Ikk-alpha inhibitors

Abstract

The present invention relates to IKK-alpha inhibitory compounds, or a pharmaceutically acceptable salts, hydrates or solvates thereof, having the structural Formula (I), shown below: (I) wherein R1, R2, R3 R4 and X1 are each as defined herein. The present invention also relates to processes for the preparation of these compounds, to pharmaceutical compositions comprising them, and to their use in the treatment of proliferative disorders, such as cancer, as well as other diseases or conditions in which IKK-alpha activity is implicated.

Description

IKK-ALPHA INHIBITORSINTRODUCTION

[0001] The present invention relates to certain compounds that function as inhibitors of inhibitory-κB kinase (IKK) activity, and especially the alpha subunit of IKK ( IKKα). The compounds of the present invention may therefore be used to treat disease or conditions mediated, at least in part, by aberrant or inappropriate IKK (and especially IKKα) activity. Cancer is an example of condition associated with aberrant or inappropriate IKK (and especially IKKα) activity. The invention furthermore relates to the use of the compounds as for treating diseases or conditions in which IKK (and especially IKKα) activity is implicated, to processes for making these compounds and to pharmaceutical compositions comprising them.BACKGROUND OF THE INVENTION

[0002] Cancer is caused by altered cellular proliferation. Precisely what causes a cell to become malignant and proliferate in an uncontrolled and unregulated manner has been the focus of intense research over recent decades. This research has led to the identification of molecular targets associated with key pathways that enable such malignancies.

[0003] Nuclear Factor kappa-B (NF-κB), from Nuclear factor kappa-light-chain enhancer of B- cells, represents a family of five transcription factors involved in diverse biological responses that underpin phenotypic outcomes of inflammation, modulation of immune responses, cell growth, proliferation, apoptosis and aspects of differentiation and development [1-5], NF-κB signalling is now appreciated as either canonical (classical) or non-canonical (alternative) pathways via the mobilisation of both homo — and hetero-dimer complexes of these family members. Collectively the NF-κB proteins are five distinct isoforms; RelA (p65), RelB, c-Rel, NF-κB1 (p105 / p50) and NF-κB2 (p100 / p52) [1-5]. In an inactive state these proteins are typically associated with inhibitory-κB (IκB) proteins, including isoforms of IkBα, Iκκβ, and IκBε and in the case of p105 and p100 proteins it is their intrinsic protein structure that maintains them in a self-bound inhibitory form by virtue of their C-terminal iκB-like structures (IκBδ and IκBγ respectively) composed of ankyrin repeats [1-5], Activation and liberation of NF-κB proteins occurs typically in response to a number of extracellular ligands, as well as agents that generate a DNA Damage response (DDR), resulting in the nuclear localisation of DNA-binding protein dimers following dissociation from IκB molecules [1-5].The canonical pathway can be activated in response to cytokines such as TNFa and IL-1 [3, and pathogen-associated molecular profiles (PAMPs) such aass the bacterial endotoxin lipopolysaccharide (LPS) [6, 7], This response is typically rapid and transient, mediated by theclassical inhibitory-κB kinase (IKK) complex (IKKα / β / y) with a requirement for IKKβ-mediated phosphorylation of selected IκB proteins [6, 7], In contrast, activation of the non-canonical NF- κB pathway is relatively slower and over a period of hours results in an IKKα-mediated liberation of predominately p52-RelB dimers to drive gene transcription [1-7]. This slower response reflects reliance upon protein expression / stabilisation within the upstream components of the pathway. Whilst TNFa and IL-1 β have the ability to activate the non- canonical NF-κB pathway it is typically alternative members of the greater TNF superfamily that drive activation [3, 4], This includes lymphotoxin-p (LT-P), the related tumor necrosis factor superfamily member 14 (TNFSF14) known as LIGHT, TNF-like weak inducer of apoptosis (TWEAK), CD40 ligand (CD40L), Receptor-activator of NF-κB ligand (RANKL) and B-cell activating factor (BAFF) [1 , 3, 4],

[0004] A combination of molecular and genetic studies has shown that receptor mediated- non-canonical NF-κB activation is built around the paradigm of a TNF super family ligand activating its cognate receptor via recruitment of a sequence of identifiable adaptor molecules of the TNF-Receptor associated factor (TRAF) family, notably TRAF2 and TRAF3, modulators of ubiquitination and associated protein degradation in the form of the cellular inhibitors of apoptosis (clAPs). These proteins enable engagement and activation of the cellular kinases NF-κB-inducing kinase (NIK), the 14thmember of the MAP kinase kinase kinase (MAP3K) family, and IKKα to determine the liberation of p52-RelB protein complexes.

[0005] In a cellular setting, under resting non-stimulated conditions, NIK is maintained at a low expression level based upon NIK-focussed proteasomal degradation. However, upon receptor activation NIK is stabilised, protein expression is increased to enable pathway activation

[0016] , It is TRAF3 that acts as the crucial regulator of NIK expression by controlling the extent of its proteasome-mediated degradation

[0016] . Upon receptor activation the focus of proteasome-mediated protein degradation switches from NIK to that of TRAF2 and TRAF3 which stabilises NIK expression to initiate the sequence of signalling events toward p100 processing [17-20], The clAP proteins that function as ubiquitin ligases to ubiquitinate NIK then target TRAF3 for degradation to increase NIK protein levels.

[0006] Upon NIK protein stabilisation, as the first component of the non-canonical NF-κB pathway it catalyses is the phosphorylation of IKKα and supports IKKα recruitment to and phosphorylation of p100 to drive subsequent p100 ubiquitination and proteasome-mediated degradation to liberate p52

[0016] . Under basal conditions p100 exists typically in dimer complexes with RelB and upon stimulated degradation generates p52-RelB dimers able to translocate to the nucleus to initiate the transcription of distinct genes.

[0007] Both NIK and IKKα play critical roles in the phosphorylation of p100 to liberate mature p52-RelB protein dimers. However, whilst IKKα is now viewed as the key modulator of p100 phosphorylation there is a co-dependence on NIK to deliver coupled phosphorylation and processing of p100 to generate mature p52 that is transcriptionally active

[0022] . In transfected cells, NIK can stimulate the phosphorylation, ubiqultination and processing of p100 [23, 24], however recombinant NIK itself does not display any phosphorylation of p100 in vitro [24, 25], In the cell-based setting, NIK mediates downstream signalling by engaging and activating IKKα resulting in the phosphorylation of the C-terminal region of p100

[0025] , and this is independent of the other IKK isoforms, p and y associated with canonical NF-κB activation [26, 27]. Whilst IKKα phosphorylates p100 and regulated non-canonical NF-κB activation alone, it is not as effective at inducing p100 processing as NIK

[0023] , With these observations, further studies then identified NIK to have a critical role in regulating p100 processing via the recruitment of IKKα to and binding with p100 as a protein substrate

[0022] . Collectively, NIK-IKKα interaction with p100 results in the phosphorylation of pi 00 at specific serine residues, primarily Ser868 / 870

[0024] , These sites are components of the phospho-degron within the p100 C- terminal NIK-responsive domain (NRD) and when phosphorylated lead to pTrCP binding as part of the SCFβTrCPubiquitin ligase complex that drives the eventual processing of p100 to generate p52.

[0008] Independent of the non-canonical NF-κB pathway, a number of studies have identified that at the NIK-IKKα kinase level there are also examples of signal bifurcation. These can be dependent on differing extracellular conditions

[0029] and demonstrate that pi 00 is not the only substrate for IKKα-mediated phosphorylation. IKKα via catalysed phosphorylation, regulates directly a number of cellular proteins that then either directly or indirectly regulate cellular transcription [6, 7], This includes transcription factors distinct from the NF-κB family, for example E2F1 [30, 31], p-catenin

[0032] , CBP

[0033] , as well as the suppressors of transcription such as the silencing mediator for retinoic acid and thyroid hormone receptor (SMRT)

[0034] and cell cycle regulator cyclin D1

[0035] , Additional substrates also include the Protein inhibitor of activated STAT1 (PIAS1) as a modulator of transcription / inflammation

[0036] , the oestrogen (ER)

[0037] and androgen receptors (AR)

[0038] of the steroid hormone family receptor along with their associated steroid receptor co-factor (SRC)-3 [37, 39, 40] and Aurora kinase A [41 , 42] that contributes to the mitotic process. Direct modulation of the status of these proteins by IKKα has bearing on the transcription of additional regulatory proteins such as p53 [43, 44] and EZH2

[0044] and additional mitotic kinase Polo-like kinase (PLK) 4

[0045] , IKKα therefore serves as a key switch in the coordinated regulation of both NF-κB-dependent and NF-κB-independent gene transcription and this underpins the outcomes associated with events that initiate and / or perpetuate the development of acquired characteristics, or phenotypes, we now recognise ascancer ‘Hallmarks’ as Identified and defined by Hanahan & Weinberg [46, 47]. The transcriptional modulation driven by IKKα-mediated signalling, divulged using a number of experimental approaches such as genetic deletion and reconstitution [48, 49], siRNA ‘run- down’

[0035] and over-expression strategies

[0050] , may be in excess of 200 genes and these gene / protein induction / repression events support the acquisition of characteristics of specific ‘Hallmarks’, particularly the ability of tumours to ‘sustain proliferative signalling’, ‘resist cell death’, ‘evade growth suppressors’ and encourage ‘genomic instability and mutation’. More striking is the role of IKKα in regulating genes / protein that help to underpin the phenotypes associated with longer term tumour development : ‘inducing angiogenesis’ and ‘activating invasion and metastasis’ by way of regulating cytokine (e.g. IL-1 β, IL-6 [48, 49]) and chemokine (e.g. CCL19, CCL21 , CXCL12, CXCL13 and BAFF [27, 51 , 52]) induction and modulation of adhesion molecule (e.g. VCAM; [48-50]), maspin [50; 53] and MMPs

[0050] expression in different cellular / tissue situations. It is also evident that in particular sub-types of cancer the acquisition of a specific mutation, C250T in the hTERT promoter

[0054] that supports tumour reactivation has identified the potential for tumours to become ‘addicted’ to IKKα-mediated non-canonical NF-κB signalling thus ‘enabling replicative potential’. Collectively, perturbation of this enzyme could have wide-ranging effects on the multiple hallmarks of tumour cells described above. Moreover, given the impact of IKKα in regulating major cytokine, chemokine and matrix metalloproteinase isoforms, intervention against this enzyme may have significant effects on tumour-stromal communication and matrix composition within the tumour microenvironment and define a better understanding of ‘tumour-promoting inflammation’.

[0009] Additional complexities to the regulation of IKKα-dependent, NF-κB-dependent and - independent gene transcription are also now apparent in the cancer setting, as we now appreciate that this transcriptional process is not wholly driven by receptor-mediated activation. For both solid tumour (e.g. pancreatic adenocarcinomas) and haematological settings (e.g. multiple myeloma) constitutive activation of IKKα-mediated signalling has been reported as a result of modulation of expression of upstream TRAF and clAP components in the pathways or mutation in these very same components that ultimately results in constitutive activation of the pathway in the absence of agonist. Furthermore, a truncated p45 form of IKKα has been identified in a number of colorectal cancers [55, 56], particularly those with a recognised B- RafV600Emutant background. This drives p45 IKKα-mediated nuclear signalling in a TNF superfamily member-independent manner and so brings additional mechanistic and transcriptional diversity to tumour development, which has implications for potential intervention therapeutically.

[0010] In recent years the role of the non-canonical NF-κB pathway and IKKα within it have increasingly been implicated in the development and progression of multiple solid tumours andhaematological cancers. As a consequence, there Is a need and a desire to identify potentially useful IKKα inhibitors

[0011] The present invention was devised with the foregoing in mind.References[1] Sun SC. Non-canonical NF-κB signaling pathway. Cell Res. 2011 Jan;21(1):71-85.[2] Razani B, Reichardt AD, Cheng G. Non-canonical NF-κB signaling activation and regulation: principles and perspectives. Immunol Rev. 2011 Nov;244(1):44-54.[3] Cildir G, Low KC, Tergaonkar V. Noncanonical NF-κB Signaling in Health and Disease. Trends Mol Med. 2016 May;22(5):414-429.[4] Sun SC. The non-canonical NF-κB pathway in immunity and inflammation. Nat Rev Immunol. 2017 Sep; 17(9): 545-558.[5] Xia L, Tan S, Zhou Y, Lin J, Wang H, Oyang L, Tian Y, Liu L, Su M, Wang H, Cao D, Liao Q. Role of the NFκB-signaling pathway in cancer. Onco Targets Ther. 2018 Apr 11;11:2063-2073.[6] Perkins ND. Integrating cell-signalling pathways with NF-kappaB and IKK function. Nat Rev Mol Cell Biol. 2007 Jan;8(1 ):49-62.[7] Gamble C, McIntosh K, Scott R, Ho KH, Plevin R, Paul A. Inhibitory kappa B Kinases as targets for pharmacological regulation. Br J Pharmacol. 2012 Feb;165(4):802-19.

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[0055] Margalef P, Fernandez-Majada V, Villanueva A, Garcia-Carbonell R, Iglesias M, Lopez L, Marti'nez-lniesta M, Villa-Freixa J, Mulero MC, Andreu M, Torres F, Mayo MW, Bigas A, Espinosa L. A truncated form of IKKα is responsible for specific nuclear IKK activity in colorectal cancer. Cell Rep. 2012 Oct 25;2(4):840-54.

[0056] Margalef P, Colomer C, Villanueva A, Montagut C, Iglesias M, Bellosillo B, Salazar R, Marti'nez-lniesta M, Bigas A, Espinosa L. BRAF-induced tumorigenesis is IKKα-dependent but NF-κB-independent. Sci Signal. 2015 Apr 21;8(373):ra38.SUMMARY OF THE INVENTION

[0012] According to a first aspect of the present invention there is provided a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein.

[0013] According to a further aspect of the present invention, there is provided a pharmaceutical composition comprising a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in admixture with a pharmaceutically acceptable diluent or carrier.

[0014] According to a further aspect of the present invention, there is provided a method of inhibiting IKKα activity, in vitro or in vivo, said method comprising contacting a cell with an effective amount of a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein.

[0015] According to a further aspect of the present invention, there is provided a method of treating a disease or disorder In which IKKα activity is implicated in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.

[0016] According to a further aspect of the present invention, there is provided a method of treating a proliferative disorder in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.

[0017] According to a further aspect of the present invention, there is provided a method of treating cancer in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.

[0018] According to a further aspect of the present invention, there is provided a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein, for use in therapy.

[0019] According to a further aspect of the present invention, there is provided a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein, for use as a medicament.

[0020] According to a further aspect of the present invention, there is provided a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein, for use in the treatment of a proliferative disorder.

[0021] According to a further aspect of the present invention, there is provided a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein for use in the treatment of cancer. In a particular embodiment, the cancer is human cancer.

[0022] According to a further aspect of the present invention, there is provided a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein for use in the inhibition of IKKct activity.

[0023] According to a further aspect of the present invention, there is provided a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein for use in thetreatment of a disease or disorder in which IKKα activity is implicated.

[0024] 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 disorder.

[0025] According to a further aspect of the present invention, there is provided the use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein in the manufacture of a medicament for the treatment of cancer.

[0026] According to a further aspect of the present invention, there is provided a use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein in the manufacture of a medicament for the inhibition of IKKα activity.

[0027] According to a further aspect of the present invention, there is provided a use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein in the manufacture of a medicament for the treatment of a disease or disorder in which IKKα activity is implicated.

[0028] According to a further aspect of the present invention, there is provided a process for preparing a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein.

[0029] According to a further aspect of the present invention, there is provided a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, obtainable by, or obtained by, or directly obtained by a process of preparing a compound as defined herein.

[0030] 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.

[0031] Features, including optional, suitable, and preferred features in relation to one aspect of the invention may also be features, including optional, suitable and preferred features in relation to any other aspect of the invention.DETAILED DESCRIPTION OF THE INVENTIONDefinitions

[0032] Unless otherwise stated, the following terms used in the specification and claims have the following meanings set out below.

[0033] It is to be appreciated that references to “treating” or “treatment” include prophylaxis as well as the alleviation of established symptoms of a condition. “Treating” or “treatment” of astate, disorder or condition therefore Includes: (1 ) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a human that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition, (2) inhibiting the state, disorder or condition, i.e., arresting, reducing or delaying the development of the disease or a relapse thereof (in case of maintenance treatment) or at least one clinical or subclinical symptom thereof, or (3) relieving or attenuating the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.

[0034] A “therapeutically effective amount" means the amount of a compound that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated. It should be understood that in, for example, a human or other mammal, a therapeutically effective amount can be determined experimentally in a laboratory or clinical setting, or a therapeutically effective amount may be the amount required by the guidelines of the United States Food and Drug Administration (FDA) or equivalent foreign regulatory body, for the particular disease and subject being treated. It should be appreciated that determination of proper dosage forms, dosage amounts, and routes of administration is within the level of ordinary skill in the pharmaceutical and medical arts.

[0035] As used herein by themselves or in conjunction with another term or terms, “subject(s)” and “patient(s)”, refer to animals (e.g. mammals), particularly humans. Suitably, the “subject(s)” and “patient(s)” may be a non-human animal (e.g. livestock and domestic pets) or a human.

[0036] As used herein by itself or in conjunction with another term or terms, “pharmaceutically acceptable” refers to materials that are generally chemically and / or physically compatible with other ingredients (such as, for example, with reference to a formulation), and / or is generally physiologically compatible with the recipient (such as, for example, a subject) thereof.

[0037] In this specification the term “alkyl" includes both straight and branched chain alkyl groups. References to individual alkyl groups such as “propyl” are specific for the straight chain version only and references to individual branched chain alkyl groups such as “isopropyl” are specific for the branched chain version only. For example, “(1 -6C)alkyl” includes (1-4C)alkyl, (1- 3C)alkyl, propyl, isopropyl and t-butyl.

[0038] The term "(m-nC)" or "(m-nC) group" used alone or as a prefix, refers to any group having m to n carbon atoms.

[0039] An “alkylene” group is an alkyl group that is positioned between and serves to connect two other chemical groups. Thus, “(1-6C)alkylene” means a linear saturated divalenthydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms, for example, methylene (-CH2-), the ethylene isomers (- CH(CH3)- and -CH2CH2-), the propylene isomers (-CH(CH3)CH2-, -CH(CH2CH3)-, -C(CH3)2- , and -CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), and the like.

[0040] The term “alkyenyl” refers to straight and branched chain alkyl groups comprising 2 or more carbon atoms, wherein at least one carbon-carbon double bond is present within the group. Examples of alkenyl groups include ethenyl, propenyl and but-2, 3-enyl and includes all possible geometric (E / Z) isomers.

[0041] The term “alkynyl” refers to straight and branched chain alkyl groups comprising 2 or more carbon atoms, wherein at least one carbon-carbon triple bond is present within the group. Examples of alkynyl groups include acetylenyl and propynyl.

[0042] “(m-nC)cycloalkyl” means a saturated hydrocarbon ring system containing from m to n number of carbon atoms. Exemplary cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and blcyclo[2.2.1]heptyl.

[0043] The term “alkoxy” refers to O-linked straight and branched chain alkyl groups. Examples of alkoxy groups include methoxy, ethoxy and τ-butoxy.

[0044] The term “haloalkyl” is used herein to refer to an alkyl group in which one or more hydrogen atoms have been replaced by halogen (e.g. fluorine) atoms. Examples of haloalkyl groups include -CH2F, -CHF2and -CF3.

[0045] The term “halo” or “halogeno” refers to fluoro, chloro, bromo and iodo, suitably fluoro, chloro and bromo, more suitably, fluoro and chloro.

[0046] The term “carbocyclyl”, “carbocyclic” or “carbocycle" means a non-aromatic saturated or partially saturated monocyclic, fused, bridged, or spiro bicyclic carbon-containing ring system(s). Monocyclic carbocyclic rings contain from about 3 to 12 (suitably from 3 to 7) ring atoms. Bicyclic carbocycles contain from 6 to 17 member atoms, suitably 7 to 12 member atoms, in the ring. Bicyclic carbocyclic(s) rings may be fused, spiro, or bridged ring systems. Examples of carbocyclic groups include cyclopropyl, cyclobutyl, cyclohexyl, cyclohexenyl and spiro[3.3]heptanyl.

[0047] The term “heterocyclyl”, “heterocyclic” or “heterocycle” means a non-aromatic saturated or partially saturated monocyclic, fused, bridged, or spiro bicyclic heterocyclic ring system(s). Monocyclic heterocyclic rings contain from about 3 to 12 (suitably from 3 to 7) ring atoms, with from 1 to 5 (suitably 1 , 2 or 3) heteroatoms selected from nitrogen, oxygen or sulfur in the ring. Bicyclic heterocycles contain from 7 to 17 member atoms, suitably 7 to 12 member atoms, in the ring. Bicyclic heterocyclic(s) rings may be fused, spiro, or bridged ring systems. Examplesof heterocyclic groups include cyclic ethers such as oxiranyl, oxetanyl, tetrahydrofuranyl, dioxanyl, and substituted cyclic ethers. Heterocycles containing nitrogen include, for example, azetldinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrotrlazinyl, tetrahydropyrazolyl, and the like. Typical sulfur containing heterocycles include tetrahydrothienyl, dihydro-1 , 3-dithiol, tetrahydro-2H-thiopyran, and hexahydrothiepine. Other heterocycles Include dihydro-oxathiolyl, tetrahydro-oxazolyl, tetrahydro-oxadiazolyl, tetrahydrodioxazolyl, tetrahydro-oxathiazolyl, hexahydrotriazinyl, tetrahydro-oxazinyl, morpholinyl, thiomorpholinyl, tetrahydropyrimidinyl, dioxolinyl, octahydrobenzofuranyl, octahydrobenzimidazolyl, and octahydrobenzothiazolyl. For heterocycles containing sulfur, the oxidized sulfur heterocycles containing SO or SO2groups are also included. Examples include the sulfoxide and sulfone forms of tetrahydrothienyl and thiomorpholinyl such as tetrahydrothiene 1 ,1-dioxide and thiomorpholinyl 1 ,1-dioxide. Heterocycles may comprise 1 or 2 oxo (=O) or thioxo (=S) substituents. A suitable value for a heterocyclyl group which bears 1 or 2 oxo (=0) or thioxo (=S) substituents is, for example, 2-oxopyrrolidinyl, 2-thioxopyrrolidinyl, 2-oxoimidazolidinyl, 2-thioxoimidazolidinyl, 2-oxopiperidinyl, 2,5-dioxopyrrolidinyl, 2,5-dioxoimidazolidinyl or 2,6-dioxopiperidinyl. Particular heterocyclyl groups are saturated monocyclic 3 to 7 membered heterocyclyls containing 1 , 2 or 3 heteroatoms selected from nitrogen, oxygen or sulfur, for example azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, tetrahydrothienyl, tetrahydrothienyl 1,1-dioxide, thiomorpholinyl, thiomorpholinyl 1 ,1-dioxide, piperidinyl, homopiperidinyl, piperazinyl or homopiperazinyl. As the skilled person would appreciate, any heterocycle may be linked to another group via any suitable atom, such as via a carbon or nitrogen atom. However, reference herein to piperidino or morpholino refers to a piperidin-1-yl or morpholin-4-yl ring that is linked via the ring nitrogen.

[0048] By “bridged ring systems” is meant ring systems in which two rings share more than two atoms, see for example Advanced Organic Chemistry, by Jerry March, 4thEdition, Wiley Interscience, pages 131-133, 1992. Examples of bridged heterocyclyl ring systems include, aza-bicyclo[2.2.1]heptane, 2-oxa-5-azabicyclo[2.2.1]heptane, aza-bicyclo[2.2.2]octane, aza- bicyclo[3.2.1]octane and quinuclidine.

[0049] By “spiro bi-cyclic ring systems” we mean that the two ring systems share one common spiro carbon atom, i.e. the heterocyclic ring is linked to a further carbocyclic or heterocyclic ring through a single common spiro carbon atom. Examples of spiro ring systems include 6- azaspiro[3.4]octane, 2-oxa-6-azaspiro[3.4]octane, 2-azaspiro[3.3]heptanes, 2-oxa-6- azaspiro[3.3]heptanes, 7-oxa-2-azaspiro[3.5]nonane, 6-oxa-2-azaspiro[3.4]octane, 2-oxa-7- azaspiro[3.5]nonane and 2-oxa-6-azaspiro[3.5]nonane.

[0050] As used herein by itself or in conjunction with another term or terms, “aromatic” refers to monocyclic and polycyclic ring systems containing 4n+2 pi electrons, where n is an integer.Aromatic should be understood as referring to and including ring systems that contain only carbon atoms (i.e. “aryl”) as well as ring systems that contain at least one heteroatom selected from N, O or S (i.e. “heteroaromatic” or “heteroaryl"). An aromatic ring system can be substituted or unsubstituted.

[0051] As used herein by itself or in conjunction with another term or terms, “non-aromatic” refers to a monocyclic or polycyclic ring system having at least one double bond that is not part of an extended conjugated pi system. As used herein, non-aromatic refers to and includes ring systems that contain only carbon atoms as well as ring systems that contain at least one heteroatom selected from N, O or S. A non-aromatic ring system can be substituted or unsubstituted.

[0052] The term “heteroaryl” or “heteroaromatic” means an aromatic mono-, bi-, or polycyclic ring incorporating one or more (for example 1-4, particularly 1 , 2 or 3) heteroatoms selected from nitrogen, oxygen or sulfur. The term heteroaryl includes both monovalent species and divalent species. Examples of heteroaryl groups are monocyclic and bicyclic groups containing from five to twelve ring members, and more usually from five to ten ring members. The heteroaryl group can be, for example, a 5- or 6-membered monocyclic ring or a 9- or 10- membered bicyclic ring, for example a bicyclic structure formed from fused five and six membered rings or two fused six membered rings. Each ring may contain up to about four heteroatoms typically selected from nitrogen, sulfur and oxygen. Typically the heteroaryl ring will contain up to 3 heteroatoms, more usually up to 2, for example a single heteroatom. In one embodiment, the heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atoms in the heteroaryl rings can be basic, as in the case of an imidazole or pyridine, or essentially non- basic as in the case of an indole or pyrrole nitrogen. In general the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents of the ring, will be less than five.

[0053] Examples of heteroaryl include furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazenyl, benzofuranyl, indolyl, isoindolyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzothiazolyl, indazolyl, purinyl, benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, cinnolinyl, pteridinyl, naphthyridinyl, carbazolyl, phenazinyl, benzisoquinolinyl, pyridopyrazinyl, thieno[2,3-b]furanyl, 2H-furo[3,2-b]-pyranyl, 5H-pyrido[2,3-b]-o-oxazinyl, 1 H-pyrazolo[4,3-d]-oxazolyl, 4H-imidazo[4,5-d]thiazolyl, pyrazino[2,3-b]pyridazinyl, imidazo[2, 1 -b]thiazolyl, imidazo[1 , 2-b] [1 ,2,4]triazinyl. “Heteroaryl” also covers partially aromatic bi- or polycyclic ring systems wherein at least one ring is an aromatic ring and one or more of the other ring(s) is a non-aromatic, saturated or partially saturated ring, provided at least one ring contains one or more heteroatoms selected fromnitrogen, oxygen or sulfur. Examples of partially aromatic heteroaryl groups include for example, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 2-oxo-1 ,2,3,4-tetrahydroquinolinyl, dihydrobenzthienyl, dihydrobenzfuranyl, 2,3-dihydro-benzo[1,4]dioxinyl, benzo[1 ,3]dioxolyl, 2,2- dioxo-1 ,3-dihydro-2-benzothienyl, 4,5,6,7-tetrahydrobenzofuranyl, indolinyl,1.2.3.4-tetrahydro-1 ,8-naphthyridinyl, 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazinyl and3.4-dihydro-2H-pyrido[3,2-b][1 ,4]oxazinyl.

[0054] Examples of five membered heteroaryl groups include but are not limited to pyrrolyl, furanyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl and tetrazolyl groups.

[0055] Examples of six membered heteroaryl groups include but are not limited to pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl and triazinyl.

[0056] A bicyclic heteroaryl group may be, for example, a group selected from: a benzene ring fused to a 5- or 6-membered ring containing 1 , 2 or 3 ring heteroatoms; a pyridine ring fused to a 5- or 6-membered ring containing 1 , 2 or 3 ring heteroatoms; a pyrimidine ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; a pyrrole ring fused to a 5- or 6-membered ring containing 1 , 2 or 3 ring heteroatoms; a pyrazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; a pyrazine ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; an imidazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; an oxazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; an isoxazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; a thiazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; an isothiazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; a thiophene ring fused to a 5- or 6-membered ring containing 1 , 2 or 3 ring heteroatoms; a furan ring fused to a 5- or 6-membered ring containing 1 , 2 or 3 ring heteroatoms; a cyclohexyl ring fused to a 5- or 6-membered heteroaromatic ring containing 1, 2 or 3 ring heteroatoms; and a cyclopentyl ring fused to a 5- or 6-membered heteroaromatic ring containing 1 , 2 or 3 ring heteroatoms.

[0057] Particular examples of bicyclic heteroaryl groups containing a six membered ring fused to a five membered ring include but are not limited to benzfuranyl, benzthiophenyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, benzisothiazolyl, isobenzofuranyl,indolyl, isoindolyl, indolizinyl, indolinyl, isoindolinyl, purinyl (e.g., adeninyl, guaninyl), indazolyl, benzodioxolyl and pyrazolopyridinyl groups.

[0058] Particular examples of bicyclic heteroaryl groups containing two fused six membered rings include but are not limited to quinolinyl, isoquinolinyl, chromanyl, thiochromanyl, chromenyl, isochromenyl, chromanyl, isochromanyl, benzodioxanyl, quinolizinyl, benzoxazinyl, benzodiazinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl and pteridinyl groups.

[0059] The term “aryl” means a cyclic or polycyclic aromatic ring having from 5 to 12 carbon atoms. The term aryl includes both monovalent species and divalent species. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl and the like. In a particular embodiment, an aryl is phenyl.

[0060] This specification also makes use of several composite terms to describe groups comprising more than one functionality. Such terms will be understood by a person skilled in the art. For example (3-6C)cycloalkyl(m-nC)alkyl comprises (m-nC)alkyl substituted by (3- 6C)cycloalkyl.

[0061] The term "optionally substituted" refers to either groups, structures, or molecules that are substituted and those that are not substituted. The term “wherein a / any CH, CH2, CH3group or heteroatom (i.e. NH) within a R1group is optionally substituted” suitably means that (any) one of the hydrogen radicals of the R1group is substituted by a relevant stipulated group.

[0062] 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. In some embodiments, one or more refers to one, two or three. In another embodiment, one or more refers to one or two. In a particular embodiment, one or more refers to one.

[0063] The phrase “compound of the invention” means those compounds which are disclosed herein, both generically and specifically.

[0064] "About" when used herein in conjunction with a measurable value such as, for example, an amount or a period of time and the like, is meant to encompass reasonable variations of the value, for instance, to allow for experimental error in the measurement of said value.Compounds

[0065] In one aspect, the present invention relates to compounds, or pharmaceutically acceptable salts, hydrates or solvates thereof, having the structural Formula (I), shown below:wherein:RI is selected from hydrogen, halogen, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (3- 7C)cycloalkyl, aryl, heteroaryl and heterocyclyl, wherein said (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (3-7C)cycloalkyl, aryl, heteroaryl and heterocyclyl are optionally substituted by one or more R10s0ubstituents; wherein each R100is independently selected from halo, (1-2C)haloalkyl (e.g. trifluoromethyl), (1-2C)haloalkoxy e.g, (trifluoromethoxy), cyano, hydroxyl, (1-4C)alkyl, (1- 4C)hydroxyalkyl, (CH2)xORf, (CH2)xC(O)Rf, (CH2)xC(O)ORf, (CH2)xOC(O)Rf, (CH2)xC(O)N(Rj)Rh, (CH2)xN(R3)C(O)Rf, (CH2)xS(O)yiRf, (CH2)xSO2N(Rj)Rh, (CH2)xN(Rg)SO2Rf, (CH2)xNRjRh, (CH2)x(3-7C)cycloalkyl, (CH2)xheterocyclyl, (CH2)xheteroaryl, (CH2)xaryl; and wherein:(i) Rr and Rgare each independently selected from hydrogen, (1-6C)alkyl or phenyl; and wherein Rhand R, are each independently selected from hydrogen, (1- 6C)alkyl or phenyl or Rhand Rjtogether with the nitrogen atom to which they are attached form a 3-7 membered ring which may optionally include further heteroatoms and is optionally further substituted by one or more substituents selected from halo, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, carboxyl, carbamoyl, sulphamoyl, and (1-2C)alkyl; and any (1-4C)alkyl, (3-7C)cycloalkyl, heterocyclyl, heteroaryl or aryl in a R100substituent group is optionally further substituted by one or more substituents selected from halo, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, (1- 2C)alkyl, (1-2C)haloalkyl, (1-2C)hydroxyalkyl, ORk, C(O)Rk, C(O)ORk, OC(O)Rk, C(O)N(Ri)Rk, N(Rl)C(O)Rk, S(O)y2Rk, SO2N(Rl)Rk, N(Rl)SOzRk, or NRiRk, wherein Rkand Riare selected from hydrogen or (1-2C)alkyl;R2is hydrogen;R3is selected from hydrogen, (1 -8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (3-7C)cycloalkyl, aryl, heteroaryl, heterocyclyl, (CH2)0-3(3-7C)cycloalkyl, (CH2)0-3heterocyclyl, (CH2)0-3heteroaryl, (CH2)0.3aryl, -C(O)-(CH2)0-3(3-7C)cycloalkyl, -C(O)-(CH2)0.3heterocyclyl, -C(0)-(CH2)o- sheteroaryl, -C(0)-(CH2)0-3aryl or -C(O)O(1-8C)alkyl, -C(O)NR3a-(1-8C)alkyl, -C(O)NR3a-(CH2)0-3(3-7C)cycloalkyl, -C(0)NR3a-(CH2)0-3heterocyclyl, -C(O)NR3a-(CH2)0.3heteroaryl, -C(O)NR3a- (CH2)0-3aryl; wherein R3ais hydrogen or (1 -2C)alkyl; wherein any (1-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (3-7C)cycloalkyl, aryl, heteroaryl and heterocyclyl moiety is optionally substituted by one or more R200substituents; wherein R200is selected from halo, (1-2C)haloalkyl (e.g. trifluoromethyl), (1- 2C)haloalkoxy (e.g. trifluoromethoxy), cyano, hydroxyl, nitro, (1-4C)alkyl, (1-4C)hydroxyalkyl, (CH2)zORm, (CH2)zC(O)Rm, (CH2)zC(O)ORm, (CH2)zOC(O)Rm, (CH2)zC(O)N(Ro)Rp, (CH2)zN(Rn)C(O)Rm, (CH2)zN(Rn)C(O)ORm, (CH2)zS(O)y3Rm, (CH2)ZSO2N(RO)RP, (CH2)zN(Rn)SO2Rm, (CH2)zNR0Rp, (CH2)z(3-7C)cycloalkyl, (CH2)zheterocyclyl, (CH2)zheteroaryl, (CH2)zaryl; and wherein:(i) Rmand Rnare each independently selected from hydrogen, (1-6C)alkyl or (CH2)03phenyl; Roand Rpare each independently selected from hydrogen, (1-6C)alkyl or phenyl or Roand Rptogether with the nitrogen atom to which they are attached form a 3-7 membered ring which may optionally include further heteroatoms, and wherein any 3-7 membered ring formed Roand Rp, and any alkyl or phenyl group present for Rm, Rn, Roand Rpis optionally further substituted by one or more substituents selected from halo, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, carboxyl, carbamoyl, sulphamoyl, and (1- 2C)alkyl; and(ii) any (3-7C)cycloalkyl, heterocyclyl, heteroaryl or aryl moiety in a R200substituent group is optionally further substituted by one or more substituents selected from halo, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, (1-2C)alkyl, (1- 2C)haloalkyl, (1-2C)hydroxyalkyl, ORq, C(O)Rq, C(O)ORq, OC(O)Rq, C(O)N(Rq)Rr, N(Rr)C(O)Rq, S(O)y4Rq, SO2N(Rr)Rq, N(Rr)SO2Rq, or NRrRq, wherein Rqis hydrogen, (1-2C)alkyl or phenyl, and Rrare selected from hydrogen or (1-2C)alkyl; or R2and R3are linked such that together they form a -X2=CQ- group;X2is selected from N and CRa; wherein Rais selected from hydrogen, fluoro, chloro, methyl, cyano, difluoromethyl, and trifluoromethyl; andQ is hydrogen, halo, cyano or a group of the formula:-L1- Y1-L2-Q1wherein: L1is absent or (1-4C)alkylene; Y1is absent or O, S, SO, SO2, N(Ry1), C(O), C(O)O, OC(O), C(O)N(Ry1), or N(Ry1)C(O), wherein Ryi is selected from hydrogen or (1 -6C)alkyl; L1is absent or (1-3C)alkylene; and Q1is hydrogen, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, aryl, (3-8C)cycloalkyl, heteroaryl or heterocyclyl; wherein Q is optionally further substituted by one or more substituent groups independently selected from oxo, (1-6C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)haloalkoxy, (1-4C)aminoalkyl, (1-4C)hydroxyalkyl, cyano, or by one or more group(s) of the formula:-L3-Y2-L4-WI wherein: L3is absent or (1-4C)alkylene;Y2is absent or selected from or O, S, SO, SO2, N(Ry2), C(O), C(O)O, OC(O), C(O)N(Ry2), N(Ry2)C(O) or S(O)2N(Ry2), N(Ry2)SO2wherein Ry2is selected from hydrogen or (1-4C)alkyl; L4is absent or (1-3C)alkylene; andW1is hydrogen, (1-6C)alkyl, aryl, (3-8C)cycloalkyl, heteroaryl or heterocyclyl; wherein W1is optionally substituted by one or more substituents selected from oxo, (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1- 4C)alkoxy, amino, (1-4C)alkylamino, di[(1-4C)alkyl]amino C(O)OH, C(O)O(1-4C)alkyl, (CH2)0-3-heterocyclyl or cyano;R4is selected from hydrogen or halo;X1is N or CR5, wherein R5is selected from hydrogen, halo, cyano, or amino; x is independently selected from 0, 1 , 2 or 3; y1 , y2, y3 and y4 are each independently selected from 0, 1 or 2; z is independently selected from 0, 1 , 2 or 3;with the proviso that:X1and X2are only N when Q is hydrogen; when X1and X2are CR5or CRa, Q is not hydrogen; Q1is not hydrogen when L4, Y1, and L2are all absent; and at least one of R1, Q, R3, R4or R5is a substituent other than hydrogen.

[0066] Particular compounds of the invention include, for example, compounds of the Formula (I), or pharmaceutically acceptable salts, hydrates and / or solvates thereof, defined herein having one of the structural formulae (la), (lb) or (Ic) shown below:wherein R1, R3, R4, Rs, Q, X1and X2are each as defined herein.

[0067] Particular compounds of the invention include, for example, compounds of the Formula (I) [including sub-formulae (la), (lb) or (Ic), or pharmaceutically acceptable salts, hydrates and / or solvates thereof, wherein, unless otherwise stated, each of R1, R2, R3, R4, X1and any associated substituent groups has any of the meanings defined hereinbefore or in any of paragraphs (1 ) to (49) hereinafter:(1 ) R1is selected from hydrogen, halogen, (2-6C)alkynyl, (3-7C)cycloalkyl, phenyl, a 5 or 6- membered heteroaryl or a 4 to 7-membered heterocyclyl, wherein said (2-6C)alkynyl, (3-7C)cycloalkyl, phenyl, heteroaryl and heterocyclyl are optionally substituted by one or more R100substituents; and wherein each R100is independently selected from halo, (1-2C)haloalkyl (e.g. trifluoromethyl) (1-2C)haloalkoxy e.g. trifluoromethoxy, cyano, hydroxyl, (1-4C)alkyl, (1- 4C)hydroxyalkyl, (CH2)zORf, (CH2)zC(O)Rf, (CH2)zC(O)ORf, (CH2)zOC(O)Rf, (CH2)zC(O)N(Rj)Rh, (CH2)zN(Ra)C(O)Rf, (CH2)zS(O)yiRf, (CH2)zSO2N(Rj)Rh, (CH2)zN(Rg)SO2Rf, (CH2)zNRjRh, (CH2)z(3-7C)cycloalkyl, (CHz)zheterocyclyl, (CH2)zheteroaryl (CH2)zaryl;and wherein:(i) Rfand Rgare each independently selected from hydrogen or (1-2C)alkyl; and wherein Rhand Rjare each independently selected from hydrogen or (1- 2C)alkyl or Rhand Rjtogether with the nitrogen atom to which they are attached form a 3-7 membered ring which may optionally include further heteroatoms; and any (1-4C)alkyl, (3-7C)cycloalkyl, heterocyclyl, heteroaryl or aryl moiety in a R100substituent group is optionally further substituted by one or more substituents selected from halo, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, (1-2C)alkyl, (1- 2C)haloalkyl, (1-2C)hydroxyalkyl, ORk, C(O)Rk, C(O)ORk, OC(O)Rk, C(O)N(R,)Rk, N(Ri)C(O)Rk, S(O)y2Rk, SO2N(Ri)Rk, N(Ri)SO2Rk, or NRiRk, wherein Rkand Riare selected from hydrogen or (1-2C)alkyl.(2) R1is selected from hydrogen, halogen, (2-6C)alkynyl, phenyl or a 5 or 6-membered heteroaryl, wherein said (2-6C)alkynyl, phenyl or heteroaryl are optionally substituted by one or more R100substituents; and wherein each R100is independently selected from halo, (1-2C)haloalkyl (e.g. trifluoromethyl), (1-2C)haloalkoxy e.g. (trifluoromethoxy), cyano, hydroxyl, (1-4C)alkyl, (1-4C)hydroxyalkyl, (CH2)xORf, (CH2)xC(O)Rf, (CH2)xC(O)ORf, (CH2)xOC(O)Rf, (CH2)xC(O)N(Rj)Rh, (CH2)xN(Rg)C(O)Rf, (CH2)xS(O)yiRf, (CH2)xSO2N(RJ)Rh, (CH2)xN(Rg)SO2Rf, (CH2)xNRjRh, (CH2)x(3-7C)cycloalkyl, (CH2)x-[4-6 membered heterocyclyl], (CH2)x-[5 or 6 membered heteroaryl] or (CH2)xphenyl; and wherein:(■) Rfand Rgare each independently selected from hydrogen or (1-2C)alkyl; and wherein Rhand Rjare each Independently selected from hydrogen or (1- 2C)alkyl or Rhand Rjtogether with the nitrogen atom to which they are attached form a 3-7 membered ring which may optionally include further heteroatoms; and any (1-4C)alkyl, (3-7C)cycloalkyl, heterocyclyl, heteroaryl or aryl moiety in a R100substituent group is optionally further substituted by one or more substituents selected from halo, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, (1-2C)alkyl, (1- 2C)haloalkyl, (1-2C)hydroxyalkyl ORk, C(O)Rk, C(O)ORk, OC(O)Rk, C(O)N(Ri)Rk, N(Ri)C(O)Rk, S(O)y2Rk, SO2N(Ri)Rk, N(Ri)SO2Rk, or NRiRk, wherein Rkand Ri are selected from hydrogen or (1-2C)alkyl.(3) R1is selected from hydrogen, halogen, (2-6C)alkynyl, phenyl or a 5 or 6-membered heteroaryl, wherein said (2-6C)alkynyl, phenyl or heteroaryl are optionally substituted by one or more R10s0ubstituents; and wherein each R100is independently selected from halo, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, (1-4C)alkyl, (1-4C)hydroxyalkyl, (CH2)xORf, (CH2)xC(O)Rf, (CH2)xC(O)ORf, (CH2)xOC(O)Rf, (CH2)xC(O)N(Rj)Rh, (CH2)xN(Rg)C(O)Rf, (CH2)xS(O)y1Rf, (CH2)xSO2N(Rj)Rh, (CH2)xN(Rg)SO2Rf, (CH2)xNRjRh, (CH2)X(3- 7C)cycloalkyl, (CH2)x-[4-6 membered heterocyclyl], (CH2)x-[5 or 6 membered heteroaryl] or (CH2)xphenyl; and wherein:(i) Rfand Rgare each independently selected from hydrogen or (1-2C)alkyl; and wherein Rhand Rjare each independently selected from hydrogen or (1- 2C)alkyl; and any (1-4C)alkyl, (3-7C)cycloalkyl, heterocyclyl, heteroaryl or aryl moiety in a R100substituent group is optionally further substituted by one or more substituents selected from halo, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, (1-2C)alkyl, (1- 2C)haloalkyl, (1-2C)hydroxyalkyl or ORk, wherein Rkis selected from hydrogen or (1- 2C)alkyl.(4) R1is selected from hydrogen, halogen, (2-6C)alkynyl, phenyl or a 5 or 6-membered heteroaryl, wherein said (2-6C)alkynyl, phenyl or heteroaryl are optionally substituted by one or more R10s0ubstituents; and wherein each R100is independently selected from halo, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, (1-4C)alkyl, (1-4C)hydroxyalkyl, (CH2)xORf, C(O)Rt, C(O)ORf, OC(O)Rf, C(O)N(Rj)Rh, N(Rg)C(O)Rf, S(O)y1Rf, SO2N(Rj)Rh, N(Rg)SO2Rf, NRjRh, (CH2)x-[4-6 membered heterocyclyl], or (CH2)xphenyl; and wherein:(i) Rfand Rgare each independently selected from hydrogen or (1-2C)alkyl; and wherein Rhand Rjare each independently selected from hydrogen or (1- 2C)alkyl; and any (1-4C)alkyl, (3-7C)cycloalkyl, heterocyclyl, heteroaryl or aryl moiety in a R100sub stituent group is optionally further substituted by one or more substituents selected from halo,trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, (1-2C)alkyl, (1-2C)haloalkyl, (1- 2C)hydroxyalkyl or ORk, wherein Rkis selected from hydrogen or (1-2C)alkyl.(5) R1is selected from:(i) hydrogen or halogen;(ii) ethynyl, i.e.which is optionally substituted by R100,(ii) phenyl, which is optionally substituted by R100a 5 or 6-membered heteroaryl, which is optionally substituted by R100; and wherein each R100is independently selected from halo, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, (1-4C)alkyl, (1-4C)hydroxyalkyl, (CH2)xORf, C(O)Rf, C(O)ORf, OC(O)Rf, C(O)N(Rj)Rh, N(Rg)C(O)Rf, S(O)yiRf, SO2N(Rj)Rh, N(Rg)SO2Rf, NRjRh, (CH2)x-[4-6 membered heterocyclyl], or (CH2)xphenyl; and wherein:(i) Rfand Rgare each independently selected from hydrogen or (1-2C)alkyl; and wherein Rhand Rjare each independently selected from hydrogen or (1- 2C)alkyl; and(ii) any (1-4C)alkyl, (3-7C)cycloalkyl, heterocyclyl, heteroaryl or aryl moiety in a R100substituent group is optionally further substituted by one or more substituents selected from halo, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, (1- 2C)alkyl, (1-2C)haloalkyl, (1-2C)hydroxyalkyl or ORk, wherein RkIs selected from hydrogen or (1-2C)alkyl.(6) R1is selected from:(i) hydrogen or halogen;(ii) ethynyl, i.e.which is optionally substituted by R10 0(iii) phenyl, which Is optionally substituted by R100and wherein each R100is Independently selected from halo, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, (1-4C)alkyl, (1-4C)hydroxyalkyl, (CH2)xORf, C(O)Rf, C(O)ORf, OC(O)Rf, C(O)N(Rj)Rh, N(Rg)C(O)Rf, S(O)yiRf, SO2N(Rj)Rh, N(Rg)SO2Rf, NRjRh, (CH2)x-[4-6 membered heterocyclyl], or (CH2)xphenyl; and wherein:(i) Rfand Rgare each independently selected from hydrogen or (1-2C)alkyl; and wherein Rhand Rjare each independently selected from hydrogen or (1- 2C)alkyl; and any (1-4C)alkyl, (3-7C)cycloalkyl, heterocyclyl, heteroaryl or aryl moiety in a R10s0ubstituent group is optionally further substituted by one or more substituents selected from halo, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, (1-2C)alkyl, (1-2C)haloalkyl, (1- 2C)hydroxyalkyl or ORk, wherein Rkis selected from hydrogen or (1-2C)alkyl.(7) R1is selected from:(i) hydrogen or halogen;(ii ethynyl, i.e. which is optionally substituted by R10!0phenyl, which is optionally substituted by R100; and wherein each R100is independently selected from halo, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, (1-4C)alkyl, (1-4C)hydroxyalkyl, (CH2)xORf, C(O)Rf, C(O)N(Rj)Rh, S(O)yiRf, SO2N(Rj)Rh, N(Rg)SO2Rf, NRjRh, (CH2)x-[4-6 membered heterocyclyl], or (CH2)xphenyl; and wherein:(ii) Rfand Rgare each independently selected from hydrogen or (1-2C)alkyl; and wherein Rhand Rjare each independently selected from hydrogen or (1- 2C)alkyl.(8) R1is selected from:(i) hydrogen or halogen;(ii) ethynyl, i.e.which is optionally substituted by R100phenyl, which is optionally substituted by R100and wherein each R100is independently selected from halo, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl or (1-4C)alkyl.(9) R3is selected from hydrogen, (1-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (3- 7C)cycloalkyl, phenyl, a 5 or 6-membered heteroaryl, a 4 to 7-membered heterocyclyl, (CH2)0-3(3-7C)cycloalkyl, (CH2)0-3[4 to 7-membered heterocyclyl], (CH2)0-3[5 or 6- membered heteroaryl], (CH2)0-3phenyl, -C(0)-(CH2)0-3(3-7C)cycloalkyl, -C(0)-(CH2)0-3[4 to 7-membered heterocyclyl], -C(O)-(CH2)0-3[5 or 6-membered heteroaryl], -C(O)- (CH2)0-3phenyl, -C(O)O(1-8C)alkyl, -C(O)NR3a-(1-8C)alkyl, -C(O)NR3a-(CH2)0-3(3- 7C)cycloalkyl, -C(0)NR3a-(CH2)0-3[5 to 7-membered heterocyclyl], -C(0)NR3a-(CH2)0-3[5 or 6-membered heteroaryl], or -C(0)NR3a-(CH2)0-3phenyl; wherein R3ais hydrogen or (1-2C)alkyl; wherein any (1 -8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (3-7C)cycloalkyl, phenyl, 5 or 6- membered heteroaryl or 4 to 7-membered heterocyclyl moiety is optionally substituted by one or more R200substituents; wherein R200is selected from halo, (1-2C)haloalkyl (e.g. trifluoromethyl), (1- 2C)haloalkoxy (e.g, trifluoromethoxy), cyano, hydroxyl, nitro, (1-4C)alkyl, (1- 4C)hydroxyalkyl, (CH2)zORm, (CH2)zC(O)Rm, (CH2)zC(O)ORm, (CH2)zC(O)N(Ro)RP, (CH2)zN(Rn)C(O)Rm, (CH2)zN(Rn)C(O)ORm, (CH2)zS(O)y3Rm, (CH2)ZSO2N(RO)RP, (CH2)zN(Rn)SO2Rm, (CH2)zNRoRp, (CH2)z(3-7C)cycloalkyl, (CH2)Z[4 to 7-membered heterocyclyl], (CH2)Z[5 or 6-membered heteroaryl, (CH2)zphenyl; and wherein:(i) Rmand Rnare each independently selected from hydrogen, (1-6C)alkyl or (CH2)o- 3phenyl; Roand Rpare each independently selected from hydrogen, (1-6C)alkyl or phenyl or Roand Rptogether with the nitrogen atom to which they are attached form a 3-7 membered ring which may optionally include furtherheteroatoms, and wherein any 3-7 membered ring formed Roand Rp, and any alkyl or phenyl group present for Rm, Rn, Roand Rpis optionally further substituted by one or more substituents selected from halo, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, carboxyl, carbamoyl, sulphamoyl, and (1- 2C)alkyl; and any (3-7C)cycloalkyl, heterocyclyl, heteroaryl or phenyl moiety in a R200substituent group is optionally further substituted by one or more substituents selected from halo, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, (1-2C)alkyl, (1-2C)haloalkyl, (1- 2C)hydroxyalkyl, ORq, C(O)Rq, C(O)ORq, OC(O)Rq, C(O)N(Rq)Rr, N(Rr)C(O)Rq, S(O)y4Rq, SO2N(Rr)Rq, N(Rr)SO2Rq, or NRrRq, wherein Rqis hydrogen, (1-2C)alkyl or phenyl, and Rrare selected from hydrogen or (1-2C)alkyl.(10) R3is selected from hydrogen, (1-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (3- 7C)cycloalkyl, phenyl, a 5 or 6-membered heteroaryl, a 4 to 7-membered heterocyclyl, (CH2)0-3(3-7C)cycloalkyl, (CH2)0-3[4 to 7-membered heterocyclyl], (CH2)0-3[5 or 6- membered heteroaryl], (CH2)0-3phenyl, -C(0)-(CH2)0-3(3-7C)cycloalkyl, -C(0)-(CH2)0-3[4 to 7-membered heterocyclyl], -C(0)-(CH2)0-3[5 or 6-membered heteroaryl], -C(O)- (CH2)0-3phenyl, -C(O)O(1-8C)alkyl, -C(O)NR3a-(1-8C)alkyl, -C(O)NR3a- CH2)0-3(3- 7C)cycloalkyl, -C(0)NR3a-(CH2)o~3[5 to 7-membered heterocyclyl], -C(0)NR3a-(CH2)0-3[5 or 6-membered heteroaryl], or -C(0)NH-(CH2)o3phenyl; wherein R3ais hydrogen or (1 -2C)alkyl; wherein any (1-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (3-7C)cycloalkyl, phenyl, 5 or 6- membered heteroaryl or 4 to 7-membered heterocyclyl moiety is optionally substituted by one or more R200substituents; wherein R200is selected from halo, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, nitro, (1-4C)alkyl, (1-4C)hydroxyalkyl, (CH2)zORm, (CH2)zC(O)Rm, (CH2)zC(O)ORm,(CH2)ZC(O)N(RO)RP, (CH2)zN(Rn)C(O)Rm, (CH2)zN(Rn)C(O)ORm, (CH2)zS(O)y3Rm, (CH2)zSO2N(Ro)RP, (CH2)zN(Rn)SO2Rm, (CH2)ZNRORP, (CH2)z(3-7C)cycloalkyl, (CH2)Z[4 to 7- membered heterocyclyl], (CH2)Z[5 or 6-membered heteroaryl, (CH2)zphenyl; and wherein:(i) Rmand Rnare each independently selected from hydrogen, (1-6C)alkyl or (CH2)0sphenyl; Roand Rpare each independently selected from hydrogen, (1-6C)alkyl or phenyl or Roand Rptogether with the nitrogen atom to which they are attached form a 3-7 membered ring which may optionally include further heteroatoms, and wherein any 3-7 membered ring formed Roand Rp, and any alkyl or phenyl group present for Rm, Rn, Roand Rpis optionally furthersubstituted by one or more substituents selected from halo, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, carboxyl, carbamoyl, sulphamoyl, and (1- 2C)alkyl.(11 ) R3is selected from hydrogen, (1-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (3- 7C)cycloalkyl, phenyl, a 5 or 6-membered heteroaryl, a 4 to 7-membered heterocyclyl, (CH2)0 3(3-7C)cycloalkyl, (CH2)0-3[4 to 7-membered heterocyclyl], (CH2)0-3[5 or 6- membered heteroaryl], (CH2)0-3phenyl, -C(0)-(CH2)o3(3-7C)cycloalkyl, -C(0)-(CH2)0-3[4 to 7-membered heterocyclyl], -C(0)-(CH2)0-3[5 or 6-membered heteroaryl], -C(0)-(CH2)o sphenyl, -C(O)O(1-8C)alkyl, -C(O)NR3a-(1-8C)alkyl, -C(0)NR3a-(CH2)0-3(3-7C)cycloalkyl, -C(0)NR3a-(CH2)o3[5 to 7-membered heterocyclyl], -C(0)NR3a-(CH2)o^[5 or 6-membered heteroaryl], or -C(0)NR3a-(CH2)0-3phenyl; wherein R3ais hydrogen or (1-2C)alkyl; wherein any (1 -8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (3-7C)cycloalkyl, phenyl, 5 or 6- membered heteroaryl or 4 to 7-membered heterocyclyl moiety is optionally substituted by one or more R200substituents; wherein R200is selected from halo, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, nitro, (1-4C)alkyl, (1-4C)hydroxyalkyl, (CH2)zORm, ((CCHH22))zzCC((OO))RRmm,, (CH2)zC(O)ORm, (CH2)zC(O)N(Ro)Rp, (CH2)zN(Rn)C(O)Rm, ((CCHH22))zzNN((RRnn))CC((OO))OORRmm,, (CH2)zS(O)y3Rm, (CH2)zSO2N(Ro)Rp, (CH2)zN(Rn)SO2Rm, or (CH2)ZNRORP; and wherein:Rmand Rnare each independently selected from hydrogen, (1-6C)alkyl or phenyl; Roand Rpare each independently selected from hydrogen, (1-6C)alkyl or (CH2)o-2phenyl or Ro and Rptogether with the nitrogen atom to which they are attached form a 3-7 membered ring which may optionally include further heteroatoms, and wherein any 3-7 membered ring formed Roand Rp, and any alkyl or phenyl group present for Rm, Rn, Ro and Rpis optionally further substituted by one or more substituents selected from halo, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, carboxyl, carbamoyl, sulphamoyl, and (1-2C)alkyl.(12) R3is selected from hydrogen, (1-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (3- 7C)cycloalkyl, phenyl, a 5 or 6-membered heteroaryl, a 4 to 7-membered heterocyclyl, (CH2)0-3(3-7C)cycloalkyl, (CH2)0.3[4 to 7-membered heterocyclyl], (CH2)0-3[5 or 6- membered heteroaryl], (CH2)0-3phenyl, -C(0)-(CH2)0-3(3-7C)cycloalkyl, -C(O)-(CH2)0.3[5 or 6-membered heteroaryl], -C(O)-(CH2)0.3phenyl, -C(O)O(1-8C)alkyl, -C(O)NR3a-(1-8C)alkyl, -C(O)NR3a-(CH2)0-3(3-7C)cycloalkyl, -C(O)NR3a-(CH2)0.3[5 or 6-membered heteroaryl], or -C(0)NR3a-(CH2)0-3phenyl; wherein R3ais hydrogen or (1-2C)alkyl; wherein any (1 -8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (3-7C)cycloalkyl, phenyl, 5 or 6- membered heteroaryl or 4 to 7-membered heterocyclyl moiety is optionally substituted by one or more R200substituents; wherein R200is selected from halo, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, nitro, (1-4C)alkyl, (1-4C)hydroxyalkyl, (CH2)zORm, (CH2)zC(O)Rmm,, (CH2)zC(O)ORm, (CH2)zC(O)N(Ro)Rp, (CH2)zN(Rn)C(O)Rm, ((CCHH22))zzNN((RRnn))CC((OO))OORRmm,, (CH2)zS(O)y3Rm, (CH2)zSO2N(Ro)Rp, (CH2)zN(Rn)SO2Rm, or (CH2)ZNRORP; and wherein:Rmand Rnare each independently selected from hydrogen, (1-6C)alkyl or phenyl; Roand Rpare each independently selected from hydrogen, (1-6C)alkyl or (CH2)0.2phenyl or Roand Rptogether with the nitrogen atom to which they are attached form a 3-7 membered ring which may optionally include further heteroatoms, and wherein any 3-7 membered ring formed Roand Rp, and any alkyl or phenyl group present for Rm, Rn, Ro and Rpis optionally further substituted by one or more substituents selected from halo, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, carboxyl, carbamoyl, sulphamoyl, and (1-2C)alkyl.(13) R3is selected from hydrogen or a group of the formula:wherein any cycloalkyl, heterocyclyl, aryl or heteroaryl group above is optionally substituted by one or more R200substituents, wherein R200is as defined herein.(14) R2and R3are linked such that together they form a -X2=CQ- group;(15) X2is selected from N and CRa; wherein Rais selected from hydrogen, fluoro, chloro, methyl, or cyano.(16) X2is selected from N and CRa; wherein Rais selected from hydrogen, fluoro, chloro or methyl.(17) X2is selected from N and CRa; wherein Rais selected from hydrogen, fluoro or chloro.(18) Q is hydrogen, halo, cyano or a group of the formula:-L1-Y1-L2-Q1wherein:L1is absent or (1-4C)alkylene; Y1is absent or O, S, SO, SO2, N(Ry1), C(O), C(O)O, OC(O), C(O)N(Ry1), or N(Ry1)C(O), wherein Ryi is selected from hydrogen or (1-6C)alkyl;L2is absent or (1-3C)alkylene; and Q1is hydrogen, (1-6C)alkyl, phenyl, (3-8C)cycloalkyl, 5 or 6-membered heteroaryl or 4 to 7-membered heterocyclyl; wherein Q is optionally further substituted by one or more substituent groups independently selected from oxo, (1-6C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)haloalkoxy, (1-4C)aminoalkyl, (1-4C)hydroxyalkyl, cyano, or by one or more group(s) of the formula:-L3-Y2-L4-Q1wherein:L3is absent or (1-4C)alkylene;Y2is absent or selected from or O, S, SO, SO2, N(Ry2), C(O), C(O)O, OC(O), C(O)N(Ry2), N(Ry2)C(O) or S(O)2N(Ry2), N(Ry2)SO2wherein Ry2is selected from hydrogen or (1 -4C)alkyl;L4is absent or (1-3C)alkylene; andW1is hydrogen, (1-6C)alkyl, aryl, (3-8C)cycloalkyl, 5 or 6-membered heteroaryl or 4 to 7-membered heterocyclyl; wherein W1is optionally substituted by one or more substituents selected from oxo, (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1- 4C)alkoxy, amino, (1-4C)alkylamino, di[(1-4C)alkyl]amino C(O)OH, C(O)O(1-4C)alkyl, (CH2)0-3-[4 to 7-membered heterocyclyl] or cyano.(19) Q is hydrogen, halo, cyano or a group of the formula:-L1-Y1-L2-Q1wherein: L1is absent or (1-4C)alkylene; Y1is absent or O, S, SO, S02, N(Ry1), C(O), C(O)O, OC(O), C(O)N(Ry1), or N(Ry1)C(O), wherein Ry1is selected from hydrogen or (1-4C)alkyl; L1is absent or (1-3C)alkylene; and Q1is hydrogen, (1-6C)alkyl, phenyl, (3-8C)cycloalkyl, 5 or 6-membered heteroaryl or 4 to 7-membered heterocyclyl; wherein Q is optionally further substituted by one or more substituent groups independently selected from oxo, (1-6C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)haloalkoxy, (1-4C)aminoalkyl, (1-4C)hydroxyalkyl, cyano, or by one or more group(s) of the formula:-L3-Y2- L4-W1wherein:L3is absent or (1-3C)alkylene;Y2is absent or selected from or O, S, SO, SO2, N(Ry2), C(O), 0(0)0, 00(0), C(O)N(Ry2), N(Ry2)C(O), S(O)2N(Ry2) or N(Ry2)SO2wherein Ry2is selected from hydrogen or (1-2C)alkyl; L4is absent or (1-3C)alkylene; andW1is hydrogen, (1-6C)alkyl, aryl, (3-8C)cycloalkyl, 5 or 6-membered heteroaryl or 4 to 7-membered heterocyclyl; wherein W1is optionally substituted by one or more substituents selected from oxo, (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1- 4C)alkoxy, amino, (1-4C)alkylamino, dl[(1-4C)alkyl]amino C(O)OH, C(O)O(1-4C)alkyl, (CH2)0-3-[4 to 7-membered heterocyclyl] or cyano;(20) Q is a group of the formula:-L1Y1-L2-Q1wherein: L1is absent or (1-3C)alkylene; Y1is absent or O, S, N(Ry1), C(O), C(O)O, C(O)N(Ry1), or N(Ry1)C(O), wherein Ry1is selected from hydrogen or (1-4C)alkyl; L1is absent or methylene; and Q1is hydrogen, (1-6C)alkyl, phenyl, (3-8C)cycloalkyl, 5 or 6-membered heteroaryl or 4 to 7-membered heterocyclyl; wherein Q is optionally further substituted by one or more substituent groups independently selected from oxo, (1-6C)alkyl, halo, (1-2C)haloalkyl, (1- 2C)haloalkoxy, cyano, or by one or more group(s) of the formula:-L3-Y2-L4-W1wherein: L3is absent or (1-4C)alkylene;Y2is absent or selected from or O, SO2, N(Ry2), C(O), C(O)O, C(O)N(Ry2) or N(Ry2)SO2wherein Ry2is selected from hydrogen or (1 -2C)alkyl; L4is absent or (1-3C)alkylene; andW1is hydrogen, (1-6C)alkyl, aryl, (3-8C)cycloalkyl, 5 or 6-membered heteroaryl or 4 to 7-membered heterocyclyl; wherein W1is optionally substituted by one or more substituents selected from oxo, (1- 4C)alkyl, halo, (1-2C)haloalkyl, (1-2C)haloalkoxy, (1-4C)alkoxy, C(O)OH, C(O)O(1- 4C)alkyl, (CH2)0-3-[4 to 7-membered heterocyclyl] or cyano.(21 ) Q is a group selected from hydrogen, halo, cyano, (1-6C)alkyl, (1-6C)alkoxy, (1- 6C)haloalkyl, (1-6C)haloalkoxy, or a group of with a formula selected from:ooOwherein any cycloalkyl, heterocyclyl, aryl or heteroaryl ring above may be optionally substituted by one or more substituents selected from oxo, (1-6C)alkyl, halo, (1-2C)haloalkyl, (1- 2C)haloalkoxy, cyano, or by one or more group(s) of the formula:-L3- Y2- L4-W1wherein L3, Y2, L4and W1are as defined herein.(22) R4is hydrogen or fluoro.(23) R4is hydrogen.(24) R4is fluoro.(25) X1is N or CR5, wherein R5is selected from hydrogen, halo, or cyano,(26) x is independently selected from 0, 1 or 2;(27) x is 0;(28) x is 1;(29) x Is 2;(30) y1 is independently selected from 0, 1 or 2;(31 ) y1 is 0;(32) y1 is 1 ;(33) y1 is 2;(34) y2 is independently selected from 0, 1 or 2;(35) y2 is 0;(36) y2 is 1 ;(37) y2 is 2;(38) y3 is independently selected from 0, 1 or 2;(39) y3 is 0;(40) y3 is 1 ;(41 ) y3 is 2;(42) y4 is independently selected from 0, 1 or 2;(43) y4 is 0;(44) y4 is 1 ;(45) y4 is 2;(46) z is independently selected from 0, 1 or 2;(47) z is 0;(48) z is 1;(49) z is 2;

[0068] Suitably, R1is as defined in any one of numbered paragraphs (1) to (8) above. More suitably, R1is as defined in any one of numbered paragraphs (5) to (8) above. Most suitably, R1is as defined in numbered paragraph (7) or (8) above.

[0069] Suitably, either: a) R2hydrogen and R3is as defined in any one of numbered paragraphs (9) to (13) above, or b) R2and R3are linked such that together they form a -X2=CQ- group, X2is as defined in any one of paragraphs (15) to (17) above and Q is as defined in any one of numbered paragraphs (18) to (21) above.More suitably, either: a) R2hydrogen and R3is as defined in any one of numbered paragraphs (11 ) to (13) above, orb) R2and R3are linked such that together they form a -X2=CQ- group, X2is as defined paragraph (16) or (17) above and Q is as defined in numbered paragraph (19), (20) or (21) above.Most suitably, either: a) R2hydrogen and R3is as defined in numbered paragraph (13) above, or b) R2and R3are linked such that together they form a -X2=CQ- group, X2is as defined in numbered paragraph (17) above and Q is as defined in paragraph (20) or (21 ) above.

[0070] Suitably, R< is as defined in any one of numbered paragraphs (22) to (24) above. More suitably, R4is as defined in numbered paragraph (23) or (24) above.

[0071] Suitably, Q is as defined in any one of numbered paragraphs (18) to (21) above. More suitably, Q is as defined in numbered paragraph (19), (20) or (21 ) above. Most suitably, Q is as defined in numbered paragraph (20) or (21) above.

[0072] Suitably, X1is as defined in paragraph (24).

[0073] Suitably, X2is as defined in any one of numbered paragraphs (15) to (17) above. More suitably, X2is as defined in numbered paragraph (16) or (17) above. Most suitably, X2is as defined in numbered paragraph (17) above.

[0074] Suitably, x is as defined in any one of numbered paragraphs (26) to (29) above. More suitably, x is as defined in numbered paragraph (26) above.

[0075] Suitably, y1 is as defined in any one of numbered paragraphs (30) to (33) above. More suitably, y1 is as defined in numbered paragraph (30) above.

[0076] Suitably, y2 is as defined in any one of numbered paragraphs (34) to (37) above. More suitably, y2 is as defined in numbered paragraph (34) above.

[0077] Suitably, y3 is as defined in any one of numbered paragraphs (38) to (41 ) above. More suitably, y3 is as defined in numbered paragraph (38) above.

[0078] Suitably, y4 is as defined in any one of numbered paragraphs (42) to (45) above. More suitably, y4 is as defined in numbered paragraph (42) above.

[0079] Suitably, z is as defined in any one of numbered paragraphs (46) to (49) above. More suitably, z is as defined in numbered paragraph (46) above.

[0080] As indicated above, particular compounds of the invention include, for example, compounds of the Formula (I), or pharmaceutically acceptable salts, hydrates and / or solvates thereof, defined herein having one of the structural formulae (la), (lb) or (Ic) shown below:wherein R1, X1, X2, R3, R4, R5and Q are each as defined herein.

[0081] In a particular group of compounds of the invention, compounds have a structure according to formula la (which is a sub-definition of formula I), or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, wherein R1, X1, X2, R3, R4, R5and Q each have any one of the definitions set out herein.

[0082] In an embodiment of the compounds of formula la, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof: R1is as defined in any one of numbered paragraphs (1) to (8) above; R3is as defined in any one of numbered paragraphs (9) to (13) above; R4is as defined in any one of numbered paragraphs (22) to (24) above; and R5is as defined in numbered paragraph (25) above.

[0083] In an embodiment of the compounds of formula la, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof: R1is as defined in any one of numbered paragraphs (5) to (8) above; R3is as defined in any one of numbered paragraphs (11 ) to (13) above;R4is as defined numbered paragraph (23) or (24) above; and R5is as defined in numbered paragraph (25) above.

[0084] In an embodiment of the compounds of formula la, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof: R1is as defined in numbered paragraph (7) or (8) above;R3is as defined in paragraph (13) above;R4is as defined in numbered paragraph (23) or (24) above; and R5is as defined in numbered paragraph (25) above.

[0085] In a particular group of compounds of the invention, compounds have a structure according to formula lb (which is a sub-definition of formula I), or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, wherein R3, R4, and R5each have any one of the definitions set out herein.

[0086] In an embodiment of the compounds of formula lb, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof:R3is as defined in any one of numbered paragraphs (9) to (13) above;R4is as defined in any one of numbered paragraphs (22) to (24) above; and R5is as defined in numbered paragraph (25) above.

[0087] In an embodiment of the compounds of formula lb, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof: R3is as defined in any one of numbered paragraphs (11 ) to (13) above;R4is as defined numbered paragraph (23) or (24) above; and R5is as defined in numbered paragraph (25) above.

[0088] In an embodiment of the compounds of formula lb, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof: R3is as defined in paragraph (13) above;R4is as defined in numbered paragraph (23) or (24) above; and R5is as defined in numbered paragraph (25) above.

[0089] In a particular group of compounds of the invention, compounds have a structure according to formula Ic (which is a sub-definition of formula I), or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, wherein R1, R4, X1, X2and Q each have any one of the definitions set out herein.

[0090] In an embodiment of the compounds of formula Ic, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof: R1is as defined in any one of numbered paragraphs (1) to (8) above; R4is as defined in any one of numbered paragraphs (22) to (24) above;X1is as defined in numbered paragraph (25) above;X2is as defined in any one of numbered paragraphs (15) to (17) above; andQ is as defined in any one of numbered paragraphs (18) to (21) above.

[0091] In an embodiment of the compounds of formula Ic, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof: R1is as defined in any one of numbered paragraphs (5) to (8) above; R4is as defined numbered paragraph (23) or (24) above;X1Is as defined in numbered paragraph (25) above;X2is as defined in numbered paragraph (16) or (17) above; andQ is as defined in numbered paragraph (19), (20) or (21 ) above.

[0092] In an embodiment of the compounds of formula Ic, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof: R1is as defined in numbered paragraph (7) or (8) above;R4is as defined in numbered paragraph (23) or (24) above;X1is as defined in numbered paragraph (25) above;X2is as defined in numbered paragraph (17) above; andQ is as defined in numbered paragraph (20) or (21 ) above.

[0093] 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:5-(2-aminopyridin-4-yl)-7-chloro-1 H-indazol-3-amine5-(2-aminopyridin-4-yl)-7-methyl-1H-indazol-3-amine5-(2-aminopyridin-4-yl)-7-(trifluoromethyl)-1H-indazol-3-amine5-(2-(ethylamino)pyridin-4-yl)-1 H-indazol-3-amine5-(2-(propylamino)pyridin-4-yl)-1H-indazol-3-amine5-(2-(isopropylamino)pyridin-4-yl)-1H-indazol-3-amine5-(2-((cyclopropylmethyl)amino)pyridin-4-yl)-1 H-indazol-3-amine5-(2-(lsopentylamino)pyridln-4-yl)-1H-indazol-3-amine5-(2-(hexylamino)pyridin-4-yl)-1H-lndazol-3-amine5-(2-(cyclohexylamino)pyridin-4-yl)-1 H-lndazol-3-amine5-{2-[(Trans-4-methylcydohexyl)amino]pyridin-4-yl}-lH-indazol-3-amlne2-((4-(3-amino-1 H-indazol-5-yl)pyridin-2-yl)amino)ethan-1 -ol3-((4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)amino)propan-1-ol4-((4-(3-amino-1 H-indazol-5-yl)pyridin-2-yl)amino)butan-1 -ol5-((4-(3-amino-1 H-indazol-5-yl)pyridin-2-yl)amino)pentan-1 -ol5-{2-[(trans-4-hydroxycyclohexyl)amino]pyridin-4-yl}-lH-indazol-3-amine I5-(2-((2-methoxyethyl)amino)pyridin-4-yl)-1H-indazol-3-amine5-(2-((3-methoxypropyl)amino)pyridin-4-yl)-1H-indazol-3-amine5-(2-((3-isopropoxypropyl)amino)pyridin-4-yl)-1 H-indazol-3-amine3-((4-(3-amino-1H-indazol-5-yl)pyrimidin-2-yl)amino)propan-1-ol3-((4-(3-amino-lH-indazol-5-yl)pyridin-2-yl)(methyl)amino)propan-l-ol5-(2-((2-morpholinoethyl)amino)pyridin-4-yl)-1 H-indazol-3-amine5-(2-((2-(piperidin-1-yl)ethyl)amino)pyridin-4-yl)-1H-indazol-3-amineN1-(4-(3-amino-1 H-indazol-5-yl)pyridin-2-yl)-N3-methylpropane-1 ,3-diamine5-(2-(benzylamino)pyridin-4-yl)-1 H-indazol-3-amine3-(((4-(3-amino-1 H-indazol-5-yl)pyridin-2-yl)amino)methyl)benzonitrile5-(2-((3-methoxybenzyl)amino)pyridin-4-yl)-1 H-indazol-3-amine2-(3-(((4-(3-amino-1 H-indazol-5-yl)pyridin-2-yl)amino)methyl)phenyl)propan-2-ol5-(2-((4-(trifluoromethyl)benzyl)amino)pyridin-4-yl)-1H-indazol-3-amine4-(((4-(3-amino-1 H-indazol-5-yl)pyridin-2-yl)amino)methyl)benzonitrile5-(2-((4-(tert-butyl)benzyl)amino)pyridin-4-yl)-1 H-indazol-3-amine2-(4-(((4-(3-amino-1 H-indazol-5-yl)pyridin-2-yl)amino)methyl)phenyl)propan-2-ol5-(2-((4-(methylsulfonyl)benzyl)amino)pyridin-4-yl)-1H-indazol-3-amine5-(2-((furan-3-ylmethyl)amino)pyridin-4-yl)-1 H-indazol-3-amine5-(2-((pyridin-2-ylmethyl)amino)pyridin-4-yl)-1H-indazol-3-amine5-(2-(phenethylamino)pyridin-4-yl)-1 H-indazol-3-amine5-(2-((2-(pyridin-2-yl)ethyl)amino)pyridin-4-yl)-1H-indazol-3-amine5-(2-((2-(pyridin-3-yl)ethyl)amino)pyridin-4-yl)-1H-indazol-3-amine5-(2-((2-(pyridin-4-yl)ethyl)amino)pyridin-4-yl)-1H-indazol-3-amine5-(2-((2-(1H-indol-3-yl)ethyl)amino)pyridin-4-yl)-1 H-indazol-3-amine5-(2-((4-fluorophenethyl)amino)pyridin-4-yl)-1H-indazol-3-amine5-(2-((4-chlorophenethyl)amino)pyridin-4-yl)-1 H-indazol-3-amine4-(2-((4-(3-amino-1 H-indazol-5-yl)pyridin-2-yl)amino)ethyl)phenol5-(2-((4-methoxyphenethyl)amino)pyridin-4-yl)-1H-indazol-3-amine5-(2-((4-(tert-butyl)phenethyl)amino)pyridin-4-yl)-1 H-indazol-3-amine4-(2-((4-(3-amlno-1 H-indazol-5-yl)pyridin-2-yl)amino)ethyl)benzenesulfonamide5-(2-((3-chlorophenethyl)amino)pyridin-4-yl)-1 H-indazol-3-amine5-(2-((2-(trifluoromethyl)phenethyl)amino)pyridin-4-yl)-1 H-indazol-3-amine5-(2-((3-phenylpropyl)amino)pyridin-4-yl)-1H-indazol-3-amine5-(2-((2-phenoxyethyl)amino)pyridin-4-yl)-1H-indazol-3-amineN-(4-(3-amino-1 H-indazol-5-yl)pyridin-2-yl)cyclopropanecarboxamideN-(4-(3-amino-1 H-indazol-5-yl)pyridin-2-yl)benzamideN-(4-(3-amino-1 H-indazol-5-yl)pyridin-2-yl)-2-phenylacetamideN-(4-(3-amino-1 H-indazol-5-yl)pyridin-2-yl)-2-(3-fluorophenyl)acetamideN-(4-(3-amino-1 H-indazol-5-yl)pyridin-2-yl)-2-(3-tolyl)acetamideN-(4-(3-amino-1 H-indazol-5-yl)pyridin-2-yl)-2-(3-(trifluoromethyl)phenyl)acetamideN-(4-(3-amino-1 H-indazol-5-yl)pyridin-2-yl)-2-(3-chlorophenyl)acetamideN-(4-(3-amino-1 H-indazol-5-yl)pyridin-2-yl)-2-(3-aminophenyl)acetamideN-(4-(3-amino-1 H-indazol-5-yl)pyridin-2-yl)-2-(3-nitrophenyl)acetamideN-(4-(3-amino-1 H-indazol-5-yl)pyridin-2-yl)-2-(3-(methylsulfonyl)phenyl)acetamideN-(4-(3-amino-1 H-indazol-5-yl)pyridin-2-yl)-2-(3-methoxyphenyl)acetamideN-(4-(3-amino-1 H-indazol-5-yl)pyridin-2-yl)-2-(3-(benzyloxy)phenyl)acetamide tert-butyl (3-(2-((4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)phenyl)carbamateN-(4-(3-amino-1 H-indazol-5-yl)pyridin-2-yl)-2-(4-fluorophenyl)acetamideN-(4-(3-amino-1 H-indazol-5-yl)pyridin-2-yl)-2-(p-tolyl)acetamideN-(4-(3-amino-1 H-indazol-5-yl)pyridin-2-yl)-2-(4-(trifluoromethyl)phenyl)acetamideN-(4-(3-amino-1 H-indazol-5-yl)pyridin-2-yl)-2-(4-chlorophenyl)acetamideN-(4-(3-amino-1 H-indazol-5-yl)pyridin-2-yl)-2-(4-(methylthio)phenyl)acetamideN-(4-(3-amino-1 H-indazol-5-yl)pyridin-2-yl)-2-(4-(methylsulfonyl)phenyl)acetamideN-(4-(3-amino-1 H-indazol-5-yl)pyridin-2-yl)-2-(4-methoxyphenyl)acetamideN-(4-(3-amino-1 H-indazol-5-yl)pyridin-2-yl)-2-(4-aminophenyl)acetamide tert-butyl (4-(2-((4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)phenyl)carbamateN-(4-(3-amino-1 H-indazol-5-yl)pyridin-2-yl)-2-(2-fluorophenyl)acetamideN-(4-(3-amino-1 H-indazol-5-yl)pyridin-2-yl)-2-(o-tolyl)acetamideN-(4-(3-amino-1 H-indazol-5-yl)pyridin-2-yl)-2-(2-(trifluoromethyl)phenyl)acetamideN-(4-(3-amino-1 H-indazol-5-yl)pyrldin-2-yl)-2-(2-chlorophenyl)acetamideN-(4-(3-amino-1 H-indazol-5-yl)pyridin-2-yl)-2-(2-methoxyphenyl)acetamldeN-(4-(3-amino-1 H-indazol-5-yl)pyrldin-2-yl)-2-(pyridin-2-yl)acetamideN-(4-(3-amino-1 H-indazol-5-yl)pyridin-2-yl)-2-(pyridin-3-yl)acetamideN-(4-(3-amino-1 H-indazol-5-yl)pyridine-2-yl)-2-(pyridine-4-yl)acetamideN-(4-(3-amino-1 H-indazol-5-yl)pyrldine-2-yl)-3-phenylpropanamide ethyl (4-(3-amino-1 H-indazol-5-yl)pyrldine-2-yl)carbamate1 -(4-(3-amino-1 H-indazol-5-yl)pyridine-2-yl)-3-ethylurea1 -(4-(3-amino-1 H-indazol-5-yl)pyridine-2-yl)-3-propylurea1 -(4-(3-amino-1 H-indazol-5-yl)pyridine-2-yl)-3-isopentylurea1-(4-(3-amino-1H-indazol-5-yl)pyridine-2-yl)-3-cyclopentylurea1 -(4-(3-amino-1 H-indazol-5-yl)pyridine-2-yl)-3-cyclohexylurea1-(4-(3-amino-1H-indazol-5-yl)pyridine-2-yl)-3-(2-hydroxyethyl)urea1-(4-(3-amino-1H-indazol-5-yl)pyridine-2-yl)-3-(3-hydroxypropyl)urea1-(4-(3-amino-1H-indazol-5-yl)pyridine-2-yl)-3-(2-methoxyethyl)urea3-(4-(3-amino-1H-indazol-5-yl)pyridine-2-yl)-1-(2-hydroxyethyl)-1 -methylurea1 -(4-(3-amino-1 H-indazol-5-yl)pyridine-2-yl)-3-benzylurea1 -(4-(3-amino-1 H-indazol-5-yl)pyridine-2-yl)-3-phenethylurea1-(4-(3-amino-1H-indazol-5-yl)pyridine-2-yl)-3-(pyridine-2-ylmethyl)urea1-(4-(3-amino-1H-indazol-5-yl)pyridine-2-yl)-3-(pyridine-3-ylmethyl)urea1-(4-(3-amino-1H-indazol-5-yl)pyridine-2-yl)-3-(pyridine-4-ylmethyl)urea1 -(4-(3-amino-1 H-indazol-5-yl)pyridine-2-yl)-3-phenylurea1-(4-(3-amino-1H-indazol-5-yl)pyridine-2-yl)-3-(3-fluorophenyl)urea1-(4-(3-amino-1H-indazol-5-yl)pyridine-2-yl)-3-(3-chlorophenyl)urea1-(4-(3-amino-1H-indazol-5-yl)pyridine-2-yl)-3-(3-isopropylphenyl)urea1-(4-(3-amino-1H-indazol-5-yl)pyridine-2-yl)-3-(3-(hydroxymethyl)phenyl)urea3-(3-(4-(3-amino-1H-indazol-5-yl)pyridine-2-yl)ureido)benzamide1-(4-(3-amino-1H-indazol-5-yl)pyridine-2-yl)-3-(3-phenoxyphenyl)urea1-(4-(3-amino-1H-indazol-5-yl)pyridine-2-yl)-3-(3-(benzyloxy)phenyl)urea1-(4-(3-amino-1H-indazol-5-yl)pyridine-2-yl)-3-(3-((4-fluorobenzyl)oxy)phenyl)urea1-(4-(3-amino-1H-indazol-5-yl)pyridine-2-yl)-3-(3-((3-fluorobenzyl)oxy)phenyl)urea1-(4-(3-amino-1H-indazol-5-yl)pyridine-2-yl)-3-(3-((2-fluorobenzyl)oxy)phenyl)urea3-(3-(4-(3-amino-1H-indazol-5-yl)pyridine-2-yl)ureido)-N-phenylbenzamide1-(4-(3-amino-1H-indazol-5-yl)pyridine-2-yl)-3-(4-fluorophenyl)urea1-(4-(3-amino-1H-indazol-5-yl)pyridine-2-yl)-3-(4-chlorophenyl)urea1-(4-(3-amino-1H-indazol-5-yl)pyridine-2-yl)-3-(4-(tert-butyl)phenyl)urea1-(4-(3-amino-1H-indazol-5-yl)pyridine-2-yl)-3-(4-(methylsulfonyl)phenyl)urea1 -(4-(3-amino-1 H-indazol-5-yl)pyridin-2-yl)-3-(o-tolyl)urea1-(4-(3-amino-1H-indazol-5-yl)pyridine-2-yl)-3-(2-ethylphenyl)urea1-(4-(3-amino-1H-indazol-5-yl)pyridine-2-yl)-3-(2-isopropylphenyl)urea1-(4-(3-amino-1H-indazol-5-yl)pyridine-2-yl)-3-(pyridine-3-yl)urea 5-(2-(phenylamino)pyridine-4-yl)-1H-indazol-3-amine 5-(2-((3-lsopropylphenyl)amino)pyridine-4-yl)-1 H-indazol-3-amine3-((4-(3-amino-1H-indazol-5-yl)pyridine-2-yl)amino)phenol (3-((4-(3-amino-1 H-indazol-5-yl)pyridine-2-yl)amino)phenyl)methanol3-((4-(3-amino-1H-indazol-5-yl)pyridine-2-yl)amino)benzoic acid ethyl 3-((4-(3-amino-1H-indazol-5-yl)pyridine-2-yl)amino)benzoate3-((4-(3-amino-1H-indazol-5-yl)pyridine-2-yl)amino)benzamide3-((4-(3-amino-1H-indazol-5-yl)pyridine-2-yl)amino)-N-(2-hydroxyethyl)benzamide N1-(4-(3-amino-1 H-indazol-5-yl)pyridine-2-yl)benzene-1 ,3-diamine N-(3-((4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)amino)phenyl)acetamide N-(3-((4-(3-amino-1H-indazol-5-yl)pyridine-2-yl)amino)phenyl)benzamide 5-(2-((3-phenoxyphenyl)amino)pyridine-4-yl)-1H-indazol-3-amine 5-(2-((3-(benzyloxy)phenyl)amino)pyridine-4-yl)-1H-indazol-3-amine 5-(2-((4-fluorophenyl)amino)pyridine-4-yl)-1H-indazol-3-amine 5-(2-((4-chlorophenyl)amino)pyridine-4-yl)-1 H-indazol-3-amine4-((4-(3-amino-1H-indazol-5-yl)pyridine-2-yl)amino)phenol5-(2-((4-methoxyphenyl)amino)pyridine-4-yl)-1H-indazol-3-amine 5-(2-((4-(trifluoromethoxy)phenyl)amino)pyridine-4-yl)-1 H-indazol-3-amine 5-(2-((4-propoxyphenyl)amino)pyridine-4-yl)-1 H-indazol-3-amine2-((4-(3-amino-1H-indazol-5-yl)pyridine-2-yl)amino)phenol4-((4-(3-amino-1H-indazol-5-yl)pyridine-2-yl)amino)-2-methylphenol5-((4-(3-amino-1H-indazol-5-yl)pyridine-2-yl)amino)-2-methylphenol4-((4-(3-amino-1H-indazol-5-yl)pyridine-2-yl)amino)-3-methylphenol5-(2-((3,4-dichlorophenyl)amino)pyridine-4-yl)-1H-indazol-3-amine N-(4-(3-amino-1 H-indazol-5-yl)pyridin-2-yl)thiazol-2-amine 5-(2-(pyrimidin-2-ylamino)pyridine-4-yl)-1 H-indazol-3-amine 5-(2-(pyridine-4-ylamino)pyridine-4-yl)-1 H-indazol-3-amine 5-(2-(pyridine-3-ylamino)pyridine-4-yl)-1 H-indazol-3-amine 5-(2-(pyridine-2-ylamino)pyridine-4-yl)-1 H-indazol-3-amineN2-(4-(3-amino-1 H-indazol-5-yl)pyridine-2-yl)pyridine-2,6-diamine N2-(4-(3-amino-1 H-indazol-5-yl)pyridine-2-yl)-N6-benzylpyridine-2,6-diamine 5-(7H-pyrrolo[2,3-b]pyrimidin-4-yl)-1 H-indazol-3-amine 2-amino-4-(3-amino-1H-indazol-5-yl)-7H-pyrrolo[2,3-b]pyrimidine-5-carbonitrile 5-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-indazol-3-amine 5-(3-methyl-1 H-pyrrolo[2,3-b]pyridln-4-yl)-1 H-indazol-3-amine5-(3-chloro-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3-amine4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile5-(2-methyl-1 H-pyrrolo[2, 3-b]py rid in-4-yl)- 1 H-indazol-3-amine 5-(2-(tert-butyl)-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3-amine 5-(2-phenyl-1 H-pyrrolo[2, 3-b] pyridin-4-yl)- 1 H-indazol-3-amine4-(3-amino-1 H-indazol-5-yl)-1 H-pyrrolo[2,3-b]pyridine-2-carboxylic acid5-(5-fluoro-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3-amine 5-(5-chloro-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3-amine4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile5-(7H-pyrrolo[2,3-b]pyrimidin-4-yl)-1 H-indazol-3-amine 7-bromo-5-(7H-pyrrolo[2,3-b][2,3-b]pyrimidin-4-yl)-1 H-indazol-3-amine 5-(2-methyl-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3-amine 5-(2-(tert-butyl)-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3-amine 5-(2-cyclopropyl-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3-amine 5-(2-cyclohexyl-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3-amine 5-(2-neopentyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine 5-(2-(cyclohexylmethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3-amine 5-(2-(2-cyclohexylethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine 5-(2-benzyl-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3-amine (4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)methanol2-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)propan-2-ol3-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)pentan-3-ol 5-(2-(tert-butoxymethyl )-1 H-pyrrolo[2 , 3- b] py r id i n -4-y I )-1 H-indazol-3-am ine 5-(2-(tetrahydro-2H-pyran-4-yl)-1 H-pyrrolo[2,3-b]pyridin^l-yl)-1 H-indazol-3-amine 5-(2-(tetrahydro-2H-pyran-2-yl)-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3-amine 5-(2-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3-amine4-(3-amino-1 H-indazol-5-yl)-1 H-pyrrolo[2,3-b]pyridine-2-carboxylic acid methyl 4-(3-amino-1 H-indazol-5-yl)-1 H-pyrrolo[2,3-b]pyridine-2-carboxylate ethyl 4-(3-amino-1 H-indazol-5-yl)-1 H-pyrrolo[2,3-b]pyridine-2-carboxylate (4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)(pyrrolidin-1-yl)methanone 4-(3-amino-1H-indazol-5-yl)-N-cyclopentyl-1 H-pyrrolo[2,3-b]pyridine-2-carboxamide 4-(3-amino-1H-indazol-5-yl)-N-cyclohexyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide 4-(3-amino-1H-indazol-5-yl)-N-isopentyl-1 H-pyrrolo[2,3-b]pyridine-2-carboxamide 4-(3-amino-1H-indazol-5-yl)-N-phenethyl-1 H-pyrrolo[2,3-b]pyridine-2-carboxamide 4-(3-amino-1H-indazol-5-yl)-N-(3-phenylpropyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide 4-(3-amino-1H-indazol-5-yl)-N-(2-methoxyethyl)-1 H-pyrrolo[2,3-b]pyridine-2-carboxamide4-(3-amino-1H-lndazol-5-yl)-N-(2-aminoethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide4-(3-amino-1H-indazol-5-yl)-N-(2-(dimethylamlno)ethyl)-1H-pyrrolo[2,3-b]pyridine-2- carboxamide(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)(4-methylplperazin-1-yl)methanone4-(3-amino-1 H-indazol-5-yl)-N-(2-(piperidin-1 -yl)ethyl)-1 H-pyrrolo[2,3-b]pyridine-2- carboxamide4-(3-amino-1H-indazol-5-yl)-N-(2-(butyl(ethyl)amino)ethyl)-1 H-pyrrolo[2,3-b]pyridine-2- carboxamide4-(3-amino-1H-indazol-5-yl)-N-(2-(diisopropylamino)ethyl)-1H-pyrrolo[2,3-b]pyridine-2- carboxamide4-(3-amino-1H-indazol-5-yl)-N-(3-(dimethylamino)propyl)-1 H-pyrrolo[2,3-b]pyridine-2- carboxamide5-(2-((tert-butylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-indazol-3-amine5-(2-((isopentylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-lndazol-3-amine5-(2-(piperidin-2-yl)-1 H-pyrrolo[2,3-b]pyridine-4-yl)-1H-indazol-3-amine5-(2-((cyclohexylamino)methyl)-1 H-pyrrolo[2,3-b]pyridine-4-yl)-1H-indazol-3-amine5-(2-((phenylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-indazol-3-amine5-(2-(((2-(benzyloxy)phenyl)amino)methyl)-1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-indazol-3-amine5-(2-(((2-methoxyethyl)amino)methyl)-1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-indazol-3-amineN1-((4-(3-amino-1 H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)-N2,N2-dimethylethane-1 ,2-diamine5-(2-(((3-methoxypropyl)amino)methyl)-1 H-pyrrolo[2,3-b]pyridine-4-yl)-1 H-indazol-3-amine5-(2-(((3-isopropoxypropyl)amino)methyl)-1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-indazol-3-amineN1-((4-(3-amino-1 H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)-N3,N3- dimethylpropane-1 ,3-diamine5-(2-((isopropyl(methyl)amino)methyl)-1 H-pyrrolo[2,3-b]pyridine-4-yl)-1 H-indazol-3-amine5-(2-(piperidin-1 -ylmethyl)-1 H-pyrrolo[2,3-b]pyridine-4-yl)-1 H-indazol-3-amine5-(2-((4,4-difluoropiperidin-1-yl)methyl)-1 H-pyrrolo[2,3-b]pyridine-4-yl)-1 H-indazol-3-amine5-(2-(morpholinomethyl)-1 H-pyrrolo[2,3-b]pyridine-4-yl)-1 H-indazol-3-amine5-(2-((4-methylpiperazin-1 -yl)methyl)-1 H-pyrrolo[2,3-b]pyridine-4-yl)-1 H-indazol-3-amine5-(2-((4-(tert-butyl)piperazin-1-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine5-(2-(azepan-1-ylmethyl)-1H-pyrrolo[2,3-b]pyridine-4-yl)-1 H-indazol-3-amine5-(2-((4-methyl-1 ,4-diazepan-1 -yl)methyl)-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3-amine5-(2-(2-(piperidin-1-yl)ethyl)-1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-indazol-3-amine5-(2-(2-morpholinoethyl)-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3-amine5-(2-(3-(piperidin-1-yl)propyl)-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3-amine5-(2-(3-(cyclohexylamino)propyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine5-(2-(3-morpholinopropyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amlne5-(2-(piperidin-4-ylmethyl)-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3-amine5-(2-((1-benzylpiperidin-4-yl)methyl)-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3-amine5-(2-phenyl-1 H-pyrrolo[2, 3-b] pyridin-4-yl)- 1 H-indazol-3-amine5-(2-(3-(trifluoromethyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine3-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)benzonitrile3-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)phenol5-(2-(3-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine3-(4-(3-amino-1 H-indazol-5-yl)-1 H-pyrrolo[2,3-b]pyridin-2-yl)benzoic acid3-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)benzamide3-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-N-(2-methoxyethyl)benzamide3-(4-(3-amino-1 H-indazol-5-yl)-1 H-pyrrolo[2,3-b]pyridin-2-yl)-N-(2-(piperidin-1 - yl)ethyl)benzamide(3-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)phenyl)(4-methylpiperazin-1- yl)methanone 5-(2-(3-(morpholinomethyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine 5-(2-(3-(methylsulfonyl)phenyl)-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine 5-(2-(3-(morpholinosulfonyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine 5-(2-(3-aminophenyl)-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3-amineN-(3-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)phenyl)-3- methoxypropanamideN-(3-(4-(3-amino-1 H-indazol-5-yl)-1 H-pyrrolo[2,3-b]pyridin-2-yl)phenyl)-3-(piperidin-1 - yl)propanamide4-((3-(4-(3-amino-1 H-indazol-5-yl)-1 H-pyrrolo[2,3-b]pyridin-2-yl)phenyl)amino)-4-oxobutanoic acidN-(3-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)phenyl)methanesulfonamideN-(3-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)phenyl)-4- methylbenzenesulfonamide5-(2-(4-(morpholinomethyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amineN-(4-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)phenyl)-4- methylbenzenesulfonamide2-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)phenol5-(2-(2-ethoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine5-(2-(2-ethylphenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine5-(2-(benzo[d][1 ,3]dioxol-5-yl)-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3-amine4-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-fluorobenzonitrile5-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-(pyrrolidin-1-yl)benzonitrile5-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-(4-methylpiperazin-1- yl)benzonitrile5,5'-(1 H-pyrrolo[2,3-b]pyrldine-2,4-diyl)bis(1 H-indazol-3-amine)5-(2-(3,5-difluorophenyl)-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3-amine5-(2-(2,3,5-trifluorophenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3-amine5-(2-(pyridin-2-yl)-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine5-(2-(pyridin-3-yl)-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine5-(2-(pyridin-4-yl)-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine5-(2-(pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine4-(4-(3-amino-1 H-indazol-5-yl)-1 H-pyrrolo[2,3-b]pyridin-2-yl)pyridin-2(1 H)-one5-(2-(2-fluoropyridin-4-yl)-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3-amine5-(2-(2-fluoro-6-methylpyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amlne5-(2-(2,6-difluoropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine5-(2-(2-(piperidin-1-yl)pyridin-4-yl)-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3-amine5-(2-(2-(piperazin-1-yl)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine5-(2-(2-morpholinopyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine5-(2-(2-(4-(tert-butyl)piperazin-1-yl)pyridin-4-yl)-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3- amine4-(4-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)pyridin-2-yl)thiomorpholine 1 ,1- dioxide5-(2-(2,6-dimorpholinopyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3-amine4-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1-(4-(piperidin-1- ylmethyl)benzyl)pyridin-2(1 H)-one4-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1-(3-(piperidin-1- ylmethyl)benzyl)pyridin-2(1 H)-one4-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1-(2-(piperidin-1- ylmethyl)benzyl)pyridin-2(1 H)-one5-(2-(5-methoxypyridin-3-yl)-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine5-(2-(6-morpholinopyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine5-(2-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine5-(2-(6-((2-morphollnoethyl)amino)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-lndazol-3- amine5-(2-(2-fluoropyridin-3-yl)-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3-amine5-(2-(2-morpholinopyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine5-(2-(3-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine5-(2-(3-isobutoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine5-(2-(3-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine5-(2-(3-(2-morpholinoethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine 5-(2-(3-(benzyloxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine 5-(2-(3-((4-methoxybenzyl)oxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine 5-(2-(3-((3,5-dimethoxybenzyl)oxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine 5-(2-(3-((4-fluorobenzyl)oxy)phenyl)-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine 5-(2-(3-((2-fluorobenzyl)oxy)phenyl)-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine 5-(2-(3-(pyridin-2-ylmethoxy)phenyl)-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3-amine 3-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-fluorophenol 5-(2-(3-fluoro-5-methoxyphenyl)-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3-amine5-(2-(3-fluoro-5-(2-methoxyethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridlne-4-yl)-1H-indazol-3-amine5-(2-(3-fluoro-5-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)-1 H-pyrrolo[2,3-b]pyridine-4-yl)-1 H-indazol-3-amine5-(2-(3-(benzyloxy)-5-fluorophenyl)-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3-amine5-(2-(3-(benzyloxy)-5-(trifluoromethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3- amine methyl 3-(4-(3-amino-1 H-indazol-5-yl)-1 H-pyrrolo[2,3-b]pyridin-2-yl)-5-(benzyloxy)benzoate5-(2-(3-(benzyloxy)-5-((2-methoxyethoxy)methyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H- indazol-3-amine5-(2-(3-(benzyloxy)-5-((2-methoxyethyl)amino)phenyl)-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1 H indazol-3-amine5-(2-(3-(benzyloxy)-5-((2-morpholinoethyl)amino)phenyl)-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1H- indazol-3-amine5-(2-(2-(benzyloxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine5-(2-(4-(benzyloxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine5-(2-(5-(benzyloxy)pyridin-3-yl)-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3-amine5-(2-(2-(benzyloxy)pyridin-4-yl)-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3-amine5-(2-(6-(benzyloxy)pyridin-3-yl)-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3-amine5-(2-(4-(benzyloxy)pyridin-2-yl)-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3-amine5-(2-(2-(pyrimidin-5-ylmethoxy)pyridin-4-yl)-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine5-(2-(2-(pyridin-4-ylmethoxy)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine5-(2-(2-(pyridin-3-ylmethoxy)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amlne5-(2-(2-(pyridin-2-ylmethoxy)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine5-(2-(6-(benzylamino)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine5-(2-(2-(benzylamino)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine5-(2-(2-(benzyl(methyl)amino)pyridin-4-yl)-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3-amine5-(2-(2-(benzylthio)pyridin-4-yl)-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3-amine5-(2-(2-(benzylthio)-6-morpholinopyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3- amine5-(2-(3-phenethylphenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine 5-(2-(2-phenethoxypyridin-4-yl)-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3-amine 5-(2-(3-((phenylamino)methyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine 5-(2-(3-((tert-butylamino)methyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine 5-(2-(3-((cyclopentylamino)methyl)phenyl)-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3-amine 5-(2-(3-((cyclohexylamino)methyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine 5-(2-(3-((butylamino)methyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine 5-(2-(3-((isopentylamino)methyl)phenyl)-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3-amine 5-(2-(3-((butyl(ethyl)amino)methyl)phenyl)-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3-amine 5-(2-(3-((dibutylamino)methyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine 5-(2-(2-fluoro-6-(piperidin-1-ylmethyl)pyridin-4-yl)-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3- amine5-(2-(2-fluoro-6-(piperazin-1-ylmethyl)pyridin-4-yl)-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3- amine5-(2-(2-fluoro-6-((4-methylpiperazin-1-yl)methyl)pyridin-4-yl)-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1 H- indazol-3-amine tert-butyl 4-((4-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-6-fluoropyridin-2- yl)methyl)piperazine-1 -carboxylate5-(2-(2-((tert-butylamino)methyl)-6-fluoropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H- indazol-3-amine5-(2-(2-((cyclohexylamino)methyl)-6-fluoropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H- indazol-3-amine5-(2-(2-fluoro-6-((phenylamino)methyl)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine4-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-2,6-difluorobenzamide5-(2-(4-((dimethylamino)methyl)-3,5-difluorophenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine5-(2-(3,5-difluoro-4-(piperidin-1-ylmethyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3- amine5-(2-(3,5-difluoro-4-((isopropyl(methyl)amino)methyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3-amine5-(2-(4-((butyl(ethyl)amlno)methyl)-3,5-difluorophenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1 H- indazol-3-amine5-(2-(4-((dibutylamino)methyl)-3,5-difluorophenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-lndazol-3- amine5-(2-(3,5-difluoro-4-(3-morpholinopropyl)phenyl)-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3- amine5-(2-(3,5-difluoro-4-(3-(piperidin-1-yl)propyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine5-(2-(4-(3-(diethylamino)propyl)-3,5-difluorophenyl)-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3-amine5-(2-(4-(3-(dibutylamino)propyl)-3,5-difluorophenyl)-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3-amine7-chloro-5-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3-amine7-chloro-5-(2-(3-(morpholinomethyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine7-chloro-5-(2-(4-(morpholinomethyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine7-chloro-5-(2-(2-fluoro-6-(piperazin-1-ylmethyl)pyridin-4-yl)-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1H- indazol-3-amine4-(3-amino-7-chloro-1H-indazol-5-yl)-N-(2-(piperidin-1-yl)ethyl)-1 H-pyrrolo[2,3-b]pyridine-2- carboxamide7-chloro-5-(2-(cyclohexylmethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine7-chloro-5-(2-(morpholinomethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3-amine7-chloro-5-(2-(2-morpholinoethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3-amine7-phenyl-5-(2-phenyl-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine5-(2-(3-(morpholinomethyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-7-phenyl-1 H-indazol-3-amine5-(2-(4-(morpholinomethyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-7-phenyl-1 H-indazol-3-amine5-(2-(cyclohexylmethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-7-(3,3-dimethylbut-1-yn-1-yl)-1H- indazol-3-amine5-(2-(2-(Benzylthio)-6-fluoropyridin-4-yl)-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine.

[0094] The various functional groups and substituents making up the compounds of the Formula (I), or sub-formulae (la) to (Ic), are typically chosen such that the molecular weight of the compound of the formula (I) does not exceed 1000. More usually, the molecular weight of the compound will be less than 900, for example less than 800, or less than 750, or less than 700, or less than 650. More preferably, the molecular weight is less than 600 and, for example, is 550 or less.

[0095] A suitable pharmaceutically acceptable salt of a compound of the invention is, for example, an acid-addition salt of a compound of the invention which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic, formic, citric methane sulfonate or maleic acid. In addition, a suitable pharmaceutically acceptable salt of a compound of the invention which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a pharmaceutically acceptable cation, for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.

[0096] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers”. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”. Stereoisomers that are not mirror images of one another are termed “diastereomers" and those that are non-superimposable mirror images of each other are termed “enantiomers”. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”.

[0097] The compounds of this invention may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (S)-stereoisomers or as mixtures thereof. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see discussion in Chapter 4 of “Advanced Organic Chemistry”, 4th edition J. March, John Wiley and Sons, New York, 2001 ), for example by synthesis from optically active starting materials or by resolution of a racemic form. Some of the compounds of the invention may have geometric isomeric centres (E- and Z- isomers).

[0098] It is to be understood that the present invention encompasses all optical, diastereoisomers and geometric isomers and mixtures thereof that possess activity.

[0099] The present invention also encompasses compounds of the invention as defined herein which comprise one or more isotopic substitutions. For example, H may be in any isotopic form, including 1H, 2H(D), and 3H (T); C may be in any isotopic form, including 12C, 13C, and 14C; and O may be in any isotopic form, including 160 and18O; and the like.

[0100] It is also to be understood that certain compounds of the Formula (I), or sub-formulae (la) to (Ic), may exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms that possess activity.

[0101] It is also to be understood that certain compounds of the Formula (I), or sub-formulae (la) to (Ic), may exhibit polymorphism, and that the invention encompasses all such forms that possess activity.

[0102] Compounds of the Formula (I), or sub-formulae (la) to (Ic), may exist in a number of different tautomeric forms and references to compounds of the Formula (I), or sub-formulae (la) to (Ic), include all such forms. For the avoidance of doubt, where a compound can exist in one of several tautomeric forms, and only one is specifically described or shown, all others are nevertheless embraced by Formula (I), or sub-formulae (la) to (Ic). Examples of tautomeric forms include keto-, enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto / enol (illustrated below), imine / enamine, amide / imino alcohol, amidine / amidine, nitroso / oxime, thioketone / enethiol, and nitro / aci-nitro.

[0103] Compounds of the Formula (I), or sub-formulae (la) to (Ic), containing an amine function may also form N-oxides. A reference herein to a compound of the Formula (I), or subformulae (la) to (Ic), that contains an amine function also includes the N-oxide. Where a compound contains several amine functions, one or more than one nitrogen atom may be oxidised to form an N-oxide. Particular examples of N-oxides are the N-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle. N-Oxides can be formed by treatment of the corresponding amine with an oxidizing agent such as hydrogen peroxide or a per-acid (e.g. a peroxycarboxylic acid), see for example Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages. More particularly, N-oxides can be made by the procedure of L. W. Deady (Syn. Comm. 1977, 7, 509-514) in which the amine compound is reacted with m-chloroperoxybenzoic acid (mCPBA), for example, in an inert solvent such as dichloromethane.

[0104] The compounds of Formula (I), or sub-formulae (la) to (Ic), may be administered in the form of a pro-drug which is broken down in the human or animal body to release a compound of the invention. A pro-drug may be used to alter the physical properties and / or the pharmacokinetic properties of a compound of the invention. A pro-drug can be formed when the compound of the invention contains a suitable group or substituent to which a propertymodifying group can be attached. Examples of pro-drugs include in vivo cleavable ester derivatives that may be formed at a carboxy group or a hydroxy group in a compound of the Formula (I), or sub-formulae (la) to (Ic), 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 (la) to (Ic).

[0105] Accordingly, the present invention includes those compounds of the Formula (I), or sub-formulae (la) to (Ic), as defined hereinbefore, when made available by organic synthesis and when made available within the human or animal body by way of cleavage of a pro-drug thereof. Accordingly, the present invention includes those compounds of the Formula (I), or sub-formulae (la) to (Ic), that are produced by organic synthetic means and also such compounds that are produced in the human or animal body by way of metabolism of a precursor compound, that is a compound of the Formula (I), or sub-formulae (la) to (Ic), may be a synthetically-produced compound or a metabolically-produced compound.

[0106] A suitable pharmaceutically acceptable pro-drug of a compound of the Formula (I), or sub-formulae (la) to (Ic), is one that is based on reasonable medical judgement as being suitable for administration to the human or animal body without undesirable pharmacological activities and without undue toxicity.

[0107] Various forms of pro-drug have been described, for example in the following documents :- a) Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985); c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and Application of Pro-drugs”, by H. Bundgaard p. 113-191 (1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H. Bundgaard, et al, Journal of Pharmaceutical Sciences, 77, 285 (1988); f) N. Kakeya, et al., Chem. Pharm. Bull., 32, 692 (1984);9) T. Higuchi and V. Stella, “Pro-Drugs as Novel Delivery Systems", A.C.S. SymposiumSeries, Volume 14; and h) E. Roche (editor), “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987.

[0108] A suitable pharmaceutically acceptable pro-drug of a compound of the Formula (I), or sub-formulae (la) to (Ic), that possesses a carboxy group is, for example, an in vivo cleavable ester thereof. An in vivo cleavable ester of a compound of the Formula I, or sub-formulae (la) to (Ic), 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 or parent alcohol. Suitable pharmaceutically acceptable esters for carboxy include (1 -6C)alkyl esters such as methyl, ethyl and tert-butyl, (1-6C)alkoxymethyl esters such aass methoxymethyl esters, (1- 6C)alkanoyloxymethyl esters such as pivaloyloxymethyl esters, 3-phthalidyl esters, (3- 8C)cycloalkylcarbonyloxy-(1-6C)alkyl esters such as cyclopentylcarbonyloxymethyl and 1- cyclohexylcarbonyloxyethyl esters, 2-oxo-1 ,3-dioxolenylmethyl esters such as 5-methyl-2-oxo- 1 ,3-dioxolen-4-ylmethyl esters and (1-6C)alkoxycarbonyloxy-(1-6C)alkyl esters such as methoxycarbonyloxymethyl and 1 -methoxycarbonyloxyethyl esters.

[0109] A suitable pharmaceutically acceptable pro-drug of a compound of the Formula (I), or sub-formulae (la) to (Ic), that possesses a hydroxy group is, for example, an in vivo cleavable ester or ether thereof. An in vivo cleavable ester or ether of a compound of the Formula (I), or sub-formulae (la) to (Ic), containing a hydroxy group is, for example, a pharmaceutically acceptable ester or ether which is cleaved in the human or animal body to produce the parent hydroxy compound. Suitable pharmaceutically acceptable ester forming groups for a hydroxy group include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters). Further suitable pharmaceutically acceptable ester forming groups for a hydroxy group include (1-10C)alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, (1-10C)alkoxycarbonyl groups such as ethoxycarbonyl, N,N-(1- 6C)2carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1 -ylmethyl and 4-(1-4C)alkylpiperazin-1- ylmethyl. Suitable pharmaceutically acceptable ether forming groups for a hydroxy group include a-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.

[0110] A suitable pharmaceutically acceptable pro-drug of a compound of the Formula (I), or sub-formulae (la) to (Ic), 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 (1- 4C)alkylamine such as methylamine, a [(1-4C)alkyl]2amine such as dimethylamine, N-ethyl-N- methylamine or diethylamine, a (1-4C)alkoxy-(2-4C)alkylamine such as 2-methoxyethylamine, a phenyl-(1-4C)alkylamine such as benzylamine and amino acids such as glycine or an ester thereof.

[0111] A suitable pharmaceutically acceptable pro-drug of a compound of the Formula (I), or sub-formulae (la) to (Ic), that possesses an amino group is, for example, an in vivo cleavableamide derivative thereof. Suitable pharmaceutically acceptable amides from an amino group include, for example an amide formed with (1-10C)alkanoyl groups such as an acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N- dialkylaminomethyl, morpholinomethyl, piperazin-1 -ylmethyl and 4-(1-4C)alkyl)piperazin-1-ylmethyl.

[0112] The in vivo effects of a compound of the Formula (I), or sub-formulae (la) to (Ic), may be exerted in part by one or more metabolites that are formed within the human or animal body after administration of a compound of the Formula (I), or sub-formulae (la) to (Ic). As stated hereinbefore, the in vivo effects of a compound of the Formula (I), or sub-formulae (la) to (Ic), may also be exerted by way of metabolism of a precursor compound (a pro-drug).

[0113] Though the present invention may relate to any compound or particular group of compounds defined herein by way of optional, preferred or suitable features or otherwise in terms of particular embodiments, the present invention may also relate to any compound or particular group of compounds that specifically excludes said optional, preferred or suitable features or particular embodiments.

[0114] Suitably, the present invention excludes any individual compounds not possessing the biological activity defined herein.Synthesis

[0115] The compounds of the present invention can be prepared by any suitable technique known in the art. Particular processes for the preparation of these compounds are described further in the accompanying examples.

[0116] In the description of the synthetic methods described herein and in any referenced synthetic methods that are used to prepare the starting materials, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, can be selected by a person skilled in the art.

[0117] It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reaction conditions utilised.

[0118] It will be appreciated that during the synthesis of the compounds of the invention in the processes defined herein, or during the synthesis of certain starting materials, it may be desirable to protect certain substituent groups to prevent their undesired reaction. The skilledchemist will appreciate when such protection is required, and how such protecting groups may be put in place, and later removed.

[0119] For examples of protecting groups see one of the many general texts on the subject, for example, ‘Protective Groups in Organic Synthesis’ by Theodora Green (publisher: John Wiley & Sons). Protecting groups may be removed by any convenient method described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group with the minimum disturbance of groups elsewhere in the molecule.

[0120] 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.

[0121] By way of example, a suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl. The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed by, for example, hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an acyl group such as a fert-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulfuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.

[0122] A suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl. The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium, sodium hydroxide or ammonia. Alternatively an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.

[0123] A suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis witha base such as sodium hydroxide, or for example a t-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.

[0124] Resins may also be used as a protecting group.

[0125] The methodology employed to synthesise a compound of Formula (I), or sub-formulae (la) to (Ic), will vary depending on the nature of R1, R2, R3, R4, X1and any substituent groups or subgroups associated therewith. Suitable processes for their preparation are described further in the accompanying Examples.

[0126] Once a compound of Formula (I), or sub-formulae (la) to (Ic), has been synthesised by any one of the processes defined herein, the processes may then further comprise the additional steps of:(i) removing any protecting groups present;(ii) converting the compound Formula (I) into another compound of Formula (I);(iii) forming a pharmaceutically acceptable salt, hydrate or solvate thereof; and / or(iv) forming a prodrug thereof.

[0127] An example of (ii) above is when a compound of Formula (I) is synthesised and then one or more of the groups may be further reacted to change the nature of the group and provide an alternative compound of Formula (I).

[0128] The resultant compounds of Formula (I), or sub-formulae (la) to (Ic), can be isolated and purified using techniques well known in the art.

[0129] The compounds of Formula (I) may be synthesised by the synthetic routes shown in the Examples section below.Biological Activity

[0130] The biological assays described in the Examples section herein may be used to measure the pharmacological effects of the compounds of the present invention.

[0131] 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 IKK-alpha in vitro assay described in the Examples section, with preferred compounds showing selectivity for IKK-alpha over IKK-beta.Pharmaceutical Compositions

[0132] According to a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of the invention as defined hereinbefore, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in association with a pharmaceutically acceptable diluent or carrier.

[0133] The compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular dosing or as a suppository for rectal dosing).

[0134] The compositions of the Invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and / or preservative agents.

[0135] 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.

[0136] The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the individual treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 0.5 g of active agent (more suitably from 0.5 to 100 mg, for example from 1 to 30 mg) compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition.

[0137] 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.

[0138] In using a compound of the invention for therapeutic or prophylactic purposes it will generally be administered so that a daily dose in the range, for example, 0.1 mg / kg to 75 mg / kg body weight is received, given if required in divided doses. In general lower doses will be administered when a parenteral route is employed. Thus, for example, for intravenous or intraperitoneal administration, a dose in the range, for example, 0.1 mg / kg to 30 mg / kg bodyweight will generally be used. Similarly, for administration by inhalation, a dose in the range, for example, 0.05 mg / kg to 25 mg / kg body weight will be used. Oral administration may also be suitable, particularly in tablet form. Typically, unit dosage forms will contain about 0.5 mg to 0.5 g of a compound of this invention.Therapeutic Uses and Applications

[0139] The present invention provides compounds that function as inhibitors of IKK activity, particularly IKKα activity. Accordingly, the compounds of the present invention are suitable for the treatment of any disease or condition in which the inhibition of IKKα activity is potentially beneficial.

[0140] IKKα activity is known to play a role In cancer.The role of IKKa In cancerIKKa in solid tumours

[0141] In recent years the role of the non-canonical NF-κB pathway and IKKα within it have increasingly been implicated in the development and progression of multiple solid tumours. The non-canonical NF-κB pathway has been associated with poor prognosis in glioblastoma

[0057] and mouse orthotopic models have demonstrated that up-regulation of this pathway is associated with an aggressive glioblastoma subtype

[0057] , In prostate cancer, nuclear localisation of RelB is associated with higher grade tumours

[0058] and treatment of prostate cancer cells with androgens induces accumulation of nuclear p52

[0059] , In addition, silencing of IKKα reduces androgen receptor activity and gene expression, providing evidence that IKKα is associated with prostate cancer growth

[0058] , Therefore, IKKα is an attractive target for prostate cancer as the androgen receptor is the main driver of prostate cancer proliferation and inhibition of cell death.

[0142] In pancreatic cancer, the non-canonical NF-κB pathway is constitutively activated and associated with increased cell proliferation

[0060] , NIK is elevated in pancreatic cancer and associated with increased proliferation [61, 62] and up-regulation of RelB and p52 are associated with mutated KRAS pancreatic cancer

[0063] with IKKα-dependent gene expression being observed. In gastrointestinal tumours NF-κB2DCT,DCTmice develop tumours spontaneously, providing evidence that p100 / p52 drives oncogenesis in this setting

[0064] , In renal cancer, members of the non-canonical NF-κB pathway are associated with poor prognosis, increased disease stage and decreased local inflammation

[0065] . In lung cancer, RelB is associated with shorter overall survival, differentiation, tumour invasion, lymph node metastasis, distant metastasis and ‘tumour, node, metastasis’ (TNM) stage

[0068] . In bladdercancer, up-regulation of RelB and p52 correlate with histological grade, stage and lymph node metastasis

[0069] ,

[0143] There are also numerous studies investigating IKKα in breast cancer. IKKα, RelB and p52 are associated with decreased cancer specific survival in ER-positive breast disease [70, 71], Bcl3 can form a DNA-binding complex with p52 and has been observed as over expressed in breast cancer samples. IKKα is demonstrated to play an essential role in the proliferation of mammary epithelium and it is therefore not surprising that aberrant IKKα signalling has been reported in breast cancer

[0072] , Yang et al. 2013 reports that in HER2 positive epithelial cells nuclear IKKα can promote progression to tumourogenesis via p27

[0073] , In transgenic mice, overexpression of p100 / 52 results in a delay of mammary gland development, which is accompanied with over expression of cyclin D1 , MMP2, MMP9 and COX-2 expression and results in the mice developing multiple tumours

[0074] , In addition, constitutive RANK signalling causes elevation of non-canonical NF-κB signalling in breast cancer cell lines, which subsequently stimulates cell proliferation via increased transcription of cyclin D1 [75-77] and nuclear IKKα expression is observed in invasive ductal carcinoma and associated with disease free survival. Immuno-histochemical studies have demonstrated that the p52 subunit is expressed at a higher level in the breast cancer tissue compared to normal adjacent tissue

[0078] and Western blots of nuclear fractions extracted from cancerous and adjacent normal breast tissue confirm an increase in p52 levels in the tumour cells

[0078] , This is accompanied by an increase in mRNA levels of p52, Bcl-3 and cyclin D1 , all genes regulated by IKKα

[0078] , In addition, IKKα has been demonstrated in cervical, lung, prostate and pancreatic cell lines to regulate mTORCI and mTORC2 which control tumour cell proliferation

[0079] . Taken as a whole, there is now a large body of evidence to support the role of the IKKO-NF-κB non-canonical pathway in the development and progression of solid tumours.IKKa signalling independent of NF-KB pathways in solid tumours

[0144] In addition to the role IKKα plays in NF-κB pathways, it is also reported to have a role independent of both the canonical and non-canonical NF-κB pathways. IKKα accumulates in the nucleus, where it can phosphorylate a variety of substrates including histone H3, SMRT and nuclear co-repressor (NCoR)

[0080] . In colorectal cancer, IKKα phosphorylates SMRT, resulting in increased expression of Notch dependent genes

[0080] . In addition, IKKα has been reported to be associated with NOTCH activation in the presence of anti-oestrogens in breast cancer, resulting in up-regulation of ER-dependent gene expression and providing a mechanism for hormone resistance in an NF-κB independent manner [81, 82], Bennett et al. reported that IKKα expression and not NIK or RelB is associated with recurrence in Luminal A breast cancer, suggesting it is independent of the non-canonical NF-κB pathway

[0071] , In a second cohort of patients who received tamoxifen, the authors reported that cytoplasmic IKKαwas associated with disease-free survival and recurrence-free survival on tamoxifen in LuminalA disease, which may predict patients likely to develop resistance to tamoxifen or IKKα targeted therapies

[0071] again supporting a role for IKKα in tamoxifen resistant breast cancer. In contrast however, Roseweir et al. reported in the Tamoxifen and Exemestane Adjuvant Multinational (TEAM) clinical trial cohort that low IKKα expression is associated with increased risk of recurrence on sequential tamoxifen / exemestane therapy, suggesting that the role of IKKα in hormone therapy resistance may change depending on the mechanism of action of the therapy the patient receives

[0083] ,

[0145] In gastric cancer, Helicobacter py / or / '-mediated NF-κB activation is thought to occur via an IKKα-linked pathway that is independent of the non-canonical NF-κB pathway, but involves both IKKα and NIK to up-regulate inflammatory infiltrate and promote tumourigenesis

[0084] , Studies of IKKα independent of the non-canonical NF-κB pathway in colorectal cancer and cutaneous squamous cell carcinoma have centred on a truncated form of IKKα (p45 IKKα) that is constitutively active and specifically resides in the nucleus [55, 56]. Bennett et al. observed that nuclear IKKα in breast cancer has a stronger predictive power than cytoplasmic IKKα, and proposed that this could be due to detection of the truncated activated form of p45 IKKα as the antibody employed was unable to distinguish between full length IKKα and the truncated p45 IKKα form

[0071] , Other studies of IKKα signalling independent of the non-canonical NF-κB pathway in colorectal cancer provide additional evidence that IKKα binds to Notch-dependent gene promoters to upregulate them and release chromatin-bound SMRT, which can be restored by inhibition IKKα and results in colorectal cancer xenografts shrinking in size

[0056] , It has been reported that the truncated p45 IKKα, forms a complex with full length IKKα and NEMO and is responsible for regulating phosphorylation of SMRT and histone H3 in an NF-κB- independent fashion. In addition, p45 IKKα may be phosphorylated in a TAK1 -dependent but NF-κB-independent manner in BRAFV600Emutant colorectal tumours

[0056] , so supporting a role for nuclear IKKα independent of non-canonical NF-κB signalling.

[0146] The nuclear role of IKKα Is consistently reported as being independent of NF-κB, by activating alternative pathways such as NOTCH

[0085] , This has been observed in breast cancer, skin cancer and osteosarcoma

[0086] , In liver cancer Hepatitis B virus X protein down- regulates maspin expression via nuclear IKKα resulting in chemoresistance, suggesting that targeting IKKα could re-sensitise HCC tumours to chemotherapy

[0087] , In transgenic adenocarcinoma of the mouse prostate (TRAMP) models of prostate cancer IKKα can translocate to the nucleus to promote metastasis and development of castrate resistant disease in a maspin dependent manner, which Is accompanied by a local inflammatory response

[0088] , Similar to breast cancer, in prostate cancer nuclear IKKα appears to provide a mechanism for hormone resistance as IKKα is associated with development of castrate resistant prostatecancer

[0053] and deletion of BAG3 which is required for IKKα nuclear translocation delays development of castrate resistant disease

[0089] .IKKa association with Hallmarks of cancer in human tumours

[0147] The NF-κB pathways regulate the transcription of a wide range of genes involved in the inflammation, proliferation and apoptosis. Many of these processes are hallmarks of cancer [46, 47] and NF-κB has been hypothesised to be a link between inflammation and tumourigenesis. Whether IKKα functions as a member of the non-canonical NF-κB pathway or in its NF-κB-independent roles, it is clear that it is involved with multiple hallmarks of cancer including key roles in innate and adaptive immune responses, cell survival, cell death and inflammation [90, 91], The non-canonical NF-κB pathway has key roles in regulating processes including production of lymphoid organs (responsible for B and T lymphocyte production), B-cell development and survival, dendritic cell function and bone metabolism

[0092] and has been reported to promote development and progression of cancers via promotion of inflammatory infiltrate. Mouse model studies have demonstrated that mice with a dominant-negative, catalytically-inactive IKKα, have reduced adenoma formation, smaller colorectal tumours with a lower proliferation index when treated with a carcinogen and this was associated with increased recruitment of macrophages and other immune cell types

[0093] . In skin cancer studies, IKKα has been demonstrated to induce inflammation-related genes

[0094] , In an additional study using a model of peritoneal metastasis in immune-competent mice, intraperitoneal injection with IκBα suppressed colon cells induced an M1-like macrophage phenotype, with reduced liver and peritoneal metastases in vivo. This was associated with increased intra-tumoural activated CD4* and CD8* T cells and reduced angiogenesis

[0093] , demonstrating that NF-κB pathways work with local inflammatory infiltrate to promote colorectal cancer progression. In renal cancer the inflammatory effects of the NF-κB pathway have mainly been attributed to the canonical p65 / p50 subunits in conjunction with STAT3. However, NIK and RelB have previously been shown to be crucial for B-cell development [2], suggesting that the non-canonical NF-κB pathway also plays a role and that RelB can modulate local inflammatory infiltrate in renal cell carcinoma. IKKα is also associated with promoting expression of pro-inflammatory cytokines such as IL-8 in prostate cancer

[0095] .

[0148] Kong et al. suggests that IKKα can be phosphorylated via deleted in breast cancer 1 (DBC1 ) to regulate B cell activation via RelB activity and causing increased cell proliferation in mice

[0096] , In addition, polymerase chain reaction (PCR) array-based gene transcriptional profiling experiments demonstrated that reducing cellular IKKα expression had a significant impact on increased expression of genes associated with induction of apoptosis, in particular BAK1 and BBC3, providing evidence that IKKα is involved regulating both cell proliferation and apoptosis in ER positive breast cancer. Dan et al. demonstrates that IKKα via mTORC caninduce cell proliferation in cervical, lung, prostate and pancreatic cell lines

[0079] and in basal cell carcinoma IKKα is associated with proliferation and EMT

[0094] . Studies in vitro also demonstrate that ovarian cancer epithelial cell proliferation, migration and an invasive phenotype of the cancer were promoted via up-regulation of IKKα. In addition, NIK levels have been associated with regulating both cell proliferation and apoptosis in colorectal cancer, demonstrating that the non-canonical NF-κB pathway is involved in cell viability and tumour growth

[0097] ,IKKa in haematological malignancies

[0149] Aberrant NF-κB signalling and associated gene transcription that modulate cellular processes involved in the initiation, maintenance and progression of human malignancies are also common to haematological cells and cancers. In this regard, many B-cell leukaemias and lymphomas display abnormal NF-κB activation, implicating this family of transcription factors in these diseases and suggesting regulation of these proteins may represent promising therapeutic targets. In addition, it is now appreciated that conventional cytotoxic agents can increase NF-κB activation, contributing to the development of drug resistance via a number of distinct mechanisms. Therefore, inhibitors that target NIK-IKKα-mediated signalling may prove clinically useful as single agents and also to re-sensitise patients to chemotherapeutic drugs. Given the frequency of genetic mutations in the non-canonical NF-κB pathway and its critical role in tumour microenvironmental signalling, IKKα represents an attractive anti-cancer target.

[0150] Chronic lymphocytic leukaemia (CLL) is the commonest leukaemia in Europe and North America. It is characterised by the accumulation of mature-looking CD57CD19* B lymphocytes in the peripheral blood, bone marrow, and lymphoid tissues

[0105] . NF-κB is constitutively activated in many CLL patients and this is associated with more aggressive disease [106, 107], A number of recurrent genetic mutations in NF-κB-associated genes have been described in CLL. The most common of these is an Inactivating mutation In NFKBIE that encodes IκBE, a negative NF-κB regulator. These NFKBIE aberrations are found in approximately 7% of CLL cases and predominantly occur in poor-prognostic subgroups. This may be causal as mutations in NFKBIE result in increased nuclear translocation of RelA

[0108] . NOTCH1 mutations occur at an even higher frequency in CLL (-11%). These activating mutations are associated with poor response to chemotherapy

[0109] and this may be caused by NOTCH 1 -mediated NF-κB pathway activation [110-112]. BIRC3 mutations are found in a smaller proportion of CLL patients (~4%) but they impact upon the non-canonical NF-κB pathway due to the premature truncation of the BIRC3-encoded protein product, clAP2, resulting in the loss of its E3 ubiquitin ligase activity that is essential for NIK proteasomal degradation. As a consequence, NIK levels increase leading to the phosphorylation of IKKα, NF-κB2, the processing of p100 to p52 and the constitutive activation of non-canonical NF-κBsignalling

[0113] . Importantly, BIRC3 mutations are associated with loss of sensitivity to chemotherapy and poor prognosis

[0114] ,

[0151] In addition to the genetic causes of NF-κB dysregulation in CLL, it is now understood that the lymph node microenvironment plays a critical role in modulating the natural pathology of this disease. Signalling via the B-cell receptor (BCR), toll-like receptors (TLR) and CD40, as well as engagement of the BAFF and a proliferation-inducing ligand (APRIL) receptors TACI, BAFF-R and BCMA, create a pro-survival, pro-proliferative niche mediated by NF-κB activation [116, 117], The importance of this microenvironment is perhaps best exemplified by the remarkable clinical effects of the Bruton’s tyrosine kinase inhibitor ibrutinib. Treatment with this drug results in a marked tissue redistribution effect with leukaemia cells being excluded from the lymphoid tissues

[0118] , The partitioning of the tumour away from the sites of increased NF- κB signalling results in durable remissions, an effect that is reversed on drug withdrawal.

[0152] Diffuse large B-cell lymphomas (DLBCL) are the most common types of non-Hodgkin lymphoma. They are divided into three molecular sub-types: ABC (activated B-cell), GCB (germinal centre B-cell) and PMBL (primary mediastinal B-cell lymphoma). Initial evidence for the role of the canonical NF-κB pathway in DLBCL came from gene expression profiling studies, which showed enrichment for NF-κB target genes in the ABC sub-type. This group has the worst prognosis implicating NF-κB as a modulator of clinical outcome in DLBCL

[0123] , Constitutive NF-κB activation in the ABC sub-type can result from mutations in components of the BCR signalling cascade, which results in chronic BCR activation. These mutations often occur in the immunoreceptor tyrosine-based motif (ITAM) but also in the coiled-coil domain of the CARD11 / CARMA1 gene

[0124] , Finally, MYD88 gene mutations are found in approximately 30% of the ABC sub-type resulting in spontaneous activation of the downstream IRAK complex and NF-κB activation

[0125] . The non-canonical NF-κB pathway is also aberrantly dysregulated in 10-15% of DLBCL cases due to TRAF2 and TRAF3 mutations

[0126] and consequently identifies a sub-population of tumours that may be targetable via IKKα.

[0153] Multiple myeloma (MM) is an Incurable plasma cell malignancy accounting for approximately 13% of all haematological cancers. Disease progression involves clonal expansion of transformed plasma cells in the bone marrow. Overall, genetic abnormalities leading to constitutive NF-κB activity have been found in approximately 20% of MM patients and 40% of MM cell lines [127-129]. Most of the genetic abnormalities relating to NF-κB dysregulation in MM involve the non-canonical NF-κB pathway including aberrant expression of NIK, CD40, TRAF2, TRAF3, transmembrane activator and CAML interactor (TACI) and clAP1 / 2 [127, 128], In these studies, the majority of MM cases possessed overexpression of the positive NF-κB regulators NIK, TACI and CD40, or reduced or silenced activity of the negative NF-κB regulators TRAF2, TRAF3 and clAP1 / 2. All of these phenotypes contribute to increasedNF-κB signalling, with a preference towards non-canonical NF-κB signalling [128, 129]. In addition, other less common genetic abnormalities that also lead to constitutive NF-κB signalling in MM have been identified. These included high expression of the NFKB1 gene (p105) and abnormalities within the NFKB2 gene (p100), which results in increased canonical and non-canonical NF-κB signalling, respectively [127-129].

[0154] Although genetic abnormalities can explain some of the high NF-κB activity in MM, it is likely that a substantial portion of the NF-κB signalling in this disease arises as a consequence of interactions within the bone marrow microenvironment

[0129] , One such mechanism for NF- κB activation is via CD40-CD40L interactions [130, 131], CD40 is a cell surface marker not usually expressed on normal plasma cells but has been shown to be increased in the early stages of MM

[0132] , Furthermore, blocking the interaction of CD40 with CD40L decreases NF- κB activation

[0127] , This results in the inhibition of IL-6 and vascular endothelial growth factor (VEGF) secretion, which in turn leads to growth arrest and cell death of MM cells

[0133] . Furthermore, the bone mmaarrrrooww stromal cells (BMSC) found in the MM tumour microenvironment have also been found to express high levels of NF-κB activation that helps to support the proliferation, survival and drug resistance of malignant plasma cells within the bone marrow niche

[0134] . Adherence of MM cells to BMSCs induces NF-κB -dependent cytokine transcription and secretion of TNFa, IL-6, VEGF, RANKL and BAFF, to promote MM cell survival and growth through MM cell NF-κB activation [135, 136],References:

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[0155] Thus, according to a further aspect of the present invention, there is provided a method of inhibiting IKKα activity, in vitro or in vivo, said method comprising contacting a cell with an effective amount of a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein.

[0156] According to a further aspect of the present invention, there is provided a method of treating a disease or disorder in which IKKα activity is implicated in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.

[0157] According to a further aspect of the present invention, there is provided a method of treating a proliferative disorder in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.

[0158] 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.

[0159] According to a further aspect of the present invention, there is provided a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein, for use in therapy.

[0160] According to a further aspect of the present invention, there is provided a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein, for use as a medicament.

[0161] According to a further aspect of the present invention, there is provided a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein, for use in the treatment of a proliferative disorder.

[0162] According to a further aspect of the present invention, there is provided a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein for use in the treatment of cancer. In a particular embodiment,the cancer Is human cancer.

[0163] According to a further aspect of the present invention, there is provided a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein for use in the inhibition of IKKα activity.

[0164] According to a further aspect of the present invention, there is provided a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein for use in the treatment of a disease or disorder in which IKKα activity is implicated.

[0165] 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 disorder.

[0166] 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 cancer.

[0167] According to a further aspect of the present invention, there is provided a use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein in the manufacture of a medicament for the inhibition of IKKα activity.

[0168] According to a further aspect of the present invention, there is provided a use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein in the manufacture of a medicament for the treatment of a disease or disorder in which IKKα activity is implicated.

[0169] According to a further aspect of the present invention, there is provided a process for preparing a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein.

[0170] According to a further aspect of the present invention, there is provided a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, obtainable by, or obtained by, or directly obtained by a process of preparing a compound as defined herein.

[0171] 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.

[0172] The term "proliferative disorder", “proliferative condition" and “proliferative disease” are used interchangeably herein and pertain to an unwanted or uncontrolled cellular proliferation of excessive or abnormal cells which is undesired, such as, neoplastic or hyperplastic growth, whether in vitro or in vivo.

[0173] In the above-outlined aspects of the invention, the proliferative disorder is suitably cancer, and the cancer is suitably a human cancer. In particular, the compounds of the present invention will be useful for the treatment of any cancer in which a mls-match repair Inhibition is beneficial. Any suitable cancer may be targeted (e.g. adenoid cystic carcinoma, adrenal gland tumor, amyloidosis, anal cancer, appendix cancer, astrocytoma, ataxia-telangiectasia, Beckwith-Wiedemann Syndrome, bile duct cancer (cholangiocarcinoma), Birt-Hogg-Dube Syndrome, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, Carney Complex, central nervous system tumors, cervical cancer, colorectal cancer, Cowden Syndrome, craniopharyngioma, desmoplastic infantile ganglioglioma, ependymoma, esophageal cancer, Ewing sarcoma, eye cancer, eyelid cancer, familial adenomatous polyposis, familial GIST, familial malignant melanoma, familial non-VHL clear cell renal cell carcinoma, familial pancreatic cancer, gallbladder cancer, gastrointestinal stromal tumor - GIST, germ cell tumor, gestational trophoblastic disease, head and neck cancer, hereditary breast and ovarian cancer, hereditary diffuse gastric cancer, hereditary leiomyomatosis and renal cell cancer, hereditary mixed polyposis syndrome, hereditary pancreatitis, hereditary papillary renal carcinoma, juvenile polyposis syndrome, kidney cancer, lacrimal gland tumor, laryngeal and hypopharyngeal cancer, leukemia (acute lymphoblastic leukamia (ALL), acute myeloid leukemia (AML), B-cell prolymphocytic leukemia, hairy cell leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic T-cell lymphocytic leukemia, eosinophilic leukemia), Li-Fraumeni Syndrome, liver cancer, lung cancer (non-small cell lung cancer, small cell lung cancer), Lymphoma (Hodgkin, non-Hodgkin), Lynch Syndrome, mastocytosis, medulloblastoma, melanoma, meningioma, mesothelioma, multiple endocrine neoplasia Type 1 & 2, multiple myeloma, MUTYH (or MYH)-associated polyposis, myelodysplastic syndromes (MDS), nasal cavity and paranasal sinus Cancer, nasopharyngeal Cancer, neuroblastoma, neuroendocrine tumors (e.g. of the gastrointestinal tract, lung or pancreas), neurofibromatosis Type 1 & 2, nevoid basal cell carcinoma syndrome, oral and oropharyngeal cancer, osteosarcoma, ovarian / fallopian tube / peritoneal cancer, pancreatic cancer, parathyroid cancer, penile cancer, Peutz-Jeghers Syndrome, pheochromocytoma, paraganglioma, pituitary gland tumor, pleuropulmonary blastoma, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma (e.g. Kaposi or soft tissue), skin cancer, small bowel cancer, stomach cancer, testicular cancer, thymoma and thymic carcinoma, thyroid cancer, tuberous sclerosis complex, uterine cancer, vaginal cancer, Von Hippel-Lindau syndrome, vulvar cancer, Waldenstrom’s macroglobulinemia, Werner syndrome, Wilms Tumor and xeroderma pigmentosum). Particular cancers of interest include haematological cancers such as lymphomas (including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), Burkitt lymphoma (BL) and angiolmmunoblastlc T-cell lymphoma (AITL)), leukaemias (including acute lymphoblastic leukaemia (ALL) and chronic myeloidleukaemia (CML)), multiple myeloma, breast cancer, non-small cell lung cancer (NSCLC), colorectal cancer, endometrial cancer, gastro-oesophageal cancer, neuroendocrine cancers, osteosarcomas, prostate cancer, pancreatic cancer, small intestine cancer, bladder cancer, rectal cancer, cholangiocarcinoma, CNS cancer, thyroid cancer, head and neck cancer, oesophageal cancer, and ovarian cancer.

[0174] Particular cancers in which IKKα inhibition is anticipated to be beneficial include advanced prostate cancer, multiple myeloma, pancreatic cancer, colorectal cancer (especially metastatic colorectal cancer) and breast cancer (especially triple negative breast cancer).

[0175] Prostate cancer is of particular interest as potential therapeutic target for IKKα inhibitors. Without wishing to be bound by any particular theory, in prostate cancer, the effective targeting of IKKα may enhance androgen deprivation therapy (ADT) chemotherapy responses by concurrently inhibiting androgen-driven and androgen-independent AR (androgen receptor) activity. IKKα inhibition may also abrogate inflammatory microenvironment signalling and eliminate tumour-promoting stimuli from adjacent stroma and infiltrating monocytes. IKKα inhibitors therefore have the potential to alter disease course, restore / prolong sensitivity to AR- targeted therapy and improve survival. Moreover, their use in hormone-sensitive de novo metastatic disease may significantly extend the benefit duration of conventional therapies and reduce the overall incidence of castration-resistant prostate cancer (CRPC). As a consequence, a IKKα inhibitor may find use in clinical scenarios such as:• the last-line therapy in patients with CRPC that have failed standard-of-care treatment• combination therapy with ADT to prevent the emergence of CRPC / prolong sensitivity to ADT• combination therapy in CRPC patients to restore sensitivity to ADT / reduce resistance development to chemotherapy• single-agent therapy to prevent the emergence of CRPCRoutes of Administration

[0176] The compounds of the invention or pharmaceutical compositions comprising these compounds may be administered to a subject by any convenient route of administration, whether systemically, peripherally or topically (i.e., at the site of desired action).

[0177] Routes of administration include, but are not limited to, oral (e.g, by ingestion); buccal; sublingual; transdermal (including, e.g., by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or insufflation therapy using, e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, for example, by injection, including intratumoral, subcutaneous, intradermal, intramuscular, intravenous, intra-arterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal,subcuticular, intraarticular, subarachnoid, and intrasternal; by implant of a depot or reservoir, for example, subcutaneously or intramuscularly.Combination Therapies

[0178] The compounds of the present invention may be administered as a sole therapy or may involve, in addition to a compound of the invention, conventional surgery or radiotherapy or chemotherapy or a targeted agent. Such chemotherapy or targeted agent may include one or more of the following categories:(i) Antiproliferative / antineoplastic drugs and combinations thereof, as used in medical oncology, such as, but not limited to, alkylating agents (for example cis-platin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan, temozolamide and nitrosoureas); antimetabolites (for example gemcitabine and antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, and hydroxyurea); antitumour antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine and taxoids like taxol and taxotere and polokinase inhibitors); and topoisomerase inhibitors (for example epipodophyllotoxins like etoposide and teniposide, amsacrine, topotecan and camptothecin);(ii) cytostatic agents such as, but not limited to, antioestrogens (for example tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), steroid hormones, including progestogens (for example megestrol acetate) and corticosteroids (for example dexamethasone, prednisone and prednisolone), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5a-reductase such as finasteride;(iii) anti-invasion agents such as, but not limited to, c-Src kinase family inhibitors 4-(6-chloro- 2,3-methylenedioxyanilino)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-tetrahydropyran-4- yloxyquinazoline (AZD0530; International Patent Application WO 01 / 94341 ), N-(2-chloro- 6-methylphenyl)-2-{6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4- ylamino}thiazole-5-carboxamide (dasatinib, BMS-354825; J. Med. Chem., 2004, 47, 6658-6661 ), bosutinib (SKI-606), and metalloproteinase inhibitors such as marimastat, inhibitors of urokinase plasminogen activator receptor function or antibodies to Heparanase;(iv) inhibitors of growth factor function such as, but not limited to, growth factor antibodies and growth factor receptor antibodies (for example the anti-erbB2 antibody trastuzumab [Herceptin™], the anti-EGFR antibody panitumumab, the anti-erbB1 antibody cetuximab [Erbitux, C225] and any growth factor or growth factor receptor antibodies disclosed by Stern et al. (Critical reviews in oncology / haematology, 2005, Vol. 54, pp11-29); such inhibitors also include tyrosine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as N-(3- chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (gefitinib, ZD1839), N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) aanndd 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)- quinazolin-4-amine (Cl 1033), erbB2 tyrosine kinase inhibitors such as lapatinib); inhibitors of the hepatocyte growth factor family; inhibitors of the insulin growth factor family; inhibitors of the platelet-derived growth factor family such as imatinib and / or nilotinib (AMN107); inhibitors of serine / threonine kinases (for example Ras / Raf signalling inhibitors such as farnesyl transferase inhibitors, for example sorafenib (BAY 43-9006), tipifarnib (R115777) and lonafarnib (SCH66336)), inhibitors of cell signalling through MEK and / or AKT kinases, c-kit inhibitors, abl kinase inhibitors, PI3 kinase inhibitors, Plt3 kinase inhibitors, CSF-1R kinase inhibitors, IGF receptor (insulin-like growth factor) kinase inhibitors; aurora kinase inhibitors and cyclin dependent kinase inhibitors such as CDK2 and / or CDK4 inhibitors;(V) antiangiogenic agents such as, but not limited to, those which inhibit the effects of vascular endothelial growth factor, [for example the anti-vascular endothelial cell growth factor antibody bevacizumab (Avastin™) and for example, a VEGF receptor tyrosine kinase inhibitor such as vandetanib (ZD6474), vatalanib (PTK787), sunitinib (SU11248), axitinib (AG-013736) and pazopanib (GW 786034).(vi) vascular damaging agents such as, but not limited to, Combretastatin A4 and compounds disclosed in International Patent Applications WO 99 / 02166, WO 00 / 40529, WO 00 / 41669, WO 01 / 92224, WO 02 / 04434 and WO 02 / 08213;(vii) an endothelin receptor antagonist, for example zibotentan (ZD4054) or atrasentan;(viii) antisense therapies, such as, but not limited to, those directed to targets listed above, such as ISIS 2503, an anti-ras antisense;(ix) immunotherapy approaches, including for example cancer vaccines, antibody, viral (oncolytic viruses) and small molecule or cell therapy approaches to increase the immunogenicity of patient tumour cells and / or facilitate a cell mediated anti-tumour response. Such therapies could include, but are not limited to, 0X40 agonists, cGAS-STING agonists, A2a receptor antagonists, PI3 kinase inhibitors, TLR7 / 8 agonists, IDO inhibitors, Arginase inhibitors, BTK inhibitors and Bromodomain inhibitors; transduction with microbial vectors of cancer antigens, direct transduction of cancer antigens into antigen presenting cells, treatment with immune cells specific for cancer antigens (e.g. CAR-T), treatment with antibodies, antibody fragments and antibody drug conjugates that enable the immune system to recognise tumour cells.

[0179] The compounds of the present invention are anticipated to be particularly useful in combination with androgen deprivation therapies (ADTs) and standard chemotherapy used to treat prostate cancer and, in particular, castrate-resistant prostate cancer (CRPC).

[0180] 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.

[0181] According to this aspect of the invention there is provided a combination for use in the treatment of a cancer (for example a cancer involving a solid tumour) comprising a compound of the invention as defined hereinbefore, or a pharmaceutically acceptable salt or solvate thereof, and an anti-tumour agent.

[0182] 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 or solvate thereof, and any one of the anti-tumour agents listed herein above.

[0183] In a further aspect of the invention there is provided a compound of the invention or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of cancer in combination with another anti-tumour agent, optionally selected from one listed herein above.

[0184] In a further aspect of the invention there is provided a compound of the invention or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of cancer in combination with a tyrosine kinase inhibitor, optionally selected from one listed herein above.

[0185] Herein, where the term “combination" is used it is to be understood that this refers to simultaneous, separate or sequential administration. In oonnee aspect of the invention “combination” refers to simultaneous administration. In another aspect of the invention “combination” refers to separate administration. In a further aspect of the invention“combination” refers to sequential administration. Where the administration is sequential orseparate, the delay in administering the second component should not be such as to lose the beneficial effect of the combination.

[0186] 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 or solvate thereof, in combination with an anti-tumour agent (optionally selected from one listed herein above), in association with a pharmaceutically acceptable diluent or carrier.EXAMPLESInhibitor design and structure-activity relationship

[0187] To design ligands with selectivity for IKKα over IKKβ, their ATP-binding sites were superimposed and compared to identify specific differences between the two isoforms that could be exploited. When aligning the primary sequences in this region (residues 6 - 180, IKKα; and 1 - 180, IKKβ), it Is striking to see the level of homology between the two isoforms: 62.8% sequence identity and 77.2% sequence similarity with both having Met as the GK residue, and GK+1 / GK+3 as Glu and Cys respectively (Figure 1). However, given the number of reported structurally diverse compounds that are selective for IKKβ over IKKα that bind in or close to the ATP-binding site [1-3], there are clearly differences in the two ATP-binding sites to impart such selectivity. To explore these differences, we superimposed the kinase domain of IKKβ using the 4KIK.pdb chain B crystal structure [4] that contains two phosphorylated Ser residues in its activation loop, with the equivalent domain from IKKα taken from the SEBZ.pdb coordinates (Figure 1). To date, no group has been able to successfully crystallise IKKα and report a high-resolution structure, but Polley and co-workers [5] have generated structures of IKKα in dimeric (-150 kDa) and hexameric (-450 kDa) forms using a combination of X-ray crystallography and single-particle cryoelectron microscopy to 4.5 A. This was achieved using a recombinant form of the protein where both Ser amino acids in the activation loop had been mutated to Glu residues, thus representing a constitutively activated form of the kinase that could be superimposed with the IKKβ 4KIK crystal structure. Whilst the resolution of the IKKα structure is lower than IKKβ, encouragingly it mapped very well with the homology model we had previously reported to successfully guide structure-based inhibitor design [6].

[0188] Figure 1 shows superimposition of the IKKα (light grey) and IKKβ (dark grey) ATP- binding sites taken from SEBZ.pdb and 4KIK.pdb, respectively). A, top view of IKKα superimposed onto IKKβ binding site showing dislocation of the IKKβ G-loop containing Thr 23 (dark grey) from the IKKα position (light grey), indicated by the double-headed red arrow; B, 90° rotation to show the front view of both superimposed isoforms, with the twisted Thr 23- containing G-loop of IKKβ displaced towards the N-lobe above the ATP binding site (doubleheaded arrow). C, sequence alignment of ATP binding site amino acid residues of both IKKα and IKKβ (rmsd 1.393), with levels of similarity colour-coded as indicated.

[0189] Despite the high sequence homology, a key difference between the two isoforms involves the Thr 23-containing G-loop that is opposite the hinge-binding region, which by adopting different positions, imposes a dissimilar topography on the sites (Figure 1). In IKKα, this G-loop forms an intact wall to enclose the site on three sides (the third involving the Met 95 GK residue shown on the left in Figure 1A), and which offers additional binding sites to a ligand (Figure 2A, B). In IKKβ, this sequence is twisted and displaced to the upper section of the binding pocket (Figure 2C), which removes the wall from the opposite side of the hinge-binding region seen in IKKα and exposes the site to solvent on two sides. Whilst hydrophilic groups could potentially be accommodated in this solvent region to promote binding with IKKβ, the occlusion wall in IKKα offers putative interaction sites that could be exploited to favour binding with this isoform. Furthermore, the twisting of the G-loop in IKKβ to open up the site to solvent results in Thr 23 encroaching into the site itself to create an obstructive bulge that any ligand moiety accessing the solvent area would need to negotiate (Figure 2D). Finally, because IKKβ is exposed to solvent on two sides, there is a greater number of residues proximal to the site interior available for ligand binding (Asn 28, Asp 103, Asp 145, Lys 147, Asn 150 and Asp 166, Figure 2C) compared to that of IKKα, which only has one accessible residue; Asp 102, Figure 2B). In summary, IKKα has a more enclosed site, only open on one side to solvent adjacent to the hinge, whereas IKKβ is more open to solvent on two sides, although with a Thr 23 protrusion that interrupts contiguous solvent access from both (Figure 2D).

[0190] Figure 2 shows 3D crystal structures of the ATP binding sites of both IKKα and IKKβ (PDB ID: 5EBZ and 4KIK, respectively). A, top view of the IKKα binding site showing the hinge region at the base with the GK, GK+1 and GK+3 highlighted (Met 95, Glu 96 and Cys 98, respectively) and the G-loop segment at the top to form a wall opposite the hinge, with Thr 23 and Glu 148 highlighted; B, rotation by 90° to reveal the front view of the IKKα binding site from the solvent-accessible area, with the hinge region at the base. Asp 102 is the principal residue at the lip of this region available for ligand binding; C, top view of the IKKβ binding site showing the hinge region at the base and in the same position as IKKα, with Met 96, Glu 97 and Cys 99 highlighted. Thr 23 and Asn 28 from the G-loop are labelled, along with residues that line the lips of the two solvent exposed regions. D, rotation by 90° to reveal the front view of the IKKβ binding site, again with the hinge region at the bottom. The black dashed circle highlights the obstructive bulge from Thr 23 that must be negotiated to access the revealed solvent region, and the large number of residues that are presented at the lips of both solvent exposed areas (Asn 28, Asp 103, Asp 145, Lys 147, Asn 150 and Asp 166). The black circle in B and D showsthat the equivalent position of Thr 23 in IKKα does not protrude into the site, but instead forms the back wall to block off solvent access from the top completely.

[0191] In 2008, the aminoindazole-pyrrolo[2,3-b]pyridine (AIPP) core scaffold was identified as an inhibitor of both IKKα and IKK|3, but without revealing its potency, other than to state submicromolar activity against both isoforms in a cell-free, time-resolved FRET assay[7]. In 2017, we had identified that compound 1 SU909, a pyrrolo[2,3-d]pyrimidine, was a selective inhibitor of IKKα that recapitulated this discrimination in U2OS cells[6). To examine the pyrrolo[2,3- b]pyridines as an alternative scaffold, we adopted the AIPP core because it had similar dimensions to 1 SU909, with HBD / HBA motifs positioned at the scaffold extremities to interact with both the hinge region and the G-loop wall of IKKα, a rationale we had previously proposed as the basis for imparting selectivity. A preliminary set of AIPP derivatives was designed to explore its utility as an IKK-targeting scaffold, whilst incorporating additional functionality through which to introduce selectivity for the IKKα isoform (2-4 SU1087, SU1266 and SU1253; Figure 3). This was achieved by initially adopting two different approaches: either appending a hydrophobic moiety to the pyrrolo[2,3-b]pyridine m-tif as a fused form to afford the tricyclic derivatives 2 and 3 SU1266 and SU1087, or as a phenyl substituent to introduce flexibility with the central pyrrolo[2,3-b]pyridine moiety in 4 SU1253. When assessed against IKKα and IKKβ using our in-house DELFI A kinase assay[6] (Table 1), all three compounds showed excellent inhibitory activity against IKKα (Ki2-3 nM), which was significantly more potent than our previous hit 1 SU909 (80 nM). However, unlike 1 SU909, they had poor selectivity, inhibiting IKKβ at low nanomolar concentrations (Ki5-77 nM). This comparable activity against both isoforms could be explained by our docking studies, with all three compounds adopting similar poses in the ATP binding site of both IKKs. The pyrrolo[2,3-b]pyridine was bound to the hinge region in the classical HBA / HBD motif with the GK+3 NH and C=O backbone, whilst the aminoindazole projected towards the top of the pocket to interact with the G-loop (Figure 4A). Notably, in IKKα, the aminoindazole ring formed two HBD / HBA interactions with Thr 23 and Glu 148 in the occluded wall of the site, whereas in IKK(3, because the G-loop is rotated and there is no equivalent wall, these interactions were absent. Moreover, in IKKβ there is a noticeable shift of the whole scaffold towards the solvent-exposed regions (Figure 4B) for the aminoindazole to form a H-bond with Asp 103, which presumably compensates for the absence of any interaction with the G-loop wall and increases activity to a level comparable with IKKα. In both isoforms, the 2-phenyl moiety was oriented out from the hinge towards the exposed solvent area.

[0192] Figure 3 shows the rationale for the design of the preliminary test set of AIPPs used in this study. Tricyclic derivatives of the AIPP-based scaffold with fused hydrophobic groups were designed to study the effect of co-planarity on binding (5a, b SU1266 and SU1087). A derivative86 with a sigma bond spacer separating the hydrophobic group from the AIPP was designed to assess flexibility (5c SU1253).Table 1. The Kivalues (nM) for the preliminary test set (5a-c) against IKKa and IKKβ.

[0193] Figure 4. The predicted binding poses for 4 SU1253 with IKKa (A) and IKKβ (B). A, the pyrrolo[2,3-b]pyridine binding motif was directed to the hinge region and exhibited two H- bond interactions with Cys 98 (2.02 and 2.14 A). The aminoindazole binding motif was anchored to the G-loop by two H-bond interactions with Thr 23 (2.38 A) and Glu 148 (2.21 A) that make up the occluded wall. The 2-phenyl ring was exposed to the solvent area and exhibited hydrophobic interactions with the non-polar amino acid residues at this site (Leu 21 and Vai 151); B, 4 SU1253 in the IKKβ active site showed the same binding pose to that of IKKa. The pyrrolo[2,3-b]pyridine ring had two interactions with Cys 99 (2.58 and 2.72 A) in the hinge region, but whilst the aminoindazole was orientated towards the G-loop, it only interacted with Asp 103 (2.48 A) in the solvent exposed area, which was occluded in IKKa.

[0194] To shift the selectivity profile towards IKKa, we selected 4 SU1253 for structural optimization based on the notion that sigma-bond rotation between the phenyl ring and the pyrrolo[2,3-b]pyridine would inbuild the flexibility required to engage with the three dimensional array of residues nearby to exploit differences between the two isoforms. Furthermore, this would enable the inclusion of moieties that could also project into solvent and address solubility considerations. Small groups (NH2, OH, OMe, OEt and F) were initially introduced into the phenyl ring to evaluate their impact on the selectivity profile against both IKKs (5a-g SU1354 - SU1373, Table 2). Our goal was to achieve a 1 :50 selectivity ratio of IKKa to IKKp, with a minimum IKKβ inhibitory Kiof 500 nM.Table 2. Kivalues for series 1 compounds (5a-aa) against IKKα and IKKβ .

[0195] Not surprisingly, this minimal change in the structure did not improve the selectivity profile, which was supported by docking studies. 5a-g SU1354 - SU1373 all adopted similar binding poses to 4 SU1253, with no discriminatory interactions between these substituents and the key amino acid residues lining the solvent exposed area. Crucially however, they did not compromise activity, and offered handles for further derivatisation with substituents containing appropriately positioned HBDs and NBAs that could exploit differences between each isoform (5h-o SU1303 - SU1367; Table 2). With this set, a noticeable difference in activity between the two isoforms emerged, which appeared to be related to substituent size. Docking studies suggested that in IKKα, when the steric bulk of substituents appended to the phenyl ring was increased, the AIPP core scaffold adopted a new pose, which was essentially a 180° flip from the 4 SU1253 pose and exemplified by 5o SU1367 (Figure 5A). Here, the aminoindazole is now in the hinge region forming two H-bonds with GK+1 , penetrating deeper in the binding site (Figure 5A), and the pyrrolo[2,3-b]pyridine forms H-bonds with Thr 23 and Glu 148 in the G- loop wall. The phenyl ring and its pendant substituent point towards the solvent-exposed region and gain an additional HB interaction between the ether handle and Asp 102, potentially justifying this inversion (Figure 5A). It appears that bulky substituents appended to the phenyl handle do not permit adoption of the 4 SU1253 pose because the opening to the solvent adjacent to the hinge in IKKα is too narrow to accommodate the bulk. Docking of this bulkier series into IKKβ can explain why activity against this isoform is reduced and selectivity improved. Significantly, no poses with the aminoindazole or the pyrrolo[2,3-b]pyridine H- bonding with GK+1 or GK+3 were generated. We attribute this to the Thr 23 bulge in IKKβ preventing the inverted pose exemplified by 5o SU1367 in IKKα (Figure 5A) or the pose for 4 SU1253 (Figure 4B) from being adopted. This protrusion will not allow the phenyl group and its bulky pendant substituent to orientate into the tunnel towards the solvent whilst concomitantly having either heterocycle in the AIPP scaffold engaging with the hinge via the conventional kinase-binding HBD / HBA motif. The only pose identified for IKKβ involved a hook-likeconformation around the displaced Thr 23 protrusion, with the aminoindazole accessing the solvent under the G-loop, the phenyl substituent accessing the solvent from the hinge, but without there being any HBD / HBA interaction with the hinge region itself (Figure SB), which could explain the drop in potency.

[0196] Figure 5 shows the proposed binding orientations of 5o SU1367 to explain its selectivity for IKKα over IKKβ (Ki19 and 458 nM, respectively). A, A flipped binding orientation was observed compared to 4 SU1253 in IKKα. The aminoindazole binding motif was directed to the hinge region and showed two interactions with Cys 98 (1.89 and 2.43 A). The pyrrolo[2,3- b]pyridine ring displayed two interactions with Thr 23 and Glu 148 (2.05 and 2.25 A) in the occluded wall opposite. The pendant HBA-containing substituent interacted via H-bonding Asp 102 (3.31 A) in the solvent-exposed area; B, 5o SU1367 did not display any poses that formed conventional H-bonds to the hinge residues via either the aminoindazole or the pyrrolo[2,3- 6]pyridine moiety in IKKβ. Instead, a new orientation was generated that displayed a hook-like pose around the Thr 23 G-loop bulge that is unique to IKKβ. Here, the aminoindazole is directed into the solvent on one side of the Thr 23 protrusion and the bulky pendant substituent orientated into solvent on the other side of the bulge to form one H-bond between the ether and Asp 103 (3.34 A). C, 2D diagram of 5o SU1367 in the IKKα active site showing the occluded wall in the G-loop region that affords additional interactions with the pyrrolo[2,3-b]pyridine binding motif. H-bonds to key residues are shown as dashed lines; D, 2D diagram of 5o SU1367 in the IKKβ active site to illustrate the hook-like pose around the Thr 23 bulge that separates the two solvent exposed regions. The absence of any H-bonding to the hinge residues in this pose could explain the poor affinity of compounds with a bulky hydrophobic substituent for IKKβ.

[0197] Encouraged by the observation that compounds with larger phenyl pendant substituents (5n,o SU1550 and SU1367) tended to improve selectivity, we set out to explore whether increasing steric bulk could enhance the window further. We incorporated a range of moieties with varying degrees of saturation, bearing a diverse array of HBAs and HBDs (5p-aa SU1278 - SU1283) to further develop the SAR and the selectivity profile. The general trend observed upon increasing the steric bulk was a more pronounced reduction in IKKβ activity, with the potency generally holding up for IKKα to markedly increase selectivity across the series. The docking results for these compounds were consistent with our earlier observations: binding to IKKα inevitably returned the flipped pose wherein the aminoindazole is bound to the hinge region (Sr SU1261, Figure 6A) for each of the more sterically hindered analogues. Moreover, increasing the bulk of the phenyl substituents generally prevented any effective binding to the hinge region by the aminoindazole or pyrrolo[2,3-ti]pyridine in IKKβ, other than the unfavourable hook-like conformation around the displaced Thr 23 protrusion seen for 5oSU1367, and no H-bonding to the hinge region. This pose was consistent for those compounds that displayed the lowest activity against IKKβ (5o-r, t, w SU1367, SU1278, SU1549, SU1353, SU1324, and SU1261).

[0198] Figure 6 shows the predicted 3D binding pose for 5r SU1261 with IKKα (A) and 5x SU1335 with IKKβ (B) A, the aminoindazole binding motif of 5r SU1261 was situated at the hinge region of IKKα, exhibiting two key interactions with Cys 98 (1.99 and 2.56 A), with the pyrrolo[2,3-b]pyridine positioned at the G-Loop opposite and displaying two key interactions with Thr 23 (2.04 A) and Glu 148 (2.39 A). As with 5o SU1367, the pendant phenyl ring resided in the solvent exposed region, with the benzyl ether oxygen atom hydrogen bonding to Asp 102 (2.52 A); B, the hook-like binding pose was observed for 5x SU1335 in IKKβ, with the aminoindazole moiety making interactions with Thr 23 (2.65 A), Gly 24 (3.04 A), and Asn 28 (2.00 A). Of note were the additional interactions that were observed with the terminal polar pyran group forming an interaction with Lys 106 (2.99 A), which may compensate for an absence of H-bonding with the hinge region in IKKβ.

[0199] A number of analogues did exhibit good IKKβ inhibition despite increased steric hindrance, for example 5l,m,x,y SU1317, SU1316, SU1335 and SU1336. Notably, these derivatives all possess terminal polar groups in their pendant phenyl substituent, and whilst the docking studies consistently returned the hook-like pose in IKKβ described for 5o,t,p,q,w SU1367, SU1278, SU1549, SU1353, SU1324, and SU1261 (and exemplified by 5o SU1367 in Figure 5B), these terminal groups were able to form additional H-bonding interactions with either the protonated Lys106 residue in the case of 5x SU1335 (Figure 6B), or the Tyr 98 side chain in the case of 5y SU1336 situated in the solvent exposed region. We propose that these additional interactions could compensate for those not seen with the hinge for 5o,t,p,q,w SU1367, SU1278, SU1549, SU1353, SU1324, and SU1261 to explain the improved activity with IKKβ.

[0200] Shifting the phenyl pendant substituent to the para-position (e.g 5s, u SU1334 and SU1283) tended to improve IKKβ activity to reduce selectivity and was therefore not extensively pursued. From a docking perspective, the altered geometry of the ligand caused by para substitution generated a new pose in IKKβ which could explain this increase in activity. Here, the aminoindazole was positioned along the hinge region to H-bond with GK+1 , the pyrrolo[2,3- tijpyridine accessing the solvent adjacent to the hinge, and the para-pendant substituted phenyl ring projected upwards into the solvent exposed region below the G-loop to form an additional H-bond with the Thr 23 bulge via the ether (5s SU1334) or sulfonamide (5u SU1283). Both compounds adopted the flipped pose for IKKα that had been returned across the series.

[0201] With a rationale for selectivity established, we next sought to improve the physicochemical properties of the series via the incorporation of solubilising groups and additional heteroatoms in the central phenyl ring (6a-l SU1371 - 1621, Table 3). 5r SU1261 was selected as the starting point for the optimisation of the of the series, owing to its activity and selectivity being recapitulated in cells. The introduction of polar functional groups and additional nitrogen atoms was explored, with a view to reducing lipophilicity and improving aqueous solubility. Modifications such as linker length extension, heteroatom choice and placement were concurrently explored to see if the potency and specificity of the ligand could be further refined.Table 3. Kivalues of series 2 compounds (6a-l) against IKKα and IKKβ.

[0202] The addition of heteroatoms and polar moieties generally maintained potency for IKKα and decreased IKKβ inhibition, which ultimately improved the selectivity of these analogues. Again, similarities with the prior docking results were observed, with bulky meta-substituents on the phenyl ring positioned in the same solvent-exposed orientation in IKKα, allowing significant interaction between the AIPP core with the hinge and G-loop wall in the flipped pose to facilitate potent inhibition (6g SU1349, Figure 7A). Furthermore, most analogues had poor activityagainst IKKβ, which could generally be accounted for in silica by the familiar, unfavourable hook-like conformation shown in Figures 5B and D for 5o SU1367 being predominantly replicated in IKKβ with no H-bonding to the hinge.

[0203] Figure 7 shows proposed 3D interactions of 6g SU1349 (A) and 6c SU1365 (B) with the IKKα active site. A, the aminoindazole motif of 6g SU1349 was positioned at the hinge region, displaying two H-bond interactions with Cys 98 (2.00 and 2.62 A), the pyrrolo[2,3- b]pyridine H-bonded with Thr 23 (2.04 A) and Glu 148 (2.46 A), and the ether showed an HB interaction between the oxygen atom and Asp 102 (2.49 A); B, the aminoindazole motif of 6c SU1365 was positioned at the hinge region, displaying two interactions with Cys 98 (1.90 and 2.39 A) and the pyrrolo[2,3-b]pyridine interacted with the G-loop wall via Thr 23 (2.02 A) and Glu 148 (2.26 A). The pendant phenyl ring was positioned in the solvent exposed region, making a Tr-anion interaction with Asp 102 (2.52 A), with the benzyl ether oxygen atom hydrogen bonding to Asp 102 (2.75 A). The additional solubilising alkyl ether substituent was accommodated in the solvent exposed region.

[0204] Compounds with a supplementary solubilising long-chain polar group (6b, c SU1358 and SU1365) demonstrated similar selectivity profiles that could be explained by our model. The solvent-exposed area in IKKα was large enough for them to consistently adopt the standard flipped pose across the series associated with inhibition (6c SU1365, Figure 7B). In IKKβ, the increased steric bulk that arises from a disubstituted arrangement in two trajectories could not accommodate the Thr 23 bulge under any conditions and generated no viable binding poses.

[0205] Whilst the addition of heteroatoms and polar moieties generally maintained selectivity for these analogues, there was one exception: 6k SU1628 displayed potent inhibition against IKKβ despite possessing a bulky substituent on the phenyl ring. However, said substituent is a polar pyridyl group, which replicates the poorer selectivity seen for 5l,m,x,y SU1317, SU1316, SU1335 and SU1336, all which contain H-bonding pendant groups. Furthermore, the docked pose of 6k SU1628 was similar, with an additional H-bonding interaction seen with Lys 106, which serves to improve the affinity of the unfavourable hook-like pose (Figure 8). Together these data suggest that bulky substituents with a terminal polar functionality that can hydrogen bond to the IKKβ isoform should be avoided if selectivity is to be maintained. Finally, the parasubstituted analogue 6d SU1350 also displayed reduced selectivity, and replicated the docking pose seen for 5s, u SU1334 and SU1283 .Figure 8 shows the 3D binding pose of 6k SU1628 with IKKβ. The familiar hook-like binding pose was observed, with the aminoindazole moiety H-bonding with Thr 23 (2.64 A) and Asn 28 (2.12 A), but no interaction with the hinge residues. However, an additional interaction wasobserved between the terminal pyridyl nitrogen and Lys 106 (2.44 A), which could compensate for the absence of any H-bonding with the hinge.Chemistry

[0206] The synthetic strategy for accessing the compounds described herein began with the organoiridium(l) catalysed C-H activation of commercially available fluorobenzonitrile 7, giving rise to boronic ester intermediate 8 (Scheme 1 ) [8], This was followed by a ring closure using hydrazine, which proceeds via nucleophilic aromatic substitution at the aryl fluoride and nucleophilic attack at the nitrile carbon to afford the key aminoindazole intermediate 9 (Scheme 1). The final step in the preparation of the initial set of AIPP derivatives 2-4 was a Suzuki- Miyaura cross-coupling between boronic ester intermediate 9 and the commercially sourced pyrrolo[2,3-b]pyridine aryl chlorides 10-12 (Scheme 1) [9].

[0207] Scheme 1. Reagents and conditions, a, B2Pin2, dtbbpy, [lr(OMe)(1,5-cod)]2, MTBE, 80 °C, 18 h; b, hydrazine hydrate, EtOH, reflux, 30 h; c, PdCb(dtbpf), K3PO4, EtOH / H2O, 120 °C, 20 h.

[0208] Preparation of compounds 5 was achieved via the same route as the initial compound set 2-4 (Scheme 2). Aryl chlorides 15 were prepared via an additional Suzuki reaction of 4- chloro-2-iodo-pyrrolo[2,3-b]pyridine (13) with a range of boronic acids 14 (Scheme 2), with selectivity for the pyrrolo[2,3-b]pyridine 2-position achieved through the reduced reactivity of aryl chlorides compared with aryl iodides within the same scaffold

[0010] , This enabled two Suzuki coupling reactions to be performed selectively in sequence by judicious choice of catalyst systems with varying activity i.e., triphenylphosphine palladium catalysis at the iodide moiety, followed by chloride-directing palladium catalysis using a ferrocene-based ligand. A number of these pyrrolo[2,3-b]pyridines were further functionalised before the final coupling; Specifically, anilines 15c and 15ac were subjected to alkylation conditions to afford amide and sulfonamide intermediates 151, 15t, and 15u, carboxylic acid 15h was functionalised via amide bond formation to afford intermediate 15m, and the benzaldehyde functional handle of 15ab underwent reductive amination, giving rise to amines 15n and 15p. As before, the final couplingwas carried out between the synthesised aryl halides 15 and boronic ester 9 to afford the final compounds 5 displayed in Table 3, possessing varying degrees of steric bulk (Scheme 2).Scheme 2. Reagents and conditions, a, K2CO3, PdCI2(PPh3)2, dioxane / H2O, 100 °C, 20 h; b, (151) 3-methoxypropanoic acid, HCTU, Et3N, DMF, rt, 18 h, (15m) 2-methoxyethylamine, HCTU, Et3N, DMF, rt, 18 h, (15n) cyclopentylamine, STAB, AcOH, DMA, rt, 48 h, (15p) aniline, STAB, AcOH, DMA, rt, 48 h, (15t) TsCI, Et3N. DCM, 0 °C - rt, (15u) TsCI, Et3N, DCM, 0 °C - rt, 18 h; c, PdCb(dtbpf), K3PO4, EtOH / H2O, 120 °C, 20 h.

[0209] Considering analogues 6a— i, designed with increased solubility in mind, synthesis followed a similar route to those described above. A selection of phenyl and pyridyl boronic acids 16a-i were coupled to the aryl iodide moiety of 13, giving rise to intermediates 17. Following this, the scaffold was decorated at the chloride moiety via a Suzuki coupling with key intermediate 9 to afford compounds 6 (Scheme 3).Scheme 3. Reagents and conditions, a, K2CO3,PdCl2(PPh3)2, dioxane / H2O,100 °C, 20 h; b, PdCI2(dtbpf), K3PO4, EtOH / H2O, 120 °C, 20 h.

[0210] Intermediates in the route towards compounds 6j— I required bespoke synthesis, which began from commercially available disubstituted pyridines 18 (Scheme 4). Intermediates 20 were prepared via SN2 halide displacement of benzyl bromide in the case of 20a, or nucleophilic aromatic substitution of the aromatic fluoride in the case of 20b and 20c, then subsequently subjected to Suzuki-Miyaura borylation conditions to afford intermediates 21 (Scheme 4)

[0011] , A protecting group strategy was utilised to aid in purification to afford intermediates 23, employing either methoxymethyl (MOM) chloride or t-butyloxycarbonyl (Boc) anhydride, which were then iodinated via lithium-halogen exchange using n-Buli, giving rise to protected intermediates 24. These were then subjected to consecutive Suzuki couplings at the two- and four-position halide moieties sequentially with boronate esters 21 to first generate intermediates 25, and then boronate ester 9 to yield the final target compounds 6j— I (Scheme 4).Scheme 4. Reagents and conditions, a, (20a) CS2CO3, DMF, 0 C - rt, 4 h, (20b, c) KOt-Bu, THF, 0 °C - rt, 4 h; b, B2Pin2, Pd(dppf)CI2, KOAc, dioxane / H2O, 110 °C, 18 h. c, (23a)K2CO3, MOMCI, DMF, 0 °C - rt, 18 h, (23b) DMAP, Boc2O, DMF, rt, 18 h; d, n-Buli, l2, THF, -78 °C - rt, 2 h; e, PdCI2(dtbpf), CS2CO3, dioxane / H2O, 80 °C, 18 h; f, compound 9, PdC2(dtbpf), Cs2CO3, dioxane / H2O, 110 °C, 18 h, (6j) HCI / MeOH, reflux, 8 h, (6k, I) TBAF, THF, reflux, 8 h.Physicochemical / DMPK analysis

[0211] We next examined our series using Datawarrior, an open-source software package for the generation and analysis of physicochemical attributes. Firstly, compounds were plotted with respect to inhibition of IKKα versus IKKβ that included an initial dataset filter, dependant on an IKKα Ki< 40 nM and IKKβ Ki> 500 nM (Figure 9A).

[0212] Figure 9 shows graphical correlation between the activity and the calculated physicochemical properties. A, IKKα versus IKKβ selectivity analysis. Compounds with superior potency and selectivity profile highlighted in dark grey; B, Physicochemical property analysis. Compounds with superior potency and selectivity profile highlighted in blue.

[0213] With an initial filter applied for potency and selectivity, the data could be arranged according to the key physicochemical properties: CLog P, topological polar surface area (tPSA), and Ligand efficiency (LE), with compounds that possessed adequate potency and selectivity highlighted in dark grey (Figure 9B).

[0214] Removing the compounds with an undesirable selectivity profile, the filtered datapoints fall into a narrow region of chemical space, possessing a CLog P of ca. 3.5 - 4.5, a tPSA of 100 - 120 A2(with two outliers at 90 and 140 A2), and LE values approximately at the desirable benchmark of 0.3 for further development. All the compounds that met our selectivity and potency criteria possessed bulky hydrophobic meta-substituents, with seven of the nine derivatives bearing either a benzyl ether or thioether and a pyridyl group, the most notable example being 6g SU1349 which boasts a 209-fold selectivity for IKKα over IKKβ (Figure 10).

[0215] Figure 10 shows physicochemical property analysis.

[0216] Modification of 5r SU1261 to those derivatives in Figure 10, whilst generally improving selectivity, only improved solubility marginally (Table 4) despite the introduction of solubilising ether groups used in the development of erlotinib (6b, c SU1358 and SU1365), and herein lies the problem to further progress this series: to date, incorporating polar functionality in the solvent-exposed pendant group has improved solubility, but significantly compromised the in vitro biochemical selectivity for IKKα (vide supra). This is clearly demonstrated by comparing 6g SU1349 with 6k SU1628 - the latter has the requisite solubility but is equipotent against both isoforms, whereas the former has the essential selectivity profile, but poorer solubility. However, whilst 6g SU1349 had lower solubility than 6k SU1628, it was the most soluble in theseries that displayed selectivity, and furthermore had a sufficiently low in vitro murine clearance to be progressed to an in vivo PK evaluation (Table 5).

[0217] Table 4. Turbidimetric solubility and murine hepatocyte clearance of selected compounds from the series.

[0218] Table 5. in vivo murine PK parameters for 6g SU1349.

[0219] We profiled three compounds from the series across the kinome (Figure 11). Our original pan-IKK inhibitor 4 SU1253 proved to be very promiscuous, inhibiting 44 kinases from a panel of 231 by >80% at 1 μM. The introduction of the pendant benzyloxy substituent to generate 5r SU1261 markedly reduced off-target kinase inhibition to 10 kinases (>80% at 1 pM), most notably CDK5, CDK9, haspin, and the stress-activated kinases MKK7β and PRAK. Interestingly, exchanging the 2-phenyl pyrrolo[2,3-b]pyridine substituent of 5r SU1261 for the 2- pyridin-4-yl group in 6g SU1349 not only improved solubility and clearance, but also significantly reduced off-target inhibition of MKK7β and PRAK, although not CDK5 and CDK9. To identify the structural drivers for CDK inhibition, we obtained X-ray crystal structures of 5y and 6g SU1336 and SU1349 with CDK-2 (Figure 12A) to potentially identify possible routes towards introducing selectivity for IKKα over the CDK enzymes as well as IKKβ. The CDK2 and CDK9 active sites are comparable with IKKβ In the sense that they have an accessible pocket that is readily open to solvent on two sides and moreover, do not possess an equivalent Thr 23 bulge, resulting in a larger volume to accommodate bulky substituents, whilst allowing H- bonding to the hinge residues (Figure 13). All three derivatives form complexes with CDK2 with the pyrrolo[2,3-b]pyridine H-bonding to GK+3 (Leu 83) and the aminoindazole projected towards the G-loop (Figure 12A), forming H-bonds with Glu 51 and Lys 33 at the back of thepocket. The adoption of the 4 SU1253-type orientation, rather than the flipped pose observed in IKKα, is probably facilitated by tt-stacking between the aminoindazole and the GK residue, which in the CDKs is Rhe, rather than Met. Notably, the positioning of the pendant side chain is altered dramatically, depending on the nature of the substituent and the potential interactions made. For 6g SU1349, the hydrophobic pendant benzyloxy group points out into solvent, but can form face-to-edge TT-TT interactions with Phe 82 and His 84 from the hinge. Exchanging the hydrophobic pendant benzyloxy group for the morpholinoethyl-containing substituent in 5y SU1336 removes any direct interaction with these hinge residues, preferring to sit in a more solvent-exposed position, as befits a basic side chain that will be protonated at physiological pH (Figure 12B).Figure 11 shows kinases showing significant % inhibition by 4 SU1253, 5r SU1261 and 6g SU1349 at 1 pM from a panel of 253 kinases. Black, 4 SU1253; grey, 5r SU1261; diagonal stripes, 6g SU1349. 4 SU1253 showed >80% inhibition for all 46 kinases shown. 5r SU1261 inhibited fewer kinases compared to that of 6g SU1253 (exhibited >80% inhibition for 10 kinases). 6g SU1349 exhibited a significant reduction in off-target inhibition (>80% inhibition for only 4 kinases). All tested compounds (4 SU1253, 5r SU1261 and 6g SU1349) inhibited CDK5 and CDK9 with >80%.Figure 12 shows: A, Crystal structure of 15g SU1349 with CDK2. The aminoindazole moiety was directed to the G-loop, forming MBs with Glu51 and Lys33 (3.09 and 2.92 A, respectively), the pyrollo[2,3-b]pyridine resided at the hinge region H-bonding to Leu83 (2.94 A), and the pendant benzyl ether was positioned into the solvent-exposed region flat along the protein wall, forming TT-TT interactions with Phe82 and His84; B, Overlapped crystal structures of 13k SU1336 and 15g SU1349 with CDK2. Whilst the AIPP motif adopts a similar position in the ATP-interior for both compounds, the morpholineoethyl side chain of 13k SU1336 adopts a completely different position to the benyloxy group of 15g SU1349. In the former, this basic side chain is fully exposed to the solvent rather than interacting with specific residues in the kinase.Figure 13 shows sequence alignment of the ATP binding site amino acid residues of IKKα (residues 10 - 180), CDK2 (residues 5 - 150) and CDK9 (residues 20 - 180) (alignment rmsd 1.081 and 1.634). The homology analysis showed 16.3% sequence identity and 40.1% sequence similarity between these 3 kinases (IKKα, CDK2 and CDK9), with levels of similarity colour-coded as indicated.

[0220] One key observation from these CDK complexes is the presence of a lipophilic pocket side chain between the hinge and the adjacent solvent-exposed region, made up of the sidechains of Ile 10, Phe 82 and Leu 134. In CDK9, an equivalent hydrophobic pocket is formed from Ile 25, Phe 105 and Leu 156. These residues are positioned perfectly to make nr-alkyl and TT-sigma interactions with the central 2-phenyl / pyridyl ring present in our series. These additional interactions are possible across our compound series, and when combined with the H-bonding interactions anchoring the central AIPP core to the hinge region, provide a potential explanation for the observed off-target activity against CDK isoforms.EXPERIMENTAL SECTION

[0221] General. Unless otherwise stated, all commercially available reagents and solvents used were obtained from Sigma-Aldrich, Fluorochem Fisher Scientific, Acros, Alfa Aesar, Apollo scientific and Advanced ChemBlocks and used without further purification. Air- or moisture-sensitive reactions were carried out under argon or nitrogen atmosphere. Microwave reactions were carried out using a Biotage Initiator system. Thin-layer chromatography (TLC) was carried out on aluminium-backed S1O2 plates (Merck, silica gel 60, F254) and spots visualised using ultra-violet light (254 nm) or by staining with potassium permanganate. All tested compounds were determined to be >95 % purity by LC-MS and analytical HPLC unless otherwise stated. Flash chromatography was performed using a Biotage SP4 automated chromatography system using silica stationary phase (Fisher Scientific, 60 A, 35-70 micron; detection wavelength: 254 nm; monitoring: 280 nm) and the mobile phase used are detailed in the text. Reverse phase HPLC purifications were conducted on Shimadzu Prominance HPLC using a semi-preparative (50 x 21.2 mm) Luna 5pm C18 column at 40 °C; flow rate: 6 ml / min; detection wavelength: 254 nm eluting with an acetonitrile / water gradient with 0.1% TFA. NMR spectra were recorded on either a Bruker Avance3 / DPX400 (400 MHz), Bruker DRX500 (500 MHz), Bruker AV400 (400 MHz), Bruker AV500HD (500 MHz) or Bruker AV600 (600 MHz) instrument and analysed using Advanced Chemistry Development Labs (ACD / labs) NMR processor 12.00 or MestReNova 10.0 software. Chemical shifts (6) are recorded in parts per million (ppm) relative to an internal solvent reference (tetramethylsilane) and coupling constants (J) in Hertz (Hz). Splitting patterns were indicated as singlet (s), broad singlet (br s), doublet (d), doublet of doublet (dd), triplet (t), quartet (q) and multiplet (m). LCMS was carried out on an Agilent Technologies 1220 series LC system with Agilent 6100 series quadrupole mass spectrometer in ESI / APCI mode. Separation was achieved with an Agilent Eclipse C18 4.6x50 mm column; flow rate:1 ml / min; detection:254 nm; sample volume:10 pl; mobile phase: acetonitrile / 5mM ammonium acetate: water / 5mM ammonium acetate; 5%, 1.48 min; 5-100%, 8 min; 100%, 13.5 min; 100-5%, 16.5 min; 18 min. HRMS was carried out on an Exactive (Thermo scientific) or LTQ orbitrap (Thermo scientific).

[0222] Synthesis of 2-fluoro-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzonitrile (8). A solution of bis(pinacolato)diboron (1.3 g, 5.2 mmol), 4,4’-di-tert-butyl-2,2’-dipyridyl (43 mg, 0.16 mmol) and (1 ,5-cyclooctadiene)(methoxy)irldium(l) dimer (106 mg, 0.16 mmol) in anhydrous MTBE (10 mb) in a sealed vial (20 mb) was stirred at rt for 1 h. A solution of 2-fluorobenzonitrile (1 , 0.6 g, 5 mmol) in anhydrous MTBE (1 mb) was added. The reaction mixture was allowed to stir at 80 °C for 18 h. The reaction mixture was cooled, filtered through celite and evaporated under reduced pressure. The crude residue was used in the next step without further purification.

[0223] Synthesis of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-3-amine (9). To a solution of compound 8 (1.98 g, 8 mmol) in EtOH (100 mb), hydrazine hydrate (2.4 mb, 2.47 g, 39 mmol, 50-60%) was added and the reaction was refluxed for 30 h. The solvent was evaporated under reduced pressure. The residue was triturated with a mixture of EtOAc and petroleum ether (1 :1 , 12 mb), filtered and washed with water and petroleum ether 60-80% to give the titled product 3 as a yellow solid (1.4 g, 67%).1H NMR (400 MHz, DMSO-d6) δ ppm 12.70 (s, 1 H), 8.17 (s, 1 H), 7.49 (d, J=8.35 Hz, 1 H), 7.18 (d, J=7.91 Hz, 1 H), 5.46 (s, 2 H), 1.30 (s, 12 H).13C NMR (100 MHz, DMSO-d6) δ ppm 150.34, 143.38, 132.01 , 129.35, 114.66, 109.23, 83.74, 25.31. bC-MS: exact mass calculated for C13H18BN3O2: 259.12, found 260.1 (M+1 )4.

[0224] General procedure for synthesis of 5-(substituted pyridin-4-yl)-1H-indazol-3-amine (2- 4). To a suspension of 4-chloro-pyridine derivatives (10-12, 0.35 mmol), compound 9 (0.136 g, 0.525 mmol) and [1 ,1'-bis(di-tert-butylphosphino)ferrocene]dichloro palladium(ll) catalyst (0.011 g, 0.0175 mmol) in EtOH (1 mL) and water (1 mL), a solution of K3PO4was added (1M, 0.88 mb) and the reaction mixture was heated to 120 °C for 20 h. The reaction mixture was cooled, diluted with EtOAc and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue was purified by column chromatography (10% MeOH in EtOAc) to afford the titled products (2-4).

[0225] 5-(6,7,8,9-Tetrahydro-5H-pyrido[2,3-b]indol-4-yl)-1H-indazol-3-amine (2). Beige solid (73 mg, 69%).1H NMR (400 MHz, DMSO-d6) δ 11.46 (s, 1 H), 11.27 (s, 1H), 8.07 (d, J = 4.9 Hz, 1 H), 7.78 (s, 1H), 7.33 (d, J = 8.6 Hz, 1 H), 7.29 (d, J = 8.6 Hz, 1 H), 6.86 (d, J = 4.9 Hz, 1H), 5.43 (s, 2H), 2.71 (t, J = 5.8 Hz, 2H), 2.20 (t, J = 5.2 Hz, 2H), 1.81 - 1.77 (m, 2H), 1.66 - 1.50 (m, 2H). HRMS (ESI): exact mass calculated for CI8H17N5: 303.1552, found 304.1557 (M+1)+.

[0226] 5-(9H-pyrido[2,3-b]indol-4-yl)-1H-indazol-3-amine (3). White powder (36 mg, 35 %).1H NMR (400 MHz, DMSO-d6): δ 11.90 (br s, 1H), 11.62 (br s, 1H), 8.44 (d, J = 5.0 Hz, 1 H), 8.05 (s, 1 H), 7.57 (d, J = 8.1 Hz, 1 H), 7.54 (dd, J = 8.7, 1.4 Hz, 1H), 7.51 (d, J = 8.1 Hz, 1 H), 7.44 (d,J = 8.5 Hz, 1 H), 7.42-7.38 (m, 1 H), 7.11(d, J = 5.0 Hz, 1H), 7.02-6.98 (m, 1 H), 5.47 (br s, 2H).LC-MS: exact mass calculated for C18H13N5: 299.12, found 300.3 (M+1 )+.

[0227] 5-(2-Phenyl-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3-amine (4). Off-white solid (50 mg, 44%).1H NMR (500 MHz, DMSO-d6) δ 12.27 (s, 1H), 12.05 (s, 1H), 8.27 - 8.24 (m, 2H), 7.99 (d, J = 8.5 Hz, 1H), 7.74 (s, 1H), 7.55 - 7.49 (m, 2H), 7.40 - 7.34 (m, 3H), 7.22 (d, J = 8.5 Hz, 1 H), 7.17 (d, J = 1.9 Hz, 1 H), 5.73 (s, 2H).

[0228] General procedure for synthesis of 4-chloro-2-(substituted phenyl)-1H-pyrrolo[2,3- bjpyridine (15a-ac). A suspension of 4-chloro-2-iodo-7-azaindole (0.343 g, 1.23 mmol), substituted phenyl boronic acid (14a-ac, 1.52 mmol), K2CO3(0.483 g, 3.49 mmol) and bis(triphenylphosphine) palladium(ll) chloride (0.074 g, 0.105 mmol) in dioxane (3 mL) and water (2 mL) was degassed under nitrogen. The reaction mixture was allowed to stir at 100 °C for 20 h. The reaction mixture was cooled to rt and extracted between EtOAc (5 mL) and water (3 mL). The organic layer wash washed with brine (2 x 3 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue was used in the next step without further purification unless otherwise stated below.

[0229] 4-Chloro-2-(2-ethoxyphenyl)-1H-pyrrolo[2,3-b]pyridine (15b). The resulting solid was purified by recrystallization using DCM and hexane to afford the titled compound as an orange solid (207 mg, 62%).1H NMR (DMSO--d6): δ 12.13 (br s, 1 H), 8.17 (d, J = 5.2 Hz, 1H), 7.89 (dd, J = 1.6, .6 Hz, 1 H), 7.39 - 7.36 (m, 1H), 7.19 (d, J = 5.2 Hz, 1H), 7.16 (s, 1 H), 7.08 - 7.06 (m, 2H), 4.21 (q, J = 6.9 Hz, 2H), 1.46 (t, J = 7.0 Hz, 3H).

[0230] 3-(4-Chloro-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-fluorophenol (151). The resulting solid was purified by column chromatography (90% EtOAc in petroleum ether) to afford the titled compound as a yellow solid (69 mg, 21.5 %).1H NMR (DMSO-d6): δ 12.50 (br s, 1 H), 10.13 (s, 1 H), 8.19 (d, J = 4.8 Hz, 1 H), 7.30 (dt, J = 1.8, 10.0 Hz, 1 H), 7.23 - 7.21 (m, 2H), 6.98 (d, J = 2.4 Hz, 1 H), 6.59 (dt, J = 2.2, 10.4 Hz, 1H). LC-MS: exact mass calculated for CI3H835CIFN2O: 262.03, found 263.13 (M+1)+.

[0231] N-(3-(4-Chloro-1H-pyrrolo[2,3-b]pyridin-2-yl)phenyi)methanesuifonamide (15j). The crude solid was purified by column chromatography (90% EtOAc in petroleum ether) to afford the titled compound as a pale yellow solid (0.216 g, 64.7%).1H NMR (DMSO-de): 6 12.62 (br s, 1 H), 9.88 (br s, 1 H), 8.19 (d, J = 5.2 Hz, 1 H), 7.75 - 7.71 (m, 2H), 7.45 (t, J = 16.0 Hz, 1H), 7.22 - 7.20 (m, 2H), 6.88 (d, J = 2.0 Hz, 1H), 3.10 (s, 3H). HRMS (ESI): exact mass calculated for C14H13O2N335CIS: 322.0412, found 322.0410 (M+1 )+.

[0232] 4-Chloro-2-(3-(methylsulfonyl)phenyl)-1H-pyrrolo[2,3-b]pyridine (15k). The resulting solid was purified by column chromatography (90% EtOAc in petroleum ether) to afford thetitled compound as an off-white solid (245 mg, 62%).1H NMR (DMSO-d6): δ 12.73 (br s, 1H), 8.56 (t, J = 1.6 Hz, 1 H), 8.35 (dt, J = 1.2, 8.2 Hz, 1 H), 8.24 (d, J = 5.3 Hz, 1 H), 7.92 (dt, J = 1.2, 8.2 Hz, 1 H), 7.77 (t, J = 7.8 Hz, 1H), 7.26 (dd, J = 5.0 Hz, 1H), 7.24 (s, 1H), 3.33 (s, 3H). LC- MS: exact mass calculated for C14H1235CIN3O2S: 321.03, found 322.3 (M+1)+

[0233] 4-Chloro-2-(3-isobutoxyphenyl)-1H-pyrrolo[2,3-b]pyridine (15o). The resulting solid was purified by recrystallization using DCM and hexane to afford the titled compound as an orange solid (166 mg, 45%).1H NMR (DMSO-d6): 8 12.48 (br s, 1H), 8.17 (d, J = 5.2 Hz, 1H), 7.58 (s, 1H), 7.56 (s, 1H), 7.37 (t, J = 8.0 Hz, 1H), 7.20 (d, J = 5.2 Hz, 1 H), 7.04 (d, J = 2.4 Hz, 1 H), 6.94 - 6.92 (m, 1 H), 3.85 (d, J = 6.4 Hz, 2H), 2.08 - 2.05 (m, 1 H), 1 .02 (d, J = 6.4 Hz, 6H).

[0234] 2-(2-(Benzyloxyphenyl)-4-chloro-1H-pyrrolo[2,3-b]pyridine (15q). The resulting solid was triturated with hexane and Et2O to afford the titled compound as a light solid (378 mg, 92%).1H NMR (DMSO--d6): δ 12.19 (br s, 1H), 8.18 (d, J = 7.5 Hz, 1H), 7.92 (dd, J = 2.0, 8.8 Hz, 1 H), 7.54 (d, J = 7.5 Hz, 1H), 7.42 (t, J = 7.0 Hz, 1 H), 7.36 - 7.34 (m, 2H), 7.28 (d, J = 8.5 Hz, 1 H), 7.17 (d, J = 5.0 Hz, 1 H), 7.09 (t, J = 7.5 Hz, 1H), 7.06 (s, 1H), 5.32 (s, 2H).

[0235] 3-(4-Chloro- 1 H-pyrrolo[2, 3-b]pyridin-2-yl)phenyl)(4-methylpiperazin- 1 -yl)methanone (15v). The resulting solid was triturated with hexane and filtered through a pad of celite, concentrated under reduced pressure and dried to afford the titled compound as light solid (405 mg, 93%).1H NMR (DMSO-d6): δ 12.57 (br s, 1 H), 8.19 (d, J = 4.0 Hz, 1 H), 8.08 (d, J = 6.8 Hz, 1 H), 8.00 (s, 1 H), 7.55 (t, J = 6.2 Hz, 1H), 7.37 (d, J = 6.0 Hz, 1 H), 7.22 (d, J = 4.0 Hz, 1H), 7.11 (s, 1H), 3.66 (br s, 2H), 3.36 (br s, 2H), 2.39 (br s, 2H), 2.23 (br s, 2H), 2.21 (s, 3H).

[0236] 4-Chloro-2-(3-(pyridin-2-ylmethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridine (15w). The crude residue was purified by column chromatography (90% EtOAc in petroleum ether) to give the titled compounds as brown solid (380 mg, 92%).1H NMR (400 MHz, DMSO-d6): δ 12.52 (s, 1H), 8.60 (d, J = 4.6 Hz, 1H), 8.18 (d, J = 5.2 Hz, 1H), 7.88 - 7.84 (m, 1H), 7.73 (s, 1 H), 7.61 (d, J = 7.7 Hz, 1 H), 7.58 (d, J = 7.8 Hz, 1 H), 7.45 - 7.37 (m, 1 H), 7.36 (d, J = 7.2 Hz, 1 H), 7.21 (d, J = 5.2 Hz, 1 H), 7.06 - 7.03 (m, 2H), 5.30 (s, 2H). LC-MS: exact mass calculated for C14H1235CIN3O: 335.08, found 336.1 (M+1)+.

[0237] 2-(3-((Tetrahydro-2H-pyran-4-yl)methoxy)phenyl)-4-chloro-1H-pyrrolo[2,3-b]pyridine (15x). The crude residue was triturated with 50% EtOAc in petroleum ether to afford the titled product as brown solid (336 mg, 80%).1H NMR (400 MHz, DMSO-d6): δ 12.51 (s, 1H), 8.17 (d, J = 5.2 Hz, 1 H), 7.58 - 7.56 (m, 2H), 7.39 - 7.35 (m, 1 H), 7.20 (d, J = 5.2 Hz, 1 H), 7.05 (d, J = 2.0 Hz, 1 H), 6.94 (d, J = 7.2 Hz, 1 H), 3.93 (d, J = 6.8 Hz, 2H), 3.89 (dd, J = 11.2, 2.8 Hz, 2H), 3.37 (dd, J = 12.4, 1.6 Hz, 2H), 2.08 - 2.00 (m, 1H), 1.72 (d, J = 11.6 Hz, 2H), 1.42 - 1.31 (m, 2H). LC-MS: exact mass calculated for 1C9Hi935CIN2O2: 342.11 , found 343.3 (M+1)+.

[0238] 4-(2-(3-(4-Chioro-1H-pyrrolo[2,3-b]pyridin-2-yl)phenoxy)ethyl)morpholine (15y). The crude residue was purified by flash chromatography (10% MeOH in EtOAc) to obtain the titled compound as beige solid (136 mg, 31%).1H NMR (400 MHz, DMSO-de) 5 12.49 (s, 1 H), 8.17 (d, J = 5.2 Hz, 1 H), 7.60 (s, 1 H), 7.58 (d, J = 8.0 Hz, 1 H), 7.39 - 7.35 (m, 1 H), 7.20 (d, J = 5.2 Hz, 1 H), 7.06 (d, J = 2.0 Hz, 1H), 6.95 (dd, J = 8.1 , 2.0 Hz, 1H), 4.19 (t, J = 5.8 Hz, 2H), 3.61 - 3.58 (m, 4H), 2.73 (t, J = 5.8 Hz, 2H), 2.51-2.48 (m, 4H). LC-MS: exact mass calculated for Ci9H2035CIN3O2: 357.12, found 358.1 (M+H)+.

[0239] 4-Chloro-2-(3-((4-methoxybenzyl)oxy)phenyl)-1H-pyrrolo[2,3-b]pyridine (15z). The resulting solid was purified by column chromatography (90% EtOAc in petroleum ether) and triturated with Et2O to afford the titled compound as an orange solid (228 mg, 51%).1H NMR (DMSO--d6): δ 12.48 (br s, 1H), 8.17 (d, J = 5.2 Hz, 1H), 7.68 (t, J = 2.0 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1 H), 7.43 - 7.41 (m, 3H), 7.21 (d, J = 5.2 Hz, 1 H), 7.05 (s, 1H), 6.98 - 6.96 (m, 3H), 5.13 (s, 2H), 3.75 (s, 3H).

[0240] 4-((3-(4-Chloro-1 H-pyrrolo[2, 3-b]pyridin-2-yl)phenyl)sulfonyl)morpholine (15aa). The resulting solid was triturated with boiling MeOH, filtered and dried to afford the titled compound as brown solid (88 mg, 19%).1H NMR (DMSO--d6): δ 12.83 (br s, 1 H), 8.37 - 8.35 (m, 1H), 8.23 (d, J = 4.8 Hz, 1 H), 7.78 - 7.75 (m, 4H), 7.25 (d, J = 5.2 Hz, 1 H), 7.23 (d, J = 2.0 Hz, 1 H), 3.66 - 3.65 (m, 4H), 2.96 - 2.94 (m, 4H).

[0241] 2-(4-(Benzyloxy)phenyl)-4-chloro-1H-pyrrolo[2,3-b]pyridine (15s). The crude residue was purified by column chromatography (90% EtOAc in petroleum ether) followed by trituration to the resulting solid by a mixture of hexane / Et2O to afford the titled compound as an off-white solid (177 mg, 43%).1H NMR (DMSO-de): 6 12.38 (br s, 1 H), 8.13 (d, J = 5.5 Hz, 1H), 7.94 (d, J = 8.5 Hz, 1 H), 7.47 (d, J = 7.0 Hz, 2H), 7.41 (t, J = 7.5 Hz, 2H), 7.35 (d, J = 7.5 Hz, 1 H), 7.18 (d, J = 5.0 Hz, 1 H), 7.12 (d, J = 8.5 Hz, 1 H), 6.87 (d, J = 2.0 Hz, 1 H), 5.19 (s, 2H).

[0242] Synthesis ooff N-(3-(4-chloro-1H-pyrrolo[2,3-b]pyridin-2-yl)phenyl)-3- methoxypropanamide (151). A solution of compound 15c (0.10 g, 0,4 mmol) and 3- methoxypropanoic acid (37 pL, 0.4 mmol) in DMF (5 mL) was allowed to stir at rt for 5 min. HCTU (495 mg, 1.2 mmol) and trimethylamine (168 pL, 1 ,2 mmol) were added and the solution allowed to stir at rt for 18 h. The reaction mixture was cooled, extracted between EtOAc and water. The organic layer was dried over anhydrous sodium sulfate and removed under reduced pressure. The resulting residue was purified by column chromatography (1% Et3N and 10% MeOH in EtOAc) to give the titled product as a pale-yellow solid (95 mg, 72 %).1H NMR (500 MHz, DMSO-d6) δ 12.54 (s, 1H), 10.04 (s, 1H), 7.89 - 7.86 (m, 2H), 7.66 (d, J = 7.8 Hz, 1H), 7.57 (d, J = 7.8 Hz, 1 H), 7.47 (t, J = 10.0 Hz, 1 H), 7.22 (d, J = 6.5 Hz, 1 H), 6.81 (d, J = 1.8 Hz,1 H), 3.65 (t, J = 8.0 Hz, 2H), 3.27 (s, 3H), 2.04 (t, J = 8.0 Hz, 2H). LC-MS: exact mass calculated for C17H1635CIN3O2: 329.09, found 330.3 (M+H)+.

[0243] Synthesis ooff N-(3-(4-chloro-1H-pyrrolo[2,3-b]pyridin-2-yl)phenyl)-4- methylbenzenesulfonamide (15t). Tosyl chloride (136 pL, 1 mmol) was added to a solution of compound 15c (0.244 g, 1.04 mmol) and triethyl amine (0.3 mL, 2 mmol) in anhydrous DCM (5 mL) at 0 °C. The reaction mixture was allowed to stir at rt for 18 h. The reaction mixture was washed with saturated solution of sodium hydrogen carbonate (5 mL) and brine (5 mL), dried over anhydrous sodium sulfate and removed under reduced pressure. The crude residue was purified by column chromatography (90% EtOAc in petroleum ether) to afford the titled compound as a pale-yellow solid (301 mg, 73%).1H NMR (DMSO-d6): δ 12.57 (br s, 1 H), 10.36 (br s, 1 H), 8.19 (d, J = 5.2 Hz, 1 H), 7.71 (d, J = 8.4 Hz, 2H), 7.65 - 7.64 (m, 2H), 7.38 - 7.36 (m, 3H), 7.22 (d, J = 5.2 Hz, 1 H), 7.08 - 7.05 (m, 1 H), 6.74 (d, J = 2.0 Hz, 1 H), 2.33 (s, 3H).

[0244] Synthesis of 3-(4-chloro-1H-pyrrolo[2,3-b]pyridin-2-yl)-N-(2-methoxyethyl)benzamide (15m). A solution of compound 15h (0.11 g, 0.4 mmol) and 2-methoxyethylamine (35 pL, 0.4 mmol) in DMF (5 mL) was allowed to stir at rt for 5 min. HCTU (495 mg, 1.2 mmol) and trimethylamine (168 pL, 1.2 mmol) were added. The reaction mixture was allowed to stir at rt for 18 h. The solvent was then removed under high vacuum and the resulting residue was used in the next step without further purification.

[0245] General procedure for synthesis of N-(3-(4-chloro-1H-pyrrolo[2,3-b]pyridin-2- yl)benzyl)-N-substituted amine (15n,p). A solution of compound 15ab (0.12 g, 0.46 mmol), appropriate amine (0.6 mmol), sodium triacetoxyborohydride (0.14 g, 0.69 mmol) and acetic acid (0.036 mL, 0.59 mmol) in dimethylacetamide (2 mL) at rt for 48 h. The reaction mixture was poured into 1M sodium carbonate solution, stirred in an ice bath for 3 h and filtered.

[0246] N-[3-(4-Chloro-7-azaindole)benzyl]-N-cyclopentylamine (15n). The collected solid was purified by column chromatography (10% MeOH in EtOAc) to afford the desired compound as a white solid (102 mg, 68%),1H NMR (400 MHz, DMSO--d6): δ 12.49 (br s, 1 H), 8.17 (d, J=5.27 Hz, 1 H), 7.97 (s, 1 H), 7.84 (d, J=7.47 Hz, 1 H), 7.41 (t, J=7.69 Hz, 1 H), 7.35 (d, J=7.91 Hz, 1 H), 7.21 (d, J= 5.27 Hz, 1 H), 6.99 (s, 1 H), 3.74 (s, 2 H), 3.03 - 3.01 (m, 1 H), 1.73 - 1.71 (m, 2 H), 1.64 - 1.62 (m, 2 H), 1.47 - 1.44 (m, 2 H), 1.37 - 1.35 (m, 2 H). LC-MS: exact mass calculated for C19H2o35CIN3: 325.13, found 326.2 (M+1)+.

[0247] N-[3-(4-Chloro-7-azaindole)benzyl]-N-phenylamine (15p). The collected solid was purified by column chromatography (60% EtOAc in petroleum ether) to afford the desired compound as a white solid (118 mg, 77%).1H NMR (400 MHz, DMSO--d6): δ 12.54 (br s, 1 H), 8.17 (d, J = 5.27 Hz, 1 H), 8.04 (s, 1 H), 7.85 (d, J = 7.47 Hz, 1 H), 7.43 (t, J = 7.69 Hz, 1 H), 7.38 (d, J = 7.91 Hz, 1 H), 7.21 (d, J = 5.27 Hz, 1 H), 7.08-7.02 (m, 2 H), 6.97(s, 1 H), 6.62 (d, J= 7.47 Hz, 2 H), 6.51 (t, J = 7.25 Hz, 1 H), 6.27 (t, J = 5.93 Hz, 1 H), 4.32 (d, J = 6.15 Hz, 2 H).13C NMR (100 MHz, DMSO-d6) 5 150.07, 149.17, 144.36, 143.96, 141.78, 140.04, 134.03, 131.42, 129.53, 129.41, 128.02, 125.38, 124.48, 120.44, 116.43, 112.94, 95.56, 47.05. LC-MS: exact mass calculated for C20Hi635CIN3: 333.10, found 334.1 (M+1)*.

[0248] Synthesis ooff N-(4-(4-chloro-1H-pyrrolo[2,3-b]pyridin-2-yl)phenyl)-4- methylbenzenesulfonamide (15u). Tosyl chloride (136 μl, 1 mmol) was added to a solution of compound 15ac (0.244 g, 1 mmol) and triethyl amine (0.3 mL, 2 mmol) in anhydrous DCM (5 mL) at 0 °C. The reaction mixture was allowed to stir at rt for 18 h. The reaction mixture was quenched with saturated solution of sodium hydrogen carbonate (5 mL). The organic layer was washed with brine (5 mb), dried over anhydrous sodium sulfate and removed under reduced pressure. The crude residue was purified by column chromatography (90% EtOAc in petroleum ether) to afford the titled compound as an off-white solid (199 mg, 50%).1H NMR (DMSO--d6): δ 12.39 (br s, 1H), 10.47 (br s, 1 H), 8.13 (d, J = 5.2 Hz, 1 H), 7.85 (dd, J = 2.0, 6.8 Hz, 2H), 7.69 (dd, J = 1.6, 6.4 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 7.17 (dd, J = 0.8, 6.4 Hz, 3H), 6.87 (d, J = 2.4 Hz, 1 H), 2.33 (s, 3H).

[0249] General procedure for synthesis of 5-(2-(substituted phenyl)-1H-pyrrolo[2,3-b]pyridin- 4-yl)-1H-indazol-3-amine (5a-aa). K3PO4(1M, 1.2 mL) was added to a suspension of compounds 15 (0.37 mmol), compound 9 (0.146 g, 0.56 mmol) and [1,1'-bis(di-tert- butylphosphino)ferrocene]dichloro palladium(ll) catalyst (0.028 g, 0.04 mmol) in EtOH (3 mL). The reaction mixture was heated to 120 °C for 20 h. The reaction mixture was cooled to rt, diluted with EtOAc, washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure.

[0250] 2-(4-(3-Amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)phenol (5a). The crude residue was purified by column chromatography (80% EtOAc in petroleum ether) to give the titled product as off-white solid (10 mg, 8%).1H NMR (DMSO-d6): δ 11.67 (br s, 1 H), 11.54 (br s, 1H), 10.17 (br s, 1H), 8.23 (d, J = 5.2 Hz, 1H), 8.19 (s, 1H), 7.85 (dd, J = 1.6, 7.6 Hz, 1H), 7.69 (dd, J = 1.6, 8.4 Hz, 1 H), 7.40 (d, J = 8.8 Hz, 1 H), 7.28 (s, 1H), 7.17 - 7.15 (m, 2H), 6.98 - 6.96 (m, 1H), 6.92 - 6.89 (m, 1H), 5.50 (br s, 2H). HRMS (ESI): exact mass calculated for C2oHi5ON5: 341.1349, found 342.1346 (M+1)+.

[0251] 5-(2-(2-Ethoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine (5b). The crude residue was purified by column chromatography (90% EtOAc in petroleum ether) to afford the titled compound as an off-white solid (56 mg, 41%).1H NMR (DMSO-d6): 5 11.81 (br s, 1H), 11.54 (br s, 1H), 8.25 (d, J = 5.0 Hz, 1H), 8.22 (s, 1H), 7.92 (dd, J = 2.0, 8.0 Hz, 1H), 7.72 (dd, J = 1.5, 9.0 Hz, 1 H), 7.39 - 7.37 (m, 2H), 7.34 - 7.32 (m, 1 H), 7.18 (d, J = 5.0 Hz, 1 H), 7.14 (d, J = 6.4 Hz, 1H), 7.05 (t, J = 5.8 Hz, 1H), 5.50 (br s, 2H), 4.18 (q, J = 5.5 Hz, 2H),1.44 (t, J = 7.0 Hz, 3H). HRMS (ESI): exact mass calculated for C22H19N5O: 369.1662, found 370.1660 (M+1 )+.

[0252] 5-(2-(3-Aminophenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine (5c). The crude residue was purified by flash chromatography (90% EtOAc in petroleum ether) to obtain the titled product as beige solid (21 mg, 17%).1H NMR (500 MHz, DMSO-d6) 6 12.45 (s, 1H), 8.37 (s, 1H), 8.30 (d, J = 7.8 Hz, 1H), 7.84 (d, J = 8.0 Hz 2H), 7.54 - 7.47 (m, 3H), 7.34 (t, J = 8.0 Hz, 1 H), 7.26 (d, J = 5.0 Hz, 1H), 7.15 (s, 1 H), 5.57 (s, 2H). LC-MS: exact mass calculated for C2oHi6N6: 340.14, found 341.20 (M+1 )T

[0253] 3-(4-(3-Amino- 1 H-indazol-5-yl)-1 H-pyrrolo[2, 3-b]pyridin-2-yl)phenol (5d). The crude residue was purified by column chromatography (10% MeOH in EtOAc) to obtain the titled product as brown solid (49 mg, 39%).1H NMR (400 MHz, DMSO-de) 6 12.16 (s, 1H), 11.56 (s, 1 H), 9.56 (s, 1H), 8.25 - 8.24 (m, 2H), 7.71 (dd, J = 8.5, 2.1 Hz, 1H), 7.34 (s, 1 H), 7.44 - 7.38 (m, 2H), 7.28 - 7.24 (m, 1H), 7.19 (d, J = 5.3 Hz, 1H), 6.77 (d, J = 8.0 Hz, 1 H), 7.09 (d, J = 2.2 Hz, 1H), 5.57 (s, 2H). HRMS (ESI): exact mass calculated for Ci9Hi5N5O: 341.1301 , found 341.1401 (M+1 )+.

[0254] 5-(2-(3-Methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine (5e). The crude residue was purified by column chromatography (10% MeOH in EtOAc) to afford the titled compound as a brown solid (58 mg, 44%).1H NMR (500 MHz, DMSO) 5 12.43 (s, 1H), 8.39 (s, 1H), 8.33 (d, J = 5.1 Hz, 1H), 7.89 (d, J = 8.7 Hz, 1H), 7.61 - 7.57 (m, 2H), 7.53 (d, J = 8.7 Hz, 1 H), 7.41 (t, J = 8.2 Hz, 1 H), 7.28 (d, J = 5.2 Hz, 1 H), 7.26 (s, 1 H), 6.96 (dd, J = 8.2, 2.4 Hz, 1H), 3.87 (s, 3H). LC-MS: exact mass calculated for C21H17N5O: 355.14, found 356.14 (M+1 )+.

[0255] 3-(4-(3-Amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-fluorophenol (5f). The crude residue was purified by column chromatography (10% MeOH in EtOAc) to afford the titled compound as yellow solid (29 mg, 21.9%)1H NMR (DMSO--d6): δ 12.35 (br s, 1 H), 10.11 (s, 1 H), 8.35 (s, 1 H), 8.32 (d, J = 4.8 Hz, 1H), 7.85 (dd, J = 1.6, 8.8 Hz, 1H), 7.49 (d, J = 8.4 Hz, 1 H), 7.29 - 7.26 (m, 1 H), 7.26 (d, J = 4.8 Hz, 1 H), 7.24 (t, J = 1.6 Hz, 1 H), 7.20 (d, J = 2.0 Hz, 1 H). HRMS (ESI): exact mass calculated for C20H14FN5O: 359.1255, found 360.1252 (M+1 )+.

[0256] 5-(2-(3-Fluoro-5-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine (5g). The crude solid was purified by column chromatography (90% EtOAc in petroleum ether) to give the titled compound as a yellow solid (62 mg, 45%).1H NMR (400 MHz, DMSO-de) 5 12.31 (s, 1H), 11.59 (s, 1H), 8.29 (d, J = 4.9 Hz, 1 H), 8.24 (s, 1H), 7.73 (d, J = 8.7 Hz, 1H), 7.50 - 7.43 (m, 2H), 7.40 (d, J = 8.7 Hz, 1 H), 7.32 (s, 1H), 7.22 (d, J = 5.0 Hz, 1 H), 6.85 - 6.77 (m, 1 H), 5.58 (s, 2H), 3.86 (s, 3H). LC-MS: exact mass calculated for C21H16FN5O: 373.13, Found 374.3 (M+1)+.

[0257] 3-(4-(3-Amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)benzoic acid (5h). The crude residue was purified by column chromatography (90% EtOAc in petroleum ether) to obtain the titled compound as beige solid (34 mg, 25 %).1H NMR (500 MHz, DMSO-d6): δ 12.48 (s, 1 H), 8.53 (s, 1 H), 8.34 (s, 1 H), 8.30 (d, J = 5.0 Hz, 1 H), 8.23 (d, J = 8.1 Hz, 1 H), 7.92 (d, J = 7.0 Hz, 1 H), 7.85 (d, J = 8.5 Hz 1H), 7.61 (t, J = 7.8 Hz, 1H), 7.49 (d, J = 8.7 Hz, 1 H), 7.26 - 7.24 (m, 2H), 5.54 (s, 2H). LC-MS: exact mass calculated for C2iHi5NsO2: 369.12, found 370.2 (M+1 )4.

[0258] 3-(4-(3-Amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)benzamide (5i). The crude solid was purified by column chromatography (10% MeOH in EtOAc) to obtain the titled compound as beige solid (23 mg, 17 %).1H NMR (500 MHz, DMSO-d6) 6 12.48 (s, 1 H), 8.53 (s, 1 H), 8.34 (s, 1H), 8.30 (d, J = 5.0 Hz, 1H), 8.23 (d, J = 8.1 Hz, 1 H), 7.92 (d, J = 7.0 Hz, 1H), 7.85 (d, J = 8.5 Hz 1 H), 7.61 (t, J = 7.8 Hz, 1 H), 7.49 (d, J = 8.7 Hz, 1 H), 7.26 - 7.23 (m, 2H), 5.54 (s, 2H). LC-MS: exact mass calculated for C2iHi6N6O: 368.12, found 369.2 (M+1 )4.

[0259] N-(3-(4-(3-Amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2- yl)phenyl)methanesulfonamide (5j). The crude residue was purified by column chromatography (10% MeOH in EtOAc) and triturated with Et2O to afford the titled compound as an off-white solid (14 mg, 9%).1H NMR (DMSO-cfe): 5 12.32 (br s, 1 H), 11.57 (br s, 1H), 9.83 (br s, 1H), 8.27 (d, J = 5.2 Hz, 1H), 7.70 - 7.68 (m, 3H), 8.23 (s, 1 H), 7.42 (q, J = 8.3 Hz, 2H), 7.19 - 7.16 (m, 2H), 7.07 (d, J = 2.0 Hz, 1H), 5.56 (br s, 2H), 3.09 (s, 3H). HRMS (ESI): exact mass calculated for C21 Hi8N6O2S: 418.1285, found 419.1287 (M+1 )+.

[0260] 5-(2-(3-(Methylsulfonyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine (5k). The crude solid was purified by column chromatography (10% MeOH / EtOAc) to afford the titled compound as an off-white solid (34 mg, 23%),1H NMR (DMSO-d6): 5 12.43 (br s, 1 H), 11.57 (br s, 1 H), 8.27 (t, J = 1 .2 Hz, 1 H), 8.32 - 8.30 (m, 2H), 8.25 (s, 1 H), 7.87 (d, J = 6.4 Hz, 1 H), 7.75 - 7.73 (m, 2H), 7.42 (d, J = 6.8 Hz, 1H), 7.37 (d, J = 1.6 Hz, 1 H), 7.23 (d, J = 4.0 Hz, 1H), 3.31 (s, 3H). HRMS (ESI): exact mass calculated for C21H17N5O2S: 403.1132, found 404.1172 (M+1 )4.

[0261] N-(3-(4-(3-Amino- 1 H-indazol-5-yl)- 1 H-pyrrolo[2, 3-b]pyridin-2-yl)phenyl)-3- methoxypropanamide (51). The crude residue was purified by column chromatography (90% EtOAc in petroleum ether) to obtain the titled compound as beige solid (27 mg, 17%).1H NMR (500 MHz, DMSO-de) 5 12.45 (s, 1 H), 10.08 (s, 1H), 8.32 (d, J = 6.50 Hz, 1H), 8.15 (s, 1H), 7.88 - 7.85 (m, 1 H), 7.67 (d, J = 7.8 Hz, 1H), 7.60 (d, J = 7.8 Hz, 1 H), 7.54 (d, J = 8.0 Hz, 1H), 7.43 (t, J = 10.0 Hz, 1 H), 7.25 (d, J = 6.5 Hz, 1 H), 7.06 (d, J = 1.8 Hz, 1 H), 3.63 (t, J = 8.0 Hz, 2H), 3.25 (s, 3H), 2.58 (t, J = 8.0 Hz, 2H). LC-MS: exact mass calculated for C24H22N6O2: 426.18, found 427.20 (M+1)4.

[0262] 3-(4-(3-Amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-N-(2- methoxyethyl)benzamide (5m). The resulting residue was purified by column chromatography (1% EtjN and 10% MeOH in EtOAc) to give the titled product as an off white solid (139 mg, 88%).1H NMR (500 MHz, DMSO-de) 5 12.35 (s, 1H), 8.59 (s, 1H), 8.44 (d, J = 5.0 Hz, 1H), 8.31 (d, J = 8.1 Hz, 1 H), 8.12 (d, J = 7.0 Hz, 1 H), 7.79 (d, J = 8.5 Hz 1 H), 7.57 (t, J = 7.8 Hz, 1 H), 7.49 (d, J = 8.7 Hz, 1H), 7.25 - 7.23 (m, 2H), 5.54 (s, 2H), 3.48 (bs, 2H), 3.28 (bs, 2H), 2.08 (s, 3H). LC-MS: exact mass calculated for C24H22N6O2: 426.18, found 427.20 (M+1)T

[0263] 5-(2-(3-((Cyclopentylamino)methyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3- amine (5n). The crude solid was purified by column chromatography (1% Et3N and 20% MeOH in EtOAc) to give the titled compound as a brown solid (12.5 mg, 8%).1H NMR (400 MHz, DMSO-d6) δ 12.20 (br s, 1H), 8.28 - 8.21 (m, 2 H), 7.94 (s, 1 H), 7.84 (d, J=7.47 Hz, 1 H), 7.72 (d, J=8.79 Hz, 1 H), 7.44 - 7.37 (m, 2 H), 7.32 (d, J= 7.47 Hz, 1 H), 7.21 - 7.15 (m, 2 H), 5.56 (s, 2 H), 3.74 (s, 2 H), 3.04 - 3.01 (m, 1 H), 1.74 - 1.72 (m, 2 H), 1 .65 - 1 .64 (m, 2 H), 1.46 - 1.45 (m, 2 H), 1.38 - 1.36 (m, 2 H).13C NMR (100 MHz, DMSO-d6) δ 151.02, 150.43, 147.82, 143.71, 141.65, 141.75, 139.06, 131.98, 129.18, 128.35, 127.27, 125.70, 124.17, 120.91 , 119.11, 115.07, 115.05, 110.53, 109.70, 97.35, 59.11 , 52.20, 33.02, 24.18. HRMS (ESI): exact mass calculated for CzeHzeNe: 422.2292, found 423.2289 (M+1 )+.

[0264] 5-(2-(3-lsobutoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine (5o). The crude residue was purified by column chromatography (90% EtOAc in petroleum ether) to afford the titled compound as an off-white solid (28 mg, 19%).1H NMR (DMSO--d6): δ 12.19 (br s, 1H), 11.55 (br s, 1H), 8.26 (d, J = 4.8 Hz, 1H), 8.24 (s, 1H), 7.72 (dd, J = 1.6, 8.8 Hz, 1H), 7.57 - 7.54 (m, 2H), 7.39 - 7.37 (m, 2H), 7.20 - 7.18 (m, 2H), 6.91 - 6.89 (m, 1 H), 5.54 (br s, 2H), 3.85 (d, J = 6.4 Hz, 2H), 2.06 - 2.04 (m, 1H), 1.02 (d, J = 6.8 Hz, 6H). HRMS (ESI): exact mass calculated for C24H23N5O: 397.1975, found 398.1970 (M+1 )T

[0265] N-(3-(4-(3-Amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)phenyl)-4- methylbenzensulfonamide (5t). The crude residue was purified by column chromatography (10% MeOH in EtOAc) and triturated with Et2O to afford the titled compound as an off-white solid (53 mg, 29%).1H NMR (DMSO--d6): δ 12.25 (br s, 1H), 11.58 (br s, 1 H), 10.32 (s, 1H), 8.27 (d, J = 5.2 Hz, 1H), 8.22 (s, 1H), 7.69 - 7.66 (m, 3H), 7.61 - 7.59 (m, 2H), 7.42 (d, J = 8.4 Hz, 1 H), 7.32 (t, J = 8.0 Hz, 3H), 7.18 (d, J = 4.8 Hz, 1H), 7.05 (dd, J = 1.2, 8.0 Hz, 1 H), 6.92 (d, J = 2.0 Hz, 1 H), 5.57 (br s, 2H), 3.33 (s, 3H). HRMS (ESI): exact mass calculated for CzzH^NeOzS: 494.1598, found 495.1592 (M+1)+.

[0266] 5-(2-(3-((Phenylamino)methyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3- amine (5p). The crude residue was purified by column chromatography (90% EtOAc in petroleum ether) followed by HPLC to give the titled compound as a yellow solid (25 mg, 16%).1H NMR (400 MHz, DMSO-d6): δ 12.22 (br s, 1 H), 8.26 (d, J=5.27 Hz, 1 H), 7.85 (d, >1 Al Hz, 1 H), 7.71 (d, J=9.67 Hz, 1 H), 7.41 (d, J=7.91 Hz, 2 H), 7.36 - 7.32 (m, 1 H), 7.19 (d, J=4.83 Hz, 1 H), 7.16 (d, J=1.32 Hz, 1 H), 7.04 (t, J=1.69 Hz, 3 H), 6.61 (d, J= 7.91 Hz, 3 H), 6.54 - 6.48 (m, 1 H), 6.26 - 6.20 (m, 1 H), 5.56 (s, 2 H), 4.31 (d, J= 5.71 Hz, 2 H). HRMS (ESI): exact mass calculated for C27H22NS: 430.199, found 431.1978 (M+1 )4.

[0267] 5-(2-( 2-(Benzyloxy)phenyl) - 1 H-pyrrolo[2, 3-b]pyridin-4-yl) - 1 H-indazol-3-amine (5q). The crude solid was purified by column chromatography (10% MeOH in EtOAc) and triturated with Et2O to afford the titled compound as an off-white solid (46 mg, 29%).1H NMR (DMSO-c / e): 8 11.85 (br s, 1H), 11.54 (br s, 1H), 8.24 (d, J = 4.8 Hz, 1 H), 8.16 (s, 1 H), 7.92 (dd, J = 1.6, 7.6 Hz, 1 H), 7.57 (dd, J = 1.6, 8.8 Hz, 1H), 7.53 - 7.52 (m, 2H), 7.35 - 7.30 (m, 1 H), 7.27 7.24(m, 6H), 7.22 (d, J = 4.8 Hz, 1H), 7.11 - 6.98 (m, 1H), 5.50 (br s, 2H), 5.24 (s, 2H). HRMS (ESI): exact mass calculated for C27H21N5O: 431.1719, found 432.1814 (M+1)4.

[0268] (3-( 4-(3- Amino- 1 H-indazol-5-yl)- 1 H-pyrrolo[2, 3-b]pyridin-2-yl) phenyl) (4- methylpiperazin-1-yl)methanone (5v). The resulting solid was washed with hot DCM to afford the titled compound as a brown solid (125 mg, 75%).1H NMR (DMSO-da): 6 12.29 (br s, 1H), 11.59 (br s, 1 H), 8.28 (d, J = 4.8 Hz, 1 H), 8.26 (s, 1 H), 8.06 - 8.03 (m, 1 H), 8.00 (s, 1 H), 7.73 - 7.70 (m, 1 H), 7.54 (t, J = 7.8 Hz, 1 H), 7.40 - 7.38 (m, 1 H), 7.28 (d, J = 2.0 Hz, 1 H), 7.21 (d, J = 5.2 Hz, 1 H), 5.58 (s, 2H), 3.65 - 3.62 (m, 2H), 2.41 - 2.38 (m, 2H), 2.30 - 2.27 (m, 2H), 2.20 (s, 3H). HRMS (ESI): exact mass calculated for C26H25N7O: 451.2193, found 452.2191 (M+1)4.

[0269] 5-(2-(3-(Pyridin-2-ylmethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine (5w). The crude residue was purified by column chromatography (5% MeOH in EtOAc) to obtain the titled compound as beige solid (58 mg, 36%).1H NMR (400 MHz, DMSO-de) 5 12.24 (s, 1H), 11.57 (s, 1H), 8.60 (d, J = 4.3 Hz, 1 H), 8.26 (d, J = 5.0 Hz, 1 H), 8.24 (s, 1 H), 7.88 - 7.84 (m, 1 H), 7.75 - 7.69 (m, 2H), 7.62 - 7.57 (m, 2H), 7.44 - 7.32 (m, 3H), 7.22 (d, J = 1.9 Hz, 1 H), 7.20 (d, J = 4.9 Hz, 1H), 7.02 (d, J = 8.0 Hz, 1H), 5.57 (s, 2H), 5.29 (s, 2H). HRMS (ESI): exact mass calculated for C26H2oNeO: 432.1777, found 433.1767 (M+1)4.

[0270] 5-(2-(3-((Tetrahydro-2H-pyran-4-yl)methoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H- indazol-3-amine (5x). The crude solid was purified by column chromatography (10% MeOH in EtOAc) to obtain the titled compound as white solid (26 mg, 16%).1H NMR (400 MHz, DMSO- c / s) 5 12.22 (s, 1 H), 11.57 (s, 1H), 8.26 (d, J = 5.0 Hz, 1 H), 8.24 (s, 1 H), 7.72 (dd, J = 8.8, 1.2 Hz, 1 H), 7.58 - 7.56 (m, 2H), 7.40 (d, J = 8.8 Hz, 1H), 7.38 - 7.34 (m, 1H), 7.21 - 7.18 (m. 2H), 6.92 (d, J = 7.1 Hz, 1H), 5.56 (s, 2H), 3.94 (d, J = 6.4 Hz, 2H), 3.90 (dd, J = 11.5, 3.4 Hz, 2H), 3.42 - 3.34 (m, 2H), 2.12 - 1.95 (m, 1H), 1.72 (d, J = 11.2 Hz, 2H), 1.41 - 1.32 (m, 2H). LC- MS: exact mass calculated for C26H25N5O2: 439.20, found 440.3 (M+1 )4.

[0271] 5-(2-(3-(2-Morpholinoethoxy)phenyl)-1H-pyrrolo[2, 3-b]pyridin-4-yl)-1H-indazol-3-amine (5y). The crude solid was purified by column chromatography (10% MeOH in EtOAc) to obtain the titled compound as white solid (123 mg, 73%).1H NMR (400 MHz, DMSO-d6): δ 12.20 (s, 1 H), 11.57 (s, 1 H), 8.26 (d, J = 5.0 Hz, 1 H), 8.24 (s, 1 H), 7.73 (d, J = 8.8 Hz, 1 H), 7.59 - 7.56 (m, 2H), 7.40 (d, J = 8.4 Hz, 1H), 7.38 - 7.34 (m, 1H), 7.22 (d, J = 2.1 Hz, 1 H), 7.20 (d, J = 4.9 Hz, 1H), 6.92 (d, J = 8.4 Hz, 1H), 5.56 (s, 2H), 4.19 (t, J = 5.7 Hz, 2H), 3.63 - 3.56 (m, 4H), 2.73 (t, J = 5.7 Hz, 2H), 2.48-2.51 (m, 4H). LC-MS: exact mass calculated for CZGHZGNBOZ: 454.21, found 455.3 (M+1 )T

[0272] 5-(2-( 3-(Benzyloxy) phenyl) - 1 H-pyrrolo[2, 3-b ]pyridin-4-yl) - 1 H-indazol-3-amine (5r). The crude residue was purified by column chromatography (90% EtOAc in petroleum ether) to afford the titled compound as an off-white solid (92 mg, 58%).1H NMR (500 MHz, DMSO-d6) δ 12.23 (s, 1H), 11.59 (s, 1H), 8.31 - 8.25 (m, 2H), 7.75 (dd, J = 8.6, 1.6 Hz, 1 H), 7.71 (t, J = 2.0 Hz, 1 H), 7.61 (d, J = 7.8 Hz, 1H), 7.52 (d, J = 7.5 Hz, 2H), 7.41 (dt, J = 14.4, 8.0 Hz, 4H), 7.35 (t, J = 7.4 Hz, 1H), 7.28 - 7.18 (m, 2H), 7.01 (dd, J = 8.2, 2.4 Hz, 1 H), 5.58 (s, 2H), 5.22 (s, 2H).13C NMR (126 MHz, DMSO-d6): δ 159.35, 150.94, 143.82, 141.71 , 138.56, 137.53, 133.50, 130.46, 128.36, 127.20, 120.86, 118.9, 114.99, 112.13, 110.47, 97.79, 69.86. LC-MS: exact mass calculated for C27H21N5O: 431.17, found 432.3 (M+1)*.

[0273] 5-(2-( 3-(( 4-Methoxybenzyl)oxy)phenyl)- 1 H-pyrrolo[2, 3-b]pyridin-4-yl)-1 H-indazol-3- amine (5z). The crude residue was purified by recrystallization using MeOH / DCM and hexane to afford the titled compound as an off-white solid (109 mg, 64%).1H NMR (DMSO-d6): 5 12.19 (br s, 1 H), 11 .55 (br s, 1 H), 8.26 (d, J = 5.2 Hz, 1 H), 8.24 (s, 1 H), 7.72 (dd, J = 1 .2, 8.4 Hz, 1 H), 7.66 (s, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.39 - 7.34 (m, 4H), 7.20 - 7.16 (m, 2H), 6.98 - 6.95 (m, 3H), 5.54 (br s, 2H), 5.11 (s, 2H), 3.75 (s, 3H). HRMS (ESI): exact mass calculated for C28H23N5O2: 461.1925 found 462.1922 (M+1)+.

[0274] 5-(2-(3-(Morpholinosulfonyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine (5aa). The resulting solid was suspended in EtOAc and filtered through a pad of celite and concentrated under reduced pressure to afford the titled compound as a pale-yellow solid (17.5 mg, 10%).1H NMR (DMSO--d6): δ 12.53 (br s, 1H), 11.58 (br s, 1H), 8.32 - 8.28 (m, 2H), 8.26 (s, 1H), 7.74 - 7.69 (m, 4H), 7.41 (d, J = 8.8 Hz, 1 H), 7.34 (s, 1 H), 7.23 (d, J = 4.8 Hz, 1H), 5.55 (br s, 2H), 3.65 - 3.61 (m, 4H), 2.96 - 2.92 (m, 4H). HRMS (ESI): exact mass for C24H22N6O3S: 474.1547, found 475.1548 (M+1)+.

[0275] 5-(2-(4-Benzyloxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine (5s). The resulting solid was triturated with hexane and Et2O to afford the titled compound as a paleyellow solid (75 mg, 47%).1H NMR (DMSO--d6): δ 12.09 (br s, 1 H), 11.53 (br s, 1H), 8.22 - 8.18 (m, 2H), 7.92 (d, J = 8.8 Hz, 1H), 7.71 (d, J = 1.6, 8.8 Hz, 1H), 7.49 - 7.43 (m, 2H), 7.41 - 7.37(m, 3H), 7.34 - 7.30 (m, 1H), 7.18 (d, J = 4.8 Hz, 1H), 7.12 (d, J = 8.8 Hz, 2H), 7.07 (d. J = 2.4Hz, 1H), 5.53 (br s, 2H), 5.18 (s, 2H). HRMS (ESI): exact mass calculated for C27H2IN5O: 431.1719, found 432.1813 (M+1)+.

[0276] N-(4-(4-(3-Amino-1H-indazol-5-yl)-1H-pyrrolo[2, 3-b]pyridin-2-yl)phenyl)-4- methylbenzene sulfonamide (5u). The crude residue was purified by column chromatography (10% MeOH in EtOAc) and triturated with Et2O to afford the titled compound as an off-white solid (51 mg, 28%).1H NMR (DMSO-cfe): 5 12.10 (br s, 1 H), 11.55 (br s, 1H), 10.40 (br s, 1H), 8.22 (d, J = 4.8 Hz, 1 H), 8.20 (s, 1H), 7.83 (d, J = 8.8 Hz, 2H), 7.68 (dd, J = 2.0, 8.8 Hz, 3H), 7.37 (t, J = 9.2 Hz, 3H), 7.17 (s, 1 H), 7.15 (d, J = 4.0 Hz, 1H), 7.06 (d, J = 2.0 Hz, 1H), 5.54 (br s, 2H), 2.32 (s, 3H). HRMS (ESI): calculated for C27H22N6O2S: 494.1598, found 495.1592 (M+1)+.General procedure for synthesis of 4-chloro-2-(substituted aryl)-1 H-pyrrolo[2,3-b]pyridine (17a- i).

[0277] Followed the general procedure for synthesis of compounds 15a-ac. The crude residue was used in the next step without further purification unless otherwise stated below.

[0278] 2-(6-(Benzyloxy)pyridin-3-yl)-4-chloro-1H-pyrrolo[2,3-b]pyridine (17d). The crude residue was purified by column chromatography (70% EtOAc in petroleum ether) to afford the titled compound as white solid (181 mg, 44%).1H NMR (400 MHz, DMSO-de) 5 12.55 (s, 1H), 8.82 (d, J = 2.3 Hz, 1 H), 8.33 (dd, J = 8.7, 2.3 Hz, 1 H), 8.17 (d, J = 5.2 Hz, 1 H), 7.48 (d, J = 7.0 Hz, 2H), 7.42 - 7.38 (m, 2H), 7.35 (d, J = 7.1 Hz, 1H), 7.21 (d, J = 5.1 Hz, 1 H), 7.05 - 6.99 (m, 2H), 5.42 (s, 2H). LC-MS: exact mass calculated for CigHi435CIN3O: 335.0825, found 336.1 (M+1 )+.

[0279] 2-(5-(Benzyloxy)pyridin-3-yl)-4-chloro-1H-pyrrolo[2,3-b]pyridine (17e). The crude residue was suspended in EtOAc and filtered through a pad of celite and evaporated to give the titled product as brown solid (383 mg, 93%).1H NMR (400 MHz, DMSO-de) 5 12.67 (s, 1H), 8.84 (d, J = 1.6 Hz, 1 H), 8.34 (d, J = 2.6 Hz, 1 H), 8.22 (d, J = 5.2 Hz, 1 H), 8.11 (dd, J = 2.6, 1.6 Hz, 1 H), 7.52 (d, J = 7.1 Hz, 2H), 7.43 - 7.41 (m, 2H), 7.39 - 7.35 (m, 1H), 7.25 - 7.24 (m, 2H), 5.29 (s, 2H). LC-MS: exact mass calculated for C14H1235CIN3O: 335.0825, found 336.1 (M+1)+.

[0280] 2-(2-(Benzyloxy)pyridin-4-yl)-4-chloro-1H-pyrrolo[2,3-b]pyridine (17g). The crude solid was purified by column chromatography (90% EtOAc in petroleum ether) to give the titled product as brown solid (371 mg, 90%).1H NMR (400 MHz, DMSO-ds) 5 12.72 (s, 1 H), 8.26 - 8.24 (m, 2H), 7.63 (d, J = 5.7 Hz, 11 I), 7.52 - 7.47 (m, 3H), 7.42 - 7.38 (m, 2H), 7.35 (d, J = 7.5 Hz, 1H), 7.33 (d, J = 1.8 Hz, 1 H), 7.26 (d, J = 5.3 Hz, 1 H), 5.41 (s, 2H). LC-MS: exact mass calculated for Ci9Hi435CIN3O: 335.0825, found 336.1 (M+1 )\

[0281] General procedure for synthesis of 5-(2-substituted aryl-1H-pyrrolo[2,3-b]pyridin-4-yl)~1 H-indazol-3-amine (6a-i). Followed the general procedure for synthesis of compounds 5.

[0282] 5-(2-(3-(Benzyloxy)-5-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine (6a). The crude solid was recrystallized from EtOAc to afford the titled compound as a beige solid (88 mg, 53%).1H NMR (400 MHz, DMSO-d6): δ 12.27 (s, 1H), 11.58 (s, 1H), 8.29 (d, J = 4.9 Hz, 1 H), 8.23 (s, 1 H), 7.73 (d. J = 8.4 Hz, 1 H), 7.61 - 7.31 (m, 9H), 7.22 (d, J = 4.9 Hz, 1 H), 6.90 (d, J = 10.7 Hz, 1H), 5.56 (s, 2H), 5.22 (s, 2H). bC-MS: exact mass calculated for C27H20FN5O: 449.1652, found 450.3 (M+1 )+

[0283] 5-(2-(3-(Benzyloxy)-5-((2-methoxyethoxy)methyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)- 1 H-indazol-3-amine (6b). The crude solid was washed with water (3 mb) and hexane (3 * 3 mb) to afford the titled compound as an off-white solid (146 mg, 76%).1H NMR (400 MHz, DMSO-de) 6 12.23 (s, 1H), 11.57 (s, 1H), 8.26 (d, J = 4.9 Hz, 1 H), 8.23 (s, 1H), 7.72 (d, J = 8.8 Hz, 1 H), 7.61 (s, 1 H), 7.55 (s, 1 H), 7.51 (d, J = 7.5 Hz, 2H), 7.46 - 7.38 (m, 3H), 7.38 - 7.32 (m, 1 H), 7.22 - 7.17 (m, 2H), 6.97 (s, 1 H), 5.57 (s, 2H), 5.20 (s, 2H), 4.52 (s, 2H), 3.60 - 3.55 (m, 2H), 3.53 - 3.46 (m, 2H), 3.25 (s, 3H). bC-MS: exact mass calculated for C31H29N5O3: 519.2270, found 520.3 (M+1)+

[0284] 5-(2-(3-(Benzyloxy)-5-((2-methoxyethyl)amino)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3-amine (6c). The crude product was purified by HPLC to afford the titled compound as a pale-yellow solid (26 mg, 14%).1H NMR (500 MHz, DMSO-dB) 6 12.23 (s, 1H), 8.31 (s, 1H), 8.27 (d, J = 4.9 Hz, 1H), 7.82 (d, J = 8.4 Hz, 1H), 7.49 - 7.32 (m, 6H), 7.21 (d, J = 4.9 Hz, 1H), 7.07 (d, J = 1.7 Hz, 1H), 6.90 (s, 1 H), 6.83 (s, 1 H), 5.11 (s, 2H), 3.52 - 3.48 (m, 2H), 3.38 - 3.25 (m, 7H). LC-MS: exact mass calculated for C2oH28NB02: 504.2274, found 505.30 (M+1)*

[0285] 5-(2-(6-(Benzyloxy)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine (6d). The crude solid was purified by column chromatography (10% MeOH in EtOAc) to afford the title compound as a beige solid (43 mg, 27%).1H NMR (400 MHz, DMSO-d6) 6 12.27 (s, 1H), 11.57 (s, 1 H), 8.81 (d, J = 2.3 Hz, 1 H), 8.32 (dd, J = 8.4, 2.3 Hz, 1 H), 8.25 (d, J = 5.0 Hz, 1 H), 8.23 (s, 1H), 7.72 (d, J = 8.9 Hz, 1H), 7.50 - 7.46 (m, 2H), 7.42 - 7.36 (m, 3H), 7.34 (d, J = 7.4 Hz, 1 H), 7.21 - 7.19 (m, 2H), 7.01 (d, J = 8.9 Hz, 1H), 5.56 (s, 2H), 5.42 (s, 2H). HRMS (ESI): exact mass calculated for C26H2oN60: 432.1699, found 433.1777 (M+1)+.

[0286] 5-(2-(5-(Benzyloxy)pyridin-3-yl)- 1 H-pyrrolo[2, 3-b]pyridin-4-yl)-1H-indazol-3-amine (6e). The crude solid was purified by column chromatography (1% Et3N and 10% MeOH in EtOAc) to afford the titled compound as a beige solid (86 mg, 54%)1H NMR (400 MHz, DMSO-de) 5 12.37 (s, 1H), 11.58 (s, 1 H), 8.85 (d, J = 1.6 Hz, 1H), 8.34 - 8.27 (m, 2H), 8.24 (s, 1 H), 8.08 (s, 1 H), 7.74 (d, J = 8.6 Hz, 1 H), 7.52 (d, J = 7.5 Hz, 2H), 7.47 - 7.35 (m, 5H), 7.23 (d, J = 5.0 Hz,1 H), 5.57 (s, 2H), 5.28 (s, 2H). HRMS (ESI): exact mass calculated for CzsHzoNeO: 432.1699, found 433.1777 (M+1 )+.

[0287] 5-(2-(2-Fluoro-6-((phenylamino)methyl)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H- indazol-3-amine (6f). The crude product was purified by HPLC to afford the titled compound as a pale-yellow solid (65 mg, 39%).1H NMR (500 MHz, DMSO-d6) 6 12.38 (s, 1 H), 8.49 (t, J = 5.6 Hz, 1 H), 8.35 (d, J = 5.6 Hz, 1 H), 8.29 (s, 1 H), 7.80 (d, J = 8.4 Hz, 1 H), 7.51 (d, J = 8.5 Hz, 1 H), 7.49 (d, J = 8.5 Hz, 1H), 7.26 (d, J = 8.5 Hz, 1H), 7.17 (s, 1 H), 7.07 (t, J = 8.5 Hz, 1 H), 6.62 - 6.56 (m, 3H), 4.37 (s, 2H). LR-MS: exact mass calculated for CzeHzoFN?: 449.1764, found 450.20 (M+1)+.

[0288] 5-(2-(2-(Benzyloxy)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine (6g). The crude product was purified by column chromatography (10% MeOH in EtOAc) to afford the titled compound as white solid (78 mg, 49%).1H NMR (400 MHz, DMSO-de) 6 12.43 (s, 1H), 11.58 (s, 1 H), 8.33 (d, J = 5.0 Hz, 1 H), 8.27 - 8.20 (m, 2H), 7.73 (dd, J = 8.7, 1.6 Hz, 1 H), 7.62 (dd, J = 5.4, 1.6 Hz, 1 H), 7.53 - 7.45 (m, 4H), 7.42 - 7.38 (m, 3H), 7.34 (d, J = 7.3 Hz, 1H), 7.25 (d, J = 5.0 Hz, 1 H), 5.57 (s, 2H), 5.41 (s, 2H). HRMS (ESI): exact mass calculated for CzeHzoNeO: 432.1699, found 433.1777 (M+1)+.

[0289] 5-(2-(2-(Benzylthio)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine (6h). The crude solid was purified by HPLC to afford the titled compound as a yellow solid (33 mg, 20%).1H NMR (500 MHz, DMSO-de) 5 12.51 (s, 1 H), 8.51 (d, J = 5.3 Hz, 1 H), 8.36 (d, J = 4.9 Hz, 1 H), 8.32 (d, J = 1.5 Hz, 1H) 7.92 (s, 1H), 7.85 - 7.80 (m, 1H), 7.72 (dd, J = 5.3, 1.6 Hz, 1 H), 7.50 (d, J = 2.2 Hz, 1 H), 7.48 (d, J = 8.7 Hz, 1 H), 7.46 - 7.43 (m, 2H), 7.33 - 7.29 (m, 2H), 7.27 (d, J = 5.0 Hz, 1 H), 7.26 - 7.21 (m, 1 H), 4.50 (s, 2H). LR-MS: exact mass calculated for CzeHzoNeS: 448.1470, found 449.2 (M+1)+.

[0290] 5-(2-(2-(Benzylthio)-6-fluoropyridin-4-yl)- 1 H-pyrrolo[2, 3-b]pyridin-4-yl)~ 1 H-indazol-3- amine (6i). The crude solid was purified by HPLC to afford the titled compound as yellow (29 mg, 17%).1H NMR (500 MHz, DMSO-d6): δ 12.56 (s, 1 H), 8.40 (d, J = 4.9 Hz, 1 H), 8.33 (s, 1H), 7.91 (s, 1H), 7.84 (dd, J = 8.7, 1.7 Hz, 1H), 7.61 (d, J = 1.8 Hz, 1H), 7.51 (d, J = 2.5 Hz, 3H), 7.50 - 7.46 (m, 2H), 7.34 (t, J = 7.5 Hz, 2H), 7.31 - 7.23 (m, 2H), 4.47 (s, 2H). LR-MS: exact mass calculated for C26HI9FN6S: 466.1376, found 467.1 (M+1 )+.

[0291] Synthesis of 4-(benzyloxy)-2-bromopyridine (20a). Compound 19a (0.436 g, 0.303 mL, 2.5 mmol) was added to a mixture of compound 18a (0.376 g, 2.16 mmol) and cesium carbonate (1.037 g, 3.182 mmol) in DMF (5 mL) under argon at 0 °C. The reaction mixture was allowed to warm to rt and stirred for 4 h. The reaction mixture was poured onto ice / water (20 mL) and extracted with EtOAc (3 * 50 mL). The combined organic layers was washed with brine (3x20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressureand purified by column chromatography (50% EtOAc in petroleum ether) to afford the titled compound as a light brown solid (466 mg, 82%).1H NMR (400 MHz, DMSO-ofe) 5 8.20 (d, J = 5.8 Hz, 1H), 7.54 - 7.34 (m, 6H), 7.11 (dd, J = 5.8, 2.3 Hz, 1H), 5.24 (s, 2H). LR-MS: exact mass calculated for Ci2Hw79BrNO: 262.9946, found 264.0 (M+1 )+.

[0292] General procedure for synthesis of 4-bromo-2-(aryloxy)pyridine (20b, c). Potassium tert-butoxide (0.58 g, 1.36 mmol) in anhydrous THF (10 mL)was added to a solution of compound 18b (0.2 g, 1.136 mmol) in anhydrous THF (5 mL) at 0 °C. Compounds 19b, c (1.36 mmol) were then added, and the resulting mixtures allowed to warm to rt and stirred for 4 h. The reaction mixtures were poured onto ice / water (20 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers was washed with brine (3 x 20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue was used in the next step without further purification unless otherwise stated below.

[0293] 4-Bromo-2-(pyridin-4-ylmethoxy)pyridine (20b). The crude residue was purified by column chromatography (50% EtOAc in petroleum ether) to afford the titled compound as a light brown oil (240 mg, 80%).1H NMR (500 MHz, DMSO-d6) δ 8.56 (ddd, J = 4.8, 1.8, 0.9 Hz, 1 H), 8.07 (d, J = 5.4 Hz, 1H), 7.81 (td, J = 7.7, 1.8 Hz, 1H), 7.45 (dt, J = 7.9, 1.0 Hz, 1 H), 7.33 (ddd, J = 7.6, 4.9, 1.2 Hz, 1H), 7.29 - 7.24 (m, 2H), 5.44 (s, 2H). LR-MS: exact mass calculated for CiiH979BrN2O: 263.9898, found 265.0 (M+1 )+.

[0294] General procedure for synthesis of 2-(substituted aryl)-4,4,5,5-tetramethyl-1 ,3,2- dioxaborolane (21a-c). A suspension of 20a-c (6.3747 mmol), [1,1 - bis(diphenylphosphino)ferrocene] dichloropalladium(ll) (0.238 g, 0.325 mmol), potassium acetate (1.918 g, 19.541 mmol), and bis(pinacolato)diboron (2.15 g, 8.466 mmol) in dioxane (9 mL) and water (1 mL) under argon was allowed to stir at 110 °C for 18 h. The reaction was cooled and diluted with EtOAc (30 mL), washed with water (3 x 20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue was used in the next step without further purification unless otherwise stated below.

[0295] 2-(Pyridin-4-ylmethoxy)-4-(4, 4, 5, 5-tetramethyl-1 ,3, 2-dioxaborolan-2-yl) pyridine (21b). The crude residue was purified by column chromatography on (70% EtOAc in petroleum ether) to afford the titled compound as a brown solid (978 mg, 49%).1H NMR (500 MHz, DMSO-cfe) 6 8.64 (s, 2H), 8.18 (dd, J = 5.0, 0.8 Hz, 1H), 7.45 (s, 2H), 7.17 (dd, J = 5.0, 0.8 Hz, 1 H), 7.11 (s, 1 H), 5.43 (s, 2H), 1.30 (s, 12H). LR-MS: exact mass calculated for C17H21BN2O3: 312.1645, found 313.0 (M+1)+.

[0296] 2-Phenethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (21c). The crude residue was purified by column chromatography (50% EtOAc in petroleum ether) to afford the titled compound as a brown solid (832 mg, 40%).1H NMR (500 MHz, DMSO-d6) δ 8.19 (dd, J =4.9, 0.9 Hz, 1 H), 7.31 (d. J = 4.9 Hz, 4H), 7.22 (d, J = 4.3 Hz, 1H), 7.12 (dd, J = 4.9, 0.9 Hz, 1 H), 6.91 (d, J = 1.0 Hz, 1 H), 4.46 (t, J = 6.8 Hz, 2H), 3.02 (t, J = 6.8 Hz, 2H), 1.30 (s, 12H). LR-MS: exact mass calculated for C19H24BNO3: 325.1849, found 326.1 (M+1 )+.

[0297] Synthesis ooff 4-chloro-1 -(methoxymethyl)-l H pyrrolo[2,3-b]pyridine (23b). Methoxymethyl chloride (3.1659 g, 39.33 mmol)was added to a solution of 4-chloro-1H- pyrrolo[2,3-b]pyridine (22, 5.0 g, 32.77 mmol) and potassium carbonate (6.793 g, 49.15 mmol) in DMF (20 mL) at 0 °C. The reaction mixture was allowed to warm to rt and stirred for 18 h. The reaction was poured onto ice / water and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (3 x 20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue was purified by column chromatography (90% EtOAc in petroleum ether) to afford the titled compound as a beige solid (4.62 g, 72%).1H NMR (500 MHz, DMSO-dfi) 6 8.26 (d, J = 5.2 Hz, 1 H), 7.78 (d, J = 3.6 Hz, 1 H), 7.29 (d, J = 5.2 Hz, 1H), 6.61 (d, J = 3.6 Hz, 1 H), 5.62 (s, 2H), 3.22 (s, 3H). LR-MS: exact mass calculated for CgH935CIN2O: 196.0403, found 197.3 (M+1 )\

[0298] Synthesis of tert-butyl 4-chloro-1H-pyrrolo[2,3-b]pyridine-1 -carboxylate (23a). Di-fert- butyl dicarbonate (20.70 g, 21.81 mL, 94.85 mmol) was added to a solution of 4-chloro-1 H- pyrrolo[2,3-b]pyridine (22, 9.6 g, 62.92 mmol) and 4-dimethylaminopyridine (11.59 g, 94.85 mmol) in DMF (10 mL) under argon at rt. The reaction mixture was stirred at rt for 18 h. The reaction was extracted bewteen EtOAc and water. The combined organic layers were washed with brine (3 x 20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue was purified by column chromatography (50% EtOAc in petroleum ether) to afford the titled product as a beige solid (15.69 g, 99%).1H NMR (500 MHz, DMSO-de) 5 8.36 (d, J = 5.2 Hz, 1 H), 7.89 (d, J = 4.0 Hz, 1 H), 7.44 (dd, J = 5.2, 1.1 Hz, 1 H), 6.74 (dd, J = 4.1 , 1.2 Hz, 1H), 1.62 (s, 9H). LR-MS: exact mass calculated for CI2HI335CIN2O2: 252.0666, found 253.3 (M+1)+.

[0299] General procedure for synthesis of N-Protected-4-chloro-2-iodo-1H-pyrrolo[2,3- b]pyridine (24a, b). n-Butyllithium (8.7 mL, 8.70 mmol, 1 M solution in THF) was slowly added to a solution of compounds 23a, b (7.253 mmol) in anhydrous THF at -78 °C under argon. The reaction mixture was allowed to stir for 30 minutes at 0 °C. Iodine (1.0125 g, 7.978 mmol) in THF (10 mL) was slowly added at -78 °C. The reaction mixture was allowed to warm to rt and stirred for 2 h. The reaction was poured onto ice / H2O and extracted with EtOAc (3 * 50 mL). The combined organic layers were washed with saturated ammonium chloride (20 mL), water (20 mL) and brine (20 mL). The organic layer was dried over anhydrous sodium sulfate and removed under reduced pressure.

[0300] 4-Chloro-2-iodo-1-(methoxymethyl)-1H-pyrrolo[2,3-b]pyridine (24b). The crude residue was purified by column chromatography (90% EtOAc in petroleum ether) to afford the titled compound as a light brown solid (1 g, 43%).1H NMR (500 MHz, DMSO-c / 6) 5 8.21 (d, J = 5.2 Hz, 1 H), 7.29 (d, J = 5.2 Hz, 1H), 7.01 (s, 1 H), 5.61 (s, 2H), 3.23 (s, 3H). LR-MS: exact mass calculated for C9H835CIIN2O: 321.9370, found 323.0 (M+1)*.

[0301] tert-Butyl 4-chloro-2-iodo-1 H-pyrrolo[2,3-b]pyridine-1 -carboxylate (24a). The crude solid was purified by column chromatography (50% EtOAc in petroleum ether) to afford the titled compound as a light brown solid (1.8 g, 65%).1H NMR (500 MHz, DMSO-ofe) 6 8.19 (t, J = 1.0 Hz, 1 H), 7.53 (t, J = 1.4 Hz, 1 H), 7.05 (dd, J = 1.7, 0.9 Hz, 1H), 1.58 (s, 9H). LR-MS: exact mass calculated for Ci2Hi235CIIN2O2: 377.9632, found 379.4 (M+1 )+.

[0302] General procedure for synthesis of N-Protected-4-chloro-2-(substituted aryl)-1H- pyrrolo[2,3-b]pyridine (25a-c). A mixture of compounds 21a-c (3.139 mmol), compounds 24a, b (2.64 mmol), bis(triphenylphosphine)palladium(ll) dichloride (0.0926 g, 0.132 mmol) and cesium carbonate (2.58 g, 7.9 mmol) was suspended in dioxane (9 mL) and water (1 mL) under argon. The reaction mixture was stirred at 80 °C for 18 h. The reaction was cooled, diluted with EtOAc and washed with water (3 x 20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue was used in the next step without further purification unless otherwise stated below.

[0303] 2-(4-(Benzyloxy)pyridin-2-yl)-4-chloro-1-(methoxymethyl)-1H-pyrrolo[2,3-b]pyridine (25a). The crude residue was purified by column chromatography (1% Et3N and 50% EtOAc in petroleum ether) to afford the titled compound as a brown solid (990 mg, 99%).1H NMR (500 MHz, DMSO-d6) δ 8.54 (d, J = 5.7 Hz, 1H), 8.34 (d, J = 5.2 Hz, 1H), 7.73 (d, J = 2.4 Hz, 1H), 7.54 - 7.48 (m, 2H), 7.44 (td, J = 7.3, 6.3, 1 .5 Hz, 2H), 7.38 (dd, J = 8.0, 6.2 Hz, 2H), 7.25 (s, 1 H), 7.10 (dd, J = 5.8, 2.4 Hz, 1H), 6.21 (s, 2H), 5.33 (s, 2H), 3.08 (s, 3H). LR-MS: exact mass calculated for C2iHi835CIN3O2: 379.1088, found 380.3 (M+1 )+.

[0304] General procedure for synthesis of 5-(2-substituted aryl-1H-pyrrolo[2,3-b]pyridin-4-yl)~ 1 H-indazol-3-amine (6j-l). A mixture of compounds 25a-c (2.373 mmol), compound 9 (0.0676 g, 0.261 mmol), (1,T-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(ll) catalyst (0.0154 g, 0.0236 mmol) and cesium carbonate (0.232 g, 0.712 mmol) was suspended in dioxane (9 mL) and water (1 mL). The reaction mixture was stirred at 110 °C for 18 h. The reaction was cooled, diluted with EtOAc and washed with water (3 * 20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue was then taken up in concentrated HCI / MeOH (4:1, 5 mL) for 6j or TBAF (5 mL, 1M solution in THE) for 6k, I and refluxed for 8 h. The reaction mixture was cooled and concentrated under reduced pressure.

[0305] 5-(2-(4-(Benzyloxy)pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine (6j). The crude residue was purified by HPLC to afford the titled compound as an orange solid (35 mg, 31%)1H NMR (500 MHz, DMSO-d6): δ 12.60 (s, 2H), 8.57 (d, J = 5.9 Hz, 1 H), 8.41 (d, J = 5.1 Hz, 1H), 8.35 (d, J = 1.5 Hz, 1H), 7.95 (d, J = 2.4 Hz, 1H), 7.85 (dd, J = 8.7, 1.7 Hz, 1H), 7.63 (s, 1 H), 7.57 - 7.51 (m. 4H), 7.48 - 7.44 (m, 2H), 7.43 - 7.38 (m, 1 H), 7.32 (d, J = 5.0 Hz, 1 H), 7.17 (dd, J = 6.2, 2.4 Hz, 1H), 5.37 (s, 2H). LR-MS: exact mass calculated for C26H2oN60: 432.1699, found 433.3 (M+1)*.

[0306] 5-(2-(2-(Pyridin-4-ylmethoxy)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3- amine (6k). The crude residue was purified by HPLC to afford the titled compound as a bright yellow solid (11 mg, 10%).1H NMR (500 MHz, DMSO-de) 5 12.60 (s, 1H), 8.83 (d, J = 5.7 Hz, 2H), 8.43 - 8.38 (m, 2H), 8.21 (d, J = 5.5 Hz, 1H), 7.92 - 7.88 (m, 3H), 7.69 - 7.65 (m, 2H), 7.54 (d, J = 7.5 Hz, 2H), 7.31 (d, J = 5.0 Hz, 1H), 5.69 (s, 2H). LR-MS: exact mass calculated for C25H19N7O: 433.1651, found 434.3 (M+1)*.

[0307] 5-(2-(2-Phenethoxypyridin-4-yi)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine (61). The crude residue was purified by HPLC to afford the titled compound as a bright yellow solid (13 mg, 11%).1H NMR (400 MHz, DMSO-d6) 6 12.56 - 12.13 (m, 1H), 11.58 (s, 1 H), 8.34 (d, J = 5.0 Hz, 1 H), 8.27 - 8.23 (m, 1 H), 8.22 (d, J = 5.5 Hz, 1 H), 7.74 (dd, J = 8.7, 1.6 Hz, 1 H), 7.59 (dd, J = 5.4, 1.5 Hz, 1 H), 7.47 (d, J = 1.9 Hz, 1H), 7.44 - 7.39 (m, 2H), 7.37 - 7.30 (m, 4H), 7.25 (dd, J = 5.6, 2.1 Hz, 2H), 5.56 (s, 2H), 4.54 (t, J = 6.9 Hz, 2H), 3.08 (t, J = 6.8 Hz, 2H). LR- MS: exact mass calculated for C27H22N6O: 446.1855, found 446.3 (M+1)+.Pharmacokinetic studies

[0308] Pharmacokinetic studies were contracted to Sygnature Discovery Limited. Intrinsic clearance and half life were determined using cryopreserved pooled mouse CD1 hepatocytes. Test compounds were analysed at 1 pM in Williams Media E buffer (0.01% DMSO) at a cell density of 0.5 x 10scells mL1. Cells were incubated at 37 °C for one hour with shaking and compound depletion was measured by LC-MS / MS at six timepoints (0.25, 5, 10, 20, 40, and 60 minutes).

[0309] In vivo pharmacokinetic studies were carried out in CD1 mice in triplicate intravenously at a dose of 1 mg kg-1and intraperitoneally at a dose of 10 mg kg-1. Prior formulation / solubility assessment was performed in routine excipients e.g., DMSO: cyclodextrin or HMPC / Tween 80. Intravenous time points were taken at 5 min, 15 min, 30 min, 1, 2, 4, 8, and 24 hours and intraperitoneal time points were taken at 15 min, 30 min, 1, 2, 4, 6, 8, and 24 hours. Blood samples were prepared by protein precipitation with methanol or acetonitrile containing internal standard and then measured quantitative bioanalysis by LC-MS / MS.References1. Gamble, C., et al., Inhibitory kappa B Kinases as targets for pharmacological regulation.British journal of pharmacology, 2012. 165(4): p. 802-819.2. Cohen, M.S., et al., Structural bioinformatics-based design of selective, irreversible kinase inhibitors. Science, 2005. 308(5726): p. 1318-1321.3. Paul, A., et al., Inhibitory-KB kinase (IKK) a and nuclear factor-KB (NFKB)-inducing kinase (NIK) as anti-cancer drug targets. Cells, 2018. 7(10): p. 176.4. Liu, S., et ah, Crystal structure of a human IKB kinase (3 asymmetric dimer. Journal of Biological Chemistry, 2013. 288(31): p. 22758-22767.5. Polley, S., et al., Structural Basis for the Activation of IKK1 / a. Cell reports, 2016. 17(8): p. 1907-1914.6. Anthony, N.G., et al, Inhibitory kappa B kinase a (IKKa) inhibitors that recapitulate their selectivity in cells against isoform-related biomarkers. Journal of medicinal chemistry, 2017. 60(16): p. 7043-7066.7. Christopher John Andrew, J.D.K., Lackey Karen Elizabeth, LH-indazole-3-amine compounds as IKK1 inhibitors, S.B.C. Glaxo group LTD, Editor. 2008.8. Ishiyama, T., et al., A Stoichiometric Aromatic CD H Borylation Catalyzed by Iridium (i) / 2, 2'-Bipyridine Complexes at Room Temperature. Angewandte Chemie International Edition, 2002. 41(16): p. 3056-3058.9. Miyaura, N., K. Yamada, and A. Suzuki, A new stereospecific cross-coupling by the palladium-catalyzed reaction of 1 -alkenylboranes with 1 -alkenyl or 1-alkynyl halides. Tetrahedron Letters, 1979. 20(36): p. 3437-3440.10. D'Alterio, M.C., et al., Mechanistic Aspects of the Palladium -Catalyzed Suzuki -Miyaura Cross -Coupling Reaction. Chemistry-A European Journal, 2021. 27(54): p. 13481-13493.11. Ishiyama, T., M. Murata, and N. Miyaura, Palladium (O)-catalyzed cross-coupling reaction of alkoxydiboron with haloarenes: a direct procedure for arylboronic esters. The Journal of Organic Chemistry, 1995. 60(23): p. 7508-7510.Additional Experimental Section

[0310] General Methods. Unless otherwise stated, commercially available materials were used without further purification. Air- or moisture-sensitive reactions were carried out under a nitrogen atmosphere. Anhydrous solvents were obtained from Sigma-Aldrich. Flash chromatography was performed using silica gel under standard techniques1(Acros, 60 A, 35-70 pm) or using a Biotage SP4 automated chromatography system (SNAP KP-Sil, 60 A, 40-63 pm cartridges; detection wavelength: 254 nm; monitoring: 280 nm). NMR spectra (1H and13C) were recorded on either a JEOL ECX-400 (400 MHz); Bruker Avance3 / DPX400 (400 MHz) or Bruker Avance / DPXSOO (500 MHz) instruments. Chemical shifts (5) are quoted in parts per million (ppm) relative to an internal solvent reference. Coupling constants (J) are recorded in Hertz. Low resolution mass spectroscopy was carried out on ThermoFinnigan LCQ Duo by direct infusion, high resolution mass spectroscopy was carried out on a Exactive (thermo scientific) LCMS mass spectrometer. Reverse phase HPLC purifications were conducted on a Water HPLC system comprising a Waters 1525 binary HPLC pump, Waters 717 autosampler, Waters 2487 dual A absorbance detector (254 nm), using a semi-preparative (50 x 21 .2 mm) Luna 5p C18 column( eluting with an acetonitrile / water gradient with 0.1% TFA in each solvent using the following gradient;Time (min) Flow rate (ml / min) % Water 0.1% TFA % Acetonitrile 0.1% TFA0 6 90 1025 6 50 5030 6 30 7035 6 90 1040 0 90 10

[0311] Microwave reactions were carried out using a Biotage Initiator-8 Microwave synthesiser (operating at 2.45 GHz). Thin-layer chromatography (TLC) was carried out on aluminium-backed SiC>2 plates (Merck, silica gel 60, F254) and spots visualised using ultra-violet light (254 nm) or by staining with potassium permanganate. All tested compounds were determined to be >95 % purity by LC-MS and analytical HPLC unless otherwise stated.General procedures

[0312] All commercially available reagents and solvents used were obtained from Sigma- Aldrich, Fluorochem Fisher Scientific, Acros, Alfa Aesar, Apollo scientific and AdvancedChemBlocks and used without further purification.Air- or moisture-sensitive reactions were carried out under argon or nitrogen atmosphere.

[0313] Microwave reactions were carried out using a Biotage Initiator system.

[0314] Flash chromatography was performed using a Biotage SP4 automated chromatography system using silica stationary phase (Fisher Scientific, 60 A, 35-70 micron; detection wavelength: 254 nm; monitoring: 280 nm) and the mobile phase used are detailed in the text.

[0315] Reverse phase HPLC purifications were conducted on Shimadzu Prominance HPLC using a semi-preparative (50 x 21.2 mm) Luna 5pm C18 column at 40 °C; flow rate: 6 ml / min; detection wavelength: 254 nm eluting with an acetonitrile / water gradient with 0.1% TFA.

[0316] NMR spectra were recorded on either a Bruker Avance3 / DPX400 (400 MHz), Bruker DRX500 (500 MHz), Bruker AV400 (400 MHz), Bruker AV500HD (500 MHz) or Bruker AV600 (600 MHz) instrument and analysed using Advanced Chemistry Development Labs (ACD / labs) NMR processor 12.00 or MestReNova 10.0 software. Chemical shifts (5) are recorded in parts per million (ppm) relative to an internal solvent reference (tetramethylsilane) and coupling constants (J) in Hertz (Hz). Splitting patterns were indicated as singlet (s), broad singlet (br. s), doublet (d), doublet of doublet (dd), triplet (t), quartet (q) and multiplet (m).

[0317] LCMS was carried out on an Agilent Technologies 1220 series LC system with Agilent 6100 series quadrupole mass spectrometer in ESI / APCI mode. Separation was achieved with an Agilent Eclipse C18 4.6x50 mm column; flow rate:1 ml / min; detection:254 nm; sample volume: 10 pl; mobile phase: acetonitrile / 5mM ammonium acetate :water / 5mM ammonium acetate; 5%, 1.48 min; 5-100%, 8 min; 100%, 13.5 min; 100-5%, 16.5 min; 18 min. HRMS was carried out on an Exactive (Thermo scientific) or LTQ orbitrap (Thermo scientific).Arylalkyl substituents at position 2 of the aminopyridine ring5-[2-(Benzylamino)pyridin-4-yl]-1H-indazol-3-amine SU1067A suspension of N-benzyl-4-chloropyridin-2-amine (0.104 g, 0.48 mmol), 2-fluoro-5-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzonitrile (0.164 g, 0.66 mmol), [1 ,1 -bis(di-tert- butylphosphino)ferrocenejdichloropalladium(ll) catalyst (0.029 g, 0.04 mmol) in IPA / H2O (3:1.5 mL) was degassed with nitrogen. t-Butylamine (0.25 mL, 2.38 mmol) was then added and degassed using nitrogen. The reaction was placed in a microwave and irradiated at 160 °C for 40 min. Once cooled to room temperature the reaction mixture was concentrated under reduced pressure the suspended in EtOH (4.5 mL). To this suspension was added hydrazine hydrate (0.20 mL, 4.00 mmol) and the reaction mixture was placed in a microwave and irradiated at 165 °C for 30 min. The reaction mixture was diluted with EtOAc and concentrated under reduced pressure. Purification of the resulting solid was carried out using column chromatography (100% Hexane to 100% EtOAc). The resulting solid was triturated with Et2O and filtered under reduced pressure to give the title compound as a pale yellow solid (0.051 g, 0.16 mmol).1H NMR (400 MHz, DMSO-d6): 8 4.54 (d, J = 6.0 Hz, 2H), 5.48 (br s, 2H), 6.78- 6.80 (m, 2H), 7.09 (t, J = 6.0, Hz, 1 H), 7.20-7.23 (m, 1 H), 7.29-7.37 (m, 5H), 7.50 (d, J = 8.8 Hz, 1 H), 7.99 (d, J = 5.2 Hz, 1 H), 8.06 (s, 1 H), 11.52 (br s, 1 H). HRMS: For Ci9H18N5requires 316.1557 found 316.1553. (M+H)*3-(((4-(3-Amino-1H-indazol-5-yl)pyridin-2-yl)amino)methyl)benzonitrile SU12204-(((4-Bromopyridin-2-yl)amino)methyl)benzonitrile (0.101 g, 0.35 mmol, 1 eq), 5-(4, 4,5,5- tetramethyl-1 ,3,2-dixaboralan-2-yl)-1 / - / -indazol-3-amine (0.136 g, 0.53 mmol, 1.5 eq), [1,1 - bis(di-tert-butylphosphino)ferrocene]dichloropalladium(ll) catalyst (0.011 g, 17.5 pmol, 0.05 eq) and potassium phosphate (0.186 g, 0.88 mmol, 2.5 eq) were dissolved in ethanol (0.75 ml) andwater (0.75 ml) and heated at 100°C overnight. The solvent was removed at reduced pressure and the residue purified by preparative HPLC to give the desired compound (64 mg, 0.12 mmol, 40%) as a yellow powder1H NMR (500 MHz, DMSO) 5H 8.83 (br s, 1H), 8.32 (s, 1H), 8.04 (d, J = 6.7 Hz, 1 H), 7.90 (d, J = 1 .6 Hz, 1 H), 7.79 (d, J = 7.8 Hz, 1 H), 7.76 (d, J = 7.8 Hz, 1 H), 7.67 (dd, J = 8.8 and 1.6 Hz, 1H), 7.61 (dd, J = 7.8 and 7.8 Hz, 1H), 7.38 (d, J = 8.8 Hz, 1 H), 7.25 (s, 1H), 7.22 (d, J = 6.7 Hz, 1H), 4.73 (s, 1 H);13C NMR (125 MHz, CDCb) 5C150.5, 142.4, 132.8, 132.8, 131.8, 131.5, 131.5, 130.4, 125.7, 125.2, 125.1 , 121.3, 119.2, 119.2, 115.1 , 112.0, 112.0, 111.0, 111.045.7.5-(2-((3-Methoxybenzyl)-amino)pyridin-4-yl)-1H-indazol-3-amine SU12224-Bromo-N-(3-methoxybenzyl)pyridin-2-amine (0.101 g, 0.35 mmol, 1 eq), 5-(4, 4,5,5- tetramethyl-1 ,3,2-dixaboralan-2-yl)-1H-indazol-3-amine (0.136 g, 0.525 mmol, 1.5 eq), [1,1 - bis(di-tert-butylphosphino)ferrocene]dichloropalladium(ll) catalyst (0.011mg, 17.5 pmol, 0.05 eq) and potassium phosphate (0.186 g, 0.875 mmol, 2.5 eq) were dissolved in ethanol (0.75 ml) and water (0.75 ml) and heated at 100°C overnight. The solvent was removed at reduced pressure and the residue purified by preparative HPLC to give the desired compound (0.092 g, 0.20 mmol, 57%) as a yellow powder.1H NMR (500 MHz, DMSO) 5H 8.95 (br s, 1H), 8.34 (s, 1 H), 8.04 (d, J = 6.8 Hz, 1 H), 7.68 (d, J = 8.3 Hz, 1 H), 7.39 (d, J = 8.8 Hz, 1 H), 7.33-7.30 (m, 2H), 7.23 (d, J = 6.8 Hz, 1 H), 7.02-6.99 (m, 2H), 6.89 (dd, J = 8.3 and 2.1 Hz, 1 H), 4.64 (s, 2H), 3.76 (s, 3H);13C NMR (125 MHz, DMSO) 5c 160.0, 158.7, 153.6, 150.6, 142.4, 139.0, 130.3, 130.3, 125.7, 125.0, 121.4, 120.1 , 120.1, 115.1, 113.9, 113.5, 111.0, 110.8, 55.6.2-(3-(((4-(3-Amino-1H-indazol-5-yl)pyridin-2-yl)amino)methyl)phenyl)propan-2-ol SU12324-Bromo-A / -(3-methoxybenzyl)pyridin-2-amine (0.112 g, 0.35 mmol, 1 eq), 5-(4, 4,5,5- tetramethyl-1 ,3,2-dixaboralan-2-yl)-1H-indazol-3-amine (0.136 g, 0.525 mmol, 1.5 eq), [1,1 - bis(di-tert-butylphosphino)ferrocene]dichloropalladium(ll) catalyst (0.011 g, 17.5 pmol, 0.05 eq) and potassium phosphate (0.186 g, 0.875 mmol, 2.5 eq) were dissolved in ethanol (0.75 ml) and water (0.75 ml) and heated at 100°C overnight. The solvent was removed at reduced pressure and the residue purified by preparative HPbC to give the desired compound (0.057 g, 0.12 mmol, 33%) as a yellow powder.1H NMR (500 MHz, DMSO) 5H8.98 (br s, 1 H), 8.35 (d, J = 1.2 Hz, 1H), 8.04 (d, J = 6.8 Hz, 1H), 7.69 (dd, J = 8.8 and 1.7 Hz, 1H), 7.57 (s, 1H), 7.42- 7.39 (m, 2H), 7.35-7.32 (m, 2H), 7.25-7.22 (m, 2H), 4.66 (s, 2H), 1.43 (s, 6H);13C NMR (125 MHz, CDCb) 5C153.4, 151.6, 150.4, 142.5, 138.8, 136.5, 128.7, 128.7, 125.8, 125.8, 125.6, 125.0, 124.5, 124.5, 121.4, 115.0, 111.1, 110.7, 71.1 , 45.9, 32.5.5-(2-((4-(Trifluoromethyl)benzyl)amino)pyidin-4-yl)-fH-indazol-3-amine SU1095HN-NNH2N N HCF3A suspension of 4-chloro-A / -(4-(trifluoromethyl)benzyl)pyridine-2-amine (0.101 g, 0.35 mmol), 2- fluoro-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzonitrile (0.147 g, 0.59 mmol), [1,1 - bis(di-tert-butylphosphino)ferrocene]dichloropalladium(ll) catalyst (0.029 g, 0.04 mmol) in IPA / H2O (3:1.5 mb) was degassed with nitrogen. f-Butylamine (0.20 mb, 1.90 mmol) was then added and degassed using nitrogen. The reaction was placed in a microwave and irradiated at 160 °C for 40 min. The reaction was diluted with EtOAc and concentrated under reduced pressure. EtOH (4 mL) was added followed by hydrazine hydrate (0.2 mb, 4.0 mmol) and the mixture Irradiated at 165 °C for 30 min. The reaction mixture was then concentrated under reduced pressure and purified using column chromatography (100 % EtOAc - 20% MeOH / EtOAc). The resulting solid was recrystalised from Et2O and hexane, filtered and dried to give the title compound as an off-white solid (0.050 g, 0.13 mmol, 37 %).1H NMR (400 MHz, DMSO--d6): δ 4.63 (d, J = 6.0 Hz, 2H), 5.48 (br s, 2H), 6.80-6.82 (m, 2H), 7.23 (t, J = 6.2, Hz, 1 H), 7.30 (d, J = 8.8 Hz, 1 H), 7.51 (dd, J = 1.6, 8.8 Hz, 1 H), 7.56 (d, J = 8.0 Hz, 2H), 7.68 (d, J = 8.4 Hz, 2H), 7.98 (d, J = 6.0 Hz, 1 H), 8.07 (s, 1H), 11.52 (br s, 1H). HRMS: For C20H17N5F3 requires 384.1431 found 384.1425. (M+H)+4-(((4-(3-Amino-1H-indazol-5-yl)pyridin-2-yl)amino)methyl)benzonitrile SU12124-(((4-Bromopyridin-2-yl)amino)methyl)benzonitrile (0.432 g, 1.5 mmol, 1 eq), 5-(4, 4,5,5- tetramethyl-1 ,3,2-dixaboralan-2-yl)-1H-indazol-3-amine (0.584 mg, 2.25 mmol, 1.5 eq), [1,1 - bis(di-tert-butylphosphino)ferrocene]dichloropalladium(ll) catalyst (0.049 mg, 75 pmol, 0.05 eq) and potassium phosphate (0.796 g, 3.75 mmol, 2.5 eq) were dissolved in ethanol (3 ml) and water (3 ml) and heated at 100°C overnight. The solvent was removed at reduced pressure and the residue purified by preparative HPbC to give the desired compound (0.446 g, 0.98 mmol, 65%) as a yellow powder (bC-MS purity = 99%).1H NMR (500 MHz, DMSO) 5H 9.00 (br s, 1H), 8.35 (d, J = 1.6 Hz,1H), 8.05 (d, J = 6.7 Hz, 1 H), 7.87 (d, J = 8.3 Hz, 2H), 7.71 (dd, J = 8.8 and 1.6 Hz, 1 H), 7.61 (d, J = 8.3 Hz, 1H), 7.40 (d, J = 8.8 Hz, 1H), 7.28 (s, 1 H), 7.24 (d, J = 6.7 Hz, 1H), 4.80 (s, 1H);13C NMR (125 MHz, DMSO) 6C159.0, 153.7, 150.3, 143.5, 142.5, 133.1 , 128.7, 126.1 , 125.2, 121.5, 119.2, 115.0, 111.1, 111.1, 110.8, 45.0.5-(2-((4-(Tert-butyl)benzyl)amino)pyridin-4-yl)-1H-indazol-3-amine SU1114A suspension of 4-bromo-N-(4-fert-butyl)benzyl)pyridine-2-amine (0.087 g, 0.27 mmol), 2- fluoro-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzonitrile (0.117 g, 0.47 mmol), [1,1 - bis(di-tert-butylphosphino)ferrocene]dichloropalladium(ll) catalyst (0.017 g, 0.03 mmol) in IPA / H2O (3:1.5 mb) was degassed with nitrogen. t-Butylamine (0.15 mb, 1.43 mmol) was then added and degassed using nitrogen. The reaction was placed in a microwave and Irradiated at 160 °C for 40 min. The reaction was diluted with EtOAc and concentrated under reduced pressure. EtOH (4 mL) was added followed by hydrazine hydrate (0.2 mb, 4.00 mmol) and themixture irradiated at 165 °C for 30 min. The reaction mixture was then concentrated under reduced pressure and purified using column chromatography (100 % EtOAc 20 % Methanol / EtOAc). The resulting solid was recrystallised from methanol and hexane, filtered and dried to give the title compound as an off-white solid (0.018 g, 0.048 mmol, 17 %).1H NMR (400 MHz, DMSO-d6): 8 1.26 (s, 9H), 4.49 (d, J = 6.0 Hz, 2H), 5.45 (br s, 2H), 6.77 (s, 1H), 6.78 (dd, J = 1.6, 5.6 Hz, 1 H), 6.99 (t, J = 6.0, Hz, 1 H), 7.27-7.34 (m, 5H), 7.50 (dd, J = 2.0, 8.8 Hz, 1 H), 7.99 (d, J = 5.6 Hz, 1 H), 8.05 (s, 1 H), 11.49 (br s, 1 H). HRMS: For C23H26N5 requires 372.2183 found 372.2182. (M+H)+2-(4-(((4-(3-Amino-1H-indazol-5-yl)pyridin-2-yl)amino)methyl)phenyl)propan-2-ol SU1229N-NHH2NN N H'OH4-Bromo-N-(3-methoxybenzyl)pyridin-2-amine (0.112 g, 0.35 mmol, 1 eq), 5-(4, 4,5,5- tetramethyl-1 ,3,2-dixaboralan-2-yl)-1H-indazol-3-amine (0.136 g, 0.525 mmol, 1.5 eq), [1,1 - bis(di-tert-butylphosphino)ferrocene]dichloropalladium(ll) catalyst (0.011 mg, 17.5 pmol, 0.05 eq) and potassium phosphate (0.186 g, 0.875 mmol, 2.5 eq) were dissolved in ethanol (0.75 ml) and water (0.75 ml) and heated at 100°C overnight. The solvent was removed at reduced pressure and the residue purified by preparative HPLC to give the desired compound (0.092 g, 0.20 mmol 57%) as a yellow powder.1H NMR (500 MHz, DMSO) 5H 9.00 (br s, 1H), 8.36 (s, 1 H), 8.04 (d, J = 6.8 Hz, 1 H), 7.69 (d, J = 8.9 Hz, 1 H), 7.49 (d, J = 8.3 Hz, 2H), 7.41 (d, J = 8.8 Hz 1H), 7.35 (d, J = 8.3 Hz, 2H), 7.31 (d, J = 1.4 Hz 1 H), 7.22 (dd, J = 6.8 and 1.4 Hz, 1H), 4.63 (s, 2H), 1.41 (s, 6H);13C NMR (125 MHz, CDCI3) 5c 159.0, 158.7, 154.5, 153.4, 150.7, 150.4, 142.5, 134.5, 127.6, 125.9, 125.4, 125.1, 121.4, 115.0, 111.1 , 110.7, 71.0, 45.4, 31.4.5-(2-((4-(M...

Claims

CLAIMS1. A compound, or a pharmaceutically acceptable salt or solvate thereof, having the structural formula (I) shown below:wherein: R1is selected from hydrogen, halogen, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (3- 7C)cycloalkyl, aryl, heteroaryl and heterocyclyl, wherein said (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (3-7C)cycloalkyl, aryl, heteroaryl and heterocyclyl are optionally substituted by one or more R10s0ubstituents; wherein each R100is independently selected from halo, (1-2C)haloalkyl (e.g. trifluoromethyl), (1-2C)haloalkoxy e.g. (trifluoromethoxy), cyano, hydroxyl, (1-4C)alkyl, (1- 4C)hydroxyalkyl, (CH2)xORf, (CH2)xC(O)Rf, (CH2)xC(O)ORf, (CH2)xOC(O)Rf, (CH2)xC(O)N(Rj)Rh, (CH2)xN(Rg)C(O)Rf, (CH2)xS(O)yiRf, (CH2)xSO2N(Rj)Rh, (CH2)xN(Rg)SO2Rf, (CH2)xNRjRh, (CH2)x(3-7C)cycloalkyl, (CH2)xheterocyclyl, (CH2)xheteroaryl or (CH2)xaryl; and wherein:(i) Rfand Rgare each independently selected from hydrogen, (1-6C)alkyl or phenyl; and wherein Rhand R, are each independently selected from hydrogen, (1- 6C)alkyl or phenyl or Rhand Rjtogether with the nitrogen atom to which they are attached form a 3-7 membered ring which may optionally include further heteroatoms and is optionally further substituted by one or more substituents selected from halo, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, carboxyl, carbamoyl, sulphamoyl, and (1-2C)alkyl; and(ii) any (1-4C)alkyl, (3-7C)cycloalkyl, heterocyclyl, heteroaryl or aryl in a R100substituent group is optionally further substituted by one or more substituents selected from halo, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, (1-2C)alkyl, (1-2C)haloalkyl, (1-2C)hydroxyalkyl, ORk, C(O)Rk, C(O)ORk, OC(O)Rk, C(O)N(Ri)Rk, N(Ri)C(O)Rk, S(O)y2Rk, SO2N(Rl)Rk, N(R!)SO2Rk, or NRiRklwherein Rkand Riare selected from hydrogen or ( 1 -2C)alkyl;R2is hydrogen;R3is selected from hydrogen, (1 -8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (3-7C)cycloalkyl, aryl heteroaryl, heterocyclyl, (CH2)o3(3-7C)cycloalkyl, (CH2)0.3heterocyclyl, (CH2)0.3heteroaryl, (CH2)0-3aryl, -C(0)-(CH2)0-3(3-7C)cycloalkyl, -C(0)-(CH2)0-3heterocyclyl, -C(0)-(CH2)o- sheteroaryl, -C(0)-(CH2)0-3aryl or -C(O)O(1-8C)alkyl, -C(O)NR3a-(1-8C)alkyl, -C(0)NR3a-(CH2)o3(3-7C)cycloalkyl, -C(0)NR3a-(CH2)o.3heterocyclyl, -C(0)NR3a-(CH2)0-3heteroaryl, -C(O)NR3a- (CH2)0-3aryl; wherein R3ais hydrogen or (1 -2C)alkyl; wherein any (1-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (3-7C)cycloalkyl, aryl, heteroaryl and heterocyclyl moiety is optionally substituted by one or more R200substituents; wherein R200is selected from halo, (1-2C)haloalkyl (e.g. trifluoromethyl), (1- 2C)haloalkoxy (e.g. trifluoromethoxy), cyano, hydroxyl, nitro, (1-4C)alkyl, (1-4C)hydroxyalkyl, (CH2)zORm, (CH2)zC(O)Rm, (CH2)zC(O)ORm, (CH2)zOC(O)Rm, (CH2)zC(O)N(Ro)RP, (CH2)zN(Rn)C(O)Rm, (CH2)zN(Rn)C(O)ORm, (CH2)zS(O)y3Rm, (CH2)zSO2N(Ro)Rp, (CH2)zN(Rn)SO2Rm, (CH2)zNRoRp, (CH2)z(3-7C)cycloalkyl, (CH2)zheterocyclyl, (Ch2)zheteroaryl, (CH2)zaryl; and wherein:(i) Rmand Rnare each independently selected from hydrogen, (1-6C)alkyl or (CH2)o- aphenyl; Roand Rpare each independently selected from hydrogen, (1-6C)alkyl or phenyl or Roand Rptogether with the nitrogen atom to which they are attached form a 3-7 membered ring which may optionally include further heteroatoms, and wherein any 3-7 membered ring formed Roand Rp, and any alkyl or phenyl group present for Rm, Rn, Ro and Rpis optionally further substituted by one or more substituents selected from halo, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, carboxyl, carbamoyl, sulphamoyl, and (1- 2C)alkyl; and(ii) any (3-7C)cycloalkyl, heterocyclyl, heteroaryl or aryl moiety in a R200substituent group is optionally further substituted by one or more substituents selected from halo, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, (1-2C)alkyl, (1- 2C)haloalkyl, (1-2C)hydroxyalkyl, ORq, C(O)Rq, CC((OO))OORRqq,, OC(O)Rq, C(O)N(Rq)Rr, N(Rr)C(O)Rq, S(O)y4Rq, SO2N(Rr)Rq, NN((RRrr))SSOO22RRqq,, or NRrRq,wherein Rqis hydrogen, (1-2C)alkyl or phenyl, and Rrare selected from hydrogen or (1 -2C)alkyl; or R2and R3 are linked such that together they form a -X2=CO- group;X2is selected from N and CRa; wherein Rais selected from hydrogen, fluoro, chloro, methyl, cyano, difluoromethyl, and trifluoromethyl; andQ is hydrogen, halo, cyano or a group of the formula:-L i-Y I-L2-QI wherein: L1is absent or (1-4C)alkylene; Y1is absent or O, S, SO, SO2, N(Ry1), C(O), C(O)O, OC(O), C(O)N(Ry1), or N(Ry1)C(O), wherein Ryi is selected from hydrogen or (1-6C)alkyl; L1is absent or (1-3C)alkylene; and Q1is hydrogen, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, aryl, (3-8C)cycloalkyl, heteroaryl or heterocyclyl; wherein Q is optionally further substituted by one or more substituent groups independently selected from oxo, (1-6C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)haloalkoxy, (1-4C)aminoalkyl, (1-4C)hydroxyalkyl, cyano, or by one or more group(s) of the formula:-L3-Y2- L4-W1wherein:L3 is absent or (1-4C)alkylene;Y2is absent or selected from or O, S, SO, SO2, N(Ry2), C(O), C(O)O, 00(0), C(0)N(Ry2), N(Ry2)C(O) or S(O)2N(Ry2), N(Ry2)SO2wherein Ry2is selected from hydrogen or (1-4C)alkyl; L4is absent or (1-3C)alkylene; andW1Is hydrogen, (1-6C)alkyl, aryl, (3-8C)cycloalkyl, heteroaryl or heterocyclyl; wherein W1is optionally substituted by one or more substituents selected from oxo, (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1- 40)alkoxy, amino, (1-4C)alkylamino, di[(1-4C)alkyl]amino C(O)OH, C(O)O(1-4C)alkyl, (CH2)0-3-heterocyclyl or cyano; R4is selected from hydrogen or halo;X1is N or CR5, wherein R5is selected from hydrogen, halo, cyano, or amino; x is independently selected from 0, 1 , 2 or 3;y1 , y2, y3 and y4 are independently selected from 0, 1 or 2; z is independently selected from 0, 1 , 2 or 3; with the proviso that:X1and X2are only N when Q is hydrogen; when X1and X2are CR5or CRa, Q is not hydrogen;QI is not hydrogen when U, Yi, and L1are all absent; and at least one of R1, Q, Ra, R4or R5is a substituent other than hydrogen.

2. A compound according to claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is a compound having the structural formula (la), (lb) or (Ic) shown below:(la) (lb) (Ic) wherein R1, X1, X2, R3, Ri and R5are each as defined in claim 1.

3. A compound according to claim 1 or claim 2, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from hydrogen, halogen, (2-6C)alkynyl, (3-7C)cycloalkyl, phenyl, a 5 or 6-membered heteroaryl or a 4 to 7-membered heterocyclyl, wherein said (2-6C)alkynyl, (3-7C)cycloalkyl, phenyl, heteroaryl and heterocyclyl are optionally substituted by one or more R100substituents; and wherein R100is selected from halo, (1-2C)haloalkyl (e.g. trifluoromethyl) (1-2C)haloalkoxy e.g. trifluoromethoxy, cyano, hydroxyl, (1-4C)alkyl, (1-4C)hydroxyalkyl,(CH2)xORf, (CHz)xC(O)Rf, (CH2)xC(O)ORf, (CH2)xOC(O)Rf, (CH2)xC(O)N(Rj)Rh,(CH2)xN(Rg)C(O)Rf, (CH2)xS(O)yiRf, (CH2)xSO2N(Rj)Rh, (CH2)xN(Rg)SO2Rf, (CH2)xNRjRh, (CH2)x(3-7C)cycloalkyl, (CH2)xheterocyclyl, (Ch2)xheteroaryl (CH2)xaryl;and wherein:(i) x and y1 are as defined in claim 1 ;(ii) Rfand Rgare each independently selected from hydrogen or (1-2C)alkyl; and wherein Rhand Rjare each independently selected from hydrogen or (1- 2C)alkyl or Rhand Rjtogether with the nitrogen atom to which they are attached form a 3-7 membered ring which may optionally include further heteroatoms; and any (1-4C)alkyl, (3-7C)cycloalkyl, heterocyclyl, heteroaryl or aryl moiety in a R100substituent group is optionally further substituted by one or more substituents selected from halo, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, (1- 2C)alkyl, (1-2C)haloalkyl, (1-2C)hydroxyalkyl, ORk, C(O)Rk, C(O)ORk, OC(O)Rk, C(O)N(R,)Rk, N(Ri)C(O)Rk, S(O)y2Rk, SO2N(R,)Rk, N(R!)SO2Rk, or NRiRk, wherein Rkand Riare selected from hydrogen or (1-2C)alkyl and y2 is independently selected from 0, 1 or 2.

4. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from hydrogen, halogen, (2- 6C)alkynyl, phenyl or a 5 or 6-membered heteroaryl, wherein said (2-6C)alkynyl, phenyl or heteroaryl are optionally substituted by one or more R10s0ubstituents; and wherein R100is selected from halo, (1-2C)haloalkyl (e.g. trifluoromethyl), (1- 2C)haloalkoxy e.g. (trifluoromethoxy), cyano, hydroxyl, (1-4C)alkyl, (1-4C)hydroxyalkyl, (CH2)xORf, (CH2)xC(O)Rf, (CH2)xC(O)ORf, (CH2)xOC(O)Rf, (CH2)xC(O)N(Rj)Rh, (CH2)xN(Rg)C(O)Rf, (CH2)xS(O)yiRf, (CH2)xSO2N(Rj)Rh, (CH2)xN(Rg)SO2Rf, (CH2)xNR)Rhl(CH2)x(3-7C)cycloalkyl, (CH2)x-[4-6 membered heterocyclyl], (CH2)x-[5 or 6 membered heteroaryl] or (CH2)xphenyl; and wherein:(i) x and y1 are as defined in claim 1 ;(ii) Rfand Rgare each independently selected from hydrogen or (1-2C)alkyl; and wherein Rhand Rjare each independently selected from hydrogen or (1- 2C)alkyl or Rhand Rjtogether with the nitrogen atom to which they are attached form a 3-7 membered ring which may optionally include further heteroatoms; andany (1-4C)alkyl, (3-7C)cycloalkyl, heterocyclyl, heteroaryl or aryl moiety in a R100substituent group is optionally further substituted by one or more substituents selected from halo, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, (1- 2C)alkyl, (1-2C)haloalkyl, (1-2C)hydroxyalkyl ORk, C(O)Rk, C(O)ORk, OC(O)Rk, C(O)N(Ri)Rk, N(R,)C(O)Rk, S(O)y2Rk, SO2N(R,)RklN(Rl)SO2Rk, or NRiRk, wherein Rkand Riare selected from hydrogen or (1-2C)alkyl and y2 is independently selected from 0, 1 or 2.

5. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from hydrogen, halogen, (2- 6C)alkynyl, phenyl or a 5 or 6-membered heteroaryl, wherein said (2-6C)alkynyl, phenyl or heteroaryl are optionally substituted by one or more R10s0ubstituents; and wherein R100is selected from halo, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, (1-4C)alkyl, (1-4C)hydroxyalkyl, (CH2)xORf, (CH2)xC(O)Rf, (CH2)xC(O)ORf, (CH2)xOC(O)Rf, (CH2)xC(O)N(Rj)Rh, (CH2)xN(Rg)C(O)Rf, (CH2)xS(O)yiRf, (CH2)xSO2N(Rj)Rh, (CH2)xN(Rg)SO2Rf, (CH2)xNRjRh, (CH2)x(3-7C)cycloalkyl, (CH2)x-[4-6 membered heterocyclyl], (CH2)X-[5 or 6 membered heteroaryl] or (Ch2)xphenyl; and wherein:(i) x and y1 are as defined in claim 1 ;(ii) Rfand Rgare each independently selected from hydrogen or (1-2C)alkyl; and wherein Rhand R, are each independently selected from hydrogen or (1- 2C)alkyl; and any (1-4C)alkyl, (3-7C)cycloalkyl, heterocyclyl, heteroaryl or aryl moiety in a R100substituent group is optionally further substituted by one or more substituents selected from halo, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, (1- 2C)alkyl, (1-2C)haloalkyl, (1-2C)hydroxyalkyl or ORk, wherein Rkis selected from hydrogen or (1-2C)alkyl.

6. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from hydrogen, halogen, (2- 6C)alkynyl, phenyl or a 5 or 6-membered heteroaryl,wherein said (2-6C)alkynyl, phenyl or heteroaryl are optionally substituted by one or more R10s0ubstituents; and wherein R100is selected from halo, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, (1-4C)alkyl, (1-4C)hydroxyalkyl, (CH2)xORf, C(O)Rf, C(O)ORf, OC(O)Rf, C(O)N(Rj)Rh, N(Rg)C(O)Rf, S(O)yiRf, SO2N(Rj)Rh, N(Rg)SO2Rf, NRjRh, (CH2)x-[4-6 membered heterocyclyl], or (CH2)xphenyl; and wherein:(i) x and yi are as defined in claim 1 ;(ii) Rfand Rgare each independently selected from hydrogen or (1-2C)alkyl; and wherein Rhand Rjare each independently selected from hydrogen or (1- 2C)alkyl; and any (1-4C)alkyl, (3-7C)cycloalkyl, heterocyclyl, heteroaryl or aryl moiety in a R100substituent group is optionally further substituted by one or more substituents selected from halo, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, (1- 2C)alkyl, (1-2C)haloalkyl, (1-2C)hydroxyalkyl or ORk, wherein Rkis selected from hydrogen or (1-2C)alkyl.

7. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:(i) hydrogen or halogen;(ii) ethynyl, i.e. which is optionally substituted by R10;0(iv) phenyl, which is optionally substituted by R10;0(v) a 5 or 6-membered heteroaryl, which is optionally substituted by R100; and wherein R100is selected from halo, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, (1-4C)alkyl, (1-4C)hydroxyalkyl, (CH2)xORf, C(O)Rf, C(O)ORf, OC(O)Rf, C(O)N(Rf)Rh, N(Rg)C(O)Rt, S(O)yiRf, SO2N(Rj)Rh, N(Rg)SO2Rf, NRjRh, (CH2)x-[4-6 membered heterocyclyl], or (CH2)xphenyl; and wherein:(i) x is independently selected from 0, 1 or 2;(II) y1 Is independently selected from 0, 1 or 2; Rfand Rgare each independently selected from hydrogen or (1-2C)alkyl; and wherein Rhand Rjare each independently selected from hydrogen or (1 -2C)alkyl; and(iv) any (1-4C)alkyl, (3-7C)cycloalkyl, heterocyclyl, heteroaryl or aryl moiety in a R100substituent group is optionally further substituted by one or more substituents selected from halo, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, (1-2C)alkyl, (1-2C)haloalkyl, (1-2C)hydroxyalkyl or ORk, wherein Rkis selected from hydrogen or (1-2C)alkyl.

8. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:(i) hydrogen;(ii) ethynyl, i.e. which is optionally substituted by R10;0(v) phenyl, which is optionally substituted by R100;(vi) a 5 or 6-membered heteroaryl; and wherein R100is selected from halo, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, (1-4C)alkyl, (1-4C)hydroxyalkyl, (CH2)xORf, C(O)Rf, C(O)ORf, OC(O)Rf, C(O)N(Rj)Rh, N(Rg)C(O)Rf, S(O)yiRf, SO2N(Rj)Rh, N(Rg)SO2Rf, NRjRh, (CH2)x-[4-6 membered heterocyclyl], or (CH2)xphenyl; and wherein:0) x is independently selected from 0, 1 or 2;(ii) y1 is independently selected from 0, 1 or 2; Rfand Rgare each independently selected from hydrogen or (1-2C)alkyl; and wherein Rhand Rjare each independently selected from hydrogen or (1- 2C)alkyl; and(iv) any (1-4C)alkyl, (3-7C)cycloalkyl, heterocyclyl, heteroaryl or aryl moiety in a R100substituent group is optionally further substituted by one or more substituents selected from halo, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, (1-2C)alkyl, (1-2C)haloalkyl, (1-2C)hydroxyalkyl or ORk, wherein Rkis selected from hydrogen or (1-2C)alkyl.

9. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:(i) hydrogen or halogen;(ii) ethynyl, i.e. which is optionally substituted by R10;0phenyl, which is optionally substituted by R10;0and wherein R100is selected from halo, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl or (1-4C)alkyl.

10. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt or solvate thereof, wherein R3is selected from hydrogen, (1-8C)alkyl, (2- 8C)alkenyl, (2-8C)alkynyl, (3-7C)cycloalkyl, phenyl, a 5 or 6-membered heteroaryl, a 4 to 7- membered heterocyclyl, (CH2)0-3(3-7C)cycloalkyl, (CH2)o3[4 to 7-membered heterocyclyl], (CH2)O-S[5 or 6-membered heteroaryl], (CH2)o3phenyl, -C(0)-(CH2)o3(3-7C)cycloalkyl, -C(O)- (CH2)0.3[4 to 7-membered heterocyclyl], -C(0)-(CH2)0-3[5 or 6-membered heteroaryl], -C(O)- (CH2)0-3phenyl, -C(O)O(1-8C)alkyl, -C(O)NR3a-(1-8C)alkyl, -C(0)NR3a-(CH2)0-3(3-7C)cycloalkyl, -C(0)NR3a-(CH2)o -3[5 to 7-membered heterocyclyl], -C(O)NR3a-(CH2)<M[5 or 6-membered heteroaryl], or -C(0)NR3a-(CH2)0-3phenyl; wherein R3ais hydrogen or (1-2C)alkyl; wherein any (1-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (3-7C)cycloalkyl, phenyl, 5 or 6- membered heteroaryl or 4 to 7-membered heterocyclyl moiety is optionally substituted by one or more R200substituents; wherein R200is selected from halo, (1-2C)haloalkyl (e.g. trifluoromethyl), (1- 2C)haloalkoxy (e.g. trifluoromethoxy), cyano, hydroxyl, nitro, (1-4C)alkyl, (1-4C)hydroxyalkyl, (CH2)zORm, (CH2)zC(O)Rm, (CH2)zC(O)ORm, (CH2)zC(O)N(Ro)RP, (CHz)zN(Rn)C(O)Rm, (CH2)zN(Rn)C(O)ORm, (CH2)zS(O)y3Rm, (CH2)zSO2N(Ro)Rp, (CH2)zN(Rn)SO2Rm, (CH2)ZNRORP,(CH2)z(3-7C)cycloalkyl, (CH2)Z[4 to 7-membered heterocyclyl], (CH2)Z[5 or 6-membered heteroaryl, (CH2)zphenyl; and wherein:(i) z and y3 are as defined in claim 1 ;(ii) Rmand Rnare each independently selected from hydrogen, (1-6C)alkyl or (CH2)o- 3phenyl; Roand Rpare each independently selected from hydrogen, (1-6C)alkyl or phenyl or Roand Rptogether with the nitrogen atom to which they are attached form a 3-7 membered ring which may optionally include further heteroatoms, and wherein any 3-7 membered ring formed Roand Rp, and any alkyl or phenyl group present for Rm, Rn, Ro and Rpis optionally further substituted by one or more substituents selected from halo, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, carboxyl, carbamoyl, sulphamoyl, and (1- 2C)alkyl; and any (3-7C)cycloalkyl, heterocyclyl, heteroaryl or phenyl moiety in a R200substituent group is optionally further substituted by one or more substituents selected from halo, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, (1- 2C)alkyl, (1-2C)haloalkyl, (1-2C)hydroxyalkyl, ORq, C(O)Rq, C(O)OR ■q> OC(O)Rq, C(O)N(Rq)Rr, N(Rr)C(O)Rq, S(O)y4Rq, SO2N(Rr)Rq, N(Rr)SO2Rq, or NRrRq, wherein Rqis hydrogen, (1-2C)alkyl or phenyl, Rrare selected from hydrogen or (1-2C)alkyl; and y4 is independently selected from 0, 1 or 2.

11. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt or solvate thereof, wherein R3is selected from hydrogen, (1-8C)alkyl, (2- 8C)alkenyl, (2-8C)alkynyl, (3-7C)cycloalkyl, phenyl, a 5 or 6-membered heteroaryl, a 4 to 7- membered heterocyclyl, (CH2)0-3(3-7C)cycloalkyl, (CH2)o-s[4 to 7-membered heterocyclyl], (CH2)O-3[5 or 6-membered heteroaryl], (CH2)0-3phenyl, -C(0)-(CH2)0-3(3-7C)cycloalkyl, -C(0)-(CH2)O-3[4 to 7-membered heterocyclyl], -C(O)-(CH2)0-3[5 or 6-membered heteroaryl], - C(0)-(CH2)0-3phenyl, -C(O)O(1-8C)alkyl, -C(O)NR3a-(1-8C)alkyl, -C(0)NR3a-(CH2)0-3(3- 7C)cycloalkyl, -C(0)NR3a-(CH2)0-3[5 to 7-membered heterocyclyl], -C(0)NR3a-(CH2)o -3[5 or 6- membered heteroaryl], or -C(0)NH-(CH2)0-3phenyl; wherein R3ais hydrogen or (1-2C)alkyl; wherein any (1-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (3-7C)cycloalkyl, phenyl, 5 or 6- membered heteroaryl or 4 to 7-membered heterocyclyl moiety is optionally substituted by one or more R200substituents;wherein R2Oo is selected from halo, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, nitro, (1-4C)alkyl, (1-4C)hydroxyalkyl, (CH2)zORm, (CH2)zC(O)Rm, (CH2)zC(O)ORm, (CH2)zC(O)N(Ro)Rp, (CH2)zN(Rn)C(O)Rm, (CH2)zN(Rn)C(O)ORm, (CH2)zS(O)y3Rm, (CH2)zSO2N(Ro)Rp, (CH2)zN(Rn)SO2Rm, (CH2)ZNRORP, (CH2)z(3-7C)cycloalkyl, (CH2)Z[4 to 7- membered heterocyclyl], (CH2)Z[5 or 6-membered heteroaryl, (CH2)zphenyl; and wherein:(i) z and y3 are as defined in claim 1 ; and(ii) Rmand Rnare each independently selected from hydrogen, (1-6C)alkyl or (CH2)o 3phenyl; Roand Rpare each independently selected from hydrogen, (1-6C)alkyl or phenyl or Roand Rptogether with the nitrogen atom to which they are attached form a 3-7 membered ring which may optionally include further heteroatoms, and wherein any 3-7 membered ring formed Roand Rp, and any alkyl or phenyl group present for Rm, Rn, Ro and Rpis optionally further substituted by one or more substituents selected from halo, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, carboxyl, carbamoyl, sulphamoyl, and (1- 2C)alkyl.

12. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is selected from hydrogen, (1-8C)alkyl, (2- 8C)alkenyl, (2-8C)alkynyl, (3-7C)cycloalkyl, phenyl, a 5 or 6-membered heteroaryl, a 4 to 7- membered heterocyclyl, (CH2)0-3(3-7C)cycloalkyl, (CH2)o3[4 to 7-membered heterocyclyl], (CH2)0-3[5 or 6-membered heteroaryl], (CHaJ0-3phenyl, -C(0)-(CH2)0-3(3-7C)cycloalkyl, -C(O)- (CH2)0-3[4 to 7-membered heterocyclyl], -C(0)-(CH2)o3[5 or 6-membered heteroaryl], -C(O)- (CH2)0-3phenyl, -C(O)O(1-8C)alkyl, -C(O)NR3a-(1-8C)alkyl, -C(O)NR3a-(CH2)0-3(3-7C)cycloalkyl, -C(0)NR3a-(CH2)0-3[5 to 7-membered heterocyclyl], -C(0)NR3a-(CH2)0-3[5 or 6-membered heteroaryl], or -C(0)NR3a-(CH2)0-3phenyl; wherein R3ais hydrogen or (1-2C)alkyl; wherein any (1 -8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (3-7C)cycloalkyl, phenyl, 5 or 6- membered heteroaryl or 4 to 7-membered heterocyclyl moiety is optionally substituted by one or more R200substituents; wherein R200is selected from halo, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, nitro, (1-4C)alkyl, (1-4C)hydroxyalkyl, (CH2)zORm, (CH2)zC(O)Rm, (CH2)zC(O)ORm, (CH2)ZC(O)N(RO)RP, (CH2)zN(Rn)C(O)Rm, (CH2)zN(Rn)C(O)ORm, (CH2)zS(O)y3Rm, (CH2)zSO2N(Ro)Rp, (CH2)zN(Rn)SO2Rm, or (CH2)ZNRORP;and wherein:Rmand Rnare each independently selected from hydrogen, (1-6C)alkyl or phenyl; Roand Rpare each independently selected from hydrogen, (1-6C)alkyl or (CH2)o-2phenyl or Roand Rptogether with the nitrogen atom to which they are attached form a 3-7 membered ring which may optionally include further heteroatoms, and wherein any 3-7 membered ring formed Roand Rp, and any alkyl or phenyl group present for Rm, Rn, Roand Rpis optionally further substituted by one or more substituents selected from halo, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, carboxyl, carbamoyl, sulphamoyl, and (1-2C)alkyl; and y3 is as defined in claim 1.

13. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt or solvate thereof, wherein R3is hydrogen or is selected from;H H H N N N NNNHN s wherein any cycloalkyl, heterocyclyl, aryl or heteroaryl group above is optionally substituted by one or more R200substituents, wherein R200is as defined in any one of the preceding claims.

14. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is compound of formula (la):wherein R1, R3, R4and R5are each as defined in any one of claims 1 to 13.

15. A compound according to claim 14, or a pharmaceutically acceptable salt or solvate thereof, wherein R3is hydrogen and R1is a substituent other than hydrogen as defined in any one of claims 1 and 3 to 9.

16. A compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is compound of formula (lb):N-NHH2NR5R4N NHR3(lb) wherein R3is a substituent other than hydrogen as defined in in any one of claims 1 or 10 to 13 and R4and R5are each as defined in claim 1.

17. A compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is compound of formula (Ic):N-NHH2N R1X2Xi)^Q R4N NH(Ic) wherein R<, R4X1, X2and Q are each as defined in any one of claims 1 to 13.

18. A compound according to claim 17, or a pharmaceutically acceptable salt or solvate thereof, wherein X2is selected from N and CRa; wherein Rais selected from hydrogen, fluoro, chloro, methyl, or cyano.

19. A compound according to claim 17 or 18, or a pharmaceutically acceptable salt or solvate thereof, wherein Q is hydrogen, halo, cyano or a group of the formula:-L1-Y 1-L2-Q1 wherein: L1is absent or (1-4C)alkylene;Yi is absent or O, S, SO, SO2, N(Ry1), C(O), C(O)O, OC(O), C(O)N(Ry1), or N(Ry1)C(O), wherein Ryi is selected from hydrogen or (1-6C)alkyl; L1is absent or (1-3C)alkylene; and Q1is hydrogen, (1-6C)alkyl, phenyl, (3-8C)cycloalkyl, 5 or 6-membered heteroaryl or 4 to 7-membered heterocyclyl; wherein Q is optionally further substituted by one or more substituent groups independently selected from oxo, (1-6C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)haloalkoxy, (1-4C)aminoalkyl, (1-4C)hydroxyalkyl, cyano, or by one or more group(s) of the formula:-L3-Y2-L4-WI wherein: l_3is absent or (1-4C)alkylene;Y2is absent or selected from or O, S, SO, SO2, N(Ry2), C(O), 0(0)0, 00(0), C(O)N(Ry2), N(Ry2)C(O) or S(O)2N(Ry2), N(Ry2)SO2wherein Ry2is selected from hydrogen or (1-4C)alkyl; L4is absent or (1-3C)alkylene; andW1is hydrogen, (1-6C)alkyl, aryl, (3-8C)cycloalkyl, 5 or 6-membered heteroaryl or 4 to 7-membered heterocyclyl; wherein W1is optionally substituted by one or more substituents selected from oxo, (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1- 4C)alkoxy, amino, (1-4C)alkylamino, di[(1-4C)alkyl]amino C(O)OH, C(0)0(1-4C)alkyl, (CH2)o^-[4 to 7-membered heterocyclyl] or cyano. optionally wherein Q is a group of the formula:-L1-Y 1-L2-Q1 wherein: L1is absent or (1-4C)alkylene; Y1is absent or O, S, SO, SO2, N(Ry1), C(O), C(O)O, OC(O), C(O)N(Ry1), or N(Ry1)C(O), wherein Ryi is selected from hydrogen or (1-4C)alkyl; L1is absent or (1-3C)alkylene; and Q1is hydrogen, (1-6C)alkyl, phenyl, (3-8C)cycloalkyl, 5 or 6-membered heteroaryl or 4 to 7-membered heterocyclyl; wherein Q is optionally further substituted by one or more substituent groups independently selected from oxo, (1-6C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)aminoalkyl, (1-4C)hydroxyalkyl, cyano, or by one or more group(s) of the formula:-L3-Y2- L4-W1wherein: l_3is absent or (1-3C)alkylene;Y2is absent or selected from or O, S, SO, SO2, N(Ry2), C(O), 0(0)0, OC(O), C(O)N(Ry2), N(Ry2)C(O), S(O)2N(Ry2) or N(Ry2)SO2wherein Ry2is selected from hydrogen or (1 -2C)alkyl; L4is absent or (1-3C)alkylene; andW1is hydrogen, (1-6C)alkyl, aryl, (3-8C)cycloalkyl, 5 or 6-membered heteroaryl or 4 to 7-membered heterocyclyl; wherein W1is optionally substituted by one or more substituents selected from oxo, (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1- 4C)alkoxy, amino, (1-4C)alkylamino, di[(1-4C)alkyl]amino C(O)OH, C(O)O(1-4C)alkyl, (CH2)0-3-[4 to 7-membered heterocyclyl] or cyano; further optionally wherein: L1is absent or (1-3C)alkylene; Y1is absent or O, S, N(Ry1), C(O), C(O)O, C(O)N(Ry1), or N(Ry1)C(O), wherein Ryi is selected from hydrogen or (1-4C)alkyl; L1is absent or methylene; and Q1is hydrogen, (1-6C)alkyl, phenyl, (3-8C)cycloalkyl, 5 or 6-membered heteroaryl or 4 to 7-membered heterocyclyl; wherein Q is optionally further substituted by one or more substituent groups independently selected from oxo, (1-6C)alkyl, halo, (1-2C)haloalkyl, (1- 2C)haloalkoxy, cyano, or by one or more group(s) of the formula:-L3-Y2- L4-W1wherein:L3is absent or (1-4C)alkylene;Y2is absent or selected from or O, SO2, N(Ry2), C(O), C(O)O, C(O)N(Ry2) or N(Ry2)SO2wherein Ry2is selected from hydrogen or (1-2C)alkyl; L4is absent or (1-3C)alkylene; andW1is hydrogen, (1-6C)alkyl, aryl, (3-8C)cycloalkyl, 5 or 6-membered heteroaryl or 4 to 7-membered heterocyclyl;wherein Wi is optionally substituted by one or more substituents selected from oxo, (1-4C)alkyl, halo, (1-2C)haloalkyl, (1-2C)haloalkoxy, (1-4C)alkoxy, C(O)OH, C(O)O(1-4C)alkyl, (CH2)0-3-[4 to 7-membered heterocyclyl] or cyano.

20. A compound according to any one of claims 17 to 19, or a pharmaceutically acceptable salt or solvate thereof, wherein Q is a group selected from hydrogen, halo, cyano, (1-6C)alkyl, (1-6C)alkoxy, (1-6C)haloalkyl, (1-6C)haloalkoxy, or a group of with a formula selected from:wherein any cycloalkyl, heterocyclyl, aryl or heteroaryl ring above may be optionally substituted by one or more substituents selected from oxo, (1-6C)alkyl, halo, (1-2C)haloalkyl, (1- 2C)haloalkoxy, cyano, or by one or more group(s) of the formula:-L3-Y2- L4-W1wherein l_3, Y2, L4and Wi are as defined in any one of the preceding claims.

21. A compound according to any one of claims 17 to 20, or a pharmaceutically acceptable salt or solvate thereof, wherein R4is selected from hydrogen or fluoro.

22. A compound according to any one of claims 17 to 21 , or a pharmaceutically acceptable salt or solvate thereof, wherein X1is N or CR5, wherein R5is selected from hydrogen, halo, or cyano.

23. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt or solvate thereof, selected from:5-(2-aminopyridin-4-yl)-7-chloro-1 H-indazol-3-amine;5-(2-aminopyridin-4-yl)-7-methyl-1H-indazol-3-amine;5-(2-aminopyridin-4-yl)-7-(trifluoromethyl)-1H-indazol-3-amine;5-(2-(ethylamino)pyridin-4-yl)-1 H-indazol-3-amine;5-(2-(propylamino)pyridin-4-yl)-1H-indazol-3-amine;5-(2-(isopropylamino)pyridin-4-yl)-1H-indazol-3-amine;5-(2-((cyclopropylmethyl)amino)pyridin-4-yl)-1 H-indazol-3-amine;5-(2-(isopentylamino)pyridin-4-yl)-1H-indazol-3-amine;5-(2-(hexylamino)pyridin-4-yl)-1H-indazol-3-amine;5-(2-(cyclohexylamino)pyridin-4-yl)-1 H-indazol-3-amine;5-{2-[(Trans-4-methylcyclohexyl)amino]pyridin-4-yl}-1H-indazol-3-amine;2-((4-(3-amino-1 H-indazol-5-yl)pyridin-2-yl)amino)ethan-1 -ol;3-((4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)amino)propan-1-ol;4-((4-(3-amino-1 H-indazol-5-yl)pyridin-2-yl)amino)butan-1 -ol;5-((4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)amino)pentan-1-ol;5-{2-[(tra / 7S-4-hydroxycyclohexyl)amino]pyridin-4-yl}-1 / - / -indazol-3-amine;5-(2-((2-methoxyethyl)amino)pyridin-4-yl)-1H-indazol-3-amine;5-(2-((3-methoxypropyl)amino)pyridin-4-yl)-1H-indazol-3-amine;5-(2-((3-isopropoxypropyl)amino)pyridin-4-yl)-1 H-indazol-3-amine;3-((4-(3-amino-1H-indazol-5-yl)pyrimidin-2-yl)amino)propan-1-ol;3-((4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)(methyl)amino)propan-1-ol;5-(2-((2-morpholinoethyl)amino)pyrldin-4-yl)-1 H-indazol-3-amine;5-(2-((2-(piperidin-1-yl)ethyl)amino)pyridin-4-yl)-1H-indazol-3-amine;N1-(4-(3-amino-1 H-lndazol-5-yl)pyridin-2-yl)-N3-methylpropane-1 ,3-diamine;5-(2-(benzylamino)pyridin-4-yl)-1 H-indazol-3-amine;3-(((4-(3-amino-1 H-indazol-5-yl)pyrldin-2-yl)amino)methyl)benzonitrile;5-(2-((3-methoxybenzyl)amino)pyridin-4-yl)-1 H-indazol-3-amine;2-(3-(((4-(3-amino-1 H-indazol-5-yl)pyridin-2-yl)amino)methyl)phenyl)propan-2-ol;5-(2-((4-(trifluoromethyl)benzyl)amino)pyridin-4-yl)-1H-indazol-3-amine;4-(((4-(3-amino-1 H-indazol-5-yl)pyridin-2-yl)amino)methyl)benzonitrile;5-(2-((4-(tert-butyl)benzyl)amino)pyridin-4-yl)-1 H-indazol-3-amine;2-(4-(((4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)amino)methyl)phenyl)propan-2-ol;5-(2-((4-(methylsulfonyl)benzyl)amino)pyridin-4-yl)-1H-indazol-3-amine;5-(2-((furan-3-ylmethyl)amino)pyridin-4-yl)-1 H-indazol-3-amine;5-(2-((pyridin-2-ylmethyl)amino)pyridin-4-yl)-1H-indazol-3-amine;5-(2-(phenethylamino)pyridin-4-yl)-1 H-indazol-3-amine;5-(2-((2-(pyridin-2-yl)ethyl)amino)pyridin-4-yl)-1H-indazol-3-amine;5-(2-((2-(pyridin-3-yl)ethyl)amino)pyridin-4-yl)-1H-indazol-3-amine;5-(2-((2-(pyridin-4-yl)ethyl)amino)pyridin-4-yl)-1H-indazol-3-amine;5-(2-((2-(1H-indol-3-yl)ethyl)amino)pyridin-4-yl)-1 H-indazol-3-amine;5-(2-((4-fluorophenethyl)amino)pyridin-4-yl)-1H-indazol-3-amine;5-(2-((4-chlorophenethyl)amino)pyridin-4-yl)-1 H-indazol-3-amine;4-(2-((4-(3-amino-1 H-indazol-5-yl)pyridin-2-yl)amino)ethyl)phenol;5-(2-((4-methoxyphenethyl)amino)pyridin-4-yl)-1H-indazol-3-amine;5-(2-((4-(tert-butyl)phenethyl)amino)pyridin-4-yl)-1 H-indazol-3-amine;4-(2-((4-(3-amino-1 H-indazol-5-yl)pyridin-2-yl)amino)ethyl)benzenesulfonamide;5-(2-((3-chlorophenethyl)amino)pyridin-4-yl)-1 H-indazol-3-amine;5-(2-((2-(trifluoromethyl)phenethyl)amino)pyridin-4-yl)-1 H-indazol-3-amine;5-(2-((3-phenylpropyl)amino)pyridin-4-yl)-1H-indazol-3-amine;5-(2-((2-phenoxyethyl)amino)pyridin-4-yl)-1H-indazol-3-amine;N-(4-(3-amino-1 H-indazol-5-yl)pyridin-2-yl)cyclopropanecarboxamide;N-(4-(3-amino-1 H-indazol-5-yl)pyridin-2-yl)benzamide;N-(4-(3-amino-1 H-indazol-5-yl)pyridin-2-yl)-2-phenylacetamide;N-(4-(3-amino-1 H-indazol-5-yl)pyridin-2-yl)-2-(3-fluorophenyl)acetamide;N-(4-(3-amino-1 H-indazol-5-yl)pyridin-2-yl)-2-(3-tolyl)acetamide;N-(4-(3-amino-1 H-indazol-5-yl)pyrldin-2-yl)-2-(3-(trifluoromethyl)phenyl)acetamide;N-(4-(3-amino-1 H-indazol-5-yl)pyridin-2-yl)-2-(3-chlorophenyl)acetamide;N-(4-(3-amino-1 H-indazol-5-yl)pyrldin-2-yl)-2-(3-aminophenyl)acetamide;N-(4-(3-amino-1 H-indazol-5-yl)pyridin-2-yl)-2-(3-nitrophenyl)acetamide;N-(4-(3-amino-1 H-indazol-5-yl)pyridin-2-yl)-2-(3-(methylsulfonyl)phenyl)acetamide;N-(4-(3-amino-1 H-indazol-5-yl)pyrldin-2-yl)-2-(3-methoxyphenyl)acetamide;N-(4-(3-amino-1 H-indazol-5-yl)pyridin-2-yl)-2-(3-(benzyloxy)phenyl)acetamide; tert-butyl (3-(2-((4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)amino)-2- oxoethyl )pheny I )carbamate;N-(4-(3-amino-1 H-indazol-5-yl)pyridin-2-yl)-2-(4-fluorophenyl)acetamide;N-(4-(3-amino-1 H-indazol-5-yl)pyridin-2-yl)-2-(p-tolyl)acetamide;N-(4-(3-amino-1 H-indazol-5-yl)pyridin-2-yl)-2-(4-(trifluoromethyl)phenyl)acetamide;N-(4-(3-amino-1 H-indazol-5-yl)pyridin-2-yl)-2-(4-chlorophenyl)acetamide;N-(4-(3-amino-1 H-indazol-5-yl)pyridin-2-yl)-2-(4-(methylthio)phenyl)acetamide;N-(4-(3-amino-1 H-indazol-5-yl)pyridin-2-yl)-2-(4-(methylsulfonyl)phenyl)acetamide;N-(4-(3-amino-1 H-indazol-5-yl)pyridin-2-yl)-2-(4-methoxyphenyl)acetamide;N-(4-(3-amino-1 H-indazol-5-yl)pyridin-2-yl)-2-(4-aminophenyl)acetamide; tert-butyl (4-(2-((4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)amino)-2- oxoethyl )pheny I )carbamate;N-(4-(3-amino-1 H-indazol-5-yl)pyridin-2-yl)-2-(2-fluorophenyl)acetamide;N-(4-(3-amino-1 H-indazol-5-yl)pyridin-2-yl)-2-(o-tolyl)acetamide;N-(4-(3-amino-1 H-indazol-5-yl)pyridin-2-yl)-2-(2-(trifluoromethyl)phenyl)acetamide;N-(4-(3-amino-1 H-indazol-5-yl)pyridin-2-yl)-2-(2-chlorophenyl)acetamide;N-(4-(3-amino-1 H-indazol-5-yl)pyridin-2-yl)-2-(2-methoxyphenyl)acetamide;N-(4-(3-amino-1 H-indazol-5-yl)pyridin-2-yl)-2-(pyridin-2-yl)acetamide;N-(4-(3-amino-1 H-indazol-5-yl)pyridin-2-yl)-2-(pyridin-3-yl)acetamide;N-(4-(3-amino-1 H-indazol-5-yl)pyridine-2-yl)-2-(pyridine-4-yl)acetamide;N-(4-(3-amino-1 H-indazol-5-yl)pyridine-2-yl)-3-phenylpropanamide; ethyl (4-(3-amino-1 H-indazol-5-yl)pyridine-2-yl)carbamate;1 -(4-(3-amino-1 H-indazol-5-yl)pyridine-2-yl)-3-ethylurea;1 -(4-(3-amino-1 H-indazol-5-yl)pyridine-2-yl)-3-propylurea;1 -(4-(3-amino-1 H-indazol-5-yl)pyridine-2-yl)-3-isopentylurea;1-(4-(3-amino-1H-indazol-5-yl)pyridine-2-yl)-3-cyclopentylurea;1-(4-(3-amino-1H-indazol-5-yl)pyridine-2-yl)-3-cyclohexylurea;1-(4-(3-amino-1H-indazol-5-yl)pyridine-2-yl)-3-(2-hydroxyethyl)urea;1-(4-(3-amino-1H-indazol-5-yl)pyridine-2-yl)-3-(3-hydroxypropyl)urea;1-(4-(3-amino-1H-indazol-5-yl)pyridine-2-yl)-3-(2-methoxyethyl)urea;3-(4-(3-amino-1H-indazol-5-yl)pyridine-2-yl)-1-(2-hydroxyethyl)-1 -methylurea;1 -(4-(3-amino-1 H-indazol-5-yl)pyridine-2-yl)-3-benzylurea;1 -(4-(3-amino-1 H-indazol-5-yl)pyridine-2-yl)-3-phenethylurea;1-(4-(3-amino-1H-indazol-5-yl)pyridine-2-yl)-3-(pyridlne-2-ylmethyl)urea;1-(4-(3-amino-1H-indazol-5-yl)pyridine-2-yl)-3-(pyridine-3-ylmethyl)urea;1-(4-(3-amino-1H-indazol-5-yl)pyridine-2-yl)-3-(pyridlne-4-ylmethyl)urea;1 -(4-(3-amino-1 H-indazol-5-yl)pyridine-2-yl)-3-phenylurea;1-(4-(3-amino-1H-indazol-5-yl)pyridine-2-yl)-3-(3-fluorophenyl)urea;1-(4-(3-amino-1H-indazol-5-yl)pyridine-2-yl)-3-(3-chlorophenyl)urea;1-(4-(3-amino-1H-indazol-5-yl)pyridine-2-yl)-3-(3-isopropylphenyl)urea;1-(4-(3-amino-1H-indazol-5-yl)pyridine-2-yl)-3-(3-(hydroxymethyl)phenyl)urea;3-(3-(4-(3-amino-1H-indazol-5-yl)pyridine-2-yl)ureido)benzamide;1-(4-(3-amino-1H-indazol-5-yl)pyridine-2-yl)-3-(3-phenoxyphenyl)urea;1-(4-(3-amino-1H-indazol-5-yl)pyridine-2-yl)-3-(3-(benzyloxy)phenyl)urea;1-(4-(3-amino-1H-indazol-5-yl)pyridine-2-yl)-3-(3-((4-fluorobenzyl)oxy)phenyl)urea;1-(4-(3-amino-1H-indazol-5-yl)pyridine-2-yl)-3-(3-((3-fluorobenzyl)oxy)phenyl)urea;1-(4-(3-amino-1H-indazol-5-yl)pyridine-2-yl)-3-(3-((2-fluorobenzyl)oxy)phenyl)urea;3-(3-(4-(3-amino-1H-indazol-5-yl)pyridine-2-yl)ureido)-N-phenylbenzamide;1-(4-(3-amino-1H-indazol-5-yl)pyridine-2-yl)-3-(4-fluorophenyl)urea;1-(4-(3-amino-1H-indazol-5-yl)pyridine-2-yl)-3-(4-chlorophenyl)urea;1-(4-(3-amino-1H-indazol-5-yl)pyridine-2-yl)-3-(4-(tert-butyl)phenyl)urea;1-(4-(3-amino-1H-indazol-5-yl)pyridine-2-yl)-3-(4-(methylsulfonyl)phenyl)urea;1 -(4-(3-amino-1 H-indazol-5-yl)pyridin-2-yl)-3-(o-tolyl)urea;1-(4-(3-amino-1H-indazol-5-yl)pyridine-2-yl)-3-(2-ethylphenyl)urea;1-(4-(3-amino-1H-indazol-5-yl)pyridine-2-yl)-3-(2-isopropylphenyl)urea;1-(4-(3-amino-1H-indazol-5-yl)pyridine-2-yl)-3-(pyridine-3-yl)urea;5-(2-(phenylamino)pyridine-4-yl)-1H-indazol-3-amine;5-(2-((3-isopropylphenyl)amino)pyridine-4-yl)-1 H-indazol-3-amine;3-((4-(3-amino-1H-indazol-5-yl)pyridine-2-yl)amino)phenol;(3-((4-(3-amino-1 H-indazol-5-yl)pyridine-2-yl)amino)phenyl)methanol;3-((4-(3-amino-1H-indazol-5-yl)pyridine-2-yl)amino)benzoic acid; ethyl 3-((4-(3-amino-1H-indazol-5-yl)pyridine-2-yl)amino)benzoate;3-((4-(3-amino-1H-indazol-5-yl)pyridine-2-yl)amino)benzamide;3-((4-(3-amino-1H-indazol-5-yl)pyridine-2-yl)amino)-N-(2-hydroxyethyl)benzamide;N1-(4-(3-amino-1 H-indazol-5-yl)pyridine-2-yl)benzene-1 ,3-diamine;N-(3-((4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)amino)phenyl)acetamide;N-(3-((4-(3-amino-1H-indazol-5-yl)pyridine-2-yl)amino)phenyl)benzamide;5-(2-((3-phenoxyphenyl)amino)pyridlne-4-yl)-1H-indazol-3-amine;5-(2-((3-(benzyloxy)phenyl)amino)pyridine-4-yl)-1H-indazol-3-amine;5-(2-((4-fluorophenyl)amino)pyridine-4-yl)-1H-indazol-3-amine;5-(2-((4-chlorophenyl)amino)pyridine-4-yl)-1 H-indazol-3-amine;4-((4-(3-amino-1H-indazol-5-yl)pyridlne-2-yl)amino)phenol;5-(2-((4-methoxyphenyl)amino)pyridlne-4-yl)-1H-indazol-3-amine;5-(2-((4-(trifluoromethoxy)phenyl)amino)pyridine-4-yl)-1 H-lndazol-3-amine;5-(2-((4-propoxyphenyl)amino)pyridine-4-yl)-1 H-indazol-3-amine;2-((4-(3-amino-1H-indazol-5-yl)pyridine-2-yl)amino)phenol;4-((4-(3-amino-1H-indazol-5-yl)pyridine-2-yl)amino)-2-methylphenol;5-((4-(3-amino-1H-indazol-5-yl)pyridine-2-yl)amino)-2-methylphenol;4-((4-(3-amino-1H-indazol-5-yl)pyridine-2-yl)amino)-3-methylphenol;5-(2-((3,4-dichlorophenyl)amino)pyridine-4-yl)-1H-indazol-3-amine;N-(4-(3-amino-1 H-indazol-5-yl)pyridin-2-yl)thiazol-2-amine;5-(2-(pyrimidin-2-ylamino)pyridine-4-yl)-1 H-indazol-3-amine;5-(2-(pyridine-4-ylamino)pyridine-4-yl)-1 H-indazol-3-amine;5-(2-(pyridine-3-ylamino)pyridine-4-yl)-1 H-indazol-3-amine;5-(2-(pyridine-2-ylamino)pyridine-4-yl)-1 H-indazol-3-amine;N2-(4-(3-amino-1 H-indazol-5-yl)pyridine-2-yl)pyridine-2,6-diamine;N2-(4-(3-amino-1 H-indazol-5-yl)pyridine-2-yl)-N6-benzylpyridine-2,6-diamine;5-(7H-pyrrolo[2,3-b]pyrimidin-4-yl)-1 H-indazol-3-amine;2-amino-4-(3-amino-1H-indazol-5-yl)-7H-pyrrolo[2,3-b]pyrimidine-5-carbonitrile;5-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-indazol-3-amine;5-(3-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3-amine;5-(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine;4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;5-(2-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3-amine;5-(2-(tert-butyl)-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3-amine;5-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3-amine;4-(3-amino-1 H-indazol-5-yl)-1 H-pyrrolo[2,3-b]pyridine-2-carboxylic acid;5-(5-fluoro-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3-amine;5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine;4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2.3-b]pyridine-5-carbonitrile;5-(7H-pyrrolo[2,3-b]pyrimidin-4-yl)-1 H-indazol-3-amine;7-bromo-5-(7H-pyrrolo[2,3-b]pyrimidin-4-yl)-1H-indazol-3-amine;5-(2-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3-amine;5-(2-(tert-butyl)-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3-amine;5-(2-cyclopropyl-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3-amine;5-(2-cyclohexyl-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3-amine;5-(2-neopentyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine;5-(2-(cyclohexylmethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3-amine;5-(2-(2-cyclohexylethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine;5-(2-benzyl-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine;(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)methanol;2-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)propan-2-ol;3-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)pentan-3-ol;5-(2-(tert-butoxymethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3-amine;5-(2-(tetrahydro-2H-pyran-4-yl)-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3-amine;5-(2-(tetrahydro-2H-pyran-2-yl)-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3-amine;5-(2-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3-amine;4-(3-amino-1 H-indazol-5-yl)-1 H-pyrrolo[2,3-b]pyridine-2-carboxylic acid; methyl 4-(3-amino-1 H-indazol-5-yl)-1 H-pyrrolo[2,3-b]pyridine-2-carboxylate; ethyl 4-(3-amino-1 H-indazol-5-yl)-1 H-pyrrolo[2,3-b]pyridine-2-carboxylate;(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)(pyrrolidin-1-yl)methanone;4-(3-amino-1H-indazol-5-yl)-N-cyclopentyl-1 H-pyrrolo[2,3-b]pyridine-2-carboxamide;4-(3-amino-1H-indazol-5-yl)-N-cyclohexyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide;4-(3-amino-1H-indazol-5-yl)-N-isopentyl-1 H-pyrrolo[2,3-b]pyridine-2-carboxamide;4-(3-amino-1H-indazol-5-yl)-N-phenethyl-1 H-pyrrolo[2,3-b]pyridine-2-carboxamide;4-(3-amino-1H-indazol-5-yl)-N-(3-phenylpropyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide;4-(3-amino-1H-indazol-5-yl)-N-(2-methoxyethyl)-1 H-pyrrolo[2,3-b]pyridine-2-carboxamide;4-(3-amino-1H-indazol-5-yl)-N-(2-aminoethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide;4-(3-amino-1H-indazol-5-yl)-N-(2-(dimethylamino)ethyl)-1H-pyrrolo[2,3-b]pyridine-2- carboxamide;(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)(4-methylpiperazin-1- yl)methanone;4-(3-amino-1 H-indazol-5-yl)-N-(2-(piperidin-1 -yl)ethyl)-1 H-pyrrolo[2,3-b]pyridine-2- carboxamide;4-(3-amino-1H-indazol-5-yl)-N-(2-(butyl(ethyl)amino)ethyl)-1 H-pyrrolo[2,3-b]pyridine-2- carboxamide;4-(3-amino-1H-indazol-5-yl)-N-(2-(diisopropylamino)ethyl)-1H-pyrrolo[2,3-b]pyridine-2- carboxamide;4-(3-amino-1H-lndazol-5-yl)-N-(3-(dimethylamino)propyl)-1 H-pyrrolo[2,3-b]pyridine-2- carboxamide;5-(2-((tert-butylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-indazol-3-amine;5-(2-((isopentylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-indazol-3-amine;5-(2-(piperidln-2-yl)-1 H-pyrrolo[2,3-b]pyridine-4-yl)-1H-indazol-3-amine;5-(2-((cyclohexylamino)methyl)-1 H-pyrrolo[2,3-b]pyridine-4-yl)-1H-indazol-3-amine;5-(2-((phenylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-indazol-3-amine;5-(2-(((2-(benzyloxy)phenyl)amino)methyl)-1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-lndazol-3- amine;5-(2-(((2-methoxyethyl)amino)methyl)-1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-indazol-3-amine;N1-((4-(3-amino-1 H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)-N2,N2- dimethylethane-1 ,2-diamine;5-(2-(((3-methoxypropyl)amino)methyl)-1 H-pyrrolo[2,3-b]pyridine-4-yl)-1 H-indazol-3-amine;5-(2-(((3-isopropoxypropyl)amino)methyl)-1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-indazol-3- amine;N1-((4-(3-amino-1 H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)-N3,N3- dimethylpropane-1 ,3-diamine;5-(2-((isopropyl(methyl)amino)methyl)-1 H-pyrrolo[2,3-b]pyridine-4-yl)-1 H-indazol-3-amine5-(2-(piperid in- 1 -ylmethyl)-1 H-pyrrolo[2,3-b]pyridine-4-yl)-1 H-indazol-3-amine;5-(2-((4,4-difluoropiperidin-1 -yl)methyl)-1 H-pyrrolo[2,3-b]pyridine-4-yl)-1 H-indazol-3-amine5-(2-(morpholinomethyl)-1 H-pyrrolo[2,3-b]pyridine-4-yl)-1 H-indazol-3-amine;5-(2-((4-methylpiperazin-1 -yl)methyl)-1 H-pyrrolo[2,3-b]pyridine-4-yl)-1 H-indazol-3-amine;5-(2-((4-(tert-butyl)piperazin-1-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine;5-(2-(azepan-1-ylmethyl)-1H-pyrrolo[2,3-b]pyridine-4-yl)-1 H-indazol-3-amine;5-(2-((4-methyl-1 ,4-diazepan-1 -yl)methyl)-1 H-pyrrolo[2 ,3-b]pyridin-4-y I )-1 H-indazol-3-amine;5-(2-(2-(piperidin-1-yl)ethyl)-1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-indazol-3-amine;5-(2-(2-morpholinoethyl)-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3-amine;5-(2-(3-(piperidin-1-yl)propyl)-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3-amine;5-(2-(3-(cyclohexylamino)propyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine;5-(2-(3-morpholinopropyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine;5-(2-(piperidin-4-ylmethyl)-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3-amine;5-(2-((1-benzylpiperidin-4-yl)methyl)-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3-amine5-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3-amine;5-(2-(3-(trifluoromethyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine;3-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)benzonitrile;3-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)phenol;5-(2-(3-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine;3-(4-(3-amino-1 H-indazol-5-yl)-1 H-pyrrolo[2,3-b]pyridin-2-yl)benzoic acid;3-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)benzamide;3-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-N-(2-methoxyethyl)benzamide;3-(4-(3-amino-1 H-indazol-5-yl)-1 H-pyrrolo[2,3-b]pyridin-2-yl)-N-(2-(piperldin-1 - yl)ethyl)benzamide;(3-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)phenyl)(4-methylpiperazin-1- yl)methanone;5-(2-(3-(morpholinomethyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine;5-(2-(3-(methylsulfonyl)phenyl)-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine;5-(2-(3-(morpholinosulfonyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine;5-(2-(3-aminophenyl)-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3-amine;N-(3-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)phenyl)-3- methoxypropanamide;N-(3-(4-(3-amino-1 H-indazol-5-yl)-1 H-pyrrolo[2,3-b]pyridin-2-yl)phenyl)-3-(piperidin-1 - yl)propanamide;4-((3-(4-(3-amino-1 H-indazol-5-yl)-1 H-pyrrolo[2,3-b]pyrldin-2-yl)phenyl)amino)-4-oxobutanoic acid;N-(3-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)phenyl)methanesulfonamide N-(3-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)phenyl)-4- methylbenzenesulfonamide;5-(2-(4-(morpholinomethyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine N-(4-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)phenyl)-4- methylbenzenesulfonamide;2-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)phenol;5-(2-(2-ethoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine;5-(2-(2-ethylphenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine;5-(2-(benzo[d][1 ,3]dioxol-5-yl)-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3-amine;4-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-fluorobenzonitrile;5-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-(pyrrolidin-1-yl)benzonitrile;5-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-(4-methylpiperazin-1- yl)benzonitrile;5,5'-(1 H-pyrrolo[2,3-b]pyridine-2,4-diyl)bis(1 H-indazol-3-amine);5-(2-(3,5-difluorophenyl)-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3-amine;5-(2-(2,3,5-trifluorophenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3-amine;5-(2-(pyridin-2-yl)-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine;5-(2-(pyridin-3-yl)-1 H-pyrrolo[2,3-b]pyridln-4-yl)-1H-indazol-3-amine;5-(2-(pyridin-4-yl)-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine;5-(2-(pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine;4-(4-(3-amino-1 H-indazol-5-yl)-1 H-pyrrolo[2,3-b]pyridin-2-yl )pyridin-2( 1 H)-one;5-(2-(2-fluoropyrldin-4-yl)-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3-amine;5-(2-(2-fluoro-6-methylpyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine;5-(2-(2,6-difluoropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine;5-(2-(2-(piperldin-1-yl)pyridin-4-yl)-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3-amine;5-(2-(2-(piperazin-1-yl)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine;5-(2-(2-morpholinopyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine;5-(2-(2-(4-(tert-butyl)piperazin-1-yl)pyridin-4-yl)-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3- amine;4-(4-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)pyridin-2-yl)thiomorpholine 1 ,1 -dioxide;5-(2-(2,6-dimorpholinopyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3-amine;4-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1-(4-(piperidin-1- ylmethyl)benzyl)pyridin-2(1 H)-one;4-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1-(3-(piperidin-1- ylmethyl)benzyl)pyridin-2(1 H)-one;4-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1-(2-(piperidin-1- ylmethyl)benzyl)pyridin-2(1 H)-one;5-(2-(5-methoxypyridin-3-yl)-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine;5-(2-(6-morpholinopyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine;5-(2-(6-(4-methylpiperazin-1 -y I )py ridin-3-yl )- 1 H-pyrrolo[2, 3-b]py ridi n-4-y I)- 1 H-indazol-3- amine;5-(2-(6-((2-morpholinoethyl)amino)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3- amine;5-(2-(2-fluoropyridin-3-yl)-1 H-pyrrolo[2,3-b]pyridin^l-yl)-1 H-indazol-3-amine;5-(2-(2-morpholinopyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine;5-(2-(3-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine;5-(2-(3-isobutoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine;5-(2-(3-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H- indazol-3-amine;5-(2-(3-(2-morpholinoethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine;5-(2-(3-(benzyloxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine;5-(2-(3-((3,5-dimethoxybenzyl)oxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3- amine;5-(2-(3-((4-fluorobenzyl)oxy)phenyl)-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine;5-(2-(3-((2-fluorobenzyl)oxy)phenyl)-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine;5-(2-(3-(pyridin-2-ylmethoxy)phenyl)-1 H-pyrrolo[2,3-b]pyridln-4-yl)-1 H-indazol-3-amine;3-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-fluorophenol;5-(2-(3-fluoro-5-methoxyphenyl)-1 H-pyrrolo[2,3-b]pyrldin-4-yl)-1 H-indazol-3-amine;5-(2-(3-fluoro-5-(2-methoxyethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridlne-4-yl)-1H-indazol-3- amine;5-(2-(3-fluoro-5-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)-1 H-pyrrolo[2,3-b]pyridine-4-yl)-1 H-indazol-3-amine;5-(2-(3-(benzyloxy)-5-fluorophenyl)-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3-amine;5-(2-(3-(benzyloxy)-5-(trifluoromethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3- amine; methyl 3-(4-(3-amino-1 H-indazol-5-yl)-1 H-pyrrolo[2,3-b]pyridin-2-yl)-5-(benzyloxy)benzoate 5-(2-(3-(benzyloxy)-5-((2-methoxyethoxy)methyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H- indazol-3-amine;5-(2-(3-(benzyloxy)-5-((2-methoxyethyl)amino)phenyl)-1 H-pyrrolo[2,3-b]pyrldin-4-yl)-1 H- indazol-3-amine;5-(2-(3-(benzyloxy)-5-((2-morpholinoethyl)amino)phenyl)-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1H- indazol-3-amine;5-(2-(2-(benzyloxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine;5-(2-(4-(benzyloxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine;5-(2-(5-(benzyloxy)pyridin-3-yl)-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3-amine;5-(2-(2-(benzyloxy)pyridin-4-yl)-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3-amine;5-(2-(6-(benzyloxy)pyridin-3-yl)-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3-amine;5-(2-(4-(benzyloxy)pyridin-2-yl)-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3-amine;5-(2-(2-(pyrimidin-5-ylmethoxy)pyridin-4-yl)-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3- amine;5-(2-(2-(pyridin-4-ylmethoxy)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine;5-(2-(2-(pyridin-3-ylmethoxy)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine;5-(2-(2-(pyridin-2-ylmethoxy)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine;5-(2-(6-(benzylamino)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine;5-(2-(2-(benzylamino)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine;5-(2-(2-(benzyl(methyl)amino)pyridin-4-yl)-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3-amine;5-(2-(2-(benzylthio)pyridin-4-yl)-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3-amine;5-(2-(2-(benzylthio)-6-morpholinopyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3- amine;5-(2-(3-phenethylphenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine;5-(2-(2-phenethoxypyridin-4-yl)-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3-amine;5-(2-(3-((phenylamino)methyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine;5-(2-(3-((tert-butylamino)methyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-lndazol-3-amine;5-(2-(3-((cyclopentylamino)methyl)phenyl)-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3-amine;5-(2-(3-((cyclohexylamino)methyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine;5-(2-(3-((butylamino)methyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine;5-(2-(3-((isopentylamino)methyl)phenyl)-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3-amine5-(2-(3-((butyl(ethyl)amino)methyl)phenyl)-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3- amine;;5-(2-(3-((dibutylamino)methyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine;5-(2-(2-fluoro-6-(piperidin-1-ylmethyl)pyridin-4-yl)-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3- amine;5-(2-(2-fluoro-6-(piperazin-1-ylmethyl)pyridin-4-yl)-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3-amine;5-(2-(2-fluoro-6-((4-methylpiperazin-1-yl)methyl)pyridin-4-yl)-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3-amine; tert-butyl 4-((4-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-6-fluoropyridin-2- yl)methyl)piperazine-1 -carboxylate;5-(2-(2-((tert-butylamino)methyl)-6-fluoropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H- indazol-3-amine;5-(2-(2-((cyclohexylamino)methyl)-6-fluoropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H- indazol-3-amine;5-(2-(2-fluoro-6-((phenylamino)methyl)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine;4-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-2,6-difluorobenzamide5-(2-(4-((dimethylamino)methyl)-3,5-difluorophenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H- indazol-3-amine;5-(2-(3,5-difluoro-4-(piperidin-1-ylmethyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3- amine;5-(2-(3,5-difluoro-4-((isopropyl(methyl)amino)methyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3-amine5-(2-(4-((butyl(ethyl)amino)methyl)-3,5-difluorophenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1 H- indazol-3-amine;5-(2-(4-((dibutylamino)methyl)-3,5-difluorophenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-lndazol-3-amine;5-(2-(3,5-difluoro-4-(3-morpholinopropyl)phenyl)-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3- amine;5-(2-(3,5-difluoro-4-(3-(piperldin-1 -yl)propyl)phenyl)-1 H-pyrrol o[2 , 3-b] py ridi n-4-yl)- 1 H- indazol-3-amine;5-(2-(4-(3-(diethylamino)propyl)-3,5-difluorophenyl)-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3-amine;5-(2-(4-(3-(dibutylamino)propyl)-3,5-difluorophenyl)-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3-amine;7-chloro-5-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3-amine;7-chloro-5-(2-(3-(morpholinomethyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3- amine;7-chloro-5-(2-(4-(morpholinomethyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3- amine;7-chloro-5-(2-(2-fluoro-6-(piperazin-1-ylmethyl)pyridin-4-yl)-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1H- indazol-3-amine;4-(3-amino-7-chloro-1H-indazol-5-yl)-N-(2-(piperidin-1-yl)ethyl)-1 H-pyrrolo[2,3-b]pyridine-2- carboxamide;7-chloro-5-(2-(cyclohexylmethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine;7-chloro-5-(2-(morpholinomethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3-amine;7-chloro-5-(2-(2-morpholinoethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-indazol-3-amine;7-phenyl-5-(2-phenyl-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine;5-(2-(3-(morpholinomethyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-7-phenyl-1 H-indazol-3- amine;5-(2-(4-(morpholinomethyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-7-phenyl-1 H-indazol-3- amine;5-(2-(cyclohexylmethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-7-(3,3-dimethylbut-1-yn-1-yl)-1H- indazol-3-amine; or5-(2-(2-(Benzylthio)-6-fluoropyridin-4-yl)-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine.

24. A pharmaceutical composition comprising a compound according in any anyone of claims 1 to 23, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

25. A compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical formulation according to claim 24:(i) for use in therapy;(II for use in the treatment of a disease or condition responsive to IKKαlpha modulation;(II) for use in the treatment of a proliferative disorder (e.g. cancer); or(III for use in the treatment of inflammation.

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