WO2023166077A1 - Combination of a ctps1 inhibitor and a atr inhibitor in cancer therapy - Google Patents

Combination of a ctps1 inhibitor and a atr inhibitor in cancer therapy Download PDF

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Publication number
WO2023166077A1
WO2023166077A1 PCT/EP2023/055219 EP2023055219W WO2023166077A1 WO 2023166077 A1 WO2023166077 A1 WO 2023166077A1 EP 2023055219 W EP2023055219 W EP 2023055219W WO 2023166077 A1 WO2023166077 A1 WO 2023166077A1
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WIPO (PCT)
Prior art keywords
inhibitor
cyclopropanesulfonamido
ctps1
atr
pharmaceutically acceptable
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PCT/EP2023/055219
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French (fr)
Inventor
Philip BEER
David Chiron
Heinz Ludwig
Andrew Parker
Catherine Pellat-Deceunynck
Christina PFEIFFER
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Step Pharma S.A.S.
Wilhelminen Krebsforschung Gmbh
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Application filed by Step Pharma S.A.S., Wilhelminen Krebsforschung Gmbh filed Critical Step Pharma S.A.S.
Publication of WO2023166077A1 publication Critical patent/WO2023166077A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4995—Pyrazines or piperazines forming part of bridged ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

Definitions

  • the invention relates to combinations, in particular the combination of a CTPS1 inhibitor and an ATR inhibitor, pharmaceutical compositions and kits comprising such combinations which may be of use in the treatment of cancer and to related aspects.
  • Cancer can affect multiple cell types and tissues but the underlying cause is a breakdown in the control of cell division. This process is highly complex, requiring careful coordination of multiple pathways, many of which remain to be fully characterised.
  • Cell division requires the effective replication of the cell’s DNA and other constituents. Interfering with a cell’s ability to replicate by targeting nucleic acid synthesis has been a core approach in cancer therapy for many years. Examples of therapies acting in this way are 6-thioguanine, 6-mecaptopurine, 5- fluorouracil, cytarabine, gemcitabine and pemetrexed.
  • Cancer therapeutics against a wide array of specific targets are available.
  • Small molecule targeted therapy drugs are generally inhibitors of enzymatic domains on mutated, overexpressed, or otherwise critical proteins within the cancer cell.
  • Monoclonal antibody therapy is another strategy in which the therapeutic agent is an antibody which specifically binds to a protein on the surface of the cancer cells.
  • CTPS cytidine triphosphate synthase
  • CTPS1 and CTPS2 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.
  • CTPS inhibitors that inhibit both CTPS1 and CTPS2 have been developed for oncology indications up to phase l/ll clinical trials, but were stopped due to toxicity and efficacy issues.
  • nucleoside-analogue prodrugs (3-deazauridine (DAU), CPEC, carbodine, gemcitabine), which are converted to the active triphosphorylated metabolite by the kinases involved in pyrimidine biosynthesis: uridine/cytidine kinase, nucleoside monophosphatekinase (NMP-kinase) and nucleoside diphosphatekinase (NDP-kinase).
  • NMP-kinase nucleoside monophosphatekinase
  • NDP-kinase nucleoside diphosphatekinase
  • the remaining inhibitors (acivicin, DON) are reactive analogues of glutamine, which irreversibly inhibit the glutaminase domain of CTPS.
  • 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
  • the DNA damage response is a complex cellular pathway that is activated in response to direct damage to a cell’s DNA, and in situations where DNA damage is likely to occur, for example nucleotide deficiency, stalled replication forks and other causes of replication stress.
  • DDR activation is a feature of different cancer types, and its exploitation is a current area of interest in oncology drug development (Gorecki 2021).
  • the biological purpose of the DDR pathway is to prevent cells entering the cell cycle whilst harbouring DNA damage, by inducing a cell cycle arrest and thus providing the opportunity to carry out DNA repair ensuring an error free copy of the genome is replicated once the cell cycle resumes.
  • the DDR pathway has been shown to be activated across a diverse range of cancer types. Inhibition of this pathway may be of therapeutic benefit in cancer.
  • the role of the DDR pathway is to pause cell cycle and allow time for DNA damage to be repaired, such that inhibition of this pathway may result in cancer cells entering mitosis prematurely resulting in mitotic catastrophe and cell death (Gorecki 2021).
  • Small molecule inhibitors have been developed against different components of the DDR pathway, including ATR (ataxia telangiectasia and Rad3-related protein, also commonly referred to as FRAP-related protein 1 (FRP1)) and CHEK1 (checkpoint kinase 1 , commonly also referred to as Chk1).
  • ATR Single agent inhibition of ATR has delivered modest efficacy across different tumour types. Most of the currently active clinical trials are studying combinations of an inhibitor with chemotherapy, radiotherapy, other targeted agents such as PARP inhibitors or immunomodulatory drugs such as immune checkpoint inhibitors.
  • ATM loss has been reported to render cancer cells more sensitive to ATR inhibition, such that mutation or genomic deletion of ATM or loss of ATM protein expression may serve as biomarkers of response to ATR inhibitors (Karnitz 2015). Some clinical trials of ATR inhibitors have preselected patients with ATM loss. Other potential biomarkers of response to ATR inhibition have been reported, including genomic alterations associated with replication stress (including CCNE1 amplification, MYC amplification and FBXW7 mutation) and markers of double stranded DNA breakage such as yH2AX (Cleary 2020). Genomic alterations associated with replication stress have previously been used to select patients for clinical trials of ATR inhibitors.
  • Sun 2022 use CRISPR technology to demonstrate that combined inactivation of CTPS1 and ATR is synthetically lethal to MYC-overexpressing cancer cells.
  • CTPS1 and ATR is synthetically lethal to MYC-overexpressing cancer cells.
  • the invention provides a CTPS1 inhibitor for use in the treatment of cancer with an ATR inhibitor, wherein the CTPS1 inhibitor is defined in any one of Groups A to H (as further described herein).
  • the invention provides an ATR inhibitor for use in the treatment of cancer with a CTPS1 inhibitor, wherein the CTPS1 inhibitor is defined in any one of Groups A to H.
  • the invention provides a CTPS1 inhibitor and an ATR inhibitor for use in the treatment of cancer.
  • the invention provides the use of a CTPS1 inhibitor in the manufacture of a medicament for the treatment of cancer with an ATR inhibitor, wherein the CTPS1 inhibitor is defined in any one of Groups A to H.
  • the invention provides the use of an ATR inhibitor in the manufacture of a medicament for the treatment of cancer with a CTPS1 inhibitor, wherein the CTPS1 inhibitor is defined in any one of Groups A to H.
  • the invention provides the use of a CTPS1 inhibitor and an ATR inhibitor in the manufacture of a medicament for the treatment of cancer, wherein the CTPS1 inhibitor is defined in any one of Groups A to H.
  • the invention provides a method of treating cancer in a subject which method comprises administering to the subject a CTPS1 inhibitor and an ATR inhibitor, wherein the CTPS1 inhibitor is defined in any one of Groups A to H.
  • the invention provides a pharmaceutical composition comprising a CTPS1 inhibitor and an ATR inhibitor, wherein the CTPS1 inhibitor is defined in any one of Groups A to H.
  • the invention provides a kit of parts comprising: a) a first container comprising a CTPS1 inhibitor; and b) a second container comprising an ATR inhibitor, wherein the CTPS1 inhibitor is defined in any one of Groups A to H.
  • the invention provides a CTPS1 inhibitor for use in the treatment of cancer with an ATR inhibitor, wherein the ATR inhibitor is ceralasertib or VE821 , a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof.
  • the invention provides an ATR inhibitor for use in the treatment of cancer with a CTPS1 inhibitor, wherein the ATR inhibitor is ceralasertib or VE821 , a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof.
  • the invention provides a CTPS1 inhibitor and an ATR inhibitor for use in the treatment of cancer, wherein the ATR inhibitor is ceralasertib or VE821 , a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof.
  • the invention provides a CTPS1 inhibitor in the manufacture of a medicament for the treatment of cancer with an ATR inhibitor, wherein the ATR inhibitor is ceralasertib or VE821 , a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof.
  • the invention provides the use of an ATR inhibitor in the manufacture of a medicament for the treatment of cancer with a CTPS1 inhibitor, wherein the ATR inhibitor is ceralasertib or VE821, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof.
  • the invention provides the use of a CTPS1 inhibitor and an ATR inhibitor in the manufacture of a medicament for the treatment of cancer, wherein the ATR inhibitor is ceralasertib or VE821 , a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof.
  • the invention provides a method of treating cancer in a subject which method comprises administering to the subject a CTPS1 inhibitor and an ATR inhibitor, wherein the ATR inhibitor is ceralasertib or VE821, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a CTPS1 inhibitor and an ATR inhibitor, wherein the ATR inhibitor is ceralasertib or VE821 , a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof.
  • the invention provides a kit of parts comprising: a) a first container comprising a CTPS1 inhibitor; and b) a second container comprising an ATR inhibitor, wherein the ATR inhibitor is ceralasertib or VE821 , a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof.
  • Fig. 2 Impact of deletion of different genes in the pyrimidine synthesis pathway
  • Fig. 3 Cell cycle analysis indicating that exposure to CTPS1-IA causes cancer cells to accumulate in S phase (mantle cell lymphoma lines)
  • Fig. 4 Cell cycle analysis indicating that exposure to CTPS1-IA causes cancer cells to accumulate in S phase (myeloma lines)
  • Fig. 5 Cell cycle analysis indicating that exposure to CTPS1-IA causes cancer cells to accumulate in S phase (further myeloma lines)
  • Fig. 6 Demonstration of increased activated CHEK1 (pCHEKI) following exposure to CTPS1-IA in 4 myeloma cell lines.
  • Fig. 7 Bliss scores for 3-11 myeloma cell lines exposed to the CTPS1 inhibitor CTPS1- IA in combination with either a standard of care drug or an ATR inhibitor (ceralasertib or VE821)
  • Fig. 8 Percentage cell death myeloma cell lines exposed to the CTPS1 inhibitor CTPS1- IA combined with an ATR inhibitor (VE821); representative data from 7 cell lines tested
  • Figs. 9A to 9C Percentage cell death in 6 mantle cell lymphoma cell lines exposed to the CTPS1 inhibitor CTPS1-IA combined with an ATR inhibitor (VE821)
  • Figs. 10A to 10B Percentage cell death in primary mantle cell lymphoma samples exposed to the CTPS1 inhibitor CTPS1-IA combined with an ATR inhibitor (VE821); representative data from 11 samples tested
  • Fig. 11 Bliss scores for 36 human cancer cell lines exposed to the CTPS1 inhibitor CTPS1-IA in combination with an ATR inhibitor (ceralasertib)
  • Fig. 12 A comparison of Bliss scores for 4 human colorectal cancer cell lines exposed to an ATR inhibitor (ceralasertib) in combination with either the CTPS1 inhibitor CTPS1-IA or a chemotherapy drug (irinotecan); in all 4 cell lines tested, synergy observed with the ceralasertib CTPS1-IA combination exceeded that observed with the ceralasertib chemotherapy combination
  • CTPS1 inhibitor for use in the treatment of cancer with an ATR inhibitor.
  • a CTPS1 inhibitor is an agent which directly inhibits the enzymatic activity of the CTPS1 enzyme through interaction with the enzyme. Direct inhibition of the CTPS1 enzyme may be quantified using any suitable assay procedure, though is suitably performed using the procedure set out in Example 1.
  • CTPS1 inhibitors may demonstrate an IC50 of 10 uM or lower, such as 1uM or lower, 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 1 uM or lower, especially 100nM or lower, in respect of CTPS1 enzyme using the assay procedure set out in Example 1 .
  • CTPS1 inhibitors may demonstrate a selectivity for CTPS1 over CTPS2.
  • the inhibitors demonstrate a selectivity of at least 2-fold, such as at least 30-fold, especially at least 60-fold and in particular a least 1000-fold.
  • CTPS1 inhibitors of particular 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 a least 1000-fold using the assay procedure set out in Example 2.
  • the selectivity is for human CTPS1 over human CTPS2.
  • CTPS1 inhibition and CTPS1 vs CTPS2 selectivity should be based on human forms of the enzymes.
  • CTPS1 inhibitor may be selected from the following compounds:
  • R1 is Ci-salkyl, Co ⁇ alkyleneCs-scycloalkyl which cycloalkyl is optionally substituted by CH3, Ci-3alkyleneOCi-2alkyl, or CF3;
  • R3 is H, CH3, halo, OCi-2alkyl or CF3;
  • R4 and Rs are each independently H, Ci-salkyl, Co-2alkyleneC3-6cycloalkyl, Co-2alkyleneC3- sheterocycloalkyl, Ci-3alkyleneOCi-3alkyl, Ci-ealkylOH or Ci-ehaloalkyl, or R4 and Rs together with the carbon atom to which they are attached form a C3- scycloalkyl or Cs-sheterocycloalkyl ring;
  • R is H or Ci-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;
  • R10 is H, halo, Ci-3alkyl, OCi-2alkyl, Ci-2haloalkyl, OCi-2haloalkyl or CN;
  • R11 is H, F, Cl, CH 3 , ethyl, OCH 3 , CF 3 , OCF 3 or CN;
  • R23 is H or Ci-2alkyl
  • R24 is H or Ci-2alkyl; or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof (‘Group A’).
  • CTPS1 inhibitor is selected from the following (‘List A’) compounds: N-((2-(cyclopropanesulfonamido)thiazol-4-yl)methyl)-5-phenylpicolinamide;
  • 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.
  • a CTPS1 inhibitor may be a compound described in any one of clauses 1 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.
  • the CTPS1 inhibitor is compound of formula (II): wherein 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 R 3 together with R 5 forms a 5- or 6-membered cycloalkyl or 5 or 6 membered 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 R 4 is H
  • CTPS1 inhibitor is selected from the following (‘List B’) compounds: 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;
  • 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.
  • a CTPS1 inhibitor may be a compound described in any one of 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.
  • 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; 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- yl)phenyl)propanamide; 2-methyl-N-(2-
  • 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.
  • a CTPS1 inhibitor may be a compound described in any one of clauses 1 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 disclosed therein.
  • 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.
  • the CTPS1 inhibitor is a compound of formula (IV): wherein: (a) when R4, R5, X, Y and R1 are as follows: 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 R1 are as follows: then R4 and R5 are joined to form the following structures: (d) when W, R 4 , R 5 , X and Y are as follows: then R1 is methyl or cyclopropyl; and (e) the compound is selected from the group consisting of: and or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof (‘Group D’).
  • 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; 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-eth)-N
  • CTPS1 inhibitors are those disclosed in PCT publication number WO2020083975 which is incorporated by reference in its entirety for the purpose of the CTPS1 inhibitors disclosed therein.
  • 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 pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof.
  • the CTPS1 inhibitor is a compound of formula (V): (a) when A, V, W, X, Y, Z, R1, R10 and R12 are as follows: then R 4 and R 5 together with the carbon atom to which they attached form: or (b) when A, V, W, X, Y, Z, R 1 , R 10 and R 12 are as follows: then R4 and R5 together with the carbon atom to which they are attached form: or (c) when A, V, W, X, Y, Z, R 4 , R 5 , R 10 and R 12 are as follows: then R1 is or (d) when A, V, W, X, Y, Z, R4, R5, R10 and R12 are as follows: , then R1 is or (e) when A, X, Y, Z, R1, R4 and R5 are as follows: , then V, W, R 10 and R 12 are: or (f) when A, V, W, R 1 , R 4 , R 5
  • CTPS1 inhibitor is selected from the following (‘List E’) compounds: 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- carboxamide; 1-(6-(cyclopropanesulfonamido)pyrazin-2-yl)-N-(5-(6-ethoxypyrazin-2-yl)
  • 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 therein.
  • 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.
  • 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; 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
  • 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.
  • a CTPS1 inhibitor may be a compound described in clauses 1 to 204 of WO2020245665 or a pharmaceutically acceptable salt and/or pharmaceutically 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 pharmaceutical
  • 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 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.
  • CTPS1 inhibitors are disclosed in PCT publication number WO2021053403 which is incorporated by reference in its entirety for the purpose of the CTPS1 inhibitors disclosed therein.
  • 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.
  • 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; or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof.
  • (‘List H’) compounds 4-(2-((1-cyanocyclopropane)-1-sulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin- 2-yl)t
  • CTPS1 inhibitors are disclosed in PCT publication number WO2021053402 which is incorporated by reference in its entirety for the purpose of the CTPS1 inhibitors disclosed therein.
  • 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 acceptable solvate thereof, in particular a compound selected from P285 and P287 or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof.
  • 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 ‘CTPS-IA’): or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof.
  • CTPS-IA 4-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6- ethoxypyrazin-2-yl)pyridin-2-yl)tetrahydro-2H-pyran-4-carboxamide
  • 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 ‘CTPS-IB'): or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof.
  • CTPS-IB' N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(2- (ethylsulfonamido)pyrimidin-4-yl)tetrahydro-2H-pyran-4-carboxamide
  • CTPS-IB' N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(2- (ethylsulfonamido)pyrimidin-4-yl)tetrahydro-2H-pyran-4-
  • R 1 is selected from Ci-6 aliphatic; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; and a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring hairing 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with q instances of R A ;
  • Ring A is selected from phenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 7-11 membered fused bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • each of R L , R L ‘, and R L " is independently hydrogen, -CM, halogen, or an optionally substituted group selected from Ci ⁇ aliphatic; phenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two of R L .
  • R L and R L ” groups are taken together with the atoms to whi ch each is attached, to form an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms i ndependently selected from nitrogen, oxygen, and sulfur; or any one of R L , R L , and R 17 , together with R® forms a 7-10 membered saturated or partially unsaturated fused bicyclic ring;
  • Ring B is selected from phenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms 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 5-11 membered saturated or partially unsaturated fused, bridged, or spiro, bicyclic carbocyclic ring; a 7-11 membered fused bicyclic aryl ring; a 7-11 membered saturated or partially unsaturated fused, bridged, or spiro, bicydic heterocydic ring having 1-4 heteroatoms independently sdected from nitrogen, oxygen, and sulfur; and a 7-11 membered fused bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur:
  • Ring C is selected from a phenyl, 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 7-11 membered fused bicyclic heteroaiyl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or the bond between Ring B and Ring C is absent, and Ring B and Ring C together form a 7-11 membered saturated or partially unsaturated fused, bridged, or spiro, bicyclic carbocyclic ring; a 7-11 membered fused bicyclic aryl ring; a 7-11 membered saturated or partially unsaturated fused, bridged, or spiro, bicyclic heterocydic ring having 1-4 heteroatoms independently selected from nitrogen
  • R 1 is Ci-6 aliphatic or a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; the R group of the sulfonamide moiety is hydrogen or para-methoxybenzyl; and the R 1 - and R v or R L and R L groups are not taken together with the atoms to which each is attached to form an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfiir, or L is
  • Ring B is phenyl or a 6-membered monocyclic heteroaiyl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • Ring C is phenyl or a 6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur and Is attached to Ring B in the para position relative to the L group; them Ring A and its R A substituents are other than where * denotes attachment to the moiety and ** denotes attachment to the moiety, or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof.
  • CTPS1 inhibitors are disclosed in PCT publication number WO2022087634 which is incorporated by reference in its entirety for the purpose of the CTPS1 inhibitors disclosed therein.
  • 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 pharmaceutically acceptable solvate thereof.
  • a CTPS1 inhibitor may be a compound selected from compounds I-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 compounds Z-1 to Z-10 of WO2022087634, or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof.
  • the CTPS1 inhibitor is not a CTPS1 inhibitor disclosed in PCT publication number WO2022087634.
  • the CTPS1 inhibitor is not (i) a compound described in any one of claims 1 to 31 of WO2022087634 or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof, (ii) a compound selected from compounds I-1 to I-286 of WO2022087634, or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof, or (iii) a compound selected from compounds Z- 1 to Z-10 of WO2022087634, or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof.
  • CTPS1 inhibitors are disclosed in WO2022/087634, which is incorporated by reference in its entirety for the purpose of defining CTPS1 inhibitors.
  • the CTPS1 inhibitor is as described in WO2022/087634, such as any of compounds I-1 to I-286 or Z-1 to Z- 10, or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof. In other embodiments the CTPS1 inhibitor is not described in WO2022/087634. Suitably, the CTPS1 inhibitor is not: or a pharmaceutically acceptable salt thereof, wherein:
  • R 1 is selected from Cw aliphatic; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, and a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring; having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with q instances of R A ;
  • Ring A is selected from phenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 7-11 membered fused bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein each of R L , R L ’, and R L " is independently hydrogen, -CN, halogen, or an optionally substituted group selected from Ci-e aliphatic; phenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered mono
  • Ring B is selected from phenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms 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 5-11 membered saturated or partially unsaturated fused, bridged, or spiro, bicyclic carbocyclic ring; a 7-11 membered fused bicyclic aryl ring; a 7-11 membered saturated or partially unsaturated fused, bridged, or spiro, bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 7-11 membered fused bicyclic heteroaryl ring having 1-4 heteraatotns independently selected from nitrogen, oxygen, and sulfur: Ring C is selected from a phenyl
  • heterocyclic ring having 1-2 helertuloms independently selected liotr. nitrogen, oxygen, and sulfur; a membered niormcx die hetets ittrv ritii; haxinyr 1-4 heterodumix independently selected from nitrogen, oxygen, and sulfur an 3-10 membered bicyclic heiemaryl fug hay ing 1-4 hrfenxilunis independently selected from mzzaen. oxygen. and sulfur .
  • n b-l I membered saturated or partially unsal.irnted ?ieyc'ii- carbocyclic ring haxirie 1-2 heieroatoms independently selected from nitrogen, oxygen, and sulfur, m twoR groups are taken together with the atoms to vy hi vh each R is attached, to four an optionally substituted 3-7 membered saturated or partially unsaturated monocydic earbiKyclic ring, a 3-7 membered saturated ⁇ >r partially- unsaturated monocycl c heterocyclic ring haying 1-2 hclcioatctlis independently selected from nitrogen, oxygen, and sulfur, or m is 0, 1, or 2; n is 0, 1, or 2; p is 0, 1, or 2; each q o independently 4.
  • each r is independently 0, 1, 2,, 3, or 4; and each sis independently 0, 1, 2, 3, or 4; provided that when: fie R group til fire sul'otiaiuide moiety is hydrgen or para-methinybenzyl. and the R u and R u or R L and R L " groups are not taken together with the atoms to which each is attached to form an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or L is
  • Ring B is phenyl or a 6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulftir, and
  • Ring C is phenyl or a 6-tnembered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur and is attached to Ring B in the para position relative to the L group; then Ring A and its R A substituents are other than where * denotes attachment to the moiety and ** denotes attachment to the moiety ,
  • the CTPS1 inhibitor is not a CTPS1 inhibitor as defined in claim 1 of WO2022/087634.
  • the CTPS1 inhibitor is not a CTPS1 inhibitor as defined in WO2022/087634.
  • the CTPS1 inhibitor may be provided in the form of a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate.
  • the CTPS1 inhibitor is provided in the form of a pharmaceutically acceptable salt and pharmaceutically acceptable solvate.
  • the CTPS1 inhibitor is provided in the form of a pharmaceutically acceptable salt.
  • the CTPS1 inhibitor is provided in the form of a pharmaceutically acceptable solvate.
  • 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 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.
  • compositions 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, 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 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).
  • the CTPS1 inhibitor encompasses all isomers of the CTPS1 inhibitors disclosed herein including all geometric, 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 by conventional synthetic methods or by stereospecific or asymmetric syntheses.
  • 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 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.
  • unnatural variant isotopic form also includes embodiments in which the proportion of an atom of given atomic number having a 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 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.
  • 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 provided whereby two or more atoms exist in an unnatural variant isotopic form.
  • the CTPS1 inhibitor administered to a subject should be safe and effective, i.e.
  • Safe and effective is intended to include a compound that is effective to achieve a desirable effect in treatment of cancer.
  • 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.
  • safe and effective as recited herein can be achieved by any suitable dosage regimen.
  • references herein to administering a safe and effective CTPS1 inhibitor include achieving the safe and effective amount via a single dose or by plural doses, such as administered by the specified administration route.
  • orally administering a safe and effective CTPS1 inhibitor includes both orally administering a single dose and orally administering any plural number of doses, provided that a safe and effective dose of CTPS1 inhibitor is thereby achieved by oral administration.
  • ATR inhibitors In one aspect of the invention there is provided an ATR inhibitor for use in the treatment of cancer with a CTPS1 inhibitor.
  • An ATR inhibitor is an agent which directly inhibits ATR activity, such as ATR induced phosphorylation of CHEK1 or ATR induced phosphorylation of H2AX ( ⁇ H2AX). Direct inhibition of ATR may be quantified using any suitable assay procedure, though is suitably performed using the procedure set out in Example 3.
  • the activity of ATR inhibitors can be measured by their ability to bind and inhibit purified ATR and related proteins using a protein kinase assay, their ability to inhibit ATR induced phosphorylation of CHEK1 in a cellular assay, or their ability to inhibit ATR induced phosphorylation of H2AX ( ⁇ H2AX) in a cellular assay.
  • activity of ATR inhibitors is measured using a protein kinase assay. In one embodiment activity of ATR inhibitors is measured using ATR induced phosphorylation of CHEK1 in a cellular assay. In one embodiment activity of ATR inhibitors is measured using phosphorylation of H2AX ( ⁇ H2AX) in a cellular assay.
  • ATR inhibitors of particular interest are those demonstrating Ki values for binding to ATR of 50 nM or lower, such as 20 nM or lower, such as 10 nM or lower, such as 5 nM or lower, such as 1 nM or lower.
  • ATR inhibitors of particular interest are those demonstrating Ki values for binding to ATR of 50 nM or lower, such as 20 nM or lower, such as 10 nM or lower, such as 5 nM or lower, such as 1 nM or lower using the ATR protein kinase assay procedure, the ATR induced phosphorylation of CHEK1 assay procedure or the ATR induced phosphorylation of ⁇ H2AX assay procedure set out in Example 3.
  • selectivity of ATR inhibitors is measured using a protein kinase assay.
  • ATR inhibitors of particular interest are those demonstrating a selectivity for ATR over ATM, DNA-PK or MTOR of >5-fold, such as >10-fold.
  • ATR inhibitors of particular interest are those demonstrating a selectivity for ATR over ATM, DNA-PK or MTOR of >5-fold, such as >10- fold using the assay procedure set out in Example 4.
  • ATR inhibition and ATR vs ATM, DNA-PK and MTOR selectivity should be based on human forms of the proteins.
  • Particular ATR inhibitors include the following (clinical trial data is sourced from http://www.clinicaltrials.gov accessed November 2021 - January 2022): Ceralasertib
  • Ceralasertib The structure of ceralasertib (‘AZD6738’, imino-methyl-[1-[6-[(3R)-3-methylmorpholin-4- yl]-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl]cyclopropyl]-oxo- ⁇ 6-sulfane, CAS number 1352226-88-0) is provided below.
  • the ATR inhibitor may be ceralasertib or a pharmaceutically acceptable salt and/or a pharmaceutically acceptable solvate thereof.
  • the ATR inhibitor is ceralasertib.
  • the ATR inhibitor is a pharmaceutically acceptable salt of ceralasertib.
  • the ATR inhibitor is a pharmaceutically acceptable solvate of ceralasertib.
  • the ATR inhibitor is a pharmaceutically acceptable salt and a pharmaceutically acceptable solvate of ceralasertib.
  • the ATR inhibitor is not ceralasertib.
  • the ATR inhibitor is not ceralasertib or a pharmaceutically acceptable salt and/or a pharmaceutically acceptable solvate thereof.
  • VE821 The structure of VE821 (3-amino-6-(4-methylsulfonylphenyl)-N-phenylpyrazine-2- carboxamide, CAS number 1232410-49-9) is provided below.
  • the ATR inhibitor may therefore be VE821 or a pharmaceutically acceptable salt and/or a pharmaceutically acceptable solvate thereof.
  • the ATR inhibitor is VE821.
  • the ATR inhibitor is a pharmaceutically acceptable salt of VE821.
  • the ATR inhibitor is a pharmaceutically acceptable solvate of VE821.
  • the ATR inhibitor is a pharmaceutically acceptable salt and a pharmaceutically acceptable solvate of VE821.
  • the ATR inhibitor is not VE821.
  • the ATR inhibitor is not VE821 or a pharmaceutically acceptable salt and/or a pharmaceutically acceptable solvate thereof.
  • VE821 is disclosed in Charrier 2011, which is incorporated herein by reference in its entirety for the purpose of defining the ATR inhibitor.
  • Gartisertib The structure of gartisertib (“VX-803”, 2-amino-6-fluoro-N-[5-fluoro-4-[4-[4-(oxetan-3- yl)piperazine-1-carbonyl]piperidin-1-yl]pyridin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide) is provided below.
  • the ATR inhibitor may therefore be gartisertib or a pharmaceutically acceptable salt and/or a pharmaceutically acceptable solvate thereof.
  • the ATR inhibitor is gartisertib.
  • the ATR inhibitor is a pharmaceutically acceptable salt of gartisertib.
  • the ATR inhibitor is a pharmaceutically acceptable solvate of gartisertib. In one embodiment the ATR inhibitor is a pharmaceutically acceptable salt and a pharmaceutically acceptable solvate of gartisertib.
  • Gartisertib is disclosed in Jo 2021, which is incorporated herein by reference in its entirety for the purpose of defining the ATR inhibitor.
  • ETP-46464 The structure of ETP-46464 (2-methyl-2-[4-(2-oxo-9-quinolin-3-yl-4H-[1,3]oxazino[5,4- c]quinolin-1-yl)phenyl]propanenitrile) is provided below.
  • the ATR inhibitor may therefore be ETP-46464 or a pharmaceutically acceptable salt and/or a pharmaceutically acceptable solvate thereof.
  • the ATR inhibitor is ETP-46464.
  • the ATR inhibitor is a pharmaceutically acceptable salt of ETP- 46464.
  • the ATR inhibitor is a pharmaceutically acceptable solvate of ETP- 46464.
  • the ATR inhibitor is a pharmaceutically acceptable salt and a pharmaceutically acceptable solvate of ETP-46464.
  • ETP-46464 is disclosed in Toledo 2011, which is incorporated herein by reference in its entirety for the purpose of defining the ATR inhibitor.
  • AZ20 The structure of AZ20 ((3R)-4-[2-(1H-indol-4-yl)-6-(1- methylsulfonylcyclopropyl)pyrimidin-4-yl]-3-methylmorpholine) is provided below.
  • the ATR inhibitor may therefore be AZ20 or a pharmaceutically acceptable salt and/or a pharmaceutically acceptable solvate thereof.
  • the ATR inhibitor is AZ20.
  • the ATR inhibitor is a pharmaceutically acceptable salt of AZ20.
  • the ATR inhibitor is a pharmaceutically acceptable solvate of AZ20.
  • the ATR inhibitor is a pharmaceutically acceptable salt and a pharmaceutically acceptable solvate of AZ20.
  • AZ20 is disclosed in Foote 2013, which is incorporated herein by reference in its entirety for the purpose of defining the ATR inhibitor.
  • Elimusertib The structure of elimusertib (BAY-1895344, (3R)-3-methyl-4-[4-(2-methylpyrazol-3-yl)-8- (1H-pyrazol-5-yl)-1,7-naphthyridin-2-yl]morpholine, CAS number 1876467-74-1) is provided below.
  • the ATR inhibitor may therefore be elimusertib or a pharmaceutically acceptable salt and/or a pharmaceutically acceptable solvate thereof. In one embodiment the ATR inhibitor is elimusertib.
  • the ATR inhibitor is a pharmaceutically acceptable salt of elimusertib. In one embodiment the ATR inhibitor is a pharmaceutically acceptable solvate of elimusertib. In one embodiment the ATR inhibitor is a pharmaceutically acceptable salt and a pharmaceutically acceptable solvate of elimusertib. Elimusertib is disclosed in Wengner 2020, which is incorporated herein by reference in its entirety for the purpose of defining the ATR inhibitor.
  • Berzosertib The structure of berzosertib (M6620, VX-970, VE-822, 3-[3-[4- (methylaminomethyl)phenyl]-1,2-oxazol-5-yl]-5-(4-propan-2-ylsulfonylphenyl)pyrazin-2-amine, CAS number 1232416-25-9) is provided below.
  • the ATR inhibitor may therefore be berzosertib or a pharmaceutically acceptable salt and/or a pharmaceutically acceptable solvate thereof.
  • the ATR inhibitor is berzosertib.
  • the ATR inhibitor is a pharmaceutically acceptable salt of berzosertib.
  • the ATR inhibitor is a pharmaceutically acceptable solvate of berzosertib. In one embodiment the ATR inhibitor is a pharmaceutically acceptable salt and a pharmaceutically acceptable solvate of berzosertib. Berzosertib is disclosed in Charrier 2011, which is incorporated herein by reference in its entirety for the purpose of defining the ATR inhibitor. In one embodiment, the ATR inhibitor is selected from the group consisting of ceralasertib, VE821, gartisertib, ETP-46464, AZ20, elimusertib and berzosertib, pharmaceutically acceptable salts and/or pharmaceutically acceptable solvates of any thereof.
  • the ATR inhibitor is ceralasertib or VE821, pharmaceutically acceptable salts and/or pharmaceutically acceptable solvates thereof.
  • the ATR inhibitor is ceralasertib, pharmaceutically acceptable salts and/or pharmaceutically acceptable solvates thereof.
  • the ATR inhibitor may be provided in the form of a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate.
  • the ATR inhibitor is provided in the form of a pharmaceutically acceptable salt and pharmaceutically acceptable solvate.
  • the ATR inhibitor is provided in the form of a pharmaceutically acceptable salt.
  • the ATR inhibitor is provided in the form of a pharmaceutically acceptable solvate.
  • the ATR inhibitor is provide 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 salts include acid addition salts formed with inorganic acids e.g. hydrochloric, hydrobromic, sulphuric, nitric or phosphoric acid and organic acids e.g.
  • 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, meglumine, tromethamine, piperazine, arginine, choline, diethylamine, benzathine or lysine.
  • the ATR 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 ATR inhibitor may be prepared in crystalline or non-crystalline form and, if 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).
  • the ATR inhibitor encompasses all isomers of the ATR inhibitors disclosed herein including all geometric, 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 by conventional synthetic methods or by stereospecific or asymmetric syntheses.
  • the ATR inhibitor encompasses all isotopic forms of the ATR 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 nature (referred to herein as an “unnatural variant isotopic form”).
  • unnatural variant isotopic form also includes embodiments in which the proportion of an atom of given atomic number having a 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 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 drug and/or substrate tissue distribution studies.
  • the ATR inhibitor is provided in a natural isotopic form. In one embodiment, the ATR inhibitor is provided in an unnatural variant isotopic form. In one embodiment, the ATR inhibitor is provided whereby a single atom of the compound exists in an unnatural variant isotopic form. In another embodiment, the ATR inhibitor is provided whereby two or more atoms exist in an unnatural variant isotopic form.
  • the ATR inhibitors disclosed herein may be made according to the organic synthesis techniques known to those skilled in this field.
  • the production of berzosertib and VE821 are disclosed in Charrier 2011 and the production of AZ20 is disclosed in Foote 2013. These references are incorporated herein by reference in their entirety for the purpose of production of these ATR inhibitors.
  • the ATR inhibitor administered to a subject should be safe and effective, i.e. an ATR inhibitor providing an acceptable balance of desired benefits and undesired side effects. “Safe and effective” is intended to include a compound that is effective to achieve a desirable effect in treatment of cancer.
  • 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.
  • “safe and effective” as recited herein can be achieved by any suitable dosage regimen.
  • references herein to administering a safe and effective ATR inhibitor, 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.
  • orally administering a safe and effective ATR inhibitor includes both orally administering a single dose and orally administering any plural number of doses, provided that a safe and effective ATR inhibitor is thereby achieved by oral administration.
  • Administration The invention is typically intended for use with mammalian subjects, in particular human subjects.
  • the combination treatment will typically be administered to a subject in need thereof, in particular a mammalian subject, in particular a human subject.
  • the invention provides a CTPS1 inhibitor and an ATR inhibitor for use in the treatment of cancer, wherein the CTPS1 inhibitor is defined in any one of Groups A to H.
  • One aspect of the invention provides a CTPS1 inhibitor in the manufacture of a medicament for the treatment of cancer with an ATR inhibitor, wherein the CTPS1 inhibitor is defined in any one of Groups A to H.
  • a further aspect of the invention provides the use of an ATR inhibitor in the manufacture of a medicament for the treatment of cancer with a CTPS1 inhibitor, wherein the CTPS1 inhibitor is defined in any one of Groups A to H.
  • a further aspect of the invention provides the use of a CTPS1 inhibitor and an ATR inhibitor in the manufacture of a medicament for the treatment of cancer, wherein the CTPS1 inhibitor is defined in any one of Groups A to H.
  • a further aspect of the invention provides a method of treating cancer in a subject which method comprises administering to the subject a CTPS1 inhibitor and an ATR inhibitor, wherein the CTPS1 inhibitor is defined in any one of Groups A to H.
  • a further aspect of the invention provides a pharmaceutical composition comprising a CTPS1 inhibitor and an ATR inhibitor, suitably for use in the treatment of cancer, wherein the CTPS1 inhibitor is defined in any one of Groups A to H.
  • a further aspect of the invention provides a CTPS1 inhibitor in the manufacture of a medicament for the treatment of cancer with an ATR inhibitor, wherein the ATR inhibitor is ceralasertib or VE821, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof.
  • the invention provides a CTPS1 inhibitor and an ATR inhibitor for use in the treatment of cancer, wherein the ATR inhibitor is ceralasertib or VE821, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof.
  • a further aspect of the invention provides the use of an ATR inhibitor in the manufacture of a medicament for the treatment of cancer with a CTPS1 inhibitor, wherein the ATR inhibitor is ceralasertib or VE821, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof.
  • a further aspect of the invention provides the use of a CTPS1 inhibitor and an ATR inhibitor in the manufacture of a medicament for the treatment of cancer, wherein the ATR inhibitor is ceralasertib or VE821, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof.
  • a further aspect of the invention provides a method of treating cancer in a subject which method comprises administering to the subject a CTPS1 inhibitor and an ATR inhibitor, wherein the ATR inhibitor is ceralasertib or VE821, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof.
  • a further aspect of the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a CTPS1 inhibitor and an ATR inhibitor, suitably for use in the treatment of cancer, wherein the ATR inhibitor is ceralasertib or VE821, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof.
  • the CTPS1 inhibitor and the ATR inhibitor act synergistically in treating the cancer.
  • the CTPS1 inhibitor and the ATR inhibitor act ‘synergistically’ if their combined administration results in a beneficial effect greater than the sum of the beneficial effects of each agent administered alone.
  • the CTPS1 inhibitor and the ATR inhibitor act synergistically if they achieve a Bliss score (Bliss 1939; Zheng 2021) of greater than 10 when applied to a cancer cell line as set out in Example 6.
  • Administration of the CTPS1 inhibitor The CTPS1 inhibitor may be administered by any suitable route, which may depend on 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.
  • the CTPS1 inhibitor may suitably be delivered in a solid pharmaceutical composition (such as a tablet, capsule or lozenge) or in a liquid pharmaceutical composition (such as a suspension, emulsion or solution).
  • a liquid pharmaceutical composition such as a suspension, emulsion or solution.
  • the CTPS1 inhibitor is administered orally, such as administered orally in a solid pharmaceutical composition.
  • 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.
  • a 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.
  • the pharmaceutical composition is in unit dose form, such as a tablet, capsule or ampoule.
  • the unit dose form is for oral delivery.
  • the pharmaceutical composition may for example contain from 0.1% to 99.99% by weight, 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 0.05 mg to 2000 mg of the active material, for example from 1.0 mg to 500 mg, depending on the method of administration.
  • the pharmaceutical composition may contain from 50 mg to 1000 mg of the carrier, for example 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 cancer, the weight of the sufferer, and other similar factors.
  • suitable unit doses may be 0.05 mg to 1000 mg, more suitably 1.0 mg to 500 mg, and such unit doses may be administered more than once a day, for example two or three a day. Such therapy may extend for a number of weeks, months or longer.
  • 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 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 that is sufficient to achieve the desirable effect when the CTPS1 inhibitor is administered with the ATR inhibitor.
  • a “safe and effective amount” as recited herein can be achieved by any suitable dosage regimen.
  • references herein to administering a safe and effective amount of a compound include achieving the safe and effective amount via a single dose or by plural doses, such as administered by the specified administration route.
  • orally administering a safe and 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.
  • Administration of the ATR inhibitor The ATR inhibitor may be administered by any suitable route, which may depend on the nature of the specific agent. Exemplary routes include oral, parenteral, buccal, sublingual, nasal or rectal administration. Conveniently, the ATR inhibitor is administered orally.
  • the ATR inhibitor may be provided in the form of a pharmaceutical composition comprising the ATR inhibitor and a pharmaceutically acceptable carrier or excipient.
  • the ATR inhibitor is administered orally, such as administered orally in a solid pharmaceutical composition.
  • the ATR inhibitor may suitably be delivered in a solid pharmaceutical composition (such as a tablet, capsule or lozenge) or in a liquid pharmaceutical composition (such as a suspension, emulsion or solution).
  • a liquid formulation will generally consist of a suspension or solution of the ATR 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.
  • a 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.
  • the pharmaceutical composition is in unit dose form, such as a tablet, capsule or ampoule.
  • the unit dose form is for oral delivery.
  • the pharmaceutical composition may for example contain from 0.1% to 99.99% by weight, 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 0.05 mg to 2000 mg of the active material, for example from 1.0 mg to 500 mg, suitably 5 mg to 100 mg, such as 20 to 60 mg, depending on the method of administration. For oral administration, 20 mg may be desirable.
  • the pharmaceutical composition may contain from 50 mg to 1000 mg of the carrier, for example 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 cancer, the weight of the sufferer, and other similar factors. However, as a general guide suitable unit doses may be 0.05 mg to 1000 mg, more suitably 1.0 mg to 500 mg, and such unit doses may be administered more than once a day, for example two or three a day. Such therapy may extend for a number of weeks, months or longer.
  • a plurality of unit does such as a plurality of tablets, may be taken together.
  • the ATR inhibitor is administered daily for a period 5 weeks.
  • the ATR inhibitor may be administered at a daily dose of 20 mg for week 1, 50 mg for week 2, 100 mg for week 3, 200 mg for week 4 and 400 mg for week 5.
  • 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 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 that is sufficient to achieve the desirable effect when the CTPS1 inhibitor is administered with the ATR inhibitor.
  • a “safe and effective amount” as recited herein can be achieved by any suitable dosage regimen.
  • references herein to administering a safe and effective amount of a compound include achieving the safe and effective amount via a single dose or by plural doses, such as administered by the specified administration route.
  • orally administering a safe and 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.
  • Administration regimes The CTPS1 inhibitor and ATR inhibitor may be administered separately, sequentially or simultaneously.
  • the CTPS1 inhibitor may be administered before the ATR inhibitor.
  • the ATR inhibitor may be administered before the CTPS1 inhibitor.
  • the CTPS1 inhibitor and/or ATR inhibitor may be administered intermittently. Intermittently in this context means that the CTPS1 inhibitor and/or the ATR inhibitor are not administered every day of a treatment cycle (e.g. the CTPS1 inhibitor and/or the ATR inhibitor are administered for 4 days in each 7 day period of a treatment cycle). It will be understood that when the CTPS1 inhibitor and ATR inhibitor are both administered intermittently, they need not be administered according to the same schedule.
  • the CTPS1 inhibitor and/or ATR inhibitor may be administered continuously i.e. administered at least daily in a treatment cycle (e.g. the CTPS1 inhibitor and/or the ATR inhibitor are administered each day of a treatment cycle).
  • the CTPS1 inhibitor is administered intermittently and the ATR inhibitor is administered intermittently.
  • the CTPS1 inhibitor is administered continuously and the ATR inhibitor is administered continuously.
  • the CTPS1 inhibitor is administered intermittently and the ATR inhibitor is administered continuously.
  • the CTPS1 inhibitor is administered continuously and the ATR inhibitor is administered intermittently.
  • the CTPS1 inhibitor and the ATR inhibitor may be delivered in co-formulation (where compatible with co-formulation and whether the dosage regimes of the two agents allow) or in separate formulations.
  • the CTPS1 inhibitor and the ATR inhibitor are delivered in co-formulation or in separate formulations which are simultaneously administered.
  • the CTPS1 inhibitor and the ATR inhibitor may be delivered at different times.
  • the CTPS1 inhibitor (or a pharmaceutical composition comprising such, such as a tablet or capsule) and ATR inhibitor (or a pharmaceutical composition comprising such, such as a tablet or capsule) may be provided in separate containers.
  • the CTPS1 inhibitor and ATR inhibitor may be provided in the form of a kit of parts comprising: a) a first container comprising a CTPS1 inhibitor; and b) a second container comprising an ATR inhibitor.
  • the CTPS1 inhibitor and ATR inhibitor may be provided in the form of a kit of parts comprising a first container comprising a CTPS1 inhibitor (or a pharmaceutical composition comprising such, such as a tablet or capsule) and a second container comprising an ATR inhibitor (or a pharmaceutical composition comprising such, such as a tablet or capsule).
  • Treatment with the CTPS1 inhibitor and ATR inhibitor may be combined with one or more further pharmaceutically acceptable active ingredients, which may be selected from: anti-mitotic agents such as vinblastine, paclitaxel and docetaxel; alkylating agents, for example cisplatin, carboplatin, dacarbazine and cyclophosphamide; antimetabolites, for example 5-fluorouracil, cytosine arabinoside and hydroxyurea; intercalating agents for example adriamycin and bleomycin; topoisomerase inhibitors for example etoposide, topotecan and irinotecan; thymidylate synthase inhibitors for example raltitrexed; PI3 kinase inhibitors for example idelalisib; mTor inhibitors for example everolimus and temsirolimus; proteasome inhibitors for example bortezomib; histone deacetylase inhibitors for example
  • the CTPS1 inhibitor, ATR inhibitor and the additional pharmaceutically acceptable active ingredients may each be administered in any combination of separate, sequential or simultaneous dosing. If administered simultaneously, the CTPS1 inhibitor and ATR inhibitor may be e.g. (a) formulated together but separately from the further pharmaceutically acceptable active ingredient, (b) formulated separately from each other and separately from the further pharmaceutically acceptable active ingredient (c) formulated together with the further pharmaceutically acceptable active ingredient.
  • the CTPS1 inhibitor, the ATR inhibitor and the additional pharmaceutically acceptable active ingredients may each be administered in any combination of separate, sequential or simultaneous dosing.
  • the CTPS1 inhibitor, ATR inhibitor and the additional pharmaceutically acceptable active ingredients may be e.g.
  • the further pharmaceutically acceptable active ingredient may be selected from tyrosine kinase inhibitors such as, for example, axitinib, dasatinib, erlotinib, imatinib, nilotinib, pazopanib and sunitinib.
  • the further pharmaceutically acceptable active ingredient may be selected from azacitidine, decitabine, or cytarabine.
  • Further pharmaceutically acceptable active ingredients also include anticancer antibodies, such as those selected from the group consisting of anti-CD20 antibodies (such as obinutuzumab, ofatumumab, tositumomab or rituximab) or other antibodies such as olaratumab, daratumumab, necitumumab, dinutuximab, traztuzumab emtansine, pertuzumab, brentuximab, panitumumab, catumaxomab, bevacizumab, cetuximab, traztuzumab and gentuzumab ozogamycin.
  • anti-CD20 antibodies such as obinutuzumab, ofatumumab, tositumomab or rituximab
  • other antibodies such as olar
  • the CTPS1 inhibitor and ATR inhibitor may also be administered in combination with radiotherapy, surgery, hyperthermia therapy or cryotherapy.
  • Cancer in one embodiment the cancer is a cancer which is susceptible to replication stress or has high pre-existing levels of replication stress. By a ‘high’ level it is meant that the cancer has a pre-existing level of replication stress which is higher than an average cancer.
  • the cancer expresses ATR.
  • the cancer is a cancer which constitutively expresses MYC.
  • the cancer shows evidence of DNA damage, for example by the presence of ⁇ H2AX.
  • the cancer is a haematological cancer, such as acute myeloid leukemia, angioimmunoblastic T-cell lymphoma, B-cell acute lymphoblastic leukemia, Sweet syndrome, T- cell non-Hodgkins lymphoma (including natural killer/T-cell lymphoma, adult T-cell leukaemia/lymphoma, enteropathy type T-cell lymphoma, hepatosplenic T-cell lymphoma and ccutaneous T-cell lymphoma), T-cell acute lymphoblastic leukemia, B-cell non-Hodgkins lymphoma (including Burkitt lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, marginal Zone lymphoma), hairy cell leukemia, Hodgkin lymphoma, lymphoblastic lymphoma, lymphoplasmacytic lymphoma, mucosa-associated lymphoid tissue lymphoma, multiple my
  • T cell lymphoma Suitably T cell lymphoma, diffuse large B cell lymphoma, plasma cell myeloma, acute myeloid leukaemia, chronic lymphocytic leukaemia or peripheral T cell lymphoma.
  • a further haematological cancer of interest is T-cell prolymphocytic leukemia.
  • Other haematological cancers of interest are myelodysplastic syndromes (MDS), such as MDS with single lineage dysplasia, MDS with multilineage dysplasia or MDS with excess blasts.
  • MDS myelodysplastic syndromes
  • the cancer is a non-haematological cancer, such as selected from the group consisting of colorectal cancer, bile duct cancer, endometrial cancer, hepatic cancer, gastric cancer, oesophageal cancer, sarcoma, bladder cancer, pancreatic cancer, ovarian cancer, lung cancer, mesothelioma, melanoma, bone cancer, head and neck cancer, breast cancer, brain cancers, prostate cancer, renal cancer, thyroid cancer and neuroblastoma.
  • a non-haematological cancer such as selected from the group consisting of colorectal cancer, bile duct cancer, endometrial cancer, hepatic cancer, gastric cancer, oesophageal cancer, sarcoma, bladder cancer, pancreatic cancer, ovarian cancer, lung cancer, mesothelioma, melanoma, bone cancer, head and neck cancer, breast cancer, brain cancers, prostate cancer, renal cancer, thyroid cancer and neuroblastoma.
  • the non-haematological cancer is selected from colorectal cancer, bile duct cancer, endometrial cancer, hepatic cancer, gastric cancer, oesophageal cancer, sarcoma, bladder cancer, pancreatic cancer, ovarian cancer, lung cancer, mesothelioma and melanoma. More suitably the non-haematological cancer is selected from colorectal cancer, bile duct cancer, endometrial cancer, hepatic cancer, gastric cancer and oesophageal cancer.
  • the non- haematological cancer may be selected from prostate cancer, pancreatic cancer, ovarian cancer, lung cancer, renal cancer, colorectal cancer or breast cancer.
  • the CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit of the invention may be for administration to a subject identified as having a cancer expected to be susceptible to treatment by a CTPS1 inhibitor and an ATR inhibitor.
  • the CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit of the invention may be for administration to a subject from whom a sample containing cancer cells has been shown to be susceptible to treatment by a CTPS1 inhibitor and an ATR inhibitor.
  • a ‘susceptible’ cancer or cancer cell sample in this context is one which is associated with generally demonstrating a benefit from the treatment according to the invention relative to treatment with CTPS1 or ATR inhibitors alone, e.g.
  • the invention also provides a CTPS1 inhibitor for use in the treatment of cancer with an ATR inhibitor.
  • the invention provides an ATR inhibitor for use in the treatment of cancer with a CTPS1 inhibitor.
  • the invention provides a CTPS1 inhibitor and an ATR inhibitor for use in the treatment of cancer.
  • the invention provides the use of a CTPS1 inhibitor in the manufacture of a medicament for the treatment of cancer with an ATR inhibitor.
  • the invention provides the use of an ATR inhibitor in the manufacture of a medicament for the treatment of cancer with a CTPS1 inhibitor.
  • the invention provides the use of a CTPS1 inhibitor and an ATR inhibitor in the manufacture of a medicament for the treatment of cancer.
  • the invention provides a method of treating cancer in a subject which method comprises administering to the subject a CTPS1 inhibitor and an ATR inhibitor.
  • the invention provides a pharmaceutical composition comprising a CTPS1 inhibitor and an ATR inhibitor.
  • the invention provides a kit of parts comprising: a) a first container comprising a CTPS1 inhibitor; and b) a second container comprising an ATR inhibitor.
  • the CTPS1 inhibitor may be as further particularised elsewhere herein, such as those demonstrating an IC50 of 10 uM or lower, such as 1uM or lower, especially 100nM or lower, in respect of human CTPS1 enzyme using the assay procedure set out in Example 1, for example those demonstrating a selectivity for human CTPS1 over human CTPS2, suitably of at least 2-fold, such as at least 30-fold, especially at least 60-fold and in particular a least 1000-fold using the assay procedure set out in Example 2.
  • the ATR inhibitor may be as further particularised elsewhere herein, such as those demonstrating Ki values for binding to human ATR of 50 nM or lower, such as 20 nM or lower, such as 10 nM or lower, such as 5 nM or lower, such as 1 nM or lower using the ATR protein kinase assay procedure, the ATR induced phosphorylation of CHEK1 assay procedure or the ATR induced phosphorylation of ⁇ H2AX assay procedure set out in Example 3.
  • the invention is further exemplified by the following non-limiting examples.
  • CTPS1-IA is 4-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin- 2-yl)tetrahydro-2H-pyran-4-carboxamide.
  • CTPS-IB is N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(2-(ethylsulfonamido)pyrimidin-4- yl)tetrahydro-2H-pyran-4-carboxamide.
  • Assays for human CTPS1 were performed in 1x assay buffer containing 50mM Tris, 10mM MgCl 2 , 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-His 8 -tag 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 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 Max kit (0.31mM), GTP (0.034mM), UTP (0.48mM) and L-glutamine (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). Max reagent was added for 60 minutes (6 ⁇ L per well) and subsequently Max development reagent was added for 60 minutes (12uL per well) prior to signal detection in a microplate reader (EnVision ⁇ Multilabel Reader, Perkin Elmer).
  • a pre-mixed substrate mix UltraPure ATP from Max kit (0.31mM), GTP (0.034mM), UTP (0.48mM) and L-glutamine (0.186mM
  • assay plates were pulse centrifuged for 30 seconds at 500rpm.
  • the enzyme converts ATP to ADP and the ⁇ Max reagent subsequently depletes any remaining endogenous ATP in the reaction system.
  • the 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 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.
  • RF/MS RapidFire high-throughput mass spectrometry
  • RF/MS assays for both human CTPS1 and CTPS2 were performed in assay buffer consisting of 50mM HEPES (Merck), 20mM MgCl2, 5mM KCl, 1mM DTT, 0.01% Tween-20, pH to 8.0 accordingly.
  • Human full-length active C-terminal FLAG-His- tag CTPS1 (UniProtKB - P17812, CTPS[1-591]-GGDYKDDDDKGGHHHHHHHH, SEQ ID NO: 1) was obtained from Proteros biostructures GmbH.
  • hCTPS1 ATP (0.3mM), UTP (0.2mM), GTP (0.07mM) and L-glutamine (0.1mM).
  • 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 isoform within the determined linear phase of the reaction at 25 ⁇ C.
  • a 60uL volume of stop solution 1% formic acid with 0.5uM 13 C 9 - 15 N 3 -CTP in H 2 0 was added and the plate immediately heat-sealed and centrifuged for 10 minutes at 4,000rpm.
  • Example 3 Human ATR Inhibition ATR protein kinase assay
  • a suitable target peptide for example ASELPASQPQPFSAKKK (SEQ ID NO: 3)
  • a kinase reaction buffer containing unlabelled ATP, plus 5 nmol/L 33 P ⁇ -labelled ATP is mixed with a kinase reaction buffer containing unlabelled ATP, plus 5 nmol/L 33 P ⁇ -labelled ATP.
  • Radioactivity incorporated into the substrate which is a measure of enzymatic activity, is quantified by capturing the substrate on a suitable surface and measuring radioactivity using a liquid scintillation counter.
  • ATR induced phosphorylation of CHEK1 or ⁇ H2AX Cells from suitable cell lines are plated in each well of a 24 well tissue culture plate and allowed to recover for 24 h (for example HeLa at 7 ⁇ 10 4 or Calu-61 ⁇ 10 5 per well).
  • the cell lines are exposed to a DNA damaging agent, for example doxorubicin or gemcitabine.
  • Serial dilutions of test compound are added 24 h later and the plates incubated for an additional 2 h.
  • the cells are harvested in cold cell lysis and protein extraction buffer supplemented with phosphatase inhibitors.
  • Example 4 ATR Selectivity
  • the ATR protein kinase assay can be modified to assay the ability of test compounds to inhibit the activity of other related proteins.
  • purified human ATM or the ATM kinase domain for example derived from transfected Sf9 insect cells, is incubate with a suitable target peptide, for example DPSVEPPLSQETFSDKKK (SEQ ID NO: 4), in a dilution series of test compound is mixed with a kinase reaction buffer containing unlabelled ATP, plus 5 nmol/L 33 P ⁇ - labelled ATP.
  • Radioactivity incorporated into the substrate is quantified by capturing the substrate on a suitable surface and measuring radioactivity using a liquid scintillation counter.
  • a suitable target peptide for example EPPLSQEAFADLWKKK (SEQ ID NO: 5)
  • a kinase reaction buffer containing unlabelled ATP plus 5 nmol/L 33 P ⁇ - labelled ATP.
  • Radioactivity incorporated into the substrate which is a measure of enzymatic activity, is quantified by capturing the substrate on a suitable surface and measuring radioactivity using a liquid scintillation counter.
  • CTPS1 Involvement in the Proliferation of Cancer Cells Pathways involved in providing the key building blocks for nucleic acid replication are the purine and pyrimidine synthesis pathways, and pyrimidine biosynthesis has been observed to be up-regulated in tumors and neoplastic cells.
  • CTPS activity is upregulated in a range of tumour types of both haematological and non-haematological origin, although heterogeneity is observed among patients. Linkages have also been made between high enzyme levels and resistance to chemotherapeutic agents.
  • CTPS1 was found by the present inventors to be essential for the proliferation of human cancer cells derived from a broad range of haematological and solid tumour types, whereas CTPS2 was invariably redundant.
  • This analysis used data from the Achilles project where every gene in the human genome was independently deleted using CRIPR technology in each of 324 human cancer cell lines, and the effects of each gene deletion was assessed using an in vitro proliferation assay (Behan 2019).
  • This dataset has subsequently been expanded to include data from 1,032 human cancer cell lines (Cancer Dependency Map: https://depmap.org/). The effects of deletion of different genes in the pyrimidine synthesis pathway were assessed (see Fig.2). Deletion of CTPS2 had no effect on cancer cell proliferation.
  • CMPK1 genes in the salvage pathway (UCK1, UCK2) had minimal effect on cell proliferation.
  • CMPK1 had a marked effects on cell proliferation, consistent with CMPK1 being an essential gene.
  • CTPS1, UMPS, DHODH or CAD inhibited cancer cell proliferation with an effect that is consistent with dependency of cancer cells on the products of these genes; inhibition of CTPS1 produced the greatest impairment of cancer cell proliferation.
  • Example 6 Effect of Combined Treatment with a CTPS1 inhibitor and an ATR Inhibitor Cell cycle status was assessed by flow cytometric analysis after staining cells with propidium iodide with or without additional labelling with Bromodeoxyuridine (BrdU).
  • CTPS1 inhibitor CPS1-IA
  • the second compound were added at prespecified concentrations (above, at and below the single agent IC 50 value for the cell line being studied) and cell viability was assessed after 72 hours incubation using a metabolic reagent such as a tetrazolium salt-based colourimetric assay (Cell Counting Kit-8, Dojindo) or CellTiter-Glo (Promega).
  • a metabolic reagent such as a tetrazolium salt-based colourimetric assay (Cell Counting Kit-8, Dojindo) or CellTiter-Glo (Promega).
  • Apoptosis was assessed by flow cytometric analysis after staining cells with propidium iodide and annexin V.
  • the CTPS1 inhibitor, CTPS1-IA, and a second compound were tested in 4x4 matrices (total 16 conditions).
  • Each compound was included at concentrations producing single agent 72- hour viability of approximately 80-90%, 50-60% and 30-40%, as well as a no drug condition. Combined effects were assessed by calculating Bliss scores (Bliss 1939; Zheng 2021); a score of -10 to ⁇ 10 indicates an additive effect and a value of ⁇ 10 indicates synergy.
  • Cell cycle analysis indicates that exposure to CTPS1-IA causes cancer cells to accumulate in S phase.
  • the results of the cell cycle analysis are provided in Fig.3.
  • the results of the proliferation assays are provided in Fig.4 and Fig.5.
  • the proliferation assays include data from mantle cell lymphoma lines and myeloma cell lines.
  • FIG. 6 illustrates increased activated CHEK1 (pCHEK1) following exposure to CTPS1-IA in myeloma cell lines. Inhibition of CTPS1 via CTPS1-IA results in S phase accumulation and activation of CHEK1.
  • CTPS1 inhibitor e.g. CTPS-IA
  • ATR inhibitor e.g. ceralasertib
  • CTPS1-IA efficacy scores for myeloma cell lines exposed to the CTPS1 inhibitor CTPS1-IA in combination with either a standard of care drug or an ATR inhibitor (VE821 or ceralasertib).
  • a score of -10 to ⁇ 10 indicates an additive effect and a value of ⁇ 10 indicates synergy (open and hatched bars, respectively).
  • standard of care drugs lacalidomide, dexamethasone, melphalan or bortezomib
  • Fig.8 shows representative data from myeloma cell lines exposed to the CTPS1 inhibitor CTPS1-IA combined with an ATR inhibitor (VE821). In all cases, the combination induced a higher degree of apoptosis than either drug given alone (synergy scores were not calculated in this experiment).
  • Figs.9A to 9C show data from 6 mantle cell lymphoma cell lines exposed to the CTPS1 inhibitor CTPS1-IA combined with an ATR inhibitor (VE821). Synergy was observed in 3 of the 6 cell lines (Bliss scores 11 - 20).
  • Figs.10A to 10B show representative data from primary mantle cell lymphoma samples (i.e. mantle cell lymphoma cells taken directly from patients as opposed to cell lines) exposed to the CTPS1 inhibitor CTPS1-IA combined with an ATR inhibitor (VE821). Synergy was observed in 7 of the 11 cell lines (Bliss scores 10 - 22).
  • Fig.11 shows data from 36 human cancer lines derived from solid tumours exposed to the CTPS1 inhibitor CTPS1-IA combined with an ATR inhibitor (ceralasertib). Synergy was observed in 22 of the cell lines (Bliss scores 10 - 33).
  • Fig.12 shows a comparison of synergy in anti-tumour effects elicited by the ATR inhibitor ceralasertib in 4 human colorectal cancer cell lines in combination with either the CTPS1 inhibitor CTPS1-IA or a chemotherapy drug (irinotecan).
  • the synergy elicited by the ceralasertib CTPS1-IA combination exceeded that elicited by the ceralasertib chemotherapy combination.
  • Example 7 In vivo effect of Combined Treatment with a CTPS1 inhibitor and an ATR Inhibitor
  • a human cancer cell line to look for interactions between the antiproliferative effects of CTPS1-IA and ceralasertib.
  • CTPS1-IA was dosed at 30 mg/kg/day subcutaneously days 1-5 of a 7 day cycle for 2 cycles and then days 1-3 for 2 cycles; ceralasertib was dosed at 25 mg/kg/day orally days 2-5 of a 7 day cycle for 2 cycles and then days 1-3 for 2 cycles. Tumour size was assessed by callipers.
  • the graph in Fig. 13 shows the tumour growth in the treated and control mice, demonstrating in vivo synergy between CTPS1-IA and ceralasertib.
  • a CTPS1 inhibitor and an ATR inhibitor for use in the treatment of cancer wherein the CTPS1 inhibitor is defined in any one of Groups A to H.
  • Clause A4 Use of a CTPS1 inhibitor in the manufacture of a medicament for the treatment of cancer with an ATR inhibitor, wherein the CTPS1 inhibitor is defined in any one of Groups A to H.
  • Clause A5. Use of an ATR inhibitor in the manufacture of a medicament for the treatment of cancer with a CTPS1 inhibitor, wherein the CTPS1 inhibitor is defined in any one of Groups A to H.
  • Clause A6 Use of a CTPS1 inhibitor and an ATR inhibitor in the manufacture of a medicament for the treatment of cancer, wherein the CTPS1 inhibitor is defined in any one of Groups A to H.
  • a method of treating cancer in a subject which method comprises administering to the subject a CTPS1 inhibitor and an ATR inhibitor, wherein the CTPS1 inhibitor is defined in any one of Groups A to H.
  • Clause A8. A pharmaceutical composition comprising a CTPS1 inhibitor and an ATR inhibitor, wherein the CTPS1 inhibitor is defined in any one of Groups A to H.
  • Clause A9. A kit of parts comprising: a) a first container comprising a CTPS1 inhibitor; and b) a second container comprising an ATR inhibitor, wherein the CTPS1 inhibitor is defined in any one of Groups A to H. Clause A10.
  • Clause A11 The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause A10, wherein the CTPS1 inhibitor has an IC 50 of 1 uM or lower in respect of human CTPS1 enzyme.
  • Clause A12. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause A11, wherein the CTPS1 inhibitor has an IC 50 of 100nM or lower in respect of human CTPS1 enzyme. Clause A13.
  • Clause A14. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A1 to A13, wherein the CTPS1 inhibitor has a selectivity for human CTPS1 over human CTPS2 of at least 2-fold.
  • Clause A15 The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause A14, wherein the CTPS1 inhibitor has a selectivity for human CTPS1 over human CTPS2 of at least 30-fold.
  • CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause A15 wherein the CTPS1 inhibitor has a selectivity for human CTPS1 over human CTPS2 of at least 60-fold, such as at least 1000-fold.
  • Clause A17 The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A14 to A16, wherein the selectivity of the CTPS1 inhibitor is established using the assay procedure set out in Example 2.
  • CTPS1 inhibitor ATR inhibitor, use, method, composition or kit according to any one of clauses A1 to A17, wherein the CTPS1 inhibitor is a compound of formula (I) wherein 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, or R4 and R5 together with the carbon atom to which they are attached form a C3- 6cycloalkyl or C3-6heterocycloalkyl ring; R6 is H or C1-3alkyl; Ar1
  • CTPS1 inhibitor ATR inhibitor, use, method, composition or kit according to clause A17, wherein the CTPS1 inhibitor is selected from the compounds disclosed in List A or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof. Clause A20.
  • CTPS1 inhibitor is a compound of formula (II): wherein R 1 is C 1-5 alkyl, C 0-2 alkyleneC 3-5 cycloalkyl which cycloalkyl is optionally substituted by CH 3 , C 1-3 alkyleneOC 1-2 alkyl, or CF 3 ; R 3 is H, halo, CH 3 , OC 1-2 alkyl or CF 3 ; or R 3 together with R 5 forms a 5- or 6-membered cycloalkyl or 5 or 6 membered oxygen-containing heterocycloalkyl; R 4 and R 5 are each independently H, halo, C 1-6 alkyl, C 0-2 alkyleneC 3-6 cycloalkyl, C 0- 2 alkyleneC 3-6 heterocycloalkyl, OC 1-6 alkyl, OC 0-2 alkyleneC 3-6 cycloal
  • CTPS1 inhibitor ATR inhibitor, use, method, composition or kit according to clause A20, wherein the CTPS1 inhibitor is selected from the compounds disclosed in List B or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof. Clause A22.
  • CTPS1 inhibitor ATR inhibitor, use, method, composition or kit according to clause A22, wherein the CTPS1 inhibitor is selected from the compounds disclosed in List C or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof. Clause A23.
  • CTPS1 inhibitor ATR inhibitor, use, method, composition or kit according to clause A22, wherein the CTPS1 inhibitor is a compound of formula (IV): wherein: (a) when R4, R5, X, Y and R1 are as follows: 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 R1 are as follows: then R4 and R5 are joined to form the following structures: (d) when W, R 4 , R 5 , X and Y are as follows: then R 1 is methyl or cyclopropyl; and (e) the compound is selected from the group consisting of: and or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof (‘Group D’).
  • group D a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof
  • CTPS1 inhibitor ATR inhibitor, use, method, composition or kit according to clause A24, wherein the CTPS1 inhibitor is selected from the compounds disclosed in List D or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof.
  • CTPS1 inhibitor is a compound of formula (V): (a) when A, V, W, X, Y, Z, R 1 , R 10 and R 12 are as follows: then R 4 and R 5 together with the carbon atom to which they attached form: or (b) when A, V, W, X, Y, Z, R 1 , R 10 and R 12 are as follows: then R4 and R5 together with the carbon atom to which they are attached form: or (c) when A, V, W, X, Y, Z, R 4 , R 5 , R 10 and R 12 are as follows: : then R 1 is or (d) when A, V, W, X, Y, Z, R 4 , R 5 , R 10 and R 12 are as follows: then R 1 is or (e) when A, X, Y, Z, R1, R4 and R5 are as follows: then V, W, R10
  • CTPS1 inhibitor ATR inhibitor, use, method, composition or kit according to clause A26, wherein the CTPS1 inhibitor is selected from the compounds disclosed in List E or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof.
  • A28 The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause A26, wherein the CTPS1 inhibitor is selected from the compounds disclosed in List E or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof.
  • CTPS1 inhibitor ATR inhibitor, use, method, composition or kit according to clause A28, 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 A30.
  • CTPS1 inhibitor ATR inhibitor, use, method, composition or kit according to clause A30, wherein the CTPS1 inhibitor is selected from the compounds disclosed in List G or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof.
  • A32 The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause A30, wherein the CTPS1 inhibitor is selected from the compounds disclosed in List G or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof.
  • Clause A36 The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A1 to A35, wherein the CTPS1 inhibitor is in its free form.
  • CTPS1 inhibitor use, method, composition or kit according any one of clauses A1 to A17, wherein the CTPS1 inhibitor is 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 thereof.
  • CTPS1-IA 4-(2- (cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)tetrahydro-2H- pyran-4-carboxamide
  • CTPS1 inhibitor ATR inhibitor, use, method, composition or kit according to any one of clauses A1 to A17, wherein the CTPS1 inhibitor is N-(5-(6-ethoxypyrazin-2- yl)pyridin-2-yl)-4-(2-(ethylsulfonamido)pyrimidin-4-yl)tetrahydro-2H-pyran-4-carboxamide (‘CTPS1-IB’): or a pharmaceutically acceptable salt thereof.
  • CTPS1-IB N-(5-(6-ethoxypyrazin-2- yl)pyridin-2-yl)-4-(2-(ethylsulfonamido)pyrimidin-4-yl)tetrahydro-2H-pyran-4-carboxamide
  • CTPS1-IB N-(5-(6-ethoxypyrazin-2- yl)pyridin-2-yl)-4-(2-(ethylsulfonamido)pyr
  • A44 The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause A43, wherein the ATR inhibitor has a Ki value for binding to human ATR of 20 nM or less.
  • Clause A45 The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause A44, wherein the ATR inhibitor has a Ki value for binding to human ATR of 5 nM or less.
  • ATR inhibitor has a Ki value for binding to human ATR of 1 nM or less.
  • Clause A47 The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A43 to A46, wherein the Ki value of the ATR inhibitor for binding to human ATR is established using the ATR protein kinase assay procedure set out in Example 3. Clause A48.
  • Clause A51. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause A50, wherein the ATR inhibitor has a selectivity for human ATR over human ATM of >10- fold.
  • Clause A52. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A1 to A51, wherein the ATR inhibitor has a selectivity for human DNA-PK over human DNA-PK of >5-fold.
  • Clause A54. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A1 to A53, wherein the ATR inhibitor has a selectivity for human MTOR over human ATM of >5-fold.
  • Clause A55 The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause A54, wherein the ATR inhibitor has a selectivity for human ATR over human MTOR of >10-fold.
  • Clause A57. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A1 to A56, wherein the ATR inhibitor is selected from ceralasertib, VE821, gartisertib, ETP-46464, AZ20, elimusertib and berzosertib, pharmaceutically acceptable salts thereof and/or pharmaceutically acceptable solvates thereof.
  • CTPS1 inhibitor ATR inhibitor
  • use, method, composition or kit according to clause A57 wherein the ATR inhibitor is selected from ceralasertib or VE821, pharmaceutically acceptable salts thereof and/or pharmaceutically acceptable solvates thereof.
  • ATR inhibitor is selected from ceralasertib or VE821, pharmaceutically acceptable salts thereof and/or pharmaceutically acceptable solvates thereof.
  • CTPS1 inhibitor ATR inhibitor
  • use, method, composition or kit according to clause A58 wherein the ATR inhibitor is ceralasertib: (imino-methyl-[1-[6-[(3R)-3-methylmorpholin-4-yl]-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4- yl]cyclopropyl]-oxo- ⁇ 6-sulfane), pharmaceutically acceptable salts thereof and/or pharmaceutically acceptable solvates thereof.
  • ceralasertib ceralasertib: (imino-methyl-[1-[6-[(3R)-3-methylmorpholin-4-yl]-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4- yl]cyclopropyl]-oxo- ⁇ 6-sulfane), pharmaceutically acceptable salts thereof and/or pharmaceutically acceptable solvates thereof.
  • CTPS1 inhibitor ATR inhibitor
  • use, method, composition or kit according to clause A58 wherein the ATR inhibitor is VE821: (3-amino-6-(4-methylsulfonylphenyl)-N-phenylpyrazine-2-carboxamide), pharmaceutically acceptable salts thereof and/or pharmaceutically acceptable solvates thereof.
  • ATR inhibitor is VE821: (3-amino-6-(4-methylsulfonylphenyl)-N-phenylpyrazine-2-carboxamide), pharmaceutically acceptable salts thereof and/or pharmaceutically acceptable solvates thereof.
  • CTPS1 inhibitor ATR inhibitor
  • use, method, composition or kit according to clause A57 wherein the ATR inhibitor is gartisertib: (2-amino-6-fluoro-N-[5-fluoro-4-[4-[4-(oxetan-3-yl)piperazine-1-carbonyl]piperidin-1-yl]pyridin-3- yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide), pharmaceutically acceptable salts thereof and/or pharmaceutically acceptable solvates thereof.
  • gartisertib (2-amino-6-fluoro-N-[5-fluoro-4-[4-[4-(oxetan-3-yl)piperazine-1-carbonyl]piperidin-1-yl]pyridin-3- yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide), pharmaceutically acceptable salts thereof and/or pharmaceutically acceptable solvates thereof.
  • CTPS1 inhibitor ATR inhibitor
  • use, method, composition or kit according to clause A57 wherein the ATR inhibitor is ETP-46464: (2-methyl-2-[4-(2-oxo-9-quinolin-3-yl-4H-[1,3]oxazino[5,4-c]quinolin-1-yl)phenyl]propanenitrile), pharmaceutically acceptable salts thereof and/or pharmaceutically acceptable solvates thereof.
  • ETP-46464 (2-methyl-2-[4-(2-oxo-9-quinolin-3-yl-4H-[1,3]oxazino[5,4-c]quinolin-1-yl)phenyl]propanenitrile), pharmaceutically acceptable salts thereof and/or pharmaceutically acceptable solvates thereof.
  • CTPS1 inhibitor use, method, composition or kit according to clause A57, wherein the ATR inhibitor is AZ20: ((3R)-4-[2-(1H-indol-4-yl)-6-(1-methylsulfonylcyclopropyl)pyrimidin-4-yl]-3-methylmorpholine), pharmaceutically acceptable salts thereof and/or pharmaceutically acceptable solvates thereof.
  • ATR inhibitor is AZ20: ((3R)-4-[2-(1H-indol-4-yl)-6-(1-methylsulfonylcyclopropyl)pyrimidin-4-yl]-3-methylmorpholine), pharmaceutically acceptable salts thereof and/or pharmaceutically acceptable solvates thereof.
  • CTPS1 inhibitor ((3R)-3-methyl-4-[4-(2-methylpyrazol-3-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-2-yl]morpholine), pharmaceutically acceptable salts thereof and/or pharmaceutically acceptable solvates thereof.
  • ATR inhibitor is elimusertib: ((3R)-3-methyl-4-[4-(2-methylpyrazol-3-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-2-yl]morpholine), pharmaceutically acceptable salts thereof and/or pharmaceutically acceptable solvates thereof.
  • CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause A57 wherein the ATR inhibitor is berzosertib: (3-[3-[4-(methylaminomethyl)phenyl]-1,2-oxazol-5-yl]-5-(4-propan-2-ylsulfonylphenyl)pyrazin-2- amine), pharmaceutically acceptable salts thereof and/or pharmaceutically acceptable solvates thereof.
  • A66 The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A1 to A65, wherein the ATR inhibitor is in its free form.
  • A68. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A1 to A65, wherein the ATR inhibitor is a pharmaceutically acceptable solvate.
  • Clause A69. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A1 to A65, wherein the ATR inhibitor is a pharmaceutically acceptable salt and pharmaceutically acceptable solvate.
  • CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause A73 wherein the CTPS1 inhibitor is CTPS-IA or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof and the ATR inhibitor is VE821.
  • Clause A75 The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause A74, wherein the CTPS1 inhibitor is CTPS-IA or a pharmaceutically acceptable salt thereof and the ATR inhibitor is VE821.
  • Clause A76 The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A1 to A75, wherein the ATR inhibitor is provided in a natural isotopic form. Clause A77.
  • Clause A78. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause A77 wherein the combined administration of the CTPS1 inhibitor and the ATR inhibitor results in a beneficial effect greater than the sum of the beneficial effects of each agent administered alone.
  • Bliss score Bliss 1939; Zheng 2021
  • Clause A80 The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A1 to 79, wherein the ATR inhibitor and the CTPS1 inhibitor are administered to a mammal.
  • Clause A81. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause A80, wherein the ATR inhibitor and the CTPS1 inhibitor are administered to a human.
  • Clause A83. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause A82, wherein the CTPS1 inhibitor and the ATR inhibitor are administered separately.
  • Clause A84. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A1 to 82, wherein the CTPS1 inhibitor and the ATR inhibitor are administered simultaneously.
  • Clause A85 The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause A84, wherein the CTPS1 inhibitor and the ATR inhibitor are co-formulated.
  • Clause A87. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause A86, wherein the CTPS1 inhibitor is administered orally.
  • Clause A88. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A1 to A87, wherein the ATR inhibitor is administered by oral, parenteral, buccal, sublingual, nasal or rectal administration.
  • A90 The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A1 to A89, wherein the CTPS1 inhibitor and ATR inhibitor administered separately, sequentially or simultaneously with one or more further pharmaceutically acceptable active ingredients.
  • CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause A90 wherein the one or more further pharmaceutically acceptable active ingredients are selected from tyrosine kinase inhibitors such as, for example, axitinib, dasatinib, erlotinib, imatinib, nilotinib, pazopanib and sunitinib.
  • tyrosine kinase inhibitors such as, for example, axitinib, dasatinib, erlotinib, imatinib, nilotinib, pazopanib and sunitinib.
  • the CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause A90 wherein the one or more further pharmaceutically acceptable active ingredients are selected from zacitidine, decitabine, or cytarabine.
  • anticancer antibodies such as those selected from the group consisting of anti- CD20 antibodies (such as obinutuzumab, ofatumumab, tositumomab or rituximab) or other antibodies such as olaratumab, daratumumab, necitumumab, dinutuximab, traztuzumab emtansine, pertuzumab, brentuximab, panitumumab, catumaxomab, bevacizumab, cetuximab, traztuzumab and gentuzumab ozogamycin.
  • anti- CD20 antibodies such as obinutuzumab, ofatumumab, tositumomab or rituximab
  • other antibodies such as olaratumab, daratumumab, necitumumab, dinutuximab, traztuzumab emtans
  • Clause A94 The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A1 to A93, administered in combination with radiotherapy.
  • Clause A95 The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A1 to A94, administered in combination with surgery.
  • Clause A96 The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A1 to A95, administered in combination with hyperthermia therapy.
  • Clause A97 The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A1 to A96, administered in combination with cryotherapy.
  • Clause A99. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A1 to A98, wherein the cancer constitutively expresses c-myc.
  • Clause A100. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A1 to A99, wherein the cancer is a non-haematological cancer. Clause A101.
  • CTPS1 inhibitor use, method, composition or kit according to clause A100, wherein the cancer is selected from the group consisting of colorectal cancer, bile duct cancer, endometrial cancer, hepatic cancer, gastric cancer, oesophageal cancer, sarcoma, bladder cancer, pancreatic cancer, ovarian cancer, lung cancer, mesothelioma, melanoma, bone cancer, head and neck cancer, breast cancer, brain cancers, prostate cancer, renal cancer, thyroid cancer and neuroblastoma.
  • the cancer is selected from the group consisting of colorectal cancer, bile duct cancer, endometrial cancer, hepatic cancer, gastric cancer, oesophageal cancer, sarcoma, bladder cancer, pancreatic cancer, ovarian cancer, lung cancer, mesothelioma, melanoma, bone cancer, head and neck cancer, breast cancer, brain cancers, prostate cancer, renal cancer, thyroid cancer and neuroblastoma.
  • CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause A101 wherein the cancer is selected from the group consisting of colorectal cancer, bile duct cancer, endometrial cancer, hepatic cancer, gastric cancer, oesophageal cancer, sarcoma, bladder cancer, pancreatic cancer, ovarian cancer, lung cancer, mesothelioma and melanoma.
  • the cancer is selected from the group consisting of colorectal cancer, bile duct cancer, endometrial cancer, hepatic cancer, gastric cancer and oesophageal cancer.
  • Clause A104 The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A1 to A103, wherein the cancer is a solid tumour.
  • Clause A105 The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to either clause A100 or A104, wherein the cancer is a non-haematological cancer is selected from prostate cancer, pancreatic cancer, ovarian cancer, lung cancer, renal cancer, colorectal cancer or breast cancer.
  • Clause A106 The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A1 to A99, wherein the cancer is a haematological cancer.
  • haematological cancer is selected from the list consisting of acute myeloid leukemia, angioimmunoblastic T-cell lymphoma, B-cell acute lymphoblastic leukemia, Sweet syndrome, T-cell non-Hodgkins lymphoma (including natural killer/T-cell lymphoma, adult T-cell leukaemia/lymphoma, enteropathy type T-cell lymphoma, hepatosplenic T-cell lymphoma and cutaneous T-cell lymphoma), T-cell acute lymphoblastic leukemia, B-cell non- Hodgkins lymphoma (including Burkitt lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma), hairy cell leukemia, Hodgkin lymphoma, lymphoblastic lymphoma, lymphoplasmacytic lymph
  • CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause A107 wherein the haematological cancer is selected from the list consisting of B-cell non-Hodgkins lymphoma (including Burkitt lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma), multiple myeloma and plasma cell myeloma.
  • B-cell non-Hodgkins lymphoma including Burkitt lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma
  • multiple myeloma and plasma cell myeloma.
  • the CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause A108 wherein the haematological cancer is T cell lymphoma.
  • Clause A116. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A1 to A115, for administration to a subject identified as having a cancer expected to be susceptible to treatment by a CTPS1 inhibitor and an ATR inhibitor.
  • Clause A118. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A1 to A117, wherein the CTPS1 inhibitor and ATR inhibitor are administered orally.
  • Clause A119 The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A1 to A118, wherein the CTPS1 inhibitor is in a solid pharmaceutical composition.
  • Clause A121. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A1 to A120, wherein the CTPS1 inhibitor is in a solid pharmaceutical composition and the ATR inhibitor is in a solid pharmaceutical composition.
  • Clause A122. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A1 to A121, wherein the CTPS1 inhibitor is administered orally in a solid pharmaceutical composition.

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Abstract

The invention provides inter alia methods of treating cancer comprising administering to a subject a cytidine triphosphate synthase 1 (CTPS1) inhibitor and a ataxia telangiectasia and Rad3-related protein (ATR) inhibitor.

Description

COMBINATION OF A CTPS1 INHIBITOR AND A ATR INHIBITOR IN CANCER THERAPY
Field of the invention
The invention relates to combinations, in particular the combination of a CTPS1 inhibitor and an ATR inhibitor, pharmaceutical compositions and kits comprising such combinations which may be of use in the treatment of cancer and to related aspects.
Background of the invention
Cancer can affect multiple cell types and tissues but the underlying cause is a breakdown in the control of cell division. This process is highly complex, requiring careful coordination of multiple pathways, many of which remain to be fully characterised. Cell division requires the effective replication of the cell’s DNA and other constituents. Interfering with a cell’s ability to replicate by targeting nucleic acid synthesis has been a core approach in cancer therapy for many years. Examples of therapies acting in this way are 6-thioguanine, 6-mecaptopurine, 5- fluorouracil, cytarabine, gemcitabine and pemetrexed.
Cancer therapeutics against a wide array of specific targets are available. Small molecule targeted therapy drugs are generally inhibitors of enzymatic domains on mutated, overexpressed, or otherwise critical proteins within the cancer cell. Monoclonal antibody therapy is another strategy in which the therapeutic agent is an antibody which specifically binds to a protein on the surface of the cancer cells.
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 pyrimidine synthesis pathway is the enzyme cytidine triphosphate synthase (CTPS) which catalyses the conversion of UTP to CTP (van Kuilenburg 2000). CTPS also has two isoforms in humans (CTPS1 and CTPS2; see Fig. 1). 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).
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 CTPS inhibitors that inhibit both CTPS1 and CTPS2 have been developed for oncology indications up to phase l/ll 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, gemcitabine), which are converted to the active triphosphorylated metabolite by the kinases involved in pyrimidine biosynthesis: uridine/cytidine kinase, nucleoside monophosphatekinase (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.
The DNA damage response (DDR) is a complex cellular pathway that is activated in response to direct damage to a cell’s DNA, and in situations where DNA damage is likely to occur, for example nucleotide deficiency, stalled replication forks and other causes of replication stress. DDR activation is a feature of different cancer types, and its exploitation is a current area of interest in oncology drug development (Gorecki 2021). The biological purpose of the DDR pathway is to prevent cells entering the cell cycle whilst harbouring DNA damage, by inducing a cell cycle arrest and thus providing the opportunity to carry out DNA repair ensuring an error free copy of the genome is replicated once the cell cycle resumes.
The DDR pathway has been shown to be activated across a diverse range of cancer types. Inhibition of this pathway may be of therapeutic benefit in cancer. The role of the DDR pathway is to pause cell cycle and allow time for DNA damage to be repaired, such that inhibition of this pathway may result in cancer cells entering mitosis prematurely resulting in mitotic catastrophe and cell death (Gorecki 2021). Small molecule inhibitors have been developed against different components of the DDR pathway, including ATR (ataxia telangiectasia and Rad3-related protein, also commonly referred to as FRAP-related protein 1 (FRP1)) and CHEK1 (checkpoint kinase 1 , commonly also referred to as Chk1).
Multiple ATR inhibitors are currently being tested in clinical trials (clinicaltrials.gov, accessed November 2021 - January 2022).
Single agent inhibition of ATR has delivered modest efficacy across different tumour types. Most of the currently active clinical trials are studying combinations of an inhibitor with chemotherapy, radiotherapy, other targeted agents such as PARP inhibitors or immunomodulatory drugs such as immune checkpoint inhibitors.
ATM loss has been reported to render cancer cells more sensitive to ATR inhibition, such that mutation or genomic deletion of ATM or loss of ATM protein expression may serve as biomarkers of response to ATR inhibitors (Karnitz 2015). Some clinical trials of ATR inhibitors have preselected patients with ATM loss. Other potential biomarkers of response to ATR inhibition have been reported, including genomic alterations associated with replication stress (including CCNE1 amplification, MYC amplification and FBXW7 mutation) and markers of double stranded DNA breakage such as yH2AX (Cleary 2020). Genomic alterations associated with replication stress have previously been used to select patients for clinical trials of ATR inhibitors.
Sun 2022 use CRISPR technology to demonstrate that combined inactivation of CTPS1 and ATR is synthetically lethal to MYC-overexpressing cancer cells. There remains a need for new approaches to cancer therapies, such approaches may demonstrate high in vivo efficacy, reduction in the dose required for effect in vivo, an improved safety profile/reduced side effects, or the like.
Summary of the invention
The invention provides a CTPS1 inhibitor for use in the treatment of cancer with an ATR inhibitor, wherein the CTPS1 inhibitor is defined in any one of Groups A to H (as further described herein).
In a further aspect the invention provides an ATR inhibitor for use in the treatment of cancer with a CTPS1 inhibitor, wherein the CTPS1 inhibitor is defined in any one of Groups A to H.
In a further aspect the invention provides a CTPS1 inhibitor and an ATR inhibitor for use in the treatment of cancer.
In a further aspect the invention provides the use of a CTPS1 inhibitor in the manufacture of a medicament for the treatment of cancer with an ATR inhibitor, wherein the CTPS1 inhibitor is defined in any one of Groups A to H.
In a further aspect the invention provides the use of an ATR inhibitor in the manufacture of a medicament for the treatment of cancer with a CTPS1 inhibitor, wherein the CTPS1 inhibitor is defined in any one of Groups A to H.
In a further aspect the invention provides the use of a CTPS1 inhibitor and an ATR inhibitor in the manufacture of a medicament for the treatment of cancer, wherein the CTPS1 inhibitor is defined in any one of Groups A to H.
In a further aspect the invention provides a method of treating cancer in a subject which method comprises administering to the subject a CTPS1 inhibitor and an ATR inhibitor, wherein the CTPS1 inhibitor is defined in any one of Groups A to H.
In a further aspect the invention provides a pharmaceutical composition comprising a CTPS1 inhibitor and an ATR inhibitor, wherein the CTPS1 inhibitor is defined in any one of Groups A to H.
In a further aspect the invention provides a kit of parts comprising: a) a first container comprising a CTPS1 inhibitor; and b) a second container comprising an ATR inhibitor, wherein the CTPS1 inhibitor is defined in any one of Groups A to H.
In a further aspect the invention provides a CTPS1 inhibitor for use in the treatment of cancer with an ATR inhibitor, wherein the ATR inhibitor is ceralasertib or VE821 , a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof.
In a further aspect the invention provides an ATR inhibitor for use in the treatment of cancer with a CTPS1 inhibitor, wherein the ATR inhibitor is ceralasertib or VE821 , a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof. In a further aspect the invention provides a CTPS1 inhibitor and an ATR inhibitor for use in the treatment of cancer, wherein the ATR inhibitor is ceralasertib or VE821 , a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof.
In a further aspect the invention provides a CTPS1 inhibitor in the manufacture of a medicament for the treatment of cancer with an ATR inhibitor, wherein the ATR inhibitor is ceralasertib or VE821 , a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof.
In a further aspect the invention provides the use of an ATR inhibitor in the manufacture of a medicament for the treatment of cancer with a CTPS1 inhibitor, wherein the ATR inhibitor is ceralasertib or VE821, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof.
In a further aspect the invention provides the use of a CTPS1 inhibitor and an ATR inhibitor in the manufacture of a medicament for the treatment of cancer, wherein the ATR inhibitor is ceralasertib or VE821 , a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof.
In a further aspect the invention provides a method of treating cancer in a subject which method comprises administering to the subject a CTPS1 inhibitor and an ATR inhibitor, wherein the ATR inhibitor is ceralasertib or VE821, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof.
In a further aspect the invention provides a pharmaceutical composition comprising a CTPS1 inhibitor and an ATR inhibitor, wherein the ATR inhibitor is ceralasertib or VE821 , a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof.
In a further aspect the invention provides a kit of parts comprising: a) a first container comprising a CTPS1 inhibitor; and b) a second container comprising an ATR inhibitor, wherein the ATR inhibitor is ceralasertib or VE821 , a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof.
Summary of the sequences
SEQ ID NO: 1 FLAG-HiSs-tag
SEQ ID NO: 2 FLAG-His-Avi tag
SEQ ID NO: 3 ATR target peptide example
SEQ ID NO: 4 ATM target peptide example
SEQ ID NO: 5 DNA-PK target peptide example
Summary of the figures
Fig. 1 De novo CTP production pathway
Fig. 2 Impact of deletion of different genes in the pyrimidine synthesis pathway Fig. 3 Cell cycle analysis indicating that exposure to CTPS1-IA causes cancer cells to accumulate in S phase (mantle cell lymphoma lines)
Fig. 4 Cell cycle analysis indicating that exposure to CTPS1-IA causes cancer cells to accumulate in S phase (myeloma lines)
Fig. 5 Cell cycle analysis indicating that exposure to CTPS1-IA causes cancer cells to accumulate in S phase (further myeloma lines)
Fig. 6 Demonstration of increased activated CHEK1 (pCHEKI) following exposure to CTPS1-IA in 4 myeloma cell lines.
Fig. 7 Bliss scores for 3-11 myeloma cell lines exposed to the CTPS1 inhibitor CTPS1- IA in combination with either a standard of care drug or an ATR inhibitor (ceralasertib or VE821)
Fig. 8 Percentage cell death myeloma cell lines exposed to the CTPS1 inhibitor CTPS1- IA combined with an ATR inhibitor (VE821); representative data from 7 cell lines tested
Figs. 9A to 9C Percentage cell death in 6 mantle cell lymphoma cell lines exposed to the CTPS1 inhibitor CTPS1-IA combined with an ATR inhibitor (VE821)
Figs. 10A to 10B Percentage cell death in primary mantle cell lymphoma samples exposed to the CTPS1 inhibitor CTPS1-IA combined with an ATR inhibitor (VE821); representative data from 11 samples tested
Fig. 11 Bliss scores for 36 human cancer cell lines exposed to the CTPS1 inhibitor CTPS1-IA in combination with an ATR inhibitor (ceralasertib)
Fig. 12 A comparison of Bliss scores for 4 human colorectal cancer cell lines exposed to an ATR inhibitor (ceralasertib) in combination with either the CTPS1 inhibitor CTPS1-IA or a chemotherapy drug (irinotecan); in all 4 cell lines tested, synergy observed with the ceralasertib CTPS1-IA combination exceeded that observed with the ceralasertib chemotherapy combination
Fig. 13 In vivo tumour growth studies performed investigating the effects of CTPS1-IA and ceralasertib using a human cancer cell line
Detailed description of the invention
CTPS1 inhibitors
In one aspect of the invention there is provided a CTPS1 inhibitor for use in the treatment of cancer with an ATR inhibitor.
A CTPS1 inhibitor, as used herein, is an agent which directly inhibits the enzymatic activity of the CTPS1 enzyme through interaction with the enzyme. Direct inhibition of the CTPS1 enzyme may be quantified using any suitable assay procedure, though is suitably performed using the procedure set out in Example 1. CTPS1 inhibitors may demonstrate an IC50 of 10 uM or lower, such as 1uM or lower, 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 1 uM or lower, especially 100nM or lower, in respect of CTPS1 enzyme using the assay procedure set out in Example 1 .
CTPS1 inhibitors may demonstrate a selectivity for CTPS1 over CTPS2. Suitably the inhibitors demonstrate a selectivity of at least 2-fold, such as at least 30-fold, especially at least 60-fold and in particular a least 1000-fold. CTPS1 inhibitors of particular 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 a least 1000-fold using the assay procedure set out in Example 2. Desirably the selectivity is for human CTPS1 over human CTPS2.
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.
Suitably the CTPS1 inhibitor may be selected from the following compounds:
A compound of formula (I)
Figure imgf000007_0001
wherein
R1 is Ci-salkyl, Co^alkyleneCs-scycloalkyl which cycloalkyl is optionally substituted by CH3, Ci-3alkyleneOCi-2alkyl, or CF3;
R3 is H, CH3, halo, OCi-2alkyl or CF3;
R4 and Rs are each independently H, Ci-salkyl, Co-2alkyleneC3-6cycloalkyl, Co-2alkyleneC3- sheterocycloalkyl, Ci-3alkyleneOCi-3alkyl, Ci-ealkylOH or Ci-ehaloalkyl, or R4 and Rs together with the carbon atom to which they are attached form a C3- scycloalkyl or Cs-sheterocycloalkyl ring;
Rs is H or Ci-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;
R10 is H, halo, Ci-3alkyl, OCi-2alkyl, Ci-2haloalkyl, OCi-2haloalkyl or CN;
R11 is H, F, Cl, CH3, ethyl, OCH3, CF3, OCF3 or CN;
R12 is attached to Ar2 in the meta or ortho position relative to Ar1 and R12 is H, halo, C1- 4alkyl, C2-4alkynyl, C(=O)Ci-2alkyl, Co^alkyleneCs-scycloalkyl, OCi-4alkyl, C1- salkyleneOCi-salkyl, Ci-4haloalkyl, OCi-4haloalkyl, CN, OCo^alkyleneCs-scycloalkyl, OCH2CH2N(CH3)2, OH, Ci.4alkylOH, NR23R24, SO2CH3, C(O)N(CH3)2, NHC(O)Ci-3alkyl, or a Cs-sheterocycloalkyl 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+-0‘ );
R23 is H or Ci-2alkyl;
R24 is H or Ci-2alkyl; or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof (‘Group A’).
More suitably the CTPS1 inhibitor is selected from the following (‘List A’) compounds: N-((2-(cyclopropanesulfonamido)thiazol-4-yl)methyl)-5-phenylpicolinamide;
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;
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);
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- 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- 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;
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;
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;
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;
5-(6-chloropyrazin-2-yl)-N-(2-(2-(cyclopropanesulfonamido)thiazol-4-yl)propan-2- yl)picolinamide;
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;
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- 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- 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;
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,T-biphenyl]- 4-carboxamide;
N-(2-(2-(cyclopropanesulfonamido)thiazol-4-yl)propan-2-yl)-4-(6-ethylpyrazin-2-yl)-2- fluorobenzamide;
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- 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;
N-(2-(2-(cyclopropanesulfonamido)thiazol-4-yl)propan-2-yl)-4-(6-ethoxypyrazin-2-yl)-2-
(trifluoromethyl)benzamide;
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;
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;
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- 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;
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- 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;
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);
N-(1-(2-(cyclopropanesulfonamido)thiazol-4-yl)propyl)-4-(5-fluoropyridin-3-yl)benzamide (S enantiomer);
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);
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)- 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;
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-
(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- 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;
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- (trifluoromethyl)pyrazin-2-yl)benzamide; N-(1-(2-(cyclopropanesulfonamido)thiazol-4-yl)-3-methoxypropyl)-4-(6-ethoxypyrazin-2-yl)-2- fluorobenzamide; 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; 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- 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 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):
Figure imgf000012_0001
wherein 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 membered 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 6 membered oxygen-containing heterocycloalkyl, or R4 and R5 together 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; or R4 is O and R5 is absent; R6 is H or C1-3alkyl, 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 is 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; 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 C2alkylene 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, 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; 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 acceptable solvate thereof (‘Group B’). More suitably the CTPS1 inhibitor is selected from the following (‘List B’) compounds: 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;
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;
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;
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;
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- 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;
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;
2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(3'-methoxy-[1 , 1 '-bi pheny l]-4-y l)-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;
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- methylpropanamide;
2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(5-(6-(trifluoromethyl)pyrazin-2- yl)pyridin-2-yl)propanamide;
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;
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- (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 ;
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- 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;
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- 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; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(4-(6-morpholinopyrazin-2- yl)phenyl)propanamide;
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;
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- 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;
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;
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;
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;
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- 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;
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;
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;
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;
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;
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;
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- 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- yl)phenyl)butanamide;
(R)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methoxy-N-(4-(6-methoxypyrazin-2- yl)phenyl)acetamide; (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;
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- 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;
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;
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- 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- 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;
2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(2-fluoro-4-(5-fluoropyridin-3-yl)phenyl)-2- methylpropanamide;
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;
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- 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;
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- 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;
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- 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;
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;
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;
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;
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- 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;
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- 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;
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;
2-(cyclopropanesulfonamido)-N-(5-(6-(trifluoromethyl)pyrazin-2-yl)pyridin-2-yl)-5,6-dihydro-4H- cyclopenta[d]thiazole-4-carboxamide;
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; 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- 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;
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;
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- 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;
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;
2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)butanamide (racemic);
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;
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- 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- 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;
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;
(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- 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;
2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(5-(difluoromethoxy)pyridin-3-yl)-2- fluorophenyl)butanamide;
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;
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- 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;
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;
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;
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- 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;
N-(5'-chloro-5-fluoro-[3,3'-bipyridin]-6-yl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2- methylpropanamide;
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;
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- 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;
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;
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;
N-(4'-(tert-butyl)-[1,T-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;
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- methylpropanamide;
2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-methoxy-5-methylpyridin-3-yl)phenyl)-2- methylpropanamide;
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;
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- 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;
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;
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- 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;
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- methylpropanamide;
2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(4-(6-(trifluoromethyl)pyridin-2- yl)phenyl)propanamide;
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;
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- 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;
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- 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;
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- 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;
N-(4-(5-chloropyridin-3-yl)-3-methylphenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2- methylpropanamide;
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;
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- 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;
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;
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- 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;
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;
2-(2-(cyclobutanesulfonamido)thiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2- methylpropanamide;
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;
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- 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;
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;
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- 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;
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;
2-amino-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-ethoxypyrazin-2- yl)phenyl)acetamide;
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;
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- 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; 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;
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- 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;
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)-
2-methylpropanamide;
N-(4-(5-chloropyridin-3-yl)-2-(trifluoromethyl)phenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4- yl)-2-methylpropanamide;
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;
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- 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; 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- 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;
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- 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;
2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(2-isopropyl-4-(6-(trifluoromethyl)pyrazin-2- yl)phenyl)-2-methylpropanamide;
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;
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- 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;
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- 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;
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- 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;
2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-hydroxypyrazin-2-yl)phenyl)-2- methylpropanamide;
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;
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;
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- 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;
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;
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- 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;
2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(2-fluoro-4-(6-(trifluoromethyl)pyrazin-2- yl)phenyl)-4-methoxybutanamide;
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;
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- 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; 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- 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;
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- 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;
(R)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(2-fluoro-4-(5-(trifluoromethyl)pyridin-3- yl)phenyl)butanamide;
(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)-/V-(5-(6-(trifluoromethyl)pyrazin-2- yl)pyridin-2-yl)acetamide hydrochloride;
2-Amino-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-/V-(2-fluoro-4-(6-(trifluoromethyl)pyrazin-
2-yl)phenyl)acetamide;
2-Amino-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-/\/-(4-(6-ethoxypyrazin-2-yl)-2- fluorophenyl)acetamide hydrochloride;
2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-2-(dimethylamino)-/\/-(2-fluoro-4-(6- (trifluoromethyl)pyrazin-2-yl)phenyl)acetamide;
2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-2-(dimethylamino)-/\/-(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;
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; 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- 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;
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)- 2-methylpropanamide;
N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2-methyl-2-(2-(methylsulfonamido)thiazol-4- yl)propanamide;
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;
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- 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;
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)-/V-(4-(6-(ethylamino)pyrazin-2- yl)phenyl)butanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)-3-fluoropyridin-2-yl)-2- m ethoxy aceta m i d e ;
2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2- m ethoxy aceta m i d e ;
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- (trifluoromethyl)phenyl)-2-methoxyacetamide;
N-(2-chloro-4-(6-ethoxypyrazin-2-yl)phenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2- m ethoxy aceta m i d e ;
N-(2-cyano-4-(6-ethoxypyrazin-2-yl)phenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2- m ethoxy aceta m i d e ;
N-(2-fluoro-4-(6-(trifluoromethyl)pyrazin-2-yl)phenyl)-2-methoxy-2-(2-
(methylsulfonamido)thiazol-4-yl)acetamide;
2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2,6-difluorophenyl)-2- m ethoxy aceta m i d e ;
2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2- (trifluoromethoxy)phenyl)-2-methoxyacetamide;
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);
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- 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;
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- 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 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):
Figure imgf000036_0001
wherein 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; 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; 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 C3-6cycloalkyl 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; 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; 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)-: 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; 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 acceptable solvate thereof (‘Group C’). 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; 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- 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- 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; 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- 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;
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;
2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-(2,2,2-trifluoroethoxy)pyrazin-2- yl)phenyl)acetamide;
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;
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- 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;
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;
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- 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;
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- methylpropanamide;
2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(2-fluoro-4-(6-isopropoxypyrazin-2-yl)phenyl)- 2-methylpropanamide;
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;
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- 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;
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)-
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; 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- 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;
2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(5-ethoxypyridin-3-yl)phenyl)-2- methylpropanamide;
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;
2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-2-methyl-N-(3'-(trifluoromethyl)-[1,T-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- methylpropanamide;
2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(3'-ethoxy-[1 , 1 b i ph eny l]-4-y l)-2- methylpropanamide;
2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-2-methyl-N-(4-(6-(trifluoromethyl)pyrazin-2- yl)phenyl)propanamide;
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- 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;
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- 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;
N-(5-(6-ethoxypyrazin-2-yl)-3-fluoropyridin-2-yl)-2-methyl-2-(2-(methylsulfonamido)pyrimidin-4- yl)propanamide;
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;
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- 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;
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- 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- 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;
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;
2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(2-fluoro-4-(6-(trifluoromethyl)pyrazin-2- yl)phenyl)butanamide;
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;
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;
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;
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- 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;
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)- 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;
4-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2- yl)tetrahydro-2H-pyran-4-carboxamide;
2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-/\/-(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;
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;
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- 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;
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- 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; 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- yl)cyclopentane-1 -carboxamide;
4-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)tetrahydro-
2H-pyran-4-carboxamide;
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;
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) 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;
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) 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- 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; 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- yl)butanamide;
2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-methoxypyrazin-2-yl)pyridin-2- yl)butanamide;
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;
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-
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;
2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2- m ethoxy aceta m i d e ;
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)- 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;
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;
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;
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;
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;
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- 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- 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- 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;
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- 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;
2-(6-(cyclopropanesulfonamido)pyrazin-2-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2- fluorobutanamide;
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- m ethoxy aceta m i d e ;
2-(6-(cyclopropanesulfonamido)pyrazin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2- m ethoxy aceta m i d e ;
2-(6-(cyclopropanesulfonamido)pyrazin-2-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2- methoxypropanamide;
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- 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-
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;
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;
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; N-(2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)butan-2-yl)-4-(6-ethoxypyrazin-2-yl)-2- fluorobenzamide; 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; 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)- 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 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 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. More suitably, the CTPS1 inhibitor is a compound of formula (IV):
Figure imgf000048_0001
wherein: (a) when R4, R5, X, Y and R1 are as follows:
Figure imgf000049_0001
then W is N, CH or CF; (b) when R4, R5, X, W and R1 are as follows:
Figure imgf000049_0002
then Y is CH or N; (c) when W, X, Y and R1 are as follows:
Figure imgf000049_0003
then R4 and R5 are joined to form the following structures:
Figure imgf000049_0004
(d) when W, R4, R5, X and Y are as follows:
Figure imgf000049_0005
then R1 is methyl or cyclopropyl; and (e) the compound is selected from the group consisting of:
Figure imgf000050_0001
and
Figure imgf000050_0002
or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof (‘Group D’). 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; 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- 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; 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- 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; (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; or a pharmaceutically acceptable salt and/or a pharmaceutically acceptable solvate thereof. Such CTPS1 inhibitors are those disclosed in PCT publication number WO2020083975 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 selected from P112, P113, P114, P115, P136, P137, P139, P143, P145, P165, P166, P186, P197, P206 and P207 or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof. Alternatively, the CTPS1 inhibitor is a compound of formula (V):
Figure imgf000051_0001
(a) when A, V, W, X, Y, Z, R1, R10 and R12 are as follows:
Figure imgf000051_0002
then R4 and R5 together with the carbon atom to which they attached form:
Figure imgf000051_0003
or (b) when A, V, W, X, Y, Z, R1, R10 and R12 are as follows:
Figure imgf000051_0004
then R4 and R5 together with the carbon atom to which they are attached form:
Figure imgf000051_0005
or (c) when A, V, W, X, Y, Z, R4, R5, R10 and R12 are as follows:
Figure imgf000051_0006
then R1 is
Figure imgf000052_0001
or (d) when A, V, W, X, Y, Z, R4, R5, R10 and R12 are as follows:
Figure imgf000052_0002
, then R1 is
Figure imgf000052_0003
or (e) when A, X, Y, Z, R1, R4 and R5 are as follows:
Figure imgf000052_0004
, then V, W, R10 and R12 are:
Figure imgf000052_0005
or (f) when A, V, W, R1, R4, R5, R10 and R12 are as follows:
Figure imgf000052_0006
, then Z, X and Y are
Figure imgf000052_0007
or (g) when A, V, W, R1, R4, R5, R10 and R12 are as follows:
Figure imgf000052_0008
then Z, X and Y are
Figure imgf000053_0001
or (h) when A, V, W, R1, R4, R5, R10 and R12 are as follows
Figure imgf000053_0002
then Z, X and Y are
Figure imgf000053_0003
or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof (‘Group E’). More suitably the CTPS1 inhibitor is selected from the following (‘List E’) compounds: 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- 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; 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2- yl)cyclobutane-1-carboxamide; 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; 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- 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; 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- 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; 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- 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; 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 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. Alternatively, the CTPS1 inhibitor is a compound of formula (VI):
Figure imgf000054_0001
wherein ring B is selected from the group consisting of:
Figure imgf000054_0002
(B-a) wherein X, Y and Z are as defined below; and
Figure imgf000055_0001
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):
Figure imgf000055_0002
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)-; 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 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: R1aa is NR32aR33a; R1ba is 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; 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, 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 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- 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 the C3-6heterocycloalkyl 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 C1-3alkyl or OC1-3alkyl; or R4aa and R5aa 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)2R29a; or R4ba and R5ba are each independently H, C1-6alkyl, C1-6alkylOH, C1-6haloalkyl, C0- 2alkyleneC3-6cycloalkyl, C0-2alkyleneC3-6heterocycloalkyl, C1-3alkyleneOC1-3alkyl, or R4ba and R5ba together with the carbon atom to which they are attached form a C3-6cycloalkyl or C3-6heterocycloalkyl; and when 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; 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, 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- 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 C4-6heterocycloalkyl; R22a is H or CH3; R23a is H or C1-2alkyl; and R24a is H or C1-2alkyl R29a 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; R32a is C1-3alkyl and R33 is C1-3alkyl; or R32a and R33a together with the nitrogen atom to which they are attached form a C3- 5heterocycloalkyl; wherein R1a is R1aa; and/or R4a and R5a are R4aa and R5aa; and/or Aa is Aaa; and wherein when B is (B-bc) and R3b3c is R3b, the compound of formula (VI) is a compound of formula (VI-b):
Figure imgf000057_0001
wherein: Ab is Aab or Abb; wherein: Aab is -NR6bCH2- or -NR6b-; Abb is -NR6bC(=O)-; R1b is R1ab or R1bb; wherein: R1ab is NR32bR33b; R1bb is C1-5alkyl, C0-2alkyleneC3-5cycloalkyl which cycloalkyl is optionally substituted by CH3, C1-3alkyleneOC1-2alkyl, or CF3; R3b is H, halo, CH3, OC1-2alkyl or CF3; or R3b together with R5bb forms a 5- or 6-membered cycloalkyl or 5 or 6 membered oxygen-containing heterocycloalkyl; 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 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 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, 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 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 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 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 or NR21bR22b, or R4bb is H and R5bb together with R3b form a 5- or 6-membered cycloalkyl 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; 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 R4bb 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; R11b is H, F, Cl, CH3, ethyl, OCH3, CF3, OCF3 or CN, or R11b, when in the ortho-position to group Ab, together with R6b are a C2alkylene chain forming a 5-membered ring; R12b is attached to Ar2b in the ortho or meta position relative to Ar1b and R12b 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, 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-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; 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; 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; 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 formula (VI-c):
Figure imgf000060_0001
wherein: Ac is Aac or Abc; wherein: Aac is -CH2NR6c-; Abc is -C(=O)NR6c-; R1c is R1ac or R1bc; wherein: R1ac is NR32cR33c; 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; 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, C1-3haloalkyl, 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 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 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 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 C3- 6heterocycloalkyl comprising one nitrogen atom, wherein said nitrogen atom is substituted by -S(O)2R29c; or R4bc and R5bc are each independently H, C1-6alkyl, C0-2alkyleneC3-6cycloalkyl, C0- 2alkyleneC3-6heterocycloalkyl, C1-3alkyleneOC1-3alkyl, C1-6alkylOH or C1- 6haloalkyl, or R4bc and R5bc together with the carbon atom to which they are attached form a C3-6cycloalkyl or C3-6heterocycloalkyl ring; R6c is H or C1-3alkyl; Ar1c is a 6-membered aryl or heteroaryl; Ar2c is a 6-membered aryl or heteroaryl and is attached to Ar1c in the para position relative to group Ac; R10c is H, halo, C1-3alkyl, OC1-2alkyl, C1-2haloalkyl, OC1-2haloalkyl or CN; R11c is H, F, Cl, CH3, ethyl, OCH3, CF3, OCF3 or CN; 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 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; 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 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: 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 (‘Group F'). 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; 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- 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); 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; 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- 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; 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- 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; 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- 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; 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; 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; 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- (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; 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- (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); 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- (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); 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); 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); 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- (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; 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 clauses 1 to 204 of WO2020245665 or a pharmaceutically acceptable salt and/or pharmaceutically 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 thereof. Alternatively, the CTPS1 inhibitor is a compound of formula (VII):
Figure imgf000065_0001
wherein 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 -NHC(=O)-; B is
Figure imgf000065_0002
or
Figure imgf000065_0003
; 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; 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; 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-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: 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 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 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 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 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- 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- 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; 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, 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-: 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; 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 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 acceptable solvate thereof (‘Group G’). 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 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 disclosed 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):
Figure imgf000067_0001
wherein 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 -NHC(=O)-; B is
Figure imgf000067_0002
or
Figure imgf000067_0003
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; 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; 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-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: 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 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 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 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 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- 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- 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; 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, 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-: 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; 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 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 acceptable solvate thereof (‘Group H'). 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; 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 disclosed therein. 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 acceptable solvate thereof, in particular a compound selected from P285 and P287 or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof. 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 ‘CTPS-IA’):
Figure imgf000070_0001
or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof. 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 ‘CTPS-IB'):
Figure imgf000070_0002
or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof. The compounds described above (and methods for making these compounds) are disclosed in PCT publication numbers WO2019106156, WO2019180244, WO2019106146, WO2019179652, WO2020245665, WO2020245664, WO2021053403, WO2021053402 or WO2020083975. The CTPS1 inhibitor may be a compound of formula (IX):
Figure imgf000070_0003
or a pharmaceutically acceptable salt thereof, wherein:
R1 is selected from Ci-6 aliphatic; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; and a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring hairing 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with q instances of RA;
Ring A is selected from phenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 7-11 membered fused bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
Figure imgf000071_0001
wherein each of RL, RL‘, and RL" is independently hydrogen, -CM, halogen, or an optionally substituted group selected from Ci^ aliphatic; phenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two of RL. RL‘. and RL” groups are taken together with the atoms to whi ch each is attached, to form an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms i ndependently selected from nitrogen, oxygen, and sulfur; or any one of RL, RL , and R17, together with R® forms a 7-10 membered saturated or partially unsaturated fused bicyclic ring;
Ring B is selected from phenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms 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 5-11 membered saturated or partially unsaturated fused, bridged, or spiro, bicyclic carbocyclic ring; a 7-11 membered fused bicyclic aryl ring; a 7-11 membered saturated or partially unsaturated fused, bridged, or spiro, bicydic heterocydic ring having 1-4 heteroatoms independently sdected from nitrogen, oxygen, and sulfur; and a 7-11 membered fused bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur:
Ring C is selected from a phenyl, 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 7-11 membered fused bicyclic heteroaiyl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or the bond between Ring B and Ring C is absent, and Ring B and Ring C together form a 7-11 membered saturated or partially unsaturated fused, bridged, or spiro, bicyclic carbocyclic ring; a 7-11 membered fused bicyclic aryl ring; a 7-11 membered saturated or partially unsaturated fused, bridged, or spiro, bicyclic heterocydic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-11 membered fused bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R\ RB, and Rc is independently oxo, halogen, -CN, -Nth, -OR, -
Figure imgf000072_0001
optionally substituted group selected from CM aliphatic; phenyl; naphthalenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, phosphorous, silicon and sulfur; or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic heteroaiyl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-8 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-10 membered saturated or partially unsaturated spirocydic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 6-11 membered saturated or partially unsaturated bi cycl ic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with r instances of R and s instances of RD, or two Rc groups are optionally taken together with the atoms to which each RC is attached, to form an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-7 membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
Figure imgf000073_0001
each R is independently hydrogen, -CN, halogen, or an optionally substituted group selected from aliphatic; phenyl; naphthdenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-8 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-10 membered saturated or partially unsaturated spirocydic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-11 membered saturated or partially unsaturated bicyclic carbocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R groups are taken together with the atoms to which each R is attached, to form an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfiir; or m is O, 1, or 2; n is 0, 1, or 2; p is 0, 1 , or 2; each q is independently 0, 1 , 2, 3, or 4; each r is independently 0, 1, 2, 3, or 4; and each sis independently 0, 1, 2, 3, or 4; provided that when:
R1 is Ci-6 aliphatic or a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; the R group of the sulfonamide moiety is hydrogen or para-methoxybenzyl;
Figure imgf000074_0001
Figure imgf000074_0002
and the R1- and Rv or RL and RL groups are not taken together with the atoms to which each is attached to form an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfiir, or L is
Figure imgf000074_0003
Ring B is phenyl or a 6-membered monocyclic heteroaiyl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and
Ring C is phenyl or a 6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur and Is attached to Ring B in the para position relative to the L group; them Ring A and its RA substituents are other than
Figure imgf000074_0004
where * denotes attachment to the
Figure imgf000074_0005
Figure imgf000074_0006
moiety and ** denotes attachment to the
Figure imgf000074_0007
moiety, or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof. Such CTPS1 inhibitors are disclosed in PCT publication number WO2022087634 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 claims 1 to 31 of WO2022087634 or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof. A CTPS1 inhibitor may be a compound selected from compounds I-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 compounds Z-1 to Z-10 of WO2022087634, or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof. In one embodiment the CTPS1 inhibitor is not a CTPS1 inhibitor disclosed in PCT publication number WO2022087634. In a further embodiment, the CTPS1 inhibitor is not (i) a compound described in any one of claims 1 to 31 of WO2022087634 or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof, (ii) a compound selected from compounds I-1 to I-286 of WO2022087634, or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof, or (iii) a compound selected from compounds Z- 1 to Z-10 of WO2022087634, or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof. CTPS1 inhibitors are disclosed in WO2022/087634, which is incorporated by reference in its entirety for the purpose of defining CTPS1 inhibitors. In some embodiments the CTPS1 inhibitor is as described in WO2022/087634, such as any of compounds I-1 to I-286 or Z-1 to Z- 10, or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof. In other embodiments the CTPS1 inhibitor is not described in WO2022/087634. Suitably, the CTPS1 inhibitor is not:
Figure imgf000075_0001
or a pharmaceutically acceptable salt thereof, wherein:
R1 is selected from Cw aliphatic; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, and a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring; having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with q instances of RA;
Ring A is selected from phenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 7-11 membered fused bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
Figure imgf000076_0001
wherein each of RL, RL’, and RL" is independently hydrogen, -CN, halogen, or an optionally substituted group selected from Ci-e aliphatic; phenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteraatoms independently selected from nitrogen, oxygen, and sulfur, or two of RL» RL', and RL’ groups are taken together with the atoms to which each is attached, to form an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms i ndependently selected from nitrogen, oxygen, and sulfur; or any one of RL, RL , and RL", together with R® forms a 7-10 membered saturated or partially unsaturated fused bicyclic ring;
Ring B is selected from phenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms 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 5-11 membered saturated or partially unsaturated fused, bridged, or spiro, bicyclic carbocyclic ring; a 7-11 membered fused bicyclic aryl ring; a 7-11 membered saturated or partially unsaturated fused, bridged, or spiro, bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 7-11 membered fused bicyclic heteroaryl ring having 1-4 heteraatotns independently selected from nitrogen, oxygen, and sulfur: Ring C is selected from a phenyl, 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 7-11 membered fused bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or the bond between Ring B and Ring C is absent, and Ring B and Ring C together form a 7-11 membered saturated or partially unsaturated fused, bridged, or spiro, bicyclic carbocyclic ring; a 7-11 membered fused bicyclic aryl ring; a 7-11 membered saturated or partially unsaturated fused, bridged, or spiro, bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-11 membered fused bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of RA, RB, and Rc is independently oxo, halogen, -CN, -NCh, -OR, -
Figure imgf000077_0001
optionally substituted group selected from CM aliphatic; phenyl; naphthalenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, phosphorous, silicon and sulfur; or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-8 membered saturated or partially unsaturated bridged bicyclic ring havi ng 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-10 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 6-11 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with r instances of R and s instances ofRD; or two Rc groups are optionally taken together with the atoms to which each Rc is attached, to form an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-7 membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
Figure imgf000078_0001
1 heterocyclic ring having 1-2 helertuloms independently selected liotr. nitrogen, oxygen, and sulfur; a membered niormcx die hetets ittrv ritii; haxinyr 1-4 heterodumix independently selected from nitrogen, oxygen, and sulfur an 3-10 membered bicyclic heiemaryl fug hay ing 1-4 hrfenxilunis independently selected from mtrugen. oxygen. and sulfur . a 7-12 membered saturated ar partially unsaturated bicyclic helc-ucy die nnu haying 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-8 membered saturated or partially uiKiiturated bridged bicyclic ring having 0-3 heteroatoms independently selected from mtrogen. oxygen. and sulfur, a 6-10 membered sutur.'.tcd ui pailially tnisati;r tiled xpirocyvlic ring having 0-3 heteroatoms independently selected from, nitrogen. oxygen, arid sulfur . n b-l I membered saturated or partially unsal.irnted ?ieyc'ii- carbocyclic ring haxirie 1-2 heieroatoms independently selected from nitrogen, oxygen, and sulfur, m twoR groups are taken together with the atoms to vy hi vh each R is attached, to four an optionally substituted 3-7 membered saturated or partially unsaturated monocydic earbiKyclic ring, a 3-7 membered saturated <>r partially- unsaturated monocycl c heterocyclic ring haying 1-2 hclcioatctlis independently selected from nitrogen, oxygen, and sulfur, or m is 0, 1, or 2; n is 0, 1, or 2; p is 0, 1, or 2; each q o independently 4. 1,2. 3. ui -I. each r is independently 0, 1, 2,, 3, or 4; and each sis independently 0, 1, 2, 3, or 4; provided that when:
Figure imgf000078_0003
Figure imgf000078_0004
fie R group til lire sul'otiaiuide moiety is hydrgen or para-methinybenzyl.
Figure imgf000078_0002
Figure imgf000079_0001
and the Ru and Ru or RL and RL" groups are not taken together with the atoms to which each is attached to form an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or L is
Figure imgf000079_0002
Ring B is phenyl or a 6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulftir, and
Ring C is phenyl or a 6-tnembered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur and is attached to Ring B in the para position relative to the L group; then Ring A and its RA substituents are other than
Figure imgf000079_0003
Figure imgf000079_0004
where * denotes attachment to the
Figure imgf000079_0005
moiety and ** denotes attachment to the
Figure imgf000079_0006
moiety ,
Suitably, the CTPS1 inhibitor is not a CTPS1 inhibitor as defined in claim 1 of WO2022/087634. Suitably, the CTPS1 inhibitor is not a CTPS1 inhibitor as defined in WO2022/087634.
Depending on the nature of the specific CTPS1 inhibitor, the CTPS1 inhibitor may be provided in the form of a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate. In some embodiments the CTPS1 inhibitor is provided in the form of a pharmaceutically acceptable salt and pharmaceutically acceptable solvate. In other embodiments the CTPS1 inhibitor is provided in the form of a pharmaceutically acceptable salt. In further embodiments the CTPS1 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 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, 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 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). The CTPS1 inhibitor encompasses all isomers of the CTPS1 inhibitors disclosed herein including all geometric, 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 by conventional synthetic methods or by stereospecific or asymmetric syntheses. 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 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 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 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 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 provided whereby two or more atoms exist in an unnatural variant isotopic form. The CTPS1 inhibitor administered to a subject should be safe and effective, i.e. a CTPS1 inhibitor providing an acceptable balance of desired benefits and undesired side effects. “Safe and effective" is intended to include a compound that is effective to achieve a desirable effect in treatment of cancer. 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. For avoidance of doubt, “safe and effective” as recited herein can be achieved by any suitable dosage regimen. Hence, for example, references herein to administering a safe and effective CTPS1 inhibitor, 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 effective CTPS1 inhibitor includes both orally administering a single dose and orally administering any plural number of doses, provided that a safe and effective dose of CTPS1 inhibitor is thereby achieved by oral administration. ATR inhibitors In one aspect of the invention there is provided an ATR inhibitor for use in the treatment of cancer with a CTPS1 inhibitor. An ATR inhibitor, as used herein, is an agent which directly inhibits ATR activity, such as ATR induced phosphorylation of CHEK1 or ATR induced phosphorylation of H2AX (γH2AX). Direct inhibition of ATR may be quantified using any suitable assay procedure, though is suitably performed using the procedure set out in Example 3. The activity of ATR inhibitors can be measured by their ability to bind and inhibit purified ATR and related proteins using a protein kinase assay, their ability to inhibit ATR induced phosphorylation of CHEK1 in a cellular assay, or their ability to inhibit ATR induced phosphorylation of H2AX (γH2AX) in a cellular assay. In one embodiment activity of ATR inhibitors is measured using a protein kinase assay. In one embodiment activity of ATR inhibitors is measured using ATR induced phosphorylation of CHEK1 in a cellular assay. In one embodiment activity of ATR inhibitors is measured using phosphorylation of H2AX (γH2AX) in a cellular assay. ATR inhibitors of particular interest are those demonstrating Ki values for binding to ATR of 50 nM or lower, such as 20 nM or lower, such as 10 nM or lower, such as 5 nM or lower, such as 1 nM or lower. ATR inhibitors of particular interest are those demonstrating Ki values for binding to ATR of 50 nM or lower, such as 20 nM or lower, such as 10 nM or lower, such as 5 nM or lower, such as 1 nM or lower using the ATR protein kinase assay procedure, the ATR induced phosphorylation of CHEK1 assay procedure or the ATR induced phosphorylation of γH2AX assay procedure set out in Example 3. In one embodiment selectivity of ATR inhibitors is measured using a protein kinase assay. ATR inhibitors of particular interest are those demonstrating a selectivity for ATR over ATM, DNA-PK or MTOR of >5-fold, such as >10-fold. ATR inhibitors of particular interest are those demonstrating a selectivity for ATR over ATM, DNA-PK or MTOR of >5-fold, such as >10- fold using the assay procedure set out in Example 4. In the case of medicaments intended for human use, ATR inhibition and ATR vs ATM, DNA-PK and MTOR selectivity should be based on human forms of the proteins. Particular ATR inhibitors include the following (clinical trial data is sourced from http://www.clinicaltrials.gov accessed November 2021 - January 2022): Ceralasertib The structure of ceralasertib (‘AZD6738’, imino-methyl-[1-[6-[(3R)-3-methylmorpholin-4- yl]-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl]cyclopropyl]-oxo-λ6-sulfane, CAS number 1352226-88-0) is provided below.
Figure imgf000082_0001
The ATR inhibitor may be ceralasertib or a pharmaceutically acceptable salt and/or a pharmaceutically acceptable solvate thereof. In one embodiment the ATR inhibitor is ceralasertib. In one embodiment the ATR inhibitor is a pharmaceutically acceptable salt of ceralasertib. In one embodiment the ATR inhibitor is a pharmaceutically acceptable solvate of ceralasertib. In one embodiment the ATR inhibitor is a pharmaceutically acceptable salt and a pharmaceutically acceptable solvate of ceralasertib. In one embodiment, the ATR inhibitor is not ceralasertib. Suitably, the ATR inhibitor is not ceralasertib or a pharmaceutically acceptable salt and/or a pharmaceutically acceptable solvate thereof. Ceralasertib is disclosed in Vendetti 2015, which is incorporated herein by reference in its entirety for the purpose of defining the ATR inhibitor. VE821 The structure of VE821 (3-amino-6-(4-methylsulfonylphenyl)-N-phenylpyrazine-2- carboxamide, CAS number 1232410-49-9) is provided below.
Figure imgf000083_0001
The ATR inhibitor may therefore be VE821 or a pharmaceutically acceptable salt and/or a pharmaceutically acceptable solvate thereof. In one embodiment the ATR inhibitor is VE821. In one embodiment the ATR inhibitor is a pharmaceutically acceptable salt of VE821. In one embodiment the ATR inhibitor is a pharmaceutically acceptable solvate of VE821. In one embodiment the ATR inhibitor is a pharmaceutically acceptable salt and a pharmaceutically acceptable solvate of VE821. In one embodiment, the ATR inhibitor is not VE821. Suitably, the ATR inhibitor is not VE821 or a pharmaceutically acceptable salt and/or a pharmaceutically acceptable solvate thereof. VE821 is disclosed in Charrier 2011, which is incorporated herein by reference in its entirety for the purpose of defining the ATR inhibitor. Gartisertib The structure of gartisertib (“VX-803”, 2-amino-6-fluoro-N-[5-fluoro-4-[4-[4-(oxetan-3- yl)piperazine-1-carbonyl]piperidin-1-yl]pyridin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide) is provided below.
Figure imgf000083_0002
The ATR inhibitor may therefore be gartisertib or a pharmaceutically acceptable salt and/or a pharmaceutically acceptable solvate thereof. In one embodiment the ATR inhibitor is gartisertib. In one embodiment the ATR inhibitor is a pharmaceutically acceptable salt of gartisertib. In one embodiment the ATR inhibitor is a pharmaceutically acceptable solvate of gartisertib. In one embodiment the ATR inhibitor is a pharmaceutically acceptable salt and a pharmaceutically acceptable solvate of gartisertib. Gartisertib is disclosed in Jo 2021, which is incorporated herein by reference in its entirety for the purpose of defining the ATR inhibitor. ETP-46464 The structure of ETP-46464 (2-methyl-2-[4-(2-oxo-9-quinolin-3-yl-4H-[1,3]oxazino[5,4- c]quinolin-1-yl)phenyl]propanenitrile) is provided below.
Figure imgf000084_0001
The ATR inhibitor may therefore be ETP-46464 or a pharmaceutically acceptable salt and/or a pharmaceutically acceptable solvate thereof. In one embodiment the ATR inhibitor is ETP-46464. In one embodiment the ATR inhibitor is a pharmaceutically acceptable salt of ETP- 46464. In one embodiment the ATR inhibitor is a pharmaceutically acceptable solvate of ETP- 46464. In one embodiment the ATR inhibitor is a pharmaceutically acceptable salt and a pharmaceutically acceptable solvate of ETP-46464. ETP-46464 is disclosed in Toledo 2011, which is incorporated herein by reference in its entirety for the purpose of defining the ATR inhibitor. AZ20 The structure of AZ20 ((3R)-4-[2-(1H-indol-4-yl)-6-(1- methylsulfonylcyclopropyl)pyrimidin-4-yl]-3-methylmorpholine) is provided below.
Figure imgf000084_0002
The ATR inhibitor may therefore be AZ20 or a pharmaceutically acceptable salt and/or a pharmaceutically acceptable solvate thereof. In one embodiment the ATR inhibitor is AZ20. In one embodiment the ATR inhibitor is a pharmaceutically acceptable salt of AZ20. In one embodiment the ATR inhibitor is a pharmaceutically acceptable solvate of AZ20. In one embodiment the ATR inhibitor is a pharmaceutically acceptable salt and a pharmaceutically acceptable solvate of AZ20. AZ20 is disclosed in Foote 2013, which is incorporated herein by reference in its entirety for the purpose of defining the ATR inhibitor. Elimusertib The structure of elimusertib (BAY-1895344, (3R)-3-methyl-4-[4-(2-methylpyrazol-3-yl)-8- (1H-pyrazol-5-yl)-1,7-naphthyridin-2-yl]morpholine, CAS number 1876467-74-1) is provided below.
Figure imgf000085_0001
The ATR inhibitor may therefore be elimusertib or a pharmaceutically acceptable salt and/or a pharmaceutically acceptable solvate thereof. In one embodiment the ATR inhibitor is elimusertib. In one embodiment the ATR inhibitor is a pharmaceutically acceptable salt of elimusertib. In one embodiment the ATR inhibitor is a pharmaceutically acceptable solvate of elimusertib. In one embodiment the ATR inhibitor is a pharmaceutically acceptable salt and a pharmaceutically acceptable solvate of elimusertib. Elimusertib is disclosed in Wengner 2020, which is incorporated herein by reference in its entirety for the purpose of defining the ATR inhibitor. Berzosertib The structure of berzosertib (M6620, VX-970, VE-822, 3-[3-[4- (methylaminomethyl)phenyl]-1,2-oxazol-5-yl]-5-(4-propan-2-ylsulfonylphenyl)pyrazin-2-amine, CAS number 1232416-25-9) is provided below.
Figure imgf000085_0002
The ATR inhibitor may therefore be berzosertib or a pharmaceutically acceptable salt and/or a pharmaceutically acceptable solvate thereof. In one embodiment the ATR inhibitor is berzosertib. In one embodiment the ATR inhibitor is a pharmaceutically acceptable salt of berzosertib. In one embodiment the ATR inhibitor is a pharmaceutically acceptable solvate of berzosertib. In one embodiment the ATR inhibitor is a pharmaceutically acceptable salt and a pharmaceutically acceptable solvate of berzosertib. Berzosertib is disclosed in Charrier 2011, which is incorporated herein by reference in its entirety for the purpose of defining the ATR inhibitor. In one embodiment, the ATR inhibitor is selected from the group consisting of ceralasertib, VE821, gartisertib, ETP-46464, AZ20, elimusertib and berzosertib, pharmaceutically acceptable salts and/or pharmaceutically acceptable solvates of any thereof. More suitably the ATR inhibitor is ceralasertib or VE821, pharmaceutically acceptable salts and/or pharmaceutically acceptable solvates thereof. Most suitably the ATR inhibitor is ceralasertib, pharmaceutically acceptable salts and/or pharmaceutically acceptable solvates thereof. Depending on the nature of the specific ATR inhibitor, the ATR inhibitor may be provided in the form of a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate. In some embodiments the ATR inhibitor is provided in the form of a pharmaceutically acceptable salt and pharmaceutically acceptable solvate. In other embodiments the ATR inhibitor is provided in the form of a pharmaceutically acceptable salt. In further embodiments the ATR inhibitor is provided in the form of a pharmaceutically acceptable solvate. In some embodiments the ATR inhibitor is provide 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 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, meglumine, tromethamine, piperazine, arginine, choline, diethylamine, benzathine or lysine. The ATR 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 ATR inhibitor may be prepared in crystalline or non-crystalline form and, if 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). The ATR inhibitor encompasses all isomers of the ATR inhibitors disclosed herein including all geometric, 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 by conventional synthetic methods or by stereospecific or asymmetric syntheses. The ATR inhibitor encompasses all isotopic forms of the ATR 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 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 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 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 drug and/or substrate tissue distribution studies. In one embodiment, the ATR inhibitor is provided in a natural isotopic form. In one embodiment, the ATR inhibitor is provided in an unnatural variant isotopic form. In one embodiment, the ATR inhibitor is provided whereby a single atom of the compound exists in an unnatural variant isotopic form. In another embodiment, the ATR inhibitor is provided whereby two or more atoms exist in an unnatural variant isotopic form. In general, the ATR inhibitors disclosed herein may be made according to the organic synthesis techniques known to those skilled in this field. The production of berzosertib and VE821 are disclosed in Charrier 2011 and the production of AZ20 is disclosed in Foote 2013. These references are incorporated herein by reference in their entirety for the purpose of production of these ATR inhibitors. The ATR inhibitor administered to a subject should be safe and effective, i.e. an ATR inhibitor providing an acceptable balance of desired benefits and undesired side effects. “Safe and effective" is intended to include a compound that is effective to achieve a desirable effect in treatment of cancer. 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. For avoidance of doubt, “safe and effective” as recited herein can be achieved by any suitable dosage regimen. Hence, for example, references herein to administering a safe and effective ATR inhibitor, 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 effective ATR inhibitor includes both orally administering a single dose and orally administering any plural number of doses, provided that a safe and effective ATR inhibitor is thereby achieved by oral administration. Administration The invention is typically intended for use with mammalian subjects, in particular human subjects. The combination treatment will typically be administered to a subject in need thereof, in particular a mammalian subject, in particular a human subject. In a further aspect the invention provides a CTPS1 inhibitor and an ATR inhibitor for use in the treatment of cancer, wherein the CTPS1 inhibitor is defined in any one of Groups A to H. One aspect of the invention provides a CTPS1 inhibitor in the manufacture of a medicament for the treatment of cancer with an ATR inhibitor, wherein the CTPS1 inhibitor is defined in any one of Groups A to H. A further aspect of the invention provides the use of an ATR inhibitor in the manufacture of a medicament for the treatment of cancer with a CTPS1 inhibitor, wherein the CTPS1 inhibitor is defined in any one of Groups A to H. A further aspect of the invention provides the use of a CTPS1 inhibitor and an ATR inhibitor in the manufacture of a medicament for the treatment of cancer, wherein the CTPS1 inhibitor is defined in any one of Groups A to H. A further aspect of the invention provides a method of treating cancer in a subject which method comprises administering to the subject a CTPS1 inhibitor and an ATR inhibitor, wherein the CTPS1 inhibitor is defined in any one of Groups A to H. A further aspect of the invention provides a pharmaceutical composition comprising a CTPS1 inhibitor and an ATR inhibitor, suitably for use in the treatment of cancer, wherein the CTPS1 inhibitor is defined in any one of Groups A to H. A further aspect of the invention provides a CTPS1 inhibitor in the manufacture of a medicament for the treatment of cancer with an ATR inhibitor, wherein the ATR inhibitor is ceralasertib or VE821, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof. In a further aspect the invention provides a CTPS1 inhibitor and an ATR inhibitor for use in the treatment of cancer, wherein the ATR inhibitor is ceralasertib or VE821, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof. A further aspect of the invention provides the use of an ATR inhibitor in the manufacture of a medicament for the treatment of cancer with a CTPS1 inhibitor, wherein the ATR inhibitor is ceralasertib or VE821, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof. A further aspect of the invention provides the use of a CTPS1 inhibitor and an ATR inhibitor in the manufacture of a medicament for the treatment of cancer, wherein the ATR inhibitor is ceralasertib or VE821, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof. A further aspect of the invention provides a method of treating cancer in a subject which method comprises administering to the subject a CTPS1 inhibitor and an ATR inhibitor, wherein the ATR inhibitor is ceralasertib or VE821, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof. A further aspect of the invention provides a pharmaceutical composition comprising a CTPS1 inhibitor and an ATR inhibitor, suitably for use in the treatment of cancer, wherein the ATR inhibitor is ceralasertib or VE821, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof. Suitably the CTPS1 inhibitor and the ATR inhibitor act synergistically in treating the cancer. The CTPS1 inhibitor and the ATR inhibitor act ‘synergistically’ if their combined administration results in a beneficial effect greater than the sum of the beneficial effects of each agent administered alone. Suitably the CTPS1 inhibitor and the ATR inhibitor act synergistically if they achieve a Bliss score (Bliss 1939; Zheng 2021) of greater than 10 when applied to a cancer cell line as set out in Example 6. Administration of the CTPS1 inhibitor The CTPS1 inhibitor may be administered by any suitable route, which may depend on 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 pharmaceutical composition (such as a tablet, capsule or lozenge) or in a liquid pharmaceutical composition (such as a suspension, emulsion or solution). Suitably, the CTPS1 inhibitor is administered orally, such as administered orally in a solid pharmaceutical composition. 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. A 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, capsule or ampoule. Suitably the unit dose form is for oral delivery. The pharmaceutical composition may for example contain from 0.1% to 99.99% by weight, 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 0.05 mg to 2000 mg of the active material, for example from 1.0 mg to 500 mg, depending on the method of administration. The pharmaceutical composition may contain from 50 mg to 1000 mg of the carrier, for example from 100 mg to 400 mg depending on the method of administration. A plurality of unit does, such as a plurality of tablets, may be taken together. The dose of the compound used will vary in the usual way with the seriousness of the cancer, the weight of the sufferer, and other similar factors. However, as a general guide suitable unit doses may be 0.05 mg to 1000 mg, more suitably 1.0 mg to 500 mg, and such unit doses may be administered more than once a day, for example two or three a day. Such therapy may extend for a number of weeks, months or longer. 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 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 that is sufficient to achieve the desirable effect when the CTPS1 inhibitor is administered with the ATR inhibitor. 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 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. Administration of the ATR inhibitor The ATR inhibitor may be administered by any suitable route, which may depend on the nature of the specific agent. Exemplary routes include oral, parenteral, buccal, sublingual, nasal or rectal administration. Conveniently, the ATR inhibitor is administered orally. The ATR inhibitor may be provided in the form of a pharmaceutical composition comprising the ATR inhibitor and a pharmaceutically acceptable carrier or excipient. Suitably, the ATR inhibitor is administered orally, such as administered orally in a solid pharmaceutical composition. If delivered orally, the ATR inhibitor may suitably be delivered in a solid pharmaceutical composition (such as a tablet, capsule or lozenge) or in a liquid pharmaceutical composition (such as a suspension, emulsion or solution). A liquid formulation will generally consist of a suspension or solution of the ATR 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. A 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, capsule or ampoule. Suitably the unit dose form is for oral delivery. The pharmaceutical composition may for example contain from 0.1% to 99.99% by weight, 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 0.05 mg to 2000 mg of the active material, for example from 1.0 mg to 500 mg, suitably 5 mg to 100 mg, such as 20 to 60 mg, depending on the method of administration. For oral administration, 20 mg may be desirable. The pharmaceutical composition may contain from 50 mg to 1000 mg of the carrier, for example 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 cancer, the weight of the sufferer, and other similar factors. However, as a general guide suitable unit doses may be 0.05 mg to 1000 mg, more suitably 1.0 mg to 500 mg, and such unit doses may be administered more than once a day, for example two or three a day. Such therapy may extend for a number of weeks, months or longer. A plurality of unit does, such as a plurality of tablets, may be taken together. In one embodiment the ATR inhibitor is administered daily for a period 5 weeks. The ATR inhibitor may be administered at a daily dose of 20 mg for week 1, 50 mg for week 2, 100 mg for week 3, 200 mg for week 4 and 400 mg for week 5. 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 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 that is sufficient to achieve the desirable effect when the CTPS1 inhibitor is administered with the ATR inhibitor. 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 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. Administration regimes The CTPS1 inhibitor and ATR inhibitor may be administered separately, sequentially or simultaneously. The CTPS1 inhibitor may be administered before the ATR inhibitor. Alternatively, the ATR inhibitor may be administered before the CTPS1 inhibitor. To maintain therapeutic efficacy whilst controlling toxicity, the CTPS1 inhibitor and/or ATR inhibitor may be administered intermittently. Intermittently in this context means that the CTPS1 inhibitor and/or the ATR inhibitor are not administered every day of a treatment cycle (e.g. the CTPS1 inhibitor and/or the ATR inhibitor are administered for 4 days in each 7 day period of a treatment cycle). It will be understood that when the CTPS1 inhibitor and ATR inhibitor are both administered intermittently, they need not be administered according to the same schedule. Suitably, the CTPS1 inhibitor and/or ATR inhibitor may be administered continuously i.e. administered at least daily in a treatment cycle (e.g. the CTPS1 inhibitor and/or the ATR inhibitor are administered each day of a treatment cycle). Suitably, the CTPS1 inhibitor is administered intermittently and the ATR inhibitor is administered intermittently. Suitably, the CTPS1 inhibitor is administered continuously and the ATR inhibitor is administered continuously. Suitably, the CTPS1 inhibitor is administered intermittently and the ATR inhibitor is administered continuously. Suitably, the CTPS1 inhibitor is administered continuously and the ATR inhibitor is administered intermittently. The CTPS1 inhibitor and the ATR inhibitor may be delivered in co-formulation (where compatible with co-formulation and whether the dosage regimes of the two agents allow) or in separate formulations. Most suitably the CTPS1 inhibitor and the ATR inhibitor are delivered in co-formulation or in separate formulations which are simultaneously administered. Alternatively, if delivered in separate formulations, the CTPS1 inhibitor and the ATR inhibitor may be delivered at different times. If separately formulated, the CTPS1 inhibitor (or a pharmaceutical composition comprising such, such as a tablet or capsule) and ATR inhibitor (or a pharmaceutical composition comprising such, such as a tablet or capsule) may be provided in separate containers. If separately formulated, the CTPS1 inhibitor and ATR inhibitor may be provided in the form of a kit of parts comprising: a) a first container comprising a CTPS1 inhibitor; and b) a second container comprising an ATR inhibitor. More suitably, the CTPS1 inhibitor and ATR inhibitor may be provided in the form of a kit of parts comprising a first container comprising a CTPS1 inhibitor (or a pharmaceutical composition comprising such, such as a tablet or capsule) and a second container comprising an ATR inhibitor (or a pharmaceutical composition comprising such, such as a tablet or capsule). Combinations with further agents Treatment with the CTPS1 inhibitor and ATR inhibitor may be combined with one or more further pharmaceutically acceptable active ingredients, which may be selected from: anti-mitotic agents such as vinblastine, paclitaxel and docetaxel; alkylating agents, for example cisplatin, carboplatin, dacarbazine and cyclophosphamide; antimetabolites, for example 5-fluorouracil, cytosine arabinoside and hydroxyurea; intercalating agents for example adriamycin and bleomycin; topoisomerase inhibitors for example etoposide, topotecan and irinotecan; thymidylate synthase inhibitors for example raltitrexed; PI3 kinase inhibitors for example idelalisib; mTor inhibitors for example everolimus and temsirolimus; proteasome inhibitors for example bortezomib; histone deacetylase inhibitors for example panobinostat or vorinostat; and hedgehog pathway blockers such as vismodegib. The CTPS1 inhibitor, ATR inhibitor and the additional pharmaceutically acceptable active ingredients may each be administered in any combination of separate, sequential or simultaneous dosing. If administered simultaneously, the CTPS1 inhibitor and ATR inhibitor may be e.g. (a) formulated together but separately from the further pharmaceutically acceptable active ingredient, (b) formulated separately from each other and separately from the further pharmaceutically acceptable active ingredient (c) formulated together with the further pharmaceutically acceptable active ingredient. The CTPS1 inhibitor, the ATR inhibitor and the additional pharmaceutically acceptable active ingredients may each be administered in any combination of separate, sequential or simultaneous dosing. The CTPS1 inhibitor, ATR inhibitor and the additional pharmaceutically acceptable active ingredients may be e.g. (a) formulated together but separately from the further pharmaceutically acceptable active ingredient, (b) formulated separately from each other and separately from the further pharmaceutically acceptable active ingredient, (c) formulated together with the further pharmaceutically acceptable active ingredient; (d) formulated separately from each other, but one of the CTPS1 inhibitor or ATR inhibitor formulated together with the further pharmaceutically acceptable active ingredient. The further pharmaceutically acceptable active ingredient may be selected from tyrosine kinase inhibitors such as, for example, axitinib, dasatinib, erlotinib, imatinib, nilotinib, pazopanib and sunitinib. Alternatively, the further pharmaceutically acceptable active ingredient may be selected from azacitidine, decitabine, or cytarabine. Further pharmaceutically acceptable active ingredients also include anticancer antibodies, such as those selected from the group consisting of anti-CD20 antibodies (such as obinutuzumab, ofatumumab, tositumomab or rituximab) or other antibodies such as olaratumab, daratumumab, necitumumab, dinutuximab, traztuzumab emtansine, pertuzumab, brentuximab, panitumumab, catumaxomab, bevacizumab, cetuximab, traztuzumab and gentuzumab ozogamycin. The CTPS1 inhibitor and ATR inhibitor may also be administered in combination with radiotherapy, surgery, hyperthermia therapy or cryotherapy. Cancer In one embodiment the cancer is a cancer which is susceptible to replication stress or has high pre-existing levels of replication stress. By a ‘high’ level it is meant that the cancer has a pre-existing level of replication stress which is higher than an average cancer. Suitably the cancer expresses ATR. Suitably the cancer is a cancer which constitutively expresses MYC. Suitably the cancer shows evidence of DNA damage, for example by the presence of γH2AX. Suitably the cancer is a haematological cancer, such as acute myeloid leukemia, angioimmunoblastic T-cell lymphoma, B-cell acute lymphoblastic leukemia, Sweet syndrome, T- cell non-Hodgkins lymphoma (including natural killer/T-cell lymphoma, adult T-cell leukaemia/lymphoma, enteropathy type T-cell lymphoma, hepatosplenic T-cell lymphoma and ccutaneous T-cell lymphoma), T-cell acute lymphoblastic leukemia, B-cell non-Hodgkins lymphoma (including Burkitt lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, marginal Zone lymphoma), hairy cell leukemia, Hodgkin lymphoma, lymphoblastic lymphoma, lymphoplasmacytic lymphoma, mucosa-associated lymphoid tissue lymphoma, multiple myeloma, myelodysplastic syndrome, plasma cell myeloma, primary mediastinal large B-cell lymphoma, chronic myeloproliferative disorders (such as chronic myeloid leukemia, primary myelofibrosis, essential thrombocythemia, polycytemia vera) or chronic lymphocytic leukemia. Suitably T cell lymphoma, diffuse large B cell lymphoma, plasma cell myeloma, acute myeloid leukaemia, chronic lymphocytic leukaemia or peripheral T cell lymphoma. A further haematological cancer of interest is T-cell prolymphocytic leukemia. Other haematological cancers of interest are myelodysplastic syndromes (MDS), such as MDS with single lineage dysplasia, MDS with multilineage dysplasia or MDS with excess blasts. Alternatively, the cancer is a non-haematological cancer, such as selected from the group consisting of colorectal cancer, bile duct cancer, endometrial cancer, hepatic cancer, gastric cancer, oesophageal cancer, sarcoma, bladder cancer, pancreatic cancer, ovarian cancer, lung cancer, mesothelioma, melanoma, bone cancer, head and neck cancer, breast cancer, brain cancers, prostate cancer, renal cancer, thyroid cancer and neuroblastoma. More suitably the non-haematological cancer is selected from colorectal cancer, bile duct cancer, endometrial cancer, hepatic cancer, gastric cancer, oesophageal cancer, sarcoma, bladder cancer, pancreatic cancer, ovarian cancer, lung cancer, mesothelioma and melanoma. More suitably the non-haematological cancer is selected from colorectal cancer, bile duct cancer, endometrial cancer, hepatic cancer, gastric cancer and oesophageal cancer. The non- haematological cancer may be selected from prostate cancer, pancreatic cancer, ovarian cancer, lung cancer, renal cancer, colorectal cancer or breast cancer. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit of the invention may be for administration to a subject identified as having a cancer expected to be susceptible to treatment by a CTPS1 inhibitor and an ATR inhibitor. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit of the invention may be for administration to a subject from whom a sample containing cancer cells has been shown to be susceptible to treatment by a CTPS1 inhibitor and an ATR inhibitor. A ‘susceptible’ cancer or cancer cell sample in this context is one which is associated with generally demonstrating a benefit from the treatment according to the invention relative to treatment with CTPS1 or ATR inhibitors alone, e.g. additive or, suitably, synergistic effects - high in vivo efficacy, reduction in the dose required for effect in vivo and/or an improved safety profile/reduced side effects. The invention also provides a CTPS1 inhibitor for use in the treatment of cancer with an ATR inhibitor. In a further aspect the invention provides an ATR inhibitor for use in the treatment of cancer with a CTPS1 inhibitor. In a further aspect the invention provides a CTPS1 inhibitor and an ATR inhibitor for use in the treatment of cancer. In a further aspect the invention provides the use of a CTPS1 inhibitor in the manufacture of a medicament for the treatment of cancer with an ATR inhibitor. In a further aspect the invention provides the use of an ATR inhibitor in the manufacture of a medicament for the treatment of cancer with a CTPS1 inhibitor. In a further aspect the invention provides the use of a CTPS1 inhibitor and an ATR inhibitor in the manufacture of a medicament for the treatment of cancer. In a further aspect the invention provides a method of treating cancer in a subject which method comprises administering to the subject a CTPS1 inhibitor and an ATR inhibitor. In a further aspect the invention provides a pharmaceutical composition comprising a CTPS1 inhibitor and an ATR inhibitor. In a further aspect the invention provides a kit of parts comprising: a) a first container comprising a CTPS1 inhibitor; and b) a second container comprising an ATR inhibitor. The CTPS1 inhibitor may be as further particularised elsewhere herein, such as those demonstrating an IC50 of 10 uM or lower, such as 1uM or lower, especially 100nM or lower, in respect of human CTPS1 enzyme using the assay procedure set out in Example 1, for example those demonstrating a selectivity for human CTPS1 over human CTPS2, suitably of at least 2-fold, such as at least 30-fold, especially at least 60-fold and in particular a least 1000-fold using the assay procedure set out in Example 2. The ATR inhibitor may be as further particularised elsewhere herein, such as those demonstrating Ki values for binding to human ATR of 50 nM or lower, such as 20 nM or lower, such as 10 nM or lower, such as 5 nM or lower, such as 1 nM or lower using the ATR protein kinase assay procedure, the ATR induced phosphorylation of CHEK1 assay procedure or the ATR induced phosphorylation of γH2AX assay procedure set out in Example 3. The invention is further exemplified by the following non-limiting examples. EXAMPLES Example 1: Human CTPS1 Enzyme Inhibition Enzyme inhibitory activities of compounds CTPS1-IA and CTPS1-IB The enzyme inhibitory activities of compounds CTPS1-IA and CTPS1-IB against CTPS1 were determined using the ADP-Glo ^ Max assay (Promega, UK). CTPS1-IA is 4-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin- 2-yl)tetrahydro-2H-pyran-4-carboxamide. CTPS-IB is N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(2-(ethylsulfonamido)pyrimidin-4- yl)tetrahydro-2H-pyran-4-carboxamide. 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-tag 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 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
Figure imgf000097_0006
Max kit (0.31mM), GTP (0.034mM), UTP (0.48mM) and L-glutamine (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).
Figure imgf000097_0004
Max reagent was added for 60 minutes (6μL per well) and subsequently
Figure imgf000097_0005
Max development reagent was added for 60 minutes (12uL per well) prior to signal detection in a microplate reader (EnVision ^ Multilabel Reader, Perkin Elmer). Following each reagent addition over the course of the assay, assay plates were pulse centrifuged for 30 seconds at 500rpm. In all cases, the enzyme converts ATP to ADP and the
Figure imgf000097_0002
^ Max reagent subsequently depletes any remaining endogenous ATP in the reaction system. The
Figure imgf000097_0003
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 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:
Figure imgf000097_0001
Percentage inhibition was then plotted against compound concentration, and the 50% inhibitory concentration (IC50) was determined from the resultant concentration-response curve. The data for the tested compounds are presented below. Table 1: Human CTPS1 Enzyme Inhibition data
Figure imgf000097_0007
Both compounds were found to demonstrate inhibition of CTPS1 enzyme in this assay. Consequently, these compounds may be expected to have utility in the inhibition of CTPS1. Example 2: RapidFire/MS-based CTPS1 Enzyme Selectivity Assays Human CTPS1 versus CTPS2 Selectivity Assessment by RapidFire/MS Analysis. The enzyme inhibitory activities against each target isoform of interest were determined for compounds using an optimised RapidFire high-throughput mass spectrometry (RF/MS) assay format. RF/MS assays for both human CTPS1 and CTPS2 were performed in assay buffer consisting of 50mM HEPES (Merck), 20mM MgCl2, 5mM KCl, 1mM DTT, 0.01% Tween-20, pH to 8.0 accordingly. Human full-length active C-terminal FLAG-His- 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 Procedure Human CTPS (1 or 2) protein was prepared in 1x assay buffer to the final working protein concentration required for the reaction. A 2uL volume per well of 2x CTPS (1 or 2) protein was mixed with 40nL of compound using acoustic (ECHO) delivery and incubated for 10 minutes at 25˚C. Each isoform enzymatic reaction was subsequently initiated by addition of 2uL per well of a 2x substrate mix in assay buffer. For hCTPS1: ATP (0.3mM), UTP (0.2mM), GTP (0.07mM) 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 isoform within 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-sealed and centrifuged for 10 minutes at 4,000rpm. Following centrifugation, plates were loaded onto the Agilent RapidFire microfluidic solid phase extraction system coupled to an API4000 triple quadrupole mass spectrometer (RF/MS) for analysis. In all cases, the enzyme converts UTP to CTP. Highly specific and sensitive multiple reaction monitoring (MRM) MS methods may be optimised for the detection of the enzymatic reaction product, CTP, and the stable isotope labelled product standard 13C9-15N3-CTP. Readout for data analysis was calculated as the ratio between the peak area of the product CTP and the internal standard 13C9-15N3-CTP. For data reporting, the following equation was used:
Figure imgf000098_0001
(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 median of the respective control values was used for calculation of percent inhibition according to the following equation:
Figure imgf000099_0001
(I = Inhibition, Rneg =median of negative control readout values, Rpos =median of positive control readout values, Rsample = sample readout value) Percentage inhibition was then plotted against compound concentration, and the 50% inhibitory concentration (IC50) was determined from the resultant concentration-response curve. Fold selectivity between CTPS1 and CTPS2 was subsequently calculated according to the following equation: Fold selectivity =
Figure imgf000099_0002
CTPS1-IA and CTPS1-IB were tested for selectivity. The results are presented below. Table 2: Selectivity data
Figure imgf000099_0003
This compound may be expected to have utility in the treatment of diseases whereby a selective CTPS1 compound is beneficial. Example 3: Human ATR Inhibition ATR protein kinase assay Purified human ATR or the ATR kinase domain, for example derived from transfected Sf9 insect cells, is incubated with a suitable target peptide, for example ASELPASQPQPFSAKKK (SEQ ID NO: 3), in a dilution series of test compound is mixed with a kinase reaction buffer containing unlabelled ATP, plus 5 nmol/L 33P γ-labelled ATP. Radioactivity incorporated into the substrate, which is a measure of enzymatic activity, is quantified by capturing the substrate on a suitable surface and measuring radioactivity using a liquid scintillation counter. This method is disclosed in Charrier 2011, which is incorporated herein by reference in its entirety for the purpose of disclosing details of this protein kinase assay. ATR induced phosphorylation of CHEK1 or γH2AX Cells from suitable cell lines are plated in each well of a 24 well tissue culture plate and allowed to recover for 24 h (for example HeLa at 7 × 104 or Calu-61 × 105 per well). The cell lines are exposed to a DNA damaging agent, for example doxorubicin or gemcitabine. Serial dilutions of test compound are added 24 h later and the plates incubated for an additional 2 h. The cells are harvested in cold cell lysis and protein extraction buffer supplemented with phosphatase inhibitors. Each well is scraped and the lysate sonicated for 45 s in an ice-water bath. Lysates are diluted in sample buffer and heated at 95 °C for 5 min. Proteins are detected by immunoblotting with a pCHEK1 (S296) antibody or with a phosphorylated H2AX (Ser139, also known as γH2AX) antibody. A similar method uses immunofluorescence to measure protein levels in situ. A similar method analyses proteins by flow cytometry. This method is disclosed in Reaper 2011, which is incorporated herein by reference in its entirety for the purpose of disclosing details of this ATR induced phosphorylation assay. Example 4: ATR Selectivity The ATR protein kinase assay can be modified to assay the ability of test compounds to inhibit the activity of other related proteins. As an example, purified human ATM or the ATM kinase domain, for example derived from transfected Sf9 insect cells, is incubate with a suitable target peptide, for example DPSVEPPLSQETFSDKKK (SEQ ID NO: 4), in a dilution series of test compound is mixed with a kinase reaction buffer containing unlabelled ATP, plus 5 nmol/L 33P γ- labelled ATP. Radioactivity incorporated into the substrate, which is a measure of enzymatic activity, is quantified by capturing the substrate on a suitable surface and measuring radioactivity using a liquid scintillation counter. As an example, purified human DNA-PK or the DNA-PK kinase domain, for example derived from transfected Sf9 insect cells, is incubate with a suitable target peptide, for example EPPLSQEAFADLWKKK (SEQ ID NO: 5), in a dilution series of test compound is mixed with a kinase reaction buffer containing unlabelled ATP, plus 5 nmol/L 33P γ- labelled ATP. Radioactivity incorporated into the substrate, which is a measure of enzymatic activity, is quantified by capturing the substrate on a suitable surface and measuring radioactivity using a liquid scintillation counter. Example 5: CTPS1 Involvement in the Proliferation of Cancer Cells Pathways involved in providing the key building blocks for nucleic acid replication are the purine and pyrimidine synthesis pathways, and pyrimidine biosynthesis has been observed to be up-regulated in tumors and neoplastic cells. CTPS activity is upregulated in a range of tumour types of both haematological and non-haematological origin, although heterogeneity is observed among patients. Linkages have also been made between high enzyme levels and resistance to chemotherapeutic agents. In an analysis of published data, CTPS1 was found by the present inventors to be essential for the proliferation of human cancer cells derived from a broad range of haematological and solid tumour types, whereas CTPS2 was invariably redundant. This analysis used data from the Achilles project where every gene in the human genome was independently deleted using CRIPR technology in each of 324 human cancer cell lines, and the effects of each gene deletion was assessed using an in vitro proliferation assay (Behan 2019). This dataset has subsequently been expanded to include data from 1,032 human cancer cell lines (Cancer Dependency Map: https://depmap.org/). The effects of deletion of different genes in the pyrimidine synthesis pathway were assessed (see Fig.2). Deletion of CTPS2 had no effect on cancer cell proliferation. Deletion of genes in the salvage pathway (UCK1, UCK2) had minimal effect on cell proliferation. Deletion of CMPK1 had a marked effects on cell proliferation, consistent with CMPK1 being an essential gene. Deletion of CTPS1, UMPS, DHODH or CAD inhibited cancer cell proliferation with an effect that is consistent with dependency of cancer cells on the products of these genes; inhibition of CTPS1 produced the greatest impairment of cancer cell proliferation. These findings indicate that the majority of cancer cells are dependent on CTPS1 for cell proliferation, whereas CTPS2 is not required. In recent work, the CTPS1 isoform has shown higher enzymatic activity than CTPS2. Taken together with the CRISPR study analysis outlined above, these findings highlight CTPS1 as the more potent CTP synthase enzyme and identify a non-redundant role for CTPS1 in the proliferation of human cancer cells, thus identifying CTPS1 as a potential therapeutic target in a wide range of human malignancies. Example 6: Effect of Combined Treatment with a CTPS1 inhibitor and an ATR Inhibitor Cell cycle status was assessed by flow cytometric analysis after staining cells with propidium iodide with or without additional labelling with Bromodeoxyuridine (BrdU). Expression of activated (phosphorylated) CHEK1 was measured by western blotting using antibodies against the control protein GAPDH, native CHEK1 and pCHEK1; pCHEK1 levels were normalised to both total CHEK1 and GAPDH. In vitro proliferation assays were performed using human cancer cell lines to assess synergy between the antiproliferative effects of a CTPS1 inhibitor (CTPS1-IA) and inhibitors of ATR. Cell lines (available from commercial repositories, such as Deutsche Sammlung von Mikroorganismen und Zellkulturen) were plated in triplicate. The CTPS1 inhibitor (CTPS1-IA) and the second compound were added at prespecified concentrations (above, at and below the single agent IC50 value for the cell line being studied) and cell viability was assessed after 72 hours incubation using a metabolic reagent such as a tetrazolium salt-based colourimetric assay (Cell Counting Kit-8, Dojindo) or CellTiter-Glo (Promega). Apoptosis was assessed by flow cytometric analysis after staining cells with propidium iodide and annexin V. The CTPS1 inhibitor, CTPS1-IA, and a second compound were tested in 4x4 matrices (total 16 conditions). Each compound was included at concentrations producing single agent 72- hour viability of approximately 80-90%, 50-60% and 30-40%, as well as a no drug condition. Combined effects were assessed by calculating Bliss scores (Bliss 1939; Zheng 2021); a score of -10 to <10 indicates an additive effect and a value of ≥10 indicates synergy. Cell cycle analysis indicates that exposure to CTPS1-IA causes cancer cells to accumulate in S phase. The results of the cell cycle analysis are provided in Fig.3. The results of the proliferation assays are provided in Fig.4 and Fig.5. The proliferation assays include data from mantle cell lymphoma lines and myeloma cell lines. Exposure of cells to the CTPS1 inhibitor CTPS1-IA results in activation of the DDR pathway, specifically activation of CHEK1. Fig. 6 illustrates increased activated CHEK1 (pCHEK1) following exposure to CTPS1-IA in myeloma cell lines. Inhibition of CTPS1 via CTPS1-IA results in S phase accumulation and activation of CHEK1. These findings indicated that combining a CTPS1 inhibitor (e.g. CTPS-IA) with an ATR inhibitor (e.g. ceralasertib) may lead to increased therapeutic efficacy. Fig. 7 provides efficacy scores (Bliss scores) for myeloma cell lines exposed to the CTPS1 inhibitor CTPS1-IA in combination with either a standard of care drug or an ATR inhibitor (VE821 or ceralasertib). A score of -10 to <10 indicates an additive effect and a value of ≥10 indicates synergy (open and hatched bars, respectively). Combining CTPS1-IA with standard of care drugs (lenalidomide, dexamethasone, melphalan or bortezomib) produced either no or inconsistent, moderate synergy. Combining the CTPS1 inhibitor CTPS1-IA with an ATR inhibitor (ceralasertib or VE821) produced marked and consistent synergy. Fig.8 shows representative data from myeloma cell lines exposed to the CTPS1 inhibitor CTPS1-IA combined with an ATR inhibitor (VE821). In all cases, the combination induced a higher degree of apoptosis than either drug given alone (synergy scores were not calculated in this experiment). Figs.9A to 9C show data from 6 mantle cell lymphoma cell lines exposed to the CTPS1 inhibitor CTPS1-IA combined with an ATR inhibitor (VE821). Synergy was observed in 3 of the 6 cell lines (Bliss scores 11 - 20). Figs.10A to 10B show representative data from primary mantle cell lymphoma samples (i.e. mantle cell lymphoma cells taken directly from patients as opposed to cell lines) exposed to the CTPS1 inhibitor CTPS1-IA combined with an ATR inhibitor (VE821). Synergy was observed in 7 of the 11 cell lines (Bliss scores 10 - 22). Fig.11 shows data from 36 human cancer lines derived from solid tumours exposed to the CTPS1 inhibitor CTPS1-IA combined with an ATR inhibitor (ceralasertib). Synergy was observed in 22 of the cell lines (Bliss scores 10 - 33). Synergy was observed for at least one cell line in each of the 7 tumour types tested - prostate cancer, pancreatic cancer, ovarian cancer, lung cancer, renal cancer, colorectal cancer or breast cancer. Fig.12 shows a comparison of synergy in anti-tumour effects elicited by the ATR inhibitor ceralasertib in 4 human colorectal cancer cell lines in combination with either the CTPS1 inhibitor CTPS1-IA or a chemotherapy drug (irinotecan). In all cases, the synergy elicited by the ceralasertib CTPS1-IA combination exceeded that elicited by the ceralasertib chemotherapy combination. Example 7: In vivo effect of Combined Treatment with a CTPS1 inhibitor and an ATR Inhibitor In vivo tumour growth studies were performed using a human cancer cell line to look for interactions between the antiproliferative effects of CTPS1-IA and ceralasertib. Human colorectal cancer cells (COLO205) were transplanted subcutaneously into immunodeficient mice (BALB/c Nude strain). Treatment was initiated when the tumours reached approximately 120-150 mm3; n=10 mice per group. CTPS1-IA was dosed at 30 mg/kg/day subcutaneously days 1-5 of a 7 day cycle for 2 cycles and then days 1-3 for 2 cycles; ceralasertib was dosed at 25 mg/kg/day orally days 2-5 of a 7 day cycle for 2 cycles and then days 1-3 for 2 cycles. Tumour size was assessed by callipers. The graph in Fig. 13 shows the tumour growth in the treated and control mice, demonstrating in vivo synergy between CTPS1-IA and ceralasertib. 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 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 and 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. Clauses of the invention: A series of clauses setting out embodiments of the invention are as follows. Clause A1. A CTPS1 inhibitor for use in the treatment of cancer with an ATR inhibitor, wherein the CTPS1 inhibitor is defined in any one of Groups A to H. Clause A2. An ATR inhibitor for use in the treatment of cancer with a CTPS1 inhibitor, wherein the CTPS1 inhibitor is defined in any one of Groups A to H. Clause A3. A CTPS1 inhibitor and an ATR inhibitor for use in the treatment of cancer, wherein the CTPS1 inhibitor is defined in any one of Groups A to H. Clause A4. Use of a CTPS1 inhibitor in the manufacture of a medicament for the treatment of cancer with an ATR inhibitor, wherein the CTPS1 inhibitor is defined in any one of Groups A to H. Clause A5. Use of an ATR inhibitor in the manufacture of a medicament for the treatment of cancer with a CTPS1 inhibitor, wherein the CTPS1 inhibitor is defined in any one of Groups A to H. Clause A6. Use of a CTPS1 inhibitor and an ATR inhibitor in the manufacture of a medicament for the treatment of cancer, wherein the CTPS1 inhibitor is defined in any one of Groups A to H. Clause A7. A method of treating cancer in a subject which method comprises administering to the subject a CTPS1 inhibitor and an ATR inhibitor, wherein the CTPS1 inhibitor is defined in any one of Groups A to H. Clause A8. A pharmaceutical composition comprising a CTPS1 inhibitor and an ATR inhibitor, wherein the CTPS1 inhibitor is defined in any one of Groups A to H. Clause A9. A kit of parts comprising: a) a first container comprising a CTPS1 inhibitor; and b) a second container comprising an ATR inhibitor, wherein the CTPS1 inhibitor is defined in any one of Groups A to H. Clause A10. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A1 to A9, wherein the CTPS1 inhibitor has an IC50 of 10 uM or lower in respect of human CTPS1 enzyme. Clause A11. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause A10, wherein the CTPS1 inhibitor has an IC50 of 1 uM or lower in respect of human CTPS1 enzyme. Clause A12. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause A11, wherein the CTPS1 inhibitor has an IC50 of 100nM or lower in respect of human CTPS1 enzyme. Clause A13. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A10 to A12, wherein the IC50 of the CTPS1 inhibitor is established using the assay procedure set out in Example 1. Clause A14. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A1 to A13, wherein the CTPS1 inhibitor has a selectivity for human CTPS1 over human CTPS2 of at least 2-fold. Clause A15. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause A14, wherein the CTPS1 inhibitor has a selectivity for human CTPS1 over human CTPS2 of at least 30-fold. Clause A16. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause A15, wherein the CTPS1 inhibitor has a selectivity for human CTPS1 over human CTPS2 of at least 60-fold, such as at least 1000-fold. Clause A17. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A14 to A16, wherein the selectivity of the CTPS1 inhibitor is established using the assay procedure set out in Example 2. Clause A18. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A1 to A17, wherein the CTPS1 inhibitor is a compound of formula (I)
Figure imgf000105_0001
wherein 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, or R4 and R5 together with the carbon atom to which they are attached form a C3- 6cycloalkyl or C3-6heterocycloalkyl ring; R6 is 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; 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; R12 is attached to Ar2 in the meta or ortho position relative to Ar1 and R12 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, 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 R12 together with a nitrogen atom to which it is attached forms an N-oxide (N+-O-); R23 is H or C1-2alkyl; R24 is H or C1-2alkyl; or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof (‘Group A’). Clause A19. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause A17, wherein the CTPS1 inhibitor is selected from the compounds disclosed in List A or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof. Clause A20. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A1 to A17, wherein the CTPS1 inhibitor is a compound of formula (II):
Figure imgf000106_0001
wherein 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 membered 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 6 membered oxygen-containing heterocycloalkyl, or R4 and R5 together 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; or R4 is O and R5 is absent; R6 is H or C1-3alkyl, 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 is 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; 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 C2alkylene 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, 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; 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 acceptable solvate thereof (‘Group B’). Clause A21. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause A20, wherein the CTPS1 inhibitor is selected from the compounds disclosed in List B or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof. Clause A22. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A1 to A17, wherein the CTPS1 inhibitor is a compound of formula (III):
Figure imgf000107_0001
wherein 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; 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; 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 C3-6cycloalkyl 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; 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; 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)-: 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; 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 acceptable solvate thereof (‘Group C’). Clause A23. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause A22, wherein the CTPS1 inhibitor is selected from the compounds disclosed in List C or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof. Clause A23. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause A22, wherein the CTPS1 inhibitor is a compound of formula (IV):
Figure imgf000109_0001
wherein: (a) when R4, R5, X, Y and R1 are as follows:
Figure imgf000109_0002
then W is N, CH or CF; (b) when R4, R5, X, W and R1 are as follows:
Figure imgf000109_0003
then Y is CH or N; (c) when W, X, Y and R1 are as follows:
Figure imgf000109_0004
then R4 and R5 are joined to form the following structures:
Figure imgf000110_0001
(d) when W, R4, R5, X and Y are as follows:
Figure imgf000110_0002
then R1 is methyl or cyclopropyl; and (e) the compound is selected from the group consisting of:
Figure imgf000110_0003
and
Figure imgf000110_0004
or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof (‘Group D’). Clause A25. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause A24, wherein the CTPS1 inhibitor is selected from the compounds disclosed in List D or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof. Clause A26. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause A22, wherein the CTPS1 inhibitor is a compound of formula (V):
Figure imgf000110_0005
(a) when A, V, W, X, Y, Z, R1, R10 and R12 are as follows:
Figure imgf000110_0006
then R4 and R5 together with the carbon atom to which they attached form:
Figure imgf000111_0001
or (b) when A, V, W, X, Y, Z, R1, R10 and R12 are as follows:
Figure imgf000111_0002
then R4 and R5 together with the carbon atom to which they are attached form:
Figure imgf000111_0003
or (c) when A, V, W, X, Y, Z, R4, R5, R10 and R12 are as follows:
Figure imgf000111_0004
: then R1 is
Figure imgf000111_0005
or (d) when A, V, W, X, Y, Z, R4, R5, R10 and R12 are as follows:
Figure imgf000111_0006
then R1 is
Figure imgf000111_0007
or (e) when A, X, Y, Z, R1, R4 and R5 are as follows:
Figure imgf000111_0008
then V, W, R10 and R12 are:
Figure imgf000112_0001
or
Figure imgf000112_0002
or (f) when A, V, W, R1, R4, R5, R10 and R12 are as follows:
Figure imgf000112_0003
then Z, X and Y are
Figure imgf000112_0004
or (g) when A, V, W, R1, R4, R5, R10 and R12 are as follows:
Figure imgf000112_0005
then Z, X and Y are
Figure imgf000112_0006
; or (h) when A, V, W, R1, R4, R5, R10 and R12 are as follows
Figure imgf000112_0007
then Z, X and Y are
Figure imgf000112_0008
or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof (‘Group E’). Clause A27. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause A26, wherein the CTPS1 inhibitor is selected from the compounds disclosed in List E or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof. Clause A28. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A1 to A17, wherein the CTPS1 inhibitor is a compound of formula (VI):
Figure imgf000113_0001
wherein ring B is selected from the group consisting of:
Figure imgf000113_0002
(B-a) wherein X, Y and Z are as defined below; and
Figure imgf000113_0003
(B-bc); 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):
Figure imgf000113_0004
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)-; 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 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: R1aa is NR32aR33a; R1ba is 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; 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, 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 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- 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 the C3- 6heterocycloalkyl 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 C1-3alkyl or OC1-3alkyl; or R4aa and R5aa 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)2R29a; or R4ba and R5ba are each independently H, C1-6alkyl, C1-6alkylOH, C1-6haloalkyl, C0- 2alkyleneC3-6cycloalkyl, C0-2alkyleneC3-6heterocycloalkyl, C1-3alkyleneOC1-3alkyl, or R4ba and R5ba together with the carbon atom to which they are attached form a C3-6cycloalkyl or C3-6heterocycloalkyl; and when 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; 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, 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- 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 C4- 6heterocycloalkyl; R22a is H or CH3; R23a is H or C1-2alkyl; and R24a is H or C1-2alkyl R29a 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; R32a is C1-3alkyl and R33 is C1-3alkyl; or R32a and R33a together with the nitrogen atom to which they are attached form a C3- 5heterocycloalkyl; wherein R1a is R1aa; and/or R4a and R5a are R4aa and R5aa; and/or Aa is Aaa; and wherein when B is (B-bc) and R3b3c is R3b, the compound of formula (VI) is a compound of formula (VI-b):
Figure imgf000115_0001
wherein: Ab is Aab or Abb; wherein: Aab is -NR6bCH2- or -NR6b-; Abb is -NR6bC(=O)-; R1b is R1ab or R1bb; wherein: R1ab is NR32bR33b; R1bb is C1-5alkyl, C0-2alkyleneC3-5cycloalkyl which cycloalkyl is optionally substituted by CH3, C1-3alkyleneOC1-2alkyl, or CF3; R3b is H, halo, CH3, OC1-2alkyl or CF3; or R3b together with R5bb forms a 5- or 6-membered cycloalkyl or 5 or 6 membered oxygen- containing heterocycloalkyl; 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 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 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, 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 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 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 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 or NR21bR22b, or R4bb is H and R5bb together with R3b form a 5- or 6-membered cycloalkyl 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; 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 R4bb 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; R11b is H, F, Cl, CH3, ethyl, OCH3, CF3, OCF3 or CN, or R11b, when in the ortho-position to group Ab, together with R6b are a C2alkylene chain forming a 5-membered ring; R12b is attached to Ar2b in the ortho or meta position relative to Ar1b and R12b 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, 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-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; 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; 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; 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 formula (VI-c):
Figure imgf000118_0001
wherein: Ac is Aac or Abc; wherein: Aac is -CH2NR6c-; Abc is -C(=O)NR6c-; R1c is R1ac or R1bc; wherein: R1ac is NR32cR33c; 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; 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, C1-3haloalkyl, 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 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 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 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 C3- 6heterocycloalkyl comprising one nitrogen atom, wherein said nitrogen atom is substituted by -S(O)2R29c; or R4bc and R5bc are each independently H, C1-6alkyl, C0-2alkyleneC3-6cycloalkyl, C0- 2alkyleneC3-6heterocycloalkyl, C1-3alkyleneOC1-3alkyl, C1-6alkylOH or C1-6haloalkyl, or R4bc and R5bc together with the carbon atom to which they are attached form a C3-6cycloalkyl or C3-6heterocycloalkyl ring; R6c is H or C1-3alkyl; Ar1c is a 6-membered aryl or heteroaryl; Ar2c is a 6-membered aryl or heteroaryl and is attached to Ar1c in the para position relative to group Ac; R10c is H, halo, C1-3alkyl, OC1-2alkyl, C1-2haloalkyl, OC1-2haloalkyl or CN; R11c is H, F, Cl, CH3, ethyl, OCH3, CF3, OCF3 or CN; 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 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; 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 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: 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 (‘Group F’). Clause A29. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause A28, 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 A30. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A1 to A17, wherein the CTPS1 inhibitor is a compound of formula (VII):
Figure imgf000120_0001
wherein 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 -NHC(=O)-; B is
Figure imgf000120_0002
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; 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; 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-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: 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 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 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 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 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, C0-2alkyleneC3- 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- 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; 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, 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-: 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; 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 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 acceptable solvate thereof (‘Group G’). Clause A31. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause A30, wherein the CTPS1 inhibitor is selected from the compounds disclosed in List G or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof. Clause A32. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A1 to A17, wherein the CTPS1 inhibitor is compound of formula (VIII):
Figure imgf000123_0001
wherein 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 -NHC(=O)-;
Figure imgf000123_0002
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; 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; 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-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: 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 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 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 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 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, C0-2alkyleneC3- 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- 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; 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, 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-: 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; 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 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 acceptable solvate thereof (‘Group H’). Clause A33. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause A32, wherein the CTPS1 inhibitor is selected from the compounds disclosed in List H or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof. Clause A34. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A1 to A17, wherein the CTPS1 inhibitor is 4-(2- (cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)tetrahydro-2H- pyran-4-carboxamide:
Figure imgf000125_0001
or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof. Clause A35. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A1 to A17, wherein the CTPS1 inhibitor is N-(5-(6-ethoxypyrazin-2- yl)pyridin-2-yl)-4-(2-(ethylsulfonamido)pyrimidin-4-yl)tetrahydro-2H-pyran-4-carboxamide:
Figure imgf000125_0002
or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof. Clause A36. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A1 to A35, wherein the CTPS1 inhibitor is in its free form. Clause A37. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A1 to A35, wherein the CTPS1 inhibitor is a pharmaceutically acceptable salt. Clause A38. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A1 to A35, wherein the CTPS1 inhibitor is a pharmaceutically acceptable solvate. Clause A39. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A1 to A35, wherein the CTPS1 inhibitor is a pharmaceutically acceptable salt and a pharmaceutically acceptable solvate. Clause A40. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according any one of clauses A1 to A17, wherein the CTPS1 inhibitor is 4-(2- (cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)tetrahydro-2H- pyran-4-carboxamide (‘CTPS1-IA’):
Figure imgf000126_0001
or a pharmaceutically acceptable salt thereof. Clause A41. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A1 to A17, wherein the CTPS1 inhibitor is N-(5-(6-ethoxypyrazin-2- yl)pyridin-2-yl)-4-(2-(ethylsulfonamido)pyrimidin-4-yl)tetrahydro-2H-pyran-4-carboxamide (‘CTPS1-IB’):
Figure imgf000126_0002
or a pharmaceutically acceptable salt thereof. Clause A42. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A1 to A41, wherein the CTPS1 inhibitor is provided in a natural isotopic form. Clause A43. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A1 to A42, wherein the ATR inhibitor has a Ki value for binding to human ATR of 50 nM or less. Clause A44. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause A43, wherein the ATR inhibitor has a Ki value for binding to human ATR of 20 nM or less. Clause A45. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause A44, wherein the ATR inhibitor has a Ki value for binding to human ATR of 5 nM or less. Clause A46. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause A45, wherein the ATR inhibitor has a Ki value for binding to human ATR of 1 nM or less. Clause A47. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A43 to A46, wherein the Ki value of the ATR inhibitor for binding to human ATR is established using the ATR protein kinase assay procedure set out in Example 3. Clause A48. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A43 to A46, wherein the Ki value of the ATR inhibitor for binding to human ATR is established using the ATR induced phosphorylation of CHEK1 assay procedure set out in Example 3. Clause A49. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A43 to A46, wherein the Ki value of the ATR inhibitor for binding to human ATR is established using the ATR induced phosphorylation of γH2AX assay procedure set out in Example 3. Clause A50. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A1 to A49, wherein the ATR inhibitor has a selectivity for human ATR over human ATM of >5-fold. Clause A51. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause A50, wherein the ATR inhibitor has a selectivity for human ATR over human ATM of >10- fold. Clause A52. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A1 to A51, wherein the ATR inhibitor has a selectivity for human DNA-PK over human DNA-PK of >5-fold. Clause A53. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause A52, wherein the ATR inhibitor has a selectivity for human ATR over human DNA-PK of >10-fold. Clause A54. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A1 to A53, wherein the ATR inhibitor has a selectivity for human MTOR over human ATM of >5-fold. Clause A55. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause A54, wherein the ATR inhibitor has a selectivity for human ATR over human MTOR of >10-fold. Clause A56. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A50 to A55, wherein the selectivity of the ATR inhibitor is established using the assay procedure set out in Example 4. Clause A57. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A1 to A56, wherein the ATR inhibitor is selected from ceralasertib, VE821, gartisertib, ETP-46464, AZ20, elimusertib and berzosertib, pharmaceutically acceptable salts thereof and/or pharmaceutically acceptable solvates thereof. Clause A58. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause A57, wherein the ATR inhibitor is selected from ceralasertib or VE821, pharmaceutically acceptable salts thereof and/or pharmaceutically acceptable solvates thereof. Clause A59. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause A58, wherein the ATR inhibitor is ceralasertib:
Figure imgf000128_0001
(imino-methyl-[1-[6-[(3R)-3-methylmorpholin-4-yl]-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4- yl]cyclopropyl]-oxo-λ6-sulfane), pharmaceutically acceptable salts thereof and/or pharmaceutically acceptable solvates thereof. Clause A60. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause A58, wherein the ATR inhibitor is VE821:
Figure imgf000128_0002
(3-amino-6-(4-methylsulfonylphenyl)-N-phenylpyrazine-2-carboxamide), pharmaceutically acceptable salts thereof and/or pharmaceutically acceptable solvates thereof. Clause A61. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause A57, wherein the ATR inhibitor is gartisertib:
Figure imgf000128_0003
(2-amino-6-fluoro-N-[5-fluoro-4-[4-[4-(oxetan-3-yl)piperazine-1-carbonyl]piperidin-1-yl]pyridin-3- yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide), pharmaceutically acceptable salts thereof and/or pharmaceutically acceptable solvates thereof. Clause A62. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause A57, wherein the ATR inhibitor is ETP-46464:
Figure imgf000129_0001
(2-methyl-2-[4-(2-oxo-9-quinolin-3-yl-4H-[1,3]oxazino[5,4-c]quinolin-1-yl)phenyl]propanenitrile), pharmaceutically acceptable salts thereof and/or pharmaceutically acceptable solvates thereof. Clause A63. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause A57, wherein the ATR inhibitor is AZ20:
Figure imgf000129_0002
((3R)-4-[2-(1H-indol-4-yl)-6-(1-methylsulfonylcyclopropyl)pyrimidin-4-yl]-3-methylmorpholine), pharmaceutically acceptable salts thereof and/or pharmaceutically acceptable solvates thereof. Clause A64. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause A57, wherein the ATR inhibitor is elimusertib:
Figure imgf000129_0003
((3R)-3-methyl-4-[4-(2-methylpyrazol-3-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-2-yl]morpholine), pharmaceutically acceptable salts thereof and/or pharmaceutically acceptable solvates thereof. Clause A65. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause A57, wherein the ATR inhibitor is berzosertib:
Figure imgf000130_0001
(3-[3-[4-(methylaminomethyl)phenyl]-1,2-oxazol-5-yl]-5-(4-propan-2-ylsulfonylphenyl)pyrazin-2- amine), pharmaceutically acceptable salts thereof and/or pharmaceutically acceptable solvates thereof. Clause A66. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A1 to A65, wherein the ATR inhibitor is in its free form. Clause A67. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A1 to A65, wherein the ATR inhibitor is a pharmaceutically acceptable salt. Clause A68. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A1 to A65, wherein the ATR inhibitor is a pharmaceutically acceptable solvate. Clause A69. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A1 to A65, wherein the ATR inhibitor is a pharmaceutically acceptable salt and pharmaceutically acceptable solvate. Clause A70. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause A59, wherein the ATR inhibitor is ceralasertib:
Figure imgf000130_0002
(imino-methyl-[1-[6-[(3R)-3-methylmorpholin-4-yl]-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4- yl]cyclopropyl]-oxo-λ6-sulfane). Clause A71. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause A70, wherein the CTPS1 inhibitor is CTPS-IA or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof and the ATR inhibitor is ceralasertib. Clause A72. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause A71, wherein the CTPS1 inhibitor is CTPS-IA or a pharmaceutically acceptable salt thereof and the ATR inhibitor is ceralasertib. Clause A73. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause A60, wherein the ATR inhibitor is VE821:
Figure imgf000131_0001
(3-amino-6-(4-methylsulfonylphenyl)-N-phenylpyrazine-2-carboxamide). Clause A74. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause A73, wherein the CTPS1 inhibitor is CTPS-IA or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof and the ATR inhibitor is VE821. Clause A75. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause A74, wherein the CTPS1 inhibitor is CTPS-IA or a pharmaceutically acceptable salt thereof and the ATR inhibitor is VE821. Clause A76. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A1 to A75, wherein the ATR inhibitor is provided in a natural isotopic form. Clause A77. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A1 to A76 wherein the CTPS1 inhibitor and the ATR inhibitor act synergistically in treating the cancer. Clause A78. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause A77 wherein the combined administration of the CTPS1 inhibitor and the ATR inhibitor results in a beneficial effect greater than the sum of the beneficial effects of each agent administered alone. Clause A79. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause A77 or A78 wherein the CTPS1 inhibitor and the ATR inhibitor achieve a Bliss score (Bliss 1939; Zheng 2021) of ≥10 when applied to a cancer cell line as set out in Example 6. Clause A80. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A1 to 79, wherein the ATR inhibitor and the CTPS1 inhibitor are administered to a mammal. Clause A81. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause A80, wherein the ATR inhibitor and the CTPS1 inhibitor are administered to a human. Clause A82. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A1 to A81, wherein the CTPS1 inhibitor and the ATR inhibitor are separately formulated. Clause A83. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause A82, wherein the CTPS1 inhibitor and the ATR inhibitor are administered separately. Clause A84. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A1 to 82, wherein the CTPS1 inhibitor and the ATR inhibitor are administered simultaneously. Clause A85. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause A84, wherein the CTPS1 inhibitor and the ATR inhibitor are co-formulated. Clause A86. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A1 to A85, wherein the CTPS1 inhibitor is administered by oral, parenteral, buccal, sublingual, nasal or rectal administration. Clause A87. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause A86, wherein the CTPS1 inhibitor is administered orally. Clause A88. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A1 to A87, wherein the ATR inhibitor is administered by oral, parenteral, buccal, sublingual, nasal or rectal administration. Clause A89. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause A88, wherein the ATR inhibitor is administered orally. Clause A90. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A1 to A89, wherein the CTPS1 inhibitor and ATR inhibitor administered separately, sequentially or simultaneously with one or more further pharmaceutically acceptable active ingredients. Clause A91. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause A90, wherein the one or more further pharmaceutically acceptable active ingredients are selected from tyrosine kinase inhibitors such as, for example, axitinib, dasatinib, erlotinib, imatinib, nilotinib, pazopanib and sunitinib. Clause A92. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause A90, wherein the one or more further pharmaceutically acceptable active ingredients are selected from zacitidine, decitabine, or cytarabine. Clause A93. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause A90, wherein the one or more further pharmaceutically acceptable active ingredients are selected from anticancer antibodies, such as those selected from the group consisting of anti- CD20 antibodies (such as obinutuzumab, ofatumumab, tositumomab or rituximab) or other antibodies such as olaratumab, daratumumab, necitumumab, dinutuximab, traztuzumab emtansine, pertuzumab, brentuximab, panitumumab, catumaxomab, bevacizumab, cetuximab, traztuzumab and gentuzumab ozogamycin. Clause A94. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A1 to A93, administered in combination with radiotherapy. Clause A95. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A1 to A94, administered in combination with surgery. Clause A96. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A1 to A95, administered in combination with hyperthermia therapy. Clause A97. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A1 to A96, administered in combination with cryotherapy. Clause A98. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A1 to A97, wherein the cancer is a cancer displaying high replicative stress. Clause A99. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A1 to A98, wherein the cancer constitutively expresses c-myc. Clause A100. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A1 to A99, wherein the cancer is a non-haematological cancer. Clause A101. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause A100, wherein the cancer is selected from the group consisting of colorectal cancer, bile duct cancer, endometrial cancer, hepatic cancer, gastric cancer, oesophageal cancer, sarcoma, bladder cancer, pancreatic cancer, ovarian cancer, lung cancer, mesothelioma, melanoma, bone cancer, head and neck cancer, breast cancer, brain cancers, prostate cancer, renal cancer, thyroid cancer and neuroblastoma. Clause A102. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause A101, wherein the cancer is selected from the group consisting of colorectal cancer, bile duct cancer, endometrial cancer, hepatic cancer, gastric cancer, oesophageal cancer, sarcoma, bladder cancer, pancreatic cancer, ovarian cancer, lung cancer, mesothelioma and melanoma. Clause A103. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause A102, wherein the cancer is selected from the group consisting of colorectal cancer, bile duct cancer, endometrial cancer, hepatic cancer, gastric cancer and oesophageal cancer. Clause A104. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A1 to A103, wherein the cancer is a solid tumour. Clause A105. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to either clause A100 or A104, wherein the cancer is a non-haematological cancer is selected from prostate cancer, pancreatic cancer, ovarian cancer, lung cancer, renal cancer, colorectal cancer or breast cancer. Clause A106. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A1 to A99, wherein the cancer is a haematological cancer. Clause A107. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause A106, wherein the haematological cancer is selected from the list consisting of acute myeloid leukemia, angioimmunoblastic T-cell lymphoma, B-cell acute lymphoblastic leukemia, Sweet syndrome, T-cell non-Hodgkins lymphoma (including natural killer/T-cell lymphoma, adult T-cell leukaemia/lymphoma, enteropathy type T-cell lymphoma, hepatosplenic T-cell lymphoma and cutaneous T-cell lymphoma), T-cell acute lymphoblastic leukemia, B-cell non- Hodgkins lymphoma (including Burkitt lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma), hairy cell leukemia, Hodgkin lymphoma, lymphoblastic lymphoma, lymphoplasmacytic lymphoma, mucosa-associated lymphoid tissue lymphoma, multiple myeloma, myelodysplastic syndrome, plasma cell myeloma, primary mediastinal large B-cell lymphoma, chronic myeloproliferative disorders (such as chronic myeloid leukemia, primary myelofibrosis, essential thrombocythemia, polycytemia vera) or chronic lymphocytic leukemia. Clause A108. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause A107, wherein the haematological cancer is selected from the list consisting of B-cell non-Hodgkins lymphoma (including Burkitt lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma), multiple myeloma and plasma cell myeloma. Clause A109. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause A108, wherein the haematological cancer is T cell lymphoma. Clause A110. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause A108, wherein the haematological cancer is diffuse large B cell lymphoma. Clause A111. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause A108, wherein the haematological cancer is plasma cell myeloma. Clause A112. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause A108, wherein the haematological cancer is acute myeloid leukaemia. Clause A113. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause A108, wherein the haematological cancer is chronic lymphocytic leukaemia. Clause A114. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause A108, wherein the haematological cancer is peripheral T cell lymphoma. Clause A115. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause A106, wherein the haematological cancer is T-cell prolymphocytic leukemia. Clause A116. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A1 to A115, for administration to a subject identified as having a cancer expected to be susceptible to treatment by a CTPS1 inhibitor and an ATR inhibitor. Clause A117. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A1 to A115, for administration to a subject from whom a sample of cancer cells has been shown to be susceptible to treatment by a CTPS1 inhibitor and an ATR inhibitor. Clause A118. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A1 to A117, wherein the CTPS1 inhibitor and ATR inhibitor are administered orally. Clause A119. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A1 to A118, wherein the CTPS1 inhibitor is in a solid pharmaceutical composition. Clause A120. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A1 to A119, wherein the ATR inhibitor is in a solid pharmaceutical composition. Clause A121. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A1 to A120, wherein the CTPS1 inhibitor is in a solid pharmaceutical composition and the ATR inhibitor is in a solid pharmaceutical composition. Clause A122. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A1 to A121, wherein the CTPS1 inhibitor is administered orally in a solid pharmaceutical composition. Clause A123. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A1 to A122, wherein the ATR inhibitor is administered orally in a solid pharmaceutical composition. Clause A124. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A1 to A123 wherein the CTPS1 inhibitor is administered orally in a solid pharmaceutical composition and the ATR inhibitor is administered orally in a solid pharmaceutical composition. Clause A125. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A1 to A124, wherein the CTPS1 inhibitor is: N-(5-(6-ethoxypyrazin-2-yl)pyridine-2-yl)-4-(2-(ethylsulfonamido)pyrimidin-4-yl)tetrahydro-2H- pyran-4-carboxamide:
Figure imgf000135_0001
or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof; and the ATR inhibitor is ceralasertib, or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof. Clause A126. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A1 to A124, wherein the CTPS1 inhibitor is: 4-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2- yl)tetrahydro-2H-pyran-4-carboxamide:
Figure imgf000136_0001
or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof; and the ATR inhibitor is ceralasertib, or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof. Clause A127. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A1 to A124, wherein the CTPS1 inhibitor is: N-(5-(6-ethoxypyrazin-2-yl)pyridine-2-yl)-4-(2-(ethylsulfonamido)pyrimidin-4-yl)tetrahydro-2H- pyran-4-carboxamide:
Figure imgf000136_0002
or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof; and the ATR inhibitor is VE821, or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof. Clause A128. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A1 to A124, wherein the CTPS1 inhibitor is: 4-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2- yl)tetrahydro-2H-pyran-4-carboxamide:
Figure imgf000136_0003
or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof; and the ATR inhibitor is VE821, or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof. Clause A129. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A1 to A124, wherein the ATR inhibitor is not ceralasertib. Clause A130. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause A129, wherein the ATR inhibitor is not ceralasertib, or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof. Clause A131. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A1 to A124, wherein the ATR inhibitor is not VE821. Clause A132. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause A131, wherein the ATR inhibitor is not VE821, or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof. Clause A133. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A1 to A132, wherein the CTPS1 inhibitor is not a CTPS1 inhibitor as defined in claim 1 of WO2022/087634. Clause A134. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A1 to A132, wherein the CTPS1 inhibitor is not a CTPS1 inhibitor as defined in WO2022/087634. Clause A135. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A1 to A132, wherein the CTPS1 inhibitor is a CTPS1 inhibitor disclosed in PCT publication number WO2022087634. Clause A136. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A1 to A132, wherein the CTPS1 inhibitor is (i) a compound described in any one of claims 1 to 31 of WO2022087634 or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof, (ii) a compound selected from compounds I-1 to I- 286 of WO2022087634, or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof, or (iii) a compound selected from compounds Z-1 to Z-10 of WO2022087634, or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof. Clause A137. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A1 to A132, wherein the CTPS1 inhibitor is not a CTPS1 inhibitor disclosed in PCT publication number WO2022087634. Clause A138. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses A1 to A132, wherein the CTPS1 inhibitor is not (i) a compound described in any one of claims 1 to 31 of WO2022087634 or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof, (ii) a compound selected from compounds I-1 to I- 286 of WO2022087634, or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof, or (iii) a compound selected from compounds Z-1 to Z-10 of WO2022087634, or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof. Further clauses of the invention: A series of further clauses setting out embodiments of the invention are as follows. Clause B1. A CTPS1 inhibitor for use in the treatment of cancer with an ATR inhibitor, wherein the ATR inhibitor is ceralasertib or VE821, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof. Clause B2. An ATR inhibitor for use in the treatment of cancer with a CTPS1 inhibitor, wherein the ATR inhibitor is ceralasertib or VE821, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof. Clause B3. A CTPS1 inhibitor and an ATR inhibitor for use in the treatment of cancer, wherein the ATR inhibitor is ceralasertib or VE821, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof. Clause B4. Use of a CTPS1 inhibitor in the manufacture of a medicament for the treatment of cancer with an ATR inhibitor, wherein the ATR inhibitor is ceralasertib or VE821, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof. Clause B5. Use of an ATR inhibitor in the manufacture of a medicament for the treatment of cancer with a CTPS1 inhibitor, wherein the ATR inhibitor is ceralasertib or VE821, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof. Clause B6. Use of a CTPS1 inhibitor and an ATR inhibitor in the manufacture of a medicament for the treatment of cancer, wherein the ATR inhibitor is ceralasertib or VE821, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof. Clause B7. A method of treating cancer in a subject which method comprises administering to the subject a CTPS1 inhibitor and an ATR inhibitor, wherein the ATR inhibitor is ceralasertib or VE821, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof. Clause B8. A pharmaceutical composition comprising a CTPS1 inhibitor and an ATR inhibitor, wherein the ATR inhibitor is ceralasertib or VE821, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof. Clause B9. A kit of parts comprising: a) a first container comprising a CTPS1 inhibitor; and b) a second container comprising an ATR inhibitor, wherein the ATR inhibitor is ceralasertib or VE821, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof. Clause B10. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses B1 to B9, wherein the CTPS1 inhibitor has an IC50 of 10 uM or lower in respect of human CTPS1 enzyme. Clause B11. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause B10, wherein the CTPS1 inhibitor has an IC50 of 1 uM or lower in respect of human CTPS1 enzyme. Clause B12. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause B11, wherein the CTPS1 inhibitor has an IC50 of 100nM or lower in respect of human CTPS1 enzyme. Clause B13. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses B10 to B12, wherein the IC50 of the CTPS1 inhibitor is established using the assay procedure set out in Example 1. Clause B14. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses B1 to B13, wherein the CTPS1 inhibitor has a selectivity for human CTPS1 over human CTPS2 of at least 2-fold. Clause B15. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause B14, wherein the CTPS1 inhibitor has a selectivity for human CTPS1 over human CTPS2 of at least 30-fold. Clause B16. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause B15, wherein the CTPS1 inhibitor has a selectivity for human CTPS1 over human CTPS2 of at least 60-fold, such as at least 1000-fold. Clause B17. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses B14 to B16, wherein the selectivity of the CTPS1 inhibitor is established using the assay procedure set out in Example 2. Clause B18. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses B1 to B17, wherein the CTPS1 inhibitor is a compound of formula (I)
Figure imgf000139_0001
wherein 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, or R4 and R5 together with the carbon atom to which they are attached form a C3- 6cycloalkyl or C3-6heterocycloalkyl ring; R6 is 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; 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; R12 is attached to Ar2 in the meta or ortho position relative to Ar1 and R12 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, 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 R12 together with a nitrogen atom to which it is attached forms an N-oxide (N+-O-); R23 is H or C1-2alkyl; R24 is H or C1-2alkyl; or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof. Clause B 19. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause B18, wherein the CTPS1 inhibitor is selected from the compounds disclosed in List A or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof. Clause B20. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses B1 to B17, wherein the CTPS1 inhibitor is a compound of formula (II):
Figure imgf000140_0001
wherein 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 membered 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 6 membered oxygen-containing heterocycloalkyl, or R4 and R5 together 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; or R4 is O and R5 is absent; R6 is H or C1-3alkyl, 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 is 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; 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 C2alkylene 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, 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; 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 acceptable solvate thereof. Clause B21. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause B20, wherein the CTPS1 inhibitor is selected from the compounds disclosed in List B or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof. Clause B22. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses B1 to B17, wherein the CTPS1 inhibitor is a compound of formula (III):
Figure imgf000141_0001
wherein 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; 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; 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 C3-6cycloalkyl 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; 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; 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)-: 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; 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 acceptable solvate thereof. Clause B23. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause B22, wherein the CTPS1 inhibitor is selected from the compounds disclosed in List C or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof. Clause B24. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause B22, wherein the CTPS1 inhibitor is a compound of formula (IV):
Figure imgf000143_0001
wherein: (a) when R4, R5, X, Y and R1 are as follows:
Figure imgf000143_0002
then W is N, CH or CF; (b) when R4, R5, X, W and R1 are as follows:
Figure imgf000143_0003
then Y is CH or N; (c) when W, X, Y and R1 are as follows:
Figure imgf000143_0004
then R4 and R5 are joined to form the following structures:
Figure imgf000144_0001
(d) when W, R4, R5, X and Y are as follows:
Figure imgf000144_0002
then R1 is methyl or cyclopropyl; and (e) the compound is selected from the group consisting of:
Figure imgf000144_0003
or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof. Clause B25. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause B24, wherein the CTPS1 inhibitor is selected from the compounds disclosed in List D or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof. Clause B26. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause B22, wherein the CTPS1 inhibitor is a compound of formula (V):
Figure imgf000144_0004
(a) when A, V, W, X, Y, Z, R1, R10 and R12 are as follows:
Figure imgf000144_0005
, then R4 and R5 together with the carbon atom to which they attached form:
Figure imgf000145_0001
or (b) when A, V, W, X, Y, Z, R1, R10 and R12 are as follows:
Figure imgf000145_0002
then R4 and R5 together with the carbon atom to which they are attached form:
Figure imgf000145_0003
or (c) when A, V, W, X, Y, Z, R4, R5, R10 and R12 are as follows:
Figure imgf000145_0004
: then R1 is
Figure imgf000145_0005
or (d) when A, V, W, X, Y, Z, R4, R5, R10 and R12 are as follows:
Figure imgf000145_0006
then R1 is
Figure imgf000145_0007
or (e) when A, X, Y, Z, R1, R4 and R5 are as follows:
Figure imgf000145_0008
then V, W, R10 and R12 are:
Figure imgf000146_0001
or (f) when A, V, W, R1, R4, R5, R10 and R12 are as follows:
Figure imgf000146_0002
then Z, X and Y are
Figure imgf000146_0003
or (g) when A, V, W, R1, R4, R5, R10 and R12 are as follows:
Figure imgf000146_0004
then Z, X and Y are
Figure imgf000146_0005
or (h) when A, V, W, R1, R4, R5, R10 and R12 are as follows
Figure imgf000146_0006
then Z, X and Y are
Figure imgf000146_0007
or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof. Clause B27. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause B25, wherein the CTPS1 inhibitor is selected from the compounds disclosed in List E or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof. Clause B28. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses B1 to B17, wherein the CTPS1 inhibitor is a compound of formula (VI):
Figure imgf000147_0001
wherein ring B is selected from the group consisting of:
Figure imgf000147_0002
wherein X, Y and Z are as defined below; and
Figure imgf000147_0003
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):
Figure imgf000147_0004
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)-; 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 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: R1aa is NR32aR33a; R1ba is 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; 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, 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 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- 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 the C3- 6heterocycloalkyl 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 C1-3alkyl or OC1-3alkyl; or R4aa and R5aa 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)2R29a; or R4ba and R5ba are each independently H, C1-6alkyl, C1-6alkylOH, C1-6haloalkyl, C0- 2alkyleneC3-6cycloalkyl, C0-2alkyleneC3-6heterocycloalkyl, C1-3alkyleneOC1-3alkyl, or R4ba and R5ba together with the carbon atom to which they are attached form a C3-6cycloalkyl or C3-6heterocycloalkyl; and when 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; 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, 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- 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 C4- 6heterocycloalkyl; R22a is H or CH3; R23a is H or C1-2alkyl; and R24a is H or C1-2alkyl R29a 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; R32a is C1-3alkyl and R33 is C1-3alkyl; or R32a and R33a together with the nitrogen atom to which they are attached form a C3- 5heterocycloalkyl; wherein R1a is R1aa; and/or R4a and R5a are R4aa and R5aa; and/or Aa is Aaa; and wherein when B is (B-bc) and R3b3c is R3b, the compound of formula (VI) is a compound of formula (VI-b):
Figure imgf000149_0001
( ) wherein: Ab is Aab or Abb; wherein: Aab is -NR6bCH2- or -NR6b-; Abb is -NR6bC(=O)-; R1b is R1ab or R1bb; wherein: R1ab is NR32bR33b; R1bb is C1-5alkyl, C0-2alkyleneC3-5cycloalkyl which cycloalkyl is optionally substituted by CH3, C1-3alkyleneOC1-2alkyl, or CF3; R3b is H, halo, CH3, OC1-2alkyl or CF3; or R3b together with R5bb forms a 5- or 6-membered cycloalkyl or 5 or 6 membered oxygen- containing heterocycloalkyl; 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 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 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, 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 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 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 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 or NR21bR22b, or R4bb is H and R5bb together with R3b form a 5- or 6-membered cycloalkyl 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; 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 R4bb 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; R11b is H, F, Cl, CH3, ethyl, OCH3, CF3, OCF3 or CN, or R11b, when in the ortho-position to group Ab, together with R6b are a C2alkylene chain forming a 5-membered ring; R12b is attached to Ar2b in the ortho or meta position relative to Ar1b and R12b 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, 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-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; 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; 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; 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 formula (VI-c):
Figure imgf000152_0001
wherein: Ac is Aac or Abc; wherein: Aac is -CH2NR6c-; Abc is -C(=O)NR6c-; R1c is R1ac or R1bc; wherein: R1ac is NR32cR33c; 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; 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, C1-3haloalkyl, 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 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 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 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 C3- 6heterocycloalkyl comprising one nitrogen atom, wherein said nitrogen atom is substituted by -S(O)2R29c; or R4bc and R5bc are each independently H, C1-6alkyl, C0-2alkyleneC3-6cycloalkyl, C0- 2alkyleneC3-6heterocycloalkyl, C1-3alkyleneOC1-3alkyl, C1-6alkylOH or C1-6haloalkyl, or R4bc and R5bc together with the carbon atom to which they are attached form a C3-6cycloalkyl or C3-6heterocycloalkyl ring; R6c is H or C1-3alkyl; Ar1c is a 6-membered aryl or heteroaryl; Ar2c is a 6-membered aryl or heteroaryl and is attached to Ar1c in the para position relative to group Ac; R10c is H, halo, C1-3alkyl, OC1-2alkyl, C1-2haloalkyl, OC1-2haloalkyl or CN; R11c is H, F, Cl, CH3, ethyl, OCH3, CF3, OCF3 or CN; 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 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; 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 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: 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. Clause B29. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause B28, 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 B30. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses B1 to B17, wherein the CTPS1 inhibitor is a compound of formula (VII):
Figure imgf000154_0001
wherein 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 -NHC(=O)-;
Figure imgf000154_0002
; 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; 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; 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-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: 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 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 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 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 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, C0-2alkyleneC3- 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- 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; 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, 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-: 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; 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 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 acceptable solvate thereof. Clause B31. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause B30, wherein the CTPS1 inhibitor is selected from the compounds disclosed in List G or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof. Clause B32. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses B1 to B17, wherein the CTPS1 inhibitor is compound of formula (VIII):
Figure imgf000157_0001
wherein 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 -NHC(=O)-;
Figure imgf000157_0002
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; 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; 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-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: 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 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 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 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 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, C0-2alkyleneC3- 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- 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; 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, 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-: 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; 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 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 acceptable solvate thereof. Clause B33. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause B32, wherein the CTPS1 inhibitor is selected from the compounds disclosed in List H or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof. Clause B34. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses B1 to B17, wherein the CTPS1 inhibitor is 4-(2- (cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)tetrahydro-2H- pyran-4-carboxamide:
Figure imgf000159_0001
or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof. Clause B35. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses B1 to B17, wherein the CTPS1 inhibitor is N-(5-(6-ethoxypyrazin-2- yl)pyridin-2-yl)-4-(2-(ethylsulfonamido)pyrimidin-4-yl)tetrahydro-2H-pyran-4-carboxamide:
Figure imgf000159_0002
or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof. Clause B36. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses B1 to B35, wherein the CTPS1 inhibitor is in its free form. Clause B37. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses B1 to B35, wherein the CTPS1 inhibitor is a pharmaceutically acceptable salt. Clause B38. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses B1 to B35, wherein the CTPS1 inhibitor is a pharmaceutically acceptable solvate. Clause B39. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses 1 to 35, wherein the CTPS1 inhibitor is a pharmaceutically acceptable salt and a pharmaceutically acceptable solvate. Clause B40. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses B1 to B17, wherein the CTPS1 inhibitor is 4-(2- (cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)tetrahydro-2H- pyran-4-carboxamide (‘CTPS1-IA’):
Figure imgf000160_0001
or a pharmaceutically acceptable salt thereof. Clause B41. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses B1 to B17, wherein the CTPS1 inhibitor is N-(5-(6-ethoxypyrazin-2- yl)pyridin-2-yl)-4-(2-(ethylsulfonamido)pyrimidin-4-yl)tetrahydro-2H-pyran-4-carboxamide (‘CTPS1-IB’):
Figure imgf000160_0002
or a pharmaceutically acceptable salt thereof. Clause B42. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses B1 to B41, wherein the CTPS1 inhibitor is provided in a natural isotopic form. Clause B43. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses B1 to B41, wherein the ATR inhibitor has a Ki value for binding to human ATR of 50 nM or less. Clause B44. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause B43, wherein the ATR inhibitor has a Ki value for binding to human ATR of 20 nM or less. Clause B45. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause B44, wherein the ATR inhibitor has a Ki value for binding to human ATR of 5 nM or less. Clause B46. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause B45, wherein the ATR inhibitor has a Ki value for binding to human ATR of 1 nM or less. Clause B47. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses B43 to B46, wherein the Ki value of the ATR inhibitor for binding to human ATR is established using the ATR protein kinase assay procedure set out in Example 3. Clause B48. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses B43 to B46, wherein the Ki value of the ATR inhibitor for binding to human ATR is established using the ATR induced phosphorylation of CHEK1 assay procedure set out in Example 3. Clause B49. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses B43 to B46, wherein the Ki value of the ATR inhibitor for binding to human ATR is established using the ATR induced phosphorylation of γH2AX assay procedure set out in Example 3. Clause B50. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses B1 to B49, wherein the ATR inhibitor has a selectivity for human ATR over human ATM of >5-fold. Clause B51. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause B50, wherein the ATR inhibitor has a selectivity for human ATR over human ATM of >10- fold. Clause B52. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses B1 to B51, wherein the ATR inhibitor has a selectivity for human DNA-PK over human DNA-PK of >5-fold. Clause B53. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause B52, wherein the ATR inhibitor has a selectivity for human ATR over human DNA_PK of >10-fold. Clause B54. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses B1 to B53, wherein the ATR inhibitor has a selectivity for human MTOR over human ATM of >5-fold. Clause B55. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause B54, wherein the ATR inhibitor has a selectivity for human ATR over human MTOR of >10-fold. Clause B56. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clausesB 50 to B55, wherein the selectivity of the ATR inhibitor is established using the assay procedure set out in Example 4. Clause B57. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses B1 to B56, wherein the ATR inhibitor is ceralasertib:
Figure imgf000162_0001
(imino-methyl-[1-[6-[(3R)-3-methylmorpholin-4-yl]-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4- yl]cyclopropyl]-oxo-λ6-sulfane), pharmaceutically acceptable salts thereof and/or pharmaceutically acceptable solvates thereof. Clause B58. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses B1 to B56, wherein the ATR inhibitor is VE821:
Figure imgf000162_0002
(3-amino-6-(4-methylsulfonylphenyl)-N-phenylpyrazine-2-carboxamide), pharmaceutically acceptable salts thereof and/or pharmaceutically acceptable solvates thereof. Clause B59. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses B1 to B58, wherein the ATR inhibitor is in its free form. Clause B60. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses B1 to B58, wherein the ATR inhibitor is a pharmaceutically acceptable salt. Clause B61. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses B1 to B58, wherein the ATR inhibitor is a pharmaceutically acceptable solvate. Clause B62. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses B1 to B58, wherein the ATR inhibitor is a pharmaceutically acceptable salt and pharmaceutically acceptable solvate. Clause B63. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause B57, wherein the ATR inhibitor is ceralasertib:
Figure imgf000162_0003
(imino-methyl-[1-[6-[(3R)-3-methylmorpholin-4-yl]-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4- yl]cyclopropyl]-oxo-λ6-sulfane). Clause B64. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause B63, wherein the CTPS1 inhibitor is CTPS-IA or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof and the ATR inhibitor is ceralasertib. Clause B65. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause B64, wherein the CTPS1 inhibitor is CTPS-IA or a pharmaceutically acceptable salt thereof and the ATR inhibitor is ceralasertib. Clause B66. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause B58, wherein the ATR inhibitor is VE821:
Figure imgf000163_0001
(3-amino-6-(4-methylsulfonylphenyl)-N-phenylpyrazine-2-carboxamide). Clause B67. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause B66, wherein the CTPS1 inhibitor is CTPS-IA or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof and the ATR inhibitor is VE821. Clause B68. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause B67, wherein the CTPS1 inhibitor is CTPS-IA or a pharmaceutically acceptable salt thereof and the ATR inhibitor is VE821. Clause B69. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses B1 to B68, wherein the ATR inhibitor is provided in a natural isotopic form. Clause B70. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses B1 to B69 wherein the CTPS1 inhibitor and the ATR inhibitor act synergistically in treating the cancer. Clause B71. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses B1 to B70 wherein the combined administration of the CTPS1 inhibitor and the ATR inhibitor results in a beneficial effect greater than the sum of the beneficial effects of each agent administered alone. Clause B72. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause B70 or B71 wherein the CTPS1 inhibitor and the ATR inhibitor achieve a Bliss score (Bliss 1939; Zheng 2021) of ≥10 when applied to a cancer cell line as set out in Example 6. Clause B73. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses B1 to B72, wherein the ATR inhibitor and the CTPS1 inhibitor are administered to a mammal. Clause B74. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause B73, wherein the ATR inhibitor and the CTPS1 inhibitor are administered to a human. Clause B75. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses B1 to B74, wherein the CTPS1 inhibitor and the ATR inhibitor are separately formulated. Clause B76. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause B75, wherein the CTPS1 inhibitor and the ATR inhibitor are administered separately. Clause B77. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses B1 to B75, wherein the CTPS1 inhibitor and the ATR inhibitor are administered simultaneously. Clause B78. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause B77, wherein the CTPS1 inhibitor and the ATR inhibitor are co-formulated. Clause B79. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses B1 to B78, wherein the CTPS1 inhibitor is administered by oral, parenteral, buccal, sublingual, nasal or rectal administration. Clause B80. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause B79, wherein the CTPS1 inhibitor is administered orally. Clause B81. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses B1 to B80, wherein the ATR inhibitor is administered by oral, parenteral, buccal, sublingual, nasal or rectal administration. Clause B82. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause B81, wherein the ATR inhibitor is administered orally. Clause B83. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses B1 to B82, wherein the CTPS1 inhibitor and ATR inhibitor administered separately, sequentially or simultaneously with one or more further pharmaceutically acceptable active ingredients. Clause B84. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause B83, wherein the one or more further pharmaceutically acceptable active ingredients are selected from tyrosine kinase inhibitors such as, for example, axitinib, dasatinib, erlotinib, imatinib, nilotinib, pazopanib and sunitinib. Clause B85. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause B83, wherein the one or more further pharmaceutically acceptable active ingredients are selected from zacitidine, decitabine, or cytarabine. Clause B86. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause B83, wherein the one or more further pharmaceutically acceptable active ingredients are selected from anticancer antibodies, such as those selected from the group consisting of anti- CD20 antibodies (such as obinutuzumab, ofatumumab, tositumomab or rituximab) or other antibodies such as olaratumab, daratumumab, necitumumab, dinutuximab, traztuzumab emtansine, pertuzumab, brentuximab, panitumumab, catumaxomab, bevacizumab, cetuximab, traztuzumab and gentuzumab ozogamycin. Clause B87. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses B1 to B86, administered in combination with radiotherapy. Clause B88. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses B1 to B87, administered in combination with surgery. Clause B89. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses B1 to B88, administered in combination with hyperthermia therapy. Clause B90. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses B1 to B89, administered in combination with cryotherapy. Clause B91. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses B1 to B90, wherein the cancer constitutively expresses c-myc. Clause B92. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses B1 to B91, wherein the cancer is a non-haematological cancer. Clause B93. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause B92, wherein the cancer is selected from the group consisting of colorectal cancer, bile duct cancer, endometrial cancer, hepatic cancer, gastric cancer, oesophageal cancer, sarcoma, bladder cancer, pancreatic cancer, ovarian cancer, lung cancer, mesothelioma, melanoma, bone cancer, head and neck cancer, breast cancer, brain cancers, prostate cancer, renal cancer, thyroid cancer and neuroblastoma. Clause B94. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause B93, wherein the cancer is selected from the group consisting of colorectal cancer, bile duct cancer, endometrial cancer, hepatic cancer, gastric cancer, oesophageal cancer, sarcoma, bladder cancer, pancreatic cancer, ovarian cancer, lung cancer, mesothelioma and melanoma. Clause B95. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause B94, wherein the cancer is selected from the group consisting of colorectal cancer, bile duct cancer, endometrial cancer, hepatic cancer, gastric cancer and oesophageal cancer. Clause B96. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses B1 to B95, wherein the cancer is a solid tumour. Clause B97. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to either clauses B92 or B96, wherein the cancer is a non-haematological cancer is selected from prostate cancer, pancreatic cancer, ovarian cancer, lung cancer, renal cancer, colorectal cancer or breast cancer. Clause B98. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses B1 to B91, wherein the cancer is a haematological cancer. Clause B99. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause B98, wherein the haematological cancer is selected from the list consisting of acute myeloid leukemia, angioimmunoblastic T-cell lymphoma, B-cell acute lymphoblastic leukemia, Sweet syndrome, T-cell non-Hodgkins lymphoma (including natural killer/T-cell lymphoma, adult T-cell leukaemia/lymphoma, enteropathy type T-cell lymphoma, hepatosplenic T-cell lymphoma and cutaneous T-cell lymphoma), T-cell acute lymphoblastic leukemia, B-cell non- Hodgkins lymphoma (including Burkitt lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma), hairy cell leukemia, Hodgkin lymphoma, lymphoblastic lymphoma, lymphoplasmacytic lymphoma, mucosa-associated lymphoid tissue lymphoma, multiple myeloma, myelodysplastic syndrome, plasma cell myeloma, primary mediastinal large B-cell lymphoma, chronic myeloproliferative disorders (such as chronic myeloid leukemia, primary myelofibrosis, essential thrombocythemia, polycytemia vera) or chronic lymphocytic leukemia. Clause B100. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause B99, wherein the haematological cancer is selected from the list consisting of B-cell non- Hodgkins lymphoma (including Burkitt lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma), multiple myeloma and plasma cell myeloma. Clause B101. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause B98, wherein the haematological cancer is selected from the list consisting of T cell lymphoma, diffuse large B cell lymphoma, plasma cell myeloma, acute myeloid leukaemia, chronic lymphocytic leukaemia and peripheral T cell lymphoma. Clause B102. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause B101, wherein the haematological cancer is T cell lymphoma. Clause B103. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause B101, wherein the haematological cancer is diffuse large B cell lymphoma. Clause B104. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause B101, wherein the haematological cancer is plasma cell myeloma. Clause B105. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause B101, wherein the haematological cancer is acute myeloid leukaemia. Clause B106. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause B101, wherein the haematological cancer is chronic lymphocytic leukaemia. Clause B107. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause B101, wherein the haematological cancer is peripheral T cell lymphoma. Clause B108. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause B98, wherein the haematological cancer is T-cell prolymphocytic leukemia. Clause B109. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses B1 to B108, for administration to a subject identified as having a cancer expected to be susceptible to treatment by a CTPS1 inhibitor and an ATR inhibitor. Clause B110. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses B1 to B108, for administration to a subject from whom a sample of cancer cells has been shown to be susceptible to treatment by a CTPS1 inhibitor and an ATR inhibitor. Clause B111. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses B1 to B110, wherein the CTPS1 inhibitor and ATR inhibitor are administered orally. Clause B112. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses B1 to B111, wherein the CTPS1 inhibitor is in a solid pharmaceutical composition. Clause B113. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses B1 to B112, wherein the ATR inhibitor is in a solid pharmaceutical composition. Clause B114. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses B1 to B113, wherein the CTPS1 inhibitor is in a solid pharmaceutical composition and the ATR inhibitor is in a solid pharmaceutical composition. Clause B115. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses B1 to B114, wherein the CTPS1 inhibitor is administered orally in a solid pharmaceutical composition. Clause B116. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses B1 to B115, wherein the ATR inhibitor is administered orally in a solid pharmaceutical composition. Clause B117. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses B1 to B116 wherein the CTPS1 inhibitor is administered orally in a solid pharmaceutical composition and the ATR inhibitor is administered orally in a solid pharmaceutical composition. Clause B118. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses B1 to B117, wherein the CTPS1 inhibitor is: N-(5-(6-ethoxypyrazin-2-yl)pyridine-2-yl)-4-(2-(ethylsulfonamido)pyrimidin-4-yl)tetrahydro-2H- pyran-4-carboxamide:
Figure imgf000167_0001
or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof; and the ATR inhibitor is ceralasertib, or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof. Clause B119. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses B1 to B117, wherein the CTPS1 inhibitor is: 4-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2- yl)tetrahydro-2H-pyran-4-carboxamide:
Figure imgf000168_0001
, or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof; and the ATR inhibitor is ceralasertib, or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof. Clause B120. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses B1 to B117, wherein the CTPS1 inhibitor is: N-(5-(6-ethoxypyrazin-2-yl)pyridine-2-yl)-4-(2-(ethylsulfonamido)pyrimidin-4-yl)tetrahydro-2H- pyran-4-carboxamide:
Figure imgf000168_0002
or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof; and the ATR inhibitor is VE821, or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof. Clause B121. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses B1 to B117, wherein the CTPS1 inhibitor is: 4-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2- yl)tetrahydro-2H-pyran-4-carboxamide:
Figure imgf000168_0003
or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof; and the ATR inhibitor is VE821, or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof. Clause B122. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses B1 to B117, wherein the ATR inhibitor is not ceralasertib. Clause B123. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause B122, wherein the ATR inhibitor is not ceralasertib, or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof. Clause B124. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses B1 to B117, wherein the ATR inhibitor is not VE821. Clause B125. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to clause B124, wherein the ATR inhibitor is not VE821, or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof. Clause B126. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses B1 to B125, wherein the CTPS1 inhibitor is not a CTPS1 inhibitor as defined in claim 1 of WO2022/087634. Clause B127. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses B1 to B126, wherein the CTPS1 inhibitor is not a CTPS1 inhibitor as defined in WO2022/087634. Clause B128. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses B1 to B125, wherein the CTPS1 inhibitor is a CTPS1 inhibitor disclosed in PCT publication number WO2022087634. Clause B129. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses B1 to B125, wherein the CTPS1 inhibitor is (i) a compound described in any one of claims 1 to 31 of WO2022087634 or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof, (ii) a compound selected from compounds I-1 to I- 286 of WO2022087634, or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof, or (iii) a compound selected from compounds Z-1 to Z-10 of WO2022087634, or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof. Clause B130. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses B1 to B125, wherein the CTPS1 inhibitor is not a CTPS1 inhibitor disclosed in PCT publication number WO2022087634. Clause B131. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of clauses B1 to B125, wherein the CTPS1 inhibitor is not (i) a compound described in any one of claims 1 to 31 of WO2022087634 or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof, (ii) a compound selected from compounds I-1 to I- 286 of WO2022087634, or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof, or (iii) a compound selected from compounds Z-1 to Z-10 of WO2022087634, or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof. REFERENCES Behan et al. Nature.2019 Apr;568(7753):511-516. BioGPS; http://biogps.org/ Bliss Ann. Appl. Biol.193926, 585–615. Cancer Dependency Map: https://depmap.org/ Charrier et al. J Med Chem.2011 Apr 14;54(7):2320-2330. Cleary et al. Mol Cell.2020 Jun 18;78(6):1070-1085. EMBL-EBI Expression Atlas: https://www.ebi.ac.uk/gxa/home Foote et al. J Med Chem.2013 Mar 14;56(5):2125-2138. Gorecki et al. J. Cancers (Basel).2021 Feb 14;13(4):795. Jo et al. Mol Cancer Ther.2021 Aug;20(8):1431-1441. Karnitz et al. Clin Cancer Res.2015 Nov 1;21(21):4780-4785. Martin et al. Nature.2014 Jun 12;510(7504):288-292. Martin et al. JCI Insight.2020 Mar 12;5(5):e133880. Pelletier et al. Nat Rev Cancer.2018 Jan;18(1):51-63. Sun et al. Cancer Res.2022 Jan 12;canres.1707.2021 doi: 10.1158/0008-5472 Toledo et al. Nat Struct Mol Biol.2011 Jun;18(6):721-727 van Kuilenburg et al. Biochim Biophys Acta.2000 Jul 24;1492(2-3):548-552. Vendetti et al. Oncotarget.2015 Dec 29;6(42):44289-44305. Wengner et al. Mol Cancer Ther.2020 Jan;19(1):26-38. Zheng et al. SynergyFinder Plus: towards a better interpretation and annotation of drug combination screening datasets. bioRxiv, 2021.06.01.446564. WO2019106146 WO2019106156 WO2019179652 WO2019180244 WO2020083975 WO2020245664 WO2020245665 WO2021053402 WO2021053403 WO2022/087634

Claims

Claims 1. A CTPS1 inhibitor for use in the treatment of cancer with an ATR inhibitor, wherein the CTPS1 inhibitor is defined in any one of Groups A to H.
2. An ATR inhibitor for use in the treatment of cancer with a CTPS1 inhibitor, wherein the CTPS1 inhibitor is defined in any one of Groups A to H.
3. A pharmaceutical composition comprising a CTPS1 inhibitor and an ATR inhibitor, wherein the CTPS1 inhibitor is defined in any one of Groups A to H.
4. Use of a CTPS1 inhibitor in the manufacture of a medicament for the treatment of cancer with an ATR inhibitor, wherein the CTPS1 inhibitor is defined in any one of Groups A to H.
5. Use of an ATR inhibitor in the manufacture of a medicament for the treatment of cancer with a CTPS1 inhibitor, wherein the CTPS1 inhibitor is defined in any one of Groups A to H.
6. A method of treating cancer in a subject which method comprises administering to the subject a CTPS1 inhibitor and an ATR inhibitor, wherein the CTPS1 inhibitor is defined in any one of Groups A to H.
7. A kit of parts comprising: a) a first container comprising a CTPS1 inhibitor; and b) a second container comprising an ATR inhibitor, wherein the CTPS1 inhibitor is defined in any one of Groups A to H.
8. A CTPS1 inhibitor for use in the treatment of cancer with an ATR inhibitor, wherein the ATR inhibitor is ceralasertib or VE821, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof.
9. An ATR inhibitor for use in the treatment of cancer with a CTPS1 inhibitor, wherein the ATR inhibitor is ceralasertib or VE821, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof.
10. A pharmaceutical composition comprising a CTPS1 inhibitor and an ATR inhibitor, wherein the ATR inhibitor is ceralasertib or VE821, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof.
11. Use of a CTPS1 inhibitor in the manufacture of a medicament for the treatment of cancer with an ATR inhibitor, wherein the ATR inhibitor is ceralasertib or VE821, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof.
12. Use of an ATR inhibitor in the manufacture of a medicament for the treatment of cancer with a CTPS1 inhibitor, wherein the ATR inhibitor is ceralasertib or VE821 , a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof.
13. A method of treating cancer in a subject which method comprises administering to the subject a CTPS1 inhibitor and an ATR inhibitor, wherein the ATR inhibitor is ceralasertib or VE821, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof.
14. A kit of parts comprising: a) a first container comprising a CTPS1 inhibitor; and b) a second container comprising an ATR inhibitor, wherein the ATR inhibitor is ceralasertib or VE821, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof.
15. The CTPS1 inhibitor, ATR inhibitor, composition, method, use or kit according to any one of claims 1 to 14, wherein the CTPS1 inhibitor has an IC50 of 1uM or lower, established using the assay procedure set out in Example 1.
16. The CTPS1 inhibitor, ATR inhibitor, composition, method, use or kit according to any one of claims 1 to 15, wherein the CTPS1 inhibitor has a selectivity for CTPS1 over CTPS2 of >30 fold, established using the assay procedure set out in Example 2.
17. The CTPS1 inhibitor, ATR inhibitor, composition, method, use or kit according to any one of claims 1 to 16, wherein the CTPS1 inhibitor is a compound of formula (III):
Figure imgf000172_0001
wherein 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; 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; 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 C3-6cycloalkyl 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; 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; 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)-: 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; 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 acceptable solvate thereof (‘Group C’).
18. The CTPS1 inhibitor, ATR inhibitor, composition, method, use or kit according to claim 17, wherein the CTPS1 inhibitor is N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(2- (ethylsulfonamido)pyrimidin-4-yl)tetrahydro-2H-pyran-4-carboxamide:
Figure imgf000174_0001
or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof.
19. The CTPS1 inhibitor, ATR inhibitor, composition, method, use or kit according to claim 18, wherein the CTPS1 inhibitor is 4-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5- (6-ethoxypyrazin-2-yl)173yridine-2-yl)tetrahydro-2H-pyran-4-carboxamide:
Figure imgf000174_0002
or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof.
20. The CTPS1 inhibitor, ATR inhibitor, composition, method, use or kit according to any one of claims 1 to 16, wherein the CTPS1 inhibitor 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.
21. The CTPS1 inhibitor, ATR inhibitor, composition, method, use or kit according to any one of claims 1 to 20, wherein the ATR inhibitor has a Ki value for binding to ATR of 50 nM or lower, established using the ATR protein kinase assay procedure, the ATR induced phosphorylation of CHEK1 assay procedure or the ATR induced phosphorylation of γH2AX assay procedure set out in Example 3.
22. The CTPS1 inhibitor, ATR inhibitor, composition, method, use or kit according to any one of claims 1 to 21, wherein the ATR inhibitor has a selectivity for ATR over ATM, DNA-PK and/or MTOR of >5-fold, established using the assay procedure set out in Example 4.
23. The CTPS1 inhibitor, ATR inhibitor, composition, method, use or kit according to any one of claims 1 to 7 or 15 to 22, wherein the ATR inhibitor is selected from ceralasertib, VE821, gartisertib, ETP-46464, AZ20, elimusertib and berzosertib, pharmaceutically acceptable salts thereof and/or pharmaceutically acceptable solvates thereof.
24. The CTPS1 inhibitor, ATR inhibitor, composition, method, use or kit according to any one of claims 1 to 23, wherein the ATR inhibitor is ceralasertib, or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof.
25. The CTPS1 inhibitor, ATR inhibitor, composition, method, use or kit according to any one of claims 1 to 23, wherein the ATR inhibitor is VE821, or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof.
26. The CTPS1 inhibitor, ATR inhibitor, composition, method, use or kit according to any one of claims 1 to 24 wherein the CTPS1 inhibitor is: N-(5-(6-ethoxypyrazin-2-yl)pyridine-2-yl)-4-(2-(ethylsulfonamido)pyrimidin-4- yl)tetrahydro-2H-pyran-4-carboxamide:
Figure imgf000175_0001
or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof; and the ATR inhibitor is ceralasertib, or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof.
27. The CTPS1 inhibitor, ATR inhibitor, composition, method, use or kit according to any one of claims 1 to 24, wherein the CTPS1 inhibitor is: 4-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2- yl)tetrahydro-2H-pyran-4-carboxamide:
Figure imgf000176_0001
or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof; and the ATR inhibitor is ceralasertib, or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof.
28. The CTPS1 inhibitor, ATR inhibitor, composition, method, use or kit according to any one of claims 1 to 23 or 25 wherein the CTPS1 inhibitor is: N-(5-(6-ethoxypyrazin-2-yl)pyridine-2-yl)-4-(2-(ethylsulfonamido)pyrimidin-4- yl)tetrahydro-2H-pyran-4-carboxamide:
Figure imgf000176_0002
or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof; and the ATR inhibitor is VE821, or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof.
29. The CTPS1 inhibitor, ATR inhibitor, composition, method, use or kit according to any one of claims 1 to 23 or 25 wherein the CTPS1 inhibitor is: 4-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2- yl)tetrahydro-2H-pyran-4-carboxamide:
Figure imgf000176_0003
or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof; and the ATR inhibitor is VE821, or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof.
30. The CTPS1 inhibitor, ATR inhibitor, composition or kit according to any one of claims 1 to 29, wherein the cancer is a haematological cancer.
31. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to claim 30, wherein the haematological cancer is T cell lymphoma.
32. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to claim 30, wherein the haematological cancer is diffuse large B cell lymphoma.
33. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to claim 30, wherein the haematological cancer is plasma cell myeloma.
34. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to claim 30, wherein the haematological cancer is acute myeloid leukaemia.
35. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to claim 30, wherein the haematological cancer is chronic lymphocytic leukaemia.
36. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to claim 30, wherein the haematological cancer is peripheral T cell lymphoma.
37. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to claim 30, wherein the haematological cancer is a myelodysplastic syndrome (MDS), such as MDS with single lineage dysplasia, MDS with multilineage dysplasia or MDS with excess blasts.
38. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to claim 30, wherein the haematological cancer is cutaneous T-cell lymphoma.
39. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to claim 30, wherein the haematological cancer is follicular lymphoma.
40. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to claim 30, wherein the haematological cancer is mantle cell lymphoma.
41. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to claim 30, wherein the haematological cancer is marginal zone lymphoma.
42. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to any one of claims 1 to 29, wherein the cancer is a non-haematological cancer.
43. The CTPS1 inhibitor, ATR inhibitor, use, method, composition or kit according to claim 42, wherein the cancer is a non-haematological cancer selected from prostate cancer, pancreatic cancer, ovarian cancer, lung cancer, renal cancer, colorectal cancer or breast cancer.
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