Small molecule inhibitors of acetyl coenzyme A synthetase short chain 2 (ACSS2)

The present invention relates to small molecules for use in inhibiting the enzymatic activity of the acetyl coenzyme A synthetase short chain 2 (ACSS2) protein.

Accordingly, the small molecules may be for use in the treatment of diseases, such as cancer, cardiac disorders, metabolic disorders, neurological disorders, fibrotic disease, aging disorders, bacterial and viral infections and so on. The invention extends to the compounds per se pharmaceutical compositions, methods of making the compounds and methods of inhibiting the ACSS2 protein.

Acetyl CoA synthetases (ACSS 1 to 3) are a family of cellular enzymes that carry out the first enzymatic step in the conversion of acetate to the multifunctional metabolite acetyl coenzyme A (acetyl-CoA) through ligation of acetate with CoA in an ATP-driven process (Knowles, SE; Jarrett, IG; Filsell, OH; Ballard, FJ, Biochem. J., 1974, 142, 401-411). ACSS1 and ACSS3 are predominantly expressed in the mitochondria of cells, while ACSS2 is expressed in both nuclear and cytoplasmic compartments (Fujino, T.; Kondo, J.; Ishikawa, M.; Morikawa, K.; Yamamoto, TT, J. Biol Chem., 2001, 276, 11423-11426; Luong, A.; Hannah, VC; Brown, MS; Goldstein, JL, J. Biol. Chem., 2000, 275, 26458-26466; Ariyannur, PS; Moffett, JR; Madhavarao, CN; Arun, P. et. al., J. Comp. Neurol., 2010, 518, 2952-2977).

Acetyl-CoA fulfills a central role in cellular metabolism and is involved in multiple cellular processes (Pietrocola, F.; Galluzzi, L.; Bravo-San Pedro, JM et. al., Cell.

Metab., 2015, 21, 805-821). In well-nourished mammalian cells, acetyl-CoA enters the citric acid cycle by condensing with oxaloacetate to form citrate and therefrom a range of other metabolites (Srere, PA, J. Biol. Chem., 1959, 234, 2544-2547). It is a key intermediate of carbon sources and is an essential building block for the synthesis of fatty acids, amino acids and sterols.

Cell growth and proliferation are closely co-ordinated with metabolism and the availability of acetyl-CoA. One of the hallmarks of cancer is rapid, uncontrolled cellular proliferation, which requires increased production of energy and biomass via ATP and lipid production. This involves changes in both the way extracellular nutrients are captured and how they are metabolised. Targeting the strategies adopted by cancer

cells to increase rates of metabolism and enhance proliferative capacity under nutrient-limited conditions is an attractive anti-cancer therapeutic approach. It is especially compelling to target sources of the key cytosolic regulator of lipid, cholesterol and amino acid synthesis, namely acetyl-CoA.

In nutrient-limited conditions, such as in cancer cells, aerobic glycolysis takes place and the pyruvate formed from glucose metabolism is preferentially converted by reduction into lactate instead of being taken on to synthesise acetyl-CoA (the 'Warburg Effect'). In response, both acetate uptake and ACSS2 are upregulated and there is a significant shift in the sourcing of acetyl-CoA from other nutrients, a process which relies heavily on ACSS2 for acetyl-CoA synthesis.

Acetate is taken up and metabolized to biomass by proliferating hypoxic and lipid depleted tumor cells (Corbet, C.; Feron, O., Curr. Op. Clin. Nutr. Metab. Care, 2015, 18, 346-353). The propensity of certain tumors for acetate uptake has been exploited for over a decade to detect primary tumors and identify distant metastases by using 11 C-acetate guided positron emission tomography (PET) imaging to detect or grade gliomas, hepatocellular carcinomas, non-small cell lung cancer and metastases in prostate cancer patients. This reinforces early studies demonstrating that tumor cells take up significant amounts of acetate often in preference to glucose as a nutrient to satisfy their increased demand for acetyl-CoA (Yoshimoto, M.; Waki, A.; Yonekura, Y.; Sadato, N et al., Nucl. Med. Biol., 2001, 28, 117-122).

There is an increasing body of clinical evidence that places acetate and ACSS2 at a critical metabolic node in tumor cells under nutritional and hypoxic stress. Genome analysis reveals that ACSS2 copy number is associated with higher and more invasive stages of breast cancer and metastatic prostate cancer (Schug, ZT; Peck, B.; Jones, DT; Zhang, Q.; Grosskurth, S. et. al., Cancer Cell, 2015, 27, 57-71).

Immunohistochemistry (IHC) using anti-ACSS2 antibodies on human breast, ovarian, kidney and lung tumor samples showed significant expression compared to matched normal samples which showed little or no ACSS2 expression. Survival analyzes of patients with grade-2/3 gliomas (Mashimo, T.; Pichumani, K.; Vemireddy, V.;

Hatanpaa, KJ, Cell, 2014, 159, 1603-1614) or triple negative breast cancer

(Comerford, SA; Huang, Z.; Du, X.; Wang, Y. et. al., Cell, 2014, 159, 1591-1602) reveal that high ACSS2 expression is associated with shorter overall survival. These clinical findings show a strong correlation between acetate uptake, ACSS2 expression and

cancer progression. This suggests that inhibiting ACSS2 activity could benefit patients with acetate metabolizing tumors.

Hypoxic tumor cells express high levels of cytosolic ACSS2. Knockdown of ACSS2 by RNA interference in tumor cells enhanced tumor cell death under long term hypoxia in vitro and slowed tumor growth in vivo (Yoshii, Y.; Furukawa, T.; Yoshii, H.; Mori, T. et. al., Cancer Sci., 2009, 100, 821-827), supporting a role for ACSS2 in tumor progression and providing the rationale for a pharmacological inhibitor. Interfering with the metabolism of acetate by curtailing ACSS2 activity would deprive resilient tumor cells of a critical nutrient source and could arrest or terminate the growth of intractable tumors.

ACSS2 contributes acetyl-CoA for histone acetyltransferases to acetylate lysine residues on histones (Takahashi, H.; McCaffery, JM; Irizarry, RA; Boeke, JD, Mol. Cell, 2006, 23, 207-217) and thereby regulate transcription of growth genes through epigenetic modification of chromatin (Kaelin, WG; McKnight, SL, Cell, 2013, 153, 56-69). Aberrant regulation of chromatin can affect diverse cellular processes relating on acetylation such as glucose homeostasis, neuronal gene transcription, autophagy and mitochondrial respiration and is linked to conditions such as neurodegeneration, neurological disorders, immunodeficiency and metabolic disease (Mirabella, AC; Foster, BM; Bartke, T., Chromosoma, 2016, 125, 75-93). Given the extent to which cancer cells exploit metabolic adaptations to meet their elevated energy and biomass demands,

The heterodimeric stress-responsive transcription factor Hypoxia Inducible Factor 2a (HIF-2a) is regulated through acetylation by Creb binding protein (CBP), and this acetylation is in turn regulated by acetyl-CoA production by ACSS2 (Chen, R.; Xu, M.; Nagati, JS; Hogg, RT; Das, A. et. al., PLoS One, 2015, 10, e0116515). Knockdown of ACCS2 or HIF-2a in tumor cells impairs cell proliferation, cell migration and invasion during hypoxia and leads to significant reduction in tumor burden in mice carrying HT1080 flank tumors.

ACSS2 is post-translationally modified by the NAD-dependent deacetylase sirtuins. Sirtuins play a central role in energy homeostasis and ageing and it has therefore been proposed that the regulation of ACSS2 and acetate metabolism may also play a central role in ageing (Shimazu, T.; Hirschey, M.D.; Huang, Y.; Ho, L.T.Y.; Verdin, E., Mech. Ageing Develop., 2010, 131, 511-516).

The causes of aging are multifactorial but are manifest in a progressive decline in metabolic performance. As individuals age, there is an accompanying build-up of cellular damage and changes to the endogenous repair and detoxification processes. Healthy aging depends on the efficient removal of damaged cellular material that is mediated in part by autophagy (Eisenberg, T.; Schroeder, S.; Andryushkova, A. et. al., Cell Metab., 2014, 19, 431-444) . Knockdown of ACCS2 in mammalian cells results in a strong induction of autophagy and maintenance of lifespan, while nutrient starvation of cells achieves the same effect (Marino, G.; Pietrocola, F.; Eisenberg, T.; Kong, Y. et. al ., Mol. Cell, 2014, 53, 710-725).

Human cytomegalovirus (HCMV) induces a robust increase in lipid synthesis to boost the chances of a productive infection. It has recently been shown that in ACSS2 knockout human fibroblasts both HCMV induced lipogenesis and viral growth were sharply reduced compared to normal controls (Vysochan, A.; Sengupta, A.; Weljie, AM; Alwine, JC; Yu, Y., PNAS , 2017, 114, E1528-E1535) suggesting that impairment of ACSS2 may have some utility as an antiviral therapy in some types of infections. Martinez-Micaelo and. para. have shown that ACSS2 is a nutrient-sensing protein and a key regulator of metabolic homeostasis (Martinez-Micaelo, N.; Gonzalez-Abuin, N.; Terra, X.; Ardevol, A.; Pinent, M. et. al. , Disease Mod Mechan., 2016, 9, 1231-1239). ACSS2 gene expression was correlated with hepatic concentrations of TCA-involved metabolites and with plasma glucose levels. Phosphoprotein analysis of mice fed with a high fat diet (Shaik, AA; Qiu, B.; Wee, S.; Choi, H. et. al., Nature, 2016, 6, 25844) showed an array of phosphorylation changes on several enzymes involved in lipid and glucose homeostasis, including reduced phosphorylation of ACSS2, indicating a role in obesity for this protein. Huang and. para. observed significant reductions in body weight and hepatic steatosis in a diet-induced obesity model following knockdown of ACSS2. ACSS2 deficiency appears to reduce dietary lipid absorption, lipid transport to the liver (Huang, Z.; Zhang, M.; Plec, AA; Estill, SJ et. al., PNAS, 2018, 115, E9499-E9506) and controls systemic lipid metabolism according to acetate availability.

This developing knowledge has stimulated considerable research into possible therapeutic applications of ACSS2 inhibition.

Accordingly, there remains a need in the art for improved therapies for treating diseases, such as cancer, neurological disorders and metabolic disorders, which can be refractory to traditional therapeutic approaches. There is a need to develop improved compositions and methods in this field. In particular, there is a need for compounds that inhibit the human ACSS2 protein, as well as methods for treating diseases that can benefit from such modulation.

The present invention has arisen from the inventors work in attempting to identify ACSS2 protein inhibitors.

In a first aspect of the invention, there is provided a compound of formula (I):

, wherein X is CR 3 or N;

Y is CR 4 or N;

Z is CR 5 or N;

L is NR 8 or is absent;

R and R 1 are each independently selected from the group consisting of H, mono or bicyclic optionally substituted C 6 -C 12 aryl, mono or bicyclic optionally substituted 5 to 10 membered heteroaryl, optionally substituted C 1 -C 10 alkyl, optionally substituted mono or bicyclic C 3 -C 6 cycloalkyl, optionally substituted mono or bicyclic C 3 -C 6 cycloalkenyl, optionally substituted C 2 -C 10 alkenyl, optionally substituted C 2 -C 10alkynyl, optionally substituted mono or bicyclic 3 to 8 membered heterocycle, optionally substituted C 1 -C 10 alkoxy and NR 9 R 10 ;

R 2 is H, halogen, COOR 9 , CN, CONR 9 R 10 , NR 9 SO 2 R 10 , SO 2 NR 9 R 10 , NR 9 COR 10 , optionally substituted C 1 -C 10 alkyl, optionally substituted mono or bicyclic 3 to 8 membered heterocycle, optionally substituted C 1 -C 10 alkylsulfonyl, NR 9 R 10 , optionally substituted C 1 -C 10 alkoxy, mono or bicyclic optionally substituted C 6-C 12 aryl or mono or bicyclic optionally substituted 5 to 10 membered heteroaryl;

R 3 is H, CN, halogen, COOH, CONR 9 R 10 , NR 9 R 10 , NO 2 , optionally substituted C 1 -C 10 alkyl, optionally substituted mono or bicyclic C 3 -C 6 cycloalkyl, optionally substituted mono or bicyclic C 3 -C 6 cycloalkenyl, optionally substituted C 2 -C 10 alkenyl, optionally substituted C 2 -C 10 alkynyl, optionally substituted mono or bicyclic 3 to 8 membered heterocycle, optionally substituted C 1 -C 10alkoxy, mono or bicyclic optionally

substituted C 6 -C 12 aryl or mono or bicyclic optionally substituted 5 to 10 membered heteroaryl;

R 4 and R 5 are each independently selected from the group consisting of H, halogen, OH, CN, mono or bicyclic optionally substituted C 6 -C 12 aryl, optionally substituted C 1 -C 10 alkyl, optionally substituted mono or bicyclic 3 to 8 membered heterocycle, optionally substituted C 1 -C 10 alkoxy and optionally substituted mono or bicyclic C 3 -C 6 cycloalkyl; R 6 is H or optionally substituted C 1 -C 10 alkyl;

R 7 is H, optionally substituted C 1 -C 10 alkyl, optionally substituted C 2 -C 10 alkenyl, optionally substituted C 2 -C 10 alkynyl, mono or bicyclic optionally substituted C 6 -C 12 aryl, mono or bicyclic optionally substituted 5 to 10 membered heteroaryl, optionally substituted mono or bicyclic C 3 -C 6 cycloalkyl, or optionally substituted mono or bicyclic 3 to 8 membered heterocycle;

R 8 is selected from the group consisting of H, halogen and optionally substituted C 1 -C 10 alkyl; and

R 9 and R 10 are each independently selected from the group consisting of H, mono or bicyclic optionally substituted C 6 -C 12 aryl, mono or bicyclic optionally substituted 5 to 10 membered heteroaryl, optionally substituted C 1 -C 10 alkyl, optionally substituted mono or bicyclic C 3 -C 6 cycloalkyl, optionally substituted mono or bicyclic C 3 -C 6 cycloalkenyl, optionally substituted C 2 -C 10 alkenyl, optionally substituted C 2 -C 10 alkynyl, optionally substituted C 1 -C10 alkoxy and NH 2 ;

gold a pharmaceutically acceptable complex, salt, solvate, tautomeric form gold

polymorphic form thereof.

The inventors have found that the compounds of formula (I) are useful in therapy or as a medicament.

The invention also extends to a conjugate of a compound of formula (I).

Accordingly, in a second aspect of the invention, there is provided a conjugate of formula (II):

Claims
1. A compound of formula (I):

, wherein X is CR 3 or N;

Y is CR 4 or N;

Z is CR 5 or N;

L is NR 8 or is absent;

R and R 1 are each independently selected from the group consisting of H, mono or bicyclic optionally substituted C 6 -C 12 aryl, mono or bicyclic optionally substituted 5 to 10 membered heteroaryl, optionally substituted C 1 -C 10 alkyl, optionally substituted mono or bicyclic C 3 -C 6 cycloalkyl, optionally substituted mono or bicyclic C 3 -C 6 cycloalkenyl, optionally substituted C 2 -C 10 alkenyl, optionally substituted C 2 -C 10alkynyl, optionally substituted mono or bicyclic 3 to 8 membered heterocycle, optionally substituted C 1 -C 10 alkoxy and NR 9 R 10 ;

R 2 is H, halogen, COOR 9 , CN, CONR 9 R 10 , NR 9 SO 2 R 10 , SO 2 NR 9 R 10 , NR 9 COR 10 , optionally substituted C 1 -C 10 alkyl, optionally substituted mono or bicyclic 3 to 8 membered heterocycle, optionally substituted C 1 -C 10 alkylsulfonyl, NR 9 R 10 , optionally substituted C 1 -C 10 alkoxy, mono or bicyclic optionally substituted C 6-C 12 aryl or mono or bicyclic optionally substituted 5 to 10 membered heteroaryl;

R 3 is H, CN, halogen, COOH, CONR 9 R 10 , NR 9 R 10 , NO 2 , optionally substituted C 1 -C 10 alkyl, optionally substituted mono or bicyclic C 3 -C 6 cycloalkyl, optionally substituted mono or bicyclic C 3 -C 6 cycloalkenyl, optionally substituted C 2 -C 10 alkenyl, optionally substituted C 2 -C 10 alkynyl, optionally substituted mono or bicyclic 3 to 8 membered heterocycle, optionally substituted C 1 -C 10alkoxy, mono or bicyclic optionally

substituted C 6 -C 12 aryl or mono or bicyclic optionally substituted 5 to 10 membered heteroaryl;

R 4 and R 5 are each independently selected from the group consisting of H, halogen, OH, CN, mono or bicyclic optionally substituted C 6 -C 12 aryl, optionally substituted C 1 -C 10 alkyl, optionally substituted mono or bicyclic 3 to 8 membered heterocycle, optionally substituted C 1 -C 10 alkoxy and optionally substituted mono or bicyclic C 3 -C 6 cycloalkyl; R 6 is H or optionally substituted C 1 -C 10 alkyl;

R 7 is H, optionally substituted C 1 -C 10 alkyl, optionally substituted C 2 -C 10 alkenyl, optionally substituted C 2 -C 10 alkynyl, mono or bicyclic optionally substituted C 6 -C 12 aryl, mono or bicyclic optionally substituted 5 to 10 membered heteroaryl, optionally substituted mono or bicyclic C 3 -C 6 cycloalkyl, or optionally substituted mono or bicyclic 3 to 8 membered heterocycle;

R 8 is selected from the group consisting of H, halogen and optionally substituted C 1 -C 10 alkyl; and

R 9 and R 10 are each independently selected from the group consisting of H, mono or bicyclic optionally substituted C 6 -C 12 aryl, mono or bicyclic optionally substituted 5 to 10 membered heteroaryl, optionally substituted C 1 -C 10 alkyl, optionally substituted mono or bicyclic C 3 -C 6 cycloalkyl, optionally substituted mono or bicyclic C 3 -C 6 cycloalkenyl, optionally substituted C 2 -C 10 alkenyl, optionally substituted C 2 -C 10 alkynyl, optionally substituted C 1 -C10 alkoxy and NH 2 ;

gold a pharmaceutically acceptable complex, salt, solvate, tautomeric form gold

polymorphic form thereof.

2. The compound according to claim 1, wherein R and R 1 are each independently be selected from the group consisting of H, mono or bicyclic optionally substituted C 6 -C 12 aryl, mono or bicyclic optionally substituted 5 to 10 membered heteroaryl, optionally substituted C 1 -C 6 alkyl, optionally substituted mono or bicyclic C 3 -C 6 cycloalkyl, optionally substituted mono or bicyclic C 3 -C 6 cycloalkenyl, optionally substituted C 2 -C 6 alkenyl and optionally substituted C 2 -C 6 alkynyl.

3. The compound according to claim 2, wherein R and R 1 are each independently selected from an optionally substituted phenyl ring, an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 2 -C 6 alkenyl, an optionally substituted C 2 -C 6 alkynyl or an optionally substituted 5 or 6 membered heteroaryl.

4. The compound according to claim 3, wherein R and R 1 are each an optionally substituted phenyl ring or methyl.

5. The compound according to any preceding claim, wherein R 2 is H, COOR 9 , CONR 9 R 10 , CN, NR 9 COR 10 , NR 9 R 10 , NR 9 SO 2 R 10 , optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxy, mono or bicyclic optionally substituted C 6 -C 12 aryl or a mono or bicyclic optionally substituted 5 to 10 membered heteroaryl.

6. The compound according to any preceding claim, wherein X is CR 3 , Y is CR 4 and Z is CR 5 .

7. The compound according to any one of claims 1 to 5, wherein:

- X is N, Y is CR 4 and Z is CR 5 ;

- X is N, Y is N and Z is CR 5 ;

- X is N, Y is CR 4 and Z is N;

- X is CR 3 , Y is N and Z is CR 5 ; gold

- X is CR 3 , Y is CR 4 and Z is N.

8. The compound according to any preceding claim, wherein R 3 is H, CN, halogen, COOH, CONR 2 , NR 2 , NO 2 , optionally substituted C 1 -C 6 alkyl, optionally substituted mono or bicyclic C 3 -C 6 cycloalkyl, optionally substituted mono or bicyclic C 3 -C 6 cycloalkenyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 1 -C 6 alkoxy, mono or bicyclic optionally substituted C 6-C 12 aryl, mono or bicyclic optionally substituted 5 to 10 membered heteroaryl.

9. The compound according to claim 8, wherein R 3 is H, CN, halogen, optionally substituted C 1 -C 6 alkyl, mono or bicyclic optionally substituted C 6 -C 12 aryl, optionally substituted mono or bicyclic C 3 -C 6 cycloalkyl or mono or bicyclic optionally substituted 5 to 10 membered heteroaryl.

10. The compound according to any preceding claim, wherein R 4 and R 5 are each independently selected from the group consisting of H, halogen, OH, CN, mono or bicyclic optionally substituted C 6 -C 12 aryl, optionally substituted C 1 - C 6 alkyl, optionally substituted C 1 -C 6 alkoxy or optionally substituted mono or bicyclic C 3 -C 6 cycloalkyl.

11. The compound according to claim 10, wherein R 4 and R 5 are H, halogen, OH, CN or an optionally substituted C 1 -C 6 alkyl.

12. The compound according to claim 11, wherein R 4 and R 5 are H.

13. The compound according to any preceding claim, wherein R 6 is H or optionally substituted C 1 -C 6 alkyl.

14. The compound according to any preceding claim, wherein R 7 is H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, mono or bicyclic optionally substituted C 6 -C 12 aryl, mono or bicyclic optionally substituted 5 to 10 membered heteroaryl, optionally substituted mono or bicyclic C 3 -C 6 cycloalkyl, or optionally substituted mono or bicyclic 3 to 8 membered heterocycle.

15. The compound according to claim 14, wherein R 7 is optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted phenyl, optionally substituted 5 or 6 membered heteroaryl, optionally substituted C 3 -C 6 cycloalkyl, or optionally substituted 3 to 6 membered heterocycle.

16. The compound according to any preceding claim, wherein L is absent.

17. The compound according to any one of claims 1 to 15, wherein L is NR 8 and R 8 is H or an optionally substituted C 1 -C 6 alkyl.

18. The compound according to claim 1, wherein the compound is:

1-(2,3-diphenylquinolin-6-yl)-3-(2-hydroxybutyl)urea;

(R)-1-(2,3-diphenylquinolin-6-yl)-3-(2-hydroxybutyl)urea;

1-Butyl-3-(2,3-diphenylquinolin-6-yl)urea;

1-(2,3-bis(2-fluorophenyl)quinolin-6-yl)-3-(2-hydroxybutyl)urea;

1-Butyl-3-(5-(2-hydroxypyridin-3-yl)-2,3-diphenylquinolin-6-yl)urea;

1-(2,3-bis(2-methoxyphenyl)quinolin-6-yl)-3-(2-hydroxybutyl)urea;

1-(3-(2-fluorophenyl)-2-phenylquinolin-6-yl)-3-(2-hydroxybutyl)urea;

1-(2-(2-fluorophenyl)-3-phenylquinolin-6-yl)-3-(2-hydroxybutyl)urea;

1-(2,3-bis(2-methoxypyridin-4-yl)quinolin-6-yl)-3-(2-hydroxybutyl)urea;

1-(2-hydroxybutyl)-3-(3-(2-methoxyphenyl)-2-phenylquinolin-6-yl)urea;

1-(2,3-bis(6-methoxypyridin-3-yl)quinolin-6-yl)-3-(2-hydroxybutyl)urea;

1-(2-hydroxybutyl)-3-(2-(2-methoxyphenyl)-3-phenylquinolin-6-yl)urea;

1-(2,3-bis(2-methoxypyridin-3-yl)quinolin-6-yl)-3-(2-hydroxybutyl)urea;

1-(2,3-bis(2-fluorophenyl)quinolin-6-yl)-3-butylurea;

(R)-1-(3-(2-fluorophenyl)-2-phenylquinolin-6-yl)-3-(2-hydroxybutyl)urea;

1-Butyl-3-(3-(2-fluorophenyl)-2-phenylquinolin-6-yl)urea;

1-(2,3-bis(4-fluorophenyl)quinolin-6-yl)-3-(2-hydroxybutyl)urea;

1-(3-(2-fluorophenyl)-2-(2-methoxyphenyl)quinolin-6-yl)-3-(2-hydroxybutyl)urea; 1-(2,3-di(pyridin-3-yl)quinolin-6-yl)-3-(2-hydroxybutyl)urea;

(R)-1-(2,3-bis(2-fluorophenyl)quinolin-6-yl)-3-(2-hydroxybutyl)urea;

1-(2,3-bis(3-acetylphenyl)quinolin-6-yl)-3-(2-hydroxybutyl)urea;

1-(2,3-di(1H-pyrazol-4-yl)quinolin-6-yl)-3-(2-hydroxybutyl)urea;

1-Butyl-3-(3-(2-methoxyphenyl)-2-phenylquinolin-6-yl)urea;

1-(2,3-di(pyridin-4-yl)quinolin-6-yl)-3-(2-hydroxybutyl)urea;

1-(2,3-bis(3-fluorophenyl)quinolin-6-yl)-3-(2-hydroxybutyl)urea;

1-(2-(2-fluorophenyl)-3-(2-methoxyphenyl)quinolin-6-yl)-3-(2-hydroxybutyl)urea; 1-(2,3-bis(6-oxo-1,6-dihydropyridin-3-yl)quinolin-6-yl)-3-(2-hydroxybutyl)urea;

(S)-1-(2,3-bis(2-fluorophenyl)quinolin-6-yl)-3-(2-hydroxybutyl)urea;

1-(2,3-bis(2-hydroxypyridin-4-yl)quinolin-6-yl)-3-(2-hydroxybutyl)urea;

(S)-1-(2,3-diphenylquinolin-6-yl)-3-(2-hydroxybutyl)urea;

1-(3-(2-fluorophenyl)-2-(pyridin-3-yl)quinolin-6-yl)-3-(2-hydroxybutyl)urea;

1-(2-(cyclohex-1-en-1-yl)-3-(2-fluorophenyl)quinolin-6-yl)-3-(2-hydroxybutyl)urea; 1-(2-(2-(dimethylamino)phenyl)-3-(2-fluorophenyl)quinolin-6-yl)-3-(2-hydroxybutyl)urea;

1-(3-(2-fluorophenyl)-2-(pyridin-4-yl)quinolin-6-yl)-3-(2-hydroxybutyl)urea;

(R)-1-(3-(2-fluorophenyl)-2-(2-methoxyphenyl)quinolin-6-yl)-3-(2-hydroxybutyl)urea; (S)-1-(3-(2-fluorophenyl)-2-(2-methoxyphenyl)quinolin-6-yl)-3-(2-hydroxybutyl)urea; 1-Butyl-3-(3-(2-fluorophenyl)-2-(2-methoxyphenyl)quinolin-6-yl)urea;

1-(2-hydroxybutyl)-3-(3-phenyl-2-(pyridin-2-yl)quinolin-6-yl)urea;

1-(2-cyclohexyl-3-(2-fluorophenyl)quinolin-6-yl)-3-(2-hydroxybutyl)urea;

1-(2-cyclopropyl-3-phenylquinolin-6-yl)-3-(2-hydroxybutyl)urea;

1-(2-hydroxybutyl)-3-(3-phenyl-2-(pyridin-3-yl)quinolin-6-yl)urea;

1-(2,3-bis(2-hydroxypyridin-3-yl)quinolin-6-yl)-3-(2-hydroxybutyl)urea;

1-(2-hydroxybutyl)-3-(2-(1-methyl-1H-pyrazol-4-yl)-3-phenylquinolin-6-yl)urea;

1-(3-(2-fluorophenyl)-2-phenylquinolin-6-yl)-3-(2-methoxybutyl)urea;

1-(2,2-difluorobutyl)-3-(3-(2-fluorophenyl)-2-phenylquinolin-6-yl)urea;

1-(3-(2-fluorophenyl)-2-(3-fluorophenyl)quinolin-6-yl)-3-(2-hydroxybutyl)urea;

1-(3-(2-fluorophenyl)-2-(4-fluorophenyl)quinolin-6-yl)-3-(2-hydroxybutyl)urea;

methyl 6-(3-(2-hydroxybutyl)ureido)-2,3-diphenylquinoline-4-carboxylate;

6-(3-(2-hydroxybutyl)ureido)-2,3-diphenylquinoline-4-carboxamide;

(E)-1-(2-hydroxybutyl)-3-(3-phenyl-2-styrylquinolin-6-yl)urea;

N-(2-(3-(2-fluorophenyl)-6-(3-(2-hydroxybutyl)ureido)quinolin-2-yl)phenyl)acetamide;

1-(2-hydroxybutyl)-3-(2-methyl-3-phenylquinolin-6-yl)urea;

1-(2-(2-cyanophenyl)-3-(2-fluorophenyl)quinolin-6-yl)-3-(2-hydroxybutyl)urea; 1-(2-(2-aminophenyl)-3-(2-fluorophenyl)quinolin-6-yl)-3-(2-hydroxybutyl)urea; 1-(2-([1,1'-biphenyl]-4-yl)-3-phenylquinolin-6-yl)-3-(2-hydroxybutyl)urea;

1-(2-hydroxybutyl)-3-(2-phenethyl-3-phenylquinolin-6-yl)urea;

(R)-6-(3-(2-hydroxybutyl)ureido)-2,3-diphenylquinoline-4-carboxamide;

1-(2-(2-ethoxyphenyl)-3-phenylquinolin-6-yl)-3-(2-hydroxybutyl)urea;

1-(2-hydroxybutyl)-3-(2-(2-isobutoxyphenyl)-3-phenylquinolin-6-yl)urea;

1-(2-ethynyl-3-phenylquinolin-6-yl)-3-(2-hydroxybutyl)urea;

1-(2-ethyl-3-phenylquinolin-6-yl)-3-(2-hydroxybutyl)urea;

6-(3-(2-hydroxybutyl)ureido)-N-methyl-2,3-diphenylquinoline-4-carboxamide; 6-(3-(2-hydroxybutyl)ureido)-N,N-dimethyl-2,3-diphenylquinoline-4-carboxamide; N-cyclopropyl-6-(3-(2-hydroxybutyl)ureido)-2,3-diphenylquinoline-4-carboxamide; 6-(3-(2-hydroxybutyl)ureido)-2,3-diphenylquinoline-4-carboxylic acid;

6-(3-(2-hydroxybutyl)ureido)-2-methyl-3-phenylquinoline-4-carboxamide;

(S)-1-(3-(2-fluorophenyl)-2-phenylquinolin-6-yl)-3-(2-hydroxybutyl)urea;

(S)-1-(2,3-diphenylquinolin-6-yl)-3-(2-hydroxybutyl)urea;

6-(3-(2-hydroxybutyl)ureido)-2,3-dimethylquinoline-4-carboxamide;

1-(4-cyano-2,3-diphenylquinolin-6-yl)-3-(2-hydroxybutyl)urea;

6-(3-(2-hydroxybutyl)ureido)-3-phenylquinoline-4-carboxamide;

(R)-1-(2-hydroxybutyl)-3-(2-methyl-3-phenylquinolin-6-yl)urea;

3-(2-fluorophenyl)-6-(3-(2-hydroxybutyl)ureido)-2-methylquinoline-4-carboxamide; 6-(3-(2-hydroxybutyl)ureido)-2-methylquinoline-4-carboxamide;

1-(3-(2-fluorophenyl)-2-methylquinolin-6-yl)-3-(2-hydroxybutyl)urea;

1-Butyl-3-(2-methyl-3-phenylquinolin-6-yl)urea;

1-(2-methoxybutyl)-3-(2-methyl-3-phenylquinolin-6-yl)urea;

1-(2-methoxyethyl)-3-(2-methyl-3-phenylquinolin-6-yl)urea;

1-(2-hydroxybutyl)-3-(2-methyl-3-(pyridin-3-yl)quinolin-6-yl)urea;

1-(2-hydroxybutyl)-3-(2-methyl-3-(o-tolyl)quinolin-6-yl)urea;

1-(3-(2-chlorophenyl)-2-methylquinolin-6-yl)-3-(2-hydroxybutyl)urea;

1-(2-hydroxybutyl)-3-(2-methyl-3-(1-methyl-1H-pyrazol-4-yl)quinolin-6-yl)urea; (R)-1-(2-hydroxybutyl)-3-(2-methyl-3-(o-tolyl)quinolin-6-yl)urea;

N-(6-(3-(2-hydroxybutyl)ureido)-2,3-diphenylquinolin-4-yl)acetamide;

1-(2,5-dimethyl-3-phenylquinolin-6-yl)-3-(2-hydroxybutyl)urea;

1-(5-cyclopropyl-2-methyl-3-phenylquinolin-6-yl)-3-(2-hydroxybutyl)urea;

1-(5-bromo-2-methyl-3-phenylquinolin-6-yl)-3-(2-hydroxybutyl)urea;

1-(2-hydroxybutyl)-3-(3-phenyl-2-(trifluoromethyl)quinolin-6-yl)urea;

(S)-1-(2-hydroxybutyl)-3-(2-methyl-3-phenylquinolin-6-yl)urea;

(R)-1-(7-fluoro-2,3-diphenylquinolin-6-yl)-3-(2-hydroxybutyl)urea;

1-(4-(dimethylamino)-2,3-diphenylquinolin-6-yl)-3-(2-hydroxybutyl)urea;

(R)-N-(6-(3-(2-hydroxybutyl)ureido)-2,3-diphenylquinolin-4-yl)cyclopropanecarboxamide;

N-(6-(3-(2-hydroxybutyl)ureido)-2-methyl-3-phenylquinolin-4-yl)acetamide;

N-(6-(3-(2-hydroxybutyl)ureido)-2,3-diphenylquinolin-4-yl)methanesulfonamide; 1-(4-amino-2,3-diphenylquinolin-6-yl)-3-(2-hydroxybutyl)urea;

(R)-1-(2-hydroxybutyl)-3-(2-methyl-5-(1-methyl-1H-pyrazol-4-yl)-3-phenylquinolin-6-yl)urea;

1-(2-hydroxybutyl)-3-(4-(oxazol-2-yl)-2,3-diphenylquinolin-6-yl)urea;

1-(4-cyano-2-methyl-3-phenylquinolin-6-yl)-3-(2-hydroxybutyl)urea;

N-(1-(3-(2-methyl-3-phenylquinolin-6-yl)ureido)butan-2-yl)acetamide;

(R)-1-(3-(2-fluorophenyl)-2-methylquinolin-6-yl)-3-(2-hydroxybutyl)urea;

(R)-1-(2-hydroxybutyl)-3-(4-methoxy-2,3-diphenylquinolin-6-yl)urea;

(R)-1-(2-hydroxybutyl)-3-(4-methoxy-2-methyl-3-phenylquinolin-6-yl)urea;

(R)-1-(2-hydroxybutyl)-3-(4-methyl-2,3-diphenylquinolin-6-yl)urea;

(R)-N-benzyl-6-(3-(2-hydroxybutyl)ureido)-3-methyl-2-phenylquinoline-4-carboxamide;

1-(2,2-difluorobutyl)-3-(2-methyl-3-phenylquinolin-6-yl)urea;

6-(3-(2,2-difluorobutyl)ureido)-2,3-diphenylquinoline-4-carboxamide;

1-(2,2-difluorobutyl)-3-(2,3-diphenylquinolin-6-yl)urea;

(R)-6-(3-(2-hydroxybutyl)ureido)-N,3-dimethyl-2-phenylquinoline-4-carboxamide; (R)-6-(3-(2-hydroxybutyl)ureido)-3-methyl-2-phenylquinoline-4-carboxamide;

1-(2,2-difluorobutyl)-3-(3-(2-fluorophenyl)-2-methylquinolin-6-yl)urea;

(R)-1-(3-(2-fluorophenyl)-2-methyl-5-(2-oxo-1,2-dihydropyridin-3-yl)quinolin-6-yl)-3-(2-hydroxybutyl) urea;

(R)-6-(3-(2-hydroxybutyl)ureido)-N-(1-methyl-1H-pyrazol-3-yl)-2,3-diphenylquinoline-4-carboxamide;

(R)-1-(2,4-dimethyl-3-phenylquinolin-6-yl)-3-(2-hydroxybutyl)urea;

(R)-6-(3-(2-hydroxybutyl)ureido)-3-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-2-phenylquinoline-4-carboxamide;

(R)-6-(3-(2-hydroxybutyl)ureido)-3-methyl-N-(1-methyl-1H-pyrazol-3-yl)-2-phenylquinoline-4-carboxamide;

1-(3-(2-fluorophenyl)-2-methylquinolin-6-yl)-3-(2-methoxyethyl)urea;

(R)-1-(3-(3-(2-fluorophenyl)-2-phenylquinolin-6-yl)ureido)butan-2-yl dihydrogen phosphate;

N-(2,3-diphenylquinolin-6-yl)hexanamide;

N-(2,3-bis(2-methoxyphenyl)quinolin-6-yl)hexanamide;

N-(2-(2-methoxyphenyl)-3-phenylquinolin-6-yl)-4-oxohexanamide;

N-(2,3-bis(2-fluorophenyl)quinolin-6-yl)hexanamide;

N-(2,3-diphenylquinolin-6-yl)-2,2-difluorohexanamide;

N-(2-(2-fluorophenyl)-3-phenylquinolin-6-yl)-4-oxohexanamide;

N-(2,3-bis(2-fluorophenyl)quinolin-6-yl)-4-oxohexanamide;

N-(2,3-diphenylquinolin-6-yl)-4-oxohexanamide;

N-(3-(2-fluorophenyl)-2-(2-methoxyphenyl)quinolin-6-yl)-4-oxohexanamide; N-(2,3-diphenylquinolin-6-yl)-4-hydroxyhexanamide;

N-(2,3-bis(2-fluorophenyl)quinolin-6-yl)-4-hydroxyhexanamide;

N-(3-(2-fluorophenyl)-2-methylquinolin-6-yl)-4-hydroxyhexanamide;

4-hydroxy-N-(2-methyl-3-phenylquinolin-6-yl)hexanamide;

1-cyclohexyl-3-(2,3-diphenylquinolin-6-yl)urea;

N-(2,3-diphenylquinolin-6-yl)-4-methylpiperazine-1-carboxamide;

4-acetyl-N-(2,3-diphenylquinolin-6-yl)piperazine-1-carboxamide;

1-allyl-3-(2,3-diphenylquinolin-6-yl)urea;

1-(2,3-diphenylquinolin-6-yl)-3-(prop-2-yn-1-yl)urea;

1-(2,3-diphenylquinolin-6-yl)-3-(2-hydroxycyclopentyl)urea;

1-(2,3-diphenylquinolin-6-yl)-3-(tetrahydro-2H-pyran-4-yl)urea;

N-(2,3-diphenylquinolin-6-yl)-3-methoxypyrrolidine-1-carboxamide;

1-(2,3-diphenylquinolin-6-yl)-3-(pyridin-2-yl)urea;

1-(2,3-diphenylquinolin-6-yl)-3-phenylurea;

1-(2,3-diphenylquinolin-6-yl)-3-(1-methylpyrrolidin-3-yl)urea;

1-(2,3-diphenylquinolin-6-yl)-3-(pyridin-4-yl)urea;

1-(2,3-diphenylquinolin-6-yl)-3-(1-(hydroxymethyl)cyclopentyl)urea;

1-(2,3-diphenylquinolin-6-yl)-3-(1-methyl-1H-pyrazol-4-yl)urea;

1-(6,7-diphenyl-1,8-naphthyridin-3-yl)-3-(2-hydroxybutyl)urea;

1-(6,7-diphenyl-1,5-naphthyridin-2-yl)-3-(2-hydroxybutyl)urea;

1-(2,3-diphenyl-1,7-naphthyridin-6-yl)-3-(2-hydroxybutyl)urea;

(R)-1-(6,7-diphenyl-1,8-naphthyridin-3-yl)-3-(2-hydroxybutyl)urea;

(R)-1-(6,7-diphenyl-1,5-naphthyridin-2-yl)-3-(2-hydroxybutyl)urea;

(R)-1-(2,3-diphenyl-1,7-naphthyridin-6-yl)-3-(2-hydroxybutyl)urea;

N-(6,7-diphenyl-1,8-naphthyridin-3-yl)-3-methoxypyrrolidine-1-carboxamide;

N-(6,7-diphenyl-1,5-naphthyridin-2-yl)-3-methoxypyrrolidine-1-carboxamide; or N-(2,3-diphenyl-1,7-naphthyridin-6-yl)-3-methoxypyrrolidine-1-carboxamide.

19. A conjugate of formula (II):

wherein, C is a compound of formula (I), as defined by any one of claims 1 to 18;

L 1 and L 2 are linkers;

T is a targeting moiety; and

a is an integer between 1 and 5;

b is an integer between 1 and 10; and

z is an integer between 1 and 5.

20. A pharmaceutical composition comprising a compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt, solvate, tautomeric form or polymorphic form thereof, or a conjugate according to claim 19, and a pharmaceutically acceptable vehicle.

21. A compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt, solvate, tautomeric form or polymorphic form thereof, a conjugate according to claim 19, or a pharmaceutical composition according to claim 20, for use in therapy.

22. A compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt, solvate, tautomeric form or polymorphic form thereof, a conjugate according to claim 19, or a pharmaceutical composition according to claim 20, for use in modulating the acetyl coenzyme A synthetase short chain 2 (ACSS2) protein.

23. A compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt, solvate, tautomeric form or polymorphic form thereof, a conjugate according to claim 19, or a pharmaceutical composition according to claim 20, for use in treating, ameliorating or preventing a disease selected from cancer, bacterial infection, viral infection, parasitic infection, fungal infection, neurodegenerative disease, neurological disorder, cerebrovascular disease, cardiovascular disease, non-alcoholic fatty liver disease and obesity or for use in promoting healthy aging.

24. A compound, conjugate or pharmaceutical composition for use according to claim 23, wherein the disease is cancer, and the cancer is selected from the group consisting of colorectal cancer, aero-digestive squamous cancer, gastrointestinal stromal tumors, lung cancer, brain cancer , neuroblastoma, glial tumors, astrocytoma, glioblastoma, liver cancer, stomach cancer, sarcoma, leukemia, lymphoma, multiple myeloma, ovarian cancer, uterine cancer, breast cancer, melanoma, prostate cancer, bladder cancer, pancreatic carcinoma or renal carcinoma.

25. A compound, conjugate or pharmaceutical composition for use according to claim 23, wherein the disease is a viral infection, and the viral infection is a hepatitis C virus (HCV) infection or a human cytomegalovirus (HCMV) infection.