6-Substituted naphthalene-1,3-disulfonic acid derivatives as modulators of extracellular nicotinamide phosphoribosyltransferase (ENAMPT), e.g. for the treatment of diabetes

Abstract

The present invention relates to therapeutic 6-substituted naphthalene-1,3-disulfonic acid derivatives of formula (I) (Formula (I)). More specifically, the present invention relates to compounds of formula (I) useful as modulators of extracellular nicotinamide phosphoribosyltransferase (eNAMPT), which stabilize the protein in its dimeric form. Furthermore, the present invention contemplates pharmaceutical compositions comprising the compounds, processes for preparing the compounds, and compounds for use in methods of medical treatment, for example, (i) diabetes, (ii) cardiovascular disease, (iii) inflammatory bowel conditions, (iv) cancer, (v) liver disease, (vi) inflammatory skin conditions, (vii) pulmonary conditions, (viii) arthritis, (ix) renal disease (e.g., chronic kidney disease), or (x) sepsis. An exemplary compound is, for example, 6-(2-fluoro-5-((3-(4-(piperidin-1-ylsulfonyl)phenyl)ureido)methyl)phenyl)-4-(trioxidanylthio)naphthalene-2-sulfonic acid (Example 1). [Case 1] JPEG2024529445000142.jpg68165 [Table 1] JPEG2024529445000143.jpg144165

Description

[Technical field]

[0001] The present invention relates to therapeutic compounds. More specifically, the present invention relates to compounds that inhibit extracellular nicotinamide phosphoribosyltransferase (eNAMPT) activity. Furthermore, the present invention contemplates pharmaceutical compositions containing the compounds, processes for the preparation of the compounds, and uses of the compounds. [Background technology]

[0002] Extracellular nicotinamide phosphoribosyltransferase has been shown to act as a mediator of inflammation in many indications, including diabetes, inflammatory bowel disease (IBD), nonalcoholic fatty liver disease (NAFLD), pulmonary arterial hypertension (PAH), acute lung injury (ALI), radiation-induced lung injury (RILI), cardiovascular disease, rheumatoid arthritis, and cancer, among others. Activating polymorphisms in the NAMPT locus have been associated with elevated IL-6 levels and worse outcomes or more severe disease in acute lung injury and pulmonary arterial hypertension and cardiovascular disease.

[0003] Nicotinamide phosphoribosyltransferase homodimers are nicotinamide adenine dinucleotide (NAD + ) has enzymatic activity in both the synthesis of the precursor nicotinamide mononucleotide (NAD) and in the hydrolysis / exchange of adenosine triphosphate (ATP) to form adenosine diphosphate (ADP) and adenosine tetraphosphate. However, studies using enzymatically inactive monomeric mutants have demonstrated that the proinflammatory effects of eNAMPT are not driven by this activity, supporting the hypothesis that eNAMPT acts via binding to one or more cellular receptors. Further evidence for this is provided by the fact that eNAMPT can directly bind to both TLR4 and CCR5, and that TLR4 function is essential for the proinflammatory effects of exogenously administered eNAMPT in mice.

[0004] Although proinflammatory monomeric eNAMPT levels are elevated in patients with type 2 diabetes and monomeric protein is also released by tumor cells in vitro, monomer / dimer ratios are not routinely examined across all disease areas where eNAMPT is involved in disease pathogenesis.

[0005] Monoclonal antibodies blocking the pro-inflammatory effects of eNAMPT have been shown to have beneficial effects in cellular and animal models of diabetes, inflammatory bowel disease (IBD), pulmonary arterial hypertension (PAH), acute lung injury (ALI), and radiation-induced lung injury (RILI).

[0006] Small molecule NAMPT inhibitors inhibit cellular NAD + Due to their ability to reduce the levels of erythrocytes, they have been studied in various disease conditions, especially cancer, resulting in cell phenotype changes and cell death induction.However, due to the relative non-specificity of these molecules across different cell types, they tend to show negligible therapeutic window; up to now, compounds have only progressed to clinical trials in oncology indications, and no compound has shown a usable therapeutic window.

[0007] Objective of the invention One object of certain embodiments of the present invention is to provide compounds that inhibit the pro-inflammatory effects of monomeric extracellular nicotinamide phosphoribosyltransferase (eNAMPT), optionally by stabilizing the protein in a dimeric form, inhibiting the formation of monomeric eNAMPT, and / or by inducing a conformational change in the protein.

[0008] A further object of certain embodiments of the present invention is to provide compounds that selectively suppress the pro-inflammatory effects of extracellular NAMPT without exhibiting significant inhibition of intracellular NAMPT activity.

[0009] The present invention has been devised with the above in mind. Summary of the Invention

[0010] In one aspect, the present invention provides a compound defined herein, or a pharma- ceutically acceptable salt or solvate thereof.

[0011] In another aspect, the present invention provides a compound defined herein, or a pharma- ceutically acceptable salt or solvate thereof, for use as a medicine.

[0012] In another aspect, the present invention provides a compound as defined herein, or a pharma- ceutically acceptable salt or solvate thereof, for use in the treatment of a disease or condition in which the inhibition of eNAMPT activity is beneficial.Suitably, the compound as defined herein, or a pharma- ceutically acceptable salt or solvate thereof, is for use in the treatment of a disease or condition in which the inhibition of monomeric eNAMPT activity is beneficial.

[0013] In another aspect, the present invention provides a compound as described herein, or a pharma- ceutically acceptable salt or solvate thereof, for use in treating: (i) Diabetes; (ii) cardiovascular disease (e.g., pulmonary arterial hypertension, acute coronary syndrome (ACS), congestive heart failure (CHF) or left ventricular hypertrophy); (iii) inflammatory bowel conditions (e.g., inflammatory bowel disease (IBD), Crohn's disease or ulcerative colitis) (iv) cancer (e.g., breast cancer, prostate cancer, or chronic lymphocytic leukemia (CLL)); (v) liver disease (e.g., nonalcoholic fatty liver disease (NAFLD), especially nonalcoholic steatohepatitis (NASH)); (vi) inflammatory skin conditions (e.g., psoriasis); (vii) pulmonary conditions (acute lung injury (ALI), ventilator-induced lung injury (VILI), radiation-induced lung injury (RILI), pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis)); (viii) arthritis (e.g., osteoarthritis or rheumatoid arthritis); (ix) renal disease (e.g., chronic kidney disease); or (x) Sepsis.

[0014] In another aspect, the present invention provides a compound as described herein, or a pharma- ceutically acceptable salt or solvate thereof, for use in treating: (i) Diabetes; (ii) cardiovascular disease (e.g., pulmonary arterial hypertension, acute coronary syndrome (ACS), congestive heart failure (CHF) or left ventricular hypertrophy); (iii) inflammatory bowel conditions (e.g., inflammatory bowel disease (IBD), Crohn's disease or ulcerative colitis) (iv) cancer (e.g., breast cancer, prostate cancer, or chronic lymphocytic leukemia (CLL)); (v) liver disease (e.g., nonalcoholic fatty liver disease (NAFLD), especially nonalcoholic steatohepatitis (NASH)); hepatic steatosis, hepatic fibrosis or cirrhosis); (vi) pulmonary conditions (acute lung injury (ALI), ventilator-induced lung injury (VILI), radiation-induced lung injury (RILI), pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis)); (vii) Renal disease (e.g., chronic kidney disease).

[0015] In another aspect, the present invention provides a compound as described herein, or a pharma- ceutically acceptable salt or solvate thereof, for use in treating: (i) Diabetes; (ii) pulmonary arterial hypertension, acute coronary syndrome (ACS), congestive heart failure (CHF) or left ventricular hypertrophy; (iii) inflammatory bowel disease (IBD), Crohn's disease or ulcerative colitis; (iv) breast cancer, prostate cancer, or chronic lymphocytic leukemia (CLL) (v) nonalcoholic fatty liver disease (NAFLD), especially nonalcoholic steatohepatitis (NASH), hepatic steatosis, hepatic fibrosis or cirrhosis); (vi) psoriasis; (vii) acute lung injury (ALI), ventilator-induced lung injury (VILI), radiation-induced lung injury (RILI), pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis); (viii) osteoarthritis or rheumatoid arthritis; (ix) chronic kidney disease; or (x) Sepsis.

[0016] In another aspect, the present invention provides a compound as described herein, or a pharma- ceutically acceptable salt or solvate thereof, for use in treating: (i) Diabetes; (ii) pulmonary arterial hypertension; (iii) inflammatory bowel disease (IBD), Crohn's disease or ulcerative colitis; (iv) nonalcoholic fatty liver disease (NAFLD), especially nonalcoholic steatohepatitis (NASH); (v) acute lung injury (ALI), ventilator-induced lung injury (VILI), radiation-induced lung injury (RILI); or (vi) Chronic kidney disease.

[0017] In another aspect, the present invention provides a compound as defined herein, or a pharma- ceutically acceptable salt or solvate thereof, for use in the treatment of inflammatory bowel disease (IBD), Crohn's disease or ulcerative colitis.

[0018] In another aspect, the present invention provides a compound as described herein, or a pharma- ceutically acceptable salt or solvate thereof, for use in the treatment of diabetes.

[0019] In another aspect, the present invention provides a compound as described herein, or a pharma- ceutically acceptable salt or solvate thereof, for use in the treatment of pulmonary arterial hypertension.

[0020] In another aspect, the present invention provides a compound as defined herein, or a pharma- ceutically acceptable salt or solvate thereof, for use in the treatment of non-alcoholic fatty liver disease (NAFLD), in particular non-alcoholic steatohepatitis (NASH).

[0021] In another aspect, the present invention provides a compound as defined herein, or a pharma- ceutically acceptable salt or solvate thereof, for use in the treatment of acute lung injury (ALI), ventilator-induced lung injury (VILI), or radiation-induced lung injury (RILI).

[0022] In another aspect, the present invention provides a compound as described herein, or a pharma- ceutically acceptable salt or solvate thereof, for use in the treatment of chronic kidney disease.

[0023] Suitably, the compounds defined herein, or pharma- ceutically acceptable salts or solvates thereof, are for use in the treatment of pulmonary arterial hypertension, IBD, Crohn's disease, ulcerative colitis, diabetes (especially in subjects with cardiovascular disease comorbidities), chronic kidney disease, ventilator-induced pulmonary injury (VILI) (e.g., in subjects treated for COVID-19), acute lung injury (ALI), acute respiratory distress syndrome (ARDS), idiopathic pulmonary fibrosis, non-alcoholic fatty liver disease (for example, but not limited to, hepatic steatosis due to inflammatory non-alcoholic steatohepatitis (NASH)), fibrosis or cirrhosis) or radiation-induced lung injury (RILI).

[0024] In another aspect, the present invention provides a compound as defined herein, or a pharma- ceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in inhibiting eNAMPT activity.Suitably, the present invention provides a compound as defined herein, or a pharma- ceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in inhibiting monomeric eNAMPT activity.

[0025] In another aspect, the present invention provides a method for suppressing eNAMPT activity in vitro or in vivo, said method comprising contacting a sample containing eNAMPT with an effective amount of a compound as defined herein, or a pharma- ceutically acceptable salt or solvate thereof.Suitably, said method is a method for suppressing monomeric eNAMPT activity.

[0026] In a further aspect, the present invention provides a method of treating: (i) Diabetes; (ii) cardiovascular disease (e.g., pulmonary arterial hypertension, acute coronary syndrome (ACS), congestive heart failure (CHF) or left ventricular hypertrophy); (iii) inflammatory bowel conditions (e.g., inflammatory bowel disease (IBD), Crohn's disease or ulcerative colitis) (iv) cancer (e.g., breast cancer, prostate cancer, or chronic lymphocytic leukemia (CLL)); (v) liver disease (e.g., nonalcoholic fatty liver disease (NAFLD), especially nonalcoholic steatohepatitis (NASH)); (vi) inflammatory skin conditions (e.g., psoriasis); (vii) pulmonary conditions (acute lung injury (ALI), ventilator-induced lung injury (VILI), radiation-induced lung injury (RILI), pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis)); (viii) arthritis (e.g., osteoarthritis or rheumatoid arthritis); (ix) renal disease (e.g., chronic kidney disease); or (x) sepsis; In a patient in need of such treatment, the method comprises administering to the patient a therapeutically effective amount of a compound defined herein, or a pharma- ceutically acceptable salt or solvate thereof, or a pharmaceutical composition defined herein.

[0027] In another aspect, in certain embodiments, the present invention provides a method of treating: (i) Diabetes; (ii) cardiovascular disease (e.g., pulmonary arterial hypertension, acute coronary syndrome (ACS), congestive heart failure (CHF) or left ventricular hypertrophy); (iii) inflammatory bowel conditions (e.g., inflammatory bowel disease (IBD), Crohn's disease or ulcerative colitis) (iv) cancer (e.g., breast cancer, prostate cancer, or chronic lymphocytic leukemia (CLL)); (v) liver disease (e.g., nonalcoholic fatty liver disease (NAFLD), especially nonalcoholic steatohepatitis (NASH)); hepatic steatosis, hepatic fibrosis or cirrhosis); (vi) a pulmonary condition (acute lung injury (ALI), ventilator-induced lung injury (VILI), radiation-induced lung injury (RILI), pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis)); or (vii) renal disease (e.g., chronic kidney disease); In a patient in need of such treatment, the method comprises administering to the patient a therapeutically effective amount of a compound defined herein, or a pharma- ceutically acceptable salt or solvate thereof, or a pharmaceutical composition defined herein.

[0028] In another aspect, in certain embodiments, the present invention provides a method of treating: (i) Diabetes; (ii) pulmonary arterial hypertension, acute coronary syndrome (ACS), congestive heart failure (CHF) or left ventricular hypertrophy; (iii) inflammatory bowel disease (IBD), Crohn's disease or ulcerative colitis; (iv) breast cancer, prostate cancer, or chronic lymphocytic leukemia (CLL) (v) nonalcoholic fatty liver disease (NAFLD), especially nonalcoholic steatohepatitis (NASH), hepatic steatosis, hepatic fibrosis or cirrhosis); (vi) psoriasis; (vii) acute lung injury (ALI), ventilator-induced lung injury (VILI), radiation-induced lung injury (RILI), pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis); (viii) osteoarthritis or rheumatoid arthritis; (ix) chronic kidney disease; or (x) sepsis; In a patient in need of such treatment, the method comprises administering to the patient a therapeutically effective amount of a compound defined herein, or a pharma- ceutically acceptable salt or solvate thereof, or a pharmaceutical composition defined herein.

[0029] In another aspect, in certain embodiments, the present invention provides a method of treating: (i) Diabetes; (ii) pulmonary arterial hypertension; (iii) inflammatory bowel disease (IBD), Crohn's disease or ulcerative colitis; (iv) nonalcoholic fatty liver disease (NAFLD), especially nonalcoholic steatohepatitis (NASH); (v) acute lung injury (ALI), ventilator-induced lung injury (VILI), radiation-induced lung injury (RILI); or (vi) chronic kidney disease; In a patient in need of such treatment, the method comprises administering to the patient a therapeutically effective amount of a compound defined herein, or a pharma- ceutically acceptable salt or solvate thereof, or a pharmaceutical composition defined herein.

[0030] In another aspect, in certain embodiments, the present invention provides a method of treating inflammatory bowel disease (IBD), Crohn's disease or ulcerative colitis in a patient in need of such treatment, comprising administering to said patient a therapeutically effective amount of a compound as defined herein, or a pharma- ceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein.

[0031] In another aspect, in certain aspects, the present invention provides a method of treating diabetes in a patient in need of such treatment, comprising administering to said patient a therapeutically effective amount of a compound as defined herein, or a pharma- ceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein.

[0032] In another aspect, in certain embodiments, the present invention provides a method of treating pulmonary arterial hypertension in a patient in need of such treatment, comprising administering to said patient a therapeutically effective amount of a compound as defined herein, or a pharma- ceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein.

[0033] In another aspect, in a particular aspect, the present invention provides a method of treating non-alcoholic fatty liver disease (NAFLD), in particular non-alcoholic steatohepatitis (NASH), in a patient in need of such treatment, comprising administering to said patient a therapeutically effective amount of a compound as defined herein, or a pharma- ceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein.

[0034] In another aspect, in certain aspects, the present invention provides a method of treating chronic kidney disease in a patient in need of such treatment, comprising administering to said patient a therapeutically effective amount of a compound as defined herein, or a pharma- ceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein.

[0035] In another aspect, the present invention provides the use of a compound as defined herein, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of: (i) Diabetes; (ii) cardiovascular disease (e.g., pulmonary arterial hypertension, acute coronary syndrome (ACS), congestive heart failure (CHF) or left ventricular hypertrophy); (iii) inflammatory bowel conditions (e.g., inflammatory bowel disease (IBD), Crohn's disease or ulcerative colitis) (iv) cancer (e.g., breast cancer, prostate cancer, or chronic lymphocytic leukemia (CLL)); (v) liver disease (e.g., nonalcoholic fatty liver disease (NAFLD), especially nonalcoholic steatohepatitis (NASH)); (vi) inflammatory skin conditions (e.g., psoriasis); (vii) pulmonary conditions (acute lung injury (ALI), ventilator-induced lung injury (VILI), radiation-induced lung injury (RILI), pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis)); (viii) arthritis (e.g., osteoarthritis or rheumatoid arthritis); (ix) renal disease (e.g., chronic kidney disease); or (x) Sepsis.

[0036] In another aspect, the present invention provides the use of a compound as defined herein, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of: (i) Diabetes; (ii) cardiovascular disease (e.g., pulmonary arterial hypertension, acute coronary syndrome (ACS), congestive heart failure (CHF) or left ventricular hypertrophy); (iii) inflammatory bowel conditions (e.g., inflammatory bowel disease (IBD), Crohn's disease or ulcerative colitis) (iv) cancer (e.g., breast cancer, prostate cancer, or chronic lymphocytic leukemia (CLL)); (v) liver disease (e.g., nonalcoholic fatty liver disease (NAFLD), especially nonalcoholic steatohepatitis (NASH)); hepatic steatosis, hepatic fibrosis or cirrhosis); (vi) pulmonary conditions (acute lung injury (ALI), ventilator-induced lung injury (VILI), radiation-induced lung injury (RILI), pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis)); (vii) Renal disease (e.g., chronic kidney disease).

[0037] In another aspect, the present invention provides the use of a compound as defined herein, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of: (i) Diabetes; (ii) pulmonary arterial hypertension, acute coronary syndrome (ACS), congestive heart failure (CHF) or left ventricular hypertrophy; (iii) inflammatory bowel disease (IBD), Crohn's disease or ulcerative colitis; (iv) breast cancer, prostate cancer, or chronic lymphocytic leukemia (CLL) (v) nonalcoholic fatty liver disease (NAFLD), especially nonalcoholic steatohepatitis (NASH), hepatic steatosis, hepatic fibrosis or cirrhosis); (vi) psoriasis; (vii) acute lung injury (ALI), ventilator-induced lung injury (VILI), radiation-induced lung injury (RILI), pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis); (viii) osteoarthritis or rheumatoid arthritis; (ix) chronic kidney disease; or (x) Sepsis.

[0038] In another aspect, the present invention provides the use of a compound as defined herein, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of: (i) Diabetes; (ii) pulmonary arterial hypertension; (iii) inflammatory bowel disease (IBD), Crohn's disease or ulcerative colitis; (iv) nonalcoholic fatty liver disease (NAFLD), especially nonalcoholic steatohepatitis (NASH); (v) acute lung injury (ALI), ventilator-induced lung injury (VILI), radiation-induced lung injury (RILI); or (vi) Chronic kidney disease.

[0039] In another aspect, the invention provides the use of a compound as defined herein, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of inflammatory bowel disease (IBD), Crohn's disease or ulcerative colitis.

[0040] In another aspect, the invention provides the use of a compound defined herein, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of diabetes.

[0041] In another aspect, the invention provides the use of a compound defined herein, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of pulmonary arterial hypertension.

[0042] In another aspect, the present invention provides the use of a compound as defined herein, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of non-alcoholic fatty liver disease (NAFLD), in particular non-alcoholic steatohepatitis (NASH).

[0043] In another aspect, the present invention provides the use of a compound as defined herein, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of acute lung injury (ALI), ventilator-induced lung injury (VILI), or radiation-induced lung injury (RILI).

[0044] In another aspect, the present invention provides the use of a compound as defined herein, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of chronic kidney disease:

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

[0046] In another aspect, the present invention provides a pharmaceutical composition as defined herein comprising a compound as defined herein, or a pharma- ceutically acceptable salt or solvate thereof, and one or more pharma- ceutically acceptable excipients.

[0047] Any suitable optional feature of any one particular embodiment of the present invention may also be any suitable optional feature of any other embodiment.

[0048] In one aspect, the invention provides a combination comprising a compound defined herein, or a pharma- ceutically acceptable salt thereof, together with one or more further therapeutic agents.

[0049] The present invention further provides methods of synthesizing the compounds defined herein, or a pharma- ceutically acceptable salt. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0050] definition Unless otherwise stated, the following terms used in the specification and claims have the meanings indicated below.

[0051] References to "treating" or "treatment" should be understood to include prevention and alleviation of confirmed symptoms of a condition. Thus, "treating" or "treatment" of a condition, disorder, or condition includes (1) preventing or delaying the appearance of clinical symptoms of the condition, disorder, or condition from developing in a human who may be afflicted with or predisposed to the condition, disorder, or condition, but who is not experiencing or exhibiting clinical or subclinical symptoms of the condition, disorder, or condition, (2) inhibiting the condition, disorder, or condition, i.e., arresting, reducing, or delaying the onset of the disease or its recurrence (in the case of maintenance therapy) or at least one clinical or subclinical symptom thereof, or (3) relieving, ameliorating, or regressing the disease, i.e., causing regression of the condition, disorder, or condition, or at least one clinical or subclinical symptom thereof.

[0052] "Therapeutically effective amount" means the amount of a compound that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity, and the age, weight, etc., of the mammal being treated.

[0053] As used herein, the term "alkyl" includes both straight-chain and branched-chain alkyl groups and their analogs. References to individual alkyl groups such as "propyl" are specific to the straight-chain version only, and references to individual branched-chain alkyl groups such as "isopropyl" are specific to the branched-chain version only. For example, "(1-6C)-alkyl" includes (1-4C)alkyl, (1-3C)alkyl, propyl, isopropyl, and t-butyl. A similar convention applies to other groups, for example, "phenyl(1-6C)alkyl" includes phenyl(1-4C)alkyl, benzyl, 1-phenylethyl, and 2-phenylethyl.

[0054] The term "(m-nC)" or "(m-nC) group" used alone or as a prefix, refers to any group having m to n carbon atoms.

[0055] An "alkylene," "alkenylene," or "alkynylene" group is an alkyl, alkenyl, or alkynyl group that is positioned between and serves to connect two other chemical groups. Thus, "(1-6C)alkylene" means a linear saturated divalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated divalent hydrocarbon radical of 3 to 6 carbon atoms, e.g., methylene, ethylene, propylene, 2-methylpropylene, pentylene, and the like.

[0056] "(2-6C)alkenylene" means a linear divalent hydrocarbon group of 2 to 6 carbon atoms or a branched divalent hydrocarbon group of 3 to 6 carbon atoms containing at least one double bond, such as, for example, ethenylene, 2,4-pentadienylene, and the like.

[0057] "(2-6C)alkynylene" means a linear divalent hydrocarbon radical of 2 to 6 carbon atoms or a branched divalent hydrocarbon radical of 3 to 6 carbon atoms containing at least one triple bond, such as, for example, ethynylene, propynylene, and butynylene.

[0058] "(3-8C)cycloalkyl" means a hydrocarbon ring containing 3 to 8 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or bicyclo[2.2.1]heptyl.

[0059] "(3-8C)cycloalkenyl" means a hydrocarbon ring containing at least one double bond, for example cyclobutenyl, cyclopentenyl, cyclohexenyl or cycloheptenyl, for example 3-cyclohexen-1-yl, or cyclooctenyl.

[0060] "(3-8C)cycloalkyl-(1-6C)alkylene" means a (3-8C)cycloalkyl group covalently linked to a (1-6C)alkylene group, both of which are defined herein.

[0061] The term "halo" or "halogeno" refers to fluoro, chloro, bromo, and iodo.

[0062] The term "heterocyclyl", "heterocyclic" or "heterocycle" refers to a non-aromatic saturated or partially saturated monocyclic, fused, bridged, or spiro bicyclic heterocyclic ring system(s). The term heterocyclyl includes both monovalent and divalent species. A monocyclic heterocycle contains about 3 to 12 (suitably 3 to 7) ring atoms, while a bicyclic heterocycle having 1 to 5 (suitably 1, 2 or 3) heteroatoms selected from nitrogen, oxygen or sulfur in the ring contains 7 to 17 ring atoms, suitably 7 to 12 ring atoms in the ring. A bicyclic heterocycle contains about 7 to about 17 ring atoms, suitably 7 to 12 ring atoms. The bicyclic heterocycle(s) may be a fused, spiro, or bridged ring system.

[0063] Examples of heterocyclic groups include cyclic ethers such as oxiranyl, oxetanyl, tetrahydrofuranyl, dioxanyl, and substituted cyclic ethers. Heterocycles containing nitrogen include, for example, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrotriazinyl, tetrahydropyrazolyl, and the like. Exemplary sulfur-containing heterocycles include tetrahydrothienyl, dihydro-1,3-dithiol, tetrahydro-2H-thiopyran, and hexahydrothiepin. Other heterocycles include dihydro-oxathiolyl, tetrahydro-oxazolyl, tetrahydro-oxadiazolyl, tetrahydrodioxazolyl, tetrahydro-oxathiazolyl, hexahydrotriazinyl, tetrahydro-oxazinyl, morpholinyl, thiomorpholinyl, tetrahydropyrimidinyl, dioxolinyl, octahydrobenzofuranyl, octahydrobenzimidazolyl, and octahydrobenzothiazolyl. For heterocycles containing sulfur, oxidized sulfur heterocycles containing SO or SO2 groups are also included. Examples include the sulfoxides and sulfones of tetrahydrothienyl and thiomorpholinyl, such as tetrahydrothienyl 1,1-dioxide and thiomorpholinyl 1,1-dioxide. Suitable values ​​for heterocyclyl groups having one or two oxo (=O) or thioxo (=S) substituents are, for example, 2-oxopyrrolidinyl, 2-thioxopyrrolidinyl, 2-oxoimidazolidinyl, 2-thiooxoimidazolidinyl, 2-oxopiperidinyl, 2,5-dioxoimidazolidinyl, 2,5-dioxoimidazolidinyl or 2,6-dioxopiperidinyl. Exemplary heterocyclyl groups are saturated monocyclic 3- to 7-membered heterocyclyls containing 1, 2 or 3 heteroatoms selected from nitrogen, oxygen or sulfur, such as azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, tetrahydrothienyl, tetrahydrothienyl 1,1-dioxide, thiomorpholinyl, thiomorpholinyl 1,1-dioxide, piperidinyl, homopiperidinyl, piperazinyl or homopiperazinyl. As will be appreciated by those skilled in the art, any heterocycle may be linked to another group through any suitable atom, for example, through a carbon or nitrogen atom.However, references herein to piperidino or morpholino refer to a piperidin-1-yl or morpholin-4-yl ring linked via the ring nitrogen.

[0064] Suitably, the nitrogen atom in the heterocyclic ring system may be in the form of an alkylammonium salt, for example a dimethylpiperidin-1-ium salt: [ka]

[0065] "Bridged ring system" means a ring system in which two rings share more than two atoms, see, for example, Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages 131-133, 1992. Examples of bridged heterocyclyl ring systems include aza-bicyclo[2.2.1]heptane, 2-oxa-5-azabicyclo[2.2.1]heptane, aza-bicyclo[2.2.2]octane, aza-bicyclo[3.2.1]octane, and quinuclidine.

[0066] "Heterocyclyl(1-6C)alkyl" means a heterocyclyl group covalently linked to a (1-6C)alkylene group, both of which are defined herein.

[0067] The term "heteroaryl" or "heteroaromatic" refers to an aromatic monocyclic, bicyclic or polycyclic ring incorporating one or more (e.g., 1 to 4, particularly 1, 2 or 3) heteroatoms selected from nitrogen, oxygen or sulfur. The term heteroaryl includes both monovalent and divalent species. Examples of heteroaryl groups are monocyclic and bicyclic groups containing 5 to 12 ring members, more usually 5 to 10 ring members. Heteroaryl groups can be, for example, 5- or 6-membered monocyclic rings or 9- or 10-membered bicyclic rings, e.g., fused 5- and 6-membered rings or a bicyclic structure formed from two fused 6-membered rings. Each ring may contain up to about 4 heteroatoms, typically selected from nitrogen, sulfur and oxygen. Typically, heteroaryl rings will contain up to 3 heteroatoms, more usually up to 2 heteroatoms, e.g., a single heteroatom. In one embodiment, the heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atoms in the heteroaryl ring may 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. Generally, the number of basic nitrogen atoms present in a heteroaryl group, including any amino group substituents on the ring, will be fewer than five.

[0068] Examples of heteroaryl include furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazenyl, benzofuranyl, indolyl, isoindolyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzothiazolyl, indazolyl, purinyl, benzofurazanyl, quinolyl, and isoquinolyl. aryl, quinazolinyl, quinoxalinyl, cinnolinyl, pteridinyl, naphthyridinyl, carbazolyl, phenazinyl, benzisoquinolinyl, pyridopyrazinyl, thieno[2,3-b]furanyl, 2H-furo[3,2-b]-pyranyl, 5H-pyrido[2,3-d]-o-oxazinyl, 1H-pyrazolo[4,3-d]-oxazolyl, 4H-imidazo[4,5-d]thiazolyl, pyrazino[2,3-d]pyridazinyl, imidazo[2,1-b]thiazolyl, and imidazo[1,2-b][1,2,4]triazinyl. "Heteroaryl" also covers partially aromatic bicyclic or polycyclic ring systems in which at least one ring is aromatic and one or more of the other ring(s) is non-aromatic, saturated or partially saturated, provided that at least one ring contains one or more heteroatoms selected from nitrogen, oxygen or sulfur. Examples of partially aromatic heteroaryl groups include, for example, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 2-oxo-1,2,3,4-tetrahydroquinolinyl, dihydrobenzthienyl, dihydrobenzofuranyl, 2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,3]dioxolyl, 2,2-dioxo-1,3-dihydro-2-benzothienyl, 4,5,6,7-tetrahydrobenzofuranyl, indolinyl, 1,2,3,4-tetrahydro-1,8-naphthyridinyl, 1,2,3,4-tetrahydropyrido[2,3-bpyrazinyl, and 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl.

[0069] Examples of 5-membered heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl and tetrazolyl groups.

[0070] Examples of 6-membered heteroaryl groups include, but are not limited to, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, and triazinyl.

[0071] The bicyclic heteroaryl group may be, for example, a group selected from the following: a benzene ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; a pyridine ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; a pyrimidine ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; a pyrrole ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; a pyrazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; a pyrazine ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; an imidazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; an oxazole ring fused to a 5- or 6-membered ring containing one or two ring heteroatoms; an isoxazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; a thiazole ring fused to a 5- or 6-membered ring containing one or two ring heteroatoms; an isothiazole ring fused to a 5- or 6-membered ring containing one or two ring heteroatoms; a thiophene ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; a furan ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; a cyclohexyl ring fused to a 5- or 6-membered heteroaromatic ring containing 1, 2, or 3 ring heteroatoms; and A cyclopentyl ring fused to a 5- or 6-membered heteroaromatic ring containing 1, 2, or 3 ring heteroatoms.

[0072] Illustrative examples of bicyclic heteroaryl groups containing a 6-membered ring fused to a 5-membered ring include, but are not limited to, benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzisothiazolyl, benzisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, indolinyl, isoindolinyl, purinyl (e.g., adeninyl, guaninyl), indazolyl, benzodioxolyl, and pyrazolopyridinyl groups.

[0073] Illustrative examples of bicyclic heteroaryl groups containing two fused six-membered rings include, but are not limited to, quinolinyl, isoquinolinyl, chromanyl, thiochromanyl, chromenyl, isochromanyl, chromanyl, isochromanyl, benzodioxanyl, quinolidinyl, benzoxazinyl, benzodiazinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, and pteridinyl groups.

[0074] "Heteroaryl(1-6C)alkyl" means a heteroaryl group covalently linked to a (1-6C)alkylene group, both of which are defined herein. Examples of heteroaralkyl groups include pyridin-3-ylmethyl, 3-(benzofuran-2-yl)propyl, and the like.

[0075] The term "aryl" refers to a cyclic or polycyclic aromatic ring having from 5 to 12 carbon atoms. The term aryl includes both monovalent and divalent species. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, and the like. In certain embodiments, aryl is phenyl.

[0076] The term "aryl(1-6C)alkyl" means an aryl group covalently linked to a (1-6C)alkylene group, both of which are defined herein. Examples of aryl-(1-6C)alkyl groups include benzyl, phenylethyl, and the like.

[0077] Multiple compound terms are also used herein to describe groups that contain multiple functions. Such terms are understood by those skilled in the art. For example, heterocyclyl(m-nC)alkyl includes (m-nC)alkyl substituted with heterocyclyl.

[0078] The term "optionally substituted" refers to groups, structures, or molecules that are substituted and to groups, structures, or molecules that are not substituted. 1 The term "any CH, CH2, CH3 group or heteroatom (i.e., NH) within a group is optionally substituted" is suitably used in R 1 It means that (any) one of the hydrogen radicals of the group is replaced with the associated defined group.

[0079] When any substituent is selected from "one or more" groups, this definition should be understood to include all substituents selected from one of the specified groups, or substituents selected from two or more of the specified groups.

[0080] The term "compounds of the invention" refers to the compounds (both generically and specifically) disclosed herein.

[0081] Compounds of the Invention In one aspect, the present invention relates to a compound of formula I, as shown below, or a pharma- ceutically acceptable salt or solvate thereof: [ka] wherein R1 is selected from the following: (i) a group of formula II: [ka] During the ceremony: Ring A is selected from phenyl or 5- or 6-membered heteroaryl; n is 0, 1 or 2; Each R group, if present, is selected from: halo, nitro, cyano, R 2a , -[CH2] q -NR 2a R 2b , -[CH2] q -OR 2a , -[CH2] q -C(O)R 2a , -[CH2] q -C(O)OR 2a , -[CH2] q -OC(O)R 2a , -[CH2] q -C(O)N(R 2b )R 2a , -[CH2] q -N(R 2b )C(O)R 2a , -[CH2] q -N(R 2c )-C(O)-N(R 2b )R 2a , -[CH2] q -S(O) p R 2a( where p is 0, 1 or 2), -[CH2] q -SO2N(R 2b )R 2a , -[CH2] q -N(R 2b )SO2R 2a ; wherein q is 0, 1, 2, or 3; R 2ais hydrogen or (1-4C)alkyl, optionally substituted with halo, hydroxy, amino or cyano; and R 2b and R 2c is hydrogen, or (1-2C)alkyl; R N is selected from hydrogen or methyl; or R groups and R N is linked to form a fused 5- or 6-membered heterocycle to Ring A, wherein the fused 5- or 6-membered heterocycle contains 1 or 2 N atoms and is optionally substituted with halo, hydroxy, (1-2C)alkyl, (1-2C)haloalkyl, cyano or amino; W1 is: [ka] wherein A1, A2, A3 or A4 is selected from CH, N or CF, with the proviso: Only one or two of A1, A2, A3 or A4 may be N; and Only one or two of A1, A2, A3 or A4 may be CF; X1 is a linker group of the formula: -[CH2] n1 -L1-[CH2] n2 - During the ceremony, n1 and n2 are selected from 0 or 1; L1 is -O-, -S-, -SO-, -SO2-, -N(R x1a )-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R x1a )-, -N(R x1a )C(O)-, -N(R x1b )C(O)N(R x1a )-, -N(R x1a )C(O)O-, -OC(O)N(R x1a )-, -S(O)2N(R x1a ), -N(R x1a )SO2-, or -C(O)N(R x1a )SO2-, or -SO2N(Rx1a )C(O)-; and wherein R x1a and R x1b are each independently selected from hydrogen or (1-2C)alkyl; Y is selected from carbocycle, aryl, heteroaryl, or heterocycle, which is optionally selected from halo, nitro, cyano, R y1a , -[CH2] r -NR y1a R y1b , -[CH2] r -OR y1a , -[CH2] r -C(O)R y1a , -[CH2] r -C(O)OR y1a , -[CH2] r -OC(O)R y1a , -[CH2] r -C(O)N(R y1b )R y1a , -[CH2] r -N(R y1b )C(O)R y1a , -[CH2] r -N(R y1c )-C(O)-N(R y1b )R y1a , -[CH2] r -S(O) p R y1a (wherein p is 0, 1 or 2), -[CH2] r -SO2N(R y1b )R y1a , or -[CH2] r -N(R y1b )SO2R y1a Replaced by; wherein r is 0, 1, 2, or 3; R y1 is hydrogen or (1-4C)alkyl, optionally substituted with halo, hydroxy, amino or cyano; and R y1b and R y1c is hydrogen or (1-2C)alkyl; (ii) a group of formula III: [ka] During the ceremony: Ring B is selected from phenyl or 5- or 6-membered heteroaryl; m is 0, 1, or 2; Each R group, if present, is selected from the following: halo, nitro, cyano, R 3a , -[CH2] q1 -NR 3a R 3b , -[CH2] q1 -OR 3a , -[CH2] q1 -C(O)R 3a , -[CH2] q1 -C(O)OR 3a , -[CH2] q1 -OC(O)R 3a , -[CH2] q1 -C(O)N(R 3b )R 3a , -[CH2] q1 -N(R 3b )C(O)R 3a , -[CH2] q1 -N(R 3c )-C(O)-N(R 3b )R 3a , -[CH2] q1 -S(O) p R 3a (wherein p is 0, 1 or 2), -[CH2] q1 -SO2N(R 3b )R 3a , -[CH2] q1 -N(R 3b )SO2R 3a Selected from; In the formula, q1 is 0, 1, 2, or 3; R 3a is hydrogen or (1-4C)alkyl, optionally substituted with halo, hydroxy, amino or cyano; and R 3b and R 3c is hydrogen or (1-2C)alkyl; V2 is -C(R v2a R v2b )C(R v2c R v2d)-or-C(R v2a )=C(R v2c )-, wherein R v2a , R v2b , R v2c and R v2d are each independently selected from hydrogen or methyl, or R v2a and R v2c are linked to form a cyclopropyl ring; Z2 is a 4C alkylene linker optionally substituted with one or more fluoro atoms; W2 is a carbocycle, aryl, heteroaryl or heterocycle, which optionally includes halo, nitro, cyano, R w2a , -[CH2] s -NR w2a R w2b , -[CH2] s -OR w2a , -[CH2] s -C(O)R w2a , -[CH2] s -C(O)OR w2a , -[CH2] s -OC(O)R w2a , -[CH2] s -C(O)N(R w2b )R w2a , -[CH2] s -N(R w2b )C(O)R w2a , -[CH2] s -N(R w2c )-C(O)-N(R w2b )R w2a , -[CH2] s -S(O) p R w2a (wherein p is 0, 1 or 2), -[CH2] s -SO2N(R w2b )R w2a , or -[CH2] s -N(R w2b )SO2R w2a is substituted by; s is 0, 1, or 2; R w2ais hydrogen or (1-4C)alkyl, optionally substituted with halo, hydroxy, amino or cyano; and R w2b and R w2c is hydrogen, or (1-2C)alkyl; X2 is a linker group of the formula: -[CH2] m1 -L2-[CH2] m2 - During the ceremony m1 and m2 are selected from 0 or 1; L2 is -O-, -S-, -SO-, -SO2-, -N(R x2a )-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R x2a )-, -N(R x2a )C(O)-, -N(R x2b )C(O)N(R x2a )-, -N(R x2a )C(O)O-, -OC(O)N(R x2a )-, -S(O)2N(R x2a ), N(R x2a )SO2, or C(O)N(R x2a )SO2, or -SO2N(R x2a )C(O)—; and wherein R x2a and R x2b are each independently selected from hydrogen or (1-2C)alkyl; Y2 is selected from carbocycle, aryl, heteroaryl, or heterocycle, which is optionally selected from halo, nitro, cyano, R y2a , -[CH2] t -NR y2a R y2b , -[CH2] t -OR y2a , -[CH2] t -C(O)R y2a , -[CH2] t -C(O)OR y2a , -[CH2] t -OC(O)R y2a , -[CH2] t -C(O)N(R y2b )R y2a , -[CH2]t -N(R y2b )C(O)R y2a , -[CH2] t -N(R y2c )-C(O)-N(R y2b )R y2a , -[CH2] t -S(O) p R y2a (wherein p is 0, 1 or 2), -[CH2] t -SO2N(R y2b )R y2a , or -[CH2] t -N(R y2b )SO2R y2a has been replaced by; wherein t is 0, 1, 2, or 3; R y2a is hydrogen or (1-4C)alkyl, optionally substituted with halo, hydroxy, amino or cyano; and R y2b and R y2c is hydrogen, or (1-2C)alkyl; (iii) a group of formula IV: [ka] During the ceremony, Ring C is selected from phenyl, 5- or 6-membered heteroaryl; k is 0, 1, or 2; Each R group, if present, is selected from the following: halo, nitro, cyano, R 4a , -[CH2] q2 -NR 4a R 4b , -[CH2] q2 -OR 4a , -[CH2] q2 -C(O)R 4a , -[CH2] q2 -C(O)OR 4a , -[CH2] q2 -OC(O)R 4a , -[CH2] q2 -C(O)N(R 4b )R 4a , -[CH2] q2-N(R 4b )C(O)R 4a , -[CH2] q2 -N(R 4c )-C(O)-N(R 4b )R 4a , -[CH2] q2 -S(O) p R 4a (wherein p is 0, 1 or 2), -[CH2] q2 -SO2N(R 4b )R 4a , -[CH2] q2 -N(R 4b )SO2R 4a Selected from; In the formula, q2 is 0, 1, 2, or 3; R 4a is hydrogen or (1-4C)alkyl, optionally substituted with halo, hydroxy, amino or cyano; and R 4b and R 4c is hydrogen or (1-2C)alkyl; L is a 6C alkylene linker optionally substituted with one or more fluoro atoms; X is -O-, -CR xa R xb -, -S-, -SO-, -SO2-, -N(R xa )—, —C(O)—; and wherein R xa and R xb are each independently selected from hydrogen or methyl; A 30 and A 31 is selected from CH, N, or CF; A 32 and A 33 is selected from CH or N; However, A 30 , A 31 , A 32 and A 33 Only one or two of may be N; A 34 and A 35 is CH, N, or CR 30 Selected from; A36 , A 37 and A 38 is selected from CH or N; However, A 34 , A 35 , A 36 , A 37 and A 38 may be N; And, in the formula, R 30 are halo, nitro, cyano, R 30a , -[CH2] t -NR 30a R 30b , -[CH2] t -OR 30a , -[CH2] t -C(O)R 30a , -[CH2] t -C(O)OR 30a , -[CH2] t -OC(O)R 30a , -[CH2] t -C(O)N(R 30b )R 30a , -[CH2] t -N(R 30b )C(O)R 30a , -[CH2] t -N(R 30c )-C(O)-N(R 30b )R 30a , -[CH2] t -S(O) p R 30a (wherein p is 0, 1 or 2), -[CH2] t -SO2N(R 30b )R 30a , or -[CH2] t -N(R 30b )SO2R 30a is selected from: t is 0, 1, 2, or 3; R 30a is hydrogen or (1-4C)alkyl, optionally substituted with halo, hydroxy, amino or cyano; and R 30b and R 30c is hydrogen or (1-2C)alkyl; (iv) a group of formula V or VI: [ka] During the ceremony: A 40 is selected from NH, NMe, or O; A 42 , A 43 , A 44 and A 46 are each independently selected from CH, N, or CR2; A 41 and A 45 are each independently selected from C or N; However, the following conditions are met: (i)A 40 , A 41 , A 42 , A 43 , A 44 , A 45 and A 46 Only up to three of the are N; (ii)A 41 and A 45 cannot both be N; (iii)A 40 , A 42 , A 43 , A 44 and A 46 Only one or two of the may be CR2; A 51 is selected from NH, NMe, CH or CR2; A 50 , A 53 , A 54 and A 55 are each independently selected from CH, N, or CR2; A 52 and A 56 are each independently selected from C or N; However, the following conditions are met: (i)A 50 , A 51 , A 52 , A 53 , A 54 , A 55 and A56 up to three of which are N; (ii)A 52 and A 56 cannot both be N; (iii)A 50 , A 51 , A 53 , A 54 and A 55 Only one or two of the may be CR2; wherein R2 is as defined above; W4 is: [ka] In the formula, A 4a , A 4b , A 4c , or A 4d is selected from CH, N or CF, with the proviso: A 4a , A 4b , A 4c Or A 4d and A 4a , A 4b , A 4c Or A 4d only one or two of may be CF; X4 is a linker group of the formula: -[CH2] j1 -L4-[CH2] j2 - During the ceremony, j1 and j2 are selected from 0 or 1; L4 is -O-, -S-, -SO-, -SO2-, -N(R x4a )-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R x4a )-, -N(R x4a )C(O)-, -N(R x4b )C(O)N(R x4a )-, -N(R x4a )C(O)O-, -OC(O)N(R x4a )-, -S(O)2N(R x4a ), -N(Rx4a )SO2-, or -C(O)N(R x4a )SO2-, or -SO2N(R x4a )C(O)—; and wherein R x4a and R x4b are each independently selected from hydrogen or (1-2C)alkyl; Y4 is selected from carbocycle, aryl, heteroaryl or heterocycle, which is optionally selected from halo, nitro, cyano, R y4a , -[CH2] u -NR y4a R y4b , -[CH2] u -OR y4a , -[CH2] u -C(O)R y4a , -[CH2] u -C(O)OR y4a , -[CH2] u -OC(O)R y4a , -[CH2] u -C(O)N(R y4b )R y4a , -[CH2] u -N(R y4b )C(O)R y4a , -[CH2] u -N(R y4c )-C(O)-N(R y4b )R y4a , -[CH2] u -S(O) p R y4a (wherein p is 0, 1 or 2), -[CH2] u -SO2N(R y4b )R y4a , or -[CH2] u -N(R y4b )SO2R y4a has been replaced by; wherein u is 0, 1, 2, or 3; R y4 is hydrogen or (1-4C)alkyl, optionally substituted with halo, hydroxy, amino or cyano; and R y4b and R y4c is hydrogen or (1-2C)alkyl.

[0082] Specific compounds of the present invention include, for example, compounds of formula I or any subformula thereof, or pharma- ceutically acceptable salts and / or solvates thereof, where, unless otherwise specified, R1, and any associated substituents, have the meanings defined hereinbefore or in any of paragraphs (1) to (33) hereinbelow: (1) R1 is selected from the following: (i) a group of formula II: [ka] During the ceremony: Ring A is selected from phenyl or 5- or 6-membered heteroaryl; n is 0, 1 or 2; Each R group, when present, is selected from the following: halo, nitro, cyano, R 2a , -[CH2] q -NR 2a R 2b , -[CH2] q -OR 2a , -[CH2] q -C(O)R 2a , -[CH2] q -C(O)OR 2a , -[CH2] q -OC(O)R 2a , -[CH2] q -C(O)N(R 2b )R 2a , -[CH2] q -N(R 2b )C(O)R 2a , or -[CH2] q -S(O) p R 2a where p is 0, 1 or 2; wherein q is 0, 1, or 2; R 2a is hydrogen or (1-4C)alkyl, optionally substituted with halo, hydroxy, amino or cyano; and R 2b , and R 2cis hydrogen or (1-2C)alkyl; R N is selected from hydrogen or methyl; or R groups and R N is linked to form a fused 5- or 6-membered heterocycle to Ring A, wherein said fused 5- or 6-membered heterocycle contains 1 or 2 N atoms and is optionally substituted with halo, hydroxy, (1-2C)alkyl, (1-2C)haloalkyl, cyano or amino; W1 is: [ka] wherein A1, A2, A3 or A4 is selected from CH, N or CF, provided that: Only one or two of A1, A2, A3 or A4 may be N; Only one or two of A1, A2, A3 or A4 may be CF; X1 is a linker group of the formula: -[CH2] n1 -L1-[CH2] n2 - During the ceremony, n1 and n2 are selected from 0 or 1; L1 is -O-, -S-, -SO-, -SO2-, -N(R x1a )-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R x1a )-, -N(R x1a )C(O)-, -N(R x1b )C(O)N(R x1a )-, -N(R x1a )C(O)O- or -OC(O)N(R x1a )-; and wherein R x1a and R x1b are each independently selected from hydrogen or (1-2C)alkyl; Y1 is selected from carbocycle, aryl, heteroaryl or heterocycle, which is optionally selected from halo, nitro, cyano, R y1a , -[CH2] r -NRy1a R y1b , -[CH2] r -OR y1a , -[CH2] r -C(O)R y1a , -[CH2] r -C(O)OR y1a , -[CH2] r -OC(O)R y1a , -[CH2] r -C(O)N(R y1b )R y1a , -[CH2] r -N(R y1b )C(O)R y1a or -[CH2] r -S(O) p R y1a where p is 0, 1 or 2; where r is 0, 1, or 2; R y1 is hydrogen or (1-4C)alkyl, optionally substituted with halo, hydroxy, amino or cyano; and R y1b and R y1c is hydrogen or (1-2C)alkyl; (ii) a group of formula III: [ka] During the ceremony: Ring B is selected from phenyl or 5- or 6-membered heteroaryl; m is 0, 1, or 2; Each R group, if present, is selected from the following: halo, nitro, cyano, R 3a , -[CH2] q1 -NR 3a R 3b , -[CH2] q1 -OR 3a , -[CH2] q1 -C(O)R 3a , -[CH2] q1 -C(O)OR 3a , -[CH2] q1 -OC(O)R 3a , -[CH2]q1 -C(O)N(R 3b )R 3a , -[CH2] q1 -N(R 3b )C(O)R 3a or -[CH2] q1 -S(O) p R 3a( where p is 0, 1 or 2; In the formula, q1 is 0, 1, or 2; R 3a is hydrogen or (1-4C)alkyl, optionally substituted with halo, hydroxy, amino or cyano; and R 3b and R 3c is hydrogen or (1-2C)alkyl; V2 is -C(R v2a R v2b )C(R v2c R v2d )-or-C(R v2a )=C(R v2c )-, wherein R v2a , R v2b , R v2c and R v2d are each independently selected from hydrogen or methyl, or R v2a and R v2c are linked to form a cyclopropyl ring; Z2 is a 4C alkylene linker optionally substituted with one or more fluoro atoms; W2 is a carbocycle, aryl, heteroaryl or heterocycle, which is optionally selected from halo, nitro, cyano, R w2a , -[CH2] s -NR w2a R w2b , -[CH2] s -OR w2a , -[CH2] s -C(O)R w2a , -[CH2] s -C(O)OR w2a , -[CH2] s -OC(O)R w2a , -[CH2] s -C(O)N(Rw2b )R w2a , -[CH2] s -N(R w2b )C(O)R w2a or -[CH2] s -S(O) p R w2a where p is 0, 1 or 2; s is 0, 1, or 2; R w2a is hydrogen or (1-4C)alkyl, optionally substituted with halo, hydroxy, amino or cyano; and R w2b is hydrogen or (1-2C)alkyl; X2 is a linker group of the formula: -[CH2] m1 -L2-[CH2] m2 - During the ceremony, m1 and m2 are selected from 0 or 1; L2 is -O-, -S-, -SO-, -SO2-, -N(R x2a )-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R x2a )-, -N(R x2a )C(O)-, -N(R x2b )C(O)N(R x2a )-, -N(R x2a )C(O)O- or -OC(O)N(R x2a )-; and wherein R x2a and R x2b are each independently selected from hydrogen or (1-2C)alkyl; Y2 is selected from carbocycle, aryl, heteroaryl or heterocycle, which is optionally selected from halo, nitro, cyano, R y2a , -[CH2] t -NR y2a R y2b , -[CH2] t -OR y2a , -[CH2] t -C(O)R y2a , -[CH2] t -C(O)OR y2a, -[CH2] t -OC(O)R y2a , -[CH2] t -C(O)N(R y2b )R y2a , -[CH2] t -N(R y2b )C(O)R y2a or -[CH2] t -S(O) p R y2a where p is 0, 1 or 2; where t is 0, 1, or 2; R y2a is hydrogen or (1-4C)alkyl, optionally substituted with halo, hydroxy, amino or cyano; and R y2b and R y2c is hydrogen, or (1-2C)alkyl; (iii) a group of formula IV: [ka] During the ceremony: Ring C is selected from phenyl, 5- or 6-membered heteroaryl; k is 0, 1, or 2; Each R group, if present, is selected from the following: halo, nitro, cyano, R 4a , -[CH2] q2 -NR 4a R 4b , -[CH2] q2 -OR 4a , -[CH2] q2 -C(O)R 4a , -[CH2] q2 -C(O)OR 4a , -[CH2] q2 -OC(O)R 4a , -[CH2] q2 -C(O)N(R 4b )R 4a or -[CH2] q2 -N(R 4b )C(O)R 4a , -[CH2] q2 -S(O) p R4a where p is 0, 1 or 2; In the formula, q2 is 0, 1, 2, or 3; R 4a is hydrogen or (1-4C)alkyl, optionally substituted with halo, hydroxy, amino or cyano; and R 4b and R 4c is hydrogen or (1-2C)alkyl; L is a 6C alkylene linker optionally substituted with one or more fluoro atoms; X is -O-, -CR xa R xb -, -S-, -SO-, -SO2-, -N(R xa )—, —C(O)—; and wherein R xa and R xb are each independently selected from hydrogen or methyl; A 30 and A 31 is selected from CH, N, or CF; A 32 and A 33 is selected from CH or N; However, A 30 , A 31 , A 32 and A 33 may be N; A 34 and A 35 is CH, N, or CR 30 Selected from; A 36 , A 37 and A 38 is selected from CH or N; However, A 34 , A 35 , A 36 , A 37 and A 38 Only one or two of may be N; And, in the formula, R 30 are halo, nitro, cyano, R 30a , -[CH2] t -NR30a R 30b , -[CH2] t -OR 30a , -[CH2] t -C(O)R 30a , -[CH2] t -C(O)OR 30a , -[CH2] t -OC(O)R 30a , -[CH2] t -C(O)N(R 30b )R 30a , -[CH2] t -N(R 30b )C(O)R 30a or -[CH2] t -S(O) p R 30a where p is 0, 1 or 2; t is 0, 1, or 2; R 30a is hydrogen or (1-4C)alkyl, optionally substituted with halo, hydroxy, amino or cyano; and R 30b and R 30c is hydrogen or (1-2C)alkyl; (iv) a group of formula V or VI: [ka] During the ceremony: A 40 is selected from NH, NMe, or O; A 42 , A 43 , A 44 and A 46 are each independently selected from CH, N, or CR2; A 41 and A 45 are each independently selected from C or N; However, the following conditions are met: (i)A 40 , A 41 , A 42 , A 43 , A 44 , A 45 and A 46Only up to three of the are N; (ii)A 41 and A 45 cannot both be N; (iii)A 40 , A 42 , A 43 , A 44 and A 46 Only one or two of the may be CR2; A 51 is selected from NH, NMe, CH or CR2; A 50 , A 53 , A 54 and A 55 are each independently selected from CH, N, or CR2; A 52 and A 56 are each independently selected from C or N; However, the following conditions are met: (i)A 50 , A 51 , A 52 , A 53 , A 54 , A 55 and A 56 up to three of which are N; (ii)A 52 and A 56 cannot both be N; (iii)A 50 , A 51 , A 53 , A 54 and A 55 Only one or two of the may be CR2; wherein R2 is as defined above; W4 is: [ka] In the formula, A 4a , A 4b , A 4c , or A 4d is selected from CH, N or CF, with the proviso that: A 4a , A 4b, A 4c Or A 4d and A 4a , A 4b , A 4c Or A 4d only one or two of may be CF; X4 is a linker group of the formula: -[CH2] j1 -L4-[CH2] j2 - During the ceremony, j1 and j2 are selected from 0 or 1; L4 is -O-, -S-, -SO-, -SO2-, -N(R x4a )-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R x4a )-, -N(R x4a )C(O)-, -N(R x4b )C(O)N(R x4a )-, -N(R x4a )C(O)O- or -OC(O)N(R x4a )-; and wherein R x4a and R x4b are each independently selected from hydrogen or (1-2C)alkyl; Y4 is selected from carbocycle, aryl, heteroaryl or heterocycle, which is optionally selected from halo, nitro, cyano, R y4a , -[CH2] u -NR y4a R y4b , -[CH2] u -OR y4a , -[CH2] u -C(O)R y4a , -[CH2] u -C(O)OR y4a , -[CH2] u -OC(O)R y4a , -[CH2] u -C(O)N(R y4b )R y4a , -[CH2] u -N(R y4b )C(O)R y4a or -[CH2] u-N(R y4c )-C(O)-N(R y4b )R y4a has been replaced by; wherein u is 0, 1, or 2; R y4 is hydrogen or (1-4C)alkyl, optionally substituted with halo, hydroxy, amino or cyano; and R y4b and R y4c is hydrogen or (1-2C)alkyl. (2) R1 is selected from the following: (i) a group of formula II: [ka] During the ceremony: Ring A is selected from phenyl or 5- or 6-membered heteroaryl; n is 0, 1 or 2; Each R group, when present, is: halo, nitro, cyano, R 2a , -[CH2] q -NR 2a R 2b , -[CH2] q -OR 2a , -[CH2] q -C(O)R 2a , -[CH2] q -C(O)OR 2a or -[CH2] q -OC(O)R 2a Selected from; wherein q is 0, 1, or 2; R 2a is hydrogen or (1-2C)alkyl, optionally substituted with halo, hydroxy, amino or cyano; and R 2b is hydrogen or (1-2C)alkyl; R N is selected from hydrogen or methyl; or R groups and R Nis linked to ring A to form a fused 5- or 6-membered heterocycle, the fused 5- or 6-membered heterocycle containing 1 or 2 N atoms and optionally substituted with halo, hydroxy, (1-2C)alkyl, (1-2C)haloalkyl, cyano or amino; W1 is: [ka] wherein A1, A2, A3 or A4 is selected from CH, N or CF, provided that: Only one or two of A1, A2, A3 or A4 may be N; and Only one or two of A1, A2, A3 or A4 may be CF; X1 is a linker group of the formula: -[CH2] n1 -L1-[CH2] n2 - During the ceremony, n1 and n2 are selected from 0 or 1; L1 is -O-, -S-, -SO-, -SO2-, -N(R x1a )-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R x1a )-or-N(R x1a )C(O)—; and wherein R x1a and R x1b are each independently selected from hydrogen or (1-2C)alkyl; Y1 is selected from carbocycle, aryl, heteroaryl or heterocycle, which is optionally selected from halo, nitro, cyano, R y1a , -[CH2] r -NR y1a R y1b , -[CH2] r -OR y1a , -[CH2] r -C(O)R y1a , -[CH2] r -C(O)OR y1a or -[CH2] r -OC(O)R y1a has been replaced by; wherein r is 0 or 1; R y1a is hydrogen or (1-2C)alkyl, optionally substituted with halo, hydroxy, amino or cyano; and R y1b and R y1c is hydrogen or (1-2C)alkyl; (ii) a group of formula III: [ka] During the ceremony: Ring B is selected from phenyl or 5- or 6-membered heteroaryl; m is 0, 1, or 2; Each R group, if present, is selected from the following: halo, nitro, cyano, R 3a , -[CH2] q1 -NR 3a R 3b , -[CH2] q1 -OR 3a , -[CH2] q1 -C(O)R 3a , -[CH2] q1 -C(O)OR 3a or -[CH2] q1 -OC(O)R 3a Selected from; In the formula, q1 is 0, 1, or 2; R 3a is hydrogen or (1-2C)alkyl, optionally substituted with halo, hydroxy, amino or cyano; and R 3b is hydrogen or (1-2C)alkyl; V2 is -C(R v2a R v2b )C(R v2c R v2d )-or-C(R v2a )=C(R v2c )-, wherein R v2a , R v2b , R v2c and R v2d are each independently selected from hydrogen or methyl, or Rv2a and R v2c are linked to form a cyclopropyl ring; Z2 is a 4C alkylene linker optionally substituted with one or more fluoro atoms; W2 is a carbocycle, aryl, heteroaryl or heterocycle, which is optionally selected from halo, nitro, cyano, R w2a , -[CH2] s -NR w2a R w2b , -[CH2] s -OR w2a , -[CH2] s -C(O)R w2a , -[CH2] s -C(O)OR w2a or -[CH2] s -OC(O)R w2a has been replaced by; During the ceremony s is 0, 1, or 2; R w2a is hydrogen or (1-4C)alkyl, optionally substituted with halo, hydroxy, amino or cyano; and R w2b and R w2c is hydrogen, or (1-2C)alkyl; X2 is a linker group of the formula: -[CH2] m1 -L2-[CH2] m2 - During the ceremony m1 and m2 are selected from 0 or 1; L2 is -O-, -S-, -SO-, -SO2-, -N(R x2a )-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R x2a )-or-N(R x2a )C(O)-, and wherein R x2a and R x2b are each independently selected from hydrogen or (1-2C)alkyl; Y2 is selected from carbocycle, aryl, heteroaryl or heterocycle, which is optionally selected from halo, nitro, cyano, Ry2a , -[CH2] t -NR y2a R y2b , -[CH2] t -OR y2a , -[CH2] t -C(O)R y2a , -[CH2] t -C(O)OR y2a or -[CH2] t -OC(O)R y2a has been replaced by; t is 0 or 1; R y2a is hydrogen or (1-2C)alkyl and is optionally substituted with halo, hydroxy, amino or cyano; and R y2b is hydrogen, or (1-2C) alkyl; (iii) a group of formula IV: [ka] During the ceremony: Ring C is selected from phenyl, 5- or 6-membered heteroaryl; k is 0, 1, or 2; Each R group, if present, is selected from the following: halo, nitro, cyano, R 4a , -[CH2] q2 -NR 4a R 4b , -[CH2] q2 -OR 4a , -[CH2] q2 -C(O)R 4a , -[CH2] q2 -C(O)OR 4a or -[CH2] q2 -OC(O)R 4a Selected from; In the formula, q2 is 0, 1, 2, or 3; R 4a is hydrogen or (1-4C)alkyl, optionally substituted with halo, hydroxy, amino or cyano; and R 4b is hydrogen or (1-2C)alkyl; L is a 6C alkylene linker optionally substituted with one or more fluoro atoms; X is -O-, -CR xa R xb -, -S-, -SO-, -SO2-, -N(R xa )-, or -C(O)-; and xa and R xb are each independently selected from hydrogen or methyl; A 30 and A 31 is selected from CH, N, or CF; A 32 and A 33 is selected from CH or N; However, A 30 , A 31 , A 32 and A 33 may be N; A 34 and A 35 is CH, N or CR 30 Selected from; A 36 , A 37 and A 38 is selected from CH or N; However, A 34 , A 35 , A 36 , A 37 and A 38 may be N; And in the formula, R 30 are halo, nitro, cyano, R 30a , -[CH2] t -NR 30a R 30b , -[CH2] t -OR 30a , -[CH2] t -C(O)R 30a , -[CH2] t -C(O)OR 30a or -[CH2] t -OC(O)R 30a is selected from: t is 0, 1, or 2; R 30a is hydrogen or (1-4C)alkyl, optionally substituted with halo, hydroxy, amino or cyano; and R 30b and R 30c is hydrogen or (1-2C)alkyl; (iv) a group of formula V or VI: [ka] During the ceremony: A 40 is selected from NH, NMe, or O; A 42 , A 43 , A 44 and A 46 are each independently selected from CH, N, or CR2; A 41 and A 45 are each independently selected from C or N; However, the following conditions are met: (i)A 40 , A 41 , A 42 , A 43 , A 44 , A 45 and A 46 up to three of are N; (ii)A 41 and A 45 cannot both be N; (iii)A 40 , A 42 , A 43 , A 44 and A 46 only one or two of may be CR2; A 51 is selected from NH, NMe, CH or CR2; A 50 , A 53 , A 54 and A 55 are each independently selected from CH, N, or CR2; A 52 and A 56 are each independently selected from C or N; However, the following conditions are met: (i)A 50 , A 51 , A 52 , A 53 , A 54 , A 55 and A 56 up to three of which are N; (ii)A 52 and A 56 cannot both be N; (iii)A 50 , A 51 , A 53 , A 54 and A 55 only one or two of the can be CR2; wherein R2 is as defined above; W4: [ka] In the formula, A 4a , A 4b , A 4c , or A 4d is selected from CH, N or CF, with the proviso that: A 4a , A 4b , A 4c Or A 4d and A 4a , A 4b , A 4c Or A 4d Only one or two of the following may be CF; X4 is a linker group of the formula: -[CH2] j1 -L4-[CH2] j2 - During the ceremony, j1 and j2 are selected from 0 or 1; L4 is -O-, -S-, -SO-, -SO2-, -N(R x4a )-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R x4a )-or-N(R x4a)C(O)-, -; and wherein R x4a and R x4b are each independently selected from hydrogen or (1-2C)alkyl; Y4 is selected from carbocycle, aryl, heteroaryl or heterocycle, which is optionally selected from halo, nitro, cyano, R y4a , -[CH2] u -NR y4a R y4b , -[CH2] u -OR y4a , -[CH2] u -C(O)R y4a , -[CH2] u -C(O)OR y4a or -[CH2] u -OC(O)R y4a has been replaced by; u is 0 or 1; R y4a is hydrogen or (1-2C)alkyl, optionally substituted with halo, hydroxy, amino or cyano; and R y4b , and R y4c is hydrogen, or (1-2C)alkyl. (3)R 1 is selected from: (i) a group of formula II: [ka] During the ceremony: Ring A is selected from phenyl or 5- or 6-membered heteroaryl; n is 0, 1 or 2; Each R group, when present, is: halo, nitro, cyano, R 2a , -[CH2] q -NR 2a R 2b , -[CH2] q -OR 2a , -[CH2] q -C(O)R 2a , selected from; q is 0 or 1; R 2ais hydrogen or methyl; and R 2b is hydrogen or methyl; R N is selected from hydrogen or methyl; or R groups and R N is linked to form a 5- or 6-membered heterocycle fused to ring A, which fused 5- or 6-membered heterocycle contains 1 or 2 N atoms and may be optionally substituted by halo, hydroxy, methyl, halomethyl, cyano, or amino; W1 is: [ka] wherein A1, A2, A3 or A4 is selected from CH or CF, provided that: Only one or two of A1, A2, A3 or A4 may be CF; X1 is a linker group of the formula: -[CH2] n1 -L1-[CH2] n2 - During the ceremony n1 and n2 are selected from 0 or 1; L1 is -O-, -S-, -SO-, -SO2-, -N(R x1a )- or -C(O)-; and wherein R x1a is selected from hydrogen or methyl; Y1 is selected from phenyl, heteroaryl or heterocycle, which is optionally selected from halo, nitro, cyano, R y1a , -NR y1a R y1b , -OR y1a Or -C(O)R y1a has been replaced by; R y1a is hydrogen or methyl; and R y1b is hydrogen or methyl; (ii) a group of formula III: [ka] During the ceremony: Ring B is selected from phenyl or 5- or 6-membered heteroaryl; m is 0, 1, or 2; Each R group, if present, is selected from the following: halo, nitro, cyano, R 3a , -[CH2] q1 -NR 3a R 3b , -[CH2] q1 -OR 3a or -[CH2] q1 -C(O)R 3a Selected from; In the formula, q1 is 0 or 1; R 3a is hydrogen or methyl; and R 3b is hydrogen or methyl; V2 is -C(R v2a R v2b )C(R v2c R v2d )-or-C(R v2a )=C(R v2c )-, wherein R v2a , R v2b , R v2c and R v2d are each independently selected from hydrogen or methyl, or R v2a and R v2c are linked to form a cyclopropyl ring; Z2 is a 4C alkylene linker optionally substituted with one or more fluoro atoms; W2 is a carbocycle or heterocycle, which optionally includes halo, nitro, cyano, R w2a , -[CH2] s -NR w2a R w2b , -[CH2] s -OR w2a or -[CH2] s -C(O)R w2a and is substituted by s is 0 or 1; R w2ais hydrogen or (1-2C)alkyl, optionally substituted with halo, hydroxy, amino or cyano; and R w2b and R w2c is hydrogen, or (1-2C)alkyl; X2 is a linker group of the formula: -[CH2] m1 -L2-[CH2] m2 - During the ceremony, m1 and m2 are selected from 0 or 1; L2 is -O-, -S-, -SO-, -SO2-, -N(R x2a )- or -C(O)-, and wherein R x2a is selected from hydrogen or methyl; Y2 is selected from phenyl, heteroaryl or heterocycle, which is optionally selected from halo, nitro, cyano, R y2a , N.R. y2a R y2b , OR y2a or C(O)R y2a has been replaced by; R y2a is hydrogen or methyl; and R y2b is hydrogen or methyl; (iii) a group of formula IV: [ka] During the ceremony: Ring C is selected from phenyl, 5- or 6-membered heteroaryl; k is 0, 1, or 2; Each R group, if present, is selected from the following: halo, nitro, cyano, R 4a , -[CH2] q2 -NR 4a R 4b , -[CH2] q2 -OR 4a , or -[CH2] q2 -C(O)R 4a Selected from; q2 is 0 or 1; R4a is hydrogen or methyl; and R 4b is hydrogen or methyl; L is a 6C alkylene linker optionally substituted with one or more fluoro atoms; X is -O-, -CR xa R xb -, -S-, -SO-, -SO2-, -N(R xa )-, or -C(O)-; and xa and R xb are each independently selected from hydrogen or methyl; A 30 and A 31 is selected from CH, N or CF; A 32 and A 33 is selected from CH or N; However, A 30 , A 31 , A 32 and A 33 may be N; A 34 and A 35 is CH, N or CR 30 Selected from; A 36 , A 37 and A 38 is selected from CH or N; However, A 34 , A 35 , A 36 , A 37 and A 38 may be N; And in the formula, R 30 are halo, nitro, cyano, R 30a , --NR 30a R 30b , -OR 30a or -C(O)R 30a is selected from: R 30a is hydrogen or methyl; and R 30b is hydrogen or methyl; (iv) a group of formula V or VI: [ka] During the ceremony, A 40 is selected from NH, NMe, or O; A 42 , A 43 , A 44 and A 46 are each independently selected from CH, N, or CR2; A 41 and A 45 are each independently selected from C or N; However, the following conditions are met: (i)A 40 , A 41 , A 42 , A 43 , A 44 , A 45 and A 46 up to three of are N; (ii)A 41 and A 45 cannot both be N; (iii)A 40 , A 42 , A 43 , A 44 and A 46 only one or two of may be CR2; A 51 is selected from NH, NMe, CH or CR2; A 50 , A 53 , A 54 and A 55 are each independently selected from CH, N, or CR2; A 52 and A 56 are each independently selected from C or N; However, the following conditions are met: (i)A 50 , A 51 , A 52 , A 53 , A 54 , A 55 and A56 up to three of which are N; (ii)A 52 and A 56 cannot both be N; (iii)A 50 , A 51 , A 53 , A 54 and A 55 only one or two of the can be CR2; wherein R2 is as defined above; W4 is: [ka] In the formula, A 4a , A 4b , A 4c , or A 4d is selected from CH, or CF, where: A 4a , A 4b , A 4c Or A 4d Only one or two of the following may be CF; X4 is a linker group of the formula: -[CH2] j1 -L4-[CH2] j2 - During the ceremony, j1 and j2 are selected from 0 or 1; L4 is -O-, -S-, -SO-, -SO2-, -N(R x4a )- or -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R x4a )-or-N(R x4a )C(O)-, -; and wherein R x4a and R x4b are each independently selected from hydrogen or methyl; Y4 is selected from phenyl, heteroaryl or heterocycle, which is optionally selected from halo, nitro, cyano, R y4a , -NR y4a R y4b , -OR y4a Or -C(O)R y4a has been replaced by; During the ceremony, R y4a is hydrogen or methyl; and R y4b is hydrogen or methyl. (4)R 1 is selected from: (i) a group of formula II: [ka] During the ceremony: Ring A is selected from phenyl or 6-membered heteroaryl; n is 0 or 1; Each R group, when present, is selected from the following: halo, nitro, cyano, R 2a , -NR 2a R 2b , -OR 2a Or -C(O)R 2a Selected from; R 2a is hydrogen or methyl; and R 2b is hydrogen or methyl; or R groups and R N is linked to form a 5- or 6-membered heterocycle fused to ring A, the fused 5- or 6-membered heterocycle containing 1 or 2 N atoms and optionally substituted by halo, hydroxy, methyl, halomethyl, cyano, or amino; W1 is: [ka] X1 is a linker group of the formula: -[CH2] n1 -L1-[CH2] n2 - During the ceremony, n1 and n2 are selected from 0 or 1; L1 is selected from -O-, -S-, -SO2- or -C(O)-; Y1 is selected from phenyl, heteroaryl or heterocycle, which is optionally selected from halo, nitro, cyano, R y1a-OR y1a has been replaced by; R y1a is hydrogen or methyl; and R y1b is hydrogen or methyl; (ii) a group of formula III: [ka] During the ceremony: Ring B is selected from phenyl or 5- or 6-membered heteroaryl; m is 0 or 1; Each R group, if present, is selected from the following: halo, nitro, cyano, R 3a , -NR 3a R 3b , -OR 3a Or -C(O)R 3a Selected from; R 3a is hydrogen or methyl; and R 3b is hydrogen or methyl; V2 is -C(R v2a R v2b )C(R v2c R v2d )-or-C(R v2a )=C(R v2c )-, wherein R v2a , R v2b , R v2c and R v2d are each independently selected from hydrogen or methyl, or R v2a and R v2c are linked to form a cyclopropyl ring; Z2 is a 4C alkylene linker optionally substituted with one or more fluoro atoms; W2 is a carbocycle or heterocycle, which optionally includes halo, nitro, cyano, R w2a , -NR w2a R w2b , -OR w2a Or -C(O)R w2a and is substituted by R w2ais hydrogen or methyl; and R w2b and R w2c is hydrogen or methyl; X2 is a linker group of the formula: -[CH2] m1 -L2-[CH2] m2 - During the ceremony, m1 and m2 are selected from 0 or 1; L2 is selected from -O-, -S-, -SO2- or -C(O)-; Y2 is selected from phenyl, heteroaryl or heterocycle, which is optionally selected from halo, nitro, cyano, hydrogen, methyl or OR; y2a has been replaced by; In the formula, R y2a is hydrogen or methyl; (iii) a group of formula IV: [ka] During the ceremony: Ring C is selected from phenyl or 6-membered heteroaryl; k is 0 or 1; Each R group, when present, is selected from the following: halo, nitro, cyano, R 4a , -NR 4a R 4b , -OR 4a Or -C(O)R 4a Selected from; R 4a is hydrogen or methyl; and R 4b is hydrogen or methyl; L is a 6C alkylene linker optionally substituted with one or more fluoro atoms; X is selected from -O-, -S-, -SO2- or -C(O)-; A 30 and A 31 is selected from CH or CF; A 32 and A 33 is CH; A34 and A 35 is CH or CR 30 Selected from; A 36 , A 37 and A 38 is CH; And in the formula, R 30 is halo, nitro, cyano, hydrogen, methyl, -NR 30a R 30b , -OR 30a or -C(O)R 30a is selected from: R 30a is hydrogen or methyl; and R 30b is hydrogen or methyl; (iv) a group of formula V or VI: [ka] During the ceremony: A 40 is selected from NH or O; A 42 , A 43 , A 44 and A 46 are each independently selected from CH or CR2; A 41 and A 45 are C, respectively; A 51 is selected from NH, NMe, CH or CR2; A 50 , A 53 , A 54 and A 55 are each independently selected from CH or CR2; A 52 and A 56 are C, respectively; wherein R2 is as defined above; W4 is: [ka] X4 is a linker group of the formula: -L4- During the ceremony, L4 is -O-, -S-, -SO-, -SO2-, -N(R x4a )- or -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R x4a )-or-N(R x4a )C(O)—; and wherein R x4a and R x4b are each independently selected from hydrogen or methyl; Y4 is selected from phenyl, heteroaryl or heterocycle, which is optionally substituted by halo, nitro, cyano or methyl; (5)R 1 is selected from: (i) a group of formula II: [ka] During the ceremony: Ring A is selected from phenyl or 6-membered heteroaryl; n is 0 or 1; Each R group, if present, is selected from the following: halo or -OR 2a Selected from; In the formula, R 2a is hydrogen or methyl; and R N is hydrogen or or R groups and R N is linked to form a 5- or 6-membered heterocycle fused to ring A, which fused 5- or 6-membered heterocycle contains 1 or 2 N atoms and may be optionally substituted by halo, hydroxy, methyl, halomethyl, cyano, or amino; W1 is: [ka] X1 is a linker group of the formula: -[CH2] n1 -L1-[CH2] n2 - During the ceremony, n1 and n2 are selected from 0 or 1; L1 is selected from -O-, -S-, -SO2- or -C(O)-; Y1 is selected from phenyl, or a heterocycle, which is optionally selected from halo, nitro, cyano, hydrogen, methyl, or -OR y1a has been replaced by; R y1a is hydrogen or methyl; (ii) a group of formula III: [ka] During the ceremony: Ring B is selected from phenyl or 5- or 6-membered heteroaryl; m is 0 or 1; Each R group, if present, is selected from the following: halo, or -OR. 3a Selected from; In the formula, R 3a is hydrogen or methyl; V2 is -C(R v2a R v2b )C(R v2c R v2d )-or-C(R v2a )=C(R v2c )-, wherein R v2a , R v2b , R v2c and R v2d are each independently selected from hydrogen or methyl, or R v2a and R v2c are linked to form a cyclopropyl ring; Z2 is a 4C alkylene linker, which is optionally substituted with one or more fluoro atoms; W2 is a heterocycle, which is optionally selected from halo, -OR w2a and is substituted by R w2a is hydrogen or methyl; X2 is a linker group of the formula: -L2- During the ceremony, L2 is selected from -O-, -S-, -SO2- or -C(O)-; Y2 is phenyl or a heterocycle, which is optionally selected from halo, nitro, cyano, hydrogen, methyl, or OR; y2a has been replaced by; R y2a is hydrogen or methyl; (iii) a group of formula IVa: [ka] During the ceremony: Ring C is selected from phenyl or 6-membered heteroaryl; k is 0 or 1; Each R group, if present, is selected from the following: halo, or -OR. 4a Selected from; In the formula, R 4a is hydrogen or methyl; L is a 6C alkylene linker optionally substituted with one or more fluoro atoms; X is selected from -O-, -S-, -SO2-, or -C(O)-; (iv) a group of formula Va or VIa: [ka] During the ceremony: A 40 is selected from NH or O; A 51 is selected from NH, NMe, CH or CR2; wherein R2 is as defined above; W4 is: [ka] X4 is a linker group of the formula: -L4- During the ceremony, L4 is -SO2-, --C(O)N(R x4a )-or-N(R x4a )C(O)—; and wherein R x4a is selected from hydrogen or methyl; Y4 is phenyl or a heterocycle, which is optionally substituted with halo, nitro, cyano or methyl. (6)R 1 is selected from: (i) a group of formula II: [ka] During the ceremony: Ring A is selected from phenyl or 6-membered heteroaryl; n is 0 or 1; Each R group, if present, is selected from the following: halo or -OR 2a Selected from; In the formula, R 2a is hydrogen or methyl; and R N is hydrogen or or R groups and R N is linked to ring A to form a fused 5-membered heterocycle, the fused 5-membered heterocycle containing 1 or 2 N atoms; W1 is: [ka] X1 is a linker group of the formula: -[CH2] n1 -L1-[CH2] n2 - During the ceremony, n1 and n2 are selected from 0 or 1; L1 is selected from -SO2-; Y1 is selected from phenyl, or a heterocycle, which is optionally selected from halo, or -OR y1a has been replaced by; In the formula, R y1a is hydrogen or methyl; (ii) a group of formula III: [ka] During the ceremony: Ring B is selected from phenyl or 6-membered heteroaryl; m is 0 or 1; Each R group, if present, is selected from the following: halo, or -OR. 3a Selected from; In the formula, R 3a is hydrogen or methyl; V2 is -C(R v2a R v2b )C(R v2c R v2d )-or-C(R v2a )=C(R v2c )-, wherein R v2a , R v2b , R v2c and R v2d are each hydrogen or R v2a and R v2c are linked to form a cyclopropyl ring; Z2 is a 4C alkylene linker; W2 is a heterocycle, which is optionally selected from halo, -OR w2a wherein R w2a is hydrogen or methyl; X2 is a linker group of the formula: -L2- During the ceremony, L2 is selected from -C(O)-; Y2 is a phenyl ring, which is optionally selected from halo, or OR y2a and is substituted by R y2a is hydrogen or methyl; (iii) a group of formula IVa: [ka] During the ceremony: Ring C is selected from phenyl or 6-membered heteroaryl; k is 0 or 1; Each R group, if present, is selected from the following: halo, or -OR. 4a Selected from; In the formula, R 4a is hydrogen or methyl; L is a 6C alkylene linker; X is -O-; (iv) a group of formula Va or VIa: [ka] During the ceremony: A 40 is selected from NH or O; A 51 is selected from NH, NMe, CH or CR2; wherein R2 is as defined above; W4 is: [ka] X4 is a linker group of the formula: -L4- During the ceremony L4 is -SO2- or -C(O)N(R x4a )-; and wherein R x4a is independently selected from hydrogen or methyl; Y4 is a 5- or 6-membered heterocycle. (7) In the formula, R 1 is selected from: (i) a group of formula IIa or IIb: [ka] During the ceremony: Ring A is selected from phenyl or 6-membered heteroaryl; n is 0 or 1; Each R group, if present, is selected from the following: halo or -OR 2a Selected from; In the formula, R 2a is hydrogen or methyl; and R N is hydrogen or or R groups and R N is linked to ring A to form a fused 5-membered heterocycle, the fused 5-membered heterocycle containing 1 or 2 N atoms; W1 is: [ka] X1 is a linker group of the formula: -[CH2] n1 -L1-[CH2] n2 - During the ceremony, n1 and n2 are selected from 0 or 1; L1 is selected from -SO2-; Y1 is selected from phenyl, or a heterocycle, which is optionally selected from halo, or -OR y1a has been replaced by; In the formula, R y1a is hydrogen or methyl; (ii) a group of formula IIIa: [ka] During the ceremony: m is 0 or 1; Each R group, if present, is selected from the following: halo, or -OR. 3a Selected from; In the formula, R 3a is hydrogen or methyl; V2 is -C(R v2a R v2b )C(R v2c R v2d )-or-C(R v2a )=C(R v2c )-, wherein R v2a , R v2b , R v2c and R v2d are each hydrogen or R v2a and R v2c are linked to form a cyclopropyl ring; Z2 is a 4C alkylene linker; W2 is a heterocycle, which is optionally selected from halo, -OR w2a wherein R w2a is hydrogen or methyl; X2 is a linker group of the formula: -L2- During the ceremony, L2 is selected from -C(O)-; Y2 is a phenyl ring, which is optionally selected from halo, or OR y2a and is substituted by R y2a is hydrogen or methyl; (iii) a group of formula IVb: [ka] During the ceremony: k is 0 or 1; Each R group, if present, is selected from the following: halo, or -OR. 4a Selected from; In the formula, R 4a is hydrogen or methyl; L is a 6C alkylene linker; X is -O-; (iv) a group of formula Vb, Vc, VIb or VIc: [ka] During the ceremony: W4 is: [ka] X4 is a linker group of the formula: -L4- During the ceremony, L4 is selected from -SO2- or -C(O)N(H)-; Y4 is a 5- or 6-membered heterocycle.

[0083] Suitably, a heteroaryl or heterocyclyl group as defined herein is a monocyclic 5- or 6-membered heteroaryl or 5- or 6-membered heterocyclyl group containing 1, 2 or 3 heteroatoms selected from N, O or S.

[0084] Suitably, the heteroaryl is a 5- or 6-membered heteroaryl ring containing 1, 2 or 3 heteroatoms selected from N, O or S.

[0085] Suitably, the heterocyclyl group is a 5-, 6-membered heterocyclyl ring containing 1, 2 or 3 heteroatoms selected from N, O or S; or an 8-, 9- or 10-membered spiro-fused heterocyclyl ring system containing 1, 2 or 3 heteroatoms selected from N, O or S. Most suitably, the heterocyclyl group is a 5- or 6-membered ring containing 1, 2 or 3 heteroatoms selected from N, O or S, such as morpholinyl (e.g. 4-morpholinyl), pyridinyl, piperazinyl or pyrrolidinonyl. Suitably, the heterocyclyl group is an 8-, 9- or 10-membered spiro-fused heterocyclyl ring system containing 1, 2 or 3 heteroatoms selected from N, O or S.

[0086] Suitably, R1 is as defined in any one of paragraphs (1) to (7). More suitably, R1 is as defined in any one of paragraphs (4) to (7). Most suitably, R1 is as defined in paragraphs (6) or (7).

[0087] Suitably, R1 is selected from any one of formulas II, III, IV, V, VI, and any related subformulas defined herein, where any related subgroups are as defined in any one of paragraphs (1) to (7). More suitably, the related subgroups are as defined in any one of paragraphs (4) to (7). Most suitably, the related subgroups are as defined in paragraphs (6) or (7).

[0088] In a particular group of compounds of the invention, R 1 is a group of formula II: [ka] In the formula, ring A, n, R2, R N , W1, X1 and Y1 are as defined above.

[0089] Suitably, ring A, n, R2, R N , W1, X1 and Y1 are as defined in any one of paragraphs (1) to (7). More suitably, ring A, n, R2, R N , W1, X1 and Y1 are as defined in any one of paragraphs (4) to (7). Most suitably, ring A, n, R2, R N , W1, X1 and Y1 are as defined in paragraph (6) or (7).

[0090] In a particular group of compounds of the invention, R 1 is a radical of formula IIa or IIb: [ka] In the formula n, R2, R N , W1, X1 and Y1 are as defined above.

[0091] Appropriately, n, R2, R N , W1, X1 and Y1 are as defined in any one of paragraphs (1) to (7). More suitably, n, R2, R N , W1, X1 and Y1 are as defined in any one of paragraphs (4) to (7). Most suitably, n, R2, R N , W1, X1 and Y1 are as defined in paragraph (6) or (7).

[0092] In a particular group of compounds of the invention, R 1 is a group of formula III: [ka] In the formula, ring B, R3, m, V2, Z Z , W2, X2 and Y2 are as defined above.

[0093] Suitably, rings B, m, R3, V2, Z Z , W2, X2 and Y2 are as defined in any one of paragraphs (1) to (7). More suitably, rings B, m, R3, V2, Z Z, W2, X2 and Y2 are as defined in any one of paragraphs (4) to (7). Most suitably, rings B, m, R3, V2, Z Z , W2, X2 and Y2 are as defined in paragraph (6) or (7).

[0094] In a particular group of compounds of the invention, R 1 is a group of formula IIIa: [ka] In the formula, ring B, R3, m, V2, Z Z , W2, X2 and Y2 are as defined above.

[0095] Appropriately, m, R3, V2, Z Z , W2, X2 and Y2 are as defined in any one of paragraphs (1) to (7). More suitably, m, R3, V2, Z Z , W2, X2 and Y2 are as defined in any one of paragraphs (4) to (7). Most suitably, m, R3, V2, Z Z , W2, X2 and Y2 are as defined in paragraph (6) or (7).

[0096] In a particular group of compounds of the invention, R 1 is a group of formula IV: [ka] In the formula, ring C, R4, k, L, X, A 33 , A 34 , A 35 , A 36 , A 37 and A 38 is as defined herein.

[0097] Suitably, rings C, R4, k, L, X, A 33 , A 34 , A 35 , A 36 , A 37 and A 38is as defined in any one of paragraphs (1) to (7). More suitably, rings C, R4, k, L, X, A 33 , A 34 , A 35 , A 36 , A 37 and A 38 is as defined in any one of paragraphs (4) to (7). Most suitably, rings C, R4, k, L, X, A 33 , A 34 , A 35 , A 36 , A 37 and A 38 is as defined in paragraph (6) or (7).

[0098] In a particular group of compounds of the invention, R 1 is a group of formula IVa: [ka] In the formula, ring C, R4, k, L and X are as defined above.

[0099] Suitably, rings C, R4, k, L and X are as defined in any one of paragraphs (1) to (7). More suitably, rings C, R4, k, L and X are as defined in any one of paragraphs (4) to (7). Most suitably, rings C, R4, k, L and X are as defined in paragraphs (6) or (7).

[0100] In a particular group of compounds of the invention, R 1 is a group of formula V or VI: [ka] In the formula, A 43 , A 54 , A 55 , A 46 , A 47 , A 50 , A 51 , A 52 , A 53 , A 54 , A55、 A 56 , W4, X4 and Y4 are as defined herein.

[0101] Appropriately, A 43 , A 54 , A 55 , A 46 , A 47 , A 50 , A 51 , A 52 , A 53 , A 54 , A 55、 A 56 , W4, X4 and Y4 are as defined in any one of paragraphs (1) to (7). More particularly, 43 , A 54 , A 55 , A 46 , A 47 , A 50 , A 51 , A 52 , A 53 , A 54 , A 55、 A 56 , W4, X4 and Y4 are as defined in any one of paragraphs (4) to (7). Most suitably, A 43 , A 54 , A 55 , A 46 , A 47 , A 50 , A 51 , A 52 , A 53 , A 54 , A 55、 A 56 , W4, X4 and Y4 are as defined in paragraph (6) or (7).

[0102] In a particular group of compounds of the invention, R 1 is a radical of formula Va or VIa: [ka] In the formula, A 40 , A 51 , W4, X4 and Y4 are as defined herein above.

[0103] Appropriately, A 40 , A 51 , W4, X4 and Y4 are as defined in any one of paragraphs (1) to (7). More particularly, 40 , A 51 , W4, X4 and Y4 are as defined in any one of paragraphs (4) to (7). Most suitably, A 40 , A 51 , W4, X4 and Y4 are as defined in paragraph (6) or (7).

[0104] Particular compounds of the invention include any of the compounds exemplified in this application, or a pharma- ceutically acceptable salt or solvate thereof, in particular any of the following: 6-(2-fluoro-5-((3-(4-(piperidin-1-ylsulfonyl)phenyl)ureido)methyl)phenyl)-4-(trioxidanylthio)naphthalene-2-sulfonic acid; (E)-6-(5-(3-((4-(1-benzoylpiperidin-4-yl)butyl)amino)-3-oxoprop-1-en-1-yl)-2-fluorophenyl)-4-(trioxidanylthio)naphthalene-2-sulfonic acid; 6-(2-fluoro-5-((3-(4-(phenylsulfonyl)phenyl)ureido)methyl)phenyl)-4-(trioxidanylthio)naphthalene-2-sulfonic acid; 6-(3-(1-(6-([1,1'-biphenyl]-2-yloxy)hexyl)-1H-1,2,3-triazol-4-yl)phenyl)-4-(trioxidanylthio)naphthalene-2-sulfonic acid; 6-(3-((3-(4-(piperidin-1-ylsulfonyl)phenyl)ureido)methyl)phenyl)-4-(trioxidanylthio)naphthalene-2-sulfonic acid; 6-(4-fluoro-3-((3-(4-(piperidin-1-ylsulfonyl)phenyl)ureido)methyl)phenyl)-4-(trioxidanylthio)naphthalene-2-sulfonic acid; 6-(2-Methoxy-5-((3-(4-(piperidin-1-ylsulfonyl)phenyl)ureido)methyl)phenyl)-4-(trioxidanylthio)naphthalene-2-sulfonic acid; 6-(5-((3-(4-((8-oxa-3-azabicyclo[3.2.1]octan-3-yl)sulfonyl)phenyl)ureido)methyl)-2-fluorophenyl)-4-(trioxidanylthio)naphthalene-2-sulfonic acid; 6-(2-((4-(piperidin-1-ylsulfonyl)benzyl)carbamoyl)-1H-indol-5-yl)-4-(trioxidanylthio)naphthalene-2-sulfonic acid; (S)-6-(2-((4-(((tetrahydrofuran-3-yl)methyl)carbamoyl)phenyl)carbamoyl)isoindolin-5-yl)-4-(trioxidanylthio)naphthalene-2-sulfonic acid.

[0105] The various functional groups and substituents which make up the compound of formula I are typically selected so that the molecular weight of the compound of formula I does not exceed 1000. More typically, the molecular weight of the compound will be less than 900, such as less than 800, or less than 700, or less than 650, or less than 600. More preferably, the molecular weight is less than 550, such as 500 or less.

[0106] Suitable pharma- ceutically acceptable salts of the compounds of the invention are, for example, acid addition salts of the compounds of the invention that are sufficiently basic, for example, with inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, formic acid, citric acid methanesulfonate or maleic acid.Furthermore, suitable pharma- ceutically acceptable salts of the compounds of the invention that are sufficiently acidic are alkali metal salts, for example, sodium salts or potassium salts, alkaline earth metal salts, for example, calcium salts or magnesium salts, ammonium salts, or salts with organic bases that provide pharma- ceutically acceptable cations, for example, salts with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.

[0107] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are called "isomers". Isomers that differ in the arrangement of their atoms in space are called "stereoisomers". Stereoisomers that are not mirror images of one another are called "diastereomers" and stereoisomers that are non-superimposable mirror images of one another are called "enantiomers". When a compound has an asymmetric center, for example, when it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and described by the Cahn-Ingold-Prelog R and S ordering rules or by the way the molecule rotates the plane of polarized light and is designated as dextrorotatory or levorotatory (i.e., (+) or (-) isomer, respectively). Chiral compounds can exist as either individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture".

[0108] The compounds of the present invention may have one or more asymmetric centers; therefore, such compounds may be produced as individual (R) or (S) stereoisomers or mixtures thereof. Unless otherwise indicated, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemates or other mixtures. Methods for determining stereochemistry and separating stereoisomers are well known in the art (see discussion in Chapter 4 of "Advanced Organic Chemistry", 4th edition J. March, John Wiley and Sons, New York, 2001), for example, by synthesis from optically active starting materials or by resolution of racemates. Some of the compounds of the present invention may have geometric isomeric centers (E and Z isomers). It should be understood that the present invention encompasses all optical, diastereomeric and geometric isomers and mixtures thereof that have antiproliferative activity.

[0109] The present invention also includes compounds of the invention as defined herein that contain one or more isotopic substitutions. For example, H is 1 H, 2 H(D), and 3 H(T) may be any isotope; C may be 12 C. 13 C, and 14 C may be any isotope, including C; and O may be 16 O and 18 It may be any isotope, including O;

[0110] It should also be understood that certain compounds of formula I can exist in solvated as well as unsolvated forms, including, for example, hydrated forms, and it should be understood that the present invention encompasses all such solvated forms that possess antiproliferative activity.

[0111] It is also to be understood that certain compounds of formula I may exhibit polymorphism, and that the invention encompasses all such forms which possess antiproliferative activity.

[0112] Compounds of formula I may exist in a number of different tautomeric forms, and references to compounds of formula I include all such forms. For the avoidance of doubt, where a compound may exist in one of several tautomeric forms and only one is specifically described or illustrated, all others are nevertheless encompassed by formula I. Examples of tautomers include, for example, the following tautomeric pairs, e.g., keto, enol, and enolate forms, such as keto / enol (illustrated below), imine / enamine, amide / iminoalcohol, amidine / amidine, nitroso / oxime, thioketone / ethyol, and nitro / acid nitro. [ka]

[0113] Compounds of formula I having an amine function may form N-oxides. In this specification, reference to compounds of formula I having an amine function also includes N-oxides. When a compound contains several amine functions, one or more nitrogen atoms may be oxidized to form N-oxides. Particular examples of N-oxides are the N-oxides of tertiary amines or nitrogen atoms of nitrogen-containing heterocycles. N-oxides may be formed by treating the corresponding amines with an oxidizing agent, such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid). See, for example, Advanced Organic Chemistry, Jerry March, 4 th (See pages 1996, Edition, Wiley Interscience.) More specifically, the N-oxides can be made by the procedure of LW Deady (Syn. comm. 1977, 7, 509-514), in which the amine compound is reacted with m-chloroperoxybenzoic acid (mCPBA) in an inert solvent such as, for example, dichloromethane.

[0114] The compounds of formula I may be administered in the form of prodrugs that are degraded in the human or animal body to release the compounds of the present invention. Prodrugs may be used to change the physical properties and / or pharmacokinetic properties of the compounds of the present invention. When the compounds of the present invention contain a suitable group or substituent to which a property-modifying group can be attached, a prodrug may be formed. Examples of prodrugs include in vivo cleavable ester derivatives that may be formed at the carboxy or hydroxy group of the compounds of formula I, and in vivo cleavable amide derivatives that may be formed at the carboxy or amino group of the compounds of formula I.

[0115] The present invention therefore includes compounds of formula I as defined herein above when they are made available by organic synthesis and when they are made available in the human or animal body by cleavage of a prodrug thereof. Thus, in addition to compounds of formula I produced by organic synthetic means, the present invention also includes compounds produced in the human or animal body by metabolism of a precursor compound, i.e. compounds of formula I may be synthetically produced compounds or metabolically produced compounds.

[0116] Suitable pharma- ceutically acceptable prodrugs of compounds of formula I are those prodrugs that, based on sound medical judgment, are suitable for administration to the human or animal body without undesirable pharmacological effects and without undue toxicity.

[0117] Various forms of prodrugs are described, for example, in the following documents: a) Methods in Enzymology, Vol. 42, p. 309-396, (edited by K. Widder, et al.) (Academic Press, 1985); b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985); c)A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H.Bundgaard,Chapter 5 “Design and Application of Pro-drugs”, by H.Bundgaard p.113-191(1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); f) N.Kakeya,et al.,Chem.Pharm.Bull.,32,692(1984); g) T. Higuchi and V. Stella, “Pro-Drugs as Novel Delivery Systems”, ACSSymposium Series, Volume 14; and h) E. Roche (editor), “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987.

[0118] Suitable pharma- ceutically acceptable prodrugs of compounds of formula I with a carboxyl group are, for example, in vivo cleavable esters thereof. In vivo cleavable esters of compounds of formula I with a carboxyl group are, for example, pharma- ceutically acceptable esters that are cleaved in the human or animal body to produce the parent acid. Suitable pharma- ceutically acceptable esters for carboxy include: C 1-6 Alkyl esters, such as methyl, ethyl and tert-butyl, C 1-6 Alkoxy esters, e.g. methoxymethyl esters, C 1-6 Alkanoyloxymethyl esters, for example pivaloyloxymethyl esters, 3-Phthalidyl ester, C 3-8 Cycloalkylcarbonyloxy-C 1-6 Alkyl esters, e.g. cyclopentylcarbonyloxymethyl and 1-cyclohexylcarbonyloxyethyl esters, 2-Oxo-1,3-dioxolenylmethyl esters, such as 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl ester and C 1-6 Alkoxycarbonyloxy-C 1-6 Alkyl esters include, for example, methoxycarbonyloxymethyl and 1-methoxycarbonyloxyethyl esters.

[0119] Suitable pharma- ceutically acceptable prodrugs of the compounds of formula I with hydroxyl groups are, for example, in vivo cleavable esters or ethers thereof. The in vivo cleavable esters or ethers of the compounds of formula I with hydroxyl groups are, for example, pharma- ceutically acceptable esters or ethers that cleave in the human or animal body to produce the parent hydroxyl compound. Suitable pharma-ceutically acceptable ester-forming groups for hydroxyl groups include inorganic esters, for example, phosphate esters (including phosphoramide cyclic esters). Further suitable pharma-ceutically acceptable ester-forming groups for hydroxyl groups include C 1-10 -Alkanoyl groups, such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, C 1-10 -Alkoxycarbonyl groups, such as ethoxycarbonyl, N,N-(C 1-6 ) 2 carbamoyl, 2-dialkylaminoacetyl, and 2-carboxyacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups are aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl, and 4-(C 1-4 Suitable pharma- ceutical acceptable ether forming groups for a hydroxy group include acetoxymethyl and α-acyloxyalkyl groups, such as pivaloyloxymethyl.

[0120] Suitable pharma- ceutically acceptable prodrugs of compounds of formula I having a carboxy group include, for example, their in vivo cleavable amides, amines such as ammonia, C-alkyl groups such as methylamines, etc. 1-4 (C) such as alkylamines, dimethylamine, N-ethyl-N-methylamine or diethylamine 1-4 C alkyl) 2 amine, 2-methoxyethylamine, etc. 1-4 Alkoxy-C 2-4 Phenyl-C such as alkylamines and benzylamines 1-4 amides formed with alkylamines, as well as amino acids such as glycine or their esters.

[0121] Suitable pharma- ceutically acceptable prodrugs of compounds of formula I having an amino group are, for example, their in vivo cleavable amides. Suitable pharma- ceutically acceptable amides from an amino group include, for example, C-type acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups. 1-10 Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl, and 4-(C 1-4 and alkyl)piperazin-1-ylmethyl.

[0122] The in vivo effects of the compounds of formula I may be exerted in part by one or more metabolic products formed in the human or animal body following administration of the compounds of formula I. As mentioned above, the in vivo effects of the compounds of formula I may be exerted by metabolism of a precursor compound (prodrug).

[0123] The present invention may relate to any compound or particular group of compounds defined herein with respect to any, preferred or suitable feature or particular embodiment, but the present invention may also relate to any compound or particular group of compounds that specifically excludes said any, preferred or suitable feature or particular embodiment.

[0124] synthesis The compounds of the present invention may be prepared by any suitable technique known in the art. Certain methods for the preparation of these compounds are further illustrated in the accompanying Examples.

[0125] In the description of synthetic methods described herein, and in any reference synthetic methods used to prepare starting materials, it should be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment, and work-up procedures, can be selected by one of ordinary skill in the art.

[0126] It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reaction conditions employed.

[0127] It will be appreciated that during the synthesis of the compounds of the invention in the processes defined herein, or during the synthesis of certain starting materials, it may be desirable to protect certain substituents to prevent their undesired reactions. Those skilled in the art will understand when such protection is necessary and how such protecting groups can be put in place and subsequently removed.

[0128] For examples of protecting groups, see one of the many general texts on the subject matter, such as "Protective Groups in Organic Synthesis" by Theodora Green, published by John Wiley & Sons. Protecting groups can be removed by any convenient method described in the literature or known to those skilled in the art as suitable for removing the protecting group in question, such a method being chosen to effect removal of the protecting group with minimal disruption of groups elsewhere in the molecule.

[0129] Thus, if reactants contain groups such as amino, carboxy or hydroxy, it may be desirable to protect the group in some of the reactions mentioned herein.

[0130] For example, suitable protecting groups for amino or alkylamino are, for example, acyl groups, such as alkanoyl groups, for example acetyl, alkoxycarbonyl groups, for example methoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl groups, arylmethoxycarbonyl groups, for example benzyloxycarbonyl groups, or aroyl groups, for example benzoyl groups. The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, acyl groups, such as alkanoyl or alkoxycarbonyl groups, or aroyl groups, can be removed by hydrolysis with a suitable base, for example, alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively, acyl groups such as the tert-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid, such as hydrochloric acid, sulfuric acid or phosphoric acid or trifluoroacetic acid, and arylmethoxycarbonyl groups, such as the benzyloxycarbonyl group, may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid, for example boron tris(trifluoroacetic acid).A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or hydrazine.

[0131] Suitable protecting groups for hydroxyl groups are, for example, acyl groups, for example alkanoyl groups such as acetyl, aroyl groups, for example benzoyl groups, or arylmethyl groups, for example benzyl. The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, acyl groups, such as alkanoyl groups or aroyl aroyl groups, can be removed, for example, by hydrolysis with a suitable base, for example, an alkali metal hydroxide, for example lithium, sodium hydroxide or ammonia. Alternatively, arylmethyl groups, such as benzyl groups, can be removed, for example, by hydrogenation with a catalyst, for example, palladium-on-carbon.

[0132] Suitable protecting groups for carboxyl groups are, for example, esterifying groups, such as methyl or ethyl groups, which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or, for example, t-butyl groups, which may be removed, for example, by treatment with an acid, for example an organic acid, such as trifluoroacetic acid, or, for example, benzyl groups, which may be removed by hydrogenation over a catalyst such as palladium-on-carbon.

[0133] The resin may also be used as a protecting group.

[0134] The methodology used to synthesize compounds of formula I will vary depending on the nature of R1 and any substituents associated therewith. Processes suitable for their preparation are further described in the accompanying Examples.

[0135] When a compound of formula I has been synthesised by any one of the processes defined herein, the process may then further comprise the following additional steps: (i) removing any protecting groups present; (ii) converting said compound of formula I to another compound of formula I; (iii) forming a pharma- ceutically acceptable salt, hydrate or solvate thereof; and / or (iv) forming a prodrug thereof;

[0136] An example of (ii) above is where a compound of formula I is synthesised and then one or more of the groups associated with R1 are further reacted to change the nature of that group to provide an alternative compound of formula I.

[0137] The resulting compounds of formula I can be isolated and purified using techniques well known in the art.

[0138] biological activity The pharmacological effects of the compounds of the invention may be determined using enzymatic and in vitro cell-based assays described in the accompanying Examples section or elsewhere in the literature.

[0139] Although the pharmacological properties of the compounds of formula I vary with structural changes, as expected, the compounds of the invention were found to be active in these enzyme assays.

[0140] Pharmaceutical Compositions According to a further aspect of the present invention, there is provided a pharmaceutical composition comprising the compound of the present invention defined hereinabove or its pharmaceutically acceptable salt, its hydrate or solvate together with pharmaceutically acceptable diluent or carrier.For example, solid oral form may comprise, together with active compound, diluent such as lactose, dextrose, saccharose, cellulose, corn starch or potato starch; lubricant such as silica, talc, stearic acid, magnesium or calcium stearate and / or polyethylene glycol; binder; such as starch, gum arabic, gelatin, methylcellulose, carboxymethylcellulose or polyvinylpyrrolidone; anti-agglomerating agent such as starch, alginic acid, alginate or sodium starch glycolate; effervescent mixture; dye; sweetener; wetting agent such as lecithin, polysorbate, lauryl sulfate; and generally non-toxic and pharmacologically inactive substances used in pharmaceutical preparations. Such pharmaceutical compositions may be manufactured by conventional methods known in the art, for example by mixing, granulating, tabletting, sugar-coating, or film-coating processes.

[0141] The compositions of the present invention may be in a suitable form for oral use (e.g., as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups, or elixirs), for topical use (e.g., as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (e.g., as fine powders or liquid aerosols), for administration by insufflation (e.g., as fine powders) or for parenteral administration (e.g., as sterile aqueous or oily solutions for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular administration, or as suppositories for rectal administration). Suitably, oral or parenteral administration is preferred. Most suitably, oral administration is preferred.

[0142] The compositions of the invention can be obtained by conventional procedures using conventional pharmaceutical excipients well known in the art. Thus, compositions intended for oral use may contain, for example, one or more coloring agents, sweeteners, flavoring agents and / or preservatives.

[0143] An effective amount of a compound of the invention for use in therapy is an amount sufficient to treat or prevent, slow the progression of, and / or alleviate the symptoms associated with the proliferative conditions referred to herein.

[0144] The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending on the individual treated and the particular route of administration. For example, formulations intended for oral administration to humans will generally contain, for example, 0.5 mg to 0.5 g of active agent (more suitably, 0.5 to 100 mg, e.g., 1 to 30 mg), combined with an appropriate and convenient amount of an excipient, which may vary from about 5 to about 98% by weight of the total composition.

[0145] The magnitude of therapeutic or prophylactic administration of a compound of formula I will, of course, vary in accordance with well-known pharmaceutical principles depending on the nature and severity of the condition, the age and sex of the animal or patient, and the route of administration.

[0146] When using the compounds of the invention for therapeutic or prophylactic purposes, they will generally be administered to receive a daily dose, for example, 0.1 mg / kg to 75 mg / kg of body weight, in divided doses if required. Generally, smaller doses will be administered when parenteral routes are used. Thus, for example, for intravenous or intraperitoneal administration, generally, doses in the range of, for example, 0.1 mg / kg to 30 mg / kg of body weight will be used. Similarly, for administration by inhalation, doses in the range of, for example, 0.05 mg / kg to 25 mg / kg of body weight will be used. Oral administration may also be suitable, particularly in tablet form. Typically, a unit dosage form contains about 0.5 mg to 0.5 g of the compound of the invention.

[0147] Therapeutic Uses and Applications The present invention provides compounds that function as regulators or inhibitors of eNAMPT activity.

[0148] Thus, the present invention provides a method for inhibiting eNAMPT activity in vitro or in vivo, comprising administering an effective amount of a compound, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition defined herein.

[0149] The present invention also provides a method of treating a disease or disorder in which eNAMPT activity is implicated in a patient in need of such treatment, comprising administering to said patient a therapeutically effective amount of a compound, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

[0150] The present invention provides a compound as defined herein or a pharma- ceutically acceptable salt thereof for use in the treatment of a disease or disorder in which eNAMPT activity is implicated.Suitably, the disease or disorder is any of those listed herein.

[0151] In another aspect, the present invention provides a compound as defined herein, or a pharma- ceutically acceptable salt or solvate thereof, for use in the treatment of a disease or condition in which the inhibition of eNAMPT activity is beneficial.Suitably, the compound as defined herein, or a pharma- ceutically acceptable salt or solvate thereof, is for use in the treatment of a disease or condition in which the inhibition of monomeric eNAMPT activity is beneficial.

[0152] In another aspect, the present invention provides a compound as described herein, or a pharma- ceutically acceptable salt or solvate thereof, for use in treating: (i) Diabetes; (ii) cardiovascular disease (e.g., pulmonary arterial hypertension, acute coronary syndrome (ACS), congestive heart failure (CHF) or left ventricular hypertrophy); (iii) inflammatory bowel conditions (e.g., inflammatory bowel disease (IBD), Crohn's disease or ulcerative colitis) (iv) cancer (e.g., breast cancer, prostate cancer, or chronic lymphocytic leukemia (CLL)); (v) liver disease (e.g., nonalcoholic fatty liver disease (NAFLD), especially nonalcoholic steatohepatitis (NASH)); (vi) inflammatory skin conditions (e.g., psoriasis); (vii) pulmonary conditions (acute lung injury (ALI), ventilator-induced lung injury (VILI), radiation-induced lung injury (RILI), pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis)); (viii) arthritis (e.g., osteoarthritis or rheumatoid arthritis); (ix) renal disease (e.g., chronic kidney disease); or (x) Sepsis.

[0153] In another aspect, the present invention provides a compound as described herein, or a pharma- ceutically acceptable salt or solvate thereof, for use in the treatment of: (i) Diabetes; (ii) cardiovascular disease (e.g., pulmonary arterial hypertension, acute coronary syndrome (ACS), congestive heart failure (CHF) or left ventricular hypertrophy); (iii) inflammatory bowel conditions (e.g., inflammatory bowel disease (IBD), Crohn's disease or ulcerative colitis) (iv) cancer (e.g., breast cancer, prostate cancer, or chronic lymphocytic leukemia (CLL)); (v) liver disease (e.g., nonalcoholic fatty liver disease (NAFLD), especially nonalcoholic steatohepatitis (NASH)); hepatic steatosis, hepatic fibrosis or cirrhosis); (vi) pulmonary conditions (acute lung injury (ALI), ventilator-induced lung injury (VILI), radiation-induced lung injury (RILI), pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis)); (vii) Renal disease (e.g., chronic kidney disease).

[0154] In another aspect, the present invention provides a compound as described herein, or a pharma- ceutically acceptable salt or solvate thereof, for use in treating: (i) Diabetes; (ii) pulmonary arterial hypertension, acute coronary syndrome (ACS), congestive heart failure (CHF) or left ventricular hypertrophy; (iii) inflammatory bowel disease (IBD), Crohn's disease or ulcerative colitis; (iv) breast cancer, prostate cancer, or chronic lymphocytic leukemia (CLL) (v) nonalcoholic fatty liver disease (NAFLD), especially nonalcoholic steatohepatitis (NASH), hepatic steatosis, hepatic fibrosis or cirrhosis); (vi) psoriasis; (vii) acute lung injury (ALI), ventilator-induced lung injury (VILI), radiation-induced lung injury (RILI), pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis); (viii) osteoarthritis or rheumatoid arthritis; (ix) chronic kidney disease; or (x) Sepsis.

[0155] In another aspect, the present invention provides a compound as described herein, or a pharma- ceutically acceptable salt or solvate thereof, for use in treating: (i) Diabetes; (ii) pulmonary arterial hypertension; (iii) inflammatory bowel disease (IBD), Crohn's disease or ulcerative colitis; (iv) nonalcoholic fatty liver disease (NAFLD), especially nonalcoholic steatohepatitis (NASH); (v) acute lung injury (ALI), ventilator-induced lung injury (VILI), radiation-induced lung injury (RILI); or (vi) Chronic kidney disease.

[0156] In another aspect, the present invention provides a compound as defined herein, or a pharma- ceutically acceptable salt or solvate thereof, for use in the treatment of inflammatory bowel disease (IBD), Crohn's disease or ulcerative colitis.

[0157] In another aspect, the present invention provides a compound as described herein, or a pharma- ceutically acceptable salt or solvate thereof, for use in the treatment of diabetes.

[0158] In another aspect, the present invention provides a compound as described herein, or a pharma- ceutically acceptable salt or solvate thereof, for use in the treatment of pulmonary arterial hypertension.

[0159] In another aspect, the present invention provides a compound as defined herein, or a pharma- ceutically acceptable salt or solvate thereof, for use in the treatment of non-alcoholic fatty liver disease (NAFLD), in particular non-alcoholic steatohepatitis (NASH).

[0160] In another aspect, the present invention provides a compound as defined herein, or a pharma- ceutically acceptable salt or solvate thereof, for use in the treatment of acute lung injury (ALI), ventilator-induced lung injury (VILI), or radiation-induced lung injury (RILI).

[0161] In another aspect, the present invention provides a compound as described herein, or a pharma- ceutically acceptable salt or solvate thereof, for use in the treatment of chronic kidney disease.

[0162] Suitably, the compounds defined herein, or pharma- ceutically acceptable salts or solvates thereof, are for use in the treatment of pulmonary arterial hypertension, IBD, Crohn's disease, ulcerative colitis, diabetes (especially in subjects with cardiovascular disease comorbidities), chronic kidney disease, ventilator-induced pulmonary injury (VILI) (e.g., in subjects treated for COVID-19), acute lung injury (ALI), acute respiratory distress syndrome (ARDS), idiopathic pulmonary fibrosis, non-alcoholic fatty liver disease (for example, but not limited to, hepatic steatosis due to inflammatory non-alcoholic steatohepatitis (NASH)), fibrosis or cirrhosis) or radiation-induced lung injury (RILI).

[0163] In another aspect, the present invention provides a compound as defined herein, or a pharma- ceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in inhibiting eNAMPT activity.Suitably, the present invention provides a compound as defined herein, or a pharma- ceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in inhibiting monomeric eNAMPT activity.

[0164] In another aspect, the present invention provides a method for inhibiting eNAMPT activity in vitro or in vivo, said method comprising contacting a sample containing eNAMPT with an effective amount of a compound as defined herein, or a pharma- ceutically acceptable salt or solvate thereof.Suitably, said method is a method for inhibiting monomeric eNAMPT activity.

[0165] In a further aspect, the present invention provides a method of treating: (i) Diabetes; (ii) cardiovascular disease (e.g., pulmonary arterial hypertension, acute coronary syndrome (ACS), congestive heart failure (CHF) or left ventricular hypertrophy); (iii) inflammatory bowel conditions (e.g., inflammatory bowel disease (IBD), Crohn's disease or ulcerative colitis) (iv) cancer (e.g., breast cancer, prostate cancer, or chronic lymphocytic leukemia (CLL)); (v) liver disease (e.g., nonalcoholic fatty liver disease (NAFLD), especially nonalcoholic steatohepatitis (NASH)); (vi) inflammatory skin conditions (e.g., psoriasis); (vii) pulmonary conditions (acute lung injury (ALI), ventilator-induced lung injury (VILI), radiation-induced lung injury (RILI), pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis)); (viii) arthritis (e.g., osteoarthritis or rheumatoid arthritis); (ix) renal disease (e.g., chronic kidney disease); or (x) sepsis; In a patient in need of such treatment, the method comprises administering to the patient a therapeutically effective amount of a compound defined herein, or a pharma- ceutically acceptable salt or solvate thereof, or a pharmaceutical composition defined herein.

[0166] In another aspect, in certain embodiments, the present invention provides a method of treating: (i) Diabetes; (ii) cardiovascular disease (e.g., pulmonary arterial hypertension, acute coronary syndrome (ACS), congestive heart failure (CHF) or left ventricular hypertrophy); (iii) inflammatory bowel conditions (e.g., inflammatory bowel disease (IBD), Crohn's disease or ulcerative colitis) (iv) cancer (e.g., breast cancer, prostate cancer, or chronic lymphocytic leukemia (CLL)); (v) liver disease (e.g., nonalcoholic fatty liver disease (NAFLD), particularly nonalcoholic steatohepatitis (NASH), hepatic steatosis, hepatic fibrosis or cirrhosis); (vi) a pulmonary condition (acute lung injury (ALI), ventilator-induced lung injury (VILI), radiation-induced lung injury (RILI), pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis)); or (vii) renal disease (e.g., chronic kidney disease); In a patient in need of such treatment, the method comprises administering to the patient a therapeutically effective amount of a compound defined herein, or a pharma- ceutically acceptable salt or solvate thereof, or a pharmaceutical composition defined herein.

[0167] In another aspect, in certain embodiments, the present invention provides a method of treating: (i) Diabetes; (ii) pulmonary arterial hypertension, acute coronary syndrome (ACS), congestive heart failure (CHF) or left ventricular hypertrophy; (iii) inflammatory bowel disease (IBD), Crohn's disease or ulcerative colitis; (iv) breast cancer, prostate cancer, or chronic lymphocytic leukemia (CLL) (v) nonalcoholic fatty liver disease (NAFLD), especially nonalcoholic steatohepatitis (NASH), hepatic steatosis, hepatic fibrosis or cirrhosis); (vi) psoriasis; (vii) acute lung injury (ALI), ventilator-induced lung injury (VILI), radiation-induced lung injury (RILI), pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis); (viii) osteoarthritis or rheumatoid arthritis; (ix) chronic kidney disease; or (x) sepsis; In a patient in need of such treatment, the method comprises administering to the patient a therapeutically effective amount of a compound defined herein, or a pharma- ceutically acceptable salt or solvate thereof, or a pharmaceutical composition defined herein.

[0168] In another aspect, in certain embodiments, the present invention provides methods of treating: (i) Diabetes; (ii) pulmonary arterial hypertension; (iii) inflammatory bowel disease (IBD), Crohn's disease or ulcerative colitis; (iv) nonalcoholic fatty liver disease (NAFLD), especially nonalcoholic steatohepatitis (NASH); (v) acute lung injury (ALI), ventilator-induced lung injury (VILI), radiation-induced lung injury (RILI); or (vi) chronic kidney disease; In a patient in need of such treatment, the method comprises administering to the patient a therapeutically effective amount of a compound defined herein, or a pharma- ceutically acceptable salt or solvate thereof, or a pharmaceutical composition defined herein.

[0169] In another aspect, in certain embodiments, the present invention provides a method of treating inflammatory bowel disease (IBD), Crohn's disease or ulcerative colitis in a patient in need of such treatment, comprising administering to said patient a therapeutically effective amount of a compound as defined herein, or a pharma- ceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein.

[0170] In another aspect, in certain aspects, the present invention provides a method of treating diabetes in a patient in need of such treatment, comprising administering to said patient a therapeutically effective amount of a compound as defined herein, or a pharma- ceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein.

[0171] In another aspect, in certain embodiments, the present invention provides a method of treating pulmonary arterial hypertension in a patient in need of such treatment, comprising administering to said patient a therapeutically effective amount of a compound as defined herein, or a pharma- ceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein.

[0172] In another aspect, in a particular aspect, the present invention provides a method of treating non-alcoholic fatty liver disease (NAFLD), in particular non-alcoholic steatohepatitis (NASH), in a patient in need of such treatment, comprising administering to said patient a therapeutically effective amount of a compound as defined herein, or a pharma- ceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein.

[0173] In another aspect, in certain aspects, the present invention provides a method of treating chronic kidney disease in a patient in need of such treatment, comprising administering to said patient a therapeutically effective amount of a compound as defined herein, or a pharma- ceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein.

[0174] In another aspect, the invention provides the use of a compound defined herein, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of: (i) Diabetes; (ii) cardiovascular disease (e.g., pulmonary arterial hypertension, acute coronary syndrome (ACS), congestive heart failure (CHF) or left ventricular hypertrophy); (iii) inflammatory bowel conditions (e.g., inflammatory bowel disease (IBD), Crohn's disease or ulcerative colitis) (iv) cancer (e.g., breast cancer, prostate cancer, or chronic lymphocytic leukemia (CLL)); (v) liver disease (e.g., nonalcoholic fatty liver disease (NAFLD), especially nonalcoholic steatohepatitis (NASH)); (vi) inflammatory skin conditions (e.g., psoriasis); (vii) pulmonary conditions (acute lung injury (ALI), ventilator-induced lung injury (VILI), radiation-induced lung injury (RILI), pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis)); (viii) arthritis (e.g., osteoarthritis or rheumatoid arthritis); (ix) renal disease (e.g., chronic kidney disease); or (x) Sepsis.

[0175] In another aspect, the present invention provides the use of a compound as defined herein, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of: (i) Diabetes; (ii) cardiovascular disease (e.g., pulmonary arterial hypertension, acute coronary syndrome (ACS), congestive heart failure (CHF) or left ventricular hypertrophy); (iii) inflammatory bowel conditions (e.g., inflammatory bowel disease (IBD), Crohn's disease or ulcerative colitis) (iv) cancer (e.g., breast cancer, prostate cancer, or chronic lymphocytic leukemia (CLL)); (v) liver disease (e.g., nonalcoholic fatty liver disease (NAFLD), particularly nonalcoholic steatohepatitis (NASH), hepatic steatosis, hepatic fibrosis or cirrhosis); (vi) pulmonary conditions (acute lung injury (ALI), ventilator-induced lung injury (VILI), radiation-induced lung injury (RILI), pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis)); (vii) Renal disease (e.g., chronic kidney disease).

[0176] In another aspect, the present invention provides the use of a compound as defined herein, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of: (i) Diabetes; (ii) pulmonary arterial hypertension, acute coronary syndrome (ACS), congestive heart failure (CHF) or left ventricular hypertrophy; (iii) inflammatory bowel disease (IBD), Crohn's disease or ulcerative colitis; (iv) breast cancer, prostate cancer, or chronic lymphocytic leukemia (CLL) (v) nonalcoholic fatty liver disease (NAFLD), especially nonalcoholic steatohepatitis (NASH), hepatic steatosis, hepatic fibrosis or cirrhosis); (vi) psoriasis; (vii) acute lung injury (ALI), ventilator-induced lung injury (VILI), radiation-induced lung injury (RILI), pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis); (viii) osteoarthritis or rheumatoid arthritis; (ix) chronic kidney disease; or (x) Sepsis.

[0177] In another aspect, the present invention provides the use of a compound as defined herein, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of: (i) Diabetes; (ii) pulmonary arterial hypertension; (iii) inflammatory bowel disease (IBD), Crohn's disease or ulcerative colitis; (iv) nonalcoholic fatty liver disease (NAFLD), especially nonalcoholic steatohepatitis (NASH); (v) acute lung injury (ALI), ventilator-induced lung injury (VILI), radiation-induced lung injury (RILI); or (vi) Chronic kidney disease.

[0178] In another aspect, the invention provides the use of a compound as defined herein, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of inflammatory bowel disease (IBD), Crohn's disease or ulcerative colitis.

[0179] In another aspect, the present invention provides the use of a compound as defined herein, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of diabetes:

[0180] In another aspect, the present invention provides the use of a compound as defined herein, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of pulmonary arterial hypertension:

[0181] In another aspect, the present invention provides the use of a compound as defined herein, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of non-alcoholic fatty liver disease (NAFLD), in particular non-alcoholic steatohepatitis (NASH).

[0182] In another aspect, the present invention provides the use of a compound as defined herein, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of acute lung injury (ALI), ventilator-induced lung injury (VILI), or radiation-induced lung injury (RILI).

[0183] In another aspect, the invention provides the use of a compound defined herein, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of chronic kidney disease.

[0184] In another aspect, the present invention provides the use of a compound as defined herein, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for the inhibition of eNAMPT activity.

[0185] Route of Administration The compounds of the invention, or pharmaceutical compositions containing these compounds, may be administered to a subject by any convenient route of administration, either systemically / peripherally or locally (ie, at the site of desired action).

[0186] Routes of administration include, but are not limited to, oral (e.g., by ingestion); buccal; sublingual; transdermal (including, e.g., by patches, bandages, etc.); transmucosal (including, e.g., by patches, bandages, etc.); intranasal (e.g., by nose drops); ocular (e.g., by eye drops); pulmonary (e.g., via aerosols, etc., e.g., inhalation or insufflation therapy through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., pessary); parenteral, e.g., by injection, including, for example, subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcutaneous, intraarticular, subarachnoid, and intrasternal; e.g., by implanting a depot or reservoir subcutaneously or intramuscularly. [Brief description of the drawings]

[0187] With reference to the accompanying drawings, [Figure 1] Figure 1 shows the unique mass spectra of NAMPT alone (top) or incubated with Example 1 (middle) or FK866 (bottom). The major peak for NAMPT dimer is observed in the range of 5,500-6,750 in all samples. The major peak for NAMPT monomer is observed in the range of 4,000-4,800, but not in the sample from Example 1, indicating the absence of monomeric protein under these conditions. [Diagram 2]Figure 2 shows the region from m / z 6125 to 6500 of the native mass spectrum of NAMPT alone (top) or incubated with Example 1 (middle) or FK866 (bottom). The main peak of the NAMPT dimer is observed at approximately 6240 (18+). Under these conditions, the mass of a stable 2+2 complex between NAMPT and Example 1 is observed at m / z approximately 6320, while the FK866 complex dissociates, resulting in the detection of only NAMPT. [Diagram 3] Figure 3 shows the region of m / z 2950-5200 of the native mass spectrum of NAMPT alone (top) or incubated with Example 1 (middle) or FK866 (bottom). The major peak of NAMPT monomer is observed in the range of 4,000-4,800 but not in the sample from Example 1, indicating the absence of monomeric protein under these conditions. EXAMPLES

[0188] Synthesis of starting materials Warhead: [ka] 7-Iodonaphthalene-1,3-disulfonic acid (Intermediate A): A suspension of 7-aminonaphthalene-1,3-disulfonic acid (16.5 mmol, 5.0 g) and HCl (37%, 3.6 mL) in HO (11 mL) was cooled to 0 °C, forming a white sludge. An ice-cold solution of NANO (16.5 mmol, 1.1 g) in water (9 mL) was added dropwise via cannula. The mixture was stirred at 0 °C for 1 h. A solution of NAI (53.0 mmol, 7.9 g) and HCl (37%, 3.6 mL) in HO (15 mL) at 0 °C was added dropwise via cannula. The resulting dark mixture was allowed to reach room temperature, concentrated under reduced pressure, and recrystallized in boiling water. The resulting light brown solid was washed with ice-cold water (40 mL), EtO (20 mL), and dried in air to give the product as a beige solid (3.1 g, 44% yield). 1H NMR (400MHz, DMSO-d6) δ9.18 (d, J = 1.3 Hz, 1H), 8.23 ​​(d, J = 1.7 Hz, 1H), 8.09 (d, J = 1.7 Hz, 1H), 7.78 (br.s, 2H).

[0189] Tail precursor: [ka] (E)-3-(3-Bromo-4-fluorophenyl)acrylic acid (Intermediate 1). A mixture of 3-bromo-4-fluorobenzaldehyde (5.03 mmol, 930 mg), malonic acid (11.05 mmol, 1150 mg), piperidine (10 mol%, 0.05 mL) and pyridine (2.5 mL) was combined in a high pressure tube and stirred at 115° C. for 3 h. The mixture was allowed to reach room temperature and poured into 200 mL of 2M HCl. A white precipitate formed and was isolated by filtration and dried under vacuum to give the desired product (640 mg, 52%). 1 H NMR(500MHz,DMSO-d6)δ12.49(br.,1H),8.13(dd,J=6.8,2.1Hz,1H),7.79(ddd,J=8.7,4. 9,2.2Hz,1H),7.57(d,J=16.0Hz,1H),7.43(app.t,J=8.7Hz,1H),6.60(d,J=16.0Hz,1H); 13 C NMR(101MHz,DMSO-d6)δ167.8,159.5(d,J=248.9Hz),141.8,133.7,133.2(d,J=3.8 Hz), 130.1(d,J=7.8Hz),121.1,117.6(d,J=22.6Hz),109.2(d,J=21.5Hz) + (ES + )243.0,245.0;t R = 2.35 min. HPLC Method 2 (base).

[0190] [ka] (4-(4-Azidobutyl)piperidin-1-yl)(phenyl)methanone (Intermediate 2). (4-(4-Hydroxybutyl)piperidin-1-yl)(phenyl)methanone (2.22 mmol, 545 mg) was dissolved in anhydrous DMF (6 mL), degassed and cooled on ice. DPPA (6.67 mmol, 1.4 mL), DBU (6.67 mmol, 1.0 mL) were added and the mixture was stirred at 0° C. for 30 min, followed by sodium azide (2.22 mmol, 144 mg) and stirring at 100° C. for 4 h. The mixture was allowed to reach room temperature, diluted with Et2O (40 mL), washed with water (2×20 mL) and brine (30 mL), dried over MgSO4, filtered, concentrated under reduced pressure and purified by reverse phase column chromatography (0.1% HCOOH modifier) ​​to give the desired product as a brown oil (364 mg, 57%). 1 H NMR(400MHz,CDCl3)δ7.45-7.37(s,5H),4.80-4.67(m,1H),3.82-3.70(m,1H),3.30(t,J=6.8Hz,2H),3.03-2.90 (m,1H),2.82-2.69(m,1H),1.90-1.78(m,1H),1.76-1.49(m,4H),1.47-1.38(m,2H),1.36-1.01(m,4H);m / z(M+H) + (ES + )287.4;t R = 2.67 min. . HPLC Method 2 (Base).

[0191] [ka] (4-(4-Aminobutyl)piperidin-1-yl)(phenyl)methanone (Intermediate 3). (4-(4-azidobutyl)piperidin-1-yl)(phenyl)methanone (Intermediate 2; 1.27 mmol, 364 mg) was dissolved in MeOH:DCM (1:1, 10 mL) under inert atmosphere. Pd / C (10% w / w, 10 mol%, 80 mg) was added and H2 (1 atm) was bubbled through the solution. The mixture was stirred for 1 h, then filtered through Celite®, washed with DCM (20 mL), MeOH (20 mL) and concentrated under reduced pressure to give a colorless oil (184 mg, 55%). The crude was carried on to the next step without further purification. m / z (M+H) + (ES + )261.4, 263.4;t R = 1.76 min. HPLC Method 2 (Base).

[0192] [ka] 2-((6-azidohexyl)oxy)-1,1'-biphenyl (Intermediate 4). 6-([1,1'-biphenyl]-2-yloxy)hexan-1-ol (0.89 mmol, 240 mg) was dissolved in anhydrous DMF (3 mL), degassed and cooled on ice. DPPA (2.68 mmol, 0.57 mL), DBU (2.68 mmol, 0.40 mL) were added and the mixture was stirred at 0° C. for 30 min, followed by sodium azide (0.89 mmol, 58 mg) and stirring at 100° C. for 4 h. The mixture was allowed to reach room temperature, diluted with Et2O (40 mL), washed with water (2×20 mL) and brine (30 mL), dried over MgSO4, filtered, concentrated under reduced pressure and used in the next step without further purification (200 mg, 76%). m / z (M+H) + (ES + )296.1;t R = 3.16 min. HPLC Method 2 (Base).

[0193] [ka] 1-Bromo-3-ethynylbenzene (Intermediate 5). 1-Bromo-3-iodobenzene (2.12 mmol, 0.27 mL), TEA (8.48 mmol, 1.19 mL) and ethynyltrimethylsilane (2.40 mmol, 0.32 mL) were dissolved in anhydrous THF (12 mL) and degassed with Ar for 20 min. PdCl2(PPh3)2 (0.11 mmol, 74 mg) and CuI (0.06 mmol, 12 mg) were added and the mixture was stirred at room temperature for 4 h. The mixture was concentrated, redissolved in Et2O (30 mL), washed with water (2 x 20 mL) and brine (20 mL). The organic phase was dried over MgSO4, filtered, concentrated under reduced pressure and purified by filtration onto a small pad of silica (ca. 2-3 g) and eluted with hexane:AcOEt (95:5). The solution was concentrated under reduced pressure and redissolved in MeOH (10 mL). K2CO3 (5.30 mmol, 736 mg) was added and the mixture was stirred for 1 h. The mixture was concentrated and filtered through a pad of silica (ca. 2-3 g) and eluted with HeX:AcOEt (95:5) to give a colorless oil (365 mg, 95%). m / z (M+H) + (ES + )181.3;t R = 3.25 min. HPLC Method 2 (Base).

[0194] [ka] (3-Bromo-4-methoxyphenyl)methanamine hydroformate (Intermediate 6). 1-Bromo-4-methoxybenzonitrile (1.0 g, 4.72 mmol) was dissolved in THF (20 mL). Borane (1 M solution in THF, 14.15 mL) was added dropwise at room temperature for 10 min, then the mixture was stirred at reflux for 2 h. The mixture was cooled to 0° C., slowly quenched with MeOH (10 mL), and concentrated under reduced pressure. The reaction mixture was diluted with water (20 mL), extracted with CHCl (3×15 mL), and washed with brine (15 mL). The organic phase was dried over MgSO, filtered, concentrated, and purified by reverse phase chromatography (0.1% HCOOH modifier) ​​to give the desired product as a white solid (443 mg, 43%). 1H NMR(500MHz,CDCl3)δ8.54(s,1H),7.70(d,J=2.2Hz,1H),7.43(dd,J=8.5,2.3Hz,1H),7.11(d,J=8.5Hz,1H),4.06(s,2H),3.92(s,3H).m / z(M+H) + (ES + )216.2,218.2;t R = 2.08 min. HPLC Method 2 (Base).

[0195] [ka] 4-(Piperidin-1-ylsulfonyl)benzonitrile (Intermediate 7). 3-Cyanobenzenesulfonyl chloride (500 mg, 2.47 mmol) was dissolved in DCM (6 mL). Piperidine (0.37 mL, 3.71 mmol) and TEA (0.69 mL, 4.94 mmol) were added to the mixture and stirred overnight. The mixture was concentrated under reduced pressure and purified by reverse phase chromatography (0.1% HCOOH modifier) ​​to give the desired product as a white solid (470 mg, 76%). m / z:t R = 2.39 min. HPLC Method 2 (Base).

[0196] [ka] (4-(Piperidin-1-ylsulfonyl)phenyl)methanamine (Intermediate 8). 4-(Piperidin-1-ylsulfonyl)benzonitrile (Intermediate 7; 100 g, 0.40 mmol) was dissolved in THF (20 mL). Borane (1 M solution in THF, 1.2 mL) was added dropwise at room temperature for 10 min, then the mixture was stirred at reflux for 1 h. The mixture was cooled to 0° C., slowly quenched with MeOH (10 mL), and concentrated under reduced pressure. The mixture was diluted with MeOH (1 mL), loaded onto an SCX cartridge (washed with 2 volumes of MeOH), washed with MeOH (3 mL), eluted with NH3 in MeOH (7 M, 2 mL), and concentrated under reduced pressure to give the desired product as a white solid (95 mg, 93%). m / z (M+H)+ (ES + )255.3,t R = 1.68 min. HPLC Method 2 (Base).

[0197] Tail: [ka] 1-(3-Bromo-4-fluorobenzyl)-3-(4-(piperidin-1-ylsulfonyl)phenyl)urea (Intermediate 9). 3-Bromo-4-fluorobenzylamine hydrochloride (2.30 mmol, 553 mg) and TEA (5.06 mmol, 0.35 mL) were added to a light-protected solution of 4-(chlorosulfonyl)phenyl isocyanate (2.30 mmol, 500 mg) in THF (20 mL) at -40°C. The mixture was stirred for 2 h and allowed to reach room temperature before piperidine (2.30 mmol, 0.23 mL) and TEA (5.06 mmol, 0.35 mL) were added. The mixture was stirred for an additional 2 h, then concentrated under reduced pressure, redissolved in DCM (ca. 30 mL), washed with water (2 x 20 mL) and brine (20 mL), dried over MgSO4, filtered, concentrated, and purified by flash chromatography on silica gel (1% MeOH in DCM) to give the desired product as a white solid (458 mg, 42%). 1 H NMR(400MHz,DMSO-d6)δ9.19(s,1H),7.68-7.53(m,5H),7.40-7.31(m,2H),6.91(t,J=6.0H) z,1H),4.30(d,J=5.9Hz,2H),2.83(t,J=5.3Hz,4H),1.62-1.46(m,4H),1.42-1.17(m,2H); 13 C NMR(101MHz,DMSO-d6)δ157.6(d,J=243.4Hz),155.2,145.1,139.0(d,J=3.5Hz),132.4,129.2,129.0( m / z(M+H) + (ES +)470.2,472.2;t R = 2.62 min. HPLC Method 2 (Base).

[0198] [ka] 1-(4-((8-oxa-3-azabicyclo[3.2.1]octan-3-yl)sulfonyl)phenyl)-3-(3-bromo-4-fluorobenzyl)urea (intermediate 10). 3-Bromo-4-fluorobenzylamine hydrochloride (0.98 mmol, 200 mg) and DIPEA (1.03 mmol, 0.18 mL) were added to a light-protected solution of 4-(chlorosulfonyl)phenyl isocyanate (0.98 mmol, 213 mg) in MeCN (20 mL) at -40°C. The mixture was stirred for 2 h and allowed to reach room temperature before adding 8-oxa-3-azabicyclo[3.2.1]octane (1.11 mmol, 122 mg) and DIPEA (1.03 mmol, 0.18 mL). The mixture was stirred for an additional 2 h, then concentrated under reduced pressure, redissolved in DCM (ca. 30 mL), washed with water (2 x 20 mL) and brine (20 mL), dried over MgSO4, filtered, concentrated, and purified by reverse phase column chromatography (0.1% HCOOH modifier). The product was eluted along with impurities and was carried on to the next step without further purification. m / Z(M+H) + (ES + )498.1, 500.1;t R = 2.50 min. HPLC Method 2 (Base).

[0199] [ka] (E)-N-(4-(1-benzoylpiperidin-4-yl)butyl)-3-(3-bromo-4-fluorophenyl)acrylamide (intermediate 11). A mixture of intermediate 3 (0.77 mmol, 200 mg) and intermediate 1 (0.77 mmol, 183 mg) was dissolved in anhydrous DMF (5 mL). HATU (1.15 mmol, 439 mg) and DIPEA (1.54 mmol, 0.26 mL) were added and the mixture was stirred at room temperature overnight. The mixture was extracted with AcOEt (30 mL) and washed with brine (3×20 mL). The organic phase was dried over MgSO4, filtered, concentrated under reduced pressure and purified by reverse phase column chromatography (0.1% HCOOH modifier) ​​to give the desired compound as a colorless oil (300 mg, 80%). 1 H NMR(500MHz,CDCl3)δ7.61(dd,J=6.6,2.1Hz,1H),7.43(d,J=15.6Hz,1H),7.35-7.26(m,5H), 7.20(s,1H),7.03(app.t,J=8.3Hz,1H),6.25(d,J=15.5Hz,1H),5.96(t,J=5.9Hz,1H),4.77-4 .53(m,1H),3.66(d,J=13.4Hz,1H),3.28(app.q,J=6.7Hz,2H),2.95-2.83(m,1H),2.72-2.60 (m,1H),1.85-1.68(m,2H),1.60-1.50(m,1H),1.50-1.38(m,3H),1.36-0.89(m,5H).m / z(M+H) + (ES + )487.3,489.3;t R = 2.65 min. HPLC Method 2 (Base).

[0200] [ka] 1-(6-([1,1'-biphenyl]-2-yloxy)hexyl)-4-(3-bromophenyl)-1H-1,2,3-triazole (Intermediate 12). A mixture of intermediate 4 (164 mg, 0.55 mmol), intermediate 5 (100 mg, 0.55 mmol), copper sulfate (5 mg, 5 mol%) and sodium ascorbate (11 mg, 10 mol%) in THF:HO (5:1, 6 mL) was stirred at room temperature for 1 h. The reaction mixture was extracted with AcOEt (30 mL), washed with brine (2×20 mL), dried over MgSO, filtered, concentrated under reduced pressure and purified by reverse phase column chromatography (0.1% formic acid modifier) ​​to give the desired product as a colorless oil (96 mg, 37%). 1 H NMR(500MHz,CDCl3)δ7.84(app.t,J=1.8Hz,1H),7.62(app.dt,J=7.8,1.3Hz,1H),7.53(s,1H),7.42 -7.38(m,2H),7.33(app.dd,J=8.0,2.1Hz,1H),7.28-7.22(m,2H),7.22-7.14(m,3H),7.13(s,1H),6 .90(app.td,J=7.5,1.1Hz,1H),6.83(dd,J=8.2,1.2Hz,1H),4.18(app.t,J=7.2Hz,2H),3.83(app.t ,J=6.1Hz,2H),1.76(app.p,J=7.4Hz,2H),1.62-1.54(m,2H),1.36-1.26(m,2H),1.24-1.15(m,2H); 13 C NMR(126MHz, CDCl3)δ155.9,146.3,138.7,132.7,131.0,131.0,130.9,130.4,129.6,128.7,128. m / z(M+H) + (ES + )476.3;t R = 3.18 min. HPLC Method 2 (Base).

[0201] [ka] 1-(3-Bromobenzyl)-3-(4-(piperidin-1-ylsulfonyl)phenyl)urea (Intermediate 13). A mixture of 3-bromobenzylamine (201 mg, 1.08 mmol), phenyl(4-(cyclohexylsulfonyl)phenyl)carbamate (300 mg, 0.83 mmol) and TEA (0.35 mL, 2.49 mmol) in dioxane (10 mL) was stirred at 60° C. for 2 h. Upon cooling, the product crashed as a white solid. The mixture was concentrated, redissolved in AcOEt (10 mL) and washed with water (10 mL) and brine (10 mL). The organic phase was separated, dried over MgSO4, filtered, concentrated under reduced pressure and purified by reverse phase column chromatography (0.1% ammonia modifier) ​​to give the desired product as a white solid (190 mg, 50%). m / z (M+H) + (ES + )452.2, 454.4, t R = 2.63 min. HPLC Method 2 (Base).

[0202] [ka] 1-(5-Bromo-2-fluorobenzyl)-3-(4-(piperidin-1-ylsulfonyl)phenyl)urea (Intermediate 14). A mixture of 5-bromo-2-fluorobenzylamine (216 mg, 0.90 mmol), phenyl(4-(cyclohexylsulfonyl)phenyl)carbamate (250 mg, 0.69 mmol) and TEA (0.29 mL, 2.07 mmol) in dioxane (10 mL) was stirred at 60° C. for 4 h. Upon cooling, the product crashed as a white solid. The mixture was concentrated, redissolved in AcOEt (10 mL) and washed with water (10 mL) and brine (10 mL). The organic phase was separated, dried over MgSO4, filtered and concentrated under reduced pressure. The resulting white solid was triturated with Et2O (ca. 10 mL) and dried to give the pure product (400 mg, 85%). m / z (M+H) + (ES + )470.2,472.2;t R = 2.66 min. HPLC Method 2 (Base). 1H NMR(500MHz,CDCl3)δ7.66-7.60(m,2H),7.53(dd,J=6.6,2.5Hz,1H),7.52-7.48(m,2H),7.41-7.31(m,1H),7.16(br.s,1H),6.95(app .t,J=9.1Hz,1H),4.49(d,J=6.0Hz,2H),2.96(app.t,J=5.4Hz,4H),1.69-1.63(m,4H),1.43(app.tq,J=8.8,5.4,4.4Hz,2H).m / z(M+H) + (ES + )470.2,472.2;t R = 2.66 min. HPLC Method 2 (Base).

[0203] [ka] 1-(3-Bromo-4-methoxybenzyl)-3-(4-(piperidin-1-ylsulfonyl)phenyl)urea (Intermediate 15). A mixture of (3-bromo-4-methoxyphenyl)methanamine hydroformate (245 mg, 0.55 mmol), phenyl(4-(piperidin-1-ylsulfonyl)phenyl)carbamate (200 mg, 0.55 mmol) and TEA (0.23 mL, 1.65 mmol) in dioxane (10 mL) was stirred at 60° C. for 2 h. Upon cooling, the product crashed as a white solid. The mixture was concentrated, redissolved in AcOEt (10 mL) and washed with water (10 mL) and brine (10 mL). The organic phase was separated, dried over MgSO4, filtered and concentrated under reduced pressure. The resulting white solid was purified by flash chromatography in silica gel (hexane:AcOEt 2:3) to give the desired product as a colorless oil (262 mg, 99%). m / z (M+H) + (ES + )482.2, 484.2, t R =2.59 minutes. HPLC method 2 (acid).

[0204] [ka] 5-Bromo-N-(4-(piperidin-1-ylsulfonyl)benzyl)-1H-indole-2-carboxamide (Intermediate 16). A mixture of 5-bromo-1H-indole-2-carboxylic acid (60 mg, 0.37 mmol), intermediate 8 (95 mg, 0.37 mmol), HATU (200 mg, 0.56 mmol) and DIPEA (0.13 mL, 0.74 mmol) in DMF (3 mL) was stirred at room temperature overnight. The reaction mixture was extracted with Et2O (20 mL) and washed with water (10 mL) and brine (10 mL). The organic phase was separated, dried over MgSO4, filtered and concentrated under reduced pressure. The resulting white solid was purified by reverse phase column chromatography (0.1% HCOOH modifier) ​​to give the desired product as a pale yellow oil (57 mg, 32%). m / z (M+H) + (ES + )476.2, 478.2, t R =2.70 minutes. HPLC method 2 (acid).

[0205] [ka] Ethyl 4-(5-bromoisoindoline-2-carboxamido)benzoate (Intermediate 17). 5-Bromoisoindoline (387 mg, 1.51 mmol), ethyl 4-isocyanatobenzoate (339 mg, 01.77 mmol) were combined in THF (3 mL) at 0° C. and the mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure, suspended in ice-cold AcOEt (5 mL) and filtered. The yellow solid obtained was washed with ice-cold AcOEt (5 mL) and taken to the next step (418 mg, 71%) without further purification. m / z (M+H) + (ES + )389.2, 391.2;t R = 2.96 min. HPLC Method 2 (Base).

[0206] [ka] 4-(5-Bromoisoindoline-2-carboxamido)benzoic acid (Intermediate 18). A solution of ethyl 4-(5-bromoisoindoline-2-carboxamido)benzoate (Intermediate 17; 200 mg, 0.51 mmol) in THF:MeOH:H2O (3:1:1, 5 mL) was stirred with lithium hydroxide monohydrate (2.06 mmol, 84 mg) at room temperature overnight. The mixture was concentrated under reduced pressure, redissolved in H2O (30 mL), washed with AcOEt (20 mL), acidified to pH 3, and extracted with AcOEt (2 x 30 mL). The organic phases were combined, dried over MgSO4, filtered, and concentrated under reduced pressure. The yellow solid obtained was carried on to the next step without further purification (176 mg, 96%). m / z (M+H) + (ES + )375.2, 377.2;t R = 2.89 min. HPLC Method 2 (Base).

[0207] [ka] (S)-5-Bromo-N-(4-(((tetrahydrofuran-3-yl)methyl)carbamoyl)phenyl)isoindoline-2-carboxamide (Intermediate 19). 4-(5-Bromoisoindoline-2-carboxamido)benzoic acid (Intermediate 18; 120 mg, 0.33 mmol) was dissolved in anhydrous DMF (5 mL). HATU (0.50 mmol, 188 mg), DIPEA (1.32 mmol, 0.23 mL) and (S)-(tetrahydrofuran-3-yl)methanamine (0.40 mmol, 42 μL) were added successively and the mixture was stirred at room temperature for 3 h. The mixture was extracted with AcOEt (30 mL) and washed with brine (3×20 mL). The organic phase was dried over MgSO4, filtered, concentrated under reduced pressure and purified by reverse phase column chromatography (0.1% HCOOH modifier) ​​to give the desired compound as a pale yellow solid (120 mg, 82%). m / z (M+H) + (ES + )444.3, 446.3, t R =2.72 minutes. HPLC method 2 (acid).

[0208] Synthesis of NAMPT inhibitors: [ka] General procedure: A solution of the corresponding haloarene / heteroarene derivative (1.0 equiv.), bis(pinacolato)diboron (1.5 equiv.) and potassium acetate (1.5-3.0 equiv.) in dioxane (0.1 M) was degassed with N2 for 15 min. Bis(dibenzylideneacetone)palladium(0) (5 mol%) and triscyclohexylphosphine (10 mol%) were added and the mixture was stirred at 90°C until all the starting halogen derivatives were converted to the corresponding boronic esters (the formation of the boronic acid was monitored by LCMS). The mixture was allowed to reach room temperature and then 7-iodonaphthalene-1,3-disulfonic acid (intermediate A; 1.0-1.2 equiv.), bis(triphenylphosphine)palladium(II) dichloride (10 mol%), potassium carbonate (3.0 equiv.) and degassed water (0.3 M) were added. The mixture was stirred at 100° C. until all the boronic ester derivatives were converted to the desired products (monitored by LCMS). The mixture was allowed to reach room temperature, filtered, washed with MeOH (5 mL), concentrated under reduced pressure, and purified by reverse phase column chromatography (5-100% MeCN in HO, modifiers as indicated) to give the corresponding disulfonate derivatives.

[0209] [ka] 6-(2-fluoro-5-((3-(4-(piperidin-1-ylsulfonyl)phenyl)ureido)methyl)phenyl)-4-(trioxidanylthio)naphthalene-2-sulfonic acid (Example 1). Intermediate 9 (0.64 mmol, 300 mg), bis(pinacolato)diboron (0.96 mmol, 247 mg), potassium acetate (1.92 mmol, 188 mg), dioxane (4 mL), bis(dibenzylideneacetone)palladium(0) (0.06 mmol, 37 mg) and triscyclohexylphosphine (0.06 mmol, 13 mg) were stirred at 90° C. for 2 hours. Then, 7-iodonaphthalene-1,3-disulfonic acid (Intermediate A; 0.70 mmol, 291 mg), bis(triphenylphosphine)palladium(II) dichloride (0.06 mmol, 45 mg), potassium carbonate (1.92 mmol, 267 mg) and degassed water (1 mL) were stirred at 100° C. for 1 hour. After purification by reverse phase column chromatography (0.1% NH4OH modifier), the desired product was isolated as a white crystalline solid (264 mg, 61%). mp. 167-169 °C; 1 H NMR(400MHz,DMSO-d6)δ9.17(s,1H),8.97(d,J=1.6Hz,1H),8.29(d,J=1.8Hz,1H),8.15(d, J=1.7Hz,1H),8.05(d,J=8.5Hz,1H),7.68-7.60(m,3H),7.59-7.54(m,2H),7.48(dd,J=7.6 ,2.3Hz,1H),7.43-7.37(m,1H),7.32(dd,J=10.4,8.4Hz,1H),6.99(t,J=5.8Hz,1H),4.39( d,J=5.8Hz,2H),2.82(app.t,J=5.4Hz,4H),1.52(app.t,J=5.9Hz,4H),1.39-1.29(m,2H); 13 C NMR(101MHz,DMSO-d6)δ158.7(d,J=244.9Hz),155.2,145.2,144.8,144.2,137.1(d,J=3.4Hz),133.5,132.6,130.3,129.4-128 .8(m,3C),127.9,127.2(d,J=2.2Hz),127.1,125.6,123.8,117.6,117.6,116.6,116.4,49.1,47.0,42.7,25.1,23.3;m / z(M+H) + (ES + )678.2;t R=1.76 minutes. HPLC method 1; HRMS (ES-TOF): m / zC 29 H 26 FN3O9S: Theoretical value 337.5402, Measured value 337.5408 [M-2H] 2- . 1 H-NMR Lacking 2H signals from exchangeable protons.

[0210] [ka] (E)-6-(5-(3-((4-(1-benzoylpiperidin-4-yl)butyl)amino)-3-oxoprop-1-en-1-yl)-2-fluorophenyl)-4-(trioxidanylthio)naphthalene-2-sulfonic acid (Example 2). Intermediate 11 (0.15 mmol, 70 mg), bis(pinacolato)diboron (0.21 mmol, 53 mg), potassium acetate (0.21 mmol, 21 mg), dioxane (3 mL), bis(dibenzylideneacetone)palladium(0) (0.02 mmol, 9 mg) and triscyclohexylphosphine (0.03 mmol, 6 mg) were stirred overnight at 90° C. Then, 7-iodonaphthalene-1,3-disulfonic acid (Intermediate A; 0.15 mmol, 62 mg), bis(triphenylphosphine)palladium(II) dichloride (0.02 mmol, 10 mg), potassium carbonate (0.30 mmol, 42 mg) and degassed water (0.75 mL) were stirred at 100° C. for 2 hours. After purification by reverse phase column chromatography (0.1% NH4OH conditioning), the desired product was isolated as a white crystalline solid (4.6 mg, 5%) as the diammonium salt. 1H NMR(400MHz,DMSO-d6)δ8.99(s,1H),8.28(d,J=1.7Hz,1H),8.18-8.10(m,2H),8.07(d,J=8.5Hz) ,1H),7.75-7.61(m,3H),7.48(d,J=15.8Hz,1H),7.45-7.40(m,4H),7.38-7.30(m,2H),7.10(s, 8H),6.66(d,J=15.8Hz,1H),4.55-4.38(m,1H),4.14-4.05(m,1H),3.59-3.38(m,1H),3.06-2.9 1(m,1H),2.82-2.65(m,1H),1.80-1.65(m,1H),1.65-1.40(m,5H),1.38-1.17(m,6H);m / z(M+H) + (ES + )695.3;t R = 2.21 min. HPLC Method 2 (Base).

[0211] [ka] 6-(2-Fluoro-5-((3-(4-(phenylsulfonyl)phenyl)ureido)methyl)phenyl)-4-(trioxidanylthio)naphthalene-2-sulfonic acid (Example 3). (Using a method similar to the synthesis of intermediate 9, 1-(3-bromo-4-fluorobenzyl)-3-(4-(phenylsulfonyl)phenyl)urea (0.13 mmol, 60 mg), prepared from phenyl(4-(phenylsulfonyl)phenyl)carbamate, CAS 1439358-24-3, was added to a mixture of bis(pinacolato)diboron (0.19 mmol, 50 mg), potassium acetate (0.26 mmol, 26 mg), dioxane (3 mL), bis(dibenzylidenepalladium)(0) (0.01 mmol, 7 mg) and tris(cyclohexylphosphine) (0.03 mmol, 6 mg) at 90 °C for 1 h. The mixture was stirred for 2 h at 100° C. After purification by reverse phase column chromatography (0.1% NH4OH modifier), the desired product was isolated as a white crystalline solid (25 mg, 29%). 1 H NMR(500MHz,DMSO-d6)δ9.21(s,1H),8.97(s,1H),8.30(d,J=1.6Hz,1H),8.1 6(d,J=1.7Hz,1H),8.05(d,J=8.5Hz,1H),7.90(d,J=7.3Hz,2H),7.79(d,J=8 .8Hz,2H),7.69-7.55(m,6H),7.47(dd,J=7.6,2.3Hz,1H),7.42-7.35(m,1H) ,7.31(dd,J=10.4,8.4Hz,1H),7.00(t,J=5.9Hz,1H),4.37(d,J=5.8Hz,2H); 13C NMR(126MHz,DMSO-d6)δ158.7(d,J=245.1Hz),155.1,145.9,144.7,144.2,142.6,137.0(d,J=3.2Hz),133.7,133.5,132.6(d,J=2.2Hz),130.3(d ,J=2.5Hz),130.1,129.2,129.2,129.1,129.0,129.0,128.9,127.9,127 .4,127.3(d,J=2.2Hz),125.6,123.8,118.0,116.0(d,J=22.7Hz),42.7; 19 F NMR(471MHz,DMSO-d6)δ-120.53;m / z(M+H) + (ES + )688.2;t R = 1.77 min. HPLC Method 2 (Base).

[0212] [ka] 6-(3-(1-(6-([1,1'-biphenyl]-2-yloxy)hexyl)-1H-1,2,3-triazol-4-yl)phenyl)-4-(trioxidanylthio)naphthalene-2-sulfonic acid (Example 4). Intermediate 12 (0.19 mmol, 90 mg), bis(pinacolato)diboron (0.28 mmol, 72 mg), potassium acetate (0.38 mmol, 37 mg), dioxane (3 mL), bis(dibenzylideneacetone)palladium(0) (0.01 mmol, 7 mg) and triscyclohexylphosphine (0.02 mmol, 4 mg) were stirred at 90° C. for 1 hour. Then, 7-iodonaphthalene-1,3-disulfonic acid (Intermediate A; 0.19 mmol, 78 mg), bis(triphenylphosphine)palladium(II) dichloride (0.02 mmol, 13 mg), potassium carbonate (0.57 mmol, 78 mg) and degassed water (0.75 mL) were stirred at 100° C. for 1 hour. After purification by reverse phase column chromatography (0.1% NH4OH conditioning), the desired product was isolated as a white crystalline solid (30 mg, 24%) as the diammonium salt. 1H NMR(500MHz,DMSO-d6)δ9.16(s,1H),8.71(s,1H),8.30(s,1H),8.23(s,1H),8.17(s,1H),8.10(d,J=8.5Hz,1H),7 .93-7.86(m,2H),7.69(app.dt,J=7.7,1.5Hz,1H),7.62(app.t,J=7.7Hz,1H),7.49(d,J=6.8Hz,1H),7.39(app.t ,J=7.6Hz,2H),7.33-7.25(m,3H),7.14(br.,8H),7.08(d,J=8.1Hz,1H),7.00(app.td,J=7.4,1.0Hz,1H),4.39(t ,J=7.2Hz,2H),3.96(t,J=6.3Hz,2H),1.92-1.81(m,2H),1.69-1.60(m,2H),1.42-1.36(m,2H),1.34-1.24(m,2H); 13 C NMR(126MHz,DMSO-d6)δ155.9,146.7,144.5,144.5,144.3,141.8,138.7,138.1,132.7,132.1,130.9,130.4,130.1,129.8,129.7,129 m / z(M+H) + (ES + )684.3;t R = 1.93 min. HPLC Method 2 (Base).

[0213] [ka] 6-(3-((3-(4-(piperidin-1-ylsulfonyl)phenyl)ureido)methyl)phenyl)-4-(trioxidanylthio)naphthalene-2-sulfonic acid (Example 5). Intermediate 13 (0.22 mmol, 100 mg), bis(pinacolato)diboron (0.33 mmol, 84 mg), potassium acetate (0.44 mmol, 43 mg), dioxane (3 mL), bis(dibenzylideneacetone)palladium(0) (0.02 mmol, 13 mg) and triscyclohexylphosphine (0.04 mmol, 8 mg) were stirred for 1 hour at 100° C. Then, 7-iodonaphthalene-1,3-disulfonic acid (Intermediate A; 0.22 mmol, 83 mg), bis(triphenylphosphine)palladium(II) dichloride (0.02 mmol, 13 mg), potassium carbonate (0.66 mmol, 83 mg) and degassed water (0.75 mL) were stirred for 2 hours at 100° C. After purification by reverse phase column chromatography (0.1% NH4OH modifier), the desired product was isolated as a white crystalline solid (70 mg, 48%). 1 H NMR(500MHz,DMSO-d6)δ9.16(s,1H),9.13-9.04(m,1H),8.27(d,J=1.9Hz,1H),8.14-8.10 (m,1H),8.04(d,J=8.6Hz,1H),7.82-7.77(m,1H),7.69-7.59(m,4H),7.56(d,J=8.5Hz,2H ),7.50(app.t,J=7.6Hz,1H),7.36(d,J=7.6Hz,1H),6.97(t,J=5.9Hz,1H),4.43(d,J=5.8 Hz,2H),2.82(app.t,J=5.3Hz,4H),1.52(app.t,J=5.8Hz,4H),1.33(app.t,J=5.8Hz,2H); 13 C NMR(126MHz,DMSO-d6)δ155.3,145.3,144.6,144.3,141.2,141.2,138.2,132.6,129.7,129.5,129.5,1 m / z(M+H) + (ES + )660.2;t R = 1.77 min. HPLC Method 2 (base).

[0214] [ka] 6-(4-Fluoro-3-((3-(4-(piperidin-1-ylsulfonyl)phenyl)ureido)methyl)phenyl)-4-(trioxidanylthio)naphthalene-2-sulfonic acid (Example 6). Intermediate 14 (0.21 mmol, 100 mg), bis(pinacolato)diboron (0.32 mmol, 81 mg), potassium acetate (0.63 mmol, 62 mg), dioxane (3 mL), bis(dibenzylideneacetone)palladium(0) (0.02 mmol, 12 mg) and triscyclohexylphosphine (0.04 mmol, 8 mg) were stirred at 90° C. for 1 hour. Then, 7-iodonaphthalene-1,3-disulfonic acid (Intermediate A; 0.25 mmol, 110 mg), bis(triphenylphosphine)palladium(II) dichloride (0.02 mmol, 15 mg), potassium carbonate (0.63 mmol, 87 mg) and degassed water (0.75 mL) were stirred at 100° C. for 2 hours. After purification by reverse phase column chromatography (0.1% NH4OH modifier), the desired product was isolated as a white crystalline solid (96 mg, 67%). 1 H NMR(500MHz,DMSO-d6)δ9.24(s,1H),9.02(d,J=1.8Hz,1H),8.24(d,J=1.8Hz,1H),8 .08(d,J=1.8Hz,1H),7.97(d,J=8.5Hz,1H),7.73-7.67(m,2H),7.59(app.d,J=8.7Hz ,3H),7.51(d,J=8.5Hz,2H),7.31(t,J=9.2Hz,1H),7.12-7.04(m,1H),4.42(d,J=5. 1Hz,2H),2.77(app.t,J=5.4Hz,4H),1.47(app.t,J=5.7Hz,4H),1.34-1.25(m,2H);; 19 F NMR(471MHz,DMSO-d6)δ-121.08;m / z(M+H) + (ES + )678.2;t R = 1.68 min. HPLC Method 2 (Base).

[0215] [ka] 6-(2-Methoxy-5-((3-(4-(piperidin-1-ylsulfonyl)phenyl)ureido)methyl)phenyl)-4-(trioxidanylthio)naphthalene-2-sulfonic acid (Example 7). Intermediate 15 (0.30 mmol, 145 mg), bis(pinacolato)diboron (0.45 mmol, 115 mg), potassium acetate (0.90 mmol, 88 mg), dioxane (3 mL), bis(dibenzylideneacetone)palladium(0) (0.03 mmol, 17 mg) and triscyclohexylphosphine (0.06 mmol, 12 mg) were stirred at 90° C. for 3 hours. Then, 7-iodonaphthalene-1,3-disulfonic acid (Intermediate A; 0.33 mmol, 136 mg), bis(triphenylphosphine)palladium(II) dichloride (0.03 mmol, 21 mg), potassium carbonate (0.90 mmol, 125 mg) and degassed water (0.75 mL) were stirred at 100° C. for 2 hours. After purification by two reverse phase column chromatographies (first 0.1% NH4OH modifier, second 0.1 HCOOH), the desired product was isolated as a white crystalline solid (3 mg, 2%). 1 H NMR(500MHz,DMSO-d6)δ9.07(s,1H),8.83(d,J=1.7Hz,1H),8.24(d,J=1.6Hz,1H),8.09( s,1H),7.93(d,J=8.5Hz,1H),7.64-7.58(m,2H),7.58-7.53(m,3H),7.34(dd,J=8.4,2.3H z,1H),7.27(d,J=2.2Hz,1H),7.12(d,J=8.5Hz,1H),6.86(br.,1H),4.33(d,J=4.2Hz,2H) ,3.76(s,3H),2.82(app.t,J=5.5Hz,4H),1.57-1.45(m,4H),1.40-1.28(m,2H);m / z(M+H) + (ES + )690.2;t R = 1.74 min. HPLC Method 2 (Base).

[0216] [ka] 6-(5-((3-(4-((8-oxa-3-azabicyclo[3.2.1]octan-3-yl)sulfonyl)phenyl)ureido)methyl)-2-fluorophenyl)-4-(trioxidanylthio)naphthalene-2-sulfonic acid (Example 8). Intermediate 10 (0.30 mmol, 150 mg), bis(pinacolato)diboron (0.45 mmol, 115 mg), potassium acetate (0.90 mmol, 88 mg), dioxane (3 mL), bis(dibenzylideneacetone)palladium(0) (0.03 mmol, 17 mg) and triscyclohexylphosphine (0.06 mmol, 12 mg) were stirred for 3 hours at 90° C. Then, 7-iodonaphthalene-1,3-disulfonic acid (Intermediate A; 0.30 mmol, 124 mg), bis(triphenylphosphine)palladium(II) dichloride (0.03 mmol, 21 mg), potassium carbonate (0.90 mmol, 125 mg) and degassed water (0.75 mL) were stirred for 1 hour at 100° C. After purification by two reverse-phase column chromatography (0.1% NH4OH conditioning), the desired product was isolated as a white crystalline solid (12 mg, 6%) as the diammonium salt. 1 H NMR(400MHz,DMSO-d6)δ9.19(s,1H),8.98(d,J=1.7Hz,1H),8.30(d,J=1.8Hz,1H),8.16(d,J=1. 8Hz,1H),8.06(d,J=8.5Hz,1H),7.68-7.62(m,3H),7.58-7.52(m,2H),7.50(dd,J=7.6,2.3Hz,1 H),7.45-7.37(m,1H),7.34(dd,J=10.4,8.4Hz,1H),7.17(s,8H),6.99(t,J=5.9Hz,1H),4.41(d ,J=5.8Hz,2H),4.33(s,1H),3.27-3.14(m,2H),2.43(dd,J=11.4,2.3Hz,2H),1.86-1.71(m,4H); 19 F NMR(376MHz,DMSO)δ-120.51;m / z(M+H) + (ES + )706.2;t R = 1.68 min. HPLC Method 2 (Base).

[0217] [ka] 6-(2-((4-(piperidin-1-ylsulfonyl)benzyl)carbamoyl)-1H-indol-5-yl)-4-(trioxidanylthio)naphthalene-2-sulfonic acid (Example 9). Intermediate 16 (0.12 mmol, 55 mg), bis(pinacolato)diboron (0.17 mmol, 44 mg), potassium acetate (0.36 mmol, 35 mg), dioxane (3 mL), bis(dibenzylideneacetone)palladium(0) (0.01 mmol, 7 mg) and triscyclohexylphosphine (0.01 mmol, 2 mg) were stirred for 2 hours at 90° C. Then, 7-iodonaphthalene-1,3-disulfonic acid (Intermediate A; 0.13 mmol, 54 mg), bis(triphenylphosphine)palladium(II) dichloride (0.01 mmol, 8 mg), potassium carbonate (0.39 mmol, 54 mg) and degassed water (0.75 mL) were stirred at 100° C. overnight. After purification by reverse phase column chromatography (0.1% NH4OH conditioning), the desired product was isolated as a pale yellow oil (8 mg, 11%) as the diammonium salt. 1 H NMR(400MHz,DMSO-d6)δ11.80(s,1H),9.28(app.t,J=6.1Hz,1H),9.13(s,1H),8.2 7(s,1H),8.14(s,1H),8.05(d,J=8.5Hz,1H),8.01(s,1H),7.92-7.89(m,1H),7.85- 7.79(m,1H),7.74(d,J=8.1Hz,2H),7.65-7.60(m,3H),7.34(s,1H),4.67(d,J=6.0 Hz,2H),2.89(app.t,J=5.4Hz,4H),1.60-1.49(m,4H),1.43-1.34(m,2H);m / z(M+H) + (ES + )684.3;t R = 1.69 min. HPLC Method 2 (base).

[0218] [ka] (S)-6-(2-((4-(((tetrahydrofuran-3-yl)methyl)carbamoyl)phenyl)carbamoyl)isoindolin-5-yl)-4-(trioxidanylthio)naphthalene-2-sulfonic acid (Example 10). Intermediate 19 (0.22 mmol, 96 mg), bis(pinacolato)diboron (0.32 mmol, 82 mg), potassium acetate (0.66 mmol, 65 mg), dioxane (3 mL), bis(dibenzylideneacetone)palladium(0) (0.02 mmol, 13 mg) and triscyclohexylphosphine (0.02 mmol, 4 mg) were stirred at 80° C. for 1.5 hours. Then, 7-iodonaphthalene-1,3-disulfonic acid (Intermediate A; 0.24 mmol, 100 mg), bis(triphenylphosphine)palladium(II) dichloride (0.02 mmol, 15 mg), potassium carbonate (0.66 mmol, 92 mg) and degassed water (0.75 mL) were stirred at 100° C. for 1.5 hours. After purification by reverse phase column chromatography (0.1% NH4OH conditioning), the desired product was isolated as a white solid (20 mg, 14%) as the diammonium salt. 1 H NMR(500MHz,DMSO)δ9.13(s,1H),8.66(s,1H),8.44(app.t,J=5.8Hz,1H),8.29(d,J=1.7Hz,1H),8.16(s, 1H),8.08(d,J=8.6Hz,1H),7.86(dd,J=8.6,1.9Hz,1H),7.82-7.77(m,2H),7.74-7.67(m,4H),7.53(d,J= 7.9Hz,1H),4.91(s,2H),4.87(s,2H),3.79-3.71(m,1H),3.69(dd,J=8.5,6.9Hz,1H),3.66-3.58(m,1H), 3.49(dd,J=8.5,5.2Hz,1H),3.31-3.17(m,2H),2.51-2.43(m,1H),2.00-1.87(m,1H),1.67-1.54(m,1H); 13C NMR (126MHz, DMSO) δ166.5,154.1,144.5,144.2,143.7,140.4,138.2,138.0,136.7,132.6,129.8,129.5,128. 2,127.9,126.9,125.6,125.6,125.5,123.9,123.8,121.7,118.7,71.0,67.3,42.3,40.9,39.4,30.0;m / z(M+H) + (ES + )652.3;t R =1.54 points. HPLC method 2 (base).

[0219] ネイティブ mass analysis method Proteins were expressed and isolated as described previously and, on the day of analysis, buffer exchanged into 100 mM ammonium acetate (Fisher Scientific, Loughborough, UK) pH 6.9 using micro Bio-Spin chromatography columns (Micro Bio-Spin 6 Columns, Bio-Rad, Watford, UK) following the instructions specified by the manufacturer. This procedure was repeated twice and diluted to obtain a final concentration of NAMPT (5 μmol / l), which was incubated with compound (5 μmol / l) for 12 h before analysis. Native MS data were acquired on a Synapt G2S HDMS (Waters, Manchester, UK). NanoESI capillaries were prepared in-house from thin-walled borosilicate capillaries (0.9 mm inner diameter, 1.2 mm outer diameter, World Precision Instruments, Stevenage, UK) using a Flaming / Brown P-1000 micropipette puller (Sutter Instrument Company, Novato, CA, USA). A positive voltage was applied to the solution via a platinum wire (Goodfellow Cambridge Ldt, Huntington, UK) inserted into the capillary. Mild source conditions were applied to preserve naturally occurring structures: capillary voltage 1.2-1.5 kV, sampling cone 50-200 V, source temperature 70 °C. The trap collision energy was 4 V and the transfer collision energy was set to 0 V. Nitrogen was the carrier gas. External calibration of the spectra was achieved using a solution of cesium iodide (2 mg / mL in 50:50 water:isopropanol). Data were acquired and processed with MassLynx software (Waters, Manchester, UK).Figures 1, 2 and 3 show mass spectra of NAMPT alone or incubated with FK866 ((E)-N-[4-(1-benzoylpiperidin-4-yl)butyl]-3-pyridin-3-ylprop-2-enamide (a known NAMPT inhibitor used for comparison purposes) or 6-(2-fluoro-5-((3-(4-(piperidin-1-ylsulfonyl)phenyl)ureido)methyl)phenyl)-4-(trioxidanylthio)naphthalene-2-sulfonic acid (Example 1).

[0220] Enzyme assays In a 96-well opaque black plate, NAMPT (30 nM - all concentrations shown as final), PRPP (50 μM) and ATP (2 mM) were incubated with or without test compound (11 concentrations, prepared by 3-fold dilutions from a final concentration of 30 mM, all in triplicate) in TMD buffer (50 mM Tris-HCl, 10 mM MgCl2, 2 mM DTT, pH 7.5) for 20 min at 37° C. The enzyme reaction was initiated by the addition of NAM (25 μM) and the plate was incubated for 20 min at 37° C. 20 μL of 20% acetophenone (in DMSO) and 20 μL of 2M KOH were added to each well and incubated for 5 minutes at ambient temperature, then 90 μL of 100% formic acid was added to each well and the plate was incubated at 37° C. for 20 minutes before being read on a Hides Sense plate reader (Ex / Em=355 / 460 nm). Data was analyzed in Excel and IC fitted using GraphPad Prism. 50 % of control in the curve. Data are reported from fitting of n=3 individual repeats.

[0221] Tm shift assay Thermal melting experiments were performed using an Applied Biosystem StepOnePlus qPCR instrument. NAMPT (1 μM) was assayed at a final concentration of 2 μM in a volume of 50 μL in 96-well plates buffered in 10 mM HEPES, pH 7.5, 140 mM NaCl. Compounds were added at a final concentration of 100 μM and SYPRO Orange was added as a fluorescent probe at a dilution of 1:5000 (V / V). Temperature was increased from 25 to 96 °C in steps of 1 °C / min and fluorescence readings were taken at each time interval. Experiments were performed in triplicate and the observed temperature shift was recorded as the difference between the transition midpoint of the sample and a reference well containing protein without ligand in the same plate, determined by nonlinear least-squares fitting, and reported in °C as the average of values ​​obtained from three independent repeats.

[0222] THP-1 WST-1 assay THP-1 cells were plated at 30,000 cells per well (400,000 cells per mL) in a final volume of 150 μL of medium (RPMI-1640 containing 10% v / v FBS) containing 1 μM of test compound. Samples were incubated for 48 hours, at which point 15 μL of WST-1 solution (Sigma-Aldrich) was added. Light was excluded and samples were incubated for an additional 2 hours. The absorbance of the wells was read at 450 nm and 630 nm using a Hidex Sense plate reader. Metabolic inhibition was determined by absorbance at 450 nM and converted to % control using Excel. Data reported are the average of triplicates. [Table 1] *Compound fluorescence prevents detection in the Sypro orange channel. **Compound effectively completely suppresses melting events, Tm shift values ​​fitting to the obtained profile, but unreliably. ***Values ​​from literature; Acta Pharmacologica Sinica (2018) 39:294-301 1FK866 is the compound (E)-N-[4-(1-benzoylpiperidin-4-yl)butyl]-3-pyridin-3-ylprop-2-enamide, which is a known NAMPT inhibitor used for comparison purposes.

Claims

1. A compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, as shown below: 【Chemical 1】 where R １ is as follows: (i) A group of formula II: 【Chemical 2】 Wherein: Ring A is selected from phenyl or a 5- or 6-membered heteroaryl; n is 0, 1 or 2; Each R ２ group, when present, is as follows: halo, nitro, cyano, R ２ａ , -[CH ２ ｑ -[NR ２ａ R ２ｂ , -[CH ２ ｑ -[OR ２ａ , -[CH ２ ｑ -[C(O)R ２ａ , -[CH ２ ｑ -[C(O)OR ２ａ , -[CH ２ ｑ -[OC(O)R ２ａ , -[CH ２ ｑ -[C(O)N(R ２ｂ )R ２ａ , -[CH ２ ｑ -[N(R ２ｂ )C(O)R ２ａ , -[CH ２ ｑ -[N(R ２ｂ )-C(O)-N(R ２ｃ )R ２ｂ , -[CH ２ａ ２ -[S(O) ｑ R ｐ (wherein p is 0, 1 or 2), -[CH ２ａ ２ -[SO ｑ N(R ２ )R ２ｂ , -[CH ２ａ ２ -[N(R ｑ )SO ２ｂ R ２ ２ａ is selected from;​​​​​​​​​​ Wherein q is 0, 1, 2, or 3; R ２ａ is hydrogen or (1-4C)alkyl, optionally substituted with halo, hydroxy, amino or cyano; and R ２ｂ and R ２ｃ is hydrogen or (1-2C) alkyl; R Ｎ is selected from hydrogen or methyl; Alternatively R ２ group and R Ｎ are linked so as to form a 5- or 6-membered heterocyclic ring fused to ring A, where the fused 5- or 6-membered heterocyclic ring contains one or two N atoms and is optionally substituted with halo, hydroxy, (1-2C)alkyl, (1-2C)haloalkyl, cyano or amino. W １ is as follows: 【Chemical Formula 3】 In the formula, A １ , A ２ , A ３ or A ４ is selected from CH, N, or C-F, provided that: A １ 、 A ２ 、 A ３ or A ４ only one or two of them may be N; and A １ 、 A ２ 、 A ３ or A ４ Only one or two of them may be C-F; X １ is a linker group of the following formula: - [CH ２ ｎ１ - L １ - [CH ２ ｎ２ -​​ Wherein, n1 and n2 are selected from 0 or 1; L １ is selected from -O-, -S-, -SO-, -SO ２ -, -N(R ｘ１ａ )-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R ｘ１ａ )-, -N(R ｘ１ａ )C(O)-, -N(R ｘ１ｂ )C(O)N(R ｘ１ａ )-, -N(R ｘ１ａ )C(O)O-, -OC(O)N(R ｘ１ａ )-, -S(O) ２ N(R ｘ１ａ )-, -N(R ｘ１ａ )SO ２ -, or -C(O)N(R ｘ１ａ )SO ２ -, or -SO ２ N(R ｘ１ａ )C(O)-; and in the formula, R ｘ１ａ and R ｘ１ｂ are each independently selected from hydrogen or (1-2C) alkyl; Y １ is selected from a carbocyclic ring, aryl, heteroaryl or heterocyclic ring, which is optionally halo, nitro, cyano, R ｙ１ａ , -[CH ２ ｒ -NR ｙ１ａ R ｙ１ｂ , -[CH ２ ｒ -OR ｙ１ａ , -[CH ２ ｒ -C(O)R ｙ１ａ , -[CH ２ ｒ -C(O)OR ｙ１ａ , -[CH ２ ｒ -OC(O)R ｙ１ａ , -[CH ２ ｒ -C(O)N(R ｙ１ｂ )R ｙ１ａ , -[CH ２ ｒ -N(R ｙ１ｂ )C(O)R ｙ１ａ , -[CH ２ ｒ -N(R ｙ１ｃ )-C(O)-N(R ｙ１ｂ )R ｙ１ａ , -[CH ２ ｒ -S(O) ｐ R ｙ１ａ (wherein p is 0, 1 or 2), -[CH ２ ｒ -SO ２ N(R ｙ１ｂ )R ｙ１ａ , or -[CH ２ ｒ -N(R ｙ１ｂ )SO ２ R ｙ１ａ and is substituted by; Wherein r is 0, 1, 2, or 3; R ｙ１ is hydrogen or (1-4C)alkyl, optionally substituted with halo, hydroxy, amino or cyano; and R ｙ１ｂ and R ｙ１ｃ is hydrogen or (1-2C) alkyl; (ii) A group of formula III: 【Chemical Formula 4】 Wherein: Ring B is selected from phenyl or a 5- or 6-membered heteroaryl; m is 0, 1, or 2; Each R ３ group, when present, is as follows: halo, nitro, cyano, R ３ａ , -[CH ２ ｑ１ -NR ３ａ R ３ｂ , -[CH ２ ｑ１ -OR ３ａ , -[CH ２ ｑ１ -C(O)R ３ａ , -[CH ２ ｑ１ -C(O)OR ３ａ , -[CH ２ ｑ１ -OC(O)R ３ａ , -[CH ２ ｑ１ -C(O)N(R ３ｂ )R ３ａ , -[CH ２ ｑ１ -N(R ３ｂ )C(O)R ３ａ , -[CH ２ ｑ１ -N(R ３ｃ )-C(O)-N(R ３ｂ )R ３ａ , -[CH ２ ｑ１ -S(O) ｐ R ３ａ (wherein p is 0, 1 or 2), -[CH ２ ｑ１ -SO ２ N(R ３ｂ )R ３ａ , -[CH ２ ｑ１ -N(R ３ｂ )SO ２ R ３ａ is selected from; Wherein q1 is 0, 1, 2, or 3; R ３ａ is hydrogen or (1-4C)alkyl, optionally substituted with halo, hydroxy, amino or cyano; and R ３ｂ and R ３ｃ is hydrogen or (1-2C)alkyl; V ２ is -C(R ｖ２ａ R ｖ２ｂ )C(R ｖ２ｃ R ｖ２ｄ )- or -C(R ｖ２ａ )= Selected from C(R ｖ２ｃ ), where R ｖ２ａ , R ｖ２ｂ , R ｖ２ｃ and R ｖ２ｄ are each independently selected from hydrogen or methyl, or R ｖ２ａ and R ｖ２ｃ are linked to form a cyclopropyl ring; Z ２ is a 4C alkylene linker optionally substituted with one or more fluoro atoms; W ２ is a carbocyclic ring, aryl, heteroaryl or heterocyclic ring, which is optionally halo, nitro, cyano, R ｗ２ａ , -[CH ２ ｓ -NR ｗ２ａ R ｗ２ｂ , -[CH ２ ｓ -OR ｗ２ａ , -[CH ２ ｓ -C(O)R ｗ２ａ , -[CH ２ ｓ -C(O)OR ｗ２ａ , -[CH ２ ｓ -OC(O)R ｗ２ａ , -[CH ２ ｓ -C(O)N(R ｗ２ｂ )R ｗ２ａ , -[CH ２ ｓ -N(R ｗ２ｂ )C(O)R ｗ２ａ , -[CH ２ ｓ -N(R ｗ２ｃ )-C(O)-N(R ｗ２ｂ )R ｗ２ａ , -[CH ２ ｓ -S(O) ｐ R ｗ２ａ (where p is 0, 1 or 2), -[CH ２ ｓ -SO ２ N(R ｗ２ｂ )R ｗ２ａ , or -[CH ２ ｓ -N(R ｗ２ｂ )SO ２ R ｗ２ａ is substituted by; Wherein, ​​​​​​​​​​​ s is 0, 1, 2, or 3; R ｗ２ａ is hydrogen or (1-4C)alkyl, optionally substituted with halo, hydroxy, amino or cyano; and R ｗ２ｂ and R ｗ２ｃ is hydrogen or (1-2C) alkyl; X ２ is a linker group of the following formula: - [CH ２ ｍ１ - L ２ - [CH ２ ｍ２ -​​ Wherein, m1 and m2 are selected from 0 or 1; L ２ is selected from -O-, -S-, -SO-, -SO ２ -, -N(R ｘ２ａ ), -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R ｘ２ａ ), -N(R ｘ２ａ ), -N(R ｘ２ｂ ), -N(R ｘ２ａ ), -N(R ｘ２ａ ), -OC(O)N(R ｘ２ａ ), -S(O) ２ N(R ｘ２ａ ), N(R ｘ２ａ ), SO ２ or C(O)N(R ｘ２ａ ), SO ２ or -SO ２ N(R ｘ２ａ ), -C(O)-; and in the formula, R ｘ２ａ and R ｘ２ｂ are each independently selected from hydrogen or (1-2C) alkyl; Y ２ is selected from a carbocyclic ring, aryl, heteroaryl or heterocyclic ring, which is optionally halo, nitro, cyano, R ｙ２ａ , -[CH ２ ｔ -NR ｙ２ａ R ｙ２ｂ , -[CH ２ ｔ -OR ｙ２ａ , -[CH ２ ｔ -C(O)R ｙ２ａ , -[CH ２ ｔ -C(O)OR ｙ２ａ , -[CH ２ ｔ -OC(O)R ｙ２ａ , -[CH ２ ｔ -C(O)N(R ｙ２ｂ )R ｙ２ａ , -[CH ２ ｔ -N(R ｙ２ｂ )C(O)R ｙ２ａ , -[CH ２ ｔ -N(R ｙ２ｃ )-C(O)-N(R ｙ２ｂ )R ｙ２ａ , -[CH ２ ｔ -S(O) ｐ R ｙ２ａ (wherein p is 0, 1 or 2), -[CH ２ ｔ -SO ２ N(R ｙ２ｂ )R ｙ２ａ , or -[CH ２ ｔ -N(R ｙ２ｂ )SO ２ R ｙ２ａ and is substituted by;​​​​​​​​​​​ Wherein t is 0, 1, 2, or 3; R ｙ２ａ is hydrogen or (1-4C)alkyl, optionally substituted with halo, hydroxy, amino or cyano; and R ｙ２ｂ and R ｙ２ｃ is hydrogen or (1-2C) alkyl; (iii) A group of formula IV: 【Chemical Formula 5】 Wherein: Ring C is selected from phenyl, a 5- or 6-membered heteroaryl; k is 0, 1, or 2; Each R ４ group, when present, is as follows: halo, nitro, cyano, R ４ａ , -[CH ２ ｑ２ -NR ４ａ R ４ｂ , -[CH ２ ｑ２ -OR ４ａ , -[CH ２ ｑ２ -C(O)R ４ａ , -[CH ２ ｑ２ -C(O)OR ４ａ , -[CH ２ ｑ２ -OC(O)R ４ａ , -[CH ２ ｑ２ -C(O)N(R ４ｂ )R ４ａ , -[CH ２ ｑ２ -N(R ４ｂ )C(O)R ４ａ , -[CH ２ ｑ２ -N(R ４ｃ )-C(O)-N(R ４ｂ )R ４ａ , -[CH ２ ｑ２ -S(O) ｐ R ４ａ (wherein p is 0, 1 or 2), -[CH ２ ｑ２ -SO ２ N(R ４ｂ )R ４ａ , -[CH ２ ｑ２ -N(R ４ｂ )SO ２ R ４ａ is selected from; Wherein q2 is 0, 1, 2, or 3; R ４ａ is hydrogen or (1-4C)alkyl, optionally substituted with halo, hydroxy, amino or cyano; and R ４ｂ and R ４ｃ is hydrogen or (1-2C) alkyl; L is an optionally substituted 6C alkylene linker with one or more fluoro atoms; X is selected from -O-, -CR ｘａ R ｘｂ -, -S-, -SO-, -SO ２ -, -N(R ｘａ ), -C(O)-; and in the formula, R ｘａ and R ｘｂ are each independently selected from hydrogen or methyl; A ３０ and A ３１ is selected from CH, N or C-F; A ３２ and A ３３ is selected from CH or N; However, A ３０ , A ３１ , A ３２ and A ３３ only one or two of them may be N; A ３４ and A ３５ is selected from CH, N, or C—R ３０ is selected from; A ３６ 、 A ３７ and A ３８ is selected from CH or N; However, A ３４ , A ３５ , A ３６ , A ３７ and A ３８ only one or two of them may be N; and wherein R ３０ is halo, nitro, cyano, R ３０ａ , -[CH ２ ｔ -NR ３０ａ R ３０ｂ , -[CH ２ ｔ -OR ３０ａ , -[CH ２ ｔ -C(O)R ３０ａ , -[CH ２ ｔ -C(O)OR ３０ａ , -[CH ２ ｔ -OC(O)R ３０ａ , -[CH ２ ｔ -C(O)N(R ３０ｂ )R ３０ａ , -[CH ２ ｔ -N(R ３０ｂ )C(O)R ３０ａ , -[CH ２ ｔ -N(R ３０ｂ )-C(O)-N(R ３０ａ )R ２ , -[CH ｔ ３０ｃ -N(R ３０ｂ )-C(O)-N(R ３０ａ )R ２ , -[CH ｔ ｐ -S(O) ｐ R ３０ａ (wherein p is 0, 1 or 2), -[CH ２ ｔ -SO ２ N(R ３０ｂ )R ３０ａ , or -[CH ２ ｔ -N(R ３０ｂ )SO ２ R ３０ａ ３０ａ is selected from;​ Wherein, t is 0, 1, 2, or 3; R ３０ａ is hydrogen or (1-4C)alkyl, optionally substituted with halo, hydroxy, amino or cyano; and R ３０ｂ and R ３０ｃ is hydrogen or (1-2C) alkyl; (iv) A group of formula V or VI: 【Chemical Formula 6】 Wherein: A ４０ is selected from NH, NMe or O; A ４２ 、 A ４３ 、 A ４４ and A ４６ each independently is selected from CH, N or CR ２ ; A ４１ and A ４５ are each independently selected from C or N; Provided that the following conditions are met: (iv) A ４０ , A ４１ , A ４２ , A ４３ , A ４４ , A ４５ and A ４６ Only the maximum of three of them are N; (v) A ４１ and A ４５ cannot both be N; (vi) A ４０ , A ４２ , A ４３ , A ４４ and A ４６ Only one or two of ２ can be CR A ５１ is selected from NH, NMe, CH or CR ２ ; A ５０ 、 A ５３ 、 A ５４ and A ５５ each independently is selected from CH, N or CR ２ ; A ５２ and A ５６ are each independently selected from C or N; Provided that the following conditions are met: (iv) A ５０ , A ５１ , A ５２ , A ５３ , A ５４ , A ５５ and A ５６ up to a maximum of three of them are N; (v) A ５２ and A ５６ cannot both be N; (vi) A ５０ , A ５１ , A ５３ , A ５４ and A ５５ Only one or two of ２ can be CR wherein, R ２ is as defined above; W ４ is as follows: 【Chemical Formula 7】 wherein, A ４ａ , A ４ｂ , A ４ｃ , or A ４ｄ is selected from CH, N or C-F, Provided that: A ４ａ 、 A ４ｂ 、 A ４ｃ or A ４ｄ only one or two of them can be N; and A ４ａ 、 A ４ｂ 、 A ４ｃ or A ４ｄ only one or two of them may be C-F; X ４ is a linker group of the following formula: - [CH ２ ｊ１ - L ４ - [CH ２ ｊ２ -​​ Wherein, j1 and j2 are selected from 0 or 1; L ４ is selected from -O-, -S-, -SO-, -SO ２ -, -N(R ｘ４ａ ), -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R ｘ４ａ ), -N(R ｘ４ａ ), -N(R ｘ４ｂ ), -N(R ｘ４ａ ), -N(R ｘ４ａ ), -N(R ｘ４ａ ), -S(O) ２ N(R ｘ４ａ ), -N(R ｘ４ａ ), -SO ２ -, or -C(O)N(R ｘ４ａ ), -SO ２ -, or -SO ２ N(R ｘ４ａ ), -C(O)-; and in the formula, R ｘ４ａ and R ｘ４ｂ are each independently selected from hydrogen or (1-2C) alkyl; Y ４ is selected from a carbocyclic ring, aryl, heteroaryl or heterocyclic ring, which is optionally halo, nitro, cyano, R ｙ４ａ , -[CH ２ ｕ -NR ｙ４ａ R ｙ４ｂ , -[CH ２ ｕ -OR ｙ４ａ , -[CH ２ ｕ -C(O)R ｙ４ａ , -[CH ２ ｕ -C(O)OR ｙ４ａ , -[CH ２ ｕ -OC(O)R ｙ４ａ , -[CH ２ ｕ -C(O)N(R ｙ４ｂ )R ｙ４ａ , -[CH ２ ｕ -N(R ｙ４ｂ )C(O)R ｙ４ａ , -[CH ２ ｕ -N(R ｙ４ｃ )-C(O)-N(R ｙ４ｂ )R ｙ４ａ , -[CH ２ ｕ -S(O) ｐ R ｙ４ａ (wherein p is 0, 1 or 2), -[CH ２ ｕ -SO ２ N(R ｙ４ｂ )R ｙ４ａ , or -[CH ２ ｕ -N(R ｙ４ｂ )SO ２ R ｙ４ａ and is substituted by; Wherein u is 0, 1, 2, or 3; R ｙ４ is hydrogen or (1-4C)alkyl, optionally substituted with halo, hydroxy, amino or cyano; and R ｙ４ｂ and R ｙ４ｃ is hydrogen or (1-2C) alkyl.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R １ is selected from the following: (i) A group of formula II: 【Chemical 8】 Wherein: Ring A is selected from phenyl or a 5- or 6-membered heteroaryl; n is 0, 1 or 2; Each R ２ group, when present, is as follows: halo, nitro, cyano, R ２ａ , -[CH ２ ｑ -NR ２ａ R ２ｂ , -[CH ２ ｑ -OR ２ａ , -[CH ２ ｑ -C(O)R ２ａ , -[CH ２ ｑ -C(O)OR ２ａ , -[CH ２ ｑ -OC(O)R ２ａ , -[CH ２ ｑ -C(O)N(R ２ｂ )R ２ａ , -[CH ２ ｑ -N(R ２ｂ )C(O)R ２ａ , -[CH ２ ｑ -N(R ２ｃ )-C(O)-N(R ２ｂ )R ２ａ is selected from; Wherein q is 0, 1, or 2; R ２ａ is hydrogen or (1-4C)alkyl, optionally substituted with halo, hydroxy, amino or cyano; and R ２ｂ and R ２ｃ is hydrogen or (1-2C) alkyl; R Ｎ is selected from hydrogen or methyl; Alternatively, R ２ groups and R Ｎ are linked so as to form a 5- or 6-membered heterocyclic ring fused to ring A, where the fused 5- or 6-membered heterocyclic ring contains one or two N atoms and is optionally substituted with halo, hydroxy, (1-2C)alkyl, (1-2C)haloalkyl, cyano or amino. W １ is as follows: 【Chemical Formula 9】 wherein, A １ , A ２ , A ３ or A ４ is selected from CH, N, or C-F, provided that: A １ 、 A ２ 、 A ３ or A ４ only one or two of them may be N; and A １ 、 A ２ 、 A ３ or A ４ only one or two of them may be C-F; X １ is a linker group of the following formula: - [CH ２ ｎ１ - L １ - [CH ２ ｎ２ -​​ Wherein, n1 and n2 are selected from 0 or 1; L １ is selected from -O-, -S-, -SO-, -SO ２ -, -N(R ｘ１ａ ), -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R ｘ１ａ ), -N(R ｘ１ａ ), -N(R ｘ１ｂ ), -N(R ｘ１ａ ), -N(R ｘ１ａ ), -C(O)O- or -OC(O)N(R ｘ１ａ ); and in the formula, R ｘ１ａ and R ｘ１ｂ are each independently selected from hydrogen or (1-2C) alkyl; Y １ is selected from a carbocycle, aryl, heteroaryl or heterocycle, which is optionally substituted by halo, nitro, cyano, R ｙ１ａ , -[CH ２ < ｒ -NR ｙ１ａ R ｙ１ｂ , -[CH ２ < ｒ -OR ｙ１ａ , -[CH ２ < ｒ -C(O)R ｙ１ａ , -[CH ２ < ｒ -C(O)OR ｙ１ａ , -[CH ２ < ｒ -OC(O)R ｙ１ａ , -[CH ２ < ｒ -C(O)N(R ｙ１ｂ )R ｙ１ａ , -[CH ２ < ｒ -N(R ｙ１ｂ )C(O)R ｙ１ａ or -[CH ２ < ｒ -N(R ｙ１ｃ )-C(O)-N(R ｙ１ｂ )R ｙ１ａ , and is substituted thereby; Wherein r is 0, 1, or 2; R ｙ１ is hydrogen or (1-4C)alkyl, optionally substituted with halo, hydroxy, amino or cyano; and R ｙ１ｂ and R ｙ１ｃ is hydrogen or (1-2C) alkyl; (ii) A group of formula III: 【Chemical Formula 10】 Wherein: Ring B is selected from phenyl or a 5- or 6-membered heteroaryl; m is 0, 1, or 2; Each R ３ group, when present, is as follows: halo, nitro, cyano, R ３ａ , -[CH ２ ｑ１ -NR ３ａ R ３ｂ , -[CH ２ ｑ１ -OR ３ａ , -[CH ２ ｑ１ -C(O)R ３ａ , -[CH ２ ｑ１ -C(O)OR ３ａ , -[CH ２ ｑ１ -OC(O)R ３ａ , -[CH ２ ｑ１ -C(O)N(R ３ｂ )R ３ａ , -[CH ２ ｑ１ -N(R ３ｂ )C(O)R ３ａ or -[CH ２ ｑ１ -N(R ３ｃ )-C(O)-N(R ３ｂ )R ３ａ is selected from;​​​​​​​​ Wherein q1 is 0, 1, or 2; R ３ａ is hydrogen or (1-4C)alkyl, optionally substituted with halo, hydroxy, amino or cyano; and R ３ｂ and R ３ｃ is hydrogen or (1-2C)alkyl; V ２ is selected from -C(R ｖ２ａ R ｖ２ｂ )(R ｖ２ｃ R ｖ２ｄ )- or -C(R ｖ２ａ )(R ｖ２ｃ )=C(R ｖ２ａ ), R ｖ２ｂ , R ｖ２ｃ and R ｖ２ｄ are each independently selected from hydrogen or methyl, or R ｖ２ａ and R ｖ２ｃ are linked to form a cyclopropyl ring; Z ２ is an optionally 1 or more fluoro atom-substituted 4C alkylene linker; W ２ is a carbocyclic ring, aryl, heteroaryl or heterocyclic ring, which is optionally substituted by halo, nitro, cyano, R ｗ２ａ , -[CH ２ ｓ -NR ｗ２ａ R ｗ２ｂ , -[CH ２ ｓ -OR ｗ２ａ , -[CH ２ ｓ -C(O)R ｗ２ａ , -[CH ２ ｓ -C(O)OR ｗ２ａ , -[CH ２ ｓ -OC(O)R ｗ２ａ , -[CH ２ ｓ -C(O)N(R ｗ２ｂ )R ｗ２ａ , -[CH ２ ｓ -N(R ｗ２ｂ )C(O)R ｗ２ａ or -[CH ２ ｓ -N(R ｗ２ｃ )-C(O)-N(R ｗ２ｂ )R ｗ２ａ ; wherein s is 0, 1, or 2; R ｗ２ａ is hydrogen or (1-4C)alkyl, optionally substituted with halo, hydroxy, amino or cyano; and R ｗ２ｂ is hydrogen or (1-2C) alkyl; X ２ is a linker group of the following formula: - [CH ２ ｍ１ - L ２ - [CH ２ ｍ２ -​​ Wherein, m1 and m2 are selected from 0 or 1; L ２ is selected from -O-, -S-, -SO-, -SO ２ -, -N(R ｘ２ａ ), -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R ｘ２ａ ), -N(R ｘ２ａ ), -N(R ｘ２ｂ ), -N(R ｘ２ａ ), -N(R ｘ２ａ ), -C(O)O- or -OC(O)N(R ｘ２ａ ); and in the formula, R ｘ２ａ and R ｘ２ｂ are each independently selected from hydrogen or (1-2C) alkyl; Y ２ is selected from a carbocycle, aryl, heteroaryl or heterocycle, which is optionally substituted with halo, nitro, cyano, R ｙ２ａ , -[CH ２ ｔ -NR ｙ２ａ R ｙ２ｂ , -[CH ２ ｔ -OR ｙ２ａ , -[CH ２ ｔ -C(O)R ｙ２ａ , -[CH ２ ｔ -C(O)OR ｙ２ａ , -[CH ２ ｔ -OC(O)R ｙ２ａ , -[CH ２ ｔ -C(O)N(R ｙ２ｂ )R ｙ２ａ , -[CH ２ ｔ -N(R ｙ２ｂ )C(O)R ｙ２ａ or -[CH ２ ｔ -N(R ｙ２ｃ )-C(O)-N(R ｙ２ｂ )R ｙ２ａ and is substituted therewith; Wherein t is 0, 1, or 2; R ｙ２ａ is hydrogen or (1-4C)alkyl, optionally substituted with halo, hydroxy, amino or cyano; and R ｙ２ｂ and R ｙ２ｃ is hydrogen or (1-2C) alkyl; (iii) A group of formula IV: 【Chemical 11】 Wherein: Ring C is selected from phenyl, a 5- or 6-membered heteroaryl; k is 0, 1, or 2; Each R ４ group, when present, is as follows: halo, nitro, cyano, R ４ａ , -[CH ２ ｑ２ -NR ４ａ R ４ｂ , -[CH ２ ｑ２ -OR ４ａ , -[CH ２ ｑ２ -C(O)R ４ａ , -[CH ２ ｑ２ -C(O)OR ４ａ , -[CH ２ ｑ２ -OC(O)R ４ａ , -[CH ２ ｑ２ -C(O)N(R ４ｂ )R ４ａ or -[CH ２ ｑ２ -N(R ４ｂ )C(O)R ４ａ , -[CH ２ ｑ２ -N(R ４ｃ )-C(O)-N(R ４ｂ )R ４ａ and is selected from;​​​​​​​​ Wherein q2 is 0, 1, 2, or 3; R ４ａ is hydrogen or (1-4C)alkyl, optionally substituted with halo, hydroxy, amino or cyano; and R ４ｂ and R ４ｃ is hydrogen or (1-2C) alkyl; L is an optionally substituted 6C alkylene linker with one or more fluoro atoms; X is selected from -O-, -CR ｘａ R ｘｂ -, -S-, -SO-, -SO ２ -, -N(R ｘａ ), -C(O)-; and in the formula, R ｘａ and R ｘｂ are each independently selected from hydrogen or methyl; A ３０ and A ３１ is selected from CH, N or C-F; A ３２ and A ３３ is selected from CH or N; However, A ３０ , A ３１ , A ３２ and A ３３ may be only one or two of them being N; A ３４ and A ３５ is selected from CH, N, or C—R ３０ ; and A ３６ , A ３７ and A ３８ is selected from CH or N; However, A ３４ , A ３５ , A ３６ , A ３７ and A ３８ only one or two of them may be N; and in the formula, R ３０ is halo, nitro, cyano, R ３０ａ , -[CH ２ ｔ -NR ３０ａ R ３０ｂ , -[CH ２ ｔ -OR ３０ａ , -[CH ２ ｔ -C(O)R ３０ａ , -[CH ２ ｔ -C(O)OR ３０ａ , -[CH ２ ｔ -OC(O)R ３０ａ , -[CH ２ ｔ -C(O)N(R ３０ｂ )R ３０ａ , -[CH ２ ｔ -N(R ３０ｂ )C(O)R ３０ａ or -[CH ２ ｔ -N(R ３０ｃ )-C(O)-N(R ３０ｂ )R ３０ａ and is selected from;​​​​​​​​ Wherein, t is 0, 1, or 2; R ３０ａ is hydrogen or (1-4C)alkyl, optionally substituted with halo, hydroxy, amino or cyano; and R ３０ｂ and R ３０ｃ is hydrogen or (1-2C) alkyl; (iv) A group of formula V or VI: 【Chemical Formula 12】 Wherein: A ４０ is selected from NH, NMe or O; A ４２ 、 A ４３ 、 A ４４ and A ４６ are each independently selected from CH, N or CR ２ ; A ４１ and A ４５ are each independently selected from C or N; Provided that the following conditions are met: (vii) A ４０ , A ４１ , A ４２ , A ４３ , A ４４ , A ４５ and A ４６ Only a maximum of three of them are N; (viii) A ４１ and A ４５ cannot both be N; (ix) A ４０ , A ４２ , A ４３ , A ４４ and A ４６ Only one or two of ２ can be CR A ５１ is selected from NH, NMe, CH or CR ２ ; A ５０ 、 A ５３ 、 A ５４ and A ５５ each independently is selected from CH, N or CR ２ ; A ５２ and A ５６ are each independently selected from C or N; Provided that the following conditions are satisfied: (vii) A ５０ , A ５１ , A ５２ , A ５３ , A ５４ , A ５５ and A ５６ up to a maximum of three of them are N; (viii) A ５２ and A ５６ cannot both be N; (ix) A ５０ , A ５１ , A ５３ , A ５４ and A ５５ Only one or two of them can be CR ２ and can be; wherein R ２ is as defined above; W ４ is as follows: 【Chemical 13】 wherein, A ４ａ , A ４ｂ , A ４ｃ , or A ４ｄ is selected from CH, N or C-F, Provided that: A ４ａ 、 A ４ｂ 、 A ４ｃ or A ４ｄ only one or two of them can be N; and A ４ａ 、 A ４ｂ 、 A ４ｃ or A ４ｄ only one or two of them may be C-F; X ４ is a linker group of the following formula: - [CH ２ ｊ１ - L ４ - [CH ２ ｊ２ -​​ In the formula, j1 and j2 are selected from 0 or 1; L ４ is selected from -O-, -S-, -SO-, -SO ２ -, -N(R ｘ４ａ ), -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R ｘ４ａ ), -N(R ｘ４ａ ), -N(R ｘ４ｂ ), -N(R ｘ４ａ ), -N(R ｘ４ａ ), -C(O)O- or -OC(O)N(R ｘ４ａ ); and in the formula, R ｘ４ａ and R ｘ４ｂ are each independently selected from hydrogen or (1-2C) alkyl; Y ４ is selected from a carbocyclic ring, aryl, heteroaryl or heterocyclic ring, which is optionally substituted with halo, nitro, cyano, R ｙ４ａ , -[CH ２ ｕ -NR ｙ４ａ R ｙ４ｂ , -[CH ２ ｕ -OR ｙ４ａ , -[CH ２ ｕ -C(O)R ｙ４ａ , -[CH ２ ｕ -C(O)OR ｙ４ａ , -[CH ２ ｕ -OC(O)R ｙ４ａ , -[CH ２ ｕ -C(O)N(R ｙ４ｂ )R ｙ４ａ , -[CH ２ ｕ -N(R ｙ４ｂ )C(O)R ｙ４ａ or -[CH ２ ｕ -N(R ｙ４ｃ )-C(O)-N(R ｙ４ｂ )R ｙ４ａ and is substituted thereby;​​​​​​​​ In the formula, u is 0, 1 or 2; R ｙ４ is hydrogen or (1-4C)alkyl, optionally substituted with halo, hydroxy, amino or cyano; and R ｙ４ｂ and R ｙ４ｃ is hydrogen or (1-2C) alkyl, said compound, or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R １ is selected from the following: (i) The group of formula II: 【Chemical 14】 In the formula: Ring A is selected from phenyl or a 5- or 6-membered heteroaryl; n is 0, 1 or 2; Each R ２ group, when present, is as follows: halo, nitro, cyano, R ２ａ , -[CH ２ ｑ -NR ２ａ R ２ｂ , -[CH ２ ｑ -OR ２ａ , -[CH ２ ｑ -C(O)R ２ａ , -[CH ２ ｑ -C(O)OR ２ａ or -[CH ２ ｑ -OC(O)R ２ａ , and is selected from; In the formula, q is 0, 1, or 2; R ２ａ is hydrogen or (1-2C)alkyl, optionally substituted with halo, hydroxy, amino or cyano; and R ２ｂ is hydrogen or (1-2C)alkyl; R Ｎ is selected from hydrogen or methyl; Alternatively R ２ group and R Ｎ are linked so as to form a 5- or 6-membered heterocyclic ring fused to ring A, said fused 5- or 6-membered heterocyclic ring containing one or two N atoms and optionally being substituted with halo, hydroxy, (1-2C)alkyl, (1-2C)haloalkyl, cyano or amino; W １ is as follows: 【Chemical Formula 15】 In the formula, A １ , A ２ , A ３ or A ４ is selected from CH, N, or C-F, provided that: A １ 、 A ２ 、 A ３ or A ４ only one or two of them may be N; and A １ 、 A ２ 、 A ３ or A ４ only one or two of them may be C-F; X １ is a linker group of the following formula: - [CH ２ ｎ１ - L １ - [CH ２ ｎ２ -​​ In the formula, n1 and n2 are selected from 0 or 1; L １ is selected from -O-, -S-, -SO-, -SO ２ -, -N(R ｘ１ａ ), -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R ｘ１ａ ), or -N(R ｘ１ａ ), and in the formula, R ｘ１ａ and R ｘ１ｂ are each independently selected from hydrogen or (1-2C) alkyl; Y １ is selected from a carbocyclic ring, aryl, heteroaryl or heterocyclic ring, which is optionally halo, nitro, cyano, R ｙ１ａ , -[CH ２ ｒ -NR ｙ１ａ R ｙ１ｂ , -[CH ２ ｒ -OR ｙ１ａ , -[CH ２ ｒ -C(O)R ｙ１ａ , -[CH ２ ｒ -C(O)OR ｙ１ａ or -[CH ２ ｒ -OC(O)R ｙ１ａ and is substituted therewith;​​​​​ In the formula, r is 0 or 1; R ｙ１ａ is hydrogen or (1-2C)alkyl, optionally substituted with halo, hydroxy, amino or cyano; and R ｙ１ｂ and R ｙ１ｃ is hydrogen or (1-2C) alkyl; (ii) The group of formula III: 【Chemical 16】 In the formula: Ring B is selected from phenyl or a 5- or 6-membered heteroaryl; m is 0, 1, or 2; Each R ３ group, when present, is as follows: halo, nitro, cyano, R ３ａ , -[CH ２ ｑ１ -NR ３ａ R ３ｂ , -[CH ２ ｑ１ -OR ３ａ , -[CH ２ ｑ１ -C(O)R ３ａ , -[CH ２ ｑ１ -C(O)OR ３ａ or -[CH ２ ｑ１ -OC(O)R ３ａ and is selected from; In the formula, q1 is 0, 1, or 2; R ３ａ is hydrogen or (1-2C)alkyl, optionally substituted with halo, hydroxy, amino or cyano; and R ３ｂ is hydrogen or (1-2C) alkyl; V ２ is selected from -C(R ｖ２ａ R ｖ２ｂ )(R ｖ２ｃ R ｖ２ｄ )- or -C(R ｖ２ａ )(R ｖ２ｃ )=C(R ｖ２ａ ), R ｖ２ｂ ), R ｖ２ｃ and R ｖ２ｄ are each independently selected from hydrogen or methyl, or R ｖ２ａ and R ｖ２ｃ are linked to form a cyclopropyl ring; Z ２ is an optionally 1- or more-fluorine-atom-substituted 4C alkylene linker; W ２ is a carbocyclic ring, aryl, heteroaryl or heterocyclic ring, which is optionally substituted by halo, nitro, cyano, R ｗ２ａ , -[CH ２ ｓ -NR ｗ２ａ R ｗ２ｂ , -[CH ２ ｓ -OR ｗ２ａ , -[CH ２ ｓ -C(O)R ｗ２ａ , -[CH ２ ｓ -C(O)OR ｗ２ａ or -[CH ２ ｓ -OC(O)R ｗ２ａ ; In the formula, ​​​​​ s is 0, 1, or 2; R ｗ２ａ is hydrogen or (1-4C)alkyl, optionally substituted with halo, hydroxy, amino or cyano; and R ｗ２ｂ and R ｗ２ｃ is hydrogen or (1-2C) alkyl; X ２ is a linker group of the following formula: - [CH ２ ｍ１ - L ２ - [CH ２ ｍ２ -​​ In the formula, m1 and m2 are selected from 0 or 1; L ２ is selected from -O-, -S-, -SO-, -SO ２ -, -N(R ｘ２ａ ), -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R ｘ２ａ ), or -N(R ｘ２ａ ), and in the formula, R ｘ２ａ and R ｘ２ｂ are each independently selected from hydrogen or (1-2C) alkyl; Y ２ is selected from a carbocyclic ring, aryl, heteroaryl or heterocyclic ring, which is optionally halo, nitro, cyano, R ｙ２ａ , -[CH ２ ｔ -NR ｙ２ａ R ｙ２ｂ , -[CH ２ ｔ -OR ｙ２ａ , -[CH ２ ｔ -C(O)R ｙ２ａ , -[CH ２ ｔ -C(O)OR ｙ２ａ or -[CH ２ ｔ -OC(O)R ｙ２ａ and is substituted therewith;​​​​​ In the formula, t is 0 or 1; R ｙ２ａ is hydrogen or (1-2C)alkyl and is optionally substituted with halo, hydroxy, amino or cyano; and R ｙ２ｂ is hydrogen or (1-2C)alkyl; (iii) The group of formula IV: 【Chemical 17】 In the formula: Ring C is selected from phenyl, a 5- or 6-membered heteroaryl; k is 0, 1, or 2; Each R ４ group, when present, is as follows: halo, nitro, cyano, R ４ａ , -[CH ２ ｑ２ -[CH ４ａ ４ｂ R ２ , -[CH ｑ２ ４ａ -[CH ２ ｑ２ -C(O)R ４ａ , -[CH ２ ｑ２ -C(O)OR ４ａ or -[CH ２ ｑ２ -OC(O)R ４ａ and is selected from;​​​​​​ In the formula, q2 is 0, 1, 2, or 3; R ４ａ is hydrogen or (1-4C)alkyl, optionally substituted with halo, hydroxy, amino or cyano; and R ４ｂ is hydrogen or (1-2C) alkyl; L is an optionally substituted 6C alkylene linker with one or more fluoro atoms; X is selected from -O-, -CR ｘａ R ｘｂ -, -S-, -SO-, -SO ２ -, -N(R ｘａ ), -C(O)-; and in the formula, R ｘａ and R ｘｂ are each independently selected from hydrogen or methyl; A ３０ and A ３１ is selected from CH, N, or C—F; A ３２ and A ３３ is selected from CH or N; However, A ３０ , A ３１ , A ３２ and A ３３ only one or two of them may be N; A ３４ and A ３５ is selected from CH, N, or C—R ３０ ; and A ３６ 、 A ３７ and A ３８ and A are selected from CH or N; However, A ３４ , A ３５ , A ３６ , A ３７ and A ３８ only one or two of them may be N; and wherein R ３０ is halo, nitro, cyano, R ３０ａ , -[CH ２ ｔ -NR ３０ａ R ３０ｂ , -[CH ２ ｔ -OR ３０ａ , -[CH ２ ｔ -C(O)R ３０ａ , -[CH ２ ｔ -C(O)OR ３０ａ or -[CH ２ ｔ -OC(O)R ３０ａ is selected from; In the formula, t is 0, 1, or 2; R ３０ａ is hydrogen or (1-4C)alkyl, optionally substituted with halo, hydroxy, amino or cyano; and R ３０ｂ and R ３０ｃ is hydrogen or (1-2C)alkyl; (iv) The group of formula V or VI: 【Chemical Formula 18】 In the formula: A ４０ is selected from NH, NMe or O; A ４２ , A ４３ , A ４４ and A ４６ each independently is selected from CH, N or CR ２ ; A ４１ and A ４５ are each independently selected from C or N; Provided that the following conditions are satisfied: (i) A ４０ , A ４１ , A ４２ , A ４３ , A ４４ , A ４５ and A ４６ up to a maximum of three of them are N; (ii) A ４１ and A ４５ cannot both be N; (iii) A ４０ , A ４２ , A ４３ , A ４４ and A ４６ Only one or two of ２ may be CR A ５１ is selected from NH, NMe, CH or CR ２ ; and A ５０ 、 A ５３ 、 A ５４ and A ５５ each independently is selected from CH, N or CR ２ ; A ５２ and A ５６ are each independently selected from C or N; Provided that the following conditions are satisfied: (i) A ５０ , A ５１ , A ５２ , A ５３ , A ５４ , A ５５ and A ５６ up to a maximum of three of them are N; (ii) A ５２ and A ５６ cannot both be N; (iii) A ５０ , A ５１ , A ５３ , A ５４ and A ５５ Only one or two of them can be CR ２ ; may be wherein, R ２ is as defined above; W ４ is as follows: 【Chemical Formula 19】 In the formula, A ４ａ , A ４ｂ , A ４ｃ , or A ４ｄ is selected from CH, N or C-F, Provided that: A ４ａ 、 A ４ｂ 、 A ４ｃ or A ４ｄ only one or two of them can be N; and A ４ａ 、 A ４ｂ 、 A ４ｃ or A ４ｄ only one or two of them may be C-F; X ４ is a linker group of the following formula: - [CH ２ ｊ１ - L ４ - [CH ２ ｊ２ -​​ In the formula, j1 and j2 are selected from 0 or 1; L ４ is selected from -O-, -S-, -SO-, -SO ２ -, -N(R ｘ４ａ ), -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R ｘ４ａ ), or -N(R ｘ４ａ ), and in the formula, R ｘ４ａ and R ｘ４ｂ are each independently selected from hydrogen or (1-2C) alkyl; Y ４ is selected from a carbocyclic ring, aryl, heteroaryl or heterocyclic ring, which is optionally halo, nitro, cyano, R ｙ４ａ , -[CH ２ ｕ -NR ｙ４ａ R ｙ４ｂ , -[CH ２ ｕ -OR ｙ４ａ , -[CH ２ ｕ -C(O)R ｙ４ａ , -[CH ２ ｕ -C(O)OR ｙ４ａ or -[CH ２ ｕ -OC(O)R ｙ４ａ ; and is substituted by; u is 0 or 1; R ｙ４ａ is hydrogen or (1-2C)alkyl, optionally substituted with halo, hydroxy, amino or cyano; and R ｙ４ｂ and R ｙ４ｃ is hydrogen or (1-2C) alkyl, said compound, or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R １ is selected from the following: (i) The group of formula II: 【Chemical 20】 In the formula: Ring A is selected from phenyl or a 5- or 6-membered heteroaryl; n is 0, 1 or 2; Each R ２ group, when present, is as follows: halo, nitro, cyano, R ２ａ , -[CH ２ ｑ -NR ２ａ R ２ｂ , -[CH ２ ｑ -OR ２ａ , -[CH ２ ｑ -C(O)R ２ａ , and is selected from; In the formula, q is 0 or 1; R ２ａ is hydrogen or methyl; and R ２ｂ is hydrogen or methyl; R Ｎ is selected from hydrogen or methyl; Alternatively, R ２ group and R Ｎ are linked so as to form a 5- or 6-membered heterocyclic ring fused to ring A, said fused 5- or 6-membered heterocyclic ring containing one or two N atoms and optionally being substituted by halo, hydroxy, methyl, halomethyl, cyano or amino; W １ is: 【Chemical 21】 wherein, A １ , A ２ , A ３ or A ４ is selected from CH or C-F, provided that the following conditions are satisfied: A １ 、 A ２ 、 A ３ or A ４ only one or two of them may be C-F; X １ is a linker group of the formula: - [CH ２ ｎ１ - L １ - [CH ２ ｎ２ -​​ In the formula, n1 and n2 are selected from 0 or 1; L １ is selected from -O-, -S-, -SO-, -SO ２ -, -N(R ｘ１ａ )- or -C(O)-; and in the formula, R ｘ１ａ is selected from hydrogen or methyl; Y １ is selected from phenyl, heteroaryl or a heterocycle, which is optionally substituted by halo, nitro, cyano, R ｙ１ａ , -NR ｙ１ａ R ｙ１ｂ , -OR ｙ１ａ or -C(O)R ｙ１ａ ; R ｙ１ａ is hydrogen or methyl; and R ｙ１ｂ is hydrogen or methyl; (ii) The group of formula III: 【Chemical 22】 In the formula: Ring B is selected from phenyl or a 5- or 6-membered heteroaryl; m is 0, 1, or 2; Each R ３ group, when present, is as follows: halo, nitro, cyano, R ３ａ , -[CH ２ ｑ１ -NR ３ａ R ３ｂ , -[CH ２ ｑ１ -OR ３ａ or -[CH ２ ｑ１ -C(O)R ３ａ and is selected from; In the formula, q1 is 0 or 1; R ３ａ is hydrogen or methyl; and R ３ｂ is hydrogen or methyl; V ２ is selected from -C(R ｖ２ａ R ｖ２ｂ )(R ｖ２ｃ R ｖ２ｄ )- or -C(R ｖ２ａ )(R ｖ２ｃ )=C(R ｖ２ａ ), R ｖ２ｂ ), R ｖ２ｃ and R ｖ２ｄ are each independently selected from hydrogen or methyl, or R ｖ２ａ and R ｖ２ｃ are linked to form a cyclopropyl ring; Z ２ is an optionally substituted 4C alkylene linker having one or more fluoro atoms; W ２ is a carbocyclic or heterocyclic ring which is optionally substituted with halo, nitro, cyano, R ｗ２ａ , -[CH ２ ｓ -NR ｗ２ａ R ｗ２ｂ , -[CH ２ ｓ -OR ｗ２ａ or -[CH ２ ｓ -C(O)R ｗ２ａ ; wherein​​​ s is 0 or 1; R ｗ２ａ is hydrogen or (1-2C)alkyl, optionally substituted with halo, hydroxy, amino or cyano; and R ｗ２ｂ and R ｗ２ｃ is hydrogen or (1-2C) alkyl; X ２ is a linker group of the following formula: - [CH ２ ｍ１ - L ２ - [CH ２ ｍ２ -​​ In the formula, m1 and m2 are selected from 0 or 1; L ２ is selected from -O-, -S-, -SO-, -SO ２ -, -N(R ｘ２ａ )- or -C(O)-, and in the formula, R ｘ２ａ is selected from hydrogen or methyl; Y ２ is selected from phenyl, heteroaryl or heterocycle, which is optionally substituted by halo, nitro, cyano, R ｙ２ａ , NR ｙ２ａ R ｙ２ｂ , OR ｙ２ａ or C(O)R ｙ２ａ ; ； R ｙ２ａ is hydrogen or methyl; and R ｙ２ｂ is hydrogen or methyl; (iii) The group of formula IV: 【Chemical 23】 In the formula: Ring C is selected from phenyl, a 5- or 6-membered heteroaryl; k is 0, 1, or 2; Each R ４ group, when present, is as follows: halo, nitro, cyano, R ４ａ , -[CH ２ ｑ２ -NR ４ａ R ４ｂ , -[CH ２ ｑ２ -OR ４ａ , -[CH ２ ｑ２ -C(O)R ４ａ and is selected from; In the formula, q2 is 0 or 1; R ４ａ is hydrogen or methyl; and R ４ｂ is hydrogen or methyl; L is an optionally substituted 6C alkylene linker with one or more fluoro atoms; X is selected from -O-, -CR ｘａ R ｘｂ -, -S-, -SO-, -SO ２ -, -N(R ｘａ ), -C(O)-; and in the formula, R ｘａ and R ｘｂ are each independently selected from hydrogen or methyl; A ３０ and A ３１ is selected from CH, N, or C-F; A ３２ and A ３３ is selected from CH or N; However, A ３０ , A ３１ , A ３２ and A ３３ only one or two of them may be N; A ３４ and A ３５ is selected from CH, N, or C—R ３０ ; and A ３６ 、 A ３７ and A ３８ is selected from CH or N; However, A ３４ , A ３５ , A ３６ , A ３７ and A ３８ only one or two of them may be N; and in the formula, R ３０ is selected from halo, nitro, cyano, R ３０ａ , --NR ３０ａ R ３０ｂ , -OR ３０ａ or -C(O)R ３０ａ ; in the formula, R ３０ａ is hydrogen or methyl; and R ３０ｂ is hydrogen or methyl; (iv) The group of formula V or VI: 【Chemical 24】 In the formula: A ４０ is selected from NH, NMe or O; A ４２ 、 A ４３ 、 A ４４ and A ４６ each independently is selected from CH, N or CR ２ ; A ４１ and A ４５ are each independently selected from C or N; Provided that the following conditions are satisfied: (i) A ４０ , A ４１ , A ４２ , A ４３ , A ４４ , A ４５ and A ４６ up to a maximum of three of them are N; (ii) A ４１ and A ４５ cannot both be N; (iii) A ４０ , A ４２ , A ４３ , A ４４ and A ４６ Only one or two of them may be CR ２ and it may be; A ５１ is selected from NH, NMe, CH or CR ２ ; and A ５０ 、 A ５３ 、 A ５４ and A ５５ each independently is CH, N or CR ２ selected from; A ５２ and A ５６ are each independently selected from C or N; Provided that the following conditions are satisfied: (i) A ５０ , A ５１ , A ５２ , A ５３ , A ５４ , A ５５ and A ５６ up to a maximum of three of them are N; (ii) A ５２ and A ５６ cannot both be N; (iii) A ５０ , A ５１ , A ５３ , A ５４ and A ５５ Only one or two of ２ can be CR wherein R ２ is as defined above; W ４ is as follows: 【Chemical 25】 wherein, A ４ａ , A ４ｂ , A ４ｃ , or A ４ｄ is selected from CH or C-F, provided that: A ４ａ 、 A ４ｂ 、 A ４ｃ or A ４ｄ only one or two of them may be C-F; X ４ is a linker group of the following formula: - [CH ２ ｊ１ - L ４ - [CH ２ ｊ２ -​​ In the formula, j1 and j2 are selected from 0 or 1; L ４ is selected from -O-, -S-, -SO-, -SO ２ -, -N(R ｘ４ａ ), -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R ｘ４ａ ), -N(R ｘ４ａ ), -N(R ｘ４ａ and R ｘ４ｂ are each independently selected from hydrogen or methyl; Y ４ is selected from phenyl, heteroaryl or heterocycle, which is optionally halo, nitro, cyano, R ｙ４ａ , -NR ｙ４ａ R ｙ４ｂ , --OR ｙ４ａ or -C(O)R ｙ４ａ selected from; In the formula, R ｙ４ａ is hydrogen or methyl; and R ｙ４ｂ wherein R is hydrogen or methyl, or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R １ is selected from the following: (i) The group of formula II: 【Chemical 26】 In the formula: Ring A is selected from phenyl or a 6-membered heteroaryl; n is 0 or 1; Each R ２ group, when present, is as follows: halo, nitro, cyano, R ２ａ , -NR ２ａ R ２ｂ , -OR ２ａ , -C(O)R ２ａ , and is selected from; ； R ２ａ is hydrogen or methyl; and R ２ｂ is hydrogen or methyl; Alternatively, R ２ groups and R Ｎ are linked so as to form a 5- or 6-membered heterocyclic ring fused to ring A, said fused 5- or 6-membered heterocyclic ring containing one or two N atoms and optionally being substituted by halo, hydroxy, methyl, halomethyl, cyano or amino; W １ is as follows: 【Chemical 27】 X １ is a linker group of the following formula: - [CH ２ ｎ１ - L １ - [CH ２ ｎ２ -​​ In the formula, n1 and n2 are each independently selected from 0 or 1; L １ is selected from -O-, -S-, -SO ２ -, or -C(O)-; Y １ is selected from phenyl, heteroaryl or heterocycle, which is optionally substituted by halo, nitro, cyano, R ｙ１ａ or -OR ｙ１ａ ; R ｙ１ａ is hydrogen or methyl; and R ｙ１ｂ is hydrogen or methyl; (ii) a group of formula III: 【Chemical 28】 wherein: ring B is selected from phenyl or a 5- or 6-membered heteroaryl; m is 0 or 1; Each R ３ group, when present, is as follows: halo, nitro, cyano, R ３ａ , -NR ３ａ R ３ｂ , -OR ３ａ or -C(O)R ３ａ and is selected from; R ３ａ is hydrogen or methyl; and R ３ｂ is hydrogen or methyl; V ２ is selected from -C(R ｖ２ａ R ｖ２ｂ )C(R ｖ２ｃ R ｖ２ｄ )- or -C(R ｖ２ａ )=C(R ｖ２ｃ )-, wherein R ｖ２ａ , R ｖ２ｂ , R ｖ２ｃ and R ｖ２ｄ are each independently selected from hydrogen or methyl, or R ｖ２ａ and R ｖ２ｃ are linked to form a cyclopropyl ring; Z ２ is an optionally substituted 4C alkylene linker substituted with one or more fluoro atoms; W ２ is a carbocyclic or heterocyclic ring which is optionally substituted by halo, nitro, cyano, R ｗ２ａ , -NR ｗ２ａ R ｗ２ｂ , -OR ｗ２ａ or -C(O)R ｗ２ａ ; wherein R ｗ２ａ is hydrogen or methyl; and R ｗ２ｂ and R ｗ２ｃ is hydrogen or methyl; X ２ is a linker group of the following formula: - [CH ２ ｍ１ -L ２ - [CH ２ ｍ２ -​​ wherein, m1 and m2 are each independently selected from 0 or 1; L ２ is selected from -O-, -S-, -SO ２ -, or -C(O)-; Y ２ is selected from phenyl, heteroaryl or heterocyclic ring, which is optionally substituted by halo, nitro, cyano, hydrogen, methyl or OR ｙ２ａ and is substituted by; R ｙ２ａ is hydrogen or methyl; and R ｙ２ｂ is hydrogen or methyl; (iii) a group of formula IV: 【Chemical Formula 29】 wherein: ring C is selected from phenyl or a 6-membered heteroaryl; k is 0 or 1; Each R ４ group, when present, is as follows: halo, nitro, cyano, R ４ａ , -NR ４ａ R ４ｂ , -OR ４ａ , -C(O)R ４ａ and is selected from; R ４ａ is hydrogen or methyl; and R ４ｂ is hydrogen or methyl; L is an optionally substituted 6C alkylene linker with one or more fluoro atoms; X is selected from -O-, -S-, -SO ２ -, or -C(O)-; A ３０ and A ３１ is selected from CH or C-F; A ３２ and A ３３ is CH; A ３４ and A ３５ is selected from CH or C—R ３０ ; and A ３６ 、 A ３７ and A ３８ is CH; and wherein R ３０ is halo, nitro, cyano, hydrogen, methyl, -NR ３０ａ R ３０ｂ , - OR ３０ａ or -C(O)R ３０ａ selected from; wherein, R ３０ａ is hydrogen or methyl; and R ３０ｂ is hydrogen or methyl; (iv) a group of formula V or VI: 【Chemical 30】 wherein: A ４０ is selected from NH or O; A ４２ , A ４３ , A ４４ and A ４６ are each independently selected from CH or CR ２ ; A ４１ and A ４５ are each C; A ５１ is selected from NH, NMe, CH or CR ２ ; A ５０ , A ５３ , A ５４ and A ５５ are each independently selected from CH or CR ２ ; A ５２ and A ５６ are each C; ； wherein R ２ is as defined above; W ４ is as follows: 【Chemical 31】 X ４ is a linker group of the following formula: -L ４ - wherein, L ４ is selected from -O-, -S-, -SO-, -SO ２ -, -N(R ｘ４ａ ), -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R ｘ４ａ ), -N(R ｘ４ａ ), -N(R ｘ４ａ and R ｘ４ｂ are each independently selected from hydrogen or methyl; Y ４ wherein Y is selected from phenyl, heteroaryl or heterocyclic ring, which is optionally substituted by halo, nitro, cyano or methyl, said compound, or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R １ is selected from the following: (i) a group of formula II: 【Chemical 32】 wherein: ring A is selected from phenyl or a 6-membered heteroaryl; n is 0 or 1; Each R ２ group, when present, is as follows: halo or -OR ２ａ is selected from; wherein, R ２ａ is hydrogen or methyl; and R Ｎ is hydrogen or Alternatively, R ２ groups and R Ｎ are linked so as to form a 5- or 6-membered heterocyclic ring fused to ring A, said fused 5- or 6-membered heterocyclic ring containing one or two N atoms and optionally being substituted by halo, hydroxy, methyl, halomethyl, cyano or amino; W １ is as follows: 【Chemical 33】 X １ is a linker group of the following formula: - [CH ２ ｎ１ - L １ - [CH ２ ｎ２ -​​ wherein, n1 and n2 are each independently selected from 0 or 1; L １ is selected from -O-, -S-, -SO ２ -, or -C(O)-; Y １ is selected from phenyl or a heterocyclic ring, which is optionally substituted by halo, nitro, cyano, hydrogen, methyl, or -OR ｙ１ａ ; R ｙ１ａ is hydrogen or methyl; (ii) a group of formula III: 【Chemical 34】 wherein: ring B is selected from phenyl or a 5- or 6-membered heteroaryl; m is 0 or 1; Each R ３ group, when present, is as follows: halo, or -OR ３ａ is selected from; wherein R ３ａ is hydrogen or methyl; V ２ is selected from -C(R ｖ２ａ R ｖ２ｂ )C(R ｖ２ｃ R ｖ２ｄ )- or -C(R ｖ２ａ )=C(R ｖ２ｃ )-, wherein R ｖ２ａ , R ｖ２ｂ , R ｖ２ｃ and R ｖ２ｄ are each independently selected from hydrogen or methyl, or R ｖ２ａ and R ｖ２ｃ are linked to form a cyclopropyl ring; Z ２ is a 4C alkylene linker which is optionally substituted with one or more fluoro atoms; W ２ is a heterocyclic ring optionally substituted by a halo or -OR ｗ２ａ ; wherein R ｗ２ａ is hydrogen or methyl; X ２ is a linker group of the following formula: -L ２ - wherein, L ２ is selected from -O-, -S-, -SO ２ -, or -C(O)-; Y ２ is phenyl or a heterocyclic ring, which is optionally substituted by halo, nitro, cyano, hydrogen, methyl or OR ｙ２ａ ; R ｙ２ａ is hydrogen or methyl; (iii) a group of formula IVa: 【Chemical 35】 wherein: ring C is selected from phenyl or a 6-membered heteroaryl; k is 0 or 1; Each R ４ group, when present, is selected from the following: halo, or -OR ４ａ ; wherein, R ４ａ is hydrogen or methyl; L is an optionally substituted 6C alkylene linker with one or more fluoro atoms; X is selected from -O-, -S-, -SO ２ -, or -C(O)-; (iv) a group of formula Va or VIa: 【Chemical 36】 wherein: A ４０ is selected from NH or O; A ５１ is selected from NH, NMe, CH or CR ２ ; wherein, R ２ is as defined above; W ４ is as follows: 【Chemical 37】 X ４ is a linker group of the following formula: -L ４ - wherein, L ４ is selected from -SO ２ -, -C(O)N(R ｘ４ａ )- or -N(R ｘ４ａ )C(O)-; and in the formula, R ｘ４ａ is selected from hydrogen or methyl; Y ４ is phenyl or a heterocyclic ring, which is optionally substituted by halo, nitro, cyano or methyl, said compound, or a pharmaceutically acceptable salt thereof.

7. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R １ is selected from the following: (i) a group of formula II: 【Chemical 38】 wherein: ring A is selected from phenyl or a 6-membered heteroaryl; n is 0 or 1; Each R ２ group, when present, is as follows: halo or -OR ２ａ is selected from; In the formula, R ２ａ is hydrogen or methyl; and R Ｎ is hydrogen or Alternatively, R ２ group and R Ｎ are linked so as to form a 5-membered heterocyclic ring fused to ring A, said fused 5-membered heterocyclic ring containing one or two N atoms; W １ is as follows: 【Chemical Formula 39】 X １ is a linker group of the following formula: - [CH ２ ｎ１ - L １ - [CH ２ ｎ２ -​​ wherein, n1 and n2 are each independently selected from 0 or 1; L １ is selected from -SO ２ -; Y １ is selected from phenyl or a heterocyclic ring, which is optionally substituted by halo or -OR ｙ１ａ ; In the formula, R ｙ１ａ is hydrogen or methyl; (ii) a group of formula III: 【Chemical 40】 wherein: ring B is selected from phenyl or a 6-membered heteroaryl; m is 0 or 1; Each R ３ group, when present, is as follows: halo, or -OR ３ａ is selected from; wherein, R ３ａ is hydrogen or methyl; V ２ is selected from -C(R ｖ２ａ R ｖ２ｂ )C(R ｖ２ｃ R ｖ２ｄ )- or -C(R ｖ２ａ )=C(R ｖ２ｃ )-, wherein R ｖ２ａ , R ｖ２ｂ , R ｖ２ｃ and R ｖ２ｄ are each hydrogen, or R ｖ２ａ and R ｖ２ｃ are linked to form a cyclopropyl ring; Z ２ is a 4C alkylene linker; W ２ is a complex ring, which is optionally substituted by halo or -OR ｗ２ａ ; wherein R ｗ２ａ is hydrogen or methyl; X ２ is a linker group of the following formula: -L ２ - wherein, L ２ is selected from -C(O)-; Y ２ is a phenyl ring which is optionally substituted by halo or OR ｙ２ａ ; wherein R ｙ２ａ is hydrogen or methyl; (iii) a group of formula IVa: 【Chemical Formula 41】 wherein: ring C is selected from phenyl or a 6-membered heteroaryl; k is 0 or 1; Each R ４ When present, the group is as follows: halo, or -OR ４ａ is selected from; wherein, R ４ａ is hydrogen or methyl; L is a 6C alkylene linker; X is -O-; (iv) a group of formula Va or VIa: 【Chemical Formula 42】 wherein: A ４０ is selected from NH or O; A ５１ is NH, NMe, CH or CR ２ is selected from; where R ２ is as defined above; W ４ is as follows: 【Chemical 43】 X ４ is a linker group of the following formula: -L ４ - wherein, L ４ is selected from -SO ２ - or -C(O)N(R ｘ４ａ )-; and in the formula, R ｘ４ａ is independently selected from hydrogen or methyl; Y ４ The compound, or a pharmaceutically acceptable salt thereof, wherein Y is a complex ring.

8. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R １ is selected from the following: (i) a group of formula IIa or IIb: 【Chemical 44】 wherein: ring A is selected from phenyl or a 6-membered heteroaryl; n is 0 or 1; Each R ２ group, when present, is as follows: halo or -OR ２ａ and is selected from; In the formula, R ２ａ is hydrogen or methyl; and R Ｎ is hydrogen or Alternatively, R ２ group and R Ｎ are linked so as to form a 5-membered heterocyclic ring fused to ring A, said fused 5-membered heterocyclic ring containing one or two N atoms; W １ is as follows: 【Chemical 45】 X １ is a linker group of the following formula: - [CH ２ ｎ１ - L １ - [CH ２ ｎ２ -​​ wherein, n1 and n2 are each independently selected from 0 or 1; L １ is selected from -SO ２ -; Y １ is selected from phenyl or a heterocyclic ring, which is optionally substituted by halo or -OR ｙ１ａ ; wherein R ｙ１ａ is hydrogen or methyl; (ii) a group of formula IIIa: 【Chemical 46】 wherein: m is 0 or 1; Each R ３ group, when present, is as follows: halo, or -OR ３ａ is selected from; wherein, R ３ａ is hydrogen or methyl; V ２ is selected from -C(R ｖ２ａ R ｖ２ｂ )C(R ｖ２ｃ R ｖ２ｄ )- or -C(R ｖ２ａ )=C(R ｖ２ｃ )-, wherein R ｖ２ａ , R ｖ２ｂ , R ｖ２ｃ and R ｖ２ｄ are each hydrogen, or R ｖ２ａ and R ｖ２ｃ are linked to form a cyclopropyl ring; Z ２ is a 4C alkylene linker; W ２ is a complex ring, which is optionally substituted by halo or -OR ｗ２ａ ; wherein R ｗ２ａ is hydrogen or methyl; X ２ is a linker group of the following formula: -L ２ - wherein, L ２ is selected from -C(O)-; Y ２ is a phenyl ring which is optionally substituted by halo or OR ｙ２ａ with ; wherein, R ｙ２ａ is hydrogen or methyl; (iii) a group of formula IVb: 【Chemical 47】 wherein: k is 0 or 1; Each R ４ group, when present, is as follows: halo, or -OR ４ａ is selected from; wherein R ４ａ is hydrogen or methyl; L is a 6C alkylene linker; X is -O-; (iv) a group of formula Vb, Vc, Vib or Vic: 【Chemical 48】 wherein: W ４ is as follows: 【Chemical 49】 X ４ is a linker group of the following formula: -L ４ - wherein, L ４ is - SO ２ - and; Y ４ The compound, or a pharmaceutically acceptable salt thereof, wherein Y is a 5- or 6-membered heterocyclic ring.

9. The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is as follows: 6-(2-Fluoro-5-(((3-(4-(piperidin-1-ylsulfonyl)phenyl)ureido)methyl)phenyl)-4-(trioxidan-1-ylthio)naphthalene-2-sulfonic acid; (E)-6-(5-(3-(((4-(1-benzoylpiperidin-4-yl)butyl)amino)-3-oxoprop-1-en-1-yl)-2-fluorophenyl)-4-(trioxidan-1-ylthio)naphthalene-2-sulfonic acid; 6-(2-Fluoro-5-(((3-(4-(phenylsulfonyl)phenyl)ureido)methyl)phenyl)-4-(trioxidan-1-ylthio)naphthalene-2-sulfonic acid; 6-(3-(1-(6-([1,1'-biphenyl]-2-yloxy)hexyl)-1H-1,2,3-triazol-4-yl)phenyl)-4-(trioxidan-1-ylthio)naphthalene-2-sulfonic acid; 6-(3-(((3-(4-(piperidin-1-ylsulfonyl)phenyl)ureido)methyl)phenyl)-4-(trioxidan-1-ylthio)naphthalene-2-sulfonic acid; 6-(4-Fluoro-3-(((3-(4-(piperidin-1-ylsulfonyl)phenyl)ureido)methyl)phenyl)-4-(trioxidan-1-ylthio)naphthalene-2-sulfonic acid; 6-(2-Methoxy-5-(((3-(4-(piperidin-1-ylsulfonyl)phenyl)ureido)methyl)phenyl)-4-(trioxidan-1-ylthio)naphthalene-2-sulfonic acid; 6-(5-(((3-(4-(((8-oxa-3-azabicyclo[3.2.1]octan-3-yl)sulfonyl)phenyl)ureido)methyl)-2-fluorophenyl)-4-(trioxidan-1-ylthio)naphthalene-2-sulfonic acid; 6-(2-(((4-(piperidin-1-ylsulfonyl)benzyl)carbamoyl)-1H-indol-5-yl)-4-(trioxidan-1-ylthio)naphthalene-2-sulfonic acid; and (S)-6-(2-(((4-((((tetrahydrofuran-3-yl)methyl)carbamoyl)phenyl)carbamoyl)isoindolin-5-yl)-4-(trioxidan-1-ylthio)naphthalene-2-sulfonic acid selected from the list consisting of a compound, or a pharmaceutically acceptable salt or solvate thereof. ​ A pharmaceutical composition comprising the compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

11. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, for use in the following treatments: (i) Diabetes; (ii) Cardiovascular diseases; (iii) Inflammatory bowel conditions; (iv) Cancer; (vi) Inflammatory skin conditions; (vii) Lung conditions; (viii) Arthritis; (ix) Kidney diseases; or (x) Sepsis.

12. The pharmaceutical composition according to claim 10, for use in the following treatments: (i) Diabetes; (ii) Cardiovascular diseases; (iii) Inflammatory bowel conditions; (iv) Cancer; (v) Liver diseases; (vi) Inflammatory skin conditions; (vii) Lung conditions; (viii) Arthritis; (ix) Kidney diseases; or (x) Sepsis.

13. The compound according to claim 11, for use in the following treatments: (i) Diabetes; (ii) Pulmonary arterial hypertension, acute coronary syndrome (ACS), congestive heart failure (CHF) or left ventricular hypertrophy; (iii) Inflammatory bowel disease (IBD), Crohn's disease or ulcerative colitis; (iv) Breast cancer, prostate cancer, or chronic lymphocytic leukemia (CLL) (v) Non-alcoholic fatty liver disease (NAFLD), particularly non-alcoholic steatohepatitis (NASH), hepatic steatosis, hepatic fibrosis or cirrhosis); (vi) Psoriasis; (vii) Acute lung injury (ALI), ventilator-induced lung injury (VILI), radiation-induced lung injury (RILI), pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis); (viii) Osteoarthritis or rheumatoid arthritis; (ix) Chronic kidney disease; or (x) Sepsis.

14. The pharmaceutical composition according to claim 12, for use in the following treatments: (i) Diabetes; (ii) Pulmonary arterial hypertension, acute coronary syndrome (ACS), congestive heart failure (CHF) or left ventricular hypertrophy; (iii) Inflammatory bowel disease (IBD), Crohn's disease or ulcerative colitis; (iv) Breast cancer, prostate cancer, or chronic lymphocytic leukemia (CLL) (v) Non-alcoholic fatty liver disease (NAFLD), particularly non-alcoholic steatohepatitis (NASH), hepatic steatosis, hepatic fibrosis or cirrhosis); (vi) Psoriasis; (vii) Acute lung injury (ALI), ventilator-induced lung injury (VILI), radiation-induced lung injury (RILI), pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis); (viii) Osteoarthritis or rheumatoid arthritis; (ix) Chronic kidney disease; or (x) Septicemia.

15. The compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof for use in the treatment of non-alcoholic fatty liver disease, such as hepatic steatosis, inflammatory non-alcoholic steatohepatitis (NASH), fibrosis, or cirrhosis.

16. The pharmaceutical composition according to claim 10 for use in the treatment of non-alcoholic fatty liver disease, such as hepatic steatosis, inflammatory non-alcoholic steatohepatitis (NASH), fibrosis, or cirrhosis.

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