FIELD OF THE INVENTION

[0001] The present invention relates to certain compounds that function as inhibitors of METTL3 (N6-adenosine-methyltransferase 70 kDa subunit) activity. The present invention also relates to processes for the preparation of these compounds, to pharmaceutical compositions comprising them, and to their use in the treatment of proliferative disorders, such as cancer, autoimmune, neurological, infectious and inflammatory diseases, as well as other diseases or conditions in which METTL3 activity is implicated.

BACKGROUND OF THE INVENTION

[0002] N6-methyladenosine (m6A) is the most common and abundant covalent modification of messenger RNA, modulated by‘writers’,‘erasers’ and‘readers’ of this mark (Meyer & Jaffrey 2014, Niu Y et al, 2013, Yue et al 2015). Approximately 0.1 to 0.5% of all mRNA adenosines are m6A modified (Li Y et al 2015). In vitro data have shown that m6A influences fundamental aspects of mRNA biology, mainly mRNA expression, splicing, stability, localisation and translation (Meyer et al, 2015; Sledz & Jinek 2016). M6A modifications are tissue specific and there is significant variability in their occurrence profiles in non-diseased tissues (eg brain, heart, kidney) and diseased tissues and cells (lung, renal, breast, and leukeamic cancer cells) (Meyer et al 2012).

[0003] The m6A modifications and its erasers and writers such as FTO, ALKBH5, methyltransferese like 3 (METTL3) and METTL14 are associated with major diseases such as solid organ cancers, leukaemia, type 2 diabetes, neuropsychiatric behavioural and depressive disorders (Chandola et al 2015; Koranda et al 2018).

[0004] The RNA methyltransferase, METTL3, is the major, but not the sole enzyme, that catalyses m6A modification of RNA. It exists as a hetero-trimeric complex with METTL14 (Liu et al 2014, Wang et al 2016) and Wilm’s Tumour Associated Protein (WTAP) (Ping et al 2014). Catalytic activity resides in METTL3, which transfers a methyl group from the co-factor S- adenosyl methionine to the substrate RNA and METTL14 facilitates substrate RNA binding. WTAP localises the complex in specific nuclear regions and also localises RNA substrates to the complex (Wang X et al 2016).

[0005] METTL3 has been reported to play a role in many aspects of the development of cancer (Fry et al 2018). Genetic knockdown of METTL3 in lung cancer cell lines (A549, H1299 and H1792) and HeLa cells leads to decreased growth, survival and invasion of human lung cancer cells (Lin S et al 2016). METTL3 is significantly up-regulated in human bladder cancer (Cheng et al 2019). Knockdown of METTL3 drastically reduced bladder cancer cell proliferation, invasion, and survival in vitro and tumorigenicity in vivo. AF4/FMR2 family member 4 (AFF4), two key regulators of NF-kB pathway (IKBKB and RELA) and MYC were further identified as direct targets of METTL3-mediated m6A modification. In renal carcinoma cell lines (CAK-1, CAK-2 and ACHN), genetic knockdown reduced cell proliferation via the phosphatidinylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signalling pathway (Li X et al 2017).

[0006] Recently Barbieri et al (2017), defined a set of RNA-modifying enzymes that are necessary for AML leukaemia and identified a key leukaemic pathway for the METTL3 RNA methyltransferase. In this pathway, METTL3 is stably recruited by the CCAAT-box binding transcription factor CEBPZ to promoters of a specific set of active genes, resulting in m6A methylation of the respective mRNAs and increased translation. One important target is SP1, an oncogene in several cancers, which regulates c-MYC expression. Consistent with these findings, it has been reported that METTL3 can methylate its targets co-transcriptionally.

[0007] The pathway described by Barbieri et al., is critical for AML leukaemia, as three of its components are required for AML cell growth: (i) the m6A RNA methyltransferase METTL3; (ii) the transcription factor CEBPZ, which targets this enzyme to promoters; and (iii) SP1, whose translation is dependent upon the m6A modification by METTL3. Together, the observations of Barbieri et al define METTL3 enzymatic activity as a new candidate target for the treatment of AML.

[0008] In separate, independent studies it has been reported that METTL3 plays an essential role in controlling myeloid differentiation of mammalian normal hematopoietic and leukemic cells (Vu et al 2017). Forced expression of wild type METTL3, but not a mutant METTL3 (with defect in catalytic activity), significantly promotes cell proliferation and inhibits cell differentiation of human cord blood-derived CD34+ haematopoietic stem/progenitor cells (HSPCs). Genetic knockdown of METTL3 has the opposite effects. METTL3 is highly expressed in AML compared to normal HSPCs or other types of cancers. Knockdown of METTL3 in human AML cell lines significantly induces cell differentiation and apoptosis and inhibits leukemia progression in mice xeno-transplanted with MOLM-13 AML cells. The biological function of METTL3 is likely attributed to the promotion of translation of its mRNA targets such as MYC, BCL-2, and PTEN in an m6A-dependent manner.

[0009] Recently, METTL3 mediated m6A modification has been demonstrated to play an important role in T cell homeostasis and signal dependent induction of mRNA degradation in CD4 positive T cell lineages (Li et al 2017). Deletion of METTL3 in mouse T cells disrupts T cell homeostasis and differentiation. In a lymphopenic mouse adoptive transfer model, naive Mettl3-deficient T cells failed to undergo homeostatic expansion and remained in the naive state for up to 12 weeks, thereby preventing colitis. Consistent with these observations, the mRNAs of SOCS family genes encoding the STAT signalling inhibitory proteins SOCS1, SOCS3 and CISH were marked by m6A, exhibited slower mRNA decay and showed increased mRNAs and levels of protein expression in Mettl3-deficient naive T cells. This increased SOCS family activity consequently inhibited IL-7-mediated STAT5 activation and T cell homeostatic proliferation and differentiation. Thus METTL3 mediated m6A methylation has important roles for inducible degradation of Socs mRNAs in response to IL-7 signalling in order to reprogram naive T cells for proliferation and differentiation, pointing to a role in auto-immunity.

[0010] Recent studies have revealed that depletion of METTL3 leads to alterations in the propagation of diverse viruses (Winkler et al). Following viral infection or stimulation of cells with an inactivated virus, deletion of the m6A‘writer’ METTL3 led to an increase in the induction of interferon-stimulated genes. Consequently, propagation of different viruses was suppressed in an interferon-signaling-dependent manner. Significantly, the mRNA of IFNB, was m6A modified and was stabilized following repression of METTL3. m6A serves as a negative regulator of interferon response by dictating the fast turnover of interferon mRNAs and consequently facilitating viral propagation. Therefore METTL3 inhibitors may provide a novel therapeutic approach to a range of infectious and inflammatory diseases.

References

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[0032] An object of this invention is to provide inhibitors of METTL3 activity.

SUMMARY OF THE INVENTION

[0033] In one aspect, the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt thereof. [0034] In another aspect, the present invention provides a pharmaceutical composition as defined herein which comprises a compound as defined herein, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0035] In another aspect, the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, for use in therapy.

[0036] In another aspect, the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, for use in the treatment of a proliferative condition.

[0037] In another aspect, the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, for use in the treatment of cancer. In a particular embodiment, the cancer is a human cancer.

[0038] In another aspect, the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, for use in the inhibition of METTL3 activity.

[0039] In another aspect, the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, for use in the treatment of an autoimmune disease.

[0040] In another aspect, the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, for use in the treatment of a neurological disease.

[0041] In another aspect, the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, for use in the treatment of an infectious disease.

[0042] In another aspect, the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, for use in the treatment of an inflammatory disease.

[0043] In another aspect, the present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of a proliferative condition.

[0044] In another aspect, the present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of cancer. In a particular embodiment, the medicament is for use in the treatment of human cancers.

[0045] In another aspect, the present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the inhibition of METTL3 activity.

[0046] In another aspect, the present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of an autoimmune disease.

[0047] In another aspect, the present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of a neurological disease.

[0048] In another aspect, the present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of an infectious disease.

[0049] In another aspect, the present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of an inflammatory disease.

[0050] In another aspect, the present invention provides a method of inhibiting METTL3 activity in vitro or in vivo, said method comprising contacting a cell with an effective amount of a compound as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

[0051] In another aspect, the present invention provides a method of inhibiting cell proliferation in vitro or in vivo, said method comprising contacting a cell with an effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, or a pharmaceutical composition as defined herein.

[0052] In another aspect, the present invention provides a method of inhibiting metastasis in vitro or in vivo, said method comprising contacting a cell with an effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, or a pharmaceutical composition as defined herein.

[0053] In another aspect, the present invention provides a method of treating a proliferative disorder, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, or a pharmaceutical composition as defined herein. [0054] In another aspect, the present invention provides a method of treating cancer, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, or a pharmaceutical composition as defined herein.

[0055] In another aspect, the present invention provides a method of treating an autoimmune disease, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, or a pharmaceutical composition as defined herein.

[0056] In another aspect, the present invention provides a method of treating a neurological disease, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, or a pharmaceutical composition as defined herein.

[0057] In another aspect, the present invention provides a method of treating an infectious disease, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, or a pharmaceutical composition as defined herein.

[0058] In another aspect, the present invention provides a method of treating an inflammatory disease, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, or a pharmaceutical composition as defined herein.

[0059] In one aspect, the present invention provides a combination comprising a compound as defined herein, or a pharmaceutically acceptable salt thereof, with one or more additional therapeutic agents.

[0060] The present invention further provides a method of synthesising a compound, or a pharmaceutically acceptable salt, as defined herein.

[0061] In another aspect, the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt, obtainable by, or obtained by, or directly obtained by a method of synthesis as defined herein.

[0062] In another aspect, the present invention provides novel intermediates as defined herein which are suitable for use in any one of the synthetic methods as set out herein.

[0063] Preferred, suitable, and optional features of any one particular aspect of the present invention are also preferred, suitable, and optional features of any other aspect. BRIEF DESCRIPTION OF THE DRAWINGS

[0064] For a better understanding of the invention, and to show how embodiments of the same are put into effect, reference is now made, by way of example, to the following figures, in which:

Figure 1: Schematic of the MOLM13 AML proliferation assay with measurement of m6A levels Figure 2: m6A levels in total RNA from MOLM13 (+IFNy) day 4

Figure 3: Inhibition of MOLM13 proliferation 6 days

Figure 4: Inhibition of MOLM13 CD14 expression 6 days

Figure 5: Inhibition of MOLM14, Kasumi-1, NOMO-1 and THP.1 proliferation 7 days (IFNy treated)

Figure 6: Inhibition of KCL-22 proliferation 6 days (IFNy treated)

DETAILED DESCRIPTION OF THE INVENTION

Definitions

[0065] Unless otherwise stated, the following terms used in the specification and claims have the following meanings set out below.

[0066] It is to be appreciated that references to“treating” or“treatment” include prophylaxis as well as the alleviation of established symptoms of a condition.“Treating” or“treatment” of a state, disorder or condition therefore includes: (1) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a human that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition, (2) inhibiting the state, disorder or condition, i.e., arresting, reducing or delaying the development of the disease or a relapse thereof (in case of maintenance treatment) or at least one clinical or subclinical symptom thereof, or (3) relieving or attenuating the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.

[0067] 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.

[0068] 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,“C _1-6 alkyl” includes C _1-4 alkyl, C _1-3 alkyl, propyl, isopropyl and t-butyl. A similar convention applies to other radicals, for example “phenyl(C _1-6 alkyl)” includes phenyl(C _1-4 alkyl), benzyl, 1-phenylethyl and 2-phenylethyl.

[0069] The term "(m-nC)" or“Cm-n”, or "(m-nC) group" or“Cm-n” used alone or as a prefix, refers to any group having m to n carbon atoms.

[0070] The term "alkenyl", as used herein, refers to an aliphatic group containing at least one double bond and is intended to include both "unsubstituted alkenyls" and "substituted alkenyls", the latter of which refers to alkenyl moieties having substituents replacing a hydrogen on one or more carbons of the alkenyl group. Such substituents may occur on one or more carbons that are included or not included in one or more double bonds. Moreover, such substituents include all those contemplated for alkyl groups, as discussed below, except where stability is prohibitive. For example, substitution of alkenyl groups by one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups is contemplated.

[0071] The term "alkynyl", as used herein, refers to an aliphatic group containing at least one triple bond and is intended to include both "unsubstituted alkynyls" and "substituted alkynyls", the latter of which refers to alkynyl moieties having substituents replacing a hydrogen on one or more carbons of the alkynyl group. Such substituents may occur on one or more carbons that are included or not included in one or more triple bonds. Moreover, such substituents include all those contemplated for alkyl groups, as discussed above, except where stability is prohibitive. For example, substitution of alkynyl groups by one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups is contemplated.

[0072] An“alkylene” group is an alkyl group that is positioned between and serves to connect two other chemical groups. Thus, “C1-3alkylene” means a linear saturated divalent hydrocarbon radical of one to three carbon atoms or a branched saturated divalent hydrocarbon radical of three atoms, for example, methylene, ethylene, propylene, and the like.

[0073] The term“Cm-ncycloalkyl” means a hydrocarbon ring containing from m to n carbon atoms, for example“C _3-6 cycloalkyl” means a hydrocarbon ring containing from 3 to 6 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. The term“Cm-ncycloalkyl” also encompasses non-aromatic saturated or partially saturated monocyclic, fused, bridged, or spiro bicyclic carbocyclic ring system(s). The term“Cm-ncycloalkyl” includes both monovalent species and divalent species. Monocyclic“Cm-ncycloalkyl” rings contain from about 3 to 12 (suitably from 3 to 8, most suitably from 5 to 6) ring carbon atoms. Bicyclic“Cm- ncycloalkyl” contain from 7 to 17 ring carbon atoms, suitably 7 to 12 ring carbon atoms. Bicyclic “Cm-ncycloalkyl” rings may be fused, spiro (e.g. spiro[3,3]heptane), or bridged ring systems (e.g. bicyclo[2.2.1]hept-2-ene and bicyclo[1.1.1]pentanyl). [0074] The term“halo” or“halogeno” refers to fluoro, chloro, bromo and iodo.

[0075] The term “heterocyclyl”, “heterocyclic” or “heterocycle” means a non-aromatic saturated or partially saturated monocyclic, fused, bridged, or spiro bicyclic heterocyclic ring system(s). The term heterocyclyl includes both monovalent species and divalent species. Monocyclic heterocyclic rings contain from about 3 to 12 (suitably from 3 to 7, most suitably from 5 to 6) 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 heterocycles contain from about 7 to about 17 ring atoms, suitably from 7 to 12 ring atoms. Bicyclic heterocyclic(s) rings may be fused, spiro, or bridged ring systems. Examples of heterocyclic groups include cyclic ethers such as oxiranyl, oxetanyl, tetrahydrofuranyl, dioxanyl, and substituted cyclic ethers. Heterocycles containing nitrogen include, for example, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrotriazinyl, tetrahydropyrazolyl, and the like. Typical sulfur containing heterocycles include tetrahydrothienyl, dihydro-1,3-dithiol, tetrahydro-2H-thiopyran, and hexahydrothiepine. Other heterocycles include 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 SO ₂ groups are also included. Examples include the sulfoxide and sulfone forms of tetrahydrothienyl and thiomorpholinyl such as tetrahydrothiene 1,1-dioxide and thiomorpholinyl 1,1-dioxide. A suitable value for a heterocyclyl group which bears 1 or 2 oxo (=O) or thioxo (=S) substituents is, for example, 2-oxopyrrolidinyl, 2-thioxopyrrolidinyl, 2-oxoimidazolidinyl, 2-thioxoimidazolidinyl, 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.

[0076] 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, 4 ^th Edition, Wiley Interscience, pages 131-133, 1992. Examples of bridged heterocyclyl ring systems include, aza-bicyclo[2.2.1]heptane, 2-oxa-5-azabicyclo[2.2.1]heptane, aza-bicyclo[2.2.2]octane, aza- bicyclo[3.2.1]octane, quinuclidine, 6-azabicyclo[3.1.1]heptane, 8-azabicyclo[3.2.1]octane, bicyclo[3.2.1]octane, 7-oxabicyclo[2.2.1]hept-2-ene and 3-oxa-8-azabicyclo[3.2.1]octane .

[0077] 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.

[0078] Examples of heteroaryl include furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazenyl, benzofuranyl, indolyl, isoindolyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzothiazolyl, indazolyl, purinyl, benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, cinnolinyl, pteridinyl, naphthyridinyl, carbazolyl, phenazinyl, benzisoquinolinyl, pyridopyrazinyl, thieno[2,3-b]furanyl, 2H-furo[3,2-b]-pyranyl, 5H-pyrido[2,3-d]-o-oxazinyl, 1H-pyrazolo[4,3-d]-oxazolyl, 4H-imidazo[4,5-d]thiazolyl, pyrazino[2,3-d]pyridazinyl, imidazo[2,1-b]thiazolyl, imidazo[1,2-b][1,2,4]triazinyl.“Heteroaryl” also covers partially aromatic bi- or polycyclic ring systems wherein at least one ring is an aromatic ring and one or more of the other ring(s) is a non-aromatic, saturated or partially saturated ring, provided at least one ring contains one or more heteroatoms selected from nitrogen, oxygen or sulfur. Examples of partially aromatic heteroaryl groups include for example, tetrahydroisoquinolinyl, 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 and 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl. [0079] 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.

[0080] Examples of six membered heteroaryl groups include but are not limited to pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl and triazinyl.

[0081] 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.

[0082] 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.

[0083] 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.

[0084] The term“aryl” means a cyclic or polycyclic aromatic ring having from 5 to 12 carbon atoms. The term aryl includes both monovalent species and divalent species. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl and the like. In particular embodiment, an aryl is phenyl.

[0085] The term "optionally substituted" refers to either groups, structures, or molecules that are substituted and those that are not substituted.

[0086] 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.

[0087] The phrase“compound of the invention” means those compounds which are disclosed herein, both generically and specifically.

Compounds of the invention

[0088] In one aspect, the present invention relates to compounds of the formula (I), or a pharmaceutically acceptable salt thereof,

X– Y– Z

(I)

wherein:

X is selected from:

wherein:

R1a, R1b, R1c, R1d, R1e and R1f are independently selected from hydrogen, cyano, halo or a group of the formula:

-L _1a -L _1b -Q ₁

wherein

L _1a is absent or selected from C _1-3 alkylene and C _3-5 cycloalkylene, wherein C _{1- 3} alkylene and C _3-5 cycloalkylene are optionally substituted by one or more

substituents selected from aryl, aryl-(1-2C)alkyl, heteroaryl, aryl-(1-2C)alkyl, C _1-3 alkyl, cyano, C _1-3 alkoxy, halo, hydroxy, C _1-3 haloalkoxy, -O-C _3-4 cycloalkyl, NH ₂ or oxo;

wherein any -O-C _3-6 cycloalkyl aryl, aryl-(1-2C)alkyl, heteroaryl, aryl-(1-2C)alkyl or C _{1- 3} alkyl is optionally further substituted by one or more substituents selected from cyano, hydroxy, C _1-3 alkoxy, halo, C _1-3 haloalkoxy, -O-C _3-4 cycloalkyl, or NH ₂ ; wherein - O-C _3-6 cycloalkyl is optionally further subsitutued with halo, cyano or hydroxy; ; or C _{1- 3} alkylene is optionally spiro-fused to a a 3- to 5-membered cycloalkyl or heterocyclic ring, or a spirocyclic ring system, each of which is optionally substituted by one or more substituents selected from C _1-2 alkyl, C _1-2 haloalkyl, cyano, hydroxy, C _1-2 alkoxy, halo or C _1-2 haloalkoxy;

L _1b is absent or selected from O, S, SO, SO ₂ , N(R _r ), C(O), C(O)O, OC(O), C(O)N(R _r ), N(R _r )C(O), N(R _r )C(O)N(R _s ), S(O) ₂ N(R _r ), or N(R _r )SO ₂ , wherein R _r and R _s are each independently selected from hydrogen or C _1-3 alkyl, wherein C _1-3 alkyl is optionally further substituted by cyano, hydroxy, C _1-2 alkoxy, halo, C _1-2 haloalkoxy, NH2, C _3-6 - cycloalkyl or a 3 to 6 membered heterocyclyl, wherein the C _3-6 cycloalkyl or a 3 to 6 membered heterocyclyl in turn are optionally further substituted by halo, hydroxy, C1- 2alkoxy or C _1-2 haloalkoxy; and

Q1 is hydrogen, cyano, C _1-6 alkyl, C3-8cycloalkyl (including a spirocyclic carbocyclic and a bridged C3-8cycloalkyl), C2-3alkenyl, C2-3alkynyl, aryl, heterocyclyl (including a mono- or bicyclic-heterocyclic ring system, a spirocyclic heterocyclic ring system, or a bridged heterocyclic ring system) or heteroaryl; and wherein Q1 is optionally substituted by one or more substituents selected from C _1-4 alkyl, halo, trifluoromethyl, trifluoromethoxy, amino, oxo, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, NR _t R _u , OR _t , C(O)R _t , C(O)OR _t , OC(O)R _t , C(O)N(R _t )R _u , N(R _t )C(O)R _u , -S(O) _0-2 R _t R _u , S(O) _y R _t (where y is 0, 1 or 2), SO ₂ N(R _t )R _u , N(R _t )SO ₂ R _u or (CH ₂ ) _z NR _t R _u (where z is 1, 2 or 3), wherein C _1-4 alkyl is in turn optionally substituted by one more substituents selected from cyano, hydroxy, C _1-2 alkoxy, halo, C _1-2 haloalkoxy, -O-C ₃ cycloalkyl, wherein -O-C ₃ cycloalkyl is optionally subsitutued with halo, cyano or hydroxy; and wherein R _t and R _u are each independently selected from hydrogen or C _1-4 alkyl; or Q ₁ is optionally substituted by one or more groups of the formula:

-L _1c -L _1d -Z ₁

wherein

L _1c is absent or C _1-3 alkylene optionally substituted by C _1-2 alkyl or oxo;

L _1d is absent or selected from C(O), O, C(O)O, OC(O), C(O)N(R _v ), N(R _v )C(O), N(R _v )C(O)N(R _w ), S(O) ₂ N(R _v ), or N(R _v )SO ₂ , wherein R _v and R _w are each

independently selected from hydrogen or C _1-2 alkyl; and

Z ₁ is C _3-8 cycloalkyl (including a spirocyclic carbocyclic and a bridged C _3-8 cycloalkyl), heterocyclyl (including a mono- or bicyclic-heterocyclic ring system, a spirocyclic heterocyclic ring system, or a bridged heterocyclic ring system), aryl or heteroaryl, ; wherein Z1 is optionally substituted by one or more substituents selected from C1- 4alkyl, C _3-6 cycloalkyl, heterocyclyl, halo, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _1-4 alkoxy, cyano, hydroxyl, NR _t1 R _u1 , OR _t1 , C(O)R _t1 , C(O)OR _t1 , OC(O)R _t1 , C(O)N(R _t1 )R _u1 , N(R _t1 )C(O)R _u1 , -S(O) _0-2 R _t1 R _u1 , S(O)yR _t1 (where y is 0, 1 or 2), SO ₂ N(R _t1 )R _u1 ,

N(R _t1 )SO ₂ R _u1 or (CH2)zNR _t1 R _u1 (where z is 1, 2 or 3), wherein R _t1 and R _u1 are each independently selected from hydrogen or C _1-4 alkyl; and when Z1 is C3-8cycloalkyl or heterocyclyl, Z1 is optionally spiro-fused to a C _3-6 cycloalkyl or heterocyclyl ring;

R1a’ is selected from hydrogen, halo and methyl;

R _2a , R _2b and R _2c are selected from hydrogen, halo or a group of the formula:

-L _2a -L _2b -Q ₂

wherein

L2a is absent or C _1-3 alkylene optionally substituted by C _1-2 alkyl or oxo;

L2b is absent or selected from O, S, SO, SO ₂ , N(Rn), C(O), C(O)O, OC(O),

C(O)N(Rn), N(Rn)C(O), N(Rn)C(O)N(Ro), S(O)2N(Rn), or N(Rn)SO ₂ , wherein R _n and Ro are each independently selected from hydrogen or C _1-2 alkyl; and Q ₂ is hydrogen, cyano, C _1-6 alkyl, C _3-6 cycloalkyl, aryl, heterocyclyl or heteroaryl, each of which is optionally substituted by one or more substituents selected from halo, trifluoromethyl, trifluoromethoxy, amino, cyano, hydroxy, amino, carboxy, carbamoyl, sulphamoyl, C _1-4 alkyl, NR _p R _q , OR _p , C(O)R _p , C(O)OR _p , OC(O)R _p , C(O)N(R _p )R _q , N(R _r )C(O)R _p , S(O) _y R _p (where y is 0, 1 or 2), SO ₂ N(R _p )R _q , N(R _r )SO ₂ R _p or (CH ₂ ) _z NR _p R _q (where z is 1, 2 or 3), wherein R _p and R _q are each independently selected from hydrogen or C _1-4 alkyl;

Y is selected from:

,

wherein:

R3a1, R3b1, R3c1, R3d1, R3e1, R3f1, R3g1, R3h1, R3i1, R3j1, R3k1, R3l1, R3m1, R3n1, R3o1, R3p1,R3q1, R3r1 and R3s1 are independently selected from hydrogen (including deuterium), C _1-6 alkyl, C _3-4 cycloalkyl, hydroxy, and halo; and wherein C ₁ - ₆ alkyl, or C _3-4 cycloalkyl is optionally substituted with one or more substituents selected from halo, amino, cyano, and hydroxy;

R _3a2 , R _3b2 , R _3c2 , R _3d2 , R _3e2 , R _3f2 , R _3g2 , R _3h2 , R _3i2 , R _3j2 , R _3k2 , R _3l2 , R _3m2 , R _3n2, R _3o2, R _3p2- ,R _3q2 , R _3r2 and R _3s2 are hydrogen or halo;

with the proviso that R _3a1 , R _3b1 , R _3i1 , R _3l1 , R _3o1 , R _3r1 , R _3a2 , R _3b2 , R _3i2 , R _3l2 , R _3o2 and R _3s1 cannot be halo when n=1 or when n=2 and the carbon atom to which they are attached is linked to an oxygen or nitrogen atom;

or R _3a1 and R _3a2 , R _3b1 and R _3b2 , R _3c1 and R _3c2 , R _3d1 and R _3d2 , R _3e1 and R _3e2 , R _3f1 and R _3f2 , R _3g1 and R _3g2 , R _3h1 and R _3h2 , R _3i1 and R _3i2 , R _3j1 and R _3j2 , R _3k1 and R _3k2 , R _3l1 and R _3l2 , R _3m1 and R _3m2 , R _3n1 and R _3n2 , R _3o1 and R _3o2 , R _3p1 and R _3p2 , R _3q1 and R _3q2 , or R _3r1 and R _3r2 or R _3s1 and R _3s2 may be linked such that, together with the carbon atom to which they are attached, they form a spiro-fused C _3-4 cycloalkyl which is optionally substituted with one or more substituents selected from halo, methyl, amino, cyano, and hydroxy;

Z is selected from:

wherein:

R4, R7, R4a and R7a are independently selected from hydrogen, halo, cyano and methyl;

R5, R5a, R5b and R5c are independently selected from hydrogen, halo, cyano and methyl;

R6, R8, R6a and R8a are independently selected from hydrogen, halo, cyano and methyl;

R9, R9a, R10 and R11 are independently selected from hydrogen, NH2, halo, cyano, and C _1-6 alkyl; or

R9 and R10 may be linked together to form a fused 5- or 6-membered saturated or unsaturated ring system or R10 and R11 may be linked together to form a fused 5- or 6-membered saturated or unsaturated ring system; wherein either of the fused 5- or 6-membered saturated or unsaturated ring system may be optionally subsitutued by one or more substituents selected from C _1-2 alkyl, cyano, C _1-2 haloalkyl, hydroxy, C1- ₂ alkoxy, halo, C _1-2 haloalkoxy, NR _1ia R _1ja or -S(O) _0-2 R _1ia R _1ja , wherein R _1ia and R _1ja are H or C _1-2 alky;

R _Z1 and R _Z1a are selected from hydrogen, C _1-4 alkyl, cyano, halo, C _1-4 haloalkyl, C _{1- 4} haloalkoxy, C _1-4 alkoxy, C _3-6 cycloalkyl and -O-C _3-6 cycloalkyl, wherein C _3-6 cycloalkyl and -O-C _3-6 cycloalkyl are optionally subsitutued by one or more of halo, methyl or methoxy;

R _Z2 and R _Z2a are selected from hydrogen, C _1-4 alkyl, cyano, halo, NH ₂ and C _1-4 alkoxy; R _Z3a is selected from hydrogen, C _1-4 alkyl, cyano, halo, NH ₂ and C _1-4 alkoxy

A ₁ is selected from CR ₁₂ and N;

A ₂ is selected from CR ₁₃ and N;

A ₃ is selected from CR ₁₄ and N;

A ₄ is selected from CR ₁₅ and N;

A ₅ is selected from CR ₁₆ and N;

A ₆ is selected from CR ₁₇ and N;

A ₇ is selected from CR ₁₈ and N;

A8 is selected from CR19R20 and NR21;

A9 is selected from CR22R23 and NR24;

A10 is selected from CR25R26 and NR27;

A11 is selected from CR28R29 and NR30;

R12 and R14 are independently selected from hydrogen, halo, cyano and C _1-4 alkyl; R13 is selected from hydrogen, halo, cyano, methoxy and methyl;

R15 is selected from hydrogen, halo, cyano methoxy and methyl;

R16 is selected from hydrogen, halo, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C1- 4haloalkoxy, C3-4cycloalkyl, a 3- to 4-membered heterocyclyl and C3-4cycloalkoxy; R17 is selected from hydrogen, hydroxy, halo, cyano, C1-5 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _2-4 alkenyl, C _2-4 alkynyl, phenyl, a 5- or 6-membered or heteroaryl, C _3-6 cycloalkyl, -O-C _3-6 cycloalkyl, heterocyclyl, -O-heterocyclyl (carbon- linked), -(OCH2CH2)m-NRqRr, -(OCH2CH2)m-OCH3 wherein m is an integer from 1 to 6, NRqRr, -C(O)-NRqRr, -C(O)ORq; wherein R _q and R _r are each independently hydrogen, C _1-5 alkyl, C _3-6 cycloalkyl, a 3- to 6- membered carbon-linked heterocyclyl, wherein C _1-5 alkyl, C _3-6 cycloalkyl, a 3- to 6- membered carbon-linked heterocyclyl may be optionally substituted by one or more substituents selected from C _1-2 alkyl, cyano, C _1-2 haloalkyl, hydroxy, C _1-2 alkoxy, halo, C _1-2 haloalkoxy, NR _1ea R _1fa or -S(O) _0-2 R _1ea R _1fa , wherein R _1ea and R _1fa are H or C _1-2 alkyl; or R _q and R _r are linked together such that, together with the nitrogen atom to which they are attached, they form a 3- to 6-membered heterocyclic ring, which may be optionally substituted by one or more substituents selected from C _1-2 alkyl, cyano, C _{1- 2} haloalkyl, hydroxy, C _1-2 alkoxy, halo, C _1-2 haloalkoxy;

wherein any C _1-5 alkyl, C _1-4 alkoxy, C _2-4 alkenyl, C _2-4 alkynyl, phenyl, 5- or 6-membered or heteroaryl, C _3-6 cycloalkyl, -O-C _3-6 cycloalkyl, heterocyclyl or -O-heterocyclyl (carbon-linked)is optionally further substituted by one or more substituents selected from C _1-2 alkyl, cyano, C _1-2 haloalkyl, hydroxy, C _1-2 alkoxy, halo, C _1-2 haloalkoxy, NR _1ea R _1fa or -S(O) _0-2 R _1ea R _1fa , wherein R _1ea and R _1fa are H or C _1-2 alkyl;

R ₁₈ is selected from hydrogen, halo, cyano, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, a 5- or 6-membered heteroaryl, C _1-4 alkoxy, C _1-4 haloalkyl, C _1-4 haloalkoxy, C3-4cycloalkyl, a 3- to 4-membered heterocyclyl and C3-4cycloalkoxy;

R19, R20, R25 and R26 are selected from hydrogen, halo, cyano and C _1-4 alkyl;

R22 and R23 are selected from hydrogen, halo, cyano and methyl;

R28 and R29 are selected from hydrogen, methoxy and methyl;

R21, R24, R27 and R30 are hydrogen; and

n is 0, 1 or 2;

with the proviso that the compound is not:

2-((1H-benzo[d]imidazol-2-yl)methyl)-5-(pyridin-3-yl)-1,3,4- oxadiazole;

2-((6-chloro-1-phenyl-1H-benzo[d]imidazol-2-yl)methyl)-5-(py ridin-3-yl)-1,3,4- oxadiazole;

N-({6-methylimidazo[1,2-a]pyridin- 2- yl}methyl)-1H-indazole-5-carboxamide.

[0089] In one aspect, the present invention relates to compounds of the formula (I), or a pharmaceutically acceptable salt thereof,

X– Y– Z (I)

wherein:

X is selected from:

wherein:

R1a, R1b, R1c, R1d, R1e and R1f are independently selected from hydrogen, cyano, halo or a group of the formula:

-L _1a -L _1b -Q ₁

wherein

L1a is absent or C1-3alkylene, C3-4cycloalkylene, optionally substituted by one or more substituents selected from aryl, aryl-(1-2C)alkyl, heteroaryl, aryl-(1-2C)alkyl, C _1-2 alkyl, cyano, halo, hydroxy, or oxo; wherein any aryl, aryl-(1-2C)alkyl, heteroaryl, aryl-(1- 2C)alkyl or C _1-2 alkyl is optionally further substituted by one or more substituents selected from halo, cyano or hydroxy;

L1b is absent or selected from O, S, SO, SO ₂ , N(Rr), C(O), C(O)O, OC(O), C(O)N(Rr), N(Rr)C(O), N(Rr)C(O)N(Rs), S(O)2N(Rr), or N(Rr)SO ₂ , wherein Rr and Rs are each independently selected from hydrogen or C _1-2 alkyl, wherein C _1-2 alkyl is optionally further substituted by C _3-6 cycloalkyl or a 3 to 6 membered heterocyclyl, which in turn are optionally further substituted by halo, hydroxy, C _1-2 alkoxy or C _1-2 haloalkoxy; and Q ₁ is hydrogen, cyano, C _1-6 alkyl, C _3-8 cycloalkyl (e.g. C _3-6 cycloalkyl), C _2-3 alkenyl, C _{2- 3} alkynyl, aryl, heterocyclyl or heteroaryl; and wherein Q ₁ is optionally substituted by one or more substituents selected from C _1-4 alkyl, halo, trifluoromethyl, trifluoromethoxy, amino, oxo, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, NR _t R _u , OR _t , C(O)R _t , C(O)OR _t , OC(O)R _t , C(O)N(R _t )R _u , N(R _t )C(O)R _u , S(O) _y R _t (where y is 0, 1 or 2), SO ₂ N(R _t )R _u , N(R _t )SO ₂ R _u or (CH ₂ ) _z NR _t R _u (where z is 1, 2 or 3), wherein R _t and R _u are each independently selected from hydrogen or C _1-4 alkyl; or

Q ₁ is optionally substituted by one or more groups of the formula:

-L _1c -L _1d -Z ₁

wherein

L1c is absent or C1-3alkylene optionally substituted by C _1-2 alkyl or oxo;

L _1d is absent or selected from C(O), O, C(O)O, OC(O), C(O)N(R _v ), N(R _v )C(O), N(R _v )C(O)N(R _w ), S(O) ₂ N(R _v ), or N(R _v )SO ₂ , wherein R _v and R _w are each

independently selected from hydrogen or C _1-2 alkyl; and

Z1 is C3-8cycloalkyl, heterocyclyl, phenyl or 5-6 membered heteroaryl; wherein Z1 is optionally substituted by one or more substituents selected from C _1-4 alkyl, C3- 6cycloalkyl, heterocyclyl, halo, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _1-4 alkoxy, cyano, hydroxyl, NR _t1 R _u1 , OR _t1 , C(O)R _t1 , C(O)OR _t1 , OC(O)R _t1 , C(O)N(R _t1 )R _u1 , N(R _t1 )C(O)R _u1 , S(O)yR _t1 (where y is 0, 1 or 2), SO ₂ N(R _t1 )R _u1 , N(R _t1 )SO ₂ R _u1 or (CH2)zNR _t1 R _u1 (where z is 1, 2 or 3), wherein R _t1 and R _u1 are each independently selected from hydrogen or C _1-4 alkyl; and when Z1 is C3-8cycloalkyl or heterocyclyl, Z1 is optionally spiro-fused to a C _3-6 cycloalkyl or heterocyclyl ring;

R1a’ is selected from hydrogen, halo and methyl;

R2a, R2b and R2c are selected from hydrogen, halo or a group of the formula:

-L2a-L2b-Q2

wherein

L2a is absent or C1-3alkylene optionally substituted by C _1-2 alkyl or oxo;

L2b is absent or selected from O, S, SO, SO ₂ , N(Rn), C(O), C(O)O, OC(O),

C(O)N(Rn), N(Rn)C(O), N(Rn)C(O)N(Ro), S(O)2N(Rn), or N(Rn)SO ₂ , wherein Rn and Ro are each independently selected from hydrogen or C _1-2 alkyl; and Q ₂ is hydrogen, cyano, C _1-6 alkyl, C _3-6 cycloalkyl, aryl, heterocyclyl or heteroaryl, each of which is optionally substituted by one or more substituents selected from halo, trifluoromethyl, trifluoromethoxy, amino, cyano, hydroxy, amino, carboxy, carbamoyl, sulphamoyl, C _1-4 alkyl, NR _p R _q , OR _p , C(O)R _p , C(O)OR _p , OC(O)R _p , C(O)N(R _p )R _q , N(R _r )C(O)R _p , S(O) _y R _p (where y is 0, 1 or 2), SO ₂ N(R _p )R _q , N(R _r )SO ₂ R _p or (CH ₂ ) _z NR _p R _q (where z is 1, 2 or 3), wherein R _p and R _q are each independently selected from hydrogen or C _1-4 alkyl;

Y is selected from:

,

;

wherein:

R _3a1 , R _3b1 , R _3c1 , R _3d1 , R _3e1 , R _3f1 , R _3g1 , R _3h1 , R _3i1 , R _3j1 , R _3k1 , R _3l1 , R _3m1 , R _3n1 , R _3o1 , R _3p1 ,R _3q1 , R _3r1 and R _3s1 are independently selected from hydrogen (including deuterium), C _1-6 alkyl, C _3-4 cycloalkyl, hydroxy, and halo; and wherein C ₁ - ₆ alkyl, or C _3-4 cycloalkyl is optionally substituted with one or more substituents selected from halo, amino, cyano, and hydroxy;

R _3a2 , R _3b2 , R _3c2 , R _3d2 , R _3e2 , R _3f2 , R _3g2 , R _3h2 , R _3i2 , R _3j2 , R _3k2 , R _3l2 , R _3m2 , R _3n2, R _3o2, R _3p2 ,R _3q2 , R _3r2 and R _3s2 are hydrogen or halo;

with the proviso that R _3a1 , R _3b1 , R _3i1 , R _3l1 , R _3o1 , R _3r1 , R _3a2 , R _3b2 , R _3i2 , R _3l2 , R _3o2 and R _3s2 cannot be halo when n=1 or when n=2 and the carbon atom to which they are attached is linked to an oxygen or nitrogen atom;

or R3a1 and R3a2, R3b1 and R3b2, R3c1 and R3c2, R3d1 and R3d2, R3e1 and R3e2, R3f1 and R3f2, R3g1 and R3g2, R3h1 and R3h2, R3i1 and R3i2, R3j1 and R3j2, R3k1 and R3k2, R3l1 and R3l2, R3m1 and R3m2, R3n1 and R3n2, R3o1 and R3o2, R3p1 and R3p2, R3q1 and R3q2, R3r1 and R3r2 or R3s1 and R3s2 may be linked such that, together with the carbon atom to which they are attached, they form a spiro-fused C3-4cycloalkyl which is optionally substituted with one or more substituents selected from halo, methyl, amino, cyano, and hydroxy; Z is selected from:

,

wherein:

R4, R7, R4a and R7a are independently selected from hydrogen, halo, cyano and methyl; R5, R5a, R5b and R5c are independently selected from hydrogen, halo, cyano and methyl; R6, R8, R6a and R8a are independently selected from hydrogen, halo, cyano and methyl; R9, R9a, R10 and R11 are independently selected from hydrogen, NH2, halo, cyano, and C _1-6 alkyl; or

R9 and R10 may be linked together to form a fused 5- or 6-membered saturated or unsaturated ring system or R10 and R11 may be linked together to form a fused 5- or 6- membered saturated or unsaturated ring system; wherein either of the fused 5- or 6- membered saturated or unsaturated ring system may be optionally subsitutued by one or more substituents selected from C _1-2 alkyl, cyano, C _1-2 haloalkyl, hydroxy, C _1-2 alkoxy, halo, C _1-2 haloalkoxy, NR _1ia R _1ja or -S(O) _0-2 R _1ia R _1ja , wherein R _1ia and R _1ja are H or C _1-2 alky; R _Z1 and R _Z1a are selected from hydrogen, C _1-4 alkyl, cyano, halo, C _1-4 haloalkyl, C _{1- 4} haloalkoxy, C _1-4 alkoxy, C _3-6 cycloalkyl and -O-C _3-6 cycloalkyl, wherein C _3-6 cycloalkyl and - O-C _3-6 cycloalkyl are optionally subsitutued by one or more of halo, methyl or methoxy; R _Z2 and R _Z2a are selected from hydrogen, C _1-4 alkyl, cyano, halo, NH ₂ and C _1-4 alkoxy; R _Z3a is selected from hydrogen, C _1-4 alkyl, cyano, halo, NH ₂ and C _1-4 alkoxy

A ₁ is selected from CR ₁₂ and N;

A ₂ is selected from CR ₁₃ and N;

A ₃ is selected from CR ₁₄ and N;

A ₄ is selected from CR ₁₅ and N;

A ₅ is selected from CR ₁₆ and N;

A ₆ is selected from CR ₁₇ and N;

A ₇ is selected from CR ₁₈ and N;

A ₈ is selected from CR ₁₉ R ₂₀ and NR ₂₁ ;

A ₉ is selected from CR ₂₂ R ₂₃ and NR ₂₄ ;

A ₁₀ is selected from CR ₂₅ R ₂₆ and NR ₂₇ ;

A11 is selected from CR28R29 and NR30;

R12 and R14 are independently selected from hydrogen, halo, cyano and C _1-4 alkyl;

R13 is selected from hydrogen, halo, cyano, methoxy and methyl;

R15 is selected from hydrogen, halo, cyano methoxy and methyl;

R16 is selected from hydrogen, halo, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C1- 4haloalkoxy, C3-4cycloalkyl, a 3- to 4-membered heterocyclyl and C3-4cycloalkoxy;

R17 is selected from hydrogen, hydroxy, halo, cyano, C1-5 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _2-4 alkenyl, C _2-4 alkynyl, phenyl, a 5- or 6-membered or heteroaryl, C _3-6 cycloalkyl, -O- C _3-6 cycloalkyl, heterocyclyl, -O-heterocyclyl (carbon- linked), -(OCH2CH2)m-NRqRr, -(OCH2CH2)m-OCH3 wherein m is an integer from 1 to 6, NRqRr, -C(O)-NRqRr, -C(O)ORq;

wherein Rq and Rr are each independently hydrogen, C1-5 alkyl, C _3-6 cycloalkyl, a 3- to 6- membered carbon-linked heterocyclyl, wherein C1-5 alkyl, C _3-6 cycloalkyl, a 3- to 6- membered carbon-linked heterocyclyl may be optionally substituted by one or more substituents selected from C _1-2 alkyl, cyano, C _1-2 haloalkyl, hydroxy, C _1-2 alkoxy, halo, C _1-2 haloalkoxy, NR1eaR1fa or -S(O) _0-2 R1eaR1fa, wherein R1ea and R1fa are H or C _1-2 alkyl; or R _q and R _r are linked together such that, together with the nitrogen atom to which they are attached, they form a 3- to 6-membered heterocyclic ring, which may be optionally substituted by one or more substituents selected from C _1-2 alkyl, cyano, C _{1- 2} haloalkyl, hydroxy, C _1-2 alkoxy, halo, C _1-2 haloalkoxy;

wherein any C _1-5 alkyl, C _1-4 alkoxy, C _2-4 alkenyl, C _2-4 alkynyl, phenyl, 5- or 6-membered or heteroaryl, C _3-6 cycloalkyl, -O-C _3-6 cycloalkyl, heterocyclyl or -O-heterocyclyl (carbon- linked)is optionally further substituted by one or more substituents selected from C _1-2- alkyl, cyano, C _1-2 haloalkyl, hydroxy, C _1-2 alkoxy, halo, C _1-2 haloalkoxy, NR _1ea R _1fa or -S(O) _{0- 2} R _1ea R _1fa , wherein R _1ea and R _1fa are H or C _1-2 alkyl;

R ₁₈ is selected from hydrogen, halo, cyano, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, a 5- or 6- membered heteroaryl, C _1-4 alkoxy, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _3-4 cycloalkyl, a 3- to 4- membered heterocyclyl and C _3-4 cycloalkoxy;

R ₁₉ , R ₂₀ , R ₂₅ and R ₂₆ are selected from hydrogen, halo, cyano and C _1-4 alkyl;

R ₂₂ and R ₂₃ are selected from hydrogen, halo, cyano and methyl;

R ₂₈ and R ₂₉ are selected from hydrogen, methoxy and methyl;

R21, R24, R27 and R30 are hydrogen; and

n is 0, 1 or 2.

[0090] In one aspect, the present invention relates to compounds of the formula (I), or a pharmaceutically acceptable salt thereof,

X– Y– Z

(I)

wherein:

X is selected from:

,

R1a, R1b, R1c, R1d, R1e and R1f are independently selected from hydrogen, cyano, halo or a group of the formula:

-L _1a -L _1b -Q ₁

wherein

L1a is absent or C1-3alkylene, C3-4cycloalkylene, optionally substituted by one or more substituents selected from C _1-2 alkyl, halo, hydroxy, or oxo;

L _1b is absent or selected from O, S, SO, SO ₂ , N(R _r ), C(O), C(O)O, OC(O), C(O)N(R _r ), N(R _r )C(O), N(R _r )C(O)N(R _s ), S(O) ₂ N(R _r ), or N(R _r )SO ₂ , wherein R _r and R _s are each independently selected from hydrogen or C _1-2 alkyl; and

Q ₁ is hydrogen, cyano, C _1-6 alkyl, C _3-6 cycloalkyl, C _2-3 alkenyl, C _2-3 alkynyl, aryl, heterocyclyl or heteroaryl; and wherein Q ₁ is optionally substituted by one or more substituents selected from C _1-4 alkyl, halo, trifluoromethyl, trifluoromethoxy, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, NR _t R _u , OR _t , C(O)R _t , C(O)OR _t , OC(O)R _t , C(O)N(R _t )R _u , N(R _t )C(O)R _u , S(O) _y R _t (where y is 0, 1 or 2), SO ₂ N(R _t )R _u , N(R _t )SO ₂ R _u or (CH ₂ ) _z NR _t R _u (where z is 1, 2 or 3), wherein R _t and R _u are each independently selected from hydrogen or C _1-4 alkyl; or

Q ₁ is optionally substituted by one or more groups of the formula:

-L _1c -L _1d -Z ₁

wherein

L _1c is absent or C _1-3 alkylene optionally substituted by C _1-2 alkyl or oxo; L _1d is absent or selected from C(O), O, C(O)O, OC(O), C(O)N(R _v ), N(R _v )C(O), N(R _v )C(O)N(R _w ), S(O) ₂ N(R _v ), or N(R _v )SO ₂ , wherein R _v and R _w are each

independently selected from hydrogen or C _1-2 alkyl; and

Z ₁ is C _3-8 cycloalkyl, heterocyclyl, phenyl or 5-6 membered heteroaryl; wherein Z ₁ is optionally substituted by one or more substituents selected from C _1-4 alkyl, C _{3- 6} cycloalkyl, heterocyclyl, halo, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _1-4 alkoxy, cyano, hydroxyl, NR _t1 R _u1 , OR _t1 , C(O)R _t1 , C(O)OR _t1 , OC(O)R _t1 , C(O)N(R _t1 )R _u1 , N(R _t1 )C(O)R _u1 , S(O) _y R _t1 (where y is 0, 1 or 2), SO ₂ N(R _t1 )R _u1 , N(R _t1 )SO ₂ R _u1 or (CH ₂ ) _z NR _t1 R _u1 (where z is 1, 2 or 3), wherein R _t1 and R _u1 are each independently selected from hydrogen or C _1-4 alkyl; and when Z ₁ is C _3-8 cycloalkyl or heterocyclyl, Z ₁ is optionally spiro-fused to a C _3-6 cycloalkyl or heterocyclyl ring;

R1a’ is selected from hydrogen and methyl;

R _2a , R _2b and R _2c are selected from hydrogen or a group of the formula:

-L _2a -L _2b -Q ₂

wherein

L2a is absent or C1-3alkylene optionally substituted by C _1-2 alkyl or oxo;

L2b is selected from O, S, SO, SO ₂ , N(Rn), C(O), C(O)O, OC(O), C(O)N(Rn),

N(Rn)C(O), N(Rn)C(O)N(Ro), S(O)2N(Rn), or N(Rn)SO ₂ , wherein Rn and Ro are each independently selected from hydrogen or C _1-2 alkyl; and

Q2 is hydrogen, cyano, C _1-6 alkyl, C _3-6 cycloalkyl, aryl, heterocyclyl or heteroaryl, each of which is optionally substituted by one or more substituents selected from halo, trifluoromethyl, trifluoromethoxy, amino, cyano, hydroxy, amino, carboxy, carbamoyl, sulphamoyl, C _1-4 alkyl, NRpRq, ORp, C(O)Rp, C(O)ORp, OC(O)Rp, C(O)N(Rp)Rq, N(Rr)C(O)Rp, S(O)yRp (where y is 0, 1 or 2), SO ₂ N(Rp)Rq, N(Rr)SO ₂ Rp or (CH ₂ )zNRpRq (where z is 1, 2 or 3), wherein Rp and Rq are each independently selected from hydrogen or C _1-4 alkyl;

Y is selected from:

wherein:

R _3a1 , R _3b1 , R _3c1 , R _3d1 , R _3e1 , R _3f1 , R _3g1 , R _3h1 , R _3i1 , R _3j1 , R _3k1 , R _3l1 , R _3m1 , R _3n1 and R _3o1 are independently selected from hydrogen, C _1-6 alkyl, C _3-4 cycloalkyl, hydroxy, and halo; and wherein C ₁ - ₆ alkyl, or C _3-4 cycloalkyl is optionally substituted with one or more substituents selected from halo, amino, cyano, and hydroxy;

R _3a2 , R _3b2 , R _3c2 , R _3d2 , R _3e2 , R _3f2 , R _3g2 , R _3h2 , R _3i2 , R _3j2 , R _3k2 , R _3l2 , R _3m2 , R _3n2 and R _3o2 are hydrogen;

or R _3a1 and R _3a2 , R _3b1 and R _3b2 , R _3c1 and R _3c2 , R _3d1 and R _3d2 , R _3e1 and R _3e2 , R _3f1 and R _3f2 , R _3g1 and R _3g2 , R _3h1 and R _3h2 , R _3i1 and R _3i2 , R _3j1 and R _3j2 , R _3k1 and R _3k2 , R _3l1 and R _3l2 , R _3m1 and R _3m2 , R _3n1 and R _3n2 , or R _3o1 and R _3o2 may be linked to form a spiro-fused C _{3- 4} cycloalkyl which is optionally substituted with one or more substituents selected from halo, amino, cyano, and hydroxy;

Z is selected from:

,

wherein:

R4, R7 R4a and R7a are independently selected from hydrogen and methyl;

R5, R5a and R5b are independently selected from hydrogen and halo;

R6, R8, R6a and R8a are independently selected from hydrogen, halo and methyl; R ₉ , R ₁₀ and R ₁₁ are independently selected from hydrogen, NH ₂ , halo, cyano, and C _1-6 alkyl; or

R ₉ and R ₁₀ may be linked together to form a fused 5- or 6-membered saturated or unsaturated ring system or R ₁₀ and R ₁₁ may be linked together to form a fused 5- or 6- membered saturated or unsaturated ring system;

A ₁ is selected from CR ₁₂ and N;

A ₂ is selected from CR ₁₃ and N;

A ₃ is selected from CR ₁₄ and N;

A ₄ is selected from CR ₁₅ and N;

A ₅ is selected from CR ₁₆ and N;

A ₆ is selected from CR ₁₇ and N;

A ₇ is selected from CR ₁₈ and N;

A ₈ is selected from CR ₁₉ R ₂₀ and NR ₂₁ ;

A ₉ is selected from CR ₂₂ R ₂₃ and NR ₂₄ ;

A ₁₀ is selected from CR ₂₅ R ₂₆ and NR ₂₇ ;

A11 is selected from CR28R29 and NR30;

R12 and R14 are independently selected from hydrogen, halo, cyano and C _1-4 alkyl; R13 is selected from hydrogen, halo, cyano and methyl;

R15 is selected from hydrogen, methoxy and methyl;

R16 is selected from hydrogen, halo, cyano and C _1-4 alkyl;

R17 is selected from hydrogen, halo, cyano, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl and a 5- or 6-membered heteroaryl;

R18 is selected from hydrogen, halo, cyano, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl and a 5- or 6-membered heteroaryl;

R19, R20, R25 and R26 are selected from hydrogen, halo, cyano and C _1-4 alkyl;

R22 and R23 are selected from hydrogen, halo, cyano and methyl;

R28 and R29 are selected from hydrogen, methoxy and methyl;

R21, R24, R27 and R30 are hydrogen; and

n is 0, 1 or 2. [0091] In one aspect, the present invention relates to compounds of formula (I) shown below, or a pharmaceutically acceptable salt thereof:

X– Y– Z

(I)

wherein:

X is selected from:

wherein:

R _1a , R _1b , R _1c , R _1d , R _1e and R _1f are independently selected from hydrogen, cyano, halo or a group of the formula:

-L _1a -L _1b -Q ₁

wherein

L _1a is absent or C _1-3 alkylene, C _3-4 cycloalkylene, optionally substituted by one or more substituents selected from C _1-2 alkyl, halo, hydroxy, or oxo;

L _1b is absent or selected from O, S, SO, SO ₂ , N(R _r ), C(O), C(O)O, OC(O), C(O)N(R _r ), N(R _r )C(O), N(R _r )C(O)N(R _s ), S(O) ₂ N(R _r ), or N(R _r )SO ₂ , wherein R _r and R _s are each independently selected from hydrogen or C _1-2 alkyl; and

Q ₁ is hydrogen, cyano, C _1-6 alkyl, C _3-8 cycloalkyl (e.g. C _3-6 cycloalkyl),C _2-3 alkenyl, C _2-3 alkynyl, aryl, heterocyclyl or heteroaryl; and wherein Q ₁ is optionally substituted by one or more substituents selected from C _1-4 alkyl, halo, trifluoromethyl, trifluoromethoxy, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, NR _t R _u , OR _t , C(O)R _t , C(O)OR _t , OC(O)R _t , C(O)N(R _t )R _u , N(R _t )C(O)R _u , S(O) _y R _t (where y is 0, 1 or 2), SO ₂ N(R _t )R _u , N(R _t )SO ₂ R _u or (CH ₂ ) _z NR _t R _u (where z is 1, 2 or 3), wherein R _t and R _u are each independently selected from hydrogen or C _1-4 alkyl; or

Q ₁ is optionally substituted by one or more groups of the formula:

-L _1c -L _1d -Z ₁

wherein

L _1c is absent or C _1-3 alkylene optionally substituted by C _1-2 alkyl or oxo;

L _1d is absent or selected from C(O), C(O)O, OC(O), C(O)N(R _v ), N(R _v )C(O), N(R _v )C(O)N(R _w ), S(O) ₂ N(R _v ), or N(R _v )SO ₂ , wherein R _v and R _w are each independently selected from hydrogen or C _1-2 alkyl; and

Z ₁ is phenyl or 5-6 membered heteroaryl; wherein Z ₁ is optionally substituted by one or more substituents selected from C _1-4 alkyl, halo, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _1-4 alkoxy, C _{1- 4} alkylamino, amino, cyano, hydroxyl, carboxy, carbamoyl or sulphamoyl;

R _1a’ is selected from hydrogen and methyl;

R _2a , R _2b and R _2c are selected from hydrogen or a group of the formula:

-L _2a -L _2b -Q ₂

wherein

L2a is absent or C1-3alkylene optionally substituted by C _1-2 alkyl or oxo;

L2b is selected from O, S, SO, SO ₂ , N(Rn), C(O), C(O)O, OC(O), C(O)N(Rn), N(Rn)C(O), N(Rn)C(O)N(Ro), S(O)2N(Rn), or N(Rn)SO ₂ , wherein Rn and Ro are each independently selected from hydrogen or C _1-2 alkyl; and

Q2 is hydrogen, cyano, C _1-6 alkyl, C _3-6 cycloalkyl, aryl, heterocyclyl or heteroaryl, each of which is optionally substituted by one or more substituents selected from halo,

trifluoromethyl, trifluoromethoxy, amino, cyano, hydroxy, amino, carboxy, carbamoyl, sulphamoyl, C _1-4 alkyl, NRpRq, ORp, C(O)Rp, C(O)ORp, OC(O)Rp, C(O)N(Rp)Rq, N(Rr)C(O)Rp, S(O)yRp (where y is 0, 1 or 2), SO ₂ N(Rp)Rq, N(Rr)SO ₂ Rp or (CH2)zNRpRq (where z is 1, 2 or 3), wherein Rp and Rq are each independently selected from hydrogen or C _1-4 alkyl;

Y is selected from:

wherein:

R3a1, R3b1, R3c1, R3d1, R3e1, R3f1, R3g1, R3h1, R3i1, R3j1, R3k1, R3l1, R3m1, R3n1 and R3o1 are independently selected from hydrogen, C _1-6 alkyl, C3-4 cycloalkyl, hydroxy, and halo; and wherein C _1-6 alkyl, or C3-4 cycloalkyl is optionally substituted with one or more substituents selected from halo, amino, cyano, and hydroxy; R _3a2 , R _3b2 , R _3c2 , R _3d2 , R _3e2 , R _3f2 , R _3g2 , R _3h2 , R _3i2 , R _3j2 , R _3k2 , R _3l2 , R _3m2 , R _3n2 and R _3o2 are hydrogen;

or R _3a1 and R _3a2 , R _3b1 and R _3b2 , R _3c1 and R _3c2 , R _3d1 and R _3d2 , R _3e1 and R _3e2 , R _3f1 and R _3f2 , R _3g1 and R _3g2 , R _3h1 and R _3h2 , R _3i1 and R _3i2 , R _3j1 and R _3j2 , R _3k1 and R _3k2 , R _3l1 and R _3l2 , R _3m1 and R _3m2 , R _3n1 and R _3n2 , and R _3o1 and R _3o2 may be linked to form a spiro-fused C _3-4 cycloalkyl which is optionally substituted with one or more substituents selected from halo, amino, cyano, and hydroxy;

Z is selected from:

,

wherein:

R ₄ , R ₇ , R _4a and R _7a are independently selected from hydrogen and methyl;

R ₅ , R _5a and R _5b are independently selected from hydrogen and halo;

R ₆ , R _8, R _6a and R _8a are independently selected from hydrogen, halo and methyl;

R ₉ , R ₁₀ and R ₁₁ are independently selected from hydrogen, NH ₂ , halo, cyano, and C _1-6 alkyl; or R ₉ and R ₁₀ may be linked together to form a fused 5- or 6-membered saturated or unsaturated ring system or R ₁₀ and R ₁₁ may be linked together to form a fused 5- or 6- membered saturated or unsaturated ring system;

A ₁ is selected from CR ₁₂ and N;

A ₂ is selected from CR ₁₃ and N;

A ₃ is selected from CR ₁₄ and N;

A ₄ is selected from CR ₁₅ and N;

A ₅ is selected from CR ₁₆ and N;

A ₆ is selected from CR ₁₇ and N;

A ₇ is selected from CR ₁₈ and N;

A ₈ is selected from CR ₁₉ R ₂₀ and NR ₂₁ ;

A ₉ is selected from CR ₂₂ R ₂₃ and NR ₂₄ ;

A ₁₀ is selected from CR ₂₅ R ₂₆ and NR ₂₇ ;

A ₁₁ is selected from CR ₂₈ R ₂₉ and NR ₃₀ ;

R ₁₂ and R ₁₄ are independently selected from hydrogen, halo, cyano and C _1-4 alkyl;

R13 is selected from hydrogen, halo, cyano and methyl;

R15 is selected from hydrogen, methoxy and methyl;

R16 is selected from hydrogen, halo, cyano and C _1-4 alkyl;

R17 is selected from hydrogen, halo, cyano, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl and a 5- or 6- membered heteroaryl;

R18 is selected from hydrogen, halo, cyano, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl and a 5- or 6- membered heteroaryl;

R19, R20, R25 and R26 are selected from hydrogen, halo, cyano and C _1-4 alkyl;

R22 and R23 are selected from hydrogen, halo, cyano and methyl;

R28 and R29 are selected from hydrogen, methoxy and methyl;

R21, R24, R27 and R30 are hydrogen; and

n is 0, 1 or 2.

[0092] Particular compounds of the invention include, for example, compounds of formula (I), or pharmaceutically acceptable salts thereof, wherein, unless otherwise stated, each of X, Y, Z, R _1a , R _1b , R _1c , R _1d , R _1e , R _1f , R _1a’, R _2a , R _2b , R _2c , R _3a1 , R _3a2 , R _3b1 , R _3b2 , R _3c1 , R _3c2 , R _3d1 , R _3d2 , R _3e1 , R _3e2, R _3f1 , R _3f2 , R _3g1 , R _3g2 , R _3h1 , R _3h2 , R _3i1 , R _3i2, R _3j1 , R _3j2 , R _3k1 , R _3k2 , R _3l1 , R _3l2 , R _3m1 ¸R _3m2 , R _3n1 , R _3n2 , R _3o1 , R _3o2 , n, R ₄ , R _4a , R ₅ , R _5a , R _5b , R _5c , R ₆ , R _6a , R ₇ , R _7a , R ₈ , R _8a , R ₉ , R ₁₀ , R ₁₁ , R ₁₂ , R ₁₃ , R ₁₄ , R ₁₅ , R ₁₆ , R ₁₇ , R ₁₈ , R ₁₉ , R ₂₀ , R ₂₁ , R ₂₂ , R ₂₃ , R ₂₄ , R ₂₅ , R ₂₆ , R ₂₇ , R ₂₈ , R ₂₉ , R ₃₀ , A ₁ , A ₂ , A ₃ , A ₄ , A ₅ ,A ₆ , A ₇ , A ₈ , A ₉ , A ₁₀ and A ₁₁ and any associated substituent groups has any of the meanings defined hereinbefore or in any one of paragraphs (1) to (111b) hereinafter:- (1) One of R _1a and R _1b , R _1c and R _1d , R _1e and R _1f is selected from hydrogen, halo, C _1-6- alkyl, C _2-3 alkenyl or -O-C _1-6 alkyl,

and the other is selected from hydrogen, cyano, halo or a group of the formula:

-L _1a -L _1b -Q ₁

wherein

L _1a is absent or C _1-3 alkylene, C _3-4 cycloalkylene, optionally substituted by one or more substituents selected from C _1-2 alkyl, halo, hydroxy, or oxo;

L _1b is absent or selected from O, S, SO, SO ₂ , N(R _r ), C(O), C(O)O, OC(O), C(O)N(R _r ), N(R _r )C(O), N(R _r )C(O)N(R _s ), S(O) ₂ N(R _r ), or N(R _r )SO ₂ , wherein R _r and R _s are each independently selected from hydrogen or C _1-2 alkyl; and

Q1 is hydrogen, cyano, C _1-6 alkyl, C _3-6 cycloalkyl, C2-3alkenyl, C2-3alkynyl, aryl, heterocyclyl or heteroaryl; and wherein Q1 is optionally substituted by one or more substituents selected from C _1-4 alkyl, halo, trifluoromethyl, trifluoromethoxy, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, NRtRu, ORt, C(O)Rt, C(O)ORt, OC(O)Rt, C(O)N(Rt)Ru, N(Rt)C(O)Ru, S(O)yRt (where y is 0, 1 or 2), SO ₂ N(Rt)Ru, N(Rt)SO ₂ Ru or (CH2)zNRtRu (where z is 1, 2 or 3), wherein Rt and Ru are each independently selected from hydrogen or C _1-4 alkyl; or

Q1 is optionally substituted by one or more groups of the formula:

-L _1c -L _1d -Z ₁

wherein

L1c is absent or C1-3alkylene optionally substituted by C _1-2 alkyl or oxo;

L1d is absent or selected from C(O), C(O)O, OC(O), C(O)N(Rv), N(Rv)C(O),

N(Rv)C(O)N(Rw), S(O)2N(Rv), or N(Rv)SO ₂ , wherein Rv and Rw are each

independently selected from hydrogen or C _1-2 alkyl; and

Z1 is phenyl or 5-6 membered heteroaryl; wherein Z1 is optionally substituted by one or more substituents selected from C _1-4 alkyl, halo, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _1-4 alkoxy, C _1-4 alkylamino, amino, cyano, hydroxyl, carboxy, carbamoyl or

sulphamoyl;

(1a) One of R _1a and R _1b , R _1c and R _1d , R _1e and R _1f is selected from hydrogen, halo, C _1-6- alkyl, C _2-3 alkenyl or -O-C _1-6 alkyl,

and the other is selected from hydrogen, cyano, halo or a group of the formula:

-L _1a -L _1b -Q ₁

wherein

L _1a is absent or C _1-3 alkylene, C _3-4 cycloalkylene, optionally substituted by one or more substituents selected from C _1-2 alkyl, halo, hydroxy, or oxo;

L _1b is absent or selected from O, S, SO, SO ₂ , N(R _r ), C(O), C(O)O, OC(O), C(O)N(R _r ), N(R _r )C(O), N(R _r )C(O)N(R _s ), S(O) ₂ N(R _r ), or N(R _r )SO ₂ , wherein R _r and R _s are each independently selected from hydrogen or C _1-2 alkyl; and

Q ₁ is hydrogen, cyano, C _1-6 alkyl, C _3-8 cycloalkyl (e.g. C _3-6 cycloalkyl), C _2-3 alkenyl, C _{2- 3} alkynyl, aryl, heterocyclyl or heteroaryl; and wherein Q ₁ is optionally substituted by one or more substituents selected from C _1-4 alkyl, halo, trifluoromethyl, trifluoromethoxy, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, NRtRu, ORt, C(O)Rt, C(O)ORt, OC(O)Rt, C(O)N(Rt)Ru, N(Rt)C(O)Ru, S(O)yRt (where y is 0, 1 or 2), SO ₂ N(Rt)Ru, N(Rt)SO ₂ Ru or (CH2)zNRtRu (where z is 1, 2 or 3), wherein Rt and Ru are each independently selected from hydrogen or C _1-4 alkyl; or

Q1 is optionally substituted by one or more groups of the formula:

-L _1c -L _1d -Z ₁

wherein

L1c is absent or C1-3alkylene optionally substituted by C _1-2 alkyl or oxo;

L1d is absent or selected from C(O), O, C(O)O, OC(O), C(O)N(Rv), N(Rv)C(O), N(Rv)C(O)N(Rw), S(O)2N(Rv), or N(Rv)SO ₂ , wherein Rv and Rw are each

independently selected from hydrogen or C _1-2 alkyl; and

Z1 is C3-8cycloalkyl (including a spirocyclic carbocyclic and a bridged C3-8cycloalkyl), heterocyclyl (including a mono- or bicyclic-heterocyclic ring system, a spirocyclic heterocyclic ring system, or a bridged heterocyclic ring system), phenyl or 5-6 membered heteroaryl; wherein Z1 is optionally substituted by one or more

substituents selected from C _1-4 alkyl, C _3-6 cycloalkyl, heterocyclyl, halo, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _1-4 alkoxy, cyano, hydroxyl, NR _t1 R _u1 , OR _t1 , C(O)R _t1 , C(O)OR _t1 , OC(O)R _t1 , C(O)N(R _t1 )R _u1 , N(R _t1 )C(O)R _u1 , S(O)yR _t1 (where y is 0, 1 or 2), SO ₂ N(R _t1 )R _u1 , N(R _t1 )SO ₂ R _u1 or (CH ₂ ) _z NR _t1 R _u1 (where z is 1, 2 or 3), wherein R _t1 and R _u1 are each independently selected from hydrogen or C _1-4 alkyl; and when Z ₁ is C _{3- 8} cycloalkyl or heterocyclyl, Z ₁ is optionally spiro-fused to a C _3-6 cycloalkyl or heterocyclyl ring;

(1b) One of R _1a and R _1b , R _1c and R _1d , R _1e and R _1f is selected from hydrogen, halo, C _1-6- alkyl, C _2-3 alkenyl or -O-C _1-6 alkyl,

and the other is selected from hydrogen, cyano, halo or a group of the formula:

-L _1a -L _1b -Q ₁

wherein

L _1a is absent or C _1-3 alkylene, C _3-4 cycloalkylene, optionally substituted by one or more substituents selected from aryl, aryl-(1-2C)alkyl, heteroaryl, aryl-(1-2C)alkyl, C _1-2 alkyl, cyano, halo, hydroxy, or oxo, wherein any aryl, aryl-(1-2C)alkyl, heteroaryl, aryl-(1- 2C)alkyl or C _1-2 alkyl is optionally further substituted by one or more substituents selected from halo, cyano or hydroxy;

L _1b is absent or selected from O, S, SO, SO ₂ , N(R _r ), C(O), C(O)O, OC(O), C(O)N(R _r ), N(Rr)C(O), N(Rr)C(O)N(Rs), S(O)2N(Rr), or N(Rr)SO ₂ , wherein Rr and Rs are each independently selected from hydrogen or C _1-2 alkyl, wherein C _1-2 alkyl is optionally further substituted by C _3-6 cycloalkyl or a 3 to 6 membered heterocyclyl, which in turn are optionally further substituted by halo, hydroxy, C _1-2 alkoxy or C _1-2 haloalkoxy; and Q1 is hydrogen, cyano, C _1-6 alkyl, C _3-8 cycloalkyl (e.g. C _3-6 cycloalkyl), C2-3alkenyl, C2- 3alkynyl, aryl, heterocyclyl or heteroaryl; and wherein Q1 is optionally substituted by one or more substituents selected from C _1-4 alkyl, halo, trifluoromethyl, trifluoromethoxy, amino, oxo cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, NRtRu, ORt, C(O)Rt, C(O)ORt, OC(O)Rt, C(O)N(Rt)Ru, N(Rt)C(O)Ru, S(O)yRt (where y is 0, 1 or 2), SO ₂ N(Rt)Ru, N(Rt)SO ₂ Ru or (CH2)zNRtRu (where z is 1, 2 or 3), wherein Rt and Ru are each independently selected from hydrogen or C _1-4 alkyl; or

Q1 is optionally substituted by one or more groups of the formula:

-L _1c -L _1d -Z ₁

wherein

L1c is absent or C1-3alkylene optionally substituted by C _1-2 alkyl or oxo;

L1d is absent or selected from C(O), O, C(O)O, OC(O), C(O)N(Rv), N(Rv)C(O), N(Rv)C(O)N(Rw), S(O)2N(Rv), or N(Rv)SO ₂ , wherein Rv and Rw are each

independently selected from hydrogen or C _1-2 alkyl; and Z ₁ is C _3-8 cycloalkyl (including a spirocyclic carbocyclic and a bridged C _3-8 cycloalkyl), heterocyclyl (including a mono- or bicyclic-heterocyclic ring system, a spirocyclic heterocyclic ring system, or a bridged heterocyclic ring system), phenyl or 5-6 membered heteroaryl; wherein Z ₁ is optionally substituted by one or more

substituents selected from C _1-4 alkyl, C _3-6 cycloalkyl, heterocyclyl, halo, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _1-4 alkoxy, cyano, hydroxyl, NR _t1 R _u1 , OR _t1 , C(O)R _t1 , C(O)OR _t1 , OC(O)R _t1 , C(O)N(R _t1 )R _u1 , N(R _t1 )C(O)R _u1 , S(O) _y R _t1 (where y is 0, 1 or 2),

SO ₂ N(R _t1 )R _u1 , N(R _t1 )SO ₂ R _u1 or (CH ₂ ) _z NR _t1 R _u1 (where z is 1, 2 or 3), wherein R _t1 and R _u1 are each independently selected from hydrogen or C _1-4 alkyl; and when Z ₁ is C _{3- 8} cycloalkyl or heterocyclyl, Z ₁ is optionally spiro-fused to a C _3-6 cycloalkyl or heterocyclyl ring;

(2) R _1a , R _1c and R _1e are selected from hydrogen, halo, C _1-6 alkyl, C _2-3 alkenyl or -O-C _{1- 6} alkyl

and R _1b , R _1d , and R _1f are selected from hydrogen, cyano, halo or a group of the formula:

-L _1a -L _1b -Q ₁

wherein

L1a is absent or C1-3alkylene, C3-4cycloalkylene, optionally substituted by one or more substituents selected from C _1-2 alkyl, halo, hydroxy, or oxo;

L1b is absent or selected from O, S, SO, SO ₂ , N(Rr), C(O), C(O)O, OC(O), C(O)N(Rr), N(Rr)C(O), N(Rr)C(O)N(Rs), S(O)2N(Rr), or N(Rr)SO ₂ , wherein Rr and Rs are each independently selected from hydrogen or C _1-2 alkyl; and

Q1 is hydrogen, cyano, C _1-6 alkyl, C _3-6 cycloalkyl, C2-3alkenyl, C2-3alkynyl, aryl, heterocyclyl or heteroaryl; and wherein Q1 is optionally substituted by one or more substituents selected from C _1-4 alkyl, halo, trifluoromethyl, trifluoromethoxy, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, NRtRu, ORt, C(O)Rt, C(O)ORt, OC(O)Rt, C(O)N(Rt)Ru, N(Rt)C(O)Ru, S(O)yRt (where y is 0, 1 or 2), SO ₂ N(Rt)Ru, N(Rt)SO ₂ Ru or (CH2)zNRtRu (where z is 1, 2 or 3), wherein Rt and Ru are each independently selected from hydrogen or C _1-4 alkyl; or

Q1 is optionally substituted by one or more groups of the formula:

-L _1c -L _1d -Z ₁

wherein

L1c is absent or C1-3alkylene optionally substituted by C _1-2 alkyl or oxo; L _1d is absent or selected from C(O), C(O)O, OC(O), C(O)N(R _v ), N(R _v )C(O),

N(R _v )C(O)N(R _w ), S(O) ₂ N(R _v ), or N(R _v )SO ₂ , wherein R _v and R _w are each

independently selected from hydrogen or C _1-2 alkyl; and

Z ₁ is phenyl or 5-6 membered heteroaryl; wherein Z ₁ is optionally substituted by one or more substituents selected from C _1-4 alkyl, halo, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _1-4 alkoxy, C _1-4 alkylamino, amino, cyano, hydroxyl, carboxy, carbamoyl or

sulphamoyl;

(3) R _1a , R _1c and R _1e are selected from hydrogen, halo, C _1-4 alkyl, C _2-3 alkenyl and -O-C _{1- 4} alkyl;

(4) R _1a , R _1c and R _1e are selected from hydrogen, fluoro, bromo, chloro, methyl, ethyl, propyl, butyl, ethenyl, -O-methyl, -O-ethyl, -O-propyl and -O-butyl;

(5) R _1a , R _1c and R _1e are selected from hydrogen, fluoro, bromo, chloro, methyl, ethyl, -O- methyl, ethenyl and -O-ethyl;

(6) R _1a , R _1c and R _1e are selected from hydrogen, fluoro, bromo, methyl, ethenyl and -O- methyl;

(6a) R1b, R1d and R1f are selected from hydrogen, cyano, halo or a group of the formula:

-L _1a -L _1b -Q ₁

wherein

L1a is absent or C1-3alkylene, C3-4cycloalkylene, optionally substituted by one or more substituents selected from C _1-2 alkyl, halo, hydroxy, or oxo;

L1b is absent or selected from O, S, SO, SO ₂ , N(Rr), C(O), C(O)O, OC(O), C(O)N(Rr), N(Rr)C(O), N(Rr)C(O)N(Rs), S(O)2N(Rr), or N(Rr)SO ₂ , wherein Rr and Rs are each independently selected from hydrogen or C _1-2 alkyl; and

Q1 is hydrogen, cyano, C _1-6 alkyl, C3-8cycloalkyl (e.g. C _3-6 cycloalkyl), C2-3alkenyl, C2- 3alkynyl, aryl, heterocyclyl or heteroaryl; and wherein Q1 is optionally substituted by one or more substituents selected from C _1-4 alkyl, halo, trifluoromethyl, trifluoromethoxy, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, NRtRu, ORt, C(O)Rt, C(O)ORt, OC(O)Rt, C(O)N(Rt)Ru, N(Rt)C(O)Ru, S(O)yRt (where y is 0, 1 or 2), SO ₂ N(Rt)Ru, N(Rt)SO ₂ Ru or (CH2)zNRtRu (where z is 1, 2 or 3), wherein Rt and Ru are each independently selected from hydrogen or C _1-4 alkyl; or

Q1 is optionally substituted by one or more groups of the formula:

-L _1c -L _1d -Z ₁

wherein L _1c is absent or C _1-3 alkylene optionally substituted by C _1-2 alkyl or oxo;

L _1d is absent or selected from C(O), O, C(O)O, OC(O), C(O)N(R _v ), N(R _v )C(O), N(R _v )C(O)N(R _w ), S(O) ₂ N(R _v ), or N(R _v )SO ₂ , wherein R _v and R _w are each

independently selected from hydrogen or C _1-2 alkyl; and

Z ₁ is C _3-8 cycloalkyl (including a spirocyclic carbocyclic and a bridged C _3-8 cycloalkyl), heterocyclyl (including a mono- or bicyclic-heterocyclic ring system, a spirocyclic heterocyclic ring system, or a bridged heterocyclic ring system), phenyl or 5-6 membered heteroaryl; wherein Z ₁ is optionally substituted by one or more

substituents selected from C _1-4 alkyl, C _3-6 cycloalkyl, heterocyclyl, halo, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _1-4 alkoxy, cyano, hydroxyl, NR _t1 R _u1 , OR _t1 , C(O)R _t1 , C(O)OR _t1 , OC(O)R _t1 , C(O)N(R _t1 )R _u1 , N(R _t1 )C(O)R _u1 , S(O) _y R _t1 (where y is 0, 1 or 2),

SO ₂ N(R _t1 )R _u1 , N(R _t1 )SO ₂ R _u1 or (CH ₂ ) _z NR _t1 R _u1 (where z is 1, 2 or 3), wherein R _t1 and R _u1 are each independently selected from hydrogen or C _1-4 alkyl; and when Z ₁ is C _{3- 8} cycloalkyl or heterocyclyl, Z ₁ is optionally spiro-fused to a C _3-6 cycloalkyl or heterocyclyl ring;

(6b) R1b, R1d and R1f are selected from hydrogen, cyano, halo or a group of the formula:

-L _1a -L _1b -Q ₁

wherein

L1a is absent or C1-3alkylene, C3-4cycloalkylene, optionally substituted by one or more substituents selected from aryl, aryl-(1-2C)alkyl, heteroaryl, aryl-(1-2C)alkyl, C _1-2 alkyl, cyano, halo, hydroxy, or oxo, wherein any aryl, aryl-(1-2C)alkyl, heteroaryl, aryl-(1- 2C)alkyl or C _1-2 alkyl is optionally further substituted by one or more substituents selected from halo, cyano or hydroxy;

L1b is absent or selected from O, S, SO, SO ₂ , N(Rr), C(O), C(O)O, OC(O), C(O)N(Rr), N(Rr)C(O), N(Rr)C(O)N(Rs), S(O)2N(Rr), or N(Rr)SO ₂ , wherein Rr and Rs are each independently selected from hydrogen or C _1-2 alkyl, wherein C _1-2 alkyl is optionally further substituted by C _3-6 cycloalkyl or a 3 to 6 membered heterocyclyl, which in turn are optionally further substituted by halo, hydroxy, C _1-2 alkoxy or C _1-2 haloalkoxy; and Q1 is hydrogen, cyano, C _1-6 alkyl, C3-8cycloalkyl (e.g. C _3-6 cycloalkyl), C2-3alkenyl, C2- 3alkynyl, aryl, heterocyclyl or heteroaryl; and wherein Q1 is optionally substituted by one or more substituents selected from C _1-4 alkyl, halo, trifluoromethyl, trifluoromethoxy, amino, oxo, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, NRtRu, ORt, C(O)Rt, C(O)ORt, OC(O)Rt, C(O)N(Rt)Ru, N(Rt)C(O)Ru, S(O)yRt (where y is 0, 1 or 2), SO ₂ N(R _t )R _u , N(R _t )SO ₂ R _u or (CH ₂ ) _z NR _t R _u (where z is 1, 2 or 3), wherein R _t and R _u are each independently selected from hydrogen or C _1-4 alkyl; or

Q ₁ is optionally substituted by one or more groups of the formula:

-L _1c -L _1d -Z ₁

wherein

L _1c is absent or C _1-3 alkylene optionally substituted by C _1-2 alkyl or oxo;

L _1d is absent or selected from C(O), O, C(O)O, OC(O), C(O)N(R _v ), N(R _v )C(O), N(R _v )C(O)N(R _w ), S(O) ₂ N(R _v ), or N(R _v )SO ₂ , wherein R _v and R _w are each

independently selected from hydrogen or C _1-2 alkyl; and

Z ₁ is C _3-8 cycloalkyl (including a spirocyclic carbocyclic and a bridged C _3-8 cycloalkyl), heterocyclyl (including a mono- or bicyclic-heterocyclic ring system, a spirocyclic heterocyclic ring system, or a bridged heterocyclic ring system), phenyl or 5-6 membered heteroaryl; wherein Z ₁ is optionally substituted by one or more

substituents selected from C _1-4 alkyl, C _3-6 cycloalkyl, heterocyclyl, halo, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _1-4 alkoxy, cyano, hydroxyl, NR _t1 R _u1 , OR _t1 , C(O)R _t1 , C(O)OR _t1 , OC(O)R _t1 , C(O)N(R _t1 )R _u1 , N(R _t1 )C(O)R _u1 , S(O)yR _t1 (where y is 0, 1 or 2),

SO ₂ N(R _t1 )R _u1 , N(R _t1 )SO ₂ R _u1 or (CH2)zNR _t1 R _u1 (where z is 1, 2 or 3), wherein R _t1 and R _u1 are each independently selected from hydrogen or C _1-4 alkyl; and when Z1 is C3- 8cycloalkyl or heterocyclyl, Z1 is optionally spiro-fused to a C _3-6 cycloalkyl or heterocyclyl ring;

(7) R1b, R1d and R1f are selected from hydrogen, cyano, halo or a group of the formula:

-L _1a -L _1b -Q ₁

wherein

L1a is absent or C1-3alkylene, C3-4cycloalkylene, optionally substituted by one or more substituents selected from C _1-2 alkyl, halo, hydroxy, or oxo;

L1b is absent or selected from O, S, SO, SO ₂ , N(Rr), C(O), C(O)O, OC(O), C(O)N(Rr), N(Rr)C(O), N(Rr)C(O)N(Rs), S(O)2N(Rr), or N(Rr)SO ₂ , wherein Rr and Rs are each independently selected from hydrogen or C _1-2 alkyl; and

Q1 is hydrogen, cyano, C _1-6 alkyl, C _3-6 cycloalkyl, C2-3alkenyl, C2-3alkynyl, aryl, heterocyclyl or heteroaryl; and wherein Q1 is optionally substituted by one or more substituents selected from C _1-4 alkyl, halo, trifluoromethyl, trifluoromethoxy, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, NRtRu, ORt, C(O)Rt, C(O)ORt, OC(O)Rt, C(O)N(Rt)Ru, N(Rt)C(O)Ru, S(O)yRt (where y is 0, 1 or 2), SO ₂ N(Rt)Ru, N(R _t )SO ₂ R _u or (CH ₂ ) _z NR _t R _u (where z is 1, 2 or 3), wherein R _t and R _u are each independently selected from hydrogen or C _1-4 alkyl; or

Q ₁ is optionally substituted by one or more groups of the formula:

-L _1c -L _1d -Z ₁

wherein

L _1c is absent or C _1-3 alkylene optionally substituted by C _1-2 alkyl or oxo;

L _1d is absent or selected from C(O), C(O)O, OC(O), C(O)N(R _v ), N(R _v )C(O),

N(R _v )C(O)N(R _w ), S(O) ₂ N(R _v ), or N(R _v )SO ₂ , wherein R _v and R _w are each

independently selected from hydrogen or C _1-2 alkyl; and

Z ₁ is phenyl or 5-6 membered heteroaryl; wherein Z ₁ is optionally substituted by one or more substituents selected from C _1-4 alkyl, halo, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _1-4 alkoxy, C _1-4 alkylamino, amino, cyano, hydroxyl, carboxy, carbamoyl or

sulphamoyl;

(7a) R _1b , R _1d and R _1f are selected from hydrogen, cyano, halo or a group of the formula:

-L _1a -L _1b -Q ₁

wherein

L1a is absent or C1-3alkylene, C3-4cycloalkylene, optionally substituted by one or more substituents selected from C _1-2 alkyl, halo, hydroxy, or oxo;

L1b is absent or selected from O, S, SO, SO ₂ , N(Rr), C(O), C(O)O, OC(O), C(O)N(Rr), N(Rr)C(O), N(Rr)C(O)N(Rs), S(O)2N(Rr), or N(Rr)SO ₂ , wherein Rr and Rs are each independently selected from hydrogen or C _1-2 alkyl; and

Q1 is hydrogen, cyano, C _1-6 alkyl, C3-8cycloalkyl (e.g. C _3-6 cycloalkyl), C2-3alkenyl, C2- 3alkynyl, aryl, heterocyclyl or heteroaryl; and wherein Q1 is optionally substituted by one or more substituents selected from C _1-4 alkyl, halo, trifluoromethyl, trifluoromethoxy, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, NRtRu, ORt, C(O)Rt, C(O)ORt, OC(O)Rt, C(O)N(Rt)Ru, N(Rt)C(O)Ru, S(O)yRt (where y is 0, 1 or 2), SO ₂ N(Rt)Ru, N(Rt)SO ₂ Ru or (CH2)zNRtRu (where z is 1, 2 or 3), wherein Rt and Ru are each independently selected from hydrogen or C _1-4 alkyl; or

Q1 is optionally substituted by one or more groups of the formula:

-L _1c -L _1d -Z ₁

wherein

L1c is absent or C1-3alkylene optionally substituted by C _1-2 alkyl or oxo; L _1d is absent or selected from C(O), O, C(O)O, OC(O), C(O)N(R _v ), N(R _v )C(O), N(R _v )C(O)N(R _w ), S(O) ₂ N(R _v ), or N(R _v )SO ₂ , wherein R _v and R _w are each

independently selected from hydrogen or C _1-2 alkyl; and

Z ₁ is C _3-8 cycloalkyl (including a spirocyclic carbocyclic and a bridged C _3-8 cycloalkyl), heterocyclyl (including a mono- or bicyclic-heterocyclic ring system, a spirocyclic heterocyclic ring system, or a bridged heterocyclic ring system), phenyl or 5-6 membered heteroaryl; wherein Z ₁ is optionally substituted by one or more

substituents selected from C _1-4 alkyl, C _3-6 cycloalkyl, heterocyclyl, halo, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _1-4 alkoxy, cyano, hydroxyl, NR _t1 R _u1 , OR _t1 , C(O)R _t1 , C(O)OR _t1 , OC(O)R _t1 , C(O)N(R _t1 )R _u1 , N(R _t1 )C(O)R _u1 , S(O) _y R _t1 (where y is 0, 1 or 2),

SO ₂ N(R _t1 )R _u1 , N(R _t1 )SO ₂ R _u1 or (CH ₂ ) _z NR _t1 R _u1 (where z is 1, 2 or 3), wherein R _t1 and R _u1 are each independently selected from hydrogen or C _1-4 alkyl; and when Z ₁ is C _{3- 8} cycloalkyl or heterocyclyl, Z ₁ is optionally spiro-fused to a C _3-6 cycloalkyl or heterocyclyl ring;

(7b) R _1b , R _1d and R _1f are selected from hydrogen, cyano, halo or a group of the formula:

-L _1a -L _1b -Q ₁

wherein

L1a is absent or C1-3alkylene, C3-4cycloalkylene, optionally substituted by one or more substituents selected from aryl, aryl-(1-2C)alkyl, heteroaryl, aryl-(1-2C)alkyl, C _1-2 alkyl, cyano, halo, hydroxy, or oxo, wherein any aryl, aryl-(1-2C)alkyl, heteroaryl, aryl-(1- 2C)alkyl or C _1-2 alkyl is optionally further substituted by one or more substituents selected from halo, cyano or hydroxy;

L1b is absent or selected from O, S, SO, SO ₂ , N(Rr), C(O), C(O)O, OC(O), C(O)N(Rr), N(Rr)C(O), N(Rr)C(O)N(Rs), S(O)2N(Rr), or N(Rr)SO ₂ , wherein Rr and Rs are each independently selected from hydrogen or C _1-2 alkyl, wherein C _1-2 alkyl is optionally further substituted by C _3-6 cycloalkyl or a 3 to 6 membered heterocyclyl, which in turn are optionally further substituted by halo, hydroxy, C _1-2 alkoxy or C _1-2 haloalkoxy; and Q1 is hydrogen, cyano, C _1-6 alkyl, C3-8cycloalkyl (e.g. C _3-6 cycloalkyl), C2-3alkenyl, C2- 3alkynyl, aryl, heterocyclyl or heteroaryl; and wherein Q1 is optionally substituted by one or more substituents selected from C _1-4 alkyl, halo, trifluoromethyl, trifluoromethoxy, amino, oxo, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, NRtRu, ORt, C(O)Rt, C(O)ORt, OC(O)Rt, C(O)N(Rt)Ru, N(Rt)C(O)Ru, S(O)yRt (where y is 0, 1 or 2), SO ₂ N(Rt)Ru, N(Rt)SO ₂ Ru or (CH2)zNRtRu (where z is 1, 2 or 3), wherein Rt and Ru are each independently selected from hydrogen or C _1-4 alkyl; or Q ₁ is optionally substituted by one or more groups of the formula:

-L _1c -L _1d -Z ₁

wherein

L _1c is absent or C _1-3 alkylene optionally substituted by C _1-2 alkyl or oxo;

L _1d is absent or selected from C(O), O, C(O)O, OC(O), C(O)N(R _v ), N(R _v )C(O), N(R _v )C(O)N(R _w ), S(O) ₂ N(R _v ), or N(R _v )SO ₂ , wherein R _v and R _w are each

independently selected from hydrogen or C _1-2 alkyl; and

Z ₁ is C _3-8 cycloalkyl (including a spirocyclic carbocyclic and a bridged C _3-8 cycloalkyl), heterocyclyl (including a mono- or bicyclic-heterocyclic ring system, a spirocyclic heterocyclic ring system, or a bridged heterocyclic ring system), phenyl or 5-6 membered heteroaryl; wherein Z ₁ is optionally substituted by one or more

substituents selected from C _1-4 alkyl, C _3-6 cycloalkyl, heterocyclyl, halo, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _1-4 alkoxy, cyano, hydroxyl, NR _t1 R _u1 , OR _t1 , C(O)R _t1 , C(O)OR _t1 , OC(O)R _t1 , C(O)N(R _t1 )R _u1 , N(R _t1 )C(O)R _u1 , S(O) _y R _t1 (where y is 0, 1 or 2),

SO ₂ N(R _t1 )R _u1 , N(R _t1 )SO ₂ R _u1 or (CH ₂ ) _z NR _t1 R _u1 (where z is 1, 2 or 3), wherein R _t1 and R _u1 are each independently selected from hydrogen or C _1-4 alkyl; and when Z1 is C3- 8cycloalkyl or heterocyclyl, Z1 is optionally spiro-fused to a C _3-6 cycloalkyl or heterocyclyl ring;

(8) R1b, R1d and R1f are selected from hydrogen, halo, cyano or from a group of formula:

-L _1a -L _1b -Q ₁

wherein

L1a is absent or C1-3alkylene, optionally substituted by one or more hydroxy;

L1b is absent or N(Rr) wherein Rr is hydrogen; and

Q1 is C _1-6 alkyl, C2-3alkenyl, C3-8cycloalkyl (e.g. C _3-6 cycloalkyl), aryl, heterocyclyl or heteroaryl; and wherein Q1 is optionally substituted by one or more substituents selected from halo, carboxy, trifluoromethyl, NRtRu, ORt wherein Rt and Ru are independently selected from hydrogen or C _1-4 alkyl; or

Q1 is optionally substituted by one or more groups of the formula:

-L _1c -L _1d -Z ₁

wherein

L1c is absent;

L1d is absent; and Z ₁ is phenyl or 5-6 membered heteroaryl; wherein Z ₁ is optionally substituted by one or more C _1-4 alkyl;

(8a) R _1b , R _1d and R _1f are selected from hydrogen, halo, cyano or from a group of formula:

-L _1a -L _1b -Q ₁

wherein

L _1a is absent or C _1-3 alkylene, optionally substituted by one or more hydroxy;

L _1b is absent or N(R _r ) wherein R _r is hydrogen or C _1-4 alkyl; and

Q ₁ is C _1-6 alkyl, C _2-3 alkenyl, C _3-6 cycloalkyl, aryl, heterocyclyl or heteroaryl; and wherein Q ₁ is optionally substituted by one or more substituents selected from halo, carboxy, trifluoromethyl, NR _t R _u , OR _t wherein R _t and R _u are independently selected from hydrogen or C _1-4 alkyl; or

Q ₁ is optionally substituted by one or more groups of the formula:

-L _1c -L _1d -Z ₁

wherein

L _1c is absent;

L1d is absent; and

Z1 is is phenyl, 5-6 membered heteroaryl, C3-8cycloalkyl (including a spirocyclic carbocyclic and a bridged C3-8cycloalkyl) or heterocyclyl (including a mono- or bicyclic-heterocyclic ring system, a spirocyclic heterocyclic ring system, or a bridged heterocyclic ring system); wherein Z1 is optionally substituted by one or more substituents selected from C _1-4 alkyl, C _3-6 cycloalkyl, heterocyclyl, halo, C _1-4 haloalkyl, OR _t1 , C(O)R _t1 , C(O)OR _t1 , OC(O)R _t1 , wherein R _t1 and R _u1 are each independently selected from hydrogen or C _1-4 alkyl; and Z1 is optionally spiro-fused to a C3- 6cycloalkyl or heterocyclyl ring;

(8b) R1b, R1d and R1f are selected from hydrogen, halo, cyano or from a group of formula:

-L _1a -L _1b -Q ₁

wherein

L1a is C1-3alkylene,;

L1b is N(Rr) wherein Rr is hydrogen or C _1-4 alkyl; and Q ₁ is C _1-6 alkyl, heterocyclyl or heteroaryl; and wherein Q ₁ is optionally substituted by one or more substituents selected from halo, carboxy, trifluoromethyl, NR _t R _u , OR _t wherein R _t and R _u are independently selected from hydrogen or C _1-4 alkyl; or

Q ₁ is optionally substituted by one or more groups of the formula:

-L _1c -L _1d -Z ₁

wherein

L _1c is absent;

L _1d is absent; and

Z ₁ is C _3-8 cycloalkyl (including a spirocyclic carbocyclic and a bridged C _3-8 cycloalkyl) or heterocyclyl (including a mono- or bicyclic-heterocyclic ring system, a spirocyclic heterocyclic ring system, or a bridged heterocyclic ring system); wherein Z ₁ is optionally substituted by one or more substituents selected from C _1-4 alkyl, C _{3- 6} cycloalkyl, heterocyclyl, halo, C _1-4 haloalkyl, OR _t1 , C(O)R _t1 , C(O)OR _t1 , OC(O)R _t1 , wherein R _t1 is selected from hydrogen or C _1-4 alkyl; and Z ₁ is optionally spiro-fused to a C _3-6 cycloalkyl or heterocyclyl ring;

(8c) R1b, R1d and R1f are selected from hydrogen or from a group of formula:

-L _1a -L _1b -Q ₁

wherein

L1a is C1-3alkylene,;

L1b is N(Rr) wherein Rr is hydrogen or C _1-4 alkyl; and

Q1 is C _1-6 alkyl; and wherein Q1 is optionally substituted by one or more substituents selected from halo, carboxy, trifluoromethyl, NRtRu, ORt wherein Rt and Ru are independently selected from hydrogen or C _1-4 alkyl; or

Q1 is optionally substituted by one or more groups of the formula:

-L _1c -L _1d -Z ₁

wherein

L1c is absent;

L1d is absent; and

Z1 is C3-8cycloalkyl (including a spirocyclic carbocyclic and a bridged C3-8cycloalkyl); wherein Z1 is optionally substituted by one or more substituents selected from C1- 4alkyl, C _3-6 cycloalkyl, heterocyclyl, halo, C _1-4 haloalkyl, OR _t1 or C(O)OR _t1 , wherein R _t1 is selected from hydrogen or C _1-4 alkyl; and Z ₁ is optionally spiro-fused to a C _{3- 6} cycloalkyl or heterocyclyl ring;

(8d) R _1b , R _1d and R _1f are selected from hydrogen or from a group of formula:

-L _1a -L _1b -Q ₁

wherein

L _1a is C _1-3 alkylene,;

L _1b is N(R _r ) wherein R _r is hydrogen; and

Q ₁ is C _1-6 alkyl; and wherein Q ₁ is optionally substituted by one or more substituents selected from halo, carboxy, trifluoromethyl, NR _t R _u , OR _t wherein R _t and R _u are independently selected from hydrogen or C _1-4 alkyl; or

Q ₁ is optionally substituted by one or more groups of the formula:

-L _1c -L _1d -Z ₁

wherein

L _1c is absent;

L _1d is absent; and

Z1 is C3-8cycloalkyl (including a spirocyclic carbocyclic and a bridged C3-8cycloalkyl); wherein Z1 is optionally substituted by one or more substituents selected from C1- 4alkyl or halo, C _1-4 haloalkyl, OR _t1 or C(O)OR _t1 , wherein R _t1 is selected from hydrogen or C _1-4 alkyl;

(8e) R1b, R1d and R1f are selected from hydrogen or from a group of formula:

-L _1a -L _1b -Q ₁

wherein

L1a is C1-3alkylene,;

L1b is N(Rr) wherein Rr is hydrogen; and

Q1 is C _1-6 alkyl substituted by one or more groups of the formula:

-L _1c -L _1d -Z ₁

wherein

L1c is absent;

L1d is absent; and Z ₁ is C _3-8 cycloalkyl (including a spirocyclic carbocyclic and a bridged C _3-8 cycloalkyl) that is is optionally substituted by one or more substituents selected from C _1-4 alkyl or halo;

(9) R _1b , R _1d and R _1f are selected from hydrogen, halo, cyano or from a group of formula:

-L _1a -L _1b -Q ₁

wherein

L _1a is absent or C _1-3 alkylene;

L _1b is absent or N(R _r ) wherein R _r is hydrogen; and

Q ₁ is C _1-6 alkyl, and wherein

Q ₁ is substituted by a group of the formula:

-L _1c -L _1d -Z ₁

wherein

L _1c is absent;

L _1d is absent; and

Z1 is phenyl;

(9a) R1b, R1d and R1f are selected from hydrogen, halo, cyano or from a group of formula:

-L _1a -L _1b -Q ₁

wherein

L1a is absent or C1-3alkylene, optionally substituted by one or more hydroxy;

L1b is absent; and

Q1 is a 5- or 6-membered aryl, a 5- or 6-membered heteroaryl, a 5- or 6-membered heterocyclyl or a 7, 8 or 9 membered bridged heterocycle, wherein Q1 is optionally substituted by one or more substituents selected from halo, NRtRu, ORt, wherein Rt and Ru are independently selected from hydrogen or C _1-4 alkyl; or

Q1 is optionally substituted by one or more groups of the formula:

-L _1c -L _1d -Z ₁

wherein

L1c is absent; L _1d is absent; and

Z ₁ is 5-6 membered heteroaryl; wherein Z ₁ is optionally substituted by one or more C _1-4 alkyl;

(10) R _1b , R _1d and R _1f are selected from hydrogen, halo, cyano or from a group of formula:

-L _1a -L _1b -Q ₁

wherein

L _1a is absent or C _1-3 alkylene, optionally substituted by one or more hydroxy;

L _1b is absent or N(R _r ) wherein R _r is hydrogen; and

Q ₁ is a 5- or 6-membered aryl, a 5- or 6-membered heteroaryl, or a 5- or 6-membered heterocyclyl, wherein Q ₁ is optionally substituted by one or more substituents selected from halo, NRtRu, ORt wherein Rt and Ruare independently selected from hydrogen or C _1-4 alkyl; or

Q1 is optionally substituted by one or more groups of the formula:

-L _1c -L _1d -Z ₁

wherein

L _1c is absent;

L1d is absent; and

Z1 is 5-6 membered heteroaryl; wherein Z1 is optionally substituted by one or more C _1-4 alkyl;

(11) R1b, R1d and R1f are selected from hydrogen, halo, cyano or from a group of formula:

-L _1a -L _1b -Q ₁

wherein

L1a is absent or C1-3alkylene optionally substituted by one hydroxy;

L1b is absent or N(Rr) wherein Rr is hydrogen; and

Q1 is phenyl, pyrazolyl, piperazinyl or pyrindinyl, wherein Q1 is optionally substituted by one or more substituents selected from chloro and methoxy;

(12) R1b, R1d and R1f are selected from hydrogen, halo, cyano or from a group of formula:

-L _1a -L _1b -Q ₁

wherein

L1a is absent; L _1b is absent or N(R _r ) wherein R _r is hydrogen; and

Q ₁ is C _1-6 alkyl optionally substituted with 5-6 membered heteroaryl; wherein 5-6 membered heteroaryl is optionally substituted by one or more substituents selected from C _1-4 alkyl, halo, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _1-4 alkoxy, C _1-4 alkylamino, amino, cyano, hydroxyl, carboxy, carbamoyl or sulphamoyl;

(13) R _1b , R _1d and R _1f are selected from hydrogen, halo, cyano or from a group of formula:

-L _1a -L _1b -Q ₁

wherein

L _1a is absent;

L _1b is absent or N(R _r ) wherein R _r is hydrogen; and

Q ₁ is C _1-6 alkyl optionally substituted with piperazinyl, imidazolyl or pyridyl, wherein the imidazolyl is optionally substituted with C _1-4 alkyl;

(14) R _1b , R _1d and R _1f are selected from hydrogen; halo; cyano; hydroxy; C _1-6 alkyl optionally substituted with OH, NH ₂ , a 5-6 membered aryl, carboxy and/or a 5-6 membered heterocyclyl; C _1-6 alkyloxy; C _2-3 alkenyl; C _3-6 cycloalkyl; -C _1-3 alkylene-NH-C _1-6 alkyl wherein the C _1-6 alkyl is optionally substituted with OH, trifluoromethyl, carboxy or phenyl; -NH-heteroaryl wherein the heteroaryl is a 5- or 6-membered heteroaryl; 5- or 6-membered heteroaryl; 5- or 6-membered heterocyclic; 5- or 6-membered aryl optionally substituted with -OC _1-4 alkyl or halo; and -NH-C _1-6 alkyl wherein the C _1-6 alkyl is optionally substituted with a 5- or 6-membered heteroaryl and wherein the 5- or 6- membered heteroaryl is optionally substituted with C _1-4 alkyl;

(14a) R1b, R1d and R1f are independently selected from hydrogen, halo, cyano, hydroxy, C1- 4alkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, or a group of the formula:

–(CR1c’R1d’)p–NR1e’R1f’;

wherein

p is an integer selected from 1 or 2;

R1c’ and R1d' are independently selected from:

(i) hydrogen (including deuterium),

(ii) C1-3alkyl which is optionally substituted by one more substituents selected from cyano, hydroxy, C1-3alkoxy, halo, C1-3haloalkoxy, -O-C3-4cycloalkyl, or NH2; wherein -O-C _3-6 cycloalkyl is optionally subsitutued with halo, cyano or hydroxy, (iii) or R _1c’ and R _1d’ are linked together such that, together with the carbon atom to which they are attached, they form a 3- to 5-membered cycloalkyl or heterocyclic ring, or a spirocyclic ring system, each of which is optionally substituted by one or more substituents selected from C _1-2 alkyl, C _1-2 haloalkyl, cyano, hydroxy, C _1-2 alkoxy, halo or C _1-2 haloalkoxy;

R _1e’ is selected from:

(i) hydrogen (including deuterium);

(ii) C _1-3 alkyl which is optionally substituted by one more substituents selected from cyano, hydroxy, C _1-2 alkoxy, halo, C _1-2 haloalkoxy and NH ₂ ;

R _1f’ is a group with the formula:

–(CR _1g R _1h ) _q –T ₁

wherein:

q is 0, 1 or 2 (e.g. q is 1 or 2);

R _1g and R _1h are independently selected from:

a) hydrogen (including deuterium); or

b) C1-3alkyl, which is optionally substituted by one more substituents

selected from cyano, hydroxy, C _1-2 alkoxy, halo, C _1-2 haloalkoxy, -O- C3cycloalkyl, wherein -O-C3cycloalkyl is optionally subsitutued with halo, cyano or hydroxy;

and T1 is selected from C3-8cycloalkyl, aryl, heterocyclyl, heteroaryl, a spirocyclic carbocyclic or heterocyclic ring system, a bridged C3-8cycloalkyl, or a bridged heterocyclic ring system, each of which is optionally substituted by one or more substituents selected from C _1-2 alkyl, C _1-2 haloalkyl, cyano, hydroxy, C _1-2 alkoxy, halo or C _1-2 haloalkoxy;

or R1e’ and R1f’ are linked such that, together with the nitrogen atom to which they are attached, they form a mono- or bicyclic-heterocyclic ring, which is optionally substituted by one or more substituents selected from C _1-2 alkyl, C _1-2 haloalkyl, cyano, hydroxy, C _1-2 alkoxy, halo, C _1-2 haloalkoxy, NR1iR1j or -S(O) _0-2 R1iR1j, wherein R1i and R1j are H or C _1-2 alkyl, and/or the mono- or bicyclic hetereocyclic ring formed by R1e and R1f is optionally spiro-fused to a C _3-6 cycloalkyl or a heterocyclic ring, which in turn is optionally substituted by one or more substituents selected from C _1-2 alkyl, cyano, hydroxy, C _1-2 alkoxy, halo, C _1-2 haloalkoxy, NR1iR1j or -S(O) _0-2 R1iR1j, wherein R1i and R1j are H or C _1-2 alkyl. (14b) R _1d and R _1f are independently selected from hydrogen, halo, cyano, hydroxy, C _1-4- alkyl, C _1-4 alkoxy and C _1-4 haloalkoxy; and R _1b is a group of the formula:

–(CR _1c’ R _1d’ ) _p –NR _1e’ R _1f’ ;

wherein

p is an integer selected from 1 or 2;

R _1c’ and R _1d’ are independently selected from:

(i) hydrogen (including deuterium) or

(ii) C _1-3 alkyl which is optionally substituted by one more substituents selected from cyano, hydroxy, C _1-2 alkoxy, halo, C _1-2 haloalkoxy, -O-C ₃ cycloalkyl;

R _1e’ is selected from hydrogen (including deuterium) or C _1-2 alkyl; and

R _1f’ is a group with the formula:

–(CR _1g R _1h ) _q –T ₁

wherein:

q is 0, 1 or 2 (e.g. q is 1 or 2); R _1g and R _1h are independently selected from:

a) hydrogen (including deuterium); or

b) C _1-2 alkyl, which is optionally substituted by one more substituents selected from cyano, hydroxy, C _1-2 alkoxy, halo or C _1-2 haloalkoxy; and T1 is selected from C3-8cycloalkyl, aryl, heterocyclyl, heteroaryl, a spirocyclic carbocyclic or heterocyclic ring system, a bridged C3-8cycloalkyl, or a bridged heterocyclic ring system, each of which is optionally substituted by one or more substituents selected from C _1-2 alkyl, C _1-2 haloalkyl, cyano, hydroxy, C _1-2 alkoxy, halo or C _1-2 haloalkoxy;

or R1e’ and R1f’ are linked such that, together with the nitrogen atom to which they are attached, they form a mono- or bicyclic-heterocyclic ring, which is optionally substituted by one or more substituents selected from C _1-2 alkyl, C1- 2haloalkyl, cyano, hydroxy, C _1-2 alkoxy, halo or C _1-2 haloalkoxy, and/or the mono- or bicyclic hetereocyclic ring formed by R1e and R1f is optionally spiro- fused to a C _3-6 cycloalkyl or a heterocyclic ring, which in turn is optionally substituted by one or more substituents selected from C _1-2 alkyl, C _1-2 haloalkyl, cyano, hydroxy, C _1-2 alkoxy, halo or C _1-2 haloalkoxy. (14c) R _1d and R _1f are independently selected from hydrogen, halo, cyano, hydroxy, C _1-4- alkyl, C _1-4 alkoxy and C _1-4 haloalkoxy; and R _1b is a group of the formula:

–(CR _1c’ R _1d’ ) _p –NR _1e’ R _1f’ ;

wherein

p is an integer selected from 1 or 2;

R _1c’ and R _1d’ are independently selected from hydrogen (including deuterium) or C _{1- 2} alkyl;

R _1e’ is selected from hydrogen (including deuterium) or C _1-2 alkyl; and

R _1f’ is a group with the formula:

–(CR _1g R _1h ) _q –T ₁

wherein:

q is 0, 1 or 2 (e.g. q is 1 or 2);R _1g and R _1h are independently selected from hydrogen (including deuterium) or C _1-2 alkyl;

and T ₁ is selected from C _3-4 cycloalkyl, heterocyclyl, a spirocyclic carbocyclic or heterocyclic ring system, a bridged C _3-8 cycloalkyl, or a bridged heterocyclic ring system, each of which is optionally substituted by one or more substituents selected from C _1-2 alkyl, C _1-2 haloalkyl, cyano, hydroxy, C _1-2 alkoxy, halo or C _1-2 haloalkoxy;

or R1e’ and R1f’ are linked such that, together with the nitrogen atom to which they are attached, they form a mono- or bicyclic-heterocyclic ring, which is optionally substituted by one or more substituents selected from C _1-2 alkyl, C1- 2haloalkyl, cyano, hydroxy, C _1-2 alkoxy, halo or C _1-2 haloalkoxy, and/or the mono- or bicyclic hetereocyclic ring formed by R1e and R1f is optionally spiro- fused to a C _3-6 cycloalkyl or a heterocyclic ring, which in turn is optionally substituted by one or more substituents selected from C _1-2 alkyl, C _1-2 haloalkyl, cyano, hydroxy, C _1-2 alkoxy, halo or C _1-2 haloalkoxy.

(14d) R1d and R1f are independently selected from hydrogen, halo, cyano, hydroxy, methyl and methoxy; and R1b is a group of the formula:

–(CR1c’R1d’)p–NR1e’R1f’;

wherein

p is 1; R _1c’ and R _1d’ are independently selected from hydrogen (including deuterium) or C _1-2 alkyl;

R _1e’ is selected from hydrogen (including deuterium) or C _1-2 alkyl; and

R _1f’ is a group with the formula:

–(CR _1g R _1h ) _q –T ₁

wherein:

q is 0, 1 or 2 (e.g. q is 1 or 2);R _1g and R _1h are independently selected from hydrogen (including deuterium) or C _1-2 alkyl;

and T ₁ is selected from C _3-4 cycloalkyl, heterocyclyl, a spirocyclic carbocyclic or heterocyclic ring system, a bridged C _3-8 cycloalkyl, or a bridged heterocyclic ring system, each of which is optionally substituted by one or more substituents selected from C _1-2 alkyl, C _1-2 haloalkyl, cyano, hydroxy, C _1-2 alkoxy, halo or C _1-2 haloalkoxy;

or R _1e’ and R _1f’ are linked such that, together with the nitrogen atom to which they are attached, they form a mono- or bicyclic-heterocyclic ring, which is optionally substituted by one or more substituents selected from C _1-2 alkyl, C1- 2haloalkyl, cyano, hydroxy, C _1-2 alkoxy, halo or C _1-2 haloalkoxy, and/or the mono- or bicyclic hetereocyclic ring formed by R1e and R1f is optionally spiro- fused to a C _3-6 cycloalkyl or a heterocyclic ring; which in turn is optionally substituted by one or more substituents selected from C _1-2 alkyl, C _1-2 haloalkyl, cyano, hydroxy, C _1-2 alkoxy, halo or C _1-2 haloalkoxy.

(14e) R1d and R1f are independently selected from hydrogen, halo, cyano, hydroxy, methyl and methoxy; and R1b is a group of the formula:

–(CR1c’R1d’)p–NR1e’R1f’;

wherein

p is 1;

R1c’ and R1d’ are independently selected from hydrogen (including deuterium) or C _1-2 alkyl;

R1e’ is selected from hydrogen (including deuterium) or C _1-2 alkyl; and

R1f’ is a group with the formula:

–(CR1gR1h)q–T1

wherein: q is 1;

R _1g and R _1h are independently selected from hydrogen (including deuterium) or C _1-2 alkyl;

and T ₁ is selected from C _3-4 cycloalkyl, heterocyclyl, a spirocyclic carbocyclic or heterocyclic ring system, a bridged C _3-8 cycloalkyl, or a bridged heterocyclic ring system, each of which is optionally substituted by one or more substituents selected from C _1-2 alkyl, C _1-2 haloalkyl, cyano, hydroxy, C _1-2 alkoxy, halo or C _1-2 haloalkoxy.

(14f) R _1d and R _1f are independently selected from hydrogen, halo, cyano, hydroxy, methyl and methoxy; and R _1b is a group of the formula:

–(CR _1c’ R _1d’ ) _p –NR _1e’ R _1f’ ;

wherein

p is 1;

R _1c’ and R _1d’ are independently selected from hydrogen (including deuterium) or C _1-2 alkyl; and

R1e’ and R1f’ are linked such that, together with the nitrogen atom to which they are attached, they form a mono- or bicyclic-heterocyclic ring, which is optionally substituted by one or more substituents selected from C _1-2 alkyl, C1- 2haloalkyl, cyano, hydroxy, C _1-2 alkoxy, halo or C _1-2 haloalkoxy, and/or the mono- or bicyclic hetereocyclic ring formed by R1e’ and R1f’ is optionally spiro- fused to a C _3-6 cycloalkyl or a heterocyclic ring, which in turn is optionally substituted by one or more substituents selected from C _1-2 alkyl, C _1-2 haloalkyl, cyano, hydroxy, C _1-2 alkoxy, halo or C _1-2 haloalkoxy.

(14g) R1d and R1f are independently selected from hydrogen, halo, cyano, hydroxy, methyl and methoxy; and R1b is a group of the formula ,

wherein T ₁ is selected from C _3-4 cycloalkyl, heterocyclyl, a spirocyclic carbocyclic or heterocyclic ring system, a bridged C _3-8 cycloalkyl, or a bridged heterocyclic ring system, each of which is optionally substituted by one or more substituents selected from C _1-2 alkyl, C _1-2 haloalkyl, cyano, hydroxy, C _1-2 alkoxy, halo or C _1-2 haloalkoxy.

(15) R _1b , R _1d and R _1f are selected from hydrogen; bromo; chloro; fluoro; cyano; methyl; hydroxy; methoxy;

(15a) R1d and R1f are selected from hydrogen; bromo; chloro; fluoro; cyano; methyl; methoxy;

and R1b is selected from:

; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ;

(15b) R1b, R1d and R1f are selected from hydrogen; bromo; chloro; fluoro; cyano; methyl; methoxy,

;

;

(15c) R _1b , R _1d and R _1f are selected from hydrogen; bromo; chloro; fluoro; cyano; methyl;

(15d) R1b, R1d and R1f are selected from: ; ;

; ; ; ; ; ; ; ;

; ; ;

; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; (15e) R _1b , R _1d and R _1f are selected from;

(15f) R _1b , R _1d and R _1f are selected from;

(15g) R _1b , R _1d and R _1f are;

(16) R _1a’ is selected from hydrogen, halo and methyl;

(16a) R _1a’ is selected from hydrogen and methyl;

(17) R _1a’ is hydrogen;

(18) R _2a , R _2b and R _2c are selected from hydrogen, halo or a group of the formula:

-L _2a -L _2b -Q ₂

wherein

L _2a is absent or C _1-3 alkylene optionally substituted by C _1-2 alkyl or oxo;

L _2b is absent or selected from O, S, SO, SO ₂ , N(R _n ), C(O), C(O)O, OC(O),

C(O)N(R _n ), N(R _n )C(O), N(R _n )C(O)N(R _o ), S(O) ₂ N(R _n ), or N(R _n )SO ₂ , wherein R _n and R _o are each independently selected from hydrogen or C _1-2 alkyl; and

Q ₂ is hydrogen, cyano, C _1-6 alkyl, C _3-6 cycloalkyl, aryl, heterocyclyl or heteroaryl, each of which is optionally substituted by one or more substituents selected from halo, trifluoromethyl, trifluoromethoxy, amino, cyano, hydroxy, amino, carboxy, carbamoyl, sulphamoyl, C _1-4 alkyl, NRpRq, ORp, C(O)Rp, C(O)ORp, OC(O)Rp, C(O)N(Rp)Rq, N(Rr)C(O)Rp, S(O)yRp (where y is 0, 1 or 2), SO ₂ N(Rp)Rq, N(Rr)SO ₂ Rp or (CH2)zNRpRq (where z is 1, 2 or 3), wherein R _p and R _q are each independently selected from hydrogen or C _1-4 alkyl;

(19) R2a, R2b and R2c are hydrogen;

(20) , wherein R _1a , R _1b , R _1a’ and R _2a are as herein defined;

(21) , wherein R1c, R1d and R2b are as herein defined;

(22) wherein R1e, R1f and R2c are as herein defined; (23) X is selected from

,

, ,

, , ,

,

,

(24) X is

(24a) X is

(25) R3a1, R3b1, R3c1, R3d1, R3e1, R3f1, R3g1, R3h1, R3i1, R3j1, R3k1, R3l1, R3m1, R3n1 and R3o1 are independently selected from hydrogen, C _1-6 alkyl, C _3-4 cycloalkyl, hydroxy, and halo; and wherein C _1-6 alkyl, or C3-4 cycloalkyl is optionally substituted with one or more substituents selected from halo, amino, cyano, and hydroxy; and R3a2, R3b2, R3c2, R3d2, R3e2, R3f2, R3g2, R3h2, R3i2, R3j2, R3k2, R3l2, R3m2, R3n2 and R3o2 are hydrogen;

(25a) R3a1, R3b1, R3c1, R3d1, R3e1, R3f1, R3g1, R3h1, R3i1, R3j1, R3k1, R3l1, R3m1, R3n1, R3o1, R3p1 and R3q1 are independently selected from hydrogen, C _1-6 alkyl, C3-4 cycloalkyl, hydroxy, and halo; and wherein C _1-6 alkyl, or C3-4 cycloalkyl is optionally substituted with one or more substituents selected from halo, amino, cyano, and hydroxy; and R3a2, R3b2, R3c2, R3d2, R3e2, R3f2, R3g2, R3h2, R3i2, R3j2, R3k2, R3l2, R3m2, R3n2, R3o2, R3p2 and R3q2 are hydrogen;

(25b) R3a1, R3b1, R3c1, R3d1, R3e1, R3f1, R3g1, R3h1, R3i1, R3j1, R3k1, R3l1, R3m1, R3n1, R3o1, R3p1, R3q1, R3r1 and R3s1 are independently selected from hydrogen, C _1-6 alkyl, C3-4 cycloalkyl, hydroxy, and halo; and wherein C _1-6 alkyl, or C3-4 cycloalkyl is optionally substituted with one or more substituents selected from halo, amino, cyano, and hydroxy; and R3a2, R3b2, R3c2, R3d2, R3e2, R3f2, R3g2, R3h2, R3i2, R3j2, R3k2, R3l2, R3m2, R3n2, R _3o2, R _3p2 R _3q2 , R _3r2 and R _3s2 are hydrogen;

(26) R _3a1 , R _3b1 , R _3c1 , R _3d1 , R _3e1 , R _3f1 , R _3g1 , R _3h1 , R _3i1 , R _3j1 , R _3k1 , R _3l1 , R _3m1 , R _3n1 and R _3o1 are independently selected from hydrogen and C _1-6 alkyl; and wherein C _1-6 alkyl is optionally substituted with one or more hydroxy substituents;

(26a) R3a1, R3b1, R3c1, R3d1, R3e1, R3f1, R3g1, R3h1, R3i1, R3j1, R3k1, R3l1, R3m1, R3n1, R3o1, R3p1 and R _3q1 are independently selected from hydrogen and C _1-6 alkyl; and wherein C ₁ - 6alkyl is optionally substituted with one or more hydroxy substituents; (26b) R _3a1 , R _3b1 , R _3c1 , R _3d1 , R _3e1 , R _3f1 , R _3g1 , R _3h1 , R _3i1 , R _3j1 , R _3k1 , R _3l1 , R _3m1 , R _3n1 , R _3o1 , R _3p1, R _3q1 , R _3r1 and R _3s1 are independently selected from hydrogen and C _1-6 alkyl; and wherein C ₁ - ₆ alkyl is optionally substituted with one or more hydroxy substituents; (27) R _3a1 , R _3b1 , R _3c1 , R _3d1 , R _3e1 , R _3f1 , R _3g1 , R _3h1 , R _3i1 , R _3j1 , R _3k1 , R _3l1 , R _3m1 , R _3n1 and R _3o1 are independently selected from hydrogen and methyl; and wherein methyl is optionally substituted with one or more hydroxy substituents;

(27a) R _3a1 , R _3b1 , R _3c1 , R _3d1 , R _3e1 , R _3f1 , R _3g1 , R _3h1 , R _3i1 , R _3j1 , R _3k1 , R _3l1 , R _3m1 , R _3n1 , R _3o1 , R _3p1 and R _3q1 are independently selected from hydrogen and methyl; and wherein methyl is optionally substituted with one or more hydroxy substituents;

(27b) R _3a1 , R _3b1 , R _3c1 , R _3d1 , R _3e1 , R _3f1 , R _3g1 , R _3h1 , R _3i1 , R _3j1 , R _3k1 , R _3l1 , R _3m1 , R _3n1 , R _3o1 , R _3p1 and R _3q1 are independently selected from hydrogen and methyl; and wherein methyl is optionally substituted with one or more hydroxy substituents;

(28) R _3a1 , R _3b1 , R _3c1 , R _3d1 , R _3e1 , R _3f1 , R _3g1 , R _3h1 , R _3i1 , R _3j1 , R _3k1 , R _3l1 , R _3m1 , R _3n1 and R _3o1 are independently selected from hydrogen and methyl; and wherein methyl is substituted with a hydroxy substituent;

(28a) R3a1, R3b1, R3c1, R3d1, R3e1, R3f1, R3g1, R3h1, R3i1, R3j1, R3k1, R3l1, R3m1, R3n1, R3o1, R3p1 and R3q1 are independently selected from hydrogen and methyl; and wherein methyl is substituted with a hydroxy substituent;

(28b) R3a1, R3b1, R3c1, R3d1, R3e1, R3f1, R3g1, R3h1, R3i1, R3j1, R3k1, R3l1, R3m1, R3n1, R3o1, R3p1, R3q1, R3r1 and R3s1 are independently selected from hydrogen and methyl; and wherein methyl is substituted with a hydroxy substituent; (29) R3a2, R3b2, R3c2, R3d2, R3e2, R3f2, R3g2, R3h2, R3i2, R3j2, R3k2, R3l2, R3m2, R3n2 and R3o2 are hydrogen;

(29a) R3a2, R3b2, R3c2, R3d2, R3e2, R3f2, R3g2, R3h2, R3i2, R3j2, R3k2, R3l2, R3m2, R3n2, R3o2, R3p2 and R3q2 are hydrogen;

(29b) R3a2, R3b2, R3c2, R3d2, R3e2, R3f2, R3g2, R3h2, R3i2, R3j2, R3k2, R3l2, R3m2, R3n2, R3o2, R3p2, R3q2, R3r2 and R3s2 are hydrogen;

(30) R3a1 and R3a2, R3b1 and R3b2, R3c1 and R3c2, R3d1 and R3d2, R3e1 and R3e2, R3f1 and R3f2, R3g1 and R3g2, R3h1 and R3h2, R3i1 and R3i2, R3j1 and R3j2, R3k1 and R3k2, R3l1 and R3l2, R3m1 and R3m2, R3n1 and R3n2, or R3o1 and R3o2 are hydrogen;

(30a) R3a1 and R3a2, R3b1 and R3b2, R3c1 and R3c2, R3d1 and R3d2, R3e1 and R3e2, R3f1 and R3f2, R3g1 and R3g2, R3h1 and R3h2, R3i1 and R3i2, R3j1 and R3j2, R3k1 and R3k2, R3l1 and R3l2, R3m1 and R3m2, R3n1 and R3n2, R3o1 and R3o2, R3p1 and R3p2, R3q1 and R3q2 are hydrogen. (30b) R _3a1 and R _3a2 , R _3b1 and R _3b2 , R _3c1 and R _3c2 , R _3d1 and R _3d2 , R _3e1 and R _3e2 , R _3f1 and R _3f2 , R _3g1 and R _3g2 , R _3h1 and R _3h2 , R _3i1 and R _3i2, R _3j1 and R _3j2 , R _3k1 and R _3k2 , R _3l1 and R _3l2 , R _3m1 and R _3m2 , R _3n1 and R _3n2 , R _3o1 and R _3o2 , R _3p1 and R _3p2 , R _3q1 and R _3q2 , R _3r1 and R3r2, and R3s1 and R3s2 are hydrogen.

(31) R _3a1 and R _3a2 , R _3b1 and R _3b2 , R _3c1 and R _3c2 , R _3d1 and R _3d2 , R _3e1 and R _3e2 , R _3f1 and R _3f2 , R _3g1 and R _3g2 , R _3h1 and R _3h2 , R _3i1 and R _3i2 , R _3j1 and R _3j2 , R _3k1 and R _3k2 , R _3l1 and R _3l2 , R _3m1 and R _3m2 , R _3n1 and R _3n2 , R _3o1 and R _3o2 may be linked to form a spiro-fused C _{3- 4} cycloalkyl which is optionally substituted with one or more substituents selected from halo, amino, cyano, and hydroxy;

(31a) R _3a1 and R _3a2 , R _3b1 and R _3b2 , R _3c1 and R _3c2 , R _3d1 and R _3d2 , R _3e1 and R _3e2 , R _3f1 and R _3f2 , R _3g1 and R _3g2 , R _3h1 and R _3h2 , R _3i1 and R _3i2, R _3j1 and R _3j2 , R _3k1 and R _3k2 , R _3l1 and R _3l2 , R _3m1 and R _3m2 , R _3n1 and R _3n2 , R _3o1 and R _3o2 , R _3p1 and R _3p2 , R _3q1 and R _3q2 may be linked to form a spiro-fused C _3-4 cycloalkyl which is optionally substituted with one or more substituents selected from halo, amino, cyano, and hydroxy;

(31b) R _3a1 and R _3a2 , R _3b1 and R _3b2 , R _3c1 and R _3c2 , R _3d1 and R _3d2 , R _3e1 and R _3e2 , R _3f1 and R _3f2 , R _3g1 and R _3g2 , R _3h1 and R _3h2 , R _3i1 and R _3i2, R _3j1 and R _3j2 , R _3k1 and R _3k2 , R _3l1 and R _3l2 , R _3m1 and R _3m2 , R _3n1 and R _3n2 , R _3o1 and R _3o2 , R _3p1 and R _3p2 , and R _3q1 and R _3q2 , may be linked to form a spiro-fused C _3-4 cycloalkyl which is optionally substituted with one or more substituents selected from halo, amino, cyano, and hydroxy;

(32) n is 0, 1 or 2;

(33) n is 1;

(34) Y is wherein R _3a1 , R _3a2 and n are as herein defined;

(34a) Y is wherein n is 1, and R3a1, R3a2 are as herein defined; (35) Y is wherein n is herein defined;

(36) Y is wherein R3b1, R3b2 and n are as herein defined; (37) Y is wherein R _3c1 , R _3c2 and n are as herein defined; (38) Y is wherein R3d1, R3d2 and n are as herein defined; (39) Y is wherein R _3e1 , R _3e2 and n are as herein defined; (40) Y is

(41) Y is wherein R3f1, R3f2 and n are as herein defined;

(42) Y wherein R3g1, R3g2 and n are as herein defined; (43) Y wherein R _3h1 , R _3h2 and n are as herein defined (44) Y is wherein R3i1, R3i2 and n are as herein defined; (45) Y is wherein R3j1, R3j2 and n are as herein defined; (46) Y is wherein R _3k1 , R _3k2 and n are as herein defined; (47) Y is wherein R _3l1 , R _3l2 and n are as herein defined;

(48) Y is wherein R3m1, R3m2 and n are as herein defined; (49) Y is wherein R3n1, R3n2 and n are as herein defined; (50) Y is wherein R3o1, R3o2 and n are as herein defined; (50a) Y is wherein R3p1, R3p2 and n are as herein defined; (50b) Y is wherein R3q1, R3q2 and n are as herein defined; (50c) Y is wherein R3r1, R3r2 and n are as herein defined;

(50d) Y is wherein R _3s1 , R _3s2 and n are as herein defined;

(51) Y is selected from

(52) Y is

(52a) Y is selected from

(53) R ₄ is selected from hydrogen and methyl;

(54) R ₄ is hydrogen;

(55) R ₅ is selected from hydrogen and halo;

(56) R ₅ is hydrogen; (57) R ₆ is selected from hydrogen, halo and methyl;

(58) R ₆ is hydrogen;

(59) R ₄ , R ₅ and R ₆ are hydrogen;

(60) A ₁ is selected from CR ₁₂ and N, wherein R ₁₂ is selected from hydrogen, halo, cyano and C _1-4 alkyl;

(61) A ₁ is CH;

(62) A ₂ is selected from CR ₁₃ and N, wherein R ₁₃ is selected from hydrogen, halo, cyano and methyl;

(63) Suitably A ₂ is CH;

(64) A ₁ is CH and A ₂ is CH;

(65) R ₇ is selected from hydrogen, halo and methyl;

(65a) R ₇ is selected from hydrogen and methyl;

(66) R ₇ is hydrogen;

(67) R ₈ is selected from hydrogen, halo and methyl;

(68) R ₈ is hydrogen;

(69) R7 and R8 are hydrogen;

(70) A3 is selected from CR14 and N, wherein R14 is selected from hydrogen, halo, cyano and C _1-4 alkyl;

(71) A3 is CR14, wherein R14 is selected from hydrogen and chloro;

(72) A3 is CH;

(73) A4 is selected from CR15 and N, wherein R15 is selected from hydrogen, methoxy and methyl;

(74) A4 is CH;

(75) A3 is CH and A4 is CH;

(76) A5 is selected from CR16 and N, wherein R16 is selected from hydrogen, halo, cyano and C _1-4 alkyl;

(76a) A5 is selected from CR16 and N, wherein R16 is selected from hydrogen, halo, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _1-4 haloalkoxy and C3-4cycloalkoxy;

(76b) A5 is selected from CR16 and N, wherein R16 is selected from hydrogen, halo, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl and C _1-4 haloalkoxy;

(76c) A5 is selected from CR16 and N, wherein R16 is selected from hydrogen, halo, cyano and C _1-4 alkoxy;

(77) A5 is CH;

(78) A6 is selected from CR17 and N, wherein R17 is selected from hydrogen, halo, cyano, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl and a 5- or 6-membered heteroaryl;

(78a) A ₆ is selected from CR ₁₇ and N, wherein R ₁₇ is selected from hydrogen, halo, cyano, C _1-5 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _2-4 alkenyl, C _2-4 alkynyl, phenyl, a 5- or 6-membered or heteroaryl, C _3-6 cycloalkyl, -O-C _3-6 cycloalkyl, heterocyclyl, -O- heterocyclyl (carbon-linked), -(OCH ₂ CH ₂ ) _m -OCH ₃ wherein m is an integer from 1 to 6, NR _q R _r ,

wherein R _q and R _r are each independently hydrogen, C _1-5 alkyl, C _3-6 cycloalkyl, a 3- to 6- membered carbon-linked heterocyclyl, wherein C _1-5 alkyl, C _3-6 cycloalkyl, a 3- to 6- membered carbon-linked heterocyclyl may be optionally substituted by one or more substituents selected from C _1-2 alkyl, cyano, C _1-2 haloalkyl, hydroxy, C _1-2 alkoxy, halo, C _1-2 haloalkoxy, NR _1ea R _1fa or -S(O) _0-2 R _1ea R _1fa , wherein R _1ea and R _1fa are H or C _1-2 alkyl;

or R _q and R _r are linked together such that, together with the nitrogen atom to which they are attached, they form a 3- to 6-membered heterocyclic ring which may be optionally substituted by one or more substituents selected from C _1-2 alkyl, cyano, C _1-2 haloalkyl, hydroxy, C _1-2 alkoxy, halo, C _1-2 haloalkoxy; wherein any C _1-5 alkyl, C _1-4 alkoxy, C _2-4 alkenyl, C _2-4 alkynyl , phenyl, 5- or 6-membered or heteroaryl, C _3-6 cycloalkyl, -O-C _3-6 cycloalkyl, heterocyclyl or -O-heterocyclyl (carbon- linked) is optionally further subsitutued by one or more substituents selected from C1- 2alkyl, cyano, C _1-2 haloalkyl, hydroxy, C _1-2 alkoxy, halo, C _1-2 haloalkoxy, NR1eaR1fa or - S(O) _0-2 R1eaR1fa, wherein R1ea and R1fa are H or C _1-2 alkyl. (78b) A6 is selected from CR17 and N, wherein R17 is selected from hydrogen, halo, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _2-4 alkenyl, C _2-4 alkynyl, phenyl a 5- or 6-membered or heteroaryl, C _3-6 cycloalkyl, -O-C _3-6 cycloalkyl, heterocyclyl, -O- heterocyclyl (carbon-linked), -(OCH2CH2)m-OCH3 wherein m is an integer from 1 to 6, NRqRr, wherein Rq and Rr are each independently hydrogen, C _1-2 alkyl or Rq and Rr are linked together such that, together with the nitrogen atom to which they are attached, they form a 3- to 6-membered heterocyclic ring;

wherein any C1- alkyl, C _2-4 alkenyl, C _2-4 alkynyl, phenyl, 5- or 6-membered or heteroaryl, C _3-6 cycloalkyl, -O-C _3-6 cycloalkyl, heterocyclyl or -O-heterocyclyl (carbon- linked) is optionally further substituted by one or more substituents selected from C1- 2alkyl, cyano, C _1-2 haloalkyl, hydroxy, C _1-2 alkoxy, halo, C _1-2 haloalkoxy, NR1eaR1fa or - S(O) _0-2 R1eaR1fa, wherein R1ea and R1fa are H or C _1-2 alkyl. (78c) A6 is selected from CR17 and N, wherein R17 is selected from hydrogen, halo, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _2-4 alkenyl, C _2-4 alkynyl, phenyl, a 5- or 6-membered heteroaryl, C _3-6 cycloalkyl, -O-C _3-6 cycloalkyl, heterocyclyl, -O- heterocyclyl (carbon-linked), -(OCH ₂ CH ₂ ) _m -OCH ₃ wherein m is 1, 2 or 3, NR _q R _r , wherein R _q and R _r are each independently hydrogen, C _1-4 alkyl; or R _q and R _r are linked together such that, together with the nitrogen atom to which they are attached, they form a 3- to 6-membered heterocyclic ring;

wherein any C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, phenyl, 5- or 6-membered or heteroaryl, C _{3- 6} cycloalkyl, -O-C _3-6 cycloalkyl, heterocyclyl or -O-heterocyclyl (carbon-linked) is optionally further substituted by one or more substituents selected from C _1-2 alkyl, C _{1- 2} haloalkyl, cyano, hydroxy, C _1-2 alkoxy, halo and C _1-2 haloalkoxy. (78d) A ₆ is selected from CR ₁₇ and N, wherein R ₁₇ is selected from selected from hydrogen, halo, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, -O-C _3-4 cycloalkyl, heterocyclyl, -(OCH ₂ CH ₂ ) _m -OCH ₃ wherein m is 1, 2 or 3, NR _q R _r , wherein R _q and R _r are each independently hydrogen or C _1-2 alkyl;

wherein any C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, -O-C _3-4 cycloalkyl,

heterocyclyl, system is optionally further substituted by one or more substituents selected from C _1-2 alkyl, C _1-2 haloalkyl, cyano, hydroxy, C _1-2 alkoxy, halo and C _1-2- haloalkoxy.

(79) A6 is CR17, wherein R17 is selected from hydrogen, halo, C _2-4 alkynyl and 5- or 6- membered heteroaryl;

(79a) A6 is CR17, wherein R17 is selected from hydrogen, halo, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _2-4 alkynyl and 5- or 6-membered heteroaryl;

(79b) A6 is CR17, wherein R17 is selected from hydrogen, halo, C _1-4 alkoxy or C _1-4

haloalkoxy; (80) A6 is CR17, wherein R17 is selected from hydrogen, bromo, ethynyl, and pyrazolyl; (80a) A6 is CR17, wherein R17 is selected from hydrogen, methoxy, bromo, ethynyl, and pyrazolyl; (81) A5 is CH and A6 is CR17, wherein R17 is selected from hydrogen, halo, C _2-4 alkynyl and 5- or 6-membered heteroaryl;

(82) R9, R10 and R11 are independently selected from hydrogen, NH2, halo, cyano, and C _1-6 alkyl;

(82a) R9, R9a, R10 and R11 are independently selected from hydrogen, NH2, halo, cyano, and C _1-6 alkyl

(82c) R9, R10 and R11 are independently selected from hydrogen, NH2, halo, cyano, and C _1-6 alkyl; and R9a is hydrogen; (83) R ₉ and R ₁₀ may be linked together to form a fused 5- or 6-membered saturated or unsaturated ring system or R ₁₀ and R ₁₁ may be linked together to form a fused 5- or 6-membered saturated or unsaturated ring system;

(83a) R ₉ and R ₁₀ may be linked together to form a fused 5- or 6-membered saturated or unsaturated ring system or R ₁₀ and R ₁₁ may be linked together to form a fused 5- or 6-membered saturated or unsaturated ring system; wherein either of the fused 5- or 6-membered saturated or unsaturated ring system may be optionally subsitutued by one or more substituents selected from C _1-2 alkyl, cyano, C _1-2 haloalkyl, hydroxy, C _{1- 2} alkoxy, halo, C _1-2 haloalkoxy, NR _1ia R _1ja or -S(O) _0-2 R _1ia R _1ja , wherein R _1ia and R _1ja are H or C _1-2 alky;

(84) A ₇ is selected from CR ₁₈ and N, wherein R ₁₈ is selected from hydrogen, halo, cyano, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl and a 5- or 6-membered heteroaryl;

(85a) A ₇ is selected from CR ₁₈ and N, wherein R ₁₈ is selected from hydrogen, halo, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _1-4 haloalkoxy and C _3-4 cycloalkoxy;

(85b) A ₇ is selected from CR ₁₈ and N, wherein R ₁₈ is selected from hydrogen, halo, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl and C _1-4 haloalkoxy;

(85c) A7 is selected from CR18 and N, wherein R18 is selected from hydrogen, halo, cyano and C _1-4 alkoxy;

(85) A7 is CH;

(86) R4a is selected from hydrogen, halo and methyl;

(86a) R4a is selected from hydrogen and methyl; (87) R4a is hydrogen;

(88) R5a is selected from hydrogen and halo;

(89) R5a is hydrogen;

(90) R6a is selected from hydrogen, halo and methyl;

(91) R6a is hydrogen;

(92) R4a, R5a and R6a are hydrogen;

(93) A8 is selected from CR19R20 and NR21, wherein R19 and R20 are selected from

hydrogen, halo, cyano and C _1-4 alkyl, and R21 is hydrogen;

(94) A9 is selected from CR22R23 and NR24, wherein R22 and R23 are selected from

hydrogen, halo, cyano and methyl, and R24 is hydrogen;

(95) R5b is selected from hydrogen and halo;

(96) R5b is hydrogen;

(96a) R _5c is selected from hydrogen and halo; (96b) R _5c is hydrogen;

(97) R _7a is selected from hydrogen, halo and methyl;

(97a) R _7a is selected from hydrogen and methyl; (98) R _7a is hydrogen;

(99) R _8a is selected from hydrogen, halo and methyl;

(100) R _8a is hydrogen;

(101) R _5b , R _7a and R _8a are hydrogen;

(102) A ₁₀ is selected from CR ₂₅ R ₂₆ and NR ₂₇ , wherein R ₂₅ and R ₂₆ are selected from

hydrogen, halo, cyano and C _1-4 alkyl, and R ₂₇ is hydrogen;

(103) A ₁₁ is selected from CR ₂₈ R ₂₉ and NR ₃₀ , wherein R ₂₈ and R ₂₉ are selected from

hydrogen, methoxy and methyl, and R ₃₀ is hydrogen;

(104a) R _Z1 and R _Z1a are selected from hydrogen, C _1-4 alkyl, cyano, halo, C _1-4 haloalkyl, C _{1- 4} haloalkoxy, C _1-4 alkoxy, C _3-6 cycloalkyl and -O-C _3-6 cycloalkyl, wherein C _3-6 cycloalkyl and -O-C _3-6 cycloalkyl are optionally subsitutued by one or more of halo, methyl or methoxy;

(104b) RZ1 and RZ1a are selected from selected from hydrogen, C _1-2 alkyl, cyano, halo, C1- 2haloalkyl, C _1-2 haloalkoxy, C _1-2 alkoxy;

(104c) RZ1 and RZ1a are selected from selected from hydrogen, C _1-2 alkyl, cyano and halo; (104d) RZ1 and RZ1a are hydrogen;

(104e) RZ2 and RZ2a are selected from hydrogen, C _1-4 alkyl, cyano, halo or C _1-4 alkoxy; (104f) RZ2 and RZ2a are selected from hydrogen, cyano or halo;

(104g) RZ2 and RZ2a are hydrogen; (104h) RZ3a is selected from hydrogen, C _1-4 alkyl, cyano, halo or C _1-4 alkoxy;

(104i) RZ3a is selected from from hydrogen, cyano or halo;

(104j) RZ3a is hydrogen;

(104k) Z is selected from: wherein R4, R4a, R5, R5a, R5b, R5c, R6, R6a, R7, R7a, R8, R8a, RZ1, RZ1a, RZ2, RZ2a, RZ3a, A1, A2, A3, A4, A5, A6, A7, A8, A9, A10 and A11 are as herein defined.

(104) Z is wherein R _4, R ₅ , R ₆ , A ₁ and A ₂ are as herein defined;

(105) Z is wherein R7, R8, A3 and A4 are as herein defined;

(105a) Z is wherein R5c, R7, R8, A3 and A4 are as herein defined (106) Z is wherein A5 and A6 are as herein defined;

(106a) Z is wherein R _Z1 , R _Z2 , A ₅ and A ₆ are as herein defined; (107) Z is wherein R ₉ , R ₁₀ and R ₁₁ are as herein defined; (107a) Z is wherein R ₉ , R _9a , R ₁₀ and R ₁₁ are as herein defined;

(108) Z is wherein A7 is as herein defined;

(108a) Z is wherein RZ1a, RZ2a, RZ3a and A7 is as herein defined;

(109) Z is wherein R _4a , R _5a , R _6a , A ₈ and A ₉ are as herein defined;

(110) Z is wherein R5b, R7a, R8a, A10 and A11 are as herein

defin ed;

(111) Z is selected from:

(111a) Z is selected from:

, . (111b) Z is selected from:

[0093] Suitably, a heteroaryl or heterocyclyl group as defined herein is a monocyclic heteroaryl or heterocyclyl group comprising one, two or three heteroatoms selected from N, O or S.

[0094] Suitably, a heteroaryl is a 5- or 6-membered heteroaryl ring comprising one, two or three heteroatoms selected from N, O or S.

[0095] Suitably, a heterocyclyl group is a 4-, 5- or 6-membered heterocyclyl ring comprising one, two or three heteroatoms selected from N, O or S. Most suitably, a heterocyclyl group is a 5- or 6-membered ring comprising one, two or three heteroatoms selected from N, O or S [e.g. morpholinyl (e.g. 4-morpholinyl), oxetane, methyloxetane (e.g. 3-methyloxetane), pyrrolidinone (e.g. pyrrolidin-2-one)].

[0096] Suitably, an aryl group is phenyl.

[0097] Suitably, X is as defined in any one of paragraphs (20) to (24) above. Most suitably, X is as defined in paragraph (20).

[0098] Suitably, X is as defined in any one of paragraphs (20) to (24a) above. Most suitably, X is as defined in paragraph (20) or (24a).

[0099] Suitably, R1a, R1c and R1e are as defined in any one of paragraphs (1) to (6) above. Most suitably, R1a, R1c and R1e are as defined in paragraph (6).

[00100] Suitably, R1b, R1d and R1f are as defined in any one of paragraphs (1), (2), and from paragraphs (7) to (15) above. Most suitably, R1b, R1d and R1f are as defined in paragraph (15). [00101] Suitably, R _1b , R _1d and R _1f are as defined in any one of paragraphs (1), (2), and from paragraphs (6a) to (15a) above. Most suitably, R _1b , R _1d and R _1f are as defined in paragraph (15a).

[00102] Suitably, R _1b , R _1d and R _1f are as defined in any one of paragraphs (14a) to (15c) above. Suitably, R _1b , R _1d and R _1f are as defined in any one of paragraphs (14d) to (15c). Suitably, R _1b , R _1d and R _1f are as defined in paragraph (15c).

[00103] Suitably, R _1b , R _1d and R _1f are as defined in any one of paragraphs (14a) to (15g) above. Suitably, R _1b , R _1d and R _1f are as defined in any one of paragraphs (14a) to (14g). Suitably, R _1b , R _1d and R _1f are as defined in any one of paragraphs (15d) to (15g). Most suitably, R _1b , R _1d and R _1f are as defined in paragraph (15g).

[00104] Suitably, R _1a’ is as defined in paragraphs (16) and (17) above. Most suitably, R _1a’ is as defined in paragraph (17) above.

[00105] Suitably, R _2a , R _2b and R _2c are as defined in any one of paragraphs (18) and (19) above. Most suitably, R _2a , R _2b and R _2c are as defined in paragraph (19).

[00106] Suitably, Y is as defined in any one of paragraphs (34) to (52) above. Suitably, Y is as defined in paragraphs (34), (34a), (36), (39), (40), (43) and (50c). Suitably, Y is as defined in paragraphs (34a) or (43) above. Most suitably, Y is as defined in paragraph (52a)

[00107] Suitably, n is as defined in any one of paragraphs (32) and (33) above. Most suitably, n is as defined in paragraph (33).

[00108] Suitably, R3a1, R3b1, R3c1, R3d1, R3e1, R3f1, R3g1, R3h1, R3i1, R3j1, R3k1, R3l1, R3m1, R3n1 and R3o1 are as defined in any one of paragraphs (25) to (28), and paragraphs (30) to (31) above. Most suitably, R3a1, R3b1, R3c1, R3d1, R3e1, R3f1, R3g1, R3h1, R3i1, R3j1, R3k1, R3l1, R3m1, R3n1 and R3o1 are as defined in paragraph (28).

[00109] Suitably, R3a2, R3b2, R3c2, R3d2, R3e2, R3f2, R3g2, R3h2, R3i2, R3j2, R3k2, R3l2, R3m2, R3n2 and R3o2 are as defined in any one of paragraphs (25), (29), (30) and (31) above. Most suitably, R3a2, R3b2, R3c2, R3d2, R3e2, R3f2, R3g2, R3h2, R3i2, R3j2, R3k2, R3l2, R3m2, R3n2 and R3o2 are as defined in paragraph (29).

[00110] Suitably, R3a1, R3b1, R3c1, R3d1, R3e1, R3f1, R3g1, R3h1, R3i1, R3j1, R3k1, R3l1, R3m1, R3n1, R3o1, R3p1 and R3q1 are as defined in any one of paragraphs (25) to (28a), and paragraphs (30) to (31a) above. Most suitably, R3a1, R3b1, R3c1, R3d1, R3e1, R3f1, R3g1, R3h1, R3i1, R3j1, R3k1, R3l1, R3m1, R3n1, R3o1, R3p1 and R3q1 are as defined in paragraph (28a).

[00111] Suitably, R3a2,R3b2, R3c2, R3d2, R3e2, R3f2, R3g2, R3h2, R3i2, R3j2, R3k2, R3l2, R3m2, R3n2, R3o2, R3p2 and R3q2 are as defined in any one of paragraphs (25), (25a), (29), (29a) (30), (30a), (31) and (31a) above. Most suitably, R _3a2 , R _3b2 , R _3c2 , R _3a2 , R _3b2 , R _3c2 , R _3d2 , R _3e2 , R _3f2 , R _3g2 , R _3h2 , R _3i2 , R _3j2 , R _3k2 , R _3l2 , R _3m2 , R _3n2, R _3o2, R _3p2 and R _3q2 are as defined in paragraph (29a).

[00112] Suitably, R _3a1 , R _3b1 , R _3c1 , R _3d1 , R _3e1 , R _3f1 , R _3g1 , R _3h1 , R _3i1 , R _3j1 , R _3k1 , R _3l1 , R _3m1 , R _3n1 , R _3o1 , R _3p1, R _3q1 , R _3r1 and R _3s1 are as defined in any one of paragraphs (25) to (28b), and paragraphs (30a) to (31b) above. Most suitably, R _3a1 , R _3b1 , R _3c1 , R _3d1 , R _3e1 , R _3f1 , R _3g1 , R _3h1 , R _3i1 , R _3j1 , R _3k1 , R _3l1 , R _3m1 , R _3n1 , R _3o1 , R _3p1, R _3q1 , R _3r1 and R _3s1 are as defined in paragraph (28b).

[00113] Suitably, R _3a2 ,R _3b2 , R _3c2 , R _3d2 , R _3e2 , R _3f2 , R _3g2 , R _3h2 , R _3i2 , R _3j2 , R _3k2 , R _3l2 , R _3m2 , R _3n2, R _3o2, R _3p2 , R _3q2 , R _3r2 and R _3s2 are as defined in any one of paragraphs (25), (25a), (25b), (29), (29a), (29b), (30), (30a), (30b), (31), (31a) and (31b) above. Most suitably, R _3a2 , R _3b2 , R _3c2 , R _3d2 , R _3e2 , R _3f2 , R _3g2 , R _3h2 , R _3i2 , R _3j2 , R _3k2 , R _3l2 , R _3m2 , R _3n2, R _3o2, R _3p2 , R _3q2 , R _3r2 and R _3s2 are as defined in paragraph (29b).

[00114] Suitably, Z is as defined in any one of paragraphs from (104k) and (104) to (111b) above. Suitably, Z is as defined in any one of paragraphs from (104) to (111a) above. Suitably, Z is as defined in any one of paragraphs from (104) to (111) above. Suitably, Z is as defined in any one of paragraphs (104) to (106a). Suitably, Z is as defined in paragraphs (104), (105a) and (106a). Most suitably, Z is as defined in any one of paragraphs (104) to (106). Most suitably, Z is as defined in paragraph (111b) above.

[00115] Suitably, R4 is as defined in any one of paragraphs (53), (54) and (59) above. Most suitably, R4 is as defined in paragraph (54).

[00116] Suitably, R5 is as defined in any one of paragraphs (55), (56) and (59) above. Most suitably, R5 is as defined in paragraph (56).

[00117] Suitably, R6 is as defined in any one of paragraphs (57), (58) and (59) above. Most suitably, R6 is as defined in paragraph (58).

[00118] Suitably, A1 is as defined in any one of paragraphs (60), (61) and (64) above. Most suitably, A1 is as defined in paragraph (61).

[00119] Suitably, A2 is as defined in any one of paragraphs (62), (63) and (64) above. Most suitably, A1 is as defined in paragraph (63).

[00120] Suitably, R7 is as defined in any one of paragraphs (65), (66) and (69) above. Most suitably, R7 is as defined in paragraph (66).

[00121] Suitably, R8 is as defined in any one of paragraphs (67), (68) and (69) above. Most suitably, R8 is as defined in paragraph (68).

[00122] Suitably, A3 is as defined in any one of paragraphs (70), (71), (72) and (75) above. Most suitably, A3 is as defined in paragraph (71). [00123] Suitably, A ₄ is as defined in any one of paragraphs (73), (74) and (75) above. Most suitably, A ₄ is as defined in paragraph (74).

[00124] Suitably, A ₅ is as defined in any one of paragraphs (76), (76a), (76b), (76c), (77) and (81) above. Suitably, A ₅ is as defined in any one of paragraphs (76), (77) and (81) above. Most suitably, A ₅ is as defined in paragraph (77).

[00125] Suitably, A ₆ is as defined in any one of paragraphs from (78) to (81) above. Suitably, A ₆ is as defined in paragraph (79). Suitably, A ₆ is as defined in paragraphs (78a), (78b), (78c), (79a) and (79b). Most suitably, A ₆ is as defined in paragraph (79b).

[00126] Suitably, R ₉ , R ₁₀ and R ₁₁ are as defined in any one of paragraphs (82) to (83a). Suitably, R ₉ , R ₁₀ and R ₁₁ are as defined in paragraphs (82) and (83).

[00127] Suitably, A ₇ is as defined in any one of paragraphs (84) to (85c) above. Suitably, A ₇ is as defined in any one of paragraphs (84) to (85) above.

[00128] Suitably R _4a is as defined in any one of paragraphs (86), (86a), (87) and (92) above. Most suitably, R _4a is as defnied in paragraph (87).

[00129] Suitably R _5a is as defined in any one of paragraphs (88), (89) and (92) above. Most suitably, R5a is as defnied in paragraph (89).

[00130] Suitably R6a is as defined in any one of paragraphs (90) to (92) above. Most suitably, R6a is as defnied in paragraph (91).

[00131] Suitably A8 is as defined in any one of paragraphs (93) above.

[00132] Suitably A9 is as defined in any one of paragraphs (94) above.

[00133] Suitably R5b is as defined in any one of paragraphs (95) and (96) above. Most suitably, R5b is as defnied in paragraph (96).

[00134] Suitably R7a is as defined in any one of paragraphs (97), (97a) and (98) above. Most suitably, R7a is as defnied in paragraph (98).

[00135] Suitably R8a is as defined in any one of paragraphs (99) and (100) above. Most suitably, R8a is as defnied in paragraph (100).

[00136] Suitably A10 is as defined in any one of paragraphs (102) above.

[00137] Suitably A11 is as defined in any one of paragraphs (103) above.

[00138] Suitably, RZ1 and RZ1a are as defined in any one of paragraphs (104a) to (104d) above. Most suitably, RZ1 and RZ1a are as defined in paragraph (104d).

[00139] Suitably, RZ2 and RZ2a are as defined in any one of paragraphs (104e) to (104g) above. Most suitably, RZ2 and RZ2a are as defined in paragraph (104g). [00140] Suitably, R _Z3a is as defined in any one of paragraphs (104h) to (104j) above. Most suitably, R _Z3a is as defined in paragraph (104j).

[00141] In a particular group of compounds of the invention, Y is as defined in paragraph (34), i.e. the compounds have the structural formula (II) (a sub-definition of formula (1)) shown below:

wherein X, R _3a1 , R _3a2 , n and Z each having any one of the meanings defined herein; or a pharmaceutically acceptable salt thereof.

[00142] In an embodiment of the compounds of formula (II):

X is as defined in any one of paragraphs (20) to (24) above, suitably X is as defined in paragraph (24a);

R _3a1 is as defined in any one of paragraphs from (25) to (28), and paragraphs (30) and (31) above;

R _3a2 is as defined in any one of paragraphs (25), (29), (30) and (31) above;

n is as defined in any one of paragraphs (32) and (33) above; and

Z is as defined in any one of paragraphs (104) to (111b) above. Suitably, Z is as defined in any one of paragraphs (104) to (111) above.

[00143] In an embodiment of the compounds of formula (II):

X is as defined in paragraph (20) above;

R _3a1 is as defined in paragraph (28) above;

R3a2 is as defined in paragraph (29) above;

n is as defined in paragraph (33) above; and

Z is as defined in any one of paragraphs (104) to (106) above.

[00144] In a particular group of the compounds of formula (II):

X is as defined in paragraph (20), (21) or (22) above and R1b, R1d and R1f are each as defined in any one of paragraphs (8a) to (8e) above;

R3a1 is as defined in paragraph (28) above; R _3a2 is as defined in paragraph (29) above;

n is as defined in paragraph (33) above; and

Z is as defined in any one of paragraphs (104) to (106) above.

[00145] In a particular group of the compounds of formula (II):

X is as defined in paragraph (20) above and R _1b is as defined in any one of paragraphs (14a) to (14g) above; suitably R _1b is as defined in any one of paragraphs (14a) to (15g) above. Suitably, R _1b , is as defined in any one of paragraphs (15d) to (15g). Most suitably, R _1b is as defined in paragraph (15g);

R _3a1 is as defined in paragraph (28) above;

R _3a2 is as defined in paragraph (29) above;

n is as defined in paragraph (33) above; and

Z is as defined in any one of paragraphs (104) to (106) above.

[00146] In a particular group of the compounds of formula (II):

X is as defined in paragraph (20) above and R _1b is as defined in any one of paragraphs (8a) to (8e) above;

R3a1 is as defined in paragraph (28) above;

R3a2 is as defined in paragraph (29) above;

n is as defined in paragraph (33) above; and

Z is as defined in any one of paragraphs (104) to (106) above.

[00147] In a particular group of compounds of the invention, Y is as defined in paragraph (36), i.e. the compounds have the structural formula (III) (a sub-definition of formula (1)) shown below:

wherein X, R3b1, R3b2, n and Z each having any one of the meanings defined herein; or a pharmaceutically acceptable salt thereof.

[00148] In an embodiment of the compounds of formula (III):

X is as defined in any one of paragraphs (20) to (24) above; R _3b1 is as defined in any one of paragraphs from (25) to (28), and paragraphs (30) and (31) above;

R _3b2 is as defined in any one of paragraphs (25), (29), (30) and (31) above;

n is as defined in any one of paragraphs (32) and (33) above; and

Z is as defined in any one of paragraphs (104) to (111) above.

[00149] In an embodiment of the compounds of formula (III):

X is as defined in paragraph (20) above;

R _3b1 is as defined in paragraph (28) above;

R _3b2 is as defined in paragraph (29) above;

n is as defined in paragraph (33) above; and

Z is as defined in any one of paragraphs (104) to (106) above.

[00150] In a particular group of the compounds of formula (III):

X is as defined in paragraph (20), (21) or (22) above and R _1b , R _1d and R _1f are each as defined in any one of paragraphs (8a) to (8e) above;

R _3a1 is as defined in paragraph (28) above;

R3a2 is as defined in paragraph (29) above;

n is as defined in paragraph (33) above; and

Z is as defined in any one of paragraphs (104) to (106) above.

[00151] In a particular group of the compounds of formula (III):

X is as defined in paragraph (20) above and R1b is as defined in any one of paragraphs (8a) to (8e) above;

R3a1 is as defined in paragraph (28) above;

R3a2 is as defined in paragraph (29) above;

n is as defined in paragraph (33) above; and

Z is as defined in any one of paragraphs (104) to (106) above.

[00152] In a particular group of compounds of the invention, X is as defined in paragraph (20), i.e. the compounds have the structural formula (IV) (a sub-definition of formula (I)) shown below:

wherein R _1a , R _1b , R _1a’, R _2a , Y and Z each having any one of the meanings defined herein; or a pharmaceutically acceptable salt thereof.

[00153] In an embodiment of the compounds of formula (IV):

R _1a is as defined in any one of paragraphs (1) to (6) above;

R _1b is as defined in any one of paragraphs (1), (2), from paragraphs (7) to (15a) above; R _1a’ is as defined in paragraphs (16) and (17) above;

R _2a is as defined in any one of paragraphs (18) to (19) above;

Y is as defined in any one of paragraphs (34) to (52); and

Z is as defined in any one of paragraphs (104) to (111) above.

[00154] In an embodiment of the compounds of formula (IV):

R _1a is as defined in any one of paragraphs (1) to (6) above;

R _1b is as defined in any one of paragraphs (14a) to (14g) above;

R _1a’ is as defined in paragraphs (16) and (17) above;

R _2a is as defined in any one of paragraphs (18) to (19) above;

Y is as defined in any one of paragraphs (34) to (52); and

Z is as defined in any one of paragraphs (104) to (111) above.

[00155] In an embodiment of the compounds of formula (IV):

R1a is as defined in paragraph (6) above;

R1b is as defined in paragraph (15) or (15a) above;

R1a’ is as defined in paragraph (17) above;

R2a is as defined in paragraph (19) above;

Y is as defined in paragraphs (34), (36), (39) and (40) above; and

Z is as defined in any one of paragraphs (104) to (106) above. [00156] In a particular group of the compounds of formula (IV):

R _1a is as defined in any one of paragraphs (1) to (6) above;

R _1b is as defined in any one of paragraphs (8a) to (8e) or (15a) above;

R _1a’ is as defined in paragraphs (16) and (17) above;

R _2a is as defined in any one of paragraphs (18) to (19) above;

Y is as defined in any one of paragraphs (34) to (52); and

Z is as defined in any one of paragraphs (104) to (111) above.

[00157] In a particular group of the compounds of formula (IV):

R _1a is as defined in paragraph (6) above;

R _1b is as defined in paragraph (8e) or (15a) above;

R _1a’ is as defined in paragraph (17) above;

R _2a is as defined in paragraph (19) above;

Y is as defined in paragraphs (34), (36), (39) and (40) above; and

Z is as defined in any one of paragraphs (104) to (111b) above.

[00158] In an embodiment of the compounds of formula (IV):

R1a is as defined in paragraph (6) above;

R1b is as defined in any one of paragraphs (14a) to (14g) above; more suitably R1b is as defined in paragraphs (15a) to (15g) above;

R1a’ is as defined in paragraph (17) above;

R2a is as defined in paragraph (19) above;

Y is as defined in any one of paragraphs (34) to (52a); and

Z is as defined in any one of paragraphs (104) to (111b) above.

[00159] In a particular group of the compounds of formula (IV):

R1a is as defined in any one of paragraphs (1) to (6) above;

R1b is as defined in any one of paragraphs (15d), (15e), (15f) or (15g) above;

R1a’ is as defined in paragraphs (16) and (17) above;

R2a is as defined in any one of paragraphs (18) to (19) above;

Y is as defined in any one of paragraphs (34), (34a), (36), (39) and (40) above; and Z is as defined in any one of paragraphs (104) to (111b) above.

[00160] In a particular group of the compounds of formula (IV):

R _1a is as defined in paragraph (6) above;

R _1b is as defined in paragraph (15g) above;

R _1a’ is as defined in paragraph (17) above;

R _2a is as defined in paragraph (19) above;

Y is as defined in any one of paragraphs (34), (36), (39) and (40) above; more suitably Y is as defined in paragraph (52a) above; and

Z is as defined in any one of paragraphs (111) to (111b) above; more suitably Z is as defined in paragraph (111b) above.

[00161] In a particular group of compounds of the invention, X is as defined in paragraph (20) and Y is as defined in paragraph (34), i.e. the compounds have the structural formula (V) (a sub-definition of formula (I)) shown below:

wherein R _1a , R _1b , R _1a’ , R _2a , R _3a1 , R _3a2 , n and Z each having any one of the meanings defined herein; or a pharmaceutically acceptable salt thereof.

[00162] In an embodiment of the compounds of formula (V):

R _1a is as defined in any one of paragraphs (1) to (6) above;

R _1b is as defined in any one of paragraphs (1), (2), and from paragraphs (7) to (15g) above; R _1a’ is as defined in paragraphs (16) and (17) above;

R _2a is as defined in any one of paragraphs (18) to (19) above;

R _3a1 is as defined in any one of paragraphs from (25) to (28), and paragraphs (30) and (31) above;

R _3a2 is as defined in any one of paragraphs (25), (29), (30) and (31) above; n is as defined in any one of paragraphs (32) and (33) above; and

Z is as defined in any one of paragraphs (104) to (111) above.

[00163] In an embodiment of the compounds of formula (V):

R _1a is as defined in paragraph (6) above;

R _1b is as defined in paragraph (15) or (15a) above;

R _1a’ is as defined in paragraph (17) above;

R _2a is as defined in paragraph (19) above;

R _3a1 is as defined in paragraph (28) above;

R _3a2 is as defined in paragraph (29) above;

n is as defined in paragraph (33) above; and

Z is as defined in any one of paragraphs (104) to (106) above.

[00164] In a particular group of the compounds of formula (V):

R _1a is as defined in any one of paragraphs (1) to (6) above;

R _1b is as defined in any one of paragraphs (8a) to (8e) or (15a) above;

R _1a’ is as defined in paragraphs (16) and (17) above;

R2a is as defined in any one of paragraphs (18) to (19) above;

R3a1 is as defined in any one of paragraphs from (25) to (28), and paragraphs (30) and (31) above;

R3a2 is as defined in any one of paragraphs (25), (29), (30) and (31) above;

n is as defined in any one of paragraphs (32) and (33) above; and

Z is as defined in any one of paragraphs (104) to (111) above.

[00165] In a particular group of the compounds of formula (V):

R1a is as defined in paragraph (6) above;

R1b is as defined in paragraph (8e) or (15a) above;

R1a’ is as defined in paragraph (17) above;

R2a is as defined in paragraph (19) above;

R3a1 is as defined in paragraph (28) above;

R3a2 is as defined in paragraph (29) above; n is as defined in paragraph (33) above; and

Z is as defined in any one of paragraphs (104) to (106) above.

[00166] In an embodiment of the compounds of formula (V):

R _1a is as defined in paragraph (6) above;

R _1b is as defined in paragraph (15g) above;

R _1a’ is as defined in paragraph (17) above;

R _2a is as defined in paragraph (19) above;

R _3a1 is as defined in paragraph (28) above;

R _3a2 is as defined in paragraph (29) above;

n is as defined in paragraph (33) above; and

Z is as defined in any one of paragraphs (104k) and (104) to (106) above.

[00167] In a particular group of the compounds of formula (V):

R _1a is as defined in any one of paragraphs (1) to (6) above;

R _1b is as defined in any one of paragraphs (15g) above;

R _1a’ is as defined in paragraphs (16) and (17) above;

R2a is as defined in any one of paragraphs (18) to (19) above;

R3a1 is as defined in any one of paragraphs from (25) to (28), and paragraphs (30) and (31) above;

R3a2 is as defined in any one of paragraphs (25), (29), (30) and (31) above;

n is as defined in any one of paragraphs (32) and (33) above; and

Z is as defined in any one of paragraphs (104k) and (104) to (111) above.

[00168] In a particular group of the compounds of formula (V):

R1a is as defined in paragraph (6) above;

R1b is as defined in paragraph (15g) above;

R1a’ is as defined in paragraph (17) above;

R2a is as defined in paragraph (19) above;

R3a1 is as defined in paragraph (28) above;

R3a2 is as defined in paragraph (29) above; n is as defined in paragraph (33) above; and

Z is as defined in paragraph (111b) above.

[00169] In a particular group of compounds of the invention, X is as defined in paragraph (20), R _1a’ is as defined in paragraph (17) and Y is as defined in paragraph (36), i.e. the compounds have the structural formula (VI) (a sub-definition of formula (I)) shown below:

wherein R1a, R1b, R2a, R3b1, R3b2, n and Z each having any one of the meanings defined herein; or a pharmaceutically acceptable salt thereof.

[00170] In an embodiment of the compounds of formula (VI):

R _1a is as defined in any one of paragraphs (1) to (6) above;

R _1b is as defined in any one of paragraphs (1), (2), and paragraphs (7) to (15g) above;

R _2a is as defined in any one of paragraphs (18) to (19) above;

R _3b1 is as defined in any one of paragraphs from (25) to (28) and paragraphs (30) to (31) above;

R _3b2 is as defined in any one of paragraphs (25), (29), (30) and (31) above;

n is as defined in any one of paragraphs (32) and (33) above; and

Z is as defined in any one of paragraphs (104k) or (104) to (111) above.

[00171] In an embodiment of the compounds of formula (VI):

R _1a is as defined in paragraph (6) above;

R _1b is as defined in paragraph (15) or (15a) above;

R _2a is as defined in paragraph (19) above;

R _3b1 is as defined in paragraph (28) above;

R _3b2 is as defined in paragraph (29) above;

n is as defined in paragraph (33) above; and Z is as defined in any one of paragraphs (104) to (106) above.

[00172] In a particular group of the compounds of formula (VI):

R _1a is as defined in any one of paragraphs (1) to (6) above;

R _1b is as defined in any one of paragraphs (8a) to (8e) or (15a) above;

R _2a is as defined in any one of paragraphs (18) to (19) above;

R _3b1 is as defined in any one of paragraphs from (25) to (28) and paragraphs (30) to (31) above;

R _3b2 is as defined in any one of paragraphs (25), (29), (30) and (31) above;

n is as defined in any one of paragraphs (32) and (33) above; and

Z is as defined in any one of paragraphs (104) to (111b) above.

[00173] In a particular group of the compounds of formula (VI):

R _1a is as defined in paragraph (6) above;

R _1b is as defined in paragraph (8e) or (15a) above;

R _2a is as defined in paragraph (19) above;

R _3b1 is as defined in paragraph (28) above;

R3b2 is as defined in paragraph (29) above;

n is as defined in paragraph (33) above; and

Z is as defined in any one of paragraphs (104) to (106) above.

[00174] In an embodiment of the compounds of formula (VI):

R1a is as defined in paragraph (6) above;

R1b is as defined in paragraph (15) to (15g) above;

R2a is as defined in paragraph (19) above;

R3b1 is as defined in paragraph (28) above;

R3b2 is as defined in paragraph (29) above;

n is as defined in paragraph (33) above; and

Z is as defined in any one of paragraphs (104k), (104) to (106a) and (111) to (111b) above.

[00175] In a particular group of the compounds of formula (VI):

R1a is as defined in any one of paragraphs (1) to (6) above; R _1b is as defined in any one of paragraphs (15) to (15g) above;

R _2a is as defined in any one of paragraphs (18) to (19) above;

R _3b1 is as defined in any one of paragraphs from (25) to (28) and paragraphs (30) to (31) above;

R _3b2 is as defined in any one of paragraphs (25), (29), (30) and (31) above;

n is as defined in any one of paragraphs (32) and (33) above; and

Z is as defined in any one of paragraphs (105) to (106a) and (111b) above.

[00176] In a particular group of the compounds of formula (VI):

R _1a is as defined in paragraph (6) above;

R _1b is as defined in paragraph (15g) above;

R _2a is as defined in paragraph (19) above;

R _3b1 is as defined in paragraph (28) above;

R _3b2 is as defined in paragraph (29) above;

n is as defined in paragraph (33) above; and

Z is as defined in paragraph (111b) above.

[00177] In a particular group of compounds of the invention, Y is as defined in paragraph (34) and Z is defined as paragraph (106), i.e. the compounds have the structural formula (VII) (a sub-definition of formula (I)) shown below:

wherein X, R3a1, R3a2, n, A5 and A6 each having any one of the meanings defined herein; or a pharmaceutically acceptable salt thereof.

[00178] In an embodiment of the compounds of formula (VII):

X is as defined in any one of paragraphs (20) to (24) above;

R3a1 is as defined in any one of paragraphs from (25) to (28), and paragraphs (30) to (31) above; R _3a2 is as defined in any one of paragraphs (25), (29), (30) and (31) above;

n is as defined in any one of paragraphs (32) and (33) above;

A ₅ is as defined in any one of paragraphs (76), (77) and (81) above; and

A ₆ is as defined in any one of paragraphs from (78) to (81) above.

[00179] In an embodiment of the compounds of formula (VII):

X is as defined in paragraph (20) above;

R _3a1 is as defined in paragraph (28) above;

R _3a2 is as defined in paragraph (29) above;

n is as defined in paragraph (33) above;

A ₅ is as defined in paragraph (77) above;

A ₆ is as defined in paragraph (79) above or A ₆ is as defined in paragraph (79a) above.

[00180] In a particular group of the compounds of formula (VII):

X is as defined in any one of paragraphs (20) to (22) above and R _1b , R _1d and R _1f are each as defined in any one of paragraphs (8a) to (8e) above;

R _3a1 is as defined in any one of paragraphs from (25) to (28), and paragraphs (30) to (31) above;

R3a2 is as defined in any one of paragraphs (25), (29), (30) and (31) above;

n is as defined in any one of paragraphs (32) and (33) above;

A5 is as defined in any one of paragraphs (76), (77) and (81) above; and

A6 is as defined in any one of paragraphs from (78) to (81) above.

[00181] In a particular group of the compounds of formula (VII):

X is as defined in paragraph (20) above and R1b is as defined in any one of paragraphs (8a) to (8e) above;

R3a1 is as defined in paragraph (28) above;

R3a2 is as defined in paragraph (29) above;

n is as defined in paragraph (33) above;

A5 is as defined in paragraph (77) above;

A6 is as defined in paragraph (79) above.

[00182] In a particular group of the compounds of formula (VII): X is as defined in paragraph (20) above, R _1a , R _1b , R _1a’ and R _2a are hydrogen, and R _1b is as defined in any one of paragraphs (15e) to (15g) above, suitably R _1b is as defined in paragraph (15g);

R _3a1 is as defined in paragraph (28) above;

R _3a2 is as defined in paragraph (29) above;

n is as defined in paragraph (33) above;

A ₃ is as defined in paragraph (71) above;

A ₄ is as defined in paragraph (74) above;

R ₇ is as defined in paragraph (66) above; and

R ₈ is as defined in paragraph (68) above.

[00183] In a particular group of compounds of the invention, Y is as defined in paragraph (34) and Z is defined as paragraph (105), i.e. the compounds have the structural formula (VIII) (a sub-definition of formula (I)) shown below:

wherein X, R _3a1 , R _3a2 , n, A ₃ , A ₄ , R ₇ and R ₈ each having any one of the meanings defined herein; or a pharmaceutically acceptable salt thereof.

[00184] In an embodiment of the compounds of formula (VIII):

X is as defined in any one of paragraphs (20) to (24) and (24a) above;

R _3a1 is as defined in any one of paragraphs from (25) to (28), and paragraphs (30) to (31) above;

R _3a2 is as defined in any one of paragraphs (25), (29), (30) and (31) above;

n is as defined in any one of paragraphs (32) and (33) above;

A ₃ is as defined in any one of paragraphs (70), (71), (72) and (75) above;

A ₄ is as defined in any one of paragraphs from (73) to (75) above; R ₇ is as defined in any one of paragraphs (65), (66) and (69) above; and

R ₈ is as defined in any one of paragraphs (67), (68) and (69) above.

[00185] In an embodiment of the compounds of formula (VIII):

X is as defined in paragraph (20) above;

R _3a1 is as defined in paragraph (28) above;

R _3a2 is as defined in paragraph (29) above;

n is as defined in paragraph (33) above;

A ₃ is as defined in paragraph (71) above;

A ₄ is as defined in paragraph (74) above;

R ₇ is as defined in paragraph (66) above; and

R ₈ is as defined in paragraph (68) above.

[00186] In a particular group of the compounds of formula (VIII):

X is as defined in any one of paragraphs (20) to (22) above and R _1b , R _1d and R _1f are each as defined in any one of paragraphs (8a) to (8e) above;

R _3a1 is as defined in any one of paragraphs from (25) to (28), and paragraphs (30) to (31) above;

R3a2 is as defined in any one of paragraphs (25), (29), (30) and (31) above;

n is as defined in any one of paragraphs (32) and (33) above;

A3 is as defined in any one of paragraphs (70), (71), (72) and (75) above;

A4 is as defined in any one of paragraphs from (73) to (75) above;

R7 is as defined in any one of paragraphs (65), (66) and (69) above; and

R8 is as defined in any one of paragraphs (67), (68) and (69) above.

[00187] In a particular group of the compounds of formula (VIII):

X is as defined in paragraph (20) above and R1b is as defined in any one of paragraphs (8a) to (8e) above;

R3a1 is as defined in paragraph (28) above;

R3a2 is as defined in paragraph (29) above;

n is as defined in paragraph (33) above;

A3 is as defined in paragraph (71) above; A ₄ is as defined in paragraph (74) above;

R ₇ is as defined in paragraph (66) above; and

R ₈ is as defined in paragraph (68) above.

[00188] In a particular group of the compounds of formula (VIII):

X is as defined in paragraph (20) above, R _1a , R _1b , R _1a’ and R _2a are hydrogen, and R _1b is as defined in any one of paragraphs (15e) to (15g) above, suitably R _1b is as defined in paragraph (15g);

R _3a1 is as defined in paragraph (28) above;

R _3a2 is as defined in paragraph (29) above;

n is as defined in paragraph (33) above;

A ₃ is as defined in paragraph (71) above;

A ₄ is as defined in paragraph (74) above;

R ₇ is as defined in paragraph (66) above; and

R ₈ is as defined in paragraph (68) above.

[00189] Particular compounds of the present invention include any of the compounds exemplified in the present application, or a pharmaceutically acceptable salt thereof, and, in particular, any of the following:

N-({6-methylimidazo[1,2-a]pyridin-2-yl}methyl)-1H-indazol e-4-carboxamide;

N-({7-bromoimidazo[1,2-a]pyridin-2-yl}methyl)-1H-indazole -4-carboxamide;

N-({6-bromoimidazo[1,2-a]pyridin-2-yl}methyl)-1H-indazole -4-carboxamide;

N-({6-chloroimidazo[1,2-a]pyridin-2-yl}methyl)-1H-indazol e-4-carboxamide;

N-({7-fluoroimidazo[1,2-a]pyridin-2-yl}methyl)-1H-indazol e-4-carboxamide;

N-({6-fluoroimidazo[1,2-a]pyridin-2-yl}methyl)-1H-indazol e-4-carboxamide;

N-({7-methoxyimidazo[1,2-a]pyridin-2-yl}methyl)-1H-indazo le-4-carboxamide;

N-({6-methylimidazo[1,2-a]pyridin-2-yl}methyl)-6-(1H-pyra zol-5-yl)-1H-indazole-4- carboxamide;

N-({7-methylimidazo[1,2-a]pyridin-2-yl}methyl)-1H-indazol e-4-carboxamide;

6-bromo-N-({6-methylimidazo[1,2-a]pyridin-2-yl}methyl)-1H -indazole-4-carboxamide;

6-bromo-N-({7-methylimidazo[1,2-a]pyridin-2-yl}methyl)-1H -indazole-4-carboxamide;

N-({6-methylimidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H-c hromene-2-carboxamide;

N-({imidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H-chromene- 2-carboxamide; 6-ethynyl-N-({6-methylimidazo[1,2-a]pyridin-2-yl}methyl)-1H- indazole-4-carboxamide;

N-({6-methylimidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H-p yrido[1,2-a]pyrimidine-2- carboxamide;

N-({7-methylimidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H-c hromene-2-carboxamide;

N-({7-methylimidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H-p yrido[1,2-a]pyrimidine-2- carboxamide;

N-({6-cyanoimidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H-py rido[1,2-a]pyrimidine-2- carboxamide;

8-methoxy-N-({6-methylimidazo[1,2-a]pyridin-2-yl}methyl)- 4-oxo-4H-pyrido[1,2-a]pyrimidine- 2-carboxamide;

N-({6-methylimidazo[1,2-a]pyridin-2-yl}methyl)-1H-indazol e-5-carboxamide;

7-chloro-N-({6-methylimidazo[1,2-a]pyridin-2-yl}methyl)-4 -oxo-4H-pyrido[1,2-a]pyrimidine-2- carboxamide;

N-({6-fluoroimidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H-p yrido[1,2-a]pyrimidine-2- carboxamide;

N-({6-bromoimidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H-py rido[1,2-a]pyrimidine-2- carboxamide;

N-({6-methoxyimidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H- pyrido[1,2-a]pyrimidine-2- carboxamide;

N-({7-methoxyimidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H- pyrido[1,2-a]pyrimidine-2- carboxamide;

N-({imidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H-pyrido[1, 2-a]pyrimidine-2-carboxamide; N-({8-methylimidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H-pyri do[1,2-a]pyrimidine-2- carboxamide;

N-({6-methylimidazo[1,2-a]pyridin-2-yl}methyl)-1H-pyrazol o[4,3-c]pyridine-4-carboxamide; N-({7-bromoimidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H-pyrid o[1,2-a]pyrimidine-2- carboxamide;

N-(2-hydroxy-1-{6-methylimidazo[1,2-a]pyridin-2-yl}ethyl) -1H-indazole-4-carboxamide; 4-(3-{imidazo[1,2-a]pyridin-2-yl}-2,5-dihydro-1H-pyrrole-1-c arbonyl)-1H-indazole;

N-[(6-{[(pyridin-3-yl)methyl]amino}imidazo[1,2-a]pyridin- 2-yl)methyl]-1H-indazole-4- carboxamide;

N-[(6-{[(1-methyl-1H-imidazol-4-yl)methyl]amino}imidazo[1 ,2a]pyridin-2-yl)methyl]-1H- indazole-4-carboxamide;

N-{[6-(3-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl]methyl} -1H-indazole-4-carboxamide; N-{[6-(1H-pyrazol-5-yl)imidazo[1,2-a]pyridin-2-yl]methyl}-1H -indazole-4-carboxamide;

N-[[6-(3-chlorophenyl)imidazo[1,2-a]pyridin-2-yl]methyl]- 1H-indazole-4-carboxamide; N-({6-[(pyridin-3-yl)amino]imidazo[1,2-a]pyridin-2-yl}methyl )-1H-indazole-4-carboxamide; N-({6-[(piperazin-1-yl)methyl]imidazo[1,2-a]pyridin-2-yl}met hyl)-1H-indazole-4-carboxamide; N-{[6-(aminomethyl)imidazo[1,2-a]pyridin-2-yl]methyl}-1H-ind azole-4-carboxamide;

N-{[6-(acetamidomethyl)imidazo[1,2-a]pyridin-2-yl]methyl} -1H-indazole-4-carboxamide; {6-methylimidazo[1,2-a]pyridin-2-yl}methyl 1H-indazole-4-carboxylate;

{6-methylimidazo[1,2-a]pyridin-2-yl}methyl 1H-indazole-4-carboxylate hydrochloride;

N-{[6-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl]methyl}-1 H-indazole-4-carboxamide;

N-({6-hydroxyimidazo[1,2-a]pyridin-2-yl}methyl)-1H-indazo le-4-carboxamide;

N-({6-[(methylamino)methyl]imidazo[1,2-a]pyridin-2-yl}met hyl)-1H-indazole-4-carboxamide; N-({6-[(methylamino)methyl]imidazo[1,2-a]pyridin-2-yl}methyl )-1H-indazole-4-carboxamide dihydrochloride;

N-[(6-{[(2-hydroxyethyl)amino]methyl}imidazo[1,2-a]pyridi n-2-yl)methyl]-1H-indazole-4- carboxamide;

N-[(6-{[(2,2,2-trifluoroethyl)amino]methyl}imidazo[1,2-a] pyridin-2-yl)methyl]-1H-indazole-4- carboxamide;

N-{[6-(1-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl]methyl}- 1H-indazole-4-carboxamide;

N-({6-[hydroxy(phenyl)methyl]imidazo[1,2-a]pyridin-2-yl}m ethyl)-1H-indazole-4-carboxamide; N-({6-formylimidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H-pyri do[1,2-a]pyrimidine-2- carboxamide;

N-{[6-(aminomethyl)imidazo[1,2-a]pyridin-2-yl]methyl}-4-o xo-4H-pyrido[1,2-a]pyrimidine-2- carboxamide;

4-oxo-N-[(6-{[(2,2,2-trifluoroethyl)amino]methyl}imidazo[ 1,2-a]pyridin-2-yl)methyl]-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-[(6-{[(2-hydroxyethyl)amino]methyl}imidazo[1,2-a]pyridi n-2-yl)methyl]-4-oxo-4H-pyrido[1,2- a]pyrimidine-2-carboxamide;

4-oxo-N-[(6-{[(2-phenylethyl)amino]methyl}imidazo[1,2-a]p yridin-2-yl)methyl]-4H-pyrido[1,2- a]pyrimidine-2-carboxamide;

N-({6-[(benzylamino)methyl]imidazo[1,2-a]pyridin-2-yl}met hyl)-4-oxo-4H-pyrido[1,2- a]pyrimidine-2-carboxamide;

4-oxo-N-[(6-{[(3-phenylpropyl)amino]methyl}imidazo[1,2-a] pyridin-2-yl)methyl]-4H-pyrido[1,2- a]pyrimidine-2-carboxamide;

N-({6-[hydroxy(phenyl)methyl]imidazo[1,2-a]pyridin-2-yl}m ethyl)-4-oxo-4H-pyrido[1,2- a]pyrimidine-2-carboxamide;

N-{[6-(1-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl]methyl}- 4-oxo-4H-pyrido[1,2-a]pyrimidine-2- carboxamide; N-({6-ethenylimidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H-pyr ido[1,2-a]pyrimidine-2- carboxamide;

N-({6-cyclopropylimidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo -4H-pyrido[1,2-a]pyrimidine-2- carboxamide;

N-({7-ethenylimidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H- pyrido[1,2-a]pyrimidine-2- carboxamide;

N-{[6-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl]methyl}-4 -oxo-4H-pyrido[1,2-a]pyrimidine-2- carboxamide; and

2-(1H-indazol-4-yl)-5-[(6-methylimidazo[1,2-a]pyridin-2-y l)methyl]-1,3,4-oxadiazole.

[00190] Particular compounds of the present invention include any of the compounds exemplified in the present application, or a pharmaceutically acceptable salt thereof, and, in particular, any of the following:

N-({6-methylimidazo[1,2-a]pyridin-2-yl}methyl)-1H-indazol e-4-carboxamide;

N-({7-bromoimidazo[1,2-a]pyridin-2-yl}methyl)-1H-indazole -4-carboxamide;

N-({6-bromoimidazo[1,2-a]pyridin-2-yl}methyl)-1H-indazole -4-carboxamide;

N-({6-chloroimidazo[1,2-a]pyridin-2-yl}methyl)-1H-indazol e-4-carboxamide;

N-({7-fluoroimidazo[1,2-a]pyridin-2-yl}methyl)-1H-indazol e-4-carboxamide;

N-({6-fluoroimidazo[1,2-a]pyridin-2-yl}methyl)-1H-indazol e-4-carboxamide;

N-({7-methoxyimidazo[1,2-a]pyridin-2-yl}methyl)-1H-indazo le-4-carboxamide;

N-({6-methylimidazo[1,2-a]pyridin-2-yl}methyl)-6-(1H-pyra zol-5-yl)-1H-indazole-4- carboxamide;

N-({7-methylimidazo[1,2-a]pyridin-2-yl}methyl)-1H-indazol e-4-carboxamide;

6-bromo-N-({6-methylimidazo[1,2-a]pyridin-2-yl}methyl)-1H -indazole-4-carboxamide;

6-bromo-N-({7-methylimidazo[1,2-a]pyridin-2-yl}methyl)-1H -indazole-4-carboxamide;

N-({6-methylimidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H-c hromene-2-carboxamide;

N-({imidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H-chromene- 2-carboxamide;

6-ethynyl-N-({6-methylimidazo[1,2-a]pyridin-2-yl}methyl)- 1H-indazole-4-carboxamide;

N-({6-methylimidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H-p yrido[1,2-a]pyrimidine-2- carboxamide;

N-({7-methylimidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H-c hromene-2-carboxamide;

N-({7-methylimidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H-p yrido[1,2-a]pyrimidine-2- carboxamide;

N-({6-cyanoimidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H-py rido[1,2-a]pyrimidine-2- carboxamide;

8-methoxy-N-({6-methylimidazo[1,2-a]pyridin-2-yl}methyl)- 4-oxo-4H-pyrido[1,2-a]pyrimidine- 2-carboxamide; N-({6-methylimidazo[1,2-a]pyridin-2-yl}methyl)-1H-indazole-5 -carboxamide;

7-chloro-N-({6-methylimidazo[1,2-a]pyridin-2-yl}methyl)-4 -oxo-4H-pyrido[1,2-a]pyrimidine-2- carboxamide;

N-({6-fluoroimidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H-p yrido[1,2-a]pyrimidine-2- carboxamide;

N-({6-bromoimidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H-py rido[1,2-a]pyrimidine-2- carboxamide;

N-({6-methoxyimidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H- pyrido[1,2-a]pyrimidine-2- carboxamide;

N-({7-methoxyimidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H- pyrido[1,2-a]pyrimidine-2- carboxamide;

N-({imidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H-pyrido[1, 2-a]pyrimidine-2-carboxamide; N-({8-methylimidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H-pyri do[1,2-a]pyrimidine-2- carboxamide;

N-({6-methylimidazo[1,2-a]pyridin-2-yl}methyl)-1H-pyrazol o[4,3-c]pyridine-4-carboxamide; N-({7-bromoimidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H-pyrid o[1,2-a]pyrimidine-2- carboxamide;

N-(2-hydroxy-1-{6-methylimidazo[1,2-a]pyridin-2-yl}ethyl) -1H-indazole-4-carboxamide; 4-(3-{imidazo[1,2-a]pyridin-2-yl}-2,5-dihydro-1H-pyrrole-1-c arbonyl)-1H-indazole;

N-[(6-{[(pyridin-3-yl)methyl]amino}imidazo[1,2-a]pyridin- 2-yl)methyl]-1H-indazole-4- carboxamide;

N-[(6-{[(1-methyl-1H-imidazol-4-yl)methyl]amino}imidazo[1 ,2a]pyridin-2-yl)methyl]-1H- indazole-4-carboxamide;

N-{[6-(3-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl]methyl} -1H-indazole-4-carboxamide; N-{[6-(1H-pyrazol-5-yl)imidazo[1,2-a]pyridin-2-yl]methyl}-1H -indazole-4-carboxamide;

N-[[6-(3-chlorophenyl)imidazo[1,2-a]pyridin-2-yl]methyl]- 1H-indazole-4-carboxamide;

N-({6-[(pyridin-3-yl)amino]imidazo[1,2-a]pyridin-2-yl}met hyl)-1H-indazole-4-carboxamide; N-({6-[(piperazin-1-yl)methyl]imidazo[1,2-a]pyridin-2-yl}met hyl)-1H-indazole-4-carboxamide; N-{[6-(aminomethyl)imidazo[1,2-a]pyridin-2-yl]methyl}-1H-ind azole-4-carboxamide;

N-{[6-(acetamidomethyl)imidazo[1,2-a]pyridin-2-yl]methyl} -1H-indazole-4-carboxamide; {6-methylimidazo[1,2-a]pyridin-2-yl}methyl 1H-indazole-4-carboxylate;

{6-methylimidazo[1,2-a]pyridin-2-yl}methyl 1H-indazole-4-carboxylate hydrochloride;

N-{[6-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl]methyl}-1 H-indazole-4-carboxamide;

N-({6-hydroxyimidazo[1,2-a]pyridin-2-yl}methyl)-1H-indazo le-4-carboxamide;

N-({6-[(methylamino)methyl]imidazo[1,2-a]pyridin-2-yl}met hyl)-1H-indazole-4-carboxamide; N-({6-[(methylamino)methyl]imidazo[1,2-a]pyridin-2-yl}methyl )-1H-indazole-4-carboxamide dihydrochloride;

N-[(6-{[(2-hydroxyethyl)amino]methyl}imidazo[1,2-a]pyridi n-2-yl)methyl]-1H-indazole-4- carboxamide;

N-[(6-{[(2,2,2-trifluoroethyl)amino]methyl}imidazo[1,2-a] pyridin-2-yl)methyl]-1H-indazole-4- carboxamide;

N-{[6-(1-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl]methyl}- 1H-indazole-4-carboxamide;

N-({6-[hydroxy(phenyl)methyl]imidazo[1,2-a]pyridin-2-yl}m ethyl)-1H-indazole-4-carboxamide; N-({6-formylimidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H-pyri do[1,2-a]pyrimidine-2- carboxamide;

N-{[6-(aminomethyl)imidazo[1,2-a]pyridin-2-yl]methyl}-4-o xo-4H-pyrido[1,2-a]pyrimidine-2- carboxamide;

4-oxo-N-[(6-{[(2,2,2-trifluoroethyl)amino]methyl}imidazo[ 1,2-a]pyridin-2-yl)methyl]-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-[(6-{[(2-hydroxyethyl)amino]methyl}imidazo[1,2-a]pyridi n-2-yl)methyl]-4-oxo-4H-pyrido[1,2- a]pyrimidine-2-carboxamide;

4-oxo-N-[(6-{[(2-phenylethyl)amino]methyl}imidazo[1,2-a]p yridin-2-yl)methyl]-4H-pyrido[1,2- a]pyrimidine-2-carboxamide;

N-({6-[(benzylamino)methyl]imidazo[1,2-a]pyridin-2-yl}met hyl)-4-oxo-4H-pyrido[1,2- a]pyrimidine-2-carboxamide;

4-oxo-N-[(6-{[(3-phenylpropyl)amino]methyl}imidazo[1,2-a] pyridin-2-yl)methyl]-4H-pyrido[1,2- a]pyrimidine-2-carboxamide;

N-({6-[hydroxy(phenyl)methyl]imidazo[1,2-a]pyridin-2-yl}m ethyl)-4-oxo-4H-pyrido[1,2- a]pyrimidine-2-carboxamide;

N-{[6-(1-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl]methyl}- 4-oxo-4H-pyrido[1,2-a]pyrimidine-2- carboxamide;

N-({6-ethenylimidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H- pyrido[1,2-a]pyrimidine-2- carboxamide;

N-({6-cyclopropylimidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo -4H-pyrido[1,2-a]pyrimidine-2- carboxamide;

N-({7-ethenylimidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H- pyrido[1,2-a]pyrimidine-2- carboxamide;

N-{[6-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl]methyl}-4 -oxo-4H-pyrido[1,2-a]pyrimidine-2- carboxamide;

2-(1H-indazol-4-yl)-5-[(6-methylimidazo[1,2-a]pyridin-2-y l)methyl]-1,3,4-oxadiazole; N-{[6-(2-aminoethyl)imidazo[1,2-a]pyridin-2-yl]methyl}-4-oxo -4H-pyrido[1,2-a]pyrimidine-2- carboxamide;

N-({6-methylimidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H,6 H,7H,8H,9H-pyrido[1,2- a]pyrimidine-2-carboxamide;

4-oxo-N-{[6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl]m ethyl}-4H-pyrido[1,2-a]pyrimidine-2- carboxamide;

tert-butyl N-(2-{2-[({4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl}formamido)me thyl]imidazo[1,2- a]pyridin-6-yl}ethyl)carbamate;

N-benzyl-2-[({4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl}formam ido)methyl]imidazo[1,2-a]pyridine- 6-carboxamide;

N-[(6-{[(cyclohexylmethyl)amino]methyl}imidazo[1,2-a]pyri din-2-yl)methyl]-4-oxo-4H- chromene-2-carboxamide;

7-chloro-N-[(6-{[(cyclohexylmethyl)amino]methyl}imidazo[1 ,2-a]pyridin-2-yl)methyl]-4-oxo- 4H-chromene-2-carboxamide;

6-chloro-N-[(6-{[(cyclohexylmethyl)amino]methyl}imidazo[1 ,2-a]pyridin-2-yl)methyl]-4-oxo- 4H-chromene-2-carboxamide;

N-[(6-{[(cyclohexylmethyl)amino]methyl}imidazo[1,2-a]pyri din-2-yl)methyl]-4-oxo- 4H,6H,7H,8H,9H-pyrido[1,2-a]pyrimidine-2-carboxamide;

6-amino-N-[(6-{[(cyclohexylmethyl)amino]methyl}imidazo[1, 2-a]pyridin-2-yl)methyl]pyridine- 3-carboxamide;

N-({6-[(benzyloxy)methyl]imidazo[1,2-a]pyridin-2-yl}methy l)-4-oxo-4H-pyrido[1,2- a]pyrimidine-2-carboxamide;

N-({6-[(benzylamino)methyl]imidazo[1,2-a]pyridin-2-yl}met hyl)-1H-indazole-4-carboxamide; N-[(6-{[(cyclohexylmethyl)amino]methyl}imidazo[1,2-a]pyridin -2-yl)methyl]-7-fluoro-4-oxo-4H- chromene-2-carboxamide;

N-[(6-{[(cyclohexylmethyl)amino]methyl}imidazo[1,2-a]pyri din-2-yl)methyl]-7-methyl-4-oxo- 4H-chromene-2-carboxamide;

N-[(6-{[(cyclohexylmethyl)amino]methyl}imidazo[1,2-a]pyri din-2-yl)methyl]-1H-indazole-4- carboxamide;

8-chloro-N-[(6-{[(cyclohexylmethyl)amino]methyl}imidazo[1 ,2-a]pyridin-2-yl)methyl]-4-oxo- 4H-chromene-2-carboxamide;

6-bromo-N-[(6-{[(cyclohexylmethyl)amino]methyl}imidazo[1, 2-a]pyridin-2-yl)methyl]-1H- indazole-4-carboxamide;

N-[(6-{[(cyclohexylmethyl)amino]methyl}imidazo[1,2-a]pyri din-2-yl)methyl]quinoline-3- carboxamide; N-[(6-{1-[(cyclohexylmethyl)amino]ethyl}imidazo[1,2-a]pyridi n-2-yl)methyl]-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

6-chloro-N-[(6-{[(cyclohexylmethyl)amino]methyl}imidazo[1 ,2-a]pyridin-2-yl)methyl]-1H- indazole-4-carboxamide;

4-[5-({6-methylimidazo[1,2-a]pyridin-2-yl}methyl)-1,3,4-t hiadiazol-2-yl]-1H-indazole;

4-[1-({6-methylimidazo[1,2-a]pyridin-2-yl}methyl)-1H-1,2, 3-triazol-4-yl]-1H-indazole;

N-[(6-{[(3-chlorophenyl)amino]methyl}imidazo[1,2-a]pyridi n-2-yl)methyl]-4-oxo-4H-pyrido[1,2- a]pyrimidine-2-carboxamide;

N-[(6-{[(1-cyclohexyl-2-hydroxyethyl)amino]methyl}imidazo [1,2-a]pyridin-2-yl)methyl]-4-oxo- 4H-pyrido[1,2-a]pyrimidine-2-carboxamide;

4-oxo-N-{[6-({[(pyridin-3-yl)methyl]amino}methyl)imidazo[ 1,2-a]pyridin-2-yl]methyl}-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-{[6-({[(4-methoxyphenyl)methyl]amino}methyl)imidazo[1,2 -a]pyridin-2-yl]methyl}-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-[(6-{[(cyclohexylmethyl)amino]methyl}imidazo[1,2-a]pyri din-2-yl)methyl]-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-{[6-({[(4- chlorophenyl)methyl]amino}methyl)imidazo[1,2-a]pyridin-2-yl] methyl}-4-oxo-4H-pyrido[1,2- a]pyrimidine-2-carboxamide;

N-[(6-{[benzyl(methyl)amino]methyl}imidazo[1,2-a]pyridin- 2-yl)methyl]-4-oxo-4H-pyrido[1,2- a]pyrimidine-2-carboxamide;

4-oxo-N-{[6-({[(1R)-1-phenylethyl]amino}methyl)imidazo[1, 2-a]pyridin-2-yl]methyl}-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

4-oxo-N-{[6-({[(1S)-1-phenylethyl]amino}methyl)imidazo[1, 2-a]pyridin-2-yl]methyl}-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-{[6-({[(2-fluorophenyl)methyl]amino}methyl)imidazo[1,2- a]pyridin-2-yl]methyl}-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

4-oxo-N-[(6-{[(2-phenylpropan-2-yl)amino]methyl}imidazo[1 ,2-a]pyridin-2-yl)methyl]-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-{[6-({[(3-fluorophenyl)methyl]amino}methyl)imidazo[1,2- a]pyridin-2-yl]methyl}-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-{[6-({[(4-fluorophenyl)methyl]amino}methyl)imidazo[1,2- a]pyridin-2-yl]methyl}-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

4-oxo-N-[(6-{[(4,4,4-trifluorobutyl)amino]methyl}imidazo[ 1,2-a]pyridin-2-yl)methyl]-4H- pyrido[1,2-a]pyrimidine-2-carboxamide; N-{[6-({[(oxan-4-yl)methyl]amino}methyl)imidazo[1,2-a]pyridi n-2-yl]methyl}-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-{[6-({[(3,3-difluorocyclobutyl)methyl]amino}methyl)imid azo[1,2-a]pyridin-2-yl]methyl}-4-oxo- 4H-pyrido[1,2-a]pyrimidine-2-carboxamide;

N-[(6-{[(cyclopropylmethyl)amino]methyl}imidazo[1,2-a]pyr idin-2-yl)methyl]-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

4-oxo-N-[(6-{[(3,3,3-trifluoropropyl)amino]methyl}imidazo [1,2-a]pyridin-2-yl)methyl]-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-({6-[(cyclohexylamino)methyl]imidazo[1,2-a]pyridin-2-yl }methyl)-4-oxo-4H-pyrido[1,2- a]pyrimidine-2-carboxamide;

4-oxo-N-({6-[({[3-(trifluoromethyl)bicyclo[1.1.1]pentan-1 -yl]methyl}amino)methyl]imidazo[1,2- a]pyridin-2-yl}methyl)-4H-pyrido[1,2-a]pyrimidine-2-carboxam ide;

N-{[6-({[(oxan-2-yl)methyl]amino}methyl)imidazo[1,2-a]pyr idin-2-yl]methyl}-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

4-oxo-N-[(6-{[(3-phenyloxetan-3-yl)amino]methyl}imidazo[1 ,2-a]pyridin-2-yl)methyl]-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-{[6-({[(oxan-3-yl)methyl]amino}methyl)imidazo[1,2-a]pyr idin-2-yl]methyl}-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-{[6-({[(1-fluorocyclohexyl)methyl]amino}methyl)imidazo[ 1,2-a]pyridin-2-yl]methyl}-4-oxo- 4H-pyrido[1,2-a]pyrimidine-2-carboxamide;

N-{[6-({[(3-cyclopropylphenyl)methyl]amino}methyl)imidazo [1,2-a]pyridin-2-yl]methyl}-4-oxo- 4H-pyrido[1,2-a]pyrimidine-2-carboxamide;

N-[(6-{[(3,3-dimethylbutyl)amino]methyl}imidazo[1,2-a]pyr idin-2-yl)methyl]-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

4-oxo-N-{[6-({[2-(trifluoromethoxy)ethyl]amino}methyl)imi dazo[1,2-a]pyridin-2-yl]methyl}-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

4-oxo-N-{[6-({[(oxolan-2-yl)methyl]amino}methyl)imidazo[1 ,2-a]pyridin-2-yl]methyl}-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-[(6-{[(2-methanesulfonylethyl)amino]methyl}imidazo[1,2- a]pyridin-2-yl)methyl]-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

4-oxo-N-({6-[(3-phenylpyrrolidin-1-yl)methyl]imidazo[1,2- a]pyridin-2-yl}methyl)-4H-pyrido[1,2- a]pyrimidine-2-carboxamide;

N-[(6-{[(1-cyclohexylcyclopropyl)amino]methyl}imidazo[1,2 -a]pyridin-2-yl)methyl]-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

4-oxo-N-{[6-({[(1,3-thiazol-5-yl)methyl]amino}methyl)imid azo[1,2-a]pyridin-2-yl]methyl}-4H- pyrido[1,2-a]pyrimidine-2-carboxamide; tert-butyl 3-{[({2-[({4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl}formamido)me thyl]imidazo[1,2- a]pyridin-6-yl}methyl)amino]methyl}piperidine-1-carboxylate;

N-{[6-({[(4,4-difluorocyclohexyl)methyl]amino}methyl)imid azo[1,2-a]pyridin-2-yl]methyl}-4- oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide;

tert-butyl 2-{[({2-[({4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl}formamido)me thyl]imidazo[1,2- a]pyridin-6-yl}methyl)amino]methyl}piperidine-1-carboxylate;

N-[(6-{[(2-cyclopropylethyl)amino]methyl}imidazo[1,2-a]py ridin-2-yl)methyl]-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

4-oxo-N-({6-[(piperidin-1-yl)methyl]imidazo[1,2-a]pyridin -2-yl}methyl)-4H-pyrido[1,2- a]pyrimidine-2-carboxamide;

4-oxo-N-({6-[({[1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl] methyl}amino)methyl]imidazo[1,2- a]pyridin-2-yl}methyl)-4H-pyrido[1,2-a]pyrimidine-2-carboxam ide;

N-{[6-({[(1-methylcyclohexyl)methyl]amino}methyl)imidazo[ 1,2-a]pyridin-2-yl]methyl}-4-oxo- 4H-pyrido[1,2-a]pyrimidine-2-carboxamide;

4-oxo-N-{[6-({[2-(pyridin-3-yl)ethyl]amino}methyl)imidazo [1,2-a]pyridin-2-yl]methyl}-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-{[6-({[(1,4-dioxan-2-yl)methyl]amino}methyl)imidazo[1,2 -a]pyridin-2-yl]methyl}-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-({6-[(cyclopropylamino)methyl]imidazo[1,2-a]pyridin-2-y l}methyl)-4-oxo-4H-pyrido[1,2- a]pyrimidine-2-carboxamide;

N-[(6-{[(3,3-difluorocyclobutyl)amino]methyl}imidazo[1,2- a]pyridin-2-yl)methyl]-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-{[6-({[(oxetan-3-yl)methyl]amino}methyl)imidazo[1,2-a]p yridin-2-yl]methyl}-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

4-oxo-N-{[6-({[(1R,2R)-2-(trifluoromethyl)cyclopropyl]ami no}methyl)imidazo[1,2-a]pyridin-2- yl]methyl}-4H-pyrido[1,2-a]pyrimidine-2-carboxamide;

N-[(6-{[(2,2-dimethylpropyl)amino]methyl}imidazo[1,2-a]py ridin-2-yl)methyl]-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-[(6-{[(cyclohexylmethyl)(methyl)amino]methyl}imidazo[1, 2-a]pyridin-2-yl)methyl]-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-[(6-{[(4,4-difluorocyclohexyl)amino]methyl}imidazo[1,2- a]pyridin-2-yl)methyl]-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-({6-[({bicyclo[1.1.1]pentan-1-yl}amino)methyl]imidazo[1 ,2-a]pyridin-2-yl}methyl)-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

4-oxo-N-({6-[({[(2S)-oxolan-2-yl]methyl}amino)methyl]imid azo[1,2-a]pyridin-2-yl}methyl)-4H- pyrido[1,2-a]pyrimidine-2-carboxamide; 4-oxo-N-({6-[({[(2R)-oxolan-2-yl]methyl}amino)methyl]imidazo [1,2-a]pyridin-2-yl}methyl)-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-[(6-{[(2,2-difluoroethyl)amino]methyl}imidazo[1,2-a]pyr idin-2-yl)methyl]-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

4-oxo-N-{[6-({[(oxolan-3-yl)methyl]amino}methyl)imidazo[1 ,2-a]pyridin-2-yl]methyl}-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-{[6-({[(1-methylcyclopropyl)methyl]amino}methyl)imidazo [1,2-a]pyridin-2-yl]methyl}-4-oxo- 4H-pyrido[1,2-a]pyrimidine-2-carboxamide;

4-oxo-N-[(6-{[(oxolan-3-yl)amino]methyl}imidazo[1,2-a]pyr idin-2-yl)methyl]-4H-pyrido[1,2- a]pyrimidine-2-carboxamide;

methyl 3-methyl-2-[({2-[({4-oxo-4H-pyrido[1,2-a]pyrimidin-2- yl}formamido)methyl]imidazo[1,2-a]pyridin-6-yl}methyl)amino] butanoate;

N-[(6-{[(oxan-3-yl)amino]methyl}imidazo[1,2-a]pyridin-2-y l)methyl]-4-oxo-4H-pyrido[1,2- a]pyrimidine-2-carboxamide;

4-oxo-N-{[6-({[(2S)-3,3,3-trifluoro-2-hydroxypropyl]amino }methyl)imidazo[1,2-a]pyridin-2- yl]methyl}-4H-pyrido[1,2-a]pyrimidine-2-carboxamide;

N-({6-[(cyclobutylamino)methyl]imidazo[1,2-a]pyridin-2-yl }methyl)-4-oxo-4H-pyrido[1,2- a]pyrimidine-2-carboxamide; N-({6-[(tert-butylamino)methyl]imidazo[1,2-a]pyridin-2-yl}me thyl)-4-oxo-4H-pyrido[1,2- a]pyrimidine-2-carboxamide;

N-[(6-{[(2-fluoroethyl)amino]methyl}imidazo[1,2-a]pyridin -2-yl)methyl]-4-oxo-4H-pyrido[1,2- a]pyrimidine-2-carboxamide;

N-({6-[(4,4-difluoropiperidin-1-yl)methyl]imidazo[1,2-a]p yridin-2-yl}methyl)-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

4-oxo-N-({6-[(4-phenylpiperazin-1-yl)methyl]imidazo[1,2-a ]pyridin-2-yl}methyl)-4H-pyrido[1,2- a]pyrimidine-2-carboxamide;

4-oxo-N-({6-[(1,2,3,4-tetrahydroisoquinolin-2-yl)methyl]i midazo[1,2-a]pyridin-2-yl}methyl)-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-({6-[(diethylamino)methyl]imidazo[1,2-a]pyridin-2-yl}me thyl)-4-oxo-4H-pyrido[1,2- a]pyrimidine-2-carboxamide;

4-oxo-N-({6-[(pyrrolidin-1-yl)methyl]imidazo[1,2-a]pyridi n-2-yl}methyl)-4H-pyrido[1,2- a]pyrimidine-2-carboxamide;

4-oxo-N-[(6-{[3-(pyridin-2-yl)azetidin-1-yl]methyl}imidaz o[1,2-a]pyridin-2-yl)methyl]-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-[(6-{[(dicyclopropylmethyl)amino]methyl}imidazo[1,2-a]p yridin-2-yl)methyl]-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide; N-[(6-{[(cyclopropylmethyl)(methyl)amino]methyl}imidazo[1,2- a]pyridin-2-yl)methyl]-4-oxo- 4H-pyrido[1,2-a]pyrimidine-2-carboxamide;

N-({6-[(4-methylpiperidin-1-yl)methyl]imidazo[1,2-a]pyrid in-2-yl}methyl)-4-oxo-4H-pyrido[1,2- a]pyrimidine-2-carboxamide;

4-oxo-N-[(6-{[4-(trifluoromethyl)piperidin-1-yl]methyl}im idazo[1,2-a]pyridin-2-yl)methyl]-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-({6-[(3-methylpiperidin-1-yl)methyl]imidazo[1,2-a]pyrid in-2-yl}methyl)-4-oxo-4H-pyrido[1,2- a]pyrimidine-2-carboxamide;

4-oxo-N-[(6-{[({spiro[2.2]pentan-1-yl}methyl)amino]methyl }imidazo[1,2-a]pyridin-2-yl)methyl]- 4H-pyrido[1,2-a]pyrimidine-2-carboxamide;

N-({6-[(3,3-dimethylpiperidin-1-yl)methyl]imidazo[1,2-a]p yridin-2-yl}methyl)-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

4-oxo-N-[(6-{[3-(trifluoromethyl)piperidin-1-yl]methyl}im idazo[1,2-a]pyridin-2-yl)methyl]-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-{[6-({[(5,5-dimethyloxolan-2-yl)methyl]amino}methyl)imi dazo[1,2-a]pyridin-2-yl]methyl}-4- oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide;

N-({6-[(4-fluoropiperidin-1-yl)methyl]imidazo[1,2-a]pyrid in-2-yl}methyl)-4-oxo-4H-pyrido[1,2- a]pyrimidine-2-carboxamide;

N-[(6-{[(3-methoxypropyl)amino]methyl}imidazo[1,2-a]pyrid in-2-yl)methyl]-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-[(6-{[(1-methylcyclohexyl)amino]methyl}imidazo[1,2-a]py ridin-2-yl)methyl]-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-{[6-({[(4,4-dimethyloxolan-2-yl)methyl]amino}methyl)imi dazo[1,2-a]pyridin-2-yl]methyl}-4- oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide;

N-[(6-{[(1-methylcyclopentyl)amino]methyl}imidazo[1,2-a]p yridin-2-yl)methyl]-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

4-oxo-N-({6-[(propylamino)methyl]imidazo[1,2-a]pyridin-2- yl}methyl)-4H-pyrido[1,2- a]pyrimidine-2-carboxamide;

N-{[6-({[(3,3-dimethyloxolan-2-yl)methyl]amino}methyl)imi dazo[1,2-a]pyridin-2-yl]methyl}-4- oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide;

N-[(6-{[(2-methylpropyl)amino]methyl}imidazo[1,2-a]pyridi n-2-yl)methyl]-4-oxo-4H-pyrido[1,2- a]pyrimidine-2-carboxamide;

N-{[6-({[2-(tert-butoxy)ethyl]amino}methyl)imidazo[1,2-a] pyridin-2-yl]methyl}-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-[(6-{[(4-chlorophenyl)amino]methyl}imidazo[1,2-a]pyridi n-2-yl)methyl]-4-oxo-4H-pyrido[1,2- a]pyrimidine-2-carboxamide; N-{[6-({[2-(oxan-2-yl)ethyl]amino}methyl)imidazo[1,2-a]pyrid in-2-yl]methyl}-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-({6-[(4-benzylpiperidin-1-yl)methyl]imidazo[1,2-a]pyrid in-2-yl}methyl)-4-oxo-4H-pyrido[1,2- a]pyrimidine-2-carboxamide;

4-oxo-N-({6-[(4-phenoxypiperidin-1-yl)methyl]imidazo[1,2- a]pyridin-2-yl}methyl)-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-{[6-({[(2,2-difluorocyclopropyl)methyl]amino}methyl)imi dazo[1,2-a]pyridin-2-yl]methyl}-4- oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide;

N-{[6-({[(2,2-dimethylcyclopropyl)methyl]amino}methyl)imi dazo[1,2-a]pyridin-2-yl]methyl}-4- oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide;

N-{[6-({[(2-methyloxolan-2-yl)methyl]amino}methyl)imidazo [1,2-a]pyridin-2-yl]methyl}-4-oxo- 4H-pyrido[1,2-a]pyrimidine-2-carboxamide;

N-({6-[(4-tert-butylpiperidin-1-yl)methyl]imidazo[1,2-a]p yridin-2-yl}methyl)-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-[(6-{[(4-tert-butylcyclohexyl)amino]methyl}imidazo[1,2- a]pyridin-2-yl)methyl]-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-[(6-{[(2-cyclopentylethyl)amino]methyl}imidazo[1,2-a]py ridin-2-yl)methyl]-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-[(6-{[4-(2,2-dimethylpropanoyl)piperazin-1-yl]methyl}im idazo[1,2-a]pyridin-2-yl)methyl]-4- oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide;

N-({6-[(4-acetylpiperazin-1-yl)methyl]imidazo[1,2-a]pyrid in-2-yl}methyl)-4-oxo-4H-pyrido[1,2- a]pyrimidine-2-carboxamide;

N-{[6-({7-azabicyclo[2.2.1]heptan-7-yl}methyl)imidazo[1,2 -a]pyridin-2-yl]methyl}-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-({6-[(4,4-dimethylpiperidin-1-yl)methyl]imidazo[1,2-a]p yridin-2-yl}methyl)-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-({6-[(2,2-dimethylpiperidin-1-yl)methyl]imidazo[1,2-a]p yridin-2-yl}methyl)-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

4-oxo-N-[(6-{[(2,3,3-trimethylbutan-2-yl)amino]methyl}imi dazo[1,2-a]pyridin-2-yl)methyl]-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-[(6-{[(5-fluoropyridin-2-yl)amino]methyl}imidazo[1,2-a] pyridin-2-yl)methyl]-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-({6-[({[1,1'-bi(cyclopropane)]-1-yl}amino)methyl]imidaz o[1,2-a]pyridin-2-yl}methyl)-4-oxo- 4H-pyrido[1,2-a]pyrimidine-2-carboxamide;

N-{[6-({[(1-fluorocyclopentyl)methyl]amino}methyl)imidazo [1,2-a]pyridin-2-yl]methyl}-4-oxo- 4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-({6-[(2,6-dimethylmorpholin-4-yl)methyl]imidazo[1,2-a]pyri din-2-yl}methyl)-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

methyl 1-({2-[({4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl}formamido)meth yl]imidazo[1,2-a]pyridin- 6-yl}methyl)piperidine-3-carboxylate;

N-[(6-{[(2-fluoro-2-methylpropyl)amino]methyl}imidazo[1,2 -a]pyridin-2-yl)methyl]-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-[(6-{[(1-cyclohexylethyl)amino]methyl}imidazo[1,2-a]pyr idin-2-yl)methyl]-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-[(6-{[(2-cyclopropylethyl)(methyl)amino]methyl}imidazo[ 1,2-a]pyridin-2-yl)methyl]-4-oxo- 4H-pyrido[1,2-a]pyrimidine-2-carboxamide;

N-[(6-{[(2,2-dimethylpropyl)(methyl)amino]methyl}imidazo[ 1,2-a]pyridin-2-yl)methyl]-4-oxo- 4H-pyrido[1,2-a]pyrimidine-2-carboxamide;

N-{[6-({[(1-fluorocyclobutyl)methyl]amino}methyl)imidazo[ 1,2-a]pyridin-2-yl]methyl}-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-({6-[(4-fluoro-4-methylpiperidin-1-yl)methyl]imidazo[1, 2-a]pyridin-2-yl}methyl)-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-({6-[(3,3-difluoropiperidin-1-yl)methyl]imidazo[1,2-a]p yridin-2-yl}methyl)-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-{[6-({[(1-hydroxycyclohexyl)methyl]amino}methyl)imidazo [1,2-a]pyridin-2-yl]methyl}-4-oxo- 4H-pyrido[1,2-a]pyrimidine-2-carboxamide;

N-[(6-{[(cyclopentylmethyl)amino]methyl}imidazo[1,2-a]pyr idin-2-yl)methyl]-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-{[6-({[(3,3-difluorocyclopentyl)methyl]amino}methyl)imi dazo[1,2-a]pyridin-2-yl]methyl}-4- oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide;

N-[(6-{[(cyclobutylmethyl)amino]methyl}imidazo[1,2-a]pyri din-2-yl)methyl]-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-{[6-({[2-(3,3-difluorocyclobutyl)ethyl]amino}methyl)imi dazo[1,2-a]pyridin-2-yl]methyl}-4- oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide;

N-{[6-({[(2-fluorocyclobutyl)methyl]amino}methyl)imidazo[ 1,2-a]pyridin-2-yl]methyl}-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-{[6-({[(2S)-3,3-dimethylbutan-2-yl]amino}methyl)imidazo [1,2-a]pyridin-2-yl]methyl}-4-oxo- 4H-pyrido[1,2-a]pyrimidine-2-carboxamide;

N-{[6-({6-azaspiro[2.5]octan-6-yl}methyl)imidazo[1,2-a]py ridin-2-yl]methyl}-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

4-oxo-N-({6-[({[(1r,3r)-3-fluorocyclobutyl]methyl}amino)m ethyl]imidazo[1,2-a]pyridin-2- yl}methyl)-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; 4-oxo-N-({6-[(2-phenylethyl)amino]imidazo[1,2-a]pyridin-2-yl }methyl)-4H-pyrido[1,2- a]pyrimidine-2-carboxamide;

N-({6-[2-(benzylamino)ethyl]imidazo[1,2-a]pyridin-2-yl}me thyl)-4-oxo-4H-pyrido[1,2- a]pyrimidine-2-carboxamide;

N-({6-[2-(cyclohexylamino)ethyl]imidazo[1,2-a]pyridin-2-y l}methyl)-4-oxo-4H-pyrido[1,2- a]pyrimidine-2-carboxamide;

4-oxo-N-({6-[(phenylformamido)methyl]imidazo[1,2-a]pyridi n-2-yl}methyl)-4H-pyrido[1,2- a]pyrimidine-2-carboxamide;

N-({6-[(cyclohexylformamido)methyl]imidazo[1,2-a]pyridin- 2-yl}methyl)-4-oxo-4H-pyrido[1,2- a]pyrimidine-2-carboxamide;

4-oxo-N-{[6-({[(piperidin-3-yl)methyl]amino}methyl)imidaz o[1,2-a]pyridin-2-yl]methyl}-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

4-oxo-N-{[6-({[(piperidin-2-yl)methyl]amino}methyl)imidaz o[1,2-a]pyridin-2-yl]methyl}-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-[(6-{[(azetidin-3-yl)amino]methyl}imidazo[1,2-a]pyridin -2-yl)methyl]-4-oxo-4H-pyrido[1,2- a]pyrimidine-2-carboxamide;

N-({6-[(cyclohexylamino)methyl]imidazo[1,2-a]pyridin-2-yl }methyl)-4-oxo-4H-chromene-2- carboxamide;

N-[(6-{[(2-cyclopropylethyl)amino]methyl}imidazo[1,2-a]py ridin-2-yl)methyl]-4-oxo-4H- chromene-2-carboxamide;

4-oxo-N-({6-[(piperidin-1-yl)methyl]imidazo[1,2-a]pyridin -2-yl}methyl)-4H-chromene-2- carboxamide;

N-{[6-({[(4-chlorophenyl)methyl]amino}methyl)imidazo[1,2- a]pyridin-2-yl]methyl}-4-oxo-4H- chromene-2-carboxamide;

N-({6-[(benzylamino)methyl]imidazo[1,2-a]pyridin-2-yl}met hyl)-4-oxo-4H-chromene-2- carboxamide;

N-{[6-({[(1-methylcyclohexyl)methyl]amino}methyl)imidazo[ 1,2-a]pyridin-2-yl]methyl}-4-oxo- 4H-chromene-2-carboxamide;

N-[(6-{[(2,2-dimethylpropyl)amino]methyl}imidazo[1,2-a]py ridin-2-yl)methyl]-4-oxo-4H- chromene-2-carboxamide;

4-oxo-N-[(7-{[(2-phenylethyl)amino]methyl}imidazo[1,2-a]p yridin-2-yl)methyl]-4H-pyrido[1,2- a]pyrimidine-2-carboxamide;

N-[(7-{[(cyclohexylmethyl)amino]methyl}imidazo[1,2-a]pyri din-2-yl)methyl]-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-[(7-{[(cyclopropylmethyl)amino]methyl}imidazo[1,2-a]pyr idin-2-yl)methyl]-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide; N-[(6-{1-[(cyclohexylmethyl)amino]cyclopropyl}imidazo[1,2-a] pyridin-2-yl)methyl]-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-{[6-(2-amino-3-phenylpropyl)imidazo[1,2-a]pyridin-2-yl] methyl}-4-oxo-4H-pyrido[1,2- a]pyrimidine-2-carboxamide;

(cyclohexylmethyl)[(2-{[4-(1H-indazol-4-yl)-1H-1,2,3-tria zol-1-yl]methyl}imidazo[1,2-a]pyridin- 6-yl)methyl]amine;

N-(cyclohexylmethyl)-2-{[4-(1H-indazol-4-yl)-1H-1,2,3-tri azol-1-yl]methyl}imidazo[1,2- a]pyridine-6-carboxamide;

(2,2-dimethylpropyl)[(2-{[4-(1H-indazol-4-yl)-1H-1,2,3-tr iazol-1-yl]methyl}imidazo[1,2- a]pyridin-6-yl)methyl]amine;

4-[1-({6-[(4,4-dimethylpiperidin-1-yl)methyl]imidazo[1,2- a]pyridin-2-yl}methyl)-1H-1,2,3- triazol-4-yl]-1H-indazole;

[(2-{[4-(6-bromo-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl]m ethyl}imidazo[1,2-a]pyridin-6- yl)methyl][(3,3-difluorocyclobutyl)methyl]amine;

[(2-{[4-(6-bromo-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl]m ethyl}imidazo[1,2-a]pyridin-6- yl)methyl](2,2-dimethylpropyl)amine;

[(2-{[4-(6-bromo-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl]m ethyl}imidazo[1,2-a]pyridin-6- yl)methyl](cyclohexylmethyl)amine;

6-bromo-4-[1-({6-[(4,4-dimethylpiperidin-1-yl)methyl]imid azo[1,2-a]pyridin-2-yl}methyl)-1H- 1,2,3-triazol-4-yl]-1H-indazole;

(2-{[4-(6-bromo-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl]me thyl}imidazo[1,2-a]pyridin-6- yl)methanol;

(2,2-dimethylpropyl)[(2-{[4-(1H-indazol-5-yl)-1H-1,2,3-tr iazol-1-yl]methyl}imidazo[1,2- a]pyridin-6-yl)methyl]amine;

((cyclohexylmethyl)[1-(2-{[4-(1H-indazol-4-yl)-1H-1,2,3-t riazol-1-yl]methyl}imidazo[1,2- a]pyridin-6-yl)ethyl]amine;

(2,2-dimethylpropyl)({2-[(4-{1H-pyrazolo[3,4-c]pyridin-4- yl}-1H-1,2,3-triazol-1- yl)methyl]imidazo[1,2-a]pyridin-6-yl}methyl)amine;

{2-[(4-{1H-pyrazolo[3,4-c]pyridin-4-yl}-1H-1,2,3-triazol- 1-yl)methyl]imidazo[1,2-a]pyridin-6- yl}methanol;

N-({6-[(3R,5S)-5-tert-butylmorpholin-3-yl]imidazo[1,2-a]p yridin-2-yl}methyl)-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-({6-[(3S,5R)-5-tert-butylmorpholin-3-yl]imidazo[1,2-a]p yridin-2-yl}methyl)-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-({6-[(3S,5R)-5-cyclohexylmorpholin-3-yl]imidazo[1,2-a]p yridin-2-yl}methyl)-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide; N-({6-[(3S,5R)-5-cyclohexylmorpholin-3-yl]imidazo[1,2-a]pyri din-2-yl}methyl)-1H-indazole-4- carboxamide;

N-({6-[(3S,5R)-5-cyclohexylmorpholin-3-yl]imidazo[1,2-a]p yridin-2-yl}methyl)-4-oxo-4H- chromene-2-carboxamide;

N-({6-[4-(2,2-dimethylpropyl)morpholin-3-yl]imidazo[1,2-a ]pyridin-2-yl}methyl)-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-({6-[(3S,5R)-5-methylmorpholin-3-yl]imidazo[1,2-a]pyrid in-2-yl}methyl)-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide; and

N-{[6-(9-methoxy-2,3,4,5-tetrahydro-1,4-benzoxazepin-3-yl )imidazo[1,2-a]pyridin-2- yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide.

[00191] Particular compounds of the present invention include any of the compounds exemplified in the present application, or a pharmaceutically acceptable salt thereof, and, in particular, any of the following:

N-({6-methylimidazo[1,2-a]pyridin-2-yl}methyl)-1H-indazol e-4-carboxamide;

N-({7-bromoimidazo[1,2-a]pyridin-2-yl}methyl)-1H-indazole -4-carboxamide;

N-({6-bromoimidazo[1,2-a]pyridin-2-yl}methyl)-1H-indazole -4-carboxamide;

N-({6-chloroimidazo[1,2-a]pyridin-2-yl}methyl)-1H-indazol e-4-carboxamide;

N-({7-fluoroimidazo[1,2-a]pyridin-2-yl}methyl)-1H-indazol e-4-carboxamide;

N-({6-fluoroimidazo[1,2-a]pyridin-2-yl}methyl)-1H-indazol e-4-carboxamide;

N-({7-methoxyimidazo[1,2-a]pyridin-2-yl}methyl)-1H-indazo le-4-carboxamide;

N-({6-methylimidazo[1,2-a]pyridin-2-yl}methyl)-6-(1H-pyra zol-5-yl)-1H-indazole-4- carboxamide;

N-({7-methylimidazo[1,2-a]pyridin-2-yl}methyl)-1H-indazol e-4-carboxamide;

6-bromo-N-({6-methylimidazo[1,2-a]pyridin-2-yl}methyl)-1H -indazole-4-carboxamide;

6-bromo-N-({7-methylimidazo[1,2-a]pyridin-2-yl}methyl)-1H -indazole-4-carboxamide;

N-({6-methylimidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H-c hromene-2-carboxamide;

N-({imidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H-chromene- 2-carboxamide;

6-ethynyl-N-({6-methylimidazo[1,2-a]pyridin-2-yl}methyl)- 1H-indazole-4-carboxamide;

N-({6-methylimidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H-p yrido[1,2-a]pyrimidine-2- carboxamide;

N-({7-methylimidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H-c hromene-2-carboxamide;

N-({7-methylimidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H-p yrido[1,2-a]pyrimidine-2- carboxamide;

N-({6-cyanoimidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H-py rido[1,2-a]pyrimidine-2- carboxamide; 8-methoxy-N-({6-methylimidazo[1,2-a]pyridin-2-yl}methyl)-4-o xo-4H-pyrido[1,2-a]pyrimidine- 2-carboxamide;

N-({6-methylimidazo[1,2-a]pyridin-2-yl}methyl)-1H-indazol e-5-carboxamide;

7-chloro-N-({6-methylimidazo[1,2-a]pyridin-2-yl}methyl)-4 -oxo-4H-pyrido[1,2-a]pyrimidine-2- carboxamide;

N-({6-fluoroimidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H-p yrido[1,2-a]pyrimidine-2- carboxamide;

N-({6-bromoimidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H-py rido[1,2-a]pyrimidine-2- carboxamide;

N-({6-methoxyimidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H- pyrido[1,2-a]pyrimidine-2- carboxamide;

N-({7-methoxyimidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H- pyrido[1,2-a]pyrimidine-2- carboxamide;

N-({imidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H-pyrido[1, 2-a]pyrimidine-2-carboxamide; N-({8-methylimidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H-pyri do[1,2-a]pyrimidine-2- carboxamide;

N-({6-methylimidazo[1,2-a]pyridin-2-yl}methyl)-1H-pyrazol o[4,3-c]pyridine-4-carboxamide; N-({7-bromoimidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H-pyrid o[1,2-a]pyrimidine-2- carboxamide;

N-(2-hydroxy-1-{6-methylimidazo[1,2-a]pyridin-2-yl}ethyl) -1H-indazole-4-carboxamide; 4-(3-{imidazo[1,2-a]pyridin-2-yl}-2,5-dihydro-1H-pyrrole-1-c arbonyl)-1H-indazole;

N-[(6-{[(pyridin-3-yl)methyl]amino}imidazo[1,2-a]pyridin- 2-yl)methyl]-1H-indazole-4- carboxamide;

N-[(6-{[(1-methyl-1H-imidazol-4-yl)methyl]amino}imidazo[1 ,2a]pyridin-2-yl)methyl]-1H- indazole-4-carboxamide;

N-{[6-(3-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl]methyl} -1H-indazole-4-carboxamide; N-{[6-(1H-pyrazol-5-yl)imidazo[1,2-a]pyridin-2-yl]methyl}-1H -indazole-4-carboxamide;

N-[[6-(3-chlorophenyl)imidazo[1,2-a]pyridin-2-yl]methyl]- 1H-indazole-4-carboxamide;

N-({6-[(pyridin-3-yl)amino]imidazo[1,2-a]pyridin-2-yl}met hyl)-1H-indazole-4-carboxamide; N-({6-[(piperazin-1-yl)methyl]imidazo[1,2-a]pyridin-2-yl}met hyl)-1H-indazole-4-carboxamide; N-{[6-(aminomethyl)imidazo[1,2-a]pyridin-2-yl]methyl}-1H-ind azole-4-carboxamide;

N-{[6-(acetamidomethyl)imidazo[1,2-a]pyridin-2-yl]methyl} -1H-indazole-4-carboxamide; {6-methylimidazo[1,2-a]pyridin-2-yl}methyl 1H-indazole-4-carboxylate;

{6-methylimidazo[1,2-a]pyridin-2-yl}methyl 1H-indazole-4-carboxylate hydrochloride;

N-{[6-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl]methyl}-1 H-indazole-4-carboxamide;

N-({6-hydroxyimidazo[1,2-a]pyridin-2-yl}methyl)-1H-indazo le-4-carboxamide; N-({6-[(methylamino)methyl]imidazo[1,2-a]pyridin-2-yl}methyl )-1H-indazole-4-carboxamide; N-({6-[(methylamino)methyl]imidazo[1,2-a]pyridin-2-yl}methyl )-1H-indazole-4-carboxamide dihydrochloride;

N-[(6-{[(2-hydroxyethyl)amino]methyl}imidazo[1,2-a]pyridi n-2-yl)methyl]-1H-indazole-4- carboxamide;

N-[(6-{[(2,2,2-trifluoroethyl)amino]methyl}imidazo[1,2-a] pyridin-2-yl)methyl]-1H-indazole-4- carboxamide;

N-{[6-(1-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl]methyl}- 1H-indazole-4-carboxamide;

N-({6-[hydroxy(phenyl)methyl]imidazo[1,2-a]pyridin-2-yl}m ethyl)-1H-indazole-4-carboxamide; N-({6-formylimidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H-pyri do[1,2-a]pyrimidine-2- carboxamide;

N-{[6-(aminomethyl)imidazo[1,2-a]pyridin-2-yl]methyl}-4-o xo-4H-pyrido[1,2-a]pyrimidine-2- carboxamide;

4-oxo-N-[(6-{[(2,2,2-trifluoroethyl)amino]methyl}imidazo[ 1,2-a]pyridin-2-yl)methyl]-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-[(6-{[(2-hydroxyethyl)amino]methyl}imidazo[1,2-a]pyridi n-2-yl)methyl]-4-oxo-4H-pyrido[1,2- a]pyrimidine-2-carboxamide;

4-oxo-N-[(6-{[(2-phenylethyl)amino]methyl}imidazo[1,2-a]p yridin-2-yl)methyl]-4H-pyrido[1,2- a]pyrimidine-2-carboxamide;

N-({6-[(benzylamino)methyl]imidazo[1,2-a]pyridin-2-yl}met hyl)-4-oxo-4H-pyrido[1,2- a]pyrimidine-2-carboxamide;

4-oxo-N-[(6-{[(3-phenylpropyl)amino]methyl}imidazo[1,2-a] pyridin-2-yl)methyl]-4H-pyrido[1,2- a]pyrimidine-2-carboxamide;

N-({6-[hydroxy(phenyl)methyl]imidazo[1,2-a]pyridin-2-yl}m ethyl)-4-oxo-4H-pyrido[1,2- a]pyrimidine-2-carboxamide;

N-{[6-(1-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl]methyl}- 4-oxo-4H-pyrido[1,2-a]pyrimidine-2- carboxamide;

N-({6-ethenylimidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H- pyrido[1,2-a]pyrimidine-2- carboxamide;

N-({6-cyclopropylimidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo -4H-pyrido[1,2-a]pyrimidine-2- carboxamide;

N-({7-ethenylimidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H- pyrido[1,2-a]pyrimidine-2- carboxamide;

N-{[6-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl]methyl}-4 -oxo-4H-pyrido[1,2-a]pyrimidine-2- carboxamide;

2-(1H-indazol-4-yl)-5-[(6-methylimidazo[1,2-a]pyridin-2-y l)methyl]-1,3,4-oxadiazole; N-{[6-(2-aminoethyl)imidazo[1,2-a]pyridin-2-yl]methyl}-4-oxo -4H-pyrido[1,2-a]pyrimidine-2- carboxamide;

N-({6-methylimidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H,6 H,7H,8H,9H-pyrido[1,2- a]pyrimidine-2-carboxamide;

4-oxo-N-{[6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl]m ethyl}-4H-pyrido[1,2-a]pyrimidine-2- carboxamide;

tert-butyl N-(2-{2-[({4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl}formamido)me thyl]imidazo[1,2- a]pyridin-6-yl}ethyl)carbamate;

N-benzyl-2-[({4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl}formam ido)methyl]imidazo[1,2-a]pyridine- 6-carboxamide;

N-[(6-{[(cyclohexylmethyl)amino]methyl}imidazo[1,2-a]pyri din-2-yl)methyl]-4-oxo-4H- chromene-2-carboxamide;

7-chloro-N-[(6-{[(cyclohexylmethyl)amino]methyl}imidazo[1 ,2-a]pyridin-2-yl)methyl]-4-oxo- 4H-chromene-2-carboxamide;

6-chloro-N-[(6-{[(cyclohexylmethyl)amino]methyl}imidazo[1 ,2-a]pyridin-2-yl)methyl]-4-oxo- 4H-chromene-2-carboxamide;

N-[(6-{[(cyclohexylmethyl)amino]methyl}imidazo[1,2-a]pyri din-2-yl)methyl]-4-oxo- 4H,6H,7H,8H,9H-pyrido[1,2-a]pyrimidine-2-carboxamide;

6-amino-N-[(6-{[(cyclohexylmethyl)amino]methyl}imidazo[1, 2-a]pyridin-2-yl)methyl]pyridine- 3-carboxamide;

N-({6-[(benzyloxy)methyl]imidazo[1,2-a]pyridin-2-yl}methy l)-4-oxo-4H-pyrido[1,2- a]pyrimidine-2-carboxamide;

N-({6-[(benzylamino)methyl]imidazo[1,2-a]pyridin-2-yl}met hyl)-1H-indazole-4-carboxamide; N-[(6-{[(cyclohexylmethyl)amino]methyl}imidazo[1,2-a]pyridin -2-yl)methyl]-7-fluoro-4-oxo-4H- chromene-2-carboxamide;

N-[(6-{[(cyclohexylmethyl)amino]methyl}imidazo[1,2-a]pyri din-2-yl)methyl]-7-methyl-4-oxo- 4H-chromene-2-carboxamide;

N-[(6-{[(cyclohexylmethyl)amino]methyl}imidazo[1,2-a]pyri din-2-yl)methyl]-1H-indazole-4- carboxamide;

8-chloro-N-[(6-{[(cyclohexylmethyl)amino]methyl}imidazo[1 ,2-a]pyridin-2-yl)methyl]-4-oxo- 4H-chromene-2-carboxamide;

6-bromo-N-[(6-{[(cyclohexylmethyl)amino]methyl}imidazo[1, 2-a]pyridin-2-yl)methyl]-1H- indazole-4-carboxamide;

N-[(6-{[(cyclohexylmethyl)amino]methyl}imidazo[1,2-a]pyri din-2-yl)methyl]quinoline-3- carboxamide; N-[(6-{1-[(cyclohexylmethyl)amino]ethyl}imidazo[1,2-a]pyridi n-2-yl)methyl]-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

6-chloro-N-[(6-{[(cyclohexylmethyl)amino]methyl}imidazo[1 ,2-a]pyridin-2-yl)methyl]-1H- indazole-4-carboxamide;

4-[5-({6-methylimidazo[1,2-a]pyridin-2-yl}methyl)-1,3,4-t hiadiazol-2-yl]-1H-indazole;

4-[1-({6-methylimidazo[1,2-a]pyridin-2-yl}methyl)-1H-1,2, 3-triazol-4-yl]-1H-indazole;

N-[(6-{[(3-chlorophenyl)amino]methyl}imidazo[1,2-a]pyridi n-2-yl)methyl]-4-oxo-4H-pyrido[1,2- a]pyrimidine-2-carboxamide;

N-[(6-{[(1-cyclohexyl-2-hydroxyethyl)amino]methyl}imidazo [1,2-a]pyridin-2-yl)methyl]-4-oxo- 4H-pyrido[1,2-a]pyrimidine-2-carboxamide;

4-oxo-N-{[6-({[(pyridin-3-yl)methyl]amino}methyl)imidazo[ 1,2-a]pyridin-2-yl]methyl}-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-{[6-({[(4-methoxyphenyl)methyl]amino}methyl)imidazo[1,2 -a]pyridin-2-yl]methyl}-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-[(6-{[(cyclohexylmethyl)amino]methyl}imidazo[1,2-a]pyri din-2-yl)methyl]-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-{[6-({[(4- chlorophenyl)methyl]amino}methyl)imidazo[1,2-a]pyridin-2-yl] methyl}-4-oxo-4H-pyrido[1,2- a]pyrimidine-2-carboxamide;

N-[(6-{[benzyl(methyl)amino]methyl}imidazo[1,2-a]pyridin- 2-yl)methyl]-4-oxo-4H-pyrido[1,2- a]pyrimidine-2-carboxamide;

4-oxo-N-{[6-({[(1R)-1-phenylethyl]amino}methyl)imidazo[1, 2-a]pyridin-2-yl]methyl}-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

4-oxo-N-{[6-({[(1S)-1-phenylethyl]amino}methyl)imidazo[1, 2-a]pyridin-2-yl]methyl}-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-{[6-({[(2-fluorophenyl)methyl]amino}methyl)imidazo[1,2- a]pyridin-2-yl]methyl}-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

4-oxo-N-[(6-{[(2-phenylpropan-2-yl)amino]methyl}imidazo[1 ,2-a]pyridin-2-yl)methyl]-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-{[6-({[(3-fluorophenyl)methyl]amino}methyl)imidazo[1,2- a]pyridin-2-yl]methyl}-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-{[6-({[(4-fluorophenyl)methyl]amino}methyl)imidazo[1,2- a]pyridin-2-yl]methyl}-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

4-oxo-N-[(6-{[(4,4,4-trifluorobutyl)amino]methyl}imidazo[ 1,2-a]pyridin-2-yl)methyl]-4H- pyrido[1,2-a]pyrimidine-2-carboxamide; N-{[6-({[(oxan-4-yl)methyl]amino}methyl)imidazo[1,2-a]pyridi n-2-yl]methyl}-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-{[6-({[(3,3-difluorocyclobutyl)methyl]amino}methyl)imid azo[1,2-a]pyridin-2-yl]methyl}-4-oxo- 4H-pyrido[1,2-a]pyrimidine-2-carboxamide;

N-[(6-{[(cyclopropylmethyl)amino]methyl}imidazo[1,2-a]pyr idin-2-yl)methyl]-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

4-oxo-N-[(6-{[(3,3,3-trifluoropropyl)amino]methyl}imidazo [1,2-a]pyridin-2-yl)methyl]-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-({6-[(cyclohexylamino)methyl]imidazo[1,2-a]pyridin-2-yl }methyl)-4-oxo-4H-pyrido[1,2- a]pyrimidine-2-carboxamide;

4-oxo-N-({6-[({[3-(trifluoromethyl)bicyclo[1.1.1]pentan-1 -yl]methyl}amino)methyl]imidazo[1,2- a]pyridin-2-yl}methyl)-4H-pyrido[1,2-a]pyrimidine-2-carboxam ide;

N-{[6-({[(oxan-2-yl)methyl]amino}methyl)imidazo[1,2-a]pyr idin-2-yl]methyl}-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

4-oxo-N-[(6-{[(3-phenyloxetan-3-yl)amino]methyl}imidazo[1 ,2-a]pyridin-2-yl)methyl]-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-{[6-({[(oxan-3-yl)methyl]amino}methyl)imidazo[1,2-a]pyr idin-2-yl]methyl}-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-{[6-({[(1-fluorocyclohexyl)methyl]amino}methyl)imidazo[ 1,2-a]pyridin-2-yl]methyl}-4-oxo- 4H-pyrido[1,2-a]pyrimidine-2-carboxamide;

N-{[6-({[(3-cyclopropylphenyl)methyl]amino}methyl)imidazo [1,2-a]pyridin-2-yl]methyl}-4-oxo- 4H-pyrido[1,2-a]pyrimidine-2-carboxamide;

N-[(6-{[(3,3-dimethylbutyl)amino]methyl}imidazo[1,2-a]pyr idin-2-yl)methyl]-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

4-oxo-N-{[6-({[2-(trifluoromethoxy)ethyl]amino}methyl)imi dazo[1,2-a]pyridin-2-yl]methyl}-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

4-oxo-N-{[6-({[(oxolan-2-yl)methyl]amino}methyl)imidazo[1 ,2-a]pyridin-2-yl]methyl}-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-[(6-{[(2-methanesulfonylethyl)amino]methyl}imidazo[1,2- a]pyridin-2-yl)methyl]-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

4-oxo-N-({6-[(3-phenylpyrrolidin-1-yl)methyl]imidazo[1,2- a]pyridin-2-yl}methyl)-4H-pyrido[1,2- a]pyrimidine-2-carboxamide;

N-[(6-{[(1-cyclohexylcyclopropyl)amino]methyl}imidazo[1,2 -a]pyridin-2-yl)methyl]-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

4-oxo-N-{[6-({[(1,3-thiazol-5-yl)methyl]amino}methyl)imid azo[1,2-a]pyridin-2-yl]methyl}-4H- pyrido[1,2-a]pyrimidine-2-carboxamide; tert-butyl 3-{[({2-[({4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl}formamido)me thyl]imidazo[1,2- a]pyridin-6-yl}methyl)amino]methyl}piperidine-1-carboxylate;

N-{[6-({[(4,4-difluorocyclohexyl)methyl]amino}methyl)imid azo[1,2-a]pyridin-2-yl]methyl}-4- oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide;

tert-butyl 2-{[({2-[({4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl}formamido)me thyl]imidazo[1,2- a]pyridin-6-yl}methyl)amino]methyl}piperidine-1-carboxylate;

N-[(6-{[(2-cyclopropylethyl)amino]methyl}imidazo[1,2-a]py ridin-2-yl)methyl]-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

4-oxo-N-({6-[(piperidin-1-yl)methyl]imidazo[1,2-a]pyridin -2-yl}methyl)-4H-pyrido[1,2- a]pyrimidine-2-carboxamide;

4-oxo-N-({6-[({[1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl] methyl}amino)methyl]imidazo[1,2- a]pyridin-2-yl}methyl)-4H-pyrido[1,2-a]pyrimidine-2-carboxam ide;

N-{[6-({[(1-methylcyclohexyl)methyl]amino}methyl)imidazo[ 1,2-a]pyridin-2-yl]methyl}-4-oxo- 4H-pyrido[1,2-a]pyrimidine-2-carboxamide;

4-oxo-N-{[6-({[2-(pyridin-3-yl)ethyl]amino}methyl)imidazo [1,2-a]pyridin-2-yl]methyl}-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-{[6-({[(1,4-dioxan-2-yl)methyl]amino}methyl)imidazo[1,2 -a]pyridin-2-yl]methyl}-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-({6-[(cyclopropylamino)methyl]imidazo[1,2-a]pyridin-2-y l}methyl)-4-oxo-4H-pyrido[1,2- a]pyrimidine-2-carboxamide;

N-[(6-{[(3,3-difluorocyclobutyl)amino]methyl}imidazo[1,2- a]pyridin-2-yl)methyl]-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-{[6-({[(oxetan-3-yl)methyl]amino}methyl)imidazo[1,2-a]p yridin-2-yl]methyl}-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

4-oxo-N-{[6-({[(1R,2R)-2-(trifluoromethyl)cyclopropyl]ami no}methyl)imidazo[1,2-a]pyridin-2- yl]methyl}-4H-pyrido[1,2-a]pyrimidine-2-carboxamide;

N-[(6-{[(2,2-dimethylpropyl)amino]methyl}imidazo[1,2-a]py ridin-2-yl)methyl]-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-[(6-{[(cyclohexylmethyl)(methyl)amino]methyl}imidazo[1, 2-a]pyridin-2-yl)methyl]-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-[(6-{[(4,4-difluorocyclohexyl)amino]methyl}imidazo[1,2- a]pyridin-2-yl)methyl]-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-({6-[({bicyclo[1.1.1]pentan-1-yl}amino)methyl]imidazo[1 ,2-a]pyridin-2-yl}methyl)-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

4-oxo-N-({6-[({[(2S)-oxolan-2-yl]methyl}amino)methyl]imid azo[1,2-a]pyridin-2-yl}methyl)-4H- pyrido[1,2-a]pyrimidine-2-carboxamide; 4-oxo-N-({6-[({[(2R)-oxolan-2-yl]methyl}amino)methyl]imidazo [1,2-a]pyridin-2-yl}methyl)-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-[(6-{[(2,2-difluoroethyl)amino]methyl}imidazo[1,2-a]pyr idin-2-yl)methyl]-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

4-oxo-N-{[6-({[(oxolan-3-yl)methyl]amino}methyl)imidazo[1 ,2-a]pyridin-2-yl]methyl}-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-{[6-({[(1-methylcyclopropyl)methyl]amino}methyl)imidazo [1,2-a]pyridin-2-yl]methyl}-4-oxo- 4H-pyrido[1,2-a]pyrimidine-2-carboxamide;

4-oxo-N-[(6-{[(oxolan-3-yl)amino]methyl}imidazo[1,2-a]pyr idin-2-yl)methyl]-4H-pyrido[1,2- a]pyrimidine-2-carboxamide;

methyl 3-methyl-2-[({2-[({4-oxo-4H-pyrido[1,2-a]pyrimidin-2- yl}formamido)methyl]imidazo[1,2-a]pyridin-6-yl}methyl)amino] butanoate;

N-[(6-{[(oxan-3-yl)amino]methyl}imidazo[1,2-a]pyridin-2-y l)methyl]-4-oxo-4H-pyrido[1,2- a]pyrimidine-2-carboxamide;

4-oxo-N-{[6-({[(2S)-3,3,3-trifluoro-2-hydroxypropyl]amino }methyl)imidazo[1,2-a]pyridin-2- yl]methyl}-4H-pyrido[1,2-a]pyrimidine-2-carboxamide;

N-({6-[(cyclobutylamino)methyl]imidazo[1,2-a]pyridin-2-yl }methyl)-4-oxo-4H-pyrido[1,2- a]pyrimidine-2-carboxamide; N-({6-[(tert-butylamino)methyl]imidazo[1,2-a]pyridin-2-yl}me thyl)-4-oxo-4H-pyrido[1,2- a]pyrimidine-2-carboxamide;

N-[(6-{[(2-fluoroethyl)amino]methyl}imidazo[1,2-a]pyridin -2-yl)methyl]-4-oxo-4H-pyrido[1,2- a]pyrimidine-2-carboxamide;

N-({6-[(4,4-difluoropiperidin-1-yl)methyl]imidazo[1,2-a]p yridin-2-yl}methyl)-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

4-oxo-N-({6-[(4-phenylpiperazin-1-yl)methyl]imidazo[1,2-a ]pyridin-2-yl}methyl)-4H-pyrido[1,2- a]pyrimidine-2-carboxamide;

4-oxo-N-({6-[(1,2,3,4-tetrahydroisoquinolin-2-yl)methyl]i midazo[1,2-a]pyridin-2-yl}methyl)-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-({6-[(diethylamino)methyl]imidazo[1,2-a]pyridin-2-yl}me thyl)-4-oxo-4H-pyrido[1,2- a]pyrimidine-2-carboxamide;

4-oxo-N-({6-[(pyrrolidin-1-yl)methyl]imidazo[1,2-a]pyridi n-2-yl}methyl)-4H-pyrido[1,2- a]pyrimidine-2-carboxamide;

4-oxo-N-[(6-{[3-(pyridin-2-yl)azetidin-1-yl]methyl}imidaz o[1,2-a]pyridin-2-yl)methyl]-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-[(6-{[(dicyclopropylmethyl)amino]methyl}imidazo[1,2-a]p yridin-2-yl)methyl]-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide; N-[(6-{[(cyclopropylmethyl)(methyl)amino]methyl}imidazo[1,2- a]pyridin-2-yl)methyl]-4-oxo- 4H-pyrido[1,2-a]pyrimidine-2-carboxamide;

N-({6-[(4-methylpiperidin-1-yl)methyl]imidazo[1,2-a]pyrid in-2-yl}methyl)-4-oxo-4H-pyrido[1,2- a]pyrimidine-2-carboxamide;

4-oxo-N-[(6-{[4-(trifluoromethyl)piperidin-1-yl]methyl}im idazo[1,2-a]pyridin-2-yl)methyl]-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-({6-[(3-methylpiperidin-1-yl)methyl]imidazo[1,2-a]pyrid in-2-yl}methyl)-4-oxo-4H-pyrido[1,2- a]pyrimidine-2-carboxamide;

4-oxo-N-[(6-{[({spiro[2.2]pentan-1-yl}methyl)amino]methyl }imidazo[1,2-a]pyridin-2-yl)methyl]- 4H-pyrido[1,2-a]pyrimidine-2-carboxamide;

N-({6-[(3,3-dimethylpiperidin-1-yl)methyl]imidazo[1,2-a]p yridin-2-yl}methyl)-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

4-oxo-N-[(6-{[3-(trifluoromethyl)piperidin-1-yl]methyl}im idazo[1,2-a]pyridin-2-yl)methyl]-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-{[6-({[(5,5-dimethyloxolan-2-yl)methyl]amino}methyl)imi dazo[1,2-a]pyridin-2-yl]methyl}-4- oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide;

N-({6-[(4-fluoropiperidin-1-yl)methyl]imidazo[1,2-a]pyrid in-2-yl}methyl)-4-oxo-4H-pyrido[1,2- a]pyrimidine-2-carboxamide;

N-[(6-{[(3-methoxypropyl)amino]methyl}imidazo[1,2-a]pyrid in-2-yl)methyl]-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-[(6-{[(1-methylcyclohexyl)amino]methyl}imidazo[1,2-a]py ridin-2-yl)methyl]-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-{[6-({[(4,4-dimethyloxolan-2-yl)methyl]amino}methyl)imi dazo[1,2-a]pyridin-2-yl]methyl}-4- oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide;

N-[(6-{[(1-methylcyclopentyl)amino]methyl}imidazo[1,2-a]p yridin-2-yl)methyl]-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

4-oxo-N-({6-[(propylamino)methyl]imidazo[1,2-a]pyridin-2- yl}methyl)-4H-pyrido[1,2- a]pyrimidine-2-carboxamide;

N-{[6-({[(3,3-dimethyloxolan-2-yl)methyl]amino}methyl)imi dazo[1,2-a]pyridin-2-yl]methyl}-4- oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide;

N-[(6-{[(2-methylpropyl)amino]methyl}imidazo[1,2-a]pyridi n-2-yl)methyl]-4-oxo-4H-pyrido[1,2- a]pyrimidine-2-carboxamide;

N-{[6-({[2-(tert-butoxy)ethyl]amino}methyl)imidazo[1,2-a] pyridin-2-yl]methyl}-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-[(6-{[(4-chlorophenyl)amino]methyl}imidazo[1,2-a]pyridi n-2-yl)methyl]-4-oxo-4H-pyrido[1,2- a]pyrimidine-2-carboxamide; N-{[6-({[2-(oxan-2-yl)ethyl]amino}methyl)imidazo[1,2-a]pyrid in-2-yl]methyl}-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-({6-[(4-benzylpiperidin-1-yl)methyl]imidazo[1,2-a]pyrid in-2-yl}methyl)-4-oxo-4H-pyrido[1,2- a]pyrimidine-2-carboxamide;

4-oxo-N-({6-[(4-phenoxypiperidin-1-yl)methyl]imidazo[1,2- a]pyridin-2-yl}methyl)-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-{[6-({[(2,2-difluorocyclopropyl)methyl]amino}methyl)imi dazo[1,2-a]pyridin-2-yl]methyl}-4- oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide;

N-{[6-({[(2,2-dimethylcyclopropyl)methyl]amino}methyl)imi dazo[1,2-a]pyridin-2-yl]methyl}-4- oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide;

N-{[6-({[(2-methyloxolan-2-yl)methyl]amino}methyl)imidazo [1,2-a]pyridin-2-yl]methyl}-4-oxo- 4H-pyrido[1,2-a]pyrimidine-2-carboxamide;

N-({6-[(4-tert-butylpiperidin-1-yl)methyl]imidazo[1,2-a]p yridin-2-yl}methyl)-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-[(6-{[(4-tert-butylcyclohexyl)amino]methyl}imidazo[1,2- a]pyridin-2-yl)methyl]-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-[(6-{[(2-cyclopentylethyl)amino]methyl}imidazo[1,2-a]py ridin-2-yl)methyl]-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-[(6-{[4-(2,2-dimethylpropanoyl)piperazin-1-yl]methyl}im idazo[1,2-a]pyridin-2-yl)methyl]-4- oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide;

N-({6-[(4-acetylpiperazin-1-yl)methyl]imidazo[1,2-a]pyrid in-2-yl}methyl)-4-oxo-4H-pyrido[1,2- a]pyrimidine-2-carboxamide;

N-{[6-({7-azabicyclo[2.2.1]heptan-7-yl}methyl)imidazo[1,2 -a]pyridin-2-yl]methyl}-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-({6-[(4,4-dimethylpiperidin-1-yl)methyl]imidazo[1,2-a]p yridin-2-yl}methyl)-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-({6-[(2,2-dimethylpiperidin-1-yl)methyl]imidazo[1,2-a]p yridin-2-yl}methyl)-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

4-oxo-N-[(6-{[(2,3,3-trimethylbutan-2-yl)amino]methyl}imi dazo[1,2-a]pyridin-2-yl)methyl]-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-[(6-{[(5-fluoropyridin-2-yl)amino]methyl}imidazo[1,2-a] pyridin-2-yl)methyl]-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-({6-[({[1,1'-bi(cyclopropane)]-1-yl}amino)methyl]imidaz o[1,2-a]pyridin-2-yl}methyl)-4-oxo- 4H-pyrido[1,2-a]pyrimidine-2-carboxamide;

N-{[6-({[(1-fluorocyclopentyl)methyl]amino}methyl)imidazo [1,2-a]pyridin-2-yl]methyl}-4-oxo- 4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-({6-[(2,6-dimethylmorpholin-4-yl)methyl]imidazo[1,2-a]pyri din-2-yl}methyl)-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

methyl 1-({2-[({4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl}formamido)meth yl]imidazo[1,2-a]pyridin- 6-yl}methyl)piperidine-3-carboxylate;

N-[(6-{[(2-fluoro-2-methylpropyl)amino]methyl}imidazo[1,2 -a]pyridin-2-yl)methyl]-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-[(6-{[(1-cyclohexylethyl)amino]methyl}imidazo[1,2-a]pyr idin-2-yl)methyl]-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-[(6-{[(2-cyclopropylethyl)(methyl)amino]methyl}imidazo[ 1,2-a]pyridin-2-yl)methyl]-4-oxo- 4H-pyrido[1,2-a]pyrimidine-2-carboxamide;

N-[(6-{[(2,2-dimethylpropyl)(methyl)amino]methyl}imidazo[ 1,2-a]pyridin-2-yl)methyl]-4-oxo- 4H-pyrido[1,2-a]pyrimidine-2-carboxamide;

N-{[6-({[(1-fluorocyclobutyl)methyl]amino}methyl)imidazo[ 1,2-a]pyridin-2-yl]methyl}-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-({6-[(4-fluoro-4-methylpiperidin-1-yl)methyl]imidazo[1, 2-a]pyridin-2-yl}methyl)-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-({6-[(3,3-difluoropiperidin-1-yl)methyl]imidazo[1,2-a]p yridin-2-yl}methyl)-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-{[6-({[(1-hydroxycyclohexyl)methyl]amino}methyl)imidazo [1,2-a]pyridin-2-yl]methyl}-4-oxo- 4H-pyrido[1,2-a]pyrimidine-2-carboxamide;

N-[(6-{[(cyclopentylmethyl)amino]methyl}imidazo[1,2-a]pyr idin-2-yl)methyl]-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-{[6-({[(3,3-difluorocyclopentyl)methyl]amino}methyl)imi dazo[1,2-a]pyridin-2-yl]methyl}-4- oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide;

N-[(6-{[(cyclobutylmethyl)amino]methyl}imidazo[1,2-a]pyri din-2-yl)methyl]-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-{[6-({[2-(3,3-difluorocyclobutyl)ethyl]amino}methyl)imi dazo[1,2-a]pyridin-2-yl]methyl}-4- oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide;

N-{[6-({[(2-fluorocyclobutyl)methyl]amino}methyl)imidazo[ 1,2-a]pyridin-2-yl]methyl}-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-{[6-({[(2S)-3,3-dimethylbutan-2-yl]amino}methyl)imidazo [1,2-a]pyridin-2-yl]methyl}-4-oxo- 4H-pyrido[1,2-a]pyrimidine-2-carboxamide;

N-{[6-({6-azaspiro[2.5]octan-6-yl}methyl)imidazo[1,2-a]py ridin-2-yl]methyl}-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

4-oxo-N-({6-[({[(1r,3r)-3-fluorocyclobutyl]methyl}amino)m ethyl]imidazo[1,2-a]pyridin-2- yl}methyl)-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; 4-oxo-N-({6-[(2-phenylethyl)amino]imidazo[1,2-a]pyridin-2-yl }methyl)-4H-pyrido[1,2- a]pyrimidine-2-carboxamide;

N-({6-[2-(benzylamino)ethyl]imidazo[1,2-a]pyridin-2-yl}me thyl)-4-oxo-4H-pyrido[1,2- a]pyrimidine-2-carboxamide;

N-({6-[2-(cyclohexylamino)ethyl]imidazo[1,2-a]pyridin-2-y l}methyl)-4-oxo-4H-pyrido[1,2- a]pyrimidine-2-carboxamide;

4-oxo-N-({6-[(phenylformamido)methyl]imidazo[1,2-a]pyridi n-2-yl}methyl)-4H-pyrido[1,2- a]pyrimidine-2-carboxamide;

N-({6-[(cyclohexylformamido)methyl]imidazo[1,2-a]pyridin- 2-yl}methyl)-4-oxo-4H-pyrido[1,2- a]pyrimidine-2-carboxamide;

4-oxo-N-{[6-({[(piperidin-3-yl)methyl]amino}methyl)imidaz o[1,2-a]pyridin-2-yl]methyl}-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

4-oxo-N-{[6-({[(piperidin-2-yl)methyl]amino}methyl)imidaz o[1,2-a]pyridin-2-yl]methyl}-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-[(6-{[(azetidin-3-yl)amino]methyl}imidazo[1,2-a]pyridin -2-yl)methyl]-4-oxo-4H-pyrido[1,2- a]pyrimidine-2-carboxamide;

N-({6-[(cyclohexylamino)methyl]imidazo[1,2-a]pyridin-2-yl }methyl)-4-oxo-4H-chromene-2- carboxamide;

N-[(6-{[(2-cyclopropylethyl)amino]methyl}imidazo[1,2-a]py ridin-2-yl)methyl]-4-oxo-4H- chromene-2-carboxamide;

4-oxo-N-({6-[(piperidin-1-yl)methyl]imidazo[1,2-a]pyridin -2-yl}methyl)-4H-chromene-2- carboxamide;

N-{[6-({[(4-chlorophenyl)methyl]amino}methyl)imidazo[1,2- a]pyridin-2-yl]methyl}-4-oxo-4H- chromene-2-carboxamide;

N-({6-[(benzylamino)methyl]imidazo[1,2-a]pyridin-2-yl}met hyl)-4-oxo-4H-chromene-2- carboxamide;

N-{[6-({[(1-methylcyclohexyl)methyl]amino}methyl)imidazo[ 1,2-a]pyridin-2-yl]methyl}-4-oxo- 4H-chromene-2-carboxamide;

N-[(6-{[(2,2-dimethylpropyl)amino]methyl}imidazo[1,2-a]py ridin-2-yl)methyl]-4-oxo-4H- chromene-2-carboxamide;

4-oxo-N-[(7-{[(2-phenylethyl)amino]methyl}imidazo[1,2-a]p yridin-2-yl)methyl]-4H-pyrido[1,2- a]pyrimidine-2-carboxamide;

N-[(7-{[(cyclohexylmethyl)amino]methyl}imidazo[1,2-a]pyri din-2-yl)methyl]-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-[(7-{[(cyclopropylmethyl)amino]methyl}imidazo[1,2-a]pyr idin-2-yl)methyl]-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide; N-[(6-{1-[(cyclohexylmethyl)amino]cyclopropyl}imidazo[1,2-a] pyridin-2-yl)methyl]-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-{[6-(2-amino-3-phenylpropyl)imidazo[1,2-a]pyridin-2-yl] methyl}-4-oxo-4H-pyrido[1,2- a]pyrimidine-2-carboxamide;

(cyclohexylmethyl)[(2-{[4-(1H-indazol-4-yl)-1H-1,2,3-tria zol-1-yl]methyl}imidazo[1,2-a]pyridin- 6-yl)methyl]amine;

N-(cyclohexylmethyl)-2-{[4-(1H-indazol-4-yl)-1H-1,2,3-tri azol-1-yl]methyl}imidazo[1,2- a]pyridine-6-carboxamide;

(2,2-dimethylpropyl)[(2-{[4-(1H-indazol-4-yl)-1H-1,2,3-tr iazol-1-yl]methyl}imidazo[1,2- a]pyridin-6-yl)methyl]amine;

4-[1-({6-[(4,4-dimethylpiperidin-1-yl)methyl]imidazo[1,2- a]pyridin-2-yl}methyl)-1H-1,2,3- triazol-4-yl]-1H-indazole;

[(2-{[4-(6-bromo-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl]m ethyl}imidazo[1,2-a]pyridin-6- yl)methyl][(3,3-difluorocyclobutyl)methyl]amine;

[(2-{[4-(6-bromo-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl]m ethyl}imidazo[1,2-a]pyridin-6- yl)methyl](2,2-dimethylpropyl)amine;

[(2-{[4-(6-bromo-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl]m ethyl}imidazo[1,2-a]pyridin-6- yl)methyl](cyclohexylmethyl)amine;

6-bromo-4-[1-({6-[(4,4-dimethylpiperidin-1-yl)methyl]imid azo[1,2-a]pyridin-2-yl}methyl)-1H- 1,2,3-triazol-4-yl]-1H-indazole;

(2-{[4-(6-bromo-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl]me thyl}imidazo[1,2-a]pyridin-6- yl)methanol;

(2,2-dimethylpropyl)[(2-{[4-(1H-indazol-5-yl)-1H-1,2,3-tr iazol-1-yl]methyl}imidazo[1,2- a]pyridin-6-yl)methyl]amine;

((cyclohexylmethyl)[1-(2-{[4-(1H-indazol-4-yl)-1H-1,2,3-t riazol-1-yl]methyl}imidazo[1,2- a]pyridin-6-yl)ethyl]amine;

(2,2-dimethylpropyl)({2-[(4-{1H-pyrazolo[3,4-c]pyridin-4- yl}-1H-1,2,3-triazol-1- yl)methyl]imidazo[1,2-a]pyridin-6-yl}methyl)amine;

{2-[(4-{1H-pyrazolo[3,4-c]pyridin-4-yl}-1H-1,2,3-triazol- 1-yl)methyl]imidazo[1,2-a]pyridin-6- yl}methanol;

N-({6-[(3R,5S)-5-tert-butylmorpholin-3-yl]imidazo[1,2-a]p yridin-2-yl}methyl)-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-({6-[(3S,5R)-5-tert-butylmorpholin-3-yl]imidazo[1,2-a]p yridin-2-yl}methyl)-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-({6-[(3S,5R)-5-cyclohexylmorpholin-3-yl]imidazo[1,2-a]p yridin-2-yl}methyl)-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide; N-({6-[(3S,5R)-5-cyclohexylmorpholin-3-yl]imidazo[1,2-a]pyri din-2-yl}methyl)-1H-indazole-4- carboxamide;

N-({6-[(3S,5R)-5-cyclohexylmorpholin-3-yl]imidazo[1,2-a]p yridin-2-yl}methyl)-4-oxo-4H- chromene-2-carboxamide;

N-({6-[4-(2,2-dimethylpropyl)morpholin-3-yl]imidazo[1,2-a ]pyridin-2-yl}methyl)-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-({6-[(3S,5R)-5-methylmorpholin-3-yl]imidazo[1,2-a]pyrid in-2-yl}methyl)-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide;

N-{[6-(9-methoxy-2,3,4,5-tetrahydro-1,4-benzoxazepin-3-yl )imidazo[1,2-a]pyridin-2- yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide;

4-[1-[[6-[(cyclobutylmethylamino)methyl]imidazo[1,2-a]pyr idin-2-yl]methyl]triazol-4-yl]-1H- indazol-6-ol

4-[1-[[6-[[(1-hydroxycyclobutyl)methylamino]methyl]imidaz o[1,2-a]pyridin-2-yl]methyl]triazol- 4-yl]-1H-indazol-6-ol

1-[[[2-[[4-(5-methoxy-1H-indazol-4-yl)triazol-1-yl]methyl ]imidazo[1,2-a]pyridin-6- yl]methylamino]methyl]cyclobutanol

1-[[[2-[[4-(6-methoxy-1H-indazol-4-yl)triazol-1-yl]methyl ]imidazo[1,2-a]pyridin-6- yl]methylamino]methyl]cyclobutanol

N-(cyclobutylmethyl)-1-[2-[[4-(6-methoxy-1H-indazol-4-yl) triazol-1-yl]methyl]imidazo[1,2- a]pyridin-6-yl]methanamine

N-(cyclobutylmethyl)-1-[2-[[4-(5-methoxy-1H-indazol-4-yl) triazol-1-yl]methyl]imidazo[1,2- a]pyridin-6-yl]methanamine

4-[1-[(6-methylimidazo[1,2-a]pyridin-2-yl)methyl]triazol- 4-yl]-1H-indazol-3-amine

N-[[6-[[(1-methoxycyclobutyl)methylamino]methyl]imidazo[1 ,2-a]pyridin-2-yl]methyl]-4-oxo- pyrido[1,2-a]pyrimidine-2-carboxamide

N-[[6-(1,4-oxazepan-3-yl)imidazo[1,2-a]pyridin-2-yl]methy l]-4-oxo-pyrido[1,2-a]pyrimidine-2- carboxamide

N-[[6-[[(2-cyano-2-methyl-propyl)amino]methyl]imidazo[1,2 -a]pyridin-2-yl]methyl]-4-oxo- pyrido[1,2-a]pyrimidine-2-carboxamide

N-[[6-[[(3-fluoro-1-bicyclo[1.1.1]pentanyl)methylamino]me thyl]imidazo[1,2-a]pyridin-2- yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide

4-oxo-N-[[6-[(spiro[3.3]heptan-2-ylmethylamino)methyl]imi dazo[1,2-a]pyridin-2- yl]methyl]pyrido[1,2-a]pyrimidine-2-carboxamide

4-oxo-N-[[6-[(spiro[2.3]hexan-5-ylmethylamino)methyl]imid azo[1,2-a]pyridin-2- yl]methyl]pyrido[1,2-a]pyrimidine-2-carboxamide

N-[[6-[(1-bicyclo[1.1.1]pentanylmethylamino)methyl]imidaz o[1,2-a]pyridin-2-yl]methyl]-4-oxo- pyrido[1,2-a]pyrimidine-2-carboxamide 4-oxo-N-[[6-[(spiro[2.3]hexan-2-ylamino)methyl]imidazo[1,2-a ]pyridin-2-yl]methyl]pyrido[1,2- a]pyrimidine-2-carboxamide

N-[[6-[[(2-methoxy-2-methyl-propyl)amino]methyl]imidazo[1 ,2-a]pyridin-2-yl]methyl]-4-oxo- pyrido[1,2-a]pyrimidine-2-carboxamide

N-[[6-[[(1-methylcyclobutyl)methylamino]methyl]imidazo[1, 2-a]pyridin-2-yl]methyl]-4-oxo- pyrido[1,2-a]pyrimidine-2-carboxamide

N-[[6-(butylaminomethyl)imidazo[1,2-a]pyridin-2-yl]methyl ]-4-oxo-pyrido[1,2-a]pyrimidine-2- carboxamide

N-[[6-[[(1-hydroxycyclopentyl)methylamino]methyl]imidazo[ 1,2-a]pyridin-2-yl]methyl]-4-oxo- pyrido[1,2-a]pyrimidine-2-carboxamide

N-[[6-[(2-methylbutylamino)methyl]imidazo[1,2-a]pyridin-2 -yl]methyl]-4-oxo-pyrido[1,2- a]pyrimidine-2-carboxamide

N-[[6-[(2-cyclobutylethylamino)methyl]imidazo[1,2-a]pyrid in-2-yl]methyl]-4-oxo-pyrido[1,2- a]pyrimidine-2-carboxamide

N-[[6-[[(2-hydroxy-2-methyl-propyl)amino]methyl]imidazo[1 ,2-a]pyridin-2-yl]methyl]-4-oxo- pyrido[1,2-a]pyrimidine-2-carboxamide

N-[[6-[[(1-hydroxycyclobutyl)methylamino]methyl]imidazo[1 ,2-a]pyridin-2-yl]methyl]-4-oxo- pyrido[1,2-a]pyrimidine-2-carboxamide

N-[[6-[(2-hydroxybutylamino)methyl]imidazo[1,2-a]pyridin- 2-yl]methyl]-4-oxo-pyrido[1,2- a]pyrimidine-2-carboxamide

N-[[6-[[(3-methylcyclobutyl)methylamino]methyl]imidazo[1, 2-a]pyridin-2-yl]methyl]-4-oxo- pyrido[1,2-a]pyrimidine-2-carboxamide

N-[[6-[[(3,3-dimethylcyclobutyl)methylamino]methyl]imidaz o[1,2-a]pyridin-2-yl]methyl]-4-oxo- pyrido[1,2-a]pyrimidine-2-carboxamide

N-[[6-[(2,2-dimethylbutylamino)methyl]imidazo[1,2-a]pyrid in-2-yl]methyl]-4-oxo-pyrido[1,2- a]pyrimidine-2-carboxamide

N-[[6-[[[(2S)-2-methylbutyl]amino]methyl]imidazo[1,2-a]py ridin-2-yl]methyl]-4-oxo-pyrido[1,2- a]pyrimidine-2-carboxamide

1-[[[2-[[4-(6-bromo-1H-indazol-4-yl)triazol-1-yl]methyl]i midazo[1,2-a]pyridin-6- yl]methylamino]methyl]cyclohexanol

1-[[[2-[[4-(6-bromo-1H-indazol-4-yl)triazol-1-yl]methyl]i midazo[1,2-a]pyridin-6- yl]methylamino]methyl]cyclobutanol

1-[2-[[4-(6-bromo-1H-indazol-4-yl)triazol-1-yl]methyl]imi dazo[1,2-a]pyridin-6-yl]-N- (cyclobutylmethyl)methanamine

4-[1-[[6-[(cyclobutylmethylamino)methyl]imidazo[1,2-a]pyr idin-2-yl]methyl]triazol-4-yl]-1H- indazole-6-carboxylic acid 4-[1-[[6-[(cyclobutylmethylamino)methyl]imidazo[1,2-a]pyridi n-2-yl]methyl]triazol-4-yl]-1H- indazole-6-carboxamide

4-[1-[[6-[(cyclobutylmethylamino)methyl]imidazo[1,2-a]pyr idin-2-yl]methyl]triazol-4-yl]-N,N- dimethyl-1H-indazole-6-carboxamide

[4-[1-[[6-[(cyclobutylmethylamino)methyl]imidazo[1,2-a]py ridin-2-yl]methyl]triazol-4-yl]-1H- indazol-6-yl]-morpholino-methanone

4-[1-[[6-[(cyclobutylmethylamino)methyl]imidazo[1,2-a]pyr idin-2-yl]methyl]triazol-4-yl]-N-(2- hydroxyethyl)-1H-indazole-6-carboxamide

1-[2-[[4-(6-chloro-1H-indazol-4-yl)triazol-1-yl]methyl]im idazo[1,2-a]pyridin-6-yl]-N- (cyclobutylmethyl)methanamine

1-[[[2-[[4-(6-chloro-1H-indazol-4-yl)triazol-1-yl]methyl] imidazo[1,2-a]pyridin-6- yl]methylamino]methyl]cyclobutanol

N-[[2-[[4-(6-chloro-1H-indazol-4-yl)triazol-1-yl]methyl]i midazo[1,2-a]pyridin-6-yl]methyl]-2,2- dimethyl-propan-1-amine

N-(cyclobutylmethyl)-1-[2-[[4-(7-fluoro-1H-indazol-4-yl)t riazol-1-yl]methyl]imidazo[1,2- a]pyridin-6-yl]methanamine

1-[[[2-[[4-(7-fluoro-1H-indazol-4-yl)triazol-1-yl]methyl] imidazo[1,2-a]pyridin-6- yl]methylamino]methyl]cyclohexanol

N-(cyclohexylmethyl)-1-[2-[[4-(7-fluoro-1H-indazol-4-yl)t riazol-1-yl]methyl]imidazo[1,2- a]pyridin-6-yl]methanamine

1-[[[2-[[4-(7-fluoro-1H-indazol-4-yl)triazol-1-yl]methyl] imidazo[1,2-a]pyridin-6- yl]methylamino]methyl]cyclobutanol

1-[[[2-[[4-(7-fluoro-1H-indazol-4-yl)triazol-1-yl]methyl] imidazo[1,2-a]pyridin-6- yl]methylamino]methyl]cyclopentanamine

N-[[6-[(4,4-dimethyl-1-piperidyl)methyl]imidazo[1,2-a]pyr idin-2-yl]methyl]-5-fluoro-4-oxo- chromene-2-carboxamide

N-(cyclobutylmethyl)-1-[2-[[4-(6-morpholino-1H-indazol-4- yl)triazol-1-yl]methyl]imidazo[1,2- a]pyridin-6-yl]methanamine

6-[2-(2-aminoethoxy)ethoxy]-N-[[6-[(4,4-dimethyl-1-piperi dyl)methyl]imidazo[1,2-a]pyridin-2- yl]methyl]-1H-indazole-4-carboxamide

N-[[6-[1-(cyclobutylmethylamino)-2-phenyl-ethyl]imidazo[1 ,2-a]pyridin-2-yl]methyl]-4-oxo- pyrido[1,2-a]pyrimidine-2-carboxamide

N-[[6-[1-[bis(cyclobutylmethyl)amino]-2-phenyl-ethyl]imid azo[1,2-a]pyridin-2-yl]methyl]-4-oxo- pyrido[1,2-a]pyrimidine-2-carboxamide

1-[2-[[4-(7-chloro-1H-indazol-4-yl)triazol-1-yl]methyl]im idazo[1,2-a]pyridin-6-yl]-N- (cyclobutylmethyl)methanamine 1-[[[2-[[4-(7-chloro-1H-indazol-4-yl)triazol-1-yl]methyl]imi dazo[1,2-a]pyridin-6- yl]methylamino]methyl]cyclobutanol

[2-[[4-(6-fluoro-1H-indazol-4-yl)triazol-1-yl]methyl]imid azo[1,2-a]pyridin-6-yl]methanol N-(cyclobutylmethyl)-1-[2-[[4-(6-fluoro-1H-indazol-4-yl)tria zol-1-yl]methyl]imidazo[1,2- a]pyridin-6-yl]methanamine

1-[[[2-[[4-(6-fluoro-1H-indazol-4-yl)triazol-1-yl]methyl] imidazo[1,2-a]pyridin-6- yl]methylamino]methyl]cyclobutanol

N-(cyclohexylmethyl)-1-[2-[[4-(6-fluoro-1H-indazol-4-yl)t riazol-1-yl]methyl]imidazo[1,2- a]pyridin-6-yl]methanamine

N-[[2-[[4-(6-cyclopropyl-1H-indazol-4-yl)triazol-1-yl]met hyl]imidazo[1,2-a]pyridin-6-yl]methyl]- 2,2-dimethyl-propan-1-amine

N-[[6-[(cyclobutylmethylamino)methyl]imidazo[1,2-a]pyridi n-2-yl]methyl]-1H-indazole-4- carboxamide

N-(cyclobutylmethyl)-1-[2-[[4-(1H-pyrazolo[4,3-c]pyridin- 4-yl)triazol-1-yl]methyl]imidazo[1,2- a]pyridin-6-yl]methanamine

N-(cyclohexylmethyl)-1-[2-[[4-(1H-pyrazolo[4,3-c]pyridin- 4-yl)triazol-1-yl]methyl]imidazo[1,2- a]pyridin-6-yl]methanamine

1-[[[2-[[4-(1H-pyrazolo[4,3-c]pyridin-4-yl)triazol-1-yl]m ethyl]imidazo[1,2-a]pyridin-6- yl]methylamino]methyl]cyclobutanol

N-(cyclobutylmethyl)-1-[2-[[4-(1H-indazol-4-yl)triazol-1- yl]methyl]imidazo[1,2-a]pyridin-6- yl]methanamine

1-[[[2-[[4-(1H-indazol-4-yl)triazol-1-yl]methyl]imidazo[1 ,2-a]pyridin-6- yl]methylamino]methyl]cyclohexanol

2-[[4-(1H-indazol-4-yl)imidazol-1-yl]methyl]-6-methyl-imi dazo[1,2-a]pyridine

N-[[6-[2-cyano-1-(cyclobutylmethylamino)ethyl]imidazo[1,2 -a]pyridin-2-yl]methyl]-4-oxo- pyrido[1,2-a]pyrimidine-2-carboxamide

N-[[6-(6-methylmorpholin-3-yl)imidazo[1,2-a]pyridin-2-yl] methyl]-4-oxo-pyrido[1,2- a]pyrimidine-2-carboxamide

N-[[6-(7-bromo-9-methoxy-2,3,4,5-tetrahydro-1,4-benzoxaze pin-3-yl)imidazo[1,2-a]pyridin-2- yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide

4-oxo-N-[(6-piperazin-2-ylimidazo[1,2-a]pyridin-2-yl)meth yl]pyrido[1,2-a]pyrimidine-2- carboxamide

N-[[6-(6-cyclohexyl-4-oxo-2-piperidyl)imidazo[1,2-a]pyrid in-2-yl]methyl]-4-oxo-pyrido[1,2- a]pyrimidine-2-carboxamide

1-[2-(1H-indazol-4-yl)thiazol-5-yl]-1-(6-methylimidazo[1, 2-a]pyridin-2-yl)ethanol

2-[[1-(1H-indazol-4-yl)triazol-4-yl]methyl]imidazo[1,2-a] pyridine N-[(3,3-difluorocyclobutyl)methyl]-1-[2-[[1-(1H-indazol-4-yl )triazol-4-yl]methyl]imidazo[1,2- a]pyridin-6-yl]methanamine

4-[1-[[6-[(cyclobutylmethylamino)methyl]imidazo[1,2-a]pyr idin-2-yl]methyl]triazol-4-yl]-1H- indazole-6-carbonitrile

N-(cyclobutylmethyl)-1-[2-[[4-(1H-indazol-4-yl)imidazol-1 -yl]methyl]imidazo[1,2-a]pyridin-6- yl]methanamine

N-[[6-[[acetyl(cyclobutylmethyl)amino]methyl]imidazo[1,2- a]pyridin-2-yl]methyl]-4-oxo- pyrido[1,2-a]pyrimidine-2-carboxamide

N-(cyclobutylmethyl)-1-[2-[[3-(1H-indazol-4-yl)-1,2,4-tri azol-1-yl]methyl]imidazo[1,2-a]pyridin- 6-yl]methanamine

2-[1-[[6-[(cyclobutylmethylamino)methyl]imidazo[1,2-a]pyr idin-2-yl]methyl]triazol-4- yl]pyrido[1,2-a]pyrimidin-4-one

N-[[6-[(2-bicyclo[2.2.1]hept-5-enylmethylamino)methyl]imi dazo[1,2-a]pyridin-2-yl]methyl]-4- oxo-pyrido[1,2-a]pyrimidine-2-carboxamide

N-[[6-[[[(1R,2R,4S)-norbornan-2-yl]methylamino]methyl]imi dazo[1,2-a]pyridin-2-yl]methyl]-4- oxo-pyrido[1,2-a]pyrimidine-2-carboxamide

N-[[6-[[[(1R,2S,4S)-norbornan-2-yl]methylamino]methyl]imi dazo[1,2-a]pyridin-2-yl]methyl]-4- oxo-pyrido[1,2-a]pyrimidine-2-carboxamide

N-[[6-(2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl)imidazo [1,2-a]pyridin-2-yl]methyl]-4-oxo- pyrido[1,2-a]pyrimidine-2-carboxamide

N-[[6-(2-azabicyclo[2.2.1]heptan-2-ylmethyl)imidazo[1,2-a ]pyridin-2-yl]methyl]-4-oxo- pyrido[1,2-a]pyrimidine-2-carboxamide

N-[[6-(2-azabicyclo[2.2.2]octan-2-ylmethyl)imidazo[1,2-a] pyridin-2-yl]methyl]-4-oxo- pyrido[1,2-a]pyrimidine-2-carboxamide

N-[[6-[[(2,2-difluorospiro[3.3]heptan-6-yl)amino]methyl]i midazo[1,2-a]pyridin-2-yl]methyl]-4- oxo-pyrido[1,2-a]pyrimidine-2-carboxamide

4-oxo-N-[[6-[[[rac-(1S,2S,4S)-7-oxabicyclo[2.2.1]hept-5-e n-2- yl]methylamino]methyl]imidazo[1,2-a]pyridin-2-yl]methyl]pyri do[1,2-a]pyrimidine-2- carboxamide

4-oxo-N-[[6-[[[rac-(1S,2R,4S)-7-oxabicyclo[2.2.1]hept-5-e n-2- yl]methylamino]methyl]imidazo[1,2-a]pyridin-2-yl]methyl]pyri do[1,2-a]pyrimidine-2- carboxamide; and

N-[(1-methoxycyclobutyl)methyl]-1-[2-[[4-(6-methoxy-1H-in dazol-4-yl)triazol-1- yl]methyl]imidazo[1,2-a]pyridin-6-yl]methanamine.

[00192] The various functional groups and substituents making up the compounds of the formula (I) are typically chosen such that the molecular weight of the compound of the formula (I) does not exceed 1000. More usually, the molecular weight of the compound will be less than 900, for example less than 800, or less than 750, or less than 700, or less than 650. More preferably, the molecular weight is less than 600 and, for example, is 550 or less.

[00193] 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.

[00194] 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”.

[00195] The compounds of this invention may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (S)-stereoisomers or as mixtures thereof. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see discussion in Chapter 4 of “Advanced Organic Chemistry”, 4th edition J. March, John Wiley and Sons, New York, 2001), for example by synthesis from optically active starting materials or by resolution of a racemic form. Some of the compounds of the invention may have geometric isomeric centres (E- and Z- isomers). It is to be understood that the present invention encompasses all optical, diastereoisomers and geometric isomers and mixtures thereof that possess antiproliferative activity.

[00196]The present invention also encompasses compounds of the invention as defined herein which comprise one or more isotopic substitutions. For example, H may be in any isotopic form, including ¹ H, ² H(D), and ³ H (T); C may be in any isotopic form, including ¹² C, ¹³ C, and ¹⁴ C; and O may be in any isotopic form, including ¹⁶ O and ¹⁸ O; and the like.

[00197] It is also to be understood that certain compounds of the formula (I) (and compounds of formula (II), (III) and (IV)) may exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms that possess antiproliferative activity.

[00198] It is also to be understood that certain compounds of the formula (I) (and compounds of formula (II), (III) and (IV)) may exhibit polymorphism, and that the invention encompasses all such forms that possess antiproliferative activity.

[00199] Compounds of the formula (I) (and compounds of formula (II), (III) and (IV)) may exist in a number of different tautomeric forms and references to compounds of the formula (I) include all such forms. For the avoidance of doubt, where a compound can exist in one of several tautomeric forms, and only one is specifically described or shown, all others are nevertheless embraced by formula (I). Examples of tautomeric forms include keto-, enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto/enol (illustrated below), imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime, thioketone/enethiol, and nitro/aci-nitro.

keto enol enolate

[00200] Compounds of the formula (I) containing an amine function may also form N-oxides. A reference herein to a compound of the formula (I) that contains an amine function also includes the N-oxide. Where a compound contains several amine functions, one or more than one nitrogen atom may be oxidised to form an N-oxide. Particular examples of N-oxides are the N-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle. N- Oxides can be formed by treatment of the corresponding amine with an oxidizing agent such as hydrogen peroxide or a per-acid (e.g. a peroxycarboxylic acid), see for example Advanced Organic Chemistry, by Jerry March, 4 ^th 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.

[00201] The compounds of formula (I) may be administered in the form of a pro-drug which is broken down in the human or animal body to release a compound of the invention. A pro- drug may be used to alter the physical properties and/or the pharmacokinetic properties of a compound of the invention. A pro-drug can be formed when the compound of the invention contains a suitable group or substituent to which a property-modifying group can be attached. Examples of pro-drugs include in vivo cleavable ester derivatives that may be formed at a carboxy group or a hydroxy group in a compound of the formula (I) 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).

[00202] Accordingly, the present invention includes those compounds of the formula I as defined hereinbefore when made available by organic synthesis and when made available within the human or animal body by way of cleavage of a pro-drug thereof. Accordingly, the present invention includes those compounds of the formula (I) that are produced by organic synthetic means and also such compounds that are produced in the human or animal body by way of metabolism of a precursor compound, that is a compound of the formula (I) may be a synthetically-produced compound or a metabolically-produced compound.

[00203] A suitable pharmaceutically acceptable pro-drug of a compound of the formula (I) is one that is based on reasonable medical judgement as being suitable for administration to the human or animal body without undesirable pharmacological activities and without undue toxicity.

[00204] Various forms of pro-drug have been described, for example in the following documents :- a) Methods in Enzymology, Vol.42, p.309-396, edited by K. Widder, et al. (Academic Press, 1985);

b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985);

c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5“Design and Application of Pro-drugs”, by H. Bundgaard p.113-191 (1991);

d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992);

e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988);

f) N. Kakeya, et al., Chem. Pharm. Bull., 32, 692 (1984); g) T. Higuchi and V. Stella,“Pro-Drugs as Novel Delivery Systems”, A.C.S. Symposium Series, Volume 14; and

h) E. Roche (editor),“Bioreversible Carriers in Drug Design”, Pergamon Press, 1987.

[00205] A suitable pharmaceutically acceptable pro-drug of a compound of the formula (I) that possesses a carboxy group is, for example, an in vivo cleavable ester thereof. An in vivo cleavable ester of a compound of the formula (I) containing a carboxy group is, for example, a pharmaceutically acceptable ester which is cleaved in the human or animal body to produce the parent acid. Suitable pharmaceutically acceptable esters for carboxy include C _1-6 alkyl esters such as methyl, ethyl and tert-butyl, C _1-6 alkoxymethyl esters such as methoxymethyl esters, C _1-6 alkanoyloxymethyl esters such as pivaloyloxymethyl esters, 3-phthalidyl esters, C _3-8 cycloalkylcarbonyloxy- C _1-6 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 C _1-6 alkoxycarbonyloxy- C _1-6 alkyl esters such as methoxycarbonyloxymethyl and 1- methoxycarbonyloxyethyl esters.

[00206] A suitable pharmaceutically acceptable pro-drug of a compound of the formula (I) that possesses a hydroxy group is, for example, an in vivo cleavable ester or ether thereof. An in vivo cleavable ester or ether of a compound of the formula (I) containing a hydroxy group is, for example, a pharmaceutically acceptable ester or ether which is cleaved in the human or animal body to produce the parent hydroxy compound. Suitable pharmaceutically acceptable ester forming groups for a hydroxy group include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters). Further suitable pharmaceutically acceptable ester forming groups for a hydroxy group include C1-10alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, C1- 10alkoxycarbonyl groups such as ethoxycarbonyl, N,N–(C _1-6 )2carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and 4-(C _1-4 alkyl)piperazin-1-ylmethyl. Suitable pharmaceutically acceptable ether forming groups for a hydroxy group include a-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.

[00207] A suitable pharmaceutically acceptable pro-drug of a compound of the formula (I) that possesses a carboxy group is, for example, an in vivo cleavable amide thereof, for example an amide formed with an amine such as ammonia, a C _1-4 alkylamine such as methylamine, a (C _1-4 alkyl)2amine such as dimethylamine, N-ethyl-N-methylamine or diethylamine, a C _1-4 alkoxy- C _2-4 alkylamine such as 2-methoxyethylamine, a phenyl-C1- ₄ alkylamine such as benzylamine and amino acids such as glycine or an ester thereof.

[00208] A suitable pharmaceutically acceptable pro-drug of a compound of the formula (I) that possesses an amino group is, for example, an in vivo cleavable amide derivative thereof. Suitable pharmaceutically acceptable amides from an amino group include, for example an amide formed with C _1-10 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-(C _1-4 alkyl)piperazin-1-ylmethyl.

[00209] The in vivo effects of a compound of the formula (I) may be exerted in part by one or more metabolites that are formed within the human or animal body after administration of a compound of the formula (I). As stated hereinbefore, the in vivo effects of a compound of the formula (I) may also be exerted by way of metabolism of a precursor compound (a pro- drug).

[00210] 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.

[00211] Suitably, the present invention excludes any individual compounds not possessing the biological activity defined herein.

Synthesis

[00212] 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.

[00213] 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.

[00214] 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. [00215] It will be appreciated that during the synthesis of the compounds of the invention in the processes defined herein, or during the synthesis of certain starting materials, it may be desirable to protect certain substituent groups to prevent their undesired reaction. The skilled chemist will appreciate when such protection is required, and how such protecting groups may be put in place, and later removed.

[00216] 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.

[00217] 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.

[00218] 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 tert-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulfuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a 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.

[00219] 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.

[00220] A suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a t-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.

[00221] Resins may also be used as a protecting group.

[00222] The methodology employed to synthesise a compound of formula I will vary depending on the nature of the variable groups. Suitable processes for their preparation are described further in the accompanying Examples.

[00223] Once a compound of formula I has been synthesised by any one of the processes defined herein, the processes may then further comprise the additional steps of: (i) removing any protecting groups present;

(ii) converting the compound formula I into another compound of formula I;

(iii) forming a pharmaceutically acceptable salt, hydrate or solvate thereof; and/or (iv) forming a prodrug thereof.

[00224] The resultant compounds of formula I can be isolated and purified using techniques well known in the art.

Biological Activity

[00225] The METTL3 enzyme and cell assays described in accompanying Example section may be used to measure the pharmacological effects of the compounds of the present invention.

[00226] 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 these METTL3 assays.

[00227] In general, the compounds of the invention demonstrate an IC50 of 10 µM or less in the METTL3 enzyme assay described herein, with preferred compounds of the invention demonstrating an IC50 of 5 µM or less and the most preferred compounds of the invention demonstrating an IC50 of 2 µM or less. [00228] In the METTL3 cell assay described in the Example section, the compounds of formula (I) suitably possess an activity of less than 10 µM, with preferred compounds of the invention demonstrating an IC ₅₀ of 5 µM or less and the most preferred compounds demonstrating an activity of 2 µM or less.

Pharmaceutical Compositions

[00229] 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 thereof, and one or more pharmaceutically acceptable excipients.

[00230] 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).

[00231] 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.

[00232] 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 and/or treat or prevent an autoimmune disease referred to herein, slow its progression and/or reduce the symptoms associated with the condition and/or disease.

[00233] 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.

[00234] 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.

[00235] In using a compound of the invention for therapeutic or prophylactic purposes it will generally be administered so that a daily dose in the range, for example, 0.1 mg/kg to 75 mg/kg body weight is received, given if required in divided doses. In general lower doses will be administered when a parenteral route is employed. Thus, for example, for intravenous or intraperitoneal administration, a dose in the range, for example, 0.1 mg/kg to 30 mg/kg body weight will generally be used. Similarly, for administration by inhalation, a dose in the range, for example, 0.05 mg/kg to 25 mg/kg body weight will be used. Oral administration may also be suitable, particularly in tablet form. Typically, unit dosage forms will contain about 0.5 mg to 0.5 g of a compound of this invention.

Therapeutic Uses and Applications

[00236] The present invention provides compounds that function as inhibitors of METTL3 activity.

[00237] The present invention therefore provides a method of inhibiting METTL3 activity in vitro or in vivo, said method comprising contacting a cell with an effective amount of a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

[00238] The present invention also provides a method of treating a disease or disorder in which METTL3 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 thereof, or a pharmaceutical composition as defined herein. Suitably, the disease or disorder in which METTL3 activity is implicated is cancer, such as lung cancer, renal cancer, solid organ cancer, pancreactic cancer or leukaemia, type 2 diabetes, a neuropsychiatric behavioural disorder or a depressive disorder.

[00239] The present invention provides a method of inhibiting cell proliferation, in vitro or in vivo, said method comprising contacting a cell with an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as defined herein.

[00240] The present invention provides a method of treating a proliferative disorder, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

[00241] The present invention provides a method of treating cancer, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein. Suitably the cancer is lung cancer, renal cancer, solid organ cancer, pancreatic cancer or leukaemia suitably AML leukaemia or chronic myeloid leukaemia.

[00242] The present invention provides a method of treating leukaemia, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

[00243] The present invention provides a method of treating AML leukaemia, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

[00244] The present invention provides a method of treating an autoimmune disease, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein. Suitably the autoimmune disease is colitis, multiple sclerosis, rheumatoid arthritis, lupus, cirrhosis, or dermatitis.

[00245] The present invention provides a method of treating a neurological disease, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

[00246] The present invention provides a method of treating an infectious disease, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

[00247] The present invention provides a method of treating an inflammatory disease, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

[00248] The present invention provides a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein for use in therapy.

[00249] The present invention provides a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein for use in the treatment of a proliferative condition.

[00250] The present invention provides a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein for use in the treatment of cancer. In a particular embodiment, the cancer is human cancer. Suitably the cancer is lung cancer, renal cancer, solid organ cancer, pancreatic cancer or leukaemia suitably AML leukaemia or chronic myeloid leukaemia.

[00251] The present invention provides a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein for use in the treatment of leukaemia.

[00252] The present invention provides a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein for use in the treatment of AML leukaemia.

[00253] The present invention provides a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein for use in the inhibition of METTL3 activity.

[00254] The present invention provides a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein for use in the treatment of an autoimmune disease. Suitably the autoimmune disease is colitis, multiple sclerosis, rheumatoid arthritis, lupus, cirrhosis, or dermatitis.

[00255] The present invention provides a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein for use in the treatment of an neurological disease.

[00256] The present invention provides a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein for use in the treatment of an infectious disease.

[00257] The present invention provides a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein for use in the treatment of an inflammatory disease.

[00258] The present invention provides a compound, or a pharmaceutically acceptable salt thereof, as defined herein for use in the treatment of a disease or disorder in which METTL3 activity is implicated. Suitably, the disease or disorder in which METTL3 activity is implicated is cancer, such as lung cancer, renal cancer, solid organ cancer, pancreatic cancer or leukaemia, type 2 diabetes, a neuropsychiatric behavioural disorder or a depressive disorder.

[00259] The present invention provides a use of a compound, or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for the treatment of a proliferative condition.

[00260] The present invention provides a use of a compound, or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for the treatment of cancer. Suitably, the medicament is for use in the treatment of human cancers. Suitably the cancer is lung cancer, renal cancer, solid organ cancer, pancreatic cancer or leukaemia suitably AML leukaemia or chronic myeloid leukaemia.

[00261] The present invention provides a use of a compound, or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for the treatment of leukaemia.

[00262] The present invention provides a use of a compound, or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for the treatment of AML leukaemia.

[00263] The present invention provides a use of a compound, or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for the treatment of an autoimmune disease. Suitably the autoimmune disease is colitis, multiple sclerosis, rheumatoid arthritis, lupus, cirrhosis, or dermatitis.

[00264] The present invention provides a use of a compound, or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for the treatment of a neurological disease.

[00265] The present invention provides a use of a compound, or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for the treatment of an inflammatory disease.

[00266] The present invention provides a use of a compound, or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for the treatment of an infectious disease.

[00267] The present invention provides a use of a compound, or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for the inhibition of METTL3 activity.

[00268] The present invention provides a use of a compound, or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for the treatment of a disease or disorder in which METTL3 activity is implicated. Suitably, the disease or disorder in which METTL3 activity is implicated is cancer, such as lung cancer, renal cancer, solid organ cancer, pancreatic cancer or leukaemia, type 2 diabetes, a neuropsychiatric behavioural disorder or a depressive disorder. [00269] The term "proliferative disorder" are used interchangeably herein and pertain to an unwanted or uncontrolled cellular proliferation of excessive or abnormal cells which is undesired, such as, neoplastic or hyperplastic growth, whether in vitro or in vivo. Examples of proliferative conditions include, but are not limited to, pre-malignant and malignant cellular proliferation, including but not limited to, malignant neoplasms and tumours, cancers, leukemias, psoriasis, bone diseases, fibroproliferative disorders (e.g., of connective tissues), and atherosclerosis. Any type of cell may be treated, including but not limited to, lung, colon, breast, ovarian, prostate, liver, pancreas, brain and skin.

[00270] The anti-proliferative effects of the compounds of the present invention have particular application in the treatment of human cancers (by virtue of their inhibition of METTL3 activity).

[00271] The anti-cancer effect may arise through one or more mechanisms, including but not limited to, the regulation of cell proliferation, the inhibition of angiogenesis (the formation of new blood vessels), the inhibition of metastasis (the spread of a tumour from its origin), the inhibition of invasion (the spread of tumour cells into neighbouring normal structures), or the promotion of apoptosis (programmed cell death).

[00272] In a particular embodiment of the invention, the proliferative condition to be treated is cancer.

Routes of Administration

[00273] 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).

[00274] Routes of administration include, but are not limited to, oral (e.g, by ingestion); buccal; sublingual; transdermal (including, e.g., by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or insufflation therapy using, e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intra-arterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal; by implant of a depot or reservoir, for example, subcutaneously or intramuscularly.

Combination Therapies

[00275] The antiproliferative treatment defined hereinbefore may be applied as a sole therapy or may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy. Such chemotherapy may include one or more of the following categories of anti-tumour agents:- (i) other antiproliferative/antineoplastic drugs and combinations thereof, as used in medical oncology, such as alkylating agents (for example cis-platin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan, temozolamide and nitrosoureas); antimetabolites (for example gemcitabine and antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, and hydroxyurea); antitumour antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine and taxoids like taxol and taxotere and polokinase inhibitors); and topoisomerase inhibitors (for example epipodophyllotoxins like etoposide and teniposide, amsacrine, topotecan and camptothecin);

(ii) cytostatic agents such as antioestrogens (for example tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5 a-reductase such as finasteride;

(iii) anti-invasion agents [for example c-Src kinase family inhibitors like 4-(6-chloro-2,3- methylenedioxyanilino)-7-[2-(4-methylpiperazin-1-yl)ethoxy]- 5-tetrahydropyran-4- yloxyquinazoline (AZD0530; International Patent Application WO 01/94341), N-(2-chloro-6- methylphenyl)-2-{6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-meth ylpyrimidin-4-ylamino}thiazole- 5-carboxamide (dasatinib, BMS-354825; J. Med. Chem., 2004, 47, 6658-6661) and bosutinib (SKI-606), and metalloproteinase inhibitors like marimastat, inhibitors of urokinase plasminogen activator receptor function or antibodies to Heparanase];

(iv) inhibitors of growth factor function: for example such inhibitors include growth factor antibodies and growth factor receptor antibodies (for example the anti-erbB2 antibody trastuzumab [Herceptin™], the anti-EGFR antibody panitumumab, the anti-erbB1 antibody cetuximab [Erbitux, C225] and any growth factor or growth factor receptor antibodies disclosed by Stern et al. (Critical reviews in oncology/haematology, 2005, Vol. 54, pp11-29); such inhibitors also include tyrosine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as 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) and 6- acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropox y)-quinazolin-4-amine (CI 1033), erbB2 tyrosine kinase inhibitors such as lapatinib); inhibitors of the hepatocyte growth factor family; inhibitors of the insulin growth factor family; inhibitors of the platelet-derived growth factor family such as imatinib and/or nilotinib (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 (for example AZD1152, PH739358, VX-680, MLN8054, R763, MP235, MP529, VX-528 AND AX39459) and cyclin dependent kinase inhibitors such as CDK2 and/or CDK4 inhibitors;

(v) antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, [for example the anti-vascular endothelial cell growth factor antibody bevacizumab (Avastin™) and for example, a VEGF receptor tyrosine kinase inhibitor such as vandetanib (ZD6474), vatalanib (PTK787), sunitinib (SU11248), axitinib (AG-013736), pazopanib (GW 786034) and 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidin -1- ylpropoxy)quinazoline (AZD2171; Example 240 within WO 00/47212), compounds such as those disclosed in International Patent Applications WO97/22596, WO 97/30035, WO 97/32856 and WO 98/13354 and compounds that work by other mechanisms (for example linomide, inhibitors of integrin ^v ^3 function and angiostatin)];

(vi) vascular damaging agents such as Combretastatin A4 and compounds disclosed in International Patent Applications WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213;

(vii) an endothelin receptor antagonist, for example zibotentan (ZD4054) or atrasentan; (viii) antisense therapies, for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense;

(ix) gene therapy approaches, including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy;

(x) immunotherapy approaches, including for example ex-vivo and in-vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches using anti-idiotypic antibodies; and

(xi) Agents used to treat AML leukaemia, including for example, cytarabine, FLT3 inhibitors, BCL2 inhibitors or IDH1/2 inhibitors.

[00276] In a particular embodiment, the antiproliferative treatment defined hereinbefore may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy.

[00277] 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.

[00278] 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 thereof, and another anti-tumour agent.

[00279] 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 thereof, and any one of the anti-tumour agents listed herein above.

[00280] In a further aspect of the invention there is provided a compound of the invention or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer in combination with another anti-tumour agent, optionally selected from one listed herein above.

[00281] Herein, where the term“combination” is used it is to be understood that this refers to simultaneous, separate or sequential administration. In one aspect of the invention “combination” refers to simultaneous administration. In another aspect of the invention “combination” refers to separate administration. In a further aspect of the invention “combination” refers to sequential administration. Where the administration is sequential or separate, the delay in administering the second component should not be such as to lose the beneficial effect of the combination.

[00282] 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 thereof, in combination with an anti-tumour agent (optionally selected from one listed herein above), in association with a pharmaceutically acceptable diluent or carrier.

[00283] In another embodiment, the invention relates to a therapeutic combination comprising a compound as defined herein and another agent ised to treat AML leukeamia e.g., cytarabine, FLT3 inhibitors, BCL2 inhibitors or IDH1/2 inhibitors.

Examples

The following abbreviations have been used in the Examples:

[00284] HATU - [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]-dim ethyl- ammonium;hexafluorophosphate

[00285] DIPEA - N-ethyl-N-isopropyl-propan-2-amine

[00286] DEAD– Diethylazodicarboxylate

[00287] DMF– Dimethylformamide

[00288] RT– Retention Time

[00289] Phase sep cartridge– Telos phase separator 6 mL

Example 1: Characterisation Methodology

The following HPLC methodology was used:

Method 1:

Method 2:

Method 3:

Method 4:

The following LCMS methodologies were used:

LCMS method A refers to low pH analysis using a mobile phase consisting of 0.1% formic acid in a gradient of 5-100% MeCN in water over 1.2 min at a flow rate of 1.2 mL/min. The stationary phase consisted of a Kinetex Core-Shell C18, 2.1mmx50mm, 5 µm. The experiment was run at 40 ºC. LCMS Method B refers to high pH analysis using a mobile phase consisting of 2 mM ammonium bicarbonate, buffered to pH10 in a gradient of 5-100% MeCN in water over 2.1 min at a flow rate of 1.0 mL/min. The stationary phase consisted of a Phenomenex Gemini- NX C18, 2.0 x 50 mm, 3 µm. The experiment was run at 40 ºC. LCMS Method C refers to high pH analysis using a mobile phase consisting of 2 mM ammonium bicarbonate, buffered to pH10 in a gradient of 5-100% MeCN in water over 5.8 min at a flow rate of 0.6 mL/min. The stationary phase consisted of a Waters UPLC® BEH ^TM C18, 2.1 x 100 mm, 1.7 µm. The experiment was run at 40 ºC. LCMS Method D refers to high pH analysis using a mobile phase consisting of 2 mM ammonium bicarbonate, buffered to pH10 in a gradient of 5-100% MeCN in water over 5.9 min at a flow rate of 0.6 mL/min. The stationary phase consisted of a Phenomenex Gemini– NX C18, 2.0 x 100 mm, 3 µm. The experiment was run at 40 ºC. LCMS method E refers to low pH analysis using a mobile phase consisting of 0.1% formic acid in a gradient of 5-100% MeCN in water over 5.3 min at a flow rate of 0.6 mL/min. The stationary phase consisted of a Phenomenex Kinetix-XB C18, 2.1mm x 100 mm, 1.7 µm. The experiment was run at 40 ºC. LCMS method F refers to high pH analysis using a mobile phase consisting of 2 mM ammonium bicarbonate, buffered to pH10 in a gradient of 5-100% MeCN in water over 0.75 min at a flow rate of 1.0 mL/min. The stationary phase consisted of a Waters UPLC® BEH ^TM C18, 2.1 x 100 mm, 1.7 µm. The experiment was run at 40 ºC. Method G refers to low pH analysis using a mobile phase consisting of 0.1 % Formic acid in water (pH= 2.70) in a gradient of 3-100% of 0.1% formic acid in water: acetonitrile (10:90) over 3.00 min at a flow rate of 0.8 mL/min. The stationary phase consisted of C18,

50*2.1mm, 1.6 µm column. The experiment was run at 35 ºC. Method H refers to a high pH analysis using a mobile phase consisting of 5 mM ammonium bicarbonate, (pH 7.35) in a gradient of MeCN in water over 3.0 min at a flow rate of 0.5 mL/min. The stationary phase consisted of C18, 50*2.1mm, 2.5 µm. The experiment was run at 35 ºC. Method I refers to a high pH analysis using a mobile phase consisting of 5 mM ammonium bicarbonate, (pH 7.35) in a gradient of MeCN in water over 3.0 min at a flow rate of 0.5 mL/min. The stationary phase consisted of C18, 50*2.1mm, 2.5 µm. The experiment was run at 35 ºC.

The following preparative HPLC methodologies were used:

Preparative Method A refers to low pH purification using a mobile phase consisting of 0.1% Formic acid in a gradient of 10-95% MeCN in water over 14.4 min at a flow rate of 40 mL/min. The stationary phase consisted of a Waters Sunfire C18, 30 x 100 mm, 10 µm. Preparative Method B refers to high pH purification using a mobile phase consisting of 0.2% ammonium hydroxide in a gradient of 30-95% MeCN in water over 10 min at a flow rate of 40 mL/min. The stationary phase consisted of a Waters XBridge ^TM C18 OBD ^TM , 30 x 100 mm, 10 µm. Example 2: Chemical Synthesis and Characterisation

[00290] Synthesis of Intermediate 1: 6-bromo-1-tetrahydropyran-2-yl-indazole-4- carboxylic acid

[00291] Step 1: methyl 6-bromo-1-tetrahydropyran-2-yl-indazole-4-carboxylate

Methyl 6-bromo-1H-indazole-4-carboxylate (1.0g, 3.92mmol) and TsOH.H2O (75mg, 0.39mmol) were combined in DCM (40ml) and 3,4-dihydro-2H-pyran (1.07ml, 11.8mmol) was added. The mixture was stirred at room temperature for 20 minutes during which time the mixture darkened. The mixture was quenched with aqueous sodium hydrogen carbonate (sat, 100ml) and the mixture was stirred vigorously for 5 minutes. The phases were separated, the aqueous phase was extracted with DCM (3 x 80ml) and the combined organic extracts were dried over sodium sulfate and evaporated under vacuum. The residue was purified by chromatography on silica gel (Biotage 50 g eluting with 0-50% ethyl acetate/heptane) to afford the title compound (1.26g, 92%) as a white solid.

LCMS Method A (electrospray): m/z = 338.9/340.9 (M+H) ⁺ , RT = 1.34 min.

[00292] Step 2: 6-bromo-1-tetrahydropyran-2-yl-indazole-4-carboxylic acid

A solution of methyl 6-bromo-1-tetrahydropyran-2-yl-indazole-4-carboxylate (600mg, 1.77mol) in THF (10ml) and Water (10ml) was treated with lithium hydroxide (132mg, 5.31mmol) and the mixture was heated at 60°C for 90 minutes. The reaction mixture was cooled to room temperature and concentrated under vacuum. The residue was diluted with water (10ml) and acidified to ~pH1 using 1M HCl(aq). The mixture was then extracted with chloroform/isopropanol (3:1, 4 x 30ml) and the combined organic extracts were dried over sodium sulfate and evaporated under vacuum to afford the title compound (566mg, 97%) as a white solid.

LCMS Method A (electrospray): m/z = 324.9/326.9 (M+H) ⁺ , RT = 1.14 min.

[00293] Synthesis of Intermediate 2: 1-tetrahydropyran-2-yl-6-(2-tetrahydropyran- 2-ylpyrazol-3-yl)indazole-4-carboxylic acid

[00294] Step 1: methyl 1-tetrahydropyran-2-yl-6-(2-tetrahydropyran-2-ylpyrazol-3- yl)indazole-4-carboxylate

[00295] Methyl 6-bromo-1-tetrahydropyran-2-yl-indazole-4-carboxylate Intermediate 1 Step 1 (300mg, 0.88mmol), 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-pyrazole (295mg, 1.06mmol) and aqueous K ₂ CO ₃ (1.2M, 2.21ml, 2.65mmol) were combined in 1,4-Dioxane (6ml) and the mixture was sparged with nitrogen for 5 mins. 1,1'-bis(di-tert-butylphosphanyl)ferrocene - dichloropalladium [Pd-118] (58mg, 0.09mmol) was added and the mixture sparged for a further 5 mins. The vessel was sealed and the mixture heated at 100°C for 2 hours. The reaction mixture was cooled to RT, diluted with aqueous Sodium hydrogen carbonate (sat, 30ml) and extracted with ethyl acetate (2 x 50ml). The combined organic extracts were washed with brine (4 x 30ml), dried over sodium sulfate and evaporated under vacuum. The residue was purified by chromatography on silica gel (Biotage 25 g, eluting with 0-50% ethyl acetate/heptane) to afford the title compound (291mg, 79%) as a yellow foam.

LCMS Method A (electrospray): m/z = 433.1 (M+H) ⁺ , RT = 1.29 min. [00296] Step 2: The title compound was prepared using the procedure described in Intermediate 1 Step 2 giving (175mg, 62%) as an off-white solid.

LCMS Method A (electrospray): m/z = 395.15 (M+H) ⁺ , RT = 1.11 min. [00297] Synthesis of Intermediate 3: 6-ethynyl-1-(oxan-2-yl)-1H-indazole-4- carboxylic acid

[00298] Step 1: Methyl 1-tetrahydropyran-2-yl-6-(2-trimethylsilylethynyl)indazole-4 - carboxylate

[00299] Methyl 6-bromo-1-tetrahydropyran-2-yl-indazole-4-carboxylate (500mg, 1.47mmol), PdCl ₂ (PPh ₃ ) ₂ (104mg, 0.15mmol), CuI (28mg, 0.15mmol) and triethylamine (1.03ml, 7.37mmol) were combined in DMF (3ml) and the mixture sparged with nitrogen for 5mins. Ethynyl(trimethyl)silane (1.0ml, 7.37mmol) was added, the mixture sparged briefly and the vessel sealed. The mixture was heated at 100°C for 2.5h. The reaction mixture was cooled to RT, diluted with ethyl acetate (50ml) and washed with sat. aqueous Sodium hydrogen carbonate (50ml) and brine (5 x 50ml). The organic layer was dried over sodium sulfate and evaporated under vacuum. The residue was purified by Chromatography on silica gel [Biotage 50 g, eluting with 0-30% ethyl acetate/heptane] to afford the title compound (553mg (99% yield) as a pale brown oil.

LCMS Method A (electrospray): m/z = 357.1 (M+H) ⁺ , RT = 1.54 min. [00300] Step 2: The title compound was prepared from methyl 1-tetrahydropyran-2-yl- 6-(2-trimethylsilylethynyl)indazole-4-carboxylate using the method described in Intermediate 1 Step 2 giving (342mg, 75%) as a pale brown solid.

LCMS Method A (electrospray): m/z = 270.95 (M+H) ⁺ , RT = 1.10 min. [00301] Synthesis of Intermediate 4: 4-oxo-4H-pyrido[1,2-a]pyrimidine-2- carboxylic acid hydrochloride

[00302] A suspension of methyl 4-oxopyrido[1,2-a]pyrimidine-2-carboxylate

[Tetrahedron (2014), 70(17), 2761-2765] (5g, 24.5mmol) in THF (150ml) was treated with potassium trimethylsilanolate (6.28g, 49.0mmol) and the mixture was heated at reflux for an hour before HCl Solution (4M HCl in dioxane 15ml) was added and the heating was continued for 15 mins before cooling to room temperature. The solid was collected by filtration, washed with diethyl ether and dried under suction to afford the title compound (7.98g, 86%) as a pale yellow solid which contained ~40% residual KCl.

LCMS Method B (electrospray): m/z = 191.2 (M+H) ⁺ , RT = 0.23 min. [00303] Synthesis of Intermediate 5: 8-methoxy-4-oxo-4H-pyrido[1,2- a]pyrimidine-2-carboxylic acid

[00304] Step 1: methyl 8-methoxy-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxylate

[00305] A suspension of 4-methoxypyridin-2-amine (2g, 16.1mmol) in Water (150ml) was stirred vigorously whilst dimethyl but-2-ynedioate (2.38ml, 19.3mmol) was added slowly and the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with DCM (100ml) and allowed to stand at room temperature overnight. The phases were separated and the aqueous phase was extracted with DCM (2 x 80ml), the combined organic extracts were dried over sodium sulfate and evaporated under vacuum to a residue which was purified by chromatography on silica gel [Biotage 50 g eluting with 50- 100% ethyl acetate/heptane] to afford a crude material which was triturated with ethyl acetate/heptane. The solids were collected by filtration and washed with heptane to afford the title compound (850mg (23%) as a beige solid.

LCMS Method B (electrospray): m/z = 235.2 (M+H) ⁺ , RT = 1.20 min. [00306] Step 2: The title compound was prepared from methyl 8-methoxy-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxylate using the method described in Intermediate 1 Step 2 giving (535 mg, 67%) as a white solid.

LCMS Method B (electrospray): m/z = 221.2 (M+H) ⁺ , RT = 0.31 min. [00307] Synthesis of Intermediate 6: 7-chloro-4-oxo-4H-pyrido[1,2-a]pyrimidine- 2-carboxylic acid

[00308] The title compound was prepared from methyl 7-chloro-4-oxo-pyrido[1,2- a]pyrimidine-2-carboxylate [Tetrahedron (2014), 70(17), 2761-2765] using the method described in Intermediate 1 Step 2 giving (195 mg, 51%) as a pale yellow solid.

LCMS Method B (electrospray): m/z = 225.1 (M+H) ⁺ , RT = 0.31 min. [00309] Synthesis of Intermediate 7: {7-bromoimidazo[1,2-a]pyridin-2- yl}methanamine

Step 1: 2-[(7-bromoimidazo[1,2-a]pyridin-2-yl)methyl]isoindoline-1,3 -dione

[00310] A suspension of 4-bromopyridin-2-amine (2g, 11.6mmol) and 2-(3-bromo-2- oxo-propyl)isoindoline-1,3-dione (3.26g, 11.6mmol) (US7105508, 2006) in Ethanol (40ml) was heated at reflux for 3 hours during which time the materials slow dissolved followed by a slow precipitation. The mixture was cooled to room temperature and the solids were collected by filtration, washed with MeOH followed by diethyl ether and dried under vacuum to afford the title compound (3.09g, 51%) as a white solid.

LCMS Method B (electrospray): m/z = 356.1/358.1 (M+H) ⁺ , RT = 1.49 min. [00311] Step 2: {7-bromoimidazo[1,2-a]pyridin-2-yl}methanamine 2-[(7-bromoimidazo[1,2-a]pyridin-2-yl)methyl]isoindoline-1,3 -dione (3.09g, 5.89mmol) and hydrazine hydrate (2.9ml, 59.0mmol) were combined in Ethanol (40ml) and the mixture was stirred at room temperature for 2 hours. The solids were collected by filtration and the filtrate was left standing overnight. Further solids were collected by filtration. The filtrates were evaporated directly onto silica gel (kp-NH) and the solids were deposited onto a short plug of kp-NH silica and the system eluted with 10% MeOH/DCM. The eluent was evaporated to afford the title compound (1.09g 72% yield) as a pale yellow solid

LCMS Method B: LC-MS (electrospray): m/z = 226.1/228.1 (M+H) ⁺ , RT = 1.25 min. [00312] Synthesis of Intermediate 8: {6-chloroimidazo[1,2-a]pyridin-2- yl}methanamine

[00313] Step 1: 6-chloro-2-(chloromethyl)imidazo[1,2-a]pyridine

A suspension of 5-chloropyridin-2-amine (1.0 g, 7.78 mmol) and 1,3-dichloropropan-2-one (0.71 mL, 7.8 mmol) in ethanol (7.4 mL) was heated to 80 °C for 3 hours. The mixture was cooled to room temperature and evaporated to dryness under vacuum. The residue was diluted with Sodium hydrogen carbonate (sat, 20 mL) and extracted with DCM (3 x 15 mL). The combined organics were evaporated under vacuum and the residue was purified by chromatography on silica gel (Biotage; 50 g KPNH eluting with 0-100% ethyl

acetate/heptane) to afford the title compound (435 mg, 28 % Yield) as an orange solid.

Method A: LC-MS (electrospray): m/z = 200.85 (M+H) ⁺ , RT = 0.64 min. [00314] Step 2: (6-chloroimidazo[1,2-a]pyridin-2-yl)methanamine

A solution of 6-chloro-2-(chloromethyl)imidazo[1,2-a]pyridine (750 mg, 3.73 mmol) in ammonia solution (7M in methanol, 5.3 mL, 37.3 mmol) was stirred at room temperature for 16 hours and at 60 ^o C for 3 hours. The mixture allowed to cool to room temperature and left standing for two days before it was evaporated under vacuum. The residue was purified by chromatography on silica gel [Biotage; KP-NH 28 g eluting with 0-10% MeOH in DCM] to give the title compound (83 mg, 9.2% Yield) as a yellow sticky solid.

Method A: LC-MS (electrospray): m/z = 181.9 (M+H) ⁺ , RT = 0.23 min. [00315] Synthesis of Intermediates 9-13

[00316] The intermediates listed in table 1 were prepared in the same way as Intermediate 8 using the appropriate aminopyridine.

Table 1

[00317] Synthesis of Intermediate 14: N-[(6-bromoimidazo[1,2-a]pyridin-2- yl)methyl]-1-tetrahydropyran-2-yl-indazole-4-carboxamide

[00318] Prepared from 1-tetrahydropyran-2-ylindazole-4-carboxylic acid and (6- bromoimidazo[1,2-a]pyridin-2-yl)methanamine using the procedure described in Compound 1 and purified by chromatography on silica gel [Biotage 50 g eluting with 0-10% MeOH/DCM] to give the title compound (950 mg, 83%) as an orange solid.

LCMS Method B (electrospray): m/z = 454./456. (M+H) ⁺ , RT = 1.49 min. [00319] Synthesis of Intermediate 15: 2-amino-2-(6-methylimidazo[1,2-a]pyridin- 2-yl)ethanol

[00320] Step 1: 2-methyl-N-[(1Z)-{6-methylimidazo[1,2-a]pyridin-2- yl}methylidene]propane-2-sulfinamide

A solution of 6-methylimidazo[1,2-a]pyridine-2-carbaldehyde (550 mg, 3.43 mmol) (Eur. J. Org. Chem.2015 (18), 3957) and 2-methylpropane-2-sulfinamide (378 mg, 3.12 mmol) in DCM (20 mL),under a nitrogen atmosphere, was treated with CuSO4.5 H2O (1.0g, 6.24 mmol) and the resultant blue solution was stirred at room temperature for 85 hours. The dark green suspension was filtered through Celite washing with DCM and the filtrate was concentrated under vacuum and purified by chromatography on silica gel [Biotage 50 g eluting with 20-100% ethyl acetate/heptane] to give the title compound (553 mg, 67%) as an off white solid.

LCMS Method B (electrospray): m/z = 264.2 (M+H) ⁺ , RT = 1.37 min. [00321] Step 2: N-[2-hydroxy-1-(6-methylimidazo[1,2-a]pyridin-2-yl)ethyl]-2- methyl- propane-2-sulfinamide

[00322] 2-methyl-N-[(1Z)-{6-methylimidazo[1,2-a]pyridin-2-yl}methyli dene]propane-2- sulfinamide (430 mg, 1.63 mmol), and potassium;2-methylpropan-2-olate (550 mg, 4.90 mmol) were combined in a microwave vial, toluene (anhydrous, 2.9 mL) was added and the mixture was degassed via a stream of N ₂ and the resultant suspension was heated at 50 ^o C for 16 hours. The mixture was cooled to room temperature, degassed via a stream of N ₂ , and heated at 100 ^o C for 3 hours. The purple mixture was quenched by the addition of NH ₄ Cl (sat) and extracted with DCM (phase sep cartridge) and the organic phase was evaporated under vacuum to a purple gum 332 mg. The gum was dissolved in THF/water (6:1) 3.5 mL and treated with NaBO ₃ .4H ₂ O (440 mg, 2.85 mml) and the mixture was stirred at room temperature for an hour. The mixture was diluted with water and extracted with DCM. The organics were dried (magnesium sulfate) and evaporated under vacuum to a residue which was purified by chromatography on silica gel [Biotage KPNH 11g, eluting with 0-100% ethyl acetate/heptane] to give the title compound (mixture of diastereoisomers, 70 mg, 14%) as a dark gum.

LCMS Method B (electrospray): m/z = 295.9 (M+H) ⁺ , RT = 0.70/0.75 min. [00323] Step 3: The title compound was prepared from N-[2-hydroxy-1-(6- methylimidazo[1,2-a]pyridin-2-yl)ethyl]-2-methyl-propane-2-s ulfinamide using the procedure described in Compound 1 and purified by ion exchange [SCX-2] giving (50 mg 45%) as a dark gum.

LCMS Method B (electrospray): m/z = 192.3 (M+H) ⁺ , RT = 1.09 min. [00324] Synthesis of Intermediate 16: N-[(6-cyanoimidazo[1,2-a]pyridin-2- yl)methyl]-1-tetrahydropyran-2-yl-indazole-4-carboxamide

[00325] Prepared from 1-tetrahydropyran-2-ylindazole-4-carboxylic acid and (6- cyanoimidazo[1,2-a]pyridin-2-yl)methanamine (commercial) using the procedure described in Compound 1 and purified by trituration with cold ethyl acetate to give the title compound (3.8 g, 98%) as a light brown solid.

LCMS Method A (electrospray): m/z = 401.1 (M+H) ⁺ , RT = 0.92 min. [00326] Synthesis of Intermediate 17: 3-{imidazo[1,2-a]pyridin-2-yl}-2,5-dihydro- 1H-pyrrole dihydrochloride

[00327] Step 1: tert-butyl 3-imidazo[1,2-a]pyridin-2-yl-2,5-dihydropyrrole-1- carboxylate

[00328] A mixture of 2-bromoimidazo[1,2-a]pyridine (520mg, 2.64mmol), tert-butyl 3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydropyr role-1-carboxylate (935mg, 3.17mmol) and K ₂ CO ₃ (1.2M aqueous solution, 6.6ml, 7.92mmol) were combined in 1,4- Dioxane (12ml) and the mixture sparged with nitrogen for 5mins. Pd-118 (86mg, 0.13mmol) was added and the mixture sparged for a further 5mins. The vessel was sealed and the mixture heated at 100°C for 2.5h. The reaction mixture was cooled to room temperature diluted with ethyl acetate (100ml), washed with aqueous sodium hydrogen carbonate (sat, 80ml) and brine (3 x 80ml). The organic layer was dried over sodium sulfate and evaporated under vacuum to a residue which was purified by chromatography on silica gel (Biotage 25 g, eluting with 50-100% ethyl acetate/heptane) to afford the title compound (669mg, 89%) as a pale yellow solid

Method A: LC-MS (electrospray): m/z = 286.5 (M+H) ⁺ , RT = 0.90 min. [00329] Step 2: The title compound was prepared from tert-butyl 3-imidazo[1,2- a]pyridin-2-yl-2,5-dihydropyrrole-1-carboxylate using the procedure described in Compound 1 and purified by trituration with ethyl acetate/heptane giving (606 mg, 100%) as a white solid.

LCMS Method A (electrospray): m/z = 186.0 (M+H) ⁺ , RT = 0.14 min. [00330] Synthesis of Intermediate 18: N-({6-formylimidazo[1,2-a]pyridin-2- yl}methyl)-1-(oxan-2-yl)-1H-indazole-4-carboxamide

Isopropylmagnesium chloride lithium chloride complex (1.3M in THF, 4.1 mL, 5.35 mmol) was added dropwise to a solution of N-[(6-bromoimidazo[1,2-a]pyridin-2-yl)methyl]-1- tetrahydropyran-2-yl-indazole-4-carboxamide (Intermediate 14) (750 mg, 1.34 mmol) in THF (10 mL) at -78 ^o C. Once the addition was complete the mixture was stirred at -78 ^o C for 10 minutes and allowed to warm to 5 ^o C over 3 hours. The mixture was then allowed to warm to room temperature and stirred for 30 minutes before it was cooled to -70 ^o C and treated with DMF (414 uL, 5.35 mmol) and allowed to slowly warm to room temperature overnight. The mixture was quenched by the addition of HCl (2M, 15 mL), basified with aqueous NaOH (2M) and extracted with ethyl acetate (2 x 15 mL). The combined organics were washed with brine, dried (magnesium sulfate) evaporated to dryness under reduced pressure to afford the title compound (460 mg, 42%, 1:1 mixture with N-({imidazo[1,2-a]pyridin-2-yl}methyl)-1- (oxan-2-yl)-1H-indazole-4-carboxamide) as a brown gum which was used without further purification.

LCMS Method A (electrospray): m/z = 404.5 (M+H) ⁺ , RT = 0.90 min. [00331] Synthesis of Intermediate 19: 2-{6-methylimidazo[1,2-a]pyridin-2- yl}acetic acid

5-methylpyridin-2-amine (2g, 18.5mmol) and ethyl 4-chloro-3-oxo-butanoate (2.50ml, 18.5mmol) were combined in Ethanol (20ml) and the mixture was heated at reflux for 3 hours and then stirred at room temperature for 16 hours. The reaction mixture

was concentrated under vacuum, the residue was basified with aqueous sodium hydrogen carbonate (sat, 300ml) and extracted with DCM (4 x 150ml). The extracts were dried over sodium sulfate and evaporated under vacuum. The residue was purified by chromatography on silica gel (biotage 100 g, eluting with 0-100 % ethyl acetate/heptane) to afford a dark brown oil which was further purified by chromatography on silica gel (biotage 55 g kp-NH, eluting with 0-100 % ethyl acetate/heptane) to afford the title compound 3.3 g, 40% at 50% purity) of as a pale brown oil.

LCMS Method B (electrospray): m/z = 219.3 (M+H) ⁺ , RT = 1.34 min. [00333] Step 2: 2-{6-methylimidazo[1,2-a]pyridin-2-yl}acetic acid

The title compound was prepared from ethyl 2-(6-methylimidazo[1,2-a]pyridin-2-yl)acetate using the method described in Intermediate 1 Step 2 to give the title compound (1.35 g, 95% as a pale yellow solid.

LCMS Method A (electrospray): m/z = 190.95 (M+H) ⁺ , RT = 0.18 min. [00334] Synthesis of Compound 1: N-({6-methylimidazo[1,2-a]pyridin-2- yl}methyl)-1H-indazole-4-carboxamide

A solution of 1-tetrahydropyran-2-ylindazole-4-carboxylic acid (75 mg, 0.3 mmol) and DIPEA (271 uL, 1.52 mmol) in THF (10 mL) was treated with HATU (150mg, 0.4 mmol) and the mixture was stirred at room temperature for 20 minutes before {6-methylimidazo[1,2- a]pyridin-2-yl}methanamine dihydrochloride (85 mg, 0.37 mmol) (commercially available) was added and the solution was stirred at room temperature for 3 hours. The brown solution was diluted with water and extracted with DCM (via a phase sep cartridge) and the extracts were evaporated under vacuum to a brown gum. The gum was dissolved in Methanol (5 mL), treated with 4 M 1,4-dioxane hydrochloride (0.76 mL, 3.05 mmol) and stirred at room temperature for 16 hours. The solution was evaporated under vacuum and the residue was purified by chromatography on silica gel [Biotage 25 g eluting with 0-100% ethyl acetate/Heptane] to give the title compound (72mg, 93%) as a beige solid.

LCMS Method C (electrospray): m/z = 306.1 (M+H) ⁺ , RT = 1.99 min. [00335] Synthesis of Compounds 2-31

[00336] The compounds in Table 2 were prepared in a similar fashion to Compound 1 using the appropriate carboxylic acid and aminomethyl imidazopyridine intermediate, or commercially available materials, including deprotection where necessary. Table 2

yl)methyl]amino}imidazo[1,2-a]pyridin-2-yl)methyl]-1H-ind azole-4-carboxamide

[00338] Step 1: N-[[6-(3-pyridylmethylamino)imidazo[1,2-a]pyridin-2-yl]methy l]-1- tetrahydropyran-2-yl-indazole-4-carboxamide dihydrochloride

A mixture of N-[(6-bromoimidazo[1,2-a]pyridin-2-yl)methyl]-1-tetrahydropy ran-2-yl-indazole- 4-carboxamide (100 mg, 0.220 mmol), Intermediate 14, 3-pyridylmethanamine (273 uL, 2.20 mmol), copper iodide (6.3 mg, 0.0330 mmol), (2{S})-pyrrolidine-2-carboxylic acid (5.1 mg, 0.0440 mmol) and potassium carbonate (61 mg, 0.440 mmol) in DMSO (0.6 mL) was heated using microwave irradiation at 150 °C for 15 min. The reaction mixture was diluted with 10% MeOH in DCM (15 mL) and water (15 mL). The organic phase was collected and the aqueous phase was extracted with 10% MeOH in DCM (2 x 15 mL). The combined organics were evaporated to dryness under reduced pressure and purified by preparative HPLC (Method A) to afford the title compound (22 mg, 21%) as a yellow solid.

LCMS Method A (electrospray): m/z = 482.2 (M+H) ⁺ , RT = 0.77 min. [00339] Step 2: N-[(6-{[(pyridin-3-yl)methyl]amino}imidazo[1,2-a]pyridin-2-y l)methyl]- 1H-indazole-4-carboxamide dihydrochloride

The title compound was prepared from N-[[6-(3-pyridylmethylamino)imidazo[1,2-a]pyridin-2- yl]methyl]-1-tetrahydropyran-2-yl-indazole-4-carboxamide using the procedure described in Compound 1 giving (21 mg 96%) as a light brown solid.

LCMS Method D (electrospray): m/z = 398.3 (M+H) ⁺ , RT = 2.76 min. [00340] Synthesis of Compound 33: N-[(6-{[(1-methyl-1H-imidazol-4- yl)methyl]amino}imidazo[1,2a]pyridin-2-yl)methyl]-1H-indazol e-4-carboxamide

[00341] The compound in table 3 was prepared in the same manner as Compound 32 Table 3

[00342] Synthesis of Compound 34: N-{[6-(3-methoxyphenyl)imidazo[1,2- a]pyridin-2-yl]methyl}-1H-indazole-4-carboxamide

[00343] Step 1: N-[[6-(3-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl]methyl]-1- tetrahydropyran-2-yl-indazole-4-carboxamide

N-[(6-bromoimidazo[1,2-a]pyridin-2-yl)methyl]-1-tetrahydr opyran-2-yl-indazole-4- carboxamide (120mg, 0.25mmol), Intermediate 14, (3-methoxyphenyl)boronic acid (45mg, 0.29mmol) and K ₂ CO ₃ (1.2M aqueous, 0.61ml, 0.74mmol) were combined in 1,4-Dioxane (4ml) and the mixture sparged with nitrogen for 5mins. Dichloro[1,1'-bis(di-t- butylphosphino)ferrocene]palladium(II) (16mg, 0.02mmol) was added and the mixture sparged for a further 5mins. The vessel was sealed and the mixture heated at 100°C for 2h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate

(30ml). The mixture was washed with sat. Sodium hydrogen carbonate(aq) (30ml) and brine (2 x 30ml) and the organic layer dried over sodium sulfate and evaporated under vacuum. The residue was purified by chromatography on silica gel [Biotage 28 g kp-NH, eluting with 0-100% ethyl acetate/heptane 0-100%] to afford N-[[6-(3-methoxyphenyl)imidazo[1,2- a]pyridin-2-yl]methyl]-1-tetrahydropyran-2-yl-indazole-4-car boxamide (113mg, 96%) as a white solid.

LCMS Method A (electrospray): m/z = 482.25 (M+H) ⁺ , RT = 1.04 min. [00344] The title compound was prepared from N-[[6-(3-methoxyphenyl)imidazo[1,2- a]pyridin-2-yl]methyl]-1-tetrahydropyran-2-yl-indazole-4-car boxamide using the procedure described in Compound 1 giving (51 mg, 54%) as a white solid.

LCMS Method D (electrospray): m/z = 398.2 (M+H) ⁺ , RT = 3.50 min. [00345] Synthesis of Compounds 35-36

[00346] The compounds in Table 4 were prepared by in a similar fashion to Compound 34. Table 4

[00347] Synthesis of Compound 37: N-({6-[(pyridin-3-yl)amino]imidazo[1,2- a]pyridin-2-yl}methyl)-1H-indazole-4-carboxamide

[00348] Step1: 1-(oxan-2-yl)-N-({6-[(pyridin-3-yl)amino]imidazo[1,2-a]pyrid in-2- yl}methyl)-1H-indazole-4-carboxamide

A solution of N-[(6-bromoimidazo[1,2-a]pyridin-2-yl)methyl]-1-tetrahydropy ran-2-yl-indazole- 4-carboxamide (75 mg, 0.165 mmol), Intermediate 14, cesium carbonate (161 mg, 0.495 mmol), pyridin-3-amine (19 mg, 0.198 mmol) and XPhos Pd G3 (14 mg, 0.0165

mmol) in 1,4-Dioxane (2 mL) was stirred at 110 °C for 2 h. More pyridin-3-amine (19 mg, 0.198 mmol) and XPhos Pd G3 (14 mg, 0.0165 mmol) were added and the reaction mixture was stirred at 110 °C for 2 h. The reaction mixture was cooled to rt. diluted with water (25 mL) and extracted with ethyl acetate (2 x 25 mL). The combined organics were evaporated to dryness and purified by preparative HPLC [method B, followed by method A] to afford N- [[6-(3-pyridylamino)imidazo[1,2-a]pyridin-2-yl]methyl]-1-tet rahydropyran-2-yl-indazole-4- carboxamide as a yellow solid.

LCMS Method A (electrospray): m/z = 468.2 (M+H) ⁺ , RT = 0.8 min [00349] Step 2: The title compound was prepared from N-[[6-(3- methoxyphenyl)imidazo[1,2-a]pyridin-2-yl]methyl]-1-tetrahydr opyran-2-yl-indazole-4- carboxamide using the procedure described in Compound 1 giving (7.5mg, 92%) as a white solid.

LCMS Method D (electrospray): m/z = 384.3 (M+H) ⁺ , RT = 2.75 min [00350] Synthesis of Compound 38: N-({6-[(piperazin-1-yl)methyl]imidazo[1,2- a]pyridin-2-yl}methyl)-1H-indazole-4-carboxamide

[00351] Step 1: tert-butyl 4-[[2-[[(1-tetrahydropyran-2-ylindazole-4- carbonyl)amino]methyl]imidazo[1,2-a]pyridin-6-yl]methyl]pipe razine-1-carboxylate

A solution of N-[(6-bromoimidazo[1,2-a]pyridin-2-yl)methyl]-1-tetrahydropy ran-2-yl-indazole- 4-carboxamide (50 mg, 0.110 mmol), Intermediate 14, potassium;(4-tert- butoxycarbonylpiperazin-1-yl)methyl-trifluoro-borohydride (37 mg, 0.121 mmol), cesium carbonate (108 mg, 0.330 mmol) and Pd-118 (3.6 mg, 5.50 mmol) in THF (3.2 mL) and Water (0.8 mL), under a nitrogen atmosphere, was stirred at 85 °C overnight. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organics were evaporated to dryness under reduced pressure and purified by preparative HPLC [method A) to afford the title compound (30 mg, 48%) as a white solid. LCMS Method A (electrospray): m/z = 574.4 (M+H) ⁺ , RT = 0.88 min. [00352] Step 2: The title compound was prepared from: tert-butyl 4-[[2-[[(1- tetrahydropyran-2-ylindazole-4-carbonyl)amino]methyl]imidazo [1,2-a]pyridin-6- yl]methyl]piperazine-1-carboxylate using the procedure described in Compound 1 giving (7.5mg, 92%) as a white solid.

Method C: LC-MS (electrospray): m/z = 390.3 (M+H) ⁺ , RT = 1.55 min. [00353] Synthesis of Compound 39: N-{[6-(aminomethyl)imidazo[1,2-a]pyridin-2- yl]methyl}-1H-indazole-4-carboxamide

[00354] Step 1: tert-butyl N-[[2-[[(1-tetrahydropyran-2-ylindazole-4- carbonyl)amino]methyl]imidazo[1,2-a]pyridin-6-yl]methyl]carb amate and N-{[6- (aminomethyl)imidazo[1,2-a]pyridin-2-yl]methyl}-1-(oxan-2-yl )-1H-indazole-4-carboxamide

A solution of N-[(6-cyanoimidazo[1,2-a]pyridin-2-yl)methyl]-1-tetrahydropy ran-2-yl-indazole- 4-carboxamide (500 mg, 1.25 mmol) (Intermediate 16) and tert-butoxycarbonyl tert-butyl carbonate (545 mg, 2.50 mmol) in methanol (10 mL) was cooled to 0 ^o C and treated with nickel (II) chloride (164 mg, 1.25 mmol) followed by the addition of sodium borohydride (425 mg, 11.2 mmol) in small portions. Further NaBH ₄ (212 mg, 5.5 mmol) was added in portions and the stirring was continued for an hour at 0 ^o C before the crude reaction was evaporated under vacuum and purified by chromatography on silica gel [Biotage; 25 g KP- NH, eluting with 40-100% ethyl acetate in heptane) to afford tert-butyl N-[[2-[[(1- tetrahydropyran-2-ylindazole-4-carbonyl)amino]methyl]imidazo [1,2-a]pyridin-6- yl]methyl]carbamate (180 mg, 0.357 mmol, 50%) as a white solid.

LCMS Method A (electrospray): m/z = 505.2 (M+H) ⁺ , RT = 0.96 min. [00355] Flushing the column with 0-20% MeOH in ethyl acetate afforded N-[[6- (aminomethyl)imidazo[1,2-a]pyridin-2-yl]methyl]-1-tetrahydro pyran-2-yl-indazole-4- carboxamide (90 mg, 0.129 mmol, 18%) as a white solid.

LCMS Method A: LC-MS (electrospray): m/z = 405.1 (M+H) ⁺ , RT = 0.85 min. [00356] Step 2: N-{[6-(aminomethyl)imidazo[1,2-a]pyridin-2-yl]methyl}-1H-ind azole-4- carboxamide hydrochloride

Tert-butyl N-[[2-[[(1-tetrahydropyran-2-ylindazole-4-carbonyl)amino]met hyl]imidazo[1,2- a]pyridin-6-yl]methyl]carbamate (180 mg, 0.36 mmol) was treated with HCl (4M in dioxane 0.5 mL) and the mixture was stirred at room temperature for 65 hours. The mixture was evaporated to dryness and triturated from MeOH/ethyl acetate to afford the title compound (98 mg, 70%) as a white powder.

LCMS Method D (electrospray): m/z = 321.2 (M+H) ⁺ , RT = 2.38 min. [00357] Synthesis of Compound 40: N-{[6-(acetamidomethyl)imidazo[1,2- a]pyridin-2-yl]methyl}-1H-indazole-4-carboxamide

[00358] The title compound was prepared using the method described in Compound 39 substituting acetic anhydride for tert-butoxycarbonyl tert-butyl carbonate to give (32 mg, 31%) as a white solid. LCMS Method D: LC-MS (electrospray): m/z = 363.2 (M+H) ⁺ , RT = 2.36 min. [00359] Synthesis of Compound 41: {6-methylimidazo[1,2-a]pyridin-2-yl}methyl 1H-indazole-4-carboxylate hydrochloride

[00360] Step 1: (6-methylimidazo[1,2-a]pyridin-2-yl)methanol

6-methylimidazo[1,2-a]pyridine-2-carbaldehyde (Eur. J. Org. Chem.2015 (18), 3957) (165mg, 1.03mmol) was dissolved in methanol (20ml) and cooled in an ice/water bath. NaBH4 (195mg, 5.15mmol) was added in a single portion and the effervescent mixture stirred under cooling for 30 minutes. The reaction mixture was quenched with sodium hydrogen carbonate (Sat, 30ml) and warmed to RT. The mixture was extracted with 3:1 chloroform/isopropanol (4 x 30ml) and the combined organic extracts were dried over sodium sulfate and evaporated under vacuum. The residue was purified by Chromatography on silica gel [Biotage 28 g kp-NH, eluting with 0-20% MeOH/DCM) to afford the title compound (137mg (80% yield, 98%) as a bright yellow oily residue.

LCMS Method B (electrospray): m/z = 163.2 (M+H) ⁺ , RT = 1.11 min [00361] Step 2: The title compound was prepared from (6-methylimidazo[1,2- a]pyridin-2-yl)methanol using the procedure described in Compound 1 giving (187mg, 90%) as a white solid.

LCMS Method B: LC-MS (electrospray): m/z = 163.2 (M+H) ⁺ , RT = 1.11 min [00362] Synthesis of Compound 42: {N-{[6-(hydroxymethyl)imidazo[1,2- a]pyridin-2-yl]methyl}-1H-indazole-4-carboxamide [00363] Step 1: N-[[6-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl]methyl]-1- tetrahydropyran-2-yl-indazole-4-carboxamide

A solution of N-[(6-formylimidazo[1,2-a]pyridin-2-yl)methyl]-1-tetrahydrop yran-2-yl-indazole- 4-carboxamide (Intermediate 18) (50% purity with N-(imidazo[1,2-a]pyridin-2-ylmethyl)-1- tetrahydropyran-2-yl-indazole-4-carboxamide, 92 mg, 0.114 mmol) in ethanol (4 mL), under a nitrogen atmosphere was treated with sodium borohydride (13 mg, 0.342 mmol) and the resultant mixture was stirred at room temperature for an hour. The reaction mixture was quenched by the addition of sodium hydrogen carbonate(sat) and concentrated under vacuum. The residue was extracted with DCM (phase sep) and the extracts were evaporated under vacuum to a residue which was purified by chromatography on silica gel [Biotage KPNH 11 g, eluting with 20-80% (10% MeOH in DCM/DCM) to give the title compound (44 mg, 95%).

LCMS Method B (electrospray): m/z = 406.4 (M+H) ⁺ , RT = 1.27 min [00364] The title compound was prepared from N-[[6-(hydroxymethyl)imidazo[1,2- a]pyridin-2-yl]methyl]-1-tetrahydropyran-2-yl-indazole-4-car boxamide using the procedure described in Compound 1 giving (24 mg, 68%) as a beige solid.

LCMS Method D (electrospray): m/z = 322.3 (M+H) ⁺ , RT = 2.30 min [00365] Synthesis of Compound 43: N-({6-hydroxyimidazo[1,2-a]pyridin-2- yl}methyl)-1H-indazole-4-carboxamide

[00366] Step 1: N-({6-hydroxyimidazo[1,2-a]pyridin-2-yl}methyl)-1-(oxan-2-yl )-1H- indazole-4-carboxamide

A solution of N-[(6-bromoimidazo[1,2-a]pyridin-2-yl)methyl]-1-tetrahydropy ran-2-yl-indazole- 4-carboxamide (Intermediate 14) (100 mg, 0.220 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (126 mg, 0.495 mmol),

Pd(dppf)Cl ₂ .CH ₂ Cl ₂ (18 mg, 0.0220 mmol) and potassium acetate (65 mg, 0.660 mmol) in 1,4-Dioxane (3 mL) was stirred at 100 °C for 2 hours. The mixture was cooled to room temperature before acetic acid (25 uL, 0.440 mmol) and Water (0.06 mL) were added. The mixture was stirred for 1 hour before hydrogen peroxide (30%, 2.86 mL, 28.0 mmol) was added and the mixture was stirred for 3 hours. The mixture was quenched with sodium thiosulfate solution (sat, 15 mL), diluted with water (15 mL), extracted with ethyl acetate (2 x 25 mL) and evaporated to dryness under reduced pressure. The residue was purified by preparative HPLC [method B] to afford the title compound (25 mg, 27%) as a white powder. LCMS Method A (electrospray): m/z = 392.1 (M+H) ⁺ , RT = 0.85 min [00367] Step 2: The title compound was prepared from N-({6-hydroxyimidazo[1,2- a]pyridin-2-yl}methyl)-1-(oxan-2-yl)-1H-indazole-4-carboxami de using the procedure described in Compound 1 giving (7.3mg, 37%) as a brown powder. LCMS Method C (electrospray): m/z = 308.1 (M+H) ⁺ , RT = 1.04 min [00368] Synthesis of Compound 44: N-({6-[(methylamino)methyl]imidazo[1,2- a]pyridin-2-yl}methyl)-1H-indazole-4-carboxamide dihydrochloride

[00369] Step 1: N-({6-[(methylamino)methyl]imidazo[1,2-a]pyridin-2-yl}methyl )-1- (oxan-2-yl)-1H-indazole-4-carboxamide

A solution of N-[(6-formylimidazo[1,2-a]pyridin-2-yl)methyl]-1-tetrahydrop yran-2-yl-indazole- 4-carboxamide (Intermediate 18) (50%, 100 mg, 0.114 mmol), STAB (48 mg, 0.228 mmol) and methylamine (8M in ethanol, 16 uL, 0.125 mmol) in DCM (1 mL) was stirred at rt for 3 h.

More methylamine (8M in ethanol, 16 uL, 0.125 mmol) and STAB (48 mg, 0.228 mmol) were added in portions over 48 hours whilst stirring the reaction mixture at rt. The reaction mixture was evaporated to dryness and purified by ion exchange [SCX-2] followed by preparative HPLC [method A] to afford the title compound (46 mg, 96%) as a yellow solid.

LCMS Method A (electrospray): m/z = 419.1 (M+H) ⁺ , RT = 0.74 min [00370] Step 2: The title compound was prepared from N-[[6- (hydroxymethyl)imidazo[1,2-a]pyridin-2-yl]methyl]-1-tetrahyd ropyran-2-yl-indazole-4- carboxamide using the procedure described in Compound 1 giving (25 mg, 58%) as a beige solid.

LCMS Method C (electrospray): m/z = 390.3 (M+H) ⁺ , RT = 1.58 min [00371] Synthesis of Compounds 45-46 [00372] The compounds in table 4 was prepared in the same manner as Compound 44

Table 4

[00373] Synthesis of Compound 47: N-{[6-(1-hydroxyethyl)imidazo[1,2-a]pyridin- 2-yl]methyl}-1H-indazole-4-carboxamide

[00374] Step 1: N-{[6-(1-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl]methyl}-1-( oxan-2-yl)- 1H-indazole-4-carboxamide

A solution of magnesium bromide in ether (3M, 74 uL, 0.22 mmol) was added dropwise over 1 min to a solution of N-[(6-formylimidazo[1,2-a]pyridin-2-yl)methyl]-1-tetrahydrop yran-2-yl- indazole-4-carboxamide (intermediate 18) (75 mg, 0.186 mmol) in THF (1 mL) at -30 ^o C. The reaction mixture was then warmed to 0 ^o C and stirred for 2 h. The reaction mixture was quenched by the addition of sat. aq. NH4Cl (10 mL) and extracted with ethyl acetate (3 x 15 mL). The combined organics were dried and evaporated to dryness and the residue was purified by preparative HPLC (method B) to afford the title compound (31 mg, 40%) as an orange solid.

[00375] The title compound was prepared from N-{[6-(1-hydroxyethyl)imidazo[1,2- a]pyridin-2-yl]methyl}-1-(oxan-2-yl)-1H-indazole-4-carboxami de using the procedure described in Compound 1 giving (14.6 mg, 59%) as a white powder.

Method C: LC-MS (electrospray): m/z = 336.2 (M+H) ⁺ , RT = 1.56 min [00376] Synthesis of Compound 48

[00377] The compound in table 5 was prepared in the same manner as Compound 47

[00378] Table 5

[00379] Synthesis of Compound 49: N-({6-formylimidazo[1,2-a]pyridin-2- yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

[00380] A suspension of N-[(6-cyanoimidazo[1,2-a]pyridin-2-yl)methyl]-4-oxo- pyrido[1,2-a]pyrimidine-2-carboxamide (Compound 18) (400 mg, 1.16 mmol), in a mixture of water (6 mL), pyridine (12 mL) and acetic acid (3 mL) was treated with sodium phosphinate hydrate (985 mg, 9.29 mmol) followed by Raney nickel (50%, 1.20 g, 10.2 mmol) and the mixture was heated at 100 ^o C, under a nitrogen atmosphere, for 4.5 hours. Further Raney nickel (50%, 0.6 g, 5.1 mmol) was added and the heating was continued for an hour. The suspension was cooled to room temperature and the Ni (R) was removed by filtration through a bed of celite (washing with water). The filtrate was extracted with DCM (x4) and the extracts were dried (magnesium sulfate) and evaporated under vacuum to a suspension which contained pyridine. Further evaporation under vacuum gave a solid residue which was suspended in water and the solids were collected by filtration, washed with water followed by ether and dried under vacuum to give the title compound (205 mg, 51%) as a buff solid. The aqueous was further extracted with IPA/CHCl ₃ (1:3) and the extracts were evaporated under vacuum to dryness. The residue which was suspended in water and the solids were collected by filtration, washed with water followed by ether and dried under vacuum to give the title compound (61 mg, 15%) as a buff solid.

LCMS Method E (electrospray): m/z = 348.1 (M+H) ⁺ , RT = 1.16 min [00381] Synthesis of Compound 50: N-{[6-(aminomethyl)imidazo[1,2-a]pyridin-2- yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

[00382] The residual aqueous solution from Compound 49 was concentrated under vacuum and the residue was dissolved in MeOH and purified by ion exchange (SCX-2, 5 g) and the eluted fraction was evaporated under vacuum to a beige solid which was purified by preparative HPLC [method B] to provide the title compound (7.5 mg, 2%) as an off white solid.

LCMS Method C (electrospray): m/z = 349.2 (M+H) ⁺ , RT = 1.47 min [00383] Synthesis of Compound 51: 4-oxo-N-[(6-{[(2,2,2- trifluoroethyl)amino]methyl}imidazo[1,2-a]pyridin-2-yl)methy l]-4H-pyrido[1,2- a]pyrimidine-2-carboxamide

[00384] A solution of N-[(6-formylimidazo[1,2-a]pyridin-2-yl)methyl]-4-oxo-pyrido[ 1,2- a]pyrimidine-2-carboxamide (Compound 49) (50 mg, 0.144 mmol) and 2,2,2- trifluoroethanamine (29 mg, 0.288 mmol) in DCE (2 mL) was stirred at rt for 2 hours before STAB (92 mg, 0.432 mmol) was added and the reaction mixture was stirred at 50 ^o C for 18 h. The reaction mixture was cooled to RT, STAB (92 mg, 0.432 mmol) was added and the reaction mixture was stirred at 50 ^o C for 2 h. The reaction mixture was quenched with water (5 mL) and extracted with DCM (3 x 5 mL). The combined organics were dried, evaporated to dryness and purified by preparative HPLC [method B] to afford the title compound (34 mg, 53%) as a white powder.

LCMS Method E (electrospray): m/z = 431.3 (M+H) ⁺ , RT = 1.18 min [00385] Synthesis of Compounds 52-55

[00386] The compounds in table 6 was prepared in the same manner as Compound 47 Table 6

[00387] Synthesis of Compound 56: N-({6-[hydroxy(phenyl)methyl]imidazo[1,2- a]pyridin-2-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-ca rboxamide

[00388] Phenyl magnesium bromide (1M in THF, 207 uL, 0.207 mmol) was added dropwise over 1 min to a solution of N-[(6-formylimidazo[1,2-a]pyridin-2-yl)methyl]-4-oxo- pyrido[1,2-a]pyrimidine-2-carboxamide (Compound 49) (30 mg, 0.0864 mmol) in THF (2 mL) at -30 ^o C. The reaction mixture was then warmed to 0 ^o C and stirred for 2 hours. The stirring was continued for 16 hours during which time the reaction warmed to room temperature. The reaction mixture was re-cooled to -30 ^o C and treated with Phenyl magnesium bromide (1M in THF, 103 uL, 0.1 mmol) and the mixture was stirred at 0 ^o C for a further 30 minutes. The mixture was quenched by the addition of NH ₄ Cl (sat 10 mL) and extracted with DCM (3 x 15 mL) and the organics were dried and evaporated to dryness to afford a residue which was purified by Preparative HPLC [method B] and the fractions were freeze dried to afford the title compound (4.4 mg, 12%) as a white foam.

LCMS Method D (electrospray): m/z = 426.2 (M+H) ⁺ , RT = 3.10 min [00389] Synthesis of Compound 57

[00390] The compound in table 7 was prepared in a similar manner to Compound 56 Table 7

[00391] Synthesis of Compound 58: N-({6-ethenylimidazo[1,2-a]pyridin-2- yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

[00392] N-[(6-bromoimidazo[1,2-a]pyridin-2-yl)methyl]-4-oxo-pyrido[1 ,2-a]pyrimidine- 2-carboxamide (Compound 23) (150mg, 0.38mmol), potassium ethenyl(trifluoro)borate (76mg, 0.57mmol) and K2CO3 (1.2M aqueous, 941µl, 1.13mmol) were combined in 1,4- Dioxane (4ml) and the mixture was sparged with nitrogen for 5mins. Pd-118 (25mg, 0.04mmol) was added and the mixture was sparged for a further 5mins. The vessel was sealed and the mixture heated at 100°C for 2 hours. The reaction mixture was cooled to room temperature and diluted with sodium hydrogen carbonate (sat, 30ml) and extracted with chloroform/isopropanol (3:1, 3 x 50ml) and the combined organic extracts were dried over sodium sulfate and evaporated under vacuum. The residue was purified by chromatography on silica gel (Biotage 28 g kp-NH, eluting with 0-100% ethyl

acetate/heptane). The residue after evaporation was triturated with ethyl

acetate/heptane. The solids were collected by filtration, washed with heptane and dried under suction to afford the title compound (73mg, 56% yield) as a white solid.

LCMS Method E (electrospray): m/z = 346.1 (M+H) ⁺ , RT = 1.17 min [00393] Synthesis of Compounds 59-61

[00394] The compounds in table 8 was prepared in a similar manner to Compound 58

Table 8

[00395] Synthesis of Compound 62: 2-(1H-indazol-4-yl)-5-[(6-methylimidazo[1,2- a]pyridin-2-yl)methyl]-1,3,4-oxadiazole

[00396]

[00397] Step 1: ({[(benzyloxy)carbonyl]amino}amino)[1-(oxan-2-yl)-1H-indazol -4- yl]methanone

[00398] A solution of 1-tetrahydropyran-2-ylindazole-4-carboxylic acid (900mg, 3.65mmol), benzyl N-aminocarbamate (729mg, 4.39mmol) and triethylamine (1.53ml, 11.0mmol) were combined in DMF (10ml), HATU (2.08g, 5.48mmol) was added and the mixture was stirred at room temperature for 7 hours. The reaction mixture was diluted with ethyl acetate (100ml) and washed with sodium hydrogen carbonate (sat, 100ml) and brine (4 x 100ml). The organic layer was dried over sodium sulfate and evaporated under vacuum. The residue was purified by chromatography on silica gel (Biotage 50 g, eluting with 0-100% ethyl acetate/heptane) to afford the title compound (1.42g, 91%) as a pale pink solid.

LCMS Method A (electrospray): m/z = 393.15 (M-H)-, RT = 1.09 min [00399] Step 2: 1-(oxan-2-yl)-1H-indazole-4-carbohydrazide

A suspension of benzyl N-[(1-tetrahydropyran-2-ylindazole-4-carbonyl)amino]carbamat e (500mg, 1.17mmol) and Palladium on carbon (10% wt, 124mg, 0.12mmol) were suspended in ethanol (50ml) and the mixture stirred vigorously under an atmosphere of hydrogen (1 atm) at room temperature for 6h. The catalyst was removed by filtration through Celite, washing with MeOH, then ammonia in MeOH (7M) and the filtrate evaporated under vacuum. The residue was purified by ion exchange [SCX-2, 10g] and the residue triturated with ethyl acetate/heptane to afford the title compound (158 mg, 52%) as a pale yellow solid.

LCMS Method A (electrospray): m/z = 261.0 (M+H) ⁺ , RT = 0.84 min [00400] Step 3: 2-{6-methylimidazo[1,2-a]pyridin-2-yl}-N'-[1-(oxan-2-yl)-1H- indazole- 4-carbonyl]acetohydrazide

[00401] The title compound was prepared by coupling 1-(oxan-2-yl)-1H-indazole-4- carbohydrazide with Intermediate 19 using the coupling described in Compound 1 and DMF as solvent to give (178 mg, 67%) as yellow solid.

LCMS Method A (electrospray): m/z = 433.2 (M+H) ⁺ , RT = 0.84 min [00402] Step 4: 4-[5-({6-methylimidazo[1,2-a]pyridin-2-yl}methyl)-1,3,4-oxad iazol-2- yl]-1H-indazole

[00403] A suspension of N'-[2-(6-methylimidazo[1,2-a]pyridin-2-yl)acetyl]-1- tetrahydropyran-2-yl-indazole-4-carbohydrazide (150mg, 0.35mmol) in phosphoryl trichloride (5ml) was heated at 100°C for 1.5 hours. The reaction mixture was cooled to room temperature and poured slowly onto a slurry of solid K2CO3 and ice. The mixture was stirred vigorously [gas evolution; significant exotherm] until the ice had melted. The mixture was extracted with chloroform/isopropanol (3:1, 4 x 80ml). The extracts were dried over sodium sulfate and evaporated under vacuum. The residue was purified by ion exchange [SCX-2, 10g]. The residue was purified by preparative HPLC (method B) and the residue was triturated with ethyl acetate/heptane, the solids were collected by filtration, washed with heptane and dried under vacuum to afford the title compound (21.3mg, 19%) as an off-white solid.

LCMS Method D (electrospray): m/z = 331.2 (M+H) ⁺ , RT = 3.20 min Further Organic Synthesis

[00404] Intermediate 20: tert-butyl N-{2-[2-(aminomethyl)imidazo[1,2-a]pyridin-6- yl]ethyl}carbamate

[00406] 5-bromo-2-nitro-pyridine (1000 mg, 4.93 mmol), potassium;2-(tert- butoxycarbonylamino)ethyl-trifluoro-boranuide (1.36 g, 5.41 mmol), cesium carbonate (4815 mg, 14.8 mmol) and [1,1'-Bis(diphenylphosphino)ferrocene]palladium(II) chloride

dichloromethane complex (302 mg, 0.369 mmol) were combined in toluene (20 mL) and water (5 mL) and the mixture was heated at 80 ^o C for 16 hours. The reaction mixture was cooled to room temperature wherupon water (20 mL) was added and the aqueous were extracted with EtOAc (2 x 30 mL). The combined organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure to give a brown gum, which was purified by chromatography on silica gel [Biotage 100 g, eluting by 10% - 80% EtOAc in heptane] to provide the title compound (900 mg, 55%) as an off white solid.

Method A: LC-MS (electrospray): m/z = 267.9 (M+H) ⁺ , RT = 1.06 min.

Step 2: tert-butyl N-[2-(6-aminopyridin-3-yl)ethyl]carbamate

[00407] tert-butyl N-[2-(6-nitro-3-pyridyl)ethyl]carbamate (1.07 g, 4.00 mmol) and Pd/C (10%) were combined in EtOH (25 mL). The mixture placed under an atmosphere of hydrogen and the reaction mixture was stirred at room temperature for 4 hours. The catalyst was removed by filtration washing with methanol and the filtrate was evaporated under vacuum to provide the title compound (1000 mg, 95%) as a colourless oil.

[00408] Method A: LC-MS (electrospray): m/z = 238.0 (M+H) ⁺ , RT = 0.66 min.

[00409] Step 3: tert-butyl N-(2-{2-[(1,3-dioxo-2,3-dihydro-1H-isoindol-2- yl)methyl]imidazo[1,2-a]pyridin-6-yl}ethyl)carbamate

[00410] The title compound was prepared using the method described for

Intermediate 7 Step 1 and triturating with MeCN to provide the title compound (600 mg, 38%) as an off white solid.

[00411] Method A: LC-MS (electrospray): m/z = 421.55 (M+H) ⁺ , RT = 0.94 min.

[00412] Step 4: tert-butyl N-{2-[2-(aminomethyl)imidazo[1,2-a]pyridin-6- yl]ethyl}carbamate

[00413] The title compound was prepared using the method described for

Intermediate 7 Step 2 to provide the title compound (170 mg, 41%) as a yellow solid.

[00414] Method A: LC-MS (electrospray): m/z = 291.10 (M+H) ⁺ , RT = 0.70 min.

[00415] Intermediate 21: 4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-2-carboxylic acid hydrochloride [00416] A suspension of rhodium (504 mg, 4.90 mmol) in ethanol (20 mL) was placed under a nitrogen atmosphere.4-oxopyrido[1,2-a]pyrimidine-2-carboxylate hydrochloride (Intermediate 4, 60%, 1000 mg, 2.66 mmol) was added. The mixture was placed under an atmosphere of hydrogen and the mixture was stirred at room temperature for 4 hours. The catalyst was removed by filtration and the filtrate was evaporated under vacuum to afford a brown gum which crystallised on standing to give the title compound (600 mg, 97%) as beige solid.

[00417] Method B: LC-MS (electrospray): m/z = 195.2 (M+H) ⁺ , RT = 0.28 min.

[00418] Intermediate 22: 2-(aminomethyl)-N-benzylimidazo[1,2-a]pyridine-6- carboxamide

[00420] The title compound was prepared using the method described in

Intermediate 8 Step 1, to provide (741 mg, 48%) as a white solid.

[00421] Method B: LC-MS (electrospray): m/z = 225.1 (M+H) ⁺ , RT = 1.31 min.

[00422] Step 2: methyl 2-({bis[(tert-butoxy)carbonyl]amino}methyl)imidazo[1,2- a]pyridine-6-carboxylate [00423] A mixture of methyl 2-(chloromethyl)imidazo[1,2-a]pyridine-6-carboxylate (740 mg, 3.29 mmol), di-tert-butyl imidodicarbonate (1.07g, 4.94 mmol), NaI (50 mg, 0.33 mmol) and K ₂ CO ₃ (1.37g, 9.88 mmol) were combined in acetonitrile (40 mL) and the mixture stirred at room temperature for an hour before water (1 mL) was added and the mixture heated at reflux for an hour. The reaction mixture was cooled to room temperature and concentrated under vacuum. The residue was suspended in saturated aqueous sodium hydrogen carbonate (50 mL) and extracted with DCM (4 x 80 mL). The combined organic extracts were dried over sodium sulfate and evaporated under vacuum. The residue was purified by chromatography on silica gel (Biotage 50 g kp-Sil, eluting with EtOAc/heptane 0-50%) to afford the title compound (1.13g 77%, 91% purity) as a viscous yellow oil which solidified on standing.

[00424] Method B: LC-MS (electrospray): m/z = 406.2 (M+H) ⁺ , RT = 1.72 min.

[00425] Step 3: 2-({bis[(tert-butoxy)carbonyl]amino}methyl)imidazo[1,2-a]pyr idine-6- carboxylic acid

[00426] A mixture of methyl 2-(chloromethyl)imidazo[1,2-a]pyridine-6-carboxylate (740 mg, 3.29 mmol), di-tert-butyl imidodicarbonate (1.07g, 4.94 mmol), NaI (50 mg, 0.33 mmol) and K ₂ CO ₃ (1.37g, 9.88 mmol) were combined in Acetonitrile (40 mL) and the mixture stirred at room temperature for an hour before water (1 mL) was added and the mixture heated at reflux for an hour. The reaction mixture was cooled to room temperature and concentrated under vacuum. The residue was suspended in aqueous sodium hydrogen carbonate (sat, 50 mL) and extracted with DCM (4 x 80 mL). The combined organic extracts were dried over sodium sulfate and evaporated under vacuum. The residue was purified by chromatography on silica gel (Biotage 50 g kp-Sil, eluting with EtOAc/heptane 0-50%) to afford the title compound (1.13g 77%, 91% purity) as a viscous yellow oil which solidified on standing.

[00427] Method B: LC-MS (electrospray): m/z = 406.2 (M+H) ⁺ , RT = 1.72 min.

[00428] Step 3: 2-({bis[(tert-butoxy)carbonyl]amino}methyl)imidazo[1,2-a]pyr idine-6- carboxylic acid

[00429] Methyl 2-[[bis(tert-butoxycarbonyl)amino]methyl]imidazo[1,2-a]pyrid ine-6- carboxylate (500 mg, 1.23 mmol) was dissolved in THF (25 mL) and water (10 mL), lithium hydroxide (240 mg, 5.98 mmol) was added which caused instant decolourisation of the yellow solution and the mixture was stirred at room temperature for 70 minutes. The reaction mixture was acidified with HCl (2M, pH~5) and extracted with chloroform/isopropanol (3:1, 3 x 80 mL). The combined organic extracts were dried over sodium sulfate and evaporated under vacuum to afford the title compound (405 mg, 84%) as a white solid.

Method B: LC-MS (electrospray): m/z = 392.2 (M+H) ⁺ , RT = 1.17 min.

[00430] Step 4: tert-butyl N-{[6-(benzylcarbamoyl)imidazo[1,2-a]pyridin-2-yl]methyl}- N-[(tert-butoxy)carbonyl]carbamate

[00431] Prepared using the coupling conditions described in Example 1 and purified by chromatography on silica gel (Biotage 25 g kp-Sil, eluting with EtOAc/heptane 0-100%) to afford the title compound (493 mg, 99%) as a pink solid.

Method B: LC-MS (electrospray): m/z = 481.25 (M+H) ⁺ , RT = 1.13 min.

[00432] Step 5: 2-(aminomethyl)-N-benzylimidazo[1,2-a]pyridine-6-carboxamide dihydrochloride

[00433] A solution of tert-butyl N-[[6-(benzylcarbamoyl)imidazo[1,2-a]pyridin-2- yl]methyl]-N-tert-butoxycarbonyl-carbamate (493 mg, 1.03 mmol) in methanol (20 mL) was treated with HCl (4M in Dioxane, 3 mL, 12 mmol) and the mixture was heated at 50 °C for an hour. The reaction mixture was cooled to room temperature and evaporated to dryness under vacuum to afford the title compound (346 mg, 95%) as a white solid.

Method B: LC-MS (electrospray): m/z = 281.05 (M+H) ⁺ , RT = 0.71 min. [00434] Intermediate 23: 2-(azidomethyl)-6-methylimidazo[1,2-a]pyridine

[00435] A suspension of 2-(chloromethyl)-6-methyl-imidazo[1,2-a]pyridine

hydrochloride (532 mg, 2.45 mmol), triethylamine (1 mL, 7.35 mmol) and NaI (111 mg, 0.74 mmol) were suspended in DMF (5 mL) before sodium azide (175 mg, 2.70 mmol) was added and the mixture was stirred at room temperature For 16 hours. The reaction mixture was quenched with saturated aqueous sodium hydrogen carbonate (20 mL) and extracted with chloroform/isopropanol (3:1, 4 x 30 mL) and the combined organic extracts were dried over sodium sulfate and evaporated under vacuum. The residue was purified by chromatography on silica gel (Biotage 28 g kp-NH, eluting with EtOAc/heptane 0-100%) to afford the title compound (291 mg, 63%) as a colourless oil.

Method B: LC-MS (electrospray): m/z = 188.2 (M+H) ⁺ , RT = 1.33 min.

[00436] Intermediate 24: 4-ethynyl-1-(oxan-2-yl)-1H-indazole

[00437] Step 1: 4-bromo-1-tetrahydropyran-2-yl-indazole

[00438] A solution of 4-bromo-1H-indazole (2.3g, 11.7 mmol) and tosic acid monohydrate (444 mg, 2.33 mmol) in DCM (50 mL) was treated with 3,4-dihydro-2H-pyran (1.60 mL, 17.5 mmol) and the mixture was stirred at room temperature for 2 hours during which time the solution turned brown. The reaction mixture was quenched with saturated aqueous sodium hydrogen carbonate (50 mL) the phases were separated and the aqueous phase was extracted with DCM (2 x 80 mL) and the combined organic layers were dried over sodium sulfate and evaporated under vacuum. The residue was purified by chromatography on silica gel (Biotage 50 g kp-Sil, eluting with EtOAc/heptane 0-50%) to afford the title compound (3.4 g, 91%) as a pale yellow oil which solidified on standing to a white solid. Method B: LC-MS (electrospray): m/z = 281.1/283.1 (M+H) ⁺ , RT = 1.74 min.

[00439] Step 2: 1-(oxan-2-yl)-4-[2-(trimethylsilyl)ethynyl]-1H-indazole

[00440] 4-bromo-1-tetrahydropyran-2-yl-indazole (1g, 3.56 mmol), CuI (68 mg, 0.36 mmol), PdCl2(PPh3)2 (125 mg, 0.18 mmol) and triethylamine (1.5 mL, 3.03 mmol) were combined in anhydrous THF (7.5 mL) and the mixture sparged with nitrogen for 5 minutes. Ethynyl(trimethyl)silane (739µl, 5.34 mmol) was added, the vessel was sealed and the mixture heated at 80 °C for 48 hours. The reaction mixture was cooled to room temperature and diluted with EtOAc (100 mL). The mixture was washed with saturated aqueous sodium hydrogen carbonate (80 mL) and brine (2 x 80 mL) and the organic phase was dried over sodium sulfate and evaporated under vacuum. The residue was purified by chromatography on silica gel (Biotage 50 g kp-Sil, eluting with EtOAc/heptane 0-50%) to afford the crude title compound contaminated with starting material (1.15g, 52%, 48% purity) as a brown oil. Method B: LC-MS (electrospray): m/z = 299.0 (M+H) ⁺ , RT = 1.52 min.

[00441] Step 3: 4-ethynyl-1-(oxan-2-yl)-1H-indazole

[00442] A solution of trimethyl-[2-(1-tetrahydropyran-2-ylindazol-4-yl)ethynyl]sil ane (1.15g, 1.93 mmol) in methanol (30 mL) was treated with K ₂ CO ₃ (100 mg, 0.72 mmol) and the mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered and the filtrate were evaporated under vacuum. The resultant residue was purified by chromatography on silica gel (Biotage 25 g kp-Sil, eluting with TMBE/heptane 0-40%) to afford the title compound (207 mg, 39%)of as a pale yellow oil which slowly solidified on standing.

Method B: LC-MS (electrospray): m/z = 226.95 (M+H) ⁺ , RT = 1.23 min.

[00443] Intermediate 25: (6-{[(cyclohexylmethyl)amino]methyl}imidazo[1,2-a]pyridin- 2-yl)methanamine trihydrochloride

[00444] Step 1: tert-butyl N-({6-cyanoimidazo[1,2-a]pyridin-2-yl}methyl)carbamate

[00445] A suspension of 2-(aminomethyl)imidazo[1,2-a]pyridine-6-carbonitrile (2.60 g, 15.1 mmol) and N-ethyl-N-isopropyl-propan-2-amine (3.7 mL, 20.9 mmol) in THF (35 mL) and DCM (35 mL) was treated with N,N-dimethylpyridin-4-amine (0.085 g, 0.697 mmol) and tert-butoxycarbonyl tert-butyl carbonate (3.40 g, 15.6 mmol) at 0 ^o C and the mixture was allowed to warm to room temperature and stirred at room temperature for 65 hours. The reaction mixture was concentrated under vacuum, the residue was suspended in water- CH3CN (1:1, 15 mL), and sonicated for 20 min. The solid was filtered, and then treated with water-MeCN again. The obtained solid was dried under vacuum to give the title compound (2.78 g, 63%) as an off white solid. The filtrate was purified by reverse phase chromatography (Biotage 400 g eluting with 5-100% (0.1% formic acid in MeCN) in 0.1% formic acid to provide a further crop of title compound (414 mg, 10%).

Method B: LC-MS (electrospray): m/z = 273.3 (M+H) ⁺ , RT = 1.38 min.

[00446] Step 2: tert-butyl N-({6-formylimidazo[1,2-a]pyridin-2-yl}methyl)carbamate

[00447] A suspension of tert-butyl N-[(6-cyanoimidazo[1,2-a]pyridin-2- yl)methyl]carbamate (5.00 g, 18.4 mmol) and sodium phosphinate hydrate (15.57 g, 0.147 mol) in a mixture of water (50 mL), Pyridine (100 mL) and Acetic acid (50 mL) was treated with Raney nickel (50%, 18.97 g, 0.162 mol) and the mixture was heated at 100 ^o C under a nitrogen atmosphere for an hour. The Raney nickel was removed by hot filtration through a bed of Celite (washing with water, followed by methanol). The filtrate was concentrated under vacuum to remove the methanol and the blue solution was extracted with DCM (50 mL x 4). The extracts evaporated under vacuum to afford a beige gum which was triturated with water to furnish a white solid. The solid was collected by filtration, washed with water followed by ether and dried under vacuum overnight to provide the title compound (4.13 g, 82%) as an off white solid.

Method B: LC-MS (electrospray): m/z = 276.2 (M+H) ⁺ , RT = 1.33 min.

Step 3: tert-butyl N-[(6-{[(cyclohexylmethyl)amino]methyl}imidazo[1,2-a]pyridin -2- yl)methyl]carbamate

[00448] A solution of tert-butyl N-[(6-formylimidazo[1,2-a]pyridin-2- yl)methyl]carbamate (340 mg, 0.988 mmol) and cyclohexylmethanamine (224 mg, 1.98 mmol) in ethanol (6.8 mL) was stirred at 50 ° C for an hour. The reaction mixture was cooled to 0 °C and NaBH ₄ (75 mg, 1.98 mmol) was added in portions. The reaction mixture was allowed to warm to room temperature and stirring was continued for 2 hours. The reaction mixture was partitioned between DCM (80 mL) and saturated aqueous sodium hydrogen carbonate (30 mL). The organic layer was separated, washed with brine (30 mL), dried (MgSO ₄ ), concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (Biotage KP-NH 28 g, eluting with 0-20% methanol in EtOAc) to afford the title compound (360 mg, 97%) as a pale yellow oil.

Method B: LC-MS (electrospray): m/z = 373.3 (M+H) ⁺ , RT = 1.76 min.

[00449] Step 4: (6-{[(cyclohexylmethyl)amino]methyl}imidazo[1,2-a]pyridin-2- yl)methanamine trihydrochloride

[00450] To a solution of tert-butyl N-[[6-[(cyclohexylmethylamino)methyl]imidazo[1,2- a]pyridin-2-yl]methyl]carbamate (360 mg, 0.908 mmol) in methanol (4.1379 mL) was added HCl (4M in dioxane , 2.4 mL, 9.6 mmol) at room temperature The solution was stirred at 50 °C for 1 hour. The solution was cooled to room temperature, and concentrated to dryness under reduced pressure. The residue (pale yellow glass) was dissolved in methanol (~3 mL) and diethyl ether (~ 20 mL) was added drop-wise to the stirred solution. The resulting precipitate was collected by filtration and dried in the vacuum oven at 40 °C for 4 hours to afford [the title compound (359 mg, 100%) as white solid.

Method B: LC-MS (electrospray): m/z = 273.3 (M+H) ⁺ , RT = 1.77 min.

[00451] Intermediate 28: {6-[(benzyloxy)methyl]imidazo[1,2-a]pyridin-2- yl}methanamine dihydrochloride

[00452] Step 1: Methyl 2-(chloromethyl)imidazo[1,2-a]pyridine-6-carboxylate

[00453] Methyl 6-aminopyridine-3-carboxylate (8.8g, 57.8 mmol) and 1,3- dichloropropan-2-one (11.0g, 86.8 mmol) were combined in acetonitrile (120 mL) and the mixture heated at reflux. The reaction mixture was cooled to room temperature and concentrated under vacuum. The residue was basified using saturated aqueous sodium hydrogen carbonate (~150 mL) and extracted with chloroform/isopropanol (3:1, 4 x 80 mL). The combined organic extracts were dried over sodium sulfate and evaporated under vacuum. The residue was purified by chromatography on silica gel (Biotage, 100 g kp-Sil, eluting with EtOAc/heptane 0-100%) to afford the title compound (6.33g, 49%) of as an off- white solid.

Method B: LC-MS (electrospray): m/z = 225.1 (M+H) ⁺ , RT = 1.33 min.

[00454] Step 2: methyl 2-({bis[(tert-butoxy)carbonyl]amino}methyl)imidazo[1,2- a]pyridine-6-carboxylate

[00455] Methyl 2-(chloromethyl)imidazo[1,2-a]pyridine-6-carboxylate (6.33g, 28.2 mmol), di-tert-butyl imidodicarbonate (9.80g, 45.1 mmol), NaI (425 mg, 2.82 mmol) and K2CO3 (11.7g, 84.5 mmol) were combined in acetonitrile (200 mL) and water (5 mL) and the mixture heated at 70 °C for 3 hours.

[00456] The reaction mixture was cooled to room temperature and concentrated under vacuum. The residue was diluted with water (100 mL) and extracted with DCM (3 x 150 mL) and the combined organic extracts were dried over sodium sulfate and evaporated under vacuum. The residue was purified by chromatography on silica gel (Biotage 340 g kp- Sil, eluting with EtOAc/heptane 0-50%) to afford the title compound (8.51g, 74%) as a very pale yellow oil.

Method B: LC-MS (electrospray): m/z = 406.2 (M+H) ⁺ , RT = 1.71 min.

[00457] Step 3: 2-({bis[(tert-butoxy)carbonyl]amino}methyl)imidazo[1,2-a]pyr idine-6- carboxylic acid

[00458] Methyl 2-[[bis(tert-butoxycarbonyl)amino]methyl]imidazo[1,2-a]pyrid ine-6- carboxylate (2.12g, 5.23 mmol) was dissolved in THF (30 mL) and water (10 mL) and lithium hydroxide (455 mg, 18.2 mmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under vacuum to remove THF. The residue was acidified carefully using HCl(1M) to ~pH2 and extracted with chloroform/isopropanol (3:1, 3 x 80 mL). The combined organic extracts were dried over sodium sulfate and evaporated under vacuum to afford the title compound (1.99g, 97%) as a white solid.

Method B: LC-MS (electrospray): m/z = 392.3 (M+H) ⁺ , RT = 1.13 min.

[00459] Step 4: 2-({bis[(tert-butoxy)carbonyl]amino}methyl)imidazo[1,2-a]pyr idine-6- carboxylic acid

[00460] 2-[[bis(tert-butoxycarbonyl)amino]methyl]imidazo[1,2-a]pyrid ine-6-carboxylic acid (800 mg, 2.04 mmol) was dissolved in THF (anhydrous, 40 mL) and borane in THF (1M, 4.7 mL, 4.7 mmol) was added. The mixture was stirred at room temperature. Further borane THF (1M, 4.7 mL, 4.7 mmol) added and stirring continued overnight. Yellow solution after 2nd addition. The reaction mixture was quenched with methanol (40 mL) and the mixture stirred at room temperature for 30 minutes and was heated at reflux for 24 hours. The reaction mixture was cooled to room temperature and evaporated under vacuum. The residue was suspended in saturated aqueous sodium hydrogen carbonate (50 mL) and extracted with chloroform/isopropanol (3:14 x 50 mL). The combined organic extracts were dried over sodium sulfate and evaporated under vacuum. The residue was purified by chromatography on silica gel (Biotage 28 g kp-NH, eluting with methanol/DCM 0-20%) to afford the title compound (356 mg, 44%) of the title compound as a colourless oily residue. Method B: LC-MS (electrospray): m/z = 378.3 (M+H) ⁺ , RT = 1.49 min.

[00461] Step 5: {6-[(benzyloxy)methyl]imidazo[1,2-a]pyridin-2-yl}methanamine dihydrochloride

[00462] tert-butyl N-tert-butoxycarbonyl-N-[[6-(hydroxymethyl)imidazo[1,2-a]pyr idin-2- yl]methyl]carbamate (350 mg, 0.93 mmol) was dissolved in THF (anhydrous 30 mL) and cooled in an ice/water bath. Sodium hydride (60% wt in mineral oil, 371 mg, 9.27 mmol) was added and the mixture stirred under cooling for 15 minutes. Benzyl bromide (220µl, 1.85 mmol) was added and the mixture stirred whilst warming to room temperature.

Further sodium hydride (60% wt in mineral oil, 371 mg, 9.27 mmol) was added and mixture continued to stir for 16 hours. The reaction mixture was slowly quenched with water (20 mL) - gas evolution - and the mixture stirred for 5 minutes, then extracted with

chloroform/isopropanol (3:1, 4 x 30 mL) and the combined organic extracts dried over sodium sulfate and evaporated under vacuum. The residue was purified by chromatography on silica gel(Biotage 28 g kp-NH, eluting with EtOAc/heptane 0-100%) to afford the crude intermediate (356 mg, 37%, 41% purity) of as an amorphous solid. tert-butyl N-[[6- (benzyloxymethyl)imidazo[1,2-a]pyridin-2-yl]methyl]-N-tert-b utoxycarbonyl-carbamate (356 mg, 0.31 mmol, 41% purity) was dissolved in methanol (5 mL) and HCl (4M in Dioxane 1 mL, 4 mmol) was added and the mixture was stirred at room temperature for an hour and at 60 °C for 3 hours. The reaction mixture was cooled to room temperature and evaporated under vacuum to afford the title compound (252 mg, 97%, 41% purity) as a colourless foamy residue which was used without further purification.

Method B: LC-MS (electrospray): m/z = 268.3 (M+H) ⁺ , RT = 1.26 min.

[00463] Intermediate 29: {6-[(benzylamino)methyl]imidazo[1,2-a]pyridin-2- yl}methanamine dihydrochloride

[00464] The title compound was prepared in the same manner as Intermediate 25 using benzylamine to provide (99 mg, 98%) as a white solid.

Method B: LC-MS (electrospray): m/z = 267.2 (M+H) ⁺ , RT = 1.32 min.

[00465] Intermediate 30: N-({6-formylimidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H- chromene-2-carboxamide

[00466] The intermediate was prepared in the same manner as Compound 49 starting from 2-(aminomethyl)imidazo[1,2-a]pyridine-7-carbonitrile and acid giving (349 mg, 49%) as a beige solid.

Method B: LC-MS (electrospray): m/z = 348.1 (M+H) ⁺ , RT = 1.29 min.

[00467] Intermediate 31: N-({7-formylimidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide

[00468] The intermediate was prepared in the same manner as Compound 49 starting from 2-(aminomethyl)imidazo[1,2-a]pyridine-7-carbonitrile and coupling with

Intermediate 4 to give the title compound as a beige solid.

Method B: LC-MS (electrospray): m/z = 348.2 (M+H) ⁺ , RT = 1.19 min.

[00469] Intermediate 32: tert-butyl N-{1-[2-(aminomethyl)imidazo[1,2-a]pyridin-6- yl]ethyl}-N-(cyclohexylmethyl)carbamate

[00470] Step 1: 5-{1-[(cyclohexylmethyl)amino]ethyl}pyridin-2-amine

[00471] A mixture of 1-(6-amino-3-pyridyl)ethanone (1.05 g, 7.71 mmol)

and cyclohexylmethanamine (5.24 g, 46.3 mmol) in ethanol (20 mL) was stirred at 90 °C for 36 hours. The reaction mixture was cooled to 0 ^o C, and then NaBH4 (584 mg, 15.4 mmol) was added. The reaction mixture was stirred at room temperature for 2hours. The reaction mixture was cooled to 0 ^o C and quenched with water and NaOH (1M). The aqueous were extracted with IPA-CHCl ₃ (1:4, 3 x 30 mL). The combined organic layer was dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure to give a yellow gum, which was purified by acidic reverse phase chromatography (biotage100 g ) to give the title compound as a pale brown gum(1.00 g, 48%).

Method B: LC-MS (electrospray): m/z = 234.3 (M+H) ⁺ , RT = 1.51 min

[00472] Step 2: tert-butyl N-[1-[2-(chloromethyl)imidazo[1,2-a]pyridin-6-yl]ethyl]-N- (cyclohexylmethyl)carbamate

[00473] A solution of 1,3-dichloropropan-2-one (702 mg, 5.53 mmol) and 5-[1- (cyclohexylmethylamino)ethyl]pyridin-2-amine (1000 mg, 3.69 mmol) in acetonitrile (50 mL) was stirred at reflux for 2 hours. The reaction mixture was cooled to 0 ^o C and treated with tert-butoxycarbonyl tert-butyl carbonate (965 mg, 4.42 mmol), N,N-dimethylpyridin-4-amine (45 mg, 0.369 mmol) and N-ethyl-N-isopropyl-propan-2-amine (1.3 mL, 7.37 mmol) and the mixture was stirred at room temperature for 16 hours. The solvent was removed under vacuum and the residue was suspended in EtOAc (100 mL) and washed with water and brine, dried over Na2SO4, filtered and evaporated under reduced pressure to give a brown gum, which was purified by high pH reverse phases chromatography (biotage C18 Snap 100 g,) to give the title compound (400 mg, 27%) as a white solid.

Method B: LC-MS (electrospray): m/z = 406.3 (M+H) ⁺ , RT = 1.97 min.

[00474] Step 3: tert-butyl N-[1-[2-(azidomethyl)imidazo[1,2-a]pyridin-6-yl]ethyl]-N- (cyclohexylmethyl)carbamate

[00475] A suspension of tert-butyl N-[1-[2-(chloromethyl)imidazo[1,2-a]pyridin-6- yl]ethyl]-N-(cyclohexylmethyl)carbamate (400 mg, 0.985 mmol) in acetonitrile (15 mL) was treated with sodium azide (231 mg, 3.55 mmol) and sodium iodide (15 mg, 0.0985 mmol) at room temperature The mixture was stirred at reflux for 20 hours. The reaction mixture was cooled to 0 ^o C and quenched with water (50 mL). The mixture was extracted with DCM (3 x 15 mL). The combined organic layer was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound (410 mg, 98%) as a dark brown solid.

Method B: LC-MS (electrospray): m/z = 413.4 (M+H) ⁺ , RT = 1.98 min.

[00476] Step 4: tert-butyl N-[1-[2-(aminomethyl)imidazo[1,2-a]pyridin-6-yl]ethyl]-N- (cyclohexylmethyl)carbamate

[00477] tert-butyl N-[1-[2-(azidomethyl)imidazo[1,2-a]pyridin-6-yl]ethyl]-N- (cyclohexylmethyl)carbamate (300 mg, 0.727 mmol) and Pd/C (10%, 50 mg, 0.0470 mmol) were combined in EtOH (10 mL). The mixture was flushed three times with nitrogen, placed under a hydrogen atmosphere and stirred at room temperature for 16 hours. The reaction mixture was filtered through a pad of celite and the solid residue was washed with methanol. The filtrate was concentrated to dryness under vacuum to provide the title compound (280 mg, 100%) as yellow solid.

Method B: LC-MS (electrospray): m/z = 387.3 (M+H) ⁺ , RT = 1.95 min.

[00478] Intermediate 33: 6-bromo-4-ethynyl-1-(oxan-2-yl)-1H-indazole

[00479] The title compound starting from was prepared from 6-bromo-4-iodo-1H- indazole using the steps described in Intermediate 24 to give (737 mg, 96%).

Method A: LC-MS (electrospray): m/z = 304.95/306.95 (M+H) ⁺ , RT = 1.39 min

[00480] Intermediate 34: 2-[[4-(1-tetrahydropyran-2-ylindazol-4-yl)triazol-1- yl]methyl]imidazo[1,2-a]pyridine-6-carbaldehyde

[00481] Step 1: methyl 2-(chloromethyl)imidazo[1,2-a]pyridine-6-carboxylate

[00482] Methyl 6-aminopyridine-3-carboxylate (5.3g, 34.8 mmol) and 1,3- dichloropropan-2-one (6.63 g, 52.3 mmol) were combined in acetonitrile (50 mL) and the mixture heated at reflux for 6 hours. The reaction mixture was cooled to room temperature and the residue suspended in saturated aqueous sodium hydrogen carbonate (80 mL). The mixture was extracted with 3:1 chloroform/isopropanol (3 x 100 mL) and the

combinedorganic extracts dried over sodium sulfate and evaporated under vacuum. The residue was purified by Biotage Isolera™ chromatography (100 g kp-Sil, eluting with EtOAc/heptane 0-100%) to afford a crude material which was triturated with EtOAc/heptane. The solids were collected by filtration and dried under suction to afford 3.35g (43%) of the title compound as a white solid.

Method B: LC-MS (electrospray): m/z = 225.1 (M+H) ⁺ , RT = 1.32 min

[00483] Step 2: [2-(chloromethyl)imidazo[1,2-a]pyridin-6-yl]methanol [00484] A solution of methyl 2-(chloromethyl)imidazo[1,2-a]pyridine-6-carboxylate (700 mg, 3.12 mmol) in anhydrous THF (20 mL) and cooled in an ice/water bath. DIBAL (1M in PhMe, 8.6 mL, 8.6 mmol) was added slowly to give a yellow solution and the mixture stirred under cooling for 2 hours. The reaction mixture was quenched by dropwise addition of methanol (5 mL), then diluted with DCM (70 mL) and saturated aqueous sodium hydrogen carbonate (50 mL). The mixture was filtered through Celite and the residue rinsed well with DCM. The filtrates were phase-separated, the aqueous layer extracted with DCM (80 mL). The combined organic layers dried over sodium sulfate and evaporated under vacuum. The resultant residue was triturated with Et ₂ O and the solids collected by filtration to afford (384 mg 60%) of the title compound as a pale yellow solid

[00485] MS16 IPC: LC-MS (electrospray): m/z = 196.8 (M+H) ⁺ , RT = 0.31 min

[00486] Step 3: [2-(azidomethyl)imidazo[1,2-a]pyridin-6-yl]methanol

[00487]

[00488] [2-(chloromethyl)imidazo[1,2-a]pyridin-6-yl]methanol (380 mg, 1.93 mmol), NaI (29 mg, 0.19 mmol) and NaN3 (300 mg, 4.61 mmol) were combined in DMF (2 mL) and the mixture stirred at room temperature for 3 hours. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate (30 mL) and extracted with DCM (3 x 50 mL). The combined organic extracts were dried over sodium sulfate and evaporated under vacuum. The solids were carefully triturated with EtOAc/heptane and the solids collected by filtration to afford 309 mg, 79%) of the title compound as a pale yellow solid

Method B: LC-MS (electrospray): m/z = 204.2 (M+H) ⁺ , RT = 1.10 min

[00489] Step 4: [2-[[4-(1-tetrahydropyran-2-ylindazol-4-yl)triazol-1- yl]methyl]imidazo[1,2-a]pyridin-6-yl]methanol

[00490] 4-ethynyl-1-tetrahydropyran-2-yl-indazole Intermediate 24 (280 mg, 1.19 mmol), [2-(azidomethyl)imidazo[1,2-a]pyridin-6-yl]methanol (265 mg, 1.31 mmol) and copper sulfate (40 mg, 0.25 mmol) were combined in DMF (3 mL) and water (1 mL), and sodium ascorbate (261 mg, 1.31 mmol) was added. The mixture was stirred at room temperature for 45 minutes. The reaction mixture was diluted with 3:1 chloroform/isopropanol (50 mL) and water (30 mL) and the phases separated. The aqueous phase was extracted with 3:1 chloroform/isopropanol (2 x 30 mL) and the combined organic layers dried over sodium sulfate and evaporated under vacuum. The residue was purified by chromatography on silica gel (Biotage,28 g kp-NH, eluting with EtOAc/heptane 0-100% followed by 0-20%

methanol/EtOAc) to afford a crude material which was triturated with methanol/Et ₂ O/heptane and the resultant flocculant solid collected by filtration to afford the title compound (376 mg (71%) of as a white solid.

Method B: LC-MS (electrospray): m/z = 430.3 (M+H) ⁺ , RT = 1.38 min

[00491] Step 5: 2-[[4-(1-tetrahydropyran-2-ylindazol-4-yl)triazol-1- yl]methyl]imidazo[1,2-a]pyridine-6-carbaldehyde

[00492] [2-[[4-(1-tetrahydropyran-2-ylindazol-4-yl)triazol-1-yl]meth yl]imidazo[1,2- a]pyridin-6-yl]methanol (380 mg, 0.88 mmol) was suspended in DCE (30 mL) and Dess- Martin periodinane (1.13g, 2.65 mmol) was added. The mixture was stirred at 60 °C for 2 hours. The reaction mixture was cooled to room temperature, quenched with saturated aqueous sodium hydrogen carbonate (40 mL) and extracted with 3:1 chloroform/isopropanol (4 x 50 mL). The combined organic extracts were dried over sodium sulfate and evaporated under vacuum. The residue was triturated with EtOAc/heptane and the solids collected by filtration to afford the title compound (371 mg, 94%) as a beige solid

Method B: LC-MS (electrospray): m/z = 428.2 (M+H) ⁺ , RT = 1.45 min [00493] Intermediate 35: 2-[[4-(6-bromo-1-tetrahydropyran-2-yl-indazol-4-yl)triazol-1 - yl]methyl]imidazo[1,2-a]pyridine-6-carbaldehyde

[00494] The title compound was prepared from Intermediate 33 in a similar fashion to Intermediate 34 giving (906 mg, 99%) as a pale yellow solid.

Method B: LC-MS (electrospray): m/z = 506.2/508.2 (M+H) ⁺ , RT = 1.58 min

[00495] The title compound was prepared in a similar fashion to Intermediate 34 starting from 5-iodo-1H-indazole

Method B: LC-MS (electrospray): m/z = 428.2 (M+H) ⁺ , RT = 1.42 min

[00496] Intermediate 36: 5-ethynyl-1-(oxan-2-yl)-1H-indazole

[00497] The title compound was prepared from 5-iodo-1H-indazole using the steps described in Intermediate 24 giving (1.03 g, 94%) as a yellow oil.

Method A: LC-MS (electrospray): m/z = 227.10 (M+H) ⁺ , RT = 1.22 min.

[00498] Intermediate 37: 2-({4-[1-(oxan-2-yl)-1H-indazol-5-yl]-1H-1,2,3-triazol-1- yl}methyl)imidazo[1,2-a]pyridine-6-carbaldehyde

[00499] The title compound was prepared from Intermediate 36 using the steps described in Intermediate 24 giving (143 mg, 98%) as a pale yellow solid.

Method B: LC-MS (electrospray): m/z = 428.2 (M+H) ⁺ , RT = 1.42 min

[00500] Intermediate 38: 4-ethynyl-1-(oxan-2-yl)-1H-pyrazolo[3,4-c]pyridine

[00501] The title compound was prepared from 4-bromo-1H-pyrazolo[3,4-c]pyridine using the method described for Intermediate 24 giving

Method A: LC-MS (electrospray): m/z = 228.15 (M+H) ⁺ , RT = 1.078 min

[00502] Intermediate 39: [2-({4-[1-(oxan-2-yl)-1H-pyrazolo[3,4-c]pyridin-4-yl]-1H- 1,2,3-triazol-1-yl}methyl)imidazo[1,2-a]pyridin-6-yl]methano l

[00503] The intermediate was prepared from Intermediate 38 using the methods described in Intermediate 34 Step 4 giving (314 mg, 73%) as an off white solid.

Method A: LC-MS (electrospray): m/z = 431.05 (M+H) ⁺ , RT = 0.78 min

[00504] Intermediate 40: 2-({4-[1-(oxan-2-yl)-1H-pyrazolo[3,4-c]pyridin-4-yl]-1H-1,2, 3- triazol-1-yl}methyl)imidazo[1,2-a]pyridine-6-carbaldehyde

[00505] The intermediate was prepared from Intermediate 39 using the methods described in Intermediate 34 Step 5 giving (249 mg, 77%) as a pale yellow solid.

Method A: LC-MS (electrospray): m/z = 429.65 (M+H) ⁺ , RT = 0.95 min

[00506] Intermediate 42: (2,3,4,5,6-pentafluorophenyl) 3-phenylpropanoate

[00507] pentafluorophenol (135 mg, 0.732 mmol) was added to a mixture of 3- phenylpropanoic acid (100 mg, 0.666 mmol), N,N'-dicyclohexylmethanediimine (0.18 mL, 0.799 mmol) and N,N-dimethylpyridin-4-amine (8.1 mg, 0.0666 mmol) in anhydrous THF (4 mL) under nitrogen and the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was filtered and the filtrates concentrated under vacuum. The resultant residue was purified by chromatography on silica gel (Biotage kp-Sil, eluting with

EtOAc/heptane 0-30%) to afford (135 mg, 64%) as a colourless oil.

Method A: LC-MS (electrospray): does not ionise, RT = 1.46 min

[00508] Intermediate 43: {6-[(4,4-dimethylpiperidin-1-yl)methyl]imidazo[1,2-a]pyridin - 2-yl}methanamine trihydrochloride

[00509] The intermediate was prepared in the same manner as Intermediate 29 to give the title compound (390 mg, 97%) as a white solid.

Method B: LC-MS (electrospray): m/z = 273.3 (M+H) ⁺ , RT = 1.52 min

[00510] Intermediate 44: 1-Cyclohexyl-2-(tributylstannylmethoxy)ethanamine:

[00511] To a solution of 2-amino-2-cyclohexyl-ethanol (150 mg, 1.05 mmol) in anhydrous THF (3 mL) was added potassium-2-methylpropan-2-olate (153 mg, 1.36 mmol) at room temperature. The mixture stirred for 30 minutes before a solution of

tributyl(iodomethyl)stannane (451 mg, 1.05 mmol) in THF (2 mL) was added drop-wise and stirring was continued for 72 hours. The reaction mixture was cooled to 0 °C and slowly quenched with sat aq NH4Cl (5 mL) before being poured onto a mixture of EtOAc/water (4:1, 50 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with water (2 x 15 mL), brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica (Biotage KP-Sil 25 g; 0-10% 2M ammonia in

methanol/DCM) to afford the title compound (330 mg, 64%) as yellow oil.

[00512] ¹ HNMR(500 MHz, Chloroform-d) d 0.80– 0.97 (m, 15H), 0.98– 1.56 (m, 18H), 1.60– 1.84 (m, 5H), 2.02 (s, 2H), 2.67– 2.76 (m, 1H), 3.15– 3.23 (m, 1H), 3.38 (dd, J = 9.1, 3.6 Hz, 1H), 3.68 (d, J = 10.3 Hz, 1H), 3.74 (d, J = 10.3 Hz, 1H). [00513] Intermediate 45: (2S)-3,3-Dimethyl-1-(tributylstannylmethoxy)butan-2-amine:

[00514] The title compound was prepared in the same manner as Intermediate 44 from (2S)-2-amino-3,3-dimethylbutan-1-ol giving (465 mg, 85%) as a yellow oil.

[00515] ¹ HNMR(500 MHz, Chloroform-d) d 0.85– 0.93 (m, 24H), 1.24– 1.35 (m, 7H), 1.42– 1.59 (m, 7H), 2.65 (dd, J = 9.1, 2.9 Hz, 1H), 3.06– 3.14 (m, 1H), 3.43 (dd, J = 9.0, 2.9 Hz, 1H), 3.65– 3.71 (m, 1H), 3.72– 3.77 (m, 1H).

[00516] Intermediate 46: (2R)-3,3-Dimethyl-1-(tributylstannylmethoxy)butan-2-amine:

[00517] The title compound was prepared in the same manner as Intermediate 44 from (2R)-2-amino-3,3-dimethylbutan-1-ol giving (470 mg, 87%) as a yellow oil.

[00518] ¹ HNMR(500 MHz, Chloroform-d) d 0.81– 0.98 (m, 24H), 1.25– 1.34 (m, 6H), 1.35– 1.61 (m, 8H), 2.65 (dd, J = 9.1, 2.9 Hz, 1H), 3.05– 3.15 (m, 1H), 3.44 (dd, J = 8.9, 2.9 Hz, 1H), 3.64– 3.70 (m, 1H), 3.70– 3.78 (m, 1H).

[00519] Intermediate 47: [6-[rac-(3S,5R)-5-Cyclohexylmorpholin-3-yl]imidazo[1,2- a]pyridin-2yl]methanamine trihydrochloride.

[00520] Step 1: tert-Butyl N-[[6-[rac-(3S,5R)-5-cyclohexylmorpholin-3-yl]imidazo[1,2- a]pyridin-2-yl]methyl]carbamate

[00521] To a solution of tert-butyl N-[(6-formylimidazo[1,2-a]pyridin-2- yl)methyl]carbamate (Intermediate 25 step 2) (183 mg, 0.67 mmol) in 1,1,1,3,3,3- Hexafluoro-2-propanol (2.5 mL) was added a solution of 1-cyclohexyl-2- (tributylstannylmethoxy)ethanamine (90%, 330 mg, 0.665 mmol) in DCE (4 mL). The reaction mixture was stirred at 80 °C for 16 hours. Meanwhile a mixture of 2,6- dimethylpyridine (0.16 mL, 1.33 mmol), copper(2+) bis(trifluoromethanesulfonate) (484 mg, 1.33 mmol) and 1,1,1,3,3,3-Hexafluoro-2-propanol (2.5 mL) was stirred separately at room temperature for 1 hour. After cooling to room temperature, the solution of the imine was added drop-wise to the solution of the catalyst. The resulting mixture was stirred at room temperature for 3 hours forming a clear, dark green solution. The reaction mixture was diluted with DCM (25 mL) and quenched with 10% aq. NH4OH (10 mL) solution. The organic layer was separated, washed with brine (10 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (method B) to afford the title compound (152 mg, 55%) as pale yellow oil.

Method C: LC-MS (electrospray): m/z = 415.4 (M+H) ⁺ , RT = 3.66 min

[00522] Step 2: [6-[rac-(3S,5R)-5-Cyclohexylmorpholin-3-yl]imidazo[1,2-a]pyr idin- 2yl]methanamine trihydrochloride.

[00523] To a solution of tert-butyl N-[[6-[rac-(3S,5R)-5-cyclohexylmorpholin-3- yl]imidazo[1,2-a]pyridin-2-yl]methyl]carbamate (153 mg, 0.368 mmol) in methanol (2 mL) was added 4M HCl in dioxane (1 mL) at room temperature. The solution was stirred at 50 °C for 1 hour. After cooling to room temperature, the reaction mixture was concentrated to dryness under reduced pressure. The residue was dissolved in methanol (3 mL) and diethyl ether (20 mL) was added drop-wise to the stirred solution. The resulting precipitate was collected by filtration and dried in the vacuum oven at 40 °C for 4 hours to afford the title compound (129 mg, 78%) as an off-white solid.

Method C: LC-MS (electrospray): m/z = 315.3 (M+H) ⁺ for freebase, RT = 2.80 min.

[00524] Intermediate 48: tert-butyl N-[[6-[rac-(3S,5R)-5-methylmorpholin-3- yl]imidazo[1,2-a]pyridin-2-yl]methyl]carbamate

[00525] A glass vial (40 mL clear, screw cap) was charged with tert-butyl N-[(6- formylimidazo[1,2-a]pyridin-2-yl)methyl]carbamate (Intermediate 25 step 2) (138 mg, 0.500 mmol) and loaded into a SYNPLEChem capsule based synthesizer, using a H0073- Methylmorpholine cartridge. After the reaction mixture was complete (11 hour), the product containing solution was concentrated under reduced pressure. The residue was purified by preparative HPLC (method B) to afford the title compound (82 mg, 45%) as colourless oil. Method C: LC-MS (electrospray): m/z = 347.3 (M+H), RT = 2.28 min.

[00526] Intermediate 49: tert-Butyl N-[[6-(9-methoxy-2,3,4,5-tetrahydro-1,4- benzoxazepin-3-yl)imidazo[1,2-a]pyridin-2-yl]methyl]carbamat e.

[00527] The intermediate was prepared in the same manner as Intermediate 48 to afford the title compound (105 mg, 49%) as colourless oil.

Method C: LC-MS (electrospray): m/z = 425.3 (M+H), RT = 2.75 min

[00528] Intermediate 50: [6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl]methanamine

[00529] The title compound was prepared from 2-amino-5-(trifluoromethyl)pyridine in a similar manner to Intermediate 7 to give (650 mg, 65%) as a light brown solid.

Method B: LC-MS (electrospray): m/z = 216.2 (M+H) ⁺ , RT = 1.29 min.

[00530] The compounds in Table 9 were prepared in a similar fashion to Compound 1 using the appropriate carboxylic acid and aminomethyl imidazopyridine intermediate, or commercially available materials, including deprotection where necessary.

Table 9

[00531] Compound 66: 4-[5-({6-methylimidazo[1,2-a]pyridin-2-yl}methyl)-1,3,4- thiadiazol-2-yl]-1H-indazole

[00532] N'-[2-(6-methylimidazo[1,2-a]pyridin-2-yl)acetyl]-1-tetrahyd ropyran-2-yl- indazole-4-carbohydrazide (Compound 62 Step 3), (250 mg, 0.58 mmol) was suspended in 1,4-Dioxane (10 mL) and Lawesson's reagent (1.17g, 2.89 mmol) was added. The vessel was sealed and the mixture heated at 110°C and the solids dissolved upon heating. The reaction mixture was cooled to room temperature and left standing overnight. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate (50 mL) and extracted with chloroform/isopropanol (3:1, 4 x 50 mL). The combined organic extracts were dried over sodium sulfate and evaporated under vacuum. The residue was purified by chromatography on silica gel (Biotage kp-NH 28 g, eluting with EtOAc/heptane 0-100% followed by 0-20% methanol/EtOAc) to afford a crude material which was triturated with EtOAc. The solids were collected by filtration and rinsed with heptane to afford the title compound (112 mg, 56%) as a white solid.

Method D: LC-MS (electrospray): m/z = 347.2 (M+H) ⁺ , RT = 3.33 min Compound 69: 4-[1-({6-methylimidazo[1,2-a]pyridin-2-yl}methyl)-1H-1,2,3-t riazol-4-yl]-1H- indazole

Step1: 4-[1-({6-methylimidazo[1,2-a]pyridin-2-yl}methyl)-1H-1,2,3-t riazol-4-yl]-1-(oxan-2-yl)- 1H-indazole

[00533] A solution of 2-(azidomethyl)-6-methyl-imidazo[1,2-a]pyridine (Intermediate 23, 120 mg, 0.64 mmol) and 4-ethynyl-1-tetrahydropyran-2-yl-indazole (intermediate 24, 189 mg, 0.83 mmol) in DMF (3 mL) and water (0.5 mL) was treated with CuSO4 (31 mg, 0.19 mmol) and sodium ascorbate (38 mg, 0.19 mmol) and the mixture was stirred at room temperature for an hour. Precipitation noted within 30 minutes. The reaction mixture was diluted with water (20 mL), the solid was collected by filtration washed with water, then triturated successively with methanol, EtOAc and heptane and dried under suction to afford the title compound (209 mg, 79%) as a white solid.

Method D: LC-MS (electrospray): m/z = 414.3 (M+H) ⁺ , RT = 3.93 min.

[00534] A suspension of 4-[1-[(6-methylimidazo[1,2-a]pyridin-2-yl)methyl]triazol-4-y l]- 1-tetrahydropyran-2-yl-indazole (100 mg, 0.24 mmol) in methanol (5 mL) was treated with HCl (4M in Dioxane , 2 mL, 8 mmol) ) which caused dissolution. The mixture was stirred at room temperature for two hours. The reaction mixture was evaporated under vacuum and the residue was triturated with methanol/EtOAc/heptane and the solids collected by filtration. The residue was purified by preparative HPLC (method B) and the fractions evaporated to afford the title compound (13 mg, 16%) as a white solid.

Method D: LC-MS (electrospray): m/z = 330.2 (M+H) ⁺ , RT = 3.15 min. [00535] Compound 158: N-[(6-{[(3-chlorophenyl)amino]methyl}imidazo[1,2-a]pyridin- 2-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

[00536] N-[(6-formylimidazo[1,2-a]pyridin-2-yl)methyl]-4-oxo-pyrido[ 1,2-a]pyrimidine- 2-carboxamide (Compound 49) (70 mg, 0.20 mmol) and 3-chloroaniline (51 mg, 0.40 mmol) were combined in 1,1,1,3,3,3-Hexfluoro-2-propanol (2 mL) and the mixture stirred at room temperature. NaBH4 (70 mg, 1.85 mmol) was added with a few drops of methanol - gas evolution - and the mixture stirred briefly at room temperature. The reaction mixture was quenched with methanol (20 mL) - gas evolution - and the mixture evaporated under vacuum. The residue was suspended in saturated aqueous sodium hydrogen carbonate (20 mL) and extracted with chloroform/isopropanol (3:1, 3 x 30 mL). The combined organic extracts were dried over sodium sulfate and evaporated under vacuum.

[00537] The residue was purified by preparative HPLC (method B) and the clean product-containing fractions combined and evaporated under vacuum. The residue was dried in the genevac and under vacuum at 40 °C to afford the title compound (47 mg, 50%) of as a pale yellow solid.

Method C: LC-MS (electrospray): m/z = 459.3 (M+H) ⁺ , RT = 2.96 min.

[00538] Compound 168: N-[(6-{[(1-cyclohexyl-2- hydroxyethyl)amino]methyl}imidazo[1,2-a]pyridin-2-yl)methyl] -4-oxo-4H-pyrido[1,2- a]pyrimidine-2-carboxamide;

[00539] To a solution of N-[(6-formylimidazo[1,2-a]pyridin-2-yl)methyl]-4-oxo- pyrido[1,2-a]pyrimidine-2-carboxamide (Compound 49) (100 mg, 0.288 mmol)

in 1,1,1,3,3,3-Hexafluoro-2-propanol (2 mL) was added 2-amino-2-cyclohexyl-ethanol (0.062 mL, 0.317 mmol) at room temperature. The mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and the residue (pale yellow oil) was purified by preparative HPLC (Method B). The product containing fractions were combined and concentrated under reduced pressure to afford the

intermediate imine (55 mg, 38%) as white solid. To a solution of the imine (52 mg, 0.105 mmol) in ethanol (3 mL) was added NaBH4 (36 mg, 0.96 mmol) at room temperature.

The mixture was stirred at room temperature for 3 hours. The reaction mixture was partitioned between ethyl acetate (40 mL) and Na2CO3 (2M, 30 mL). The organic layer was separated, washed with brine (20 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (method B) to afford the title compound (16 mg, 31%) as white solid.

Method C: LC-MS (electrospray): m/z = 475.3 (M+H) ⁺ , RT = 2.56 min.

[00540] The compounds in table 10 was prepared in the same manner as

Compounds 51, 158 or 168 and purified by method B. Table 10

[00541] Compound 191: 4-oxo-N-({6-[(2-phenylethyl)amino]imidazo[1,2-a]pyridin-2- yl}methyl)-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

[00542] The title compound was prepared from Compound 23 using the procedure described for Compound 32 and purified by preparative HPLC (Method A) to give (29 mg, 22%) as a brown solid.

[00543] Method E: LC-MS (electrospray): m/z = 439.3 (M+H) ⁺ , RT = 1.83 min. [00544] Compound 235: N-({6-[2-(benzylamino)ethyl]imidazo[1,2-a]pyridin-2- yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

[00545] Step 1: tert-butyl N-(2-{2-[({4-oxo-4H-pyrido[1,2-a]pyrimidin-2- yl}formamido)methyl]imidazo[1,2-a]pyridin-6-yl}ethyl)carbama te

[00546] The title compound was prepared by the coupling of Intermediate 4 with intermediate 20 using the method described in Compound 1 and purified by reverse phase chromatography (400 g, High pH method) to provide (900 mg, 63%) as an off white solid. Method B: LC-MS (electrospray): m/z = 463.3 (M+H) ⁺ , RT = 1.39 min. [00547] Step 2: N-{[6-(2-aminoethyl)imidazo[1,2-a]pyridin-2-yl]methyl}-4-oxo -4H- pyrido[1,2-a]pyrimidine-2-carboxamide

[00548] The title compound was prepared using the deprotection described in

Intermediate 22 step 5 and purified by reverse phase chromatography (60 g, High pH method) to provide (100 mg, 12%) as a white solid.

Method D: LC-MS (electrospray): m/z = 363.2 (M+H) ⁺ , RT =2.67 min. [00549] Step 3: N-({6-[2-(benzylamino)ethyl]imidazo[1,2-a]pyridin-2-yl}methy l)-4-oxo- 4H-pyrido[1,2-a]pyrimidine-2-carboxamide

[00550] The title compound was prepared from benzaldehyde using the procedure described in Compound 51 and purified by preparative HPLC (method B) to give the title compound (7.8 mg, 8.9%) as a white solid.

Method D: LC-MS (electrospray): m/z = 353.2 (M+H) ⁺ , RT = 3.44 min. [00551] Compound 236: N-({6-[2-(cyclohexylamino)ethyl]imidazo[1,2-a]pyridin-2- yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

[00552] The title compound was prepared using the method described in Compound 51 and purified by preparative HPLC (method A) to give the title compound (48 mg, 56%) as an off white solid.

Method D: LC-MS (electrospray): m/z = 445.3 (M+H) ⁺ , RT = 3.78 min. [00553] Compound 237: 4-oxo-N-({6-[(phenylformamido)methyl]imidazo[1,2- a]pyridin-2-yl}methyl)-4H-pyrido[1,2-a]pyrimidine-2-carboxam ide

[00554] A stirred solution of HATU (140 mg, 0.368 mmol), benzoic acid (30 mg, 0.246 mmol) in DMF (1 mL) was treated with N-ethyl-N-isopropyl-propan-2-amine (0.128 mL, 0.737 mmol) at 0 ^o C under a nitrogen atmosphere for 30 min, and then a solution of N-[[6- (aminomethyl)imidazo[1,2-a]pyridin-2-yl]methyl]-4-oxo-pyrido [1,2-a]pyrimidine-2- carboxamide Compound 50 (122 mg, 0.245 mmol) in DMF (2 mL) was added and the reaction mixture was stirred at room temperature for 4 hours. The crude product was purified by reverse phase HPLC (method B) to provide the title product (25 mg, 21%) as an off white solid. Method D: LC-MS (electrospray): m/z = 453.1 (M+H) ⁺ , RT = 3.04 min. [00555] Compound 238: N-({6-[(cyclohexylformamido)methyl]imidazo[1,2-a]pyridin-2- yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

[00556] The title compound was prepared in the same manner as Compound 237 using cyclohexanecarboxylic acid to give the title compound (35.2 mg, 35%) as a white solid. Method D: LC-MS (electrospray): m/z = 459.2 (M+H) ⁺ , RT = 3.20 min. [00557] Compound 239: 4-oxo-N-{[6-({[(piperidin-3- yl)methyl]amino}methyl)imidazo[1,2-a]pyridin-2-yl]methyl}-4H -pyrido[1,2-a]pyrimidine-2- carboxamide

[00558] The title compound was prepared by deprotection of Compound 100 using the method described in Example 1 and the product was purified by preparative HPLC (method B) followed by ion exchange (SCX-2) giving (8 mg, 19%) as a white solid.

Method D: LC-MS (electrospray): m/z = 446.2 (M+H) ⁺ , RT = 3.18 min. [00559] Compound 2404-oxo-N-{[6-({[(piperidin-2- yl)methyl]amino}methyl)imidazo[1,2-a]pyridin-2-yl]methyl}-4H -pyrido[1,2-a]pyrimidine-2- carboxamide

[00560] The title compound was prepared in the same manner as Compound 239 to give the title compound (8 mg, 19%) as a white solid.

Method D: LC-MS (electrospray): m/z = 446.2 (M+H) ⁺ , RT = 3.18 min. [00561] Compound 241 N-[(6-{[(azetidin-3-yl)amino]methyl}imidazo[1,2-a]pyridin-2- yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

[00562] The title compound was prepared in the same manner as Compound 1 starting tert-butyl 3-aminoazetidine-1-carboxylate and the deprotection outlined in

Compound 239 was used to give the title compound (24 mg, 30%) as an off white solid. Method D: LC-MS (electrospray): m/z = 404.3 (M+H) ⁺ , RT = 2.83 min. [00563] Compound 242: N-({6-[(cyclohexylamino)methyl]imidazo[1,2-a]pyridin-2- yl}methyl)-4-oxo-4H-chromene-2-carboxamide

[00564] The title compound was prepared in a similar manner to Compound 51, using Intermediate 30 giving (16 mg, 33%) as a beige solid.

Method C: LC-MS (electrospray): m/z = 431.4 (M+H) ⁺ , RT = 2.87 min. [00565] The compounds in Table 10 were prepared in a similar manner to

Compound 242 using the appropriate amine and Intermediate 30.

Table 10

[00566] Compound 2434-oxo-N-[(7-{[(2-phenylethyl)amino]methyl}imidazo[1,2- a]pyridin-2-yl)methyl]-4H-pyrido[1,2-a]pyrimidine-2-carboxam ide

[00567] The title compound was prepared in a similar manner to Compound 51, using Intermediate 31 giving (45 mg, 69%) as a pale yellow solid.

Method C: LC-MS (electrospray): m/z = 453.3 (M+H) ⁺ , RT = 2.58 min. [00568] The compounds in Table 11 were prepared in a similar manner to

Compound 243 using the appropriate amine and Intermediate 31. Table 11

[00569] Compound 245: N-[(6-{1-[(cyclohexylmethyl)amino]cyclopropyl}imidazo[1,2- a]pyridin-2-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-ca rboxamide

[00570] A 3 neck flask containing a suspension of N-[(6-cyanoimidazo[1,2-a]pyridin-2- yl)methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide Compound 18 (300 mg, 0.871 mmol) in THF (24 mL) was cooled to - 78 ^o C and treated with tetraisopropoxytitanium (634 ^L, 2.09 mmol) followed by bromo(ethyl)magnesium (3M, 1336 ^L, 4.01 mmol) and the mixture was stirred at -78 ^o C for 30 minutes before (diethyl ether)(trifluoro)boron (438 ^L, 3.49 mmol) was added and the mixture was stirred at -78 ^o C for 30 minutes before the mixture was allowed to slowly warm to room temperature overnight. The brown mixture was cooled to - 78 ^o C and dropwise treated with tetraisopropoxytitanium (634 ^L, 2.09 mmol) followed by bromo(ethyl)magnesium (3M, 1336 ^L, 4.01 mmol) and the mixture was stirred at -78 ^o C for 30 minutes before (diethyl ether)(trifluoro)boron (438 ^L, 3.49 mmol) was added. The dark mixture was stirred at -78 ^o C for a further 30 minutes, allowed to warm to room temperature and left stirring for 7 days. The dark mixture was quenched by the addition of HCl (1M, 50 mL) and washed with DCM. The aqueous layer was basified (6M NaOH, pH ~12) which caused Ti salts to precipitate. The suspension was filtered through Celite (washing with DCM followed by IPA/CHCl3 (1:3) and the phases were separated. The extracts were evaporated under vacuum to afford a brown residue 500 mg which was further purified by ion exchange [SCX-2 washing with methanol followed by DCM and eluting with 2M ammonia in methanol]. The eluted fraction was evaporated under vacuum to afford a brown residue. The residue was suspended in DCE (2 mL) and treated with

cyclohexanecarbaldehyde (17 ^L, 0.128 mmol) followed by NaB(OAc) ₃ H (41 mg, 0.192 mmol) and the mixture was stirred at room temperature for 16 hours. The mixture was quenched by the addition of aqueous sodium hydrogen carbonate and extracted with DCM (phase separationcartridge). The organics were evaporated under vacuum and the residue was purified by preparative HPLC (method B) and the relevant fraction was evaporated under vacuum to give the title compound (2.9 mg, 9%) as a brown gum.

Method C: LC-MS (electrospray): m/z = 471.4 (M+H) ⁺ , RT = 3.31 min. [00571] Compound 247: N-{[6-(2-amino-3-phenylpropyl)imidazo[1,2-a]pyridin-2- yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

[00573] [(E)-2-nitrovinyl]benzene (1.50 g, 10.1 mmol) was added to a stirred suspension of Silica gel (604 mg, 10.1 mmol) in chloroform (75 mL) and IPA (22.5 mL). The yellow mixture was cooled to 0 °C, and NaBH4 (837 mg, 22.1 mmol) was added in 4 portions over 20 minutes. The resulting heterogeneous mixture was stirred vigorously at 0 °C for 30 minutes, then at room temperature for 30 minutes. The suspension was cooled to 0 °C, and aqueous HCl (0.2M) was added carefully until no gas evolution was observed. The mixture was filtered and washed with DCM (30 mL). The filtrate was washed with water (50 mL), the organic phase was separated, and the aqueous phase was extracted with DCM (3 x 20 mL). The combined organic phases were washed with brine (2 x 30 mL), dried over MgSO ₄ and concentrated to give the title compound (1.15 g, 61%) as a yellow oil.

Method A: LC-MS (electrospray): m/z = no mass ion (M+H) ⁺ , RT = 1.13 min. [00574] Step 2: N-[[6-[(E)-2-nitro-3-phenyl-prop-1-enyl]imidazo[1,2-a]pyridi n-2- yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide

[00575] To a stirred suspension of N-[(6-formylimidazo[1,2-a]pyridin-2-yl)methyl]-4- oxo-pyrido[1,2-a]pyrimidine-2-carboxamide Compound 49 (100 mg, 0.288 mmol) and 2- nitroethylbenzene (82 mg, 0.432 mmol) in anhydrous methanol(1 mL) at 0 °C was added acetic acid (16 ^L, 0.288 mmol) and butan-1-amine (28 ^L, 0.288 mmol), and the reaction mixture was stirred at room temperature for 17 hours. The reaction mixture was stirred at 50 °C for 2 hours before 1,1,1,3,3,3-Hexafluoro-2-propanol (2.5 mL) was added and the solution was stirred overnight at 50 °C for 5 days. The mixture was retreated with butan-1- amine (28 ^L, 0.288 mmol) and acetic acid (16 ^L, 0.288 mmol), and was stirred at room temperature for 24 hours. The solvent was removed under vacuum. The mixture was diluted with water and extracted with EtOAc (4 x 10 mL), the organic layers were washed with brine, dried over MgSO4 and concentrated under vacuum. The residue was purified by preparative HPLC (method A) to give the title compound (22 mg, 16%) as a yellow solid.

Method A: LC-MS (electrospray): m/z = 481.2 (M+H) ⁺ , RT = 1.00 min. [00576] Step 3: N-[[6-(2-amino-3-phenyl-propyl)imidazo[1,2-a]pyridin-2-yl]me thyl]-4- oxo-pyrido[1,2-a]pyrimidine-2-carboxamide

[00577] NaBH ₄ (3.8 mg, 0.101 mmol) was dissolved in ethanol (1 mL) and cooled to 0 °C. To this a solution of N-[[6-[(E)-2-nitro-3-phenyl-prop-1-enyl]imidazo[1,2-a]pyridi n-2- yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide (22 mg, 0.05 mmol) in 1,4-Dioxane (1 mL) was added slowly, and stirred at 0 °C for 20 minutes, then at room temperature for 180 minutes. The mixture was cooled to 0 °C and was quenched with NH ₄ Cl (sat). The solvent was removed under vacuum, the mixture was diluted with EtOAc (10 mL) and water (10 mL), the layers were separated, the mixture was extracted with EtOAc (3 x 10 mL), the organic layers were washed with water (10 mL) and brine (10 mL), dried over MgSO ₄ and concentrated to a yellow solid. Ammonium chloride (10 mg, 0.187 mmol) was then added to a mixture of N-[[6-(2-nitro-3-phenyl-propyl)imidazo[1,2-a]pyridin-2-yl]me thyl]-4-oxo- pyrido[1,2-a]pyrimidine-2-carboxamide (18 mg, 0.0373 mmol) in methanol (1 mL) and water (0.5 mL), the mixture was heated at 50 °C. Iron (10 mg, 0.187 mmol) was then added, and the reaction mixture was heated to 65 °C and stirred for 4.5 hours. The reaction mixture was allowed to cool to room temperature, was filtered through a pad of Celite, washed with EtOAc and the filtrate was concentrated. The mixture was purified by preparative HPLC (method A) to give the title compound (7.0 mg, 41%) as an off white solid.

Method D: LC-MS (electrospray): m/z = 453.3 (M+H) ⁺ , RT = 3.31 min. [00578] Compound 248: (cyclohexylmethyl)[(2-{[4-(1H-indazol-4-yl)-1H-1,2,3-triazol - 1-yl]methyl}imidazo[1,2-a]pyridin-6-yl)methyl]amine

[00580] 6-aminopyridine-3-carboxylic acid (500 mg, 3.62

mmol), cyclohexylmethanamine (820 mg, 7.24 mmol) and triethylamine (1.51 mL, 10.9 mmol) were combined in DMF (3 mL) and HATU (2.06g, 5.43 mmol) was added. The mixture was stirred at room temperature for 24 hours. The reaction mixture was quenched with saturated aqueous sodium hydrogen carbonate (30 mL) and extracted with 3:1 chloroform/isopropanol (3 x 80 mL). The combined organic extracts were dried over sodium sulfate and evaporated under vacuum. The residue was purified by Biotage Isolera™ chromatography (28 g kp-NH, eluting with EtOAc/heptane 0-100% followed by

methanol/EtOAc 0-20%) to afford a crude material which was further purified by Biotage Isolera™ chromatography (60 g C18-Ultra, acetonitrile+0.1%NH ₃ /water +0.1% NH ₃ 10- 100%) to afford (298 mg, 35%) of the title compound as a white solid

Method B: LC-MS (electrospray): m/z = 234.3 (M+H) ⁺ , RT = 1.36 min [00581] Step 2: 2-(chloromethyl)-N-(cyclohexylmethyl)imidazo[1,2-a]pyridine- 6- carboxamide

[00582] 6-amino-N-(cyclohexylmethyl)pyridine-3-carboxamide (290 mg, 1.24 mmol) and 1,3-dichloropropan-2-one (237 mg, 1.86 mmol) were combined in acetonitrile (10 mL) and the mixture heated at reflux for 3 days. The reaction mixture was cooled to room temperature and concentrated under vacuum. The residue was suspended in saturated aqueous sodium hydrogen carbonate (30 mL) and extracted with 3:1 chloroform/isopropanol (4 x 30 mL). The combined organic extracts were dried over sodium sulfate and evaporated under vacuum. The residue was purified by Biotage Isolera™ chromatography (25 g kp-Sil, eluting with EtOAc/heptane 0-100% followed by methanol/EtOAc 0-20%) to afford (143 mg, 38%) of the title compound as an off-white solid.

Method B: LC-MS (electrospray): m/z = 306.3 (M+H) ⁺ , RT = 1.52 min [00583] Step 3: 2-(azidomethyl)-N-(cyclohexylmethyl)imidazo[1,2-a]pyridine-6 - carboxamide

[00584] 2-(chloromethyl)-N-(cyclohexylmethyl)imidazo[1,2-a]pyridine- 6-carboxamide (140 mg, 0.46 mmol), sodium iodide (69 mg, 0.46 mmol) and NaN3 (45 mg, 0.69 mmol) were combined in DMF (2 mL) and the mixture stirred at room temperature for 22 hours. The reaction mixture was quenched with saturated aqueous sodium hydrogen carbonate (30 mL) and extracted with 3:1 chloroform/isopropanol (3 x 30 mL). The combined organic extracts were dried over sodium sulfate and evaporated under vacuum. The residue was triturated with EtOAc/heptane and the solids collected by filtration to afford (100 mg, 70%) of the title compound as a white solid

Method B: LC-MS (electrospray): m/z = 313.3 (M+H) ⁺ , RT = 1.52 min [00585] Step 4: N-(cyclohexylmethyl)-2-[[4-(1-tetrahydropyran-2-ylindazol-4- yl)triazol- 1-yl]methyl]imidazo[1,2-a]pyridine-6-carboxamide

[00586] 2-(azidomethyl)-N-(cyclohexylmethyl)imidazo[1,2-a]pyridine-6 -carboxamide (100 mg, 0.32 mmol) and 4-ethynyl-1-tetrahydropyran-2-yl-indazole Intermediate 24 (101 mg, 0.32 mmol) were dissolved in DMF (3 mL) and water (0.5 mL) and copper sulfate (10 mg, 0.06 mmol) and sodium ascorbate (64 mg, 0.32 mmol) were added. The mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with 3:1

chloroform/isopropanol (30 mL) and washed with water (20 mL). The aqueous phase was extracted with 3:1 chloroform/isopropanol (2 x 30 mL) and the combined organic layers were dried over sodium sulfate and evaporated under vacuum. The residue was purified by chromatography on silica gel (Biotage, 11 g kp-NH, eluting with EtOAc/heptane 0-100% followed by methanol/EtOAc 0-20%) to afford the title compound (171 mg, 99%) as a white solid

Method A: LC-MS (electrospray): m/z = 589.3 (M+H) ⁺ , RT = 1.18 min [00587] Step 5: N-(cyclohexylmethyl)-1-[2-[[4-(1H-indazol-4-yl)triazol-1- yl]methyl]imidazo[1,2-a]pyridin-6-yl]methanamine

[00588] N-(cyclohexylmethyl)-2-[[4-(1-tetrahydropyran-2-ylindazol-4- yl)triazol-1- yl]methyl]imidazo[1,2-a]pyridine-6-carboxamide (80 mg, 0.15 mmol) and 2-fluoropyridine (53µl, 0.62 mmol) were combined in DCM-Anhydrous (4 mL) and cooled in an ice/water bath. trifluoromethylsulfonyl trifluoromethanesulfonate (107µl, 0.63 mmol) was added dropwise to give a yellow solution which was stirred briefly, then 1,1,3,3- tetramethyldisiloxane (160µl, 0.91 mmol) and tris(pentafluorophenyl)borane (15 mg, 0.03 mmol) were added and the mixture stirred whilst warming to room temperature for 6 hours. K ₂ CO ₃ (100 mg) and methanol (20 mL) were added and the mixture incubated at room temperature for 16h and at reflux for 1 hour. The reaction mixture was cooled to room temperature and concentrated under vacuum. The residue was suspended in saturated aqueous sodium hydrogen carbonate (20 mL) and extracted with 3:1 chloroform/isopropanol (3 x 30 mL) and the combined organic extracts dried over sodium sulfate and evaporated under vacuum. The residue was triturated with EtOAc/heptane and the solids collected by filtration. The residue was purified by reverse phase chromatography (method B) and the clean product-containing fractions combined and evaporated under vacuum to afford the title compound (17 mg (26%) as a white solid.

Method C: LC-MS (electrospray): m/z = 441.4 (M+H) ⁺ , RT = 3.09 min [00589] Compound 249: N-(cyclohexylmethyl)-2-{[4-(1H-indazol-4-yl)-1H-1,2,3- triazol-1-yl]methyl}imidazo[1,2-a]pyridine-6-carboxamide

[00590] N-(cyclohexylmethyl)-2-[[4-(1-tetrahydropyran-2-ylindazol-4- yl)triazol-1- yl]methyl]imidazo[1,2-a]pyridine-6-carboxamide Compound 248 step 4 (40 mg, 0.07 mmol) was suspended in methanol (1 mL) and treated with 4M HCl in Dioxane (1 mL). The mixture was incubated at room temperature for 5h, then evaporated under vacuum. The residue was loaded to an SCX-2 cartridge (2g) and the cartridge rinsed with DCM and methanol, then eluted with 7M NH3/methanol. The basic eluent was evaporated under vacuum and the residue dried in the Genevac to afford the title compound (8 mg (23%)as an off-white solid. Method C: LC-MS (electrospray): m/z = 455.3 (M+H)+, RT = 2.88 min [00591] Compound 250: (2,2-dimethylpropyl)[(2-{[4-(1H-indazol-4-yl)-1H-1,2,3- triazol-1-yl]methyl}imidazo[1,2-a]pyridin-6-yl)methyl]amine

[00592] 2-[[4-(1-tetrahydropyran-2-ylindazol-4-yl)triazol-1-yl]methy l]imidazo[1,2- a]pyridine-6-carbaldehyde (Intermediate 34) (70 mg, 0.16 mmol) and 2,2-dimethylpropan-1- amine (57 mg, 0.66 mmol) were combined in 1,1,1,3,3,3-Hexafluoroisopropanol (2 mL) and the mixture stirred at room temperature for 1 hour. NaBH ₄ (70 mg, 1.85 mmol) was added with a few drops methanol then quenched with methanol (20 mL) and the mixture evaporated under vacuum. The residue was suspended in saturated aqueous sodium hydrogen carbonate (40 mL) and extracted with 3:1 chloroform/isopropanol (3 x 40 mL). The combined organic extracts were dried over sodium sulfate and evaporated under vacuum. The residue was dissolved in methanol (3 mL) and treated with 4M HCl in Dioxane (3 mL) and the mixture incubated at room temperature for 2h, then evaporated under vacuum. The residue was redissolved in methanol and loaded to an SCX-2 cartridge (5g). The system was rinsed with DCM and methanol, then eluted with 7N NH ₃ /methanol. The basic eluent was evaporated under vacuum. The residue was triturated with EtOAc/heptane and the solids collected by filtration to afford (45 mg, 64%) of the title compound as a white solid. Method D: LC-MS (electrospray): m/z = 415.3 (M+H) ⁺ , RT = 3.69 min [00593] Compound 251: 4-[1-({6-[(4,4-dimethylpiperidin-1-yl)methyl]imidazo[1,2- a]pyridin-2-yl}methyl)-1H-1,2,3-triazol-4-yl]-1H-indazole

[00594] Step 1: 4-[1-({6-[(4,4-dimethylpiperidin-1-yl)methyl]imidazo[1,2-a]p yridin-2- yl}methyl)-1H-1,2,3-triazol-4-yl]-1H-indazole [00595] A mixture of 2-[[4-(1-tetrahydropyran-2-ylindazol-4-yl)triazol-1- yl]methyl]imidazo[1,2-a]pyridine-6-carbaldehyde (Intermediate 34) (70 mg, 0.164 mmol) and 4,4-dimethylpiperidine (43 ^L, 0.328 mmol) in DCE (1.8 mL) was stirred at 50 °C for 5 minutes, NaB(OAc) ₃ H (104 mg, 0.49 mmol) was added, and the mixture was stirred at 50 °C for 4 hours. The reaction mixture was quenched with aqueous sodium hydrogen carbonate, diluted with 3:1 CHCl ₃ /IPA and the phases were separated, the aqueous mixture was extracted with CHCl3/IPA, the organic layers were dried by passage through a TELOS phase separation cartridge and concentrated under vacuum. The residue was dissolved

in methanol (2.5 mL) and 4M HCl in dioxane (2.5 mL), and stirred at room temperature for 2 h, then evaporated under vacuum. The residue was purified by reverse phase

chromatography (Method B) to afford the title compound (23 mg, 32%) as a white solid. Method C: LC-MS (electrospray): m/z = 441.4 (M+H) ⁺ , RT = 3.17 min [00596] Compound 252: [(2-{[4-(6-bromo-1H-indazol-4-yl)-1H-1,2,3-triazol-1- yl]methyl}imidazo[1,2-a]pyridin-6-yl)methyl][(3,3-difluorocy clobutyl)methyl]amine

[00597] 2-[[4-(6-bromo-1-tetrahydropyran-2-yl-indazol-4-yl)triazol-1 - yl]methyl]imidazo[1,2-a]pyridine-6-carbaldehyde Intermediate 35 (70 mg, 0.12 mmol), (3,3- difluorocyclobutyl)methanamine hydrochloride (37 mg, 0.24 mmol) and triethylamine (50µl, 0.36 mmol) were combined in 1,1,1,3,3,3-Hexafluoro-2-propanol (2 mL) and the mixture stirred at room temperature for 30 minutes. NaBH4 (70 mg, 1.85 mmol) was added with a few drops methanol and the mixture stirred briefly, then quenched with methanol (20 mL) and the mixture evaporated under vacuum. The residue was suspended in saturated aqueous sodium hydrogen carbonate (30 mL) and extracted with 3:1 chloroform/isopropanol (3 x 30 mL). The combined organic extracts were dried over sodium sulfate and evaporated under vacuum. The residue was redissolved in methanol (3 mL), treated with 4M HCl in Dioxane (3 mL) and incubated at room temperature for 16 hours. The reaction mixture was evaporated under vacuum. The residue was loaded to an SCX-2 cartridge (2g) and the system rinsed with DCM and methanol, then eluted with 7M NH ₃ /methanol. The basic eluent was evaporated under vacuum. The resultant residue was purified by reverse phase chromatography (Method B) to afford the title compound (17 mg, 27%) as an off-white solid. Method D: LC-MS (electrospray): m/z = 527.2/529.2 (M+H) ⁺ , RT = 3.69 min

[00598] The compounds in Table 12 were prepared in a similar fashion to Compound 252 Table 12

[00599] Compound 253: (2-{[4-(6-bromo-1H-indazol-4-yl)-1H-1,2,3-triazol-1- yl]methyl}imidazo[1,2-a]pyridin-6-yl)methanol

[00600] Step 1: [2-({4-[6-bromo-1-(oxan-2-yl)-1H-indazol-4-yl]-1H-1,2,3-tria zol-1- yl}methyl)imidazo[1,2-a]pyridin-6-yl]methanol

[00601] The title compound was prepared in the same manner as Intermediate 34 Step 4 to give (795 mg, 68%) as a grey solid.

Method A: LC-MS (electrospray): m/z = 508.15/510.15 (M+H) ⁺ , RT = 1.00 min [00602] Step 2: (2-{[4-(6-bromo-1H-indazol-4-yl)-1H-1,2,3-triazol-1- yl]methyl}imidazo[1,2-a]pyridin-6-yl)methanol

[00603] [2-[[4-(6-bromo-1-tetrahydropyran-2-yl-indazol-4-yl)triazol- 1- yl]methyl]imidazo[1,2-a]pyridin-6-yl]methanol (87 mg, 0.17 mmol) was suspended in methanol (3 mL) and treated with HCl (4M in Dioxane, 3 mL, 12 mmol). The mixture was stirred at room temperature for 1h, then evaporated under vacuum. The residue was triturated with methanol/Et2O and the solids collected by filtration. The residue was purified by preparative HPLC (method B) to afford the title compound (14 mg, 19%) as an off-white solid.

Method C: LC-MS (electrospray): m/z = 424.1/426.1 (M+H) ⁺ , RT = 2.14 min [00604] Compound 254: (2,2-dimethylpropyl)[(2-{[4-(1H-indazol-5-yl)-1H-1,2,3- triazol-1-yl]methyl}imidazo[1,2-a]pyridin-6-yl)methyl]amine

[00605] The title compound was prepared from intermediate 37 using the method described in Compound 250 giving (42 mg, 65%) as an off white solid.

Method D: LC-MS (electrospray): m/z = 415.3 (M+H) ⁺ , RT = 3.57 min [00606] Compound 255: ((cyclohexylmethyl)[1-(2-{[4-(1H-indazol-4-yl)-1H-1,2,3- triazol-1-yl]methyl}imidazo[1,2-a]pyridin-6-yl)ethyl]amine

n [00607] The title compound was prepared from Intermediate 32 Step 3 and

Intermediate 24 using the method described in Compound 248 giving (27 mg, 25%) as an off-white solid.

Method D: LC-MS (electrospray): m/z = 455.4 (M+H) ⁺ , RT = 4.03 min. [00608] Compound 256: (2,2-dimethylpropyl)({2-[(4-{1H-pyrazolo[3,4-c]pyridin-4-yl} - 1H-1,2,3-triazol-1-yl)methyl]imidazo[1,2-a]pyridin-6-yl}meth yl)amine

[00609]

[00610] The title compound was prepared from Intermediate 40 using the procedure described (Compound 250) giving (31 mg, 32%) as a pale yellow solid.

Method D: LC-MS (electrospray): m/z = 416.3 (M+H) ⁺ , RT = 3.09 min [00611] Compound 257: {2-[(4-{1H-pyrazolo[3,4-c]pyridin-4-yl}-1H-1,2,3-triazol-1- yl)methyl]imidazo[1,2-a]pyridin-6-yl}methanol

[00612] The title compound was prepared from Intermediate 39 using the procedure described in Compound 253 giving (1 mg, 2%) as a white solid.

Method D: LC-MS (electrospray): m/z = 347.2 (M+H) ⁺ , RT = 2.30 min.

[00613] ^ ^

[00614] Compound 263: N-{[6-(morpholin-3-yl)imidazo[1,2-a]pyridin-2-yl]methyl}-4- oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

[00615] To solution of N-[(6-formylimidazo[1,2-a]pyridin-2-yl)methyl]-4-oxo-pyrido[ 1,2- a]pyrimidine-2-carboxamide (Compound 49) (119 mg, 0.343 mmol) in 1,1,1,3,3,3- Hexafluoro-2-propanol (0.5 mL) was added a solution of [(2- aminoethoxy)methyl]tributylstannane (125 mg, 0.343 mmol) in DCE (4 mL). The mixture was stirred at 80 °C for 2 hours. Meanwhile a mixture of 2,6-dimethylpyridine (0.080 mL, 0.685 mmol), copper(II) bis(trifluoromethanesulfonate) (249 mg, 0.685 mmol) and 1,1,1,3,3,3- Hexafluoro-2-propanol (2 mL) was stirred separately at room temperature for 1 hour. After cooling to room temperature, the solution of the imine was added drop-wise to the solution of the catalyst. The resulting mixture was stirred at room temperature for 3 hours forming a clear, dark green solution. The reaction mixture was diluted with DCM (25 mL) and quenched with 10% aq. NH ₄ OH (10 mL) solution. The organic layer was separated, washed with brine (10 mL), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (method B) to afford the title compound (39 mg, 28%) as greenish solid.

Method C: LC-MS (electrospray): m/z = 405.3 (M+H) ⁺ , RT = 1.59 min [00616] The compounds in Table 12 were prepared in the same manner as

Compound 263

Table 13

[00617] Compound 231: N-({6-[(3S,5R)-5-cyclohexylmorpholin-3-yl]imidazo[1,2- a]pyridin-2-yl}methyl)-1H-indazole-4-carboxamide

trans racemate [00618] To a solution of 1-[rac-(2R)-tetrahydropyran-2-yl]indazole-4-carboxylic acid (35 mg, 0.142 mmol)), [6-[rac-(3S,5R)-5-cyclohexylmorpholin-3-yl]imidazo[1,2-a]pyr idin-2- yl]methanamine trihydrochloride (Intermediate 47) (60 mg, 0.142 mmol) and DIPEA (0.12 mL, 0.708 mmol) in DMF (3 mL) was added HATU (65 mg, 0.170 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was partitioned between EtOAc (30 mL) and saturated aqueous sodium hydrogen carbonate (20 mL). The organic layer was separated, washed with brine (10 mL), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to dryness. The residue was dissolved in methanol (3 mL) and 4M HCl in dioxane (1 mL) was added. The mixture was stirred at room temperature overnight. The volatiles were removed under reduced pressure and the residue was purified by preparative HPLC (method B) to afford the title compound (30 mg, 46%) as white solid. Method C: LC-MS (electrospray): m/z = 459.4 (M+H) ⁺ , RT = 2.96 min [00619] Compound 264: N-({6-[(3S,5R)-5-cyclohexylmorpholin-3-yl]imidazo[1,2- a]pyridin-2-yl}methyl)-4-oxo-4H-chromene-2-carboxamide:

[00620] To a solution of 4-oxochromene-2-carboxylic acid (22 mg, 0.118 mmol)), [6- [rac-(3S,5R)-5-cyclohexylmorpholin-3-yl]imidazo[1,2-a]pyridi n-2-yl]methanamine- trihydrochloride (50 mg, 0.118 mmol) and DIPEA (0.10 mL, 0.590 mmol) in DMF (1 mL) was added HATU (54 mg, 0.142 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was partitioned between EtOAc (30 mL) and saturated aqueous sodium hydrogen carbonate (20 mL). The organic layer was separated, washed with brine (10 mL), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (method B) to afford the title compound (15 mg, 26%) as off-white solid.

Method C: LC-MS (electrospray): m/z = 487.4 (M+H) ⁺ , RT = 3.33 min [00621] Compound 232: N-({6-[4-(2,2-dimethylpropyl)morpholin-3-yl]imidazo[1,2- a]pyridin-2-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-ca rboxamide:

[00622] To a solution of N-[(6-morpholin-3-ylimidazo[1,2-a]pyridin-2-yl)methyl]-4-oxo - pyrido[1,2-a]pyrimidine-2-carboxamide (Compound 263) (38 mg, 0.09 mmol) in DCE (1.5 mL) was added 2,2-dimethylpropanal (0.04 mL, 0.38 mmol) and acetic acid (0.011 mL, 0.188 mmol) at room temperature. The mixture was stirred for 15 minutes before NaB(OAc)3H (100 mg, 0.470 mmol) was added in small portions over a period of 2 hours. The reaction mixture was then stirred at 40 °C overnight. More 2,2-dimethylpropanal (0.041 mL, 0.376 mmol) and NaB(OAc)3H (100 mg, 0.470 mmol) were added and the reaction mixture was stirred for another 24 hours at 40 °C. The reaction mixture was diluted with DCE (20 mL), washed with saturated aqueous sodium hydrogen carbonate (10 mL) and brine (10 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (method B) to afford the title compound (14 mg, 31%) as off-white solid.

Method C: LC-MS (electrospray): m/z = 475.4 (M+H) ⁺ ,RT = 3.17 min [00623] Compound 233: N-({6-[(3S,5R)-5-methylmorpholin-3-yl]imidazo[1,2-a]pyridin- 2-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide.

[00624] To a solution of tert-butyl N-[[6-[rac-(3S,5R)-5-methylmorpholin-3- yl]imidazo[1,2-a]pyridin-2-yl]methyl]carbamate (Intermediate 48) (80 mg, 0.231 mmol) in methanol (1 mL) was added HCl (4M in dioxane, 1 mL, 4 mmol) at room temperature. The solution was stirred at 50 °C for 1 hour. After cooling to room temperature, the reaction mixture was concentrated to dryness under reduced pressure. To the residue was added DMF (2 mL), 4-oxopyrido[1,2-a]pyrimidine-2-carboxylic acid Intermediate 4 (60%, 73 mg, 0.231 mmol) and N-ethyl-N-isopropyl-propan-2-amine (0.20 mL, 1.15 mmol). The mixture was stirred for 15 minutes at room temperature before HATU (105 mg, 0.277 mmol) was added and stirring was continued overnight. The reaction mixture was then diluted with EtOAc (30 mL), washed with saturated aqueous sodium hydrogen carbonate (20 mL) and brine (10 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (method B) to afford the title compound (41 mg, 42%) as white solid.

Method C: LC-MS (electrospray): m/z = 419.3 (M+H) ⁺ , RT = 1.81 min [00625] Compound 234: N-{[6-(9-methoxy-2,3,4,5-tetrahydro-1,4-benzoxazepin-3- yl)imidazo[1,2-a]pyridin-2-yl]methyl}-4-oxo-4H-pyrido[1,2-a] pyrimidine-2-carboxamide:

[00626] The title compound was prepared in a similar manner to Compound 233 using Intermediate 49 to afford the title compound (415 mg, 38%) as white solid.

Method C: LC-MS (electrospray): m/z = 497.3 (M+H) ⁺ , RT = 2.27 min

[00627] Improved synthesis of Intermediate 4: 4-oxopyrido[1,2-a]pyrimidine-2- carboxylic acid

[00628] Step 1: methyl 4-oxopyrido[1,2-a]pyrimidine-2-carboxylate

[00629] Dimethyl but-2-ynedioate (16 mL, 0.126 mol) was added slowly to a vigorously stirred solution of pyridin-2-amine (10.00 g, 0.105 mol) in water (1000 mL), and the reaction mixture was stirred at room temperature for 18 hours.

[00630] The mixture was worked up in two batches. Each half of the material was extracted with DCM (3x100 mL), passed through a TELOS phase separator and concentrated.

[00631] The material was also purified in two batches. One half of the material was dry loaded onto KP-NH silica, loaded onto a plug of KP-NH silica, and was eluted, with EtOAc in heptane, 50%, 70% and 100% and the yellow solution was concentrated to give a pale yellow solid.

[00632] The second half of the material was diluted with DCM (150 mL), treated with loose silica, stirred for 5 minutess, then filtered. The filter cake was washed with DCM (~1 L) and the filtrate was concentrated to give a pale yellow solid.

[00633] The two batches were combined, triturated with Et ₂ O and the solid was collected by filtration to give the title compound (6.57 g, 30%) as an off-white solid.

Method A: LC-MS (electrospray): m/z = 205.1 (M+H)+, RT = 0.79 min

[00634] Step 2: 4-oxopyrido[1,2-a]pyrimidine-2-carboxylic acid

[00635] Methyl 4-oxopyrido[1,2-a]pyrimidine-2-carboxylate (6.57 g, 32.2 mmol) was dissolved in HCl (aq) (~8M, 7.5 mL) at room temperature and the solution was heated at reflux for 2 hours.

[00636] The mixture was cooled to room temperatue and the precipitate was collected by filtration and dried on the filter to give give the title compound (5.03 g, 81%) as a white solid.

Method A: LC-MS (electrospray): m/z = 191.1 (M+H)+, RT = 0.29 min

[00637] Compound 266: 4-[1-[[6-[(cyclobutylmethylamino)methyl]imidazo[1,2- a]pyridin-2-yl]methyl]triazol-4-yl]-1H-indazol-6-ol

[00638] Step 1: {[2-({4-[6-bromo-1-(oxan-2-yl)-1H-indazol-4-yl]-1H-1,2,3-tri azol-1- yl}methyl)imidazo[1,2-a]pyridin-6-yl]methyl}(cyclobutylmethy l)amine

[00639] The title compound was prepared from Intermediate 35 using the method described in Compound 250 to afford (487 mg, 48%) as a pale yellow solid.

Method B: LC-MS (electrospray): m/z = 508.3/510.3 (M+H)+, RT = 1.49 min

[00640] Step 2: 4-[1-[[6-[(cyclobutylmethylamino)methyl]imidazo[1,2-a]pyridi n-2- yl]methyl]triazol-4-yl]-1H-indazol-6-ol

[00641] A microwave vial was charged with {[2-({4-[6-bromo-1-(oxan-2-yl)-1H-indazol- 4-yl]-1H-1,2,3-triazol-1-yl}methyl)imidazo[1,2-a]pyridin-6-y l]methyl}(cyclobutylmethyl)amine (85 mg, 0.148 mmol), copper(1+) iodide (2.8 mg, 0.0148 mmol) and quinolin-8-ol 1-oxide (10 mg, 0.0591 mmol) in DMSO (1.3 mL) and water (1.3 mL), the mixture was degassed via a stream of N ₂ before a solution of caesium hydroxide (66 mg, 0.443 mmol) in water was added, the mixture was further de-oxygenated before the vial was sealed and irradiated in a microwave at 110 °C for 4.5 h.

[00642] The mixture was purified by ion exchange (SCX-210 g) washed with MeOH and eluted with ammonia solution (3M in MeOH). The eluted fraction was evaporated under vacuum.

1. The residue was diluted with MeOH (0.5 mL) and 4M HCl in dioxane (1.7 mL), and was stirred at RT for 1 h and at 40 °C for 18 hours.

2. The solvent was removed under vacuum and purified by Basic reverse phase chromatography and the relevant fractions were freeze dried to give the title compound (12 mg, 19%) as a white solid.

Method D: LC-MS (electrospray): m/z = 429.3 (M+H)+, RT = 3.02 min

[00643] Compound 267: 4-[1-[[6-[[(1- hydroxycyclobutyl)methylamino]methyl]imidazo[1,2-a]pyridin-2 -yl]methyl]triazol-4-yl]-1H- indazol-6-ol

[00644] Step 1: 1-[({[2-({4-[6-bromo-1-(oxan-2-yl)-1H-indazol-4-yl]-1H-1,2,3 -triazol-1- yl}methyl)imidazo[1,2-a]pyridin-6-yl]methyl}amino)methyl]cyc lobutan-1-ol

[00645] The title compound was prepared from Intermediate 35 using the method described in Compound 250 to afford (357 mg, 66%) as a brown solid.

Method B: LC-MS (electrospray): m/z = 591.3/593.3 (M+H)+, RT = 1.57 min

[00646] Step 2: 4-[1-[[6-[[(1-hydroxycyclobutyl)methylamino]methyl]imidazo[1 ,2- a]pyridin-2-yl]methyl]triazol-4-yl]-1H-indazol-6-ol

[00647] 1-[[[2-[[4-(6-bromo-1-tetrahydropyran-2-yl-indazol-4-yl)tria zol-1- yl]methyl]imidazo[1,2-a]pyridin-6-yl]methylamino]methyl]cycl obutanol (150mg,

0.25mmol), tBuBrettPhos Pd G3 (22mg, 0.03mmol) and NaOtBu (29mg, 0.30mmol) were combined in 1,4-Dioxane-Anhydrous (10ml) and the mixture was sparged with nitrogen for 5 mins. Propan-2-ol (0.4ml, 5.26mmol) was added, the mixture further sparged briefly and the vessel sealed and the mixture was heated at 100°C for 2 hours.

[00648] The reaction mixture was cooled to RT and evaporated under vacuum. The residue was redissolved in MeOH (3ml) and treated with HCl in Dioxane (4M, 3ml) and incubated at room temperature for 18 hours.

[00649] The reaction mixture was evaporated under vacuum and the residue purified by basic reverse phase chromatography. The product-containing fractions combined and evaporated under vacuum to afford crude material.

[00650] The residue was further purified by preparative HPLC [method B] to afford the title compound (7mg, 6%) as an off-white solid.

Method C: LC-MS (electrospray): m/z = 445.4 (M+H)+, RT = 1.53 min

[00651] Compound 268: 1-[[[2-[[4-(5-methoxy-1H-indazol-4-yl)triazol-1- yl]methyl]imidazo[1,2-a]pyridin-6-yl]methylamino]methyl]cycl obutanol

[00652] Step 1: 4-ethynyl-5-methoxy-1-(oxan-2-yl)-1H-indazole

[00653] Prepared in a similar manner to Intermediate 24 from commercial 4-bromo-5- methoxy-1H-indazole to give the title compound (296 mg, 34%) as a brown oil.

Method B: LC-MS (electrospray): m/z = 257.3 (M+H)+, RT = 1.62 min [00654] Step 2: [2-({4-[5-methoxy-1-(oxan-2-yl)-1H-indazol-4-yl]-1H-1,2,3-tr iazol-1- yl}methyl)imidazo[1,2-a]pyridin-6-yl]methanol

[00655] Prepared using 4-ethynyl-5-methoxy-1-(oxan-2-yl)-1H-indazole and

Intermediate 34 Step 3 using the method described in Intermediate 34 Step 4 to give the title compound (264 mg, 45%) as an off white solid.

Method F: LC-MS (electrospray): m/z = 460.4 (M+H)+, RT = 0.48 min

[00656] Step 3: 2-({4-[5-methoxy-1-(oxan-2-yl)-1H-indazol-4-yl]-1H-1,2,3-tri azol-1- yl}methyl)imidazo[1,2-a]pyridine-6-carbaldehyde

[00657] [2-[[4-(5-methoxy-1-tetrahydropyran-2-yl-indazol-4-yl)triazo l-1- yl]methyl]imidazo[1,2-a]pyridin-6-yl]methanol (264mg, 0.57mmol) and MnO2 (499mg, 5.75mmol) were combined in DCE (10ml) and the mixture heated at reflux for an hour.

[00658] The reaction mixture was cooled to RT and filtered through Celite. The residue was rinsed with MeOH and 3:1 chloroform/isopropanol and the combined filtrates were evaporated under vacuum to afford 265mg (80% yield, 79% purity) of the title compound as a grey solid.

[00659] Method F: LC-MS (electrospray): m/z = 458.4 (M+H)+, RT = 0.52 min [00660] Step 4: 1-[[[2-[[4-(5-methoxy-1H-indazol-4-yl)triazol-1-yl]methyl]im idazo[1,2- a]pyridin-6-yl]methylamino]methyl]cyclobutanol

[00661] The title compound was prepared in a similar fashion to Compound 252 and purified by phase chromatography (method B) to give (23 mg, 30%) as a white solid.

Method D: LC-MS (electrospray): m/z = 459.3 (M+H)+, RT = 2.97 min

[00662] Compound 269: 1-[[[2-[[4-(6-methoxy-1H-indazol-4-yl)triazol-1- yl]methyl]imidazo[1,2-a]pyridin-6-yl]methylamino]methyl]cycl obutanol

[00663] 1-[[[2-[[4-(6-bromo-1-tetrahydropyran-2-yl-indazol-4-yl)tria zol-1- yl]methyl]imidazo[1,2-a]pyridin-6-yl]methylamino]methyl]cycl obutanol (Compound 267 Step 1) (400mg, 0.68mmol), tBuBrettPhos Pd G3 (58mg, 0.07mmol) and NaOtBu (78mg, 0.81mmol) were combined in 1,4-Dioxane (15ml) and the mixture sparged with nitrogen for 5mins. Anhydrous methanol- (0.3ml, 7.41mmol) was added and the mixture further sparged briefly and the mixture was heated at 100°C for 2 hours.

[00664] The reaction mixture was cooled to room temperature and left standing overnight.

[00665] The reaction mixture was concentrated under vacuum. The residue was redissolved in methanol (10ml), treated with HCl in Dioxane (4M, 10ml) and heated at 50°C for an hour.

[00666] The reaction mixture was cooled to RT and evaporated under vacuum. The residue was purified by ion exchange (SCX-2 (10g) washing with DCM and MeOH. The system was eluted with ammonia (7N in MeOH) and the basic eluent evaporated under vacuum.

[00667] The residue was purified by basic reverse phase chromatography and the product-containing fractions combined and evaporated under vacuum. The residue was triturated with MeOH/Et2O and the solids collected by filtration to afford the title compound (87mg, 28%) as an off-white solid

Method C: LC-MS (electrospray): m/z = 459.4 (M+H)+, RT = 2.10 min

[00668] The filtrates were evaporated under vacuum to afford a second crop of desired product (72mg) as pale yellow solid which was further purified by preparative HPLC (method B) to afford further title compound (50mg, 16%) as an off-white solid.

[00669] Compound 270: N-(cyclobutylmethyl)-1-[2-[[4-(6-methoxy-1H-indazol-4- yl)triazol-1-yl]methyl]imidazo[1,2-a]pyridin-6-yl]methanamin e

[00670] The title compound was prepared in a similar manner to Compound 269 from {[2-({4-[6-bromo-1-(oxan-2-yl)-1H-indazol-4-yl]-1H-1,2,3-tri azol-1-yl}methyl)imidazo[1,2- a]pyridin-6-yl]methyl}(cyclobutylmethyl)amine (Compound 266 step 1) to give (7 mg, 30%) as a white solid.

Method D: LC-MS (electrospray): m/z = 443.3 (M+H)+, RT = 3.55 min

[00671] Compound 271: N-(cyclobutylmethyl)-1-[2-[[4-(5-methoxy-1H-indazol-4- yl)triazol-1-yl]methyl]imidazo[1,2-a]pyridin-6-yl]methanamin e

[00672] The title compound was prepared using the intermediate from Compound 268 Step 3 in a similar manner to Compound 252 and purified by basic reverse phase chromatography to give (88 mg, 68%) as a pale yellow solid.

Method D: LC-MS (electrospray): m/z = 443.3 (M+H)+, RT = 3.55 min

[00673] Compound 272: 4-[1-[(6-methylimidazo[1,2-a]pyridin-2-yl)methyl]triazol-4-y l]- 1H-indazol-3-amine

[00674] Step 1: 4-ethynyl-1H-indazol-3-amine

[00675] The title compound was prepared in a similar fashion Intermediate 24 starting from 4-iodo-1H-indazol-3-amine to give (92 mg, 31%) as a pale brown solid. Method B: LC-MS (electrospray): m/z = 158.2 (M+H)+, RT = 1.23 min

[00676] Step 2: 4-[1-[(6-methylimidazo[1,2-a]pyridin-2-yl)methyl]triazol-4-y l]-1H- indazol-3-amine

[00677] Prepared using the method described in Intermediate 34 Step 4 using 4- ethynyl-1H-indazol-3-amine and Intermediate 23 to give the title compound (38 mg, 41%) as an off white solid.

Method E: LC-MS (electrospray): m/z = 345.2 (M+H)+, RT = 1.10 min

The intermediates in Table 14 were prepared from commercial reagents and Intermediate 25 Step 2 in the same manner as Intermediate 48.

Table 14

The Examples in Table 15 were prepared from Intermediate 4 and the appropriate intermediate from Table 15 in the same manner as Compound 233

Table 15

The compounds in Table 16 were prepared from Intermediate 35 in a similar manner to Compound 252.

Table 16

[00678] Intermediate 51: 4-[1-[[6-[[tert- butoxycarbonyl(cyclobutylmethyl)amino]methyl]imidazo[1,2-a]p yridin-2-yl]methyl]triazol- 4-yl]-1-tetrahydropyran-2-yl-indazole-6-carboxylic acid

[00679] Step 1:

[00680] Step 1: methyl 4-ethynyl-1-(oxan-2-yl)-1H-indazole-6-carboxylate

[00681] The title compound was prepared from methyl 4-bromo-1H-indazole-6- carboxylate in the same manner as intermediate 24 to give (712 mg, 57%) as a brown solid.

[00682] Method A: LC-MS (electrospray): m/z = 285.05 (M+H)+, RT = 1.27 min

[00683] Step 2: methyl 4-[1-({6-formylimidazo[1,2-a]pyridin-2-yl}methyl)-1H-1,2,3- triazol-4-yl]-1-(oxan-2-yl)-1H-indazole-6-carboxylate

[00684] Prepared from intermediate 51 step 1 using the procedure described in

Intermediate 34 to provide the title compound (867 mg, 62%) as a pale brown solid.

Method B: LC-MS (electrospray): m/z = 486.3 (M+H)+, RT = 1.50 min

[00685] Step 3: methyl 4-[1-[[6-[[tert- butoxycarbonyl(cyclobutylmethyl)amino]methyl]imidazo[1,2-a]p yridin-2-yl]methyl]triazol-4-yl]- 1-tetrahydropyran-2-yl-indazole-6-carboxylate

[00686] Methyl 4-[1-[(6-formylimidazo[1,2-a]pyridin-2-yl)methyl]triazol-4-y l]-1- tetrahydropyran-2-yl-indazole-6-carboxylate (860mg, 1.77mmol) and 1- cyclobutylmethanamine (302mg, 3.54mmol) were combined in 1,1,1,3,3,3-Hexafluoro-2- propanol (8ml) and the mixture stirred at room temperature for 30 minutes before further 1- cyclobutylmethanamine (302mg, 3.54mmol) added and the stir was continued for 1.5 hours.

[00687] Sodium borohydride (536mg, 1.42mmol) was added along with with a few drops MeOH - gas evolution - and the mixture stirred briefly at room temperature.

[00688] The reaction mixture evaporated under vacuum and the residue was suspended in NaHCO3 (sat, 50ml) and extracted with chloroform/isopropanol (3:1, 3 x 80ml). The combined organic extracts were dried over sodium sulfate and evaporated under vacuum.

[00689] The residue was dissolved in MeOH (20ml) and treated with Boc2O (773mg, 3.54mmol) and the mixture stirred at room temperature for 30 minutes before further Boc2O (773mg, 3.54mmol) added and the mixture stirred for 16 hours.

[00690] Further Boc2O (773mg, 3.54mmol) added and the stir was continued for 2 hours.

[00691] The reaction mixture was evaporated under vacuum and the residue was dissolved in EtOAc (80ml), washed with NaHCO3 (sat, 2 x 50ml) and brine (50ml), and the organic layer dried over sodium sulfate and evaporated under vacuum.

[00692] The residue was purified by flushing through a short pad of silica, eluting with 0-100% EtOAc/heptane [DP elutes at ~80%] to afford the title compound (360mg, 26%) as a pale brown solid.

Method B: LC-MS (electrospray): m/z = 655.5 (M+H)+, RT = 2.02 min

[00693] Step 4: 4-[1-[[6-[[tert- butoxycarbonyl(cyclobutylmethyl)amino]methyl]imidazo[1,2-a]p yridin-2-yl]methyl]triazol-4-yl]- 1-tetrahydropyran-2-yl-indazole-6-carboxylic acid

[00694] Methyl 4-[1-[[6-[[tert- butoxycarbonyl(cyclobutylmethyl)amino]methyl]imidazo[1,2-a]p yridin-2-yl]methyl]triazol-4-yl]- 1-tetrahydropyran-2-yl-indazole-6-carboxylate (360mg, 0.55mmol) and lithium hydroxide (120mg, 5.01mmol) were combined in THF (10ml) and Water (5ml) and the mixture stirred was at room temperature for 18 hours.

[00695] The reaction mixture was concentrated under vacuum, diluted with water (15ml) and acidified with HCl (1M). The mixture was extracted with chloroform/isopropanol (3:13 x 40ml) and the combined organic extracts dried over sodium sulfate and evaporated under vacuum to afford the title compound (279mg, 72%) as a pale brown solid.

[00696] Method B: LC-MS (electrospray): m/z = 641.6 (M+H)+, RT = 1.27 min

[00697] Compound 297: 4-[1-[[6-[(cyclobutylmethylamino)methyl]imidazo[1,2- a]pyridin-2-yl]methyl]triazol-4-yl]-1H-indazole-6-carboxylic acid

[00698] 4-[1-[[6-[[tert-butoxycarbonyl(cyclobutylmethyl)amino]methyl ]imidazo[1,2- a]pyridin-2-yl]methyl]triazol-4-yl]-1-tetrahydropyran-2-yl-i ndazole-6-carboxylic acid

Intermediate 51 (50mg, 0.08mmol) was suspended in methanol (1ml) and HCl (4M in dioxane, 1ml, 4 mmol) was added and the mixture was incubated at room temperature for two hours.

[00699] The reaction mixture was concentrated under vacuum and the residue was purified by basic preparative HPLC (method B) to afford the title compound (18mg, 51%) as a pale yellow solid.

[00700] Method D: LC-MS (electrospray): m/z = 457.3 (M+H)+, RT = 2.26 min

[00701] Compound 298: 4-[1-[[6-[(cyclobutylmethylamino)methyl]imidazo[1,2- a]pyridin-2-yl]methyl]triazol-4-yl]-1H-indazole-6-carboxamid e

[00702] 4-[1-[[6-[[tert-butoxycarbonyl(cyclobutylmethyl)amino]methyl ]imidazo[1,2- a]pyridin-2-yl]methyl]triazol-4-yl]-1-tetrahydropyran-2-yl-i ndazole-6-carboxylic acid

Intermediate 51 (70mg, 0.099mmol) and triethylamine (42µl, 0.298mmol) were combined in THF-Anhydrous (5ml) and isobutyl chloroformate (19µl, 0.149mmol) was added. The resultant solution was stirred at RT for 5mins, then ammonia (28% aqueous, 0.2ml, 1.4mmol) was added, and the mixture further stirred at room temperature for 15mins.

[00703] The reaction mixture was quenched with NaHCO3 (sat, 30ml) and extracted with chloroform/isopropanol (3:1, 3 x 30ml). The combined organic extracts were dried over sodium sulfate and evaporated under vacuum.

[00704] The residue was suspended in methanol (2ml) and treated with HCl (4M in Dioxane, 2ml). The mixture was incubated at room temperature for two hours.

[00705] The reaction mixture was evaporated under vacuum. The residue was purified by preparative HPLC (method B) to afford the title compound (19mg, 42%) as a pale brown solid.

[00706] Method D: LC-MS (electrospray): m/z = 456.3 (M+H)+, RT = 3.09 min

[00707] The Examples in Table 17 were prepared in a similar manner Compound 298 using the appropriate amine.

Table 17

[00708] Intermediate 52: 2-[[4-(6-chloro-1-tetrahydropyran-2-yl-indazol-4-yl)triazol- 1- yl]methyl]imidazo[1,2-a]pyridine-6-carbaldehyde

[00709] The title compound was prepared from 6-chloro-4-iodo-1H-indazole in a similar fashion to Intermediate 34 giving (370 mg, 36%) as a beige solid.

[00710] Method B: LC-MS (electrospray): m/z = 462.3 (M+H) ⁺ , RT = 1.58 min

[00711] Example 302: 1-[2-[[4-(6-chloro-1H-indazol-4-yl)triazol-1- yl]methyl]imidazo[1,2-a]pyridin-6-yl]-N-(cyclobutylmethyl)me thanamine

[00712] The title compound was prepared from intermediate 52 using the procedure described for Compound 250 to give (41 mg, 34%) as an off-white solid.

[00713] Method D: LC-MS (electrospray): m/z = 447.3 (M+H) ⁺ , RT = 3.86 min The compounds in Table 18 were prepared from Intermediate 52 using the procedure described for Example 302.

Table 18

[00714] Intermediate 53: 2-({4-[6-chloro-1-(oxan-2-yl)-1H-indazol-4-yl]-1H-1,2,3- triazol-1-yl}methyl)imidazo[1,2-a]pyridine-6-carbaldehyde

[00715] The title compound was prepared from 4-bromo-7-fluoro-1H-indazole in a similar fashion to Intermediate 34 giving (739 mg, 95%) as a pale brown solid.

[00716] Method B: LC-MS (electrospray): m/z = 446.2 (M+H) ⁺ , RT = 1.50 min

[00717] Example 305: N-(cyclobutylmethyl)-1-[2-[[4-(7-fluoro-1H-indazol-4-yl)tria zol- 1-yl]methyl]imidazo[1,2-a]pyridin-6-yl]methanamine

[00718] The title compound was prepared from intermediate 53 using the procedure described for Compound 250 to give (15 mg, 23%) as a white solid.

[00719] Method D: LC-MS (electrospray): m/z = 431.3 (M+H) ⁺ , RT = 3.55 min [00720] The compounds in Table 19 were prepared from Intermediate 53 using the procedure described for Example 305.

Table 19

[00721] Example 309: 1-[[[2-[[4-(7-fluoro-1H-indazol-4-yl)triazol-1- yl]methyl]imidazo[1,2-a]pyridin-6-yl]methylamino]methyl]cycl opentanamine

[00722] 2-[[4-(7-fluoro-1-tetrahydropyran-2-yl-indazol-4-yl)triazol- 1- yl]methyl]imidazo[1,2-a]pyridine-6-carbaldehyde Intermediate 53 (90mg, 0.19mmol) and tert-butyl [1-(aminomethyl)cyclopentyl]carbamate (81mg, 0.38mmol) were combined in 1,1,1,3,3,3-Hexafluoro-2-propanol (3ml) and the mixture stirred at room temperature for an hour.

[00723] NaBH4 (50mg, 1.32mmol) was added along with a few drop MeOH - gas evolution - and the mixture stirred briefly at room temperature

[00724] The reaction mixture was quenched with MeOH (30ml) - gas evolution - and evaporated under vacuum. The residue was suspended in NaHCO3 (sat, 30ml) and extracted with chloroform/isopropanol (3:1, 3 x 30ml). The combined organic extracts were dried over sodium sulfate and evaporated under vacuum.

[00725] The residue was purified by chromatography on SiO ₂ (28 g kp-NH, eluting with EtOAc/heptane 0-100% followed by MeOH/EtOAc 0-20%) to afford the title compound (70mg (54%) as a colourless residue which was dissolved in methanol (3ml) and treated with HCl (4M in dioxane, 2ml) and incubated at room temperature for 16 hours.

[00726] The reaction mixture was evaporated under vacuum. The residue was purified by ion exchange (SCX-25g) washed with DCM and MeOH and eluted with

NH3/MeOH (7N). The eluent was evaporated under vacuum and the residue dried to afford the title compound (25mg, 50%) as a pale yellow solid.

Method E: LC-MS (electrospray): m/z = 460.2 (M+H) ⁺ , RT = 0.96 min

[00727] Example 310: N-[[6-[(4,4-dimethyl-1-piperidyl)methyl]imidazo[1,2-a]pyridi n-2- yl]methyl]-5-fluoro-4-oxo-chromene-2-carboxamide

[00729] A solution of 1-(2-fluoro-6-hydroxyphenyl)ethanone (700 mg, 4.54 mmol) and diethyl oxalate (1.4 mL, 10.4 mmol) in ethanol (23 ml) was treated with NaOEt (21% wt solution, 7.3 mL, 19.5 mmol) which gave a dark brown solution. The mixture was heated at reflux for 30 minutes during which time a Yellow precipitate formed.

[00730] The mixture was cooled in ice and acidified (c.HCl) during which the yellow precipitate dissolved and a white precipitate formed. The solids were removed by filtration and washed with a little EtOH and the filtrate was evaporated under vacuum.

[00731] The residue was dissolved in EtOAc (20 mL), washed with brine/water (1:1, 20ml). The aqueous phase was extracted with EtOAc (2 x 20ml). The combined organics were dried over sodium sulfate and evaporated under vacuum. The residue was purified by chromatography on SiO ₂ (Biotage, 50 g kp-Sil, eluting with EtOAc/heptane 0-50%) to afford a title compound (600 mg, 56%) as an off white solid.

Method B: LC-MS (electrospray): m/z = 237.1 (M+H) ⁺ , RT = 1.42 min

[00732] Step 2: 5-fluoro-4-oxo-chromene-2-carboxylic acid

[00733] To a solution of ethyl 5-fluoro-4-oxo-chromene-2-carboxylate (600 mg, 2.54 mmol) in acetic acid (8 mL) was added hydrogen chloride (6M, 4.0 mL, 24.0 mmol) at room temperature and the reaction was stirred at 90 ^o C for 16 hours.

[00734] The mixture was cooled to room temperature and evaporated under vacuum. The residue was suspended in CH ₃ CN-water (1:1, 5 mL) and the solid was collected by filtration, washed with a little water and CH ₃ CN, and dried under vacuum to provide the title compound (520 mg, 98%) as a beige solid.

Method E: LC-MS (electrospray): m/z = 209.0 (M+H) ⁺ , RT = 1.50 min

[00735] Step 3: N-[[6-[(4,4-dimethyl-1-piperidyl)methyl]imidazo[1,2-a]pyridi n-2- yl]methyl]-5-fluoro-4-oxo-chromene-2-carboxamide

[00736] The title compound was prepared by coupling 5-fluoro-4-oxo-chromene-2- carboxylic acid with Intermediate 43 using the procedure described in Example 1 with DMF as solvent to give (4.6 mg, 2%) as an off-white solid.

Method D: LC-MS (electrospray): m/z = 463.3 (M+H) ⁺ , RT = 4.03 min

[00737] Intermediate 54: 2-({4-[6-chloro-1-(oxan-2-yl)-1H-indazol-4-yl]-1H-1,2,3- triazol-1-yl}methyl)imidazo[1,2-a]pyridine-6-carbaldehyde

[00738] Step 1: 4-(3-bromo-5-fluoro-phenyl)morpholine

[00739] A solution of 3-bromo-5-fluoroaniline (1.00 g, 5.26 mmol), 1-bromo-2-(2- bromoethoxy)ethane (0.79 mL, 6.32 mmol) and N-ethyl-N-isopropyl-propan-2-amine (2.8 mL, 15.8 mmol) in DMF (20 mL) were stirred at 90 ^o C deg C for 16 hours.

[00740] More 1-bromo-2-(2-bromoethoxy)ethane (0.40 mL, 3.16 mmol) was added and mixture was heated at 110 ^o C for 4 hours.

[00741] The reaction was cooled to room temperature, diluted with ethyl acetate (100 mL) and washed with water (1 x 50 mL) followed by brine (5 x 50 mL). The organic layer was dried over sodium sulfate, concentrated in vacuo to give the crude material as a black oil.

[00742] The residue was purified by chromatography on SiO ₂ (Biotage KP-NH 30 g , eluting with EtOAc:Heptane 5 to 50 %) gave a mixture of desired product and starting material as an orange oil which crystallised upon standing. Further chromatography on SiO ₂ (Biotage KP-Sil 25 g eluting with EtOAc:Heptane, 0 to 30 %) which gave the title product (740 mg, 50%) as a pale yellow solid.

Method B: LC-MS (electrospray): m/z = 260.4/262.4 (M+H) ⁺ , RT = 1.74 min

[00743] Step 2: 2-bromo-6-fluoro-4-morpholino-benzaldehyde

[00744] A cold (0 ^o C) solution of 4-(3-bromo-5-fluoro-phenyl)morpholine (300 mg, 1.15 mmol) in DMF (anhydrous, 5 mL) was treated dropwise with phosphoryl trichloride (0.13 mL, 1.27 mmol). Once the addition was complete the mixture was warmed 60 ^o C and stirred for 16 hours.

[00745] The reaction was quenched via dropwise addition of the reaction mixture into an ice cold saturated solution of sodium bicarbonate (10 mL). The aqueous was extracted with ethyl acetate (3 x 10 mL) and the combined organics were washed with brine (3 x 10 mL) dried over sodium sulfate and concentrated in vacuo to give the title compound (268 mg, 65%) as a pale yellow solid.

Method A: LC-MS (electrospray): m/z = 287.9/289.9 (M+H) ⁺ , RT = 1.10 min [00746] Step 3: 4-(4-bromo-1H-indazol-6-yl)morpholine

[00747] Hydrazine (55%, 10 mL, 0.132 mol) was added to a solution of 2-bromo-6- fluoro-4-morpholino-benzaldehyde (4.30 g, 12.1 mmol) in 1,4-Dioxane (50 mL) and the reaction was stirred at 100 ^o C for 16 hours.

[00748] The reaction was cooled to room temperature and evaporated under vacuum. The residue was dissolved in EtOAc (100 ml), washed with water (100 mL) followed by brine (100 mL), dried (Na2SO4) and evaporated under reduced pressure to give a pale yellow solid, which was purified by chromatography on SiO ₂ (Biotage 25 g eluting by 10- 90 % EtOAc in Heptane) to give the title compound (2.90 g, 76%) as a pale yellow solid. Method B: LC-MS (electrospray): m/z = 282.1/284.1 (M+H) ⁺ , RT = 1.41 min

[00749] Step 4: 2-({4-[6-chloro-1-(oxan-2-yl)-1H-indazol-4-yl]-1H-1,2,3-tria zol-1- yl}methyl)imidazo[1,2-a]pyridine-6-carbaldehyde

[00750] The title compound was prepared from 4-(4-bromo-1H-indazol-6- yl)morpholine using the procedures described in Intermediate 24 steps 1, 2 and 3 and intermediate 34 steps 4 and 5 to give (1.0 g, 83%) as a beige solid.

Method B: LC-MS (electrospray): m/z = 513.3 (M+H) ⁺ , RT = 1.41 min

[00751] Example 311: N-(cyclobutylmethyl)-1-[2-[[4-(6-morpholino-1H-indazol-4- yl)triazol-1-yl]methyl]imidazo[1,2-a]pyridin-6-yl]methanamin e

[00752] The title compound was prepared from intermediate 53 using the method described for Compound 250 giving (104 mg, 26%) as a white powder.

Method C: LC-MS (electrospray): m/z = 498.4 (M+H) ⁺ , RT = 2.56 min

[00753] Example 312: 6-[2-(2-aminoethoxy)ethoxy]-N-[[6-[(4,4-dimethyl-1- piperidyl)methyl]imidazo[1,2-a]pyridin-2-yl]methyl]-1H-indaz ole-4-carboxamide

trihydrochloride.

[00754] HCl (4M in dioxane, 3.1mL, 12.4 mmol) was added to tert-butyl N-[2-[2-[4-[[6- [(4,4-dimethyl-1-piperidyl)methyl]imidazo[1,2-a]pyridin-2-yl ]methylcarbamoyl]-1- tetrahydropyran-2-yl-indazol-6-yl]oxyethoxy]ethyl]carbamate (30 mg, 0.0426 mmol) and the mixture was stirred at room temperature for 1 hour and at 50 °C for 1 hour. The solvent was removed under vacuum to give the title compound (20 mg, 72%) as a tan solid.

[00755] Method D: LC-MS (electrospray): m/z = 520.3 (M+H) ⁺ , RT = 4.11 min

[00756] Intermediate 55: tert-butyl N-[[6-[(Z)-tert-butylsulfinyliminomethyl]imidazo[1,2- a]pyridin-2-yl]methyl]carbamate

[00757] A solution of tert-butyl N-[(6-formylimidazo[1,2-a]pyridin-2- yl)methyl]carbamate Intermediate 25 Step 2 (1.00 g, 3.63 mmol) and 2-methylpropane-2- sulfinamide (533 mg, 4.40 mmol) in DCE (Anhydrous, 97 mL), under a nitrogen atmosphere, was treated with CuSO4 (1.76 g, 10.9 mmol) and the resultant blue solution was heated at reflux for 44 hours and left standing at room temperature for a further 5 days.

[00758] The dark green suspension was filtered through Celite washing with DCM and the filtrate was concentrated under vacuum and purified by chromatography on SiO2

[Biotage KPNH 28 g eluting with 50-100% EtOAc/heptane] to give the title compound (725 mg, 53%) as a pale yellow solid.

Method B: LC-MS (electrospray): m/z = 379.3 (M+H) ⁺ , RT = 1.49 min

[00759] Example 313: N-[[6-[1-(cyclobutylmethylamino)-2-phenyl-ethyl]imidazo[1,2- a]pyridin-2-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carbo xamide

[00760] Step 1: tert-butyl N-[[6-[1-(tert-butylsulfinylamino)-2-phenyl-ethyl]imidazo[1, 2- a]pyridin-2-yl]methyl]carbamate

[00761] A solution of benzylmagnesium chloride (1.5M in THF, 969 uL, 1.45 mmol) was added dropwise over 1 min to a solution of tert-butyl N-[[6-[(E)-tert- butylsulfinyliminomethyl]imidazo[1,2-a]pyridin-2-yl]methyl]c arbamate Intermediate 54 (110 mg, 0.291 mmol) in dry DCM (14mL) at room temperature and the solution was stirred for 16 hours. The reaction mixture became turbid upon the addition of the first few drops but became clear after the addition was complete.

[00762] The reaction was quenched by the addition of NH ₄ Cl (sat) and extracted with DCM (phase sep cartridge). The organics were evaporated under vacuum to a pale gum which was purified by chromatography on SiO ₂ [Biotage KPNH 11 g eluting with EtOAc] to give the title compound (2:1 mixture of diastereoisomers, 102 mg, 75%) as a beige foam. Method B: LC-MS (electrospray): m/z = 471.3 (M+H) ⁺ , RT = 1.54 & 1.59 min

[00763] Step 2: tert-butyl N-[[6-(1-amino-2-phenyl-ethyl)imidazo[1,2-a]pyridin-2- yl]methyl]carbamate

[00764] A solution of tert-butyl N-[[6-[1-(tert-butylsulfinylamino)-2-phenyl- ethyl]imidazo[1,2-a]pyridin-2-yl]methyl]carbamate (185 mg, 0.39 mmol) in THF (9.25 mL) and Water (1.85 mL) was treated with molecular iodine (20 mg, 0.08 mmol) and the mixture was warmed at 60 ^o C for 16 hours.

[00765] The mixture was cooled to room temperature, quenched by the addition of sodium thiosulfate (sat 10 ml) and extracted with DCM (phase sep cartridge). The organics were evaporated under vacuum and purified by chromatography on SiO ₂ [Biotage KPNH 11 g eluting with 50 to 100% EtOAc in heptane followed by 0 to 20 % MeOH in DCM]. To give the title compound (30 mg,7% Yield) as a white powder.

[00766] During the separation a white solid was seen between the layers. The solid was collected by filtration, washed with ether and dried to give the title compound (40 mg, 28%) as a white powder. Method B: LC-MS (electrospray): m/z = 367.3 (M+H) ⁺ , RT = 1.46 min

[00767] Step 3: tert-butyl N-[[6-[1-(cyclobutylmethylamino)-2-phenyl-ethyl]imidazo[1,2- a]pyridin-2-yl]methyl]carbamate

[00768] The title compound was prepared from tert-butyl N-[[6-(1-amino-2-phenyl- ethyl)imidazo[1,2-a]pyridin-2-yl]methyl]carbamate using the procedure described in

Compound 250 to give (21 mg, 22%) as a white powder along with the doubly alkylated product (30 mg, 31%).

Method B: LC-MS (electrospray): m/z = 435.4 (M+H) ⁺ , RT = 1.78 min

[00769] Step 4: N-[[6-[1-(cyclobutylmethylamino)-2-phenyl-ethyl]imidazo[1,2- a]pyridin- 2-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide

[00770] tert-butyl N-[[6-[1-(cyclobutylmethylamino)-2-phenyl-ethyl]imidazo[1,2- a]pyridin-2-yl]methyl]carbamate (30 mg, 0.07 mmol) was dissolved in hydrogen chloride (4M in dioxane, 0.17 mL, 0.7 mmol) and stirred at room temperature for 1 hour.

[00771] The solvent was removed in vacuo and the resulting crude material dissolved in DMF (1 mL), N-ethyl-N-isopropyl-propan-2-amine (0.06 mL, 0.35 mmol) was added and the mixture was stirred at room temperature for 10 minutes.

[00772] In a separate flask tert-butyl N-[[6-[1-(cyclobutylmethylamino)-2-phenyl- ethyl]imidazo[1,2-a]pyridin-2-yl]methyl]carbamate (30 mg, 0.07 mmol), HATU (39 mg, 0.1 mmol) and N-ethyl-N-isopropyl-propan-2-amine (0.06 mL, 0.35 mmol) in DMF (1 mL) were combined at room temperature and stirred for 5 minutes before the amine solution was added and the mixture was stirred at room temperature for 2 hours. [00773] Water (2 mL) and IPA/CHCl3 (1/4, 5 mL) were added and the layers separated (phase sep cartridge). The organic filtrate was concentrated in vacuo to give a brown oil. Purification by reverse phase chromatography (Biotage 12 g, water/MeCN + 0.1% NH3, 10 to 90 %) and subsequent freeze-drying overnight gave the title compound (8.0 mg, 23%) a pale yellow solid.

Method D: LC-MS (electrospray): m/z = 507.3 (M+H)+, RT = 4.13 min

[00774] Example 314:

[00775] The title compound was prepared from the bis alkylated product isolated in Example 313 Step 3 in the same manner as Example 313 Step 4 to give (10 mg, 25%) as a white powder.

Method C: LC-MS (electrospray): m/z = 575.4 (M+H)+, RT = 4.86 min

[00776] Intermediate 56: 2-({4-[7-chloro-1-(oxan-2-yl)-1H-indazol-4-yl]-1H- [00777] 1,2,3-triazol-1-yl}methyl)imidazo[1,2-a]pyridine-6-carbaldeh yde

[00778] The title compound was prepared from 4-bromo-7-chloro-1H-indazole in a similar fashion to Intermediate 34 using the oxidation described in Compound 268 Step 3 for the final step giving (388 mg, 75%) as a grey solid.

Method B: LC-MS (electrospray): m/z = 462.2 (M+H) ⁺ , RT = 1.54 min

[00779] Example 315: 1-[2-[[4-(7-chloro-1H-indazol-4-yl)triazol-1- yl]methyl]imidazo[1,2-a]pyridin-6-yl]-N-(cyclobutylmethyl)me thanamine

[00780] The title compound was prepared from Intermediate 56 in a similar manner to Example 305 to give (58 mg, 40%) as a white solid.

Method E: LC-MS (electrospray): m/z = 447.2 (M+H) ⁺ , RT = 1.37 min

[00781] Example 316: 1-[[[2-[[4-(7-chloro-1H-indazol-4-yl)triazol-1- yl]methyl]imidazo[1,2-a]pyridin-6-yl]methylamino]methyl]cycl obutanol

[00782] The title compound was prepared in the same manner as Example 315 to give (20 mg, 14%) as a white solid.

Method D: LC-MS (electrospray): m/z = 463.2 (M+H) ⁺ , RT = 3.09 min

[00783] Example 317: [2-[[4-(6-fluoro-1H-indazol-4-yl)triazol-1-yl]methyl]imidazo [1,2- a]pyridin-6-yl]methanol

[00784] The title compound was prepared from 4-bromo-6-fluoro-1H-indazole in a similar fashion to Compound 253 giving (20 mg, 6%) as a white solid.

Method D: LC-MS (electrospray): m/z = 364.6 (M+H) ⁺ , RT = 2.71 min

[00785] Intermediate 57: 2-({4-[6-fluoro-1-(oxan-2-yl)-1H-indazol-4-yl]-1H- 1,2,3-triazol-1-yl}methyl)imidazo[1,2-a]pyridine-6-carbaldeh yde

[00786] The title compound was prepared from 4-bromo-6-fluoro-1H-indazole in a similar fashion to Intermediate 34 giving (472 mg, 96%) as a sandy solid.

Method B: LC-MS (electrospray): m/z = 446.7 (M+H) ⁺ , RT = 1.49 min

[00787] Example 318: N-(cyclobutylmethyl)-1-[2-[[4-(6-fluoro-1H-indazol-4-yl)tria zol- 1-yl]methyl]imidazo[1,2-a]pyridin-6-yl]methanamine

[00788] The title compound was prepared from Intermediate 57 in a similar fashion to Compound 250 giving (30 mg, 29%) as an off white solid.

Method C: LC-MS (electrospray): m/z = 431.4 (M+H) ⁺ , RT = 2.79 min

[00789] The compounds in Table 20 were prepared from Intermediate 57 using the procedure described for Example 318.

[00790] Table 20

[00791] Example 321: N-[[2-[[4-(6-cyclopropyl-1H-indazol-4-yl)triazol-1- yl]methyl]imidazo[1,2-a]pyridin-6-yl]methyl]-2,2-dimethyl-pr opan-1-amine

[00792] A pressure vial charged with bromo(cyclopropyl)zinc (0.5M in THF, 0.38 mL, 0.188 mmol), THF (0.3 mL) and N-[[2-[[4-(6-bromo-1H-indazol-4-yl)triazol-1- yl]methyl]imidazo[1,2-a]pyridin-6-yl]methyl]-2,2-dimethyl-pr opan-1-amine (31 mg, 0.0628 mmol) Compound 229 was degassed with

nitrogen. Tetrakis(triphenylphosphine)palladium(0) (3.6 mg, 3.14 mmol) was added and the reaction degassed with nitrogen for 2 minutes before the reaction was heated to 50 ^o C.

[00793] Further . Tetrakis(triphenylphosphine)palladium(0) (3.6 mg, 3.14 mmol) and bromo(cyclopropyl)zinc (0.5M in THF, 0.38 mL, 0.188 mmol) were added and the reaction degassed for 5 minutes before heating to 65 ^o C for 2 hours.

[00794] [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (2.6 mg, 3.14 mmol) was added and the reaction heated to 70 ^o C for 18 hours. [00795] The reaction was cooled toroom temperature, filtered through a pad of Celite washing with MeOH (10 mL). The solvent was removed in vacuo to give a red/brown oil. The crude mixture was purified by reverse phase chromatography [water/MeCN + 0.1% NH3, 0 to 100 %] gave partially clean fractions containing product. Concentration of these fractions in vacuo gave a yellow residue (5 mg)

[00796] Repurification by reverse phase chromatography [water/MeCN + 0.1% NH3, 0 to 100 %] followed by freeze drying overnight gave the title compound (1.2 mg, 3.8% Yield) as a white solid.

Method C: LC-MS (electrospray): m/z = 455.4 (M+H) ⁺ , RT = 3.15 min

[00797] Intermediate 58: [6-[(cyclobutylmethylamino)methyl]imidazo[1,2-a]pyridin-2- yl]methanamine trihydrochloride

[00798] The title compound was prepared in a similar fashion to Intermediate 25 to give (953 mg, 95%) as a pale yellow solid.

Method C: LC-MS (electrospray): m/z = 245.1 (M+H) ⁺ , RT = 2.02 min

[00799] Example 322: N-[[6-[(cyclobutylmethylamino)methyl]imidazo[1,2-a]pyridin-2 - yl]methyl]-1H-indazole-4-carboxamide

[00800] The title compound was prepared in the same manner as Example 1 by coupling of 1-tetrahydropyran-2-ylindazole-4-carboxylic acid and Intermediate 58 folloewd by deprotection to give (7.8 mg, 10%) as a white powder.

Method C: LC-MS (electrospray): m/z = 389.4 (M+H) ⁺ , RT = 2.38 min [00801] Intermediate 59: 6-methylimidazo[1,2-a]pyridin-2-amine

[00803] A solution of 5-methylpyridin-2-amine (5.00 g, 46.2 mmol) in Pyridine (50 mL) was treated with (p-toluenesulfonyl chloride (11.47 g, 55.5 mmol) and the mixture was stirred at room temperature for 20 hours. The addition caused an orange colouration and a slight exotherm.

[00804] The solvent was removed under vacuum and the residue was triturated with MeOH, the solids were collected by filtration, washed with MeOH and dried under vacuum to provide the title compound (10.9 g, 90%) as a white solid.

Method A: LC-MS (electrospray): m/z = 263.2 (M+H) ⁺ , RT = 0.96 min

[00805] Step 2: 2-[5-methyl-2-(4-methylbenzenesulfonamido)-1,2-dihydropyridi n-1- yl]acetamide

[00806] A suspension of 4-methyl-N-(5-methyl-2-pyridyl)benzenesulfonamide (3.00 g, 11.4 mmol) and N-ethyl-N-isopropyl-propan-2-amine (2.2 mL, 12.6 mmol) in DMF-Anhydrous (36 mL), under a nitrogen atmosphere, was treated with idoacetamide (2.33 g, 12.6 mmol) and the mixture was stirred at room temperature for 20 hours. [00807] The solvent was removed under vacuum and the residue was triturated with DCM/EtOAc (30 mL) but the product was too soluble. EtOAc was added until cloud point and the mixture was aged. The solids were collected by filtration and dried on the sinter to give the title compound (5.3 g, >100%) as a white solid. The material was used without further purification.

Method A: LC-MS (electrospray): m/z = 320.0 (M+H) ⁺ , RT = 0.88 min

[00808] Step 3: 6-methylimidazo[1,2-a]pyridin-2-amine

[00809] A suspension of 2-[5-methyl-2-(4-methylbenzenesulfonamido)-1,2- dihydropyridin-1-yl]acetamide (3.60 g, 11.3 mmol) in DCM (40 mL), under a nitrogen atmosphere, was slowly treated with (2,2,2-trifluoroacetyl) 2,2,2-trifluoroacetate (7.9 mL, 56.4 mmol) and the mixture was stirred at room temperature for 16 hours. During the addition, the solids dissolved and the solution darkened to nearly black.

[00810] The dark solution was cautiously quenched by the addition of NaHCO3 (sat). The solvent was removed under vacuum and the residue was extracted with EtOAc (x2). The organics were washed with brine, dried (MgSO4) and evaporated under vacuum to a dark gum which was purified by ion exchange [SCX-2 (5 g) washing with methanol and eluting with ammonia in MeOH) to give the title compound (476 mg, 29%) as a dark gum. Method A: LC-MS (electrospray): m/z = 147.9 (M+H) ⁺ , RT = 0.17 min

[00811] Intermediate 60: 4-ethynyl-1-tetrahydropyran-2-yl-pyrazolo[4,3-c]pyridine

[00812] The title compound was prepared from 4-chloro-1H-pyrazolo[4,3-c]pyridine using the procedures described for Intermediate 24 to give the title compound (243 mg, 33%) as a brown oil. Method B: LC-MS (electrospray): m/z = 228.3 (M+H) ⁺ , RT = 1.40 min

[00813] Intermediate 61: 2-[[4-(1-tetrahydropyran-2-ylpyrazolo[4,3-c]pyridin-4- yl)triazol-1-yl]methyl]imidazo[1,2-a]pyridine-6-carbaldehyde

[00814] The title compound was prepared from Intermediate 60 using the procedures described for Intermediate 34 to give the title compound (290 mg, 95%) as a very pale yellow solid.

Method B: LC-MS (electrospray): m/z = 429.3 (M+H) ⁺ , RT = 1.39 min

[00815] Example 324: N-(cyclobutylmethyl)-1-[2-[[4-(1H-pyrazolo[4,3-c]pyridin-4- yl)triazol-1-yl]methyl]imidazo[1,2-a]pyridin-6-yl]methanamin e

[00816] The title compound was prepared from Intermediate 61 in a similar manner to Compound 250 to give (45 mg, 47%) as a white solid.

Method D: LC-MS (electrospray): m/z = 414.3 (M+H) ⁺ , RT = 3.20 min

[00817] The compounds in Table 21 were prepared in a similar manner to Example 324.

Table 21

[00818] The Compounds in Table 22 were prepared from Intermediate 34 in a similar fashion to Compound 250.

Table 22

[00819] Example 329: 2-[[4-(1H-indazol-4-yl)imidazol-1-yl]methyl]-6-methyl- imidazo[1,2-a]pyridine formate

[00821] A mixture of 4-bromo-1H-imidazole (500mg, 3.40 mmol), K ₂ CO ₃ (1.41g, 10.2 mmol) and 2-(chloromethyl)-6-methyl-imidazo[1,2-a]pyridine hydrochloride (886mg, 4.08 mmol) were combined in DMF (8ml) and stirred at room temperature for 1.5 hours before NaI (30mg, 0.20 mmol) was added and the stir was continued for 19 hours.

[00822] The reaction mixture was diluted with NaHCO ₃ (sat, 50ml) and extracted with chloroform/isopropanol (3:1, 3 x 50ml). The combined organic extracts were dried over sodium sulfate and evaporated under vacuum.

[00823] The residue was purified by chromatography on on SiO ₂ (Biotage 28 g kp- NH, eluting with EtOAc/heptane 0-100% followed by MeOH/EtOAc 0-20%) to afford the title compound (836 mg, 84%) as a white solid which contained a small amount of the regioisomeric product.

Method B: LC-MS (electrospray): m/z = 291.1/293.1 (M+H) ⁺ , RT = 1.31 min

[00824] Step 2: 4-[1-({6-methylimidazo[1,2-a]pyridin-2-yl}methyl)-1H-imidazo l-4-yl]-1- (oxan-2-yl)-1H-indazole

[00825] 1-tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxabor olan-2-yl)indazole (300mg, 0.91mmol), 2-[(4-bromoimidazol-1-yl)methyl]-6-methyl-imidazo[1,2-a]pyri dine (319mg, 1.10mmol) and K ₂ CO ₃ (1.2M aqueous, 2.28 ml, 2.74 mmol) were combined in 1,4- Dioxane (6ml) and the mixture sparged with nitrogen for 5mins. PdCl ₂ dppf (67mg, 0.09 mmol) was added and the mixture further sparged briefly and the vessel sealed. The mixture was heated at 90°C for 2 hours.

[00826] Further PdCl ₂ dppf (67mg, 0.09 mmol) was added, mixture briefly sparged with nitrogen and further heated at 100°C for 4 hours. The reaction mixture was cooled to room temperature and stood over the weekend.

[00827] The reaction mixture was diluted with NaHCO ₃ (sat, 50ml) and extracted with chloroform/isopropanol (3:1, 3 x 50ml). The combined organic extracts were dried over sodium sulfate and evaporated under vacuum.

[00828] The residue was purified by chromatography on SiO ₂ (Biotage 28 g kp-NH, eluting with EtOAc/heptane 0-100% followed by MeOH/EtOAc 0-20%) to afford the crude title compound (229mg, 27% yield, 45% purity) as a brown oil. No further purification attempted; carried direct to next step.

Method A: LC-MS (electrospray): m/z = 413.2 (M+H) ⁺ , RT = 0.87 min

[00829] Step 3: 2-[[4-(1H-indazol-4-yl)imidazol-1-yl]methyl]-6-methyl-imidaz o[1,2- a]pyridine formate

[00830] A solution of 4-[1-[(6-methylimidazo[1,2-a]pyridin-2-yl)methyl]imidazol-4- yl]-1- tetrahydropyran-2-yl-indazole (229mg, 0.56 mmol) in methanol (5ml) was treated with HCl (4M in dioxane, 5ml) and the mixture was incubated at room temperature for 18 hours.

[00831] The reaction mixture was evaporated under vacuum and the residue was purified by reverse pahse chromatography on SiO ₂ (12 g C18-Ultra, eluting with

Acetonitrile+0.1%NH3/Water+0.1%NH310-100%) the relevant fractions were combined to afford crude material which was triturated with MeOH/EtOAc/heptane. The solids were collected by filtration to give a grey solid 100 mg. [00832] The material was purified by preparative HPLC [Acidic method A] to give the title compound (20 mg, 9%) as a white solid.

Method E: LC-MS (electrospray): m/z = 329.1 (M+H) ⁺ , RT = 1.00 min

[00833] Example 330: N-[[6-[2-cyano-1-(cyclobutylmethylamino)ethyl]imidazo[1,2- a]pyridin-2-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carbo xamide

[00834] Step 1: tert-butyl N-[(6-{2-cyano-1-[(2-methylpropane-2- sulfinyl)amino]ethyl}imidazo[1,2-a]pyridin-2-yl)methyl]carba mate

[00835] An oven dried flask containing N-(propan-2-yl)propan-2-amine (0.28 mL, 2.00 mmol) in THF (2.5 mL) was cooled to -78 ^o C and a solution of n-butyllithium (1.6 M in hexanes, 1.3 mL, 2.00 mmol) was added whilst maintaining the temperature at -78 ^o C. Once the addition was complete, the mixture was stirred at ambient temperature for 20 minutes.

[00836] The mixture was cooled to -78 ^o C and a solution of acetonitrile (0.10 mL, 2.00 mmol) in THF (1 mL) was added and the mixture was stirred at -78 C for 10 minutes before a quarter of the mixture was syringed into a separate oven dried flask and cooled to -78 ^o C and stirred for 20 minutes before a solution of tert-butyl N-[[6-[(E)-tert- butylsulfinyliminomethyl]imidazo[1,2-a]pyridin-2-yl]methyl]c arbamate Intermediate 55 (190 mg, 0.502 mmol) in THF (0.5 mL) was added dropwise. The reaction was stirred at -78 ^o C for 20 minutes. [00837] A further quarter of the LDA mixture was added dropwise and the reaction was stirred for at -78 ^o C for 15 minutes.

[00838] A further quarter of the LDA mixture was added dropwise and the reaction was stirred for at -78 ^o C for 15 minutes.

[00839] The remaining LDA mixture was added dropwise and the reaction was stirred for at -78 ^o C for 15 minutes.

[00840] The reaction was quenched via dropwise addition of NH ₄ Cl (sat) and the reaction was warmed to room temperature. The mixture was diluted with EtOAc (5 mL) and the layers separated. The aqueous layer was extracted with ethyl acetate (5 mL). The organic layers were washed with brine (5 mL), dried over magnesium sulfate and concentrated in vacuo to give a red viscous oil.

[00841] The crude product was purified by reverse phase chromatography on SiO ₂ (Biotage 12 g, water/MeCN (+0.1 % NH3) at a gradient of 90:10 to 20:80) concentration of product fractions in vacuo and subsequent freeze drying overnight gave the desired product (110 mg, 52%) as an off-white solid.

[00842] Method B: LC-MS (electrospray): m/z = 420.3 (M+H) ⁺ , RT = 1.35 min

[00843] Step 2: tert-butyl N-{[6-(1-amino-2-cyanoethyl)imidazo[1,2-a]pyridin-2- yl]methyl}carbamate

[00844] A solution of tert-butyl N-[[6-[1-(tert-butylsulfinylamino)-2-cyano- ethyl]imidazo[1,2-a]pyridin-2-yl]methyl]carbamate (110 mg, 0.26 mmol) in THF (2 mL) and Water (0.2 mL) was treated with iodine (13 mg, 0.052 mmol) and the mixture was warmed at 60 ^o C for 18 hours.

[00845] Further iodine (13 mg, 0.052 mmol) was added and the heating was continued for a further 4 hours. [00846] The mixture was cooled to room temperature, quenched by the addition of sodium thiosulfate (sat 10 ml) and extracted with EtOAc, dried over sodium sulfate and concentrated in vacuo

[00847] Purification by reverse phase chromatography on SiO ₂ (12g C18 cartridge, water/MeCN + 0.1% NH3 gradient) gave the desired product (20 mg, 23%) as a yellow oil.

[00848] Method B: LC-MS (electrospray): m/z = 316.3 (M+H) ⁺ , RT = 1.23 min

[00849] Step 3: tert-butyl N-[(6-{2-cyano-1- [(cyclobutylmethyl)amino]ethyl}imidazo[1,2-a]pyridin-2-yl)me thyl]carbamate

[00850] tert-butyl N-[[6-(1-amino-2-cyano-ethyl)imidazo[1,2-a]pyridin-2- yl]methyl]carbamate (20 mg, 0.06 mmol) and N-ethyl-N-isopropyl-propan-2-amine (0.055 mL, 0.32 mmol) were combined in DCM (0.3 mL) and methanol (0.06 mL). To the yellow suspension was added cyclobutanecarbaldehyde (6.4 mg, 0.0761 mmol) and the reaction was stirred at room temperature for an hour.

[00851] The reaction was concentrated in vacuo to remove any excess aldehyde and the resulting crude yellow oil was dissolved in DCM (0.5 mL). sodium borohydride (22 mg, 0.57 mmol) was added followed by a drop of methanol and the reaction was stirred at room temperature for 30 minutes. The reaction was quenched with dropwise addition of water (3 mL). IPA/CHCl3 (1:4, 5 mL) was added and the separated (phase sep cartridge). The organic filtrate was concentrated in vacuo to give the title compound (21 mg, 75%) as a pale yellow residue, which was used without further purification.

[00852] Method B: LC-MS (electrospray): m/z = 384.4 (M+H) ⁺ , RT = 1.53 min

[00853] Step 4: N-[[6-[2-cyano-1-(cyclobutylmethylamino)ethyl]imidazo[1,2-a] pyridin- 2-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide

[00854] tert-butyl N-[[6-[2-cyano-1-(cyclobutylmethylamino)ethyl]imidazo[1,2-a] pyridin- 2-yl]methyl]carbamate (21 mg, 0.06 mmol) was dissolved in hydrogen chloride solution (4 M in dioxane, 0.14 mL, 0.55 mmol) and stirred at room temperature for an hour.

[00855] The solvent was removed in vacuo and the resulting crude material was dissolved in DMF (1 mL) and treated with N-ethyl-N-isopropyl-propan-2-amine (0.048 mL, 0.274 mmol) and stirred at RT for 10 minutes.

[00856] In a separate flask were combined (4-oxopyrido[1,2-a]pyrimidine-2- carbonyl)oxylithium (11 mg, 0.0548 mmol), HATU (31 mg, 0.0821 mmol) and N-ethyl-N- isopropyl-propan-2-amine (0.048 mL, 0.274 mmol) in DMF (1 mL) at room temperature. The mixture was stirred for 5 minutes before the amine solution was added and resultant mixture was stirred at RT for 2 hours.

[00857] Water (2 mL) and IPA/CHCl3 (1:4, 5 mL) were added and the layers separated (phase sep cartridge). The organic filtrate was concentrated in vacuo to give a green oil. Purification over silica (Reversed phase,12 g cartridge, water/MeCN + 0.1% formic acid, 10 to 90 %) and concentration of the fractions containing product in vacuo gave impure material.

[00858] The compound was further purified over silica (reversed phase 12 g cartridge, water/MeCN + 0.1% NH3, 10 to 90 %). And freeze dried to give the title compound (4.5 mg, 18%) as a white solid.

Method C: LC-MS (electrospray): m/z = 456.4 (M+H) ⁺ , RT = 2.53 min

[00859] Example 333: 4-oxo-N-[(6-piperazin-2-ylimidazo[1,2-a]pyridin-2- yl)methyl]pyrido[1,2-a]pyrimidine-2-carboxamide

[00860] The title compound was prepared from Example 49 using the procedure described for Compound 231 to give (12 mg, 15%) as a white solid.

Method C: LC-MS (electrospray): m/z = 404.2 (M+H) ⁺ , RT = 1.39 min [00861] Example 334: N-[[6-(6-cyclohexyl-4-oxo-2-piperidyl)imidazo[1,2-a]pyridin- 2- yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide

[00862] Step 1: tert-butyl N-[cyclohexyl(p-tolylsulfonyl)methyl]carbamate

[00863] A mixture of cyclohexanecarbaldehyde (2.24 g, 20.0 mmol), tert-butyl carbamate (2.34 g, 20.0 mmol), sodium;4-methylbenzenesulfinate (3.56 g, 20.0

mmol), water (40 mL), methanol (20 mL) and formic acid (5 mL) was stirred for 15 minutes (until it became homogenous) and then left standing for 18 hours at RT. The crystalline product was filtered off with suction, washed successively with water (30 mL) and diethyl ether (30 mL) and dried in the vacuum oven at 45°C for 4 hours to afford The title compound (4.81 g, 65%) as a white solid.

[00864] ¹ HNMR(500 MHz, Chloroform-d) d 1.03– 1.45 (m, 14H), 1.58– 1.72 (m, 2H), 1.74– 1.80 (m, 2H), 2.06– 2.20 (m, 1H), 2.35– 2.49 (m, 4H), 4.44– 4.70 (m, 1H), 4.87– 5.21 (m, 1H), 7.28– 7.36 (m, 2H), 7.73– 7.80 (m, 2H).

[00865] Step 2: 4-amino-4-cyclohexyl-butan-2-one hydrochloride

[00866] To a solution tert-butyl N-[cyclohexyl(p-tolylsulfonyl)methyl]carbamate (1.84 g, 5.00 mmol) in THF-Anhydrous (30 mL) was added potassium;2-methylpropan-2-olate (95%, 1.18 g, 10.0 mmol) at 0°C. The mixture was stirred for 10 minutes before a solution of tert- butyl 3-oxobutanoate (0.79 g, 5.00 mmol) in THF-Anhydrous (10 mL) was added dropwise via syringe. The reaction was allowed to warm slowly to room temperature and was stirred for 2 hours. The reaction was then cooled to 0°C (ice-bath) and quenched with NH4Cl (sat, 12.5 mL). Diethyl ether (50 mL) was added and the organic layer was separated. The aqueous layer was extracted with diethyl ether (25 mL). The combined organic layers were washed with brine (30 mL), dried (MgSO4) and concentrated at reduced pressure to give a clear colourless oil. The oil was treated with HCl (3M, 15 mL) and the mixture was heated at reflux with efficient stirring for 2 hours. Water and the excess HCl were removed at reduced pressure to afford the title compound (0.86 g, 79%) as a brown oil that was used without further purification.

[00867] ¹ HNMR(500 MHz, Methanol-d4) d 1.05– 1.90 (m, 11H), 2.23 (s, 3H), 2.80 (dd,J = 19.0, 9.1 Hz, 1H), 3.01 (dd,J = 19.0, 3.2 Hz, 1H), 3.38– 3.48 (m, 1H).

[00868] Step 3: N-[[6-(6-cyclohexyl-4-oxo-2-piperidyl)imidazo[1,2-a]pyridin- 2- yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide

[00869] To a solution of 4-amino-4-cyclohexyl-butan-2-one hydrochloride (54 mg, 0.24 mmol) in ethanol (2 mL) was added DL-Proline (5.5 mg, 0.0477 mmol), magnesium sulfate (29 mg, 0.24 mmol), triethylamine (0.033 mL, 0.24 mmol) and N-[(6-formylimidazo[1,2- a]pyridin-2-yl)methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carbo xamide Example 49 (92 mg, 0.24 mmol) and the mixture was stirred at room temperature for 6 hours. NaHCO3 (sat, 10 mL) was added and the mixture was extracted with EtOAc (3 x 15 mL). The combined extracts were washed with brine (10 mL), dried (Na ₂ SO ₄ ), and concentrated at reduced pressure.

[00870] The residue was purified by open access preparative HPLC (Method B) The product containing fractions were combined and concentrated to dryness under reduced pressure.

[00871] The residue was dissolved acetonitrile and water (1:1, 4 mL) and lyophilised to afford the title compound (24 mg, 19%) as an off-white solid as a 7:3 mixture of cis and trans diastereoisomers. Method C: LC-MS (electrospray): m/z = 499.4 (M+H) ⁺ , RT = 2.99 min

[00872] Example 335: 1-[2-(1H-indazol-4-yl)thiazol-5-yl]-1-(6-methylimidazo[1,2- a]pyridin-2-yl)ethanol

[00873] Step 1: (6-methylimidazo[1,2-a]pyridin-2-yl)-[2-(1-tetrahydropyran-2 -ylindazol- 4-yl)thiazol-5-yl]methanone

[00874] A solution of (6-methylimidazo[1,2-a]pyridin-2-yl)-[2-(1-tetrahydropyran-2 - ylindazol-4-yl)thiazol-5-yl]methanol Compound 258 Step 1 (190mg, 0.43mmol) was dissolved in DCM (5ml) was treated with Dess-Martin periodinane (271mg, 0.64mmol) and the mixture was stirred at room temperature for 2 hours.

[00875] The reaction was quenched with NaHCO3 (sat, 20ml) and extracted with chloroform/isopropanol (3:1, 3 x 20ml). The combined organic extracts were dried over sodium sulfate and evaporated under vacuum.

[00876] The residue was purified by chromatography on SiO ₂ (Biotage 25 g kp-Sil, eluting with EtOAc/heptane 0-100%) to afford the title compound (117mg 53%) as a yellow solid

Method A: LC-MS (electrospray): m/z = 444.2 (M+H) ⁺ , RT = 1.35 min

[00877] Step 2: 1-[2-(1H-indazol-4-yl)thiazol-5-yl]-1-(6-methylimidazo[1,2-a ]pyridin-2- yl)ethanol

[00878] A suspension of (6-methylimidazo[1,2-a]pyridin-2-yl)-[2-(1-tetrahydropyran-2 - ylindazol-4-yl)thiazol-5-yl]methanone (110mg, 0.25mmol) in THF (Anhydrous, 10ml) was cooled in an ice/water bath. MeMgBr (3M in Et2O, 165µl, 0.496 mmol) was added dropwise and the dark red mixture was stirred under cooling for 45 minutes.

[00879] The reaction mixture was quenched with NH4Cl (sat, 20ml), warmed to room temperature and extracted with chloroform/isopropanol (3:1, 3 x 20ml). The combined organic extracts were dried over sodium sulfate and evaporated under vacuum.

[00880] The residue was dissolved in methanol (3ml), treated with HCl (4M in

Dioxane, 3ml) and incubated at room temperature for 3 hours.

[00881] The reaction mixture was evaporated under vacuum. The residue was purified by ion exchange (SCX-2 cartridge (5g) washed with DCM and MeOH and eluted with NH ₃ /MeOH (7M) and the basic eluent evaporated under vacuum.

[00882] The residue was purified by Preparative HPLC (method B) and the clean product-containing fractions combined and evaporated under vacuum. The residue was triturated with EtOAc/heptane to afford the title compound (32mg, 34%) as an off-white solid.

[00883] Method D: LC-MS (electrospray): m/z = 376.3 (M+H) ⁺ , RT = 3.24 min

[00884] Intermediate 62: 4-azido-1H-indazole

[00886] To a solution of 4-nitro-1H-indazole (50.0 g, 153.33 mmol) in MeOH (500 ml) was added Pd/C (50% wet) (10%, 5.00 g) at room temperature. The reaction mixture was placed under a an atmosphere of hydrogen and stirred at room temperature for 5 hours. The reaction mixture was filtered through celite pad and washed with additional methanol (3 x 200 ml). The combined filtrate was concentrated under vacuum to afford the title compound (14.0 g, 34%).

Method G: LC-MS (electrospray): m/z = 134.0 (M+H) ⁺ , RT = 0.49 min

[00887] Step-2: 4-azido-1H-indazole