Combining CTPS1 and BCL2 inhibitors for cancer

Abstract

The present invention provides, inter alia, a method of treating cancer comprising administering to a subject a cytidine triphosphate synthase 1 (CTPS1) inhibitor and a B-cell lymphoma 2 (BCL2) inhibitor.

Description

[Technical field]

[0001] FIELD OF THEINVENTION The present invention relates to combinations, in particular combinations of CTPS1 inhibitors with BCL2 inhibitors, pharmaceutical compositions and kits comprising such combinations that may be useful in the treatment of cancer, and related embodiments. [Background technology]

[0002] BACKGROUND OF THEINVENTION Cancer can affect multiple cell types and tissues, but the underlying cause is a disruption in the control of cell division. This process is highly complex and requires careful coordination of multiple pathways, many of which have yet to be fully characterized. Cell division requires effective replication of the cell's DNA and other components. Interfering with the cell's ability to replicate by targeting nucleic acid synthesis has been a central approach in cancer therapy for many years. Examples of therapeutics that act in this way are 6-thioguanine, 6-mecaptopurine, 5-fluorouracil, cytarabine, gemcitabine, and pemetrexed.

[0003] A wide range of specific targeted cancer therapeutics are available. Small molecule targeted therapeutic drugs are usually inhibitors of enzymatic domains on mutated, overexpressed, or otherwise important proteins in cancer cells. Monoclonal antibody therapy is another strategy in which the therapeutic agent is an antibody that specifically binds to a protein on the surface of the cancer cell.

[0004] All proliferating cells, including tumor cells, depend on a close source of purine and pyrimidine nucleotides for DNA and RNA synthesis. Although salvage pathways may be sufficient for steady-state metabolism, DNA replication that allows cell division relies on the synthesis of nucleotides by the de novo pathway. A key bottleneck in the de novo pyrimidine synthesis pathway is the enzyme cytidine triphosphate synthase (CTPS), which catalyzes the conversion of UTP to CTP (van Kuilenburg, 2000). CTPS also has two isoforms in humans (CTPS1 and CTPS2; see Figure 1). Both isoforms are ubiquitously expressed in human normal and malignant cells (BioGPS and EMBL-EBI Expression Atlas). Human genetic studies have identified an essential and nonredundant role for CTPS1 in the proliferation of normal immune (B and T) cells (Martin, 2014; Martin, 2020).

[0005] Cancer cells depend on CTPS activity to grow, but the exact roles that CTPS1 and CTPS2 play in cancer are currently not entirely clear. Several CTPS inhibitors that inhibit both CTPS1 and CTPS2 have been developed to Phase I / II clinical trials for oncology indications, but have been discontinued due to toxicity and efficacy issues. Many of the inhibitors developed are nucleoside analogue prodrugs (3-deazauridine (DAU), CPEC, carbozine, gemcitabine) that are converted to active triphosphorylated metabolites by kinases involved in pyrimidine biosynthesis; uridine / cytidine kinase, nucleoside monophosphate kinase (NMP kinase), and nucleoside diphosphate kinase (NDP kinase). The remaining inhibitors (acivicin, DON) are reactive analogues of glutamine that irreversibly inhibit the glutaminase domain of CTPS. Importantly, none of the inhibitors of CTPS developed so far are selective for one isoform of CTPS over the other. Therefore, available CTPS inhibitors would block all CTPS activity and therefore the ability of all cells in the body to undergo cell division.

[0006] BCL2 is a member of an important family of pro-survival anti-apoptotic proteins commonly expressed in cancer cells. Inhibition of BCL2 activity can result in induction of apoptosis, leading to cell death. This is mediated by mitochondria, whereby pro-apoptotic proteins form complexes that open holes in the mitochondrial membrane, causing mitochondrial depolarization that induces apoptosis. Therapeutic inhibition of BCL2 can be achieved by drugs designed to mimic the activity of the BH3 domain of pro-apoptotic proteins. Therapeutic agents using this approach are called BH3 mimetics, which induce apoptosis by inducing mitochondrial membrane depolarization (Warren, 2019; Diepstraten, 2022).

[0007] BCL2 inhibition has shown utility in hematological cancers, most notably chronic lymphocytic leukemia and acute myeloid leukemia (Roberts, 2021). Clinical trials of BCL2 inhibitors are ongoing in solid tumor indications.

[0008] There remains a need for new approaches to cancer therapy that may demonstrate increased in vivo efficacy, reduced doses required for in vivo efficacy, improved safety profiles / reduced side effects, etc. Summary of the Invention

[0009] (Summary of the invention) The present invention provides CTPS1 inhibitors for use in the treatment of cancer with BCL2 inhibitors.

[0010] In a further aspect, the present invention provides a BCL2 inhibitor for use in the treatment of cancer with a CTPS1 inhibitor.

[0011] In a further aspect, the present invention provides a CTPS1 inhibitor and a BCL2 inhibitor for use in the treatment of cancer.

[0012] In a further aspect, the present invention provides the use of a CTPS1 inhibitor in the manufacture of a medicament for the treatment of cancer with a BCL2 inhibitor.

[0013] In a further aspect, the present invention provides the use of a BCL2 inhibitor in the manufacture of a medicament for the treatment of cancer with a CTPS1 inhibitor.

[0014] In a further aspect, the present invention provides the use of a CTPS1 inhibitor and a BCL2 inhibitor in the manufacture of a medicament for the treatment of cancer.

[0015] In a further aspect, the invention provides a method of treating cancer in a subject, comprising administering to the subject a CTPS1 inhibitor and a BCL2 inhibitor.

[0016] In a further aspect, the present invention provides a pharmaceutical composition comprising a CTPS1 inhibitor and a BCL2 inhibitor.

[0017] In a further aspect, the present invention provides a method for producing a method for the treatment of a cancer a) a first container containing a CTPS1 inhibitor; and b) a second container containing a BCL2 inhibitor. We provide a kit of parts including:

[0018] (Array Overview) SEQ ID NO: 1 FLAG-His 8 -tag SEQ ID NO: 2 FLAG-His-Avi tag [Brief description of the drawings]

[0019] (Drawing Outline) [Figure 1] De novo CTP production pathway [Diagram 2] Effects of deletion of various genes in the pyrimidine synthesis pathway [Diagram 3] Bliss scores of CTPS1-IA and venetoclax interaction for various cell lines derived from B-cell malignancies [Figure 4] Bliss scores of CTPS1-IA and venetoclax interaction in various cell lines derived from solid tumors [Diagram 5] Bliss scores of CTPS1-IA and BCL201 interactions for various cell lines derived from solid tumors [Figure 6] Bliss scores of CTPS1-IA and venetoclax interactions for various cell lines derived from human T-cell lymphoma [Figure 7] In vivo tumor growth studies were performed investigating the effects of CTPS1-IA and venetoclax using human cancer cell lines. [Figure 8]RNA transcript levels measured in human mantle cell lymphoma cell lines after 24 h exposure to either CTPS1-IA or control showing an increase in BCL2 transcripts and a decrease in MCL1 transcripts after exposure to CTPS1-IA. *P<0.05, paired t-test. [Figure 9] Protein levels assessed by Western blot analysis from human mantle cell lymphoma cell lines after 24 h exposure to either CTPS1-IA or control showing an increase in BCL2 protein and a decrease in MCL1 protein after exposure to CTPS1-IA; GAPDH is shown as a protein loading control. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0020] Detailed Description of the Invention (CTPS1 inhibitor) In one aspect of the invention there is provided a CTPS1 inhibitor for use in the treatment of cancer with a BCL2 inhibitor.

[0021] As used herein, a CTPS1 inhibitor is an agent that directly inhibits the enzymatic activity of CTPS1 enzyme through interaction with the enzyme. Direct inhibition of CTPS1 enzyme can be quantified using any suitable assay procedure, but is preferably carried out using the procedure shown in Example 1.

[0022] CTPS1 inhibitors have an IC50 of 10 uM or less, e.g., 1 uM or less, particularly 100 nM or less, with respect to the CTPS1 enzyme. 50 Particularly interesting CTPS1 inhibitors may exhibit an IC of 10 uM or less, such as 1 uM or less, especially 100 nM or less, with respect to the CTPS1 enzyme, using the assay procedure set forth in Example 1. 50 This shows that.

[0023] CTPS1 inhibitors may exhibit selectivity for CTPS1 over CTPS2. Preferably, the inhibitor exhibits at least 2-fold, such as at least 30-fold, particularly at least 60-fold, and especially at least 1000-fold selectivity. Particularly interesting CTPS1 inhibitors are those that exhibit selectivity for CTPS1 over CTPS2, preferably at least 2-fold, such as at least 30-fold, particularly at least 60-fold, and especially at least 1000-fold, using the assay procedure set forth in Example 2. Desirably, the selectivity is for human CTPS1 over human CTPS2.

[0024] For drugs intended for human use, CTPS1 inhibition and CTPS1 vs. CTPS2 selectivity should be based on the human form of the enzyme.

[0025] Suitably, the CTPS1 inhibitor is the following compound: A compound of formula (I) may be selected from: or a pharma- ceutically acceptable salt and / or a pharma- ceutically acceptable solvate thereof [ka] (In the formula, R 1 is C 1-5 Alkyl, C 0-2 Alkylene C 3-5 Cycloalkyl (wherein the cycloalkyl is CH 3 Optionally replaced by C 1-3 Alkylene OC 1-2 Alkyl or CF 3 and; R 3 , H, CH 3 , Haro, O.C. 1-2 Alkyl or CF 3 and; R 4 and R 5 are each independently H, C 1-6 Alkyl, C 0-2 Alkylene C 3-6 Cycloalkyl, C 0-2 Alkylene C 3-6Heterocycloalkyl, C 1-3 Alkylene OC 1-3 Alkyl, C 1-6 AlkylOH or C 1-6 is haloalkyl, or R 4 and R 5 together with the carbon atom to which they are attached, C 3-6 Cycloalkyl or C 3-6 forming a heterocycloalkyl ring; R 6 is H or C 1-3 is alkyl; 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; R 10 H, halo, C 1-3 Alkyl, OC 1-2 Alkyl, C 1-2 Haloalkyl, OC 1-2 haloalkyl, or CN; R 11 are H, F, Cl, CH 3 , Ethyl, OCH 3 , C.F. 3 , OCF 3 , or CN; R 12 is bonded to Ar2 at the meta or ortho position relative to Ar1, and R 12 H, halo, C 1-4 Alkyl, C 2-4 Alkynyl, C(=O)C 1-2 Alkyl, C 0-2 Alkylene C 3-5 Cycloalkyl, OC 1-4 Alkyl, C 1-3 Alkylene OC 1-3 Alkyl, C 1-4 Haloalkyl, OC 1-4 Haloalkyl, CN, OC 0-2 Alkylene C 3-5 Cycloalkyl, OCH 2 CH 2 N(CH 3 ) 2, O.H., C. 1-4 AlkylOH, NR 23 R 24 , S.O. 2 CH 3 , C(O)N(CH 3 ) 2 , NHC(O)C 1-3 C containing one nitrogen at the point of attachment to alkyl or Ar2 3-6 heterocycloalkyl or R 12 forms, together with the nitrogen atom to which it is attached, an N-oxide (N + -O - ) to form; R 23 is H or C 1-2 is alkyl; R 24 is H or C 1-2 (It is alkyl).

[0026] More preferably, the CTPS1 inhibitor is one of 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)-[1,1'-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 pharma- ceutical acceptable salt and / or a pharma- ceutical acceptable solvate thereof.

[0027] Such CTPS1 inhibitors are disclosed in PCT Publication No. WO2019106146, which is incorporated by reference in its entirety for the CTPS1 inhibitors disclosed therein. In particular, the CTPS1 inhibitor may be a compound described in any one of clauses 1-110 of WO2019106146 or a pharma- ceutically acceptable salt and / or pharma-ceutically acceptable solvate thereof, in particular compounds R1-R93 or a pharma-ceutically acceptable salt and / or pharma-ceutically acceptable solvate thereof.

[0028] Alternatively, the CTPS1 inhibitor is a compound of formula (II): or a pharma- ceutically acceptable salt and / or a pharma- ceutically acceptable solvate thereof. [ka] (In the formula, R 1 is C 1-5 Alkyl, C 0-2 Alkylene C 3-5 Cycloalkyl (wherein the cycloalkyl is CH 3 Optionally replaced by C 1-3 Alkylene OC 1-2 Alkyl or CF 3 and; R 3 H, halo, CH 3 , O.C. 1-2 Alkyl or CF 3 and; Or R 3 is R 5 together form a 5- or 6-membered cycloalkyl or a 5- or 6-membered oxygen-containing heterocycloalkyl; R 4 and R 5 are each independently H, halo, or C 1-6 Alkyl, C 0-2 Alkylene C 3-6 Cycloalkyl, C 0-2 Alkylene C 3-6 Heterocycloalkyl, OC 1-6 Alkyl, OC 0-2 Alkylene C 3-6Cycloalkyl, C 1-3 Alkylene OC 1-3 Alkyl, C 1-6 AlkylOH, C 1-6 Haloalkyl, OC 1-6 Haloalkyl or NR 21 R 22 and Or R 4 is H and R 5 is R 3 together with the group forming a 5- or 6-membered cycloalkyl or a 5- or 6-membered oxygen-containing heterocycloalkyl, Or R 4 and R 5 together with the carbon atom to which they are attached, C 3-6 Cycloalkyl or C 3-6 forming a heterocycloalkyl, Or R 4 is H and R 5 and R 6 is a C which forms a 5- or 6-membered ring 2-3 is an alkylene chain; Or R 4 is O and R 5 does not exist; R 6 is H or C 1-3 is alkyl, or R 6 is in the ortho position relative to the amide, R 11 Together with C, it forms a five-membered ring 2 is an alkylene chain, or R 5 and R 6 is a C that forms a 5- or 6-membered ring. 2-3 is an alkylene chain, and R 4 is H; 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; R 10 H, halo, C 1-3 Alkyl, OC 1-2 Alkyl, C 1-2 Haloalkyl, OC1-2 haloalkyl, or CN; R 11 are H, F, Cl, CH 3 , Ethyl, OCH 3 , C.F. 3 , OCF 3 , or CN, or R 11 is R 6 When in the ortho position to the amide, C forms a five-membered ring. 2 is an alkylene chain; R 12 is bonded to Ar2 at the ortho or meta position relative to Ar1, and R 12 H, halo, C 1-4 Alkyl, C 2-4 Alkynyl, C 0-2 Alkylene C 3-5 Cycloalkyl, OC 1-4 Alkyl, OC 0-2 Alkylene C 3-5 Cycloalkyl, OCH 2 CH 2 N(CH 3 ) 2 , O.H., C. 1-4 AlkylOH, CN, C 1-3 Alkylene OC 1-3 Alkyl, C 1-4 Haloalkyl, OC 1-4 Haloalkyl, C(=O)C 1-2 Alkyl, NR 23 R 24 , S.O. 2 C 1-4 Alkyl, SOC 1-4 Alkyl, SC 1-4 Alkyl, SH, C(O)N(CH 3 ) 2 , NHC(O)C 1-3 Alkyl, C containing one nitrogen at the attachment point to Ar2 3-6 heterocycloalkyl or R 12 forms, together with the nitrogen atom to which it is attached, an N-oxide (N + -O - ) to form; R 13 H, halo, CH3 , or OCH 3 and; R 21 , H, C 1-5 Alkyl, C(O)C 1-5 Alkyl, C(O)OC 1-5 is alkyl; R 22 is H or CH 3 and; R 23 is H or C 1-2 is alkyl; and R 24 is H or C 1-2 (It is alkyl).

[0029] More preferably, the CTPS1 inhibitor is one of 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 compound); (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 compound); (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'-biphenyl]-4-yl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(4-(pyridin-3-yl)phenyl)propanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(4-(5-methylpyridin-3-yl)phenyl)propanamide; 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 compound); 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)-[1,1'-biphenyl]-4-yl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)acetamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(pyridin-3-yl)phenyl)acetamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(pyridin-4-yl)phenyl)acetamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(2'-methoxy-[1,1'-biphenyl]-4-yl)acetamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(pyrimidin-5-yl)phenyl)acetamide; 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)-N-(5-(6-(trifluoromethyl)pyrazin-2-yl)pyridin-2-yl)acetamide hydrochloride; 2-Amino-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(2-fluoro-4-(6-(trifluoromethyl)pyrazin-2-yl)phenyl)acetamide; 2-Amino-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)acetamide hydrochloride; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-(dimethylamino)-N-(2-fluoro-4-(6-(trifluoromethyl)pyrazin-2-yl)phenyl)acetamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-(dimethylamino)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)acetamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2,2-difluoroacetamide; 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)-N-(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-methoxyacetamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2-methoxyacetamide; 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-methoxyacetamide; N-(2-cyano-4-(6-ethoxypyrazin-2-yl)phenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methoxyacetamide; 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-methoxyacetamide; 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 pharma- ceutical acceptable salt and / or a pharma- ceutical acceptable solvate thereof.

[0030] Such CTPS1 inhibitors are disclosed in PCT Publication No. WO2019106156, which is incorporated by reference in its entirety for the CTPS1 inhibitors disclosed therein. In particular, the CTPS1 inhibitor may be a compound described in any one of clauses 1-118 of WO2019106156 or a pharma- ceutically acceptable salt and / or pharma-ceutically acceptable solvate thereof, in particular compounds T1-T465 or a pharma-ceutically acceptable salt and / or pharma-ceutically acceptable solvate thereof.

[0031] Alternatively, the CTPS1 inhibitor is a compound of formula (III): or a pharma- ceutically acceptable salt and / or a pharma- ceutically acceptable solvate thereof. [ka] (In the formula, A is an amide linker having the following structure: -C(=O)NH- or -NHC(=O)-; X is N or CH; Y is N or CR 2 and; Z is N or CR 3 and; With the proviso that when at least one of X or Z is N, Y cannot be N; R 1 is C 1-5 Alkyl, C 0-2 Alkylene C 3-5 Cycloalkyl (wherein the cycloalkyl is CH 3 Optionally substituted by, or CF 3 and; R 2 H, halo, C 1-2Alkyl, OC 1-2 Alkyl, C 1-2 Haloalkyl or OC 1-2 is haloalkyl; R 3 H, halo, CH 3 , O.C.H. 3 , C.F. 3 , or OCF 3 and; Here, R 2 and R 3 at least one of is H; R 4 and R 5 are each independently H, C 1-6 Alkyl, C 1-6 AlkylOH, C 1-6 Haloalkyl, C 0-2 Alkylene C 3-6 Cycloalkyl, C 0-2 Alkylene C 3-6 Heterocycloalkyl, C 1-3 Alkylene OC 1-3 alkyl or R 4 and R 5 together with the carbon atom to which they are attached, C 3-6 Cycloalkyl or C 3-6 forming a heterocycloalkyl; and When A is -NHC(=O)-: R 4 and R 5 Ha, Hello, OC 1-6 Haloalkyl, OC 0-2 Alkylene C 3-6 Cycloalkyl, OC 0-2 Alkylene C 3-6 Heterocycloalkyl, OC 1-6 Alkyl and NR 21 R 22 may further be selected from; 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; R 10 H, halo, C 1-3 Alkyl, C1-2 Haloalkyl, OC 1-2 Alkyl, OC 1-2 haloalkyl, or CN; R 11 are H, F, Cl, and C. 1-2 Alkyl, CF 3 , O.C.H. 3 , or CN; R 12 is bonded to Ar2 at the ortho or meta position relative to Ar1, and R 12 H, halo, C 1-4 Alkyl, C 2-4 Alkenyl, C 0-2 Alkylene C 3-5 Cycloalkyl, OC 1-4 Alkyl, OC 0-2 Alkylene C 3-5 Cycloalkyl, C 1-4 Haloalkyl, OC 1-4 Haloalkyl, Hydroxy, C 1-4 Alkyl OH, SO 2 C 1-2 Alkyl, C(O)N(C 1-2 Alkyl) 2 , NHC(O)C 1-3 Alkyl or NR 23 R 24 and When A is -NHC(=O)-: R 12 CN, OCH 2 CH 2 N(CH 3 ) 2 and C containing one nitrogen atom at the attachment point to Ar2 3-6 heterocycloalkyl, or R 12 forms, together with the nitrogen atom to which it is attached, an N-oxide (N + -O - ) to form; R 13 is H or halo; R 21 , H, C 1-5 Alkyl, C(O)C 1-5 Alkyl, C(O)OC 1-5 is alkyl; R 22 is H or CH 3 and; R 23 is H or C 1-2 is alkyl; and R 24 is H or C 1-2 (It is alkyl).

[0032] More preferably, the CTPS1 inhibitor is one of 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)-[1,1'-biphenyl]-4-yl)propanamide; N-(3'-chloro-[1,1'-biphenyl]-4-yl)-2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-2-methylpropanamide; N-(3'-cyano-[1,1'-biphenyl]-4-yl)-2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(3'-ethoxy-[1,1'-biphenyl]-4-yl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-2-methyl-N-(4-(6-(trifluoromethyl)pyrazin-2-yl)phenyl)propanamide; 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)-N-(5-(6-isopropylpyrazin-2-yl)pyridin-2-yl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)-2,2-difluoroacetamide; 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)pyrazin2-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-methoxyacetamide; N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2-fluoro-2-(2-(methylsulfonamido)pyrimidin-4-yl)-(R)-butanamide; N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2-fluoro-2-(2-(methylsulfonamido)pyrimidin-4-yl)-(S)-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-methoxyacetamide; 2-(6-(cyclopropanesulfonamido)pyrazin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2-methoxyacetamide; 2-(6-(cyclopropanesulfonamido)pyrazin-2-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2-methoxypropanamide; 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 pharma- ceutical acceptable salt and / or a pharma- ceutical acceptable solvate thereof.

[0033] Such CTPS1 inhibitors are disclosed in PCT Publication No. WO2019179652, which is incorporated by reference in its entirety for the CTPS1 inhibitors disclosed therein. In particular, the CTPS1 inhibitor may be a compound described in any one of clauses 1-148 of WO2019179652 or a pharma- ceutically acceptable salt and / or pharma-ceutically acceptable solvate thereof, in particular compounds P1-P225 or a pharma-ceutically acceptable salt and / or pharma-ceutically acceptable solvate thereof.

[0034] Such CTPS1 inhibitors are also disclosed in PCT Publication No. WO2019180244, which is incorporated by reference in its entirety for the CTPS1 inhibitors disclosed therein. In particular, the CTPS1 inhibitor may be a compound described in any one of clauses 1-148 of WO2019180244 or a pharma- ceutically acceptable salt and / or pharma-ceutically acceptable solvate thereof, in particular compounds P1-P225 or a pharma-ceutically acceptable salt and / or pharma-ceutically acceptable solvate thereof.

[0035] More preferably, the CTPS1 inhibitor is a compound of formula (IV): or a pharma- ceutically acceptable salt and / or a pharma- ceutically acceptable solvate thereof [ka] (In the formula: (a)R 4 , R 5 , X, Y, and R 1 But as follows: [ka] when W is N, CH, or CF; (b)R 4 , R 5 , X, W, and R 1 But as follows: [ka] when Y is CH or N; (c) W, X, Y, and R 1 But as follows: [ka] If R 4 and R 5 combine to form the following structure: [ka] Forming; (d) W, R 4 , R 5 , X, and Y are as follows: [ka] If R 1 is methyl or cyclopropyl; and (e) the compound is [ka] :) selected from the group consisting of:

[0036] More preferably, the CTPS1 inhibitor is one of 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 pharma- ceutical acceptable salt and / or a pharma- ceutical acceptable solvate thereof.

[0037] Such CTPS1 inhibitors are disclosed in PCT Publication No. WO2020083975, which is incorporated by reference in its entirety for the CTPS1 inhibitors disclosed therein. In particular, the CTPS1 inhibitor can be a compound selected from P112, P113, P114, P115, P136, P137, P139, P143, P145, P165, P166, P186, P197, P206, and P207, or a pharma- ceutically acceptable salt and / or a pharma-ceutically acceptable solvate thereof.

[0038] Alternatively, the CTPS1 inhibitor is a compound of formula (V): or a pharma- ceutically acceptable salt and / or a pharma- ceutically acceptable solvate thereof. [ka] (a) A, V, W, X, Y, Z, R 1 , R 10 , and R 12 But as follows: [ka] If R 4 and R 5 along with the carbon atoms to which they are attached: [ka] Forming; or (b) A, V, W, X, Y, Z, R 1 , R 10 , and R 12 But as follows: [ka] If R 4 and R 5 along with the carbon atoms to which they are attached: [ka] Forming; or (c) A, V, W, X, Y, Z, R 4 , R 5 , R 10 , and R 12 But as follows: [ka] If R 1 teeth, [ka] or (d) A, V, W, X, Y, Z, R 4 , R 5 , R 10 , and R 12 But as follows: [ka] If R 1 teeth, [ka] or (e) A, X, Y, Z, R 1 , R 4 , and R 5 But as follows: [ka] If V, W, R 10 , and R 12 teeth, [ka] or (f) A, V, W, R 1 , R 4 , R 5 , R 10 , and R 12 But as follows: [ka] then Z, X, and Y are [ka] or (g) A, V, W, R 1 , R 4 , R 5 , R 10 , and R 12 But as follows: [ka] then Z, X, and Y are [ka] or (h) A, V, W, R 1 , R 4 , R 5 , R 10 , and R 12 But as follows [ka] then Z, X, and Y are [ka] (It is.)

[0039] More preferably, the CTPS1 inhibitor is one of 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 pharma- ceutical acceptable salt and / or a pharma- ceutical acceptable solvate thereof.

[0040] Such CTPS1 inhibitors are disclosed in PCT Publication No. WO2020245664, which is incorporated by reference in its entirety for the CTPS1 inhibitors disclosed therein. In particular, the CTPS1 inhibitor can be a compound selected from P319, P231-P234, P236, P237, P238, P239, P240, P241, P243, P245, P246, P247, P249, P250, P252, P253, P257, P259, P262, P263, and P140, or a pharma- ceutically acceptable salt and / or a pharma-ceutically acceptable solvate thereof.

[0041] Alternatively, the CTPS1 inhibitor is a compound of formula (VI): or a pharma- ceutically acceptable salt and / or a pharma- ceutically acceptable solvate thereof. [ka] (Wherein, ring B is [ka] (wherein X, Y, and Z are as defined below); and [ka] (where R 3b3c is defined as follows: 3b or R 3c is) Selected from the group consisting of: wherein when B is (Ba), the compound of formula (VI) is a compound of formula (VI-a): [ka] (In the formula: A a A aa Or A ba and; where: A aa has the following structure: -NH-, -CH 2 NH- or -NHCH 2 - an amine linker having A ba is an amide linker having the following structure: -C(=O)NH- or -NHC(=O)-; X is N or CH; Y is N or CR 2a and; Z is N or CR 3a and; With the proviso that when at least one of X or Z is N, Y cannot be N; R 2a H, halo, C 1-2 Alkyl, OC 1-2 Alkyl, C 1-2 Haloalkyl or OC 1-2 haloalkyl; and R 3a H, halo, CH 3 , O.C.H. 3 , C.F. 3 , or OCF 3 and; Here, R 2a and R 3a at least one of is H; R 1a is R 1aa or R 1ba and; where: R 1aa is NR 32a R 33a and; R 1ba is C 1-5Alkyl, C 0-2 Alkylene C 3-5 Cycloalkyl (wherein the cycloalkyl is CH 3 Optionally substituted by, or CF 3 and; R 4a and R 5a is R 4aa and R 5aa , or R 4ba and R 5ba and; where: R 4aa and R 5aa together with the carbon atom to which they are attached, C 3-6 Forms a cycloalkyl, which is: Each of the substituents is C 1-3 Alkyl, oxo, OH, C 1-3 AlkylOH, C 1-3 Haloalkyl, C 0-2 Alkylene C 3-6 Cycloalkyl, C 0-2 Alkylene C 3-6 Heterocycloalkyl, C 1-3 Alkylene OC 1-3 Alkyl, Halo, OC 1-3 Haloalkyl, OC 0-2 Alkylene C 3-6 Cycloalkyl, OC 0-2 Alkylene C 3-6 Heterocycloalkyl, OC 1-3 Alkyl and NR 21a R 22a or is substituted by one or two substituents independently selected from the group consisting of: C 3-6 One of the carbons of the cycloalkyl is a spirocyclic ring system. 3-6 Cycloalkyl rings and further C 3-6 Cycloalkyl ring or C 3-6 A spiro center such as formed by a heterocycloalkyl ring, and where R 4aa and R 5aa C formed by 3-6 Cycloalkyl means that each of the substituents, together with the carbon atom to which they are attached, is C1-3 Alkyl or OC 1-3 or may be substituted by one or two substituents independently selected from the group consisting of alkyl; R 4aa and R 5aa together with the carbon atom to which they are attached, C 3-6 heterocycloalkyl, wherein the C 3-6 One of the carbons of the heterocycloalkyl is a spirocyclic ring system. 3-6 Heterocycloalkyl rings and further C 3-6 Cycloalkyl ring or C 3-6 A spiro center such as formed by a heterocycloalkyl ring, and where R 4aa and R 5aa C formed by 3-6 Heterocycloalkyl means that each of the substituents, together with the carbon atom to which they are attached, is C 1-3 Alkyl or OC 1-3 or may be substituted by one or two substituents independently selected from the group consisting of alkyl; R 4aa and R 5aa C, which contains one nitrogen atom together with the carbon atom to which they are attached 3-6 heterocycloalkyl, where the nitrogen atom is -S(O) 2 R 29a or is replaced by R 4ba and R 5ba are each independently H, C 1-6 Alkyl, C 1-6 AlkylOH, C 1-6 Haloalkyl, C 0-2 Alkylene C 3-6 Cycloalkyl, C 0-2 Alkylene C 3-6 Heterocycloalkyl, C 1-3 Alkylene OC 1-3 alkyl or R 4ba and R 5ba together with the carbon atom to which they are attached, C 3-6 Cycloalkyl or C 3-6forming a heterocycloalkyl; and A a -NHC(=O)- or -NHCH 2 -When: R 4ba and R 5ba Ha, Hello, OC 1-6 Haloalkyl, OC 0-2 Alkylene C 3-6 Cycloalkyl, OC 0-2 Alkylene C 3-6 Heterocycloalkyl, OC 1-6 Alkyl and NR 21a R 22a may further be selected from; Ar1a is a 6-membered aryl or heteroaryl; Ar2a is a 6-membered aryl or heteroaryl and is a group A a is linked to Ar1a in the para position relative to R 10a H, halo, C 1-3 Alkyl, C 1-2 Haloalkyl, OC 1-2 Alkyl, OC 1-2 haloalkyl, or CN; R 11a are H, F, Cl, and C. 1-2 Alkyl, CF 3 , O.C.H. 3 , or CN; R 12a is bonded to Ar2 at the ortho or meta position relative to Ar1a, and R 12a H, halo, C 1-4 Alkyl, C 2-4 Alkenyl, C 0-2 Alkylene C 3-5 Cycloalkyl, OC 1-4 Alkyl, OC 0-2 Alkylene C 3-5 Cycloalkyl, C 1-4 Haloalkyl, OC 1-4 Haloalkyl, Hydroxy, C 1-4 Alkyl OH, SO 2 C 1-2 Alkyl, C(O)N(C 1-2 Alkyl) 2, NHC(O)C 1-3 Alkyl or NR 23a R 24a and A a is -NHC(=O)-, -NH-, or -NHCH 2 -When: R 12a CN, OCH 2 CH 2 N(CH 3 ) 2 and C containing one nitrogen atom at the attachment point to Ar2a 3-6 heterocycloalkyl, or R 12a forms, together with the nitrogen atom to which it is attached, an N-oxide (N + -O - ) to form; R 13a is H or halo; R 21a , H, C 1-5 Alkyl, C(O)C 1-5 Alkyl, C(O)OC 1-5 Alkyl, C 1-3 Alkyl OC 1-2 Alkyl, C 1-4 Haloalkyl, or C 4-6 is heterocycloalkyl; R 22a is H or CH 3 and; R 23a is H or C 1-2 is alkyl; and R 24a is H or C 1-2 It is an alkyl R 29a is C 1-3 Alkyl, C 0-2 Alkylene C 3-5 Cycloalkyl (wherein the cycloalkyl is CH 3 Optionally replaced by CF 3 , N(C 1-3 Alkyl) 2 or 5- or 6-membered heteroaryl, wherein the 5- or 6-membered heteroaryl is optionally substituted with methyl; R 32a is C 1-3 alkyl, and R 33 is C 1-3 is alkyl; or R 32a and R 33a C together with the nitrogen atom to which they are attached 3-5 Forming a heterocycloalkyl; Where: R 1a is R 1aa and / or R 4a and R 5a is R 4aa and R 5aa and / or A a A aa is) and where B is (B-bc) and R 3b3c R 3b When the compound of formula (VI) is a compound of formula (VI-b): [ka] (In the formula: A b A ab Or A bb and; where: A ab -NR 6b CH 2 -OR-NR 6b - and; A bb -NR 6b C(=O)-; R 1b is R 1ab or R 1bb and; where: R 1ab is NR 32b R 33b and; R 1bb is C 1-5 Alkyl, C 0-2 Alkylene C3-5 Cycloalkyl (wherein the cycloalkyl is CH 3 Optionally replaced by C 1-3 Alkylene OC 1-2 Alkyl or CF 3 and; R 3b H, halo, CH 3 , O.C. 1-2 Alkyl or CF 3 and; Or R 3b is R 5bb together form a 5- or 6-membered cycloalkyl or a 5- or 6-membered oxygen-containing heterocycloalkyl; R 4b and R 5b , R 4ab and R 5ab or R 4bb and R 5bb Either; where: R 4ab and R 5ab together with the carbon atom to which they are attached, C 3-6 Forms a cycloalkyl, which is: Each of the substituents is C 1-3 Alkyl, oxo, OH, C 1-3 AlkylOH, C 1-3 Haloalkyl, C 0-2 Alkylene C 3-6 Cycloalkyl, C 0-2 Alkylene C 3-6 Heterocycloalkyl, C 1-3 Alkylene OC 1-3 Alkyl, Halo, OC 1-3 Haloalkyl, OC 0-2 Alkylene C 3-6 Cycloalkyl, OC 0-2 Alkylene C 3-6 Heterocycloalkyl, OC 1-3 Alkyl and NR 21b R 22b or is substituted by one or two substituents independently selected from the group consisting of: C 3-6One of the carbons of the cycloalkyl is a spirocyclic ring system. 3-6 Cycloalkyl rings and further C 3-6 Cycloalkyl ring or C 3-6 A spiro center such as formed by a heterocycloalkyl ring, and where R 4ab and R 5ab C formed by 3-6 Cycloalkyl means that each of the substituents, together with the carbon atom to which they are attached, is C 1-3 Alkyl or OC 1-3 or may be substituted by one or two substituents independently selected from the group consisting of alkyl; R 4ab and R 5ab together with the carbon atom to which they are attached, C 3-6 Heterocycloalkyl, wherein the C 3-6 One of the carbons of the cycloalkyl is a spirocyclic ring system. 3-6 Cheterocycloalkyl rings and further C 3-6 Cycloalkyl ring or C 3-6 A spiro center such as formed by a heterocycloalkyl ring, and where R 4ab and R 5ab C formed by 3-6 Heterocycloalkyl means that each of the substituents, together with the carbon atom to which they are attached, is C 1-3 Alkyl or OC 1-3 or may be substituted by one or two substituents independently selected from the group consisting of alkyl; R 4ab and R 5ab C, which contains one nitrogen atom together with the carbon atom to which they are attached 3-6 heterocycloalkyl, where the nitrogen atom is -S(O) 2 R 29b or is replaced by R 4bb and R 5bb are each independently H, halo, or C 1-6 Alkyl, C 0-2 Alkylene C 3-6 Cycloalkyl, C0-2 Alkylene C 3-6 Heterocycloalkyl, OC 1-6 Alkyl, OC 0-2 Alkylene C 3-6 Cycloalkyl, C 1-3 Alkylene OC 1-3 Alkyl, C 1-6 AlkylOH, C 1-6 Haloalkyl, OC 1-6 Haloalkyl or NR 21b R 22b and Or R 4bb is H and R 5bb is R 3b together with the group forming a 5- or 6-membered cycloalkyl or a 5- or 6-membered oxygen-containing heterocycloalkyl, Or R 4bb and R 5bb together with the carbon atom to which they are attached, C 3-6 Cycloalkyl or C 3-6 forming a heterocycloalkyl, Or R 4bb is H and R 5bb and R 6b is a C which forms a 5- or 6-membered ring 2-3 is an alkylene chain; Or R 4bb is O and R 5bb does not exist; R 6b is H or C 1-3 is alkyl, Or R 6b is the group A b When it is in the ortho position to R 11b Together with C, it forms a five-membered ring 2 is an alkylene chain, Or R 5bb and R 6b is a C which forms a 5- or 6-membered ring 2-3 is an alkylene chain, and R 4bb is H; Ar1b is a 6-membered aryl or heteroaryl; Ar2b is a 6-membered aryl or heteroaryl and is a group A bis linked to Ar1b in the para position relative to R 10b H, halo, C 1-3 Alkyl, OC 1-2 Alkyl, C 1-2 Haloalkyl, OC 1-2 haloalkyl, or CN; R 11b are H, F, Cl, CH 3 , Ethyl, OCH 3 , C.F. 3 , OCF 3 , or CN, or R 11b is the group A b When it is in the ortho position to R 6b Together with C, it forms a five-membered ring 2 is an alkylene chain; R 12b is bonded to Ar2b at the ortho or meta position relative to Ar1b, and R 12b H, halo, C 1-4 Alkyl, C 2-4 Alkynyl, C 0-2 Alkylene C 3-5 Cycloalkyl, OC 1-4 Alkyl, OC 0-2 Alkylene C 3-5 Cycloalkyl, OCH 2 CH 2 N(CH 3 ) 2 , O.H., C. 1-4 AlkylOH, CN, C 1-3 Alkylene OC 1-3 Alkyl, C 1-4 Haloalkyl, OC 1-4 Haloalkyl, C(=O)C 1-2 Alkyl, NR 23b R 24b , S.O. 2 C 1-4 Alkyl, SOC 1-4 Alkyl, SC 1-4 Alkyl, SH, C(O)N(CH 3 ) 2 , NHC(O)C 1-3 Alkyl, C containing one nitrogen at the attachment point to Ar2b 3-6heterocycloalkyl or R 12b forms, together with the nitrogen atom to which it is attached, an N-oxide (N + -O - ) to form; R 13b H, halo, CH 3 , or OCH 3 and; R 21b , H, C 1-5 Alkyl, C(O)C 1-5 Alkyl, C(O)OC 1-5 Alkyl, C 1-3 Alkyl OC 1-2 Alkyl, C 1-4 Haloalkyl or C 4-6 is heterocycloalkyl; R 22b is H or CH 3 and; R 23b is H or C 1-2 is alkyl; R 24b is H or C 1-2 is alkyl; R 29b is C 1-3 Alkyl, C 0-2 Alkylene C 3-5 Cycloalkyl (wherein the cycloalkyl is CH 3 Optionally replaced by CF 3 , N(C 1-3 Alkyl) 2 or a 5- or 6-membered heteroaryl, wherein the 5- or 6-membered heteroaryl is optionally substituted with methyl; and R 32b is C 1-3 alkyl, and R 33b is C 1-3 is alkyl; or R 32b and R 33b together with the nitrogen atom to which they are attached, C 3-5 Forming a heterocycloalkyl; where: R 1b is R 1aband / or R 4b and R 5b is R 4ab and R 5ab and / or A is A ab is) or where B is (B-bc) and R 3b3c R 3c When the compound of formula (VI) is a compound of formula (VI-c): [ka] (In the formula: A c A ac Or A bc and; where: A ac -CH 2 NR 6c - and; A bc is -C(=O)NR 6c - and; R 1c is R 1ac or R 1bc and; where: R 1ac is NR 32c R 33c and; R 1bc is C 1-5 Alkyl, C 0-2 Alkylene C 3-5 Cycloalkyl (wherein the cycloalkyl is CH 3 Optionally replaced by C 1-3 Alkylene OC 1-2 Alkyl or CF 3 and; R 3c , H, CH 3 , Haro, O.C. 1-2 Alkyl or CF 3 and; R 4c and R 5c is R 4ac and R5ac or R 4bc and R 5bc Either; where: R 4ac and R 5ac together with the carbon atom to which they are attached, C 3-6 Forms a cycloalkyl, which is: Each of the substituents is C 1-3 Alkyl, oxo, OH, C 1-3 AlkylOH, C 1-3 Haloalkyl, C 0-2 Alkylene C 3-6 Cycloalkyl, C 0-2 Alkylene C 3-6 Heterocycloalkyl, C 1-3 Alkylene OC 1-3 Alkyl, Halo, OC 1-3 Haloalkyl, OC 0-2 Alkylene C 3-6 Cycloalkyl, OC 0-2 Alkylene C 3-6 Heterocycloalkyl, OC 1-3 Alkyl and NR 21c R 22c or is substituted by one or two substituents independently selected from the group consisting of: C 3-6 One of the carbons of the cycloalkyl is a spirocyclic ring system. 3-6 Cycloalkyl rings and further C 3-6 Cycloalkyl ring or C 3-6 A spiro center such as formed by a heterocycloalkyl ring, and where R 4ac and R 5ac C formed by 3-6 Cycloalkyl means that each of the substituents, together with the carbon atom to which they are attached, is C 1-3 Alkyl or OC 1-3 or may be substituted by one or two substituents independently selected from the group consisting of alkyl; R 4ac and R 5ac together with the carbon atom to which they are attached, C 3-6Heterocycloalkyl, wherein the C 3-6 One of the carbons of the cycloalkyl is a spirocyclic ring system. 3-6 Cheterocycloalkyl rings and further C 3-6 Cycloalkyl ring or C 3-6 A spiro center such as formed by a heterocycloalkyl ring, and where R 4ac and R 5ac C formed by 3-6 Heterocycloalkyl means that each of the substituents, together with the carbon atom to which they are attached, is C 1-3 Alkyl or OC 1-3 or may be substituted by one or two substituents independently selected from the group consisting of alkyl; R 4ac and R 5ac C, which contains one nitrogen atom together with the carbon atom to which they are attached 3-6 heterocycloalkyl, where the nitrogen atom is -S(O) 2 R 29c or is replaced by R 4bc and R 5bc are each independently H, C 1-6 Alkyl, C 0-2 Alkylene C 3-6 Cycloalkyl, C 0-2 Alkylene C 3-6 Heterocycloalkyl, C 1-3 Alkylene OC 1-3 Alkyl, C 1-6 AlkylOH or C 1-6 is haloalkyl, Or R 4bc and R 5bc together with the carbon atom to which they are attached, C 3-6 Cycloalkyl or C 3-6 forming a heterocycloalkyl ring; R 6c is H or C 1-3 is alkyl; Ar1c is a 6-membered aryl or heteroaryl; Ar2c is a 6-membered aryl or heteroaryl and is a group Ac is bound to Ar1c in the para position relative to R 10c H, halo, C 1-3 Alkyl, OC 1-2 Alkyl, C 1-2 Haloalkyl, OC 1-2 haloalkyl, or CN; R 11c are H, F, Cl, CH 3 , Ethyl, OCH 3 , C.F. 3 , OCF 3 , or CN; R 12c is bonded to Ar2c at the meta or ortho position relative to Ar1c, and R 12c H, halo, C 1-4 Alkyl, C 2-4 Alkynyl, C(=O)C 1-2 Alkyl, C 0-2 Alkylene C 3-5 Cycloalkyl, OC 1-4 Alkyl, C 1-3 Alkylene OC 1-3 Alkyl, C 1-4 Haloalkyl, OC 1-4 Haloalkyl, CN, OC 0-2 Alkylene C 3-5 Cycloalkyl, OCH 2 CH 2 N(CH 3 ) 2 , O.H., C. 1-4 AlkylOH, NR 23c R 24c , S.O. 2 CH 3 , C(O)N(CH 3 ) 2 , NHC(O)C 1-3 C containing one nitrogen atom at the point of attachment to the alkyl or Ar2c 3-6 heterocycloalkyl or R 12c forms, together with the nitrogen atom to which it is attached, an N-oxide (N + -O - ) to form; R 21c , H, C 1-5 Alkyl, C(O)C1-5 Alkyl, C(O)OC 1-5 Alkyl, C 1-3 Alkyl OC 1-2 Alkyl, C 1-4 Haloalkyl or C 4-6 is heterocycloalkyl; R 22c is H or CH 3 and; R 23c is H or C 1-2 is alkyl; R 24c is H or C 1-2 is alkyl; R 29c is C 1-3 Alkyl, C 0-2 Alkylene C 3-5 Cycloalkyl (wherein the cycloalkyl is CH 3 Optionally replaced by CF 3 , N(C 1-3 Alkyl) 2 or a 5- or 6-membered heteroaryl, wherein the 5- or 6-membered heteroaryl is optionally substituted with methyl; and R 32c is C 1-3 alkyl, and R 33c is C 1-3 is alkyl; or R 32c and R 33c together with the nitrogen atom to which they are attached, C 3-5 Forming a heterocycloalkyl; where: R 1c is R 1ac and / or R 4c and R 5c is R 4ac and R 5ac and / or A c A ac (It is.)

[0042] More preferably, the CTPS1 inhibitor is one of 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)cyclopropanesulfonamide alboxamide; 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 pharma- ceutical acceptable salt and / or a pharma- ceutical acceptable solvate thereof.

[0043] Such CTPS1 inhibitors are disclosed in PCT Publication No. WO2020245665, which is incorporated by reference in its entirety for the CTPS1 inhibitors disclosed therein. In particular, the CTPS1 inhibitors include compounds described in any one of clauses 1-204 of WO2020245665 or pharma- ceutically acceptable salts and / or pharma-ceutically acceptable solvates thereof, in particular 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, P318, P319, P320, P321, P322, P323, P324, P325, P326, P327, P328, P329, P330, P335, P336, P337, P338, P339, P340, P341, P342, P343, P344, P345, P346, P347, P348, P350, P351, P352, P353, P354, P355 , 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 pharma- ceutically acceptable salt and / or a pharma-ceutically acceptable solvate thereof.

[0044] Alternatively, the CTPS1 inhibitor is a compound of formula (VII): or a pharma- ceutically acceptable salt and / or a pharma- ceutically acceptable solvate thereof. [ka] (In the formula, A is A a Or A b and; Where: A a has the following structure: -NH-, -CH 2 NH- or -NHCH 2 - an amine linker having A b is an amide linker having the following structure: -C(=O)NH- or -NHC(=O)-; B is, [ka] and; X is N or CH; Y is N or CR 2 and; Z is N or CR 3 and; With the proviso that when at least one of X or Z is N, Y cannot be N; R 1 is C 1-5 fluoroalkyl, where R 1 CF 3 rather than; R 2 H, halo, C 1-2 Alkyl, OC 1-2 Alkyl, C 1-2 Haloalkyl or OC 1-2 is haloalkyl; R 3 H, halo, CH 3 , O.C.H. 3 , C.F. 3 , or OCF 3 and; Here, R 2 and R 3 at least one of is H; R 3' H, halo, CH 3 , O.C. 1-2 Alkyl or CF 3 and When A is -NHC(=O)-, R 3' is R 5 together form a 5- or 6-membered cycloalkyl or a 5- or 6-membered oxygen-containing heterocycloalkyl; R 4 and R 5 is R 4a and R 5a or R 4b and R 5b and; Where: R 4a and R 5a together with the carbon atom to which they are attached, C 3-6 Forms a cycloalkyl, which is: Each of the substituents is C 1-3 Alkyl, oxo, OH, C 1-3AlkylOH, C 1-3 Haloalkyl, C 0-2 Alkylene C 3-6 Cycloalkyl, C 0-2 Alkylene C 3-6 Heterocycloalkyl, C 1-3 Alkylene OC 1-3 Alkyl, Halo, OC 1-3 Haloalkyl, OC 0-2 Alkylene C 3-6 Cycloalkyl, OC 0-2 Alkylene C 3-6 Heterocycloalkyl, OC 1-3 Alkyl and NR 21 R 22 or is substituted by one or two substituents independently selected from the group consisting of: C 3-6 One of the carbons of the cycloalkyl is a spirocyclic ring system. 3-6 Cycloalkyl rings and further C 3-6 Cycloalkyl ring or C 3-6 A spiro center such as formed by a heterocycloalkyl ring, and where R 4a and R 5a C formed by 3-6 Cycloalkyl means that each of the substituents, together with the carbon atom to which they are attached, is C 1-3 Alkyl or OC 1-3 or may be substituted by one or two substituents independently selected from the group consisting of alkyl; R 4a and R 5a together with the carbon atom to which they are attached, C 3-6 heterocycloalkyl, wherein the C 3-6 One of the carbons of the heterocycloalkyl is a spirocyclic ring system. 3-6 Heterocycloalkyl rings and further C 3-6 Cycloalkyl ring or C 3-6 A spiro center such as formed by a heterocycloalkyl ring, and where R 4a and R 5a C formed by 3-6Heterocycloalkyl means that each of the substituents, together with the carbon atom to which they are attached, is C 1-3 Alkyl or OC 1-3 or may be substituted by one or two substituents independently selected from the group consisting of alkyl; R 4a and R 5a C, which contains one nitrogen atom together with the carbon atom to which they are attached 3-6 heterocycloalkyl, where the nitrogen atom is -S(O) 2 R 29 or is replaced by R 4b and R 5b are each independently H, C 1-6 Alkyl, C 1-6 AlkylOH, C 1-6 Haloalkyl, C 0-2 Alkylene C 3-6 Cycloalkyl, C 0-2 Alkylene C 3-6 Heterocycloalkyl, C 1-3 Alkylene OC 1-3 alkyl or R 4b and R 5b together with the carbon atom to which they are attached, C 3-6 Cycloalkyl or C 3-6 forming a heterocycloalkyl; and A is -NHC(=O)- or -NHCH 2 -When: R 4b and R 5b Ha, Hello, OC 1-6 Haloalkyl, OC 0-2 Alkylene C 3-6 Cycloalkyl, OC 0-2 Alkylene C 3-6 Heterocycloalkyl, OC 1-6 Alkyl and NR 21 R 22 may further be selected from; 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; R 10 H, halo, C 1-3 Alkyl, C 1-2 Haloalkyl, OC 1-2 Alkyl, OC 1-2 haloalkyl, or CN; R 11 are H, F, Cl, and C. 1-2 Alkyl, CF 3 , O.C.H. 3 , or CN; R 12 is bonded to Ar2 at the ortho or meta position relative to Ar1, and R 12 H, halo, C 1-4 Alkyl, C 2-4 Alkenyl, C 0-2 Alkylene C 3-5 Cycloalkyl, OC 1-4 Alkyl, OC 0-2 Alkylene C 3-5 Cycloalkyl, C 1-4 Haloalkyl, OC 1-4 Haloalkyl, Hydroxy, C 1-4 Alkyl OH, SO 2 C 1-2 Alkyl, C(O)N(C 1-2 Alkyl) 2 , NHC(O)C 1-3 Alkyl or NR 23 R 24 and A is -NHC(=O)-, -NH-, or -NHCH 2 -When: R 12 CN, OCH 2 CH 2 N(CH 3 ) 2 and C containing one nitrogen atom at the attachment point to Ar2 3-6 heterocycloalkyl, or R 12 forms, together with the nitrogen atom to which it is attached, an N-oxide (N + -O - ) to form; R13 is H or halo; R 21 , H, C 1-5 Alkyl, C(O)C 1-5 Alkyl, C(O)OC 1-5 is alkyl; R 22 is H or CH 3 and; R 23 is H or C 1-2 is alkyl; and R 24 is H or C 1-2 is alkyl; R 29 is C 1-3 Alkyl, C 0-2 Alkylene C 3-5 Cycloalkyl (wherein the cycloalkyl is CH 3 Optionally substituted by, or CF 3 and; R 32 is C 1-3 alkyl, and R 33 is C 1-3 is alkyl; or R 32 and R 33 together with the nitrogen atom to which they are attached, C 3-5 forming a heterocycloalkyl).

[0045] More preferably, the CTPS1 inhibitor is one of 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 pharma- ceutical acceptable salt and / or a pharma- ceutical acceptable solvate thereof.

[0046] Such CTPS1 inhibitors are disclosed in PCT Publication No. WO2021053403, which is incorporated by reference in its entirety for the CTPS1 inhibitors disclosed therein. In particular, the CTPS1 inhibitor may be a compound described in any one of clauses 1-191 of WO2021053403 or a pharma- ceutically acceptable salt and / or pharma-ceutically acceptable solvate thereof, in particular a compound selected from P271 and P284 or a pharma-ceutically acceptable salt and / or pharma-ceutically acceptable solvate thereof.

[0047] Alternatively, the CTPS1 inhibitor is a compound of formula (VIII): or a pharma- ceutically acceptable salt and / or a pharma- ceutically acceptable solvate thereof. [ka] (In the formula, A is A a Or A b and; Where: A a has the following structure: -NH-, -CH 2 NH- or -NHCH 2 - an amine linker having A b is an amide linker having the following structure: -C(=O)NH- or -NHC(=O)-; B is, [ka] and; X is N or CH; Y is N or CR 2 and; Z is N or CR 3 and; With the proviso that when at least one of X or Z is N, Y cannot be N; R 1 is C 1-5 Alkyl or C 0-2 Alkylene C 3-5cycloalkyl, wherein the alkyl or (alkylene)cycloalkyl is substituted by CN; R 2 H, halo, C 1-2 Alkyl, OC 1-2 Alkyl, C 1-2 Haloalkyl or OC 1-2 is haloalkyl; R 3 H, halo, CH 3 , O.C.H. 3 , C.F. 3 , or OCF 3 and; Here, R 2 and R 3 at least one of is H; R 3' H, halo, CH 3 , O.C. 1-2 Alkyl or CF 3 and When A is -NHC(=O)-, R 3' is R 5 together form a 5- or 6-membered cycloalkyl or a 5- or 6-membered oxygen-containing heterocycloalkyl; R 4 and R 5 is R 4a and R 5a or R 4b and R 5b and; Where: R 4a and R 5a together with the carbon atom to which they are attached, C 3-6 Forms a cycloalkyl, which is: Each of the substituents is C 1-3 Alkyl, oxo, OH, C 1-3 AlkylOH, C 1-3 Haloalkyl, C 0-2 Alkylene C 3-6 Cycloalkyl, C 0-2 Alkylene C 3-6 Heterocycloalkyl, C 1-3 Alkylene OC 1-3 Alkyl, Halo, OC 1-3Haloalkyl, OC 0-2 Alkylene C 3-6 Cycloalkyl, OC 0-2 Alkylene C 3-6 Heterocycloalkyl, OC 1-3 Alkyl and NR 21 R 22 or is substituted by one or two substituents independently selected from the group consisting of: C 3-6 One of the carbons of the cycloalkyl is a spirocyclic ring system. 3-6 Cycloalkyl rings and further C 3-6 Cycloalkyl ring or C 3-6 A spiro center such as formed by a heterocycloalkyl ring, and where R 4a and R 5a C formed by 3-6 Cycloalkyl means that each of the substituents, together with the carbon atom to which they are attached, is C 1-3 Alkyl or OC 1-3 or may be substituted by one or two substituents independently selected from the group consisting of alkyl; R 4a and R 5a together with the carbon atom to which they are attached, C 3-6 heterocycloalkyl, wherein the C 3-6 One of the carbons of the heterocycloalkyl is a spirocyclic ring system. 3-6 Heterocycloalkyl rings and further C 3-6 Cycloalkyl ring or C 3-6 A spiro center such as that formed by a heterocycloalkyl ring, and where R 4a and R 5a C formed by 3-6 Heterocycloalkyl means that each of the substituents, together with the carbon atom to which they are attached, is C 1-3 Alkyl or OC 1-3 or may be substituted by one or two substituents independently selected from the group consisting of alkyl; R 4a and R 5aC, which contains one nitrogen atom together with the carbon atom to which they are attached 3-6 heterocycloalkyl, where the nitrogen atom is -S(O) 2 R 29 or is replaced by R 4b and R 5b are each independently H, C 1-6 Alkyl, C 1-6 AlkylOH, C 1-6 Haloalkyl, C 0-2 Alkylene C 3-6 Cycloalkyl, C 0-2 Alkylene C 3-6 Heterocycloalkyl, C 1-3 Alkylene OC 1-3 alkyl or R 4b and R 5b together with the carbon atom to which they are attached, C 3-6 Cycloalkyl or C 3-6 forming a heterocycloalkyl; and A is -NHC(=O)- or -NHCH 2 -When: R 4b and R 5b Ha, Hello, OC 1-6 Haloalkyl, OC 0-2 Alkylene C 3-6 Cycloalkyl, OC 0-2 Alkylene C 3-6 Heterocycloalkyl, OC 1-6 Alkyl and NR 21 R 22 may further be selected from; 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; R 10 H, halo, C 1-3 Alkyl, C 1-2 Haloalkyl, OC 1-2 Alkyl, OC 1-2 haloalkyl, or CN; R 11 are H, F, Cl, and C.1-2 Alkyl, CF 3 , O.C.H. 3 , or CN; R 12 is bonded to Ar2 at the ortho or meta position relative to Ar1, and R 12 H, halo, C 1-4 Alkyl, C 2-4 Alkenyl, C 0-2 Alkylene C 3-5 Cycloalkyl, OC 1-4 Alkyl, OC 0-2 Alkylene C 3-5 Cycloalkyl, C 1-4 Haloalkyl, OC 1-4 Haloalkyl, Hydroxy, C 1-4 Alkyl OH, SO 2 C 1-2 Alkyl, C(O)N(C 1-2 Alkyl) 2 , NHC(O)C 1-3 Alkyl or NR 23 R 24 and A is -NHC(=O)-, -NH-, or -NHCH 2 -When: R 12 CN, OCH 2 CH 2 N(CH 3 ) 2 and C containing one nitrogen atom at the attachment point to Ar2 3-6 heterocycloalkyl, or R 12 forms, together with the nitrogen atom to which it is attached, an N-oxide (N + -O - ) to form; R 13 is H or halo; R 21 , H, C 1-5 Alkyl, C(O)C 1-5 Alkyl, C(O)OC 1-5 is alkyl; R 22 is H or CH 3 and; R 23 is H or C1-2 is alkyl; and R 24 is H or C 1-2 is alkyl; R 29 is C 1-3 Alkyl, C 0-2 Alkylene C 3-5 Cycloalkyl (wherein the cycloalkyl is CH 3 Optionally substituted by, or CF 3 and; R 32 is C 1-3 alkyl, and R 33 is C 1-3 is alkyl; or R 32 and R 33 together with the nitrogen atom to which they are attached, C 3-5 forming a heterocycloalkyl).

[0048] More preferably, the CTPS1 inhibitor is one of 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 pharma- ceutical acceptable salt and / or a pharma- ceutical acceptable solvate thereof.

[0049] Such CTPS1 inhibitors are disclosed in PCT Publication No. WO2021053402, which is incorporated by reference in its entirety for the CTPS1 inhibitors disclosed therein. In particular, the CTPS1 inhibitor may be a compound described in any one of clauses 1-191 of WO2021053402 or a pharma- ceutically acceptable salt and / or pharma-ceutically acceptable solvate thereof, in particular a compound selected from P285 and P287 or a pharma-ceutically acceptable salt and / or pharma-ceutically acceptable solvate thereof.

[0050] The CTPS1 inhibitor is 4-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)tetrahydro-2H-pyran-4-carboxamide (herein referred to as "CTPS-IA"): [ka] or a pharma- ceutical acceptable salt and / or a pharma- ceutical acceptable solvate thereof.

[0051] Alternatively, the CTPS1 inhibitor is N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(2-(ethylsulfonamido)pyrimidin-4-yl)tetrahydro-2H-pyran-4-carboxamide (herein referred to as "CTPS-IB"): [ka] or a pharma- ceutical acceptable salt and / or a pharma- ceutical acceptable solvate thereof.

[0052] The above compounds (and methods of making these compounds) are disclosed in PCT Publication Nos. WO2019106156, WO2019180244, WO2019106146, WO2019179652, WO2020245665, WO2020245664, WO2021053403, WO2021053402, or WO2020083975.

[0053] Depending on the nature of the specific CTPS1 inhibitor, the CTPS1 inhibitor can be provided in the form of a pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate. In some embodiments, the CTPS1 inhibitor is provided in the form of a pharmaceutically acceptable salt and a pharmaceutically acceptable solvate (i.e., a pharmaceutically acceptable solvate of a pharmaceutically acceptable salt). 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 a solvate).

[0054] Suitable pharma- ceutically acceptable salts will be apparent to those skilled in the art. Pharmaceutically acceptable salts include those in Remington's Pharmaceutical Sciences, 17th Edition, Mack Publishing Company, Easton, PA, 1985, p.1418. Such pharma- ceutically acceptable salts include acid addition salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, or phosphoric acid, and organic acids, such as succinic acid, maleic acid, acetic acid, fumaric acid, citric acid, tartaric acid, benzoic acid, p-toluenesulfonic acid, methanesulfonic acid, or naphthalenesulfonic acid. Pharmaceutically acceptable salts can also be formed with metal ions, such as metal salts, such as sodium salts or potassium salts, and organic bases, such as basic amines, for example, with ammonia, meglumine, tromethamine, piperazine, arginine, choline, diethylamine, benzathine, or lysine.

[0055] CTPS1 inhibitors can 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.

[0056] CTPS1 inhibitors may be prepared in crystalline or non-crystalline form and, if crystalline, may be optionally solvated, for example, as a hydrate. The invention includes within its scope stoichiometric solvates (e.g., hydrates) as well as compounds containing variable amounts of solvent (e.g., water).

[0057] CTPS1 inhibitors include all isomers of CTPS1 inhibitors disclosed herein, including all geometric, tautomeric and optical forms, and mixtures thereof (e.g., racemic mixtures). If additional chiral centers are present, the present invention includes within its scope all possible diastereoisomers, including mixtures thereof. Different isomeric forms can be separated or resolved from one another by conventional methods, or any given isomer can be obtained by conventional synthetic methods or by stereospecific or asymmetric synthesis.

[0058] CTPS1 inhibitors encompass all isotopic forms of CTPS1 inhibitors provided herein, whether (i) all atoms of a given atomic number have the mass number (or mixture of mass numbers) that predominates in nature (herein referred to as "natural isotopic forms"), or (ii) one or more atoms are replaced by atoms with the same atomic number, but the mass number is different from the mass number of the atoms that predominate in nature (herein referred to as "non-natural variant isotopic forms"). It is understood that atoms may naturally exist as a mixture of mass numbers. The term "non-natural variant isotopic forms" also includes embodiments in which the ratio of atoms of a given atomic number that have mass numbers that are less commonly found in nature (herein referred to as "non-common isotopes") is increased compared to that occurring in nature, for example, to a level of >20%, >50%, >75%, >90%, >95%, or >99% by number of atoms of that atomic number (the latter embodiment is referred to as "isotopically enriched variant forms"). The term "non-natural variant isotopic form" also includes embodiments in which the ratio of uncommon isotopes is reduced compared to those occurring in nature. Isotopic forms can also include radioactive forms (i.e., those incorporating a radioactive isotope) and non-radioactive forms. Radioactive forms are usually isotopically enriched variant forms.

[0059] Non-natural variant isotopic forms containing radioactive isotopes can be used, for example, in drug and / or substrate tissue distribution studies.

[0060] In one embodiment, the CTPS1 inhibitor is provided in natural isotopic form.

[0061] In one embodiment, the CTPS1 inhibitor is provided in a non-natural variant isotopic form.

[0062] In one embodiment, a CTPS1 inhibitor is provided in which a single atom of the compound exists in a non-natural variant isomeric form. In another embodiment, a CTPS1 inhibitor is provided in which two or more atoms exist in a non-natural variant isomeric form.

[0063] The CTPS1 inhibitor administered to a subject should be safe and effective, i.e., the CTPS1 inhibitor should provide an acceptable balance between desired benefits and undesired side effects. "Safe and effective" is intended to include a compound that is effective in achieving a desired effect in the treatment of cancer. The desired effect is usually clinically meaningful and / or measurable, for example, in relation to (a) inhibiting a disease state, i.e., delaying or stopping its development; and / or (b) alleviating a disease state, i.e., causing regression of the disease state or relief of associated symptoms.

[0064] For the avoidance of doubt, "safe and effective" as recited herein can be achieved by any suitable dosing regimen.Thus, for example, the reference herein to administering a safe and effective CTPS1 inhibitor by a specific administration route includes achieving a safe and effective amount via a single dose, or, for example, by multiple doses administered by the designated administration route.For example, orally administering a safe and effective CTPS1 inhibitor includes both orally administering a single dose and orally administering any multiple doses, provided that a safe and effective dose of the CTPS1 inhibitor is achieved by oral administration.

[0065] The CTPS1 inhibitor may be a compound of formula (IX): or a pharma- ceutically acceptable salt thereof or a pharma- ceutically acceptable salt and / or a pharma- ceutically acceptable solvate thereof [ka] (In the formula: R 1 is C 1-6 aliphatic; 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is selected from q R A has been replaced with the example; Ring A is selected from phenyl; a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5- to 6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 7- to 11-membered fused bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L is [ka] and; Here, R L , R L' , and R L'' Each of is independently hydrogen, -CN, halogen, or C 1-6 an optionally substituted group selected from aliphatic; phenyl; a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or R L , R L' , and R L'' two of the groups, together with the atom to which each is attached, form an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; or a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or R L , R L' , and R L'' One of the following is R B together with, form 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 heteroatoms independently selected from nitrogen, oxygen, and sulfur: Ring C is selected from phenyl, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5- to 6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 7- to 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; R A , R B , and R C Each example is independently oxo, halogen, -CN, -NO 2 , -OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)NR 2 , -C(O)R, -C(O)OR, -C(O)NR2 , -C(O)N(R)OR, -OC(0)R, -OC(O)NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , -N(R)C(NR)NR 2 , -N(R)NR 2 , -N(R)S(O) 2 NR 2 , -N(R)S(O) 2 R, -N=S(O)R 2 , -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, -P(O)(R)NR 2 , -P(O)(R)OR, or -P(O)R 2 or R C Each example of 1-6 Aliphatic;Phenyl;Naphthalenyl; an optionally substituted group selected from a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, phosphorus, silicon, and sulfur; or a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8- to 10-membered bicyclic heteroaryl ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 8-membered saturated or partially unsaturated bridged bicyclic ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6- to 10-membered saturated or partially unsaturated spirocyclic ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 6- to 11-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is an optionally substituted group selected from r instances of R and s instances of R D or two R C The group may optionally be Ctogether with the atom to which it is attached form an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5- to 7-membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R D Each example is independently oxo, halogen, -CN, -NO 2 , -OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)NR 2 , -C(O)R, -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, -0C(0)R, -OC(O)NR 2 , -N(R)C(O)OR, -N(R)C(0)R, -N(R)C(0)NR 2 , -N(R)C(NR)NR 2 , -N(R)NR 2 , -N(R)S(O) 2 NR 2 , -N(R)S(O) 2 R, -N=S(O)R 2 , -S(NR(O)R, -N(R)S(O)R, -N(R)CN, -P(O)(R)NR 2 , -P(O)(R)OR, or -P(O)R 2 and; Each R is independently hydrogen, -CN, halogen, or C 1-6aliphatic; phenyl; naphthalenyl; 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 7- to 8-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an optionally substituted group selected from: a 5- to 12-membered saturated or partially unsaturated bicyclic heterocyclic ring; a 5- to 8-membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6- to 10-membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6- to 11-membered saturated or partially unsaturated bicyclic carbocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; two R groups, together with the atom to which each R is attached, form an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms 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 is independently 0, 1, 2, 3, or 4; each r is independently 0, 1, 2, 3, or 4; and each s is independently 0, 1, 2, 3, or 4; however: R 1 C 1-6 an aliphatic or 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; Sulfonamide moiety [ka] R group is hydrogen or para-methoxybenzyl; L, [ka] and R L and R L' Or R L and R L'' The groups, together with the atoms to which they are each attached, do not form an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or L is [ka] and; Ring B is phenyl or a 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and when Ring C is phenyl or a 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and is attached to Ring B in the para position relative to the L group; Ring A and its R A The substituents are [ka] (where: * teeth, [ka] means a bond to a moiety, and ** teeth, [ka] (other than meaning a bond to a moiety).

[0066] Such CTPS1 inhibitors are disclosed in PCT Publication No. WO2022087634, which is incorporated by reference in its entirety for the CTPS1 inhibitors disclosed therein. In particular, the CTPS1 inhibitor may be a compound described in any one of claims 1-31 of WO2022087634, or a pharma- ceutical acceptable salt and / or a pharma- ceutical acceptable solvate thereof. The CTPS1 inhibitor may be a compound selected from compounds I-1 to I-286 of WO2022087634, or a pharma- ceutical acceptable salt and / or a pharma- ceutical acceptable solvate thereof. The CTPS1 inhibitor may be a compound selected from compounds Z-1 to Z-10 of WO2022087634, or a pharma- ceutical acceptable salt and / or a pharma- ceutical acceptable solvate thereof.

[0067] In one embodiment, the CTPS1 inhibitor is not a CTPS1 inhibitor disclosed in PCT Publication No. 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 pharma- ceutically acceptable salt and / or a pharma-ceutically acceptable solvate thereof, (ii) a compound selected from compounds I-1 to I-286 of WO2022087634 or a pharma-ceutically acceptable salt and / or a pharma-ceutically acceptable solvate thereof, or (iii) a compound selected from compounds Z-1 to Z-10 of WO2022087634 or a pharma-ceutically acceptable salt and / or a pharma-ceutically acceptable solvate thereof.

[0068] 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, e.g., any of compounds I-1 to I-286 or Z-1 to Z-10, or a pharma- ceutically acceptable salt and / or pharma-ceutically acceptable solvate thereof. In other embodiments, the CTPS1 inhibitor is not described in WO2022 / 087634.

[0069] Suitably, the CTPS1 inhibitor is 1. A compound of formula I: or a pharma- ceutically acceptable salt thereof [ka] (In the formula: R 1 is C 1-6 aliphatic; 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is selected from q R A has been replaced with the example; Ring A is selected from phenyl; a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5- to 6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 7- to 11-membered fused bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L is [ka] and; Here, R L , R L' , and R L'' Each of is independently hydrogen, -CN, halogen, or C 1-6an optionally substituted group selected from aliphatic; phenyl; a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or R L , R L' , and R L'' two of the groups, together with the atom to which each is attached, form an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; or a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or R L , R L' , and R L'' One of the following is R B together with, form 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 heteroatoms independently selected from nitrogen, oxygen, and sulfur: Ring C is selected from phenyl, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5- to 6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 7- to 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; R A , R B , and R C Each example is independently oxo, halogen, -CN, -NO 2 , -OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)NR 2 , -C(O)R, -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, -OC(0)R, -OC(O)NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , -N(R)C(NR)NR 2 , -N(R)NR 2 , -N(R)S(O) 2 NR 2 , -N(R)S(O) 2 R, -N=S(O)R 2 , -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, -P(O)(R)NR 2 , -P(O)(R)OR, or -P(O)R 2 or RC Each example of 1-6 Aliphatic;Phenyl;Naphthalenyl; an optionally substituted group selected from a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, phosphorus, silicon, and sulfur; or a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8- to 10-membered bicyclic heteroaryl ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 8-membered saturated or partially unsaturated bridged bicyclic ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6- to 10-membered saturated or partially unsaturated spirocyclic ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 6- to 11-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is an optionally substituted group selected from r instances of R and s instances of R D or two R C The group may optionally be C together with the atom to which it is attached form an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5- to 7-membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R D Each example is independently oxo, halogen, -CN, -NO 2 , -OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)NR 2 , -C(O)R, -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, -0C(0)R, -OC(O)NR 2 , -N(R)C(O)OR, -N(R)C(0)R, -N(R)C(0)NR 2, -N(R)C(NR)NR 2 , -N(R)NR 2 , -N(R)S(O) 2 NR 2 , -N(R)S(O) 2 R, -N=S(O)R 2 , -S(NR(O)R, -N(R)S(O)R, -N(R)CN, -P(O)(R)NR 2 , -P(O)(R)OR, or -P(O)R 2 and; Each R is independently hydrogen, -CN, halogen, or C 1-6 aliphatic; phenyl; naphthalenyl; 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 7- to 8-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an optionally substituted group selected from: a 5- to 12-membered saturated or partially unsaturated bicyclic heterocyclic ring; a 5- to 8-membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6- to 10-membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6- to 11-membered saturated or partially unsaturated bicyclic carbocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; two R groups, together with the atom to which each R is attached, form an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms 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 is independently 0, 1, 2, 3, or 4; each r is independently 0, 1, 2, 3, or 4; and each s is independently 0, 1, 2, 3, or 4; however: R 1 C 1-6 an aliphatic or 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; Sulfonamide moiety [ka] R group is hydrogen or para-methoxybenzyl; L, [ka] and R L and R L' Or R L and R L'' The groups, together with the atoms to which they are each attached, do not form an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or L is [ka] and; Ring B is phenyl or a 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and when Ring C is phenyl or a 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and is attached to Ring B in the para position relative to the L group; Ring A and its R A The substituents are [ka] (where: * teeth, [ka] means a bond to a moiety, and ** teeth, [ka] (other than meaning a bond to a moiety).

[0070] Preferably, the CTPS1 inhibitor is not a CTPS1 inhibitor as defined in claim 1 of WO2022 / 087634. ​​Preferably, the CTPS1 inhibitor is not a CTPS1 inhibitor as defined in WO2022 / 087634.

[0071] (BCL2 inhibitor) In one aspect of the invention there is provided a BCL2 inhibitor for use in the treatment of cancer with a CTPS1 inhibitor.

[0072] As used herein, a BCL2 inhibitor is an agent that directly inhibits BCL2 activity, such as inhibiting BCL2-induced apoptosis. Direct inhibition of BCL2 can be quantified using any suitable assay procedure, but is preferably performed using the procedure shown in Example 3.

[0073] The activity of BCL2 inhibitors has been determined using competitive fluorescence polarization and time-resolved fluorescence resonance energy transfer binding affinity assays to calculate inhibition constant (Ki) values ​​for binding to BCL2 to determine potency, and to related proteins such as BCL2L1 to determine specificity (Souers 2013; Tse 2008; Zhang 2002).

[0074] BCL2 inhibitors of particular interest are those that exhibit a Ki value for binding to BCL2 of 50 nM or less, such as 20 nM or less, such as 10 nM or less, such as 5 nM or less, such as 1 nM or less.

[0075] BCL2 inhibitors of particular interest are those that exhibit a Ki value for binding to BCL2 of 50 nM or less, such as 20 nM or less, for example 10 nM or less, such as 5 nM or less, for example 1 nM or less, using the assay procedure set forth in Example 3.

[0076] BCL2 inhibitors of particular interest are those that exhibit >2-fold, e.g., >5-fold, e.g., >10-fold selectivity for BCL2 over BCL2L1, e.g., >2-fold, e.g., >5-fold, e.g., >10-fold selectivity for BCL2 over BCL2L1, using the assay procedure set forth in Example 4.

[0077] Further BCL2 inhibitors of particular interest are those that exhibit >2-fold, such as >5-fold, for example >10-fold selectivity for BCL2 over MCL1, e.g. >2-fold, such as >5-fold, for example >10-fold selectivity for BCL2 over BCL2L1, using the assay procedure set forth in Example 4.

[0078] For agents intended for human use, BCL2 inhibition and BCL2 versus BCL2L1 selectivity should be based on the human form of the protein.

[0079] Suitably, the BCL2 inhibitor is a BH-3 mimetic. BH-3 mimetics are agents that mimic the activity of the BH3 domain of pro-apoptotic proteins and bind to and block anti-apoptotic BCL2 proteins. Specific BH-3 mimetics include (clinical trial data sourced from .clinicaltrials.gov accessed 21 December 2021):

[0080] (Venetoclax) Venetoclax (4-[4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexen-1-yl]methyl]piperazin-1-yl]-N-[3-nitro-4-(oxan-4-ylmethylamino)phenyl]sulfonyl-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide, CAS number 1257044-40-8, trade name Venclyxto®) is a BCL2-specific BH3 mimetic. It is approved by the FDA as a single agent or in combination with anti-CD20 monoclonal antibodies for the treatment of chronic lymphocytic leukemia and small lymphocytic lymphoma, and in combination with azacitidine, decitabine, or low-dose cytarabine for the treatment of acute myeloid leukemia. Venetoclax is usually administered orally up to a dose of 400-600 mg once daily. Of the 197 clinical trials of venetoclax currently recruiting, 97.5% are enrolling only patients with hematologic malignancies, and 2.5% are enrolling patients with solid tumors. The structure of venetoclax is shown below. [ka]

[0081] Therefore, the BCL2 inhibitor may be ventoclax or a pharma- ceutically acceptable salt and / or a pharma- ceutically acceptable solvate thereof. In one embodiment, the BCL2 inhibitor is venetoclax. In one embodiment, the BCL2 inhibitor is a pharma- ceutically acceptable salt of venetoclax. In one embodiment, the BCL2 inhibitor is a pharma- ceutically acceptable solvate of venetoclax. In one embodiment, the BCL2 inhibitor is a pharma- ceutically acceptable salt and a pharma- ceutically acceptable solvate of venetoclax.

[0082] In one embodiment, the BCL2 inhibitor is not venetoclax. Suitably, the BCL2 inhibitor is not venetoclax or a pharma- ceutically acceptable salt and / or a pharma-ceutically acceptable solvate thereof.

[0083] Venetoclax is disclosed in Park, 2008, which is incorporated by reference in its entirety for purposes of defining a BCL2 inhibitor.

[0084] (Navitoclax) Navitoclax (4-[4-[[2-(4-chlorophenyl)-5,5-dimethylcyclohexen-1-yl]methyl]piperazin-1-yl]-N-[4-[[(2R)-4-morpholin-4-yl-1-phenylsulfanylbutan-2-yl]amino]-3-(trifluoromethylsulfonyl)phenyl]sulfonylbenzamide, CAS number 923564-51-6, also known as ABT-263) is a BH3 mimetic with activity against BCL2L1 (BCL-XL) and BCL2. It has not yet been approved for any indication. Clinical trials are currently recruiting patients with hematological and solid tumors. It is usually administered orally. Clinical development has been hampered by thrombocytopenia due to inhibition of BCL2L1. The structure of navitoclax is shown below. [ka]

[0085] Therefore, the BCL2 inhibitor can be navitoclax or its pharmaceutically acceptable salt and / or pharmaceutically acceptable solvate. In one embodiment, the BCL2 inhibitor is navitoclax. In one embodiment, the BCL2 inhibitor is a pharmaceutically acceptable salt of navitoclax. In one embodiment, the BCL2 inhibitor is a pharmaceutically acceptable solvate of navitoclax. In one embodiment, the BCL2 inhibitor is a pharmaceutically acceptable salt and pharmaceutically acceptable solvate of navitoclax.

[0086] Navitoclax is disclosed in Tse, 2008, which is incorporated by reference in its entirety for purposes of defining BCL2 inhibitors.

[0087] (Obatoclax) Obatoclax ((2Z)-2-[(5Z)-5-[(3,5-dimethyl-1H-pyrrol-2-yl)methylidene]-4-methoxypyrrol-2-ylidene]indole, CAS number 803712-67-6, also known as GX15-070) is a BCL2-specific BH3 mimetic that has been previously tested in clinical trials for a variety of hematological and solid tumor indications. It has not yet been approved for any disease and there are no currently recruiting clinical trials for this agent. The structure of obatoclax is shown below. [ka]

[0088] Therefore, the BCL2 inhibitor may be obatoclax or a pharma- ceutically acceptable salt and / or a pharma- ceutically acceptable solvate thereof. In one embodiment, the BCL2 inhibitor is obatoclax. In one embodiment, the BCL2 inhibitor is a pharma- ceutically acceptable salt of obatoclax. In one embodiment, the BCL2 inhibitor is a pharma- ceutically acceptable solvate of obatoclax. In one embodiment, the BCL2 inhibitor is a pharma- ceutically acceptable salt and a pharma- ceutically acceptable solvate of obatoclax.

[0089] Obatoclax is disclosed in Li, 2008, which is incorporated by reference in its entirety for purposes of defining a BCL2 inhibitor.

[0090] (BCL201) BCL201 (also known as S55746) is a BCL2-specific BH3 mimetic that has been tested in a few clinical trials for hematological malignancies to date. It has not yet been approved for any disease, and there are no currently recruiting clinical trials for this agent. The structure of BCL201 is shown below. [ka]

[0091] Therefore, the BCL2 inhibitor may be BCL201 or a pharma- ceutically acceptable salt and / or a pharma- ceutically acceptable solvate thereof. In one embodiment, the BCL2 inhibitor is BCL201. In one embodiment, the BCL2 inhibitor is a pharma- ceutically acceptable salt of BCL201. In one embodiment, the BCL2 inhibitor is a pharma- ceutically acceptable solvate of BCL201. In one embodiment, the BCL2 inhibitor is a pharma- ceutically acceptable salt and a pharma- ceutically acceptable solvate of BCL201.

[0092] BCL201 is disclosed in Casara, 2018, which is incorporated by reference in its entirety for purposes of defining a BCL2 inhibitor.

[0093] (AT101) AT101 (also known as gossypol) is a BH3 mimetic with activity against BCL2L1 (BCL-XL) and MCL1 as well as BCL2 that has been previously tested in clinical trials for a variety of hematological and solid tumor indications. It is not yet approved for any disease and there are no currently recruiting clinical trials for this agent. The structure of AT101 is shown below. [ka]

[0094] Therefore, the BCL2 inhibitor may be AT101 or a pharma- ceutically acceptable salt and / or a pharma- ceutically acceptable solvate thereof. In one embodiment, the BCL2 inhibitor is AT101. In one embodiment, the BCL2 inhibitor is a pharma- ceutically acceptable salt of AT101. In one embodiment, the BCL2 inhibitor is a pharma- ceutically acceptable solvate of AT101. In one embodiment, the BCL2 inhibitor is a pharma- ceutically acceptable salt and a pharma- ceutically acceptable solvate of AT101.

[0095] AT101 is disclosed in Wang, 2006, which is incorporated by reference in its entirety for purposes of defining a BCL2 inhibitor.

[0096] In one embodiment, the BCL2 inhibitor is selected from the group consisting of venetoclax, navitoclax, obatoclax, BCL201 and AT101, any of their pharmaceutically acceptable salts and / or pharmaceutically acceptable solvates. More preferably, the BCL2 inhibitor is selected from the group consisting of venetoclax, navitoclax, obatoclax, BCL201 and AT101, any of their pharmaceutically acceptable salts and / or pharmaceutically acceptable solvates. More preferably, the BCL2 inhibitor is selected from the list consisting of venetoclax, obatoclax, BCL201 and AT101, any of their pharmaceutically acceptable salts and / or pharmaceutically acceptable solvates. More preferably, the BCL2 inhibitor is venetoclax or a pharmaceutically acceptable salt and / or pharmaceutically acceptable solvate thereof.

[0097] Depending on the nature of the specific BCL2 inhibitor, the BCL2 inhibitor may be provided in the form of a pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate. In some embodiments, the BCL2 inhibitor is provided in the form of a pharmaceutically acceptable salt and a pharmaceutically acceptable solvate (i.e., a pharmaceutically acceptable solvate of a pharmaceutically acceptable salt). In other embodiments, the BCL2 inhibitor is provided in the form of a pharmaceutically acceptable salt. In further embodiments, the BCL2 inhibitor is provided in the form of a pharmaceutically acceptable solvate. In some embodiments, the BCL2 inhibitor is provided in free form (i.e., not a salt or a solvate).

[0098] Suitable pharma- ceutically acceptable salts will be apparent to those skilled in the art. Pharmaceutically acceptable salts include those in Remington's Pharmaceutical Sciences, 17th Edition, Mack Publishing Company, Easton, PA, 1985, p.1418. Such pharma- ceutically acceptable salts include acid addition salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, or phosphoric acid, and organic acids, such as succinic acid, maleic acid, acetic acid, fumaric acid, citric acid, tartaric acid, benzoic acid, p-toluenesulfonic acid, methanesulfonic acid, or naphthalenesulfonic acid. Pharmaceutically acceptable salts can also be formed with metal ions, such as metal salts, such as sodium salts or potassium salts, and organic bases, such as basic amines, for example, with ammonia, meglumine, tromethamine, piperazine, arginine, choline, diethylamine, benzathine, or lysine.

[0099] The BCL2 inhibitors can 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.

[0100] The BCL2 inhibitors may be prepared in crystalline or non-crystalline form and, if crystalline, may be optionally solvated, for example, as a hydrate. The present invention includes within its scope stoichiometric solvates (e.g., hydrates) as well as compounds containing variable amounts of solvent (e.g., water).

[0101] BCL2 inhibitors encompass all isomers of the BCL2 inhibitors disclosed herein, including all geometric, tautomeric and optical forms, as well as mixtures thereof (e.g., racemic mixtures). If additional chiral centers are present, the present invention includes within its scope all possible diastereoisomers, including mixtures thereof. The different isomeric forms can be separated or resolved one from the other by conventional methods, or any given isomer can be obtained by conventional synthetic methods or by stereospecific or asymmetric synthesis.

[0102] BCL2 inhibitors encompass all isotopic forms of the BCL2 inhibitors provided herein, whether (i) in a form in which all atoms of a given atomic number have the mass number (or mixture of mass numbers) that predominates in nature (herein referred to as "natural isotopic forms"), or (ii) in a form in which one or more atoms are replaced by an atom having the same atomic number, but the mass number is different from the mass number of the atom that predominates in nature (herein referred to as "non-natural variant isotopic forms"). It is understood that atoms may naturally exist as a mixture of mass numbers. The term "non-natural variant isotopic forms" also includes embodiments in which the proportion of atoms of a given atomic number that have mass numbers that are less commonly found in nature (herein referred to as "non-common isotopes") is increased compared to that occurring in nature, for example, to a level of >20%, >50%, >75%, >90%, >95%, or >99% by number of atoms of that atomic number (the latter embodiment is referred to as "isotopically enriched variant forms"). The term "non-natural variant isotopic form" also includes embodiments in which the ratio of uncommon isotopes is reduced compared to those occurring in nature. Isotopic forms can also include radioactive forms (i.e., those incorporating a radioactive isotope) and non-radioactive forms. Radioactive forms are usually isotopically enriched variant forms.

[0103] Non-natural variant isotopic forms containing radioactive isotopes can be used, for example, in drug and / or substrate tissue distribution studies.

[0104] In one embodiment, the BCL2 inhibitor is provided in natural isotopic form.

[0105] In one embodiment, the BCL2 inhibitor is provided in a non-natural variant isotopic form.

[0106] In one embodiment, BCL2 inhibitors are provided in which a single atom of the compound exists in a non-natural variant isomeric form. In another embodiment, BCL2 inhibitors are provided in which two or more atoms exist in a non-natural variant isomeric form.

[0107] Generally, the BCL2 inhibitors disclosed herein can be made according to organic synthesis techniques known to those skilled in the art.For example, the preparation of venetoclax is described in Park, 2008, which is incorporated herein by reference in its entirety for the method of producing the BCL2 inhibitor venetoclax disclosed herein.

[0108] The BCL2 inhibitor administered to a subject should be safe and effective, i.e., the BCL2 inhibitor should provide an acceptable balance of desired benefits and undesired side effects. "Safe and effective" is intended to include a compound that is effective in achieving a desired effect in the treatment of cancer. The desired effect is usually clinically meaningful and / or measurable, for example, in relation to (a) inhibiting a disease state, i.e., delaying or halting its onset; and / or (b) alleviating a disease state, i.e., causing regression of the disease state or relief of associated symptoms.

[0109] For the avoidance of doubt, the "safe and effective" recited herein can be achieved by any suitable dosing regimen. Thus, for example, a reference herein to administering a safe and effective BCL2 inhibitor by a specific administration route includes achieving a safe and effective amount via a single dose or, for example, by multiple doses administered by the specified administration route. For example, orally administering a safe and effective BCL2 inhibitor includes both orally administering a single dose and orally administering any multiple doses, provided that a safe and effective dose of the BCL2 inhibitor is achieved by oral administration.

[0110] (Administration) The present invention is generally intended for use with mammalian subjects, particularly human subjects. The combination therapy is generally administered to a subject in need thereof, particularly a mammalian subject in need thereof, particularly a human subject in need thereof.

[0111] In a further aspect, the present invention provides a CTPS1 inhibitor and a BCL2 inhibitor for use in the treatment of cancer.

[0112] One aspect of the invention provides the use of a CTPS1 inhibitor in the manufacture of a medicament for the treatment of cancer with a BCL2 inhibitor.

[0113] A further aspect of the invention provides the use of a BCL2 inhibitor in the manufacture of a medicament for the treatment of cancer with a CTPS1 inhibitor.

[0114] A further aspect of the invention provides the use of a CTPS1 inhibitor and a BCL2 inhibitor in the manufacture of a medicament for the treatment of cancer.

[0115] A further aspect of the invention provides a method of treating cancer in a subject, comprising administering to the subject a CTPS1 inhibitor and a BCL2 inhibitor.

[0116] A further aspect of the present invention preferably provides a pharmaceutical composition comprising a CTPS1 inhibitor and a BCL2 inhibitor for use in the treatment of cancer.

[0117] Preferably, the CTPS1 inhibitor and the BCL2 inhibitor act synergistically in treating cancer. The CTPS1 inhibitor and the BCL2 inhibitor act "synergistically" if their combined administration results in a beneficial effect that is greater than the sum of the beneficial effects of each agent administered alone. Preferably, the CTPS1 inhibitor and the BCL2 inhibitor act synergistically if they achieve a Bliss score of 10 or more (Bliss, 1939; Zheng, 2021) when applied to a cancer cell line such as that shown in Example 6.

[0118] (Administration of CTPS1 inhibitor) The CTPS1 inhibitor can be administered by any suitable route, which can depend on the nature of the specific drug.Exemplary routes include oral, parenteral, buccal, sublingual, nasal, or rectal administration.Advantageously, the CTPS1 inhibitor is administered orally.

[0119] The CTPS1 inhibitor may be provided in the form of a pharmaceutical composition comprising the CTPS1 inhibitor and a pharma- ceutically acceptable carrier or excipient.

[0120] When delivered orally, the CTPS1 inhibitor may be suitably delivered in a solid pharmaceutical composition (eg, a tablet, capsule, or lozenge) or in a liquid pharmaceutical composition (eg, a suspension, emulsion, or solution).

[0121] Liquid formulations usually consist of a suspension or solution of the CTPS1 inhibitor in a suitable liquid carrier, such as an aqueous solvent, such as water, ethanol, or glycerin, or a non-aqueous solvent, such as polyethylene glycol or oil. The formulation may also contain a suspending agent, a preservative, a flavoring agent, and / or a coloring agent.

[0122] Tablet formulations can be prepared using any suitable pharmaceutical carrier routinely used for preparing solid formulations, such as magnesium stearate, starch, lactose, sucrose, and cellulose.

[0123] Preferably the pharmaceutical composition is in unit dosage form, for example a tablet, capsule or ampoule. Preferably the unit dosage form is for oral delivery.

[0124] The pharmaceutical composition may contain, for example, 0.1% by weight to 99.99% by weight, for example, 10 to 60% by weight, of the active material, depending on the method of administration. The pharmaceutical composition may contain, for example, 0.01% by weight to 99% by weight, for example, 40% by weight to 90% by weight, of the carrier, depending on the method of administration. The pharmaceutical composition may contain, for example, 0.05 mg to 2000 mg, for example, 1.0 mg to 500 mg, of the active material, depending on the method of administration. The pharmaceutical composition may contain, for example, 50 mg to 1000 mg, for example, 100 mg to 400 mg, of the carrier, depending on the method of administration.

[0125] The dose of the compound used will vary in the usual manner depending on the severity of the cancer, the weight of the patient, and other similar factors. However, as a general guide, a suitable unit dose may be 0.05 mg to 1000 mg, more preferably 1.0 mg to 500 mg, and such a unit dose may be administered multiple times a day, for example, 2 to 3 times a day. Such therapy may extend for weeks, months, or longer. Multiple unit doses, for example multiple tablets, may be taken together.

[0126] Suitably, the CTPS1 inhibitor is administered orally, for example in a solid pharmaceutical composition.

[0127] The dose provided to the subject is usually a safe and effective dose, i.e., an amount that provides an acceptable balance between the desired benefit and undesired side effects. "Safe and effective amount" is intended to include an amount of a compound that is effective to achieve a desired effect in the treatment of a disease state. The desired effect is usually clinically meaningful and / or measurable, for example, in relation to (a) inhibiting a disease state, i.e., delaying or stopping its occurrence; and / or (b) alleviating a disease state, i.e., causing regression of a disease state or relief of associated symptoms. A safe and effective amount is an amount that is sufficient to achieve a desired effect when a CTPS1 inhibitor is administered together with a BCL2 inhibitor.

[0128] For the avoidance of doubt, the "safe and effective amount" described herein can be achieved by any suitable dosing regimen.Thus, for example, a reference herein to administering a safe and effective amount of a compound by a specific administration route includes achieving a safe and effective amount via a single dose or, for example, by multiple doses administered by the designated administration route.For example, orally administering a safe and effective amount includes both orally administering a single dose and orally administering any multiple doses, provided that a safe and effective amount is achieved by oral administration.

[0129] (Administration of BCL2 inhibitors) The BCL2 inhibitor can be administered by any suitable route, which can depend on the nature of the specific drug.Exemplary routes include oral, parenteral, buccal, sublingual, nasal, or rectal administration.Conveniently, the BCL2 inhibitor is administered orally.The BCL2 inhibitor can be provided in the form of a pharmaceutical composition comprising the BCL2 inhibitor and a pharma-ceutical acceptable carrier or excipient.

[0130] When delivered orally, the BCL2 inhibitor may be suitably delivered in a solid pharmaceutical composition (eg, a tablet, capsule, or lozenge) or in a liquid pharmaceutical composition (eg, a suspension, emulsion, or solution).

[0131] Liquid formulations usually consist of a suspension or solution of the BCL2 inhibitor in a suitable liquid carrier, such as an aqueous solvent, such as water, ethanol, or glycerin, or a non-aqueous solvent, such as polyethylene glycol or an oil. The formulation may also contain a suspending agent, a preservative, a flavoring agent, and / or a coloring agent.

[0132] Tablet formulations can be prepared using any suitable pharmaceutical carrier routinely used for preparing solid formulations, such as magnesium stearate, starch, lactose, sucrose, and cellulose.

[0133] Preferably the pharmaceutical composition is in unit dosage form, for example a tablet, capsule or ampoule. Preferably the unit dosage form is for oral delivery.

[0134] The pharmaceutical composition may contain, for example, 0.1% by weight to 99.99% by weight, for example, 10 to 60% by weight, of the active material, depending on the method of administration. The pharmaceutical composition may contain, for example, 0.01% by weight to 99% by weight, for example, 40% by weight to 90% by weight, of the carrier, depending on the method of administration. The pharmaceutical composition may contain, for example, 0.05 mg to 2000 mg, for example, 1.0 mg to 500 mg, preferably 5 mg to 15 mg, for example, 10 mg, of the active material, depending on the method of administration. For oral administration, 10 mg may be desirable. The pharmaceutical composition may contain, for example, 50 mg to 1000 mg, for example, 100 mg to 400 mg, of the carrier, depending on the method of administration.

[0135] The dose of the compound used will vary, as usual, depending on the severity of the cancer, the weight of the patient, and other similar factors. However, as a general guide, a suitable unit dose may be 0.05 mg to 1000 mg, more preferably 1.0 mg to 500 mg, and such a unit dose may be administered multiple times a day, for example, 2 to 3 times a day. Such therapy may extend for weeks, months, or longer. Multiple unit doses, for example, multiple tablets, may be taken together.

[0136] In one embodiment, the BCL2 inhibitor is administered daily for five weeks. The BCL2 inhibitor may be administered at a daily dose of 20 mg in week 1, 50 mg in week 2, 100 mg in week 3, 200 mg in week 4, and 400 mg in week 5.

[0137] The BCL2 inhibitor may be administered at a daily dose of up to 600 mg, preferably between 1.0 mg and 500 mg.

[0138] Suitably, the BCL2 inhibitor is administered orally, for example in a solid pharmaceutical composition.

[0139] The dose provided to the subject is usually a safe and effective dose, i.e., an amount that provides an acceptable balance between the desired benefit and undesired side effects. "Safe and effective amount" is intended to include an amount of a compound that is effective to achieve a desired effect in the treatment of a disease state. The desired effect is usually clinically meaningful and / or measurable, for example, in relation to (a) inhibiting a disease state, i.e., delaying or stopping its occurrence; and / or (b) alleviating a disease state, i.e., causing regression of a disease state or relief of associated symptoms. A safe and effective amount is an amount that is sufficient to achieve a desired effect when a CTPS1 inhibitor is administered together with a BCL2 inhibitor.

[0140] For the avoidance of doubt, the "safe and effective amount" described herein can be achieved by any suitable dosing regimen.Thus, for example, a reference herein to administering a safe and effective amount of a compound by a specific administration route includes achieving a safe and effective amount via a single dose, or, for example, by multiple doses administered by the designated administration route.For example, orally administering a safe and effective amount includes both orally administering a single dose and orally administering any multiple doses, provided that a safe and effective amount is achieved by oral administration.

[0141] (Administration regime) The CTPS1 inhibitor and the BCL2 inhibitor can be administered separately, sequentially, or simultaneously.

[0142] The CTPS1 inhibitor may be administered prior to the BCL2 inhibitor. Alternatively, the BCL2 inhibitor may be administered prior to the CTPS1 inhibitor.

[0143] In order to maintain therapeutic efficacy while controlling toxicity, the CTPS1 inhibitor and / or the BCL2 inhibitor may be administered intermittently. Intermittently in this context means that the CTPS1 inhibitor and / or the BCL2 inhibitor are not administered every day of a treatment cycle (e.g., the CTPS1 inhibitor and / or the BCL2 inhibitor are administered for 4 days out of each 7 days of a treatment cycle). It will be understood that when both the CTPS1 inhibitor and the BCL2 inhibitor are administered intermittently, they do not have to be administered according to the same schedule.

[0144] Suitably, the CTPS1 inhibitor and / or the BCL2 inhibitor may be administered continuously, i.e., at least every day in a treatment cycle (e.g., the CTPS1 inhibitor and / or the BCL2 inhibitor are administered every day of a treatment cycle).

[0145] Preferably, the CTPS1 inhibitor is administered intermittently and the BCL2 inhibitor is administered intermittently. Preferably, the CTPS1 inhibitor is administered continuously and the BCL2 inhibitor is administered continuously. Preferably, the CTPS1 inhibitor is administered intermittently and the BCL2 inhibitor is administered continuously. Preferably, the CTPS1 inhibitor is administered continuously and the BCL2 inhibitor is administered intermittently.

[0146] The CTPS1 inhibitor and the BCL2 inhibitor can be delivered in a co-formulation (if the co-formulation is compatible and the dosing regimen of the two drugs allows) or in separate formulations. Most preferably, the CTPS1 inhibitor and the BCL2 inhibitor are delivered in a co-formulation or in separate formulations that are administered simultaneously. Alternatively, when delivered in separate formulations, the CTPS1 inhibitor and the BCL2 inhibitor can be delivered at different times.

[0147] When delivered separately, the CTPS1 inhibitor (or a pharmaceutical composition comprising such, e.g., a tablet or capsule) and the BCL2 inhibitor (or a pharmaceutical composition comprising such, e.g., a tablet or capsule) may be provided in separate containers.

[0148] When formulated separately, the CTPS1 inhibitor and the BCL2 inhibitor may a) a first container containing a CTPS1 inhibitor; and b) a second container containing a BCL2 inhibitor. It may be provided in the form of a kit of parts including:

[0149] More preferably, the CTPS1 inhibitor and the BCL2 inhibitor may be provided in the form of a kit of parts comprising a first container comprising the CTPS1 inhibitor (or a pharmaceutical composition comprising such, e.g., a tablet or capsule) and a second container comprising the BCL2 inhibitor (or a pharmaceutical composition comprising such, e.g., a tablet or capsule).

[0150] (Combination with additional drugs) Treatment with CTPS1 and BCL2 inhibitors includes antimitotic agents such as vinblastine, paclitaxel, and docetaxel; alkylating agents such as cisplatin, carboplatin, dacarbazine, and cyclophosphamide; antimetabolites such as 5-fluorouracil, cytosine arabinoside, and hydroxyurea; intercalating agents such as adriamycin and bleomycin; topoisomerase inhibitors such as etoposide, topotecan, and irinotecan; thymidylate synthase inhibitors such as raltitrexed; PI3 kinase inhibitors such as idelalisib; It may be combined with one or more further pharma- ceutically acceptable active ingredients which may be selected from: mTOR inhibitors, such as everolimus and temsirolimus; proteasome inhibitors, such as bortezomib; histone deacetylase inhibitors, such as panobinostat or vorinostat; and hedgehog pathway blockers, such as vismodegib.

[0151] The CTPS1 inhibitor, the BCL2 inhibitor, and the additional pharma- ceutically acceptable active ingredient can each be administered in any combination of separate, sequential, or simultaneous administration. When administered simultaneously, the CTPS1 inhibitor and the BCL2 inhibitor can be, for example, (a) formulated together but separately from the additional pharma- ceutically acceptable active ingredient, (b) formulated separately from each other and from the additional pharma- ceutically acceptable active ingredient, or (c) formulated together with the additional pharma- ceutically acceptable active ingredient.

[0152] The CTPS1 inhibitor, the BCL2 inhibitor, and the additional pharma- ceutically acceptable active ingredient may be administered in any combination of individual, sequential, or simultaneous administration. The CTPS1 inhibitor, the BCL2 inhibitor, and the additional pharma-ceutically acceptable active ingredient may be, for example, (a) formulated together but separately from the additional pharma-ceutically acceptable active ingredient, (b) formulated separately from each other and from the additional pharma-ceutically acceptable active ingredient, (c) formulated together with the additional pharma-ceutically acceptable active ingredient; (d) formulated separately from each other, but one of the CTPS1 inhibitor or the BCL2 inhibitor may be formulated together with the additional pharma-ceutically acceptable active ingredient.

[0153] The further pharma- ceutically acceptable active ingredient may be selected from, for example, tyrosine kinase inhibitors such as axitinib, dasatinib, erlotinib, imatinib, nilotinib, pazopanib, and sunitinib, or may be selected from azacitidine, decitabine, or cytarabine.

[0154] Additional pharma- ceutically acceptable active ingredients also include anti-cancer antibodies, such as anti-CD20 antibodies (e.g., obinutuzumab, ofatumumab, tositumomab, or rituximab) or other antibodies, such as those selected from the group consisting of olaratumumab, daratumumab, necitumumab, dinutuximab, traztuzumab emtansine, pertuzumab, brentuximab, panitumumab, catumaxomab, bevacizumab, cetuximab, traztuzumab, and gentuzumab ozogamicin.

[0155] The CTPS1 inhibitor and the BCL2 inhibitor can also be administered in combination with radiation therapy, surgery, hyperthermia, or cryotherapy.

[0156] (cancer) Response to venetoclax has been associated with BCL2 expression (higher expression correlates with better sensitivity to venetoclax) and the ratio of BCL2 expression to BCL2L1 and MCL1 expression (higher BCL2:BCL2L1 and BCL2:MCL1 ratios correlate with better sensitivity to venetoclax) in hematological and solid tumors (Punnoose, 2016; Tutusaus, 2018). Mitochondrial priming has also been associated with response to venetoclax in chronic lymphocytic leukemia, whereby cells primed for apoptosis are more sensitive to the effects of venetoclax (Anderson, 2016).

[0157] Cross-referencing BCL2 expression with markers of replication stress allows prioritization of tumor types most likely to be sensitive to combined inhibition of BCL2 and CTPS1. Among various cancer types, hematological tumors show both the highest levels of BCL2 expression and replication stress, and combined inhibition of CTPS1 and BCL2 is shown herein to be effective against B cell lymphomas and myelomas. Solid tumors that show both high levels of BCL2 expression and replication stress are also expected to be candidates for this combination. Combining measurements of the BCL2 expression ratio [BCL2 / (BCL2L1+MCL1)] and a marker of replication stress [pCHEK1] allows for ranking of cancers by predicting their response to combined inhibition of CTPS1 and BCL2. Based on this, cancers that may be particularly amenable to combined inhibition of CTPS1 and BCL2 may be as follows: leukemia, lymphoma, lung cancer, bone cancer, melanoma, prostate cancer, brain tumor, colorectal cancer, esophageal and gastric cancer, breast cancer, endometrial cancer, kidney cancer, sarcoma, liver cancer, pancreatic cancer, bladder cancer, thyroid cancer, ovarian cancer, head and neck cancer, mesothelioma, and biliary tract cancer (data used in this analysis is available at .nci.nih.gov / rsconnect / cellminercdb / accessed February 2022). More preferably, leukemia, lymphoma, lung cancer, bone cancer, melanoma, prostate cancer, brain tumor, colorectal cancer, esophageal and gastric cancer, breast cancer, endometrial cancer kidney cancer, sarcoma, liver cancer, and pancreatic cancer; more preferably, leukemia, lymphoma, lung cancer, bone cancer, melanoma, prostate cancer, brain tumor, and colorectal cancer.

[0158] In one embodiment, the cancer is a cancer that may be susceptible to replication stress and shows high replication stress. "High" level means that the cancer shows a higher level of replication stress than the average cancer.Preferably, the cancer expresses BCL2.

[0159] In one embodiment, the cancer is a cancer that exhibits high expression of BCL2. By "high expression" is meant that the cancer exhibits a higher expression level than the average cancer.

[0160] In one embodiment, the cancer is one that exhibits a high BCL2:BCL2L1 ratio and / or a high BCL2:MCL1 ratio. By "high" ratio, it is meant that the cancer exhibits a higher ratio than the average cancer.

[0161] Preferably, the cancer is a hematological cancer, such as acute myeloid leukemia, angioimmunoblastic T-cell lymphoma, B-cell acute lymphoblastic leukemia, Sweet's syndrome, T-cell non-Hodgkin's lymphoma (including natural killer / T-cell lymphoma, adult T-cell leukemia / lymphoma, enteropathic T-cell lymphoma, hepatosplenic T-cell lymphoma, and cutaneous T-cell lymphoma), T-cell acute lymphoblastic leukemia, B-cell non-Hodgkin's lymphoma (including Burkitt's lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma), hairy cell leukemia, Hodgkin's 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 disorder (e.g., chronic myelogenous leukemia, primary myelofibrosis, essential thrombocythemia, polycythemia vera), or chronic lymphocytic leukemia. Most preferably, the cancer is T-cell lymphoma, diffuse large B-cell lymphoma, plasma cell myeloma, acute myelogenous leukemia, chronic lymphocytic leukemia, or peripheral T-cell lymphoma. A further blood cancer of interest is T-cell prolymphocytic leukemia. Other hematological cancers of interest are myelodysplastic syndromes (MDS), for example, MDS with unilineage dysplasia, MDS with multilineage dysplasia, or MDS with excess blasts.

[0162] Alternatively, the cancer is a non-hematological cancer, e.g., selected from the group consisting of lung cancer, bone cancer, melanoma, prostate cancer, brain cancer, colorectal cancer, esophagogastric cancer, breast cancer, endometrial cancer, kidney cancer, sarcoma, liver cancer, pancreatic cancer, bladder cancer, thyroid cancer, ovarian cancer, head and neck cancer, mesothelioma, and biliary tract cancer.

[0163] The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition, or kit of the present invention may be for administration to a subject identified as having a cancer that is expected to be susceptible to treatment with a CTPS1 inhibitor and a BCL2 inhibitor. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition, or kit of the present invention may be for administration to a subject whose cancer cell sample has been shown to be susceptible to treatment with a CTPS1 inhibitor and a BCL2 inhibitor. A "susceptible" cancer or cancer cell sample in this context is associated with generally showing a benefit from treatment according to the present invention, e.g., an additive or preferably synergistic effect - higher in vivo efficacy, lower dose required for in vivo effect, and / or improved safety profile / reduced side effects, compared to treatment with a CTPS1 inhibitor or a BCL2 inhibitor alone.

[0164] The present invention is further illustrated by the following non-limiting examples. EXAMPLES

[0165] (Example) Example 1: Human CTPS1 enzyme inhibition (Enzyme inhibitory activity of compounds CTPS1-IA and CTPS1-IB) The enzyme inhibitory activity of compounds CTPS1-IA and CTPS1-IB against CTPS1 was determined using the ADP-Glo™ Max assay (Promega, UK).

[0166] CTPS1-IA is 4-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)tetrahydro-2H-pyran-4-carboxamide.

[0167] CTPS-IB is N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(2-(ethylsulfonamido)pyrimidin-4-yl)tetrahydro-2H-pyran-4-carboxamide.

[0168] Assays for human CTPS1 were performed in 50 mM Tris, 10 mM MgCl, pH 8.0 as appropriate. 2 , and was performed in 1x assay buffer containing 0.01% Tween-20. Finally, L-cysteine ​​was added to 1x assay buffer to a final concentration of 2 mM immediately before use. All reagents were from Sigma-Aldrich unless otherwise specified. 8 -Tag CTPS1 [ka] was obtained from Proteros biostructures GmbH.

[0169] Assay Procedure 3x human CTPS1 protein was prepared in 1x assay buffer to the final working protein concentration required for the reaction. A volume of 2uL per well of 3x human CTPS1 protein was mixed with 2uL per well of 3x test compound (compounds prepared in 1x assay buffer to the final 3x compound appropriate to the concentration response curve designed for the compound under test) for 10 minutes at 25°C. The enzymatic reaction was then initiated by the addition of 2uL per well volume of premixed substrate mix (UltraPure ATP (0.31mM), GTP (0.034mM), UTP (0.48mM), and L-glutamine (0.186mM) from the ADP-Glo™ Max kit), and the mixture was incubated at 25°C under sealed plate conditions with constant stirring at 500 revolutions per minute (rpm) for an appropriate amount of time within the determined linear phase of the reaction. ADP-Glo™ Max reagent was added (6 μL per well) for 60 min, followed by ADP-Glo™ Max developing reagent (12 uL per well) for 60 min, after which the signal was detected in a microplate reader (EnVision® Multilabel Reader, Perkin Elmer). After each reagent addition over the assay period, the assay plate was pulse centrifuged at 500 rpm for 30 seconds.

[0170] In all cases, the enzyme converts ATP to ADP, and the ADP-Glo™ Max Reagent then depletes any remaining endogenous ATP in the reaction. The ADP-Glo™ Max Detection Reagent converts the enzymatically produced ADP to ATP and uses the ATP as a substrate with luciferin for the enzyme luciferase to generate light resulting in detectable luminescence. The measured luminescence signal is directly proportional to the amount of ADP produced by the enzymatic reaction, and a decrease in this signal upon compound treatment indicates enzyme inhibition. The percent inhibition caused by each compound concentration was calculated using the equation shown below:

number

[0171] The inhibition rate was then plotted against compound concentration, and the 50% inhibitory concentration (IC 50 ) was determined. Data for the test compounds are shown below. Table 1: Human CTPS1 enzyme inhibition data [Table 1]

[0172] Both compounds were found to exhibit inhibition of the CTPS1 enzyme in this assay and therefore may be considered to have utility in inhibiting CTPS1.

[0173] Example 2: RapidFire / MS-based CTPS1 enzyme selectivity assay (Selectivity evaluation of human CTPS1 vs. CTPS2 by RapidFire / MS analysis) Enzyme inhibitory activity against each target isoform of interest was determined for compounds using an optimized RapidFire high-throughput mass spectrometry (RF / MS) assay format. RF / MS assays for both human CTPS1 and CTPS2 were performed in 50 mM HEPES (Merck), 20 mM MgCl, pH 8.0 as appropriate.2 The assay was performed in assay buffer containing 5 mM KCl, 1 mM DTT, and 0.01% Tween-20. [ka] was obtained from Proteros biostructures GmbH. Active human full-length C-terminally FLAG-His-Avi tagged CTPS2 [ka] was obtained from Harker Bio.

[0174] 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 volume of 2uL per well of 2x CTPS (1 or 2) protein was mixed with 40nL of compound using acoustic (ECHO) delivery and incubated at 25°C for 10 minutes. Each isoform enzymatic reaction was then initiated by the addition of 2uL per well of 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 mix was incubated at 25°C for the appropriate amount of time per isoform within the determined linear phase of the reaction. 60 uL volume of stop solution (H 2 0.5uM in O 13 C 9 - 15 N 3 -CTP in 1% formic acid) was added, the plate was immediately heat sealed and centrifuged at 4,000 rpm for 10 min. After centrifugation, the plate was loaded onto an Agilent RapidFire microfluidic solid-phase extraction system coupled to an API4000 triple quadrupole mass spectrometer (RF / MS) for analysis.

[0175] In all cases, the enzyme converts UTP to CTP. A highly specific and sensitive multiple reaction monitoring (MRM) MS method detects the enzyme reaction products, CTP, and stable isotope-labeled product standards. 13 C 9 - 15 N 3 The data analysis readouts are the product CTP and the internal standard 13 C 9 - 15 N 3 -CTP. For data reporting, the following equation was used:

number

[0176] For each screening plate, the average of the negative control (DMSO) and positive control values ​​were used to calculate the respective assay window (S / B) and Z' values. The median of the respective control values ​​was used to calculate the percent inhibition according to the following equation:

number

[0177] The inhibition rate was then plotted against compound concentration, and the 50% inhibitory concentration (IC 50 ) was decided.

[0178] The fold selectivity between CTPS1 and CTPS2 was then calculated according to the following equation:

number

[0179] CTPS1-IA and CTPS1-IB were tested for selectivity, and the results are shown below. Table 2: Selectivity data [Table 2]

[0180] These compounds may be considered to have utility in the treatment of diseases in which a selective CTPS1 compound would be beneficial.

[0181] Example 3: Human BCL2 Inhibition Inhibition of BCL2 protein by small molecule inhibitors can be measured by the ability of the small molecule inhibitor to disrupt the interaction between BCL2 and its downstream protein target BAD. In this assay, a known concentration of recombinant BCL2 protein is incubated with a known concentration of a fluorescently labeled peptide derived from the BH3 protein, a known binding partner of BCL2. The fluorescently labeled BH3 peptide binds tightly to BCL2 but can be displaced by a small molecule inhibitor of BCL2. The binding efficiency of the small molecule inhibitor can then be determined by measuring the fluorescence across various concentrations of the small molecule inhibitor, with the amount of free fluorescently labeled BH3 peptide being able to be accurately quantified after excitation at a suitable wavelength and measurement of the resulting fluorescence. This method is disclosed in Zhang, 2002, which is incorporated herein by reference in its entirety for a method of measuring BCL2 inhibition.

[0182] Example 4: BCL2 selectivity To measure inhibition of MCL1 and BCL2L1, the method outlined in Example 3 can be adapted to replace recombinant human BCL2 protein with either recombinant human MCL1 or recombinant human BCL2L1 protein. The relative inhibition of BCL2 compared to BCL2L1 and MCL1 provides information about the selectivity of small molecule inhibitors of BCL2. This method is disclosed in Zhang, 2002, which is incorporated by reference in its entirety for methods of measuring the selectivity of BCL2 inhibition.

[0183] Example 5: Involvement of CTPS1 in cancer cell proliferation The pathways involved in providing the key components of nucleic acid replication are the purine and pyrimidine synthesis pathways, and pyrimidine biosynthesis has been observed to be upregulated in tumors and tumor cells. CTPS activity is upregulated in a variety of tumor types, both hematologic and non-hematologic, although heterogeneity is observed between patients. High enzyme levels have also been associated with resistance to chemotherapeutic agents.

[0184] In an analysis of published data, we found that CTPS1 was essential for the proliferation of human cancer cells derived from a wide range of hematological and solid tumor types, whereas CTPS2 was always redundant. This analysis used data from the Achilles project, in which every gene in the human genome was independently deleted in each of 324 human cancer cell lines using CRIPR technology, and the impact of each gene deletion was evaluated using an in vitro proliferation assay (Behan, 2019). We then extended this dataset to include data from 1,032 human cancer cell lines (Cancer Dependency Map: p.org / ). The impact of deletion of different genes in the pyrimidine synthesis pathway was evaluated (see Figure 2). Deletion of CTPS2 had no effect on cancer cell proliferation. Deletion of genes in the salvage pathway (UCK1, UCK2) had minimal impact on cell proliferation. Deletion of CMPK1 had a pronounced effect on cell proliferation, consistent with CMPK1 being an essential gene. Deletion of CTPS1, UMPS, DHODH, or CAD inhibited cancer cell proliferation, an effect consistent with cancer cells' dependence on the products of these genes; inhibition of CTPS1 resulted in the greatest impairment of cancer cell proliferation. These findings indicate that the majority of cancer cells depend on CTPS1 for cell proliferation, whereas CTPS2 is dispensable.

[0185] In recent studies, CTPS1 isoforms have shown higher enzymatic activity than CTPS2. Combined with the analysis of the CRISPR studies outlined above, these findings highlight CTPS1 as a more potent CTP synthase enzyme and identify a nonredundant role for CTPS1 in human cancer cell proliferation, thus identifying CTPS1 as a potential therapeutic target in a wide range of human malignancies.

[0186] Example 6: Effect of combined treatment with CTPS1 inhibitors and BCL2 inhibitors To investigate the interaction between CTPS1-IA and the anti-proliferative effects of (a) venetoclax or (b) BCL201, in vitro proliferation assays were performed using human cancer cell lines.

[0187] Cell lines (available from commercial repositories such as the German Collection of Microbial Cell Cultures (Deutsche Sammlung von Mikroorganismen und Zellkulturen) were cultured at 0.2 × 10 6 Cells were plated in triplicate at a density of 1000 x 1000 cells / ml. CTPS1-IA and venetoclax were administered at the IC 50 The compounds were added at pre-specified concentrations specific to each cell line, covering concentrations above and below the threshold, and viability was assessed using a tetrazolium salt-based colorimetric assay after 72 hours of incubation. CTPS1-IA and venetoclax were tested in a 4x4 matrix (16 conditions in total). Each compound was included at concentrations that resulted in 80-90%, 50-60%, and 30-40% 72-hour viability as single agents, as well as in a drug-free condition.

[0188] A similar assay was performed using BCL201 instead of venetoclax.

[0189] The bar graph in Figure 3 shows the Bliss scores (Bliss, 1939; Zheng, 2021) of the interaction between CTPS1-IA and venetoclax for various cell lines derived from B-cell malignancies. Values ​​of -10 to <10 indicate an additive effect, and values ​​of ≥10 indicate a synergistic effect. Synergistic effects of CTPS1-IA and venetoclax were observed in a subset of mantle cell lymphoma and myeloma cell lines. Additive effects were observed in other cell lines tested.

[0190] The bar graphs in Figures 4 and 5 show the Bliss scores of the interactions of CTPS1-IA and venetoclax and CTPS1-IA and BCL201, respectively, for cell lines derived from solid tumors, either colon or lung cancer. Values ​​of -10 to <10 indicate an additive effect, and values ​​of >= 10 indicate a synergistic effect. No synergistic effect of venetoclax or BCL201 was observed for any of the cell lines tested.

[0191] The bar graph in Figure 6 shows the Bliss score of the interaction between CTPS1-IA and venetoclax for cell lines derived from T-cell lymphoma. Values ​​of -10 to <10 indicate an additive effect, and values ​​of ≥10 indicate a synergistic effect. No synergistic effect of CTPS1-IA and venetoclax was observed for any of the T-cell lymphoma cell lines tested.

[0192] Example 7: In vivo effects of combined treatment with CTPS1 and BCL2 inhibitors To investigate the interaction between the antiproliferative effects of CTPS1-IA and venetoclax, in vivo tumor growth studies were performed using human cancer cell lines.

[0193] Human mantle cell lymphoma cells (Z138) were cultured in immunodeficient mice (NOD.Cg-Prkdc scid Il2rg tm1Wjl / SzJ (NSG) strain). 3Treatment was started when tumor size reached 100 mg / kg / day; n=5 mice per group. CTPS1-IA was administered subcutaneously at 30 mg / kg / day on days 1-4 of a 7-day cycle; venetoclax was administered orally at 75 mg / kg / day on days 2-5 of a 7-day cycle for 3 cycles. Tumor size was assessed with calipers.

[0194] The graph in Figure 7 shows tumor growth in treated and control mice, demonstrating the in vivo synergy of CTPS1-IA and venetoclax.

[0195] Example 8: RNA transcript and protein levels following exposure to CTPS1 inhibitors (RNA sequencing) RNA was obtained from cancer cell lines treated with IC50 of CTPS1-IA or a control for 24 hours. Libraries were prepared from 10 ng of total RNA. The poly(A) tails of mRNA were tagged with universal adapters, sample-specific barcodes, and unique molecular identifiers using template-switching reverse transcriptase. Barcoded cDNA from multiple samples was then pooled, amplified, and tagged using a transposon fragmentation method that enriches the 3' ends of cDNA. Libraries of 350-800 bp length were run on an Illumina NovaSeq 6000 using the NovaSeq 6000 SP Reagent Kit 100 cycles (ref #20027464). Raw fastq pairs used for analysis met the following criteria: 16 bases of the first read correspond to 6 bases of the sample-specific barcode and 10 bases of the unique molecular identifier. The second read (58 bases) corresponds to the captured poly(A) RNA sequence. These fastq pairs were demultiplexed to generate one single-end fastq for each of the 96 samples. The fastq files were then aligned with bwa against the reference mRNA sequence and the mitochondrial genome sequence (UCSC). DGE profiles were generated by parsing the alignment files (.bam) and counting the number of unique molecular identifiers associated with each RefSeq gene for each sample. Reads that aligned against multiple genes, contained multiple mismatches with the reference sequence, or contained polyA patterns were discarded. Expression values ​​corresponding to the absolute abundance of the mRNA in all samples were used for further analysis. Expression was normalized using DESeq2. Normalized counts were transformed with the vst (variance stabilizing transformation) function from the DESeq library. Batch effects were corrected with the removeBatchEffect function from the limma library.

[0196] (Western Blot) Cells were incubated with lysis buffer for 40 min on ice and then centrifuged at 11000 rpm for 30 min. Total protein extracts were collected from the supernatant and protein concentrations were determined using a colorimetric assay. 30 μg of protein was separated by SDS-PAGE using precast gels and transferred to membranes using the Trans-Blot Turbo system. Membranes were blocked for 1 h in 5% milk powder, TBS-Tween 20 solution and incubated with primary antibodies overnight at 4°C. Membranes were incubated with either peroxidase-conjugated goat anti-mouse or goat anti-rabbit secondary antibodies for at least 1 h. Chemiluminescence was determined using Clarity Western ECL substrate on a Fusion FX imaging system.

[0197] (result) Exposure of human mantle cell lymphoma cell lines to CTPS1-IA resulted in an increase in BCL2 transcripts and a decrease in MCL1 transcripts (Figure 8). These changes were confirmed at the protein level in the analysis of one of the cell lines (Figure 9). Both higher levels of BCL2 and a higher BCL2 to MCL1 ratio are associated with an increased likelihood of response to BCL2 inhibition by drugs such as venetoclax. These observations suggest that in some human cancer cells, exposure to CTPS1-IA sensitizes the cells to the antitumor effects of venetoclax.

[0198] Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", are understood to imply the inclusion of a stated integer, step, group of integers, or group of steps, but not the exclusion of any other integer, step, group of integers, or group of integers.

[0199] The application of which this description and claims form 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 following claims:

[0200] All publications cited in this specification, including but not limited to patents and patent applications, are herein incorporated by reference to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference in its entirety.

[0201] (Provisions of the invention:) A series of clauses illustrating embodiments of the present invention are as follows: Clause 1. A CTPS1 inhibitor for use in the treatment of cancer with a BCL2 inhibitor. Clause 2. A BCL2 inhibitor for use in the treatment of cancer with a CTPS1 inhibitor. Clause 3. A CTPS1 inhibitor and a BCL2 inhibitor for use in the treatment of cancer. Clause 4. Use of a CTPS1 inhibitor in the manufacture of a medicament for the treatment of cancer with a BCL2 inhibitor. Clause 5. Use of a BCL2 inhibitor in the manufacture of a medicament for the treatment of cancer with a CTPS1 inhibitor. Clause 6. Use of a CTPS1 inhibitor and a BCL2 inhibitor in the manufacture of a medicament for the treatment of cancer. Clause 7. A method of treating cancer in a subject, comprising administering to the subject a CTPS1 inhibitor and a BCL2 inhibitor. Clause 8. A pharmaceutical composition comprising a CTPS1 inhibitor and a BCL2 inhibitor. Article 9. a) a first container containing a CTPS1 inhibitor; and b) a second container containing a BCL2 inhibitor. Kit of parts including: Clause 10. The CTPS1 inhibitor has an IC of 10 uM or less with respect to the human CTPS1 enzyme. 50 The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition, or kit according to any one of clauses 1 to 9, comprising: Clause 11. The CTPS1 inhibitor has an IC of 1 uM or less with respect to the human CTPS1 enzyme. 50 11. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition or kit of clause 10, comprising: Clause 12. The CTPS1 inhibitor has an IC of 100 nM or less with respect to the human CTPS1 enzyme. 50 12. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition or kit of clause 11, comprising: Clause 13. IC of said CTPS1 inhibitor 50 The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition or kit according to any one of clauses 10 to 12, wherein the is established using the assay procedure set out in Example 1. Clause 14. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition or kit according to any one of clauses 1 to 13, wherein said CTPS1 inhibitor has at least 2-fold selectivity for human CTPS1 over human CTPS2. Clause 15. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition or kit according to clause 14, wherein said CTPS1 inhibitor has at least 30-fold selectivity for human CTPS1 over human CTPS2. Clause 16. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition or kit according to clause 15, wherein said CTPS1 inhibitor has selectivity for human CTPS1 at least 60-fold, such as at least 1000-fold, over human CTPS2. Clause 17. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition or kit according to any one of clauses 14 to 16, wherein the selectivity of said CTPS1 inhibitor is established using the assay procedure set out in Example 2. Clause 18. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition, or kit according to any one of clauses 1 to 17, wherein the CTPS1 inhibitor is a compound of formula (I) or a pharma- ceutical acceptable salt and / or a pharma-ceutical acceptable solvate thereof. [ka] (In the formula, R 1 is C 1-5 Alkyl, C 0-2 Alkylene C 3-5 Cycloalkyl (wherein the cycloalkyl is CH 3 Optionally replaced by C 1-3 Alkylene OC 1-2 Alkyl or CF 3 and; R 3 , H, CH 3 , Haro, O.C. 1-2 Alkyl or CF 3 and; R 4 and R 5 are each independently H, C 1-6 Alkyl, C 0-2 Alkylene C 3-6 Cycloalkyl, C 0-2 Alkylene C 3-6 Heterocycloalkyl, C 1-3 Alkylene OC 1-3 Alkyl, C 1-6 AlkylOH or C 1-6 is haloalkyl, or R 4 and R 5 together with the carbon atom to which they are attached, C 3-6 Cycloalkyl or C 3-6 forming a heterocycloalkyl ring; R 6 is H or C 1-3 is alkyl; 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 H, halo, C 1-3 Alkyl, OC 1-2 Alkyl, C 1-2 Haloalkyl, OC 1-2 haloalkyl, or CN; R 11 are H, F, Cl, CH 3 , Ethyl, OCH 3 , C.F. 3 , OCF 3 , or CN; R 12 is bonded to Ar2 at the meta or ortho position relative to Ar1, and R 12 H, halo, C 1-4 Alkyl, C 2-4 Alkynyl, C(=O)C 1-2 Alkyl, C 0-2 Alkylene C 3-5 Cycloalkyl, OC 1-4 Alkyl, C 1-3 Alkylene OC 1-3 Alkyl, C 1-4 Haloalkyl, OC 1-4 Haloalkyl, CN, OC 0-2 Alkylene C 3-5 Cycloalkyl, OCH 2 CH 2 N(CH 3 ) 2 , O.H., C. 1-4 AlkylOH, NR 23 R 24 , S.O. 2 CH 3 , C(O)N(CH 3 ) 2 , NHC(O)C 1-3 C containing one nitrogen at the point of attachment to alkyl or Ar2 3-6 heterocycloalkyl or R 12 forms, together with the nitrogen atom to which it is attached, an N-oxide (N + -O - ) to form; R 23 is H or C 1-2 is alkyl; R 24 is H or C 1-2(It is alkyl). Clause 19. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition or kit according to clause 18, wherein said CTPS1 inhibitor is selected from the compounds disclosed in List A or a pharma- ceutically acceptable salt and / or a pharma- ceutically acceptable solvate thereof. Clause 20. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition, or kit according to any one of clauses 1 to 17, wherein said CTPS1 inhibitor is a compound of formula (II): or a pharma- ceutically acceptable salt and / or a pharma- ceutically acceptable solvate thereof. [ka] (In the formula, R 1 is C 1-5 Alkyl, C 0-2 Alkylene C 3-5 Cycloalkyl (wherein the cycloalkyl is CH 3 Optionally replaced by C 1-3 Alkylene OC 1-2 Alkyl or CF 3 and; R 3 H, halo, CH 3 , O.C. 1-2 Alkyl or CF 3 and; Or R 3 is R 5 together form a 5- or 6-membered cycloalkyl or a 5- or 6-membered oxygen-containing heterocycloalkyl; R 4 and R 5 are each independently H, halo, or C 1-6 Alkyl, C 0-2 Alkylene C 3-6 Cycloalkyl, C 0-2 Alkylene C 3-6 Heterocycloalkyl, OC 1-6 Alkyl, OC 0-2 Alkylene C 3-6 Cycloalkyl, C 1-3 Alkylene OC 1-3 Alkyl, C 1-6 AlkylOH, C1-6 Haloalkyl, OC 1-6 Haloalkyl or NR 21 R 22 and Or R 4 is H and R 5 is R 3 together with the group forming a 5- or 6-membered cycloalkyl or a 5- or 6-membered oxygen-containing heterocycloalkyl, Or R 4 and R 5 together with the carbon atom to which they are attached, C 3-6 Cycloalkyl or C 3-6 forming a heterocycloalkyl, Or R 4 is H and R 5 and R 6 is a C which forms a 5- or 6-membered ring 2-3 is an alkylene chain; Or R 4 is O and R 5 does not exist; R 6 is H or C 1-3 is alkyl, or R 6 is in the ortho position relative to the amide, R 11 Together with C, it forms a five-membered ring 2 is an alkylene chain, or R 5 and R 6 is a C that forms a 5- or 6-membered ring. 2-3 is an alkylene chain, and R 4 is H; 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; R 10 H, halo, C 1-3 Alkyl, OC 1-2 Alkyl, C 1-2 Haloalkyl, OC 1-2 haloalkyl, or CN; R 11 are H, F, Cl, CH3 , Ethyl, OCH 3 , C.F. 3 , OCF 3 , or CN, or R 11 is R 6 When in the ortho position to the amide, C forms a five-membered ring. 2 is an alkylene chain; R 12 is bonded to Ar2 at the ortho or meta position relative to Ar1, and R 12 H, halo, C 1-4 Alkyl, C 2-4 Alkynyl, C 0-2 Alkylene C 3-5 Cycloalkyl, OC 1-4 Alkyl, OC 0-2 Alkylene C 3-5 Cycloalkyl, OCH 2 CH 2 N(CH 3 ) 2 , O.H., C. 1-4 AlkylOH, CN, C 1-3 Alkylene OC 1-3 Alkyl, C 1-4 Haloalkyl, OC 1-4 Haloalkyl, C(=O)C 1-2 Alkyl, NR 23 R 24 , S.O. 2 C 1-4 Alkyl, SOC 1-4 Alkyl, SC 1-4 Alkyl, SH, C(O)N(CH 3 ) 2 , NHC(O)C 1-3 Alkyl, C containing one nitrogen at the attachment point to Ar2 3-6 heterocycloalkyl, or R 12 forms, together with the nitrogen atom to which it is attached, an N-oxide (N + -O - ) to form; R 13 H, halo, CH 3 , or OCH 3 and; R 21 , H, C1-5 Alkyl, C(O)C 1-5 Alkyl, C(O)OC 1-5 is alkyl; R 22 is H or CH 3 and; R 23 is H or C 1-2 is alkyl; and R 24 is H or C 1-2 (It is alkyl). Clause 21. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition or kit according to clause 20, wherein said CTPS1 inhibitor is selected from the compounds disclosed in List B or a pharma- ceutically acceptable salt and / or a pharma- ceutically acceptable solvate thereof. Clause 22. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition, or kit according to any one of clauses 1 to 17, wherein said CTPS1 inhibitor is a compound of formula (III): or a pharma- ceutically acceptable salt and / or a pharma- ceutically acceptable solvate thereof. [ka] (In the formula, A is an amide linker having the following structure: -C(=O)NH- or -NHC(=O)-; X is N or CH; Y is N or CR 2 and; Z is N or CR 3 and; With the proviso that when at least one of X or Z is N, Y cannot be N; R 1 is C 1-5 Alkyl, C 0-2 Alkylene C 3-5 Cycloalkyl (wherein the cycloalkyl is CH 3 Optionally substituted by, or CF 3 and; R 2 H, halo, C 1-2 Alkyl, OC 1-2 Alkyl, C1-2 Haloalkyl or OC 1-2 is haloalkyl; R 3 H, halo, CH 3 , O.C.H. 3 , C.F. 3 , or OCF 3 and; Here, R 2 and R 3 at least one of is H; R 4 and R 5 are each independently H, C 1-6 Alkyl, C 1-6 AlkylOH, C 1-6 Haloalkyl, C 0-2 Alkylene C 3-6 Cycloalkyl, C 0-2 Alkylene C 3-6 Heterocycloalkyl, C 1-3 Alkylene OC 1-3 alkyl, or R 4 and R 5 together with the carbon atom to which they are attached, C 3-6 Cycloalkyl or C 3-6 forming a heterocycloalkyl; and When A is -NHC(=O)-: R 4 and R 5 Ha, Hello, OC 1-6 Haloalkyl, OC 0-2 Alkylene C 3-6 Cycloalkyl, OC 0-2 Alkylene C 3-6 Heterocycloalkyl, OC 1-6 Alkyl and NR 21 R 22 may further be selected from; 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; R 10 H, halo, C 1-3 Alkyl, C 1-2 Haloalkyl, OC 1-2Alkyl, OC 1-2 haloalkyl, or CN; R 11 are H, F, Cl, and C. 1-2 Alkyl, CF 3 , O.C.H. 3 , or CN; R 12 is bonded to Ar2 at the ortho or meta position relative to Ar1, and R 12 H, halo, C 1-4 Alkyl, C 2-4 Alkenyl, C 0-2 Alkylene C 3-5 Cycloalkyl, OC 1-4 Alkyl, OC 0-2 Alkylene C 3-5 Cycloalkyl, C 1-4 Haloalkyl, OC 1-4 Haloalkyl, Hydroxy, C 1-4 Alkyl OH, SO 2 C 1-2 Alkyl, C(O)N(C 1-2 Alkyl) 2 , NHC(O)C 1-3 Alkyl or NR 23 R 24 and When A is -NHC(=O)-: R 12 CN, OCH 2 CH 2 N(CH 3 ) 2 and C containing one nitrogen atom at the attachment point to Ar2 3-6 heterocycloalkyl, or R 12 forms, together with the nitrogen atom to which it is attached, an N-oxide (N + -O - ) to form; R 13 is H or halo; R 21 , H, C 1-5 Alkyl, C(O)C 1-5 Alkyl, C(O)OC 1-5 is alkyl; R 22 is H or CH3 and; R 23 is H or C 1-2 is alkyl; and R 24 is H or C 1-2 (It is alkyl). Clause 23. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition or kit according to clause 22, wherein said CTPS1 inhibitor is selected from the compounds disclosed in List C or a pharma- ceutically acceptable salt and / or a pharma- ceutically acceptable solvate thereof. Clause 24. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition or kit according to clause 22, wherein said CTPS1 inhibitor is a compound of formula (IV): or a pharma- ceutically acceptable salt and / or a pharma- ceutically acceptable solvate thereof. [ka] (In the formula: (a)R 4 , R 5 , X, Y, and R 1 But as follows: [ka] when W is N, CH, or CF; (b)R 4 , R 5 , X, W, and R 1 But as follows: [ka] when Y is CH or N; (c) W, X, Y, and R 1 But as follows: [ka] If R 4 and R 5 combine to form the following structure: [ka] Forming; (d) W, R 4 , R 5 , X, and Y are as follows: [ka] If R 1 is methyl or cyclopropyl; and (e) the compound is [ka] (selected from the group consisting of: Clause 25. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition or kit according to clause 24, wherein said CTPS1 inhibitor is selected from the compounds disclosed in List D or a pharma- ceutically acceptable salt and / or a pharma- ceutically acceptable solvate thereof. Clause 26. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition or kit according to clause 22, wherein said CTPS1 inhibitor is a compound of formula (V): or a pharma- ceutically acceptable salt and / or a pharma- ceutically acceptable solvate thereof. [ka] (a) A, V, W, X, Y, Z, R 1 , R 10 , and R 12 But as follows: [ka] If R 4 and R 5 together with the carbon atoms to which they are attached, [ka] : form; or (b) A, V, W, X, Y, Z, R 1 , R 10 , and R 12 But as follows: [ka] If R 4 and R 5 together with the carbon atoms to which they are attached, [ka] : form; or (c) A, V, W, X, Y, Z, R 4 , R 5 , R 10 , and R 12 But as follows: [ka] If R 1 teeth, [ka] and; or (d) A, V, W, X, Y, Z, R 4 , R 5 , R 10 , and R 12 But as follows: [ka] If R 1 teeth, [ka] and; or (e) A, X, Y, Z, R 1 , R 4 , and R 5 But as follows: [ka] If V, W, R 10 , and R 12 teeth, [ka] : and; or (f) A, V, W, R 1 , R 4 , R 5 , R 10 , and R 12 But as follows: [ka] then Z, X, and Y are [ka] and; or (g) A, V, W, R 1 , R 4 , R 5 , R 10 , and R 12 But as follows: [ka] then Z, X, and Y are [ka] and; or (h) A, V, W, R 1 , R 4 , R 5 , R 10 , and R 12 But as follows [ka] then Z, X, and Y are [ka] (It is.) Clause 27. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition or kit according to clause 26, wherein said CTPS1 inhibitor is selected from the compounds disclosed in List E or a pharma- ceutically acceptable salt and / or a pharma- ceutically acceptable solvate thereof. Clause 28. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition, or kit according to any one of clauses 1 to 17, wherein said CTPS1 inhibitor is a compound of formula (VI): or a pharma- ceutically acceptable salt and / or a pharma- ceutically acceptable solvate thereof. [ka] (Wherein, ring B is [ka] (wherein X, Y, and Z are as defined below); and [ka] (where R 3b3c is defined as follows: 3b or R 3c is) Selected from the group consisting of: wherein when B is (Ba), the compound of formula (VI) is a compound of formula (VI-a): [ka] (In the formula: A a A aa Or A ba and; where: A aa has the following structure: -NH-, -CH 2 NH- or -NHCH 2 - an amine linker having A ba is an amide linker having the following structure: -C(=O)NH- or -NHC(=O)-; X is N or CH; Y is N or CR 2a and; Z is N or CR 3a and; With the proviso that when at least one of X or Z is N, Y cannot be N; R2a H, halo, C 1-2 Alkyl, OC 1-2 Alkyl, C 1-2 Haloalkyl or OC 1-2 haloalkyl; and R 3a H, halo, CH 3 , O.C.H. 3 , C.F. 3 , or OCF 3 and; Here, R 2a and R 3a at least one of is H; R 1a is R 1aa or R 1ba and; where: R 1aa is NR 32a R 33a and; R 1ba is C 1-5 Alkyl, C 0-2 Alkylene C 3-5 Cycloalkyl (wherein the cycloalkyl is CH 3 Optionally substituted by, or CF 3 and; R 4a and R 5a is R 4aa and R 5aa , or R 4ba and R 5ba and; where: R 4aa and R 5aa together with the carbon atom to which they are attached, C 3-6 Forms a cycloalkyl, which is: Each of the substituents is C 1-3 Alkyl, oxo, OH, C 1-3 AlkylOH, C 1-3 Haloalkyl, C 0-2 Alkylene C 3-6 Cycloalkyl, C 0-2 Alkylene C 3-6 Heterocycloalkyl, C 1-3 Alkylene OC 1-3Alkyl, Halo, OC 1-3 Haloalkyl, OC 0-2 Alkylene C 3-6 Cycloalkyl, OC 0-2 Alkylene C 3-6 Heterocycloalkyl, OC 1-3 Alkyl and NR 21a R 22a or is substituted by one or two substituents independently selected from the group consisting of: C 3-6 One of the carbons of the cycloalkyl is a spirocyclic ring system. 3-6 Cycloalkyl rings and further C 3-6 Cycloalkyl ring or C 3-6 A spiro center such as formed by a heterocycloalkyl ring, and where R 4aa and R 5aa C formed by 3-6 Cycloalkyl means that each of the substituents, together with the carbon atom to which they are attached, is C 1-3 Alkyl or OC 1-3 or may be substituted by one or two substituents independently selected from the group consisting of alkyl; R 4aa and R 5aa together with the carbon atom to which they are attached, C 3-6 heterocycloalkyl, wherein the C 3-6 One of the carbons of the heterocycloalkyl is a spirocyclic ring system. 3-6 Heterocycloalkyl rings and further C 3-6 Cycloalkyl ring or C 3-6 A spiro center such as formed by a heterocycloalkyl ring, and where R 4aa and R 5aa C formed by 3-6 Heterocycloalkyl means that each of the substituents, together with the carbon atom to which they are attached, is C 1-3 Alkyl or OC 1-3 or may be substituted by one or two substituents independently selected from the group consisting of alkyl; R 4aa and R5aa C, which contains one nitrogen atom together with the carbon atom to which they are attached 3-6 heterocycloalkyl, where the nitrogen atom is -S(O) 2 R 29a or is replaced by R 4ba and R 5ba are each independently H, C 1-6 Alkyl, C 1-6 AlkylOH, C 1-6 Haloalkyl, C 0-2 Alkylene C 3-6 Cycloalkyl, C 0-2 Alkylene C 3-6 Heterocycloalkyl, C 1-3 Alkylene OC 1-3 alkyl or R 4ba and R 5ba together with the carbon atom to which they are attached, C 3-6 Cycloalkyl or C 3-6 forming a heterocycloalkyl; and A a -NHC(=O)- or -NHCH 2 -When: R 4ba and R 5ba Ha, Hello, OC 1-6 Haloalkyl, OC 0-2 Alkylene C 3-6 Cycloalkyl, OC 0-2 Alkylene C 3-6 Heterocycloalkyl, OC 1-6 Alkyl and NR 21a R 22a may further be selected from; Ar1a is a 6-membered aryl or heteroaryl; Ar2a is a 6-membered aryl or heteroaryl and is a group A a is linked to Ar1a in the para position relative to R 10a H, halo, C 1-3 Alkyl, C 1-2 Haloalkyl, OC 1-2 Alkyl, OC 1-2haloalkyl, or CN; R 11a are H, F, Cl, and C. 1-2 Alkyl, CF 3 , O.C.H. 3 , or CN; R 12a is bonded to Ar2 at the ortho or meta position relative to Ar1a, and R 12a H, halo, C 1-4 Alkyl, C 2-4 Alkenyl, C 0-2 Alkylene C 3-5 Cycloalkyl, OC 1-4 Alkyl, OC 0-2 Alkylene C 3-5 Cycloalkyl, C 1-4 Haloalkyl, OC 1-4 Haloalkyl, Hydroxy, C 1-4 Alkyl OH, SO 2 C 1-2 Alkyl, C(O)N(C 1-2 Alkyl) 2 , NHC(O)C 1-3 Alkyl or NR 23a R 24a and A a is -NHC(=O)-, -NH-, or -NHCH 2 -When: R 12a CN, OCH 2 CH 2 N(CH 3 ) 2 and C containing one nitrogen atom at the attachment point to Ar2a 3-6 heterocycloalkyl, or R 12a forms, together with the nitrogen atom to which it is attached, an N-oxide (N + -O - ) to form; R 13a is H or halo; R 21a , H, C 1-5 Alkyl, C(O)C 1-5 Alkyl, C(O)OC 1-5 Alkyl, C 1-3 Alkyl OC1-2 Alkyl, C 1-4 Haloalkyl, or C 4-6 is heterocycloalkyl; R 22a is H or CH 3 and; R 23a is H or C 1-2 is alkyl; and R 24a is H or C 1-2 is alkyl, R 29a is C 1-3 Alkyl, C 0-2 Alkylene C 3-5 Cycloalkyl (wherein the cycloalkyl is CH 3 Optionally replaced by CF 3 , N(C 1-3 Alkyl) 2 or 5- or 6-membered heteroaryl, wherein the 5- or 6-membered heteroaryl is optionally substituted with methyl; R 32a is C 1-3 alkyl, and R 33 is C 1-3 is alkyl; or R 32a and R 33a C together with the nitrogen atom to which they are attached 3-5 Forming a heterocycloalkyl; Where: R 1a is R 1aa and / or R 4a and R 5a is R 4aa and R 5aa and / or A a A aa is) and where B is (B-bc) and R 3b3c R 3b When the compound of formula (VI) is a compound of formula (VI-b): [ka] (In the formula: A b A ab Or A bb and; where: A ab -NR 6b CH 2 -OR-NR 6b - and; A bb -NR 6b C(=O)-; R 1b is R 1ab or R 1bb and; where: R 1ab is NR 32b R 33b and; R 1bb is C 1-5 Alkyl, C 0-2 Alkylene C 3-5 Cycloalkyl (wherein the cycloalkyl is CH 3 Optionally replaced by C 1-3 Alkylene OC 1-2 Alkyl or CF 3 and; R 3b H, halo, CH 3 , O.C. 1-2 Alkyl or CF 3 and; Or R 3b is R 5bb together form a 5- or 6-membered cycloalkyl or a 5- or 6-membered oxygen-containing heterocycloalkyl; R 4b and R 5b , R 4ab and R 5ab or R 4bb and R 5bb Either; where: R 4ab and R 5ab together with the carbon atom to which they are attached, C 3-6Forms a cycloalkyl, which is: Each of the substituents is C 1-3 Alkyl, oxo, OH, C 1-3 AlkylOH, C 1-3 Haloalkyl, C 0-2 Alkylene C 3-6 Cycloalkyl, C 0-2 Alkylene C 3-6 Heterocycloalkyl, C 1-3 Alkylene OC 1-3 Alkyl, Halo, OC 1-3 Haloalkyl, OC 0-2 Alkylene C 3-6 Cycloalkyl, OC 0-2 Alkylene C 3-6 Heterocycloalkyl, OC 1-3 Alkyl and NR 21b R 22b or is substituted by one or two substituents independently selected from the group consisting of: C 3-6 One of the carbons of the cycloalkyl is a spirocyclic ring system. 3-6 Cycloalkyl rings and further C 3-6 Cycloalkyl ring or C 3-6 A spiro center such as formed by a heterocycloalkyl ring, and where R 4ab and R 5ab C formed by 3-6 Cycloalkyl means that each of the substituents, together with the carbon atom to which they are attached, is C 1-3 Alkyl or OC 1-3 or may be substituted by one or two substituents independently selected from the group consisting of alkyl; R 4ab and R 5ab together with the carbon atom to which they are attached, C 3-6 Heterocycloalkyl, wherein the C 3-6 One of the carbons of the cycloalkyl is a spirocyclic ring system. 3-6 Cheterocycloalkyl rings and further C 3-6 Cycloalkyl ring or C 3-6A spiro center such as formed by a heterocycloalkyl ring, and where R 4ab and R 5ab C formed by 3-6 Heterocycloalkyl means that each of the substituents, together with the carbon atom to which they are attached, is C 1-3 Alkyl or OC 1-3 or may be substituted by one or two substituents independently selected from the group consisting of alkyl; R 4ab and R 5ab C, which contains one nitrogen atom together with the carbon atom to which they are attached 3-6 heterocycloalkyl, where the nitrogen atom is -S(O) 2 R 29b or is replaced by R 4bb and R 5bb are each independently H, halo, or C 1-6 Alkyl, C 0-2 Alkylene C 3-6 Cycloalkyl, C 0-2 Alkylene C 3-6 Heterocycloalkyl, OC 1-6 Alkyl, OC 0-2 Alkylene C 3-6 Cycloalkyl, C 1-3 Alkylene OC 1-3 Alkyl, C 1-6 AlkylOH, C 1-6 Haloalkyl, OC 1-6 Haloalkyl or NR 21b R 22b and Or R 4bb is H and R 5bb is R 3b together with the group forming a 5- or 6-membered cycloalkyl or a 5- or 6-membered oxygen-containing heterocycloalkyl, Or R 4bb and R 5bb together with the carbon atom to which they are attached, C 3-6 Cycloalkyl or C 3-6 forming a heterocycloalkyl, Or R 4bbis H and R 5bb and R 6b is a C which forms a 5- or 6-membered ring 2-3 is an alkylene chain; Or R 4bb is O and R 5bb does not exist; R 6b is H or C 1-3 is alkyl, or R 6b is the group A b When it is in the ortho position to R 11b Together with C, it forms a five-membered ring 2 is an alkylene chain, or R 5bb and R 6b is a C that forms a 5- or 6-membered ring. 2-3 is an alkylene chain, and R 4bb is H; Ar1b is a 6-membered aryl or heteroaryl; Ar2b is a 6-membered aryl or heteroaryl and is a group A b is linked to Ar1b in the para position relative to R 10b H, halo, C 1-3 Alkyl, OC 1-2 Alkyl, C 1-2 Haloalkyl, OC 1-2 haloalkyl, or CN; R 11b are H, F, Cl, CH 3 , Ethyl, OCH 3 , C.F. 3 , OCF 3 , or CN, or R 11b is the group A b When it is in the ortho position to R 6b Together with C, it forms a five-membered ring 2 is an alkylene chain; R 12b is bonded to Ar2b at the ortho or meta position relative to Ar1b, and R 12b H, halo, C 1-4 Alkyl, C 2-4 Alkynyl, C 0-2Alkylene C 3-5 Cycloalkyl, OC 1-4 Alkyl, OC 0-2 Alkylene C 3-5 Cycloalkyl, OCH 2 CH 2 N(CH 3 ) 2 , O.H., C. 1-4 AlkylOH, CN, C 1-3 Alkylene OC 1-3 Alkyl, C 1-4 Haloalkyl, OC 1-4 Haloalkyl, C(=O)C 1-2 Alkyl, NR 23b R 24b , S.O. 2 C 1-4 Alkyl, SOC 1-4 Alkyl, SC 1-4 Alkyl, SH, C(O)N(CH 3 ) 2 , NHC(O)C 1-3 Alkyl, C containing one nitrogen at the attachment point to Ar2b 3-6 heterocycloalkyl or R 12b forms, together with the nitrogen atom to which it is attached, an N-oxide (N + -O - ) to form; R 13b H, halo, CH 3 , or OCH 3 and; R 21b , H, C 1-5 Alkyl, C(O)C 1-5 Alkyl, C(O)OC 1-5 Alkyl, C 1-3 Alkyl OC 1-2 Alkyl, C 1-4 Haloalkyl or C 4-6 is heterocycloalkyl; R 22b is H or CH 3 and; R 23b is H or C 1-2 is alkyl; R 24b is H or C 1-2 is alkyl; R 29b is C 1-3 Alkyl, C 0-2 Alkylene C 3-5 Cycloalkyl (wherein the cycloalkyl is CH 3 Optionally replaced by CF 3 , N(C 1-3 Alkyl) 2 or a 5- or 6-membered heteroaryl, wherein the 5- or 6-membered heteroaryl is optionally substituted with methyl; and R 32b is C 1-3 alkyl, and R 33b is C 1-3 is alkyl; or R 32b and R 33b together with the nitrogen atom to which they are attached, C 3-5 Forming a heterocycloalkyl; where: R 1b is R 1ab and / or R 4b and R 5b is R 4ab and R 5ab and / or A is A ab is) or where B is (B-bc) and R 3b3c R 3c When the compound of formula (VI) is a compound of formula (VI-c): [ka] (In the formula: A c A ac Or A bc and; where: A ac is -CH 2 NR 6c - and; A bc is -C(=O)NR 6c - and; R 1c is R 1ac or R 1bc and; where: R 1ac is NR 32c R 33c and; R 1bc is C 1-5 Alkyl, C 0-2 Alkylene C 3-5 Cycloalkyl (wherein the cycloalkyl is CH 3 Optionally replaced by C 1-3 Alkylene OC 1-2 Alkyl or CF 3 and; R 3c , H, CH 3 , Haro, O.C. 1-2 Alkyl or CF 3 and; R 4c and R 5c is R 4ac and R 5ac or R 4bc and R 5bc Either; where: R 4ac and R 5ac together with the carbon atom to which they are attached, C 3-6 Forms a cycloalkyl, which is: Each of the substituents is C 1-3 Alkyl, oxo, OH, C 1-3 AlkylOH, C 1-3 Haloalkyl, C 0-2 Alkylene C 3-6 Cycloalkyl, C 0-2 Alkylene C 3-6 Heterocycloalkyl, C 1-3 Alkylene OC 1-3 Alkyl, Halo, OC 1-3 Haloalkyl, OC 0-2 Alkylene C 3-6 Cycloalkyl, OC 0-2 Alkylene C 3-6 Heterocycloalkyl, OC 1-3 Alkyl and NR 21c R22c or is substituted by one or two substituents independently selected from the group consisting of: C 3-6 One of the carbons of the cycloalkyl is a spirocyclic ring system. 3-6 Cycloalkyl rings and further C 3-6 Cycloalkyl ring or C 3-6 A spiro center such as formed by a heterocycloalkyl ring, and where R 4ac and R 5ac C formed by 3-6 Cycloalkyl means that each of the substituents, together with the carbon atom to which they are attached, is C 1-3 Alkyl or OC 1-3 or may be substituted by one or two substituents independently selected from the group consisting of alkyl; R 4ac and R 5ac together with the carbon atom to which they are attached, C 3-6 Heterocycloalkyl, wherein the C 3-6 One of the carbons of the cycloalkyl is a spirocyclic ring system. 3-6 Cheterocycloalkyl rings and further C 3-6 Cycloalkyl ring or C 3-6 A spiro center such as formed by a heterocycloalkyl ring, and where R 4ac and R 5ac C formed by 3-6 Heterocycloalkyl means that each of the substituents, together with the carbon atom to which they are attached, is C 1-3 Alkyl or OC 1-3 or may be substituted by one or two substituents independently selected from the group consisting of alkyl; R 4ac and R 5ac C, which contains one nitrogen atom together with the carbon atom to which they are attached 3-6 heterocycloalkyl, where the nitrogen atom is -S(O) 2 R 29c or is replaced by R 4bc and R5bc are each independently H, C 1-6 Alkyl, C 0-2 Alkylene C 3-6 Cycloalkyl, C 0-2 Alkylene C 3-6 Heterocycloalkyl, C 1-3 Alkylene OC 1-3 Alkyl, C 1-6 AlkylOH or C 1-6 is haloalkyl, Or R 4bc and R 5bc together with the carbon atom to which they are attached, C 3-6 Cycloalkyl or C 3-6 forming a heterocycloalkyl ring; R 6c is H or C 1-3 is alkyl; Ar1c is a 6-membered aryl or heteroaryl; Ar2c is a 6-membered aryl or heteroaryl and is a group A c is bound to Ar1c in the para position relative to R 10c H, halo, C 1-3 Alkyl, OC 1-2 Alkyl, C 1-2 Haloalkyl, OC 1-2 haloalkyl, or CN; R 11c are H, F, Cl, CH 3 , Ethyl, OCH 3 , C.F. 3 , OCF 3 , or CN; R 12c is bonded to Ar2c at the meta or ortho position relative to Ar1c, and R 12c H, halo, C 1-4 Alkyl, C 2-4 Alkynyl, C(=O)C 1-2 Alkyl, C 0-2 Alkylene C 3-5 Cycloalkyl, OC 1-4 Alkyl, C 1-3 Alkylene OC 1-3 Alkyl, C 1-4Haloalkyl, OC 1-4 Haloalkyl, CN, OC 0-2 Alkylene C 3-5 Cycloalkyl, OCH 2 CH 2 N(CH 3 ) 2 , O.H., C. 1-4 AlkylOH, NR 23c R 24c , S.O. 2 CH 3 , C(O)N(CH 3 ) 2 , NHC(O)C 1-3 C containing one nitrogen atom at the point of attachment to the alkyl or Ar2c 3-6 heterocycloalkyl or R 12c forms, together with the nitrogen atom to which it is attached, an N-oxide (N + -O - ) to form; R 21c , H, C 1-5 Alkyl, C(O)C 1-5 Alkyl, C(O)OC 1-5 Alkyl, C 1-3 Alkyl OC 1-2 Alkyl, C 1-4 Haloalkyl or C 4-6 is heterocycloalkyl; R 22c is H or CH 3 and; R 23c is H or C 1-2 is alkyl; R 24c is H or C 1-2 is alkyl; R 29c is C 1-3 Alkyl, C 0-2 Alkylene C 3-5 Cycloalkyl (wherein the cycloalkyl is CH 3 Optionally replaced by CF 3 , N(C 1-3 Alkyl) 2or a 5- or 6-membered heteroaryl, wherein the 5- or 6-membered heteroaryl is optionally substituted with methyl; and R 32c is C 1-3 alkyl, and R 33c is C 1-3 is alkyl; or R 32c and R 33c together with the nitrogen atom to which they are attached, C 3-5 Forming a heterocycloalkyl; where: R 1c is R 1ac and / or R 4c and R 5c is R 4ac and R 5ac and / or A c A ac (It is.) Clause 29. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition or kit according to clause 28, wherein said CTPS1 inhibitor is selected from the compounds disclosed in List F or a pharma- ceutically acceptable salt and / or a pharma- ceutically acceptable solvate thereof. Clause 30. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition, or kit according to any one of clauses 1 to 17, wherein said CTPS1 inhibitor is a compound of formula (VII): or a pharma- ceutically acceptable salt and / or a pharma- ceutically acceptable solvate thereof. [ka] (In the formula, A is A a Or A b and; Where: A a has the following structure: -NH-, -CH 2 NH- or -NHCH 2 - an amine linker having A bis an amide linker having the following structure: -C(=O)NH- or -NHC(=O)-; B is, [ka] and; X is N or CH; Y is N or CR 2 and; Z is N or CR 3 and; With the proviso that when at least one of X or Z is N, Y cannot be N; R 1 is C 1-5 fluoroalkyl, where R 1 CF 3 rather than; R 2 H, halo, C 1-2 Alkyl, OC 1-2 Alkyl, C 1-2 Haloalkyl or OC 1-2 is haloalkyl; R 3 H, halo, CH 3 , O.C.H. 3 , C.F. 3 , or OCF 3 and; Here, R 2 and R 3 at least one of is H; R 3' H, halo, CH 3 , O.C. 1-2 Alkyl or CF 3 and When A is -NHC(=O)-, R 3' is R 5 together form a 5- or 6-membered cycloalkyl or a 5- or 6-membered oxygen-containing heterocycloalkyl; R 4 and R 5 is R 4a and R 5a or R 4b and R 5b and; Where: R 4a and R 5a together with the carbon atom to which they are attached, C 3-6 Forms a cycloalkyl, which is: Each of the substituents is C 1-3 Alkyl, oxo, OH, C 1-3 AlkylOH, C 1-3 Haloalkyl, C 0-2 Alkylene C 3-6 Cycloalkyl, C 0-2 Alkylene C 3-6 Heterocycloalkyl, C 1-3 Alkylene OC 1-3 Alkyl, Halo, OC 1-3 Haloalkyl, OC 0-2 Alkylene C 3-6 Cycloalkyl, OC 0-2 Alkylene C 3-6 Heterocycloalkyl, OC 1-3 Alkyl and NR 21 R 22 or is substituted by one or two substituents independently selected from the group consisting of: C 3-6 One of the carbons of the cycloalkyl is a spirocyclic ring system. 3-6 Cycloalkyl rings and further C 3-6 Cycloalkyl ring or C 3-6 A spiro center such as formed by a heterocycloalkyl ring, and where R 4a and R 5a C formed by 3-6 Cycloalkyl means that each of the substituents, together with the carbon atom to which they are attached, is C 1-3 Alkyl or OC 1-3 or may be substituted by one or two substituents independently selected from the group consisting of alkyl; R 4a and R 5a together with the carbon atom to which they are attached, C 3-6 heterocycloalkyl, wherein the C 3-6 One of the carbons of the heterocycloalkyl is a spirocyclic ring system. 3-6Heterocycloalkyl rings and further C 3-6 Cycloalkyl ring or C 3-6 A spiro center such as formed by a heterocycloalkyl ring, and where R 4a and R 5a C formed by 3-6 Heterocycloalkyl means that each of the substituents, together with the carbon atom to which they are attached, is C 1-3 Alkyl or OC 1-3 or may be substituted by one or two substituents independently selected from the group consisting of alkyl; R 4a and R 5a C, which contains one nitrogen atom together with the carbon atom to which they are attached 3-6 heterocycloalkyl, where the nitrogen atom is -S(O) 2 R 29 or is replaced by R 4b and R 5b are each independently H, C 1-6 Alkyl, C 1-6 AlkylOH, C 1-6 Haloalkyl, C 0-2 Alkylene C 3-6 Cycloalkyl, C 0-2 Alkylene C 3-6 Heterocycloalkyl, C 1-3 Alkylene OC 1-3 alkyl or R 4b and R 5b together with the carbon atom to which they are attached, C 3-6 Cycloalkyl or C 3-6 forming a heterocycloalkyl; and A is -NHC(=O)- or -NHCH 2 -When: R 4b and R 5b Ha, Hello, OC 1-6 Haloalkyl, OC 0-2 Alkylene C 3-6 Cycloalkyl, OC 0-2 Alkylene C 3-6 Heterocycloalkyl, OC 1-6Alkyl and NR 21 R 22 may further be selected from; 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 group A; R 10 H, halo, C 1-3 Alkyl, C 1-2 Haloalkyl, OC 1-2 Alkyl, OC 1-2 haloalkyl, or CN; R 11 are H, F, Cl, and C. 1-2 Alkyl, CF 3 , O.C.H. 3 , or CN; R 12 is bonded to Ar2 at the ortho or meta position relative to Ar1, and R 12 H, halo, C 1-4 Alkyl, C 2-4 Alkenyl, C 0-2 Alkylene C 3-5 Cycloalkyl, OC 1-4 Alkyl, OC 0-2 Alkylene C 3-5 Cycloalkyl, C 1-4 Haloalkyl, OC 1-4 Haloalkyl, Hydroxy, C 1-4 Alkyl OH, SO 2 C 1-2 Alkyl, C(O)N(C 1-2 Alkyl) 2 , NHC(O)C 1-3 Alkyl or NR 23 R 24 and A is -NHC(=O)-, -NH-, or -NHCH 2 -When: R 12 CN, OCH 2 CH 2 N(CH 3 ) 2 and C containing one nitrogen atom at the attachment point to Ar2 3-6heterocycloalkyl, or R 12 forms, together with the nitrogen atom to which it is attached, an N-oxide (N + -O - ) to form; R 13 is H or halo; R 21 , H, C 1-5 Alkyl, C(O)C 1-5 Alkyl, C(O)OC 1-5 is alkyl; R 22 is H or CH 3 and; R 23 is H or C 1-2 is alkyl; and R 24 is H or C 1-2 is alkyl; R 29 is C 1-3 Alkyl, C 0-2 Alkylene C 3-5 Cycloalkyl (wherein the cycloalkyl is CH 3 Optionally substituted by, or CF 3 and; R 32 is C 1-3 alkyl, and R 33 is C 1-3 is alkyl; or R 32 and R 33 together with the nitrogen atom to which they are attached, C 3-5 forming a heterocycloalkyl). Clause 31. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition or kit according to clause 30, wherein said CTPS1 inhibitor is selected from the compounds disclosed in List G or a pharma- ceutically acceptable salt and / or a pharma- ceutically acceptable solvate thereof. Clause 32. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition, or kit according to any one of clauses 1 to 17, wherein said CTPS1 inhibitor is a compound of formula (VIII): or a pharma- ceutically acceptable salt and / or a pharma- ceutically acceptable solvate thereof. [ka] (In the formula, A is A a Or A b and; Where: A a has the following structure: -NH-, -CH 2 NH- or -NHCH 2 - an amine linker having A b is an amide linker having the following structure: -C(=O)NH- or -NHC(=O)-; B is, [ka] and X is N or CH; Y is N or CR 2 and; Z is N or CR 3 and; With the proviso that when at least one of X or Z is N, Y cannot be N; R 1 is C 1-5 Alkyl or C 0-2 Alkylene C 3-5 cycloalkyl, wherein the alkyl or (alkylene)cycloalkyl is substituted by CN; R 2 H, halo, C 1-2 Alkyl, OC 1-2 Alkyl, C 1-2 Haloalkyl or OC 1-2 is haloalkyl; R 3 H, halo, CH 3 , O.C.H. 3 , C.F. 3 , or OCF 3 and; Here, R 2 and R 3 at least one of is H; R 3'H, halo, CH 3 , O.C. 1-2 Alkyl or CF 3 and When A is -NHC(=O)-, R 3' is R 5 together form a 5- or 6-membered cycloalkyl or a 5- or 6-membered oxygen-containing heterocycloalkyl; R 4 and R 5 is R 4a and R 5a or R 4b and R 5b and; Where: R 4a and R 5a together with the carbon atom to which they are attached, C 3-6 Forms a cycloalkyl, which is: Each of the substituents is C 1-3 Alkyl, oxo, OH, C 1-3 AlkylOH, C 1-3 Haloalkyl, C 0-2 Alkylene C 3-6 Cycloalkyl, C 0-2 Alkylene C 3-6 Heterocycloalkyl, C 1-3 Alkylene OC 1-3 Alkyl, Halo, OC 1-3 Haloalkyl, OC 0-2 Alkylene C 3-6 Cycloalkyl, OC 0-2 Alkylene C 3-6 Heterocycloalkyl, OC 1-3 Alkyl and NR 21 R 22 or is substituted by one or two substituents independently selected from the group consisting of: C 3-6 One of the carbons of the cycloalkyl is a spirocyclic ring system. 3-6 Cycloalkyl rings and further C 3-6 Cycloalkyl ring or C 3-6 A spiro center such as formed by a heterocycloalkyl ring, and where R 4a and R5a C formed by 3-6 Cycloalkyl means that each of the substituents, together with the carbon atom to which they are attached, is C 1-3 Alkyl or OC 1-3 or may be substituted by one or two substituents independently selected from the group consisting of alkyl; R 4a and R 5a together with the carbon atom to which they are attached, C 3-6 heterocycloalkyl, wherein the C 3-6 One of the carbons of the heterocycloalkyl is a spirocyclic ring system. 3-6 Heterocycloalkyl rings and further C 3-6 Cycloalkyl ring or C 3-6 A spiro center such as formed by a heterocycloalkyl ring, and where R 4a and R 5a C formed by 3-6 Heterocycloalkyl means that each of the substituents, together with the carbon atom to which they are attached, is C 1-3 Alkyl or OC 1-3 or may be substituted by one or two substituents independently selected from the group consisting of alkyl; R 4a and R 5a C, which contains one nitrogen atom together with the carbon atom to which they are attached 3-6 heterocycloalkyl, where the nitrogen atom is -S(O) 2 R 29 or is replaced by R 4b and R 5b are each independently H, C 1-6 Alkyl, C 1-6 AlkylOH, C 1-6 Haloalkyl, C 0-2 Alkylene C 3-6 Cycloalkyl, C 0-2 Alkylene C 3-6 Heterocycloalkyl, C 1-3 Alkylene OC 1-3 alkyl or R 4b and R5b together with the carbon atom to which they are attached, C 3-6 Cycloalkyl or C 3-6 forming a heterocycloalkyl; and A is -NHC(=O)- or -NHCH 2 -When: R 4b and R 5b Ha, Hello, OC 1-6 Haloalkyl, OC 0-2 Alkylene C 3-6 Cycloalkyl, OC 0-2 Alkylene C 3-6 Heterocycloalkyl, OC 1-6 Alkyl and NR 21 R 22 may further be selected from; 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; R 10 H, halo, C 1-3 Alkyl, C 1-2 Haloalkyl, OC 1-2 Alkyl, OC 1-2 haloalkyl, or CN; R 11 are H, F, Cl, and C. 1-2 Alkyl, CF 3 , O.C.H. 3 , or CN; R 12 is bonded to Ar2 at the ortho or meta position relative to Ar1, and R 12 H, halo, C 1-4 Alkyl, C 2-4 Alkenyl, C 0-2 Alkylene C 3-5 Cycloalkyl, OC 1-4 Alkyl, OC 0-2 Alkylene C 3-5 Cycloalkyl, C 1-4 Haloalkyl, OC 1-4 Haloalkyl, Hydroxy, C 1-4 Alkyl OH, SO 2 C 1-2Alkyl, C(O)N(C 1-2 Alkyl) 2 , NHC(O)C 1-3 Alkyl or NR 23 R 24 and A is -NHC(=O)-, -NH-, or -NHCH 2 -When: R 12 CN, OCH 2 CH 2 N(CH 3 ) 2 and C containing one nitrogen atom at the attachment point to Ar2 3-6 heterocycloalkyl, or R 12 forms, together with the nitrogen atom to which it is attached, an N-oxide (N + -O - ) to form; R 13 is H or halo; R 21 , H, C 1-5 Alkyl, C(O)C 1-5 Alkyl, C(O)OC 1-5 is alkyl; R 22 is H or CH 3 and; R 23 is H or C 1-2 is alkyl; and R 24 is H or C 1-2 is alkyl; R 29 is C 1-3 Alkyl, C 0-2 Alkylene C 3-5 Cycloalkyl (wherein the cycloalkyl is CH 3 Optionally substituted by, or CF 3 and; R 32 is C 1-3 alkyl, and R 33 is C 1-3 is alkyl; or R 32 and R 33together with the nitrogen atom to which they are attached, C 3-5 forming a heterocycloalkyl). Clause 33. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition or kit according to clause 32, wherein said CTPS1 inhibitor is selected from the compounds disclosed in List H or a pharma- ceutically acceptable salt and / or a pharma- ceutically acceptable solvate thereof. Clause 34. The CTPS1 inhibitor is 4-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)tetrahydro-2H-pyran-4-carboxamide: [ka] or a pharma- ceutical acceptable salt and / or a pharma- ceutical acceptable solvate thereof. Clause 35. The CTPS1 inhibitor is N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(2-(ethylsulfonamido)pyrimidin-4-yl)tetrahydro-2H-pyran-4-carboxamide: [ka] or a pharma- ceutical acceptable salt and / or a pharma- ceutical acceptable solvate thereof. Clause 36. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition or kit according to any one of clauses 1 to 35, wherein said CTPS1 inhibitor is in its free form. Clause 37. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition, or kit according to any one of clauses 1 to 35, wherein said CTPS1 inhibitor is a pharma- ceutically acceptable salt. Clause 38. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition, or kit according to any one of clauses 1 to 35, wherein said CTPS1 inhibitor is a pharma- ceutically acceptable solvate. Clause 39. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition, or kit according to any one of clauses 1 to 35, wherein said CTPS1 inhibitor is a pharma- ceutically acceptable salt or a pharma- ceutically acceptable solvate. Clause 40. 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"): [ka] or a pharma- ceutically acceptable salt thereof. Clause 41. 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")): [ka] or a pharma- ceutically acceptable salt thereof. Clause 42. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition or kit according to any one of clauses 1 to 41, wherein said CTPS1 inhibitor is provided in natural isotopic form. Clause 43. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition or kit according to any one of clauses 1 to 42, wherein said BCL2 inhibitor has a Ki value for binding to human BCL2 of 50 nM or less. Clause 44. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition or kit of claim 43, wherein said BCL2 inhibitor has a Ki value for binding to human BCL2 of 20 nM or less. Clause 45. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition or kit of claim 44, wherein said BCL2 inhibitor has a Ki value for binding to human BCL2 of 10 nM or less. Clause 46. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition or kit of claim 45, wherein said BCL2 inhibitor has a Ki value for binding to human BCL2 of 5 nM or less. Clause 47. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition or kit of claim 46, wherein said BCL2 inhibitor has a Ki value for binding to human BCL2 of 1 nM or less. Clause 48. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition or kit according to any one of clauses 43 to 47, wherein the Ki value of the binding of said BCL2 inhibitor to human BCL2 is established using the assay procedure set out in Example 3. Clause 49. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition or kit according to any one of clauses 1 to 48, wherein said BCL2 inhibitor has >2-fold selectivity for human BCL2 over human BCL2L1. Clause 50. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition or kit according to clause 49, wherein said BCL2 inhibitor has >5-fold selectivity for human BCL2 over human BCL2L1. Clause 51. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition or kit according to clause 50, wherein said BCL2 inhibitor has >10-fold selectivity for human BCL2 over human BCL2L1. Clause 52. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition or kit according to any one of clauses 1 to 51, wherein said BCL2 inhibitor has >2-fold selectivity for human BCL2 over human MCL1. Clause 53. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition or kit according to clause 52, wherein said BCL2 inhibitor has >5-fold selectivity for human BCL2 over human MCL1. Clause 54. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition or kit according to clause 53, wherein said BCL2 inhibitor has >10-fold selectivity for human BCL2 over human MCL1. Clause 55. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition or kit according to any one of clauses 49 to 54, wherein the selectivity of said BCL2 inhibitor is established using the assay procedure set out in Example 4. Clause 56. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition or kit according to any one of clauses 1 to 55, wherein said BCL2 inhibitor is a BH-3 mimetic. Clause 57. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition or kit according to any one of clauses 1 to 55, wherein said BCL2 inhibitor is selected from venetoclax, navitoclax, obatoclax, BCL201, and AT101, pharma- ceutically acceptable salts thereof and / or pharma- ceutically acceptable solvates thereof. Clause 58. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition or kit according to clause 57, wherein said BCL2 inhibitor is selected from venetoclax, navitoclax, obatoclax, and BCL201, pharma- ceutically acceptable salts thereof and / or pharma- ceutically acceptable solvates thereof. Clause 59. The BCL2 inhibitor is venetoclax: [ka] 59. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition or kit according to clause 58, which is (4-[4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexen-1-yl]methyl]piperazin-1-yl]-N-[3-nitro-4-(oxan-4-ylmethylamino)phenyl]sulfonyl-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide), a pharma- ceutically acceptable salt thereof and / or a pharma- ceutically acceptable solvate thereof. Clause 60. The BCL2 inhibitor is Navitoclax: [ka] 59. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition or kit according to clause 58, which is (4-[4-[[2-(4-chlorophenyl)-5,5-dimethylcyclohexen-1-yl]methyl]piperazin-1-yl]-N-[4-[[(2R)-4-morpholin-4-yl-1-phenylsulfanylbutan-2-yl]amino]-3-(trifluoromethylsulfonyl)phenyl]sulfonylbenzamide), a pharma- ceutically acceptable salt thereof and / or a pharma- ceutically acceptable solvate thereof. Clause 61. The BCL2 inhibitor is obatoclax: [ka] 59. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition or kit according to clause 58, which is ((2Z)-2-[(5Z)-5-[(3,5-dimethyl-1H-pyrrol-2-yl)methylidene]-4-methoxypyrrol-2-ylidene]indole), a pharma- ceutically acceptable salt thereof and / or a pharma- ceutically acceptable solvate thereof. Clause 62. The BCL2 inhibitor is BCL201: [ka] 59. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition or kit according to clause 58, which is a pharma- ceutically acceptable salt thereof and / or a pharma- ceutically acceptable solvate thereof. Clause 63. The BCL2 inhibitor is AT101: [ka] 59. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition or kit according to clause 58, which is a pharma- ceutically acceptable salt thereof and / or a pharma- ceutically acceptable solvate thereof. Clause 64. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition or kit according to any one of clauses 1 to 63, wherein said BCL2 inhibitor is in its free form. Clause 65. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition or kit according to any one of clauses 1 to 63, wherein said BCL2 inhibitor is a pharma- ceutically acceptable salt. Clause 66. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition or kit according to any one of clauses 1 to 63, wherein said BCL2 inhibitor is a pharma- ceutically acceptable solvate. Clause 67. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition or kit according to any one of clauses 1 to 63, wherein said BCL2 inhibitor is a pharma- ceutically acceptable salt or a pharma- ceutically acceptable solvate. Clause 68. The BCL2 inhibitor is venetoclax: [ka] 60. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition or kit of clause 59, wherein the compound is (4-[4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexen-1-yl]methyl]piperazin-1-yl]-N-[3-nitro-4-(oxan-4-ylmethylamino)phenyl]sulfonyl-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide). Clause 69. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition or kit according to clause 68, wherein said CTPS1 inhibitor is CTPS-IA or a pharma- ceutically acceptable salt and / or a pharma- ceutically acceptable solvate thereof and said BCL2 inhibitor is venetoclax. Clause 70. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition or kit according to clause 69, wherein said CTPS1 inhibitor is CTPS-IA or a pharma- ceutically acceptable salt thereof and said BCL2 inhibitor is venetoclax. Clause 71. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition or kit of any one of clauses 1 to 70, wherein said BCL2 inhibitor is provided in natural isotopic form. Clause 72. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition or kit according to any one of clauses 1 to 71, wherein said CTPS1 inhibitor and said BCL2 inhibitor act synergistically in treating said cancer. Clause 73. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition or kit according to clause 72, wherein combined administration of said CTPS1 inhibitor and said BCL2 inhibitor results in a beneficial effect that is greater than the sum of the beneficial effects of each agent administered alone. Clause 74. A CTPS1 inhibitor, BCL2 inhibitor, use, method, composition, or kit according to any of clauses 72 or 73, wherein the CTPS1 inhibitor and the BCL2 inhibitor achieve a Bliss score of 10 or more (Bliss, 1939; Zheng, 2021) when applied to a cancer cell line as shown in Example 6. Clause 75. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition or kit according to any one of clauses 1 to 74, wherein said BCL2 inhibitor and said CTPS1 inhibitor are administered to a mammal. Clause 76. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition or kit according to clause 75, wherein said BCL2 inhibitor and said CTPS1 inhibitor are administered to a human. Clause 77. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition or kit according to any one of clauses 1 to 76, wherein said CTPS1 inhibitor and said BCL2 inhibitor are formulated separately. Clause 78. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition or kit according to clause 77, wherein said CTPS1 inhibitor and said BCL2 inhibitor are administered separately. Clause 79. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition or kit according to any one of clauses 1 to 77, wherein said CTPS1 inhibitor and said BCL2 inhibitor are administered simultaneously. Clause 80. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition or kit according to clause 79, wherein said CTPS1 inhibitor and said BCL2 inhibitor are co-formulated. Clause 81. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition, or kit according to any one of clauses 1 to 80, wherein said CTPS1 inhibitor is administered by oral, parenteral, buccal, sublingual, nasal, or rectal administration. Clause 82. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition or kit according to clause 81, wherein said CTPS1 inhibitor is administered orally. Clause 83. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition or kit according to any one of clauses 1 to 82, wherein said BCL2 inhibitor is administered by oral, parenteral, buccal, sublingual, nasal or rectal administration. Clause 84. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition or kit according to clause 83, wherein said BCL2 inhibitor is administered orally. Clause 85. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition or kit according to any one of clauses 1 to 84, wherein said CTPS1 inhibitor and BCL2 inhibitor are administered separately, sequentially or simultaneously with one or more further pharma- ceutically acceptable active ingredients. Clause 86. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition or kit according to clause 85, wherein the further pharma- ceutically acceptable active ingredient is selected from tyrosine kinase inhibitors such as, for example, axitinib, dasatinib, erlotinib, imatinib, nilotinib, pazopanib and sunitinib. Clause 87. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition or kit according to clause 85, wherein said one or more further pharma- ceutically acceptable active ingredients are selected from zacitidine, decitabine, or cytarabine. Clause 88. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition or kit according to clause 85, wherein said one or more further pharma- ceutically acceptable active ingredients are selected from the group consisting of anti-cancer antibodies, such as anti-CD20 antibodies (e.g., obinutuzumab, ofatumumab, tositumomab, or rituximab) or other antibodies, such as olaratumumab, daratumumab, necitumumab, dinutuximab, traztuzumab emtansine, pertuzumab, brentuximab, panitumumab, catumaxomab, bevacizumab, cetuximab, traztuzumab, and gentuzumab ozogamicin. Clause 89. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition or kit of any one of clauses 1 to 88, administered in combination with radiation therapy. Clause 90. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition or kit of any one of clauses 1 to 89, administered in combination with surgery. Clause 91. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition, or kit of any one of clauses 1 to 90, administered in combination with hyperthermia. Clause 92. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition or kit according to any one of clauses 1 to 91, administered in combination with cryotherapy. Clause 93. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition or kit according to any one of clauses 1 to 92, wherein said cancer is a cancer exhibiting high replication stress. Clause 94. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition, or kit according to any one of clauses 1 to 93, wherein said cancer is a cancer exhibiting high expression of BCL2. Clause 95. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition or kit according to any one of clauses 1 to 94, wherein said cancer is a cancer exhibiting a high BCL2:BCL2L1 ratio. Clause 96. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition or kit according to any one of clauses 1 to 95, wherein said cancer is a cancer exhibiting a high BCL2:MCL1 ratio. Clause 97. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition or kit of any one of clauses 1 to 96, wherein said cancer constitutively expresses c-myc. Clause 98. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition, or kit according to any one of clauses 1 to 97, wherein said cancer is a non-hematological cancer. Clause 99. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition, or kit according to clause 98, wherein said cancer is selected from the group consisting of bladder cancer, breast, melanoma, neuroblastoma, malignant pleural mesothelioma, and sarcoma. Clause 100. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition or kit according to any of clauses 98 or 99, wherein said cancer is a solid tumor. Clause 101. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition, or kit according to any one of clauses 1 to 97, wherein said cancer is a blood cancer. Clause 102. The blood cancer is acute myeloid leukemia, angioimmunoblastic T-cell lymphoma, B-cell acute lymphoblastic leukemia, Sweet's syndrome, T-cell non-Hodgkin's lymphoma (including natural killer / T-cell lymphoma, adult T-cell leukemia / lymphoma, enteropathic T-cell lymphoma, hepatosplenic T-cell lymphoma, and cutaneous T-cell lymphoma), T-cell acute lymphoblastic leukemia, B-cell non-Hodgkin's lymphoma (including Burkitt's lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma, etc.) 102. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition or kit according to clause 101, wherein the CTPS1 inhibitor, BCL2 inhibitor, use, method, composition or kit according to clause 102 is selected from the list consisting of myelodysplastic syndromes, plasma cell myeloma, primary mediastinal large B-cell lymphoma, chronic myeloproliferative disorder (e.g. chronic myelogenous leukemia, primary myelofibrosis, essential thrombocythemia, polycythemia vera) or chronic lymphocytic leukemia. Clause 103. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition or kit according to clause 102, wherein said hematological cancer is selected from the list consisting of B-cell non-Hodgkin's lymphoma (including Burkitt's lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma), multiple myeloma and plasma cell leukemia. Clause 104. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition or kit according to clause 103, wherein said hematological cancer is selected from the list consisting of T-cell lymphoma, diffuse large B-cell lymphoma, plasma cell myeloma, acute myeloid leukemia, chronic lymphocytic leukemia, or peripheral T-cell lymphoma. Clause 105. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition or kit according to clause 104, wherein said hematological cancer is T-cell lymphoma. Clause 106. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition or kit according to clause 104, wherein said hematological cancer is diffuse large B-cell lymphoma. Clause 107. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition or kit according to clause 104, wherein said hematological cancer is plasma cell myeloma. Clause 108. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition or kit according to clause 104, wherein said blood cancer is acute myeloid leukemia. Clause 109. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition or kit according to clause 104, wherein said hematological cancer is chronic lymphocytic leukemia. Clause 110. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition or kit according to clause 104, wherein said hematological cancer is peripheral T-cell lymphoma. Clause 111. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition or kit according to clause 101, wherein said hematological cancer is T-cell prolymphocytic leukemia. Clause 112. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition or kit according to any one of clauses 1 to 97, wherein said cancer is selected from the list consisting of leukemia, lymphoma, lung cancer, bone cancer, melanoma, prostate cancer, brain cancer, colorectal cancer, esophageal and gastric cancer, breast cancer, endometrial cancer, renal cancer, sarcoma, liver cancer, pancreatic cancer, bladder cancer, thyroid cancer, ovarian cancer, head and neck cancer, mesothelioma and biliary tract cancer. Clause 113. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition or kit according to clause 112, wherein said cancer is selected from the list consisting of leukemia, lymphoma, lung cancer, bone cancer, melanoma, prostate cancer, brain cancer, colorectal cancer, esophagogastric cancer, breast cancer, endometrial cancer, renal cancer, sarcoma, liver cancer and pancreatic cancer. Clause 114. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition or kit according to clause 113, wherein said cancer is selected from the list consisting of leukemia, lymphoma, lung cancer, bone cancer, melanoma, prostate cancer, brain cancer and colorectal cancer. Clause 115. A CTPS1 inhibitor, a BCL2 inhibitor, a use, a method, a composition, or a kit according to any one of clauses 1 to 114, for administration to a subject identified as having a cancer that is expected to be amenable to treatment with a CTPS1 inhibitor and a BCL2 inhibitor. Clause 116. A CTPS1 inhibitor, a BCL2 inhibitor, a use, a method, a composition, or a kit according to any one of clauses 1 to 114 for administration to a subject in whom a sample of cancer cells has been shown to be amenable to treatment with a CTPS1 inhibitor and a BCL2 inhibitor. Clause 117. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition or kit according to any one of clauses 1 to 116, wherein said CTPS1 inhibitor and BCL2 inhibitor are administered orally. Clause 118. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition, or kit according to any one of clauses 1 to 117, wherein said CTPS1 inhibitor is in a solid pharmaceutical composition. Clause 119. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition or kit according to any one of clauses 1 to 118, wherein said BCL2 inhibitor is in a solid pharmaceutical composition. Clause 120. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition, or kit according to any one of clauses 1 to 119, wherein said CTPS1 inhibitor is in a solid pharmaceutical composition and said BCL2 inhibitor is in a solid pharmaceutical composition. Clause 121. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition or kit according to any one of clauses 1 to 120, wherein said CTPS1 inhibitor is orally administered in a solid pharmaceutical composition. Clause 122. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition or kit according to any one of clauses 1 to 121, wherein said BCL2 inhibitor is administered orally in a solid pharmaceutical composition. Clause 123. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition or kit according to any one of clauses 1 to 117, wherein said CTPS1 inhibitor is orally administered in a solid pharmaceutical composition and said BCL2 inhibitor is orally administered in a solid pharmaceutical composition. Clause 124. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition or kit according to any one of clauses 1 to 120, wherein said BCL2 inhibitor is administered in a daily dose of up to 600 mg, preferably in a daily dose of 1.0 mg to 500 mg. Clause 125. The CTPS1 inhibitor is: N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(2-(ethylsulfonamido)pyrimidin-4-yl)tetrahydro-2H-pyran-4-carboxamide [ka] or a pharma- ceutically acceptable salt and / or a pharma- ceutically acceptable solvate thereof; and said BCL2 inhibitor is venetoclax or a pharma- ceutically acceptable salt and / or a pharma- ceutically acceptable solvate thereof. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition, or kit according to any one of clauses 1 to 121, wherein said BCL2 inhibitor is venetoclax or a pharma- ceutically acceptable salt and / or a pharma- ceutically acceptable solvate thereof. Clause 126. The CTPS1 inhibitor is: 4-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)tetrahydro-2H-pyran-4-carboxamide: [ka] or a pharma- ceutically acceptable salt and / or a pharma- ceutically acceptable solvate thereof; and said BCL2 inhibitor is venetoclax or a pharma- ceutically acceptable salt and / or a pharma- ceutically acceptable solvate thereof. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition, or kit according to any one of clauses 1 to 121, wherein said BCL2 inhibitor is venetoclax or a pharma- ceutically acceptable salt and / or a pharma- ceutically acceptable solvate thereof. Clause 127. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition or kit according to any one of clauses 1 to 124, wherein said BLC2 inhibitor is not venetoclax. Clause 128. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition or kit according to clause 127, wherein said BLC2 inhibitor is not venetoclax or a pharma- ceutically acceptable salt and / or a pharma- ceutically acceptable solvate thereof. Clause 129. A CTPS1 inhibitor, BCL2 inhibitor, use, method, composition, or kit according to any one of clauses 1 to 128, wherein the CTPS1 inhibitor is not a CTPS1 inhibitor according to claim 1 of WO2022 / 087634. Clause 130. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition, or kit according to any one of clauses 1 to 128, wherein said CTPS1 inhibitor is not a CTPS1 inhibitor as defined in WO2022 / 087634. Clause 131. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition, or kit according to any one of clauses 1 to 128, wherein said CTPS1 inhibitor is a CTPS1 inhibitor disclosed in PCT Publication No. WO2022087634. Clause 132. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition, or kit according to any one of clauses 1 to 128, wherein the CTPS1 inhibitor is (i) a compound according to any one of claims 1 to 31 of WO2022087634 or a pharma- ceutically acceptable salt and / or a pharma-ceutically acceptable solvate thereof, (ii) a compound selected from compounds I-1 to I-286 of WO2022087634 or a pharma-ceutically acceptable salt and / or a pharma-ceutically acceptable solvate thereof, or (iii) a compound selected from compounds Z-1 to Z-10 of WO2022087634 or a pharma-ceutically acceptable salt and / or a pharma-ceutically acceptable solvate thereof. Clause 133. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition, or kit according to any one of clauses 1 to 128, wherein said CTPS1 inhibitor is not a CTPS1 inhibitor disclosed in PCT Publication No. WO2022087634. Clause 134. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition, or kit according to any one of clauses 1 to 128, wherein the CTPS1 inhibitor is not (i) a compound according to any one of claims 1 to 31 of WO2022087634 or a pharma- ceutically acceptable salt and / or a pharma- ceutically acceptable solvate thereof, (ii) a compound selected from compounds I-1 to I-286 of WO2022087634 or a pharma- ceutically acceptable salt and / or a pharma- ceutically acceptable solvate thereof, or (iii) a compound selected from compounds Z-1 to Z-10 of WO2022087634 or a pharma- ceutically acceptable salt and / or a pharma- ceutically acceptable solvate thereof.

[0202] (References) [Table 3]

Claims

1. A CTPS1 inhibitor for use in the treatment of cancer with a BCL2 inhibitor.

2. A BCL2 inhibitor for use in the treatment of cancer with a CTPS1 inhibitor.

3. A pharmaceutical composition comprising a CTPS1 inhibitor and a BCL2 inhibitor.

4. Use of a CTPS1 inhibitor in the manufacture of a medicament for the treatment of cancer with a BCL2 inhibitor.

5. Use of a BCL2 inhibitor in the manufacture of a medicament for the treatment of cancer with a CTPS1 inhibitor.

6. A method for treating cancer in a subject, comprising administering to the subject a CTPS1 inhibitor and a BCL2 inhibitor.

7. a) a first container containing a CTPS1 inhibitor; and b) a second container containing a BCL2 inhibitor. Kit of parts including:

8. The CTPS1 inhibitor has an IC of 10 uM or less established using the assay procedure set forth in Example 1. 50 The CTPS1 inhibitor, BCL2 inhibitor, composition, use, method, or kit of any one of claims 1 to 7, comprising:

9. The CTPS1 inhibitor, BCL2 inhibitor, composition, use, method, or kit of any one of claims 1 to 8, wherein the CTPS1 inhibitor has at least 2-fold selectivity for CTPS1 compared to CTPS2 established using the assay procedure set forth in Example 2.

10. The CTPS1 inhibitor, BCL2 inhibitor, composition, use, method, or kit of any one of claims 1 to 9, wherein the CTPS1 inhibitor is a compound of formula (III): or a pharma- ceutically acceptable salt and / or a pharma- ceutically acceptable solvate thereof: 【Chemistry 1】 (In the formula, A is an amide linker having the following structure: -C(=O)NH- or -NHC(=O)-; X is N or CH; Y is N or CR 2 and; Z is N or CR 3 and; With the proviso that when at least one of X or Z is N, Y cannot be N; R 1 is C 1-5 Alkyl, C 0-2 Alkylene C 3-5 Cycloalkyl (wherein the cycloalkyl is CH 3 Optionally substituted by, or CF 3 and; R 2 H, halo, C 1-2 Alkyl, OC 1-2 Alkyl, C 1-2 Haloalkyl or OC 1-2 is haloalkyl; R 3 H, halo, CH 3 , O.C.H. 3 , C.F. 3 , or OCF 3 and; Here, R 2 and R 3 at least one of is H; R 4 and R 5 are each independently H, C 1-6 Alkyl, C 1-6 AlkylOH, C 1-6 Haloalkyl, C 0-2 Alkylene C 3-6 Cycloalkyl, C 0-2 Alkylene C 3-6 Heterocycloalkyl, C 1-3 Alkylene OC 1-3 alkyl or R 4 and R 5 together with the carbon atom to which they are attached, C 3-6 Cycloalkyl or C 3-6 forming a heterocycloalkyl; and When A is -NHC(=O)-: R 4 and R 5 Ha, Hello, OC 1-6 Haloalkyl, OC 0-2 Alkylene C 3-6 Cycloalkyl, OC 0-2 Alkylene C 3-6 Heterocycloalkyl, OC 1-6 Alkyl and NR 21 R 22 may further be selected from; 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; R 10 H, halo, C 1-3 Alkyl, C 1-2 Haloalkyl, OC 1-2 Alkyl, OC 1-2 haloalkyl, or CN; R 11 are H, F, Cl, and C. 1-2 Alkyl, CF 3 , O.C.H. 3 , or CN; R 12 is bonded to Ar2 at the ortho or meta position relative to Ar1, and R 12 H, halo, C 1-4 Alkyl, C 2-4 Alkenyl, C 0-2 Alkylene C 3-5 Cycloalkyl, OC 1-4 Alkyl, OC 0-2 Alkylene C 3-5 Cycloalkyl, C 1-4 Haloalkyl, OC 1-4 Haloalkyl, Hydroxy, C 1-4 Alkyl OH, SO 2 C 1-2 Alkyl, C(O)N(C 1-2 Alkyl) 2 , NHC(O)C 1-3 Alkyl or NR 23 R 24 and When A is -NHC(=O)-: R 12 CN, OCH 2 CH 2 N(CH 3 ) 2 and C containing one nitrogen atom at the attachment point to Ar2 3-6 heterocycloalkyl, or R 12 forms, together with the nitrogen atom to which it is attached, an N-oxide (N + -O - ) to form; R 13 is H or halo; R 21 , H, C 1-5 Alkyl, C(O)C 1-5 Alkyl, C(O)OC 1-5 is alkyl; R 22 is H or CH 3 and; R 23 is H or C 1-2 is alkyl; and R 24 is H or C 1-2 (It is alkyl).

11. 2 is a block diagram of a CTPS1 inhibitor comprising N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(2-(ethylsulfonamido)pyrimidin-4-yl)tetrahydro-2H-pyran-4-carboxamide: 【Chemistry 2】 or a pharma- ceutical acceptable salt and / or a pharma- ceutical acceptable solvate thereof.

12. 2 is a compound selected from the group consisting of 4-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)tetrahydro-2H-pyran-4-carboxamide; 【Chemistry 3】 or a pharma- ceutical acceptable salt and / or a pharma- ceutical acceptable solvate thereof.

13. The CTPS1 inhibitor, BCL2 inhibitor, composition, use, method, or kit of any one of claims 1 to 9, wherein the CTPS1 inhibitor is selected from the compounds disclosed in any one of Lists A to H or a pharma- ceutically acceptable salt and / or a pharma- ceutically acceptable solvate thereof.

14. The CTPS1 inhibitor, BCL2 inhibitor, composition, use, method, or kit of any one of claims 1 to 13, wherein said BCL2 inhibitor has a Ki value for binding to BCL2 of 50 nM or less established using the assay procedure set forth in Example 3.

15. The CTPS1 inhibitor, BCL2 inhibitor, composition, use, method, or kit of any one of claims 1 to 14, wherein said BCL2 inhibitor is a BH-3 mimetic.

16. The CTPS1 inhibitor, BCL2 inhibitor, composition, use, method, or kit of any one of claims 1 to 14, wherein the BCL2 inhibitor is selected from venetoclax, navitoclax, obatoclax, BCL201, and AT101, pharma- ceutically acceptable salts thereof, and / or pharma- ceutically acceptable solvates thereof.

17. The CTPS1 inhibitor, BCL2 inhibitor, composition, use, method, or kit of claim 16, wherein the BCL2 inhibitor is venetoclax, a pharma- ceutically acceptable salt thereof and / or a pharma- ceutically acceptable solvate thereof.

18. 12. The method of claim 11, 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: 【Chemistry 4】 or a pharma- ceutically acceptable salt and / or a pharma- ceutically acceptable solvate thereof; and the BCL2 inhibitor is venetoclax or a pharma- ceutically acceptable salt and / or a pharma- ceutically acceptable solvate thereof. The CTPS1 inhibitor, BCL2 inhibitor, composition, use, method, or kit of claim 1, wherein the BCL2 inhibitor is venetoclax or a pharma- ceutically acceptable salt and / or a pharma- ceutically acceptable solvate thereof.

19. 12. The method of claim 11, 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: 【Chemistry 5】 or a pharma- ceutically acceptable salt and / or a pharma- ceutically acceptable solvate thereof; and the BCL2 inhibitor is venetoclax or a pharma- ceutically acceptable salt and / or a pharma- ceutically acceptable solvate thereof. The CTPS1 inhibitor, BCL2 inhibitor, composition, use, method, or kit of claim 1, wherein the BCL2 inhibitor is venetoclax or a pharma- ceutically acceptable salt and / or a pharma- ceutically acceptable solvate thereof.

20. 17. The CTPS1 inhibitor, BCL2 inhibitor, composition, use, method, or kit of claim 16, wherein the BCL2 inhibitor is BCL201, a pharma- ceutically acceptable salt thereof, and / or a pharma- ceutically acceptable solvate thereof.

21. 12. The method of claim 11, 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: 【Chemistry 6】 or a pharma- ceutically acceptable salt and / or a pharma- ceutically acceptable solvate thereof; and said BCL2 inhibitor is BCL201 or a pharma- ceutically acceptable salt and / or a pharma- ceutically acceptable solvate thereof.

22. 12. The method of claim 11, 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: 【Chemistry 7】 or a pharma- ceutically acceptable salt and / or a pharma- ceutically acceptable solvate thereof; and said BCL2 inhibitor is BCL201 or a pharma- ceutically acceptable salt and / or a pharma- ceutically acceptable solvate thereof.

23. The CTPS1 inhibitor, BCL2 inhibitor, composition, or kit of any one of claims 1 to 22, wherein the cancer is a blood cancer.

24. 24. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition, or kit of claim 23, wherein the hematological cancer is T-cell lymphoma.

25. 24. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition, or kit of claim 23, wherein the hematological cancer is diffuse large B-cell lymphoma.

26. 24. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition, or kit of claim 23, wherein the hematological cancer is plasma cell myeloma.

27. 24. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition, or kit of claim 23, wherein the blood cancer is acute myeloid leukemia.

28. 24. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition, or kit of claim 23, wherein the hematological cancer is chronic lymphocytic leukemia.

29. 24. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition, or kit of claim 23, wherein the hematological cancer is peripheral T-cell lymphoma.

30. 24. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition, or kit of claim 23, wherein the hematological cancer is myelodysplastic syndrome (MDS), such as MDS with unilineage dysplasia, MDS with multilineage dysplasia, or MDS with excess blasts.

31. 24. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition, or kit of claim 23, wherein the blood cancer is cutaneous T-cell lymphoma.

32. 24. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition, or kit of claim 23, wherein the hematological cancer is follicular lymphoma.

33. 24. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition, or kit of claim 23, wherein the hematological cancer is mantle cell lymphoma.

34. 24. The CTPS1 inhibitor, BCL2 inhibitor, use, method, composition, or kit of claim 23, wherein the hematological cancer is marginal zone lymphoma.

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