CTPS1 inhibitors for treatment of CTPS2 deficient cancers

Abstract

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

Description

FIELD OF THE INVENTION

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

[0003] Cancer can affect a variety of cell types and tissues, but its underlying cause is disruption of cell division control. This process is very complex and requires careful coordination of multiple pathways, many of which remain to be fully characterized. Cell division requires efficient replication of the cell's DNA and other components. For many years, interfering with the replication ability of cells by targeting nucleic acid synthesis has been a core approach to cancer treatment. Examples of therapies that act in this way are 6-thioguanine, 6-mercaptopurine, 5-fluorouracil, cytarabine, gemcitabine, and pemetrexed.

[0004] Cancer therapeutics can be utilized that target a wide range of specific targets. Small molecule targeted therapeutics are typically inhibitors that target mutations, overexpressed enzyme domains, or otherwise key proteins within cancer cells. Monoclonal antibody therapies are another strategy, where the therapeutic agent is an antibody that specifically binds to a protein on the surface of cancer cells.

[0005] All proliferating cells, including tumor cells, rely on a ready supply of purine and pyrimidine nucleotides in DNA and RNA synthesis. While salvage pathways may be sufficient for steady-state metabolism, DNA replication makes cell division dependent on de novo synthesis of nucleotides. A key bottleneck in the de novo pyrimidine synthesis pathway is cytidine triphosphate synthase (CTPS), which catalyzes the conversion of UTP to CTP (van Kuilenburg 2000). CTPS also exists in two subtypes in humans (CTPS1 and CTPS2; see Figure 1 ). These two isoforms are ubiquitously expressed in normal and malignant human cells (BioGPS and EMBL-EBI expression atlases). The distinct roles of CTPS1 and CTPS2 in cell proliferation have been demonstrated (Minet 2023), and human genetic studies have identified a non-redundant and essential role of CTPS1 in normal immune (B and T) cell proliferation (Martin 2014; Martin 2020).

[0006] Although the proliferation of cancer cells depends on CTPS activity, the exact roles of CTPS1 and CTPS2 in cancer are not fully understood at present. Before phase I / II clinical trials, several CTPS inhibitors that inhibit CTPS1 and CTPS2 have been developed for oncology indications, but they were discontinued due to toxicity and efficacy issues. Most of the inhibitors developed are nucleoside analog prodrugs (3-deazauridine (DAU), CPEC, carbocyclic cytidine), which 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 (azaserine, 6-diazo-5-oxo-L-norleucine (DON)) are reactive analogs of glutamine that irreversibly inhibit the glutaminase domain of CTPS. Importantly, the CTPS inhibitors developed to date are not selective for one isoform of CTPS over the other. Thus, the available CTPS inhibitors block all CTPS activity, thereby blocking the ability of all cells in the body to divide.

[0007] Cancer is a genomic disease. The DNA of cancer cells contains different types of alterations that support the biological alterations that define the cell biology of cancer. These DNA alterations include mutations at the base level and structural alterations at the gene and chromosome levels, such as deletions, amplifications, and gene fusions. Cancer cells contain extensive genomic disruptions; however, only a small fraction of these changes directly alter cell biology, and the rest constitute collateral genomic damage or bystander effects of the mutational processes that lead to genetic alterations. For example, the deletion of genetic material in cancer cells may lead to the deletion of a specific tumor suppressor gene, which increases the fitness of cancer cells (and thus contributes to the process of cancer development); this same deletion may also lead to the deletion of other genes in the same region that have no effect on cancer cells. In some such cases, the deletion of genes that have no effect on cancer cells may create a state in which cancer cells are severely dependent on a specific metabolic pathway or enzyme, a situation that can be referred to as metabolic collateral lethality. As an example, the deletion of CTPS2 from cancer cells has no direct effect on cell fitness ( Figure 2 ), but creates a critical dependence on the activity of CTPS1 to produce the building blocks required for DNA synthesis (and thus cell division). In humans, CTPS2 was found to be located on the X chromosome (ChrX(p22.2); transcript IDs ENST00000359276.9, NM_175859; location: hg38 chrX:16,587,999-16,712,669).

[0008] Cancer treatment still requires new methods that can exhibit high in vivo efficacy, reduce the dose required for in vivo action, improved safety / reduced side effects, etc. SUMMARY OF THE INVENTION

[0010] The present invention provides a method for treating CTPS2-deficient cancer in a subject, the method comprising administering a CTPS1 inhibitor to the subject.

[0011] The present invention also provides a method for treating cancer in a subject, the method comprising the following steps:

[0012] i) identifying that the subject has CTPS2-deficient cancer; and

[0013] ii) administering a CTPS1 inhibitor to the subject.

[0014] The present invention also provides a method for treating cancer in a subject, the method comprising the following steps:

[0015] i) providing a sample from the subject;

[0016] ii) using the sample to identify that the subject has CTPS2-deficient cancer; and

[0017] iii) administering a CTPS1 inhibitor to the subject.

[0018] The present invention also provides a method for treating cancer in a subject, the method comprising the following steps:

[0019] i) obtaining a sample from the subject;

[0020] ii) using the sample to identify that the subject has CTPS2-deficient cancer; and

[0021] iii) administering a CTPS1 inhibitor to the subject.

[0022] The present invention also provides a method for treating cancer, the cancer in a subject may be prone to treatment with a CTPS1 inhibitor, the method comprising the following steps:

[0023] i) identifying that the cancer may lack CTPS2; and

[0024] ii) administering a CTPS1 inhibitor to the subject.

[0025] The present invention also provides a method for treating cancer, the cancer in a subject may be prone to treatment with a CTPS1 inhibitor, the method comprising the following steps:

[0026] i) providing a sample from the subject;

[0027] ii) identifying that the cancer may lack CTPS2 using the sample; and

[0028] iii) administering a CTPS1 inhibitor.

[0029] The present invention also provides a method for treating cancer that may be predisposed to treatment with a CTPS1 inhibitor in a subject, the method comprising the steps of:

[0030] i) obtaining a sample from the subject;

[0031] ii) identifying that the cancer may lack CTPS2 using the sample; and

[0032] iii) administering a CTPS1 inhibitor.

[0033] The present invention also provides a method for determining cancer cells that may be predisposed to treatment with a CTPS1 inhibitor, the method comprising the step of identifying that the cancer cells lack CTPS2.

[0034] The present invention also provides a method for determining cancer in a subject that may be predisposed to treatment with a CTPS1 inhibitor, the method comprising the step of identifying that the cancer lacks CTPS2.

[0035] The present invention also provides a method for determining cancer cells that may be predisposed to treatment with a CTPS1 inhibitor, the method comprising the step of identifying that the cancer cells may lack CTPS2.

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

[0037] The present invention also provides a CTPS1 inhibitor for treating CTPS2-deficient cancer. The present invention also provides a CTPS1 inhibitor for treating CTPS2-deficient cancer in a subject.

[0038] The present invention also provides a CTPS1 inhibitor for treating cancer that may lack CTPS2. The present invention also provides a CTPS1 inhibitor for treating cancer that may lack CTPS2 in a subject.

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

[0040] The present invention also provides the use of a CTPS1 inhibitor in the preparation of a medicament for treating cancers that may lack CTPS2. The present invention also provides the use of a CTPS1 inhibitor in the preparation of a medicament for treating cancers that may lack CTPS2 in a subject.

[0041] The present invention also provides a pharmaceutical composition comprising a CTPS1 inhibitor and a pharmaceutically acceptable excipient or carrier, which is used for treating CTPS2-deficient cancers. The present invention also provides a pharmaceutical composition comprising a CTPS1 inhibitor and a pharmaceutically acceptable excipient or carrier, which is used for treating cancers of CTPS2-deficient type in a subject.

[0042] The present invention also provides a pharmaceutical composition comprising a CTPS1 inhibitor and a pharmaceutically acceptable excipient or carrier, which is used for treating cancers that may lack CTPS2. The present invention also provides a pharmaceutical composition comprising a CTPS1 inhibitor and a pharmaceutically acceptable excipient or carrier, which is used for treating cancers that may lack CTPS2 in a subject.

[0043] Sequence summary

[0044] SEQ ID NO: 1 FLAG-His8-tag

[0045] SEQ ID NO: 2 FLAG-His-Avi tag

[0046] Summary of the drawings

[0047] Figure 1 : Restarted CTP production pathway.

[0048] Figure 2 : Achilles CRISPR screen of 1032 cancer cell lines; the schematic diagram shows a box plot and whisker plot representing the number of cell lines by median, interquartile range, and overall range; the x-axis shows the CERES score: 0 = no effect, <0 = reduced proliferation, -1 = median of all common essential genes.

[0049] Figure 3 : Analysis of whole-genome sequencing data of 2,348 cancer samples in the ICG CPCAWG group accessed through cBioPortal, showing the proportion of cancer type samples with homozygous deletion of CTPS2. NSCLC, non-small cell lung cancer; CNS, central nervous system.

[0050] 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 through the CellMiner CDB portal.

[0051] Figure 5 : Comparison of CTPS2 deletion determined by whole-genome sequencing data of samples in the ICGC PCAWG group with CTPS2 deletion determined by immunohistochemical analysis of tumor microarrays. DETAILED DESCRIPTION OF THE INVENTION

[0053] The present inventors have found that some cancers lack CTPS2 and may thus be particularly susceptible to treatment with CTPS1 inhibitors.

[0054] The present invention provides a method for treating CTPS2-deficient cancers in a subject, the method comprising administering a CTPS1 inhibitor to the subject.

[0055] The present invention also provides a method for treating cancer in a subject, the method comprising the following steps:

[0056] i) identifying that the subject has a CTPS2-deficient cancer; and

[0057] ii) administering a CTPS1 inhibitor to the subject.

[0058] The present invention also provides a method for treating cancer in a subject, the method comprising the following steps:

[0059] i) providing a sample from the subject;

[0060] ii) using the sample to identify that the subject has a CTPS2-deficient cancer; and

[0061] iii) administering a CTPS1 inhibitor to the subject.

[0062] The present invention also provides a method for treating cancer in a subject, the method comprising the following steps:

[0063] i) obtaining a sample from the subject;

[0064] ii) using the sample to identify that the subject has a CTPS2-deficient cancer; and

[0065] iii) administering a CTPS1 inhibitor to the subject.

[0066] The present invention also provides a method for treating cancer, the cancer in a subject may be predisposed to treatment with a CTPS1 inhibitor, the method comprising the following steps:

[0067] i) identifying that the cancer may lack CTPS2; and

[0068] ii) administering a CTPS1 inhibitor to the subject.

[0069] The present invention also provides a method for treating cancer that may be predisposed to treatment with a CTPS1 inhibitor in a subject, the method comprising the following steps:

[0070] i) providing a sample from the subject;

[0071] ii) using the sample to identify that the cancer may lack CTPS2; and

[0072] iii) administering a CTPS1 inhibitor.

[0073] The present invention also provides a method for treating cancer that may be predisposed to treatment with a CTPS1 inhibitor in a subject, the method comprising the following steps:

[0074] i) obtaining a sample from the subject;

[0075] ii) using the sample to identify that the cancer may lack CTPS2; and

[0076] iii) administering a CTPS1 inhibitor.

[0077] The present invention also provides a method for determining cancer cells that may be predisposed to treatment with a CTPS1 inhibitor, the method comprising the step of identifying that the cancer cells lack CTPS2.

[0078] The present invention also provides a method for determining the cancer of a subject that may be predisposed to treatment with a CTPS1 inhibitor, the method comprising the step of identifying that the cancer lacks CTPS2.

[0079] The present invention also provides a method for determining cancer cells that may be predisposed to treatment with a CTPS1 inhibitor, the method comprising the step of identifying that the cancer cells may lack CTPS2.

[0080] The present invention also provides a method for determining the cancer of a subject that may be predisposed to treatment with a CTPS1 inhibitor, the method comprising the step of identifying that the cancer may lack CTPS2.

[0081] The present invention also provides a CTPS1 inhibitor for treating CTPS2-deficient cancer. The present invention also provides a CTPS1 inhibitor for treating CTPS2-deficient cancer in a subject.

[0082] The present invention also provides a CTPS1 inhibitor for treating cancer that may lack CTPS2. The present invention also provides a CTPS1 inhibitor for treating cancer that may lack CTPS2 in a subject.

[0083] The present invention also provides the use of a CTPS1 inhibitor in the preparation of a medicament for treating CTPS2-deficient cancer. The present invention also provides the use of a CTPS1 inhibitor in the preparation of a medicament for treating CTPS2-deficient cancer in a subject.

[0084] The present invention also provides the use of a CTPS1 inhibitor in the preparation of a medicament for treating cancer that may be deficient in CTPS2. The present invention also provides the use of a CTPS1 inhibitor in the preparation of a medicament for treating cancer that may be deficient in CTPS2 in a subject.

[0085] The present invention also provides a pharmaceutical composition comprising a CTPS1 inhibitor and a pharmaceutically acceptable excipient or carrier, which is used for treating CTPS2-deficient cancer. The present invention also provides a pharmaceutical composition comprising a CTPS1 inhibitor and a pharmaceutically acceptable excipient or carrier, which is used for treating CTPS2-deficient cancer in a subject.

[0086] The present invention also provides a pharmaceutical composition comprising a CTPS1 inhibitor and a pharmaceutically acceptable excipient or carrier, which is used for treating CTPS2-deficient cancer. The present invention also provides a pharmaceutical composition comprising a CTPS1 inhibitor and a pharmaceutically acceptable excipient or carrier, which is used for treating CTPS2-deficient cancer in a subject.

[0087] CTPS1 inhibitor

[0088] As used herein, a CTPS1 inhibitor is an active agent that directly inhibits the enzymatic activity of CTPS1 enzyme by interacting with the enzyme. The direct inhibition of CTPS1 enzyme can be quantified using any suitable assay method. However, it can also be appropriately carried out using the method described in Example 1.

[0089] For CTPS1 enzyme, the CTPS1 inhibitor can exhibit an IC 50 , such as 1 μM or lower, especially 100 nM or lower. Particular CTPS1 inhibitors of interest are those having an IC 50 for CTPS1 enzyme of 10 μM or lower, such as 1 μM or lower, especially 100 nM or lower, as determined using the assay method described in Example 1.

[0090] Ideally, the CTPS1 inhibitor is more selective for CTPS1 than for CTPS2 (i.e., based on IC 50Ratio of values). Suitably, the inhibitor shows a selectivity of at least 2-fold, such as at least 30-fold, especially at least 60-fold, particularly at least 1000-fold. Of particular interest are CTPS1 inhibitors that are more selective for CTPS1 than CTPS2 using the assay method described in Example 2, suitably at least 2-fold, such as at least 30-fold, especially at least 60-fold, and particularly at least 1000-fold. Desirably, the selectivity for human CTPS1 is greater than that for human CTPS2.

[0091] For a drug intended for human use, CTPS1 inhibition and the selectivity of CTPS1 over CTPS2 should be based on the human form of the enzyme.

[0092] Suitably, the CTPS1 inhibitor can be selected from the following compounds:

[0093] Compounds of formula (I):

[0094]

[0095] wherein

[0096] R1 is C 1-5 alkyl, cycloalkyl optionally substituted with CH3, C 0-2 alkylene, C 3-5 cycloalkyl, C 1-3 alkylene OC 1-2 alkyl or CF3;

[0097] R3 is H, CH3, halogen, OC 1-2 alkyl or CF3;

[0098] R4 and R5 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 haloalkyl,

[0099] or R4 and R5 together with the carbon atom to which they are attached form a C 3-6 cycloalkyl or C 3-6 heterocycloalkyl ring;

[0100] R6 is H or C 1-3 alkyl;

[0101] Ar1 is a 6-membered aryl or heteroaryl;

[0102] Ar2 is a 6-membered aryl or heteroaryl group and is connected to Ar1 at the para position relative to the amide;

[0103] R 10 is H, halogen, C 1-3 alkyl, OC 1-2 alkyl, C 1-2 haloalkyl, OC 1-2 haloalkyl or CN;

[0104] R 11 is H, F, Cl, CH3, ethyl, OCH3, CF3, OCF3 or CN;

[0105] R 12 is connected to Ar2 at the meta or ortho position relative to Ar1, and R 12 is H, halogen, 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 alkyl or a C containing a nitrogen at the point of connection to Ar2 3-6 heterocycloalkyl, or R 12 together with the attached nitrogen atom forms an N-oxide (N + -O - );

[0106] R 23 is H or C 1-2 alkyl;

[0107] R 24 is H or C 1-2 alkyl;

[0108] or a pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate thereof.

[0109] More preferably, the CTPS1 inhibitor is selected from the following ('List A') compounds:

[0110] N-((2-(Cyclopropanesulfonamido)thiazol-4-yl)methyl)-5-phenylpicolinamide;

[0111] N-((2-(Cyclopropanesulfonamido)thiazol-4-yl)methyl)-4-(pyridin-3-yl)benzamide;

[0112] N-(1-(2-(Cyclopropanesulfonamido)thiazol-4-yl)propyl)-4-(5-(trifluoromethyl)pyridin-3-yl)benzamide;

[0113] N-(1-(2-(Cyclopropanesulfonamido)thiazol-4-yl)propyl)-4-(5-(trifluoromethyl)pyridin-3-yl)benzamide (R enantiomer);

[0114] N-(1-(2-(Cyclopropanesulfonamido)thiazol-4-yl)propyl)-4-(5-(trifluoromethyl)pyridin-3-yl)benzamide (S enantiomer);

[0115] N-(1-(2-(Cyclopropanesulfonamido)thiazol-4-yl)propyl)-4-(6-(trifluoromethyl)pyrazin-2-yl)benzamide;

[0116] N-(2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)propan-2-yl)-4-(6-ethoxypyrazin-2-yl)-2-fluorobenzamide;

[0117] N-(2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)propan-2-yl)-4-(6-ethoxypyrazin-2-yl)-2-methoxybenzamide;

[0118] N-((2-(Cyclopropanesulfonamido)thiazol-4-yl)methyl)-[1,1′-biphenyl]-4-carboxamide;

[0119] N-((2-(Cyclopropanesulfonamido)thiazol-4-yl)methyl)-2-fluoro-4-(6-(trifluoromethyl)pyrazin-2-yl)benzamide;

[0120] N-((2-(Cyclopropanesulfonamido)thiazol-4-yl)methyl)-4-(6-ethoxypyrazin-2-yl)-2-fluorobenzamide;

[0121] N-((2-(Cyclopropanesulfonamido)thiazol-4-yl)methyl)-4-(6-(trifluoromethyl)pyrazin-2-yl)benzamide;

[0122] N-((2-(Cyclopropanesulfonamido)thiazol-4-yl)methyl)-4-(6-isopropoxypyrazin-2-yl)benzamide;

[0123] N-((2-(Cyclopropanesulfonylamino)thiazol-4-yl)methyl)-4-(6-ethoxypyrazin-2-yl)benzamide;

[0124] N-(3-(2-(Cyclopropanesulfonylamino)thiazol-4-yl)pentan-3-yl)-4-(5-(trifluoromethyl)pyridin-3-yl)benzamide;

[0125] N-(3-(2-(Cyclopropanesulfonylamino)thiazol-4-yl)pentan-3-yl)-4-(5-fluoropyridin-3-yl)benzamide;

[0126] N-(3-(2-(Cyclopropanesulfonylamino)thiazol-4-yl)pentan-3-yl)-4-(5-methylpyridin-3-yl)benzamide;

[0127] N-(3-(2-(Cyclopropanesulfonylamino)thiazol-4-yl)pentan-3-yl)-4-(pyridin-3-yl)benzamide;

[0128] N-(3-(2-(Cyclopropanesulfonylamino)thiazol-4-yl)pentan-3-yl)-4-(6-(trifluoromethyl)pyrazin-2-yl)benzamide;

[0129] 4-(6-Chloropyrazin-2-yl)-N-(3-(2-(cyclopropanesulfonylamino)thiazol-4-yl)pentan-3-yl)benzamide;

[0130] N-(3-(2-(Cyclopropanesulfonylamino)thiazol-4-yl)pentan-3-yl)-4-(6-methylpyrazin-2-yl)benzamide;

[0131] N-(3-(2-(Cyclopropanesulfonylamino)thiazol-4-yl)pentan-3-yl)-4-(pyrazin-2-yl)benzamide;

[0132] N-(2-(2-(Cyclopropanesulfonylamino)thiazol-4-yl)propan-2-yl)-5-(6-ethoxypyrazin-2-yl)-3-fluoropyridinecarboxamide;

[0133] N-(2-(2-(Cyclopropanesulfonylamino)thiazol-4-yl)propan-2-yl)-5-(6-(trifluoromethyl)pyrazin-2-yl)pyridinecarboxamide;

[0134] 5-(6-Chloropyrazin-2-yl)-N-(2-(2-(cyclopropanesulfonylamino)thiazol-4-yl)propan-2-yl)pyridinecarboxamide;

[0135] N-(2-(2-(Cyclopropanesulfonylamino)thiazol-4-yl)propan-2-yl)-5-(6-ethoxypyrazin-2-yl)pyridinecarboxamide;

[0136] N-(2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)propan-2-yl)-[2,2'-bipyridine]-5-carboxamide;

[0137] 4-(5-Chloropyridin-3-yl)-N-(2-(2-(cyclopropanesulfonamido)thiazol-4-yl)propan-2-yl)benzamide;

[0138] N-(2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)propan-2-yl)-2-fluoro-4-(5-(trifluoromethyl)pyridin-3-yl)benzamide;

[0139] 4-(5-Chloropyridin-3-yl)-N-(2-(2-(cyclopropanesulfonamido)thiazol-4-yl)propan-2-yl)-2-fluorobenzamide;

[0140] N-(2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)propan-2-yl)-2-fluoro-4-(5-fluoropyridin-3-yl)benzamide;

[0141] N-(2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)propan-2-yl)-2-methoxy-4-(5-(trifluoromethyl)pyridin-3-yl)benzamide;

[0142] 4-(5-Acetylpyridin-3-yl)-N-(2-(2-(cyclopropanesulfonamido)thiazol-4-yl)propan-2-yl)benzamide;

[0143] N-(2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)propan-2-yl)-4-(5-(trifluoromethyl)pyridin-3-yl)benzamide;

[0144] N-(2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)propan-2-yl)-4-(5-fluoropyridin-3-yl)benzamide;

[0145] N-(2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)propan-2-yl)-4-(5-methylpyridin-3-yl)benzamide;

[0146] N-(2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)propan-2-yl)-4-(5-methoxypyridin-3-yl)benzamide;

[0147] N-(2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)propan-2-yl)-4-(pyridin-3-yl)benzamide;

[0148] N-(2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)propan-2-yl)-3'-(trifluoromethyl)-[1,1'-biphenyl]-4-carboxamide;

[0149] N-(2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)propan-2-yl)-4-(6-ethylpyrazin-2-yl)-2-fluorobenzamide;

[0150] N-(2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)propan-2-yl)-2-fluoro-4-(6-(trifluoromethyl)pyrazin-2-yl)benzamide;

[0151] N-(2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)propan-2-yl)-2-fluoro-4-(6-isopropoxypyrazin-2-yl)benzamide;

[0152] N-(2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)propan-2-yl)-2-fluoro-4-(6-(2,2,2-trifluoroethoxy)pyrazin-2-yl)benzamide;

[0153] N-(2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)propan-2-yl)-2-methyl-4-(6-(trifluoromethyl)pyrazin-2-yl)benzamide;

[0154] N-(2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)propan-2-yl)-4-(6-ethoxypyrazin-2-yl)-2-methylbenzamide;

[0155] N-(2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)propan-2-yl)-4-(6-ethoxypyrazin-2-yl)-2-(trifluoromethyl)benzamide;

[0156] N-(2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)propan-2-yl)-2-methoxy-4-(6-(trifluoromethyl)pyrazin-2-yl)benzamide;

[0157] 4-(6-Chloropyrazin-2-yl)-N-(2-(2-(cyclopropanesulfonamido)thiazol-4-yl)propan-2-yl)-2-methoxybenzamide;

[0158] 4-(6-Cyanopyrazin-2-yl)-N-(2-(2-(cyclopropanesulfonamido)thiazol-4-yl)propan-2-yl)-2-methoxybenzamide;

[0159] N-(2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)propan-2-yl)-4-(6-(trifluoromethyl)pyrazin-2-yl)benzamide;

[0160] 4-(6-Chloropyrazin-2-yl)-N-(2-(2-(cyclopropanesulfonamido)thiazol-4-yl)propan-2-yl)benzamide;

[0161] N-(2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)propan-2-yl)-4-(6-methylpyrazin-2-yl)benzamide;

[0162] N-(2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)propan-2-yl)-4-(6-methoxypyrazin-2-yl)benzamide;

[0163] N-(2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)propan-2-yl)-4-(6-ethoxypyrazin-2-yl)benzamide;

[0164] N-(2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)propan-2-yl)-4-(6-isopropoxypyrazin-2-yl)benzamide;

[0165] N-(2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)propan-2-yl)-4-(6-(2,2,2-trifluoroethoxy)pyrazin-2-yl)benzamide;

[0166] N-(2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)propan-2-yl)-4-(pyrazin-2-yl)benzamide;

[0167] N-(1-(2-(Cyclopropanesulfonamido)thiazol-4-yl)propyl)-4-(5-fluoropyridin-3-yl)benzamide;

[0168] N-(1-(2-(Cyclopropanesulfonamido)thiazol-4-yl)propyl)-4-(5-methylpyridin-3-yl)benzamide;

[0169] N-(1-(2-(Cyclopropanesulfonamido)thiazol-4-yl)propyl)-4-(pyridin-3-yl)benzamide;

[0170] N-(1-(2-(Cyclopropanesulfonamido)thiazol-4-yl)propyl)-4-(6-ethoxypyrazin-2-yl)-2-fluorobenzamide;

[0171] N-(1-(2-(Cyclopropanesulfonamido)thiazol-4-yl)propyl)-4-(6-ethoxypyrazin-2-yl)-2-fluoro-N-methylbenzamide;

[0172] N-(1-(2-(Cyclopropanesulfonamido)thiazol-4-yl)propyl)-2-fluoro-4-(6-isopropoxypyrazin-2-yl)benzamide;

[0173] 4-(6-Chloropyrazin-2-yl)-N-(1-(2-(Cyclopropanesulfonamido)thiazol-4-yl)propyl)benzamide;

[0174] N-(1-(2-(Cyclopropanesulfonamido)thiazol-4-yl)propyl)-4-(6-methylpyrazin-2-yl)benzamide;

[0175] N-(1-(2-(Cyclopropanesulfonamido)thiazol-4-yl)propyl)-4-(pyrazin-2-yl)benzamide;

[0176] N-(1-(2-(Cyclopropanesulfonamido)thiazol-4-yl)propyl)-4-(5-fluoropyridin-3-yl)benzamide (R enantiomer);

[0177] N-(1-(2-(Cyclopropanesulfonamido)thiazol-4-yl)propyl)-4-(5-fluoropyridin-3-yl)benzamide (S enantiomer);

[0178] N-(1-(2-(Cyclopropanesulfonamido)thiazol-4-yl)propyl)-4-(6-ethoxypyrazin-2-yl)-2-fluorobenzamide (R enantiomer);

[0179] N-(1-(2-(Cyclopropanesulfonamido)thiazol-4-yl)propyl)-4-(6-ethoxypyrazin-2-yl)-2-fluorobenzamide (S enantiomer);

[0180] N-(2-(2-(Cyclopropanesulfonamido)-5-methylthiazol-4-yl)propan-2-yl)-5-(6-ethoxypyrazin-2-yl)picolinamide;

[0181] N-(2-(5-chloro-2-(Cyclopropanesulfonamido)thiazol-4-yl)propan-2-yl)-5-(6-ethoxypyrazin-2-yl)picolinamide;

[0182] N-(2-(2-(Cyclopropanesulfonamido)-5-methylthiazol-4-yl)propan-2-yl)-4-(6-ethoxypyrazin-2-yl)-2-fluorobenzamide;

[0183] N-(2-(5-chloro-2-(Cyclopropanesulfonamido)thiazol-4-yl)propan-2-yl)-4-(6-ethoxypyrazin-2-yl)-2-fluorobenzamide;

[0184] N-(2-(2-(Cyclopropanesulfonamido)-5-methylthiazol-4-yl)propan-2-yl)-2-methyl-4-(6-(trifluoromethyl)pyrazin-2-yl)benzamide;

[0185] N-(2-(5-chloro-2-(Cyclopropanesulfonamido)thiazol-4-yl)propan-2-yl)-2-methyl-4-(6-(trifluoromethyl)pyrazin-2-yl)benzamide;

[0186] N-(2-(2-(Cyclopropanesulfonamido)-5-methylthiazol-4-yl)propan-2-yl)-4-(6-(trifluoromethyl)pyrazin-2-yl)benzamide;

[0187] N-(2-(5-chloro-2-(cyclopropanesulfonamido)thiazol-4-yl)propan-2-yl)-4-(6-(trifluoromethyl)pyrazin-2-yl)benzamide;

[0188] N-(1-(2-(Cyclopropanesulfonamido)thiazol-4-yl)cyclopropyl)-5-(6-ethoxypyrazin-2-yl)picolinamide;

[0189] N-(1-(2-(Cyclopropanesulfonamido)thiazol-4-yl)cyclopropyl)-4-(pyridin-3-yl)benzamide;

[0190] N-(1-(2-(Cyclopropanesulfonamido)thiazol-4-yl)cyclopropyl)-4-(6-ethoxypyrazin-2-yl)-2-fluorobenzamide;

[0191] N-(1-(2-(Cyclopropanesulfonamido)thiazol-4-yl)cyclopropyl)-2-methyl-4-(6-(trifluoromethyl)pyrazin-2-yl)benzamide;

[0192] N-(1-(2-(Cyclopropanesulfonamido)thiazol-4-yl)cyclopropyl)-4-(6-(trifluoromethyl)pyrazin-2-yl)benzamide;

[0193] N-(1-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-3-methoxypropyl)-4-(5-fluoropyridin-3-yl)benzamide;

[0194] N-(1-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-3-methoxypropyl)-4-(6-ethylpyrazin-2-yl)-2-fluorobenzamide;

[0195] N-(1-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-3-methoxypropyl)-2-fluoro-4-(6-(trifluoromethyl)pyrazin-2-yl)benzamide;

[0196] N-(1-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-3-methoxypropyl)-4-(6-ethoxypyrazin-2-yl)-2-fluorobenzamide;

[0197] N-(1-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-3-methoxypropyl)-2-fluoro-4-(6-isopropoxypyrazin-2-yl)benzamide;

[0198] N-(1-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-3-methoxypropyl)-4-(6-ethoxypyrazin-2-yl)benzamide;

[0199] N-(1-(2-(Cyclopropanesulfonamido)thiazol-4-yl)ethyl)-4-(6-ethoxypyrazin-2-yl)-2-fluorobenzamide;

[0200] N-(1-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-3-methoxypropyl)-4-(6-ethoxypyrazin-2-yl)-2-fluorobenzamide (R enantiomer); and

[0201] N-(1-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-3-methoxypropyl)-4-(6-ethoxypyrazin-2-yl)-2-fluorobenzamide (S enantiomer);

[0202] or a pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate thereof.

[0203] This CTPS1 inhibitor was disclosed in PCT Publication No. WO2019106146, and for the purpose of the CTPS1 inhibitor disclosed therein, the entire content of that patent is incorporated herein by reference. In particular, the CTPS1 inhibitor can be a compound described in any one of Items 1 - 110 of WO2019106146 or a pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate thereof, particularly the compound R1 - R93 or a pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate thereof.

[0204] Alternatively, the CTPS1 inhibitor is a compound of formula (II):

[0205]

[0206] wherein

[0207] R1 is C 1-5 alkyl, cycloalkyl optionally substituted with CH3, C 0-2 alkylene, C 3-5 cycloalkyl, C 1-3 alkylene OC 1-2 alkyl or CF3;

[0208] R3 is H, halogen, CH3, OC 1-2 alkyl or CF3;

[0209] or R3 and R5 together form a 5 - or 6 - membered cycloalkyl or a 5 - or 6 - membered oxygen - containing heterocycloalkyl;

[0210] R4 and R5 are each independently H, halogen, C 1-6 alkyl, C0-2 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 Halogenated alkyl, OC 1-6 Halogenated alkyl or NR 21 R 22 ,

[0211] or R4 is H, and R5 together with R3 forms a 5- or 6-membered cycloalkyl or a 5- or 6-membered oxygen-containing heterocycloalkyl,

[0212] or R4 and R5 together with the carbon atom to which they are attached form a C 3-6 Cycloalkyl or C 3-6 Heterocycloalkyl,

[0213] or R4 is H, and R5 and R6 are a C 2-3 Alkylene chain forming a 5- or 6-membered ring;

[0214] or R4 is O, and R5 is absent;

[0215] R6 is H or C 1-3 Alkyl,

[0216] or when in the ortho position to the amide, R6 together with R 11 is a C2 alkylene chain forming a 5-membered ring,

[0217] or R5 and R6 are a C 2-3 Alkylene chain forming a 5- or 6-membered ring, and R4 is H;

[0218] Ar1 is a 6-membered aryl or heteroaryl;

[0219] Ar2 is a 6-membered aryl or heteroaryl, and is connected to Ar1 at the para position relative to the amide;

[0220] R 10 is H, halogen, C 1-3 Alkyl, OC 1-2 Alkyl, C 1-2 Halogenated alkyl, OC 1-2 Halogenated alkyl or CN;

[0221] R 11 is H, F, Cl, CH3, ethyl, OCH3, CF3, OCF3 or CN,

[0222] Or when in the ortho position of the amide, R 11 together with R6 is a C2-alkylene chain forming a 5-membered ring;

[0223] R 12 is connected to Ar2 at the ortho or meta position relative to Ar1, and R 12 is H, halogen, 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 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, a C 3-6 heterocycloalkyl containing a nitrogen at the point of connection to Ar2 or R 12 together with the attached nitrogen atom forms an N-oxide (N + -O - );

[0224] R 13 is H, halogen, CH3 or OCH3;

[0225] R 21 is H, C 1-5 alkyl, C(O)C 1-5 alkyl, C(O)OC 1-5 alkyl;

[0226] R 22 is H or CH3;

[0227] R 23 is H or C 1-2 alkyl; and

[0228] R 24 is H or C 1-2 alkyl;

[0229] or a pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate thereof.

[0230] More preferably, the CTPS1 inhibitor is selected from the following compounds (‘List B’):

[0231] N-([1,1′-biphenyl]-4-yl)-2-(2-(methylsulfonamido)thiazol-4-yl)acetamide;

[0232] N-([1,1′-biphenyl]-4-yl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)acetamide;

[0233] 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-ethyl-N-(5-(pyrazin-2-yl)pyridin-2-yl)butyramide;

[0234] 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(4-(pyrimidin-2-yl)phenyl)propanamide;

[0235] 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(pyridin-3-yl)phenyl)butyramide (racemate);

[0236] (R)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(pyridin-3-yl)phenyl)butyramide;

[0237] (S)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(pyridin-3-yl)phenyl)butyramide;

[0238] 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(5-fluoropyridin-3-yl)phenyl)butyramide (racemate);

[0239] (R)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(5-fluoropyridin-3-yl)phenyl)butyramide;

[0240] (S)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(5-fluoropyridin-3-yl)phenyl)butyramide;

[0241] 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-3-methyl-N-(4-(pyrimidin-5-yl)phenyl)butyramide;

[0242] 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-3-methyl-N-(4-(pyridin-3-yl)phenyl)butyramide;

[0243] 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(5-methoxypyridin-3-yl)phenyl)-2-methylpropanamide;

[0244] N-(2-chloro-4-(pyridin-3-yl)phenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)acetamide;

[0245] 2-(2-(cyclopropanesulfonamido)-5-methylthiazol-4-yl)-2-methyl-N-(4-(6-(trifluoromethyl)pyrazin-2-yl)phenyl)propanamide;

[0246] 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(4-(pyrimidin-5-yl)phenyl)propanamide;

[0247] 6-(4-(2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methylpropanamido)phenyl)-N,N-dimethylpyrazine-2-carboxamide;

[0248] N-(5-(5-cyanopyridin-3-yl)pyrimidin-2-yl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methylpropanamide;

[0249] N-([1,1′-biphenyl]-4-yl)-2-(5-chloro-2-(cyclopropanesulfonamido)thiazol-4-yl)acetamide;

[0250] 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-ethynylpyrazin-2-yl)phenyl)butyramide;

[0251] 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(6-(pyrimidin-5-yl)pyridin-3-yl)acetamide;

[0252] 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(5-phenylpyridin-2-yl)acetamide;

[0253] 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4′-fluoro-[1,1′-biphenyl]-4-yl)acetamide;

[0254] 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-methyl-N-(4-(pyridin-3-yl)phenyl)acetamide;

[0255] N-([2,3′-bipyridin]-5-yl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)propanamide;

[0256] 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(3′-methoxy-[1,1′-biphenyl]-4-yl)-2-methylpropanamide;

[0257] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(4-(pyridin-3-yl)phenyl)propanamide;

[0258] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(4-(5-methylpyridin-3-yl)phenyl)propanamide;

[0259] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(4-(pyridazin-4-yl)phenyl)propanamide;

[0260] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(4-(pyrazin-2-yl)phenyl)propanamide;

[0261] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-methoxypyrazin-2-yl)phenyl)butanamide;

[0262] N-(3-Cyano-4-(pyrazin-2-yl)phenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methylpropanamide;

[0263] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(5-(6-(trifluoromethyl)pyrazin-2-yl)pyridin-2-yl)propanamide;

[0264] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(2,3-difluoro-4-(pyridin-3-yl)phenyl)-2-methylpropanamide;

[0265] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(5-(pyridin-3-yl)pyrimidin-2-yl)propanamide;

[0266] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(5-(6-propoxypyrazin-2-yl)pyridin-2-yl)propanamide;

[0267] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(3-fluoro-4-(pyrazin-2-yl)phenyl)-2-methylpropanamide;

[0268] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(4-(pyridin-3-yl)-2-(trifluoromethoxy)phenyl)propanamide;

[0269] N-(2-Chloro-4-(pyridin-3-yl)phenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methylpropanamide;

[0270] 2-(2-(Cyclopropanesulfonylamino)thiazol-4-yl)-N-(2-fluoro-4-(pyridin-3-yl)phenyl)-2-methylpropanamide;

[0271] 2-(2-(Cyclopropanesulfonylamino)thiazol-4-yl)-N-(3-methoxy-4-(pyrazin-2-yl)phenyl)-2-methylpropanamide;

[0272] 2-(2-(Cyclopropanesulfonylamino)thiazol-4-yl)-N-(4-(2-methoxypyridin-3-yl)phenyl)-2-methylpropanamide;

[0273] 2-(2-(Cyclopropanesulfonylamino)thiazol-4-yl)-N-(4-(5-(hydroxymethyl)pyridin-3-yl)phenyl)acetamide;

[0274] 2-(2-(Cyclopropanesulfonylamino)thiazol-4-yl)-N-(4-(6-methoxypyridin-3-yl)phenyl)-2-methylpropanamide;

[0275] N-(4-(5-Cyanopyridin-3-yl)phenyl)-2-(2-(cyclopropanesulfonylamino)thiazol-4-yl)-2-methylpropanamide;

[0276] 2-(2-(Cyclopropanesulfonylamino)thiazol-4-yl)-2-methyl-N-(4-(5-(trifluoromethyl)pyridin-3-yl)phenyl)propanamide;

[0277] 2-(2-(Cyclopropanesulfonylamino)thiazol-4-yl)-2-methyl-N-(4-(5-(methylsulfonyl)pyridin-3-yl)phenyl)propanamide;

[0278] 2-(2-(Cyclopropanesulfonylamino)thiazol-4-yl)-N-(2-methoxy-4-(5-methoxypyridin-3-yl)phenyl)-2-methylpropanamide;

[0279] 2-(2-(Cyclopropanesulfonylamino)thiazol-4-yl)-2-methyl-N-(5′-(trifluoromethyl)-[3,3′-bipyridin]-6-yl)propanamide;

[0280] 2-(2-(Cyclopropanesulfonylamino)thiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2-methylpropanamide;

[0281] 2-(2-(Cyclopropanesulfonylamino)thiazol-4-yl)-2-methyl-N-(4-(6-morpholinopyrazin-2-yl)phenyl)propanamide;

[0282] N-(4-(6-Cyclobutoxypyrazin-2-yl)phenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methylpropanamide;

[0283] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(4-(6-propoxypyrazin-2-yl)phenyl)propanamide;

[0284] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(2-fluoro-4-(5-methoxypyridin-3-yl)phenyl)-2-methylpropanamide;

[0285] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-2-methoxy-N-(4-(6-methoxypyrazin-2-yl)phenyl)acetamide;

[0286] N-(4-(5-Chloropyridin-3-yl)phenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-isopropoxyacetamide;

[0287] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-4-methoxy-N-(5-(6-(trifluoromethyl)pyrazin-2-yl)pyridin-2-yl)butanamide;

[0288] N-([1,1′-Biphenyl]-4-yl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2,2-difluoroacetamide;

[0289] 2-(2-(Cyclobutanesulfonamido)thiazol-4-yl)-N-(4-(6-methoxypyrazin-2-yl)phenyl)acetamide;

[0290] N-([3,3′-Bipyridin]-6-yl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)butanamide;

[0291] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(5-phenylpyridin-2-yl)propanamide;

[0292] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(5-(pyrimidin-5-yl)pyridin-2-yl)acetamide;

[0293] N-([3,3′-Bipyridin]-6-yl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)acetamide;

[0294] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(6-phenylpyridin-3-yl)acetamide;

[0295] N-([2,3′-Bipyridin]-5-yl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)acetamide;

[0296] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(4-(pyridazin-3-yl)phenyl)propanamide;

[0297] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(pyridazin-4-yl)phenyl)butyramide;

[0298] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(pyrazin-2-yl)phenyl)butyramide;

[0299] N-(4-(5-Chloropyridin-3-yl)phenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-4-methoxybutyramide;

[0300] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(5-fluoropyridin-3-yl)phenyl)butyramide;

[0301] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-(trifluoromethyl)pyrazin-2-yl)phenyl)butyramide;

[0302] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-3-methyl-N-(4-(pyrazin-2-yl)phenyl)butyramide;

[0303] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-propoxypyrazin-2-yl)phenyl)butyramide;

[0304] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-isopropoxypyrazin-2-yl)phenyl)butyramide;

[0305] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-cyclopropoxypyrazin-2-yl)phenyl)butyramide;

[0306] N-(4-(6-Chloropyrazin-2-yl)phenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)butyramide;

[0307] N-(4-(6-Cyanopyrazin-2-yl)phenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)butyramide;

[0308] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-(trifluoromethyl)pyrazin-2-yl)phenyl)butyramide;

[0309] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-methoxypyrazin-2-yl)phenyl)acetamide;

[0310] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(pyrazin-2-yl)phenyl)acetamide;

[0311] N-([1,1′-Biphenyl]-4-yl)-2-(cyclopropanesulfonamido)-4,5,6,7-tetrahydrobenzo[d]thiazole-4-carboxamide;

[0312] 2-(Cyclopropanesulfonamido)-N-(4-(pyridin-3-yl)phenyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-4-carboxamide;

[0313] N-([1,1′-Biphenyl]-4-yl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)butyramide;

[0314] N-([1,1′-Biphenyl]-4-yl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-3-methylbutyramide;

[0315] N-(3′-Chloro-[1,1′-biphenyl]-4-yl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methylpropanamide;

[0316] N-(3′-Cyano-[1,1′-biphenyl]-4-yl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methylpropanamide;

[0317] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-2,2-difluoro-N-(4-(pyridin-3-yl)phenyl)acetamide;

[0318] N-(4-(5-Fluoropyridin-3-yl)phenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)butyramide;

[0319] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-2-ethyl-N-(4-(pyridin-3-yl)phenyl)butyramide;

[0320] N-(4-(5-Cyanopyridin-3-yl)phenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-ethylbutyramide;

[0321] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(5-ethoxypyridin-3-yl)phenyl)propanamide;

[0322] N-(4-(5-chloropyridin-3-yl)phenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)propanamide;

[0323] 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(5-ethoxypyridin-3-yl)phenyl)butanamide;

[0324] N-([1,1′-biphenyl]-4-yl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methylpropanamide;

[0325] 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(4-methylpyridin-3-yl)phenyl)acetamide;

[0326] 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(5-methylpyridin-3-yl)phenyl)acetamide;

[0327] 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(2-methylpyridin-3-yl)phenyl)acetamide;

[0328] 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-methylpyridin-3-yl)phenyl)acetamide;

[0329] 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(pyridin-3-yl)phenyl)propanamide;

[0330] 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(4-(2-methylpyridin-3-yl)phenyl)propanamide;

[0331] 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-oxo-N-(4-(pyridin-3-yl)phenyl)acetamide;

[0332] 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(4-(6-methylpyridin-3-yl)phenyl)propanamide;

[0333] 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-(trifluoromethyl)pyrazin-2-yl)phenyl)butanamide;

[0334] (R)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methoxy-N-(4-(6-methoxypyrazin-2-yl)phenyl)acetamide;

[0335] (S)-2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-2-methoxy-N-(4-(6-methoxypyrazin-2-yl)phenyl)acetamide;

[0336] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(5-(6-(2,2,2-trifluoroethoxy)pyrazin-2-yl)pyridin-2-yl)propanamide;

[0337] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(3-fluoro-5-(pyrazin-2-yl)pyridin-2-yl)-2-methylpropanamide;

[0338] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)-3-fluoropyridin-2-yl)-2-methylpropanamide;

[0339] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(3-fluoro-5-(6-(trifluoromethyl)pyrazin-2-yl)pyridin-2-yl)-2-methylpropanamide;

[0340] N-(5-(6-Cyanopyrazin-2-yl)-3-fluoropyridin-2-yl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methylpropanamide;

[0341] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(5'-(2,2,2-trifluoroethoxy)-[3,3'-bipyridin]-6-yl)propanamide;

[0342] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(5'-(difluoromethoxy)-[3,3'-bipyridin]-6-yl)-2-methylpropanamide;

[0343] N-([2,3'-Bipyridin]-5-yl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methylpropanamide;

[0344] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(6-(pyrimidin-5-yl)pyridin-3-yl)propanamide;

[0345] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(5-(difluoromethoxy)pyridin-3-yl)phenyl)-2-methylpropanamide;

[0346] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-2-ethyl-N-(4-(6-methoxypyrazin-2-yl)phenyl)butanamide;

[0347] N-(4-(5-chloropyridin-3-yl)phenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-ethylbutanamide;

[0348] 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-ethyl-N-(2-fluoro-4-(pyridin-3-yl)phenyl)butanamide;

[0349] 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-ethyl-N-(4-(pyrazin-2-yl)phenyl)butanamide;

[0350] 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-ethyl-N-(4-(6-propoxypyrazin-2-yl)phenyl)butanamide;

[0351] 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(2-fluoro-4-(6-(trifluoromethyl)pyrazin-2-yl)phenyl)-2-methylpropanamide;

[0352] 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(5-ethoxypyridin-3-yl)-2-fluorophenyl)-2-methylpropanamide;

[0353] 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(2-fluoro-4-(5-fluoropyridin-3-yl)phenyl)-2-methylpropanamide;

[0354] 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(4-(6-(2,2,2-trifluoroethoxy)pyrazin-2-yl)phenyl)propanamide;

[0355] N-(4-(5-chloropyridin-3-yl)-2-fluorophenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methylpropanamide;

[0356] N-(4-(5-cyanopyridin-3-yl)-2-fluorophenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methylpropanamide;

[0357] 1-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-methoxypyrazin-2-yl)phenyl)cyclopentane-1-carboxamide;

[0358] 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(2-fluoro-4-(6-(2,2,2-trifluoroethoxy)pyrazin-2-yl)phenyl)-2-methylpropanamide;

[0359] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(2-fluoro-4-(5-(2,2,2-trifluoroethoxy)pyridin-3-yl)phenyl)-2-methylpropanamide;

[0360] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(2-fluoro-4-(5-(trifluoromethyl)pyridin-3-yl)phenyl)-2-methylpropanamide;

[0361] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)-2-methylpropanamide;

[0362] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(4-(5-(2,2,2-trifluoroethoxy)pyridin-3-yl)phenyl)propanamide;

[0363] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-ethynylpyrazin-2-yl)phenyl)-2-methylpropanamide;

[0364] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-methylphenyl)-2-methylpropanamide;

[0365] N-(4-(6-chloropyrazin-2-yl)-2-methylphenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methylpropanamide;

[0366] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(5-(difluoromethoxy)pyridin-3-yl)-2-fluorophenyl)-2-methylpropanamide;

[0367] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(5-(pyrazin-2-yl)pyridin-2-yl)propanamide;

[0368] N-(5-(6-cyclobutoxypyrazin-2-yl)pyridin-2-yl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methylpropanamide;

[0369] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(5-(6-cyclopropoxypyrazin-2-yl)pyridin-2-yl)-2-methylpropanamide;

[0370] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(5-(6-isopropoxypyrazin-2-yl)pyridin-2-yl)-2-methylpropanamide;

[0371] N-([3,3'-Bipyridin]-6-yl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-ethylbutanamide;

[0372] 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(5'-ethoxy-[3,3'-bipyridin]-6-yl)-2-ethylbutanamide;

[0373] 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(5'-propoxy-[3,3'-bipyridin]-6-yl)propanamide;

[0374] 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-ethyl-N-(5-(6-(trifluoromethyl)pyrazin-2-yl)pyridin-2-yl)butanamide;

[0375] N-([3,3'-Bipyridin]-6-yl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methylpropanamide;

[0376] 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(2-methoxy-4-(pyridin-3-yl)phenyl)-2-methylpropanamide;

[0377] 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(3-methoxy-4-(pyridin-3-yl)phenyl)-2-methylpropanamide;

[0378] 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(3-fluoro-4-(pyridin-3-yl)phenyl)-2-methylpropanamide;

[0379] N-(3-cyano-4-(pyridin-3-yl)phenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methylpropanamide;

[0380] N-(3-chloro-4-(pyridin-3-yl)phenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methylpropanamide;

[0381] N-(4-(6-cyanopyrazin-2-yl)phenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methylpropanamide;

[0382] N-(4-(6-chloropyrazin-2-yl)phenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methylpropanamide;

[0383] 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-ethyl-N-(4-(5-fluoropyridin-3-yl)phenyl)butanamide;

[0384] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(4-(5-propoxypyridin-3-yl)phenyl)propanamide;

[0385] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(5-isopropoxypyridin-3-yl)phenyl)-2-methylpropanamide;

[0386] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(2-fluoro-4-(5-isopropoxypyridin-3-yl)phenyl)-2-methylpropanamide;

[0387] N-(4-(6-Chloropyrazin-2-yl)phenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-ethylbutanamide;

[0388] N-(4-(6-Cyanopyrazin-2-yl)phenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-ethylbutanamide;

[0389] 2-Methyl-2-(2-(methylsulfonamido)thiazol-4-yl)-N-(4-(pyridin-3-yl)phenyl)propanamide;

[0390] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N,2-dimethyl-N-(4-(pyridin-3-yl)phenyl)propanamide;

[0391] 2-(Cyclopropanesulfonamido)-N-(5-(6-(trifluoromethyl)pyrazin-2-yl)pyridin-2-yl)-5,6-dihydro-4H-cyclopenta[d]thiazole-4-carboxamide;

[0392] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-4-methoxy-N-(5-(pyrazin-2-yl)pyridin-2-yl)butanamide;

[0393] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-4-methoxy-N-(5'-methoxy-[3,3'-bipyridin]-6-yl)butanamide;

[0394] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-2-isopropoxy-N-(5-(6-(trifluoromethyl)pyrazin-2-yl)pyridin-2-yl)acetamide;

[0395] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(5-(6-propoxypyrazin-2-yl)pyridin-2-yl)butanamide;

[0396] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(5-(6-isopropoxypyrazin-2-yl)pyridin-2-yl)butanamide;

[0397] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(5-(6-(trifluoromethyl)pyrazin-2-yl)pyridin-2-yl)butanamide;

[0398] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(5-(6-methoxypyrazin-2-yl)pyridin-2-yl)butanamide;

[0399] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)butanamide;

[0400] N-(5-(6-Cyanopyrazin-2-yl)pyridin-2-yl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)butanamide;

[0401] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(5'-fluoro-[3,3'-bipyridin]-6-yl)butanamide;

[0402] N-(5'-cyano-[3,3'-bipyridin]-6-yl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)butanamide;

[0403] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(5-phenylpyridin-2-yl)butanamide;

[0404] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(5-(6-(2,2,2-trifluoroethoxy)pyrazin-2-yl)pyridin-2-yl)butanamide;

[0405] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)-3-fluoropyridin-2-yl)butanamide;

[0406] N-(5-(6-Cyanopyrazin-2-yl)-3-fluoropyridin-2-yl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)butanamide;

[0407] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(5'-(2,2,2-trifluoroethoxy)-[3,3'-bipyridin]-6-yl)butanamide;

[0408] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(5'-(difluoromethoxy)-[3,3'-bipyridin]-6-yl)butanamide;

[0409] N-(5-(6-chloropyrazin-2-yl)pyridin-2-yl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)butanamide;

[0410] 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(2,3-difluoro-4-(pyridin-3-yl)phenyl)acetamide;

[0411] 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)butanamide (racemate);

[0412] 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-4-methoxy-N-(4-(6-methoxypyrazin-2-yl)phenyl)butanamide;

[0413] 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(5-fluoropyridin-3-yl)phenyl)-4-methoxybutanamide;

[0414] 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)propanamide;

[0415] 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(5-(trifluoromethyl)pyridin-3-yl)phenyl)butanamide;

[0416] N-(4-(5-cyanopyridin-3-yl)phenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)butanamide;

[0417] 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-(2,2,2-trifluoroethoxy)pyrazin-2-yl)phenyl)butanamide;

[0418] 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(2-fluoro-4-(pyrazin-2-yl)phenyl)butanamide;

[0419] 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(2-fluoro-4-(6-(trifluoromethyl)pyrazin-2-yl)phenyl)butanamide;

[0420] 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)butanamide;

[0421] 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(5-ethoxypyridin-3-yl)-2-fluorophenyl)butanamide;

[0422] 2-(2-(Cyclopropanesulfonylamino)thiazol-4-yl)-N-(2-fluoro-4-(5-fluoropyridin-3-yl)phenyl)butanamide;

[0423] 2-(2-(Cyclopropanesulfonylamino)thiazol-4-yl)-N-(2-fluoro-4-(pyridin-3-yl)phenyl)butanamide;

[0424] N-(4-(5-Cyanopyridin-3-yl)-2-fluorophenyl)-2-(2-(cyclopropanesulfonylamino)thiazol-4-yl)butanamide;

[0425] N-(4-(5-Chloropyridin-3-yl)-2-fluorophenyl)-2-(2-(cyclopropanesulfonylamino)thiazol-4-yl)butanamide;

[0426] (R)-2-(2-(Cyclopropanesulfonylamino)thiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)butanamide;

[0427] (S)-2-(2-(Cyclopropanesulfonylamino)thiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)butanamide;

[0428] N-(4-(1-(5-(6-Ethoxypyrazin-2-yl)dihydroindol-1-yl)-1-oxobutan-2-yl)thiazol-2-yl)cyclopropanesulfonamide;

[0429] 2-(2-(Cyclopropanesulfonylamino)thiazol-4-yl)-N-(2-fluoro-4-(6-(2,2,2-trifluoroethoxy)pyrazin-2-yl)phenyl)butanamide;

[0430] 2-(2-(Cyclopropanesulfonylamino)thiazol-4-yl)-N-(2-fluoro-4-(6-methoxypyrazin-2-yl)phenyl)butanamide;

[0431] 2-(2-(Cyclopropanesulfonylamino)thiazol-4-yl)-N-(4-(5-(difluoromethoxy)pyridin-3-yl)-2-fluorophenyl)butanamide;

[0432] 2-(2-(Cyclopropanesulfonylamino)thiazol-4-yl)-N-(4-(5-(difluoromethoxy)pyridin-3-yl)phenyl)butanamide;

[0433] 2-(2-(Cyclopropanesulfonylamino)thiazol-4-yl)-N-(4-(5-(2,2,2-trifluoroethoxy)pyridin-3-yl)phenyl)butanamide;

[0434] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(2-fluoro-4-(5-(2,2,2-trifluoroethoxy)pyridin-3-yl)phenyl)butanamide;

[0435] 2-(Cyclopropanesulfonamido)-N-(4-(pyridin-3-yl)phenyl)-5,6-dihydro-4H-cyclopenta[d]thiazole-4-carboxamide;

[0436] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-2-methoxy-N-(5-(6-(trifluoromethyl)pyrazin-2-yl)pyridin-2-yl)acetamide;

[0437] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(2-methoxy-4-(pyridin-3-yl)phenyl)acetamide;

[0438] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(2-fluoro-4-(pyridin-3-yl)phenyl)acetamide;

[0439] N-(4-(5-Cyanopyridin-3-yl)phenyl)-2-(cyclopropanesulfonamido)-5,6-dihydro-4H-cyclopenta[d]thiazole-4-carboxamide;

[0440] 2-(Cyclopropanesulfonamido)-N-(4-(5-fluoropyridin-3-yl)phenyl)-5,6-dihydro-4H-cyclopenta[d]thiazole-4-carboxamide;

[0441] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-2-methoxy-N-(4-(pyridin-3-yl)phenyl)acetamide;

[0442] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(2-fluoro-4-(pyridin-3-yl)phenyl)-2-methoxyacetamide;

[0443] N-(2-Chloro-4-(pyridin-3-yl)phenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)butanamide;

[0444] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-(2,2,2-trifluoroethoxy)pyrazin-2-yl)phenyl)butanamide;

[0445] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-(2,2,2-trifluoroethoxy)pyrazin-2-yl)phenyl)butanamide;

[0446] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(5′-methoxy-[3,3′-bipyridin]-6-yl)-2-methylpropanamide;

[0447] N-(5′-Chloro-[3,3′-bipyridin]-6-yl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methylpropanamide;

[0448] N-(5′-Cyano-[3,3′-bipyridin]-6-yl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methylpropanamide;

[0449] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(5-fluoro-[3,3′-bipyridin]-6-yl)-2-methylpropanamide;

[0450] N-(5′-Cyano-5-fluoro-[3,3′-bipyridin]-6-yl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methylpropanamide;

[0451] N-(5′-Chloro-5-fluoro-[3,3′-bipyridin]-6-yl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methylpropanamide;

[0452] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(5,5′-difluoro-[3,3′-bipyridin]-6-yl)-2-methylpropanamide;

[0453] N-(5-(3-Chloro-5-methylphenyl)pyridin-2-yl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methylpropanamide;

[0454] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(5-(3-methoxyphenyl)pyridin-2-yl)-2-methylpropanamide;

[0455] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(5-(3-fluoro-5-methoxyphenyl)pyridin-2-yl)-2-methylpropanamide;

[0456] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(5-(3,5-dimethoxyphenyl)pyridin-2-yl)-2-methylpropanamide;

[0457] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(5-(3-(trifluoromethyl)phenyl)pyridin-2-yl)propanamide;

[0458] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(5-(3-(trifluoromethoxy)phenyl)pyridin-2-yl)propanamide;

[0459] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(5-(3-(2-hydroxypropan-2-yl)phenyl)pyridin-2-yl)-2-methylpropanamide;

[0460] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(5-(3-morpholinophenyl)pyridin-2-yl)propanamide;

[0461] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(6-phenylpyridin-3-yl)propanamide;

[0462] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(2-fluoropyridin-3-yl)phenyl)-2-methylpropanamide;

[0463] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(5-(hydroxymethyl)pyridin-3-yl)phenyl)-2-methylpropanamide;

[0464] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(2-methoxypyrimidin-5-yl)phenyl)acetamide;

[0465] N-(4′-(tert-Butyl)-[1,1′-biphenyl]-4-yl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)acetamide;

[0466] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(pyridin-3-yl)phenyl)acetamide;

[0467] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(pyridin-4-yl)phenyl)acetamide;

[0468] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(2′-methoxy-[1,1′-biphenyl]-4-yl)acetamide;

[0469] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(pyrimidin-5-yl)phenyl)acetamide;

[0470] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(4-(2-(trifluoromethyl)pyridin-3-yl)phenyl)propanamide;

[0471] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(5′-methyl-[3,3′-bipyridin]-6-yl)propanamide;

[0472] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(2-methoxy-4-methylpyridin-3-yl)phenyl)-2-methylpropanamide;

[0473] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-methoxy-5-methylpyridin-3-yl)phenyl)-2-methylpropanamide;

[0474] N-(4-(5-Chloropyridin-3-yl)phenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methylpropanamide;

[0475] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(5-fluoropyridin-3-yl)phenyl)-2-methylpropanamide;

[0476] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(4-(4-methylpyridin-3-yl)phenyl)propanamide;

[0477] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(4-(4-(trifluoromethyl)pyridin-3-yl)phenyl)propanamide;

[0478] N-(4-(5-Chloropyridin-3-yl)-2-methoxyphenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methylpropanamide;

[0479] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(5-(dimethylamino)pyridin-3-yl)phenyl)-2-methylpropanamide;

[0480] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(2-methoxy-4-(5-methylpyridin-3-yl)phenyl)-2-methylpropanamide;

[0481] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(2-methoxy-4-(5-(trifluoromethyl)pyridin-3-yl)phenyl)-2-methylpropanamide;

[0482] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-methoxypyridin-3-yl)phenyl)acetamide;

[0483] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(5′-fluoro-[3,3′-bipyridin]-6-yl)-2-methylpropanamide;

[0484] N-(5-(6-Chloropyrazin-2-yl)pyridin-2-yl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methylpropanamide;

[0485] N-(5-(6-Cyanopyrazin-2-yl)pyridin-2-yl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methylpropanamide;

[0486] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(5-(pyrimidin-5-yl)pyridin-2-yl)propanamide;

[0487] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-methoxypyrazin-2-yl)phenyl)-2-methylpropanamide;

[0488] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(4-(6-methylpyrazin-2-yl)phenyl)propanamide;

[0489] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(4-(6-(trifluoromethyl)pyrazin-2-yl)phenyl)propanamide;

[0490] N-(4-(6-Chloropyridin-2-yl)phenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methylpropanamide;

[0491] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-methoxypyridin-2-yl)phenyl)-2-methylpropanamide;

[0492] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(4-(6-(trifluoromethyl)pyridin-2-yl)phenyl)propanamide;

[0493] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(4-methoxypyridin-2-yl)phenyl)-2-methylpropanamide;

[0494] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-isopropoxypyrazin-2-yl)phenyl)-2-methylpropanamide;

[0495] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-cyclopropoxypyrazin-2-yl)phenyl)-2-methylpropanamide;

[0496] 2-(2-(Cyclopropanesulfonylamino)thiazol-4-yl)-N-(2-fluoro-4-(pyrazin-2-yl)phenyl)-2-methylpropanamide;

[0497] 2-(2-(Cyclopropanesulfonylamino)thiazol-4-yl)-N-(2-fluoro-4-(6-methoxypyrazin-2-yl)phenyl)-2-methylpropanamide;

[0498] N-(4-(6-Chloro-3-methylpyrazin-2-yl)phenyl)-2-(2-(cyclopropanesulfonylamino)thiazol-4-yl)-2-methylpropanamide;

[0499] N-(4-(6-Chloro-5-methylpyrazin-2-yl)phenyl)-2-(2-(cyclopropanesulfonylamino)thiazol-4-yl)-2-methylpropanamide;

[0500] 2-(2-(Cyclopropanesulfonylamino)thiazol-4-yl)-2-methyl-N-(4-(6-(pyrrolidin-1-yl)pyrazin-2-yl)phenyl)propanamide;

[0501] 2-(2-(Cyclopropanesulfonylamino)thiazol-4-yl)-N-(4-(6-(2-(dimethylamino)ethoxy)pyrazin-2-yl)phenyl)-2-methylpropanamide;

[0502] 2-(2-(Cyclopropanesulfonylamino)thiazol-4-yl)-2-methyl-N-(4-(3-methylpyrazin-2-yl)phenyl)propanamide;

[0503] N-(4-(6-Acetamidopyrazin-2-yl)phenyl)-2-(2-(cyclopropanesulfonylamino)thiazol-4-yl)-2-methylpropanamide;

[0504] 2-(2-(Cyclopropanesulfonylamino)thiazol-4-yl)-N-(4-(5,6-dimethylpyrazin-2-yl)phenyl)-2-methylpropanamide;

[0505] 2-(2-(Cyclopropanesulfonylamino)thiazol-4-yl)-N-(4-(6-(hydroxymethyl)pyrazin-2-yl)phenyl)-2-methylpropanamide;

[0506] 2-(2-(Cyclopropanesulfonylamino)thiazol-4-yl)-N-(4-(3,6-dimethylpyrazin-2-yl)phenyl)-2-methylpropanamide;

[0507] 2-(2-(Cyclopropanesulfonylamino)thiazol-4-yl)-N-(4-(5-methoxypyridin-3-yl)-2-methylphenyl)-2-methylpropanamide;

[0508] N-(4-(5-Cyanopyridin-3-yl)-2-methylphenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methylpropanamide;

[0509] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(5-fluoropyridin-3-yl)-2-methylphenyl)-2-methylpropanamide;

[0510] N-(4-(5-Chloropyridin-3-yl)-3-methylphenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methylpropanamide;

[0511] N-(4-(5-Cyanopyridin-3-yl)-3-ethoxyphenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methylpropanamide;

[0512] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(5-ethoxypyridin-3-yl)phenyl)-2-methylpropanamide;

[0513] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-cyclopropylpyrazin-2-yl)phenyl)butanamide;

[0514] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(5-(5-methoxypyridin-3-yl)pyrimidin-2-yl)-2-methylpropanamide;

[0515] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(5-(5-fluoropyridin-3-yl)pyrimidin-2-yl)-2-methylpropanamide;

[0516] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(5-(5-(trifluoromethyl)pyridin-3-yl)pyrimidin-2-yl)propanamide;

[0517] N-(5-(6-Ethoxypyrazin-2-yl)pyridin-2-yl)-2-methyl-2-(2-((2-methylpropyl)sulfonamido)thiazol-4-yl)propanamide;

[0518] N-(4-(6-Ethoxypyrazin-2-yl)phenyl)-2-methyl-2-(2-((trifluoromethyl)sulfonamido)thiazol-4-yl)propanamide;

[0519] 2-Methyl-2-(2-((1-methylethyl)sulfonamido)thiazol-4-yl)-N-(4-(pyridin-3-yl)phenyl)propanamide;

[0520] N-(4-(6-Ethoxypyrazin-2-yl)phenyl)-2-methyl-2-(2-((1-methylethyl)sulfamoyl)thiazol-4-yl)propanamide;

[0521] 2-Methyl-2-(2-((1-methylcyclopropane)-1-sulfamoyl)thiazol-4-yl)-N-(4-(pyridin-3-yl)phenyl)propanamide;

[0522] N-(4-(5-Chloropyridin-3-yl)phenyl)-2-methyl-2-(2-((1-methylcyclopropane)-1-sulfamoyl)thiazol-4-yl)propanamide;

[0523] N-(4-(6-Ethoxypyrazin-2-yl)phenyl)-2-methyl-2-(2-((1-methylcyclopropane)-1-sulfamoyl)thiazol-4-yl)propanamide;

[0524] 2-Methyl-2-(2-((1-methylcyclopropane)-1-sulfamoyl)thiazol-4-yl)-N-(4-(6-(trifluoromethyl)pyrazin-2-yl)phenyl)propanamide;

[0525] 2-(2-((1,1-Dimethylethyl)sulfamoyl)thiazol-4-yl)-2-methyl-N-(4-(pyridin-3-yl)phenyl)propanamide;

[0526] 2-(2-((1,1-Dimethylethyl)sulfamoyl)thiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2-methylpropanamide;

[0527] 2-(2-((1,1-Dimethylethyl)sulfamoyl)thiazol-4-yl)-2-methyl-N-(4-(6-(trifluoromethyl)pyrazin-2-yl)phenyl)propanamide;

[0528] 2-(2-(Cyclobutanesulfamoyl)thiazol-4-yl)-2-methyl-N-(4-(pyridin-3-yl)phenyl)propanamide;

[0529] 2-(2-(Cyclobutanesulfamoyl)thiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2-methylpropanamide;

[0530] 2-(2-(Cyclobutanesulfamoyl)thiazol-4-yl)-2-methyl-N-(4-(6-(trifluoromethyl)pyrazin-2-yl)phenyl)propanamide;

[0531] N-(4-(5-Cyanopyridin-3-yl)phenyl)-2-(2-(cyclopropanesulfamoyl)thiazol-4-yl)-N,2-dimethylpropanamide;

[0532] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N,2-dimethyl-N-(4-(6-(trifluoromethyl)pyrazin-2-yl)phenyl)propanamide;

[0533] 2-Methyl-2-(2-((2-methylpropyl)sulfonamido)thiazol-4-yl)-N-(4-(pyridin-3-yl)phenyl)propanamide;

[0534] N-(4-(6-Ethoxypyrazin-2-yl)phenyl)-2-methyl-2-(2-((2-methylpropyl)sulfonamido)thiazol-4-yl)propanamide;

[0535] 2-Methyl-2-(2-((2-methylpropyl)sulfonamido)thiazol-4-yl)-N-(4-(6-(trifluoromethyl)pyrazin-2-yl)phenyl)propanamide;

[0536] N-(4-(5-Chloropyridin-3-yl)phenyl)-2-(2-(cyclopropanesulfonamido)-5-methylthiazol-4-yl)-2-methylpropanamide;

[0537] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-methyl-N-(4-(pyridin-3-yl)phenyl)butanamide;

[0538] N-(4-(5-Cyanopyridin-3-yl)phenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-methylbutanamide;

[0539] 2-(2-(Cyclopropanesulfonamido)-5-methylthiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2-methylpropanamide;

[0540] N-(4-(5-Chloropyridin-3-yl)phenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N,2-dimethylpropanamide;

[0541] 2-(2-(Cyclopropanesulfonamido)-5-methylthiazol-4-yl)-2-methyl-N-(4-(pyridin-3-yl)phenyl)propanamide;

[0542] N-(4-(5-Cyanopyridin-3-yl)-2,6-dimethylphenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methylpropanamide;

[0543] N-(4-(5-Chloropyridin-3-yl)-2,6-dimethylphenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methylpropanamide;

[0544] N-(4-(5-Cyanopyridin-3-yl)-3-methylphenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methylpropanamide;

[0545] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(pyridin-3-yl)phenyl)butanamide;

[0546] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(5-fluoropyridin-3-yl)phenyl)butanamide;

[0547] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-2-methoxy-N-(4-(6-methoxypyrazin-2-yl)phenyl)acetamide;

[0548] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)butanamide;

[0549] 2-Amino-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)acetamide;

[0550] 2-Acetamido-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)acetamide;

[0551] (1-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-2-((4-(6-ethoxypyrazin-2-yl)phenyl)amino)-2-oxoethyl)methyl carbamate;

[0552] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-2-(dimethylamino)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)acetamide;

[0553] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-4-hydroxybutanamide;

[0554] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2-methoxyacetamide;

[0555] (R)-2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2-methoxyacetamide;

[0556] (S)-2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2-methoxyacetamide;

[0557] 2-(2-((2-Methoxyethyl)sulfonylamino)thiazol-4-yl)-2-methyl-N-(5-(6-(trifluoromethyl)pyrazin-2-yl)pyridin-2-yl)propanamide;

[0558] 2-(2-(Cyclopentanesulfonylamino)thiazol-4-yl)-2-methyl-N-(4-(pyridin-3-yl)phenyl)propanamide;

[0559] 2-(2-(Cyclopentanesulfonylamino)thiazol-4-yl)-2-methyl-N-(4-(6-(trifluoromethyl)pyrazin-2-yl)phenyl)propanamide;

[0560] 2-(2-(Cyclopentanesulfonylamino)thiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2-methylpropanamide;

[0561] 2-(2-(Cyclopropanesulfonylamino)thiazol-4-yl)-N-(5-(6-isopropylpyrazin-2-yl)pyridin-2-yl)-2-methylpropanamide;

[0562] 2-(2-(Cyclopropanesulfonylamino)thiazol-4-yl)-N-(5'-ethoxy-[3,3'-bipyridin]-6-yl)-2-methylpropanamide;

[0563] 2-(2-(Cyclopropanesulfonylamino)thiazol-4-yl)-N-(5-(6-(2-hydroxypropan-2-yl)pyrazin-2-yl)pyridin-2-yl)-2-methylpropanamide;

[0564] 2-(2-(Cyclopropanesulfonylamino)thiazol-4-yl)-N-(5-(6-(2-methoxypropan-2-yl)pyrazin-2-yl)pyridin-2-yl)-2-methylpropanamide;

[0565] 2-(2-(Cyclopropanesulfonylamino)-5-methylthiazol-4-yl)-2-methyl-N-(5-(6-(trifluoromethyl)pyrazin-2-yl)pyridin-2-yl)propanamide;

[0566] 2-(2-(Cyclopropanesulfonylamino)thiazol-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2-methylpropanamide;

[0567] 2-(2-(Cyclopropanesulfonylamino)-5-methylthiazol-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2-methylpropanamide;

[0568] N-(4-(5-chloropyridin-3-yl)-2-(trifluoromethyl)phenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methylpropanamide;

[0569] N-(4-(5-cyanopyridin-3-yl)-2-(trifluoromethyl)phenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methylpropanamide;

[0570] 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(5-fluoropyridin-3-yl)-2-(trifluoromethyl)phenyl)-2-methylpropanamide;

[0571] 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(2-(trifluoromethyl)-4-(6-(trifluoromethyl)pyrazin-2-yl)phenyl)propanamide;

[0572] 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-(trifluoromethyl)phenyl)-2-methylpropanamide;

[0573] N-(4-(5-chloropyridin-3-yl)-2,6-diethylphenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methylpropanamide;

[0574] N-(4-(5-cyanopyridin-3-yl)-2,6-diethylphenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methylpropanamide;

[0575] 2-(2-(cyclopropanesulfonamido)-5-methylthiazol-4-yl)-N-(2-fluoro-4-(5-(trifluoromethyl)pyridin-3-yl)phenyl)-2-methylpropanamide;

[0576] N-(4-(5-chloropyridin-3-yl)-2,6-difluorophenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methylpropanamide;

[0577] N-(4-(5-chloropyridin-3-yl)-2-fluoro-5-methylphenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methylpropanamide;

[0578] 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(2-fluoro-4-(6-(2-methoxypropan-2-yl)pyrazin-2-yl)phenyl)-2-methylpropanamide;

[0579] 2-(2-(Cyclopropanesulfonamido)-5-methylthiazol-4-yl)-N-(2-fluoro-4-(6-(trifluoromethyl)pyrazin-2-yl)phenyl)-2-methylpropanamide;

[0580] N-(4-(6-Cyanopyrazin-2-yl)-2-fluorophenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methylpropanamide;

[0581] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-ethylpyrazin-2-yl)-2-fluorophenyl)-2-methylpropanamide;

[0582] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(2-fluoro-4-(6-isopropoxypyrazin-2-yl)phenyl)-2-methylpropanamide;

[0583] 2-(2-(Cyclopropanesulfonamido)-5-methylthiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)-2-methylpropanamide;

[0584] N-(4-(5-Chloropyridin-3-yl)-2-isopropylphenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methylpropanamide;

[0585] N-(4-(5-Cyanopyridin-3-yl)-2-isopropylphenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methylpropanamide;

[0586] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(2-isopropyl-4-(6-(trifluoromethyl)pyrazin-2-yl)phenyl)-2-methylpropanamide;

[0587] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-isopropylphenyl)-2-methylpropanamide;

[0588] N-(4-(5-Chloropyridin-3-yl)-3-fluoro-2-methylphenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methylpropanamide;

[0589] N-(4-(5-Chloropyridin-3-yl)-5-fluoro-2-methylphenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methylpropanamide;

[0590] N-(4-(5-Chloropyridin-3-yl)-2,3-dimethylphenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methylpropanamide;

[0591] N-(4-(5-chloropyridin-3-yl)-2,5-dimethylphenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methylpropanamide;

[0592] N-(4-(5-cyanopyridin-3-yl)-3-fluoro-2-methylphenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methylpropanamide;

[0593] 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(2-methyl-4-(6-(trifluoromethyl)pyrazin-2-yl)phenyl)propanamide;

[0594] N-(4-(5-chloropyridin-3-yl)-5-fluoro-2-methoxyphenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methylpropanamide;

[0595] N-(4-(5-chloropyridin-3-yl)-3-(trifluoromethyl)phenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methylpropanamide;

[0596] 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-3-methylphenyl)-2-methylpropanamide;

[0597] N-(4-(5-chloropyridin-3-yl)-3-ethoxyphenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methylpropanamide;

[0598] N-(4-(5-chloropyridin-3-yl)phenyl)-1-(2-(cyclopropanesulfonamido)thiazol-4-yl)cyclopropane-1-carboxamide;

[0599] N-(4-(5-cyanopyridin-3-yl)phenyl)-2-(2-(cyclopropanesulfonamido)-5-methylthiazol-4-yl)-2-methylpropanamide;

[0600] 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-(2-methoxypropan-2-yl)pyrazin-2-yl)phenyl)-2-methylpropanamide;

[0601] 2-(5-chloro-2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2-methylpropanamide;

[0602] 2-(2-(cyclopropanesulfonamido)-5-methoxythiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2-methylpropanamide;

[0603] N-(4-(6-(Cyclopentylmethoxy)pyrazin-2-yl)phenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methylpropanamide;

[0604] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-hydroxypyrazin-2-yl)phenyl)-2-methylpropanamide;

[0605] 2-(2-(Ethylsulfonamido)thiazol-4-yl)-2-methyl-N-(5'-(trifluoromethyl)-[3,3'-bipyridin]-6-yl)propanamide;

[0606] 2-(2-(Ethylsulfonamido)thiazol-4-yl)-2-methyl-N-(5-(6-(trifluoromethyl)pyrazin-2-yl)pyridin-2-yl)propanamide;

[0607] N-(5-(6-Ethoxypyrazin-2-yl)pyridin-2-yl)-2-(2-(ethylsulfonamido)thiazol-4-yl)-2-methylpropanamide;

[0608] 2-(2-(Ethylsulfonamido)thiazol-4-yl)-N-(2-fluoro-4-(6-isopropoxypyrazin-2-yl)phenyl)-2-methylpropanamide;

[0609] N-(4-(5-Cyanopyridin-3-yl)phenyl)-2-(2-(ethylsulfonamido)thiazol-4-yl)-2-methylpropanamide;

[0610] 2-(2-(Ethylsulfonamido)thiazol-4-yl)-N-(4-(5-fluoropyridin-3-yl)phenyl)-2-methylpropanamide;

[0611] 2-(2-(Ethylsulfonamido)thiazol-4-yl)-2-methyl-N-(4-(pyridin-3-yl)phenyl)propanamide;

[0612] 2-(2-(Ethylsulfonamido)thiazol-4-yl)-2-methyl-N-(4-(6-(trifluoromethyl)pyrazin-2-yl)phenyl)propanamide;

[0613] 2-(2-(Ethylsulfonamido)thiazol-4-yl)-N-(4-(6-isopropoxypyrazin-2-yl)phenyl)-2-methylpropanamide;

[0614] 2-Methyl-2-(2-(methylsulfonamido)thiazol-4-yl)-N-(5'-(trifluoromethyl)-[3,3'-bipyridin]-6-yl)propanamide;

[0615] N-(5-(6-Ethoxypyrazin-2-yl)pyridin-2-yl)-2-methyl-2-(2-(methylsulfonamido)thiazol-4-yl)propanamide;

[0616] N-(2-Fluoro-4-(6-(trifluoromethyl)pyrazin-2-yl)phenyl)-2-methyl-2-(2-(methylsulfonamido)thiazol-4-yl)propanamide;

[0617] N-(2-Fluoro-4-(6-isopropoxypyrazin-2-yl)phenyl)-2-methyl-2-(2-(methylsulfonamido)thiazol-4-yl)propanamide;

[0618] N-(4-(5-Chloropyridin-3-yl)phenyl)-2-methyl-2-(2-(methylsulfonamido)thiazol-4-yl)propanamide;

[0619] 2-Methyl-2-(2-(methylsulfonamido)thiazol-4-yl)-N-(4-(6-(trifluoromethyl)pyrazin-2-yl)phenyl)propanamide;

[0620] N-(4-(6-Isopropoxypyrazin-2-yl)phenyl)-2-methyl-2-(2-(methylsulfonamido)thiazol-4-yl)propanamide;

[0621] 2-(2-((Cyclopropylmethyl)sulfonamido)thiazol-4-yl)-2-methyl-N-(5-(6-(trifluoromethyl)pyrazin-2-yl)pyridin-2-yl)propanamide;

[0622] 1-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-(trifluoromethyl)pyrazin-2-yl)phenyl)cyclopropane-1-carboxamide;

[0623] 1-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)cyclopropane-1-carboxamide;

[0624] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(2-fluoro-4-(6-(trifluoromethyl)pyrazin-2-yl)phenyl)-4-methoxybutanamide;

[0625] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(2-fluoro-4-(6-isopropoxypyrazin-2-yl)phenyl)-4-methoxybutanamide;

[0626] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(5-(6-isopropylpyrazin-2-yl)pyridin-2-yl)butanamide;

[0627] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(5-(6-(2-methoxypropan-2-yl)pyrazin-2-yl)pyridin-2-yl)butanamide;

[0628] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(2-fluoro-4-(6-(2-methoxypropan-2-yl)pyrazin-2-yl)phenyl)butanamide;

[0629] N-(4-(6-Cyanopyrazin-2-yl)-2-fluorophenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)butanamide;

[0630] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-ethylpyrazin-2-yl)-2-fluorophenyl)butanamide;

[0631] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-(2-methoxypropan-2-yl)pyrazin-2-yl)phenyl)butanamide;

[0632] tert-Butyl-(1-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-((4-(6-ethoxypyrazin-2-yl)phenyl)amino)-2-oxoethyl)carbamate;

[0633] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(2-fluoro-4-(6-(trifluoromethyl)pyrazin-2-yl)phenyl)-2-methoxyacetamide;

[0634] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)-2-methoxyacetamide;

[0635] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2-methoxyacetamide;

[0636] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-isopropoxypyrazin-2-yl)phenyl)-2-methoxyacetamide;

[0637] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)butanamide;

[0638] (R)-2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)butanamide;

[0639] (S)-2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)butanamide;

[0640] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(5-(6-(trifluoromethyl)pyrazin-2-yl)pyridin-2-yl)butanamide;

[0641] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(2-fluoro-4-(5-(trifluoromethyl)pyridin-3-yl)phenyl)butanamide;

[0642] (R)-2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(2-fluoro-4-(5-(trifluoromethyl)pyridin-3-yl)phenyl)butanamide;

[0643] (S)-2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(2-fluoro-4-(5-(trifluoromethyl)pyridin-3-yl)phenyl)butanamide;

[0644] 2-Amino-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(5-(6-(trifluoromethyl)pyrazin-2-yl)pyridin-2-yl)acetamide hydrochloride;

[0645] 2-Amino-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(2-fluoro-4-(6-(trifluoromethyl)pyrazin-2-yl)phenyl)acetamide;

[0646] 2-Amino-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)acetamide hydrochloride;

[0647] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-2-(dimethylamino)-N-(2-fluoro-4-(6-(trifluoromethyl)pyrazin-2-yl)phenyl)acetamide;

[0648] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-2-(dimethylamino)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)acetamide;

[0649] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2,2-difluoroacetamide;

[0650] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)acetamide;

[0651] 2-(2-(Cyclopropanesulfonylamino)thiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)acetamide;

[0652] 2-Methyl-2-(2-(methylsulfonylamino)thiazol-4-yl)-N-(5-(6-(trifluoromethyl)pyrazin-2-yl)pyridin-2-yl)propanamide;

[0653] N-(2-Fluoro-4-(5-(trifluoromethyl)pyridin-3-yl)phenyl)-2-methyl-2-(2-(methylsulfonylamino)thiazol-4-yl)propanamide;

[0654] 2-(2-((Cyclopropylmethyl)sulfonylamino)thiazol-4-yl)-N-(2-fluoro-4-(5-(trifluoromethyl)pyridin-3-yl)phenyl)-2-methylpropanamide;

[0655] N-(4-(5-Chloro-4-methylpyridin-3-yl)phenyl)-2-(2-(cyclopropanesulfonylamino)thiazol-4-yl)-2-methylpropanamide;

[0656] N-(4-(6-Ethoxypyrazin-2-yl)-2-(trifluoromethyl)phenyl)-2-methyl-2-(2-(methylsulfonylamino)thiazol-4-yl)propanamide;

[0657] 2-(2-((Cyclopropylmethyl)sulfonylamino)thiazol-4-yl)-N-(2-fluoro-4-(6-(trifluoromethyl)pyrazin-2-yl)phenyl)-2-methylpropanamide;

[0658] N-(4-(6-Ethoxypyrazin-2-yl)-2-fluorophenyl)-2-methyl-2-(2-(methylsulfonylamino)thiazol-4-yl)propanamide;

[0659] N-(4-(6-Ethoxypyrazin-2-yl)-2-fluorophenyl)-2-(2-((2-methoxyethyl)sulfonylamino)thiazol-4-yl)-2-methylpropanamide;

[0660] 2-(2-((Cyclopropylmethyl)sulfonylamino)thiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)-2-methylpropanamide;

[0661] N-(4-(6-Ethoxypyrazin-2-yl)phenyl)-2-methyl-2-(2-(methylsulfonylamino)thiazol-4-yl)propanamide;

[0662] 2-(2-(Cyclopropanesulfonylamino)thiazol-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)-3-fluoropyridin-2-yl)-4-methoxybutanamide;

[0663] 2-(2-(Cyclopropanesulfonylamino)thiazol-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-methoxybutanamide;

[0664] 2-(2-(Cyclopropanesulfonylamino)thiazol-4-yl)-4-methoxy-N-(4-(6-(trifluoromethyl)pyrazin-2-yl)phenyl)butanamide;

[0665] 2-(2-(Cyclopropanesulfonylamino)thiazol-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)-3-methylpyridin-2-yl)butanamide;

[0666] N-(2-Chloro-4-(6-ethoxypyrazin-2-yl)phenyl)-2-(2-(cyclopropanesulfonylamino)thiazol-4-yl)butanamide;

[0667] N-(2-Cyano-4-(6-ethoxypyrazin-2-yl)phenyl)-2-(2-(cyclopropanesulfonylamino)thiazol-4-yl)butanamide;

[0668] 2-(2-(Cyclopropanesulfonylamino)thiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-methylphenyl)butanamide;

[0669] 2-(2-(Cyclopropanesulfonylamino)thiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-(trifluoromethoxy)phenyl)butanamide;

[0670] 2-(2-(Cyclopropanesulfonylamino)thiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-methoxyphenyl)butanamide;

[0671] 2-(2-(Cyclopropanesulfonylamino)thiazol-4-yl)-N-(4-(6-(ethylamino)pyrazin-2-yl)phenyl)butanamide;

[0672] 2-(2-(Cyclopropanesulfonylamino)thiazol-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)-3-fluoropyridin-2-yl)-2-methoxyacetamide;

[0673] 2-(2-(Cyclopropanesulfonylamino)thiazol-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2-methoxyacetamide;

[0674] 2-(2-(Cyclopropanesulfonylamino)thiazol-4-yl)-N-(4-(5-fluoropyridin-3-yl)-2-(trifluoromethyl)phenyl)-2-methoxyacetamide;

[0675] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(2-fluoro-4-(5-(trifluoromethyl)pyridin-3-yl)phenyl)-2-methoxyacetamide;

[0676] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-(trifluoromethyl)phenyl)-2-methoxyacetamide;

[0677] N-(2-chloro-4-(6-ethoxypyrazin-2-yl)phenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methoxyacetamide;

[0678] N-(2-cyano-4-(6-ethoxypyrazin-2-yl)phenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methoxyacetamide;

[0679] N-(2-fluoro-4-(6-(trifluoromethyl)pyrazin-2-yl)phenyl)-2-methoxy-2-(2-(methylsulfonamido)thiazol-4-yl)acetamide;

[0680] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2,6-difluorophenyl)-2-methoxyacetamide;

[0681] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-(trifluoromethoxy)phenyl)-2-methoxyacetamide;

[0682] N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2-methoxy-2-(2-(methylsulfonamido)thiazol-4-yl)acetamide;

[0683] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)-3-fluoropyridin-2-yl)butanamide (R enantiomer);

[0684] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)-3-fluoropyridin-2-yl)butanamide (S enantiomer);

[0685] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(2-fluoro-4-(6-(trifluoromethyl)pyrazin-2-yl)phenyl)-2-methoxyacetamide hydrochloride (R enantiomer);

[0686] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(2-fluoro-4-(6-(trifluoromethyl)pyrazin-2-yl)phenyl)-2-methoxyacetamide hydrochloride (S enantiomer);

[0687] 4-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)tetrahydro-2H-pyran-4-carboxamide;

[0688] 4-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(5-(6-(trifluoromethyl)pyrazin-2-yl)pyridin-2-yl)tetrahydro-2H-pyran-4-carboxamide;

[0689] 4-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)tetrahydro-2H-pyran-4-carboxamide;

[0690] N-(4-(1-(4-(5-methoxypyridin-3-yl)phenyl)-2-oxopyrrolidin-3-yl)thiazol-2-yl)cyclopropanesulfonamide;

[0691] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(5-(6-methylpyrazin-2-yl)pyridin-2-yl)propanamide; and

[0692] N-(4-(6-cyanopyrazin-2-yl)-2-methylphenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methylpropanamide;

[0693] or a pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate thereof.

[0694] This CTPS1 inhibitor was disclosed in PCT Publication No. WO2019106156. For the purpose of the CTPS1 inhibitor disclosed therein, the entire content of that patent is incorporated herein by reference. In particular, the CTPS1 inhibitor can be a compound described in any one of Clauses 1-118 of WO2019106156 or a pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate thereof, especially Compound T1-T465 or a pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate thereof.

[0695] Alternatively, the CTPS1 inhibitor is a compound of formula (III):

[0696]

[0697] wherein

[0698] A is an amide linking group having the following structure: -C(=O)NH- or -NHC(=O)-;

[0699] X is N or CH;

[0700] Y is N or CR2;

[0701] Z is N or CR3;

[0702] Provided that when at least one of X or Z is N, Y cannot be N;

[0703] R1 is C 1-5 alkyl, cycloalkyl optionally substituted with CH3, C 0-2 alkylene, C 3-5 cycloalkyl or CF3;

[0704] R2 is H, halogen, C 1-2 alkyl, OC 1-2 alkyl, C 1-2 haloalkyl or OC 1-2 haloalkyl;

[0705] R3 is H, halogen, CH3, OCH3, CF3 or OCF3;

[0706] wherein at least one of R2 and R3 is H;

[0707] R4 and R5 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 R4 and R5 together with the carbon atom to which they are attached form C 3-6 cycloalkyl or C 3-6 heterocycloalkyl; and

[0708] When A is -NHC(=O)-:

[0709] R4 and R5 can also be selected from halogen, 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 ;

[0710] Ar1 is a 6-membered aryl or heteroaryl;

[0711] Ar2 is a 6-membered aryl or heteroaryl group and is connected to Ar1 at the para position relative to the amide;

[0712] R 10 is H, halogen, C 1-3 alkyl, C 1-2 haloalkyl, OC 1-2 alkyl, OC 1-2 halo

[0713] alkyl or CN;

[0714] R 11 is H, F, Cl, C 1-2 alkyl, CF3, OCH3 or CN;

[0715] R 12 is connected to Ar2 at the ortho or meta position relative to Ar1, and R 12 is H, halogen, 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

[0716] When A is -NHC(=O)-:

[0717] R 12 can also be selected from CN, OCH2CH2N(CH3)2 and a C 3-6 heterocycloalkyl containing a nitrogen at the point of connection to Ar2, or R 12 together with the attached nitrogen atom forms an N-oxide (N + -O - );

[0718] R 13 is H or halogen;

[0719] R 21 is H, C 1-5 alkyl, C(O)C 1-5 alkyl, C(O)OC 1-5 alkyl;

[0720] R 22 is H or CH3;

[0721] R 23 is H or C 1-2 alkyl; and

[0722] R 24 is H or C 1-2 alkyl;

[0723] or a pharmaceutically acceptable salt and / or pharmaceutically acceptable solvate thereof.

[0724] More preferably, the CTPS1 inhibitor is selected from the following ('List C') compounds: N-(4-(5-chloropyridin-3-yl)phenyl)-2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)butanamide;

[0725] 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)cyclopentanecarboxamide;

[0726] 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-methoxypyrazin-2-yl)phenyl)-2-methylpropanamide;

[0727] 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-2-methyl-N-(4-(5-(trifluoromethyl)pyridin-3-yl)phenyl)propanamide;

[0728] 2-methyl-N-(2-methyl-4-(6-methylpyrazin-2-yl)phenyl)-2-(2-(methylsulfonamido)pyrimidin-4-yl)propanamide;

[0729] 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(2-fluoro-4-(pyrazin-2-yl)phenyl)butanamide;

[0730] 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(5-(trifluoromethyl)pyridin-3-yl)phenyl)butanamide;

[0731] 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-(trifluoromethyl)pyrazin-2-yl)phenyl)acetamide;

[0732] 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-isopropoxypyrazin-2-yl)pyridin-2-yl)-2-methylpropanamide;

[0733] 2-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2-ethylbutanamide;

[0734] 2-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(2-fluoro-4-(6-(trifluoromethyl)pyrazin-2-yl)phenyl)acetamide;

[0735] 2-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(2-fluoro-4-(6-isopropoxypyrazin-2-yl)phenyl)acetamide;

[0736] 2-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(5-(trifluoromethyl)pyridin-3-yl)phenyl)acetamide;

[0737] 2-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(5-(2,2,2-trifluoroethoxy)pyridin-3-yl)phenyl)acetamide;

[0738] 2-(2-(Cyclopropanesulfonamido)-5-fluoropyrimidin-4-yl)-N-(4-(pyridin-3-yl)phenyl)acetamide;

[0739] 2-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(pyridin-3-yl)phenyl)acetamide;

[0740] N-([1,1′-Biphenyl]-4-yl)-2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)acetamide;

[0741] 2-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)acetamide;

[0742] 2-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-methoxypyrazin-2-yl)phenyl)acetamide;

[0743] 2-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-(2,2,2-trifluoroethoxy)pyrazin-2-yl)phenyl)acetamide;

[0744] 2-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-isopropoxypyrazin-2-yl)phenyl)acetamide;

[0745] 2-(2-(Cyclobutanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2-methylpropanamide;

[0746] 2-(2-(Cyclobutanesulfonylamino)pyrimidin-4-yl)-N-(2-fluoro-4-(6-isopropoxypyrazin-2-yl)phenyl)-2-methylpropanamide;

[0747] 2-(2-(Cyclobutanesulfonylamino)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-methylphenyl)-2-methylpropanamide;

[0748] 2-(2-(Cyclobutanesulfonylamino)pyrimidin-4-yl)-N-(4-(6-methoxypyrazin-2-yl)phenyl)-2-methylpropanamide;

[0749] 2-(2-(Cyclobutanesulfonylamino)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2-methylpropanamide;

[0750] 2-(2-(Cyclopropanesulfonylamino)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)-3-fluoropyridin-2-yl)-2-methylpropanamide;

[0751] 2-(2-(Cyclopropanesulfonylamino)pyrimidin-4-yl)-N-(5'-ethoxy-[3,3'-bipyridin]-6-yl)-2-methylpropanamide;

[0752] N-([3,3'-Bipyridin]-6-yl)-2-(2-(cyclopropanesulfonylamino)pyrimidin-4-yl)-2-methylpropanamide;

[0753] 2-(2-(Cyclopropanesulfonylamino)pyrimidin-4-yl)-2-methyl-N-(5-(6-(trifluoromethyl)pyrazin-2-yl)pyridin-2-yl)propanamide;

[0754] 2-(2-(Cyclopropanesulfonylamino)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2yl)-2-methylpropanamide;

[0755] 2-(2-(Cyclopropanesulfonylamino)pyrimidin-4-yl)-N-(5-(6-cyclopropoxypyrazin-2-yl)pyridin-2-yl)-2-methylpropanamide;

[0756] N-(2-chloro-4-(6-ethoxypyrazin-2-yl)phenyl)-2-(2-(cyclopropanesulfonylamino)pyrimidin-4-yl)-2-methylpropanamide;

[0757] N-(2-cyano-4-(6-ethoxypyrazin-2-yl)phenyl)-2-(2-(cyclopropanesulfonylamino)pyrimidin-4-yl)-2-methylpropanamide;

[0758] 2-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(2-fluoro-4-(5-isopropoxypyridin-3-yl)phenyl)-2-methylpropanamide;

[0759] 2-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(2-fluoro-4-(pyridin-3-yl)phenyl)-2-methylpropanamide;

[0760] 2-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(2-fluoro-4-(6-(trifluoromethyl)pyrazin-2-yl)phenyl)-2-methylpropanamide;

[0761] 2-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)-2-methylpropanamide;

[0762] 2-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(2-fluoro-4-(6-isopropoxypyrazin-2-yl)phenyl)-2-methylpropanamide;

[0763] 2-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluoro-5-methylphenyl)-2-methylpropanamide;

[0764] 2-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2,6-difluorophenyl)-2-methylpropanamide;

[0765] 2-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(2-fluoro-4-(pyrazin-2-yl)phenyl)-2-methylpropanamide;

[0766] 2-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-2-methyl-N-(2-methyl-4-(6-(trifluoromethyl)pyrazin-2-yl)phenyl)propanamide;

[0767] 2-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2,3-dimethylphenyl)-2-methylpropanamide;

[0768] 2-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-5-fluoro-2-methylphenyl)-2-methylpropanamide;

[0769] 2-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2,5-dimethylphenyl)-2-methylpropanamide;

[0770] 2-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-(trifluoromethoxy)phenyl)-2-methylpropanamide;

[0771] 2-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-5-fluoro-2-methoxyphenyl)-2-methylpropanamide;

[0772] 2-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-methoxyphenyl)-2-methylpropanamide;

[0773] 2-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-2-methyl-N-(4-(pyrimidin-5-yl)phenyl)propanamide;

[0774] N-(4-(5-Chloropyridin-3-yl)phenyl)-2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-2-methylpropanamide;

[0775] N-(4-(5-Cyanopyridin-3-yl)phenyl)-2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-2-methylpropanamide;

[0776] 2-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(5-fluoropyridin-3-yl)phenyl)-2-methylpropanamide;

[0777] 2-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-2-methyl-N-(4-(5-methylpyridin-3-yl)phenyl)propanamide;

[0778] 2-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(5-(difluoromethoxy)pyridin-3-yl)phenyl)-2-methylpropanamide;

[0779] 2-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(5-methoxypyridin-3-yl)phenyl)-2-methylpropanamide;

[0780] 2-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(5-ethoxypyridin-3-yl)phenyl)-2-methylpropanamide;

[0781] 2-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(5-isopropoxypyridin-3-yl)phenyl)-2-methylpropanamide;

[0782] 2-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-2-methyl-N-(4-(pyridin-3-yl)phenyl)propanamide;

[0783] 2-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-2-methyl-N-(3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)propanamide;

[0784] N-(3′-Chloro-[1,1′-biphenyl]-4-yl)-2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-2-methylpropanamide;

[0785] N-(3′-Cyano-[1,1′-biphenyl]-4-yl)-2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-2-methylpropanamide;

[0786] 2-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(3′-ethoxy-[1,1′-biphenyl]-4-yl)-2-methylpropanamide;

[0787] 2-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-2-methyl-N-(4-(6-(trifluoromethyl)pyrazin-2-yl)phenyl)propanamide;

[0788] 2-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2-methylpropanamide;

[0789] 2-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-cyclopropoxypyrazin-2-yl)phenyl)-2-methylpropanamide;

[0790] 2-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-isopropoxypyrazin-2-yl)phenyl)-2-methylpropanamide;

[0791] 2-(2-(Cyclopropanesulfonamido)-5-fluoropyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2-methylpropanamide;

[0792] N-(4-(6-Ethoxypyrazin-2-yl)phenyl)-2-methyl-2-(2-((1-methylcyclopropane)-1-sulfonamido)pyrimidin-4-yl)propanamide;

[0793] 2-(2-(Cyclopropanesulfonamido)-5-methylpyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2-methylpropanamide;

[0794] 2-(2-(Cyclopropanesulfonylamino)pyrimidin-4-yl)-2-methyl-N-(4-(pyrazin-2-yl)phenyl)propanamide; N-(4-(6-Ethoxypyrazin-2-yl)-2-fluorophenyl)-2-(2-(ethylsulfonylamino)pyrimidin-4-yl)-2-methylpropanamide;

[0795] 2-(2-(Ethylsulfonylamino)pyrimidin-4-yl)-2-methyl-N-(4-(6-(trifluoromethyl)pyrazin-2-yl)phenyl)propanamide;

[0796] N-(4-(6-Ethoxypyrazin-2-yl)phenyl)-2-(2-(ethylsulfonylamino)pyrimidin-4-yl)-2-methylpropanamide;

[0797] N-(5-(6-Ethoxypyrazin-2-yl)-3-fluoropyridin-2-yl)-2-methyl-2-(2-(methylsulfonylamino)pyrimidin-4-yl)propanamide;

[0798] N-(5-(6-Ethoxypyrazin-2-yl)pyridin-2-yl)-2-methyl-2-(2-(methylsulfonylamino)pyrimidin-4-yl)propanamide;

[0799] N-(2-Fluoro-4-(5-isopropoxypyridin-3-yl)phenyl)-2-methyl-2-(2-(methylsulfonylamino)pyrimidin-4-yl)propanamide;

[0800] N-(2-Fluoro-4-(6-isopropoxypyrazin-2-yl)phenyl)-2-methyl-2-(2-(methylsulfonylamino)pyrimidin-4-yl)propanamide;

[0801] 2-Methyl-N-(2-methyl-4-(6-(trifluoromethyl)pyrazin-2-yl)phenyl)-2-(2-(methylsulfonylamino)pyrimidin-4-yl)propanamide;

[0802] 2-Methyl-2-(2-(methylsulfonylamino)pyrimidin-4-yl)-N-(4-(6-(trifluoromethyl)pyrazin-2-yl)phenyl)propanamide;

[0803] N-(4-(6-Ethoxypyrazin-2-yl)phenyl)-2-methyl-2-(2-(methylsulfonylamino)pyrimidin-4-yl)propanamide;

[0804] 2-(2-((1,1-Dimethylethyl)sulfonylamino)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2-methylpropanamide;

[0805] 1-(2-(Cyclopropanesulfonylamino)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)cyclopropanecarboxamide;

[0806] 2-(2-(Cyclopropanesulfonylamino)pyrimidin-4-yl)-N-(5′-(trifluoromethyl)-[3,3′-bipyridin]-6-yl)butanamide;

[0807] 2-(2-(Cyclopropanesulfonylamino)pyrimidin-4-yl)-N-(5′-(2,2,2-trifluoroethoxy)-[3,3′-bipyridin]-6-yl)butanamide;

[0808] N-([3,3′-Bipyridin]-6-yl)-2-(2-(cyclopropanesulfonylamino)pyrimidin-4-yl)butanamide;

[0809] 2-(2-(Cyclopropanesulfonylamino)pyrimidin-4-yl)-N-(5-(6-(trifluoromethyl)pyrazin-2-yl)pyridin-2-yl)butanamide;

[0810] 2-(2-(Cyclopropanesulfonylamino)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)butanamide;

[0811] 2-(2-(Cyclopropanesulfonylamino)pyrimidin-4-yl)-N-(5-(6-isopropoxypyrazin-2-yl)pyridin-2-yl)butanamide;

[0812] N-(4-(5-Chloropyridin-3-yl)-2-fluorophenyl)-2-(2-(cyclopropanesulfonylamino)pyrimidin-4-yl)butanamide; 2-(2-(Cyclopropanesulfonylamino)pyrimidin-4-yl)-N-(2-fluoro-4-(5-(2,2,2-trifluoroethoxy)pyridin-3-yl)phenyl)butanamide;

[0813] 2-(2-(Cyclopropanesulfonylamino)pyrimidin-4-yl)-N-(2-fluoro-4-(5-isopropoxypyridin-3-yl)phenyl)butanamide;

[0814] 2-(2-(Cyclopropanesulfonylamino)pyrimidin-4-yl)-N-(2-fluoro-4-(pyridin-3-yl)phenyl)butanamide;

[0815] 2-(2-(Cyclopropanesulfonylamino)pyrimidin-4-yl)-N-(2-fluoro-4-(6-(trifluoromethyl)pyrazin-2-yl)phenyl)butanamide;

[0816] 2-(2-(Cyclopropanesulfonylamino)pyrimidin-4-yl)-N-(2-fluoro-4-(6-methoxypyrazin-2-yl)phenyl)butanamide;

[0817] 2-(2-(Cyclopropanesulfonylamino)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)butanamide;

[0818] 2-(2-(Cyclopropanesulfonylamino)pyrimidin-4-yl)-N-(2-fluoro-4-(6-isopropoxypyrazin-2-yl)phenyl)butanamide;

[0819] 2-(2-(Cyclopropanesulfonylamino)pyrimidin-4-yl)-N-(2-fluoro-4-(6-(2,2,2-trifluoroethoxy)pyrazin-2-yl)phenyl)butanamide;

[0820] N-(4-(5-Cyanopyridin-3-yl)phenyl)-2-(2-(cyclopropanesulfonylamino)pyrimidin-4-yl)butanamide;

[0821] 2-(2-(Cyclopropanesulfonylamino)pyrimidin-4-yl)-N-(4-(5-(2,2,2-trifluoroethoxy)pyridin-3-yl)phenyl)butanamide;

[0822] 2-(2-(Cyclopropanesulfonylamino)pyrimidin-4-yl)-N-(4-(5-isopropoxypyridin-3-yl)phenyl)butanamide;

[0823] 2-(2-(Cyclopropanesulfonylamino)pyrimidin-4-yl)-N-(4-(pyridin-3-yl)phenyl)butanamide;

[0824] 2-(2-(Cyclopropanesulfonylamino)pyrimidin-4-yl)-N-(4-(6-(trifluoromethyl)pyrazin-2-yl)phenyl)butanamide;

[0825] N-(4-(6-Chloropyrazin-2-yl)phenyl)-2-(2-(cyclopropanesulfonylamino)pyrimidin-4-yl)butanamide;

[0826] 2-(2-(Cyclopropanesulfonylamino)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)butanamide;

[0827] 2-(2-(Cyclopropanesulfonylamino)pyrimidin-4-yl)-N-(4-(6-methoxypyrazin-2-yl)phenyl)butanamide;

[0828] 2-(2-(Cyclopropanesulfonylamino)pyrimidin-4-yl)-N-(4-(6-isopropoxypyrazin-2-yl)phenyl)butanamide;

[0829] 2-(2-(Cyclopropanesulfonylamino)pyrimidin-4-yl)-N-(4-(6-(2,2,2-trifluoroethoxy)pyrazin-2-yl)phenyl)butanamide;

[0830] 2-(2-(Cyclopropanesulfonylamino)pyrimidin-4-yl)-N-(4-(pyrazin-2-yl)phenyl)butanamide;

[0831] 2-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-4-methoxybutanamide;

[0832] 2-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(pyridin-3-yl)phenyl)acrylamide;

[0833] 2-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2-(R)-fluorobutanamide;

[0834] 2-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2-(S)-fluorobutanamide;

[0835] 2-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2-fluorobutanamide;

[0836] 4-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)tetrahydro-2H-pyran-4-carboxamide;

[0837] 2-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-isopropylpyrazin-2-yl)pyridin-2-yl)-2-methylpropanamide;

[0838] 2-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)-2,2-difluoroacetamide;

[0839] N-(((2-(Cyclopropanesulfonamido)pyrimidin-4-yl)methyl)-4-(6-ethoxypyrazin-2-yl)benzamide;

[0840] 2-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-2-methyl-N-(5-(6-(prop-1-en-2-yl)pyrazin-2-yl)pyridin-2-yl)propanamide;

[0841] 2-(2-(Cyclopropanesulfonamido)-6-methylpyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2-methylpropanamide;

[0842] 2-(2-(Cyclopropanesulfonamido)-6-(trifluoromethyl)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2-methylpropanamide;

[0843] 2-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-cyclopropylpyrazin-2-yl)pyridin-2-yl)-2-methylpropanamide;

[0844] 2-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(6-(6-ethoxypyrazin-2-yl)pyridin-3-yl)-2-methylpropanamide;

[0845] 2-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-cyclopropylpyrazin-2-yl)-2-fluorophenyl)-2-methylpropanamide;

[0846] 2-(2-(Cyclopropanesulfonamido)-6-methylpyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)-2-methylpropanamide;

[0847] 2-(2-(Cyclopropanesulfonamido)-6-(trifluoromethyl)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)-2-methylpropanamide;

[0848] 2-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-2-methyl-N-(4-(6-(prop-1-en-2-yl)pyrazin-2-yl)phenyl)propanamide;

[0849] 2-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-isopropylpyrazin-2-yl)phenyl)-2-methylpropanamide;

[0850] 2-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-(dimethylamino)pyrazin-2-yl)phenyl)-2-methylpropanamide;

[0851] 2-(2-(Cyclopropanesulfonamido)-6-methylpyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2-methylpropanamide;

[0852] 2-(2-(Cyclopropanesulfonamido)-6-(trifluoromethyl)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2-methylpropanamide;

[0853] 2-(2-(Cyclopropanesulfonamido)-6-methoxypyrimidin-4-yl)-2-methyl-N-(4-(pyridin-3-yl)phenyl)propanamide;

[0854] 1-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)cyclopentane-1-carboxamide;

[0855] 4-(2-(Cyclopropanesulfonylamino)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)tetrahydro-2H-pyran-4-carboxamide;

[0856] N-(5-(6-Ethoxypyrazin-2-yl)pyridin-2-yl)-4-(2-(methylsulfonylamino)pyrimidin-4-yl)piperidine-4-carboxamide;

[0857] tert-Butyl 4-(2-(cyclopropanesulfonylamino)pyrimidin-4-yl)-4-(((5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)amino)carbonyl)piperidine-1-carboxylate;

[0858] 4-(2-(Cyclopropanesulfonylamino)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)piperidine-4-carboxamide;

[0859] tert-Butyl 3-(2-(cyclopropanesulfonylamino)pyrimidin-4-yl)-3-(((5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)amino)carbonyl)azetidine-1-carboxylate;

[0860] tert-Butyl 4-(((5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)amino)carbonyl)-4-(2-(methylsulfonylamino)pyrimidin-4-yl)piperidine-1-carboxylate;

[0861] 4-(2-(Cyclopropanesulfonylamino)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)tetrahydro-2H-pyran-4-carboxamide;

[0862] 2-(2-(Cyclopropanesulfonylamino)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)-3-fluoropyridin-2-yl)-4-methoxybutanamide;

[0863] 2-(2-(Cyclopropanesulfonylamino)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-methoxybutanamide;

[0864] 2-(2-(Cyclopropanesulfonylamino)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)-4-methoxybutanamide;

[0865] N-(5-(6-Ethoxypyrazin-2-yl)pyridin-2-yl)-4-methoxy-2-methyl-2-(2-(methylsulfonylamino)pyrimidin-4-yl)butanamide;

[0866] N-(5′-Chloro-[3,3′-bipyridin]-6-yl)-2-(2-(cyclopropanesulfonylamino)pyrimidin-4-yl)butanamide;

[0867] N-(5′-Chloro-[3,3′-bipyridin]-6-yl)-2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-2-fluorobutanamide;

[0868] 2-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-cyclopropylpyrazin-2-yl)pyridin-2-yl)-2-fluorobutanamide;

[0869] N-(5-(6-Ethoxypyrazin-2-yl)pyridin-2-yl)-2-fluoro-2-(2-(methylsulfonamido)pyrimidin-4-yl)butanamide;

[0870] 2-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)-3-methylpyridin-2-yl)butanamide;

[0871] 2-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-cyclopropylpyrazin-2-yl)pyridin-2-yl)butanamide;

[0872] 2-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-(2,2,2-trifluoroethoxy)pyrazin-2-yl)pyridin-2-yl)butanamide;

[0873] 2-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(3-fluoro-5-(6-methoxypyrazin-2-yl)pyridin-2-yl)butanamide;

[0874] 2-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-methoxypyrazin-2-yl)pyridin-2-yl)butanamide;

[0875] 2-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-cyclopropylpyrazin-2-yl)-2-fluorophenyl)butanamide;

[0876] 2-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-methylphenyl)butanamide;

[0877] 2-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)-3-fluoropyridin-2-yl)butanamide;

[0878] 2-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2-methylbutanamide;

[0879] 2-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2-fluoro-3-methylbutanamide;

[0880] 2-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)-3-methylbutanamide;

[0881] 2-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-3-methylbutanamide;

[0882] 2-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2-methoxyacetamide;

[0883] N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2-fluoro-2-(2-(methylsulfonamido)pyrimidin-4-yl)-(R)-butanamide;

[0884] N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2-fluoro-2-(2-(methylsulfonamido)pyrimidin-4-yl)-(S)-butanamide;

[0885] 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;

[0886] 2-(6-(Cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(5-fluoropyridin-3-yl)phenyl)acetamide;

[0887] 2-(6-(Cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(5-methoxypyridin-3-yl)phenyl)acetamide;

[0888] 2-(6-(Cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(pyridin-3-yl)phenyl)acetamide;

[0889] 2-(6-(Cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(6-(trifluoromethyl)pyrazin-2-yl)phenyl)acetamide;

[0890] 2-(6-(Cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(6-methoxypyrazin-2-yl)phenyl)acetamide;

[0891] 2-(6-(Cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(pyrazin-2-yl)phenyl)acetamide;

[0892] N-([3,3′-Bipyridin]-6-yl)-2-(6-(cyclopropanesulfonamido)pyridin-2-yl)-2-methylpropanamide;

[0893] N-(4-(5-Chloropyridin-3-yl)phenyl)-2-(6-(cyclopropanesulfonamido)pyridin-2-yl)-2-methylpropanamide;

[0894] 2-(6-(Cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(5-fluoropyridin-3-yl)phenyl)-2-methylpropanamide;

[0895] 2-(6-(Cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(5-ethoxypyridin-3-yl)phenyl)-2-methylpropanamide;

[0896] 2-(6-(Cyclopropanesulfonamido)pyridin-2-yl)-2-methyl-N-(4-(pyridin-3-yl)phenyl)propanamide;

[0897] 2-(6-(Cyclopropanesulfonamido)pyridin-2-yl)-N-(2-fluoro-4-(pyrazin-2-yl)phenyl)-2-methylpropanamide;

[0898] 2-(6-(Cyclopropanesulfonamido)pyridin-2-yl)-2-methyl-N-(4-(6-(trifluoromethyl)pyrazin-2-yl)phenyl)propanamide;

[0899] N-(4-(6-Chloropyrazin-2-yl)phenyl)-2-(6-(cyclopropanesulfonamido)pyridin-2-yl)-2-methylpropanamide;

[0900] 2-(6-(Cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2-methylpropanamide;

[0901] 2-(6-(Cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(6-methoxypyrazin-2-yl)phenyl)-2-methylpropanamide;

[0902] 2-(6-(Cyclopropanesulfonamido)pyridin-2-yl)-2-methyl-N-(4-(pyrazin-2-yl)phenyl)propanamide;

[0903] 4-(6-(Cyclopropanesulfonamido)pyridin-2-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)tetrahydro-2H-pyran-4-carboxamide;

[0904] 2-(6-(Cyclopropanesulfonamido)pyridin-2-yl)-N-(5-(6-(trifluoromethyl)pyrazin-2-yl)pyridin-2-yl)butanamide;

[0905] 2-(6-(Cyclopropanesulfonamido)pyridin-2-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)butanamide;

[0906] N-(4-(5-Chloropyridin-3-yl)phenyl)-2-(6-(cyclopropanesulfonamido)pyridin-2-yl)butanamide;

[0907] 2-(6-(Cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)butanamide;

[0908] 2-(6-(Cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)butanamide;

[0909] 2-(6-(Cyclopropanesulfonamido)pyrazin-2-yl)-N-(4-(pyridin-3-yl)phenyl)acetamide;

[0910] 2-(6-(Ethylsulfonamido)pyrazin-2-yl)-N-(4-(pyridin-3-yl)phenyl)acetamide;

[0911] 2-(6-(Methylsulfonamido)pyrazin-2-yl)-N-(4-(pyridin-3-yl)phenyl)acetamide;

[0912] 2-(6-(Cyclopropanesulfonamido)pyrazin-2-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2-methylpropanamide;

[0913] 2-(6-(Cyclopropanesulfonamido)pyrazin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2-methylpropanamide;

[0914] 4-(6-(Cyclopropanesulfonamido)pyrazin-2-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)tetrahydro-2H-pyran-4-carboxamide;

[0915] 2-(6-(Cyclopropanesulfonamido)pyrazin-2-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-methoxy-2-methylbutanamide;

[0916] N-(5-(6-Ethoxypyrazin-2-yl)pyridin-2-yl)-4-methoxy-2-methyl-2-(6-(methylsulfonamido)pyrazin-2-yl)butanamide;

[0917] 2-(6-(Cyclopropanesulfonamido)pyrazin-2-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2-fluorobutanamide;

[0918] 2-(6-(Cyclopropanesulfonamido)pyrazin-2-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)butanamide;

[0919] 2-(6-(Cyclopropanesulfonamido)pyrazin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)butanamide;

[0920] 2-(6-(Cyclopropanesulfonamido)pyrazin-2-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2-methoxyacetamide;

[0921] 2-(6-(Cyclopropanesulfonamido)pyrazin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2-methoxyacetamide;

[0922] 2-(6-(Cyclopropanesulfonamido)pyrazin-2-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2-methoxypropanamide;

[0923] 2-(6-(Cyclopropanesulfonamido)pyrazin-2-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2-(R)-fluorobutanamide;

[0924] 2-(6-(Cyclopropanesulfonamido)pyrazin-2-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2-(S)-fluorobutanamide;

[0925] 2-(4-(Cyclopropanesulfonamido)pyrimidin-2-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)butanamide;

[0926] N-(1-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)cyclopropyl)-4-(6-ethoxypyrazin-2-yl)-2-fluorobenzamide;

[0927] N-(1-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)propyl)-5-(6-ethoxypyrazin-2-yl)pyridinecarboxamide;

[0928] N-(1-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)propyl)-2-fluoro-4-(5-(trifluoromethyl)pyridin-3-yl)benzamide;

[0929] 4-(5-Chloropyridin-3-yl)-N-(1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)propyl)-2-fluorobenzamide;

[0930] N-(1-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)propyl)-4-(5-(trifluoromethyl)pyridin-3-yl)benzamide;

[0931] 4-(5-Chloropyridin-3-yl)-N-(1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)propyl)benzamide;

[0932] N-(1-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)propyl)-4-(6-ethoxypyrazin-2-yl)-2-(trifluoromethyl)benzamide;

[0933] N-(1-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)propyl)-4-(6-ethoxypyrazin-2-yl)-2-fluorobenzamide;

[0934] N-(1-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)propyl)-4-(6-(trifluoromethyl)pyrazin-2-yl)benzamide;

[0935] N-(1-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)propyl)-4-(6-isopropoxypyrazin-2-yl)benzamide;

[0936] N-(1-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)propyl)-4-(6-ethoxypyrazin-2-yl)benzamide;

[0937] N-(2-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)butan-2-yl)-4-(6-ethoxypyrazin-2-yl)-2-fluorobenzamide;

[0938] N-(2-(6-(Cyclopropanesulfonamido)pyrazin-2-yl)propan-2-yl)-2-fluoro-4-(6-isopropoxypyrazin-2-yl)benzamide;

[0939] N-(2-(6-(Cyclopropanesulfonamido)pyrazin-2-yl)propan-2-yl)-4-(6-(trifluoromethyl)pyrazin-2-yl)benzamide;

[0940] N-(1-(6-(Cyclopropanesulfonamido)pyrazin-2-yl)propyl)-4-(6-ethoxypyrazin-2-yl)-2-fluorobenzamide;

[0941] N-(1-(6-(Cyclopropanesulfonamido)pyrazin-2-yl)propyl)-4-(6-ethoxypyrazin-2-yl)-2-(R)-fluorobenzamide; and

[0942] N-(1-(6-(Cyclopropanesulfonamido)pyrazin-2-yl)propyl)-4-(6-ethoxypyrazin-2-yl)-2-(S)-fluorobenzamide;

[0943] or a pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate thereof.

[0944] This type of CTPS1 inhibitor is disclosed in PCT Publication No. WO2019179652. For the purpose of the CTPS1 inhibitors disclosed therein, the entire content of this patent is incorporated herein by reference. In particular, the CTPS1 inhibitor can be a compound described in any one of Articles 1-148 of WO2019179652 or a pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate thereof, especially compound P1-P225 or a pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate thereof.

[0945] This type of CTPS1 inhibitor is disclosed in PCT Publication No. WO2019180244. For the purpose of the CTPS1 inhibitors disclosed therein, the entire content of this patent is incorporated herein by reference. In particular, the CTPS1 inhibitor can be a compound described in any one of Articles 1 to 148 of WO2019180244 or a pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate thereof, especially compound P1-P225 or a pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate thereof. Particular and especial attention is paid to the compounds or pharmaceutically acceptable salts and / or pharmaceutically acceptable solvates thereof in PCT Publication No. WO2019180244, which are selective for CTPS1 over CTPS2 (e.g., human CTPS1 over human CTPS2), such as those identified in Table 19. Particular attention is paid to those compounds or pharmaceutically acceptable salts and / or pharmaceutically acceptable solvates thereof shown in Table 19 of WO2019180244, the selectivity of which is >60-fold.

[0946] More preferably, the CTPS1 inhibitor is a compound of formula (IV):

[0947]

[0948] Wherein:

[0949] (a) When R4, R5, X, Y, and R1 are as follows:

[0950]

[0951] W is N, CH, or CF;

[0952] (b) When R4, R5, X, W, and R1 are as follows:

[0953]

[0954] Y is CH or N;

[0955] (c) When W, X, Y and R1 are as follows:

[0956]

[0957] R4 and R5 are linked to form the following structure:

[0958]

[0959] (d) When W, R4, R5, X and Y are as follows:

[0960]

[0961] R1 is methyl or cyclopropyl; and

[0962] (e) The compound is selected from:

[0963]

[0964] or a pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate thereof.

[0965] More preferably, the CTPS1 inhibitor is selected from the following compounds (‘List D’):

[0966] (R)-2-(2-(Cyclopropanesulfonylamino)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2-fluorobutanamide;

[0967] (S)-2-(2-(Cyclopropanesulfonylamino)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2-fluorobutanamide;

[0968] 4-(2-(Cyclopropanesulfonylamino)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)tetrahydro-2H-pyran-4-carboxamide;

[0969] 1-(2-(Cyclopropanesulfonylamino)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)cyclopentane-1-carboxamide;

[0970] 4-(2-(Cyclopropanesulfonylamino)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)tetrahydro-2H-pyran-4-carboxamide;

[0971] tert-Butyl 4-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-4-(((5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)amino)carbonyl)piperidine-1-carboxylate;

[0972] 4-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)tetrahydro-2H-pyran-4-carboxamide;

[0973] 2-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-methoxybutanamide;

[0974] (R)-N-(5-(6-Ethoxypyrazin-2-yl)pyridin-2-yl)-2-fluoro-2-(2-(methylsulfonamido)pyrimidin-4-yl)butanamide;

[0975] (S)-N-(5-(6-Ethoxypyrazin-2-yl)pyridin-2-yl)-2-fluoro-2-(2-(methylsulfonamido)pyrimidin-4-yl)butanamide;

[0976] 4-(6-(Cyclopropanesulfonamido)pyridin-2-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)tetrahydro-2H-pyran-4-carboxamide;

[0977] 4-(6-(Cyclopropanesulfonamido)pyrazin-2-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)tetrahydro-2H-pyran-4-carboxamide;

[0978] (R)-2-(6-(Cyclopropanesulfonamido)pyrazin-2-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2-fluorobutanamide; and

[0979] (S)-2-(6-(Cyclopropanesulfonamido)pyrazin-2-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2-fluorobutanamide;

[0980] or a pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate thereof.

[0981] This type of CTPS1 inhibitor is disclosed in PCT Publication No. WO2020083975, and for the purpose of the CTPS1 inhibitors disclosed therein, the entire content of this patent is incorporated herein by reference. 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 pharmaceutically acceptable solvate thereof.

[0982] Particular attention is paid to the compounds in PCT Publication No. WO2020083975 or pharmaceutically acceptable salts and / or pharmaceutically acceptable solvates thereof, which have a higher selectivity for CTPS1 than CTPS2 (e.g., human CTPS1 over human CTPS2), such as those identified in Table 11. Particular attention is paid to those compounds shown in Table 11 of WO2020083975 or pharmaceutically acceptable salts and / or pharmaceutically acceptable solvates thereof, with a selectivity > 60-fold.

[0983] Alternatively, the CTPS1 inhibitor is a compound of formula (V):

[0984]

[0985] (a) When A, V, W, X, Y, Z, R1, R 10 and R 12 are as follows:

[0986]

[0987] R4 and R5 together with the attached carbon atom form:

[0988]

[0989] or

[0990] (b) When A, V, W, X, Y, Z, R1, R 10 and R 12 are as follows:

[0991]

[0992] R4 and R5 together with the attached carbon atom form:

[0993]

[0994] or

[0995] (c) When A, V, W, X, Y, Z, R4, R5, R 10 and R 12When it is as follows:

[0996]

[0997] R1 is or

[0998] (d) When A, V, W, X, Y, Z, R4, R5, R 10 and R 12 are as follows:

[0999]

[1000] R1 is or

[1001] (e) When A, X, Y, Z, R1, R4 and R5 are as follows:

[1002]

[1003] V, W, R 10 and R 12 are:

[1004]

[1005] or

[1006] (f) When A, V, W, R1, R4, R5, R 10 and R 12 are as follows:

[1007]

[1008] Z, X and Y are

[1009]

[1010] or

[1011] (g) When A, V, W, R1, R4, R5, R 10 and R 12 are as follows:

[1012]

[1013] Z, X and Y are

[1014]

[1015] or

[1016] (h) When A, V, W, R1, R4, R5, R 10 and R 12 are as follows:

[1017]

[1018] Z, X, and Y are

[1019]

[1020] or a pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate thereof.

[1021] More preferably, the CTPS1 inhibitor is selected from the following compounds (‘List E’):

[1022] N-(5-(6-Ethoxypyrazin-2-yl)pyridin-2-yl)-4-(2-(methylsulfonamido)pyrimidin-4-yl)tetrahydro-2H-pyran-4-carboxamide;

[1023] 1-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)cyclohexane-1-carboxamide;

[1024] N-(5-(6-Ethoxypyrazin-2-yl)pyridin-2-yl)-1-(2-(methylsulfonamido)pyrimidin-4-yl)cyclohexane-1-carboxamide;

[1025] 1-(6-(Cyclopropanesulfonamido)pyrazin-2-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)cyclohexane-1-carboxamide;

[1026] 4-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-methylphenyl)tetrahydro-2H-pyran-4-carboxamide;

[1027] 1-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)cyclobutane-1-carboxamide;

[1028] 4-(4-(Cyclopropanesulfonamido)pyrimidin-2-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)tetrahydro-2H-pyran-4-carboxamide;

[1029] 4-(2-(Cyclopentanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)tetrahydro-2H-pyran-4-carboxamide;

[1030] N-(5-(6-Ethoxypyrazin-2-yl)pyridin-2-yl)-4-(2-((1-methylcyclopropane)-1-sulfonamido)pyrimidin-4-yl)tetrahydro-2H-pyran-4-carboxamide;

[1031] 4-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-1-methylpiperidine-4-carboxamide;

[1032] 4-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-1-isopropylpiperidine-4-carboxamide;

[1033] 4-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N4-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-N1-isopropylpiperidine-1,4-dicarboxamide;

[1034] 4-(2-((1,1-Dimethylethyl)sulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)tetrahydro-2H-pyran-4-carboxamide;

[1035] N-(4-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)tetrahydro-2H-pyran-4-yl)-5-(6-ethoxypyrazin-2-yl)picolinamide;

[1036] 1-Acetyl-4-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)piperidine-4-carboxamide;

[1037] N-(5-(6-Ethoxypyrazin-2-yl)pyridin-2-yl)-4-(2-((2-methylpropyl)sulfonamido)pyrimidin-4-yl)tetrahydro-2H-pyran-4-carboxamide;

[1038] 4-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-cyclopropylpyrazin-2-yl)pyridin-2-yl)tetrahydro-2H-pyran-4-carboxamide;

[1039] N-(5'-Chloro-[3,3'-bipyridin]-6-yl)-4-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)tetrahydro-2H-pyran-4-carboxamide;

[1040] N-(1-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)cyclopropyl)-5-(6-ethoxypyrazin-2-yl)picolinamide;

[1041] 4-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)tetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide;

[1042] N-(5-(6-Ethoxypyrazin-2-yl)pyridin-2-yl)-4-(2-(ethylsulfonamido)pyrimidin-4-yl)tetrahydro-2H-pyran-4-carboxamide;

[1043] 4-(2-(Cyclopropylmethylsulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)tetrahydro-2H-pyran-4-carboxamide; and

[1044] 4-(4-(Cyclopropanesulfonamido)pyrimidin-2-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-1-methylpiperidine-4-carboxamide;

[1045] or a pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate thereof.

[1046] This type of CTPS1 inhibitor was disclosed in PCT Publication No. WO2020245664, and for the purpose of the CTPS1 inhibitors disclosed therein, the entire content of that patent is incorporated herein by reference. 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.

[1047] Alternatively, the CTPS1 inhibitor is a compound of formula (VI):

[1048]

[1049] wherein ring B is selected from:

[1050]

[1051] wherein X, Y, and Z are defined as follows; and

[1052]

[1053] wherein R 3b3c is R 3b or R 3c as defined below,

[1054] wherein when B is (B-a), the compound of formula (VI) is a compound of formula (VI-a):

[1055]

[1056] wherein:

[1057] A a is A aa or A ba ;

[1058] Wherein:

[1059] A aa is an amine linking group having the following structure: -NH-, -CH2NH- or -NHCH2-;

[1060] A ba is an amide linking group having the following structure: -C(=O)NH- or -NHC(=O)-;

[1061] X is N or CH;

[1062] Y is N or CR 2a ;

[1063] Z is N or CR 3a ;

[1064] Provided that when at least one of X or Z is N, Y cannot be N;

[1065] R 2a is H, halogen, C 1-2 alkyl, OC 1-2 alkyl, C 1-2 haloalkyl or OC 1-2 haloalkyl; and

[1066] R 3a is H, halogen, CH3, OCH3, CF3 or OCF3;

[1067] Wherein at least one of R 2a and R 3a is H;

[1068] R 1a is R 1aa or R 1ba ;

[1069] Wherein:

[1070] R 1aa is NR 32a R 33a ;

[1071] R 1ba is C 1-5 alkyl, cycloalkyl optionally substituted by CH3, C 0-2 alkylene C 3-5 cycloalkyl or CF3;

[1072] R 4a and R 5a are R4aa and R 5aa or R 4ba and R 5ba ;

[1073] Wherein:

[1074] R 4aa and R 5aa together with the attached carbon atom form a C 3-6 cycloalkyl group which is: substituted with one or two substituents, each substituent independently selected from 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, halogen, 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 C 3-6 one of the carbons of the cycloalkyl group is a spiro center such that the spiro ring system is formed by a C 3-6 cycloalkyl ring and another C 3-6 cycloalkyl ring or C 3-6 heterocycloalkyl ring, and wherein the C 4aa formed by R 5aa and R 3-6 together with the attached carbon atom can be substituted with one or two substituents, each substituent independently selected from C 1-3 alkyl or OC 1-3 alkyl; or

[1075] R 4aa and R 5aa together with the attached carbon atom form a C 3-6 heterocycloalkyl group, wherein C 3-6 one of the carbons of the heterocycloalkyl group is a spiro center such that the spiro ring system is formed by a C 3-6 heterocycloalkyl ring and another C 3-6 cycloalkyl ring or C 3-6 heterocycloalkyl ring, and wherein the C 4aa formed by R 5aa and R 3-6 together with the attached carbon atom can be substituted with one or two substituents, each substituent independently selected from C1-3 alkyl or OC 1-3 alkyl; or

[1076] R 4aa and R 5aa together with the attached carbon atom form a C containing one nitrogen atom 3-6 heterocycloalkyl, wherein the nitrogen atom is substituted by -S(O)2R 29a substituted; or

[1077] 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 attached carbon atom form a C 3-6 cycloalkyl or C 3-6 heterocycloalkyl; and

[1078] when A a is -NHC(=O)- or -NHCH2-:

[1079] R 4ba and R 5ba can also be selected from halogen, 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 ;

[1080] Ar1a is a 6-membered aryl or heteroaryl;

[1081] Ar2a is a 6-membered aryl or heteroaryl and is attached to Ar1a at the para position relative to the group A a ;

[1082] R 10a is H, halogen, C 1-3 alkyl, C 1-2 haloalkyl, OC 1-2 alkyl, OC 1-2 haloalkyl or CN;

[1083] R11a is H, F, Cl, C 1-2 alkyl, CF3, OCH3 or CN:

[1084] R 12a is connected to Ar2 at the ortho or meta position relative to Ar1a, and R 12a is H, halogen, 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

[1085] when A a is -NHC(=O)-, -NH- or -NHCH2-:

[1086] R 12a can also be selected from CN, OCH2CH2N(CH3)2 and a C 3-6 heterocycloalkyl containing a nitrogen at the point of connection to Ar2, or R 12a together with the attached nitrogen atom forms an N-oxide (N + -O - );

[1087] R 13a is H or halogen;

[1088] 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 heterocycloalkyl;

[1089] R 22a is H or CH3;

[1090] R 23a is H or C 1-2 alkyl; and

[1091] R24a is H or C 1-2 alkyl;

[1092] R 29a is C 1-3 alkyl, cycloalkyl optionally substituted by CH3, C 0-2 alkylene C 3-5 cycloalkyl, CF3, N(C 1-3 alkyl)2 or 5- or 6-membered heteroaryl, wherein said 5- or 6-membered hetero

[1093] aryl is optionally substituted by methyl;

[1094] R 32a is C 1-3 alkyl and R 33 is C 1-3 alkyl; or

[1095] R 32a and R 33a together with the attached nitrogen atom form C 3-5 heterocycloalkyl;

[1096] wherein

[1097] R 1a is R 1aa ; and / or

[1098] R 4a and R 5a is R 4aa and R 5aa ; and / or

[1099] A a is A aa ; and

[1100] wherein when B is (B-bc) and R 3b3c is R 3b the compound of formula (VI) is the compound of formula (VI-b):

[1101]

[1102] wherein:

[1103] A b is A ab or A bb ;

[1104] wherein:

[1105] A ab is -NR 6b CH2- or -NR 6b -;

[1106] Abb is - NR 6b C(=O)-;

[1107] R 1b is R 1ab or R 1bb ;

[1108] wherein:

[1109] R 1ab is NR 32b R 33b ;

[1110] R 1bb is C 1-5 alkyl, cycloalkyl optionally substituted by CH3, C 0-2 alkylene C 3-5 cycloalkyl, C 1-3 alkylene OC 1-2 alkyl or CF3;

[1111] R 3b is H, halogen, CH3, OC 1-2 alkyl or CF3;

[1112] or R 3b together with R 5bb forms a 5 - or 6 - membered cycloalkyl or a 5 - or 6 - membered oxygen - containing heterocycloalkyl;

[1113] R 4b and R 5b is R 4ab and R 5ab or R 4bb and R 5bb ;

[1114] wherein:

[1115] R 4ab and R 5ab together with the attached carbon atom form a C 3-6 cycloalkyl which is: substituted by one or two substituents, each substituent independently selected from 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, halogen, OC 1-3 haloalkyl, OC 0-2 alkylene C 3-6 cycloalkyl, OC 0-2Alkylene C 3-6 Heterocycloalkyl, OC 1-3 Alkyl and NR 21b R 22b ; or one of the carbons of the cycloalkyl is a spiro center such that the spiro ring system is formed by a C 3-6 cycloalkyl ring and another C 3-6 cycloalkyl ring or a C 3-6 cycloalkyl ring or a C 3-6 heterocycloalkyl ring, and wherein the C 4ab formed by R 5ab and R 3-6 together with the attached carbon atom can be substituted by one or two substituents, each independently selected from C 1-3 alkyl or OC 1-3 alkyl; or

[1116] R 4ab and R 5ab together with the attached carbon atom form a C 3-6 heterocycloalkyl, wherein one of the carbons of the C 3-6 heterocycloalkyl is a spiro center such that the spiro ring system is formed by a C 3-6 c heterocycloalkyl ring and another C 3-6 cycloalkyl ring or a C 3-6 heterocycloalkyl ring, and wherein the C 4ab formed by R 5ab and R 3-6 together with the attached carbon atom can be substituted by one or two substituents, each independently selected from C 1-3 alkyl or OC 1-3 alkyl; or

[1117] R 4ab and R 5ab together with the attached carbon atom form a C 3-6 heterocycloalkyl containing one nitrogen atom, wherein the nitrogen atom is substituted by -S(O)2R 29b ; or

[1118] R 4bb and R 5bb are each independently H, halogen, 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 1-6Halogenated alkyl, OC 1-6 Halogenated alkyl or NR 21b R 22b ,

[1119] or R 4bb is H, and R 5bb together with R 3b forms a 5- or 6-membered cycloalkyl or 5- or 6-membered oxygen-containing heterocycloalkyl,

[1120] or R 4bb and R 5bb together with the attached carbon atom form a C 3-6 cycloalkyl or C 3-6 heterocycloalkyl,

[1121] or R 4bb is H, and R 5bb and R 6b are a C 2-3 alkylene chain forming a 5- or 6-membered ring;

[1122] or R 4bb is O, and R 5bb is absent;

[1123] R 6b is H or C 1-3 alkyl,

[1124] or when in the ortho position to group A b R 6b together with R 11b is a C2 alkylene chain forming a 5-membered ring,

[1125] or R 5bb and R 6b are a C 2-3 alkylene chain forming a 5- or 6-membered ring, and R 4bb is H;

[1126] Ar1b is a 6-membered aryl or heteroaryl;

[1127] Ar2b is a 6-membered aryl or heteroaryl, and is attached to Ar1b at the para position relative to group A b ;

[1128] R 10b is H, halogen, C 1-3 alkyl, OC 1-2 alkyl, C 1-2 halogenated alkyl, OC 1-2 halogenated alkyl or CN;

[1129] R 11b is H, F, Cl, CH3, ethyl, OCH3, CF3, OCF3 or CN, or when in group Ab When R is in the ortho position 11b and R 6b together form a C2 alkylene chain that forms a 5-membered ring;

[1130] R 12b is attached to Ar2b when in the ortho or meta position relative to Ar1b, and R 12b is H, halogen, 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, a C containing a nitrogen at the point of attachment to Ar2b 3-6 heterocycloalkyl or R 12b together with the attached carbon atom forms an N-oxide (N + -O - );

[1131] R 13b is H, halogen, CH3 or OCH3;

[1132] 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 heterocycloalkyl;

[1133] R 22b is H or CH3;

[1134] R 23b is H or C 1-2 alkyl;

[1135] R24b is H or C 1-2 alkyl;

[1136] R 29b is C 1-3 alkyl, cycloalkyl optionally substituted by CH3, C 0-2 alkylene C 3-5 cycloalkyl, CF3, N(C 1-3 alkyl)2 or 5- or 6-membered heteroaryl, wherein said 5- or 6-membered heteroaryl is optionally substituted by methyl; and

[1137] R 32b is C 1-3 alkyl, and R 33b is C 1-3 alkyl; or

[1138] R 32b and R 33b together with the attached nitrogen atom form a C 3-5 heterocycloalkyl;

[1139] wherein:

[1140] R 1b is R 1ab ; and / or

[1141] R 4b and R 5b is R 4ab and R 5ab ; and / or

[1142] A is A ab ; or

[1143] wherein when B is (B-bc) and R 3b3c is R 3c then the compound of formula (VI) is the compound of formula (VI-c):

[1144]

[1145] wherein:

[1146] A c is A ac or A bc ;

[1147] wherein:

[1148] A ac is -CH2NR 6c -;

[1149] A bc is -C(=O)NR 6c -;

[1150] R 1c is R 1ac or R 1bc ;

[1151] Wherein:

[1152] R 1ac is NR 32c R 33c ;

[1153] R 1bc is C 1-5 alkyl, cycloalkyl optionally substituted by CH3, C 0-2 alkylene C 3-5 cycloalkyl, C 1-3 alkylene OC 1-2 alkyl or CF3;

[1154] R 3c is H, CH3, halogen, OC 1-2 alkyl or CF3;

[1155] R 4c and R 5c is R 4ac and R 5ac or R 4bc and R 5bc ;

[1156] Wherein:

[1157] R 4ac and R 5ac together with the carbon atom to which they are attached form a C 3-6 cycloalkyl, which: is substituted by one or two substituents, each substituent independently selected from 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, halogen, OC 1-3 haloalkyl, OC 0-2 alkylene C 3-6 cycloalkyl, OC 0-2 alkylene C 3-6 heterocycloalkyl, OC 1-3 alkyl and NR 21c R 22c ; or C 3-6 One of the carbons of the cycloalkyl is a spiro center, such that the spiro ring system consists of a C 3-6 cycloalkyl ring and another C 3-6A cycloalkyl ring or a C 3-6 heterocycloalkyl ring is formed, and wherein the C 4ac formed by R 5ac and R 3-6 with the attached carbon atom can be substituted by one or two substituents, each independently selected from C 1-3 alkyl or OC 1-3 alkyl; or

[1158] R 4ac and R 5ac with the attached carbon atom form a C 3-6 heterocycloalkyl, wherein one of the carbons of the C 3-6 heterocycloalkyl is a spiro center, such that the spiro ring system is formed by a C 3-6 heterocycloalkyl ring and another C 3-6 cycloalkyl ring or a C 3-6 heterocycloalkyl ring is formed, and wherein the C 4ac formed by R 5ac and R 3-6 with the attached carbon atom can be substituted by one or two substituents, each independently selected from C 1-3 alkyl or OC 1-3 alkyl; or

[1159] R 4ac and R 5ac with the attached carbon atom form a C 3-6 heterocycloalkyl containing one nitrogen atom, wherein the nitrogen atom is substituted by -S(O)2R 29c ; or

[1160] 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 haloalkyl,

[1161] or R 4bc and R 5bc with the attached carbon atom form a C 3-6 cycloalkyl or a C 3-6 heterocycloalkyl ring;

[1162] R 6c is H or C 1-3 alkyl;

[1163] Ar1c is a 6-membered aryl or heteroaryl;

[1164] Ar2c is a 6-membered aryl or heteroaryl and is attached to Ar1c at the para-position relative to group A c ;

[1165] R 10c is H, halogen, C 1-3 alkyl, OC 1-2 alkyl, C 1-2 haloalkyl, OC 1-2 haloalkyl or CN;

[1166] R 11c is H, F, Cl, CH3, ethyl, OCH3, CF3, OCF3 or CN:

[1167] R 12c is attached to Ar2c at the meta- or ortho-position relative to Ar1c, and R 12c is H, halogen, 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 23c R 24c , SO2CH3, C(O)N(CH3)2, NHC(O)C 1-3 alkyl or a C 3-6 heterocycloalkyl containing a nitrogen at the point of attachment to Ar2, or R 12c together with the attached carbon atom forms an N-oxide (N + -O - );

[1168] 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 heterocycloalkyl;

[1169] R22c is H or CH3;

[1170] R 23c is H or C 1-2 alkyl;

[1171] R 24c is H or C 1-2 alkyl;

[1172] R 29c is C 1-3 alkyl, cycloalkyl optionally substituted by CH3, C 0-2 alkylene C 3-5 cycloalkyl, CF3, N(C 1-3 alkyl)2 or 5- or 6-membered heteroaryl, wherein said 5- or 6-membered heteroaryl is optionally substituted by methyl; and

[1173] R 32c is C 1-3 alkyl and R 33c is C 1-3 alkyl; or

[1174] R 32c and R 33c together with the nitrogen atom to which they are attached form a C 3-5 heterocycloalkyl;

[1175] wherein:

[1176] R 1c is R 1ac ; and / or

[1177] R 4c and R 5c is R 4ac and R 5ac ; and / or

[1178] A c is A ac ;

[1179] or a pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate thereof.

[1180] More preferably, the CTPS1 inhibitor is selected from the following ('List F') compounds:

[1181] 1-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-oxocyclohexanecarboxamide;

[1182] 1-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-hydroxycyclohexanecarboxamide;

[1183] 1-(2-(Cyclopropanesulfonylamino)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-hydroxycyclohexanecarboxamide (diastereomer 1);

[1184] 1-(2-(Cyclopropanesulfonylamino)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-hydroxycyclohexanecarboxamide (diastereomer 2);

[1185] 1-(2-(Cyclopropanesulfonylamino)pyrimidin-4-yl)-4-(dimethylamino)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)cyclohexane-1-carboxamide;

[1186] 1-(2-(Cyclopropanesulfonylamino)pyrimidin-4-yl)-4-(dimethylamino)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)cyclohexane-1-carboxamide (diastereomer 1);

[1187] 1-(2-(Cyclopropanesulfonylamino)pyrimidin-4-yl)-4-(dimethylamino)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)cyclohexane-1-carboxamide (diastereomer 2);

[1188] N-(4-(1-((4-(6-Ethoxypyrazin-2-yl)-2-fluorobenzyl)amino)propyl)pyrimidin-2-yl)cyclopropanesulfonamide;

[1189] 1-(2-(Cyclopropanesulfonylamino)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4,4-difluorocyclohexane-1-carboxamide;

[1190] 8-(2-(Cyclopropanesulfonylamino)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-1,4-dioxaspiro[4.5]decane-8-carboxamide;

[1191] 4-(2-((N,N-Dimethylaminosulfonyl)amino)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)tetrahydro-2H-pyran-4-carboxamide;

[1192] 4-(2-(Cyclopropanesulfonylamino)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-1-(methylsulfonyl)piperidine-4-carboxamide;

[1193] N-(4-(1-(((5-(6-Ethoxypyrazin-2-yl)pyridin-2-yl)methyl)amino)cyclopropyl)pyrimidin-2-yl)cyclopropanesulfonamide;

[1194] N-(4-(1-((4-(6-Ethoxypyrazin-2-yl)-2-fluorobenzyl)amino)cyclopropyl)pyrimidin-2-yl)cyclopropanesulfonamide;

[1195] N-(4-(4-(((4-(6-Ethoxypyrazin-2-yl)phenyl)amino)methyl)tetrahydro-2H-pyran-4-yl)pyrimidin-2-yl)cyclopropanesulfonamide;

[1196] 2-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-5,8-dioxaspiro[3.4]octane-2-carboxamide;

[1197] 1-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-methoxycyclohexane-1-carboxamide;

[1198] N-(4-(1-((4-(6-Ethoxypyrazin-2-yl)phenyl)amino)propyl)pyrimidin-2-yl)cyclopropanesulfonamide;

[1199] 4-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-1-(2-methoxyacetyl)piperidine-4-carboxamide;

[1200] 4-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-1-(ethylsulfonyl)piperidine-4-carboxamide;

[1201] 4-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-1-(cyclopropylsulfonyl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)piperidine-4-carboxamide;

[1202] 4-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-1-(N,N-dimethylaminosulfonyl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)piperidine-4-carboxamide;

[1203] 4-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-1-((trifluoromethyl)sulfonyl)piperidine-4-carboxamide;

[1204] 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;

[1205] 1-(Cyanomethyl)-4-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)piperidine-4-carboxamide;

[1206] Ethyl 2-(4-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-4-((5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)carbamoyl)piperidin-1-yl)acetate;

[1207] N-(5-(6-Ethoxypyrazin-2-yl)pyridin-2-yl)-4-(2-(ethylsulfonamido)pyrimidin-4-yl)-1-(2-methoxyacetyl)piperidine-4-carboxamide;

[1208] N-(5-(6-Ethoxypyrazin-2-yl)pyridin-2-yl)-4-(2-(ethylsulfonamido)pyrimidin-4-yl)-1-(methylsulfonyl)piperidine-4-carboxamide;

[1209] N-(5-(6-Ethoxypyrazin-2-yl)pyridin-2-yl)-4-(2-(ethylsulfonamido)pyrimidin-4-yl)-1-(ethylsulfonyl)piperidine-4-carboxamide;

[1210] 1-(Cyclopropylsulfonyl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(2-(ethylsulfonamido)pyrimidin-4-yl)piperidine-4-carboxamide;

[1211] 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;

[1212] 1-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-cyclopropylpyrazin-2-yl)pyridin-2-yl)-4-methoxycyclohexane-1-carboxamide (diastereomer 1);

[1213] 1-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-cyclopropylpyrazin-2-yl)pyridin-2-yl)-4-methoxycyclohexane-1-carboxamide (diastereomer 2);

[1214] 1-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(pyrrolidin-1-yl)cyclohexane-1-carboxamide (diastereomer 1);

[1215] 1-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(pyrrolidin-1-yl)cyclohexane-1-carboxamide (diastereomer 2);

[1216] 4-Amino-1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)cyclohexane-1-carboxamide (diastereomer 1);

[1217] 1-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-morpholinocyclohexane-1-carboxamide (diastereomer 1);

[1218] 1-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-morpholinocyclohexane-1-carboxamide (diastereomer 2);

[1219] 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);

[1220] 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);

[1221] 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);

[1222] 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);

[1223] 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);

[1224] 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);

[1225] 4-(6-(Cyclopropanesulfonamido)pyrazin-2-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-1-(methylsulfonyl)piperidine-4-carboxamide;

[1226] 4-(4-(Cyclopropanesulfonamido)pyrimidin-2-yl)-N-(5-(6-cyclopropylpyrazin-2-yl)pyridin-2-yl)-1-(methylsulfonyl)piperidine-4-carboxamide;

[1227] 4-(4-(Cyclopropanesulfonamido)pyrimidin-2-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-1-(methylsulfonyl)piperidine-4-carboxamide;

[1228] 4-(4-(Cyclopropanesulfonamido)pyrimidin-2-yl)-N-(5-(6-cyclopropylpyrazin-2-yl)pyridin-2-yl)-1-(ethylsulfonyl)piperidine-4-carboxamide; and

[1229] 4-(4-(Cyclopropanesulfonamido)pyrimidin-2-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-1-(ethylsulfonyl)piperidine-4-carboxamide;

[1230] or a pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate thereof.

[1231] This type of CTPS1 inhibitor is disclosed in PCT Publication No. WO2020245665, and for the purpose of the CTPS1 inhibitor disclosed therein, the entire content of this patent is incorporated herein by reference. In particular, the CTPS1 inhibitor can be a compound or a pharmaceutically acceptable salt and / or pharmaceutically acceptable solvate thereof as described in any one of Articles 1 to 204 of WO2020245665, especially a compound selected from P226, P227, P228, P229, P230, P235, P242, P244, P248, P251, P254, P255, P256, P258, P260, P261, P288, P289, P290, P291, P292, P293, P294, P295, P296, P297, P298, P299, P300, P301, P302, P303, P304, P305, P306, P307, P308, P309, P310, P311, P312, P313, P314, P315, P316, P317 and P318 or a pharmaceutically acceptable salt and / or pharmaceutically acceptable solvate thereof.

[1232] Alternatively, the CTPS1 inhibitor is a compound of formula (VII):

[1233]

[1234] wherein

[1235] A is A a or A b ;

[1236] wherein

[1237] A a is an amine linking group having the following structure: -NH-, -CH2NH- or -NHCH2-;

[1238] A b is an amide linking group having the following structure: -C(=O)NH- or -NHC(=O)-; B is

[1239] X is N or CH;

[1240] Y is N or CR2;

[1241] Z is N or CR3;

[1242] provided that when at least one of X or Z is N, Y cannot be N;

[1243] R1 is C 1-5 fluoroalkyl, provided that R1 is not CF3;

[1244] R2 is H, halogen, C 1-2 alkyl, OC 1-2 alkyl, C 1-2 haloalkyl or OC 1-2 haloalkyl;

[1245] R3 is H, halogen, CH3, OCH3, CF3 or OCF3;

[1246] wherein at least one of R2 and R3 is H;

[1247] R 3’ is H, halogen, CH3, OC 1-2 alkyl or CF3; and

[1248] when A is -NHC(=O)-, R 3’ also forms a 5- or 6-membered cycloalkyl or 5- or 6-membered oxygen-containing heterocycloalkyl together with R5;

[1249] R4 and R5 are R 4a and R 5a , or R 4b and R 5b ;

[1250] wherein

[1251] R 4a and R 5a together with the attached carbon atom form a C 3-6 cycloalkyl which: is substituted by one or two substituents, each substituent independently selected from 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, halogen, 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 one of the carbons of the C 3-6 cycloalkyl is a spiro center such that the spiro ring system is formed by a C 3-6 cycloalkyl ring and another C 3-6 cycloalkyl ring or a C 3-6 heterocycloalkyl ring, and wherein by R 4a and R5a Together with the attached carbon atom, form a C 3-6 The cycloalkyl can be substituted with one or two substituents, each independently selected from C 1-3 alkyl or OC 1-3 alkyl; or

[1252] R 4a and R 5a Together with the attached carbon atom, form a C 3-6 heterocycloalkyl, where one of the carbons of the C 3-6 heterocycloalkyl is a spiro center, such that the spiro ring system is composed of a C 3-6 heterocycloalkyl ring and another C 3-6 cycloalkyl ring or a C 3-6 heterocycloalkyl ring is formed, and where the C 4a formed by R 5a and R 3-6 together with the attached carbon atom can be substituted with one or two substituents, each independently selected from C 1-3 alkyl or OC 1-3 alkyl; or

[1253] R 4a and R 5a Together with the attached carbon atom, form a C heterocycloalkyl containing one nitrogen atom, where the nitrogen atom is substituted with -S(O)2R 3-6 ; or 29 substituted; or

[1254] 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 attached carbon atom, form a C 3-6 cycloalkyl or a C 3-6 heterocycloalkyl; and

[1255] When A is -NHC(=O)- or -NHCH2-:

[1256] R 4b and R 5b can also be selected from halogen, OC 1-6 haloalkyl, OC 0-2 alkylene C 3-6Cycloalkyl, OC 0-2 Alkylene C 3-6 Heterocycloalkyl, OC 1-6 Alkyl and NR 21 R 22 ;

[1257] Ar1 is a 6 - membered aryl or heteroaryl;

[1258] Ar2 is a 6 - membered aryl or heteroaryl and is connected to Ar1 at the para - position relative to group A;

[1259] R 10 is H, halogen, C 1-3 alkyl, C 1-2 haloalkyl, OC 1-2 alkyl, OC 1-2 haloalkyl or CN;

[1260] R 11 is H, F, Cl, C 1-2 alkyl, CF3, OCH3 or CN:

[1261] R 12 is connected to Ar2 at the ortho - or meta - position relative to Ar1, and R 12 is H, halogen, 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

[1262] when A is - NHC(=O)-, - NH - or - NHCH2 -:

[1263] R 12 can also be selected from CN, OCH2CH2N(CH3)2 and a C 3-6 heterocycloalkyl containing a nitrogen at the point of connection to Ar2, or R 12 together with the nitrogen atom to which it is attached forms an N - oxide (N + - O - );

[1264] R13 is H or a halogen;

[1265] R 21 is H, C 1-5 alkyl, C(O)C 1-5 alkyl, C(O)OC 1-5 alkyl;

[1266] R 22 is H or CH3;

[1267] R 23 is H or C 1-2 alkyl; and

[1268] R 24 is H or C 1-2 alkyl;

[1269] R 29 is C 1-3 alkyl, cycloalkyl optionally substituted by CH3, C 0-2 alkylene C 3-5 cycloalkyl

[1270] or CF3;

[1271] R 32 is C 1-3 alkyl and R 33 is C 1-3 alkyl; or

[1272] R 32 and R 33 together with the nitrogen atom to which they are attached form a C 3-5 heterocycloalkyl;

[1273] or a pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate thereof.

[1274] More preferably, the CTPS1 inhibitor is selected from the following compounds (‘List G’):

[1275] 4-(2-((2,2-difluoroethyl)sulfonylamino)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)tetrahydro-2H-pyran-4-carboxamide; and

[1276] 2-(2-((2,2-difluoroethyl)sulfonylamino)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2-fluorobutyramide;

[1277] or a pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate thereof.

[1278] Such CTPS1 inhibitors are disclosed in PCT Publication No. WO2021053403, and for the purposes of the CTPS1 inhibitors disclosed therein, the entire content of that patent is incorporated herein by reference. In particular, the CTPS1 inhibitor can be a compound or a pharmaceutically acceptable salt and / or pharmaceutically acceptable solvate thereof as described in any one of clauses 1-191 of WO2021053403, particularly a compound selected from P271 and P284 or a pharmaceutically acceptable salt and / or pharmaceutically acceptable solvate thereof.

[1279] Alternatively, the CTPS1 inhibitor is a compound of formula (VIII):

[1280]

[1281] wherein

[1282] A is A a or A b ;

[1283] wherein

[1284] A a is an amine linking group having the following structure: -NH-, -CH2NH- or -NHCH2-;

[1285] A b is an amide linking group having the following structure: -C(=O)NH- or -NHC(=O)-; B is

[1286] X is N or CH;

[1287] Y is N or CR2;

[1288] Z is N or CR3;

[1289] provided that when at least one of X or Z is N, Y cannot be N;

[1290] R1 is C 1-5 alkyl or C 0-2 alkylene C 3-5 cycloalkyl, wherein the alkyl or (alkylene) cycloalkyl is substituted with CN;

[1291] R2 is H, halogen, C 1-2 alkyl, OC 1-2 alkyl, C 1-2 haloalkyl or OC 1-2 haloalkyl;

[1292] R3 is H, halogen, CH3, OCH3, CF3 or OCF3;

[1293] wherein at least one of R2 and R3 is H;

[1294] R 3’ is H, halogen, CH3, OC 1-2 alkyl or CF3; and

[1295] when A is -NHC(=O)-, R 3’ also forms a 5- or 6-membered cycloalkyl or 5- or 6-membered oxygen-containing heterocycloalkyl together with R5;

[1296] R4 and R5 are R 4a and R 5a , or R 4b and R 5b ;

[1297] wherein

[1298] R 4a and R 5a together with the attached carbon atom form a C 3-6 cycloalkyl which: is substituted by one or two substituents, each independently selected from 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, halogen, 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 one of the carbons of the C 3-6 cycloalkyl is a spiro center, such that the spiro ring system is formed by a C 3-6 cycloalkyl ring and another C 3-6 cycloalkyl ring or a C 3-6 heterocycloalkyl ring, and wherein the C 4a formed by R 5a and R 3-6 together with the attached carbon atom can be substituted by one or two substituents, each independently selected from C 1-3 alkyl or OC 1-3 alkyl; or

[1299] R 4a and R 5a together with the attached carbon atom form a C 3-6Heterocycloalkyl, wherein one of the carbons of the C 3-6 heterocycloalkyl is a spiro center such that the spiro ring system is composed of C 3-6 heterocycloalkyl ring and another C 3-6 cycloalkyl ring or C 3-6 heterocycloalkyl ring is formed, and wherein the C 4a formed by R 5a and R 3-6 together with the attached carbon atom can be substituted by one or two substituents, each independently selected from C 1-3 alkyl or OC 1-3 alkyl; or

[1300] R 4a and R 5a together with the attached carbon atom form a C 3-6 hetero

[1301] cycloalkyl, wherein the nitrogen atom is substituted by -S(O)2R29; 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 attached carbon atom form C 3-6 cycloalkyl or C 3-6 heterocycloalkyl; and

[1302] when A is -NHC(=O)- or -NHCH2-:

[1303] R 4b and R 5b can also be selected from halogen, OC 1-6 haloalkyl, OC 0-2 alkylene C 3-6

[1304] cycloalkyl, OC 0-2 alkylene C 3-6 heterocycloalkyl, OC 1-6 alkyl and NR 21 R 22 ;

[1305] Ar1 is a 6-membered aryl or heteroaryl;

[1306] Ar2 is a 6-membered aryl or heteroaryl group and is connected to Ar1 at the para position relative to group A;

[1307] R 10 is H, a halogen, C 1-3 alkyl, C 1-2 haloalkyl, OC 1-2 alkyl, OC 1-2 haloalkyl or CN;

[1308] R 11 is H, F, Cl, C 1-2 alkyl, CF3, OCH3 or CN:

[1309] R 12 is connected to Ar2 at the ortho or meta position relative to Ar1, and R 12 is H, a halogen, 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

[1310] when A is -NHC(=O)-, -NH- or -NHCH2-:

[1311] R 12 can also be selected from CN, OCH2CH2N(CH3)2 and a C 3-6 heterocycloalkyl containing a nitrogen at the point of connection to Ar2, or R 12 together with the attached carbon atom forms an N-oxide (N + -O-);

[1312] R 13 is H or a halogen;

[1313] R 21 is H, C 1-5 alkyl, C(O)C 1-5 alkyl, C(O)OC 1-5 alkyl;

[1314] R 22 is H or CH3;

[1315] R 23 is H or C 1-2 alkyl; and

[1316] R 24 is H or C 1-2 alkyl;

[1317] R 29 is C 1-3 alkyl, cycloalkyl optionally substituted with CH3, C 0-2 alkylene C 3-5 cycloalkyl or CF3;

[1318] R 32 is C 1-3 alkyl and R 33 is C 1-3 alkyl; or

[1319] R 32 and R 33 together with the nitrogen atom to which they are attached form a C 3-5 heterocycloalkyl;

[1320] or a pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate thereof.

[1321] More preferably, the CTPS1 inhibitor is selected from the following ('List H') compounds:

[1322] 4-(2-((1-cyanocyclopropane)-1-sulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)tetrahydro-2H-pyran-4-carboxamide; and

[1323] 4-(2-((cyanomethyl)sulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)tetrahydro-2H-pyran-4-carboxamide;

[1324] or a pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate thereof.

[1325] Such CTPS1 inhibitors are disclosed in PCT Publication No. WO2021053402, and for the purposes of the CTPS1 inhibitors disclosed therein, the entire contents of that patent are incorporated herein by reference. In particular, the CTPS1 inhibitor can be a compound described in any one of Clauses 1-191 of WO2021053402 or a pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate thereof, particularly a compound selected from P285 and P287 or a pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate thereof.

[1326] The CTPS1 inhibitor can be 4-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)tetrahydro-2H-pyran-4-carboxamide (referred to herein as 'CTPS-IA'):

[1327]

[1328] or a pharmaceutically acceptable salt and / or pharmaceutically acceptable solvate thereof. CTPS-IA is a potent and selective inhibitor of CTPS1 (see, for example, WO2020083975).

[1329] Alternatively, the CTPS1 inhibitor can be N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(2-(ethylsulfonamido)pyrimidin-4-yl)tetrahydro-2H-pyran-4-carboxamide (referred to herein as 'CTPS-IB'):

[1330]

[1331] or a pharmaceutically acceptable salt and / or pharmaceutically acceptable solvate thereof. CTPS-IB is a potent and selective inhibitor of CTPS1 (see, for example, WO2020245664).

[1332] The above compounds (and methods for preparing these compounds) are disclosed in PCT Publication Nos. WO2019106156, WO2019180244, WO2019106146, WO2019179652, WO2020245665, WO2020245664, WO2021053403, WO2021053402 or WO2020083975.

[1333] Alternatively, the CTPS1 inhibitor is a compound of formula (IX):

[1334]

[1335] or a pharmaceutically acceptable salt thereof, wherein:

[1336] R 1 is selected from C 1-6 aliphatic groups; 3-7 membered saturated or partially unsaturated monocyclic carbocycles; and 3-7 membered saturated or partially unsaturated monocyclic heterocycles having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, each of which is substituted with q instances of R A ;

[1337] 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;

[1338] L is

[1339] wherein R L , R L’ or R L” are each independently H, -CN, halogen, or an optionally substituted group selected from C 1-6 aliphatic group; phenyl; a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or

[1340] R L , R L’ or R L” together with two atoms each connected thereto 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

[1341] R L , R L’ or R L” any one of which together with R B forms a 7- to 10-membered saturated or partially unsaturated fused bicyclic ring;

[1342] Ring B is selected from phenyl; a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5- to 6-membered saturated or partially unsaturated 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 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 to 4 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;

[1343] Ring C is selected from phenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; and a 7-11 membered fused bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[1344] The valence bond between Ring B and Ring C does not exist, and Ring B and Ring C together form a 7-11 membered saturated or partially unsaturated fused, bridged, or spiro, bicyclic carbocyclic ring; a saturated or partially unsaturated fused, bridged, or spiro, bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 7-11 membered fused bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[1345] R A 、R B and R C Each instance of 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; or each instance of R C is independently an optionally substituted group selected from C 1-6 aliphatic group; phenyl; naphthyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, phosphorus, silicon, sulfur; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 5-8 membered saturated or partially unsaturated bridged bicyclic having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 6-10 membered saturated or partially unsaturated spiro ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 6-11 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; each of them being substituted by r instances of R and R Dbe replaced by an s instance; or two Rs C groups and each R C together with the atom to which each R is attached form an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; a 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;

[1346] R D Each instance of R 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)(N, -P(O)(R)NR2, -P(O)(R)OR or -P(OR2;

[1347] Each R is independently hydrogen, -CN, halogen, or an optionally substituted group selected from C 1-6 aliphatic group; phenyl; naphthyl; 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; 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 5- to 8-membered saturated or partially unsaturated bridged bicyclic ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 6- to 10-membered saturated or partially unsaturated spiro ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 6- to 11-membered saturated or partially unsaturated bicyclic carbocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or

[1348] two R groups together with the atom to which each R is attached form an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or

[1349] m is 0, 1, or 2;

[1350] n is 0, 1, or 2;

[1351] p is 0, 1, or 2;

[1352] Each q is independently 0, 1, 2, 3, or 4;

[1353] Each r is independently 0, 1, 2, 3 or 4; and

[1354] Each s is independently 0, 1, 2, 3 or 4;

[1355] Provided that when there is a situation as follows:

[1356] R 1 is C 1-6 an aliphatic group or a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring,

[1357] the sulfonamide moiety the R group of is hydrogen or p-methoxybenzyl;

[1358] L is and R L and R L’ or RL and R L’ do not together with the atoms to which they are respectively attached form an optionally substituted saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur; or L is

[1359] Ring B is phenyl or a 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur, and

[1360] Ring C is phenyl or a 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur, and is attached to Ring B at the para position relative to the L group;

[1361] Ring A and its R A substituents are not

[1362]

[1363] where * represents attachment to the moiety and ** represents attachment to the moiety, or a pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate thereof.

[1364] This type of CTPS1 inhibitor is disclosed in PCT Publication No. WO2022087634, and for the purpose of the CTPS1 inhibitors disclosed therein, the entire content of that patent is incorporated herein by reference. In particular, the CTPS1 inhibitor can be a compound as claimed in any one of claims 1-31 of WO2022087634 or a pharmaceutically acceptable salt and / or pharmaceutically acceptable solvate thereof. The CTPS1 inhibitor can be a compound selected from Compounds I-1 to I-286 of WO2022087634 or a pharmaceutically acceptable salt and / or pharmaceutically acceptable solvate thereof. The CTPS1 inhibitor can be a compound selected from Compounds Z-1 to Z-10 of WO2022087634 or a pharmaceutically acceptable salt and / or pharmaceutically acceptable solvate thereof.

[1365] Depending on the nature of the particular CTPS1 inhibitor, the CTPS1 inhibitor can be provided in the form of a pharmaceutically acceptable salt and / or pharmaceutically acceptable solvate. In some embodiments, the CTPS1 inhibitor is provided in the form of a pharmaceutically acceptable salt and a pharmaceutically acceptable solvate (i.e., a 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 as a salt or solvate).

[1366] Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art. Pharmaceutically acceptable salts include those in Remington′s Pharmaceutical Sciences, 17th Edition, Mack Publishing Company, Easton, PA, 1985, p. 1418. Such pharmaceutically acceptable salts include acid addition salts formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid) and organic acids (e.g., 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, e.g., sodium or potassium salts, and organic bases, such as basic amines, e.g., ammonia, meglumine, tromethamine, piperazine, arginine, choline, diethylamine, benzathine penicillin or lysine.

[1367] The CTPS1 inhibitor can form acid or base addition salts with one or more equivalents of an acid or base. The present invention includes within its scope all possible stoichiometric and non-stoichiometric forms.

[1368] CTPS1 inhibitors can be prepared in crystalline or non-crystalline form, and if crystalline, may optionally be solvated, such as as a hydrate. The present invention includes within its scope stoichiometric solvates (such as hydrates) and compounds containing variable amounts of solvent (such as water).

[1369] Unless defined as part of a formula or compound structure, CTPS1 inhibitors include all isomers of the CTPS1 inhibitors disclosed herein, including all geometric, tautomeric, and optical forms, as well as mixtures thereof (such as racemic mixtures). In the presence of additional chiral centers, the present invention includes within its scope all possible diastereoisomers, including mixtures thereof. Different isomers can be separated or resolved one by one by conventional methods, or any given isomer can be obtained by conventional synthetic methods or stereospecific methods or asymmetric synthesis.

[1370] CTPS1 inhibitors include all isotopic forms of the CTPS1 inhibitors provided herein, whether in the form of: (i) all atoms with a specified atomic number having the mass numbers (or mixtures of mass numbers) that are predominant in nature (referred to herein as "naturally occurring isotopic forms"); or (ii) one or more atoms being replaced by atoms having the same atomic number but mass numbers different from the mass numbers of the atoms predominant in nature (referred to herein as "non-naturally occurring variant isotopic forms"). It should be understood that atoms can occur naturally in the form of mixtures of mass numbers. The term "non-naturally occurring variant isotopic form" also includes embodiments in which the proportion of atoms with a given atomic number having mass numbers that are less common in nature (referred to herein as "uncommon isotopes") is increased relative to the number of atoms occurring naturally, such as increased to levels of >20%, >50%, >75%, >90%, >95%, or >99% of the number of atoms of that atomic number (the latter embodiment being referred to as "isotope-enriched variant forms"). The term "non-naturally occurring variant isotopic form" also includes embodiments in which the proportion of uncommon isotopes is decreased relative to the naturally occurring proportion. Isotopic forms can include radioactive forms (i.e., they incorporate radioactive isotopes) and non-radioactive forms. Radioactive forms are typically isotope-enriched variant forms.

[1371] For example, non-naturally occurring variant isotopic forms containing radioactive isotopes can be used for drug and / or matrix tissue distribution studies.

[1372] In one embodiment, the CTPS1 inhibitor is provided in a naturally occurring isotopic form.

[1373] In one embodiment, the CTPS1 inhibitor is provided in a non-naturally occurring variant isotopic form.

[1374] In one embodiment, CTPS1 inhibitors are provided, wherein individual atoms of the compound are present in the form of unnatural variant isotopes. In another embodiment, CTPS1 inhibitors are provided, wherein two or more atoms are present in the form of unnatural variant isotopes.

[1375] Therapeutic uses and applications

[1376] The present invention can be used to treat cancers lacking CTPS2. As used herein, CTPS2 deficiency refers to a severe defect in CTPS2 function, particularly a complete loss of CTPS2 function. The defect in CTPS2 function may be caused by genomic alterations and / or epigenetic alterations.

[1377] The defect in CTPS2 function may be caused by genomic alterations or changes, such as:

[1378] (i) The complete loss of the CTPS2 gene due to genomic deletion;

[1379] (ii) The partial loss of the CTPS2 gene due to genomic deletion;

[1380] (iii) The CTPS2 gene is disrupted by a structural DNA variant, such as an inversion, duplication, or translocation within the gene footprint; or

[1381] (iv) The CTPS2 gene mutates such that CTPS2 expression is significantly reduced or most appropriately completely lost.

[1382] The defect in CTPS2 function may be caused by epigenetic alterations or changes, such as alterations in CTPS2 gene expression, such as due to changes in regulatory elements, which are attributed to altered methylation and / or histone modification, such that CTPS2 expression is significantly reduced or most appropriately completely lost.

[1383] Suitably, the defect in CTPS2 function may be caused by a complete deletion of the CTPS2 gene due to genomic deletion (homozygous deletion in tumors produced by females or hemizygous deletion in tumors produced by males).

[1384] The presence of CTPS2 deficiency is typically determined by analyzing a sample from a subject. The sample used herein will be understood to be an appropriate sample suitable for the intended analytical method, i.e., a sample that allows determination of CTPS2 deficiency or other deficiencies. For example, the sample may be a biopsy containing cancer cells (such as a tumor biopsy), or it may be a sample containing circulating cancer cells, or it may be a sample containing cell-free cancer DNA. The sample can be obtained or provided by any suitable method known in the art.

[1385] Methods for determining CTPS2 deficiency include:

[1386] (i) Methods for detecting DNA alterations, including analyzing tumor-derived DNA obtained from tumor tissue, circulating tumor cells, cell-free DNA, or cell-free exosomes, and using appropriate techniques to detect genomic changes that may lead to severe defects in CTPS2 function, particularly 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, droplet digital PCR, in situ hybridization, or fluorescence in situ hybridization;

[1387] (ii) Methods for detecting RNA alterations, including analyzing appropriate RNA samples, such as RNA samples obtained from tumor tissue, circulating tumor cells, or cell-free exosomes, using appropriate techniques for detecting CTPS2 RNA (e.g., RNA sequencing, gene expression arrays, real-time quantitative PCR, droplet digital PCR, or in situ hybridization);

[1388] (iii) Methods for detecting epigenetic alterations, including (a) analyzing tumor-derived DNA obtained from tumor tissue, circulating tumor cells, or cell-free DNA using appropriate techniques to detect epigenetic alterations that may lead to loss of CTPS2 expression, including DNA methylation analysis or characterization of histone modifications, or (b) analyzing appropriate RNA samples, such as those obtained from tumor tissue, circulating tumor cells, or cell-free exosomes, and analyzing them by RNA sequencing, gene expression arrays, real-time quantitative PCR, droplet digital PCR, or in situ hybridization; and / or

[1389] (iv) Methods for detecting protein alterations, including analyzing tumor tissue or circulating tumor cells using appropriate techniques for detecting CTPS2 protein (e.g., immunohistochemistry, flow cytometry, or mass cytometry).

[1390] It should be understood that multiple analytical techniques can be applied in combination.

[1391] Suitably, the steps for identifying a subject with a cancer having CTPS2 deficiency include: (i) applying an appropriate method for determining CTPS2 deficiency, such as a technique for detecting relevant 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 significant deficiency in CTPS2 function, particularly complete loss of CTPS2 function.

[1392] For cancers with genomic alterations that may result in significant lack of CTPS2 function, particularly 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 may result in severe defects in 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, droplet digital PCR, in situ hybridization, or fluorescence in situ hybridization. Additionally, genomic alterations that may result in severe defects in CTPS2 function can be detected in suitable RNA samples obtained from tissue biopsies, circulating tumor cells, or cell-free exosomes and analyzed by RNA sequencing, gene expression arrays, real-time quantitative PCR, droplet digital PCR, or in situ hybridization. Furthermore, genomic alterations that may result in severe defects in 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.

[1393] For cancers with epigenetic changes that may result in severe lack of CTPS2, detection will require suitable DNA samples obtained from tissue biopsies, circulating tumor cells, or cell-free DNA. Suitable techniques for detecting epigenetic changes that may result in severe lack of CTPS2 include DNA methylation analysis or histone modification profiling. Additionally, epigenetic changes that may result in severe lack of CTPS2 function can be detected in suitable RNA samples obtained from tissue biopsies, circulating tumor cells, or cell-free exosomes and analyzed by RNA sequencing, gene expression arrays, real-time quantitative PCR, droplet digital PCR, or in situ hybridization. Furthermore, epigenetic changes that may result in severe lack of CTPS2 function can be detected in suitable RNA samples obtained from tissue biopsies, circulating tumor cells, or cell-free exosomes and analyzed by RNA sequencing, gene expression arrays, real-time quantitative PCR, droplet digital PCR, or in situ hybridization. Additionally, epigenetic changes that may result in severe lack 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.

[1394] Susceptibility to CTPS1 treatment

[1395] The present invention can be used to determine whether cancer cells or cancer is predisposed to treatment with a CTPS1 inhibitor. In the context of this disclosure, a 'predisposed' cancer or cancer cell is one that has been identified as having an increased probability of benefiting from treatment according to the present invention relative to cancers or cancer cells that are known not to be predisposed to treatment with a CTPS1 inhibitor (e.g., showing high in vivo efficacy, reduced dose required for in vivo action, and / or improved safety / reduced side effects).

[1396] It is expected that predisposed cancers or cancer cells lack CTPS2 (i.e., are likely to lack CTPS2), and appropriately, predisposed cancers or cancer cells lack CTPS2.

[1397] Those cancers or cancer cells that have been identified as having an increased probability of CTPS2 deficiency or those cancers and cells that have been identified as being expected to have CTPS2 deficiency can be, for example: (i) cancers or cancer cells of a type identified as having a more prevalent CTPS2 deletion than more common cancers or (ii) cancers or cancer cells identified as having CTPS2 deficiency or (iii) cancers or cancer cells identified as being more likely to have a defective CTPS2 using a method whose certainty may be uncertain.

[1398] Predisposed cancers or cancer cells can be identified by analyzing DNA and detecting genomic alterations in CTPS2 that may lead to a significant loss of CTPS2 activity.

[1399] It is expected that cancers or cancer cells may have genomic alterations in CTPS2 that may lead to a significant loss of CTPS2 activity, making them susceptible to treatment with a CTPS1 inhibitor.

[1400] Predisposed cancers or cancer cells can be identified by analyzing RNA and detecting a decrease in CTPS2 expression that may lead to a significant loss of CTPS2 activity.

[1401] Predisposed cancers or cancer cells can be identified by analyzing proteins and detecting a decrease in CTPS2 expression that may lead to a significant loss of CTPS2 activity.

[1402] It is expected that cancers or cancer cells may have a decreased CTPS2 expression that may lead to a significant loss of CTPS2 activity, making them susceptible to treatment with a CTPS1 inhibitor.

[1403] Predisposed cancers or cancer cells can be identified by analyzing epigenetic patterns and detecting alterations in DNA methylation or histone modification that may lead to a significant loss of CTPS2 activity.

[1404] It is expected that the DNA of cancers or cancer cells may have alterations in DNA methylation or histone modification that may lead to a significant loss of CTPS2 activity, making them susceptible to treatment with a CTPS1 inhibitor.

[1405] Susceptible cancers or cancer cells can be identified by culturing cancer cells (such as human cancer cells) in the presence of a selective CTPS1 inhibitor, wherein the growth pattern of the cancer cells shows sensitivity to CTPS1 inhibition. The sensitivity to CTPS1 inhibition can be attributed to a significant loss of CTPS2 activity. The selectivity is suitably at least 2-fold, such as at least 30-fold, especially at least 60-fold, particularly at least 1000-fold, especially for human CTPS1 over human CTPS2.

[1406] Cancers or cancer cells may have a growth pattern of cancer cells, which indicates sensitivity to CTPS1 inhibition, presumably attributed to a significant loss of CTPS2 activity.

[1407] A CTPS1 inhibitor can be used to administer to a subject identified as having a cancer expected to be susceptible to treatment with a CTPS1 inhibitor (e.g., the cancer is CTPS2-deficient). A CTPS1 inhibitor can be used to administer to a subject in which a cancer cell sample has shown susceptibility to treatment with a CTPS1 inhibitor (e.g., the cancer is CTPS2-deficient).

[1408] Suitably, the cancer is selected from 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 kidney cancer. Suitably, the cancer is a cancer for which no other suitable available therapy exists.

[1409] Suitably, the cancer is selected from ovarian cancer, esophageal cancer, bladder cancer, non-small cell lung cancer, and gastric cancer.

[1410] Suitably, the cancer is ovarian cancer, such as serous ovarian cancer.

[1411] The cancer can be lung cancer, such as non-small cell lung cancer.

[1412] The cancer can be gastroesophageal cancer. The cancer can be esophageal cancer, or, the cancer can be gastric cancer.

[1413] The cancer can be head and neck cancer.

[1414] The cancer can be bladder cancer.

[1415] The cancer can be sarcoma.

[1416] In one embodiment, the cancer is a blood cancer. In one embodiment, the cancer is a non-blood cancer. Suitably, the cancer is not T-cell leukemia, such as T-cell acute lymphoblastic leukemia.

[1417] Suitably, the cancer or cancer cells are from a cancer type in which at least 10% of the cells lack CTPS2, such as at least 15% of the cells lack CTPS2, particularly at least 18% of the cells lack CTPS2. The defect in CTPS2 function can be attributed to homozygous deletion in females or hemizygous deletion in males.

[1418] Suitably, the cancer or cancer cells are from a cancer type in which at least 10% of the cells lack CTPS2, such as at least 15% of the cells lack CTPS2, particularly at least 20% of the cells lack CTPS2, especially at least 40% of the cells lack CTPS2. The defect in CTPS2 function can be determined by immunohistochemistry, such as the absence of CTPS2 staining.

[1419] Administration

[1420] The present invention is typically used in mammalian subjects, particularly human subjects. A CTPS1 inhibitor is typically administered to a subject in need thereof, particularly a mammalian subject in need thereof, particularly a human subject in need thereof. The human subject can be an adult, such as 18 to 65 years old. Alternatively, the human subject can be 66 years old or older. Alternatively, the human subject can be less than 18 years old, such as 4 to 17 years old. The human subject can be male. Alternatively, the human subject can be female.

[1421] The CTPS2 gene is located on the human X chromosome and is not imprinted in human females. Therefore, compared with human male subjects (i.e., subjects with XY chromosomes), the CTPS2 expression level is expected to be higher in human female subjects because CTPS2 is expressed on each X chromosome in human female subjects. In human female subjects, CTPS2 deficiency may be caused by genomic alterations and / or epigenetic alterations in one or both XX chromosomes, suitably both XX chromosomes.

[1422] Suitably, when the human subject is male, a defect in CTPS2 function can be caused by: (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 by a structural DNA variant, such as an inversion, duplication, or translocation within the gene footprint; (iv) mutation of the CTPS2 gene such that CTPS2 expression is significantly reduced or completely lost; or (v) alteration of CTPS2 gene expression, such as due to alteration of regulatory elements resulting from altered methylation and / or histone modification, such that CTPS2 expression is significantly reduced or completely lost, particularly complete loss of the CTPS2 gene due to genomic deletion. In particular, when the human subject is male, a defect in CTPS2 function can be caused by complete deletion of the CTPS2 gene due to genomic deletion.

[1423] Suitably, when the human subject is female (i.e., a subject with two X chromosomes), a defect in CTPS2 function can be caused by complete deletion of the CTPS2 gene on the first X chromosome due to genomic deletion, and (i) complete deletion of the CTPS2 gene on the second X chromosome due to genomic deletion; (ii) partial deletion of the CTPS2 gene on the second X chromosome due to genomic deletion; (iii) disruption of the CTPS2 gene on the second X chromosome by a structural DNA variant that falls within the gene footprint, such as an inversion, duplication, or translocation; (iv) mutation of the CTPS2 gene on the second X chromosome such that CTPS2 expression is significantly reduced or completely lost; or (v) alteration of CTPS2 gene expression on the second X chromosome, such as due to alteration of regulatory elements resulting from altered methylation and / or histone modification, such that CTPS2 expression is significantly reduced or completely lost.

[1424] Suitably, when the human subject is female, a defect in CTPS2 function can be caused by complete deletion of the CTPS2 gene on the first X chromosome due to genomic deletion, and complete deletion of the CTPS2 gene on the second X chromosome due to complete deletion.

[1425] Administration of a CTPS1 inhibitor

[1426] The CTPS1 inhibitor can be administered by any suitable route, which can depend on the properties of the particular active agent. Exemplary routes include oral, parenteral, buccal, sublingual, nasal, or rectal administration. Conveniently, the CTPS1 inhibitor is administered orally.

[1427] The CTPS1 inhibitor can be provided in the form of a pharmaceutical composition comprising the CTPS1 inhibitor and a pharmaceutically acceptable carrier or excipient.

[1428] If delivered orally, the CTPS1 inhibitor can be suitably delivered in the form of a solid pharmaceutical composition (such as tablets, capsules or lozenges) or a liquid pharmaceutical composition (such as suspensions, emulsions or solutions).

[1429] Liquid formulations generally consist of a suspension or solution of the CTPS1 inhibitor in a suitable liquid carrier, which is, for example, an aqueous solvent such as water, ethanol or glycerol, or a non-aqueous solvent such as polyethylene glycol or an oil. The formulation may also contain suspending agents, preservatives, flavoring agents and / or coloring agents.

[1430] Tablet formulations can be prepared using any suitable pharmaceutical carriers commonly used for preparing solid formulations, such as magnesium stearate, starch, lactose, sucrose and cellulose.

[1431] Suitably, the pharmaceutical composition is in unit dosage form, such as tablets, capsules or ampoules. Suitably, the unit dosage form is for oral delivery.

[1432] The pharmaceutical composition may, for example, contain 0.1%-99.99% by weight, such as 10%-60% by weight, of the active substance, depending on the method of administration. The pharmaceutical composition may contain 0.01%-99% by weight, such as 40%-90% by weight, of the carrier, depending on the method of administration. The pharmaceutical composition may contain 0.05 mg - 2000 mg of the active substance, such as 1.0 mg - 500 mg, depending on the method of administration. The pharmaceutical composition may contain 50 mg - 1000 mg of the carrier, such as 100 mg - 400 mg, depending on the method of administration.

[1433] The dosage of the compound used will vary in the usual way depending on the severity of the cancer, the weight of the patient and other similar factors. However, as a general guideline, a suitable unit dose can be 0.05 mg - 1000 mg, more suitably 1.0 mg - 500 mg, and such unit doses can be administered more than once a day, such as twice or three times a day. Such therapy can continue for weeks, months or longer. Multiple unit doses can be taken together, such as multiple tablets.

[1434] Suitably, the CTPS1 inhibitor is administered orally, for example in the form of a solid pharmaceutical composition by oral administration.

[1435] The dose administered to a subject is typically a safe and effective dose, i.e., an amount that provides an acceptable balance of desired benefits and undesired side effects. "Safe and effective dose" is intended to include the amount of a compound that effectively achieves the desired effect in treating a disease state. The desired effect typically has clinical significance and / or is measurable, such as in the case of (a) inhibiting a disease state, i.e., slowing or preventing its progression and / or (b) alleviating a disease state, i.e., causing regression of the disease state or reduction of related symptoms. A safe and effective amount is an amount sufficient to achieve the desired effect when a CTPS1 inhibitor is administered.

[1436] To avoid doubt, the "safe and effective amount" as described herein can be achieved by any suitable dosing regimen. Thus, for example, the administration of a safe and effective amount of a compound as referred to herein, such as by a particular route of administration including achieving a safe and effective amount by a single dose or multiple doses, as administered by the specified route of administration. For example, oral administration of a safe and effective amount includes oral administration of a single dose and oral administration of any number of doses, provided that a safe and effective amount is thereby achieved by oral administration.

[1437] Administration of a CTPS1 inhibitor is typically once or twice daily. The administration can be continuous, e.g., at least once daily for multiple cycles, or can be intermittent, e.g., once daily for one week, followed by one week without administration, followed by at least once daily for another week.

[1438] Combination with additional active agents

[1439] Treatment with a CTPS1 inhibitor can be combined with one or more other pharmaceutically acceptable active ingredients, which can be selected from: antimitotic agents such as vinblastine, paclitaxel, and docetaxel; alkylating and DNA cross-linking agents such as cisplatin, carboplatin, dacarbazine, and cyclophosphamide; antimetabolites such as 5-fluorouracil, cytarabine, and hydroxyurea; intercalating agents such as doxorubicin 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; IAP inhibitors such as LCL161; VEGF inhibitors such as bevacizumab or pan-kinase inhibitors such as sorafenib and sunitinib.

[1440] The CTPS1 inhibitor and an additional pharmaceutically acceptable active ingredient can each be administered in any combination of separate, sequential, or simultaneous administration. If administered simultaneously, the CTPS1 inhibitor can, for example, (a) be formulated separately from the other pharmaceutically acceptable active ingredient; or (b) be formulated together with another pharmaceutically acceptable active ingredient.

[1441] The other pharmaceutically acceptable active ingredients can be selected from tyrosine kinase inhibitors such as axitinib, dasatinib, erlotinib, imatinib, nilotinib, pazopanib, and sunitinib. Alternatively, the other pharmaceutically acceptable active ingredients can be selected from azacitidine, decitabine, or cytarabine.

[1442] The other pharmaceutically acceptable active ingredients also include anti-cancer antibodies such as those selected from anti-CD20 antibodies (such as atezolizumab, ofatumumab, tositumomab, or rituximab) or other antibodies such as olatumumab, daratumumab, tucotuzumab, denosumab, trastuzumab, enfortumab, pertuzumab, brentuximab vedotin, pembrolizumab, catumaxomab, bevacizumab, cetuximab, trastuzumab, and gemtuzumab ozogamicin.

[1443] The CTPS1 inhibitor can also be administered in combination with radiotherapy, surgery, thermotherapy, and / or cryotherapy.

[1444] In some embodiments, the subject receives chemotherapy, radiotherapy, surgery, thermotherapy, and / or cryotherapy prior to the administration of CTPS1.

[1445] In some embodiments, the subject receives chemotherapy, radiotherapy, surgery, thermotherapy, and / or cryotherapy simultaneously with the administration of CTPS1.

[1446] In some embodiments, the subject receives chemotherapy, radiotherapy, surgery, thermotherapy, and / or cryotherapy after the administration of CTPS1.

[1447] The present invention is further illustrated by the following non-limiting examples. Examples

[1448] Example 1: Inhibition of Human CTPS1 Enzyme

[1449] The enzyme inhibitory activity of the compound against CTPS1 can be determined using the ADP-Glo TM Max assay (Promega, UK).

[1450] The assay of human CTPS1 was performed in 1x assay buffer containing 50 mM Tris, 10 mM MgCl2, 0.01% Tween-20, pH 8.0. Finally, L-cysteine was added to the 1x assay buffer immediately before use to a final concentration of 2 mM. All reagents were from Sigma-Aldrich unless otherwise stated. Human full-length active C-terminal FLAG-His8-tag CTPS1 (UniProtKB-P17812, CTPS[1-591]-GGDYKDDDDKGGHHHHHHHH, SEQ ID NO: 1) was obtained from Proteros biostructures GmbH.

[1451] Assay method

[1452] Prepare 3x human CTPS1 protein in 1x assay buffer to the final working protein concentration required for the reaction. At 25 °C, mix 2 μL volume of 3x human CTPS1 protein per well with 2 μL of 3x test compound per well (compound prepared in 1x assay buffer, reaching the appropriate final 3x compound concentration according to the concentration-response curve designed for the test compound) for 10 minutes. Then, start the enzyme reaction by adding 2 μL volume of pre-mixed substrate mixture per well (UltraPure ATP (0.31 mM), GTP (0.034 mM), UTP (0.48 mM), and L-glutamine (0.186 mM) from the ADP-Glo TM Max kit), and incubate this mixture for an appropriate time period within the determined linear reaction phase under sealed plate conditions at 25 °C with constant stirring at 500 revolutions per minute (rpm). Before detecting the signal in a microplate reader ( MultilabelReader, Perkin Elmer), add ADP-Glo TM Max reagent for 60 minutes (6 μL / well), and then add ADP-Glo TM Max developer reagent for 60 minutes (12 μL / well). After each reagent addition during the assay, centrifuge the assay plate at 500 rpm for 30 seconds in pulses.

[1453] In all cases, the enzyme converts ATP to ADP, and ADP-Glo TM Max reagent then depletes any remaining endogenous ATP in the reaction system. ADP-Glo TMThe Max assay reagent converts ADP produced by the enzyme back to ATP and uses ATP as a substrate with luciferin for luciferase to generate light that produces a detectable luminescence. The measured luminescence signal is proportional to the amount of ADP produced by the enzyme reaction, and a decrease in this signal upon compound treatment indicates enzyme inhibition. The percentage of inhibition produced by each concentration of the compound is calculated using the following equation:

[1454]

[1455] The percentage of inhibition is then plotted against the compound concentration, and the 50% inhibitory concentration (IC 50 ) is determined from the resulting concentration-response curve.

[1456] Example 2: RapidFire / MS-based CTPS1 Enzyme Selectivity Assay

[1457] Evaluation of the selectivity of human CTPS1 and CTPS2 by RapidFire / MS analysis.

[1458] The enzyme inhibitory activity of compounds against each target isoform of interest was determined using an optimized RapidFire high-throughput mass spectrometry (RF / MS) assay format. The RF / MS assays for human CTPS1 and CTPS2 were performed in an assay buffer consisting of 50 mM HEPES (Merck), 20 mM MgCl2, 5 mM KCl, 1 mM DTT, 0.01% Tween-20, pH 8.0. Human full-length active C-terminal FLAG-His-tagged CTPS1 (UniProtKB-P17812, CTPS[1-591]-GGDYKDDDDKGGHHHHHHHH, SEQ ID NO: 1) was obtained from Proteros biostructures GmbH. Human full-length active C-terminal FLAG-His-Avi-tagged CTPS2 (UniProtKB-Q9NRF8, CTPS2[1-586]-DYKDDDDKHHHHHHGLNDIFEAQKIEWHE, SEQ ID NO: 2) was obtained from Harker Bio.

[1459] Assay Method

[1460] Prepare human CTPS(1 or 2) protein in 1x assay buffer until the final working protein concentration required for the reaction. Mix 2 μL volume of 2x CTPS(1 or 2) protein with 40 nL of the compound per well using acoustic (ECHO) delivery and incubate at 25 °C for 10 minutes. Subsequently, initiate each isotype enzyme reaction by adding 2 μL of 2x substrate mixture per well in the 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). Incubate each mixture with each isotype for an appropriate time period at 25 °C within the determined linear phase of the reaction. Add 60 μL volume of the termination solution (1% formic acid with 0.5 μM 13 C9- 15 N3-CTP) contained in H2O, immediately heat-seal the plate and centrifuge at 4,000 rpm for 10 minutes. After centrifugation, load the plate onto an Agilent RapidFire microfluidic solid-phase extraction system coupled to an API 4000 triple quadrupole mass spectrometer (RF / MS) for analysis.

[1461] In all cases, the enzyme converts UTP to CTP. A highly specific and sensitive multiple reaction monitoring (MRM) MS method can be optimized for detecting the enzyme reaction product CTP and the stable isotope-labeled product standard 13 C9- 15 N3-CTP. Calculate the readings of the data analysis as the ratio of the peak area of the product CTP to the internal standard 13 C9- 15 N3-CTP. For data reporting, the following equation was used:

[1462]

[1463] (R = ratio / readings, P = product signal area, IS = internal standard signal area)

[1464] For each screening plate, use the average of the negative (DMSO) and positive control values to calculate the corresponding assay window (S / B) and Z’ value. Calculate the percentage of inhibition using the median of the corresponding control values according to the following equation:

[1465]

[1466] (I = inhibition rate, R neg = median of the negative control reading values, R pos = median of the positive control reading values, R 样品= Sample reading value)

[1467] Then, a graph of the percentage of inhibition versus the compound concentration is plotted, and the 50% inhibitory concentration (IC 50 ) is determined from the resulting concentration - response curve.

[1468] Subsequently, the fold selectivity between CTPS1 and CTPS2 is calculated according to the following equation:

[1469]

[1470] Example 3: Cells require CTPS enzyme activity to proliferate

[1471] In vitro cell proliferation assays have been used to establish the important role of CTP synthase activity and to evaluate the differential activities of CTPS1 and CTPS2 isoforms.

[1472] Cells engineered to not express CTPS isoforms (i.e., lacking CTPS1 and CTPS2) die rapidly by apoptosis (Martin 2014, Martin 2020, Minet 2022).

[1473] Human embryonic kidney (HEK) cells lacking CTPS1 or CTPS2 were generated using CRISPR technology, and the lack of expression of the relevant proteins was confirmed by Western blotting (Minet 2022). Cells were cultured at 37 °C and 5% CO2; viable cells were counted using CellTiter Glo2.0 reagent (Promega). HEK cells expressing only CTPS2 proliferated more slowly than cells expressing only CTPS1, indicating that the enzyme activity of the CTPS1 isoform is higher (Minet 2022). This is consistent with recent work and also shows that the CTPS1 isoform has higher enzyme activity than CTPS2 (Lynch 2021).

[1474] In summary, these findings indicate that CTP synthase activity is a requirement for cell survival and that the enzyme activity of the CTPS1 isoform is higher than that of CTPS2.

[1475] Example 4: CTPS1 is involved in cancer cell proliferation

[1476] The pathways involved in providing key building blocks for nucleic acid replication are the purine and pyrimidine synthesis pathways, and upregulation of pyrimidine biosynthesis has been observed in tumors and tumor cells. CTPS activity is upregulated in a series of tumor types of hematological and non - hematological origin; however, heterogeneity has been observed in patients. A correlation has been established between high enzyme levels and resistance to chemotherapeutic drugs.

[1477] In the analysis of public data, the present inventors found that CTPS1 is essential for the proliferation of human cancer cells derived from a wide range of blood and solid tumor types, while CTPS2 is consistently overabundant. This analysis used data from the Achilles project, in which each of 324 human cancer cell lines had each gene in the human genome independently deleted using CRISPR technology, and the effect of each gene deletion was evaluated using an in vitro proliferation assay (Behan 2019). This dataset was subsequently expanded to include data from 1,032 human cancer cell lines (Cancer Dependency Map: p.org / ). The effects of deletions of different genes in the pyrimidine synthesis pathway were evaluated (see Figure 2 ). Deletion of CTPS2 had no effect on cancer cell proliferation. Deletion of genes in the salvage pathway (CDA, UCK1, UCK2, or CMPK2) had little effect 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, consistent with the dependence of cancer cells on these gene products; inhibition of CTPS1 caused the greatest damage to cancer cell proliferation. These findings indicate that most cancer cells rely on CTPS1 for cell proliferation, which can be attributed to its enhanced enzyme activity, and do not require CTPS2.

[1478] Example 5: Deletion of CTPS2 in a small group of cancers

[1479] The above studies indicate that CTP synthase activity plays a crucial role, and the lack of CTP synthase leads to cell death due to apoptosis. The studies also indicate that many cancer cells rely on the activity of CTPS1, which is the more active of the two CTPS isoforms, and cancer cells that are less sensitive to deletion or inhibition of CTPS1 can utilize CTPS2 activity to survive and proliferate. Consistent with this concept, in certain physiological situations, the expression of CTPS2 can increase (Martin 2014), further increasing the likelihood that increased CTPS2 expression may be associated with acquired resistance to CTPS1 inhibitor therapy. Thus, cancer cells lacking CTPS2 expression due to genetic deletion of the CTPS2 gene may be highly sensitive to CTPS1 inhibition. It can also be noted from the above studies that the genetic deletion of CTPS2 itself is not harmful to cancer cells due to the continued availability of CTPS1 enzyme activity.

[1480] Loss of genetic material due to genomic deletions is a common phenomenon in cancer and may confer a selective advantage due to the loss of tumor suppressor genes. It has also been recognized that such genomic deletions can lead to bystander deletions of genes that do not confer a selective advantage to cancer cells; however, this collateral damage may expose therapeutic vulnerabilities in cancer cells (Achreja 2022).

[1481] In an analysis of publicly available data (ICGC 2020), it was found that CTPS2 was deleted in a small subset of cancer samples, with the highest incidence in ovarian, esophageal, and bladder cancers (see Figure 3 ). These findings identify a mechanism that can identify cancer patients predicted to be highly sensitive to CTPS1 inhibitor therapy.

[1482] Example 6: CTPS2 expression level predicts cellular response to CTPS2 deletion

[1483] In an analysis of publicly available data, the inventors found that CTPS2 expression level was correlated with the sensitivity of CRISPR knockout to CTPS1 deletion. In this analysis, which combined data from 573 human cancer cell lines from the Achilles project and the Cancer Cell Line Encyclopedia, lower CTPS2 expression (measured by RNA abundance) was correlated with increased sensitivity of CRISPR to CTPS1 deletion ( Figure 4 , Pearson correlation r = 0.23, P-value = 4.9x10-8). No correlation was found between CTPS1 expression and the sensitivity of CRISPR to CTPS1 deletion (P-value = 0.075).

[1484] It was also found that CTPS2 expression level was correlated with the IC50 value of CTPS-IA. Human cancer cell lines were cultured in triplicate at 37 °C and 5% CO2 in the presence of different concentrations of CTPS-IA or in the presence of vehicle alone, and viable cells were counted after 72 hours using CellTiter-Glo 2.0 reagent (Promega) or an equivalent reagent. The half-maximal inhibitory concentration (IC 50)。The CTPS1 and CTPS2 expression levels measured by RNA abundance were generated by RNA sequencing or retrieved from the publicly available Cancer Cell Line Encyclopedia. In a small panel of 19 human cancer cell lines derived from blood cancers, lower CTPS2 expression was associated with increased sensitivity to CTPS-IA (Pearson correlation r = 0.50, P-value = 0.0007). In 60 human cancer cell lines encompassing common cancer types, lower CTPS2 expression was correlated with increased sensitivity to CTPS-IA (Pearson correlation r = 0.24, P-value = <0.0001). In a small panel of 103 human cancer cell lines encompassing common cancer types, lower CTPS2 expression was associated with increased sensitivity to CTPS-IA (Pearson correlation r = 0.24, P-value = <0.0001). In any of these three experiments, the CTPS1 expression level was not associated with sensitivity to CTPS-IA (P-values > 0.05 in all cases).

[1485] Collectively, these data indicate that the expression level of CTPS2, rather than CPTS1, is associated with sensitivity to CRISPR or pharmacological inhibition resulting in CTPS1 deletion or inhibition, respectively. Cancer cell lines with low CTPS2 expression exhibit enhanced sensitivity to CTPS1 deletion or inhibition.

[1486] Example 7: Absence of CTPS2 protein in a small panel of human cancers

[1487] CTPS2 protein expression in primary human cancer samples was analyzed by immunohistochemistry. A CTPS2 monoclonal antibody was validated using CTPS1 and CTPS2 knockout cell lines and normal human tissues. After demonstrating selective staining of CTPS2 in these experiments, the antibody was used to examine tissue microarrays of primary human cancer samples. CTPS2-negative samples were determined based on the absence of CTPS2 staining (non-specific staining was detected using an isotype control antibody).

[1488] Analysis of samples from 117 patients diagnosed with high-grade serous ovarian cancer identified a tumor prevalence of 24% with absent CTPS2 protein expression as shown by immunohistochemistry. Analysis of samples from 80 patients diagnosed with gastroesophageal adenocarcinoma identified a tumor prevalence of 18% with absent CTPS2 protein expression as shown by immunohistochemistry. For both of these cancer types, the prevalence of CTPS2 deletion in genomic studies was closely correlated with the prevalence of CTPS2 deletion assessed by immunohistochemistry ( Figure 5 ).

[1489] Analysis of samples from 208 patients diagnosed with lung cancer identified a prevalence of 65% of tumors showing loss of CTPS2 protein expression by immunohistochemistry. Analysis of samples from 208 patients diagnosed with bladder cancer identified a prevalence of 37% 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 prevalence of 66% of tumors showing loss of CTPS2 protein expression by immunohistochemistry. For these three cancer types, although both immunohistochemistry and genomic studies confirmed that a significant proportion of cancers lacked CTPS2, the prevalence of CTPS2 loss as assessed by immunohistochemistry was higher than the incidence of CTPS2 loss observed in genomic studies( Figure 5 ). Possible explanations for this difference include partial gene deletion of CTPS2 that was not detected by genomic studies but resulted in loss of protein expression; differences in cancer stage in the groups evaluated by genomics and immunohistochemistry (e.g., the group of samples undergoing whole-genome sequencing is typically biased towards patients with early-stage disease who are undergoing surgical resection because there is usually sufficient sequencing material available); or loss of protein expression due to epigenetic regulation such as methylation.

[1490] Example 8: Further characterization of reduced prevalence or absence of CTPS2 expression in target cancers

[1491] Further characterization of reduced prevalence or absence of CTPS2 expression can be performed in target cancers such as ovarian cancer by analyzing tissue samples from tumors of multiple patients, e.g., using tumor microarrays, using an appropriately qualified method for detecting CTPS2 expression, e.g., immunohistochemical assays.

[1492] Further characterization of the cellular consequences of CTPS2 loss of expression can be examined by generating isogenic human cancer cell line pairs in which CTPS2 is expressed and in which CTPS2 expression is eliminated in cell subclones, e.g., by disrupting the CTPS2 gene using CRISPR (clustered regularly interspaced short palindromic repeats) technology, and then comparing key cellular characteristics between isogenic cells with and without CTPS2 expression (including proliferation and apoptosis in the presence or absence of a CTPS2 inhibitor).

[1493] Further information can be obtained by evaluating isogenic human cancer cell line pairs with and without CTPS2 expression in an in vivo transplantation model, e.g., transplanted into immunocompromised mice, e.g., by measuring and comparing the growth kinetics of isogenic human cancer cell lines with and without CTPS2 expression to determine the effect of treatment with a CTPS1 inhibitor when transplanted mice are treated with a CTPS1 inhibitor.

[1494] By comparing primary patient-derived tumor samples that express CTPS2 protein or have lost CTPS2 protein expression, further features of the cellular consequences of CTPS2 expression loss can be examined, for example, by analyzing CTPS2 protein expression in primary tumor samples by immunohistochemistry and comparing key cellular features of CTPS2-expressing and CTPS2-deficient tumors, including proliferation and apoptosis in the presence or absence of a CTPS1 inhibitor in vitro, or by evaluating primary tumor samples with and without CTPS2 expression in an in vivo transplantation model, such as transplantation into immunodeficient mice, where, for example, when the transplanted mice are treated with a CTPS1 inhibitor, the effect of treatment with the CTPS1 inhibitor is determined by measuring and comparing the growth kinetics of primary human cancers with and without CTPS2 expression.

[1495] Throughout this specification and the following claims, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", are to be interpreted as having an inclusive meaning - that is, to imply the inclusion of the stated integers, steps, integer groups or groups of steps, but not to exclude any other integers, steps, integer groups or groups of steps.

[1496] The application of which this specification and claims form part may be used as the basis for the priority 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, method or use claims and, by way of example, may include, but are not limited to, the following claims.

[1497] All publications cited in this specification, including but not limited to patents and patent applications, are hereby incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as if fully set forth.

[1498] The terms of the present invention:

[1499] A series of terms setting forth embodiments of the present invention are as follows.

[1500] Clause 1. A method of treating a CTPS2-deficient cancer in a subject, the method comprising administering a CTPS1 inhibitor to the subject.

[1501] Clause 2. A method of treating a cancer in a subject, the method comprising the steps of:

[1502] i) identifying that the subject has a CTPS2-deficient cancer; and

[1503] ii) administering a CTPS1 inhibitor to the subject.

[1504] Clause 3. A method for treating cancer in a subject, the method comprising the following steps:

[1505] i) providing a sample from the subject;

[1506] ii) identifying that the subject has cancer lacking CTPS2; and

[1507] iii) administering a CTPS1 inhibitor to the subject.

[1508] Clause 4. A method for treating cancer in a subject, the method comprising the following steps:

[1509] i) obtaining a sample from the subject;

[1510] ii) identifying that the subject has cancer lacking CTPS2; and

[1511] iii) administering a CTPS1 inhibitor to the subject.

[1512] Clause 5. A method for treating cancer that may be predisposed to treatment with a CTPS1 inhibitor in a subject, the method comprising the following steps:

[1513] i) identifying that the cancer lacks CTPS2; and

[1514] ii) administering a CTPS1 inhibitor.

[1515] Clause 6. A method for treating cancer that may be predisposed to treatment with a CTPS1 inhibitor in a subject, the method comprising the following steps:

[1516] i) providing a sample from the subject;

[1517] ii) identifying that the cancer lacks CTPS2; and

[1518] iii) administering a CTPS1 inhibitor.

[1519] Clause 7. A method for treating cancer that may be predisposed to treatment with a CTPS1 inhibitor in a subject, the method comprising the following steps:

[1520] i) obtaining a sample from the subject;

[1521] ii) identifying that the cancer lacks CTPS2; and

[1522] iii) administering a CTPS1 inhibitor.

[1523] Clause 8. A method for determining cancer cells that may be predisposed to treatment with a CTPS1 inhibitor, the method comprising the step of identifying that the cancer cells lack CTPS2.

[1524] Article 9. Method for determining a cancer of a subject likely to be treated with a CTPS1 inhibitor,

[1525] The method comprises the step of identifying that the cancer lacks CTPS2.

[1526] Article 10. CTPS1 inhibitor for treating CTPS2-deficient cancer.

[1527] Article 11. Pharmaceutical composition comprising a CTPS1 inhibitor and a pharmaceutically acceptable excipient or carrier, the pharmaceutical composition being for treating CTPS2-deficient cancer.

[1528] Article 12. Use of a CTPS1 inhibitor in the preparation of a medicament for treating CTPS2-deficient cancer.

[1529] Article 13. Method, CTPS1 inhibitor used, pharmaceutical composition used or use according to any one of Articles 1-12, wherein the CTPS2-deficient cancer is selected from 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.

[1530] Article 14. Method, CTPS1 inhibitor used, pharmaceutical composition used or use according to Article 13, wherein the CTPS2-deficient cancer is selected from ovarian cancer, esophageal cancer, bladder cancer, non-small cell lung cancer and gastric cancer.

[1531] Article 15. Method, CTPS1 inhibitor used, pharmaceutical composition used or use according to any one of Articles 1-12, wherein the CTPS2-deficient cancer is ovarian cancer.

[1532] Article 16. Method, CTPS1 inhibitor used, pharmaceutical composition used or use according to Article 15, wherein the CTPS2-deficient cancer is serous ovarian cancer.

[1533] Article 17. Method, CTPS1 inhibitor used, pharmaceutical composition used or use according to any one of Articles 1-12, wherein the CTPS2-deficient cancer is lung cancer.

[1534] Article 18. Method, CTPS1 inhibitor used, pharmaceutical composition used or use according to Article 17, wherein the CTPS2-deficient cancer is non-small cell lung cancer.

[1535] Article 19. Method, CTPS1 inhibitor used, pharmaceutical composition used or use according to any one of Articles 1-12, wherein the CTPS2-deficient cancer is esophageal cancer.

[1536] Clause 20. The method according to any one of Clauses 1 - 12, the CTPS1 inhibitor used, the pharmaceutical composition used, or the use, wherein the CTPS2-deficient cancer is gastric cancer.

[1537] Clause 21. The method according to any one of Clauses 1 - 12, the CTPS1 inhibitor used, the pharmaceutical composition used, or the use, wherein the CTPS2-deficient cancer is head and neck cancer.

[1538] Clause 22. The method according to any one of Clauses 1 - 12, the CTPS1 inhibitor used, the pharmaceutical composition used, or the use, wherein the CTPS2-deficient cancer is bladder cancer.

[1539] Clause 23. The method according to any one of Clauses 1 - 12, the CTPS1 inhibitor used, the pharmaceutical composition used, or the use, wherein the CTPS2-deficient cancer is sarcoma.

[1540] Clause 24. The method according to any one of Clauses 1 - 12, the CTPS1 inhibitor used, the pharmaceutical composition used, or the use, wherein the cancer is a blood cancer.

[1541] Clause 25. The method according to any one of Clauses 1 - 12, the CTPS1 inhibitor used, the pharmaceutical composition used, or the use, wherein the cancer is a non-blood cancer.

[1542] Clause 26. The method according to any one of Clauses 1 - 25, the CTPS1 inhibitor used, the pharmaceutical composition used, or the use, wherein the cancer is not T-cell leukemia, such as T-cell acute lymphoblastic leukemia.

[1543] Clause 27. The method according to any one of Clauses 1 - 26, the CTPS1 inhibitor used, the pharmaceutical composition used, or the use, wherein the IC of the CTPS1 inhibitor for the human CTPS1 enzyme 50 is 10 uM or lower.

[1544] Clause 28. The method according to Clause 27, the CTPS1 inhibitor used, the pharmaceutical composition used, or the use, wherein the IC of the CTPS1 inhibitor for the human CTPS1 enzyme 50 is 1 uM or lower.

[1545] Clause 29. The method according to Clause 28, the CTPS1 inhibitor used, the pharmaceutical composition used, or the use, wherein the IC of the CTPS1 inhibitor for the human CTPS1 enzyme 50 is 100 nM or lower.

[1546] Clause 30. The method, the CTPS1 inhibitor used, the pharmaceutical composition used, or the use according to any one of Clauses 27 - 29, wherein the IC of the CTPS1 inhibitor 50 is established using the assay method described in Example 1.

[1547] Clause 31. The method, the CTPS1 inhibitor used, the pharmaceutical composition used, or the use according to any one of Clauses 1 - 30, wherein the selectivity of the CTPS1 inhibitor for human CTPS1 is at least 2-fold that for human CTPS2.

[1548] Clause 32. The method, the CTPS1 inhibitor used, the pharmaceutical composition used, or the use according to Clause 31, wherein the selectivity of the CTPS1 inhibitor for human CTPS1 is at least 30-fold that for human CTPS2.

[1549] Clause 33. The method, the CTPS1 inhibitor used, the pharmaceutical composition used, or the use according to Clause 32, wherein the selectivity of the CTPS1 inhibitor for human CTPS1 is at least 60-fold, such as at least 1000-fold, that for human CTPS2.

[1550] Clause 34. The method, the CTPS1 inhibitor used, the pharmaceutical composition used, or the use according to any one of Clauses 31 - 33, wherein the selectivity of the CTPS1 inhibitor is established using the assay method described in Example 2.

[1551] Clause 35. The method, the CTPS1 inhibitor used, the pharmaceutical composition used, or the use according to any one of Clauses 1 - 34, wherein the CTPS1 inhibitor is a compound of formula (I)

[1552]

[1553] wherein

[1554] R1 is C 1-5 alkyl, cycloalkyl optionally substituted by CH3, C 0-2 alkylene, C 3-5 cycloalkyl, C 1-3 alkylene OC 1-2 alkyl or CF3;

[1555] R3 is H, CH3, halogen, OC 1-2 alkyl or CF3;

[1556] R4 and R5 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 1-3Alkylene OC 1-3 Alkyl, C 1-6 Alkyl OH or C 1-6 Haloalkyl,

[1557] or R4 and R5 together with the attached carbon atom form a C 3-6 Cycloalkyl or C 3-6 Heterocycloalkyl ring;

[1558] R6 is H or C 1-3 Alkyl;

[1559] Ar1 is a 6-membered aryl or heteroaryl;

[1560] Ar2 is a 6-membered aryl or heteroaryl and is attached to Ar1 at the para position relative to the amide;

[1561] R 10 is H, halogen, C 1-3 Alkyl, OC 1-2 Alkyl, C 1-2 Haloalkyl, OC 1-2 Haloalkyl or CN;

[1562] R 11 is H, F, Cl, CH3, ethyl, OCH3, CF3, OCF3 or CN:

[1563] R 12 is attached to Ar2 at the meta or ortho position relative to Ar1, and R 12 is H, halogen, 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 Alkyl or a C containing a nitrogen at the point of attachment to Ar2 3-6 Heterocycloalkyl, or R 12 together with the attached carbon atom forms an N-oxide (N + -O - )

[1564] R 23 is H or C 1-2 alkyl;

[1565] R 24 is H or C 1-2 alkyl;

[1566] or a pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate thereof.

[1567] Clause 36. The method according to Clause 35, the CTPS1 inhibitor used, the pharmaceutical composition used or the use, wherein the CTPS1 inhibitor is selected from the compounds disclosed in List A or a pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate thereof.

[1568] Clause 37. The method according to any one of Clauses 1 - 34, the CTPS1 inhibitor used, the pharmaceutical composition used or the use, wherein the CTPS1 inhibitor is a compound of formula (II):

[1569]

[1570] wherein

[1571] R1 is C 1-5 alkyl, cycloalkyl optionally substituted by CH3, C 0-2 alkylene C 3-5 cycloalkyl, C 1-3 alkylene OC 1-2 alkyl or CF3;

[1572] R3 is H, halogen, CH3, OC 1-2 alkyl or CF3;

[1573] or R3 and R5 together form a 5 - or 6 - membered cycloalkyl or a 5 - or 6 - membered oxygen - containing heterocycloalkyl;

[1574] R4 and R5 are each independently H, halogen, 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 ,

[1575] or R4 is H, and R5 together with R3 forms a 5- or 6-membered cycloalkyl or 5- or 6-membered oxygen-containing heterocycloalkyl,

[1576] or R4 and R5 together with the attached carbon atom form a C 3-6 cycloalkyl or a C 3-6 heterocycloalkyl,

[1577] or R4 is H, and R5 and R6 are a C 2-3 alkylene chain forming a 5- or 6-membered ring;

[1578] or R4 is O, and R5 is absent;

[1579] R6 is H or C 1-3 alkyl,

[1580] or when in the ortho position of the amide, R6 together with R 11 is a C2 alkylene chain forming a 5-membered ring,

[1581] or R5 and R6 are a C 2-3 alkylene chain forming a 5- or 6-membered ring, and R4 is H;

[1582] Ar1 is a 6-membered aryl or heteroaryl;

[1583] Ar2 is a 6-membered aryl or heteroaryl, and is attached to Ar1 in the para position relative to the amide;

[1584] R 10 is H, halogen, C 1-3 alkyl, OC 1-2 alkyl, C 1-2 haloalkyl, OC 1-2 haloalkyl or CN;

[1585] R 11 is H, F, Cl, CH3, ethyl, OCH3, CF3, OCF3 or CN, or when in the ortho position of the amide, R 11 together with R6 is a C2 alkylene chain forming a 5-membered ring;

[1586] R 12 is attached to Ar2 in the ortho or meta position relative to Ar1, and R 12 is H, halogen, 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 1-4Alkyl 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 a nitrogen at the point of attachment to Ar2 3-6 Heterocycloalkyl, or R 12 Together with the attached nitrogen atom forms an N-oxide (N + -O - );

[1587] R 13 is H, halogen, CH3 or OCH3;

[1588] R 21 is H, C 1-5 Alkyl, C(O)C 1-5 Alkyl, C(O)OC 1-5 Alkyl;

[1589] R 22 is H or CH3;

[1590] R 23 is H or C 1-2 Alkyl; and

[1591] R 24 is H or C 1-2 Alkyl;

[1592] or a pharmaceutically acceptable salt and / or pharmaceutically acceptable solvate thereof.

[1593] Clause 38. The method according to Clause 37, the CTPS1 inhibitor used, the pharmaceutical composition used or the use, wherein the CTPS1 inhibitor is selected from the compounds disclosed in List B or a pharmaceutically acceptable salt and / or pharmaceutically acceptable solvate thereof.

[1594] Clause 39. The method according to any one of Clauses 1 - 34, the CTPS1 inhibitor used, the pharmaceutical composition used or the use, wherein the CTPS1 inhibitor is a compound of formula (III):

[1595]

[1596] Wherein

[1597] A is an amide linking group having the following structure: -C(=O)NH- or -NHC(=O)-;

[1598] X is N or CH;

[1599] Y is N or CR2;

[1600] Z is N or CR3;

[1601] Provided that when at least one of X or Z is N, Y cannot be N;

[1602] R1 is C 1-5 alkyl, cycloalkyl optionally substituted by CH3, C 0-2 alkylene, C 3-5 cycloalkyl or CF3;

[1603] R2 is H, halogen, C 1-2 alkyl, OC 1-2 alkyl, C 1-2 haloalkyl or OC 1-2 haloalkyl;

[1604] R3 is H, halogen, CH3, OCH3, CF3 or OCF3;

[1605] wherein at least one of R2 and R3 is H;

[1606] R4 and R5 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 R4 and R5 together with the carbon atom to which they are attached form C 3-6 cycloalkyl or C 3-6 heterocycloalkyl; and

[1607] When A is -NHC(=O)-:

[1608] R4 and R5 can also be selected from halogen, 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 ;

[1609] Ar1 is a 6-membered aryl or heteroaryl group;

[1610] Ar2 is a 6-membered aryl or heteroaryl group and is connected to Ar1 at the para-position relative to the amide;

[1611] R 10 is H, a halogen, C 1-3 alkyl, C 1-2 haloalkyl, OC 1-2 alkyl, OC 1-2 haloalkyl or CN;

[1612] R 11 is H, F, Cl, C 1-2 alkyl, CF3, OCH3 or CN;

[1613] R 12 is connected to Ar2 at the ortho- or meta-position relative to Ar1, and R 12 is H, a halogen, 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

[1614] When A is -NHC(=O)-:

[1615] R 12 can also be selected from CN, OCH2CH2N(CH3)2 and a C 3-6 heterocycloalkyl containing a nitrogen at the point of connection to Ar2, or R 12 together with the nitrogen atom to which it is attached forms an N-oxide (N + -O - );

[1616] R 13 is H or a halogen;

[1617] R 21 is H, C 1-5 alkyl, C(O)C 1-5 alkyl, C(O)OC 1-5 alkyl;

[1618] R 22 is H or CH3;

[1619] R 23 is H or C 1-2 alkyl; and

[1620] R 24 is H or C 1-2 alkyl;

[1621] or a pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate thereof.

[1622] Clause 40. The method according to Clause 37, the CTPS1 inhibitor used, the pharmaceutical composition used or the use, wherein the CTPS1 inhibitor is selected from the compounds disclosed in List C or a pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate thereof.

[1623] Clause 41. The method according to Clause 37, the CTPS1 inhibitor used, the pharmaceutical composition used or the use, wherein the CTPS1 inhibitor is a compound of formula (IV):

[1624]

[1625] wherein:

[1626] (a) When R4, R5, X, Y and R1 are as follows:

[1627]

[1628] W is N, CH or CF;

[1629] (b) When R4, R5, X, W and R1 are as follows:

[1630]

[1631] Y is CH or N;

[1632] (c) When W, X, Y and R1 are as follows:

[1633] R4 and R5 are joined to form the following structure:

[1634]

[1635] (d) When W, R4, R5, X and Y are as follows:

[1636]

[1637] R1 is methyl or cyclopropyl; and

[1638] (e) The compound is selected from:

[1639]

[1640] or a pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate thereof.

[1641] Clause 42. The method according to Clause 41, the CTPS1 inhibitor used, the pharmaceutical composition used or the use, wherein the CTPS1 inhibitor is selected from the compounds disclosed in List D or a pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate thereof.

[1642] Clause 43. The method according to Clause 39, the CTPS1 inhibitor used, the pharmaceutical composition used or the use, wherein the CTPS1 inhibitor is a compound of formula (V):

[1643]

[1644] (a) When A, V, W, X, Y, Z, R1, R 10 and R 12 are as follows:

[1645]

[1646] R4 and R5 together with the carbon atom to which they are attached form:

[1647]

[1648] or

[1649] (b) When A, V, W, X, Y, Z, R1, R 10 and R 12 are as follows:

[1650]

[1651] R4 and R5 together with the carbon atom to which they are attached form:

[1652]

[1653] or

[1654] (c) When A, V, W, X, Y, Z, R4, R5, R 10 and R 12 are as follows:

[1655]

[1656] R1 is

[1657] or

[1658] (d) When A, V, W, X, Y, Z, R4, R5, R 10 and R 12 are as follows:

[1659]

[1660] R1 is

[1661] or

[1662] (e) When A, X, Y, Z, R1, R4 and R5 are as follows:

[1663]

[1664] V, W, R 10 and R 12 are:

[1665]

[1666] or

[1667] (f) When A, V, W, R1, R4, R5, R 10 and R 12 are as follows:

[1668]

[1669] Z, X and Y are

[1670]

[1671] or

[1672] (g) When A, V, W, R1, R4, R5, R 10 and R 12 are as follows:

[1673]

[1674] Z, X and Y are

[1675]

[1676] or

[1677] (h) When A, V, W, R1, R4, R5, R 10 and R 12 are as follows

[1678]

[1679] Z, X and Y are

[1680]

[1681] or a pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate thereof.

[1682] Clause 44. The method according to Clause 43, the CTPS1 inhibitor used, the pharmaceutical composition used or the use, wherein the CTPS1 inhibitor is selected from the compounds disclosed in List E or a pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate thereof.

[1683] Clause 45. The method according to any one of Clauses 1-34, the CTPS1 inhibitor used, the pharmaceutical composition used or the use, wherein the CTPS1 inhibitor is a compound of formula (VI):

[1684]

[1685] wherein ring B is selected from:

[1686]

[1687] wherein X, Y and Z are defined as follows; and

[1688]

[1689] wherein R 3b3c is R 3b or R 3c as defined below,

[1690] wherein when B is (B-a), the compound of formula (VI) is a compound of formula (VI-a):

[1691]

[1692] wherein:

[1693] A a is A aa or A ba ;

[1694] wherein:

[1695] A aa is an amine linking group having the following structure: -NH-, -CH2NH- or -NHCH2-;

[1696] A ba is an amide linking group having the following structure: -C(=O)NH- or -NHC(=O)-;

[1697] X is N or CH;

[1698] Y is N or CR 2a ;

[1699] Z is N or CR 3a ;

[1700] Provided that when at least one of X or Z is N, Y cannot be N;

[1701] R 2a is H, halogen, C 1-2 alkyl, OC 1-2 alkyl, C 1-2 haloalkyl or OC 1-2 haloalkyl; and

[1702] R 3a is H, halogen, CH3, OCH3, CF3 or OCF3;

[1703] wherein R 2a and R 3a at least one of which is H;

[1704] R 1a is R 1aa or R 1ba ;

[1705] wherein:

[1706] R 1aa is NR 32a R 33a ;

[1707] R 1ba is C 1-5 alkyl, cycloalkyl optionally substituted by CH3, C 0-2 alkylene C 3-5 cycloalkyl or CF3;

[1708] R 4a and R 5a are R 4aa and R 5aa or R 4ba and R 5ba ;

[1709] wherein:

[1710] R 4aa and R 5aa together with the carbon atom to which they are attached form a C 3-6 cycloalkyl, which:

[1711] is substituted by one or two substituents, each substituent independently selected from C 1-3 alkyl, oxo, OH, C 1-3 alkyl OH, C 1-3 haloalkyl, C 0-2 alkylene C 3-6 cycloalkyl, C 0-2Alkylene C 3-6 Heterocycloalkyl, C 1-3 Alkylene OC 1-3 Alkyl, halogen, OC 1-3 Halogenated alkyl, 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

[1712] C 3-6 One of the carbons of the cycloalkyl is a spiro center such that the spiro ring system is composed of a C 3-6 cycloalkyl ring and another C 3-6 cycloalkyl ring or a C 3-6 heterocycloalkyl ring, and wherein the C 4aa formed by R 5aa and R 3-6 with the attached carbon atom can be substituted by one or two substituents, each substituent independently selected from C 1-3 alkyl or OC 1-3 alkyl; or

[1713] R 4aa and R 5aa together with the attached carbon atom form a C 3-6 heterocycloalkyl, wherein the C 3-6 one of the carbons of the heterocycloalkyl is a spiro center such that the spiro ring system is composed of a C 3-6 heterocycloalkyl ring and another C 3-6 cycloalkyl ring or a C 3-6 heterocycloalkyl ring, and wherein the C 4aa formed by R 5aa and R 3-6 with the attached carbon atom can be substituted by one or two substituents, each substituent independently selected from C 1-3 alkyl or OC 1-3 alkyl; or

[1714] R 4aa and R 5aa together with the attached carbon atom form a C 3-6 heterocycloalkyl containing one nitrogen atom, wherein the nitrogen atom is substituted by -S(O)2R 29a ; or

[1715] R 4ba and R 5ba are each independently H, C 1-6 alkyl, C 1-6 alkyl OH, C 1-6haloalkyl, 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 attached carbon atom forms C 3-6 cycloalkyl or C 3-6 heterocycloalkyl; and

[1716] when A a is -NHC(=O)- or -NHCH2-:

[1717] R 4ba and R 5ba may also be selected from halogen, OC 1-6 haloalkyl, OC 0-2 alkylene C 3-6 cycloalkyl, OC 0-2 alkylene C 3-6 cycloalkyl, OC 1-6 alkyl and NR 21a R 22a ;

[1718] Ar1a is a 6 - membered aryl or heteroaryl;

[1719] Ar2a is a 6 - membered aryl or heteroaryl, and is attached to Ar1a at the para - position relative to the group A a ;

[1720] R 10a is H, halogen, C 1-3 alkyl, C 1-2 haloalkyl, OC 1-2 alkyl, OC 1-2 haloalkyl or CN;

[1721] R 11a is H, F, Cl, C 1-2 alkyl, CF3, OCH3 or CN;

[1722] R 12a is attached to Ar2 at the ortho - or meta - position relative to Ar1a, and R 12a is H, halogen, 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, OC1-4 haloalkyl, hydroxy, C 1-4 alkylOH, SO2C 1-2 alkyl, C(O)N(C 1-2 alkyl)2, NHC(O)C 1-3 alkyl or NR 23a R 24a ; and

[1723] When A a is -NHC(=O)-, -NH- or -NHCH2-:

[1724] R 12a may also be selected from CN, OCH2CH2N(CH3)2 and a C 3-6 heterocycloalkyl containing a nitrogen at the point of attachment to Ar2, or R 12a together with the attached nitrogen atom forms an N-oxide (N + -O - );

[1725] R 13a is H or halogen;

[1726] R 21a is H, C 1-5 alkyl, C(O)C 1-5 alkyl, C(O)OC 1-5 alkyl, C 1-3 alkylOC 1-2 alkyl, C 1-4 haloalkyl or C 4-6 heterocycloalkyl;

[1727] R 22a is H or CH3;

[1728] R 23a is H or C 1-2 alkyl; and

[1729] R 24a is H or C 1-2 alkyl

[1730] R 29a is C 1-3 alkyl, cycloalkyl optionally substituted by CH3, C 0-2 alkylene C 3-5 cycloalkyl, CF3, N(C 1-3 alkyl)2 or a 5- or 6-membered heteroaryl, wherein the 5- or 6-membered heteroaryl is optionally substituted by methyl;

[1731] R 32a is C 1-3 alkyl and R 33 is C 1-3alkyl; or

[1732] R 32a and R 33a together with the attached nitrogen atom form a C 3-5 heterocycloalkyl;

[1733] wherein

[1734] R 1a is R 1aa ; and / or

[1735] R 4a and R 5a are R 4aa and R 5aa ; and / or

[1736] A a is A aa ; and

[1737] wherein when B is (B-bc) and R 3b3c is R 3b the compound of formula (VI) is the compound of formula (VI-b):

[1738]

[1739] wherein:

[1740] A b is A ab or A bb ;

[1741] wherein:

[1742] A ab is -NR 6b CH2- or -NR 6b -;

[1743] A bb is -NR 6b C(=O)-;

[1744] R 1b is R 1ab or R 1bb ;

[1745] wherein:

[1746] R 1ab is NR 32b R 33b ;

[1747] R 1bb is C 1-5 alkyl, cycloalkyl optionally substituted by CH3, C 0-2 alkylene C 3-5Naphthenyl, C 1-3 alkylene OC 1-2 alkyl or CF3;

[1748] R 3b is H, halogen, CH3, OC 1-2 alkyl or CF3;

[1749] or R 3b together with R 5bb forms a 5- or 6-membered naphthenyl or 5- or 6-membered oxygen-containing heteronaphthenyl;

[1750] R 4b and R 5b is R 4ab and R 5ab or R 4bb and R 5bb ;

[1751] Wherein:

[1752] R 4ab and R 5ab together with the attached carbon atom form a C 3-6 naphthenyl, which: is substituted with one or two substituents, each substituent independently selected from C 1-3 alkyl, oxo, OH, C 1-3 alkyl OH, C 1-3 haloalkyl, C 0-2 alkylene C 3-6 naphthenyl, C 0-2 alkylene C 3-6 heteronaphthenyl, C 1-3 alkylene OC 1-3 alkyl, halogen, OC 1-3 haloalkyl, OC 0-2 alkylene C 3-6 naphthenyl, OC 0-2 alkylene C 3-6 heteronaphthenyl, OC 1-3 alkyl and NR 21b R 22b ; or C 3-6 one of the carbons of the naphthenyl is a spiro center, such that the spiro ring system is formed by a C 3-6 naphthenyl ring and another C 3-6 naphthenyl ring or C 3-6 heteronaphthenyl ring, and wherein the C 4ab formed by R ab and R5 3-6 together with the attached carbon atom can be substituted with one or two substituents, each substituent independently selected from C 1-3 alkyl or OC 1-3 alkyl; or

[1753] R 4ab and R 5ab together with the attached carbon atom form a C 3-6 heterocycloalkyl, where one of the carbons of the C 3-6 heterocycloalkyl is a spiro center such that the spiro ring system is composed of a C 3-6 c heterocycloalkyl ring and another C 3-6 cycloalkyl ring or a C 3-6 heterocycloalkyl ring is formed, and where the C 4ab formed by R 5ab and R 3-6 together with the attached carbon atom can be substituted by one or two substituents, each independently selected from C 1-3 alkyl or OC 1-3 alkyl; or

[1754] R 4ab and R 5ab together with the attached carbon atom form a C 3-6 heterocycloalkyl containing one nitrogen atom, where the nitrogen atom is substituted by -S(O)2R 29b ; or

[1755] R 4bb and R 5bb are each independently H, halogen, 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 ,

[1756] or R 4bb is H, and R 5bb together with R 3b forms a 5- or 6-membered cycloalkyl or a 5- or 6-membered oxygen-containing heterocycloalkyl,

[1757] or R 4bb and R 5bb together with the attached carbon atom form a C 3-6 cycloalkyl or a C 3-6 heterocycloalkyl,

[1758] or R 4bbis H, and R 5bb and R 6b is a C 2-3 alkylene chain forming a 5- or 6-membered ring;

[1759] or R 4bb is O, and R 5bb is absent;

[1760] R 6b is H or C 1-3 alkyl,

[1761] or when in the ortho position to group A b then R 6b and R 11b together form a C2 alkylene chain forming a 5-membered ring,

[1762] or R 5bb and R 6b are a C 2-3 alkylene chain forming a 5- or 6-membered ring, and R 4bb is H;

[1763] Ar1b is a 6-membered aryl or heteroaryl;

[1764] Ar2b is a 6-membered aryl or heteroaryl and is connected to Ar1b in the para position relative to group Ab;

[1765] R 10b is H, halogen, C 1-3 alkyl, OC 1-2 alkyl, C 1-2 haloalkyl, OC 1-2 haloalkyl or CN;

[1766] R 11b is H, F, Cl, CH3, ethyl, OCH3, CF3, OCF3 or CN, or when in the ortho position to group A b then R 11b and R 6b together form a C2 alkylene chain forming a 5-membered ring;

[1767] R 12b is connected to Ar2b in the ortho or meta position relative to Ar1b, and R 12b is H, halogen, 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, C1-3 Alkylene OC 1-3 Alkyl, C 1-4 Halogenated alkyl, OC 1-4 Halogenated alkyl, 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 a nitrogen at the point of attachment to Ar2 3-6 Heterocyclic alkyl, or R 12b Together with the attached nitrogen atom forms an N-oxide (N + -O - );

[1768] R 13b is H, halogen, CH3 or OCH3;

[1769] R 21b is H, C 1-5 Alkyl, C(O)C 1-5 Alkyl, C(O)OC 1-5 Alkyl, C 1-3 Alkylene OC 1-2 Alkyl, C 1-4 Halogenated alkyl or C 4-6 Heterocyclic alkyl;

[1770] R 22b is H or CH3;

[1771] R 23b is H or C 1-2 Alkyl;

[1772] R 24b is H or C 1-2 Alkyl;

[1773] R 29b is C 1-3 Alkyl, C cycloalkyl optionally substituted by CH3 0-2 Alkylene C 3-5 Cycloalkyl, CF3, N(C 1-3 Alkyl)2 or 5- or 6-membered heteroaryl, where the 5- or 6-membered heteroaryl is optionally substituted by methyl; and

[1774] R 32b is C 1-3 Alkyl and R 33b is C 1-3 Alkyl; or

[1775] R32b and R 33b together with the attached nitrogen atom form a C 3-5 heterocycloalkyl;

[1776] wherein:

[1777] R 1b is R 1ab ; and / or

[1778] R 4b and R 5b are R 4ab and R 5ab ; and / or

[1779] A is A ab ; or

[1780] wherein when B is (B-bc) and R 3b3c is R 3c the compound of formula (VI) is the compound of formula (VI-c):

[1781]

[1782] wherein:

[1783] A c is A ac or A bc ;

[1784] wherein:

[1785] A ac is -CH2NR 6c -;

[1786] A bc is -C(=O)NR 6c -;

[1787] R 1c is R 1ac or R 1bc ;

[1788] wherein:

[1789] R 1ac is NR 32c R 33c ;

[1790] R 1bc is C 1-5 alkyl, cycloalkyl optionally substituted by CH3, C 0-2 alkylene C 3-5 cycloalkyl, C 1-3 alkylene OC 1-2 alkyl or CF3;

[1791] R 3c is H, CH3, halogen, OC 1-2 alkyl or CF3;

[1792] R 4c and R 5c is R 4ac and R 5ac or R 4bc and R 5bc ;

[1793] wherein:

[1794] R 4ac and R 5ac together with the attached carbon atom form a C 3-6 cycloalkyl which is: substituted with one or two substituents, each substituent independently selected from 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, halogen, OC 1-3 haloalkyl, OC 0-2 alkylene C 3-6 cycloalkyl, OC 0-2 alkylene C 3-6 heterocycloalkyl, OC 1-3 alkyl and NR 21c R 22c ; or C 3-6 one of the carbons of the cycloalkyl is a spiro center such that the spiro ring system is formed by a C 3-6 cycloalkyl ring and another C 3-6 cycloalkyl ring or C 3-6 heterocycloalkyl ring, and wherein the C 4ac formed by R 5ac and R 3-6 together with the attached carbon atom can be substituted with one or two substituents, each substituent independently selected from C 1-3 alkyl or OC 1-3 alkyl; or

[1795] R 4ac and R 5ac together with the attached carbon atom form a C 3-6 heterocycloalkyl, wherein C 3-6 one of the carbons of the heterocycloalkyl is a spiro center such that the spiro ring system is formed by a C 3-6 heterocycloalkyl ring and another C 3-6A cycloalkyl ring or a C 3-6 heterocycloalkyl ring is formed, and wherein R 4ac and R5 ac together with the attached carbon atom form a C 3-6 heterocycloalkyl which may be substituted by one or two substituents, each independently selected from C 1-3 alkyl or OC 1-3 alkyl; or

[1796] R 4ac and R 5ac together with the attached carbon atom form a C 3-6 heterocycloalkyl containing one nitrogen atom, wherein the nitrogen atom is substituted by -S(O)2R 29c ; or

[1797] 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 haloalkyl,

[1798] or R 4bc and R5 bc together with the attached carbon atom form a C 3-6 cycloalkyl or C 3-6 heterocycloalkyl ring;

[1799] R 6c is H or C 1-3 alkyl;

[1800] Ar1c is a 6-membered aryl or heteroaryl;

[1801] Ar2c is a 6-membered aryl or heteroaryl and is attached to Ar1c at the para position relative to the group A c ;

[1802] R 10c is H, halogen, C 1-3 alkyl, OC 1-2 alkyl, C 1-2 haloalkyl, OC 1-2 haloalkyl or CN;

[1803] R 11c is H, F, Cl, CH3, ethyl, OCH3, CF3, OCF3 or CN;

[1804] R 12c is attached to Ar2c at the meta- or ortho-position relative to the group Arc1, and R 12c is H, halogen, 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 23c R 24c , SO2CH3, C(O)N(CH3)2, NHC(O)C 1-3 alkyl or a C containing a nitrogen at the point of attachment to Ar2c 3-6 heterocycloalkyl, or R 12c together with the attached nitrogen atom forms an N-oxide (N + -O - );

[1805] 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 heterocycloalkyl;

[1806] R 22c is H or CH3;

[1807] R 23c is H or C 1-2 alkyl;

[1808] R 24c is H or C 1-2 alkyl;

[1809] R 29c is C 1-3 alkyl, cycloalkyl optionally substituted by CH3 C 0-2 alkylene C 3-5 cycloalkyl, CF3, N(C 1-3 alkyl)2 or a 5- or 6-membered heteroaryl, wherein the 5- or 6-membered heteroaryl is optionally substituted by methyl; and

[1810] R 32c is C 1-3 alkyl and R 33c is C 1-3 alkyl; or

[1811] R 32c and R 33c together with the attached nitrogen atom form a C 3-5 heteroalkyl;

[1812] wherein:

[1813] R 1c is R 1ac ; and / or

[1814] R 4c and R 5c are R 4ac and R 5ac ; and / or

[1815] A c is A ac ;

[1816] or a pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate thereof.

[1817] Clause 46. The method, the CTPS1 inhibitor used, the pharmaceutical composition used or the use according to Clause 45, wherein the CTPS1 inhibitor is selected from the compounds disclosed in List F or a pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate thereof.

[1818] Clause 47. The method, the CTPS1 inhibitor used, the pharmaceutical composition used or the use according to any one of Clauses 1 - 34, wherein the CTPS1 inhibitor is a compound of formula (VII):

[1819]

[1820] wherein

[1821] A is A a or A b ;

[1822] wherein

[1823] A a is an amine linking group having the following structure: -NH-, -CH2NH- or -NHCH2-;

[1824] A b is an amide linking group having the following structure: -C(=O)NH- or -NHC(=O)-;

[1825] B is X is N or CH;

[1826] Y is N or CR2;

[1827] Z is N or CR3;

[1828] Provided that when at least one of X or Z is N, Y cannot be N;

[1829] R1 is C 1-5 fluoroalkyl, provided that R1 is not CF3;

[1830] R2 is H, halogen, C 1-2 alkyl, OC 1-2 alkyl, C 1-2 haloalkyl or OC 1-2 haloalkyl;

[1831] R3 is H, halogen, CH3, OCH3, CF3 or OCF3;

[1832] wherein at least one of R2 and R3 is H;

[1833] R 3’ is H, halogen, CH3, OC 1-2 alkyl or CF3; and

[1834] when A is -NHC(=O)-, R 3’ also forms a 5- or 6-membered cycloalkyl or a 5- or 6-membered oxygen-containing heterocycloalkyl together with R5;

[1835] R4 and R5 are R 4a and R 5a or R 4b and R 5b ;

[1836] wherein

[1837] R 4a and R 5a together with the attached carbon atom form a C 3-6 cycloalkyl which: is substituted with one or two substituents, each substituent independently selected from 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, halogen, 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 21 R 22 ; or

[1838] C 3-6 One of the carbons of the cycloalkyl is a spiro center such that the spiro ring system is formed by a C 3-6 cycloalkyl ring and another C 3-6 cycloalkyl ring or a C 3-6 heterocycloalkyl ring, and wherein the C 4a formed by R 5a and R 3-6 with the attached carbon atom can be substituted by one or two substituents, each independently selected from C 1-3 alkyl or OC 1-3 alkyl; or

[1839] R 4a and R 5a form a C 3-6 heterocycloalkyl with the attached carbon atom, wherein the C 3-6 one of the carbons of the heterocycloalkyl is a spiro center such that the spiro ring system is formed by a C 3-6 heterocycloalkyl ring and another C 3-6 cycloalkyl ring or a C 3-6 heterocycloalkyl ring, and wherein the C 4a formed by R 5a and R 3-6 with the attached carbon atom can be substituted by one or two substituents, each independently selected from C 1-3 alkyl or OC 1-3 alkyl; or

[1840] R 4a and R 5a form a C 3-6 heterocycloalkyl containing one nitrogen atom, wherein the nitrogen atom is substituted by -S(O)2R 29 ; or

[1841] 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 R4b and R 5b together with the attached carbon atom form a C 3-6 cycloalkyl or C 3-6 heterocycloalkyl; and

[1842] when A is -NHC(=O)- or -NHCH2-:

[1843] R 4b and R 5b may also be selected from halogen, 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 ;

[1844] Ar1 is a 6 - membered aryl or heteroaryl;

[1845] Ar2 is a 6 - membered aryl or heteroaryl and is attached to Ar1 at the para - position relative to the group A;

[1846] R 10 is H, halogen, C 1-3 alkyl, C 1-2 haloalkyl, OC 1-2 alkyl, OC 1-2 haloalkyl or CN;

[1847] R 11 is H, F, Cl, C 1-2 alkyl, CF3, OCH3 or CN;

[1848] R 12 is attached to Ar2 at the ortho - or meta - position relative to Ar1, and R 12 is H, halogen, 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

[1849] When A is -NHC(=O)-, -NH-, or -NHCH2-:

[1850] R 12 may also be selected from CN, OCH2CH2N(CH3)2, and a C containing a nitrogen at the point of attachment to Ar2 3-6 heterocycloalkyl, or R 12 together with the attached nitrogen atom forms an N-oxide (N + -O - );

[1851] R 13 is H or a halogen;

[1852] R 21 is H, C 1-5 alkyl, C(O)C 1-5 alkyl, C(O)OC 1-5 alkyl;

[1853] R 22 is H or CH3;

[1854] R 23 is H or C 1-2 alkyl; and

[1855] R 24 is H or C 1-2 alkyl;

[1856] R 29 is C 1-3 alkyl, cycloalkyl optionally substituted by CH3, C 0-2 alkylene C 3-5 cycloalkyl, or CF3;

[1857] R 32 is C 1-3 alkyl and R 33 is C 1-3 alkyl; or

[1858] R 32 and R 33 together with the attached nitrogen atom form a C 3-5 heterocycloalkyl;

[1859] or a pharmaceutically acceptable salt and / or pharmaceutically acceptable solvate thereof.

[1860] Clause 48. The method, CTPS1 inhibitor used, pharmaceutical composition used, or use according to clause 47, wherein the CTPS1 inhibitor is selected from the compounds disclosed in List G or a pharmaceutically acceptable salt and / or pharmaceutically acceptable solvate thereof.

[1861] Clause 49. The method according to any one of Clauses 1 - 34, the CTPS1 inhibitor used, the pharmaceutical composition used, or the use, wherein the CTPS1 inhibitor is a compound of formula (VIII):

[1862]

[1863] wherein

[1864] A is A a or A b ;

[1865] wherein

[1866] A a is an amine linking group having the following structure: -NH-, -CH2NH-, or -NHCH2-;

[1867] A b is an amide linking group having the following structure: -C(=O)NH- or -NHC(=O)-;

[1868] B is X is N or CH;

[1869] Y is N or CR2;

[1870] Z is N or CR3;

[1871] provided that when at least one of X or Z is N, Y cannot be N;

[1872] 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;

[1873] R2 is H, halogen, C 1-2 alkyl, OC 1-2 alkyl, C 1-2 haloalkyl or OC 1-2 haloalkyl;

[1874] R3 is H, halogen, CH3, OCH3, CF3, or OCF3;

[1875] wherein at least one of R2 and R3 is H;

[1876] R 3’ is H, halogen, CH3, OC 1-2 alkyl, or CF3; and

[1877] when A is -NHC(=O)-, R 3’ also forms a 5 - or 6 - membered cycloalkyl or a 5 - or 6 - membered oxygen - containing heterocycloalkyl together with R5;

[1878] R4 and R5 are R 4a and R 5a , or R 4b and R 5b ;

[1879] wherein

[1880] R 4a and R 5a together with the attached carbon atom form a C 3-6 cycloalkyl group which is: substituted with one or two substituents, each substituent independently selected from 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, halogen, 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

[1881] C 3-6 One of the carbons of the cycloalkyl is a spiro center such that the spiro ring system is formed by a C 3-6 cycloalkyl ring and another C 3-6 cycloalkyl ring or C 3-6 heterocycloalkyl ring, and wherein the C 4a formed by R 5a and R 3-6 together with the attached carbon atom can be substituted with one or two substituents, each substituent independently selected from C 1-3 alkyl or OC 1-3 alkyl; or

[1882] R 4a and R 5a together with the attached carbon atom form a C 3-6 heterocycloalkyl, wherein C 3-6 One of the carbons of the heterocycloalkyl is a spiro center such that the spiro ring system is formed by a C 3-6 heterocycloalkyl ring and another C 3-6 cycloalkyl ring or C 3-6 heterocycloalkyl ring, and wherein the C 4a formed by R5a C formed together with the attached carbon atom 3-6 The heterocycloalkyl group may be substituted by one or two substituents, each independently selected from C 1-3 alkyl or OC 1-3 alkyl; or

[1883] R 4a and R 5a together with the attached carbon atom form a C containing one nitrogen atom 3-6 heterocycloalkyl group, wherein the nitrogen atom is substituted by -S(O)2R 29 substituted; or

[1884] 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 attached carbon atom form C 3-6 cycloalkyl or C 3-6 heterocycloalkyl; and

[1885] When A is -NHC(=O)- or -NHCH2-:

[1886] R 4b and R 5b may also be selected from halogen, 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 ;

[1887] Ar1 is a 6-membered aryl or heteroaryl group;

[1888] Ar2 is a 6-membered aryl or heteroaryl group and is attached to Ar1 at the para position relative to group A;

[1889] R 10 is H, halogen, C 1-3 alkyl, C 1-2 haloalkyl, OC 1-2 alkyl, OC 1-2haloalkyl or CN;

[1890] R 11 is H, F, Cl, C 1-2 alkyl, CF3, OCH3 or CN;

[1891] R 12 is connected to Ar2 at the ortho- or meta-position relative to Ar1, and R 12 is H, halogen, 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

[1892] when A is -NHC(=O)-, -NH- or -NHCH2-:

[1893] R 12 can also be selected from CN, OCH2CH2N(CH3)2 and a C 3-6 heterocycloalkyl containing a nitrogen at the point of attachment to Ar2, or R 12 together with the attached nitrogen atom forms an N-oxide (N + -O - );

[1894] R 13 is H or halogen;

[1895] R 21 is H, C 1-5 alkyl, C(O)C 1-5 alkyl, C(O)OC 1-5 alkyl;

[1896] R 22 is H or CH3;

[1897] R 23 is H or C 1-2 alkyl; and

[1898] R 24 is H or C 1-2 alkyl;

[1899] R 29 is C 1-3 alkyl, cycloalkyl optionally substituted by CH3, C 0-2 alkylene C 3-5 cycloalkyl or CF3;

[1900] R 32 is C 1-3 alkyl and R 33 is C 1-3 alkyl; or

[1901] R 32 and R 33 together with the attached nitrogen atom form a C 3-5 heterocycloalkyl;

[1902] or a pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate thereof.

[1903] Clause 50. The method, the CTPS1 inhibitor used, the pharmaceutical composition used or the use according to Clause 49, wherein the CTPS1 inhibitor is selected from the compounds disclosed in List H or a pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate thereof.

[1904] Clause 51. The method, the CTPS1 inhibitor used, the pharmaceutical composition used or the use according to any one of Clauses 1 - 34, 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:

[1905]

[1906] or a pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate thereof.

[1907] Clause 52. The method, the CTPS1 inhibitor used, the pharmaceutical composition used or the use according to any one of Clauses 1 - 31, wherein the CTPS1 inhibitor is N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(2-(ethylsulfonamido)pyrimidin-4-yl)tetrahydro-2H-pyran-4-carboxamide:

[1908]

[1909] or a pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate thereof.

[1910] Clause 53. The method, the CTPS1 inhibitor used, the pharmaceutical composition used or the use according to any one of Clauses 1 - 52, wherein the CTPS1 inhibitor is in its free form.

[1911] Clause 54. The method according to any one of Clauses 1 - 52, the CTPS1 inhibitor used, the pharmaceutical composition used, or the use, wherein the CTPS1 inhibitor is a pharmaceutically acceptable salt. Clause 55. The method according to any one of Clauses 1 - 52, the CTPS1 inhibitor used, the pharmaceutical composition used, or the use, wherein the CTPS1 inhibitor is a pharmaceutically acceptable solvate.

[1912] Clause 56. The method according to any one of Clauses 1 - 52, the CTPS1 inhibitor used, the pharmaceutical composition used, or the use, wherein the CTPS1 inhibitor is a pharmaceutically acceptable salt and a pharmaceutically acceptable solvate.

[1913] Clause 57. The method according to any one of Clauses 1 - 34, the CTPS1 inhibitor used, the pharmaceutical composition used, or the use, wherein the CTPS1 inhibitor is 4-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)tetrahydro-2H-pyran-4-carboxamide (‘CTPS1-IA’):

[1914]

[1915] or a pharmaceutically acceptable salt thereof.

[1916] Clause 58. The method according to any one of Clauses 1 - 34, the CTPS1 inhibitor used, the pharmaceutical composition used, or the use, wherein the CTPS1 inhibitor is N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(2-(ethylsulfonamido)pyrimidin-4-yl)tetrahydro-2H-pyran-4-carboxamide (‘CTPS1-IB’):

[1917]

[1918] or a pharmaceutically acceptable salt thereof.

[1919] Clause 59. The method according to any one of Clauses 1 - 58, the CTPS1 inhibitor used, the pharmaceutical composition used, or the use, wherein the CTPS1 inhibitor is provided in a natural isotopic form.

[1920] Clause 60. The method according to any one of Clauses 1 - 59, the CTPS1 inhibitor used, the pharmaceutical composition used, or the use, wherein the CTPS1 inhibitor is the CTPS1 inhibitor as defined in Claim 1 of WO2022 / 087634.

[1921] Article 61. The method, the CTPS1 inhibitor used, the pharmaceutical composition used or the use according to any one of Articles 1 - 59, wherein the CTPS1 inhibitor is a CTPS1 inhibitor as defined in WO2022 / 087634.

[1922] Article 62. The method, the CTPS1 inhibitor used, the pharmaceutical composition used or the use according to any one of Articles 1 - 59, wherein the CTPS1 inhibitor is not a CTPS1 inhibitor as defined in claim 1 of WO2022 / 087634.

[1923] Article 63. The method, the CTPS1 inhibitor used, the pharmaceutical composition used or the use according to any one of Articles 1 - 59, wherein the CTPS1 inhibitor is not a CTPS1 inhibitor as defined in WO2022 / 087634.

[1924] Article 64. The method, the CTPS1 inhibitor used, the pharmaceutical composition used or the use according to any one of Articles 1 - 63, wherein the defect of CTPS2 is caused by genomic alteration or variation and / or epigenetic alteration or variation.

[1925] Article 65. The method, the CTPS1 inhibitor used, the pharmaceutical composition used or the use according to any one of Articles 1 - 64, wherein the defect of CTPS2 is caused by genomic alteration or variation.

[1926] Article 66. The method, the CTPS1 inhibitor used, the pharmaceutical composition used or the use according to Article 64 or 65, wherein the genomic alteration or variation is the complete loss of the CTPS2 gene due to genomic deletion.

[1927] Article 67. The method, the CTPS1 inhibitor used, the pharmaceutical composition used or the use according to any one of Articles 64 - 66, wherein the genomic alteration or variation is the partial loss of the CTPS2 gene due to genomic deletion.

[1928] Article 68. The method, the CTPS1 inhibitor used, the pharmaceutical composition used or the use according to any one of Articles 64 - 67, wherein the genomic alteration or variation is that the CTPS2 gene is disrupted by a structural DNA variant, such as an inversion, duplication or translocation within the gene footprint. Article 69. The method, the CTPS1 inhibitor used, the pharmaceutical composition used or the use according to any one of Articles 64 - 68, wherein the genomic alteration or variation is a CTPS2 gene mutation such that the CTPS2 expression is significantly reduced or most appropriately completely lost.

[1929] Clause 70. A method, a CTPS1 inhibitor used, a pharmaceutical composition used, or a use according to any one of Clauses 64-68, wherein the lack of CTPS2 is caused by epigenetic changes. Clause 71. A method, a CTPS1 inhibitor used, a pharmaceutical composition used, or a use according to Clause 70, wherein the epigenetic change is an alteration in the expression of the CTPS2 gene, such as a change in regulatory elements resulting from alterations in methylation and / or histone modifications, such that the expression of CTPS2 is significantly reduced or optimally completely lost.

[1930] Clause 72. A method, a CTPS1 inhibitor used, a pharmaceutical composition used, or a use according to any one of Clauses 1-71, wherein the sample is a biopsy containing cancer cells (such as a tumor biopsy), a sample containing circulating cancer cells, or a sample containing cell-free cancer DNA.

[1931] Clause 73. A method, a CTPS1 inhibitor used, a pharmaceutical composition used, or a use according to any one of Clauses 1-72, wherein the step of identifying a subject with cancer having CTPS2 deficiency comprises:

[1932] (i) applying a suitable method to determine CTPS2 deficiency, such as a technique for detecting DNA, RNA, or protein-related alterations,

[1933] (ii) analyzing the data generated by the method, and

[1934] (iii) interpreting the data generated by the method to determine the likelihood of a severe defect in CTPS2 function, particularly the likelihood of a complete loss of CTPS2 function.

[1935] Clause 74. A method, a CTPS1 inhibitor used, a pharmaceutical composition used, or a use according to Clause 73, wherein the method for determining CTPS2 deficiency is a method for detecting DNA alterations, such as whole-genome sequencing, whole-exome sequencing, targeted gene sequencing based on capture enrichment, targeted gene sequencing based on PCR enrichment, real-time quantitative PCR, droplet digital PCR, in situ hybridization, or fluorescence in situ hybridization.

[1936] Clause 75. A method, a CTPS1 inhibitor used, a pharmaceutical composition used, or a 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 arrays, real-time quantitative PCR, droplet digital PCR, or in situ hybridization.

[1937] Article 76. The method, the CTPS1 inhibitor used, the pharmaceutical composition used, or the use according to any one of Articles 73 - 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, droplet digital PCR, or in situ hybridization.

[1938] Article 77. The method, the CTPS1 inhibitor used, the pharmaceutical composition used, or the use according to any one of Articles 73 - 76, wherein the method for determining CTPS2 deficiency is a method for detecting protein changes, such as immunohistochemistry, flow cytometry, or mass cytometry. Article 78. The method, the CTPS1 inhibitor used, the pharmaceutical composition used, or the use according to Article 77, wherein the method for determining CTPS2 deficiency is immunohistochemistry, such as the absence of CTPS2 staining.

[1939] Article 79. The method, the CTPS1 inhibitor used, the pharmaceutical composition used, or the use according to any one of Articles 1 - 78, wherein the subject is a human subject.

[1940] Article 80. The method, the CTPS1 inhibitor used, the pharmaceutical composition used, or the use according to Article 79, wherein the human subject is an adult, such as 18 - 65 years old. Article 81. The method, the CTPS1 inhibitor used, the pharmaceutical composition used, or the use according to Article 79, wherein the human subject is under 18 years old, such as 4 - 17 years old. Article 82. The method, the CTPS1 inhibitor used, the pharmaceutical composition used, or the use according to Article 79, wherein the human subject is 66 years old or older.

[1941] Article 83. The method, the CTPS1 inhibitor used, the pharmaceutical composition used, or the use according to any one of Articles 79 - 82, wherein the human subject is male.

[1942] Article 84. The method, the CTPS1 inhibitor used, the pharmaceutical composition used, or the use according to Article 83, wherein the defect of CTPS2 is caused by a genomic deletion resulting in the complete loss of the CTPS2 gene.

[1943] Article 85. The method, the CTPS1 inhibitor used, the pharmaceutical composition used, or the use according to any one of Articles 79 - 82, wherein the human subject is female.

[1944] Article 86. The method, the CTPS1 inhibitor used, the pharmaceutical composition used, or the use according to Article 85, wherein the CTPS2 deficiency is caused by genomic alterations and / or epigenetic changes of one or two XX chromosomes (appropriately two).

[1945] Clause 87. A method according to Clause 85 or 86, a CTPS1 inhibitor used, a pharmaceutical composition used, or a use, wherein the lack of CTPS2 is due to the complete deletion of the CTPS2 gene on the first X chromosome due to a genomic deletion, and:

[1946] (i) The complete deletion of the CTPS2 gene on the second X chromosome due to a genomic deletion; (ii) The partial deletion of the CTPS2 gene on the second X chromosome due to a genomic deletion; (iii) The disruption of the CTPS2 gene on the second X chromosome by a structural DNA variant falling within the gene footprint, such as an inversion, duplication, or translocation;

[1947] (iv) A mutation in the CTPS2 gene on the second X chromosome such that CTPS2 expression is significantly reduced or completely lost; or (v) An alteration in the expression of the CTPS2 gene on the second X chromosome, such as due to a change in regulatory elements resulting from altered methylation and / or histone modification, such that CTPS2 expression is significantly reduced or completely lost.

[1948] Clause 88. A method according to Clause 86 or 87, a CTPS1 inhibitor used, a pharmaceutical composition used, or a use, wherein the defect of CTPS2 is due to the complete deletion of the CTPS2 gene on the first X chromosome due to a genomic deletion, and the complete deletion of the CTPS2 genome on the second X chromosome due to a genomic deletion.

[1949] Clause 89. A method according to any one of Clauses 1-88, a CTPS1 inhibitor used, a pharmaceutical composition used, or a use, wherein the lack of CTPS2 is caused by a homozygous deletion in cancer cells.

[1950] Clause 90. A method according to any one of Clauses 1-89, a CTPS1 inhibitor used, a pharmaceutical composition used, or a use, wherein the CTPS1 inhibitor is administered orally.

[1951] Clause 91. A method according to Clause 90, a CTPS1 inhibitor used, a pharmaceutical composition used, or a use, wherein the CTPS1 inhibitor is administered in the form of a solid composition (such as a tablet, capsule, or lozenge).

[1952] Clause 92. A method according to Clause 90, a CTPS1 inhibitor used, a pharmaceutical composition used, or a use, wherein the CTPS1 inhibitor is administered in the form of a liquid pharmaceutical composition (such as a suspension, emulsion, or solution).

[1953] Clause 93. The method, the CTPS1 inhibitor used, the pharmaceutical composition used or the use according to any one of Clauses 1-92, wherein the CTPS1 inhibitor is administered in unit doses of 0.05 mg - 1000 mg, more preferably 1.0 mg - 500 mg.

[1954] Clause 94. The method, the CTPS1 inhibitor used, the pharmaceutical composition used or the use according to any one of Clauses 1-93, wherein the CTPS1 inhibitor is administered more than once or twice a day, such as twice or three times a day.

[1955] Clause 95. The method, the CTPS1 inhibitor used, the pharmaceutical composition used or the use according to any one of Clauses 1-94, wherein the CTPS1 inhibitor is administered continuously, such as at least once a day, for a period of multiple weeks.

[1956] Clause 96. The method, the CTPS1 inhibitor used, the pharmaceutical composition used or the use according to any one of Clauses 1-94, wherein the CTPS1 inhibitor is administered intermittently, such as at least once a day for one week, followed by one week without administration, and then at least once a day for another week.

[1957] Clause 97. The method, the CTPS1 inhibitor used, the pharmaceutical composition used or the use according to any one of Clauses 1-96, wherein the CTPS1 inhibitor is administered in combination with one or more additional pharmaceutically acceptable ingredients, and the additional pharmaceutically acceptable active ingredients are selected from: 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, cytarabine and hydroxyurea; intercalating agents such as doxorubicin 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; IAP inhibitors such as LCL161; VEGF inhibitors such as bevacizumab; pan-kinase inhibitors such as sorafenib and sunitinib; tyrosine kinase inhibitors such as axitinib, dasatinib, erlotinib, imatinib, nilotinib, pazopanib and sunitinib; azacitidine, decitabine and cytarabine.

[1958] Clause 98. The method according to any one of Clauses 1-97, the CTPS1 inhibitor used, the pharmaceutical composition used, or the use, wherein the CTPS1 inhibitor is administered in combination with one or more anti-cancer antibodies, such as (for example, atezolizumab, ofatumumab, tositumomab, or rituximab), orlatumumab, daratumumab, tucotuzumab, denosumab, ado-trastuzumab emtansine, pertuzumab, brentuximab vedotin, pembrolizumab, catumaxomab, bevacizumab, cetuximab, trastuzumab, and gemtuzumab ozogamicin.

[1959] Clause 99. The method according to any one of Clauses 1-98, the CTPS1 inhibitor used, the pharmaceutical composition used, or the use, wherein the CTPS1 inhibitor is administered in combination with chemotherapy, radiotherapy, surgery, thermotherapy, and / or cryotherapy.

[1960] Clause 100. The method according to any one of Clauses 1-99, the CTPS1 inhibitor used, the pharmaceutical composition used, or the use, wherein the subject receives chemotherapy, radiotherapy, surgery, thermotherapy, and / or cryotherapy before the administration of CTPS1.

[1961] Clause 101. The method according to any one of Clauses 1-100, the CTPS1 inhibitor used, the pharmaceutical composition used, or the use, wherein the subject receives chemotherapy, radiotherapy, surgery, thermotherapy, and / or cryotherapy simultaneously with the administration of CTPS1.

[1962] Clause 102. The method according to any one of Clauses 1-101, the CTPS1 inhibitor used, the pharmaceutical composition used, or the use, wherein the subject receives chemotherapy, radiotherapy, surgery, thermotherapy, and / or cryotherapy after the administration of CTPS1.

[1963] Clause 103. The method according to any one of Clauses 1-102, the CTPS1 inhibitor used, the pharmaceutical composition used, or the use, wherein the cancer or cancer cells are from a cancer type in which at least 10% of the cells lack CTPS2, such as at least 15% of the cells lack CTPS2, particularly at least 18% of the cells lack CTPS2.

[1964] Clause 104. The method according to Clause 103, the CTPS1 inhibitor used, the pharmaceutical composition used, or the use, wherein the defect in CTPS2 function is attributed to homozygous deletion in females or hemizygous deletion in males.

[1965] Clause 105. A method, a CTPS1 inhibitor used, a pharmaceutical composition used, or a use according to any one of Clauses 1-104, wherein the cancer or cancer cells are from such a cancer type that at least 10% of the cells lack CTPS2, such as at least 15% of the cells lack CTPS2, in particular at least 20% of the cells lack CTPS2, especially at least 40% of the cells lack CTPS2.

[1966] Clause 106. A method, a CTPS1 inhibitor used, a pharmaceutical composition used, or a use according to Clause 105, wherein the defect in CTPS2 function is determined by immunohistochemistry, such as the absence of CTPS2 staining.

[1967] References

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Claims

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

2. A method for treating cancer in a subject, the method comprising the following steps: i) identifying that the subject has CTPS2-deficient cancer; and ii) administering a CTPS1 inhibitor to the subject.

3. A method for treating cancer in a subject, the method comprising the following steps: i) providing a sample from the subject; ii) identifying that the subject has cancer lacking CTPS2; and iii) administering a CTPS1 inhibitor to the subject.

4. A method for treating cancer in a subject, the method comprising the following steps: i) obtaining a sample from the subject; ii) identifying that the subject has cancer lacking CTPS2; and iii) administering a CTPS1 inhibitor to the subject.

5. A method for treating cancer, the cancer in a subject may be predisposed to treatment with a CTPS1 inhibitor, the method comprising the following steps: i) identifying that the cancer lacks CTPS2; and ii) administering a CTPS1 inhibitor.

6. A method for treating cancer, the cancer in a subject may be predisposed to treatment with a CTPS1 inhibitor, the method comprising the following steps: i) providing a sample from the subject; ii) identifying that the cancer lacks CTPS2; and iii) administering a CTPS1 inhibitor.

7. A method for treating cancer, the cancer in a subject may be predisposed to treatment with a CTPS1 inhibitor, the method comprising the following steps: i) obtaining a sample from the subject; ii) identifying that the cancer lacks CTPS2; and iii) administering a CTPS1 inhibitor.

8. A method for determining cancer cells that may be predisposed to treatment with a CTPS1 inhibitor, the method comprising the step of identifying that the cancer cells lack CTPS2.

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

10. A CTPS1 inhibitor for treating CTPS2-deficient cancer.

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

12. Use of a CTPS1 inhibitor in the preparation of a medicament for treating CTPS2-deficient cancer.

13. The method, the CTPS1 inhibitor used, the pharmaceutical composition used or the use according to any one of claims 1-12, wherein the CTPS2-deficient cancer is selected from 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 used, the pharmaceutical composition used or the use according to any one of claims 1-12, wherein the cancer is ovarian cancer, such as serous ovarian cancer.

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

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

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

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

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

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

21. The method according to any one of claims 1-20, the CTPS1 inhibitor used, the pharmaceutical composition used or the use, wherein the CTPS1 inhibitor is a compound of formula (III): Wherein A is an amide linking group 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, cycloalkyl optionally substituted by CH3, C 0-2 alkylene C 3-5 cycloalkyl or CF3; R2 is H, halogen, C 1-2 alkyl, OC 1-2 alkyl, C 1-2 haloalkyl or OC 1-2 haloalkyl; R3 is H, halogen, CH3, OCH3, CF3 or OCF3; Wherein at least one of R2 and R3 is H; R4 and R5 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 R4 and R5 together with the carbon atom to which they are attached form a C 3-6 cycloalkyl or C 3-6 heterocycloalkyl; and When A is -NHC(=O)-: R4 and R5 may also be selected from halogen, 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 ; Ar1 is a 6-membered aryl or heteroaryl; Ar2 is a 6-membered aryl or heteroaryl and is linked to Ar1 at the para position relative to the amide; R 10 is H, halogen, C 1-3 alkyl, C 1-2 haloalkyl, OC 1-2 alkyl, OC 1-2 haloalkyl or CN; R 11 is H, F, Cl, C 1-2 alkyl, CF3, OCH3 or CN: R 12 is connected to Ar2 at the ortho- or meta-position relative to Ar1, and R 12 is H, halogen, 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 may also be selected from CN, OCH2CH2N(CH3)2, and C containing a nitrogen at the point of attachment to Ar2 3-6 heterocycloalkyl, or R 12 together with the attached nitrogen atom forms an N-oxide (N + -O - )); R 13 is H or a halogen; R 21 is H, C 1-5 alkyl, C(O)C 1-5 alkyl, C(O)OC 1-5 alkyl; R 22 is H or CH3; R 23 is H or C 1-2 alkyl; and R 24 is H or C 1-2 alkyl; Or a pharmaceutically acceptable salt and / or pharmaceutically acceptable solvate thereof.

22. The method according to claim 21, the CTPS1 inhibitor used, the pharmaceutical composition used or the use, 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: Or a pharmaceutically acceptable salt and / or pharmaceutically acceptable solvate thereof.

23. The method according to any one of claims 1-22, the CTPS1 inhibitor used, the pharmaceutical composition used or the use, wherein the CTPS2 deficiency is caused by genomic alteration or change and / or epigenetic alteration or change.

24. The method according to claim 23, the CTPS1 inhibitor used, the pharmaceutical composition used or the use, wherein the genomic alteration or change is a complete deletion of the CTPS2 gene by genomic deletion.

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

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

27. The method according to any one of claims 1-26, the CTPS1 inhibitor used, the pharmaceutical composition used, or the use, wherein the lack of CTPS2 is caused by homozygous deletion in cancer cells.

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

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

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

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

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