Small molecule inhibitor of acetyl-CoA synthetase short chain 2 (ACSS2)

Abstract

The present invention relates to a compound of formula (I). The compound can be used to regulate acetyl-coenzyme A synthetase short chain 2 (ACSS2) protein, thereby 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. Alternatively or additionally, the compound can be used to promote healthy aging.

Description

Detailed Description of the Invention

[0001] The present invention relates to small molecules for use in inhibiting the enzymatic activity of acetyl-CoA synthetase short chain 2 (ACSS2) protein. Thus, the small molecules may be for use in the treatment of diseases such as cancer, heart disorders, metabolic disorders, neuropathies, fibrotic diseases, age-related disorders, bacterial and viral infections, and the like. The present invention extends to the compound itself, pharmaceutical compositions, methods of manufacturing the compound, and methods of inhibiting the ACSS2 protein.

[0002] Acetyl-CoA synthetase (ACSS1-3) is a family of cellular enzymes that perform the first enzymatic step in the conversion of acetate to the multifunctional metabolite acetyl coenzyme A (acetyl-CoA) through the ligation of acetate with CoA in an ATP-driven process (Knowles, S.E.; Jarrett, I.G.; Filsell, O.H.; Ballard, F.J., Biochem. J., 1974, 142, 401-411). ACSS1 and ACSS3 are mainly expressed in the mitochondria of cells, while ACSS2 is expressed in both the nuclear and cytoplasmic compartments (Fujino, T.; Kondo, J.; Ishikawa, M.; Morikawa, K.; Yamamoto, T.T., J. Biol. Chem., 2001, 276, 11423-11426; Luong, A.; Hannah, V.C.; Brown, M.S.; Goldstein, J.L., J. Biol. Chem., 2000, 275, 26458-26466; Ariyannur, P.S.; Moffett, J.R.; Madhavarao, C.N.; Arun, P. et al., J. Comp. Neurol, 2010, 518, 2952-2977).

[0003] Acetyl-CoA plays a central role in cellular metabolism and is involved in multiple cellular processes (Pietrocola, F.; Galluzzi, L.; Bravo-San Pedro, J.M. 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 produce citrate, and various other metabolites are generated from citrate (Srere, P.A., J. Biol. Chem., 1959, 234, 2544-2547). Acetyl-CoA is a key intermediate in the carbon source and an essential building block for the synthesis of fatty acids, amino acids, and sterols.

[0004] Cell growth and proliferation are closely coordinated with metabolism and the availability of acetyl-CoA. One of the hallmarks of cancer is rapid, uncontrolled cell proliferation, which requires an increase in the production of energy and biomass via ATP and lipid production. This is accompanied by changes in both the way extracellular nutrients are captured and how extracellular nutrients are metabolized. Targeting the strategies adopted by cancer cells to increase the metabolic rate and enhance the proliferative capacity under nutrient-limited conditions is an attractive anti-cancer therapeutic approach. Targeting acetyl-CoA, the source of key cytoplasmic regulators for lipid, cholesterol, and amino acid synthesis, is particularly compelling.

[0005] Under nutrient-limited conditions such as in cancer cells, aerobic glycolysis occurs, and pyruvate generated from glucose metabolism is preferentially converted to lactate by reduction instead of being taken up for the synthesis of acetyl-CoA (the "Warburg effect"). Accordingly, both acetate uptake and ACSS2 are upregulated, and there are significant changes in the procurement of acetyl-CoA from other nutrients, which is a process that largely depends on ACSS2 for acetyl-CoA synthesis.

[0006] Acetic acid is taken up and metabolized into biomass by growing hypoxic and lipid-depleted tumor cells (Corbet, C.; Feron, O., Curr. Op Clin. Nutr. Metab Care, 2015, 18, 346 - 353). For the purpose of detecting metastases or performing grade classifications in patients with glioblastoma, hepatocellular carcinoma, non-small cell lung cancer, and prostate cancer, 11 The tendency of acetate uptake in certain tumors has been utilized over a 10-year period by using C-acetate-induced positron emission tomography (PET) imaging to detect primary tumors and confirm distant metastases. This reinforces initial studies showing that tumor cells often preferentially take up significant amounts of acetate over glucose as a nutrient to meet the increased demand of tumor cells for acetyl-CoA (Yoshimoto, M.; Waki, A.; Yonekura, Y.; Sadato, N. et al., Nucl. Med Biol., 2001, 28, 117 - 122).

[0007] Clinical evidence is increasingly accumulating that acetic acid and ACSS2 are pivotal metabolic hubs in tumor cells under nutrient and hypoxia stress. Genomic analysis reveals that ACSS2 copy number is associated with more advanced and invasive stages of breast cancer and metastatic prostate cancer (Schug, Z.T.; Peck, B.; Jones, D.T.; Zhang, Q.; Grosskurth, S. et al., Cancer Cell, 2015, 27, 57 - 71). Immunohistochemistry (IHC) using anti - ACSS2 antibody on human breast, ovarian, kidney, and lung tumor samples showed significant expression compared to corresponding normal samples that showed little or no ACSS2 expression. Survival analysis of patients with grade - 2 / 3 glioma (Mashimo, T.; Pichumani, K.; Vemireddy, V.; Hatanpaa, K.J., Cell, 2014, 159, 1603 - 1614) or triple - negative breast cancer (Comerford, S.A.; Huang, Z.; Du, X.; Wang, Y. et al., Cell, 2014, 159, 1591 - 1602) indicates that high ACSS2 expression is associated with shorter overall survival. These clinical findings demonstrate a strong correlation between acetate uptake, ACSS2 expression, and cancer progression. This suggests that inhibition of ACSS2 activity may benefit patients with acetate - metabolizing tumors.

[0008] Hypoxic tumor cells express high levels of cytoplasmic ACSS2. Knockdown of ACSS2 by RNA interference in tumor cells enhanced tumor cell death in vitro under long - term hypoxia and retarded tumor growth in vivo (Yoshii, Y.; Furukawa, T.; Yoshii, H.; Mori, T. et al., Cancer Sci., 2009, 100, 821 - 827). This supports the role of ACSS2 in tumor progression and provides a theoretical basis for pharmacological inhibitors. Interference with acetate metabolism by restricting ACSS2 activity would deprive resilient tumor cells of a crucial nutrient source and could halt or terminate the growth of refractory tumors.

[0009] ACSS2 supplies acetyl-CoA to histone acetyltransferases, acetylating lysine residues of histones (Takahashi, H.; McCaffery, J. M.; Irizarry, R. A.; Boeke, J. D., Mol. Cell, 2006, 23, 207-217), thereby controlling the transcription of growth genes through epigenetic modification of chromatin (Kaelin, W. G.; McKnight, S. L., Cell, 2013, 153, 56-69). Aberrant control of chromatin can affect diverse acetylation-dependent cellular processes such as glucose homeostasis, neuronal gene transcription, autophagy, and mitochondrial respiration, and is associated with conditions such as neurodegeneration, neuropathy, immunodeficiency, and metabolic diseases (Mirabella, A. C.; Foster, B. M.; Bartke, T., Chromosoma, 2016, 125, 75-93). Considering the extent to which cancer cells utilize metabolic adaptation to meet their increased energy and biomass demands, it has been proposed that cancer cells can also undergo large changes in their epigenetic footprint to aid tumor growth and survival (Lu, C.; Thompson, C. B., Cell Metab., 2012, 16, 9-17).

[0010] The heterodimeric stress-responsive transcription factor hypoxia-inducible factor 2α (HIF-2α) 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, J. S.; Hogg, R. T.; Das, A. et al., PLoS One, 2015, 10, e0116515). Knockdown of ACCS2 or HIF-2α in tumor cells impairs cell proliferation, cell migration, and invasion during hypoxia, leading to a marked decrease in tumor burden in mice bearing HT1080 flank tumors.

[0011] ACSS2 is post-translationally modified by the NAD-dependent deacetylase sirtuin. Sirtuin plays a central role in energy homeostasis and aging, and thus it has been proposed that the regulation of ACSS2 and acetate metabolism may also play a central role in aging (Shimazu, T.; Hirschey, M.D.; Huang, Y.; Ho, L.T.Y.; Verdin, E., Mech. Ageing Develop., 2010, 131, 511~516).

[0012] The causes of aging are multifactorial, but are evident in the progressive decline of metabolic capacity. As an individual ages, there is an accompanying accumulation of cell damage and changes to endogenous repair and detoxification processes. Healthy aging depends on the efficient removal of damaged cellular material, which 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 strong induction of autophagy and lifespan maintenance, while cellular nutrient starvation achieves the same effect (Marino, G.; Pietrocola, F.; Eisenberg, T.; Kong, Y. et al., Mol. Cell, 2014, 53, 710~725).

[0013] Human cytomegalovirus (HCMV) induces a robust increase in lipid synthesis, increasing the opportunity for productive infection. In ACSS2 knockout human fibroblasts, it has recently been shown that both HCMV-induced lipid biosynthesis and viral growth were sharply reduced compared to normal controls (Vysochan, A.; Sengupta, A.; Weljie, A.M.; Alwine, J.C.; Yu, Y., PNAS, 2017, 114, E1528 - E1535), suggesting that impairment of ACSS2 may have some utility as an antiviral therapy in several types of infection. Martinez-Micaelo et al. showed that ACSS2 is a nutrient-sensing protein and a key regulatory factor for 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 correlated with hepatic concentrations of metabolites involved in the TCA and glucose plasma levels. Phosphoproteomic analysis of mice fed a high-fat diet (Shaik, A.A.; Qiu, B.; Wee, S.; Choi, H. et al., Nature, 2016, 6, 25844) showed a series of phosphorylation changes in several enzymes involved in lipid and glucose homeostasis, including a decrease in phosphorylation of ACSS2. This indicates the role of this protein in obesity. Huang et al. observed a significant decrease in body weight and fatty liver in a diet-induced obesity model after knockdown of ACSS2. Deficiency of ACSS2 appears to reduce the absorption of dietary lipids and lipid transport to the liver (Huang, Z.; Zhang, M.; Plec, A.A.; Estill, S.J. et al., PNAS, 2018, 115, E9499 - E9506), and controls whole-body lipid metabolism according to acetate availability. These studies indicate that selective inhibitors of ACSS2 may have therapeutic benefits in obesity and non-alcoholic fatty liver disease.

[0014] This evolving knowledge has spurred considerable research into the potential therapeutic uses of ACSS2 inhibition.

[0015] Accordingly, there is still a need in the art for improved therapies for treating diseases such as cancer, neuropathy, and metabolic disorders that may be resistant to conventional treatment approaches. There is a need to develop improved compositions and methods in the art. In particular, there is a need for compounds that inhibit human ACSS2 protein, and methods for treating diseases that can obtain the benefits of such regulation.

[0016] The present invention arose from the research of the inventors who attempted to identify ACSS2 protein inhibitors.

[0017] In a first aspect of the present invention, there is provided a compound of formula (I) or a pharmaceutically acceptable complex, salt, solvate, tautomer or polymorph thereof.

Chemical formula

[0018] The inventors have found that the compounds of formula (I) are useful in therapy or as medicaments.

[0019] The present invention also extends to conjugates of the compounds of formula (I).

[0020] Accordingly, in a second aspect of the present invention, conjugates of formula (II) are provided.

Chemical formula

[0021] Hydrogen may be removed from the compound of formula (I), and L may be attached at a position where hydrogen would otherwise be present. 1 It can be understood that it may be attached.

[0022] Such conjugates may be designed to specifically target certain cell types or tumor types via a targeting moiety, which will direct the compound of formula (I) precisely to those cells or tumors and deliver the ACSS2 inhibitor in a cell-specific manner. The principle of this targeted delivery is known to those skilled in the art to be closely related to ADC (antibody-drug conjugate) technology, as described, for example, in Polakis, P., Pharmacol. Revs, 2016, 68, 3 - 19. The linker will then be designed to cleave, and the active compound will then diffuse intracellularly and contact the ACSS2 protein.

[0023] Accordingly, in a third aspect, there is provided a compound of formula (I), or a pharmaceutically acceptable complex, salt, solvate, tautomer or polymorph thereof, or a conjugate of formula (II) for use in therapy.

[0024] The inventors have also found that the compounds of formula (I) and the conjugates of formula (II) are useful in the regulation of acetyl-CoA synthetase short chain 2 (ACSS2) protein.

[0025] Accordingly, in a fourth aspect, there is provided a compound of formula (I), or a pharmaceutically acceptable complex, salt, solvate, tautomer or polymorph thereof, or a conjugate of formula (II) for use in the regulation of acetyl-CoA synthetase short chain 2 (ACSS2) protein.

[0026] Preferably, the compound of formula (I) or the conjugate of formula (II) is for use in the inhibition or inactivation of the ACSS2 protein. The compound of formula (I) or the conjugate of formula (II) may be for use in the inhibition or inactivation of ACSS2 enzyme activity as evidenced by a decrease in one or more biological effects selected from the group consisting of the production of acetyl-CoA, the uptake of acetate into lipids, the uptake of acetate into histones, and the uptake of acetate into tumor cells.

[0027] By inhibiting the ACSS2 protein, it is possible to treat, alleviate or prevent cancer, bacterial infections, viral infections, parasitic infections, neurodegenerative diseases, cardiovascular diseases, fatty liver diseases, metabolic disorders, and to promote healthy aging.

[0028] Advantageously, the compounds and conjugates of the present invention selectively inhibit only one subtype of the human ACCS family of proteins. The compounds of the present invention are potent inhibitors of ACSS2 but do not inhibit ACSS1 or ACSS3.

[0029] By inhibiting the ACSS2 protein, it is possible to treat, alleviate or prevent cancer, bacterial infections, viral infections, parasitic infections, fungal infections, neurodegenerative diseases, neuropathy, cerebrovascular diseases, cardiovascular diseases, non-alcoholic fatty liver diseases, obesity, and to promote healthy aging.

[0030] Accordingly, in a fifth aspect, there is provided a compound of formula (I), or a pharmaceutically acceptable complex, salt, solvate, tautomer or polymorph thereof, or a conjugate of formula (II) for use in the treatment, alleviation or prevention of a disease selected from cancer, bacterial infections, viral infections, parasitic infections, fungal infections, neurodegenerative diseases, neuropathy, cerebrovascular diseases, cardiovascular diseases, non-alcoholic fatty liver diseases and obesity, or for use in promoting healthy aging.

[0031] Preferably, the disease is cancer.

[0032] In a sixth aspect, there is provided a method of inhibiting ACSS2 protein in a subject, the method comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable complex, salt, solvate, tautomer or polymorph thereof, or a conjugate of formula (II).

[0033] Preferably, the method comprises the step of inhibiting the ACSS2 protein.

[0034] In a seventh aspect, there is provided a method of treating, alleviating or preventing a disease selected from cancer, bacterial infection, viral infection, parasitic infection, fungal infection, neurodegenerative disease, neuropathy, cerebrovascular disease, cardiovascular disease, metabolic disorder, non-alcoholic fatty liver disease and obesity, or a method of promoting healthy aging, the method comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable complex, salt, solvate, tautomer or polymorph thereof, or a conjugate of formula (II).

[0035] It can be understood that the term "preventing" can mean "reducing the likelihood of".

[0036] The neurodegenerative disorder may be amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease or Huntington's disease. The neuropathy may be anxiety, depression, autism or post-traumatic stress disorder.

[0037] The parasitic infection may be malaria.

[0038] The metabolic disorder may be obesity or fatty liver disease, such as non-alcoholic steatohepatitis.

[0039] Promotion of healthy aging may include restoration or enhancement of autophagy and autophagic protein clearance.

[0040] In one preferred embodiment, the disease is cancer. The cancer may be selected from the group consisting of colorectal cancer, airway-gastrointestinal squamous cell carcinoma, gastrointestinal stromal tumor, lung cancer, brain cancer, neuroblastoma, glioma, astrocytoma, glioblastoma, liver cancer, stomach cancer, sarcoma, leukemia, lymphoma, multiple myeloma, ovarian cancer, uterine cancer, breast cancer, melanoma, prostate cancer, bladder cancer, pancreatic cancer or kidney cancer. In some embodiments, the cancer may have upregulated ACSS2 expression and / or ACSS2 activity in the tissue as compared to that of a healthy subject.

[0041] In an alternative preferred embodiment, the disease is a viral infection. The viral infection may be a hepatitis C virus (HCV) infection or a human cytomegalovirus (HCMV) infection.

[0042] Unless the context specifically indicates otherwise, the following definitions are used in connection with the compounds of the present invention.

[0043] Throughout the description and claims of this specification, the word "comprise", and other forms such as "comprising" and "comprises", means including but not limited to, and is not intended to exclude, for example, other additives, components, integers, or steps.

[0044] As used in this description and the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a composition" includes mixtures of two or more such compositions.

[0045] "Optional" or "optionally" means that the subsequent described event, operation or situation may or may not occur, and the description includes examples where the event, operation or situation occurs and examples where the event, operation or situation does not occur.

[0046] As used herein, the term "alkyl" refers to saturated straight or branched hydrocarbons, unless otherwise specified. In certain embodiments, the alkyl group is a primary, secondary, or tertiary hydrocarbon. In certain embodiments, the alkyl group has 1 to 10 carbon atoms, i.e., C 1 ~C 10 alkyl. C 1 ~C 10 alkyl includes, for example, methyl, ethyl, n-propyl (1-propyl) and isopropyl (2-propyl, 1-methylethyl), butyl, pentyl, hexyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, isohexyl, heptyl, octyl, nonyl, and decyl. The alkyl group can be unsubstituted or substituted with halogen, OH, optionally substituted C 1 ~C 6 alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, NR 9 R 10 、C(O)R 9 、CN, oxo, azide, OP(O)(OH) 2 、OC(O)R 9 、COOR 9 、C 1 ~C 6 alkenyl, =NOR 9 、NR 9 C(O)R 10 、SO 2 R 9 、SO 2 NR 9 R 10 、optionally substituted C 6 ~C 12 aryl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted C 3 ~C 6 cycloalkyl, and one or more of optionally substituted 3- to 8-membered heterocycles. Thus, optionally substituted C 1 ~C 10 alkyl can be substituted with one or more of optionally substituted C 1 ~C 10Haloalkyl, i.e., substituted with at least one halogen and OH, optionally substituted C 1 ~C 6 alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, NR 9 R 10 , CONR 9 R 10 , CN, oxo, azide, OP(O)(OH) 2 , OC(O)R 9 , COOR 9 , C 1 ~C 6 alkenyl, =NOR 9 , NR 9 C(O)R 10 , SO 2 R 9 , SO 2 , NR 9 R 10 , optionally substituted C 6 ~C 12 aryl, optionally substituted 5- to 10-membered heteroaryl, C 3 ~C 6 cycloalkyl and optionally further substituted with one or more of optionally substituted 3- to 8-membered heterocycles C 1 ~C 10 alkyl may be. Optionally substituted C 1 ~C 10 alkyl is polyfluoroalkyl, preferably C 1 ~C 3 polyfluoroalkyl may be. R 9 and R 10 may be as defined for the first aspect. R 9 and R 10 are each independently selected from the group consisting of H, halogen and optionally substituted C 1 ~C 6 alkyl.

[0047] The term "alkylene", as used herein, unless otherwise specified, refers to a divalent saturated straight-chain or branched hydrocarbon. In certain embodiments, the alkylene group is a primary, secondary, or tertiary hydrocarbon. In certain embodiments, the alkylene group has 1 to 6 carbon atoms, i.e., C 1 ~C 6 including alkylene. C 1 ~C 6 Alkylene includes, for example, methylene, ethylene, n-propylene and isopropylene, butylene, pentylene, hexylene, isobutylene, sec-butylene, tert-butylene, isopentylene, neopentylene, and isohexylene. The alkylene group may be unsubstituted or optionally substituted with C 1 ~C 6 alkyl, halogen, OH, optionally substituted C 1 ~C 6 alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, NR 9 R 10 , C(O)NR 9 R 10 , CN, oxo, azide, OP(O)(OH) 2 , OC(O)R 9 , COOR 9 , C 1 ~C 6 alkenyl, =NOR 9 , NR 9 C(O)R 10 , SO 2 R 9 , SO 2 , NR 9 R 10 , optionally substituted C 6 ~C 12 aryl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted C 3 ~C 6 cycloalkyl and optionally substituted 3- to 8-membered heterocyclic ring, one or more of which may be substituted. Thus, optionally substituted C 1 ~C 6 alkylene is optionally substituted with C 1 ~C6 Haloalkylene, i.e., C substituted with at least one halogen and optionally substituted 1 ~C 6 alkyl, OH, optionally substituted C 1 ~C 6 alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, NR 9 R 10 , CONR 9 R 10 , CN, oxo, azide, azide, OP(O)(OH) 2 , OC(O)R 9 , COOR 9 , C 1 ~C 6 alkenyl, =NOR 9 , NR 9 C(O)R 10 , SO 2 R 9 , SO 2 , NR 9 R 10 , optionally substituted C 6 ~C 12 aryl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted C 3 ~C 6 cycloalkyl and optionally substituted 3- to 8-membered heterocyclic ring, one or more of which are optionally further substituted with C 1 ~C 6 alkylene. It will be understood that it may be optionally substituted C 1 ~C 6 alkylene may be optionally substituted polyfluoroalkylene, preferably C 1 ~C 3 polyfluoroalkylene. It will be understood that R 9 and R 10 may be as defined for the first aspect. R 9 and R 10 may each independently be selected from the group consisting of H, halogen, and optionally substituted C 1 ~C 6 alkyl.

[0048] The term "halo" or "halogen" includes fluoro (-F), chloro (-Cl), bromo (-Br), and iodo (-I).

[0049] The term "polyfluoroalkyl" represents a C 1 ~C 3 alkyl group in which two or more hydrogen atoms are replaced by fluorine atoms. This term may include perfluoroalkyl groups, i.e., C 1 ~C 3 alkyl groups in which all hydrogen atoms are replaced by fluorine atoms. Thus, the term C 1 ~C 3 polyfluoroalkyl includes, but is not limited to, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3,3,3-trifluoropropyl, 2,2,3,3,3-pentafluoropropyl, and 2,2,2-trifluoro-1-(trifluoromethyl)ethyl.

[0050] "Alkoxy" means R 11 wherein R is an optionally substituted C 1 ~C 6 alkyl group, an optionally substituted C 3 ~C 6 cycloalkyl group, an optionally substituted C 2 ~C 6 alkenyl or an optionally substituted C 2 ~C 6 alkynyl group R 11 -O-. Exemplary C 1 ~C 6 alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy (1-propoxy), n-butoxy, and tert-butoxy. The alkoxy group may be unsubstituted or substituted with halogen, OH, NR 9 R 10 , C(O)R 9 , CN, oxo, azide, OP(O)(OH) 2 , OC(O)R 9 , COOR 9, C 1 ~C 6 Alkenyl, =NOR 9 , NR 9 C(O)R 10 , SO 2 R 9 , SO 2 , NR 9 R 10 , Optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted C 6 ~C 12 Aryl, optionally substituted 5- to 10-membered heteroaryl, C 3 ~C 6 Cycloalkyl and one or more of 3- to 8-membered heterocycles may be substituted. R 9 and R 10 may be as defined for the first aspect. R 9 and R 10 are each independently selected from the group consisting of H, halogen and optionally substituted C 1 ~C 6 alkyl.

[0051] "Aryl" refers to an aromatic 6- to 12-membered hydrocarbon group. C 6 ~C 12 Examples of aryl groups include, but are not limited to, phenyl, α-naphthyl, β-naphthyl, biphenyl, tetrahydronaphthyl and indanyl. An aryl group may be unsubstituted or optionally substituted with C 1 ~C 6 alkyl, optionally substituted C 1 ~C 6 alkenyl, optionally substituted C 1 ~C 6 alkynyl, halogen, OH, optionally substituted C 1 ~C 6 alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, NR 9 R 10 , C(O)R 9 , CN, azide, OP(O)(OH) 2 , OC(O)R 9, COOR 9 , C 1 ~C 6 alkenyl, =NOR 9 , NR 9 C(O)R 10 , SO 2 R 9 , SO 2 , NR 9 R 10 , optionally substituted C 6 ~C 12 aryl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted C 3 ~C 6 cycloalkyl and one or more of optionally substituted 3- to 8-membered heterocycles may be substituted. R 9 and R 10 may be as defined for the first aspect. R 9 and R 10 are each independently selected from the group consisting of H, halogen, and optionally substituted C 1 ~C 6 alkyl.

[0052] "Arylene" refers to a divalent aromatic 5- to 10-membered hydrocarbon group. The arylene group may be as defined above for the aryl group, but a hydrogen atom has been removed from the aryl group and the group is divalent.

[0053] "Aryloxy" refers to the group aryl-O- where "aryl" is an optionally substituted C 6 ~C 12 aryl group.

[0054] As used herein, the term "bicyclic" or "bicyclic ring" refers to a molecule characterized by two fused rings, where the fused rings are cycloalkyl, heterocyclyl, or heteroaryl. In one embodiment, the rings are fused across a bond between two atoms. The bicyclic moiety formed by the fusion shares the bond between the rings. In another embodiment, the bicyclic moiety is formed by fusing two rings across a series of atoms of a ring to form a bridgehead. Similarly, a "bridge" is an unbranched chain of one or more atoms connecting two bridgeheads of a polycyclic compound. In another embodiment, the bicyclic molecule is a "spiro" or "spirocyclic" moiety. A spirocyclic group is bonded to a single carbon atom of a carbocyclic or heterocyclic moiety via a single carbon atom of the spirocyclic moiety C 3 ~C 6 may be cycloalkyl or a monocyclic or bicyclic 3- to 8-membered heterocycle. In one embodiment, the spirocyclic group is cycloalkyl and is bonded to another cycloalkyl. In another embodiment, the spirocyclic group is cycloalkyl and is bonded to heterocyclyl. In a further embodiment, the spirocyclic group is heterocyclyl and is bonded to another heterocyclyl. In yet another embodiment, the spirocyclic group is heterocyclyl and is bonded to cycloalkyl. The spirocyclic group may be unsubstituted or optionally substituted C 1 ~C 6 alkyl, optionally substituted C 1 ~C 6 alkenyl, optionally substituted C 1 ~C 6 alkynyl, halogen, OH, optionally substituted C 1 ~C 6 alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, NR 9 R 10 , C(O)R 9 , CN, oxo, azide, OP(O)(OH) 2 , OC(O)R 9 , COOR 9 , C 1 ~C 6Alkenyl, =NOR 9 , NR 9 C(O)R 10 , SO 2 R 9 , SO 2 , NR 9 R 10 , optionally substituted C 6 ~C 12 aryl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted C 3 ~C 6 cycloalkyl and optionally substituted 3- to 8-membered heterocyclic ring, one or more of which may be substituted. R 9 and R 10 may be as defined for the first aspect. R 9 and R 10 are each independently selected from the group consisting of H, halogen, and optionally substituted C 1 ~C 6 alkyl.

[0055] "Cycloalkyl" refers to a 3- to 6-membered ring system of non-aromatic, saturated, partially saturated, monocyclic, bicyclic or polycyclic hydrocarbons. C 3 ~C 6 Representative examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. The cycloalkyl group may be unsubstituted or optionally substituted with C 1 ~C 6 alkyl, optionally substituted C 1 ~C 6 alkenyl, optionally substituted C 1 ~C 6 alkynyl, halogen, OH, optionally substituted C 1 ~C 6 alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, NR 9 R 10 , C(O)R 9 , CN, oxo, azide, OP(O)(OH) 2 , OC(O)R 9 , COOR 9 , C1 ~C 6 Alkenyl, =NOR 9 , NR 9 C(O)R 10 , SO 2 R 9 , SO 2 , NR 9 R 10 , optionally substituted C 6 ~C 12 aryl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted C 3 ~C 6 cycloalkyl and one or more of optionally substituted 3- to 8-membered heterocycles, which may be substituted. R 9 and R 10 may be as defined for the first aspect. R 9 and R 10 are each independently selected from the group consisting of H, halogen, and optionally substituted C 1 ~C 6 alkyl.

[0056] "Cycloalkylene" refers to a 3- to 6-membered ring system of a divalent non-aromatic, saturated, partially saturated, monocyclic, bicyclic or polycyclic hydrocarbon. The cycloalkylene group may be as defined above for the cycloalkyl group, but a hydrogen atom has been removed from the cycloalkyl group and the group is divalent.

[0057] "Heteroaryl" refers to a monocyclic or bicyclic aromatic 5- to 10-membered ring system in which at least one ring atom is a heteroatom. Each of these heteroatoms may be independently selected from the group consisting of oxygen, sulfur, and nitrogen. Examples of 5- to 10-membered heteroaryl groups include furan, thiophene, indole, azaindole, oxazole, thiazole, isoxazole, isothiazole, imidazole, N-methylimidazole, pyridine, pyrimidine, pyrazine, pyrrole, N-methylpyrrole, pyrazole, N-methylpyrazole, 1,3,4-oxadiazole, 1,2,4-triazole, 1-methyl-1,2,4-triazole, 1H-tetrazole, 1-methyltetrazole, benzoxazole, benzothiazole, benzofuran, benzoisoxazole, benzimidazole, N-methylbenzimidazole, azabenzimidazole, indazole, quinazoline, quinoline, and isoquinoline. Bicyclic 5- to 10-membered heteroaryl groups include those in which a phenyl, pyridine, pyrimidine, pyrazine, or pyridazine ring is fused to a 5- or 6-membered monocyclic heteroaryl ring. The heteroaryl group may be unsubstituted or optionally substituted with C 1 ~C 6 alkyl, optionally substituted C 1 ~C 6 alkenyl, optionally substituted C 1 ~C 6 alkynyl, halogen, OH, optionally substituted C 1 ~C 6 alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, NR 9 R 10 , C(O)R 9 , CN, oxo, azide, OP(O)(OH) 2 , OC(O)R 9 , COOR 9 , C 1 ~C 6 alkenyl, =NOR 9 , NR 9 C(O)R 10 , SO 2 R 9 , SO 2 NR9 R 10 and optionally substituted C 6 ~C 12 aryl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted C 3 ~C 6 cycloalkyl and optionally substituted 3- to 8-membered heterocyclic ring, and may be substituted with one or more of them. R 9 and R 10 may be as defined for the first aspect. R 9 and R 10 are each independently selected from the group consisting of H, halogen, and optionally substituted C 1 ~C 6 alkyl.

[0058] "Heteroaryloxy" refers to the group heteroaryl-O- where "heteroaryl" is an optionally substituted 5- to 10-membered heteroaryl group.

[0059] "Heteroarylene" refers to a divalent monocyclic or bicyclic aromatic 5- to 10-membered ring system in which at least one ring atom is a heteroatom. The heteroarylene group may be as defined above for the heteroaryl group, but a hydrogen atom has been removed from the heteroaryl group and the group is divalent.

[0060] "Complex ring" or "heterocyclyl" refers to a 3- to 8-membered monocyclic, bicyclic or bridged molecule in which at least one ring atom is a heteroatom. Each of these heteroatoms may be independently selected from the group consisting of oxygen, sulfur and nitrogen. The heterocyclic ring may be saturated or partially saturated. Exemplary 3- to 8-membered heterocyclyl groups include, but are not limited to, aziridine, oxirane, oxylene, thiirane, pyrroline, pyrrolidine, dihydrofuran, tetrahydrofuran, dihydrothiophene, tetrahydrothiophene, dithiolane, piperidine, 1,2,3,6-tetrahydropyridin-1-yl, tetrahydropyran, pyran, morpholine, piperazine, thian, thiin, piperazine, azepane, diazepane, oxazine. The heterocyclyl group may be unsubstituted or optionally substituted with a C 1 ~C 6 alkyl, optionally substituted C 1 ~C 6 alkenyl, optionally substituted C 1 ~C 6 alkynyl, halogen, OH, optionally substituted C 1 ~C 6 alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, NR 9 R 10 , C(O)R 9 , CN, oxo, azide, OP(O)(OH) 2 , OC(O)R 9 , COOR 9 , C 1 ~C 6 alkenyl, =NOR 9 , NR 9 C(O)R 10 , SO 2 R 9 , SO 2 , NR 9 R 10 , optionally substituted C 6 ~C 12 aryl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted C 3 ~C 6It may be substituted with one or more of cycloalkyl and optionally substituted 3- to 8-membered heterocycles. R 9 and R 10 may be as defined for the first aspect. R 9 and R 10 are each independently selected from the group consisting of H, halogen, and optionally substituted C 1 ~C 6 alkyl.

[0061] "Heterocycle" refers to a divalent 3- to 8-membered monocyclic, bicyclic, or bridged molecule in which at least one ring atom is a heteroatom. The heterocyclic group may be as defined above for the heterocyclic group, but a hydrogen atom has been removed from the heterocyclic group and the group is divalent.

[0062] "Alkenyl" refers to an olefinically unsaturated hydrocarbon group that may be unbranched or branched. In certain embodiments, the alkenyl group has 2 to 6 carbons, i.e., the alkenyl group is C 2 ~C 6 alkenyl. C 2 ~C 6 Alkenyl includes, for example, vinyl, allyl, propenyl, butenyl, pentenyl, and hexenyl. The alkenyl group may be unsubstituted or optionally substituted C 1 ~C 6 alkyl, optionally substituted C 1 ~C 6 alkynyl, halogen, OH, optionally substituted C 1 ~C 6 alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, NR 9 R 10 , C(O)R 9 , CN, oxo, azide, OP(O)(OH) 2 , OC(O)R 9 , COOR 9 , C 1 ~C 6 alkenyl, =NOR 9 , NR 9 C(O)R10 , SO 2 R 9 , SO 2 NR 9 R 10 , optionally substituted C 6 ~C 12 aryl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted C 3 ~C 6 cycloalkyl and optionally substituted 3- to 8-membered heterocyclic ring, one or more of which may be substituted. R 9 and R 10 may be as defined for the first aspect. R 9 and R 10 are each independently selected from the group consisting of H, halogen and optionally substituted C 1 ~C 6 alkyl.

[0063] "Alkynyl" refers to an acetylenically unsaturated hydrocarbon group which may be unbranched or branched. In certain embodiments, the alkynyl group has 2 to 6 carbons, i.e., the alkynyl group is C 2 ~C 6 alkynyl. C 2 ~C 6 Alkynyl includes, for example, propargyl, propynyl, butynyl, pentynyl and hexynyl. The alkynyl group may be unsubstituted or optionally substituted C 1 ~C 6 alkyl, optionally substituted C 2 ~C 6 alkenyl, halogen, OH, optionally substituted C 1 ~C 6 alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, NR 9 R 10 , C(O)R 9 , CN, oxo, azide, OP(O)(OH) 2 , OC(O)R 9 , COOR 9 , C 1 ~C 6 alkenyl, =NOR9 , NR 9 C(O)R 10 , SO 2 R 9 , SO 2 , NR 9 R 10 , optionally substituted C 6 ~C 12 aryl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted C 3 ~C 6 cycloalkyl and one or more of optionally substituted 3- to 8-membered heterocycles may be substituted. R 9 and R 10 may be as defined for the first aspect. R 9 and R 10 are each independently selected from the group consisting of H, halogen, and optionally substituted C 1 ~C 6 alkyl.

[0064] The term "alkyne", as used herein, unless otherwise specified, refers to a divalent unsaturated straight-chain or branched hydrocarbon. In certain embodiments, the alkyne group is a primary, secondary, or tertiary hydrocarbon. In certain embodiments, the alkyne group has 1 to 6 carbon atoms, i.e., C 2 ~C 6 alkyne. C 2 ~C 6 alkyne includes, for example, ethyne, propyne, butyne, pentyne, or hexyne. The alkyne group may be unsubstituted or optionally substituted C 1 ~C 6 alkyl, optionally substituted C 1 ~C 6 alkenyl, optionally substituted C 1 ~C 6 alkynyl, halogen, OH, optionally substituted C 1 ~C 6 alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, NR 9 R 10 , C(O)R9 , CN, oxo, azido, OP(O)(OH) 2 , OC(O)R 9 , COOR 9 , C 1 ~C 6 alkenyl, =NOR 9 , NR 9 C(O)R 10 , SO 2 R 9 , SO 2 , NR 9 R 10 , optionally substituted C 6 ~C 12 aryl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted C 3 ~C 6 cycloalkyl and can be substituted with one or more of optionally substituted 3- to 8-membered heterocycles. Thus, optionally substituted C 2 ~C 6 alkynyl can be optionally substituted C 2 ~C 6 haloalkynyl, i.e., substituted with at least one halogen and optionally substituted C 1 ~C 6 alkyl, optionally substituted C 1 ~C 6 alkenyl, optionally substituted C 1 ~C 6 alkynyl, halogen, OH, optionally substituted C 1 ~C 6 alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, NR 9 R 10 , C(O)R 9 , CN, oxo, azido, OP(O)(OH) 2 , OC(O)R 9 , COOR 9 , C 1 ~C 6 alkenyl, =NOR 9 , NR 9 C(O)R 10 , SO 2 R 9 , SO 2NR 9 R 10 and optionally substituted C 6 ~C 12 aryl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted C 3 ~C 6 cycloalkyl and optionally substituted 3- to 8-membered heterocyclic ring, optionally further substituted with one or more of C 2 ~C 6 It will be understood that it may be alkynyl. Optionally substituted C 2 ~C 6 It will be understood that the alkynyl may be optionally substituted polyfluoroalkynyl. R 9 and R 10 may be as defined above. R 9 and R 10 may each independently be selected from the group consisting of H, halogen and optionally substituted C 1 ~C 6 alkyl.

[0065] "Alkylsulfonyl" means that the alkyl is optionally substituted C 1 ~C 6 alkyl and refers to the group alkyl-SO 2 - as defined above.

[0066] The complex of the compound of formula (I) can be understood to be a multi-component complex in which the drug and at least one other component are present in stoichiometric or non-stoichiometric amounts. The complex may be other than a salt or solvate. This type of complex includes clathrates (drug-host inclusion complexes) and co-crystals. The latter are typically defined as crystalline complexes of neutral molecular components that are bound to each other through non-covalent interactions, but can also be complexes of neutral molecules with salts. Co-crystals may be prepared by melt crystallization, recrystallization from a solvent, or by physically grinding the components together - see Chem Commun, 17, 1889 - 1896 by O. Almarsson and M. J. Zaworotko (2004), which is incorporated herein by reference. For a general review of multi-component complexes, see J Pharm Sci, 64(8), 1269 - 1288 by Haleblian (August 1975), which is incorporated herein by reference.

[0067] The term "pharmaceutically acceptable salt" can be understood to refer to any salt of the compounds described herein that retains its biological properties and is not toxic or otherwise undesirable for pharmaceutical use. Such salts may be derived from a variety of organic and inorganic counterions well known in the art.Such salts include, but are not limited to: (1) acid addition salts formed by organic or inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, sulfamic acid, acetic acid, adipic acid, aspartic acid, trifluoroacetic acid, trichloroacetic acid, propionic acid, hexanoic acid, cyclopentylpropionic acid, glycolic acid, glutaric acid, pyruvic acid, lactic acid, malonic acid, succinic acid, sorbic acid, ascorbic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, picric acid, cinnamic acid, mandelic acid, phthalic acid, lauric acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphoric acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, benzoic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, cyclohexylsulfamic acid, quinic acid, muconic acid and similar acids; or (2) base addition salts formed when the acidic proton present in the parent compound is coordinated by (a) metal ions such as alkali metal ions, alkaline earth metal ions or aluminum ions, or alkali metal or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, aluminum hydroxide, lithium hydroxide, zinc hydroxide, and barium hydroxide, ammonia, or (b) organic bases such as ammonia, methylamine, dimethylamine, diethylamine, picoline, ethanolamine, diethanolamine, triethanolamine, ethylenediamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylene-diamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, N-methylglucamine, piperazine, tris(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide and other aliphatic, alicyclic, or aromatic organic amines.

[0068] Pharmaceutically acceptable salts may include sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, etc., and when the compound contains a basic functional group, hydrohalic acid salts such as hydrochloride, hydrobromide and hydroiodide, carbonate or bicarbonate, sulfate or bisulfate, borate, phosphate, hydrogen phosphate, dihydrogen phosphate, pyroglutamate, saccharate, stearate, sulfamate, nitrate, orotate, oxalate, palmitate, pamoate, acetate, trifluoroacetate, trichloroacetate, propionate, hexanoate, cyclopentylpropionate, glycolate, glutarate, pyruvate, lactate, malonate, succinate, tannate, tartrate, tosylate, sorbate, ascorbate, malate, maleate, fumarate, tartrate, camsylate, citrate, cyclamate, benzoate, isethionate, esylate, formate, 3-(4-hydroxybenzoyl)benzoate, picrate, cinnamate, mandelate, phthalate, laurate, methanesulfonate (mesylate), methyl sulfate, naphthylate, 2-naphthylate, nicotinate, ethanesulfonate, 1,2-ethane-disulfonate, 2-hydroxyethanesulfonate, benzenesulfonate (besylate), 4-chlorobenzenesulfonate, 2-naphthalenesulfonate, 4-toluenesulfonate, borneate, camphorsulfonate, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylate, glucoheptonate, 3-phenylpropionate, trimethylacetate, tert-butylacetate, lauryl sulfate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, benzoate, glutamate, hydroxynaphthoate, salicylate, stearate, cyclohexylsulfamate, quinate, muconate, xinafoate, etc., and may contain salts of non-toxic organic or inorganic acids.

[0069] Hemisalts of acids and bases, such as hemisulfates, may also be formed. Those skilled in the art will understand that the salts described above include salts in which the counterion is optically active, such as D-lactate, or salts that are racemic, such as DL-tartrate.

[0070] For a general review of suitable salts, see "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[0071] Pharmaceutically acceptable salts of the compounds of formula (I) may be prepared by one or more of the following three methods: (i) A method by reacting a compound of formula (I) with a desired acid or base; (ii) A method by removing an acid- or base-labile protecting group from a suitable precursor of a compound of formula (I) using a desired acid or base, or (iii) A method by reacting with a suitable acid or base or by converting a salt of a compound of formula (I) to another salt using a suitable ion exchange column.

[0072] All three reactions are typically carried out in solution. The resulting salt can be precipitated and collected by filtration or recovered by evaporation of the solvent. The degree of ionization in the resulting salt may vary from almost completely ionized to almost non-ionized.

[0073] The term "solvate" can be understood to refer to the compounds or salts thereof described herein that further include a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. When the solvent is water, the solvate is a hydrate. Pharmaceutically acceptable solvates according to the present invention may be those in which the crystallization solvent may be replaced by an isotope, such as D 2 O, d 6 -acetone and d 6 -DMSO.

[0074] The currently accepted classification system for organic hydrates defines isolated sites, channels, or metal ion coordination hydrates - see Polymorphism in Pharmaceutical Solids by K.R. Morris (edited by H.G. Brittain, Marcel Dekker, 1995), which is incorporated herein by reference. Isolated site hydrates are hydrates in which water molecules are isolated from direct contact with each other by intervening organic molecules. In channel hydrates, water molecules are in lattice channels adjacent to other water molecules. In metal ion coordination hydrates, water molecules are bound to metal ions.

[0075] When the solvent or water is strongly bound, the complex will have a definite stoichiometry independent of humidity. However, when the solvent or water is weakly bound, as in channel solvates and hygroscopic compounds, the water / solvent content will depend on humidity and drying conditions. In such cases, non-stoichiometry will be the norm.

[0076] The compounds of the present invention may exist in a continuous range of solid states from completely amorphous to completely crystalline, including polymorphs of the crystalline materials. The term "amorphous" refers to a state in which the material lacks long-range order at the molecular level and may exhibit physical properties characteristic of a solid or a liquid depending on temperature. Typically, such materials do not give a distinct X-ray diffraction pattern and, while exhibiting solid properties, are more formally described as liquids. Upon heating, a change in state occurs, typically characterized by a secondary ("glass transition") change from solid to liquid properties. The term "crystalline" refers to a solid phase in which the material has a regularly arranged internal structure at the molecular level and gives a distinct X-ray diffraction pattern with sharp peaks. Such materials will also exhibit liquid properties when heated sufficiently, but the change from solid to liquid is characterized by a phase change, typically a primary ("melting point").

[0077] When the compounds of the present invention are exposed to suitable conditions, they may exist in an intermediate state (mesophase or liquid crystal). The intermediate state is intermediate between the true crystalline state and the true liquid state (either a melt or a solution). Liquid crystallinity resulting from a change in temperature is described as "thermotropic", and liquid crystallinity resulting from the addition of a second component such as water or another solvent is described as "lyotropic". Compounds having the potential to form lyotropic mesophases are described as "amphiphilic" and consist of molecules having polar head groups that are ionic (-COO - Na + 、-COO - K + 、or -SO 3 - Na + etc.) or non-ionic (-N - N + (CH 3 ) 3 etc.). For further information, see Crystals and the Polarizing Microscope, 4th Edition (Edward Arnold, 1970) by N.H. Hartshorne and A. Stuart, which is incorporated herein by reference.

[0078] R and R 1 are each independently selected from the group consisting of H, monocyclic or bicyclic optionally substituted C 6 ~C 12 aryl, monocyclic or bicyclic optionally substituted 5- to 10-membered heteroaryl, optionally substituted C 1 ~C 6 alkyl, optionally substituted monocyclic or bicyclic C 3 ~C 6 cycloalkyl, optionally substituted monocyclic or bicyclic 3- to 8-membered heterocyclic ring, optionally substituted monocyclic or bicyclic C 3 ~C 6 cycloalkenyl, optionally substituted C 2 ~C 6 alkenyl and optionally substituted C 2 ~C 6 alkynyl. More preferably, R and R1 is independently selected from a phenyl ring optionally substituted, a C 1 ~C 6 alkyl, a C 2 ~C 6 alkenyl, an alkynyl or a 5- or 6-membered heteroaryl optionally substituted. Most preferably, R and R 2 ~C 6 are each a phenyl ring optionally substituted or methyl. 1

[0079] R and / or R 1 when being an optionally substituted C 6 ~C 12 aryl, the aryl is preferably an optionally substituted phenyl. The phenyl may be unsubstituted or substituted with one or more of halogen, an optionally substituted C 1 ~C 6 alkyl, an optionally substituted C 1 ~C 6 alkoxy, COR, NR 9 R 10 , CN, R 9 COR 10 , an optionally substituted C 6 ~C 12 aryl or an optionally substituted 5- to 10-membered heteroaryl. In the formula, R 9 and R 10 are each H or an optionally substituted C 1 ~C 6 alkyl. More preferably, the phenyl is unsubstituted or substituted with one or more of fluorine, C 1 ~C 6 alkoxy, COR 9 , NR 9 R 10 , CN, R 9 COR 10 or C 6 ~C 12 aryl. In the formula, R 9 and R 10is each H or C 1 ~C 6 is alkyl. Most preferably, phenyl is unsubstituted or substituted with one or more of fluorine, OH, OCH 3 、OCH 2 CH 3 、OCH 2 CH(CH 3 ) 2 、COCH 3 、N(CH 3 ) 2 、NH 2 、CN, NHC(O)CH 3 or one or more of phenyl.

[0080] When R and / or R 1 is optionally substituted 5- to 10-membered heteroaryl, the heteroaryl is preferably optionally substituted 5- or 6-membered heteroaryl, more preferably optionally substituted pyridinyl or optionally substituted pyrazolyl. The heteroaryl may be unsubstituted or substituted with optionally substituted C 1 ~C 6 alkyl, optionally substituted C 1 ~C 6 alkoxy or OH. More preferably, the heteroaryl is unsubstituted or substituted with one or more of C 1 ~C 6 alkyl, C 1 ~C 6 alkoxy or OH. Most preferably, the heteroaryl is unsubstituted or substituted with one or more of methyl, OCH 3 or OH.

[0081] When R and / or R 1 is optionally substituted monocyclic or bicyclic C 3 ~C 6 cycloalkyl, the cycloalkyl is preferably unsubstituted.

[0082] When R and / or R 1 is optionally substituted C1 ~C 6 alkyl, optionally substituted C 2 ~C 6 alkenyl or optionally substituted C 2 ~C 6 When it is alkynyl, alkyl, alkenyl or alkynyl is preferably optionally substituted C 1 ~C 3 alkyl, optionally substituted C 2 ~C 3 alkenyl or optionally substituted C 2 ~C 3 alkynyl, more preferably optionally substituted C 1 ~C 2 alkyl, optionally substituted C 2 alkenyl or optionally substituted C 2 is alkynyl. Alkyl, alkenyl or alkynyl may be unsubstituted or substituted with one or more of halogen, optionally substituted C 6 ~C 12 aryl or optionally substituted 5- to 10-membered heteroaryl. Preferably, alkyl, alkenyl or alkynyl is unsubstituted or substituted with one or more of fluorine or C 6 ~C 12 aryl. Most preferably, alkyl, alkenyl or alkynyl is unsubstituted or substituted with one or more of fluorine or phenyl.

[0083] 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 monocyclic or bicyclic 3- to 8-membered heterocyclic ring, optionally substituted C1 ~C 6 alkoxy, optionally substituted monocyclic or bicyclic C 6 ~C 12 It may also be aryl or optionally substituted monocyclic or bicyclic 5- to 10-membered heteroaryl.

[0084] R 2 is COOR 9 , CONR 9 R 10 , CN, NR 9 COR 10 , NR 9 R 10 or NR 9 SO 2 R 10 When it is, R 9 and R 10 are independently H or optionally substituted C 1 ~C 6 alkyl, optionally substituted monocyclic or bicyclic C 3 ~C 6 cycloalkyl, optionally substituted monocyclic or bicyclic C 6 ~C 12 It may also be aryl or optionally substituted monocyclic or bicyclic 5- to 10-membered heteroaryl. More preferably, R 9 and R 10 are independently H or optionally substituted C 1 ~C 3 alkyl, C 3 ~C 6 cycloalkyl, optionally substituted phenyl or optionally substituted 5- or 6-membered heteroaryl. R 9 and R 10 may be H, optionally substituted methyl, cyclopropyl or optionally substituted pyrazolyl. R 9 or R 10 When it is optionally substituted alkyl or cycloalkyl, the alkyl or cycloalkyl is optionally substituted monocyclic or bicyclic C 6 ~C 12Aryl or a monocyclic or bicyclic optionally substituted 5- to 10-membered heteroaryl, preferably optionally substituted phenyl or a monocyclic or bicyclic optionally substituted 5- or 6-membered heteroaryl, more preferably phenyl or optionally substituted pyrazolyl, may be substituted. R 9 Or R 10 When it is an optionally substituted heteroaryl, the heteroaryl is C 1 ~C 6 alkyl, more preferably C 1 ~C 3 alkyl, most preferably methyl, may be substituted. Thus, R 2 is H, COOH, COOCH 3 , CONH 2 , CONHCH 3 , CON(CH 3 ) 2 ,

Chemical formula

Chemical formula

Chemical formula

[0085] R 2 When it is an optionally substituted C 1 ~C 6 alkyl or an optionally substituted C 1 ~C 6 alkoxy, R 2 is an optionally substituted C 1 ~C 3 alkyl or an optionally substituted C1 ~C 3 may be alkoxy, preferably CH 3 or OCH 3 and is.

[0086] R 2 When is a monocyclic or bicyclic optionally substituted 5- to 10-membered heteroaryl, the heteroaryl may be an optionally substituted 5- or 6-membered heteroaryl or an optionally substituted oxazolyl. The heteroaryl may be unsubstituted.

[0087] X may be CR 3 and is.

[0088] Y may be CR 4 and is.

[0089] Z may be CR 5 and is.

[0090] In a preferred embodiment, X is CR 3 and Y is CR 4 and Z is CR 5 and is.

[0091] Alternatively, X may be N. Y may be CR 4 and Z may be CR 5 and is. Thus, in an alternative embodiment, X is N, Y is CR 4 and Z is CR 5 and is. Alternatively, Y may be N and Z may be CR 5 and is. Thus, in a further alternative embodiment, X is N, Y is N, and Z is CR 5 and is. Alternatively, Y may be CR 4 and Z may be N. Thus, in a further alternative embodiment, X is N, Y is CR 4 and Z is N.

[0092] Alternatively, Y may be N. X may be CR3 may also be, and Z is CR 5 may be. Thus, in a further alternative embodiment, X is CR 3 is, Y is N, and Z is CR 5 is.

[0093] Alternatively, Z may be N. X is CR 3 may also be, and Y is CR 4 may be. Thus, in yet another embodiment, X is CR 3 is, Y is CR 4 is, and Z is N.

[0094] R 3 is H, CN, halogen, COOH, CONR 2 , NR 2 , NO 2 , optionally substituted C 1 ~C 6 alkyl, optionally substituted monocyclic or bicyclic C 3 ~C 6 cycloalkyl, optionally substituted monocyclic 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, optionally substituted monocyclic or bicyclic C 6 ~C 12 aryl, optionally substituted monocyclic or bicyclic 5- to 10-membered heteroaryl, optionally substituted monocyclic or bicyclic 3- to 8-membered heterocyclic ring may be. Preferably, R 3 is H, CN, halogen, optionally substituted C 1 ~C 6 alkyl, optionally substituted monocyclic or bicyclic C 6 ~C 12 aryl, optionally substituted monocyclic or bicyclic C 3 ~C 6It is a cycloalkyl or a monocyclic or bicyclic optionally substituted 5- to 10-membered heteroaryl. More preferably, R 3 is H, CN, F, Br, cyclopropyl or an optionally substituted 5- or 6-membered heteroaryl. Most preferably, R 3 is H.

[0095] When R 3 is a halogen, the halogen may be F, Cl, Br or I, and more preferably Br.

[0096] When R 3 is an optionally substituted C 1 ~C 6 alkyl, the optionally substituted C 1 ~C 6 alkyl is preferably an optionally substituted C 1 ~C 3 alkyl, and more preferably an optionally substituted methyl. Preferably, the C 1 ~C 6 alkyl is unsubstituted.

[0097] When R 3 is an optionally substituted C 3 ~C 6 cycloalkyl, the optionally substituted C 3 ~C 6 cycloalkyl is preferably an optionally substituted cyclopropyl. Preferably, the C 3 ~C 6 cycloalkyl is unsubstituted.

[0098] When R 3 is an optionally substituted 5- to 10-membered heteroaryl, the heteroaryl is preferably an optionally substituted 5- or 6-membered heteroaryl, more preferably an optionally substituted pyridinyl or pyrazolyl. The heteroaryl may be unsubstituted or substituted with an optionally substituted C 1 ~C 6 alkyl, an optionally substituted C 1 ~C6 It may be substituted with alkoxy or OH. More preferably, the heteroaryl is unsubstituted or C 1 ~C 6 alkyl, C 1 ~C 6 substituted with one or more of alkoxy or OH. Most preferably, the heteroaryl is unsubstituted or substituted with one or more of methyl, OCH 3 or OH.

[0099] R 4 and R 5 are each independently selected from the group consisting of H, halogen, OH, CN, monocyclic or bicyclic optionally substituted C 6 ~C 12 aryl, optionally substituted C 1 ~C 6 alkyl, optionally substituted C 1 ~C 6 alkoxy, optionally substituted monocyclic or bicyclic 3- to 8-membered heterocyclic ring, or optionally substituted monocyclic or bicyclic C 3 ~C 6 cycloalkyl. More preferably, R 4 and R 5 are H, halogen, OH, CN or optionally substituted C 1 ~C 6 alkyl. Most preferably, R 4 and R 5 are H.

[0100] R 4 and / or R 5 When halogen is halogen, the halogen may be F, Cl, Br or I, more preferably F.

[0101] R 6 is H or optionally substituted C 1 ~C 6 alkyl. Most preferably, R 6 is H.

[0102] R 7 is H, C optionally substituted with 1 ~C 10 alkyl or monocyclic or bicyclic C optionally substituted with 3 ~C 6 cycloalkyl. More preferably, R 7 is C optionally substituted with 1 ~C 10 alkyl or monocyclic or bicyclic C optionally substituted with 3 ~C 6 cycloalkyl. Even more preferably, R 7 is C optionally substituted with 1 ~C 6 alkyl, and most preferably C optionally substituted with 3 ~C 5 alkyl.

[0103] R 7 is H, C optionally substituted with 1 ~C 6 alkyl, C optionally substituted with 2 ~C 6 alkenyl, C optionally substituted with 2 ~C 6 alkynyl, monocyclic or bicyclic C optionally substituted with 6 ~C 12 aryl, monocyclic or bicyclic 5- to 10-membered heteroaryl optionally substituted with, monocyclic or bicyclic C optionally substituted with 3 ~C 6 cycloalkyl, or monocyclic or bicyclic 3- to 8-membered heterocyclic ring optionally substituted with. More preferably, R 7 is C optionally substituted with 1 ~C 6 alkyl, C optionally substituted with 2 ~C 6 alkenyl, C optionally substituted with 2 ~C 6 alkynyl, phenyl optionally substituted with, 5- or 6-membered heteroaryl optionally substituted with, C optionally substituted with 3 ~C6 It is a cycloalkyl or an optionally substituted 3- to 6-membered heterocyclic ring.

[0104] R 7 When R is an optionally substituted alkyl, an optionally substituted alkenyl or an optionally substituted alkynyl, the alkyl, alkenyl or alkynyl may be unsubstituted or may be substituted with one or more substituents selected from the group consisting of halogen, -OH, oxo, optionally substituted C 1 ~C 6 alkoxy, NR 9 R 10 , C(O)R 9 , OC(O)R 9 , COOR 9 , OP(O)(OH) 2 and NR 9 C(O)R 10 . R 9 and R 10 are each independently H, optionally substituted C 1 ~C 6 alkyl, optionally substituted C 2 ~C 6 alkenyl or optionally substituted C 2 ~C 6 alkynyl. More preferably, the alkyl, alkenyl or alkynyl may be unsubstituted or may be substituted with one or more substituents selected from the group consisting of F, -OH, oxo, C 1 ~C 3 alkoxy, C(O)R 9 , OP(O)(OH) 2 and NHC(O)R 10 , wherein R 9 and R 10 are each independently H or C 1 ~C 6 alkyl. Most preferably, the alkyl, alkenyl or alkynyl may be unsubstituted or may be substituted with one or more substituents selected from the group consisting of F, -OH, oxo, OCH 3 , C(O)CH 3 , OP(O)(OH) 2 and NHC(O)CH 3It may be substituted with one or more substituents selected from the group consisting of.

[0105] R 7 When is a heteroaryl optionally substituted, a cycloalkyl optionally substituted or a heterocyclic ring optionally substituted, the heteroaryl, cycloalkyl or heterocyclic ring may be unsubstituted or halogen, -OH, oxo, C optionally substituted 1~6 alkyl, C optionally substituted 1 ~C 6 alkenyl, C optionally substituted 1 ~C 6 alkynyl, C optionally substituted 1 ~C 6 alkoxy, NR 9 R 10 , C(O)R 9 , OC(O)R 9 , COOR 9 , OP(O)(OH) 2 and NR 9 C(O)R 10 It may be substituted with one or more substituents selected from the group consisting of. R 9 and R 10 are each independently H, C optionally substituted 1 ~C 6 alkyl, C optionally substituted 2 ~C 6 alkenyl or C optionally substituted 2 ~C 6 alkynyl. When the heteroaryl, cycloalkyl or heterocyclic ring is directly or indirectly substituted with alkyl, alkenyl and / or alkynyl, this alkyl, alkenyl or alkynyl or each alkyl, alkenyl or alkynyl may be unsubstituted or halogen, -OH And may be substituted with one or more substituents selected from the group consisting of oxo. Preferably, the heteroaryl, cycloalkyl or heterocyclic ring is unsubstituted or F, -OH, oxo, C optionally substituted 1~3 alkyl, C optionally substituted 1 ~C 3Alkenyl, optionally substituted C 1 ~C 3 Alkynyl, C 1 ~C 3 Alkoxy, C(O)R 9 , OP(O)(OH) 2 And NHC(O)R 10 Is substituted with one or more substituents selected from the group consisting of, wherein R 9 And R 10 Are each H or C 1 ~C 6 Alkyl. Most preferably, heteroaryl, cycloalkyl or heterocycle may be unsubstituted or substituted with one or more substituents selected from the group consisting of F, -OH, oxo, CH 3 , CH 2 OH, OCH 3 , C(O)CH 3 , OP(O)(OH) 2 And NHC(O)CH 3 May be substituted with one or more substituents selected from the group consisting of.

[0106] R 7 When is optionally substituted aryl, the aryl may be unsubstituted or halogen, -OH, optionally substituted C 1~6 Alkyl, optionally substituted C 1 ~C 6 Alkenyl, optionally substituted C 1 ~C 6 Alkynyl, optionally substituted C 1 ~C 6 Alkoxy, NR 9 R 10 , C(O)R 9 , OC(O)R 9 , COOR 9 , OP(O)(OH) 2 And NR 9 C(O)R 10 May be substituted with one or more substituents selected from the group consisting of. R 9 And R 10 Are each H, optionally substituted C 1 ~C 6Alkyl, optionally substituted C 2 ~C 6 Alkenyl or optionally substituted C 2 ~C 6 May be alkynyl. When the aryl is directly or indirectly substituted with alkyl, alkenyl and / or alkynyl, this alkyl, alkenyl or alkynyl or each alkyl, alkenyl or alkynyl may be unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, -OH and oxo. Preferably, the aryl is unsubstituted or F, -OH, optionally substituted C 1~3 Alkyl, optionally substituted C 1 ~C 3 Alkenyl, optionally substituted C 1 ~C 3 Alkynyl, C 1 ~C 3 Alkoxy, C(O)R 9 , OP(O)(OH) 2 And NHC(O)R 10 Is substituted with one or more substituents selected from the group consisting of, wherein R 9 And R 10 Are each H or C 1 ~C 6 Alkyl. Most preferably, the aryl may be unsubstituted or substituted with one or more substituents selected from the group consisting of F, -OH, CH 3 , CH 2 OH, OCH 3 , C(O)CH 3 , OP(O)(OH) 2 And NHC(O)CH 3 May be substituted with one or more substituents selected from the group consisting of.

[0107] In some embodiments, R 7 Is butyl, pentyl, cyclohexyl,

Chemical formula

[0108] In some embodiments, L is absent. In alternative embodiments, L is NR 8 is. R 8 is H or optionally substituted C 1 ~C 6 alkyl may be. More preferably, R 8 is H.

[0109] The compound of formula (I) may contain one or more asymmetric centers and thus may exist as optical isomers such as enantiomers and diastereomers. All such isomers and mixtures thereof are included within the scope of the present invention.

[0110] The asymmetric center may occur among any of the groups R and R 1 ~R 9 of.

[0111] It will be understood that the above compounds may exist as enantiomer and diastereoisomer pairs. These isomers also represent further embodiments of the present invention.

[0112] Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of racemates (or racemates of salts or derivatives) using, for example, chiral high performance liquid chromatography (HPLC).

[0113] Alternatively, the racemate (or racemic precursor) may be reacted with a suitable optically active compound, such as an alcohol, or, if the compound of formula (I) contains an acidic or basic moiety, a base or acid such as 1-phenylethylamine or tartaric acid. The resulting mixture of diastereomers can be separated by chromatography and / or fractional crystallization, and one or both of the diastereoisomers can be converted to the corresponding pure enantiomer(s) by means well known to those skilled in the art.

[0114] The chiral compounds (and their chiral precursors) of the present invention may be obtained in enantiomerically enriched form using chromatography on an asymmetric resin, typically HPLC, with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing 0 to 50% by volume, typically 2% to 20% isopropanol, and 0 to 5% by volume of an alkylamine, typically 0.1% diethylamine. Concentration of the eluate gives a concentrated mixture.

[0115] A mixture of stereoisomers can be separated by conventional techniques known to those skilled in the art; see, for example, “Stereochemistry of Organic Compounds” by E.L. Eliel and S.H. Wilen (Wiley, New York, 1994).

[0116] Structure (-L 1 -) a -L 2 - may be referred to as a “linker”.

[0117] L 1 may not be present, or: -A-W-D- [wherein, A is absent or -L 3 -,-X 4 L 3 -,-L 3 X 4 -,-C(O)X 4 ,-L 3 C(O)X 4 ,

Chemical Formula

Chem.

[0118] L 2 may not be present, or: -G-(S-) z [wherein, G is absent or (-G 1 ) a -G 2 -(G 3 -) z and, wherein this G 1 or each G 1 either does not exist independently or is -L 3 -,-(X 4 L 3 ) p -,-(L 3 X 4 ) p -,-L 4 -,-X 4 -,-X 8 -,-X 4 -C(O)-,-C(O)X 4 -

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chem.

Chem.

Chem.

Chem.

[0119] a may be 1, 2, 3, 4 or 5. Preferably, a is an integer between 1 and 3.

[0120] z may be 1, 2, 3, 4 or 5. Preferably, z is an integer between 1 and 3.

[0121] -L 9 - is

Chemical formula

[0122] Preferably, L 1 and L 2 at least one of them exists.

[0123] Preferably, no more than 3 of A, W, D, G and S exist, more preferably no more than 2 or no more than 1 of A, W, D, G and S exists. In some embodiments, none of A, W, D, G and S is absent.

[0124] A is -L 3 - may be. L 3 is optionally substituted C 1 ~C 6 alkylene may be. Preferably, L 3 is optionally substituted C 1 ~C 2 alkylene or optionally substituted C 1 alkylene.

[0125] A is -L 3 X 4 - may be. L 3 is optionally substituted C 1 ~C 6 alkylene may be, preferably -CH 2 CH 2- or -CH 2 CH 2 CH 2 -. Therefore, A is -CH 2 CH 2 O-, -CH 2 CH 2 NH-, -CH 2 CH 2 S-, -CH 2 CH 2 CH 2 O-, -CH 2 CH 2 CH 2 NH- or -CH 2 CH 2 CH 2 S- may also be.

[0126] A is -C(O)X 4 or -L 3 C(O)X 4 may also be. X 4 may be O. L 3 is optionally substituted C 1 ~C 6 alkylene may also be, preferably C 1 ~C 3 alkylene, most preferably -CH 2 -. Therefore, A may be -C(O)O- or -CH 2 C(O)O-.

[0127] A is

Chemical formula

[0128] Therefore, A is

Chemical formula

[0129] Thus, A is

Chemical formula

[0130] A is

Chemical formula

[0131] Thus, A is

Chemical formula

[0132] A is

Chemical formula

Chemical Structure

[0133] Preferably, L 3 is optionally substituted C 1 ~C 2 alkylene or optionally substituted C 1 alkylene is

[0134] A is

Chemical Structure

[0135] X 5 is -O- or -NR 16 - may also be. A is

Chemical Structure

[0136] A is

Chemical Structure

Chemical formula

[0137] A is

Chemical formula

[0138] A is -X 4 L 3 L 4 - or -X 4 L 3 L 4 L 5 - may also be. X 4 may be -O-. L 3 is optionally substituted C 1 ~C 6 may be alkylene, preferably C 1 ~C 2 is alkylene, more preferably -CH 2 - is. L 4 is optionally substituted 3- to 12-membered heterocyclic ring may also be, preferably L 4 is optionally substituted 3- to 8-membered heterocyclic ring may also be, most preferably L 4 is optionally substituted 5- or 6-membered heterocyclic ring. L 4 is

Chemical formula

[0139] A may be -L 3 X 4 L 4 X 5 L 6 -. L 3 and L 6 are independently optionally substituted C 1 ~C 6 alkylene, preferably independently C 1 ~C 2 alkylene. L 3 may be -CH 2 CH 2 -. L 6 may be -CH 2 -. X 4 may be -O-. X 5 may be -O-. L4 may be an optionally substituted 3- to 12-membered heterocyclic ring. L 4is preferably a 6- to 12-membered bicyclic heterocyclic ring, more preferably a 6- to 12-membered spirocyclic heterocyclic ring, which is optionally substituted. Therefore, L 4 may be

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0140] A may be

Chemical formula

Chemical formula

[0141] As described above, W is -L 7 NH-, -L 3 L 7 NH-, -L 7 NHC(O)-, -L 3 L 7 NHC(O)-, -L 7 L 8 NH-, -L 3 L 7 L 8 NH-, -L 7 L 8 NHC(O)-, or -L 3 L 7 L 8 NHC(O)-.

[0142] L 3 is optionally substituted C 1 ~C 6 alkylene or C 1 ~C 6 alkynylene, preferably C 1 ~C 3 alkylene or C 1 ~C 3 alkynylene, and most preferably -CH 2 - or -CH 2 CHCH-.

[0143] Preferably, L 7 and L 8 are each independently monocyclic or bicyclic C 6 ~C 12Aryl; or monocyclic or bicyclic 5- to 10-membered heteroaryl, where the aryl or heteroaryl is optionally substituted with one -OR 18 group.

[0144] L 7 may be a phenyl, naphthalenyl or 2H-chromen-2-onyl group, where each group may be further substituted with one -OR 18 group.

[0145] L 8 is preferably phenyl.

[0146] R 18 is preferably an optionally substituted monocyclic or bicyclic 3- to 8-membered heterocyclic ring. More preferably, R 18 is an optionally substituted 6-membered heterocyclic ring, most preferably an optionally substituted tetrahydropyranyl. Preferably, the heterocyclic ring is substituted with substituents between 1 and 9, more preferably between 2 and 7 or between 3 and 5, and most preferably 4 substituents. The substituents may be selected from C 1 ~C 6 alkoxy, OH and COOH. Preferably, C 1 ~C 6 alkoxy is C 1 ~C 4 alkoxy, more preferably C 1 ~C 2 alkoxy, most preferably -CH 2 OH. Preferably, the heterocyclic ring is substituted with OH groups between 1 and 9, more preferably between 2 and 5, and most preferably 3 OH groups.

[0147] Preferably, the heterocyclic ring has C 1 ~C 6 alkoxy and / or COOH groups between 1 and 9, more preferably C 1 ~C 6 alkoxy and / or COOH groups between 1 and 5, and most preferably 1 C 1 ~C 6It is substituted with an alkoxy or COOH group.

[0148] R 18 is

Chem.

Chem.

[0149] Therefore, W is

Chem.

[0150] D 1 has the general formula

Chem.

[0151] Sc is H, optionally substituted C 1 ~C 6 alkyl, optionally substituted monocyclic or bicyclic C 6 ~C 12 aryl, optionally monocyclic or bicyclic 5- to 10-membered heteroaryl, optionally C 3 ~C 12 cycloalkyl, or optionally monocyclic or bicyclic 3- to 12-membered heterocycle. Preferably, Sc is H, optionally substituted C 1 ~C 6 alkyl, monocyclic or bicyclic C 6 ~C 12 aryl, monocyclic or bicyclic 5- to 10-membered heteroaryl, C 3 ~C 12 cycloalkyl, or monocyclic or bicyclic 3- to 12-membered heterocycle.

[0152] Sc is optionally substituted C 1 ~C 6 In embodiments where the alkyl is, the alkyl is NR 9 R 10 , NHC(NH)NH 2 , OH, COOH, CONR 9 R 10 , SeH, SR 9 , optionally substituted C 6 ~C 12 aryl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted C 3 ~C 6 cycloalkyl or at least one of optionally substituted 3- to 8-membered heterocycles. When the alkyl is NR 9 R 10 substituted, R 10 may be H. R 9 may also be H. Alternatively, R 9 may be C(O)NH 2 . Thus, the alkyl may be substituted with NHC(O)NH 2 . When the alkyl is CONR 9 R 10 substituted, R 10 may be H. R 9 may also be H. Alternatively, R 9 may be C(O)NH 2 . When the alkyl is SR 9 substituted, R 9 is H or C 1 ~C 6 alkyl, preferably R 9 is H or methyl. When the alkyl is optionally substituted C 6 ~C 12 aryl substituted, optionally substituted C 6 ~C 12Aryl is preferably phenyl optionally substituted. The phenyl may optionally be substituted with -OH. When the alkyl is substituted with a 5- to 10-membered heteroaryl optionally substituted, the 5- to 10-membered heteroaryl optionally substituted is preferably imidazolyl or 1H-indolyl.

[0153] Sc is NC(O)R 9 In the embodiment where it is 9 R 1 ~C 6 alkyl may be, preferably methyl.

[0154] Thus, in some embodiments, Sc is H, or NH 2 , NHC(NH)NH 2 , OH, COOH, CONR 9 H, SeH, SH, SCH 3 , phenyl optionally substituted with OH, imidazolyl and 1H-indolyl, and C 1 ~C 6 alkyl optionally substituted with at least one substituent selected from the group consisting of.

[0155] Preferably, Sc is NHC(O)NH 2 or C optionally substituted with COOH 1 ~C 6 alkyl. More preferably, Sc is methyl, isopropyl, -CH 2 CH 2 CH 2 NHC(O)NH 2 or -CH 2 CH 2 COOH.

[0156] Alternatively, D 1 is

Chemical formula

Chemical formula

[0157] q may be an integer between 1 and 10, more preferably between 2 and 7, and most preferably between 3 and 5.

[0158] Therefore, D is [Chemical Formula] may also be.

[0159] G 1 and G 3 may each independently be -L 3 -, -(X 4 L 3 ) p - or -(L 3 X 4 -) p p may be 1 or 2. L 3 is optionally substituted C 1 ~C 15 alkylene, more preferably optionally substituted C 1 ~C 10 alkylene, most preferably optionally substituted C 1 ~C 6 alkylene. L 3 is optionally substituted with one or more C 1 ~C 6 alkyl. Preferably, C 1 ~C 6 alkyl is unsubstituted. Therefore, G 1 and G 3 may each independently be substituted with one or more methyl groups. G 1 and G 3 may each independently be -CH 2 -, -(CH 2 ) 2 -, -(CH 2 ) 3 -, -(CH 2 ) 4-, -(CH 2 ) 5 -, -CH 2 C(Me)H-, CH 2 CMe 2 -, -CH 2 CMe 2 S--CH 2 O-, -CH 2 CH 2 O-, -CH 2 CH 2 OCH 2 CH 2 O- or -(CH 2 ) 5 NH- may also be. G 2 and G 3 In embodiments where G and G 2 do not exist, G is -CH 2 ) 2 -, -(CH 2 ) 3 -, -(CH 2 ) 4 -, -(CH 2 ) 5 -, -CH 2 C(Me)H-, CH 2 CMe 2 -, -CH 2 CMe 2 S- or -(CH 2 ) 5 NH- may also be. G 1 and G 3 exist, but in some embodiments where G 2 does not exist, G may be -CH 2 OCH 2 CH 2 OCH 2 CH 2 O-.

[0160] G 1 and G 3 are each independently

Chemical formula

Chemical formula

Chemical formula

[0161] G 1 and G 3 are each independently, -L 3 X 4 C(O)- or -C(O)L 3 X 4 C(O)L 6 - may also be used.

[0162] Preferably, L 3 is optionally substituted C 1 ~C 15 alkylene, more preferably optionally substituted C 1 ~C 10 alkylene, most preferably optionally substituted C 1 ~C 6 alkylene. The alkylene is optionally substituted C 1 ~C 6 alkyl or -COOH may be substituted. The alkyl may be substituted with NH 2 It may also be substituted. Preferably X 4 is -NH-. L 6 is preferably optionally substituted C 1 ~C 15An alkylene, more preferably an optionally substituted C 1 ~C 10 alkylene, most preferably an optionally substituted C 1 ~C 6 alkylene. The alkylene is an optionally substituted C 1 ~C 6 alkyl or -COOH. The alkyl may be substituted with NH 2 . Alternatively, the alkylene may be unsubstituted. Thus, G 1 and G 3 are each independently, -(CH 2 ) 5 NHC(O)-,

Chemical formula

Chemical formula

Chemical formula

[0163] G 1 and G 3 are each independently, an optionally substituted C 3 ~C 6 cycloalkyl, a monocyclic or bicyclic optionally substituted C 6 ~C 12It may be aryl, a monocyclic or bicyclic optionally substituted 5- to 10-membered heteroaryl, or a monocyclic or bicyclic optionally substituted 5- to 10-membered heterocyclic ring.

[0164] In some embodiments, G is -L 3 X 4 C(O)- may also be. G 2 May not exist. G 3 May be -L 4 -.

[0165] Therefore, G is

Chemical formula

Chemical formula

[0166] G 1 And G 3 Are each independently, -O-, -S-, -NR 9 -, -S(O)-, -SO 2 -, -C(O)L 3 -, -C(O)L 3 C(O)-, -OC(O)-, -C(O)O-, -OC(O)O-, -L 3 OC(O)-, -L 3 C(O)O-, -(OL 3 ) p -, -(L 3 O) p -, -C(O)NR 9 -, -NR 9 C(O)O- or -NR 9 C(O)NR 10 - may also be. In some embodiments, G 1 And G 3 Are each independently, -C(O)L 3 - or -C(O)L 3 C(O)- may also be, wherein L 3is optionally substituted C 1 ~C 6 alkylene, more preferably optionally substituted C 4 ~C 5 alkylene. G 2 and G 3 in embodiments where it is absent, G is -C(O)L 3 - or -C(O)L 3 C(O)- may be, where L 3 is optionally substituted C 1 ~C 6 alkylene, more preferably optionally substituted C 4 ~C 5 alkylene.

[0167] G 1 and / or G 3 may be -L 4 -. Thus, G 1 and / or G 3 may be optionally substituted monocyclic or bicyclic C 6 ~C 12 aryl. G 1 and / or G 3 may be optionally substituted phenyl. G 2 and G 3 in embodiments where it is absent, G is

Chemical formula

[0168] G 1 and / or G 3 may be a poly(ethylene glycol) (PEG) chain between 1 and 25 units. The PEG chain may be a cyclic PEG chain, a branched PEG chain or a linear PEG chain.

[0169] G 1 and / or G 3 may be cyclodextrin. The cyclodextrin may be α, β or γ cyclodextrin.

[0170] G 1 and / or G 3 is -C(O)L 9 L 3 -, -L 9 L 3 C(O)-, -C(O)L 9 L 3 C(O)- or -L 9 L 3 - may be. L 3 is optionally substituted C 1 ~C 6 alkylene may be, more preferably methylene or ethylene. G 1 and / or G 3 is

Chemical formula

Chemical formula

[0171] G 2 is

Chemical formula

Chemical formula

[0172] Alternatively, G 2 is [Chemical formula] may also be, preferably [Chemical formula] and more preferably [Chemical formula] is. In one embodiment, R 20 is -L 9 H, -C(O)L 9 H, -X 4 L 9 H, -X 4 C(O)L 9 H or -C(O)X 4 L 9 H may be. Preferably R 20 is -C(O)X 4 L 9 H. X 4 may be -NH-. L 9 - is [Chemical formula] may be. p may be an integer between 2 and 10, more preferably between 3 and 5, and most preferably 4. Therefore, G 2 is [Chemical formula] It may be, more preferably [Chemical formula] is.

[0173] G 1 and G 3 are each independently optionally substituted C 1 ~C 10 alkylene, more preferably optionally substituted C 1 ~C 6 alkylene may be. G 1 may be ethylene. G 3 may be pentylene. Therefore, G is [Chemical formula] it may be, preferably [Chemical formula] is.

[0174] In an alternative embodiment, R 20 is optionally substituted C 1 ~C 6 alkyl, optionally substituted C 2 ~C 6 alkenyl or optionally substituted C 2 ~C 6 alkynyl may be. More preferably, R 20 is optionally substituted C 1 ~C 3 alkyl, most preferably optionally substituted methyl. Preferably, alkyl, alkenyl or C 2 ~C 6 alkynyl is substituted with -NR 9 R 10 Preferably, R 9 and R10 is H. Therefore, G 2 is [Chemical formula] may be, more preferably [Chemical formula] is.

[0175] G 1 is optionally substituted C 1 ~C 10 alkylene, more preferably optionally substituted C 1 ~C 6 alkylene may be. G 1 may be ethylene. G 3 may not exist. Therefore, G is [Chemical formula] may be, preferably [Chemical formula] is.

[0176] In an alternative embodiment, G 2 is [Chemical formula] may be, in the case of -L 3 -, one G 4 does not exist. -L 3 - is optionally substituted C 1 ~C 12 alkylene, more preferably optionally substituted C 1 ~C 6 alkylene, most preferably methylene or ethylene may be. Therefore, G 2 is [Chemical formula] It may be. R 20 is optionally substituted C 1 ~C 6 alkyl, and in some embodiments is methyl. Thus, G 2 is [Chemical formula] It may be.

[0177] G 1 and G 3 may not exist. Thus, in some embodiments, G is [Chemical formula] It may be.

[0178] In some embodiments, G 2 is [Chemical formula] It may be. Each G 4 may independently not exist, or -L 3 X 4 C(O)-, -C(O)X 4 L 3 -, -L 3 C(O)X 4 -, -X 4 C(O)L 3 -, -X 4 L 3 C(O)X 5 -, -X 4 C(O)L 3 X 5 -, -L 3 X 4 L 6 C(O)X 5 - and -X 4 C(O)L 3 X 5L 3 - may be selected from the group consisting of. At least one G 4 group is -X 4 C(O)L 3 - may be. X 4 may be -NH-. -L 3 - is optionally substituted C 1 ~C 12 alkylene, more preferably optionally substituted C 1 ~C 6 alkylene, most preferably methylene or ethylene may be. At least one G 4 group is -L 3 X 4 L 6 C(O)X 5 - may be. Preferably, at least two or at least three G 4 groups are -L 3 X 4 L 6 C(O)X 5 - is. Each X 4 may be -NH-. Each X % may be -NH-. Each -L 3 - and -L 6 - are independently optionally substituted C 1 ~C 12 alkylene, more preferably optionally substituted C 1 ~C 6 alkylene, most preferably methylene or ethylene may be. Therefore, G 2 is

Chemical formula

[0179] Each G 1 and G 3 do not have to exist independently, or -L 3 -, -L 9 -, -X 4 L 9 -, -L 9 L 3 -, -L 3 X4 C(O)-, -L 3 C(O)X 4 , -L 3 X 4 C(O)L 6 - or -L 3 C(O)X 4 L 6 - may also be used.

[0180] The G group may contain at least one G 1 group. Therefore, a may be 1, 2, or 3. Preferably, a is 1. G 1 is, -L 9 - or -X 4 L 9 - may also be used. Preferably, G 1 is -X 4 L 9 -. Preferably, X 4 is -O-. Preferably, -L 9 - is [Chemical formula] and p is an integer between 1 and 10, more preferably between 2 and 5, and most preferably p is 3. Therefore, G 1 is [Chemical formula] may also be used.

[0181] The G group may contain at least one, at least two, or at least three G 3 groups. Therefore, z may be 1, 2, or 3. Preferably, z is 3. G 3 is, -L 3 X 4 C(O)-, -L 3 C(O)X 4 , -L 3 X 4 C(O)L 6 - or -L 3 C(O)X 4 L 6- may be. Preferably, G 3 is -L 3 X 4 C(O)L 6 - is. -L 3 - and -L 6 - are, independently, optionally substituted C 1 ~C 12 alkylene, more preferably optionally substituted C 1 ~C 6 alkylene, most preferably C 2 ~C 5 alkylene may be. Preferably, X 4 is -NH-. Therefore, each G 3 is

Chemical formula

[0182] Therefore, in some embodiments, G is

Chemical formula

[0183] G 2 is

Chemical formula

Chemical formula

Chemical formula

[0184] Preferably, R 20 is -C(O)X 4 L 9 H. Preferably, -L 9 - is

Chemical formula

[0185] Therefore, G 2 is

Chemical formula

[0186] G 1 may not exist. G 3 is -L 3 -, -L 9 -, or -L 9 L 3 - may be. Preferably, -L 9 - is [Chemical formula] It is, and p is an integer between 1 and 10, more preferably between 2 and 5, and most preferably p is 4. -L 3 - is optionally substituted C 1 ~C 12 alkylene, more preferably optionally substituted C 1 ~C 6 alkylene, and most preferably ethylene may be.

[0187] Therefore, G is [Chemical formula] It may be, more preferably [Chemical formula] It is.

[0188] S is -L 3 - may be. L 3 is optionally substituted C 1 ~C 10 alkylene, more preferably optionally substituted C 1 ~C 6 alkylene may be. Preferably, the alkylene is unsubstituted.

[0189] S is -X 4 L 3 - may also be. X 4 may also be -NH-. L 3 is C 1 ~ C 12 alkylene optionally substituted with, more preferably C 1 ~ C 6 alkylene optionally substituted with, most preferably methylene or ethylene may also be. Therefore, S may be -NHCH 2 - may also be.

[0190] S is optionally substituted monocyclic or bicyclic C 6 ~ C 12 aryl, optionally substituted monocyclic or bicyclic 5- to 10-membered heteroaryl, optionally substituted C 3 ~ C 12 cycloalkyl, or optionally substituted monocyclic or bicyclic 3- to 12-membered heterocyclic ring may also be. Preferably, S is optionally substituted monocyclic or bicyclic 5- to 10-membered heteroaryl or optionally substituted monocyclic or bicyclic 3- to 12-membered heterocyclic ring. More preferably, S is optionally substituted monocyclic or bicyclic 5-membered heteroaryl or optionally substituted monocyclic or bicyclic 5-membered heterocyclic ring. In some embodiments, G is a succinimidyl group, a triazolyl group or a tetrazolyl group. The triazolyl group may be a 1,2,3-triazolyl group. Therefore, S is [Chemical formula] may also be, wherein the wavy line and the asterisk indicate the bond of the group S to the targeting moiety T. When two bonding sites are shown, it can be understood that S may be bonded to the same targeting moiety at two separate points.

[0191] S may also be -O-, -NH-, -S- or -C(O)-.

[0192] S may be L 3 or L 3 is optionally substituted C 1 ~C 15 alkylene, more preferably optionally substituted C 1 ~C 10 alkylene, most preferably optionally substituted C 1 ~C 6 alkylene. In some embodiments, the alkylene is unsubstituted.

[0193] S is -X 4 C(X 9 )L 3 -, -X 4 C(X 9 )-, -X 4 C(X 9 )L 3 C(O)-, -X 8 L 3 -, -X 4 X 8 L 3 - or -X 8 L 3 C(O)-. X 4 may be NH. X 9 may be O or S. L 3 is optionally substituted C 1 ~C 6 alkylene, more preferably optionally substituted C 1 ~C 2 alkylene. The alkylene may be substituted with COOH or COOH or SO 2 R 9 optionally substituted C 1 ~C 6 alkyl. Thus, S is

Chemical formula

[0194] S is [Chemical formula] may also be. Preferably, X 4 and X 5 is O.

[0195] S is [Chemical formula] may also be.

[0196] Preferably, X 4 is O or NH. Therefore, S is [Chemical formula] may also be, wherein the wavy line and the asterisk indicate the bond of the group S with the targeting moiety T.

[0197] S may be -L 4 L 3 -. L 3 is optionally substituted C 1 ~C 6 alkylene, more preferably C 1 ~C 2 alkylene may also be. L 4 is optionally substituted monocyclic or bicyclic C 6 ~C 12 aryl or optionally substituted monocyclic or bicyclic 5- to 10-membered heteroaryl may also be, preferably phenyl or 6-membered heteroaryl. Therefore, S is [Chemical formula] may also be, wherein the wavy line and the asterisk indicate the bond of the group S with the targeting moiety T.

[0198] S may be -L 4 L 3 L 5 C(O)- may also be. L3 is optionally substituted C 1 ~C 6 alkylene, more preferably C 1 ~C 2 alkylene, most preferably methylene. L 4 is optionally substituted C 3 ~C 12 cycloalkyl or an optionally substituted monocyclic or bicyclic 3- to 12-membered heterocyclic ring, more preferably optionally substituted C 3 ~C 6 cycloalkyl or an optionally substituted monocyclic or bicyclic 3- to 6-membered heterocyclic ring, even more preferably an optionally substituted monocyclic or bicyclic 5-membered heterocyclic ring, and most preferably succinimidyl. L 5 is optionally substituted C 3 ~C 12 cycloalkyl or an optionally substituted monocyclic or bicyclic 3- to 12-membered heterocyclic ring, more preferably optionally substituted C 3 ~C 6 cycloalkyl or an optionally substituted monocyclic or bicyclic 3- to 6-membered heterocyclic ring, and most preferably cyclohexyl.

[0199] Therefore, S is

Chemical Formula

[0200] S may be -L 3 C(O)L 4 C(O)-. L 3 is optionally substituted C 1 ~C 6 alkylene, more preferably C 1 ~C 2 alkylene, most preferably methylene. L 4 is optionally substituted C 3 ~C 12It may be a cycloalkyl or an optionally substituted monocyclic or bicyclic 3- to 12-membered heterocyclic ring, more preferably an optionally substituted C 3 ~C 6 It may be a cycloalkyl or an optionally substituted monocyclic or bicyclic 3- to 6-membered heterocyclic ring, and most preferably a monocyclic or bicyclic 6-membered heterocyclic ring. Therefore, S is

Chemical formula

[0201] In a preferred embodiment, A may be absent or -L 3 X 4 -, -C(O)X 4 -, -L 3 C(O)X 4 ,

Chemical formula

Chemical formula

[0202] In the embodiment where A is -L 3 X 4 -, L 3 may be an optionally substituted C 1 ~C 12 alkylene, preferably C 1 ~C 6 alkylene, more preferably -CH 2 -, -CH 2 CH 2 - or -CH 2 CH 2 CH 2 -. Preferably X 4 is O. Therefore, A is -CH2 O-, -CH 2 CH 2 O- or -CH 2 CH 2 CH 2 may be O-.

[0203] In an embodiment where A is -C(O)X 4 - or -L 3 C(O)X 4 in which case, X 4 may be -O-. L 3 is optionally substituted C 1 ~C 6 alkylene, preferably C 1 ~C 3 alkylene, and most preferably -CH 2 -. Thus, A may be -C(O)O- or -CH 2 C(O)O-.

[0204] When A is

Chemical formula

Chemical formula

[0205] In an embodiment where A is -X 4 L 3 L 4 - in which case, X 4 is preferably -O-. L 3 is an optionally substituted C 1 ~C 6 alkylene, preferably C 1 ~C 2 alkylene, more preferably -CH 2 -. L 4 is an optionally substituted 3- to 12-membered heterocyclic ring, preferably L 4may be an optionally substituted 3- to 8-membered heterocyclic ring, most preferably L 4 is an optionally substituted 5- or 6-membered heterocyclic ring. L 4 is

Chemical formula

[0206] Therefore, A is

Chemical formula

[0207] When A is

Chemical formula

Chemical formula

[0208] In a preferred embodiment, W is absent or -L 3 L 7 is NH-. More preferably, W is

Chemical formula

[0209] In a preferred embodiment, D is absent or -(D 1 ) q C(O)-, where q is an integer between 2 and 10, more preferably between 3 and 4. Preferably, D 1 has the general formula

Chemical formula

Chemical formula

[0210] In a preferred embodiment, S is -L 3 -, -X 4 -, -X 4 L 3 -, -C(X 9 )-, -L 4 -, -X 4 C(X 9 )L 3 -, -X 8 L 3 -, -X 4 X 8 L 3 -,

Chemical formula

[0211] When S is -X 4 L 3 - in the embodiment, X 4 may be -NH-. L 3 is C 1 ~C 12 alkylene optionally substituted with, more preferably C 1 ~C 6 alkylene optionally substituted with, most preferably methylene or ethylene may be.

[0212] When S is -L 4 - in the embodiment, S may be a monocyclic or bicyclic 5- to 10-membered heteroaryl optionally substituted or a monocyclic or bicyclic 3- to 12-membered heterocyclic ring optionally substituted. More preferably, S is a monocyclic or bicyclic 5-membered heteroaryl optionally substituted or a monocyclic or bicyclic 5-membered heterocyclic ring optionally substituted.

[0213] When S is -X 4 C(X 9 )L 3 -, -X 8 L 3 - or -X 4 X 8 L 3 - in the embodiment, X 4 may be NH. X 9 may be O. C 8 may be -SO 2 -. L 3 is optionally substituted C 1 ~C 6 alkylene, more preferably optionally substituted C 1 ~C 2 alkylene may be. The alkylene may be unsubstituted or substituted with COOH or C optionally substituted with COOH 1 ~C 6 alkyl may be substituted.

[0214] S is -L 4 L 3 In an embodiment where it is -, L 3 is optionally substituted C 1 ~C 6 alkylene, more preferably C 1 ~C 2 alkylene. L 4 is optionally substituted monocyclic or bicyclic C 6 ~C 12 aryl or optionally monocyclic or bicyclic 5- to 10-membered heteroaryl, preferably phenyl or 6-membered heteroaryl.

[0215] 2 ) 5 -, -NH-, -S-, -C(O)-, -NHCH 2 -,

Chemical formula

[0216] A, W, D, G, and S may all be present. In some embodiments, a is 1 and z is 1. Accordingly, the linker is

Chemical formula

[0217] All of W, D, G, and S may be present. A may be absent. In some embodiments, a is 1 and z is 1. Thus, the linker is [Chemical formula] JPEG0007691974000128.jpg113149 It may also be the case that, in the formula, the wavy line and the asterisk indicate the binding of the linker to the targeting moiety T, and the absence of the wavy line and the asterisk indicates the binding of the linker to the active compound C.

[0218] All of A, G, and S may be present. D may be absent. W may be absent. In some embodiments, a is 1 and z is 1. Thus, the linker is [Chemical formula] It may also be the case that, in the formula, the wavy line and the asterisk indicate the binding of the linker to the targeting moiety T, and the absence of the wavy line and the asterisk indicates the binding of the linker to the active compound C.

[0219] All of A, W, G, and S may be present. D may be absent. In some embodiments, a is 1 and z is 1. Thus, the linker is [Chemical formula] JPEG0007691974000131.jpg77149 It may also be the case that in the formula, the wavy line and the asterisk indicate the binding of the linker to the targeting moiety T, and the absence of the wavy line and the asterisk indicates the binding of the linker to the active compound C.

[0220] Both A and G may be present. D may be absent. W may be absent. S may be absent. In some embodiments, a is 1 and z is 1. Thus, the linker is

Chemical formula

[0221] In some embodiments, a is 1 and z is 2 or 3. Thus, a may be 1 and z may be 3. In some embodiments, both G and S may be present. A may be absent. D may be absent. W may be absent. Thus, the linker is

Chemical formula

[0222] In some embodiments, a is 2 or 3 and z is a. Thus, a may be 2 and z may be a. In some embodiments, all of W, D, G, and S may be present. A may be absent. Thus, the linker is

Chemical formula

[0223] Linkers are known to those skilled in the art as "stable" linkers that are resistant to degradation both intracellularly and in the systemic circulation, or "cleavable" linkers or "conditionally labile" linkers that are designed to degrade intracellularly and / or in the systemic circulation after a defined trigger event that can be a change in metabolic processes such as pH or ester or amide hydrolysis. The conjugates of the present invention may include two or more cleavage elements selected from acid-induced cleavage, protease-induced cleavage (e.g., peptide linkers cleaved by intracellular proteases such as lysosomal proteases or endosomal proteases, see Trout et al., 1982, PNAS USA, 79, 626-629), esterase-induced cleavage, glycosidase-induced cleavage, glucuronidase-induced cleavage, phosphodiesterase-induced cleavage, phosphatase-induced cleavage, lipase-induced cleavage, or disulfide bond cleavage. Certain intracellular compartments such as endosomes and lysosomes have an acidic pH (pH 4.5) and provide conditions suitable for cleaving acid-labile linkers. Specific hydrolysis processes have been described, such as the protease cleavage of dipeptides, e.g., the valine-citrulline dipeptide moiety contained in the clinically precedent ADC brentuximab vedotin, phenylalanine-lysine dipeptide, maleimidocaproyl or maleimidocaproyl-valine-citrulline linkers (Ducry et al., Bioconj.Chem, 2010, 21, 5-13). The self-destructive group para-aminobenzyloxycarbonyl (PABC) can also be incorporated, for example, into a maleimidocaproyl-valine-citrulline-PABC linker as part of a linker structure that will detach from the conjugate upon receiving a suitable trigger event to release the parent structure (Carl et al., J.Med.Chem., 1981, 24, 479 and Chakravarty et al., J.Med.Chem., 1983, 26, 638). Other linkers include linkers that are cleaved at a specific pH or pH range, such as the hydrazone in gemtuzumab ozogamicin.

[0224] The non-cleavable linker may be protease-insensitive. Non-cleavable linkers include those found in the clinically precedent ADC trastuzumab emtansine, where intracellular degradation of the conjugate is required to release the active drug C. See, for example; Wong, Chemistry of Protein Conjugation and Cross-Linking, CRC Press Inc., Boca Raton, 1991.

[0225] In that more than one small molecule C may be covalently attached to the targeting moiety through a branched polyfunctional unit, the linker may be dendrimeric in nature (U.S. Patent Application Publication No. 2006 / 116422, U.S. Patent Application Publication No. 2005 / 271615). Dendrimeric linkers can increase the molar ratio of drug to targeting group, which is relevant to the potency of the conjugate. Thus, if the targeting group contains, for example, only a single thiol group, multiple small molecules can be attached through a dendrimeric or branched linker.

[0226] The linker may be attached to the targeting moiety T in various ways through the reactive groups of the targeting moiety at any suitable available position of the targeting moiety. Examples of suitable reactive groups include surface lysine, oxidized carbohydrates, and cysteine residues. Suitable reactive groups will be known to those skilled in the art. For example, various antibody-drug conjugate (ADC) conjugation techniques are known in the art, including via alkylation, reductive amination, transesterification, amidation, and thiol Michael addition. The resulting linkages include hydrazone, disulfide, maleimide, succinimide, and peptide-based functional groups. For example, a thiol group, or a cysteine residue, may be attached to the linker or spacer group via a maleimide group. Alternative conjugation chemistries include lysine-reactive groups such as succinyl or HOBt esters, pentafluorophenyl esters, β-lactam amides, isocyanates, and isothiocyanates; azide-reactive groups such as alkynes and strained alkynes; cysteine-reactive groups such as maleimide, α-haloacetamides, pyridyldisulfides, and vinyl sulfoxides; and ketone-reactive groups such as hydroxylamine, hydrazine, and acyl hydrazides.

[0227] In some embodiments, the number of conjugated drug / linker moieties per antibody molecule ranges from 1 to 10. The drug-to-antibody ratio (DAR) is typically from 1 to 10, and may be from 2 to 5 or from 2 to 3. Thus, b may be 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0228] Such conjugates may be designed to specifically target certain cell types or tumor types via a targeting moiety. Thus, the targeting moiety may be configured to direct the compound of formula (I) to a specific cell type or tumor type, thereby delivering the STING modulator in a cell-specific manner. Accordingly, the conjugate can be used as appropriate in a therapeutic setting. The principle of this targeted delivery is well known to those skilled in the art to be closely related to ADC technology, as described, for example, in Polakis, P., Pharmacol. Revs, 2016, 68, 3-19 and Beck et al., Nat. Revs. Drug Disc., 2017, 16, 315-337. The conjugate may then be taken up intracellularly or intratumorally through receptor-mediated endocytosis. The target antigen or receptor may be part of a cell or tumor, or may be an extracellular matrix protein within the microenvironment of a cell or tumor. Once inside the cell or tumor, one or more specific peptide sequences within the conjugate can be hydrolytically cleaved by one or more cell or tumor proteases. For example, tumor-associated proteases, cathepsin B, C or D, or plasmin proteases that cleave the linker and release the active compound either intracellularly in the target cell or within the tumor microenvironment of the target cell. The active drug then freely moves intracellularly or within the microenvironment, thereby contacting the STING protein and subsequently modulating the STING protein. In some embodiments, the active drug can be cleaved from the targeting moiety outside the cell or tumor, and the active drug can then act on the cell surface or enter the cell or tumor.

[0229] T is a targeting moiety and may include an antibody, antibody fragment, nucleic acid-based molecule, carbohydrate, peptide, modified peptide or small molecule.

[0230] In one embodiment, T may be configured to target a tumor antigen.Therefore, T may be configured to target human epidermal growth factor receptor (EGFR), plasminogen activator, cytotoxic T lymphocyte-associated antigen (CTLA) such as CTLA-4, vascular endothelial growth factor (VEGF), neurotrophic factors such as BDNF, fibroblast growth factor receptor (FGFR), nerve growth factor, platelet-derived growth factor (PDGF), transforming growth factor (TGF), tissue factor (TF), EpCAM, CEACAM5, CEACAM6, colorectal specific antigen p, FLT3, PSA, PSMA, PSCA, STEAP, BCMA, CEA, folate receptor, cathepsin D, estrogen receptor, progesterone receptor, NCA-95, NCA-90, A3, A33, Ep-CAM, CD33 / CD30 / CD37 / CD52 / CD66e, CD56 / CD74 / CD79 / CD22 receptor, SLC34A2 gene product, SLC44A4, mesothelin protein, integrin αvβ3, PD-1, PD-L1, EGP-1, EGP-2, EphA2 tyrosine kinase, mucin cell-surface antigen such as MUC16, hLewis Y antigen, carbonic anhydrase IX, 5T4, EFNA4, DLL4, Axl, B7, ALK, Fyn3, HLA, HIF, IGF, CC49, AFP, NaPi2b, brc-abl, caspase-8, guanylyl cyclase C, CD19, CD20, CD21, CD22, CD40, CD79a, CD79b, CD98, CD123, PTK7, CDK4, RANTES, CD44, CD48, CD133, CD70, CD72, CD74, CD166, c-kit, cMet, ErbB2 / Her2, ErbB3 / Her3, ErbB4 / Her4, OX40, p53, alpha-fetoprotein, R1, PAP, PAX3, PAX5, Ras, Rho, ROR2, nectin-4, E-cadherin, P-cadherin, cadherin-6, LRRC15, BMPR1B, E16, Sema 5b, ETBR, MSG783, Trop2, TRPM4, ENPP3, SLITRK6, LIV-1, CRIPTO, FcRH1, IRTA2, TENB2, FcRH2, NCA, MDP, IL30Rα, ERK, gpNMB, LYPD3, GEDA, CXCR5, HLA-DOB, P2X5, LY64 or LY75.

[0231] In a preferred embodiment, T is configured to target Her2. HER2, also sometimes called Erbb2, can be understood to be a biomarker for breast cancer, gastric cancer, ovarian cancer, and / or lung cancer.

[0232] In a preferred embodiment, T is an antibody or a fragment thereof. Certain antibodies have conventionally been applied in the field of immuno-oncology. Exemplary anti-PD1 antibodies include pembrolizumab (MK-3475, Merck), nivolumab (BMS-936558, Bristol-Myers Squibb), AMP-224 (Merck), and pidilizumab (CT-011, Curetech Ltd.). Known anti-PDL1 antibodies include MDX-1105 (Medarex), MEDI4736 (Medimmune), MPDL4280A (Genentech), and BMS-936559 (Bristol-Myers Squibb). Exemplary anti-CTLA4 antibodies include ipilimumab (Yervoy, Bristol-Myers Squibb) and tremelimumab (Pfizer). Exemplary anti-ErbB2 / Her2 antibodies include trastuzumab (Roche), pertuzumab (Genentech), margetuximab (Macrogenics), and HT-19 (Mersana Therapeutics). In a preferred embodiment, T is trastuzumab or a fragment or derivative thereof.

[0233] As an example, conjugates containing anti-HER2 antibodies can specifically target HER2-positive cancer cells or tumors. Trastuzumab (Herceptin or Herclon) is a humanized monoclonal antibody that binds to the membrane-proximal portion of the extracellular domain of the HER2 receptor (Hudis et al., N. Engl. J. Med., 2007, 357, 39-51; Cho et al., Nature, 2003, 421, 756-760). Trastuzumab received US FDA approval in September 1998 for the treatment of metastatic breast cancer in patients whose tumors overexpress HER2 and who have received one or more chemotherapy regimens for their metastatic disease.

[0234] The present invention extends to both whole antibodies and antigen-binding fragments or regions of the corresponding full-length antibodies.

[0235] The antibody or its antigen-binding fragment may be monovalent, bivalent or multivalent. A monovalent antibody is a dimer (HL) containing a heavy (H) chain associated with a light (L) chain by a disulfide bridge. A bivalent antibody is a tetramer (H2L3) containing two dimers associated by at least one disulfide bridge. Multivalent antibodies may also be prepared, for example, by binding multiple dimers. The basic structure of an antibody molecule consists of two identical light chains and two identical heavy chains that associate non-covalently and are linked by disulfide bonds. Each heavy and light chain contains an amino-terminal variable region of approximately 110 amino acids and a constant sequence for the remainder of the chain. The variable region forms the antigen-binding site of the antibody molecule and contains several hypervariable regions, or complementarity-determining regions (CDRs), that determine the specificity of the antibody molecule for an antigen or its variant or fragment (e.g., epitope). On either side of the CDRs of the heavy and light chains are framework regions, relatively conserved sequences of amino acids that fix and orient the CDRs. Antibody fragments may include bispecific antibodies (BsAbs) or chimeric antigen receptors (CARs).

[0236] The constant region consists of one of five heavy chain sequences (μ, γ, ζ, α, or ε) and one of two light chain sequences (κ or λ). The heavy chain constant region sequence determines the antibody isotype and the effector function of the molecule.

[0237] Preferably, the antibody or antigen-binding fragment thereof is isolated or purified.

[0238] In one preferred embodiment, the antibody or antigen-binding fragment thereof comprises a polyclonal antibody, or an antigen-binding fragment thereof. The antibody or antigen-binding fragment thereof may be produced in rabbits, mice or rats.

[0239] In another preferred embodiment, the antibody or antigen-binding fragment thereof comprises a monoclonal antibody or an antigen-binding fragment thereof. Preferably, the antibody is a human antibody. As used herein, the term "human antibody" can mean an antibody such as a monoclonal antibody that contains substantially the same heavy and light chain CDR amino acid sequences found in a specific human antibody that exhibits immune specificity. An amino acid sequence that is substantially the same as a heavy or light chain CDR exhibits a substantial amount of sequence identity when compared to the reference sequence. Such identity is either determinatively known or can be recognized as representing the amino acid sequence of a specific human antibody. Substantially the same heavy and light chain CDR amino acid sequences can have, for example, minor amino acid modifications or conservative substitutions.

[0240] The term "human monoclonal antibody" can include monoclonal antibodies produced by recombinant methods such as phage libraries, lymphocytes or hybridoma cells that contain substantially or entirely human CDR amino acid sequences.

[0241] The term "humanized antibody" can mean an antibody from a non-human species (e.g., mouse or rabbit) whose protein sequence has been modified to increase its similarity to the protein sequence of antibodies naturally produced in humans.

[0242] The antibody may be a recombinant antibody. The term "recombinant human antibody" may include human antibodies made using recombinant DNA technology.

[0243] The term "antigen-binding region" may mean the region of an antibody that has specific binding affinity for a target antigen of the antibody or a variant or fragment thereof. Preferably, the fragment is an epitope. The binding region may be a hypervariable CDR or a functional portion thereof. The term "functional portion" of a CDR may mean the sequence within the CDR that exhibits specific affinity for the target antigen. The functional portion of a CDR may include a ligand that specifically binds to the target antigen or a fragment thereof.

[0244] The term "CDR" may mean the hypervariable regions of the heavy and light variable chains. One, two, three or more CDRs may be present in each of the heavy and light chains of an antibody. Usually, when composed together, at least three CDRs that form the antigen-binding site, i.e., the three-dimensional binding site to which the antigen binds or specifically reacts, are present in each chain. However, it is hypothesized that some antibodies may have four CDRs in the heavy chain.

[0245] The definition of a CDR also includes an overlap or subset of amino acid residues when compared to each other. The exact number of residues encompassing a particular CDR or a functional portion thereof will vary depending on the sequence and size of the CDR. One of ordinary skill in the art can routinely determine which residues are included in a particular CDR given the amino acid sequence of the variable region of an antibody.

[0246] The term "functional fragment" of an antibody can mean a part of an antibody that retains functional activity. The functional activity can be, for example, antigen-binding activity or specificity. The functional activity can also be, for example, an effector function provided by the antibody constant region. The term "functional fragment" is also intended to include fragments produced, for example, by protease digestion or reduction of a human monoclonal antibody and recombinant DNA methods known to those skilled in the art. Functional fragments of a human monoclonal antibody include, for example, individual heavy or light chains such as VL, VH, and Fd and fragments thereof; monovalent fragments such as Fv, Fab, and Fab'; F(ab')[ 2 [ and other divalent fragments; single-chain Fv (scFv); and Fc fragments. [

[0247] [ [ The term "VL fragment" can mean a fragment of the light chain of a human monoclonal antibody that includes all or part of the variable region of the light chain that includes the CDRs. The VL fragment can further include the light chain constant region sequence. [

[0248] [ [ The term "VH fragment" can mean a fragment of the heavy chain of a human monoclonal antibody that includes all or part of the variable region of the heavy chain that includes the CDRs. [

[0249] [ [ The term "Fd fragment" can mean the variable region of the heavy chain bound to the first heavy chain constant region, i.e., VH and CH-1. The "Fd fragment" does not include the light chain or the second and third constant regions of the heavy chain. [

[0250] [ [ The term "Fv fragment" can mean a monovalent antigen-binding fragment of a human monoclonal antibody that includes all or part of the variable regions of the heavy and light chains and in which the constant regions of the heavy and light chains are absent. The variable regions of the heavy and light chains include, for example, the CDRs. For example, the Fv fragment includes all or part of the amino-terminal variable regions of both the heavy and light chains of about 110 amino acids. [

[0251] [ [The term "Fab fragment" can mean a monovalent antigen-binding fragment of a human monoclonal antibody that is larger than an Fv fragment. For example, a Fab fragment includes the variable regions, and all or part of the first constant domains of the heavy and light chains. Thus, a Fab fragment additionally includes, for example, about 110 to about 220 amino acid residues of the heavy and light chains.

[0252] The term "Fab' fragment" can mean a monovalent antigen-binding fragment of a human monoclonal antibody that is larger than a Fab fragment. For example, a Fab' fragment includes all of the light chain, all of the variable region of the heavy chain, and all or part of the first and second constant domains of the heavy chain. For example, a Fab' fragment can additionally include some or all of amino acid residues 220 to 330 of the heavy chain.

[0253] 「F(ab’) 2 The term "fragment" can mean a bivalent antigen-binding fragment of a human monoclonal antibody. F(ab’) 2 The fragment includes, for example, all or part of the variable regions of two heavy chains and two light chains, and can further include all or part of the first constant domains of the two heavy chains and two light chains.

[0254] The term "single-chain Fv (scFv)" can mean a fusion of the variable regions of the heavy (VH) and light (VL) chains connected by a short linker peptide.

[0255] The term "bispecific antibody (BsAb)" can mean a bispecific antibody that includes two scFvs linked to each other by a shorter linker peptide.

[0256] Those skilled in the art know that the exact boundaries of the antibody fragments are not important as long as the fragments maintain functional activity. Using well-known recombinant methods, those skilled in the art can manipulate the polynucleotide sequence to express a functional fragment that includes any endpoints desired for a particular application. The functional fragments of an antibody can include, or consist of, fragments that include substantially the same heavy and light chain variable regions as a human antibody.

[0257] The antigen-binding fragment may comprise or consist of any fragment selected from the group consisting of VH, VL, Fd, Fv, Fab, Fab’, scFv, F(ab’) 2 and may include or consist of any one of the fragments selected from the group consisting of Fc fragments.

[0258] The antigen-binding fragment may comprise or consist of any one of the antigen-binding region sequences of VL, any one of the antigen-binding region sequences of VH, or a combination of the VL and VH antigen-binding regions of a human antibody. The appropriate number and combination of VH and VL antigen-binding region sequences can be determined by those skilled in the art according to the desired affinity and specificity and the intended use of the antigen-binding fragment. Functional fragments or antigen-binding fragments of antibodies can be readily prepared and isolated using methods well known to those skilled in the art. Such methods include, for example, proteolytic methods, recombinant methods, and chemical synthesis. Proteolytic methods for the isolation of functional fragments include the use of human antibodies as starting materials. Enzymes suitable for the proteolysis of human immunoglobulins can include, for example, papain and pepsin. Suitable enzymes can be readily selected by those skilled in the art depending on, for example, whether a monovalent or divalent fragment is required. For example, papain cleavage yields two monovalent Fab’ fragments that bind antigen and an Fc fragment. Pepsin cleavage yields, for example, a divalent F(ab’) fragment. The F(ab’) 2 fragment of the present invention can be further reduced using, for example, DTT or 2-mercaptoethanol to produce two monovalent Fab’ fragments.

[0259] Functional fragments or antigen-binding fragments of antibodies produced by proteolysis can be purified by affinity and column chromatography procedures. For example, undigested antibodies and Fc fragments can be removed by binding to protein A. In addition, functional fragments can be purified by their charge and size, for example, using ion exchange and gel filtration chromatography. Such methods are well known to those skilled in the art.

[0260] Antibodies or antigen-binding fragments thereof may be made using techniques well known in the art. For example, by recombinant methodologies (see U.S. Patent No. 4,816,567), hybridoma technology (Kohler et al., Nature, 1975, 256, 495), phage display technology (e.g., see Clackson et al., Nature, 1991, 352, 624 and Marks et al., J. Mol. Biol., 1991, 222, 581), synthetic techniques or combinations of such techniques. Preferably, polynucleotides encoding the desired regions of the antibody heavy and light chains are first isolated. Such regions may include, for example, all or part of the variable regions of the heavy and light chains. Preferably, such regions may specifically include the antigen-binding regions of the heavy and light chains, preferably the antigen-binding site, most preferably the CDRs.

[0261] Polynucleotides encoding antibodies or antigen-binding fragments thereof according to the present invention can be made using methods known to those skilled in the art. Polynucleotides encoding antibodies or antigen-binding fragments thereof can be synthesized directly by methods of oligonucleotide synthesis known in the art. Alternatively, smaller fragments can be synthesized and ligated using recombinant methods known in the art to generate larger functional fragments. Antibodies for use can be obtained commercially from a variety of known sources, such as the American Type Culture Collection (ATCC, Manassas, Va.). Many antibodies against a variety of disease targets and tumor-associated antigens are deposited at the ATCC and / or have published variable region sequences and are available for use in the claimed methods and compositions.

[0262] The cysteine-engineered antibody is designed as a Fab antibody fragment (ThioFab) and expressed as a full-length IgG monoclonal (thioMab) antibody (U.S. Patent No. 7,521,541). The ThioFab and ThioMab antibodies are conjugated through a linker at the newly introduced cysteine thiol to prepare site-specific antibody-drug conjugates (U.S. Patent No. 7,521,541, U.S. Patent Application Publication No. 2008 / 0050310, International Publication No. 2008 / 052187).

[0263] Polytherics has described a method for synthesizing homogeneous drug-loaded ADCs by cross-linking a pair of sulfhydryl groups contained in an antibody protein, which is induced by reduction of the native disulfide hinge (Badescu et al., Bioconjugate Chem., 2014, 25, 1124-1136). Similar methods have been described by Concortis (U.S. Patent No. 0105540, April 26, 2015), Thiologics (Schumacher et al., Org Biomol.Chem., 2014, 12, 7261-7269) and Igenica (Behrens et al., Mol.Pharm., 2015, 12, 3986-3998). Related methods have been described by Frigerio et al., Curr.Top.Med.Chem., 2018, 18, 1-32.

[0264] Other recent methods used to target homogeneous drug-loaded ADCs involve the incorporation of unnatural amino acids such as selenocysteine (Hofer, T. et al., Biochem., 2009, 48, 12047-12057) groups or formylglycine (Drake, P.M. et al., Bioconj. Chem., 2014, 25, 1331-1341) groups onto antibodies. Glycosylation engineering has been used to introduce sialic acid residues at specific sites (Zhou, Q. et al., Bioconj. Chem., 2014, 25, 510-520), and transglutaminase has been used to enzymatically conjugate primary amine-containing linkers / payloads to glutamine residues (Dorywalska, M. et al., Bioconj. Chem., 2015, 26, 650-659). These and other methods are described in Sochaj, A.M. et al., Biotech. Adv., 2015, 33, 775-784.

[0265] As used herein, the term "immunospecificity" can mean that the binding region can immunoreact with target antigens, or variants or fragments thereof, by specifically binding to them. An antibody or antigen-binding fragment thereof can selectively interact with an antigen having an affinity constant of approximately 10 -5 ~10 -13 M -1 preferably 10 -6 ~10 -9 M -1 even more preferably 10 -10 ~10 -12 M -1

[0266] The term "immunoreact" can mean that the binding region can induce an immune response when it binds to a target antigen, or an epitope thereof.

[0267] The term "epitope" can mean any region of an antigen that has the ability to induce and combine with the binding regions of an antibody or antigen-binding fragment thereof.

[0268] In one embodiment, T comprises a nucleic acid-based molecule. The nucleic acid-based molecule may be an aptamer. The nucleic acid-based molecule can target a CD33 / CD34 antigen as described in Zaimy, M.A. et al., Cancer Gene Ther., 2016, 23, 315-320 or a PSMA tumor antigen such as A9, A10 and A9L described by Lupold, S.E. et al., Cancer Res., 2002, 62, 4029-4033; Dassie, J.P. et al., Nat. Biotech., 2009, 27, 839-849; Rockey, W.M. et al., Nucleic Acid Ther., 2011, 21, 299-314, or any other tumor antigen known to those skilled in the art such as, for example, as described in Orava, E., Biochem. Biophys. Acta, 2010, 1798, 2190-2200.

[0269] An aptamer is a nucleic acid or peptide molecule that adopts a specific sequence-dependent shape and binds to a specific target ligand based on a lock-and-key fit between the aptamer and the ligand. Typically, an aptamer can comprise either a single-stranded or double-stranded DNA molecule (ssDNA or dsDNA) or a single-stranded RNA molecule (ssRNA). A peptide aptamer consists of a short variable peptide domain attached at both ends to a protein scaffold. Aptamers can be used to bind both nucleic acid and non-nucleic acid targets.

[0270] Suitable aptamers can be selected from a random sequence pool from which specific aptamers that bind to the selected antigen with high affinity can be identified. Methods for the generation and selection of aptamers with desired specificities are well known to those skilled in the art and include the SELEX (Systematic Evolution of Ligands by Exponential Enrichment) process. Briefly, a large library of oligonucleotides is generated, enabling the isolation of large amounts of functional nucleic acids by an iterative process of in vitro selection and subsequent amplification by polymerase chain reaction. Preferred methodologies for making aptamers include those disclosed in WO 2004 / 042083.

[0271] In an alternative embodiment, T comprises a peptide or a modified peptide. The peptide or modified peptide may include an RGD sequence motif as described in Mousavizadeh, A., Colloids Surfaces B., 2017, 158, 507-517, and may include a linear RGD peptide sequence or a cyclized version thereof as described in Belvisi, L. et al., Curr. Top., Med Chem., 2016, 16, 314-329. Exemplary embodiments of RGD ligands that the targeting moiety can target and bind to are as follows:

Chemical formula

[0272] In alternative embodiments, T comprises a carbohydrate or modified carbohydrate molecule that can target a target tumor and the tumor-associated carbohydrate antigen receptors of cells. For example, sphingoglycolipids, gangliosides, sialic acid, and mucins exhibit malignant transformation and abnormal glycosylation patterns in cancer cells (as reviewed in Feng, D. et al., ACS Chem. Biol. 2016, 11, 850 - 863; Hakomori, S., Ann. Rev Immunol., 1984, 2, 103 - 126; Dube, D. H. and Bertozzi, C. R., Nat. Rev. Drug Disc., 2005, 4, 477 - 488), and carbohydrate molecule-based targeting ligands, such as mannose, galactose, or cerebrosidase derivatives, have been designed against them. In related methods, cell surface receptors of the tissue of interest may also be targeted, and recent examples include derivatives of N-acetyl-galactosamine (GalNAc) developed to target the asialoglycoprotein receptor of hepatocytes (reviewed in D’Souza, A. et al., J. Controlled Rel., 2015, 203, 126 - 139, and recent examples in Sanhueza, C. A. et al., JACS, 2017, 139, 3528 - 3536). Exemplary embodiments of carbohydrates that may be used as targeting moieties are as follows:

Chemical formula

Chemical formula

[0273] In another embodiment, T comprises a small molecule ligand having an affinity for a cell or tumor surface receptor. For example, folic acid or its derivatives can be used to target folic acid receptors α, β, or γ (FRα, FRβ, and FRγ). FRα is particularly known to be expressed in multiple endothelial tumor types such as breast, lung, and kidney (see Fernandez, M. et al., 2018, 4, 790-810 for a recent review), and conjugates of folic acid derivatives and toxins have been previously described (Vlahov, I. and Leamon, C.P., Bioconjugate Chem., 2012, 23, 1357-1369).

[0274] The linker may be linked to the compound of formula (I) through a C atom, an O atom, an N atom, or an S atom.

[0275] The linker may be cleavable, non-cleavable, hydrophilic, or hydrophobic. A cleavable linker may be sensitive to an enzyme and may be cleaved by an enzyme such as a protease. For example, a cleavable linker may be a valine-citrulline linker or a valine-alanine linker. For example:

Chemical formula

[0276] The inventors have found that the compounds of the present invention can be functionalized with various linkers and spacers at various positions to provide conjugate molecules. The linker may include a self-destructive group (e.g., p-aminobenzyl ether or amine and / or valine-citrulline unit) designed to release the parent ACSS2 inhibitor upon a hydrolysis event, for example, after amide, peptide, or carbamate hydrolysis.

[0277] The term "ACSS2" refers to acetyl-CoA synthetase short chain 2, an ATP-dependent enzyme that catalyzes the synthesis of acetyl-CoA from acetate. ACSS2 is responsible for the role of acetate uptake into cells, including the uptake of acetate into lipids and histones.

[0278] It will be understood that "antagonist", or "inhibitor", when these are related to a ligand and ACSS2, includes molecules, combinations of molecules, or complexes that inhibit, suppress, down-regulate, and / or desensitize ACSS2 activity. "Antagonist" encompasses any reagent that inhibits the constitutive activity of ACSS2. Constitutive activity is that which is evident in the absence of ligand / ACSS2 interaction. "Antagonist" also encompasses any reagent that inhibits or prevents the stimulated (or regulated) activity of ACSS2.

[0279] Preferably, the compound of formula (I) or the conjugate of formula (II) is an inhibitor of the ACSS2 protein.

[0280] It will be understood that the compounds described herein or their pharmaceutically acceptable salts, solvates, tautomers or polymorphs may be used in a pharmaceutical for use in monotherapy (i.e., the use of the compound alone) to modulate the ACSS2 protein and / or to treat, alleviate or prevent a disease.

[0281] Alternatively, the compound or its pharmaceutically acceptable salts, solvates, tautomers or polymorphs may be used as an adjunct to a known therapy or in combination with a known therapy to modulate the ACSS2 protein and / or to treat, alleviate or prevent a disease.

[0282] Accordingly, in one aspect, a second therapeutic agent may be administered with a compound of formula (I) or a conjugate of formula (II). The compound of formula (I) or the conjugate of formula (II) may be administered before, after, and / or together with the second therapeutic agent. The second therapeutic agent may include an antiviral agent, an anti-inflammatory agent, conventional chemotherapy, an anticancer vaccine, and / or hormonal therapy. Alternatively or additionally, the second therapeutic agent may include a B7 co-stimulatory molecule, interleukin-2, interferon-g, GM-CSF, a CTLA-4 antagonist (such as ipilimumab and tremelimumab), an IDO inhibitor or an IDO / TDO inhibitor (such as epacadostat and GDC-0919), a PD-1 inhibitor (such as nivolumab, pembrolizumab, pidilizumab, AMP-224, and MDX-1106), a PD-L1 inhibitor (such as durvalumab, avelumab, and atezolizumab), OX-40 ligand, a LAG3 inhibitor, CD40 ligand, 41BB / CD137 ligand, CD27 ligand, Bacillus Calmette-Guerin (BCG), liposomes, alum, Freund's complete or incomplete adjuvant, a TLR agonist (such as Poly I:C, MPL, LPS, bacterial flagellin, imiquimod, resiquimod, roquinimex, and CpG dinucleotides) and / or a detoxified endotoxin.

[0283] Methods for co-administration with additional therapeutic agents are well known in the art (Hardman et al. (eds.), Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 10th ed., 2001, McGraw-Hill New York, NY; Poole and Peterson (eds.), Pharmacotherapeutics for Advanced Practice: A Practical Approach, 2001, Lippincott, Williams and Wilkins, Philadelphia, PA; Chabner and Longo (eds.), Cancer Chemotherapy and Biotherapy, 2001, Lippincott, Williams and Wilkins, Philadelphia, PA).

[0284] In one aspect, the disease is cancer and the chemotherapeutic agent may be administered together with a compound of formula (I) or a conjugate of formula (II). The chemotherapeutic agent may be selected from the further group consisting of cancer vaccines, targeted drugs, targeted antibodies, antibody fragments, antimetabolites, antineoplastic agents, antifolates, toxins, alkylating agents, DNA strand breakers, DNA minor groove binders, pyrimidine analogs, ribonucleotide reductase inhibitors, tubulin interacting agents, antihormonal agents, immunomodulators, antiadrenal agents, cytokines, radiation therapy, cell therapy, cell depletion therapies such as B-cell depletion therapy and hormonal therapy. Alternatively or additionally, the chemotherapeutic agent may comprise abiraterone, altretamine, anhydrovinblastine, auristatin, bexarotene, bicalutamide, bleomycin, calicheamicin, cemadotin, chlorambucil, cyclophosphamide, docetaxel, docetaxel, carboplatin, cisplatin, cytarabine, dactinomycin, daunorubicin, decitabine, doxorubicin, etoposide, 5-fluorouracil, finasteride, flutamide, hydroxyurea, streptozocin, mitomycin, methotrexate, taxanes, tamoxifen, vinblastine, vincristine and / or vindesine.

[0285] The compound of formula (I) or the conjugate of formula (II) may be combined in a composition having several different forms, depending in particular on the method in which the composition is to be used. Thus, for example, the composition may be in the form of a powder, tablet, capsule, liquid, ointment, cream, gel, hydrogel, aerosol, spray, micellar solution, transdermal patch, liposomal suspension, or any other suitable form that can be administered to a human or animal in need of treatment. It will be understood that the vehicle of the medicament according to the invention should be one that shows good tolerance by the subject to which it is administered.

[0286] The medicaments containing the compounds described herein may be used in several ways. Suitable modes of administration include oral, intratumoral, parenteral, topical, inhalation / intranasal, rectal / vaginal, and ophthalmic / otic administration.

[0287] Formulations suitable for the aforementioned modes of administration may be formulated for immediate and / or modified release. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, targeted release, and programmed release.

[0288] The compounds of the present invention may be administered orally. Oral administration may include swallowing such that the compound enters the gastrointestinal tract, or buccal or sublingual administration such that the compound enters the bloodstream directly from the mouth. Formulations suitable for oral administration include solid formulations such as tablets, microparticles, liquids, or capsules containing powders, lozenges (including liquid-filled lozenges), chewable tablets, multi- and nano-microparticles, gels, solid solutions, liposomes, films, ovules, sprays, liquid formulations, and buccal / mucoadhesive patches.

[0289] Liquid formulations include suspensions, solutions, syrups, and elixirs. Such formulations may be used as fillers for soft or hard capsules and typically contain a carrier such as water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, as well as one or more emulsifying and / or suspending agents. Liquid formulations can also be prepared by reconstitution of a solid, for example, from sachets.

[0290] The compounds of the present invention can also be used in fast-dissolving and fast-disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents, 11(6), 981-986 by Liang and Chen (2001).

[0291] For tablet dosage forms, depending on the dosage, the drug may constitute 1% to 80% by weight of the dosage form, more typically 5% to 60% by weight of the dosage form. In addition to the drug, tablets generally contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinized starch, and sodium alginate. Generally, the disintegrant will constitute 1% to 25% by weight of the dosage form, preferably 5% to 20% by weight.

[0292] Binders are generally used to impart adhesiveness to tablet formulations. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic rubbers, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose, and hydroxypropyl methyl cellulose. Tablets can also contain diluents such as lactose (monohydrate, spray-dried monohydrate, anhydrous, etc.), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch, and dicalcium phosphate dihydrate.

[0293] The tablets may optionally contain surfactants such as sodium lauryl sulfate and polysorbate 80, and lubricants such as silicon dioxide and talc. When present, the surfactant may constitute 0.2% to 5% by weight of the tablets, and the lubricant may constitute 0.2% to 1% by weight of the tablets. The tablets generally also contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulfate. The lubricant generally constitutes 0.25% to 10% by weight of the tablets, preferably 0.5% to 3% by weight. Other possible ingredients include antioxidants, coloring agents, flavoring agents, preservatives, and taste modifiers.

[0294] Exemplary tablets contain up to about 80% drug, about 10% to about 90% by weight binder, about 0% to about 85% by weight diluent, about 2% to about 10% by weight disintegrant, and about 0.25% to about 10% by weight lubricant. The tablet blend can be compressed directly or by rollers to form tablets. The tablet blend or a portion of the blend may alternatively be wet granulated, dry granulated, or melt granulated, melt solidified, or extruded prior to tableting. The final formulation may contain one or more layers, may or may not be coated, and may even be encapsulated. The formulation of tablets is discussed in "Pharmaceutical Dosage Forms: Tablets", Volume 1, by H. Lieberman and L. Lachman (Marcel Dekker, New York, 1980).

[0295] A controlled release formulation suitable for the purposes of the present invention is described in U.S. Patent No. 6,106,864. Details of other suitable release techniques such as high energy dispersion and osmotic and coated particles can be found in "Pharmaceutical Technology On-line", 25(2), 1 - 14, by Verma et al. (2001). The use of chewing gum to achieve controlled release is described in International Publication No. 00 / 35298.

[0296] The compounds of the present invention may be administered directly into the bloodstream, muscle, or viscera. Means suitable for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intracerebroventricular, intraurethral, intrasternal, intracranial, intramuscular, and subcutaneous. Devices suitable for parenteral administration include needles (including microneedles) syringes, needleless syringes, and infusion techniques. Parenteral formulations are typically aqueous solutions that may contain excipients such as salts, carbohydrates, and buffering agents (preferably to a pH of 3-9), but for some applications, parenteral formulations may be more preferably formulated as a sterile non-aqueous solution or in a dry form to be used in conjunction with a suitable vehicle such as sterile pyrogen-free water.

[0297] The preparation of parenteral formulations under sterile conditions, for example by lyophilization, can be readily achieved using standard pharmaceutical techniques well known to those skilled in the art.

[0298] The solubility of the compounds of formula (I) and the conjugates of formula (II) used in the preparation of parenteral solutions can be increased by the use of appropriate formulation techniques such as the incorporation of solubilizing agents. Formulations for parenteral administration may be formulated for immediate and / or modified release. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, targeted release, and programmed release. Thus, the compounds of the present invention may be formulated as solids, semi-solids, or thixotropic liquids for administration as implantable depots that achieve modified release of the active compound. Examples of such formulations include drug-coated stents and poly(dl-lactic-co-glycolic) acid (PGLA) microspheres.

[0299] The compounds of the invention may be administered topically to the skin or mucosa, i.e., to the skin or transdermally. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, powders, dressings, foams, films, skin patches, oblatum, implants, sponges, fibers, bandages, and microemulsions. Liposomes may also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol, and propylene glycol. Penetration enhancers may be incorporated - see, for example, J Pharm Sci, 88(10), 955-958 by Finnin and Morgan (October 1999).

[0300] Other means of topical administration include electroporation, iontophoresis, phonophoresis, sonophoresis, and delivery by micro needles or needleless (e.g., Powderject™, Bioject™, etc.) injection.

[0301] The compounds of the invention may also be administered nasally or by inhalation, typically in the form of a dry powder from a dry powder inhaler (alone, as a mixture in a dry blend, e.g., with lactose, or as mixed component particles, e.g., mixed with phospholipids such as phosphatidylcholine), or as an aerosol spray from a pressurized container, pump, spray, atomizer (preferably an atomizer using electrohydrodynamics to produce a fine mist), or nebulizer, with or without the use of a suitable propellant such as 1,1,1,2 - tetrafluoroethane or 1,1,1,2,3,3,3 - heptafluoropropane. For nasal use, the powder may contain a bioadhesive, e.g., chitosan or cyclodextrin.

[0302] A pressurized container, pump, spray, atomizer, or nebulizer contains a solution or suspension of the (one or more) compounds of the invention, for example, an alternative agent suitable for the dispersion, solubilization, or extended release of ethanol, aqueous ethanol, or an active substance, a (one or more) propellant as a solvent, and an optional surfactant such as sorbitan trioleate, oleic acid, or oligolactic acid.

[0303] Prior to use in a dry powder or suspension formulation, the pharmaceutical product is micronized to a size suitable for delivery by inhalation (typically less than 5 microns). This can be achieved by any suitable milling method such as spiral jet mill milling, fluidized bed jet mill milling, supercritical fluid processing to produce nanoparticles, high pressure homogenization, or spray drying.

[0304] Capsules (e.g., made from gelatin or hydroxypropylmethylcellulose), blisters, and cartridges for use in inhalers or injectors may be formulated to contain a powder mixture of the compounds of the invention, a suitable powder base such as lactose or starch, and a performance modifier such as L-leucine, mannitol, or magnesium stearate. Lactose may be anhydrous or in the form of a monohydrate, and preferably the latter. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose.

[0305] Solution formulations suitable for use in atomizers that use electrohydrodynamics to generate a fine mist may contain from 1 μg to 20 mg of the compounds of the invention per actuation, and the actuation volume may vary from 1 μl to 100 μl. Typical formulations may contain a compound of formula (I) or a conjugate of formula (II), propylene glycol, sterile water, ethanol, and sodium chloride. Alternative solvents that may be used in place of propylene glycol include glycerol and polyethylene glycol.

[0306] Suitable fragrances such as menthol and levomenthol, or sweeteners such as saccharin or sodium saccharin may be added to the pharmaceutical preparations of the present invention intended for inhalation / intranasal administration.

[0307] In the case of dry powder inhalers and aerosols, the dosage unit is determined by a valve that delivers a metered amount. The units according to the present invention are typically prepared to administer a metered dose or "puff" containing from 1 μg to 100 mg of a compound of formula (I) or a conjugate of formula (II). The total daily dose typically ranges from 1 μg to 200 mg, which may be administered as a single dose or, more commonly, as divided doses throughout the day.

[0308] The compounds of the present invention may be administered rectally or vaginally, for example, in the form of suppositories, pessaries, bactericides, vaginal rings or enemas. Cocoa butter is a conventional suppository base, but various alternatives may be used as appropriate.

[0309] The compounds of the present invention may be administered directly to the eye or ear, typically in the form of droplets of a micronized suspension or solution in isotonic, pH-adjusted, sterile physiological saline. Other formulations suitable for ocular and otic administration include ointments, biodegradable (e.g., absorbable gel sponges, collagen) and non-biodegradable (e.g., silicone) implants, oblatum, lenses, and particulate or vesicular systems such as niosomes or liposomes. Polymers such as crosslinked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, cellulose-based polymers such as hydroxypropylmethylcellulose, hydroxyethylcellulose, or methylcellulose, or heteropolysaccharide polymers such as gellan gum may be incorporated together with preservatives such as benzalkonium chloride. Such formulations can also be delivered by iontophoresis.

[0310] The compounds of the present invention may be administered directly to the site of interest by injection of a solution or suspension containing the active pharmaceutical substance. The site of interest may be a tumor, and the compound may be administered via intratumoral injection. Typical injection solutions consist of propylene glycol, sterile water, ethanol, and sodium chloride. Alternative solvents that may be used instead of propylene glycol include glycerol and polyethylene glycol.

[0311] The compounds of the present invention may be combined with soluble macromolecular entities such as cyclodextrin and suitable derivatives thereof or polyethylene glycol-containing polymers to improve their solubility, dissolution rate, taste masking, bioavailability, and / or stability for use in any of the aforementioned modes of administration.

[0312] Drug-cyclodextrin complexes, for example, have been found to be generally useful for most dosage forms and routes of administration. Both inclusion and non-inclusion complexes may be used. As an alternative to direct complex formation with the drug, cyclodextrin may be used as an auxiliary additive, i.e., as a carrier, diluent, or solubilizing agent. Most commonly used for these purposes are alpha-, beta-, and gamma-cyclodextrin, examples of which can be found in International Patent Application Publication Nos. WO 91 / 11172, WO 94 / 02518, and WO 98 / 55148.

[0313] The amount of the compound required is determined by the biological activity and bioavailability of the compound, and thus it will be understood that this depends on the mode of administration, the physicochemical properties of the compound, and whether the compound is being used as monotherapy or in combination therapy. The dosing frequency will also be affected by the half-life of the compound within the subject being treated. The optimal dosage to be administered can be determined by those skilled in the art and will vary depending on the particular compound in use, the strength of the pharmaceutical composition, the mode of administration, and the progression of the disease. Additional factors depending on the particular subject being treated, including the age, weight, sex, diet, and time of administration of the subject, will necessitate adjustment of the dosage.

[0314] Generally, for administration to humans, the total daily dose of the compounds of the present invention is typically in the range of 1 mg to 1 g, such as 10 mg to 500 mg, etc., 100 μg to 10 g. For example, oral administration may require a total daily dose of 25 mg to 250 mg. The total daily dose may be administered as a single dose or divided doses and may, at the discretion of the physician, deviate from the typical ranges described herein. These dosages are based on an average human subject having a body weight of about 60 kg to 70 kg. The physician will be able to readily determine dosages for subjects whose body weights deviate from this range, such as infants and the elderly.

[0315] The present compound may be administered before, during, or after the onset of the disease to be treated.

[0316] Using known procedures such as those conventionally used in the pharmaceutical industry (e.g., in vivo experiments, clinical trials, etc.), specific formulations containing the compounds according to the present invention can be produced to form an accurate treatment regimen (such as the daily dose and dosing frequency of the compound). The inventors believe that they are the first to describe pharmaceutical compositions for treating diseases based on the use of the compounds of the present invention.

[0317] Accordingly, in an eighth aspect of the present invention, there is provided a pharmaceutical composition comprising a compound according to the first aspect, or a pharmaceutically acceptable salt, solvate, tautomer or polymorph thereof, or a conjugate according to the second aspect, and a pharmaceutically acceptable vehicle.

[0318] In a ninth aspect of the present invention, there is provided a process for manufacturing a composition according to the eighth aspect, the process comprising the step of contacting a therapeutically effective amount of the compound of the first aspect, or a pharmaceutically acceptable salt, solvate, tautomer or polymorph thereof, or a conjugate according to the second aspect, with a pharmaceutically acceptable vehicle.

[0319] The "subject" may be a vertebrate, a mammal, or a domesticated animal. Thus, the compounds, compositions and medicaments according to the present invention may be used to treat any mammal, such as livestock (e.g., horses), pets, or may be used in other veterinary applications. However, most preferably, the subject is a human.

[0320] The "therapeutically effective amount" of a compound is any amount that, when administered to a subject, treats a target disease or produces a desired effect, i.e., the amount of drug required to inhibit the ACSS2 protein. For example, the therapeutically effective amount of the compound used may be from about 0.01 mg to about 800 mg, preferably from about 0.01 mg to about 500 mg. It is preferred that the amount of the compound is in the range of about 0.1 mg to about 250 mg, most preferably in the range of about 0.1 mg to about 20 mg.

[0321] The "pharmaceutically acceptable vehicle" referred to herein is any known compound or combination of known compounds that are known to those skilled in the art to be useful in the formulation of pharmaceutical compositions.

[0322] In one embodiment, the pharmaceutically acceptable vehicle may be solid and the composition may be in the form of a powder or a tablet. The solid pharmaceutically acceptable vehicle may include one or more substances that may also act as flavoring agents, lubricants, solubilizing agents, suspending agents, dyes, fillers, glidants, compression aids, inert binders, sweeteners, preservatives, dyes, coatings, or tablet disintegrants. The vehicle may also be an encapsulating material. In the powder, the vehicle is a micronized solid mixed with the micronized active agent (i.e., the compound according to the first, second, and third aspects) according to the present invention. In the tablet, the active compound may be mixed with the vehicle having the required compression properties in a suitable ratio and compressed into the desired shape and size. The powder and the tablet preferably contain up to 99% of the active compound. Suitable solid vehicles include, for example, calcium phosphate, magnesium stearate, talc, sugar, lactose, dextrin, starch, gelatin, cellulose, polyvinylpyrrolidine, low melting wax, and ion exchange resins. In another embodiment, the pharmaceutical vehicle may be a gel and the composition may be in the form of a cream or the like.

[0323] However, the pharmaceutical vehicle may be liquid and the pharmaceutical composition is in the form of a solution. Liquid vehicles are used in the preparation of solutions, suspensions, emulsions, syrups, elixirs and pressurized compositions. The compounds according to the invention may be dissolved or suspended in a pharmaceutically acceptable liquid vehicle such as water, an organic solvent, a mixture of both or a pharmaceutically acceptable oil or fat. The liquid vehicle may contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, coloring agents, viscosity modifiers, stabilizers or osmotic pressure regulators. Suitable examples of liquid vehicles for oral and parenteral administration are water (water containing additives such as those described above, for example cellulose derivatives, preferably sodium carboxymethylcellulose solution), alcohols (including monohydric and polyhydric alcohols such as glycols) and their derivatives, and oils (such as fractionated coconut oil and arachis oil). For parenteral administration, the vehicle may also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid vehicles are useful in sterile liquid form compositions for parenteral administration. Liquid vehicles for pressurized compositions may be halogenated hydrocarbons or other pharmaceutically acceptable propellants.

[0324] Liquid pharmaceutical compositions that are sterile solutions or suspensions can be utilized, for example, by intramuscular, intrathecal, epidural, intraperitoneal, intravenous, and particularly subcutaneous injection. The compound may be prepared as a sterile solid composition that may be dissolved or suspended at the time of administration using sterile water, physiological saline, or other suitable sterile injectable media.

[0325] The compounds and compositions of the present invention may be administered in the form of a sterile solution or suspension containing other solutes or suspending agents (e.g., physiological saline or glucose sufficient to make the solution isotonic), bile salts, acacia, gelatin, sorbitan monoleate, polysorbate 80 (oleic acid esters of sorbitol and its anhydrides copolymerized with ethylene oxide), and the like. The compounds used in accordance with the present invention can also be administered orally in either liquid or solid composition form. Compositions suitable for oral administration include solid forms such as pills, capsules, granules, tablets, and powders, as well as liquid forms such as solutions, syrups, elixirs, and suspensions. Forms useful for parenteral administration include sterile solutions, emulsions, and suspensions.

[0326] It will be known to those skilled in the art that the active pharmaceutical ingredient may be converted to a prodrug, which is a metabolically unstable derivative that is converted to the active drug substance in the body. Also included within the scope of the present invention are prodrugs that are compounds of formula (I) containing a metabolically or hydrolytically unstable moiety that is converted to the active drug of formula (I) in vivo. The processes by which prodrugs are converted to the active drug substance include, but are not limited to, ester or carbonate or carbamate hydrolysis, phosphate ester hydrolysis, S-oxidation, N-oxidation, dealkylation, and metabolic oxidation as described in Beaumont et al., Curr. Drug Metab., 2003, 4, 461-485 and Huttenen et al., Pharmacol. Revs., 2011, 63, 750-771. Such prodrug derivatives may provide improved solubility, stability, or permeability compared to the parent drug substance, or may better enable the drug substance to be administered by an alternative route of administration, e.g., as an intravenous solution.

[0327] Also included within the scope of the present invention are soft drugs or prodrugs which are compounds of formula (I) containing a metabolically or hydrolytically labile moiety which is converted in vivo into an inactive derivative. The processes by which the active drug substance is converted into an inactive derivative include, for example, ester hydrolysis, S-oxidation, N-oxidation, dealkylation and metabolic oxidation as described in Pearce et al., Drug Metab. Dispos., 2006, 34, 1035-1040 and Comprehensive Medicinal Chemistry II, Volume 5, Elsevier, Oxford, 2007, pages 1009-1041, B. Testa, Prodrug and Soft Drug Design and Bodor, N. Chem. Tech. 1984, 14, 28-38, but are not limited thereto.

[0328] The scope of the present invention includes all pharmaceutically acceptable isotopically labeled compounds of the present invention in which one or more atoms are replaced by atoms having the same atomic number but a different atomic mass or mass number than the atomic mass or mass number which is predominant in nature.

[0329] Examples of isotopes suitable for inclusion in the compounds of the present invention are 2 H and 3 H and other hydrogens, 11 C, 13 C and 14 C and other carbons, 36 Cl and other chlorines, 18 F and other fluorines, 123 I and 125 I and other iodines, 13 N and 15 N and other nitrogens, 15 O, 17 O and 18 O and other oxygens, 32 P and other phosphors, and 35 S and other sulfur isotopes.

[0330] Certain isotopically labeled compounds of the present invention, such as those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotope tritium, i.e.,3 H, and carbon-14, i.e., 14 C, are particularly useful for this purpose in view of their ease of incorporation and rapid detection means. Substitution with isotopes such as deuterium, i.e., 2 H, etc. may result in certain therapeutic advantages such as increased metabolic stability, e.g., extended in vivo half-life or reduced dosage requirements, and may therefore be preferred in certain situations. 11 C, 18 F, 15 O and 13 substitution with positron-emitting isotopes such as N can be useful in positron emission tomography (PET) studies for examining substrate receptor occupancy.

[0331] Isotope-labeled compounds of formula (I) or conjugates of formula (II) can generally be prepared by using appropriate isotope-labeled reagents instead of the conventionally used unlabeled reagents and by processes similar to the conventional techniques known to those skilled in the art or the processes described in the appended examples and preparations.

[0332] All features described herein (including any appended claims, drawings, and abstract), and / or all steps of any method or process so disclosed, may be combined in any combination with any of the above aspects, except combinations in which at least some of such features and / or steps are mutually exclusive.

[0333] General scheme General Scheme 1: Compounds of formula (III) may be prepared from compounds of formula (IV) and (V) using a urea bond-forming reaction, as shown below.

Chemical formula

[0334] Typical reaction conditions for the activation of the aromatic amine of the compound of formula (V) involve using 4-nitrophenyl chloroformate to generate an intermediate, which can be attacked by a suitable nucleophile such as amine (IV) to give a urea such as the compound of formula (III). Preferred organic bases include DIPEA or TEA in a suitable organic solvent such as DCM, DMF, DMA or MeCN. The reaction may be shaken or stirred at room temperature.

[0335] The compounds of formula (IV) and (V) may be commercially available or synthesized by those skilled in the art. In particular, methods for synthesizing the compounds of formula (V) are described in general schemes 3 - 10.

[0336] General Scheme 2: The compound of formula (VI) may be prepared from the compounds of formula (V) and (VII) using an amide bond formation reaction as shown below.

Chemical formula

[0337] The compounds of formula (V) and (VII) may be commercially available or synthesized by those skilled in the art. In particular, methods for synthesizing the compounds of formula (V) or its derivatives are described in general schemes 3 - 10.

[0338] General Scheme 3: The compound of formula (V) may be prepared from the nitro compound of formula (VIII) by simple reduction.

Chemical formula

[0339] The compounds of formula (VIII) may be commercially available or may be synthesized by those skilled in the art. In particular, methods for synthesizing the compounds of formula (VIII) are described in the general schemes 6, 7, 9 and 11-14 shown below.

[0340] General Scheme 4: The compounds of formula (V) may be prepared from the haloaromatic compounds of formula (IX) by direct ammonolysis reaction.

Chemical formula

[0341] Typical amination conditions use a liquid or aqueous solution of ammonia in the presence of a suitable catalyst, typically CuI, in the presence of suitable activating ligands such as dimethylethylenediamine (DMEDA), amino acids such as proline, pyridine-based ligands such as phenanthroline, and diols and diketones. Alternatively, the halide may be aminated with para-methoxybenzylamine and then deprotected using methods known to those skilled in the art, e.g., using TFA, ammonium cerium nitrate or Pd-catalyzed hydrogenation reaction.

[0342] The compounds of formula (IX) may be commercially available or may be synthesized by those skilled in the art. In particular, methods for synthesizing the compounds of formula (IX) are described in the general schemes 8 and 10 shown below.

[0343] General Scheme 5: The amine of formula (V) may be further functionalized at the X position according to the following scheme. [Chemistry]

[0344] The compound of formula (V) may be halogenated, for example brominated using bromine in AcOH to give the bromide of formula (XII). Then, said bromide is generally reacted at reflux temperature, optionally in the presence of a catalyst such as tetrakistriphenylphosphine palladium(0), with a suitable cyanide source such as CuCN or Zn(CN) in a suitable polar solvent such as DMF, DMA, NMP or pyridine to give the nitrile of formula (XI). Alternatively, the bromide of formula (XII) is reacted in the presence of a transition metal catalyst, typically Pd, such as Pd(OAc), Pd dba, or Pd(dppf)Cl, a suitable base such as KO Bu, K PO, K CO, Cs CO, or Na CO, and a suitable solvent system such as THF-water, ethanol-water, DMF, dioxane or toluene, via a Suzuki reaction with a suitable boronic acid R -B(OH) or boronic acid ester. The reaction is typically heated to give the R -functionalized amine (X). 2 etc., to give the nitrile of formula (XI). Alternatively, the bromide of formula (XII) is reacted in the presence of a transition metal catalyst, typically Pd, such as Pd(OAc) 2 、Pd 2 dba 3 or Pd(dppf)Cl 2 、KO t Bu、K 3 PO 4 、K 2 CO 3 、Cs 2 CO 3 or Na 2 CO 3 etc., and a suitable solvent system such as THF-water, ethanol-water, DMF, dioxane or toluene, via a Suzuki reaction with a suitable boronic acid R -B(OH) or boronic acid ester. The reaction is typically heated to give the R -functionalized amine (X). 3 -B(OH) 2 or boronic acid ester. The reaction is typically heated to give the R -functionalized amine (X). 3

[0345] General Scheme 6: The nitro compound of formula (XIII) may be synthesized starting from the benzopyridone of formula (XX). [Chemistry]

[0346] ​The benzopyridone of formula (XX) may typically undergo a nitration reaction at room temperature, for example, in a mixture of sulfuric acid and fuming nitric acid, to give a nitro compound of formula (XIX). These nitro compounds may then be halogenated, for example, brominated with a strong acid such as sodium bromate and aqueous HBr under heating, to give a bromo derivative of formula (XVIII). Treatment of the compound of formula (XVIII) with POBr 3 converts pyridine to the corresponding bromopyridine, giving a dibromo compound of formula (XVII). The compound of formula (XVII) may then be subjected to a Suzuki reaction with a boronate or boric acid R 1 -B(OH) 2 and / or R-B(OH) 2 to give a quinoline of formula (XVI) via a Suzuki reaction as described in general scheme 5. Alternatively, the bromopyridone of formula (XVIII) may be reacted in a Suzuki reaction with a boronate or boric acid of formula R 1 -B(OH) 2 to give a functionalized pyridine of formula (XV), which may then be further brominated to bromopyridine (XIV) and subjected to a Suzuki reaction with a boronate or boric acid R-B(OH) 2 to give a quinoline of formula (XIII).

[0347] The compound of formula (XX) may be commercially available or synthesized by those skilled in the art.

[0348] General Scheme 7: Starting from the nitroaniline of formula (XXII) and the acetic acid derivative of formula (XXVI), nitro-quinoline can also be produced according to the following scheme.

Chemical formula

[0349] The acid of formula (XXVI) may be converted to the Weinreb amide of formula (XXV) with, for example, N,O-dimethyl-hydroxylamine using a suitable organic base and a suitable coupling agent. Preferred coupling agents are EDCI and HOBt, T3 It is any one of P, HATU, HBTU or BOP. Preferred organic bases include DIPEA or TEA in a suitable organic solvent such as DCM, DMF, DMA or MeCN. The reaction may be shaken or stirred at room temperature. The Weinreb amide is then reacted with a suitable nucleophile, typically a Grignard or organolithium reagent, in a suitable solvent such as THF or diethyl ether to give a ketone of formula (XXIV). Treatment of the ketone of formula (XXIV) with POCl 3 in gives a vinylogous aldehyde of formula (XXIII), which can give a functionalized quinoline of formula (XXI) when combined with aniline of formula (XXII) in a suitable solvent such as DMF, DMA or DMSO.

[0350] The compounds of formula (XXVI) and (XXII) may be commercially available or synthesized by those skilled in the art.

[0351] General Scheme 8: The bromoquinoline of formula (XXVII) may be prepared starting from a nitrocarbonyl compound of formula (XXIX), such as a ketone or an aldehyde.

Chemical formula

[0352] The nitrocarbonyl compound of formula (XXIX) may be subjected to reduction of the nitro group using, for example, a suitable acid, such as Fe in HCl, and, for example, a transition metal catalyst. Alternative reduction methods include any of those described in the general Scheme 3. The product of the reduction is an aniline compound of formula (XXVIII), which has the group R 2Depending on the nature, either a strong base such as KOH or NaOH in a suitable solvent such as THF, dioxane or ethanol, or alternatively a strong acid such as sulfuric acid or para-toluenesulfonic acid in a suitable solvent such as AcOH may be used for condensation in the Friedländer quinoline synthesis with the ketone of formula (XXIV). The product of the condensation reaction is the quinoline of formula (XXVII).

[0353] General Scheme 9: An alternative synthesis of the nitro-quinoline of formula (XXX) starts from the bromo-nitrobenzaldehyde of formula (XXXII). The halide is typically substituted at high temperature using a nitrogen nucleophile such as NaN 3 or KN 3 to give the azide compound of formula (XXXI).

Chemical formula

[0354] Subsequently, the azide compound of formula (XXXI) may undergo reaction with a suitable reagent such as TMSOTf or AgNTf 2 in a suitable solvent such as an alkyne and MeOH to give the functionalized quinoline compound of formula (XXX).

[0355] General Scheme 10: A flexible method for producing halo-quinoline is shown in the following scheme starting from the oxindole of formula (XXXVIII). The oxindole compound of formula (XXXVIII) is reacted with the ketone of formula (XXIV) typically with heating or under reflux conditions in the presence of a strong base such as NaOH or KOH to give the key intermediate bromo-quinoline carboxylic acid of formula (XXXVII).

Chemical formula

[0356] Subsequently, the acid group of (XXXVII) is R according to the above scheme2 It may be synthesized into several different functional groups at the position. For example, the acid of formula (XXXVII) may be converted into an α-acylaminocarbonyl compound, and then this can generate the oxazole compound of formula (XXXVI) through a dehydrative cyclization reaction. Typically, this conversion will involve the activation of the carboxylic acid and subsequent treatment with an aminocarbonyl reagent such as 2-aminoacetaldehyde or its derivatives. Preferred activators include DCC, CDI, T 3 P, HATU, HBTU, or treatment of the acid with oxalyl chloride and a catalytic amount of DMF. Preferred organic bases include DIPEA or TEA in a suitable organic solvent such as DCM, DMF, DMA or MeCN. The reaction may be shaken or stirred at room temperature. Subsequently, the intermediate α-acylaminocarbonyl compound is then treated with a strong acid such as H 2 SO 4 to give the oxazole of formula (XXXVI).

[0357] Alternatively, the acid of formula (XXXVII) may be converted into the nitrile of formula (XXXV) in a two-step process that first converts the acid into a primary carboxamide. Typical conditions use activation of the carboxylic acid of the compound of formula (XXXVII) with a suitable organic base and a suitable activator, followed by treatment of the activated acid with an ammonia source. Preferred activators are DCC, CDI, T 3 P, HATU, HBTU, or treatment of the acid with oxalyl chloride and a catalytic amount of DMF. Preferred organic bases include DIPEA or TEA in a suitable organic solvent such as DCM, DMF, DMA or MeCN. Preferred ammonia sources are NH 4 OH and NH 4 OAc. The reaction may be shaken or stirred at room temperature. The primary carboxamide thus produced may subsequently be dehydrated to give the nitrile of formula (XXXV). Typical conditions involve treatment of the carboxamide with a suitable reagent at a temperature between room temperature and reflux, preferably SOCl 2 、Vilsmeier reagent, POCl 3 or TFAA to give the nitrile of formula (XXXV).

[0358] Alternatively, the acid of formula (XXXVII) may be converted to the amide of formula (XXXIV) using the method described in general Scheme 2. Typical conditions use activation of the carboxylic acid of the compound of formula (XXXVII) using a suitable organic base and a suitable coupling agent. Preferred coupling agents are any of EDCI and HOBt, T 3 P, HATU, HBTU or BOP. Preferred organic bases include DIPEA or TEA in a suitable organic solvent such as DCM, DMF, DMA or MeCN. The reaction may be shaken or stirred at room temperature.

[0359] Alternatively, the acid of formula (XXXVII) may be converted to the amine of formula (XXXIII) using a suitable azide reagent such as diphenyl phosphorazide in a suitable solvent such as DMF, DMA, MeCN or NMP in the presence of a suitable base such as DIPEA or TEA. The reaction is typically carried out at room temperature. The intermediate acyl azide thus produced is then typically treated with water under heating conditions or reflux conditions to give the amine of formula (XXXIII).

[0360] General synthetic procedures General Purification and Analysis Methods All final compounds were purified either by Combi-flash or prep-HPLC purification and analyzed for purity and product identity by UPLC or LCMS according to one of the following methods.

[0361] prep-HPLC Fractional HPLC was performed using a Waters automatic purification apparatus with a YMC Triart C18 column (250×20 mm, 5 μm) or a phenylhexyl column (250×21.2 mm, 5 μm) or a Kinetex C18 column (250×21.2 mm, 10 μm) operating at a flow rate of 16.0 - 50.0 mL / min between ambient temperature and 50°C. Mobile phase 1: A = 20 mM ammonium bicarbonate in water, B = acetonitrile; gradient profile: initial composition of 80% A and 20% B of the mobile phase, then 60% A and 40% B after 3 minutes, then 30% A and 70% B after 20 minutes, then 5% A and 95% B after 21 minutes, held at this composition for 1 minute for column washing, and then returned to the initial composition over 3 minutes.

[0362] Mobile phase 2: A = 10 mM ammonium acetate in water, B = acetonitrile; gradient profile: initial composition of 90% A and 10% B of the mobile phase, then 70% A and 30% B after 2 minutes, then 20% A and 80% B after 20 minutes, then 5% A and 95% B after 21 minutes, held at this composition for 1 minute for column washing, and then returned to the initial composition over 3 minutes.

[0363] Mobile phase 3: A = 0.1% formic acid in water, B = acetonitrile; gradient profile: initial composition of 90% A and 10% B of the mobile phase, then 70% A and 30% B after 2 minutes, then 20% A and 80% B after 20 minutes, then 5% A and 95% B after 21 minutes, held at this composition for 1 minute for column washing, and then returned to the initial composition over 3 minutes.

[0364] LCMS method General 5 - minute method: Operate on a Zorbax Extend C18 column (50×4.6 mm, 5 μm) or Luna C18 column (50×4.6 mm, 5 μm) at ambient temperature with a flow rate of 1.2 mL / min. Mobile phase: A = 10 mM ammonium acetate in water, B = acetonitrile; Gradient profile: From 90% A and 10% B to 70% A and 30% B in 1.5 minutes, then to 10% A and 90% B in 3.0 minutes, held at this composition for 1.0 minute, and finally returned to the initial composition over 2.0 minutes.

[0365] UPLC method UPLC was performed on a Waters automated purification device using a Zorbax Extend C18 column (50×4.6 mm, 5 μm) or a Kinetex Evo C18 column (100×2.1 mm, 1.7 μm) at ambient temperature with a flow rate of 0.3 - 1.5 ml / min.

[0366] Mobile phase 1: A = 5 mM ammonium acetate in water, B = 90 / 10 acetonitrile / 5 mM ammonium acetate in water; Gradient profile: From 95% A and 5% B to 65% A and 35% B in 2 minutes, then to 10% A and 90% B in 3.0 minutes, held at this composition for 4.0 minutes, and finally returned to the initial composition over 5.0 minutes.

[0367] Mobile phase 2: A = 0.05% formic acid in water, B = acetonitrile; Gradient profile: From 98% A and 2% B over 1 minute, then to 90% A and 10% B over 1 minute, then to 2% A and 98% B over 2 minutes, and then back to the initial composition over 3 minutes.

[0368] General Procedure 1: Urea Formation [Chemical formula] To a stirred solution of aromatic amine (V) (1.0 equiv) in a suitable solvent such as DCM, DMF, MeCN or THF (8 mL / mmol), p-nitrophenyl chloroformate (1.1 equiv) was added at 0 - 5 °C and the whole was stirred at room temperature for 1 - 3 h. Then, TEA or DIPEA (6 equiv) and amine R 8 -NH-R 7 (IV) (2.0 equiv) was added dropwise and the whole was further stirred at room temperature for 1 - 5 h. The progress of the reaction was monitored by TLC / LCMS and after completion, the reaction mass was diluted with EtOAc and washed finally with a dilute solution of a suitable inorganic base such as NaHCO 3 or 1N NaOH and then with brine. The organic layer was dried over anhydrous Na 2 SO 4 and evaporated in vacuo to give a residue which was purified by column chromatography or combi-flash or prep-HPLC to afford the compound of formula (III) (yield 4 - 80%) as an off-white to white solid. All ureas of formula (III) can be synthesized according to a similar procedure.

[0369] General Procedure 2: Amidation

Chemical formula

[0370] General Procedure 3: Nitro Group Reduction

Chemical formula

[0371] Option B: To a stirred solution of the compound of formula (VIII) (1.0 equiv) in a suitable solvent such as EtOAc, EtOH or MeOH (7 mL / mmol) was added 10% Pd - C (68 mg / mmol, 50% w / w in water) under an inert atmosphere, and the resulting reaction mixture was stirred at room temperature under H 2 gas balloon pressure for 2 - 12 h. The progress of the reaction was monitored by TLC and UPLC - MS, which showed complete conversion of the nitro group to its corresponding amino group. H 2The gas balloon was removed and the reaction mixture was filtered under an inert atmosphere. The resulting filtrate was evaporated in vacuo to give the compound of formula (V) as a crude product, which was used in the next step without further purification.

[0372] General Procedure 4: Amination

Chemical formula

[0373] Option A: Amination with Aqueous NH3 A solution of the compound of formula (IX) (1.0 equivalent), CuI (0.05 equivalent), BINAP, a suitable ligand such as N1,N2-bis(4-phenoxyphenyl)oxalamide, trans-4-hydroxy-L-proline or L-proline (0.05 equivalent) and a suitable base such as KHCO 3 , K 3 PO 4 or K 2 CO 3 (1.0 equivalent) in DMSO (11 mL / mmol) was purged with argon for 30 minutes, then aqueous NH 3 (0.5 mL / mmol, 36% w / w in water) was added and the whole was stirred at 60 - 100 °C for 4 - 16 hours. After completion of the reaction (monitored by TLC and LCMS), the reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na 2 SO 4 and concentrated in vacuo to give the title compound as a crude brown solid.

[0374] Option B: Amination Using p-Methoxybenzylamine To a stirred solution of the compound of formula (IX) (1.0 equivalent) in a suitable solvent such as DMF or DMSO (4 mL / mmol) under an inert atmosphere, p-methoxybenzylamine (6 equivalents) was added followed by KHCO 3 , K 3 PO 4 or K 2 CO 3A suitable base (2.5 equivalents) such as etc. was added. Then, CuI (1.0 equivalent) and a suitable ligand (0.5 equivalent) such as BINAP, N1,N2-bis(4-phenoxyphenyl)oxalamide, trans-4-hydroxy-L-proline or L-proline was added. The resulting reaction mixture was transferred to a sealed tube and heated at 60 - 100 °C for 4 - 16 hours. The progress of the reaction was monitored by LCMS. After completion, the reaction mixture was poured into ice water. The aqueous reaction mixture was extracted with EtOAc and washed with brine. The organic layer was dried over anhydrous Na 2 SO 4 and concentrated in vacuo to give a residue, which was stirred with a suitable acid such as HCl or TFA at room temperature. The resulting reaction mixture was quenched in ice water and basified with solid K 2 CO 3 and extracted with EtOAc. The combined organic layers were washed with brine, dried and concentrated in vacuo to give a crude product, which was purified by column chromatography / combi-flash to give the compound of formula (V) (yield 60 - 90%) as a light brown to yellow solid.

[0375] General Procedure 5: Bromination [Chemical formula] To a stirred solution of the compound of formula (V) (1.0 equivalent) in AcOH (8 mL / mmol) was added Br 2 (1.0 equivalent) in AcOH (2 mL / mmol) at 0 - 5 °C. The whole was stirred at room temperature for 1 - 4 hours. The progress of the reaction was monitored by LCMS. After completion, the reaction mixture was quenched with a saturated aqueous solution of sodium metabisulfite. The aqueous mass was basified with solid NaHCO 3 and extracted with EtOAc, washed with brine, dried and concentrated to give a crude product, which was purified by column chromatography to give the compound of formula (XII) (yield 80 - 95%) as an off-white solid.

[0376] General Procedure 6: Cyanation [Chemical formula] To a stirred solution of the compound of formula (XII) (1.0 equiv) in NMP (3 mL / mmol), CuCN (4 equiv) was added and the whole was stirred at 100 - 120 °C for 10 - 16 h in a sealed tube. The progress of the reaction was monitored by TLC / LCMS. After completion, the reaction mixture was diluted with water and extracted with MTBE. The organic layer was washed with a saturated solution of NH 4 Cl and finally with brine, dried and concentrated in vacuo to give the crude product, which was purified by column chromatography to give the compound of formula (XI) (yield 60 - 80%) as an off - white to light brown solid.

[0377] General Procedure 7: Suzuki-Miyaura Cross-Coupling Reaction [Chemical formula] The compound of formula XII (4.805 mmol, 1.0 equiv), R 3 -B(OH) 2 (2.0 equiv) and a solution of a suitable base such as K 2 CO 3 , TEA, NaHCO 3 or K 3 PO 4 (3.0 equiv) in a mixture of the solvent 1,4 - dioxane (4 mL / mmol) and water (0.5 mL / mmol) was degassed with argon for 30 min and then a suitable transition metal catalyst such as Pd(OAc) 2 , Pd(PPh 3 ) 4 , Pd(PPh 3 ) 2 Cl 2 or Pd 2 (dba) 3 (0.1 equiv) and BINAP or PCy 3A suitable ligand such as (0.2 eq) was added. The resulting reaction mixture was stirred at 80 - 100 °C for 4 - 16 h under an inert atmosphere. The progress of the reaction was monitored by TLC / LCMS. After completion, the reaction mixture was diluted with EtOAc, filtered, and the filtrate was partitioned by the addition of water. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na 2 SO 4 and concentrated in vacuo to give a crude product, which was purified by column chromatography to give the compound of the formula as a pale yellow solid (yield 50 - 80%).

[0378] General Procedure 8: Nitration

Chemical formula

[0379] General Procedure 9: Bromination with Aqueous HBr

Chemical formula

[0380] General Procedure 10: Bromination with POBr 3 General Procedure 11: Weinreb Amide Formation

Chemical formula

[0381] General Procedure 12: Grignard Reaction

Chemical formula

[0382] General Procedure 13: Vilsmeier-Haack Reaction

Chem.

[0383] General Procedure 14: Condensation

Chem.

[0384] General Procedure 15: Condensation

Chemical formula

[0385] General Procedure 16: Condensation

Chemical formula

[0386] General Procedure 17: Azide Formation

Chemical Structure

[0387] General Procedure 18: Condensation

Chemical Structure

[0388] General Procedure 19: Fittig Reaction

Chemical formula

[0389] General Procedure 20: Oxazole Formation

Chemical formula

[0390] General Procedure 21: Amide / Cyanide via Acid Chloride Formation

Chem.

[0391] The resulting amide intermediate (1.0 equiv) was dissolved in methanesulfonic acid (5 mL / mmol) at room temperature and then P 2 O 5(3.0 equivalents) was added. The whole was heated at 120 - 130 °C for 3 - 5 hours. The progress of the reaction was monitored by TLC. After complete consumption of the amide, the reaction mixture was poured into ice water and extracted with EtOAc. The combined organics were washed with brine and dried over anhydrous Na 2 SO 4 and concentrated in vacuo to give the crude product, which was purified by column chromatography to give the compound of formula (XXXVI) (yield 35 - 40%) as an off - white solid.

[0392] General Procedure 22: Burgess Reaction

Chemical formula

[0393] General Procedure 23: Curtius Reaction The resulting amide intermediate (1.0 equivalent) was dissolved in dry THF (12 mL / mmol), and then Burgess reagent (2.0 equivalents) was added at 0 - 5 °C. The whole was heated at 50 - 60 °C for 1 - 2 hours under an inert atmosphere. After completion of the reaction (monitored by TLC / LCMS), the resulting solid was filtered off, the filtrate was diluted with water and extracted with 5% MeOH in DCM. The combined organic layers were washed with brine and dried over anhydrous Na2 SO 4 It was dried with SO and concentrated in vacuo to give the compound of formula (XXXV) (yield 70 - 80%) as a white solid.

[0394] Example 45: 1-(2,2-Difluorobutyl)-3-(3-(2-Fluorophenyl)-2-Phenylquinolin-6-Yl)Urea

Chem.

Example

[0395] The nuclear magnetic resonance (NMR) spectra were in agreement with the proposed structures in all cases. Characteristic chemical shifts (δ) were given in parts per million downfield from tetramethylsilane ( 1 for 1H - NMR) and parts per million upfield from trichloro - fluoro - methane ( 19 for 19F NMR) using the conventional abbreviations for the designations of the major peaks: e.g., s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad. For common solvents, the following abbreviations were used: CDCl 3 , deuterochloroform; d 6 -DMSO, deuterodimethylsulfoxide; and CD 3 OD, deuteromethanol.

[0396] The mass spectrum, MS (m / z), was recorded using electrospray ionization (ESI). Relatedly, unless otherwise specified, the m / z data presented are for 19 F, 35 Cl, 79 Br and 127 I.

[0397] All chemicals, reagents, and solvents were purchased from commercial sources and used without further purification. Unless otherwise specified, all reactions were carried out under a nitrogen atmosphere.

[0398] Flash column chromatography was performed using prepacked silica gel cartridges on a Combi-Flash platform. Prep-HPLC purification was carried out according to the general purification and analytical methods described above. Thin-layer chromatography (TLC) was performed on Merck silica gel 60 plates (5729). Unless otherwise specified, all final compounds had a purity of greater than 95% as determined by the LCMS or UPLC analytical methods described in the general purification and analytical methods above.

[0399] Preparation 1: 3-(2-Fluorophenyl)-2-Phenylquinolin-6-Amine

Chemical Structure

[0400] Step 1: 2-(2-Fluorophenyl)-1-Phenylethanone

Chemical Structure

Chemical Structure

[0401] Step 3: 3-(2-Fluorophenyl)-6-Nitro-2-Phenylquinoline

Chemical Structure

[0402] Step 4: 3-(2-Fluorophenyl)-2-Phenylquinolin-6-Amine

Chemical Structure

[0403] Preparation 2: 1-(2,2-Difluorobutyl)-3-(3-(2-Fluorophenyl)-2-Phenylquinolin-6-Yl)Urea (Example 45)

Chemical formula

[0404] Example 15: (R)-1-(3-(2-Fluorophenyl)-2-Phenylquinolin-6-Yl)-3-(2-Hydroxybutyl)Urea

Chemical formula

[0405] Example 72: (R)-1-(2-Hydroxybutyl)-3-(2-Methyl-3-Phenylquinolin-6-Yl)Urea [Chemical formula] Example 15 was prepared according to the method described for the preparation of Example 45 and the method described below.

[0406] To a stirred solution of 3-(2-fluorophenyl)-2-phenylquinolin-6-amine (Preparation 1, Step 4) (9.0 g, 28.66 mmol) in THF (90 mL) was added p-nitrophenyl chloroformate (6.4 g, 31.526 mmol) at 0 - 5 °C and the whole was stirred at room temperature for 3 h. Then, TEA (11.58 g, 114.64 mmol) and (R)-1-aminobutan-2-ol (2.55 g, 28.66 mmol) were added dropwise and stirring was continued at room temperature for a further 2 h. The progress of the reaction was monitored by TLC / LCMS and after completion, the reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with 1N NaOH solution to remove all p-nitrophenol, washed with 1N HCl to remove unreacted amine and finally washed with brine solution. The organic layer was dried over anhydrous Na 2 SO 4 and concentrated in vacuo to give the crude product which was purified by trituration with acetone and hexane to afford the title compound (7.0 g, 57% yield) as a white solid. LCMS m / z: 430.34 [M+H]; purity 99.46%; 1 HNMR (500 MHz; DMSO-d 6 ): δ 0.90 (t, J = 7.4Hz, 3H), 1.34 - 1.46 (m 2H), 2.99 - 3.03 (m, 1H), 3.23 - 3.28 (m, 1H), 3.44 (t, J =6.5 Hz, 1H), 4.80 (d, J = 5.15 Hz, 1H), 6.34 (t, J = 5.55 Hz, 1H), 7.11 (t, J =8.95 Hz, 1H), 7.25 - 7.29 (m, 4H), 7.35 - 7.46 (m, 3H), 7.46 - 7.49 (m, 1H), 7.74 (d,J = 6.9 Hz, 1H), 7.97 (d, J = 9.05 Hz, 1H), 8.13 (d, J = 2.1 Hz, 1H), 8.25 (s,1H), 9.06 (s, 1H).

[0407] Preparation 3: 2-Methyl-3-Phenylquinolin-6-Amine

Chemical Structure

[0408] Step 1: N-Methoxy-N-Methyl-2-Phenylacetamide

Chem.

Chem.

[0409] ​

Chem.

[0410] Step 3: 6-Bromo-2-methyl-3-phenylquinoline

Chemical Structure

[0411] Step 4: N-(4-Methoxybenzyl)-2-methyl-3-phenylquinolin-6-amine

Chemical Structure

[0412] Step 5: 2-Methyl-3-phenylquinolin-6-amine

Chemical Structure

[0413] Preparation 4: (R)-1-(2-Hydroxybutyl)-3-(2-methyl-3-phenylquinolin-6-yl)urea (Example 72) [Chemical] To a stirred solution of 2-methyl-3-phenylquinolin-6-amine (Preparation 3, Step 5) (644 mg, 2.751 mmol) in THF (6 mL), p-nitrophenyl chloroformate (609.8 mg, 3.026 mmol) was added and the whole was stirred at room temperature for 1 h. After complete consumption of the amine by TLC, TEA (1.535 mL, 11.00 mmol) and (R)-1-aminobutan-2-ol (269.68 mg, 3.025 mmol) were added dropwise and the combined mixture was stirred at room temperature for a further 3 h. The progress of the reaction was monitored by TLC / LCMS and after completion, the reaction mixture was diluted with EtOAc and washed three times with 1N NaOH solution, followed by brine and 1N HCl solution, and again with brine. The organic layer was dried over anhydrous Na 2 SO 4 and concentrated in vacuo to give the crude product, which was purified by crystallization from acetone and hexane to give the title compound (393 mg, 41% yield) as a white solid. LCMS m / z: 350.22 [M+H]; purity 99.71%; 1 HNMR (400 MHz; DMSO-d 6 ): δ 0.88 (t, J = 7.44Hz, 3H), 1.28-1.44 (m, 2H), 2.50 (s, 3H), 2.93-2.99 (m, 1H), 3.18-3.32 (m, 1H),3.40 (d, J = 4.84 Hz, 1H), 4.76 (d, J = 4.96 Hz, 1H), 6.25 (t, J = 5.72 Hz,1H), 7.40-7.50 (m, 5H), 7.61-7.64 (m, 1H), 7.82 (d, J = 9.0 Hz, 1H), 7.95 (s,1H), 7.99 (s, 1H), 8.90 (s, 1H).

[0414] Example 101: (R)-1-(2-Hydroxybutyl)-3-(4-methoxy-2,3-diphenylquinolin-6-yl)urea [Chemical] Example 101 was prepared according to the methods described in General Procedures 1, 3, 17, 18 and the method described below.

[0415] Preparation 5: 4-Methoxy-2,3-diphenylquinolin-6-amine

Chem.

Chem.

[0416] Step 2: 4-Methoxy-6-nitro-2,3-diphenylquinoline

Chem.

[0417] Step 3: 4-Methoxy-2,3-diphenylquinolin-6-amine

Chem.

[0418] Preparation 6: (R)-1-(2-Hydroxybutyl)-3-(4-methoxy-2,3-diphenylquinolin-6-yl)urea (Example 101)

Chem.

[0419] Example 20: (R)-1-(2,3-Bis(2-fluorophenyl)quinolin-6-yl)-3-(2-hydroxybutyl)urea

Chemical Structure

[0420] Preparation 7: 2,3-Bis(2-fluorophenyl)quinolin-6-amine

Chem.

Chem.

[0421] Step 2: 3-Bromo-6-nitroquinolin-2(1H)-one

Chem.

[0422] Step 3: 2,3-Dibromo-6-nitroquinoline

Chemical formula

[0423] Step 4: 2,3-Bis(2-fluorophenyl)-6-nitroquinoline

Chemical formula

[0424] Step 5: 2,3-Bis(2-fluorophenyl)quinolin-6-amine

Chemical Structure

[0425] Preparation 8: (R)-1-(2,3-Bis(2-fluorophenyl)quinolin-6-yl)-3-(2-hydroxybutyl)urea (Example 20)

Chemical Structure

[0426] Example 115: (R)-6-(3-(2-Hydroxybutyl)ureido)-3-methyl-N-(1-methyl-1H-pyrazol-3-yl)-2-phenylquinoline-4-carboxamide [Chemical Structure] Example 115 was prepared according to the methods described in General Procedures 1, 4, 19, 23 and the method described below.

[0427] Preparation 9: 6-Amino-3-methyl-N-(1-methyl-1H-pyrazol-3-yl)-2-phenylquinoline-4-carboxamide

Chem.

Chem.

[0428] Step 2: 6-Bromo-3-methyl-N-(1-methyl-1H-pyrazol-3-yl)-2-phenylquinoline-4-carboxamide

Chem.

[0429] Step 3: 6-((4-Methoxybenzyl)amino)-3-methyl-N-(1-methyl-1H-pyrazol-3-yl)-2-phenylquinoline-4-carboxamide

Chemical Structure

[0430] Step 4: 6-Amino-3-methyl-N-(1-methyl-1H-pyrazol-3-yl)-2-phenylquinoline-4-carboxamide

Chem.

[0431] Preparation 10: (R)-6-(3-(2-Hydroxybutyl)ureido)-3-methyl-N-(1-methyl-1H-pyrazol-3-yl)-2-phenylquinoline-4-carboxamide (Example 115)

Chem.

[0432] Example 95: 1-(4-Amino-2,3-diphenylquinolin-6-yl)-3-(2-hydroxybutyl)urea [Chemical Structure] Example 95 was prepared according to the methods described in General Procedures 1, 4, 19, 22 and the method described below.

[0433] Preparation 11: 2,3-Diphenylquinoline-4,6-diamine

Chem.

Chem.

[0434] Step 2: N6-(4-Methoxybenzyl)-2,3-diphenylquinoline-4,6-diamine

Chem.

[0435] Step 3: 2,3-Diphenylquinoline-4,6-diamine

Chemical Structure

[0436] Preparation 12: 1-(4-Amino-2,3-diphenylquinolin-6-yl)-3-(2-hydroxybutyl)urea (Example 95)

Chemical Structure

[0437] Example 94: N-(6-(3-(2-Hydroxybutyl)ureido)-2,3-diphenylquinolin-4-yl)methanesulfonamide

Chemical Structure

[0438] Preparation 13: N-(6-Amino-2,3-diphenylquinolin-4-yl)methanesulfonamide

Chemical Structure

Chem.

[0439] Step 2: N-(6-Bromo-2,3-diphenylquinolin-4-yl)methanesulfonamide

Chem.

[0440] Step 3: N-(6-((4-Methoxybenzyl)amino)-2,3-diphenylquinolin-4-yl)methanesulfonamide [Chemical formula] To a stirred solution of N-(6-bromo-2,3-diphenylquinolin-4-yl)methanesulfonamide (Preparation 13, Step 2) (383 mg, 0.84 mmol) in DMSO (15 mL) under an inert atmosphere was added p-methoxybenzylamine (0.667 mL, 5.06 mmol), followed by K 2 CO 3 (289.8 mg, 2.1 mmol), then CuI (80 mg, 0.50 mmol) and L-proline (39 mg, 0.336 mmol) were added. The resulting reaction mixture was transferred to a sealed tube and heated at 90 °C for 16 h. The progress of the reaction was monitored by LCMS and, after completion, the reaction mixture was poured into ice water. The aqueous reaction mixture was extracted with EtOAc and washed with brine. The organic layer was dried over anhydrous Na 2 SO 4 and concentrated in vacuo to give a crude product, which was purified by column chromatography to give the title compound (300 mg, 69.7% yield) as a yellow solid. LCMS m / z: 510.37 [M+H].

[0441] Step 4: N-(6-Amino-2,3-diphenylquinolin-4-yl)methanesulfonamide [Chemical formula] A solution of N-(6-((4-methoxybenzyl)amino)-2,3-diphenylquinolin-4-yl)methanesulfonamide (Preparation 13, Step 3) (293 mg, 0.575 mmol) in TFA (4 mL) was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC / LCMS and, after completion, the reaction mixture was diluted with water, neutralized with solid NaHCO 3 and extracted with EtOAc, washed with a saturated solution of NaHCO 3 and then with brine. The combined organics were dried over anhydrous Na 2 SO 4It was dried and concentrated in vacuo to give the title compound (400 mg, crude) as a yellow rubbery semi-solid, which was used in the next step without further purification. LCMS m / z: 390.31 [M+H].

[0442] Preparation 14: N-(6-(3-(2-Hydroxybutyl)ureido)-2,3-diphenylquinolin-4-yl)methanesulfonamide (Example 94) [Chemical formula] To a stirred solution of N-(6-amino-2,3-diphenylquinolin-4-yl)methanesulfonamide (Preparation 13, Step 4) (400 mg, 1.02 mmol) in THF (5 mL) was added p-nitrophenyl chloroformate (258.86 mg, 1.28 mmol), and the whole was stirred at room temperature for 1 h. After complete consumption of the amine by TLC, TEA (0.58 mL, 4.207 mmol) and 1-aminobutan-2-ol (0.12 mL, 1.28 mmol) were added dropwise, and the combined mixture was stirred at room temperature for an additional 3 h. The progress of the reaction was monitored by TLC / LCMS, and after completion, the reaction mixture was diluted with EtOAc and washed with 0.5 N NaOH solution, followed by brine. The organic layer was dried over anhydrous Na 2 SO 4 and concentrated in vacuo to give the crude product, which was purified by prep-HPLC to give the title compound (150 mg, 29% yield) as a white solid. LCMS m / z: 505.37 [M+H]; purity 98.16%; 1 HNMR (500 MHz; DMSO-d 6 ): δ 0.90 (t, J = 7.4Hz, 3H), 1.34 - 1.46 (m, 2H), 2.24 (s, 3H), 2.98 - 3.03 (m, 1H), 3.24 - 3.35 (m, 1H),3.45 (s, 1H), 4.81 (d, J = 5.1 Hz, 1H), 6.36 (d, J = 5.1 Hz, 1H), 7.22 - 7.34 (m,10H), 7.97 (d, J = 9 Hz, 1H), 8.05 (d, J = 9.15 Hz, 1H), 8.17 (s, 1H), 9.16 (s,1H), 9.56 (bs, 1H).

[0443] Example 145: 1-(6,7-Diphenyl-1,8-naphthyridin-3-yl)-3-(2-hydroxybutyl)urea

Chem.

[0444] Preparation 16: 6,7-Diphenyl-1,8-naphthyridin-3-amine

Chem.

Chem.

[0445] Step-2: N-(4-Methoxybenzyl)-6,7-diphenyl-1,8-naphthyridin-3-amine

Chem.

[0446] Step-3: 6,7-Diphenyl-1,8-naphthyridin-3-amine

Chemical Structure

[0447] Preparation 17: 1-(6,7-Diphenyl-1,8-naphthyridin-3-yl)-3-(2-hydroxybutyl)urea (Example 145) [Chemistry] To a stirred solution of 6,7-diphenyl-1,8-naphthyridin-3-amine (Preparation 16, Step 3) (150 mg, 0.504 mmol) in THF (3 mL) was added p-nitrophenyl chloroformate (152.51 mg, 0.757 mmol) at 0 - 5 °C, and the whole was stirred at room temperature for 3 h. TEA (0.352 mL, 2.52 mmol) and 1-aminobutan-2-ol (0.053 mL, 0.555 mmol) were added to the reaction mixture at the same temperature, and the whole was stirred for an additional 6 h. The reaction was monitored by LCMS, and after completion, the solvent was evaporated to give a crude product. The crude was purified by reverse phase prep-HPLC to give the title compound (23 mg, yield 11%) as an off-white solid. LCMS m / z: 413.5 [M+H]; purity 99.45%; 1 HNMR (400 MHz; DMSO-d 6 ): δ 0.89 (t, J = 7.4Hz, 3H), 1.32 - 1.39 (m, 1H), 1.41 - 1.48 (m, 1H), 2.98 - 3.05 (m, 1H), 3.23 - 3.28 (m,1H), 3.45 (d, J = 4.8 Hz, 1H), 4.78 (d, J = 5.08 Hz, 1H), 6.48 (d, J = 5.32 Hz,1H), 7.26 - 7.39 (m, 10H), 8.35 (s, 1H), 8.57 (d, J = 2.72 Hz, 1H), 8.93 (d, J =2.72 Hz, 1H), 9.28 (s, 1H).

[0448] Preparation 18: 6-Chloro-2,3-diphenyl-1,5-naphthyridine [Chemistry] Step-1: 3-Amino-6-chloropicolinamide [Chemistry] To a stirred solution of commercially available 3-amino-6-chloropicolinonitrile (4.0 g, 26.1 mmol) in EtOH (40.0 mL), SnCl2 (9.92 g, 52.3 mmol) was added and the reaction mixture was stirred at 90 °C for 16 h. The progress of the reaction was monitored by LCMS. After completion of the reaction, the excess solvent was concentrated under reduced pressure and the reaction mixture was quenched with 2M NaOH solution to pH 8 - 9, then the product was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine solution (1 × 30 mL) and dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under reduced pressure to afford the title compound (3.2 g, yield 71.2%) as a crude pale yellow solid, which was used in the next step without further purification. LCMS m / z: 172.0 [M+H].

[0449] Step-2: 3-Amino-6-chloropicolinic acid

Chemical Structure

[0450] Step-3: (3-Amino-6-chloropyridin-2-yl)methanol

Chemical Structure

[0451] Step-4: 3-Amino-6-chloropicolin aldehyde

Chemical formula

[0452] Step-5: 6-Chloro-2,3-diphenyl-1,5-naphthyridine

Chemical formula

[0453] Preparation 19: N-(4-Methoxybenzyl)-2,3-diphenyl-1,7-naphthyridin-6-amine [Chemical formula] Step-1: 6-Chloro-2,3-diphenyl-1,7-naphthyridine [Chemical formula] To a stirred solution of commercially available 5 - amino - 2 - chloroisonicotinaldehyde (300 mg, 1.92 mmol) in DMF (6.0 mL), K 2 CO 3 (265.7 mg, 1.92 mmol) and 1,2 - diphenylethan - 1 - one (377 mg, 1.92 mmol) were added, and the reaction mixture was stirred at 90 °C for 16 h. The progress of the reaction was monitored by LCMS. After completion, the reaction mixture was quenched with crushed ice and cold water (20 mL). The product was extracted using EtOAc (3 × 20 mL), and the combined organic layers were washed with brine solution (3 × 20 mL), dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by preparative TLC (20% EtOAc - hexane) to obtain the title compound (240 mg, yield 34.9%) as an off - white solid. LCMS m / z: 316.9 [M + H].

[0454] Step-2: N-(4-Methoxybenzyl)-2,3-diphenyl-1,7-naphthyridin-6-amine [Chemical formula] To a degassed solution of 6-chloro-2,3-diphenyl-1,7-naphthyridine (Preparation 19, Step-1) (100 mg, 0.32 mmol) in toluene (1 mL), p-methoxybenzylamine (0.08 mL, 0.63 mmol), K 3 PO 4 (201 mg, 0.95 mmol), BrettPhos (57.23 mg, 0.063 mmol) and BrettPhos-Pd-G1 (50.43 mg, 0.063 mmol) were added. The entire reaction mixture was capped and stirred at 130 °C in a microwave for 1 hour. After completion of the reaction (monitored by LCMS), the reaction mixture was quenched with water and extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with brine solution (1 × 10 mL) and dried over anhydrous Na 2 SO 4 and evaporated to give a crude product, which was purified by column chromatography (silica gel, eluent: 50% EtOAc in hexane), followed by prep-TLC to give the title compound (10 mg, crude) as a brown solid. LCMS m / z: 418.0 [M+H].

Table 1

Table 2

[0455] Example 128: N-(2,3-Bis(2-fluorophenyl)quinolin-6-yl)-4-hydroxyhexanamide

Chem.

[0456] Preparation 15: N-(2,3-Bis(2-fluorophenyl)quinolin-6-yl)-4-oxohexanamide (Example 124)

Chem.

[0457] Preparation 16: N-(2,3-Bis(2-fluorophenyl)quinolin-6-yl)-4-hydroxyhexanamide (Example 128)

Chem.

Table 3

[0458] Biological assay ACSS2 enzyme assay New compounds were screened in a human ACSS2 enzyme assay. Briefly, the ACSS2 enzyme reaction was monitored by directly measuring acetyl-CoA production. The cytoplasmic fraction of BT474 cells was used as the source of the ACSS2 enzyme. A short protocol for this assay is described below.

[0459] Preparation of cytoplasmic fraction from BT474 cells 9×10 6 cells were harvested by trypsinization followed by centrifugation. The cell pellet was washed with PBS and resuspended in 500 μl of STM buffer (50 mM Tris-HCl pH 7.4, 250 mM sucrose, 5 mM MgCl 2 and protease-phosphatase inhibitor cocktail), homogenized on ice at 600 - 1000 rpm for 1 minute, and then incubated for 30 minutes with intermittent vortexing. The supernatant was collected by centrifugation at 800 g for 15 minutes at 4°C. The cytoplasmic fraction was prepared by further centrifugation of the supernatant at 12000 g for 15 minutes at 4°C. The total protein content of the cytoplasmic fraction was estimated and diluted to a concentration of 1 mg / ml in storage buffer (25 mM Tris-HCl pH 7.4, 1 mM MgCl 2 , 1 mM DTT and 10% glycerol) and stored at -80°C for further use.

[0460] Assay protocol 25 mM Tris-HCl pH 7.4 1 mM MgCl 2100 ng of cytoplasmic fraction in a buffer composed of 1 mM DTT and 0.05% Tween 20 was pre-incubated for 5 minutes with a novel compound at the desired concentration while maintaining 1% DMSO. The reaction was initiated by the addition of a substrate mixture (100 μM acetic acid, CoA, and ATP) and incubated at 25 °C for 2 hours with constant shaking at 500 rpm. After incubation, the reaction was stopped by the addition of 10% TCA, followed by a 5-fold dilution in water. The reaction mixture was centrifuged at 800 g for 10 minutes at room temperature, and acetyl-CoA was detected in the supernatant by LC-MS / MS (QTrap5500 ABSCIEX).

[0461] Cell-based 14 C] Acetic acid uptake assay In cell assays, ACSS2 inhibitors were screened against 14 C] acetic acid uptake into macromolecules. 4 × 10 4 BT474 cells were seeded in a 96-well plate in growth medium composed of DMEM and 10% FBS and incubated overnight in a 37 °C, 5% CO 2 incubator. The next day, the cells were washed in HBSS, and the assay was performed in 100 μl of HBSS. 50 μl of 4× compound in 4% DMSO was added to the cells and pre-incubated at 37 °C for 10 minutes. 50 μl of acetic acid solution (0.1 μCi 14 C acetic acid + 10 μM 12 C acetic acid) was added to each well of the plate, and the plate was incubated in a 37 °C, 5% CO 2 incubator for 3 hours. After incubation, the cells were harvested in water onto a GF / C filter mat pre-soaked with polyethyleneimine (PEI), air-dried, and the radioactivity count was recorded with a Trilux microbeta liquid scintillation counter (PerkinElmer).

[0462] The following table lists the IC 50 value ranges of exemplary compounds. IC 50The range is indicated as "A" for values less than 100 nM, "B" for values up to 1 μM, "C" for values up to 10 μM, and "D" for values greater than 10 μM.

[0463] ACSS2 activity [Table 4] JPEG0007691974000302.jpg225149 JPEG0007691974000303.jpg200149

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt, solvate or tautomer thereof. 【Chemical 1】 [Wherein, X is CR ３ and Y is CR ４ and Z is CR ５ or N, and L is NR ８ and R is selected from the group consisting of H, optionally substituted C of monocyclic or bicyclic ６ -C １２ aryl, optionally substituted 5- to 10-membered heteroaryl of monocyclic or bicyclic, optionally substituted C １ -C ６ alkyl, optionally substituted monocyclic or bicyclic C ３ -C ６ cycloalkyl, optionally substituted monocyclic or bicyclic C ３ -C ６ cycloalkenyl, optionally substituted C ２ -C ６ alkenyl, and optionally substituted C ２ -C ６ alkynyl, R １ is selected from the group consisting of monocyclic or bicyclic optionally substituted C ６ -C １２ aryl, monocyclic or bicyclic optionally substituted 5- to 10-membered heteroaryl, optionally substituted C １ -C ６ alkyl, optionally substituted monocyclic or bicyclic C ３ -C ６ cycloalkyl, optionally substituted monocyclic or bicyclic C ３ -C ６ cycloalkenyl, and when R １ is optionally substituted alkyl, the alkyl is unsubstituted or substituted with one or more of halogen, optionally substituted C ６ -C １２ aryl or optionally substituted 5- to 10-membered heteroaryl. R ２ is H, halogen, COOR ９ , CN, CONR ９ R １０ , NR ９ R １０ , NR ９ SO ２ R １０ , SO ２ NR ９ R １０ , NR ９ COR １０ , optionally substituted C １ -C ６ alkyl, optionally substituted monocyclic or bicyclic 3- to 8-membered heterocycle, optionally substituted C １ -C ６ alkoxy, optionally substituted monocyclic or bicyclic C ６ -C １２ aryl or optionally substituted monocyclic or bicyclic 5- to 10-membered heteroaryl, R ３ is H, halogen, optionally substituted C １ to C ６ alkyl, optionally substituted monocyclic or bicyclic C ３ to C ６ cycloalkyl, optionally substituted monocyclic or bicyclic 3- to 8-membered heterocyclic ring, optionally substituted C １ to C ６ alkoxy, monocyclic or bicyclic optionally substituted C ６ to C １２ aryl or monocyclic or bicyclic optionally substituted 5- to 10-membered heteroaryl, R ４ and R ５ are each independently selected from the group consisting of H and halogen, R ６ is H, R ７ is H, C optionally substituted with ３ -C ６ alkyl, C optionally substituted with ２ -C ６ alkenyl, C optionally substituted with ２ -C ６ alkynyl, monocyclic or bicyclic C optionally substituted with ６ -C １２ aryl, monocyclic or bicyclic 5- to 10-membered heteroaryl optionally substituted with, monocyclic or bicyclic C optionally substituted with ３ -C ６ cycloalkyl, or monocyclic or bicyclic 3- to 8-membered heterocyclic optionally substituted with, and R ８ is H, R ９ and R １０ are each independently selected from the group consisting of H, optionally substituted monocyclic or bicyclic C ６ -C １２ aryl, optionally substituted monocyclic or bicyclic 5- to 10-membered heteroaryl, optionally substituted C １ -C ６ alkyl, optionally substituted monocyclic or bicyclic C ３ -C ６ cycloalkyl, optionally substituted monocyclic 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 and NH ２ and are each independently selected from the group consisting of: Unless otherwise specified, The optionally substituted alkyl is unsubstituted or is halogen, OH, optionally substituted C １ -C ６ -alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, NR ９ R １０ , C(O)R ９ , CN, oxo, azide, OP(O)(OH) ２ , OC(O)R ９ , COOR ９ , C １ -C ６ -alkenyl, =NOR ９ , NR ９ C(O)R １０ , SO ２ R ９ , SO ２ , NR ９ R １０ , optionally substituted C ６ -C １２ -aryl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted C ３ -C ６ -cycloalkyl and one or more of optionally substituted 3- to 8-membered heterocycles, The alkenyl optionally substituted is unsubstituted or is optionally substituted C １ -C ６ alkyl, optionally substituted C １ -C ６ alkynyl, halogen, OH, optionally substituted C １ -C ６ alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, NR ９ R １０ , C(O)R ９ , CN, oxo, azide, OP(O)(OH) ２ , OC(O)R ９ , COOR ９ , C １ -C ６ alkenyl, =NOR ９ , NR ９ C(O)R １０ , SO ２ R ９ , SO ２ , NR ９ R １０ , optionally substituted C ６ -C １２ aryl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted C ３ -C ６ cycloalkyl and is substituted with one or more of optionally substituted 3- to 8-membered heterocycles, The optionally substituted alkynyl is unsubstituted or is optionally substituted C １ -C ６ alkyl, optionally substituted C ２ -C ６ alkenyl, halogen, OH, optionally substituted C １ -C ６ alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, NR ９ R １０ 、C(O)R ９ 、CN, oxo, azide, OP(O)(OH) ２ 、OC(O)R ９ 、COOR ９ 、C １ -C ６ alkenyl, =NOR ９ 、NR ９ C(O)R １０ 、SO ２ R ９ 、SO ２ NR ９ R １０ 、optionally substituted C ６ -C １２ aryl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted C ３ -C ６ cycloalkyl and is substituted with one or more of optionally substituted 3- to 8-membered heterocycles, The optionally substituted alkoxy is unsubstituted or is halogen, OH, NR ９ R １０ , C(O)R ９ , CN, oxo, azide, OP(O)(OH) ２ , OC(O)R ９ , COOR ９ , C １ ~C ６ alkenyl, =NOR ９ , NR ９ C(O)R １０ , SO ２ R ９ , SO ２ , NR ９ R １０ , optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted C ６ ~C １２ aryl, optionally substituted 5- to 10-membered heteroaryl, C ３ ~C ６ cycloalkyl and one or more of 3- to 8-membered heterocycles, and The optionally substituted aryl is unsubstituted or optionally substituted C １ -C ６ alkyl, optionally substituted C １ -C ６ alkenyl, optionally substituted C １ -C ６ alkynyl, halogen, OH, optionally substituted C １ -C ６ alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, NR ９ R １０ , C(O)R ９ , CN, azide, OP(O)(OH) ２ , OC(O)R ９ , COOR ９ , C １ -C ６ alkenyl, =NOR ９ , NR ９ C(O)R １０ , SO ２ R ９ , SO ２ , NR ９ R １０ , optionally substituted C ６ -C １２ aryl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted C ３ -C ６ substituted with one or more of cycloalkyl and optionally substituted 3- to 8-membered heterocycles, The optionally substituted aryloxy is C where the aryl is optionally substituted ６ ~C １２ refers to an aryl-O-group which is an aryl group The cycloalkyl or cycloalkenyl optionally substituted is unsubstituted or optionally substituted C １ -C ６ alkyl, optionally substituted C １ -C ６ alkenyl, optionally substituted C １ -C ６ alkynyl, halogen, OH, optionally substituted C １ -C ６ alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, NR ９ R １０ , C(O)R ９ , CN, oxo, azide, OP(O)(OH) ２ , OC(O)R ９ , COOR ９ , C １ -C ６ alkenyl, =NOR ９ , NR ９ C(O)R １０ , SO ２ R ９ , SO ２ , NR ９ R １０ , optionally substituted C ６ -C １２ aryl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted C ３ -C ６ cycloalkyl and is substituted with one or more of optionally substituted 3- to 8-membered heterocycles, The heteroaryl optionally replaced is unsubstituted or is optionally substituted with C １ -C ６ alkyl, optionally substituted C １ -C ６ alkenyl, optionally substituted C １ -C ６ alkynyl, halogen, OH, optionally substituted C １ -C ６ alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, NR ９ R １０ , C(O)R ９ , CN, oxo, azide, OP(O)(OH) ２ , OC(O)R ９ , COOR ９ , C １ -C ６ alkenyl, =NOR ９ , NR ９ C(O)R １０ , SO ２ R ９ , SO ２ , NR ９ R １０ , optionally substituted C ６ -C １２ aryl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted C ３ -C ６ cycloalkyl and is substituted with one or more of optionally substituted 3- to 8-membered heterocycles, The optionally substituted complex ring is unsubstituted or optionally substituted C １ -C ６ alkyl, optionally substituted C １ -C ６ alkenyl, optionally substituted C １ -C ６ alkynyl, halogen, OH, optionally substituted C １ -C ６ alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, NR ９ R １０ , C(O)R ９ , CN, oxo, azide, OP(O)(OH) ２ , OC(O)R ９ , COOR ９ , C １ -C ６ alkenyl, =NOR ９ , NR ９ C(O)R １０ , SO ２ R ９ , SO ２ , NR ９ R １０ , optionally substituted C ６ -C １２ aryl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted C ３ -C ６ cycloalkyl and one or more of optionally substituted 3- to 8-membered complex rings. ]

2. R is selected from the group consisting of 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, and an optionally substituted 5- or 6-membered heteroaryl, the compound according to claim 1 or a pharmaceutically acceptable salt, solvate or tautomer thereof.

3. R １ is a phenyl ring optionally substituted, C １ to C ６ alkyl, or a 5- or 6-membered heteroaryl optionally substituted, the compound according to claim 1 or a pharmaceutically acceptable salt, solvate or tautomer thereof.

4. R and R １ The compound according to claim 1, or a pharmaceutically acceptable salt, solvate or tautomer thereof, wherein R and R are each a phenyl ring optionally substituted or methyl.

5. 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 to C ６ alkyl, optionally substituted C １ to C ６ alkoxy, monocyclic or bicyclic optionally substituted C ６ to C １２ aryl or monocyclic or bicyclic optionally substituted 5- to 10-membered heteroaryl, the compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt, solvate or tautomer thereof.

6. X is CR ３ and Y is CR ４ and Z is CR ５ The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, solvate or tautomer thereof.

7. X is CR ３ wherein Y is CR ４ wherein Z is N, the compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, solvate or tautomer thereof.

8. R ３ is H, halogen, optionally substituted C １ -C ６ -C alkyl, monocyclic or bicyclic optionally substituted C ６ -C １２ -C aryl, monocyclic or bicyclic optionally substituted C ３ -C ６ -C cycloalkyl or monocyclic or bicyclic optionally substituted 5- to 10-membered heteroaryl, a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt, solvate or tautomer thereof.

9. R ４ and / or R ５ is halogen, and the halogen is F, the compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, solvate or tautomer thereof.

10. R ４ and R ５ is H, a compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt, solvate or tautomer thereof.

11. R ７ is optionally substituted C ３ to C ６ alkyl, optionally substituted C ２ to C ６ alkenyl, optionally substituted C ２ to C ６ alkynyl, optionally substituted phenyl, optionally substituted 5- or 6-membered heteroaryl, optionally substituted C ３ to C ６ cycloalkyl, or an optionally substituted 3- to 6-membered heterocyclic ring, a compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt, solvate or tautomer thereof.

12. 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; 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; 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; (R)-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; (R)-1-Cyclohexyl-3-(2,3-diphenylquinolin-6-yl)urea; (R)-1-Allyl-3-(2,3-diphenylquinolin-6-yl)urea; (R)-1-(2,3-Diphenylquinolin-6-yl)-3-(prop-2-yn-1-yl)urea; (R)-1-(2,3-Diphenylquinolin-6-yl)-3-(2-hydroxycyclopentyl)urea; (R)-1-(2,3-Diphenylquinolin-6-yl)-3-(tetrahydro-2H-pyran-4-yl)urea; (R)-1-(2,3-Diphenylquinolin-6-yl)-3-(pyridin-2-yl)urea; (R)-1-(2,3-Diphenylquinolin-6-yl)-3-phenylurea; (R)-1-(2,3-Diphenylquinolin-6-yl)-3-(1-methylpyrrolidin-3-yl)urea; (R)-1-(2,3-Diphenylquinolin-6-yl)-3-(pyridin-4-yl)urea; (R)-1-(2,3-Diphenylquinolin-6-yl)-3-(1-(hydroxymethyl)cyclopentyl)urea; (R)-1-(2,3-Diphenylquinolin-6-yl)-3-(1-methyl-1H-pyrazol-4-yl)urea; (R)-1-(6,7-Diphenyl-1,8-naphthyridin-3-yl)-3-(2-hydroxybutyl)urea; or (R)-1-(6,7-Diphenyl-1,8-naphthyridin-3-yl)-3-(2-hydroxybutyl)urea The compound according to claim 1, or a pharmaceutically acceptable salt, solvate or tautomer thereof.

13. A pharmaceutical composition comprising the compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt, solvate or tautomer thereof, and a pharmaceutically acceptable vehicle.

14. The pharmaceutical composition according to claim 13 for use in therapy.

15. The pharmaceutical composition according to claim 13 for use in the treatment, remission or prevention of a disease selected from cancer, bacterial infection, viral infection, parasitic infection, fungal infection, neurodegenerative disease, neuropathy, cerebrovascular disease, cardiovascular disease, non-alcoholic fatty liver disease and obesity.

16. wherein the disease is cancer and the cancer is selected from the group consisting of colorectal cancer, airway-gastrointestinal squamous cell carcinoma, gastrointestinal stromal tumor, lung cancer, brain cancer, neuroblastoma, glioma, astrocytoma, glioblastoma, liver cancer, gastric cancer, sarcoma, leukemia, lymphoma, multiple myeloma, ovarian cancer, uterine cancer, breast cancer, melanoma, prostate cancer, bladder cancer, pancreatic cancer or renal cancer, or wherein the disease is a viral infection and the viral infection is a hepatitis C virus (HCV) infection or a human cytomegalovirus (HCMV) infection, the pharmaceutical composition according to claim 15.

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