y3-Q3 wherein: Y3 is C(O), C(O)N(Ry), C(O)N(Ry)O, N(Ry)(O)C, C(O)O, OC(O), N(Ry)C(O)N(Ry1), SO2N(Ry), N(Ry)SO2, oxazolyl, triazolyl, oxadiazolyl, thiazolyl, imidazolyl, pyrazolyl or tetrazolyl, wherein Ry and Ry1 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, cycloalkenyl, heteroaryl or heterocyclyl; wherein Q3 is optionally further tuted by one or more tuent groups independently selected from (1-4C)alkyl, halo, haloalkyl, (1- 4C)haloalkoxy, amino, cyano, hydroxy, y, oyl, 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: -L4-LQ4-Z4 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(O)O, OC(O), C(O)N(Rab), N(Rab)C(O), S(O)2N(Rab), or N(Rab)SO2, n 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(O)Rad, C(O)ORad, OC(O)Rad, C(O)N(Rae)Rad, N(Rae)C(O)Rad, S(O)yeRad (where ye is 0, 1 or 2), SO2N(Rae)Rad, SO2Rad or (CH2)zeNRadRae (where ze is 1, 2 or 3); wherein Rad and Rae are each independently selected from hydrogen, 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 ed heterocyclic ring which is optionally substituted by one or more tuents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano or hydroxyl; (55) R3 is selected from a group of the formula: -Y3-Q3 wherein: Y3 is C(O), C(O)N(Ry), N(Ry)(O)C, C(O)O, OC(O), triazolyl, oxadiazolyl or tetrazolyl, wherein Ry is ed from hydrogen or (1-2C)alkyl; and Q3 is hydrogen, alkyl, aryl, aryl(1-2C)alkyl, (3-8C)cycloalkyl, (3- 8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Q3 is optionally r 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, moyl, 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: -L4-LQ4-Z4 wherein: L4 is absent or (1-3C)alkylene optionally substituted by one or more substituents selected from alkyl or oxo; LQ4 is absent or selected from or O, S, SO, SO2, N(Rab), C(O), C(O)O, OC(O), C(O)N(Rab), C(O), N(Rac)C(O)N(Rab), N(Rab)C(O)O, OC(O)N(Rab), S(O)2N(Rab), or N(Rab)SO2, 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, alkoxy, (1-4C)alkylamino, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, mercapto, ureido, aryl, heteroaryl, cycyl, (3-6C)cycloalkyl, NRadRae, ORad, C(O)Rad, C(O)ORad, OC(O)Rad, C(O)N(Rae)Rad, N(Rae)C(O)Rad, S(O)yeRad (where ye is 0, 1 or 2), SO2N(Rae)Rad, N(Rae)SO2Rad or eNRadRae (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 ed from a group of the a: -Y3-Q3 Y3 is C(O), C(O)N(Ry), C(O)N(Ry)O, N(Ry)(O)C, C(O)O, OC(O), (O)N(Ry1), N(Ry)SO2, oxazoyl, triazolyl, oxadiazolyl, azolyl or tetrazolyl, wherein Ry and Ry1 are independently selected from hydrogen or (1-2C)alkyl; and Q3 is hydrogen, (1-6C)alkyl, (1-6C)alkoxy, aryl, -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, oyl, 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: -L4-LQ4-Z4 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(O)O, OC(O), C(O)N(Rab), N(Rab)C(O), S(O)2N(Rab), or N(Rab)SO2, wherein Rab is selected from hydrogen or (1-2C)alkyl; and Z4 is hydrogen, 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, y, carboxy, carbamoyl, sulphamoyl, mercapto, ureido, aryl, heteroaryl, heterocycyl, (3-6C)cycloalkyl, e, ORad, C(O)Rad, C(O)ORad, OC(O)Rad, C(O)N(Rae)Rad, N(Rae)C(O)Rad, S(O)yeRad (where ye is 0, 1 or 2), SO2N(Rae)Rad, N(Rae)SO2Rad 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 en atom to which they are attached, they form a 4-7 membered heterocyclic ring which is optionally tuted by one or more tuents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)haloalkoxy, alkoxy, (1-4C)alkylamino, amino, cyano or hydroxyl; (57) R3 is selected from a group of the formula: -Y3-Q3 wherein: Y3 is C(O), C(O)N(Ry), C(O)N(Ry)O, N(Ry)(O)C, C(O)O, OC(O), wherein Ry is selected from hydrogen or 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 ally further substituted by one or more substituent groups independently selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)haloalkoxy, amino, cyano, y, 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: -L4-LQ4-Z4 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(O)O, OC(O), C(O)N(Rab), N(Rab)C(O), S(O)2N(Rab), or SO2, wherein Rab is ed 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(O)Rad, C(O)ORad, ad, C(O)N(Rae)Rad, N(Rae)C(O)Rad, S(O)yeRad (where ye is 0, 1 or 2), SO2N(Rae)Rad, N(Rae)SO2Rad 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; (58) R3 is selected from a group of the formula: -Y3-Q3 Y3 is C(O), C(O)N(Ry), C(O)N(Ry)O, N(Ry)(O)C, C(O)O, OC(O), n Ry is selected from hydrogen or alkyl; and Q3 is hydrogen, alkyl, (1-6C)alkoxy, aryl, aryl(1-2C)alkyl, (3- 8C)cycloalkyl, 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 a: -L4-LQ4-Z4 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 ed from or O, N(Rab), C(O), C(O)O, OC(O), C(O)N(Rab), N(Rab)C(O), (Rab), or N(Rab)SO2, wherein Rab is selected from en 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, y, carbamoyl, sulphamoyl, mercapto, ureido, aryl, heteroaryl, heterocycyl, (3-6C)cycloalkyl, NRadRae, ORad, C(O)Rad, ad, OC(O)Rad, C(O)N(Rae)Rad, N(Rae)C(O)Rad, S(O)yeRad (where ye is 0, 1 or 2), SO2N(Rae)Rad, SO2Rad 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 ed 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 yl; (59) R3 is selected from a group of the formula: -Y3-Q3 wherein: Y3 is C(O), C(O)N(Ry), N(Ry)(O)C, C(O)N(Ry)O, C(O)O, OC(O), wherein Ry is selected from en 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, y, 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: -L4-LQ4-Z4 wherein: L4 is absent or (1-3C)alkylene; LQ4 is absent or selected from or O, N(Rab), C(O), C(O)O, OC(O), Rab), N(Rab)C(O), (Rab), or N(Rab)SO2, wherein Rab is selected from hydrogen or (1-2C)alkyl; and Z4 is en, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, (3- loalkyl, (3-8C)cycloalkenyl, heteroaryl or cyclyl; 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, y, carboxy, carbamoyl, sulphamoyl, mercapto, ureido, aryl, heteroaryl, heterocycyl, (3-6C)cycloalkyl, NRadRae, ORad, C(O)Rad, C(O)ORad, OC(O)Rad, C(O)N(Rae)Rad, N(Rae)C(O)Rad, Rad (where ye is 0, 1 or 2), SO2N(Rae)Rad, N(Rae)SO2Rad 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: -Y3-Q3 wherein: Y3 is C(O)N(Ry), wherein Ry is selected from hydrogen or (1-2C)alkyl; Q3 is hydrogen, (1-6C)alkyl, 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, haloalkyl, (1- 4C)haloalkoxy, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, NRzRaa, ORz, wherein Rz and Raa are each independently ed from hydrogen, (1-4C)alkyl or (3-6C)cycloalkyl; or Q3 is optionally substituted by a group of the formula: -L4-LQ4-Z4 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, S, SO, SO2, N(Rab), C(O), C(O)O, OC(O), C(O)N(Rab), N(Rab)C(O), N(Rac)C(O)N(Rab), N(Rab)C(O)O, OC(O)N(Rab), S(O)2N(Rab), or N(Rab)SO2, wherein Rab and Rac are each independently selected from hydrogen or (1-2C)alkyl; and Z4 is hydrogen, (1-6C)alkyl, aryl, -2C)alkyl, (3- loalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Z4 is ally 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, moyl, mercapto, ureido, aryl, heteroaryl, heterocycyl, (3-6C)cycloalkyl, NRadRae, ORad, C(O)Rad, C(O)ORad, OC(O)Rad, C(O)N(Rae)Rad, N(Rae)C(O)Rad, S(O)yeRad (where ye is 0, 1 or 2), SO2N(Rae)Rad, N(Rae)SO2Rad 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 ed, they form a 4-6 membered heterocyclic ring which is ally substituted by one or more substituents selected from (1-4C)alkyl, halo, haloalkyl, (1- 4C)haloalkoxy, (1-4C)alkoxy, alkylamino, amino, cyano or hydroxyl; (61) R3 is selected from a group of the formula: -Y3-Q3 wherein: Y3 is C(O)N(Ry), wherein Ry is selected from hydrogen or (1-2C)alkyl; 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 tuted by one or more substituent groups independently selected from (1-4C)alkyl, halo, haloalkyl, (1- 4C)haloalkoxy, amino, cyano, hydroxy, y, carbamoyl, sulphamoyl, , 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: L4 is absent or (1-3C)alkylene optionally substituted by one or more substituents ed from (1-2C)alkyl or oxo; LQ4 is absent or selected from or O, S, SO, SO2, N(Rab), C(O), C(O)O, OC(O), C(O)N(Rab), N(Rab)C(O), N(Rac)C(O)N(Rab), N(Rab)C(O)O, (Rab), S(O)2N(Rab), or N(Rab)SO2, 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 ally 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(O)Rad, C(O)ORad, OC(O)Rad, C(O)N(Rae)Rad, C(O)Rad, Rad (where ye is 0, 1 or 2), SO2N(Rae)Rad, N(Rae)SO2Rad 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: -Y3-Q3 wherein: Y3 is C(O)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 ally 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 ally substituted by a group of the formula: -L4-LQ4-Z4 wherein: L4 is absent or (1-3C)alkylene; LQ4 is absent or selected from or O, N(Rab), C(O), C(O)O, or C(O)N(Rab), wherein Rab is selected from hydrogen or (1- yl; and Z4 is hydrogen, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, (3- 8C)cycloalkyl, cycloalkenyl, aryl or heterocyclyl; wherein Z4 is ally 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: -Y3-Q3 wherein: Y3 is C(O), C(O)N(Ry), N(Ry)(O)C or C(O)O, wherein Ry is selected from hydrogen or (1-2C)alkyl; and Q3 is en, (1-6C)alkyl, 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, y, carboxy, carbamoyl, sulphamoyl, NRzRaa, ORz, wherein Rz and Raa are each independently ed from hydrogen, (1-4C)alkyl or (3-6C)cycloalkyl; or Q3 is optionally substituted by a group of the formula: -L4-LQ4-Z4 wherein: L4 is absent or (1-3C)alkylene; LQ4 is absent or selected from or O, , C(O), C(O)O, or C(O)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- oalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano or y; (64) R3 is ed from a group of the formula: -Y3-Q3 wherein: Y3 is C(O)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- oalkoxy, 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: -LQ4-Z4 wherein: LQ4 is absent or selected from or O, , C(O), C(O)O, or C(O)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- loalkyl, 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, alkylamino, amino, cyano or hydroxy; (65) R3 is selected from a group of the formula: -Y3-Q3 wherein: Y3 is C(O)NH; and Q3 is 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, y, carbamoyl, sulphamoyl, NRzRaa, ORz, wherein Rz and Raa are each independently selected from hydrogen or (1-4C)alkyl; or Q3 is optionally tuted by a group of the formula: -LQ4-Z4 wherein: LQ4 is absent or selected from or O, , C(O), C(O)O, or C(O)N(Rab), wherein Rab is selected from en 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: -Y3-Q3 wherein: Y3 is C(O), C(O)O or C(O)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 ally 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: -Y3-Q3 wherein: Y3 is C(O)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; n Q3 is optionally further substituted by one or more substituent groups independently ed from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)haloalkoxy, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, NRzRaa, ORz, n Rz and Raa are each independently selected from hydrogen or (1-4C)alkyl; (68) R3 is selected from a group of the formula: -Y3-Q3 wherein: Y3 is C(O)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 ndently 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. ly, a heteroaryl or heterocyclyl group as d herein is a clic heteroaryl or cyclyl group comprising one, two or three heteroatoms selected from N, O or S.

Suitably, a heteroaryl is a 5- or 6-membered heteroaryl ring sing one, two or three heteroatoms selected from N, O or S.

Suitably, a cyclyl group is a 4-, 5- or 6-membered heterocyclyl ring comprising one, two or three heteroatoms ed 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].

Suitably an aryl group is phenyl.

Suitably, HET is as defined in any one of paragraphs (1) to (7). Most suitably, HET is as defined in paragraph (7).

Suitably, R1 is as defined in any one of paragraphs (8) to (20). More suitably, R1 is as defined in any one of paragraphs (12) to (20). Most ly, R1 is as defined in paragraph (20).

Suitably R1a and R1b are as d in any one of paragraphs (21) to (24). Most suitably, R1a and R1b are as defined in paragraph (24).

Suitably, W is as defined in any one of paragraphs (25) to (26). Most suitably, W is as defined in paragraph (26).

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).

Suitably, X1 and X2 are as defined in any one of paragraphs (29) to (34). Most suitably, X1 and X2 are as defined in paragraph (34).

Suitably, X3 is as d in any one of paragraphs (35) to (40). Most suitably, X3 is as defined in paragraph (40).

Suitably, X4 is as defined in any one of paragraphs (41) to (48). Most suitably, X4 is as defined in paragraph (48).

Suitably, R2 is as defined in any one of paragraphs (49) to (53). More suitably, R2 is as d in any one of aphs (51) to (53). Most suitably, R2 is as defined in paragraph (53).

Suitably, R3 is as d in any one of paragraphs (54) to (68). Most suitably, R3 is as defined in paragraph (68).

In a particular group of compounds of the invention, the nds have the structural Formula Ia (a sub-definition of formula (I)) shown below, or a pharmaceutically acceptable salt, hydrate and/or solvate thereof: X2 Q3 X1 a N c X3 Ry wherein HET, bonds a, b, c and d, X1, X2, X3, X4, R2, Q3 and Ry each have any one of the meanings defined .

In an embodiment of the compounds of Formula Ia: HET is as defined in any one of aphs (1) to (7) above; R1 is as defined in any one of paragraphs (8) to (20) above; R1a and R1b 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; X1 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).

In another embodiment of the compounds of Formula Ia: HET is as defined in paragraph (7) above; R1 is as defined in paragraph (20) above; R1a and R1b are as d in paragraph (24) above; bonds a, b, c and d are as d in paragraph (28) above; X1 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).

In a particular group of nds of the invention, the compounds have the structural Formula Ib (a sub-definition of formula (I)) shown below, or a pharmaceutically acceptable salt, hydrate and/or solvate thereof: wherein R1, bonds a, b, c and d, X1, X2, X3, X4, R2, Q3 and Ry each have any one of the meanings defined herein.

In an embodiment of the compounds of Formula Ib: R1 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 aphs (27) to (28) above; X1 and X2 are as defined in any one of paragraphs (29) to (34) above; X3 is as defined in any one of aphs (35) to (40) above; X4 is as defined in any one of aphs (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).

In another embodiment of the compounds of Formula Ib: R1 is as d in paragraph (20) above; bonds a, b, c and d are as defined in paragraph (28) above; X1 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.

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: wherein R1, X1, X2, X3, X4, R2, Q3 and Ry each have any one of the meanings defined herein.

In an embodiment of the compounds of Formula Ic: R1 is as defined in any one of paragraphs (8) to (20) above; X1 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).

In another embodiment of the compounds of Formula Ic: R1 is as d in any one of aphs (8) to (20) above; X1 and X2 are as d 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).

In yet another embodiment of the compounds of a Ic: R1 is as defined in paragraph (20) above; X1 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 d in paragraph (68) above.

In an alternative embodiment of the compounds of Formula Ic: R1 is as defined in paragraph (20) above; X1 and X2 are as defined in paragraph (34) above; X3 is as d in paragraph (40) above; X4 is CH; R2 is as defined in aph (53) above; Ry is hydrogen; and Q3 is as defined in paragraph (68) above In a particular group of compounds of the invention, the compounds have the structural a Id (a sub-definition of formula (I)) shown below, or a pharmaceutically acceptable salt, hydrate and/or solvate thereof: wherein R1, X4, R2 and Q3 each have any one of the meanings defined herein.

In an embodiment of the compounds of Formula Id: R1 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 d in any one of paragraphs (49) to (53) above; and Q3 is as defined in any one of paragraphs (54) to (68) above.

In another embodiment of the compounds of Formula Id: R1 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.

In an alternative embodiment of the compounds of Formula Id: R1 is as defined in paragraph (20) above; X4 is CH; R2 is as defined in paragraph (53) above; and Q3 is as d in paragraph (68) above.

In a particular group of nds of the invention, the compounds have the structural Formula Ie (a sub-definition of formula (I)) shown below, or a pharmaceutically acceptable salt, e and/or solvate thereof: wherein HET, X1, X2, X3, R2, R3 and Ro each have any one of the meanings defined herein.

In an embodiment of the compounds of Formula Ie: HET is as defined in any one of paragraphs (1) to (7) above; R1 is as d in any one of paragraphs (8) to (20) above; R1a and R1b are as defined in any one of paragraphs (21) to (24) above; X1 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 d in any one of paragraphs (49) to (53) above; and R3 is as defined in any one of paragraphs (54) to (68).

In r embodiment of the compounds of Formula Ie: HET is as defined in aph (7) above; R1 is as defined in paragraph (20) above; R1a and R1b are as d in paragraph (24) above; X1 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).

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: X2 Q3 X1 N X3 Ry wherein HET, X1, X2, X3, R2, Ro, Q3 and Ry each have any one of the gs defined In an embodiment of the compounds of Formula If: HET is as defined in any one of paragraphs (1) to (7) above; R1 is as defined in any one of paragraphs (8) to (20) above; R1a and R1b are as defined in any one of paragraphs (21) to (24) above; X1 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).

In another embodiment of the compounds of Formula If: HET is as defined in paragraph (7) above; R1 is as defined in paragraph (20) above; R1a and R1b are as d in paragraph (24) above; X1 and X2 are as defined in paragraph (34) above; X3 is as defined in paragraph (40) above; Ro is halo, ally ; R2 is as defined in paragraph (53) above; Ry is hydrogen; and Q3 is as defined in paragraph (68).

In a particular group of compounds of the invention, the compounds have the structural Formula Ig (a finition of a (I)) shown below, or a pharmaceutically acceptable salt, hydrate and/or solvate thereof: wherein X1, X2, X3, R1, R2, Ro, Q3 and Ry each have any one of the meanings defined herein.

In an embodiment of the compounds of Formula Ig: R1 is as defined in any one of paragraphs (8) to (20) above; X1 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 aphs (54) to (63) above; and Q3 is as defined in any one of paragraphs (54) to (68).

In another embodiment of the compounds of Formula Ig: R1 is as defined in paragraph (20) above; X1 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 en; and Q3 is as defined in paragraph (68).

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(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidinyl)chloro-N-methyl-1H- indolecarboxamide; minoisopropyl-1H-pyrazolo[3,4-d]pyrimidinyl)-N-methyl-1H-indole carboxamide; 2-(4-Amino(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidinyl)-N-(1-methyl-1H-pyrazol yl)-1H-indolecarboxamide; or 2-(4-Amino(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidinyl)-N-methyl-1H-indole amide.

Further particular nds of the present ion 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: mino(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidinyl)chloro-N-methyl-1H- indolecarboxamide; 2-(4-Aminoisopropyl-1H-pyrazolo[3,4-d]pyrimidinyl)-N-methyl-1H-indole carboxamide; 2-(4-Amino(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidinyl)-N-(1-methyl-1H-pyrazol yl)-1H-indolecarboxamide; 2-(4-Amino(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidinyl)-N-methyl-1H-indole carboxamide; 2-(4-Aminoisopropyl-1H-pyrazolo[3,4-d]pyrimidinyl)chloro-N-methyl-1H- indolecarboxamide; 2-(4-Aminoisopropyl-7H-pyrrolo[2,3-d]pyrimidinyl)-N-methyl-1H-indole carboxamide; 2-(4-aminoisopropyl-7H-pyrrolo[2,3-d]pyrimidinyl)chloro-N-methyl-1H-indole- 6-carboxamide; 2-(4-amino(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidinyl)bromo-N-methyl-1H- indolecarboxamide; or 2-(8-aminoisopropylimidazo[1,5-a]pyrazinyl)chloro-N-methyl-1H-indole carboxamide.

Further particular compounds of the present invention e any of the compounds exemplified in the present application, or a pharmaceutically able salt or solvate f, and, in particular, any of the ing: 2-(4-Aminoisopropyl-pyrazolo[3,4-d]pyrimidinyl)-N-methyl-1H-indole carboxamide; 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidinyl)-N-methyl-1H-indole carboxamide; 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidinyl)-N-(1-methylpyrazolyl)-1H- indolecarboxamide; 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidinyl)-1H-indolecarboxamide; 2-(4-Aminoisopropyl-pyrazolo[3,4-d]pyrimidinyl)chloro-N-methyl-1H-indole carboxamide; 2-(4-Amino(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidinyl)bromo-N-methyl-1H- indolecarboxamide; 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidinyl)chloro-N-(2-methoxyethyl)- 1H-indolecarboxamide; 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidinyl)chloro-N-[2- (dimethylamino)ethyl]-1H-indolecarboxamide; 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidinyl)chloro-N-(2-morpholinoethyl)- 1H-indolecarboxamide; 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidinyl)chloro-N-(3- morpholinopropyl)-1H-indolecarboxamide; 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidinyl)chloro-N-methoxy-1H-indole- 6-carboxamide; [2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidinyl)chloro-1H-indolyl]- pyrrolidinyl-methanone; 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidinyl)chloro-N,N-dimethyl-1H- indolecarboxamide; 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidinyl)chloro-N-[2-(2- methoxyethoxy)ethyl]-1H-indolecarboxamide; minotert-butyl-pyrazolo[3,4-d]pyrimidinyl)chloro-N-(3-methoxypropyl)- 1H-indolecarboxamide; 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidinyl)chloro-N-(2-hydroxyethyl)-1H- indolecarboxamide; 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidinyl)chloro-N-[2-(2- morpholinoethoxy)ethyl]-1H-indolecarboxamide; 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidinyl)chloro-N-[2-[2- hylamino)ethoxy]ethyl]-1H-indolecarboxamide; 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidinyl)chloro-N-[3- (dimethylamino)propyl]-1H-indolecarboxamide; 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidinyl)chloro-N-[3-(1- piperidyl)propyl]-1H-indolecarboxamide; 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidinyl)chloro-N-(3- isopropoxypropyl)-1H-indolecarboxamide; 2-[4-Amino(2-hydroxyethyl)pyrazolo[3,4-d]pyrimidinyl]chloro-N-methyl-1H- carboxamide; 2-[4-Amino(3-methoxypropyl)pyrazolo[3,4-d]pyrimidinyl]chloro-N-methyl-1H- indolecarboxamide; 2-[4-Amino(1-methylsulfonylpiperidyl)pyrazolo[3,4-d]pyrimidinyl]chloro-N- methyl-1H-indolecarboxamide; 2-(4-Aminomethyl-pyrazolo[3,4-d]pyrimidinyl)chloro-N-methyl-1H-indole carboxamide; 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidinyl)chloro-N-[1-(2- methoxyethyl)pyrazolyl]-1H-indolecarboxamide; 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidinyl)chloro-N-[1-(2- morpholinoethyl)pyrazolyl]-1H-indolecarboxamide; minotert-butyl-pyrazolo[3,4-d]pyrimidinyl)chloro-N-[1-[2- (dimethylamino)ethyl]pyrazolyl]-1H-indolecarboxamide; 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidinyl)chloro-N-[1-[2-(4- methylpiperazinyl)ethyl]pyrazolyl]-1H-indolecarboxamide; 2-[4-Amino(2-aminoethyl)pyrazolo[3,4-d]pyrimidinyl]chloro-N-methyl-1H- indolecarboxamide; 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidinyl)chloro-N-[1-(2- hydroxyethyl)pyrazolyl]-1H-indolecarboxamide; 2-{4-Aminocyclobutyl-1H-pyrazolo[3,4-d]pyrimidinyl}chloro-N-methyl-1H- indolecarboxamide; minocyclohexyl-1H-pyrazolo[3,4-d]pyrimidinyl}-N-methyl-1H-indole carboxamide; minocyclopentyl-1H-pyrazolo[3,4-d]pyrimidinyl}-N-methyl-1H-indole carboxamide; 2-(4-Aminoisopropyl-7H-pyrrolo[2,3-d]pyrimidinyl)-N-methyl-1H-indole carboxamide; 2-(8-Aminoisopropylimidazo[1,5-a]pyrazinyl)chloro-N-methyl-1H-indole carboxamide; 2-(8-Aminoisopropyl-imidazo[1,5-a]pyrazinyl)-N-methyl-1H-indole carboxamide; 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidinyl)-N-methyl-3H-benzimidazole carboxamide; 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidinyl)fluoro-N-methyl-1H-indole carboxamide; 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidinyl)chloro-N-methyl-1H-indole carboxamide; 2-(4-Aminocyclohexyl-1H-pyrazolo[3,4-d]pyrimidinyl)chloro-N-methyl-1H- indolecarboxamide; 2-(4-aminoisopropyl-7H-pyrrolo[2,3-d]pyrimidinyl)chloro-N-methyl-1H-indole- 6-carboxamide; 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidinyl)chloro-1H-indolecarboxylic acid; 2-{4-Aminotert-butyl-1H-pyrazolo[3,4-d]pyrimidinyl}chloro-N-(oxanyl)-1H- carboxamide; 2-{4-Aminotert-butyl-1H-pyrazolo[3,4-d]pyrimidinyl}chloro-N-(propanyl)- 1H-indolecarboxamide; 2-{4-Aminotert-butyl-1H-pyrazolo[3,4-d]pyrimidinyl}chloro-N-ethyl-1H-indole- 6-carboxamide; 2-{4-Aminotert-butyl-1H-pyrazolo[3,4-d]pyrimidinyl}chloro-N-cyclopropyl-1H- indolecarboxamide; 2-{4-Aminotert-butyl-1H-pyrazolo[3,4-d]pyrimidinyl}chloro-N-phenyl-1H- carboxamide; 2-[4-Amino(propanyl)-1H-pyrazolo[4,3-c]pyridinyl]-N-methyl-1H-indole carboxamide; 2-[4-Amino(propanyl)-1H-pyrazolo[4,3-c]pyridinyl]chloro-N-methyl-1H- indolecarboxamide; 2-[4-Amino(propanyl)-1H-pyrazolo[4,3-c]pyridinyl]bromo-N-methyl-1H- indolecarboxamide; 2-{4-Aminothieno[2,3-d]pyrimidinyl}chloro-N-methyl-1H-indolecarboxamide; 2-{4-Aminothieno[2,3-d]pyrimidinyl}-N-methyl-1H-indolecarboxamide; mino(propanyl)pyrrolo[2,1-f][1,2,4]triazinyl]-N-methyl-1H-indole carboxamide; 2-[4-Amino(propanyl)pyrrolo[2,1-f][1,2,4]triazinyl]chloro-N-methyl-1H- indolecarboxamide; 2-[4-Amino(propanyl)imidazo[4,3-f][1,2,4]triazinyl]chloro-N-methyl-1H- indolecarboxamide; 2-[4-Aminochloro(propanyl)-1H-pyrazolo[4,3-c]pyridinyl]-N-methyl-1H- indolecarboxamide; 2-{4-Aminotert-butyl-1H-pyrazolo[3,4-d]pyrimidinyl}chloro-N-methyl-1H- pyrrolo[2,3-b]pyridinecarboxamide; 2-{4-Aminotert-butyl-1H-pyrazolo[3,4-d]pyrimidinyl}-N-methyl-1H-pyrrolo[2,3- b]pyridinecarboxamide; 2-(4-Amino(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidinyl)methyl-1H-indole carboxylic acid; 2-(4-Amino(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidinyl)chloro-N-methyl-1H- indolecarboxamide; N-(2-{4-Aminotert-butyl-1H-pyrazolo[3,4-d]pyrimidinyl}-1H-indolyl)acetamide; 1-(2-{4-Aminotert-butyl-1H-pyrazolo[3,4-d]pyrimidinyl}chloro-1H-indol yl)propanone; 2-{4-Aminotert-butyl-1H-pyrazolo[3,4-d]pyrimidinyl}-N,1-dimethyl-1H-indole carboxamide; 2-(4-Amino(1-methylpiperidinyl)-1H-pyrazolo[3,4-d]pyrimidinyl)chloro-N- cyclopropyl-1H-indolecarboxamide; 3-[3-Chloro(1,3,4-thiadiazolyl)-1H-indolyl]isopropyl-pyrazolo[3,4- d]pyrimidinamine; 3-(3-Chlorooxazolyl-1H-indolyl)isopropyl-pyrazolo[3,4-d]pyrimidin amine; 1-Isopropyl[6-(1,3,4-thiadiazolyl)-1H-indolyl]pyrazolo[3,4-d]pyrimidin amine; or ropyl(6-oxazolyl-1H-indolyl)pyrazolo[3,4-d]pyrimidinamine.

Further particular compounds of the present invention include any of the nds ified in the present application, or a pharmaceutically acceptable salt or solvate thereof, and, in particular, any of the following: 2-(4-Aminoisopropyl-pyrazolo[3,4-d]pyrimidinyl)chloro-N-methyl-1H-indole amide; 2-(4-Amino(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidinyl)bromo-N-methyl-1H- indolecarboxamide; 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidinyl)chloro-N-(2-methoxyethyl)- 1H-indolecarboxamide; 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidinyl)chloro-N-[2- (dimethylamino)ethyl]-1H-indolecarboxamide; 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidinyl)chloro-N-(2-morpholinoethyl)- 1H-indolecarboxamide; 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidinyl)chloro-N-(3- morpholinopropyl)-1H-indolecarboxamide; 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidinyl)chloro-N-methoxy-1H-indole- 6-carboxamide; [2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidinyl)chloro-1H-indolyl]- pyrrolidinyl-methanone; 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidinyl)chloro-N,N-dimethyl-1H- indolecarboxamide; 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidinyl)chloro-N-[2-(2- methoxyethoxy)ethyl]-1H-indolecarboxamide; minotert-butyl-pyrazolo[3,4-d]pyrimidinyl)chloro-N-(3-methoxypropyl)- 1H-indolecarboxamide; 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidinyl)chloro-N-(2-hydroxyethyl)-1H- indolecarboxamide; 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidinyl)chloro-N-[2-(2- morpholinoethoxy)ethyl]-1H-indolecarboxamide; 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidinyl)chloro-N-[2-[2- (dimethylamino)ethoxy]ethyl]-1H-indolecarboxamide; 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidinyl)chloro-N-[3- (dimethylamino)propyl]-1H-indolecarboxamide; 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidinyl)chloro-N-[3-(1- piperidyl)propyl]-1H-indolecarboxamide; minotert-butyl-pyrazolo[3,4-d]pyrimidinyl)chloro-N-(3- poxypropyl)-1H-indolecarboxamide; 2-[4-Amino(2-hydroxyethyl)pyrazolo[3,4-d]pyrimidinyl]chloro-N-methyl-1H- indolecarboxamide; 2-[4-Amino(3-methoxypropyl)pyrazolo[3,4-d]pyrimidinyl]chloro-N-methyl-1H- indolecarboxamide; 2-[4-Amino(1-methylsulfonylpiperidyl)pyrazolo[3,4-d]pyrimidinyl]chloro-N- methyl-1H-indolecarboxamid; 2-(4-Aminomethyl-pyrazolo[3,4-d]pyrimidinyl)chloro-N-methyl-1H-indole carboxamide; 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidinyl)chloro-N-[1-(2- methoxyethyl)pyrazolyl]-1H-indolecarboxamide; 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidinyl)chloro-N-[1-(2- morpholinoethyl)pyrazolyl]-1H-indolecarboxamide; 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidinyl)chloro-N-[1-[2- (dimethylamino)ethyl]pyrazolyl]-1H-indolecarboxamide; 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidinyl)chloro-N-[1-[2-(4- methylpiperazinyl)ethyl]pyrazolyl]-1H-indolecarboxamide; 2-[4-Amino(2-aminoethyl)pyrazolo[3,4-d]pyrimidinyl]chloro-N-methyl-1H- carboxamide; 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidinyl)chloro-N-[1-(2- hydroxyethyl)pyrazolyl]-1H-indolecarboxamide; 2-{4-Aminocyclobutyl-1H-pyrazolo[3,4-d]pyrimidinyl}chloro-N-methyl-1H- indolecarboxamide; 2-(8-Aminoisopropylimidazo[1,5-a]pyrazinyl)chloro-N-methyl-1H-indole carboxamide; 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidinyl)fluoro-N-methyl-1H-indole carboxamide; 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidinyl)chloro-N-methyl-1H-indole carboxamide; minocyclohexyl-1H-pyrazolo[3,4-d]pyrimidinyl)chloro-N-methyl-1H- indolecarboxamide; 2-(4-aminoisopropyl-7H-pyrrolo[2,3-d]pyrimidinyl)chloro-N-methyl-1H-indole- 6-carboxamide; 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidinyl)chloro-1H-indolecarboxylic acid; 2-{4-Aminotert-butyl-1H-pyrazolo[3,4-d]pyrimidinyl}chloro-N-(oxanyl)-1H- indolecarboxamide; minotert-butyl-1H-pyrazolo[3,4-d]pyrimidinyl}chloro-N-(propanyl)- 1H-indolecarboxamide; 2-{4-Aminotert-butyl-1H-pyrazolo[3,4-d]pyrimidinyl}chloro-N-ethyl-1H-indole- 6-carboxamide; 2-{4-Aminotert-butyl-1H-pyrazolo[3,4-d]pyrimidinyl}chloro-N-cyclopropyl-1H- indolecarboxamide; 2-{4-Aminotert-butyl-1H-pyrazolo[3,4-d]pyrimidinyl}chloro-N-phenyl-1H- indolecarboxamide; 2-[4-Amino(propanyl)-1H-pyrazolo[4,3-c]pyridinyl]chloro-N-methyl-1H- indolecarboxamide; 2-[4-Amino(propanyl)-1H-pyrazolo[4,3-c]pyridinyl]bromo-N-methyl-1H- carboxamide; 2-{4-Aminothieno[2,3-d]pyrimidinyl}chloro-N-methyl-1H-indolecarboxamide; 2-[4-Amino(propanyl)pyrrolo[2,1-f][1,2,4]triazinyl]chloro-N-methyl-1H- indolecarboxamide; 2-[4-Amino(propanyl)imidazo[4,3-f][1,2,4]triazinyl]chloro-N-methyl-1H- indolecarboxamide; 2-{4-Aminotert-butyl-1H-pyrazolo[3,4-d]pyrimidinyl}chloro-N-methyl-1H- pyrrolo[2,3-b]pyridinecarboxamide; 1-(2-{4-Aminotert-butyl-1H-pyrazolo[3,4-d]pyrimidinyl}chloro-1H-indol yl)propanone; 2-(4-Amino(1-methylpiperidinyl)-1H-pyrazolo[3,4-d]pyrimidinyl)chloro-N- cyclopropyl-1H-indolecarboxamide; 3-[3-Chloro(1,3,4-thiadiazolyl)-1H-indolyl]isopropyl-pyrazolo[3,4- d]pyrimidinamine; or 3-(3-Chlorooxazolyl-1H-indolyl)isopropyl-pyrazolo[3,4-d]pyrimidin amine.

Further particular nds of the present ion include any of the compounds exemplified in the present application, or a pharmaceutically acceptable salt or solvate f, and, in particular, any of the following: 2-(4-Aminoisopropyl-pyrazolo[3,4-d]pyrimidinyl)-N-methyl-1H-indole carboxamide; 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidinyl)-N-methyl-1H-indole carboxamide; 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidinyl)-N-(1-methylpyrazolyl)-1H- carboxamide; 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidinyl)-1H-indolecarboxamide; 2-{4-Aminocyclohexyl-1H-pyrazolo[3,4-d]pyrimidinyl}-N-methyl-1H-indole amide; 2-{4-Aminocyclopentyl-1H-pyrazolo[3,4-d]pyrimidinyl}-N-methyl-1H-indole carboxamide; 2-(4-Aminoisopropyl-7H-pyrrolo[2,3-d]pyrimidinyl)-N-methyl-1H-indole carboxamide; 2-(8-Aminoisopropyl-imidazo[1,5-a]pyrazinyl)-N-methyl-1H-indole carboxamide; 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidinyl)-N-methyl-3H-benzimidazole carboxamide; 2-[4-Amino(propanyl)-1H-pyrazolo[4,3-c]pyridinyl]-N-methyl-1H-indole carboxamide; 2-{4-Aminothieno[2,3-d]pyrimidinyl}-N-methyl-1H-indolecarboxamide; 2-[4-Amino(propanyl)pyrrolo[2,1-f][1,2,4]triazinyl]-N-methyl-1H-indole carboxamide; minochloro(propanyl)-1H-pyrazolo[4,3-c]pyridinyl]-N-methyl-1H- indolecarboxamide; 2-{4-Aminotert-butyl-1H-pyrazolo[3,4-d]pyrimidinyl}-N-methyl-1H-pyrrolo[2,3- b]pyridinecarboxamide; 2-(4-Amino(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidinyl)methyl-1H-indole carboxylic acid; 2-(4-Amino(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidinyl)chloro-N-methyl-1H- indolecarboxamide; N-(2-{4-Aminotert-butyl-1H-pyrazolo[3,4-d]pyrimidinyl}-1H-indolyl)acetamide; 2-{4-Aminotert-butyl-1H-pyrazolo[3,4-d]pyrimidinyl}-N,1-dimethyl-1H-indole carboxamide; 1-Isopropyl[6-(1,3,4-thiadiazolyl)-1H-indolyl]pyrazolo[3,4-d]pyrimidin amine; or 1-Isopropyl(6-oxazolyl-1H-indolyl)pyrazolo[3,4-d]pyrimidinamine.

The various onal groups and substituents making up the compounds of the Formula (I), and sub-formulae Ia 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 ably, the molecular weight is less than 600 and, for example, is 550 or less.

A suitable pharmaceutically acceptable salt of a compound of the ion 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 e, an inorganic or organic acid, for example hydrochloric, hydrobromic, ic, phosphoric, trifluoroacetic, formic, citric methane sulfonate or maleic acid. In addition, a suitable pharmaceutically acceptable salt of a compound of the ion 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 um 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.

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". isomers 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 le. 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 zed 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 ion may possess one or more tric centers; such compounds can therefore be produced as individual (R)- or (S)-stereoisomers or as es thereof. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both dual 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 c 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 ric isomers and mixtures thereof that possess antiproliferative activity.

The present invention also asses compounds of the invention as defined herein which comprise one or more isotopic tutions. For example, H may be in any isotopic form, including 1H, 2H(D), and 3H (T); C may be in any isotopic form, including 12C, 13C, and 14C; and O may be in any isotopic form, including 16O and18O; and the like.

It is also to be understood that certain compounds of the Formula (I), or sub-formulae Ia 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.

It is also to be understood that certain compounds of the Formula I, or sub-formulae Ia to Ig, may exhibit polymorphism, and that the invention encompasses all such forms that possess antiproliferative activity.

Compounds of the Formula I, and sub-formulae Ia to Ig, may exist in a number of different tautomeric forms and references to compounds of the Formula I, and rmulae Ia 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 Ia to Ig. Examples of tautomeric forms include keto-, enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto/enol trated below), enamine, amide/imino alcohol, e/amidine, nitroso/oxime, thioketone/enethiol, and aci-nitro.

H O OH H+ OC C C C C C keto enol enolate ] Compounds of the Formula I, and sub-formulae Ia to Ig, containing an amine function may also form N-oxides. A nce herein to a compound of the Formula I, or sub-formulae Ia 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 es of a tertiary amine or a en 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 id (e.g. a peroxycarboxylic acid), see for example Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages. More particularly, es 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.

The compounds of Formula (I), and sub-formulae Ia 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 ion. A pro-drug may be used to alter the physical properties and/or the pharmacokinetic properties of a nd of the invention. A pro-drug can be formed when the compound of the invention contains a suitable group or substituent to which a propertymodifying group can be attached. Examples of pro-drugs include in vivo ble ester derivatives that may be formed at a carboxy group or a hydroxy group in a compound of the Formula (I), or sub-formulae Ia to Ig, and o cleavable amide derivatives that may be formed at a carboxy group or an amino group in a compound of the Formula (I), or subformulae Ia to Ig.

Accordingly, the present invention includes those nds of the Formula (I), and sub-formulae Ia to Ig, as defined before, 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 es those compounds of the Formula I, and sub-formulae Ia 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 nd of the Formula (I) or sub-formulae Ia 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 Ia 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 ty.

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. mic Press, 1985); b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985); c) A ok of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 "Design and Application of Pro-drugs", by H. Bundgaard p. 113-191 (1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H. Bundgaard, et al., Journal of ceutical 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 ry s", A.C.S. Symposium Series, Volume 14; and h) E. Roche (editor), "Bioreversible Carriers in Drug Design", Pergamon Press, 1987.

A suitable pharmaceutically able pro-drug of a compound of the a I, or sub-formulae Ia 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 Ia 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 kyl esters such as methyl, ethyl and tert-butyl, C1-6alkoxymethyl esters such as methoxymethyl esters, C1-6alkanoyloxymethyl esters such as pivaloyloxymethyl esters, 3-phthalidyl esters, C3-8cycloalkylcarbonyloxy- C1-6alkyl esters such as cyclopentylcarbonyloxymethyl and 1-cyclohexylcarbonyloxyethyl esters, 1,3-dioxolenylmethyl esters such as 5-methyloxo-1,3-dioxolenylmethyl 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 rmulae Ia 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 Ia 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 e C1-10alkanoyl groups such as acetyl, l, phenylacetyl and substituted benzoyl and phenylacetyl , C1-10alkoxycarbonyl groups such as ethoxycarbonyl, N,N –(C1-6)2carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N- alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazinylmethyl and 4- (C1-4alkyl)piperazinylmethyl. Suitable pharmaceutically acceptable ether forming groups for a hydroxy group include α-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.

] A suitable pharmaceutically acceptable pro-drug of a compound of the Formula (I), or rmulae Ia 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 koxy- C2-4alkylamine such as 2-methoxyethylamine, a phenyl-C1-4alkylamine such as benzylamine and amino acids such as glycine or an ester thereof.

A suitable ceutically able pro-drug of a nd of the Formula I, or sub-formulae Ia 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 acetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N- dialkylaminomethyl, morpholinomethyl, piperazinylmethyl and 4-(C1-4alkyl)piperazinylmethyl.

The in vivo effects of a compound of the Formula (I), or sub-formulae Ia 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 Ia to Ig. As stated hereinbefore, the in vivo s of a compound of the a (I), or sub-formulae Ia to Ig, may also be exerted by way of metabolism of a precursor compound (a ug).

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 ically excludes said optional, preferred or suitable features or particular embodiments. ] ly, the present invention excludes any individual compounds not possessing the biological activity defined herein.

Synthesis ] The nds of the present ion 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.

In the description of the synthetic methods bed herein and in any referenced synthetic methods that are used to prepare the starting materials, it is to be tood 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.

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.

It will be iated that during the synthesis of the compounds of the invention in the processes defined herein, or during the synthesis of certain starting als, 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.

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). ting groups may be removed by any ient method described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in on, such methods being chosen so as to effect removal of the protecting group with the minimum bance of groups elsewhere in the molecule.

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.

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 ide.

Alternatively an acyl group such as a tert-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, ic or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a oxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as ium-on-carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate). A suitable alternative protecting group for a y amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for e 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 l, or an thyl group, for example benzyl. The deprotection ions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for e, 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.

A suitable protecting group for a carboxy group is, for example, an fying 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.

Resins may also be used as a protecting group.

The methodology employed to synthesise a compound of Formula (I) will vary depending on the nature of HET, R1, R1a, R1b, W, X1, X2, X3, X4, R2 and R3 and any substituent groups associated therewith. Suitable processes for their preparation are described further in the accompanying Examples.

Once a compound of Formula (I) has been synthesised by any one of the processes d 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) g a prodrug thereof.

An e of (ii) above is when a compound of formula (I) is synthesised and then one or more of the groups of HET, R1, R1a, R1b, W, X1, X2, X3, X4, R2 and R3, may be further d 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 en.

The resultant compounds of formula (I) can be isolated and purified using techniques well known in the art.

Biological ty The biological assays described in the Examples n herein may be used to measure the pharmacological effects of the compounds of the present invention. gh 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 bed in the Examples section.

In general, the nds of the invention demonstrate an IC50 of 1 µM 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 ion demonstrating an IC50 of 50 nM or less.

Suitably the ratio of RET activity to KDR activity ed in the RET and KDR assays set out in the Examples section herein is greater than 5, more suitably greater than , yet more suitably greater than 25, and most suitably greater than 100.

In the RETV804M enzyme assay described herein in the Examples section, the compounds of Formula I suitably possess an activity of less than 1 μM, 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.

In the RET cell assay described herein in the Examples section, the compounds of Formula I suitably possess an activity of less than 1 μM, with the preferred compounds demonstrating an activity of 250 nM or less and the most preferred nds of the ion demonstrating an IC50 of 100 nM or less.

In the 4M cell assay described herein in the Examples section, the compounds of Formula I suitably possess an activity of less than 1 μM, 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 red compounds of the invention demonstrating an IC50 of 50 nM or less.

The following compounds were tested but did not exhibit the desired activity in the assays described in the Examples section hereinbelow: 2-(4-aminotert-butyl-pyrazolo[3,4-d]pyrimidinyl)-N-methyl-1H-indolecarboxamide; 2-{4-aminotert-butyl-1H-pyrazolo[3,4-d]pyrimidinyl}chloro-N-cyclohexyl-1H-indole carboxamide; 2-{4-aminotert-butyl-1H-pyrazolo[3,4-d]pyrimidinyl}chloro-N-(1-methylpiperidinyl)- 1H-indolecarboxamide.

Pharmaceutical Compositions 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 f, in association with a pharmaceutically acceptable diluent or carrier.

The itions of the invention may be in a form le 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 stration 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).

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 e, one or more colouring, sweetening, flavouring and/or preservative agents.

An effective amount of a nd 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 ient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the individual treated and the ular route of administration. For example, a formulation intended for oral administration to humans will generally n, for e, 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 ient 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 ing to the nature and severity of the ions, the age and sex of the animal or patient and the route of administration, according to nown principles of medicine.

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 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 ed selectivity for RET, or mutant forms thereof (e.g. RET V804M ), ve to KDR (i.e. they are potent tors of RET and poor tors 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 t in need of such treatment, said method comprising stering to said patient a therapeutically effective amount of a compound, or a ceutically able 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 ting a cell with an effective amount of a compound, or a pharmaceutically able salt, hydrate or solvate thereof, as defined herein.

The present invention es a method of treating a proliferative er in a t 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 e thereof, or a ceutical composition as defined herein.

The present invention es a method of treating cancer in a patient in need of such treatment, said method comprising administering to said patient a eutically effective amount of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein.

The present invention es a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a ceutical 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 f, or a pharmaceutical composition as defined herein for use in the ent of cancer. In a particular embodiment, the cancer is human cancer.

The t invention provides a compound, or a pharmaceutically acceptable salt, e 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, e 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 e 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 es a use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein in the manufacture of a ment for the treatment of cancer. Suitably, the medicament is for use in the treatment of human cancers.

The present invention es a use of a nd, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein in the manufacture of a medicament for the tion of RET kinase enzyme activity, or mutant forms thereof (e.g.

RETV804M ).

The present invention provides a use of a compound, or a pharmaceutically able salt, hydrate or solvate thereof, as defined herein in the manufacture of a medicament for the ive 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 ty is ated.

The term "proliferative disorder" are used hangeably 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, ing but not limited to, malignant neoplasms and tumours, s, leukemias, psoriasis, bone es, 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, te, 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 ty).

] 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).

In a particular embodiment of the invention, the proliferative condition to be d is cancer, for example medullary thyroid cancer (MTC) or all cell lung cancer (NSCLC).

Routes of Administration 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 d action).

Routes of administration include, but are not limited to, oral (e.g, by ingestion); buccal; gual; transdermal ding, e.g., by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); asal (e.g., by nasal spray); ocular (e.g., by eye drops); ary (e.g., by inhalation or insufflation therapy using, e.g., via an l, 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, racheal, subcuticular, intraarticular, subarachnoid, and intrasternal; by implant of a depot or reservoir, for example, subcutaneously or intramuscularly.

Combination Therapies The antiproliferative treatment defined hereinbefore may be applied as a sole y or may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy. Such chemotherapy may e 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 atin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan, temozolamide and oureas); antimetabolites (for example gemcitabine and antifolates such as fluoropyrimidines like 5-fluorouracil and r, rexed, methotrexate, cytosine arabinoside, and hydroxyurea); antitumour otics (for example anthracyclines like adriamycin, cin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids like vincristine, vinblastine, vindesine and lbine 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, trant, toremifene, raloxifene, droloxifene and iodoxyfene), antiandrogens (for example tamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, relin and buserelin), progestogens (for example megestrol e), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5α-reductase such as finasteride; (iii) anti-invasion agents [for example c-Src kinase family inhibitors like 4-(6-chloro-2,3- methylenedioxyanilino)[2-(4-methylpiperazinyl)ethoxy]tetrahydropyran yloxyquinazoline 30; International Patent Application WO 01/94341), N-(2-chloro methylphenyl){6-[4-(2-hydroxyethyl)piperazinyl]methylpyrimidinylamino}thiazole- -carboxamide (dasatinib, BMS-354825; J. Med. Chem., 2004, 47, 661) 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 dy 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 N-(3-chloro fluorophenyl)methoxy(3-morpholinopropoxy)quinazolinamine (gefitinib, ZD1839), N- (3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolinamine (erlotinib, OSI-774) and 6- mido-N-(3-chlorofluorophenyl)(3-morpholinopropoxy)-quinazolinamine (CI 1033), erbB2 tyrosine kinase inhibitors such as lapatinib); inhibitors of the hepatocyte growth factor family; tors of the insulin growth factor family; inhibitors of the platelet-derived growth factor family such as imatinib and/or nilotinib (AMN107); tors of serine/threonine kinases (for example Ras/Raf signalling tors such as farnesyl transferase inhibitors, for example sorafenib (BAY 43-9006), tipifarnib 77) and lonafarnib 336)), inhibitors of cell signalling through MEK and/or AKT kinases, c-kit inhibitors, abl kinase inhibitors, PI3 kinase inhibitors, Plt3 kinase inhibitors, CSF-1R kinase inhibitors, IGF or (insulin-like growth factor) kinase inhibitors; aurora kinase inhibitors (for example 2, PH739358, VX-680, MLN8054, R763, MP235, MP529, VX-528 AND AX39459) and cyclin dependent kinase inhibitors such as CDK2 and/or CDK4 tors; (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-fluoromethylindolyloxy)methoxy(3-pyrrolidin ylpropoxy)quinazoline (AZD2171; Example 240 within WO 00/47212), compounds such as those disclosed in International Patent Applications WO97/22596, WO 97/30035, WO 97/32856 and WO 98/13354 and compounds that work by other mechanisms (for example linomide, inhibitors of integrin αvβ3 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 ntan (ZD4054) or atrasentan; (viii) antisense therapies, for e those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense; (ix) gene y approaches, including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT (gene-directed enzyme ug therapy) ches 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 genicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, eukin 4 or ocyte-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.

In a particular embodiment, the antiproliferative treatment defined hereinbefore may involve, in addition to the compound of the invention, tional y or radiotherapy or chemotherapy, wherein the chemotherapy may e 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 ts employ the compounds of this invention within the dosage range described hereinbefore and the other ceutically-active agent within its ed dosage range.

] According to this aspect of the ion 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.

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 ceutically acceptable salt, hydrate or solvate thereof, and any one of the anti-tumour agents listed herein above.

In a further aspect of the invention there is ed 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.

Herein, where the term "combination" is used it is to be understood that this refers to aneous, 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 nation" 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.

According to a r aspect of the invention there is provided a ceutical composition which comprises a compound of the invention, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in ation 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 CDCl3 Chloroform DMAP 4-(dimethylamino) pyridine DCM Dichloromethane (methylene chloride) DIPEA N,N,-di-isopropyethylamine, Hunig’s base DMF methylformamide DMSO Dimethylsulfoxide.

EDCI.HCl 1-Ethyl(3-dimethylaminopropyl)carbodiimide hydrochloride EtBr Ethylbromide (bromoethane) EtOAc Ethyl acetate EtOH Ethanol (ethyl alcohol) Fcc Flash column chromatography HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3- oxid hexafluorophosphate) HCl Hydrochloric acid HPLC High Pressure Liquid Chromatography Hz Hertz J Coupling constant K2CO3 ium ate KOAc Potassium acetate LCMS Liquid Chromatography-Mass Spectrometry LiOH.H2O Lithium hydroxide monohydrate m let MeOH Methanol (methyl alcohol) MgSO4 Magnesium sulphate MHz Mega hertz N2 Nitrogen NaHCO3 Sodium Bicarbonate Na2SO4 Sodium sulphate NH4Cl Ammonium chloride NMR Nuclear Magnetic Resonance POCl3 Phosphorus oxychloride q t s singlet t triplet THF ydrofuran 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(II) METHODS l Experimental Flash column chromatography refers to automated tography using pre- packed silica cartridges.

Generally, in the experimental procedures described hereinbelow, flash chromatography was performed using pre-packed silica gel cartridge and thin layer chromatography was ted with 5 × 10 cm plates coated with Merck Type 60 F254 silica gel to a thickness of 0.25 mm. Typically, reagents obtained from cial sources were used without further purification unless stated otherwise. Anhydrous solvents were commonly obtained from the Sigma-Aldrich al Company Ltd. or Fisher Chemicals Ltd., and used without further drying. HPLC grade solvents were predominately obtained from Fisher Chemicals Ltd. 1H NMR spectroscopy was carried out using s spectrometers in the stated solvent at room temperature unless stated otherwise. In all cases, NMR data were consistent with the proposed ure. 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.

Generally, in the experimental procedures described hereinbelow, proton (1H) NMR a were recorded on a 300 MHz or 400 MHz Bruker spectrometer. Solutions were typically prepared in either deuterochloroform (CDCl3) 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 It will be appreciated that various LC-MS conditions may be used in the analysis of the compounds of the t invention. Examples of some non-limiting LC-MS conditions are provided below.

Illustrative LC-MS conditions LC-MS analyses may be performed on, for example, a Waters Acquity UPLC system fitted with BEH C18 1.7 µM columns (2.1 × 50 mm or 2.1 × 100 mm), with UV diode array ion 00 nm). Positive and negative mass ion detection may also be performed using, for example, a Waters SQD detector. es may then be performed with either buffered acidic or basic solvents, using nts such as those detailed below.

Examples of suitable solvent gradients Low pH: Solvent A – Water + 10mM ammonium e + 0.1% formic acid Solvent B – Acetonitrile + 5% water + 0.1% formic acid High pH: Solvent A – Water + 10mM ammonium en carbonate + 0.1% a 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 ] Preparative HPLC refers to mass-directed reverse-phase chromatography using various water:MeCN eluent gradients. It will be appreciated that various preparative HPLC es and/or conditions may be used to purify the nds of the present invention, and the person skilled in the art will be well versed in selecting appropriate ions for each respective compound. Nonetheless, details of some non-limiting examples of suitable HPLC conditions are provided below.

Illustrative preparative HPLC conditions Compounds may be purified by preparative HPLC on, for e, a Waters FractionLynx MS autopurification system, with a column such as a Waters XBridge 5 µm C18, 100 mm × 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 s may then be assessed using a -50 μL test injection and a standard gradient, and then purified using an appropriately chosen focussed gradient as detailed below, based upon observed retention time.

Some typically examples of suitable solvent nts include: Low pH: Solvent A – Water + 10mM ammonium e + 0.1% formic acid t B – Acetonitrile + 5% water +0.1% formic acid High pH: Solvent A – Water + 10mM ammonium formate + 0.1% ammonia solution t 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: % Solvent B Retention time on rd gradient (min.) Time Flow rate 0 – 5.2 4.9 – 6.6 6.3 – 7.5 7.3 – 9.5 9.3 - 12 (mL/min) 0 20 10 10 10 10 10 0.25 20 10 10 10 10 10 0.35 20 10 20 35 45 60 20 45 55 65 75 98 12 20 98 98 98 98 98 12.5 0 98 98 98 98 98 Synthetic methods ] 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.

] Where the preparation of starting materials is not bed, 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 ts and temperature can be modified for each specific reaction and that it may be desirable or necessary to employ ent reagents, catalysts, work-up or purification techniques.

General Synthetic Schemes Scheme 1 – Preparation of Indolyl Pyrazolopyrimidines D Substituted pyrazolopyrimidines C were ed either via the known 3-step procedure from an riately 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 l c acid derivatives (General Method 4) returned product D. Where necessary, further elaboration was conducted.

Scheme 2 – Elaboration of Indolyl Pyrazolopyrimidines O O R2 O O N H O NH2 NH X NH2 NH NH2 NSEM N N N N N N N N N N N N R1 R1 H E F G Elaboration of esters E to amides F (where X = H, Cl, 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 = Cl, 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 al Method 9).

General Methods for Intermediates and Examples ] 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 HCl or TFA was included if deprotection did not occur thermally under the reaction conditions.

General Method 1 – representative procedure ocyclohexyl-1H-pyrazolo[3,4-d]pyrimidinamine Step 1 To a mixture of Et3N (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 e was taken up in EtOAc (50 mL) and washed with water (2 × 25 mL). The organic phase was dried over MgSO4, filtered and trated in vacuo to return ocyclohexyl-pyrazolecarbonitrile (1.95 g, 103%) as an orange solid which was used without further purification. 1H NMR (300 MHz, CDCl3) δ 7.49 (s, 1H), 4.45 (s, 2H), 3.77 (tt, J = 11.2, 4.2 Hz, 1H), 1.88 (ddt, J = 17.4, 11.4, .4 Hz, 6H), 1.83-1.65 (m, 1H), 1.49-1.32 (m, 1H), 1.38-1.15 (m, 2H).

Step 2 A suspension of 5-aminocyclohexyl-pyrazolecarbonitrile (1.95 g, 10 mmol) in formamide (15 mL) was heated at 180 oC for 1 hour in the MW. The reaction was cooled to room temperature then diluted with water (50 mL) and extracted with EtOAc (3 × 50 mL). The combined organics were washed with brine (50 mL), dried over MgSO4, filtered and concentrated in vacuo to return 1-cyclohexylpyrazolo[3,4-d]pyrimidinamine (2.01 g, 90%) as a light brown solid which was used without further purification. 1H NMR (300 MHz, DMSO- d6) δ 8.15 (s, 1H), 8.06 (s, 1H), 7.64 (br s, 1H), 4.57 (tt, J = 9.5, 4.9 Hz, 1H), 2.0-1.78 (m, 6H), 1.69 (d, J = 13.0 Hz, 1H), 1.48-1.13 (m, 3H).

Step 3 To a suspension of 1-cyclohexylpyrazolo[3,4-d]pyrimidinamine (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 × 50 mL).

The combined cs were washed sequentially with with 5% aq. sodium bisulfite (25 mL), sat. aq. NaHCO3 (25 mL) and brine (25 mL), dried over MgSO4, filtered and concentrated in vacuo to return the title compound (1.58 g, 58%) as an orange solid which was used t r purification. LCMS [M+H]+ 296 and 298; 1H NMR (300 MHz, DMSO-d6) δ 8.19 (s, 1H), 7.92 (s, 2H), 4.57 (dt, J = 9.5, 5.2 Hz, 1H), 1.92-1.72 (m, 5H), 1.67 (d, J = 12.9 Hz, 1H), 1.52- 1.31 (m, 2H), 1.31-1.12 (m, 1H).

Other intermediates prepared by this method include: 3-Bromoethyl-1H-pyrazolo[3,4-d]pyrimidinamine Step 1 1.8 g (16%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 7.52 (s, 1H), 6.54 (s, 2H), 3.89 (q, J = 7.2 Hz, 2H), 1.20 (t, J = 7.2 Hz, 3H).

Step 2 850 mg (39%) as a yellow solid. LCMS [M-H]- 162.0; 1H NMR (300 MHz, DMSO-d6) δ 8.16 (s, 1H), 8.07 (s, 1H), 7.70 (s, 2H), 4.30 (q, J = 7.2 Hz, 2H), 1.36 (t, J = 7.2 Hz, 3H).

Step 3 870 mg (62%) as a solid. LCMS [M+H]+ 242.0 and 244.0; 1H NMR (300 MHz, DMSO-d6) δ 8.21 (s, 1H), 7.88 (s, 1H), 6.99 (s, 1H), 4.28 (q, J = 7.2 Hz, 2H), 1.36 (t, J = 7.2 Hz, 3H).

General Method 2 – representative procedure 2-(4-Aminobromo-pyrazolo[3,4-d]pyrimidinyl)ethanol (Intermediate 1) ] To a solution of 3-bromo-1H-pyrazolo[3,4-d]pyrimidinamine (250 mg, 1.2 mmol) and K2CO3 (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 en for 17 hours. Water (5 mL) was added, the mixture stirred for 0.25 h, filtered, washed with water (2 × 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; 1H NMR (300 MHz, DMSO-d6) δ 8.21 (s, 1H), 4.87 (s, 1H), 4.29 (t, J = 5.7 Hz, 2H), 3.78 (t, J = 5.7 Hz, 2H).

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(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidinyl)-1H-indolecarboxylate (Intermediate 23) A mixture of methyl 2-bromo-1H-indolecarboxylate (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(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidin 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 Na2SO4, filtered and trated in vacuo. The e was purified by fcc (0-100% EtOAc in e) to return the title compound (228 mg, 31%) as a yellow solid LCMS [M+H]+ 365.1; 1H NMR (400 MHz, CDCl3) δ 9.09 (br s, 1H), 8.40 (s, 1H), 8.22 (s, 1H), 7.86 (dd, J = 1.40, 8.36 Hz, 1H), 7.69 (d, J = 8.36 Hz, 1H), 6.93 (dd, J = 0.85, 2.08 Hz, 1H), 5.78 (s, 2H), 3.96 (s, 3H), 1.86 (s, 9H).

General Method 4 – representative procedure Methyl 2-(4-aminoisopropyl-1H-pyrazolo[3,4-d]pyrimidinyl)-1H-indolecarboxylate (Intermediate 27) A mixture of oisopropyl-1H-pyrazolo[3,4-d]pyrimidinamine (0.4 g, 1.56 mmol) and methyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-indole carboxylate (0.47 g, 1.56 mmol) in 1,4-dioxane (10 mL) was degassed with en. f)Cl2·DCM (32 mg, 0.04 mmol) was added ed by 1.8 M K2CO3 (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 × 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 fcc (0-100% EtOAc in isohexane) to return the title compound (438 mg, 80%) as a yellow solid. LCMS [M+H]+ 351.2; 1H NMR (300 MHz, 6) δ 11.98 (br s, 1H), 8.28 (s, 1H), 8.15 (s, 1H), 7.65-7.74 (m, 2H), 7.16 (br s, 1H), 6.96 (s, 1H), 5.12 (quin, J = 6.64 Hz, 1H), 3.88 (s, 3H), 1.55 (d, J = 6.78 Hz, 6H).

On occasion, the corresponding 3-iodoisopropyl-1H-pyrazolo[3,4- d]pyrimidinamine 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(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidinyl)-1H-indolecarboxylic acid (Intermediate 26) To a solution of methyl 2-(4-aminotert-butyl-pyrazolo[3,4-d]pyrimidinyl)-1H- indolecarboxylate (228 mg, 0.63 mmol) in THF (1.5 mL), MeOH (1.5 mL) and water (1.5 mL) was added LiOH.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 e was ied with 1M HCl and extracted with EtOAc (3×).

The combined organics extracts were dried over Na2SO4, 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-indolecarboxamide mediate 34) ] To a mixture of 2-bromo-1H-indolecarboxylic acid (311 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 (3×). The combined extracts were dried over Na2SO4, filtered and concentrated under d pressure. The residue was ated with DCM to return the title compound (204 mg, 64%) as an ite solid. LCMS [M+H]+ 253.0 and 255.0; 1H NMR (300 MHz, DMSO-d6) δ 12.13 (s, 1H), 8.36 (br d, J = 4.14 Hz, 1H), 7.83 (s, 1H), 7.49-7.53 (m, 2H), 6.59 (s, 1H), 2.79 (d, J = 4.52 Hz, 3H).

General Method 7 – representative procedure Example 5 - 2-(4-Aminoisopropyl-1H-pyrazolo[3,4-d]pyrimidinyl)chloro-N-methyl-1H- indolecarboxamide To a suspension of methyl 2-(4-aminoisopropyl-pyrazolo[3,4-d]pyrimidin yl)chloro-1H-indolecarboxylate (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 AlMe3 (1.0 M solution in heptane, 3.95 mL, 3.95 mmol) dropwise. The resulting sion 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 × 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 fcc (0 to 10% MeOH in DCM) to return the title compound (170 mg, 45%) as a white solid. LCMS [M+H]+ 384.2; 1H NMR (300 MHz, DMSO- d6) δ 12.16 (s, 1H), 8.45-8.52 (m, 1H), 8.27 (s, 1H), 8.00 (s, 1H), 7.69 (dd, J = 2.35, 8.57 Hz, 1H), 7.61 (d, J = 8.57 Hz, 1H), 5.12 (sept, J = 6.64 Hz, 1H), 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 minoisopropyl-1H-pyrazolo[3,4-d]pyrimidinyl)chloro-1H-indole carboxylate (Intermediate 28) To a solution of methyl 2-(4-aminoisopropyl-pyrazolo[3,4-d]pyrimidinyl)-1H- indolecarboxylate (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 tion, 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; 1H NMR (300 MHz, DMSO-d6) δ 12.29 (s, 1H), 8.27 (s, 1H), 8.12 (s, 1H), 7.79 (dd, J = 1.79, 8.58 Hz, 1H), 7.68 (d, J = 8.16 Hz, 1H), 5.12 (quin, J = 6.73 Hz, 1H), 3.89 (s, 3H), 1.53 (d, J = 6.69 Hz, 6H). lly, treatment of substrates with 1 eq NCS resulted in varying tions of unreacted starting al, desired product and a bischlorinated impurity. A variety of cations techniques were employed, dependent on the ratio of product. Precipitation and/or fcc 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(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidinyl]chloro- N-methyl-1H-indolecarboxamide Step 1 A mixture of methyl mino-1H-pyrazolo[3,4-d]pyrimidinyl)chloro((2- (trimethylsilyl)ethoxy)methyl)-1H-indolecarboxylate (308 mg, 0.651 mmol), 1,1,1-trifluoro- 2-iodoethane (70.6 µL, 0.716 mmol) and K2CO3 (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 × 10 mL). The combined organic extracts were washed with water (2 × 10 mL), brine (2 × 10 mL), dried and concentrated in vacuo to return methyl mino(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidinyl)chloro ((2-(trimethylsilyl) ethoxy)methyl)-1H-indolecarboxylate (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 Methyl 2-(4-amino(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidinyl)chloro- 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indolecarboxylate (389 mg, 0.701 mmol) and conc.

HCl (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 conc. HCl (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 NaHCO3 (5 mL). The organic layer was separated and retained and the aq phase was extracted with further EtOAc (2 × 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(2,2,2-trifluoroethyl)-1H- pyrazolo[3,4-d]pyrimidinyl)chloro-1H-indolecarboxylic acid. LCMS [M+H]+ 410. This material was used in the uent step without additional purification.

Step 3 ] A mixture of ethyl mino(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin yl)chloro-1H-indolecarboxylate and methyl 2-(4-amino(2,2,2-trifluoroethyl)-1H- pyrazolo [3,4-d]pyrimidinyl)chloro-1H-indolecarboxylate (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 AlMe3 solution (2.0 M in heptane, 0.26 mL) se over 5 min. The resulting e was maintained at this temperature for 30 min then heated at 60 °C for 3 h. After cooling back to 0 °C, le’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 × 10 mL) and the combined organic extracts washed with water (2 × 10 mL), brine (10 mL), dried and evaporated in vacuo. The crude product was purified by fcc (0-15% MeOH in DCM) to return the title compound (22 mg, 40% yield) as a white solid. LCMS [M+H]+ 424; 1H NMR (400 MHz, DMSO-d6) δ 12.23 (s, 1H), 8.49 (br q, 1H), 8.35 (s, 1H), 8.01 (app s, 1H), 7.70 (br dd, 1H), 7.62 (br d, 1H), 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 synthesis General Intermediate Name Structure Method 2-(4-Aminobromo- 1 lo[3,4-d]pyrimidin 2 yl)ethanol Methyl 2-(4-amino(2- hydroxyethyl)-1H-pyrazolo[3,4- 2 d]pyrimidinyl)-1H-indole 4 carboxylate Methyl 2-(4-amino(2- yethyl)-1H-pyrazolo[3,4- 3 8 d]pyrimidinyl)chloro-1H- indolecarboxylate 3-Bromo(3-methoxypropyl)- 4 1H-pyrazolo[3,4-d]pyrimidin 2 amine Methyl 2-(4-amino(3- methoxypropyl)-1H-pyrazolo[3,4- d]pyrimidinyl)-1H-indole 4 ylate Methyl 2-(4-amino(3- methoxypropyl)-1H-pyrazolo[3,4- 6 d]pyrimidinyl)chloro-1H- 8 indolecarboxylate 3-Bromo(1- 7 (methylsulfonyl)piperidinyl)-1H- 2 pyrazolo[3,4-d]pyrimidinamine Methyl 2-(4-amino(1- (methylsulfonyl)piperidinyl)-1H- 8 pyrazolo[3,4-d]pyrimidinyl)-1H- 4 indolecarboxylate Methyl 2-(4-amino(1- (methylsulfonyl)piperidinyl)-1H- 9 8 pyrazolo[3,4-d]pyrimidinyl) chloro-1H-indolecarboxylate tert-Butyl (2-(4-aminobromo- 1H-pyrazolo[3,4-d]pyrimidin 2 yl)carbamate Methyl 2-(4-amino(2-((tertbutoxycarbonyl )amino)ethyl)-1H- 11 pyrazolo[3,4-d]pyrimidinyl)-1H6-carboxylate Methyl 2-(4-amino(2-((tertbutoxycarbonyl )amino)ethyl)-1H- 12 pyrazolo[3,4-d]pyrimidinyl) 8 chloro-1H-indolecarboxylate NH2 Br 3-Bromocyclobutyl-1H- N 13 N 2 pyrazolo[3,4-d]pyrimidinamine N N Methyl 2-(4-aminocyclobutyl- 1H-pyrazolo[3,4-d]pyrimidinyl)- 14 4 1H-indolecarboxylate Methyl 2-(4-aminocyclobutyl- 1H-pyrazolo[3,4-d]pyrimidinyl)- 8 3-chloro-1H-indolecarboxylate 3-Bromocyclopentyl-1H- 16 2 pyrazolo[3,4-d]pyrimidinamine Methyl 2-(4-aminocyclopentyl- 1H-pyrazolo[3,4-d]pyrimidinyl)- 17 4 1H-indolecarboxylate 3-Bromomethyl-1H- See pyrazolo[3,4-d]pyrimidinamine Below Methyl 2-(4-aminomethyl-1H- pyrazolo[3,4-d]pyrimidinyl)-1H- 19 4 indolecarboxylate Methyl 2-(4-aminomethyl-1H- pyrazolo[3,4-d]pyrimidinyl) 8 chloro-1H-indolecarboxylate Methyl 2-(4-aminocyclohexyl- 1H-pyrazolo[3,4-d]pyrimidinyl)- 21 4 1H-indolecarboxylate Methyl 2-(4-aminoethyl-1H- pyrazolo[3,4-d]pyrimidinyl)-1H- 22 4 carboxylate Methyl mino(tert-butyl)- 1H-pyrazolo[3,4-d]pyrimidinyl)- 23 3 1H-indolecarboxylate Methyl 2-(4-amino(tert-butyl)- 1H-pyrazolo[3,4-d]pyrimidinyl)- See 3-bromo-1H-indolecarboxylate Below Methyl 2-(4-amino(tert-butyl)- 1H-pyrazolo[3,4-d]pyrimidinyl)- Below 3-fluoro-1H-indolecarboxylate mino(tert-butyl)-1H- pyrazolo[3,4-d]pyrimidinyl)-1H- 26 5 indolecarboxylic acid Methyl 2-(4-aminoisopropyl- 27 1H-pyrazolo[3,4-d]pyrimidinyl)- 4 1H-indolecarboxylate Methyl 2-(4-aminoisopropyl- 28 1H-pyrazolo[3,4-d]pyrimidinyl)- 8 ro-1H-indolecarboxylate tert-Butyl N-(3-bromo-1H- 29 pyrazolo[3,4-d]pyrimidinyl)-NBelow tert-butoxycarbonyl-carbamate tert-Butyl N-(3-bromo cyclopropyl-pyrazolo[3,4- See d]pyrimidinyl)-N-tert- Below butoxycarbonyl-carbamate Methyl 2-(4-aminocyclopropyl- 1H-pyrazolo[3,4-d]pyrimidinyl)- 31 4 1H-indolecarboxylate CO2Me Methyl 2-(4-aminoisopropyl- 7H-pyrrolo[2,3-d]pyrimidinyl)- 32 NH2 NH 4 1H-indolecarboxylate N N 2-Bromo-1H-indolecarboxylic 33 5 2-Bromo-N-methyl-1H-indole 34 6 carboxamide Methyl mino(1- methylpiperidinyl)-1H- See pyrazolo[3,4-d]pyrimidinyl) below chloro-1H-indolecarboxylate Methyl 2-(8-amino isopropylimidazo[1,5-a]pyrazin 36 yl)chloro-1H-indole 8 carboxylate tert-Butyl minobromo- 37 1H-pyrazolo[3,4-d]pyrimidin 2 yl)piperidinecarboxylate Methyl 2-(4-amino(1-(tertbutoxycarbonyl )piperidinyl)- 38 4 1H-pyrazolo[3,4-d]pyrimidinyl)- 1H-indolecarboxylate Methyl 2-(4-amino(1-(tertbutoxycarbonyl )piperidinyl)- 39 8 1H-pyrazolo[3,4-d]pyrimidinyl)- 3-chloro-1H-indolecarboxylate 3-(4-Aminobromo-1HSee 40 pyrazolo[3,4-d]pyrimidin Below lopentanol Methyl 2-(4-amino(3- hydroxycyclopentyl)-1H- 41 4 pyrazolo[3,4-d]pyrimidinyl)-1H- indolecarboxylate Methyl 2-(4-amino(3- hydroxycyclopentyl)-1H- 42 8 pyrazolo[3,4-d]pyrimidinyl) chloro-1H-indolecarboxylate Methyl 2-(4-amino(tert-butyl)- 1H-pyrazolo[3,4-d]pyrimidinyl)- See 1H-benzo[d]imidazole Below carboxylate 4-Chloroiodoisopropyl-1H- See pyrazolo[4,3-c]pyridine Below 3-Iodoisopropyl-1H- See pyrazolo[4,3-c]pyridinamine Below Methyl 2-(4-aminoisopropyl- 46 1H-pyrazolo[4,3-c]pyridinyl)- 4 1H-indolecarboxylate Methyl 2-(4-aminothieno[2,3- 47 d]pyrimidinyl)chloro-1H- 8 indolecarboxylate Methyl 2-(4-aminothieno[2,3- 48 d]pyrimidinyl)-1H-indole 4 carboxylate Methyl 2-(4-amino isopropylpyrrolo[2,1- 49 4 f][1,2,4]triazinyl)-1H-indole carboxylate Aminooxo-4,5-dihydro- 50 triazin Below yl)methyl)isobutyramide 2-Aminoisopropylimidazo[5,1- See f][1,2,4]triazin-4(3H)-one Below 2-Aminoiodo 52 isopropylimidazo[5,1- Below f][1,2,4]triazin-4(3H)-one -Iodoisopropylimidazo[5,1- 53 f][1,2,4]triazin-4(3H)-one Below -Iodoisopropylimidazo[5,1- See ,4]triazinamine Below Methyl 2-(4-amino pylimidazo[5,1- 55 4 f][1,2,4]triazinyl)-1H-indole carboxylate Methyl 2-(4-amino isopropylimidazo[5,1- 56 8 f][1,2,4]triazinyl)chloro-1H- indolecarboxylate 1-(tert-Butyl) 57 ethylsilyl)ethynyl)-1HBelow pyrazolo[3,4-d]pyrimidinamine 1-(tert-Butyl)ethynyl-1H- See pyrazolo[3,4-d]pyrimidinamine Below 6-Amino((4-amino(tertbutyl )-1H-pyrazolo[3,4- See d]pyrimidinyl)ethynyl)-N- Below methylpicolinamide 1-tert-Butyl 6-methyl 5-chloro-1H- See indole-1,6-dicarboxylate Below (1-(tert-Butoxycarbonyl)chloro- 61 6-(methoxycarbonyl)-1H-indol Below yl)boronic acid Methyl 2-(4-amino(tert-butyl)- 62 1H-pyrazolo[3,4-d]pyrimidinyl)- 4 -chloro-1H-indolecarboxylate tert-Butyl 6-[bis(tert- 63 carbonyl)amino]indole Below carboxylate [6-[Bis(tertbutoxycarbonyl )amino]tert- See butoxycarbonyl-indolyl]boronic Below 3-(6-Amino-1H-indolyl)(tert1H-pyrazolo[3,4- 4 d]pyrimidinamine (2-(4-Amino(tert-butyl)-1HSee 66 pyrazolo[3,4-d]pyrimidinyl) Below chloro-1H-indolyl) methanol 2-(4-Amino(tert-butyl)-1HSee 67 pyrazolo[3,4-d]pyrimidinyl) Below chloro-1H-indolecarbaldehyde 1-(2-(4-Amino(tert-butyl)-1HSee 68 pyrazolo[3,4-d]pyrimidinyl)-1HBelow indolyl)propanol mino(tert-butyl)-1H- pyrazolo[3,4-d]pyrimidinyl) 69 4 methyl-1H-indolecarboxylic 7-Chloroiodoisopropyl-1H- See pyrazolo[4,3-c]pyridinamine Below Methyl 2-(4-aminochloro isopropyl-1H-pyrazolo[4,3- 71 c]pyridinyl)-1H-indole 4 carboxylate 1-tert-Butyl 6-methyl 4-chloro-1H- See indole-1,6-dicarboxylate Below (1-(tert-Butoxycarbonyl)chloro- 73 6-(methoxycarbonyl)-1H-indol Below yl)boronic acid.

Methyl 2-(4-amino(tert-butyl)- 74 1H-pyrazolo[3,4-d]pyrimidinyl)- 4 4-chloro-1H-indolecarboxylate Methyl 2-bromomethyl-1H- See indolecarboxylate Below Methyl 3-methyl(4,4,5,5- 76 tetramethyl-1,3,2-dioxaborolan Below yl)-1H-indolecarboxylate Methyl mino(tert-butyl)- 77 1H-pyrazolo[3,4-d]pyrimidinyl)- 4 yl-1H-indolecarboxylate (6-(Methoxycarbonyl)((2- 78 (trimethylsilyl)ethoxy)methyl)-1HBelow indolyl)boronic acid Methyl 2-(4-amino-1H- pyrazolo[3,4-d] pyrimidinyl) 79 4 ((2-(trimethylsilyl)ethoxy) methyl)- 1H-indolecarboxylate Methyl mino-1H- pyrazolo[3,4-d]pyrimidinyl) 80 chloro((2- 8 (trimethylsilyl)ethoxy)methyl)-1H- indolecarboxylate romo-1H-indolyl) 81 isopropyl-1H-pyrazolo[3,4- 4 d]pyrimidinamine Phenyl (2-(4-amino(tert-butyl)- 82 1H-pyrazolo[3,4-d]pyrimidinyl)- Below 1H-indolyl)carbamate Table B - List of intermediates Prepared Using General Methods Yield Intermediate Adduct m/z 1H NMR (300 or 400MHz, DMSO-d 12.09 (s, 1H), 8.29 (s, 1H), 8.13 (s, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.20 (s, 2H), 2 76 [M-H]- 351 6.98 (s, 1H), 4.95 (t, J = 5.7 Hz, 1H), 4.44 (t, J = 5.8 Hz, 2H), 3.95-3.82 (m, 5H). 3 92* [M-H]- and ND 286 8.21 (s, 1H), 7.97 (s, 1H), 6.92 (s, 1H), 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, 1H), 8.29 (s, 1H), 8.13 (s, 1H), 7.76 - 7.64 86 [M-H]- 379 (m, 2H), 7.19 (s, 2H), 6.98 (s, 1H), 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). 6 99* [M-H]- and ND 7 17 [M+H]+ 376 ND 12.00 (s, 1H), 8.29 (s, 1H), 8.14 (s, 1H), 7.76-7.63 (m, 2H), 7.23 (s, 2H), 6.99 (s, 1H), 4.99-4.84 (m, 8 73 [M-H]- 468 1H), 3.88 (s, 3H), 3.83-3.69 (m, 2H), .99 (m, 2H), 2.96 (s, 3H), 2.36-2.21 (m, 2H), 2.16-2.02 (m, 12.30 (s, 1H), 8.29 (s, 1H), 8.12 (s, 1H), 7.79 (d, J = 8.7 Hz, 1H), 7.67 (d, J = 8.3 Hz, 1H), 5.00-4.85 (m, 9 45 [M-H]- and 1H), 3.89 (s, 3H), .67 (m, 2H), 3.12-2.99 (m, 2H), 2.95 (s, 3H), 2.34-2.03 (m, 4H). 8.19 (s, 1H), 6.89 (t, J = 6.0 Hz, 1H), 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, 1H), 8.28 (s, 1H), 8.13 (s, 1H), 7.78-7.58 (m, 2H), 7.19 (s, 2H), 6.97 (s, 1H), 4.42 (t, J = 6.3 11 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). 12 78* [M-H]- and ND 266 8.20 (s, 1H), 7.87 (s, 1H), 6.97 (s, 1H), 5.24 (p, J = 13 48 [M-H]- and 8.5 Hz, 1H), 2.60 (m, 2H), 2.47-2.28 (m, 2H), 1.85 268 (td, J = 10.1, 5.6 Hz, 2H). 12.06 (s, 1H), 8.28 (s, 1H), 8.16 (s, 1H), 7.78-7.63 (m, 2H), 7.20 (s, 2H), 6.98 (s, 1H), 5.39 (p, J = 8.6 14 98 [M-H]- 361 Hz, 1H), 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). 34* [M-H]- and ND 8.21 (s, 1H), 7.96 (s, 1H), 6.99 (s, 1H), 5.15 (tt, J = 16 32 [M-H]- and 8.1, 6.3 Hz, 1H), 2.16-1.57 (m, 8H). 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), 17 60 [M+H]+ 377 .28 (p, J = 7.4 Hz, 1H), 3.88 (s, 3H), 2.16-2.07 (m, 1H), 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 19 70 [M-H]- 321 (m, 1H), 7.77-7.61 (m, 2H), 7.21 (s, 2H), 6.98 (d, J = 0.9 Hz, 1H), 4.01 (s, 3H), 3.87 (d, J = 1.0 Hz, 3H). 91* [M-H]- and ND 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, 21 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 22 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), .62 (m, 2H), 7.18 (s, 2H), 6.96 (s, 1H), 3.97-3.83 (m, 31 49 [M+H]+ 349 1H), 3.88 (s, 3H), 1.34-1.19 (m, 2H), 1.25-1.07 (m, 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), 32 72 [M+H]+ ND .01 (sept, J = 6.8 Hz, 1H), 3.33 (s, 3H), 1.50 (d, J = 6. 8 Hz, 6H). 33 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, 36 70 [M+H]+ 384 1H), 7.64 (d, J = 8.41 Hz, 1H), 7.12 (d, J = 4.97 Hz, 1H), 6.20 (br s, 2H), 3.89 (s, 3H), 3.50 (p, J = 6.76 Hz, 1H), 1.36 (d, J = 6.81 Hz, 6H). 37 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 (br s, 38 75 [M-H]- ND 2H), 6.98 (s, 1H), 5.00-4.88 (m, 1H), 4.13 (d, J = 11.37 Hz, 1H), 3.88 (s, 3H), 3.04 (br s, 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 (br s, 2H), 4.98 (tt, J = 39 61 [M-H]- 525 4.96, 10.53 Hz, 1H), 4.10 (d, J = 13.24 Hz, 2H), 3.90 (s, 3H), 3.04 (br s, 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, 1H), 7.18 (br s, 2H), 6.97 (s, 1H), 41 48 [M-H]- 391 .21 (p, J = 8.27 Hz, 1H), 4.96 (d, J = 4.89 Hz, 1H), 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 (br s, 2H), 5.23 42 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), .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 = 46 77 [M+H]+ 350 8.3, 1.4 Hz, 1H), 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). 47 95* [M+H]+ 358 ND 48 31* [M+H]+ 325 ND 49 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), 55 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 (br s, 1H), 8.09 (br dd, 1H), 7.97 56 54 [M+H]+ 385 (s, 1H), 7.77 (dd, J = 8.4, 1.4 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H), 6.77 (br s, 1H), 3.88 (s, 3H), 3.57 (hept, J = 7.0 Hz, 1H), 1.38 (d, J = 7.0 Hz, 6H). 12.02 (s, 1H), 8.27 (s, 1H), 8.00 (s, 1H), 7.80 (s, 62 23 [M+H]+ 399 1H), 7.11 (br, 2H), 6.89 (s, 1H), 3.87 (s, 3H), 1.79 (s, 9H). .90 (s, 1H), 8.23 (s, 1H), 7.26 (d, J = 8.4 Hz, 1H), 6.95 (br 2H), 6.64-6.63 (m, 1H), 6.59-6.58 (m, 1H), 65 72 [M+H]+ 322 6.44 (dd, J = 8.4, 2.0 Hz, 1H), 4.88 (s, 2H), 1.77 (9H, s). 69 71* [M+H]+ 365 ND 71 41 [M+H]+ 384 ND 12.30 (s, 1H), 8.28 (s, 1H), 8.10 (app t, J = 1.1 Hz, 74 36 [M+H]+ 399 1H), 7.67 (d, J = 1.2 Hz, 1H), 7.11 (br s, 2H), 6.90 (s, 1H), 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, 1H), 8.27 (s, 1H), 7.63 (d, J = 1.76 Hz, 1H), 7.59 (d, J = 8.43 Hz, 1H), 7.18 (dd, J = 1.82, 81 38 [M+H]+ 373 8.41 Hz, 1H), 7.11 (br s, 2H), 6.88 (s, 1H), 5.10 (p, J = 6.72 Hz, 1H), 1.54 (d, J = 6.74 Hz, 6H).

ND = no data * tes material was impure but used without further purification.

Synthesis of Other Intermediates 3-Bromomethyl-1H-pyrazolo[3,4-d]pyrimidinamine (Intermediate 18) To a suspension of 3-bromo-1H-pyrazolo[3,4-d]pyrimidinamine (1.75 g, 8.18 mmol), triphenylphosphine (4.29 g, 16.35 mmol) and MeOH (1 mL) in THF (50 mL) at 0 °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. HCl (1M, 50 mL) and washed with EtOAc (2 × 50 mL). The aqueous phase was ed with aq.

NaOH (1M, 50 mL) then extracted with 20 % MeOH:DCM (3 × 50 mL). The combined cs 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; 1H NMR (300 MHz, DMSO-d6) δ 8.22 (s, 1H), 3.86 (s, 3H).

Methyl mino(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidinyl)bromo-1H-indole carboxylate (Intermediate 24) To a solution of methyl 2-(4-aminotert-butyl-pyrazolo[3,4-d]pyrimidinyl)- 1H-indolecarboxylate (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 × 20 mL) and dried in vacuo at 50 °C. The crude product was purified by fcc (0- 100 % EtOAc in isohexane) to return a dark red oil. The oil was triturated with Et2O, filtered, washed with a minimum amount of Et2O 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; 1H NMR (300 MHz, DMSO-d6) δ 12.38 (s, 1H), 8.27 (s, 1H), 8.11 (s, 1H), 7.80 (dd, J = 1.32, 8.38 Hz, 1H), 7.60 (d, J = 8.38 Hz, 1H), 3.89 (s, 3H), 1.79 (s, 9H).

Methyl 2-(4-amino(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidinyl)fluoro-1H-indole carboxylate (Intermediate 25) To a suspension of methyl 2-(4-aminotert-butyl-pyrazolo[3,4-d]pyrimidin yl)-1H-indolecarboxylate (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. NaHCO3 (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 t was purified by fcc (0-100 % EtOAc in isohexane) to return the title compound (116 mg, 44%, 43% pure by HPLC) as orange .

LCMS [M-H]- 381.2. Used directly in the next step. tert-Butyl N-(3-bromo-1H-pyrazolo[3,4-d]pyrimidinyl)-N-tert-butoxycarbonyl-carbamate mediate 29) A suspension of 3-bromo-1H-pyrazolo[3,4-d]pyrimidinamine (1.0 g, 4.7 mmol), Boc2O (4.08 g, 18.7 mmol) and DMAP (57 mg, 0.47 mmol) in THF (20 mL) was d at room temperature for 24 h. The solvent was concentrated in vacuo then the crude mixture was ved in methanol (20 mL). Aq. sat. (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 × 50 mL). The ed organics were passed through a hydrophobic frit and concentrated in vacuo. The crude product was purified by fcc (0-10% CM) to return the title compound (1.55 g, 80%) as a pale yellow solid. LCMS [M-H]- 414.1 and 412.2. utyl N-(3-bromocyclopropyl-pyrazolo[3,4-d]pyrimidinyl)-N-tert-butoxycarbonylcarbamate (Intermediate 30) To a solution of tert-butyl N-(3-bromo-1H-pyrazolo[3,4-d]pyrimidinyl)-N-tertbutoxycarbonyl-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(II) acetate (877 mg, 4.83 mmol). The reaction mixture was stirred under an here of air at room temperature for 24 h then concentrated in vacuo. The crude product was purified by fcc (0-30% EtOAc in isohexane) to return the title compound (285 mg, 26%). 1H NMR (300 MHz, 6) δ 9.06 (s, 1H), 3.94 (tt, J = 7.3, 3.6 Hz, 1H), 1.39 (s, 18H), 1.30-1.23 (m, 2H), 1.23-1.10 (m, 2H).

Methyl 2-(4-amino(1-methylpiperidinyl)-1H-pyrazolo[3,4-d]pyrimidinyl)chloro-1H- indolecarboxylate (Intermediate 35) Step 1 To methyl 2-[4-amino(1-tert-butoxycarbonylpiperidyl)pyrazolo[3,4- d]pyrimidinyl]chloro-1H-indolecarboxylate (250 mg, 0.48 mmol) in 1,4-dioxane (10 mL) was added HCl 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(4-piperidyl)pyrazolo[3,4-d]pyrimidinyl]chloro-1H-indole carboxylate hydrochloride (188 mg, 86%) as an off white powder. LCMS [M-H]- 424.7.

Step 2 To a suspension of methyl 2-[4-amino(4-piperidyl)pyrazolo[3,4-d]pyrimidin- 3-yl]chloro-1H-indolecarboxylate hydrochloride (133 mg, 0.29 mmol) in ol (10 mL) was added formaldehyde (37% wt. % in H2O, 5.0 mL, 180 mmol), aq. HCl (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 × 20 mL). The combined filtrate was concentrated in vacuo, then the resulting residue was suspended in sat. aq. NaHCO3 (20 mL) and ted with DCM (3 × 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 . Taken directly onto the next step without any further purification. LCMS [M-H]- 438.7. 3-(4-Aminobromo-1H-pyrazolo[3,4-d]pyrimidinyl)cyclopentanol (Intermediate 40) Step 1 To a solution of o-1H-pyrazolo[3,4-d]pyrimidinamine (2.00 g, 9.34 mmol) and 2-cyclopentenone (1.53 g, 18.69 mmol) in THF (20 mL) was added HfCl4 (111 mg, 0.3 mmol). The reaction was heated at reflux for 15 h, then cooled to room temperature and trated in vacuo. The e was treated with water and extracted with EtOAc. The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo to return the crude product which was purified by fcc to return 3-(4-aminobromo-1H- pyrazolo[3,4-d]pyrimidinyl)cyclopentanone (750 mg, 27%) which was used without further purification.

Step 2 To a solution of 3-(4-aminobromo-1H-pyrazolo[3,4-d]pyrimidin yl)cyclopentanone (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 Na2SO4, ed and concentrated in vacuo to return the title compound (750 mg, 100%). LCMS [M-H]- 298.6; 1H NMR (300 MHz, DMSO-d6) δ 8.19 (s, 1H), 8.00 (s, 1H), 6.87 (s, 1H), 5.07 (p, J = 8.2 Hz, 1H), 4.86 (d, J = 4.8 Hz, 1H), 4.17 (h, J = 6.0 Hz, 1H), 2.36 (ddd, J = 13.0, 8.4, 6.5 Hz, 1H), 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-amino(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidinyl)-1H-benzo[d]imidazole carboxylate (Intermediate 43) A on of 4-aminotert-butyl-pyrazolo[3,4-d]pyrimidinecarbaldehyde (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 on 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 × 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 fcc (0-100% EtOAc in isohexane) to return methyl 2-(4-aminotert-butylpyrazolo [3,4-d]pyrimidinyl)-3H-benzimidazolecarboxylate (39 mg, 31%) as an orange solid. LCMS [M-H]- 364.2. Material was impure (80% by HPLC) but used without any further purification. roiodoisopropyl-1H-pyrazolo[4,3-c]pyridine (Intermediate 44) To a suspension of 4-chloroiodo-1H-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 n sat aq NH4Cl (20 mL) and EtOAc (20 mL).

The organic layer was separated and retained and the aq phase was extracted with further EtOAc (2 × 20 mL). The combined organic extracts were washed with brine (50 mL), dried and concentrated in vacuo. The residue obtained was purified by fcc (0-100% EtOAc in isohexane) to return the title nd (478 mg, 51%) as an off-white solid. LCMS [M+H]+ 322; 1H NMR (400 MHz, CDCl3) δ 8.15 (d, J = 6.0 Hz, 1H), 7.31 (d, J = 6.0 Hz, 1H), 4.78 (hept, J = 6.7 Hz, 1H), 1.60 (d, J = 6.7 Hz, 6H). 3-Iodoisopropyl-1H-pyrazolo[4,3-c]pyridinamine (Intermediate 45) To a solution of 4-chloroiodoisopropyl-1H-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 sion 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; 1H NMR (400MHz, DMSO-d6) δ 7.71 (d, J = 6.3 Hz, 1H), 7.35 (br, 2H), 6.99 (d, J = 6.3 Hz, 1H), 4.84 (hept, J = 6.6 Hz, 1H), 1.42 (d, J = 6.6 Hz, 6H).

N-((3-Aminooxo-4,5-dihydro-1,2,4-triazinyl)methyl)isobutyramide (Intermediate 50) ] To a suspension 3-amino(aminomethyl)-4H-1,2,4-triazinone dihydrochloride (1.20 g, 5.61 mmol) in water (30 mL) at 0 °C was added aq. NaHCO3 (1.0 M, 12.5 mL), the resulting mixture was warmed to room temperature and then a solution of (2,5- dioxopyrrolidinyl) 2-methylpropanoate (1.47 g, 7.14 mmol) in THF:acetonitrile (1:1, 20 mL) was added. This mixture was d at room temperature for 67 h and then further NaHCO3 (1.0 M, 6.0 mL) and (2,5-dioxopyrrolidinyl) 2-methylpropanoa te (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 ed and washed with TBME (2 × 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-Aminoisopropylimidazo[5,1-f][1,2,4]triazin-4(3H)-one (Intermediate 51) To a suspension N-((3-aminooxo-4,5-dihydro-1,2,4-triazin 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 × 50 mL).

The resin was then washed with 1% NH3 in MeOH (3 × 50 mL) and the on 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-Aminoiodoisopropylimidazo[5,1-f][1,2,4]triazin-4(3H)-one (Intermediate 52) To a solution of 2-aminoisopropylimidazo[5,1-f][1,2,4]triazin-4(3H)-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 ted. The aq layer was further extracted with EtOAc (50 mL) and the ed organic extracts washed sequentially with aq. Na2S2O3 solution (1.0 M, 2 × 20 mL) and brine (3 × 20 mL), then dried and concentrated in vacuo to return the title nd (700 mg, 66%) as a yellow solid. LCMS [M+H]+ 320 ; 1H NMR (400MHz, DMSO-d6) δ 10.79 (s, 1H), 6.14 (s, 2H), 3.27 (hept, J = 6.9 Hz, 1H), 1.23 (d, J = 6.9 Hz, 6H).

-Iodoisopropylimidazo[5,1-f][1,2,4]triazin-4(3H)-one (Intermediate 53) To a solution of oiodoisopropylimidazo[5,1-f][1,2,4]triazin-4(3H)- one (690 mg, 2.12 mmol) in F (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 fcc (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 cation.

-Iodoisopropylimidazo[5,1-f][1,2,4]triazinamine (Intermediate 54) Phosphorus oxychloride (0.500 mL, 5.36 mmol) was added to a on of 1H- 1,2,4-triazole (1.04 g, 15.1 mmol) in ne (10 mL) and then stirred at room temperature for min. A solution of 5-iodoisopropylimidazo[5,1-f][1,2,4]triazin-4(3H)-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 trated in vacuo. The crude product was partitioned between EtOAc (75 mL) and sat. aq NaHCO3 (75 mL) and the layers separated. The aq layer was further extracted with EtOAc (3 × 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 fcc (0-2% CM) to return the title compound (390 mg, 77%) as a dark yellow solid. LCMS [M+H]+ 304; 1H NMR (400MHz, DMSO-d6) δ 8.43 (br s, 1H), 7.86 (s, 1H), 6.76 (br s, 1H), 3.43 (hept, J = 7.0 Hz, 1H), 1.27 (d, J = 7.0 Hz, 6H). 1-(tert-Butyl)((trimethylsilyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidinamine (Intermediate A mixture of 3-bromo(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidinamine (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 CuI (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), PdCl2(PPh3)2 (195 mg, 0.290 mmol) and CuI (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 CeliteTM (ca. 20 g). The layers were then separated and the aq phase extracted with further EtOAc (2 × 30 mL). The c ts were combined, washed with water (3 × 60 mL), brine (30 mL), then dried and concentrated in vacuo. The crude product was purified by fcc (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-(tert-Butyl)ethynyl-1H-pyrazolo[3,4-d]pyrimidinamine (Intermediate 58) A e of 1-(tert-butyl)((trimethylsilyl)ethynyl)-1H-pyrazolo[3,4- d]pyrimidinamine (1.32 g, 4.13 mmol) and K2CO3 (0.857 g, 6.20 mmol) in MeOH (30 mL) was d at room temperature for 2 h. The solvent was concentrated in vacuo and the resulting e 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 × 30 mL).

The ed organic extracts were washed with water (20 mL), brine (20 mL), dried and concentrated in vacuo. The crude product was purified by fcc (0-2% MeOH (+ 1% NH3) in DCM). The crude product was then slurried with TBME:isohexane (1:4, 10 mL), ed 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; 1H NMR (400MHz, DMSO-d6) δ 8.21 (s, 1H), 8.12-7.40 (br, 1H), 6.94-6.01 (br, 1H), 4.60 (s, 1H), 1.69 (s, 9H). 6-Amino((4-amino(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidinyl)ethynyl)-N- methylpicolinamide (Intermediate 59) A mixture of 1-(tert-butyl)ethynyl-1H-pyrazolo[3,4-d]pyrimidinamine (200 mg, 0.930 mmol) and 6-aminobromo- N-methyl-pyridinecarboxamide (214 mg, 0.930 mmol) in HF (17:3, 10 mL) was degassed with nitrogen. Pd(PPh3)4 (107 mg, 0.0930 mmol) and CuI (26.0 mg, 0.140 mmol) were added and the resulting e heated in the microwave at 80 °C for 1 h. The solvent was concentrated in vacuo and the resulting e 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 × 20 mL). The combined organic extracts were washed with water (3 × 10 mL), brine (10 mL), dried and concentrated in vacuo. The crude product was purified by fcc (0-5% MeOH (+ 1% NH3) in DCM) to return the title compound (138 mg, 41%) as a pale yellow solid. LCMS [M+H]+365; 1H NMR (400MHz, DMSO-d6 ) δ 8.27-8.22 (over-lapping m, 2H), 7.92 (d, J = 7.7 Hz, 1H), 7.24 (d, J = 7.7 Hz, 1H), 6.49 (s, 2H), 2.82 (d, J = 5.0 Hz, 3H), 1.73 (s, 9H). NH2 signals not t. 1-tert-Butyl 6-methyl 5-chloro-1H-indole-1,6-dicarboxylate (Intermediate 60) A mixture of methyl 5-chloro-1 H-indolecarboxylate (500 mg, 2.39 mmol), Boc2O (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 fcc (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; 1H NMR (400MHz, DMSO-d6) δ 8.59 (s, 1H), 7.91 (d, J = 3.7 Hz, 1H), 7.86 (s, 1H), 6.77 (dd, J = 3.7, 0.7 Hz, 1H), 3.88 (s, 3H), 1.63 (s, (1-(tert-Butoxycarbonyl)chloro(methoxycarbonyl)-1H-indolyl)boronic acid (Intermediate 61) To a mixture of 1-tert-butyl 6-methyl ro-1H-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 s olution 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 NaHCO3 and diluted with EtOAc (50 mL). The organic layer was separated and retained and the aq phase was extracted with further EtOAc (2 × 50 mL). The ed 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]indolecarboxylate (Intermediate 63) To a solution of tert-butyl N-(1H-indolyl)carbamate (760 mg, 3.17 mmol) in DCM (15 mL) was added Boc2O (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 Boc2O (850 mg, 3.90 mmol) and Et3N (600 µL, 4.31 mmol) was added and the mixture stirred for a further 24 h. The solvent was concentrated in vacuo and the crude product ed by fcc (0-20% EtOAc in ane) to return the title compound (1.35 g, 98%) as a colourless gum. LCMS + 455; 1H NMR (400MHz, DMSO-d6) δ 7.81 (s, 1H), 7.72 (d, J = 3.7 Hz, 1H), 7.61 (d, J = 8.3 Hz, 1H), 7.05 (dd, J = 8.3, 2.0 Hz, 1H), 6.74 (d, J = 4.5 Hz, 1H), 1.62 (s, 9H), 1.41 (s, 18H). [6-[Bis(tert-butoxycarbonyl)amino]tert-butoxycarbonyl-indolyl]boronic acid (Intermediate To a solution of tert-butyl 6-[bis(tert-butoxycarbonyl)amino]indole ylate (910 mg, 2.06 mmol) and triisopropyl borate (1.00 m L, 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 o f 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 ted with r EtOAc (2 × 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 is was difficult and therefore this material was taken forward into the next step. (2-(4-Amino(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidinyl)chloro-1H-indolyl) methanol mediate 66) To a solution of methyl 2-(4-amino(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidin yl)chloro-1H-indolecarboxylate (500 mg, 1.25 mmol) in THF (12 mL) at 0 °C was added LiAlH4 (2.0 M in THF, 2.19 mL). The resulting mixture was warmed to room temperature, maintained at this temperature for 45 min, then ed 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 × 20 mL) and the combined organic extracts dried and concentrated in vacuo. The crude product was ed by fcc (0-5% MeOH in DCM) to return the title compound (346 mg, 75%) as an ite solid. LCMS [M+H]+ 371; 1H NMR (400MHz, DMSO-d6 ) δ 11.79 (s, 1H), 8.26 (s, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.44 (dd, J = 1.4, 0.8 Hz, 1H), 7.14 (dd, J = 8.0, 1.4 Hz, 1H), 7.00-6.61 (br, 2H), 5.21 (t, J = 5.8 Hz, 1H), 4.63 (d, J = 5.8 Hz, 2H), 1.78 (s, 9H). 2-(4-Amino(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidinyl)chloro-1H-indole carbaldehyde (Intermediate 67) To a solution of (2-(4-amino(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidinyl) chloro-1H-indolyl)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-Amino(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidinyl)chloro-1H-indolyl)propan- 1-ol (Intermediate 68) To a solution of 2-(4-amino(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidinyl) chloro-1H-indolecarbaldehyde (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) . The resulting e was stirred at room temperature for 1 h then partitioned between EtOAc (10 mL) and sat aq NH4Cl (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 fcc (0-5% MeOH in DCM) to return the title nd (32 mg, 34%) as a pale brown oil. LCMS [M+H]+ 399. This material was used in the subsequent step without additional purification. 7-Chloroiodoisopropyl-1H-pyrazolo[4,3-c]pyridinamine (Intermediate 70) To 3-iodoisopropyl-pyrazolo[4,3- c ]pyridinamine (200 mg, 0.66 mmol) in MeCN (5 mL) was added NCS (89 mg, 0.66 mmol) and the ing solution was stirred at 70 °C for 3 h. The solvent was concentrated in vacuo and the residue obtained purified by fcc (0- % MeOH in DCM) to return the title compound (80 mg, 36%) as a brown solid. LCMS [M+H]+ 336; 1H NMR (400MHz, DMSO-d6) δ 7.72 (s, 1H), 6.53 (br, 2H), 5.46 (hept, J = 6.5 Hz, 1H), 1.46 (d, J = 6.5 Hz, 6H). 1-tert-Butyl 6-methyl 4-chloro-1H-indole-1,6-dicarboxylate (Intermediate 72) Prepared according to a similar ure to that used for 1-tert-butyl yl -chloro-1H-indole-1,6-dicarboxylate from methyl 4-chloro-1 H -indolecarboxylate (250 mg, 1.19 mmol) for a reaction time of 3 h and purified by fcc % EtOAc in isohexane) to return the title compound (327 mg, 89%) as white solid. LCMS [M+H]+ 310; 1H NMR (400MHz, DMSO-d6) δ 8.69 (app t, 1H), 7.99 (d, J = 3.7 Hz, 1H), 7.82 (d, J = 1.3 Hz, 1H), 6.83 (dd, J = 3.7, 0.9 Hz, 1H), 3.90 (s, 3H), 1.65 (s, 9H). (1-(tert-Butoxycarbonyl)chloro(methoxycarbonyl)-1H-indolyl)boronic acid (Intermediate 73) Prepared according to a r procedure to that used for (1-(tert-butoxy carbonyl)chloro(methoxycarbonyl)-1H-indolyl) boronic acid from 1-tert-butyl 6-methyl 4-chloro-1H-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-bromomethyl-1H-indolecarboxylate (Intermediate 75) To a solution of methyl 3-methyl-1 H-indolecarboxylate (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(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-indolecarboxylate mediate 76) A mixture of methyl 2-bromomethyl-1H-indolecarboxylate (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 en. Pd(PPh3)2Cl2 (24.0 mg, 0.0330 mmol) was added and the ing 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(PPh3)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 CeliteTM (ca. 2 g), washing with r EtOAc (2 × 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)((2-(trimethylsilyl)ethoxy)methyl)-1H-indolyl)boronic acid mediate 78) 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 0 °C was added LDA (1.0 M, 10.3 mL). The resulting e was maintaine d at 0 °C for 2 h then quenched through the on of water (5 mL) and sat aq NaHCO3 (x mL). After stirring for 5 min the volatile solvents were concentrated in vacuo and the e obtained diluted with EtOAc (50 mL). The organic layer was separated and retained and the aq phase was ted with further EtOAc (2 × 50 mL). The combined organic extracts were washed with water (2 × mL), brine (2 × 20 mL), dried and concentrated in vacuo to return the title nd (2.61 g, 60% pure by HPLC) as a brown solid. This material was used in the subsequent step without additional cation.

Phenyl (2-(4-Amino(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidinyl)-1H-indolyl) carbamate (Intermediate 82) To a solution of 3-(6-amino-1H-indolyl)(tert-butyl)-1H-pyrazolo[3,4- d]pyrimidinamine (39 mg, 0.11 mmol) and DMAP (2.0 mg, 0.020 mmol) in DMF (1 mL) was added phenyl chloroformate (20 µL, 0.16 mmol). The resulting mixture was stirred at room ature 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 × 20 mL) and the combined organic extracts washed with brine (4 × 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 EXAMPLE NAME STRUCTURE 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidin- N-methyl-1H-indolecarboxamide 2 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidin- 3-yl)-N-(1-methylpyrazolyl)-1H-indole carboxamide 3 2-(4-Aminoisopropyl-pyrazolo[3,4-d]pyrimidin- 3-yl)-N-methyl-1H-indolecarboxamide minotert-butyl-pyrazolo[3,4-d]pyrimidin- 4 3-chloro-N-methyl-1H-indole carboxamide 2-(4-Aminoisopropyl-pyrazolo[3,4-d]pyrimidin- 3-yl)chloro-N-methyl-1H-indole carboxamide 6 2-(4-Aminoisopropyl-7H-pyrrolo[2,3- d]pyrimidinyl)-N-methyl-1H-indole carboxamide 2-(4-Aminoisopropyl-7H-pyrrolo[2,3- d]pyrimidinyl)chloro-N-methyl-1H-indole carboxamide 8 2-(4-Amino(tert-butyl)-1H-pyrazolo[3,4- d]pyrimidinyl)bromo-N-methyl-1H-indole carboxamide 2-(8-Aminoisopropylimidazo[1,5-a]pyrazin yl)chloro-N-methyl-1H-indolecarboxamide 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidin- 3-yl)-N-methyl-3H-benzimidazolecarboxamide 11 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidin- 3-yl)-1H-indolecarboxamide Methyl 2-(8-aminoisopropylimidazo[1,5- a]pyrazinyl)-1H-indolecarboxylate 2-(8-Aminoisopropyl-imidazo[1,5-a]pyrazin yl)-N-methyl-1H-indolecarboxamide 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidin- 14 3-yl)chloro-N-(2-methoxyethyl)-1H-indole carboxamide 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidin- 3-yl)chloro-N-[2-(dimethylamino)ethyl]-1H- indolecarboxamide 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidin- 16 3-yl)chloro-N-(2-morpholinoethyl)-1H-indole carboxamide minotert-butyl-pyrazolo[3,4-d]pyrimidin- 17 3-yl)chloro-N-(3-morpholinopropyl)-1H-indole- 6-carboxamide 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidin- 18 3-yl)chloro-N-methoxy-1H-indole carboxamide [2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidin- 19 3-yl)chloro-1H-indolyl]-pyrrolidinylmethanone 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidin- 3-yl)chloro-N,N-dimethyl-1H-indole carboxamide 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidin- 21 3-yl)chloro-N-[2-(2-methoxyethoxy)ethyl]-1H- carboxamide 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidin- 22 3-yl)chloro-N-(3-methoxypropyl)-1H-indole carboxamide 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidin- 23 3-yl)chloro-N-(2-hydroxyethyl)-1H-indole amide 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidin- 24 3-yl)chloro-N-[2-(2-morpholinoethoxy)ethyl]- 1H-indolecarboxamide 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidin- 3-yl)chloro-N-[2-[2- (dimethylamino)ethoxy]ethyl]-1H-indole carboxamide minotert-butyl-pyrazolo[3,4-d]pyrimidin- 26 3-yl)chloro-N-[3-(dimethylamino)propyl]-1H- indolecarboxamide 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidin- 27 3-yl)chloro-N-[3-(1-piperidyl)propyl]-1H-indole- 6-carboxamide 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidin- 28 3-yl)chloro-N-(3-isopropoxypropyl)-1H-indole- 6-carboxamide 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidin- 3-yl)fluoro-N-methyl-1H-indolecarboxamide 2-[4-Amino(2-hydroxyethyl)pyrazolo[3,4- d]pyrimidinyl]chloro-N-methyl-1H-indole carboxamide 2-[4-Amino(3-methoxypropyl)pyrazolo[3,4- 31 d]pyrimidinyl]chloro-N-methyl-1H-indole carboxamide 2-[4-Amino(1-methylsulfonyl 32 piperidyl)pyrazolo[3,4-d]pyrimidinyl]chloro- N-methyl-1H-indolecarboxamide minotert-butyl-1H-pyrazolo[3,4- 33 d]pyrimidinyl}chloro-N-(oxanyl)-1H- indolecarboxamide 2-(4-Aminomethyl-pyrazolo[3,4-d]pyrimidin yl)chloro-N-methyl-1H-indolecarboxamide 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidin- 3-yl)chloro-N-[1-(2-methoxyethyl)pyrazolyl]- 1H-indolecarboxamide 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidin- 36 3-yl)chloro-N-[1-(2-morpholinoethyl)pyrazol yl]-1H-indolecarboxamide 2-[4-Amino(propanyl)-1H-pyrazolo[4,3- 37 c]pyridinyl]-N-methyl-1H-indole carboxamide 2-[4-Amino(propanyl)-1H-pyrazolo[4,3- 38 c]pyridinyl]chloro-N-methyl-1H-indole carboxamide mino(propanyl)-1H-pyrazolo[4,3- 39 c]pyridinyl]bromo-N-methyl-1H-indole carboxamide 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidin- 3-yl)chloro-N-[1-[2- (dimethylamino)ethyl]pyrazolyl]-1H-indole carboxamide 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidin- 41 3-yl)chloro-N-[1-[2-(4-methylpiperazin yl)ethyl]pyrazolyl]-1H-indolecarboxamide 2-[4-Amino(2-aminoethyl)pyrazolo[3,4- 42 d]pyrimidinyl]chloro-N-methyl-1H-indole carboxamide minotert-butyl-pyrazolo[3,4-d]pyrimidin- 43 3-yl)chloro-N-[1-(2-hydroxyethyl)pyrazolyl]- 1H-indolecarboxamide 2-{4-Aminothieno[2,3-d]pyrimidinyl}chloro- N-methyl-1H-indolecarboxamide 2-{4-Aminothieno[2,3-d]pyrimidinyl}-N-methyl- 1H-indolecarboxamide 2-(4-Amino(tert-butyl)-1H-pyrazolo[3,4- 46 d]pyrimidinyl)chloro-1H-indolecarboxylic 2-[4-Amino(propanyl)pyrrolo[2,1- 47 ,4]triazinyl]-N-methyl-1H-indole carboxamide 2-[4-Amino(propanyl)pyrrolo[2,1- 48 f][1,2,4]triazinyl]chloro-N-methyl-1H-indole- 6-carboxamide 2-[4-Amino(propanyl)imidazo[4,3- 49 f][1,2,4]triazinyl]chloro-N-methyl-1H-indole- 6-carboxamide 2-{4-Aminotert-butyl-1H-pyrazolo[3,4- 50 d]pyrimidinyl}chloro-N-methyl-1H- pyrrolo[2,3-b]pyridinecarboxamide 2-{4-Aminotert-butyl-1H-pyrazolo[3,4- 51 d]pyrimidinyl}-N-methyl-1H-pyrrolo[2,3- b]pyridinecarboxamide Methyl 2-(4-amino(tert-butyl)-1H-pyrazolo[3,4- 52 d]pyrimidinyl)chloro-1H-indole carboxylate 2-(4-Amino(tert-butyl)-1H-pyrazolo[3,4- 53 d]pyrimidinyl)chloro-N-methyl-1H-indole amide N-(2-{4-Aminotert-butyl-1H-pyrazolo[3,4- d]pyrimidinyl}-1H-indolyl)acetamide 1-(2-{4-Aminotert-butyl-1H-pyrazolo[3,4- 55 midinyl}chloro-1H-indolyl)propan 2-{4-Aminotert-butyl-1H-pyrazolo[3,4- 56 d]pyrimidinyl}chloro-N-(propanyl)-1H- indolecarboxamide 2-{4-Aminotert-butyl-1H-pyrazolo[3,4- 57 d]pyrimidinyl}chloro-N-ethyl-1H-indole carboxamide 2-{4-Aminotert-butyl-1H-pyrazolo[3,4- 58 d]pyrimidinyl}chloro-N-cyclopropyl-1H- indolecarboxamide 2-{4-Aminotert-butyl-1H-pyrazolo[3,4- 59 d]pyrimidinyl}chloro-N-phenyl-1H-indole carboxamide 2-{4-Aminotert-butyl-1H-pyrazolo[3,4- 60 d]pyrimidinyl}-N,1-dimethyl-1H-indole amide 2-[4-Aminochloro(propanyl)-1H- 61 pyrazolo[4,3-c]pyridinyl]-N-methyl-1H-indole- 6-carboxamide 2-{4-Aminocyclobutyl-1H-pyrazolo[3,4- 62 d]pyrimidinyl}chloro-N-methyl-1H-indole carboxamide minocyclohexyl-1H-pyrazolo[3,4- 63 d]pyrimidinyl}-N-methyl-1H-indole carboxamide 2-{4-Aminocyclopentyl-1H-pyrazolo[3,4- 64 d]pyrimidinyl}-N-methyl-1H-indole carboxamide 2-(4-Aminocyclohexyl-1H-pyrazolo[3,4- 65 d]pyrimidinyl)chloro-N-methyl-1H-indole carboxamide 2-{4-Aminoethyl-1H-pyrazolo[3,4-d]pyrimidin- N-methyl-1H-indolecarboxamide 2-{4-Aminocyclopropyl-1H-pyrazolo[3,4- 67 d]pyrimidinyl}-N-methyl-1H-indole carboxamide 2-{4-Aminotert-butyl-1H-pyrazolo[3,4- 68 d]pyrimidinyl}chloro-1H-indole carboxamide 2-{4-Aminotert-butyl-1H-pyrazolo[3,4- 69 d]pyrimidinyl}-3,5-dichloro-N-methyl-1H- indolecarboxamide N-(2-(4-Amino(tert-butyl)-1H-pyrazolo[3,4- 70 d]pyrimidinyl)-1H-indolyl) methanesulfonamide 1-(2-(4-Amino(tert-butyl)-1H-pyrazolo[3,4- midinyl)-1H-indolyl)methylurea 2-{4-Aminotert-butyl-1H-pyrazolo[3,4- 72 d]pyrimidinyl}chloro-N-(2- methanesulfonylethyl)-1H-indolecarboxamide 2-{4-Aminotert-butyl-1H-pyrazolo[3,4- 73 d]pyrimidinyl}chloro-N-(pyridinyl)-1H- indolecarboxamide 2-{4-Aminotert-butyl-1H-pyrazolo[3,4- 74 d]pyrimidinyl}chloro-N-methyl-1H-indole carboxamide 2-{4-Aminotert-butyl-1H-pyrazolo[3,4- 75 d]pyrimidinyl}-N-benzylchloro-1H-indole carboxamide 2-{4-Aminotert-butyl-1H-pyrazolo[3,4- 76 d]pyrimidinyl}chloro-N-(2-phenylethyl)-1H- indolecarboxamide 2-{4-Aminotert-butyl-1H-pyrazolo[3,4- 77 d]pyrimidinyl}chloro-N-(3,3,3- trifluoropropyl)-1H-indolecarboxamide 2-{4-Aminotert-butyl-1H-pyrazolo[3,4- d]pyrimidinyl}chloro-N-[2- (trifluoromethoxy)ethyl]-1H-indole carboxamide 2-{4-Aminotert-butyl-1H-pyrazolo[3,4- 79 midinyl}chloro-N-(1,3-thiazol ylmethyl)-1H-indolecarboxamide 2-{4-Aminotert-butyl-1H-pyrazolo[3,4- 80 d]pyrimidinyl}chloro-N-(oxanylmethyl)- 1H-indolecarboxamide mino(tert-butyl)-1H-pyrazolo[3,4- 81 d]pyrimidinyl)-N,3-dimethyl-1H-indole carboxamide N-(2-{4-Aminotert-butyl-1H-pyrazolo[3,4- 82 d]pyrimidinyl}chloro-1H-indol yl)acetamide 2-(4-Amino(tert-butyl)-1H-pyrazolo[3,4- 83 midinyl)chloro-N,1-dimethyl-1H- indolecarboxamide 2-{4-Aminoethyl-1H-pyrazolo[3,4-d]pyrimidin- 84 3-chloro-N-methyl-1H-indole carboxamide 2-{4-Aminocyclopropyl-1H-pyrazolo[3,4- 85 d]pyrimidinyl}chloro-N-methyl-1H-indole carboxamide 2-{4-Aminocyclopentyl-1H-pyrazolo[3,4- 86 d]pyrimidinyl}chloro-N-methyl-1H-indole carboxamide 2-{4-Aminotert-butyl-1H-pyrazolo[3,4- 87 d]pyrimidinyl}-3,4-dichloro-N-methyl-1H- indolecarboxamide 2-{4-Aminotert-butyl-1H-pyrazolo[3,4- 88 d]pyrimidinyl}chloro-N-(1,3-thiazolyl)-1H- indolecarboxamide 2-[4-Amino(1-methanesulfonylpiperidinyl)- 89 1H-pyrazolo[3,4-d]pyrimidinyl]chloro-N- cyclopropyl-1H-indolecarboxamide tert-Butyl mino[3-chloro (cyclopropylcarbamoyl)-1H-indolyl]-1H- pyrazolo[3,4-d]pyrimidinyl}piperidine ylate 2-{4-Aminotert-butyl-1H-pyrazolo[3,4- 91 d]pyrimidinyl}chloro-N-propyl-1H-indole carboxamide 2-(4-Aminochloroisopropyl-1H- 92 pyrazolo[4,3-c]pyridinyl)chloro-N-methyl- 1H-indolecarboxamide 2-[4-Amino(piperidinyl)-1H-pyrazolo[3,4- 93 d]pyrimidinyl]chloro-N-cyclopropyl-1H- indolecarboxamide hydrochloride 2-[4-Amino(oxanylmethyl)-1H-pyrazolo[3,4- 94 d]pyrimidinyl]chloro-N-methyl-1H-indole carboxamide 2-[4-Amino(oxanyl)-1H-pyrazolo[3,4- 95 d]pyrimidinyl]chloro-N-propyl-1H-indole carboxamide 2-[4-Amino(oxanylmethyl)-1H-pyrazolo[3,4- 96 d]pyrimidinyl]chloro-N-cyclopropyl-1H- carboxamide 2-{4-Aminotert-butyl-1H-pyrazolo[3,4- 97 d]pyrimidinyl}chloro(difluoromethyl)-N- methyl-1H-indolecarboxamide 2-[4-Amino(oxolanyl)-1H-pyrazolo[3,4- 98 d]pyrimidinyl]chloro-N-propyl-1H-indole carboxamide 2-[4-Amino(2,2,2-trifluoroethyl)-1H- 99 pyrazolo[3,4-d]pyrimidinyl]chloro-N-ethyl- 1H-indolecarboxamide 2-[4-Amino(2,2,2-trifluoroethyl)-1H- 100 lo[3,4-d]pyrimidinyl]chloro-N-methyl- 1H-indolecarboxamide 2-[4-Amino(oxolanyl)-1H-pyrazolo[3,4- 101 d]pyrimidinyl]chloro-N-cyclopropyl-1H- indolecarboxamide 2-[4-Amino(2,2,2-trifluoroethyl)-1H- 102 pyrazolo[3,4-d]pyrimidinyl]chloro-N- cyclopropyl-1H-indolecarboxamide 2-[4-Amino(oxanyl)-1H-pyrazolo[3,4- 103 midinyl]chloro-N-cyclopropyl-1H- indolecarboxamide 2-[4-Amino(3-hydroxycyclopentyl)-1H- 104 pyrazolo[3,4-d]pyrimidinyl]chloro-N- cyclopropyl-1H-indolecarboxamide 2-(4-Amino(1-methylpiperidinyl)-1H- pyrazolo[3,4-d]pyrimidinyl)chloro-N- cyclopropyl-1H-indolecarboxamide 106 1-Isopropyl[6-(1,3,4-thiadiazolyl)-1H-indol- 2-yl]pyrazolo[3,4-d]pyrimidinamine NH2 NH N N 107 3-[3-Chloro(1,3,4-thiadiazolyl)-1H-indol yl]isopropyl-pyrazolo[3,4-d]pyrimidinamine 108 1-Isopropyl(6-oxazolyl-1H-indol azolo[3,4-d]pyrimidinamine 109 3-(3-Chlorooxazolyl-1H-indolyl) isopropyl-pyrazolo[3,4-d]pyrimidinamine Table D - Examples Prepared Using General Methods l Yield (%) EXAMPLE FORMULA MW ADDUCT m/z Method 1 C19H21N7O 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 C19H20ClN7O 397.86 [M-H]- 396.3 8 40 C18H18ClN7O 383.83 [M+H]+ 384.2 7 45 6 C19H20N6O 348.4 [M+H]+ 349.2 7 78 7 C19H19ClN6O 382.85 [M+H]+ 383.2 8 28 8 C19H20BrN7O 442.31 [M-H]- 440.2 7 47 9 C19H19ClN6O 382.85 [M+H]+ 383.3 8 67 C18H20N8O 364.4 [M-H]- 363.3 4 31 11 C18H19N7O 349.39 [M+H]+ 350.2 6 20 12 C19H19N5O2 349.39 [M+H]+ 350.2 4 85 13 C19H20N6O 348.4 [M+H]+ 349.2 7 48 14 C21H24ClN7O2 441.91 [M-H]- 440.3 7 99 C22H27ClN8O 454.96 [M-H]- 453.3 7 97 16 C24H29ClN8O2 496.99 [M-H]- 495.4 7 88 17 C25H31ClN8O2 511.02 [M-H]- 509.4 7 90 18 ClN7O2 413.86 [M-H]- 412.2 7 43 19 C22H24ClN7O 437.93 [M-H]- 436.4 7 64 C20H22ClN7O 411.89 [M-H]- 410.3 7 65 21 C23H28ClN7O3 485.97 [M-H]- 484.4 7 68 22 C22H26ClN7O2 455.94 [M-H]- 454.4 7 58 23 C20H22ClN7O2 427.89 [M-H]- 426.4 7 11 24 C26H33ClN8O3 541.05 [M-H]- 539.5 7 9 C24H31ClN8O2 499.01 [M-H]- 497.4 7 59 26 C23H29ClN8O 468.98 [M-H]- 467.4 7 55 27 C26H33ClN8O 509.05 [M-H]- 507.5 7 57 28 C24H30ClN7O2 483.99 [M-H]- 482.5 7 53 29 C19H20FN7O 381.41 [M-H]- 380.3 7 20 ClN7O2 385.81 [M-H]- 384.2 7 13 31 C19H20ClN7O2 413.86 [M-H]- 412.2 7 16 32 C21H23ClN8O3S 502.98 [M-H]- 501.3 7 26 33 C23H26ClN7O2 467.95 [M+H]+ 468.5 7 6 34 C16H14ClN7O 355.78 [M-H]- 354.1 7 18 C24H26ClN9O2 507.98 [M+H]+ 508.3 7 65 36 C27H31ClN10O2 563.05 [M+H]+ 563.3 7 5 37 C19H20N6O 348.4 [M+H]+ 349.0 7 52 38 C19H19ClN6O 382.85 [M+H]+ 383.0 8 19 39 C19H19BrN6O 427.3 [M+H]+ 428.0 See Below 25 40 C25H29ClN10O 521.02 [M+H]+ 521.3 7 31 41 C28H34ClN11O 576.1 [M+H]+ 576.4 7 1 42 C17H17ClN8O 384.82 [M-H]- 383.2 7 34 43 C23H24ClN9O2 493.95 [M+H]+ 494.3 7 28 44 C16H12ClN5OS 357.82 [M+H]+ 358.3 8 18 45 C16H13N5OS 323.37 [M+H]+ 324.3 7 52 46 C18H17ClN6O2 384.82 [M+H]+ 385.2 5 36 47 C19H20N6O 348.4 [M+H]+ 349.4 7 51 48 C19H19ClN6O 382.85 [M+H]+ 383.4 8 39 49 C18H18ClN7O 383.83 [M+H]+ 384.3 7 68 50 C18H19ClN8O 398.85 [M+H]+ 399.4 8 40 51 C18H20N8O 364.4 [M+H]+ 365.4 See Below 16 52 C19H19ClN6O2 398.85 [M-H]- 397.1 8 24 53 C19H20ClN7O 397.86 [M+H]+ 398.5 7 30 54 C19H21N7O 363.42 [M+H]+ 364.4 See Below 53 55 ClN6O 396.87 [M+H]+ 397.1 See Below 29 56 C21H24ClN7O 425.91 [M+H]+ 426.4 7 33 57 C20H22ClN7O 411.89 [M+H]+ 412.4 7 65 58 C21H22ClN7O 423.9 [M+H]+ 424.4 7 50 59 C24H22ClN7O 459.93 [M+H]+ 460.4 7 6 60 N7O 377.44 [M+H]+ 378.3 6 39 61 C19H19ClN6O 382.85 [M+H]+ 383.4 7 46 62 C19H18ClN7O 395.85 [M+H]+ 396.2 7 11 63 C21H23N7O 389.45 [M+H]+ 390.3 7 50 64 C20H21N7O 375.43 [M+H]+ 376.3 7 54 65 C21H22ClN7O 423.9 [M+H]+ 424.2 8 17 66 C17H17N7O 335.36 [M+H]+ 336.2 7 61 67 C18H17N7O 347.37 [M+H]+ 348.1 7 16 68 C18H18ClN7O 383.83 [M+H]+ 384.3 7 43 69 C19H19Cl2N7O 432.31 [M+H]+ 432.3 8 20 70 C18H21N7O2S 399.47 [M+H]+ 400 See Below 20 71 C19H22N8O 378.43 [M+H]+ 379.5 See Below 10 72 C21H24ClN7O3S 489.98 [M+H]+ 490.4 7 56 73 C23H21ClN8O 460.92 [M+H]+ 461.5 7 49 74 ClN7O 397.86 [M+H]+ 398.4 4 80 75 C25H24ClN7O 473.96 [M+H]+ 474.4 7 70 76 C26H26ClN7O 487.98 [M+H]+ 488.5 7 55 77 C21H21ClF3N7O 479.89 [M+H]+ 480.4 7 56 78 C21H21ClF3N7O2 495.89 [M+H]+ 496.4 7 27 79 C22H21ClN8OS 480.97 [M+H]+ 481.4 7 42 80 C24H28ClN7O2 481.98 [M+H]+ 482.4 7 55 81 C20H23N7O 377.44 [M+H]+ 378.4 7 39 82 C19H20ClN7O 397.86 [M+H]+ 398.4 8 52 83 C20H22ClN7O 411.89 [M+H]+ 412.2 8 99 84 C17H16ClN7O 369.81 [M+H]+ 370.6 8 37 85 C18H16ClN7O 381.82 [M+H]+ 382.7 8 57 86 C20H20ClN7O 409.87 [M+H]+ 410.7 8 23 87 C19H19Cl2N7O 432.31 [M+H]+ 432.7 8 45 88 C21H19ClN8OS 466.95 [M+H]+ 467.4 7 21 89 C23H25ClN8O3S 529.01 [M+H]+ 529.7 7 29 90 C27H31ClN8O3 551.04 [M+H]+ 551.7 7 43 91 C21H24ClN7O 425.91 [M+H]+ 426.5 8 4 92 C19H18Cl2N6O 417.29 [M+H]+ 417.4 8 90 93 C22H23ClN8O 450.92 [M+H]+ 451.7 See Below 94 C21H22ClN7O2 439.9 [M+H]+ 440.5 9 87 95 C22H24ClN7O2 453.92 [M+H]+ 454.3 9 2 96 C23H24ClN7O2 465.94 [M+H]+ 466.2 9 21 97 C20H20ClF2N7O 447.87 [M+H]+ 448.2 See Below 10 98 C21H22ClN7O2 439.9 [M+H]+ 440.5 9 27 99 ClF3N7O 437.81 [M+H]+ 438.7 9 28 C17H13ClF3N7O 423.78 [M+H]+ 424.4 9 40 101 C21H20ClN7O2 437.88 [M+H]+ 438.4 9 31 102 C19H15ClF3N7O 449.82 [M+H]+ 450.4 9 26 103 C22H22ClN7O2 451.91 [M+H]+ 452.4 9 20 104 C22H22ClN7O2 451.91 [M+H]+ 452.7 9 10 105 ClN8O 464.95 [M-H]- 463.7 7 7 106 C18H16N8S 376.44 [M-H]- 375.2 3 2 107 C18H15ClN8S 410.88 [M+H]+ 411.1 8 30 108 C19H17N7O 359.38 [M+H]+ 360.2 3 14 109 C19H16ClN7O 393.83 [M+H]+ 394.2 8 21 Table E - 1H NMR data for Examples EXAMPLE 1H NMR (300 or 400 MHz, DMSO-d 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 1H), 7.56 (d, J = 8.61 Hz, 1H), 7.04 (br s, 2H), 6.86 (s, 1H), 2.81 (d, J = 4.46 Hz, 3H), 1.80 (s, 9H). 11.87 (br s, 1H), 8.37 (q, J = 4.22 Hz, 1H), 8.27 (s, 1H), 8.00 (s, 1H), 7.65 (d, J = 3 8.31 Hz, 1H), 7.56 (dd, J = 1.50, 8.34 Hz, 1H), 7.10 (br s, 2H), 6.89 (s, 1H), 5.11 (spt, J = 6.66 Hz, 1H), 2.82 (d, J = 4.46 Hz, 3H), 1.54 (d, J = 6.66 Hz, 6H). 11.88 (br s, 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 (br d, J = 19.01 Hz, 2H), 6.89 (s, 1H), 6.62 (d, J = 2.20 Hz, 1H), 3.97 (br s, 1H), 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 (br s, 2H), 2.82 (d, J = 4.52 Hz, 3H), 1.79 (s, 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 (br s, 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, 1H), 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 11 (dd, J = 1.29, 8.22 Hz, 1H), 7.20 (s, 1H), 7.04 (s, 1H), 6.87 (d, J = 1.32 Hz, 1H), 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 6 (m, 2H), 6.56 (s, 1H), 6.43 (br s, 2H), 5.00 (sept, J = 6.64 Hz, 1H), 2.81 (d, J = 4.43 Hz, 3H), 1.50 (d, J = 6.78 Hz, 6H). 11.90 (br s, 1H), 8.41-8.50 (m, J = 4.60 Hz, 1H), 8.19 (s, 1H), 7.94 (s, 1H), 7.64- 7 7.74 (m, 2H), .57 (m, 1H), 6.26 (br s, 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 (br d, J = 4.43 Hz, 1H), 8.28 (s, 1H), 8.01 (s, 1H), 7.62-7.80 (m, 8 1H), 7.54 (d, J = 8.38 Hz, 1H), 6.92 (br s, 2H), 2.83 (d, J = 4.43 Hz, 3H), 1.79 (s, 12.10 (br s, 1H), 8.46 (br d, J = 4.52 Hz, 1H), 7.98 (s, 1H), 7.63-7.71 (m, 2H), 7.57 9 (d, J = 7.16 Hz, 1H), 7.10 (d, J = 4.90 Hz, 1H), 6.15 (br s, 2H), 3.49 (quin, J = 6.80 Hz, 1H), 2.82 (d, J = 4.43 Hz, 3H), 1.36 (d, J = 6.78 Hz, 6H). 11.85 (br s, 1H), 8.13 (s, 1H), 7.57-7.70 (m, 3H), 7.11 (br d, J = 4.99 Hz, 1H), 6.77 12 (s, 1H), 6.47 (br s, 2H), 3.87 (s, 3H), 3.49 (sept, J = 6.8 Hz, 1H), 1.38 (d, J = 6.8 Hz, 11.74 (s, 1H), 8.33 (q, J = 4.32 Hz, 1H), 7.98 (d, J = 1.33 Hz, 1H), 7.64 (d, J = 4.97 Hz, 1H), 7.60 (d, J = 8.34 Hz, 1H), 7.53 (dd, J = 1.52, 8.33 Hz, 1H), 7.09 (d, J = 4.93 Hz, 1H), 6.70 (s, 1H), 6.45 (s, 2H), 3.48 (p, J = 6.83 Hz, 1H), 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, 14 1H), 7.60 (d, J = 8.39 Hz, 1H), 6.95 (br s, 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, 1H), 7.59 (d, J = 8.42 Hz, 1H), 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, 16 8.44 Hz, 1H), 7.60 (d, J = 8.44 Hz, 1H), 6.95 (br s, 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 × 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, 17 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 × 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 (br s, 2H), 3.74 (s, 3H), 1.79 (s, 9H). 12.06 (s, 1H), 8.26 (s, 1H), 7.65-7.61 (m, 1H), 7.59 (d, J = 8.24 Hz, 1H), 7.35 (dd, J 19 = 1.39, 8.27 Hz, 1H), 6.98 (br s, 2H), 3.56-3.42 (m, 4H), 1.89-1.79 (m, 4H), 1.79 (s, 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 (br s, 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, 21 8.41 Hz, 1H), 7.60 (d, J = 8.42 Hz, 1H), 6.95 (br s, 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 22 Hz, 1H), 7.59 (d, J = 8.41 Hz, 1H), 6.96 (br s, 2H), 3.40 (t, J = 6.33 Hz, 2H), 3.26 (s, 3H), 1.79 (s, 9H). 1 × CH2 under tBu peak at 1.79 ppm. 1 × CH2 under solvent peak. 11.94 (s, 1H), 8.28 (t, J = 5.50 Hz, 1H), 8.07 (s, 1H), 7.81 (s, 1H), 7.52 (dd, J = 1.43, 23 8.38 Hz, 1H), 7.40 (d, J = 8.41 Hz, 1H), 6.78 (br s, 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, 24 8.45 Hz, 1H), 7.59 (d, J = 8.38 Hz, 1H), 7.04 (br s, 2H), 3.58-3.39 (m, 8H), 2.50- 2.42 (m, 2H), 2.44-2.34 (m, 4H), 1.79 (s, 9H). 1 × 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 (br s, 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 26 (d, J = 8.17 Hz, 1H), 6.99 (br s, 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 × CH2 under t 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 27 (d, J = 8.02 Hz, 1H), 6.98 (br s, 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), .43 (m, 1H), 8.27 (s, 1H), 7.99 (s, 1H), 7.69 (d, J = 8.47 Hz, 1H), 7.59 (d, J = 8.38 Hz, 1H), 6.93 (br s, 2H), 3.54 (p, J = 6.08 Hz, 1H), 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, 1H), 8.46 (q, J = 4.05 Hz, 1H), 8.26 (s, 1H), 8.00-7.92 (m, 1H), 7.65-7.61 (m, 2H), 7.03 (br s, 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, 1H), 7.08 (br s, 2H), 4.96 (t, J = 5.60 Hz, 1H), 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 31 Hz, 1H), 7.60 (d, J = 8.36 Hz, 1H), 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 (br s, 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 = 34 1.44, 8.39 Hz, 1H), 7.59 (d, J = 8.41 Hz, 1H), 7.12 (br s, 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, 1H), 7.62 (d, J = 8.47 Hz, 1H), 6.97 (br s, 2H), 6.63 (d, J = 2.32 Hz, 1H), 4.21 (t, J = 5.27 Hz, 2H), 3.70 (t, J = 5.29 Hz, 2H), 3.25 (s, 3H), 1.80 (s, 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, 1H), 7.68 (d, J = 2.20 Hz, 1H), 7.62 (d, J = 8.51 Hz, 1H), 6.96 (br s, 2H), 6.63 (d, J = 2.25 Hz, 1H), 4.18 (t, J = 6.68 Hz, 2H), .54 (m, 4H), 2.77-2.68 (m, 2H), 2.42 (s, 4H), 1.80 (s, 9H). 11.85 (br, 1H), 8.37 (q, J = 4.7 Hz, 1H), 8.00 (s, 1H), 7.79 (d, J = 6.1 Hz, 1H), 7.65 (d, J = 8.3 Hz, 1H), 7.56 (dd, J = 8.3, 1.6 Hz, 1H), 6.95 (d, J = 6.1 Hz, 1H), 6.88 (br, 1H), 6.14 (br, 2H), 4.94 (hept, J = 6.6 Hz, 1H), 2.82 (d, J = 4.4 Hz, 3H), 1.53 (d, J = 6.6 Hz, 6H). 12.25 (s, 1H), 8.53 (q, J = 4.3 Hz, 1H), 8.04-7.97 (m, 1H), 7.79 (d, J = 6.2 Hz, 1H), 7.70 (dd, J = 8.4, 1.4 Hz, 1H), 7.61 (d, J = 8.4 Hz, 1H), 6.99 (d, J = 6.2 Hz, 1H), .98 (s, 2H), 4.97 (hept, J = 6.7 Hz, 1H), 2.82 (d, J = 4.5 Hz, 3H), 1.52 (d, J = 6.7 Hz, 6H). 12.35 (s, 1H), 8.53 (q, J = 4.3 Hz, 1H), 8.02-7.98 (m, 1H), 7.79 (d, J = 6.2 Hz, 1H), 7.71 (dd, J = 8.4, 1.4 Hz, 1H), 7.54 (d, J = 8.4 Hz, 1H), 6.99 (d, J = 6.2 Hz, 1H), .95 (s, 2H), 4.97 (hept, J = 6.7 Hz, 1H), 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, 1H), 7.67 (d, J = 2.32 Hz, 1H), 7.61 (d, J = 8.48 Hz, 1H), 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, 1H), 7.66 (d, J = 2.26 Hz, 1H), 7.61 (d, J = 8.45 Hz, 1H), 6.98 (br s, 2H), 6.63 (d, J = 2.26 Hz, 1H), 4.16 (t, J = 6.61 Hz, 2H), 2.71 (t, J = 6.62 Hz, 2H), 2.44 (br s, 4H), 2.34 (br s, 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 = 42 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, 43 1H), 7.67-7.57 (m, 2H), 6.95 (br s, 2H), 6.63 (d, J = 2.27 Hz, 1H), 4.90 (t, J = 5.30 Hz, 1H), 4.09 (t, J = 5.65 Hz, 2H), 3.75 (q, J = 5.57 Hz, 2H), 1.80 (s, 9H). 12.21 (br s, 1H), 8.51 (app q, 1H), 8.38 (s, 1H), 7.98 (s, 1H), 7.88 (s, 1H), 7.71 (dd, 44 J = 8.4, 1.4 Hz, 1H), 7.59 (d, J = 8.4 Hz, 1H), 2.81 (d, J = 4.4 Hz, 3H). NH2 signals not t. 11.92 (s, 1H), 8.42-8.36 lapping m, 2H), 7.96 (s, 1H), 7.76 (s, 1H), 7.64 (d, J = 45 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, 1H), 1.82 (s, 9H). NH2 signals not present. 11.71 (s, 1H), 8.37 (q, J = 4.5 Hz, 1H), 7.96 (s, 1H), 7.92 (s, 1H), 7.59-7.53 (over- 47 lapping m, 2H), 7.43-6.82 (br s, 2H), 6.76 (s, 1H), 6.57 (d, J = 1.1 Hz, 1H), 3.45 (hept, J = 6.9 Hz, 1H), 2.81 (d, J = 4.5 Hz, 3H), 1.34 (d, J = 6.9 Hz, 6H). 11.94 (s, 1H), 8.47 (q, J = 4.3 Hz, 1H), 7.98 (s, 1H), 7.93 (d, J = 1.5 Hz, 1H), 7.67 48 (dd, J = 8.4, 1.5 Hz, 1H), 7.53 (d, J = 8.4 Hz, 1H), 6.74 (s, 1H), 3.46 (hept, J = 7.0 Hz, 1H), 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 (app q, 1H), 8.34 (br s, 1H), 7.98-7.97 (m, 1H), 7.97 (s, 1H), 7.67 49 (dd, J = 8.4, 1.5 Hz, 1H), 7.56 (d, J = 8.4 Hz, 1H), 6.65 (br s, 1H), 3.56 (hept, J = 7.0 Hz, 1H), 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 (br s, 2H), 2.88 (d, J = 4.8 Hz, 3H), 1.78 (s, 9H). 51 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, 1H), 7.01 (s, 2H), 3.89 (s, 3H), 1.79 (s, 9H). 11.83 (s, 1H), 8.27 (s, 1H), 8.24 (d, J = 4.6 Hz, 1H), 7.70 (s, 1H), 7.49 (s, 1H), 7.04 (br, 2H), 6.84 (s, 1H), 2.79 (d, J = 4.6 Hz, 3H), 1.79 (s, 9H). 11.44 (s, 1H), 9.89 (s, 1H), 8.25 (s, 1H), 8.06 (app s, 1H), 7.50 (d, J = 8.5 Hz 1H), 54 7.09 (dd, J = 8.5, 1.9 Hz, 1H), 6.99 (br, 2H), .75 (br dd, 1H), 2.06 (s, 3H), 1.78 (s, 9H). 12.24 (s, 1H), 8.27 (s, 1H), 8.09 (br dd, 1H), 7.81 (dd, J = 8.5, 1.5 Hz, 1H), 7.65 (d, 55 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 (br s, 1H), 8.00 (app s, 1H), 7.72 (dd, J = 8.4, 1.5 56 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 (br t, 1H), 8.27 (s, 1H), 8.00 (app s, 1H), 7.70 (dd, J = 8.4, 1.5 57 Hz, 1H), 7.59 (d, J = 8.4 Hz, 1H), 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 (br d, J = 4.3 Hz, 1H), 8.27 (s, 1H), 7.98 (app s, 1H), 7.68 (dd, J 58 = 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 (app d, 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, 1H), 8.28 (s, 1H), 8.11 (app s, 1H), 7.68 (app d, J = 8.3 Hz, 60 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). NH 2 signals not present. 11.90 (s, 1H), 8.38 (br q, J = 4.6 Hz, 1H), 8.01 (app s, 1H), 7.79 (s, 1H), 7.67 (d, J = 61 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, 1H), 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 (br s, 2H), 5.39 (p, J = 8.46 Hz, 1H), 2.82 (d, J = 4.39 Hz, 3H), 2.79-2.64 (m, 2H), .39 (m, 2H), 1.98- 1.81 (m, 2H). 11.88 (s, 1H), 8.39 (d, J = 4.21 Hz, 1H), 8.27 (s, 1H), 8.00 (s, 1H), 7.65 (d, J = 8.34 Hz, 1H), 7.56 (dd, J = 1.54, 8.41 Hz, 1H), 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, 11.84 (s, 1H), 8.37 (d, J = 4.99 Hz, 1H), 8.27 (s, 1H), 8.00 (s, 1H), 7.65 (d, J = 8.35 Hz, 1H), 7.55 (dd, J = 1.25, 8.45 Hz, 1H), 7.11 (br s, 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, 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 65 (d, J = 8.38 Hz, 1H), 7.02 (br s, 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, 1H), 8.37 (d, J = 4.70 Hz, 1H), 8.29 (s, 1H), 7.99 (s, 1H), 7.65 (d, J = 8.43 66 Hz, 1H), 7.55 (dd, J = 1.54, 8.37 Hz, 1H), 7.15 (br s, 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 67 Hz, 1H), 7.55 (dd, J = 1.50, 8.28 Hz, 1H), 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), .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), .80 (br, 2H), 1.79 (s, 9H). 12.20 (s, 1H), 8.31 (br q, 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, 1H), 9.51 (br s, 1H), 8.25 (s, 1H), 7.56 (d, J = 8.5 Hz 1H), 7.44-7.40 (m, 1H), 7.01 (br, 2H), 6.97 (dd, J = 8.5, 1.9 Hz, 1H), 6.79 (br d, 1H), 2.92 (s, 3H), 1.78 (s, 9H). 11.31 (s, 1H), 8.43 (s, 1H), 8.24 (s, 1H), 7.82 (app s, 1H), 7.43 (d, J = 8.5 Hz, 1H), 6.99 (br, 2H), 6.89 (dd, J = 8.5, 1.9 Hz, 1H), 6.70- 6.69 (m, 1H), 5.92 (q, J = 4.6 Hz, 1H), 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 = 72 8.5, 1.5 Hz, 1H), 7.62 (d, J = 8.5 Hz, 1H), 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 73 (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). 12.18 (s, 1H), 8.50 (br q, 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, 1H), 7.62 (d, J = 8.5 Hz, 1H), 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 (app t, 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, 1H), 7.62 (d, J = 8.4 Hz, 1H), 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), 7.77-7.74 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 (br t, J = 6.0 Hz, 1H), 8.27 (s, 1H), 8.00 (app s, 1H), 7.71 (dd, J = 8.4, 1.5 Hz, 1H), 7.59 (d, J = 8.4 Hz, 1H), 6.92 (br, 2H), 3.87-3.84 (m, 2H), 3.28 (td, ed 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), .16 (m, 2H). 11.50 (s, 1H), 8.38 (br q, 1H), 8.26 (s, 1H), 7.93 (app s, 1H), 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) 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 (br dd, 1H), 6.84 (br, 2H), 2.07 (s, 3H), 1.77 (s, 9H). 8.49 (q, J = 4.4 Hz, 1H), 8.27 (s, 1H), 8.17 (br, 1H), 7.74 (dd, J = 8.4, 1.4 Hz, 1H), 83 7.63 (app d, J = 8.4 Hz, 1H), 3.74 (s, 3H), 2.85 (d, J = 4.4 Hz, 3H), 1.79 (s, 9H). NH2 signals not present. 11.97 (s, 1H), 8.25 (d, J = 4.67 Hz, 1H), 8.05 (s, 1H), 7.77 (d, J = 1.23 Hz, 1H), 7.46 84 (dd, J = 1.42, 8.45 Hz, 1H), 7.37 (d, J = 8.44 Hz, 1H), 6.86 (br s, 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 (br s, 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 (br s, 2H), 5.29 (p, J = 7.19 Hz, 1H), 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, 12.49 (s, 1H), 8.57 (br q, J = 4.4 Hz, 1H), 8.26 (s, 1H), 7.94 (d, J = 1.2 Hz, 1H), 7.66 (s, 1H), 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, 88 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 (br s, 2H), 89 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 × CH2 not 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 (br s, 2H), 5.06-4.89 (m, 1H), 4.10 (d, J = 13.01 Hz, 2H), 3.03 (br s, 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 (br t, J = 5.6 Hz, 1H), 8.27 (s, 1H), 8.00 (app s, 1H), 7.71 (dd, J 91 = 8.4, 1.5 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 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 (br q, J = 4.5 Hz, 1H), 8.01 (app s, 1H), 7.80 (s, 1H), 7.71 (dd, J 92 = 8.4, 1.5 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 6.06 (s, 2H), 5.60 (hept, J = 6.6 Hz, 1H), 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, 1H), 8.52 (s, 1H), 8.03 (s, 1H), 7.71 (dd, J = 1.42, 8.46 Hz, 1H), 7.61 (d, J 93 = 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, 1H), 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 (br q, 1H), 8.28 (s, 1H), 8.00 (s, 1H), 7.70 (br d, 1H), 7.60 (br d, 94 1H), 7.04 (br, 2H), 4.31 (d, J = 7.0 Hz, 2H), 3.85-3.81 (m, 2H), 3.26 (br t, 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). 95 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 = 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, 1H), 8.32 (br s, 1H), 8.27 (s, 1H), 7.90 (dd, J = 8.4, 1.4 Hz, 97 1H), 7.76 (t, J = 57.3 Hz, 1H), 7.74 (app d, J = 8.4 Hz, 1H), 7.21 (br, 2H), 2.85 (d, J = 4.4 Hz, 3H), 1.77 (s, 9H). 12.14 (s, 1H), 8.50 (br t, 1H), 8.29 (s, 1H), 8.01 (app s, 1H), 7.71 (br dd, 1H), 7.60 (br d, 1H), 5.58-5.52 (m, 1H), 4.17-4.07 (over-lapping m, 1H), .07 (m, 1H), 3.99 (dd, J = 9.2, 4.4 Hz, 1H), 3.94-3.89 (m, 1H), 3.29-3.23 (m, 2H), .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 (br t, 1H), 8.35 (s, 1H), 8.01 (app s, 1H), 7.71 (br d, 1H), 7.61 (br 99 d, 1H), 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 (br q, 1H), 8.35 (s, 1H), 8.01 (app s, 1H), 7.70 (br dd, 1H), 7.62 100 (br d, 1H), 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 (br d,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), 4.15 101 (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), .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 (br d, 1H), 8.35 (s, 1H), 7.99 (app s, 1H), 7.69 (br d, 1H), 7.60 102 (br d, 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 = 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 (app t, 2H), 2.91-2.87 (m, 1H), 2.28-2.18 (m, 2H), .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, 1H), 8.27 (s, 1H), 7.99 (s, 1H), 7.68 (dd, J = 1.44, 8.45 Hz, 1H), 7.58 (d, J = 8.39 Hz, 1H), 7.16 (br s, 2H), 5.23 (p, J = 8.14 Hz, 1H), 4.95 (s, 104 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. 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, 1H), 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 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, 1H), 7.20 (d, J = 0.8 Hz, 1H), 4.93 (p, J = 6.7 Hz, 1H), 1.34 (d, J = 6.7 Hz, 6H). NH 2 s not observed.

Synthesis of Other Examples Example 39 - 2-[4-Amino(propanyl)-1H-pyrazolo[4,3-c]pyridinyl]bromo-N-methyl- 1H-indolecarboxamide Prepared according to a similar procedure to that used in General Method 8 from 2- (4-aminoisopropyl-1H-pyrazolo [4,3-c]pyridinyl)-N-methyl-1H-indolecarboxamide (100 mg, 0.287 mmol) and NBS (56 mg, 0.32 mmol) for a reaction time of 1 h (7:3 e of mono- and dibrominated products observed by HPLC) and purified by fcc (0-5% MeOH:DCM) to return the title compound (31 mg, 25%) as a brown solid.

Example 51 - 2-{4-Aminotert-butyl-1H-pyrazolo[3,4-d]pyrimidinyl}-N-methyl-1H- pyrrolo[2,3-b]pyridinecarboxamide ] A mixture of 6-amino((4-amino(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidin ynyl)-N-methylpicolinamide (138 mg, 0.38 mmol) and potassium utoxide (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 fcc (0-5% MeOH (+ 1% NH3) in DCM) to return the title compound (22 mg, 91% pure by HPLC, 16%) as a yellow solid. e 54 - N-(2-{4-Aminotert-butyl-1H-pyrazolo[3,4-d]pyrimidinyl}-1H-indol yl)acetamide To a solution of 3-(6-amino-1H-indolyl)(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidin- 4-amine (51 mg, 0.15 mmol) in DCM (2 mL) was added pyridine (20 µL, 0.25 mmol) then acetic anhydride (20 µL, 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 c layer was washed with sat aq NH4Cl (10 mL), sat aq NaHCO3 (10 mL) and brine (2 × 10 mL), then dried and concentrated in vacuo. The crude t was purified by fcc (0- % MeOH in DCM) to return the title compound (29 mg, 53%) as an off-white solid.

Example 55 - 1-(2-{4-Aminotert-butyl-1H-pyrazolo[3,4-d]pyrimidinyl}chloro-1H-indol- 6-yl)propanone To a solution of 1-(2-(4-amino(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidinyl) chloro-1H-indolyl)propanol (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 ature 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 fcc (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(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidinyl)-1H-indolyl) methanesulfonamide To a mixture of 3-(6-amino-1H-indolyl)(tert-butyl)-1H-pyrazolo[3,4- d]pyrimidinamine (40 mg, 0.12 mmol) and pyridine (20 µL, 0.25 mmol) in DCM (1 mL) at 0 °C was added methanesulfonyl chloride (15 µL, 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 HCl (1.0 M) and sat aq NaHCO3 and the layer separated. The aq layer was extracted with further DCM (2 × 10 mL) and the combined organic extracts washed with brine (2 × 10 mL), passed through a phase tor and concentrated in vacuo. The result thus obtained was purified by fcc (0-100% EtOAc in isohexane then 0-10% MeOH in DCM). The orange solid isolated was further purified by ative HPLC to return the title compound (9 mg, 20% yield) as a pale yellow solid.

Example 71 – 1-(2-(4-Amino(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidinyl)-1H-indolyl) methylurea To a solution of phenyl (2-(4-amino(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidin- 3-yl)-1H-indolyl)carbamate (57 mg, 0.11 mmol) in THF (1 mL) was added methylamine (2.0 M in THF, 0.10 mL) and the ing mixture stirred at room ature 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 NaHCO3 (20 mL) and the biphasic mixture separated. The aq layer was ted with further EtOAc (20 mL) and the combined organic extracts washed with brine (2 × 20 mL), dried and concentrated in vacuo. The crude product was purified by fcc (0-10% MeOH in DCM) to return the title compound (4 mg, 10% yield) as a pale yellow solid. e 93 - 2-[4-amino(piperidinyl)-1H-pyrazolo[3,4-d]pyrimidinyl]chloro-N- cyclopropyl-1H-indolecarboxamide hydrochloride ] To a solution of tert-butyl mino[3-chloro(cyclopropylcarbamoyl)-1H-indol- 2-yl]pyrazolo[3,4-d]pyrimidinyl]piperidinecarboxylate (30 mg, 0.05 mmol) in 1,4-dioxane (4 mL) at room temperature was added HCl (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 trated in vacuo to return return the tile compound (24 mg, 90%) as a yellow solid.

Example 97 - 2-{4-aminotert-butyl-1H-pyrazolo[3,4-d]pyrimidinyl}chloro (difluoromethyl)-N-methyl-1H-indolecarboxamide To a mixture of 2-(4-amino tert-butyl-pyrazolo[3,4-d]pyrimidinyl)chloro-N- methyl-1H-indolecarboxamide (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 e 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 × 50 mL). The combined organic extracts were washed with brine (50 mL), dried and concentrated in vacuo. The crude product was purified by fcc (0-100% EtOAc in isohexane) to return the title compound (3.7 mg, 10%) as a white solid.

Biological data RET, RETV804M and KDR Enzyme Assays Kinase activity was detected using CisBio HTRF kinEASE kit based on time-resolved fluorescence er (FRET). The assay was performed in 384-well white plates (Corning #3574) in a reaction volume of 10 µL containing 1X CisBio enzymatic buffer supplemented with a final tration of 5 mM MgCl2, 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 MnCl2.

RETV804M buffer used 1X CisBio enzymatic buffer mented with a final concentration of 2 mM MgCl2, 1mM DTT, 20 nM SEB and 0.01% Triton X100. tors were pre-incubated in the plate for 15 mins with 5 µL kinase and assay buffer at the following concentrations; 13 pM RET (Carna Biosciences; 08-159), 30 pM RETV804M (Millipore; 14-760) and 150 pM KDR (Millipore; 14-630). The reaction was initiated by the addition of 5 µL ATP and ate at 2X final reaction concentrations. For RET, this was 18 µM and 2 µM; for RETV804M, this was 4 µM and 1.5 µM and for KDR, this was 16 µM and 1 µM, respectively. Reactions were performed at ATP Km for each target. The assay was allowed to proceed at room temperature for 30 mins before ating with the addition of 10 µL 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.

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 RETV804MEnzyme EXAMPLE IC50 (μM) IC50 (μM) IC50 (μM) 1 0.0172 5.98 0.7 2 0.0186 2.02 0.838 3 0.0232 11.1 >1 4 0.0177 5.35 0.019 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 8.14 >>30 >30 11 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 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 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 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 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 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 11.2 0.0434 40 6 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 0.114 >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 6.11 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 0.0111 1.05 83 0.0536 11.4 0.225 84 0.0215 >30 0.0648 85 0.0322 11.3 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 0.0311 8.37 0.0951 96 0.013 1.08 0.0207 97 11.2 >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 6 0.924 0.0222 104 0.00425 0.245 0.00848 105 0.0318 5.31 0.114 106 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 The system originally ped by Daley and Baltimore16 was used, y IL3- dependent BaF3 cells are modified to express an activated recombinant kinase. Following removal of IL3, the modified cells are dependent on the ty of the recombinant kinase for survival and proliferation. The BaF3 cell lines, expressing 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 µL 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 µL CellTiter-Glo t (Promega) and measurement of luminescence.

] 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(μM) (μM) (μM) (μM) 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 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 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 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 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 0.21 >10 1.35 >10 26 0.46 >10 0.538 6 27 0.475 4.91 0.556 4.88 28 0.0896 4.24 0.0678 6.4 29 0.0191 4.64 0.151 9.73 >10 >10 >10 >10 31 1.19 >10 4.29 >10 32 5.91 >10 >10 >10 33 0.555 >10 0.308 >10 34 1.51 >10 3.87 >10 0.0199 2.07 0.0264 >10 36 0.0164 1.01 0.0338 6.56 37 0.17 >10 2.55 >10 38 0.101 8.24 0.235 >10 39 0.185 >10 0.602 >10 40 0.0159 0.905 0.0779 4.29 41 0.05 3.56 0.129 6.85 42 >10 >10 >10 >10 43 0.0537 5.03 0.083 >10 44 3.15 >10 6.94 >10 45 3.43 >10 >10 >10 46 >10 >10 >10 >10 47 0.0417 1.39 0.445 4.6 48 0.0685 6.38 0.117 >10 49 0.0502 5.88 0.0985 >10 50 0.192 9.09 0.361 >10 51 0.71 4.02 1.2 >10 52 0.0576 6.11 0.243 >10 52 0.0863 >10 2.58 >10 54 0.0137 1.54 0.195 1.75 55 0.308 >10 0.525 >10 56 0.101 6.83 0.116 >10 57 0.0245 3.55 0.0345 >10 58 0.0137 0.754 0.0137 >10 59 0.0804 3.62 0.12 >10 60 0.252 7.42 1.32 9.11 61 0.0383 5.11 0.469 >10 62 0.0716 9.44 0.112 >10 63 0.091 4.53 0.565 4.37 64 0.0689 3.23 0.55 2.94 65 0.0235 5.4 0.0587 >10 66 0.488 >10 3.11 >10 67 0.467 >10 3.02 >10 68 0.0407 >10 0.0758 >10 69 0.0303 4.63 0.161 >10 70 0.1 1.79 1.77 >10 71 5 0.051 0.0244 0.0539 72 1.75 >10 2.07 >10 73 0.0661 2.23 0.0588 >10 74 0.0724 3.95 0.509 3.42 75 0.106 5.7 0.143 >10 76 0.28 6.78 0.239 7.45 77 0.153 5.7 0.125 8.44 78 0.0926 4.53 0.147 >10 79 0.223 >10 0.208 >10 80 1.49 >10 0.561 >10 81 0.111 >10 0.34 >10 82 0.0072 0.871 0.0112 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 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 d in the art without departing from the scope of the invention as defined by the appended claims.

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Claims (25)

1. A compound, or compounds, or pharmaceutically acceptable salt, hydrate or solvate thereof, having the structural formula (Id) shown below: HET is selected from one of the following: wherein denotes the point of attachment; R1 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, SO2, N(Ra), C(O), C(O)O, OC(O), C(O)N(Ra), N(Ra)C(O), N(Ra)C(O)N(Rb), N(Ra)C(O)O, OC(O)N(Ra), S(O)2N(Ra), or N(Ra)SO2, n 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- cloalkyl, (3-10C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Q is optionally further tuted by one or more substituent groups ndently 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(O)ORc, c, C(O)N(Rd)Rc, N(Rd)C(O)Rc, S(O)yRc (where y is 0, 1 or 2), SO2N(Rd)Rc, N(Rd)SO2Rc, Si(Rd)(Rc)Re or (CH2)zNRcRd (where z is 1, 2 or 3); wherein Rc, Rd and Re are each ndently 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 cyclic ring which is optionally substituted by one or more substituents selected from (1- 4C)alkyl, halo, (1-4C)haloalkyl, haloalkoxy, (1-4C)alkoxy, (1- 4C)alkylamino, amino, cyano or hydroxyl; or Q is optionally substituted by a group of the formula: -L1-LQ1-Z1 wherein: L1 is absent or (1-3C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkyl or oxo; LQ1 is absent or selected from or O, S, SO, SO2, N(Rf), C(O), C(O)O, OC(O), C(O)N(Rf), N(Rf)C(O), N(Rg)C(O)N(Rf), N(Rf)C(O)O, OC(O)N(Rf), (Rf), or N(Rf)SO2, wherein Rf and Rg are each independently selected from hydrogen or (1- yl; and Z1 is hydrogen, alkyl, aryl, aryl(1-2C)alkyl, (3- 8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Z1 is optionally tuted by one or more substituents selected from 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(O)Rh, C(O)ORh, OC(O)Rh, C(O)N(Ri)Rh, N(Ri)C(O)Rh, S(O)yaRh (where ya is 0, 1 or 2), i)Rh, N(Ri)SO2Rh or (CH2)zaNRiRh (where za is 1, 2 or 3); wherein Rh and Ri are each independently selected from hydrogen, (1-4C)alkyl or (3- 6C)cycloalkyl; R1a and R1b 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 to; W is selected from O, S or NRj, wherein Rj is selected from H or (1-2C)alkyl; X1 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(O)Rk1, C(O)ORk1, OC(O)Rk1, C(O)N(Rk2)Rc, N(Rk2)C(O)Rk1, S(O)ybRk1 (where yb is 0, 1 or 2), SO2N(Rk2)Rk1, N(Rk2)SO2Rk1 or (CH2)zbNRk1Rk2 (where zb is 1, 2 or 3); wherein said (1-4C)alkyl is optionally tuted by one or more substituents selected from amino, hydroxy, (1-2C)alkoxy or halo; and Rk1 and Rk2 are each independently selected from hydrogen or (1- 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(O)Rm1, C(O)ORm1, OC(O)Rm1, C(O)N(Rm2)Rm1, N(Rm2)C(O)Rm1, S(O)ycRm1 (where yc is 0, 1 or 2), SO2N(Rm2)Rm1, N(Rm2)SO2Rm1 or (CH2)zcNRm1Rm2 (where zc is 1, 2 or 3); wherein said (1-4C)alkyl is optionally substituted by one or more substituents selected from amino, y, (1-2C)alkoxy or halo; and Rm1 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(O)Ro1, C(O)ORo1, OC(O)Ro1, C(O)N(Ro2)Ro1, N(Ro2)C(O)Ro1, S(O)ydRo1 (where yd is 0, 1 or 2), SO2N(Ro2)Ro1, N(Ro2)SO2Ro1 or (CH2)zdNRo1Ro2 (where zd is 1, 2 or 3); n said (1-4C)alkyl is optionally substituted by one or more substituents ed from amino, hydroxy, (1-2C)alkoxy or halo; and Ro1 and Ro2 are each independently ed from hydrogen or (1-4C)alkyl; R2 is selected from en, (1-4C)alkyl or a group of the a: -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(O)O, C(O)N(Rp), wherein Rp is selected from hydrogen or (1-4C)alkyl; and Q2 is hydrogen, (1-6C)alkyl, aryl, cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Q2 is optionally further tuted by one or more substituent groups independently selected from (1- 4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, amino, cyano, hydroxy, carboxy, oyl, sulphamoyl, NRqRr, ORq, n 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: -Y3-Q3 wherein: Y3 is C(O), C(O)N(Ry), C(O)N(Ry)O, N(Ry)(O)C, C(O)O, OC(O), N(Ry)C(O)N(Ry1), SO2N(Ry), N(Ry)SO2, oxazolyl, triazolyl, oxadiazolyl, thiazolyl, imidazolyl, thiadiazolyl, pyridinyl, pyrazolyl, pyrrolyl or tetrazolyl, wherein Ry and Ry1 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, aryl or heterocyclyl; n Q3 is optionally r 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 tuted by a group of the formula: 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 ed from or O, S, SO, SO2, N(Rab), C(O), C(O)O, OC(O), C(O)N(Rab), N(Rab)C(O), N(Rac)C(O)N(Rab), N(Rab)C(O)O, OC(O)N(Rab), (Rab), or N(Rab)SO2, 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, , aryl, heteroaryl, heterocycyl, (3-6C)cycloalkyl, NRadRae, ORad, C(O)Rad, C(O)ORad, OC(O)Rad, C(O)N(Rae)Rad, N(Rae)C(O)Rad, S(O)yeRad (where ye is 0, 1 or 2), ae)Rad, N(Rae)SO2Rad or eNRadRae (where ze is 1, 2 or 3); n 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 en 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 X1, X2 or X3 can be N.

2. A compound, or pharmaceutically acceptable salt, hydrate or solvate thereof, according to claim 1, n HET is selected from one of the following: wherein R1, R1a and R1b are each as defined in claim 1; or a pharmaceutically acceptable salt, hydrate or e thereof.

3. 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: wherein R1, R1a and R1b are each as defined in claim 1; or a pharmaceutically acceptable salt, e or e thereof.

4. A compound, or pharmaceutically acceptable salt, e or solvate thereof, according to any one of claims 1 to 3, wherein the compound has the structural Formula If shown below: X2 Q3 X1 N X3 Ry wherein HET, X1, X2, X3, Ro, R2, Q3 and Ry are each as defined in claim 1.

5. A compound, or pharmaceutically acceptable salt, hydrate or solvate thereof, according to any one of claims 1 to 4, wherein X1 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 able 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, n Rm is selected from hydrogen, halo, (1-4C)alkyl or amino.

7. A compound, or pharmaceutically acceptable salt, e or solvate thereof, according to any one of claims 1 to 6, wherein Ro 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: -Y3-Q3 wherein: Y3 is C(O), Ry), C(O)N(Ry)O, N(Ry)(O)C, C(O)O, OC(O), n 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; n Q3 is optionally further tuted 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 a: -L4-LQ4-Z4 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(O)O, OC(O), C(O)N(Rab), N(Rab)C(O), S(O)2N(Rab), or SO2, wherein Rab is ed 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, alkylamino, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, mercapto, ureido, aryl, heteroaryl, heterocycyl, (3-6C)cycloalkyl, NRadRae, ORad, d, C(O)ORad, OC(O)Rad, C(O)N(Rae)Rad, N(Rae)C(O)Rad, S(O)yeRad (where ye is 0, 1 or 2), SO2N(Rae)Rad, N(Rae)SO2Rad or (CH2)zeNRadRae (where ze is 1, 2 or 3); wherein Rad and Rae are each independently ed from hydrogen, (1-4C)alkyl or (3- 6C)cycloalkyl; or Q3 and Ry are linked such that they form a 4-7 ed 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 f, according to any preceding claim, wherein the compound has the structural Formula Ig shown below: wherein R1, Ro, R2, Ry and Q3 are each as defined in any one of claims 1 to 8.

10. A compound, or pharmaceutically able salt, hydrate or solvate thereof, according to any preceding claim, wherein Ro is selected from halo, (1-4C)alkyl or amino.

11. A compound, or ceutically acceptable salt, hydrate or e thereof, according to any preceding claim, wherein Ro is a halogen.

12. A compound, or pharmaceutically acceptable salt, hydrate or solvate thereof, according to any preceding claim, wherein R1 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 ed from (1-2C)alkyl or oxo; Y is absent or C(O), C(O)O, OC(O), C(O)N(Ra) or N(Ra)C(O), n Ra and Rb are each independently selected from hydrogen or (1- 4C)alkyl; and Q is hydrogen, (1-6C)alkyl, (2-6C)alkenyl, alkynyl, aryl, (3- 10C)cycloalkyl, (3-10C)cycloalkenyl, heteroaryl or cyclyl; 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(O)Rc, C(O)ORc, OC(O)Rc, C(O)N(Rd)Rc, N(Rd)C(O)Rc, S(O)yRc (where y is 0, 1 or 2), SO2N(Rd)Rc, O2Rc, 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 cycloalkyl.

13. A compound, or pharmaceutically acceptable salt, hydrate or solvate thereof, ing to any preceding claim, wherein R1 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 alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, amino, (1-4C)aminoalkyl, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, mercapto, , NRcRd, ORc, C(O)Rc, C(O)ORc, OC(O)Rc, C(O)N(Rd)Rc, N(Rd)C(O)Rc, S(O)yRc (where y is 0, 1 or 2), SO2N(Rd)Rc, N(Rd)SO2Rc, Si(Rd)(Rc)Re or NRdRc (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, e or solvate f, according to any preceding claim, wherein R1 is selected from hydrogen, 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; n Rc, Rd and Re are each independently selected from hydrogen or (1-4C)alkyl.

15. A nd, or ceutically 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: -Y2-Q2 Y2 is C(O)N(Rp), wherein Rp is selected from hydrogen or (1-4C)alkyl; Q2 is (1-6C)alkyl, aryl, (3-8C)cycloalkyl, heteroaryl or cyclyl; 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.

16. A compound, or pharmaceutically acceptable salt, hydrate or e f, according to any preceding claim, wherein R2 is hydrogen.

17. A compound, or pharmaceutically acceptable salt, hydrate or solvate thereof, according to claims 9 to 16, wherein Q3 is hydrogen, (1-6C)alkyl, alkoxy, aryl, -2C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Q3 is ally 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: -L4-LQ4-Z4 wherein: L4 is absent or (1-3C)alkylene; LQ4 is absent or selected from or O, N(Rab), C(O), C(O)O, or C(O)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- loalkenyl, 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 ceutically acceptable salt, hydrate or solvate thereof, according to claims 9 to 17, wherein Q3 is hydrogen, alkyl, (1-6C)alkoxy, aryl, aryl(1-2C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Q3 is optionally further tuted by one or more substituent groups independently selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, amino, cyano, hydroxy, carboxy, oyl, sulphamoyl, NRzRaa, ORz, n Rz and Raa are each independently selected from hydrogen or (1-4C)alkyl; or Q3 is ally substituted by a group of the formula: -LQ4-Z4 wherein: LQ4 is absent or selected from or O, N(Rab), C(O), C(O)O, or C(O)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 ally 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-Aminoisopropyl-pyrazolo[3,4-d]pyrimidinyl)-N-methyl-1H-indole carboxamide; 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidinyl)-N-methyl-1H-indole carboxamide; 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidinyl)-N-(1-methylpyrazolyl)-1H- indolecarboxamide; 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidinyl)-1H-indolecarboxamide; 2-(4-Aminoisopropyl-pyrazolo[3,4-d]pyrimidinyl)chloro-N-methyl-1H-indole carboxamide; 2-(4-Amino(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidinyl)bromo-N-methyl-1H- indolecarboxamide; 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidinyl)chloro-N-(2-methoxyethyl)- 1H-indolecarboxamide; 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidinyl)chloro-N-[2- (dimethylamino)ethyl]-1H-indolecarboxamide; minotert-butyl-pyrazolo[3,4-d]pyrimidinyl)chloro-N-(2-morpholinoethyl)- 1H-indolecarboxamide; 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidinyl)chloro-N-(3- morpholinopropyl)-1H-indolecarboxamide; 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidinyl)chloro-N-methoxy-1H-indole- 6-carboxamide; [2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidinyl)chloro-1H-indolyl]- pyrrolidinyl-methanone; 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidinyl)chloro-N,N-dimethyl-1H- indolecarboxamide; minotert-butyl-pyrazolo[3,4-d]pyrimidinyl)chloro-N-[2-(2- methoxyethoxy)ethyl]-1H-indolecarboxamide; 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidinyl)chloro-N-(3-methoxypropyl)- 1H-indolecarboxamide; 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidinyl)chloro-N-(2-hydroxyethyl)-1H- indolecarboxamide; 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidinyl)chloro-N-[2-(2- morpholinoethoxy)ethyl]-1H-indolecarboxamide; 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidinyl)chloro-N-[2-[2- (dimethylamino)ethoxy]ethyl]-1H-indolecarboxamide; 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidinyl)chloro-N-[3- (dimethylamino)propyl]-1H-indolecarboxamide; 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidinyl)chloro-N-[3-(1- piperidyl)propyl]-1H-indolecarboxamide; 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidinyl)chloro-N-(3- isopropoxypropyl)-1H-indolecarboxamide; mino(2-hydroxyethyl)pyrazolo[3,4-d]pyrimidinyl]chloro-N-methyl-1H- indolecarboxamide; 2-[4-Amino(3-methoxypropyl)pyrazolo[3,4-d]pyrimidinyl]chloro-N-methyl-1H- indolecarboxamide; 2-[4-Amino(1-methylsulfonylpiperidyl)pyrazolo[3,4-d]pyrimidinyl]chloro-N- methyl-1H-indolecarboxamide; 2-(4-Aminomethyl-pyrazolo[3,4-d]pyrimidinyl)chloro-N-methyl-1H-indole carboxamide; 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidinyl)chloro-N-[1-(2- methoxyethyl)pyrazolyl]-1H-indolecarboxamide; 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidinyl)chloro-N-[1-(2- morpholinoethyl)pyrazolyl]-1H-indolecarboxamide; 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidinyl)chloro-N-[1-[2- (dimethylamino)ethyl]pyrazolyl]-1H-indolecarboxamide; 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidinyl)chloro-N-[1-[2-(4- methylpiperazinyl)ethyl]pyrazolyl]-1H-indolecarboxamide; 2-[4-Amino(2-aminoethyl)pyrazolo[3,4-d]pyrimidinyl]chloro-N-methyl-1H- indolecarboxamide; 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidinyl)chloro-N-[1-(2- hydroxyethyl)pyrazolyl]-1H-indolecarboxamide; 2-{4-Aminocyclobutyl-1H-pyrazolo[3,4-d]pyrimidinyl}chloro-N-methyl-1H- carboxamide; 2-{4-Aminocyclohexyl-1H-pyrazolo[3,4-d]pyrimidinyl}-N-methyl-1H-indole carboxamide; minocyclopentyl-1H-pyrazolo[3,4-d]pyrimidinyl}-N-methyl-1H-indole carboxamide; 2-(4-Aminoisopropyl-7H-pyrrolo[2,3-d]pyrimidinyl)-N-methyl-1H-indole carboxamide; minoisopropylimidazo[1,5-a]pyrazinyl)chloro-N-methyl-1H-indole carboxamide; 2-(8-Aminoisopropyl-imidazo[1,5-a]pyrazinyl)-N-methyl-1H-indole carboxamide; 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidinyl)-N-methyl-3H-benzimidazole carboxamide; 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidinyl)fluoro-N-methyl-1H-indole amide; 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidinyl)chloro-N-methyl-1H-indole carboxamide; 2-(4-Aminocyclohexyl-1H-pyrazolo[3,4-d]pyrimidinyl)chloro-N-methyl-1H- indolecarboxamide; 2-(4-aminoisopropyl-7H-pyrrolo[2,3-d]pyrimidinyl)chloro-N-methyl-1H-indole- 6-carboxamide; 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidinyl)chloro-1H-indolecarboxylic acid; 2-{4-Aminotert-butyl-1H-pyrazolo[3,4-d]pyrimidinyl}chloro-N-(oxanyl)-1H- indolecarboxamide; 2-{4-Aminotert-butyl-1H-pyrazolo[3,4-d]pyrimidinyl}chloro-N-(propanyl)- 1H-indolecarboxamide; 2-{4-Aminotert-butyl-1H-pyrazolo[3,4-d]pyrimidinyl}chloro-N-ethyl-1H-indole- 6-carboxamide; 2-{4-Aminotert-butyl-1H-pyrazolo[3,4-d]pyrimidinyl}chloro-N-cyclopropyl-1H- indolecarboxamide; minotert-butyl-1H-pyrazolo[3,4-d]pyrimidinyl}chloro-N-phenyl-1H- indolecarboxamide; 2-[4-Amino(propanyl)-1H-pyrazolo[4,3-c]pyridinyl]-N-methyl-1H-indole carboxamide; mino(propanyl)-1H-pyrazolo[4,3-c]pyridinyl]chloro-N-methyl-1H- indolecarboxamide; 2-[4-Amino(propanyl)-1H-pyrazolo[4,3-c]pyridinyl]bromo-N-methyl-1H- indolecarboxamide; 2-{4-Aminothieno[2,3-d]pyrimidinyl}chloro-N-methyl-1H-indolecarboxamide; 2-{4-Aminothieno[2,3-d]pyrimidinyl}-N-methyl-1H-indolecarboxamide; 2-[4-Amino(propanyl)pyrrolo[2,1-f][1,2,4]triazinyl]-N-methyl-1H-indole carboxamide; 2-[4-Amino(propanyl)pyrrolo[2,1-f][1,2,4]triazinyl]chloro-N-methyl-1H- indolecarboxamide; 2-[4-Amino(propanyl)imidazo[4,3-f][1,2,4]triazinyl]chloro-N-methyl-1H- carboxamide; 2-[4-Aminochloro(propanyl)-1H-pyrazolo[4,3-c]pyridinyl]-N-methyl-1H- indolecarboxamide; 2-{4-Aminotert-butyl-1H-pyrazolo[3,4-d]pyrimidinyl}chloro-N-methyl-1H- pyrrolo[2,3-b]pyridinecarboxamide; 2-{4-Aminotert-butyl-1H-pyrazolo[3,4-d]pyrimidinyl}-N-methyl-1H-pyrrolo[2,3- b]pyridinecarboxamide; 2-(4-Amino(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidinyl)methyl-1H-indole carboxylic acid; 2-(4-Amino(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidinyl)chloro-N-methyl-1H- indolecarboxamide; N-(2-{4-Aminotert-butyl-1H-pyrazolo[3,4-d]pyrimidinyl}-1H-indolyl)acetamide; 1-(2-{4-Aminotert-butyl-1H-pyrazolo[3,4-d]pyrimidinyl}chloro-1H-indol yl)propanone; 2-{4-Aminotert-butyl-1H-pyrazolo[3,4-d]pyrimidinyl}-N,1-dimethyl-1H-indole carboxamide; 2-(4-Amino(1-methylpiperidinyl)-1H-pyrazolo[3,4-d]pyrimidinyl)chloro-N- cyclopropyl-1H-indolecarboxamide; 3-[3-Chloro(1,3,4-thiadiazolyl)-1H-indolyl]isopropyl-pyrazolo[3,4- d]pyrimidinamine; 3-(3-Chlorooxazolyl-1H-indolyl)isopropyl-pyrazolo[3,4-d]pyrimidin amine; 1-Isopropyl[6-(1,3,4-thiadiazolyl)-1H-indolyl]pyrazolo[3,4-d]pyrimidin amine; or 1-Isopropyl(6-oxazolyl-1H-indolyl)pyrazolo[3,4-d]pyrimidinamine.

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 ition comprising a nd according to any one of claims 1 to 19, or a pharmaceutically acceptable salt or hydrate thereof and a pharmaceutically acceptable r 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 ent, 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 e thereof, or a pharmaceutical composition according to claim 21.

25. A method according to claim 24, wherein said cancer is medullary d cancer or non-small cell lung cancer.