NZ786565A

NZ786565A - Heterocyclic compounds as ret kinase inhibitors

Info

Publication number: NZ786565A
Application number: NZ786565A
Authority: NZ
Inventors: Allan Jordan; Rebecca Newton; Bohdan Waszkowycz; Jonathan Mark Sutton; George Hynd; Silvia Paoletta; Euan Alexander FORDYCE
Original assignee: Cancer Research
Filing date: 2017-04-18
Publication date: 2022-04-29

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 , which is the national phase entry in New Zealand of PCT international application (published as reference.

INTRODUCTION The present invention relates to certain compounds that on as inhibitors of RET (rearranged during ection) kinase enzyme activity. The present ion 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 ions in which RET kinase activity is implicated.

BACKGROUND OF THE INVENTION Cancer is caused by uncontrolled and unregulated ar proliferation. Precisely what causes a cell to become malignant and erate in an uncontrolled and unregulated manner has been the focus of e research over recent decades. This research has led to the identification of a number of molecular targets ated with key metabolic pathways that are known to be associated with malignancy.

RET (REarranged during Transfection) is a receptor tyrosine kinase (RTK) that forms part of a macromolecular receptor complex ning dimerized RET receptor, two coreceptors and a bound ligand. The glial d 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 eptor triggers RET dimerization followed by trans-phosphorylation of intracellular signalling cascades. These downstream signalling networks play a key role in regulating cell survival, differentiation, proliferation, migration and axis.

Activating mutations in RET have been identified in familial and sporadic forms of medullary thyroid carcinomas (MTC) (Santoro & Carlomagno 2006; Schulmberger et al. 2008; Wells & Santoro 2009) and these correlate with aggressive disease progression (Elisei et al. 2008). al benefit has been observed in MTC patients using the small molecule VEGFR2/EGFR inhibitor vandetanib (Wells et al. 2011) which has recently been approved by the FDA & EMEA. RET inhibition is a secondary pharmacology of this agent, which also targets VEGFR2 (Vascular endothelial growth factor receptor, also known as KDR - kinase insert domain receptor) and EGFR (epidermal growth factor receptor). The clinical benefit in MTC is considered to be due to RET inhibition but is unfortunately anied by significant side effects (rash, hypertension, diarrhoea) due to inhibition of EGFR and/or VEGFR.

Furthermore, vandetanib also exhibits off-target activity versus hERG. Collectively all of these unwanted pharmacological ties may compromise its use in advanced MTC and also its extrapolation into earlier 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) be 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 important ative disease segment in which a specific RET inhibitor would offer clinical benefit.

Mutation at the RET gatekeeper residue (V804) is predicted to confer resistance to first line therapies such as vandetanib and cabozantinib. Although not yet confirmed in this t 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 tors 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 disease settings.

It is therefore an object of the present invention to provide further inhibitors of RET kinase enzyme activity and mutants thereof (e.g. 4M).

Another object of the present invention is to provide inhibitors of RET kinase enzyme activity that show a greater ivity for the inhibition of RET kinase relative to the inhibition of KDR.

Y OF THE INVENTION According to a first aspect of the present invention, there is provided a compound, or a pharmaceutically acceptable salt, hydrate or e thereof, as defined herein. ing 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 ceutically acceptable diluent or carrier.

According to a further aspect of the present invention, there is provided a method of inhibiting RET kinase enzyme activity, or mutant forms thereof (e.g. RETV804M), in vitro or in vivo, said method comprising contacting a cell with an effective amount of a compound or a pharmaceutically acceptable salt, hydrate or solvate f as defined herein.

According to a further aspect of the present invention, there is ed a method of selectively inhibiting RET kinase enzyme activity, or mutant forms thereof (e.g. 4M), 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 .

According to a further aspect of the present invention, there is provided a method of inhibiting cell proliferation, in vitro or in vivo, said method comprising contacting a cell with an effective amount of a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.

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

According to a further aspect of the present invention, there is provided a method of treating cancer in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.

According to a further aspect of the t invention, there is provided a compound, or a ceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical ition as defined herein for use in therapy.

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

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

According to a r aspect of the present invention, there is provided a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein for use in the inhibition of mutant forms of RET kinase enzyme activity (e.g. RET V804M kinase enzyme activity). 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 selective inhibition of RET kinase enzyme ty, or mutant forms thereof (e.g. RETV804M), relative to KDR enzyme activity.

According to a further aspect of the t invention, there is provided a compound, or a ceutically acceptable salt, hydrate or solvate thereof, as defined herein for use in the treatment of a e or disorder in which RET kinase ty is implicated.

According to a further aspect of the present invention, there is provided the use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein in the manufacture of a medicament for the treatment of a proliferative ion.

Suitably, the proliferative er is cancer, suitably a human cancer (for example medullary thyroid cancer (MTC) or non-small cell lung cancer).

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

According to a r aspect of the present invention, there is provided a use of a compound, or a pharmaceutically acceptable salt, e or solvate thereof, as d 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 t invention, there is provided a use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate f, as defined herein in the manufacture of a medicament for the selective inhibition of RET kinase enzyme activity, or mutant forms thereof (e.g. RETV804M), relative to KDR enzyme activity.

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 d 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 process for preparing a compound, or a pharmaceutically able salt, hydrate or solvate thereof, as defined herein. ing to a further aspect of the present invention, there is provided a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, obtainable by, or obtained by, or directly obtained by a process of preparing a compound as defined herein.

According to a further aspect of the present invention, there are provided novel intermediates as defined herein which are suitable for use in any one of the synthetic methods set out herein.

Features, including optional, suitable, and preferred features in relation to one aspect of the invention may also be features, including al, suitable and preferred features in on 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 nces to "treating" or ment" include prophylaxis as well as the alleviation of established ms of a condition. "Treating" or "treatment" of a state, disorder or condition therefore includes: (1) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a human that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition, (2) inhibiting the state, disorder or condition, i.e., arresting, reducing or delaying the pment of the disease or a relapse thereof (in case of maintenance treatment) or at least one clinical or subclinical symptom thereof, or (3) relieving or attenuating the disease, i.e., causing sion of the state, er or condition or at least one of its clinical or subclinical symptoms.

A "therapeutically effective amount" means the amount of a compound that, when administered to a mammal for treating a e, is sufficient to effect such treatment for the disease. The "therapeutically ive amount" will vary depending on the compound, the e and its severity and the age, weight, etc., of the mammal to be treated.

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

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," ylene," or "alkynylene" group is an alkyl, alkenyl, or alkynyl group that is positioned between and serves to connect two other chemical groups. Thus, "(1- 6C)alkylene" means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms, for example, methylene, ethylene, ene, 2-methylpropylene, pentylene, and the like. "(2-6C)alkenylene" means a linear nt hydrocarbon radical of two to six carbon atoms or a branched nt arbon radical of three to six carbon atoms, containing at least one double bond, for example, as in ethenylene, 2,4-pentadienylene, and the like. "(2-6C)alkynylene" means a linear divalent hydrocarbon radical of two to six carbon atoms or a branched divalent hydrocarbon radical of three to six carbon atoms, containing at least one triple bond, for example, as in ethynylene, propynylene, and butynylene and the like. "(3-8C)cycloalkyl" means a hydrocarbon ring containing from 3 to 8 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or bicyclo[2.2.1]heptyl. "(3-8C)cycloalkenyl" means a hydrocarbon ring containing from 3 to 8 carbon atoms and at least one double bond, for example, cyclobutenyl, cyclopentenyl, cyclohexenyl or cycloheptenyl, such as 3-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 herein.

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

The term ocyclyl", "heterocyclic" or "heterocycle" means a non-aromatic saturated or partially saturated monocyclic, fused, bridged, or spiro bicyclic heterocyclic ring system(s). Monocyclic cyclic rings contain from about 3 to 12 (suitably from 3 to 7) ring atoms, with from 1 to 5 bly 1, 2 or 3) heteroatoms selected from nitrogen, oxygen or sulfur in the ring. Bicyclic cycles 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 e cyclic ethers such as oxiranyl, oxetanyl, tetrahydrofuranyl, dioxanyl, and substituted cyclic ethers. Heterocycles containing en e, for example, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrotriazinyl, tetrahydropyrazolyl, and the like. Typical sulfur containing heterocycles include tetrahydrothienyl, dihydro-1,3-dithiol, ydro-2H-thiopyran, and hexahydrothiepine. Other cycles include dihydro-oxathiolyl, tetrahydro-oxazolyl, tetrahydro-oxadiazolyl, tetrahydrodioxazolyl, tetrahydro-oxathiazolyl, hexahydrotriazinyl, tetrahydro-oxazinyl, morpholinyl, thiomorpholinyl, tetrahydropyrimidinyl, dioxolinyl, octahydrobenzofuranyl, octahydrobenzimidazolyl, and octahydrobenzothiazolyl. For heterocycles containing , the oxidized sulfur heterocycles containing SO or SO2 groups are also included. es include the sulfoxide and e forms of tetrahydrothienyl and thiomorpholinyl such as tetrahydrothiene 1,1-dioxide and thiomorpholinyl 1,1-dioxide. A suitable value for a heterocyclyl group which bears 1 or 2 oxo (=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 heteroatoms selected from nitrogen, oxygen or sulfur, for example azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, tetrahydrothienyl, tetrahydrothienyl 1,1-dioxide, thiomorpholinyl, thiomorpholinyl 1,1-dioxide, piperidinyl, homopiperidinyl, zinyl or homopiperazinyl. As the skilled person would iate, any heterocycle may be linked to another group via any suitable atom, such as via a carbon or nitrogen atom. However, nce herein to piperidino or morpholino refers to a piperidin yl or morpholinyl ring that is linked via the ring nitrogen.

By "bridged ring s" is meant ring systems in which two rings share more than two atoms, see for example Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages 131-133, 1992. Examples of bridged heterocyclyl ring systems include, aza-bicyclo[2.2.1]heptane, 2-oxaazabicyclo[2.2.1]heptane, aza-bicyclo[2.2.2]octane, azabicyclo [3.2.1]octane and quinuclidine.

By "spiro bi-cyclic ring systems" we mean that the two ring systems share one common spiro carbon atom, i.e. the heterocyclic ring is linked to a further carbocyclic or heterocyclic ring through a single common spiro carbon atom. Examples of spiro ring systems e 6- azaspiro[3.4]octane, 2-oxaazaspiro[3.4]octane, 2-azaspiro[3.3]heptanes, 2-oxa azaspiro[3.3]heptanes, 7-oxaazaspiro[3.5]nonane, 6-oxaazaspiro[3.4]octane, 2-oxa azaspiro[3.5]nonane and 2-oxaazaspiro[3.5]nonane.

"Heterocyclyl(1-6C)alkyl" means a heterocyclyl group ntly 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 incorporating one or more (for example 1-4, particularly 1, 2 or 3) heteroatoms ed from nitrogen, oxygen or sulfur. The term heteroaryl es both lent species and divalent species. Examples of heteroaryl groups are monocyclic and bicyclic groups containing from five to twelve ring members, and more usually from five to ten ring members.

The heteroaryl group can be, for example, a 5- or 6-membered monocyclic ring or a 9- or 10- membered bicyclic ring, for example a bicyclic ure formed from fused five and six membered rings or two fused six membered rings. Each ring may n up to about four heteroatoms typically selected from nitrogen, sulfur and oxygen. Typically the heteroaryl ring will contain up to 3 heteroatoms, more y up to 2, for example a single atom. 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 non-basic as in the case of an indole or pyrrole nitrogen. In general the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents of the ring, will be less than five.

Examples of heteroaryl include furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, azolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazenyl, benzofuranyl, indolyl, isoindolyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzothiazolyl, lyl, purinyl, benzofurazanyl, quinolyl, isoquinolyl, olinyl, quinoxalinyl, cinnolinyl, inyl, naphthyridinyl, carbazolyl, phenazinyl, benzisoquinolinyl, pyridopyrazinyl, thieno[2,3-b]furanyl, 2H-furo[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 omatic, saturated or partially saturated ring, provided at least one ring contains one or more heteroatoms selected from nitrogen, oxygen or sulfur. Examples of partially aromatic heteroaryl groups include for example, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 2-oxo- 1,2,3,4-tetrahydroquinolinyl, dihydrobenzthienyl, dihydrobenzfuranyl, 2,3-dihydrobenzo [1,4]dioxinyl, benzo[1,3]dioxolyl, oxo-1,3-dihydrobenzothienyl, 4,5,6,7- tetrahydrobenzofuranyl, indolinyl, 1,2,3,4-tetrahydro-1,8-naphthyridinyl, 1,2,3,4-tetrahydropyrido[2,3-b]pyrazinyl and 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl. es of five membered heteroaryl groups include but are not limited to pyrrolyl, furanyl, thienyl, olyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, lyl and tetrazolyl groups.

Examples of six membered aryl groups include but are not limited to pyridyl, pyrazinyl, zinyl, pyrimidinyl and triazinyl.

A bicyclic heteroaryl group may be, for example, a group selected from: a benzene ring fused to a 5- or 6-membered ring ning 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 atoms; 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 ered 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 atoms; a thiazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; an isothiazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; a thiophene ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; a furan ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; a exyl ring fused to a 5- or 6-membered heteroaromatic ring ning 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, benzisoxazolyl, benzthiazolyl, benzisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, indolinyl, isoindolinyl, purinyl (e.g., adeninyl, guaninyl), indazolyl, ioxolyl and pyrazolopyridinyl groups. ular examples of bicyclic heteroaryl groups containing two fused six membered rings include but are not limited to quinolinyl, isoquinolinyl, chromanyl, thiochromanyl, chromenyl, isochromenyl, chromanyl, isochromanyl, benzodioxanyl, izinyl, benzoxazinyl, benzodiazinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, azinyl, naphthyridinyl and pteridinyl groups.

"Heteroaryl(1-6C)alkyl" means a heteroaryl group covalently attached to a (1- 6C)alkylene group, both of which are d herein. Examples of heteroaralkyl groups e pyridinylmethyl, zofuranyl)propyl, and the like.

The term "aryl" means a cyclic or polycyclic aromatic ring having from 5 to 12 carbon atoms. The term aryl includes both monovalent species and divalent species. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl and the like. In particular embodiment, an aryl is phenyl.

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

This specification also makes use of several composite terms to describe groups sing more than one onality. Such terms will be understood by a person d 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 tuted 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 ated group.

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

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

Compounds of the invention 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 ment; 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 tuted 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), 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, wherein Ra and Rb are each independently selected from hydrogen or (1-4C)alkyl; and Q is hydrogen, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, aryl, (3- 10C)cycloalkyl, (3-10C)cycloalkenyl, heteroaryl or heterocyclyl; 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, y, 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), d)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 selected from (1- 4C)alkyl, halo, (1-4C)haloalkyl, 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 (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), 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 hydrogen, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, (3- 8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Z1 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, hydroxy, carboxy, oyl, sulphamoyl, mercapto, , 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), SO2N(Ri)Rh, N(Ri)SO2Rh or (CH2)zaNRiRh (where za is 1, 2 or 3); wherein Rh and Ri are each ndently ed from hydrogen, alkyl or (3- 6C)cycloalkyl; R1a and R1b are each independently selected from hydrogen, (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano, y, carboxy, oyl, sulphamoyl or mercapto; W is ed from O, S or NRj, wherein Rj is selected from hydrogen or (1- 2C)alkyl; bonds a, b, c and d are independently selected from a single or double bond; X1 and X2 are each ndently 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 ed from hydrogen, halo, (1-4C)alkyl, (1-4C)alkoxy, amino, (1-4C)alkylamino, 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 (1-4C)alkyl is optionally substituted by one or more substituents ed from amino, hydroxy, (1-2C)alkoxy or halo; Rl is selected from hydrogen or (1-4C)alkyl; and Rk1 and Rk2 are each independently ed from hydrogen or (1- 4C)alkyl; X3 is selected from N or CRm when bond b is a double bond, or NRn or CRmRn when bond b is a single bond; wherein Rm is selected from hydrogen, halo, (1-4C)alkyl, (1-4C)alkoxy, amino, (1-4C)alkylamino, (1-4C)dialkylamino, cyano, (2C)alkynyl, 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, hydroxy, (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, (1-4C)dialkylamino, cyano, (2C)alkynyl, 1, 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 ed from amino, hydroxy, (1-2C)alkoxy or halo; Rx is selected from hydrogen or (1-4C)alkyl; and Ro1 and Ro2 are each independently selected from en or (1- 4C)alkyl; R2 is selected from hydrogen, (1-4C)alkyl or a group of the formula: -L2-Y2-Q2 wherein: L2 is absent or (1-3C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkyl or oxo; Y2 is absent or C(O), C(O)O, C(O)N(Rp), wherein Rp is ed from hydrogen or (1-4C)alkyl; and Q2 is hydrogen, (1-6C)alkyl, aryl, (3-8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Q2 is optionally further substituted by one or more substituent groups ndently selected from (1- 4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, NRqRr, ORq, wherein Rq and Rr are each independently selected from hydrogen, (1-4C)alkyl or (3- loalkyl; 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), (O)N(Ry1), y), N(Ry)SO2, oxazolyl, triazolyl, oxadiazolyl, thiazolyl, imidazolyl, thiadiazolyl, pyridinyl, pyrazolyl, pyrrolyl or tetrazolyl, wherein Ry and Ry1 are independently ed from hydrogen or (1-2C)alkyl; and Q3 is en, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, (3-8C)cycloalkyl, (3- loalkenyl, 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 tuted 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), 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 alkyl; and Z4 is hydrogen, alkyl, aryl, aryl(1-2C)alkyl, (3- 8C)cycloalkyl, (3-8C)cycloalkenyl, aryl 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, 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, alkyl or (3- 6C)cycloalkyl; or Q3 and Ry are linked such that, together with the nitrogen atom to which they are attached, they form a 4-7 membered heterocyclic ring which is optionally substituted by one or more substituents selected from (1- 4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1- 4C)alkylamino, amino, cyano or hydroxyl; with the proviso that only one or two of X1, X2, X3 or X4 can be N.

Particular compounds of the invention include, for example, compounds of the Formula I, or pharmaceutically acceptable salts and/or solvates thereof, wherein, unless ise 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) after:- (1) HET is ed from one of the following: (2) HET is selected from one of the ing: (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 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 ed 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 tuent groups independently selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, 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 en, (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 heterocyclic ring which is optionally substituted by one or more substituents selected from (1- 4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1- 4C)alkylamino, amino, cyano or hydroxy; or Q is optionally substituted by a group of the formula: -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 selected from hydrogen or (1- 2C)alkyl; and Z1 is hydrogen, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, (3- 8C)cycloalkyl, (3-8C)cycloalkenyl, aryl or heterocyclyl; wherein Z1 is optionally substituted by one or more tuents 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, NRhRi or ORh, wherein Rh and Ri are each independently selected from hydrogen, (1-4C)alkyl or (3-6C)cycloalkyl; (9) R1 is ed 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 tuted 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 N(Ra)SO2, wherein Ra is ed from hydrogen or (1- 4C)alkyl; and Q is hydrogen, (1-6C)alkyl, (2-6C)alkenyl, alkynyl, aryl, (3- 10C)cycloalkyl, )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, 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; or Rc and Rd can be linked such that, together with the nitrogen atom to which they are attached, they form a 4-7 membered heterocyclic ring which is optionally substituted by one or more substituents selected from (1- 4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1- 4C)alkylamino, amino, cyano or hydroxy; or Q is optionally substituted by a group of the formula: -L1-LQ1-Z1 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 hydrogen or (1-2C)alkyl; and Z1 is hydrogen, 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, 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 ally 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 N(Ra)SO2, n Ra is selected from hydrogen or (1- yl; and Q is hydrogen, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, aryl, (3- 10C)cycloalkyl, (3-10C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Q is optionally further substituted by one or more substituent groups independently ed 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, 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 ed from hydrogen, (1-6C)alkyl or (3-6C)cycloalkyl; or Rc and Rd can be linked such that, together with the nitrogen atom to which they are attached, they form a 4-7 membered heterocyclic ring which is optionally substituted by one or more substituents selected from (1- 4C)alkyl, halo, (1-4C)haloalkyl, haloalkoxy, (1-4C)alkoxy, (1- ylamino, 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 tuents 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 ally 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, 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), 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 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 cyclyl; wherein each of said substituents is optionally further substituted by one or more substituent groups independently selected from (1-4C)alkyl, halo, (1- 4C)haloalkyl, (1-4C)haloalkoxy, amino, (1-4C)aminoalkyl, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, mercapto, ureido, NRcRd, ORc, C(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), SO2N(Rd)Rc, N(Rd)SO2Rc, Si(Rd)(Rc)Re or (CH2)zNRdRc (where z is 1, 2 or 3); n Rc, Rd and Re are each independently selected from hydrogen, alkyl or (3-6C)cycloalkyl; (13) R1 is selected from hydrogen, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-6C)alkyl, (3- cloalkyl 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, aminoalkyl, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, mercapto, ureido, NRcRd, ORc or Si(Rd)(Rc)Re; wherein Rc, Rd and Re are each independently selected from en or alkyl; (14) R1 is selected from hydrogen, (1-6C)alkyl, 4-7 membered heterocyclyl or (3- 10C)cycloalkyl; wherein each of said substituents is optionally further tuted by one or more substituent groups independently selected from (1-4C)alkyl, halo, amino, (1-4C)aminoalkyl, cyano, hydroxy, y, 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 membered heterocyclyl; wherein each of said substituents is optionally 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 en or (1-4C)alkyl; (16) R1 is selected from hydrogen, (1-6C)alkyl or )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; (157) R1 is selected from hydrogen, (1-6C)alkyl or (3-6C)cycloalkyl; wherein each of said substituents is optionally r substituted by one or more substituent groups independently selected from (1-4C)alkyl, ORc or Si(Rd)(Rc)Re; wherein Rc, Rd and Re are each independently ed from hydrogen or (1-2C)alkyl; (18) R1 is a (1-6C)alkyl or cycloalkyl; (19) R1 is a (4-6C)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, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano or hydroxy; (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 selected from hydrogen or (1-4C)alkyl; (24) R1a and R1b are each hydrogen; (25) W is selected from O or S; (26) W is O; (27) bonds a, b, c and d are all double bonds; (28) bonds a, b, c and d are all single bonds; (29) 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; Rk is selected from hydrogen, halo, (1-4C)alkyl, (1-4C)alkoxy, amino, alkylamino, (1-4C)dialkylamino, cyano, (2C)alkynyl, n 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 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; 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 ndently 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 selected from hydrogen, halo, (1-4C)alkyl, (1-4C)alkoxy, amino, (1- 4C)alkylamino, (1-4C)dialkylamino, cyano, (2C)alkynyl, wherein said (1- 4C)alkyl is optionally substituted by one or more substituents selected from amino, hydroxy, (1-2C)alkoxy or halo; and Rn is selected from hydrogen or alkyl; (36) 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 selected from hydrogen, halo, 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 ed from hydrogen, halo, (1-4C)alkyl or amino; (38) X3 is CRm and bond b is a double bond, wherein Rm is selected from hydrogen, halo, (1-4C)alkyl or amino; (39) X3 is selected 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 ed from hydrogen, halo, (1-4C)alkyl, (1-4C)alkoxy, amino, (1-4C)alkylamino, (1-4C)dialkylamino, cyano, (2C)alkynyl, wherein said alkyl is ally tuted 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; wherein Ro is selected from hydrogen, halo, (1-4C)alkyl, (1-4C)alkoxy, amino, (1-4C)alkylamino, (1-4C)dialkylamino, cyano or (2C)alkynyl; and Rx is ed from hydrogen or (1-4C)alkyl; (43) X4 is ed 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, hydroxy, (1-2C)alkoxy or halo; and wherein Ro1 and Ro2 are each independently selected 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- (48) X4 is CRo and bond d is a double bond, wherein Ro is a halogen (e.g. , bromo or fluoro, ularly chloro); (49) R2 is selected from en, (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 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 r substituted by one or more substituent groups independently selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- oalkoxy, amino, cyano, hydroxy, NRqRr, ORq, wherein Rq and Rr are each independently selected from hydrogen or (1-4C)alkyl; (50) R2 is selected from hydrogen, (1-4C)alkyl or a group of the formula: -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, hydroxy, NRqRr, ORq, wherein Rq and Rr are each independently selected from hydrogen or (1-4C)alkyl; (51) R2 is selected from hydrogen, (1-4C)alkyl or a group of the formula: -Y2-Q2 wherein: Y2 is C(O)N(Rp), wherein Rp is selected from hydrogen or (1-4C)alkyl; and Q2 is (1-6C)alkyl, aryl, (3-8C)cycloalkyl, heteroaryl or heterocyclyl; n Q2 is optionally further substituted by one or more substituent groups independently selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)haloalkoxy, amino, cyano or hydroxy; (52) R2 is selected from hydrogen or (1-4C)alkyl; (53) R2 is hydrogen; (54) R3 is selected from a group of the formula: -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 en, (1-6C)alkyl, (1-6C)alkoxy, aryl, aryl(1-2C)alkyl, (3- 8C)cycloalkyl, 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, 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 alkylene optionally substituted by one or more substituents ed from alkyl or oxo; LQ4 is absent or selected from or O, N(Rab), C(O), C(O)O, OC(O), C(O)N(Rab), C(O), S(O)2N(Rab), or N(Rab)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, moyl, 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), 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- oalkoxy, (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 olyl, wherein Ry is selected from hydrogen or (1-2C)alkyl; and Q3 is hydrogen, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, (3-8C)cycloalkyl, (3- 8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Q3 is optionally further substituted by one or more tuent groups independently ed 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 ally 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), 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- oalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, mercapto, ureido, aryl, heteroaryl, heterocycyl, (3-6C)cycloalkyl, NRadRae, ORad, d, 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); n Rad and Rae are each independently selected from hydrogen, (1-4C)alkyl or (3- 6C)cycloalkyl; (56) R3 is selected from a group of the 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), (O)N(Ry1), N(Ry)SO2, oxazoyl, triazolyl, oxadiazolyl, thiadiazolyl 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 substituted by one or more substituent groups ndently 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 en, (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, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, (3- loalkyl, cycloalkenyl, aryl or heterocyclyl; wherein Z4 is ally substituted 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, cycyl, (3-6C)cycloalkyl, NRadRae, ORad, C(O)Rad, C(O)ORad, OC(O)Rad, 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; (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), 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; 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 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, 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 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, 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); n Rad and Rae are each ndently ed from en, (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 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 (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 ed 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 SO2, wherein Rab is selected from hydrogen or (1-2C)alkyl; and Z4 is en, (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); n Rad and Rae are each independently ed 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 membered heterocyclic ring which is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano or hydroxyl; (59) R3 is selected from a group of the formula: -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), n 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 tuent 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 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, N(Rab), C(O), C(O)O, OC(O), Rab), N(Rab)C(O), S(O)2N(Rab), or N(Rab)SO2, wherein Rab is selected from en or (1-2C)alkyl; and Z4 is en, (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, oyl, 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), ae)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 en, (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 tuent 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 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, 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- 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, , 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 (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, together with the nitrogen atom to which they are attached, they form a 4-6 membered heterocyclic ring which is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)haloalkoxy, (1-4C)alkoxy, alkylamino, amino, cyano or hydroxyl; (61) R3 is selected from a group of the formula: -Y3-Q3 wherein: Y3 is Ry), wherein Ry is selected from hydrogen or (1-2C)alkyl; 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 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, , 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: -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, 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), 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, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano, hydroxy, carboxy, oyl, sulphamoyl, mercapto, ureido, aryl, heteroaryl, heterocycyl, (3-6C)cycloalkyl, NRadRae, ORad, C(O)Rad, C(O)ORad, ad, 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; (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, 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, n 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, 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 tuted 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 y; (63) R3 is selected from a group of the a: -Y3-Q3 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 hydrogen, (1-6C)alkyl, (1-6C)alkoxy, aryl, aryl(1-2C)alkyl, (3- 8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Q3 is optionally further substituted by one or more substituent groups independently selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)haloalkoxy, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, NRzRaa, ORz, wherein Rz and Raa are each independently selected from en, (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, (3-8C)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 or hydroxy; (64) R3 is selected from a group of the formula: -Y3-Q3 wherein: Y3 is C(O)NH; and Q3 is hydrogen, alkyl, (1-6C)alkoxy, aryl, aryl(1-2C)alkyl, (3- 8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or cyclyl; wherein Q3 is optionally further substituted by one or more tuent 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 ndently 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, 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; n Z4 is optionally tuted by one or more substituents selected from (1- 4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano or hydroxy; (65) R3 is selected from a group of the formula: -Y3-Q3 wherein: Y3 is C(O)NH; and Q3 is (1-6C)alkyl, (1-6C)alkoxy, aryl, aryl(1-2C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Q3 is optionally further 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 ed 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, 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, 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 a: -Y3-Q3 wherein: Y3 is C(O), C(O)O or ; 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 ed 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 en 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- loalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Q3 is optionally further substituted by one or more tuent groups independently selected from alkyl, halo, (1-4C)haloalkyl, (1- oalkoxy, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, NRzRaa, ORz, wherein Rz and Raa are each independently ed 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 independently selected from (1-4C)alkyl, halo, (1- 4C)haloalkyl, (1-4C)haloalkoxy, amino, cyano, hydroxy, NRzRaa or ORz, wherein Rz and Raa are each independently selected from hydrogen or (1-2C)alkyl.

Suitably, a heteroaryl or heterocyclyl group as defined herein is a clic heteroaryl or heterocyclyl group comprising one, two or three heteroatoms selected from N, O or S.

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

Suitably, a heterocyclyl group is a 4-, 5- or 6-membered heterocyclyl ring comprising one, two or three atoms selected from N, O or S. Most suitably, a heterocyclyl group is a 5-, 6- or 7-membered ring comprising one, two or three heteroatoms selected from N, O or S [e.g. morpholinyl (e.g. 4-morpholinyl), pyridinyl, piperazinyl, homopiperazinyl or pyrrolidinonyl].

Suitably an aryl group is phenyl.

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

Suitably, R1 is as defined in any one of aphs (8) to (20). More suitably, R1 is as defined in any one of paragraphs (12) to (20). Most suitably, 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 ly, W is as defined in paragraph (26).

Suitably, bonds a, b, c and d are as d in any one of paragraphs (27) to (28).

Suitably, bonds a, b, c and d are as defined in aph (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 defined 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 defined in any one of paragraphs (51) to (53). Most suitably, R2 is as defined in paragraph (53).

Suitably, R3 is as defined 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 compounds have the structural Formula Ia (a sub-definition of a (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 herein.

In an embodiment of the compounds of Formula Ia: 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 d 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 d in paragraph (7) above; R1 is as defined in aph (20) above; R1a and R1b are as d in paragraph (24) above; bonds a, b, c and d are as defined in aph (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 a (I)) shown below, or a ceutically 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 ment 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 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; 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 defined 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 aph (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 ular 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 nds 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 aphs (49) to (53) above; Ry is as defined in any one of paragraphs (54) to (63) above; and Q3 is as d in any one of paragraphs (54) to (68).

In another 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 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 Formula 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 defined in paragraph (68) above.

In an alternative embodiment of the nds 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 CH; 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 nds have the structural Formula Id (a sub-definition of formula (I)) shown below, or a pharmaceutically acceptable salt, hydrate and/or e thereof: wherein R1, X4, R2 and Q3 each have any one of the gs 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 defined in any one of paragraphs (49) to (53) above; and Q3 is as d 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 d 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 defined in paragraph (68) above.

In a particular group of compounds of the invention, the compounds have the structural Formula Ie (a finition of formula (I)) shown below, or a ceutically acceptable salt, hydrate 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 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 d in any one of paragraphs (35) to (40) above; Ro is as defined in any one of paragraphs (41) to (48) above; R2 is as defined in any one of paragraphs (49) to (53) above; and R3 is as d in any one of paragraphs (54) to (68).

In another embodiment of the compounds of Formula Ie: HET is as defined in paragraph (7) above; R1 is as defined in paragraph (20) above; R1a and R1b are as defined 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 meanings d 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 d in any one of paragraphs (8) to (20) above; R1a and R1b are as d 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 defined in aph (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; 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 formula (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 .

In an embodiment of the nds 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 d 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 aphs (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 aph (40) above; Ro is halo, especially chloro; R2 is as defined in paragraph (53) above; Ry is hydrogen; and Q3 is as defined in paragraph (68).

Particular nds of the present invention 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-Amino(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; or 2-(4-Amino(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidinyl)-N-methyl-1H-indole carboxamide.

Further particular compounds of the t invention include any of the compounds exemplified in the present application, or a pharmaceutically acceptable salt or e thereof, and, in particular, any of the following: 2-(4-Amino(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; mino(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidinyl)-N-methyl-1H-indole amide; 2-(4-Aminoisopropyl-1H-pyrazolo[3,4-d]pyrimidinyl)chloro-N-methyl-1H- carboxamide; 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 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-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- linopropyl)-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; 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-indolecarboxamide; minomethyl-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; minotert-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; 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-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- 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; minotert-butyl-1H-pyrazolo[3,4-d]pyrimidinyl}chloro-N-cyclopropyl-1H- carboxamide; 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; 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; 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- 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- ropyl-1H-indolecarboxamide; 3-[3-Chloro(1,3,4-thiadiazolyl)-1H-indolyl]isopropyl-pyrazolo[3,4- midinamine; 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.

Further particular compounds of the t 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-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]- idinyl-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; 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidinyl)chloro-N-(3-methoxypropyl)- 1H-indolecarboxamide; minotert-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; 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-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- yethyl)pyrazolyl]-1H-indolecarboxamide; minotert-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- 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; 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; minotert-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; 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-Amino(propanyl)pyrrolo[2,1-f][1,2,4]triazinyl]chloro-N-methyl-1H- indolecarboxamide; mino(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 compounds of the present invention include any of the compounds exemplified in the present application, or a pharmaceutically acceptable salt or e thereof, 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- indolecarboxamide; 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidinyl)-1H-indolecarboxamide; minocyclohexyl-1H-pyrazolo[3,4-d]pyrimidinyl}-N-methyl-1H-indole carboxamide; 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 amide; 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-Aminochloro(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 ylic 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 s functional groups and substituents making up the compounds of the Formula (I), and rmulae 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 invention is, for example, an acid-addition salt of a compound of the invention which is sufficiently basic, for example, an acid-addition salt with, for example, an nic or organic acid, for e hydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic, , citric methane sulfonate or maleic acid. In addition, a suitable pharmaceutically acceptable salt of a compound of the invention which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a pharmaceutically able cation, for example a salt with amine, 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 ement of their atoms in space are termed "stereoisomers". Stereoisomers that are not mirror images of one another are termed "diastereomers" and those that are non-superimposable mirror images of each other are termed "enantiomers". When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of zed light and ated 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 The compounds of this invention may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or ereoisomers or as mixtures thereof. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see discussion in Chapter 4 of "Advanced Organic Chemistry", 4th edition J. March, John Wiley and Sons, New York, 2001), for example by synthesis from optically active starting materials or by resolution of a racemic form. Some of the compounds of the invention may have geometric ic centres (E- and Z- isomers). It is to be understood that the present invention encompasses all optical, diastereoisomers and geometric isomers and mixtures thereof that possess antiproliferative activity.

The present ion also encompasses compounds of the invention as defined herein which comprise one or more ic substitutions. For e, H may be in any ic 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 ic 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 e, hydrated forms. It is to be understood that the invention encompasses all such solvated forms that s antiproliferative activity.

It is also to be tood 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 bed or shown, all others are nevertheless embraced by Formula I, and sub-formulae Ia to Ig. Examples of tautomeric forms include keto-, enol-, and e-forms, as in, for example, the following tautomeric pairs: keto/enol (illustrated below), imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime, thioketone/enethiol, and nitro/aci-nitro.

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 ons, one or more than one nitrogen atom may be oxidised to form an N-oxide. Particular examples of N-oxides are the N-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle. N-Oxides can be formed by treatment of the corresponding amine with an oxidizing agent such as hydrogen peroxide or a per-acid (e.g. a peroxycarboxylic acid), see for example Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages. More particularly, N-oxides can be made by the ure of L. W. Deady (Syn. Comm. 1977, 7, 509-514) in which the amine compound is d 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 invention. A pro-drug may be used to alter the al properties and/or the pharmacokinetic properties of a compound of the invention. A pro-drug can be formed when the compound of the invention ns a suitable group or substituent to which a propertymodifying group can be attached. Examples of pro-drugs include in vivo cleavable ester derivatives that may be formed at a y group or a hydroxy group in a compound of the Formula (I), or sub-formulae Ia to Ig, and in-vivo cleavable amide derivatives that may be formed at a carboxy group or an amino group in a compound of the Formula (I), or subformulae Ia to Ig.

Accordingly, the present invention includes those compounds of the Formula (I), and sub-formulae Ia to Ig, as defined hereinbefore, when made available by organic synthesis and when made available within the human or animal body by way of cleavage of a pro-drug thereof. Accordingly, the present ion includes those compounds of the Formula I, and sub-formulae Ia to Ig, that are ed 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 ties and t undue toxicity.

] Various forms of pro-drug have been described, for example in the following documents :- a) Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985); c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 n and Application of Pro-drugs", by H. Bundgaard p. 113-191 (1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); f) N. Kakeya, et al., Chem. Pharm. Bull., 32, 692 (1984); g) T. Higuchi and V. Stella, "Pro-Drugs as Novel Delivery s", A.C.S. Symposium Series, Volume 14; and h) E. Roche (editor), "Bioreversible Carriers in Drug Design", Pergamon Press, 1987.

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 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 , ethyl and tert-butyl, koxymethyl esters such as methoxymethyl esters, C1-6alkanoyloxymethyl esters such as pivaloyloxymethyl esters, 3-phthalidyl esters, C3-8cycloalkylcarbonyloxy- C1-6alkyl esters such as entylcarbonyloxymethyl and 1-cyclohexylcarbonyloxyethyl esters, 2-oxo-1,3-dioxolenylmethyl esters such as 5-methyloxo-1,3-dioxolenylmethyl esters and C1-6alkoxycarbonyloxy- kyl esters such as ycarbonyloxymethyl and 1- methoxycarbonyloxyethyl esters.

A suitable pharmaceutically acceptable pro-drug of a compound of the Formula (I), or sub-formulae 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 rmulae 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 ceutically acceptable ester forming groups for a hydroxy group include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters). Further suitable ceutically acceptable ester forming groups for a hydroxy group include C1-10alkanoyl groups such as , l, phenylacetyl and substituted benzoyl and phenylacetyl groups, C1-10alkoxycarbonyl groups such as ethoxycarbonyl, N,N –(C1-6)2carbamoyl, kylaminoacetyl 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 ceutically acceptable 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 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- kylamine such as 2-methoxyethylamine, a -C1-4alkylamine such as benzylamine and amino acids such as glycine or an ester thereof.

A suitable pharmaceutically acceptable pro-drug of a compound 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 ceutically acceptable amides from an amino group e, for example an amide formed with C1-10alkanoyl groups such as an acetyl, benzoyl, phenylacetyl and tuted benzoyl and phenylacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups e 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 effects of a compound of the Formula (I), or sub-formulae Ia to Ig, may also be exerted by way of lism of a precursor compound (a pro-drug).

Though the present invention may relate to any nd or particular group of nds defined herein by way of optional, preferred or suitable features or otherwise in terms of particular ments, the present invention may also relate to any compound or particular group of nds that specifically excludes said optional, preferred or suitable features or particular embodiments.

Suitably, the present invention excludes any individual compounds not possessing the biological activity defined herein.

Synthesis The compounds of the present invention can be prepared by any suitable technique known in the art. Particular processes for the preparation of these compounds are described r in the accompanying es.

In the description of the synthetic methods described herein and in any referenced synthetic methods that are used to prepare the starting materials, it is to be understood that all proposed reaction conditions, including choice of solvent, on atmosphere, reaction temperature, duration of the experiment and workup procedures, can be ed by a person skilled in the art.

It is understood by one skilled in the art of c synthesis that the functionality present on various ns of the molecule must be compatible with the reagents and reaction conditions utilised.

It will be appreciated that during the synthesis of the compounds of the invention in the processes defined herein, or during the synthesis of certain starting materials, it may be desirable to protect certain tuent groups to prevent their red reaction. The skilled chemist will appreciate when such protection is ed, 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 t, for e, ‘Protective Groups in Organic Synthesis’ by Theodora Green (publisher: John Wiley & Sons). Protecting groups may be d by any convenient method described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group with the minimum disturbance of groups elsewhere in the molecule.

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 le 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 e benzyloxycarbonyl, or an aroyl group, for e 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 d by, for example, hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.

Alternatively an acyl group such as a tert-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulfuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a st such as palladium-on-carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.

A suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl. The deprotection conditions for the above protecting groups will necessarily vary with the choice of ting group. Thus, for example, an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for e lithium, sodium hydroxide or ammonia. atively 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 e, 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 nd 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 ated therewith. Suitable ses for their preparation are described further in the accompanying Examples.

Once a nd of Formula (I) has been synthesised by any one of the processes d , the processes may then further comprise the additional steps of: (i) removing any protecting groups present; (ii) converting the compound Formula (I) into another compound of formula (I); (iii) forming a pharmaceutically acceptable salt, hydrate or solvate thereof; and/or (iv) forming a prodrug thereof.

] An example of (ii) above is when a nd 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 reacted to change the nature of the group and provide an alternative compound of formula (I).

For e, the compound can be reacted to t any R group into a substituent group other than en.

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

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

] Although the pharmacological properties of the compounds of Formula I vary with structural change, as expected, the compounds of the invention were found to be active in the RET assays described in the Examples n.

In general, the compounds 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 invention demonstrating an IC50 of 50 nM or less.

Suitably the ratio of RET activity to KDR activity measured in the RET and KDR assays set out in the es 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 red nds of the invention demonstrating an IC50 of 50 nM or less.

In the RET cell assay described herein in the es 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 compounds of the ion demonstrating an IC50 of 100 nM or less.

In the RETV804M cell assay described herein in the Examples section, the compounds of Formula I suitably s 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 preferred 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 before, or a ceutically acceptable salt, hydrate or solvate thereof, in association with a pharmaceutically acceptable diluent or carrier.

The itions of the invention may be in a form suitable for oral use (for e as tablets, lozenges, hard or soft es, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for l 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 l), for administration by insufflation (for example as a finely divided ) 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 ion may be obtained by conventional procedures using conventional pharmaceutical ents, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents.

An effective amount of a compound of the present invention for use in therapy is an amount sufficient to treat or prevent a proliferative condition referred to herein, slow its progression and/or reduce the symptoms associated with the condition.

The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the individual treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 0.5 g of active agent (more ly 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 according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well-known principles of medicine.

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 stered 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 ations The present invention provides compounds that function as inhibitors of RET or mutant forms thereof (e.g. RET V804M ). Furthermore, the compounds of the present invention demonstrate an improved selectivity for RET, or mutant forms f (e.g. RET V804M ), relative to KDR (i.e. they are potent inhibitors of RET and poor inhibitors of KDR).

The present invention therefore provides a method of inhibiting RET kinase enzyme activity, or mutant forms thereof (e.g. RET V804M), in vitro or in vivo, said method comprising contacting a cell with an effective amount of a compound, or a pharmaceutically acceptable salt, hydrate or solvate f, as defined herein.

The present invention also es a method of selectively ting 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 f, as defined herein.

The t invention also provides a method of treating a disease or disorder in which RET kinase activity is implicated in a patient in need of such treatment, said method comprising stering to said patient a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein.

The present invention provides a method of inhibiting cell eration, in vitro or in vivo, said method comprising contacting a cell with an effective amount of a compound, or a ceutically acceptable salt, hydrate or e thereof, as defined herein.

The present invention provides a method of treating a proliferative disorder in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, hydrate or solvate f, or a pharmaceutical composition as defined herein.

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

The present invention provides a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein for use in therapy.

The present invention provides a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a ceutical composition as defined herein for use in the ent of a proliferative condition.

The present invention provides a compound, or a pharmaceutically acceptable salt, hydrate or solvate f, or a pharmaceutical ition as defined herein for use in the treatment of cancer. In a particular embodiment, the cancer is human cancer.

The present invention provides a compound, or a pharmaceutically able salt, hydrate or solvate f, as defined herein for use in the inhibition of RET kinase enzyme ty or mutant forms thereof (e.g. RET V804M ).

The present invention provides a compound, or a pharmaceutically acceptable salt, hydrate or e f, as defined herein for use in 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 compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein for use in the treatment of a disease or disorder in which RET kinase activity is implicated.

The present invention provides a use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein in the manufacture of a medicament for the treatment of a proliferative condition.

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

The t invention provides 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 inhibition of RET kinase enzyme activity, or mutant forms thereof (e.g.

RETV804M ).

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 ive inhibition of RET kinase enzyme activity, or mutant forms f (e.g. RET V804M ), over KDR enzyme activity.

The present invention provides a use of a compound, or a pharmaceutically acceptable salt, hydrate or e 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.

The term "proliferative disorder" are used interchangeably herein and pertain to an unwanted or uncontrolled cellular proliferation of excessive or abnormal cells which is red, such as, neoplastic or hyperplastic growth, whether in vitro or in vivo. es of proliferative conditions include, but are not limited to, pre-malignant and malignant cellular proliferation, including but not limited to, malignant neoplasms and tumours, cancers, leukemias, sis, bone diseases, fibroproliferative disorders (e.g., of connective tissues), and atherosclerosis. Any type of cell may be treated, including but not limited to, lung, colon, breast, ovarian, te, liver, as, brain, and skin.

The anti-proliferative effects of the nds of the present invention have particular application in the treatment of human cancers (by virtue of their inhibition of RET kinase enzyme ty, and/or the selective inhibition of RET kinase enzyme activity over KDR enzyme activity).

The anti-cancer effect may arise through one or more mechanisms, including but not limited to, the regulation of cell proliferation, the tion of angiogenesis (the formation of new blood vessels), the inhibition of metastasis (the spread of a tumour from its ), the inhibition of on (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 treated is , for example medullary thyroid cancer (MTC) or non-small 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, r systemically/ peripherally or topically (i.e., at the site of desired action).

Routes of administration include, but are not limited to, oral (e.g, by ingestion); buccal; sublingual; transdermal (including, e.g., by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by tion or insufflation therapy using, e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intra-arterial, ardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, racheal, subcuticular, intraarticular, subarachnoid, and intrasternal; by implant of a depot or oir, for example, subcutaneously or intramuscularly.

Combination Therapies The antiproliferative treatment defined hereinbefore may be applied as a sole therapy or may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or herapy. Such chemotherapy may include one or more of the following categories of anti-tumour agents:- (i) other antiproliferative/antineoplastic drugs and combinations thereof, as used in medical oncology, such as ting agents (for example cis-platin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen d, melphalan, chlorambucil, busulphan, temozolamide and oureas); antimetabolites (for example abine and antifolates such as fluoropyrimidines like 5-fluorouracil and r, raltitrexed, methotrexate, cytosine arabinoside, and yurea); antitumour antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, icin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine and taxoids like taxol and taxotere and polokinase inhibitors); and topoisomerase inhibitors (for example epipodophyllotoxins like etoposide and teniposide, amsacrine, topotecan and camptothecin); (ii) cytostatic agents such as antioestrogens (for example tamoxifen, fulvestrant, toremifene, fene, droloxifene and iodoxyfene), antiandrogens (for example bicalutamide, flutamide, nilutamide and erone acetate), LHRH antagonists or LHRH agonists (for example lin, leuprorelin and lin), progestogens (for e megestrol acetate), aromatase tors (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 (AZD0530; International Patent Application WO 01/94341), hloro methylphenyl){6-[4-(2-hydroxyethyl)piperazinyl]methylpyrimidinylamino}thiazole- -carboxamide (dasatinib, BMS-354825; J. Med. Chem., 2004, 47, 6658-6661) and bosutinib (SKI-606), and metalloproteinase inhibitors like marimastat, inhibitors of urokinase plasminogen activator receptor function or antibodies to Heparanase]; (iv) inhibitors of growth factor function: for example such inhibitors include growth factor antibodies and growth factor receptor antibodies (for e the rbB2 antibody trastuzumab [Herceptin™], the anti-EGFR antibody panitumumab, the anti-erbB1 antibody cetuximab [Erbitux, C225] and any growth factor or growth factor receptor antibodies disclosed by Stern et al. (Critical reviews in oncology/haematology, 2005, Vol. 54, pp11-29); such inhibitors also include tyrosine kinase inhibitors, for e inhibitors of the epidermal growth factor family (for example EGFR family ne 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- acrylamido-N-(3-chlorofluorophenyl)(3-morpholinopropoxy)-quinazolinamine (CI 1033), erbB2 tyrosine kinase inhibitors such as lapatinib); tors of the hepatocyte growth factor family; inhibitors of the n 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 inhibitors such as farnesyl transferase inhibitors, for example nib (BAY 43-9006), tipifarnib (R115777) and lonafarnib (SCH66336)), inhibitors of cell ling through MEK and/or AKT kinases, c-kit inhibitors, abl kinase inhibitors, PI3 kinase inhibitors, Plt3 kinase inhibitors, CSF-1R kinase inhibitors, IGF receptor (insulin-like growth factor) kinase inhibitors; aurora kinase inhibitors (for e AZD1152, 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 t 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), nib (PTK787), sunitinib (SU11248), axitinib 3736), 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 ations WO97/22596, WO 97/30035, WO 97/32856 and WO 98/13354 and compounds that work by other mechanisms (for example de, inhibitors of integrin αvβ3 on and angiostatin)]; (vi) ar damaging agents such as Combretastatin A4 and compounds disclosed in ational Patent Applications WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213; (vii) an endothelin receptor antagonist, for example zibotentan 4) or atrasentan; (viii) antisense therapies, for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense; (ix) gene therapy approaches, including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to herapy or radiotherapy such as multi-drug resistance gene therapy; and (x) immunotherapy approaches, including for example ex-vivo and in-vivo approaches to se the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches using anti-idiotypic antibodies.

In a particular embodiment, the antiproliferative treatment defined before may involve, in addition to the compound of the invention, tional surgery or herapy or chemotherapy, wherein the herapy may include one or more anti-tumour agents selected from bazine, carmustine, lomustine, irinotecan, temozolomide, tin, carboplatin, methotrexate, etoposide, cyclophosphamide, ifosfamide, and vincristine.

Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment. Such combination products employ the compounds of this invention within the dosage range described hereinbefore and the other pharmaceutically-active agent within its approved dosage range.

] According to this aspect of the invention there is provided a combination for use in the treatment of a cancer (for example a cancer involving a solid tumour) comprising a compound of the invention as defined before, or a pharmaceutically acceptable salt, hydrate or e 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 pharmaceutically 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 provided a compound of the invention or a pharmaceutically able salt, hydrate or solvate f, for use in the treatment of cancer in ation with r 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 simultaneous, separate or sequential administration. In one aspect of the invention "combination" refers to aneous administration. In another aspect of the invention "combination" refers to separate administration. In a further aspect of the invention "combination" refers to sequential administration. Where the administration is sequential or separate, the delay in administering the second component should not be such as to lose the beneficial effect of the combination.

According to a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of the invention, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in ation with an umour agent (optionally selected from one listed herein above), in association with a pharmaceutically acceptable diluent or carrier.

ABBREVIATIONS B2(OH)4 Tetrahydroxyborate br s broad singlet d doublet dd doublet of ts CDCl3 Chloroform DMAP 4-(dimethylamino) pyridine DCM Dichloromethane (methylene de) DIPEA N,N,-di-isopropyethylamine, Hunig’s base DMF N,N-dimethylformamide 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 (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 Potassium carbonate KOAc Potassium e LCMS Liquid Chromatography-Mass Spectrometry LiOH.H2O Lithium hydroxide monohydrate m multiplet MeOH Methanol (methyl alcohol) MgSO4 Magnesium sulphate MHz Mega hertz N2 Nitrogen NaHCO3 Sodium Bicarbonate Na2SO4 Sodium sulphate NH4Cl Ammonium chloride NMR r Magnetic Resonance POCl3 Phosphorus oxychloride q quartet s singlet t triplet THF Tetrahydrofuran XPhos 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl XPhos-Pd-G2 Chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2- (2′-amino-1,1′-biphenyl)]palladium(II) l Experimental Flash column chromatography refers to automated chromatography using pre- packed silica cartridges. ] lly, in the experimental procedures described below, flash chromatography was performed using pre-packed silica gel cartridge and thin layer chromatography was conducted with 5 × 10 cm plates coated with Merck Type 60 F254 silica gel to a thickness of 0.25 mm. Typically, reagents obtained from commercial sources were used t further purification unless stated otherwise. Anhydrous solvents were commonly obtained from the Sigma-Aldrich Chemical Company Ltd. or Fisher Chemicals Ltd., and used without further drying. HPLC grade solvents were predominately obtained from Fisher Chemicals Ltd. 1H NMR spectroscopy was carried out using various spectrometers in the stated solvent at room temperature unless stated ise. In all cases, NMR data were consistent with the ed structure. Characteristic chemical shifts (δ) are given in parts-per-million using conventional abbreviations for designation of major peaks e.g. s, singlet; d, doublet; t, triplet; q, quartet; dd, doublet of doublets; br, broad. LCMS was run using various spectrometers to generate low resolution mass spectra under electron spray ionisation (ESI) conditions.

Generally, in the mental procedures described hereinbelow, proton (1H) NMR spectra 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 nced to tetramethylsilane (TMS) or ated 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 s (2.1 × 50 mm or 2.1 × 100 mm), with UV diode array detection (210–400 nm). Positive and negative mass ion detection may also be performed using, for example, a Waters SQD or. es may then be performed with either buffered acidic or basic solvents, using gradients such as those detailed below.

Examples of suitable t 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 hydrogen carbonate + 0.1% ammonia solution Solvent B – Acetonitrile + 0.1% ammonia solution An Example of a Standard LC-MS Solvent Gradient: Time Flow rate (mL/min) % Solvent A % Solvent B 0 0.6 95 5 1.2 0.6 5 95 1.7 0.6 5 95 1.8 0.6 95 5 Preparative HPLC Preparative HPLC refers to mass-directed reverse-phase chromatography using various water:MeCN eluent nts. It will be appreciated that s preparative HPLC es and/or conditions may be used to purify the compounds of the present invention, and the person skilled in the art will be well versed in selecting appropriate conditions for each respective compound. Nonetheless, details of some non-limiting examples of suitable HPLC conditions are provided below. rative preparative HPLC conditions Compounds may be purified by preparative HPLC on, for example, a Waters FractionLynx MS autopurification system, with a column such as a Waters XBridge 5 µm C18, 100 mm × 19 mm i.d. column, running at a typical flow rate of 20 mL/min with UV diode array ion (210–400 nm) and mass-directed collection using both positive and negative mass ion detection. cations may also be performed using buffered acidic or basic solvent systems, as appropriate. Compound retention times on such systems may then be assessed using a -50 μL test ion 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 gradients include: Low pH: Solvent A – Water + 10mM um formate + 0.1% formic acid Solvent B – Acetonitrile + 5% water +0.1% formic acid High pH: Solvent A – Water + 10mM ammonium formate + 0.1% a solution Solvent B – Acetonitrile + 5% water + 0.1% ammonia solution An Example of a Standard HPLC Gradient: Time Flow rate % Solvent % Solvent (mL/min) A B 0 20 90 10 0.3 20 90 10 8.5 20 2 98 12 20 2 98 12.5 0 2 98 Examples of Some Focussed HPLC Gradients: % Solvent B Retention time on standard 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 tic methods Several methods for the chemical synthesis of the compounds of the present invention are described . These and/or other nown methods may be modified and/or adapted in known ways in order to facilitate the sis of additional compounds within the scope of the present invention.

Where the preparation of starting materials is not described, these are commercially available, known in the literature, or readily obtained by those skilled in the art using standard procedures. Where it is stated that compounds were ed analogously to earlier examples or intermediates, using General Methods, it will be appreciated by the skilled person that the reaction time, number of equivalents of reagents and temperature can be modified for each specific reaction and that it may be desirable or necessary to employ different reagents, catalysts, p or purification techniques.

General Synthetic Schemes Scheme 1 – Preparation of Indolyl Pyrazolopyrimidines D tuted pyrazolopyrimidines C were prepared either via the known 3-step procedure from an riately substituted hydrazine A (General Method 1) or via elaboration of the unsubstituted lopyrimidine B al Method 2). X is usually Br or I. Suzuki coupling of intermediate C with either 2-halo indole derivatives (General Method 3) or indolyl boronic acid derivatives (General Method 4) returned product D. Where necessary, further elaboration was conducted.

Scheme 2 – Elaboration of Indolyl Pyrazolopyrimidines 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. atively, ester G could be alkylated, ected and converted to the amide (General Method 9).

General Methods for Intermediates and es 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 onal treatment with HCl or TFA was included if deprotection did not occur thermally under the reaction conditions. l Method 1 – representative procedure 3-Bromocyclohexyl-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 residue was taken up in EtOAc (50 mL) and washed with water (2 × 25 mL). The organic phase was dried over MgSO4, filtered and concentrated in vacuo to return 5-aminocyclohexyl-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 d 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 ohexylpyrazolo[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 organics were washed tially 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 without further 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), .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 mediate 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 nitrogen 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 o-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 ed 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 ed 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 on mixture was cooled to room temperature, diluted with water and extracted with EtOAc (3×).

The combined extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by fcc (0-100% EtOAc in pentane) 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 3-bromoisopropyl-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 nitrogen.

Pd(dppf)Cl2·DCM (32 mg, 0.04 mmol) was added followed 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 ature, diluted with EtOAc (50 mL) and washed with water (2 × 25 mL). The ed 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, DMSO-d6) 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- midinamine was used as one of the coupling partners e.g. in the synthesis of Intermediate 81. Additionally, other aryls 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 2O (106 mg, 2.52 mmol). The reaction was stirred at room temperature for 1 hour then at reflux for 2.5 hours. The reaction was cooled to room temperature and concentrated in vacuo. The residue was acidified with 1M HCl and extracted with EtOAc (3×).

The combined organics extracts were dried over Na2SO4, ed and concentrated in vacuo to return the title compound (200 mg, 91%) as a yellow solid. LCMS [M+H]+ 351.1.

General Method 6 – entative procedure 2-Bromo-N-methyl-1H-indolecarboxamide (Intermediate 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 e 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 reduced pressure. The residue was ated with DCM to return the title compound (204 mg, 64%) as an off-white 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 minoisopropyl-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 ing suspension was stirred at room ature 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 2-(4-aminoisopropyl-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- carboxylate (0.4 g, 1.14 mmol) in DMF (10 mL) was added NCS (0.15 g, 1.14 mmol) at room temperature. The orange solution was stirred at room temperature for 1 hour whereupon a suspension . The reaction mixture was diluted with water (150 mL) and stirred at room ature for 30 mins. The solid was isolated by filtration, washed with water and dried in vacuo at 50 °C to return the title compound (3.8 g, 86%) as a sandy coloured solid. LCMS [M+H]+ 385.2; 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).

Typically, treatment of substrates with 1 eq NCS resulted in varying proportions of unreacted starting material, desired product and a bischlorinated impurity. A variety of purifications techniques were employed, dependent on the ratio of product. itation 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 mes 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 2-(4-amino-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 d 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 2-(4-amino(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 mino(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 t was concentrated in vacuo and the residue taken up into 1,4-dioxane (5 mL) and treated with r 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 ed 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 subsequent step without additional purification.

Step 3 ] A mixture of ethyl 2-(4-amino(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 e, 0.26 mL) dropwise over 5 min. The resulting mixture was maintained at this temperature for 30 min then heated at 60 °C for 3 h. After cooling back to 0 °C, Rochelle’s salt (20% w/v, 5 mL) was added and the mixture warmed to room temperature and stirred for 30 min. EtOAc (10 mL) was added and the biphasic mixture separated. The aq layer was extracted with further EtOAc (2 × 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 s not ed.

Synthesis of Intermediates Table A - List of Intermediates and their method of synthesis General Intermediate Name Structure Method minobromo- 1 pyrazolo[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- hydroxyethyl)-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 carboxylate Methyl 2-(4-amino(3- methoxypropyl)-1H-pyrazolo[3,4- 6 d]pyrimidinyl)chloro-1H6-carboxylate 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)ethyl)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 minocyclobutyl- 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 minocyclopentyl- 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 indolecarboxylate Methyl 2-(4-amino(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 2-(4-Amino(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 azolo[3,4-d]pyrimidinyl)- 8 3-chloro-1H-indolecarboxylate tert-Butyl N-(3-bromo-1H- 29 pyrazolo[3,4-d]pyrimidinyl)-NBelow tert-butoxycarbonyl-carbamate tert-Butyl romo 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 2-(4-amino(1- piperidinyl)-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 utyl 4-(4-aminobromo- 37 1H-pyrazolo[3,4-d]pyrimidin 2 yl)piperidinecarboxylate Methyl 2-(4-amino(1-(tertbutoxycarbonyl )piperidinyl)- 38 4 azolo[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 yl)cyclopentanol 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 roiodoisopropyl-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 ylate Methyl mino isopropylpyrrolo[2,1- 49 4 f][1,2,4]triazinyl)-1H-indole carboxylate N-((3-Aminooxo-4,5-dihydro- 50 1,2,4-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 f][1,2,4]triazinamine Below Methyl 2-(4-amino isopropylimidazo[5,1- 55 4 f][1,2,4]triazinyl)-1H-indole carboxylate Methyl 2-(4-amino pylimidazo[5,1- 56 8 f][1,2,4]triazinyl)chloro-1H- indolecarboxylate 1-(tert-Butyl) 57 ((trimethylsilyl)ethynyl)-1HBelow lo[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 yl 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 azolo[3,4-d]pyrimidinyl)- 4 -chloro-1H-indolecarboxylate tert-Butyl (tert- 63 butoxycarbonyl)amino]indole Below carboxylate [6-[Bis(tertbutoxycarbonyl )amino]tert- See butoxycarbonyl-indolyl]boronic Below 3-(6-Amino-1H-indolyl)(tert- 65 butyl)-1H-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 2-(4-Amino(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 ro-1H- See indole-1,6-dicarboxylate Below (1-(tert-Butoxycarbonyl)chloro- 73 hoxycarbonyl)-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 2-(4-amino(tert-butyl)- 77 azolo[3,4-d]pyrimidinyl)- 4 3-methyl-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 2-(4-amino-1H- pyrazolo[3,4-d]pyrimidinyl) 80 chloro((2- 8 (trimethylsilyl)ethoxy)methyl)-1H- indolecarboxylate 3-(6-Bromo-1H-indolyl) 81 pyl-1H-pyrazolo[3,4- 4 d]pyrimidinamine Phenyl (2-(4-amino(tert-butyl)- 82 azolo[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), .69 (m, 2H), 3.11-2.99 (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), 3.80-3.67 (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 ed 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), .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), 7.76-7.62 (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), 2.32-1.99 (m, 3H), 1.99-1.70 (m, 2H). 11.96 (s, 1H), 8.15 (d, J = 1.4 Hz, 1H), 7.79 (d, J = 6.1 Hz, 1H), 7.72 (d, J = 8.3 Hz, 1H), 7.68 (dd, J = 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 s 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), .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 * indicates al 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 basified with aq.

NaOH (1M, 50 mL) then extracted with 20 % MeOH:DCM (3 × 50 mL). The combined organics were filtered through a hydrophobic frit and then concentrated in vacuo to return the title compound (1.16 g, 62%) as a yellow powder which was used without further purification.

LCMS [M+H]+ 228.0 and 230.0; 1H NMR (300 MHz, DMSO-d6) δ 8.22 (s, 1H), 3.86 (s, 3H).

Methyl 2-(4-amino(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 m 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 sion 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, ioned 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 hobic frit and the solvent removed in vacuo. The crude product was purified by fcc (0-100 % EtOAc in isohexane) to return the title compound (116 mg, 44%, 43% pure by HPLC) as orange powder.

LCMS [M-H]- 381.2. Used directly in the next step. utyl N-(3-bromo-1H-pyrazolo[3,4-d]pyrimidinyl)-N-tert-butoxycarbonyl-carbamate (Intermediate 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 stirred at room temperature for 24 h. The solvent was concentrated in vacuo then the crude mixture was dissolved in methanol (20 mL). Aq. sat. (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 combined organics were passed through a hydrophobic frit and concentrated in vacuo. The crude product was purified by fcc (0-10% MeOH:DCM) to return the title nd (1.55 g, 80%) as a pale yellow solid. LCMS [M-H]- 414.1 and 412.2. tert-Butyl N-(3-bromocyclopropyl-pyrazolo[3,4-d]pyrimidinyl)-N-tert-butoxycarbonylcarbamate (Intermediate 30) To a on 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 d 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, DMSO-d6) 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 d 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 methanol (10 mL) was added dehyde (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 te was concentrated in vacuo, then the resulting residue was suspended in sat. aq. NaHCO3 (20 mL) and extracted 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 powder. 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 3-bromo-1H-pyrazolo[3,4-d]pyrimidinamine (2.00 g, 9.34 mmol) and opentenone (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 concentrated in vacuo. The residue 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, filtered and concentrated in vacuo to return the title nd (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 s 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 solution of 4-aminotert-butyl-pyrazolo[3,4-d]pyrimidinecarbaldehyde (60 mg, 0.27 mmol) and methyl aminobenzoate (45 mg, 0.27 mmol) in DMF (4.0 mL) was treated with OXONE® (42 mg, 0.27 mmol) and the ing mixture was stirred at room temperature for 90 mins before adding further OXONE® (42 mg, 0.27 mmol). The reaction was stirred for 17 h at room temperature before adding further OXONE® (42 mg, 0.27 mmol) and stirred for another 16 h. The reaction e was diluted with aq. K2CO3 (0.5M, 10 mL) and extracted with EtOAc (2 × 15 mL). The combined organics were washed with water, filtered h a hobic 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. 4-Chloroiodoisopropyl-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 between 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 ed organic ts 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 compound (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 oxane (30 mL) was added NH4OH (28% NH3, 205 mL) and the resulting suspension was heated in a sealed 500 mL pressure vessel at 140 °C for 19 h. Further NH4OH (28% NH3, 100 mL) was added and the mixture heated at 120 °C for 18 h. After cooling to room temperature the solvent was trated 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 stirred 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 filtered 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. oisopropylimidazo[5,1-f][1,2,4]triazin-4(3H)-one (Intermediate 51) To a sion 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 oride (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 ater (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 solution obtained concentrated in vacuo to return the title compound (430 mg, 89% pure by HPLC, 99%) as a tan brown solid. LCMS [M+H]+ 194. This material was used in the subsequent step without additional purification. 2-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 d at room temperature for 18 h. EtOAc (50 mL) and water (50 mL) were added and the layers separated. The aq layer was r extracted with EtOAc (50 mL) and the combined organic extracts washed sequentially with aq. Na2S2O3 solution (1.0 M, 2 × 20 mL) and brine (3 × 20 mL), then dried and trated in vacuo to return the title compound (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 2-aminoiodoisopropylimidazo[5,1-f][1,2,4]triazin-4(3H)- one (690 mg, 2.12 mmol) in THF:DMF (6:1, 70 mL) was added t-butyl nitrite (1.20 mL, 10.1 mmoL) dropwise. The resulting mixture was stirred at room ature 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 purification.

-Iodoisopropylimidazo[5,1-f][1,2,4]triazinamine (Intermediate 54) Phosphorus oxychloride (0.500 mL, 5.36 mmol) was added to a solution of 1H- 1,2,4-triazole (1.04 g, 15.1 mmol) in pyridine (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, ined at this temperature for 75 mins and then concentrated 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 ted 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% MeOH:DCM) to return the title compound (390 mg, 77%) as a dark yellow solid. LCMS [M+H]+ 304; 1H NMR (400MHz, 6) 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 o(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 ed 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. r 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 organic extracts 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 mediate 58) ] A mixture 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 stirred 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 c layer was separated and retained and the aq phase was extracted with further EtOAc (2 × 30 mL).

The combined organic extracts were washed with water (20 mL), brine (20 mL), dried and concentrated in vacuo. The crude product was purified by fcc (0-2% MeOH (+ 1% NH3) in DCM). The crude product was then slurried with TBME:isohexane (1:4, 10 mL), filtered and washed with further isohexane (10 mL) to return the title compound (0.78 g, 88%) as a pale yellow solid. LCMS [M+H]+ 216; 1H NMR (400MHz, DMSO-d6) δ 8.21 (s, 1H), 8.12-7.40 (br, 1H), .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 Et3N:THF (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 mixture heated in the microwave at 80 °C for 1 h. The solvent was concentrated in vacuo and the resulting residue partitioned between EtOAc (50 mL) and water (30 mL). The organic layer was separated and retained and the aq phase was ted with further EtOAc (2 × 20 mL). The combined organic extracts were washed with water (3 × 10 mL), brine (10 mL), dried and trated 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 present.

-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 z, 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 e of 1-tert-butyl 6-methyl 5-chloro-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 ed 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 e 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 e stirred for a further 24 h. The t was concentrated in vacuo and the crude product purified by fcc (0-20% EtOAc in isohexane) to return the title compound (1.35 g, 98%) as a colourless gum. LCMS [M+Na]+ 455; 1H NMR (400MHz, 6) 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 carboxylate (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 ic mixture separated. The aq layer was extracted with further 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 analysis 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 (Intermediate 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, ined at this temperature for 45 min, then recooled to 0 °C. NaOH (2.0 M, 20 mL) and water (20 mL) were added, the mixture was warmed to room temperature and stirred for 15 min. EtOAc (20 mL) was added and the biphasic mixture separated. The aq layer was ted with further EtOAc (2 × 20 mL) and the combined organic extracts dried and concentrated in vacuo. The crude product was purified by fcc (0-5% MeOH in DCM) to return the title compound (346 mg, 75%) as an off-white solid. LCMS [M+H]+ 371; 1H NMR (400MHz, 6 ) 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). mino(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 sion 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) slowly. The resulting mixture 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 isopropyl-pyrazolo[4,3- c ]pyridinamine (200 mg, 0.66 mmol) in MeCN (5 mL) was added NCS (89 mg, 0.66 mmol) and the resulting solution was stirred at 70 °C for 3 h. The solvent was concentrated in vacuo and the residue obtained purified by fcc (0- % MeOH in DCM) to return the title nd (80 mg, 36%) as a brown solid. LCMS [M+H]+ 336; 1H NMR z, 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 ro-1H-indole-1,6-dicarboxylate (Intermediate 72) ed according to a similar procedure to that used for 1-tert-butyl 6-methyl -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 (10-20% EtOAc in isohexane) to return the title compound (327 mg, 89%) as white solid. LCMS [M+H]+ 310; 1H NMR z, 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 similar 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 on 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 ed 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 (Intermediate 76) A e 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 nitrogen. Pd(PPh3)2Cl2 (24.0 mg, 0.0330 mmol) was added and the resulting mixture heated at 90 °C for 18 h. After being cooled to room temperature, a second portion of bis(pinacolato)diboron (72.0 mg, 0.274 mmol) and 3)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 h a pad of CeliteTM (ca. 2 g), washing with further EtOAc (2 × 10 mL). The volatile solvents were concentrated in vacuo and the crude t 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 t additional purification. (6-(Methoxycarbonyl)((2-(trimethylsilyl)ethoxy)methyl)-1H-indolyl)boronic acid (Intermediate 78) To a solution of methyl 1-(2-trimethylsilylethoxymethyl)indole- oxylate (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 mixture was maintaine d at 0 °C for 2 h then quenched through the addition of water (5 mL) and sat aq NaHCO3 (x mL). After stirring for 5 min the volatile ts were concentrated in vacuo and the mixture obtained diluted with EtOAc (50 mL). The organic layer was separated and retained and the aq phase was extracted with further EtOAc (2 × 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 compound (2.61 g, 60% pure by HPLC) as a brown solid. This material was used in the subsequent step t additional purification.

Phenyl (2-(4-Amino(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidinyl)-1H-indolyl) ate (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 temperature for 3.5 h, then partitioned between EtOAc (20 mL) and water (10 mL) and separated. The aq layer was extracted with further EtOAc (2 × 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 uent step t 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- 3-yl)-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 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidin- 4 3-yl)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- midinyl)-N-methyl-1H-indole carboxamide minoisopropyl-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 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidin- 17 3-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-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- indolecarboxamide 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 carboxamide minotert-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 2-(4-Aminotert-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-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 2-{4-Aminotert-butyl-1H-pyrazolo[3,4- 33 midinyl}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 amide 2-[4-Amino(propanyl)-1H-pyrazolo[4,3- 38 c]pyridinyl]chloro-N-methyl-1H-indole carboxamide 2-[4-Amino(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 2-(4-Aminotert-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 mino(tert-butyl)-1H-pyrazolo[3,4- 46 d]pyrimidinyl)chloro-1H-indolecarboxylic 2-[4-Amino(propanyl)pyrrolo[2,1- 47 f][1,2,4]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 mino(propanyl)imidazo[4,3- 49 f][1,2,4]triazinyl]chloro-N-methyl-1H-indole- 6-carboxamide minotert-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 carboxamide N-(2-{4-Aminotert-butyl-1H-pyrazolo[3,4- d]pyrimidinyl}-1H-indolyl)acetamide 1-(2-{4-Aminotert-butyl-1H-pyrazolo[3,4- 55 d]pyrimidinyl}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 midinyl}-N,1-dimethyl-1H-indole carboxamide 2-[4-Aminochloro(propanyl)-1H- 61 lo[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 2-{4-Aminocyclohexyl-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- 3-yl}-N-methyl-1H-indolecarboxamide 2-{4-Aminocyclopropyl-1H-pyrazolo[3,4- 67 midinyl}-N-methyl-1H-indole carboxamide minotert-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) esulfonamide 1-(2-(4-Amino(tert-butyl)-1H-pyrazolo[3,4- d]pyrimidinyl)-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 yl)-1H-indolecarboxamide 2-{4-Aminotert-butyl-1H-pyrazolo[3,4- 80 d]pyrimidinyl}chloro-N-(oxanylmethyl)- 1H-indolecarboxamide 2-(4-Amino(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 d]pyrimidinyl)chloro-N,1-dimethyl-1H- indolecarboxamide 2-{4-Aminoethyl-1H-pyrazolo[3,4-d]pyrimidin- 84 3-yl}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 midinyl}-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- ropyl-1H-indolecarboxamide tert-Butyl 4-{4-amino[3-chloro (cyclopropylcarbamoyl)-1H-indolyl]-1H- pyrazolo[3,4-d]pyrimidinyl}piperidine carboxylate 2-{4-Aminotert-butyl-1H-pyrazolo[3,4- 91 d]pyrimidinyl}chloro-N-propyl-1H-indole carboxamide minochloroisopropyl-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- indolecarboxamide 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- olecarboxamide 2-[4-Amino(2,2,2-trifluoroethyl)-1H- 100 pyrazolo[3,4-d]pyrimidinyl]chloro-N-methyl- 1H-indolecarboxamide mino(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 d]pyrimidinyl]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- yrazolo[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 ropyl(6-oxazolyl-1H-indol yl)pyrazolo[3,4-d]pyrimidinamine 109 3-(3-Chlorooxazolyl-1H-indolyl) isopropyl-pyrazolo[3,4-d]pyrimidinamine Table D - Examples Prepared Using General Methods General Yield (%) EXAMPLE FORMULA MW ADDUCT m/z Method 1 C19H21N7O 363.42 [M+H]+ 364.2 6 32 2 N9O 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 C19H20ClN7O2 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 C17H16ClN7O2 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 ClN7O2 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 BrN6O 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 ClN6O 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 C20H21ClN6O 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 C20H23N7O 377.44 [M+H]+ 378.3 6 39 61 C19H19ClN6O 382.85 [M+H]+ 383.4 7 46 62 ClN7O 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 C19H20ClN7O 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 ClN7O 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 ClN7O 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 C18H15ClF3N7O 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 C23H25ClN8O 464.95 [M-H]- 463.7 7 7 106 C18H16N8S 376.44 [M-H]- 375.2 3 2 107 ClN8S 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), 7.50-7.57 (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), .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), .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 solvent peak. 12.14 (s, 1H), 8.56 (s, 1H), 8.26 (s, 1H), 7.98 (s, 1H), 7.67 (d, J = 8.85 Hz, 1H), 7.58 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), 8.52-8.43 (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), .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), 3.60-3.54 (m, 4H), .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), .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 present. 11.92 (s, 1H), 8.42-8.36 (over-lapping m, 2H), 7.96 (s, 1H), 7.76 (s, 1H), 7.64 (d, J = 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 t. 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), 6.77-6.75 (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), .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), .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), 2.49-2.39 (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), 1.23-1.07 (m, 2H). 12.14 (s, 1H), 8.27 (s, 1H), 8.05-7.99 (over-lapping m, 2H), 7.73 (dd, J = 8.4, 1.4 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.28 (br, 1H), 7.05-6.80 (br, 2H), 1.79 (s, 9H). 12.20 (s, 1H), 8.31 (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), .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 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), .84 (m, 2H), 3.28 (td, obscured by solvent assume 2H), 3.19 (app t, J = 6.3 Hz, 2H), .74 (m, 1H), 1.78 (s, 9H), 1.65-1.58 (m, 2H), 1.27-1.16 (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 .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 visible. 12.13 (s, 1H), 8.50 (d, J = 4.27 Hz, 1H), 8.28 (s, 1H), 7.99 (s, 1H), 8.02-7.95 (m, 1H), 7.69 (d, J = 8.40 Hz, 1H), 7.59 (d, J = 8.45 Hz, 1H), 7.06 (br s, 2H), 5.06-4.89 (m, 1H), 4.10 (d, J = 13.01 Hz, 2H), 3.03 (br s, 2H), .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), .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), 4.14-4.07 (m, 1H), 3.99 (dd, J = 9.2, 4.4 Hz, 1H), 3.94-3.89 (m, 1H), 3.29-3.23 (m, 2H), 2.48-2.43 (m, 2H), 1.57 (app sext, 2H), 0.91 (t, J = 7.4 Hz, 3H). NH2 signals not observed. 12.22 (s, 1H), 8.52 (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), 3.94-3.89 (m, 1H), 2.92-2.86 (m, 1H), 2.47-2.42 (m, 2H), 0.73-0.68 (m, 2H), 0.63- 0.59 (m, 2H). 12.21 (s, 1H), 8.50 (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), .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), .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 signals 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 mixture of mono- and inated 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 tert-butoxide (1.0 M in THF, 1.89 mL) in DMF (7 mL) was stirred at room temperature for 20 h and then at 90 °C for 16 h. The solvent was concentrated in vacuo and the resulting residue taken up in MeOH (10 mL) and ped with heptane (20 mL). The solid that formed was dissolved in MeOH (10 mL) and ed 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.

Example 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 organic 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 product was ed 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 on 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 temperature for 45 mins, then diluted with aq NaOH (1.0 M, 30 mL) and stirred for a further 15 mins. EtOAc (30 mL) was added and the biphasic mixture ted. 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 ne (20 µL, 0.25 mmol) in DCM (1 mL) at 0 °C was added esulfonyl 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 on 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 ts washed with brine (2 × 10 mL), passed through a phase separator 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 ed was further purified by preparative HPLC to return the title compound (9 mg, 20% yield) as a pale yellow solid.

Example 71 – 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 resulting mixture stirred at room temperature for 23 h. THF (1 mL) was added, the mixture was stirred at room temperature for 30 min and then further methylamine (2.0 M in THF, 0.10 mL) was added. The resulting mixture was stirred for 24 h then onal 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 extracted 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.

Example 93 - 2-[4-amino(piperidinyl)-1H-pyrazolo[3,4-d]pyrimidinyl]chloro-N- cyclopropyl-1H-indolecarboxamide hydrochloride ] To a solution of tert-butyl 4-[4-amino[3-chloro(cyclopropylcarbamoyl)-1H-indol- 2-yl]pyrazolo[3,4-d]pyrimidinyl]piperidinecarboxylate (30 mg, 0.05 mmol) in oxane (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 concentrated 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 utyl-pyrazolo[3,4-d]pyrimidinyl)chloro-N- methyl-1H-indolecarboxamide (32 mg, 0.08 mmol) and NaOH (64 mg, 1.6 mmol) in ater (15:1, 3.2 mL) at -5 °C was added diethyl(bromodifluoromethyl)phosphonate (43 mg, 0.16 mmol). The resulting mixture was stirred at 0 °C for 15 mins, then warmed to room temperature and maintained at this temperature for a further 2 h. A 2:1 mixture of unreacted starting material and product was observed by HPLC. The solvent was concentrated in vacuo and the resulting residue partitioned between EtOAc (50 mL) and water (15 mL). The organic layer was ted and ed and the aq phase was extracted with further EtOAc (2 × 50 mL). The combined organic ts 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 scence transfer (FRET). The assay was performed in ll white plates (Corning #3574) in a reaction volume of 10 µL containing 1X CisBio tic buffer supplemented with a final concentration 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 supplemented with a final concentration of 2 mM MgCl2, 1mM DTT, 20 nM SEB and 0.01% Triton X100.

Inhibitors 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 substrate 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 d at room temperature for 30 mins before terminating with the addition of 10 µL HTRF detection buffer containing EDTA mented 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 ion 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 0.00736 0.0667 0.00555 41 0.0212 0.142 42 0.607 >30 2.95 43 0.00566 0.566 0.00583 44 0.153 >30 2.6 45 0.114 >30 >30 46 0.194 >30 1.96 47 4 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 9 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 0.00866 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 developed by Daley and Baltimore16 was used, whereby IL3- dependent BaF3 cells are modified to s 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 KIF5B-RET (gift from Pasi Janne7), KDR and RETV804M (Advanced Cellular Dynamics, San Diego) were maintained in 640 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, ity was determined by addition of 10 µL ter-Glo reagent (Promega) and measurement of luminescence.

Cell activity data is presented in Table 2 below.

Table 2 – BaF3 Cell activity data KIF5B-RET KDR IC50 T(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 skilled in the art without departing from the scope of the invention as defined by the appended claims.

REFERENCES Carlomagno, F., Guida, T., Anagantil, S., Vecchio, G., Fusco, A., Ryan, A., Billaud, M., Santoro, M. (2004). Disease associated mutations at valine 804 in the RET receptor tyrosine kinase confer resistance to selective kinase inhibitors. Oncogene 23, 063 Chao, B., witz, R., Villalona-Calero, M. (2012) RET fusion genes in Non-Small-Cell Lung Cancer. JCO 30, 4439-4441.

Dinér, P., Alao, J., Söderland, J., Sunnerhagen, P. Grotli, M. (2012) J Med Chem 2012 55 (10) 4872-6 Elisei, R., Cosci, B., Romei, C., Bottici, V., Renzini, G., ro, E., Agate, L., Vivaldi, A., Faviana, P., Basolo, F., Miccoli, P., Berti, P., Pacini, F., Pinchera, A. (2008) RET genetic screening in patients with medullary thyroid cancer and their relatives: experience with 807 individuals at one center. Journal of Clinical Endocrinology and lism 93, 682-687.

Ju, Y., Lee, W., Shin, J., Lee, S., Bleazard, T., Won, J., Kim, Y., Kim, J., Kang, J., Seo, J. (2011). A transforming KIF5B and RET gene fusion in lung adenocarcinoma revealed from wholegenome and transcriptome sequencing. Genome Res. 3, 436-445.

Kohno, T., Ichikawa, H., Totoki, Y., Yasuda, K., Hiramoto, M., Nammo, T., Sakamoto, H., Tsuta, K., Furuta, K., Shimada, Y., Iwakawa, R., Ogiwara, H., Oike, T., Enari, M., Schetter, A., Okayama, H., Haugen, A., Skaug, V. Chiku, S., Yamanaka, I., Arai, Y., Watanabe, S., Sekine, I., Ogawa, S., Harris, C., Tsuda, H., Yoshida, T., Yokota, J., Shibata, T. (2012) KIF5B-RET fusions in lung arcinoma. Nat Med. 12, 7.

Lipson, D., etti, M., Yelensky, R., Otto, G., Parker, A., Jaroszi, M., Curran, J., Balasubramanian, S., Bloom, T., Brennan, K., Donahue, A., Downing, S., Frampton, G., Garcia, L., Juhn, F., Mitchell, K., White, E., White, J., Zwirko, Z., Peretz, T., Nechushtan, H., Soussan- Gutman, L., Kim, J., Sasaki, H., Kim, H., Park, S., Ercan, D., Sheehan, C., Ross, J. Cronin, M., Jänne, P., Stephens, P. (2012) Identification of new ALK and RET gene fusions from ctal and lung cancer biopsies. Nat Med. 12, 382-384. ara, D., Kanai, Y., wa, S., Ohara, S., Yoshimoto, T., Sakatani, T., Oguni, S., , T., Kataoka, H., Endo, S., Murakami, Y., Aburatani, H., Fukayama, M., Niki, T. (2012).

Identification of CCDC6-RET fusion in the human lung adenocarcinoma cell line, LC-2/ad. J Thorac Oncol. 12, 1872-6.

Nagilla, M., Brown, R., Cohen, E. (2012). Cabozantinib for the ent of Advanced Medullary Thyroid Cancer. Adv Ther 11, 925-934.

Santoro, M. and Carlomagno, F. (2006). Drug insight: Small-molecule inhibitors of protein kinases in the ent of thyroid cancer.Nature Clinical Practice: Endocrinology and lism 2, 42-52.

Verbeek. H.H., Alves, M.M., de Groot, J.W., Osinga J, Plukker, J.T., Links, T.P., Hofstra, R.M. (2011). The s of four different tyrosine kinase tors on medullary and papillary thyroid cancer cells. J Clin Endocrinol Metab. 96, 2010-2381.

Vitagliano, D., De Falco, V., Tamburrino, A., Coluzzi, S., Troncone, G., etta, G., Ciardiello, F., Tortora, G., Fagin, J., Ryan, A., Carlomagno, F., Santoro, (2011). The tyrosine inhibitor ZD6474 blocks proliferation of RET mutant medullary thyroid carcinoma cells. Endocrinerelated Cancer 18, 1-11.

Wang, R., Hu, H., Pan, Y., Li, Y., Ye, T., Li, C., Luo, X., Wang, L., Li, H., Zhang, Y., Li, F., Lu, Y., Lu, Q., Xu, J., Garfield, D., Shen, L., Ji, H., Pao, W., Sun, Y., Chen, H. (2012). RET fusions define a unique molecular and clinicopathologic subtype of non-small-cell lung cancer. JCO 30, Wells, S. and Santoro, M. (2009) Targeting the RET y in thyroid cancer. Clin Can Res. 15, 7119-7123.

Wells, S., l, J., Gagel, R., Moley, J., Pfister, D., Sosa, J., Skinner, M., Krebs, A., Vasselli, J., Schlumberger, M. (2012). Vandetanib in patients with locally ed or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial. JCO 10, 134-141.

Daley, G. Q.; Baltimore, D. Transformation of an interleukin 3-dependent hematopoietic cell line by the c myelogenous leukemia-specific P210bcr/abl protein. Proc. Natl. Acad. Sci.

U. S. A. 1988, 85, 9312-16.

Claims

1. A compound, or compounds, or pharmaceutically acceptable salt, hydrate or solvate f, having the structural formula (Id) shown below: wherein: HET is selected from one of the following: wherein denotes the point of attachment; R1 is selected from en, (1-4C)haloalkyl, (1-4C)haloalkoxy or a group of the formula: -L-Y-Q wherein: L is absent or (1-5C)alkylene ally 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), 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, 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; 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, y, carboxy, carbamoyl, moyl, 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), 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 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), S(O)2N(Rf), or N(Rf)SO2, wherein Rf and Rg are each independently selected from hydrogen or (1- yl; and Z1 is en, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, (3- 8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl 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, 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 selected from en, (1-4C)alkyl, halo, (1- 4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, alkylamino, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl or mercapto; W is selected from O, S or NRj, wherein Rj is selected from H or (1-2C)alkyl; 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, 1, 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 substituted by one or more substituents selected from amino, hydroxy, alkoxy or halo; and Rk1 and Rk2 are each independently selected from hydrogen or (1- X3 is ed from N or CRm; wherein Rm is selected from hydrogen, halo, (1-4C)alkyl, (1-4C)alkoxy, amino, (1-4C)alkylamino, dialkylamino, cyano, (2C)alkynyl, C(O)Rm1, C(O)ORm1, OC(O)Rm1, 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 tuents selected from amino, hydroxy, (1-2C)alkoxy or halo; and Rm1 and Rm2 are each independently selected from hydrogen or (1- 4C)alkyl; Ro is ed from halo, alkyl, (1-4C)alkoxy, amino, (1-4C)alkylamino, (1-4C)dialkylamino, cyano, (2C)alkynyl, C(O)Ro1, C(O)ORo1, OC(O)Ro1, Ro2)Ro1, 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 ally substituted by one or more substituents selected from amino, hydroxy, (1-2C)alkoxy or halo; and Ro1 and Ro2 are each independently selected from hydrogen or alkyl; R2 is selected from hydrogen, (1-4C)alkyl or a group of the formula: -L2-Y2-Q2 wherein: L2 is absent or (1-3C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkyl or oxo; Y2 is absent or C(O), C(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, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Q2 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, 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), Ry)O, N(Ry)(O)C, C(O)O, OC(O), N(Ry)C(O)N(Ry1), SO2N(Ry), O2, oxazolyl, triazolyl, oxadiazolyl, thiazolyl, imidazolyl, thiadiazolyl, pyridinyl, lyl, pyrrolyl or olyl, 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, heteroaryl or heterocyclyl; wherein Q3 is optionally further substituted by one or more substituent groups independently selected from alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, NRzRaa, ORz, wherein Rz and Raa are each ndently 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, 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 ed from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- oalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano, hydroxy, carboxy, carbamoyl, moyl, 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 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 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, wherein HET is selected from one of the following: n R1, R1a and R1b are each as defined in claim 1; or a ceutically acceptable salt, hydrate or solvate thereof.

3. A compound, or pharmaceutically acceptable salt, hydrate or solvate thereof, according to claims 1 or 2, 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 solvate thereof.

4. A compound, or ceutically acceptable salt, hydrate or solvate thereof, according to any one of claims 1 to 3, wherein the compound has the structural Formula If shown below: 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 acceptable salt, hydrate or solvate thereof, according to any one of claims 1 to 5, n X3 is selected from N or CRm and bond b is a double bond, wherein Rm is selected from hydrogen, halo, (1-4C)alkyl or amino.

7. A compound, or pharmaceutically acceptable salt, hydrate or solvate thereof, according to any one of claims 1 to 6, wherein 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, ing to claims 1 to 3, wherein R3 is selected from a group of the formula: -Y3-Q3 Y3 is C(O), C(O)N(Ry), C(O)N(Ry)O, O)C, C(O)O, OC(O), wherein Ry is selected from hydrogen or (1-2C)alkyl; and Q3 is hydrogen, (1-6C)alkyl, (1-6C)alkoxy, aryl, aryl(1-2C)alkyl, (3- 8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Q3 is optionally r 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, alkyl or (3-6C)cycloalkyl; or Q3 is optionally tuted 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 (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 hydrogen or (1-2C)alkyl; and Z4 is hydrogen, alkyl, aryl, aryl(1-2C)alkyl, (3- 8C)cycloalkyl, 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, aryl, 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 they form a 4-7 membered heterocyclic ring which is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano or hydroxyl.

9. A compound, or pharmaceutically acceptable salt, hydrate or solvate thereof, according to any preceding claim, wherein the nd 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 acceptable salt, e or solvate thereof, according to any preceding claim, n Ro is selected from halo, (1-4C)alkyl or amino.

11. A compound, or pharmaceutically acceptable salt, e or solvate thereof, ing 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 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 and Rb are each independently selected from hydrogen or (1- 4C)alkyl; and Q is hydrogen, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, aryl, (3- 10C)cycloalkyl, (3-10C)cycloalkenyl, aryl or heterocyclyl; wherein Q is optionally r 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, 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)zNRdRc (where z is 1, 2 or 3); wherein Rc, Rd and Re are each independently selected from hydrogen, (1-6C)alkyl or (3-6C)cycloalkyl.

13. A compound, or pharmaceutically acceptable salt, hydrate or e thereof, ing to any preceding claim, wherein R1 is selected from hydrogen, (1- oalkyl, (1-4C)haloalkoxy, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, aryl, (3- 10C)cycloalkyl, (3-10C)cycloalkenyl, heteroaryl or cyclyl; 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, y, 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 cycloalkyl.

14. A compound, or pharmaceutically acceptable salt, hydrate or solvate thereof, according to any preceding claim, wherein R1 is selected from en, (1-6C)alkyl or (3-10C)cycloalkyl; wherein each of said substituents is optionally further substituted by one or more substituent groups independently selected from (1- yl, halo, amino, (1-4C)aminoalkyl, cyano, hydroxy, carboxy, NRcRd, ORc or Si(Rd)(Rc)Re; wherein Rc, Rd and Re are each independently ed from hydrogen or (1-4C)alkyl.

15. A compound, or pharmaceutically acceptable salt, hydrate or solvate thereof, according to any preceding claim, wherein R2 is selected from hydrogen, (1-4C)alkyl or a group of the formula: -Y2-Q2 wherein: Y2 is C(O)N(Rp), n Rp is selected from hydrogen or (1-4C)alkyl; Q2 is (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 or hydroxy.

16. A compound, or ceutically acceptable salt, hydrate or solvate thereof, according to any preceding claim, wherein R2 is en.

17. A compound, or pharmaceutically acceptable salt, e or solvate thereof, according to claims 9 to 16, wherein Q3 is en, (1-6C)alkyl, (1-6C)alkoxy, 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, oyl, 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, , C(O), C(O)O, or C(O)N(Rab), 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 tuents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1- 4C)alkylamino, amino, cyano or hydroxy.

18. A compound, or pharmaceutically acceptable salt, hydrate or solvate thereof, according to claims 9 to 17, n 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 r substituted by one or more substituent groups independently ed 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 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, 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 tuted 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

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; 2-(4-Aminotert-butyl-pyrazolo[3,4-d]pyrimidinyl)chloro-N-(2-morpholinoethyl)- 1H-indolecarboxamide; minotert-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; minotert-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; 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; minotert-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; 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-indolecarboxamide; minomethyl-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; minocyclobutyl-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; 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-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- 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- oxamide; 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- midinamine; 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 nd according to any one of the preceding claims, or a pharmaceutically acceptable salt or hydrate thereof, for use in therapy.

21. A ceutical composition comprising a compound according to any one of claims 1 to 19, or a ceutically acceptable salt or hydrate thereof and a pharmaceutically acceptable carrier or excipient.

22. A compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition according to claim 21, for use in the ent of cancer.

23. A compound or a pharmaceutical composition ing to claim 22, wherein said cancer is medullary thyroid cancer or non-small cell lung cancer.

24. A method for the treatment of cancer in a subject in need of such treatment, said method comprising stering a therapeutically effective amount of a compound according to any of claims 1 to 19, or a pharmaceutically acceptable salt or hydrate f, or a pharmaceutical composition according to claim 21.

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