CTPS1 inhibitors for use in the treatment of CTPS2-deficient cancers

Abstract

The present invention provides, inter alia, methods and related embodiments for treating CTPS2-deficient cancers by administering a CTPS1 inhibitor.

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present invention relates to methods and related aspects of treating CTPS2-deficient cancers by administering CTPS1 inhibitors. [Background technology]

[0002] BACKGROUND OF THE INVENTION 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, requiring the careful coordination of multiple pathways, many of which have not yet been fully characterized. Cell division requires the efficient 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 therapies that act in this manner are 6-thioguanine, 6-mercaptopurine, 5-fluorouracil, cytarabine, gemcitabine, and pemetrexed.

[0003] A wide range of specific targeted cancer treatments are available. Small molecule targeted therapy drugs are typically 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 cancer cells.

[0004] All proliferating cells, including tumor cells, depend on a readily available source of purine and pyrimidine nucleotides for DNA and RNA synthesis. While salvage pathways may be sufficient for steady-state metabolism, DNA replication, which enables 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 normal and malignant human cells (BioGPS and EMBL-EBI Expression Atlas). Differential roles for CTPS1 and CTPS2 have been demonstrated in cell proliferation (Minet 2023), and human genetic studies have identified an essential and non-redundant role for CTPS1 in normal immune (B and T) cell proliferation (Martin 2014; Martin 2020).

[0005] Cancer cells depend on CTPS activity for proliferation, but the precise 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 for oncology indications and have progressed to phase I / II clinical trials, but have been discontinued due to toxicity and efficacy issues. Many of the developed inhibitors are nucleoside analog prodrugs (3-deazauridine (DAU), CPEC, and carbozine) 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). Other inhibitors, such as acivicin and 6-diazo-5-oxo-L-norleucine (DON), are reactive analogs of glutamine that irreversibly inhibit the glutaminase domain of CTPS. Importantly, none of the CTPS inhibitors developed to date are selective for one CTPS isoform over the other, so available CTPS inhibitors block all CTPS activity and therefore the ability of all cells in the body to undergo cell division.

[0006] Cancer is a genomic disease. Cancer cells harbor various types of alterations in their DNA that underpin the biological changes in cellular biology that define cancer. These DNA alterations include base-level mutations and structural alterations at the gene and chromosome levels, such as deletions, amplifications, and gene fusions. Cancer cells harbor extensive genomic disruptions; however, only a small fraction of these alterations directly alter cellular biology, while the rest represent collateral genomic damage or bystander effects from the mutational process that leads to genetic changes. For example, the loss of genetic material in cancer cells can cause the loss of specific tumor suppressor genes that increase the adaptive capacity of cancer cells (thus contributing to the process of cancer development); this same loss can also cause the loss of other genes in the same region that are not essential for the cancer cells. In some such cases, the loss of genes that are not essential for the cancer cells can result in a state in which the cancer cells are critically dependent on specific metabolic pathways or enzymes, a situation sometimes referred to as metabolic collateral lethality. For example, deletion of CTPS2 from cancer cells does not directly affect cellular fitness (Figure 2), but creates a critical dependency on CTPS1 activity to generate components required for DNA synthesis (and thus cell division). In humans, CTPS2 is found on the X chromosome (ChrX(p22.2); transcript ID: ENST00000359276.9, NM_175859; location: hg38 chrX:16,587,999-16,712,669).

[0007] There remains a need for new approaches to cancer therapy that may exhibit increased in vivo efficacy, lower doses required for in vivo efficacy, improved safety profiles / reduced side effects, etc. Summary of the Invention

[0008] (Summary of the Invention) The present invention provides a method for treating a CTPS2-deficient cancer in a subject, the method comprising administering to the subject a CTPS1 inhibitor.

[0009] The present invention provides a method for treating cancer in a subject, comprising: i) identifying the subject as having a cancer that is deficient in CTPS2; and ii) administering a CTPS1 inhibitor to the subject. Also provided is a method, including:

[0010] The present invention provides a method for treating cancer in a subject, comprising: i) providing a sample from said subject; ii) using the sample to identify the subject as having a cancer that is deficient in CTPS2; and iii) administering a CTPS1 inhibitor to the subject. Also provided is a method, including:

[0011] The present invention provides a method for treating cancer in a subject, comprising: i) obtaining a sample from said subject; ii) using the sample to identify the subject as having a cancer that is deficient in CTPS2; and iii) administering a CTPS1 inhibitor to the subject. Also provided is a method, including:

[0012] The present invention provides a method for treating a cancer in a subject that may be susceptible to treatment with a CTPS1 inhibitor, comprising: i) identifying that the cancer is likely to be deficient in CTPS2; and ii) administering a CTPS1 inhibitor to the subject. Also provided is a method, including:

[0013] The present invention provides a method for treating a cancer in a subject that may be susceptible to treatment with a CTPS1 inhibitor, comprising: i) providing a sample from said subject; ii) using the sample to identify that the cancer is likely to be deficient in CTPS2; and iii) administering a CTPS1 inhibitor Also provided is a method, including:

[0014] The present invention provides a method for treating a cancer in a subject that may be susceptible to treatment with a CTPS1 inhibitor, comprising: i) obtaining a sample from said subject; ii) using the sample to identify that the cancer is likely to be deficient in CTPS2; and iii) administering a CTPS1 inhibitor Also provided is a method, including:

[0015] The present invention also provides a method for determining whether a cancer cell may be susceptible to treatment with a CTPS1 inhibitor, the method comprising identifying that the cancer cell is deficient in CTPS2.

[0016] The present invention also provides a method for determining that a cancer in a subject may be susceptible to treatment with a CTPS1 inhibitor, the method comprising identifying that the cancer is deficient in CTPS2.

[0017] The present invention also provides a method for determining whether a cancer cell may be sensitive to treatment with a CTPS1 inhibitor, the method comprising identifying that the cancer cell may be deficient in CTPS2.

[0018] The present invention also provides a method for determining whether a cancer in a subject may be sensitive to treatment with a CTPS1 inhibitor, the method comprising identifying that the cancer may be deficient in CTPS2.

[0019] The present invention also provides a CTPS1 inhibitor for use in treating a CTPS2-deficient cancer.The present invention also provides a CTPS1 inhibitor for use in treating a CTPS2-deficient cancer in a subject.

[0020] The present invention also provides a CTPS1 inhibitor for use in treating a cancer that may be deficient in CTPS2. The present invention also provides a CTPS1 inhibitor for use in treating a cancer that may be deficient in CTPS2 in a subject.

[0021] The present invention also provides the use of a CTPS1 inhibitor in the manufacture of a medicament for the treatment of a CTPS2-deficient cancer.The present invention also provides the use of a CTPS1 inhibitor in the manufacture of a medicament for the treatment of a CTPS2-deficient cancer in a subject.

[0022] The present invention also provides the use of a CTPS1 inhibitor in the manufacture of a medicament for treating a cancer that may be deficient in CTPS2.The present invention also provides the use of a CTPS1 inhibitor in the manufacture of a medicament for treating a cancer that may be deficient in CTPS2 in a subject.

[0023] The present invention also provides a pharmaceutical composition comprising a CTPS1 inhibitor and a pharmaceutically acceptable excipient or carrier for use in treating CTPS2-deficient cancer.The present invention also provides a pharmaceutical composition comprising a CTPS1 inhibitor and a pharmaceutically acceptable excipient or carrier for use in treating CTPS2-deficient cancer in a subject.

[0024] The present invention also provides a pharmaceutical composition comprising a CTPS1 inhibitor and a pharmaceutically acceptable excipient or carrier for use in treating a cancer that may be CTPS2 deficient.The present invention also provides a pharmaceutical composition comprising a CTPS1 inhibitor and a pharmaceutically acceptable excipient or carrier for use in treating a cancer that may be CTPS2 deficient in a subject.

[0025] (Array Overview) SEQ ID NO: 1 FLAG-His8-tag SEQ ID NO: 2 FLAG-His-Avi tag [Brief explanation of the drawings]

[0026] (Drawing summary) [Figure 1] De novo CTP production pathway [Figure 2] Achilles CRISPR screen containing 1032 cancer cell lines; graph shows box plot representing number of cell lines by median, interquartile range, and total range; x-axis shows CERES score: 0=no effect, <0=reduced proliferation, -1=median of all common essential genes. [Figure 3] Analysis of whole-genome sequencing data of 2,348 cancer samples in the ICGC PCAWG cohort accessed via cBioPortal, showing the proportion of samples by cancer type with homozygous deletion of CTPS2. NSCLC, non-small cell lung cancer; CNS, central nervous system. [Figure 4] Analysis of 573 cancer cell lines using CTPS1 knockout data from the Achilles project and CTPS2 RNA expression from the Cancer Cell Line Encyclopedia; data accessed via the CellMinerCDB portal. [Figure 5] Comparison of CTPS2 loss confirmed by whole-genome sequencing data from samples within the ICGC PCAWG cohort with CTPS2 loss confirmed by immunohistochemistry analysis of tumor microarrays. DETAILED DESCRIPTION OF THE INVENTION

[0027] (Detailed Description of the Invention) The present inventors have identified that some cancers are deficient in CTPS2 and therefore may be particularly amenable to treatment with CTPS1 inhibitors.

[0028] The present invention provides a method for treating a CTPS2-deficient cancer in a subject, the method comprising administering to the subject a CTPS1 inhibitor.

[0029] The present invention provides a method for treating cancer in a subject, comprising: i) identifying the subject as having a cancer that is deficient in CTPS2; and ii) administering a CTPS1 inhibitor to the subject. Also provided is a method, including:

[0030] The present invention provides a method for treating cancer in a subject, comprising: i) providing a sample from said subject; ii) using the sample to identify the subject as having a cancer that is deficient in CTPS2; and iii) administering a CTPS1 inhibitor to the subject. Also provided is a method, including:

[0031] The present invention provides a method for treating cancer in a subject, comprising: i) obtaining a sample from said subject; ii) using the sample to identify the subject as having a cancer that is deficient in CTPS2; and iii) administering a CTPS1 inhibitor to the subject. Also provided is a method, including:

[0032] The present invention provides a method for treating a cancer in a subject that may be susceptible to treatment with a CTPS1 inhibitor, comprising: i) identifying that the cancer is likely to be deficient in CTPS2; and ii) administering a CTPS1 inhibitor to the subject. Also provided is a method, including:

[0033] The present invention provides a method for treating a cancer in a subject that may be susceptible to treatment with a CTPS1 inhibitor, comprising: i) providing a sample from said subject; ii) using the sample to identify that the cancer is likely to be deficient in CTPS2; and iii) administering a CTPS1 inhibitor Also provided is a method, including:

[0034] The present invention provides a method for treating a cancer in a subject that may be susceptible to treatment with a CTPS1 inhibitor, comprising: i) obtaining a sample from said subject; ii) using the sample to identify that the cancer is likely to be deficient in CTPS2; and iii) administering a CTPS1 inhibitor Also provided is a method, including:

[0035] The present invention also provides a method for determining whether a cancer cell may be susceptible to treatment with a CTPS1 inhibitor, the method comprising identifying that the cancer cell is deficient in CTPS2.

[0036] The present invention also provides a method for determining that a cancer in a subject may be susceptible to treatment with a CTPS1 inhibitor, the method comprising identifying that the cancer is deficient in CTPS2.

[0037] The present invention also provides a method for determining whether a cancer cell may be sensitive to treatment with a CTPS1 inhibitor, the method comprising identifying that the cancer cell may be deficient in CTPS2.

[0038] The present invention also provides a method for determining whether a cancer in a subject may be sensitive to treatment with a CTPS1 inhibitor, the method comprising identifying that the cancer may be deficient in CTPS2.

[0039] The present invention also provides a CTPS1 inhibitor for use in treating a CTPS2-deficient cancer.The present invention also provides a CTPS1 inhibitor for use in treating a CTPS2-deficient cancer in a subject.

[0040] The present invention also provides a CTPS1 inhibitor for use in treating a cancer that may be deficient in CTPS2. The present invention also provides a CTPS1 inhibitor for use in treating a cancer that may be deficient in CTPS2 in a subject.

[0041] The present invention also provides the use of a CTPS1 inhibitor in the manufacture of a medicament for the treatment of a CTPS2-deficient cancer.The present invention also provides the use of a CTPS1 inhibitor in the manufacture of a medicament for the treatment of a CTPS2-deficient cancer in a subject.

[0042] The present invention also provides the use of a CTPS1 inhibitor in the manufacture of a medicament for treating a cancer that may be deficient in CTPS2.The present invention also provides the use of a CTPS1 inhibitor in the manufacture of a medicament for treating a cancer that may be deficient in CTPS2 in a subject.

[0043] The present invention also provides a pharmaceutical composition comprising a CTPS1 inhibitor and a pharmaceutically acceptable excipient or carrier for use in treating CTPS2-deficient cancer.The present invention also provides a pharmaceutical composition comprising a CTPS1 inhibitor and a pharmaceutically acceptable excipient or carrier for use in treating CTPS2-deficient cancer in a subject.

[0044] The present invention also provides a pharmaceutical composition comprising a CTPS1 inhibitor and a pharmaceutically acceptable excipient or carrier for use in treating a cancer that may be CTPS2 deficient.The present invention also provides a pharmaceutical composition comprising a CTPS1 inhibitor and a pharmaceutically acceptable excipient or carrier for use in treating a cancer that may be CTPS2 deficient in a subject.

[0045] (CTPS1 inhibitor) As used herein, a CTPS1 inhibitor is an agent that directly inhibits the enzymatic activity of the CTPS1 enzyme through interaction with the enzyme. Direct inhibition of the CTPS1 enzyme can be determined using any suitable assay procedure, but is preferably carried out using the procedure shown in Example 1.

[0046] CTPS1 inhibitors have an IC50 of 10 uM or less, e.g., 1 uM or less, especially 100 nM or less, with respect to the CTPS1 enzyme. 50CTPS1 inhibitors of particular interest 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.

[0047] CTPS1 inhibitors ideally have a higher activity against CTPS1 than CTPS2 (i.e., IC 50 The inhibitors exhibit selectivity (based on the ratio of β- and β-values). Preferably, the inhibitors exhibit at least 2-fold, e.g., at least 30-fold, particularly at least 60-fold, and especially at least 1000-fold selectivity. CTPS1 inhibitors of particular interest are those that exhibit at least 2-fold, e.g., at least 30-fold, particularly at least 60-fold, and especially at least 1000-fold selectivity for CTPS1 over CTPS2, using the assay procedure set forth in Example 2. Desirably, the selectivity is for human CTPS1 over human CTPS2.

[0048] For drugs intended for human use, CTPS1 inhibition and CTPS1 versus CTPS2 selectivity should be based on the human form of the enzyme.

[0049] Suitably, the CTPS1 inhibitor is the following compound: A compound of formula (I): or a pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate thereof [ka] (In the formula, R1 is C 1-5 Alkyl, C 0-2 Alkylene C 3-5 cycloalkyl (wherein the cycloalkyl is optionally substituted with CH3), C 1-3 Alkylene OC 1-2 alkyl, or CF3; R3 is H, CH3, halo, OC 1-2 alkyl, or CF3; R4 and R5 each independently represent H, C 1-6Alkyl, 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 Alkyl OH or C 1-6 is haloalkyl, or R4 and R5 together with the carbon atom to which they are attached form C 3-6 Cycloalkyl or C 3-6 forming a heterocycloalkyl ring; R6 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 is H, F, Cl, CH3, ethyl, OCH3, CF3, OCF3, 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, OCH2CH2N(CH3)2, OH, C 1-4 Alkyl OH, NR 23 R 24, SO2CH3, C(O)N(CH3)2, NHC(O)C 1-3 C containing one nitrogen atom at the point of attachment to alkyl or Ar2 3-6 heterocycloalkyl or R 12 together with the nitrogen atom to which it is attached form an N-oxide (N + -O - ) form; R 23 is H or C 1-2 is alkyl; R 24 is H or C 1-2 (It is alkyl).

[0050] 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 pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate thereof.

[0051] 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 can be a compound described in any one of clauses 1 to 110 of WO2019106146 or a pharmaceutically acceptable salt and / or solvate thereof, particularly compounds R1 to R93 or a pharmaceutically acceptable salt and / or solvate thereof.

[0052] Alternatively, the CTPS1 inhibitor is a compound of formula (II): or a pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate thereof [ka] (In the formula, R1 is C 1-5 Alkyl, C 0-2 Alkylene C 3-5 cycloalkyl (wherein the cycloalkyl is optionally substituted with CH3), C 1-3 Alkylene OC 1-2 alkyl, or CF3; R3 is H, halo, CH3, OC 1-2 alkyl, or CF3; or R3 together with R5 form a 5- or 6-membered cycloalkyl or a 5- or 6-membered oxygen-containing heterocycloalkyl; R4 and R5 are each independently H, halo, 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 Alkyl OH, C 1-6 Haloalkyl, OC 1-6 Haloalkyl, or NR21 R 22 and or R4 is H and R5 together with R3 form a 5- or 6-membered cycloalkyl or a 5- or 6-membered oxygen-containing heterocycloalkyl; or R4 and R5 together with the carbon atom to which they are attached form C 3-6 Cycloalkyl or C 3-6 forming a heterocycloalkyl, or R4 is H and R5 and R6 are C 2-3 is an alkylene chain; or R4 is O and R5 is absent; R6 is H or C 1-3 is alkyl, or R6 when in the ortho position relative to the amide 11 is a C2 alkylene chain that forms a five-membered ring together with or R5 and R6 form a 5- or 6-membered ring 2-3 is an alkylene chain and R4 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 is H, F, Cl, CH3, ethyl, OCH3, CF3, OCF3, or CN; or R 11 is a C2 alkylene chain that, together with R6, forms a five-membered ring when in the ortho position relative to the amide; 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 C3-5 Cycloalkyl, OC 1-4 Alkyl, OC 0-2 Alkylene C 3-5 Cycloalkyl, OCH2CH2N(CH3)2, OH, C 1-4 Alkyl OH, 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 , SO2C 1-4 Alkyl, SOC 1-4 Alkyl, SC 1-4 Alkyl, SH, C(O)N(CH3)2, NHC(O)C 1-3 Alkyl, C containing one nitrogen at the point of attachment to Ar2 3-6 heterocycloalkyl or R 12 together with the nitrogen atom to which it is attached form an N-oxide (N + -O - ) form; R 13 is H, halo, CH3, or OCH3; R 21 is H, C 1-5 Alkyl, C(O)C 1-5 Alkyl, C(O)OC 1-5 is alkyl; R 22 is H or CH3; R 23 is H or C 1-2 is alkyl; and R 24 is H or C 1-2 (It is alkyl).

[0053] 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 pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate thereof.

[0054] 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 to 118 of WO2019106156 or a pharmaceutically acceptable salt and / or solvate thereof, particularly compounds T1 to T465 or a pharmaceutically acceptable salt and / or solvate thereof.

[0055] Alternatively, the CTPS1 inhibitor is a compound of formula (III): or a pharmaceutically acceptable salt and / or a pharmaceutically 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 CR2; Z is N or CR3; provided that when at least one of X or Z is N, Y cannot be N; R1 is C 1-5 Alkyl, C 0-2 Alkylene C 3-5 cycloalkyl (wherein the cycloalkyl is optionally substituted with CH3), or CF3; R2 is H, halo, C 1-2 Alkyl, OC 1-2 Alkyl, C 1-2 Haloalkyl or OC 1-2 is haloalkyl; R3 is H, halo, CH3, OCH3, CF3, or OCF3; wherein at least one of R2 and R3 is H; R4 and R5 each independently represent H, C 1-6 Alkyl, C 1-6 Alkyl OH, C 1-6 Haloalkyl, C0-2 Alkylene C 3-6 Cycloalkyl, C 0-2 Alkylene C 3-6 Heterocycloalkyl, C 1-3 Alkylene OC 1-3 alkyl, or R4 and R5 together with the carbon atom to which they are attached are C 3-6 Cycloalkyl or C 3-6 forming a heterocycloalkyl; and When A is -NHC(=O)-: R4 and R5 are halo, 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, C 1-2 alkyl, CF3, OCH3, 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 1-4Haloalkyl, hydroxy, C 1-4 Alkyl OH, SO2C 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 is a C-type aryl group containing CN, OCH2CH2N(CH3)2, and one nitrogen atom at the point of attachment to Ar2. 3-6 heterocycloalkyl, or R 12 together with the nitrogen atom to which it is attached form an N-oxide (N + -O - ) form; R 13 is H or halo; R 21 is H, C 1-5 Alkyl, C(O)C 1-5 Alkyl, C(O)OC 1-5 is alkyl; R 22 is H or CH3; R 23 is H or C 1-2 is alkyl; and R 24 is H or C 1-2 (It is alkyl).

[0056] 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)pyrazin-2-yl)pyridin-2-yl)propanamide; 2-(2-(cyclopropanesulfonamido)-6-methylpyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)-6-(trifluoromethyl)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-cyclopropylpyrazin-2-yl)pyridin-2-yl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(6-(6-ethoxypyrazin-2-yl)pyridin-3-yl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-cyclopropylpyrazin-2-yl)-2-fluorophenyl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)-6-methylpyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)-6-(trifluoromethyl)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-2-methyl-N-(4-(6-(prop-1-en-2-yl)pyrazin-2-yl)phenyl)propanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-isopropylpyrazin-2-yl)phenyl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-(dimethylamino)pyrazin-2-yl)phenyl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)-6-methylpyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)-6-(trifluoromethyl)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)-6-methoxypyrimidin-4-yl)-2-methyl-N-(4-(pyridin-3-yl)phenyl)propanamide; 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)cyclopentane-1-carboxamide; 4-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)tetrahydro-2H-pyran-4-carboxamide; N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(2-(methylsulfonamido)pyrimidin-4-yl)piperidine-4-carboxamide; tert-butyl 4-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-4-((5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)carbamoyl)piperidine-1-carboxylate; 4-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)piperidine-4-carboxamide; tert-butyl 3-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-3-((5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)carbamoyl)azetidine-1-carboxylate; tert-butyl 4-((5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)carbamoyl)-4-(2-(methylsulfonamido)pyrimidin-4-yl)piperidine-1-carboxylate; 4-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)tetrahydro-2H-pyran-4-carboxamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)-3-fluoropyridin-2-yl)-4-methoxybutanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-methoxybutanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)-4-methoxybutanamide; N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-methoxy-2-methyl-2-(2-(methylsulfonamido)pyrimidin-4-yl)butanamide; N-(5'-chloro-[3,3'-bipyridin]-6-yl)-2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)butanamide; N-(5'-chloro-[3,3'-bipyridin]-6-yl)-2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-2-fluorobutanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-cyclopropylpyrazin-2-yl)pyridin-2-yl)-2-fluorobutanamide; N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2-fluoro-2-(2-(methylsulfonamido)pyrimidin-4-yl)butanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)-3-methylpyridin-2-yl)butanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-cyclopropylpyrazin-2-yl)pyridin-2-yl)butanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-(2,2,2-trifluoroethoxy)pyrazin-2-yl)pyridin-2-yl)butanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(3-fluoro-5-(6-methoxypyrazin-2-yl)pyridin-2-yl)butanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-methoxypyrazin-2-yl)pyridin-2-yl)butanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-cyclopropylpyrazin-2-yl)-2-fluorophenyl)butanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-methylphenyl)butanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)-3-fluoropyridin-2-yl)butanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2-methylbutanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2-fluoro-3-methylbutanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)-3-methylbutanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-3-methylbutanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2-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 pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate thereof.

[0057] 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 to 148 of WO2019179652 or a pharmaceutically acceptable salt and / or solvate thereof, particularly compounds P1 to P225 or a pharmaceutically acceptable salt and / or solvate thereof.

[0058] 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 can be a compound described in any one of clauses 1-148 of WO2019180244 or a pharmaceutically acceptable salt and / or solvate thereof, particularly compounds P1-P225 or a pharmaceutically acceptable salt and / or solvate thereof. Of particular interest are compounds of PCT Publication No. WO2019180244 or a pharmaceutically acceptable salt and / or solvate thereof that are selective for CTPS1 over CTPS2 (e.g., human CTPS1 over human CTPS2), such as those identified in Table 19. Of particular interest are compounds having a selectivity of >60 fold as shown in Table 19 of WO2019180244, or a pharmaceutically acceptable salt and / or pharmaceutically acceptable solvate thereof.

[0059] More preferably, the CTPS1 inhibitor is a compound of formula (IV): or a pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate thereof [ka] (In the formula: (a) R4, R5, X, Y, and R1 are as follows: [ka] when W is N, CH, or CF; (b) R4, R5, X, W, and R1 are as follows: [ka] when Y is CH or N; (c) W, X, Y, and R1 are as follows: [ka] when R4 and R5 combine to form the following structure: [ka] Forming; (d) W, R4, R5, X, and Y are as follows: [ka] when R1 is methyl or cyclopropyl; and (e) the compound is [ka] :) selected from the group consisting of:

[0060] 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 pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate thereof.

[0061] 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 pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate thereof.

[0062] Of particular interest are compounds of PCT Publication No. WO2020083975, or pharmaceutically acceptable salts and / or pharmaceutically acceptable solvates thereof, that are selective for CTPS1 over CTPS2 (e.g., human CTPS1 over human CTPS2), such as those identified in Table 11. Of particular interest are compounds, or pharmaceutically acceptable salts and / or pharmaceutically acceptable solvates thereof, that have a selectivity of >60-fold as shown in Table 11 of WO2020083975.

[0063] Alternatively, the CTPS1 inhibitor is a compound of formula (V): or a pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate thereof [ka] ((a)A, V, W, X, Y, Z, R1, R 10 , and R 12 But as follows: [ka] When R4 and R5 together with the carbon atom to which they are attached are: [ka] Forming; or (b)A, V, W, X, Y, Z, R1, R 10 , and R 12 But as follows: [ka] When R4 and R5 together with the carbon atom to which they are attached are: [ka] Forming; or (c)A, V, W, X, Y, Z, R4, R5, R 10 , and R 12 But as follows: [ka] If so, then R1 is [ka] is; or (d)A, V, W, X, Y, Z, R4, R5, R 10 , and R 12 But as follows: [ka] If so, then R1 is [ka] is; or (e) A, X, Y, Z, R1, R4, and R5 are as follows: [ka] If V, W, R 10 , and R 12 teeth, [ka] is; or (f)A, V, W, R1, R4, R5, R 10 , and R 12 But as follows: [ka] then Z, X, and Y are [ka] is; or (g)A, V, W, R1, R4, R5, R 10 , and R 12 But as follows: [ka] then Z, X, and Y are [ka] is; or (h)A, V, W, R1, R4, R5, R 10 , and R 12 But as follows [ka] then Z, X, and Y are [ka] (It is).

[0064] 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 pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate thereof.

[0065] 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 pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate thereof.

[0066] Alternatively, the CTPS1 inhibitor is a compound of formula (VI): or a pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate thereof [ka] (Wherein, ring B is [ka] (where 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 is A aa or A ba and; where: A aa is an amine linker having the following structure: -NH-, -CHNH-, or -NHCH-; 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; provided 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 is H, halo, CH3, OCH3, CF3, or OCF3; where R 2a and R 3a at least one of is H; R 1a is R1aa 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 optionally substituted with CH3), or CF3; 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 atoms to which they are attached, C 3-6 Forms a cycloalkyl, which is: Each substituent is C 1-3 Alkyl, oxo, OH, C 1-3 Alkyl OH, 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: The 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 3-6a spiro center formed by a heterocycloalkyl ring, and wherein R 4aa and R 5aa C formed by 3-6 Cycloalkyl is a group in which each of the substituents, together with the carbon atom to which they are attached, is C 1-3 Alkyl or OC 1-3 and optionally substituted with one or two substituents independently selected from the group consisting of alkyl; or R 4aa and R 5aa together with the carbon atoms 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 formed by a heterocycloalkyl ring, and wherein 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 and optionally substituted with one or two substituents independently selected from the group consisting of alkyl; or R 4aa and R 5aa C, which contains one nitrogen atom along with the carbon atom to which they are attached 3-6 heterocycloalkyl, where the nitrogen atom is —S(O)R 29a is replaced by; or R 4ba and R 5ba are each independently H, C 1-6 Alkyl, C 1-6 Alkyl OH, C 1-6 Haloalkyl, C 0-2 Alkylene C 3-6 Cycloalkyl, C 0-2 Alkylene C 3-6 Heterocycloalkyl, C 1-3 Alkylene OC1-3 alkyl or R 4ba and R 5ba together with the carbon atoms to which they are attached, C 3-6 Cycloalkyl or C 3-6 forming a heterocycloalkyl; and A a When is -NHC(=O)- or -NHCH2-: 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, C 1-2 alkyl, CF3, OCH3, 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 1-4Alkyl OH, SO2C 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 When is -NHC(=O)-, -NH-, or -NHCH2-: R 12a is a C-type aryl group containing CN, OCH2CH2N(CH3)2, and one nitrogen atom at the point of attachment to Ar2a. 3-6 heterocycloalkyl, or R 12a together with the nitrogen atom to which it is attached form an N-oxide (N + -O - ) form; R 13a is H or halo; R 21a is 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 CH3; 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 optionally substituted with CH), CF, 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 R33 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 is 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 is A ab or A bb and; where: A ab is -NR 6b CH2- or -NR 6b - and; A bb is -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 optionally substituted with CH3), C 1-3 Alkylene OC1-2 alkyl, or CF3; R 3b H, halo, CH3, OC 1-2 alkyl, or CF3; 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 atoms to which they are attached, C 3-6 Forms a cycloalkyl, which is: Each substituent is C 1-3 Alkyl, oxo, OH, C 1-3 Alkyl OH, 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: The 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 formed by a heterocycloalkyl ring, and wherein R 4aband R 5ab C formed by 3-6 Cycloalkyl is a group in which each of the substituents, together with the carbon atom to which they are attached, is C 1-3 Alkyl or OC 1-3 and optionally substituted with one or two substituents independently selected from the group consisting of alkyl; or R 4ab and R 5ab together with the carbon atoms to which they are attached, C 3-6 Form a 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 formed by a heterocycloalkyl ring, and wherein 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 and optionally substituted with one or two substituents independently selected from the group consisting of alkyl; or R 4ab and R 5ab C, which contains one nitrogen atom along with the carbon atom to which they are attached 3-6 heterocycloalkyl, where the nitrogen atom is —S(O)R 29b is replaced by; or 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 1-6Alkyl OH, 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 form 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 atoms 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 that 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 is a C2 alkylene chain that forms a five-membered ring together with 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 attached 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; R11b is H, F, Cl, CH3, ethyl, OCH3, CF3, OCF3, or CN; or R 11b is the group A b When it is in the ortho position to R 6b is a C2 alkylene chain that forms a five-membered ring together with 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, OCH2CH2N(CH3)2, OH, C 1-4 Alkyl OH, 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 , SO2C 1-4 Alkyl, SOC 1-4 Alkyl, SC 1-4 Alkyl, SH, C(O)N(CH3)2, NHC(O)C 1-3 Alkyl, C containing one nitrogen atom at the point of attachment to Ar2b 3-6 heterocycloalkyl or R 12b together with the nitrogen atom to which it is attached form an N-oxide (N + -O - ) form; R 13b is H, halo, CH3, or OCH3; R 21b is 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 C4-6 is heterocycloalkyl; R 22b is H or CH3; 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 optionally substituted with CH), CF, N(C 1-3 alkyl), or 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) 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 is A ac or A bc and; where: A ac is -CH2NR 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 optionally substituted with CH3), C 1-3 Alkylene OC 1-2 alkyl, or CF3; R 3c H, CH3, Halo, OC 1-2 alkyl, or CF3; 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 atoms to which they are attached, C 3-6 Forms a cycloalkyl, which is: Each substituent is C 1-3 Alkyl, oxo, OH, C 1-3 Alkyl OH, 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 3-6Cycloalkyl, 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: The 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 formed by a heterocycloalkyl ring, and wherein R 4ac and R 5ac C formed by 3-6 Cycloalkyl is a group in which each of the substituents, together with the carbon atom to which they are attached, is C 1-3 Alkyl or OC 1-3 and optionally substituted with one or two substituents independently selected from the group consisting of alkyl; or R 4ac and R 5ac together with the carbon atoms to which they are attached, C 3-6 Form a 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 formed by a heterocycloalkyl ring, and wherein 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 and optionally substituted with one or two substituents independently selected from the group consisting of alkyl; or R 4ac and R 5ac C, which contains one nitrogen atom along with the carbon atom to which they are attached 3-6heterocycloalkyl, where the nitrogen atom is —S(O)R 29c is replaced by; or 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 Alkyl OH or C 1-6 is haloalkyl, or R 4bc and R 5bc together with the carbon atoms 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 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 is H, F, Cl, CH3, ethyl, OCH3, CF3, OCF3, 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 1-3Alkylene OC 1-3 Alkyl, C 1-4 Haloalkyl, OC 1-4 Haloalkyl, CN, OC 0-2 Alkylene C 3-5 Cycloalkyl, OCH2CH2N(CH3)2, OH, C 1-4 Alkyl OH, NR 23c R 24c , SO2CH3, C(O)N(CH3)2, NHC(O)C 1-3 C containing one nitrogen atom at the point of attachment to alkyl or Ar2c 3-6 heterocycloalkyl or R 12c together with the nitrogen atom to which it is attached form an N-oxide (N + -O - ) form; R 21c is 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 CH3; 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 optionally substituted with CH), CF, N(C 1-3 alkyl), or 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 is A ac (It is).

[0067] 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 pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate thereof.

[0068] 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 to 204 of WO2020245665 or pharmaceutically acceptable salts and / or pharmaceutically acceptable solvates thereof, particularly 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, P310, P311, P312, P313, P314, P315, P316, P317, P318, P319, P320, P321, P322, P323, P324, P325, P326, P327, P328, P329, P330, P331, P332, P333, P334, P335, P336, P337, P338, P340, P341, P342, P343, P344, P345, P346, P347, P348, P351, P354, P355, P356, P358, P359, , P292, P293, P294, P295, P296, P297, P298, P299, P300, P301, P302, P303, P304, P305, P306, P307, P308, P309, P310, P311, P312, P313, P314, P315, P316, P317, and P318, or a pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate thereof.

[0069] Alternatively, the CTPS1 inhibitor is a compound of formula (VII): or a pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate thereof [ka] (In the formula, A is A a or A b and; where: A a is an amine linker having the following structure: -NH-, -CHNH-, or -NHCH-; Ab 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 CR2; Z is N or CR3; provided that when at least one of X or Z is N, Y cannot be N; R1 is C 1-5 fluoroalkyl with the proviso that R1 is not CF3; R2 is H, halo, C 1-2 Alkyl, OC 1-2 Alkyl, C 1-2 Haloalkyl or OC 1-2 is haloalkyl; R3 is H, halo, CH3, OCH3, CF3, or OCF3; wherein at least one of R2 and R3 is H; R 3' H, halo, CH3, OC 1-2 alkyl, or CF3; and When A is -NHC(=O)-, R 3' together with R5 form a 5- or 6-membered cycloalkyl or a 5- or 6-membered oxygen-containing heterocycloalkyl; R4 and R5 are R 4a and R 5a or R 4b and R 5b and; where: R 4a and R 5a together with the carbon atoms to which they are attached, C 3-6 Forms a cycloalkyl, which is: Each substituent is C 1-3 Alkyl, oxo, OH, C 1-3 Alkyl OH, C 1-3 Haloalkyl, C 0-2Alkylene 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: The 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 formed by a heterocycloalkyl ring, and wherein R 4a and R 5a C formed by 3-6 Cycloalkyl is a group in which each of the substituents, together with the carbon atom to which they are attached, is C 1-3 Alkyl or OC 1-3 and optionally substituted with one or two substituents independently selected from the group consisting of alkyl; or R 4a and R 5a together with the carbon atoms 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 formed by a heterocycloalkyl ring, and wherein 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 1-3Alkyl or OC 1-3 and optionally substituted with one or two substituents independently selected from the group consisting of alkyl; or R 4a and R 5a C, which contains one nitrogen atom along with the carbon atom to which they are attached 3-6 heterocycloalkyl, where the nitrogen atom is —S(O)R 29 is replaced by; or R 4b and R 5b are each independently H, C 1-6 Alkyl, C 1-6 Alkyl OH, 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 atoms to which they are attached, C 3-6 Cycloalkyl or C 3-6 forming a heterocycloalkyl; and When A is -NHC(=O)- or -NHCH2-: 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, OC1-2 Alkyl, OC 1-2 haloalkyl, or CN; R 11 are H, F, Cl, C 1-2 alkyl, CF3, OCH3, 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, SO2C 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)-, -NH-, or -NHCH2-: R 12 is a C-type aryl group containing CN, OCH2CH2N(CH3)2, and one nitrogen atom at the point of attachment to Ar2. 3-6 heterocycloalkyl, or R 12 together with the nitrogen atom to which it is attached form an N-oxide (N + -O - ) form; R 13 is H or halo; R 21 is H, C 1-5 Alkyl, C(O)C 1-5 Alkyl, C(O)OC 1-5 is alkyl; R 22 is H or CH3; R 23 is H or C 1-2 is alkyl; and R24 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 optionally substituted with CH3), or CF3; 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).

[0070] 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 pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate thereof.

[0071] 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 can be a compound described in any one of clauses 1 to 191 of WO2021053403 or a pharmaceutically acceptable salt and / or solvate thereof, particularly a compound selected from P271 and P284 or a pharmaceutically acceptable salt and / or solvate thereof.

[0072] Alternatively, the CTPS1 inhibitor is a compound of formula (VIII): or a pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate thereof: [ka] (In the formula, A is A a or A b and; where: A a is an amine linker having the following structure: -NH-, -CHNH-, or -NHCH-; 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 CR2; Z is N or CR3; provided that when at least one of X or Z is N, Y cannot be N; R1 is C 1-5 Alkyl or C 0-2 Alkylene C 3-5 cycloalkyl, wherein the alkyl or (alkylene)cycloalkyl is substituted by CN; R2 is H, halo, C 1-2 Alkyl, OC 1-2 Alkyl, C 1-2 Haloalkyl or OC 1-2 is haloalkyl; R3 is H, halo, CH3, OCH3, CF3, or OCF3; wherein at least one of R2 and R3 is H; R 3' H, halo, CH3, OC 1-2 alkyl, or CF3; and When A is -NHC(=O)-, R3' together with R5 form a 5- or 6-membered cycloalkyl or a 5- or 6-membered oxygen-containing heterocycloalkyl; R4 and R5 are R 4a and R 5a or R 4b and R 5b and; where: R 4a and R 5a together with the carbon atoms to which they are attached, C 3-6 Forms a cycloalkyl, which is: Each substituent is C 1-3 Alkyl, oxo, OH, C 1-3 Alkyl OH, 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: The 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 formed by a heterocycloalkyl ring, and wherein R 4a and R 5a C formed by 3-6 Cycloalkyl is a group in which each of the substituents, together with the carbon atom to which they are attached, is C 1-3 Alkyl or OC 1-3and optionally substituted with one or two substituents independently selected from the group consisting of alkyl; or R 4a and R 5a together with the carbon atoms 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 formed by a heterocycloalkyl ring, and wherein 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 and optionally substituted with one or two substituents independently selected from the group consisting of alkyl; or R 4a and R 5a C, which contains one nitrogen atom along with the carbon atom to which they are attached 3-6 heterocycloalkyl, where the nitrogen atom is —S(O)R 29 is replaced by; or R 4b and R 5b are each independently H, C 1-6 Alkyl, C 1-6 Alkyl OH, 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 atoms to which they are attached, C 3-6 Cycloalkyl or C 3-6 forming a heterocycloalkyl; and When A is -NHC(=O)- or -NHCH2-: 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, C 1-2 alkyl, CF3, OCH3, 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, SO2C 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)-, -NH-, or -NHCH2-: R 12 is a C-type aryl group containing CN, OCH2CH2N(CH3)2, and one nitrogen atom at the point of attachment to Ar2. 3-6 heterocycloalkyl, or R 12 together with the nitrogen atom to which it is attached form an N-oxide (N + -O - ) form; R 13 is H or halo; R 21 is H, C 1-5 Alkyl, C(O)C 1-5 Alkyl, C(O)OC 1-5 is alkyl; R 22 is H or CH3; 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 optionally substituted with CH3), or CF3; 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).

[0073] 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 pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate thereof.

[0074] 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 to 191 of WO2021053402 or a pharmaceutically acceptable salt and / or solvate thereof, particularly a compound selected from P285 and P287 or a pharmaceutically acceptable salt and / or solvate thereof.

[0075] The CTPS1 inhibitor is 4-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)tetrahydro-2H-pyran-4-carboxamide (referred to herein as "CTPS-IA"): [ka] or a pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate thereof. CTPS-IA is a potent and selective inhibitor of CTPS1 (see, for example, WO2020083975).

[0076] 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 (referred to herein as "CTPS-IB"): [ka] or a pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate thereof. CTPS-IB is a potent and selective inhibitor of CTPS1 (see, for example, WO2020245664).

[0077] 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.

[0078] Alternatively, the CTPS1 inhibitor may be a compound of formula (IX): or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable salt and / or a pharmaceutically 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 of; 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 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 7- to 11-membered fused bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L is [ka] and; where R L, R L' , and R L'' each independently represents 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; or 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 atoms to which they are each 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 form a 7- to 10-membered saturated or partially unsaturated fused bicyclic ring; Ring B 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 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 11-membered saturated or partially unsaturated fused, bridged, or spiro bicyclic carbocyclic ring; a 7- to 11-membered fused bicyclic aryl ring; a 7- to 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- to 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- to 11-membered saturated or partially unsaturated fused, bridged, or spiro bicyclic carbocyclic ring; a 7- to 11-membered fused bicyclic aryl ring; a 7- to 11-membered saturated or partially unsaturated fused, bridged, or spiro bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7- to 11-membered fused bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R A , R B , and R C Each example is independently oxo, halogen, —CN, —NO, —OR, —SR, —NR, —S(O)R, —S(O)NR, —S(O)R, —S(O)NR, —C(O)R, —C(O)OR, —C(O)NR, —C(O)N(R)OR, —OC(O)R, —OC(O)NR, —N(R)C(O)OR, —N(R) -C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, -N=S(O)R2, -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, -P(O)(R)NR2, -P(O)(R)OR, or -P(O)R2; or R C Each instance of 1-6Aliphatic; 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 a group selected from each R C together with the atom to which it is attached to form an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5- to 7-membered heteroaryl ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 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; R D Each example is independently oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N( -R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, -N=S(O)R2, -S(NR(O)R, -N(R)S(O)R, -N(R)CN, -P(O)(R)NR2, -P(O)(R)OR, or -P(O)R2; 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: an 1 to 12-membered saturated or partially unsaturated bicyclic heterocyclic ring; 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 carbocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; two R groups, taken together with the atoms 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] wherein the R group is hydrogen or para-methoxybenzyl; L, [ka] and R L and R L' Or R L and R L'' groups together with the atom 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 to 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 bonded 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] (meaning a bond to a moiety).

[0079] 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 to 31 of WO2022087634, or a pharmaceutically acceptable salt and / or solvate thereof. The CTPS1 inhibitor may be a compound selected from compounds I-1 to I-286 of WO2022087634, or a pharmaceutically acceptable salt and / or solvate thereof. The CTPS1 inhibitor may be a compound selected from compounds Z-1 to Z-10 of WO2022087634, or a pharmaceutically acceptable salt and / or solvate thereof.

[0080] Depending on the properties 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).

[0081] Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art. Pharmaceutically acceptable salts include those described in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, 1985, p. 1418. Such pharmaceutically acceptable salts include acid addition salts formed with inorganic acids, 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 or potassium salts, and organic bases, such as basic amines, for example, ammonia, meglumine, tromethamine, piperazine, arginine, choline, diethylamine, benzathine, or lysine.

[0082] 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.

[0083] CTPS1 inhibitors may be prepared in crystalline or non-crystalline form, and, if crystalline, may optionally be 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).

[0084] Unless otherwise defined as part of a formula or compound structure, CTPS1 inhibitors encompass all isomers of the 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. 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 syntheses.

[0085] CTPS1 inhibitors encompass all isotopic forms of the CTPS1 inhibitors provided herein, whether they are (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 (referred to herein as "natural isotopic forms"), or (ii) in a form in which one or more atoms are replaced by atoms of the same atomic number, but with a mass number different from that of the atoms that predominate in nature (referred to herein as "unnatural variant isotopic forms"). It is understood that atoms may naturally exist as a mixture of mass numbers. The term "unnatural 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 (referred to herein as "uncommon isotopes") is increased compared to that occurring in nature, for example, by >20%, >50%, >75%, >90%, >95%, or >99% of the number of atoms of that atomic number (the latter embodiment is referred to as an "isotopically enriched variant form"). The term "non-natural variant isotopic form" also includes embodiments in which the proportion of an uncommon isotope is reduced compared to that found in nature. Isotopic forms can also include radioactive forms (i.e., those incorporating a radioactive isotope) and non-radioactive forms. Radioactive forms are typically isotopically enriched variant forms.

[0086] Non-natural variant isotopic forms containing radioactive isotopes can be used, for example, in drug and / or substrate tissue distribution studies.

[0087] In one embodiment, the CTPS1 inhibitor is provided in natural isotopic form.

[0088] In one embodiment, the CTPS1 inhibitor is provided in a non-natural variant isotopic form.

[0089] 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.

[0090] Therapeutic Uses and Applications The present invention may be useful in treating cancers that are deficient in CTPS2. As used herein, "CTPS2 deficient" refers to a substantial lack of CTPS2 function, particularly a complete loss of CTPS2 function. The lack of CTPS2 function may be due to genomic and / or epigenetic alterations.

[0091] Loss of CTPS2 function can be caused by genomic alteration(s), such as: (i) complete loss of the CTPS2 gene due to genomic deletion; (ii) partial loss of the CTPS2 gene due to genomic deletion; (iii) a disruption of the CTPS2 gene by a structural DNA mutation, such as an inversion, duplication, or translocation, within the footprint of the gene; or (iv) a mutation in the CTPS2 gene such that CTPS2 expression is substantially reduced or, most preferably, completely abolished. This can be attributed to:

[0092] The loss of CTPS2 function can be due to epigenetic alterations(s), e.g., alterations in the expression of the CTPS2 gene, e.g., due to alterations in regulatory elements, e.g., due to changes in methylation and / or histone modifications, such that CTPS2 expression is substantially reduced or, most preferably, completely lost.

[0093] Preferably, the loss of CTPS2 function can result from a complete loss of the CTPS2 gene due to a genomic deletion (a homozygous deletion occurring in females or a hemizygous deletion occurring in males).

[0094] The presence of CTPS2 deficiency is usually determined by analyzing a sample from a subject. It will be understood that the sample used herein is a sample appropriate for the intended analysis method, i.e., a sample that allows the determination of CTPS2 deficiency or otherwise. For example, the sample may be a biopsy containing cancer cells (e.g., a tumor biopsy), a sample containing circulating cancer cells, or a sample containing cell-free cancer DNA. The sample may be obtained or provided by any suitable method known in the art.

[0095] Methods for determining CTPS2 deficiency include: (i) a method of detecting DNA alterations, comprising analysis of tumor-derived DNA obtained from tumor tissue, circulating tumor cells, cell-free DNA, or cell-free exosomes, using a suitable technique for detecting genomic alterations that are likely to result in a substantial loss of CTPS2 function, particularly a complete loss of CTPS2 function, including whole genome sequencing, whole exome sequencing, targeted gene sequencing using capture-based enrichment, targeted gene sequencing using PCR-based enrichment, real-time quantitative PCR, digital droplet PCR, in situ hybridization, or fluorescent in situ hybridization; (ii) a method for detecting RNA alterations, comprising analysis of a suitable sample of RNA obtained, e.g., from tumor tissue, circulating tumor cells, or cell-free exosomes, using a suitable technique for detection of CTPS2 RNA, e.g., RNA sequencing, gene expression arrays, real-time quantitative PCR, digital droplet PCR, or in situ hybridization; (iii) a method of detecting epigenetic changes, comprising: (a) analysis of tumor-derived DNA obtained from tumor tissue, circulating tumor cells, or cell-free DNA using a suitable technique for detecting epigenetic changes likely to result in loss of CTPS2 expression, including DNA methylation analysis or histone modification characterization, or (b) analysis of a suitable sample of RNA obtained from tumor tissue, circulating tumor cells, or cell-free exosomes and analyzed by, for example, RNA sequencing, gene expression array, real-time quantitative PCR, digital droplet PCR, or in situ hybridization; and / or (iv) methods for detecting protein alterations, including analysis of tumor tissue or circulating tumor cells using suitable techniques for detecting CTPS2 protein, such as immunohistochemistry, flow cytometry, or mass cytometry; : are listed.

[0096] It will be appreciated that multiple analytical techniques may be applied in combination.

[0097] Preferably, the step of identifying a subject as having a cancer that is deficient in CTPS2 includes (i) applying a suitable method for determining CTPS2 deficiency, e.g., a technique for detecting associated alterations in DNA, RNA, or protein, (ii) analyzing the data generated by the method, and (iii) interpreting the data generated by the method to determine the likelihood of a substantial loss of CTPS2 function, particularly a complete loss of CTPS2 function.

[0098] For cancers that have genomic alterations that are likely to result in a substantial loss of CTPS2 function, particularly a complete loss of CTPS2 function, detection can be performed using suitable DNA samples obtained from tissue biopsies, circulating tumor cells, or cell-free DNA. Suitable techniques for detecting genomic alterations that are likely to result in a substantial loss of CTPS2 function include whole genome sequencing, whole exome sequencing, targeted gene sequencing using capture-based enrichment, targeted gene sequencing using PCR-based enrichment, real-time quantitative PCR, digital droplet PCR, in situ hybridization, or fluorescent in situ hybridization. Furthermore, genomic alterations that are likely to result in a substantial loss of CTPS2 function can be detected from suitable RNA samples obtained from tissue biopsies, circulating tumor cells, or cell-free exosomes, and analyzed by RNA sequencing, gene expression array, real-time quantitative PCR, digital droplet PCR, or in situ hybridization. Furthermore, genomic alterations likely to result in substantial loss of CTPS2 function can be detected in suitable tumor cell samples obtained from tissue biopsies or circulating tumor cells and analyzed by immunohistochemistry, flow cytometry, or mass cytometry.

[0099] For cancers harboring epigenetic alterations likely to result in a substantial loss of CTPS2, detection requires a suitable DNA sample obtained from a tissue biopsy, circulating tumor cells, or cell-free DNA. Suitable techniques for detecting epigenetic alterations likely to result in a substantial loss of CTPS2 include DNA methylation analysis or histone modification characterization. Furthermore, epigenetic alterations likely to result in a substantial loss of CTPS2 function can be detected from a suitable RNA sample obtained from a tissue biopsy, circulating tumor cells, or cell-free exosomes and analyzed by RNA sequencing, gene expression array, real-time quantitative PCR, digital droplet PCR, or in situ hybridization. Furthermore, epigenetic alterations likely to result in a substantial loss of CTPS2 function can be detected from a suitable tumor cell sample obtained from a tissue biopsy or circulating tumor cells and analyzed by immunohistochemistry, flow cytometry, or mass cytometry.

[0100] (CTPS1 treatment sensitivity) The present invention can be used to determine whether a cancer cell or cancer may be sensitive to treatment with a CTPS1 inhibitor. In this context, a "sensitive" cancer or cancer cell is one that has been identified as having a high probability of benefiting from treatment according to the present invention (e.g., exhibiting higher in vivo efficacy, lower doses required for in vivo efficacy, and / or an improved safety profile / reduced side effects) compared to a cancer or cancer cell that is not known to be sensitive to treatment with a CTPS1 inhibitor.

[0101] Susceptible cancers or cancer cells may be considered to be deficient in CTPS2 (i.e., likely to be deficient in CTPS2), and preferably susceptible cancers or cancer cells are deficient in CTPS2.

[0102] Cancers or cancer cells that are identified as having a high probability of being CTPS2 deficient or identified as being likely to be CTPS2 deficient may, for example, (i) be identified as a type of cancer or cancer cell in which CTPS2 deficiency is more prevalent than in cancers overall, or (ii) be identified as being CTPS2 deficient, or (iii) be identified using methods that may be inconclusive as being more likely to be CTPS2 deficient than others.

[0103] Susceptible cancers or cancer cells can be identified by analyzing DNA and detecting genomic alterations in CTPS2 that are likely to result in substantial loss of CTPS2 activity.

[0104] Cancers or cancer cells can be considered to have genomic alterations in CTPS2 that likely result in a substantial loss of CTPS2 activity, making them susceptible to treatment with CTPS1 inhibitors.

[0105] Susceptible cancers or cancer cells can be identified by analyzing RNA and detecting a decrease in CTPS2 expression, which likely results in a substantial loss of CTPS2 activity.

[0106] Susceptible cancers or cancer cells can be identified by protein analysis and detection of decreased expression of CTPS2, which likely results in a substantial loss of CTPS2 activity.

[0107] Cancers or cancer cells can be considered to have reduced expression of CTPS2, which likely results in a substantial loss of CTPS2 activity, making them susceptible to treatment with CTPS1 inhibitors.

[0108] Susceptible cancers or cancer cells can be identified by analyzing epigenetic patterns and detecting changes in DNA methylation or histone modifications that are likely to result in substantial loss of CTPS2 activity.

[0109] Cancers or cancer cells can be considered to have alterations in DNA methylation or histone modifications that result in a substantial loss of CTPS2 activity and likely make them sensitive to treatment with CTPS1 inhibitors.

[0110] Sensitive cancers or cancer cells can be identified by culturing cancer cells (e.g., human cancer cells) in the presence of a selective CTPS1 inhibitor, where the growth pattern of the cancer cells indicates sensitivity to CTPS1 inhibition. Sensitivity to CTPS1 inhibition can be due to substantial loss of CTPS2 activity. Sensitivity is preferably at least 2-fold, e.g., at least 30-fold, particularly at least 60-fold, and particularly at least 1000-fold, more particularly to human CTPS1 than to human CTPS2.

[0111] The cancer or cancer cells may have a cancer cell growth pattern that suggests sensitivity to CTPS1 inhibition, which may be due to a substantial loss of CTPS2 activity.

[0112] It is contemplated that the CTPS1 inhibitor may be for administration to a subject identified as having a cancer believed to be sensitive to treatment with a CTPS1 inhibitor (e.g., the cancer is deficient in CTPS2). The CTPS1 inhibitor may be for administration to a subject in which a sample of cancer cells has been shown to be sensitive to treatment with a CTPS1 inhibitor (e.g., the cancer is deficient in CTPS2).

[0113] Preferably, the cancer is selected from the group consisting of ovarian cancer, esophageal cancer, bladder cancer, non-small cell lung cancer, gastric cancer, sarcoma, head and neck cancer, pancreatic adenocarcinoma, pancreatic neuroendocrine tumors, biliary tract cancer, melanoma, endometrial cancer, hepatocellular carcinoma, cervical cancer, bone cancer, central nervous system cancer, breast cancer, prostate cancer, colorectal cancer, and kidney cancer. Preferably, the cancer is one for which no other suitable treatment is available.

[0114] Preferably, the cancer is selected from the group consisting of ovarian cancer, esophageal cancer, bladder cancer, non-small cell lung cancer, and gastric cancer.

[0115] Suitably, the cancer is ovarian cancer, for example serous ovarian cancer.

[0116] The cancer can be lung cancer, for example, non-small cell lung cancer.

[0117] The cancer can be gastroesophageal cancer. The cancer can be esophageal cancer. Alternatively, the cancer can be gastric cancer.

[0118] The cancer may be head and neck cancer.

[0119] The cancer may be bladder cancer.

[0120] The cancer may be a sarcoma.

[0121] In one embodiment, the cancer is a blood cancer. In one embodiment, the cancer is a non-blood cancer. Preferably, the cancer is not a T-cell leukemia, such as T-cell acute lymphoblastic leukemia.

[0122] Preferably, the cancer or cancer cells are from a cancer type that is at least 10% CTPS2 deficient, for example, at least 15% CTPS2 deficient, especially at least 18% CTPS2 deficient. The loss of CTPS2 function can be due to a homozygous deletion occurring in females or a hemizygous deletion occurring in males.

[0123] Preferably, the cancer or cancer cells are from a cancer type that is at least 10% CTPS2 deficient, e.g., at least 15% CTPS2 deficient, particularly at least 20% CTPS2 deficient, and especially at least 40% CTPS2 deficient. Loss of CTPS2 function can be determined by immunohistochemistry, e.g., lack of CTPS2 staining.

[0124] (Administration) The present invention is generally intended for use with mammalian subjects, particularly human subjects. CTPS1 inhibitors are generally administered to a subject in need thereof, particularly a mammalian subject in need thereof, and particularly a human subject in need thereof. The human subject may be an adult, for example, between 18 and 65 years of age. Alternatively, the human subject may be 66 years of age or older. Alternatively, the human subject may be under 18 years of age, for example, between 4 and 17 years of age. The human subject may be male. Alternatively, the human subject may be female.

[0125] The CTPS2 gene is located on the human X chromosome and is not imprinted in human females; therefore, the level of CTPS2 expression is thought to be higher in human female subjects (i.e., those with XX chromosomes) compared to human male subjects (i.e., those with XY chromosomes) because CTPS2 is expressed from each of the X chromosomes in human female subjects. In human female subjects, CTPS2 deficiency can be due to genomic and / or epigenetic alterations in one or both XX chromosomes, preferably both XX chromosomes.

[0126] Preferably, when the human subject is male, the loss of CTPS2 function can be due to (i) complete loss of the CTPS2 gene due to genomic deletion; (ii) partial loss of the CTPS2 gene due to genomic deletion; (iii) disruption of the CTPS2 gene due to a structural DNA mutation, such as an inversion, duplication, or translocation, within the footprint of the gene; (iv) a mutation in the CTPS2 gene, such that CTPS2 expression is substantially reduced or completely lost; or (v) a change in expression of the CTPS2 gene due to a change in regulatory elements, for example, due to changes in methylation and / or histone modification, such that CTPS2 expression is substantially reduced or completely lost, in particular, complete loss of the CTPS2 gene due to genomic deletion. In particular, when the human subject is male, the loss of CTPS2 function can be due to complete loss of the CTPS2 gene due to genomic deletion.

[0127] Suitably, if the human subject is female (i.e., one having two X chromosomes), the loss of CTPS2 function can be due to complete loss of the CTPS2 gene on the first X chromosome due to a genomic deletion, and (i) complete loss of the CTPS2 gene on the second X chromosome due to a genomic deletion; (ii) partial loss of the CTPS2 gene on the second X chromosome due to a genomic deletion; (iii) disruption of the CTPS2 gene on the second X chromosome due to a structural DNA mutation, such as an inversion, duplication, or translocation, within the footprint of the gene; (iv) a mutation in the second X chromosome CTPS2 gene, resulting in a substantial reduction or complete loss of CTPS2 expression; or (v) altered expression of the CTPS2 gene on the second X chromosome due to an alteration in a regulatory element, e.g., due to changes in methylation and / or histone modifications, resulting in a substantial reduction or complete loss of CTPS2 expression.

[0128] Preferably, when the human subject is female, the loss of CTPS2 function can result from a complete loss of the CTPS2 gene on the first X chromosome due to a genomic deletion and a complete loss of the CTPS2 gene on the second X chromosome due to a genomic deletion.

[0129] (Administration of CTPS1 inhibitor) The CTPS1 inhibitor can be administered by any suitable route, which can depend on the properties of the specific drug.Exemplary routes include oral, parenteral, buccal, sublingual, nasal, or rectal administration.Advantageously, the CTPS1 inhibitor is administered orally.

[0130] The CTPS1 inhibitor may be provided in the form of a pharmaceutical composition comprising the CTPS1 inhibitor and a pharmaceutically acceptable carrier or excipient.

[0131] 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).

[0132] 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 suspending agents, preservatives, flavoring agents, and / or coloring agents.

[0133] 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.

[0134] 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.

[0135] The pharmaceutical composition may contain, for example, 0.1% to 99.99% by weight, e.g., 10 to 60% by weight, of the active ingredient, depending on the method of administration. The pharmaceutical composition may contain 0.01% to 99% by weight, e.g., 40% to 90% by weight, of the carrier, depending on the method of administration. The pharmaceutical composition may contain 0.05 mg to 2000 mg, e.g., 1.0 mg to 500 mg, of the active ingredient, depending on the method of administration. The pharmaceutical composition may contain 50 mg to 1000 mg, e.g., 100 mg to 400 mg, of the carrier, depending on the method of administration.

[0136] The dosage of the compound used will vary in the usual way depending on the severity of the cancer, the patient's weight, 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 be extended for several weeks, several months, or longer. Multiple unit doses, for example, multiple tablets, may be taken together.

[0137] Suitably, the CTPS1 inhibitor is administered orally, for example in a solid pharmaceutical composition.

[0138] The dose provided to a subject is usually a safe and effective dose, i.e., an amount that provides an acceptable balance between desired benefits 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 treating a disease state. The desired effect is usually clinically significant 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 alleviation 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.

[0139] 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 the safe and effective amount through a single dose or, for example, by multiple doses administered by the specified 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 the safe and effective amount is achieved by oral administration.

[0140] Administration of the CTPS1 inhibitor may typically be once or twice daily. Administration may be continuous, e.g., at least daily for multiple weeks, or discontinuous, e.g., at least daily for one week, followed by a week without administration, and then at least daily for another week.

[0141] (Combination with additional drugs) Treatment with CTPS1 inhibitors includes antimitotic agents such as vinblastine, paclitaxel, and docetaxel; alkylating agents and DNA cross-linking 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; mTOR inhibitors such as everolimus and temsirolimus; proteasome inhibitors such as bortezomib; histone deacetylase inhibitors such as panobinostat or vorinostat; hedgehog pathway blockers such as vismodegib; It may be combined with one or more further pharmaceutically acceptable active ingredients which may be selected from: IAP inhibitors, e.g., LCL161; VEGF inhibitors, e.g., bevacizumab; or pan-kinase inhibitors, e.g., sorafenib and sonitinib.

[0142] The CTPS1 inhibitor and the additional pharmaceutically acceptable active ingredient can be administered individually, sequentially, or simultaneously in any combination. The CTPS1 inhibitor and the additional pharmaceutically acceptable active ingredient can be, for example, (a) formulated separately from the additional pharmaceutically acceptable active ingredient, or (b) formulated together with the additional pharmaceutically acceptable active ingredient.

[0143] The further pharmaceutically 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.

[0144] Additional pharmaceutically 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.

[0145] The CTPS1 inhibitor may also be administered in combination with radiation therapy, surgery, hyperthermia, and / or cryotherapy.

[0146] In some embodiments, the subject underwent chemotherapy, radiation therapy, surgery, hyperthermia, and / or cryotherapy prior to administration of CTPS1.

[0147] In some embodiments, the subject received chemotherapy, radiation therapy, surgery, hyperthermia, and / or cryotherapy concurrently with CTPS1 administration.

[0148] In some embodiments, the subject subsequently underwent chemotherapy, radiation therapy, surgery, hyperthermia, and / or cryotherapy after administration of CTPS1.

[0149] The present invention is further illustrated by the following non-limiting examples. [Example]

[0150] (Example) Example 1: Human CTPS1 enzyme inhibition The enzyme inhibitory activity of compounds against CTPS1 can be determined using the ADP-Glo™ Max assay (Promega, UK).

[0151] Assays for human CTPS1 were performed in 1x assay buffer containing 50 mM Tris, 10 mM MgCl2, 0.01% Tween-20, pH adjusted appropriately to 8.0. Finally, L-cysteine ​​was added to the 1x assay buffer to a final concentration of 2 mM immediately before use. All reagents were from Sigma-Aldrich unless otherwise specified. Active human full-length C-terminal FLAG-His8-tagged CTPS1 [ka] was obtained from Proteros biostructures GmbH.

[0152] Assay Procedure 3x human CTPS1 protein was prepared in 1x assay buffer to the final working protein concentration required for the reaction. A 2uL volume of 3x human CTPS1 protein per well was mixed with 2uL of 3x test compound per well (prepared in 1x assay buffer to the final 3x compound appropriate for the concentration-response curve designed for the compound under test) at 25°C for 10 minutes. The enzymatic reaction was then initiated by the addition of 2uL per well 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). The mixture was incubated at 25°C under sealed plate conditions with constant agitation 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 minutes, followed by ADP-Glo™ Max developing reagent (12 μL per well) for 60 minutes, 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.

[0153] In all cases, the enzyme converts ATP to ADP, and then the ADP-Glo™ Max Reagent 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, generating light that results 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 below:

number

[0154] The percentage of inhibition was then plotted against the compound concentration, and the 50% inhibitory concentration (IC 50 ) was decided.

[0155] Example 2: RapidFire / MS-based CTPS1 enzyme selectivity assay (Evaluation of human CTPS1 vs. CTPS2 selectivity by RapidFire / MS analysis) The 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 an assay buffer containing 50 mM HEPES (Merck), 20 mM MgCl, 5 mM KCl, 1 mM DTT, and 0.01% Tween-20, pH 8.0 as appropriate. Active human full-length C-terminal FLAG-His-tagged CTPS1 [ka] was obtained from Proteros biostructures GmbH. Active human full-length C-terminally FLAG-His-Avi tagged CTPS2 [ka] was obtained from Harker Bio.

[0156] Assay Procedure Human CTPS (1 or 2) protein was prepared in 1x assay buffer to the final working protein concentration required for the reaction. 2 µL of 2x CTPS (1 or 2) protein per well was mixed with 40 nL 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 2 µL of 2x substrate mix per well in assay buffer. For hCTPS1: ATP (0.3 mM), UTP (0.2 mM), GTP (0.07 mM), and L-glutamine (0.1 mM). For hCTPS2: ATP (0.1 mM), UTP (0.04 mM), GTP (0.03 mM), and L-glutamine (0.1 mM). Each mixture 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 (0.5 uM in HO 13 C9- 15 N3-CTP in 1% formic acid was added, and the plate was immediately heat-sealed and centrifuged at 4,000 rpm for 10 minutes. 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.

[0157] In all cases, the enzyme converts UTP to CTP. A highly specific and sensitive multiple reaction monitoring (MRM) MS method analyzes the enzyme reaction product, CTP, and stable isotope-labeled product standards. 13 C9- 15 The data analysis readout can be optimized for the detection of product CTP and internal standard N3-CTP. 13 C9- 15 The ratio between the peak areas of N3-CTP and N3-CTP was calculated. For data reporting, the following equation was used:

number

[0158] For each screening plate, the mean of the negative control (DMSO) and positive control values ​​was used to calculate the respective assay window (S / B) and Z' value. The median of each control value was used to calculate the percent inhibition according to the following equation:

number

[0159] The percentage of inhibition was then plotted against the compound concentration, and the 50% inhibitory concentration (IC 50 ) was decided.

[0160] The fold selectivity between CTPS1 and CTPS2 was then calculated according to the following equation:

number

[0161] Example 3: Cells require CTPS enzyme activity to proliferate To demonstrate the essential role of CTP synthase activity and to assess the differential activities of the CTPS1 and CTPS2 isoforms, an in vitro cell proliferation assay was used.

[0162] Cells engineered to not express either CTPS isoform (i.e., lacking CTPS1 and CTPS2) undergo rapid cell death by apoptosis (Martin 2014, Martin 2020, Minet 2022).

[0163] Human embryonic kidney (HEK) cells lacking either CTPS1 or CTPS2 were generated using CRISPR technology, and the lack of expression of the associated proteins was confirmed by Western blot (Minet, 2022). Cells were cultured at 37°C and 5% CO2; viable cells were counted using CellTiter-Glo 2.0 reagent (Promega). HEK cells expressing only CTPS2 proliferated at a slower rate than HEK cells expressing only CTPS1, suggesting greater enzymatic activity of the CTPS1 isoform (Minet, 2022). This is consistent with a recent study also showing that the CTPS1 isoform has higher enzymatic activity than CTPS2 (Lynch, 2021).

[0164] Taken together, these findings indicate that CTP synthase activity is a requirement for cell viability and that the CTPS1 isoform has higher enzymatic activity than CTPS2.

[0165] Example 4: Involvement of CTPS1 in cancer cell proliferation The pathways involved in providing 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 various tumor types, both hematopoietic and non-hematopoietic, although heterogeneity is observed between patients. High enzyme levels have also been associated with resistance to chemotherapeutic agents.

[0166] In an analysis of published data, we found that CTPS1 is essential for the proliferation of human cancer cells derived from a wide range of hematological and solid tumor types, whereas CTPS2 was consistently 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 effects of each gene deletion were assessed using in vitro proliferation assays (Behan, 2019). We then expanded this dataset to include data from 1,032 human cancer cell lines (Cancer Dependency Map: p.org / ). We assessed the effects of deleting different genes in the pyrimidine synthesis pathway (see Figure 2). Deletion of CTPS2 did not affect cancer cell proliferation. Deletion of genes in the salvage pathway (CDA, UCK1, UCK2, or CMPK2) had minimal effects on cell proliferation. Deletion of CMPK1 had a significant 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, possibly through enhanced enzymatic activity, whereas CTPS2 is dispensable.

[0167] Example 5: CTPS2 is lost in a subset of cancers The studies outlined above demonstrate the essential role of CTP synthase activity, and its absence leads to apoptotic cell death. Studies have also shown that many cancer cells depend on the activity of CTPS1, the more active of the two CTPS isoforms. Cancer cells that are less sensitive to the loss or inhibition of CTPS1 may be able to utilize the activity of CTPS2 for survival and proliferation. Consistent with this idea, CTPS2 expression can be increased under certain physiological conditions (Martin, 2014), raising the further possibility that increased CTPS2 expression is associated with the development of resistance to treatment with CTPS1 inhibitors. Therefore, cancer cells lacking CTPS2 expression due to genetic deletion of the CTPS2 gene may be highly sensitive to CTPS1 inhibition. Therefore, the studies outlined above also suggest that genetic deletion of CTPS2 is not, in itself, detrimental to cancer cells, since CTPS1 enzymatic activity remains available.

[0168] Loss of genetic material through genomic deletions is a common phenomenon in cancer, potentially conferring a selective advantage through the loss of tumor suppressor genes. It is also recognized that such deletions can result in bystander gene loss that does not confer a selective advantage to cancer cells; however, this collateral damage may expose the therapeutic vulnerability of cancer cells (Achreja 2022).

[0169] In an analysis of published data (ICGC 2020), CTPS2 was found to be deleted in a subset of cancer samples, with the highest prevalence seen in ovarian, esophageal, and bladder cancers (see Figure 3). These findings identify a mechanism for identifying cancer patients predicted to be highly sensitive to treatment with CTPS1 inhibitors.

[0170] Example 6: Levels of CTPS2 expression predict cellular response to CTPS2 loss In an analysis of publicly available data, we found that CTPS2 expression levels correlated with sensitivity to CTPS1 loss by CRISPR knockout. In this analysis, which combined data from the Achilles Project and the Cancer Cell Line Encyclopedia for 573 human cancer cell lines, lower CTPS2 expression (measured by RNA abundance) was associated with increased sensitivity to CRISPR-mediated CTPS1 loss (Figure 4, Pearson correlation r = 0.23, P value = 4.9 × 10 -8 ). No association was found between CTPS1 expression and susceptibility to CRISPR-mediated CTPS1 loss (P value = 0.075).

[0171] CTPS2 expression levels were significantly associated with IC of CTPS-IA. 50 Human cancer cell lines were cultured in triplicate in the presence of different concentrations of CTPS-IA or vehicle alone at 37°C, 5% CO2, and viable cells were enumerated after 72 hours using CellTiter-Glo 2.0 reagent (Promega) or an equivalent reagent. A nonlinear regression model was used to calculate the half-maximal inhibitory concentration (IC 50) was calculated. CTPS1 and CTPS2 expression levels, measured by RNA abundance, were either generated by RNA sequencing or retrieved from the publicly available Cancer Cell Line Encyclopedia. In a set of 19 human cancer cell lines derived from hematologic malignancies, lower CTPS2 expression was associated with increased sensitivity to CTPS-IA (Pearson correlation r = 0.50, P value = 0.0007). In a set of 60 human cancer cell lines covering common cancer types, lower CTPS2 expression was associated with increased sensitivity to CTPS-IA (Pearson correlation r = 0.24, P value = < 0.0001). In an independent set of 103 human cancer cell lines covering common cancer types, lower CTPS2 expression was associated with increased sensitivity to CTPS-IA (Pearson correlation r = 0.14, P value = < 0.0001). The level of CTPS1 expression was not associated with susceptibility to CTPS-IA in any of these three experiments (P values ​​> 0.05 in all cases).

[0172] Collectively, these data indicate that CTPS2, but not CTPS1, expression levels correlate with sensitivity to CRISPR-mediated CTPS1 loss or pharmacological inhibition, respectively. Cancer cell lines with low CTPS2 expression show enhanced sensitivity to CTPS1 loss or inhibition.

[0173] Example 7: CTPS2 protein is absent in a subset of human cancers Primary human cancer samples were analyzed for CTPS2 protein expression by immunohistochemistry. CTPS2 monoclonal antibodies were validated using CTPS1 and CTPS2 knockout cell lines and normal human tissues. Once selective staining for CTPS2 was demonstrated in these experiments, these antibodies were used to probe tissue microarrays of primary human cancer samples. CTPS2-negative samples were defined by the absence of CTPS2 staining (an isotype control antibody was used to detect nonspecific staining).

[0174] Analysis of samples from 117 patients diagnosed with high-grade serous ovarian cancer identified a 24% prevalence of tumors showing loss of CTPS2 protein expression by immunohistochemistry. Analysis of samples from 80 patients diagnosed with gastroesophageal adenocarcinoma identified an 18% prevalence of tumors showing loss of CTPS2 protein expression by immunohistochemistry. For both of these cancer types, the prevalence of CTPS2 loss by genomic studies correlated well with the prevalence of CTPS2 loss assessed by immunohistochemistry (Figure 5).

[0175] Analysis of samples from 208 patients diagnosed with lung cancer identified a 65% prevalence of tumors showing loss of CTPS2 protein expression by immunohistochemistry. Analysis of samples from 208 patients diagnosed with bladder cancer identified a 37% prevalence of tumors showing loss of CTPS2 protein expression by immunohistochemistry. Analysis of samples from 208 patients diagnosed with head and neck squamous cell carcinoma identified a 66% prevalence of tumors showing loss of CTPS2 protein expression by immunohistochemistry. For these three cancer types, both immunohistochemistry and genomic studies confirmed that a significant proportion of cancers lacked CTPS2, but the prevalence of CTPS2 loss assessed by immunohistochemistry was higher than the prevalence of CTPS2 loss observed in genomic studies (Figure 5). Possible explanations for this discrepancy include partial gene deletions of CTPS2 that are not detected by genomic studies but result in loss of protein expression; differences in the stage of cancer in cohorts evaluated by genomic studies and immunohistochemistry (e.g., cohorts of samples that have undergone whole-genome sequencing are often biased toward patients with early-stage disease treated by surgical resection, where sufficient material for sequencing is generally available); or loss of protein expression due to epigenetic regulation such as gene methylation.

[0176] Example 8: Further characterization of the prevalence of reduced or absent CTPS2 expression in targeted cancers Further characterization of the prevalence of reduced or absent CTPS2 expression can be performed in a target cancer, e.g., ovarian cancer, using a suitably qualified assay for detection of CTPS2 expression, e.g., an immunohistochemistry assay, by analysis of tissue samples from multiple patient tumors, e.g., using a tumor microarray.

[0177] Further characterization of the cellular effects of loss of CTPS2 expression can be investigated by generating pairs of syngeneic human cancer cell lines in which CTPS2 expression is abrogated in subclones of cells, for example, using CRISPR (clustered regularly interspaced short palindromic repeats) technology to disrupt the CTPS2 gene, and then comparing key cellular characteristics (including proliferation and apoptosis in the presence or absence of CTPS2 inhibitors) between syngeneic cells that express CTPS2 and those that do not.

[0178] Further information can be obtained by evaluating pairs of syngeneic human cancer cell lines that express CTPS2 and those that do not express CTPS2 in an in vivo transplant model, for example, transplantation into immunodeficient mice, and in this case the effect of treatment with a CTPS1 inhibitor can be confirmed, for example, by measuring and comparing the growth rates of the syngeneic human cancer cell lines that express CTPS2 and those that do not express CTPS2 when the transplanted mice are treated with a CTPS1 inhibitor.

[0179] Further characterization of the cellular effects of loss of CTPS2 expression can be investigated by comparing patient-derived primary tumor samples that either express or have lost CTPS2 protein expression, for example, by analyzing primary tumor samples for CTPS2 protein expression by immunohistochemistry and comparing key cellular characteristics of CTPS2-expressing and CTPS2-deficient tumors in vitro, including proliferation and apoptosis, in the presence or absence of a CTPS1 inhibitor, or by evaluating CTPS2-expressing and non-CTPS2-expressing primary tumor samples in an in vivo transplant model, for example, transplantation into immunodeficient mice, in which case the effect of treatment with a CTPS1 inhibitor is confirmed, for example, by measuring and comparing the growth rates of CTPS2-expressing and non-CTPS2-expressing primary human cancers when the transplanted mice are treated with a CTPS1 inhibitor.

[0180] Throughout this specification and the claims that follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer, step, group of integers, or group of steps, but not the exclusion of any other integer, step, group of integers, or group of integers.

[0181] 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 not limitation, the following claims:

[0182] All publications cited herein, 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 as if fully set forth.

[0183] (Provisions of the present invention:) A series of clauses illustrating embodiments of the present invention are as follows: Clause 1. A method for treating a CTPS2-deficient cancer in a subject, the method comprising administering to the subject a CTPS1 inhibitor. Clause 2. A method for treating cancer in a subject, comprising: i) identifying the subject as having a cancer that is deficient in CTPS2; and ii) administering a CTPS1 inhibitor to the subject. The method comprising: Clause 3. A method for treating cancer in a subject, comprising: i) providing a sample from said subject; ii) identifying the subject as having a cancer that is deficient in CTPS2; and iii) administering a CTPS1 inhibitor to the subject. The method comprising: Clause 4. A method for treating cancer in a subject, comprising: i) obtaining a sample from said subject; ii) identifying the subject as having a cancer that is deficient in CTPS2; and iii) administering a CTPS1 inhibitor to the subject. The method comprising: Clause 5. A method for treating a cancer in a subject that may be susceptible to treatment with a CTPS1 inhibitor, comprising: i) identifying the cancer as deficient in CTPS2; and ii) administering a CTPS1 inhibitor The method comprising: Clause 6. A method for treating a cancer in a subject that may be susceptible to treatment with a CTPS1 inhibitor, comprising: i) providing a sample from said subject; ii) identifying the cancer as deficient in CTPS2; and iii) administering a CTPS1 inhibitor The method comprising: Clause 7. A method for treating a cancer in a subject that may be susceptible to treatment with a CTPS1 inhibitor, comprising: i) obtaining a sample from said subject; ii) identifying the cancer as deficient in CTPS2; and iii) administering a CTPS1 inhibitor The method comprising: Clause 8. A method for determining that a cancer cell may be susceptible to treatment with a CTPS1 inhibitor, the method comprising the step of identifying that the cancer cell is deficient in CTPS2. Clause 9. A method for determining that a cancer in a subject may be susceptible to treatment with a CTPS1 inhibitor, the method comprising identifying that the cancer is deficient in CTPS2. Clause 10. A CTPS1 inhibitor for use in the treatment of CTPS2-deficient cancer. Clause 11. A pharmaceutical composition comprising a CTPS1 inhibitor and a pharmaceutically acceptable excipient or carrier for use in treating CTPS2-deficient cancer. Clause 12. Use of a CTPS1 inhibitor in the manufacture of a medicament for the treatment of cancer, namely CTPS2-deficient cancer. Clause 13. The method, the CTPS1 inhibitor for use, the pharmaceutical composition for use, or the use according to any one of clauses 1 to 12, wherein said CTPS2-deficient cancer is selected from the group consisting of ovarian cancer, esophageal cancer, bladder cancer, non-small cell lung cancer, gastric cancer, sarcoma, head and neck cancer, pancreatic adenocarcinoma, pancreatic neuroendocrine tumor, biliary tract cancer, melanoma, endometrial cancer, hepatocellular carcinoma, cervical cancer, bone cancer, central nervous system cancer, breast cancer, prostate cancer, colorectal cancer, and renal cancer. Clause 14. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, or use according to clause 13, wherein the CTPS2-deficient cancer is selected from the group consisting of ovarian cancer, esophageal cancer, bladder cancer, non-small cell lung cancer, and gastric cancer. Clause 15. The method, the CTPS1 inhibitor for use, the pharmaceutical composition for use, or the use according to any one of clauses 1 to 12, wherein said CTPS2-deficient cancer is ovarian cancer. Clause 16. The method, the CTPS1 inhibitor for use, the pharmaceutical composition for use, or the use according to clause 15, wherein said CTPS2-deficient cancer is serous ovarian cancer. Clause 17. The method, the CTPS1 inhibitor for use, the pharmaceutical composition for use, or the use according to any one of clauses 1 to 12, wherein said CTPS2-deficient cancer is lung cancer. Clause 18. The method, the CTPS1 inhibitor for use, the pharmaceutical composition for use, or the use according to Clause 17, wherein the CTPS2-deficient cancer is non-small cell lung cancer. Clause 19. The method, the CTPS1 inhibitor for use, the pharmaceutical composition for use, or the use according to any one of clauses 1 to 12, wherein said CTPS2-deficient cancer is esophageal cancer. Clause 20. The method, the CTPS1 inhibitor for use, the pharmaceutical composition for use, or the use according to any one of clauses 1 to 12, wherein said CTPS2-deficient cancer is gastric cancer. Clause 21. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, or use according to any one of clauses 1 to 12, wherein said CTPS2-deficient cancer is head and neck cancer. Clause 22. The method, the CTPS1 inhibitor for use, the pharmaceutical composition for use, or the use according to any one of clauses 1 to 12, wherein said CTPS2-deficient cancer is bladder cancer. Clause 23. The method, the CTPS1 inhibitor for use, the pharmaceutical composition for use, or the use according to any one of clauses 1 to 12, wherein said CTPS2-deficient cancer is a sarcoma. Clause 24. The method, the CTPS1 inhibitor for use, the pharmaceutical composition for use, or the use according to any one of clauses 1 to 12, wherein said cancer is a blood cancer. Clause 25. The method, the CTPS1 inhibitor for use, the pharmaceutical composition for use, or the use according to any one of clauses 1 to 12, wherein said cancer is a non-hematological cancer. Clause 26. The method, the CTPS1 inhibitor for use, the pharmaceutical composition for use, or the use according to any one of clauses 1 to 25, wherein said cancer is not T-cell leukemia, for example T-cell acute lymphoblastic leukemia. Clause 27. The CTPS1 inhibitor has an IC of 10 uM or less with respect to the human CTPS1 enzyme. 50 27. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, or use according to any one of clauses 1 to 26, comprising: Clause 28. The CTPS1 inhibitor has an IC of 1 uM or less with respect to the human CTPS1 enzyme. 50 28. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, or use according to clause 27, comprising: Clause 29. The CTPS1 inhibitor has an IC of 100 nM or less with respect to the human CTPS1 enzyme. 50 29. The method, the CTPS1 inhibitor for use, the pharmaceutical composition for use, or the use according to clause 28, Clause 30. IC of said CTPS1 inhibitor 50 30. The method, the CTPS1 inhibitor for use, the pharmaceutical composition for use, or the use according to any one of clauses 27 to 29, wherein the CTPS1 inhibitor is established using the assay procedure described in Example 1. Clause 31. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, or use according to any one of clauses 1 to 30, wherein said CTPS1 inhibitor has at least 2-fold selectivity for human CTPS1 over human CTPS2. Clause 32. The method, the CTPS1 inhibitor for use, the pharmaceutical composition for use, or the use according to clause 31, wherein said CTPS1 inhibitor has at least 30-fold selectivity for human CTPS1 over human CTPS2. Clause 33. The method, the CTPS1 inhibitor for use, the pharmaceutical composition for use, or the use according to clause 32, wherein said CTPS1 inhibitor has at least 60-fold, such as at least 1000-fold, selectivity for human CTPS1 over human CTPS2. Clause 34. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, or use according to any one of clauses 31 to 33, wherein the selectivity of said CTPS1 inhibitor is established using the assay procedure described in Example 2. Clause 35. The method, the CTPS1 inhibitor for use, the pharmaceutical composition for use, or the CTPS1 inhibitor for use according to any one of clauses 1 to 34, wherein the CTPS1 inhibitor is a compound of formula (I) or a pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate thereof. [ka] (In the formula, R1 is C 1-5 Alkyl, C 0-2 Alkylene C 3-5 cycloalkyl (wherein the cycloalkyl is optionally substituted with CH3), C 1-3 Alkylene OC 1-2 alkyl, or CF3; R3 is H, CH3, halo, OC 1-2 alkyl, or CF3; R4 and R5 each independently represent 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 Alkyl OH or C 1-6 is haloalkyl, or R4 and R5 together with the carbon atom to which they are attached form C 3-6 Cycloalkyl or C 3-6 forming a heterocycloalkyl ring; R6 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 10H, halo, C 1-3 Alkyl, OC 1-2 Alkyl, C 1-2 Haloalkyl, OC 1-2 haloalkyl, or CN; R 11 is H, F, Cl, CH3, ethyl, OCH3, CF3, OCF3, 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, OCH2CH2N(CH3)2, OH, C 1-4 Alkyl OH, NR 23 R 24 , SO2CH3, C(O)N(CH3)2, NHC(O)C 1-3 C containing one nitrogen atom at the point of attachment to alkyl or Ar2 3-6 heterocycloalkyl or R 12 together with the nitrogen atom to which it is attached form an N-oxide (N + -O - ) form; R 23 is H or C 1-2 is alkyl; R 24 is H or C 1-2 (It is alkyl). Clause 36. The method, the CTPS1 inhibitor for use, the pharmaceutical composition for use, or the use according to clause 35, wherein said CTPS1 inhibitor is selected from the compounds disclosed in List A or a pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate thereof. Clause 37. The method, the CTPS1 inhibitor for use, the pharmaceutical composition for use, or the use according to any one of clauses 1 to 34, wherein said CTPS1 inhibitor is a compound of formula (II): or a pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate thereof: [ka] (In the formula, R1 is C 1-5 Alkyl, C 0-2 Alkylene C 3-5 cycloalkyl (wherein the cycloalkyl is optionally substituted with CH3), C 1-3 Alkylene OC 1-2 alkyl, or CF3; R3 is H, halo, CH3, OC 1-2 alkyl, or CF3; or R3 together with R5 form a 5- or 6-membered cycloalkyl or a 5- or 6-membered oxygen-containing heterocycloalkyl; R4 and R5 are each independently H, halo, 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 Alkyl OH, C 1-6 Haloalkyl, OC 1-6 Haloalkyl, or NR 21 R 22 and or R4 is H and R5 together with R3 form a 5- or 6-membered cycloalkyl or a 5- or 6-membered oxygen-containing heterocycloalkyl; or R4 and R5 together with the carbon atom to which they are attached form C 3-6 Cycloalkyl or C 3-6 forming a heterocycloalkyl, or R4 is H and R5 and R6 are C 2-3 is an alkylene chain; or R4 is O and R5 is absent; R6 is H or C 1-3 is alkyl, or R6 when in the ortho position relative to the amide 11 is a C2 alkylene chain that forms a five-membered ring together with or R5 and R6 form a 5- or 6-membered ring 2-3 is an alkylene chain and R4 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 is H, F, Cl, CH3, ethyl, OCH3, CF3, OCF3, or CN; or R 11 is a C2 alkylene chain that, together with R6, forms a five-membered ring when in the ortho position relative to the amide; 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, OCH2CH2N(CH3)2, OH, C 1-4 Alkyl OH, CN, C 1-3 Alkylene OC 1-3 Alkyl, C 1-4 Haloalkyl, OC 1-4 Haloalkyl, C(=O)C1-2 Alkyl, NR 23 R 24 , SO2C 1-4 Alkyl, SOC 1-4 Alkyl, SC 1-4 Alkyl, SH, C(O)N(CH3)2, NHC(O)C 1-3 Alkyl, C containing one nitrogen at the point of attachment to Ar2 3-6 heterocycloalkyl, or R 12 together with the nitrogen atom to which it is attached form an N-oxide (N + -O - ) form; R 13 is H, halo, CH3, or OCH3; R 21 is H, C 1-5 Alkyl, C(O)C 1-5 Alkyl, C(O)OC 1-5 is alkyl; R 22 is H or CH3; R 23 is H or C 1-2 is alkyl; and R 24 is H or C 1-2 (It is alkyl). Clause 38. The method, the CTPS1 inhibitor for use, the pharmaceutical composition for use or the use according to clause 37, wherein said CTPS1 inhibitor is selected from the compounds disclosed in List B or a pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate thereof. Clause 39. The method, the CTPS1 inhibitor for use, the pharmaceutical composition for use, or the use according to any one of clauses 1 to 34, wherein said CTPS1 inhibitor is a compound of formula (III): or a pharmaceutically acceptable salt and / or a pharmaceutically 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 CR2; Z is N or CR3; provided that when at least one of X or Z is N, Y cannot be N; R1 is C 1-5 Alkyl, C 0-2 Alkylene C 3-5 cycloalkyl (wherein the cycloalkyl is optionally substituted with CH3), or CF3; R2 is H, halo, C 1-2 Alkyl, OC 1-2 Alkyl, C 1-2 Haloalkyl or OC 1-2 is haloalkyl; R3 is H, halo, CH3, OCH3, CF3, or OCF3; wherein at least one of R2 and R3 is H; R4 and R5 each independently represent H, C 1-6 Alkyl, C 1-6 Alkyl OH, 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 R4 and R5 together with the carbon atom to which they are attached are C 3-6 Cycloalkyl or C 3-6 forming a heterocycloalkyl; and When A is -NHC(=O)-: R4 and R5 are halo, 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, C 1-2 alkyl, CF3, OCH3, 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, SO2C 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 is a C-type aryl group containing CN, OCH2CH2N(CH3)2, and one nitrogen atom at the point of attachment to Ar2. 3-6 heterocycloalkyl, or R 12 together with the nitrogen atom to which it is attached form an N-oxide (N + -O - ) form; R 13 is H or halo; R 21 is H, C 1-5 Alkyl, C(O)C 1-5 Alkyl, C(O)OC 1-5 is alkyl; R 22 is H or CH3; R 23 is H or C 1-2 is alkyl; and R 24 is H or C 1-2 (It is alkyl). Clause 40. The method, the CTPS1 inhibitor for use, the pharmaceutical composition for use or the use according to clause 37, wherein said CTPS1 inhibitor is selected from the compounds disclosed in List C or a pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate thereof. Clause 41. The method, the CTPS1 inhibitor for use, the pharmaceutical composition for use, or the use according to Clause 37, wherein said CTPS1 inhibitor is a compound of formula (IV): or a pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate thereof: [ka] (In the formula: (a) R4, R5, X, Y, and R1 are as follows: [ka] when W is N, CH, or CF; (b) R4, R5, X, W, and R1 are as follows: [ka] when Y is CH or N; (c) W, X, Y, and R1 are as follows: [ka] when R4 and R5 combine to form the following structure: [ka] Forming; (d) W, R4, R5, X, and Y are as follows: [ka] when R1 is methyl or cyclopropyl; and (e) the compound is [ka] (selected from the group consisting of: Clause 42. The method, the CTPS1 inhibitor for use, the pharmaceutical composition for use or the use according to clause 41, wherein said CTPS1 inhibitor is selected from the compounds disclosed in List D or a pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate thereof. Clause 43. The method, the CTPS1 inhibitor for use, the pharmaceutical composition for use, or the use according to Clause 39, wherein said CTPS1 inhibitor is a compound of formula (V): or a pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate thereof: [ka] (a)A, V, W, X, Y, Z, R1, R 10 , and R 12 But as follows: [ka] when R4 and R5 together with the carbon atoms to which they are attached [ka] : form; or (b)A, V, W, X, Y, Z, R1, R 10 , and R 12 But as follows: [ka] when R4 and R5 together with the carbon atoms to which they are attached [ka] : form; or (c)A, V, W, X, Y, Z, R4, R5, R 10 , and R 12 But as follows: [ka] If so, then R1 is [ka] and; or (d)A, V, W, X, Y, Z, R4, R5, R 10 , and R 12 But as follows: [ka] If so, then R1 is [ka] and; or (e) A, X, Y, Z, R1, R4, and R5 are as follows: [ka] If V, W, R 10 , and R 12 teeth, [ka] :and; or (f)A, V, W, R1, R4, R5, R 10 , and R 12 But as follows: [ka] then Z, X, and Y are [ka] and; or (g)A, V, W, R1, R4, R5, R 10 , and R12 But as follows: [ka] then Z, X, and Y are [ka] and; or (h)A, V, W, R1, R4, R5, R 10 , and R 12 But as follows [ka] then Z, X, and Y are [ka] (It is). Clause 44. The method, the CTPS1 inhibitor for use, the pharmaceutical composition for use, or the use according to clause 43, wherein said CTPS1 inhibitor is selected from the compounds disclosed in List E or a pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate thereof. Clause 45. The method, the CTPS1 inhibitor for use, the pharmaceutical composition for use, or the use according to any one of clauses 1 to 34, wherein said CTPS1 inhibitor is a compound of formula (VI): or a pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate thereof: [ka] (Wherein, ring B is [ka] (where 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 is A aa or A ba and; where: A aa is an amine linker having the following structure: -NH-, -CHNH-, or -NHCH-; 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; provided 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 is H, halo, CH3, OCH3, CF3, or OCF3; where 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 3-5cycloalkyl (wherein the cycloalkyl is optionally substituted with CH3), or CF3; 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 atoms to which they are attached, C 3-6 Forms a cycloalkyl, which is: Each substituent is C 1-3 Alkyl, oxo, OH, C 1-3 Alkyl OH, 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: The 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 formed by a heterocycloalkyl ring, and wherein R 4aa and R 5aa C formed by 3-6 Cycloalkyl is a group in which each of the substituents, together with the carbon atom to which they are attached, is C 1-3 Alkyl or OC 1-3and optionally substituted with one or two substituents independently selected from the group consisting of alkyl; or R 4aa and R 5aa together with the carbon atoms 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 formed by a heterocycloalkyl ring, and wherein 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 and optionally substituted with one or two substituents independently selected from the group consisting of alkyl; or R 4aa and R 5aa C, which contains one nitrogen atom along with the carbon atom to which they are attached 3-6 heterocycloalkyl, where the nitrogen atom is —S(O)R 29a is replaced by; or R 4ba and R 5ba are each independently H, C 1-6 Alkyl, C 1-6 Alkyl OH, 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 atoms to which they are attached, C 3-6 Cycloalkyl or C 3-6 forming a heterocycloalkyl; and A aWhen is -NHC(=O)- or -NHCH2-: 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, C 1-2 alkyl, CF3, OCH3, 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, SO2C 1-2 Alkyl, C(O)N(C 1-2 alkyl)2, NHC(O)C 1-3 Alkyl or NR 23a R 24a and A aWhen is -NHC(=O)-, -NH-, or -NHCH2-: R 12a is a C-type aryl group containing CN, OCH2CH2N(CH3)2, and one nitrogen atom at the point of attachment to Ar2a. 3-6 heterocycloalkyl, or R 12a together with the nitrogen atom to which it is attached form an N-oxide (N + -O - ) form; R 13a is H or halo; R 21a is 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 CH3; 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 optionally substituted with CH), CF, 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 is 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 is A ab or A bb and; where: A ab is -NR 6b CH2- or -NR 6b - and; A bb is -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 optionally substituted with CH3), C 1-3 Alkylene OC 1-2 alkyl, or CF3; R 3b H, halo, CH3, OC 1-2 alkyl, or CF3; or R 3b is R 5bbtogether 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 atoms to which they are attached, C 3-6 Forms a cycloalkyl, which is: Each substituent is C 1-3 Alkyl, oxo, OH, C 1-3 Alkyl OH, 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: The 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 formed by a heterocycloalkyl ring, and wherein R 4ab and R 5ab C formed by 3-6 Cycloalkyl is a group in which each of the substituents, together with the carbon atom to which they are attached, is C 1-3 Alkyl or OC 1-3and optionally substituted with one or two substituents independently selected from the group consisting of alkyl; or R 4ab and R 5ab together with the carbon atoms to which they are attached, C 3-6 Form a 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 formed by a heterocycloalkyl ring, and wherein 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 and optionally substituted with one or two substituents independently selected from the group consisting of alkyl; or R 4ab and R 5ab C, which contains one nitrogen atom along with the carbon atom to which they are attached 3-6 heterocycloalkyl, where the nitrogen atom is —S(O)R 29b is replaced by; or 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 Alkyl OH, C 1-6 Haloalkyl, OC 1-6 Haloalkyl, or NR 21b R 22b and or R 4bbis H and R 5bb is R 3b together form 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 atoms 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 that 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 is a C2 alkylene chain that forms a five-membered ring together with 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 attached 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 is H, F, Cl, CH3, ethyl, OCH3, CF3, OCF3, or CN; or R 11b is the group A b When it is in the ortho position to R6b is a C2 alkylene chain that forms a five-membered ring together with 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, OCH2CH2N(CH3)2, OH, C 1-4 Alkyl OH, 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 , SO2C 1-4 Alkyl, SOC 1-4 Alkyl, SC 1-4 Alkyl, SH, C(O)N(CH3)2, NHC(O)C 1-3 Alkyl, C containing one nitrogen atom at the point of attachment to Ar2b 3-6 heterocycloalkyl or R 12b together with the nitrogen atom to which it is attached form an N-oxide (N + -O - ) form; R 13b is H, halo, CH3, or OCH3; R 21b is 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 CH3; 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 optionally substituted with CH), CF, N(C 1-3 alkyl), or 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) 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 is A ac or A bc and; where: A ac is -CH2NR 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 optionally substituted with CH3), C 1-3 Alkylene OC 1-2 alkyl, or CF3; R 3c H, CH3, Halo, OC 1-2 alkyl, or CF3; 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 atoms to which they are attached, C 3-6 Forms a cycloalkyl, which is: Each substituent is C 1-3 Alkyl, oxo, OH, C 1-3 Alkyl OH, 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 22cor is substituted by one or two substituents independently selected from the group consisting of: The 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 formed by a heterocycloalkyl ring, and wherein R 4ac and R 5ac C formed by 3-6 Cycloalkyl is a group in which each of the substituents, together with the carbon atom to which they are attached, is C 1-3 Alkyl or OC 1-3 and optionally substituted with one or two substituents independently selected from the group consisting of alkyl; or R 4ac and R 5ac together with the carbon atoms to which they are attached, C 3-6 Form a 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 formed by a heterocycloalkyl ring, and wherein 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 and optionally substituted with one or two substituents independently selected from the group consisting of alkyl; or R 4ac and R 5ac C, which contains one nitrogen atom along with the carbon atom to which they are attached 3-6 heterocycloalkyl, where the nitrogen atom is —S(O)R 29c is replaced by; or R 4bc and R 5bc are each independently H, C1-6 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 Alkyl OH or C 1-6 is haloalkyl, or R 4bc and R 5bc together with the carbon atoms 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 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 is H, F, Cl, CH3, ethyl, OCH3, CF3, OCF3, 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 3-5Cycloalkyl, OCH2CH2N(CH3)2, OH, C 1-4 Alkyl OH, NR 23c R 24c , SO2CH3, C(O)N(CH3)2, NHC(O)C 1-3 C containing one nitrogen atom at the point of attachment to alkyl or Ar2c 3-6 heterocycloalkyl or R 12c together with the nitrogen atom to which it is attached form an N-oxide (N + -O - ) form; R 21c is 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 CH3; 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 optionally substituted with CH), CF, N(C 1-3 alkyl), or 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 is A ac (It is). Clause 46. The method, the CTPS1 inhibitor for use, the pharmaceutical composition for use or the use according to clause 45, wherein said CTPS1 inhibitor is selected from the compounds disclosed in List F or a pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate thereof. Clause 47. The method, the CTPS1 inhibitor for use, the pharmaceutical composition for use, or the use according to any one of clauses 1 to 34, wherein the CTPS1 inhibitor is a compound of formula (VII): or a pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate thereof: [ka] (In the formula, A is A a or A b and; where: A a is an amine linker having the following structure: -NH-, -CHNH-, or -NHCH-; 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 CR2; Z is N or CR3; provided that when at least one of X or Z is N, Y cannot be N; R1 is C 1-5 fluoroalkyl with the proviso that R1 is not CF3; R2 is H, halo, C 1-2 Alkyl, OC 1-2 Alkyl, C 1-2 Haloalkyl or OC 1-2 is haloalkyl; R3 is H, halo, CH3, OCH3, CF3, or OCF3; wherein at least one of R2 and R3 is H; R 3' H, halo, CH3, OC 1-2 alkyl, or CF3; and When A is -NHC(=O)-, R 3' together with R5 form a 5- or 6-membered cycloalkyl or a 5- or 6-membered oxygen-containing heterocycloalkyl; R4 and R5 are R 4a and R 5a or R 4b and R 5b and; where: R 4a and R 5a together with the carbon atoms to which they are attached, C 3-6 Forms a cycloalkyl, which is: Each substituent is C 1-3 Alkyl, oxo, OH, C 1-3 Alkyl OH, 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: The C3-6 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 formed by a heterocycloalkyl ring, and wherein R 4a and R 5a C formed by 3-6 Cycloalkyl is a group in which each of the substituents, together with the carbon atom to which they are attached, is C 1-3 Alkyl or OC 1-3 and optionally substituted with one or two substituents independently selected from the group consisting of alkyl; or R 4a and R 5a together with the carbon atoms 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 formed by a heterocycloalkyl ring, and wherein 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 and optionally substituted with one or two substituents independently selected from the group consisting of alkyl; or R 4a and R 5a C, which contains one nitrogen atom along with the carbon atom to which they are attached 3-6 heterocycloalkyl, where the nitrogen atom is —S(O)R 29 is replaced by; or R 4b and R 5b are each independently H, C 1-6 Alkyl, C 1-6 Alkyl OH, C 1-6 Haloalkyl, C0-2 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 atoms to which they are attached, C 3-6 Cycloalkyl or C 3-6 forming a heterocycloalkyl; and When A is -NHC(=O)- or -NHCH2-: 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, C 1-2 alkyl, CF3, OCH3, 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 3-5Cycloalkyl, C 1-4 Haloalkyl, OC 1-4 Haloalkyl, hydroxy, C 1-4 Alkyl OH, SO2C 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)-, -NH-, or -NHCH2-: R 12 is a C-type aryl group containing CN, OCH2CH2N(CH3)2, and one nitrogen atom at the point of attachment to Ar2. 3-6 heterocycloalkyl, or R 12 together with the nitrogen atom to which it is attached form an N-oxide (N + -O - ) form; R 13 is H or halo; R 21 is H, C 1-5 Alkyl, C(O)C 1-5 Alkyl, C(O)OC 1-5 is alkyl; R 22 is H or CH3; 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 optionally substituted with CH3), or CF3; 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, C3-5 forming a heterocycloalkyl). Clause 48. The method, the CTPS1 inhibitor for use, the pharmaceutical composition for use or the use according to clause 47, wherein said CTPS1 inhibitor is selected from the compounds disclosed in List G or a pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate thereof. Clause 49. The method, the CTPS1 inhibitor for use, the pharmaceutical composition for use, or the use according to any one of clauses 1 to 34, wherein said CTPS1 inhibitor is a compound of formula (VIII): or a pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate thereof: [ka] (In the formula, A is A a or A b and; where: A a is an amine linker having the following structure: -NH-, -CHNH-, or -NHCH-; 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 CR2; Z is N or CR3; provided that when at least one of X or Z is N, Y cannot be N; R1 is C 1-5 Alkyl or C 0-2 Alkylene C 3-5 cycloalkyl, wherein the alkyl or (alkylene)cycloalkyl is substituted by CN; R2 is H, halo, C 1-2 Alkyl, OC 1-2 Alkyl, C 1-2 Haloalkyl or OC1-2 is haloalkyl; R3 is H, halo, CH3, OCH3, CF3, or OCF3; wherein at least one of R2 and R3 is H; R 3' H, halo, CH3, OC 1-2 alkyl, or CF3; and When A is -NHC(=O)-, R 3' together with R5 form a 5- or 6-membered cycloalkyl or a 5- or 6-membered oxygen-containing heterocycloalkyl; R4 and R5 are R 4a and R 5a or R 4b and R 5b and; where: R 4a and R 5a together with the carbon atoms to which they are attached, C 3-6 Forms a cycloalkyl, which is: Each substituent is C 1-3 Alkyl, oxo, OH, C 1-3 Alkyl OH, 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: The 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 C3-6 a spiro center formed by a heterocycloalkyl ring, and wherein R 4a and R 5a C formed by 3-6 Cycloalkyl is a group in which each of the substituents, together with the carbon atom to which they are attached, is C 1-3 Alkyl or OC 1-3 and optionally substituted with one or two substituents independently selected from the group consisting of alkyl; or R 4a and R 5a together with the carbon atoms 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 formed by a heterocycloalkyl ring, and wherein 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 and optionally substituted with one or two substituents independently selected from the group consisting of alkyl; or R 4a and R 5a C, which contains one nitrogen atom along with the carbon atom to which they are attached 3-6 heterocycloalkyl, where the nitrogen atom is —S(O)R 29 is replaced by; or R 4b and R 5b are each independently H, C 1-6 Alkyl, C 1-6 Alkyl OH, C 1-6 Haloalkyl, C 0-2 Alkylene C 3-6 Cycloalkyl, C 0-2 Alkylene C 3-6 Heterocycloalkyl, C 1-3Alkylene OC 1-3 alkyl or R 4b and R 5b together with the carbon atoms to which they are attached, C 3-6 Cycloalkyl or C 3-6 forming a heterocycloalkyl; and When A is -NHC(=O)- or -NHCH2-: 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, C 1-2 alkyl, CF3, OCH3, 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, SO2C 1-2Alkyl, 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)-, -NH-, or -NHCH2-: R 12 is a C-type aryl group containing CN, OCH2CH2N(CH3)2, and one nitrogen atom at the point of attachment to Ar2. 3-6 heterocycloalkyl, or R 12 together with the nitrogen atom to which it is attached form an N-oxide (N + -O - ) form; R 13 is H or halo; R 21 is H, C 1-5 Alkyl, C(O)C 1-5 Alkyl, C(O)OC 1-5 is alkyl; R 22 is H or CH3; 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 optionally substituted with CH3), or CF3; 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 50. The method, the CTPS1 inhibitor for use, the pharmaceutical composition for use or the use according to clause 49, wherein said CTPS1 inhibitor is selected from the compounds disclosed in List H or a pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate thereof. Clause 51. 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 pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate thereof. Clause 52. 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 pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate thereof. Clause 53. The method, the CTPS1 inhibitor for use, the pharmaceutical composition for use, or the use according to any one of clauses 1 to 52, wherein said CTPS1 inhibitor is in its free form. Clause 54. The method, the CTPS1 inhibitor for use, the pharmaceutical composition for use, or the use according to any one of clauses 1 to 52, wherein said CTPS1 inhibitor is a pharmaceutically acceptable salt. Clause 55. The method, the CTPS1 inhibitor for use, the pharmaceutical composition for use, or the use according to any one of clauses 1 to 52, wherein said CTPS1 inhibitor is a pharmaceutically acceptable solvate. Clause 56. The method, the CTPS1 inhibitor for use, the pharmaceutical composition for use, or the use according to any one of clauses 1 to 52, wherein said CTPS1 inhibitor is a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate. Clause 57. 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 pharmaceutically acceptable salt thereof. Clause 58. 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 pharmaceutically acceptable salt thereof. Clause 59. The method, the CTPS1 inhibitor for use, the pharmaceutical composition for use, or the use according to any one of clauses 1 to 58, wherein said CTPS1 inhibitor is provided in natural isotopic form. Clause 60. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, or use according to any one of clauses 1 to 59, wherein the CTPS1 inhibitor is a CTPS1 inhibitor as defined in claim 1 of WO2022 / 087634. Clause 61. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, or use according to any one of clauses 1 to 59, wherein said CTPS1 inhibitor is a CTPS1 inhibitor as defined in WO2022 / 087634. Clause 62. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, or use according to any one of clauses 1 to 59, wherein the CTPS1 inhibitor is not a CTPS1 inhibitor as defined in claim 1 of WO2022 / 087634. Clause 63. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, or use according to any one of clauses 1 to 59, wherein said CTPS1 inhibitor is not a CTPS1 inhibitor as defined in WO2022 / 087634. Clause 64. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, or use according to any one of clauses 1 to 63, wherein the deficiency of CTPS2 is due to genomic alteration(s) and / or epigenetic alteration(s). Clause 65. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, or use according to any one of clauses 1 to 64, wherein the deficiency of CTPS2 is due to genomic alteration(s). Clause 66. The method, the CTPS1 inhibitor for use, the pharmaceutical composition for use, or the use according to clause 64 or 65, wherein said genomic alteration(s) is complete loss of said CTPS2 gene due to a genomic deletion. Clause 67. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, or use according to any one of clauses 64 to 66, wherein said genomic alteration(s) is partial loss of said CTPS2 gene due to a genomic deletion. Clause 68. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, or use according to any one of clauses 64 to 67, wherein said genomic alteration(s) is a disruption of said CTPS2 gene due to a structural DNA mutation such as an inversion, duplication, or translocation within the footprint of said gene. Clause 69. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, or use according to any one of clauses 64 to 68, wherein said genomic alteration(s) is a mutation in said CTPS2 gene such that CTPS2 expression is substantially reduced or, most preferably, completely lost. Clause 70. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, or use according to any one of clauses 64 to 68, wherein the deficiency of CTPS2 is due to epigenetic alteration(s). Clause 71. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, or use according to clause 70, wherein said epigenetic alteration(s) is a change in expression of said CTPS2 gene, for example by alteration of a regulatory element by alteration of methylation and / or histone modification, such that CTPS2 expression is substantially reduced or, most preferably, completely lost. Clause 72. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, or use of any one of clauses 1 to 71, wherein the sample is a biopsy containing cancer cells (e.g., a tumor biopsy), a sample containing circulating cancer cells, or a sample containing cell-free cancer DNA. Clause 73. The step of identifying said subject as having a cancer that is deficient in CTPS2 comprises: (i) applying a suitable method for determining CTPS2 deficiency, e.g., a technique for detecting relevant alterations in DNA, RNA, or protein; (ii) analysis of data generated by the method; and (iii) Interpretation of data generated by the method for determining the likelihood of substantial loss of CTPS2 function, particularly complete loss of CTPS2 function. 73. The method, the CTPS1 inhibitor for use, the pharmaceutical composition for use, or the use according to any one of clauses 1 to 72, comprising: Clause 74. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, or use according to Clause 73, wherein the method for determining CTPS2 deficiency is a method of detecting DNA alterations, such as whole genome sequencing, whole exome sequencing, targeted gene sequencing using capture-based enrichment, targeted gene sequencing using PCR-based enrichment, real-time quantitative PCR, digital droplet PCR, in situ hybridization, or fluorescent in situ hybridization. Clause 75. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, or use according to clause 73 or 74, wherein the method for determining CTPS2 deficiency is a method for detecting RNA alterations, such as RNA sequencing, gene expression array, real-time quantitative PCR, digital droplet PCR, or in situ hybridization. Clause 76. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, or use according to any one of clauses 73 to 75, wherein the method for determining CTPS2 deficiency is a method for detecting epigenetic changes, such as DNA methylation analysis, histone modification characterization, RNA sequencing, gene expression array, real-time quantitative PCR, digital droplet PCR, or in situ hybridization. Clause 77. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, or use according to any one of clauses 73 to 76, wherein the method for determining CTPS2 deficiency is a method for detecting protein alterations, such as immunohistochemistry, flow cytometry, or mass cytometry. Clause 78. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, or use according to Clause 77, wherein the method for determining CTPS2 deficiency is immunohistochemistry, for example, lack of staining for CTPS2. Clause 79. The method, the CTPS1 inhibitor for use, the pharmaceutical composition for use, or the use according to any one of clauses 1 to 78, wherein said subject is a human subject. Clause 80. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, or use according to clause 79, wherein the human subject is, for example, an adult aged 18 to 65 years. Clause 81. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, or use according to clause 79, wherein the human subject is under 18 years of age, for example between 4 and 17 years of age. Clause 82. The method, the CTPS1 inhibitor for use, the pharmaceutical composition for use, or the use according to clause 79, wherein said human subject is 66 years of age or older. Clause 83. The method, the CTPS1 inhibitor for use, the pharmaceutical composition for use, or the use according to any one of clauses 79 to 82, wherein said human subject is male. Clause 84. The method, the CTPS1 inhibitor for use, the pharmaceutical composition for use, or the use according to Clause 83, wherein the deficiency of CTPS2 results from complete loss of said CTPS2 gene due to a genomic deletion. Clause 85. The method, the CTPS1 inhibitor for use, the pharmaceutical composition for use, or the use according to any one of clauses 79 to 82, wherein said human subject is female. Clause 86. The method, the CTPS1 inhibitor for use, the pharmaceutical composition for use, or the use according to Clause 85, wherein the CTPS2 deficiency is due to genomic and / or epigenic alterations in one or both XX chromosomes, preferably both XX chromosomes. Article 87. The deficiency of CTPS2 is due to a genomic deletion resulting in the complete loss of the CTPS2 gene on the first X chromosome, and: (i) complete loss of the CTPS2 gene on the second X chromosome due to a genomic deletion; (ii) partial loss of the CTPS2 gene on the second X chromosome due to a genomic deletion; (iii) disruption of the CTPS2 gene on the second X chromosome due to a structural DNA mutation, such as an inversion, duplication, or translocation, within the footprint of the gene; (iv) a mutation in the CTPS2 gene on the second X chromosome such that CTPS2 expression is substantially reduced or completely abolished; or (v) an alteration in expression of the CTPS2 gene on the second X chromosome due to a change in a regulatory element, e.g., by changes in methylation and / or histone modifications, such that CTPS2 expression is substantially reduced or completely abolished. 87. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, or use according to clause 85 or 86, resulting from Article 88. The method, the CTPS1 inhibitor for use, the pharmaceutical composition for use, or the use according to Article 86 or 87, wherein the deficiency of CTPS2 results from a complete loss of the CTPS2 gene on the first X chromosome due to a genomic deletion and a complete loss of the CTPS2 gene on the second X chromosome due to a genomic deletion. Clause 89. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, or use according to any one of clauses 1 to 88, wherein the deficiency of CTPS2 is due to a homozygous deletion in cancer cells. Clause 90. The method, the CTPS1 inhibitor for use, the pharmaceutical composition for use, or the use according to any one of clauses 1 to 89, wherein said CTPS1 inhibitor is administered orally. Clause 91. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, or use according to clause 90, wherein said CTPS1 inhibitor is administered in a solid pharmaceutical composition (e.g., a tablet, capsule, or lozenge). Clause 92. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, or use according to clause 90, wherein said CTPS1 inhibitor is administered in a liquid pharmaceutical composition (e.g., a suspension, emulsion, or solution). Clause 93. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, or use according to any one of clauses 1 to 92, wherein the CTPS1 inhibitor is administered in a unit dose of 0.05 mg to 1000 mg, more preferably 1.0 mg to 500 mg. Clause 94. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, or use according to any one of clauses 1 to 93, wherein the CTPS1 inhibitor is administered more than once or twice a day, for example, twice or three times a day. Clause 95. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, or use according to any one of clauses 1 to 94, wherein the CTPS1 inhibitor is administered continuously, for example at least daily for several weeks. Clause 96. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, or use according to any one of clauses 1 to 94, wherein the CTPS1 inhibitor is administered discontinuously, for example, at least daily for one week, followed by one week without administration, and then at least daily for another week. Clause 97. The CTPS1 inhibitor is selected from the group consisting of antimitotic agents such as vinblastine, paclitaxel, and docetaxel; alkylating agents and DNA cross-linking 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; MTOR inhibitors, such as everolimus and temsirolimus; proteasome inhibitors, such as bortezomib; histone deacetylase inhibitors, such as panobinostat or vorinostat; hedgehog pathway blockers, such as vismodegib; 97. The method, the CTPS1 inhibitor for use, the pharmaceutical composition for use, the pharmaceutical composition for use, or the use according to any one of clauses 1 to 96, administered in combination with one or more further pharmaceutically acceptable active ingredients selected from the group consisting of: an IAP inhibitor such as LCL161; a VEGF inhibitor such as bevacizumab; a pan-kinase inhibitor such as sorafenib and sunitinib; a tyrosine kinase inhibitor such as axitinib, dasatinib, erlotinib, imatinib, nilotinib, pazopanib, and sunitinib; azacitidine, decitabine, and cytarabine. Clause 98. The method, the CTPS1 inhibitor for use, the pharmaceutical composition for use, the pharmaceutical composition for use, or the use of any one of clauses 1 to 97, wherein said CTPS1 inhibitor is administered in combination with one or more anti-cancer antibodies, such as (e.g., obinutuzumab, ofatumumab, tositumomab, or rituximab), olaratumumab, daratumumab, necitumumab, dinutuximab, traztuzumab emtansine, pertuzumab, brentuximab, panitumumab, catumaxomab, bevacizumab, cetuximab, traztuzumab, and gentuzumab ozogamicin. Clause 99. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, pharmaceutical composition for use, or use according to any one of clauses 1 to 98, wherein the CTPS1 inhibitor is administered in combination with radiation therapy, surgery, hyperthermia, and / or cryotherapy. Clause 100. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, pharmaceutical composition for use, or use according to any one of clauses 1 to 99, wherein said subject has undergone chemotherapy, radiation therapy, surgery, hyperthermia, and / or cryotherapy prior to administration of CTPS1. Clause 101. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, pharmaceutical composition for use, or use according to any one of clauses 1 to 100, wherein said subject has undergone chemotherapy, radiation therapy, surgery, hyperthermia, and / or cryotherapy concomitantly with CTPS1 administration. Clause 102. The method, the CTPS1 inhibitor for use, the pharmaceutical composition for use, the pharmaceutical composition for use, or the use according to any one of clauses 1 to 101, wherein the subject has undergone chemotherapy, radiation therapy, surgery, hyperthermia, and / or cryotherapy after administration of CTPS1. Clause 103. The method, the CTPS1 inhibitor for use, the pharmaceutical composition for use, the pharmaceutical composition for use, or the use according to any one of clauses 1 to 102, wherein said cancer or cancer cells are from a cancer type in which at least 10% are CTPS2 deficient, for example at least 15% are CTPS2 deficient, in particular at least 18% are CTPS2 deficient. Clause 104. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, pharmaceutical composition for use, or use according to clause 103, wherein the lack of CTPS2 function is due to a homozygous deletion occurring in females or a hemizygous deletion occurring in males. Clause 105. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, pharmaceutical composition for use or use according to any one of clauses 1 to 104, wherein said cancer or cancer cells are derived from a cancer type in which at least 10% are CTPS2 deficient, for example at least 15% are CTPS2 deficient, particularly at least 20% are CTPS2 deficient, particularly at least 40% are CTPS2 deficient. Clause 106. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, pharmaceutical composition for use, or use according to clause 105, wherein the lack of CTPS2 function is determined by immunohistochemistry, for example, by lack of staining for CTPS2.

[0184] (References) [Table 1] TIFF2025542211000097.tif202170

Claims

1. A method for treating a CTPS2-deficient cancer in a subject, the method comprising administering to the subject a CTPS1 inhibitor.

2. 1. A method for treating cancer in a subject, comprising: i) identifying the subject as having a cancer that is deficient in CTPS2; and ii) administering a CTPS1 inhibitor to the subject. The method comprising:

3. 1. A method for treating cancer in a subject, comprising: i) providing a sample from said subject; ii) identifying the subject as having a cancer that is deficient in CTPS2; and iii) administering a CTPS1 inhibitor to the subject. The method comprising:

4. 1. A method for treating cancer in a subject, comprising: i) obtaining a sample from said subject; ii) identifying the subject as having a cancer that is deficient in CTPS2; and iii) administering a CTPS1 inhibitor to the subject. The method comprising:

5. 1. A method for treating a cancer in a subject that may be susceptible to treatment with a CTPS1 inhibitor, comprising: i) identifying the cancer as deficient in CTPS2; and ii) administering a CTPS1 inhibitor The method comprising:

6. 1. A method for treating a cancer in a subject that may be susceptible to treatment with a CTPS1 inhibitor, comprising: i) providing a sample from said subject; ii) identifying the cancer as deficient in CTPS2; and iii) administering a CTPS1 inhibitor The method comprising:

7. 1. A method for treating a cancer in a subject that may be susceptible to treatment with a CTPS1 inhibitor, comprising: i) obtaining a sample from said subject; ii) identifying the cancer as deficient in CTPS2; and iii) administering a CTPS1 inhibitor The method comprising:

8. A method for determining whether a cancer cell may be sensitive to treatment with a CTPS1 inhibitor, the method comprising a step of identifying that the cancer cell is deficient in CTPS2.

9. A method for determining whether a cancer in a subject may be susceptible to treatment with a CTPS1 inhibitor, the method comprising a step of identifying that the cancer is deficient in CTPS2.

10. A CTPS1 inhibitor for use in the treatment of CTPS2-deficient cancers.

11. A pharmaceutical composition comprising a CTPS1 inhibitor and a pharmaceutically acceptable excipient or carrier for use in treating CTPS2-deficient cancer.

12. Use of a CTPS1 inhibitor in the manufacture of a medicament for the treatment of CTPS2-deficient cancer.

13. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, or use according to any one of claims 1 to 12, wherein the CTPS2-deficient cancer is selected from the group consisting of ovarian cancer, esophageal cancer, bladder cancer, non-small cell lung cancer, gastric cancer, sarcoma, head and neck cancer, pancreatic adenocarcinoma, pancreatic neuroendocrine tumor, biliary tract cancer, melanoma, endometrial cancer, hepatocellular carcinoma, cervical cancer, bone cancer, central nervous system cancer, breast cancer, prostate cancer, colorectal cancer, and renal cancer.

14. The method, the CTPS1 inhibitor for use, the pharmaceutical composition for use, or the use according to any one of claims 1 to 12, wherein the cancer is ovarian cancer, for example, serous ovarian cancer.

15. The method, the CTPS1 inhibitor for use, the pharmaceutical composition for use, or the use according to any one of claims 1 to 12, wherein the cancer is lung cancer, for example, non-small cell lung cancer.

16. The method, the CTPS1 inhibitor for use, the pharmaceutical composition for use, or the use according to any one of claims 1 to 12, wherein the cancer is esophageal cancer.

17. The method, the CTPS1 inhibitor for use, the pharmaceutical composition for use, or the use according to any one of claims 1 to 12, wherein the cancer is gastric cancer.

18. The method, the CTPS1 inhibitor for use, the pharmaceutical composition for use, or the use according to any one of claims 1 to 12, wherein the cancer is head and neck cancer.

19. The method, the CTPS1 inhibitor for use, the pharmaceutical composition for use, or the use according to any one of claims 1 to 12, wherein the cancer is bladder cancer.

20. The method, the CTPS1 inhibitor for use, the pharmaceutical composition for use, or the use according to any one of claims 1 to 12, wherein the cancer is a sarcoma.

21. 21. The method, the CTPS1 inhibitor for use, the pharmaceutical composition for use, or the use according to any one of claims 1 to 20, wherein the CTPS1 inhibitor is a compound of formula (III): or a pharmaceutically acceptable salt and / or a pharmaceutically 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; provided 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 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 , OCH 3 , C.F. 3 , or OCF 3 and; where 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 Alkyl OH, 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 atoms 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, C 1-2 Alkyl, CF 3 , OCH 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 together with the nitrogen atom to which it is attached form an N-oxide (N + -O - ) form; R 13 is H or halo; R 21 is 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 alkyl).

22. 10. The CTPS1 inhibitor, 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 2】 or a pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate thereof.

23. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, or use according to any one of claims 1 to 22, wherein the deficiency of CTPS2 is due to genomic alteration(s) and / or epigenetic alteration(s).

24. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, or use of claim 23, wherein the genomic alteration(s) is complete loss of the CTPS2 gene due to a genomic deletion.

25. The method, the CTPS1 inhibitor for use, the pharmaceutical composition for use, or the use according to any one of claims 1 to 24, wherein the subject is a human male.

26. The method, the CTPS1 inhibitor for use, the pharmaceutical composition for use, or the use according to any one of claims 1 to 23, wherein the subject is a human female.

27. 27. The method, the CTPS1 inhibitor for use, the pharmaceutical composition for use, or the use according to any one of claims 1 to 26, wherein the deficiency of CTPS2 is due to a homozygous deletion in cancer cells.

28. The method, the CTPS1 inhibitor for use, the pharmaceutical composition for use, or the use according to any one of claims 1 to 27, wherein the deficiency of CTPS2 is determined by a method for detecting DNA alterations.

29. The method, the CTPS1 inhibitor for use, the pharmaceutical composition for use, or the use according to any one of claims 1 to 28, wherein the deficiency of CTPS2 is determined by a method of detecting RNA alterations.

30. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, or use according to any one of claims 1 to 29, wherein CTPS2 deficiency is determined by a method of detecting epigenetic changes.

31. The method, CTPS1 inhibitor for use, pharmaceutical composition for use, or use according to any one of claims 1 to 30, wherein the deficiency of CTPS2 is determined by a method for detecting protein changes, such as immunohistochemistry.

Images