CTPS1 inhibitors for the treatment of myeloproliferative neoplasms

Abstract

The invention provides, inter alia, a CTPS1 inhibitor for use in the treatment of a myeloproliferative neoplasm (MPN) in a human subject.

Description

[0001] STP-P3718PCT 1 NOVEL METHODS Field of the invention The invention relates to methods of treating myeloproliferative neoplasms in human 5 subjects by administering CTPS1 inhibitors, and related aspects. Background of the invention Myeloproliferative neoplasms (MPN) are a group of clonal haemopoietic stem celldisorders characterised by over-production of one or more mature myeloid blood lineages. MPN,10 or analogous conditions, occur in both humans and animals. MPN are ‘atypical cancers’ in that(a) cell proliferation is generally not completely uncontrolled, (b) cell proliferation does not impactthe patient directly; negative impacts are usually an indirect consequence of proliferation, such as thrombosis and (c) MPN management does not aim to entirely block formation of the bloodcells which are being over-produced. 15 Examples of MPN are essential thrombocythaemia (ET), polycythaemia vera (PV) and myelofibrosis (MF) (Godfrey et al.2023, How et al.2023).ET is characterised by overproduction of platelets and, to a lesser extent, granulocytes. Platelets are formed when megakaryocytes in the bone marrow produce cytoplasmic projections called proplatelets. These proplatelets bud off, encapsulated by a lipid bilayer. Platelets are20 unique in lacking nucleic acids because they are cytoplasmic fragments, not full cells. They inherit proteins and other functional molecules from megakaryocytes, but not the nucleus, making them DNA-free and RNA-free. Platelet formation therefore does not depend directly onreplication of DNA or RNA (in contrast to typical cancer cell proliferation). PV is characterised by overproduction of red cells, and, to a lesser extent, platelets and25 granulocytes. MF is characterised by proliferation of megakaryocytes resulting in bone marrowfibrosis associated with variable overproduction of granulocytes and occasionally platelets. The three conditions show overlapping phenotypes and a predisposition to evolve, such that patients with ET can develop PV, and either ET or PV can progress to MF. MF is a more advanced phaseof disease associated with a higher degree of genomic perturbation and a worse prognosis. All 30 three conditions can evolve into a more serious myeloid cancer such as myelodysplasia or acute myeloid leukaemia. There is overlap in the somatic genomic alterations that drive these three disorders. The JAK2 V617F mutation is present in around 50% of ET, 95% of PV and 50% of MF. Mutations inCALR are present in around 20-25% of ET and MF (but not PV); mutations in MPL are present35 in around 5-10% of ET and MF (but not PV). Mutations in JAK2, CALR or MPL are consideredto be the primary drivers of the disease, resulting in activation of cellular pathways that result in the overproduction of mature myeloid cells. Additional mutations in other genes may modulate STP-P3718PCT 2 the disease phenotype or increase the propensity to progression to a more aggressive disease; such mutations are more prevalent in MF, consistent with MF representing a more advanced phase of disease. JAK2 mutations have been reported in dogs with PV and commercial testing services for the condition in dogs is available. 5ET is a rare human condition with incidence 1.5-2 per 100,000 population per year;however, survival is long, often 20+ years from diagnosis, such that the prevalence of ET is higher, in the order of 25-50 per 100,000 population. The most feared complication of ET is thrombosis which can be arterial or venous and can result in death or significant morbidity. Quality of life for those living with ET is also impacted 10 by a number of troublesome symptoms including fatigue, itch and vasomotor disturbance affecting the extremities (for example, erythromelalgia). Patients aged >60 years and those with a prior history of thrombosis require treatment to reduce the risk of thrombotic complications. The aim of therapy is typically to normalise theplatelet count. Notably, the degree of thrombocytopaenia is not associated with the risk of15 thrombosis, although a high white cell count has been reported as a risk factor (Campbell et al.2012). This had led to the notion that optimal therapy for ET should normalise both the plateletand white cell counts. Current first line therapy is the antimetabolite hydroxycarbamide (also known as hydroxyurea). Interferon alpha is also occasionally used in the first line setting. 20-25% of 20 patients fail hydroxycarbamide either due to lack of efficacy or due to toxicity, especially intractable leg ulceration. This group of patients require second line therapy; however, currently available choices such as anagrelide and interferon are suboptimal. Anagrelide is associated with cardiac toxicity (including cardiac failure and arrythmias) and is suboptimal in preventingthrombosis. Interferon alpha is associated with short to medium term fatigue and flu-like25 symptoms and long-term neuropsychiatric complications. To date, CTPS1 inhibitors have been developed for oncology indications up to phase I / IIclinical trials. However, a seminal study into CTPS1-deficient patients (Martin et al 2014) foundthat “…most of [the] patients had variable lymphopenia…whereas other blood cell counts were usually normal…”. Data provided in Supplemental Table 2 of the publication, confirm normal30 platelet counts for the five CTPS1-deficient patients where detail was provided. In view of thisdisclosure that CTPS1-deficient patients demonstrate normal blood cell counts, it would not beexpected that CTPS1 inhibitors would impact blood cell counts (aside from lymphocytes).There remains a need for new approaches to MPN therapies. Such approaches maydemonstrate higher in vivo efficacy, reduced or more convenient dose required for effect in vivo35 (e.g. reduced and / or amount), an improved or distinct safety profile / reduced side effects, or may demonstrate a desirable balance of effects, or the like. STP-P3718PCT 3 Summary of the invention As discussed above, administration of a CTPS1 inhibitor (which inhibits production of DNA and RNA) would not have been expected to result in a decrease in platelet counts because (a) CTPS1-deficient individuals demonstrate normal platelet counts and (b) platelet formation5 does not depend directly on replication of DNA or RNA. The inventors have surprisingly found that CTPS1 inhibitors can lower blood cell countsin human subjects and therefore may be of utility in the treatment of MPN in humans.The invention provides a CTPS1 inhibitor for use in the treatment of amyeloproliferative neoplasm (MPN) in a human subject.10 The invention also provides a pharmaceutical composition comprising a CTPS1 inhibitor for use in the treatment of an MPN in a human subject. The invention also provides a pharmaceutical composition comprising a CTPS1inhibitor and a pharmaceutically acceptable excipient or carrier for use in the treatment of an MPN in a human subject. 15 The invention also provides the use of a CTPS1 inhibitor in the manufacture of a medicament for the treatment of an MPN in a human subject. The invention also provides a method for the treatment of an MPN in a human subject,the method comprising administering a CTPS1 inhibitor to the subject. The invention also provides a method for reducing the frequency of thrombosis in a20 human subject in need thereof, the method comprising administering a CTPS1 inhibitor to thesubject. The invention also provides a method for preventing increase in blood cell count in a human subject, the method comprising administering a CTPS1 inhibitor to the subject. The invention also provides a method for reducing blood cell count in a human subject,25 the method comprising administering a CTPS1 inhibitor to the subject. The invention also provides a method for maintaining blood cell count in a human subject, the method comprising administering a CTPS1 inhibitor to the subject. The invention also provides a method for controlling platelet production in a humansubject, the method comprising administering a CTPS1 inhibitor to the subject. 30 The invention also provides a method for reducing the incidence of ET to MF progression in a population of human subjects, the method comprising administering a CTPS1 inhibitor to the population. The invention also provides a method for reducing the likelihood of ET to MF progression in a human subject, the method comprising administering a CTPS1 inhibitor to the35 subject. The invention also provides a method for delaying progression of ET to MF in a humansubject, the method comprising administering a CTPS1 inhibitor to the subject. STP-P3718PCT 4 The invention also provides a method for reducing the likelihood of ET to myelodysplasia or acute myeloid leukaemia progression in a human subject, the methodcomprising administering a CTPS1 inhibitor to the subject. The invention also provides a method for reducing the incidence of ET to 5myelodysplasia or acute myeloid leukaemia progression in a population of human subjects, themethod comprising administering a CTPS1 inhibitor to the population. The invention also provides a method for delaying the rate of progression of ET tomyelodysplasia or acute myeloid leukaemia in a human subject, the method comprisingadministering a CTPS1 inhibitor to the subject. 10 Further embodiments of the invention will be apparent from the text below. Summary of the sequences SEQ ID NO: 1 FLAG-His8-tagSEQ ID NO: 2 FLAG-His-Avi tag15 Summary of the figures Fig.1: Mean change in platelets over time for cohorts 1-3 receiving CTPS1 inhibitor Fig.2: Mean change in neutrophils over time for cohorts 1-3 receiving CTPS1 inhibitor Fig. 3: Fall in platelet count vs exposure to CTPS1 inhibitor20 Fig. 4: Change in platelets over time for cohorts 1-4 receiving CTPS1 inhibitorFig. 5: Change in platelets over time for cohorts 5-8 receiving CTPS1 inhibitorDetailed description of the invention CTPS1 inhibitors 25 All proliferating cells, including neoplastic cells, are reliant on a ready source of purine and pyrimidine nucleotides for DNA and RNA synthesis. Whilst salvage pathways may be sufficient for steady state metabolism, DNA replication to enable cell division is dependent on synthesis of nucleotides via the de novo pathway. A key bottleneck in the de novo pyrimidinesynthesis pathway is the enzyme cytidine triphosphate synthase (CTPS) which catalyses the 30 conversion of UTP to CTP (van Kuilenburg 2000). CTPS has two isoforms in humans (CTPS1 and CTPS2). Both isoforms are ubiquitously expressed in normal and malignant human cells (BioGPS and EMBL-EBI Expression Atlas). Human genetic studies have identified an essential and non-redundant role for CTPS1 in the proliferation of normal immune (B and T) cells (Martin 2014, Martin 2020).35 Whilst cancer cells are dependent on CTPS activity in order to proliferate, the precise role that CTPS1 and CTPS2 play in cancer is currently not completely clear. Several CTPSinhibitors that inhibit both CTPS1 and CTPS2 have been developed for oncology indications up STP-P3718PCT 5 to phase I / II clinical trials, but were stopped due to toxicity and efficacy issues. Most of the developed inhibitors are nucleoside-analogue prodrugs (3-deazauridine (DAU), CPEC, carbodine) which are converted to the active triphosphorylated metabolite by the kinasesinvolved in pyrimidine biosynthesis: uridine / cytidine kinase, nucleoside monophosphate-kinase 5 (NMP-kinase) and nucleoside diphosphatekinase (NDP-kinase). The remaining inhibitors (acivicin, DON) are reactive analogues of glutamine, which irreversibly inhibit the glutaminase domain of CTPS. Importantly, none of the inhibitors of CTPS developed to date are selective for one isoform of CTPS over the other. As such, available CTPS inhibitors block all CTPS activity and, therefore, block the ability of all cells in the body to undergo cell division.10 A CTPS1 inhibitor, as used herein, is an agent which directly inhibits the enzymaticactivity of the CTPS1 enzyme through interaction with the enzyme. Direct inhibition of theCTPS1 enzyme may be quantified using any suitable assay procedure, though is suitablyperformed using the procedure set out in Example 1.CTPS1 inhibitors may demonstrate an IC50 of 10 uM or lower, such as 1uM or lower, 15 especially 100nM or lower, in respect of CTPS1 enzyme. CTPS1 inhibitors of particular interest are those demonstrating an IC50 of 10 uM or lower, such as 1uM or lower, especially 100nM or lower, in respect of CTPS1 enzyme using the assay procedure set out in Example 1.CTPS1 inhibitors ideally demonstrate a selectivity for CTPS1 over CTPS2 (i.e. by ratioof IC50 values). Suitably the inhibitors demonstrate a selectivity of at least 2-fold, such as at20 least 30-fold, especially at least 60-fold and in particular at least 1000-fold. CTPS1 inhibitors ofparticular interest are those demonstrating a selectivity for CTPS1 over CTPS2, suitably of at least 2-fold, such as at least 30-fold, especially at least 60-fold and in particular at least 1000-fold using the assay procedure set out in Example 2. Desirably the selectivity is for humanCTPS1 over human CTPS2. 25 In the case of medicaments intended for human use, CTPS1 inhibition and CTPS1 vs CTPS2 selectivity should be based on human forms of the enzymes. The CTPS2 gene is located on the human X chromosome and is not imprinted in humanfemales (i.e. those with XX chromosomes), as CTPS2 is expressed from each of the Xchromosomes in human female subjects. In human female subjects, CTPS2 deficiency may 30 result from genomic alteration(s) and / or epigenic change(s) in one or both XX chromosomes, suitably both XX chromosomes. A deficiency in CTPS2 function may be due to homozygous deletion arising in females or hemizygous deletion arising in males (i.e. those with XYchromosomes). STP-P3718PCT 6 Suitably the CTPS1 inhibitor may be selected from the following compounds:A compound of formula (I): wherein 5 R1 is C1-5alkyl, C0-2alkyleneC3-5cycloalkyl which cycloalkyl is optionally substituted by CH3, C1-3alkyleneOC1-2alkyl, or CF3; R3 is H, CH3, halo, OC1-2alkyl or CF3; R4 and R5 are each independently H, C1-6alkyl, C0-2alkyleneC3-6cycloalkyl, C0-2alkyleneC3- 6heterocycloalkyl, C1-3alkyleneOC1-3alkyl, C1-6alkylOH or C1-6haloalkyl, 10 or R4and R5together with the carbon atom to which they are attached form a C3-6cycloalkyl or C3-6heterocycloalkyl ring; R6is H or C1-3alkyl; Ar1 is a 6-membered aryl or heteroaryl; Ar2 is a 6-membered aryl or heteroaryl and is attached to Ar1 in the para position relative15 to the amide; R10is H, halo, C1-3alkyl, OC1-2alkyl, C1-2haloalkyl, OC1-2haloalkyl or CN; R11is H, F, Cl, CH3, ethyl, OCH3, CF3, OCF3or CN; R12is attached to Ar2 in the meta or ortho position relative to Ar1 and R12is H, halo, C1-4alkyl, C2-4alkynyl, C(=O)C1-2alkyl, C0-2alkyleneC3-5cycloalkyl, OC1-4alkyl, C1-203alkyleneOC1-3alkyl, C1-4haloalkyl, OC1-4haloalkyl, CN, OC0-2alkyleneC3-5cycloalkyl, OCH2CH2N(CH3)2, OH, C1-4alkylOH, NR23R24, SO2CH3, C(O)N(CH3)2, NHC(O)C1-3alkyl, or a C3-6heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2, or R12together with a nitrogen atom to which it is attached forms an N-oxide (N+-O- ); 25 R23is H or C1-2alkyl; R24is H or C1-2alkyl; or a pharmaceutically acceptable salt and / or pharmaceutically acceptable solvate thereof. More suitably the CTPS1 inhibitor is selected from the following (‘List A’) compounds: N-((2-(cyclopropanesulfonamido)thiazol-4-yl)methyl)-5-phenylpicolinamide; 30 N-((2-(cyclopropanesulfonamido)thiazol-4-yl)methyl)-4-(pyridin-3-yl)benzamide; N-(1-(2-(cyclopropanesulfonamido)thiazol-4-yl)propyl)-4-(5-(trifluoromethyl)pyridin-3- yl)benzamide; STP-P3718PCT 7 N-(1-(2-(cyclopropanesulfonamido)thiazol-4-yl)propyl)-4-(5-(trifluoromethyl)pyridin-3- yl)benzamide (R enantiomer); N-(1-(2-(cyclopropanesulfonamido)thiazol-4-yl)propyl)-4-(5-(trifluoromethyl)pyridin-3- yl)benzamide (S enantiomer); 5 N-(1-(2-(cyclopropanesulfonamido)thiazol-4-yl)propyl)-4-(6-(trifluoromethyl)pyrazin-2- yl)benzamide; N-(2-(2-(cyclopropanesulfonamido)thiazol-4-yl)propan-2-yl)-4-(6-ethoxypyrazin-2-yl)-2- fluorobenzamide; N-(2-(2-(cyclopropanesulfonamido)thiazol-4-yl)propan-2-yl)-4-(6-ethoxypyrazin-2-yl)-2-10 methoxybenzamide; N-((2-(cyclopropanesulfonamido)thiazol-4-yl)methyl)-[1,1'-biphenyl]-4-carboxamide; N-((2-(cyclopropanesulfonamido)thiazol-4-yl)methyl)-2-fluoro-4-(6-(trifluoromethyl)pyrazin-2- yl)benzamide; N-((2-(cyclopropanesulfonamido)thiazol-4-yl)methyl)-4-(6-ethoxypyrazin-2-yl)-2-15 fluorobenzamide; N-((2-(cyclopropanesulfonamido)thiazol-4-yl)methyl)-4-(6-(trifluoromethyl)pyrazin-2- yl)benzamide; N-((2-(cyclopropanesulfonamido)thiazol-4-yl)methyl)-4-(6-isopropoxypyrazin-2-yl)benzamide; N-((2-(cyclopropanesulfonamido)thiazol-4-yl)methyl)-4-(6-ethoxypyrazin-2-yl)benzamide; 20 N-(3-(2-(cyclopropanesulfonamido)thiazol-4-yl)pentan-3-yl)-4-(5-(trifluoromethyl)pyridin-3- yl)benzamide; N-(3-(2-(cyclopropanesulfonamido)thiazol-4-yl)pentan-3-yl)-4-(5-fluoropyridin-3-yl)benzamide; N-(3-(2-(cyclopropanesulfonamido)thiazol-4-yl)pentan-3-yl)-4-(5-methylpyridin-3-yl)benzamide; N-(3-(2-(cyclopropanesulfonamido)thiazol-4-yl)pentan-3-yl)-4-(pyridin-3-yl)benzamide; 25 N-(3-(2-(cyclopropanesulfonamido)thiazol-4-yl)pentan-3-yl)-4-(6-(trifluoromethyl)pyrazin-2- yl)benzamide; 4-(6-chloropyrazin-2-yl)-N-(3-(2-(cyclopropanesulfonamido)thiazol-4-yl)pentan-3-yl)benzamide; N-(3-(2-(cyclopropanesulfonamido)thiazol-4-yl)pentan-3-yl)-4-(6-methylpyrazin-2- yl)benzamide; 30 N-(3-(2-(cyclopropanesulfonamido)thiazol-4-yl)pentan-3-yl)-4-(pyrazin-2-yl)benzamide; N-(2-(2-(cyclopropanesulfonamido)thiazol-4-yl)propan-2-yl)-5-(6-ethoxypyrazin-2-yl)-3- fluoropicolinamide; N-(2-(2-(cyclopropanesulfonamido)thiazol-4-yl)propan-2-yl)-5-(6-(trifluoromethyl)pyrazin-2- yl)picolinamide; 35 5-(6-chloropyrazin-2-yl)-N-(2-(2-(cyclopropanesulfonamido)thiazol-4-yl)propan-2- yl)picolinamide; STP-P3718PCT 8 N-(2-(2-(cyclopropanesulfonamido)thiazol-4-yl)propan-2-yl)-5-(6-ethoxypyrazin-2- yl)picolinamide; N-(2-(2-(cyclopropanesulfonamido)thiazol-4-yl)propan-2-yl)-[2,2'-bipyridine]-5-carboxamide; 4-(5-chloropyridin-3-yl)-N-(2-(2-(cyclopropanesulfonamido)thiazol-4-yl)propan-2-yl)benzamide; 5 N-(2-(2-(cyclopropanesulfonamido)thiazol-4-yl)propan-2-yl)-2-fluoro-4-(5- (trifluoromethyl)pyridin-3-yl)benzamide; 4-(5-chloropyridin-3-yl)-N-(2-(2-(cyclopropanesulfonamido)thiazol-4-yl)propan-2-yl)-2- fluorobenzamide; N-(2-(2-(cyclopropanesulfonamido)thiazol-4-yl)propan-2-yl)-2-fluoro-4-(5-fluoropyridin-3-10 yl)benzamide; N-(2-(2-(cyclopropanesulfonamido)thiazol-4-yl)propan-2-yl)-2-methoxy-4-(5- (trifluoromethyl)pyridin-3-yl)benzamide; 4-(5-acetylpyridin-3-yl)-N-(2-(2-(cyclopropanesulfonamido)thiazol-4-yl)propan-2-yl)benzamide; N-(2-(2-(cyclopropanesulfonamido)thiazol-4-yl)propan-2-yl)-4-(5-(trifluoromethyl)pyridin-3-15 yl)benzamide; N-(2-(2-(cyclopropanesulfonamido)thiazol-4-yl)propan-2-yl)-4-(5-fluoropyridin-3-yl)benzamide; N-(2-(2-(cyclopropanesulfonamido)thiazol-4-yl)propan-2-yl)-4-(5-methylpyridin-3-yl)benzamide; N-(2-(2-(cyclopropanesulfonamido)thiazol-4-yl)propan-2-yl)-4-(5-methoxypyridin-3- yl)benzamide; 20 N-(2-(2-(cyclopropanesulfonamido)thiazol-4-yl)propan-2-yl)-4-(pyridin-3-yl)benzamide; N-(2-(2-(cyclopropanesulfonamido)thiazol-4-yl)propan-2-yl)-3'-(trifluoromethyl)-[1,1'-biphenyl]- 4-carboxamide; N-(2-(2-(cyclopropanesulfonamido)thiazol-4-yl)propan-2-yl)-4-(6-ethylpyrazin-2-yl)-2- fluorobenzamide; 25 N-(2-(2-(cyclopropanesulfonamido)thiazol-4-yl)propan-2-yl)-2-fluoro-4-(6- (trifluoromethyl)pyrazin-2-yl)benzamide; N-(2-(2-(cyclopropanesulfonamido)thiazol-4-yl)propan-2-yl)-2-fluoro-4-(6-isopropoxypyrazin-2- yl)benzamide; N-(2-(2-(cyclopropanesulfonamido)thiazol-4-yl)propan-2-yl)-2-fluoro-4-(6-(2,2,2-30 trifluoroethoxy)pyrazin-2-yl)benzamide; N-(2-(2-(cyclopropanesulfonamido)thiazol-4-yl)propan-2-yl)-2-methyl-4-(6- (trifluoromethyl)pyrazin-2-yl)benzamide; N-(2-(2-(cyclopropanesulfonamido)thiazol-4-yl)propan-2-yl)-4-(6-ethoxypyrazin-2-yl)-2- methylbenzamide; 35 N-(2-(2-(cyclopropanesulfonamido)thiazol-4-yl)propan-2-yl)-4-(6-ethoxypyrazin-2-yl)-2- (trifluoromethyl)benzamide; STP-P3718PCT 9 N-(2-(2-(cyclopropanesulfonamido)thiazol-4-yl)propan-2-yl)-2-methoxy-4-(6- (trifluoromethyl)pyrazin-2-yl)benzamide; 4-(6-chloropyrazin-2-yl)-N-(2-(2-(cyclopropanesulfonamido)thiazol-4-yl)propan-2-yl)-2- methoxybenzamide; 5 4-(6-cyanopyrazin-2-yl)-N-(2-(2-(cyclopropanesulfonamido)thiazol-4-yl)propan-2-yl)-2- methoxybenzamide; N-(2-(2-(cyclopropanesulfonamido)thiazol-4-yl)propan-2-yl)-4-(6-(trifluoromethyl)pyrazin-2- yl)benzamide; 4-(6-chloropyrazin-2-yl)-N-(2-(2-(cyclopropanesulfonamido)thiazol-4-yl)propan-2-yl)benzamide;10 N-(2-(2-(cyclopropanesulfonamido)thiazol-4-yl)propan-2-yl)-4-(6-methylpyrazin-2- yl)benzamide; N-(2-(2-(cyclopropanesulfonamido)thiazol-4-yl)propan-2-yl)-4-(6-methoxypyrazin-2- yl)benzamide; N-(2-(2-(cyclopropanesulfonamido)thiazol-4-yl)propan-2-yl)-4-(6-ethoxypyrazin-2-15 yl)benzamide; N-(2-(2-(cyclopropanesulfonamido)thiazol-4-yl)propan-2-yl)-4-(6-isopropoxypyrazin-2- yl)benzamide; N-(2-(2-(cyclopropanesulfonamido)thiazol-4-yl)propan-2-yl)-4-(6-(2,2,2-trifluoroethoxy)pyrazin- 2-yl)benzamide; 20 N-(2-(2-(cyclopropanesulfonamido)thiazol-4-yl)propan-2-yl)-4-(pyrazin-2-yl)benzamide; N-(1-(2-(cyclopropanesulfonamido)thiazol-4-yl)propyl)-4-(5-fluoropyridin-3-yl)benzamide; N-(1-(2-(cyclopropanesulfonamido)thiazol-4-yl)propyl)-4-(5-methylpyridin-3-yl)benzamide; N-(1-(2-(cyclopropanesulfonamido)thiazol-4-yl)propyl)-4-(pyridin-3-yl)benzamide; N-(1-(2-(cyclopropanesulfonamido)thiazol-4-yl)propyl)-4-(6-ethoxypyrazin-2-yl)-2-25 fluorobenzamide; N-(1-(2-(cyclopropanesulfonamido)thiazol-4-yl)propyl)-4-(6-ethoxypyrazin-2-yl)-2-fluoro-N- methylbenzamide; N-(1-(2-(cyclopropanesulfonamido)thiazol-4-yl)propyl)-2-fluoro-4-(6-isopropoxypyrazin-2- yl)benzamide; 30 4-(6-chloropyrazin-2-yl)-N-(1-(2-(cyclopropanesulfonamido)thiazol-4-yl)propyl)benzamide; N-(1-(2-(cyclopropanesulfonamido)thiazol-4-yl)propyl)-4-(6-methylpyrazin-2-yl)benzamide; N-(1-(2-(cyclopropanesulfonamido)thiazol-4-yl)propyl)-4-(pyrazin-2-yl)benzamide; N-(1-(2-(cyclopropanesulfonamido)thiazol-4-yl)propyl)-4-(5-fluoropyridin-3-yl)benzamide (R enantiomer); 35 N-(1-(2-(cyclopropanesulfonamido)thiazol-4-yl)propyl)-4-(5-fluoropyridin-3-yl)benzamide (S enantiomer); STP-P3718PCT 10 N-(1-(2-(cyclopropanesulfonamido)thiazol-4-yl)propyl)-4-(6-ethoxypyrazin-2-yl)-2- fluorobenzamide (R enantiomer); N-(1-(2-(cyclopropanesulfonamido)thiazol-4-yl)propyl)-4-(6-ethoxypyrazin-2-yl)-2- fluorobenzamide (S enantiomer); 5 N-(2-(2-(cyclopropanesulfonamido)-5-methylthiazol-4-yl)propan-2-yl)-5-(6-ethoxypyrazin-2- yl)picolinamide; N-(2-(5-chloro-2-(cyclopropanesulfonamido)thiazol-4-yl)propan-2-yl)-5-(6-ethoxypyrazin-2- yl)picolinamide; N-(2-(2-(cyclopropanesulfonamido)-5-methylthiazol-4-yl)propan-2-yl)-4-(6-ethoxypyrazin-2-yl)- 10 2-fluorobenzamide; N-(2-(5-chloro-2-(cyclopropanesulfonamido)thiazol-4-yl)propan-2-yl)-4-(6-ethoxypyrazin-2-yl)- 2-fluorobenzamide; N-(2-(2-(cyclopropanesulfonamido)-5-methylthiazol-4-yl)propan-2-yl)-2-methyl-4-(6- (trifluoromethyl)pyrazin-2-yl)benzamide; 15 N-(2-(5-chloro-2-(cyclopropanesulfonamido)thiazol-4-yl)propan-2-yl)-2-methyl-4-(6- (trifluoromethyl)pyrazin-2-yl)benzamide; N-(2-(2-(cyclopropanesulfonamido)-5-methylthiazol-4-yl)propan-2-yl)-4-(6- (trifluoromethyl)pyrazin-2-yl)benzamide; N-(2-(5-chloro-2-(cyclopropanesulfonamido)thiazol-4-yl)propan-2-yl)-4-(6- 20 (trifluoromethyl)pyrazin-2-yl)benzamide; N-(1-(2-(cyclopropanesulfonamido)thiazol-4-yl)cyclopropyl)-5-(6-ethoxypyrazin-2- yl)picolinamide; N-(1-(2-(cyclopropanesulfonamido)thiazol-4-yl)cyclopropyl)-4-(pyridin-3-yl)benzamide; N-(1-(2-(cyclopropanesulfonamido)thiazol-4-yl)cyclopropyl)-4-(6-ethoxypyrazin-2-yl)-2- 25 fluorobenzamide; N-(1-(2-(cyclopropanesulfonamido)thiazol-4-yl)cyclopropyl)-2-methyl-4-(6- (trifluoromethyl)pyrazin-2-yl)benzamide; N-(1-(2-(cyclopropanesulfonamido)thiazol-4-yl)cyclopropyl)-4-(6-(trifluoromethyl)pyrazin-2- yl)benzamide; 30 N-(1-(2-(cyclopropanesulfonamido)thiazol-4-yl)-3-methoxypropyl)-4-(5-fluoropyridin-3- yl)benzamide; N-(1-(2-(cyclopropanesulfonamido)thiazol-4-yl)-3-methoxypropyl)-4-(6-ethylpyrazin-2-yl)-2- fluorobenzamide; N-(1-(2-(cyclopropanesulfonamido)thiazol-4-yl)-3-methoxypropyl)-2-fluoro-4-(6- 35 (trifluoromethyl)pyrazin-2-yl)benzamide; N-(1-(2-(cyclopropanesulfonamido)thiazol-4-yl)-3-methoxypropyl)-4-(6-ethoxypyrazin-2-yl)-2- fluorobenzamide; STP-P3718PCT 11 N-(1-(2-(cyclopropanesulfonamido)thiazol-4-yl)-3-methoxypropyl)-2-fluoro-4-(6- isopropoxypyrazin-2-yl)benzamide; N-(1-(2-(cyclopropanesulfonamido)thiazol-4-yl)-3-methoxypropyl)-4-(6-ethoxypyrazin-2- yl)benzamide; 5 N-(1-(2-(cyclopropanesulfonamido)thiazol-4-yl)ethyl)-4-(6-ethoxypyrazin-2-yl)-2- fluorobenzamide; N-(1-(2-(cyclopropanesulfonamido)thiazol-4-yl)-3-methoxypropyl)-4-(6-ethoxypyrazin-2-yl)-2- fluorobenzamide (R enantiomer); and N-(1-(2-(cyclopropanesulfonamido)thiazol-4-yl)-3-methoxypropyl)-4-(6-ethoxypyrazin-2-yl)-2-10 fluorobenzamide (S enantiomer); or a pharmaceutically acceptable salt and / or pharmaceutically acceptable solvate thereof. Such CTPS1 inhibitors are disclosed in PCT publication number WO2019106146 which is incorporated by reference in its entirety for the purpose of the CTPS1 inhibitors disclosed therein. In particular a CTPS1 inhibitor may be a compound described in any one of clauses 1 15 to 110 of WO2019106146 or a pharmaceutically acceptable salt and / or pharmaceutically acceptable solvate thereof, in particular a compound R1 to R93 or a pharmaceutically acceptable salt and / or pharmaceutically acceptable solvate thereof. Alternatively, the CTPS1 inhibitor is compound of formula (II): 20 wherein R1is C1-5alkyl, C0-2alkyleneC3-5cycloalkyl which cycloalkyl is optionally substituted by CH3, C1-3alkyleneOC1-2alkyl, or CF3; R3is H, halo, CH3, OC1-2alkyl or CF3; or R3 together with R5 forms a 5- or 6-membered cycloalkyl or 5 or 6 membered25 oxygen-containing heterocycloalkyl; R4and R5are each independently H, halo, C1-6alkyl, C0-2alkyleneC3-6cycloalkyl, C0-2alkyleneC3-6heterocycloalkyl, OC1-6alkyl, OC0-2alkyleneC3-6cycloalkyl, C1-3alkyleneOC1- 3alkyl, C1-6alkylOH, C1-6haloalkyl, OC1-6haloalkyl or NR21R22, or R4 is H and R5 together with R3 form a 5- or 6-membered cycloalkyl or 5 or 630 membered oxygen-containing heterocycloalkyl, or R4and R5together with the carbon atom to which they are attached form a C3-6cycloalkyl or C3-6heterocycloalkyl, STP-P3718PCT 12 or R4 is H and R5 and R6 are a C2-3alkylene chain forming a 5- or 6-memberedring; or R4is O and R5is absent; R6 is H or C1-3alkyl, 5 or R6 together with R11 when in the ortho-position to the amide are a C2alkylene chain forming a 5-membered ring, or R5 and R6 are a C2-3alkylene chain forming a 5- or 6-membered ring and R4 isH; Ar1 is 6-membered aryl or heteroaryl; 10 Ar2 is a 6-membered aryl or heteroaryl and is attached to Ar1 in the para position relative to the amide; R10 is H, halo, C1-3alkyl, OC1-2alkyl, C1-2haloalkyl, OC1-2haloalkyl or CN; R11 is H, F, Cl, CH3, ethyl, OCH3, CF3, OCF3 or CN, or R11, when in the ortho-position to the amide, together with R6 are a C2alkylene15 chain forming a 5-membered ring; R12 is attached to Ar2 in the ortho or meta position relative to Ar1 and R12 is H, halo, C1- 4alkyl, C2-4alkynyl, C0-2alkyleneC3-5cycloalkyl, OC1-4alkyl, OC0-2alkyleneC3-5cycloalkyl, OCH2CH2N(CH3)2, OH, C1-4alkylOH, CN, C1-3alkyleneOC1-3alkyl, C1-4haloalkyl, OC1- 4haloalkyl, C(=O)C1-2alkyl, NR23R24, SO2C1-4alkyl, SOC1-4alkyl, SC1-4alkyl, SH, 20 C(O)N(CH3)2, NHC(O)C1-3alkyl, C3-6heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2, or R12 together with a nitrogen atom to which it is attached forms an N-oxide (N+-O-); R13 is H, halo, CH3 or OCH3; R21is H, C1-5alkyl, C(O)C1-5alkyl, C(O)OC1-5alkyl; 25 R22is H or CH3; R23is H or C1-2alkyl; and R24is H or C1-2alkyl; or a pharmaceutically acceptable salt and / or pharmaceutically acceptable solvate thereof. More suitably the CTPS1 inhibitor is selected from the following (‘List B’) compounds:30 N-([1,1'-biphenyl]-4-yl)-2-(2-(methylsulfonamido)thiazol-4-yl)acetamide; N-([1,1'-biphenyl]-4-yl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)acetamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-ethyl-N-(5-(pyrazin-2-yl)pyridin-2-yl)butanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(4-(pyrimidin-2- yl)phenyl)propanamide; 35 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(pyridin-3-yl)phenyl)butanamide (racemic); (R)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(pyridin-3-yl)phenyl)butanamide; (S)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(pyridin-3-yl)phenyl)butanamide; STP-P3718PCT 13 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(5-fluoropyridin-3-yl)phenyl)butanamide (racemic); (R)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(5-fluoropyridin-3-yl)phenyl)butanamide; (S)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(5-fluoropyridin-3-yl)phenyl)butanamide; 5 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-3-methyl-N-(4-(pyrimidin-5-yl)phenyl)butanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-3-methyl-N-(4-(pyridin-3-yl)phenyl)butanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(5-methoxypyridin-3-yl)phenyl)-2- methylpropanamide; N-(2-chloro-4-(pyridin-3-yl)phenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)acetamide;10 2-(2-(cyclopropanesulfonamido)-5-methylthiazol-4-yl)-2-methyl-N-(4-(6-(trifluoromethyl)pyrazin- 2-yl)phenyl)propanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(4-(pyrimidin-5- yl)phenyl)propanamide; 6-(4-(2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methylpropanamido)phenyl)-N,N-15 dimethylpyrazine-2-carboxamide; N-(5-(5-cyanopyridin-3-yl)pyrimidin-2-yl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2- methylpropanamide; N-([1,1'-biphenyl]-4-yl)-2-(5-chloro-2-(cyclopropanesulfonamido)thiazol-4-yl)acetamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-ethynylpyrazin-2-yl)phenyl)butanamide;20 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(6-(pyrimidin-5-yl)pyridin-3-yl)acetamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(5-phenylpyridin-2-yl)acetamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4'-fluoro-[1,1'-biphenyl]-4-yl)acetamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-methyl-N-(4-(pyridin-3-yl)phenyl)acetamide; N-([2,3'-bipyridin]-5-yl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)propanamide; 25 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(3'-methoxy-[1,1'-biphenyl]-4-yl)-2- methylpropanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(4-(pyridin-3-yl)phenyl)propanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(4-(5-methylpyridin-3- yl)phenyl)propanamide; 30 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(4-(pyridazin-4- yl)phenyl)propanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(4-(pyrazin-2-yl)phenyl)propanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-methoxypyrazin-2-yl)phenyl)butanamide; N-(3-cyano-4-(pyrazin-2-yl)phenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-35 methylpropanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(5-(6-(trifluoromethyl)pyrazin-2- yl)pyridin-2-yl)propanamide; STP-P3718PCT 14 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(2,3-difluoro-4-(pyridin-3-yl)phenyl)-2- methylpropanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(5-(pyridin-3-yl)pyrimidin-2- yl)propanamide; 5 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(5-(6-propoxypyrazin-2-yl)pyridin-2- yl)propanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(3-fluoro-4-(pyrazin-2-yl)phenyl)-2- methylpropanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(4-(pyridin-3-yl)-2- 10 (trifluoromethoxy)phenyl)propanamide; N-(2-chloro-4-(pyridin-3-yl)phenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2- methylpropanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(2-fluoro-4-(pyridin-3-yl)phenyl)-2- methylpropanamide ; 15 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(3-methoxy-4-(pyrazin-2-yl)phenyl)-2- methylpropanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(2-methoxypyridin-3-yl)phenyl)-2- methylpropanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(5-(hydroxymethyl)pyridin-3-20 yl)phenyl)acetamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-methoxypyridin-3-yl)phenyl)-2- methylpropanamide; N-(4-(5-cyanopyridin-3-yl)phenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2- methylpropanamide; 25 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(4-(5-(trifluoromethyl)pyridin-3- yl)phenyl)propanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(4-(5-(methylsulfonyl)pyridin-3- yl)phenyl)propanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(2-methoxy-4-(5-methoxypyridin-3-yl)phenyl)-2- 30 methylpropanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(5'-(trifluoromethyl)-[3,3'-bipyridin]-6- yl)propanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2- methylpropanamide; 35 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(4-(6-morpholinopyrazin-2- yl)phenyl)propanamide; STP-P3718PCT 15 N-(4-(6-cyclobutoxypyrazin-2-yl)phenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2- methylpropanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(4-(6-propoxypyrazin-2- yl)phenyl)propanamide; 5 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(2-fluoro-4-(5-methoxypyridin-3-yl)phenyl)-2- methylpropanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methoxy-N-(4-(6-methoxypyrazin-2- yl)phenyl)acetamide; N-(4-(5-chloropyridin-3-yl)phenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-10 isopropoxyacetamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-4-methoxy-N-(5-(6-(trifluoromethyl)pyrazin-2- yl)pyridin-2-yl)butanamide; N-([1,1'-biphenyl]-4-yl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2,2-difluoroacetamide; 2-(2-(cyclobutanesulfonamido)thiazol-4-yl)-N-(4-(6-methoxypyrazin-2-yl)phenyl)acetamide;15 N-([3,3'-bipyridin]-6-yl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)butanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(5-phenylpyridin-2-yl)propanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(5-(pyrimidin-5-yl)pyridin-2-yl)acetamide; N-([3,3'-bipyridin]-6-yl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)acetamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(6-phenylpyridin-3-yl)acetamide; 20 N-([2,3'-bipyridin]-5-yl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)acetamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(4-(pyridazin-3- yl)phenyl)propanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(pyridazin-4-yl)phenyl)butanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(pyrazin-2-yl)phenyl)butanamide; 25 N-(4-(5-chloropyridin-3-yl)phenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-4- methoxybutanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(5-fluoropyridin-3-yl)phenyl)butanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-(trifluoromethyl)pyrazin-2- yl)phenyl)butanamide; 30 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-3-methyl-N-(4-(pyrazin-2-yl)phenyl)butanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-propoxypyrazin-2-yl)phenyl)butanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-isopropoxypyrazin-2- yl)phenyl)butanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-cyclopropoxypyrazin-2-35 yl)phenyl)butanamide; N-(4-(6-chloropyrazin-2-yl)phenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)butanamide; N-(4-(6-cyanopyrazin-2-yl)phenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)butanamide; STP-P3718PCT 16 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-(trifluoromethyl)pyrazin-2- yl)phenyl)butanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-methoxypyrazin-2-yl)phenyl)acetamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(pyrazin-2-yl)phenyl)acetamide; 5 N-([1,1'-biphenyl]-4-yl)-2-(cyclopropanesulfonamido)-4,5,6,7-tetrahydrobenzo[d]thiazole-4- carboxamide; 2-(cyclopropanesulfonamido)-N-(4-(pyridin-3-yl)phenyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-4- carboxamide; N-([1,1'-biphenyl]-4-yl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)butanamide; 10 N-([1,1'-biphenyl]-4-yl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-3-methylbutanamide; N-(3'-chloro-[1,1'-biphenyl]-4-yl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2- methylpropanamide; N-(3'-cyano-[1,1'-biphenyl]-4-yl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2- methylpropanamide; 15 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2,2-difluoro-N-(4-(pyridin-3-yl)phenyl)acetamide; N-(4-(5-fluoropyridin-3-yl)phenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)butanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-ethyl-N-(4-(pyridin-3-yl)phenyl)butanamide; N-(4-(5-cyanopyridin-3-yl)phenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2- ethylbutanamide; 20 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(5-ethoxypyridin-3-yl)phenyl)propanamide; N-(4-(5-chloropyridin-3-yl)phenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)propanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(5-ethoxypyridin-3-yl)phenyl)butanamide; N-([1,1'-biphenyl]-4-yl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(4-methylpyridin-3-yl)phenyl)acetamide;25 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(5-methylpyridin-3-yl)phenyl)acetamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(2-methylpyridin-3-yl)phenyl)acetamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-methylpyridin-3-yl)phenyl)acetamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(pyridin-3-yl)phenyl)propanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(4-(2-methylpyridin-3-30 yl)phenyl)propanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-oxo-N-(4-(pyridin-3-yl)phenyl)acetamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(4-(6-methylpyridin-3- yl)phenyl)propanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-(trifluoromethyl)pyrazin-2-35 yl)phenyl)butanamide; (R)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methoxy-N-(4-(6-methoxypyrazin-2- yl)phenyl)acetamide; STP-P3718PCT 17 (S)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methoxy-N-(4-(6-methoxypyrazin-2- yl)phenyl)acetamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(5-(6-(2,2,2-trifluoroethoxy)pyrazin-2- yl)pyridin-2-yl)propanamide; 5 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(3-fluoro-5-(pyrazin-2-yl)pyridin-2-yl)-2- methylpropanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)-3-fluoropyridin-2-yl)-2- methylpropanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(3-fluoro-5-(6-(trifluoromethyl)pyrazin-2-10 yl)pyridin-2-yl)-2-methylpropanamide; N-(5-(6-cyanopyrazin-2-yl)-3-fluoropyridin-2-yl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2- methylpropanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(5'-(2,2,2-trifluoroethoxy)-[3,3'- bipyridin]-6-yl)propanamide; 15 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(5'-(difluoromethoxy)-[3,3'-bipyridin]-6-yl)-2- methylpropanamide; N-([2,3'-bipyridin]-5-yl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(6-(pyrimidin-5-yl)pyridin-3- yl)propanamide; 20 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(5-(difluoromethoxy)pyridin-3-yl)phenyl)-2- methylpropanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-ethyl-N-(4-(6-methoxypyrazin-2- yl)phenyl)butanamide; N-(4-(5-chloropyridin-3-yl)phenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-25 ethylbutanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-ethyl-N-(2-fluoro-4-(pyridin-3- yl)phenyl)butanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-ethyl-N-(4-(pyrazin-2-yl)phenyl)butanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-ethyl-N-(4-(6-propoxypyrazin-2-30 yl)phenyl)butanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(2-fluoro-4-(6-(trifluoromethyl)pyrazin-2- yl)phenyl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(5-ethoxypyridin-3-yl)-2-fluorophenyl)-2- methylpropanamide; 35 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(2-fluoro-4-(5-fluoropyridin-3-yl)phenyl)-2- methylpropanamide; STP-P3718PCT 18 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(4-(6-(2,2,2-trifluoroethoxy)pyrazin-2- yl)phenyl)propanamide; N-(4-(5-chloropyridin-3-yl)-2-fluorophenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2- methylpropanamide; 5 N-(4-(5-cyanopyridin-3-yl)-2-fluorophenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2- methylpropanamide; 1-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-methoxypyrazin-2-yl)phenyl)cyclopentane- 1-carboxamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(2-fluoro-4-(6-(2,2,2-trifluoroethoxy)pyrazin-2-10 yl)phenyl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(2-fluoro-4-(5-(2,2,2-trifluoroethoxy)pyridin-3- yl)phenyl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(2-fluoro-4-(5-(trifluoromethyl)pyridin-3- yl)phenyl)-2-methylpropanamide; 15 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)-2- methylpropanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(4-(5-(2,2,2-trifluoroethoxy)pyridin-3- yl)phenyl)propanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-ethynylpyrazin-2-yl)phenyl)-2-20 methylpropanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-methylphenyl)-2- methylpropanamide; N-(4-(6-chloropyrazin-2-yl)-2-methylphenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2- methylpropanamide; 25 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(5-(difluoromethoxy)pyridin-3-yl)-2- fluorophenyl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(5-(pyrazin-2-yl)pyridin-2- yl)propanamide; N-(5-(6-cyclobutoxypyrazin-2-yl)pyridin-2-yl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2- 30 methylpropanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(5-(6-cyclopropoxypyrazin-2-yl)pyridin-2-yl)-2- methylpropanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(5-(6-isopropoxypyrazin-2-yl)pyridin-2-yl)-2- methylpropanamide; 35 N-([3,3'-bipyridin]-6-yl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-ethylbutanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(5'-ethoxy-[3,3'-bipyridin]-6-yl)-2- ethylbutanamide; STP-P3718PCT 19 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(5'-propoxy-[3,3'-bipyridin]-6- yl)propanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-ethyl-N-(5-(6-(trifluoromethyl)pyrazin-2- yl)pyridin-2-yl)butanamide; 5 N-([3,3'-bipyridin]-6-yl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(2-methoxy-4-(pyridin-3-yl)phenyl)-2- methylpropanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(3-methoxy-4-(pyridin-3-yl)phenyl)-2- methylpropanamide; 10 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(3-fluoro-4-(pyridin-3-yl)phenyl)-2- methylpropanamide; N-(3-cyano-4-(pyridin-3-yl)phenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2- methylpropanamide; N-(3-chloro-4-(pyridin-3-yl)phenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-15 methylpropanamide; N-(4-(6-cyanopyrazin-2-yl)phenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2- methylpropanamide; N-(4-(6-chloropyrazin-2-yl)phenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2- methylpropanamide; 20 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-ethyl-N-(4-(5-fluoropyridin-3- yl)phenyl)butanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(4-(5-propoxypyridin-3- yl)phenyl)propanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(5-isopropoxypyridin-3-yl)phenyl)-2-25 methylpropanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(2-fluoro-4-(5-isopropoxypyridin-3-yl)phenyl)-2- methylpropanamide; N-(4-(6-chloropyrazin-2-yl)phenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2- ethylbutanamide; 30 N-(4-(6-cyanopyrazin-2-yl)phenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2- ethylbutanamide; 2-methyl-2-(2-(methylsulfonamido)thiazol-4-yl)-N-(4-(pyridin-3-yl)phenyl)propanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N,2-dimethyl-N-(4-(pyridin-3- yl)phenyl)propanamide; 35 2-(cyclopropanesulfonamido)-N-(5-(6-(trifluoromethyl)pyrazin-2-yl)pyridin-2-yl)-5,6-dihydro-4H- cyclopenta[d]thiazole-4-carboxamide; STP-P3718PCT 20 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-4-methoxy-N-(5-(pyrazin-2-yl)pyridin-2- yl)butanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-4-methoxy-N-(5'-methoxy-[3,3'-bipyridin]-6- yl)butanamide; 5 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-isopropoxy-N-(5-(6-(trifluoromethyl)pyrazin-2- yl)pyridin-2-yl)acetamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(5-(6-propoxypyrazin-2-yl)pyridin-2- yl)butanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(5-(6-isopropoxypyrazin-2-yl)pyridin-2-10 yl)butanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(5-(6-(trifluoromethyl)pyrazin-2-yl)pyridin-2- yl)butanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(5-(6-methoxypyrazin-2-yl)pyridin-2- yl)butanamide; 15 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2- yl)butanamide; N-(5-(6-cyanopyrazin-2-yl)pyridin-2-yl)-2-(2-(cyclopropanesulfonamido)thiazol-4- yl)butanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(5'-fluoro-[3,3'-bipyridin]-6-yl)butanamide;20 N-(5'-cyano-[3,3'-bipyridin]-6-yl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)butanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(5-phenylpyridin-2-yl)butanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(5-(6-(2,2,2-trifluoroethoxy)pyrazin-2-yl)pyridin- 2-yl)butanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)-3-fluoropyridin-2-25 yl)butanamide; N-(5-(6-cyanopyrazin-2-yl)-3-fluoropyridin-2-yl)-2-(2-(cyclopropanesulfonamido)thiazol-4- yl)butanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(5'-(2,2,2-trifluoroethoxy)-[3,3'-bipyridin]-6- yl)butanamide; 30 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(5'-(difluoromethoxy)-[3,3'-bipyridin]-6- yl)butanamide; N-(5-(6-chloropyrazin-2-yl)pyridin-2-yl)-2-(2-(cyclopropanesulfonamido)thiazol-4- yl)butanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(2,3-difluoro-4-(pyridin-3-yl)phenyl)acetamide; 35 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)butanamide (racemic); STP-P3718PCT 21 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-4-methoxy-N-(4-(6-methoxypyrazin-2- yl)phenyl)butanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(5-fluoropyridin-3-yl)phenyl)-4- methoxybutanamide; 5 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)propanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(5-(trifluoromethyl)pyridin-3- yl)phenyl)butanamide; N-(4-(5-cyanopyridin-3-yl)phenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)butanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-(2,2,2-trifluoroethoxy)pyrazin-2-10 yl)phenyl)butanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(2-fluoro-4-(pyrazin-2-yl)phenyl)butanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(2-fluoro-4-(6-(trifluoromethyl)pyrazin-2- yl)phenyl)butanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-15 fluorophenyl)butanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(5-ethoxypyridin-3-yl)-2- fluorophenyl)butanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(2-fluoro-4-(5-fluoropyridin-3- yl)phenyl)butanamide; 20 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(2-fluoro-4-(pyridin-3-yl)phenyl)butanamide; N-(4-(5-cyanopyridin-3-yl)-2-fluorophenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4- yl)butanamide; N-(4-(5-chloropyridin-3-yl)-2-fluorophenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4- yl)butanamide; 25 (R)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-ethoxypyrazin-2- yl)phenyl)butanamide; (S)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-ethoxypyrazin-2- yl)phenyl)butanamide; N-(4-(1-(5-(6-ethoxypyrazin-2-yl)indolin-1-yl)-1-oxobutan-2-yl)thiazol-2-30 yl)cyclopropanesulfonamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(2-fluoro-4-(6-(2,2,2-trifluoroethoxy)pyrazin-2- yl)phenyl)butanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(2-fluoro-4-(6-methoxypyrazin-2- yl)phenyl)butanamide; 35 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(5-(difluoromethoxy)pyridin-3-yl)-2- fluorophenyl)butanamide; STP-P3718PCT 22 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(5-(difluoromethoxy)pyridin-3- yl)phenyl)butanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(5-(2,2,2-trifluoroethoxy)pyridin-3- yl)phenyl)butanamide; 5 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(2-fluoro-4-(5-(2,2,2-trifluoroethoxy)pyridin-3- yl)phenyl)butanamide; 2-(cyclopropanesulfonamido)-N-(4-(pyridin-3-yl)phenyl)-5,6-dihydro-4H-cyclopenta[d]thiazole- 4-carboxamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methoxy-N-(5-(6-(trifluoromethyl)pyrazin-2-10 yl)pyridin-2-yl)acetamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(2-methoxy-4-(pyridin-3-yl)phenyl)acetamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(2-fluoro-4-(pyridin-3-yl)phenyl)acetamide; N-(4-(5-cyanopyridin-3-yl)phenyl)-2-(cyclopropanesulfonamido)-5,6-dihydro-4H- cyclopenta[d]thiazole-4-carboxamide; 15 2-(cyclopropanesulfonamido)-N-(4-(5-fluoropyridin-3-yl)phenyl)-5,6-dihydro-4H- cyclopenta[d]thiazole-4-carboxamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methoxy-N-(4-(pyridin-3-yl)phenyl)acetamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(2-fluoro-4-(pyridin-3-yl)phenyl)-2- methoxyacetamide; 20 N-(2-chloro-4-(pyridin-3-yl)phenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)butanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-(2,2,2-trifluoroethoxy)pyrazin-2- yl)phenyl)butanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-(2,2,2-trifluoroethoxy)pyrazin-2- yl)phenyl)butanamide; 25 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(5'-methoxy-[3,3'-bipyridin]-6-yl)-2- methylpropanamide; N-(5'-chloro-[3,3'-bipyridin]-6-yl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2- methylpropanamide; N-(5'-cyano-[3,3'-bipyridin]-6-yl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-30 methylpropanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(5-fluoro-[3,3'-bipyridin]-6-yl)-2- methylpropanamide; N-(5'-cyano-5-fluoro-[3,3'-bipyridin]-6-yl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2- methylpropanamide; 35 N-(5'-chloro-5-fluoro-[3,3'-bipyridin]-6-yl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2- methylpropanamide; STP-P3718PCT 23 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(5,5'-difluoro-[3,3'-bipyridin]-6-yl)-2- methylpropanamide; N-(5-(3-chloro-5-methylphenyl)pyridin-2-yl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2- methylpropanamide; 5 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(5-(3-methoxyphenyl)pyridin-2-yl)-2- methylpropanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(5-(3-fluoro-5-methoxyphenyl)pyridin-2-yl)-2- methylpropanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(5-(3,5-dimethoxyphenyl)pyridin-2-yl)-2-10 methylpropanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(5-(3-(trifluoromethyl)phenyl)pyridin-2- yl)propanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(5-(3-(trifluoromethoxy)phenyl)pyridin- 2-yl)propanamide; 15 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(5-(3-(2-hydroxypropan-2-yl)phenyl)pyridin-2- yl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(5-(3-morpholinophenyl)pyridin-2- yl)propanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(6-phenylpyridin-3-yl)propanamide;20 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(2-fluoropyridin-3-yl)phenyl)-2- methylpropanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(5-(hydroxymethyl)pyridin-3-yl)phenyl)-2- methylpropanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(2-methoxypyrimidin-5-yl)phenyl)acetamide;25 N-(4'-(tert-butyl)-[1,1'-biphenyl]-4-yl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)acetamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(pyridin-3-yl)phenyl)acetamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(pyridin-4-yl)phenyl)acetamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(2'-methoxy-[1,1'-biphenyl]-4-yl)acetamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(pyrimidin-5-yl)phenyl)acetamide; 30 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(4-(2-(trifluoromethyl)pyridin-3- yl)phenyl)propanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(5'-methyl-[3,3'-bipyridin]-6- yl)propanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(2-methoxy-4-methylpyridin-3-yl)phenyl)-2- 35 methylpropanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-methoxy-5-methylpyridin-3-yl)phenyl)-2- methylpropanamide; STP-P3718PCT 24 N-(4-(5-chloropyridin-3-yl)phenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2- methylpropanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(5-fluoropyridin-3-yl)phenyl)-2- methylpropanamide; 5 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(4-(4-methylpyridin-3- yl)phenyl)propanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(4-(4-(trifluoromethyl)pyridin-3- yl)phenyl)propanamide; N-(4-(5-chloropyridin-3-yl)-2-methoxyphenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2- 10 methylpropanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(5-(dimethylamino)pyridin-3-yl)phenyl)-2- methylpropanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(2-methoxy-4-(5-methylpyridin-3-yl)phenyl)-2- methylpropanamide; 15 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(2-methoxy-4-(5-(trifluoromethyl)pyridin-3- yl)phenyl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-methoxypyridin-3-yl)phenyl)acetamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(5'-fluoro-[3,3'-bipyridin]-6-yl)-2- methylpropanamide; 20 N-(5-(6-chloropyrazin-2-yl)pyridin-2-yl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2- methylpropanamide; N-(5-(6-cyanopyrazin-2-yl)pyridin-2-yl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2- methylpropanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(5-(pyrimidin-5-yl)pyridin-2-25 yl)propanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-methoxypyrazin-2-yl)phenyl)-2- methylpropanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(4-(6-methylpyrazin-2- yl)phenyl)propanamide; 30 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(4-(6-(trifluoromethyl)pyrazin-2- yl)phenyl)propanamide; N-(4-(6-chloropyridin-2-yl)phenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2- methylpropanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-methoxypyridin-2-yl)phenyl)-2-35 methylpropanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(4-(6-(trifluoromethyl)pyridin-2- yl)phenyl)propanamide; STP-P3718PCT 25 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(4-methoxypyridin-2-yl)phenyl)-2- methylpropanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-isopropoxypyrazin-2-yl)phenyl)-2- methylpropanamide; 5 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-cyclopropoxypyrazin-2-yl)phenyl)-2- methylpropanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(2-fluoro-4-(pyrazin-2-yl)phenyl)-2- methylpropanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(2-fluoro-4-(6-methoxypyrazin-2-yl)phenyl)-2-10 methylpropanamide; N-(4-(6-chloro-3-methylpyrazin-2-yl)phenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2- methylpropanamide; N-(4-(6-chloro-5-methylpyrazin-2-yl)phenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2- methylpropanamide; 15 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(4-(6-(pyrrolidin-1-yl)pyrazin-2- yl)phenyl)propanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-(2-(dimethylamino)ethoxy)pyrazin-2- yl)phenyl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(4-(3-methylpyrazin-2-20 yl)phenyl)propanamide; N-(4-(6-acetamidopyrazin-2-yl)phenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2- methylpropanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(5,6-dimethylpyrazin-2-yl)phenyl)-2- methylpropanamide; 25 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-(hydroxymethyl)pyrazin-2-yl)phenyl)-2- methylpropanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(3,6-dimethylpyrazin-2-yl)phenyl)-2- methylpropanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(5-methoxypyridin-3-yl)-2-methylphenyl)-2-30 methylpropanamide; N-(4-(5-cyanopyridin-3-yl)-2-methylphenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2- methylpropanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(5-fluoropyridin-3-yl)-2-methylphenyl)-2- methylpropanamide; 35 N-(4-(5-chloropyridin-3-yl)-3-methylphenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2- methylpropanamide; STP-P3718PCT 26 N-(4-(5-cyanopyridin-3-yl)-3-ethoxyphenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2- methylpropanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(5-ethoxypyridin-3-yl)phenyl)-2- methylpropanamide; 5 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-cyclopropylpyrazin-2- yl)phenyl)butanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(5-(5-methoxypyridin-3-yl)pyrimidin-2-yl)-2- methylpropanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(5-(5-fluoropyridin-3-yl)pyrimidin-2-yl)-2-10 methylpropanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(5-(5-(trifluoromethyl)pyridin-3- yl)pyrimidin-2-yl)propanamide; N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2-methyl-2-(2-((2-methylpropyl)sulfonamido)thiazol-4- yl)propanamide; 15 N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2-methyl-2-(2-((trifluoromethyl)sulfonamido)thiazol-4- yl)propanamide; 2-methyl-2-(2-((1-methylethyl)sulfonamido)thiazol-4-yl)-N-(4-(pyridin-3-yl)phenyl)propanamide; N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2-methyl-2-(2-((1-methylethyl)sulfonamido)thiazol-4- yl)propanamide; 20 2-methyl-2-(2-((1-methylcyclopropane)-1-sulfonamido)thiazol-4-yl)-N-(4-(pyridin-3- yl)phenyl)propanamide; N-(4-(5-chloropyridin-3-yl)phenyl)-2-methyl-2-(2-((1-methylcyclopropane)-1- sulfonamido)thiazol-4-yl)propanamide; N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2-methyl-2-(2-((1-methylcyclopropane)-1-25 sulfonamido)thiazol-4-yl)propanamide; 2-methyl-2-(2-((1-methylcyclopropane)-1-sulfonamido)thiazol-4-yl)-N-(4-(6- (trifluoromethyl)pyrazin-2-yl)phenyl)propanamide; 2-(2-((1,1-dimethylethyl)sulfonamido)thiazol-4-yl)-2-methyl-N-(4-(pyridin-3- yl)phenyl)propanamide; 30 2-(2-((1,1-dimethylethyl)sulfonamido)thiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2- methylpropanamide; 2-(2-((1,1-dimethylethyl)sulfonamido)thiazol-4-yl)-2-methyl-N-(4-(6-(trifluoromethyl)pyrazin-2- yl)phenyl)propanamide; 2-(2-(cyclobutanesulfonamido)thiazol-4-yl)-2-methyl-N-(4-(pyridin-3-yl)phenyl)propanamide;35 2-(2-(cyclobutanesulfonamido)thiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2- methylpropanamide; STP-P3718PCT 27 2-(2-(cyclobutanesulfonamido)thiazol-4-yl)-2-methyl-N-(4-(6-(trifluoromethyl)pyrazin-2- yl)phenyl)propanamide; N-(4-(5-cyanopyridin-3-yl)phenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N,2- dimethylpropanamide; 5 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N,2-dimethyl-N-(4-(6-(trifluoromethyl)pyrazin-2- yl)phenyl)propanamide; 2-methyl-2-(2-((2-methylpropyl)sulfonamido)thiazol-4-yl)-N-(4-(pyridin-3- yl)phenyl)propanamide; N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2-methyl-2-(2-((2-methylpropyl)sulfonamido)thiazol-4-10 yl)propanamide; 2-methyl-2-(2-((2-methylpropyl)sulfonamido)thiazol-4-yl)-N-(4-(6-(trifluoromethyl)pyrazin-2- yl)phenyl)propanamide; N-(4-(5-chloropyridin-3-yl)phenyl)-2-(2-(cyclopropanesulfonamido)-5-methylthiazol-4-yl)-2- methylpropanamide; 15 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-methyl-N-(4-(pyridin-3-yl)phenyl)butanamide; N-(4-(5-cyanopyridin-3-yl)phenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N- methylbutanamide; 2-(2-(cyclopropanesulfonamido)-5-methylthiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2- methylpropanamide; 20 N-(4-(5-chloropyridin-3-yl)phenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N,2- dimethylpropanamide; 2-(2-(cyclopropanesulfonamido)-5-methylthiazol-4-yl)-2-methyl-N-(4-(pyridin-3- yl)phenyl)propanamide; N-(4-(5-cyanopyridin-3-yl)-2,6-dimethylphenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-25 methylpropanamide; N-(4-(5-chloropyridin-3-yl)-2,6-dimethylphenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2- methylpropanamide; N-(4-(5-cyanopyridin-3-yl)-3-methylphenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2- methylpropanamide; 30 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(pyridin-3-yl)phenyl)butanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(5-fluoropyridin-3-yl)phenyl)butanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methoxy-N-(4-(6-methoxypyrazin-2- yl)phenyl)acetamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)butanamide;35 2-amino-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-ethoxypyrazin-2- yl)phenyl)acetamide; STP-P3718PCT 28 2-acetamido-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-ethoxypyrazin-2- yl)phenyl)acetamide; methyl(1-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-((4-(6-ethoxypyrazin-2-yl)phenyl) amino)- 2-oxoethyl)carbamate; 5 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-(dimethylamino)-N-(4-(6-ethoxypyrazin-2- yl)phenyl)acetamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-4- hydroxybutanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2- 10 methoxyacetamide; (R)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2- methoxyacetamide; (S)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2- methoxyacetamide; 15 2-(2-((2-methoxyethyl)sulfonamido)thiazol-4-yl)-2-methyl-N-(5-(6-(trifluoromethyl)pyrazin-2- yl)pyridin-2-yl)propanamide; 2-(2-(cyclopentanesulfonamido)thiazol-4-yl)-2-methyl-N-(4-(pyridin-3-yl)phenyl)propanamide; 2-(2-(cyclopentanesulfonamido)thiazol-4-yl)-2-methyl-N-(4-(6-(trifluoromethyl)pyrazin-2- yl)phenyl)propanamide; 20 2-(2-(cyclopentanesulfonamido)thiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2- methylpropanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(5-(6-isopropylpyrazin-2-yl)pyridin-2-yl)-2- methylpropanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(5'-ethoxy-[3,3'-bipyridin]-6-yl)-2-25 methylpropanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(5-(6-(2-hydroxypropan-2-yl)pyrazin-2- yl)pyridin-2-yl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(5-(6-(2-methoxypropan-2-yl)pyrazin-2- yl)pyridin-2-yl)-2-methylpropanamide; 30 2-(2-(cyclopropanesulfonamido)-5-methylthiazol-4-yl)-2-methyl-N-(5-(6-(trifluoromethyl)pyrazin- 2-yl)pyridin-2-yl)propanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2- methylpropanamide; 2-(2-(cyclopropanesulfonamido)-5-methylthiazol-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-35 2-methylpropanamide; N-(4-(5-chloropyridin-3-yl)-2-(trifluoromethyl)phenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4- yl)-2-methylpropanamide; STP-P3718PCT 29 N-(4-(5-cyanopyridin-3-yl)-2-(trifluoromethyl)phenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4- yl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(5-fluoropyridin-3-yl)-2- (trifluoromethyl)phenyl)-2-methylpropanamide; 5 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(2-(trifluoromethyl)-4-(6- (trifluoromethyl)pyrazin-2-yl)phenyl)propanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2- (trifluoromethyl)phenyl)-2-methylpropanamide; N-(4-(5-chloropyridin-3-yl)-2,6-diethylphenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-10 methylpropanamide; N-(4-(5-cyanopyridin-3-yl)-2,6-diethylphenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2- methylpropanamide; 2-(2-(cyclopropanesulfonamido)-5-methylthiazol-4-yl)-N-(2-fluoro-4-(5-(trifluoromethyl)pyridin- 3-yl)phenyl)-2-methylpropanamide; 15 N-(4-(5-chloropyridin-3-yl)-2,6-difluorophenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2- methylpropanamide; N-(4-(5-chloropyridin-3-yl)-2-fluoro-5-methylphenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4- yl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(2-fluoro-4-(6-(2-methoxypropan-2-yl)pyrazin-2-20 yl)phenyl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)-5-methylthiazol-4-yl)-N-(2-fluoro-4-(6-(trifluoromethyl)pyrazin- 2-yl)phenyl)-2-methylpropanamide; N-(4-(6-cyanopyrazin-2-yl)-2-fluorophenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2- methylpropanamide; 25 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-ethylpyrazin-2-yl)-2-fluorophenyl)-2- methylpropanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(2-fluoro-4-(6-isopropoxypyrazin-2-yl)phenyl)-2- methylpropanamide; 2-(2-(cyclopropanesulfonamido)-5-methylthiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-30 fluorophenyl)-2-methylpropanamide; N-(4-(5-chloropyridin-3-yl)-2-isopropylphenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2- methylpropanamide; N-(4-(5-cyanopyridin-3-yl)-2-isopropylphenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2- methylpropanamide; 35 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(2-isopropyl-4-(6-(trifluoromethyl)pyrazin-2- yl)phenyl)-2-methylpropanamide; STP-P3718PCT 30 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-isopropylphenyl)-2- methylpropanamide; N-(4-(5-chloropyridin-3-yl)-3-fluoro-2-methylphenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4- yl)-2-methylpropanamide; 5 N-(4-(5-chloropyridin-3-yl)-5-fluoro-2-methylphenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4- yl)-2-methylpropanamide; N-(4-(5-chloropyridin-3-yl)-2,3-dimethylphenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2- methylpropanamide; N-(4-(5-chloropyridin-3-yl)-2,5-dimethylphenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-10 methylpropanamide; N-(4-(5-cyanopyridin-3-yl)-3-fluoro-2-methylphenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4- yl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(2-methyl-4-(6-(trifluoromethyl)pyrazin- 2-yl)phenyl)propanamide; 15 N-(4-(5-chloropyridin-3-yl)-5-fluoro-2-methoxyphenyl)-2-(2-(cyclopropanesulfonamido)thiazol- 4-yl)-2-methylpropanamide; N-(4-(5-chloropyridin-3-yl)-3-(trifluoromethyl)phenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4- yl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-3-methylphenyl)-2-20 methylpropanamide; N-(4-(5-chloropyridin-3-yl)-3-ethoxyphenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2- methylpropanamide; N-(4-(5-chloropyridin-3-yl)phenyl)-1-(2-(cyclopropanesulfonamido)thiazol-4-yl)cyclopropane-1- carboxamide; 25 N-(4-(5-cyanopyridin-3-yl)phenyl)-2-(2-(cyclopropanesulfonamido)-5-methylthiazol-4-yl)-2- methylpropanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-(2-methoxypropan-2-yl)pyrazin-2- yl)phenyl)-2-methylpropanamide; 2-(5-chloro-2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2-30 methylpropanamide; 2-(2-(cyclopropanesulfonamido)-5-methoxythiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2- methylpropanamide; N-(4-(6-(cyclopentylmethoxy)pyrazin-2-yl)phenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)- 2-methylpropanamide; 35 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-hydroxypyrazin-2-yl)phenyl)-2- methylpropanamide; STP-P3718PCT 31 2-(2-(ethylsulfonamido)thiazol-4-yl)-2-methyl-N-(5'-(trifluoromethyl)-[3,3'-bipyridin]-6- yl)propanamide; 2-(2-(ethylsulfonamido)thiazol-4-yl)-2-methyl-N-(5-(6-(trifluoromethyl)pyrazin-2-yl)pyridin-2- yl)propanamide; 5 N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2-(2-(ethylsulfonamido)thiazol-4-yl)-2- methylpropanamide; 2-(2-(ethylsulfonamido)thiazol-4-yl)-N-(2-fluoro-4-(6-isopropoxypyrazin-2-yl)phenyl)-2- methylpropanamide; N-(4-(5-cyanopyridin-3-yl)phenyl)-2-(2-(ethylsulfonamido)thiazol-4-yl)-2-methylpropanamide;10 2-(2-(ethylsulfonamido)thiazol-4-yl)-N-(4-(5-fluoropyridin-3-yl)phenyl)-2-methylpropanamide; 2-(2-(ethylsulfonamido)thiazol-4-yl)-2-methyl-N-(4-(pyridin-3-yl)phenyl)propanamide; 2-(2-(ethylsulfonamido)thiazol-4-yl)-2-methyl-N-(4-(6-(trifluoromethyl)pyrazin-2- yl)phenyl)propanamide; 2-(2-(ethylsulfonamido)thiazol-4-yl)-N-(4-(6-isopropoxypyrazin-2-yl)phenyl)-2-15 methylpropanamide; 2-methyl-2-(2-(methylsulfonamido)thiazol-4-yl)-N-(5'-(trifluoromethyl)-[3,3'-bipyridin]-6- yl)propanamide; N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2-methyl-2-(2-(methylsulfonamido)thiazol-4- yl)propanamide; 20 N-(2-fluoro-4-(6-(trifluoromethyl)pyrazin-2-yl)phenyl)-2-methyl-2-(2-(methylsulfonamido)thiazol- 4-yl)propanamide; N-(2-fluoro-4-(6-isopropoxypyrazin-2-yl)phenyl)-2-methyl-2-(2-(methylsulfonamido)thiazol-4- yl)propanamide; N-(4-(5-chloropyridin-3-yl)phenyl)-2-methyl-2-(2-(methylsulfonamido)thiazol-4-yl)propanamide;25 2-methyl-2-(2-(methylsulfonamido)thiazol-4-yl)-N-(4-(6-(trifluoromethyl)pyrazin-2- yl)phenyl)propanamide; N-(4-(6-isopropoxypyrazin-2-yl)phenyl)-2-methyl-2-(2-(methylsulfonamido)thiazol-4- yl)propanamide; 2-(2-((cyclopropylmethyl)sulfonamido)thiazol-4-yl)-2-methyl-N-(5-(6-(trifluoromethyl)pyrazin-2-30 yl)pyridin-2-yl)propanamide; 1-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-(trifluoromethyl)pyrazin-2- yl)phenyl)cyclopropane-1-carboxamide; 1-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)cyclopropane- 1-carboxamide; 35 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(2-fluoro-4-(6-(trifluoromethyl)pyrazin-2- yl)phenyl)-4-methoxybutanamide; STP-P3718PCT 32 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(2-fluoro-4-(6-isopropoxypyrazin-2-yl)phenyl)-4- methoxybutanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(5-(6-isopropylpyrazin-2-yl)pyridin-2- yl)butanamide; 5 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(5-(6-(2-methoxypropan-2-yl)pyrazin-2- yl)pyridin-2-yl)butanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(2-fluoro-4-(6-(2-methoxypropan-2-yl)pyrazin-2- yl)phenyl)butanamide; N-(4-(6-cyanopyrazin-2-yl)-2-fluorophenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-10 yl)butanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-ethylpyrazin-2-yl)-2- fluorophenyl)butanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-(2-methoxypropan-2-yl)pyrazin-2- yl)phenyl)butanamide; 15 tert-butyl-(1-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-((4-(6-ethoxypyrazin-2- yl)phenyl)amino)-2-oxoethyl)carbamate; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(2-fluoro-4-(6-(trifluoromethyl)pyrazin-2- yl)phenyl)-2-methoxyacetamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)-2-20 methoxyacetamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2- methoxyacetamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-isopropoxypyrazin-2-yl)phenyl)-2- methoxyacetamide; 25 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2- fluorophenyl)butanamide; (R)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2- fluorophenyl)butanamide; (S)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-30 fluorophenyl)butanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(5-(6-(trifluoromethyl)pyrazin-2-yl)pyridin-2- yl)butanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(2-fluoro-4-(5-(trifluoromethyl)pyridin-3- yl)phenyl)butanamide; 35 (R)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(2-fluoro-4-(5-(trifluoromethyl)pyridin-3- yl)phenyl)butanamide; STP-P3718PCT 33 (S)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(2-fluoro-4-(5-(trifluoromethyl)pyridin-3- yl)phenyl)butanamide; 2-Amino-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(5-(6-(trifluoromethyl)pyrazin-2- yl)pyridin-2-yl)acetamide hydrochloride; 5 2-Amino-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(2-fluoro-4-(6-(trifluoromethyl)pyrazin- 2-yl)phenyl)acetamide; 2-Amino-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2- fluorophenyl)acetamide hydrochloride; 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-2-(dimethylamino)-N-(2-fluoro-4-(6-10 (trifluoromethyl)pyrazin-2-yl)phenyl)acetamide; 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-2-(dimethylamino)-N-(4-(6-ethoxypyrazin-2-yl)-2- fluorophenyl)acetamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2,2- difluoroacetamide; 15 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2- fluorophenyl)acetamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)acetamide; 2-methyl-2-(2-(methylsulfonamido)thiazol-4-yl)-N-(5-(6-(trifluoromethyl)pyrazin-2-yl)pyridin-2- yl)propanamide; 20 N-(2-fluoro-4-(5-(trifluoromethyl)pyridin-3-yl)phenyl)-2-methyl-2-(2-(methylsulfonamido)thiazol- 4-yl)propanamide; 2-(2-((cyclopropylmethyl)sulfonamido)thiazol-4-yl)-N-(2-fluoro-4-(5-(trifluoromethyl)pyridin-3- yl)phenyl)-2-methylpropanamide; N-(4-(5-chloro-4-methylpyridin-3-yl)phenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2- 25 methylpropanamide; N-(4-(6-ethoxypyrazin-2-yl)-2-(trifluoromethyl)phenyl)-2-methyl-2-(2- (methylsulfonamido)thiazol-4-yl)propanamide; 2-(2-((cyclopropylmethyl)sulfonamido)thiazol-4-yl)-N-(2-fluoro-4-(6-(trifluoromethyl)pyrazin-2- yl)phenyl)-2-methylpropanamide; 30 N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)-2-methyl-2-(2-(methylsulfonamido)thiazol-4- yl)propanamide; N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)-2-(2-((2-methoxyethyl)sulfonamido)thiazol-4-yl)-2- methylpropanamide; 2-(2-((cyclopropylmethyl)sulfonamido)thiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)- 35 2-methylpropanamide; N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2-methyl-2-(2-(methylsulfonamido)thiazol-4- yl)propanamide; STP-P3718PCT 34 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)-3-fluoropyridin-2-yl)-4- methoxybutanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4- methoxybutanamide; 5 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-4-methoxy-N-(4-(6-(trifluoromethyl)pyrazin-2- yl)phenyl)butanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)-3-methylpyridin-2- yl)butanamide; N-(2-chloro-4-(6-ethoxypyrazin-2-yl)phenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4- 10 yl)butanamide; N-(2-cyano-4-(6-ethoxypyrazin-2-yl)phenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4- yl)butanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2- methylphenyl)butanamide; 15 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2- (trifluoromethoxy)phenyl)butanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2- methoxyphenyl)butanamide; 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-(ethylamino)pyrazin-2-20 yl)phenyl)butanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)-3-fluoropyridin-2-yl)-2- methoxyacetamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2- methoxyacetamide; 25 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(5-fluoropyridin-3-yl)-2- (trifluoromethyl)phenyl)-2-methoxyacetamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(2-fluoro-4-(5-(trifluoromethyl)pyridin-3- yl)phenyl)-2-methoxyacetamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2- 30 (trifluoromethyl)phenyl)-2-methoxyacetamide; N-(2-chloro-4-(6-ethoxypyrazin-2-yl)phenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2- methoxyacetamide; N-(2-cyano-4-(6-ethoxypyrazin-2-yl)phenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2- methoxyacetamide; 35 N-(2-fluoro-4-(6-(trifluoromethyl)pyrazin-2-yl)phenyl)-2-methoxy-2-(2- (methylsulfonamido)thiazol-4-yl)acetamide; STP-P3718PCT 35 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2,6-difluorophenyl)-2- methoxyacetamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2- (trifluoromethoxy)phenyl)-2-methoxyacetamide; 5 N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2-methoxy-2-(2-(methylsulfonamido)thiazol-4-yl)acetamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)-3-fluoropyridin-2- yl)butanamide (R enantiomer); 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)-3-fluoropyridin-2- yl)butanamide (S enantiomer); 10 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(2-fluoro-4-(6-(trifluoromethyl)pyrazin-2- yl)phenyl)-2-methoxyacetamide (R enantiomer); 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(2-fluoro-4-(6-(trifluoromethyl)pyrazin-2- yl)phenyl)-2-methoxyacetamide (S enantiomer); 4-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2- 15 fluorophenyl)tetrahydro-2H-pyran-4-carboxamide; 4-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(5-(6-(trifluoromethyl)pyrazin-2-yl)pyridin-2- yl)tetrahydro-2H-pyran-4-carboxamide; 4-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)tetrahydro- 2H-pyran-4-carboxamide; 20 N-(4-(1-(4-(5-methoxypyridin-3-yl)phenyl)-2-oxopyrrolidin-3-yl)thiazol-2- yl)cyclopropanesulfonamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(5-(6-methylpyrazin-2-yl)pyridin-2- yl)propanamide; and N-(4-(6-cyanopyrazin-2-yl)-2-methylphenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-25 methylpropanamide; or a pharmaceutically acceptable salt and / or pharmaceutically acceptable solvate thereof. Such CTPS1 inhibitors are disclosed in PCT publication number WO2019106156, which is incorporated by reference in its entirety for the purpose of the CTPS1 inhibitors disclosed therein. In particular a CTPS1 inhibitor may be a compound described in any one of 30 clauses 1 to 118 of WO2019106156, or a pharmaceutically acceptable salt and / or pharmaceutically acceptable solvate thereof, in particular a compound T1 to T465 or a pharmaceutically acceptable salt and / or pharmaceutically acceptable solvate thereof. Alternatively, the CTPS1 inhibitor is a compound formula (III): STP-P3718PCT 36 wherein Ais an amide linker having the following structure: -C(=O)NH- or -NHC(=O)-;X is N or CH; Y is N or CR2; 5 Z is N or CR3; with the proviso that when at least one of X or Z is N, Y cannot be N; R1 is C1-5alkyl, C0-2alkyleneC3-5cycloalkyl which cycloalkyl is optionally substituted by CH3, or CF3; R2 is H, halo, C1-2alkyl, OC1-2alkyl, C1-2haloalkyl or OC1-2haloalkyl; 10 R3 is H, halo, CH3, OCH3, CF3 or OCF3; wherein at least one of R2 and R3 is H; R4 and R5 are each independently H, C1-6alkyl, C1-6alkylOH, C1-6haloalkyl, C0- 2alkyleneC3-6cycloalkyl, C0-2alkyleneC3-6heterocycloalkyl, C1-3alkyleneOC1-3alkyl, or R4 and R5 together with the carbon atom to which they are attached form a C3-6cycloalkyl15 or C3-6heterocycloalkyl; and when A is -NHC(=O)-: R4 and R5 may additionally be selected from halo, OC1-6haloalkyl, OC0- 2alkyleneC3-6cycloalkyl, OC0-2alkyleneC3-6heterocycloalkyl, OC1-6alkyl and NR21R22; 20 Ar1 is a 6-membered aryl or heteroaryl; Ar2 is a 6-membered aryl or heteroaryl and is attached to Ar1 in the para position relative to the amide; R10 is H, halo, C1-3alkyl, C1-2haloalkyl, OC1-2alkyl, OC1-2haloalkyl or CN; R11is H, F, Cl, C1-2alkyl, CF3, OCH3or CN; 25 R12is attached to Ar2 in the ortho or meta position relative to Ar1 and R12is H, halo, C1-4alkyl, C2-4alkenyl, C0-2alkyleneC3-5cycloalkyl, OC1-4alkyl, OC0-2alkyleneC3-5cycloalkyl, C1-4haloalkyl, OC1-4haloalkyl,hydroxy, C1-4alkylOH, SO2C1-2alkyl, C(O)N(C1-2alkyl)2, NHC(O)C1-3alkyl or NR23R24; and when A is -NHC(=O)-: 30 R12may additionally be selected from CN, OCH2CH2N(CH3)2and a C3-6heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2, or R12together with a nitrogen atom to which it is attached forms an N- oxide (N+-O-); R13is H or halo; 35 R21is H, C1-5alkyl, C(O)C1-5alkyl, C(O)OC1-5alkyl; R22is H or CH3; R23is H or C1-2alkyl; and STP-P3718PCT 37 R24is H or C1-2alkyl; or a pharmaceutically acceptable salt and / or pharmaceutically acceptable solvate thereof. More suitably, the CTPS1 inhibitor is selected from the following (‘List C’) compounds:N-(4-(5-chloropyridin-3-yl)phenyl)-2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)butanamide; 5 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2- yl)phenyl)cyclopentanecarboxamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-methoxypyrazin-2-yl)phenyl)-2- methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-2-methyl-N-(4-(5-(trifluoromethyl)pyridin-3-10 yl)phenyl)propanamide; 2-methyl-N-(2-methyl-4-(6-methylpyrazin-2-yl)phenyl)-2-(2-(methylsulfonamido)pyrimidin-4- yl)propanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(2-fluoro-4-(pyrazin-2-yl)phenyl)butanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(5-(trifluoromethyl)pyridin-3-15 yl)phenyl)butanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-(trifluoromethyl)pyrazin-2- yl)phenyl)acetamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-isopropoxypyrazin-2-yl)pyridin-2-yl)-2- methylpropanamide; 20 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2- ethylbutanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(2-fluoro-4-(6-(trifluoromethyl)pyrazin-2- yl)phenyl)acetamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(2-fluoro-4-(6-isopropoxypyrazin-2-25 yl)phenyl)acetamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(5-(trifluoromethyl)pyridin-3- yl)phenyl)acetamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(5-(2,2,2-trifluoroethoxy)pyridin-3- yl)phenyl)acetamide; 30 2-(2-(cyclopropanesulfonamido)-5-fluoropyrimidin-4-yl)-N-(4-(pyridin-3-yl)phenyl)acetamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(pyridin-3-yl)phenyl)acetamide; N-([1,1'-biphenyl]-4-yl)-2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)acetamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)acetamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-methoxypyrazin-2-yl)phenyl)acetamide;35 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-(2,2,2-trifluoroethoxy)pyrazin-2- yl)phenyl)acetamide; STP-P3718PCT 38 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-isopropoxypyrazin-2- yl)phenyl)acetamide; 2-(2-(cyclobutanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2- methylpropanamide; 5 2-(2-(cyclobutanesulfonamido)pyrimidin-4-yl)-N-(2-fluoro-4-(6-isopropoxypyrazin-2-yl)phenyl)- 2-methylpropanamide; 2-(2-(cyclobutanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-methylphenyl)-2- methylpropanamide; 2-(2-(cyclobutanesulfonamido)pyrimidin-4-yl)-N-(4-(6-methoxypyrazin-2-yl)phenyl)-2-10 methylpropanamide; 2-(2-(cyclobutanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2- methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)-3-fluoropyridin-2-yl)- 2-methylpropanamide; 15 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5'-ethoxy-[3,3'-bipyridin]-6-yl)-2- methylpropanamide; N-([3,3'-bipyridin]-6-yl)-2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-2-methyl-N-(5-(6-(trifluoromethyl)pyrazin-2- yl)pyridin-2-yl)propanamide; 20 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2- methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-cyclopropoxypyrazin-2-yl)pyridin-2-yl)- 2-methylpropanamide; N-(2-chloro-4-(6-ethoxypyrazin-2-yl)phenyl)-2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-2-25 methylpropanamide; N-(2-cyano-4-(6-ethoxypyrazin-2-yl)phenyl)-2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-2- methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(2-fluoro-4-(5-isopropoxypyridin-3-yl)phenyl)- 2-methylpropanamide; 30 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(2-fluoro-4-(pyridin-3-yl)phenyl)-2- methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(2-fluoro-4-(6-(trifluoromethyl)pyrazin-2- yl)phenyl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)-2-35 methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(2-fluoro-4-(6-isopropoxypyrazin-2-yl)phenyl)- 2-methylpropanamide; STP-P3718PCT 39 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluoro-5- methylphenyl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2,6-difluorophenyl)- 2-methylpropanamide; 5 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(2-fluoro-4-(pyrazin-2-yl)phenyl)-2- methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-2-methyl-N-(2-methyl-4-(6- (trifluoromethyl)pyrazin-2-yl)phenyl)propanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2,3-10 dimethylphenyl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-5-fluoro-2- methylphenyl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2,5- dimethylphenyl)-2-methylpropanamide; 15 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2- (trifluoromethoxy)phenyl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-5-fluoro-2- methoxyphenyl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-methoxyphenyl)-20 2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-2-methyl-N-(4-(pyrimidin-5- yl)phenyl)propanamide; N-(4-(5-chloropyridin-3-yl)phenyl)-2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-2- methylpropanamide; 25 N-(4-(5-cyanopyridin-3-yl)phenyl)-2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-2- methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(5-fluoropyridin-3-yl)phenyl)-2- methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-2-methyl-N-(4-(5-methylpyridin-3-30 yl)phenyl)propanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(5-(difluoromethoxy)pyridin-3-yl)phenyl)-2- methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(5-methoxypyridin-3-yl)phenyl)-2- methylpropanamide; 35 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(5-ethoxypyridin-3-yl)phenyl)-2- methylpropanamide; STP-P3718PCT 40 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(5-isopropoxypyridin-3-yl)phenyl)-2- methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-2-methyl-N-(4-(pyridin-3- yl)phenyl)propanamide; 5 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-2-methyl-N-(3'-(trifluoromethyl)-[1,1'-biphenyl]- 4-yl)propanamide; N-(3'-chloro-[1,1'-biphenyl]-4-yl)-2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-2- methylpropanamide; N-(3'-cyano-[1,1'-biphenyl]-4-yl)-2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-2-10 methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(3'-ethoxy-[1,1'-biphenyl]-4-yl)-2- methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-2-methyl-N-(4-(6-(trifluoromethyl)pyrazin-2- yl)phenyl)propanamide; 15 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2- methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-cyclopropoxypyrazin-2-yl)phenyl)-2- methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-isopropoxypyrazin-2-yl)phenyl)-2-20 methylpropanamide; 2-(2-(cyclopropanesulfonamido)-5-fluoropyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2- methylpropanamide; N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2-methyl-2-(2-((1-methylcyclopropane)-1- sulfonamido)pyrimidin-4-yl)propanamide; 25 2-(2-(cyclopropanesulfonamido)-5-methylpyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2- methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-2-methyl-N-(4-(pyrazin-2- yl)phenyl)propanamide; N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)-2-(2-(ethylsulfonamido)pyrimidin-4-yl)-2-30 methylpropanamide; 2-(2-(ethylsulfonamido)pyrimidin-4-yl)-2-methyl-N-(4-(6-(trifluoromethyl)pyrazin-2- yl)phenyl)propanamide; N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2-(2-(ethylsulfonamido)pyrimidin-4-yl)-2- methylpropanamide; 35 N-(5-(6-ethoxypyrazin-2-yl)-3-fluoropyridin-2-yl)-2-methyl-2-(2-(methylsulfonamido)pyrimidin-4- yl)propanamide; STP-P3718PCT 41 N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2-methyl-2-(2-(methylsulfonamido)pyrimidin-4- yl)propanamide; N-(2-fluoro-4-(5-isopropoxypyridin-3-yl)phenyl)-2-methyl-2-(2-(methylsulfonamido)pyrimidin-4- yl)propanamide; 5 N-(2-fluoro-4-(6-isopropoxypyrazin-2-yl)phenyl)-2-methyl-2-(2-(methylsulfonamido)pyrimidin-4- yl)propanamide; 2-methyl-N-(2-methyl-4-(6-(trifluoromethyl)pyrazin-2-yl)phenyl)-2-(2- (methylsulfonamido)pyrimidin-4-yl)propanamide; 2-methyl-2-(2-(methylsulfonamido)pyrimidin-4-yl)-N-(4-(6-(trifluoromethyl)pyrazin-2-10 yl)phenyl)propanamide; N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2-methyl-2-(2-(methylsulfonamido)pyrimidin-4- yl)propanamide; 2-(2-((1,1-dimethylethyl)sulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2- methylpropanamide; 15 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2- yl)phenyl)cyclopropanecarboxamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5'-(trifluoromethyl)-[3,3'-bipyridin]-6- yl)butanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5'-(2,2,2-trifluoroethoxy)-[3,3'-bipyridin]-6-20 yl)butanamide; N-([3,3'-bipyridin]-6-yl)-2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)butanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-(trifluoromethyl)pyrazin-2-yl)pyridin-2- yl)butanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-25 yl)butanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-isopropoxypyrazin-2-yl)pyridin-2- yl)butanamide; N-(4-(5-chloropyridin-3-yl)-2-fluorophenyl)-2-(2-(cyclopropanesulfonamido)pyrimidin-4- yl)butanamide; 30 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(2-fluoro-4-(5-(2,2,2-trifluoroethoxy)pyridin-3- yl)phenyl)butanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(2-fluoro-4-(5-isopropoxypyridin-3- yl)phenyl)butanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(2-fluoro-4-(pyridin-3-yl)phenyl)butanamide;35 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(2-fluoro-4-(6-(trifluoromethyl)pyrazin-2- yl)phenyl)butanamide; STP-P3718PCT 42 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(2-fluoro-4-(6-methoxypyrazin-2- yl)phenyl)butanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2- fluorophenyl)butanamide; 5 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(2-fluoro-4-(6-isopropoxypyrazin-2- yl)phenyl)butanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(2-fluoro-4-(6-(2,2,2-trifluoroethoxy)pyrazin-2- yl)phenyl)butanamide; N-(4-(5-cyanopyridin-3-yl)phenyl)-2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)butanamide;10 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(5-(2,2,2-trifluoroethoxy)pyridin-3- yl)phenyl)butanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(5-isopropoxypyridin-3- yl)phenyl)butanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(pyridin-3-yl)phenyl)butanamide; 15 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-(trifluoromethyl)pyrazin-2- yl)phenyl)butanamide; N-(4-(6-chloropyrazin-2-yl)phenyl)-2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)butanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)butanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-methoxypyrazin-2-20 yl)phenyl)butanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-isopropoxypyrazin-2- yl)phenyl)butanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-(2,2,2-trifluoroethoxy)pyrazin-2- yl)phenyl)butanamide; 25 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(pyrazin-2-yl)phenyl)butanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-4- methoxybutanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(pyridin-3-yl)phenyl)propenamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2-(R)-30 fluorobutanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2-(S)- fluorobutanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2- fluorobutanamide; 35 4-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2- yl)tetrahydro-2H-pyran-4-carboxamide; STP-P3718PCT 43 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-isopropylpyrazin-2-yl)pyridin-2-yl)-2- methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)-2,2- difluoroacetamide; 5 N-((2-(cyclopropanesulfonamido)pyrimidin-4-yl)methyl)-4-(6-ethoxypyrazin-2-yl)benzamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-2-methyl-N-(5-(6-(prop-1-en-2-yl)pyrazin-2- yl)pyridin-2-yl)propanamide; 2-(2-(cyclopropanesulfonamido)-6-methylpyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2- yl)-2-methylpropanamide; 10 2-(2-(cyclopropanesulfonamido)-6-(trifluoromethyl)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2- yl)pyridin-2-yl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-cyclopropylpyrazin-2-yl)pyridin-2-yl)-2- methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(6-(6-ethoxypyrazin-2-yl)pyridin-3-yl)-2-15 methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-cyclopropylpyrazin-2-yl)-2- fluorophenyl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)-6-methylpyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2- fluorophenyl)-2-methylpropanamide; 20 2-(2-(cyclopropanesulfonamido)-6-(trifluoromethyl)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)- 2-fluorophenyl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-2-methyl-N-(4-(6-(prop-1-en-2-yl)pyrazin-2- yl)phenyl)propanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-isopropylpyrazin-2-yl)phenyl)-2-25 methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-(dimethylamino)pyrazin-2-yl)phenyl)-2- methylpropanamide; 2-(2-(cyclopropanesulfonamido)-6-methylpyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2- methylpropanamide; 30 2-(2-(cyclopropanesulfonamido)-6-(trifluoromethyl)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2- yl)phenyl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)-6-methoxypyrimidin-4-yl)-2-methyl-N-(4-(pyridin-3- yl)phenyl)propanamide; 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-35 yl)cyclopentane-1-carboxamide; 4-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)tetrahydro- 2H-pyran-4-carboxamide; STP-P3718PCT 44 N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(2-(methylsulfonamido)pyrimidin-4-yl)piperidine-4- carboxamide; tert-butyl 4-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-4-((5-(6-ethoxypyrazin-2-yl)pyridin-2- yl)carbamoyl)piperidine-1-carboxylate; 5 4-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2- yl)piperidine-4-carboxamide; tert-butyl 3-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-3-((5-(6-ethoxypyrazin-2-yl)pyridin-2- yl)carbamoyl)azetidine-1-carboxylate; tert-butyl 4-((5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)carbamoyl)-4-(2-(methylsulfonamido) 10 pyrimidin-4-yl)piperidine-1-carboxylate; 4-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2- fluorophenyl)tetrahydro-2H-pyran-4-carboxamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)-3-fluoropyridin-2-yl)- 4-methoxybutanamide; 15 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4- methoxybutanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)-4- methoxybutanamide; N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-methoxy-2-methyl-2-(2-(methylsulfonamido) 20 pyrimidin-4-yl)butanamide; N-(5'-chloro-[3,3'-bipyridin]-6-yl)-2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)butanamide; N-(5'-chloro-[3,3'-bipyridin]-6-yl)-2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-2- fluorobutanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-cyclopropylpyrazin-2-yl)pyridin-2-yl)-2-25 fluorobutanamide; N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2-fluoro-2-(2-(methylsulfonamido)pyrimidin-4- yl)butanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)-3-methylpyridin-2- yl)butanamide; 30 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-cyclopropylpyrazin-2-yl)pyridin-2- yl)butanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-(2,2,2-trifluoroethoxy)pyrazin-2- yl)pyridin-2-yl)butanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(3-fluoro-5-(6-methoxypyrazin-2-yl)pyridin-2-35 yl)butanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-methoxypyrazin-2-yl)pyridin-2- yl)butanamide; STP-P3718PCT 45 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-cyclopropylpyrazin-2-yl)-2- fluorophenyl)butanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2- methylphenyl)butanamide; 5 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)-3-fluoropyridin-2- yl)butanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2- methylbutanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2-fluoro-10 3-methylbutanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)-3- methylbutanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-3- methylbutanamide; 15 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2- methoxyacetamide; N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2-fluoro-2-(2-(methylsulfonamido)pyrimidin-4-yl)-(R)- butanamide; N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2-fluoro-2-(2-(methylsulfonamido)pyrimidin-4-yl)-(S)-20 butanamide; N-(4-(5-chloropyridin-3-yl)phenyl)-2-(6-(cyclopropanesulfonamido)pyridin-2-yl)acetamide; N-(4-(5-cyanopyridin-3-yl)phenyl)-2-(6-(cyclopropanesulfonamido)pyridin-2-yl)acetamide; 2-(6-(cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(5-fluoropyridin-3-yl)phenyl)acetamide; 2-(6-(cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(5-methoxypyridin-3-yl)phenyl)acetamide;25 2-(6-(cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(pyridin-3-yl)phenyl)acetamide; 2-(6-(cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(6-(trifluoromethyl)pyrazin-2- yl)phenyl)acetamide; 2-(6-(cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(6-methoxypyrazin-2-yl)phenyl)acetamide; 2-(6-(cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(pyrazin-2-yl)phenyl)acetamide; 30 N-([3,3'-bipyridin]-6-yl)-2-(6-(cyclopropanesulfonamido)pyridin-2-yl)-2-methylpropanamide; N-(4-(5-chloropyridin-3-yl)phenyl)-2-(6-(cyclopropanesulfonamido)pyridin-2-yl)-2- methylpropanamide; 2-(6-(cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(5-fluoropyridin-3-yl)phenyl)-2- methylpropanamide; 35 2-(6-(cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(5-ethoxypyridin-3-yl)phenyl)-2- methylpropanamide; 2-(6-(cyclopropanesulfonamido)pyridin-2-yl)-2-methyl-N-(4-(pyridin-3-yl)phenyl)propanamide; STP-P3718PCT 46 2-(6-(cyclopropanesulfonamido)pyridin-2-yl)-N-(2-fluoro-4-(pyrazin-2-yl)phenyl)-2- methylpropanamide; 2-(6-(cyclopropanesulfonamido)pyridin-2-yl)-2-methyl-N-(4-(6-(trifluoromethyl)pyrazin-2- yl)phenyl)propanamide; 5 N-(4-(6-chloropyrazin-2-yl)phenyl)-2-(6-(cyclopropanesulfonamido)pyridin-2-yl)-2- methylpropanamide; 2-(6-(cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2- methylpropanamide; 2-(6-(cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(6-methoxypyrazin-2-yl)phenyl)-2-10 methylpropanamide; 2-(6-(cyclopropanesulfonamido)pyridin-2-yl)-2-methyl-N-(4-(pyrazin-2-yl)phenyl)propanamide; 4-(6-(cyclopropanesulfonamido)pyridin-2-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)tetrahydro- 2H-pyran-4-carboxamide; 2-(6-(cyclopropanesulfonamido)pyridin-2-yl)-N-(5-(6-(trifluoromethyl)pyrazin-2-yl)pyridin-2-15 yl)butanamide; 2-(6-(cyclopropanesulfonamido)pyridin-2-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2- yl)butanamide; N-(4-(5-chloropyridin-3-yl)phenyl)-2-(6-(cyclopropanesulfonamido)pyridin-2-yl)butanamide; 2-(6-(cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-20 fluorophenyl)butanamide; 2-(6-(cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)butanamide; 2-(6-(cyclopropanesulfonamido)pyrazin-2-yl)-N-(4-(pyridin-3-yl)phenyl)acetamide; 2-(6-(ethylsulfonamido)pyrazin-2-yl)-N-(4-(pyridin-3-yl)phenyl)acetamide; 2-(6-(methylsulfonamido)pyrazin-2-yl)-N-(4-(pyridin-3-yl)phenyl)acetamide; 25 2-(6-(cyclopropanesulfonamido)pyrazin-2-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2- methylpropanamide; 2-(6-(cyclopropanesulfonamido)pyrazin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2- methylpropanamide; 4-(6-(cyclopropanesulfonamido)pyrazin-2-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)tetrahydro-30 2H-pyran-4-carboxamide; 2-(6-(cyclopropanesulfonamido)pyrazin-2-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4- methoxy-2-methylbutanamide; N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-methoxy-2-methyl-2-(6-(methylsulfonamido)pyrazin- 2-yl)butanamide; 35 2-(6-(cyclopropanesulfonamido)pyrazin-2-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2- fluorobutanamide; STP-P3718PCT 47 2-(6-(cyclopropanesulfonamido)pyrazin-2-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2- yl)butanamide; 2-(6-(cyclopropanesulfonamido)pyrazin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)butanamide; 2-(6-(cyclopropanesulfonamido)pyrazin-2-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2- 5 methoxyacetamide; 2-(6-(cyclopropanesulfonamido)pyrazin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2- methoxyacetamide; 2-(6-(cyclopropanesulfonamido)pyrazin-2-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2- methoxypropanamide; 10 2-(6-(cyclopropanesulfonamido)pyrazin-2-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2-(R)- fluorobutanamide; 2-(6-(cyclopropanesulfonamido)pyrazin-2-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2-(S)- fluorobutanamide; 2-(4-(cyclopropanesulfonamido)pyrimidin-2-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-15 yl)butanamide; N-(1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)cyclopropyl)-4-(6-ethoxypyrazin-2-yl)-2- fluorobenzamide; N-(1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)propyl)-5-(6-ethoxypyrazin-2-yl)picolinamide; N-(1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)propyl)-2-fluoro-4-(5-(trifluoromethyl)pyridin-20 3-yl)benzamide; 4-(5-chloropyridin-3-yl)-N-(1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)propyl)-2- fluorobenzamide; N-(1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)propyl)-4-(5-(trifluoromethyl)pyridin-3- yl)benzamide; 25 4-(5-chloropyridin-3-yl)-N-(1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)propyl)benzamide; N-(1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)propyl)-4-(6-ethoxypyrazin-2-yl)-2- (trifluoromethyl)benzamide; N-(1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)propyl)-4-(6-ethoxypyrazin-2-yl)-2- fluorobenzamide; 30 N-(1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)propyl)-4-(6-(trifluoromethyl)pyrazin-2- yl)benzamide; N-(1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)propyl)-4-(6-isopropoxypyrazin-2- yl)benzamide; N-(1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)propyl)-4-(6-ethoxypyrazin-2-yl)benzamide;35 N-(2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)butan-2-yl)-4-(6-ethoxypyrazin-2-yl)-2- fluorobenzamide; STP-P3718PCT 48 N-(2-(6-(cyclopropanesulfonamido)pyrazin-2-yl)propan-2-yl)-2-fluoro-4-(6-isopropoxypyrazin-2- yl)benzamide; N-(2-(6-(cyclopropanesulfonamido)pyrazin-2-yl)propan-2-yl)-4-(6-(trifluoromethyl)pyrazin-2- yl)benzamide; 5 N-(1-(6-(cyclopropanesulfonamido)pyrazin-2-yl)propyl)-4-(6-ethoxypyrazin-2-yl)-2- fluorobenzamide; N-(1-(6-(cyclopropanesulfonamido)pyrazin-2-yl)propyl)-4-(6-ethoxypyrazin-2-yl)-2-(R)- fluorobenzamide; and N-(1-(6-(cyclopropanesulfonamido)pyrazin-2-yl)propyl)-4-(6-ethoxypyrazin-2-yl)-2-(S)-10 fluorobenzamide; or a pharmaceutically acceptable salt and / or pharmaceutically acceptable solvate thereof. Such CTPS1 inhibitors are disclosed in PCT publication number WO2019179652 which is incorporated by reference in its entirety for the purpose of the CTPS1 inhibitors disclosed therein. In particular a CTPS1 inhibitor may be a compound described in any one of clauses 1 15 to 148 of WO2019179652 or a pharmaceutically acceptable salt and / or pharmaceutically acceptable solvate thereof, in particular a compound P1 to P225 or a pharmaceutically acceptable salt and / or pharmaceutically acceptable solvate thereof. Such CTPS1 inhibitors are also disclosed in PCT publication number WO2019180244 which is incorporated by reference in its entirety for the purpose of the CTPS1 inhibitors 20 disclosed therein. In particular a CTPS1 inhibitor may be a compound described in any one of clauses 1 to 148 of WO2019180244 or a pharmaceutically acceptable salt and / or pharmaceutically acceptable solvate thereof, in particular a compound P1 to P225 or a pharmaceutically acceptable salt and / or pharmaceutically acceptable solvate thereof. Especially of interest are compounds or a pharmaceutically acceptable salt and / or25 pharmaceutically acceptable solvate thereof in PCT publication number WO2019180244 whichare selective for CTPS1 over CTPS2 (e.g. human CTPS1 over human CTPS2), such as thoseidentified in Table 19. Of particular interest are those compounds or a pharmaceutically acceptable salt and / or pharmaceutically acceptable solvate thereof shown in Table 19 with aselectivity of >60 fold in WO2019180244. 30 More suitably, the CTPS1 inhibitor is a compound of formula (IV): STP-P3718PCT 49 wherein: (a) when R4, R5, X, Y and R1are as follows: then W is N, CH or CF; 5 (b) when R4, R5, X, W and R1are as follows: then Y is CH or N; (c) when W, X, Y and R1are as follows: 10 then R4 and R5 are joined to form the following structures: (d) when W, R4, R5, X and Y are as follows: STP-P3718PCT 50 then R1is methyl or cyclopropyl; and (e) the compound is selected from the group consisting of: or a pharmaceutically acceptable salt and / or pharmaceutically acceptable solvate thereof. 5 More suitably the CTPS1 inhibitor is selected from the following (‘List D’) compounds: (R)-2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2- fluorobutanamide; (S)-2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2- fluorobutanamide; 10 4-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2- yl)tetrahydro-2H-pyran-4-carboxamide; 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2- yl)cyclopentane-1-carboxamide; 4-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)tetrahydro-15 2H-pyran-4-carboxamide; tert-butyl 4-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-4-((5-(6-ethoxypyrazin-2-yl)pyridin-2- yl)carbamoyl)piperidine-1-carboxylate; 4-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2- fluorophenyl)tetrahydro-2H-pyran-4-carboxamide; 20 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4- methoxybutanamide; (R)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2-fluoro-2-(2-(methylsulfonamido)pyrimidin-4- yl)butanamide; (S)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2-fluoro-2-(2-(methylsulfonamido)pyrimidin-4-25 yl)butanamide; 4-(6-(cyclopropanesulfonamido)pyridin-2-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)tetrahydro- 2H-pyran-4-carboxamide; 4-(6-(cyclopropanesulfonamido)pyrazin-2-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)tetrahydro- 2H-pyran-4-carboxamide; STP-P3718PCT 51 (R)-2-(6-(cyclopropanesulfonamido)pyrazin-2-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2- fluorobutanamide; and (S)-2-(6-(cyclopropanesulfonamido)pyrazin-2-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2- fluorobutanamide; 5 or a pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate thereof. Such CTPS1 inhibitors are disclosed in PCT publication number WO2020083975 which is incorporated by reference in its entirety for the purpose of the CTPS1 inhibitors disclosedtherein. In particular a CTPS1 inhibitor may be a compound selected from P112, P113, P114, P115, P136, P137, P139, P143, P145, P165, P166, P186, P197, P206 and P207 or a 10 pharmaceutically acceptable salt and / or pharmaceutically acceptable solvate thereof. Especially of interest are compounds or a pharmaceutically acceptable salt and / or pharmaceutically acceptable solvate thereof in PCT publication number WO2020083975 whichare selective for CTPS1 over CTPS2 (e.g. human CTPS1 over human CTPS2), such as thoseidentified in Table 11. Of particular interest are those compounds or a pharmaceutically15 acceptable salt and / or pharmaceutically acceptable solvate thereof shown in Table 11 with aselectivity of >60 fold in WO2020083975. Alternatively, the CTPS1 inhibitor is a compound of formula (V): (a) when A, V, W, X, Y, Z, R1, R10 and R12 are as follows:20 , then R4and R5together with the carbon atom to which they attached form: or (b) when A, V, W, X, Y, Z, R1, R10 and R12 are as follows:25 , STP-P3718PCT 52 then R4and R5together with the carbon atom to which they are attached form: 510 or , then V, W, R10 and R12 are: 15 (f) when A, V, W, R1, R4, R5, R10 and R12 are as follows: , STP-P3718PCT 53 then Z, X and Y are or (g) when A, V, W, R1, R4, R5, R10 and R12 are as follows:5 , or 10 or a pharmaceutically acceptable salt and / or pharmaceutically acceptable solvate thereof. More suitably the CTPS1 inhibitor is selected from the following (‘List E’) compounds:15 N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(2-(methylsulfonamido)pyrimidin-4-yl)tetrahydro-2H- pyran-4-carboxamide; 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2- yl)cyclohexane-1-carboxamide; N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-1-(2-(methylsulfonamido)pyrimidin-4-yl)cyclohexane-1-20 carboxamide; 1-(6-(cyclopropanesulfonamido)pyrazin-2-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2- yl)cyclohexane-1-carboxamide; 4-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2- methylphenyl)tetrahydro-2H-pyran-4-carboxamide; 25 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2- yl)cyclobutane-1-carboxamide; STP-P3718PCT 54 4-(4-(cyclopropanesulfonamido)pyrimidin-2-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2- yl)tetrahydro-2H-pyran-4-carboxamide; 4-(2-(cyclopentanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2- yl)tetrahydro-2H-pyran-4-carboxamide; 5 N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(2-((1-methylcyclopropane)-1-sulfonamido)pyrimidin- 4-yl)tetrahydro-2H-pyran-4-carboxamide; 4-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-1- methylpiperidine-4-carboxamide; 4-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-1-10 isopropylpiperidine-4-carboxamide; 4-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N4-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-N1- isopropylpiperidine-1,4-dicarboxamide; 4-(2-((1,1-dimethylethyl)sulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2- yl)tetrahydro-2H-pyran-4-carboxamide; 15 N-(4-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)tetrahydro-2H-pyran-4-yl)-5-(6-ethoxypyrazin- 2-yl)picolinamide; 1-Acetyl-4-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2- yl)piperidine-4-carboxamide; N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(2-((2-methylpropyl)sulfonamido)pyrimidin-4-20 yl)tetrahydro-2H-pyran-4-carboxamide; 4-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-cyclopropylpyrazin-2-yl)pyridin-2- yl)tetrahydro-2H-pyran-4-carboxamide; N-(5'-chloro-[3,3'-bipyridin]-6-yl)-4-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)tetrahydro-2H- pyran-4-carboxamide; 25 N-(1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)cyclopropyl)-5-(6-ethoxypyrazin-2- yl)picolinamide; 4-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2- yl)tetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide; N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(2-(ethylsulfonamido)pyrimidin-4-yl)tetrahydro-2H- 30 pyran-4-carboxamide; 4-(2-(cyclopropylmethylsulfonamido) pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2- yl)tetrahydro-2H-pyran-4-carboxamide and 4-(4-(cyclopropanesulfonamido)pyrimidin-2-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-1- methylpiperidine-4-carboxamide; 35 or a pharmaceutically acceptable salt and / or pharmaceutically acceptable solvate thereof. Such CTPS1 inhibitors are disclosed in PCT publication number WO2020245664 which is incorporated by reference in its entirety for the purpose of the CTPS1 inhibitors disclosed STP-P3718PCT 55 therein. In particular a CTPS1 inhibitor may be a compound selected from P319, P231 to P234, P236, P237, P238, P239, P240, P241, P243, P245, P246, P247, P249, P250, P252, P253, P257, P259, P262, P263 and P140 or a pharmaceutically acceptable salt and / or pharmaceutically acceptable solvate thereof. 5 Alternatively, the CTPS1 inhibitor is a compound of formula (VI): wherein ring B is selected from the group consisting of: wherein X, Y and Z are as defined below; and 10 wherein R3b3c is R3b or R3c as defined below; wherein when B is (B-a) the compound of formula (VI) is a compound of formula (VI-a): 15 wherein: Aa is Aaa or Aba; wherein: Aaa is an amine linker having the following structure: -NH-, -CH2NH- or -NHCH2-;Aba is an amide linker having the following structure: -C(=O)NH- or -NHC(=O)-;20 X is N or CH; Y is N or CR2a; Z is N or CR3a; with the proviso that when at least one of X or Z is N, Y cannot be N; R2a is H, halo, C1-2alkyl, OC1-2alkyl, C1-2haloalkyl or OC1-2haloalkyl; and 25 R3a is H, halo, CH3, OCH3, CF3 or OCF3; wherein at least one of R2a and R3a is H; R1a is R1aa or R1ba; wherein: STP-P3718PCT 56 R1aais NR32aR33a; R1bais C1-5alkyl, C0-2alkyleneC3-5cycloalkyl which cycloalkyl is optionally substituted by CH3, or CF3; R4a and R5a are R4aa and R5aa, or R4ba and R5ba; 5 wherein: R4aa and R5aa together with the carbon atom to which they are attached form a C3- 6cycloalkyl which is: substituted by one or two substituents, each substituent being independently selected from the group consisting of C1-3alkyl, oxo, OH,10 C1-3alkylOH, C1-3haloalkyl, C0-2alkyleneC3-6cycloalkyl, C0-2alkyleneC3- 6heterocycloalkyl, C1-3alkyleneOC1-3alkyl, halo, OC1-3haloalkyl, OC0- 2alkyleneC3-6cycloalkyl, OC0-2alkyleneC3-6heterocycloalkyl, OC1-3alkyl and NR21aR22a; or one of the carbons of the C3-6cycloalkyl is a spiro centre such that a 15 spirocyclic ring system is formed by the C3-6cycloalkyl ring and a further C3-6cycloalkyl ring or a C3-6heterocycloalkyl ring, and wherein the C3- 6cycloalkyl formed by R4aa and R5aa together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C1-20 3alkyl or OC1-3alkyl; or R4aa and R5aa together with the carbon atom to which they are attached form a C3- 6heterocycloalkyl wherein one of the carbons of the C3-6heterocycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C3-6heterocycloalkyl ring and a further C3-6cycloalkyl ring or a C3-6heterocycloalkyl ring, and wherein 25 the C3-6heterocycloalkyl formed by R4aaand R5aatogether with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C1-3alkyl or OC1-3alkyl; or R4aa and R5aa together with the carbon atom to which they are attached form a C3- 306heterocycloalkyl comprising one nitrogen atom, wherein said nitrogen atom is substituted by -S(O)2R29a; or R4baand R5baare each independently H, C1-6alkyl, C1-6alkylOH, C1-6haloalkyl, C0-2alkyleneC3-6cycloalkyl, C0-2alkyleneC3-6heterocycloalkyl, C1-3alkyleneOC1-3alkyl, or R4baand R5batogether with the carbon atom to which they are attached form a35 C3-6cycloalkyl or C3-6heterocycloalkyl; and when Aa is -NHC(=O)- or -NHCH2-: STP-P3718PCT 57 R4baand R5bamay additionally be selected from halo, OC1-6haloalkyl, OC0-2alkyleneC3-6cycloalkyl, OC0-2alkyleneC3-6heterocycloalkyl, OC1-6alkyl and NR21aR22a; Ar1a is a 6-membered aryl or heteroaryl; 5 Ar2a is a 6-membered aryl or heteroaryl and is attached to Ar1a in the para position relative to group Aa; R10a is H, halo, C1-3alkyl, C1-2haloalkyl, OC1-2alkyl, OC1-2haloalkyl or CN; R11a is H, F, Cl, C1-2alkyl, CF3, OCH3 or CN; R12a is attached to Ar2 in the ortho or meta position relative to Ar1a and R12a is H, halo, 10 C1-4alkyl, C2-4alkenyl, C0-2alkyleneC3-5cycloalkyl, OC1-4alkyl, OC0-2alkyleneC3-5cycloalkyl, C1-4haloalkyl, OC1-4haloalkyl, hydroxy, C1-4alkylOH, SO2C1-2alkyl, C(O)N(C1-2alkyl)2, NHC(O)C1-3alkyl or NR23aR24a; and when Aa is -NHC(=O)-, -NH- or -NHCH2-:R12a may additionally be selected from CN, OCH2CH2N(CH3)2 and a C3- 15 6heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2a, or R12a together with a nitrogen atom to which it is attached forms an N- oxide (N+-O-); R13a is H or halo; R21a is H, C1-5alkyl, C(O)C1-5alkyl, C(O)OC1-5alkyl, C1-3alkylOC1-2alkyl, C1-4haloalkyl, or 20 C4-6heterocycloalkyl; R22a is H or CH3; R23a is H or C1-2alkyl; and R24a is H or C1-2alkyl R29ais C1-3alkyl, C0-2alkyleneC3-5cycloalkyl which cycloalkyl is optionally substituted by 25 CH3, CF3, N(C1-3alkyl)2, or a 5 or 6 membered heteroaryl wherein the 5 or 6 membered heteroaryl is optionally substituted by methyl; R32ais C1-3alkyl and R33is C1-3alkyl; or R32aand R33atogether with the nitrogen atom to which they are attached form a C3-5heterocycloalkyl; 30 wherein R1ais R1aa; and / or R4aand R5aare R4aaand R5aa; and / or Aais Aaa; and wherein when B is (B-bc) and R3b3cis R3b, the compound of formula (VI) is a compound of35 formula (VI-b): STP-P3718PCT 58 Abis Aabor Abb; wherein: 5Aab is -NR6bCH2- or -NR6b-;Abbis -NR6bC(=O)-; R1bis R1abor R1bb; wherein: R1abis NR32bR33b; 10 R1bbis C1-5alkyl, C0-2alkyleneC3-5cycloalkyl which cycloalkyl is optionally substituted by CH3, C1-3alkyleneOC1-2alkyl, or CF3; R3bis H, halo, CH3, OC1-2alkyl or CF3; or R3b together with R5bb forms a 5- or 6-membered cycloalkyl or 5 or 6 memberedoxygen-containing heterocycloalkyl; 15 R4b and R5b are either R4ab and R5ab or R4bb and R5bb; wherein: R4ab and R5ab together with the carbon atom to which they are attached form a C3- 6cycloalkyl which is: substituted by one or two substituents, each substituent being 20 independently selected from the group consisting of C1-3alkyl, oxo, OH, C1-3alkylOH, C1-3haloalkyl, C0-2alkyleneC3-6cycloalkyl, C0-2alkyleneC3- 6heterocycloalkyl, C1-3alkyleneOC1-3alkyl, halo, OC1-3haloalkyl, OC0- 2alkyleneC3-6cycloalkyl, OC0-2alkyleneC3-6heterocycloalkyl, OC1-3alkyl and NR21bR22b; or 25 one of the carbons of the C3-6cycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C3-6cycloalkyl ring and a further C3-6cycloalkyl ring or a C3-6heterocycloalkyl ring, and wherein the C3- 6cycloalkyl formed by R4ab and R5ab together with the carbon atom to which they are attached may be substituted by one or two substituents, each30 substituent being independently selected from the group consisting of C1- 3alkyl or OC1-3alkyl; or R4ab and R5ab together with the carbon atom to which they are attached form a C3- 6heteroycloalkyl wherein one of the carbons of the C3-6heterocycloalkyl is a spiro STP-P3718PCT 59 centre such that a spirocyclic ring system is formed by the C3-6cheterocycloalkyl ring and a further C3-6cycloalkyl ring or a C3-6heterocycloalkyl ring, and wherein the C3-6heteroycloalkyl formed by R4aband R5abtogether with the carbon atom to which they are attached may be substituted by one or two substituents, each 5 substituent being independently selected from the group consisting of C1-3alkyl or OC1-3alkyl; or R4ab and R5ab together with the carbon atom to which they are attached form a C3- 6heterocycloalkyl comprising one nitrogen atom, wherein said nitrogen atom is substituted by -S(O)2R29b; or 10 R4bb and R5bb are each independently H, halo, C1-6alkyl, C0-2alkyleneC3- 6cycloalkyl, C0-2alkyleneC3-6heterocycloalkyl, OC1-6alkyl, OC0-2alkyleneC3- 6cycloalkyl, C1-3alkyleneOC1-3alkyl, C1-6alkylOH, C1-6haloalkyl, OC1-6haloalkyl or NR21bR22b, or R4bb is H and R5bb together with R3b form a 5- or 6-membered cycloalkyl15 or 5 or 6 membered oxygen-containing heterocycloalkyl, or R4bb and R5bb together with the carbon atom to which they are attached form a C3-6cycloalkyl or C3-6heterocycloalkyl, or R4bb is H and R5bb and R6b are a C2-3alkylene chain forming a 5- or 6-membered ring; 20 or R4bb is O and R5bb is absent; R6b is H or C1-3alkyl, or R6b together with R11b when in the ortho-position to group Ab are a C2alkylene chain forming a 5-membered ring, or R5bb and R6b are a C2-3alkylene chain forming a 5- or 6-membered ring and R4bb25 is H; Ar1b is 6-membered aryl or heteroaryl; Ar2b is a 6-membered aryl or heteroaryl and is attached to Ar1b in the para position relative to group Ab; R10b is H, halo, C1-3alkyl, OC1-2alkyl, C1-2haloalkyl, OC1-2haloalkyl or CN; 30 R11bis H, F, Cl, CH3, ethyl, OCH3, CF3, OCF3or CN, or R11b, when in the ortho-position to group Ab, together with R6bare a C2alkylene chain forming a 5-membered ring; R12bis attached to Ar2b in the ortho or meta position relative to Ar1b and R12bis H, halo, C1-4alkyl, C2-4alkynyl, C0-2alkyleneC3-5cycloalkyl, OC1-4alkyl, OC0-2alkyleneC3-5cycloalkyl,35 OCH2CH2N(CH3)2, OH, C1-4alkylOH, CN, C1-3alkyleneOC1-3alkyl, C1-4haloalkyl, OC1-4haloalkyl, C(=O)C1-2alkyl, NR23bR24b, SO2C1-4alkyl, SOC1-4alkyl, SC1-4alkyl, SH, C(O)N(CH3)2, NHC(O)C1-3alkyl, C3-6heterocycloalkyl comprising one nitrogen located at STP-P3718PCT 60 the point of attachment to Ar2b, or R12btogether with a nitrogen atom to which it is attached forms an N-oxide (N+-O-); R13bis H, halo, CH3or OCH3; R21b is H, C1-5alkyl, C(O)C1-5alkyl, C(O)OC1-5alkyl, C1-3alkylOC1-2alkyl, C1-4haloalkyl, or 5 C4-6heterocycloalkyl; R22b is H or CH3; R23b is H or C1-2alkyl; R24b is H or C1-2alkyl; R29b is C1-3alkyl, C0-2alkyleneC3-5cycloalkyl which cycloalkyl is optionally substituted by 10 CH3, CF3, N(C1-3alkyl)2, or a 5 or 6 membered heteroaryl wherein the 5 or 6 membered heteroaryl is optionally substituted by methyl; and R32b is C1-3alkyl and R33b is C1-3alkyl; or R32b and R33b together with the nitrogen atom to which they are attached form a C3- 5heterocycloalkyl; 15 wherein: R1b is R1ab; and / or R4b and R5b are R4ab and R5ab; and / or A is Aab; or wherein when B is (B-bc) and R3b3c is R3c, the compound of formula (VI) is a compound of formula20 (VI-c): wherein: Acis Aacor Abc; wherein: 25 Aacis -CH2NR6c-; Abcis -C(=O)NR6c-; R1c is R1ac or R1bc; wherein: R1ac is NR32cR33c; 30 R1bc is C1-5alkyl, C0-2alkyleneC3-5cycloalkyl which cycloalkyl is optionally substituted by CH3, C1-3alkyleneOC1-2alkyl, or CF3; R3c is H, CH3, halo, OC1-2alkyl or CF3; R4c and R5c are either R4ac and R5ac or R4bc and R5bc; STP-P3718PCT 61 wherein: R4acand R5actogether with the carbon atom to which they are attached form a C3-6cycloalkyl which is: substituted by one or two substituents, each substituent being 5 independently selected from the group consisting of C1-3alkyl, oxo, OH, C1-3alkylOH, C1-3haloalkyl, C0-2alkyleneC3-6cycloalkyl, C0-2alkyleneC3- 6heterocycloalkyl, C1-3alkyleneOC1-3alkyl, halo, OC1-3haloalkyl, OC0- 2alkyleneC3-6cycloalkyl, OC0-2alkyleneC3-6heterocycloalkyl, OC1-3alkyl and NR21cR22c; or 10 one of the carbons of the C3-6cycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C3-6cycloalkyl ring and a further C3-6cycloalkyl ring or a C3-6heterocycloalkyl ring, and wherein the C3- 6cycloalkyl formed by R4ac and R5ac together with the carbon atom to which they are attached may be substituted by one or two substituents, each15 substituent being independently selected from the group consisting of C1- 3alkyl or OC1-3alkyl; or R4ac and R5ac together with the carbon atom to which they are attached form a C3- 6heteroycloalkyl wherein one of the carbons of the C3-6heterocycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C3-6cheterocycloalkyl 20 ring and a further C3-6cycloalkyl ring or a C3-6heterocycloalkyl ring, and wherein the C3-6heteroycloalkyl formed by R4ac and R5ac together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C1-3alkyl or OC1-3alkyl; or 25 R4acand R5actogether with the carbon atom to which they are attached form a C3-6heterocycloalkyl comprising one nitrogen atom, wherein said nitrogen atom is substituted by -S(O)2R29c; or R4bcand R5bcare each independently H, C1-6alkyl, C0-2alkyleneC3-6cycloalkyl, C0-2alkyleneC3-6heterocycloalkyl, C1-3alkyleneOC1-3alkyl, C1-6alkylOH or C1- 306haloalkyl, or R4bcand R5bctogether with the carbon atom to which they are attached form a C3-6cycloalkyl or C3-6heterocycloalkyl ring; R6cis H or C1-3alkyl; Ar1c is a 6-membered aryl or heteroaryl; 35 Ar2c is a 6-membered aryl or heteroaryl and is attached to Ar1c in the para position relative to group Ac; R10cis H, halo, C1-3alkyl, OC1-2alkyl, C1-2haloalkyl, OC1-2haloalkyl or CN; STP-P3718PCT 62 R11cis H, F, Cl, CH3, ethyl, OCH3, CF3, OCF3or CN; R12cis attached to Ar2c in the meta or ortho position relative to Ar1c and R12cis H, halo, C1-4alkyl, C2-4alkynyl, C(=O)C1-2alkyl, C0-2alkyleneC3-5cycloalkyl, OC1-4alkyl, C1-3alkyleneOC1-3alkyl, C1-4haloalkyl, OC1-4haloalkyl, CN, OC0-2alkyleneC3-5cycloalkyl, 5 OCH2CH2N(CH3)2, OH, C1-4alkylOH, NR23cR24c, SO2CH3, C(O)N(CH3)2, NHC(O)C1-3alkyl, or a C3-6heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2c, or R12c together with a nitrogen atom to which it is attached forms an N-oxide (N+- O-); R21c is H, C1-5alkyl, C(O)C1-5alkyl, C(O)OC1-5alkyl, C1-3alkylOC1-2alkyl, C1-4haloalkyl, or 10 C4-6heterocycloalkyl; R22c is H or CH3; R23c is H or C1-2alkyl; R24c is H or C1-2alkyl; R29c is C1-3alkyl, C0-2alkyleneC3-5cycloalkyl which cycloalkyl is optionally substituted by 15 CH3, CF3, N(C1-3alkyl)2, or a 5 or 6 membered heteroaryl wherein the 5 or 6 membered heteroaryl is optionally substituted by methyl; and R32c is C1-3alkyl and R33c is C1-3alkyl; or R32c and R33c together with the nitrogen atom to which they are attached form a C3- 5heterocycloalkyl; 20 wherein: R1c is R1ac; and / or R4c and R5c are R4ac and R5ac; and / or Ac is Aac; or a pharmaceutically acceptable salt and / or pharmaceutically acceptable solvate thereof.25 More suitably the CTPS1 inhibitor is selected from the following (‘List F’) compounds:1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4- oxocyclohexanecarboxamide; 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4- hydroxycyclohexanecarboxamide; 30 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4- hydroxycyclohexanecarboxamide (diastereomer 1); 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4- hydroxycyclohexanecarboxamide (diastereomer 2); 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-4-(dimethylamino)-N-(5-(6-ethoxypyrazin-2-35 yl)pyridin-2-yl)cyclohexane-1-carboxamide; 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-4-(dimethylamino)-N-(5-(6-ethoxypyrazin-2- yl)pyridin-2-yl)cyclohexane-1-carboxamide (diastereomer 1); STP-P3718PCT 63 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-4-(dimethylamino)-N-(5-(6-ethoxypyrazin-2- yl)pyridin-2-yl)cyclohexane-1-carboxamide (diastereomer 2); N-(4-(1-((4-(6-Ethoxypyrazin-2-yl)-2-fluorobenzyl)amino)propyl)pyrimidin-2- yl)cyclopropanesulfonamide; 5 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4,4- difluorocyclohexane-1-carboxamide; 8-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-1,4- dioxaspiro[4.5]decane-8-carboxamide; 4-(2-((N,N-dimethylsulfamoyl)amino)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-10 yl)tetrahydro-2H-pyran-4-carboxamide; 4-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-1- (methylsulfonyl)piperidine-4-carboxamide; N-(4-(1-(((5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)methyl)amino)cyclopropyl)pyrimidin-2- yl)cyclopropanesulfonamide; 15 N-(4-(1-((4-(6-ethoxypyrazin-2-yl)-2-fluorobenzyl)amino)cyclopropyl)pyrimidin-2- yl)cyclopropanesulfonamide; N-(4-(4-(((4-(6-ethoxypyrazin-2-yl)phenyl)amino)methyl)tetrahydro-2H-pyran-4-yl)pyrimidin-2- yl)cyclopropanesulfonamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-5,8- 20 dioxaspiro[3.4]octane-2-carboxamide; 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4- methoxycyclohexane-1-carboxamide; N-(4-(1-((4-(6-ethoxypyrazin-2-yl)phenyl)amino)propyl)pyrimidin-2- yl)cyclopropanesulfonamidearboxamide; 25 4-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-1-(2- methoxyacetyl)piperidine-4-carboxamide; 4-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-1- (ethylsulfonyl)piperidine-4-carboxamide; 4-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-1-(cyclopropylsulfonyl)-N-(5-(6-ethoxypyrazin- 30 2-yl)pyridin-2-yl)piperidine-4-carboxamide; 4-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-1-(N,N-dimethylsulfamoyl)-N-(5-(6- ethoxypyrazin-2-yl)pyridin-2-yl)piperidine-4-carboxamide; 4-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-1- ((trifluoromethyl)sulfonyl)piperidine-4-carboxamide; 35 4-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-1-((1- methyl-1H-pyrazol-3-yl)sulfonyl)piperidine-4-carboxamide; STP-P3718PCT 64 1-(cyanomethyl)-4-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2- yl)pyridin-2-yl)piperidine-4-carboxamide; ethyl 2-(4-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-4-((5-(6-ethoxypyrazin-2-yl)pyridin-2- yl)carbamoyl)piperidin-1-yl)acetate; 5 N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(2-(ethylsulfonamido)pyrimidin-4-yl)-1-(2- methoxyacetyl)piperidine-4-carboxamide; N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(2-(ethylsulfonamido)pyrimidin-4-yl)-1- (methylsulfonyl)piperidine-4-carboxamide; N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(2-(ethylsulfonamido)pyrimidin-4-yl)-1-10 (ethylsulfonyl)piperidine-4-carboxamide; 1-(Cyclopropylsulfonyl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(2- (ethylsulfonamido)pyrimidin-4-yl)piperidine-4-carboxamide; N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(2-(ethylsulfonamido)pyrimidin-4-yl)-1-((1-methyl-1H- pyrazol-3-yl)sulfonyl)piperidine-4-carboxamide; 15 1-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-cyclopropylpyrazin-2-yl)pyridin-2-yl)-4- methoxycyclohexane-1-carboxamide (diastereomer 1); 1-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-cyclopropylpyrazin-2-yl)pyridin-2-yl)-4- methoxycyclohexane-1-carboxamide (diastereomer 2); 1-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-20 (pyrrolidin-1-yl)cyclohexane-1-carboxamide (diastereomer 1); 1-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4- (pyrrolidin-1-yl)cyclohexane-1-carboxamide (diastereomer 2); 4-amino-1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2- yl)cyclohexane-1-carboxamide (diastereomer 1); 25 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4- morpholinocyclohexane-1-carboxamide (diastereomer 1); 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4- morpholinocyclohexane-1-carboxamide (diastereomer 2); 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-30 (methyl(oxetan-3-yl)amino)cyclohexane-1-carboxamide (diastereomer 1); 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-((2- methoxyethyl)(methyl)amino)cyclohexane-1-carboxamide (diastereomer 1); 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-((2- methoxyethyl)(methyl)amino)cyclohexane-1-carboxamide (diastereomer 2); 35 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-4-((2,2-difluoroethyl)(methyl)amino)-N-(5-(6- ethoxypyrazin-2-yl)pyridin-2-yl)cyclohexane-1-carboxamide (diastereomer 1); STP-P3718PCT 65 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(4- methylpiperazin-1-yl)cyclohexane-1-carboxamide (diastereomer 1); 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(4- methylpiperazin-1-yl)cyclohexane-1-carboxamide (diastereomer 2); 5 4-(6-(cyclopropanesulfonamido)pyrazin-2-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-1- (methylsulfonyl)piperidine-4-carboxamide; 4-(4-(cyclopropanesulfonamido)pyrimidin-2-yl)-N-(5-(6-cyclopropylpyrazin-2-yl)pyridin-2-yl)-1- (methylsulfonyl)piperidine-4-carboxamide; 4-(4-(cyclopropanesulfonamido)pyrimidin-2-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-1-10 (methylsulfonyl)piperidine-4-carboxamide; 4-(4-(cyclopropanesulfonamido)pyrimidin-2-yl)-N-(5-(6-cyclopropylpyrazin-2-yl)pyridin-2-yl)-1- (ethylsulfonyl)piperidine-4-carboxamide; and 4-(4-(cyclopropanesulfonamido)pyrimidin-2-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-1- (ethylsulfonyl)piperidine-4-carboxamide; 15 or a pharmaceutically acceptable salt and / or pharmaceutically acceptable solvate thereof. Such CTPS1 inhibitors are disclosed in PCT publication number WO2020245665 which is incorporated by reference in its entirety for the purpose of the CTPS1 inhibitors disclosed therein. In particular a CTPS1 inhibitor may be a compound described in any one of clauses 1 to 204 of WO2020245665 or a pharmaceutically acceptable salt and / or pharmaceutically 20 acceptable solvate thereof, in particular a compound selected from P226, P227, P228, P229, P230, P235, P242, P244, P248, P251, P254, P255, P256, P258, P260, P261, P288, P289, P290, P291, P292, P293, P294, P295, P296, P297, P298, P299, P300, P301, P302, P303, P304, P305, P306, P307, P308, P309, P310, P311, P312, P313, P314, P315, P316, P317 and P318 or a pharmaceutically acceptable salt and / or pharmaceutically acceptable solvate 25 thereof. Alternatively, the CTPS1 inhibitor is a compound of formula (VII): wherein A is Aa or Ab; 30 wherein Aa is an amine linker having the following structure: -NH-, -CH2NH- or -NHCH2-;Ab is an amide linker having the following structure: -C(=O)NH- or -NHC(=O)-; STP-P3718PCT 66 X is N or CH; Y is N or CR2; Z is N or CR3; 5 with the proviso that when at least one of X or Z is N, Y cannot be N; R1 is C1-5fluoroalkyl, with the proviso that R1 is not CF3; R2 is H, halo, C1-2alkyl, OC1-2alkyl, C1-2haloalkyl or OC1-2haloalkyl; R3 is H, halo, CH3, OCH3, CF3 or OCF3; wherein at least one of R2 and R3 is H; 10 R3’is H, halo, CH3, OC1-2alkyl or CF3; and when A is -NHC(=O)-, additionally R3’ together with R5 forms a 5- or 6-memberedcycloalkyl or 5 or 6 membered oxygen-containing heterocycloalkyl; R4and R5are R4aand R5a, or R4band R5b; wherein 15 R4aand R5atogether with the carbon atom to which they are attached form a C3-6cycloalkyl which is: substituted by one or two substituents, each substituent being independently selected from the group consisting of C1-3alkyl, oxo, OH, C1-3alkylOH, C1-3haloalkyl, C0-2alkyleneC3-6cycloalkyl, C0-2alkyleneC3-206heterocycloalkyl, C1-3alkyleneOC1-3alkyl, halo, OC1-3haloalkyl, OC0-2alkyleneC3-6cycloalkyl, OC0-2alkyleneC3-6heterocycloalkyl, OC1-3alkyl and NR21R22; or one of the carbons of the C3-6cycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C3-6cycloalkyl ring and a further25 C3-6cycloalkyl ring or a C3-6heterocycloalkyl ring, and wherein the C3-6cycloalkyl formed by R4aand R5atogether with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C1- 3alkyl or OC1-3alkyl; or 30 R4a and R5a together with the carbon atom to which they are attached form a C3- 6heterocycloalkyl wherein one of the carbons of the C3-6heterocycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C3-6heterocycloalkyl ring and a further C3-6cycloalkyl ring or a C3-6heterocycloalkyl ring, and wherein the C3-6heterocycloalkyl formed by R4a and R5a together with the carbon atom to 35 which they are attached may be substituted by one or two substituents, each STP-P3718PCT 67 substituent being independently selected from the group consisting of C1-3alkyl or OC1-3alkyl; or R4aand R5atogether with the carbon atom to which they are attached form a C3-6heterocycloalkyl comprising one nitrogen atom, wherein said nitrogen atom is 5 substituted by -S(O)2R29; or R4b and R5b are each independently H, C1-6alkyl, C1-6alkylOH, C1-6haloalkyl, C0- 2alkyleneC3-6cycloalkyl, C0-2alkyleneC3-6heterocycloalkyl, C1-3alkyleneOC1-3alkyl, or R4b and R5b together with the carbon atom to which they are attached form a C3-6cycloalkyl or C3-6heterocycloalkyl; and10 when A is -NHC(=O)- or -NHCH2-:R4b and R5b may additionally be selected from halo, OC1-6haloalkyl, OC0- 2alkyleneC3-6cycloalkyl, OC0-2alkyleneC3-6heterocycloalkyl, OC1-6alkyl and NR21R22; Ar1 is a 6-membered aryl or heteroaryl; 15 Ar2 is a 6-membered aryl or heteroaryl and is attached to Ar1 in the para position relative to group A; R10 is H, halo, C1-3alkyl, C1-2haloalkyl, OC1-2alkyl, OC1-2haloalkyl or CN; R11 is H, F, Cl, C1-2alkyl, CF3, OCH3 or CN; R12 is attached to Ar2 in the ortho or meta position relative to Ar1 and R12 is H, halo, C1-20 4alkyl, C2-4alkenyl, C0-2alkyleneC3-5cycloalkyl, OC1-4alkyl, OC0-2alkyleneC3-5cycloalkyl, C1- 4haloalkyl, OC1-4haloalkyl, hydroxy, C1-4alkylOH, SO2C1-2alkyl, C(O)N(C1-2alkyl)2, NHC(O)C1-3alkyl or NR23R24; and when A is -NHC(=O)-, -NH- or -NHCH2-:R12may additionally be selected from CN, OCH2CH2N(CH3)2and a C3-256heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2, or R12together with a nitrogen atom to which it is attached forms an N-oxide (N+-O-); R13is H or halo; R21 is H, C1-5alkyl, C(O)C1-5alkyl, C(O)OC1-5alkyl; 30 R22is H or CH3; R23is H or C1-2alkyl; and R24is H or C1-2alkyl; R29is C1-3alkyl, C0-2alkyleneC3-5cycloalkyl which cycloalkyl is optionally substituted by CH3, or CF3; 35 R32is C1-3alkyl and R33is C1-3alkyl; or R32and R33together with the nitrogen atom to which they are attached form a C3-5heterocycloalkyl; STP-P3718PCT 68 or a pharmaceutically acceptable salt and / or pharmaceutically acceptable solvate thereof. More suitably the CTPS1 inhibitor is selected from the following (‘List G’) compounds:4-(2-((2,2-difluoroethyl)sulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2- yl)tetrahydro-2H-pyran-4-carboxamide; and 5 2-(2-((2,2-difluoroethyl)sulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2- fluorobutanamide; or a pharmaceutically acceptable salt and / or pharmaceutically acceptable solvate thereof.Such CTPS1 inhibitors are disclosed in PCT publication number WO2021053403 which is incorporated by reference in its entirety for the purpose of the CTPS1 inhibitors disclosed10 therein. In particular a CTPS1 inhibitor may be a compound described in any one of clauses 1 to 191 of WO2021053403 or a pharmaceutically acceptable salt and / or pharmaceutically acceptable solvate thereof, in particular a compound selected from P271 and P284 or a pharmaceutically acceptable salt and / or pharmaceutically acceptable solvate thereof. Alternatively, the CTPS1 inhibitor is compound of formula (VIII): 15 wherein A is Aa or Ab; wherein Aa is an amine linker having the following structure: -NH-, -CH2NH- or -NHCH2-;20 Ab is an amide linker having the following structure: -C(=O)NH- or -NHC(=O)-; X is N or CH; Y is N or CR2; Z is N or CR3; 25 with the proviso that when at least one of X or Z is N, Y cannot be N; R1 is C1-5alkyl or C0-2alkyleneC3-5cycloalkyl, which alkyl or (alkylene)cycloalkyl is substituted by CN; R2 is H, halo, C1-2alkyl, OC1-2alkyl, C1-2haloalkyl or OC1-2haloalkyl; R3 is H, halo, CH3, OCH3, CF3 or OCF3; 30 wherein at least one of R2 and R3 is H; R3’ is H, halo, CH3, OC1-2alkyl or CF3; and when A is -NHC(=O)-, additionally R3’ together with R5 forms a 5- or 6-memberedcycloalkyl or 5 or 6 membered oxygen-containing heterocycloalkyl; STP-P3718PCT 69 R4and R5are R4aand R5a, or R4band R5b; wherein R4aand R5atogether with the carbon atom to which they are attached form a C3-6cycloalkyl which is: 5 substituted by one or two substituents, each substituent being independently selected from the group consisting of C1-3alkyl, oxo, OH, C1-3alkylOH, C1-3haloalkyl, C0-2alkyleneC3-6cycloalkyl, C0-2alkyleneC3- 6heterocycloalkyl, C1-3alkyleneOC1-3alkyl, halo, OC1-3haloalkyl, OC0- 2alkyleneC3-6cycloalkyl, OC0-2alkyleneC3-6heterocycloalkyl, OC1-3alkyl and10 NR21R22; or one of the carbons of the C3-6cycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C3-6cycloalkyl ring and a further C3-6cycloalkyl ring or a C3-6heterocycloalkyl ring, and wherein the C3- 6cycloalkyl formed by R4a and R5a together with the carbon atom to which 15 they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C1- 3alkyl or OC1-3alkyl; or R4a and R5a together with the carbon atom to which they are attached form a C3- 6heterocycloalkyl wherein one of the carbons of the C3-6heterocycloalkyl is a spiro 20 centre such that a spirocyclic ring system is formed by the C3-6heterocycloalkyl ring and a further C3-6cycloalkyl ring or a C3-6heterocycloalkyl ring, and wherein the C3-6heterocycloalkyl formed by R4a and R5a together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C1-3alkyl or25 OC1-3alkyl; or R4aand R5atogether with the carbon atom to which they are attached form a C3-6heterocycloalkyl comprising one nitrogen atom, wherein said nitrogen atom is substituted by -S(O)2R29; or R4b and R5b are each independently H, C1-6alkyl, C1-6alkylOH, C1-6haloalkyl, C0-302alkyleneC3-6cycloalkyl, C0-2alkyleneC3-6heterocycloalkyl, C1-3alkyleneOC1-3alkyl, or R4band R5btogether with the carbon atom to which they are attached form a C3-6cycloalkyl or C3-6heterocycloalkyl; and when A is -NHC(=O)- or -NHCH2-:R4band R5bmay additionally be selected from halo, OC1-6haloalkyl, OC0-352alkyleneC3-6cycloalkyl, OC0-2alkyleneC3-6heterocycloalkyl, OC1-6alkyl and NR21R22; Ar1 is a 6-membered aryl or heteroaryl; STP-P3718PCT 70 Ar2 is a 6-membered aryl or heteroaryl and is attached to Ar1 in the para position relative to group A; R10is H, halo, C1-3alkyl, C1-2haloalkyl, OC1-2alkyl, OC1-2haloalkyl or CN; R11 is H, F, Cl, C1-2alkyl, CF3, OCH3 or CN; 5 R12 is attached to Ar2 in the ortho or meta position relative to Ar1 and R12 is H, halo, C1- 4alkyl, C2-4alkenyl, C0-2alkyleneC3-5cycloalkyl, OC1-4alkyl, OC0-2alkyleneC3-5cycloalkyl, C1- 4haloalkyl, OC1-4haloalkyl, hydroxy, C1-4alkylOH, SO2C1-2alkyl, C(O)N(C1-2alkyl)2, NHC(O)C1-3alkyl or NR23R24; and when A is -NHC(=O)-, -NH- or -NHCH2-:10 R12 may additionally be selected from CN, OCH2CH2N(CH3)2 and a C3- 6heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2, or R12 together with a nitrogen atom to which it is attached forms an N-oxide (N+-O-); R13 is H or halo; 15 R21 is H, C1-5alkyl, C(O)C1-5alkyl, C(O)OC1-5alkyl; R22 is H or CH3; R23 is H or C1-2alkyl; and R24 is H or C1-2alkyl; R29 is C1-3alkyl, C0-2alkyleneC3-5cycloalkyl which cycloalkyl is optionally substituted by20 CH3, or CF3; R32 is C1-3alkyl and R33 is C1-3alkyl; or R32 and R33 together with the nitrogen atom to which they are attached form a C3-5heterocycloalkyl; or a pharmaceutically acceptable salt and / or pharmaceutically acceptable solvate thereof.25 More suitably the CTPS1 inhibitor is selected from the following (‘List H’) compounds:4-(2-((1-cyanocyclopropane)-1-sulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin- 2-yl)tetrahydro-2H-pyran-4-carboxamide; and 4-(2-((cyanomethyl)sulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2- yl)tetrahydro-2H-pyran-4-carboxamide; 30 or a pharmaceutically acceptable salt and / or pharmaceutically acceptable solvate thereof. Such CTPS1 inhibitors are disclosed in PCT publication number WO2021053402 which is incorporated by reference in its entirety for the purpose of the CTPS1 inhibitors disclosedtherein. In particular a CTPS1 inhibitor may be a compound described in any one of clauses 1 to 191 of WO2021053402 or a pharmaceutically acceptable salt and / or pharmaceutically 35 acceptable solvate thereof, in particular a compound selected from P285 and P287 or a pharmaceutically acceptable salt and / or pharmaceutically acceptable solvate thereof. STP-P3718PCT 71 The CTPS1 inhibitor may be 4-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)tetrahydro-2H-pyran-4-carboxamide (referred to herein as ‘CTPS1-IA’): , 5or a pharmaceutically acceptable salt and / or pharmaceutically acceptable solvate thereof.CTPS1-IA is a potent and selective inhibitor of CTPS1 (see e.g. WO2020083975).Alternatively, the CTPS1 inhibitor may be N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(2-(ethylsulfonamido)pyrimidin-4-yl)tetrahydro-2H-pyran-4-carboxamide (referred to herein as‘CTPS1-IB'): 10 , or a pharmaceutically acceptable salt and / or pharmaceutically acceptable solvate thereof. CTPS1-IB is a potent and selective inhibitor of CTPS1 (see e.g. WO2020245664). The compounds described above (and methods for making these compounds) are disclosed in PCT publication numbers WO2019106156, WO2019180244, WO2019106146,15 WO2019179652, WO2020245665, WO2020245664, WO2021053403, WO2021053402 or WO2020083975. Alternatively, the CTPS1 inhibitor is a compound of formula (IX): or a pharmaceutically acceptable salt thereof, wherein.

[0002] R* is selected fio-n uh-diaric. a:-7 membered salinated or pHrtuiHv uimtui cited immuimlic carb ixtvdte ring; and a 3-7 memhered sat u "a ted or partial y unsaturated monocyclic heterocyclic ring having 1 -2 heteiualotns indcttetidetill y selected front nitrogen, oxygen, and snlfui . each ol’ which is substituted with q i nstances of RA.

[0003] Ri rg \ i s selected frnni phe-n k a 1-7 membered saturated or ptmiallv unsatirated monwvclic carbrKyclic ring: a 5-b membered monocyclic hcteroaryl ring having 1 -4 heteroatoms i-idcpeiidenlly selected fiorr ri It ugen. oxy gen, mid sulfui. a 3-7 rm.Titn.n cul saturated or panidlh unsaturated niu’iccyx ic ticteiocydi c ring has iiH: I -? hvtei oate'T s i ridcyenderilh sniveled from mitogen. uwgsn. and sul fur; and a 7- ' I numbered used bicyc'ic heteroarvl ring having I 4 licleroatimrs independently selected fmm nilmgcn, oxygen, and sul fur. wherein each ol' R1. R1. and Rkis independently hydrogen. -C.\, halogen, or an optionally substituted group selected from Ci-,, aliphati c, phery l. a 3-7 membered sc limited or partially insal j membei wJ moniKiydic heterocyclic ring having 1 -2 heteroatnms independently selected from nitrogen, oxygen, card sulfur, a 5-6 nienibei cd rrunocy clic helc-i oar yl ring hav ing ! -■ lielcroatiTis independently selected from nitrogea, oxygen, and sulfur; or two ol’R.1-, RL, and R- groups arc taken together with the alums to which each is attachec, to form an iipliomil lv substituted i-7 merrbei ed salin ated or paninllv u-isdt m ated monucvclii: carbocyclic ring, o- .i 3-7 rie inhered salt rated nr partially unsaturated monocy clic heterocy cl ic ring hnv irg 1 -2 liclctoniunts independently selected I’win nitrogen. oxy gen, arid sulfur . or any one of R1, R . and R1. togclhei will' RHfbiriis a 7- 1 '1 mernbei ed saturated in par'.ially unsaturated fused bicyclic ring;

[0004] Ring B is selected from pher.yl. a 3-7 membered saturated or partially unsaturated nionocydic cdibiK-yclif line, a .'-ft nicnihe-cd nKniocyc.ic hclviotnyl ling hm-rig I --I helcHialoii is independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur: a 5- 1 I membered saturated or partially unsaturated fused, hedged. or spire, bios die carbocydiL' ring, a 7-! I membered fused bicv die ary ring. a 7- 1 I membered saturated or pnirinlh unsaturated fused. bri deed. ra spiro, bicu-lic heternm JR: rirg hav ing 1 -4 heleroaioms independently selectee from nitrogen, oxygen and sulfur; and a 7-1 1 nrembeicd fused bicyclic holer um I ring having 1 -4 hctcroa'.onis irdepeude-idy selected from nitrogen, oxygen, and sulfur;

[0005] Ri rg € is selected from a phervl, t-7 membered saturated or paniallv tmsa treated monocyclic carbnvyclic ring, a 5-ft membered monocyclic heteioaryl ring having 1-4 heteroatoms independently selected fioir ritiugen. uxy uen, and sulfui. a 3-7 membered satuialed or partially unsaturated monocyclic heterccvdic rirg hav ing 1-2 heteroatoms indepciidwulv selected from nitiogeii oxygen, and sulfur; and a 7- I membered fused bicyc le heteroaiyl ring having 1 -4 lietcroatnms independently selected from nitrogen, oxygen, and sulfur, or the bond between Ring B and Ring C is absent, and Ring 13 and Ring U together form a 7-1 1 membered salt. rated or partinlh i.nsahirated fused, bri dyed, or spi ro bicy clic carhncyclie ring, a 7- I riembereti fused him, ci c aryl ring; a 7- 1 membered saturated nr partially unsaturated fused, budged, or spiio. bicyclic hclerocydk ting having 1 -t hctcroalmns independently selected from nitrogen, oxygen, and sulfur; or a 7-1 1 membered fused bicyclic heteroaryl ring having I -4 heteroatonts independently selected from nitrogen, oxygen, and sulfur each instance of R< R". and Rcis independently oxo. halogen. CN. XO-, OR. - SR, -NRu -MO.bR,

[0006] -SiOBXR.. -S(())R. -S(())NR.v -(’KM -C(O)OR. -CfOjNR-, -(’tOiN(R)OR, X(R )CX. PtOKRjXRrt IWtl R lOR or PiOiRj . or eac i instance of R1- is independently an (mtiunally substituted gloup selected funu C i-, aliphatic, phenyl, nap-ithalcnyl. a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a. 3-7 membered saturated or partially unsaturated nionceydic heterocy die ring having 1 -2 heteroatoms v idcpei idc-ntly selected I’-oiu nitreger. oxygen. phosphoKkis. silktn: and sidlui . <n a 5-ft membered monocyclic hetemaryl ring having 1-4 hetaxMtoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered hicvvlic heteroary' ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and snlF.tr: A 5-8 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 hetsoatams independently selected hen mtioyen. uw -'.en. ai’d sulfu-. a o-'ii membered saturated or tra-iial h unsaturated spinxrydic ring hating 0-3 hcleroaioirs mdependently selected from nitrogen, oxyger, and sulfur, ai a e-11 niciribuTcd saturated or par :rally unsaturated bicyclic heterocyclic rng hating 1-2 -irtekiHtoms ii’drpcndriit v selected iron -ririiwi. imurv. and sulfur, eaci of ulwi is substituted with r instances of R and s instances of R°; or two Rcgroups are optionally taken together with rhe atoms to which each R:is attached, to fonn an optionally substituted 3-7 membered saturated or partially unsaturated inonocy die caikicychc ring, a 5-7 membcicd heteroaiyl 'inu having 1-2 hrtew.toms irdependenf v selected frnni nitrogen, oxygen, and sulfur; or a 3-7 membered saturated nr parthflv unsaturated riunucydic hderocydie ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and suliirr: each instance of R? is mdeperwerih o.\o. halagtr. -CN, -NCh, -OR. -SR. -XR;. -S(Oj-R,

[0007] -(X’l'OlR. -(M’(O)NRx -N(R)C(O)OR. -X(R)C(OtR. -XtRK'(OjNR>, -X(R (Ct XRjNR

[0008] N(RJMU -X(R)S|(HAR:;X(RtS(()),R. X StO|R2. SfNRllOlR. X(R)StO)R. -

[0009] XUOCX. P(())(R)XR-, PfOitlOORcr P(O)Rj . each R is independentiy hydrogen. -OX. halogen, or an optionally substituted group selected from (’• i aliphatic: phenyl, naphthaienyl. a 3-7 membered saturated or partially unsaturated memxrydic caibocvchc ring, a 3-~ iremlrated saturated tn part-ally un-rakrated nnmocvclic heterocyclic ring having 1-2 heteroatoms independently- selected from nitrogen, oxygen, and sulfur: n membered morion die heteuiarv ring having 1-4 htierodumis indepardently selected from nitrogen, oxygen, and sulfur: an S- 10 membered bicyclic heiemaryl rng having 1- 1 I‘c1eidatui:is independently selected fi'isni nitrogen, oxygen, mid sulfur, a7-12 membered saturated in pa-lially urise.lu- aled bicyclic helc-ucyclic ling having 1-4 huteiraloms independently selected from nitrogen, oxygen, and sulfim a 5-B membered saturated or partially i in s;it united budged bicyclic ring huving i M heteroaloms independently selected from nitrogen, oxygen, and sulfur, a ft-10 mcrrbeicd saturated in pallidly unsaturated spinn-ydic ring having 0-3 heteroaioms independently selected from nitrogen, oxygen, and sulfur; a 6-11 membered saturated or part ally unsaturated bi cyclic carbocyclic ring having 1-2 heteroatoms independently selected from nitrogen oxygen, and sulfur, nr two R groups are taken together with the atoms to which each R is attached, to form an optional ly substituted 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 3-7 membered -saturated or partially unsaturated monocyclic heterocyclic ring haxing 1-2 hcteroatoms independently seiec-.ed from nitrogen.. oxygen, and sulfur . <n

[0010] :m is 0, I, or 2; n isO, 1, or 2; p is 0, 1, or 2; each i| is independently u. 1, 2. 3. or -I. each r is independently n. 1.2. < or 4. and each s is independently 0. I. 2. 3, o- 4. pnox iced that when

[0011] R is C ,, a iphalic or a 3-7 membered saturated or pat ti all v ur saturated monocyclic rafwwlii’ ring

[0012] ! 'ie R yr imp ol llic sul tor imni de morels :s hvcnmvri or p ar .r -in ethoxy heir A I

[0013] US and the R and R1orlV and R’ groups are not ta^en toy, ether with the atoms to which each A attached tn form an optionally substituted 3-7 membered saturated or partially unsaturated murocyclic Iwterocyck one having 1-21‘eleroatoms independently ^elected from nitrogen owgeii. and stiifur. orLis

[0014] Ring B is phenyl or a P-memhered mirimcxclic Intoroarx I riru having 1-4 heteronhmis independently selected from, nitrogc:!, oxygen, and sulfur, and

[0015] RriigC is phenyl or a o-mcrirbuted rnonocxclrc helcroaryl ring having 1-4 hctcToatimis independently selected I’torr nitiogwr. rAxgen. and sulfur and isaltac'tedto Ring B in the para position relative to the 1. group; STP-P3718PCT 76 or a pharmaceutically acceptable salt and / or pharmaceutically acceptable solvate thereof.Such CTPS1 inhibitors are disclosed in PCT publication number WO2022087634 whichis incorporated by reference in its entirety for the purpose of the CTPS1 inhibitors disclosed5 therein. In particular a CTPS1 inhibitor may be a compound described in any one of claims 1 to 31 of WO2022087634 or a pharmaceutically acceptable salt and / or pharmaceuticallyacceptable solvate thereof. A CTPS1 inhibitor may be a compound selected from compoundsI-1 to I-286 of WO2022087634, or a pharmaceutically acceptable salt and / or pharmaceutically acceptable solvate thereof. A CTPS1 inhibitor may be a compound selected from compounds10 Z-1 to Z-10 of WO2022087634, or a pharmaceutically acceptable salt and / or pharmaceuticallyacceptable solvate thereof. Alternatively, the CTPS1 inhibitor is a compound of formula (X): v. hcrcir R10 hydnwcn w opunmihy Mihslilulcd Ci.-. tiliphaur untl one tri R:or R " H hydrogen and the other ol' R1nr R1k -1:-R\ wherein:

[0016] R“ i'. '•lydmgcn, htilnpxn, -OR, -XR;. nn optionally subxitutcd eyelic group salaried fmm a 3-S nicmburcd xitn ruled or puri 011 y .inxttur n ed nionocydic c.irbocydic ritui. a 7-12 membered vilurnkd u- partially inxilunilvd hiodic earbuejeiie ring, phenyl, an b-; n meir.bercs.. Meydie arum.mc eaibocvdic nag. a 5-S membered Mitiijatcd or

[0017] partially unsaturated n n mi uyclic hctcrucy die ring ihming 1-2 he' croat on is independently selected Ironi nitrogen. oxygen. and sullur’i. u 7-12 membered saturated or purlially unsaturated bicyclic’ heterocyclic ring that is optionally bridged bicyclic during 1-4 licteroamms independently selected from nitrogen, oxygen, and sullurt, a 7-12 memhered siitmated or partially unsaturated spimcxdic IxUrno during liming 1-4 l-ctcroalnms indcpcnden'h selected from nitrogen. oxygen, and Mil lurk a s-6 membered monocyclic net crime mat ic ring (Inn inn 1-4 hctcmiiloms indqx mdcmly sdvded Iroin tuiiogcn. oxygen. and su'l'ur). and an S-Hl membered bicyclic licleronroriidlic ring (hating 1-5 I'.etcro.itoms indcpcridentiy ■'elected li'oru nitrogen, oxygen., ar.d sidiur): and

[0018] L’ is a covalent bund or a saturated er unsaturated. straight or branched, optionally stib.sim.1cd bivalent ( ' i. j hydrocarbon chain, wherein (t 2 methylene units id' I. arc independently replaced by -O-. -XIR-, -S-. -Ot.(C))-. -C(O)O-. -SiOp-.

[0019] -t. iSt- A ■ Kl - ARNO.i- -SK d \t<-. -XA( ilJi-.-i i ( JtXR- -iXiOjXK- - \R(.'iO)C)-. or-\RL(O)\R-. or

[0020] R1- is hydrogen or uptiandly substituted Cra aliphatic and an R1and R1group arc take i tugether ’,x ilh the atmi to \v hicli they are attached. Io lortu an opli i mul lx subslilutcxl 3-7 membered saturated or partial lx unsaturated monocyclic carbocyclic ring: ora 37 membered uplmually substituted satutaled impartially unsaturated nionney d:c helcrocy eke ring having 1-2 livlennilunis. independently selected I'rmn nitrogen, oxygen, and sulliir:

[0021] Ring B is selected from phenyl: a 3-7 membered Mitimned er parlic.lK unsaturated monocyclic carbocyclic "ini’; n 5-6 membered mnnncyc’ic hcicrriaryl ring, haxing 1-4 hctcroaioms ndcpendenih selected I'rorn nitrogen oxygon, and sulliir: a membered Mihiralcd or partially unsaiuniicd mnmxyJic hcicrraxclic ring ho.iim i-1 hektromoms iiKlcpcndcnily selectee h'orii nitrogen, oxygen, and sullar. a 5-1 I membered s.itiaatcd in jtailially itns.ituralcd fused, bridged, or spiro, bicyclic carhucxulic ring: a 7- 11 rmri ibered fused bwydiu aryl ring: a 7-12 incnibcrcd sanitated or partially unsaturated bicyclic heterocyclic ling that is iipliuimly bridged bicyclic fhaxing I-l licLcroaluins irdepcndcrit'y selected I'roni nitrogen, uxxgcri. and sulfur;, a7-l2 membered saturated or partiidly unsaturated spimeyclic heterocyclic ring ihacing I-- hclcroaionis independently scrcetcd from nitrogen, oxygen, and suUyri: and a 7- I I membered lust'd hicy dic hetcrmiryl ring Inn ing I - 1 belertuloms mdependeriily sulcclcd from ni’.iwn. oxygen. and sulfur'

[0022] Ring C is selected frrnn a phenyl. 3-7 menibcrcil sulunilcd irr partLIly unsuLuruk’d inonocyclk' carbocyclic ring: a 5-6 ntcmhvrcd inonueydic hclcnuiryl ring hav ing 1 -4 hckTou.lt mis n.kpcridcntly selected from niiroi’cn. oxy gen, and -»,iUur: a 3-" membered siihirincd ir pnriirdly uns.i i urn lea monocyclic heterocyclic ri ng Inn mg I -2 hcicroatonis independent ly selected, from nitrogen, nxynem and sulfur; and ;i - I I membered fused bicy clic hcicmary’ ring Inn irig 1-- Ik'icroutoms independently sciccicc. Irnm uitmgrn. oxy gen, mid suH m .

[0023] I'uch iistarice of R \ R'\ and R' is independently optionally sumstitnted Ci : aliphatic, o.xo. hamgen. C.\, NCb. -OR, -SR, NR;. SfOHR. -SiOj-NRn -S(f))R. -S(O)NRn -OiO)R. R ’lO fOR. f« ))NR'. -Cl'();-N(R J()R.

[0024] (X (O)R. -OOi f RNRy -NfRKG WR- -Nt RjC((BR, -NiR j( V))NR;. -N(R iGNRlNR;.

[0025] N(R )N'Rj, -Ni Ry$(CHAR ■. WlOf R. X”S|O)R>. S(\!Ri{O|R. NiRtSKljR, Nl R lCN. P(( )}( R JNR PlOn R)( )R. rr IhOjR y each R is independently hydrogen, -C N. halogen, or an opt • anally substituted itmup selected from aliphatic: phenyl, iviphthukriyl; ;i 3-7 membered saturnu-J nr puniidh n iis.i'iimled tiimiui'ycitc carbocyJm ring: a 3-7 inciiibctcd saturated m parimlly unsaiunilcd tuiHiOLyclic hclcrucy clic ring haung 1 2 lielurualonis independently selected Irnm mlrogcrt. oxygen, ;mc sulliir: a 5-6 membered mmiocy die hulcrcaryi ring hax mg I-t heteroalonm independently selectee. Iron: nitrogen, oxygen, and stdliir: an -N lit inciiibercd htcy clic hcleroaryl ring hax ing 1 -4 hclcroalonis independently selected from ttimij’cn, oxygen. :nd suitin', a 7-12 membered saturated or "tartially unsaturated bicyclic hctcrncydic ring having. 1-4 lid cron toms ndependemly selected I rnm nitrojtdi, oxygen, and sidfitr: a 0-1 ? membered saliimicd or partially unsniutdcd bridged hicyr lie ring hm. inn '4-3 hdcimitliiins independently sdcddJ fmm rnlrogeit. oxyget., and s.tlliir; a 6- i(l niunihered sidtu'aied or partially unsaturated spimcydtc ring having R d liclcnndoms independently <clcclec Ircru nitrogen, oxygen, and sulfur; a 6 1 1 membered satin lik'd or partial ly ui isa’urated bicyclic curbocyclic ring, or fan R groups arc taken '.ogethc- with the atoms to M hidi eudi R is alladicd. tu iorni ati nplmnally sub-timicd 3-7 membered saturated or par'dally unsninralcd monocyclic STP-P3718PCT 80 or a pharmaceutically acceptable salt and / or pharmaceutically acceptable solvate thereof.Such CTPS1 inhibitors are disclosed in PCT publication number WO2023205475 whichis incorporated by reference in its entirety for the purpose of the CTPS1 inhibitors disclosed5 therein. In particular a CTPS1 inhibitor may be a compound described in any one of claims 1 to 25 of WO2023205475 or a pharmaceutically acceptable salt and / or pharmaceuticallyacceptable solvate thereof. A CTPS1 inhibitor may be a compound selected from compoundsI-1 to I-293 of WO2023205475, or a pharmaceutically acceptable salt and / or pharmaceuticallyacceptable solvate thereof. A CTPS1 inhibitor may be a compound selected from compounds10 II-1 to II-21 of WO2023205475, or a pharmaceutically acceptable salt and / or pharmaceuticallyacceptable solvate thereof. Alternatively, the CTPS1 inhibitor is a compound of formula (XI): or a pharmaceutically acceptable salt and / or pharmaceutically acceptable solvate thereof, as15 defined in claim 1 of WO2024153247. Such CTPS1 inhibitors are disclosed in PCT publication number WO2024153247 whichis incorporated by reference in its entirety for the purpose of the CTPS1 inhibitors disclosedtherein. In particular a CTPS1 inhibitor may be a compound described in any one of claims 1 to 14 of WO2024153247 or a pharmaceutically acceptable salt and / or pharmaceutically20 acceptable solvate thereof. A CTPS1 inhibitor may be a compound selected from compounds1 to 75 of WO2024153247, or a pharmaceutically acceptable salt and / or pharmaceuticallyacceptable solvate thereof. A CTPS1 inhibitor may be a compound selected from compoundsof claim 14 of WO2024153247, or a pharmaceutically acceptable salt and / or pharmaceuticallyacceptable solvate thereof.25 Depending on the nature of the specific CTPS1 inhibitor, the CTPS1 inhibitor may beprovided in the form of a pharmaceutically acceptable salt and / or pharmaceutically acceptable STP-P3718PCT 81 solvate. In some embodiments the CTPS1 inhibitor is provided in the form of a pharmaceutically acceptable salt and pharmaceutically acceptable solvate (i.e. a pharmaceutically acceptablesolvate of a pharmaceutically acceptable salt). In other embodiments the CTPS1 inhibitor isprovided in the form of a pharmaceutically acceptable salt. In further embodiments the CTPS1 5 inhibitor is provided in the form of a pharmaceutically acceptable solvate. In some embodiments the CTPS1 inhibitor is provided in free form (i.e. not a salt or solvate).Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art. Pharmaceutically acceptable salts include those Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, 1985, p.1418. Such pharmaceutically acceptable 10 salts include acid addition salts formed with inorganic acids e.g. hydrochloric, hydrobromic, sulphuric, nitric or phosphoric acid and organic acids e.g. succinic, maleic, acetic, fumaric, citric, tartaric, benzoic, p-toluenesulfonic, methanesulfonic or naphthalenesulfonic acid. Pharmaceutically acceptable salts may also be formed with metal ions such as metal salts, such as sodium or potassium salts, and organic bases such as basic amines e.g. with ammonia,15 meglumine, tromethamine, piperazine, arginine, choline, diethylamine, benzathine or lysine. The CTPS1 inhibitor may form acid or base addition salts with one or more equivalents of the acid or base. The present invention includes within its scope all possible stoichiometric and non-stoichiometric forms. The CTPS1 inhibitor may be prepared in crystalline or non-crystalline form and, if 20 crystalline, may optionally be solvated, e.g. as the hydrate. This invention includes within its scope stoichiometric solvates (e.g. hydrates) as well as compounds containing variable amounts of solvent (e.g. water). Unless defined for as part of a formula or compound structure, the CTPS1 inhibitorencompasses all isomers of the CTPS1 inhibitors disclosed herein including all geometric, 25 tautomeric and optical forms, and mixtures thereof (e.g. racemic mixtures). Where additional chiral centres are present, the present invention includes within its scope all possible diastereoisomers, including mixtures thereof. The different isomeric forms may be separated or resolved one from the other by conventional methods, or any given isomer may be obtained byconventional synthetic methods or by stereospecific or asymmetric syntheses. 30 The CTPS1 inhibitor encompasses all isotopic forms of the CTPS1 inhibitors provided herein, whether in a form (i) wherein all atoms of a given atomic number have a mass number (or mixture of mass numbers) which predominates in nature (referred to herein as the “natural isotopic form”) or (ii) wherein one or more atoms are replaced by atoms having the same atomic number, but a mass number different from the mass number of atoms which predominates in 35 nature (referred to herein as an “unnatural variant isotopic form”). It is understood that an atom may naturally exist as a mixture of mass numbers. The term “unnatural variant isotopic form” also includes embodiments in which the proportion of an atom of given atomic number having a STP-P3718PCT 82 mass number found less commonly in nature (referred to herein as an “uncommon isotope”) has been increased relative to that which is naturally occurring e.g. to the level of >20%, >50%, >75%, >90%, >95% or >99% by number of the atoms of that atomic number (the latter embodiment referred to as an "isotopically enriched variant form"). The term “unnatural variant 5 isotopic form” also includes embodiments in which the proportion of an uncommon isotope has been reduced relative to that which is naturally occurring. Isotopic forms may include radioactive forms (i.e. they incorporate radioisotopes) and non-radioactive forms. Radioactive forms will typically be isotopically enriched variant forms. Unnatural variant isotopic forms comprising radioisotopes may, for example, be used for 10 drug and / or substrate tissue distribution studies. In one embodiment, the CTPS1 inhibitor is provided in a natural isotopic form. In one embodiment, the CTPS1 inhibitor is provided in an unnatural variant isotopic form. In one embodiment, the CTPS1 inhibitor is provided whereby a single atom of the compound exists in an unnatural variant isotopic form. In another embodiment, the CTPS1 inhibitor is 15 provided whereby two or more atoms exist in an unnatural variant isotopic form. In one embodiment there is provided 4-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N- (5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)tetrahydro-2H-pyran-4-carboxamide (‘CTPS1-IA’): , or a pharmaceutically acceptable salt and / or pharmaceutically acceptable solvate20 thereof, for use in the treatment of ET in a human subject.In a further embodiment there is provided 4-(2-(cyclopropanesulfonamido)pyrimidin-4- yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)tetrahydro-2H-pyran-4-carboxamide (‘CTPS1-IA’): , for use in the treatment of ET in a human subject.25 Certain embodiments of the invention relate to the treatment of myeloproliferative neoplasms (MPN). Diagnostic criteria for MPN, including essential thrombocythaemia (ET), STP-P3718PCT 83 polycythaemia vera (PV) and myelofibrosis (MF), may be found in Arber et al.2016 and Tefferiet al. 2013.In one embodiment the MPN is ET. In a further embodiment the MPN is PV. In a further embodiment the MPN is MF. Most suitably the MPN is ET. 5In one embodiment the subject has one or more of a JAK2 mutation in myeloid orlymphoid lineage cells (such as a JAK2 V617F mutation), a CALR mutation in hematopoieticstem cells or an MPL mutation in hematopoietic stem cells. Suitably, the MPN is ET and thesubject has one or more of a JAK2 mutation in myeloid or lymphoid lineage cells (such as aJAK2 V617F mutation), a CALR mutation in hematopoietic stem cells or an MPL mutation in10 hematopoietic stem cells, particularly a JAK2 V617F mutation in myeloid or lymphoid lineagecells. Treatment of an MPN is typically clinically significant and / or measurable, for instance inthe context of (a) inhibiting the disease-state, i.e., slowing or arresting its development; and / or (b) relieving the disease-state, i.e., causing regression of the disease state or a reduction in15 associated symptoms. Treatment may more specifically refer to any one or more of (a)preventing increase in blood cell count of at least one blood cell type in a subject or reducingan elevated blood cell count of at least one blood cell type in a subject, (b) reduction insymptoms of the MPN in the subject (e.g. as self-reported or established by physician enquiry such as via a survey), (c) extension of the life span of the subject, (d) delay or prevention of20 progression of the MPN or (d) reduction in the frequency of thrombosis in a subject. Treatmentmay also more specifically refer to maintaining blood cell count of at least one blood cell type in a subject. Delay or prevention of progression of the MPN may for example be quantified by observation of the level of thrombosis, haemorrhage, infections, symptom burden (e.g. pruritus, night sweats), extent of bone marrow fibrosis, driver gene mutational allele burden, 25 and clonal evolution. Delay or prevention of progression of the MPN may also for example be quantified by a lack of evolution from ET to PV, ET to post-ET-MF, PV to post-PV-MF, or pre- PMF to overt PMF, and / or lack of transformation of any of these subtypes to myelodysplastic neoplasms or acute leukemia. Suitably, delay or prevention of progression of the MPN may be quantified by an increase in the mean time taken for evolution from ET to PV, ET to post-ET- 30 MF, PV to post-PV-MF, or pre-PMF to overt PMF, and / or lack of transformation of any of these subtypes to myelodysplastic neoplasms or acute leukemia, in a population compared to the expected (or measured) mean time taken for the same evolution in a comparable but untreated population. The clinical consequences of ET, specifically thrombotic complications, are thought to35 be caused by the increase in the thrombocyte and neutrophil counts. Treatment of ET, andprevention of thrombotic complications, is conventionally achieved using drugs to reduce the platelet and neutrophil counts into the normal range. Control of blood counts may also reduce STP-P3718PCT 84 the risk of patients with ET progressing to MF. Given the effects of CPTS1 inhibition illustrated in the examples on the platelet and neutrophil counts in a phase 1 clinical trial of patients withlymphoma, CTPS1 inhibition is expected to be effective in treating patients with an MPN. The clinical consequences of PV are mainly due to the increase in haemoglobin level 5 and red blood cell counts. This can often be managed by regular removal of blood (venesection) which effectively lowers the haemoglobin level and red blood cell count. In some patients, the thrombocyte and neutrophil counts are also elevated, or become elevatedfollowing venesection. Accordingly, if the MPN to be treated is PV, then in one embodiment the subject has elevated thrombocyte and / or neutrophil levels. Such patients may benefit from10 CTPS1 inhibition to control the increased thrombocyte and neutrophil counts, in order tomaintain these in the normal range. MF can arise de novo or following an initial phase of ET or PV. In MF, bone marrowfibrosis is driven by abnormal proliferation of megakaryocyte precursors. Some patients with MF have raised platelet counts whilst in others the platelet count is reduced due to15 enlargement of the spleen. The findings set out in the examples indicate that CTPS1 inhibitionmay reduce the proliferation of abnormal megakaryocyte precursors, thereby reducing platelet counts and potentially slowing the progression of disease.Cell counts may be expressed as a concentration of a particular cell type in the blood ofa subject (e.g. thrombocytes or leukocytes), or the concentration of two or more particular cell 20 types in the blood of a subject (e.g. thrombocytes and leukocytes). A blood cell count may be established by taking a blood sample from the subject, suitably from a vein. Certain embodiments of the invention relate to cell count, including preventing increase in or providing a reduction of a cell count. Certain embodiments of the invention relate to cellcount, including maintaining cell count. Suitably, the cell count is prevented from increasing25 above a therapeutically beneficial range. Alternatively, the cell count may be reduced to atherapeutically beneficial range. A cell count in a therapeutically beneficial range is a cell concentration in the blood which cures or alleviates symptoms or progression of an MPN. Aphysiologically normal cell count range is a cell concentration in the blood which is considered normal for the subject in standard medical practice. 30 In one embodiment a physiologically normal cell count range is one wherein the subject’s thrombocyte count is 30x109 / L to 1500x109 / L, such as 90x109 / L to 1000x109 / L, suchas 100x109 / L to 750x109 / L, such as to 110x109 / L to 500x109 / L, such as 120x109 / L to400x109 / L, such as 130x109 / L to 370x109 / L.In one embodiment, the subject has an elevated (i.e. above physiologically normal) 35 thrombocyte count. In another embodiment, the subject has an elevated leukocyte count. In another embodiment, the subject has an elevated neutrophil count. STP-P3718PCT 85 In one embodiment, the subject has an elevated (i.e. above physiologically normal) thrombocyte count before initiation of treatment. In another embodiment, the subject has an elevated leukocyte count before initiation of treatment. In another embodiment, the subject has an elevated neutrophil count before initiation of treatment.5 Particular types of blood cells of interest include thrombocytes (also known as‘platelets’), erythrocytes (also known as ‘red blood cells’), megakaryocytes and leukocytes(also known as ‘white blood cells’). Leukocytes include granulocytes and agranulocytes. Granulocytes include neutrophils, eosinophils and basophils. Agranulocytes include lymphocytes and monocytes. In one embodiment the cell type for the purpose of a cell count10 are thrombocytes and / or leukocytes, such as thrombocytes and / or granulocytes, such as thrombocytes and / or neutrophils. Suitably the concentration of thrombocytes in the subject’s blood after administration of the CTPS1 inhibitor (i.e. thrombocyte count) is 4000x109 / L or lower, such as 2000x109 / L orlower, such as 1000x109 / L or lower, such as 900x109 / L or lower, such as 700x109 / L or lower,15 such as 500x109 / L or lower, such as 400x109 / L or lower. Alternatively, or additionally, theconcentration of thrombocytes in the subject’s blood after administration of the CTPS1 inhibitor (i.e. thrombocyte count) is suitably 30x109 / L or higher, such as 90x109 / L or higher, such as110x109 / L or higher, such as 120x109 / L or higher, such as 130x109 / L or higher, such as140x109 / L or higher, such as 150x109 / L or higher. More suitably, the concentration of20 thrombocytes in the subject’s blood after administration of the CTPS1 inhibitor (i.e. thrombocyte count) is 130x109 / L to 700x109 / L, such as 140x109 / L to 500x109 / L such as150x109 / L to 400x109 / L.Suitably the concentration of thrombocytes in the subject’s blood (i.e. thrombocyte count) before treatment with the CTPS1 inhibitor according to the invention is 400x109 / L or25 higher, such as 500x109 / L or higher, such as 700x109 / L or higher, such as 900x109 / L or higher,such as 1000x109 / L or higher, such as 2000x109 / L, such as 4000x109 / L or higher.Suitably the concentration of thrombocytes in the subject’s blood after administration of the CTPS1 inhibitor (i.e. thrombocyte count) is reduced by at least 10%, such as at least 20%, such as at least 30%, such as at least 40%, such as at least 50%, such as at least 60%, such 30 as at least 70%, such as at least 80%, relative to the concentration of thrombocytes in the subject’s blood before administration of the CTPS1 inhibitor according to the invention. Suitably the concentration of thrombocytes in the subject’s blood after administration of the CTPS1 inhibitor (i.e. thrombocyte count) is reduced by no greater than 80%, such as no greater than 70%, such as no greater than 60%, such as no greater than 50%, such as no35 greater than 40%, such as no greater than 30% relative to the concentration of thrombocytesin the subject’s blood before administration of the CTPS1 inhibitor according to the invention. STP-P3718PCT 86 Suitably the concentration of leukocytes in the subject’s blood after administration of the CTPS1 inhibitor (i.e. leukocyte count) is 15x109 / L or lower, such as 13x109 / L or lower, suchas 12x109 / L or lower, such as 11.0x109 / L or lower, such as 10.5x109 / L or lower, such as10.3x109 / L or lower, such as 10.0x109 / L or lower. Alternatively, or in addition, the5 concentration of leukocytes in the subject’s blood after administration of the CTPS1 inhibitor (i.e. leukocyte count) is suitably 1x109 / L or higher, such as 2x109 / L or higher, such as 3x109 / Lor higher, such as 3.5x109 / L or higher, such as 4.0x109 / L or higher, such as 4.3x109 / L orhigher, such as 4.5x109 / L or higher. More suitably the concentration of leukocytes in thesubject’s blood after administration of the CTPS1 inhibitor (i.e. leukocyte count) is 4.0x109 / L to10 10.5x109 / L such as 4.3x109 / L to 10.3x109 / L such as 4.5x109 / L to 10.0x109 / L.Suitably the concentration of neutrophils in the subject’s blood after administration of the CTPS1 inhibitor (i.e. neutrophil count) is 13x109 / L or lower, such as 12x109 / L or lower,such as 11x109 / L or lower, such as 10x109 / L or lower, such as 9x109 / L or lower, such as8x109 / L or lower, such as 7x109 / L or lower. Alternatively, or in addition, the concentration of15 neutrophils in the subject’s blood after administration of the CTPS1 inhibitor (i.e. cell count) is suitably 0.5x109 / L or higher, such as 1.0.0x109 / L or higher, such as 1.5x109 / L or higher, suchas 2.0x109 / L or higher, such as 2.2x109 / L or higher, such as 2.4x109 / L or higher, such as2.5x109 / L or higher. More suitably the concentration of neutrophils in the subject’s blood afteradministration of the CTPS1 inhibitor (i.e. cell count) is 2.2x109 / L to 9x109 / L such as 2.4x109 / L20 to 8x109 / L such as 2.5x109 / L to 7.0x109 / L.In one embodiment the method comprises the step of establishing the thrombocyte and / or neutrophil count of the subject after administration of the CTPS1 inhibitor, after anadequate period of treatment with the CTPS1 inhibitor and (a) if the count is greater than a desired (e.g. physiologically normal) cell count range, administering the CTPS1 inhibitor again25 at an increased daily dose or (b) if the count is less than the desired (e.g. physiologicallynormal) cell count range, administering the CTPS1 inhibitor again at a reduced daily dose or(c) if the count is within the desired (e.g. physiologically normal) cell count range, administeringthe CTPS1 inhibitor again at the same daily dose; and optionally repeating this step, such as for the duration of treatment. 30 An ‘adequate period’ as used above refers to a length of time of multiple administrations of the CTPS1 inhibitor which may be expected to significantly impact the cell count of interest. In one embodiment the method comprises the steps of (a) administering an initial daily dose of CTPS1 inhibitor and 35 (b) establishing the thrombocyte count of the subject, wherein if the thrombocyte count of the subject is greater than a physiologically normalcell count range, administering the CTPS1 inhibitor again at an increased daily dose, then STP-P3718PCT 87 repeating steps (a) and (b), or if the thrombocyte count of the subject is within a physiologically normal cell count range, administering the CTPS1 inhibitor again at the previous daily dose. Certain embodiments of the invention relate to a ‘total blood cell count’. The total blood cell count is the total number of (all types of) cells present in the subject’s blood.5 For convenience, in appropriate circumstances total blood cell count may be used as a surrogate for a blood concentration measurement of solely thrombocytes. Blood counts should be established after sufficient time to accurately observe the impact of administration(s) of the CTPS1 inhibitor, such as to establish if blood counts have been prevented from increasing or reduced. Such counts may be compared to a count 10 established before commencing treatment. A blood count has been prevented from increasing if after a suitable period of administration of a CTPS1 inhibitor according to the invention the blood count is not substantially higher, such as not higher, than the blood count established before treatment. A blood count has been reduced if after a suitable period of administration of a CTPS1 inhibitor according to the invention the blood count is lower, such as substantially 15 lower, than the blood count established before treatment. If the impact of CTPS1 administration is insufficient for the desired effect, the dose of CTPS1 inhibitor may beadjusted accordingly for further treatment. Blood cell counts may be established 50 days or fewer, such as 40 days or fewer, such as 30 days or fewer, such as 20 days or fewer, such as 15 days or fewer, such as 10 days or 20 fewer, such as 8 days or fewer, such as 5 days or fewer, such as 2 days or fewer after the initial administration of the CTPS1 inhibitor according to the invention.Blood cell counts may be established 1 day or more, such as 3 days or more, such as 5 days or more, such as 10 days or more, such as 15 days or more, such as 20 days or more, such as 30 days or more, such as 40 days or more, such as 50 days or more after the initial25 administration of the CTPS1 inhibitor according to the invention.Suitably the blood cell count is established 2 to 14 days after the initial administration ofthe CTPS1 inhibitor, more suitably 5 to 7 days after the initial administration of the CTPS1inhibitor according to the invention.Suitably, the cell count (for any one or more particular blood cell types, such as 30 thrombocytes) is prevented from increasing above a therapeutically beneficial range and / or reduced to a therapeutically beneficial range for at least 3 months, such as at least 6 months, such as at least 12 months, such as at least 2 years, such as at least 3 years, such as at least 4 years, such as at least 5 years, such as at least 10 years, such as the lifetime of the subject. Blood cell count may be established periodically, such as weekly. Blood cell count may 35 be established, monthly, every three months, every 6 months or even yearly. Most suitably the blood cell count is established repeatedly at convenient intervals over the period of treatment. STP-P3718PCT 88 Suitably the blood cell count is ascertained from a blood sample taken from the subject, more suitably taken from a vein of the subject. The invention provides a method for reducing the risk of thrombosis in a subject inneed thereof. An indication that a subject’s risk of thrombosis has reduced is if the frequency 5 of thrombosis is reduced. In this context, a subject is in need of reduction in risk of thrombosis if the subject has an increased risk of thrombosis relative to the risk level of the general population. A subject may have an increased risk of thrombosis if, for example, they suffer from an MPN, such as ET. In one embodiment, the reduction in the risk of thrombosis is in a subject 10 having an MPN, such as ET. Alternatively, or in addition, a subject may have an increased risk of thrombosis if, forexample (a) they are undergoing cancer treatment such as chemotherapy, (b) their age isgreater than 60 years, (c) they are severely dehydrated, (d) they suffer from a thrombophilia, heart disease, metabolic; endocrine or respiratory pathologies; acute infectious diseases or 15 inflammatory conditions), (e) they are obese (i.e. having a body mass index of greater than 30 kg / m2), (f) they have a first-degree relative with a history of thrombosis, (g) they use hormone replacement therapy, (h) they use oestrogen-containing contraceptive therapy, (i) they have varicose veins with phlebitis, (j) they are pregnant or within 6 weeks postpartum, (k) they have had significantly reduced mobility for 3 days or more, (l) they have had surgery such as 20 surgery lasting greater than 90 minutes, (m) they have suffered a broken bone such as a hip fracture, (n) they have been admitted to critical care, (o) they suffer from hypertension, (p) theyhave been travelling for significant period of time, or (q) they have suffered trauma to a vein. Administration25 The CTPS1 inhibitor is administered to a human subject in need thereof. A human subjectmay be an adult, such as aged 18 to 65. Alternatively, a human subject may be 66 years old or older. Alternatively, a human subject may be less than 18 years of age, such as 4 to 17 years old. A human subject may be male. Alternatively, a human subject may be female. The CTPS1 inhibitor may be administered by any suitable route, which may depend on 30 the nature of the specific agent. Exemplary routes include oral, parenteral, buccal, sublingual, nasal or rectal administration. Conveniently, the CTPS1 inhibitor is administered orally.The CTPS1 inhibitor may be provided in the form of a pharmaceutical composition comprising the CTPS1 inhibitor and a pharmaceutically acceptable carrier or excipient. If delivered orally, the CTPS1 inhibitor may suitably be delivered in a solid pharmaceutical35 composition (such as a tablet, capsule or lozenge) or in a liquid pharmaceutical composition(such as a suspension, emulsion or solution). STP-P3718PCT 89 A liquid formulation will generally consist of a suspension or solution of the CTPS1 inhibitor in a suitable liquid carrier e.g. an aqueous solvent such as water, ethanol or glycerine,or a non-aqueous solvent, such as polyethylene glycol or an oil. The formulation may also contain a suspending agent, preservative, flavouring and / or colouring agent. 5A tablet formulation can be prepared using any suitable pharmaceutical carrier(s)routinely used for preparing solid formulations, such as magnesium stearate, starch, lactose, sucrose and cellulose. Suitably, the pharmaceutical composition is in unit dose form, such as a tablet, capsuleor ampoule. Suitably the unit dose form is for oral delivery.10 The pharmaceutical composition may for example contain from 0.1% to 99.99% byweight, for example from 10 to 60% by weight, of the active material, depending on the method of administration. The pharmaceutical composition may contain from 0.01% to 99% by weight, for example 40% to 90% by weight, of the carrier, depending on the method of administration. The pharmaceutical composition may contain from 50 mg to 1000 mg of the carrier, for example15 from 100 mg to 400 mg, depending on the method of administration. The dose of the compound used will vary in the usual way with the seriousness of the condition, the weight of the sufferer, and other similar factors. Such therapy may extend for a number of weeks, months or longer. A plurality of unit does, such as a plurality of tablets, maybe taken together.20 Suitably, the CTPS1 inhibitor is administered orally, such as administered orally in a solidpharmaceutical composition. The dose provided to a subject will typically be a safe and effective dose, i.e. an amount providing an acceptable balance of desired benefits and undesired side effects. A “safe and effective amount" is intended to include an amount of a compound that is effective to achieve a 25 desirable effect in treatment of a disease-state. A desirable effect is typically clinically significant and / or measurable, for instance in the context of (a) inhibiting the disease-state, i.e., slowing or arresting its development; and / or (b) relieving the disease-state, i.e., causing regression of the disease state or a reduction in associated symptoms. The safe and effective amount is one thatis sufficient to achieve the desirable effect when the CTPS1 inhibitor is administered. 30 For avoidance of doubt, a “safe and effective amount” as recited herein can be achieved by any suitable dosage regimen. Hence, for example, references herein to administering a safe and effective amount of a compound, such as by a particular administration route, include achieving the safe and effective amount via a single dose or by plural doses, such as administered by the specified administration route. For instance, orally administering a safe and 35 effective amount includes both orally administering a single dose and orally administering any plural number of doses, provided that a safe and effective amount is thereby achieved by oral administration. STP-P3718PCT 90 Suitably the CTPS1 inhibitor is administered repeatedly (e.g. in order to prevent increase in the subject’s blood cell count or reduce the subject’s blood cell count). Desirable blood cell counts may be achieved by adjusting the dose and / or frequency of dosing. Most suitably the CTPS1 inhibitor is provided in a regimen of continual dosing every day.5 Very large gaps in dosing may result in undesirable increases in blood cell count.Suitably the therapeutically beneficial range or the physiologically normal range isachieved within 28 days, such as 14 days of repeated administration of the CTPS1 inhibitor. A desired level of target engagement may be achieved using an appropriate daily dose. Ideally the daily dose administered to the subject results in the subject having an exposure level10 to the CTPS1 inhibitor which maintains the subject’s blood cell count at one or more of thedesirable levels set out herein, such as that which maintains the subject’s platelet count from 150 x109 / L to 400 x109 / L. For example, based on modelling performed by the inventors, suitablythe daily dose administered to the subject is that which achieves a blood exposure (AUC tau) inthe subject of about 14,000 h.ng / mL to about 26,000 h.ng / mL. Modelling by the inventors 15 indicates that a 62.5 mg to 100 mg daily dose may be expected to achieve such an exposure range. A particularly suitable formulation of specific CTPS1 inhibitor CTPS1-IA is Formulation F-B as detailed below under Example A. In one embodiment the CTPS1 inhibitor is FormulationF-B or a formulation of CTPS1-IA with similar biological properties, more suitably the CTPS120 inhibitor is Formulation F-B. Suitably the dosage form of the CTPS1 inhibitor is capable with a single oral dose at 10 mg / kg in dogs (such as in the model of Example AD) of achieving a mean AUClast of at least 35000 h*ng / mL. More suitably the dosage form is capable of achieving a mean AUClast of atleast 40000 h*ng / mL. More suitably the dosage form is capable of achieving a mean AUClast25 of at least 45000 h*ng / mL. Suitably the dosage form is capable of achieving a mean Cmax of at least 12000ng / mL, such as at least 14000 ng / mL, especially at least 14000 ng / mL. Suitably the dosage form is capable of achieving a median Tmax of between 0.5 and 4hours, such as between 1 to 3 hours. 30 Formulation F-B is a suitable formulation for achieving the above the AUClast, Cmax and Tmax dosage form parameters. A daily dose is the mass of CTPS1 inhibitor administered per day. One, two, or more administrations may be performed per day, the sum of which resulting in the daily dose. A single administration per day (QD) of 1 mg CTPS1 inhibitor is a daily dose of 1 mg CTPS1 inhibitor.35 Two administrations per day of 1 mg CTPS1 inhibitor is a daily dose of 2 mg CTPS1 inhibitor. In one embodiment, the daily dose is 25 mg or greater, such as 30 mg or greater, suchas 35 mg or greater. In a further embodiment, the daily dose is 40 mg or greater, such as 45 STP-P3718PCT 91 mg or greater, such as 50 mg or greater. In another embodiment, the daily dose is 55 mg orgreater, such as 60 mg or greater, such as 65 mg or greater. In one embodiment, the daily doseis 70 mg or greater, such as 75 mg or greater, such as 80 mg or greater. In a further embodiment, the daily dose is 85 mg or greater, such as 90 mg or greater, such as 95 mg or5 greater. In one embodiment, the daily dose is 95 mg or lower, such as 90 mg or lower, such as 85 mg or lower. In a further embodiment, the daily dose is 80 mg or lower, such as 75 mg or lower, such as 70 mg or lower. In another embodiment, the daily dose is 65 mg or lower, such as 60 mg or lower, such as 55 mg or lower. In one embodiment, the daily dose is 50 mg or 10 lower, such as 45 mg or lower, such as 40 mg or lower. In a further embodiment, the daily dose is 35 mg or lower, such as 30 mg or lower, such as 25 mg or lower. In one embodiment, the daily dose is 25 to 100 mg. In a further embodiment, the dailydose is 35 to 100 mg. In another embodiment, the daily dose is 40 to 100 mg. In a furtherembodiment, the daily dose is 45 to 100 mg. In one embodiment, the daily dose is 50 to 10015 mg. Suitably the daily dose is about 25 mg, such as 25 mg; or about 50 mg, such as 50 mg;or about 75 mg, such as 75 mg; or about 100 mg, such as 100 mg.In a particular embodiment the daily dose is about 75 mg, such as 75 mg.“About” as used herein refers to a range of + / - 10% of the stated value, more suitably + / -20 5% of the stated value, more suitably + / - 1% of the stated value.In certain embodiments the regimen requires a defined daily dose of CTPS1 inhibitor. The daily dose is suitably provided in one to three administrations per day. The sum of administrations in the day result in the daily dose. A single administration is the quantity of CTPS1 inhibitor administered to the subject at a single timepoint (which may itself arise from a25 plurality of dosage forms taken at substantially the same time, such as two tablets). A daily dose is the total quantity of CTPS1 inhibitor administered to the subject during a day.A plurality of discrete dosage forms may be taken substantially together which in sumprovide the defined administration, such as two tablets taken orally at substantially the same time wherein each tablet contains 25 mg of CTPS1 inhibitor, therefore providing an30 administration of 50 mg of CTPS1 inhibitor. If provided in the form of a pharmaceutically acceptable salt and / or pharmaceutically acceptable solvate, the amounts can be adjusted accordingly. These dosage forms are administered at substantially the same time. Dosageforms (e.g. such as capsules or tablets) may, for example, provide the CTPS1 inhibitor in anamount of 1 to 100 mg e.g.5 to 75 mg, such as 10 to 50 mg, e.g.5, 25, 10, 20, 30, 40 or 50 mg.35 CTPS1-IA is capable of forming a large number of crystalline forms. One form, the useof which is referred to herein and which is particularly thermodynamically and polymorphically stable (amongst other favourable properties), is known as Form B. Form B is a crystalline form STP-P3718PCT 92 of CTPS1-IA characterised by significant peaks in an XRPD diffraction patterns (as obtainedusing CuKα radiation) ato2θ positions 8.1, 12.6, 16.2, 17.2 and 22.8 and optionally also ato2θ positions 6.2, 14.4, 16.0, 19.0, 22.0 and 25.5 and optionally also ato2θ positions 12.4, 18.3, 20.5, 24.9 and 27.1 and optionally also ato2θ positions 7.5, 13.8, 20.0, 23.7, 24.4, 25.8 and 5 29.3. Suitably, the XRPD pattern does not comprise peaks at positions 5.4 and 10.6 and optionally also does not comprise a peak at 18.6o2θ. All the aforesaid peak positions are ±0.2 o2θ. Suitably the aforesaid peaks have a relative intensity in the XRPD pattern of > 4% e.g. > 5% e.g. > 10% e.g. > 15%. XRPD patterns may for example be obtained using methods described in General Methods GM1A or GM1B. Crystalline Form B of CTPS1-IA has a melting10 point of ca 189 to 196 °C e.g.191 to 196 °C e.g. around 191 to 192 °C as determined by mDSC. The melting point is indicated by the maximum endothermic point in an endothermic peak in the mDSC thermograph (i.e. Tpeak), particularly when acquired at 10 °C / min. mDSCthermograms may for example be obtained using methods described in General Method GM2. Crystalline Form B of CTPS1-IA may be prepared by crystallisation of the crystalline15 form upon cooling of a solution of CTPS1-IA in hot MIBK. For example, CTPS1-IA may bedissolved in a mixture of THF and water (e.g.4:1 mixture by volume) and atmospherically solvent switched to MIBK at constant volume and cooled to produce crystalline Form B of CTPS1-IA. Crystalline Form B of CTPS1-IA may also be prepared by generation of thecrystalline form upon slurrying of a solid form of CTPS1-IA in hot ethanol e.g. at or above 5020 °C e.g. for 6 hours or more. Acrystalline form of CTPS1-IA may be used in the preparation of a hot melt extrusionproduct. Thus, a crystalline form of CTPS1-IA may be combined with a carrier and heated andextruded to form a dispersion of CTPS1-IA in amorphous form in the carrier. The extrudedproduct may then be size reduced and combined with capsule or tablet excipients to form a 25 capsule or tablet composition. A capsule composition may be filled into a capsule and tablet composition may be compressed into a tablet. The carrier may comprise or consist of one or more polymeric or non-polymeric carrier substances but suitably comprises or consists of one or more polymeric substances. Suitably the carrier is a thermoplastic carrier. Thermoplastic carriers may be crystalline or amorphous. 30 Thermoplastic carriers are intended to melt below the temperature (particularly the maximum temperature) to which the composition is heated in the process, and for example have melting points (Mp) or glass transition temperature (Tg) in the range 150°C - 210°C such as 170°C to200°C. Examples of non-polymeric carrier substances include waxes, such as carnauba wax. Polymeric carrier substances may for example be selected from polyvinylpyrrolidone (PVP), 35 polyvinylpyrrolidone copolymers (such as polyvinylpyrrolidone-vinyl acetate), polyethylene copolymers (such as polyethylene-co-vinyl acetate), polyethylene glycol, cellulose esters, cellulose acrylates, polyethylene oxides, polymethacrylates and poloxamers. In particular, the STP-P3718PCT 93 one or more polymeric carrier substances may be selected from polyvinylpyrrolidone and polyvinylpyrrolidone copolymers especially a polyvinylpyrrolidone copolymer such as polyvinylpyrrolidone-vinyl acetate. Thus, in an embodiment, the carrier is polyvinylpyrrolidone- vinyl acetate. In one favoured embodiment the polyvinylpyrrolidone-vinyl acetate is a co- 5 polymer of 1-vinyl-2-pyrrolidone and vinyl acetate (sometimes referred to as copovidone VP / VAc) for example in a mass ratio of ca 6:4 (sometimes referred to as copovidone VP / VAc 60 / 40) and for example is sold under the brand name Kollidon® VA 64 (supplier: BASF Pharma). The carrier may also optionally comprise a plasticiser, typically a low molecular weight 10 substance to aid softening of the carrier upon heating. Optional inclusion of a plasticiser may conveniently lower the temperature required to soften the carrier which can help reduce degradation of the active ingredient during the extrusion process. Typical examples of plasticisers include triacetin, low molecular weight polyethylene glycols (PEG), and citrate esters. One skilled in the art would be familiar with ‘low molecular weight’ PEG but, typically a 15 ‘low molecular weight’ PEG possesses a Mw of less than 1000, more typically less than 800, even more typically less than 500 and in some cases less than 300 although usually more than 200. Suitably a plasticiser is not included. Other carrier components known in the art to be suitable for hot melt extrusion processes may also be used.20 In an embodiment, the hot melt extrusion product consists of (i) CTPS1-IA and (ii) oneor more polymeric carrier substances selected from polyvinylpyrrolidone and polyvinylpyrrolidone copolymers especially a polyvinylpyrrolidone copolymer such as polyvinylpyrrolidone-vinyl acetate e.g. a co-polymer of 1-vinyl-2-pyrrolidone and vinyl acetate in a mass ratio of ca 6:4. 25 Capsules may be prepared by filing an empty capsule with a capsule composition. A capsule composition typically comprises CTPS1-IA and one or more capsule excipients.Typical capsule excipients are selected from fillers, disintegrants, lubricants, stabilisers, anti- oxidants, taste masking agents and release modifying aids. Exemplary binders include mannitol such as D-mannitol. Exemplary lubricants include magnesium stearate, sodium lauryl 30 sulfate, sodium dodecyl sulfate and sodium stearyl sulfate. Exemplary disintegrants include crospovidone, croscarmellose sodium and sodium starch glycolate. Capsules such as HPLC capsules of various sizes including size 0 may be obtained from commercial sources, e.g. Capsugel® VCaps® from Lonza. Tablets may be prepared by combining a hot melt extrusion product with one or more 35 tabletting excipients to form a tablet mixture and compressing the tablet mixture in a tabletting die to form a tablet. Typical tabletting excipients are selected from binders, fillers, disintegrants, lubricants stabilisers, anti-oxidants, taste masking agents and release modifying STP-P3718PCT 94 aids. Exemplary binders and / or fillers include mannitol such as D-mannitol, ;lactose, sucrose and starch. Exemplary lubricants include magnesium stearate, sodium lauryl sulfate, sodium dodecyl sulfate and sodium stearyl sulfate. Exemplary disintegrants include crospovidone, croscarmellose sodium and sodium starch glycolate. 5Capsules and tablets may, for example, include CTPS1-IA in an amount of 5 to 50%w / w such as 8 to 40% w / w e.g.8 to 12% w / w or 35 to 50% w / w. An exemplary composition suitable for a capsule comprises, consists essentially of or consists of: (a) Hot melt extrusion product: 65 to 90% w / w e.g. 67 to 75% w / w e.g. 70 to 72% w / w e.g.10 around 71% w / w; (b) Filler (such as mannitol such as D-mannitol): 5-32% w / w e.g. 18 to 22% w / w e.g.19 to21% w / w e.g. around 20% w / w; and (c) Disintegrant (such as crospovidone): 3 to 12% w / w e.g. 7 to 11% w / w e.g.8 to 10%w / w e.g. around 9% w / w. 15 Such a composition comprises suitably 40 to 60% w / w e.g.45 to 55% w / w e.g. around 50% w / w CTPS1-IA. For use in the process to prepare a hot melt extrusion product, a crystalline form ofCTPS1-IA may suitably be size reduced for example by micronisation. Micronisation may beachieved e.g. by wet bead milling. For example, the D90 of a crystalline form may be less than 20 15 µm e.g. less than 10 µm e.g. less than 5 µm, if necessary following a process of size reduction. In the mixture the weight ratio of CTPS1-IA to carrier is typically in the range 3:1 to 1:3such as 2:1 to 1:2 e.g.1:1 to 1:2. The mixture is heated to promote the dissolution of the active ingredient in the carrier 25 as a solid dispersion and its conversion to the amorphous phase and to permit its extrusion. Heating may be achieved by application of external heat together possibly with heat generated in the extrusion apparatus as a result of friction. Suitably the mixture is heated to a temperature of 150 °C to 210 °C such as 170 °C to 200 °C e.g.180 °C to 190 °C e.g. around 180 °C to 185 °C or around 185 °C to 190 °C. The heat, taking into account the cycling time, 30 should be sufficient to melt the mixture and lead to formation of the dispersion of the active ingredient in amorphous form in the carrier but should not be so great as to lead to degradation of the active ingredient or the carrier. The maximum temperature may be chosen to be close to (say + / - 5 oC) the melting point of the input form of CTPS1-IA. The die temperature istypically cooler, for example, the die temperature may be in the range 140 °C to 170 °C such 35 as around 165 °C. Typically, the mixture is extruded through a heated extrusion barrel comprising a screw extruder and a die. In general, the temperature graduates across different zones of the STP-P3718PCT 95 extruder e.g. rises towards the maximum temperature in the extrusion barrel and falls towards the die. Exemplary screw extruders are single-screw extruders, twin-screw extruders and multi- screw extruders and in particular the screw extruder may be a twin-screw extruder. In twin 5 extruders the two screws mesh and can co-rotate (i.e. rotate in the same direction) or counter- rotate (rotate in the opposite direction). See an exemplary twin-screw extruder shown in Figure 1 of Patil et al (2016) AAPS PharmSciTech, 17(1) 20-42. In multi-screw extruders, the screws can co-rotate or counter-rotate where they mesh. In use, mixture inputted into theextrusion barrel e.g. via a hopper is moved along the barrel by rotation of the screw(s) in which 10 the flights of the screw(s) and the inner surface of the barrel form a flow channel. In the course of moving along the barrel the mixture is mixed, comes into contact with heat and melts. The molten mixture exits the barrel by being forced through the die. Screw extruders conveniently allow the process to proceed in a continuous mode or a batch mode, as desired. Screw extruders particularly twin-screw or multi-screw extruders have a number of 15 specific merits. These include generally short cycling times, good mixing ability, the ability to operate continuously, and the ability to “self clean” since the flight of one screw cleans the root of the adjacent intermeshing screw which reduces waste. In general, single screw extruders generate more internal heat due to friction than twin or multi-screw extruders and in general heat generation in twin or multi-screw extruders is independent of screw speed which is an 20 advantage for these types of extruders. Thus with twin or multi-screw extruders the heat is supplied (entirely or nearly entirely) by external heating which allows for better control. The pressure applied by the extruder to force the mixture through the die can typically be in the range 3 to 15 bar. The cycling time i.e. the total time required to complete one full extrusion cycle can25 typically be in the range 0.5-10 minutes e.g.1 to 5 minutes. The rotation speed of the screw(s), which rotation is driven by a motor, can be adapted to achieve the desired cycling time, bearing in mind the dimensions of the screw(s) and barrel. Screw rotation speeds may typically be in the range 40 to 500 RPM e.g.50 to 500 e.g.100 to 500 e.g. around 300 to 400 RPM. 30 Screw diameters are typically in the range 10 to 120 mm e.g.15 to 50 mm. Die diameters are typically in the range 1 to 5 mm e.g. around 3 mm. Feed rates may be, for example, in the range 5 to 20 g / min e.g.5 to 10 g / min. Screw extruders are commercially available and supplied by companies including Thermo Fisher Scientific, Leistritz, Gabler and Coperion Brabendon. An example extruder35 from Thermo Fisher Scientific is the HAAKE™ Rheomix MiniLab II CTW5 twin screw extruder(for small scale) or a Pharma 16 twin screw extruder (for larger scale). STP-P3718PCT 96 Although the process of hot melt extrusion may comprise mixing, particularly though the action of a screw extruder, it will typically be appropriate to pre-mix the composition comprising the CTPS1-IA prior to its input into the extruder to achieve good homogeneity. Pre-mixing steps may also comprise co-milling steps. 5 The output from the die (i.e. the extrudate) is suitably stored at ambient temperature (e.g. 20 to 25 °C) to cure, typically for a period of at least 4 hours e.g. at least 8 hours such as8 to 24 hours. The extrudate may be broken up or size reduced e.g. milled and thereafter sieved for example with sieve size of 250 to 500 µm. It may thereafter be used in preparation of an oral dosage form such as a capsule or tablet. 10 The process may also comprise the step of curing the output from the die before milling. Further details of possible suitable hot melt extrusion process conditions may be obtained by reference to Patil et al (2016) AAPS PharmSciTech, 17(1) 20-42, see Figure 1 thereof (incorporated herein by reference). 15 The CTPS1 inhibitor may be administered with a further agent. The further agent may be a further CTPS1 inhibitor or may be selected from hydroxycarbamide (also known ashydroxyurea), anagrelide, interferon alpha or a JAK inhibitor (such as ruxolitinib).The further agent may be selected from hydroxycarbamide (also known as hydroxyurea),anagrelide, interferon alpha or a JAK inhibitor (such as ruxolitinib). 20 Administration with a further agent may be separate, sequential or simultaneous. The invention is further exemplified by the following non-limiting examples. EXAMPLES 25 General Methods GM1A: X-Ray Powder Diffraction (XRPD) - Method AThe X-ray powder diffraction studies are performed using a Bruker AXS D8 discover HTS, equipment #3198 using a Cu anode at 40kV, 40 mA; Göbel mirror, line optics. Detector: 30 Linear detector LYNXEYE XE with receiving slit 2.95° detector opening. Measurement conditions: scan range 2 to 45° 2°, 1s / step, 0.005° / step, and all measuring conditions are logged in the instrument control file. As system suitability, Corundum powder is measured. The software used for data collection is Diffrac.Commander v7.3.0.0. Data analysis is doneusing Diffrac.Eva v4.2.1. No background correction or smoothing is applied to the patterns. 35 STP-P3718PCT 97 GM1B: X-Ray Powder Diffraction (XRPD) - Method BThis method is the same as General Methods GM1A with the following variation: Measurement conditions: scan range 2 to 45° 2°, 0.1s / step, 0.01° / step. 5GM2: Modulated Differential Scanning Calorimetry (mDSC) analysismDSC is performed using a Mettler Toledo DSC1 / DSC3+ STARe System, equipment#1564 / #3168. The samples are made using Al crucibles (40 µl; pierced). Typically, 1 to 8 mgof sample is loaded onto a pre-weighed Al crucible and is kept at 20 °C for 5 minutes, afterwhich it is heated at 10 °C / min from 20 °C to 350 °C and kept at 350 °C for 1 minute. A10 nitrogen purge of 40 ml / min is maintained over the sample. The software used for datacollection and evaluation is STARe Software v15.00 build 8668. No corrections were applied tothe thermogram. As system suitability check indium and zinc were measured. For calibration indium, lead and zinc were used as references. 15 Example A: Production, formulation and characterisation of CTPS1 inhibitor CTPS1-IA A. Preparation of Active Ingredient20 Example A1 – Preparation of crude 4-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)tetrahydro-2H-pyran-4-carboxamide Step 1 – Preparation of 5-(6-ethoxypyrazin-2-yl)pyridin-2-amine25 Step 1a – Preparation of 2-chloro-6-ethoxypyrazine To a solution of 2,6-dichloropyrazine (186 g, 1.25 mol, 1.00 equiv) in 2-MeTHF (930 mL, 30 5.00 rel. vol.) was added sodium ethoxide (20 wt% solution in ethanol, 460 g, 1.37 mol, 1.09 equiv.) over 90 min, while maintain the temperature at 30oC. The reaction mixture was stirred at 30oC for 1 h until completion. Water (558 mL, 3.00 rel. vol.) was added and the phases were separated. The organic phase was cooled to 3oC, stirred overnight, and filtered. The solids were STP-P3718PCT 98 washed with 2-MeTHF (930 mL, 5.00 rel. vol.) and the combine filtrate was collected to obtain1.61 kg 2-MeTHF solution of 2-chloro-6-ethoxypyrazine (1.25 mol, 100% yield). 5Step 1b – Preparation of 2-aminopyrid-5-yl-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneIn parallel, 5-bromopyridin-2-amine (0.250 kg, 1.45 mol, 1.00 equiv.), potassium acetate (285 g, 2.90 mol, 2.00 equiv), bis(pinacolato)diboron (403 g, 1.59 mol, 1.10 equiv) and 2-MeTHF (3.0 L, 12.0 rel. vol.) was degassed under slight reflux at 35 °C. Then, 250 mL 2-MeTHF was removed via vacuum distillation and discharged. Thereafter, another 250 mL MeTHF was10 removed via vacuum distillation and used to add Pd(dppf)Cl2.DCM (11.8 g, 14.4 mmol, 0.01equiv) as a slurry to the reactor. After another degassing cycle under slight reflux at 35 °C, the mixture was heated to 83 °C and stirred overnight until completion. The mixture was cooled to 40 °C, MeOH (630 mL, 2.50 rel. vol.) was added and the mixture was stirred for 1 h. The suspension was then filtered and the solids washed with a mixture of 2-MeTHF (1.0 L, 4.00 rel. 15 vol.) and MeOH (250 mL, 1.00 rel. vol.). The reactor was cleaned with methanol and the filtrate was added with vacuum distillation at constant volume (1.25 L, 5.00 rel. vol.). Thereafter, a solvent switch at constant volume to cyclohexane with cyclohexane (3.75 L, 15.0 rel. vol.) was performed. Then, cyclohexane (2.50 L, 10.0 rel. vol.) was added at 50 °C followed by cooling to 10 °C and the mixture was stirred overnight. The resulting suspension was then filtered and the 20 solids washed once actively with cyclohexane (1.25 L, 5.00 rel. vol.) and once passively with cyclohexane (750 mL, 3.00 rel. vol.). The product was dried at ambient temperature under flow of nitrogen to afford 424 g of crude 2-aminopyrid-5-yl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.15 mol, 79% yield) as a brown solid with an1H NMR assay of 59.5 w / w%.25 Step 1c – Preparation of 5-(6-ethoxypyrazin-2-yl)pyridin-2-amine Crude 2-aminopyrid-5-yl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (422 g, 59.5 wt%, 1.14mol, 1.00 equiv.)potassium acetate (392 g, 4.0 mol, 3.50 equiv), 1.608 kg of 2-chloro-6- ethoxypyrazine solution in 2-MeTHF (1.25 mol, 1.10 equiv.), 2-MeTHF (777 mL, 3.00 rel. vol.) 30 and water (251 mL, 1.00 rel. vol.) were combined and degassed at 30 °C under slight reflux. Then, 0.200L 2-MeTHF was removed via vacuum distillation and used to add Pd(dppf)Cl2.DCM(36.6 g, 42.9 mmol 0.02 equiv) as a slurry to the reactor followed by another degassing cycle. Thereafter, the mixture was heated to 77 °C and stirred overnight until completion. The mixture STP-P3718PCT 99 was then cooled to 20 °C, filtered and the solids washed with a mixture of 2-MeTHF (752 mL, 3.00 rel. vol.) and water (100 mL, 0.400 rel. vol.). The reactor was cleaned with 30% aq. HCl and water. The filtrate was then charged back to the reactor, the aqueous phase was removed, and the mixture was concentrated to approx.1.00 L (4.00 rel. vol.). Thereafter, a solvent swap 5 at constant volume with methyl isobutyl ketone (2.00 L, 8.00 rel. vol.) was performed and cyclohexane (1.50 L, 6.00 rel. vol.) was added at 50 °C followed by cooling down to 3 °C. After stirring overnight at 3 °C, the resulting suspension was filtered, washed twice with cyclohexane(750 mL, 3.00 rel. vol.) and dried over three days at 35 °C followed by one night at 45 °C to obtain 399 g crude 5-(6-ethoxypyrazin-2-yl)pyridin-2-amine (972 mmol, 84% yield) with an1H10 NMR assay of 52.7 w / w%. Crude 5-(6-ethoxypyrazin-2-yl)pyridin-2-amine (366 g, 52.7 w / w%, 892 mmol, 1.00 equiv.), DCM (1.55 L, 8.00 rel. vol.) and water (1.93 L, 10.0 rel. vol.) were mixed together and heated to 30 °C with vigorous stirring. After 20 min, the phases were separated. The aqueous phase was washed with DCM (580 mL, 3.00 rel. vol.) at 30 °C. The reactor was cleaned with 15 water and THF. Then, the combined organic phases were charged to reactor and concentrated to 1.0L (5.0 rel. vol.) by atmospheric distillation. Thereafter, a solvent swap to THF was performed with THF (2.32 L, 12.0 rel. vol.) at constant volume by atmospheric distillation. The mixture was slowly cooled over 1 h to 3 °C and stirred overnight. The suspension was filteredand washed twice with cold THF (386 mL, 2.00 rel. vol.) and dried in the vacuum oven overnight 20 at 45 °C to obtain 5-(6-ethoxypyrazin-2-yl)pyridin-2-amine (HPLC purity: 99.9% a / a,1H NMR assay: 100.5 w / w%). Step 2 – Preparation of methyl 4-(2-(methylsulfonyl)pyrimidine-4-yl)tetrahydro-2H-pyran-4-carboxylate 25 Step 2a – Preparation of methyl 4-(2-(methylthio)pyrimidine-4-yl)tetrahydro-2H-pyran-4-carboxylate A solution of diisopropylamine (555 g, 5.48 mol, 1.40 equiv.) in 2-MeTHF (4.36 L, 7.0030 rel. vol.) was cooled to 0 oC and n-BuLi (2.46 M in hexanes, 1.416 kg, 5.09 mol, 1.30 equiv.) wasadded over 1 h while maintaining the temperature at – 5 to 5 oC. The mixture was diluted with2-MeTHF (150 mL, 0.25 rel. vol.) and stirred for 30 min at 1oC. Methyl tetrahydro-2H-pyran-4- carboxylate (669 g, 4.64 mol, 1.20 equiv.) was added over 40 minutes while maintaining the temperature at – 5 to 5 oC. The mixture was diluted with 2-MeTHF (150 mL, 0.25 rel. vol.) and35 stirred for 20 min at 0oC.4-chloro-2-(methylthio)pyrimidine (620 g, 3.86 mol, 1.00 equiv.) was STP-P3718PCT 100 added over 35 minutes while maintaining the temperature at 0 to 5 oC. The mixture was dilutedwith 2-MeTHF (150 mL, 0.25 rel. vol.) and stirred for 16 h at 2oC, until completion. Trifluoroacetic acid (710 g, 6.23 mol, 1.60 equiv.) was added over 80 minutes while maintaining the temperature at 0 to 10oC. The mixture was diluted with 2-MeTHF (150 mL, 0.25 rel. vol.), warmed to 20oC 5 and stirred for 70 minutes at 20oC. The resulting suspension was filtered and the solids washed with 2-MeTHF (1.3 L, 2.00 rel. vol.). The combined filtrates were heated to 45oC and water (3.12 L, 5.00 rel. vol.) was added. The pH was adjusted from 8.74 to 7.02 with HCl-30, and the mixture was stirred for 70 minutes. The phases were separated, and the organic phase was washed with water (2 × 1.5 L, 2.5 rel. vol.). The organic phase was concentrated by distillation at atmospheric10 pressure to a volume of approximately 2.4 L. The solvent was switched to toluene via two cycles of addition of toluene (2 × 3.2 L, 2 × 5.00 rel. vol.) and concentration by distillation under reduced pressure to a volume of 1.8–1.9 L. The mixture was then distilled while maintaining constant volume via the addition of 1-propanol (2.82 L, 6.00 rel. vol.) to obtain 1.482 kg solution of methyl 4-(2-(methylthio)pyrimidine-4-yl)tetrahydro-2H-pyran-4-carboxylate in 1-propanol which was15 telescoped to the next stage. Step 2b – Preparation of methyl 4-(2-(methysulphonyl)pyrimidine-4-yl)tetrahydro-2H-pyran-4-carboxylate 20 Methyl 4-(2-(methylthio)pyrimidine-4-yl)tetrahydro-2H-pyran-4-carboxylate in 1-propanol (1850 g [785 g methyl 4-(2-(methylthio)pyrimidine-4-yl)tetrahydro-2H-pyran-4-carboxylate, 2.93 mol, 1.00 equiv.), sodium tungstate dihydrate (9.62 g, 29.2 mmol, 0.010 equiv.), water (784 g; 1.00 rel. vol.), phenylphosphonic acid (9.67 g, 57.7 mmol, 0.021 equiv.) in 1-propanol (1.03 L, 0.84 rel. vol.). and 1-propanol (1.59 L; 1.31 rel. vol.) were charged to a reactor. The mixture was 25 heated to 60oC and 35% aq. H2O2(625 g, 2.20 equiv) was added over 3.5 h. Water (125 mL, 0.16 rel. vol.) was used to rinse the lines and the mixture was stirred for 1.5 h at 65oC, then cooled to 10oC and stirred for a further 15.5 h.20 wt% sodium metabisulfite (650 g [130 g sodium metabisulfite, 0.683 mol, 0.234 equiv.; 520 mL water, 0.66 rel. vol.) was added over 30 min while maintain the temperature at 10–20 °C and the mixture was stirred for 30 min. The pH was 30 adjusted from 2.1 to 6.9 over 1 h with 1 M NaOH and the mixture was stirred for 3 h then cooled to -7 °C and stirred for a further 2.5 h. The solids were isolated by filtration and dried for 16 h on the filter, then washed once actively with water (1.175 L, 1.50 rel. vol.) and once passively with water (590 mL, 0.75 mL). The solids were dried in vacuo at 50 oC to obtain methyl 4-(2- STP-P3718PCT 101 (methysulphonyl)pyrimidine-4-yl)tetrahydro-2H-pyran-4-carboxylate (645 g, 2.15 mol, 73% yield, HPLC purity: 99.6% a / a). Step 3 – Preparation of methyl 4-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)tetrahydro-5 2H-pyran-4-carboxylate Methyl 4-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)tetrahydro-2H-pyran-4- carboxylate was prepared by nucleophilic substitution of methyl 4-(2-(methylsulfonyl)pyrimidin- 4-yl)tetrahydro-2H-pyran-4-carboxylate (1.85 kg, 6.17 mol, 1.00 equiv.) with 10 cyclopropanesulfonamide (895 g, 7.39 mol, 1.20 equiv.) in the presence of potassium carbonate (1.71 kg, 12.3 mol, 2.00 eqiv.) in acetonitrile (13.9 L, 7.50 rel. vol.) and at 80oC. After completion (36 h), the temperature was adjusted to approximately 65oC and the mixture was treated with trifluoroacetic acid (1.94 L, 2.89 kg, 25.3 mol, 4.10 equiv.), followed by acetonitrile (925 mL, 0.500 rel. vol.). The mixture was concentrated by distillation at atmospheric pressure and15 approximately 90 oC to a volume of 9 L, then distilled while maintaining constant volume via theaddition of acetonitrile (7.40 L, 4.00 rel. vol.). The temperature was adjusted to 0 ± 5oC over approximately 80 minutes and then stirred at 0 ± 5oC for approximately 19 h. The resulting suspension was filtered and the filter cake washed with acetonitrile (3 × 3.70 L, 3 × 2.00 rel. vol.) at 15 ± 5oC. The filter cake was dried at ambient temperature under a flow of nitrogen for 24 h20 to afford methyl 4-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)tetrahydro-2H-pyran-4- carboxylate (1.76 kg, 5.16 mol, 84% yield). Step 4 - Preparation of crude 4-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)tetrahydro-2H-pyran-4-carboxamide 25 4-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)tetrahydro-2H-pyran-4-carboxylate (1.76 kg, 5.15 mol, 1.00 equiv.) and 5-(6-ethoxypyrazin-2-yl)pyridin-2-amine (1.22 kg, 5.65 mol, 1.10 equiv.) were suspended in a mixture of THF (27.1 L, 15.5 rel. vol.) and DMSO (2.63 L, 1.50 rel. vol.) and stirred until the solids were evenly dispersed. The mixture was concentrated by STP-P3718PCT 102 distillation at atmospheric pressure and approximately 70 oC to a volume of 15 L. Thetemperature was adjusted to 20 ± 5oC, potassium tert-butoxide (6.92 kg 20 wt% solution in THF, 12.3 mol, 2.40 equiv.) was added over 1 h and the reaction mixture stirred at 20 ± 5oC for 70 minutes until completion. THF (880 mL, 0.500 rel vol.) was charged, followed by acetic acid (7805 mL, 820 g, 13.6 mol, 2.64 equiv.) over 10 minutes, followed by methanol (4.40 L, 2.50 rel. vol.), followed by water (13.2 L, 7.50 rel. vol.) over 35 minutes. The mixture was stirred at 20 ± 5oC for 15 minutes and then 16 h at 0 ± 5oC. The resulting suspension was filtered and washed with water (2 × 8.80 L, 2 × 5.00 rel. vol.), followed by methanol (4.40 L, 2.50 rel. vol.) The filter cake was dried at 35oC under a flow of nitrogen for 20 h to afford crude 4-(2-10 (cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)tetrahydro- 2H-pyran-4-carboxamide (“CTPS1-IA”).Example A2 – Purification of 4-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)tetrahydro-2H-pyran-4-carboxamide (CTPS1-IA) and15 crystallisation Crude 4-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2- yl)pyridin-2-yl)tetrahydro-2H-pyran-4-carboxamide (CTPS1-IA, the product of Example A1) was dissolved in a mixture of THF (26.0 L, 14.8 rel. vol.) and water (6.51 L, 3.70 rel. vol.) at 60 ± 5 oC. After polishing filtration of the mixture, the mixture was concentrated by distillation at20 atmospheric pressure and approximately 60 oC to a volume of 22 L, then distilled at atmosphericpressure and approximately 110oC while maintaining constant volume via the addition of MIBK (58.6 L, 33.3 rel. vol.). The mixture was allowed to cool to 20 ± 10oC overnight and the resulting suspension filtered. The filter cake was washed with MIBK (2 × 4.40 L, 2 × 2.50 rel. vol.) at 20 ± 10oC. The filter cake was dried at 41oC under a flow of nitrogen for 21 h to afford the pure 25 product (1.97 kg, 3.74 mol, 73%, 99.5% a / a by HLPC). Example A3 – Alternative preparation and purification of 4-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2- yl)tetrahydro-2H-pyran-4-carboxamide (CTPS1-IA) and crystallisation30 In a variant of the protocol described in Example A1 Step 4, 4-(2- (cyclopropanesulfonamido)pyrimidin-4-yl)tetrahydro-2H-pyran-4-carboxylate (500 g, 1.46 mol, 1.00 equiv.) and 5-(6-ethoxypyrazin-2-yl)pyridin-2-amine (347 g, 1.61 mol, 1.10 equiv.) were suspended in a mixture of THF (3.75 L, 7.50 rel. vol.) and DMSO (1.25 L, 2.50 rel. vol.). Potassium tert-butoxide (307 g, 4.38 mol, 3.00 equiv.) in THF (3.00 L, 6.00 rel. vol.) was added35 and the mixture stirred for 4 h at – 5 oC until completion. Acetic acid (438 g, 7.30 mol, 5.00 equiv.)was added dropwise, while maintaining the temperature at – 5 oC. The mixture was allowed towarm to room temperature and then diluted with water (10.0 L, 20.0 rel. vol.) added over 1 h. STP-P3718PCT 103 The resulting suspension was stirred overnight at room temperature, then filtered, and the solids washed with water (10.0 L, 20.0 rel.vol.) and dried under vacuum to afford 556 g crude 4-(2- (cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)tetrahydro- 2H-pyran-4-carboxamide. Additional batches of the title compound were prepared via an 5 analogous protocol to afford a total of 1.34 kg of the title compound. The combined 1.34 kg of 4-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6- ethoxypyrazin-2-yl)pyridin-2-yl)tetrahydro-2H-pyran-4-carboxamide was suspended in 13.4 L absolute ethanol. The suspension was slowly warmed to 50 °C (internal temperature) and stirred for 48 hours. The heating was switched off and the suspension was allowed to cool to room10 temperature overnight. The suspension was filtered and the collected solids were washed onthe filter with ethanol (2 ×2 L). The material was dried under vacuum to afford 1.25 kg of the titlecompound (93% recovery). Example A4 – Micronisation of CTPS1-IA as crystalline Form B15 Micronisation of the CTPS1-IA was successfully completed following wet bead milling for1 hour at 530 RPM. Micronisation was conducted using a wet bead milling method (pulverisette 6, Fritsch). A single batch was prepared using a Fritsch planetary mill (Serial no 06.2000 / 01996) equipped with an Automaxion SARAL milling vessel. 500 mg of active pharmaceutical ingredient (CTPS1-IA, “API”) was accurately weighed and transferred to a 30 mL screw cap clear glass 20 vial. 1 mm diameter zirconium silica milling beads were added to give an API:bead ratio of 1:10 w / w. 5 mL of anti-solvent 2H, 3H-decafluoropentane was then added dropwise to the API containing vial until the API and milling media were wetted and a layer of supernatant suspending solution was obtained. The glass vial was closed, vortexed to ensure complete wetting and dispersion of the API and placed into the milling vessel. Milling was started at 530 RPM and 25 after every 30 minutes, this was stopped and the particle size monitored using an optical microscope. The milling was continued until the target size was achieved (D90 <5 µm). At the end of the cycle, the suspension was separated from the beads by decantation followed by 2 to 3 washes with 2H, 3H-decafluoropentane. The suspension was then transferred onto a petri dish and left at room temperature (ca 25 °C) to allow for the evaporation of the anti-solvent (ca. 30 16h). The D10, D50 and D90 parameters before and after micronisation are shown in the Table below. XRPD and mDSC showed that no change to the physical form of the compound was observed as a result of micronisation (data not shown). STP-P3718PCT 104 B. Preparations of compositionsExample B1 - Preparation of a composition by hot melt extrusion (laboratory scale)Amorphous solid dispersions of CTPS1-IA were prepared by hot melt extrusion using a5 HAAKE™Rheomix MiniLab II CTW5 twin screw extruder. The composition was formulated as follows: The required amount of CTPS1-IA (Form B micronised) and carrier was weighed into a 60mL borosilicate glass vial and mixed for 10 minutes at 60 RPM using a Turbula Mixer. The 10 mixture was manually fed into the extruder and processed at 200 °C / 190 °C using a screw rotation speed of 50 RPM. The extruded product was then grounded using a bench top grinder, followed by sieving through 250 µm sieve. The product was a beige solid. C. Preparation of dosage forms15 Example C1 - Capsule formulations and dissolution testing in FaSSGFCapsule formulations were prepared which contained 75 mg or 150 mg of CTPS1-IA asfollows: The capsule formulations were filled into Capsugel® VCaps® HPLC size 0 capsule (Lonza). 20 STP-P3718PCT 105 D. In vivo testingExample D1 - Pharmacokinetic studies by single oral administration of hot melt extrusionformulation in male Beagle dogs The pharmacokinetics properties of CTPS1-IA in the above formulations of Example C15 were investigated in male beagle dogs following single oral administration. CTPS1-IA was givento 3 male dogs (2-7 years old on the day of dosing) in an ad libitum food regimen.Individual serial plasma profiles were drawn from each animal. Pharmacokinetic parameters were evaluated after test composition administration. Body weights were within the normal range for animals of this strain and age. No clinical signs were observed after test 10 composition administration. The test sample was extracted from dog plasma using acetonitrile containing an internal standard. Extracts were analysed by LC-MS / MS using TurboIonSpray™ interface with positive ion multiple reaction monitoring. This method was qualified over the range 5 to 5000 ng / mL using a 10 µL aliquot of dog plasma. Calibration standards were freshly prepared; Quality Control samples were prepared within one week from the sample receipt and15 were stored at -80°C together with the study samples until use. All analytical batches from which concentration results were reported met the acceptance criteria. The following formulation was tested: 20 The powder was filled into oral HPMC capsules. Formulation F-B was administered toanimals in oral HPMC capsules (capsule size 00) at 10 mg / kg. Summaries of plasma pharmacokinetic parameters of CTPS1-IA in dogs following singleoral administration, are presented in the tables below. 25 Study with Formulation F-B STP-P3718PCT 106 *AUClast means area under the plasma concentration time curve (AUC) from the time of dosingto the last measurable concentration ^Frel calculated as percentage of AUClast from Formulation F-B (Frel calculated as percentage of AUC0-8h from Formulation F-B) 5&Value is median not mean **Tlast means last plasma collection timepoint Example 1: Human CTPS1 Enzyme Inhibition The enzyme inhibitory activities of compounds against CTPS1 may be determined using10 the ADP-Glo^ Max assay (Promega, UK).Assays for human CTPS1 were performed in 1x assay buffer containing 50mM Tris, 10mM MgCl2, 0.01% Tween-20, pH to 8.0 accordingly. Finally, immediately before use, L- cysteine was added to the 1x assay buffer to a final concentration of 2mM. All reagents are from Sigma-Aldrich unless specified otherwise. Human full length active C-terminal FLAG-His8-tag15 CTPS1 (UniProtKB - P17812, CTPS[1-591]-GGDYKDDDDKGGHHHHHHHH, SEQ ID NO: 1)was obtained from Proteros biostructures GmbH. Assay Procedure 3x human CTPS1 protein was prepared in 1x assay buffer to the final working protein concentration required for the reaction. A 2uL volume per well of 3x human CTPS1 protein was 20 mixed with 2uL per well of 3x test compound (compound prepared in 1x assay buffer to an appropriate final 3x compound concentration respective to the concentration response curve designed for the compounds under test) for 10 minutes at 25°C. The enzymatic reaction was then initiated by addition of a 2uL per well volume of a pre-mixed substrate mix (UltraPure ATP from ADP-Glo^ Max kit (0.31mM), GTP (0.034mM), UTP (0.48mM) and L-glutamine25 (0.186mM)) and the mixture was incubated for an appropriate amount of time within the determined linear phase of the reaction at 25°C under sealed plate conditions with constant agitation at 500 revolutions per minute (rpm). ADP-Glo^ Max reagent was added for 60 minutes(6μL per well) and subsequently ADP-Glo^Max development reagent was added for 60 minutes (12uL per well) prior to signal detection in a microplate reader (EnVision^ Multilabel Reader,30 Perkin Elmer). Following each reagent addition over the course of the assay, assay plates were pulse centrifuged for 30 seconds at 500rpm. STP-P3718PCT 107 In all cases, the enzyme converts ATP to ADP and the ADP-Glo^ Max reagentsubsequently depletes any remaining endogenous ATP in the reaction system. The ADP-Glo^ Max detection reagent converts the ADP that has been enzymatically produced back into ATP and using ATP as a substrate together with luciferin for the enzyme luciferase, light is generated 5 which produces a detectable luminescence. The luminescent signal measured is directly proportional to the amount of ADP produced by the enzyme reaction and a reduction in this signal upon compound treatment demonstrates enzyme inhibition. The percentage inhibition produced by each concentration of compound was calculated using the equation shown below: 100 10 Percentage inhibition was then plotted against compound concentration, and the 50% inhibitory concentration (IC50) was determined from the resultant concentration-response curve. Example 2: RapidFire / MS-based CTPS1 Enzyme Selectivity AssaysHuman CTPS1 versus CTPS2 Selectivity Assessment by RapidFire / MS Analysis.15 The enzyme inhibitory activities against each target isoform of interest were determinedfor compounds using an optimised RapidFire high-throughput mass spectrometry (RF / MS)assay format. RF / MS assays for both human CTPS1 and CTPS2 were performedin assay buffer consisting of 50mM HEPES (Merck), 20mM MgCl2, 5mM KCl, 1mMDTT, 0.01% Tween-20, pH to 8.0 accordingly. Human full-length active C-terminal FLAG-His-20 tag CTPS1 (UniProtKB - P17812, CTPS[1-591]-GGDYKDDDDKGGHHHHHHHH, SEQ ID NO:1) was obtained from Proteros biostructures GmbH. Human full length active C-terminal FLAG-His-Avi tagged CTPS2 (UniProtKB – Q9NRF8, CTPS2 [1-586]-DYKDDDDKHHHHHHGLNDIFEAQKIEWHE, SEQ ID NO: 2) was obtained from Harker Bio. Assay Procedure25 Human CTPS (1 or 2) protein was prepared in 1x assay buffer to the final workingprotein concentration required for the reaction. A 2uL volume per well of 2x CTPS (1 or 2) proteinwas mixed with 40nL of compound using acoustic (ECHO) delivery and incubated for 10 minutesat 25˚C. Each isoform enzymatic reaction was subsequently initiated by addition of 2uL per wellof a 2x substrate mix in assay buffer. For hCTPS1: ATP (0.3mM), UTP (0.2mM), GTP (0.07mM)30 and L-glutamine (0.1mM). For hCTPS2: ATP (0.1mM), UTP (0.04mM), GTP (0.03mM) and L-glutamine (0.1mM). Each mixture was incubated for an appropriate amount of time per isoformwithin the determined linear phase of the reaction at 25˚C. A 60uL volume of stop solution (1% formic acid with 0.5uM 13C9-15N3-CTP in H20) was added and the plate immediately heat-sealedand centrifuged for 10 minutes at 4,000rpm. Following centrifugation, plates were loaded onto STP-P3718PCT 108 the Agilent RapidFire microfluidic solid phase extraction system coupled to an API4000 triplequadrupole mass spectrometer (RF / MS) for analysis. In all cases, the enzyme converts UTP to CTP. Highly specific and sensitive multiplereaction monitoring (MRM) MS methods may be optimised for the detection of the enzymatic 5reaction product, CTP, and the stable isotope labelled product standard 13C9-15N3-CTP. Readoutfor data analysis was calculated as the ratio between the peak area of the product CTP and theinternal standard 13C9-15N3-CTP. For data reporting, the following equation was used:R= P IS 10 (R = ratio / readout, P = product signal area, IS = internal standard signal area) For each screening plate, the means of the negative (DMSO) and positive control values were used for the calculation of the respective assay window (S / B) and Z’ values. The medianof the respective control values was used for calculation of percent inhibition according to thefollowing equation:15 (I = Inhibition, Rneg =median of negative control readout values, Rpos =median of positivecontrol readout values, Rsample = sample readout value)Percentage inhibition was then plotted against compound concentration, and the 50%20 inhibitory concentration (IC50) was determined from the resultant concentration-response curve. Fold selectivity between CTPS1 and CTPS2 was subsequently calculated according tothe following equation: Fold selectivity = CTPS2 IC50CTPS1 IC5025 Example 3: Administration of a CTPS1 Inhibitor and Impact on Blood Cell Count in MiceCTPS1-IA (a CTPS1 inhibitor) was administered to mice at a dose which inhibited CTPS1(100 mg / kg / day, for 28 days). CTPS1-IA is 4-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5- (6-ethoxypyrazin-2-yl)pyridin-2-yl)tetrahydro-2H-pyran-4-carboxamide. Platelet and neutrophil30 cell counts were not impacted (data not shown). STP-P3718PCT 109 Example 4: Administration of a CTPS1 Inhibitor and Impact on Blood Cell Count in DogsCTPS1-IA was administered to dogs. Platelet cell counts were not impacted at tolerateddoses where CTPS1 inhibition occurred (10 mg / kg / day). A mild decrease in platelets wasobserved in dogs only at dose levels that exceeded the maximum tolerated dose (30 mg / kg / day).5 A modest and inconsistent decrease in neutrophils was observed in only a subset of animals(data not shown). Example 5: Administration of a CTPS1 Inhibitor and Impact on Blood Cell Count inHumans 10 CTPS1-IA (specifically dencatistat, a CTPS1 inhibitor) entered a clinical trial in September 2022 (NCT05463263). CTPS1-IA has been administered to 41 relapsed / refractorylymphoma patients in the trial. Administration of CTPS1-IA was associated with a doseproportional decrease in the platelet count, and (to a lesser extent) a decrease in neutrophilcount. The impact on platelet count is illustrated in Fig.1 for cohorts 1-3, comprising 16 patients.15 Patients in cohort 1 generally received drug continually, although several patients undertookdrug holidays. Patients in cohort 2 received drug for 3 weeks followed by a 1 week drug holiday, repeating on a four weekly cycle. Patients in cohort 3 received drug for 10 days followed by a 4day drug holiday, repeating on a 2 weekly cycle. Administration of CTPS1-IA (Formulation F-B) resulted in a swift decrease in platelet20 count that was reversible upon drug withdrawal. CTPS1-IA also lowered the neutrophil count asshown in Fig.2. Further cohorts were added to the relapsed / refractory lymphoma trial with the objectiveof limiting impact on blood cell count. It was found that certain discontinuous dosage regimes enabled impact on blood cell count to be mitigated, highlighting that continuous dosing in the 25 context of MPNs such as ET may be desirable. The dosage regimes for the initial cohorts 4 onwards are detailed in the table below. STP-P3718PCT 110 Changes in platelet counts are illustrated in Fig.4 and Fig.5 (wherein ‘total dose’ refersto daily dose during on period). Administration of CTPS1-IA resulted in a swift decrease in platelet count that was reversible upon drug withdrawal. 5 It was also noted that, in cohorts where CTPS1-IA was administered continually for 10 days or more, the fall in platelet count was proportional to drug exposure (see Fig. 3). CTPS1-IA was well-tolerated in the patients receiving therapy on the clinical trial.The substantial reductions in platelet and neutrophil counts in humans described abovewere surprising in view of the lack of, or very limited, effects observed when CTPS1-IA was10 administered to other species (see Example 3 above). The distinct impacts on neutrophil count vs platelet count were also noteworthy. Current data (Campbell et al.2012, Carobbio et al.2007, Carobbio et al.2019) suggest that both platelet count and neutrophil count should ideally be normalised in individuals with ET in order to prevent thrombosis. Response criteria reflect this with a complete response to drug requiring a normal 15 platelet count and neutrophil count. The effect of CTPS1-IA on neutrophils (see Fig.2), being less than the effect on platelets(see Fig.1), may represent an ideal balance, as ET is associated with markedly raised platelet counts and mildly raised neutrophil counts. This impact has been further illustrated by modelling of drug effect on proliferation rate constant (Kprol) vs concentration of CTPS1-IA, which indicates20 a Sigmoid Emax model with an EC50 of 443 ng / mL and hill coefficient of 5.52 for platelets, butan Emax model with an EC50 of 740 ng / mL and hill coefficient of 1 for neutrophils (data notshown). Example 6: Mode of Action of CTPS1-IA in Reducing Platelet Counts in Humans25 It has been established that CTPS1-IA induces cell death in typical cancers by preventingDNA replication (Pfeiffer et al.2024). In contrast, CTPS1-IA does not appear to induce cell death in megakaryocytes (nor platelets, nor neutrophils). Instead, CTPS1-IA appears to interfere with phospholipid synthesisin the formation of platelets for release from megakaryocytes. This mechanism seems 30 supported by (a) the swift decrease in platelet count being quickly reversible upon drug withdrawal as discussed above and (b) work on staining normal human bone marrow sections STP-P3718PCT 111 for CTPS2 by immunohistochemistry, where it was found that CTPS2 is expressed in progenitor cells but not in mature platelet-producing megakaryocytes (data not shown). Furthermore, it has also been established from megakaryocyte RNA sequencing data that murine megakaryocytes comprise transcripts of both CTPS1 and CTPS2, whereas human 5 megakaryocytes comprise transcripts of CTPS1 only. It appears that human megakaryocytes are deficient in CTPS2 and this observation offers a possible mechanistic explanation for thedistinct effects on platelet counts when administering CTPS1-IA to mice vs humans as set out in Examples 3 and 5 above. Accordingly, and without wishing to be bound by theory, the inventors believe that it is 10 the combination of (a) interference with platelet production (without inducing cell death) and (b) human megakaryocyte CTPS1-essentiality, which give rise to the surprising impact of CTPS1-IA on human platelet counts demonstrated above. Conclusion15 Despite the suggestion in the art that CTPS1 would have no effect on human plateletcounts, and was found to have no effect on platelets in mice (Example 3), the humanexperiments outlined above have surprisingly identified the potential for CTPS1 inhibition as a mechanism to control platelet levels. It has also been observed that CTPS1 inhibition may achieve an ideal balance of moderate impact on neutrophil count and more significant impact on 20 platelet count. CTPS1 inhibitors are therefore a surprising approach having utility in the treatment of human MPN, and in particular ET. Example 7: Administration of a CTPS1 inhibitor (CTPS1-IA) to essential thrombocythemia patients 25 CTPS1-IA will be administered to essential thrombocythaemia (ET) patients in a phase 1b clinical trial. The trial will recruit up to 20 participants with high risk ET who are refractory to or intolerant of hydroxycarbamide (also known as hydroxyurea). 25 mg of CTPS1-IA will be administered to the first patients, continually once daily (OD), orally. The dose of CTPS1-IA willbe titrated on a two weekly, per participant basis in order to achieve optimal control of the platelet30 and white cell counts, as per standard response criteria. Primary study endpoints will be efficacy,safety and tolerability; secondary endpoints will be durability of response and impact of drug ondisease complications. As of 23 July 2025, five clinical sites are open and the first potential participant is in screening. The planned dose levels for testing in the trial are set out in the table below. 35 STP-P3718PCT 112 Throughout the specification and the claims which follow, unless the context requires otherwise, the word ‘comprise’, and variations such as ‘comprises’ and ‘comprising’, will be understood to imply the inclusion of a stated integer, step, group of integers or group of steps 5 but not to the exclusion of any other integer, step, group of integers or group of steps. The application of which this description and claims forms part may be used as a basis for priority in respect of any subsequent application. The claims of such subsequent application may be directed to any feature or combination of features described herein. They may take the form of product, composition, process, or use claims and may include, by way of example and10 without limitation, the claims which follow. All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth. 15 Clauses of the invention: A series of clauses setting out embodiments of the invention are as follows. Clause 1. A CTPS1 inhibitor for use in the treatment of a myeloproliferative neoplasm(MPN) in a human subject.20 Clause 2. A pharmaceutical composition comprising a CTPS1 inhibitor for use in thetreatment of an MPN in a human subject. Clause 3. A pharmaceutical composition comprising a CTPS1 inhibitor and apharmaceutically acceptable excipient or carrier for use in the treatment of an MPN in a human subject. STP-P3718PCT 113 Clause 4. Use of a CTPS1 inhibitor in the manufacture of a medicament for the treatmentof an MPN in a human subject. Clause 5. A method for the treatment of an MPN in a human subject, the methodcomprising administering a CTPS1 inhibitor to the subject. 5Clause 6. The method of clause 5 wherein the method comprises the step of establishingthe thrombocyte and / or neutrophil count of the subject after administration of the CTPS1 inhibitor, after an adequate period of treatment with the CTPS1 inhibitor and (a) if the count is greater than a desired (e.g. physiologically normal) cell count range, administering the CTPS1 inhibitor again at an 10 increased daily dose or (b) if the count is less than the desired (e.g. physiologically normal) cell count range, administering the CTPS1 inhibitor again at a reduced daily dose or (c) if the count is within the desired (e.g. physiologically normal) cell count range, administering the CTPS1 inhibitor again at the same daily dose; and optionally repeating this step, such as for the15 duration of treatment. Clause 7. The method of clause 5 wherein the method comprises the steps of(a) administering an initial daily dose of CTPS1 inhibitor and (b) establishing the thrombocyte count of the subject, wherein if the thrombocyte count of the subject is greater than a physiologically 20 normal cell count range, administering the CTPS1 inhibitor again at an increased daily dose, then repeating steps (a) and (b), or if the thrombocyte count of the subject is within a physiologically normal cell count range, administering the CTPS1 inhibitor again at the previous daily dose. Clause 8. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, or25 use according to any one of clauses 1 to 7 wherein the MPN is essential thrombocythaemia (ET). Clause 9. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, oruse according to any one of clauses 1 to 7 wherein the MPN is polycythaemia vera (PV).30 Clause 10. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, oruse according to any one of clauses 1 to 7 wherein the MPN is myelofibrosis(MF). Clause 11. A method for reducing the risk of thrombosis in a human subject in needthereof, the method comprising administering a CTPS1 inhibitor to the subject.35 Clause 12. A method for maintaining blood cell count in a human subject, the methodcomprising administering a CTPS1 inhibitor to the subject. STP-P3718PCT 114 Clause 13. A method for controlling platelet production in a human subject, the methodcomprising administering a CTPS1 inhibitor to the subject. Clause 14 A method for reducing the likelihood of ET to MF progression in a humansubject, the method comprising administering a CTPS1 inhibitor to the subject. 5Clause 15. A method for delaying progression of ET to MF in a human subject, the methodcomprising administering a CTPS1 inhibitor to the subject. Clause 16. A method for reducing the likelihood of ET to myelodysplasia or acute myeloidleukaemia progression in a human subject, the method comprisingadministering a CTPS1 inhibitor to the subject.10 Clause 17. A method for delaying the rate of progression of ET to myelodysplasia or acutemyeloid leukaemia in a human subject, the method comprising administering aCTPS1 inhibitor to the subject. Clause 18. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, oruse according to any one of clauses 1 to 17 wherein the subject’s cell count for15 one or more blood cell types is reduced after administration of the CTPS1 inhibitor. Clause 19. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, oruse according to any one of clauses 1 to 17 wherein increase in the subject’scell count for one or more blood cell types is prevented after administration of 20 the CTPS1 inhibitor. Clause 20. A method for preventing increase in cell count for one or more blood cell typesin a human subject, the method comprising administering a CTPS1 inhibitor to the subject. Clause 21. A method for reducing cell count for one or more blood cell types in a human25 subject, the method comprising administering a CTPS1 inhibitor to the subject. Clause 22. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, oruse according to any one of clauses 1 to 21 wherein increase in the subject’scell count for one or more blood cell types is prevented or the subject’s cellcount for one or more blood cell types is reduced, by repeated administration of30 the CTPS1 inhibitor. Clause 23. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, oruse according to any one of clauses 18 to 22 wherein the subject’s cell count forone or more blood cell types is prevented from increasing above, or reduced to,a therapeutically beneficial range or physiologically normal range.35 Clause 24. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, oruse according to any one of clauses 18 to 22 wherein increase in the subject’scell count for one or more blood cell types is prevented or the subject’s cell STP-P3718PCT 115 count is reduced, by adjusting the dose and / or frequency of dosing of theCTPS1 inhibitor. Clause 25. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, oruse according to either one of clauses 23 or 24 wherein the therapeutically5 beneficial range or the physiologically normal range is achieved within 28 days,such as 14 days of repeated administration of the CTPS1 inhibitor. Clause 26. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, oruse according to any one of clauses 18 to 25 wherein the cell count is athrombocyte cell count.10 Clause 27. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, oruse according to clause 26 wherein the physiologically normal cell count rangeis one wherein the subject’s thrombocyte count is 30x109 / L to 1500x109 / L, suchas 90x109 / L to 1000x109 / L, such as 100x109 / L to 750x109 / L, such as to110x109 / L to 500x109 / L, such as 120x109 / L to 400x109 / L, such as 130x109 / L to15 370x109 / L. Clause 28. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, oruse according to any one of clauses 18 to 25 wherein the cell count is aerythrocyte cell count. Clause 29. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, or20 use according to any one of clauses 18 to 25 wherein the cell count is amegakaryocyte cell count. Clause 30. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, oruse according to any one of clauses 18 to 25 wherein the cell count is aleukocyte cell count.25 Clause 31. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, oruse according to any one of clauses 18 to 25 wherein increase in the subject’sthrombocyte count is prevented and increase in the subject’s leukocyte cell count is prevented after administration of the CTPS1 inhibitor.Clause 32. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, or30 use according to any one of clauses 18 to 25 wherein increase in the subject’sthrombocyte count is prevented and increase in the subject’s granulocyte cell count is prevented after administration of the CTPS1 inhibitor.Clause 33. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, oruse according to any one of clauses 18 to 25 wherein increase in the subject’s35 thrombocyte count is prevented and increase in the subject’s neutrophil cellcount is prevented after administration of the CTPS1 inhibitor. STP-P3718PCT 116 Clause 34. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, oruse according to any one of clauses 18 to 25 wherein increase in the subject’stotal blood cell count is prevented after administration of the CTPS1 inhibitor.Clause 35. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, or5 use according to any one of clauses 18 to 25 wherein the subject’s thrombocytecount is reduced and the subject’s leukocyte count is reduced afteradministration of the CTPS1 inhibitor. Clause 36. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, oruse according to any one of clauses 18 to 25 wherein the subject’s thrombocyte10 count is reduced and the subject’s granulocyte count is reduced after administration of the CTPS1 inhibitor. Clause 37. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, oruse according to any one of clauses 18 to 25 wherein the subject’s thrombocytecount is reduced and the subject’s neutrophil cell count is reduced after15 administration of the CTPS1 inhibitor. Clause 38. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, oruse according to any one of clauses 18 to 25 wherein the subject’s total bloodcell count is reduced after administration of the CTPS1 inhibitor.Clause 39. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, or20 use according to either one of clauses 30 or 31 wherein the leukocytes aregranulocytes. Clause 40. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, oruse according to any one of clauses 32, 36 or 39 wherein the granulocytes areneutrophils.25 Clause 41. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, oruse according to any one of clauses 32, 36 or 39 wherein the granulocytes areeosinophils. Clause 42. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, oruse according to any one of clauses 32, 36 or 39 wherein the granulocytes are30 basophils. Clause 43. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, oruse according to either one of clauses 30 or 31 wherein the leukocytes areagranulocytes. Clause 44. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, or35 use according to clause 43 wherein the agranulocytes are lymphocytes.Clause 45. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, oruse according to clause 43 wherein the agranulocytes are monocytes. STP-P3718PCT 117 Clause 46. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, oruse according to any one of clauses 1 to 45 wherein the subject’s thrombocytecount after administration of the CTPS1 inhibitor is 4000x109 / L or lower, such as2000x109 / L or lower, such as 1000x109 / L or lower.5 Clause 47. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, oruse according to clause 46 wherein the subject’s thrombocyte count afteradministration of the CTPS1 inhibitor is 900x109 / L or lower, such as 700x109 / Lor lower, such as 500x109 / L or lower.Clause 48. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, or10 use according to clause 47 wherein the subject’s thrombocyte count afteradministration of the CTPS1 inhibitor is 400x109 / L or lower.Clause 49. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, oruse according to clause 1 to 48 wherein the subject’s thrombocyte count afteradministration of the CTPS1 inhibitor is 30x109 / L or higher, such as 90x109 / L or15 higher, such as 110x109 / L or higher.Clause 50. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, oruse according to clause 49 wherein the subject’s thrombocyte count afteradministration of the CTPS1 inhibitor is 120x109 / L or higher, such as 130x109 / Lor higher, such as 140x109 / L or higher.20 Clause 51. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, oruse according to clause 50 wherein the subject’s thrombocyte count afteradministration of the CTPS1 inhibitor is 150x109 / L or higher.Clause 52. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, oruse according to any one of clauses 1 to 45 wherein the subject’s thrombocyte25 count after administration of the CTPS1 inhibitor is 130x109 / L to 700x109 / L,such as 140x109 / L to 500x109 / L such as 150x109 / L to 400x109 / L.Clause 53. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, oruse according to any one of clauses 1 to 52 wherein the subject’s leukocytecount after administration of the CTPS1 inhibitor is 15x109 / L or lower, such as30 13x109 / L or lower, such as 12x109 / L or lower.Clause 54. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, oruse according to clause 53 wherein the subject’s leukocyte count afteradministration of the CTPS1 inhibitor is 11.0x109 / L or lower, such as 10.5x109 / Lor lower, such as 10.3x109 / L or lower.35 Clause 55. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, oruse according to clause 54 wherein the subject’s leukocyte count afteradministration of the CTPS1 inhibitor is 10.0x109 / L or lower. STP-P3718PCT 118 Clause 56. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, oruse according to any one of clauses 1 to 55 wherein the subject’s leukocytecount after administration of the CTPS1 inhibitor is 1x109 / L or higher, such as2x109 / L or higher, such as 3x109 / L or higher.5 Clause 57. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, oruse according to clause 56 wherein the subject’s leukocyte count afteradministration of the CTPS1 inhibitor is 3.5x109 / L or higher, such as 4.0x109 / Lor higher, such as 4.3x109 / L or higher.Clause 58. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, or10 use according to clause 57 wherein the subject’s leukocyte count afteradministration of the CTPS1 inhibitor is 4.5x109 / L or higher.Clause 59. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, oruse according to any one of clauses 1 to 52 wherein the subject’s leukocytecount after administration of the CTPS1 inhibitor is 4.0x109 / L to 10.5x109 / L such15 as 4.3x109 / L to 10.3x109 / L such as 4.5x109 / L to 10.0x109 / L.Clause 60. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, oruse according to any one of clauses 1 to 59 wherein the subject’s neutrophilcount after administration of the CTPS1 inhibitor is 13x109 / L or lower, such as12x109 / L or lower, such as 11x109 / L or lower.20 Clause 61. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, oruse according to clause 60 wherein the subject’s neutrophil count afteradministration of the CTPS1 inhibitor is 10x109 / L or lower, such as 9x109 / L orlower, such as 8x109 / L or lower.Clause 62. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, or25 use according to clause 61 wherein the subject’s neutrophil count afteradministration of the CTPS1 inhibitor is 7x109 / L or lower.Clause 63. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, oruse according to any one of clauses 1 to 62 wherein the subject’s neutrophilcount after administration of the CTPS1 inhibitor is 0.5x109 / L or higher, such as30 1.0x109 / L or higher, such as 1.5x109 / L or higher.Clause 64. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, oruse according to clause 63 wherein the subject’s neutrophil count afteradministration of the CTPS1 inhibitor is 2.0x109 / L or higher, such as 2.2x109 / Lor higher, such as 2.4x109 / L or higher.35 Clause 65. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, oruse according to clause 64 wherein the subject’s neutrophil count afteradministration of the CTPS1 inhibitor is 2.5x109 / L or higher. STP-P3718PCT 119 Clause 66. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, oruse according to any one of clauses 1 to 59 wherein the subject’s neutrophilcount after administration of the CTPS1 inhibitor is 2.2x109 / L to 9x109 / L such as2.4x109 / L to 8x109 / L such as 2.5x109 / L to 7.0x109 / L.5 Clause 67. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, oruse according to any one of clauses 1 to 66 wherein the CTPS1 inhibitor isadministered repeatedly. Clause 68. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, oruse according to any one of clauses 18 to 67 wherein the cell count is10 established 50 days or fewer, such as 40 days or fewer, such as 30 days or fewer after the initial administration of the CTPS1 inhibitor. Clause 69. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, oruse according to clause 68 wherein the cell count is established 20 days orfewer, such as 15 days or fewer, such as 10 days or fewer after the initial15 administration of the CTPS1 inhibitor. Clause 70. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, oruse according to any one of clauses 18 to 69 wherein the subject’s cell count forone or more blood cell types is a total blood cell count. Clause 71. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, or20 use according to any one of clauses 18 to 70 wherein the cell count isestablished 1 day or more, such as 3 days or more, such as 5 days or moreafter the initial administration of the CTPS1 inhibitor. Clause 72. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, oruse according to clause 71 wherein the cell count is established 10 days or25 more, such as 15 days or more, such as 20 days or more after the initialadministration of the CTPS1 inhibitor. Clause 73. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, oruse according to clause 72 wherein the cell count is established 30 days ormore, such as 40 days or more, such as 50 days or more after the initial30 administration of the CTPS1 inhibitor. Clause 74. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, oruse according to any one of clauses 18 to 73 wherein the cell count isestablished every week, every two weeks or every three weeks duringtreatment; preferably every two weeks.35 Clause 75. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, oruse according to any one of clauses 18 to 74 wherein the cell count isestablished 2 to 14 days after the initial administration of the CTPS1 inhibitor. STP-P3718PCT 120 Clause 76. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, oruse according to clause 75 wherein the cell count is established 5 to 7 daysafter the initial administration of the CTPS1 inhibitor. Clause 77. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, or5 use according to any one of clauses 18 to 76 wherein the cell count isestablished repeatedly at convenient intervals over a clinically relevant period of time and the dosage of the CTPS1 inhibitor is adjusted continuously. Clause 78. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, oruse according to any one of clauses 18 to 77 wherein the cell count ascertained10 from a blood sample taken from the subject. Clause 79. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, oruse according to clause 78 wherein the blood sample is taken from a vein of thesubject. Clause 80. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, or15 use according to any one of clauses 1 to 79 wherein the concentration ofthrombocytes in the subject’s blood after administration of the CTPS1 inhibitor (i.e. thrombocyte count) is reduced by at least 10%, such as at least 20%, such as at least 30%, such as at least 40%, such as at least 50%, such as at least 60%, such as at least 70%, such as at least 80%, relative to the concentration 20 of thrombocytes in the subject’s blood before administration of the CTPS1 inhibitor. Clause 81. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, oruse according to any one of clauses 1 to 80 wherein the concentration ofthrombocytes in the subject’s blood after administration of the CTPS1 inhibitor 25 (i.e. thrombocyte count) is reduced by no greater than 80%, such as no greater than 70%, such as no greater than 60%, such as no greater than 50%, such as no greater than 40%, such as no greater than 30% relative to the concentration of thrombocytes in the subject’s blood before administration of the CTPS1 inhibitor.30 Clause 82. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, oruse according to any one of clauses 1 to 81 wherein the concentration ofthrombocytes in the subject’s blood (i.e. thrombocyte count) before treatment with the CTPS1 inhibitor is 400x109 / L or higher, such as 500x109 / L or higher, such as 700x109 / L or higher, such as 900x109 / L or higher, such as 1000x109 / L 35 or higher, such as 2000x109 / L, such as 4000x109 / L or higher. Clause 83. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, oruse according to any one of clauses 1 to 82 wherein the cell count (e.g. STP-P3718PCT 121 thrombocyte count) is prevented from increasing above a therapeutically beneficial range and / or reduced to a therapeutically beneficial range for at least 3 months, such as at least 6 months, such as at least 12 months, such as at least 2 years, such as at least 3 years, such as at least 4 years, such as at least5 5 years, such as at least 10 years, such as the life time of the subject. Clause 84. The method, CTPS1 inhibitor for use, pharmaceutical composition for use oruse according to any one of clauses 1 to 83, wherein the CTPS1 inhibitor has an IC50 of 10 uM or lower in respect of human CTPS1 enzyme. Clause 85. The method, CTPS1 inhibitor for use, pharmaceutical composition for use or10 use according to clause 84, wherein the CTPS1 inhibitor has an IC50 of 1 uM or lower in respect of human CTPS1 enzyme. Clause 86. The method, CTPS1 inhibitor for use, pharmaceutical composition for use oruse according to clause 85, wherein the CTPS1 inhibitor has an IC50 of 100nM or lower in respect of human CTPS1 enzyme.15 Clause 87. The method, CTPS1 inhibitor for use, pharmaceutical composition for use oruse according to any one of clauses 84 to 86, wherein the IC50 of the CTPS1inhibitor is established using the assay procedure set out in Example 1. Clause 88. The method, CTPS1 inhibitor for use, pharmaceutical composition for use oruse according to any one of clauses 1 to 87, wherein the CTPS1 inhibitor has a20 selectivity for human CTPS1 over human CTPS2 of at least 2-fold. Clause 89. The method, CTPS1 inhibitor for use, pharmaceutical composition for use oruse according to clause 88, wherein the CTPS1 inhibitor has a selectivity for human CTPS1 over human CTPS2 of at least 30-fold. Clause 90. The method, CTPS1 inhibitor for use, pharmaceutical composition for use or25 use according to clause 89 wherein the CTPS1 inhibitor has a selectivity forhuman CTPS1 over human CTPS2 of at least 60-fold, such as at least 1000- fold. Clause 91. The method, CTPS1 inhibitor for use, pharmaceutical composition for use oruse according to any one of clauses 88 to 90, wherein the selectivity of the30 CTPS1 inhibitor is established using the assay procedure set out in Example 2. Clause 92. The method, CTPS1 inhibitor for use, pharmaceutical composition for use oruse according to any one of clauses 1 to 91, wherein the CTPS1 inhibitor is a compound of formula (I) STP-P3718PCT 122 wherein R1 is C1-5alkyl, C0-2alkyleneC3-5cycloalkyl which cycloalkyl is optionally substituted by CH3, C1-3alkyleneOC1-2alkyl, or CF3; 5 R3 is H, CH3, halo, OC1-2alkyl or CF3; R4 and R5 are each independently H, C1-6alkyl, C0-2alkyleneC3-6cycloalkyl, C0- 2alkyleneC3-6heterocycloalkyl, C1-3alkyleneOC1-3alkyl, C1-6alkylOH or C1- 6haloalkyl, or R4 and R5 together with the carbon atom to which they are attached form a10 C3-6cycloalkyl or C3-6heterocycloalkyl ring; R6is H or C1-3alkyl; Ar1 is a 6-membered aryl or heteroaryl; Ar2 is a 6-membered aryl or heteroaryl and is attached to Ar1 in the para position relative to the amide; 15 R10is H, halo, C1-3alkyl, OC1-2alkyl, C1-2haloalkyl, OC1-2haloalkyl or CN; R11is H, F, Cl, CH3, ethyl, OCH3, CF3, OCF3or CN; R12is attached to Ar2 in the meta or ortho position relative to Ar1 and R12is H, halo, C1-4alkyl, C2-4alkynyl, C(=O)C1-2alkyl, C0-2alkyleneC3-5cycloalkyl, OC1-4alkyl, C1-3alkyleneOC1-3alkyl, C1-4haloalkyl, OC1-4haloalkyl, CN, OC0-2alkyleneC3-205cycloalkyl, OCH2CH2N(CH3)2, OH, C1-4alkylOH, NR23R24, SO2CH3, C(O)N(CH3)2, NHC(O)C1-3alkyl, or a C3-6heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2, or R12together with a nitrogen atom to which it is attached forms an N-oxide (N+-O-); R23is H or C1-2alkyl; 25 R24is H or C1-2alkyl; or a pharmaceutically acceptable salt and / or pharmaceutically acceptable solvate thereof. Clause 93. The method, CTPS1 inhibitor for use, pharmaceutical composition for use oruse according to clause 92, wherein the CTPS1 inhibitor is selected from the 30 compounds disclosed in List A or a pharmaceutically acceptable salt and / or pharmaceutically acceptable solvate thereof. STP-P3718PCT 123 Clause 94. The method, CTPS1 inhibitor for use, pharmaceutical composition for use oruse according to any one of clauses 1 to 91, wherein the CTPS1 inhibitor is a 5 R1 is C1-5alkyl, C0-2alkyleneC3-5cycloalkyl which cycloalkyl is optionally substituted by CH3, C1-3alkyleneOC1-2alkyl, or CF3; R3 is H, halo, CH3, OC1-2alkyl or CF3; or R3 together with R5 forms a 5- or 6-membered cycloalkyl or 5 or 6 membered10 oxygen-containing heterocycloalkyl; R4 and R5 are each independently H, halo, C1-6alkyl, C0-2alkyleneC3-6cycloalkyl, C0-2alkyleneC3-6heterocycloalkyl, OC1-6alkyl, OC0-2alkyleneC3-6cycloalkyl, C1- 3alkyleneOC1-3alkyl, C1-6alkylOH, C1-6haloalkyl, OC1-6haloalkyl or NR21R22, or R4 is H and R5 together with R3 form a 5- or 6-membered cycloalkyl or 5 or 615 membered oxygen-containing heterocycloalkyl, or R4and R5together with the carbon atom to which they are attached form a C3-6cycloalkyl or C3-6heterocycloalkyl, or R4 is H and R5 and R6 are a C2-3alkylene chain forming a 5- or 6-membered ring; 20 or R4is O and R5is absent; R6is H or C1-3alkyl, or R6together with R11when in the ortho-position to the amide are a C2alkylene chain forming a 5-membered ring, or R5 and R6 are a C2-3alkylene chain forming a 5- or 6-membered ring and R4 is25 H; Ar1 is 6-membered aryl or heteroaryl; Ar2 is a 6-membered aryl or heteroaryl and is attached to Ar1 in the para position relative to the amide; R10is H, halo, C1-3alkyl, OC1-2alkyl, C1-2haloalkyl, OC1-2haloalkyl or CN; 30 R11is H, F, Cl, CH3, ethyl, OCH3, CF3, OCF3or CN, or R11, when in the ortho-position to the amide, together with R6are a C2alkylene chain forming a 5-membered ring; STP-P3718PCT 124 R12is attached to Ar2 in the ortho or meta position relative to Ar1 and R12is H, halo, C1-4alkyl, C2-4alkynyl, C0-2alkyleneC3-5cycloalkyl, OC1-4alkyl, OC0-2alkyleneC3-5cycloalkyl, OCH2CH2N(CH3)2, OH, C1-4alkylOH, CN, C1-3alkyleneOC1-3alkyl, C1-4haloalkyl, OC1-4haloalkyl, C(=O)C1-2alkyl, NR23R24, 5 SO2C1-4alkyl, SOC1-4alkyl, SC1-4alkyl, SH, C(O)N(CH3)2, NHC(O)C1-3alkyl, C3- 6heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2, or R12 together with a nitrogen atom to which it is attached forms an N- oxide (N+-O-); R13 is H, halo, CH3 or OCH3; 10 R21 is H, C1-5alkyl, C(O)C1-5alkyl, C(O)OC1-5alkyl; R22 is H or CH3; R23 is H or C1-2alkyl; and R24 is H or C1-2alkyl; or a pharmaceutically acceptable salt and / or pharmaceutically acceptable15 solvate thereof. Clause 95. The method, CTPS1 inhibitor for use, pharmaceutical composition for use oruse according to clause 94, wherein the CTPS1 inhibitor is selected from the compounds disclosed in List B or a pharmaceutically acceptable salt and / or pharmaceutically acceptable solvate thereof.20 Clause 96. The method, CTPS1 inhibitor for use, pharmaceutical composition for use oruse according to any one of clauses 1 to 91, wherein the CTPS1 inhibitor is a compound of formula (III): wherein25 A is an amide linker having the following structure: -C(=O)NH- or -NHC(=O)-;X is N or CH; Y is N or CR2; Z is N or CR3;with the proviso that when at least one of X or Z is N, Y cannot30 be N; R1is C1-5alkyl, C0-2alkyleneC3-5cycloalkyl which cycloalkyl is optionally substituted by CH3, or CF3; R2is H, halo, C1-2alkyl, OC1-2alkyl, C1-2haloalkyl or OC1-2haloalkyl; R3is H, halo, CH3, OCH3, CF3or OCF3; STP-P3718PCT 125 wherein at least one of R2and R3is H; R4and R5are each independently H, C1-6alkyl, C1-6alkylOH, C1-6haloalkyl, C0-2alkyleneC3-6cycloalkyl, C0-2alkyleneC3-6heterocycloalkyl, C1-3alkyleneOC1-3alkyl, or R4 and R5 together with the carbon atom to which they are attached form a 5 C3-6cycloalkyl or C3-6heterocycloalkyl; and when A is -NHC(=O)-: R4 and R5 may additionally be selected from halo, OC1-6haloalkyl, OC0- 2alkyleneC3-6cycloalkyl, OC0-2alkyleneC3-6heterocycloalkyl, OC1-6alkyl and NR21R22; 10 Ar1 is a 6-membered aryl or heteroaryl; Ar2 is a 6-membered aryl or heteroaryl and is attached to Ar1 in the para position relative to the amide; R10 is H, halo, C1-3alkyl, C1-2haloalkyl, OC1-2alkyl, OC1-2haloalkyl or CN; R11 is H, F, Cl, C1-2alkyl, CF3, OCH3 or CN; 15 R12 is attached to Ar2 in the ortho or meta position relative to Ar1 and R12 is H, halo, C1-4alkyl, C2-4alkenyl, C0-2alkyleneC3-5cycloalkyl, OC1-4alkyl, OC0- 2alkyleneC3-5cycloalkyl, C1-4haloalkyl, OC1-4haloalkyl, hydroxy, C1-4alkylOH, SO2C1-2alkyl, C(O)N(C1-2alkyl)2, NHC(O)C1-3alkyl or NR23R24; and when A is -NHC(=O)-: 20 R12 may additionally be selected from CN, OCH2CH2N(CH3)2 and a C3- 6heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2, or R12 together with a nitrogen atom to which it is attached forms an N- oxide (N+-O-); R13is H or halo; 25 R21is H, C1-5alkyl, C(O)C1-5alkyl, C(O)OC1-5alkyl; R22is H or CH3; R23is H or C1-2alkyl; and R24is H or C1-2alkyl; or a pharmaceutically acceptable salt and / or pharmaceutically acceptable30 solvate thereof. Clause 97. The method, CTPS1 inhibitor for use, pharmaceutical composition for use oruse according to clause 96, wherein the CTPS1 inhibitor is selected from the compounds disclosed in List C or a pharmaceutically acceptable salt and / or pharmaceutically acceptable solvate thereof.35 Clause 98. The method, CTPS1 inhibitor for use, pharmaceutical composition for use oruse according to clause 96, wherein the CTPS1 inhibitor is a compound offormula (IV): STP-P3718PCT 126 (a) when R4, R5, X, Y and R1 are as follows: 5 then W is N, CH or CF; (b) when R4, R5, X, W and R1 are as follows: then Y is CH or N; (c) when W, X, Y and R1are as follows: 10 then R4 and R5 are joined to form the following structures: (d) when W, R4, R5, X and Y are as follows: STP-P3718PCT 127 then R1is methyl or cyclopropyl; and (e) the compound is selected from the group consisting of: 5 or a pharmaceutically acceptable salt and / or pharmaceutically acceptable solvate thereof. Clause 99. The method, CTPS1 inhibitor for use, pharmaceutical composition for use oruse according to clause 98, wherein the CTPS1 inhibitor is selected from the10 compounds disclosed in List D or a pharmaceutically acceptable salt and / orpharmaceutically acceptable solvate thereof. Clause 100. The method, CTPS1 inhibitor for use, pharmaceutical composition for use oruse according to clause 96, wherein the CTPS1 inhibitor is a compound offormula (V): 15 (a) when A, V, W, X, Y, Z, R1, R10 and R12 are as follows: STP-P3718PCT 128 , then R4and R5together with the carbon atom to which they attached form: 5 , then R4 and R5 together with the carbon atom to which they are attached form: or10 (c) when A, V, W, X, Y, Z, R4, R5, R10 and R12 are as follows: or (d) when A, V, W, X, Y, Z, R4, R5, R10 and R12 are as follows:15 , or (e) when A, X, Y, Z, R1, R4 and R5 are as follows: STP-P3718PCT 129 5 1015 then Z, X and Y are STP-P3718PCT 130 or a pharmaceutically acceptable salt and / or pharmaceutically acceptable solvate thereof. Clause 101. The method, CTPS1 inhibitor for use, pharmaceutical composition for use oruse according to clause 100, wherein the CTPS1 inhibitor is selected from the 5 compounds disclosed in List E or a pharmaceutically acceptable salt and / or pharmaceutically acceptable solvate thereof. Clause 102. The method, CTPS1 inhibitor for use, pharmaceutical composition for use oruse according to any one of clauses 1 to 91, wherein the CTPS1 inhibitor is a compound of formula (VI): 10 wherein ring B is selected from the group consisting of: 15 wherein R3b3c is R3b or R3c as defined below; wherein when B is (B-a) the compound of formula (VI) is a compound of formula 20 wherein: Aa is Aaa or Aba; wherein: Aaa is an amine linker having the following structure: -NH-, - CH2NH- or -NHCH2-;25 Aba is an amide linker having the following structure: -C(=O)NH- or -NHC(=O)-; X is N or CH; Y is N or CR2a; STP-P3718PCT 131 Z is N or CR3a;with the proviso that when at least one of X or Z is N, Y cannot be N; R2ais H, halo, C1-2alkyl, OC1-2alkyl, C1-2haloalkyl or OC1-2haloalkyl; and R3a is H, halo, CH3, OCH3, CF3 or OCF3; 5 wherein at least one of R2a and R3a is H; R1a is R1aa or R1ba; wherein: R1aa is NR32aR33a; R1ba is C1-5alkyl, C0-2alkyleneC3-5cycloalkyl which cycloalkyl is optionally10 substituted by CH3, or CF3; R4a and R5a are R4aa and R5aa, or R4ba and R5ba; wherein: R4aa and R5aa together with the carbon atom to which they are attached form a C3-6cycloalkyl which is: 15 substituted by one or two substituents, each substituent being independently selected from the group consisting of C1-3alkyl, oxo, OH, C1-3alkylOH, C1- 3haloalkyl, C0-2alkyleneC3-6cycloalkyl, C0-2alkyleneC3-6heterocycloalkyl, C1- 3alkyleneOC1-3alkyl, halo, OC1-3haloalkyl, OC0-2alkyleneC3-6cycloalkyl, OC0- 2alkyleneC3-6heterocycloalkyl, OC1-3alkyl and NR21aR22a; or 20 one of the carbons of the C3-6cycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C3-6cycloalkyl ring and a further C3-6cycloalkyl ring or a C3-6heterocycloalkyl ring, and wherein the C3-6cycloalkyl formed by R4aa and R5aa together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently25 selected from the group consisting of C1-3alkyl or OC1-3alkyl; or R4aaand R5aatogether with the carbon atom to which they are attached form a C3-6heterocycloalkyl wherein one of the carbons of the C3-6heterocycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C3-6heterocycloalkyl ring and a further C3-6cycloalkyl ring or a C3-6heterocycloalkyl 30 ring, and wherein the C3-6heterocycloalkyl formed by R4aaand R5aatogether with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C1-3alkyl or OC1-3alkyl; or R4aaand R5aatogether with the carbon atom to which they are attached form a 35 C3-6heterocycloalkyl comprising one nitrogen atom, wherein said nitrogen atom is substituted by -S(O)2R29a; or STP-P3718PCT 132 R4baand R5baare each independently H, C1-6alkyl, C1-6alkylOH, C1-6haloalkyl, C0-2alkyleneC3-6cycloalkyl, C0-2alkyleneC3-6heterocycloalkyl, C1-3alkyleneOC1-3alkyl, or R4baand R5batogether with the carbon atom to which they are attached form a C3-6cycloalkyl or C3-6heterocycloalkyl; and 5when Aa is -NHC(=O)- or -NHCH2-:R4ba and R5ba may additionally be selected from halo, OC1-6haloalkyl, OC0- 2alkyleneC3-6cycloalkyl, OC0-2alkyleneC3-6heterocycloalkyl, OC1-6alkyl and NR21aR22a; Ar1a is a 6-membered aryl or heteroaryl; 10 Ar2a is a 6-membered aryl or heteroaryl and is attached to Ar1a in the para position relative to group Aa; R10a is H, halo, C1-3alkyl, C1-2haloalkyl, OC1-2alkyl, OC1-2haloalkyl or CN; R11a is H, F, Cl, C1-2alkyl, CF3, OCH3 or CN; R12a is attached to Ar2 in the ortho or meta position relative to Ar1a and R12a is15 H, halo, C1-4alkyl, C2-4alkenyl, C0-2alkyleneC3-5cycloalkyl, OC1-4alkyl, OC0- 2alkyleneC3-5cycloalkyl, C1-4haloalkyl, OC1-4haloalkyl, hydroxy, C1-4alkylOH, SO2C1-2alkyl, C(O)N(C1-2alkyl)2, NHC(O)C1-3alkyl or NR23aR24a; and when Aa is -NHC(=O)-, -NH- or -NHCH2-:R12a may additionally be selected from CN, OCH2CH2N(CH3)2 and a C3- 20 6heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2a, or R12a together with a nitrogen atom to which it is attached forms an N- oxide (N+-O-); R13a is H or halo; R21ais H, C1-5alkyl, C(O)C1-5alkyl, C(O)OC1-5alkyl, C1-3alkylOC1-2alkyl, C1-254haloalkyl, or C4-6heterocycloalkyl; R22ais H or CH3; R23ais H or C1-2alkyl; and R24ais H or C1-2alkyl R29a is C1-3alkyl, C0-2alkyleneC3-5cycloalkyl which cycloalkyl is optionally 30 substituted by CH3, CF3, N(C1-3alkyl)2, or a 5 or 6 membered heteroaryl wherein the 5 or 6 membered heteroaryl is optionally substituted by methyl; R32ais C1-3alkyl and R33is C1-3alkyl; or R32aand R33atogether with the nitrogen atom to which they are attached form a C3-5heterocycloalkyl; 35 wherein R1ais R1aa; and / or R4aand R5aare R4aaand R5aa; and / or STP-P3718PCT 133 Aais Aaa; and wherein when B is (B-bc) and R3b3cis R3b, the compound of formula (VI) is a 5 Abis Aabor Abb; wherein: Aab is -NR6bCH2- or -NR6b-;Abb is -NR6bC(=O)-; 10 R1bis R1abor R1bb; wherein: R1abis NR32bR33b; R1bbis C1-5alkyl, C0-2alkyleneC3-5cycloalkyl which cycloalkyl is optionally substituted by CH3, C1-3alkyleneOC1-2alkyl, or CF3; 15 R3bis H, halo, CH3, OC1-2alkyl or CF3; or R3b together with R5bb forms a 5- or 6-membered cycloalkyl or 5 or 6membered oxygen-containing heterocycloalkyl; R4band R5bare either R4aband R5abor R4bband R5bb; wherein: 20 R4aband R5abtogether with the carbon atom to which they are attached form a C3-6cycloalkyl which is: substituted by one or two substituents, each substituent being independently selected from the group consisting of C1-3alkyl, oxo, OH, C1-3alkylOH, C1- 3haloalkyl, C0-2alkyleneC3-6cycloalkyl, C0-2alkyleneC3-6heterocycloalkyl, C1-25 3alkyleneOC1-3alkyl, halo, OC1-3haloalkyl, OC0-2alkyleneC3-6cycloalkyl, OC0- 2alkyleneC3-6heterocycloalkyl, OC1-3alkyl and NR21bR22b; or one of the carbons of the C3-6cycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C3-6cycloalkyl ring and a further C3-6cycloalkyl ring or a C3-6heterocycloalkyl ring, and wherein the C3-6cycloalkyl formed by R4ab and 30 R5ab together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C1-3alkyl or OC1-3alkyl; or STP-P3718PCT 134 R4aband R5abtogether with the carbon atom to which they are attached form a C3-6heteroycloalkyl wherein one of the carbons of the C3-6heterocycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C3-6cheterocycloalkyl ring and a further C3-6cycloalkyl ring or a C3-6heterocycloalkyl 5 ring, and wherein the C3-6heteroycloalkyl formed by R4ab and R5ab together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C1-3alkyl or OC1-3alkyl; or R4ab and R5ab together with the carbon atom to which they are attached form a 10 C3-6heterocycloalkyl comprising one nitrogen atom, wherein said nitrogen atom is substituted by -S(O)2R29b; or R4bb and R5bb are each independently H, halo, C1-6alkyl, C0-2alkyleneC3- 6cycloalkyl, C0-2alkyleneC3-6heterocycloalkyl, OC1-6alkyl, OC0-2alkyleneC3- 6cycloalkyl, C1-3alkyleneOC1-3alkyl, C1-6alkylOH, C1-6haloalkyl, OC1-6haloalkyl or15 NR21bR22b, or R4bb is H and R5bb together with R3b form a 5- or 6-membered cycloalkyl or 5or 6 membered oxygen-containing heterocycloalkyl, or R4bb and R5bb together with the carbon atom to which they are attached form a C3-6cycloalkyl or C3-6heterocycloalkyl,20 or R4bb is H and R5bb and R6b are a C2-3alkylene chain forming a 5- or 6-membered ring; or R4bb is O and R5bb is absent; R6b is H or C1-3alkyl, or R6btogether with R11bwhen in the ortho-position to group Abare a C2alkylene25 chain forming a 5-membered ring, or R5bb and R6b are a C2-3alkylene chain forming a 5- or 6-membered ring andR4bbis H; Ar1b is 6-membered aryl or heteroaryl; Ar2b is a 6-membered aryl or heteroaryl and is attached to Ar1b in the para30 position relative to group Ab; R10bis H, halo, C1-3alkyl, OC1-2alkyl, C1-2haloalkyl, OC1-2haloalkyl or CN; R11bis H, F, Cl, CH3, ethyl, OCH3, CF3, OCF3or CN, or R11b, when in the ortho-position to group Ab, together with R6bare a C2alkylene chain forming a 5-membered ring; 35 R12bis attached to Ar2b in the ortho or meta position relative to Ar1b and R12bis H, halo, C1-4alkyl, C2-4alkynyl, C0-2alkyleneC3-5cycloalkyl, OC1-4alkyl, OC0-2alkyleneC3-5cycloalkyl, OCH2CH2N(CH3)2, OH, C1-4alkylOH, CN, C1- STP-P3718PCT 135 3alkyleneOC1-3alkyl, C1-4haloalkyl, OC1-4haloalkyl, C(=O)C1-2alkyl, NR23bR24b, SO2C1-4alkyl, SOC1-4alkyl, SC1-4alkyl, SH, C(O)N(CH3)2, NHC(O)C1-3alkyl, C3-6heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2b, or R12b together with a nitrogen atom to which it is attached forms an N- 5 oxide (N+-O-); R13b is H, halo, CH3 or OCH3; R21b is H, C1-5alkyl, C(O)C1-5alkyl, C(O)OC1-5alkyl, C1-3alkylOC1-2alkyl, C1- 4haloalkyl, or C4-6heterocycloalkyl; R22b is H or CH3; 10 R23b is H or C1-2alkyl; R24b is H or C1-2alkyl; R29b is C1-3alkyl, C0-2alkyleneC3-5cycloalkyl which cycloalkyl is optionally substituted by CH3, CF3, N(C1-3alkyl)2, or a 5 or 6 membered heteroaryl wherein the 5 or 6 membered heteroaryl is optionally substituted by methyl; and15 R32b is C1-3alkyl and R33b is C1-3alkyl; or R32b and R33b together with the nitrogen atom to which they are attached form a C3-5heterocycloalkyl; wherein: R1b is R1ab; and / or 20 R4b and R5b are R4ab and R5ab; and / or A is Aab; or wherein when B is (B-bc) and R3b3c is R3c, the compound of formula (VI) is a25 Acis Aacor Abc; wherein: Aac is -CH2NR6c-; Abc is -C(=O)NR6c-; 30 R1c is R1ac or R1bc; wherein: R1ac is NR32cR33c; STP-P3718PCT 136 R1bcis C1-5alkyl, C0-2alkyleneC3-5cycloalkyl which cycloalkyl is optionally substituted by CH3, C1-3alkyleneOC1-2alkyl, or CF3; R3cis H, CH3, halo, OC1-2alkyl or CF3; R4c and R5c are either R4ac and R5ac or R4bc and R5bc; 5 wherein: R4ac and R5ac together with the carbon atom to which they are attached form a C3-6cycloalkyl which is: substituted by one or two substituents, each substituent being independently selected from the group consisting of C1-3alkyl, oxo, OH, C1-3alkylOH, C1-10 3haloalkyl, C0-2alkyleneC3-6cycloalkyl, C0-2alkyleneC3-6heterocycloalkyl, C1- 3alkyleneOC1-3alkyl, halo, OC1-3haloalkyl, OC0-2alkyleneC3-6cycloalkyl, OC0- 2alkyleneC3-6heterocycloalkyl, OC1-3alkyl and NR21cR22c; or one of the carbons of the C3-6cycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C3-6cycloalkyl ring and a further C3-6cycloalkyl ring 15 or a C3-6heterocycloalkyl ring, and wherein the C3-6cycloalkyl formed by R4ac and R5ac together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C1-3alkyl or OC1-3alkyl; or R4ac and R5ac together with the carbon atom to which they are attached form a 20 C3-6heteroycloalkyl wherein one of the carbons of the C3-6heterocycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C3- 6cheterocycloalkyl ring and a further C3-6cycloalkyl ring or a C3-6heterocycloalkyl ring, and wherein the C3-6heteroycloalkyl formed by R4ac and R5ac together with the carbon atom to which they are attached may be substituted by one or two 25 substituents, each substituent being independently selected from the group consisting of C1-3alkyl or OC1-3alkyl; or R4acand R5actogether with the carbon atom to which they are attached form a C3-6heterocycloalkyl comprising one nitrogen atom, wherein said nitrogen atom is substituted by -S(O)2R29c; or 30 R4bcand R5bcare each independently H, C1-6alkyl, C0-2alkyleneC3-6cycloalkyl, C0-2alkyleneC3-6heterocycloalkyl, C1-3alkyleneOC1-3alkyl, C1-6alkylOH or C1-6haloalkyl, or R4bcand R5bctogether with the carbon atom to which they are attached form a C3-6cycloalkyl or C3-6heterocycloalkyl ring; 35 R6cis H or C1-3alkyl; Ar1c is a 6-membered aryl or heteroaryl; STP-P3718PCT 137 Ar2c is a 6-membered aryl or heteroaryl and is attached to Ar1c in the para position relative to group Ac; R10cis H, halo, C1-3alkyl, OC1-2alkyl, C1-2haloalkyl, OC1-2haloalkyl or CN; R11c is H, F, Cl, CH3, ethyl, OCH3, CF3, OCF3 or CN; 5 R12c is attached to Ar2c in the meta or ortho position relative to Ar1c and R12c is H, halo, C1-4alkyl, C2-4alkynyl, C(=O)C1-2alkyl, C0-2alkyleneC3-5cycloalkyl, OC1- 4alkyl, C1-3alkyleneOC1-3alkyl, C1-4haloalkyl, OC1-4haloalkyl, CN, OC0- 2alkyleneC3-5cycloalkyl, OCH2CH2N(CH3)2, OH, C1-4alkylOH, NR23cR24c, SO2CH3, C(O)N(CH3)2, NHC(O)C1-3alkyl, or a C3-6heterocycloalkyl comprising one 10 nitrogen located at the point of attachment to Ar2c, or R12c together with a nitrogen atom to which it is attached forms an N-oxide (N+-O-); R21c is H, C1-5alkyl, C(O)C1-5alkyl, C(O)OC1-5alkyl, C1-3alkylOC1-2alkyl, C1- 4haloalkyl, or C4-6heterocycloalkyl; R22c is H or CH3; 15 R23c is H or C1-2alkyl; R24c is H or C1-2alkyl; R29c is C1-3alkyl, C0-2alkyleneC3-5cycloalkyl which cycloalkyl is optionally substituted by CH3, CF3, N(C1-3alkyl)2, or a 5 or 6 membered heteroaryl wherein the 5 or 6 membered heteroaryl is optionally substituted by methyl; and 20 R32c is C1-3alkyl and R33c is C1-3alkyl; or R32c and R33c together with the nitrogen atom to which they are attached form a C3-5heterocycloalkyl; wherein: R1cis R1ac; and / or 25 R4cand R5care R4acand R5ac; and / or Acis Aac; or a pharmaceutically acceptable salt and / or pharmaceutically acceptable solvate thereof. Clause 103. The method, CTPS1 inhibitor for use, pharmaceutical composition for use or30 use according to clause 102, wherein the CTPS1 inhibitor is selected from the compounds disclosed in List F or a pharmaceutically acceptable salt and / or pharmaceutically acceptable solvate thereof. Clause 104. The method, CTPS1 inhibitor for use, pharmaceutical composition for use oruse according to any one of clauses 1 to 91, wherein the CTPS1 inhibitor is a35 compound of formula (VII): STP-P3718PCT 138 wherein A is Aaor Ab; wherein 5 Aais an amine linker having the following structure: -NH-, - CH2NH- or -NHCH2-;Ab is an amide linker having the following structure: -C(=O)NH- or - 10 X is N or CH; Y is N or CR2; Z is N or CR3; with the proviso that when at least one of X or Z is N, Y cannot be N; R1is C1-5fluoroalkyl, with the proviso that R1is not CF3; 15 R2is H, halo, C1-2alkyl, OC1-2alkyl, C1-2haloalkyl or OC1-2haloalkyl; R3 is H, halo, CH3, OCH3, CF3 or OCF3; wherein at least one of R2 and R3 is H; R3’ is H, halo, CH3, OC1-2alkyl or CF3; and when A is -NHC(=O)-, additionally R3’ together with R5 forms a 5- or 6-20 membered cycloalkyl or 5 or 6 membered oxygen-containing heterocycloalkyl; R4and R5are R4aand R5a, or R4band R5b; wherein R4aand R5atogether with the carbon atom to which they are attached form a C3-6cycloalkyl which is: 25 substituted by one or two substituents, each substituent being independently selected from the group consisting of C1-3alkyl, oxo, OH, C1-3alkylOH, C1-3haloalkyl, C0-2alkyleneC3-6cycloalkyl, C0-2alkyleneC3-6heterocycloalkyl, C1-3alkyleneOC1-3alkyl, halo, OC1-3haloalkyl, OC0-2alkyleneC3-6cycloalkyl, OC0-2alkyleneC3-6heterocycloalkyl, OC1-3alkyl and NR21R22; or 30 one of the carbons of the C3-6cycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C3-6cycloalkyl ring and a further C3-6cycloalkyl ring or a C3-6heterocycloalkyl ring, and wherein the C3-6cycloalkyl formed by R4a and R5a together with the carbon atom to which they are attached may be STP-P3718PCT 139 substituted by one or two substituents, each substituent being independently selected from the group consisting of C1-3alkyl or OC1-3alkyl; or R4aand R5atogether with the carbon atom to which they are attached form a C3-6heterocycloalkyl wherein one of the carbons of the C3-6heterocycloalkyl is a 5 spiro centre such that a spirocyclic ring system is formed by the C3- 6heterocycloalkyl ring and a further C3-6cycloalkyl ring or a C3-6heterocycloalkyl ring, and wherein the C3-6heterocycloalkyl formed by R4a and R5a together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group10 consisting of C1-3alkyl or OC1-3alkyl; or R4a and R5a together with the carbon atom to which they are attached form a C3- 6heterocycloalkyl comprising one nitrogen atom, wherein said nitrogen atom is substituted by -S(O)2R29; or R4b and R5b are each independently H, C1-6alkyl, C1-6alkylOH, C1-6haloalkyl, C0- 15 2alkyleneC3-6cycloalkyl, C0-2alkyleneC3-6heterocycloalkyl, C1-3alkyleneOC1-3alkyl, or R4b and R5b together with the carbon atom to which they are attached form a C3-6cycloalkyl or C3-6heterocycloalkyl; and when A is -NHC(=O)- or -NHCH2-:R4b and R5b may additionally be selected from halo, OC1-6haloalkyl, OC0- 20 2alkyleneC3-6cycloalkyl, OC0-2alkyleneC3-6heterocycloalkyl, OC1-6alkyl and NR21R22; Ar1 is a 6-membered aryl or heteroaryl; Ar2 is a 6-membered aryl or heteroaryl and is attached to Ar1 in the para position relative to group A; 25 R10is H, halo, C1-3alkyl, C1-2haloalkyl, OC1-2alkyl, OC1-2haloalkyl or CN; R11is H, F, Cl, C1-2alkyl, CF3, OCH3or CN; R12is attached to Ar2 in the ortho or meta position relative to Ar1 and R12is H, halo, C1-4alkyl, C2-4alkenyl, C0-2alkyleneC3-5cycloalkyl, OC1-4alkyl, OC0-2alkyleneC3-5cycloalkyl, C1-4haloalkyl, OC1-4haloalkyl, hydroxy, C1-4alkylOH, 30 SO2C1-2alkyl, C(O)N(C1-2alkyl)2, NHC(O)C1-3alkyl or NR23R24; and when A is -NHC(=O)-, -NH- or -NHCH2-:R12may additionally be selected from CN, OCH2CH2N(CH3)2and a C3-6heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2, or R12together with a nitrogen atom to which it is attached forms an N- 35 oxide (N+-O-); R13is H or halo; R21is H, C1-5alkyl, C(O)C1-5alkyl, C(O)OC1-5alkyl; STP-P3718PCT 140 R22is H or CH3; R23is H or C1-2alkyl; and R24is H or C1-2alkyl; R29 is C1-3alkyl, C0-2alkyleneC3-5cycloalkyl which cycloalkyl is optionally 5 substituted by CH3, or CF3; R32 is C1-3alkyl and R33 is C1-3alkyl; or R32 and R33 together with the nitrogen atom to which they are attached form a C3-5heterocycloalkyl; or a pharmaceutically acceptable salt and / or pharmaceutically acceptable10 solvate thereof. Clause 105. The method, CTPS1 inhibitor for use, pharmaceutical composition for use oruse according to clause 104, wherein the CTPS1 inhibitor is selected from the compounds disclosed in List G or a pharmaceutically acceptable salt and / or pharmaceutically acceptable solvate thereof.15 Clause 106. The method, CTPS1 inhibitor for use, pharmaceutical composition for use oruse according to any one of clauses 1 to 91, wherein the CTPS1 inhibitor is compound of formula (VIII): wherein 20 A is Aa or Ab; wherein Aa is an amine linker having the following structure: -NH-, - CH2NH- or -NHCH2-;Ab is an amide linker having the following structure: -C(=O)NH- or -25 X is N or CH; Y is N or CR2; Z is N or CR3;30 with the proviso that when at least one of X or Z is N, Y cannot be N; R1 is C1-5alkyl or C0-2alkyleneC3-5cycloalkyl, which alkyl or (alkylene)cycloalkyl is substituted by CN; R2 is H, halo, C1-2alkyl, OC1-2alkyl, C1-2haloalkyl or OC1-2haloalkyl; STP-P3718PCT 141 R3is H, halo, CH3, OCH3, CF3or OCF3; wherein at least one of R2and R3is H; R3’is H, halo, CH3, OC1-2alkyl or CF3; and when A is -NHC(=O)-, additionally R3’ together with R5 forms a 5- or 6-5 membered cycloalkyl or 5 or 6 membered oxygen-containing heterocycloalkyl; R4 and R5 are R4a and R5a, or R4b and R5b; wherein R4a and R5a together with the carbon atom to which they are attached form a C3- 6cycloalkyl which is: 10 substituted by one or two substituents, each substituent being independently selected from the group consisting of C1-3alkyl, oxo, OH, C1-3alkylOH, C1- 3haloalkyl, C0-2alkyleneC3-6cycloalkyl, C0-2alkyleneC3-6heterocycloalkyl, C1- 3alkyleneOC1-3alkyl, halo, OC1-3haloalkyl, OC0-2alkyleneC3-6cycloalkyl, OC0- 2alkyleneC3-6heterocycloalkyl, OC1-3alkyl and NR21R22; or 15 one of the carbons of the C3-6cycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C3-6cycloalkyl ring and a further C3-6cycloalkyl ring or a C3-6heterocycloalkyl ring, and wherein the C3-6cycloalkyl formed by R4a and R5a together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently20 selected from the group consisting of C1-3alkyl or OC1-3alkyl; or R4a and R5a together with the carbon atom to which they are attached form a C3- 6heterocycloalkyl wherein one of the carbons of the C3-6heterocycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C3- 6heterocycloalkyl ring and a further C3-6cycloalkyl ring or a C3-6heterocycloalkyl 25 ring, and wherein the C3-6heterocycloalkyl formed by R4aand R5atogether with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C1-3alkyl or OC1-3alkyl; or R4a and R5a together with the carbon atom to which they are attached form a C3- 306heterocycloalkyl comprising one nitrogen atom, wherein said nitrogen atom is substituted by -S(O)2R29; or R4band R5bare each independently H, C1-6alkyl, C1-6alkylOH, C1-6haloalkyl, C0-2alkyleneC3-6cycloalkyl, C0-2alkyleneC3-6heterocycloalkyl, C1-3alkyleneOC1-3alkyl, or R4band R5btogether with the carbon atom to which they are attached form a35 C3-6cycloalkyl or C3-6heterocycloalkyl; and when A is -NHC(=O)- or ...

Claims

1. STP-P3718PCT 153 Claims 1. A CTPS1 inhibitor for use in the treatment of a myeloproliferative neoplasm (MPN) in ahuman subject.

52. The CTPS1 inhibitor for use according to claim 1 wherein the MPN is essentialthrombocythaemia (ET).

3. The CTPS1 inhibitor for use according to either claim 1 or 2 wherein the subject’s cellcount for one or more blood cell types is reduced after administration of the CTPS1 inhibitor.10 4. The CTPS1 inhibitor for use according to either claim 1 or 2 wherein increase in thesubject’s cell count for one or more blood cell types is prevented after administration of the CTPS1 inhibitor.

5. The CTPS1 inhibitor for use according to any one of claims 1 to 4 wherein the subject’scell count for one or more blood cell types is reduced to a physiologically normal range.15 6. The CTPS1 inhibitor for use according to any one of claims 1 to 5 wherein the bloodcell type is thrombocytes.

7. The CTPS1 inhibitor for use according to any one of claims 1 to 5 wherein the bloodcell type is neutrophils.

8. The CTPS1 inhibitor for use according to any one of claims 1 to 5 wherein the subject’s20 thrombocyte count after administration of the CTPS1 inhibitor is 900x109 / L or lower,such as 700x109 / L or lower, such as 500x109 / L or lower.

9. The CTPS1 inhibitor for use according to any one of claims 1 to 5 wherein the subject’sthrombocyte count after administration of the CTPS1 inhibitor is 150 x109 / L to 400x109 / L.25 10. The CTPS1 inhibitor for use according to any one of claims 1 to 5 wherein the subject’sneutrophil count after administration of the CTPS1 inhibitor is 13.0x109 / L or lower, suchas 10x109 / L or lower, such as 7x109 / L or lower.

11. The CTPS1 inhibitor for use according to any one of claims 1 to 10 wherein theconcentration of thrombocytes in the subject’s blood after administration of the CTPS130 inhibitor (i.e. thrombocyte count) is reduced by at least 30%, such as at least 50%, relative to the concentration of thrombocytes in the subject’s blood before administration of the CTPS1 inhibitor.

12. The CTPS1 inhibitor for use according to any one of claims 1 to 11 wherein theconcentration of thrombocytes in the subject’s blood (i.e. thrombocyte count) before 35 treatment with the CTPS1 inhibitor is 500x109 / L or higher.

13. The CTPS1 inhibitor for use according to any one of claims 1 to 12, wherein the CTPS1inhibitor has an IC50of 10 uM or lower in respect of human CTPS1 enzyme. STP-P3718PCT 154 14. The CTPS1 inhibitor for use according to claim 13 wherein the IC50 of the CTPS1inhibitor is established using the assay procedure set out in Example 1.

15. The CTPS1 inhibitor for use according to any one of claims 1 to 14, wherein the CTPS1inhibitor has a selectivity for human CTPS1 over human CTPS2 of at least 2-fold, 5 established using the assay procedure set out in Example 2.

16. The CTPS1 inhibitor for use according to any one of claims 1 to 15, wherein the CTPS1inhibitor is a compound of formula (III): wherein10 A is an amide linker having the following structure: -C(=O)NH- or -NHC(=O)-;X is N or CH; Y is N or CR2; Z is N or CR3;with the proviso that when at least one of X or Z is N, Y cannot be N; 15 R1is C1-5alkyl, C0-2alkyleneC3-5cycloalkyl which cycloalkyl is optionally substituted by CH3, or CF3; R2is H, halo, C1-2alkyl, OC1-2alkyl, C1-2haloalkyl or OC1-2haloalkyl; R3is H, halo, CH3, OCH3, CF3or OCF3; wherein at least one of R2 and R3 is H; 20 R4 and R5 are each independently H, C1-6alkyl, C1-6alkylOH, C1-6haloalkyl, C0- 2alkyleneC3-6cycloalkyl, C0-2alkyleneC3-6heterocycloalkyl, C1-3alkyleneOC1-3alkyl, or R4and R5together with the carbon atom to which they are attached form a C3-6cycloalkyl or C3-6heterocycloalkyl; and when A is -NHC(=O)-: 25 R4 and R5 may additionally be selected from halo, OC1-6haloalkyl, OC0-2alkyleneC3- 6cycloalkyl, OC0-2alkyleneC3-6heterocycloalkyl, OC1-6alkyl and NR21R22; Ar1 is a 6-membered aryl or heteroaryl; Ar2 is a 6-membered aryl or heteroaryl and is attached to Ar1 in the para position relative to the amide; 30 R10 is H, halo, C1-3alkyl, C1-2haloalkyl, OC1-2alkyl, OC1-2haloalkyl or CN; R11 is H, F, Cl, C1-2alkyl, CF3, OCH3 or CN; R12 is attached to Ar2 in the ortho or meta position relative to Ar1 and R12 is H, halo, C1- 4alkyl, C2-4alkenyl, C0-2alkyleneC3-5cycloalkyl, OC1-4alkyl, OC0-2alkyleneC3-5cycloalkyl, STP-P3718PCT 155 C1-4haloalkyl, OC1-4haloalkyl,hydroxy, C1-4alkylOH, SO2C1-2alkyl, C(O)N(C1-2alkyl)2, NHC(O)C1-3alkyl or NR23R24; and when A is -NHC(=O)-: R12 may additionally be selected from CN, OCH2CH2N(CH3)2 and a C3-6heterocycloalkyl 5 comprising one nitrogen located at the point of attachment to Ar2, or R12 together with a nitrogen atom to which it is attached forms an N-oxide (N+-O-); R13 is H or halo; R21 is H, C1-5alkyl, C(O)C1-5alkyl, C(O)OC1-5alkyl; R22 is H or CH3; 10 R23 is H or C1-2alkyl; and R24 is H or C1-2alkyl; or a pharmaceutically acceptable salt and / or pharmaceutically acceptable solvate thereof.

17. The CTPS1 inhibitor for use according to any one of claims 1 to 16, wherein the CTPS115 inhibitor is N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(2-(ethylsulfonamido)pyrimidin-4- yl)tetrahydro-2H-pyran-4-carboxamide: , or a pharmaceutically acceptable salt and / or pharmaceutically acceptable solvate thereof.20 18. The CTPS1 inhibitor for use according to any one of claims 1 to 16, wherein the CTPS1inhibitor is 4-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2- yl)pyridin-2-yl)tetrahydro-2H-pyran-4-carboxamide: , or a pharmaceutically acceptable salt and / or pharmaceutically acceptable solvate 25 thereof.

19. The CTPS1 inhibitor for use according to any one of claims 1 to 16, wherein the CTPS1inhibitor is selected from the compounds disclosed in any one of Lists A to H or a pharmaceutically acceptable salt and / or pharmaceutically acceptable solvate thereof.

20. The CTPS1 inhibitor for use according to any one of claims 1 to 19, wherein the CTPS130 inhibitor is administered orally. STP-P3718PCT 156 21. The CTPS1 inhibitor for use according to any one of claims 1 to 20, wherein the CTPS1inhibitor is administered continuously.

22. 4-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)tetrahydro-2H-pyran-4-carboxamide (‘CTPS1-IA’): 5 , or a pharmaceutically acceptable salt and / or pharmaceutically acceptable solvate thereof, for use in the treatment of ET in a human subject.

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