Piperidine-2, 6-dione derivatives pharmaceutical compounds

Abstract

The invention provides new pyrazine derivatives of formula (I): (I) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof, wherein the substituents are as defined herein. The invention also provides pharmaceutical compositions comprising said compounds and to the use of said compounds in the treatment of diseases, e.g. cancer.

Description

[0001] PIPERIDINE-2, 6-DIONE DERIVATIVES PHARMACEUTICAL COMPOUNDS

[0002] FIELD OF THE INVENTION

[0003] The invention relates to new cyclic imide derivatives, to pharmaceutical compositions comprising said compounds and to the use of said compounds in the treatment of diseases, e.g. cancer.

[0004] SEQUENCE LISTING

[0005] The present specification makes reference to a Sequence Listing (submitted electronically as a .xml file named “P52387 Sequence Listing”). The .xml file was generated on 26 September 2025 and is 2 KB in size. The entire contents of the sequence listing are herein incorporated by reference.

[0006] BACKGROUND OF THE INVENTION

[0007] Histone lysine residues are subject to a wide range of post-translational modifications including methylation, acetylation, and ubiquitination to regulate DNA processes including replication and transcription. Distinct classes of enzymes such as histone acetyltransferases and histone deacetylases catalyse the acetylation or deacetylation of histones, respectively.

[0008] The lysine acetyltransferase paralogues CREBBP (CBP) and EP300 (p300) are ubiquitously expressed, highly homologous, multidomain enzymes with high sequence homology between the bromodomain (BRD) and catalytic histone acetyltransferase (HAT) domains. The catalytic activity of the CBP / p300 HAT domain refers specifically to the attachment of an acetyl group to a lysine side chain of histones and acetylated histones are associated with increased gene expression.

[0009] CBP / p300 are involved in many cellular processes including proliferation, cell cycle and cell differentiation and act as transcriptional coactivators to regulate gene expression by directing chromatin accessibility via acetylation of histones. Missense mutations in CBP cluster around the region encoding the HAT domain which ablates transcriptional coactivation activity. Additionally, gross deletions and protein-truncating mutations can occur. Dysregulation can lead to oncogenic gene expression and signalling; hence aberrant activity has been associated with cancer and disease processes involving the immune system, haematopoiesis and the heart. Chemical inhibition of CBP / p300 therefore has therapeutic potential in cancer and other diseases (Chen Q, Yang B, Liu X, et al. Histone acetyltransferases CBP / p300 in tumorigenesis and CBP / p300 inhibitors as promising novel anticancer agents; Theranostics, 2022 ;12(11):4935-4948).

[0010] The present invention describes a novel series of compounds that inhibit CBP / p300 and that have anticancer activity.

[0011] SUMMARY OF THE INVENTION

[0012] In a first aspect the invention provides a compound of formula (I):

[0013] or a tautomer or a solvate or a pharmaceutically acceptable salt thereof, wherein:

[0014] Ring X is selected from an aryl, cycloalkenyl, heteroaryl and partially unsaturated heterocyclyl group, wherein the heteroaryl or partially unsaturated heterocyclyl group comprises one or more (e.g. 1 , 2 or 3) heteroatoms selected from O, N or S; t is selected from 0, 1 , 2, 3 and 4

[0015] Raand R2are independently selected from hydrogen, halogen, nitro, nitrile, C1-6alkoxy, haloC1-6alkoxy, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, haloC1-6alkyl, -(CH2)k-O- C1-6alkyl, -(CH2)k-S-C1-6alkyl, hydroxyl, hydroxyC1-6alkyl, -SC1-6alkyl, -SH, -NHe(C1-4alkyl)2-e, C3-6cycloalkyl, C3-6cycloalkenyl and heterocyclic group (e.g. an aromatic ring or a non-aromatic ring) wherein the heterocyclic group has 3 to 6 ring members and wherein the heterocyclic group comprises one or more (e.g. 1 , 2 or 3) heteroatoms selected from N, O, S and oxidised forms thereof; or when t is 2 or more and the two Ragroups are joined to the same carbon, the two Ragroups together with the carbon to which they are attached join to form an =O (oxo), =CH2, spirocyclic C3-6carbocyclic group or a spirocyclic non-aromatic heterocyclic group with 3 to 6 ring-members containing one or more (e.g. 1 , 2 or 3) heteroatoms selected from O, N or S or oxidised forms thereof; wherein either:

[0016] • A is CR32, NR3’ or O; B is O; R3are independently selected from hydrogen, halogen and C1-4alkyl; R3’ is selected from hydrogen and C1-4alkyl; and R4is Ring Y wherein Ring Y is selected from a cycloalkyl, aryl group or a heterocyclyl group (e.g. an aromatic ring or a non-aromatic ring), wherein the heterocyclyl group comprises one or more (e.g.1 , 2, or 3) heteroatoms selected from N, O and S and wherein the cycloalkyl, aryl or heterocyclyl group is optionally substituted with one or more (e.g. 1 , 2 or 3) R6groups, or

[0017] • A is CR32, NR3’ or O; B is NR5; R3are independently selected from hydrogen, halogen and C1-4alkyl; R3’ is selected from hydrogen and C1-4alkyl; and R4and R5together with the atoms to which they are attached join to form a heterocyclic group (e.g. an aromatic ring or a non-aromatic ring), wherein the heterocyclic group optionally comprises one or more additional heteroatoms selected from N, O or S, and oxidised forms thereof, wherein the heterocyclic group may optionally be substituted with one or more (e.g. 1 , 2 or 3) R6groups; or

[0018] • A is CR32 or NR3’; B is NR5; R5and R3’ or one R3group together with the atoms to which they are attached join to form a heterocyclic group (e.g. an aromatic ring or a non-aromatic ring), wherein the heterocyclic group optionally comprises one or more additional heteroatoms selected from N, O or S, and oxidised forms thereof, wherein the heterocyclic group may optionally be substituted with one or more (e.g. 1 , 2 or 3) R6groups; the other R3group is selected from hydrogen, halogen and C1-4alkyl; and R4is selected from hydrogen and Cwalkyl; n is selected from 0, 1 , 2, 3 or 4;

[0019] R1and R6are independently selected from hydroxyl, halogen, nitro, nitrile, C1-6alkyl, nitrileC1-6alkyl, C1-6alkoxy, haloC1-6alkyl, C2-6alkenyl, C2-6alkynyl, =O (oxo), -C(=O)C1-6alkyl, -SH, -SC1-6alkyl, -SO2C1-6alkyl, C1-6alkylSO2C1-6alkyl, -SO2NRxRy, -C1-6alkyl-SO2NRxRy-NRxRy, -C(=O)NRxRy, -NRxC(=O)C1-6alkyl, C1-6alkylNHC(=O)C1-6alkyl, -(CH2)k-O-C1-6alkyl, hydroxyC1-6alkyl, hydroxyC1-6alkoxy, haloC1-6alkoxy, - C(=O)C1-6alkyl-OH, -C(=O)C1-6alkyl-N(H)e(C1-6alkyl)2-e, CO2C1-6alkyl, C1-6alkylCO2C1-6alkyl, -(CRxRy)v- CONRxRy, -CO2H, -C1-6alkylCO2H, -C1-6alkyl-NRxRy, -P(=O)(Rx)(Ry), C3-8cycloalkyl, C3-8cycloalkenyl, C8- waryl, and heterocyclic groups (e.g. an aromatic ring or a non-aromatic ring) with 3 to 8 ring members wherein the heterocyclic group comprises one or more (e.g.1 , 2, or 3) heteroatoms selected from N, O, S and oxidised forms thereof, wherein the C1-6alkyl groups is optionally substituted with a C3-8cycloalkyl, C3-8cycloalkenyl, C6-10aryl or 3 to 8 membered heterocyclic group (e.g. an aromatic ring or non-aromatic ring) containing one or more (e.g. 1 , 2 or 3) heteroatoms selected from O, N or S and wherein in each case the C3-8cycloalkyl, C3-8cycloalkenyl, Ce-waryl and 3 to 8 membered heterocyclic groups are optionally further substituted with one or more (e.g. 1 , 2 or 3) Rzgroups , or two R1or two R6groups together with the atoms to which they are attached join to form a C3-8cycloalkyl, C3-8cycloalkenyl, Ce-waryl or heterocyclic group with 3 to 8 ring members (e.g. an aromatic ring or a non-aromatic ring), wherein the heterocyclic group contains one or more (e.g. 1 , 2 or 3) heteroatoms selected from N, O, S and oxidised forms thereof and wherein the C3-8cycloalkyl, C3-8cycloalkenyl, Ce-ioaryl group or 3- to 8-membered heterocyclic ring be substituted by one or more Rzgroups;

[0020] RxRyand Rzare independently selected from hydrogen, halogen, nitro, nitrile, hydroxyl, =O (oxo), C1-ealkyl, haloC1-6alkyl, C2-6alkenyl, C2-6alkynyl, hydroxyC1-6alkyl, C1-6alkoxy, -NHe(C1-6alkyl)2-e, -C1-6alkylNHe(C1-6alkyl)2-e, hydroxyC1-6alkoxy, -(CH2)k-O- C1-6alkyl, -C(=O)C1-6alkyl, -(CH2)jCO2C1-6alkyl, - (CH2)k-C(=O)N(H)e(C1-6alkyl)2-e, -C(=O)C1-8alkyl-N(H)e(C1-6alkyl2-e, -(CH2)qCO2H C3-8cycloalkyl, C3-8cycloalkenyl and heterocyclic groups (e.g. an aromatic ring or a non-aromatic ring) with 3 to 8 ring members, wherein the heterocyclic group comprises one or more (e.g.1 , 2, or 3) heteroatoms selected from N, O, S and oxidised forms thereof; or Rxand Ry, or two Rzgroups, together with the atom(s) to which they are attached, join to form a C3-8cycloalkyl, C3-8cycloalkenyl, or heterocyclic group with 3 to 8 ring members (e.g. an aromatic ring or a non-aromatic ring), wherein the heterocyclic group comprises one or more (e.g.1 , 2, or 3) heteroatoms selected from N, O, S and oxidised forms thereof; wherein when Rxand Ryare C3-8cycloalkyl, C3-8cycloalkenyl or a heterocyclic group with 3 to 8 ring members or when Rxand Rytogether with the atom to which they are attached, join to form a C3-8cycloalkyl, C3 -8cycloalkenyl, or heterocyclic group with 3 to 8 ring members then the C3-8cycloalkyl, C3-8cycloalkenyl or heterocyclic group with 3 to 8 ring members is optionally further substituted with one or more (e.g. 1 , 2 or 3) Rzgroups; e, j, k and q are independently selected from 0, 1 and 2; v is selected from 0 and 1 .

[0021] In a second aspect, the invention provides a compound of formula (I): or a tautomer or a solvate or a pharmaceutically acceptable salt thereof, wherein:

[0022] Ring X is selected from an aryl, cycloalkenyl, heteroaryl and partially unsaturated heterocyclyl group, wherein the heteroaryl or partially unsaturated heterocyclyl group comprises one or more (e.g. 1 , 2 or 3) heteroatoms selected from O, N or S; t is selected from 0, 1 , 2, 3 and 4

[0023] R2is selected from halogen, nitro, nitrile, C1-6alkoxy, haloC1-6alkoxy, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, haloC1-6alkyl, -(CH2)k-O-C1-6alkyl, -(CH2)k-S-C1-6alkyl, hydroxyl, hydroxyC1-6alkyl, -SH, -NHe(C1-4alkyl)2-e, C3-6cycloalkyl, C3-6cycloalkenyl and heterocyclic group (e.g. an aromatic ring or a non-aromatic ring) wherein the heterocyclic group has 3 to 6 ring members and wherein the heterocyclic group comprises one or more (e.g. 1 , 2 or 3) heteroatoms selected from N, O, S and oxidised forms thereof;

[0024] Rais independently selected from hydrogen, halogen, nitro, nitrile, C1-6alkoxy, haloC1-6alkoxy, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, haloC1-6alkyl, -(CH2)k-O-C1-6alkyl, -(CH2)k-S-C1-6alkyl, hydroxyl, hydroxyC1-ealkyl, -SH, -NHe(C1-4alkyl)2-e, C3-6cycloalkyl, C3-6cycloalkenyl and heterocyclic group (e.g. an aromatic ring or a non-aromatic ring) wherein the heterocyclic group has 3 to 6 ring members and wherein the heterocyclic group comprises one or more (e.g. 1 , 2 or 3) heteroatoms selected from N, O, S and oxidised forms thereof; or when t is 2 or more and the two Ragroups are joined to the same carbon, the two Ragroups together with the carbon to which they are attached join to form an =O (oxo), =CH2, spirocyclic C3-6carbocyclic group or a spirocyclic non-aromatic heterocyclic group with 3 to 6 ring-members containing one or more (e.g. 1 , 2 or 3) heteroatoms selected from O, N or S or oxidised forms thereof; wherein either:

[0025] • A is CR32, NR3’ or O; B is O; R3are independently selected from hydrogen, halogen and C1-4alkyl; R3’ is selected from hydrogen and C1-4alkyl; and R4is Ring Y wherein Ring Y is selected from a cycloalkyl, aryl group or a heterocyclyl group (e.g. an aromatic ring or a non-aromatic ring), wherein the heterocyclyl group comprises one or more (e.g.1 , 2, or 3) heteroatoms selected from N, O and S and wherein the cycloalkyl, aryl or heterocyclyl group is optionally substituted with one or more (e.g. 1 , 2 or 3) R6groups, or

[0026] • A is CR32, NR3’ or O; B is NR5; R3are independently selected from hydrogen, halogen and C1-4alkyl; R3’ is selected from hydrogen and C1-4alkyl; and R4and R5together with the atoms to which they are attached join to form a heterocyclic group (e.g. an aromatic ring or a non-aromatic ring), wherein the heterocyclic group optionally comprises one or more additional heteroatoms selected from N, O or S, and oxidised forms thereof, wherein the heterocyclic group may optionally be substituted with one or more (e.g. 1 , 2 or 3) R6groups; or

[0027] • A is CR32 or NR3’; B is NR5; R5and R3’ or one R3group together with the atoms to which they are attached join to form a heterocyclic group (e.g. an aromatic ring or a non-aromatic ring), wherein the heterocyclic group optionally comprises one or more additional heteroatoms selected from N, O or S, and oxidised forms thereof, wherein the heterocyclic group may optionally be substituted with one or more (e.g. 1 , 2 or 3) R6groups; the other R3group is selected from hydrogen, halogen and C1-4alkyl; and R4is selected from hydrogen and Chalky!; n is selected from 0, 1 , 2, 3 or 4;

[0028] R1and R6are independently selected from hydroxyl, halogen, nitro, nitrile, C1-6alkyl, nitrileC1-6alkyl, C1-6alkoxy, haloC1-6alkyl, C2-6alkenyl, C2-6alkynyl, =O (oxo), -C(=O)C1-6alkyl, -SH, -SC1-6alkyl, -SO2C1-6alkyl, C1-6alkylSO2C1-6alkyl, -SO2NRxRy, -C1-6alkyl-SO2NRxRy, -NRxRy, -C(=O)NRxRy, -NRxC(=O)C1-6alkyl, C1-6alkylNHC(=O)C1-6alkyl, -(CH2)k-O-C1-6alkyl, hydroxyC1-6alkyl, hydroxyC1-6alkoxy, haloC1-6alkoxy, - C(=O)C1-6alkyl-OH, -C(=O)C1-6alkyl-N(H)e(C1-6alkyl)2-e, CCteC1-6alkyl, C1-6alkylCO2C1-6alkyl, -(CRxRy)v- CONRxRy, -CO2H, -C1-6alkylCO2H, -C1-6alkyl-NRxRy, -P(=O)(Rx)(Ry), C3-8cycloalkyl, C3-8cycloalkenyl, Ce- waryl, and heterocyclic groups (e.g. an aromatic ring or a non-aromatic ring) with 3 to 8 ring members wherein the heterocyclic group comprises one or more (e.g.1 , 2, or 3) heteroatoms selected from N, O, S and oxidised forms thereof, wherein the C1-6alkyl groups is optionally substituted with a C3-8cycloalkyl, C3-8cycloalkenyl, Ce-waryl or 3 to 8 membered heterocyclic group (e.g. an aromatic ring or non-aromatic ring) containing one or more (e.g. 1 , 2 or 3) heteroatoms selected from O, N or S and wherein in each case the C3-8cycloalkyl, C3-8cycloalkenyl, Cs-waryl and 3 to 8 membered heterocyclic groups are optionally further substituted with one or more (e.g. 1 , 2 or 3) Rzgroups, or two R1or two R6groups together with the atoms to which they are attached join to form a C3-8cycloalkyl, C3-8cycloalkenyl, Cs-waryl or heterocyclic group with 3 to 8 ring members (e.g. an aromatic ring or a non-aromatic ring), wherein the heterocyclic group contains one or more (e.g. 1 , 2 or 3) heteroatoms selected from N, O, S and oxidised forms thereof and wherein the C3-8cycloalkyl, C3-8cycloalkenyl, Ce-waryl group or 3- to 8-membered heterocyclic ring can be substituted by one or more Rzgroups;

[0029] RxRyand Rzare independently selected from hydrogen, halogen, nitro, nitrile, hydroxyl, =O (oxo), Ci- salkyl, haloC1-6alkyl, C2-salkenyl, C2-salkynyl, hydroxyC1-6alkyl, C1-salkoxy, -NHe(C1-6alkyl)2-e, -C1-6alkylNHe(C1-6alkyl)2-e, hydroxyC1-salkoxy, -(CH2)k-O-C1-6alkyl, -C(=O)C1-6alkyl, -(CH2)jCO2C1-6alkyl, - (CH2)k-C(=O)N(H)e(C1-6alkyl)2-e, -C(=O) C1-6alkyl-N(H)e(C1-6alkyl)2-e, -(CH2)qCO2H C3-8cycloalkyl, C3-8cycloalkenyl and heterocyclic groups (e.g. an aromatic ring or a non-aromatic ring) with 3 to 8 ring members, wherein the heterocyclic group comprises one or more (e.g.1 , 2, or 3) heteroatoms selected from N, O, S and oxidised forms thereof; or Rxand Ry, or two Rzgroups, together with the atom(s) to which they are attached, join to form a C3-8cycloalkyl, C3-8cycloalkenyl, or heterocyclic group with 3 to 8 ring members (e.g. an aromatic ring or a non-aromatic ring), wherein the heterocyclic group comprises one or more (e.g.1 , 2, or 3) heteroatoms selected from N, O, S and oxidised forms thereof; wherein when Rxand Ryare C3-8cycloalkyl, C3-8cycloalkenyl or a heterocyclic group with 3 to 8 ring members or when Rxand Rytogether with the atom to which they are attached, join to form a C3-8cycloalkyl, C3-8cycloalkenyl, or heterocyclic group with 3 to 8 ring members then the C3-8cycloalkyl, C3-8cycloalkenyl or heterocyclic group with 3 to 8 ring members is optionally further substituted with one or more (e.g, 1 , 2 or 3) Rzgroups; e, j, k and q are independently selected from 0, 1 and 2; v is selected from 0 and 1 .

[0030] In further aspects of the invention there is provided a compound of formula (I) for use in the prophylaxis or treatment of a disease or condition as described herein, methods for the prophylaxis or treatment of a disease or condition as described herein comprising administering to a patient a compound of formula (I), pharmaceutical compositions comprising a compound of formula (I) and processes for the synthesis of a compound of formula (I).

[0031] DEFINITIONS

[0032] Unless the context indicates otherwise, references to formula (I) in all sections of this document (including the uses, methods and other aspects of the invention) include references to all other sub- formula, sub-groups, embodiments and examples as defined herein.

[0033] “Potency” is a measure of drug activity expressed in terms of the amount required to produce an effect of given intensity. A highly potent drug evokes a larger response at low concentrations. Potency is proportional to affinity and efficacy. Affinity is the ability of the drug to bind to a receptor. Efficacy is the relationship between receptor occupancy and the ability to initiate a response at the molecular, cellular, tissue or system level.

[0034] The term “inhibitor” refers to an enzyme inhibitor that is a type of ligand or drug that blocks or dampens biological responses mediated by CBP / p300. Inhibitors mediate their effects by binding to the active site or to allosteric sites on enzymes, or they may interact at unique binding sites not normally involved in the biological regulation of the enzyme’s activity. The inhibition may arise directly or indirectly, and may be mediated by any mechanism and at any physiological level. As a result, inhibition by ligands or drugs may under different circumstances manifest itself in functionally different ways. Inhibitory activity may be reversible or irreversible depending on the longevity of the inhibitor-enzyme complex, which, in turn, depends on the nature of inhibitor-enzyme binding.

[0035] As used herein, the term “mediated”, as used e.g. in conjunction with CBP / p300 as described herein (and applied for example to various physiological processes, diseases, states, conditions, therapies, treatments or interventions) is intended to operate limitatively so that the various processes, diseases, states, conditions, treatments and interventions to which the term is applied are those in which the protein plays a biological role. In cases where the term is applied to a disease, state or condition, the biological role played by the protein may be direct or indirect and may be necessary and / or sufficient forthe manifestation of the symptoms of the disease, state or condition (or its aetiology or progression).

[0036] Thus, the protein function (and in particular aberrant levels of function, e.g. over- or under-expression) need not necessarily be the proximal cause of the disease, state or condition: rather, it is contemplated that the mediated diseases, states or conditions include those having multifactorial aetiologies and complex progressions in which the protein in question is only partially involved. In cases where the term is applied to treatment, prophylaxis or intervention, the role played by the protein may be direct or indirect and may be necessary and / or sufficient for the operation of the treatment, prophylaxis or outcome of the intervention. Thus, a disease state or condition mediated by a protein includes the development of resistance to any particular cancer drug or treatment.

[0037] The term "treatment" as used herein in the context of treating a condition i.e. state, disorder or disease, pertains generally to treatment and therapy, whether for a human or an animal (e.g. in veterinary applications), in which some desired therapeutic effect is achieved, for example, the inhibition of the progress of the condition, and includes a reduction in the rate of progress, a halt in the rate of progress, amelioration of the condition, diminishment or alleviation of at least one symptom associated or caused by the condition being treated and cure of the condition. For example, treatment can be diminishment of one or several symptoms of a disorder or complete eradication of a disorder.

[0038] The term “prophylaxis” (i.e. use of a compound as prophylactic measure) as used herein in the context of treating a condition i.e. state, disorder or disease, pertains generally to the prophylaxis or prevention, whether for a human or an animal (e.g. in veterinary applications), in which some desired preventative effect is achieved, for example, in preventing occurrence of a disease or guarding from a disease. Prophylaxis includes complete and total blocking of all symptoms of a disorder for an indefinite period of time, the mere slowing of the onset of one or several symptoms of the disease, or making the disease less likely to occur. References to the prophylaxis or treatment of a disease state or condition such as cancer include within their scope alleviating or reducing the incidence e.g. of cancer.

[0039] The combinations of the invention may produce a therapeutically efficacious effect relative to the therapeutic effect of the individual compounds / agents when administered separately.

[0040] The term ‘efficacious’ includes advantageous effects such as additivity, synergism, reduced side effects, reduced toxicity, increased time to disease progression, increased time of survival, sensitization or resensitization of one agent to another, or improved response rate. Advantageously, an efficacious effect may allow for lower doses of each or either component to be administered to a patient, thereby decreasing the toxicity of chemotherapy, whilst producing and / or maintaining the same therapeutic effect. A “synergistic” effect in the present context refers to a therapeutic effect produced by the combination which is larger than the sum of the therapeutic effects of the agents of the combination when presented individually. An “additive” effect in the present context refers to a therapeutic effect produced by the combination which is larger than the therapeutic effect of any of the agents of the combination when presented individually. The term “response rate” as used herein refers, in the case of a solid tumour, to the extent of reduction in the size of the tumour at a given time point, for example 12 weeks. Thus, for example, a 50% response rate means a reduction in tumour size of 50%.

[0041] As used herein, the term “combination”, as applied to two or more compounds and / or agents, is intended to define material in which the two or more agents are associated. The terms “combined” and “combining” in this context are to be interpreted accordingly.

[0042] The association of the two or more compounds / agents in a combination may be physical or non- physical. Examples of physically associated combined compounds / agents include:

[0043] • compositions (e.g. unitary formulations) comprising the two or more compounds / agents in admixture (for example within the same unit dose);

[0044] • compositions comprising material in which the two or more compounds / agents are chemically / physicochemically linked (for example by crosslinking, molecular agglomeration or binding to a common vehicle moiety);

[0045] • compositions comprising material in which the two or more compounds / agents are chemically / physicochemically co-packaged (for example, disposed on or within lipid vesicles, particles (e.g. micro- or nanoparticles) or emulsion droplets);

[0046] • pharmaceutical kits, pharmaceutical packs or patient packs in which the two or more compounds / agents are co-packaged or co-presented (e.g. as part of an array of unit doses);

[0047] Examples of non-physically associated combined compounds / agents include:

[0048] • material (e.g. a non-unitary formulation) comprising at least one of the two or more compounds / agents together with instructions for the extemporaneous association of the at least one compound to form a physical association of the two or more compounds / agents; • material (e.g. a non-unitary formulation) comprising at least one of the two or more compounds / agents together with instructions for combination therapy with the two or more compounds / agents;

[0049] • material comprising at least one of the two or more compounds / agents together with instructions for administration to a patient population in which the other(s) of the two or more compounds / agents have been (or are being) administered;

[0050] • material comprising at least one of the two or more compounds / agents in an amount or in a form which is specifically adapted for use in combination with the other(s) of the two or more compounds / agents.

[0051] As used herein, the term “combination therapy” is intended to define therapies which comprise the use of a combination of two or more compounds / agents (as defined above). Thus, references to “combination therapy”, “combinations” and the use of compounds / agents “in combination” in this application may refer to compounds / agents that are administered as part of the same overall treatment regimen. As such, the posology of each of the two or more compounds / agents may differ: each may be administered at the same time or at different times. It will therefore be appreciated that the compounds / agents of the combination may be administered sequentially (e.g. before or after) or simultaneously, either in the same pharmaceutical formulation (i.e. together), or in different pharmaceutical formulations (i.e. separately). Simultaneously in the same formulation is as a unitary formulation whereas simultaneously in different pharmaceutical formulations is non-unitary. The posologies of each of the two or more compounds / agents in a combination therapy may also differ with respect to the route of administration.

[0052] As used herein, the term “pharmaceutical kit” defines an array of one or more unit doses of a pharmaceutical composition togetherwith dosing means (e.g. measuring device) and / or delivery means (e.g. inhaler or syringe), optionally all contained within common outer packaging. In pharmaceutical kits comprising a combination of two or more compounds / agents, the individual compounds / agents may unitary or non-unitary formulations. The unit dose(s) may be contained within a blister pack. The pharmaceutical kit may optionally further comprise instructions for use.

[0053] As used herein, the term “pharmaceutical pack” defines an array of one or more unit doses of a pharmaceutical composition, optionally contained within common outer packaging. In pharmaceutical packs comprising a combination of two or more compounds / agents, the individual compounds / agents may unitary or non-unitary formulations. The unit dose(s) may be contained within a blister pack. The pharmaceutical pack may optionally further comprise instructions for use.

[0054] The term ‘optionally substituted’ as used herein refers to a group which may be unsubstituted or substituted by a substituent as herein defined.

[0055] The prefix “Cx y” (where x and y are integers) as used herein refers to the number of carbon atoms in a given group. Thus, a C1-6alkyl group contains from 1 to 6 carbon atoms, a C3-6cycloalkyl group contains from 3 to 6 carbon atoms, a C1-4alkoxy group contains from 1 to 4 carbon atoms, and so on. The term ‘amino’ as used herein refers to the group -NH2.

[0056] The term ‘halo’ or ‘halogen’ as used herein refers to fluorine, chlorine, bromine or iodine, in particular fluorine or chlorine.

[0057] Each and every hydrogen in the compound (such as in an alkyl group or where referred to as hydrogen) includes all isotopes of hydrogen, in particular1H and2H (deuterium).

[0058] The term ‘oxo’ as used herein refers to the group =O.

[0059] The term ‘C1-4al ky I’ as used herein as a group or part of a group refers to a linear or branched saturated hydrocarbon group containing from 1 to 4 carbon atoms respectively. Examples of such groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert butyl and the like.

[0060] The term ‘C2-4alkenyl’ or ‘C2-6alkenyl’ as used herein as a group or part of a group refers to a linear or branched hydrocarbon group containing from 2 to 4, or 2 to 6 carbon atoms, respectively, and containing one or more (usually one) carbon carbon double bond(s). Examples of such groups include C3-4alkenyl or C3-6alkenyl groups, such as ethenyl (vinyl), 1 -propenyl, 2-propenyl (allyl), isopropenyl, butenyl, buta- 1 ,4-dienyl, pentenyl, and hexenyl.

[0061] The term ‘C2-4alkynyl’ or ‘C2-6alkynyr as used herein as a group or part of a group refers to a linear or branched hydrocarbon group having from 2 to 4 or 2 to 6 carbon atoms, respectively, and containing a carbon carbon triple bond. Examples of such groups include C3-4alkynyl or C3-6alkynyl groups such as ethynyl and 2 propynyl (propargyl) groups.

[0062] The term ‘C1-4alkoxy’ as used herein as a group or part of a group refers to an -O-C1-4alkyl group wherein C1-4alkyl is as defined herein. Examples of such groups include methoxy, ethoxy, propoxy, butoxy, and the like.

[0063] The term ‘cycloalkyl’ as used herein refers to a saturated monocyclic hydrocarbon ring. The term ‘C3-6cycloalkyl’ as used herein refers to a saturated monocyclic hydrocarbon ring of 3 to 6 carbon atoms. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl and the like.

[0064] The term ‘cycloalkenyl’ as used herein refers to a fully or partially unsaturated monocyclic aliphatic hydrocarbon ring. The term ‘C3-6cycloalkenyl’ as used herein refers to a fully or partially unsaturated monocyclic aliphatic hydrocarbon ring of 3 to 6 carbon atoms having one or more (usually one) carbon carbon double bond(s). Examples of such groups include cyclopentenyl, cyclohexenyl, and cyclohexadienyl.

[0065] The term “aryl group” is used herein to denote a cycloalkyl group having aromatic character. The term “aryl group” embraces polycyclic (e.g. bicyclic) ring systems. The term “C6-12aryl” means a 6 to 12- membered ring system having aromatic character. Likewise, the term “C6aryl” means a 6- membered ring system having aromatic character. Examples of aryl groups include phenyl and napthalenyl.

[0066] The term ‘hydroxyC1-4alkyl’ as used herein as a group or part of a group refers to a C1-4alkyl group as defined herein wherein one or more than one (e.g. 1 , 2 or 3) hydrogen atom is replaced with a hydroxyl group. The term ‘hydroxyC1-4alkyl’ therefore includes monohydroxy C1-4alkyl, and also polyhydroxyC1-4alkyl. There may be one, two, three or more hydrogen atoms replaced with a hydroxyl group, so the hydroxyC1-4alkyl may have one, two, three or more hydroxyl groups. Examples of such groups include hydroxymethyl, hydroxyethyl, hydroxypropyl and the like.

[0067] The term ‘haloC1-4alkyl’ as used herein as a group or part of a group refers to a C1-4alkyl group as defined herein wherein one or more than one (e.g. 1 , 2 or 3) hydrogen atom is replaced with a halogen. The term ‘haloC1-4alkyl’ therefore includes monohaloC1-4alkyl and also polyhaloC1-4alkyl. There may be one, two, three or more hydrogen atoms replaced with a halogen, so the haloC1-4alkyl may have one, two, three or more halogens. Examples of such groups include fluoroethyl, fluoromethyl, difluoromethyl, trifluoromethyl or trifluoroethyl and the like.

[0068] The term ‘haloC1-4alkoxy’ as used herein as a group or part of a group refers to a -O-C1-4alkyl group as defined herein wherein one or more than one (e.g. 1 , 2 or 3) hydrogen atom is replaced with a halogen. The terms ‘haloC1-4alkoxy’ therefore include monohaloC1-4alkoxy, and also polyhaloC1-4alkoxy. There may be one, two, three or more hydrogen atoms replaced with a halogen, so the haloC1-4alkoxy may have one, two, three or more halogens. Examples of such groups include fluoroethyloxy, difluoromethoxy or trifluoromethoxy and the like.

[0069] The term “heterocyclyl group” as used herein shall, unless the context indicates otherwise, include both aromatic and non-aromatic ring systems. Thus, for example, the term “heterocyclyl group” include within their scope aromatic, non-aromatic, unsaturated, partially saturated and saturated heterocyclyl ring systems. In general, unless the context indicates otherwise, such groups may be monocyclic or bicyclic (including fused, spiro and bridged bicyclic groups) and may contain, for example, 3 to 12 ring members, more usually 5 to 10 ring members. Reference to 4 to 7 ring members includes 4, 5, 6 or 7 atoms in the ring and reference to 4 to 6 ring members include 4, 5, or 6 atoms in the ring. Examples of monocyclic groups are groups containing 3, 4, 5, 6, 7 and 8 ring members, more usually 3 to 7, or 4 to 7 and preferably 5, 6 or 7 ring members, more preferably 5 or 6 ring members. Examples of bicyclic groups are those containing 8, 9, 10, 11 and 12 ring members, and more usually 9 or 10 ring members. Bicyclic heterocyclyl groups can include a heteroatom in one ring, or in both rings, and likewise for tricyclic and other polycyclic groups. The heterocyclyl groups can be heteroaryl groups having from 5 to 12 ring members, more usually from 5 to 10 ring members. Where reference is made herein to a heterocyclyl group, the heterocyclyl ring can, unless the context indicates otherwise, be optionally substituted i.e. unsubstituted or substituted, by one or more (e.g. 1 , 2, 3, or 4 in particular one or two) substituents as defined herein.

[0070] The heterocyclyl group can be, for example, a five membered or six membered monocyclic ring or a bicyclic structure formed from fused five and six membered rings or two fused six membered rings, or two fused five membered rings. Unless the context indicates otherwise, each ring may contain up to five heteroatoms particularly selected from nitrogen, sulfur and oxygen and oxidised forms of nitrogen or sulfur. Particularly the heterocyclyl ring will contain up to 4 heteroatoms, more particularly up to 3 heteroatoms, more usually up to 2, for example a single heteroatom. In one embodiment, the heterocyclyl ring will contain one or two heteroatoms selected from N, O, S and oxidised forms of N or S. In one embodiment, the heterocyclyl ring contains at least one ring nitrogen atom. The nitrogen atoms in the heterocyclyl 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 heterocyclyl group, including any amino group substituents of the ring, will be less than five.

[0071] The term “partially unsaturated heterocyclyl” as used herein refers to a heterocyclic ring system that contains at least one unsaturated bond (for example double or triple bond) and that also contains at least one saturated (single) bond.

[0072] The heterocyclyl groups can be attached via a carbon atom or a heteroatom (e.g. nitrogen). Equally the heterocyclyl groups can be substituted on a carbon atom or on a heteroatom (e.g. nitrogen).

[0073] Examples of five membered aromatic heterocyclyl groups include but are not limited to pyrrolyl, furanyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, pyrazolyl, triazolyl and tetrazolyl groups.

[0074] Examples of six membered aromatic heterocyclic groups include but are not limited to pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl and triazinyl.

[0075] The term “heteroaryl” is used herein to denote a heterocyclyl group having aromatic character. The term “heteroaryl” embraces polycyclic (e.g. bicyclic) ring systems wherein one or more rings are non- aromatic, provided that at least one ring is aromatic. In such polycyclic systems, the group is attached by the aromatic ring. The term “heteroaryl” also embraces polycyclic (e.g. bicyclic) ring systems wherein one or more rings do not contain a heteroatom, provided that at least one ring does contain at least one heteroatom. In such polycyclic systems, the group may be attached by an aromatic ring containing at least one heteroatom or an aromatic ring that does not contain a heteroatom.

[0076] 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.

[0077] Examples of five membered heteroaryl groups include but are not limited to pyrrole, furan, thiophene, imidazole, furazan, oxazole, oxadiazole, oxatriazole, isoxazole, thiazole, thiadiazole, isothiazole, pyrazole, triazole and tetrazole groups.

[0078] Examples of six membered heteroaryl groups include but are not limited to pyridine, pyrazine, pyridazine, pyrimidine and triazine.

[0079] A bicyclic heteroaryl group may be, for example, a group selected from: a) a benzene ring fused to a 5- or 6-membered ring containing 1 , 2 or 3 ring heteroatoms; b) a pyridine ring fused to a 5- or 6-membered ring containing 0, 1 , 2 or 3 ring heteroatoms; c) a pyrimidine ring fused to a 5- or 6-membered ring containing 0, 1 or 2 ring heteroatoms; d) a pyrrole ring fused to a 5- or 6-membered ring containing 0, 1 , 2 or 3 ring heteroatoms; e) a pyrazole ring fused to a 5- or 6-membered ring containing 0, 1 or 2 ring heteroatoms; f) an imidazole ring fused to a 5- or 6-membered ring containing 0, 1 or 2 ring heteroatoms; g) an oxazole ring fused to a 5- or 6-membered ring containing 0, 1 or 2 ring heteroatoms; h) an isoxazole ring fused to a 5- or 6-membered ring containing 0, 1 or 2 ring heteroatoms; i) a thiazole ring fused to a 5- or 6-membered ring containing 0, 1 or 2 ring heteroatoms; j) an isothiazole ring fused to a 5- or 6-membered ring containing 0, 1 or 2 ring heteroatoms; k) a thiophene ring fused to a 5- or 6-membered ring containing 0, 1 , 2 or 3 ring heteroatoms; l) a furan ring fused to a 5- or 6-membered ring containing 0, 1 , 2 or 3 ring heteroatoms; m) a cyclohexyl ring fused to a 5- or 6-membered ring containing 1 , 2 or 3 ring heteroatoms; and n) a cyclopentyl ring fused to a 5- or 6-membered ring containing 1 , 2 or 3 ring heteroatoms.

[0080] Particular examples of bicyclic heteroaryl groups containing a five membered ring fused to another five membered ring include but are not limited to imidazothiazole (e.g. imidazo[2,1-b]thiazole) and imidazoimidazole (e.g. imidazo[1 ,2-a]imidazole).

[0081] Particular examples of bicyclic heteroaryl groups containing a six membered ring fused to a five membered ring include but are not limited to benzofuran, 2,3-dihydrobenzofuran, benzothiophene, benzimidazole, benzoxazole, isobenzoxazole, benzisoxazole, benzothiazole, benzisothiazole, benzodiazole, isobenzofuran, indole, dihydroindole (e.g. 2,3-dihydroindole), azaindole (e.g. 4- azaindole), imidazopyridinyl (e.g. imidazo[1 ,2-a]pyridine, imidazo[1 ,5-a]pyridinyl), isoindole, indolizine, indoline, isoindoline, purine (e.g., adenine, guanine), indazole, pyrazolopyrimidine (e.g. pyrazolo[1 ,5- a]pyrimidine), triazolopyrimidine (e.g. [1 ,2,4]triazolo[1 ,5-a]pyrimidine), benzodioxole, imidazopyridine, quinazoline, dihydroquinazoline (e.g. 2,3-dihydroquinazoline) and pyrazolopyridine (e.g. pyrazolo[1 ,5- a]pyridine) groups.

[0082] Particular examples of bicyclic heteroaryl groups containing two fused six membered rings include but are not limited to quinoline, isoquinoline, chroman, thiochroman, isochroman, chromene, isochromene, benzodioxan, benzodioxin, quinolizine, benzoxazine, pyridopyridine, quinoxaline, dihydroquinoxalin (e.g. 3,4-dihydroquinoxalin), quinazoline, cinnoline, phthalazine, naphthyridine and pteridine groups.

[0083] Examples of polycyclic heteroaryl groups containing an aromatic ring and a non-aromatic ring include, tetrahydroisoquinoline, tetrahydroquinoline, dihydrobenzthiophene, dihydrobenzofuran, 2,3-dihydro- benzo[1 ,4]dioxine, benzo[1 ,3]dioxole, 4,5,6,7-tetrahydrobenzofuran, tetrahydrotriazolopyrazine (e.g. 5,6,7,8-tetrahydro-[1 ,2,4]triazolo[4,3-a]pyrazine), chroman, thiochroman, isochroman, chromene, isochromene, benzodioxan, benzoxazine, benzodiazepine, and indoline groups.

[0084] A nitrogen-containing heteroaryl ring must contain at least one ring nitrogen atom. The nitrogen- containing heteroaryl ring can be N-linked or C-linked. Each ring may, in addition, contain up to about four other heteroatoms particularly selected from nitrogen, sulfur and oxygen. Particularly the heteroaryl ring will contain up to 3 heteroatoms, for example 1 , 2 or 3, more usually up to 2 nitrogens, for example a single nitrogen. 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.

[0085] Examples of nitrogen-containing heteroaryl groups include, but are not limited to, monocyclic groups such as pyridyl, pyrrolyl, imidazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, furazanyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl (e.g., 1 ,2,3- triazolyl, 1 ,2,4-triazolyl), tetrazolyl, and bicyclic groups such as quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, benzisoxazole, benzothiazolyl and benzisothiazole, indolyl, 3H-indolyl, isoindolyl, indolizinyl, isoindolinyl, purinyl (e.g., adenine [6-aminopurine], guanine [2-amino-6-hydroxypurine]), indazolyl, quinolizinyl, benzoxazinyl, benzodiazepinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl and pteridinyl.

[0086] Examples of nitrogen-containing polycyclic heteroaryl groups containing an aromatic ring and a non- aromatic ring include tetrahydroisoquinolinyl, tetrahydroquinolinyl, and indolinyl.

[0087] The term “non-aromatic” embraces, unless the context indicates otherwise, unsaturated ring systems without aromatic character, partially saturated and saturated heterocyclyl ring systems. The terms “unsaturated” and “partially saturated” referto rings wherein the ring structure(s) contains atoms sharing more than one valence bond i.e. the ring contains at least one multiple bond e.g. a C=C, C≡C or N=C bond. The term “saturated” refers to rings where there are no multiple bonds between ring atoms. Saturated heterocyclyl groups include piperidinyl, morpholinyl, and thiomorpholinyl. Partially saturated heterocyclyl groups include pyrazolinyl, for example pyrazolin-2-yl and pyrazolin-3-yl.

[0088] Examples of non-aromatic heterocyclyl groups are groups having from 3 to 12 ring members, more usually 5 to 10 ring members. Such groups can be monocyclic or bicyclic, for example, have 3 to 7 ring members in particular 4 to 6 ring members. Such groups particularly have from 1 to 5 or 1 to 4 heteroatom ring members (more usually 1 , 2, or 3 heteroatom ring members), usually selected from nitrogen, oxygen and sulfur and oxidised forms thereof. The heterocyclyl groups can contain, for example, cyclic ether moieties (e.g. as in tetrahydrofuran and dioxane), cyclic thioether moieties (e.g. as in tetrahydrothiophene and dithiane), cyclic amine moieties (e.g. as in pyrrolidine), cyclic amide moieties (e.g. as in pyrrolidone), cyclic thioamides, cyclic thioesters, cyclic ureas (e.g. as in imidazolidin- 2-one), cyclic ester moieties (e.g. as in butyrolactone), cyclic sulfones (e.g. as in sulfolane and sulfolene), cyclic sulfoxides, cyclic sulfonamides and combinations thereof (e.g. thiomorpholine). Particular examples include morpholinyl, piperidinyl (e.g. piperidin-1-yl, piperidin-2-yl, piperidin-3-yl and piperidin-4-yl), piperidinonyl, pyrrolidinyl (e.g. pyrrolidin-1 -yl, pyrrolidin-2-yl and pyrrolidin-3-yl), pyrrolidonyl, azetidinyl, pyranyl (2H-pyran or 4H-pyran), dihydrothienyl, dihydropyranyl, dihydrofuranyl, dihydrothiazolyl, tetrahydrofuranyl, tetrahydrothienyl, dioxanyl, oxanyl (also known as tetrahydropyranyl) (e.g. oxan-4-yl), imidazolinyl, imidazolidinonyl, oxazolinyl, thiazolinyl, pyrazolin-2-yl, pyrazolidinyl, piperazinonyl, piperazinyl, and N-alkyl piperazines such as N-methyl piperazinyl. In general, typical non-aromatic heterocyclyl groups include saturated groups such as piperidinyl, pyrrolidinyl, azetidinyl, morpholinyl, piperazinyl and N-alkyl piperazines such as N-methyl piperazinyl.

[0089] In a nitrogen-containing non-aromatic heterocyclyl ring the ring must contain at least one ring nitrogen atom. The nitrogen-containing heterocyclyl ring can be N-linked or C-linked. The heterocylic groups can contain, for example, cyclic amine moieties (e.g. as in pyrrolidinyl), cyclic amides (such as a pyrrolidinonyl, piperidinonyl or caprolactamyl), cyclic sulfonamides (such as an isothiazolidinyl 1 ,1- dioxide, [1 ,2]thiazinanyl 1 ,1-dioxide or [1 ,2]thiazepanyl 1 ,1-dioxide) and combinations thereof.

[0090] Particular examples of nitrogen-containing non-aromatic heterocyclyl groups include aziridinyl, morpholinyl, thiomorpholinyl, piperidinyl (e.g. piperidin-1-yl, piperidin-2yl, piperidin-3-yl and piperidin-4- yl), pyrrolidinyl; (e.g. pyrrolidin-1 -yl, pyrrolidin-2-yl and pyrrolidin-3-yl), pyrrolidonyl, dihydrothiazolyl, imidazolinyl, imidazolidinonyl, oxazolinyl, thiazolinyl, 6H-1 ,2,5-thiadiazinyl, pyrazolin-2-yl, pyrazolin-3- yl, pyrazolidinyl, piperazinyl, and N-alkyl piperazines such as N-methyl piperazinyl.

[0091] The heterocyclyl groups can be polycyclic fused ring systems or bridged ring systems such as the oxa- and aza analogues of bicycloalkanes, tricycloalkanes (e.g. adamantane and oxa-adamantane). For an explanation of the distinction between fused and bridged ring systems, see Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages 131-133, 1992.

[0092] Where, in a definition of a cyclic group or ring, it is stated that the cyclic group contains a certain number of heteroatom ring members, e.g. as in the phrase “a 5 or 6 membered ring containing 0, 1 or 2 nitrogen ring members”, this is to be taken as meaning that apart from the certain number of heteroatom ring members specified, the remaining ring members are carbon atoms.

[0093] The compound of formula (I) may contain saturated cyclic groups that can be joined to the rest of the molecule by one or more bonds. When the cyclic group is joined to the rest of the molecule by two or more bonds, these bonds (or two of these bonds) can be made to the same atom (usually a carbon atom) of the ring or different atoms of the ring. Where the bonds are made to the same atom of the ring, this results in a cyclic group with a single atom (usually a quaternary carbon) bound to two groups. In other words, when the compound of formula (I) includes a cyclic group that group may either be linked to the rest of the molecule by a bond or the cyclic group and the rest of the molecule can have an atom in common e.g. a spiro compound.

[0094] The heterocyclyl group can each be unsubstituted or substituted by one or more (e.g. 1 , 2 or 3) substituent groups. For example, heterocyclyl or cycloalkyl groups can be unsubstituted or substituted by 1 , 2, 3 or 4 substituents and particularly it is unsubstituted or has 1 , 2 or 3 substituents as defined herein. Where the cyclic group is saturated there may be 2 substituents joined to the same carbon (where the substituents are the same so called geminal or ‘gem’ di-substitution).

[0095] A combination of substituents is permissible only if such as combination results in a stable or chemically feasible compound (i.e. one that is not substantially altered when kept at 40°C or less for at least a week).

[0096] The various functional groups and substituents making up the compounds of the invention are particularly chosen such that the molecular weight of the compound of the invention does not exceed 1000. More usually, the molecular weight of the compound will be less than 750, for example less than 700, or less than 650, or less than 600, or less than 550. More particularly, the molecular weight is less than 525 and, for example, is 500 or less.

[0097] DETAILED DESCRIPTION OF THE INVENTION

[0098] The invention provides a compound of formula (I) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof: wherein Ring X, R1, R2, R4, Ra, A, B and n are as defined herein.

[0099] The compounds of formula (I) include a stereocentre at the position indicated below with a "*"and are chiral non-racemic. Compounds of formula (I) have the stereochemistry shown by the hashed and solid wedged bonds and this stereoisomer predominates.

[0100] The compounds may also include one or more further chiral centres (for example in the R1group or R4group). Typically, at least 55% (e.g. at least 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95%) of the compound of the formula (I) is present as the shown stereoisomer. In one general embodiment, 97% (e.g. 99%) or more (e.g. substantially all) of the total amount of the compound of the formula (I) may be present as a single stereoisomer.

[0101] For the purposes of this section, the cyclic imide ring is numbered as follows:

[0102] When numbers are given for substituents on rings other than the cyclic imide core, for example at Ring X, for the purposes of describing the invention the position number is defined relative to the point of attachment to the core. A non-limiting example is as follows:

[0103] Compounds are named in accordance with protocols utilized by chemical naming software packages.

[0104] Ring X

[0105] Ring X is selected from an aryl, cycloalkenyl, heteroaryl and partially unsaturated heterocyclyl group, wherein the heteroaryl or partially unsaturated heterocyclyl group comprises one or more (e.g. 1 , 2 or 3) heteroatoms selected from O, N or S.

[0106] In one embodiment, Ring X is selected from an aryl group and a heteroaryl group, wherein the heteroaryl group comprises one or more (e.g. 1 , 2 or 3) heteroatoms selected from O, N and S and oxidised forms thereof.

[0107] In one embodiment, Ring X is a Ce ^aryl group or a heteroaryl group with 5 to 12 ring members, wherein the heteroaryl group comprises one or more (e.g. 1 , 2 or 3) heteroatoms selected from O, N or S.

[0108] In one embodiment, Ring X is monocyclic. In one embodiment, Ring X is an aromatic monocyclic ring or a bicyclic ring including two or more fused rings wherein the ring directly attached to the imide core is aromatic.

[0109] In one embodiment, Ring X is a six-membered aryl group or a 5- or 6-membered heteroaryl group wherein the heteroaryl group comprises one or more (e.g. 1 , 2 or 3) heteroatoms selected from O, N and S and oxidised forms thereof.

[0110] In one embodiment, Ring X is phenyl or a 6-membered heteroaryl group wherein the heteroaryl group comprises one or more (e.g. 1 , 2 or 3) heteroatoms selected from O, N and S and oxidised forms thereof.

[0111] In one embodiment, Ring X is selected from phenyl, napthalenyl, pyridinyl (for example, pyridin-2-yl, pyridin-3-yl or pyridin-4-yl), pyrimidinyl (for example, pyrimidin-2-yl, pyrimidin-4-yl, pyrimdin-5-yl and pyrimidin-6-yl), pyrrolyl (for example, pyrrol-1 -yl, pyrrol-2-yl and pyrrol-3-yl), furanyl (for example, furan- 2-yl and furan-3-yl), thiophenyl (for example, thiophen-2-yl and thiophen-3-yl), pyrazolyl (for example, pyrazol-1-yl, pyrazol-3-yl, pyrazole-4-yl or pyrazol-5-yl), imidazolyl (for example, imidazol-1-yl, imidazol- 2-yl, imidazol-4-yl and imidazol-5-yl), triazolyl (for example, triazol-1-yl and triazol-5-yl), oxazolyl (for example, oxazol-2-yl, oxazol-4-yl or oxazol-5-yl), isooxazolyl (for example, isoxazol-3-yl, isoxazol-4-yl or isoxazol-5-yl), thiazolyl (for example, thiazol-2-yl, thiazol-4-yl or thiazol-5-yl), indolyl (for example, indol-1 -yl, indol-2-yl, indol-3-yl, indol-4-yl, indol-5-yl, indol-6-yl and indol-7-yl), indazolyl (for example indazol-1 -yl, indazol-3-yl, indazol-4-yl, indazole-5-yl, indazol-6-yl and indazol-7-yl), benzimidazolyl (for example, benzimidazol-1-yl, benzimidazol-2-yl, benzimidazol-4-yl, benzimidazol-5-yl, benzimidazol-6- yl and benzimidazol-7-yl), benzofuranyl (for example, benzofuran-2-yl, benzofuran-3-yl, benzofuran-4- yl, benzofuran-5-yl, benzofuran-6-yl and benzofuran-7-yl).

[0112] In each of these embodiments, Ring X is optionally substituted by up to four (i.e. 1 , 2, 3 or 4) substituents R1. In one embodiment, Ring X is substituted by 0, 1 or 2 substituents R1, for example 1 or 2 substituents R1, for example 1 substituent R1.

[0113] In one embodiment, Ring X is a six-membered aryl or six-membered heteroaryl group and the compound of formula (I) is a compound of formula (II) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof: wherein W1, W2, W3, W* and W5are independently selected from N, CH and CR1, wherein no more than two of W1, W2, W3, W4and W5are N and no more than four of W1, W2, W3, W* and W5are CR1, and wherein R1, R2, RaA, B, and R4are as defined herein.

[0114] In one embodiment, the compound of formula (I) is a compound of formula (Ila) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof: wherein W1is selected from CH and N and W2and W3are independently selected from N, CH and CR1and wherein R1, R2, Rat, A, B, and R4are as defined herein.

[0115] In one embodiment, the compound of formula (I) is a compound of formula (lib) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof: wherein W1and W2are independently selected from N and CH and R1, R2, Ra, t, A, B and R4are as defined herein.

[0116] In one embodiment, Ring X is selected from phenyl, pyridine, pyrazine, pyrimidine and pyridazine. In another embodiment, Ring X is selected from phenyl, pyridine and pyrimidine.

[0117] In one embodiment, Ring X is selected from phenyl and pyridine. In another embodiment, Ring X is phenyl.

[0118] In one embodiment, the compound of formula (I) is a compound of formula (Ila’) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof:

[0119] wherein W1is selected from CH and N and W2and W3are independently selected from N, CH and CR1and wherein R2, A, B and R4are as defined herein.

[0120] In one embodiment, the compound of formula (I) is a compound of formula (Ila’) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof and Ring X is selected from phenyl and pyridine. In one such embodiment, Ring X is phenyl.

[0121] In one embodiment, Ring X is not selected from options a) to e) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof: wherein the wavy line denotes the point of attachment to the cyclic imide core, and wherein options a) to e) may be substituted with 0, 1 , 2, 3 or 4 R1substituents. In one embodiment, the point of attachment within Ring X is a carbon atom. In one embodiment, the point of attachment within Ring X is a not a nitrogen atom.

[0122] R1and n R1are the substituent(s) on Ring X. n is 0, 1 , 2, 3 or 4. In other words, Ring X may have 0, 1 , 2, 3 or 4 substituents R1.

[0123] In one embodiment n is 0, 1 or 2. In one embodiment n is 1 or 2. In another embodiment n is 1 .

[0124] When n is 2 or more (i.e. Ring X is substituted with more than one R1) the substituents R1may be the same or different (i.e. are independently selected from the definitions of R1). When Ring X is a six-membered aromatic ring, R1may be attached at the 2-, 3-, 4-, 5- or 6- position of Ring X wherein the position is defined relative to the point of attachment of Ring X to the cyclic imide, as illustrated above. When Ring X is phenyl, R1may be attached at the ortho-, meta- or para- position relative to the point of attachment of Ring X to the cyclic imide.

[0125] R1is independently selected from hydroxyl, halogen, nitro, nitrile, C1-8alkyl, nitrileC1-8alkyl, C1-8alkoxy, haloC1-6alkyl, C2-6alkenyl, C2-6alkynyl, =O (oxo), -C(=O)C1-6alkyl, -SH, -SC1-8alkyl, -SO2C1-6alkyl, C1-6alkylSO2C1-6alkyl, -SO2NRxRy, -C1-8alkyl-SO2NRxRy, -NRxRy, -C(=O)NRxRy, -NRxC(=O)C1-6alkyl, C1-6alkylNHC(=O)C1-6alkyl, -(CH2)k-O-C1-6alkyl, hydroxyC1-8alkyl, hydroxyC1-8alkoxy, haloC1-8alkoxy, - C(=O)C1-6alkyl-OH, -C(=O)C1-6alkyl-N(H)e(C1-6alkyl)2-e, CO2C1-6alkyl, C1-6alkylCO2C1-6alkyl, -(CRxRy)v- CONRxRy, -CO2H, -C1-6alkylCO2H, -C1-6alkyl-NRxRy, -P(=O)(Rx)(Ry), C3-8cycloalkyl, C3-8cycloalkenyl, C8. waryl, and heterocyclic groups (e.g. an aromatic ring or a non-aromatic ring) with 3 to 8 ring members wherein the heterocyclic group comprises one or more (e.g.1 , 2, or 3) heteroatoms selected from N, O, S and oxidised forms thereof, wherein the C1-6alkyl groups is optionally substituted with a C3-8cycloalkyl, C3-8cycloalkenyl, Cs-waryl or 3 to 8 membered heterocyclic group (e.g. an aromatic ring or non-aromatic ring) containing one or more (e.g. 1 , 2 or 3) heteroatoms selected from O, N or S and wherein in each case the C3-8cycloalkyl, C3-8cycloalkenyl, Ce-ioaryl and 3 to 8 membered heterocyclic groups are optionally further substituted with one or more (e.g. 1 , 2 or 3) Rzgroups, or two R1groups together with the atoms to which they are attached join to form a C3-8cycloalkyl, C38cycloalkenyl, Ce-waryl or heterocyclic group with 3 to 8 ring members (e.g. an aromatic ring or a non- aromatic ring), wherein the heterocyclic group contains one or more (e.g. 1 , 2 or 3) heteroatoms selected from N, O, S and oxidised forms thereof and wherein the C3-8cycloalkyl, C3-8cycloalkenyl, C8waryl group or 3- to 8-membered heterocyclic ring be substituted by one or more Rzgroups.

[0126] In one embodiment, R1is selected from hydroxyl, halogen, nitro, nitrile, C1-8alkyl, nitrileC1-8alkyl, C1-6alkoxy, haloC1-8alkyl, C2-6alkenyl, C2-6alkynyl, -C(=O)C1-6alkyl, -SH, -SC1-8alkyl, -SO2C1-6alkyl, C1-8alkylSO2C1-8alkyl, -SO2NRxRy, -C1-6alkyl-SO2NRxRy-NRxRy, -C(=O)NRxRy, -NRxC(=O)C1-6alkyl, C1-6alkylNHC(=O)C1-6alkyl, -(CH2)k-O-C1-6alkyl, hydroxyC1-8alkyl, hydroxyC1-8alkoxy, haloC1-8alkoxy, - C(=O)C1-6alkyl-OH, -C(=O)C1-8alkyl-N(H)e(C1-8alkyl)2-e, CO2C1-8alkyl, C1-8alkylCO2C1-8alkyl, -(CRxRy)v- CONRxRy, -CO2H, -C1-6alkylCO2H, -C1-6alkyl-NRxRy, -P(=O)(Rx)(Ry), C3-8cycloalkyl, C3-8cycloalkenyl, C8-waryl, and heterocyclic groups (e.g. an aromatic ring or a non-aromatic ring) with 3 to 8 ring members wherein the heterocyclic group comprises one or more (e.g.1 , 2, or 3) heteroatoms selected from N, O, S and oxidised forms thereof, wherein the O-ealkyl groups is optionally substituted with a C3-8cycloalkyl, C3-8cycloalkenyl, Ce-waryl or 3 to 8 membered heterocyclic group (e.g. an aromatic ring or non-aromatic ring) containing one or more (e.g. 1 , 2 or 3) heteroatoms selected from O, N or S and wherein in each case the C3-8cycioaikyl, C3-8cycioaikenyi, Ce-ioaryl and 3 to 8 membered heterocyclic groups are optionally further substituted with one or more (e.g. 1 , 2 or 3) Rzgroups; or two R1groups together with the atoms to which they are attached join to form a C3-8cycloalkyl, C38cycloalkenyl, C8-ioaryl or heterocyclic group with 3 to 8 ring members (e.g. an aromatic ring or a non- aromatic ring), wherein the heterocyclic group contains one or more (e.g. 1 , 2 or 3) heteroatomsselected from N, O, S and oxidised forms thereof and wherein the C3-8cycloalkyl, C3-8cycloalkenyl, Ca waryl group or 3- to 8-membered heterocyclic ring be substituted by one or more Rzgroups.

[0127] In one embodiment, R1is not =O (oxo). In one embodiment, R1are selected from halogen, nitro, nitrile, hydroxyl, C1-6alkyl, haloC1-6alkyl, C1-6alkoxy, haloC1-6alkoxy, hydroxyC1-6alkyl, C1-6alkoxyC1-6alkylene, C1-6alkylSO2C1-6alkyl, SO2C1-6alkyl, C1-6alkylsulfide, NRxRy, C1-6alkylNRxRy, -C(=O)NRxRy, C1-6alkyl- C(=O)NRxRy, NHC(=O)C1-6alkyl, C1-6alkylNHC(=O)C1-6alkyl, -SO2NRxRy, C1-6alkyl-SO2NRxRy, P(=O)RxRy, - CO2H, -C1-6alkylCO2H, CC^C1-6alkyl, C1-6alkylCO2C1-6alkyl and the following groups:

[0128] • C3-8cycloalkyl,

[0129] • C3-8cycloalkenyl,

[0130] • Cearyl,

[0131] • 3 to 8 membered heterocyclic group (e.g. an aromatic ring or a non-aromatic ring) group containing one or more (e.g. 1 , 2 or 3) heteroatoms selected from O, N or S; wherein in each case the cycloalkyl, cycloalkenyl or heterocyclic groups are optionally substituted with one or more Rzgroups; or, when n is 2 or more, two R1groups, together with the atoms to which they are attached, join to form a C3-8cycloalkyl, C3-8cycloalkenyl, Cearyl or a heterocyclic group with 3 to 8 ring members (e.g. an aromatic ring or a non-aromatic ring), wherein the heterocyclic group comprises one or more (e.g.1 , 2, or 3) heteroatoms selected from N, O, S and oxidised forms thereof, wherein the C3-8cycloalkyl, C3-8cycloalkenyl, phenyl or a heterocyclic group are optionally substituted with one or more Rzgroups.

[0132] In one embodiment, R1is selected from halogen, nitrile, C1-6alkyl, -C1-6alkylNRxRy, -NRxRy, C1-6alkoxy, haloC1-6alkyl, hydroxyC1-6alkyl, -C(=O)NRxRy, -C1-6alkylNHC(=O)C1-6alkyl, -NHC(=O)C1-6alkyl, - SO2NRxRy, -SO2C1-6alkyl , -P[=O]RxRy, -CO2H, haloC1-6alkoxy or a 3 to 8 membered heterocyclic group (e.g. an aromatic ring or a non-aromatic ring) group containing one or more (e.g. 1 , 2 or 3) heteroatoms selected from O, N and S, wherein the 3 to 8 membered heterocyclic groups are optionally substituted with one or more Rzgroups; or, when n is 2 or more, two R1groups, together with the atoms to which they are attached, join to form a heterocyclic group with 3 to 6 ring members (e.g. an aromatic ring or a non-aromatic ring), wherein the heterocyclic group comprises one or more (e.g.1 , 2, or 3) heteroatoms selected from N, O, S and oxidised forms thereof, wherein the heterocyclic group is optionally substituted with one or more Rzgroups.

[0133] In another embodiment, R1is selected from halogen (such as fluoro, chloro, bromo or iodo, for example fluoro or chloro), nitrile (i.e. -CN), C1-6alkyl (for example methyl, ethyl or propyl, e.g. methyl), -C1-ealkylNRxRy, -NRxRy, C1-6alkoxy (such as methoxy or ethoxy, e.g. methoxy), haloC1-6alkyl (such as CH2F, CHF2, CF3, CH2CI, CHCI2, CCI3or CH2CH2F, e.g. CF3), hydroxyC1-8alkyl (such as CH2OH or CH2CH2OH), -C(=O)NRxRy, -C1-6alkylNHC(=O)C1-6alkyl (such as CH2NHC(=O)CH3or CH2CH2NHC(=O)CH3, e.g. CH2NHC(=O)CH3), -NHC(=O)C1-6alkyl (such as NHC(=O)CH3or NHC(=O)CH2CH3), -SO2NRxRy, -SO2C1-6alkyl (e.g. -SO2CH3or -SO2CH2CH3, e.g. -SO2CH3), - P[=O]RxRy(such as P[=O]Me2, P[=O]Et2, e.g. P[O]Me2), -CO2H, haloC1-8alkoxy (e.g. OCH2CH2F or OCF3, e.g. OCF3) or a 3 to 8 membered heterocyclic group (e.g. an aromatic ring or a non-aromatic ring) group containing one or more (e.g. 1 , 2 or 3) heteroatoms selected from O, N or S (for example azetidinyl, morpholinyl, piperazinyl, pyrrolidinyl, oxazolyl, thiazolyl, furanyl, thiohenyl, pyridinyl, pyrimidinyl, pyridazinyl or pyraziny I, e.g. morpholinyl) wherein the 3 to 8 membered heterocyclic groups are optionally substituted with one or more Rzgroups; wherein Rxand Ryare independently selected from hydrogen, Cvsalkyl (e.g. methyl or ethyl, for example methyl), hydroxyCi -salkyl (such as hydroxymethyl, hydroxyethyl or hydroxypropyl, e.g. hydroxyethyl or hydroxypropyl), -(CH2)kOC1-8alkyl (for example CH2OCH3, CH2CH2OCH3or CH2CH2OCH2CH3, e.g. CH2CH2OCH3) or wherein Rxand Ry, together with the atom to which they are attached, join to form a heterocyclic ring with 4 to 6 ring members, wherein the heterocyclic group comprises one or more (e.g.1 , 2, or 3) heteroatoms selected from N, O, S and oxidised forms thereof (for example, azetidinyl, morpholinyl, piperazinyl, pyrrolidinyl, oxazolidinyl (for example 1 ,3-oxazolidin-3-yl)), wherein the heterocyclic group is optionally substituted with one or more Rzgroups; or, when n is 2, the two R1groups, together with the atoms to which they are attached, join to form a heterocyclic group with 3 to 6 ring members (e.g. an aromatic ring or a non-aromatic ring), wherein the heterocyclic group comprises one or more (e.g.1 , 2, or 3) heteroatoms selected from N, O, S and oxidised forms thereof, wherein the heterocyclic group is optionally substituted with one or more Rzgroups.

[0134] In another embodiment, R1is selected from halogen (for example fluoro or chloro), nitrile (-CN), -NRxRy, C1-6alkoxy (for example methoxy or ethoxy, e.g. methoxy), haloC1-8alkyl (such as -CH2F, -CHF2, -CF3, - CH2CI, -CHCI2, - CCI3or -CH2CH2F, e.g. -CF3), hydroxyC1-8alkyl (such as -CH2OH or -CH2CH2OH), - C(=O)NRxRy, -C1-8alkylNHC(=O)C1-8alkyl (such as -CH2NHC(=O)CH3or -CH2CH2NHC(=O)CH3, e.g. - CH2NHC(=O)CH3), -NHC(=O)C1-8alkyl (such as -NHC(=O)CH3or -NHC(=O)CH2CH3), -SO2NRxRy, - SO2C1-8alkyl (e.g. -SO2CH3or-SO2CH2CH3, e.g. -SO2CH3), -P[=O]RxRy(such as -P[=O]Me2, -P[=O]Et2, e.g. -P[O]Me2), -CO2H, haloC1-8alkoxy (e.g. -OCH2CH2F or -OCF3, e.g. -OCF3) or a 5 or 6 membered heterocyclic group (e.g. an aromatic ring or a non-aromatic ring) group containing one or more (e.g. 1 , 2 or 3) heteroatoms selected from O, N or S wherein the heterocyclic group is optionally substituted with one or more Rzgroups; wherein Rxand Ryare independently selected from hydrogen, Cvsalkyl (e.g. methyl or ethyl, for example methyl), hydroxyCi. salkyl (such as hydroxymethyl, hydroxyethyl or hydroxypropyl, e.g. hydroxyethyl or hydroxypropyl), -(CH2)kOC1-8alkyl (for example CH2OCH3, CH2CH2OCH3or CH2CH2OCH2CH3, e.g. CH2CH2OCH3) or wherein Rxand Ry, together with the atom to which they are attached, join to form a heterocyclic ring with 4 to 6 ring members, wherein the heterocyclic group comprises one or more (e.g.1 , 2, or 3) heteroatoms selected from N, O, S and oxidised forms thereof (for example, azetidinyl, morpholinyl, piperazinyl, pyrrolidinyl, oxazolidinyl (for example 1 ,3-oxazolidin-3-yl)), wherein the heterocyclic group is optionally substituted with one or more Rzgroups; or, when n is 2, the two R1groups, together with the atoms to which they are attached, join to form a heteroaryl group with 5 or 6 ring members, wherein the heteroaryl group comprises one or more (e.g.1 , 2, or 3) heteroatoms selected from N, O, S and oxidised forms thereof, wherein the heteroaryl group is optionally substituted with one or more Rzgroups.

[0135] In one embodiment, R1is selected from halo, nitrile, C1-6alkyl, -C1-6alkylNRxRy, -NRxRy, C1-6alkoxy, haloC1-6alkyl, hydroxyC1-6alkyl, -C(=O)NRxRy, -C1-6alkylNHC(=O)C1-6alkyl, -NHC(=O)C1-6alkyl, - NHC(=O)C1-6alkyl, -SO2NRxRy, -SO2C1-6alkyl, -P[=O]RxRy, -CO2H, haloC1-6alkoxy or a 3 to 8 membered heterocyclic group (e.g. an aromatic ring or a non-aromatic ring) group containing one or more (e.g. 1 , 2 or 3) heteroatoms selected from O, N or S.

[0136] In another embodiment, R1is selected from nitrile, -NRxRy, C1-6alkoxy (for example methoxy or ethoxy, e.g. methoxy), hydroxyC1-6alkyl (such as CH2OH or CH2CH2OH), -C(=O)NRxRy, or a 5 or 6 membered heterocyclic group (e.g. an aromatic ring or a non-aromatic ring) group containing one or more (e.g. 1 , 2 or 3) heteroatoms selected from O, N or S, wherein Rxand Ryare independently selected from hydrogen and C1-6alkyl or wherein Rxand Ry, together with the atom to which they are attached, join to form a heterocyclic ring with 4 to 6 ring members, wherein the heterocyclic group comprises one or more (e.g.1 , 2, or 3) heteroatoms selected from N, O, S and oxidised forms thereof (for example, azetidinyl, morpholinyl, piperazinyl, pyrrolidinyl, oxazolidinyl (for example 1 ,3-oxazolidin-3-yl)), wherein the heterocyclic group is optionally substituted with one or more Rzgroups.

[0137] In one embodiment, R1is -NRxRyor -C(=O)NRxRy, wherein Rxand Ryare independently selected from hydrogen, C1-6alkyl (e.g. methyl or ethyl, for example methyl), hydroxyC1-6alkyl (such as hydroxymethyl, hydroxyethyl or hydroxypropyl, e.g. hydroxyethyl or hydroxypropyl), -(CH2)k-OC1-6alkyl (for example - CH2OCH3, -CH2CH2OCH3or -CH2CH2OCH2CH3, e.g. -CH2CH2OCH3) or wherein Rxand Ry, together with the atom to which they are attached, join to form a heterocyclic ring with 4 to 6 ring members, wherein the heterocyclic group comprises one or more (e.g.1 , 2, or 3) heteroatoms selected from N, O, S and oxidised forms thereof (for example, azetidinyl, morpholinyl, piperazinyl, pyrrolidinyl, oxazolidinyl (for example 1 ,3-oxazolidin-3-yl)), wherein the heterocyclic group is optionally substituted with one or more Rzgroups, for example wherein the heterocyclic group is substituted with one Rzgroup that is hydroxy. In this embodiment, one of the heteroatoms in the heterocyclic ring is the nitrogen to which Rxand Ryare attached.

[0138] In one embodiment, R1is -NRxRy, wherein Rxand Ryare independently selected from hydrogen, C1-salkyl (e.g. methyl or ethyl, for example methyl), hydroxyC1-6alkyl (such as hydroxymethyl, hydroxyethyl or hydroxypropyl, e.g. hydroxyethyl or hydroxypropyl), -(CH2)k-OC1-6alkyl (for example -CH2OCH3, - CH2CH2OCH3or -CH2CH2OCH2CH3, e.g. -CH2CH2OCH3) or wherein Rxand Ry, together with the atom to which they are attached, join to form a heterocyclic ring with 4 to 6 ring members, wherein the heterocyclic group comprises one or more (e.g.1 , 2, or 3) heteroatoms selected from N, O, S and oxidised forms thereof (for example, azetidinyl, morpholinyl, piperazinyl, pyrrolidinyl, oxazolidinyl (for example 1 ,3-oxazolidin-3-yl)), wherein the heterocyclic group is optionally substituted with one or more Rzgroups. In one embodiment, R1is -NRxRy, wherein Rxand Rytogether with the atom to which they are attached, join to form a heterocyclic ring with 4 to 6 ring members, wherein the heterocyclic group comprises one or more (e.g.1 , 2, or 3) heteroatoms selected from N, O, S and oxidised forms thereof (for example, azetidinyi, morpholinyl, piperazinyl, pyrrolidinyl, oxazoiidinyl (for example 1 ,3-oxazolidin-3-yl)), wherein the heterocyclic group is optionally substituted with one or more Rzgroups.

[0139] In one embodiment, R1is -NRxRy, wherein Rxand Rytogether with the atom to which they are attached, join to form an azetidinyi ring that is optionally substituted with one or more Rzgroups.

[0140] In one embodiment, R1is -NRxRy, wherein Rxand Rytogether with the atom to which they are attached, join to form a pyrrolyl ring that is optionally substituted with one or more Rzgroups.

[0141] In one embodiment, R1is -NRxRy, wherein Rxand Rytogether with the atom to which they are attached, join to form a piperazinyl ring that is optionally substituted with one or more Rzgroups.

[0142] In one embodiment, R1is -NRxRy, wherein Rxand Rytogether with the atom to which they are attached, join to form a morpholinyl ring that is optionally substituted with one or more Rzgroups.

[0143] In one embodiment, R!is -C(=O)NRxRy, wherein Rxand Ryare independently selected from hydrogen, Cvsalkyl (e.g. methyl or ethyl, for example methyl), hydroxyC1-6alkyl (such as hydroxymethyl, hydroxyethyl or hydroxypropyl, e.g. hydroxyethyl or hydroxypropyl), -(CH2)k-OC1-6alkyl (for example - CH2OCH3, -CH2CH2OCH3or -CH2CH2OCH2CH3, e.g. -CH2CH2OCH3) or wherein Rxand Ry, together with the atom to which they are attached, join to form a heterocyclic ring with 4 to 6 ring members, wherein the heterocyclic group comprises one or more (e.g.1 , 2, or 3) heteroatoms selected from N, O, S and oxidised forms thereof (for example, azetidinyi, morpholinyl, piperazinyl, pyrrolidinyl, oxazoiidinyl (for example 1 ,3-oxazolidin-3-yl)), wherein the heterocyclic group is optionally substituted with one or more Rzgroups.

[0144] In one embodiment, R1is -C(O)NRxRy, wherein Rxand Rytogether with the atom to which they are attached, join to form a heterocyclic ring with 4 to 6 ring members, wherein the heterocyclic group comprises one or more (e.g.1 , 2, or 3) heteroatoms selected from N, O, S and oxidised forms thereof (for example, azetidinyi, morpholinyl, piperazinyl, pyrrolidinyl, oxazoiidinyl (for example 1 ,3-oxazolidin- 3-yl)), wherein the heterocyclic group is optionally substituted with one or more Rzgroups.

[0145] In one embodiment, R1is -C(O)NRxRy, wherein Rxand Rytogether with the atom to which they are attached, join to form an azetidinyi ring that is optionally substituted with one or more Rzgroups.

[0146] In one embodiment, R1is -C(O)NRxRy, wherein Rxand Rytogether with the atom to which they are attached, join to form a pyrrolyl ring that is optionally substituted with one or more Rzgroups.

[0147] In one embodiment, R1is -C(O)NRxRywherein Rxand Rytogether with the atom to which they are attached, join to form a piperazinyl ring that is optionally substituted with one or more Rzgroups.

[0148] In one embodiment, R1is -C(O)NRxRy, wherein Rxand Rytogether with the atom to which they are attached, join to form a morpholinyl ring that is optionally substituted with one or more Rzgroups. In one embodiment, n is 1. Typically, when n is 1 and Ring X is a six-membered cyclic group, R1is located in the 3- or 4- position relative to the cyclic imide, i.e. in the meta- or para- position. In one embodiment, Ring X is a six-membered cyclic group, n is 1 and R1is in the 4- position relative to the cyclic imide core.

[0149] In one embodiment, Ring X is a six-membered cyclic group, n is 1 , R1is in the 4- position relative to the cyclic imide core and is R1is -NRxRy, -C1-5alkylNRxRyor -C(=0)NRxRy.

[0150] In one embodiment, Ring X is a six-membered ring, n is 1 and R1is 4-NH2, 4-NMez, 4-NH(CHzOH) or 4-NH(CH2CH2OH), wherein the position is defined relative to the point of attachment of Ring X to the core.

[0151] In another embodiment:

[0152] • Ring X is phenyl;

[0153] • n is 1 ;

[0154] • R1is in the para- position;

[0155] • R1is selected from nitrile (i.e. -CN),, -NRxRy, C1-6alkoxy (such as methoxy or ethoxy, e.g. methoxy), hydroxyC1-6alkyl (such as -CH2OH or -CH2CH2OH) and -C(=O)NRxRy;

[0156] • Rxand Ryare independently selected from hydrogen and C1-6alkyl;

[0157] • or Rxand Rytogether with the atom to which they are attached join to form a non-aromatic heterocyclic group with 3 to 6 ring members wherein the heterocyclic group comprises one or more (e.g.1 , 2, or 3) heteroatoms selected from N, O, S, and oxidised forms thereof, wherein the heterocyclic group is optionally substituted with one or more Rzgroups;

[0158] • wherein Rzis selected from C1-6alkyl , hydroxy and nitrile.

[0159] In another embodiment:

[0160] • Ring X is phenyl;

[0161] • R1is in the para- position;

[0162] • R1is selected from -NRxRyand -C(=O)NRxRy;

[0163] • Rxand Ryare independently selected from hydrogen and -C1-6alkyl;

[0164] • or Rxand Rytogether with the atom to which they are attached join to form a non-aromatic heterocyclic group with 3 to 6 ring members wherein the heterocyclic group comprises one or more (e.g.1 , 2, or 3) heteroatoms selected from N, O, S, and oxidised forms thereof, wherein the heterocyclic group is optionally substituted with one or more Rzgroups;

[0165] • wherein Rzis selected from C1-6alkyl and hydroxy.

[0166] In one embodiment, the compound is a compound of formula (lie):

[0167] • W1and W2are CH; and

[0168] • Rxand Ryare selected from hydrogen and C1-6alkyl (for example methyl) or Rxand Rytogether with the nitrogen atom to which they are attached join to form a heterocyclic group with 3-6 ring members, wherein the heterocyclic group comprises one or more (e.g.1 , 2, or 3) heteroatoms selected from N, O, S and oxidised forms thereof (for example, azetidinyl, morpholinyl, piperazinyl, pyrrolidinyl or oxazolidinyl (for example 1 ,3-oxazolidin-3-yl))

[0169] • and wherein R2, A, B and R4are as defined herein.

[0170] In one embodiment, the compound is a compound of formula (lid):

[0171] • W and W2are CH; and

[0172] • Rxand Ryare selected from hydrogen and C1-6alkyl (for example methyl) or Rxand Rytogether with the nitrogen atom to which they are attached join to form a heterocyclic group with 3-6 ring members, wherein the heterocyclic group comprises one or more (e.g.1 , 2, or 3) heteroatoms selected from N, O, S and oxidised forms thereof (for example, azetidinyl, morpholinyl, piperazinyl, pyrrolidinyl or oxazolidinyl (for example 1 ,3-oxazolidin-3-yl))

[0173] • and wherein R2, A, B and R4are as defined herein. When R!is chiral, the compound of formula (I) can exist as at least two different diastereoisomers. For the avoidance of doubt, the general formula (i) and all subformulae cover both individual diastereoisomers and mixtures of the diastereoisomers which are related as epimers at the R1group.

[0174] E!

[0175] In one embodiment, R2is selected from hydrogen, halogen, nitro, nitrile, Cv6alkoxy, haloC1-6alkoxy, C1-ealkyl, C2-6alkenyl, C2-6alkynyl, haloC1-6alkyl, -(CH2)k-O-C1-6alkyl, -(CH2)k-S-C1-6alkyl, hydroxyl, hydroxyC1-6alkyl, -SH, -NHe(C1-4alkyl)2-e, C3-6cycloalkyl, C3-6cycloalkenyl and heterocyclic group (e.g. an aromatic ring or a non-aromatic ring) wherein the heterocyclic group has 3 to 6 ring members and wherein the heterocyclic group comprises one or more (e.g. 1 , 2 or 3) heteroatoms selected from N, O, S and oxidised forms thereof.

[0176] In one embodiment, R2is selected from halogen, nitro, nitrile, Cv6alkoxy, haloC1-6alkoxy, C1-6alkyl, C2- ealkenyl, C2-6alkynyl, haloC1-6alkyl, -(CH2)k-O-C1-6alkyl, -(CH2)k-S-C1-6alkyl, hydroxyl, hydroxyC1-6alkyl, - SH, -NHe(C1-4alkyl)2-e, C3-6cycloalkyl, C3-6cycloalkenyl and heterocyclic group (e.g. an aromatic ring or a non-aromatic ring) wherein the heterocyclic group has 3 to 6 ring members and wherein the heterocyclic group comprises one or more (e.g. 1 , 2 or 3) heteroatoms selected from N, O, S and oxidised forms thereof.

[0177] In one embodiment R2is selected from hydrogen, halogen (e.g. fluoro or chloro), nitro, nitrile, Cv6alkoxy (e.g. methoxy, ethoxy or propoxy), haloC1-6alkoxy (e.g. -OCH2F, -OCH2CH2F, -OCF3), -Oo.i-C1-6alkyl- CO2H (e.g. -CO2H, -CH2CO2H, -OCH2CO2H), C1-6alkyl (e.g. methyl, ethyl or isopropyl), C2-6alkenyl (e.g. -CH2CHCH2), -C2-ealkynyl (e.g. -CH2-CCH), haloC1-6alkyl (e.g. -CH2F, -CH2CF3, -CH2CH2F, -CF3, - CH2CF2H), (CH2)k-O- C1-6alkyl, (e.g. -CH2OCH2CH3, -CH2OCH3), -C(=O)NHe(C1-6alkyl)2-e(for example -C(=O)NH2or -C(=O)NHCH3), C1-6alkyl-C(=O)NHe(C1-6alkyl)2-e, (CH2)k-S-C1-6alkyl (e.g. -CH2Set, - CH2Sme), hydroxyl, hydroxyC1-6alkyl (e.g. -CH2OH or -CH2CH2OH), -SC1-8alkyl (e.g. -Sme, -Set or - SiPr), SH, (CH2)j-0-(hydroxyC1-6alkyl) (such as -CH2-OCH2OH, -CH2CH2-OCH2OH), -NHe(C1-4alkyl)2-e, (e.g. -NH2or -NHMe) and C1-6alkyl-NHe(C1-4alkyl)2-e(e.g. -CH2NH2, -CH2NHMe, -CH2CH2Nme2 or - CH2Net2).

[0178] In one embodiment R2is selected from Cv6alkoxy (e.g. methoxy, ethoxy or propoxy), haloC1-6alkoxy (e.g. -OCH2F, -OCH2CH2F, -OCF3), Cvealkyl (e.g. methyl, ethyl or isopropyl), C2- ealkenyl (e.g. - CH2CHCH2), haloC1-6alkyl (e.g. -CH2F, -CH2CF3, -CH2CH2F, -CF3, -CH2CF2H), (CH2)k-O-C1-6alkyl, (e.g. -CH2OCH2CH3, -CH2OCH3), (CH2)k-S-C1-6alkyl (e.g. -CH2SEt, -CH2SMe), -SC1-6alkyl (e.g. -SMe, -SEt or -SiPr) and SH.

[0179] In one embodiment R2is selected from C1-6alkyl (e.g. methyl, ethyl or isopropyl), haloC1-6alkyl (e.g. - CH2F, -CH2CF3, -CH2CH2F, -CF3, -CH2CF2H), -(CH2)k-O-C1-6alkyl, (e.g. -CH2OCH2CH3, -CH2OCH3) and -SC1-6alkyl (e.g. -SMe, -SEt or -SiPr). In one embodiment, R2is selected from C1-6alkyl (such as methyl, ethyl, propyl and iso-propyl, e.g. methyl and ethyl) and haloC1-6alkyl (for example -CH2F, -CH2CF3, -CH2CH(CH3)CF3, -CH2CH2F, -CF3and -CH2CF2H).

[0180] In one embodiment, R2is C1-6alkyl, for example methyl, ethyl or isopropyl, e.g. ethyl.

[0181] In one embodiment, R2is selected from methyl, ethyl, propyl and iso-propyl -CH2CF2H, -CH2CF3, - CH2CH2F, CF2OCH3and SMe. In particular, R2is ethyl.

[0182] In one embodiment, R2is not hydrogen.

[0183] Raand t t is selected from 0, 1 , 2, 3 and 4.

[0184] Raare independently selected from halogen, nitro, nitrile, C1-6alkoxy, haloC1-6alkoxy, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, haloC1-6alkyl, -(CH2)k-O-C1-6alkyl, -(CH2)k-S-C1-6alkyl, hydroxyl, hydroxyC1-6alkyl, - SH, -NHe(C1-4alkyl)2-e, C3-6cycloalkyl, C3-6cycloalkenyl and heterocyclic group (e.g. an aromatic ring or a non-aromatic ring) wherein the heterocyclic group has 3 to 6 ring members and wherein the heterocyclic group comprises one or more (e.g. 1 , 2 or 3) heteroatoms selected from N, O, S and oxidised forms thereof; or when t is 2 or more and the two Ragroups are joined to the same carbon, the two Ragroups together with the carbon to which they are attached join to form an =O (oxo), =CH2, spirocyclic C3-6carbocyclic group or a spirocyclic non-aromatic heterocyclic group with 3 to 6 ring-members containing one or more (e.g. 1 , 2 or 3) heteroatoms selected from O, N or S or oxidised forms thereof;

[0185] Raare independently selected from halogen, hydroxyl, -SH, -NHe(C1-2alkyl)2-e, nitrile, nitro and C1-2alkyl wherein optionally one or more (e.g. 1 , 2 or 3) of the carbon atoms in the C1-2alkyl group is replaced with a heteroatom selected from O, N and S or oxidised forms thereof; or, two Ragroups together with the carbon to which they are attached join to form =O (oxo), =CH2or spirocyclic C3-6cycloalkyl group or a spirocyclic non-aromatic heterocyclic group with 3 to 4 ring - members containing one or more (e.g. 1 or 2) heteroatoms selected from O, N or S.

[0186] In one embodiment, Raare selected from fluoro, hydroxyl, -SH and nitrile or two Ragroups together with the carbon to which they are attached join to form =O (oxo), =CH2or spirocyclic C8cycloakyl group or a spirocyclic non-aromatic heterocyclic group with 3 ring-members containing one heteroatom selected from O, N or S. Preferably, in this embodiment, t is 1 .

[0187] In one embodiment, t is 0 or 1 .

[0188] In one embodiment, t is 0 and the compound of formula (I) is a compound of formula (I’) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof:

[0189] wherein Ring X, R1, R2, A, B, R4and n are as defined herein.

[0190] A, B and R4

[0191] A, B and R4are defined as follows:

[0192] • A is CR32, NR3’ or O; B is O; R3are independently selected from hydrogen, halogen and C1-4alkyl; R3’ is selected from hydrogen and C1-4alkyl; and R4is Ring Y wherein Ring Y is selected from a cycloalkyl, aryl group or a heterocyclyl group (e.g. an aromatic ring or a non- aromatic ring), wherein the heterocyclyl group comprises one or more (e.g.1 , 2, or 3) heteroatoms selected from N, O and S and wherein the cycloalkyl, aryl or heterocyclyl group is optionally substituted with one or more (e.g. 1 , 2 or 3) R6groups, or

[0193] • A is CR32, NR3’ or O; B is NR5; R3are independently selected from hydrogen, halogen and C1-4alkyl; R3’ is selected from hydrogen and C1-4alkyl; and R4and R5together with the atoms to which they are attached join to form a heterocyclic group (e.g. an aromatic ring or a non- aromatic ring), wherein the heterocyclic group optionally comprises one or more additional heteroatoms selected from N, O or S, and oxidised forms thereof, wherein the heterocyclic group may optionally be substituted with one or more (e.g. 1 , 2 or 3) R6groups; or

[0194] • A is CR32 or NR3’; B is NR5; R5and R3’ or one R3group together with the atoms to which they are attached join to form a heterocyclic group (e.g. an aromatic ring or a non-aromatic ring), wherein the heterocyclic group optionally comprises one or more additional heteroatoms selected from N, O or S, and oxidised forms thereof, wherein the heterocyclic group may optionally be substituted with one or more (e.g. 1 , 2 or 3) R6groups; the other R3group is selected from hydrogen, halogen and C1-4alkyl; and R4is selected from hydrogen and C1-4alkyl.

[0195] In one embodiment:

[0196] • A is CR32, NR3’ or O; B is O; R3are independently selected from hydrogen, halogen and C1-4alkyl; R3’ is selected from hydrogen and C1-4alkyl; and R4is selected from a cycloalkyl, aryl group or a heterocyclyl group (e.g. an aromatic ring or a non-aromatic ring), wherein the heterocyclyl group comprises one or more (e.g.1 , 2, or 3) heteroatoms selected from N, O and S and wherein the cycloalkyl, aryl or heterocyclyl group is optionally substituted with one or more (e.g. 1 , 2 or 3) R6groups, or • A is CR32, NR3’ or O; B is NR5; R3are independently selected from hydrogen, halogen and C1-4alkyl; R3’ is selected from hydrogen and C1-4alkyl; and R4and R5together with the atoms to which they are attached join to form a heterocyclic group (e.g. an aromatic ring or a non- aromatic ring), wherein the heterocyclic group optionally comprises one or more additional heteroatoms selected from N, O or S, and oxidised forms thereof, wherein the heterocyclic group may optionally be substituted with one or more (e.g. 1 , 2 or 3) R6groups; or

[0197] In one embodiment:

[0198] • A is CH2or NH, B is O, and R4is Ring Y, wherein Ring Y is an aryl group with 6 ring members or a heterocyclyl group with 5 or 6 ring members, wherein the heterocyclyl group comprises one or more (e.g.1 , 2, or 3) heteroatoms selected from N, O and S, and oxidised forms thereof, wherein the aryl or heterocyclyl group is optionally substituted with one or more (e.g. 1 , 2 or 3) R6groups; or

[0199] • A is CH2or NH, B is NR5, and R4and R5together with the atoms to which they are attached join to form a 5- to 10-membered heteroaryl group, wherein the heteroaryl group optionally comprises one or more additional heteroatoms selected from N, O or S, and oxidised forms thereof, wherein the heterocyclic group may optionally be substituted with one or more (e.g. 1 , 2 or 3) R6groups; or

[0200] • A is NR3’ and B is NR5, R5and R3’ together with the atoms to which they are attached join to form a heterocyclic group, wherein the heterocyclic group comprises one additional nitrogen atom, wherein the heterocyclic group may optionally be substituted with one or more (e.g. 1 , 2 or 3) R6groups selected from hydrogen, halogen and C1-4a Iky I and R4is selected from hydrogen and C1-4alkyl.

[0201] In one embodiment:

[0202] • A is CR32, NR3’ or O; B is O; R3are independently selected from hydrogen, halogen and C1-4alkyl; R3’ is selected from hydrogen and C1-4alkyl; and R4is Ring Y wherein Ring Y selected from a cycloalkyl, aryl group or a heterocyclyl group (e.g. an aromatic ring or a non-aromatic ring), wherein the heterocyclyl group comprises one or more (e.g.1 , 2, or 3) heteroatoms selected from N, O and S and wherein the cycloalkyl, aryl or heterocyclyl group is optionally substituted with one or more (e.g. 1 , 2 or 3) R6groups and wherein Ring Y is not saturated and wherein the point of attachment of Ring Y is not a nitrogen atom, or

[0203] • A is CR32, NR3’ or O; B is NR5; R3are independently selected from hydrogen, halogen and C1-4alkyl; R3’ is selected from hydrogen and C1-4alkyl; and R4and R5together with the atoms to which they are attached join to form a 6-membered heterocyclic group (e.g. an aromatic ring or a non-aromatic ring), wherein the 6-membered heterocyclic group optionally comprises one or more additional heteroatoms selected from N, O or S, and oxidised forms thereof, wherein the 6-membered heterocyclic group may optionally be substituted with one or more (e.g. 1 , 2 or 3) R6groups; or • A is CR32 or NR3’; B is NR5; R5and R3’ or one R3group together with the atoms to which they are attached join to form a 6-membered heterocyclic group (e.g. an aromatic ring or a non- aromatic ring), wherein the 6-membered heterocyclic group optionally comprises one or more additional heteroatoms selected from N, O or S, and oxidised forms thereof, wherein the 6- membered heterocyclic group may optionally be substituted with one or more (e.g. 1 , 2 or 3) R6groups; the other R3group is selected from hydrogen, halogen and C1-4alkyl; and R4is selected from hydrogen and C1-4alkyl;

[0204] In one embodiment, A is selected from CH2and NH.

[0205] In one embodiment, A is CR32, wherein R3are independently selected from hydrogen and C1-4alkyl, for example hydrogen, methyl and ethyl.

[0206] In one embodiment, A is CR32, wherein both R3are hydrogen, i.e. A is CH2.

[0207] In one embodiment, A is CR32, NR3’ or O; B is O; R3are independently selected from hydrogen, halogen and C1-4alkyl; R3’ is selected from hydrogen and C1-4alkyl; and R4is Ring Y wherein Ring Y is selected from a cycloalkyl, aryl group or a heterocyclyl group (e.g. an aromatic ring or a non-aromatic ring), wherein the heterocyclyl group comprises one or more (e.g.1 , 2, or 3) heteroatoms selected from N, O and S and wherein the cycloalkyl, aryl or heterocyclyl group is optionally substituted with one or more (e.g. 1 , 2 or 3) R6groups.

[0208] In one embodiment the compound of formula (I) is a compound of formula (III0) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof: wherein Ra, R1, R2, R3, R6, Ring X, Ring Y, t and n are as defined herein and wherein m is selected from 0, 1 , 2 and 3.

[0209] In one embodiment, the compound of formula (I) is a compound of formula (III0) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof and Ring Y is an aryl group with 6 to 10 ring members or a heterocyclyl group with 5 to 12 ring members, wherein the heterocyclyl group comprises one or more (e.g.1 , 2, or 3) heteroatoms selected from N, O and S, and oxidised forms thereof, wherein the aryl or heterocyclyl group is optionally substituted with one or more (e.g. 1 , 2 or 3) R6groups In one embodiment, the compound of formula (I) is a compound of formula (III0) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof and Ring Y is selected from azaindolyl, pyrazolyl, indazolyl, imidazolyl, indolyl, isoindolyl, thiophenyl, pyrrolidinyl, phenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, benzodiazolyl, pyrazolopyridinyl (for example, pyrazolo[4,3-b]pyridinyl, pyrazolo[1 ,5- a]pyridinyl or pyrazolo[3,4-c]pyridinyl), pyrrolopyridinyl (for example, pyrrolo[3,2-b]-pyridinyl), pyrrolopyrimidinyl (for example, pyrrolo[2,3-d]pyrimidinyl), imidazopyridinyl (for example, imidazo[1 ,2- a]pyridinyl and imidazo[1 ,5-a]pyridinyl), pyrrolopyrazolyl (for example pyrrolo[3,4-c]pyrazolyl), dihydropyrazolyl (for example, dihydropyrrolo[3,4-c]pyrazol-5H-yl), quinazolinyl, phthalazinyl, cinnolinyl, dihydrobenzofuranyl, dihydrobenzodioxinyl, thiazolyl, pyrazinyl, furanyl, and dihydroquinoxalinyl groups.

[0210] In one embodiment, the compound of formula (I) is a compound of formula (III0) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof and Ring Y is selected from pyrazolyl, indazolyl, imidazolyl, indolyl, thiophenyl, pyrrolidinyl, phenyl, pyridinyl, pyrazinyl, pyridazinyl, benzodiazolyl, pyrazolopyridinyl (for example, pyrazolo[4,3-b]pyridinyl, pyrazolo[1 ,5-a]pyridinyl or pyrazolo[3,4- c]pyridinyl), pyrrolopyridinyl (for example, pyrrolo[3,2-b]-pyridinyl), pyrrolopyrimidinyl (for example, pyrrolo[2,3-d]pyrimidinyl), imidazopyridinyl (for example, imidazo[1 ,2-a]pyridinyl and imidazo[1 ,5- a]pyridinyl), pyrrolopyrazolyl (for example pyrrolo[3,4-c]pyrazolyl), dihydropyrazolyl (for example, dihydropyrrolo[3,4-c]pyrazol-5H-yl), dihydrobenzofuranyl, dihydrobenzodioxinyl, and dihydroquinoxalinyl groups.

[0211] In one embodiment, the compound of formula (I) is a compound of formula (III0), or a tautomer or a solvate or a pharmaceutically acceptable salt thereof, wherein Ring Y is selected from phenyl, pyridine, pyrimidine, pyrazine and pyridazine, for example phenyl and pyridine.

[0212] In one embodiment, the compound of formula (I) is a compound of formula (III0) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof and Ring Y is phenyl or pyridine.

[0213] In one embodiment, the compound of formula (I) is a compound of formula (III0) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof and Ring Y is phenyl.

[0214] In one embodiment, the compound of formula (I) is a compound of formula (III0) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof and Ring Y is pyridine.

[0215] In one embodiment, the compound of formula (I) is a compound of formula (III0) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof, m is 1 and R6is at the 4-position of Ring Y relative to the point of attachment to the core.

[0216] In one embodiment the compound of formula (I) is a compound of formula (III) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof:

[0217] wherein Ra, R1, R2, R6, Ring X, Ring Y, t and n are as defined herein and wherein m is selected from 0, 1 , 2 and 3.

[0218] In one embodiment, the compound of formula (I) is a compound of formula (III) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof and Ring Y is an aryl group with 6 to 10 ring members or a heterocyclyl group with 5 to 12 ring members, wherein the heterocyclyl group comprises one or more (e.g.1 , 2, or 3) heteroatoms selected from N, O and S, and oxidised forms thereof, wherein the aryl or heterocyclyl group is optionally substituted with one or more (e.g. 1 , 2 or 3) R6groups.

[0219] In one embodiment, the compound of formula (I) is a compound of formula (III) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof and Ring Y is an aryl group with 6 ring members or a heterocyclyl group with 5 or 6 ring members, wherein the heterocyclyl group comprises one or more (e.g.1 , 2, or 3) heteroatoms selected from N, O and S, and oxidised forms thereof, wherein the aryl or heterocyclyl group is optionally substituted with one or more (e.g. 1 , 2 or 3) R6groups.

[0220] In one embodiment, the compound of formula (I) is a compound of formula (III) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof and Ring Y is selected from azaindolyl, pyrazolyl, indazolyl, imidazolyl, indolyl, isoindolyl, thiophenyl, pyrrolidinyl, phenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, benzodiazolyl, pyrazolopyridinyl (for example, pyrazolo[4,3-b]pyridinyl, pyrazolo[1 ,5- a]pyridinyl or pyrazolo[3,4-c]pyridinyl), pyrrolopyridinyl (for example, pyrrolo[3,2-b]-pyridinyl), pyrrolopyrimidinyl (for example, pyrrolo[2,3-d]pyrimidinyl), imidazopyridinyl (for example, imidazo[1 ,2- a]pyridinyl and imidazo[1 ,5-a]pyridinyl), pyrrolopyrazolyl (for example pyrrolo[3,4-c]pyrazolyl), dihydropyrazolyl (for example, dihydropyrrolo[3,4-c]pyrazol-5H-yl), quinazolinyl, phthalazinyl, cinnolinyl, dihydrobenzofuranyl, dihydrobenzodioxinyl, thiazolyl, pyrazinyl, furanyl, and dihydroquinoxalinyl groups.

[0221] In one embodiment, the compound of formula (I) is a compound of formula (III) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof and Ring Y is selected from pyrazolyl, indazolyl, imidazolyl, indolyl, thiophenyl, pyrrolidinyl, phenyl, pyridinyl, pyrazinyl, pyridazinyl, benzodiazolyl, pyrazolopyridinyl (for example, pyrazolo[4,3-b]pyridinyl, pyrazolo[1 ,5-a]pyridinyl or pyrazolo[3,4- c]pyridinyl), pyrrolopyridinyl (for example, pyrrolo[3,2-b]-pyridinyl), pyrrolopyrimidinyl (for example, pyrrolo[2,3-d]pyrimidinyl), imidazopyridinyl (for example, imidazo[1 ,2-a]pyridinyl and imidazo[1 ,5- a]pyridinyl), pyrrolopyrazolyl (for example pyrrolo[3,4-c]pyrazolyl), dihydropyrazolyl (for example, dihydropyrrolo[3,4-c]pyrazol-5H-yl), dihydrobenzofuranyl, dihydrobenzodioxinyl, and dihydroquinoxalinyl groups.

[0222] In one embodiment, the compound of formula (I) is a compound of formula (III), or a tautomer or a solvate or a pharmaceutically acceptable salt thereof, wherein Ring Y is selected from phenyl, pyridine, pyrimidine, pyrazine and pyridazine, for example phenyl and pyridine.

[0223] In one embodiment, the compound of formula (I) is a compound of formula (III) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof and Ring Y is phenyl or pyridine.

[0224] In one embodiment, the compound of formula (I) is a compound of formula (III) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof and Ring Y is phenyl.

[0225] In one embodiment, the compound of formula (I) is a compound of formula (III) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof and Ring Y is pyridine.

[0226] In one embodiment, the compound of formula (I) is a compound of formula (III) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof, m is 1 and R6is at the 4-position of Ring Y relative to the point of attachment to the core.

[0227] In one embodiment, the compound of formula (I) is a compound of formula (III’) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof: wherein R1, R2, R6, Ring X, Ring Y and n are as defined herein and wherein m is selected from 0, 1 , 2, 3 and 4.

[0228] In one embodiment, the compound of formula (I) is a compound of formula (Illa) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof:

[0229] wherein Y1, Y2, Y3, Y4and Y5are independently selected from N, CH and CR6, wherein no more than two of Y1, Y2, Y3, Y4and Y5are N and no more than four of Y1, Y2, Y3, Y4and Y5are CR6and wherein R1, R2, Ra, R6, t and Ring X are as defined herein.

[0230] In one embodiment, the compound of formula (I) is a compound of formula (Illa) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof and Y1, Y2, Y3, Y4and Y5are all CH or CR6, wherein no more than four of Y1, Y2, Y3, Y4and Y5are CR6, i.e. Ring Y is phenyl and is optionally substituted by up to 4 R6groups, for example 0, 1 , 2 or 3 R6groups.

[0231] In one embodiment, the compound of formula (I) is a compound of formula (Illa) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof and Ring Y is unsubstituted phenyl.

[0232] In one embodiment the compound of formula (I) is a compound of formula (Illa) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof and

[0233] • Y1is N and Y2, Y3, Y4and Y5are CH or CR6; or

[0234] • Y2is N and Y1, Y3, Y4and Y5are CH or CR6; or

[0235] • Y3is N and Y1, Y2, Y4and Y5are CH or CR6; or

[0236] • Y1and Y4are N and Y2and Y5are CH or CR6; or

[0237] • Y1, Y2, Y3, Y4and Y5are all CH or CR6wherein no more than four of Y1, Y2, Y3, Y4and Y5are CR6.

[0238] In one embodiment, the compound of formula (I) is a compound of formula (lllb) or a solvate or a tautomer or a pharmaceutically acceptable salt thereof:

[0239] wherein Y1is CH or N, m is 0, 1 , 2, 3 or 4 and R1, R2, Ra, R6, t and Ring X are as defined herein.

[0240] In one embodiment, the compound of formula (I) is a compound of formula (II lb’) or a solvate or a tautomer or a pharmaceutically acceptable salt thereof: wherein Y1is CH or N, m is 0, 1 , 2, 3 or 4 and R1, R2, Ra, R6, t and Ring X are as defined herein.

[0241] In one embodiment, the compound of formula (I) is a compound of formula (II lb’) or a solvate or a tautomer or a pharmaceutically acceptable salt thereof, m is 1 and R6is in the 4-position relative to the point of attachment to the core. For the avoidance of doubt, the general formula (I) and all subformulae cover both individual diastereoisomers and mixtures of the diastereoisomers which are related as epimers.

[0242] Additional stereochemical centres can also be introduced by Reor Rz. For the avoidance of doubt, the general formula (I) and all subformulae cover both individual diastereoisomers and mixtures of the diastereoisomers which are related as epimers at the R6and Rzgroup. R6

[0243] R6is the substituent that is optionally pending from Ring Y or from the cyclic group formed by the joining of R4and R5or from the cyclic group that is formed by the joining of R3and R5. R6is independently selected from hydroxyl, halogen, nitro, nitrile, C1-6alkyl, nitrileC1-6alkyl, C1-6alkoxy, haloC1-6alkyl, C2-6alkenyl, C2-6alkynyl, =O (oxo), -C(=O)C1-6alkyl, -SH, -SC1-6alkyl, -SO2C1-6alkyl, C1-6alkylSO2C1-6alkyl, -SO2NRxRy, -C1-6alkyl-SO2NRxRy, -NRxRy, -C(=O)NRxRy, -NRxC(=O)C1-6alkyl, C1-6alkylNHC(=O)C1-6alkyl, -(CH2)k-O-C1-6alkyl, hydroxyC1-6alkyl, hydroxyC1-6alkoxy, haloC1-6alkoxy, - C(=O)C1-6alkyl-OH, -C(=O)C1-6alkyl-N(H)e(C1-6alkyl)2-e, CO2C1-6alkyl, C1-6alkylCO2C1-6alkyl, -(CRxRy)v- CONRxRy, -CO2H, -C1-6alkylCO2H, -C1-6alkyl-NRxRy, -P(=O)(Rx)(Ry), C3-8cycloalkyl, C3-8cycloalkenyl, Ce- waryl, and heterocyclic groups (e.g. an aromatic ring or a non-aromatic ring) with 3 to 8 ring members wherein the heterocyclic group comprises one or more (e.g.1 , 2, or 3) heteroatoms selected from N, O, S and oxidised forms thereof, wherein the O-ealkyl groups is optionally substituted with a C3-8cycloalkyl, Cs-acycloalkenyl, Ce-waryl or 3 to 8 membered heterocyclic group (e.g. an aromatic ring or non-aromatic ring) containing one or more (e.g. 1 , 2 or 3) heteroatoms selected from O, N or S and wherein in each case the C3-8cycloalkyl, C3-8cycloalkenyl, Ce-ioaryl and 3 to 8 membered heterocyclic groups are optionally further substituted with one or more (e.g. 1 , 2 or 3) Rzgroups, or two R6groups together with the atoms to which they are attached join to form a Cs-acycloalkyl, C3-8cycloalkenyl, Ce-waryl or heterocyclic group with 3 to 8 ring members (e.g. an aromatic ring or a non- aromatic ring), wherein the heterocyclic group contains one or more (e.g. 1 , 2 or 3) heteroatoms selected from N, O, S and oxidised forms thereof and wherein the C3-8cycloalkyl, C3-8cycloalkenyl, Ca waryl group or 3- to 8-membered heterocyclic ring be substituted by one or more Rzgroups.

[0244] In one embodiment, R6are independently selected from hydroxyl, halogen, nitro, nitrile, C1-6alkyl, C1-6alkoxy, haloC1-6alkyl, C2-6alkenyl, =O (oxo), C(=O)C1-6alkyl, -SC1-6alkyl, haloC1-6alkyl, NRxRy, C(=O)NRxRy, -NHC(=O)C1-6alkyl, -(CH2)k-O-C1-6alkyl, hydroxyC1-aalkyl, haloC1-6alkoxy, -(CRxRy)v- CO2C1-6alkyl, -(CRxRy)v-CON(C1-6alkyl)2, -C1-6alkyl-N(H)e(C1-6alkyl)2-e, -SC1-aalkyl, C3-8cycloalkyl, C3-8cycloalkenyl and heterocyclic groups (e.g. an aromatic ring or a non-aromatic ring) with 3 to 6 ring members wherein the heterocyclic group comprises one or more (e.g.1 , 2, or 3) heteroatoms selected from N, O, S and oxidised forms thereof and wherein the C3-6cycloalkyl, C3-8cycloalkenyl and heterocyclic groups are optionally further substituted with one or more (e.g. 1 , 2 or 3) Rzgroups; or two R6groups together with the atoms to which they are attached join to form a C3 ecycloalkyl, C3-8cycloalkenyl, Csaryl or heterocyclic group with 5 or 6 ring members (e.g. an aromatic ring or a non- aromatic ring), wherein the heterocyclic group contains one or more (e.g. 1 , 2 or 3) heteroatoms selected from N, O, S and oxidised forms thereof and wherein the C38cycloalkyl, C3-8cycloalkenyl, Csaryl or heterocyclic ring is optionally substituted by one or more Rzgroups.

[0245] In one embodiment, R6is halogen, nitrile, oxo, C1-6alkyl, -SC1-6alkyl, haloC1-6alkyl, -NRxRy, - C(=O)NRxRy, --NHC(=O)C1-6alkyl, C1-6alkoxy, hydroxyC1-6alkyl, -C1-6alkyl-NRxRyor heterocyclic group with 4 to 6 ring members (e.g. an aromatic ring or a non-aromatic ring), wherein the heterocyclic group comprises one or more (e.g. 1 , 2 or 3) heteroatoms selected from N, O and S, and oxidised forms thereof, wherein the heterocyclic ring is optionally substituted by one or more (e.g. 1 , 2 or 3) Rzgroups; or two R6groups together with the atoms to which they are attached join to form a Csaryl group or a heterocyclic group with five or six ring members (e.g, an aromatic ring or a non-aromatic ring), wherein the heterocyclic group contains one or more (e.g. 1 , 2 or 3) heteroatoms selected from N. O, S and oxidised forms thereof and wherein the aryl or heterocyclic ring is optionally substituted by one or more Rzgroups.

[0246] In one embodiment, R6is halogen (for example, fluoro, chloro or bromo), nitrile, oxo (=O), C1-6alkyl (e.g. methyl, ethyl and isopropyl, e.g. methyl), C1-6alkoxy (for example, methoxy and ethoxy, e.g. methoxy), - SC1-6alkyl (for example -SCH3, -SCH2CH3and -SCH(CH3)2, e.g. -SCH3), haloC1-6alkyl (for example - CH2F, CHF2, -CF3and -CH2CH2F, e.g. -CHF2), -NRxRy(for example NH2, NHMe, NMe2, NH(CH2N(CH3)2) and NH(CH2CH2N(CH3)2)), -C(=O)NRxRy(for example, C(=O)NH2, C(=O)NH(CH3), C(=O)N(CH3)2), -NHC(=O)C1-6alkyl (for example -NHC(=O)CH3, -NHC(=O)CH2CH3, e.g. - NHC(=O)CH3), hydroxyC1-6alkyl (for example, -CH2OH, -CH2CH2OH, -CH(CH3)OH and -C(CH3)2OH), - C1-6alkyl-NRxRy(for example CH2NH2) or heterocyclic group with 4 to 6 ring members (e.g. an aromatic ring or a non-aromatic ring), wherein the heterocyclic group comprises one or more (e.g. 1 , 2 or 3) heteroatoms selected from N, O and S, and oxidised forms thereof (for example, pyrazolyl, pyrazolidine, pyrimidine and azetidine), wherein the heterocyclic ring is optionally substituted by one or more (e.g. 1 , 2 or 3) Rzgroups; or two R6groups together with the atoms to which they are attached join to form a Csaryl group or a heterocyclic group with five or six ring members (e.g. an aromatic ring or a non-aromatic ring), wherein the heterocyclic group contains one or more (e.g. 1 , 2 or 3) heteroatoms selected from N, O, S and oxidised forms thereof (e.g. phenyl, pyrazolyl, tetrahydrofuranyl, dioxanyl and pyrrolyl), and wherein the aryl or heterocyclic ring is optionally substituted by one or more Rzgroups.

[0247] In one such embodiment, R6is selected from NRxRywherein Rxand Ryare independently selected from hydrogen and C1-6alkyl, e.g. wherein R6is NH2.

[0248] In one embodiment, the compound of formula (I) is a compound of formula (III): wherein:

[0249] • m is 1 , 2 or 3; and

[0250] • R6is halogen (for example, fluoro, chloro or bromo), oxo (=O), C1-6alkyl (e.g. methyl, ethyl and isopropyl, e.g. methyl), C1-6alkoxy (for example, methoxy and ethoxy, e.g. methoxy), - SC1-6alkyl (for example -SCH3, -SCH2CH3and -SCH(CH3)2, e.g. -SCH3), haloC1-6alkyl (for example -CH2F, CHF2, -CF3and -CH2CH2F, e.g. -CHF2), -NRxRy(for example NH2, NHMe, NMe2, NH(CH2N(CH3)2) and NH(CH2CH2N(CH3)2)), -C(=O)NRxRy(for example, C(=O)NH2, C(=O)NH(CH3), C(=O)N(CH3)2), -NHC(=O)C1-6alkyl (for example -NHC(=O)CH3, - NHC(=O)CH2CH3, e.g. -NHC(=O)CH3), hydroxyC1-8alkyl (for example, -CH2OH, - CH2CH2OH, -CH(CH3)OH and -C(CH3)2OH), -C1-6alkyl-NRxRy(for example CH2NH2) or heterocyclic group with 4 to 6 ring members (e.g. an aromatic ring or a non-aromatic ring), wherein the heterocyclic group comprises one or more (e.g. 1 , 2 or 3) heteroatoms selected from N, O and S, and oxidised forms thereof (for example, pyrazolyl, pyrazolidine, pyrimidine and azetidine), wherein the heterocyclic ring is optionally substituted by one or more (e.g. 1 , 2 or 3) Rzgroups;

[0251] • or two R6groups together with the atoms to which they are attached join to form a Cearyl group or a heterocyclic group with five or six ring members (e.g. an aromatic ring or a non- aromatic ring), wherein the heterocyclic group contains one or more (e.g. 1 , 2 or 3) heteroatoms selected from N, O, S and oxidised forms thereof (e.g. phenyl, pyrazolyl, tetrahydrofuranyl, dioxanyl and pyrrolyl), and wherein the aryl or heterocyclic ring is optionally substituted by one or more Rzgroups;

[0252] • R1, R2, Ra, n, t and Ring X and Ring Y are as described herein.

[0253] In one embodiment, the compound of formula (I) is a compound of formula (III), wherein:

[0254] • m is 1 , 2 or 3 and R6is selected from C1-6alkyl, halogen and NRxRy, wherein Rxand Ryare independently selected from hydrogen and C1-6alkyl; or

[0255] • m is 2 or 3 and two R6join to form a five-membered heterocyclic group containing 1 or 2 heteroatoms that are N, wherein when m is 3 one R6is selected from C1-6alkyl, halogen and NHe(C1-6alkyl)2-e, for example NHe(C1-6alkyl)2-e, e.g. NH2, NHMe or NMe2.

[0256] In one embodiment, the compound of formula (I) is a compound of formula (III), m is 1 , 2 or 3 and R6is selected from:

[0257] • halogen (for example chloro or fluoro), -NRxRy, wherein Rxand Ryare independently selected from hydrogen and C1-6alkyl; or

[0258] • when m is 2 or 3, two R6join to form a five-membered heterocyclic group containing 1 or 2 heteroatoms that are N. m denotes the number of R6substituents on Ring Y. m can be 0, 1 , 2 or 3.

[0259] In one embodiment, m is selected from 1 , 2 or 3, for example m is 1 or 2.

[0260] In one embodiment, m is 1 . In another embodiment, m is 2.

[0261] In one embodiment, R6is attached to a six-membered cyclic group. In otherwords, Ring Y, orthe cyclic group formed by the joining of R4and R5, or the cyclic group that is formed by the joining of R3and R5, is a six-membered cyclic group. In this embodiment, R6can be in the 2-, 3- or 4- position relative to the point of attachment to the cyclic imide core. In one embodiment, m is 1 , R6is joined to a six-membered cyclic group and R6is in the 2-, 3- or 4- position relative to the point of attachment to the cyclic imide core, for example in the 3- or 4- position, e.g. in the 4- position.

[0262] In one embodiment, m is 1 , R6is joined to a six-membered cyclic group and R6is in the 4-position, for example wherein R6is in the 4-position and is -NHe(C1-6alkyl)2-e, for example -NMe2, -NHMe or -NH2, e.g. -NH2.

[0263] In one embodiment, R6are joined to a six-membered cyclic group and:

[0264] • m is 2, R6are in the 3- and 4- position and R6are halogen (e.g. chloro) and -NHe(C1-6alkyl)2-efor example -NMe2, -NHMe or -NH2, e.g. -NH2; or

[0265] • m is 2, R6are in the 2- and 4- position and R6are halogen (e.g. fluoro) and -NHe(C1-6alkyl)2-efor example -NMe2, -NHMe or -NH2, e.g. -NH2; or

[0266] • m is 3, R6are in the 2-, 3- and 4- positions and R6are independently selected from halogen (e.g. chloro) and -NHe(C1-6alkyl)2-e, for example two R6are fluoro and one R6is -NH2;

[0267] • m is 1 , R6is joined to a six-membered cyclic group, R6is in the 4-position and is NHe(C1-6alkyl)2- e, for example -NMe2, -NHMe or -NH2, e.g. -NH2; or

[0268] • m is 2, R6are located in the 2- and 3- positions and join to form a five-membered heterocyclic ring with 1 or 2, for example 2N; or

[0269] • m is 3, two R6are located in the 2- and 3- positions and join to form a five-membered heterocyclic ring with 1 or 2, for example 2N, and the third R6group is -NHe(C1-6alkyl)2-ewherein in each case the position is defined relative to the point of attachment to the cyclic imide core.

[0270] Rxand Ry

[0271] Rxand Ryare independently selected from hydrogen, halogen, nitro, nitrile, hydroxyl, =O (oxo), C1-ealkyl, haloC1-6alkyl, C2-6alkenyl, C2-6alkynyl, hydroxyC1-6alkyl, C1-6alkoxy, -NHe(C1-6alkyl)2-e, -C1-6alkylNHe(C1-6alkyl)2-e, hydroxyC1-6alkoxy, -(CH2)k-O-C1-6alkyl, -C(=O)C1-6alkyl, --(CH2)jCO2Ci 6alkyl, - (CH2)k-C(=O)N(H)e(C1-6alkyl)2-e, -C(=O)C1-6alkyl-N(H)e(Ci ^alkyl)2-e, -(CH2)qCO2H C3-8cycloalkyl, C3-8cycloalkenyl and heterocyclic groups (e.g. an aromatic ring or a non-aromatic ring) with 3 to 8 ring members, wherein the heterocyclic group comprises one or more (e.g.1 , 2, or 3) heteroatoms selected from N, O, S and oxidised forms thereof; or Rxand Ry, together with the atom(s) to which they are attached, join to form a C3-8cycloalkyl, C3-8cycloalkenyl, or heterocyclic group with 3 to 8 ring members (e.g. an aromatic ring or a non-aromatic ring), wherein the heterocyclic group comprises one or more (e.g.1 , 2, or 3) heteroatoms selected from N, O, S and oxidised forms thereof; wherein when Rxand Ryare C3-8cycloalkyl, C3-8cycloalkenyl or a heterocyclic group with 3 to 8 ring members or when Rxand Rytogether with the atom to which they are attached, join to form a C3-8cycloalkyl, C3-8cycloalkenyl, or heterocyclic group with 3 to 8 ring members then the C3-8cycloalkyl, C3-8cycloalkenyl or heterocyclic group with 3 to 8 ring members is optionally further substituted with one or more (e.g. 1 , 2 or 3) Rzgroups. In one embodiment Rxand Ryare independently selected from hydrogen, halogen, nitro, nitrile, hydroxyl, C1-6alkyl, haloC1-6alkyl, C2-6alkenyl, C2-6alkynyl, hydroxyC1-6alkyl, C1-6alkoxy, NHe(C1-6alkyl)2-e, C1-6alkylNHe(C1-6alkyl)2-e, hydroxyC1-6alkoxy, (CH2)v-O-C1-6alkyl, -CO2C1-6alkyl, -(CH2)k-C(=O)N(H)e(C1-6alkyl)2-e, C3-6cycloalkyl, C3-8cycloalkyl, C3-8cycloalkenyl and heterocyclic groups (e.g. an aromatic ring or a non-aromatic ring) with 3 to 8 ring members wherein the heterocyclic group comprises one or more (e.g.1 , 2, or 3) heteroatoms selected from N, O, S and oxidised forms thereof and wherein the 3-8cycloalkyl, C3-8cycloalkenyl and heterocyclic groups are optionally further substituted with one or more (e.g. 1 , 2 or 3) Rzgroups; or Rxand Ry, together with the atom to which they are attached, join to form a CH2group or a C3-8cycloalkyl, C38cycloalkenyl or non-aromatic heterocylic group with 3 to 8 ring members, wherein the heterocyclic group comprises one or more (e.g.1 , 2, or 3) heteroatoms selected from N, O, S and oxidised forms thereof and wherein the C3-8cycloalkyl, C3-8cycloalkenyl or non-aromatic heterocyclic groups are optionally further substituted with one or more (e.g. 1 , 2 or 3) Rzgroups.

[0272] In one embodiment Rxand Ryare independently selected from hydrogen, C1-6alkyl, hydroxyC1-6alkyl, Cv6alkoxy, -C1-6alkylNHq(C1-6alkyl)2-q, -(CH2)j-O- C1-6alkyl; or Rxand Ry, together with the atom to which they are attached, join to form a non-aromatic heterocylic group with 3 to 6 ring members, wherein the non-aromatic heterocyclic group comprises one or more (e.g.1 , 2, or 3) heteroatoms selected from N, O, S and oxidised forms thereof and wherein the non- aromatic heterocyclic groups are optionally further substituted with one or more (e.g. 1 , 2 or 3) Rzgroups.

[0273] In one embodiment Rxand Ryare independently selected from hydrogen, C1-6alkyl (for example ethyl or methyl, e.g. methyl), hydroxyC1-6alkyl (for example -CH2OH, -CH2CH2OH, -CH2CH2CH2OH and - CH2CH(CH3)OH, e.g. -CH2OH, -CH2CH2OH and -CH2CH2CH2OH), C1-8alkoxy (for example, - CH2OCH3, -CH2CH2OCH3, -CH2CH2O CH2CH2, e.g. -CH2CH2OCH3), -C1-6alkylNHq(C1-6alkyl)2-q (for example CH2NHCH3, CH2CH2N(CH3)2, e.g. CH2CH2N(CH3)2), (CH2)v-O-C1-6alkyl (for example, CH2CH2OCH3, CH2OCH3and CH2CH2OCH3, e.g. CH2CH2OCH3) or Rxand Ry, together with the atom to which they are attached, join to form a non-aromatic heterocylic group with 3 to 6 ring members, wherein the non-aromatic heterocyclic group comprises one or more (e.g.1 , 2, or 3) heteroatoms selected from N, O, S and oxidised forms thereof (for example wherein the non-aromatic heterocylic group with 3 to 6 ring members are selected from azetidine, morpholine, piperazine, pyrrolidine and tetrahydrooxazole) and wherein the non-aromatic heterocyclic groups are optionally further substituted with one or more (e.g. 1 , 2 or 3) Rzgroups.

[0274] In one embodiment Rxand Ryare independently selected from hydrogen and C1-6alkyl (for example ethyl or methyl, e.g. methyl, or Rxand Ry, together with the atom to which they are attached, join to form a non-aromatic heterocylic group with 4 to 6 ring members, wherein the non-aromatic heterocyclic group comprises one or more (e.g.1 , 2, or 3) heteroatoms selected from N and O (for example wherein the non-aromatic heterocylic group with 3 to 6 ring members are selected from azetidine, morpholine and pyrrolidine) and wherein the non-aromatic heterocyclic groups are optionally further substituted with one or more (e.g. 1 , 2 or 3) Rzgroups.

[0275] Rzis selected from hydrogen, halogen, nitro, nitrile, hydroxyl, =O (oxo), C1-6alkyl, haloC1-6alkyl, C2. ealkenyl, C2-6alkynyl, hydroxyC1-6alkyl, C1-6alkoxy, -NHe(C1-6alkyl)2-e, -C1-6alkylNHe(C1-6alkyl)2-e, hydroxyC1-6alkoxy, -(CH2)k-O-C1-6alkyl, -C(=O)C1-6alkyl, --(CH2)jCO2C1-6alkyl, -(CH2)k-C(=O)N(H)e(C1-6alkyl)2-e, -C(=O)C1-6alkyl-N(H)e(C1-6alkyl)2-e, -(CH2)qCO2H C3-8cycloalkyl, C3-8cycloalkenyl and heterocyclic groups (e.g, an aromatic ring or a non-aromatic ring) with 3 to 8 ring members, wherein the heterocyclic group comprises one or more (e.g,1 , 2, or 3) heteroatoms selected from N, O, S and oxidised forms thereof; or two Rzgroups, together with the atom(s) to which they are attached, join to form a C3-8cycloalkyl, C3-8cycloalkenyl, or heterocyclic group with 3 to 8 ring members (e.g. an aromatic ring or a non-aromatic ring), wherein the heterocyclic group comprises one or more (e.g.1 , 2, or 3) heteroatoms selected from N, O, S and oxidised forms thereof.

[0276] In one embodiment Rzare independently selected from halogen, hydroxyl, nitrile, C1-6alkyl, C1-6alkoxy, C(=O)C1-6alkyl, NHe(C1-6alkyl)2-e, C1-6alkylNHe(C1-6alkyl)2-e, haloC1-6alkyl, oxo (=O), hydroxyC1-6alkyl, hydroxyC1-6alkoxy, -C(=O)C1-6alkyl, -N(H)e(C1-6alkyl)2-e, -C1-6alkyl-N(H)e(C1-6alkyl)2-e, C3-8cycloalkyl and heterocyclic groups (e.g. an aromatic ring or a non-aromatic ring) with 3 to 8 ring members wherein the heterocyclic group comprises one or more (e.g.1 , 2, or 3) heteroatoms selected from N, O, S and oxidised forms thereof; or two Rzgroups, together with the atom or atoms to which they are attached, join to form a C3-8cycloalkyl group or heterocyclic group with 3 to 6 ring members (e.g. an aromatic ring or a non-aromatic ring) wherein the heterocyclic group comprises one or more (e.g.1 , 2, or 3) heteroatoms selected from N, O, S and oxidised forms thereof.

[0277] In one embodiment Rzis selected from halogen hydroxyl, nitrile, C1-6alkyl, C1-salkoxy, oxo, -C(=O)C1-salkyl and -NHe(C1-6alkyl)2-e; or two Rzgroups, together with the atom or atoms to which they are attached, join to form a heterocyclic group with 3 to 6 ring members wherein the heterocyclic group comprises one or more (e.g.1 , 2, or 3) heteroatoms selected from N, O, S and oxidised forms thereof.

[0278] In one embodiment, Rzis selected from hydroxyl, nitrile or methyl.

[0279] In one embodiment, R1is unsubstituted or is substituted by one or two Rz, and Rzare selected from hydroxy and C1-6alkyl.

[0280] Combinations of substituents In one embodiment, the compound of formula (I) is a compound of formula (II) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof: wherein W1, W2, W3, W* and W5are independently selected from N, CH and CR1, wherein no more than two of W1, W2, W3, W4and W5are N and no more than four of W1, W2, W3, W* and W5are CR1; t is selected from 0, 1 , 2, 3 and 4

[0281] Raand R2are independently selected from hydrogen, halogen, nitro, nitrile, C1-6alkoxy, haloC1-6alkoxy, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, haloC1-6alkyl, -(CH2)k-O-C1-6alkyl, -(CH2)k-S-C1-6alkyl, hydroxyl, hydroxyC1-6alkyl, -SH, -NHe(C1-4alkyl)2-e, C3-6cycloalkyl, C3-6cycloalkenyl and heterocyclic group (e.g. an aromatic ring or a non-aromatic ring) wherein the heterocyclic group has 3 to 6 ring members and wherein the heterocyclic group comprises one or more (e.g. 1 , 2 or 3) heteroatoms selected from N, O, S and oxidised forms thereof; or when t is 2 or more and the two Ragroups are joined to the same carbon, the two Ragroups together with the carbon to which they are attached join to form an =O (oxo), =CH2, spirocyclic C3-6carbocyclic group or a spirocyclic non-aromatic heterocyclic group with 3 to 6 ring-members containing one or more (e.g. 1 , 2 or 3) heteroatoms selected from O, N or S or oxidised forms thereof; wherein either:

[0282] • A is CR32, NR3’ or O; B is O; R3are independently selected from hydrogen, halogen and C1-4alkyl; R3’ is selected from hydrogen and C1-4alkyl; and R4is Ring Y wherein Ring Y is selected from a cycloalkyl, aryl group or a heterocyclyl group (e.g. an aromatic ring or a non-aromatic ring), wherein the heterocyclyl group comprises one or more (e.g.1 , 2, or 3) heteroatoms selected from N, O and S and wherein the cycloalkyl, aryl or heterocyclyl group is optionally substituted with one or more (e.g. 1 , 2 or 3) R6groups, or

[0283] • A is CR32, NR3’ or O; B is NR5; R3are independently selected from hydrogen, halogen and C1-4alkyl; R3’ is selected from hydrogen and C1-4alkyl; and R4and R5together with the atoms to which they are attached join to form a heterocyclic group (e.g. an aromatic ring or a non-aromatic ring), wherein the heterocyclic group optionally comprises one or more additional heteroatoms selected from N, O or S, and oxidised forms thereof, wherein the heterocyclic group may optionally be substituted with one or more (e.g. 1 , 2 or 3) R6groups; or

[0284] • A is CR32 or NR3’; B is NR5; R5and R3’ or one R3group together with the atoms to which they are attached join to form a heterocyclic group (e.g. an aromatic ring or a non-aromatic ring), wherein the heterocyclic group optionally comprises one or more additional heteroatoms selected from N, O or S, and oxidised forms thereof, wherein the heterocyclic group may optionally be substituted with one or more (e.g. 1 , 2 or 3) R6groups; the other R3group is selected from hydrogen, halogen and C1-4alkyl; and R4is selected from hydrogen and Cwalkyl;

[0285] R1and R6are independently selected from hydroxyl, halogen, nitro, nitrile, C1-6alkyl, nitrileC1-6alkyl, C1-6alkoxy, haloC1-6alkyl, C2-6alkenyl, C2-6alkynyl, =O (oxo), -C(=O)C1-6alkyl, -SH, -SC1-6alkyl, -SO2C1-6alkyl, C1-6alkylSO2C1-6alkyl, -SO2NRxRy, -C1-6alkyl-SO2NRxRy-NRxRy, -C(=O)NRxRy, -NRxC(=O)C1-6alkyl, C1-6alkylNHC(=O)C1-6alkyl, -(CH2)k-O-C1-6alkyl, hydroxyC1-6alkyl, hydroxyC1-6alkoxy, haloC1-6alkoxy, - C(=O)C1-6alkyl-OH, -C(=O)C1-6alkyl-N(H)e(C1-6alkyl)2-e, CCteC1-6alkyl, C1-6alkylCO2C1-6alkyl, -(CRxRy)v- CONRxRy, -CO2H, -C1-6alkylCO2H, -C1-6alkyl-NRxRy, -P(=O)(Rx)(Ry), C3-8cycloalkyl, C3-8cycloalkenyl, Ce- waryl, and heterocyclic groups (e.g. an aromatic ring or a non-aromatic ring) with 3 to 8 ring members wherein the heterocyclic group comprises one or more (e.g.1 , 2, or 3) heteroatoms selected from N, O, S and oxidised forms thereof, wherein the C1-6alkyl groups is optionally substituted with a C3-8cycloalkyl, C3-8cycloalkenyl, Ce-waryl or 3 to 8 membered heterocyclic group (e.g. an aromatic ring or non-aromatic ring) containing one or more (e.g. 1 , 2 or 3) heteroatoms selected from O, N or S and wherein in each case the C3-8cycloalkyl, C3-8cycloalkenyl, Cs-waryl and 3 to 8 membered heterocyclic groups are optionally further substituted with one or more (e.g. 1 , 2 or 3) Rzgroups, or two R1or two R6groups together with the atoms to which they are attached join to form a C3-8cycloalkyl, C3-8cycloalkenyl, Ce-waryl or heterocyclic group with 3 to 8 ring members (e.g. an aromatic ring or a non-aromatic ring), wherein the heterocyclic group contains one or more (e.g. 1 , 2 or 3) heteroatoms selected from N, O, S and oxidised forms thereof and wherein the C3-8cycloalkyl, C3-gcycloalkenyl, Ce-ioaryl group or 3- to 8-membered heterocyclic ring can be substituted by one or more Rzgroups;

[0286] RxRyand Rzare independently selected from hydrogen, halogen, nitro, nitrile, hydroxyl, =O (oxo), C1-ealkyl, haloC1-6alkyl, C2-6alkenyl, C2-6alkynyl, hydroxyC1-6alkyl, C1-6alkoxy, -NHe(C1-6alkyl)2-e, -C1-6alkylNHe(C1-6alkyl)2-e, hydroxyC1-6alkoxy, -(CH2)k-O-C1-6alkyl, -C(=O)C1-6alkyl, -(CHzjjCCkC1-6alkyl, - (CH2)k-C(=O)N(H)e(C1-6alkyl)2-e, -C(=O)C1-6alkyl-N(H)e(C1-4alkyl)2-e, -(CH2)qCO2H C3-8cycloalkyl, C3-8cycloalkenyl and heterocyclic groups (e.g. an aromatic ring or a non-aromatic ring) with 3 to 8 ring members, wherein the heterocyclic group comprises one or more (e.g.1 , 2, or 3) heteroatoms selected from N, O, S and oxidised forms thereof; or Rxand Ry, or two Rzgroups, together with the atom(s) to which they are attached, join to form a C3-8cycloalkyl, C3-8cycloalkenyl, or heterocyclic group with 3 to 8 ring members (e.g. an aromatic ring or a non-aromatic ring), wherein the heterocyclic group comprises one or more (e.g.1 , 2, or 3) heteroatoms selected from N, O, S and oxidised forms thereof; wherein when Rxand Ryare C3-8cycloalkyl, C3-8cycloalkenyl or a heterocyclic group with 3 to 8 ring members or when Rxand Rytogether with the atom to which they are attached, join to form a C3-8cycloalkyl, C3 acycloalkenyl, or heterocyclic group with 3 to 8 ring members then the C3-8cycloalkyl, C3-8cycloalkenyl or heterocyclic group with 3 to 8 ring members is optionally further substituted with one or more (e.g. 1 , 2 or 3) Rzgroups; e, j, k and q are independently selected from 0, 1 and 2; v is selected from 0 and 1 .In one embodiment, the compound is a compound of formula (i) is a compound of formula (II) and R2is selected from halogen, nitro, nitrile, C1-6alkoxy, haloC1-6alkoxy, C1-ealkyl, C2-6alkenyl, C2-6alkynyl, haloC1-6alkyl, -(CH2)k-O-C1-6alkyl, -(CH2)k-S-C1-6alkyl, hydroxyl, hydroxyC1-6alkyl, -SH, -NHe(C1-4alkyl)2-e, C3-6cycloalkyl, C3-6cycloalkenyl and heterocyclic group (e.g. an aromatic ring or a non-aromatic ring) wherein the heterocyclic group has 3 to 6 ring members and wherein the heterocyclic group comprises one or more (e.g. 1 , 2 or 3) heteroatoms selected from N, O, S and oxidised forms thereof.

[0287] In one embodiment, the compound is a compound of formula (I) is a compound of formula (II) and R1is selected from R1hydroxyl, halogen, nitro, nitrile, C1-6alkyl, nitrileC1-6alkyl, C1-6alkoxy, haloC1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C(=O)C1-6alkyl, -SH, -SC1-6alkyl, -SO2C1-6alkyl, C1-6alkylSO2C1-6alkyl, - SO2NRxRy, -C1-6alkyl-SO2NRxRy-NRxRy, -C(=O)NRxRy, -NRxC(=O)C1-6alkyl, C1-6alkylNHC(=O)C1-ealkyl, -(CH2)k-O-C1-6alkyl, hydroxyC1-6alkyl, hydroxyC1-6alkoxy, haloC1-6alkoxy, -C(=O)C1-6alkyl-OH, - C(=O)Ci.6alkyl-N(H)e(Ci.6alkyl)2-e, CO2C1-6alkyl, C1-6alkylCO2C1-6alkyl, -(CR^R^CONRW, -CO2H, -C1-ealkylCO2H, -C1-6alkyl-NRxRy, -P(=O)(Rx)(Ry), Cs8cycloalkyl, C3-8cycloalkenyl, Ce-waryl, and heterocyclic groups (e.g. an aromatic ring or a non-aromatic ring) with 3 to 8 ring members wherein the heterocyclic group comprises one or more (e.g,1 , 2, or 3) heteroatoms selected from N, O, S and oxidised forms thereof, wherein the C1-6alkyl groups is optionally substituted with a Cs-acycloalkyl, C3-8cycloalkenyl, Cs-waryl or 3 to 8 membered heterocyclic group (e.g. an aromatic ring or non-aromatic ring) containing one or more (e.g. 1 , 2 or 3) heteroatoms selected from O, N or S and wherein in each case the C3-8cycloalkyl, C3-8cycioalkenyi, Cs-ioaryl and 3 to 8 membered heterocyclic groups are optionally further substituted with one or more (e.g. 1 , 2 or 3) Rzgroups, or two R1groups together with the atoms to which they are attached join to form a C38cycloalkyl, C3-acycloalkenyl, Ce-waryl or heterocyclic group with 3 to 8 ring members (e.g. an aromatic ring or a non- aromatic ring), wherein the heterocyclic group contains one or more (e.g. 1 , 2 or 3) heteroatoms selected from N, O, S and oxidised forms thereof and wherein the C3-8cycloalkyl, Cs8cycloalkenyl, Ca waryl group or 3- to 8-membered heterocyclic ring can be substituted by one or more Rzgroups.

[0288] In one embodiment, the compound of formula (II) is a compound of formula (II’) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof:

[0289] wherein W1, W2, W3, W* and W5are independently selected from N, CH and CR1, wherein no more than two of W1, W2, W3, W4and W5are N and no more than four of W1, W2, W3, W4and V^ are CR1and wherein R1, R2, R4, A and B are as described herein.

[0290] In one embodiment, the compound of formula (I) is a compound of formula (II) or (II’), wherein:

[0291] • A is CR32, NR3’ or O; B is O; R3are independently selected from hydrogen, halogen and C1-4alkyl; R3’ is selected from hydrogen and C1-4alkyl; and R4is Ring Y wherein Ring Y is selected from a cycloalkyl, aryl group or a heterocyclyl group (e.g. an aromatic ring or a non- aromatic ring), wherein the heterocyclyl group comprises one or more (e.g.1 , 2, or 3) heteroatoms selected from N, O and S and wherein the cycloalkyl, aryl or heterocyclyl group is optionally substituted with one or more (e.g. 1 , 2 or 3) R6groups, or

[0292] • A is CR32, NR3’ or O; B is NR5; R3are independently selected from hydrogen, halogen and C1-4alkyl; R3’ is selected from hydrogen and C1-4alkyl; and R4and R5together with the atoms to which they are attached join to form a heterocyclic group (e.g. an aromatic ring or a non- aromatic ring), wherein the heterocyclic group optionally comprises one or more additional heteroatoms selected from N, O or S, and oxidised forms thereof, wherein the heterocyclic group may optionally be substituted with one or more (e.g. 1 , 2 or 3) R6groups and wherein the heterocyclic group is not triazole or thiazole; or

[0293] • A is CR32 or NR3’; B is NR5; R5and R3’ or one R3group together with the atoms to which they are attached join to form a heterocyclic group (e.g. an aromatic ring or a non-aromatic ring), wherein the heterocyclic group optionally comprises one or more additional heteroatoms selected from N, O or S, and oxidised forms thereof, wherein the heterocyclic group may optionally be substituted with one or more (e.g. 1 , 2 or 3) R6groups; the other R3group is selected from hydrogen, halogen and C1-4alkyl; and R4is selected from hydrogen and Ci ^alkyl.

[0294] In one embodiment, the compound of formula (I) is a compound of formula (II’) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof, wherein:

[0295] W1, W2W3and W4are independently selected from N, CH and CR1wherein no more than two of W1, W2, W3, W* and W5are N and that no more than two of W1, W2, W3, W4and V^ are CR1; R1is selected from halogen nitrile, C1-6alkyl, -C1-6alkylNRxRy, -NRxRy, C1-6alkoxy, haloC1-6alkyl, hydroxyC1-6alkyl, -C(=O)NRxRy, -C1-6alkylNHC(=O)C1-6alkyl, -NHC(=O)C1-6alkyl, -SO2NRxRy, -SO2C1-ealkyl, -P[=O]RxRy, -CO2H, haloC1-6alkoxy and a 3 to 8 membered heterocyclic group containing one or more heteroatoms selected from O, N or S; or, when n is 2, the two R1groups, together with the atoms to which they are attached, join to form a heterocyclic group with 3 to 6 ring members (e.g. an aromatic ring or a non-aromatic ring), wherein the heterocyclic group comprises one or more (e.g,1 , 2, or 3) heteroatoms selected from N, O, S and oxidised forms thereof, wherein the heterocyclic group is optionally substituted with one or more Rzgroups;

[0296] R2is selected from C1-6alkyl, haloC1-6alkyl, -(CH2)k-O-C1-6alkyl and -SC1-6alkyl; wherein:

[0297] • A is CH2or NH, B is O, and R4is Ring Y, wherein Ring Y is an aryl group with 6 ring members or a heterocyclyl group with 5 or 6 ring members, wherein the heterocyclyl group comprises one or more (e.g.1 , 2, or 3) heteroatoms selected from N, O and S, and oxidised forms thereof, wherein the aryl or heterocyclyl group is optionally substituted with one or more (e.g. 1 , 2 or 3) R6groups; or

[0298] • A is CH2or NH, B is NR5, and R4and R5together with the atoms to which they are attached join to form a 5- to 10-membered heteroaryl group, wherein the heteroaryl group optionally comprises one or more additional heteroatoms selected from N, O or S, and oxidised forms thereof, wherein the heterocyclic group may optionally be substituted with one or more (e.g. 1 , 2 or 3) R6groups; or

[0299] • A is NR3’ and B is NR5, R5and R3’ together with the atoms to which they are attached join to form a heterocyclic group, wherein the heterocyclic group comprises one additional nitrogen atom, wherein the heterocyclic group may optionally be substituted with one or more (e.g. 1 , 2 or 3) R6groups selected from hydrogen, halogen and Ci -ea Iky I and R4is selected from hydrogen and Cvealkyl

[0300] R6are independently selected from halogen, nitrile, oxo, C1-6alkyl, -OC1-6alkyl.-SC1-6alkyl, haloC1-6alkyl, -NRxRy, -C(=O)NRxRy, -NHC(=O)C1-6alkyl, C1-6alkoxy, hydroxyC1-6alkyl and heterocyclic group with 4 to 6 ring members (e.g. an aromatic ring or a non-aromatic ring), wherein the heterocyclic group comprises one or more (e.g. 1 , 2 or 3) heteroatoms selected from N, O and S, and oxidised forms thereof wherein the heterocyclic ring is optionally substituted by one or more (e.g. 1 , 2 or 3) Rzgroups; or two R6groups together with the atoms to which they are attached join to form a Csaryl group or a heterocyclic group with five or six ring members (e.g. an aromatic ring or a non-aromatic ring), wherein the heterocyclic group contains one or more (e.g. 1 , 2 or 3) heteroatoms selected from N, O, S and oxidised forms thereof and wherein the aryl or heterocyclic ring is optionally substituted by one or more Rzgroups; Rxand Ryare independently selected from hydrogen, C1-6alkyl, hydroxyC1-6alkyl, C1-6alkoxy, -C1-6alkylNHq(C1-6alkyl)2-qand -(CH2)j-O- C1-6alkyl; or Rxand Ry, together with the atom to which they are attached, join to form a non-aromatic heterocyclic group with 3 to 6 ring members, wherein the non-aromatic heterocyclic group comprises one or more (e.g.1 , 2, or 3) heteroatoms selected from N, O, S and oxidised forms thereof and wherein the non- aromatic heterocyclic groups are optionally further substituted with one or more (e.g. 1 , 2 or 3) Rzgroups; and

[0301] Rzis selected from halogen hydroxyl, nitrile, C1-6alkyl, C1-6alkoxy, oxo, -C(=O)C1-6alkyl, -NHe(C1-6alkyl)2-e, and heterocyclic group with 5 ring members, wherein the heterocyclic group comprises one or more (e.g. 1 , 2 or 3) heteroatoms selected from N, O and S, and oxidised forms thereof; or two Rzgroups, together with the atom or atoms to which they are attached, join to form a heterocyclic group with 3 to 6 ring members wherein the heterocyclic group comprises one or more (e.g .1 , 2, or 3) heteroatoms selected from N, O, S and oxidised forms thereof; wherein e, q and j are selected from 0, 1 or 2.

[0302] In one embodiment, the compound of formula (I) is a compound of formula (IV) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof: wherein W1, W2and W3are selected from N, CH and CR1, wherein no more than one of W1, W2and W3is N, and wherein m is selected from 0, 1 , 2 and 3 and wherein R1, R2, R6, Ring Y and m are as described herein.

[0303] In one embodiment, the compound of formula (I) is a compound of formula (IV) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof, wherein

[0304] W1, W2and W3are independently selected from N, CH and CR1and wherein no more than one of W1, W2and W3is N;

[0305] R1is selected from halogen nitrile, C1-6alkyl, -C1-6alkylNRxRy, -NRxRy, C1-6alkoxy, haloC1-6alkyl, hydroxyC1-6alkyl, -C(=O)NRxRy, -C1-6alkylNHC(=O)C1-6alkyl, -NHC(=O)C1-6alkyl, -SO2NRxRy, -SO2C1-6alkyl, -P[=O]RxRy, -CO2H, haloC1-6alkoxy or a 3 to 8 membered heterocyclic group containing one or more heteroatoms selected from O, N or S or oxidised forms thereof; or, there are two or more R1groups, two R1groups, together with the atoms to which they are attached, join to form a heterocyclic group with 3 to 6 ring members (e.g. an aromatic ring or a non-aromatic ring), wherein the heterocyclic group comprises one or more (e.g.1 , 2, or 3) heteroatoms selected from N, O, S and oxidised forms thereof, wherein the heterocyclic group is optionally substituted with one or more Rzgroups;

[0306] R2is selected from C1-6alkyl, haloC1-6alkyl, -(CH2)k-O-C1-6alkyl and -SC1-6alkyl;

[0307] Ring Y is an aryl group with 6 ring members or a heterocyclyl group with 5 or 6 ring members, wherein the heterocyclyl group comprises one or more (e.g.1 , 2, or 3) heteroatoms selected from N, O and S, and oxidised forms thereof, wherein the aryl or heterocyclyl group is optionally substituted with one or more (e.g. 1 , 2 or 3) R6groups;

[0308] R6are independently selected from halogen, nitrile, oxo, C1-6alkyl, -OC1-6alkyl.-SC1-6alkyl, haloC1-6alkyl, -NRxRy, -C(=O)NRxRy, -C1-6alkyl-NRxRy, -NHC(=O)C1-6alkyl, C1-6alkoxy, hydroxyC1-6alkyl and heterocyclic group with 4 to 6 ring members (e.g. an aromatic ring or a non-aromatic ring), wherein the heterocyclic group comprises one or more (e.g. 1 , 2 or 3) heteroatoms selected from N, O or S, and oxidised forms thereof, wherein the heterocyclic ring is optionally substituted by one or more (e.g. 1 , 2 or 3) Rzgroups; or two R6groups together with the atoms to which they are attached join to form a Csaryl group or a heterocyclic group with five or six ring members (e.g. an aromatic ring or a non-aromatic ring), wherein the heterocyclic group contains one or more (e.g. 1 , 2 or 3) heteroatoms selected from N, O, S and oxidised forms thereof and wherein the aryl or heterocyclic ring is optionally substituted by one or more Rzgroups;

[0309] Rxand Ryare independently selected from hydrogen, C1-6alkyl, hydroxyC1-6alkyl, C1-6alkoxy, -C1-6alkylNHq(C1-6alkyl)2-q and -(CH2)j-O-C1-6alkyl; or Rxand Ry, together with the atom to which they are attached, join to form a non-aromatic heterocyclic group with 3 to 6 ring members, wherein the non-aromatic heterocyclic group comprises one or more (e.g.1 , 2, or 3) heteroatoms selected from N, O, S and oxidised forms thereof and wherein the non- aromatic heterocyclic groups are optionally further substituted with one or more (e.g. 1 , 2 or 3) Rzgroups; and

[0310] Rzis selected from halogen hydroxyl, nitrile, C1-6alkyl, C1-6alkoxy, oxo, -C(=O)C1-6alkyl and -NHe(C1-6alkyl)2-e; or two Rz groups, together with the atom or atoms to which they are attached, join to form a heterocyclic group with 3 to 6 ring members wherein the heterocyclic group comprises one or more (e.g.1 , 2, or 3) heteroatoms selected from N, O, S and oxidised forms thereof; wherein e, q and j are selected from 0, 1 or 2 and m is selected from 0, 1 , 2 and 3.

[0311] In one embodiment, the compound of formula (I) is a compound of formula (V) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof: wherein W1and W2are selected from N and CH, wherein no more than 1 of W1and W2is N; Y1, Y2, Y3and Y4are selected from N, CH and CR6; wherein at least one of Y1, Y2, Y3and Y4is CR6and no more than 2 (for example 0, 1 or 2) of Y1, Y2, Y3and Y4are N, wherein R1, R2and R6are as defined herein.

[0312] In one such embodiment, Y1is N and all of Y2, Y3and Y4are selected from CH and CR6for example wherein Y1is N, Y3is CR6and Y3and Y4are CH.

[0313] In another such embodiment, all ofY1, Y2, Y3and Y4are selected from CH and CR6, forexample wherein Y1, Y2and Y4are CH and Y3is CR6.

[0314] In one embodiment:

[0315] • Y1is N, Y3is CR6and Y3and Y4are CH; or

[0316] • Y1, Y2and Y4are CH and Y3is CR6.

[0317] Optionally, in this embodiment, R1is selected from -NRxRyand -C(=O)NRxRy, wherein Rxand Ryare selected from hydrogen, C1-6alkyl and hydroxyC1-6alkyl or Rxand Ry, together with the nitrogen atom to which they are attached, join to form a non-aromatic heterocyclic group with 4 or 5 ring members, wherein the non-aromatic heterocyclic group comprises one nitrogen and wherein the non-aromatic heterocyclic groups are optionally substituted by one or more (e.g. 1 or 2) Rzgroups.

[0318] In yet another such embodiment, R6is selected from C1-6alkyl, halogen and -NRxRy, wherein Rxand Ryare independently selected from hydrogen, C1-6alkyl and -C1-6alkylNHe(C1-6alkyl)2-e, or wherein Rxand Rytogether with the atom to which they are attached join to form a 3-6 membered heterocyclic ring optionally comprising one or more further heteroatoms selected from N, O, S and oxidised forms thereof. For example, R6is -NRxRy, wherein Rxand Ryare independently selected from hydrogen and C1-4alkyl, e.g. hydrogen. In one embodiment, the compound is a compound of formula (V) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof, wherein:

[0319] • W1and W2are both CH;

[0320] • R1is selected from -NRxRyand -C(=O)NRxRy, wherein Rxand Ryare selected from hydrogen and C1-6alkyl (for example methyl and ethyl) or Rxand Rytogether with the nitrogen atom to which they are attached join to form a non-aromatic heterocyclic group with 4 or 5 ring members, wherein the non-aromatic heterocyclic group comprises one nitrogen and optionally one further heteroatom selected from N, O and S (for example, azetidine, pyrrolidine, piperazine or morpholine), and wherein the non-aromatic heterocyclic groups are unsubstituted or substituted by one or more (e.g. 1 or 2) Rzgroups;

[0321] • R2is selected from C1-6alkyl (e.g. methyl, ethyl or isopropyl), haloC1-6alkyl (e.g. -CH2F, -CH2CF3, -CH2CH2F, -CF3, -CH2CF2H), -(CH2)k-O-C1-6alkyl, (e.g. -CH2OCH2CH3, -CH2OCH3) and -SC1-ealkyl (e.g. -SMe, -SEt or -SiPr);

[0322] • Y1, Y2and Y4are selected from CH and N;

[0323] • Y3is CR6and R6is selected from C1-6alkyl, halogen and NRxRy, wherein Rxand Ryare independently selected from hydrogen and C1-6alkyl (for example NHe(C1-6alkyl)2-e, wherein e is selected from 0, 1 and 2, for example NH2); and

[0324] • Rzare independently selected from hydroxyl, nitrile, C1-6alkyl (for example methyl or ethyl, e.g. methyl) and C1-6alkoxy (for example ethoxy and methoxy, e.g. methoxy).

[0325] In one embodiment, the compound of formula (I) is a compound of formula (V) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof, wherein:

[0326] • W1and W2are both CH;

[0327] • R1is selected from nitrile, C1-6alkoxy, hydroxyC1-6alkyl, -NRxRyand -C(=O)NRxRy, wherein Rxand Ryare independently selected from hydrogen and C1-6alkyl or Rxand Rytogether with the nitrogen atom to which they are attached join to form a non-aromatic heterocyclic group with 4 or 5 ring members, wherein the non-aromatic heterocyclic group comprises one nitrogen or one nitrogen and one oxygen and wherein the non-aromatic group is optionally substituted by one or two Rzgroups;

[0328] • Rzis selected from C1-6alkyl and hydroxy;

[0329] • R2is selected from C1-6alkyl (e.g. methyl, ethyl or isopropyl);

[0330] • Y3is CR6and R6is selected from C1-6alkyl, halogen and NRxRy, wherein Rxand Ryare independently selected from hydrogen and C1-6alkyl (for example NHe(C1-6alkyl)2-e, wherein e is selected from 0, 1 and 2, for example NH2);

[0331] • either Y1, Y2and Y4are selected from N, CH, and CR6, wherein no more than two ofY1, Y2and Y4are N and wherein R6is selected from halogen and C1-6alkyl;

[0332] • or Y1and Y2are CR6, R6is selected from halogen and C1-6alkyl or the two R6groups join to form a five-membered heterocyclic ring containing 1 or 2 N and Y4is selected from N and CH. In one embodiment, the compound of formula (I) is a compound of formula (V) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof, wherein:

[0333] • W1and W2are both CH;

[0334] • R1is selected from nitrile, C1-6alkoxy, hydroxyC1-6alkyl, -NRxRyand -C(=O)NRxRy, wherein Rxand Ryare independently selected from hydrogen and C1-6alkyl or Rxand Rytogether with the nitrogen atom to which they are attached join to form a non-aromatic heterocyclic group with 4 or 5 ring members, wherein the non-aromatic heterocyclic group comprises one nitrogen or one nitrogen and one oxygen and wherein the non-aromatic group is optionally substituted by one or two Rzgroups;

[0335] • Rzis selected from C1-6alkyl and hydroxy;

[0336] • R2is selected from C1-6alkyl (e.g. methyl, ethyl or isopropyl);

[0337] • Y1is selected from N, CH, CF, CCI, C(CH3);

[0338] • Y2and Y4are selected from CH, CF and CCI; and

[0339] • Y3is CNHe(C1-6alkyl)2-ewherein e is selected from 0, 1 and 2.

[0340] In one embodiment, the compound of formula (I) is a compound of formula (VI) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof: wherein W1and W2are selected from CH and N, wherein no more than 1 of W1and W2are N, Y1, Y2, Y3and Y4are selected from N, CH and CR6; wherein at least one of Y1, Y2, Y3and Y4is CR6and no more than 2 (for example 0, 1 or 2) of Y1, Y2, Y3and Y4are N and R2, Rx, Ryand R6are as defined herein.

[0341] In one embodiment, the compound of formula (I) is a compound of formula (VI) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof, wherein

[0342] • W1and W2are selected from CH and N, wherein no more than 1 of W1and W2are N,

[0343] • Rxand Ryare selected from hydrogen and C1-6alkyl or wherein Rxand Rytogether with the atom to which they are attached join to form a non-aromatic heterocyclic group with 3 to 6 ring members, wherein the non-aromatic heterocyclic group comprises one or more (e.g.1 , 2, or 3) heteroatoms selected from N, O, S and oxidised forms thereof and wherein the non-aromatic heterocyclic groups are optionally further substituted with one or more (e.g. 1 , 2 or 3) Rzgroups; Y1, Y2, Y3and Y4are selected from N, CH and CR6; wherein at least one of Y1, Y2, Y3and Y4is CR6and no more than 2 (for example 0, 1 or 2) of Y1, Y2, Y3and Y4are N.

[0344] In one embodiment, the compound of formula (I) is a compound of formula (VI) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof, wherein

[0345] • W1and W2are selected from CH and N, wherein no more than 1 of W1and W2are N,

[0346] • Rxand Rytogether with the atom to which they are attached join to form a non-aromatic heterocyclic group with 4, 5 or 6 ring members, wherein the non-aromatic heterocyclic group comprises one or more (e.g.1 , 2, or 3) heteroatoms selected from N, O, S and oxidised forms thereof (for example, azetidine, pyrrolidine or piperidine, e.g. azetidine) and wherein the non- aromatic heterocyclic groups are optionally further substituted with one or more (e.g. 1 , 2 or 3) Rzgroups;

[0347] • Y1is selected from CH and N

[0348] • Y2and Y4are CH

[0349] • Y3is CR6and R6is selected from C1-6alkyl, halogen and NRxRy, wherein Rxand Ryare independently selected from hydrogen and C1-6alkyl (for example NHe(C1-6alkyl)2-e, wherein e is selected from 0, 1 and 2, for example NH2);

[0350] • R2is as defined herein.

[0351] In one embodiment, the compound of formula (I) is a compound of formula (VI) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof, wherein

[0352] • W1and W2are selected from CH and N, wherein no more than 1 of W1and W2are N,

[0353] • Rxand Ryare selected from hydrogen and C1-6alkyl;

[0354] • Y1is selected from CH and N

[0355] • Y2and Y4are CH

[0356] • Y3is CR6and R6is selected from C1-6alkyl, halogen and NRxRy, wherein Rxand Ryare independently selected from hydrogen and Ci -ealky I (for example wherein R6 is NHe(C1-6alkyl)2- e, wherein e is selected from 0, 1 and 2);

[0357] • R2and Rzare as defined herein.

[0358] In one embodiment, the compound of formula (I) is a compound of formula (VII) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof: wherein W1and W2are selected from CH and N, wherein no more than one of W1and W2are N, Y1, Y2, Y3and Y4are selected from N, CH and CR6; wherein at least one of Y1, Y2, Y3and Y4is CR6and no more than 2 (for example 0, 1 or 2) of Y1, Y2, Y3and Y4are N, and wherein Rx, Ry, R2and R6are as disclosed herein.

[0359] In one embodiment, the compound of formula (I) is a compound of formula (VII) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof, wherein

[0360] • W1and W2are selected from CH and N, wherein no more than 1 of W1and W2are N,

[0361] • Rxand Ryare independently selected from hydrogen and C1-6alkyl or wherein Rxand Rytogether with the atom to which they are attached join to form a non-aromatic heterocyclic group with 3 to 6 ring members, wherein the non-aromatic heterocyclic group comprises one or more (e.g.1 , 2, or 3) heteroatoms selected from N, O, S and oxidised forms thereof and wherein the non-aromatic heterocyclic groups are optionally further substituted with one or more (e.g. 1 , 2 or 3) Rzgroups;

[0362] • Y1, Y2, Y3and Y4are selected from N, CH and CR6; wherein at least one of Y1, Y2, Y3and Y4is CR6and no more than 2 (for example 0, 1 or 2) of Y1, Y2, Y3and Y4are N.

[0363] In one embodiment, the compound of formula (I) is a compound of formula (VII) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof, wherein

[0364] • W1and W2are selected from CH and N, wherein no more than 1 of W1and W2are N,

[0365] • Rxand Rytogether with the atom to which they are attached join to form a non-aromatic heterocyclic group with 4, 5 or 6 ring members, wherein the non-aromatic heterocyclic group comprises one or more (e.g.1 , 2, or 3) heteroatoms selected from N, O, S and oxidised forms thereof (for example, azetidine, pyrrolidine or piperidine, e.g. azetidine) and wherein the non- aromatic heterocyclic groups are optionally further substituted with one or more (e.g. 1 , 2 or 3) R?- groups;

[0366] • Y1is selected from CH and N

[0367] • Y2and Y4are CH

[0368] • Y3is CR6and R6is selected from C1-6alkyl, halogen and NRxRy, wherein Rxand Ryare independently selected from hydrogen and C1-6alkyl (for example NHe(C1-6alkyl)2-e, wherein e is selected from 0, 1 and 2, for example NH2); R2and Rzare as defined herein.

[0369] In one embodiment, the compound of formula (I) is a compound of formula (VII) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof, wherein

[0370] • W1and W2are selected from CH and N, wherein no more than 1 of W1and W2are N,

[0371] • Rxand Ryare selected from hydrogen and C1-6alkyl;

[0372] • Y1is selected from CH and N;

[0373] • Y2and Y4are CH;

[0374] • Y3is CR6and R6is selected from C1-6alkyl, halogen and NRxRy, wherein Rxand Ryare independently selected from hydrogen and Ci -ealky I (for example wherein R6 is NHe(C1-6alkyl)2- e, wherein e is selected from 0, 1 and 2); and

[0375] • R2and Rzare as defined herein.

[0376] In one embodiment, the compound of formula (I) is a compound of formula (lie) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof wherein W1and W2are independently selected from N and CH and wherein no more than one of W1and W2are N and wherein Rx, Ry, R2, A, B and R4are as defined herein.

[0377] In one embodiment, the compound of formula (I) is a compound of formula (lie) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof wherein:

[0378] • W1and W2are independently selected from N and CH; and

[0379] • Rxand Ryare independently selected from hydrogen, C1-6alkyl (e.g. methyl), hydroxyC1-6alkyl (e.g. hydroxyethyl or hydroxypropyl) and -(CH2)j-O- C1-6alkyl (e.g. -(CH2)2OCH3) or Rxand Ry, together with the atom to which they are attached, join to form a non-aromatic heterocyclic group with 3 to 6 ring members (e.g. 4 or 6 ring members), wherein the non-aromatic heterocyclic group comprises one or more (e.g.1 , 2, or 3) heteroatoms selected from N, O, S and oxidised forms thereof (e.g. N and O) and wherein the non-aromatic heterocyclic groups are optionally further substituted with one or more (e.g. 1 , 2 or 3) Rzgroups

[0380] • Optionally, in this embodiment, Rzis selected from hydroxyl, nitrile, C1-6alkyl C1-6alkoxy, halogen, oxo (=O) or two Rzjoin to form a 4-membered heterocyclic group containing one O. In one embodiment, the compound of formula (I) is a compound of formula (lid) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof wherein W1and W2are independently selected from N and CH and wherein no more than 1 of W1and W2are N, and wherein Rx, Ry, R2, A, B and R4are as defined herein.

[0381] In one embodiment, the compound of formula (I) is a compound of formula (lid) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof and:

[0382] W1and W2are independently selected from N and CH; and

[0383] Rxand Ryare independently selected from hydrogen, C1-6alkyl, hydroxyC1-6alkyl and -(CH2)j-O- C1-6alkyl (for example hydrogen, methyl or hydroxyethyl) or Rxand Ry, together with the atom to which they are attached, join to form a non-aromatic heterocyclic group with 3 to 6 ring members, wherein the non-aromatic heterocyclic group comprises one or more (e.g.1 , 2, or 3) heteroatoms selected from N, O, S and oxidised forms thereof and wherein the non-aromatic heterocyclic groups are optionally further substituted with one or more (e.g. 1 , 2 or 3) Rzgroups.

[0384] In one embodiment, the compound of formula (I) is a compound of formula (II Ic) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof: wherein:

[0385] Y1, Y2and Y4are selected from CH and N, wherein no more than 2 of Y1, Y2and Y4are N; and

[0386] Y3is CR6; and

[0387] R1, R2, R6, Ring X and n are as defined herein. In one embodiment, the compound of formula (I) is a compound of formula (II Ic) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof: wherein:

[0388] • Y1, Y2and Y4are selected from CH, CR6and N;

[0389] • Y3is CNHe(C1-6alkyl)2-ewherein e is selected from 0, 1 and 2; and

[0390] • R6is selected from halogen and C1-6alkyl or two R6groups together with the atoms to which they are attached join to form a heterocyclic group with 4, 5 or 6 ring members (e.g. an aromatic ring or a non-aromatic ring), wherein the heterocyclic group contains one or more (e.g. 1 , 2 or 3) heteroatoms selected from N, O and S or oxidised forms thereof and wherein heterocyclic ring is optionally substituted by one or more Rzgroups; and

[0391] • R1, R2, R6, Rzand Ring X are as defined herein.

[0392] In one embodiment, the compound of formula (I) is a compound of formula (VI 11) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof: wherein

[0393] • W1, W2and W3are selected from N, CH and CR1, wherein no more than 1 of W1, W2and W3are N;

[0394] • Y1, Y2and Y4are selected from N, CH and CR6wherein no more than 2 of Y1, Y2and Y4are N;

[0395] • Y3is CNHe(C1-6alkyl)2-ewherein e is selected from 0, 1 and 2;

[0396] • R1and R2are as defined herein; and

[0397] • R6is selected from halogen and C1-6alkyl or two R6groups together with the atoms to which they are attached join to form a heterocyclic group with 4, 5 or 6 ring members (e.g. an aromatic ring or a non-aromatic ring), wherein the heterocyclic group contains one or more (e.g. 1 , 2 or 3) heteroatoms selected from N, O and S or oxidised forms thereof and wherein heterocyclic ring is optionally substituted by one or more Rzgroups, wherein Rzis as defined herein.

[0398] In one embodiment, the compound of formula (I) is a compound of formula (IX) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof:

[0399] wherein Y1is selected from CH and N, and R1, R2and R6are as defined herein.

[0400] In one embodiment, the compound of formula (I) is a compound of formula (IX) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof, wherein:

[0401] • R1is NRxRy, wherein Rxand Ryare selected from hydrogen and C1-6alkyl or Rxand Rytogether with the nitrogen atom to which they are attached join to form a non-aromatic heterocyclic group with 3 to 6 ring members, wherein the non-aromatic heterocyclic group comprises one nitrogen and wherein the non-aromatic heterocyclic groups are unsubstituted;

[0402] • Y1is selected from CH and N; and

[0403] • R6is -NHe(C1-6alkyl)2-e, wherein e is selected from 0, 1 and 2.

[0404] In one embodiment, the compound of formula (I) is a compound of formula (IX) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof, wherein:

[0405] • R1is -C(=O)NRxRy, wherein Rxand Ryare selected from hydrogen and C1-6alkyl or Rxand Rytogether with the nitrogen atom to which they are attached join to form a non-aromatic heterocyclic group with 3 to 6 ring members, wherein the non-aromatic heterocyclic group comprises one nitrogen (for example azetidine, pyrrolidine or piperidine) and wherein the non- aromatic heterocyclic groups are unsubstituted;

[0406] • Y1is selected from CH and N; and

[0407] • R6is -NHe(C1-6alkyl)2-e, wherein e is selected from 0, 1 and 2.

[0408] Disclaimed compounds

[0409] In one embodiment, the compound of formula (I) is not:

[0410] (CAS no. 2728367-61 -9).

[0411] In one embodiment, the compound of formula (I) is not:

[0412] (CAS no. 3089704-61-7).

[0413] In one embodiment, the compound of formula (I) is not:

[0414] (CAS no. 2728604-22-4).

[0415] In one embodiment, the compound of formula (I) is not:

[0416] (CAS no. 3071317-38-6).

[0417] In one embodiment, the compound of formula (I) is not:

[0418] (CAS no. 3089770-02-2).

[0419] In one embodiment, the compound of formula (I) is not: no. 2746390-68-9).

[0420] In one embodiment, the compound of formula (I) is not:

[0421] (CAS no. 2746390-58-7).

[0422] In one embodiment, the compound of formula (I) is not:

[0423] (CAS no. 2746390-53-2).

[0424] In one embodiment, the compound of formula (I) is not:

[0425] (CAS no. 2361655-32-3).

[0426] In one embodiment, the compound of formula (I) is not:

[0427] (CAS no. 69557-30-8).

[0428] In one embodiment, the compound of formula (I) is not: no. 3071360-97-6).

[0429] In one embodiment, the compound of formula (I) is not:

[0430] (CAS no. 2746390-65-6). In one embodiment, the compound of formula (I) is not:

[0431] (CAS no. 2746390-60-1).

[0432] In one embodiment, the compound of formula (I) is not:

[0433] (CAS no. 2746390-55-4).

[0434] In one embodiment, the compound of formula (I) is not:

[0435] (CAS no. 2361670-18-8).

[0436] In one embodiment, the compound of formula (I) is not: no. 2920764-06-1).

[0437] In one embodiment, the compound of formula (I) is not: no. 2746390-67-8).

[0438] In one embodiment, the compound of formula (I) is not:

[0439] (CAS no. 2746390-57-6).

[0440] In one embodiment, the compound of formula (I) is not:

[0441] (CAS no. 2746390-52-1).

[0442] In one embodiment, the compound of formula (I) is not:

[0443] (CAS no. 1427894-13-0).

[0444] In one embodiment, the compound of formula (I) is not: no. 2746390-69-0).

[0445] In one embodiment, the compound of formula (I) is not:

[0446] (CAS no. 2746390-59-8).

[0447] In one embodiment, the compound of formula (I) is not:

[0448] (CAS no. 2746390-54-3).

[0449] In one embodiment, the compound of formula (I) is not:

[0450] (CAS no. 2361667-11-8).

[0451] In one embodiment, the compound of formula (I) is not:

[0452] (CAS no. 3078057-53-8).

[0453] In one embodiment, the compound of formula (I) is not:

[0454] (CAS no. 2920764-05-0).

[0455] In one embodiment, the compound of formula (I) is not:

[0456] (CAS no. 2746390-66-7).

[0457] In one embodiment, the compound of formula (I) is not:

[0458] (CAS no. 2746390-56-5).

[0459] In one embodiment, the compound of formula (I) is not:

[0460] (CAS no. 2361676-64-2).

[0461] In one embodiment, the compound of formula (I) is not: (CAS no. 2361662-92-0).

[0462] In one embodiment, the compound of formula (I) is not:

[0463] (CAS no. 2361669-64-7).

[0464] In one embodiment, the compound of formula (I) is not:

[0465] (CAS no. 2361654-80-8). In one embodiment, the compound of formula (I) is not:

[0466] (CAS no. 2361663-87-6). sin one embodiment, the compound of formula (I) is not any of the compounds listed under “Disclaimed compounds”.

[0467] Particular compounds In one embodiment, the invention provides a compound of formula (I) which is selected from Examples 1-232 or is a tautomer, pharmaceutically acceptable salt or solvate thereof.

[0468] In one embodiment, the invention provides a compound of formula (I) which is selected from the following compounds, or a tautomer, pharmaceutically acceptable salt or solvate thereof:

[0469] (3S)-3-(4-aminophenyl)-3-ethyl-1 -(2-oxo-2-phenylethyl)piperidine-2, 6-dione (3S)-3-ethyl-1-(2-oxo-2-phenylethyl)-3-(pyridin-4-yl)piperidine-2, 6-dione 4-[(3S)-3-ethyl-2,6-dioxo-1-(2-oxo-2-phenylethyl)piperidin-3-yl]benzonitrile N-{4-[(3S)-3-ethyl-2,6-dioxo-1-(2-oxo-2-phenylethyl)piperidin-3-yl]phenyl}acetamide (3S)-3-(4-aminophenyl)-3-ethyl-1-[2-(1 H-indazol-4-yl)-2-oxoethyl]piperidine-2, 6-dione (3S)-3-(4-aminophenyl)-1 -[2-(4-aminophenyl)-2-oxoethyl]-3-ethylpiperidine-2, 6-dione (3S)-3-(4-aminophenyl)-1 -{2-[4-(dimethylamino)phenyl]-2-oxoethyl}-3-ethylpiperidine-2, 6-dione N-(4-{2-[(3S)-3-(4-aminophenyl)-3-ethyl-2,6-dioxopiperidin-1-yl]acetyl}phenyl)acetamide (3S)-3-(4-aminophenyl)-3-ethyl-1-[2-(4-methoxyphenyl)-2-oxoethyl]piperidine-2, 6-dione (3S)-3-(4-aminophenyl)-3-ethyl-1 -[2-(4-fluorophenyl)-2-oxoethyl]piperidine-2, 6-dione (3S)-3-(4-aminophenyl)-3-ethyl-1-[2-(4-methylphenyl)-2-oxoethyl]piperidine-2, 6-dione (3S)-3-(4-aminophenyl)-1-[2-(4-chlorophenyl)-2-oxoethyl]-3-ethylpiperidine-2, 6-dione

[0470] (3S)-3-(4-aminophenyl)-1-[2-(4-{[2-(dimethylamino)ethyl]amino}phenyl)-2-oxoethyl]-3-ethylpiperidine- 2,6-dione

[0471] (3S)-3-(4-aminophenyl)-1-[2-(3-chlorophenyl)-2-oxoethyl]-3-ethylpiperidine-2, 6-dione 4-[(3S)-3-ethyl-2,6-dioxo-1-(2-oxo-2-phenylethyl)piperidin-3-yl]benzoic acid (3S)-3-(4-aminophenyl)-1-[2-(4-bromophenyl)-2-oxoethyl]-3-ethylpiperidine-2, 6-dione (3S)-3-(4-aminophenyl)-1-[2-(3-aminophenyl)-2-oxoethyl]-3-ethylpiperidine-2, 6-dione 4-[(3S)-3-ethyl-2,6-dioxo-1-(2-oxo-2-phenylethyl)piperidin-3-yl]-N,N-dimethylbenzamide (3S)-3-ethyl-3-(1-methyl-1 H-indazol-6-yl)-1-(2-oxo-2-phenylethyl)piperidine-2, 6-dione 4-[(3S)-1-[2-(4-aminophenyl)-2-oxoethyl]-3-ethyl-2,6-dioxopiperidin-3-yl]benzonitrile (3S)-1-[2-(4-aminophenyl)-2-oxoethyl]-3-ethyl-3-(4-methoxyphenyl)piperidine-2, 6-dione (3S)-3-(6-aminopyridin-3-yl)-3-ethyl-1-(2-oxo-2-phenylethyl)piperidine-2, 6-dione (3S)-1-[2-(4-aminophenyl)-2-oxoethyl]-3-ethyl-3-[4-(trifluoromethyl)phenyl]piperidine-2, 6-dione (3S)-1-[2-(4-aminophenyl)-2-oxoethyl]-3-ethyl-3-phenylpiperidine-2, 6-dione

[0472] (3S)-1-[2-(4-aminophenyl)-2-oxoethyl]-3-ethyl-3-(4-methanesulfonylphenyl)piperidine-2, 6-dione N-{4-[(3S)-1 -[2-(4-aminophenyl)-2-oxoethyl]-3-ethyl-2,6-dioxopiperidin-3-yl]phenyl}acetamide (3S)-1-[2-(4-aminophenyl)-2-oxoethyl]-3-(4-chlorophenyl)-3-ethylpiperidine-2, 6-dione (3S)-1-[2-(4-aminophenyl)-2-oxoethyl]-3-ethyl-3-(4-fluorophenyl)piperidine-2, 6-dione (3S)-3-(4-aminophenyl)-3-ethyl-1-[2-(3-methylphenyl)-2-oxoethyl]piperidine-2, 6-dione (3S)-3-(4-aminophenyl)-3-ethyl-1 -[2-(3-fluorophenyl)-2-oxoethyl]piperidine-2, 6-dione (3S)-1-[2-(4-aminophenyl)-2-oxoethyl]-3-ethyl-3-[4-(trifluoromethoxy)phenyl]piperidine-2, 6-dione (3S)-3-[4-(aminomethyl)phenyl]-1-[2-(4-aminophenyl)-2-oxoethyl]-3-ethylpiperidine-2, 6-dione (3S)-3-(3-aminophenyl)-1-[2-(4-aminophenyl)-2-oxoethyl]-3-ethylpiperidine-2, 6-dione (3S)-1-[2-(4-aminophenyl)-2-oxoethyl]-3-ethyl-3-(3-methoxyphenyl)piperidine-2, 6-dione (3S)-1-[2-(4-aminophenyl)-2-oxoethyl]-3-ethyl-3-[3-(trifluoromethyl)phenyl]piperidine-2, 6-dione (3S)-3-(4-aminophenyl)-1-[2-(2-chlorophenyl)-2-oxoethyl]-3-ethylpiperidine-2, 6-dione (3S)-3-(4-aminophenyl)-1-[2-(3-chloro-4-methoxyphenyl)-2-oxoethyl]-3-ethylpiperidine-2, 6-dione (3S)-3-(4-aminophenyl)-3-ethyl-1-[2-oxo-2-(thiophen-3-yl)ethyl]piperidine-2, 6-dione

[0473] (3S)-3-(4-aminophenyl)-3-ethyl-1-[2-oxo-2-(thiophen-2-yl)ethyl]piperidine-2, 6-dione

[0474] (3S)-1-[2-(4-aminophenyl)-2-oxoethyl]-3-ethyl-3-(3-fluorophenyl)piperidine-2, 6-dione

[0475] (3S)-1-[2-(4-aminophenyl)-2-oxoethyl]-3-(3-chlorophenyl)-3-ethylpiperidine-2, 6-dione

[0476] (3S)-1-[2-(4-aminophenyl)-2-oxoethyl]-3-ethyl-3-(3-methylphenyl)piperidine-2, 6-dione

[0477] (3S)-3-(4-amino-3-fluorophenyl)-1-[2-(4-aminophenyl)-2-oxoethyl]-3-ethylpiperidine-2, 6-dione (3S)-3-(4-aminophenyl)-1-[2-(2,3-dihydro-1-benzofuran-5-yl)-2-oxoethyl]-3-ethylpiperidine-2, 6-dione (3S)-3-(4-aminophenyl)-1-[2-(5-chlorothiophen-2-yl)-2-oxoethyl]-3-ethylpiperidine-2, 6-dione

[0478] (3S)-3-(4-aminophenyl)-1-[2-(2,3-dihydro-1 ,4-benzodioxin-6-yl)-2-oxoethyl]-3-ethylpiperidine-2,6- dione

[0479] 3-[(3S)-1-[2-(4-aminophenyl)-2-oxoethyl]-3-ethyl-2,6-dioxopiperidin-3-yl]benzonitrile

[0480] (3S)-3-[3-(aminomethyl)phenyl]-1-[2-(4-aminophenyl)-2-oxoethyl]-3-ethylpiperidine-2, 6-dione

[0481] 4-[(3S)-1-[2-(4-aminophenyl)-2-oxoethyl]-3-ethyl-2,6-dioxopiperidin-3-yl]-N,N-dimethylbenzamide (3S)-3-ethyl-3-(2-methyl-2H-indazol-6-yl)-1-(2-oxo-2-phenylethyl)piperidine-2, 6-dione

[0482] (3S)-1-[2-(4-aminophenyl)-2-oxoethyl]-3-ethyl-3-(1-methyl-1 H-indazol-6-yl)piperidine-2, 6-dione

[0483] (3S)-1-[2-(4-aminophenyl)-2-oxoethyl]-3-ethyl-3-[4-(methylamino)phenyl]piperidine-2, 6-dione

[0484] (3S)-1-[2-(4-aminophenyl)-2-oxoethyl]-3-[4-(dimethylamino)phenyl]-3-ethylpiperidine-2, 6-dione

[0485] (3S)-3-(4-amino-3-methylphenyl)-1-[2-(4-aminophenyl)-2-oxoethyl]-3-ethylpiperidine-2, 6-dione (3S)-3-(4-aminophenyl)-3-ethyl-1-[2-(1 H-indazol-5-yl)-2-oxoethyl]piperidine-2, 6-dione

[0486] (3S)-3-(4-aminophenyl)-3-ethyl-1-{2-[4-(1-methyl-1 H-pyrazol-4-yl)phenyl]-2-oxoethyl}piperidine-2,6- dione

[0487] (3S)-1-[2-(3-amino-4-chlorophenyl)-2-oxoethyl]-3-(4-aminophenyl)-3-ethylpiperidine-2, 6-dione

[0488] (3S)-3-(4-amino-3-chlorophenyl)-1-[2-(4-aminophenyl)-2-oxoethyl]-3-ethylpiperidine-2, 6-dione

[0489] (3S)-1-[2-(3-amino-4-methylphenyl)-2-oxoethyl]-3-(4-aminophenyl)-3-ethylpiperidine-2, 6-dione (3S)-3-(4-aminophenyl)-3-ethyl-1-{2-[4-(methylsulfanyl)phenyl]-2-oxoethyl}piperidine-2, 6-dione 4-[(3S)-3-ethyl-1-[2-(1 H-indazol-4-yl)-2-oxoethyl]-2,6-dioxopiperidin-3-yl] benzonitrile

[0490] N-{4-[(3S)-3-ethyl-1-[2-(1 H-indazol-4-yl)-2-oxoethyl]-2,6-dioxopiperidin-3-yl]phenyl}acetamide (3S)-3-(4-aminophenyl)-3-ethyl-1-[2-(1 H-indol-5-yl)-2-oxoethyl]piperidine-2, 6-dione (3S)-3-(4-aminophenyl)-3-ethyl-1-[2-(1 H-indazol-6-yl)-2-oxoethyl]piperidine-2, 6-dione

[0491] (3S)-1-[2-(4-amino-3-chlorophenyl)-2-oxoethyl]-3-(4-aminophenyl)-3-ethylpiperidine-2, 6-dione (3S)-3-(4-aminophenyl)-1-[2-(6-aminopyridin-3-yl)-2-oxoethyl]-3-ethylpiperidine-2, 6-dione 4-[(3S)-1-[2-(4-aminophenyl)-2-oxoethyl]-3-ethyl-2,6-dioxopiperidin-3-yl]-N-methylbenzamide

[0492] 4-{2-[(3S)-3-(4-aminophenyl)-3-ethyl-2,6-dioxopiperidin-1-yl]acetyl}-N-methylbenzamide

[0493] (3S)-3-(4-amino-3-methoxyphenyl)-1-[2-(4-aminophenyl)-2-oxoethyl]-3-ethylpiperidine-2, 6-dione (3S)-1-[2-(4-amino-3-methylphenyl)-2-oxoethyl]-3-(4-aminophenyl)-3-ethylpiperidine-2, 6-dione (3S)-1-[2-(4-aminophenyl)-2-oxoethyl]-3-ethyl-3-[4-(hydroxymethyl)phenyl]piperidine-2, 6-dione

[0494] (3S)-3-(4-aminophenyl)-1-[2-(1 H-1 ,3-benzodiazol-5-yl)-2-oxoethyl]-3-ethylpiperidine-2, 6-dione (3S)-3-(4-aminophenyl)-3-ethyl-1-[2-(7-methyl-1 H-indazol-4-yl)-2-oxoethyl]piperidine-2, 6-dione (3S)-3-(4-aminophenyl)-1-[2-(7-chloro-1 H-indazol-4-yl)-2-oxoethyl]-3-ethylpiperidine-2, 6-dione 4-[(3S)-3-ethyl-1-[2-(1 H-indazol-5-yl)-2-oxoethyl]-2,6-dioxopiperidin-3-yl]-N,N-dimethylbenzamide 4-[(3S)-1-[2-(6-aminopyridin-3-yl)-2-oxoethyl]-3-ethyl-2,6-dioxopiperidin-3-yl]benzonitrile

[0495] 4-[(3S)-3-ethyl-1-[2-(1 H-indazol-4-yl)-2-oxoethyl]-2,6-dioxopiperidin-3-yl]-N,N-dimethylbenzamide (3S)-1-[2-(4-aminophenyl)-2-oxoethyl]-3-(6-aminopyridin-3-yl)-3-ethylpiperidine-2, 6-dione 4-{2-[(3S)-3-(4-aminophenyl)-3-ethyl-2,6-dioxopiperidin-1-yl]acetyl}-N-methylthiophene-2- carboxamide

[0496] 4-[(3S)-1-[2-(4-aminophenyl)-2-oxoethyl]-3-ethyl-2,6-dioxopiperidin-3-yl]benzoic acid

[0497] (3S)-3-(4-aminophenyl)-1-(2-{4-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]phenyl}-2-oxoethyl)-3- ethylpiperidine-2, 6-dione

[0498] (3S)-3-(4-aminophenyl)-1-(2-{4-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]phenyl}-2-oxoethyl)-3- ethylpiperidine-2, 6-dione

[0499] (3S)-1-[2-(4-aminophenyl)-2-oxoethyl]-3-ethyl-3-[4-(morpholin-4-yl)phenyl]piperidine-2, 6-dione (3S)-3-(4-aminophenyl)-3-ethyl-1-[2-(6-methyl-1 H-indazol-4-yl)-2-oxoethyl]piperidine-2, 6-dione (3S)-3-(4-aminophenyl)-3-ethyl-1-[2-oxo-2-(3-oxo-3,4-dihydroquinoxalin-6-yl)ethyl]piperidine-2, 6-dione 4-[(3S)-3-ethyl-1-{2-[7-(methylamino)-1 H-indazol-4-yl]-2-oxoethyl}-2,6-dioxopiperidin-3-yl]-N,N- dimethylbenzamide

[0500] 4-[(3S)-3-ethyl-1-[2-(1 H-indol-5-yl)-2-oxoethyl]-2,6-dioxopiperidin-3-yl]-N,N-dimethylbenzamide

[0501] 4-[(3S)-3-ethyl-1-[2-(2-methyl-2H-indazol-5-yl)-2-oxoethyl]-2,6-dioxopiperidin-3-yl]-N,N- dimethylbenzamide

[0502] (3S)-1-{2-[4-(aminomethyl)phenyl]-2-oxoethyl}-3-(4-aminophenyl)-3-ethylpiperidine-2, 6-dione (3S)-3-(4-aminophenyl)-1-[2-(5-aminopyridin-2-yl)-2-oxoethyl]-3-ethylpiperidine-2, 6-dione 4-[(3S)-3-ethyl-1-{2-[4-(hydroxymethyl)phenyl]-2-oxoethyl}-2,6-dioxopiperidin-3-yl]-N,N- dimethylbenzamide

[0503] (3S)-1-[2-(4-aminophenyl)-2-oxoethyl]-3-ethyl-3-[4-(morpholine-4-carbonyl)phenyl]piperidine-2,6- dione

[0504] 4-[(3S)-1-[2-(4-aminophenyl)-2-oxoethyl]-3-ethyl-2,6-dioxopiperidin-3-yl]-N-(2-hydroxyethyl)-N- methylbenzamide

[0505] (3S)-1-[2-(4-aminophenyl)-2-oxoethyl]-3-ethyl-3-[4-(4-methylpiperazine-1-carbonyl)phenyl]piperidine- 2,6-dione

[0506] (3S)-1-[2-(4-aminophenyl)-2-oxoethyl]-3-[4-(azetidine-1-carbonyl)phenyl]-3-ethylpiperidine-2, 6-dione (3S)-1-[2-(4-aminophenyl)-2-oxoethyl]-3-ethyl-3-(4-{2-oxa-6-azaspiro[3.3]heptane-6- carbonyl}phenyl)piperidine-2, 6-dione

[0507] (3S)-1-[2-(4-aminophenyl)-2-oxoethyl]-3-ethyl-3-[4-(3-hydroxyazetidine-1-carbonyl)phenyl]piperidine- 2,6-dione

[0508] 4-[(3S)-1-[2-(4-aminophenyl)-2-oxoethyl]-3-ethyl-2,6-dioxopiperidin-3-yl]-N-(3-hydroxypropyl)-N- methylbenzamide

[0509] 4-[(3S)-3-ethyl-2,6-dioxo-1-(2-oxo-2-{1 H-pyrazolo[3,4-c]pyridin-5-yl}ethyl)piperidin-3-yl]-N,N- dimethylbenzamide 4-[(3S)-3-ethyl-1 -{2-[5-(1 -methyl-1 H-pyrazol-4-yl)pyridin-2-yl]-2-oxoethyl}-2,6-dioxopiperidin-3-yl]-N,N- dimethylbenzamide 4-[(3S)-3-ethyl-2,6-dioxo-1-[2-oxo-2-(2-oxo-2,3-dihydro-1 H-indol-5-yl)ethyl]piperidin-3-yl]-N,N- dimethylbenzamide

[0510] 4-[(3S)-3-ethyl-2,6-dioxo-1-(2-oxo-2-{1 H-pyrazolo[4,3-b]pyridin-5-yl}ethyl)piperidin-3-yl]-N,N- dimethylbenzamide

[0511] 4-[(3S)-3-ethyl-1-(2-{imidazo[1 ,2-a]pyridin-2-yl}-2-oxoethyl)-2,6-dioxopiperidin-3-yl]-N,N- dimethylbenzamide

[0512] 4-[(3S)-1-[2-(5-aminopyridin-2-yl)-2-oxoethyl]-3-ethyl-2,6-dioxopiperidin-3-yl]-N,N-dimethylbenzamide (3S)-1-[2-(4-aminophenyl)-2-oxoethyl]-3-[4-(dimethylphosphoryl)phenyl]-3-ethylpiperidine-2, 6-dione 4-[(3S)-1-[2-(4-aminophenyl)-2-oxoethyl]-3-ethyl-2,6-dioxopiperidin-3-yl]-N-methylbenzene-1- sulfonamide

[0513] 4-[(3S)-3-ethyl-2,6-dioxo-1-(2-oxo-2-{1 H,4H,5H,6H-pyrrolo[3,4-c]pyrazol-5-yl}ethyl)piperidin-3-yl]-N,N- dimethylbenzamide (3S)-3-ethyl-3-[4-(3-hydroxyazetidine-1-carbonyl)phenyl]-1-[2-(1 H-indol-5-yl)-2-oxoethyl]piperidine-

[0514] 2,6-dione

[0515] (3S)-3-[4-(azetidine-1-carbonyl)phenyl]-3-ethyl-1 -[2-(1 H-indazol-5-yl)-2-oxoethyl]piperidine-2, 6-dione (3S)-3-ethyl-3-[4-(3-hydroxyazetidine-1-carbonyl)phenyl]-1-[2-(1 H-indazol-5-yl)-2-oxoethyl]piperidine-

[0516] 2,6-dione

[0517] (3S)-3-[4-(azetidine-1-carbonyl)phenyl]-3-ethyl-1 -[2-(1 H-indol-5-yl)-2-oxoethyl]piperidine-2, 6-dione (3S)-1-[2-(4-aminophenyl)-2-oxoethyl]-3-[4-(azetidin-1-yl)phenyl]-3-ethylpiperidine-2, 6-dione (3S)-3-[4-(azetidine-1-carbonyl)phenyl]-3-ethyl-1 -[2-(1 H-indazol-4-yl)-2-oxoethyl]piperidine-2, 6-dione (3S)-1-[2-(4-aminophenyl)-2-oxoethyl]-3-ethyl-3-[4-(3-hydroxyazetidin-1-yl)phenyl]piperidine-2, 6-dione

[0518] (3S)-3-ethyl-1-[2-(1 H-indazol-4-yl)-2-oxoethyl]-3-[4-(morpholin-4-yl)phenyl]piperidine-2, 6-dione (3S)-3-ethyl-1-[2-(1 H-indol-5-yl)-2-oxoethyl]-3-[4-(morpholin-4-yl)phenyl]piperidine-2, 6-dione (3S)-3-ethyl-3-[4-(3-hydroxy-3-methylazetidine-1 -carbonyl)phenyl]-1 -[2-(1 H-indazol-4-yl)-2- oxoethyl]piperidine-2, 6-dione

[0519] (3S)-3-ethyl-3-[4-(3-hydroxyazetidine-1-carbonyl)phenyl]-1-[2-(1 H-indazol-4-yl)-2-oxoethyl]piperidine-

[0520] 2,6-dione

[0521] (3S)-3-ethyl-1-[2-(1 H-indazol-4-yl)-2-oxoethyl]-3-[4-(3-methoxyazetidine-1-carbonyl)phenyl]piperidine-

[0522] 2,6-dione

[0523] (3S)-3-ethyl-1-[2-(1 H-indazol-4-yl)-2-oxoethyl]-3-(4-{6-oxa-1-azaspiro[3.3]heptane-1- carbonyl}phenyl)piperidine-2, 6-dione 4-[(3S)-3-ethyl-1-[2-(1 H-indazol-4-yl)-2-oxoethyl]-2,6-dioxopiperidin-3-yl]-N-(2-hydroxyethyl)-N- methylbenzamide

[0524] 4-[(3S)-3-ethyl-1-[2-(1 H-indazol-4-yl)-2-oxoethyl]-2,6-dioxopiperidin-3-yl]-N-(2-methoxyethyl)-N- methylbenzamide

[0525] (3S)-1-[2-(5-aminopyridin-2-yl)-2-oxoethyl]-3-[4-(azetidine-1-carbonyl)phenyl]-3-ethylpiperidine-2,6- dione

[0526] (3S)-3-ethyl-1-[2-(1 H-indazol-5-yl)-2-oxoethyl]-3-[4-(morpholin-4-yl)phenyl]piperidine-2, 6-dione (3S)-1-[2-(5-aminopyridin-2-yl)-2-oxoethyl]-3-ethyl-3-[4-(3-hydroxyazetidine-1- carbonyl)phenyl]piperidine-2, 6-dione (3S)-1-[2-(5-aminopyridin-2-yl)-2-oxoethyl]-3-ethyl-3-[4-(morpholin-4-yl)phenyl]piperidine-2, 6-dione

[0527] 4-[(3S)-3-ethyl-2,6-dioxo-1-(2-oxo-2-{1 H-pyrrolo[3,2-b]pyridin-5-yl}ethyl)piperidin-3-yl]-N,N- dimethylbenzamide

[0528] (3S)-1-[2-(4-aminophenyl)-2-oxoethyl]-3-ethyl-3-[4-(4-methylpiperazin-1-yl)phenyl]piperidine-2, 6-dione

[0529] (3S)-1-[2-(4-aminophenyl)-2-oxoethyl]-3-ethyl-3-[5-(morpholin-4-yl)pyridin-2-yl]piperidine-2, 6-dione

[0530] (3S)-1-[2-(4-aminophenyl)-2-oxoethyl]-3-ethyl-3-[6-(morpholin-4-yl)pyridin-3-yl]piperidine-2, 6-dione 4-[(3S)-1-[2-(4-aminophenyl)-2-oxoethyl]-3-ethyl-2,6-dioxopiperidin-3-yl]-N,N-dimethylbenzene-1- sulfonamide

[0531] (3S)-1-[2-(4-amino-3-chlorophenyl)-2-oxoethyl]-3-[4-(azetidine-1-carbonyl)phenyl]-3-ethylpiperidine-

[0532] 2,6-dione

[0533] (3S)-1-[2-(4-aminophenyl)-2-oxoethyl]-3-ethyl-3-[4-(pyrrolidin-1-yl)phenyl]piperidine-2, 6-dione

[0534] (3S)-1-[2-(5-amino-6-methylpyridin-2-yl)-2-oxoethyl]-3-[4-(azetidine-1-carbonyl)phenyl]-3- ethylpiperidine-2, 6-dione (3S)-1-[2-(4-aminophenyl)-2-oxoethyl]-3-ethyl-3-{4-[(3R)-3-hydroxypyrrolidin-1-yl]phenyl}piperidine-

[0535] 2,6-dione

[0536] (3S)-1-[2-(4-aminophenyl)-2-oxoethyl]-3-ethyl-3-[4-(3-hydroxy-3-methylazetidin-1-yl)phenyl]piperidine-

[0537] 2,6-dione

[0538] (3S)-1-[2-(4-aminophenyl)-2-oxoethyl]-3-[4-(azetidine-1-sulfonyl)phenyl]-3-ethylpiperidine-2, 6-dione

[0539] (3S)-3-[4-(azetidine-1-carbonyl)phenyl]-3-ethyl-1-[2-(1 H-indazol-6-yl)-2-oxoethyl]piperidine-2, 6-dione

[0540] 4-[(3R)-1-[2-(4-aminophenyl)-2-oxoethyl]-2,6-dioxo-3-(2,2,2-trifluoroethyl)piperidin-3-yl]-N,N- dimethylbenzamide (3S)-3-ethyl-3-[4-(3-hydroxyazetidin-1-yl)phenyl]-1-[2-(1 H-indazol-4-yl)-2-oxoethyl]piperidine-2, 6-dione

[0541] (3R)-1-[2-(4-aminophenyl)-2-oxoethyl]-3-[4-(azetidine-1-carbonyl)phenyl]-3-(2,2,2- trifluoroethyl)piperidine-2, 6-dione 4-[(3R)-1-[2-(5-aminopyridin-2-yl)-2-oxoethyl]-2,6-dioxo-3-(2,2,2-trifluoroethyl)piperidin-3-yl]-N,N- dimethylbenzamide

[0542] (3S)-1-[2-(4-aminophenyl)-2-oxoethyl]-3-ethyl-3-{4-[(3S)-3-hydroxypyrrolidin-1-yl]phenyl}piperidine-

[0543] 2,6-dione

[0544] (3S)-1-[2-(4-aminophenyl)-2-oxoethyl]-3-ethyl-3-{4-[(2-hydroxyethyl)(methyl)amino]phenyl}piperidine-

[0545] 2,6-dione

[0546] (3S)-1-[2-(4-aminophenyl)-2-oxoethyl]-3-ethyl-3-[6-(hydroxymethyl)pyridin-3-yl]piperidine-2, 6-dione

[0547] (3S)-1-[2-(5-aminopyridin-2-yl)-2-oxoethyl]-3-ethyl-3-[4-(3-hydroxyazetidin-1-yl)phenyl]piperidine-2,6- dione

[0548] (3S)-3-ethyl-3-[4-(3-hydroxyazetidin-1-yl)phenyl]-1-[2-(1 H-indazol-5-yl)-2-oxoethyl]piperidine-2, 6-dione

[0549] (3S)-1-[2-(5-aminopyridin-2-yl)-2-oxoethyl]-3-[4-(3,3-difluoroazetidine-1-carbonyl)phenyl]-3- ethylpiperidine-2, 6-dione (3S)-1-[2-(5-aminopyrazin-2-yl)-2-oxoethyl]-3-[4-(azetidine-1-carbonyl)phenyl]-3-ethylpiperidine-2,6- dione (3S)-1-[2-(5-aminopyridin-2-yl)-2-oxoethyl]-3-ethyl-3-[4-(3-methoxyazetidin-1-yl)phenyl]piperidine-2,6- dione

[0550] (3S)-1-[2-(6-aminopyridazin-3-yl)-2-oxoethyl]-3-[4-(azetidine-1-carbonyl)phenyl]-3-ethylpiperidine-2,6- dione

[0551] (3S)-1-[2-(4-aminophenyl)-2-oxoethyl]-3-ethyl-3-{4-[(3-hydroxyazetidin-1-yl)sulfonyl]phenyl}piperidine-

[0552] 2,6-dione

[0553] (3S)-1-[2-(5-aminopyridin-2-yl)-2-oxoethyl]-3-ethyl-3-[4-(hydroxymethyl)phenyl]piperidine-2, 6-dione (3S)-1-[2-(5-aminopyridin-2-yl)-2-oxoethyl]-3-[4-(3,3-difluoroazetidin-1-yl)phenyl]-3-ethylpiperidine-2,6- dione

[0554] (3S)-1-[2-(5-aminopyridin-2-yl)-2-oxoethyl]-3-[4-(azetidine-1-carbonyl)phenyl]-3-propylpiperidine-2,6- dione

[0555] (3S)-1-[2-(5-aminopyridin-2-yl)-2-oxoethyl]-3-ethyl-3-[4-(3-hydroxy-3-methylazetidin-1- yl)phenyl]piperidine-2, 6-dione 4-[(3S)-1-[2-(5-aminopyridin-2-yl)-2-oxoethyl]-3-ethyl-2,6-dioxopiperidin-3-yl]benzonitrile

[0556] (3S)-1-[2-(5-aminopyridin-2-yl)-2-oxoethyl]-3-ethyl-3-{4-[(3R)-3-hydroxypyrrolidin-1- yl]phenyl}piperidine-2, 6-dione (3S)-1-[2-(4-amino-3-chlorophenyl)-2-oxoethyl]-3-ethyl-3-[4-(3-hydroxyazetidin-1-yl)phenyl]piperidine-

[0557] 2,6-dione

[0558] (3S)-1-[2-(4-amino-3-chlorophenyl)-2-oxoethyl]-3-ethyl-3-{4-[(3R)-3-hydroxypyrrolidin-1- yl]phenyl}piperidine-2, 6-dione (3S)-1-[2-(5-aminopyridin-2-yl)-2-oxoethyl]-3-ethyl-3-{4-[(3-hydroxyazetidin-1- yl)sulfonyl]phenyl}piperidine-2, 6-dione

[0559] (3S)-1-[2-(5-aminopyridin-2-yl)-2-oxoethyl]-3-[4-(azetidine-1-carbonyl)-3-fluorophenyl]-3- ethylpiperidine-2, 6-dione

[0560] (3S)-1-[2-(5-aminopyridin-2-yl)-2-oxoethyl]-3-[6-(azetidine-1-carbonyl)pyridin-3-yl]-3-ethylpiperidine-

[0561] 2,6-dione

[0562] (3S)-1-[2-(4-amino-3-chlorophenyl)-2-oxoethyl]-3-ethyl-3-{4-[(3S)-3-hydroxypyrrolidin-1- yl]phenyl}piperidine-2, 6-dione

[0563] (3S)-1-[2-(5-aminopyridin-2-yl)-2-oxoethyl]-3-ethyl-3-{4-[(3S)-3-hydroxypyrrolidin-1- yl]phenyl}piperidine-2, 6-dione

[0564] N-({4-[(3S)-1-[2-(5-aminopyridin-2-yl)-2-oxoethyl]-3-ethyl-2,6-dioxopiperidin-3- yl]phenyl}methyl)acetamide (3S)-3-[4-(azetidine-1-carbonyl)phenyl]-3-ethyl-1-[2-oxo-2-(pyridin-2-yl)ethyl]piperidine-2, 6-dione (3S)-3-[4-(azetidine-1-carbonyl)phenyl]-1-[2-(5-chloropyridin-2-yl)-2-oxoethyl]-3-ethylpiperidine-2,6- dione

[0565] (3S)-1-[2-(4-amino-2-fluorophenyl)-2-oxoethyl]-3-[4-(azetidine-1-carbonyl)phenyl]-3-ethylpiperidine-

[0566] 2,6-dione

[0567] (3S)-1-[2-(5-aminopyridin-2-yl)-2-oxoethyl]-3-[4-(azetidine-1-carbonyl)phenyl]-3-methylpiperidine-2,6- dione (3S)-3-[4-(azetidine-1 -carbonyl)phenyl]-3-ethyl-1 -[2-(5-fluoropyridin-2-yl)-2-oxoethyl]piperidine-2,6- dione (3S)-1-[2-(4-amino-3-fluorophenyl)-2-oxoethyl]-3-[4-(azetidine-1-carbonyl)phenyl]-3-ethylpiperidine-

[0568] 2,6-dione

[0569] (3S)-1-[2-(5-amino-6-methylpyridin-2-yl)-2-oxoethyl]-3-ethyl-3-[4-(3-hydroxyazetidin-1- yl)phenyl]piperidine-2, 6-dione

[0570] 1-{4-[(3S)-1-[2-(5-aminopyridin-2-yl)-2-oxoethyl]-3-ethyl-2,6-dioxopiperidin-3-yl]phenyl}azetidine-3- carbonitrile

[0571] (3S)-3-[4-(azetidine-1-carbonyl)phenyl]-3-ethyl-1-(2-oxo-2-{1 H-pyrrolo[3,2-b]pyridin-3- yl}ethyl)piperidine-2, 6-dione

[0572] (3S)-1 -{2-[5-(azetidin-1 -yl)pyridin-2-yl]-2-oxoethyl}-3-[4-(azetidine-1 -carbonyl)phenyl]-3- ethylpiperidine-2, 6-dione (3S)-1-[2-(5-amino-6-methylpyridin-2-yl)-2-oxoethyl]-3-ethyl-3-{4-[(3R)-3-hydroxypyrrolidin-1- yl]phenyl}piperidine-2, 6-dione

[0573] (3S)-1-[2-(5-amino-6-methylpyridin-2-yl)-2-oxoethyl]-3-ethyl-3-{4-[(3S)-3-hydroxypyrrolidin-1- yl]phenyl}piperidine-2, 6-dione

[0574] (3S)-3-[4-(azetidine-1-carbonyl)phenyl]-3-ethyl-1-(2-oxo-2-{pyrazolo[1 ,5-a]pyridin-2-yl}ethyl)piperidine-

[0575] 2, 6-dione

[0576] (3S)-3-[4-(azetidine-1-carbonyl)phenyl]-3-ethyl-1-(2-{imidazo[1 ,5-a]pyridin-8-yl}-2-oxoethyl)piperidine-

[0577] 2, 6-dione

[0578] (3S)-3-[4-(azetidine-1-carbonyl)phenyl]-3-ethyl-1-[2-(5-methoxypyridin-2-yl)-2-oxoethyl]piperidine-2,6- dione

[0579] (3S)-1-[2-(5-aminopyridin-2-yl)-2-oxoethyl]-3-ethyl-3-[4-((1S)-1-hydroxyethyl)phenyl]piperidine-2,6- dione

[0580] (3S)-1-[2-(5-aminopyridin-2-yl)-2-oxoethyl]-3-ethyl-3-[4-((1 R)-1-hydroxyethyl)phenyl]piperidine-2,6- dione

[0581] (3S)-1-[2-(5-amino-4-methylpyridin-2-yl)-2-oxoethyl]-3-[4-(azetidine-1-carbonyl)phenyl]-3- ethylpiperidine-2, 6-dione

[0582] (3R)-1-[2-(5-aminopyridin-2-yl)-2-oxoethyl]-3-[4-(azetidine-1-carbonyl)phenyl]-3-(pro pan-2- yl)piperidine-2, 6-dione

[0583] (3S)-3-[4-(azetidine-1-carbonyl)phenyl]-3-ethyl-1-{2-[5-(1-methyl-1 H-pyrazol-4-yl)pyridin-2-yl]-2- oxoethyl}piperidine-2, 6-dione

[0584] (3S)-3-[4-(azetidine-1-carbonyl)phenyl]-3-ethyl-1-(2-{2-methyl-2H-pyrazolo[3,4-c]pyridin-5-yl}-2- oxoethyl)piperidine-2, 6-dione

[0585] (3R)-1-[2-(5-aminopyridin-2-yl)-2-oxoethyl]-3-[4-(azetidine-1-carbonyl)phenyl]-3-(2,2- difluoroethyl)piperidine-2, 6-dione (3S)-3-[4-(azetidine-1-carbonyl)phenyl]-3-ethyl-1-[2-oxo-2-(pyridin-3-yl)ethyl]piperidine-2, 6-dione

[0586] (3S)-3-[4-(azetidine-1-carbonyl)phenyl]-3-ethyl-1-[2-(2-methylpyridin-4-yl)-2-oxoethyl]piperidine-2,6- dione (3R)-1-[2-(5-aminopyridin-2-yl)-2-oxoethyl]-3-[4-(azetidine-1-carbonyl)phenyl]-3-(2- fluoroethyl)piperidine-2, 6-dione

[0587] (3S)-1-[2-(5-aminopyridin-2-yl)-2-oxoethyl]-3-[4-(3-hydroxyazetidin-1-yl)phenyl]-3-propylpiperidine-2,6- dione

[0588] (3S)-3-[4-(azetidine-1-carbonyl)phenyl]-3-ethyl-1-{2-[5-(methylamino)pyridin-2-yl]-2- oxoethyl}piperidine-2, 6-dione

[0589] (3S)-3-[4-(azetidine-1-carbonyl)phenyl]-3-ethyl-1-[2-(6-methylpyridin-3-yl)-2-oxoethyl]piperidine-2,6- dione

[0590] (3S)-3-[4-(azetidine-1-carbonyl)phenyl]-3-ethyl-1-[2-oxo-2-(pyridin-4-yl)ethyl]piperidine-2, 6-dione

[0591] (3R)-1-[2-(5-aminopyridin-2-yl)-2-oxoethyl]-3-[4-(azetidine-1-carbonyl)phenyl]-3-(2,2,2- trifluoroethyl)piperidine-2, 6-dione

[0592] (3S)-3-[4-(azetidine-1-carbonyl)phenyl]-3-ethyl-1-[2-(6-methylpyridin-2-yl)-2-oxoethyl]piperidine-2,6- dione

[0593] (3S)-1-[2-(4-amino-3,5-difluorophenyl)-2-oxoethyl]-3-[4-(azetidine-1-carbonyl)phenyl]-3- ethylpiperidine-2, 6-dione

[0594] (3S)-3-ethyl-3-[4-(3-hydroxyazetidin-1 -y I) ph e n y I]- 1 -{2-[7-(methylamino)-1 H-indazol-4-yl]-2- oxoethyl}piperidine-2, 6-dione

[0595] (3S)-1-[2-(4-amino-2,3-difluorophenyl)-2-oxoethyl]-3-[4-(azetidine-1-carbonyl)phenyl]-3- ethylpiperidine-2, 6-dione

[0596] (3S)-1-[2-(5-aminopyridin-2-yl)-2-oxoethyl]-3-ethyl-3-[4-(3-methylazetidine-1- carbonyl)phenyl]piperidine-2, 6-dione

[0597] 1-{4-[(3S)-1-[2-(5-aminopyridin-2-yl)-2-oxoethyl]-3-ethyl-2,6-dioxopiperidin-3-yl]benzoyl}azetidine-3- carbonitrile

[0598] (3S)-3-[4-(4-acetylpiperazin-1-yl)phenyl]-1-[2-(5-aminopyridin-2-yl)-2-oxoethyl]-3-ethylpiperidine-2,6- dione

[0599] (3S)-3-[4-(azetidine-1-carbonyl)phenyl]-1-{2-[4-(difluoromethyl)phenyl]-2-oxoethyl}-3-ethylpiperidine-

[0600] 2,6-dione

[0601] (3S)-1-[2-(5-aminopyridin-2-yl)-2-oxoethyl]-3-{4-[(3S)-3-hydroxypyrrolidin-1-yl]phenyl}-3- methylpiperidine-2, 6-dione

[0602] 1-{4-[(3S)-1-[2-(5-aminopyridin-2-yl)-2-oxoethyl]-3-methyl-2,6-dioxopiperidin-3-yl]phenyl}azetidine-3- carbonitrile

[0603] (3S)-1-[2-(5-aminopyridin-2-yl)-2-oxoethyl]-3-ethyl-3-{4-[(2R)-2-methylazetidine-1- carbonyl]phenyl}piperidine-2, 6-dione

[0604] (3S)-1-[2-(5-aminopyridin-2-yl)-2-oxoethyl]-3-ethyl-3-{4-[(2S)-2-methylazetidine-1- carbonyl]phenyl}piperidine-2, 6-dione

[0605] (3S)-1-[2-(5-aminopyridin-2-yl)-2-oxoethyl]-3-ethyl-3-[4-(3-oxopiperazin-1-yl)phenyl]piperidine-2,6- dione

[0606] (3S)-1-[2-(5-amino-6-methylpyridin-2-yl)-2-oxoethyl]-3-{4-[(3S)-3-hydroxypyrrolidin-1-yl]phenyl}-3- methylpiperidine-2, 6-dione (3S)-1-[2-(5-amino-6-methylpyridin-2-yl)-2-oxoethyl]-3-[4-(azetidine-1-carbonyl)phenyl]-3- methylpiperidine-2, 6-dione

[0607] (3S)-1-[2-(5-aminopyridin-2-yl)-2-oxoethyl]-3-[4-(azetidine-1-carbonyl)phenyl]-3-

[0608] (methoxymethyl)piperidine-2, 6-dione

[0609] (3S)-3-[4-(azetidine-1-carbonyl)phenyl]-3-methyl-1-{2-[5-(methylamino)pyridin-2-yl]-2- oxoethyl}piperidine-2, 6-dione

[0610] N,N-dimethyl-4-[(3S)-3-methyl-1-{2-[5-(methylamino)pyridin-2-yl]-2-oxoethyl}-2,6-dioxopiperidin-3- yl] benzamide

[0611] 4-[(3S)-1-[2-(5-amino-6-methylpyridin-2-yl)-2-oxoethyl]-3-methyl-2,6-dioxopiperidin-3-yl]-N,N- dimethylbenzamide

[0612] (3R)-1-[2-(5-aminopyridin-2-yl)-2-oxoethyl]-3-[4-(azetidine-1-carbonyl)phenyl]-3-

[0613] (methylsulfanyl)piperidine-2, 6-dione

[0614] (3S)-1-[2-(5-aminopyridin-2-yl)-2-oxoethyl]-3-methyl-3-[4-(2-oxo-1 ,3-oxazolidin-3-yl)phenyl]piperidine-

[0615] 2, 6-dione

[0616] 1-[2-(4-aminophenyl)-2-oxoethyl]-3-ethyl-3-[6-(hydroxymethyl)pyridin-3-yl]piperidine-2, 6-dione

[0617] (3S)-3-(4-aminophenyl)-3-ethyl-1-{[4-(1 H-pyrazol-5-yl)pyridin-2-yl]methyl}piperidine-2, 6-dione

[0618] (3S)-3-(4-aminophenyl)-1-[(1 ,2-benzothiazol-3-yl)methyl]-3-ethylpiperidine-2, 6-dione

[0619] (3S)-3-(4-aminophenyl)-3-ethyl-1 -{[6-(1 -methyl-1 H-pyrazol-4-yl)-1 ,2-benzoxazol-3- yl]methyl}piperidine-2, 6-dione

[0620] (3S)-1-[(6-amino-1 ,2-benzoxazol-3-yl)methyl]-3-(4-aminophenyl)-3-ethylpiperidine-2, 6-dione

[0621] 2-{[(3S)-3-(4-aminophenyl)-3-ethyl-2,6-dioxopiperidin-1-yl]methyl}pyridine-3-carbonitrile

[0622] N-[(3S)-3-(4-aminophenyl)-3-ethyl-2,6-dioxopiperidin-1-yl]-3-chlorobenzamide

[0623] 4-amino-N-[(3S)-3-(4-aminophenyl)-3-ethyl-2,6-dioxopiperidin-1-yl]benzamide

[0624] (3S)-3-(4-aminophenyl)-3-ethyl-1-[(4-{7H-pyrrolo[2,3-d]pyrimidin-4-yl}pyridin-2-yl)methyl]piperidine-

[0625] 2,6-dione

[0626] (3S)-1-[(5-amino-1 ,2-benzoxazol-3-yl)methyl]-3-(4-aminophenyl)-3-ethylpiperidine-2, 6-dione

[0627] 4-[(3S)-1-[(6-amino-1 ,2-benzoxazol-3-yl)methyl]-3-ethyl-2,6-dioxopiperidin-3-yl]-N,N- dimethylbenzamide

[0628] 4-[(3S)-3-ethyl-1 -{[6- (1 -methyl-1 H-pyrazol-4-yl)-[1 ,2]oxazolo[4,5-b]pyridin-3-yl]methyl}-2,6- dioxopiperidin-3-yl]-N,N-dimethylbenzamide

[0629] 5-amino-N-[(3S)-3-(4-aminophenyl)-3-ethyl-2,6-dioxopiperidin-1-yl]pyridine-2-carboxamide

[0630] 4-[(3S)-3-ethyl-2,6-dioxo-1-(4-oxo-3,4-dihydroquinazolin-3-yl)piperidin-3-yl]-N,N-dimethylbenzamide, atropisomer 1

[0631] 4-[(3S)-3-ethyl-2,6-dioxo-1-(4-oxo-3,4-dihydroquinazolin-3-yl)piperidin-3-yl]-N,N-dimethylbenzamide, atropisomer 2

[0632] In one embodiment, the invention provides a compound of formula (I) which is selected from the following compounds:

[0633] 4-[(3S)-1-[2-(4-aminophenyl)-2-oxoethyl]-3-ethyl-2,6-dioxopiperidin-3-yl]-N,N-dimethylbenzamide

[0634] (3S)-1-[2-(4-aminophenyl)-2-oxoethyl]-3-[4-(azetidine-1-carbonyl)phenyl]-3-ethylpiperidine-2, 6-dione 4-[(3S)-1-[2-(5-aminopyridin-2-yl)-2-oxoethyl]-3-ethyl-2,6-dioxopiperidin-3-yl]-N,N-dimethylbenzamide; and

[0635] (3S)-1-[2-(5-aminopyridin-2-yl)-2-oxoethyl]-3-[4-(azetidine-1-carbonyl)phenyl]-3-ethylpiperidine-2,6- dione or a tautomer, / V-oxide, pharmaceutically acceptable salt or solvate thereof.

[0636] In one embodiment, the invention provides a compound of formula (I) which is the following compound, or a tautomer, pharmaceutically acceptable salt or solvate thereof:

[0637] 4-[(3S)-1-[2-(4-aminophenyl)-2-oxoethyl]-3-ethyl-2,6-dioxopiperidin-3-yl]-N,N-dimethylbenzamide.

[0638] In one embodiment, the invention provides a compound of formula (I) which is the following compound, or a tautomer, pharmaceutically acceptable salt or solvate thereof:

[0639] (3S)-1-[2-(4-aminophenyl)-2-oxoethyl]-3-[4-(azetidine-1-carbonyl)phenyl]-3-ethylpiperidine-2, 6-dione.

[0640] In one embodiment, the invention provides a compound of formula (I) which is the following compound, or a tautomer, pharmaceutically acceptable salt or solvate thereof:

[0641] 4-[(3S)-1-[2-(5-aminopyridin-2-yl)-2-oxoethyl]-3-ethyl-2,6-dioxopiperidin-3-yl]-N,N-dimethylbenzamide.

[0642] In one embodiment, the invention provides a compound of formula (I) which is the following compound, or a tautomer, pharmaceutically acceptable salt or solvate thereof:

[0643] (3S)-1-[2-(5-aminopyridin-2-yl)-2-oxoethyl]-3-[4-(azetidine-1-carbonyl)phenyl]-3-ethylpiperidine-2,6- dione.

[0644] For the avoidance of doubt, it is to be understood that each general and specific embodiment and example for one substituent may be combined with each general and specific embodiment and example for one or more, in particular all, other substituents as defined herein and that all such embodiments are embraced by this application.

[0645] SALTS, SOLVATES, TAUTOMERS, ISOMERS, N-OXIDES, ESTERS, PRODRUGS AND ISOTOPES

[0646] A reference to a compound of the formula (I), sub-groups thereof (e.g. formulae (I), (I’), (II), (II’), (Ila), (Ila’), (lib), (lie), (lid), (III), (III0), (III’), (Illa), (lllb), (lllb’), (lllc), (IV), (V), (VI), (VII), (VIII) and (IX)) and any example also includes ionic forms, salts, solvates, isomers (including geometric and stereochemical isomers unless specified), tautomers, N-oxides, esters, prodrugs, isotopes and protected forms thereof, for example, as discussed below; in particular, the salts or tautomers or isomers or N-oxides or solvates thereof; and more particularly the salts or tautomers or N-oxides or solvates thereof. In one embodiment reference to a compound of the formula (I), sub-groups thereof (e.g. formulae (I), (I’), (II), (II’), (Ila), (Ila’), (lib), (lie), (lid), (III), (III0), (III’), (Illa), (lllb), (lllb’), (lllc), (IV), (V), (VI), (VII), (VIII) and (IX)) and any example also includes the salts or tautomers or solvates thereof.

[0647] Salts

[0648] Many compounds of the formula (I) can exist in the form of salts, for example acid addition salts or, in certain cases salts of organic and inorganic bases such as carboxylate, sulfonate and phosphate salts. All such salts are within the scope of this invention, and references to compounds of the formula (I) include the salt forms of the compounds. The salts of the present invention can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods such as methods described in Pharmaceutical Salts: Properties, Selection, and Use, P. Heinrich Stahl (Editor), Camille G. Wermuth (Editor), ISBN: 3-90639- 026-8, Hardcover, 388 pages, August 2002. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are used.

[0649] Acid addition salts (mono- or di-salts) may be formed with a wide variety of acids, both inorganic and organic. Examples of acid addition salts include mono- or di-salts formed with an acid selected from acetic, 2,2-dichloroacetic, adipic, alginic, ascorbic (e.g. L-ascorbic), L-aspartic, benzenesulfonic, benzoic, 4-acetamidobenzoic, butanoic, (+) camphoric, camphor-sulfonic, (+)-(1 S)-camphor-10- sulfonic, capric, caproic, caprylic, cinnamic, citric, cyclamic, dodecylsulfuric, ethane-1 ,2-disulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, formic, fumaric, galactaric, gentisic, glucoheptonic, D- gluconic, glucuronic (e.g. D-glucuronic), glutamic (e.g. L-glutamic), a-oxoglutaric, glycolic, hippuric, hydrohalic acids (e.g. hydrobromic, hydrochloric, hydriodic), isethionic, lactic (e.g. (+)-L-lactic, (±)-DL- lactic), lactobionic, maleic, malic, (-)-L-malic, malonic, (±)-DL-mandelic, methanesulfonic, naphthalene- 2-sulfonic, naphthalene-1 ,5-disulfonic, 1-hydroxy-2-naphthoic, nicotinic, nitric, oleic, orotic, oxalic, palmitic, pamoic, phosphoric, propionic, pyruvic, L-pyroglutamic, salicylic, 4-amino-salicylic, sebacic, stearic, succinic, sulfuric, tannic, (+)-L-tartaric, thiocyanic, p-toluenesulfonic, undecylenic and valeric acids, as well as acylated amino acids and cation exchange resins.

[0650] One particular group of salts consists of salts formed from acetic, hydrochloric, hydriodic, phosphoric, nitric, sulfuric, citric, lactic, succinic, maleic, malic, isethionic, fumaric, benzenesulfonic, toluenesulfonic, methanesulfonic (mesylate), ethanesulfonic, naphthalenesulfonic, valeric, acetic, propanoic, butanoic, malonic, glucuronic and lactobionic acids. One particular salt is the hydrochloride salt.

[0651] If the compound is anionic, or has a functional group which may be anionic (e.g., -COOH may be -COO ), then a salt may be formed with an organic or inorganic base, generating a suitable cation. Examples of suitable inorganic cations include, but are not limited to, alkali metal ions such as Li+, Na+and K+, alkaline earth metal cations such as Ca2+and Mg2+, and other cations such as Al3+or Zn+. Examples of suitable organic cations include, but are not limited to, ammonium ion (i.e., NH4+) and substituted ammonium ions (e.g., NHsR+, NH2R2+, NHRs+, NR4+). Examples of some suitable substituted ammonium ions are those derived from: methylamine, ethylamine, diethylamine, propylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, as well as amino acids, such as lysine and arginine. An example of a common quaternary ammonium ion is N(CH3)4+.

[0652] Where the compounds of the formula (I) contain an amine function, these may form quaternary ammonium salts, for example by reaction with an alkylating agent according to methods well known to the skilled person. Such quaternary ammonium compounds are within the scope of formula (I). The compounds of the invention may exist as mono- or di-salts depending upon the pKa of the acid from which the salt is formed.

[0653] The salt forms of the compounds of the invention are typically pharmaceutically acceptable salts, and examples of pharmaceutically acceptable salts are discussed in Berge et al., 1977, "Pharmaceutically Acceptable Salts," J. Pharm. Sci., Vol. 66, pp. 1-19. However, salts that are not pharmaceutically acceptable may also be prepared as intermediate forms which may then be converted into pharmaceutically acceptable salts. Such non-pharmaceutically acceptable salt forms, which may be useful, for example, in the purification or separation of the compounds of the invention, also form part of the invention.

[0654] In one embodiment of the invention, there is provided a pharmaceutical composition comprising a solution (e.g. an aqueous solution) containing a compound of the formula (I) and sub-groups and examples thereof as described herein in the form of a salt in a concentration of greater than 10 mg / ml, typically greater than 15 mg / ml and typically greater than 20 mg / ml.

[0655] N-Oxides

[0656] Compounds of the formula (I) containing an amine function may also form N-oxides. A reference herein to a compound of the formula (I) that contains an amine function also includes the N-oxide.

[0657] Where a compound contains several amine functions one, or more than one, nitrogen atom may be oxidised to form an N-oxide. Particular examples of N-oxides are the N-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocyclylic group.

[0658] N-Oxides can be formed by treatment of the corresponding amine with an oxidizing agent such as hydrogen peroxide or a per-acid (e.g. a peroxycarboxylic acid), see for example Advanced Organic Chemistry, by Jerry March, 4thEdition, Wiley Interscience, pages. More particularly, N-oxides can be made by the procedure of L. W. Deady (Syn. Comm. 1977, 7, 509-514) in which the amine compound is reacted with m-chloroperoxybenzoic acid (MCPBA), for example, in an inert solvent such as dichloromethane.

[0659] Geometric isomers and tautomers

[0660] Compounds of the formula (I) may exist in a number of different geometric isomeric, and tautomeric forms and references to compounds of the formula (I) include all such forms. For the avoidance of doubt, where a compound can exist in one of several geometric isomeric or tautomeric forms and only one is specifically described or shown, all others are nevertheless embraced by formula (I).

[0661] For example, certain heteroaryl rings can exist in the two tautomeric forms such as A and B shown below. For simplicity, a formula may illustrate one form but the formula is to be taken as embracing both tautomeric forms.

[0662] Other examples of tautomeric forms include, for example, keto-, enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto / enol (illustrated below), imine / enamine, amide / imino alcohol, amidine / enediamines, nitroso / oxime, thioketone / enethiol, and nitro / aci-nitro. keto enol enolate

[0663] Stereoisomers

[0664] Unless otherwise mentioned or indicated, the chemical designation of compounds denotes the mixture of all possible stereochemically isomeric forms.

[0665] Stereocentres are illustrated in the usual fashion, using ‘hashed’ or ‘solid’ wedged lines, e.g.

[0666] Where a compound is described as a mixture of two diastereoisomers / epimers, the configuration of the stereocentre is not specified and is represented by straight lines.

[0667] Where compounds of the formula (I) contain one or more chiral centres, and can exist in the form of two or more optical isomers, references to compounds of the formula (I) include all optical isomeric forms thereof (e.g. enantiomers, epimers and diastereoisomers), either as individual optical isomers, or mixtures (e.g. racemic or scalemic mixtures) or two or more optical isomers, unless the context requires otherwise.

[0668] The optical isomers may be characterised and identified by their optical activity (i.e. as + and - isomers, or d and I isomers) or they may be characterised in terms of their absolute stereochemistry using the “R and S” nomenclature developed by Cahn, Ingold and Prelog, see Advanced Organic Chemistry by Jerry March, 4thEdition, John Wiley & Sons, New York, 1992, pages 109-114, and see also Cahn, Ingold & Prelog, Ange w. Chem. Int. Ed. Engl., 1966, 5, 385-415.

[0669] Optical isomers can be separated by a number of techniques including chiral chromatography (chromatography on a chiral support) and such techniques are well known to the person skilled in the art.

[0670] As an alternative to chiral chromatography, optical isomers can be separated by forming diastereoisomeric salts with chiral acids such as (+)-tartaric acid, (-)-pyroglutamic acid, (-)-di-toluoyl-L- tartaric acid, (+)-mandelic acid, (-)-malic acid, and (-)-camphorsulfonic acid, separating the diastereoisomers by preferential crystallisation, and then dissociating the salts to give the individual enantiomer of the free base.

[0671] Additionally, enantiomeric separation can be achieved by covalently linking an enantiomerically pure chiral auxiliary onto the compound and then performing diastereisomer separation using conventional methods such as chromatography. This is then followed by cleavage of the aforementioned covalent linkage to generate the appropriate enantiomerically pure product.

[0672] Where compounds of the formula (I) exist as two or more optical isomeric forms, one enantiomer in a pair of enantiomers may exhibit advantages over the other enantiomer, for example, in terms of biological activity. Thus, in certain circumstances, it may be desirable to use as a therapeutic agent only one of a pair of enantiomers, or only one of a plurality of diastereoisomers.

[0673] Accordingly, the invention provides compositions containing a compound of the formula (I) having one or more chiral centres, wherein at least 55% (e.g. at least 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95%) of the compound of the formula (I) is present as a single optical isomer (e.g. enantiomer or diastereoisomer). In one general embodiment, 99% or more (e.g. substantially all) of the total amount of the compound of the formula (I) may be present as a single optical isomer (e.g. enantiomer or diastereoisomer).

[0674] Compounds encompassing double bonds can have an E (entgegen) or Z (zusammen) stereochemistry at said double bond. Substituents on bivalent cyclic or (partially) saturated radicals may have either the cis- or frans-configuration. The terms cis and trans when used herein are in accordance with Chemical Abstracts nomenclature (J. Org. Chem. 1970, 35 (9), 2849-2867), and refer to the position of the substituents on a ring moiety.

[0675] Of special interest are those compounds of formula (I) which are stereochemically pure. When a compound of formula (I) is for instance specified as R, this means that the compound is substantially free of the S isomer. If a compound of formula (I) is for instance specified as E, this means that the compound is substantially free of the Z isomer. The terms cis, trans, R, S, E and Z are well known to a person skilled in the art.

[0676] Isotopic variations

[0677] The present invention includes all pharmaceutically acceptable isotopically-labeled compounds of the invention, i.e. compounds of formula (I), wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.

[0678] Examples of isotopes suitable for inclusion in the compounds of the invention comprise isotopes of hydrogen, such as2H (D) and3H (T), carbon, such as11C,13C and14C, chlorine, such as36CI, fluorine, such as18F, iodine, such as123l,125l and1311, nitrogen, such as13N and15N, oxygen, such as15O,17O and18O, phosphorus, such as32P, and sulfur, such as35S.

[0679] Certain isotopically-labelled compounds of formula (I), for example, those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The compounds of formula (I) can also have valuable diagnostic properties in that they can be used for detecting or identifying the formation of a complex between a labelled compound and other molecules, peptides, proteins, enzymes or receptors. The detecting or identifying methods can use compounds that are labelled with labelling agents such as radioisotopes, enzymes, fluorescent substances, luminous substances (for example, luminol, luminol derivatives, luciferin, aequorin and luciferase), etc. The radioactive isotopes tritium, i.e.3H (T), and carbon-14, i.e.14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.

[0680] Substitution with heavier isotopes such as deuterium, i.e.2H (D), may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be used in some circumstances.

[0681] In particular, every reference to hydrogen in the application should be construted to cover1H and2H, whether hydrogen is defined explicitly, or hydrogen is present implicitly to satisfy the relevant atom’s (in particular carbon’s) valency.

[0682] Substitution with positron emitting isotopes, such as11C,18F,15O and13N, can be useful in Positron Emission Topography (PET) studies for examining target occupancy.

[0683] Isotopically-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labeled reagents in place of the non- labeled reagent previously employed.

[0684] Esters

[0685] Esters such as carboxylic acid esters, acyloxy esters and phosphate esters of the compounds of formula (I) bearing a carboxylic acid group or a hydroxyl group are also embraced by Formula (I). Examples of esters are compounds containing the group -C(=O)OR, wherein R is an ester substituent, for example, a C1-7 alkyl group, a C3-i2 heterocyclyl group, or a Cs ^ aryl group, typically a C1-6alkyl group. Particular examples of ester groups include, but are not limited to, -C(=O)OCH3, -C(=O)OCH2CH3, -C(=O)OC(CH3)3, and -C(=O)OPh. Examples of acyloxy (reverse ester) groups are represented by -OC(=O)R, wherein R is an acyloxy substituent, for example, a C1-6alkyl group, a C3-12 heterocyclyl group, or a Cs ^ aryl group, typically a C1-6alkyl group. Particular examples of acyloxy groups include, but are not limited to, -OC(=O)CH3(acetoxy), -OC(=O)CH2CH3, -OC(=O)C(CH3)3, -OC(=O)Ph, and -OC(=O)CH2Ph. Examples of phosphate esters are those derived from phosphoric acid.

[0686] In one embodiment of the invention, formula (I) includes within its scope esters of compounds of the formula (I) bearing a carboxylic acid group or a hydroxyl group. In another embodiment of the invention, formula (I) does not include within its scope esters of compounds of the formula (I) bearing a carboxylic acid group or a hydroxyl group.

[0687] Solvates and Crystalline forms

[0688] Also encompassed by formula (I) are any polymorphic forms of the compounds, and solvates such as hydrates, alcoholates and the like.

[0689] The compounds of the invention may form solvates, for example with water (i.e., hydrates) or common organic solvents. As used herein, the term “solvate” means a physical association of the compounds of the present invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. The term “solvate” is intended to encompass both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include compounds of the invention in combination with water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid or ethanolamine and the like. The compounds of the invention may exert their biological effects whilst they are in solution.

[0690] Solvates are well known in pharmaceutical chemistry. They can be important to the processes for the preparation of a substance (e.g. in relation to their purification), the storage of the substance (e.g. its stability) and the ease of handling of the substance and are often formed as part of the isolation or purification stages of a chemical synthesis. A person skilled in the art can determine by means of standard and long used techniques whether a hydrate or other solvate has formed by the isolation conditions or purification conditions used to prepare a given compound. Examples of such techniques include thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), X-ray crystallography (e.g. single crystal X-ray crystallography or X-ray powder diffraction) and Solid State NMR (SS-NMR, also known as Magic Angle Spinning NMR or MAS-NMR). Such techniques are as much a part of the standard analytical toolkit of the skilled chemist as NMR, IR, HPLC and MS.

[0691] Alternatively, the skilled person can deliberately form a solvate using crystallisation conditions that include an amount of the solvent required for the particular solvate. Thereafter the standard methods described herein, can be used to establish whether solvates had formed.

[0692] Furthermore, the compounds of the present invention may have one or more polymorph or amorphous crystalline forms and as such are intended to be included in the scope of the invention.

[0693] Complexes

[0694] Formula (I) also includes within its scope complexes (e.g. inclusion complexes or clathrates with compounds such as cyclodextrins, or complexes with metals) of the compounds. Inclusion complexes, clathrates and metal complexes can be formed by means of methods well known to the skilled person. Prod rugs

[0695] Also encompassed by formula (I) are any pro-drugs of the compounds of the formula (I). By “prodrugs” is meant for example any compound that is converted in vivo into a biologically active compound of the formula (I).

[0696] For example, some prodrugs are esters of the active compound (e.g., a physiologically acceptable metabolically labile ester). During metabolism, the ester group (-C(=O)OR) is cleaved to yield the active drug. Such esters may be formed by esterification, for example, of any of the carboxylic acid groups (- C(=O)OH) in the parent compound, with, where appropriate, prior protection of any other reactive groups present in the parent compound, followed by deprotection if required.

[0697] Examples of such metabolically labile esters include those of the formula -C(=O)OR wherein R is: C1-yalkyl (e.g., -Me, -Et, -nPr, -iPr, -nBu, -sBu, -iBu, -tBu); C1-7aminoalkyl (e.g., aminoethyl; 2-(N,N- diethylamino)ethyl; 2-(4-morpholino)ethyl); and acyloxy-C1-7alkyl (e.g., acyloxymethyl; acyloxyethyl; pivaloyloxymethyl; acetoxy methyl; 1 -acetoxyethyl; 1-(1-methoxy-1-methyl)ethyl-carbonxyloxyethyl; 1 - (benzoyloxy)ethyl; isopropoxy-carbonyloxymethyl; 1 -isopropoxy-carbonyloxyethyl; cyclohexyl- carbonyloxymethyl; 1-cyclohexyl-carbonyloxyethyl; cyclohexyloxy-carbonyloxymethyl; 1 - cyclohexyloxy-carbonyloxyethyl; (4-oxanyloxy) carbonyloxymethyl; 1 -(4-oxanyloxy)carbonyloxyethyl; (4-oxanyl)carbonyloxymethyl; and 1-(4-tetrahydropyranyl)carbonyloxyethyl).

[0698] Also, some prodrugs are activated enzymatically to yield the active compound, or a compound which, upon further chemical reaction, yields the active compound (for example, as in antigen-directed enzyme pro-drug therapy (ADEPT), gene-directed enzyme pro-drug therapy (GDEPT), and ligand-directed enzyme pro-drug therapy (LIDEPT), etc.). For example, the prodrug may be a sugar derivative or other glycoside conjugate, or may be an amino acid ester derivative. In one embodiment formula (I) does not include pro-drugs of the compounds of the formula (I) within its scope.

[0699] METHODS FOR THE PREPARATION OF COMPOUNDS OF FORMULA (I)

[0700] In this section, as in all other sections of this application unless the context indicates otherwise, references to formula (I) also include all other subformulae (e.g. formulae (I), (I’), (II), (II’), (Ila), (Ila’), (lib), (lie), (lid), (III), (III’), (Illa), (lllb), (lllb’), (lllc), (IV), (V), (VI), (VII), (VIII) and (IX)) and examples thereof as defined herein, unless the context indicates otherwise.

[0701] Compounds of the formula (I) can be prepared in accordance with synthetic methods well known to the skilled person. Several key intermediates are disclosed below. The invention includes intermediates for making the inventive CBP / p300 inhibitor compounds.

[0702] According to a further aspect of the invention there is provided a process for preparing a compound of formula (III) as hereinbefore described which comprises:

[0703] (a) alkylation of the N-unsubstituted cyclic imide of formula (XI) with a reagent of formula (XII) wherein Ra, t, Ring X, R1, R2, Ring Y, R6, n and m are as defined herein and LG represents a leaving group; and / or

[0704] (b) interconversion of a compound of formula (III) or a protected derivative thereof to a further compound of formula (III) or a protected derivative thereof; and / or

[0705] (c) deprotecting a protected derivative of a compound of formula (III); and / or

[0706] (d) providing a compound of formula (III) and forming a pharmaceutically acceptable salt of the compound.

[0707] In one embodiment, LG is a halogen or an activated alcohol. Activated alcohols are well known in the art. In one embodiment, the alcohol is activated by protonation, by conversion to a sulfonate or by conversion to a phosphonium intermediate. For example, in one embodiment, the activated alcohol is a sulfonate (e.g. p-toluenesulfonate or methanesulfonate) or a phosphonium intermediate (i.e. a phosphonium cation). In one embodiment, the leaving group is selected from halogen, a sulfonate (for example, p-toluenesulfonate and methanesulfonate) and a phosphonium intermediate. In one embodiment, the leaving group is selected from halogen and a sulfonate (for example, p- toluenesulfonate and methanesulfonate). In one embodiment, process (a) is performed in the presence of a base.

[0708] GENERAL SYNTHETIC ROUTES

[0709] The required intermediates are either commercially available, known in the literature, prepared by methods analogous to those in the literature or prepared by methods analogous to those described in the example experimental procedures below. Other compounds may be prepared by functional group interconversion of the groups using methods well known in the art.

[0710] A general synthetic scheme for synthesis of compounds of formula (III) is outlined in Scheme 1 below.

[0711] Scheme 1

[0712] Example reagents and conditions for Scheme 1 : Cs2CO3, DMF, 0°C to room temperature. In Scheme 1 , Ra, t, Ring X, R1, R2, Ring Y, R6, n and m are as defined herein and LG represents a leaving group. Examples of leaving groups (LG) include halogen and activated alcohol (for example a sulfonate, e.g. p-toluenesulfonate or methanesulfonate).

[0713] A general synthetic scheme for synthesis of compounds of formula (XI’), a key intermediate in the production of compounds of formula (III’) is outlined in Scheme 2 below.

[0714] Scheme 2

[0715] Example reagents and conditions for Scheme 2: A) alkylating reagent, NaOtBu, THF, 0°C to RT; B) KOH, TEBA, MeCN, 0°C to RT; C) H2SO4, AcOH, 110°C; D) KOtBu, THF, 0°C to RT; separation and isolation of the desired enantiomer can be achieved at this stage by chiral chromatography.

[0716] In Scheme 2, Ring X, R1, and R2are as defined herein and Aik represents an alkyl group (for example C1-6alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl or tertiarybutyl). In one embodiment, the alkylating used in step A is an alkyl halide under basic conditions. In one embodiment, the cyclisation step, step D, is performed under either acidic or basic conditions, for example under basic conditions. An alternative general synthetic scheme for the synthesis of compounds of formula (XI’) is outlined in Scheme 3, below. Example reagents and conditions for Scheme 3: A) alkylating reagent, NaOtBu, THF, 0°C to RT; B) NaOtBu, DMF, 0°C to RT; separation and isolation of the desired enantiomer can be achieved at this stage by chiral chromatography.

[0717] In Scheme 3, Ring X, R1, and R2are as defined herein and Aik represents an alkyl group. In one embodiment, the alkylating agent used in step A is an alkyl halide under basic conditions.

[0718] Scheme 4 outlines the same process as a one-pot reaction.

[0719] (XIII) (XVIII) (XI')

[0720] Scheme 4

[0721] Example reagents and conditions for Scheme 4: Alkyl halide as alkylating agent, KOtBu, DMF, 0°C to RT then KOtBu, acrylamide, 0°C to RT; separation and isolation of the desired enantiomer can be achieved at this stage by chiral chromatography.

[0722] Racan be introduced using compounds of formula (XV*) or (XVIII*) in Schemes 2 to 4 above, as appropriate:

[0723] Ra

[0724] RalyCONH2

[0725] 0

[0726] (XVIII*) R1can be modified at multiple stages in the synthesis. Scheme 5 shows a general synthetic scheme for the modification of R1from ester to amide. In this scheme, M can be H or a substituted cyclic imide. Therefore, this step can be performed before or after substitution of the cyclic imide.

[0727] Scheme 5 Example reagents and conditions for Scheme 5: A) c.HCI, 70 °C; B) DIPEA, T3P, HNRxRy, THF 0°C to RT; separation and isolation of the desired enantiomer can be achieved at this stage by chiral chromatography.

[0728] In Scheme 5, Ring X, R2, Ra, t, Rxand Ryare as defined herein, Aik represents an alkyl group, M represents H or substituted cyclic imide.

[0729] This chemistry can also be conducted before formation of the cyclic imide as shown in Scheme 6.

[0730] (XXII) (XXIII)

[0731] Scheme 6

[0732] Example reagents and conditions for Scheme 6: HATU, EtsN, DMF

[0733] In Scheme 6, Ring X, Rxand Ryare as defined herein and Aik represents an alkyl group.

[0734] Scheme 7 shows the modification of R1 from halogen to amino.

[0735] Scheme 7

[0736] Example reagents and conditions for Scheme 7: NRxRy, tBuXPhos Pd G3, KHMDS, MTBE, 80°C; separation and isolation of the desired enantiomer can be achieved at this stage by chiral chromatography.

[0737] In Scheme 7, Ring X, R2, Ra, t, Rxand Ryare as defined herein and halo represents a halogen group (e.g. F, Cl, Br or I). M represents H or substituted cyclic imide.

[0738] Scheme 8 shows the synthesis of alkylating reagents suitable for coupling to an unsubstituted cyclic imide.

[0739] (XXVII)

[0740] Scheme 8

[0741] Example reagents and conditions for Scheme 8: A) MeMgCI, THF, 0°C to RT; B) tributyl(1- ethoxyvinyl)stannane, Pd(PPh3)2Cl2, dioxane 120°C to RT, then HCI; C) HBr, Br2, AcOH In Scheme 8, R4is as defined herein and halo represents halogen (e.g. F, Cl, Br or I).

[0742] A general synthetic scheme for synthesis of compounds where A=NR5and B=O is outlined in Scheme 9 below. Where R4is a 2-nitrophenyl-containing group, cyclisation is possible by reduction to an aniline and subsequent intramolecular cyclisation (step C). Scheme 9

[0743] Example reagents and conditions for Scheme 9: A) NH2NH2 then xylene 130°C. B) nitrobenzoic acid, TCFH, ACN. C) Pd / C, H2 then triethoxy methane, H2SO4, 120°C; separation and isolation of the desired enantiomer can be achieved at any stage by chiral chromatography.

[0744] In Scheme 9, Ring X, R1, R2, Ra, and t are as defined herein. A general synthetic scheme for synthesis of compounds where B is NR5and R5and R3together with the atoms to which they are attached join to form a heterocyclic group is outlined in Scheme 10 below. In this scheme, an N-unsubstituted cyclic imide is coupled to a second reactant. An alkylation reaction can achieve the desired reaction whereby LG represents a leaving group (e.g. halogen or activated alcohol).

[0745] (XXXIII)

[0746] Scheme 10

[0747] Example reagents and conditions for Scheme 10: Cs2CO3, Acetone, 0°C to room temperature (same conditions for both reactions); separation and isolation of the desired enantiomer can be achieved at any stage by chiral chromatography.

[0748] In Scheme 10, Ring X, R1, R2, Ra, and t are as defined herein and halo represents halogen (e.g. fluoro, chloro, bromo or iodo).

[0749] Separation of the desired enantiomer can be achieved by preparative chromatography at one of multiple steps during synthesis once chirality is in place. For example, the final compound, a protected version of the final compound, and unsubstituted cyclic imide are common stages for separation.

[0750] General

[0751] If appropriate, the reactions previously described Schemes 1 to 10 are followed or preceded by one or more reactions known to the skilled of the art and are performed in an appropriate order to achieve the requisite substitutions defined above to afford other compounds of formula (I). Non-limiting examples of such reactions whose conditions can be found in the literature include: protection of reactive functions, deprotection of reactive functions, halogenation, dehalogenation, dealkylation, alkylation and arylation of amine, aniline, alcohol and phenol,

[0752] Mitsunobu reaction on hydroxyl groups, cycloaddition reactions on appropriate groups, reduction of nitro, esters, cyano, aldehydes, transition metal-catalyzed coupling reactions, acylation, sulfonylation / introduction of sulfonyl groups, saponification / hydrolysis of esters groups, amidification or transesterification of ester groups, esterification or amidification of carboxylic groups, halogen exchange, nucleophilic substitution with amine, thiol or alcohol, reductive amination, oxime formation on carbonyl and hydroxylamine groups,

[0753] S-oxidation,

[0754] N-oxidation, and salification.

[0755] A wide range of well known functional group interconversions are known by a person skilled in the art for converting a precursor comound to a compound of formula I and are described in Advanced Organic Chemistry by Jerry March, 4th Edition, John Wiley & Sons, 1992. For example, possible metal catalysed functionalisations such as using organo-tin reagents (the Stille reaction), Grignard reagents and reactions with nitrogen nucleophiles are described in ‘Palladium Reagents and Catalysts’ [Jiro Tsuji, Wiley, ISBN 0-470-85032-9] and Handbook of OrganoPalladium Chemistry for Organic Synthesis [Volume 1 , Edited by Ei-ichi Negishi, Wiley, ISBN 0-471-31506-0],

[0756] Protecting Groups

[0757] In many of the reactions described above, it may be necessary to protect one or more groups to prevent reaction from taking place at an undesirable location on the molecule. Examples of protecting groups, and methods of protecting and deprotecting functional groups, can be found in Protective Groups in Organic Synthesis (T. Green and P. Wuts; 3rd Edition; John Wiley and Sons, 1999).

[0758] A hydroxy group may be protected, for example, as an ether (-OR) or an ester (-OC(=O)R), for example, as: a t-butyl ether; a tetrahydropyranyl (THP) ether; a benzyl, benzhydryl (diphenylmethyl), or trityl (triphenylmethyl) ether; a trimethylsilyl or t-butyldimethylsilyl ether; or an acetyl ester (-OC(=O)CH3). An aldehyde or ketone group may be protected, for example, as an acetal (R-CH(OR)2) or ketal (R2C(OR)2), respectively, in which the carbonyl group (>C=O) is treated with, for example, a primary alcohol. The aldehyde or ketone group is readily regenerated by hydrolysis using a large excess of water in the presence of acid.

[0759] An amine group may be protected, for example, as an amide (-NRCO-R) or a carbamate (-NRCO-OR), for example, as: a methyl amide (-NHCO-CH3); a benzyl carbamate (-NHCO-OCH2C6H5, -NH-Cbz or NH-Z); as a t-butyl carbamate (-NHCO-OC(CH3)3, -NH-Boc); a 2-biphenyl-2-propyl carbamate (-NHCO- OC(CH3)2C6H4CeH5, -NH-Bpoc), as a 9-fluorenylmethyl carbamate (-NH-Fmoc), as a 6-nitroveratryl carbamate (-NH-Nvoc), as a 2-trimethylsilylethyl carbamate (-NH-Teoc), as a 2,2,2-trichloroethyl carbamate (-NH-Troc), as an allyl carbamate (-NH-Alloc), or as a 2(-phenylsulfonyl)ethyl carbamate (-NH-Psec).

[0760] For example, in compounds of formula I contains an amino group, the amino group can be protected by means of a protecting group as hereinbefore defined, one preferred group being the tert- butyloxycarbonyl (Boc) group while the additional functionalisation is introduced. Where no subsequent modification of the amino group is required, the protecting group can be carried through the reaction sequence to give an N-protected form of a compound of the formula (I) which can then be de-protected by standard methods (e.g. treatment with acid in the case of the Boc group) to give the compound of formula (I).

[0761] Other protecting groups for amines, such as cyclic amines and heterocyclic N-H groups, include toluenesulfonyl (tosyl), N,N’-dimethylsulfonamide (N,N-dimethylsulfamoyl) and methanesulfonyl (mesyl) groups, benzyl groups such as a para-methoxybenzyl (PMB) group and tetrahydropyranyl (THP) groups.

[0762] A carboxylic acid group may be protected as an ester for example, as: an C1-7 alkyl ester (e.g., a methyl ester; a t-butyl ester); a C1-7 haloalkyl ester (e.g., a C1-7 trihaloalkyl ester); a triC1-7 alkylsilyl-C1-7alkyl ester; or a Cs-2o aryl-C1-7 alkyl ester (e.g., a benzyl ester; a nitrobenzyl ester; para-methoxybenzyl ester. A thiol group may be protected, for example, as a thioether (-SR), for example, as: a benzyl thioether; an acetamidomethyl ether (-S-CH2NHC(=O)CH3).

[0763] Isolation and purification of the compounds of the invention

[0764] The compounds of the invention can be isolated and purified according to standard techniques well known to the person skilled in the art and examples of such methods include chromatographic techniques such as column chromatography (e.g. flash chromatography) and HPLC. One technique of particular usefulness in purifying the compounds is preparative liquid chromatography using mass spectrometry as a means of detecting the purified compounds emerging from the chromatography column.

[0765] Preparative LC-MS is a standard and effective method used for the purification of small organic molecules such as the compounds described herein. The methods for the liquid chromatography (LC) and mass spectrometry (MS) can be varied to provide better separation of the crude materials and improved detection of the samples by MS. Optimisation of the preparative gradient LC method will involve varying columns, volatile eluents and modifiers, and gradients. Methods are well known in the art for optimising preparative LC-MS methods and then using them to purify compounds. Such methods are described in Rosentreter U, Huber U.; Optimal fraction collecting in preparative LC / MS; J Comb Chem.; 2004; 6(2), 159-64 and Leister W, Strauss K, Wisnoski D, Zhao Z, Lindsley C., Development of a custom high-throughput preparative liquid chromatography / mass spectrometer platform for the preparative purification and analytical analysis of compound libraries; J Comb Chem.; 2003; 5(3); 322- 9. An example of such a system for purifying compounds via preparative LC-MS is described below in the Examples section of this application (under the heading “Mass Directed Purification LC-MS System”).

[0766] Methods of recrystallisation of compounds of formula (I) and salt thereof can be carried out by methods well known to the skilled person - see for example (P. Heinrich Stahl (Editor), Camille G. Wermuth (Editor), ISBN: 3-90639-026-8, Handbook of Pharmaceutical Salts: Properties, Selection, and Use, Chapter 8, Publisher Wiley-VCH). Products obtained from an organic reaction are seldom pure when isolated directly from the reaction mixture. If the compound (or a salt thereof) is solid, it may be purified and / or crystallized by recrystallisation from a suitable solvent. A good recrystallisation solvent should dissolve a moderate quantity of the substance to be purified at elevated temperatures but only a small quantity of the substance at lowertemperature. It should dissolve impurities readily at low temperatures or not at all. Finally, the solvent should be readily removed from the purified product. This usually means that it has a relatively low boiling point and a person skilled in the art will know recrystallising solvents for a particular substance, or if that information is not available, test several solvents. To get a good yield of purified material, the minimum amount of hot solvent to dissolve all the impure material is used. In practice, 3-5% more solvent than necessary is used so the solution is not saturated. If the impure compound contains an impurity which is insoluble in the solvent it may then be removed by filtration and then allowing the solution to crystallize. In addition, if the impure compound contains traces of coloured material that are not native to the compound, it may be removed by adding a small amount of decolorizing agent e.g. activating charcoal to the hot solution, filtering it and then allowing it to crystallize. Usually crystallization spontaneously occurs upon cooling the solution. If it is not, crystallization may be induced by cooling the solution below room temperature or by adding a single crystal of pure material (a seed crystal). Recrystallisation can also be carried out and / or the yield optimized by the use of an anti-solvent or co-solvent. In this case, the compound is dissolved in a suitable solvent at elevated temperature, filtered and then an additional solvent in which the required compound has low solubility is added to aid crystallization. The crystals are then typically isolated using vacuum filtration, washed and then dried, for example, in an oven or via desiccation.

[0767] Other examples of methods for purification include sublimation, which includes a heating step under vacuum for example using a cold finger, and crystallization from melt (Crystallization Technology Handbook 2nd Edition, edited by A. Mersmann, 2001).

[0768] BIOLOGICAL EFFECTS

[0769] It is envisaged that the compound of the invention will be useful in medicine ortherapy. The compounds of the invention, subgroups and examples thereof, have been shown to inhibit CBP / p300. Histone lysine residues are subject to a wide range of post-translational modifications including methylation, acetylation, and ubiquitination to regulate DNA processes including replication and transcription. Distinct classes of enzymes such as histone acetyltransferases and histone deacetylases catalyse the acetylation or deacetylation of histones, respectively.

[0770] The lysine acetyltransferase paralogues CREBBP (CBP) and EP300 (p300) are ubiquitously expressed, highly homologous, multidomain enzymes with high sequence homology between the bromodomain (BRD) and catalytic histone acetyltransferase (HAT) domains. The catalytic activity of the CBP / p300 HAT domain refers specifically to the attachment of an acetyl group to a lysine side chain of histones and acetylated histones are associated with increased gene expression.

[0771] CBP / p300 are involved in many cellular processes including proliferation, cell cycle and cell differentiation and act as transcriptional coactivators to regulate gene expression by directing chromatin accessibility via acetylation of histones. Missense mutations in CBP cluster around the region encoding the HAT domain which ablates transcriptional coactivation activity. Additionally, gross deletions and protein-truncating mutations can occur. Dysregulation can lead to oncogenic gene expression and signalling; hence aberrant activity has been associated with cancer and disease processes involving the immune system, haematopoiesis and the heart. Chemical inhibition of CBP / p300 therefore has therapeutic potential in cancer and other diseases.

[0772] Thus, for example, it is envisaged that the compounds of the invention will be useful in alleviating or reducing the incidence of cancer, preventing or treating diseases or conditions mediated by CBP / p300, including for example diseases or conditions such as cancers in which nuclear hormone receptors such as androgen and estrogen receptors (AR and ER, respectively) play a role. The compounds of the present invention may be useful forthe treatment of the adult population. The compounds of the present invention may be useful for the treatment of the paediatric population.

[0773] The compounds of the present invention have been shown to be good inhibitors of CBP and p300. The compounds of formula (I) are capable of binding to CBP and p300 and exhibiting potency for CBP and p300 inhibition. The potencies of the compounds of the present invention have been determined against CBP and p300 using the assay protocols described herein and other methods known in the art. More particularly, the compounds of the formula (I) and sub-groups thereof have potency for CBP / p300 inhibition.

[0774] Certain compounds of the invention are those having p300 inhibitory IC50values of less than 0.1 μM in particular less than 0.01 or 0.005 μM.

[0775] Certain compounds of the invention are also those having CBP inhibitory IC50values of less than 5 μM.

[0776] As a consequence of their activity against CBP / p300 it is anticipated that the compounds may prove useful in treating or preventing proliferative disorders such as cancers.

[0777] Examples of cancers (and their benign counterparts) which may be treated (or inhibited) include, but are not limited to tumours of epithelial origin (adenomas and carcinomas of various types including adenocarcinomas, squamous carcinomas, transitional cell carcinomas and other carcinomas) such as carcinomas of the bladder and urinary tract, breast, gastrointestinal tract (including the esophagus, stomach (gastric), small intestine, colon, bowel, colorectal, rectum and anus), liver (hepatocellular carcinoma), gall bladder and biliary system, exocrine pancreas, kidney (for example renal cell carcinoma), lung (for example adenocarcinomas, small cell lung carcinomas, non-small cell lung carcinomas, bronchioalveolar carcinomas and mesotheliomas), head and neck (for example cancers of the tongue, buccal cavity, larynx, pharynx, nasopharynx, tonsil, salivary glands, nasal cavity and paranasal sinuses), ovary, fallopian tubes, peritoneum, vagina, vulva, penis, testes, cervix, myometrium, endometrium, thyroid (for example thyroid follicular carcinoma), brain, adrenal, prostate, skin and adnexae (for example melanoma, basal cell carcinoma, squamous cell carcinoma, keratoacanthoma, dysplastic naevus); haematological malignancies (i.e. leukemias, lymphomas) and premalignant haematological disorders and disorders of borderline malignancy including haematological malignancies and related conditions of lymphoid lineage (for example acute lymphocytic leukemia [ALL], chronic lymphocytic leukemia [CLL], B-cell lymphomas such as diffuse large B-cell lymphoma [DLBCL], follicular lymphoma, Burkitt’s lymphoma, mantle cell lymphoma, T-cell lymphomas and leukaemias, natural killer [NK] cell lymphomas, Hodgkin’s lymphomas, hairy cell leukaemia, monoclonal gammopathy of uncertain significance, plasmacytoma, multiple myeloma, and post- transplant lymphoproliferative disorders), and haematological malignancies and related conditions of myeloid lineage (for example acute myelogenous leukemia [AML], chronic myelogenous leukemia [CML], chronic myelomonocytic leukemia [CMML], hypereosinophilic syndrome, myeloproliferative disorders such as polycythaemia vera, essential thrombocythaemia and primary myelofibrosis, myeloproliferative syndrome, myelodysplastic syndrome, and promyelocytic leukemia); tumours of mesenchymal origin, for example sarcomas of soft tissue, bone or cartilage such as osteosarcomas, fibrosarcomas, chondrosarcomas, rhabdomyosarcomas, leiomyosarcomas, liposarcomas, angiosarcomas, Kaposi’s sarcoma, Ewing’s sarcoma, synovial sarcomas, epithelioid sarcomas, gastrointestinal stromal tumours, benign and malignant histiocytomas, and dermatofibrosarcoma protuberans; tumours of the central or peripheral nervous system (for example astrocytomas (e.g. gliomas), neuromas and glioblastomas, meningiomas, ependymomas, pineal tumours and schwannomas); endocrine tumours (for example pituitary tumours, adrenal tumours, islet cell tumours, parathyroid tumours, carcinoid tumours and medullary carcinoma of the thyroid); ocular and adnexal tumours (for example retinoblastoma); germ cell and trophoblastic tumours (for example teratomas, seminomas, dysgerminomas, hydatidiform moles and choriocarcinomas); and paediatric and embryonal tumours (for example medulloblastoma, neuroblastoma, Wilms tumour, and primitive neuroectodermal tumours); or syndromes, congenital or otherwise, which leave the patient susceptible to malignancy (for example Xeroderma Pigmentosum).

[0778] Growth of cells is a closely controlled function. Cancer, a condition of abnormal cell growth, results when cells replicate in an uncontrolled manner (increasing in number), uncontrollably grow (getting larger) and / or experience reduced cell death by apoptosis (programmed cell death), necrosis, or annoikis. In one embodiment abnormal cell growth is selected from uncontrolled cell proliferation, excessive cell growth or reduced programmed cell death. In particular, the condition or disease of abnormal cell growth is a cancer. Thus, in the pharmaceutical compositions, uses or methods of this invention for treating a disease or condition comprising abnormal cell growth (i.e. uncontrolled and / or rapid cell growth), the disease or condition comprising abnormal cell growth in one embodiment is a cancer.

[0779] The compounds of the invention may be useful in the treatment of metastasis and metastatic cancers. Metastasis or metastatic disease is the spread of a disease from one organ or part to another non- adjacent organ or part. The cancers which can be treated by the compounds of the invention include primary tumours (i.e. cancer cells at the originating site), local invasion (cancer cells which penetrate and infiltrate surrounding normal tissues in the local area), and metastatic (or secondary) tumours ie. tumours that have formed from malignant cells which have circulated through the bloodstream (haematogenous spread) or via lymphatics or across body cavities (trans-coelomic) to other sites and tissues in the body. In particular, the compounds of the invention may be useful in the treatment of metastasis and metastatic cancers.

[0780] In one embodiment the haematological malignancies is a leukaemia. In another embodiment the haematological malignancies is a lymphoma. In one embodiment the cancer is AML. In another embodiment the cancer is CLL.

[0781] In one embodiment the compound of the invention is for use in the prophylaxis ortreatment of leukemia, such as acute or chronic leukaemia, in particular acute myeloid leukaemia (AML), acute lymphocytic leukaemia (ALL), chronic lymphocytic leukaemia (CLL), or chronic myeloid leukemia (CML). In one embodiment the compound of the invention is for use in the prophylaxis ortreatment of lymphoma, such as acute or chronic lymphoma, in particular Burkitt lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma or difuse large B-cell lymphoma.

[0782] In one embodiment the compound of the invention is for use in the prophylaxis or treatment of acute myeloid leukaemia (AML) or acute lymphocytic leukaemia (ALL).

[0783] The cancers may be cancers which are sensitive to treatment with CBP / p300 inhibitors. The cancers may be cancers with functionally inactive or decrease expression and activity of CBP. The cancer may be cancers which are CBP / p300 wild-type. The cancer may be cancers which are mutant CBP / p300. In one embodiment the cancer has inactivating mutations in CBP / p300. In one embodiment, the cancer has CBP loss of function.

[0784] Particular cancers include hepatocellular carcinoma, melanoma, oesophageal, renal, colon, colorectal, lung e.g. NSCLC, mesothelioma or lung adenocarcinoma, breast, bladder, gastrointestinal, ovarian and prostate cancers.

[0785] Particular cancers include those with inactivated CBP / p300 (inactivating mutations, decreased expression and activity), for example, hepatocellular carcinoma, breast, lung, colorectal and neuroblastoma.

[0786] Particular cancers include those with CBP or p300 loss of function mutations. Particular cancers also include p300 mutant cancers (such as prostate, bladder, colorectal and breast cancer) and CBP mutant, p300 dependent cancers. Particular cancers include solid cancers, for example lung cancer (e.g. small cell lung cancer and non- small cell lung cancer), hepatocellular carcinoma, prostate cancer (for example castration-resistant prostate cancer, e.g. metastatic castration-resistant prostate cancer), bladder cancer, ovarian cancer, uterine cancer, breast cancer, renal cell carcinoma and colorectal cancer.

[0787] Further cancers include haematological malignancies, for example leukaemia, such as acute myeloid leukaemia, lymphoma, such as non-Hodgkin lymphoma and multiple myeloma.

[0788] The compounds can be used alone or in combination with further therapy. In one embodiment, the compounds are for use in the treatment of cancer, wherein the compounds are given as monotherapy. In another embodiment, the compounds are for use in the treatment of cancer, wherein the compounds are given as part of a combination therapy.

[0789] In one aspect, the compounds can be used alone or in combination with dexamethasone for the treatment of multiple myeloma.

[0790] In another aspect, the compounds can be used in combination with hormone therapy for the treatment of solid tumours, for example metastatic castration-resistant prostate cancer, hormone receptor positive breast cancer, ovarian cancer, cervical cancer and uterine cancer. For example, the compounds can be used in combination with antiandrogens (see Targeting the p300 / CBP Axis in Lethal Prostate Cancer, Welti et al, Cancer Discov. (2021) 11 (5): 1118-1137).

[0791] In another aspect, the compounds can be used in combination with PARP inhibitors or immune checkpoint inhibitors (for example, anti-PD1 or anti-PDL1 therapies). For example, this combination is suitable for use in the treatment of solid tumours (for example metastatic castration-resistant prostate cancer, hormone receptor positive breast cancer, ovarian cancer, cervical cancer and uterine cancer, e.g. metastatic castration-resistant prostate cancer).

[0792] In yet another aspect, the compounds can be administered in combination with KRAS inhibitors, EGFR inhibitors or androgen receptor inhibitors for the treatment of solid tumours.

[0793] Whether a particular cancer is one which is sensitive to CBP / p300 inhibitors, may be determined by a method as set out in the section headed “Methods of Diagnosis”.

[0794] A further aspect provides the use of a compound for the manufacture of a medicament for the treatment of a disease or condition as described herein, in particular cancer.

[0795] Certain cancers are resistant to treatment with particular drugs. This can be due to the type of the tumour (most common epithelial malignancies are inherently chemoresistant and prostate is relatively resistant to currently available regimens of chemotherapy or radiation therapy) or resistance can arise spontaneously as the disease progresses or as a result of treatment. In this regard, references to prostate includes prostate with resistance towards anti-androgen therapy, in particular abiraterone or enzalutamide, or castrate-resistant prostate. Similarly references to multiple myeloma includes bortezomib-insensitive multiple myeloma or refractory multiple myeloma and references to chronic myelogenous leukemia includes imitanib-insensitive chronic myelogenous leukemia and refractory chronic myelogenous leukemia. In this regard, references to breast includes breast with resistance towards anti-oestrogen therapy, in particular tamoxifen or fulvestrant.

[0796] The compounds may also be useful in the treatment of tumour growth, pathogenesis, resistance to chemo- and radio-therapy by sensitising cells to chemotherapy and as an anti-metastatic agent.

[0797] Therapeutic anticancer interventions of all types increase responses by the target tumour cells. Inhibitors of CBP / p300 represent a class of chemotherapeutics with the potential for: (i) sensitizing malignant cells to anticancer drugs and / or treatments; (ii) alleviating or reducing the incidence of resistance to anticancer drugs and / or treatments; (iii) reversing resistance to anticancer drugs and / or treatments; (iv) potentiating the activity of anticancer drugs and / or treatments; (v) delaying or preventing the onset of resistance to anticancer drugs and / or treatments.

[0798] In one embodiment the invention provides a compound for use in the treatment of a disease or condition which is mediated by p300. In a further embodiment the invention provides a compound for use in the treatment of a disease or condition which is mediated by CBP. In a further embodiment the invention provides a compound for use in the treatment of a disease or condition which is mediated by CBP and p300. In a further embodiment the disease or condition which is mediated by CBP / p300 is a cancer which is characterised by reduced expression and / or activity of CBP / p300.

[0799] A further aspect provides the use of a compound for the manufacture of a medicament for the treatment of a disease or condition as described herein, in particular cancer.

[0800] In one embodiment there is provided a compound for use in the prophylaxis or treatment of a disease or condition mediated by CBP / p300.

[0801] In one embodiment there is provided a pharmaceutical composition comprising an effective amount of at least one compound as defined. In a further aspect of the present invention, there is provided a compound as defined herein.

[0802] In one embodiment there is provided a method for the prophylaxis or treatment of cancer comprising the steps of administering to a mammal a medicament comprising at least one compound as defined herein.

[0803] In one embodiment, there is provided a compound of formula (I) for use in the treatment of a disease or condition as discussed hereinabove, wherein the compound of formula (I) is not a compound listed under the ‘Disclaimer’ section. For example, said disease or condition can be cancer. Preferably, said disease or condition is mediated by P300, for example cancer mediated by P300.

[0804] METHODS OF DIAGNOSIS

[0805] Priorto administration of a compound of the formula (I), a patient may be screened to determine whether a disease or condition from which the patient is or may be suffering is one which would be susceptible to treatment with a compound which inhibits CBP / p300. The term ‘patient’ includes human and veterinary subjects such as primates, in particular human patients. For example, a biological sample taken from a patient may be analysed to determine whether a condition or disease, such as cancer, that the patient is or may be suffering from is one which is characterised by a genetic abnormality or abnormal protein expression which leads to decreased activity of CBP / p300 or is driven by a cancer associated transcription factor or biochemical pathway dependent on CBP / p300.

[0806] Examples of such abnormalities that result in inactivation or sensitisation of CBP / p300 include cytogenetic aberrations or presence of mutant variants which decrease CBP / p300 function and activity. Cancers which are dependent on the coactivator activity of CBP / p300 such as cancers driven by the nuclear hormone receptors (for example, androgen and oestrogen receptors) may be particularly sensitive to inhibitors of CBP / p300. Cancers with dysregulated transcription factors such as MYC may also be sensitised and have been detected in cell lines and primary tumours but not limited to AML and multiple myeloma.

[0807] The diagnostic tests and screens are typically conducted on a biological sample (i.e. body tissue or body fluids) selected from tumour biopsy samples, blood samples (isolation and enrichment of shed tumour cells), cerebrospinal fluid, plasma, serum, saliva, stool biopsies, sputum, chromosome analysis, pleural fluid, peritoneal fluid, buccal smears, skin biopsy or urine.

[0808] Methods of identification and analysis of cytogenetic aberration, genetic amplification, mutations and up-regulation of proteins are known to a person skilled in the art. Screening methods could include, but are not limited to, standard methods such as DNA sequence analysis by conventional Sanger or next- generation sequencing methods, reverse-transcriptase polymerase chain reaction (RT-PCR), RNA sequencing (RNAseq), nanostring hybridisation proximity RNA nCounter assays, or in-situ hybridization such as fluorescence in situ hybridization (FISH) or allele-specific polymerase chain reaction (PCR). Newer, next-generation sequencing (NGS) technologies, such as massively parallel sequencing allow for whole exome sequencing or whole genome sequencing.

[0809] In screening by RT-PCR, the level of mRNA in the tumour is assessed by creating a cDNA copy of the mRNA followed by amplification of the cDNA by PCR. Methods of PCR amplification, the selection of primers, and conditions for amplification, are known to a person skilled in the art. Nucleic acid manipulations and PCR are carried out by standard methods, as described for example in Ausubel, F.M. et al., eds. (2004) Current Protocols in Molecular Biology, John Wiley & Sons Inc., or Innis, M.A. et al., eds. (1990) PCR Protocols: a guide to methods and applications, Academic Press, San Diego. Reactions and manipulations involving nucleic acid techniques are also described in Sambrook et al., (2001), 3rdEd, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press. Alternatively a commercially available kit for RT-PCR (for example Roche Molecular Biochemicals) may be used, or methodology as set forth in United States patents 4,666,828; 4,683,202; 4,801 ,531 ; 5,192,659, 5,272,057, 5,882,864, and 6,218,529 and incorporated herein by reference. An example of an in-situ hybridisation technique for assessing mRNA expression would be fluorescence in-situ hybridisation (FISH) (see Angerer (1987) Meth. Enzymol., 152: 649). Generally, in situ hybridization comprises the following major steps: (1) fixation of tissue to be analyzed; (2) prehybridization treatment of the sample to increase accessibility of target nucleic acid, and to reduce nonspecific binding; (3) hybridization of the mixture of nucleic acids to the nucleic acid in the biological structure or tissue; (4) post-hybridization washes to remove nucleic acid fragments not bound in the hybridization, and (5) detection of the hybridized nucleic acid fragments. The probes used in such applications are typically labelled, for example, with radioisotopes or fluorescent reporters. Certain probes are sufficiently long, for example, from about 50, 100, or 200 nucleotides to about 1000 or more nucleotides, to enable specific hybridization with the target nucleic acid(s) under stringent conditions. Standard methods for carrying out FISH are described in Ausubel, F.M. et al., eds. (2004) Current Protocols in Molecular Biology, John Wiley & Sons Inc and Fluorescence In Situ Hybridization: Technical Overview by John M. S. Bartlett in Molecular Diagnosis of Cancer, Methods and Protocols, 2nd ed.; ISBN: 1-59259-760-2; March 2004, pps. 077-088; Series: Methods in Molecular Medicine.

[0810] Methods for gene expression profiling are described by (DePrimo et al. (2003), BMC Cancer, 3:3). Briefly, the protocol is as follows: double-stranded cDNA is synthesized from total RNA using a (dT)24 oligomer for priming first-strand cDNA synthesis from polyadenylated mRNA, followed by second strand cDNA synthesis with random hexamer primers. The double-stranded cDNA is used as a template for in vitro transcription of cRNA using biotinylated ribonucleotides. cRNA is chemically fragmented according to protocols described by Affymetrix (Santa Clara, CA, USA), and then hybridized overnight to gene-specific oligonucleotide probes on Human Genome Arrays. Alternatively, single nucleotide polymorphism (SNP) arrays, a type of DNA microarray, can be used to detect polymorphisms within a population.

[0811] Alternatively, the protein products expressed from the mRNAs may be assayed by immunohistochemistry of tumour samples, solid phase immunoassay with microtitre plates, Western blotting, 2-dimensional SDS-polyacrylamide gel electrophoresis, ELISA, flow cytometry and other methods known in the art for detection of specific proteins e.g. capillary electrophoresis. Detection methods would include the use of site-specific antibodies. The skilled person will recognize that all such well-known techniques can be used for detection of upregulation of CBP / p300 levels, detection of CBP / p300 or CBP / p300 variants or mutants, or loss of negative regulators of CBP / p300 in the present case.

[0812] Abnormal levels of proteins such as p300 and CBP can be measured using standard protein assays, for example, those assays described herein. Elevated levels could also be detected in a tissue sample, for example, a tumour tissue by measuring the protein levels with an assay such as that from Chemicon International. The protein of interest would be immunoprecipitated from the sample lysate and its levels measured. Assay methods also include the use of markers.

[0813] In other words, p300 and CBP levels or mutant p300 and CBP can be measured by tumour biopsy.

[0814] Methods for assessing gene copy changes include techniques commonly used in cytogenetic laboratories such as MLPA (Multiplex Ligation-dependent Probe Amplification) a multiplex PCR method detecting abnormal copy numbers, or other PCR techniques which can detect gene amplification, gain and deletion. Ex-functional assays could also be utilised where appropriate, for example measurement of circulating tumour cells in a cancer patient, to assess the response to challenge with a CBP / p300 inhibitor.

[0815] Therefore all of these techniques could also be used to identify tumours particularly suitable for treatment with the compounds of the invention.

[0816] Therefore in a further aspect of the invention includes use of a compound according to the invention for the manufacture of a medicament for the treatment or prophylaxis of a disease state or condition in a patient who has been screened and has been determined as suffering from, or being at risk of suffering from, a disease or condition which would be susceptible to treatment with a CBP / p300 inhibitor.

[0817] Another aspect of the invention includes a compound of the invention for use in the prophylaxis or treatment of cancer in a patient selected from a sub-population possessing amplification of CBP / p300.

[0818] Another aspect of the invention includes a compound of the invention for use in the prophylaxis or treatment of cancer in a patient possessing loss of a CBP / p300 negative regulator.

[0819] Another aspect of the invention includes a compound of the invention for use in the prophylaxis or treatment of cancer in a patient possessing cancer associated transcription factors.

[0820] MRI determination of vessel normalization (e.g. using MRI gradient echo, spin echo, and contrast enhancement to measure blood volume, relative vessel size, and vascular permeability) in combination with circulating biomarkers may also be used to identify patients suitable for treatment with a compound of the invention.

[0821] Thus a further aspect of the invention is a method for the diagnosis and treatment of a disease state or condition mediated by CBP / p300, which method comprises (i) screening a patient to determine whether a disease or condition from which the patient is or may be suffering is one which would be susceptible to treatment with CBP / p300 inhibitor; and (ii) where it is indicated that the disease or condition from which the patient is thus susceptible, thereafter administering to the patient a compound of formula (I) and sub-groups or examples thereof as defined herein.

[0822] Advantages of Compounds of the Invention

[0823] The compounds of the formula (I) have a number of advantages over prior art compounds. Compounds of the invention may have particular advantage in one or more of the following aspects:

[0824] (i) Superior potency;

[0825] (ii) Superior in vivo efficacy

[0826] (iii) Superior PK;

[0827] (iv) Superior metabolic stability;

[0828] (v) Superior oral bioavailabilty;

[0829] (vi) Superior physiochemical properties; and / or

[0830] (vii) Superior safety profile or therapeutic index (Tl).

[0831] Superior potency and in vivo efficacy The compounds of the formula (I) have increased affinity for CBP / p300 and in particular increased cell potency against cell lines known to be sensitive to CBP / p300 antagonists.

[0832] Enhanced target engagement is a highly desirable property in a pharmaceutical compound as it allows for a reduced dosage of drug and a good separation (‘therapeutic window’) between CBP / p300 activity and toxic effects.

[0833] The compounds of the formula (I) have improved cell potency and / or improved selectivity for CBP / p300 cell lines. As a result of increased potency against CBP / p300, compounds of the invention may have increased in vivo efficacy in cancer cell lines and in vivo models.

[0834] Superior PK and metabolic stability

[0835] The compounds of the formula (I) may have advantageous ADMET properties for example better metabolic stability (for example as determined with mouse liver microsomes), a better P450 profile, short half-life and / or beneficial clearance (e.g. low or high clearance). It has also been found that many compounds of the formula (I) have an improved PK profile.

[0836] These features could confer the advantage of having more drug available in the systemic circulation to reach the appropriate site of action to exert its therapeutic effect. Increased drug concentrations to exert pharmacological action in tumours potentially leads to improved efficacy which thereby allows reduced dosages to be administered. Thus, the compounds of formula (I) should exhibit reduced dosage requirements and should be more readily formulated and administered.

[0837] This results in a good separation (‘therapeutic window’) between p300 activity and toxic effects. Many compounds of the formula (I) have a reduction in Cmax required for efficacy (due to better p300 potency and / or PK).

[0838] Superior oral bioavailability

[0839] Potentially the compounds of the invention have physiochemical properties suitable for oral exposure (oral exposure or AUC). In particular, compounds of the formula (I) may exhibit improved oral bioavailability or improved reproducibility of oral absorption. Oral bioavailability can be defined as the ratio (F) of the plasma exposure of a compound when dosed by the oral route to the plasma exposure of the compound when dosed by the intravenous (i.v.) route, expressed as a percentage.

[0840] Compounds having an oral bioavailability (F value) of greaterthan 10%, 20% or 30%, more particularly greater than 40%, are particularly advantageous in that they may be administered orally rather than, or as well as, by parenteral administration.

[0841] Superior physiochemical properties

[0842] The compounds of the formula (I) may have advantageous physiochemical properties in particular chemical stability in acidic conditions and reduced lipophilicity.

[0843] Lipophilicity can be measured using a partition-coefficient (logP) or a distribution-coefficient (logD). The partition coefficient is a ratio of concentrations of un-ionized compound between two immiscible phases (n-octanol and water) at equilibrium whereas the distribution coefficient is the ratio of the sum of the concentrations of all forms of the compound (ionized plus un-ionized) in each of the two phases. High lipophilicity is associated with poor drug like properties such us low aqueous solubility, poor pharmacokinetics properties (low oral bioavailability), undesired drug metabolism and high promiscuity. Compounds with optimal lipophilicity might have greater chances of success in drug development. However redued logP (or calculated logP, clogP) can be challenging to achieve whilst retaining an acceptable level of potency for inhibition of protein-protein interactions (PPIs) due to the lipophilic nature of the targets involved.

[0844] Superior safety profile or therapeutic index (Tl)

[0845] In the late 1990s a number of drugs, approved by the US FDA, had to be withdrawn from sale in the US when it was discovered they were implicated in deaths caused by heart malfunction. It was subsequently found that a side effect of these drugs was the development of arrhythmias caused by the blocking of hERG channels in heart cells. The hERG channel is one of a family of potassium ion channels the first member of which was identified in the late 1980s in a mutant Drosophila melanogaster fruitfly (see Jan, L.Y. and Jan, Y.N. (1990). A Superfamily of Ion Channels. Nature, 345(6277):672). The biophysical properties of the hERG potassium ion channel are described in Sanguinetti, M.C., Jiang, C., Curran, M.E., and Keating, M.T. (1995). A Mechanistic Link Between an Inherited and an Acquired Cardiac Arrhythmia: HERG encodes the Ikr potassium channel. Cell, 81 :299-307, and Trudeau, M.C., Warmke, J.W., Ganetzky, B., and Robertson, G.A. (1995). HERG, a Human Inward Rectifier in the Voltage-Gated Potassium Channel Family. Science, 269:92-95. Therefore, elimination of hERG blocking activity remains an important consideration in the development of any new drug.

[0846] Compounds that have reduced hERG activity and / or a good separation between activity and hERG activity have a greater ‘therapeutic window’ or ‘therapeutic index’. One method for measurement of hERG activity is the patch clamp electrophysiology method. Alternative methods for measurement of functional hERG activity include hERG binding assays, which can use commercially available membranes isolated from cells stably expressing the hERG channel or commercially available cell lines expressing the hERG channel.

[0847] Compounds can also have an improved Cardiac Safety Index (CSI) [CSI = hERG IC50 I Cmax(unbound)] (Shultz et al, J. Med. Chem., 2011 ; Redfern et al, Cardiovasc. Res., 2003). This can be due to an increase in hERG IC50 or a reduction in Cmax required for efficacy (due to better potency and / or PK). Particular compounds may show CV advantage in vivo.

[0848] Particular compounds have reduced hERG ion channel blocking activity. Compounds can have mean IC50values against hERG that are greater than 30 times, or greater than 40 times, or greater than 50 times the IC50values of the compounds in cellular proliferation assays.

[0849] Certain compounds of the invention may have the advantage of not causing significant reduction in platelets or other haematological alterations on administration.

[0850] PHARMACEUTICAL FORMULATIONS

[0851] While it is possible for the active compound to be administered alone, it is generally presented as a pharmaceutical composition (e.g. formulation). Thus, the present invention further provides pharmaceutical compositions, as defined above, and methods of making a pharmaceutical composition comprising (e.g admixing) at least one compound of formula (I) (and sub-groups thereof as defined herein), together with one or more pharmaceutically acceptable excipients and optionally other therapeutic or prophylactic agents as described herein.

[0852] The pharmaceutically acceptable excipient(s) can be selected from, for example, carriers (e.g. a solid, liquid or semi-solid carrier), adjuvants, diluents, fillers or bulking agents, granulating agents, coating agents, release-controlling agents, binding agents, disintegrants, lubricating agents, preservatives, antioxidants, buffering agents, suspending agents, thickening agents, flavouring agents, sweeteners, taste masking agents, stabilisers or any other excipients conventionally used in pharmaceutical compositions. Examples of excipients for various types of pharmaceutical compositions are set out in more detail below.

[0853] The term “pharmaceutically acceptable” as used herein pertains to compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of a subject (e.g. a human subject) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. Each excipient must also be “acceptable” in the sense of being compatible with the other ingredients of the formulation.

[0854] Pharmaceutical compositions containing compounds of the formula (I) can be formulated in accordance with known techniques, see for example, Remington’s Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, USA.

[0855] The pharmaceutical compositions can be in any form suitable for oral, parenteral, topical, intranasal, intrabronchial, sublingual, ophthalmic, otic, rectal, intra-vaginal, or transdermal administration. Where the compositions are intended for parenteral administration, they can be formulated for intravenous, intramuscular, intraperitoneal, subcutaneous administration or for direct delivery into a target organ or tissue by injection, infusion or other means of delivery. The delivery can be by bolus injection, short- term infusion or longer term infusion and can be via passive delivery or through the utilisation of a suitable infusion pump or syringe driver.

[0856] Pharmaceutical formulations adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats, co-solvents, surface active agents, organic solvent mixtures, cyclodextrin complexation agents, emulsifying agents (for forming and stabilizing emulsion formulations), liposome components for forming liposomes, gellable polymers for forming polymeric gels, lyophilisation protectants and combinations of agents for, inter alia, stabilising the active ingredient in a soluble form and rendering the formulation isotonic with the blood of the intended recipient. Pharmaceutical formulations for parenteral administration may also take the form of aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents (R. G. Strickly, Solubilizing Excipients in oral and injectable formulations, Pharmaceutical Research, Vol 21 (2) 2004, p 201-230).

[0857] The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules, vials and prefilled syringes, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. In one embodiment, the formulation is provided as an active pharmaceutical ingredient in a bottle for subsequent reconstitution using an appropriate diluent.

[0858] The pharmaceutical formulation can be prepared by lyophilising a compound of formula (I), or sub- groups thereof. Lyophilisation refers to the procedure of freeze-drying a composition. Freeze-drying and lyophilisation are therefore used herein as synonyms.

[0859] Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.

[0860] Pharmaceutical compositions of the present invention for parenteral injection can also comprise pharmaceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as sunflower oil, safflower oil, corn oil or olive oil), and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of thickening materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0861] The compositions of the present invention may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include agents to adjust tonicity such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.

[0862] In one typical embodiment of the invention, the pharmaceutical composition is in a form suitable for i.v. administration, for example by injection or infusion. For intravenous administration, the solution can be dosed as is, or can be injected into an infusion bag (containing a pharmaceutically acceptable excipient, such as 0.9% saline or 5% dextrose), before administration.

[0863] In another typical embodiment, the pharmaceutical composition is in a form suitable for sub-cutaneous (s.c.) administration.

[0864] Pharmaceutical dosage forms suitable for oral administration include tablets (coated or uncoated), capsules (hard or soft shell), caplets, pills, lozenges, syrups, solutions, powders, granules, elixirs and suspensions, sublingual tablets, wafers or patches such as buccal patches.

[0865] Thus, tablet compositions can contain a unit dosage of active compound together with an inert diluent or carrier such as a sugar or sugar alcohol, eg; lactose, sucrose, sorbitol or mannitol; and / or a non- sugar derived diluent such as sodium carbonate, calcium phosphate, calcium carbonate, or a cellulose or derivative thereof such as microcrystalline cellulose (MCC), methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, and starches such as corn starch. Tablets may also contain such standard ingredients as binding and granulating agents such as polyvinylpyrrolidone, disintegrants (e.g. swellable crosslinked polymers such as crosslinked carboxymethylcellulose), lubricating agents (e.g. stearates), preservatives (e.g. parabens), antioxidants (e.g. BHT), buffering agents (for example phosphate or citrate buffers), and effervescent agents such as citrate / bicarbonate mixtures. Such excipients are well known and do not need to be discussed in detail here.

[0866] Tablets may be designed to release the drug either upon contact with stomach fluids (immediate release tablets) or to release in a controlled manner (controlled release tablets) over a prolonged period of time or with a specific region of the Gl tract.

[0867] Capsule formulations may be of the hard gelatin or soft gelatin variety and can contain the active component in solid, semi-solid, or liquid form. Gelatin capsules can be formed from animal gelatin or synthetic or plant derived equivalents thereof.

[0868] The solid dosage forms (eg; tablets, capsules etc.) can be coated or un-coated. Coatings may act either as a protective film (e.g. a polymer, wax or varnish) or as a mechanism for controlling drug release or for aesthetic or identification purposes. The coating (e.g. a Eudragit ™ type polymer) can be designed to release the active component at a desired location within the gastro-intestinal tract. Thus, the coating can be selected so as to degrade under certain pH conditions within the gastrointestinal tract, thereby selectively release the compound in the stomach or in the ileum, duodenum, jejenum or colon.

[0869] Instead of, or in addition to, a coating, the drug can be presented in a solid matrix comprising a release controlling agent, for example a release delaying agent which may be adapted to release the compound in a controlled manner in the gastrointestinal tract. Alternatively the drug can be presented in a polymer coating e.g. a polymethacrylate polymer coating, which may be adapted to selectively release the compound under conditions of varying acidity or alkalinity in the gastrointestinal tract. Alternatively, the matrix material or release retarding coating can take the form of an erodible polymer (e.g. a maleic anhydride polymer) which is substantially continuously eroded as the dosage form passes through the gastrointestinal tract. In another alternative, the coating can be designed to disintegrate under microbial action in the gut. As a further alternative, the active compound can be formulated in a delivery system that provides osmotic control of the release of the compound. Osmotic release and other delayed release or sustained release formulations (for example formulations based on ion exchange resins) may be prepared in accordance with methods well known to those skilled in the art.

[0870] The compound of formula (I) may be formulated with a carrier and administered in the form of nanoparticles, the increased surface area of the nanoparticles assisting their absorption. In addition, nanoparticles offer the possibility of direct penetration into the cell. Nanoparticle drug delivery systems are described in “Nanoparticle Technology for Drug Delivery”, edited by Ram B Gupta and Uday B. Kompella, Informa Healthcare, ISBN 9781574448573, published 13thMarch 2006. Nanoparticles for drug delivery are also described in J. Control. Release, 2003, 91 (1 -2), 167-172, and in Sinha et al., Mol. Cancer Ther. August 1 , (2006) 5, 1909. The pharmaceutical compositions typically comprise from approximately 1 % (w / w) to approximately 95% active ingredient and from 99% (w / w) to 5% (w / w) of a pharmaceutically acceptable excipient or combination of excipients. Typically, the compositions comprise from approximately 20% (w / w) to approximately 90%,% (w / w) active ingredient and from 80% (w / w) to 10% of a pharmaceutically acceptable excipient or combination of excipients. The pharmaceutical compositions comprise from approximately 1 % to approximately 95%, typically from approximately 20% to approximately 90%, active ingredient. Pharmaceutical compositions according to the invention may be, for example, in unit dose form, such as in the form of ampoules, vials, suppositories, pre-filled syringes, dragees, tablets or capsules.

[0871] The pharmaceutically acceptable excipient(s) can be selected according to the desired physical form of the formulation and can, for example, be selected from diluents (e.g solid diluents such as fillers or bulking agents; and liquid diluents such as solvents and co-solvents), disintegrants, buffering agents, lubricants, flow aids, release controlling (e.g. release retarding or delaying polymers or waxes) agents, binders, granulating agents, pigments, plasticizers, antioxidants, preservatives, flavouring agents, taste masking agents, tonicity adjusting agents and coating agents.

[0872] The skilled person will have the expertise to select the appropriate amounts of ingredients for use in the formulations. For example tablets and capsules typically contain 0-20% disintegrants, 0-5% lubricants, 0-5% flow aids and / or 0-99% (w / w) fillers / or bulking agents (depending on drug dose). They may also contain 0-10% (w / w) polymer binders, 0-5% (w / w) antioxidants, 0-5% (w / w) pigments. Slow release tablets would in addition contain 0-99% (w / w) polymers (depending on dose). The film coats of the tablet or capsule typically contain 0-10% (w / w) release-controlling (e.g. delaying) polymers, 0-3% (w / w) pigments, and / or 0-2% (w / w) plasticizers.

[0873] Parenteral formulations typically contain 0-20% (w / w) buffers, 0-50% (w / w) cosolvents, and / or 0-99% (w / w) Water for Injection (WFI) (depending on dose and if freeze dried). Formulations for intramuscular depots may also contain 0-99% (w / w) oils.

[0874] Pharmaceutical compositions for oral administration can be obtained by combining the active ingredient with solid carriers, if desired granulating a resulting mixture, and processing the mixture, if desired or necessary, after the addition of appropriate excipients, into tablets, dragee cores or capsules. It is also possible for them to be incorporated into a polymer or waxy matrix that allow the active ingredients to diffuse or be released in measured amounts.

[0875] The compounds of the invention can also be formulated as solid dispersions. Solid dispersions are homogeneous extremely fine disperse phases of two or more solids. Solid solutions (molecularly disperse systems), one type of solid dispersion, are well known for use in pharmaceutical technology (see Chiou and Riegelman, J. Pharm. Sci., 60, 1281-1300 (1971)) and are useful in increasing dissolution rates and increasing the bioavailability of poorly water-soluble drugs.

[0876] This invention also provides solid dosage forms comprising the solid solution described herein. Solid dosage forms include tablets, capsules, chewable tablets and dispersible or effervescent tablets. Known excipients can be blended with the solid solution to provide the desired dosage form. For example, a capsule can contain the solid solution blended with (a) a disintegrant and a lubricant, or (b) a disintegrant, a lubricant and a surfactant. In addition a capsule can contain a bulking agent, such as lactose or microcrystalline cellulose. A tablet can contain the solid solution blended with at least one disintegrant, a lubricant, a surfactant, a bulking agent and a glidant. A chewable tablet can contain the solid solution blended with a bulking agent, a lubricant, and if desired an additional sweetening agent (such as an artificial sweetener), and suitable flavours. Solid solutions may also be formed by spraying solutions of drug and a suitable polymer onto the surface of inert carriers such as sugar beads (‘non- pareils’). These beads can subsequently be filled into capsules or compressed into tablets.

[0877] The pharmaceutical formulations may be presented to a patient in “patient packs” containing an entire course of treatment in a single package, usually a blister pack. Patient packs have an advantage over traditional prescriptions, where a pharmacist divides a patient’s supply of a pharmaceutical from a bulk supply, in that the patient always has access to the package insert contained in the patient pack, normally missing in patient prescriptions. The inclusion of a package insert has been shown to improve patient compliance with the physician’s instructions.

[0878] Compositions for topical use and nasal delivery include ointments, creams, sprays, patches, gels, liquid drops and inserts (for example intraocular inserts). Such compositions can be formulated in accordance with known methods.

[0879] Examples of formulations for rectal or intra-vaginal administration include pessaries and suppositories which may be, for example, formed from a shaped moldable or waxy material containing the active compound. Solutions of the active compound may also be used for rectal administration.

[0880] Compositions for administration by inhalation may take the form of inhalable powder compositions or liquid or powder sprays, and can be administrated in standard form using powder inhaler devices or aerosol dispensing devices. Such devices are well known. For administration by inhalation, the powdered formulations typically comprise the active compound together with an inert solid powdered diluent such as lactose.

[0881] The compounds of the formula (I) will generally be presented in unit dosage form and, as such, will typically contain sufficient compound to provide a desired level of biological activity. For example, a formulation may contain from 1 nanogram to 2 grams of active ingredient, e.g. from 1 nanogram to 2 milligrams of active ingredient. Within these ranges, particular sub-ranges of compound are 0.1 milligrams to 2 grams of active ingredient (more usually from 10 milligrams to 1 gram, e.g. 50 milligrams to 500 milligrams), or 1 microgram to 20 milligrams (for example 1 microgram to 10 milligrams, e.g. 0.1 milligrams to 2 milligrams of active ingredient).

[0882] For oral compositions, a unit dosage form may contain from 1 milligram to 2 grams, more typically 10 milligrams to 1 gram, for example 50 milligrams to 1 gram, e.g. 100 miligrams to 1 gram, of active compound.

[0883] The active compound will be administered to a patient in need thereof (for example a human or animal patient) in an amount sufficient to achieve the desired therapeutic effect. Degrader molecules could be made from compounds. This could be achieved, for example, by attachment of an E3 ligase ligand via a linker. These new molecules would enable degradation of one or both of p300 and CBP. Such molecules could be used as treatments described herein.

[0884] METHODS OF TREATMENT

[0885] The compounds of the formula (I) and sub-groups as defined herein may be useful in the prophylaxis or treatment of a range of disease states or conditions mediated by CBP / p300. Examples of such disease states and conditions are set out above.

[0886] The compounds are generally administered to a subject in need of such administration, for example a human or animal patient, typically a human.

[0887] The compounds will typically be administered in amounts that are therapeutically or prophylactically useful and which generally are non-toxic. However, in certain situations (for example in the case of life threatening diseases), the benefits of administering a compound of the formula (I) may outweigh the disadvantages of any toxic effects or side effects, in which case it may be considered desirable to administer compounds in amounts that are associated with a degree of toxicity.

[0888] The compounds may be administered over a prolonged term to maintain beneficial therapeutic effects or may be administered for a short period only. Alternatively they may be administered in a continuous manner or in a manner that provides intermittent dosing (e.g. a pulsatile manner).

[0889] A typical daily dose of the compound of formula (I) can be in the range from 100 picograms to 100 milligrams per kilogram of body weight. The compounds of the invention can also be administered by bolus or continuous infusion.

[0890] The quantity of compound administered and the type of composition used will be commensurate with the nature of the disease or physiological condition being treated and will be at the discretion of the physician.

[0891] It may be beneficial to use a compound of the invention as a single agent or to combine the compound of the invention with another agent which acts via a different mechanism to regulate cell growth thus treating two of the characteristic features of cancer development. Combination experiments can be performed, for example, as described in Chou TC, Talalay P. Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regulat 1984;22: 27-55.

[0892] The compounds as defined herein can be administered as the sole therapeutic agent or they can be administered in combination therapy with one of more other compounds (or therapies) for treatment of a particular disease state, for example a neoplastic disease such as a cancer as hereinbefore defined.

[0893] In one embodiment the combination therapy comprises a compound of formula I and one or more other anticancer compounds (or therapies) for treatment of cancer. For the treatment of the above conditions, the compounds of the invention may be advantageously employed in combination with one or more other medicinal agents, more particularly, with other anti-cancer agents or adjuvants (supporting agents in the therapy) in cancer therapy. Examples of cytostatic and cytotoxic agents or other therapeutic agents or treatments that may be administered together (whether concurrently or at different time intervals) with the compounds of the formula (I) include but are not limited to:

[0894] I. Platinum compounds;

[0895] II. Taxane compounds;

[0896] III. Topoisomerase I inhibitors;

[0897] IV. Topoisomerase II inhibitors;

[0898] V. Vinca alkaloids;

[0899] VI. Nucleoside derivatives;

[0900] VII. Antimetabolites;

[0901] VIII. Alkylating agents;

[0902] IX. Other cytotoxics;

[0903] X. Anthracyclines, anthracenediones and related drugs;

[0904] XI. Epothilones;

[0905] XII. Antifolates;

[0906] XIII. Cytotoxic antibiotics;

[0907] XIV. Tubulin-binding agents;

[0908] XV. Kinase inhibitors and modulators

[0909] XVI. Agents that modulate the activity of regulators of cell death

[0910] XVII. Agents that modulate the activity of DNA damage repair regulators

[0911] XVIII. Agents that target proteins in epigenetic complexes

[0912] XIX. Agents that target RAS isoforms

[0913] XX. Phosphatase inhibitors and modulators

[0914] XXI. Other targeted agents

[0915] XXII. Therapeutic Antibodies, antibody derivatives and "antibody-like" therapeutic proteins or other therapeutic proteins and related agents;

[0916] XXIII. Protein proximity inducers and similar bifunctional molecules;

[0917] XXIV. Estrogen receptor antagonists or selective estrogen receptor modulators (SERMs) or inhibitors of estrogen synthesis;

[0918] XXV. Aromatase inhibitors and related drugs;

[0919] XXVI. Antiandrogens (i.e. androgen receptor antagonists) and related agents;

[0920] XXVII. Hormones and analogues thereof;

[0921] XXVIII. Steroids ;

[0922] XXIX. Glucocorticoids;

[0923] XXX. Differentiating agents;

[0924] XXXI. Photodynamic drugs;

[0925] XXXII. Marine organism-derived anticancer agents;

[0926] XXXIII. Radiolabelled drugs for radioimmunotherapy;

[0927] XXXIV. Recombinant interferons and interleukins;

[0928] XXXV. Selective immunoresponse modulators; XXXVI. Therapeutic Vaccines;

[0929] XXXVII. Cytokine-activating agents;

[0930] XXXVIII. Cytokine-conjugates;

[0931] XXXIX. Arsenic trioxide;

[0932] XL. Inhibitors of G-protein coupled receptors (GPCRs)

[0933] XLI. Enzymes;

[0934] XLII. Agonists of Death receptor;

[0935] XLIII. Oncolytic viruses and virotherapies;

[0936] XLIV. Gene therapies;

[0937] XLV. Cell therapies;

[0938] XLVI. Gene modifiers or editors;

[0939] XLVII. RNA or DNA therapeutics or RNA-targeting therapeutics;

[0940] XLVIII. Radiotherapy for radical, palliative or prophylactic purposes (or, for adjuvant or neoadjuvant purposes);

[0941] XLIX. Microbial-based therapies; and / or

[0942] L. Prophylactic agents (adjuncts); i.e. agents that reduce or alleviate some of the side effects associated with chemotherapy agents.

[0943] In one embodiment the combination therapy comprises a compound of formula I and one or more other anticancer compounds (or therapies) fortreatment of cancer optionally in combination with radiotherapy and / or prophylactic agents. In one embodiment the combination therapy comprises a compound of formula I in combination with radiotherapy and / or prophylactic agents.

[0944] Particular examples of anti-cancer agents or adjuvants (or salts thereof), include but are not limited to any of the agents selected from groups (I) - (L), below:

[0945] I. Platinum compounds, for example cisplatin (optionally combined with amifostine), carboplatin, oxaliplatin, dicycloplatin, heptaplatin, lobaplatin, nedaplatin, satraplatin or triplatin tetranitrate, in particular cisplatin, carboplatin, or oxaliplatin;

[0946] II. Taxane compounds, for example paclitaxel, paclitaxel protein bound particles (Abraxane™), docetaxel, cabazitaxel, larotaxel; ortataxel, tesetaxel, or simotaxel, in particular paclitaxel, paclitaxel protein bound particles (Abraxane™), or docetaxel;

[0947] III. Topoisomerase I inhibitors, for example camptothecin compounds, for example camptothecin, irinotecan (CPT11), SN-38, topotecan, bryostatin, callystatin, nogitecan, belotecan, exatecan, rubitecan or lurtotecan, in particular camptothecin, irinotecan or topotecan;

[0948] IV. Topoisomerase II inhibitors, for example anti-tumour epipodophyllotoxins or podophyllotoxin derivatives for example etoposide, teniposide, sobuzoxane, edotecarin, amonafide, amrubicin or pixantrone, in particular etoposide or teniposide;

[0949] V. Vinca alkaloids, for example vinblastine, vincristine, liposomal vincristine (Onco-TCS), vinorelbine, vindesine, vinflunine, vinvesir, eribulin, or thaliblastine; in particular vinblastine, vincristine or vinorelbine; VI. Nucleoside derivatives, for example 5-fluorouracil (5-FU, optionally in combination with leucovorin, e.g. LV5FU2), gemcitabine, capecitabine, tegafur (optionally in combination with uracil known as UFT, or in combination with gimeracil and oteracil potassium known as TS-1 or S1), cladribine, cytarabine (Ara-C, cytosine arabinoside), fludarabine, clofarabine, nelarabine; forodesine, doxifluridine, galocitabine, sapacitabine, emitefur, or troxacitabine;

[0950] VII. Antimetabolites, for example clofarabine, aminopterin, or methotrexate, azacitidine, cytarabine, floxuridine, pentostatin, thioguanine, thiopurine, 6-mercaptopurine, hydroxyurea (hydroxycarbamide) or trifluridine (optionally in combination with tipiracil);

[0951] VIII. Alkylating agents, such as nitrogen mustards or nitrosourea, for example cyclophosphamide, chlorambucil, carmustine (BCNU), ambamustine, bendamustine, thiotepa, melphalan, treosulfan, lomustine (CCNU), busulfan.dacarbazine, estramustine, fotemustine, ifosfamide (optionally in combination with mesna), pipobroman, procarbazine, streptozocin, temozolomide, uracil, mechlorethamine, mechlorethamine oxide hydrochloride, methylcyclohexylchloroethylnitrosurea, nimustine (ACNU), prednimustine, meclorethamine, etoglucid; streptozotocin, irofulven, mitolactol, glufosfamide, evofosfamide, ethylenimines or methylamelamines including altretamine, triethylenemelamine, trimethylolomelamine, triethylenephosphoramide, triethylenethiophosphoramide, or trimemylolomelamine;

[0952] IX. Other cytotoxics, such as dolastatin, eleutherobin, pancratistatin, sarcodictyin A, or spongistatin;

[0953] X. Anthracyclines, anthracenediones and related drugs, for example daunorubicin, doxorubicin (optionally in combination with dexrazoxane), liposomal formulations of doxorubicin (eg. Caelyx™, Myocet™, Doxil™), idarubicin, mitoxantrone, epirubicin, amsacrine, or valrubicin;

[0954] XI. Epothilones, for example ixabepilone, patupilone, BMS-310705, epothilone A, epothilone B, desoxyepothilone B (also known as epothilone D or KOS-862), aza-epothilone B (also known as BMS-247550), aulimalide, isolaulimalide, or luetherobin;

[0955] XII. Antifolates, for example methotrexate, pemetrexed disodium, raltitrexed, pralatrexate, edatrexate or trimetrexate;

[0956] XIII. Cytotoxic antibiotics, for example actinomycin D, bleomycin, mitomycin C, dactinomycin, carminomycin, daunomycin, levamisole, plicamycin, mithramycin, aclarubicin, pirarubicin, anthramycin, azaserine, cactinomycin, calicheamicin, carabicin, carzinophilin, chromomycins, detorubicin, esorubicin, esperamicins, geldanamycin.marcellomycin, olivomycins, peplomycin, puromycin, quelamycin, rebeccamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, dynemicin including dynemicin A, centanamycin (CC-1065), including its adozelesin, carzelesin, and bizelesin synthetic analogue, duocarmycin, including the synthetic analogue pibrozelesin (KW-2189), or zinostatin;

[0957] XIV. Tubulin-binding agents, for example combrestatin, colchicines, demecolcine, noscapine, or nocod azole;

[0958] XV. Kinase inhibitors and modulators targeting kinases including but not limited to ABL1 (for example Asciminib, Dasatinib, Imatinib, Nilotinib, Bosutinib), AKT1 / 2 / 3 (multiple or selective, for example Capivasertib, Ipatasertib, Afuresertib, Miransertib, Uprosertib, Vevorisertib, Pifusertib), ALK (for example Alectinib, Brigatinib, Ceritinib, Crizotinib, Entrectinib, Gilteritinib, Lorlatinib), ARAF / BRAF / CRAF (multiple or selective) (for example Dabrafenib, Encorafenib, Regorafenib, Sorafenib, Vemurafenib, Belvarafenib, Naporafenib, Tovorafenib, Agerafenib, Lifirafenib), ATM (for example Lartesertib, SYH2051), ATR (Berzosertib, Ceralasertib, Elimusertib, Gartisertib), AURKA / B / C (multiple or selective, for example Alisertib, Danusertib, llorasertib, Tozasertib, Cenisertib, Barasertib, Chiauranib), AXL (for example Bemcentinib, Dubermatinib), BTK (for example Acalabrutinib, Ibrutinib, Zanubrutinib, Evobrutinib, Fenebrutinib, Pirtobrutinib), CDC7 (for example BMS863233, SGR2921 , Monzosertib, LY3177833, NMS1116354, Simurosertib), CDK (multiple, for example Milciclib, Riviciclib, Roniciclib, Avotaciclib, Fadraciclib, Zotiraciclib), CDK2 (for example Tagtociclib, BLU-222, INCB123667, AZD8421), CDK4 (for example Atirmociclib, BGB-43395), CDK4 / 6 (for example Ribociclib, Abemaciclib, Palbociclib), CDK7 (for example Samuraciclib, Q901 , EXS617, SY5609, LY3405105, XL102), CDK9 (for example Enitociclib, AZD4573, Atuveciclib), CDK12 / 13 (multiple or selective, for example CT7439), CHEK1 / 2 (multiple or selective, for example Prexasertib, Rabusertib), c-KIT (for example Avapritinib, Ripretinib), CLK1 / 2 / 3 / 4 (multiple or selective, for example Rogocekib, BH30326), CSF1 R (for example Pexidartinib, Vimseltinib), CSNK2A1 / 2 (also CK2a1 / 2, for example Silmitasertib), EGFR (for example Brigatinib, Erlotinib, Gefitinib, Neratinib, Osimertinib, Lazertinib, Olmutinib), ERK1 / 2 (for example Ulixertinib, Rinerterkib, Tizaterkib, Temuterkib, Beroterkib, ERAS007), FGFR1 / 2 / 3 / 4 (multiple or selective, for example Erdafitinib, Futibatinib, Infigratinib), FLT3 (for example Fedratinib, Gilteritinib, Midostaurin), FYN (for example Saracatinib), HER2 / ERBB2 (for example Lapatinib, Neratinib, Tucatinib), IGF1 R (for example Linsitinib), IRAK4 (for example Emavusertib, Zimlovisertib), ITK (for example Soquelitinib), JAK1 / 2 / 3 (multiple or selective, for example Abrocitinib, Baricitinib, Fedratinib, Momelotinib, Pacritinib, Filgotinib, Ruxolitinib, Tofacitinib, Upadacitinib, INCB160058), JNK1 / 2 (for example Bentamapimod, CC-90001), LCK and / or LYN (for example Nintedanib, Bosutinib), MAP2K4 / MKK4 (for example Darizmetinib, PLX8725), MEK1 / 2 (for example Trametinib, Selumetinib, Binimetinib, Cobimetinib), MERTK (for example Adrixetinib, Ningetinib, Tamnorzatinib), MET / HGFR (for example Capmatinib, Glumetinib, Tepotinib), MNK1 / 2 (for example Tomivosertib), MST1 R / RON (for example Glesatinib, Merestinib, BMS777607), MTOR (for example Sirolimus, Everolimus, Temserolimus), NTRK1 / 2 / 3 (also TRKA / B / C, multiple or selective, for example Entrectinib, Larotrectinib, Repotrectinib), P38a / b / g / d (also MAPK11 / 12 / 13 / 14, multiple or selective, for example Emprumapimod, Losmapimod, Ralimetinib, Pexmetinib), PAK4 or other PAK isoforms (for example Padnarsertib), PDGFRA / B (for example Crenolanib), PIKCA / B / D / G (multiple or selective, for example Alpelisib, Buparlisib, Copanlisib, Duvelisib, Idelalisib, Umbralisib, Paxalisib, Gedatolisib, Roginolisib, Samotolisib, Parsaclisib, STX478, RLY2608, LY3849524, OKI219), PIM1 / 2 / 3 (for example Uzansertib, TP3654), PKMYT1 (for example Lunresertib, SGR3515), PLK1 / 2 / 3 / 4 (multiple or selective, for example Rigosertib, Volasertib, Onvansertib, Plogosertib, CFI400945, RP1664), PKC family members (multiple or selective, for example Darovasertib, EXS4318), PTK2 / B (also FAK1 / 2, for example Defactinib, Ifebemtinib), RET (for example Selpercatinib, Praseltinib), ROCK1 / 2 (multiple or selective, for example Belumosudil, Fasudil, Netarsudil), ROS1 (for example Lorlatinib, Repotrectinib), RPS6KB1 / 2 (also p70S6Ka / b, for example Rupitasertib), SRC (for example Saracatinib, NXP900), SYK (for example Sovleplenib), TGFBR1 / 2 (multiple or selective, for example Galunisertib, Vactosertib), TIE1 / 2 (multiple or selective, for example Altiratinib, Cabozantinib), TTK / MPS1 (for example Empesertib, Luvixasertib, NMS153), TYK2 (for example Deucravacitinib), VEGFR1 / 2 / 3 (for example Sunitinib, Sorafenib, Pazopanib, Cabozantinib, Lenvatinib, Fruquintinib), WEE1 / 2 (for example Adavosertib, Azenosertib, Debio0123), or YESI (for example NXP900, Nintedanib);

[0959] XVI. Agents that modulate the activity of regulators of cell death such as BCL2 protein family members (for example Venetoclax, Sonrotoclax, Navitoclax, BKX001), MDM2 (for example Idasanutlin, Milademetan, Brigimadlin, Navtemadlin, Siremadlin, Alrizomadlin, ASTX295), or CIAP1 / 2 and XIAP (for example Xevinapant, Tolinapant, Birinapant, Dasminapant);

[0960] XVII. Agents that modulate the activity of DNA damage repair regulators such as ATM (for example Lartesertib, SYH2051), ATR (for example Berzosertib, Ceralasertib, Elimusertib, Gartisertib), DNA-PK or PRKDC (for example Peposertib), PARP1 / 2 (multiple or selective, for example Olaparib, Niraparib, Talazoparib, Rucaparib, Saruparib), PARG (for example IDE161 , ETX19477), RAD51 (for example Emzadirib);

[0961] XVIII. Agents that target proteins in epigenetic complexes such as ASH1 L, BRD4 or other BET proteins (multiple or selective, for example Trotabresib, Ezobresib, PLX51107, AZD5153, SF1126, Mivebresib, Molibresib, Birabresib, Amredobresib, BAY1238097, Pelabresib, INCB054329, INCB057643, FT1101 , ODM207, ZEN3694, RG6870810, OPN2853), CBP / KAT3A and / or EP300 / KAT3B (multiple or selective, for example Inobrodib, Pocenbrodib), DNMT (for example 5’-Azacytidine, Decitabine, Guadecitabine), DOT1 L / KMT4 (for example Pinometostat), EZH1 / 2 (multiple or selective, for example Tazemetostat, Valemetostat, Mevrometostat), HDACs (multiple or selective, for example Romidepsin, Vorinostat, Belinostat, Panobinostat, Tucidinostat, Entinostat, Citarinostat, KA2507, Abexinostat, Pracinostat, Fimepinostat, Quisinostat, Ricolinostat, Nanatinostat, Ivaltinostat, CUDC101 , MPT0E028), LSD1 / KDM1A (for example Bomedemstat, Seclidemstat, ladademstat, GSK2879552, INCB059872, CC-90011), MEN1 / KDM2A (for example Revumenib, Ziftomenib, BMF219, JNJ75276617, DSP-5336, DS1594b), KMT2A / B / C / D / E (also MLL1 / 2 / 3 / 4 / 5, multiple or selective, for example Revumenib, Ziftomenib, BMF219, JNJ75276617, DSP-5336, DS1594b), PRMT5 (for example Onametostat, Pemrametostat, AZD3470, PRT811 , PRT543, TNG462, TNG908, MRTX1719, JBI778, AMG193, PF06939999);

[0962] XIX. Agents that target RAS isoforms (mutant or wildtype, multiple or selective) such as Sotorasib, Adagrasib, Fulzerasib, Divarasib, Olomorasib;

[0963] XX. Phosphatase inhibitors and modulators such as Batoprofatib, Migoprofatib, Vociprofatib, ERAS601 ;

[0964] XXI. Other targeted agents such as compounds modulating the activity of A2A / B-R (also ADORA2A / B, multiple or selective, for example Etrumadenant, Inupadenant, Taminadenant, EXS21546, M1069, JNJ86974680, INCB106385, Imaradenant), CCR4 (for example Tivumecirnon), CD47 (for example Evorpacept, Timdarpacept, AUR103, TQB2928), CD73 (for example Quemliclustat, ORIC533, ATG037), CYP17 (for example Abiraterone, Seviteronel, Galeterone, Orteronel), DHODH (for example Laflunimus, Brequinar, Farudodstat, AG-636, Orludodstat, Emvododstat, RP-7214, Vidofludimus, JNJ6665), EIF4A / E (multiple or selective, for example Zotatifin, FEP633), Farnesyltransferases (for example Lonafarnib, Tipifarnib, BMS214662), Gonadotropin releasing hormone agonists or antagonists (also GnRAs, for example abarelix, goserelin acetate, histrelin acetate, leuprolide acetate, triptorelin, buserelin, deslorelin; leuprorelin, or nafarelin),HIF1-alpha (for example PX478, IDF11774, BAY872243), HIF2-alpha / EPAS1 (for example Belzutifan, Casdatifan, NKT2152, BPI452080, DFF332), HSP90 (for example Pimitespib, Cemdomespib, Luminespib, Onalespib), IDH1 / 2 (multiple or selective, for example Ivosidenib, Enasidenib, Olutasidenib, Vorasidenib), IDO1 (for example Epacadostat, Linrodostat, BMS986242, PF06840003, MK1762, M4112), INSR (for example Linsitinib), KIF18A (for example Sovilsenib, VLSI 488), MMP protein family members (multiple or selective, for example Batimastat, Marimastat, Prinostat, Metastat), MTH1 (for example Karonudib), MYC protein family members (multiple orselective, forexample Omomyc, IDP121), NMT1 / 2 (multiple or selective, for example Zelenirstat), PARP7 (for example Atamparib, BY101921 , JAB26766), PD-1 and / or PD-L1 (for example CA170, INCB086550, INCB99280, INCB99318, GS4224, ABSK043, CCX559, AN4005, BPI371153, ASC61 , CS23546), drugs targeting the ubiquitin-proteasome pathway including proteasome inhibitors (for example Bortezomib, Ixazomib, Carfilzomib), RBM39 (for example Tasisulam, indisulam, ST00937, REC204), STING / TMEM173 (for example Ulevostinag, ADU-S100, E7766, VENT03, IMSB301 , BMS986301 , GSK3745417, BI1387446, TAK676, ONO7914), Telomerase (for example Imetelstat), or XPOl (for example Selinexor, Felezonexor);

[0965] XXII. Therapeutic antibodies including unconjugated or conjugated to radioisotopes, toxins or other agents e.g. cytotoxic anticancer agents, such as antibody-drug conjugates, antibody derivatives, bispecific or trispecific antibodies , T cell engagers and "antibody-like" therapeutic proteins (such as DARTs®, Duobodies®, Bites®, XmAbs®, TandAbs®, or Fab derivatives), or other therapeutic proteins or peptides and related agents.

[0966] This includes monoclonal antibodies and immunomodulating antibodies (including against immune checkpoints) such anti-ACRVRL1 / anti-ALK1 (ascrinvacumab), anti-B7-H4 / anti-VTCN1 (for example NC-762, A-20502), anti-CALR (for example INCA-033989), anti-CA125 (for example abagovomab, oregovomab), anti-CCR4 (for example mogamulizumab), anti-CD4 (for example zanolimumab), anti-CD19 (for example tafasitamab, inebilizumab, LY3541860), anti- CD20 (for example rituximab, afutuzumab / obinutuzumab, ofatumumab, divozilimab, tositumomab, veltuzumab), anti-CD22 (for example epratuzumab, suciraslimab), anti-CD33 (for example lintuzumab, BI836858), anti-CD38 (for example isatuximab, daratumumab, felzartamab, mezagitamab), anti-CD39 or anti-ENTPDI (for example TTX-030, IPH-5201), anti- CD40 (for example dacetuzumab, giloralimab, iscalimab, sotigalimab, YH-003, SEA-CD40), anti-CD52 (for example alemtuzumab, ALLO-647, GZ-402668), anti-CD73 / anti-NT5E (for example oleclumab, uliledlimab, dresbuxelimab, JAB-BX102), anti-CD80 (for example galiximab), anti-CD105 or anti-endoglin (for example carotuximab), anti-CD137 (for example urelumab), anti-CSF1 R (for example emactuzumab, AMB-05X, axatilimab), anti-CTLA4 (for example ipilimumab, tremelimumab (formerly ticilimumab), gotistobart, botensilimab, quavonlimab), anti-EGFR (for example cetuximab, matuzumab, panitumumab, necitumumab, nimotuzumab, zalutumumab), anti-EpCAM (for example edrecolomab, adecatumumab), anti- FGFR (for example vofatamab, bemarituzumab), anti-FOLR1 (for example farletuzumab), anti- GARP / anti-LRRC32 (for example livmoniplimab, HLX60), anti-GD2 (for example dinutuximab, naxitamab), anti-GD3 (for example mitumomab, KW-2871 , ecromeximab), anti-HER2 (for example trastuzumab, pertuzumab, margetuximab, inetetamab), anti-HGF (for example ficlatuzumab, rilotumumab), anti-IGF1 R / anti-CD221 (for example teprotumumab, figitumumab, ganitumab, dalotuzumab), anti-IL6 (for example siltuximab, olokizumab), anti-IL1 RAP (for example nadunolimab), anti-lntegrins (for example abituzumab, intetumumab, etaracicumab, volociximab), anti-LAG3 / anti-CD223 (for example relatlimab, fianlimab, eftilagimod alpha (a solubale LAG-3 protein)), a fixed dose combination of an anti-LAG3 antibody with an anti-PD1 antibody (for example relatlimab / nivolumab sold under the brand name Opdualag or favezelimab / pembrolizumab), anti-LILRB1 / 2 or anti-ILT2 / 4 (for example SAR-444881 , ADA- 011), anti-cMET (for example emibetuzumab, onartuzumab), anti-MICA / B for example CLN- 619, DM-919), anti-NKG2D / anti-KLRK1 (for example tesnatilimab), anti-OX40 / anti-CD134 (for example INBRX106, BGB-A445, pogalizumab, INCAGN-01949, BMS-986178), anti-PD1 (for example pembrolizumab (formerly lambrolizumab), nivolumab, cemiplimab, camrelizumab, toripalimab, sintilimab, tislelizumab, dostarlimab, zimberelimab, penpulimab, serplulimab, pucotenlimab, retifanlimab, prolgolimab, genolimzumab, spartalizumab), anti-PD-L1 / anti- CD274 (for example atezolizumab, durvalumab, avelumab, envafolimab, sugemalimab, adebrelimab, socazolimab, benmelstobart, cosibelimab), anti-PDGFR (for example olaratumab, tovetumab), anti-RANKL / anti-TNFSF11 (for example denosumab), anti SLAMF7 (for example elotuzumab), anti-TGFbeta and / or anti-TGFBR (for example luspatercept, BMS986416, SAR439459, fresolimumab, SRK-181 , nisevokitug), anti-TNFR2 (for example Bl- 1808, LBL-019), anti-TIGIT (for example vibostolimab, ociperlimab, belrestotug, domvanalimab, tiragolumab), anti-TLRs (for example tomaralimab, DS-7011), anti-TRAILR (for example mapatumumab, ozekibart, drozitumab, conatumumab, tigatuzumab), anti-VEGF or anti-VEGFR family members (for example bevacizumab, ramucirumab, ranibizumab, brolucizumab, sevacizumab, aflibercept (AVE-0005, a VEGF trap)), or anti-VISTA (for example onvatilimab, SNS-101 , KVA-12123, K01401 -020, HMBD-002);

[0967] Or bispecific or trispecific antibodies, T cell engagers or fusion proteins targeting for example 5T4 / TPBG, B7-H4, BCMA, CALR, CD16, CD19, CD20, CD3, CD33, CD73, CD137 / 4-1 BB, cMET, CTLA4, DLL3, EGFR, ENPP3, EpCAM, GARP, GP100, GPRC5D, HER2, HER3, IGF1 R, LAG3, LGR5, LILRB1 / 2 or ILT2 / 4, mucins, NKG2D, 0X40, PD-1 , PD-L1 , PSMA, STEAP1 , TGFbeta, TIGIT, or VEGF, including agents like blinatumomab (CD3 xCD19), tebentafusp (CD3 x GP100), mosunetuzumab (CD20 x CD3), glofitamab (CD20 x CD3), talquetamab (GPRC5D x CD3), elranatamab (BCMA x CD3), AZD0486 (CD19 x CD3), amivantamab (EGFR x cMET), catumaxumab (EpCAM x CD3), teclistamab (CD3 and BCMA), ertumaxomab (HER2 x CD3), rilvegostomig (anti-PD-1 xTIGIT), volrustomig (anti-PD1 x CTLA4), cadonilimab (CTLA4 x PD- 1), catumaxomab (EpCAM x CD3), cadonilimab (CTLA-4 x PD-1), epcoritamab (CD20 x CD3), linvoseltamab (BCMA x CD3), odronextamab (CD20 x CD3), tarlatamab (DLL3 x CD3), zanidatamab (HER2 x HER2), NGM-707 (ILT2 x ILT4), PF-07826390 (ILT2 x ILT4), ivonescimab (PD-1 x VEGF), vixtimotamab (CD3 x CD33), petosemtamab (EGFR x LGR5), izalontamab (EGFR x HER3), zenocutuzumab (HER2 x HER3), istiratumab (HER3 x IGF1 R), tebotelimab (LAG3 x PD-1), davutamig (cMET x cMET), MCLA-129 (EGFR x cMET), KN052 (0X40 x PD-L1), BNT-327 (PD-L1 x VEGF), retlirafusp alfa (PD-L1 x TGFbeta fusion protein), ALG.APV-527 (CD137 x 5T4), GEN-1044 (CD3 x 5T4), GEN-1047 (CD3 x B7-H4), JYB1907 (GARP x TGFbeta), JNJ-87890387 (CD3 x ENPP3), ES014 (CD39 x TGFbeta), CLN-418 (CD137 x B7-H4), BCA101 (EGFR x TGFbeta), PM8001 (PD-L...

Claims

Claims1 . A compound of formula (I):or a tautomer or a solvate or a pharmaceutically acceptable salt thereof, wherein:Ring X is selected from an aryl, cycloalkenyl, heteroaryl and partially unsaturated heterocyclyl group, wherein the heteroaryl or partially unsaturated heterocyclyl group comprises one or more (e.g. 1 , 2 or 3) heteroatoms selected from O, N or S; t is selected from 0, 1 , 2, 3 and 4;R2is selected from halogen, nitro, nitrile, C1-6alkoxy, haloC1-6alkoxy, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, haloC1-6alkyl, -(CH2)k-O-C1-6alkyl, -(CH2)k-S-C1-6alkyl, hydroxyl, hydroxyC1-6alkyl, -SH, -NHe(C1-4alkyl)2-e, C3-6cycloalkyl, C3-6cycloalkenyl and heterocyclic group (e.g. an aromatic ring or a non-aromatic ring) wherein the heterocyclic group has 3 to 6 ring members and wherein the heterocyclic group comprises one or more (e.g. 1 , 2 or 3) heteroatoms selected from N, O, S and oxidised forms thereof;Rais independently selected from hydrogen, halogen, nitro, nitrile, C1-6alkoxy, haloC1-6alkoxy, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, haloC1-6alkyl, -(CH2)k-O-C1-6alkyl, -(CH2)k-S-C1-6alkyl, hydroxyl, hydroxyC1-ealkyl, -SH, -NHe(C1-4alkyl)2-e, C3-6cycloalkyl, C3-6cycloalkenyl and heterocyclic group (e.g. an aromatic ring or a non-aromatic ring) wherein the heterocyclic group has 3 to 6 ring members and wherein the heterocyclic group comprises one or more (e.g. 1 , 2 or 3) heteroatoms selected from N, O, S and oxidised forms thereof; or when t is 2 or more and the two Ragroups are joined to the same carbon, the two Ragroups together with the carbon to which they are attached join to form an =O (oxo), =CH2, spirocyclic C3-6carbocyclic group or a spirocyclic non-aromatic heterocyclic group with 3 to 6 ring-members containing one or more (e.g. 1 , 2 or 3) heteroatoms selected from O, N or S or oxidised forms thereof; wherein either:• A is CR32, NR3’ or O; B is O; R3are independently selected from hydrogen, halogen and C1-4alkyl; R3’ is selected from hydrogen and C1-4alkyl; and R4is Ring Y wherein Ring Y is selected from a cycloalkyl, aryl group or a heterocyclyl group (e.g. an aromatic ring or a non-aromatic ring), whereinthe heterocyclyl group comprises one or more (e.g.1 , 2, or 3) heteroatoms selected from N, O and S and wherein the cycloalkyl, aryl or heterocyclyl group is optionally substituted with one or more (e.g. 1 , 2 or 3) R6groups, or• A is CR32, NR3’ or O; B is NR5; R3are independently selected from hydrogen, halogen and C1-4alkyl; R3’ is selected from hydrogen and C1-4alkyl; and R4and R5together with the atoms to which they are attached join to form a heterocyclic group (e.g. an aromatic ring or a non-aromatic ring), wherein the heterocyclic group optionally comprises one or more additional heteroatoms selected from N, O or S, and oxidised forms thereof, wherein the heterocyclic group may optionally be substituted with one or more (e.g. 1 , 2 or 3) R6groups; or• A is CR32 or NR3’; B is NR5; R5and R3’ or one R3group together with the atoms to which they are attached join to form a heterocyclic group (e.g. an aromatic ring or a non-aromatic ring), wherein the heterocyclic group optionally comprises one or more additional heteroatoms selected from N, O or S, and oxidised forms thereof, wherein the heterocyclic group may optionally be substituted with one or more (e.g. 1 , 2 or 3) R6groups; the other R3group is selected from hydrogen, halogen and C1-4alkyl; and R4is selected from hydrogen and C1-4alkyl; n is selected from 0, 1 , 2, 3 or 4;R1and R6are independently selected from hydroxyl, halogen, nitro, nitrile, C1-6alkyl, nitrileC1-6alkyl, C1-6alkoxy, haloC1-6alkyl, C2-6alkenyl, C2-6alkynyl, =O (oxo), -C(=O)C1-6alkyl, -SH, -SC1-6alkyl, -SO2C1-6alkyl, C1-6alkylSO2C1-6alkyl, -SO2NRxRy, -C1-6alkyl-SO2NRxRy, -NRxRy, -C(=O)NRxRy, -NRxC(=O)C1-6alkyl, C1-6alkylNHC(=O)C1-6alkyl, -(CH2)k-O-C1-6alkyl, hydroxyC1-6alkyl, hydroxyC1-6alkoxy, haloC1-6alkoxy, - C(=O)C1-6alkyl-OH, -C(=O)C1-6alkyl-N(H)e(C1-6alkyl)2-e, CCteC1-6alkyl, C1-6alkylCO2C1-6alkyl, -(CRxRy)v- CONRxRy, -CO2H, -C1-6alkylCO2H, -C1-6alkyl-NRxRy, -P(=O)(Rx)(Ry), C3-8cycloalkyl, Cs-acycloalkenyl, Ca- waryl, and heterocyclic groups (e.g. an aromatic ring or a non-aromatic ring) with 3 to 8 ring members wherein the heterocyclic group comprises one or more (e.g.1 , 2, or 3) heteroatoms selected from N, O, S and oxidised forms thereof, wherein the C1-aalkyl groups is optionally substituted with a Cs-acycloalkyl, Cs-acycloalkenyl, Ce-ioaryl or 3 to 8 membered heterocyclic group (e.g. an aromatic ring or non-aromatic ring) containing one or more (e.g. 1 , 2 or 3) heteroatoms selected from O, N or S and wherein in each case the Cs-acycloalkyl, Cs-acycloalkenyl, Ce-ioaryl and 3 to 8 membered heterocyclic groups are optionally further substituted with one or more (e.g. 1 , 2 or 3) Rzgroups, or two R1or two R6groups together with the atoms to which they are attached join to form a C3-8cycloalkyl, Cs-acycloalkenyl, Ce-ioaryl or heterocyclic group with 3 to 8 ring members (e.g. an aromatic ring or a non-aromatic ring), wherein the heterocyclic group contains one or more (e.g. 1 , 2 or 3) heteroatoms selected from N, O, S and oxidised forms thereof and wherein the Cs-acycloalkyl, C3-8cycloalkenyl, Ca-ioaryl group or 3- to 8-membered heterocyclic ring can be substituted by one or more Rzgroups;RxRyand Rzare independently selected from hydrogen, halogen, nitro, nitrile, hydroxyl, =O (oxo), C1-©alkyl, haloC1-6alkyl, C2-aalkenyl, C2-aalkynyl, hydroxyC1-aalkyl, C1-aalkoxy, -NHe(C1-6alkyl)2-e, -C1-6alkylNHe(C1-6alkyl)2-e, hydroxyC1-aalkoxy, -(CH2)k-O-C1-6alkyl, -C(=O)C1-6alkyl, -(CHzJjCOzC1-aalkyl, -(CH2)k-C(=O)N(H)e(C1-6alkyl)2-e, -C(=O)C1-6alkyl-N(H)e(C1-4alkyl)2-e, -(CH2)qCO2H C3-8cycloalkyl, C3-8cycloalkenyl and heterocyclic groups (e.g. an aromatic ring or a non-aromatic ring) with 3 to 8 ring members, wherein the heterocyclic group comprises one or more (e.g.1 , 2, or 3) heteroatoms selected from N, O, S and oxidised forms thereof; or Rxand Ry, or two Rzgroups, together with the atom(s) to which they are attached, join to form a C3-8cycloalkyl, C3-8cycloalkenyl, or heterocyclic group with 3 to 8 ring members (e.g. an aromatic ring or a non-aromatic ring), wherein the heterocyclic group comprises one or more (e.g.1 , 2, or 3) heteroatoms selected from N, O, S and oxidised forms thereof; wherein when Rxand Ryare C3-8cycloalkyl, C3-8cycloalkenyl or a heterocyclic group with 3 to 8 ring members or when Rxand Rytogether with the atom to which they are attached, join to form a C3-8cycloalkyl, Cs8cycloalkenyl, or heterocyclic group with 3 to 8 ring members then the C3-8cycloalkyl, C38cycloalkenyl or heterocyclic group with 3 to 8 ring members is optionally further substituted with one or more (e.g, 1 , 2 or 3) Rzgroups; e, j, k and q are independently selected from 0, 1 and 2; v is selected from 0 and 1 .

2. A compound according to claim 1 , or a tautomer or a solvate or a pharmaceutically acceptable salt thereof, wherein t is 0.

3. A compound according to claim 1 or 2, or a tautomer or a solvate or a pharmaceutically acceptable salt thereof, wherein Ring X is selected from an aryl group and a heteroaryl group, wherein the heteroaryl group comprises one or more (e.g. 1 , 2 or 3) heteroatoms selected from O, N and S and oxidised forms thereof.

4. A compound according to any one of claims 1 to 3, or a tautomer or a solvate or a pharmaceutically acceptable salt thereof, wherein Ring X is selected from phenyl and a 6-membered heteroaryl group wherein the heteroaryl group comprises one or more (e.g. 1 , 2 or 3) heteroatoms selected from O, N and S and oxidised forms thereof, such as phenyl, pyridine, pyrazine, pyrimidine and pyridazine, for example phenyl and pyridine, e.g. phenyl.

5. A compound according to claim 4, or a tautomer or a solvate or a pharmaceutically acceptable salt thereof, wherein n is 1 and R1is at the 4- position of Ring X relative to the position of attachment to the cyclic imide.

6. A compound according to any preceding claim, or a tautomer or a solvate or a pharmaceutically acceptable salt thereof, wherein R1is selected from halogen, nitrile, C1-6alkyl, -C1-6alkylNRxRy, -NRxRy, C1-6alkoxy, haloC1-6alkyl, hydroxyC1-6alkyl, -C(=O)NRxRy, -C1-6alkylNHC(=O)C1-6alkyl, -NHC(=O)C1-©alkyl , -SO2NRxRy, -SO2C1-6alkyl, -P[=O]RxRy, -CO2H, haloC1-6alkoxy or a 3 to 8 membered heterocyclic group (e.g. an aromatic ring or a non-aromatic ring) group containing one or more (e.g. 1 , 2 or 3) heteroatoms selected from O, N or S; orwhen n is 2 or more, two R1groups, together with the atoms to which they are attached, join to form a heterocyclic group with 3 to 6 ring members (e.g. an aromatic ring or a non-aromatic ring), wherein the heterocyclic group comprises one or more (e.g.1 , 2, or 3) heteroatoms selected from N, O, S and oxidised forms thereof, wherein the heterocyclic group is optionally substituted with one or more Rzgroups.

7. A compound according to any preceding claim, or a tautomer or a solvate or a pharmaceutically acceptable salt thereof, wherein R1is selected from -NRxRyand -C(=O)NRxRy, wherein Rxand Ryare independently selected from hydrogen, C1-6alkyl, hydroxyC1-6alkyl and -(CH2)k-OC1-6alkyl orwherein Rxand Ry, together with the atom to which they are attached, join to form a heterocyclic ring with 4 to 6 ring members, wherein the heterocyclic group comprises one or more (e.g.1 , 2, or 3) heteroatoms selected from N, O, S and oxidised forms thereof, wherein the heterocyclic group is optionally substituted with one or more Rzgroups, for example wherein the heterocyclic group is substituted with one R?- group that is hydroxy.

8. A compound according to any preceding claim, or a tautomer or a solvate or a pharmaceutically acceptable salt thereof, wherein R2is selected from C1-6alkyl, haloC1-6alkyl, -(CH2)k-O-C1-6alkyl and - SC1-6alkyl.

9. A compound according to any preceding claim, or a tautomer or a solvate or a pharmaceutically acceptable salt thereof, wherein R2is selected from methyl, ethyl and isopropyl, for example ethyl.

10. A compound according to any preceding claim, or a tautomer or a solvate or a pharmaceutically acceptable salt thereof, wherein A is CR32, NR3’ or O; B is O; R3are independently selected from hydrogen, halogen and C1-4alkyl; R3’ is selected from hydrogen and C1-4alkyl; and R4is Ring Y wherein Ring Y is selected from a cycloalkyl, aryl group or a heterocyclyl group (e.g. an aromatic ring or a non- aromatic ring), wherein the heterocyclyl group comprises one or more (e.g.1 , 2, or 3) heteroatoms selected from N, O and S and wherein the cycloalkyl, aryl or heterocyclyl group is optionally substituted with one or more (e.g. 1 , 2 or 3) R6groups.

11. A compound according to any preceding claim, or a tautomer or a solvate or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (III0):or a tautomer or a solvate or a pharmaceutically acceptable salt thereof,wherein m is selected from 0, 1 , 2 and 3.

12. A compound according to claim 12 wherein R3is hydrogen, and the compound is a compound of formula (III):

13. A compound according to claim 11 or 12, or a tautomer or a solvate or a pharmaceutically acceptable salt thereof, wherein Ring Y is selected from phenyl, pyridine, pyrazine, pyrimidine and pyridazine, for example phenyl and pyridine.

14. A compound according to any one of claims 11 to 13, or a tautomer or a solvate or a pharmaceutically acceptable salt thereof, wherein R6is halogen, nitrile, oxo, C1-6alkyl, -SC1-6alkyl, haloC1-6alkyl, NRxRy, C(=O)NRxRy, -NHC(=O)C1-6alkyl, C1-6alkoxy, hydroxyC1-6alkyl, -C1-6alkyl-NRxRyor heterocyclic group with 4 to 6 ring members (e.g. an aromatic ring or a non-aromatic ring), wherein the heterocyclic group comprises one or more (e.g. 1 , 2 or 3) heteroatoms selected from N, O and S, and oxidised forms thereof, wherein the heterocyclic ring is optionally substituted by one or more (e.g. 1 , 2 or 3) Rzgroups; or two R6groups together with the atoms to which they are attached join to form a Csaryl group or a heterocyclic group with five or six ring members (e.g. an aromatic ring or a non-aromatic ring), wherein the heterocyclic group contains one or more (e.g. 1 , 2 or 3) heteroatoms selected from N. O, S and oxidised forms thereof and wherein the aryl or heterocyclic ring is optionally substituted by one or more Rzgroups, for example wherein R6is selected from NRxRywherein Rxand Ryare independently selected from hydrogen and C1-6alkyl.

15. A compound according to any one of claims 11 to 14, wherein:• m is 1 , 2 or 3 and R6is selected from C1-6alkyl, halogen and NRxRy, wherein Rxand Ryare independently selected from hydrogen and C1-6alkyl; or• m is 2 or 3 and two R6join to form a five-membered heterocyclic group containing 1 or 2 heteroatoms that are N, wherein when m is 3 one R6is selected from C1-6alkyl , halogen and NHe(C1-salkyl)2-e, for example NHe(C1-6alkyl)2-e, e.g. NH2, NHMe or NMe2.

16. A compound according to any one of claims 11 to 15, or a tautomer or a solvate or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (lllc)• Y1, Y2and Y4are selected from CH and N, wherein no more than two of Y1, Y2and Y4are N; and• Y3is CR6.

17. A compound according claim 1 , or a tautomer or a solvate or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (V)wherein:• W1and W2are independently selected from N and CH, wherein no more than 1 of W1and W2is N;• Y1, Y2, Y3and Y4are selected from N, CH and CR6, wherein at least one of Y1, Y2, Y3and Y4is CR6and no more than 2 (for example 0, 1 or 2) of Y1, Y2, Y3and Y4are N.

18. A compound according to claim 17, or a tautomer or a solvate or a pharmaceutically acceptable salt thereof, wherein:Y1is N, Y3is CR6and Y2and Y4are CH; or Y1, Y2and Y4are CH and Y3is CR6.

19. A compound according to claims 17 or 18, or a tautomer or a solvate or a pharmaceutically acceptable salt thereof, wherein R6is selected from NRxRy, wherein Rxand Ryare independently selected from hydrogen and C1-6alkyl.

20. A compound according to claim 1 , or a tautomer or a solvate or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (VI):wherein• W1and W2are independently selected from N and CH, wherein no more than 1 of W1and W2is N; and• Y1, Y2, Y3and Y4are selected from N, CH and CR6; wherein at least one of Y1, Y2, Y3and Y4is CR6and no more than 2 (for example 0, 1 or 2) of Y1, Y2, Y3and Y4are N.21 . A compound according to claim 1 , or a tautomer or a solvate or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (VII):wherein W1and W2are selected from CH and N, wherein no more than 1 of W1and W2are N; Y1, Y2, Y3and Y4are selected from N, CH and CR6; wherein at least one of Y1, Y2, Y3and Y4is CR6and no more than 2 (for example 0, 1 or 2) of Y1, Y2, Y3and Y4are N.

22. A compound according to claim 20 or 21 , or a tautomer or a solvate or a pharmaceutically acceptable salt thereof, wherein Rxand Ryare selected from hydrogen and C1-6alkyl or wherein Rxand Rytogether with the atom to which they are attached join to form a non-aromatic heterocyclic group with 3 to 6 ring members, wherein the non-aromatic heterocyclic group comprises one or more (e.g.1 , 2, or3) heteroatoms selected from N, O, S and oxidised forms thereof and wherein the non-aromatic heterocyclic groups are optionally further substituted with one or more (e.g. 1 , 2 or 3) Rzgroups.

23. A compound, or a tautomer or a solvate or a pharmaceutically acceptable salt thereof, wherein the compound is selected from Examples 1-232.

24. A combination comprising a compound of formula (I) as defined in any of claims 1 to 23 with one or more (e.g. 1 or 2) other therapeutic agents (e.g. anti-cancer agents).

25. A pharmaceutical composition comprising a compound of formula (I) as defined in any of claims 1 to 21 or a combination as defined in claim 24.

26. A compound as defined in any of claims 1 to 23, a combination according to claim 24, or a pharmaceutical composition according to claim 25 for use in therapy.

27. A compound as defined in any of claims 1 to 23, a combination according to claim 24 or a pharmaceutical composition according to claim 25 for use in the prophylaxis or treatment of a disease state or condition mediated by CBP / p300.

28. A compound as defined in any of claims 1 to 23, a combination according to claim 24, or a pharmaceutical composition according to claim 25 for use in the prophylaxis or treatment of a disease state or condition as described herein.

29. A compound as defined in any of claims 1 to 23, a combination according to claim 24, or a pharmaceutical composition according to claim 25 for use in the prophylaxis or treatment of cancer.

30. The use of a compound as defined in any of claims 1 to 23, a combination according to claim 24, or a pharmaceutical composition according to claim 25 for the manufacture of a medicament for use in the prophylaxis or treatment of a disease state or condition as described herein.

31. A method for the prophylaxis or treatment of a disease or condition as described herein comprising administering to a patient a compound as defined in any of claims 1 to 23, a combination according to claim 24, or a pharmaceutical composition according to claim 25.

32. A compound as defined in any of claims 1 to 23, or a pharmaceutical composition according to claim 25 for use in the prophylaxis or treatment of cancer, wherein the compound is used in combination with one or more other therapeutic agents (e.g. anti-cancer agents) or therapies.

33. A process for preparing a compound of formula (III) as defined in claim 12, which comprises:(a) alkylation of the N-unsubstituted cyclic imide of formula (XI) with a reagent of formula (XII)wherein Ra, t, Ring X, R1, R2, Ring Y, R6, n and m are as defined herein and LG represents a leaving group; and / or(b) interconversion of a compound of formula (III) or a protected derivative thereof to a further compound of formula (III) or a protected derivative thereof; and / or (c) deprotecting a protected derivative of a compound of formula (III); and / or(d) providing a compound of formula (III) and forming a pharmaceutically acceptable salt of the compound.

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