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.

[0011] METTL3-dependent m6A on HBV and HCV viral genome regulates recognition of the viral genome by RIG-I RNA sensor. Depletion of METTL3 enhances viral dsRNA recognition and induces an anti-viral immune response (Kim et al.).

[0012] Therefore METTL3 inhibitors may provide a novel therapeutic approach to a range of infectious and inflammatory diseases. In particular, they provide a potential treatments for viral diseases (e.g. DNA and RNA virsues).

[0013] Furthermore, METTL3-dependent m6A on endogenous mRNAs regulates recognition of by MAVS-dependent RNA sensors. Depletion of METTL3 enhances endogenous dsRNA recognition and induces an auto-immune response (Gao et al.). This implies that an antitumour immune response might be enhanced by METTL3 inhibition.

[0014] Thus, METTL3 inhibitors may also provide a novel therapeutic approach to enhance an anti-tumour immune response.

References

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[0036] Yimeng Gao, Radovan Vasic, Yuanbin Song, Rhea Teng, Chengyang Liu , Rana Gbyli, Giulia Biancon, Raman Nelakanti, Kirsten Lobben, Eriko Kudo, Wei Liu, Anastasia Ardasheva, Xiaoying Fu, Xiaman Wang, Poorval Joshi, Veronica Lee, Burak Dura, Gabriella Viero, Akiko Iwasaki, Rong Fan, Andrew Xiao, Richard A Flavell, Hua-Bing Li, Toma Tebaldi, Stephanie Halene; Immunity (16 June 2020; Volume 52; 6; p887-1132).

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[0038] An object of this invention is to provide inhibitors of METTL3 activity.

SUMMARY OF THE INVENTION

[0039] In one aspect, the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt thereof.

[0040] 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.

[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 therapy.

[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 a proliferative condition. [0043] 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.

[0044] 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.

[0045] 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 promoting an immune response (e.g. anti-viral or anti-tumour immune response).

[0046] 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 increasing an innate immune response in a subject.

[0047] 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 increasing or enhancing an anti-tumour immune response during immune-oncology therapy.

[0048] 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.

[0049] 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.

[0050] 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.

[0051] 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 viral infection. Suitably, the viral infection is a RNA viral infection. Suitably, the viral infection is human papillomavirus (HPV) or hepatitis.

[0052] 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. [0053] 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.

[0054] 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.

[0055] 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.

[0056] 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 promoting an immune response (e.g. anti-viral or anti-tumour immune response).

[0057] 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 for use in increasing an innate immune response in a subject.

[0058] 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 increasing or enhancing an anti-tumour immune response during immune-oncology therapy.

[0059] 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.

[0060] 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.

[0061] 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.

[0062] 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 viral infection. Suitably, the viral infection is a RNA viral infection. Suitably, the viral infection is human papillomavirus (HPV) or hepatitis. [0063]Inanotheraspect,the presentinvention providesthe use ofa compoundasdefined herein,orapharmaceuticallyacceptablesaltthereof,inthemanufac tureofamedicamentfor useinthetreatmentofaninflammatorydisease.

[0064]In anotheraspect,the presentinvention provides a method ofinhibiting METTL3 activityinvitroorin vivo,saidmethodcomprisingcontactingacellwithaneffectiveamoun tofa compound as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceuticalcompositionasdefinedherein.

[0065]In another aspect, the present invention provides a method of inhibiting cell proliferationinvitroorinvivo,saidmethodcomprisingcontactinga cellwithaneffectiveamount ofacompoundasdefinedherein,orapharmaceuticallyacceptablesalt ,ora pharmaceutical compositionasdefinedherein.

[0066]Inanotheraspect,the presentinventionprovidesa methodofinhibitingmetastasisin vitroorinvivo,saidmethodcomprisingcontactingacellwithaneffec tiveamountofacompound asdefinedherein,orapharmaceuticallyacceptablesalt,orapharmac euticalcompositionas definedherein.

[0067]Inanotheraspect,the presentinvention providesa methodofpromotingan immune response (e.g.anti-viraloranti-tumourimmune response)ina subjectinneedthereof,said method comprising administering to the subject a therapeutically effective amountofa compound as defined herein,ora pharmaceutically acceptable salt,ora pharmaceutical compositionasdefinedherein.

[0068]In anotheraspect,the presentinvention provides a method ofincreasing an innate immune response inasubjectinneedthereof,said method comprising administeringtothe subject a therapeutically effective amount of a compound as defined herein, or a pharmaceuticallyacceptablesalt,orapharmaceuticalcompositiona sdefinedherein.

[0069]Inanotheraspect,thepresentinventionprovidesamethodo fincreasingorenhancing ananti-tumourimmune response during immune-oncologytherapy,said methodcomprising administeringtoasubjectinneedthereofatherapeuticallyeffectiv eamountofacompoundas defined herein,ora pharmaceutically acceptable salt,ora pharmaceuticalcomposition as definedherein.

[0070]Inanotheraspect,the presentinventionprovidesa method oftreating a proliferative disorder,said method comprisingadministeringtoa subjectinneedthereofatherapeutically effectiveamountofacompoundasdefinedherein,orapharmaceuticall yacceptablesalt,ora pharmaceuticalcompositionasdefinedherein. [0071] 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.

[0072] 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.

[0073] 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.

[0074] 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.

[0075] In another aspect, the present invention provides a method of treating a viral infection, 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. Suitably, the viral infection is a RNA viral infection. Suitably, the viral infection is human papillomavirus (HPV) or hepatitis.

[0076] 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.

[0077] 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.

[0078] The present invention further provides a method of synthesising a compound, or a pharmaceutically acceptable salt, as defined herein.

[0079] 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. [0080] 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.

[0081] 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.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

[0082] Unless otherwise stated, the following terms used in the specification and claims have the following meanings set out below.

[0083] 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.

[0084] 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.

[0085] 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.

[0086] 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.

[0087] 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.

[0088] 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.

[0089] An “alkylene” group is an alkyl group that is positioned between and serves to connect two other chemical groups. Thus, “ C _1-3 alkylene” 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.

[0090] The term “C _m-n cycloalkyl” 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 “C _m-n cycloalkyl” also encompasses non-aromatic saturated or partially saturated monocyclic, fused, bridged, or spiro bicyclic carbocyclic ring system(s). The term “C _m-n cycloalkyl” includes both monovalent species and divalent species. Monocyclic “C _m-n cycloalkyl” rings contain from about 3 to 12 (suitably from 3 to 8, most suitably from 5 to 6) ring carbon atoms. Bicyclic “C _{m- n} cycloalkyl” contain from 7 to 17 ring carbon atoms, suitably 7 to 12 ring carbon atoms. Bicyclic “C _m-n cycloalkyl” 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).

[0091] The term “halo” or “halogeno” refers to fluoro, chloro, bromo and iodo.

[0092] 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-2/7-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.

[0093] 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 .

[0094] 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.

[0095] 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.

[0096] 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.

[0097] Examples of six membered heteroaryl groups include but are not limited to pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl and triazinyl.

[0098] 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.

[0099] 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.

[00100] 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.

[00101] 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.

[00102] The term "optionally substituted" refers to either groups, structures, or molecules that are substituted and those that are not substituted. [00103] 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.

[00104] The phrase “compound of the invention” means those compounds which are disclosed herein, both generically and specifically.

Compounds of the invention

[00105] In one aspect, the present invention relates to compounds of the formula (I), or a pharmaceutically acceptable salt thereof, wherein:

X is selected from: , and 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 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, NH ₂ , 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, C _{1- 2} alkoxy or C _1-2 haloalkoxy; and

Q ₁ is hydrogen, cyano, C _1-6 alkyl, C _3-8 cycloalkyl (including a spirocyclic carbocyclic and a bridged C _3-8 cycloalkyl), C _2-3 alkenyl, C _2-3 alkynyl, 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 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) _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; ortionally 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 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) _0-2 R _t1 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;

R _1a’ 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 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, 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 _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; n is 0, 1 or 2; and

Z is selected from one of the following structures: i) wherein:

B ₁ is A ₅ , wherein A ₅ is selected from CR ₁₆ and N, wherein R ₁₆ 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;

B ₂ is A ₆ , wherein A ₆ is selected from N or CR ₁₇ , wherein R ₁₇ , R _H2 , R _H4 and R _H5 are selected from hydrogen, hydroxy, 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-NR _q R _r , - (OCH ₂ CH ₂ )m-OCH ₃ wherein m is an integer from 1 to 6, NR _q R _r , -C(O)-NR _q R _r , -C(O)OR _q , 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, 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 _1-5 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 , whereinR _1ea and R _1fa are H or C _1-2 alkyl;

B ₃ is N or CR _z1 , wherein R _z1 is 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 substituted by one or more of halo, methyl or methoxy;

B ₄ is selected from C or N;

B ₅ is selected from CR _Zi1b or NR _B5N , wherein: R _Zi1b is selected from hydrogen, C _1-4 alkyl, cyano, halo, NH ₂ and C _1-4 alkoxy; and R _B5N is selected from hydrogen or C _1-4 alkyl;

B ₇ is N, NR _Z2N or CR _Z2 , wherein R _Z2 is selected from hydrogen, C _1-4 alkyl, cyano, halo, NH ₂ and C _1-4 alkoxy; and R _Z2N is selected from hydrogen or C _1-4 alkyl;

B ₈ is selected from C or N; with the proviso that no more than four of B ₁ to B ₈ are N.

Y ₂ is A ₇ , wherein 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, C _3-4 cycloalkyl, a 3- to 4- membered heterocyclyl and C _3-4 cycloalkoxy;

Y ₃ is N or CR _z1a wherein R _z1a , is selected from hydrogen, hydroxy, 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;

Y ₄ is C or N

Y ₅ is C-R _Y5 or NR _Y5N , wherein:

R _Y5 is selected from hydrogen, C _1-4 alkyl, cyano, halo, NH ₂ and C _1-4 alkoxy;

R _Y5N is selected from hydrogen or C _1-4 alkyl;

Y ₆ is C-R _Zi2e or N, wherein R _Zi2e is selected from hydrogen, C _1-4 alkyl, cyano, halo, NH ₂ and C _1-4 alkoxy

Y ₇ is O, S, CR _Z2a or N, wherein R _Z2a is selected from hydrogen, C _1-4 alkyl, cyano, halo, NH ₂ and C _1-4 alkoxy;

Y ₈ IS C or N;

Y ₉ is CR _Z3a or N; wherein

R _Z3a is selected from hydrogen, C _1-4 alkyl, cyano, halo, NH ₂ and C _1-4 alkoxy; with the proviso that no more than four of Y ₁ to Y ₈ are N.

X ₁ is N or C-R _Z9 , wherein R _Z9 is selected from hydrogen, halo, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy;

X ₂ is selected from N or CR ₄ wherein: R ₄ is selected from hydrogen, halo, cyano, C1-4 alkyl, C1-4 haloalkyl, C1-4alkoxy, C1-4 haloalkoxy (e.g. hydrogen, halo, cyano and methyl);

X ₃ is N;

X ₄ is N or C;

X ₅ is selected from N, CR ₅ and CR _x5a R _x5b wherein:

R ₅ is selected from hydrogen, halo, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy (e.g. hydrogen, halo, cyano and methyl);

Rx _5a and R _x5b are independently selected from hydrogen, halo, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy (e.g. hydrogen, halo, cyano and methyl); either:

X ₆ is A ₁ and X ₇ is A ₂ ; or

X ₆ is A ₈ and X ₇ is A ₉ or A ₁₁ , wherein:

A1 is selected from CR ₁₂ and N; wherein R ₁₂ is selected from selected from hydrogen, halo, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy and C _1-4 haloalkoxy (e.g. hydrogen, halo, cyano and C _1-4 alkyl); A ₂ is selected from CR ₁₃ and N; wherein R ₁₃ selected from hydrogen, halo, cyano, C _{1- 4} alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy (e.g. hydrogen, halo, cyano, methoxy and methyl);

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

R ₁₉ and R ₂₀ are independently selected from hydrogen, halo, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy (e.g hydrogen, halo, cyano and C _1-4 alkyl);

R ₂₁ is hydrogen or C _1-4 alkyl; A ₉ is selected from CR ₂₂ R ₂₃ and NR ₂₄ ; wherein: R ₂₂ and R ₂₃ are independently selected from selected from hydrogen, halo, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy (e.g. hydrogen, halo, cyano and methyl); R ₂₄ is selected from hydrogen or C _1-4 alkyl A ₁₁ is selected from CR ₂₈ R ₂₉ and NR ₃₀ ; wherein: R ₂₈ and R ₂₉ are selected from hydrogen, halo, methoxy and methyl; R ₃₀ is selected from hydrogen or C _1-4 alkyl.

Xs is selected from CR ₆ , N or CR _X6a R _X6b ; wherein: R ₆ is selected from hydrogen, halo, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy and C _1-4 haloalkoxy;

Rxea and Rxeb are each independently selected from hydrogen, halo, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy and C _1-4 haloalkoxy;

Xg is N or C; with the proviso that no more than four of X ₂ to X ₉ are N. (iv)

Z ₁₀ is N or C-R _Z10 , wherein R _Z10 is selected from hydrogen, halo, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy;;

Z ₁₁ is N or C-R _Z11 , wherein R _Z11 is selected from hydrogen, halo, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy;;

Z ₁₂ is N or C-R _Z12 , wherein R _Z12 is selected from hydrogen, halo, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy;

Z ₁₃ is N or C-R _Z13 , wherein R _Z13 is selected from hydrogen, halo, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy;

Z ₁₄ is N or C-R _Z14 , wherein R _Z14 is selected from hydrogen, halo, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy;

Z ₁₅ is N or C-R _Z15 , wherein R _Z15 is selected from hydrogen, halo, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy;

Z ₁₆ is N or C-R _Z16 , wherein R _Z16 is selected from hydrogen, halo, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy; with the proviso that no more than three of Z ₁₀ to Z ₁₆ are N;

(V)

Q ₇ is CR ₇ or N;

Q ₈ is CR ₈ or N;

Q ₉ is CR ₉ or N;

Q ₁₀ is CR ₁₀ or N;

Q ₁₁ is CR ₁₁ or N;

Q _11a is NR _11N Or CR _11a R _11b , wherein: R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , R _11a and R _11b are each independently selected from hydrogen, NH ₂ , heterocyclyl, halo, cyano, C _1-4 alkoxy, C _1-4 haloalkoxy, C _1-6 alkyl, -CH ₂ OCH ₃ , - CH ₂ SO ₂ CH ₃ , -SO ₂ CH ₃ , -NHC(O)CH ₃ and -C(O)NR _v1 R _v2 , wherein R _v1 and R _v2 are independently selected from hydrogen and methyl; and R _11N is selected from hydrogen, NH ₂ , halo, cyano, and C _1-6 alkyl; or R ₉ and R ₁₀ may be linked together such that, together to the atoms to which they are attached, they form a fused 5- or 6-membered saturated or unsaturated ring system, or R ₁₀ and R ₁₁ may be linked together such that, together to the atoms to which they are attached, they 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 systems, or the heterocyclyl, 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 _1j a, wherein R _1ia and R _1ja are H or C _1-2 alkyl; with the proviso that no more than three of Q ₇ to Q ₁₁ are N; wherein the compound is subject to the following provisos:

(i) Z is not one of the following structures:

wherein:

R ₄ , is selected from hydrogen, halo, cyano and methyl;

R ₅ is selected from hydrogen, halo, cyano and methyl;

R ₆ is selected from hydrogen, halo, cyano and methyl; R ₈ , 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; 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 _z1 a are selected from hydrogen, C _1-4 alkyl, cyano, halo, C _1-4 haloalkyl, C _1- 4haloalkoxy, 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 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 ₁₁ is selected from CR ₂₈ R ₂₉ and NR ₃₀ ;

R ₁₂ is selected from hydrogen, halo, cyano and C _1-4 alkyl; R ₁₃ is selected from hydrogen, halo, cyano, methoxy and methyl; R ₁₆ is selected from hydrogen, halo, cyano, C _1-4 alkyl, 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 ₁₇ is selected from hydrogen, hydroxy, 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 -NR _q R _r , -(OCH ₂ CH ₂ ) _m -OCH ₃ wherein m is an integer from 1 to 6, NR _q R _r , -C(O)-NR _q R _r , -C(O)OR _q ; 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 Rq 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- salkyl, 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 and R ₂₀ 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;

R ₂₁ , R ₂₄ and R ₃₀ are hydrogen; and

(ii) the compound is not:

4-[1-[(6-methylimidazo[1,2-a]pyridin-2-yl)methyl]triazol- 4- yl]isoquinoline; tert-butyl N-[[2-[[4-(4-isoquinolyl)triazol-1-yl]methyl]imidazo[1,2-a]p yridin-6- yl]methyl]carbamate;

N-(cyclobutylmethyl)-1-[2-[[4-(4-isoquinolyl)triazol-1- yl]methyl]imidazo[1,2-a]pyridin- 6-yl]methanamine.

[00106] In another 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:

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 R _1c , R _1d and R _1f are selected from:

(i) C _1-4 alkyl or C _1-4 alkoxy, each of which being optionally subsutited by halo, cyano, hydroxy, C _3-6 cycloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, aryl or heteroaryl; or

(ii) a group of the formula:

—(CR _1c R _1d ) _p -NR _1e R _1f ; wherein p is an integer selected from 0, 1, 2 or 3

R _1c and R _1d are independently selected from:

(i) hydrogen (including deuterium),

(ii) C _1-6 alkyl which is optionally substituted by one more substituents selected from cyano, oxo, hydroxy, C _1-4 alkoxy, halo, C _1-4 haloalkoxy, C _3-6 cycloalkyl, -O-C _3-6 cycloalkyl, NR _1ca R _1da or -S(O) _0-2 R _1ca R _1da , wherein R _1ca and R _1da are H or C _1-2 alkyl; and wherein C _3-6 cycloalkyl and -O-C _3-6 cycloalkyl are optionally further subsitutued with halo, cyano or hydroxy;

(iii) C _3-4 cycloalkyl or 3 to 5 membered heterocyclyl, each of which is optionally substituted by C _1-4 alkyl, C _1-4 haloalkyl, cyano, hydroxy, C _1- 2alkoxy, halo, C _1-2 haloalkoxy, NR _1ca R _1da or -S(O) _0-2 R _1ca R _1da , wherein R _1ca and R _1da are H or C _1-2 alkyl; and;

(iv) 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 6- 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, C _1-2 haloalkoxy, N R _1ca R _1da or -S(O) _0-2 R _1ca R _1da , wherein R _1ca and R _1da are H or C _1-2 alkyl;

R _1e and R _1f are each independently selected from:

(i) hydrogen (including deuterium);

(ii) C _1-6 alkyl which is optionally substituted by one more substituents selected from cyano, oxo, 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;

(iii) a group with the formula:

— (CR _1g R _1h ) _q — T ₁ wherein: q is 0, 1, 2, 3, 4, 5 or 6;

R _1g and R _1h are independently selected from: a) hydrogen (including deuterium); b) C _1-6 alkyl which is optionally substituted by one more substituents selected from cyano, oxo, hydroxy, C _1-4 alkoxy, halo, C _1-4 haloalkoxy, -O-C _3-6 cycloalkyl, NR _1ga R _1ha or -S(O) _{0- 2} R _1ga R _1ha , wherein R _1ga and R _1ha are H or C _1-2 alkyl; and wherein -O-C _3-6 cycloalkyl is optionally subsitutued with halo, cyano or hydroxy; c) an aryl-C _1-6 alkyl, heteroarylC _1-6 alkyl, C _3-6 cycloalkyl or C _3-6- cycloalkylC _1-6 alkyl group, each of which is 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 _1ga R _1ha or -S(O) _0-2 R _1ga R _1ha , wherein R _1ga and R _1ha are H or C _1-2 alkyl; or d) or R _1g and R _1h are optionally linked together such that, together with the carbon atom to which they are attached, they form a 3- to 6-membered cycloalkyl or heterocyclic ring which is 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 _1ga R _1ha or -S(O) _0-2 R _1ga R _1ha , wherein R _1ga and R _1ha are H or C _1-2 alkyl; and T ₁ is selected from hydrogen, cyano, hydroxy, NR _1t R _2t or S(O) _0-2 R _1t R _2t (wherein R _1t and R _2t are H or C _1-4 alkyl), C _{3- 8} cycloalkyl, C _2-3 alkenyl, C _2-3 alkynyl, aryl, heterocyclyl, heteroaryl, a spirocyclic carbocyclic or heterocyclic ring system, a bridged C _{3- 8} cycloalkyl, a bridged bicyclic C _5-12 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, C _1-2 haloalkoxy, NR _3t R _4t or -S(O) _{0- 2} R _3t R _4t , wherein R _3t and R _4t are H or C _1-2 alkyl; 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 _1-4 alkyl, C _{1- 4} haloalkyl, cyano, hydroxy, C _1-4 alkoxy, halo, C _1-4 haloalkoxy, N R _1i R _1j or -S(O) _{0- 2} R _1i R _1j , wherein R _1i and R _1j are H or C _1-4 alkyl, and/or the mono- or bicyclic hetereocyclic ring formed by R _1e and R _1f 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 _1-4 alkyl, C _1-4 haloalkyl, cyano, hydroxy, C _{1- 4} alkoxy, halo, C _1-4 haloalkoxy, NR _1i R _1j or -S(O) _0-2 R _1i R _1j , wherein R _1i and R _1j are H or C _1-4 alkyl;

R _1a’ 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: 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, 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 _3i1 , 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 _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; n is 0, 1 or 2; and

Z is selected from:

wherein:

R ₄ is selected from hydrogen, halo, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy (e.g. hydrogen, halo, cyano and methyl);

R ₅ is selected from hydrogen, halo, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy (e.g. hydrogen, halo, cyano and methyl); R ₆ is selected from hydrogen, halo, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy (e.g. hydrogen, halo, cyano and methyl); R ₁₂ is selected from hydrogen, halo, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy (e.g. hydrogen, halo, cyano and C _1-4 alkyl); R ₁₃ is selected from hydrogen, halo, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy (e.g. hydrogen, halo, cyano, methoxy and methyl); R ₇ , R ₉ and R ₁₁ are independently selected from hydrogen, NH ₂ , halo, cyano, C _1-4 alkoxy, C _1-4 haloalkoxy and C _1-6 alkyl; R ₈ and R ₁₀ are independently selected from halo, cyano, C _1-4 alkoxy, C _1-4 haloalkoxy, C _1-6 alkyl, -CH ₂ OCH ₃ , -CH ₂ SO ₂ CH ₃ , -SO ₂ CH ₃ , -NHC(O)CH ₃ and - C(O)NR _v1 R _v2 , wherein R _v1 and R _v2 are independently selected from hydrogen and methyl;

R _11N is selected from hydrogen and C _1-6 alkyl; R _Z1 and R _Z1 a 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;

R _Zi1b is selected from hydrogen, C _1-4 alkyl, cyano, halo, NH ₂ and C _1-4 alkoxy;

R _Zi2e is selected from hydrogen, C _1-4 alkyl, cyano, halo, NH ₂ and C _1-4 alkoxy;

R _Y5N is C _1-4 alkyl R _Z2N is selected from hydrogen or C _1-4 alkyl

R _Z9 is selected from hydrogen, halo, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy;

R _Z10 is selected from hydrogen, halo, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy; R _Z11 is selected from hydrogen, halo, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy;

R _Z12 is selected from hydrogen, halo, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy;

R _Z13 is selected from hydrogen, halo, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy;

R _Z14 is selected from hydrogen, halo, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy;

R _Z15 is selected from hydrogen, halo, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy;

R _Z16 is selected from hydrogen, halo, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy;;

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;

R ₁₅ is selected from hydrogen, halo, cyano, methoxy and methyl; R ₁₆ and R ₁₈ , are selected from hydrogen, halo, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _1- 4haloalkyl, C _1-4 haloalkoxy, C _3-4 cycloalkyl, a 3- to 4-membered heterocyclyl and C _3-4 - cycloalkoxy; R ₁₇ 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), - (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, 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 _1-5 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 ₁₉ is selected from hydrogen, halo, cyano and C _1-4 alkyl; and R ₂₂ is selected from hydrogen, halo, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy (e.g. hydrogen, halo, cyano and methyl).

[00107] In another aspect, the present invention relates to compounds of the formula (I), or a pharmaceutically acceptable salt thereof,

X - Y - Z

(l) wherein:

X is selected from: , and wherein:

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

R _1b , R _1d and R _1f are selected from:

(i) C _1-4 alkyl or C _1-4 alkoxy, each of which being optionally subsutited by halo, cyano, hydroxy, C _3-6 cycloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, aryl or heteroaryl; or

(ii) a group of the formula:

—(CR _1c R _1d ) _p -NR _1e R _1f ; wherein p is an integer selected from 0, 1, 2 or 3; R _1c and R _1d are independently selected from:

(i) hydrogen (including deuterium),

(ii) C _1-6 alkyl which is optionally substituted by one more substituents selected from cyano, oxo, hydroxy, C _1-4 alkoxy, halo, C _1-4 haloalkoxy, C _3-6 cycloalkyl, -O-C _3-6 cycloalkyl, NR _1ca R _1da or -S(O) _0-2 R _1ca R _1da , wherein R _1ca and R _1da are H or C _1-2 alkyl; and wherein C _3-6 cycloalkyl and -O-C _3-6 cycloalkyl are optionally further subsitutued with halo, cyano or hydroxy;

(iii) C _3-4 cycloalkyl or 3 to 5 membered heterocyclyl, each of which is optionally substituted by C _1-4 alkyl, C _1-4 haloalkyl, cyano, hydroxy, C _1- 2alkoxy, halo, C _1-2 haloalkoxy, NR _1ca R _1da or -S(O) _0-2 R _1ca R _1da , wherein R _1ca and R _1da are H or C _1-2 alkyl; and; (iv) 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 6-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, C _1-2 haloalkoxy, NR _1ca R _1d a or -S(O) _0-2 R _1ca R _1da , wherein R _1ca and R _1da are H or C _1-2 alkyl;

R _1e and R _1f are each independently selected from:

(i) hydrogen (including deuterium);

(ii) C _1-6 alkyl which is optionally substituted by one more substituents selected from cyano, oxo, 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;

(iii) a group with the formula:

—(CR _1g R _1h ) _q —T ₁ wherein: q is 0, 1 , 2, 3, 4, 5 or 6; R _1g and R _1h are independently selected from: a) hydrogen (including deuterium); b) C _1-6 alkyl which is optionally substituted by one more substituents selected from cyano, oxo, hydroxy, C _1-4 alkoxy, halo, C _1-4- haloalkoxy, -O-C _3-6 cycloalkyl, NR _1ga R _1ha or -S(O) _0-2 R _1ga R _1ha , wherein R _1ga and R _1ha are H or C _1-2 alkyl; and wherein -O-C _{3- 6} cycloalkyl is optionally subsitutued with halo, cyano or hydroxy; c) an aryl-C _1-6 alkyl , heteroarylC _1-6 alkyl, C _3-6 cycloalkyl or C _3-6 cycloalkylC _1-6 alkyl group, each of which is 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 _1ga R _1ha or -S(O) _0-2 R _1ga R _1ha , wherein R _1ga and R _1ha are H or C _1-2 alkyl; or d) or R _1g and R _1h are optionally linked together such that, together with the carbon atom to which they are attached, they form a 3- to 6-membered cycloalkyl or heterocyclic ring which is 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 _1ga R _1ha or -S(O) ₀ -2R _1ga R _1ha , wherein R _1ga and R _1ha are H or C _{1- 2} alkyl; and T ₁ is selected from hydrogen, cyano, hydroxy, NR _1t R _2t or S(O) _0-2 R _1t R _2t (wherein R _1t and R _2t are H or C _1-4 alkyl), C _3-8 cycloalkyl, C _{2- 3} alkenyl, C _2-3 alkynyl, aryl, heterocyclyl, heteroaryl, a spirocyclic carbocyclic or heterocyclic ring system, a bridged C _3-8 cycloalkyl, a bridged bicyclic C _5-12 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, C _1-2 haloalkoxy, NR _3t R _4t or -S(O) _0-2 R _3t R _4t , wherein R _3t and R _4t are H or C _1-2 alkyl; 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 _1-4 alkyl, C _{1- 4} haloalkyl, cyano, hydroxy, C _1-4 alkoxy, halo, C _1-4 haloalkoxy, N R _1i R _1j or -S(O) _{0- 2} R _1i R _1j , wherein R _1i and R _1j are H or C _1-4 alkyl, and/or the mono- or bicyclic hetereocyclic ring formed by R _1e and R _1f 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 _1-4 alkyl, C _1-4 haloalkyl, cyano, hydroxy, C _{1- 4} alkoxy, halo, C _1-4 haloalkoxy, NR _1i R _1j or -S(O) _0-2 R _1i R _1j , wherein R _1i and R _1j are H or C _1-4 alkyl;

R _1a’ 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 L _2a is absent or Cisalkylene 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, 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 _3i1 , 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 _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; n is 0, 1 or 2; and

Z is selected from:

and wherein:

R ₄ is selected from hydrogen, halo, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy (e.g. hydrogen, halo, cyano and methyl);

R ₅ is selected from hydrogen, halo, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy (e.g. hydrogen, halo, cyano and methyl);

R ₆ is selected from hydrogen, halo, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy (e.g. hydrogen, halo, cyano and methyl); R ₁₂ is selected from hydrogen, halo, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy (e.g. hydrogen, halo, cyano and C _1-4 alkyl); R ₁₃ is selected from hydrogen, halo, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy (e.g. hydrogen, halo, cyano, methoxy and methyl); either: a) R ₇ , R ₉ and R ₁₁ are independently selected from hydrogen, NH ₂ , halo, cyano, C _1-4 alkoxy, C _1-4 haloalkoxy and C _1-6 alkyl; R ₈ and R ₁₀ are independently selected from halo, cyano, C _1-4 alkoxy, C _1-4 haloalkoxy, C _1-6 alkyl, -CH ₂ OCH ₃ , -CH ₂ SO ₂ CH ₃ , -SO ₂ CH ₃ , - NHC(O)CH ₃ and -C(O)NR _v1 R _v2 , wherein R _v1 and R _v2 are independently selected from hydrogen and methyl; or b) R ₈ , R ₉ , R ₁₀ and R ₁₁ are independently selected from hydrogen, NH ₂ , halo, cyano, C _1-4 alkoxy, C _1-4 haloalkoxy and C _1-6 alkyl, -CH ₂ OCH ₃ , - CH ₂ SO ₂ CH ₃ , -SO ₂ CH ₃ , -NHC(O)CH ₃ and -C(O)NR _v1 R _v2 , wherein R _v1 and R _v2 are independently selected from hydrogen and methyl with the proviso that at least one of R ₈ , R ₉ , R ₁₀ and R ₁₁ is C _1-4 alkoxy or C _1-4 haloalkoxy;

R _11N is selected from hydrogen and C _1-6 alkyl; R _Z1 and R _Z1a selected from hydrogen, C _1-4 alkyl, cyano, halo, C _1-4 haloalkyl, C _1- 4haloalkoxy, 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;

R _Zi1b is selected from hydrogen, C _1-4 alkyl, cyano, halo, NH ₂ and C _1-4 alkoxy;

R _Zi2e is selected from hydrogen, C _1-4 alkyl, cyano, halo, NH ₂ and C _1-4 alkoxy;

R _Y5N is C _1-4 alkyl R _Z2N is selected from hydrogen or C _1-4 alkyl

R _Z9 is selected from hydrogen, halo, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy;

R _Z10 is selected from hydrogen, halo, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy; R _Z11 is selected from hydrogen, halo, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy;

R _Z12 is selected from hydrogen, halo, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy;

R _Z13 is selected from hydrogen, halo, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy;

R _Z14 is selected from hydrogen, halo, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy;

R _Z15 is selected from hydrogen, halo, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy;

R _Z16 is selected from hydrogen, halo, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy;;

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;

R ₁₅ is selected from hydrogen, halo, cyano, methoxy and methyl; R ₁₆ and R ₁₈ are selected from hydrogen, halo, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _1- 4haloalkyl, C _1-4 haloalkoxy, C _3-4 cycloalkyl, a 3- to 4-membered heterocyclyl and C _3-4 - cycloalkoxy; R ₁₇ 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), - (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, 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 _1-5 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 ₁₉ is selected from hydrogen, halo, cyano and C _1-4 alkyl; and R ₂₂ is selected from hydrogen, halo, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy (e.g. hydrogen, halo, cyano and methyl).

[00108] 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 _3oI , R _3o2 , R _3p1 , R _3p2 , R _3q1 , R _3q2 , R _3r1 , R _3r2 , R _3s1 , R _3s2 , n, R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , R _11N , R ₁₂ , R ₁₃ , R ₁₆ , R ₁₇ , R ₁₈ , R ₁₉ , R ₂₀ , R ₂₁ , R ₂₂ , R ₂₃ , R ₂₄ , R ₂₅ , R ₂₆ , R ₂₈ , R ₂₉ , R ₃₀ , R _Z1 , R _Z1a , R _Z2 , R _Z2a , R _Z3a , R _Zi1b , R _Zi2e , A ₅ , A ₆ , A ₇ , R _Z2N , R _Y5N , R _11N and any associated substituent groups has any of the meanings defined hereinbefore or in any one of paragraphs (1) to (176) hereinafter: -

(1) 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;

(2) 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;

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

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

(5) R _1a , R _1c and R _1e are hydrogen;

(6) R _1b , R _1d and R _1f are selected from:

(i) C _1-4 alkyl or C _1-4 alkoxy, each of which being optionally subsutited by halo, cyano, hydroxy, C _3-6 cycloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, aryl or heteroaryl; or

(ii) a group of the formula:

— (CR _1c R _1d ) _p - NR _1e R _1f ; wherein p is an integer selected from 0, 1, 2 or 3 R _1c and R _1d are independently selected from:

(i) hydrogen (including deuterium),

(ii) C _1-6 alkyl which is optionally substituted by one more substituents selected from cyano, oxo, hydroxy, C _1-4 alkoxy, halo, C _1-4 haloalkoxy, C _{3- 6} cycloalkyl, -O-C _3-6 cycloalkyl, NR _1ca R _1da or -S(O) _0-2 R _1ca R _1da , wherein R _1ca and R _1da are H or C _1-2 alkyl; and wherein C _3-6 cycloalkyl and -O-C _{3- 6} cycloalkyl are optionally further subsitutued with halo, cyano or hydroxy;

(iii) C _3-4 cycloalkyl or 3 to 5 membered heterocyclyl, each of which is optionally substituted by C _1-4 alkyl, C _1-4 haloalkyl, cyano, hydroxy, C _{1- 2} alkoxy, halo, C _1-2 haloalkoxy, NR _1ca R _1da or -S(O) _0-2 R _1ca R _1da , wherein R _1ca and R _1da are H or C _1-2 alkyl; and;

(iv) 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 6-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, C _1-2- haloalkoxy, NR _1ca R _1da or -S(O) _0-2 R _1ca R _1da , wherein R _1ca and R _1da are H or C _1-2 alkyl; R _1e and R _1f are each independently selected from:

(i) hydrogen (including deuterium);

(ii) C _1-6 alkyl which is optionally substituted by one more substituents selected from cyano, oxo, 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;

(iii) a group with the formula:

—(CR _1g R _1h ) _q —T ₁ wherein: q is 0, 1 , 2, 3, 4, 5 or 6; R _1g and R _1h are independently selected from: a) hydrogen (including deuterium); b) C _1-6 alkyl which is optionally substituted by one more substituents selected from cyano, oxo, hydroxy, C _1-4 alkoxy, halo, C _1-4 haloalkoxy, -O-C _3-6 cycloalkyl, NR _1ga R _1ha or -S(O)o- 2R _1ga R _1ha , wherein R _1ga and R _1ha are H or C _1-2 alkyl; and wherein -O-C _3-6 cycloalkyl is optionally subsitutued with halo, cyano or hydroxy; c) an aryl-C _1-6 alkyl, heteroarylC _1-6 alkyl, C _3-6 cycloalkyl or C _3-6 cycloalkylC _1-6 alkyl group, each of which is 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 _1ga R _1ha or -S(O) _0-2 R _1ga R _1ha , wherein R _1ga and R _1ha are H or C _1-2 alkyl; or d) or R _1g and R _1h are optionally linked together such that, together with the carbon atom to which they are attached, they form a 3- to 6-membered cycloalkyl or heterocyclic ring which is 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 _1ga R _1ha or -S(O) _0-2 R _1ga R _1ha , wherein R _1ga and R _1ha are H or C _1-2 alkyl; and T1 is selected from hydrogen, cyano, hydroxy, NR _1t R _2t or S(O) _0-2 R _1t R _2t (wherein R _1t and R _2t are H or C _1-4 alkyl), C _3-8 cycloalkyl, C _{2- 3} alkenyl, C _2-3 alkynyl, aryl, heterocyclyl, heteroaryl, a spirocyclic carbocyclic or heterocyclic ring system, a bridged C _3-8 cycloalkyl, a bridged bicyclic C _5-12 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, C _1-2 haloalkoxy, NR _3t R _4t or -S(O) _0-2 R _3t R _4t , wherein R _3t and R _4t are H or C _1-2 alkyl; 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 _1-4 alkyl, C _{1- 4} haloalkyl, cyano, hydroxy, C _1-4 alkoxy, halo, C _1-4 haloalkoxy, NR _1i R _1j or -S(O) _{0- 2} R _1i R _1j , wherein R _1i and R _1j are H or C _1-4 alkyl, and/or the mono- or bicyclic hetereocyclic ring formed by R _1e and R _1f 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 _1-4 alkyl, C _1-4 haloalkyl, cyano, hydroxy, C _{1- 4} alkoxy, halo, C _1-4 haloalkoxy, NR _1i R _1j or -S(O) _0-2 R _1i R _1j , wherein R _1i and R _1j are H or C _1-4 alkyl;

(7) R _1b , R _1d and R _1f are selected from: (i) C _1-4 alkyl optionally subsutited by halo, cyano, hydroxy, C _3-6 cycloalkyl, a 3 to 6 membered heterocyclyl, C _1-4 alkoxy, C _1-4 haloalkoxy, aryl or heteroaryl; or

(ii) 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),

(ii) C _1-3 alkyl which is optionally substituted by one more substituents selected from cyano, oxo, hydroxy, C _1-4 alkoxy, halo, C _1-4 haloalkoxy, - O-C _3-6 cycloalkyl, NR _1ca R _1da or -S(O) _0-2 R _1ca R _1da , wherein R _1ca and R _1da are H or C _1-2 alkyl; and wherein C _3-6 cycloalkyl and -O-C _3-6 cycloalkyl are optionally subsitutued with halo, cyano or hydroxy;

(iii) C _3-4 cycloalkyl or 3 to 5 membered heterocyclyl, each of which is optionally substituted by C _1-4 alkyl, C _1-4 haloalkyl, cyano, hydroxy, C _{1- 2} alkoxy, halo, C _1-2 haloalkoxy, NR _1ca R _1da or -S(O) _0-2 R _1ca R _1da , wherein R _1ca and R _1da are H or C _1-2 alkyl; and;

(iv) 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, C _1-2 - haloalkoxy, NR _1ca R _1da or -S(O) _0-2 R _1ca R _1da , wherein R _1ca and R _1da are H or C _1-2 alkyl; R _1e and R _1f are each independently selected from:

(i) hydrogen (including deuterium);

(ii) C _1-6 alkyl which is optionally substituted by one more substituents selected from cyano, oxo, 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;

(iii) a group with the formula:

—(CR _1g R _{1 h} ) _q —T ₁ wherein: q is 0, 1, 2 or 3; R _1g and R _1h are independently selected from: a) hydrogen (including deuterium); or b) C _1-3 alkyl which is optionally substituted by one more substituents selected from cyano, oxo, hydroxy, C _1-3 alkoxy, halo, C _1-4 haloalkoxy, -O-C _3-4 cycloalkyl, wherein -O-C _{3- 4} cycloalkyl is optionally subsitutued with halo, cyano or hydroxy, NR _1ca R _1da or -S(O) _0-2 R _1ca R _1da , wherein R _1ca and R _1da are H or C _1-2 alkylNR _1ga R _1ha or -S(O) _0-2 R _1ga R _1ha , wherein R _1ga and R _1ha are H or C _1-2 alkyl; c) or R _1g and R _1h are optionally linked together such that, together with the carbon atom to which they are attached, they form a 3- to 6-membered cycloalkyl or 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, NR _1ga R _1ha or -S(O) _0-2 R _1ga R _1ha , wherein R _1ga and R _1ha are H or C _1-2 alkyl; and T ₁ is selected from hydrogen, halo, C _1-4 alkyl, C _1-4 haloalkyl, cyano, hydroxy, NR _1t R _2t or -S(O) _0-2 R _1t R _2t (wherein R _1t and R _2t are H or C _1-4 alkyl), C _3-8 cycloalkyl, C _2-3 alkenyl, C _2-3 alkynyl, aryl, heterocyclyl, a mono- or bicyclic heteroaryl, a spirocyclic carbocyclic or heterocyclic ring system, a bridged C _3-8 cycloalkyl, a bridged bicyclic C _5-12 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, C _1-2 - haloalkoxy, C _3-6 cycloalkyl, NR _3t R _4t or -S(O) _0-2 R _3t R _4t , wherein R _3t and R _4t are H or C _1-2 alkyl;

(iv) 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 _1-4 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, cyano, hydroxy, C _1-4 alkoxy, halo, C _1-4 haloalkoxy, NR _1i R _1j or -S(O) _0-2 R _1i R _1j , wherein R _1i and R _1j are H or C _1-4 alkyl, and/or the mono- or bicyclic hetereocyclic ring formed by R _1e and R _1f 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 _1-4 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, cyano, hydroxy, C _1-4 alkoxy, halo, C _1-4 haloalkoxy, NR _1i R _1j or -S(O) _{0- 2} R _1i R _1j , wherein R _1i and R _1j are H or C _1-4 alkyl; wherein any alkyl, alkoxy or C _3-6 cycloalkyl is further optionally substituted by one or more substituents selected from cyano, hydroxy, halo, NR _1k R _1l or -S(O) _0-2 R _1k R _1l , wherein R _1k and R _1l are H or C _1-4 alkyl;

(8) R _1b , R _1d and R _1f are 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, oxo, 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 subsitutued with halo, cyano or hydroxy,

(iii) C _3-4 cycloalkyl which is optionally substituted by C _1-4 alkyl, C _1-4 haloalkyl, cyano, hydroxy, C _1-2 alkoxy, halo, C _1-2 haloalkoxy or NR _1ca R _1da ; and;

(iv) 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, C _1-2 - haloalkoxy, NR _1ca R _1da or -S(O) _0-2 R _1ca R _1da , wherein R _1ca and R _1da are H or C _1-2 alkyl; R _1e and R _1f are each independently selected from:

(i) hydrogen (including deuterium);

(ii) C _1-6 alkyl which is optionally substituted by one more substituents selected from cyano, oxo, hydroxy, C _1-2 alkoxy, halo, C _1-2 haloalkoxy, NH ₂ ;

(iii) a group with the formula: —(CR _1g R _{1 h} ) _q —T ₁ wherein: q is 0, 1 , 2 or 3; R _1g and R _1h are independently selected from: a) hydrogen (including deuterium); or b) C _1-6 alkyl which is optionally substituted by one more substituents selected from cyano, oxo, hydroxy, C _1-4 alkoxy, halo, C _1-4 haloalkoxy, -O-C _{3- 6} cycloalkyl, NR _1ca R _1da or -S(O) _0-2 R _1ca R _1da , wherein R _1ca and R _1da are H or Ci.

₂ alkylNR _1ga R _1ha or -S(O) _0-2 R _1ga R _1ha , wherein R _1ga and R _1ha are H or C _1-2 alkyl; and wherein -O-C _{3- 6} cycloalkyl is optionally subsitutued with halo, cyano or hydroxy, c) or R _1g and R _1h are optionally linked together such that, together with the carbon atom to which they are attached, they form a 3- to 6- membered cycloalkyl or 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, NR _1ga R _1ha or -S(O) _0-2 R _1ga R _1ha , wherein R _1ga and R _1ha are H or C _1-2 alkyl; and T ₁ is selected from hydrogen, halo, C _1-4 alkyl, C _1-4 haloalkyl, cyano, hydroxy, NR _1t R _2t or -S(O) _0-2 R _1t R _2t (wherein R _1t and R ₂ t are H or C _1-4 alkyl) , C _3-8 cycloalkyl, C _2-3 alkenyl, C _2-3 alkynyl, aryl, heterocyclyl, a mono- or bicyclic heteroaryl, a spirocyclic carbocyclic or heterocyclic ring system, a bridged C _{3- 6} cycloalkyl, a bridged bicyclic C _5-12 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, C _1-2 haloalkoxy, C _3-6 cycloalkyl, NR _3t R _4t or -S(O) _0-2 R _3t R _4t , wherein R _3t and R _4t are H or C _1-2 alkyl; (iv) 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 _1-4 alkyl, C _{1- 4} haloalkyl, C _3-6 cycloalkyl, cyano, hydroxy, C _1-4 alkoxy, halo, C _1-4 haloalkoxy, NR _1i R _1j or -S(O) _0-2 R _1i R _1j , wherein R _1i and R _1j are H or C _1-4 alkyl, and/or the mono- or bicyclic hetereocyclic ring formed by R _1e and R _1f 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 _1-4 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, cyano, hydroxy, C _1-4 alkoxy, halo, C _1-4 haloalkoxy, NR _1i R _1j or -S(O) _0-2 R _1i R _1j , wherein R _1i and R _1j are H or C _1-4 alkyl; wherein any alkyl, alkoxy or C _3-6 cycloalkyl is further optionally substituted by one or more substituents selected from cyano, hydroxy, halo, NR _1k R _1l or -S(O) _0-2 R _1k R _1l , wherein R _1k and R _1l are H or C _1-4 alkyl.

(9) R _1b , R _1d and R _1f are 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),

(ii) C _1-3 alkyl which is optionally substituted by one more substituents selected from cyano, oxo, hydroxy, C _1-3 alkoxy, halo, C _1-43 haloalkoxy, -O-C _3-4 cycloalkyl, or NH ₂ ; 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, C _1-2 haloalkoxy, NR _1ca R _1da or -S(O) _0-2 R _1ca R _1da , wherein R _1ca and R _1da are H or C _1-2 alkyl; R ₁ e _e is selected from:

(i) hydrogen (including deuterium);

(ii) C _1-3 alkyl which is optionally substituted by one more substituents selected from cyano, oxo, hydroxy, C _1-2 alkoxy, halo, C _1-2 haloalkoxy and NH ₂ ; and R _1f is selected from:

(i) C _1-6 alkyl which is optionally substituted by one more substituents selected from cyano, oxo, hydroxy, C _1-2 alkoxy, halo, C _1-2 haloalkoxy and NH ₂ ;

(ii) a group with the formula:

—(CR _1g R _{1 h} ) _q —T ₁ wherein: q is 1 , 2 or 3; R _1g and R _1h are independently selected from: a) hydrogen (including deuterium); or b) C _1-6 alkyl which is optionally substituted by one more substituents selected from cyano, oxo, hydroxy, C _1-4 alkoxy, halo, C _1-4 haloalkoxy, -O-C _{3- 6} cycloalkyl, NR _1ca R _1da or -S(O) _0-2 R _1ca R _1da , wherein R _1ca and R _1da are H or C _{1- 2} alkylNR _1ga R _1ha or -S(O) _0-2 R _1ga R _1ha , wherein R _1ga and R _1ha are H or C _1-2 alkyl; and wherein -O-C _3-6 cycloalkyl is optionally subsitutued with halo, cyano or hydroxy; c) or R _1g and R _1h are optionally linked together such that, together with the carbon atom to which they are attached, they form a 3- to 4-membered cycloalkyl or 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, NR _1ga R _1ha or -S(O) _0-2 R _1ga R _1ha , wherein R _1ga and R _1ha are H or C _1-2 alkyl; and T ₁ is selected from hydrogen, halo, C _1-4 alkyl, C _1-4 haloalkyl, cyano, hydroxy, NR _1t R _2t or -S(O) _0-2 R _1t R _2t (wherein R _1t and R _2t are H or C _1-4 alkyl) , C _{3- 8} cycloalkyl, C _2-3 alkenyl, C _2-3 alkynyl, aryl, heterocyclyl, a mono- or bicyclic heteroaryl, a spirocyclic carbocyclic or heterocyclic ring system, a bridged C _{3- 8} cycloalkyl, a bridged bicyclic C _5-12 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, C _1-2- haloalkoxy, C _3-6 cycloalkyl, NR _3t R _4t or -S(O) _0-2 R _3t R _4t , wherein R _3t and R _4t are H or C _1-2 alkyl; 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 _1-4 alkyl, C _1-4 haloalkyl, C _{3- 6} cycloalkyl, cyano, hydroxy, C _1-4 alkoxy, halo, C _1-4 haloalkoxy, NR _1i R _1j or -S(O) _{0- 2} R _1i R _1j , wherein R _1i and R _1j are H or C _1-4 alkyl, and/or the mono- or bicyclic hetereocyclic ring formed by R _1e and R _1f 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 _1-4 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, cyano, hydroxy, C _1-4 alkoxy, halo, C _1-4 haloalkoxy, NR _1i R _1j or -S(O) _0-2 R _1i R _1j , wherein R _1i and R _1j are H or C _1-4 alkyl; wherein any alkyl, alkoxy or C _3-6 cycloalkyl is further optionally substituted by one or more substituents selected from cyano, hydroxy, halo, NR _1k R _1l or -S(O) _0-2 R _1k R _1l , wherein R _1k and R _1l are H or C _1-4 alkyl.

(10) R _1b , R _1d and R _1f are 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);

(ii) C _1-3 alkyl which is optionally substituted by one more substituents selected from cyano, oxo, 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 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, oxo, hydroxy, C _1-2 alkoxy, halo, C _1-2 haloalkoxy and NH ₂ ; R _1f is a group with the formula:

—(CR _1g R _{1 h} ) _q —T ₁ wherein: q is 1 , 2 or 3; R _1g and R _1h are independently selected from: a) hydrogen (including deuterium); or b) C _1-3 alkyl which is optionally substituted by one more substituents selected from cyano, oxo, hydroxy, C _{1- 4} alkoxy, halo, C _1-4 haloalkoxy, -O-C _3-6 cycloalkyl, wherein -O-C _3-6 cycloalkyl is optionally subsitutued with halo, cyano or hydroxy; c) or R _1g and R _1h are optionally linked together such that, together with the carbon atom to which they are attached, they form a 3- to 4-membered cycloalkyl or 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 or C _1-2- haloalkoxy; and T ₁ is selected from halo, C _1-4 alkyl, C _1-4 haloalkyl, cyano, hydroxy, NR _1t R _2t or -S(O) _0-2 R _1t R _2t (wherein R _1t and R _2t are H or C _1-4 alkyl), C _3-8 cycloalkyl, C _{2- 3} alkenyl, C _2-3 alkynyl, aryl, heterocyclyl, a mono- or bicyclic heteroaryl, a spirocyclic carbocyclic or heterocyclic ring system, a bridged C _3-8 cycloalkyl, a bridged bicyclic C _5-12 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, C _1-2 haloalkoxy, C _{3- 6} cycloalkyl, NR _3t R _4t or -S(O) _0-2 R _3t R _4t , wherein R _3t and R _4t are H or C _1-2 alkyl; 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 _1-4 alkyl, C _1-4 haloalkyl, C _{3- 6} cycloalkyl, cyano, hydroxy, C _1-4 alkoxy, halo, C _1-4 haloalkoxy, NR _1i R _1j or -S(O) _0-2 R _1i R _1j , wherein R _1i and R _1j are H or C _1-4 alkyl, and/or the mono- or bicyclic hetereocyclic ring formed by R _1e and R _1f 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 _1-4 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, cyano, hydroxy, C _1-4 alkoxy, halo, C _1- 4haloalkoxy, NR _1i R _1j or -S(O) _0-2 R _1i R _1j , wherein R _1i and R _1j are H or C _1-4 alkyl; wherein any alkyl, alkoxy or C _3-6 cycloalkyl is further optionally substituted by one or more substituents selected from cyano, hydroxy, halo, NR _1k R _1l or -S(O) _0-2 R _1k R _1l , wherein R _1k and R _1l are H or C _1-4 alkyl.

(11) R _1b , R _1d and R _1f are 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),

(ii) C _1-3 alkyl which is optionally substituted by one more substituents selected from cyano, oxo, 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 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, oxo, hydroxy, C _1-2 alkoxy, halo, C _1-2 haloalkoxy and NH ₂ ; R _1f is a group with the formula:

—(CR _1g R _{1 h} ) _q —T ₁ wherein: q is 1 or 2; R _1g and R _1h are independently selected from: a) hydrogen (including deuterium); or b) C _1-3 alkyl, which is optionally substituted by one more substituents selected from cyano, oxo, 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 T ₁ is selected from C _1-4 alkyl, C _3-8 cycloalkyl, aryl, heterocyclyl, heteroaryl, a spirocyclic carbocyclic or heterocyclic ring system, a bridged C _3-8 cycloalkyl, a bridged bicyclic C _5-12 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, C _1-2 haloalkoxy or C _{3- 6} cycloalkyl,; 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, C _1-2 haloalkyl, C _{3- 6} cycloalkyl, cyano, hydroxy, C _1-2 alkoxy, halo, C _1-2 haloalkoxy, NR _1i R _1j or-S(O) _0-2 R _1i R _1j , wherein R _1i and R _1j are H or C _1-2 alkyl, and/or the mono- or bicyclic hetereocyclic ring formed by R _1e and R _1f 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 _3-6 cycloalkyl, cyano, hydroxy, C _1-2 alkoxy, halo, C _1-2 haloalkoxy, NR _1i R _1j or - S(O) _0-2 R _1i R _1j , wherein R _1i and R _1j are H or C _1-2 alkyl; wherein any alkyl, alkoxy or C _3-6 cycloalkyl is further optionally substituted by one or more substituents selected from cyano, hydroxy, halo, NR _1k R _1l or -S(O) _0-2 R _1k R _1l , wherein R _1k and R _1l are H or C _1-4 alkyl.

(12) R _1b , R _1d and R _1f are 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, oxo, 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 _{1 h} ) _q —T ₁ wherein: 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, oxo, hydroxy, C _1-2 alkoxy, halo or C _1-2 haloalkoxy; and T ₁ is selected from C _1-4 alkyl, C _3-8 cycloalkyl, aryl, heterocyclyl, a mono- or bicyclic heteroaryl, a spirocyclic carbocyclic or heterocyclic ring system, a bridged C _3-8 cycloalkyl, a bridged bicyclic C _5-12 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, C _1-2 haloalkoxy or C _3-6 cycloalkyl; 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, C _1-2 haloalkyl, C _{3- 6} cycloalkyl, cyano, hydroxy, C _1-2 alkoxy, halo or C _1-2 haloalkoxy, and/or the mono- or bicyclic hetereocyclic ring formed by R _1e and R _1f 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, C _3-6 cycloalkyl, cyano, hydroxy, C _1-2 alkoxy, halo or C _1-2 haloalkoxy; wherein any alkyl, alkoxy or C _3-6 cycloalkyl is further optionally substituted by one or more substituents selected from cyano, hydroxy, halo, NR _1k R _1l or -S(O) _0-2 R _1k R _1l , wherein R _1k and R _1l are H or C _1-4 alkyl.

(13) R _1b , R _1d and R _1f are 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 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 _1-4 alkyl, C _3-4 cycloalkyl, heterocyclyl, a mono- or bicyclic heteroaryl, a spirocyclic carbocyclic or heterocyclic ring system, a bridged C _3-8 cycloalkyl, a bridged bicyclic C _5-12 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, C _1-2 haloalkoxy or C _3-6 cycloalkyl; 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, C _1-2 haloalkyl, C _{3- 6} cycloalkyl, cyano, hydroxy, C _1-2 alkoxy, halo or C _1-2 haloalkoxy, and/or the mono- or bicyclic hetereocyclic ring formed by R _1e and R _1f 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, C _3-6 cycloalkyl, cyano, hydroxy, C _1-2 alkoxy, halo or C _1-2 haloalkoxy; wherein any alkyl, alkoxy or C _3-6 cycloalkyl is further optionally substituted by one or more substituents selected from cyano, hydroxy, halo, NR _1k R _1l or -S(O) _0-2 R _1k R _1l , wherein R _1k and R _1l are H or C _1-4 alkyl.

(14) R _1b , R _1d and R _1f are 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; 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 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 mono- or bicyclic heteroaryl, a spirocyclic carbocyclic or heterocyclic ring system, a bridged C _{3- 8} cycloalkyl, a bridged bicyclic C _5-12 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, C _1-2- haloalkoxy or C _3-6 cycloalkyl; 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, C _1-2 haloalkyl, C _{3- 6} cycloalkyl, cyano, hydroxy, C _1-2 alkoxy, halo or C _1-2 haloalkoxy, and/or the mono- or bicyclic hetereocyclic ring formed by R _1e and R _1f 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, C _3-6 cycloalkyl, cyano, hydroxy, C _1-2 alkoxy, halo or C _1-2 haloalkoxy, wherein any alkyl, alkoxy or C _{3- 6} cycloalkyl is further optionally substituted by one or more substituents selected from cyano, hydroxy, halo, NR _1k R _1l or -S(O) _0-2 R _1k R _1l , wherein R _1k and R _1l are H or C _1-4 alkyl.

(15) R _1b , R _1d and R _1f are 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; 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 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, a bridged bicyclic C _{5- 12} 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, C _1-2 haloalkoxy or C _3-6 cycloalkyl, wherein any alkyl or alkoxy is optionally further substituted by one or more substituents selected from cyano, hydroxy or halo.

(16) R _1b , R _1d and R _1f are 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 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, C _{1- 2} haloalkyl, C _3-6 cycloalkyl, cyano, hydroxy, C _1-2 alkoxy, halo or C _1-2 haloalkoxy, and/or the mono- or bicyclic hetereocyclic ring formed by R _1e and R _1f 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- 2haloalkyl, cyano, hydroxy, C _1-2 alkoxy, halo or C _1-2 haloalkoxy.

(17) R _1b , R _1d and R _1f are a group of the formula: wherein T ₁ is as defined herein.

(18) R _1b , R _1d and R _1f are 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, a bridged bicyclic C _5-12 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-

2alkoxy, halo or C _1-2 haloalkoxy.

(19) R _1b , R _1d and R _1f are selected from:

(20) R _1b , R _1d and R _1f are selected from:

(21) R _1b , R _1d and R _1f are selected from :

and

(22) R _1b , R _1d and R _1f are selected from:

(23) R _1b , R _1d and R _1f are selected from: (24) R _1b , R _1d and R _1f are selected from: (25) R _1b ,, R _1d and R _1f are selected from: (26) R _1b , R _1d and R _1f are selected from: and

(27) R _1b , R _1d and R _1f are:

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

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

(30) R _1a’ is hydrogen;

(31) 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, NR _p R _q , OR _p , C(O)R _p , C(O)OR _p , OC(O)R _p , C(O)N(R _p )Rq, 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;

(32) R _2a , R _2b and R _2c are hydrogen;

(33) X is , wherein R _1a , R _1b , R _1a’ and R _2a are as herein defined; (34) X is , wherein R _1c , R _1d and R _2b are as herein defined;

(35) X is , wherein R _1e , R _1f and R _2c are as herein defined;

(36) X is selected from and

(37) X is (38) R _3a1 , R _3b1 , R _3c1 , R _3d1 , R _3e1 , R _3f1 , R _3g1 , R _3h1 , R _3i1 , R _3j1 , R _3k1 , R _3I1 , R _3m1 , R _3n1 , R _3o1 , R _3p1 , R _3q1 , R _3r1 and R _3s1 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; and 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;

(39) R _3a1 , R _3b1 , R _3c1 , R _3d1 , R _3e1 , R _3f1 , R _3g1 , R _3h1 , R _3i1 , R _3j1 , R _3k1 , R _3I1 , 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;

(40) R _3a1 , R _3b1 , R _3c1 , R _3d1 , R _3e1 , R _3f1 , R _3g1 , R _3h1 , R _3i1 , R _3j1 , R _3k1 , R _3I1 , R _3m1 , R _3n1 , R _3o1 , R _3p1 , R _3q1 , R _3r1 and R _3s1 are independently selected from hydrogen and methyl; and wherein methyl is optionally substituted with one or more hydroxy substituents;

(41) R _3a1 , R _3b1 , R _3c1 , R _3d1 , R _3e1 , R _3f1 , R _3g1 , R _3h1 , R _3i1 , R _3j1 , R _3k1 , R _3I1 , R _3m1 , R _3n1 , R _3o1 , R _3p1 , R _3q1 , R _3r1 and R _3s1 are independently selected from hydrogen and methyl; and wherein methyl is substituted with a hydroxy substituent;

(42) 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;

(43) 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 _3r1 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 R _3r2 , and R _3s1 and R _3s2 are hydrogen.

(44) 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 _3ji and R _3j2 , R _3k1 and R _3k2 , R _3r1 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 , R _3r1 and R _3r2 , and R _3s1 and R _3s2 are 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;

(45) n is 0, 1 or 2;

(46) n is 1 ; (47) Y is wherein R _3a1 , R _3a2 and n are as herein defined;

(48) Y is wherein n is 1, and R _3a1 , R _3a2 are as herein defined;

(49) Yis wherein n is herein defined;

(50) Yis wherein R _3b1 , R _3b2 and n are as herein defined;

(51) Yis wherein R _3c1 , R _3c2 and n are as herein defined;

(52) Yis wherein R _3d1 , R _3d2 and n are as herein defined; (53) Y is wherein R _3e1 , R _3e2 and n are as herein defined;

(54) Yis

(55) Yis wherein R _3f1 , R _3f2 and n are as herein defined;

(56) Yis wherein R _3g1 , R _3g2 and n are as herein defined;

(57) Yis wherein R _3h1 , R _3h2 and n are as herein defined (58) Y is wherein R _3i1 , R _3j2 and n are as herein defined;

(59) Y is wherein R _3j2 , R _3j2 and n are as herein defined;

(60) Y is wherein R _3k1 , R _3k2 and n are as herein defined;

(61) Y is wherein R _3l1 , R _3l1 and n are as herein defined;

(62) Y is wherein R _3m1 , R _3m2 and n are as herein defined; (63) Y is wherein R _3n1 , R _3n2 and n are as herein defined;

(64) Y is wherein R _3o1 , R _3o2 and n are as herein defined;

(65) Y is wherein R _3p1 , R _3p2 and n are as herein defined;

(66) Y is wherein R _3q1 , R _3q2 and n are as herein defined;

(67) Y is wherein R _3r1 , R _3r2 and n are as herein defined; (68) wherein R _3s1 , R _3s2 and n are as herein defined;

(69) Y is selected from: ; wherein R _3a1 , R _3a2 ,

R _3b1 , R _3b2 , R _3e1 , R _3e2 , R _3i1 , R _3i2 , R _3j1 , R _3j2 , R _3i1 and R _3i2 , are as defined herein;

(70) Y is selected from:

(71) Y is selected from

(72) Y is

(73) Z is selected from:

wherein:

R ₄ is selected from hydrogen, halo, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy (e.g. hydrogen, halo, cyano and methyl);

R ₅ is selected from hydrogen, halo, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy (e.g. hydrogen, halo, cyano and methyl);

R ₆ is selected from hydrogen, halo, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy (e.g. hydrogen, halo, cyano and methyl); R ₁₂ is selected from hydrogen, halo, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy (e.g. hydrogen, halo, cyano and C _1-4 alkyl); R ₁₃ is selected from hydrogen, halo, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy (e.g. hydrogen, halo, cyano, methoxy and methyl); R ₇ , R ₉ and R ₁₁ are independently selected from hydrogen, NH ₂ , halo, cyano, C _1-4 alkoxy, C _1-4 haloalkoxy and C _1-6 alkyl; R ₈ and R ₁₀ are independently selected from halo, cyano, C _1-4 alkoxy, C _1-4 haloalkoxy, C _1-6 alkyl, -CH ₂ OCH ₃ , -CH ₂ SO ₂ CH ₃ , -SO ₂ CH ₃ , -NHC(O)CH ₃ and - C(O)NR _v1 R _v2 , wherein R _v1 and R _v2 are independently selected from hydrogen and methyl;

R _11N are independently selected from hydrogen and C _1-6 alkyl;

R _Z1 and R _Z1a selected from hydrogen, C _1-4 alkyl, cyano, halo, C _1-4 haloalkyl, C _1- 4haloalkoxy, 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; R _Zi1b is selected from hydrogen, C _1-4 alkyl, cyano, halo, NH ₂ and C _1-4 alkoxy;

R _Zi1e is selected from hydrogen, C _1-4 alkyl, cyano, halo, NH ₂ and C _1-4 alkoxy; R _Z2N is selected from hydrogen or C _1-4 alkyl

R _Y5N is selected from hydrogen or C _1-4 alkyl

R _Z9 is selected from hydrogen, halo, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy;

R _Z10 is selected from hydrogen, halo, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy; R _Z11 is selected from hydrogen, halo, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy;

R _Z12 is selected from hydrogen, halo, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy;

R _Z13 is selected from hydrogen, halo, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy;

R _Z14 is selected from hydrogen, halo, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy;

R _Z15 is selected from hydrogen, halo, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy;

R _Z16 is selected from hydrogen, halo, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy;;

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;

R ₁₅ is selected from hydrogen, halo, cyano, methoxy and methyl; R ₁₆ and R ₁₈ , are selected from hydrogen, halo, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _1- 4haloalkyl, C _1-4 haloalkoxy, C _3-4 cycloalkyl, a 3- to 4-membered heterocyclyl and C _3-4 - cycloalkoxy; R ₁₇ 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), - (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, 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- salkyl, 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 ₁₉ and 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, C _1-4 alkyl, C _1-4 haloalkyl, C _{1- 4} alkoxy, C _1-4 haloalkoxy (e.g. hydrogen, halo, cyano and methyl; R ₂₈ and R ₂₉ are selected from hydrogen, halo, methoxy and methyl; and R ₂₁ , R ₂₄ , and R ₃₀ are independently selected from hydrogen or C _1-4 alkyl

(74) Z is selected from wherein X ₂ , X ₃ , X ₄ , X ₅ , X ₆ , X ₇ , X ₈ and X ₉ are as defined herein;

(75) Z is

0 wherein X ₂ , X ₄ , X ₅ , X ₆ , X ₇ , X ₈ and X ₉ are as defined herein;

(76) wherein X ₂ , X ₄ , X ₅ , X ₆ , X ₇ , X ₈ and X ₉ are as defined herein;

(77) Z is wherein X ₂ , X ₃ , X ₄ , X ₅ , X ₆ , X ₇ , X ₈ and X ₉ are as defined herein; wherein

X ₁ is N or CR _Z9 ;

X ₂ is CR ₄ :

X ₃ is N;

X ₄ is C;

X ₅ is CR ₅ :

X ₆ is A ₁ , wherein A ₁ is CR ₁₂ X ₇ is A ₂ , wherein A ₂ is CR ₁₃

X ₈ is N or CR ₆ ,

X ₉ is N or C; wherein R _Z9 , R ₄ , R ₅ , R ₆ , R ₁₂ and R ₁₃ are as defined herein.

(79) R ₁₃ are as herein defined; (80) Z is: wherein R ₄ , R ₅ , R ₆ , R ₁₂ , R ₁₃ and

R _Z9 are as herein defined;

(81) Z is: wherein R ₄ , R ₅ , R ₆ , R ₁₉ , R ₂₂ and

R _Z9 are as herein defined;

(82) Z is: wherein R ₄ , R ₅ , R ₆ , R ₁₂ , R ₁₃ and

R _Z9 are as herein defined;

(83) Z is wherein Q ₇ , Q ₈ , Q ₉ , Q ₁₀ and Q ₁₁ are as defined herein;

(84) Z is wherein Q ₈ , Q ₉ , Q ₁₀ and Q ₁₁ are as defined herein;

(84a) Z is selected from: wherein R ₈ , R ₉ , R ₁₀ and R ₁₁ are as herein defined;

(85) Z is selected from:

and wherein R ₈ , R ₉ , R ₁₀ and R ₁₁ are as herein defined;

(86) Z is wherein R ₈ , R ₉ , R ₁₀ and R ₁₁ are as herein defined;

(87) Z is wherein: R ₈ is selected from cyano, -CH ₂ OCH ₃ , -CH ₂ SO ₂ CH ₃ , -SO ₂ CH ₃ , -NHC(O)CH ₃ and -C(O)NR _v1 R _v2 , wherein R _v1 and R _v2 are independently selected from hydrogen and methyl, ,

R ₁₀ is C _1-4 alkoxy or C _1-4 haloalkoxy;

R ₉ and R ₁₁ are as herein defined;

(87a) Z is wherein:

R ₈ is selected from hydrogen, cyano, -CH ₂ OCH ₃ , -CH ₂ SO ₂ CH ₃ , -SO ₂ CH ₃ , - NHC(O)CH ₃ and -C(O)NR _v1 R _v2 , wherein R _v1 and R _v2 are independently selected from hydrogen and methyl, ,

R ₁₀ is C _1-4 alkoxy or C _1-4 haloalkoxy;

R ₉ and R ₁₁ are as herein defined;

(88) Z is wherein R ₈ is cyano and R ₁₀ is C _1-4 alkoxy;

(88a) Z is or wherein R ₈ is hydrogen or cyano; R ₉ is hydrogen; and

R ₁₀ is selected from C _1-4 alkoxy and heterocyclyl.

(88b) wherein R ₈ is hydrogen or cyano; R ₉ is hydrogen; and

R ₁₀ is methoxy.

(89) Z is

(89a) Z is or

(89b) Zis or

(89c) Z is (90) Z is wherein Q ₈ , Q ₉ , Q ₁₀ and Q _11a are as defined herein;

(91) Z is wherein R ₇ , R ₉ and R _11N are as herein defined;

(92) Z is wherein B ₁ , B ₂ , B ₃ , B ₄ , B ₅ , B ₇ and B ₈ are as defined herein;

(93) Z is: wherein B ₁ is A ₅ , wherein A ₅ is N or C R ₁₆ ;

B ₂ is A ₆ , wherein A ₆ is CR ₁₇

B ₃ is N or CR _Z1 ;

B ₄ is N or C;

B ₅ is selected from CR _zi1b or NR _B5N B ₇ is N, N R _Z2N or CR _Z2 ;

B ₈ is selected from C or N; wherein R ₁₆ , R ₁₇ , R _Z1 , CR _zi1b , R _B5N , R _Z2 are as defined herein;

(94) Z is: wherein

B ₁ is A ₅ , wherein A ₅ is C R ₁₆ ;

B ₂ is A ₆ , wherein A ₆ is C R ₁₇

B ₃ is CR _Z1 ;

B ₄ is N or C;

B ₅ is selected from CR _zi1b or N R _B5N

B ₇ is N, NH or CR _Z2 ;

B ₈ is C; wherein R ₁₆ , R ₁₇ , R _Z1 , CR _zi1b , R _B5N , R _Z2 are as defined herein;

(95) Z is: wherein R _Z1 , R _Z2 ,R _zi1b , A ₅ and A ₆ are as herein defined;

(96)

(97) Z is: wherein R _Z1 , R _Z2 ,R _zi1b , A ₅ and A ₆ are as herein defined; (98) Z is wherein A ₅ , A ₆ , R _Z1 , R _Z2N are R _zi1b are as herein defined;

(99) Z is wherein A ₅ , A ₆ , R _Z1 , R _Z2N are R _zi1b are as herein defined;

(100) Z is: wherein R _Z1 , R _Z2 and A ₆ are as herein defined;

(101) Z is wherein

Y ₂ is A ₇ , wherein A ₇ is CR ₁₈ ;

Y ₃ is N or CR _Z1a ;

Y ₄ is C or N

Y ₅ is N R _Y5N ; Y ₆ is C-R _Zi2e or N;

Y ₇ is CR _Z2a or N;

Y ₈ is C or N;

Yg is CR _Z3a or N; wherein R ₁₈ , R _z1a , R _Y5N , R _Zi2e , R _Z2a and R _Z3a are as defined herein;

(102) Z is wherein

Y ₂ is A ₇ , wherein A ₇ is CR ₁₈ ;

Y ₄ is C or N

Y ₅ is NR _Y5N ;

Y ₆ is C-R _Zi2e or N;

Y ₇ is CR _Z2a or N;

Y ₈ is C or N;

Yg is C R _Z3a or N; wherein R ₁₈ , R _z1a , R _Y5N , R _Zi2e , R _Z2a and R _Z3a are as defined herein;

(103) Z is wherein

Y ₂ is A ₇ , wherein A ₇ is CR ₁₈ ;

Y ₄ is N

Y ₅ is C-R _Y5 ;

Y ₈ is C-R _Zi2e ;

Y ₇ is O or S;

Y ₈ is C; Y ₉ is N; wherein R ₁₈ , R _Y5 , R _Zi2e are as defined herein;

(104) Z is wherein A7, R _Z1a , R _Z2a and R _Z3a are as herein defined, and R _Y5N is C _1-4 alkyl;

(105) Z is: wherein R _Y5N , R _Z1a , R _Z2a , R _Zi2e and A ₇ are as herein defined;

(106) Z is wherein R _Y5N , R _Z1a , R _Z2a , R _Zi2e and A ₇ are as herein defined; N

(107) Z is wherein R _Y5N , R _Z2a , R _Zi2e and A ₇ are as herein defined; (108) Z is: wherein R _Y5N , R _Z1a , R _Z2a , R _Z3a , R _Zi2e and A ₇ are as herein defined;

(109) Z is: wherein A ₇ andR _Zi2e are as defined herein;

(110) Z is wherein Z ₁₀ , Z ₁₁ , Z ₁₂ , Z ₁₃ , Z ₁₄ , Z ₁₅ and Z ₁₆ are as defined herein;

_{(111) Z is} wherein

Z ₁₀ is CR _Z10 , Z ₁₁ is N;

Z ₁₂ is CR _Z12 ;

Z ₁₃ is CR _Z13 ;

Z ₁₄ is N or CR _Z14 ;

Z ₁₅ is N or CR _Z15 ;

Z ₁₆ is CR _Z16 ; wherein R _Z10 , R _Z12 , R _Z13 , R _Z14 , R _Z15 and R _Z16 are as defined herein;

(112) Z is wherein

Z ₁₀ is CR _Z10 , Z ₁₁ is CR _Z10 or N;

Z ₁₂ is CR _Z12 ;

Z ₁₃ is CR _Z13 ;

Z ₁₄ is N;

Z ₁₅ is N or CR _Z15 ;

Z ₁₆ is CR _Z16 ; wherein R _Z10 , R _Z12 , R _Z13 , R _Z14 , R _Z15 andR _Z16 are as defined herein; (113) Z is: , wherein Z ₁₀ , Z ₁₂ , Z ₁₃ , Z ₁₄ , Z ₁₅ and Z ₁₆ are as herein defined;

(114) Z is: wherein Z ₁₃ , Z ₁₄ , Z ₁₅ and Z ₁₆ are as herein defined;

(115) Z is: wherein R _Z10 , R _Z12 , R _Z13 , R _Z14 , R _Z15 and R _Z16 are as herein defined;

(116) Z is: , wherein Z ₁₀ , Z ₁₁ , Z ₁₂ , Z ₁₃ , Z ₁₅ and Z ₁₆ are as herein defined,

(117) Z is: wherein R _Z10 , R _Z11 , R _Z12 , R _Z13 , R _Z15 and R _Z16 are as herein defined;

(118) Z is selected from: wherein B ₁ , B ₂ , B ₃ , B ₄ , B ₅ , B ₇ , B ₈ ,Y ₂ , Y ₃ , Y ₄ , Y ₅ , Y ₆ , Y ₇ , Y ₈ , Y ₉ , X ₁ , X ₂ , X ₃ , X ₄ , X ₅ , X ₆ , X ₇ , X ₈ and X ₉ are as defined herein;

(119) Z is selected from:

wherein:

A ₅ , A ₆ , A ₇ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , R _11N , R ₁₂ , R ₁₃ , R ₁₉ , R ₂₂ , R _B5N , R _Y5N , R _Z1 , R _Z2 , R _Z9 , R _Z10 , R _Z11 , R _Z12 , R _Z13 , R _Z14 , R _Z15 , R _Z16 , R _Z2a , R _Z3a , R _Z1a , R _{Zi1 b} and R _Zi2e are as defined herein;

(120) Z is selected from:

wherein A ₅ , A ₆ , A ₇ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , R _11N , R ₁₂ , R ₁₃ , R ₁₉ , R ₂₂ , R _Z1 , R _Z2 , R _Z9 , R _Z10 , R _{Z1 1} , R _Z12 , R _Z13 , R _Z14 , R _Z15 , R _Z16 , R _Z2a , R _Z3a , R _Z1a , R _Zi1b and R _Zi2e are as defined herein;

(121) Z is selected from:

wherein A ₅ , A ₆ , A ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , R _Y5N , R _Z1 , R _Z2 , R _Z10 , R _Z12 , R _Z13 , R _Z14 , R _Z15 , R _Z16 ,

R _Z1a , R _Z2a , R _Z3a , R _zi1b and R _Zi2e are as defined herein;

(122) Z is selected from:

and wherein A ₅ , A ₆ , A ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , R _Y5N , R _Z1 , R _Z2 , R _Z10 , R _Z12 , R _Z13 , R _Z14 , R _Z15 , R _Z16 , R _Z2a ,

R _Z3a , R _Z1a , R _Zi2b and R _Zi2e are as defined herein.

(123) Z is selected from:

wherein A ₅ , A ₆ , A ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , R _Y5N , R _Z1 , R _Z2 , R _Z10 , R _Z12 , R _Z13 , R _Z14 , R _Z15 , R _Z16 ,, R _Z2a ,

R _Z3a , R _Z1a , R _Zi2b and R _Zi2e are as defined herein. (124) Z is selected from: wherein R ₈ , R ₁₀ , R ₁₇ , R ₁₈ and R _Z1 , are as herein defined.

(125) Z is selected from:

; and

(126) Z is selected from: and

(127) R ₄ , R ₅ and R ₆ are independently selected from hydrogen and halo; (128) R ₄ , R ₅ and R ₆ are hydrogen;

(129) when Z is , then R ₇ , R ₉ are independently selected from hydrogen, methyl, halo and cyano; and and R _11N is selected from hydrogen and methyl;

(129a) when Z is , then R ₈ , R ₉ , R ₁₀ and R ₁₁ are independently selected from hydrogen, heterocyclyl, NH ₂ , halo, cyano, C _1-4 alkoxy, C _1-4 haloalkoxy and C _1-6 alkyl, -CH ₂ OCH ₃ , -CH ₂ SO ₂ CH ₃ , -SO ₂ CH ₃ , -NHC(O)CH ₃ and - C(O)NR _v1 R _v2 , wherein R _v1 and R _v2 are independently selected from hydrogen and methyl; with the proviso that at least one of R ₈ , R ₉ , R ₁₀ and R ₁₀ is hydroxy, NR _v1 R _v2 , heterocyclyl, C _1-4 alkoxy or C _1-4 haloalkoxy;

(130) when Z is , then R ₈ , R ₉ , R ₁₀ and R ₁₁ are independently selected from hydrogen, NH ₂ , halo, cyano, C _1-4 alkoxy, C _1-4 haloalkoxy and C _1-6 alkyl, -CH ₂ OCH ₃ , -CH ₂ SO ₂ CH ₃ , -SO ₂ CH ₃ , -NHC(O)CH ₃ and -C(O)NR _v1 R _v2 , wherein R _v1 and R _v2 are independently selected from hydrogen and methyl with the proviso that at least one of R ₈ , R ₉ , R ₁₀ and R ₁₁ is C _1-4 alkoxy or C _1-4 haloalkoxy; (130a) when Z is , then R ₈ , R ₉ and R ₁₁ are independently selected from hydrogen, NH ₂ , halo, cyano, C _1-4 alkoxy, C _1.4 haloalkoxy, C _1-3 alkyl, - CH ₂ OCH ₃ , -CH ₂ SO ₂ CH ₃ , -SO ₂ CH ₃ , -NHC(O)CH ₃ and -C(O)NR _v1 R _v2 , wherein R _v1 and Rv2 are independently selected from hydrogen and methyl; and

R10 is selected from heterocyclyl, C _1-4 alkoxy or C _1-4 haloalkoxy.

(131) when Z is , then R ₈ , R ₉ and R ₁₁ are independently selected from hydrogen, NH2, halo, cyano, C _1-4 alkoxy, C _1-4 haloalkoxy, C _1-3 alkyl, - CH ₂ OCH ₃ , -CH ₂ SO ₂ CH ₃ , -SO ₂ CH ₃ , -NHC(O)CH ₃ and -C(O)NR _v1 R _v2 , wherein R _v1 and R _v2 are independently selected from hydrogen and methyl; and R ₁₀ is selected from C _1-4 alkoxy or C _1-4 haloalkoxy.

(132) when Z is , then R ₈ is cyano, -CH ₂ OCH ₃ , -

CH ₂ SO ₂ CH ₃ , -SO ₂ CH ₃ , -NHC(O)CH ₃ and -C(O)NR _v1 R _v2 , wherein R _v1 and R _v2 are independently selected from hydrogen and methyl; R ₉ is hydrogen; R ₁₀ is C _1-4 alkoxy; and R ₁₁ is hydrogen.

(133) when Z is , then R ₈ is cyano; R ₉ is hydrogen; R ₁₀ is C _1-4 alkoxy or C _1-4 haloalkoxy; and R ₁₁ is hydrogen.

(133a) when Z i s , then R ₈ is hydrogen or cyano; R ₉ is hydrogen; R ₁₀ is selected from C _1-4 alkoxy or heterocyclyl; and R ₁₁ is hydrogen.

(133b) when Z is , then R ₈ is hydrogen or cyano; R ₉ is hydrogen; R ₁₀ is C _1-4 alkoxy; and R ₁₁ is hydrogen. (133c) when Z is then R ₈ is hydrogen or cyano; R ₉ is hydrogen; R ₁₀ is C _1-4 alkoxy; and R ₁₁ is hydrogen.

(134) 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;

(135) R _Z1 and R _Z1a are selected from hydrogen, C _1-2 alkyl, cyano, halo, C _1-2 haloalkyl, C _1-2 haloalkoxy, C _1-2 alkoxy;

(136) R _Z1 and R _Z1a are selected from hydrogen, C _1-2 alkyl, cyano and halo;

(137) R _Z1 and R _Z1a are hydrogen;

(138) R _Z2 , R _Z2a , R _Z3a , R _zi1b and R _Zi2e are independently selected from hydrogen, C _1- 4alkyl, cyano, halo or C _1-4 alkoxy;

(139) R _Z2 , R _Z2a , R _Z3a , R _zi1b and R _Zi2e are independently selected from hydrogen, cyano or halo;

(140) R _Z2 , R _Z2a , R _Z3a , R _zi1b and R _Zi2e are hydrogen;

(141) R _Y5N , R _Z2N , and R _11N are selected from hydrogen or methyl;

(142) R _Y5N , R _Z2N , and R _11N are hydrogen;

(143) R _Y5N is methyl;

(144) R _Z4 , R _Z5 , R _Z6 , R _Z7 , R _Z8 , R _Z9 , R _Z10 , R _Z11 , R _Z12 , R _Z13 , R _Z14 , R _Z15 , and R _Z16 are independently selected from hydrogen, halo and cyano;

(145) R _Z4 , R _Z5 , R _Z6 , R _Z7 , R _Z8 , R _Z9 , R _Z10 , R _Z11 , R _Z12 , R _Z13 , R _Z14 , R _Z15 , and R _Z16 are independently selected from hydrogen and halo;

(146) R _Z4 , R _Z5 , R _Z6 , R _Z7 , R _Z8 , R _Z9 , R _Z10 , R _Z11 , R _Z12 , R _Z13 , R _Z14 , R _Z15 , and R _Z16 are hydrogen ;

(147) R ₁₂ , R ₁₃ , R ₁₆ , R ₁₉ , R ₂₀ , R ₂₁ , R ₂₂ and R ₂₃ are independently selected from hydrogen, halo, cyano and methyl;

(148) R ₁₂ , R ₁₃ , R ₁₆ , R ₁₉ , R ₂₀ , R ₂₁ , R ₂₂ and R ₂₃ are hydrogen; (149) R ₁₂ is selected from hydrogen, halo, cyano and C _1-4 alkyl;

(150) R ₁₂ is selected from hydrogen and halo;

(151) R ₁₂ is selected from hydrogen and chloro;

(152) R ₁₂ is hydrogen;

(153) R ₁₃ is selected from hydrogen, halo, methoxy, cyano and methyl;

(154) R ₁₃ is selected from hydrogen, methoxy and methyl;

(155) R ₁₃ is hydrogen;

(156) R ₁₆ and R ₁₈ are selected from hydrogen, halo, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl and C _1-4 haloalkoxy;

(157) R ₁₆ and R ₁₈ are selected from hydrogen, halo, cyano and C _1-4 alkyl;

(158) R ₁₆ and R ₁₈ are selected from hydrogen and halo;

(159) R ₁₆ and R ₁₈ are hydrogen;

(160) 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 _1-4 alkyl, C _3-6 cycloalkyl, a 3- to 6- membered carbon-linked heterocyclyl, 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 _1-5 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 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.

(161) R ₁₇ is selected from hydrogen, halo, cyano, C _1-2 alkyl, C _1-2 haloalkyl, C _1-2 alkoxy, C _1-2 haloalkoxy, C _2-3 alkenyl, C _2-3 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 _1-2 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; wherein any C _1- 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- 2alkyl, 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. (162) R ₁₇ 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- 2alkyl, C _1-2 haloalkyl, cyano, hydroxy, C _1-2 alkoxy, halo and C _1-2 haloalkoxy.

(163) R ₁₇ 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, 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- 4cycloalkyl, 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.

(164) R ₁₇ is selected from hydrogen, halo, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _2-4 alkenyl, C _2-4 alkynyl and a 5- or 6-membered aryl or heteroaryl; wherein any C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, 5- or 6-membered aryl or heteroaryl 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.

(165) R ₁₇ is selected from hydrogen, halo, C _1-4 alkoxy, C _2-4 alkynyl and 5- or 6- membered aryl or heteroaryl.

(166) R ₁₇ is selected from hydrogen, C _1-4 alkoxy, bromo, ethynyl, and pyrazoly.

(167) R ₁₉ is selected from hydrogen, halo or C _1-4 alkyl;

(168) R ₁₉ is hydrogen or methyl;

(169) R ₁₉ is hydrogen;

(170) R ₂₁ , R ₂₄ and R ₃₀ , are independently selected from hydrogen or methyl;

(171) R ₂₁ , R ₂₄ and R ₃₀ , are hydrogen;

(172) R ₂₂ is selected from hydrogen, halo, cyano and methyl;

(173) R ₂₂ is hydrogen or methyl;

(174) R ₂₂ is hydrogen; (175) R ₂₈ and R ₂₉ are selected from hydrogen or halo, methoxy and methyl;

(176) R ₂₈ and R ₂₉ are hydrogen;

[00109] In an embodiment: when X ₆ is A ₁ , A ₁ is CR ₁₂ ; when X ₇ is A ₂ , A ₂ is CR ₁₃ ;

Bi is A ₅ , wherein A ₅ is CR ₁₆ ;

B2 is A ₆ , wherein A ₆ is CR ₁₇ ;

Y2 is A ₇ , wherein A ₇ is CR ₁₈ ; when X ₆ is A ₈ , A ₈ is CR ₁₉ R ₂₀ ; when X ₇ is A ₉ , A ₉ is CR ₂₂ R ₂₃ ; when X ₇ is A ₁₁ , A ₁₁ is CR ₂₈ R ₂₉ ; and wherein R ₁₂ , R ₁₃ , R ₁₆ , R ₁₇ , R ₁₈ , R ₁₉ , R ₂₀ , R ₂₁ , R ₂₂ , R ₂₃ , R ₂₈ and R ₂₉ are as defined herein.

[00110] In an embodiment: A ₁ is CR ₁₂ ; A ₂ is CR ₁₃ ; A ₅ is CR ₁₆ ; A ₆ is CR ₁₇ ; A ₇ is CR ₁₈ ; A ₈ is CR ₁₉ R ₂₀ ; A ₉ is CR ₂₂ R ₂₃ ; A ₁₁ is CR ₂₈ R ₂₉ ; wherein R ₁₂ , R ₁₃ , R ₁₆ , R ₁₇ , R ₁₈ , R ₁₉ , R ₂₀ , R ₂₁ , R ₂₂ , R ₂₃ , R ₂₈ and R ₂₉ are as defined herein

[00111] In an embodiment:

(i) R ₄ , R ₅ , R _x5a , R _x5b , R _Y5 , R ₆ , R ₇ , R ₉ , R ₁₁ , R _11a , R _11b , R _Z2 , R _Z2a , R _Z3a , R _zi1b , R _Zi2e ,

R _Z9 , R _Z10 , R _Z11 , R _Z12 , R _Z13 , R _Z14 , R _Z15 and R _Z16 are independently selected from hydrogen, methyl, cyano or halo; and

R _B5N , R _Y5N , R _Z2N and R _11N are selected from methyl or hydrogen;

(ii) R ₈ is seleced from cyano, -CH ₂ OCH ₃ , -CH ₂ SO ₂ CH ₃ , -SO ₂ CH ₃ , -NHC(O)CH ₃ and -C(O)NR _v1 R _v2 , wherein R _v1 and R _v2 are independently selected from hydrogen and methyl;

(iii) R ₁₀ is selected from C _1-4 alkoxy or C _1-4 haloalkoxy;

(iv) 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;

(v) R ₁₂ , R ₁₃ , R ₁₆ , R ₁₈ , R ₁₉ , R ₂₀ , R ₂₁ , R ₂₂ , R ₂₃ , R ₂₄ and R ₃₀ are independently selected from hydrogen, halo, cyano and methyl;

(vi) R ₁₇ 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, -(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 _1-4 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, cyano, C _1-2 haloalkyl, hydroxy, C _1- 2alkoxy, 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.

(vii) R ₂₁ , R ₂₄ and R ₃₀ , are independently selected from hydrogen or methyl; (viii) R ₂₈ and R ₂₉ are selected from hydrogen or halo, methoxy and methyl.

[00112] In an embodiment:

(i) R ₄ , R ₅ , R _x5a , R _x5b , R _Y5 , R ₆ , R ₇ , R ₉ , R ₁₁ , R _11a , R _11b , R _Z2 , R _Z2a , R _Z3a , R _zi1b , R _Zi2e ,

R _Z9 , R _Z10 , R _Z11 , R _Z12 , R _Z13 , R _Z14 , R _Z15 and R _Z16 are independently selected from hydrogen, methyl, cyano or halo; and

R _B5N , R _Y5N , R _Z2N and R _11N are selected from methyl or hydrogen;

(ii) R ₈ , R ₉ and R ₁₁ are independently selected from hydrogen, NH ₂ , halo, cyano, C _1-4 alkoxy, C _1-4 haloalkoxy, C _1-3 alkyl, -CH ₂ OCH ₃ , -CH ₂ SO ₂ CH ₃ , -SO ₂ CH ₃ , - NHC(O)CH ₃ and -C(O)NR _v1 R _v2 , wherein R _v1 and R _v2 are independently selected from hydrogen and methyl;

(iii) R ₁₀ is selected from C _1-4 alkoxy or C _1-4 haloalkoxy;

(iv) 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;

(v) R ₁₂ , R ₁₃ , R ₁₆ , R ₁₈ , R ₁₉ , R ₂₀ , R ₂₁ , R ₂₂ , R ₂₃ , R ₂₄ and R ₃₀ are independently selected from hydrogen, halo, cyano and methyl;

(vi) R ₁₇ 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, -(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 _1-4 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, cyano, C _1-2 haloalkyl, hydroxy, C _1- 2alkoxy, 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.

(vii) R ₂₁ , R ₂₄ and R ₃₀ , are independently selected from hydrogen or methyl; (viii) R ₂₈ and R ₂₉ are selected from hydrogen or halo, methoxy and methyl.

[00113] In an embodiment:

(i) R ₄ , R ₅ , R _x5a , R _x5b , R _Y5 , R _B5N , R _Y5N , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , R _11a , R _11b , R _z2 , R _z2a , R _z3a

R _zi1b , R _Zi2e , R _Z9 , R _Z10 , R _Z11 , R _Z12 , R _Z13 , R _Z14 , R _Z15 and R _Z16 are hydrogen; R _Z2N and R _11N are selected from methyl or hydrogen;

(ii) R ₈ is cyano;

(iii) R ₁₀ is methoxy;

(iv) R _Z1 and R _Z1a are selected from hydrogen, cyano, halo, C _1-2 haloalkyl, C _1-2 haloalkoxy, C _1-2 alkoxy, C _3-6 cycloalkyl and -O-C _3-6 cycloalkyl;

(v) R ₁₂ , R ₁₃ , R ₁₆ , R ₁₈ , R ₁₉ , R ₂₀ , R ₂₁ , R ₂₂ , R ₂₃ , R ₂₄ and R ₃₀ are hydrogen;

(vi) R ₁₇ is selected from hydrogen, halo, cyano, C _1-2 alkyl, C _1-2 haloalkyl, C _1-2 alkoxy, C _1-2 haloalkoxy, C _2-3 alkenyl, C _2-3 alkynyl, phenyl a 5- or 6-membered or heteroaryl, C _3-6 cycloalkyl, -O-C _3-6 cycloalkyl, heterocyclyl, -(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- 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; 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, 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 _1f a are H or C _1-2 alkyl

(vii) R ₂₁ , R ₂₄ and R ₃₀ , are hydrogen;

(viii) R ₂₈ and R ₂₉ are hydrogen.

[00114] 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. [00115] Suitably, a heteroaryl is a 5- or 6-membered heteroaryl ring comprising one, two or three heteroatoms selected from N, O or S.

[00116] 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)].

[00117] Suitably, an aryl group is phenyl.

[00118] Suitably, X is as defined in any one of paragraphs (33) to (37) above. More suitably, X is as defined in any one of paragraphs (33) or (36) to (37) above. Most suitably, X is as defined in paragraph (33) or (37).

[00119] Suitably, R _1a , R _1c and R _1e are as defined in any one of paragraphs (1) to (5) above. Most suitably, R _1a , R _1c and R _1e are as defined in paragraph (5).

[00120] Suitably, R _1b , R _1d and R _1f are as defined in any one of paragraphs (6) to (18) above. More suitably, R _1b , R _1d and R _1f are as defined in paragraph (16), (17) or (18). Most suitably, R _1b , R _1d and R _1f are as defined in paragraph (18).

[00121] Suitably, R _1b , R _1d and R _1f are as defined in any one of paragraphs (19) to (27) above. More suitably, R _1b , R _1d and R _1f are as defined in any one of paragraphs (25) to (27). Most suitably, R _1b , R _1d and R _1f are as defined in paragraph (27).

[00122] Suitably, R _1a’ is as defined in any one of paragraphs (28) to (30) above. Most suitably, R _1a’ is as defined in paragraph (30) above.

[00123] Suitably, R _2a , R _2b and R _2c are as defined in any one of paragraphs (31) and (32) above. Most suitably, R _2a , R _2b and R _2c are as defined in paragraph (32).

[00124] Suitably, Y is as defined in any one of paragraphs (47) to (72) above. Suitably, Y is as defined in any one of paragraphs (47), (48), (49), (50), (53), (58), (59) and (61). Suitably, Y is as defined in any one of paragraphs (69) to (72). Suitably, Y is as defined in paragraphs (71) to (72) above. Most suitably, Y is as defined in paragraph (72)

[00125] Suitably, n is as defined in any one of paragraphs (45) and (46) above. Most suitably, n is as defined in paragraph (46), i.e. n is 1.

[00126] 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 (38) to (41), and paragraphs (43) and (44) above. Most suitably, R _3a1 , R _3b1 , R _3c1 , R _3d1 , R _3e1 , R _3f1 , R _3g1 , R _3b1 , R _3i1 , R _3j1 , R ₃ ki, R _3l1 ,

R _3m1 , R _3n1 , R _3o1 , R _3p1 , R _3q1 , R _3r1 and R _3s1 are as defined in paragraph (41) above). [00127] Suitably, R _3a2 , R _3b2 , R _3c2 , R _3d2 , R _3e2 , R _3f2 , R _3g2 , R _3h2 , R _3i2 , R _3j2 , R _3k2 , R _3i2 , R _3m2 , R _3n2 , R _3o2 ,

R _3p2 , R _3q2 , R _3r2 and R _3s2 are as defined in any one of paragraphs (42), (43) and (44) 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 _3i2 , R _3m2 , R _3n2 , R _3o2 ,

R _3p2 , R _3q2 , R _3r2 and R _3s2 are as defined in paragraph (42).

[00128] Suitably, Z is as defined in any one of paragraphs from (73) to (126) above. Suitably, Z is as defined in any one of paragraphs from (119) to (126) above. Suitably, Z is as defined in any one of paragraphs from (123) to (126) above. Most suitably, Z is as defined in paragraph (126) above.

[00129] Suitably, Z may also be as defined in any one of paragraphs (84a), (87a), (88a), (88b), (89a), (89b) or (89c) above.

[00130] Suitably, R ₄ is as defined in any one of paragraphs (127) and (128) above. Most suitably, R ₄ is as defined in paragraph (128).

[00131] Suitably, R ₅ is as defined in any one of paragraphs (127) and (128) above . Most suitably, R ₅ is as defined in paragraph (128).

[00132] Suitably, R ₆ is as defined in any one of paragraphs (127) and (128) above above. Most suitably, R ₆ is as defined in paragraph (128).

[00133] Suitably, R ₇ , R ₉ and R _11N are as defined in paragraph (129).

[00134] Suitably, R ₈ , R ₉ , R ₁₀ and R ₁₁ are as defined in any one of paragraphs (130) to (133). More suitably, R ₈ , R ₉ , R ₁₀ and R ₁₁ are as defined in any one of paragraphs (131) to (133) Suitably, R ₈ , R ₉ , R ₁₀ and R ₁₁ are as defined in paragraphs (132) or (133).

[00135] Suitably, R ₈ , R ₉ , R ₁₀ and R ₁₁ may also be as defined in any one of paragraphs (129a), (130a), (133a), (133b) or (133c) above. R ₈ , R ₉ , R ₁₀ and R ₁₁ may more suitably be defined in any one of paragraphs (133a), (133b) or (133c).

[00136] Suitably, R _Z1 and R _Z1a are as defined in any one of paragraphs (134) to (137) above. Most suitably, R _Z1 and R _Z1a are as defined in paragraph (137).

[00137] Suitably, R _Z2 and R _Z2a are as defined in any one of paragraphs (138) to (140) above. Most suitably, R _Z2 and R _Z2a are as defined in paragraph (140).

[00138] Suitably, R _Z3a is as defined in any one of paragraphs (138) to (140) above. Most suitably, R _Z2 and R _Z2a are as defined in paragraph (140).

[00139] Suitably, R _zi1b and R _Zi2e are as defined in any one of paragraphs (138) to (140) above. Most suitably, R _zi1b and R _Zi2e are as defined in paragraph (140), i.e. R _zi1b and R _Zi2e are hydrogen. [00140] Suitably, R _Z2N , and R _11N are as defined in any one of paragraphs (141) and (142). Most suitably, R _Z2N and R _11N are as defined in paragraph (142).

[00141] Suitably, R _Y5N is as defined in any one of paragraphs (141), (142) and (143). Most suitably, R _Y5N is as defined in paragraph (142) or (143).

[00142] Suitably, R _Z4 , R _Z5 , R _Z6 , R _Z7 , R _Z8 , R _Z9 , R _Z10 , R _Z11 , R _Z12 , R _Z13 , R _Z14 , R _Z15 , and R _Z16 are as defined in any one of paragraphs (144), (145) and (146). Most suitably, R _Z4 , R _Z5 , R _Z6 , R _Z7 ,

R _Z8 , R _Z9 , R _Z10 , R _Z11 , R _Z12 , R _Z13 , R _Z14 , R _Z15 , and R _Z16 are as defined in paragraph (146).

[00143] Suitably, R ₁₂ is as defined in any one of paragraphs (147), (148) and (149) to (152). Most suitably, R ₁₂ is as defined in paragraph (152).

[00144] Suitably, R ₁₃ is as defined in any one of paragraphs (147), (148) and (153) to (155). Most suitably, R ₁₃ is as defined in paragraph (155).

[00145] Suitably, A ₅ is CR ₁₆ , and R ₁₆ is as defined in any one of paragraphs (147), (148) and (156) to (159). Most suitably, R ₁₆ is as defined in paragraph (159).

[00146] Suitably, A ₆ is CR ₁₇ and R ₁₇ is as defined in any one of paragraphs (160) to (166). More suitably, R ₁₇ is as defined in any one of paragraphs (163) to (166). Most suitably, R ₁₇ is as defined in paragraph (166).

[00147] Suitably, A ₇ is CR ₁₈ , and R ₁₈ is as defined in any one of paragraphs (147), (148) and (156) to (159). Most suitably, R ₁₈ is as defined in paragraph (159).

[00148] Suitably, R ₁₉ is as defined in any one of in any one of paragraphs (147), (148) and (167) to (169). Most suitably, R ₁₉ is as defined in paragraph (169).

[00149] Suitably, R ₂₁ is as defined in any one of in any one of paragraphs (147), (148) and

(170) to (171). Most suitably, R ₁₉ is as defined in paragraph (171).

[00150] Suitably, R ₂₂ is as defined in any one of in any one of paragraphs (147), (148) and (172) to (174). Most suitably, R ₂₂ is as defined in paragraph (174).

[00151] Suitably, R ₂₄ and R ₃₀ are as defined in any one of in any one of paragraphs (170) to

(171). Most suitably, R ₂₄ and R ₃₀ are as defined in paragraph (171).

[00152] Suitably, R ₂₈ and R ₂₉ are as defined in any one of in any one of paragraphs (175) to (176). Most suitably, R ₂₈ and R ₂₉ are as defined in paragraph (176).

[00153] In an embodiment,

X is:

wherein

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

(ii) R ₃ ai, R _3a2 , R _3i1 and R _3i2 are as defined herein;

(iii) A ₅ , A ₆ , A ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , R _Z1 , R _Z 2, R _{Zi1 b} , R _Z10 , R _Z12 , R _Z13 , R _Z14 , R _Z15 , R _Z16 , R _Y5N ,

R _Z2a , R _Z3a , and R _Zi2e are as defined herein. [00154] In an embodiment,

X is:

Z is selected from: wherein

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

(ii) R _3a1 , R _3a2 , R _3i1 and R _3i2 are as defined herein;

(iii) R ₈ , R ₉ , R ₁₀ , R ₁₁ , A ₅ , A ₆ , R _Z1 , R _Z2 and R _zi1b are as defined herein.

[00155] In an embodiment,

Z is selected from: wherein

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

(ii) R _3a1 , R _3a2 , R _3i1 and R _3i2 are as defined herein;

(iii) R ₈ is selected from cyano, -CH ₂ OCH ₃ , -CH ₂ SO ₂ CH ₃ , -SO ₂ CH ₃ , -NHC(O)CH ₃ and -C(O)NR _v1 R _v2 , wherein R _v1 and R _v2 are independently selected from hydrogen and methyl; or R ₈ is hydrogen; R ₉ and R ₁₁ are as herein defined; R ₁₀ is C _1-4 alkoxy or C _1-4 haloalkoxy.

[00156] In an embodiment,

X is:

Z is selected from: wherein

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

(ii) R _3a1 , R _3a2 , R _3i1 , R _3i2 , R _3l1 , R _3l2 , R _3r1 , R _3r2 , are as defined herein;

(iii) A ₅ , A ₆ , R _Z1 , R _Z2 and R _zi1b are as defined herein.

[00157] In an embodiment,

X is:

Z is selected from: wherein

(i) R _1a , R _1a’ , R _1b , and R _Za are as defined herein;

(ii) R _3a1 , R _3a2 , R _3i1 , R _3i2 , R _3l1 , R _3l2 , R _3r1 , R _3r2 , R ₈ , R ₁₀ , R ₁₇ , R ₁₈ and R _Z1 are as defined herein; (iii) R ₈ , R ₁₀ , R ₁₇ , R ₁₈ and R _Z1 are as defined herein.

[00158] In a particular group of compounds of the invention, Y is as defined in paragraph (47), 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.

[00159] In an embodiment of the compounds of formula (II):

X is as defined in any one of paragraphs (33) to (35) or (36) to (37) above, suitably X is as defined in paragraph (33) or (37); and R _1b , R _1d and R _1f are each as defined in any one of paragraphs (6) to (18) or (19) to (27) above

R _3a1 is as defined in any one of paragraphs from (38) to (41), and paragraphs (43) and (44) above;

R _3a2 is as defined in any one of paragraphs (42), (43) and (44) above; n is as defined in any one of paragraphs (45) and (46) above; and

Suitably, Z is as defined in any one of paragraphs from (119) to (126) above. Suitably, Z is as defined in any one of paragraphs from (123) to (126) above.

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

X is as defined in paragraph (33), (34) or (35) above and R _1b , R _1d and R _1f are each as defined in any one of paragraphs (6) to (18) or (25) to (27) above;

R _3a1 is as defined in paragraph (41) above;

R _3a2 is as defined in paragraph (42) above; n is as defined in paragraph (46) above; and

Z is as defined in any one of paragraphs (123) to (126) above.

[00161] In an embodiment of the compounds of formula (II):

X is as defined in paragraph (33) above and R _1b , R _1d and R _1f are each as defined in any one of paragraphs (16) to (18) or (25) to (27) above;

R _3a1 is as defined in paragraph (41) above;

R _3a2 is as defined in paragraph (42) above; n is as defined in paragraph (46) above; and

Z is as defined in paragraph (126) above.

[00162] In a particular group of compounds of the invention, Y is as defined in paragraph (58), i.e. the compounds have the structural formula (III) (a sub-definition of formula (1)) shown below: wherein X, R _3i1 , R _3i2 , n and Z each having any one of the meanings defined herein; or a pharmaceutically acceptable salt thereof.

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

X is as defined in any one of paragraphs (33) to (35) or (36) to (37) above, suitably X is as defined in paragraph (33) or (37); and R _1b , R _1d and R _1f are each as defined in any one of paragraphs (6) to (18) or (19) to (27) above R _3i1 is as defined in any one of paragraphs from (38) to (41), and paragraphs (43) and (44) above; R _3i2 is as defined in any one of paragraphs (42), (43) and (44) above; n is as defined in any one of paragraphs (45) and (46) above; and

Suitably, Z is as defined in any one of paragraphs from (119) to (126) above. Suitably, Z is as defined in any one of paragraphs from (123) to (126) above.

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

X is as defined in paragraph (33), (34) or (35) above and R _1b , R _1d and R _1f are each as defined in any one of paragraphs (6) to (18) or (25) to (27) above; R _3i1 is as defined in paragraph (41) above; R _3i2 is as defined in paragraph (42) above; n is as defined in paragraph (46) above; and

Z is as defined in any one of paragraphs (123) to (126) above.

[00165] In an embodiment of the compounds of formula (III):

X is as defined in paragraph (33) above and R _1b , R _1d and R _1f are each as defined in any one of paragraphs (16) to (18) or (25) to (27) above; R _3i1 is as defined in paragraph (41) above; R _3i2 is as defined in paragraph (42) above; n is as defined in paragraph (46) above; and

Z is as defined in paragraph (126) above. [00166] In a particular group of compounds of the invention, X is as defined in paragraph (33), 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.

[00167] In an embodiment of the compounds of formula (IV): R _1a is as defined in any one of paragraphs (1) to (5) above; R _1b is as defined in any one of paragraphs (6) to (18) or (19) to (27) above; R _1a’ is as defined in any one of paragraphs (28) to (30) above; R _2a is as defined in any one of paragraphs (31) and (32) above;

Y is as defined in any one of paragraphs (47) to (72) above; and

Z is as defined in any one of paragraphs from (119) to (126) above.

[00168] In an embodiment of the compounds of formula (IV): R _1a is as defined in any one of paragraphs (3) to (5) above; R _1b is as defined in any one of paragraphs (16) to (18) or (25) to (27) above ; R _1a’ is as defined in any one of paragraphs (28) to (30) above; R _2a is as defined in any one of paragraphs (31) and (32) above;

Y is as defined in any one of paragraphs (69) to (72) above; and

Z is as defined in any one of paragraphs from (123) to (126) above.

[00169] In an embodiment of the compounds of formula (IV): R _1a is as defined in paragraph (5) above; R _1b is as defined in paragraph ((18) above; R _1a’ is as defined in paragraph (30) above; R _2a is as defined in paragraph (32) above;

Y is as defined in any one of paragraphs (71) to (72) above; and

Z is as defined in any one of paragraphs from (123) to (126) above.

[00170] In an embodiment of the compounds of formula (IV): R _1a is as defined in any one of paragraphs (3) to (5) above; R _1b is as defined in any one of paragraphs (16) to (18) or (25) to (27) above ; R _1a’ is as defined in any one of paragraphs (28) to (30) above; R _2a is as defined in any one of paragraphs (31) and (32) above;

Y is as defined in any one of paragraphs (69) to (72) above; and

Z is as defined in any one of paragraphs from (84a), (87a), (88a), (88b), (89a), (89b) or (89c) above.

[00171] In an embodiment of the compounds of formula (IV): R _1a is as defined in paragraph (5) above; R _1b is as defined in paragraph (18) above; R _1a’ is as defined in paragraph (30) above; R _2a is as defined in paragraph (32) above;

Y is as defined in any one of paragraphs (71) to (72) above; and

Z is as defined in any one of paragraphs (84a), (87a), (88a), (88b), (89a), (89b) or (89c) above.

[00172] In a particular group of compounds of the invention, X is as defined in paragraph (33) and Y is as defined in paragraph (47), 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.

[00173] In an embodiment of the compounds of formula (V): R _1a is as defined in any one of paragraphs (1) to (5) above; R _1b is as defined in any one of paragraphs (6) to (18) above or (19) to (27); R _1a’ is as defined in any one of paragraphs (28) to (30) above; R _2a is as defined in any one of paragraphs (31) and (32) above;

R _3a1 is as defined in any one of paragraphs from (38) to (41), and paragraphs (43) and (44) above;

R _3a2 is as defined in any one of paragraphs (42), (43) and (44) above; n is as defined in any one of paragraphs (45) and (46) above; and

Z is as defined in any one of paragraphs from (119) to (126) above .

[00174] In a particular group of the compounds of formula (V): R _1a is as defined in any one of paragraphs (1) to (5) above; R _1b is as defined in paragraph (10) to (18) above, or (25) to (27); R _1a’ is as defined in any one of paragraphs (28) to (30) above; R _2a is as defined in any one of paragraphs (31) and (32) above;

R _3a1 is as defined in any one of paragraphs from (38) to (41), and paragraphs (43) and (44) above;

R _3a2 is as defined in any one of paragraphs (42), (43) and (44) above; n is as defined in any one of paragraphs (45) and (46) above; and

Z is as defined in any one of paragraphs (123) to (126) above.

[00175] In an embodiment of the compounds of formula (V): R _1a is as defined in paragraph (6) above; R _1a’ is as defined in paragraph (17) above; R _1b is as defined in any one of paragraphs (16), (17) or (18) or above, or R _1b is as defined in any one of paragraphs (26) or (27); R _2a is as defined in paragraph (19) above;

R _3a1 is as defined in paragraph (41) above; R _3a2 is as defined in paragraph (42) above; n is as defined in paragraph (46) above; and

Z is as defined in paragraph (126) above.

[00176] In an embodiment of the compounds of formula (V): R _1a is as defined in any one of paragraphs (1) to (5) above; R _1b is as defined in any one of paragraphs (6) to (18) above or (19) to (27); R _1a’ is as defined in any one of paragraphs (28) to (30) above; R _2a is as defined in any one of paragraphs (31) and (32) above;

R _3a1 is as defined in any one of paragraphs from (38) to (41), and paragraphs (43) and (44) above;

R _3a2 is as defined in any one of paragraphs (42), (43) and (44) above; n is as defined in any one of paragraphs (45) and (46) above; and

Z is as defined in any one of paragraphs (84a), (87a), (88a), (88b), (89a), (89b) or (89c) above.

[00177] In a particular group of the compounds of formula (V): R _1a is as defined in any one of paragraphs (1) to (5) above; R _1b is as defined in paragraph (10) to (18) above, or (25) to (27); R _1a’ is as defined in any one of paragraphs (28) to (30) above; R _2a is as defined in any one of paragraphs (31) and (32) above;

R _3a1 is as defined in any one of paragraphs from (38) to (41), and paragraphs (43) and (44) above;

R _3a2 is as defined in any one of paragraphs (42), (43) and (44) above; n is as defined in any one of paragraphs (45) and (46) above; and

Z is as defined in any one of paragraphs (84a), (87a), (88a), (88b), (89a), (89b) or (89c) above.

[00178] In an embodiment of the compounds of formula (V): R _1a is as defined in paragraph (6) above; R _1a’ is as defined in paragraph (17) above; R _1b is as defined in any one of paragraphs (16), (17) or (18) or above, or R _1b is as defined in any one of paragraphs (26) or (27); R _2a is as defined in paragraph (19) above; R _3a1 is as defined in paragraph (41) above;

R _3a2 is as defined in paragraph (42) above; n is as defined in paragraph (46) above; and

Z is as defined in any one of paragraphs (84a), (87a), (88a), (88b), (89a), (89b) or (89c) above.

[00179] 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 R _1a , R _1b , R _2a , R _3i1 , R _3i2 , n and Z each having any one of the meanings defined herein; or a pharmaceutically acceptable salt thereof.

[00180] In an embodiment of the compounds of formula (VI): R _1a is as defined in any one of paragraphs (1) to (5) above; R _1b is as defined in any one of paragraphs (6) to (18) above or (19) to (27) above; R _1a’ is as defined in any one of paragraphs (28) to (30) above;

R _2a is as defined in any one of paragraphs (31) and (32) above; R _3i1 is as defined in any one of paragraphs from (38) to (41), and paragraphs (43) and (44) above;

R _3i2 is as defined in any one of paragraphs (42), (43) and (44) above; n is as defined in any one of paragraphs (45) and (46) above; and

Z is as defined in any one of paragraphs from (119) to (126) above .

[00181] In a particular group of the compounds of formula (VI): R _1a is as defined in any one of paragraphs (1) to (5) above; R _1b is as defined in paragraph (10) to (18) above, or (25) to (27) above; R _1a’ is as defined in any one of paragraphs (28) to (30) above; R _2a is as defined in any one of paragraphs (31) and (32) above; R _3i1 is as defined in any one of paragraphs from (38) to (41), and paragraphs (43) and (44) above;

R _3i2 is as defined in any one of paragraphs (42), (43) and (44) above; n is as defined in any one of paragraphs (45) and (46) above; and

Z is as defined in any one of paragraphs (123) to (126) above.

[00182] In an embodiment of the compounds of formula (VI): R _1a is as defined in paragraph (6) above; R _1a’ is as defined in paragraph (17) above; R _1b is as defined in any one of paragraphs (16), (17) or (18) or above, or R _1b is as defined in any one of paragraphs (26) or (27); R _2a is as defined in paragraph (19) above; R _3i1 is as defined in paragraph (41) above;

R _3i2 is as defined in paragraph (42) above; n is as defined in paragraph (46) above; and

Z is as defined in paragraph (126) above.

[00183] In an embodiment of the compounds of formula (VI): R _1a is as defined in any one of paragraphs (1) to (5) above; R _1b is as defined in any one of paragraphs (6) to (18) above or (19) to (27) above; R _1a’ is as defined in any one of paragraphs (28) to (30) above; R _2a is as defined in any one of paragraphs (31) and (32) above; R _3i1 is as defined in any one of paragraphs from (38) to (41), and paragraphs (43) and (44) above;

R _3i2 is as defined in any one of paragraphs (42), (43) and (44) above; n is as defined in any one of paragraphs (45) and (46) above; and

Z is as defined in any one of paragraphs (84a), (87a), (88a), (88b), (89a), (89b) or (89c) above.

[00184] In a particular group of the compounds of formula (VI): R _1a is as defined in any one of paragraphs (1) to (5) above; R _1b is as defined in paragraph (10) to (18) above, or (25) to (27) above; R _1a’ is as defined in any one of paragraphs (28) to (30) above; R _2a is as defined in any one of paragraphs (31) and (32) above; R _3i1 is as defined in any one of paragraphs from (38) to (41), and paragraphs (43) and (44) above;

R _3i2 is as defined in any one of paragraphs (42), (43) and (44) above; n is as defined in any one of paragraphs (45) and (46) above; and

Z is as defined in any one of paragraphs (84a), (87a), (88a), (88b), (89a), (89b) or (89c) above

[00185] In an embodiment of the compounds of formula (VI): R _1a is as defined in paragraph (6) above; R _1a’ is as defined in paragraph (17) above; R _1b is as defined in any one of paragraphs (16), (17) or (18) or above, or R _1b is as defined in any one of paragraphs (26) or (27); R _2a is as defined in paragraph (19) above; R _3i1 is as defined in paragraph (41) above; R _3i2 is as defined in paragraph (42) above; n is as defined in paragraph (46) above; and

Z is as defined in any one of paragraphs (84a), (87a), (88a), (88b), (89a), (89b) or (89c) above.

[00186] In a particular group of compounds of the invention, X is as defined in paragraph (20), Rw is as defined in paragraph (17) and Y is as defined in paragraph (36), i.e. the compounds have the structural formula (VII) (a sub-definition of formula (I)) shown below: wherein R _1a , R _1b , R _2a , R _3i1 , R _3i2 , n and Z each having any one of the meanings defined herein; or a pharmaceutically acceptable salt thereof.

[00187] In an embodiment of the compounds of formula (VII): R _1a is as defined in any one of paragraphs (1) to (5) above; R _1b is as defined in any one of paragraphs (6) to (18), or (19) to (27) above; R _2a is as defined in any one of paragraphs (31) to (32) above;

Y is as defined in any one of paragraphs (69) to (72) above; R ₈ , R ₉ , R ₁₀ and R ₁₁ are as defined in any one of paragraphs (130) to (133) above;

[00188] In an embodiment of the compounds of formula (VII): R _1a is as defined in any one of paragraphs (1) to (5) above; R _1b is as defined in paragraph (10) to (18) above, or (25) to (27) above; R _1a’ is as defined in any one of paragraphs (28) to (30) above; R _2a is as defined in any one of paragraphs (31) and (32) above;

Y is as defined in any one of paragraphs (69) to (72) above; R ₈ , R ₉ , R ₁₀ and R ₁₁ are as defined in any one of paragraphs (132) to (133) above;

[00189] In particular group of the compounds of formula (VII): R _1a is as defined paragraph (5) above; R _1b is as defined in any one of paragraphs (16), (17) or (18) or above, or R _1b is as defined in any one of paragraphs (26) or (27); R _2a is as defined in paragraph (32) above;

Y is as defined in paragraph (72) above; R ₈ , R ₉ , R ₁₀ and R ₁₁ are as defined in paragraph (133) above;

[00190] In an embodiment of the compounds of formula (VII):

Rw is as defined in any one of paragraphs (1) to (5) above; R _1b is as defined in any one of paragraphs (6) to (18), or (19) to (27) above; R _2a is as defined in any one of paragraphs (31) to (32) above;

Y is as defined in any one of paragraphs (69) to (72) above; R ₈ , R ₉ , R ₁₀ and R ₁₁ are as defined in any one of paragraphs (129a), (130a), (133a), (133b) or (133c) above; [00191] In an embodiment of the compounds of formula (VII): R _1a is as defined in any one of paragraphs (1) to (5) above; R _1b is as defined in paragraph (10) to (18) above, or (25) to (27) above; R _1a’ is as defined in any one of paragraphs (28) to (30) above;

R _2a is as defined in any one of paragraphs (31) and (32) above;

Y is as defined in any one of paragraphs (69) to (72) above; R ₈ , R ₉ , R ₁₀ and R ₁₁ are as defined in any one of paragraphs (129a), (130a), (133a), (133b) or (133c) above;

[00192] In particular group of the compounds of formula (VII): R _1a is as defined paragraph (5) above; R _1b is as defined in any one of paragraphs (16), (17) or (18) or above, or R _1b is as defined in any one of paragraphs (26) or (27);

R _2a is as defined in paragraph (32) above;

Y is as defined in paragraph (72) above; R ₈ , R ₉ , R ₁₀ and R ₁₁ are as defined in paragraph (129a), (130a), (133a), (133b) or (133c) above;

[00193] In a particular group of compounds of the invention, X is as defined in paragraph (20), Rw is as defined in paragraph (17) and Y is as defined in paragraph (36), i.e. the compounds have the structural formula (VII) (a sub-definition of formula (I)) shown below: wherein R _1a , R _1b , R _2a , R _3i1 , R _3i2 , n and Z each having any one of the meanings defined herein; or a pharmaceutically acceptable salt thereof. [00194] In an embodiment of the compounds of formula (VIII): R _1a is as defined in any one of paragraphs (1) to (5) above; R _1b is as defined in any one of paragraphs (6) to (18), or (19) to (27) above; R _2a is as defined in any one of paragraphs (31) to (32) above;

Y is as defined in any one of paragraphs (69) to (72) above;

A ₅ is CR ₁₆ , and R ₁₆ is as defined in any one of paragraphs (147), (148) and (156) to (159). above;

A ₆ is CR ₁₇ and R ₁₇ is as defined in any one of paragraphs (160) to (166) above;

R _Z1 is as defined in any one of paragraphs (134) to (137) above;

R _Z2 is as defined in any one of paragraphs (138) to (140) above; and

R _Zi2b is as defined in any one of paragraphs (138) to (140) above.

[00195] In an particular group of the compounds of formula (VIII): R _1a is as defined in any one of paragraphs (1) to (5) above; R _1b is as defined in paragraph (10) to (18) above, or (25) to (27) above; R _1a’ is as defined in any one of paragraphs (28) to (30) above;

R _2a is as defined in any one of paragraphs (31) and (32) above;

Y is as defined in any one of paragraphs (69) to (72) above;

A ₅ is CR ₁₆ , and R ₁₆ is as defined in any one of paragraphs (156) to (159). above;

A ₆ is CR ₁₇ and R ₁₇ is as defined in any one of paragraphs (163) to (166) above;

R _Z1 is as defined in any one of paragraphs (135) to (137) above;

R _Z2 is as defined in any one of paragraphs (139) to (140) above; and

R _Zi2b is as defined in any one of paragraphs (139) to (140) above.

[00196] In particular group of the compounds of formula (VIII): R _1a is as defined paragraph (5) above; R _1b is as defined in any one of paragraphs (16), (17) or (18) or above, or R _1b is as defined in any one of paragraphs (26) or (27);

R _2a is as defined in paragraph (32) above;

Y is as defined in paragraph (72) above;; A ₅ is CR ₁₆ , and R ₁₆ is as defined in paragraph (159) above;

A ₆ is CR ₁₇ and R ₁₇ is as defined in paragraph (166) above;

R _Z1 is as defined in paragraph (137) above;

R _Z2 is as defined in paragraph (140) above, i.e. R _Z2 is hydrogen; and

R _Zi2b is as defined in in paragraph (140) above, i.e. R _zi1b is hydrogen.

[00197] In certain embodiments of the invention, when

[00198] In certain embodiments of the invention, when and

[00199] 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-{[(cyclohexylmethyl)amino]methyl}imidazo[1,2-a]pyri din-2-yl)methyl]-1,2-dimethyl-6- oxo-1,6-dihydropyrimidine-4-carboxamide;

N-({6-methylimidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H-q uinolizine-2-carboxamide;

N-[(6-{[(cyclohexylmethyl)amino]methyl}imidazo[1,2-a]pyri din-2-yl)methyl]-4-oxo-4H- quinolizine-2-carboxamide;

N-[(6-{[(cyclohexylmethyl)amino]methyl}imidazo[1,2-a]pyri din-2-yl)methyl]quinoxaline-2- carboxamide;

N-[(6-{[(cyclohexylmethyl)amino]methyl}imidazo[1,2-a]pyri din-2-yl)methyl]-1H-pyrazolo[3,4- b]pyridine-4-carboxamide;

N-[(6-{[(cyclohexylmethyl)amino]methyl}imidazo[1,2-a]pyri din-2-yl)methyl]quinoline-3- carboxamide;

N-[(6-{[(cyclobutylmethyl)amino]methyl}imidazo[1,2-a]pyri din-2-yl)methyl]imidazo[1,5- a]pyridine-8-carboxamide;

N-[(6-{[(cyclobutylmethyl)amino]methyl}imidazo[1,2-a]pyri din-2-yl)methyl]imidazo[1,5- a]pyridine-5-carboxamide;

N-[(6-{[(cyclobutylmethyl)amino]methyl}imidazo[1,2-a]pyri din-2-yl)methyl]-3H-imidazo[4,5- b]pyridine-6-carboxamide;

N-[(6-{[(cyclobutylmethyl)amino]methyl}imidazo[1,2-a]pyri din-2-yl)methyl]-1H-pyrrolo[2,3- b]pyridine-5-carboxamide;

N-{[6-({[(3,3-difluorocyclobutyl)methyl]amino}methyl)imid azo[1,2-a]pyridin-2-yl]methyl}-1H- pyrrolo[2,3-b]pyridine-5-carboxamide;

N-[(6-{[(cyclobutylmethyl)amino]methyl}imidazo[1,2-a]pyri din-2-yl)methyl]-1-methyl-1H- pyrrolo[2,3-b]pyridine-5-carboxamide N-[(6-{[(cyclobutylmethyl)amino]methyl}imidazo[1,2-a]pyridin -2-yl)methyl]-1H-indole-5- carboxamide;

N-[(6-{[(cyclobutylmethyl)amino]methyl}imidazo[1,2-a]pyri din-2-yl)methyl]-5H-pyrrolo[2,3- b]pyrazine-2-carboxamide;

N-[(6-{[({3-fluorobicyclo[1.1.1]pentan-1-yl}methyl)amino] methyl}imidazo[1,2-a]pyridin-2- yl)methyl]-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-7-carboxa mide;

4-[1-[(6-methylimidazo[1,2-a]pyridin-2-yl)methyl]triazol- 4-yl]isoquinoline;

1-({6-methylimidazo[1,2-a]pyridin-2-yl}methyl)-4-{1H-pyrr olo[2,3-b]pyridin-5-yl}-1H-1,2,3- triazole;

(cyclobutylmethyl)({2-[(4-{6-methoxyimidazo[1,5-a]pyridin -8-yl}-1H-1,2,3-triazol-1- yl)methyl]imidazo[1,2-a]pyridin-6-yl}methyl)amine;

(cyclobutylmethyl)({2-[(4-{imidazo[1,5-a]pyridin-8-yl}-1H -1,2,3-triazol-1-yl)methyl]imidazo[1,2- a]pyridin-6-yl}methyl)amine;

({2-[(4-{6-chloroimidazo[1,5-a]pyridin-8-yl}-1H-1,2,3-tri azol-1-yl)methyl]imidazo[1,2-a]pyridin- 6-yl}methyl)(cyclobutylmethyl)amine;

(cyclobutylmethyl)({2-[(4-{1-fluoroimidazo[1,5-a]pyridin- 8-yl}-1H-1,2,3-triazol-1- yl)methyl]imidazo[1,2-a]pyridin-6-yl}methyl)amine;

({3-fluorobicyclo[1.1.1]pentan-1-yl}methyl)({2-[(4-{6-met hoxyimidazo[1,5-a]pyridin-8-yl}-1H- 1,2,3-triazol-1-yl)methyl]imidazo[1,2-a]pyridin-6-yl}methyl) amine;

(cyclobutylmethyl)({2-[(4-{[1,2,4]triazolo[4,3-a]pyridin- 8-yl}-1H-1,2,3-triazol-1- yl)methyl]imidazo[1,2-a]pyridin-6-yl}methyl)amine;

({bicyclo[1.1.1]pentan-1-yl}methyl)({2-[(4-{6-methoxyimid azo[1,5-a]pyridin-8-yl}-1H-1,2,3- triazol-1-yl)methyl]imidazo[1,2-a]pyridin-6-yl}methyl)amine;

2-({2-[(4-{imidazo[1,5-a]pyridin-8-yl}-1H-1,2,3-triazol-1 -yl)methyl]imidazo[1,2-a]pyridin-6- yl}methyl)-2-azaspiro[3.3]heptane;

2-({2-[(4-{6-methoxyimidazo[1,5-a]pyridin-8-yl}-1H-1,2,3- triazol-1-yl)methyl]imidazo[1,2- a]pyridin-6-yl}methyl)-2-azaspiro[3.3]heptane;

N-(cyclobutylmethyl)-1-[2-[[4-(4-isoquinolyl)triazol-1-yl ]methyl]imidazo[1,2-a]pyridin-6- yl]methanamine; bis(cyclobutylmethyl)[(2-{[4-(isoquinolin-4-yl)-1H-1,2,3-tri azol-1-yl]methyl}imidazo[1,2- a]pyridin-6-yl)methyl]amine;

(cyclobutylmethyl)({2-[(4-{1H-pyrrolo[2,3-b]pyridin-5-yl} -1H-1,2,3-triazol-1- yl)methyl]imidazo[1,2-a]pyridin-6-yl}methyl)amine;

(cyclobutylmethyl)({2-[(4-{1H-pyrrolo[2,3-b]pyridin-5-yl} -1H-imidazol-1-yl)methyl]imidazo[1,2- a]pyridin-6-yl}methyl)amine; cyclobutylmethyl)({2-[(4-{imidazo[1,5-a]pyridin-5-yl}-1H-1,2 ,3-triazol-1-yl)methyl]imidazo[1,2- a]pyridin-6-yl}methyl)amine; ({3-fluorobicyclo[1.1.1]pentan-1-yl}methyl)({2-[(4-{3-methyl imidazo[1,5-a]pyridin-8-yl}-1H- 1,2,3-triazol-1-yl)methyl]imidazo[1,2-a]pyridin-6-yl}methyl) amine;

3-{1-[(6-{[({bicyclo[1.1.1]pentan-1-yl}methyl)amino]methy l}imidazo[1,2-a]pyridin-2-yl)methyl]- 1H-1 ,2,3-triazol-4-yl}-5-methoxypyridine-2-carbonitrile.

[00200] 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-{[(cyclohexylmethyl)amino]methyl}imidazo[1,2-a]pyri din-2-yl)methyl]-1,2-dimethyl-6- oxo-1,6-dihydropyrimidine-4-carboxamide;

N-({6-methylimidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H-q uinolizine-2-carboxamide;

N-[(6-{[(cyclohexylmethyl)amino]methyl}imidazo[1,2-a]pyri din-2-yl)methyl]-4-oxo-4H- quinolizine-2-carboxamide;

N-[(6-{[(cyclohexylmethyl)amino]methyl}imidazo[1,2-a]pyri din-2-yl)methyl]quinoxaline-2- carboxamide;

N-[(6-{[(cyclohexylmethyl)amino]methyl}imidazo[1,2-a]pyri din-2-yl)methyl]-1H-pyrazolo[3,4- b]pyridine-4-carboxamide;

N-[(6-{[(cyclohexylmethyl)amino]methyl}imidazo[1,2-a]pyri din-2-yl)methyl]quinoline-3- carboxamide;

N-[(6-{[(cyclobutylmethyl)amino]methyl}imidazo[1,2-a]pyri din-2-yl)methyl]imidazo[1,5- a]pyridine-8-carboxamide;

N-[(6-{[(cyclobutylmethyl)amino]methyl}imidazo[1,2-a]pyri din-2-yl)methyl]imidazo[1,5- a]pyridine-5-carboxamide;

N-[(6-{[(cyclobutylmethyl)amino]methyl}imidazo[1,2-a]pyri din-2-yl)methyl]-3H-imidazo[4,5- b]pyridine-6-carboxamide;

N-[(6-{[(cyclobutylmethyl)amino]methyl}imidazo[1,2-a]pyri din-2-yl)methyl]-1H-pyrrolo[2,3- b]pyridine-5-carboxamide;

N-{[6-({[(3,3-difluorocyclobutyl)methyl]amino}methyl)imid azo[1,2-a]pyridin-2-yl]methyl}-1H- pyrrolo[2,3-b]pyridine-5-carboxamide;

N-[(6-{[(cyclobutylmethyl)amino]methyl}imidazo[1,2-a]pyri din-2-yl)methyl]-1-methyl-1H- pyrrolo[2,3-b]pyridine-5-carboxamide

N-[(6-{[(cyclobutylmethyl)amino]methyl}imidazo[1,2-a]pyri din-2-yl)methyl]-1H-indole-5- carboxamide;

N-[(6-{[(cyclobutylmethyl)amino]methyl}imidazo[1,2-a]pyri din-2-yl)methyl]-5H-pyrrolo[2,3- b]pyrazine-2-carboxamide;

N-[(6-{[({3-fluorobicyclo[1.1.1]pentan-1-yl}methyl)amino] methyl}imidazo[1,2-a]pyridin-2- yl)methyl]-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-7-carboxa mide; 4-[1-[(6-methylimidazo[1,2-a]pyridin-2-yl)methyl]triazol-4-y l]isoquinoline;

1-({6-methylimidazo[1,2-a]pyridin-2-yl}methyl)-4-{1H-pyrr olo[2,3-b]pyridin-5-yl}-1H-1,2,3- triazole;

(cyclobutylmethyl)({2-[(4-{6-methoxyimidazo[1,5-a]pyridin -8-yl}-1H-1,2,3-triazol-1- yl)methyl]imidazo[1,2-a]pyridin-6-yl}methyl)amine;

(cyclobutylmethyl)({2-[(4-{imidazo[1,5-a]pyridin-8-yl}-1H -1,2,3-triazol-1-yl)methyl]imidazo[1,2- a]pyridin-6-yl}methyl)amine;

({2-[(4-{6-chloroimidazo[1,5-a]pyridin-8-yl}-1H-1,2,3-tri azol-1-yl)methyl]imidazo[1,2-a]pyridin-

6-yl}methyl)(cyclobutylmethyl)amine;

(cyclobutylmethyl)({2-[(4-{1-fluoroimidazo[1,5-a]pyridin- 8-yl}-1H-1,2,3-triazol-1- yl)methyl]imidazo[1,2-a]pyridin-6-yl}methyl)amine;

({3-fluorobicyclo[1.1.1]pentan-1-yl}methyl)({2-[(4-{6-met hoxyimidazo[1,5-a]pyridin-8-yl}-1H-

1,2,3-triazol-1-yl)methyl]imidazo[1,2-a]pyridin-6-yl}meth yl)amine;

(cyclobutylmethyl)({2-[(4-{[1,2,4]triazolo[4,3-a]pyridin- 8-yl}-1H-1,2,3-triazol-1- yl)methyl]imidazo[1,2-a]pyridin-6-yl}methyl)amine;

({bicyclo[1.1.1]pentan-1-yl}methyl)({2-[(4-{6-methoxyimid azo[1,5-a]pyridin-8-yl}-1H-1,2,3- triazol-1-yl)methyl]imidazo[1,2-a]pyridin-6-yl}methyl)amine;

2-({2-[(4-{imidazo[1,5-a]pyridin-8-yl}-1H-1,2,3-triazol-1 -yl)methyl]imidazo[1,2-a]pyridin-6- yl}methyl)-2-azaspiro[3.3]heptane;

2-({2-[(4-{6-methoxyimidazo[1,5-a]pyridin-8-yl}-1H-1,2,3- triazol-1-yl)methyl]imidazo[1,2- a]pyridin-6-yl}methyl)-2-azaspiro[3.3]heptane;

N-(cyclobutylmethyl)-1-[2-[[4-(4-isoquinolyl)triazol-1-yl ]methyl]imidazo[1,2-a]pyridin-6- yl]methanamine; bis(cyclobutylmethyl)[(2-{[4-(isoquinolin-4-yl)-1H-1,2,3-tri azol-1-yl]methyl}imidazo[1,2- a]pyridin-6-yl)methyl]amine;

(cyclobutylmethyl)({2-[(4-{1H-pyrrolo[2,3-b]pyridin-5-yl} -1H-1,2,3-triazol-1- yl)methyl]imidazo[1,2-a]pyridin-6-yl}methyl)amine;

(cyclobutylmethyl)({2-[(4-{1H-pyrrolo[2,3-b]pyridin-5-yl} -1H-imidazol-1-yl)methyl]imidazo[1,2- a]pyridin-6-yl}methyl)amine; cyclobutylmethyl)({2-[(4-{imidazo[1,5-a]pyridin-5-yl}-1H-1,2 ,3-triazol-1-yl)methyl]imidazo[1,2- a]pyridin-6-yl}methyl)amine;

({3-fluorobicyclo[1.1.1]pentan-1-yl}methyl)({2-[(4-{3-met hylimidazo[1,5-a]pyridin-8-yl}-1H- 1,2,3-triazol-1-yl)methyl]imidazo[1,2-a]pyridin-6-yl}methyl) amine;

3-{1-[(6-{[({bicyclo[1.1.1]pentan-1-yl}methyl)amino]methy l}imidazo[1,2-a]pyridin-2-yl)methyl]-

1H-1,2,3-triazol-4-yl}-5-methoxypyridine-2-carbonitrile

3-{1-[(6-{[(cyclobutylmethyl)amino]methyl}imidazo[1,2-a]p yridin-2-yl)methyl]-1H-1,2,3-triazol-

4-yl}-5-methoxypyridine-2-carbonitrile; 3-[1-({6-[(4,4-dimethylpiperidin-1-yl)methyl]imidazo[1,2-a]p yridin-2-yl}methyl)-1H-1,2,3- triazol-4-yl]-5-methoxypyridine-2-carbonitrile;

3-(1-{[6-({6-azaspiro[3.4]octan-6-yl}methyl)imidazo[1,2-a ]pyridin-2-yl]methyl}-1H-1,2,3- triazol-4-yl)-5-methoxypyridine-2-carbonitrile;

3-{1-[(6-{[({3-fluorobicyclo[1.1.1]pentan-1-yl}methyl)ami no]methyl}imidazo[1,2-a]pyridin-2- yl)methyl]-1H-1,2,3-triazol-4-yl}-5-methoxypyridine-2-carbon itrile;

3-(1-{[6-({6-azaspiro[3.4]octan-6-yl}methyl)imidazo[1,2-a ]pyridin-2-yl]methyl}-1H-1,2,3- triazol-4-yl)-5-fluoropyridine-2-carbonitrile;

5-fluoro-3-{1-[(6-{[({3-fluorobicyclo[1.1.1]pentan-1-yl}m ethyl)amino]methyl}imidazo[1,2- a]pyridin-2-yl)methyl]-1H-1,2,3-triazol-4-yl}pyridine-2-carb onitrile;

({3-fluorobicyclo[1.1.1]pentan-1-yl}methyl)[(2-{[4-(6-met hoxypyrazin-2-yl)-1H-1,2,3-triazol-1- yl]methyl}imidazo[1,2-a]pyridin-6-yl)methyl]amine;

({3-fluorobicyclo[1.1.1]pentan-1-yl}methyl)[(2-{[4-(5-met hoxypyridin-3-yl)-1H-1,2,3-triazol-1- yl]methyl}imidazo[1,2-a]pyridin-6-yl)methyl]amine;

N-[(6-{[(cyclobutylmethyl)amino]methyl}imidazo[1,2-a]pyri din-2-yl)methyl]-5-methoxypyridine- 3-carboxamide;