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

Abstract

The present invention relates to compounds of formula (I). The compounds can be used to regulate acetyl-CoA synthetase short chain 2 (ACSS2) protein and can thereby treat, improve or prevent diseases 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 in addition, the compounds can be used to promote healthy aging. (I)

Description

Technical Field

[0001] The present invention relates to a method for inhibiting acetyl-CoA synthetase short-chain 2 (ACSS 2 ) protein. Thus, the small molecules can be used to treat diseases such as cancer, cardiac disorders, metabolic disorders, neurological disorders, fibrotic diseases, aging disorders, bacterial and viral infections, etc. The present invention extends to pharmaceutical compositions of the compounds themselves, methods for preparing the compounds, and methods for inhibiting ACSS 2 Protein method. Background Art

[0002] Acetyl CoA synthetase (ACSS 1-3 ) family of cellular enzymes that complete the first enzymatic step by linking acetate to CoA in an ATP-driven process, converting acetate to the multifunctional metabolite acetyl-CoA (Knowles, SE; Jarrett, IG; Filsell, OH; Ballard, FJ, Biochem. J., 1974, 142 ,401-411). ACSS 1 and ACSS 3 ACSS is mainly expressed in the mitochondria of cells. 2 Expressed in both the nuclear compartment and the cytoplasmic compartment (Fujino, T.; Kondo, J.; Ishikawa, M.; Morikawa, K.; Yamamoto, TT, J. Biol. Chem., 2001, 276 ,11423-11426; Luong, A.; Hannah, VC; Brown, MS; Goldstein, JL, Journal of Biological Chemistry, 2000, 275 , 26458-26466; Ariyannur, PS; Moffett, JR; Madhavarao, CN; Arun, P. et al., Journal of Comparative Neurology (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, JM, et al., Cell. Metab., 2015, 21 , 805-821). In well-fed mammalian cells, acetyl CoA enters the citric acid cycle by condensing with oxaloacetate to form citrate and, from this, a variety of other metabolites (Srere, PA, J. Biol. Chem., 1959, 234 , 2544-2547). It is a key intermediate in carbon sources and a basic building block for the synthesis of fatty acids, amino acids and sterols.

[0004] Cell growth and proliferation are closely related to metabolism and acetyl CoA availability. One of the hallmarks of cancer is rapid, uncontrolled cell proliferation, which requires the production of increased energy and biomass by ATP and lipid production. This relates to changes in both the capture mode of extracellular nutrients and its metabolic mode. The strategy of increasing metabolic rate and enhancing proliferation capacity adopted by targeted cancer cells under conditions of limited nutrients is an attractive anticancer treatment. It especially forces the source of the key cytoplasmic regulator (i.e. acetyl CoA) of the synthetic targeting lipids, cholesterol and amino acids.

[0005] In nutrient-limited conditions (e.g., in cancer cells), aerobic glycolysis occurs and pyruvate formed from glucose metabolism is preferentially converted to lactate by reduction rather than used to synthesize acetyl CoA (the "Warburg Effect"). In response, acetate uptake and ACSS 2 Both were upregulated and there was a significant shift in obtaining acetyl-CoA from other nutrients, a critical dependence on ACSS 2 to synthesize acetyl CoA.

[0006] Acetate is absorbed and metabolized into biomass by lipid-depleted proliferating hypoxic tumor cells (Corbet, C.; Feron, O., Curr. Op. Clin. Nutr. Metab. Care, 2015, 18 , 346-353). For more than a decade, the propensity of certain tumors to take up acetate has been used to detect primary tumors and identify distant metastases, using 11C-acetate-guided positron emission tomography (PET) imaging is used to detect or grade metastases in patients with glioma, hepatocellular carcinoma, non-small cell lung cancer, and prostate cancer. This reinforces the conclusion of earlier studies that tumor cells often take up large amounts of acetate as a nutrient in preference to glucose to meet their increased acetyl-CoA requirements (Yoshimoto, M.; Waki, A.; Yonekura, Y.; Sadato, N. et al., Nucl. Med. Biol., 2001, 28 ,117-122).

[0007] There is growing clinical evidence that acetate and ACSS 2 Located at a key metabolic node in tumor cells. Genome analysis revealed that ACSS 2 Copy number is associated with higher and more aggressive stages of breast cancer and metastatic prostate cancer (Schug, ZT; Peck, B.; Jones, DT; Zhang, Q.; Grosskurth, S. et al., Cancer Cell, 2015, 27 ,57-71). Compared with those who exhibited small or no ACSS 2 Expression of matched normal specimens was compared using anti-ACSS 2 The antibody showed significant expression in immunohistochemical analysis (IHC) performed on human breast, ovarian, kidney and lung tumor specimens. Patients with grade 2 / 3 glioma (Mashimo, T.; Pichumani, K.; Vemireddy, V.; Hatanpaa, KJ, Cell, 2014, 159 , 1603-1614) or triple-negative breast cancer (Comerford, SA; Huang, Z.; Du, X.; Wang, Y. et al., Cell, 2014, 159 ,1591-1602) revealed that high ACSS 2 These clinical findings show that acetate uptake, ACSS 2 There is a strong correlation between ACSS expression and cancer progression. This suggests that inhibition of ACSS 2 Activity may benefit patients with acetate-metabolizing tumors.

[0008] Hypoxic tumor cells express high levels of cytoplasmic ACSS 2 Knockdown of ACSS in tumor cells by RNA interference 2 It can enhance tumor cell death under long-term hypoxia in vitro and slow tumor growth in vivo (Yoshii, Y.; Furukawa, T.; Yoshii, H.; Mori, T. et al., Cancer Sci., 2009, 100 ,821-827), thus confirming that ACSS 2 The role of ACSS in tumor progression and provides a rationale for pharmacological inhibitors. 2 Interfering with acetate metabolism through activation would deprive resilient tumor cells of a key nutrient source and could arrest or terminate the growth of refractory tumors.

[0009] ACSS 2 Donates acetyl CoA to histone acetyltransferase to acetylate lysine residues on histones (Takahashi, H.; McCaffery, JM; Irizarry, RA; Boeke, JD, Mol. Cell, 2006, 23 , 207-217) and thereby regulate the transcription of growth genes by epigenetically modifying chromatin (Kaelin, WG; McKnight, SL, Cell, 2013, 153 , 56-69). Aberrant chromatin regulation can affect different cellular processes that depend on acetylation (e.g., glucose homeostasis, neuronal gene transcription, autophagy, and mitochondrial respiration) and is associated with pathologies such as neurodegeneration, neurological disorders, immune deficiencies, and metabolic diseases (Mirabella, AC; Foster, BM; Bartke, T., Chromosoma, 2016, 125 , 75-93). Given the extent to which cancer cells utilize metabolic adaptations to meet their elevated energy and biomass demands, it has been proposed that cancer cells may also produce major changes in their epigenetic footprint to favor tumor growth and survival (Lu, C.; Thompson, CB, Cell Metabolism, 2012, 16 ,9-17).

[0010] The heterodimeric stress-responsive transcription factor hypoxia-inducible factor 2α (HIF-2α) is regulated by acetylation of Creb binding protein (CBP), which in turn generates acetyl-CoA (via ACSS) 2 ) regulation (Chen, R.; Xu, M.; Nagati, JS; Hogg, RT; Das, A. et al., PLoS One, 2015, 10 ,e0116515). Knockdown of ACCS in tumor cells 2 Expression of HIF-2α or HIF-2α impaired cell proliferation, cell migration and invasion during hypoxia and resulted in a significant reduction in tumor burden in mice bearing HT1080 flank tumors.

[0011] ACSS 2 It is post-translationally modified by the NAD-dependent deacetylase sirtuin. Sirtuins play a central role in energy homeostasis and aging and have been proposed to regulate ACSS. 2 and acetate metabolism may also play a central role in aging (Shimazu, T.; Hirschey, MD; Huang, Y.; Ho, LTY; Verdin, E., Mech. Ageing Develop., 2010, 131 ,511-516).

[0012] The etiology of aging is multifactorial but manifests as a gradual decline in metabolic performance. As individuals age, there is an accumulation of cellular damage and changes in endogenous repair and detoxification processes. Healthy aging depends on the effective removal of damaged cellular material, which is mediated in part by autophagy (Eisenberg, T.; Schroeder, S.; Andryushkova, A. et al., Cell Metabolism, 2014, 19 , 431-444). Knockdown of ACCS in mammalian cells 2 It can strongly induce autophagy and maintain lifespan, while nutrient starvation of cells achieves the same effect (Marino, G.; Pietrocola, F.; Ischberg, T.; Kong, Y., et al., Molecular Cell, 2014, 53 ,710-725).

[0013] Human cytomegalovirus (HCMV) induces a steady increase in lipid synthesis to increase the chances of productive infection. 2 In knockout human fibroblasts, both HCMV-induced lipid production and viral growth were significantly reduced compared with normal controls (Vysochan, A.; Sengupta, A.; Weljie, AM; Alwine, JC; Yu, Y.), PNAS, 2017, 114 ,E1528-E1535), which indicates damage to ACSS 2 It may be useful as an antiviral therapy for some types of infections.

[0014] Martinez-Micaelo et al. have shown that ACSS 2 It is a nutrient sensing protein and a key regulator of metabolic homeostasis (Martinez-Micaelo, N.; Gonzalez-Abuin, N.; Terra, X.; Ardevol, A.; Pinent, M., et al., Disease Mod. Mechan., 2016, 9 ,1231-1239). ACSS 2 Gene expression correlates with hepatic concentrations of TCA-related metabolites and plasma levels of glucose. Phosphoprotein analysis in mice fed a high-fat diet (Shaik, AA; Qiu, B.; Wee, S.; Choi, H. et al., Nature, 2016, 6 , 25844) showed that several enzymes involved in lipid and glucose homeostasis underwent a series of phosphorylation changes (including ACSS 2 Huang et al. observed that in a diet-induced obesity model, knockdown of ACSS 2 After the treatment, the body weight and hepatic sebaceous gland disease were significantly reduced. 2 Deficiency appears to reduce dietary lipid absorption and lipid transport to the liver (Huang, Z.; Zhang, M.; Plec, AA; Estill, SJ, et al., PNAS, 2018, 115 , E9499-E9506) and controls systemic lipid metabolism according to acetate availability. These studies indicate that ACSS 2Selective inhibitors of β-lactamase may have therapeutic benefit in obesity and fatty liver disease.

[0015] This evolving knowledge has inspired the development of ACSS 2 Numerous studies have been conducted on the possible therapeutic applications of inhibition.

[0016] Therefore, there remains a need for improved therapies for treating diseases that may be difficult to treat using traditional treatment modalities, such as cancer, neurological disorders, and metabolic disorders. There is a need to develop improved compositions and methods in this area. In particular, there is a need to inhibit human ACSS 2 Protein compounds and methods of treating diseases that may benefit from such modulation. Summary of the invention

[0017] The present invention originated from the inventor's attempt to identify ACSS 2 Protein inhibitors work.

[0018] In a first aspect of the present invention, there is provided a compound of formula (I):

[0019]

[0020] , where X is CR 3 or N;

[0021] Y is CR 4 or N;

[0022] Z is CR 5 or N;

[0023] L is NR 8 or does not exist;

[0024] R and R 1 are each independently selected from the group consisting of: H, an 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 10 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 10 Alkenyl, optionally substituted C 2 -C 10 alkynyl, optionally substituted monocyclic or bicyclic 3 to 8 membered heterocycle, optionally substituted C 1 -C 10 Alkoxy and NR9 R 10 ;

[0025] R 2 H, halogen, COOR 9 、CN、CONR 9 R 10 NR 9 SO 2 R 10 、SO 2 NR 9 R 10 NR 9 COR 10 , optionally substituted C 1 -C 10 alkyl, an optionally substituted monocyclic or bicyclic 3 to 8 membered heterocycle, an optionally substituted C 1 -C 10 Alkylsulfonyl, NR 9 R 10 , optionally substituted C 1 -C 10 Alkoxy, optionally substituted monocyclic or bicyclic C 6 -C 12 aryl or optionally substituted monocyclic or bicyclic 5- to 10-membered heteroaryl;

[0026] R 3 H, CN, halogen, COOH, CONR 9 R 10 NR 9 R 10 、NO 2 , optionally substituted C 1 -C 10 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 10 Alkenyl, optionally substituted C 2 -C 10 alkynyl, optionally substituted monocyclic or bicyclic 3 to 8 membered heterocycle, optionally substituted C 1 -C 10 Alkoxy, optionally substituted monocyclic or bicyclic C 6 -C 12 aryl or optionally substituted monocyclic or bicyclic 5- to 10-membered heteroaryl;

[0027] R 4 and R 5are each independently selected from the group consisting of: H, halogen, OH, CN, an optionally substituted monocyclic or bicyclic C 6 -C 12 Aryl, optionally substituted C 1 -C 10 alkyl, an optionally substituted monocyclic or bicyclic 3 to 8 membered heterocycle, an optionally substituted C 1 -C 10 Alkoxy and optionally substituted monocyclic or bicyclic C 3 -C 6 Cycloalkyl;

[0028] R 6 is H or optionally substituted C 1 -C 10 alkyl;

[0029] R 7 is H, optionally substituted C 1 -C 10 Alkyl, optionally substituted C 2 -C 10 Alkenyl, optionally substituted C 2 -C 10 Alkynyl, 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 C 3 -C 6 cycloalkyl or an optionally substituted monocyclic or bicyclic 3 to 8 membered heterocycle;

[0030] R 8 is selected from the group consisting of H, halogen and optionally substituted C 1 -C 10 alkyl; and

[0031] R 9 and R 10 are each independently selected from the group consisting of: H, an 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 10 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 10 Alkenyl, optionally substituted C2 -C 10 Alkynyl, optionally substituted C 1 -C 10 Alkoxy and NH 2 ;

[0032] or a pharmaceutically acceptable complex, salt, solvate, tautomeric form or polymorph thereof.

[0033] The inventors have found that compounds of formula (I) are useful in therapy or as medicaments.

[0034] The present invention also extends to conjugates of compounds of formula (I).

[0035] Therefore, in a second aspect of the present invention, there is provided a conjugate of formula (II):

[0036]

[0037] Wherein, C is a compound of formula (I);

[0038] L 1 and L 2 It is a connectome;

[0039] T is a targeting moiety; and

[0040] a is an integer between 1 and 5;

[0041] b is an integer between 1 and 10; and

[0042] z is an integer between 1 and 5.

[0043] It will be appreciated that hydrogen may be removed from a compound of formula (I) and L 1 Can bond to positions where hydrogen would otherwise exist.

[0044] The conjugates can be designed to specifically target certain cell types or tumor types via a targeting moiety that directs the compound of formula (I) only to those cells or tumors and delivers the ACSS in a cell-specific manner. 2 Inhibitors. It is known to those skilled in the art that the principle of this targeted delivery is closely related to ADC (antibody-drug conjugate) technology, for example, as Polakis, P., Pharmacol. Revs., 2016, 68 , 3-19. The linker is designed to be cleaved and the active compound then diffuses into the cell and contacts the ACSS 2 protein.

[0045] Thus, in a third aspect, there is provided a compound of formula (I) or a pharmaceutically acceptable complex, salt, solvate, tautomeric form or polymorph thereof, or a conjugate of formula (II) for use in therapy.

[0046] The inventors have also found that the compound of formula (I) and the conjugate of formula (II) can be used to regulate the short chain of acetyl-CoA synthetase 2 (ACSS 2 )protein.

[0047] Therefore, in a fourth aspect, there is provided a method for regulating the short chain reaction of acetyl-CoA synthetase. 2 (ACSS 2 ) protein or a compound of formula (I) or a pharmaceutically acceptable complex, salt, solvate, tautomer or polymorph thereof or a conjugate of formula (II).

[0048] Preferably, the compound of formula (I) or the conjugate of formula (II) is used to inhibit or inactivate ACSS 2 The compound of formula (I) or the conjugate of formula (II) can be used to inhibit or inactivate ACSS 2 Enzymatic activity as evidenced by a decrease in one or more biological effects selected from the group consisting of: acetyl-CoA production, acetate incorporation into lipids, acetate incorporation into tissue proteins, and acetate incorporation in tumor cells.

[0049] By inhibiting ACSS 2 Proteins that can treat, improve or prevent cancer, bacterial infections, viral infections, parasitic infections, neurodegenerative diseases, cardiovascular diseases, fatty liver disease, metabolic disorders and promote healthy aging.

[0050] Advantageously, the compounds and conjugates of the present invention selectively inhibit only one subtype of the human ACCS protein family. 2 A strong inhibitor of , but not ACSS 1 or ACSS 3 .

[0051] By inhibiting ACSS 2 Proteins that can treat, improve or prevent cancer, bacterial infections, viral infections, parasitic infections, fungal infections, neurodegenerative diseases, neurological disorders, cerebrovascular diseases, cardiovascular diseases, non-alcoholic fatty liver disease, obesity and promote healthy aging.

[0052] Therefore, in a fifth aspect, a compound of formula (I) or a pharmaceutically acceptable complex, salt, solvate, tautomeric form or polymorph thereof or a conjugate of formula (II) is provided for use in treating, ameliorating or preventing a disease selected from cancer, bacterial infection, viral infection, parasitic infection, fungal infection, neurodegenerative disease, neurological disorder, cerebrovascular disease, cardiovascular disease, non-alcoholic fatty liver disease and obesity, or for promoting healthy aging.

[0053] Preferably, the disease is cancer.

[0054] In a sixth aspect, a method for inhibiting ACSS in an individual is provided. 2 A method for treating a protein, the method comprising administering to a subject in need of treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable complex, salt, solvate, tautomeric form or polymorph thereof, or a conjugate of formula (II).

[0055] Preferably, the method comprises inhibiting ACSS 2 protein.

[0056] In a seventh aspect, a method for 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, metabolic disorder, non-alcoholic fatty liver disease and obesity, or promoting healthy aging is provided; the method comprises administering to an individual in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable complex, salt, solvate, tautomeric form or polymorph thereof, or a conjugate of formula (II).

[0057] It will be appreciated that the term "prevent" may mean "reduce the likelihood of."

[0058] The neurodegenerative disorder may be amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease or Huntington's disease. The neurological disorder may be anxiety, depression, autism or post-traumatic stress disorder.

[0059] Parasitic infections can be malaria.

[0060] The metabolic disorder may be obesity or fatty liver disease (eg non-alcoholic steatohepatitis).

[0061] Promoting healthy aging may involve restoring or enhancing autophagy and autophagic protein clearance.

[0062] In a preferred embodiment, the disease is cancer. The cancer may be selected from the group consisting of colorectal cancer, aerodigestive tract squamous cell carcinoma, gastrointestinal stromal tumor, lung cancer, brain cancer, neuroblastoma, glial tumor, 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. In some embodiments, the cancer in the tissue may have upregulated ACSS compared to healthy individuals. 2 Expression and / or ACSS 2 active.

[0063] 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. DETAILED DESCRIPTION

[0064] Unless the context indicates otherwise, the following definitions apply in conjunction with the compounds of the present invention.

[0065] Throughout the description and claims of this specification, the word "comprise" and other forms of the word (such as "comprising and comprises") mean inclusion (but not limited to), and are not intended to exclude (for example) other additives, components, integers or steps.

[0066] As used in the specification 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 a mixture of two or more such compositions.

[0067] “Optional” or “optionally” means that the subsequently described event, action, or circumstance can or cannot occur, and that the description includes instances where the event, action, or circumstance occurs and instances where it does not.

[0068] Unless otherwise specified, the term "alkyl" as used herein refers to a saturated straight or branched hydrocarbon. In certain embodiments, the alkyl group is a primary, secondary, or tertiary hydrocarbon. In certain embodiments, the alkyl group contains one to ten carbon atoms, i.e., C 1 -C 10 Alkyl. C 1 -C 10 Alkyl groups include, 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. Alkyl groups may be unsubstituted or substituted with one or more of the following: halogen, OH, optionally substituted C1 -C 6 alkyloxy, 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 an optionally substituted 3 to 8 membered heterocycle. Thus, it is understood that the optionally substituted C 1 -C 10 The alkyl group may be an optionally substituted C 1 -C 10 Haloalkyl (i.e., C 1 -C 10 alkyl), and optionally further substituted with one or more of the following groups: OH, optionally substituted C 1 -C 6 alkyloxy, 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 12aryl, optionally substituted 5- to 10-membered heteroaryl, C 3 -C 6 cycloalkyl and an optionally substituted 3 to 8 membered heterocycle. 1 -C 10 The alkyl group may be a polyfluoroalkyl group, preferably C 1 -C 3 Polyfluoroalkyl. 9 and R 10 May be as defined in relation to the first aspect. 9 and R 10 can be each independently selected from the group consisting of: H, halogen and optionally substituted C 1 -C 6 alkyl.

[0069] Unless otherwise specified, the term "alkylene" as used herein refers to a divalent saturated straight or branched hydrocarbon. In certain embodiments, an alkylene group is a primary, secondary, or tertiary hydrocarbon. In certain embodiments, an alkylene group contains one to six carbon atoms, i.e., C 1 -C 6 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 substituted with one or more of the following groups: optionally substituted C 1 -C 6 Alkyl, halogen, OH, optionally substituted C 1 -C 6 alkyloxy, 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 12aryl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted C 3 -C 6 cycloalkyl and an optionally substituted 3 to 8 membered heterocycle. Thus, it is understood that the optionally substituted C 1 -C 6 The alkylene group may be an optionally substituted C 1 -C 6 Haloalkylene (i.e., C 1 -C 6 alkylene), and optionally further substituted with one or more of the following groups: optionally substituted C 1 -C 6 Alkyl, OH, optionally substituted C 1 -C 6 alkyloxy, 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 heterocycle. It should be understood that optionally substituted C 1 -C 6 The alkylene group may be an optionally substituted polyfluoroalkylene group, preferably C 1 -C 3 Polyfluoroalkylene. 9 and R 10 May be as defined in relation to the first aspect. 9 and R 10 can be each independently selected from the group consisting of: H, halogen and optionally substituted C 1 -C 6 alkyl.

[0070] The term "halo" or "halogen" encompasses fluorine (-F), chlorine (-Cl), bromine (-Br), and iodine (-I).

[0071] The term "polyfluoroalkyl" may refer to a C 1 -C 3 The term may include perfluoroalkyl groups, that is, C alkyl groups in which all hydrogen atoms are replaced by fluorine atoms. 1 -C 3 Therefore, the term C 1 -C 3 Polyfluoroalkyl groups include, but are 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.

[0072] "Alkoxy" refers to a group R 11 -O-, where R 11 is optionally substituted C 1 -C 6 Alkyl, optionally substituted C 3 -C 6 Cycloalkyl, optionally substituted C 2 -C 6 alkenyl or optionally substituted C 2 -C 6 Alkynyl. Example C 1 -C 6 Alkoxy includes, but is not limited to, methoxy, ethoxy, n-propoxy (1-propoxy), n-butoxy, and tert-butoxy. Alkoxy may be unsubstituted or substituted with one or more of the following groups: 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, C3 -C 6 Cycloalkyl and 3 to 8 membered heterocyclic ring. 9 and R 10 May be as defined in relation to the first aspect. 9 and R 10 can be each independently selected from the group consisting of: H, halogen and optionally substituted C 1 -C 6 alkyl.

[0073] "Aryl" refers to an aromatic 6- to 12-membered hydrocarbon group. 6 -C 12 Examples of aryl groups include, but are not limited to, phenyl, α-naphthyl, β-naphthyl, biphenyl, tetrahydronaphthyl, and dihydroindanyl. Aryl groups may be unsubstituted or substituted with one or more of the following groups: 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 alkyloxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, NR 9 R 10 、C(O)R 9 、CN、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 optionally substituted 3 to 8 membered heterocyclic ring. 9 and R 10 May be as defined in relation to the first aspect. 9 and R 10 can be each independently selected from the group consisting of: H, halogen and optionally substituted C 1 -C 6alkyl.

[0074] "Arylene" refers to a divalent aromatic 5 to 10 membered hydrocarbon group. Arylene can be as defined above for aryl, but with hydrogen atoms removed therefrom to render the group divalent.

[0075] "Aryloxy" refers to the group aryl-O-, where "aryl" is an optionally substituted C 6 -C 12 Aryl.

[0076] The term "bicycle or bicyclic" as used herein refers to a molecule with two fused rings, which are cycloalkyl, heterocyclic or heteroaryl. In one embodiment, the ring is fused across the bond between two atoms. The bicyclic moiety formed therefrom shares the bond between the rings. In another embodiment, the bicyclic moiety is formed by fusing two rings across a series of ring atoms forming bridgeheads. Similarly, a "bridge" is an unbranched chain of one or more atoms connecting two bridgeheads in a polycyclic compound. In another embodiment, the bicyclic molecule is a "spiro" or "spirocyclic" moiety. The spirocyclic group can be a C atom that is bonded to a single carbon atom of a carbocyclic or heterocyclic moiety through a single carbon atom of a spirocyclic moiety. 3 -C 6 Cycloalkyl or monocyclic or bicyclic 3 to 8 membered heterocycle. In one embodiment, the spirocyclic group is a cycloalkyl and is bound to another cycloalkyl. In another embodiment, the spirocyclic group is a cycloalkyl and is bound to a heterocyclic group. In another embodiment, the spirocyclic group is a heterocyclic group and is bound to another heterocyclic group. In yet another embodiment, the spirocyclic group is a heterocyclic group and is bound to a cycloalkyl. The spirocyclic group may be unsubstituted or substituted with one or more of the following groups: 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 alkyloxy, 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 、SO2 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. 9 and R 10 May be as defined in relation to the first aspect. 9 and R 10 can be each independently selected from the group consisting of: H, halogen and optionally substituted C 1 -C 6 alkyl.

[0077] "Cycloalkyl" refers to a non-aromatic, saturated, partially saturated, monocyclic, bicyclic or polycyclic hydrocarbon 3 to 6 membered ring system. 3 -C 6 Representative examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. The cycloalkyl group may be unsubstituted or substituted with one or more of the following groups: 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 alkyloxy, 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 optionally substituted 3 to 8 membered heterocyclic ring. 9 and R 10 May be as defined in relation to the first aspect. 9 and R 10 can be each independently selected from the group consisting of: H, halogen and optionally substituted C 1 -C 6 alkyl.

[0078] "Cycloalkylene" refers to a divalent non-aromatic, saturated, partially saturated, monocyclic, bicyclic or polycyclic hydrocarbon 3 to 6 membered ring system. Cycloalkylene may be as defined above for cycloalkyl, but with hydrogen atoms removed therefrom to render the group divalent.

[0079] "Heteroaryl" refers to a monocyclic or bicyclic aromatic 5- to 10-membered ring system in which at least one ring atom is a heteroatom. Alternatively, each heteroatom 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, benzisoxazole, 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 substituted with one or more of the following groups: an 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 alkyloxy, 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 、SO2 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. 9 and R 10 May be as defined in relation to the first aspect. 9 and R 10 can be each independently selected from the group consisting of: H, halogen and optionally substituted C 1 -C 6 alkyl.

[0080] "Heteroaryloxy" refers to the group heteroaryl-O-, where "heteroaryl" is an optionally substituted 5- to 10-membered heteroaryl.

[0081] "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. Heteroarylene may be as defined above for heteroaryl, but with hydrogen atoms removed therefrom to render the group divalent.

[0082] "Heterocycle" or "heterocyclyl" refers to a 3-8 membered monocyclic, bicyclic or bridged molecule in which at least one ring atom is a heteroatom. Alternatively, each heteroatom may be independently selected from the group consisting of oxygen, sulfur and nitrogen. The heterocycle may be saturated or partially saturated. Exemplary 3-8 membered heterocyclyls include, but are not limited to, aziridine, oxirane, ethylene oxide, thiirane, pyrroline, pyrrolidine, dihydrofuran, tetrahydrofuran, dihydrothiophene, tetrahydrothiophene, dithiolane, piperidine, 1,2,3,6-tetrahydropyridin-1-yl, tetrahydropyran, pyran, morpholine, piperazine, thiazane, thiazene, piperazine, azepane, diazepane, oxazine. The heterocyclyl may be unsubstituted or substituted with one or more of the following groups: 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 alkyloxy, 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 optionally substituted 3 to 8 membered heterocyclic ring. 9 and R 10 May be as defined in relation to the first aspect. 9 and R 10 can be each independently selected from the group consisting of: H, halogen and optionally substituted C 1 -C 6 alkyl.

[0083] "Heterocyclylene" refers to a divalent 3 to 8 membered monocyclic, bicyclic or bridged molecule in which at least one ring atom is a heteroatom. A heterocyclylene group may be as defined above for a heterocyclic group, but with hydrogen atoms removed therefrom to render the group divalent.

[0084] "Alkenyl" refers to an olefinically unsaturated hydrocarbon group which may be unbranched or branched. In certain embodiments, an alkenyl group has 2 to 6 carbon atoms, i.e., it is C 2 -C 6 Alkenyl. C 2 -C 6 Alkenyl groups include, for example, vinyl, allyl, propenyl, butenyl, pentenyl, and hexenyl. Alkenyl groups may be unsubstituted or substituted with one or more of the following groups: optionally substituted C 1 -C 6 Alkyl, optionally substituted C 1 -C 6 alkynyl, halogen, OH, optionally substituted C 1 -C 6 alkyloxy, 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 、COOR9 , 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. 9 and R 10 May be as defined in relation to the first aspect. 9 and R 10 can be each independently selected from the group consisting of: H, halogen and optionally substituted C 1 -C 6 alkyl.

[0085] "Alkynyl" refers to an acetylenic unsaturated hydrocarbon group which may be unbranched or branched. In certain embodiments, the alkynyl group has 2 to 6 carbon atoms, i.e., it is C 2 -C 6 Alkynyl. C 2 -C 6 Alkynyl groups include, for example, propargyl, propynyl, butynyl, pentynyl, and hexynyl. Alkynyl groups may be unsubstituted or substituted with one or more of the following groups: optionally substituted C 1 -C 6 Alkyl, optionally substituted C 2 -C 6 alkenyl, halogen, OH, optionally substituted C 1 -C 6 alkyloxy, 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 , 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. 9 and R 10 May be as defined in relation to the first aspect. 9 and R 10 can be each independently selected from the group consisting of: H, halogen and optionally substituted C 1 -C 6 alkyl.

[0086] Unless otherwise specified, the term "alkylene" as used herein refers to a divalent unsaturated straight or branched hydrocarbon. In certain embodiments, an alkylene group is a primary, secondary, or tertiary hydrocarbon. In certain embodiments, an alkylene group contains one to six carbon atoms, i.e., C 2 -C 6 Alkynylidene. 2 -C 6 Alkyne groups include, for example, ethynylene, propynylene, butynylene, pentynylene, or hexynylene. Alkyne groups may be unsubstituted or substituted with one or more of the following groups: 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 alkyloxy, 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 -C12 aryl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted C 3 -C 6 cycloalkyl and an optionally substituted 3 to 8 membered heterocycle. Thus, it is understood that the optionally substituted C 2 -C 6 Alkyne groups may be optionally substituted C 2 -C 6 Haloalkynylene (i.e., C 2 -C 6 alkynylene), and optionally further substituted with one or more of the following groups: 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 alkyloxy, 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 optionally substituted 3 to 8 membered heterocycle. It should be understood that optionally substituted C 2 -C 6 The alkynylene group may be an optionally substituted polyfluoroalkynylene group. 9 and R 10 May be as defined above. 9 and R 10 can be each independently selected from the group consisting of: H, halogen and optionally substituted C 1 -C 6alkyl.

[0087] "Alkylsulfonyl" refers to the group alkyl-SO 2 -, wherein alkyl is an optionally substituted C 1 -C 6 Alkyl and is as defined above.

[0088] The complex of the compound of formula (I) can be understood as 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 not be a salt or a solvate. Such complexes include clathrates (drug-host incorporated into the complex) and co-crystals. The latter is generally defined as a crystalline complex of neutral molecular components, which are bound together by non-covalent interactions, but can also be a complex of neutral molecules and salts. Co-crystals can be prepared by melt crystallization, recrystallization from a solvent, or physical grinding of the components together, see Chem Commun, 17, 1889-1896, O. Almarsson and MJ Zaworotko (2004), which are incorporated herein by reference. For a general review of multi-component complexes, see J Pharm Sci, 64 (8), 1269-1288, Haleblian (August 1975), which are incorporated herein by reference.

[0089] The term "pharmaceutically acceptable salt" is understood to refer to any salt of the compounds provided herein that retains its biological properties and is non-toxic or otherwise desirable for pharmaceutical use. The salts may be derived from various organic and inorganic counterions well known in the art. The salts include, but are not limited to: (1) acid addition salts formed using organic or inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, sulfamic acid, acetic acid, adipic acid, tartaric 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)-1-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, hydroxy or (2) base addition salts formed when an acidic proton present in the parent compound is (a) replaced by a metal ion (e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion) or an alkali metal or alkaline earth metal hydroxide (e.g., sodium, potassium, calcium, magnesium, aluminum, lithium, zinc, and barium hydroxides), ammonia, or (b) coordinated with an organic base such as an aliphatic, alicyclic, or aromatic Aromatic organic amines (e.g., ammonia, methylamine, dimethylamine, diethylamine, picoline, ethanolamine, diethanolamine, triethanolamine, ethylenediamine, lysine, arginine, ornithine, choline, N,N′-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, N-methylglucamine, piperazine, succinimidylamine, tetramethylammonium hydroxide, and the like).

[0090] Pharmaceutically acceptable salts may include sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium and the like, and, when the compound contains a basic functional group, salts of nontoxic organic or inorganic acids such as hydrohalides (e.g., hydrochlorides, hydrobromides and hydroiodides), carbonates or bicarbonates, sulfates or bisulfates, borates, phosphates, hydrogen phosphates, dihydrogen phosphates, pyroglutamate, glucarates, stearates, sulfamates, nitrates, orotates, oxalates, palmitates, pamoates, acetates, trifluoroacetates, trichloroacetates, propionates, hexanoates, cyclopentylpropionates, glycolates, glutarates, pyruvates, lactates, malonates, succinates, tannates, tartrates, toluenesulfonates, sorbates, ascorbates, malates, maleates, fumarates, tartrates, camphorsulfonates, citrates, cyclamates, benzoates, isethionates, ethanesulfonates, formates, 3-(4-hydroxybenzoate)-4-nitropropionates, 1,2-dihydro-1,2-dihydro-1,2-dihydro-1,2-dihydro-1,2-dihydro-1,2-dihydro-1,2-dihydro-1,2-dihydro-1,2-dihydro-1,2-dihydro-1,2-dihydro-1,2-dihydro-1,2-dihydro-1,2-dihydro-1,2-dihydro-1

[0013] The invention also includes but is not limited to the following: benzoate, picrate, cinnamate, mandelate, phthalate, laurate, methanesulfonate (mesylate), methylsulfate, naphthoate, 2-naphthoate, nicotinate, ethanesulfonate, 1,2-ethane-disulfonate, 2-hydroxyethanesulfonate, benzenesulfonate (benzenesulfonate, besylate), 4-chlorobenzenesulfonate, 2-naphthalenesulfonate, 4-toluenesulfonate, camphorate, camphorsulfonate, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylate, glucoheptonate, 3-phenylpropionate, pivalate, tert-butylacetate, lauryl sulfate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hydroxybenzoate, benzoate, glutamate, hydroxynaphthoate, salicylate, stearate, cyclohexylsulfamate, quinate, muconate, hydroxynaphthoate and the like.

[0091] Hemi-salts of acids and bases may also be formed, for example hemi-sulfates.

[0092] Those skilled in the art will appreciate that the above salts include those in which the counter ion is optically active (eg, D-lactate) or a racemate (eg, DL-tartrate).

[0093] For a review of suitable salts, see "Handbook of Pharmaceutical Salts: Properties, Selection, and Use", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[0094] Pharmaceutically acceptable salts of compounds of formula (I) can be prepared by one or more of the following three methods:

[0095] (i) by reacting a compound of formula (I) with a desired acid or base;

[0096] (ii) by removing an acid or base labile protecting group from a suitable precursor of a compound of formula (I) using an acid or base as required; or

[0097] (iii) by converting one salt of a compound of formula (I) into another salt by reaction with a suitable acid or base or with the aid of a suitable ion exchange column.

[0098] All three reactions are usually carried out in solution. The resulting salt may precipitate and be collected by filtration, or may be recovered by evaporation of the solvent. The degree of ionization of the resulting salt may vary from fully ionized to almost non-ionized.

[0099] The term "solvate" is understood to refer to a provided compound or salt thereof, which further includes a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. If the solvent is water, then the solvate is a hydrate. Pharmaceutically acceptable solvates of the present invention include those in which the solvent of crystallization may be isotopically (e.g., D 2 O,d 6 -acetone and d 6 -DMSO) substituted.

[0100] The currently accepted classification system for organic hydrates is that which defines isolated site, channel or metal ion coordinated hydrates, see Polymorphism in Pharmaceutical Solids, KR Morris (HG Brittain, ed., Marcel Dekker, 1995), which is incorporated herein by reference. Isolated site hydrates are those in which the water molecules are separated from each other by intervening organic molecules and are not in direct contact. In channel hydrates, the water molecules are located in the lattice channels, where they are adjacent to other water molecules. In metal ion coordinated hydrates, the water molecules are bonded to the metal ion.

[0101] When the solvent or water is tightly bound, the complex will have a well-defined stoichiometry that is independent of humidity. However, when the solvent or water is weakly bound, such 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 normal.

[0102] The compounds of the present invention may exist in a continuum of solid states ranging from completely amorphous to completely crystalline, including polymorphs of the crystalline material. The term "amorphous" refers to a state in which a material lacks long-range order at the molecular level and can exhibit physical properties of a solid or a liquid depending on the temperature. Typically, the material does not produce a characteristic X-ray diffraction pattern, and it is more formally described as a liquid when it exhibits solid properties. Upon heating, a change from solid to liquid properties occurs, characterized by a change of state, typically a secondary change ("glass transition"). The term "crystalline" refers to a solid phase in which a material has a regular, ordered internal structure at the molecular level and produces a characteristic X-ray diffraction pattern with defined peaks. Upon sufficient heating, the material will also exhibit a liquid form, but the change from solid to liquid is characterized by a phase transition, typically a primary phase transition ("melting point").

[0103] The compounds of the invention may also exist in a mesomorphic state (mesophase or liquid crystal) when subjected to suitable conditions. The mesomorphic state is an intermediate state between a true crystalline state and a true liquid state (melt or solution). Mesomorphism due to temperature changes is described as "thermotropic liquid crystals" and mesomorphism due to the addition of a second component (e.g. water or another solvent) is described as "lyotropic liquid crystals". Compounds with the potential to form lyotropic mesophases are described as "amphiphilic" and are characterized by having an ionic polar head group (e.g. -COO - Na + 、-COO - K + or -SO 3 - Na + ) or a nonionic polar head group (e.g. -N - N + (CH 3 ) 3 ) molecular composition. For more information, see Crystallography and Polarizing Microscopy ( Crystals and the Polarizing Microscope ), NH Hartshorne and A. Stuart, 4th edition (Edward Arnold, 1970), which is incorporated herein by reference.

[0104] R and R 1 can be each independently selected from the group consisting of: H, an 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 -C6 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 More preferably, R and R 1 are each independently selected from an optionally substituted benzene ring, an optionally substituted C 1 -C 6 Alkyl, optionally substituted C 2 -C 6 Alkenyl, optionally substituted C 2 -C 6 alkynyl or an optionally substituted 5- or 6-membered heteroaryl. Most preferably, R and R 1 Each is an optionally substituted benzene ring or a methyl group.

[0105] In R and / or R 1 is optionally substituted C 6 -C 12 When aryl is present, aryl is preferably an optionally substituted phenyl group. Phenyl may be unsubstituted or substituted by one or more of the following groups: halogen, optionally substituted C 1 -C 6 Alkyl, optionally substituted C 1 -C 6 Alkoxy, COR, NR 9 R 10 , CN, R 9 COR 10 , optionally substituted C 6 -C 12 aryl or optionally substituted 5- to 10-membered heteroaryl, wherein R 9 and R 10 Each is H or optionally substituted C 1 -C 6 More preferably, the phenyl group is unsubstituted or substituted with fluorine, C 1 -C 6 Alkoxy, COR 9 NR 9 R 10 , CN, R 9 COR 10 or C 6 -C 12 One or more of the aryl groups are substituted, wherein R 9 and R 10 Each is H or C 1 -C 6Most preferably, the phenyl group is unsubstituted or substituted with 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.

[0106] In R and / or R 1 When it is an optionally substituted 5- to 10-membered heteroaryl, the heteroaryl group is preferably an optionally substituted 5- or 6-membered heteroaryl group and more preferably an optionally substituted pyridyl group or an optionally substituted pyrazolyl group. The heteroaryl group may be unsubstituted or optionally substituted C 1 -C 6 Alkyl, optionally substituted C 1 -C 6 More preferably, the heteroaryl group is unsubstituted or substituted with C 1 -C 6 Alkyl, C 1 -C 6 Most preferably, the heteroaryl group is unsubstituted or substituted with methyl, OCH 3 or OH.

[0107] In R and / or R 1 is an optionally substituted monocyclic or bicyclic C 3 -C 6 When cycloalkyl is present, the cycloalkyl group is preferably unsubstituted.

[0108] In R and / or R 1 is optionally substituted C 1 -C 6 Alkyl, optionally substituted C 2 -C 6 alkenyl or optionally substituted C 2 -C 6 In the case of an alkynyl group, the alkyl, alkenyl or alkynyl group is preferably an optionally substituted C 1 -C 3 Alkyl, optionally substituted C 2 -C 3 alkenyl or optionally substituted C 2 -C 3 Alkynyl and more preferably optionally substituted C 1 -C 2Alkyl, optionally substituted C 2 alkenyl or optionally substituted C 2 Alkyl, alkenyl or alkynyl may be unsubstituted or substituted with halogen, optionally substituted C 6 -C 12 Preferably, the alkyl, alkenyl or alkynyl groups are unsubstituted or substituted with fluorine or C 6 -C 12 Most preferably, the alkyl, alkenyl or alkynyl groups are unsubstituted or substituted with one or more of fluoro or phenyl.

[0109] R 2 Can be 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, an optionally substituted monocyclic or bicyclic 3 to 8 membered heterocycle, an optionally substituted C 1 -C 6 Alkoxy, optionally substituted monocyclic or bicyclic C 6 -C 12 aryl or an optionally substituted monocyclic or bicyclic 5- to 10-membered heteroaryl.

[0110] In R 2 It is COOR 9 ,CONR 9 R 10 、CN、NR 9 COR 10 NR 9 R 10 or NR 9 SO 2 R 10 When R 9 and R 10 may independently be 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 More preferably, R 9 and R10 is independently H or optionally substituted C 1 -C 3 Alkyl, C 3 -C 6 R is cycloalkyl, optionally substituted phenyl or optionally substituted 5- or 6-membered heteroaryl. 9 and R 10 R may be H, optionally substituted methyl, cyclopropyl or optionally substituted pyrazolyl. 9 or R 10 When it is an optionally substituted alkyl or cycloalkyl group, the alkyl or cycloalkyl group may be substituted by an optionally substituted monocyclic or bicyclic C 6 -C 12 Aryl or optionally substituted monocyclic or bicyclic 5- to 10-membered heteroaryl, preferably optionally substituted phenyl or optionally substituted monocyclic or bicyclic 5- or 6-membered heteroaryl, more preferably phenyl or optionally substituted pyrazolyl. 9 or R 10 When it is an optionally substituted heteroaryl group, the heteroaryl group may be C 1 -C 6 Alkyl, more preferably C 1 -C 3 alkyl and most preferably methyl. 2 Can be H, COOH, COOCH 3 ,CONH 2 、CONHCH 3 、CON(CH 3 ) 2 , NHCOCH 3 NH 2 、N(CH 3 ) 2 , NHSO 2 CH 3 ,

[0111] In R 2 is optionally substituted C 1 -C 6 Alkyl or optionally substituted C 1 -C 6 When alkoxy, R 2 It may be an optionally substituted C 1 -C 3 Alkyl or optionally C 1 -C 3 Alkoxy and preferably CH 3 or OCH 3 .

[0112] In R 2 When it is an optionally substituted monocyclic or bicyclic 5- to 10-membered heteroaryl, the heteroaryl group may be an optionally substituted 5- or 6-membered heteroaryl group, and may be an optionally substituted oxazolyl group. The heteroaryl group may be unsubstituted.

[0113] X can be CR 3 .

[0114] Y can be CR 4 .

[0115] Z can be CR 5 .

[0116] In a preferred embodiment, X is CR 3 , Y is CR 4 and Z is CR 5 .

[0117] Alternatively, X may be N. Y may be CR 4 And Z can be CR 5 Therefore, in an alternative embodiment, X is N and Y is CR 4 and Z is CR 5 Alternatively, Y may be N and Z may be CR 5 Therefore, in another alternative embodiment, X is N, Y is N and Z is CR 5 Alternatively, Y may be CR 4 and Z may be N. Therefore, in yet another alternative embodiment, X is N, Y is CR 4 And Z is N.

[0118] Alternatively, Y may be N. X may be CR 3 And Z can be CR 5 Therefore, in another alternative embodiment, X is CR 3 , Y is N and Z is CR 5 .

[0119] Alternatively, Z may be N. X may be CR 3 And Y can be CR 4 Therefore, in yet another embodiment, X is CR 3 , Y is CR 4 And Z is N.

[0120] R 3 Can be H, CN, halogen, COOH, CONR 2 NR 2 、NO 2 , optionally substituted C 1 -C 6 alkyl, optionally substituted monocyclic or bicyclic C 3 -C6 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 heterocycle. 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 6 More preferably, R 3 is H, CN, F, Br, cyclopropyl or an optionally substituted 5- or 6-membered heteroaryl. Most preferably, R 3 It's H.

[0121] In R 3 When halogen, it may be F, Cl, Br or I, and is more preferably Br.

[0122] In R 3 is optionally substituted C 1 -C 6 When alkyl is optionally substituted, it is preferably C 1 -C 3 Preferably, C 1 -C 6 The alkyl group is unsubstituted.

[0123] In R 3 is optionally substituted C 3 -C 6 When cycloalkyl is cycloalkyl, it is preferably optionally substituted cyclopropyl. 3 -C 6 The cycloalkyl group is unsubstituted.

[0124] In R 3When it is an optionally substituted 5- to 10-membered heteroaryl, the heteroaryl group is preferably an optionally substituted 5- or 6-membered heteroaryl group and more preferably an optionally substituted pyridyl or pyrazolyl group. The heteroaryl group may be unsubstituted or optionally substituted C 1 -C 6 Alkyl, optionally substituted C 1 -C 6 More preferably, the heteroaryl group is unsubstituted or substituted with C 1 -C 6 Alkyl, C 1 -C 6 Most preferably, the heteroaryl group is unsubstituted or substituted with methyl, OCH 3 or OH.

[0125] R 4 and R 5 can be each independently selected from the group consisting of: H, halogen, OH, CN, an optionally substituted monocyclic or bicyclic C 6 -C 12 Aryl, optionally substituted C 1 -C 6 Alkyl, optionally substituted C 1 -C 6 alkyloxy, an optionally substituted monocyclic or bicyclic 3 to 8 membered heterocyclic ring, or an optionally substituted monocyclic or bicyclic C 3 -C 6 More preferably, R 4 and R 5 It can be H, halogen, OH, CN or optionally substituted C 1 -C 6 Most preferably, R 4 and R 5 It's H.

[0126] In R 4 and / or R 5 When halogen, it may be F, Cl, Br or I, and is more preferably F.

[0127] R 6 It may be H or optionally substituted C 1 -C 6 Most preferably, R 6 It's H.

[0128] R 7 It can be H, optionally substituted C 1 -C 10 alkyl or an optionally substituted monocyclic or bicyclic C 3 -C 6More preferably, R 7 It may be an optionally substituted C 1 -C 10 alkyl or an optionally substituted monocyclic or bicyclic C 3 -C 6 Even more preferably, R 7 is optionally substituted C 1 -C 6 alkyl, and most preferably optionally substituted C 3 -C 5 alkyl.

[0129] R 7 It can be H, optionally substituted C 1 -C 6 Alkyl, optionally substituted C 2 -C 6 Alkenyl, optionally substituted C 2 -C 6 Alkynyl, 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 C 3 -C 6 More preferably, R 7 is optionally substituted C 1 -C 6 Alkyl, optionally substituted C 2 -C 6 Alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted phenyl, optionally substituted 5 or 6 membered heteroaryl, optionally substituted C 3 -C 6 cycloalkyl or an optionally substituted 3- to 6-membered heterocyclic ring.

[0130] In R 7 When the alkyl group is an optionally substituted alkyl group, an optionally substituted alkenyl group or an optionally substituted alkynyl group, the alkyl group, the alkenyl group or the alkynyl group may be unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, -OH, oxo, an 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 NR9 C(O)R 10 . R 9 and R 10 can each be H, optionally substituted C 1 -C 6 Alkyl, optionally substituted C 2 -C 6 alkenyl or optionally substituted C 2 -C 6 More preferably, the alkyl, alkenyl or alkynyl group may be unsubstituted or 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 , where R 9 and R 10 Each is H or C 1 -C 6 Most preferably, the alkyl, alkenyl or alkynyl group may be unsubstituted or 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 3 .

[0131] In R 7 When R is an optionally substituted heteroaryl, an optionally substituted cycloalkyl or an optionally substituted heterocycle, the heteroaryl, cycloalkyl or heterocycle may be unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, -OH, oxo, an 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 . R 9 and R 10 can each be H, optionally substituted C 1 -C6 Alkyl, optionally substituted C 2 -C 6 alkenyl or optionally substituted C 2 -C 6 When heteroaryl, cycloalkyl or heterocycle is directly or indirectly substituted by alkyl, alkenyl and / or alkynyl, or each alkyl, alkenyl or alkynyl group may be unsubstituted or substituted by one or more substituents selected from the group consisting of halogen, -OH and oxo. Preferably, heteroaryl, cycloalkyl or heterocycle is unsubstituted or substituted by one or more substituents selected from the group consisting of F, -OH, oxo, 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 , where R 9 and R 10 Each is H or C 1 -C 6 Most preferably, the 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 .

[0132] In R 7 When it is an optionally substituted aryl group, the aryl group may be unsubstituted or substituted with one or more substituents selected from the group consisting of 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) 2and NR 9 C(O)R 10 . R 9 and R 10 can each be H, optionally substituted C 1 -C 6 Alkyl, optionally substituted C 2 -C 6 alkenyl or optionally substituted C 2 -C 6 When the aryl group is directly or indirectly substituted by an alkyl, alkenyl and / or alkynyl group, or each alkyl, alkenyl or alkynyl group may be unsubstituted or substituted by one or more substituents selected from the group consisting of halogen, -OH and oxo. Preferably, the aryl group is unsubstituted or substituted by one or more substituents selected from the group consisting of 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 , where R 9 and R 10 Each is H or C 1 -C 6 Most preferably, the aryl group 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 .

[0133] In some embodiments, R 7 It can be butyl, pentyl, cyclohexyl,

[0134] In some embodiments, L is absent. In alternative embodiments, L is NR 8 . R 8 It may be H or optionally substituted C 1 -C 6 More preferably, R 8 It's H.

[0135] The compounds of formula (I) may contain one or more stereogenic centers and may therefore exist in the form of optical isomers (eg enantiomers and diastereomers). All such isomers and mixtures thereof are included within the scope of the present invention.

[0136] Stereocenters can occur in groups R and R 1 -R 9 In any one of .

[0137] It should be understood that the above compounds can exist in the form of enantiomers and diastereoisomer pairs. These isomers also represent other embodiments of the present invention.

[0138] Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC).

[0139] Alternatively, the racemate (or racemic precursor) may be reacted with a suitable optically active compound (e.g., an alcohol) or, in the case where the compound of formula (I) contains an acidic or basic moiety, a base or acid (e.g., 1-phenylethylamine or tartaric acid). The resulting diastereomeric mixture may be separated by chromatography and / or fractional crystallization and one or both of the diastereomers converted to the corresponding pure enantiomer by means well known to those skilled in the art.

[0140] The chiral compounds of the present invention (and chiral precursors thereof) can be obtained in an enantiomerically enriched form using chromatography, typically HPLC on an asymmetric resin using 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. Concentrating the eluate can yield an enriched mixture.

[0141] Stereoisomeric mixtures can be separated by conventional techniques known to those skilled in the art; see, for example, "Stereochemistry of Organic Compounds", EL Eliel and SH Wilen (Wiley, New York, 1994).

[0142] Structure (-L 1 -) a -L 2 - can be called a "connector".

[0143] L 1 May not exist or may be:

[0144] -AWD-

[0145] in:

[0146] A does not exist or is selected from the group consisting of: -L 3 -、-X 4 L 3 -、-L 3 X 4 -、-C(O)X 4 , -L 3 C(O)X 4 , -X 4 L 4 -、-L 4 X 4 -、-X 4 L 3 L 4 -、-L 4 L 3 X 4 -、-X 4 L 3 L 4 L 5 -、-L 5 L 4 L 3 X 4 -、-L 3 L 4 -、-L 4 L 3 -、-L 3 X 4 L4-、-L 4 X 4 L 3 -、-L 3 L 4 L 6 -、-L 3 X 4 L 4 X 5 L 6 -、

[0147] W does not exist or is selected from the group consisting of: -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 L8 NHC(O)- and -L 3 L 7 L 8 NHC(O)-;

[0148] D does not exist or has the formula -(D 1 ) q -or-(D 1 ) q C(O)-, where (D 1 ) q Is a straight chain or a ring;

[0149] or each L 3 and L 6 are each independently an optionally substituted C 1 -C 25 Alkylene or optionally substituted C 2 -C 25 Alkynylidene;

[0150] L 4 and L 5 are each independently selected from the group consisting of: 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; and optionally a monocyclic or bicyclic 3 to 12 membered heterocyclic ring;

[0151] L 7 and L 8 are each independently an optionally substituted monocyclic or bicyclic C 6 -C 12 or an optionally substituted monocyclic or bicyclic 5-10 membered heteroaryl, wherein the aryl or heteroaryl is optionally further substituted with at least one -OR 18 Group substitution;

[0152] X 4 , X 5 , X 6 and X 7 or each of which is independently O, S or NR 16 ;

[0153] R 16 is selected from the group consisting of: H, halogen, CN, hydroxyl, COOH, CONR 9 R 10 NR 9 R 10 、NHCOR 9 , optionally substituted C 1 -C6 Alkyl, C 1 -C 3 Polyfluoroalkyl, optionally substituted C 1 -C 6 Alkylsulfonyl, optionally substituted monocyclic or bicyclic C 3 -C 6 Cycloalkyl, optionally substituted C 2 -C 6 Alkenyl, optionally substituted C 2 -C 6 Alkynyl, optionally substituted C 1 -C 6 Alkoxy, optionally substituted C 1 -C 6 Alkoxycarbonyl, optionally substituted monocyclic or bicyclic C 5 -C 10 aryl, optionally substituted monocyclic or bicyclic 5- to 10-membered heteroaryl, optionally substituted monocyclic or bicyclic 3- to 8-membered heterocycle, optionally substituted aryloxy, optionally substituted heteroaryloxy, and optionally substituted heterocyclyloxy;

[0154] R 17 is hydrogen or optionally substituted C 1-6 alkyl;

[0155] R 18 is optionally substituted C 3 -C 6 cycloalkyl or an optionally substituted monocyclic or bicyclic 3 to 8 membered heterocycle;

[0156] Every D 1 Independently has the general formula

[0157] Sc is a side chain of a natural or unnatural amino acid and R 19 is H, or Sc and R 19 together with the atoms to which they are attached, form a ring; and

[0158] q is an integer between 2 and 20.

[0159] L 2 May not exist or may be:

[0160] -G-(S-) z

[0161] Where G does not exist or is (-G 1 ) a -G 2 -(G 3 -) z ,

[0162] Among them, or each G 1 Independently absent or selected from the group consisting of: -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 -、 -L 3 X 4 C(O)-、-L 3 C(O)X 4 , -L 9 -、-L 9 L 3 -、-L 9 L 3 C(O)-、-C(O)L 3 -、-C(O)L 9 -、-C(O)L 3 X 4 L 6 -、-C(O)L 3 X 4 C(O)L 6 -、-C(O)L 9 L 3 -、-C(O)L 3 C(O)-、-C(O)L 9 C(O)-、-C(O)L 9 L 3 C(O)-, poly(ethylene glycol) (PEG) chains having 1 to 25 units, and cyclodextrins;

[0163] G 2 Does not exist or is selected from the group consisting of: The wavy line indicates G 2 To G 1 or (in G 1 In the embodiment not present) to L 1 Connection or G 2 To G 3 or (in G 3 In the example where there is no connection) to the 2In its present embodiment, it is connected to at least one G 1 Or in G 1 In the embodiment not present, at least one group L is connected 1 , and each G 2 In its present embodiment, it is connected to at least one G 3 Or in G 3 In the absent embodiments, the at least one group S is attached;

[0164] or every G 3 Independently absent or selected from the group consisting of: -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 -、 -L 3 X 4 C(O)-、-L 3 C(O)X 4 , -L 3 X 4 C(O)L 6 -、-L 3 C(O)X 4 L 6 -、 -L 9 -、-X 4 L 9 -、-L 9 L 3 -、-L 9 L 3 C(O)-、-C(O)L 3 -、-C(O)L 9 -、-C(O)L 3 X 4 L 6 -、-C(O)L 3 X 4 C(O)L 6 -、-C(O)L 9 L 3 -、-C(O)L 3 C(O)-、-C(O)L 9 C(O)-、-C(O)L 9 L 3C(O)-, poly(ethylene glycol) (PEG) chains having 1 to 25 units, and cyclodextrins;

[0165] or every G 4 Independently absent or selected from the group consisting of: -L 3 -、-(X 4 L 3 ) p -、-(L 3 X 4 ) p -、-X 4 -、-X 8 -、-X 4 C(O)-、-C(O)X 4 -、 -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 -、-X 4 C(O)L 3 X 5 L 3 - -L 9 -、-L 9 L 3 -、-L 9 L 3 C(O)-、-C(O)L 3 -、-C(O)L 9 -、-C(O)L 3 X 4 L 6 -、-C(O)L 3 X 4 C(O)L 6 -、-C(O)L 9 L 3 -、-C(O)L 3 C(O)-、-C(O)L 9 C(O)-、-C(O)L 9 L3 C(O)-, poly(ethylene glycol) (PEG) chains having 1 to 25 units, and cyclodextrins;

[0166] G 5 Yes-L 3 -、-(X 4 L 3 ) p -、-(L 3 X 4 ) p -、-X 4 -、-X 8 -、-X 4 C(O)-、-C(O)X 4 -、 -L 3 X 4 C(O)-、-L 3 C(O)X 4 , -L 3 X 4 C(O)L 6 -、-L 3 C(O)X 4 L 6 -、 -L 9 -、-X 4 L 9 -、-L 9 L 3 -、-L 9 L 3 C(O)-、-C(O)L 3 -、-C(O)L 9 -、-C(O)L 3 X 4 L 6 -、-C(O)L 3 X 4 C(O)L 6 -、-C(O)L 9 L 3 -、-C(O)L 3 C(O)-、-C(O)L 9 C(O)-、-C(O)L 9 L 3 C(O)-, poly(ethylene glycol) (PEG) chains having 1 to 25 units, and cyclodextrins;

[0167] S does not exist or is selected from the group consisting of: -X 4 -、-X 4 -、-X 8 -、-C(X 9 )-、-X 4C(X 9 )-、-X 4 C(X 9 )L 3 -、-X 4 C(X 9 )L 3 C(O)-、-X 8 L 3 -、-X 4 X 8 L 3 -、X 8 L 3 C(O)-、-L 3 -、-L 4 -、-L 4 L 3 -、-L 4 C(O)-、-C(O)L 4 C(O)-、-L 3 C(O)L 4 C(O)-、-L 4 L 3 L 5 -、L 4 L 3 L 5 C(O)-,

[0168] L 3 To L 8 and X 4 To X 7 is as defined above,

[0169] L 9 is a poly(ethylene glycol) (PEG) chain 1 to 25 units long;

[0170] X 8 Is -S(O)- or -SO 2 -;

[0171] X 9 is O or S;

[0172] R 20 is optionally substituted C 1 -C 6 Alkyl, optionally substituted C 2 -C 6 Alkenyl, optionally substituted C 2 -C 6 Alkynyl, -L 9 H, -C(O)L 3 H, -C(O)L 9 H, -X 4 L3 H, -X 4 L 9 H, -X 4 C(O)L 3 H, -X 4 C(O)L 9 H, -C(O)X 4 L 3 H or -C(O)X 4 L 9 H; and

[0173] p is an integer between 1 and 25.

[0174] a may be 1, 2, 3, 4 or 5. Preferably, a is an integer between 1 and 3.

[0175] z may be 1, 2, 3, 4 or 5. Preferably, z is an integer between 1 and 3.

[0176] -L 9 -Can be

[0177] Preferably, there is L 1 and L 2 At least one of .

[0178] Preferably, 3 or less of A, W, D, G and S are absent, and more preferably 2 or less or 1 or less of A, W, D, G and S are absent. In some embodiments, A, W, D, G and S are all present.

[0179] A can be -L 3 -.L 3 It may be an optionally substituted C 1 -C 6 Preferably, L 3 is optionally substituted C 1 -C 2 Alkylene or optionally substituted C 1 Alkylene.

[0180] A can be -L 3 X 4 -.L 3 It may be an optionally substituted C 1 -C 6 Alkylene, and preferably -CH 2 CH 2 -or-CH 2 CH 2 CH 2 -. Therefore, A can be -CH 2 CH 2 O-、-CH2 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-.

[0181] A can be -C(O)X 4 or -L 3 C(O)X 4 .X 4 Can be O. L 3 It may be an optionally substituted C 1 -C 6 Alkylene, and preferably C 1 -C 3 Alkylene, and most preferably -CH 2 -. Therefore, A can be -C(O)O- or -CH 2 C(O)O-.

[0182] A can be X 4 Can be -O- or -NR 16 -.X 5 Can be -O- or NR 16 -. Therefore, A can be R 16 It may be an optionally substituted C 1 -C 6 alkyl or hydrogen. 1 -C 6 The alkyl group may be optionally substituted with a C 1 -C 6 Alkoxy is substituted, and the alkoxy may be substituted by -OH. 16 Can be methyl or -CH 2 CH 2 OCH 2 CH 2 OH. Therefore, A can be

[0183] A can be X 4 It can be -O-, -S- or -NH-. 5 Can be -O- or -NR 16 -. Therefore, A can be L 3 It may be an optionally substituted C 1 -C 10 alkylene, and preferably an optionally substituted C 1 -C 6 Alkylene.

[0184] A can be X 4 Can be -O- or -NR 16 -.X 5 Can be -O- or NR 16 -.L 3 It may be an optionally substituted C 1 -C 6 Therefore, A can be Preferably, L 3 is optionally substituted C 1 -C 2 Alkylene or optionally substituted C 1 Alkylene.

[0185] A can be X 6 It can be -O-, -S- or -NH-. 4 Can be -O- or -NR 16 -.X 5 Can be -O- or -NR 16 -. A can be

[0186] A can be X 4 Can be -O-. X 5 Can be -O- or NR 16 -.L 3 It may be an optionally substituted C 1 -C 6 Alkylene, and preferably -CH 2 CH 2 -.X 6 Can be -O- or NR 16 -.X 7 Can be -O-. Therefore, A can be

[0187] A can be Preferably, X 4 Preferably, X 5 Yes -O-.

[0188] A can be -X 4 L3 L 4 -or-X 4 L 3 L 4 L 5 -.X 4 Can be -O-. 3 It may be an optionally substituted C 1 -C 6 Alkylene, and preferably C 1 -C 2 Alkylene, and more preferably -CH 2 -.L 4 It may be an optionally substituted 3 to 12-membered heterocyclic ring, preferably L 4 may be an optionally substituted 3 to 8 membered heterocyclic ring, and most preferably L 4 is an optionally substituted 5- or 6-membered heterocyclic ring. 4 Can Where R 22 Can be hydrogen, C 1 -C 6 Alkyl or monocyclic or bicyclic C 6 -C 12 Therefore, L 4 Can L 5 It may be an optionally substituted monocyclic or bicyclic C 6 -C 12 Preferably, L 5 is optionally substituted phenyl, and in some embodiments is unsubstituted phenyl. Thus, A may be

[0189] A can be -L 3 X 4 L 4 X 5 L 6 -.L 3 and L 6 may independently be optionally substituted C 1 -C 6 alkylene, and preferably independently C 1 -C 2 Alkylene. 3 Can be -CH 2 CH 2 -.L 6 Can be -CH 2 -.X 4 Can be -O-. X 5 Can be -O-. 4 It may be an optionally substituted 3- to 12-membered heterocyclic ring. 4Preferably, it is an optionally substituted 6- to 12-membered bicyclic heterocycle and more preferably an optionally substituted 6- to 12-membered spirocyclic heterocycle. 4 Can Where R 22 Can be hydrogen, C 1 -C 6 Alkyl or monocyclic or bicyclic C 6 -C 12 Therefore, L 4 Can and preferably Therefore, A can be

[0190] A can be X 4 Preferably it is -O-. 3 It may be an optionally substituted C 1 -C 6 Alkylene, and preferably C 1 -C 2 Alkylene, and more preferably -CH 2 -. R 17 It may be an optionally substituted C 1-6 Alkyl, and preferably C 1-3 X is alkyl, and more preferably methyl. 5 It is preferably -NH- or -O-. 4 It may be an optionally substituted monocyclic or bicyclic C 6 -C 12 Preferably, L 4 is optionally substituted phenyl, and in some embodiments is unsubstituted phenyl. Thus, A may be

[0191] As explained 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)-.

[0192] L 3 It may be an optionally substituted C1 -C 6 Alkylene or C 1 -C 6 Alkyne, preferably C 1 -C 3 Alkylene or C 1 -C 3 Alkyne, and most preferably -CH 2 -or-CH 2 CHCH-.

[0193] Preferably, L 7 and L 8 Each is independently a monocyclic or bicyclic C 6 -C 12 Aryl; or a monocyclic or bicyclic 5 to 10 membered heteroaryl, wherein the aryl or heteroaryl is optionally substituted by one -OR 18 Group substitution.

[0194] L 7 It can be phenyl, naphthyl or 2H-chromen-2-one, each of which can be further substituted by a -OR 18 Group substitution.

[0195] L 8 Phenyl is preferred.

[0196] R 18 Preferably, it is an optionally substituted monocyclic or bicyclic 3 to 8 membered heterocycle. More preferably, R 18 is an optionally substituted 6-membered heterocycle and most preferably an optionally substituted tetrahydropyranyl. Preferably, the heterocycle is substituted with 1 to 9 substituents, more preferably 2 to 7 or 3 to 5 substituents and most preferably 4 substituents. The substituents may be selected from C 1 -C 6 Preferably, C 1 -C 6 Alkoxy is C 1 -C 4 Alkoxy, more preferably C 1 -C 2 Alkoxy and most preferably -CH 2 OH. Preferably, the heterocyclic ring is substituted with 1 to 9 OH groups, more preferably 2 to 5 OH groups and most preferably 3 OH groups. Preferably, the heterocyclic ring is substituted with 1 to 9 C 1 -C 6 Alkoxy and / or COOH groups, more preferably 1 to 5 C 1 -C 6 Alkoxy and / or COOH groups and most preferably 1 C 1 -C 6 Alkoxy or COOH group substitution.

[0197] R 18 Can More preferably, R 18 yes or

[0198] Therefore, W can be:

[0199]

[0200] D 1 Can have the general formula

[0201] Sc may be 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 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 a monocyclic or bicyclic 3 to 12 membered heterocycle.

[0202] Where Sc is an optionally substituted C 1 -C 6 In the embodiment of the alkyl group, the alkyl group may be substituted by at least one of the following groups: 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 an optionally substituted 3 to 8 membered heterocycle. 9 R 10 When replaced, then R 10 Can be H. R 9 It can also be H. Alternatively, R 9 Can be C(O)NH 2Therefore, the alkyl group can be converted into 2 Substitution. In the alkyl group 9 R 10 When replaced, then R 10 Can be H. R 9 It can also be H. Alternatively, R 9 Can be C(O)NH 2 In the alkyl SR 9 When replaced, R 9 Can be H or C 1 -C 6 Alkyl, preferably R 9 is H or methyl. In the alkyl group, optionally substituted C 6 -C 12 When aryl is substituted, the optionally substituted C 6 -C 12 Aryl is preferably an optionally substituted phenyl. Phenyl may be substituted with -OH as appropriate. When alkyl is substituted with an optionally substituted 5- to 10-membered heteroaryl, the optionally substituted 5- to 10-membered heteroaryl is preferably imidazolyl or 1H-indolyl.

[0203] In Sc is NC(O)R 9 In the embodiment, R 9 Can be C 1 -C 6 Alkyl, and preferably methyl.

[0204] Thus, in some embodiments, Sc is H or C 1 -C 6 An alkyl group, the alkyl group being optionally substituted with at least one substituent selected from the group consisting of: NH 2 、NHC(NH)NH 2 , OH, COOH, CONR 9 H, SeH, SH, SCH 3 , phenyl optionally substituted with OH, imidazolyl and 1H-indolyl.

[0205] Preferably, Sc is optionally NHC(O)NH 2 or COOH substituted C 1 -C 6 More preferably, Sc is methyl, isopropyl, -CH 2 CH 2 CH 2 NHC(O)NH 2 or -CH 2 CH 2 COOH.

[0206] Or, D 1 Can or more preferably

[0207] q may be an integer between 1 and 10, more preferably between 2 and 7 and most preferably between 3 and 5.

[0208] Therefore, D can be:

[0209]

[0210]

[0211] G 1 and G 3 Can be independently -L 3 -、-(X 4 L 3 ) p -or-(L 3 X 4 -) p . p can be 1 or 2. L 3 It may be an optionally substituted C 1 -C 15 Alkylene, more preferably optionally substituted C 1 -C 10 Alkylene and most preferably optionally substituted C 1 -C 6 Alkylene. 3 may be substituted with one or more optionally substituted C 1 -C 6 Preferably, C 1 -C 6 The alkyl group is unsubstituted. Therefore, G 1 and G 3 Each may be independently substituted with one or more methyl groups. 1 and G 3 can 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 2O-、-CH 2 CH 2 OCH 2 CH 2 O- or -(CH 2 ) 5 NH-. In G 2 and G 3 In the embodiment where it does not exist, G may 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- or -(CH 2 ) 5 NH-. In G 1 and G 3 Existence but G 2 In some embodiments where it is not present, G may be -CH 2 OCH 2 CH 2 OCH 2 CH 2 O-.

[0212] G 1 and G 3 Can be independently L 3 and L 6 may independently be optionally substituted C 1 -C 10 Alkylene and more preferably optionally substituted C 1 -C 6 Alkylene. X 4 It can be NH. 5 can be NH. Therefore, G 1 and / or G 3 Can In G 2 and G 3 In the embodiment where it does not exist, G may be

[0213] G 1 and G 3 Can be independently -L 3 X 4C(O)-or-C(O)L 3 X 4 C(O)L 6 -. Preferably, L 3 is optionally substituted C 1 -C 15 Alkylene, more preferably optionally substituted C 1 -C 10 Alkylene and most preferably optionally substituted C 1 -C 6 The alkylene group may be optionally substituted with a C 1 -C 6 Alkyl or -COOH substituted. Alkyl can be NH 2 Preferably, X 4 It is -NH-. 6 Preferably, optionally substituted C 1 -C 15 Alkylene, more preferably optionally substituted C 1 -C 10 Alkylene and most preferably optionally substituted C 1 -C 6 The alkylene group may be optionally substituted with a C 1 -C 6 Alkyl or -COOH substituted. Alkyl can be NH 2 Alternatively, the alkylene group may be unsubstituted. Thus, G 1 and G 3 can each independently be -(CH 2 ) 5 NHC(O)-、 More preferably, G 1 and G 3 can each independently be -(CH 2 ) 5 NHC(O)-、 In G 2 and G 3 In the embodiment where it does not exist, G may be -(CH 2 ) 5 NHC(O)-、

[0214] G 1 and G 3 may each independently be an optionally substituted C 3 -C 6 Cycloalkyl, optionally substituted monocyclic or bicyclic C 6 -C 12aryl, optionally substituted monocyclic or bicyclic 5- to 10-membered heteroaryl, or optionally substituted monocyclic or bicyclic 5- to 10-membered heterocycle.

[0215] In some embodiments, G may be -L 3 X 4 C(O)-.G 2 But it does not exist. 3 Can be -L 4 -. Therefore, G can be and preferably

[0216] G 1 and G 3 can be 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 -. In some embodiments, G 1 and G 3 Can each independently be -C(O)L 3 -or-C(O)L 3 C(O)-, where L 3 is optionally substituted C 1 -C 6 Alkylene and more preferably optionally substituted C 4 -C 5 Alkylene. In G 2 and G 3 In the embodiment where it is not present, G may be -C(O)L 3 -or-C(O)L 3 C(O)-, where L 3 is optionally substituted C 1 -C 6 Alkylene and more preferably optionally substituted C 4 -C 5 Alkylene.

[0217] G 1and / or G 3 Can be -L 4 -. Therefore, G 1 and / or G 3 It may be an optionally substituted monocyclic or bicyclic C 6 -C 12 Aryl. 1 and / or G 3 It may be an optionally substituted phenyl group. 2 and G 3 In the embodiment where it does not exist, G may be

[0218] G 1 and / or G 3 It may be a poly(ethylene glycol) (PEG) chain having 1 to 25 units. The PEG chain may be a cyclic PEG chain, a branched PEG chain or a linear PEG chain.

[0219] G 1 and / or G 3 The cyclodextrin may be α, β or γ cyclodextrin.

[0220] G 1 and / or G 3 Can be -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 -.L 3 It may be an optionally substituted C 1 -C 6 Alkylene, and more preferably methylene or ethylene. 1 and / or G 3 Can p may be an integer between 1 and 15, more preferably between 2 and 10 or between 3 and 5. 2 and G 3 In the embodiment where it does not exist, G may be

[0221] G 2 Can Every G 4 It may not exist, it is -L 3 -or-X 4 C(O)-. In one embodiment, a G 4 does not exist and a G 4 Yes-X 4C(O)-.X 4 It can be -NH-. Therefore, G 2 Can Preferably and more preferably Or, G. 2 Can Preferably and more preferably In one embodiment, R 20 Can be -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. Preferably, R 20 Yes-C(O)X 4 L 9 H.X 4 It can be -NH-. 9 -Can be p may be an integer between 2 and 10, more preferably between 3 and 5 and most preferably 4. Thus, G 2 Can and more preferably

[0222] G 1 and G 3 may each independently be an optionally substituted C 1 -C 10 Alkylene, more preferably optionally substituted C 1 -C 6 Alkylene. 1 It can be ethylene. 3 Therefore, G can be and preferably

[0223] In an alternative embodiment, R 20 It may be an optionally substituted C 1 -C 6 Alkyl, optionally substituted C 2 -C 6 alkenyl or optionally substituted C 2 -C 6 More preferably, R 20 is optionally substituted C 1 -C 3 Preferably, alkyl, alkenyl or C 2-C 6 Alkynyl Hydroxy-NR 9 R 10 Preferably, R 9 and R 10 is H. Therefore, G 2 Can and more preferably

[0224] G 1 It may be an optionally substituted C 1 -C 10 Alkylene, more preferably optionally substituted C 1 -C 6 Alkylene. 1 It can be ethylene. 3 may not exist. Therefore, G can be and preferably

[0225] In an alternative embodiment, G 2 Can And a G 4 Does not exist or is -L 3 -.-L 3 - may be optionally substituted C 1 -C 12 Alkylene, more preferably optionally substituted C 1 -C 6 Alkylene and most preferably methylene or ethylene. Thus, G 2 Can R 20 It may be an optionally substituted C 1 -C 6 alkyl, and in some embodiments, methyl. Thus, G 2 Can G 1 and G 3 Therefore, in some embodiments, G may be

[0226] In some embodiments, G 2 Can Every G 4 May be absent or selected from the group consisting of: -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 4L 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 5 L 3 -. At least one G 4 The group may be -X 4 C(O)L 3 -.X 4 Can be -NH-. -L 3 - may be optionally substituted C 1 -C 12 Alkylene, more preferably optionally substituted C 1 -C 6 Alkylene and most preferably methylene or ethylene. At least one G 4 The group can be -L 3 X 4 L 6 C(O)X 5 -. Preferably, at least two or at least three G 4 The group is -L 3 X 4 L 6 C(O)X 5 -. Every X 4 It may be -NH-. Each X ％ Can be -NH-. -L 3 -and-L 6 - may each independently be optionally substituted C 1 -C 12 Alkylene, more preferably optionally substituted C 1 -C 6 Alkylene and most preferably methylene or ethylene. Thus, G 2 Can be:

[0227]

[0228] G 1 and G 3 Can be independent of each other, is -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 -.

[0229] The G group may include at least one G 1 Therefore, a can be 1, 2 or 3. Preferably, a is 1. 1 Can be -L 9 -or-X 4 L 9 -. Preferably, G 1 Yes-X 4 L 9 -. Preferably, X 4 Preferably, -L 9 -yes and p is an integer between 1 and 10, more preferably between 2 and 5, most preferably p is 3. Therefore, G 1 Can

[0230] The G group may include at least one, at least two or at least three G 3 Therefore, z can be 1, 2 or 3. Preferably, z is 3. 3 Can be -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 -. Preferably, G 3 Yes-L 3 X 4 C(O)L 6 -.-L 3 -and-L 6 - may independently be optionally substituted C 1 -C 12 Alkylene, more preferably optionally substituted C 1 -C 6 Alkylene and most preferably C 2 -C 5 Preferably, X 4 is -NH-. Therefore, each G 3 Can

[0231] Therefore, in some embodiments, G may be:

[0232]

[0233] G 2 Can Every G 4 Can not exist independently, is -L 3 -、-X 4 -、-X 8 -、-X 4 C(O)- or -C(O)X 4 -. Preferably, at least one and more preferably at least two G 4 The group is -L 3 -.-L 3 - may be optionally substituted C 1 -C 12 Alkylene, more preferably optionally substituted C 1 -C 6 Preferably, at least one G 4 The group is -X 4 C(O)-. Preferably, X 4 Preferably, G 5 Yes-X 4 C(O)- or -C(O)X 4 -. Preferably, X 4 is -NH-. Therefore, G 2 Can and more preferably R 20 Can be -X 4 C(O)L 3 H, -X 4 C(O)L 9 H, -C(O)X 4 L 3 H or -C(O)X 4 L 9 H. Preferably, X 4 Preferably, R 20 Yes-C(O)X 4 L 9 H. Preferably, -L 9 -yes and p is an integer between 1 and 10, more preferably between 2 and 5, and most preferably p is 3. Therefore, G 2 Can and more preferably

[0234] G 1 But it does not exist. 3 Can be -L 3 -、-L 9 -or-L 9 L 3 -. Preferably, -L 9 -yes and p is an integer between 1 and 10, more preferably between 2 and 5, and most preferably p is 4. -L 3 - may be optionally substituted C 1 -C 12 Alkylene, more preferably optionally substituted C 1 -C 6 Alkylene and most preferably ethylene.

[0235] Therefore, G can be and more preferably

[0236] S can be -L 3 -.L 3 Optionally substituted C 1 -C 10 Alkylene, more preferably optionally substituted C 1 -C 6 Preferably, the alkylene group is unsubstituted.

[0237] S can be -X 4 L 3 -.X 4 It can be -NH-. 3 It may be an optionally substituted C 1 -C 12 Alkylene, more preferably optionally substituted C 1 -C 6 Thus, S may be -NHCH 2 -.

[0238] S may be an 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 12cycloalkyl or an optionally substituted monocyclic or bicyclic 3 to 12 membered heterocycle. Preferably, S is an optionally substituted monocyclic or bicyclic 5 to 10 membered heteroaryl or an optionally substituted monocyclic or bicyclic 3 to 12 membered heterocycle. More preferably, S is an optionally substituted monocyclic or bicyclic 5 membered heteroaryl or an optionally substituted monocyclic or bicyclic 5 membered heterocycle. In some embodiments, G is succinimidyl, triazolyl or tetrazolyl. The triazolyl may be 1,2,3-triazolyl. Thus, S may be Wherein the wavy line and asterisk indicate the attachment of the group S to the targeting moiety T. It will be appreciated that if two attachment sites are shown, S can be attached to the same targeting moiety at two separate points.

[0239] S may be -O-, -NH-, -S- or -C(O)-.

[0240] S can be L 3 .L 3 It may be an optionally substituted C 1 -C 15 Alkylene, more preferably optionally substituted C 1 -C 10 Alkylene and most preferably optionally substituted C 1 -C 6 In some embodiments, the alkylene group is unsubstituted.

[0241] S can be -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 It can be NH. 9 Can be O or S. L 3 It may be an optionally substituted C 1 -C 6 Alkylene and more preferably optionally substituted C 1 -C 2 Alkylene. The alkylene may be via COOH or optionally via COOH or SO 2 R 9 Substituted C 1 -C 6 Therefore, S can be Therein the wavy line and asterisk indicate the attachment of the group S to the targeting moiety T.

[0242] S can be Preferably, X 4 and X 5 It's O.

[0243] S can be Preferably, X 4 is O or NH. Therefore, S can be Therein the wavy line and asterisk indicate the attachment of the group S to the targeting moiety T.

[0244] S can be -L 4 L 3 -.L 3 It may be an optionally substituted C 1 -C 6 Alkylene and more preferably C 1 -C 2 Alkylene. 4 It may be an optionally substituted monocyclic or bicyclic C 6 -C 12 aryl or an optionally substituted monocyclic or bicyclic 5 to 10 membered heteroaryl, and preferably phenyl or a 6 membered heteroaryl. Thus, S may be Therein the wavy line and asterisk indicate the attachment of the group S to the targeting moiety T.

[0245] S can be -L 4 L 3 L 5 C(O)-.L 3 It may be an optionally substituted C 1 -C 6 Alkylene, more preferably C 1 -C 2 Alkylene and most preferably methylene. 4 It may be an optionally substituted C 3 -C 12 cycloalkyl or an optionally substituted monocyclic or bicyclic 3 to 12 membered heterocycle, more preferably an optionally substituted C 3 -C 6 Cycloalkyl or an optionally substituted monocyclic or bicyclic 3 to 6-membered heterocycle, even more preferably an optionally substituted monocyclic or bicyclic 5-membered heterocycle, and most preferably succinimidyl. 5 It may be an optionally substituted C 3 -C 12 cycloalkyl or an optionally substituted monocyclic or bicyclic 3 to 12 membered heterocycle, more preferably an optionally substituted C 3 -C6 cycloalkyl or an optionally substituted monocyclic or bicyclic 3 to 6 membered heterocycle, and most preferably cyclohexyl. Thus, S may be Therein the wavy line and asterisk indicate the attachment of the group S to the targeting moiety T.

[0246] S can be -L 3 C(O)L 4 C(O)-.L 3 It may be an optionally substituted C 1 -C 6 Alkylene, more preferably C 1 -C 2 Alkylene and most preferably methylene. 4 It may be an optionally substituted C 3 -C 12 cycloalkyl or an optionally substituted monocyclic or bicyclic 3 to 12 membered heterocycle, more preferably an optionally substituted C 3 -C 6 Cycloalkyl or an optionally substituted monocyclic or bicyclic 3 to 6 membered heterocycle, most preferably a monocyclic or bicyclic 6 membered heterocycle. Thus, S may be Therein the wavy line and asterisk indicate the attachment of the group S to the targeting moiety T.

[0247] In a preferred embodiment, A may not exist, is -L 3 X 4 -、-C(O)X 4 -、-L 3 C(O)X 4 , -X 4 L 3 L 4 -or

[0248] In A is -L 3 X 4 -In the embodiment, L 3 It may be an optionally substituted C 1 -C 12 Alkylene, and preferably C 1 -C 6 Alkylene, and more preferably -CH 2 -、-CH 2 CH 2 -or-CH 2 CH 2 CH 2 -. Preferably, X 4 is O. Therefore, A can be -CH 2 O-、-CH 2 CH 2O- or -CH 2 CH 2 CH 2 O-.

[0249] In A is -C(O)X 4 -or-L 3 C(O)X 4 In the embodiment, X 4 Can be -O-. 3 It may be an optionally substituted C 1 -C 6 Alkylene, and preferably C 1 -C 3 Alkylene, and most preferably -CH 2 -. Therefore, A can be -C(O)O- or -CH 2 C(O)O-.

[0250] In A In the embodiment of

[0251] In A is -X 4 L 3 L 4 -In the embodiment, X 4 Preferably it is -O-. 3 It may be an optionally substituted C 1 -C 6 Alkylene, and preferably C 1 -C 2 Alkylene, and more preferably -CH 2 -.L 4 It may be an optionally substituted 3 to 12-membered heterocyclic ring, preferably L 4 may be an optionally substituted 3 to 8 membered heterocyclic ring, and most preferably L 4 is an optionally substituted 5- or 6-membered heterocyclic ring. 4 Can Therefore, A can be

[0252] In A is In the embodiment, X 4 Preferably it is -O-. 3 It may be an optionally substituted C 1 -C 6 Alkylene, and preferably C 1 -C 2 Alkylene, and more preferably -CH 2 -. R 17 It may be an optionally substituted C 1-6 Alkyl, and preferably C1-3 X is alkyl, and more preferably methyl. 5 It is preferably -NH- or -O-. 4 It may be an optionally substituted monocyclic or bicyclic C 6 -C 12 Preferably, L 4 is optionally substituted phenyl, and in some embodiments is unsubstituted phenyl. Thus, A may be

[0253] In a preferred embodiment, W is absent or is -L 3 L 7 NH-. More preferably, W is

[0254] In a preferred embodiment, D is absent or is -(D 1 ) q C(O)-, wherein q is an integer between 2 and 10 and more preferably between 3 and 4. Preferably, D 1 Can have the general formula Preferably, each Sc group is an optionally substituted C 1 -C 6 Preferably, the alkyl group is optionally substituted with NHC(O)NH 2 or COOH. Therefore, D can be

[0255]

[0256]

[0257] 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 -、 or -L 4 L 3 -.

[0258] In S is -X 4 L 3 -In the embodiment, X 4 It can be -NH-. 3It may be an optionally substituted C 1 -C 12 Alkylene, more preferably optionally substituted C 1 -C 6 Alkylene and most preferably methylene or ethylene.

[0259] In S is -L 4 In the embodiment of -, S can be an optionally substituted monocyclic or bicyclic 5 to 10 membered heteroaryl or an optionally substituted monocyclic or bicyclic 3 to 12 membered heterocycle. More preferably, S is an optionally substituted monocyclic or bicyclic 5 membered heteroaryl or an optionally substituted monocyclic or bicyclic 5 membered heterocycle.

[0260] In 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 It can be NH. 9 Can be O.C 8 Can be -SO 2 -.L 3 It may be an optionally substituted C 1 -C 6 Alkylene and more preferably optionally substituted C 1 -C 2 The alkylene group may be unsubstituted or substituted with COOH or a C 1 -C 6 Alkyl substitution.

[0261] In S is -L 4 L 3 -In the embodiment, L 3 It may be an optionally substituted C 1 -C 6 Alkylene and more preferably C 1 -C 2 Alkylene. 4 It may be an optionally substituted monocyclic or bicyclic C 6 -C 12 Aryl or optionally monocyclic or bicyclic 5 to 10 membered heteroaryl, and preferably phenyl or 6 membered heteroaryl.

[0262] Therefore, in a preferred embodiment, S may be -(CH 2 ) 5 -, -NH-, -S-, -C(O)-, -NHCH 2 -、

[0263] A, W, D, G and S may all be present. In some embodiments, a is 1 and z is 1. Thus, the linker may be:

[0264]

[0265]

[0266]

[0267]

[0268]

[0269]

[0270]

[0271] Therein the wavy line and asterisk indicate the connection of the linker to the targeting moiety T, and the wavy line without asterisk indicates the connection of the linker to the active compound C.

[0272] W, D, G and S may all be present. A may not be present. In some embodiments, a is 1 and z is 1. Thus, the linker may be:

[0273]

[0274]

[0275] Therein the wavy line and asterisk indicate the connection of the linker to the targeting moiety T, and the wavy line without asterisk indicates the connection of the linker to the active compound C.

[0276] A, G and S may all be present. D may not be present. W may not be present. In some embodiments, a is 1 and z is 1. Thus, the linker may be:

[0277]

[0278]

[0279] Therein the wavy line and asterisk indicate the connection of the linker to the targeting moiety T, and the wavy line without asterisk indicates the connection of the linker to the active compound C.

[0280] A, W, G and S may all be present. D may not be present. In some embodiments, a is 1 and z is 1. Thus, the linker may be:

[0281]

[0282]

[0283] Therein the wavy line and asterisk indicate the connection of the linker to the targeting moiety T, and the wavy line without asterisk indicates the connection of the linker to the active compound C.

[0284] A and G may both be present. D may not be present. W may not be present. S may not be present. In some embodiments, a is 1 and z is 1. Thus, the linker may be:

[0285]

[0286] Therein the wavy line and asterisk indicate the connection of the linker to the targeting moiety T, and the wavy line without asterisk indicates the connection of the linker to the active compound C.

[0287] 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, G and S may both be present. A may not be present. D may not be present. W may not be present. Thus, the linker may be:

[0288]

[0289] Therein the wavy line and asterisk indicate the connection of the linker to the targeting moiety T, and the wavy line without asterisk indicates the connection of the linker to the active compound C.

[0290] 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, W, D, G, and S may all be present. A may not be present. Thus, the linker may be:

[0291] Therein the wavy line and asterisk indicate the connection of the linker to the targeting moiety T, and the wavy line without asterisk indicates the connection of the linker to the active compound C.

[0292] Linkers are known to those skilled in the art in the form of "stable" linkers, which resist degradation in the cell and in the systemic circulation, or "cleavable" or "conditionally unstable" linkers, which are designed to degrade under intracellular conditions and / or in the systemic circulation following a defined triggering event, which may be a pH change or a metabolic process such as ester or amide hydrolysis. The conjugates of the invention may comprise two or more cleavage mechanisms, which may be selected from acid-induced cleavage, peptidase-induced cleavage (e.g., peptide linkers cleaved by intracellular proteases such as lysosomal 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 cleavage of acid-labile linkers. Specific hydrolysis processes have been described, such as the protease cleavage of dipeptides (e.g., valine-citrulline dipeptide moiety) contained in the clinical precedent ADC brentuximab vedotin (Ducry et al., Bioconj. Chem., 2010, 21, 5-13), phenylalanine-lysine dipeptide, maleimidocaproyl or maleimidocaproyl-valine-citrulline linkers. The p-aminobenzyloxycarbonyl (PABC) radical from the digestive group can also form part of the linker structure, which is eliminated from the conjugate in response to a suitable triggering event to release the parent structure (Carl et al., J. Med. Chem., 1981, 5). 24 ,479 and Chakravarty et al., Journal of Medicinal Chemistry, 1983, 26 , 638), such as in maleimidocaproyl-valine-citrulline-PABC linker. Other linkers include linkers that are cleaved at a specific pH or pH range, such as hydrazones, such as the hydrazone moiety in gemtuzumab-ozogamicin.

[0293] Non-cleavable linkers may be insensitive to proteases. Non-cleavable linkers include those contained in the clinical precedent ADC trastuzumab emtansine and require intracellular degradation of the conjugate to release the active drug C. See, e.g., Wong, Chemistry of Protein Conjugation and Cross-Linking, CRC Press Inc., Boca Raton, 1991.

[0294] The linker may be of a dendritic nature, wherein more than one small molecule C may be covalently linked to the targeting moiety via a branched, multifunctional unit (US2006 / 116422, US2005 / 271615). Dendritic linkers may increase the molar ratio of drug to targeting group, which is related to the efficacy of the conjugate. Thus, in the case where the targeting group contains, for example, only a single thiol group, multiple small molecules may be linked via a dendritic or branched linker.

[0295] The linker can be connected to the targeting moiety T by a reactive group thereon at any suitable available position on the targeting moiety in various ways. Examples of suitable reactive groups include surface lysine, oxidized carbohydrates and cysteine ​​residues. Suitable reactive groups are known to those skilled in the art. For example, various antibody-drug conjugate (ADC) bonding techniques are known in the industry, including by alkylation, reductive amination, transesterification, amidation and thiol Michael addition (Michael addition). The resulting linkage includes functional groups based on hydrazone, disulfide, maleimide, succinimide and peptide. For example, a thiol group or a cysteine ​​residue can be bonded to a linker or a spacer group by a maleimide group. Alternative coupling chemistries include lysine reactive groups such as succinyl or HOBt esters, pentafluorophenyl esters, β-lactams, isocyanates, and isothiocyanates; azide reactive groups such as alkynes and strained alkynes; cysteine ​​reactive groups such as maleimide, α-haloacetamide, pyridyl disulfide, and vinyl sulfoxide; and ketone reactive groups such as hydroxylamine, hydrazine, and acyl hydrazide.

[0296] In some embodiments, the number of drug / linker moieties conjugated per antibody molecule is between 1 and 10. The drug-antibody ratio (DAR) is typically 1 to 10, and may be 2 to 5 or 2 to 3. Thus, b may be 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0297] The conjugates can be designed to specifically target certain cell types or tumor types via the targeting moiety. Thus, the targeting moiety can be configured to direct the compound of formula (I) to specific cells or tumor types and thereby deliver the STING modulator in a cell-specific manner. The conjugates can thus be used accordingly in therapeutic settings. It is known to those skilled in the art that the principle of this targeted delivery is closely related to ADC technology, for example, as described in Polakis P., Pharmacological Reviews, 2016, 68 , 3-19 and Beck et al., Nature Reviews: Drug Discovery (Nat. Revs. Drug Disc.), 2017, 16 , 315-337. The conjugate can then be taken up inside the cell or tumor by 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 cell or tumor microenvironment. 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, cathepsins B, C or D or plasmin proteases can cleave the linker and release the active compound in the target cell or target cell tumor microenvironment. The active drug then migrates freely within the cell or microenvironment and thereby contacts and subsequently regulates the STING protein. In some embodiments, the active drug can be cleaved from the targeting portion outside the cell or tumor and the active drug then acts on the cell surface or penetrates the cell or tumor.

[0298] T is a targeting moiety and may include an antibody, antibody fragment, nucleic acid-based molecule, carbohydrate, peptide, modified peptide, or small molecule.

[0299] In one embodiment, T can be configured to target a tumor antigen. Thus, T cells can be configured to target human epidermal growth factor receptor (EGFR), plasminogen activator, cytotoxic T lymphocyte-associated antigen (CTLA) (e.g., CTLA-4), vascular endothelial growth factor (VEGF), neurotrophic factors (e.g., BDNF), fibroblast growth factor receptor (FGFR), nerve growth factor, platelet-derived growth factor (PDGF), transforming growth factor (TGF), tissue factor (TF), EpCAM, CEACAM5, CEACAM6, colon-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 alphaV β3, PD-1, PD-L1, EGP-1, EGP-2, EphA2 tyrosine kinase, mucin cell surface antigens (e.g., 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、α-fetoprotein、R1、PAP、PAX3、PAX5、Ras、Rho、ROR2、Connexin-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.

[0300] In a preferred embodiment, T is configured to target Her2. It is understood that HER2 may also be referred to as Erbb2 and is a biomarker for breast cancer, gastric cancer, ovarian cancer, and / or lung cancer.

[0301] In a preferred embodiment, T is an antibody or a fragment thereof. Certain antibodies have previously been used in the field of immuno-oncology. Exemplary anti-PD1 antibodies include lambrolizumab (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.

[0302] As an example, a conjugate comprising an anti-HER2 antibody 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 Trastuzumab was approved by the USFDA 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 metastatic disease.

[0303] The invention extends to whole antibodies as well as antigen-binding fragments or regions of corresponding full-length antibodies.

[0304] Antibodies or their antigen-binding fragments may be monovalent, divalent or multivalent. A monovalent antibody is a dimer (HL) comprising a heavy chain (H) and a light chain (L) associated by a disulfide bridge. A divalent antibody is a tetramer (H2L3) comprising two dimers associated by at least one disulfide bridge. Multivalent antibodies may also be produced, for example, by connecting multiple dimers. The basic structure of an antibody molecule consists of two identical light chains and two identical heavy chains, which are associated in a non-covalent manner and may be connected by disulfide bonds. Each heavy chain and light chain contains an amino-terminal variable region of about 110 amino acids, and the rest of the chain is a constant sequence. The variable region includes several hypervariable regions or complementary determining regions (CDRs), which form the antigen binding site of the antibody molecule and determine its specificity for the antigen or its variants or fragments (e.g., epitopes). On either side of the CDRs of the heavy and light chains is a framework region, which is a relatively conservative amino acid sequence that anchors and directs the CDRs. The antibody fragment may comprise a bispecific antibody (BsAb) or a chimeric antigen receptor (CAR).

[0305] 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.

[0306] Preferably, the antibody or antigen-binding fragment thereof is isolated or purified.

[0307] In a preferred embodiment, the antibody or antigen-binding fragment thereof comprises a polyclonal antibody or antigen-binding fragment thereof. The antibody or antigen-binding fragment thereof can be generated in rabbits, mice or rats.

[0308] In another preferred embodiment, the antibody or its antigen-binding fragment comprises a monoclonal antibody or its antigen-binding fragment. Preferably, the antibody is a human antibody. As used herein, the term "human antibody" may mean an antibody (e.g., a monoclonal antibody) comprising heavy chain and light chain CDR amino acid sequences substantially identical to those found in a specific human antibody exhibiting immunospecificity. When compared to a reference sequence, an amino acid sequence substantially identical to a heavy chain or light chain CDR exhibits considerable sequence identity. The identity is clearly known or identified as an amino acid sequence representing a specific human antibody. In fact, the same heavy chain and light chain CDR amino acid sequences may have, for example, minor amino acid modifications or conservative amino acid substitutions.

[0309] The term "human monoclonal antibody" may include monoclonal antibodies with substantially or completely human CDR amino acid sequences, for example, produced by recombinant methods, such as by phage libraries, by lymphocytes, or by hybridoma cells.

[0310] The term "humanized antibody" may refer to an antibody from a non-human species (eg, mouse or rabbit) whose protein sequence has been modified to increase its similarity to antibodies naturally produced in humans.

[0311] The antibody may be a recombinant antibody. The term "recombinant human antibody" may include human antibodies produced using recombinant DNA technology.

[0312] The term "antigen binding region" may refer to a region of an antibody that has specific binding affinity for its target antigen 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 refer to a sequence within a CDR that exhibits specific affinity for a target antigen. A functional portion of a CDR may include a ligand that specifically binds to a target antigen or a fragment thereof.

[0313] The term "CDR" may refer to the hypervariable regions in the heavy and light variable chains. There may be one, two, three or more CDRs in each of the heavy and light chains of an antibody. Typically, there are at least three CDRs on each chain that, when configured together, form an antigen binding site, i.e., a three-dimensional combined site that binds or specifically reacts with an antigen. However, it has been hypothesized that there may be four CDRs in the heavy chain of some antibodies.

[0314] The definition of CDR also includes overlaps or subsets of amino acid residues when compared to each other. The exact number of residues that encompass a particular CDR or a functional portion thereof may vary depending on the sequence and size of the CDR. Given the variable region amino acid sequence of an antibody, one skilled in the art can determine the residues that comprise a particular CDR in a conventional manner.

[0315] The term "functional fragment" of an antibody may mean a portion of an antibody that retains functional activity. Functional activity may be, for example, antigen binding activity or specificity. Functional activity may also be, for example, an effector function provided by an antibody constant region. The term "functional fragment" is also intended to include fragments produced, for example, by protease digestion or reduction of human monoclonal antibodies and by recombinant DNA methods known to those skilled in the art. Human monoclonal antibody functional fragments include, for example, individual heavy or light chains and fragments thereof, such as VL, VH and Fd; monovalent fragments, such as Fv, Fab and Fab'; bivalent fragments, such as F(ab'); 2 ; single-chain Fv (scFv); and Fc fragment.

[0316] The term "VL fragment" may refer to a fragment of the light chain of a human monoclonal antibody that contains all or part of the light chain variable region (including CDR). The VL fragment may further contain a light chain constant region sequence.

[0317] The term "VH fragment" may refer to a fragment of the heavy chain of a human monoclonal antibody that contains all or a portion of the heavy chain variable region (including CDR).

[0318] The term "Fd fragment" may refer to the heavy chain variable region coupled to the first heavy chain constant region, that is, VH and CH-1."Fd fragment" does not comprise the second and third constant regions of the light chain or heavy chain.

[0319] The term "Fv fragment" may refer to a monovalent antigen-binding fragment of a human monoclonal antibody, comprising all or part of the variable regions of the heavy and light chains and excluding the constant regions of the heavy and light chains. The variable regions of the heavy and light chains include, for example, CDRs. For example, an Fv fragment comprises all or part of the amino-terminal variable regions of about 110 amino acids in both the heavy and light chains.

[0320] The term "Fab fragment" may refer to a monovalent antigen-binding fragment of a human monoclonal antibody that is larger than an Fv fragment. For example, a Fab fragment comprises the variable region and all or a portion of the first constant domain of the heavy chain and the light chain. Thus, a Fab fragment additionally comprises, for example, amino acid residues about 110 to about 220 of the heavy chain and the light chain.

[0321] The term "Fab' fragment" may refer to a monovalent antigen-binding fragment of a human monoclonal antibody that is larger than a Fab fragment. For example, a Fab' fragment comprises all of the light chain, all of the variable regions of the heavy chain, and all or a portion of the first and second constant domains of the heavy chain. For example, a Fab' fragment may additionally comprise some or all of amino acid residues 220 to 330 of the heavy chain.

[0322] The term "F(ab') 2 Fragment" may refer to a bivalent antigen-binding fragment of a human monoclonal antibody. F(ab') 2 The fragments comprise, for example, all or a portion of the variable regions of two heavy chains and two light chains, and may further comprise all or a portion of the first constant domains of two heavy chains and two light chains.

[0323] The term "single-chain Fv (scFv)" may refer to a fusion of the variable regions of the heavy chain (VH) and the light chain (VL) linked using a short linker peptide.

[0324] The term "bispecific antibody (BsAb)" may refer to a bispecific antibody including two scFvs linked to each other by a shorter linker peptide.

[0325] Those skilled in the art will appreciate that the exact boundaries of an antibody fragment are not important, as long as the fragment maintains functional activity. Using well-known recombinant methods, those skilled in the art can engineer polynucleotide sequences to express functional fragments with any endpoints desired for a particular application. Functional fragments of antibodies may include or consist of fragments having substantially the same heavy and light chain variable regions as human antibodies.

[0326] The antigen-binding fragment thereof may comprise or consist of any fragment selected from the group consisting of: VH, VL, Fd, Fv, Fab, Fab', scFv, F(ab') 2 and Fc fragment.

[0327] Its antigen-binding fragment may include any antigen-binding region sequence of VL, any antigen-binding region sequence of VH, or a combination of VL and VH antigen-binding regions of human antibodies or consist thereof. The appropriate number and combination of VH and VL antigen-binding region sequences can be determined by a person skilled in the art according to the desired affinity and specificity of the antigen-binding fragment and the intended application. Functional fragments or antigen-binding fragments of antibodies can be easily produced and isolated using methods well known to a person skilled in the art. The methods include, for example, proteolytic methods, recombinant methods, and chemical synthesis. Proteolytic methods for isolating functional fragments include using human antibodies as starting materials. Enzymes suitable for proteolysis of human immunoglobulins may include, for example, papain and pepsin. Appropriate enzymes can be easily selected by a person skilled in the art according to, for example, whether monovalent or divalent fragments are required. For example, papain cleavage will produce two monovalent Fab' fragments that bind to the antigen and one Fc fragment. For example, pepsin cleavage will produce a divalent F(ab') fragment. The F(ab') of the present invention can be further reduced using, for example, DTT or 2-mercaptoethanol. 2 fragments to produce two monovalent Fab' fragments.

[0328] Functional 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 charge and size using (human) ion exchange and gel filtration chromatography. Such methods are well known to those skilled in the art.

[0329] Antibodies or antigen-binding fragments thereof can be produced using techniques well known in the art. For example, by recombinant methods (see U.S. Pat. No. 4,816,567), hybridoma technology (Kohler et al., Nature, 1975, 256 , 495), phage display technology (see, for example, Clarkson et al., Nature, 1991, 352,624 and Marks et al., Journal of Molecular Biology, 1991, 222 ,581), synthetic techniques or a combination of such techniques. Preferably, polynucleotides encoding the desired regions of the heavy and light chains of the antibody are first isolated. The regions may include, for example, all or part of the variable regions of the heavy and light chains. Preferably, the regions may particularly include the antigen binding regions, preferably antigen binding sites, and most preferably CDRs of the heavy and light chains.

[0330] The polynucleotides encoding antibodies or antigen-binding fragments thereof of the present invention can be produced using methods known to those skilled in the art. Polynucleotides encoding antibodies or antigen-binding fragments thereof can be directly synthesized by oligonucleotide synthesis methods known in the industry. Alternatively, smaller fragments can be synthesized and joined to form larger functional fragments using recombination methods known in the industry. The antibodies used can be obtained commercially from numerous known sources (e.g., American Type Culture Collection (ATCC, Manassas, Va.)). A large number of antibodies against numerous disease targets and tumor-associated antigens have been deposited at ATCC and / or have disclosed variable region sequences and can be used in the claimed methods and compositions.

[0331] Cysteine ​​engineered antibodies have been designed as Fab antibody fragments (ThioFab) and expressed as full-length IgG monoclonal (thioMab) antibodies (U.S. Pat. No. 7,521,541). ThioFab and ThioMab antibodies have been coupled to the newly introduced cysteine ​​thiols via linkers to prepare site-specific antibody-drug conjugates (U.S. Pat. No. 7,521,541, US2008 / 0050310, WO2008 / 052187).

[0332] Polytherics has described bridging a pair of sulfhydryl groups contained in antibody proteins derived from the reduction of a native disulfide hinge (Badescu et al., Bioconjugate Chemistry, 2014, 25 , 1124-1136) to synthesize homogeneous drug-loaded ADCs. Similar methods have been used by Concortis (U.S. Patent 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 in Frigerio et al., Current Topics in Medicinal Chemistry (Curr. Top. Med. Chem.), 2018, 18 ,1-32.

[0333] Other recent approaches that have been used for targeted homogeneous drug loading of ADCs include incorporating unnatural amino acid groups into antibodies (e.g., selenocysteine ​​(Hofer, T. et al., Biochem., 2009, 48 , 12047-12057) or formylglycine (Drake, PM et al., Bioconjugate Chemistry, 2014, 25 , 1331-1341)). Glycosylation has been used to introduce sialic acid residues at specific sites (Zhou, Q. et al., Bioconjugate Chemistry, 2014, 25 , 510-520), and transglutaminase is used to enzymatically couple the primary amine-containing linker / payload to the glutamate residue (Dorywalska, M. et al., Bioconjugate Chemistry, 2015, 26 , 650-659). These and other methods are described in Sochai AM et al., Biotech. Adv., 2015, 33 ,775-784.

[0334] As used herein, the term "immunospecific" may mean that the binding region is capable of immunoreacting with a target antigen or a variant or fragment thereof by specifically binding thereto. The antibody or antigen-binding fragment thereof may selectively interact with the antigen with 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 .

[0335] The term "immunoreact" may mean that the binding region is capable of inducing an immune response when binding to a target antigen or an epitope thereof.

[0336] The term "epitope" may refer to any region of an antigen that is capable of stimulating and combining with the binding region of an antibody or antigen-binding fragment thereof.

[0337] In one embodiment, T comprises a nucleic acid-based molecule. The nucleic acid-based molecule may be an aptamer. The nucleic acid-based molecule may target the CD33 / CD34 antigen, as described in Zaimy, MA et al., Cancer Gene Ther., 2016, 23 , 315-320; or PSMA tumor antigens (e.g., A9, A10, and A9L), as described in Lupold, SE et al., Cancer Res., 2002, 62 , 4029-4033; Dassie, JP et al., Nat. Biotech., 2009, 27 , 839-849; Rockey, WM et al., Nucleic Acid Ther., 2011, 21 , 299-314; or any other tumor antigen known to those skilled in the art, such as Orava, E., Biochem. Biophys. Acta, 2010, 1798 , described in 2190-2200.

[0338] Aptamers are nucleic acid or peptide molecules that are assumed to have a specific sequence-dependent shape and bind to a specific target ligand (based on the lock and key coordination between the aptamer and the ligand). Typically, aptamers can include single-stranded or double-stranded DNA molecules (ssDNA or dsDNA) or single-stranded RNA molecules (ssRNA). Peptide aptamers consist of short variable peptide domains connected to a protein framework at both ends. Aptamers can be used to bind both nucleic acid and non-nucleic acid targets.

[0339] Suitable aptamers can be selected from a pool of random sequences from which specific aptamers that bind to a selected antigen with high affinity can be identified. Methods for generating and selecting aptamers with desired specificity are well known to those skilled in the art and include the SELEX (Systematic Evolution of Ligands by Exponential Enrichment) process. Briefly, large oligonucleotide libraries are generated, allowing large numbers of functional nucleic acids to be isolated by an iterative process of in vitro selection and subsequent amplification by polymerase chain reaction. Preferred methods for generating aptamers include those disclosed in WO2004 / 042083.

[0340] In an alternative embodiment, T comprises a peptide or a modified peptide. The peptide or modified peptide may include an RGD sequence motif (e.g., Mousavizadeh, A., Colloids Surfaces B., 2017,158 , 507-517) to contain a linear RGD peptide sequence or a cyclized form thereof (as described in Belvisi, L et al., Current Topics in Medicinal Chemistry, 2016, 16 , 314-329). Exemplary embodiments of RGD ligands that the targeting moiety can target and bind to are as follows:

[0341]

[0342] The peptide or modified peptide may include transferrin or a modified form of transferrin, which has been described as exhibiting utility for targeted delivery of xenobiotics (Kratz et al., Cancer Chemother. Pharmacol., 1998, 41 , 155-160) (including crossing the blood-brain barrier (Fishman et al., J. Cell Biol., 1987, 101 , 423-427)). The peptide or modified peptide may also include albumin or a modified form of albumin, wherein the albumin may be coupled to a suitable linker via Cys34 or other suitable residues, as described in Larsen et al., Mol Cell Ther., 2016, 4 , as described in 3.

[0343] In an alternative embodiment, T comprises carbohydrates or modified carbohydrate molecules that can target tumor-associated carbohydrate antigen receptors on target tumors and cells. For example, glycosphingolipids, gangliosides, sialic acid, and mucins can indicate malignant transformation and abnormal glycosylation patterns on 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, DH and Bertozzi, CR, Nat. Rev. Drug Disc., 2005, 4, 477-488), and targeting ligands based on carbohydrate molecules (e.g., mannose, galactose, or cerebrosidase derivatives) have been designed for them. In a related approach, cell surface receptors on the tissue of interest can also be targeted; recent examples include derivatives of N-acetyl-galactosamine (GalNAc), which have been developed for targeting asialoglycoprotein receptors on hepatocytes, reviewed in D'Souza, A. et al., J. Controlled Rel., 2015, 203, 126-139, and recent examples in Sanhueza, CA et al., JACS, 2017, 139, 3528-3536. Exemplary embodiments of carbohydrates that can be used as targeting moieties are as follows:

[0344]

[0345] Therefore, T can be

[0346] In another embodiment, T comprises a small molecule ligand with affinity for a cell or tumor surface receptor. For example, folic acid or its derivatives can be used to target folate receptors α, β or γ (FRα, FRβ and FRγ). In particular, FRα is known to be expressed in multiple endothelial tumor types (e.g., breast, lung and kidney tumors) (for a recent review, see Fernandez, M. et al., 2018, 4, 790-810), and conjugates of folate derivatives and toxins have been previously described (Vlahov, I. and Leamon, CP, Bioconjugate Chemistry, 2012, 23, 1357-1369).

[0347] The linker can be attached to the compound of formula (I) via a C atom, an O atom, a N atom or a S atom.

[0348] The linker can be cleavable, non-cleavable, hydrophilic or hydrophobic. A cleavable linker can be enzyme sensitive and cleavable by an enzyme such as a protease. For example, a cleavable linker can be a valine-citrulline linker or a valine-alanine linker. For example:

[0349]

[0350] The non-cleavable linker may be insensitive to proteases.

[0351] The inventors have found that the compounds of the invention can be functionalized in various positions with various linkers and spacers to provide coupled molecules. The linkers can contain a self-cleaving group (e.g., p-aminobenzyl ether or amine and / or valine-citrulline unit) designed to release the parent ACSS after a hydrolysis event (e.g., after amide, peptide or carbamate hydrolysis). 2 Inhibitor.

[0352] The term “ACSS 2 ” refers to acetyl-CoA synthetase short chain 2 An ATP-dependent enzyme that catalyzes the synthesis of acetyl-CoA from acetate. ACSS 2 Responsible for acetate incorporation into cells, including acetate uptake into lipids and tissue proteins.

[0353] It should be understood that with respect to ligands and ACSS 2 "Antagonists" or "inhibitors" include those that inhibit, resist, downregulate and / or desensitize ACSS. 2 "Antagonist" encompasses any molecule, combination of molecules or complex that inhibits ACSS 2 Constitutive activity is the activity of the ligand / ACSS in the absence of 2 "Antagonist" also encompasses any agent that inhibits or prevents ACSS 2 An agent that stimulates (or regulates) the activity of.

[0354] Preferably, the compound of formula (I) or the conjugate of formula (II) is ACSS 2 Protein inhibitors.

[0355] It is understood that the compounds described herein, or pharmaceutically acceptable salts, solvates, tautomeric forms or polymorphs thereof, can be used in medicaments that can be used to modulate ACSS 2 Protein and / or monotherapy (i.e., using only a compound) for treating, ameliorating or preventing a disease.

[0356] Alternatively, the compound or its pharmaceutically acceptable salt, solvate, tautomeric form or polymorph may be used to assist in regulating ACSS.2 Proteins and / or known therapies for treating, ameliorating or preventing diseases, or used in combination therewith.

[0357] Therefore, in one aspect, the second therapeutic agent may be administered together with the compound of formula (I) or the 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 anti-cancer vaccine and / or a hormone therapy. Alternatively or in addition, the second therapeutic agent may include a B7 co-stimulatory molecule, interleukin-2, interferon-g, GM-CSF, a CTLA-4 antagonist (e.g., ipilimumab and tremilimumab), an IDO inhibitor or an IDO / TDO inhibitor (e.g., Epacadostat and GDC-0919), a PD-1 inhibitor (e.g., Nivolumab, Pembrolizumab, Pilivizumab, AMP-224, and MDX-1106), a PD-L1 inhibitor (e.g., Durvalumab, Avelumab, and Atezolizumab), an OX-40 ligand, a LAG3 inhibitor, a CD40 ligand, a 41BB / CD137 ligand, a CD27 ligand, a Bacille Calmette-Guérin (BCG) inhibitor, or a PD-L1 inhibitor. Calmette-Guerin, BCG), liposomes, alum, Freund's complete or incomplete adjuvant, TLR agonists (e.g., poly I:C, MPL, LPS, bacterial flagellin, imiquimod, resiquimod, loxoribine, and CpG dinucleotides), and / or detoxified endotoxin.

[0358] Methods of co-administration with another therapeutic agent are well known in the art (Hardman et al. (Eds.), Goodman and Gilman, The Pharmacological Basis of Therapeutics, 10th ed., 2001, McGraw-Hill, New York; 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).

[0359] In one aspect, the disease is cancer and a chemotherapeutic agent can be administered with a compound of formula (I) or a conjugate of formula (II). The chemotherapeutic agent can be selected from the group further consisting of: cancer vaccines, targeted drugs, targeted antibodies, antibody fragments, antimetabolites, antitumor agents, antifolates, toxins, alkylating agents, DNA strand breakers, DNA minor groove binders, pyrimidine analogs, ribonucleotide reductase inhibitors, tubulin interactors, antihormonal agents, immunomodulators, antiadrenal agents, cytokines, radiation therapy, cell therapy, cell depletion therapy (e.g., B cell depletion therapy) and hormone therapy. Alternatively or additionally, the chemotherapeutic agent may include abiraterone, altretamine, anhydrovinblastine, auristatin, bexarotene, bicalutamide, bleomycin, cachecticin, cemadotin, chlorambucil, cyclophosphamide, docetaxol, doxetaxel, carboplatin, cysplatin, cytarabin e), dactinomycin, daunorubicin, decitabine, doxorubicin, etoposide, 5-fluorouracil, finasteride, flutamdie, hydroxyurea, streptozocin, mitomycin, methotrexate, taxane, tamoxifen, vinblastine, vincristine and / or vindesine.

[0360] The compound of formula (I) or the conjugate of formula (II) can be combined in a composition having many different forms, especially depending on the mode in which the composition is to be used. Thus, for example, the composition can be in the form of a powder, tablet, capsule, liquid, ointment, cream, gel, hydrogel, aerosol, spray, colloidal solution, transdermal patch, liposomal suspension or any other suitable form that can be administered to a human or animal in need of treatment. It should be understood that the vehicle of the medicament of the present invention should be well tolerated by the individual to whom it is administered.

[0361] The medicaments comprising the compounds described herein can be used in a variety of ways. Suitable modes of administration include oral, intratumoral, parenteral, topical, inhalation / intranasal, rectal / intravaginal and ocular / aural administration.

[0362] Formulations suitable for the above modes of administration can be formulated for immediate release and / or modified release. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, targeted release, and programmed release.

[0363] The compounds of the present invention can be administered orally. Oral administration may involve swallowing so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed, whereby the compound enters the bloodstream directly from the oral cavity. Formulations suitable for oral administration include solid formulations (e.g., tablets), capsules containing microparticles, liquids or powders, lozenge-shaped tablets (including liquid fillers), chewables, multi- and nanoparticles, gels, solid solutions, liposomes, films, vaginal suppositories, sprays, liquid formulations, and buccal / mucoadhesive patches.

[0364] Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations can be used as fillers in soft or hard capsules and typically include a carrier (e.g., water, ethanol, polyethylene glycol, propylene glycol, methylcellulose or a suitable oil) and one or more emulsifiers and / or suspending agents. Liquid formulations can also be prepared, for example, by reconstituting a solid in a pouch.

[0365] The compounds of the invention may also be used in fast dissolving, fast disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents, 11(6), 981-986, Liang and Chen (2001).

[0366] For tablet dosage forms, depending on the dosage, the drug may account for 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 typically contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, cross-linked sodium carboxymethylcellulose, crospovidone, polyvinyl pyrrolidone, methylcellulose, microcrystalline cellulose, hydroxypropyl cellulose substituted with a low carbon alkyl group, starch, pregelatinized starch, and sodium alginate. Typically, the disintegrant will account for 1% to 25% by weight of the dosage form, preferably 5% to 20% by weight.

[0367] Binders are often used to impart cohesive qualities to tablet formulations. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinyl pyrrolidone, pregelatinized starch, hydroxypropyl cellulose, and hydroxypropyl methylcellulose. Tablets may also contain diluents such as lactose (monohydrate, spray-dried monohydrate, anhydrous, and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch, and dibasic calcium phosphate dihydrate.

[0368] Tablets may also optionally include surfactants (e.g., sodium lauryl sulfate and polysorbate 80) and glidants (e.g., silicon dioxide and talc). When present, surfactants may comprise 0.2% to 5% by weight of the tablet, and glidants may comprise 0.2% to 1% by weight of the tablet.

[0369] Tablets also typically contain lubricants, such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and a mixture of magnesium stearate and sodium lauryl sulfate. Lubricants typically account for 0.25% to 10% by weight, preferably 0.5% to 3% by weight of the tablet. Other possible ingredients include antioxidants, colorants, flavoring agents, preservatives, and taste masking agents.

[0370] An exemplary tablet contains up to about 80% by weight of the drug, about 10% to about 90% by weight of the binder, about 0% to about 85% by weight of the diluent, about 2% to about 10% by weight of the disintegrant, and about 0.25% to about 10% by weight of the lubricant. The tablet blend may be formed into a tablet directly or by roller compression. Alternatively, the tablet blend or blend portion may be wet, dry or melt granulated, melt coagulated, or extruded before tableting. The final formulation may include one or more layers and may be coated or uncoated; it may even be encapsulated. Tablet formulations are discussed in "Pharmaceutical Dosage Forms: Tablets", Vol. 1, H. Lieberman and L. Lachman (Marcel Dekker, New York, 1980).

[0371] Suitable modified release formulations for the purposes of the present invention are described in U.S. Pat. No. 6,106,864. Details of other suitable release technologies (e.g., high energy dispersions and osmotic and coated particles) are found in "Pharmaceutical Technology On-line", 25(2), 1-14, Verma et al. (2001). The use of chewing gum to achieve controlled release is described in WO 00 / 35298.

[0372] The compounds of the invention can also be administered directly into the bloodstream, muscle or internal organs. Suitable modes for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, ​​intrasternal, intracranial, intramuscular and subcutaneous administration. Suitable devices for parenteral administration include needle (including microneedle) syringes, needle-free syringes and infusion techniques.

[0373] Parenteral formulations are typically aqueous solutions that may contain excipients (e.g., salts, carbohydrates) and buffers (preferably pH 3 to 9), but for some applications may be more appropriately formulated as sterile non-aqueous solutions or in dry form for use in combination with a suitable vehicle (e.g., sterile, pyrogen-free water).

[0374] The preparation of parenteral formulations under sterile conditions, for example by lyophilization, is readily accomplished using standard pharmaceutical techniques well known to those skilled in the art.

[0375] The solubility of the compound of formula (I) and the conjugate of formula (II) for preparing parenteral solutions can be enhanced by appropriate formulation techniques (e.g., incorporation of solubilizers). The formulations for parenteral administration can be formulated to release directly and / or in a modified manner. The formulations released in a modified manner include delayed release, sustained release, pulsed release, controlled release, targeted release, and programmed release. Therefore, the compounds of the present invention can be formulated into solid, semisolid, or thixotropic liquids for administration in the form of implanted reservoirs, thereby releasing the active compound in a modified manner. Examples of the formulations include drug-coated stents and poly (dl-lactic-co-glycol) acid (PGLA) microspheres.

[0376] The compounds of the invention may also be administered topically to the skin or mucous membranes, i.e., transdermally or transdermally. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages, and microemulsions. Liposomes may also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerol, polyethylene glycol, and propylene glycol. Penetration enhancers may be included, see, for example, J Pharm Sci, 88(10), 955-958, Finnin and Morgan (October 1999).

[0377] Other local administration methods include electroporation, iontophoresis, phonophoresis, sonication, and microneedle or needle-free (e.g., Powderject TM 、Bioject TM etc.) for delivery by injection.

[0378] The compounds of the invention may also be administered intranasally or by inhalation, typically in the form of a dry powder from a dry powder inhaler (alone, as a mixture (e.g., a dry blend with lactose) or as mixed component particles (e.g., mixed with a phospholipid, such as phosphatidylcholine)) or as an aerosol spray from a pressurized container, pump, injector, nebulizer (preferably one that uses electrohydrodynamics to generate a fine mist) or sprayer (with or without a suitable propellant, such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane). For intranasal use, the powder may include a bioadhesive, such as chitosan or cyclodextrin.

[0379] The pressurized container, pump, spray, atomizer or nebulizer contains a solution or suspension of the compound of the invention, which includes, for example, ethanol, aqueous ethanol or a suitable alternative for dispersion, solubilization or prolonged release of the active substance, a propellant as a solvent and optionally a surfactant (for example sorbitan trioleate, oleic acid or oligolactic acid).

[0380] Before use in dry powder or suspension formulations, the drug product is micronized to a size suitable for delivery by inhalation (usually less than 5 microns). This can be achieved by any appropriate comminution method (e.g., spiral jet milling, fluidized bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization or spray drying.

[0381] Capsules (e.g. made from gelatin or hydroxypropylmethylcellulose), blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of a compound 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, the latter being preferred. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.

[0382] Solution formulations suitable for use in atomizers that use electrohydrodynamics to produce fine mist may contain 1 μg to 20 mg of the compound of the invention per actuation, and the actuation volume may vary from 1 μL to 100 μL. Typical formulations may include a compound of formula (I) or a conjugate of formula (II), propylene glycol, sterile water, ethanol, and sodium chloride. Alternative solvents that can be used to replace propylene glycol include glycerol and polyethylene glycol.

[0383] Suitable flavors (eg, menthol and levomenthol) or sweeteners (eg, saccharin or saccharin sodium) may be added to those formulations of the invention intended for inhaled / intranasal administration.

[0384] In the case of dry powder inhalers and aerosols, the dosage unit is determined by means of a valve that delivers a metered amount. The units of the invention are typically configured to administer a metered dose or "puff" containing 1 μg to 100 mg of a compound of formula (I) or a conjugate of formula (II). The overall dose will typically be in the range of 1 μg to 200 mg, which can be administered in a single dose or more typically as divided doses over a day.

[0385] The compounds of the invention may be administered rectally or vaginally, for example, in the form of a suppository, pessary, microbicide, vaginal ring or enema. Cocoa butter is a traditional suppository base, but a variety of alternatives may be used as desired.

[0386] The compounds of the invention can also be administered directly to the eye or ear, usually in the form of drops of a micronized suspension or solution in isotonic and pH-adjusted sterile saline. Other formulations suitable for administration through the eye and ear include ointments, biodegradable (e.g., absorbable gel sponges, collagen) and non-biodegradable (e.g., silicone) implants, sheets, lenses, and microparticles or vesicular systems (e.g., vesicles or liposomes). Polymers such as cross-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, cellulose polymers (e.g., hydroxypropyl methylcellulose, hydroxyethyl cellulose, or methylcellulose) or heteropolysaccharide polymers (e.g., gellan gum) can be incorporated together with preservatives (e.g., benzalkonium chloride). The formulation can also be delivered by iontophoresis.

[0387] The compounds of the invention can also be administered directly to the site of interest by injection of a solution or suspension containing the active drug substance. The site of interest may be a tumor and the compound may be administered by intratumoral injection. Typical injection solutions include propylene glycol, sterile water, ethanol, and sodium chloride. Alternative solvents that can be used to replace propylene glycol include glycerol and polyethylene glycol.

[0388] The compounds of the present invention may be used in combination with soluble macromolecules (such as cyclodextrin and suitable derivatives thereof or polyethylene glycol-containing polymers) to improve their solubility, dissolution rate, taste masking, bioavailability and / or stability when used in any of the above administration routes.

[0389] Drug-cyclodextrin complexes, for example, are generally found to be useful for most dosage forms and routes of administration. Both inclusion and non-inclusion complexes can be used. As an alternative to direct complexing with the drug, the cyclodextrin can be used as an auxiliary additive, that is, as a carrier, diluent or solubilizer. The most commonly used for these purposes are alpha, beta and gamma cyclodextrins, examples of which can be found in International Patent Applications Nos. WO 91 / 11172, WO 94 / 02518 and WO 98 / 55148.

[0390] It should be understood that the required amount of the compound is determined according to its biological activity and bioavailability, which in turn depends on the mode of administration, the physiochemical properties of the compound, and whether it is used as a monotherapy or a combination therapy. The frequency of administration is also affected by the half-life of the compound in the treated individual. The most preferred dosage can be determined by a person skilled in the art and varies with the specific compound used, the concentration of the pharmaceutical composition, the mode of administration, and the progression of the disease. Other factors according to the specific individual being treated may require adjustment of the dosage, including the age, weight, sex, diet, and administration time of the individual.

[0391] Typically, for administration to humans, the total daily dose of the compounds of the invention is typically in the range of 100 μg to 10 g (e.g., 1 mg to 1 g, e.g., 10 mg to 500 mg). For example, oral administration may require a total daily dose of 25 mg to 250 mg. The total daily dose may be administered in a single or divided dose and may be outside the typical range given herein at the discretion of the physician. These doses are based on a general human subject weighing about 60 kg to 70 kg. The physician will be able to easily determine the dose for subjects whose weight exceeds this range (e.g., infants and the elderly).

[0392] The compounds can be administered before, during or after the onset of the disease to be treated.

[0393] Specific formulations and precise treatment regimens (e.g., daily doses and frequency of administration of the compounds) including the compounds of the invention can be formulated using known procedures (e.g., those commonly used in the pharmaceutical industry, such as in vivo experiments, clinical trials, etc.). The inventors believe that they are the first to describe pharmaceutical compositions for treating diseases based on the use of the compounds of the invention.

[0394] Therefore, 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, tautomeric form or polymorph thereof or a conjugate according to the second aspect and a pharmaceutically acceptable vehicle.

[0395] In a ninth aspect, the present invention also provides a process for preparing a composition according to the eighth aspect, the process comprising contacting a therapeutically effective amount of a compound of the first aspect or a pharmaceutically acceptable salt, solvate, tautomeric form or polymorph thereof, or a conjugate according to the second aspect and a pharmaceutically acceptable vehicle.

[0396] A "subject" may be a vertebrate, a mammal, or a domestic animal. Thus, the compounds, compositions, and medicaments of the invention may be used to treat any mammal (e.g., livestock (e.g., horses), pets), or may be used in other veterinary applications. However, most preferably, the subject is a human.

[0397] A "therapeutically effective amount" of a compound is an amount that, when administered to a subject, treats the target disease or produces the desired effect (i.e., inhibits ACSS 2 Any amount of drug required for protein).

[0398] For example, the therapeutically effective amount of the compound used may be about 0.01 mg to about 800 mg and preferably about 0.01 mg to about 500 mg. Preferably, the amount of the compound is about 0.1 mg to about 250 mg and most preferably about 0.1 mg to about 20 mg.

[0399] The "pharmaceutically acceptable vehicle" referred to herein is any known compound or combination of known compounds known to those skilled in the art that can be used to formulate pharmaceutical compositions.

[0400] In one embodiment, the pharmaceutically acceptable medium can be solid, and the composition can be in the form of powder or tablet. Pharmaceutically acceptable solid medium can include one or more substances that can also be used as the following: flavoring agent, lubricant, solubilizer, suspending agent, dye, filler, glidant, compression aid, inert adhesive, sweetener, preservative, dye, coating or tablet disintegrant. The medium can also be an encapsulation material. In powder, the medium is a fine solid mixed with the fine active agent of the present invention (that is, the compound according to the first, second and third aspects). In tablets, the active compound can be mixed with the medium with the desired compression properties in a suitable proportion and compacted into the desired shape and size. Powders and tablets preferably contain up to 99% of the active compound. Suitable solid mediums include (for example) calcium phosphate, magnesium stearate, talc, sugar, lactose, dextrin, starch, gelatin, cellulose, polyvinyl pyrrolidine, low melting point wax and ion exchange resin. In another embodiment, the pharmaceutical medium can be a gel and the composition can be in the form of cream or the like.

[0401] However, the pharmaceutical vehicle can be a liquid, and the pharmaceutical composition is in the form of a solution. Liquid vehicles can be used to prepare solutions, suspensions, emulsions, syrups, elixirs and pressurized compositions. The compounds of the present invention can be dissolved or suspended in a pharmaceutically acceptable liquid vehicle (e.g., water, an organic solvent, a mixture of the two, or a pharmaceutically acceptable oil or fat). The liquid vehicle may contain other suitable pharmaceutical active agents, such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickeners, colorants, viscosity modifiers, stabilizers or osmotic regulators. Suitable examples of liquid vehicles for oral and parenteral administration include water (partially containing the above-mentioned additives, such as cellulose derivatives, preferably sodium carboxymethylcellulose solutions), alcohols (including alcohols and polyols, such as glycols) and their derivatives and oils (e.g., fractionated coconut oil and peanut oil). For parenteral administration, the vehicle may also be an oily ester, such as ethyl oleate and isopropyl myristate. Sterile liquid vehicles can be used for parenteral administration in the form of sterile liquid compositions. The liquid vehicle for pressurized compositions can be halogenated hydrocarbon or other pharmaceutically acceptable propellant.

[0402] Liquid pharmaceutical compositions (which are sterile solutions or suspensions) can be utilized by, for example, intramuscular, intrathecal, epidural, intraperitoneal, intravenous, and especially subcutaneous injection. The compound can be prepared as a sterile solid composition that can be dissolved or suspended using sterile water, saline or other suitable sterile injectable media when administered.

[0403] The compounds and compositions of the present invention can be administered in the form of sterile solutions or suspensions containing other solutes or suspending agents (e.g., sufficient saline or glucose to make the solution isotonic), bile salts, gum arabic, gelatin, sorbitan monooleate, polysorbate 80 (oleate of sorbitol and its anhydride copolymerized with ethylene oxide), and the like. The compounds used in the present invention can also be orally administered in the form of liquid or solid compositions. Compositions suitable for oral administration include solid forms (e.g., pills, capsules, granules, tablets, and powders) and liquid forms (e.g., solutions, syrups, elixirs, and suspensions). Forms useful for parenteral administration include sterile solutions, emulsions, and suspensions.

[0404] It is known to those skilled in the art that active drug ingredients can be converted into prodrugs, which are metabolically unstable derivatives that are converted into active drug substances in the body. Also included within the scope of the present invention are prodrugs, which are compounds of formula (I) containing metabolically or hydrolytically unstable moieties that are converted into active drugs of formula (I) in vivo. Processes for converting prodrugs into active drug substances include, but are not limited to, ester or carbonate or carbamate hydrolysis, phosphate 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., Pharmacological Reviews, 2011, 63, 750-771. Such prodrug derivatives may provide improved solubility, stability, or permeability compared to the parent drug substance, or may more preferably allow administration of the drug substance by alternative routes of administration, such as in the form of an intravenous solution.

[0405] Also included within the scope of the present invention are soft drugs or antedrugs, which are compounds of formula (I) containing metabolically or hydrolytically labile moieties which are converted in vivo into inert derivatives. Processes for converting active drug substances into inert derivatives include, but are not limited to, ester hydrolysis, S-oxidation, N-oxidation, dealkylation, and metabolic oxidation, as described, for example, in Pearce et al., Drug Metab. Dispos., 2006, 34, 1035-1040 and B. Testa, Prodrug and Soft Drug Design, Comprehensive Medicinal Chemistry II, Vol. 5, Elsevier, Oxford, 2007, pp. 1009-1041 and Bodor, N., Chem. Tech., 1984, 14, 28-38.

[0406] Included within the scope of the present invention are all pharmaceutically acceptable isotopically-labeled compounds of the present invention wherein one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number predominant in nature.

[0407] Examples of suitable isotopes for incorporation into the compounds of the invention include isotopes of hydrogen (e.g. 2 H and 3 H), carbon (e.g. 11 C. 13 C and 14 C), chlorine (e.g. 36Cl), fluorine (e.g. 18 F), iodine (e.g. 123 I and 125 I), nitrogen (e.g. 13 N and 15 N), oxygen (e.g. 15 O. 17 O and 18 O), phosphorus (e.g. 32 P) and sulfur (e.g. 35 S).

[0408] Certain isotopically-labeled compounds of the invention (e.g., those incorporating a radioactive isotope) are useful in drug and / or substrate tissue distribution studies. 3 H) and carbon-14 (i.e. 14 C) are particularly useful for this purpose because they are easy to incorporate and can be easily detected. The use of isotopes (e.g., deuterium, 2 H) substitution may offer certain therapeutic advantages due to greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and thus may be preferred in some circumstances. Use of positron emitting isotopes (e.g. 11 C. 18 F. 15 O and 13 N) can be used to monitor substrate receptor occupancy in positron emission tomography (PET) studies.

[0409] Isotopically labeled compounds of formula (I) or conjugates of formula (II) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying examples and preparations using an appropriate isotopically labeled reagent in place of the unlabeled reagent previously employed.

[0410] All features described herein (including any accompanying claims, drawings and abstract) and / or all steps of any method or process so disclosed may be combined with any of the above aspects in any combination, except combinations where at least some of the features and / or steps are mutually exclusive.

[0411] General reaction diagram

[0412] General reaction diagram 1:

[0413] Compounds of formula (III) can be prepared from compounds of formula (IV) and (V) using a urea bond forming reaction, as demonstrated below.

[0414]

[0415] Typical reaction conditions for activating aromatic amines of compounds of formula (V) employ 4-nitrophenyl chloroformate to generate an intermediate which can be attacked by a suitable nucleophile such as amine (IV) to afford a urea in the form of a compound of formula (III). Preferably the organic base comprises DIPEA or TEA in a suitable organic solvent such as DCM, DMF, DMA or MeCN. The reaction solution may be shaken or stirred at room temperature.

[0416] Compounds of formula (IV) and (V) are commercially available or can be synthesized by one skilled in the art. In particular, methods for synthesizing compounds of formula (V) are described in general reaction schemes 3-10.

[0417] General reaction diagram 2:

[0418] Compounds of formula (VI) can be prepared from compounds of formula (V) and (VII) using an amide bond forming reaction, as demonstrated below.

[0419] Amidation

[0420]

[0421] Typical conditions used use a suitable organic base and a suitable coupling agent to activate the carboxylic acid of the compound of formula (VII). Preferred coupling agents are EDCI / HOBt, T 3 P, HATU, HBTU or BOP. Preferably the organic base comprises DIPEA or TEA in a suitable organic solvent such as DCM, DMF, DMA or MeCN. The reaction solution can be shaken or stirred at room temperature.

[0422] Compounds of formula (V) and (VII) are commercially available or can be synthesized by one skilled in the art. In particular, methods for synthesizing compounds of formula (V) or derivatives thereof are described in general reaction schemes 3-10.

[0423] General reaction diagram 3:

[0424] The compound of formula (V) can be prepared from the nitro compound of formula (VIII) by simple reduction.

[0425]

[0426] Typical reduction conditions may include Pd-catalyzed or Ra-Ni-catalyzed hydrogenation methods or in the presence of transition metal reagents such as Fe-AcOH, Zn-AcOH or SnCl 2 -H 2 The reduction is carried out in the presence of D-(2-HCl) in a suitable solvent (such as methanol or ethanol).

[0427] Compounds of formula (VIII) are commercially available or can be synthesized by one skilled in the art. In particular, methods for synthesizing compounds of formula (VIII) are described in the general reaction schemes 6, 7, 9, and 11-14 shown below.

[0428] General reaction diagram 4:

[0429] Compounds of formula (V) can be prepared from halogenated aromatic compounds of formula (IX) by direct aminolysis reaction.

[0430]

[0431] Typical amination conditions use liquid or aqueous ammonia and are in the presence of a suitable catalyst, typically CuI, in the presence of a suitable activated ligand such as dimethylethylenediamine (DMEDA), amino acids such as proline, pyridine-based ligands such as phenanthroline, diols and diketones. Alternatively, the halide can be aminated with p-methoxybenzylamine and then deprotected using methods known to those skilled in the art such as hydrogenation reactions catalyzed by TFA, cerium ammonium nitrate or Pd.

[0432] Compounds of formula (IX) are commercially available or can be synthesized by one skilled in the art. In particular, methods for synthesizing compounds of formula (IX) are described in the general reaction schemes 8 and 10 shown below.

[0433] General reaction diagram 5:

[0434] The amine of formula (V) can be further functionalized at the X position according to the following reaction scheme.

[0435]

[0436] Compounds of formula (V) may be halogenated, for example using bromine in AcOH to provide bromides of formula (XII). The appropriate bromide may then be reacted with a suitable cyano source (e.g. CuCN or Zn(CN) 2 ) in a suitable polar solvent (e.g. DMF, DMA, NMP or pyridine) optionally in the presence of a catalyst (e.g. tetrakis-triphenylphosphine palladium (0)) typically at reflux temperature to give a nitrile of formula (XI). Alternatively, a bromide of formula (XII) can be reacted with a suitable boronic acid R 3 -B(OH) 2 or borate esters in the presence of a transition metal catalyst (usually Pd, such as Pd(OAc) 2 , Pd 2 dba 3 or Pd(dppf)Cl 2 ), a suitable base (such as KO t Bu, K 3 PO 4, K 2 CO 3 , Cs 2 CO 3 Or Na 2 CO 3 ) and a suitable solvent system (such as THF-water, ethanol-water, DMF, dioxane or toluene) to carry out Suzuki reaction. The reaction solution is usually heated to obtain R 3 Functionalized amine (X).

[0437] General reaction diagram 6:

[0438] The nitro compounds of formula (XIII) can be synthesized starting from benzopyridones of formula (XX).

[0439]

[0440] Benzopyridones of formula (XX) can be nitrated, for example, in a mixture of sulfuric acid and fuming nitric acid, usually at room temperature, to give nitro compounds of formula (XIX). These nitro compounds can then be halogenated, for example, using sodium bromate and a strong acid (e.g. aqueous HBr) under heating to provide bromo derivatives of formula (XVIII). Using POBr 3 Treatment of the compound of formula (XVIII) can convert the pyridine to the corresponding bromopyridine to give the dibromo compound of formula (XVII). The boronate ester or boronic acid R can then be used as described in general reaction scheme 5. 1 -B(OH) 2 and / or RB(OH) 2 The compound of formula (XVII) is subjected to Suzuki reaction to provide a quinoline of formula (XVI). Alternatively, a bromopyridone of formula (XVIII) can also be subjected to Suzuki reaction with a quinoline of formula R 1 -B(OH) 2 The boronate ester or boronic acid is reacted to provide a functionalized pyridine of formula (XV), which can then be further brominated to bromopyridine (XIV) and reacted using a boronate ester or boronic acid RB(OH) 2 Suzuki reaction is performed to provide quinolines of formula (XIII).

[0441] The compound of formula (XX) is commercially available or can be synthesized by one skilled in the art.

[0442] General reaction diagram 7:

[0443] Nitro-quinolines can also be constructed starting from nitroanilines of formula (XXII) and acetic acid derivatives of formula (XXVI) according to the following reaction scheme.

[0444]

[0445] The acid of formula (XXVI) can be converted to the Weinreb amide of formula (XXV) using, for example, N,O-dimethyl-hydroxylamine using a suitable organic base and a suitable coupling agent. Preferred coupling agents are EDCI / HOBt, T 3 P, HATU, HBTU or BOP. Preferably the organic base comprises DIPEA or TEA in a suitable organic solvent such as DCM, DMF, DMA or MeCN. The reaction solution may be shaken or stirred at room temperature. The Weinreb amide may then be reacted with a suitable nucleophilic substance, typically a Grignard or organolithium reagent in a suitable solvent such as THF or diethyl ether to give a ketone of formula (XXIV). Using POCl 3 Treatment of a ketone of formula (XXIV) in a suitable solvent such as DMF or DCM provides a vinylogous aldehyde of formula (XXIII) which when combined with an aniline of formula (XXII) in a suitable solvent such as DMF, DMA or DMSO can provide a functionalized quinoline of formula (XXI).

[0446] Compounds of formula (XXVI) and (XXII) are commercially available or can be synthesized by one skilled in the art.

[0447] General reaction diagram 8:

[0448] Bromoquinolines of formula (XXVII) can be prepared starting from nitrocarbonyl compounds of formula (XXIX), such as ketones or aldehydes.

[0449]

[0450] The nitro group of the nitrocarbonyl compound of formula (XXIX) can be reduced, for example, using a transition metal catalyst such as Fe in a suitable acid such as HCl. Alternative reduction methods include any of those described in general reaction scheme 3. The reduction product is an aniline compound of formula (XXVIII) which can be prepared by Friedlander quinoline synthesis using a ketone of formula (XXIV) using a strong base such as KOH or NaOH in a suitable solvent such as THF, dioxane or ethanol or alternatively using a strong acid such as sulfuric acid or p-toluenesulfonic acid in a suitable solvent such as AcOH (depending on the group R 2 The condensation product is a quinoline of formula (XXVII).

[0451] General reaction diagram 9:

[0452] An alternative synthesis of nitro-quinolines of formula (XXX) begins with bromo-nitrobenzaldehyde of formula (XXXII). Nitrogen nucleophiles (e.g. NaN 3 or KN 3 ) in a suitable solvent such as DMF, DMA or NMP, typically at elevated temperature, to afford the azide compound of formula (XXXI).

[0453]

[0454] The azide compound of formula (XXXI) can then be reacted with an alkyne and a suitable reagent (e.g., TMSOTf or AgNTf 2 ) in a suitable solvent (eg MeOH) to give a functionalized quinoline compound of formula (XXX).

[0455] General reaction diagram 10:

[0456] A flexible method for preparing halo-quinolines is shown in the following reaction scheme and starts with an oxindole of formula (XXXVIII). An oxindole compound of formula (XXXVIII) can be reacted with a ketone of formula (XXIV) in the presence of a strong base such as NaOH or KOH, typically under heating or reflux conditions to provide the key intermediate bromo-quinoline carboxylic acid of formula (XXXVII).

[0457]

[0458] The acid function of (XXXVII) can then be manipulated to R according to the above reaction scheme. 2 Several different functional groups at the position. For example, the acid of formula (XXXVII) can be converted into an α-acylaminocarbonyl compound, which can then undergo a cyclodehydration reaction to form an oxazole compound of formula (XXXVI). Typically, this transformation involves activation of the carboxylic acid and subsequent treatment with an aminocarbonyl reagent such as 2-aminoacetaldehyde or a derivative thereof. Preferred activators include DCC, CDI, T 3 P, HATU, HBTU, or the acid is treated with oxalyl chloride and a catalytic amount of DMF. Preferably, the organic base comprises DIPEA or TEA in a suitable organic solvent (e.g., DCM, DMF, DMA or MeCN). The reaction solution may be shaken or stirred at room temperature. Subsequently, a strong acid (e.g., H 2 SO 4 ) to provide the intermediate α-acylaminocarbonyl compound of formula (XXXVI).

[0459] Alternatively, the acid of formula (XXXVII) can be converted to the nitrile of formula (XXXV) in a 2-step process which first converts the acid to a primary carboxamide. Typical conditions used use a suitable organic base and a suitable activating agent to activate the carboxylic acid of the compound of formula (XXXVII), and then treat the activated acid with an ammonia source. Preferred activators are DCC, CDI, T 3 P, HATU, HBTU, or the acid is treated with oxalyl chloride and a catalytic amount of DMF. Preferably the organic base comprises DIPEA or TEA in a suitable organic solvent such as DCM, DMF, DMA or MeCN. Preferably the ammonia source is NH 4 OH and NH 4 OAc. The reaction can be shaken or stirred at room temperature. The primary carboxamide thus formed can then be dehydrated to provide the nitrile of formula (XXXV). Typical conditions involve the use of a suitable reagent, preferably SOCl 2 , Burgess' Reagent, POCl 3 Treatment of formamide with TFAA or TFAA at temperatures between room temperature and reflux provides the nitrile of formula (XXXV).

[0460] Alternatively, the acid of formula (XXXVII) can be converted to the amide of formula (XXXIV) using the method described in general reaction scheme 2. Typical conditions used use a suitable organic base and a suitable coupling agent to activate the carboxylic acid of the compound of formula (XXXVII). Preferred coupling agents are EDCI / HOBt, T 3 P, HATU, HBTU or BOP. Preferably the organic base comprises DIPEA or TEA in a suitable organic solvent such as DCM, DMF, DMA or MeCN. The reaction solution can be shaken or stirred at room temperature.

[0461] Alternatively, an acid of formula (XXXVII) can be converted to an amine of formula (XXXIII) using a suitable azido reagent (e.g., diphenylphosphine azide) in a suitable solvent (e.g., DMF, DMA, MeCN, or NMP) in the presence of a suitable base (e.g., DIPEA or TEA). The reaction is typically carried out at room temperature. The intermediate acyl azide thus formed is then typically treated with water under heating or reflux conditions to provide an amine of formula (XXXIII).

[0462] General synthetic procedure

[0463] General purification and analytical methods

[0464] All final compounds were purified by Combi-flash or preparative HPLC purification and analyzed for purity and product identity by UPLC or LCMS according to one of the following methods.

[0465] Preparative HPLC

[0466] Preparative HPLC was performed on a Waters automated purification instrument using 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) operated between ambient temperature and 50° C. at a flow rate of 16.0-50.0 mL / min.

[0467] Mobile phase 1: A = 20 mM ammonium bicarbonate in water, B = acetonitrile; Gradient profile: initial composition of mobile phase is 80% A and 20% B, then 60% A and 40% B after 3 min., then 30% A and 70% B after 20 min., then 5% A and 95% B after 21 min., keep at this composition for 1 min. for column washing, then return to the initial composition and keep for 3 min.

[0468] Mobile phase 2: A = 10 mM ammonium acetate in water, B = acetonitrile; Gradient profile: initial composition of mobile phase is 90% A and 10% B, then 70% A and 30% B after 2 min., then 20% A and 80% B after 20 min., then 5% A and 95% B after 21 min., keep at this composition for 1 min. for column washing, then return to the initial composition and keep for 3 min.

[0469] Mobile phase 3: A = 0.1% formic acid in water, B = acetonitrile; Gradient profile: initial composition of mobile phase is 90% A and 10% B, then 70% A and 30% B after 2 min., then 20% A and 80% B after 20 min., then 5% A and 95% B after 21 min., keep at this composition for 1 min. for column washing, then return to the initial composition and keep for 3 min.

[0470] LCMS method

[0471] General 5 min method: Zorbax Extend C18 column (50×4.6 mm, 5 μm) or Luna C18 column (50×4.6 mm, 5 μm), operated at ambient temperature, and 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 min, and then to 10% A and 90% B in 3.0 min, hold at this composition for 1.0 min, and finally return to the initial composition and hold for 2.0 min.

[0472] UPLC Method

[0473] UPLC was performed on a Waters automated purification instrument using a Zobax-Exted C18 column (50 x 4.6 mm, 5 μm) or a Kinetex Evo C18 column (100 x 2.1 mm, 1.7 μm) at ambient temperature and a flow rate of 0.3 ml / min to 1.5 ml / min.

[0474] Mobile phase 1: A = 5 mM ammonium acetate in water, B = 5 mM ammonium acetate in 90 / 10 acetonitrile / water; gradient profile: from 95% A and 5% B to 65% A and 35% B in 2 min., then reach 10% A and 90% B in 3.0 min., maintain at this composition for 4.0 min. and finally return to the initial composition and maintain for 5.0 min.

[0475] Mobile phase 2: A = 0.05% formic acid, B = acetonitrile in water; gradient profile: 98% A and 2% B in 1 min., then hold 90% A and 10% B for 1 min., then hold 2% A and 98% B for 2 min. and then return to initial composition for 3 min.

[0476] General Procedure 1: Urea Formation

[0477] Urea formation

[0478]

[0479] To a stirred solution of aromatic amine (V) (1.0 eq.) in a suitable solvent (e.g., DCM, DMF, MeCN, or THF) (8 mL / mmol) at 0-5°C was added p-nitrophenyl chloroformate (1.1 eq.) and the whole was stirred at room temperature for 1-3 h. Then TEA or DIPEA (6 eq.) and amine R were added dropwise. 8 -NH-R 7 (IV) (2.0 eq.) and further stirred as a whole at room temperature for 1-5 h. The reaction progress was monitored by TLC / LCMS, and after completion the reaction mass was diluted with EtOAc and a suitable inorganic base (e.g. NaHCO 3 or 1N NaOH) and finally with brine. 2 SO 4 The organic layer was dried and evaporated in vacuo to give a residue which was purified by column chromatography or Combe Flurch or preparative HPLC to afford the compound of formula (III) as an off-white to white solid (yield 4-80%). Similar procedures can be followed to synthesize all ureas of formula (III).

[0480] General procedure 2: Amidation

[0481] Amidation

[0482]

[0483] To a stirred solution of carboxylic acid (VII) (1.5 eq.) in a suitable solvent (e.g. DCM, DCE, DMA, THF, MeCN or DMF) (5 mL / mmol) was added a suitable organic base (e.g. TEA or DIPEA) (1.5 eq.) and a coupling reagent (e.g. T 3 P, HATU, EDC.HCl, HOBT, BOP, HBTU or HATU) (1.5 eq.). Stirring was continued for 10 min. and then aromatic amine (V) (1.0 eq.) was added. The whole was stirred at room temperature for 1-5 h. The reaction progress was confirmed by TLC / LCMS, and after completion, the reaction mixture was diluted with water and extracted with MTBE or EtOAc or DCM, washed with brine, and filtered through anhydrous Na 2 SO 4 Drying and evaporation in vacuo gave the crude product, which was purified by column chromatography or Combe Fluoropolymer or preparative HPLC to afford the compound of formula (VI) as an off-white to white solid (25-90%). Similar procedures can be followed to synthesize all amides of formula (VI).

[0484] General Procedure 3: Nitro Reduction

[0485]

[0486] Option A:

[0487] To a stirred solution of the compound of formula (VIII) (1.0 equiv) in a suitable solvent (e.g., DMF, EtOH, MeOH, or THF) (4 mL / mmol) at room temperature was added aqueous HCl (0.12 mL / mmol, 36% w / w in water), followed by SnCl 2 .2H 2 O or SnCl 2 (4.0 equiv.) and the resulting reaction mixture was stirred at room temperature to 100° C. for 1-5 h. The reaction progress was monitored by TLC / LCMS, and after completion the reaction mixture was diluted with EtOAc and washed with NaHCO 3 saturated solution or 0.5N NaOH solution, and finally washed with brine. 2 SO 4 The organic layer was dried and concentrated in vacuo to afford the crude product, which was purified by column chromatography to give the compound of formula (V) as an off-white to yellow solid (yield 70-80%).

[0488] Option B:

[0489] To a stirred solution of the compound of formula (VIII) (1.0 eq.) in a suitable solvent (e.g., 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 under H 2 The mixture was stirred at room temperature for 2-12 h under balloon pressure. The reaction progress was monitored by TLC and UPLC-MS, which showed that the nitro group was completely converted to its corresponding amino group. 2 Balloon and filter the reaction mixture under inert atmosphere.The filtrate obtained was evaporated in vacuo to give the crude compound of formula (V) which was used in the next step without any further purification.

[0490] General Procedure 4: Amination

[0491]

[0492] Option A: Via NH 3 Aqueous solution amination

[0493] The compound of formula (IX) (1.0 equivalent), CuI (0.05 equivalent), a suitable ligand (e.g., BINAP, N1,N2-bis(4-phenoxyphenyl)oxalamide, trans-4-hydroxy-L-proline or L-proline) (0.05 equivalent) and a suitable base (e.g., KHCO 3 , K 3 PO 4 or K 2 CO 3 ) (1.0 equiv.) and DMSO (11 mL / mmol) were purged for 30 min. Then NH 3 Aqueous solution (0.5 mL / mmol, 36% w / w in water) was added and the whole was stirred at 60-100°C for 4-16 h. After the reaction was completed (monitored by TLC and LCMS), the reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine and filtered through anhydrous Na 2 SO 4 Dry and concentrate in vacuo to give the title compound as a crude brown solid.

[0494] Option B: Amination using p-methoxybenzylamine

[0495] To a stirred solution of the compound of formula (IX) (1.0 eq.) in a suitable solvent (e.g., DMF or DMSO) (4 mL / mmol) under an inert atmosphere was added p-methoxybenzylamine (6 eq.), followed by a suitable base (e.g., KHCO 3 , K 3PO 4 or K 2 CO 3 ) (2.5 equiv.). CuI (1.0 equiv.) and a suitable ligand (e.g., BINAP, N1, N2-bis(4-phenoxyphenyl)oxalamide, trans-4-hydroxy-L-proline or L-proline) (0.5 equiv.) were then added. The resulting reaction mixture was transferred to a sealed tube and heated at 60-100°C for 4-16 h. The reaction progress was monitored by LCMS and the reaction mixture was poured into ice-water after completion. The aqueous reaction mixture was extracted with EtOAc and washed with brine. The reaction mixture was purified by anhydrous Na 2 SO 4 The organic layer was dried 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 quenched with solid K 2 CO 3 Basified and extracted with EtOAc.The combined organic layers were washed with brine, dried and concentrated in vacuo to give the crude product, which was purified by column chromatography / Compaflash to afford the compound of formula (V) as a light brown to yellow solid (yield 60-90%).

[0496] General Procedure 5: Bromination

[0497]

[0498] To a stirred solution of the compound of formula (V) (1.0 equiv) in AcOH (8 mL / mmol) at 0-5°C was added Br in AcOH (2 mL / mmol). 2 (1.0 equiv.). The whole was stirred at room temperature for 1-4 h. The reaction progress was monitored by LCMS and after completion the reaction mixture was quenched with a saturated aqueous solution of sodium metabisulfite. Solid NaHCO 3 The aqueous material was basified and extracted with EtOAc, washed with brine, dried and concentrated to give the crude product, which was purified by column chromatography to afford the compound of formula (XII) as an off-white solid (80-95% yield).

[0499] General Procedure 6: Cyanidation

[0500]

[0501] To a stirred solution of the compound of formula (XII) (1.0 eq.) in NMP (3 mL / mmol) was added CuCN (4 eq.) and the whole was stirred in a sealed tube at 100-120° C. for 10-16 h. The reaction progress was monitored by TLC / LCMS, and after completion the reaction mixture was diluted with water and extracted with MTBE. NH 4 The organic layer was washed with saturated Cl solution and finally with brine, dried and concentrated in vacuo to give the crude product, which was purified by column chromatography to afford the compound of formula (XI) as an off-white to light brown solid (60-80% yield).

[0502] General Procedure 7: Suzuki-Miyaura Cross Coupling Reaction

[0503]

[0504] The compound of formula XII (4.805 mmol, 1.0 equivalent), R 3 -B(OH) 2 (2.0 equivalents) and a suitable base (e.g. K 2 CO 3 , TEA, NaHCO 3 or K 3 PO 4 A solution of ) (3.0 equiv.) in a mixture of solvent 1,4-dioxane (4 mL / mmol) and water (0.5 mL / mmol) was degassed for 30 min., and then a suitable transition metal catalyst (e.g. Pd(OAc) 2 、Pd(PPh 3 ) 4 、Pd(PPh 3 ) 2 Cl 2 or Pd 2 (dba) 3 ) (0.1 equivalent) and a suitable ligand (e.g. BINAP or PCy 3 ) (0.2 eq.). The resulting reaction mixture was stirred at 80-100 °C under an inert atmosphere for 4-16 h. The reaction progress was monitored by TLC / LCMS and after completion the reaction mixture was diluted with EtOAc, filtered and the filtrate was partitioned by adding water. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine and purified by anhydrous Na 2 SO 4 Drying and concentration in vacuo afforded the crude product which was purified by column chromatography to afford the compound of the formula as a pale yellow solid (yield 50-80%).

[0505] General Procedure 8: Nitrification

[0506]

[0507] At -10-0°C, the compound of formula (XX) (1.0 equivalent) was added to H 2 SO 4 KNO (3 mL / mmol) was added portionwise to a stirred solution of 3 (1.1 equivalents). The whole was stirred at 0-5°C for 30 min. The reaction was confirmed to be complete by TLC / LCMS. The reaction mixture was quenched with ice-water and extracted with EtOAc. The combined organic layers were washed with brine and purified by anhydrous Na 2 SO 4 Drying and concentration in vacuo afforded the compound of formula (XIX) as a crude yellow solid.

[0508] General Procedure 9: Bromination via aqueous HBr

[0509]

[0510] To a stirred solution of the compound of formula (XIX) (1.0 eq.) in water (0.6 mL / mmol) was added NaBrO at -10-5 °C. 3 (1.2 equivalents), then dropwise add 48% HBr aqueous solution (3.5mL / mmol) at the same temperature. Then reflux as a whole at 90-100 ℃ for 2-6h. Monitor the reaction progress by TLC / LCMS, and after completion, use ice-water to quench the reaction mixture and stir for 1h at 0-5 ℃. Filter out the gained solid precipitate and use water washing to obtain solid material, use hexane slurry washing to provide formula (XVIII) compound (yield is 65-80%) in the form of yellow solid.

[0511] General Procedure 10: Through POBr 3 Bromination

[0512]

[0513] The compound of formula (XVIII) (1.0 equivalent) was dissolved in POBr 3 A solution of 5-nitropropene (2.0 equiv.) was heated at 120-140° C. for 10-16 h. The reaction progress was monitored by TLC / LCMS, and upon completion the reaction mixture was quenched with cold water and heated with NaHCO 3 The aqueous solution was basified to pH 7-8. The aqueous material was then extracted with EtOAc and washed with brine. 2 SO 4 The combined organic layers were dried and concentrated under reduced pressure to give the compound of formula (XVII) as a crude brown solid.

[0514] General Procedure 11: Weinleb amide formation

[0515]

[0516] At 0-5 ° C, a catalytic amount of DMF (2 drops) and oxalyl chloride (1.5 equivalents) were added dropwise to a stirred solution of the compound of formula (XXVI) (1.0 equivalents) in DCM (1.3 mL / mmol). At 0-5 ° C, the resulting reaction mixture was stirred at room temperature for 1-2 h and then commercially available N, O-dimethylhydroxylamine hydrochloride (1.0 equivalents) was added, followed by TEA (4.0 equivalents), and the mixture was further stirred at room temperature for 30 min. The reaction progress was monitored by TLC and LCMS, and the reaction mixture was diluted with water after completion and extracted with DCM. The reaction mixture was purified by anhydrous Na 2 SO 4 The organic layer was dried and concentrated in vacuo to give the crude product, which was purified by column chromatography or Compber Fluorolysis to afford the compound of formula (XXV) as an off-white solid (yield 65-80%).

[0517] General Procedure 12: Grignard Reaction

[0518]

[0519] To a stirred solution of the compound of formula (XXV) (1.0 equiv.) in a suitable solvent (e.g., anhydrous diethyl ether or anhydrous THF) (3.2 mL / mmol) was added R-MgBr (0.67 mL / mmol, 3 M solution in diethyl ether) at -78 °C. The mixture was warmed to room temperature and stirred at room temperature for 2-3 h. The reaction was monitored by TLC and LCMS, at which point the reaction was shown to be complete. The reaction mixture was quenched with a saturated solution of ammonium chloride and extracted with EtOAc. The organic layer was washed with brine and the column was purified by anhydrous Na 2 SO 4 Drying and concentration in vacuo gave a crude product, which was purified by column chromatography or Compber Fluorolysis to afford the compound of formula (XXIV) as a white solid (yield 80-90%).

[0520] General Procedure 13: Vilsmeier-Haack Reaction

[0521]

[0522] To stirred DMF (0.24 mL / mmol) was added POCl dropwise at 0-5 °C. 3(3.0 equivalents) and stirred as a whole at room temperature for 1-2h, then slowly added compound of formula (XXIV) (1.0 equivalent) at room temperature. The resulting reaction mixture was stirred at 55-60°C for 10-16h. The reaction progress was monitored by TLC / LCMS, and after completion, the reaction mixture was poured into crushed ice and stirred at room temperature for 1-2h. The obtained solid precipitate was collected by filtration, dissolved in EtOAc, and washed with anhydrous Na 2 SO 4 Drying and removal of the solvent in vacuo afforded the compound of formula (XXIII) as a crude off-white solid (yield 85-95%) which was used in the next step without any further purification.

[0523] General Procedure 14: Condensation

[0524]

[0525] A stirred solution of compound of formula (XXII) (1.0 equivalent) and compound of formula (XXIII) (1.0 equivalent) in AcOH (0.36 mL / mmol) was refluxed for 10-16 h. TLC showed the formation of new polar spots. The product material was confirmed by LCMS. The reaction mixture was diluted with cold water and the product was extracted with EtOAc. The organic matter was washed with water, then washed with brine, and filtered through anhydrous Na 2 SO 4 Drying and concentration under reduced pressure gave a crude product, which was purified by silica gel column chromatography or Compber Fluorolysis to afford the compound of formula (XXI) as a yellow solid (yield 30-45%).

[0526] General Procedure 15: Condensation

[0527]

[0528] To a stirred solution of the compound of formula (XXIV) (1.0 equivalent) and the compound of formula (XXVIII) (1.0 equivalent) in ethanol (8 mL / mmol) was added 33% aqueous KOH (0.81 mL / mmol) or piperidine at room temperature. The resulting reaction mixture was refluxed at 70-75 °C for 1-4 h. The reaction was monitored by TLC and LCMS and the solvent was evaporated after completion to give a residue, which was diluted with EtOAc and washed with brine. The residue was purified by anhydrous Na 2 SO 4 The organic layer was dried and concentrated in vacuo to give the crude product, which was purified by column chromatography or Compber Fluorolysis to afford the compound of formula (XXVII) as a white solid (yield 30-50%).

[0529] General Procedure 16: Condensation

[0530]

[0531] To a stirred solution of the compound of formula (XXVIII) (1.0 equiv) in glacial acetic acid (4.4 mL / mmol) was added the compound of formula (XXIV) (1.0 equiv) and concentrated H 2 SO 4 (0.1 mL / mmol). The whole was heated at 110-120° C. for 4-6 h. The reaction was monitored by TLC and LCMS and after completion the solvent was partially evaporated under reduced pressure to give a residue which was dissolved in water and extracted with EtOAc. NaHCO 3 The organic layer was washed with saturated solution and then with brine. 2 SO 4 The organic layer was dried and concentrated in vacuo to give the crude product, which was purified by column chromatography or Compber Fluorolysis to afford the compound of formula (XXVII) as a light yellow solid (yield 40-50%).

[0532] General Procedure 17: Azide Formation

[0533]

[0534] To a stirred solution of the compound of formula (XXXII) (1.0 eq.) in a suitable solvent (eg HMPA or DMF) was added NaN 3 The mixture was stirred for 30 min at 4 ℃ for 1 h. The reaction mixture was stirred for 30 min at 4 ℃ for 1 h. The mixture was stirred for 20 min at 4 ℃ for 30 min. The mixture was stirred for 10 min at 4 ℃ for 20 min. The mixture was stirred for 30 min at 4 ℃ for 20 min. The mixture was stirred for 30 min at 4 ℃ for 20 min. The mixture was stirred for 20 min. The mixture was stirred for 30 min. The mixture was stirred ...30 min. 2 SO 4 Drying and concentration in vacuo afforded the compound of formula (XXXI) as a yellow solid (yield 75-85%).

[0535] General Procedure 18: Condensation

[0536]

[0537] At room temperature, MeOH (0.16 mL / mmol) was added to a stirred solution of the compound of formula (XXXI) (1.0 equivalent) in anhydrous DCM (2.5 mL / mmol), followed by the addition of an acetylene derivative (1.0 equivalent). The reaction mixture was cooled to 0-5 ° C and then TMSOTf (4.0 equivalent) was added dropwise. The resulting reaction mixture was stirred at room temperature for 10-16 h. The progress of the reaction mixture was monitored by TLC / LCMS, and the reaction mixture was diluted with EtOAc and washed with brine after completion. The reaction mixture was purified by anhydrous Na 2 SO 4 The organic layer was dried and concentrated in vacuo to afford the crude product, which was purified by column chromatography or Compber Fluorolysis to give the compound of formula (XXX) as a yellow solid (yield 80-90%).

[0538] General Procedure 19: Pfitzinger Reaction

[0539]

[0540] A stirred solution of the compound of formula (XXXVIII) (1.0 equivalent) in 2N NaOH solution (4.5 mL / mmol) was refluxed at 85-90° C. for 30 min. The reaction mixture was then cooled to room temperature and the compound of formula (XXIV) (1.1 equivalent) was added at room temperature. The whole was refluxed at 85-90° C. for 10-16 h. The reaction progress was monitored by TLC / LCMS and the reaction mixture was filtered after completion, and the obtained solid was dissolved in water and acidified with 2N HCl solution to obtain a solid precipitate, filtered and washed with water to provide the compound of formula (XXXVII) (25-45%) in the form of a white solid.

[0541] General Procedure 20: Oxazole Formation

[0542]

[0543] To a stirred solution of the compound of formula (XXXVII) (1.0 eq.) in a suitable solvent (e.g., DCM, THF, or DMF) (2.5 mL / mmol) was added an organic base (e.g., TEA or DIPEA) (4.0 eq.) and a coupling agent (e.g., EDC.HCl (1.5 eq.) and HOBT (1.5 eq.)) at room temperature and the whole was stirred at room temperature for 10-15 min. 2,2-dimethoxyethylamine (1.2 eq.) was then added and the whole was stirred at room temperature for 10-12 h. The progress of the reaction mixture was monitored by TLC / LCMS, and after completion the reaction mixture was diluted with water and extracted with EtOAc. The combined organics were washed with brine and purified by anhydrous Na 2 SO 4Drying and concentration in vacuo gave the crude product, which was purified by column chromatography to afford the corresponding amide intermediate as an off-white solid (40-50%).

[0544] The obtained amide intermediate (1.0 equiv.) was dissolved in methanesulfonic acid (5 mL / mmol) at room temperature and then P was added. 2 O 5 (3.0 equiv.). The whole was heated at 120-130 °C for 3-5 h. The reaction progress was monitored by TLC and 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 purified by anhydrous Na 2 SO 4 Drying and concentration in vacuo gave the crude product, which was purified by column chromatography to afford the compound of formula (XXXVI) as an off-white solid (yield 35-40%).

[0545] General Procedure 21: Access to Amides / Cyanides via Acid Chloride Formation

[0546]

[0547] To a stirred solution of the compound of formula (XXXVII) (1.0 equiv) in a mixture of solvent DCM (4 mL / mmol) and DMF (0.015 mL / mmol) at -5°C to 0°C, oxalyl chloride (2.0 equiv) was added dropwise and the mixture was stirred at room temperature for 1-2 h. The formation of the corresponding acyl chloride was confirmed by LCMS. Then NH3 aqueous solution or another amine (3.0 equiv, 33% in water) was added dropwise at 0-5°C. The resulting reaction mixture was stirred at room temperature for 2-3 h. The reaction progress was confirmed by TLC / LCMS, and the obtained solid was filtered after completion and washed with hexane. The filtrate was extracted with 10% MeOH in DCM to recover the dissolved material and washed with brine. The reaction mixture was purified by anhydrous Na 2 SO 4 The combined organic layers were dried and evaporated in vacuo to afford the corresponding amide intermediate as a crude product.

[0548] General Procedure 22: Burgess Reaction

[0549] The obtained amide intermediate (1.0 eq.) was dissolved in anhydrous THF (12 mL / mmol), and then Burgess reagent (2.0 eq.) was added at 0-5 °C. The whole was heated at 50-60 °C under an inert atmosphere for 1-2 h. After the reaction was completed (monitored by TLC / LCMS), the obtained solid was filtered off and the filtrate was diluted with water and extracted with 5% MeOH in DCM. The combined organic layers were washed with brine and purified by anhydrous Na 2 SO 4Drying and concentration in vacuo afforded the compound of formula (XXXV) as a white solid (yield 70-80%).

[0550] General Procedure 23: Curtius Reaction

[0551]

[0552] At 0-5℃ and N 2 Under atmosphere, DIPEA or TEA (1.5 equivalents) and diphenylphosphorus azide (2.0 equivalents) are added to a stirred solution of the compound of formula (XXXVII) (1.0 equivalents) in DMF (6 mL / mmol). The whole is stirred at room temperature for 1-3 h, then water (6 mL / mmol) is added and the whole is refluxed for 2-6 h at 100-110 ° C. The reaction progress is monitored by LCMS and the reaction mixture is diluted with water after completion to obtain a solid precipitate, which is filtered and washed with water and then washed with hexane. The obtained solid is dried in a vacuum oven to provide a compound of formula (XXXIII) in the form of a light yellow solid (yield of 80-85%).

[0553] Examples

[0554] Nuclear magnetic resonance (NMR) spectra were consistent with the proposed structures in all cases. Characteristic chemical shifts (δ) are given in terms of downfield from tetramethylsilane ( 1 H-NMR) and high field trichloro-fluoro-methane (for 19 F NMR) are given in parts per million using conventional abbreviations to designate the major peaks: for example, s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad. The following abbreviations have been used for common solvents: CDCl 3 , deuterated chloroform; d 6 -DMSO, deuterated dimethyl sulfoxide; and CD 3 OD, deuterated methanol.

[0555] Mass spectra MS (m / z) were recorded using electrospray ionization (ESI). Where relevant and unless otherwise stated, the m / z data provided are for isotopes 19 F. 35 Cl, 79 Br and 127 I.

[0556] All chemicals, reagents and solvents were purchased from commercial sources and used without further purification. Unless otherwise stated, all reactions were performed under nitrogen atmosphere.

[0557] Flash column chromatography was performed using pre-packed silica gel columns in a Combe Flush platform. Preparative HPLC purifications were performed according to the general purification and analytical methods described above. Thin layer chromatography (TLC) was performed on Merck's silica gel 60 plates (5729). Unless otherwise stated, all final compounds were >95% pure as judged by the LCMS or UPLC analytical methods described in the general purification and analytical methods described above.

[0558] Example 45: 1-(2,2-difluorobutyl)-3-(3-(2-fluorophenyl)-2-phenylquinolin-6-yl)urea

[0559]

[0560] Example 45 was prepared according to the methods described in General Procedures 1, 3, 13, 14 and the following method.

[0561] Preparation 1: 3-(2-Fluorophenyl)-2-phenylquinolin-6-amine

[0562]

[0563] Step 1: 2-(2-Fluorophenyl)-1-phenylethanone

[0564]

[0565] To a stirred solution of commercially available 2-(2-fluorophenyl)acetic acid (35.0 g, 222.93 mmol) in benzene (350 mL) was added thionyl chloride (105 mL) at 0-5 °C and the resulting reaction mixture was slowly warmed to room temperature and then refluxed for 4 h. The solvent was removed under high vacuum and the remaining residue was diluted with benzene (105 mL). AlCl was then carefully added portionwise at 0-5 °C. 3 (32.615 g, 245.22 mmol), and then the reaction mixture was slowly warmed to room temperature and stirred at this temperature for 3 h. The reaction was monitored by TLC / LCMS and after completion the reaction mixture was poured into crushed ice, extracted with EtOAc and then washed with water, followed by brine. 2 SO 4 The organic layer was dried and concentrated under reduced pressure to give the title compound as a white solid (35 g, 73.3% yield). LCMS m / z: 215 [M+H].

[0566] Step 2: 3-Chloro-2-(2-fluorophenyl)-3-phenylacrolein

[0567]

[0568] To stirred DMF (55 mL, 700.93 mmol) was added POCl dropwise at 0-5 °C. 3(65.4mL, 700.93mmol) and stirred as a whole at room temperature for 1h, then 2-(2-fluorophenyl)-1-phenylethanone (Preparation 1, Step 1) (50.0g, 233.65mmol) was slowly added at room temperature. The resulting reaction mixture was stirred overnight at 60°C. The reaction progress was monitored by TLC / LCMS, and after completion, the reaction mixture was poured into crushed ice and stirred at room temperature for 1h. The obtained solid precipitate was collected by filtration. Dissolved in EtOAc, filtered by anhydrous Na 2 SO 4 Drying and removal of the solvent in vacuo afforded the title compound as a crude off-white solid (55.0 g, 90% yield), which was used in the next step without any further purification. LCMS m / z: 261 [M+H].

[0569] Step 3: 3-(2-Fluorophenyl)-6-nitro-2-phenylquinoline

[0570]

[0571] A stirred solution of commercially available p-nitroaniline (26.54 g, 192.307 mmol) and 3-chloro-2-(2-fluorophenyl)-3-phenylpropenal (Preparation 1, Step 2) (50.0 g, 192.307 mmol) in AcOH (70 mL) was refluxed for 16 h. TLC showed the formation of new polar spots. The product material was confirmed by LCMS. The reaction mixture was diluted with cold water and the product was extracted with EtOAc. The organics were washed with water, then washed with brine, and purified by anhydrous Na 2 SO 4 Dry and concentrate under reduced pressure to give a crude product, which was purified by silica gel column chromatography to afford the title compound as a yellow solid (21 g, 31.7% yield). LCMS m / z: 245 [M+H].

[0572] Step 4: 3-(2-Fluorophenyl)-2-phenylquinolin-6-amine

[0573]

[0574] To a stirred solution of 3-(2-fluorophenyl)-6-nitro-2-phenylquinoline (Preparation 1, Step 3) (500 mg, 1.453 mmol) in MeOH (10 mL) was added 10% Pd—C (100 mg, 50% w / w in water) under inert atmosphere and the resulting reaction mixture was stirred under H 2 The mixture was stirred at room temperature for 2 h under balloon pressure. The reaction progress was monitored by TLC and UPLC-MS, which showed that the nitro group was completely converted to its corresponding amino group. 2Balloon and filter the reaction mixture under inert atmosphere. The filtrate obtained was evaporated in vacuo to give the title compound (450 mg) in crude form, which was used in the next step without any further purification. LCMS m / z: 315 [M+H].

[0575] Preparation 2: 1-(2,2-difluorobutyl)-3-(3-(2-fluorophenyl)-2-phenylquinolin-6-yl)urea (Example 45)

[0576]

[0577] To a stirred solution of 3-(2-fluorophenyl)-2-phenylquinoline-6-amine (preparation 1, step 4) (404mg, 1.286mmol) in THF (10mL) at 0-5°C was added p-nitrophenyl chloroformate (285mg, 1.415) and stirred as a whole at room temperature for 1h. Then TEA (781mg, 7.718mmol) and 2,2-difluorobutane-1-amine (280.06mg, 2.573mmol) were added dropwise and further stirred at room temperature for 3h. The reaction progress was monitored by TLC / LCMS, and after completion, the reaction solution was diluted with EtOAc and washed with 1N NaOH solution, and finally washed with brine. By anhydrous Na 2 SO 4 The organic layer was dried and evaporated in vacuo to give a residue, which was purified by preparative HPLC to provide the title compound as a white solid (25 mg, 4% yield). LCMS m / z: 450.21 [M+H]; purity 99.86%; 1 HNMR (500 MHz; DMSO-d 6 ): δ0.99(t,J=7.5Hz.3H),1.86-1.97(m,2H),3.59-3.66(m,2H),6.71(t,J=6.2Hz,1H),7.09-7.13(m,1H),7.25-7.30(m 4H),7.35-7.42(m 3H),7.46-7.49(m,1H),7.76-7.78(m,1H),7.99(d,J=9.05Hz,1H),8.15(d,J=2.2Hz,1H),8.28(s,1H),9.08(s,1H).

[0578] Example 15: (R)-1-(3-(2-fluorophenyl)-2-phenylquinolin-6-yl)-3-(2-hydroxybutyl)urea

[0579]

[0580] Example 15 was prepared according to the method described for the preparation of Example 45 and the following method.

[0581] To a stirred solution of 3-(2-fluorophenyl)-2-phenylquinoline-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 stirred as a whole at room temperature for 3 h. TEA (11.58 g, 114.64 mmol) and (R)-1-aminobutane-2-ol (2.55 g, 28.66 mmol) were then added dropwise and further stirred at room temperature for 2 h. The reaction progress was monitored by TLC / LCMS, and the reaction mixture was diluted with water after completion and extracted with EtOAc. The organic layer was washed with 1N NaOH solution to remove any p-nitrophenol and washed with 1N HCl to remove unreacted amine, and finally washed with a saline solution. The reaction mixture was purified by anhydrous Na 2 SO 4 The organic layer was dried and concentrated in vacuo to give a crude product, which was purified by trituration with acetone and hexane to provide the title compound as a white solid (7.0 g, 57% yield). LCMS m / z: 430.34 [M+H]; purity 99.46%; 1 H NMR (500 MHz; DMSO-d 6 ): δ0.90(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=6.5Hz,1H),4.80( d,J=5.15Hz,1H),6.34(t,J=5.55Hz,1H),7.11(t,J=8.95Hz,1H),7.25-7 .29(m,4H),7.35-7.46(m,3H),7.46-7.49(m,1H),7.74(d,J=6.9Hz,1H), 7.97(d,J=9.05Hz,1H),8.13(d,J=2.1Hz,1H),8.25(s,1H),9.06(s,1H).

[0582] Example 72: (R)-1-(2-Hydroxybutyl)-3-(2-methyl-3-phenylquinolin-6-yl)urea

[0583]

[0584] Example 72 was prepared according to the methods described in General Procedures 1, 4, 11, 14, 15 and the following method.

[0585] Preparation 3: 2-Methyl-3-phenylquinolin-6-amine

[0586]

[0587] Step 1: N-methoxy-N-methyl-2-phenylacetamide

[0588]

[0589] At 0-5 ° C, a catalytic amount of DMF (2 drops) and oxalyl chloride (5.855 g, 46.135 mmol) were added dropwise to a stirred solution of commercially available phenylacetic acid (4.18 g, 30.753 mmol) in DCM (40 mL) at 0-5 ° C. The resulting reaction mixture was stirred at room temperature for 2 h and then commercially available N, O-dimethylhydroxylamine hydrochloride (3.0 g, 30.75 mmol) was added at 0-5 ° C, followed by TEA (12.45 g, 123.03 mmol), and the mixture was further stirred at room temperature for 30 min. The reaction progress was monitored by TLC and LCMS, and the reaction mixture was diluted with water and extracted with DCM after completion. The reaction mixture was purified by anhydrous Na 2 SO 4 The organic layer was dried and concentrated in vacuo to give the crude product, which was purified by column chromatography to afford the title compound as an off-white solid (4.0 g, 72.7% yield). LCMS m / z: 180 [M+H].

[0590] Step 2: 1-Phenylpropan-2-one

[0591]

[0592] At -78 ° C and inert atmosphere, to a stirred solution of N-methoxy-N-methyl-2-phenylacetamide (Preparation 3, Step 1) (1.0 g, 5.586 mmol) in anhydrous THF (18 mL) was added methylmagnesium bromide (1.332 g, 3.72 mL, 3M solution in diethyl ether) and the reaction mixture was maintained at the same temperature for 1 h. LCMS indicated that the reaction was about 60% complete. The mixture was warmed to room temperature and stirred at room temperature for 2 h. The reaction was monitored by TLC and LCMS, at which time the reaction was shown to be complete. The reaction mixture was quenched with a saturated solution of ammonium chloride and extracted with EtOAc. The organic layer was washed with brine and filtered through anhydrous Na 2 SO 4 Dry and concentrate in vacuo to give a crude product, which was purified by column chromatography to afford the title compound as a white solid (0.7 g, 93% yield). LCMS m / z: 135 [M+H].

[0593] Step 3: 6-Bromo-2-methyl-3-phenylquinoline

[0594]

[0595] To a stirred solution of 1-phenylpropane-2-one (Preparation 3, Step 2) (1.098 g, 8.146 mmol) and commercially available 2-amino-5-bromobenzaldehyde (1.646 g, 8.146 mmol) in ethanol (65 mL) was added 33% aqueous KOH (6.584 mL) at room temperature. The resulting reaction mixture was refluxed at 70 ° C for 1 h. The reaction was monitored by TLC and LCMS and the solvent was evaporated after completion to give a residue, which was diluted with EtOAc and washed with brine. The residue was purified by anhydrous Na 2 SO 4 The organic layer was dried and concentrated in vacuo to give the crude product, which was purified by column chromatography to afford the title compound as a white solid (0.94 g, 38% yield). LCMS m / z: 298 [M+H].

[0596] Step 4: N-(4-methoxybenzyl)-2-methyl-3-phenylquinolin-6-amine

[0597]

[0598] To a stirred solution of 6-bromo-2-methyl-3-phenylquinoline (Preparation 3, Step 3) (921 mg, 3.099 mmol) in DMSO (12 mL) was added p-methoxybenzylamine (2.44 mL, 18.594 mmol) under an inert atmosphere, followed by K 2 CO 3 (1070 mg, 7.747 mmol), then CuI (590 mg, 3.099 mmol) and L-proline (178.68 mg, 1.549 mmol) were added. The resulting reaction mixture was transferred to a sealed tube and heated at 90 ° C for 12 h. The reaction progress was monitored by LCMS and the reaction mixture was poured into ice-water after completion. The aqueous reaction mixture was extracted with EtOAc and washed with brine. The reaction mixture was purified by anhydrous Na 2 SO 4 The organic layer was dried and concentrated in vacuo to give a crude product, which was purified by column chromatography to afford the title compound as a yellow solid (951 mg, 87% yield). LCMS m / z: 355 [M+H].

[0599] Step 5: 2-Methyl-3-phenylquinolin-6-amine

[0600]

[0601] A solution of N-(4-methoxybenzyl)-2-methyl-3-phenylquinolin-6-amine (Preparation 3, Step 4) (920 mg, 2.137 mmol) in TFA (10 mL) was stirred at room temperature for 12 h. The reaction progress was monitored by TLC / LCMS and NaHCO was used after completion.3 The reaction mixture was neutralized with aqueous solution, extracted with EtOAc and washed with NaHCO 3 The mixture was washed with saturated solution and then with brine. 2 SO 4 The combined organics were dried and concentrated in vacuo to give the title compound as a crude solid (644 mg, 90% pure), which was used in the next step without any further purification. LCMS m / z: 235 [M+H].

[0602] Preparation 4: (R)-1-(2-hydroxybutyl)-3-(2-methyl-3-phenylquinolin-6-yl)urea (Example 72)

[0603]

[0604] To the stirred solution of 2-methyl-3-phenylquinoline-6-amine (preparation 3, step 5) (644mg, 2.751mmol) in THF (6mL), p-nitrophenyl chloroformate (609.8mg, 3.026mmol) was added and the whole was stirred at room temperature for 1h. After the amine was completely consumed by TLC, TEA (1.535mL, 11.00mmol) and (R)-1-aminobutane-2-ol (269.68mg, 3.025mmol) were added dropwise and the combined mixture was further stirred at room temperature for 3h. The reaction progress was monitored by TLC / LCMS and the reaction mixture was diluted with EtOAc after completion, washed three times with 1N NaOH solution, then washed with brine and 1N HCl solution and washed again with brine. By anhydrous Na 2 SO 4 The organic layer was dried and concentrated in vacuo to give a crude product, which was purified by crystallization using acetone and hexane to provide the title compound as a white solid (393 mg, 41% yield). LCMS m / z: 350.22 [M+H]; purity 99.71%; 1 H NMR (400 MHz; DMSO-d 6 ): δ0.88(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=4.84Hz,1H),4.76(d,J=4. 96Hz,1H),6.25(t,J=5.72Hz,1H),7.40-7.50(m,5H),7.61-7.64(m,1H),7.82(d,J=9.0Hz,1H),7.95(s,1H),7.99(s,1H),8.90(s,1H).

[0605] Example 101: (R)-1-(2-Hydroxybutyl)-3-(4-methoxy-2,3-diphenylquinolin-6-yl)urea

[0606]

[0607] Example 101 was prepared according to the methods described in General Procedures 1, 3, 17, 18 and the following method.

[0608] Preparation 5: 4-methoxy-2,3-diphenylquinolin-6-amine

[0609]

[0610] Step 1: 2-Azido-5-nitrobenzaldehyde

[0611]

[0612] To a stirred solution of commercially available 2-bromo-5-nitrobenzaldehyde (2.0 g, 8.684 mmol) in DMF at 50 °C was added NaN 3 (0.869 g, 13.378 mmol) and the reaction mixture was maintained at this temperature for 30 min. The reaction was monitored by TLC and after complete consumption of the starting material; the reaction mixture was quenched with ice-water and stirred for another 30 min. to obtain a solid precipitate, which was filtered off. The filtrate was then extracted with MTBE, washed with brine, and filtered through anhydrous Na 2 SO 4 Drying and concentration in vacuo afforded the title compound as a yellow solid (1.35 g, 80.8% yield). LCMS m / z: 193 [M+H].

[0613] Step 2: 4-Methoxy-6-nitro-2,3-diphenylquinoline

[0614]

[0615] At room temperature, MeOH (0.94 mL, 23.44 mmol) was added to a stirred solution of 2-azido-5-nitrobenzaldehyde (Preparation 5, Step 1) (1.35 g, 5.862 mmol) in anhydrous DCM, followed by diphenylacetylene (1.044 g, 5.86 mmol). The reaction mixture was cooled to 0-5 ° C and then TMSOTf (5.22 g, 23.44 mmol) was added dropwise. The resulting reaction mixture was stirred at room temperature for 12 h. The progress of the reaction mixture was monitored by TLC / LCMS, and the reaction mixture was diluted with EtOAc and washed with brine after completion. The reaction mixture was purified by anhydrous Na 2 SO 4The combined organic layers were dried and concentrated in vacuo to afford the crude product, which was purified by column chromatography to give the title compound as a yellow solid (2.2 g, 88% yield). LCMS m / z: 357.25 [M+H].

[0616] Step 3: 4-Methoxy-2,3-diphenylquinolin-6-amine

[0617]

[0618] To a stirred solution of 4-methoxy-6-nitro-2,3-diphenylquinoline (Preparation 5, Step 2) (832 mg, 2.335 mmol) in THF (10 mL) was added aqueous HCl (0.3 mL) at room temperature followed by SnCl 2 (1742 mg, 9.338 mmol), and the resulting reaction mixture was refluxed at 60 ° C for 2 h. The progress of the reaction mixture was monitored by TLC / LCMS, and after completion, the reaction mixture was diluted with EtOAc and washed with 0.5N NaOH and brine. 2 SO 4 The organic layer was dried and concentrated in vacuo to provide a crude product, which was purified by column chromatography to give the title compound as a yellow solid (605 mg, 79.5% yield). LCMS m / z: 327 [M+H].

[0619] Preparation 6: (R)-1-(2-hydroxybutyl)-3-(4-methoxy-2,3-diphenylquinolin-6-yl)urea (Example 101)

[0620]

[0621] To a stirred solution of 4-methoxy-2,3-diphenylquinoline-6-amine (preparation 5, step 3) (605 mg, 1.855 mmol) in THF (6 mL) was added p-nitrophenyl chloroformate (411.29 mg, 2.041 mmol) and stirred as a whole at room temperature for 1 h. After the amine was completely consumed by TLC, TEA (1.035 mL, 7.42 mmol) and (R)-1-aminobutane-2-ol (181.87 mg, 2.0405 mmol) were added dropwise and the combined mixture was further stirred at room temperature for 3 h. The reaction progress was monitored by TLC / LCMS and the reaction mixture was diluted with EtOAc after completion, washed three times with 1N NaOH solution, then washed with brine and 0.02N HCl solution and washed again with brine. The reaction mixture was purified by anhydrous Na 2 SO 4The organic layer was dried and concentrated in vacuo to give a crude product, which was purified by crystallization using acetone and hexane to provide the title compound as a white solid (400 mg, 49% yield). LCMS m / z: 442.27 [M+H]; purity 99.51%; 1 H NMR (400 MHz; DMSO-d 6 ): δ0.88(t,J=7.4Hz,3H),1.32-1.42(m,2H),2.96-3.01(m,1H),3.21-3 .25(m,1H),3.42(d,J=4.76Hz,1H).3.49(s,3H),4.75(d,J=5.16Hz,1H) ,6.26(t,J=5.48Hz,1H),7.16-7.33(m,10H),7.67(dd,J′=2.36Hz,J”=9.04Hz,1H),7.93(d,J=9.08Hz,1H),8.29(d,J=2.44Hz,1H),9.04(s,1H).

[0622] Example 20: (R)-1-(2,3-bis(2-fluorophenyl)quinolin-6-yl)-3-(2-hydroxybutyl)urea

[0623]

[0624] Example 20 was prepared according to the methods described in General Procedures 1, 3, 7, 8, 9, 10 and the methods described below.

[0625] Preparation 7: 2,3-Bis(2-fluorophenyl)quinolin-6-amine

[0626]

[0627] Step 1: 6-Nitroquinolin-2(1H)-one

[0628]

[0629] At -10°C to 0°C, commercially available quinolin-2(1H)-one (5.0 g, 34.44 mmol) was added to H 2 SO 4 To a stirred solution of 100 mL, 1.876 mmol, KNO was added portionwise 3 (3.83 g, 37.884 mmol). The whole was stirred at 0-5 °C for 30 min. The reaction was confirmed to be complete by TLC / LCMS. The reaction mixture was quenched with ice-water and extracted with EtOAc. The combined organic layers were washed with brine and purified by anhydrous Na 2 SO 4Drying and concentration in vacuo afforded the title compound as a yellow solid (7.4 g, crude). LCMS m / z: 188.97 [MH].

[0630] Step 2: 3-Bromo-6-nitroquinolin-2(1H)-one

[0631]

[0632] To a stirred solution of 6-nitroquinolin-2(1H)-one (Preparation 7, Step 1) (7.315 g, 38.46 mmol) in water (25.15 mL) was added NaBrO at -10 to 5 °C. 3 (6.965g, 46.16mmol), then add 48% HBr aqueous solution (133.8mL) dropwise at the same temperature. Then reflux as a whole at 100°C for 4h. Monitor the reaction progress by TLC / LCMS, and after completion, quench the reaction mixture in ice-water and stir for 1h at 0-5°C. Filter out the obtained solid precipitate and wash with water to obtain a solid material, wash with hexane (500mL) slurry to provide the title compound (8.0g, 77.3% yield) in the form of a yellow solid. LCMS m / z: 266.98[MH].

[0633] Step 3: 2,3-Dibromo-6-nitroquinoline

[0634]

[0635] 3-Bromo-6-nitroquinolin-2(1H)-one (Preparation 7, Step 2) (2.0 g, 7.435 mmol) was dissolved in POBr 3 (4.263 g, 14.869 mmol) was heated at 140 °C for 12 h. The reaction progress was monitored by TLC / LCMS, and after completion, the reaction mixture was quenched with cold water and heated with NaHCO 3 The aqueous solution was basified to pH 7-8. The aqueous mixture was extracted with EtOAc and washed with brine. 2 SO 4 The combined organic layers were dried and concentrated under reduced pressure to give the title compound as a crude brown solid (1.6 g crude). LCMS m / z: 231 [M+H].

[0636] Step 4: 2,3-Bis(2-fluorophenyl)-6-nitroquinoline

[0637]

[0638] 2,3-Dibromo-6-nitroquinoline (Preparation 7, Step 3) (1.6 g, 4.805 mmol), (2-fluorophenyl)boronic acid (1.7 g, 12.151 mmol) and K were stirred at 4 °C using argon. 3 PO 4 A solution of (4.118 g, 19.399 mmol) in a mixture of 1,4-dioxane (20 mL) and water (2 mL) was degassed for 30 min. Pd was then added 2 (dba) 3 (444 mg, 0.485 mmol) and PCy 3 (272 mg, 0.969 mmol). The resulting reaction mixture was stirred at 100 ° C under an inert atmosphere for 16 h. The reaction progress was monitored by TLC / LCMS and after completion the reaction mixture was diluted with EtOAc, filtered and the filtrate was partitioned with water. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine and filtered through anhydrous Na 2 SO 4 Drying and concentration in vacuo afforded a crude product, which was purified by column chromatography to give the title compound as a light yellow solid (1.2 g, 68.73% yield). LCMS m / z: 363 [M+H].

[0639] Step 5: 2,3-Bis(2-fluorophenyl)quinolin-6-amine

[0640]

[0641] To a stirred solution of 2,3-bis(2-fluorophenyl)-6-nitroquinoline (Preparation 7, Step 4) (1.2 g, 3.312 mmol) in THF (15 mL) was added aqueous HCl (0.2 mL) at room temperature followed by SnCl 2 .H 2 O (2.98 g, 13.22 mmol), and the resulting reaction mixture was then refluxed at 60° C. for 2 h. The progress of the reaction mixture was monitored by TLC / LCMS, and after completion the reaction mixture was diluted with EtOAc and quenched with NaHCO 3 The mixture was washed with saturated aqueous solution and brine. 2 SO 4 The organic layer was dried and concentrated in vacuo to provide a crude product, which was purified by column chromatography to give the title compound as a light yellow solid (1.0 g, 91% yield). LCMS m / z: 333 [M+H].

[0642] Preparation 8: (R)-1-(2,3-bis(2-fluorophenyl)quinolin-6-yl)-3-(2-hydroxybutyl)urea (Example 20)

[0643]

[0644] To a stirred solution of 2,3-bis(2-fluorophenyl)quinolin-6-amine (Preparation 7, Step 5) (1.0 g, 3.008 mmol) in THF (15 mL) was added p-nitrophenyl chloroformate (758 mg, 3.761 mmol) and the whole was stirred at room temperature for 2 h. After complete consumption of the amine was confirmed by TLC, TEA (1.257 g, 12.445 mmol) and (R)-1-aminobutane-2-ol (0.335 g, 3.764 mmol) were added dropwise and the combined mixture was further stirred at room temperature for 2 h. The reaction progress was monitored by TLC / LCMS and the reaction mixture was diluted with EtOAc after completion and NaHCO 3 The saturated solution was washed three times, followed by brine and 0.02N HCl solution and brine again. 2 SO 4 The organic layer was dried and concentrated in vacuo to give a crude product, which was purified by column chromatography to afford the title compound as a white solid (0.6 g, 45% yield). LCMS m / z: 448.37 [M+H]; purity 98.05%; 1 H NMR (500 MHz; DMSO-d 6 ): δ0.90(t,J=7.4Hz,3H),1.34-1.45(m,2H),2.99-3.03(m,1H),3.24-3.27( m,1H),3.44(d,J=4.9Hz,1H),4.81(d,J=5.1Hz,1H),6.39(t,J=5.45Hz,1H), 7.04-7.20(m,4H),7.30-7.36(m,3H),7.44(t,J=7.35Hz,1H),7.75-7.77(m, 1H),7.97(d,J=9.1Hz,1H),8.17(d,J=2.05Hz,1H),8.29(s,1H),9.15(s,1H)

[0645] Example 115: (R)-6-(3-(2-hydroxybutyl)ureido)-3-methyl-N-(1-methyl-1H-pyrazol-3-yl)-2-phenyl Quinoline-4-carboxamide

[0646]

[0647] Example 115 was prepared according to the methods described in General Procedures 1, 4, 19, 23 and the following method.

[0648] Preparation 9: 6-amino-3-methyl-N-(1-methyl-1H-pyrazol-3-yl)-2-phenylquinoline-4-carboxamide

[0649]

[0650] Step 1: 6-Bromo-3-methyl-2-phenylquinoline-4-carboxylic acid

[0651]

[0652] The stirred solution of commercially available 5-bromo indigo red (3.0 g, 13.272 mmol) in 2N NaOH (60 mL) solution was refluxed at 90 ° C for 30 min. The reaction mixture was then cooled to room temperature and commercially available phenylacetone (1.959 g, 14.60 mmol) was added at room temperature. The whole was refluxed for 16 h at 85-90 ° C. The reaction progress was monitored by TLC / LCMS, and after completion, the reaction mixture was filtered and the obtained solid was dissolved in water, and 2N HCl solution was acidified to obtain a solid precipitate, filtered and washed with water to provide the title compound in the form of a white solid (1.3 g, 28.6% yield). LCMS m / z: 342 [M+H].

[0653] Step 2: 6-Bromo-3-methyl-N-(1-methyl-1H-pyrazol-3-yl)-2-phenylquinoline-4-carboxamide

[0654]

[0655] At 0-5 ° C, oxalyl chloride (0.229 mL, 2.63 mmol) was added dropwise to a stirred solution of 6-bromo-3-methyl-2-phenylquinoline-4-carboxylic acid (preparation 9, step 1) (600 mg, 1.753 mmol) in a mixture of solvent DCM (10 mL) and DMF (10 mL). The whole was stirred for 1 h at room temperature and inert atmosphere. After the corresponding acyl chloride was formed (a smaller aliquot was quenched in MeOH and checked by LCMS), the excess oxalyl chloride was evaporated in vacuo to obtain a residue. A preformed mixture of 1-methyl-1H-pyrazole-3-amine (340 mg, 3.506 mmol) and TEA (0.977 mL, 7.01 mmol) in DCM (5 mL) was added dropwise at low temperature to the concentrated acyl chloride residue and the resulting reaction mixture was further stirred at room temperature for 16 h. The reaction progress was monitored by TLC / LCMS and the reaction mixture was diluted with DCM after completion, the solution was washed with brine and purified by anhydrous Na 2 SO 4 The organic layer was concentrated under reduced pressure to give a crude compound, which was purified by Combe Fraction to afford the title compound (603 mg, 79.0% yield) as a yellow solid. LCMS m / z: 421.30 [M+H].

[0656] Step 3: 6-((4-methoxybenzyl)amino)-3-methyl-N-(1-methyl-1H-pyrazol-3-yl)-2-phenylquinone 4-Methyl-1-phenoxy-1-carboxamide

[0657]

[0658] To a stirred solution of 6-bromo-3-methyl-N-(1-methyl-1H-pyrazol-3-yl)-2-phenylquinoline-4-carboxamide (Preparation 9, Step 2) (550 mg, 1.306 mmol) in DMSO (10 mL) was added p-methoxybenzylamine (899 mg, 6.527 mmol) under an inert atmosphere, followed by K 2 CO 3 (451 g, 2.263 mmol), then CuI (497 mg, 2.611 mmol) and L-proline (171 mg, 1.305 mmol) were added. The resulting reaction mixture was transferred to a sealed tube and heated at 90 ° C for 14 h. The reaction progress was monitored by LCMS and the reaction mixture was poured into ice-water after completion. The aqueous reaction mixture was extracted with EtOAc and washed with brine. The reaction mixture was purified by anhydrous Na 2 SO 4 The organic layer was dried and concentrated in vacuo to give a crude product, which was purified by column chromatography to afford the title compound as a yellow solid (484 mg, 77.5% yield). LCMS m / z: 478 [M+H].

[0659] Step 4: 6-amino-3-methyl-N-(1-methyl-1H-pyrazol-3-yl)-2-phenylquinoline-4-carboxamide

[0660]

[0661] A solution of 6-((4-methoxybenzyl)amino)-3-methyl-N-(1-methyl-1H-pyrazol-3-yl)-2-phenylquinoline-4-carboxamide (Preparation 9, Step 3) (484 mg, 1.014 mmol) in TFA (5 mL) was stirred at room temperature for 14 h. The reaction progress was monitored by TLC / LCMS and NaHCO was used after completion. 3 The reaction mixture was neutralized with aqueous solution, extracted with 5% MeOH in DCM and washed with NaHCO 3 The mixture was washed with saturated solution and then with brine. 2 SO 4 The combined organics were dried and concentrated in vacuo to give the title compound as a crude solid (450 mg, 91.69% purity), which was used in the next step without any further purification. LCMS m / z: 358.34 [M+H].

[0662] Preparation 10: (R)-6-(3-(2-hydroxybutyl)ureido)-3-methyl-N-(1-methyl-1H-pyrazol-3-yl)-2-phenyl Quinoline-4-carboxamide (Example 115)

[0663]

[0664] To a stirred solution of 6-amino-3-methyl-N-(1-methyl-1H-pyrazol-3-yl)-2-phenylquinoline-4-carboxamide (Preparation 9, Step 4) (212 mg, 0.593 mmol) in THF (5 mL) was added p-nitrophenyl chloroformate (132 mg, 0.653 mmol) and the whole was stirred at room temperature for 1 h. After complete consumption of the amine was confirmed by TLC, TEA (0.33 mL, 2.374 mmol) and (R)-1-aminobutane-2-ol (63.47 mg, 0.712 mmol) were added dropwise and the combined mixture was further stirred at room temperature for 3 h. The reaction progress was monitored by TLC / LCMS and the reaction mixture was diluted with EtOAc after completion and NaHCO 3 The saturated solution was washed three times, followed by washing with brine and 0.02N HCl solution and washing with brine again. 2 SO 4 The organic layer was dried and concentrated in vacuo to give a crude product, which was purified by preparative HPLC to provide the title compound as a white solid (89.6 mg, 32% yield). LCMS m / z: 473.5 [M+H]; purity 98.83%; 1 H NMR (500 MHz; DMSO-d 6 ): δ0.88(bs,3H),1.33-1.41(m,2H),2.31(s,3H),2.95(bs,1H),3.20(bs,1H),3.41(s,1H),3.79(s,3H),4.77(s,1H),6.20 (s,1H),6.72(s,1H),7.49-7.57(m,5H),7.68(s,1H),7.79-7.82(m,2H),7.91(d,J=10.1Hz,1H),9.07(s,1H)11.12(s,1H).

[0665] Example 95: 1-(4-amino-2,3-diphenylquinolin-6-yl)-3-(2-hydroxybutyl)urea

[0666]

[0667] Example 95 was prepared according to the methods described in General Procedures 1, 4, 19, 22 and the following method.

[0668] Preparation 11: 2,3-Diphenylquinoline-4,6-diamine

[0669]

[0670] Step 1: 6-Bromo-2,3-diphenylquinolin-4-amine

[0671]

[0672] At 0-5℃ and N 2 Under atmosphere, TEA (1.03 mL, 7.42 mmol) was added to a stirred solution of 6-bromo-2,3-diphenylquinoline-4-carboxylic acid (synthesized according to the method described in Preparation 9-Step 1) (2.0 g, 4.948 mmol) in DMF (30 mL), and diphenylphosphorus azide (2.126 mL, 9.896 mmol) was added. The whole was stirred at room temperature for 2 h, then water (30 mL) was added and refluxed at 100 ° C for 4 h. The reaction progress was monitored by LCMS and the reaction mixture was diluted with water after completion to obtain a solid precipitate, filtered and washed with water, and then washed with hexane. The obtained solid was dried in a vacuum oven to provide the title compound (1.5 g, 81% yield) in the form of a light yellow solid. LCMS m / z: 375.40 / 377.35 [M+H].

[0673] Step 2: N6-(4-methoxybenzyl)-2,3-diphenylquinoline-4,6-diamine

[0674]

[0675] To a stirred solution of 6-bromo-2,3-diphenylquinolin-4-amine (Preparation 11, Step 1) (500 mg, 1.06 mmol) in DMSO (15 mL) was added p-methoxybenzylamine (0.83 mL, 6.39 mmol) under an inert atmosphere, followed by K 2 CO 3 (365.7 mg, 2.65 mmol), then CuI (100.9 mg, 0.53 mmol) and L-proline (48.8 mg, 0.424 mmol) were added. The resulting reaction mixture was transferred to a sealed tube and heated at 90 °C for 16 h. The reaction progress was monitored by LCMS and the reaction mixture was poured into ice-water after completion. The aqueous reaction mixture was extracted with EtOAc and washed with brine. The reaction mixture was purified by anhydrous Na 2 SO 4 The organic layer was dried and concentrated in vacuo to give a crude product, which was purified by column chromatography to afford the title compound as a yellow solid (329 mg, 71.5% yield). LCMS m / z: 432.35 [M+H].

[0676] Step 3: 2,3-Diphenylquinoline-4,6-diamine

[0677]

[0678] A solution of N6-(4-methoxybenzyl)-2,3-diphenylquinoline-4,6-diamine (Preparation 11, Step 2) (320 mg, 0.742 mmol) in TFA (7 mL) was stirred at room temperature for 16 h. The reaction progress was monitored by TLC / LCMS, and after completion the reaction mixture was diluted with water and solid NaHCO 3 Neutralize, extract with EtOAc and use NaHCO 3 The mixture was washed with saturated solution and then with brine. 2 SO 4 The combined organics were dried and concentrated in vacuo to give the title compound as a crude solid (400 mg, 88% purity), which was used in the next step without any further purification. LCMS m / z: 312.19 [M+H].

[0679] Preparation 12: 1-(4-amino-2,3-diphenylquinolin-6-yl)-3-(2-hydroxybutyl)urea (Example 95)

[0680]

[0681] To a stirred solution of 2,3-diphenylquinoline-4,6-diamine (preparation 11, step 3) (80 mg, 0.257 mmol) in THF (3 mL) was added p-nitrophenyl chloroformate (64.78 mg, 0.321 mmol) and stirred as a whole at room temperature for 1 h. After the amine was completely consumed by TLC, TEA (0.14 mL, 1.06 mmol) and 1-aminobutane-2-ol (0.03 mL, 0.312 mmol) were added dropwise and the combined mixture was further stirred at room temperature for 3 h. The reaction progress 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 washing. By anhydrous Na 2 SO 4 The organic layer was dried and concentrated in vacuo to give a crude product, which was purified by preparative HPLC to provide the title compound as a white solid (20 mg, 18.3% yield). LCMS m / z: 427.37 [M+H]; purity 98.19%; 1 H NMR (500 MHz; DMSO-d 6): δ0.90(t,J=7.4Hz,3H),1.42-1.47(m,2H),2.98-3.03(m,1H),3.24-3.28(m,1H),3.44-3.45(m,1H),4.82(d,J=4 .95Hz,1H),6.53(s,1H),7.21(d,J=7.05Hz,2H),7.36-7.39(m,10H),7.87-7.92(m,2H),8.34(s,1H),8.99(s,1H).

[0682] Example 94: N-(6-(3-(2-hydroxybutyl)ureido)-2,3-diphenylquinolin-4-yl)methanesulfonamide

[0683]

[0684] Example 94 was prepared according to the methods described in General Procedures 1, 4, 19, 22 and the following method.

[0685] Preparation 13: N-(6-amino-2,3-diphenylquinolin-4-yl)methanesulfonamide

[0686]

[0687] Step 1: N-(6-bromo-2,3-diphenylquinolin-4-yl)-N-(methylsulfonyl)methanesulfonamide

[0688]

[0689] To a stirred solution of 6-bromo-2,3-diphenylquinolin-4-amine (Preparation 11, Step 1) (800 mg, 2.12 mmol) in anhydrous DMF (10 mL) was added NaH (153 mg, 6.38 mmol, 60% suspension in mineral oil) at 0-5 °C and the whole was stirred at room temperature for 20 min. Then MeSO was added dropwise at 0-5 °C. 2 Cl (0.5 mL, 6.36 mmol) was added and the whole was further stirred at room temperature for 2 h. The reaction progress was monitored by TLC / LCMS, and after completion, NH 4 The reaction mixture was quenched with a saturated solution of Cl and extracted with MTBE and washed with water followed by brine. 2 SO 4 The organic layer was dried and concentrated in vacuo to give the title compound as a yellow gummy solid (1.132 g crude). LCMS m / z: 531.25 [M+H].

[0690] Step 2: N-(6-bromo-2,3-diphenylquinolin-4-yl)methanesulfonamide

[0691]

[0692] To a stirred solution of N-(6-bromo-2,3-diphenylquinolin-4-yl)-N-(methylsulfonyl)methane-sulfonamide (Preparation 13, Step 1) (1.132 g, 2.13 mmol) in DMSO (10 mL) was added Cs 2 CO 3 (2.776 g, 8.5 mmol) and the mixture was heated at 120° C. in a sealed tube for 16 h. The reaction was checked by TLC / LCMS and after completion the reaction mixture was quenched with ice-water and extracted with EtOAc, washed with brine, and purified by anhydrous Na 2 SO 4 Dry and concentrate in vacuo to give a crude product, which was purified by Combe Flurch to afford the title compound as a brown solid (900 mg, 93% yield). LCMS m / z: 453.17 [M+H].

[0693] Step 3: N-(6-((4-methoxybenzyl)amino)-2,3-diphenylquinolin-4-yl)methanesulfonamide

[0694]

[0695] 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) 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 reaction progress was monitored by LCMS and the reaction mixture was poured into ice-water after completion. The aqueous reaction mixture was extracted with EtOAc and washed with brine. The reaction mixture was purified by anhydrous Na 2 SO 4 The organic layer was dried and concentrated in vacuo to give a crude product, which was purified by column chromatography to afford the title compound as a yellow solid (300 mg, 69.7% yield). LCMS m / z: 510.37 [M+H].

[0696] Step 4: N-(6-amino-2,3-diphenylquinolin-4-yl)methanesulfonamide

[0697]

[0698] 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 reaction progress was monitored by TLC / LCMS, and after completion the reaction mixture was diluted with water and solid NaHCO 3 Neutralize, extract with EtOAc and use NaHCO 3 The mixture was washed with saturated solution and then with brine. 2 SO 4 The combined organics were dried and concentrated in vacuo to give the title compound (400 mg, crude) as a yellow gummy semi-solid, which was used in the next step without any further purification. LCMS m / z: 390.31 [M+H].

[0699] Preparation 14: N-(6-(3-(2-hydroxybutyl)ureido)-2,3-diphenylquinolin-4-yl)methanesulfonamide (Example 94)

[0700]

[0701] To N-(6-amino-2,3-diphenylquinoline-4-yl) methanesulfonamide (preparation 13, step 4) (400mg, 1.02mmol) in THF (5mL) stirred solution was added p-nitrophenyl chloroformate (258.86mg, 1.28mmol) and stirred at room temperature for 1h. After the amine was completely consumed by TLC, TEA (0.58mL, 4.207mmol) and 1-aminobutane-2-ol (0.12mL, 1.28mmol) were added dropwise and the combined mixture was further stirred at room temperature for 3h. The reaction progress was monitored by TLC / LCMS, and after completion, the reaction mixture was diluted with EtOAc and washed with 0.5NNaOH solution, followed by brine washing. By anhydrous Na 2 SO 4 The organic layer was dried and concentrated in vacuo to give a crude product, which was purified by preparative HPLC to provide the title compound as a white solid (150 mg, 29% yield). LCMS m / z: 505.37 [M+H]; purity 98.16%; 1 H NMR (500 MHz; DMSO-d 6): δ0.90(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=5.1Hz,1H ), 6.36 (d, J = 5.1Hz, 1H), 7.22-7.34 (m, 10H), 7.97 (d, J = 9Hz, 1H), 8.05 (d, J = 9.15Hz, 1H), 8.17 (s, 1H), 9.16 (s, 1H), 9.56 (bs, 1H).

[0702] Example 145: 1-(6,7-diphenyl-1,8-naphthyridin-3-yl)-3-(2-hydroxybutyl)urea

[0703]

[0704] Example 145 was prepared according to the methods described in General Procedures 1, 4, 15 and the following method.

[0705] Preparation 16: 6,7-Diphenyl-1,8-naphthyridin-3-amine

[0706]

[0707] Step-1: 6-Bromo-2,3-diphenyl-1,8-naphthyridine

[0708]

[0709] To a stirred solution of commercially available 2-amino-5-bromonicotinaldehyde (250 mg, 1.24 mmol) in piperidine (3 mL) was added 1,2-diphenylethane-1-one (244 mg. 1.24 mmol) at room temperature and the resulting reaction mixture was heated in a sealed tube at 120 ° C. for 16 h. The reaction was monitored by LCMS and after completion of the reaction, quenched with saturated sodium bicarbonate solution and extracted with EtOAc (3×50 mL), and washed with water (3×50 mL), followed by brine (3×50 mL), filtered through anhydrous Na 2 SO 4 Dry and concentrate under reduced pressure to afford the crude product, which was purified by column chromatography on silica gel to afford the title compound as an off-white solid (200 mg, 45% yield). LCMS m / z: 361 [M+H].

[0710] Step 2: N-(4-methoxybenzyl)-6,7-diphenyl-1,8-naphthyridin-3-amine

[0711]

[0712] To a stirred solution of 6-bromo-2,3-diphenyl-1,8-naphthyridine (Preparation 16, Step 1) (400 mg, 1.108 mmol) in toluene (10 mL) were added p-methoxybenzylamine (227.70 mg, 1.66 mmol), K 3 PO 4 (704.70 mg, 3.32 mmol) and X-Phos (105.48 mg, 0.222 mmol) and using N 2 The reaction mixture was degassed for 10 min. Pd 2 (dba) 3 (101.38 mg, 0.111 mmol). The entire reaction mixture was capped and stirred at 100 °C for 16 h. The reaction was monitored by LCMS, and after the reaction was complete, the reaction mixture was quenched with water and extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine solution (3×50 mL) and purified by anhydrous Na 2 SO 4 Drying and evaporation in vacuo gave a crude product which was purified by column chromatography (silica gel, eluent: 60% EtOAc in hexanes) to afford the title compound (300 mg, 65% yield) as a reddish gummy solid. LCMS m / z: 418.0 [M+H].

[0713] Step-3: 6,7-Diphenyl-1,8-naphthyridin-3-amine

[0714]

[0715] To a stirred solution of N-(4-methoxybenzyl)-6,7-diphenyl-1,8-naphthyridin-3-amine (Preparation 16, Step 2) (190 mg, 0.455 mmol) in DCM (1 mL) was added TFA (1.8 mL) and the whole was stirred for 2 h. The reaction was monitored by LCMS, and after completion of the reaction, alkalized with saturated sodium bicarbonate solution and extracted with EtOAc (3×50 mL), washed with water (3×50 mL), then washed with brine (3×50 mL), filtered through anhydrous Na 2 SO 4 Drying and concentration under reduced pressure gave a crude product, which was purified by column chromatography (silica gel, eluent: 80% EtOAc in hexanes) to afford the title compound (100 mg, 73% yield) as a slightly yellow gum. LCMS m / z: 297.9 [M+H].

[0716] Preparation 17: 1-(6,7-diphenyl-1,8-naphthyridin-3-yl)-3-(2-hydroxybutyl)urea (Example 145)

[0717]

[0718] 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 stirred as a whole for 3 h at room temperature. TEA (0.352 mL, 2.52 mmol) and 1-aminobutane-2-ol (0.053 mL, 0.555 mmol) were added to the reaction mixture at the same temperature and stirred as a whole for another 6 h. The reaction was monitored by LCMS and the solvent was evaporated after completion to give the crude product. The crude was purified by reverse phase preparative HPLC to provide the title compound (23 mg, 11% yield) in the form of an off-white solid. LCMS m / z: 413.5 [M+H]; purity is 99.45%; 1 H NMR (400 MHz; DMSO-d 6 ): δ0.89(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=4.8Hz,1H),4.78(d, J=5.08Hz,1H),6.48(d,J=5.32Hz,1H),7.26-7.39(m,10H),8.35(s,1H),8.57(d,J=2.72Hz,1H),8.93(d,J=2.72Hz,1H),9.28(s,1H).

[0719] Preparation 18: 6-Chloro-2,3-diphenyl-1,5-naphthyridine

[0720]

[0721] Step-1: 3-Amino-6-chloropicolinamide

[0722]

[0723] To a stirred solution of commercially available 3-amino-6-chloropicolinonitrile (4.0 g, 26.1 mmol) in EtOH (40.0 mL) was added SnCl 2 (9.92 g, 52.3 mmol) and the reaction mixture was stirred at 90 ° C for 16 h. The reaction progress was monitored by LCMS and after the reaction was completed, the excess solvent was concentrated under reduced pressure and the reaction mixture was quenched using 2M NaOH solution to reach pH 8-9 and then the product was extracted using EtOAc (3×50 mL). The combined organic layers were washed with brine solution (1×30 mL) and washed with anhydrous Na 2 SO 4Dried and filtered. The filtrate was concentrated under reduced pressure to afford the title compound (3.2 g, 71.2% yield) as a crude light yellow solid, which was used in the next step without any further purification. LCMS m / z: 172.0 [M+H].

[0724] Step-2: 3-Amino-6-chloropicolinic acid

[0725]

[0726] 3-Amino-6-chloropicolinamide (Preparation 18, Step-1) (3.0 g, 17.5 mmol) was taken up in concentrated HCl (15 mL) and heated to 110 °C for 5 h. The solvent was removed under reduced pressure to afford the title compound (3.0 g, crude) as a yellow solid. The crude was used in the next step without any further purification. LCMS m / z: 173.09 [M+H].

[0727] Step-3: (3-Amino-6-chloropyridin-2-yl)methanol

[0728]

[0729] To a stirred solution of 3-amino-6-chloropicolinic acid (Preparation 18, Step-2) (3.0 g, 17.4 mmol) in THF (30.0 mL) was added BH 3 -THF (1 M in THF) (69.5 mL, 69.5 mmol) and the reaction mixture was stirred at room temperature for 48 h. The reaction progress was monitored by LCMS and after completion, HCl and H 2 O to dilute the reaction mixture, then use NaHCO 3 Neutralize and extract with EtOAc (3×30 mL). 2 SO 4 The combined organic layers were dried and filtered. The filtrate was concentrated to afford the title compound (2.5 g, crude) as a yellow sticky solid, which was used in the next step without any further purification.

[0730] Step-4: 3-Amino-6-chloropyridinecarboxaldehyde

[0731]

[0732] To a stirred solution of (3-amino-6-chloropyridin-2-yl)methanol (Preparation 18, Step-3) (2.5 g, 15.8 mmol) in DCM (50 mL) was added MnO 2 (2.75 g, 31.6 mmol). After 24 h, another portion of MnO 2(2 equivalents) was added to the mixture and the whole was further stirred at room temperature for 24 h. The reaction progress was monitored by LCMS and the reaction mixture was filtered through celite after completion, and the solvent was removed in vacuo to provide the title compound (950 mg, 38.4% yield) as a yellow solid. LCMS m / z: 156.84 [M+H].

[0733] Step-5: 6-Chloro-2,3-diphenyl-1,5-naphthyridine

[0734]

[0735] To a stirred solution of 3-amino-6-chloropicolinaldehyde (Preparation 18, Step-4) (100 mg, 0.64 mmol) in DMF (2.0 mL) was added K 2 CO 3 (88.6 mg, 0.64 mmol) and 1,2-diphenylethane-1-one (126 mg, 0.64 mmol) and the reaction mixture was stirred at 90 ° C for 16 h. The reaction progress was monitored by LCMS and the reaction mixture was quenched with crushed ice and cold water (20 mL) after completion. The product was extracted with EtOAc (3×20 mL) and the combined organic layer was washed with brine solution (1×30 mL) and washed with anhydrous Na 2 SO 4 Dry and filter. The filtrate was concentrated under reduced pressure to give a crude product, which was purified by preparative TLC (20% EtOAc-hexanes) to provide the title compound (3 mg, 1.48% yield) as an off-white solid. LCMS m / z: 316.9 [M+H]; 1 H NMR (400 MHz; DMSO-d 6 ): δ8.53(d,J=8.8Hz,1H),8.36(s,1H),7.87(d,J=8.8Hz,1H),7.31-7.40(m,10H),

[0736] Preparation 19: N-(4-methoxybenzyl)-2,3-diphenyl-1,7-naphthyridin-6-amine

[0737]

[0738] Step-1: 6-Chloro-2,3-diphenyl-1,7-naphthyridine

[0739]

[0740] To a stirred solution of commercially available 5-amino-2-chloroisonicotinaldehyde (300 mg, 1.92 mmol) in DMF (6.0 mL) was added K 2 CO 3(265.7 mg, 1.92 mmol) and 1,2-diphenylethane-1-one (377 mg, 1.92 mmol) and the reaction mixture was stirred at 90 ° C for 16 h. The reaction progress was monitored by LCMS and the reaction mixture was quenched with crushed ice and cold water (20 mL) after completion. The product was extracted with EtOAc (3×20 mL) and the combined organic layer was washed with brine solution (3×20 mL) and washed with anhydrous Na 2 SO 4 Dried and filtered. The filtrate was concentrated under reduced pressure to provide a crude product, which was purified by preparative TLC (20% EtOAc-hexanes) to provide the title compound (240 mg, 34.9% yield) as an off-white solid. LCMS m / z: 316.9 [M+H].

[0741] Step 2: N-(4-methoxybenzyl)-2,3-diphenyl-1,7-naphthyridin-6-amine

[0742]

[0743] 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) were added p-methoxybenzylamine (0.08 mL, 0.63 mmol), K 3 PO 4 (201 mg, 0.95 mmol), Brett-phos (57.23 mg, 0.063 mmol) and Brett-phos-Pd-G1 (50.43 mg, 0.063 mmol). The entire reaction mixture was capped and stirred in a microwave at 130 ° C for 1 h. After the reaction was completed (monitored by LCMS), the reaction mixture was quenched with water and extracted with EtOAc (2×20 mL). The combined organic layer solution was washed with brine (1×10 mL) and filtered through anhydrous Na 2 SO 4 Drying and evaporation gave a crude product, which was purified by column chromatography (silica gel, eluent: 50% EtOAc in hexanes) followed by preparative TLC to afford the title compound as a brown solid (10 mg, crude). LCMS m / z: 418.0 [M+H].

[0744]

[0745]

[0746]

[0747]

[0748]

[0749]

[0750]

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[0752]

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[0758]

[0759]

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[0761]

[0762]

[0763]

[0764]

[0765]

[0766]

[0767]

[0768]

[0769]

[0770]

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[0773]

[0774]

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[0777]

[0778]

[0779]

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[0781]

[0782]

[0783]

[0784]

[0785]

[0786]

[0787]

[0788]

[0789]

[0790]

[0791]

[0792]

[0793]

[0794]

[0795]

[0796]

[0797]

[0798]

[0799]

[0800]

[0801]

[0802]

[0803]

[0804]

[0805]

[0806]

[0807]

[0808]

[0809]

[0810]

[0811]

[0812]

[0813]

[0814]

[0815]

[0816]

[0817]

[0818]

[0819]

[0820]

[0821]

[0822]

[0823]

[0824]

[0825]

[0826]

[0827] Example 128: N-(2,3-bis(2-fluorophenyl)quinolin-6-yl)-4-hydroxyhexanamide

[0828]

[0829] Example 128 was prepared according to the methods described in General Procedures 1, 2, 3, 7, 8, 9, 10 and the following method.

[0830] Preparation 15: N-(2,3-bis(2-fluorophenyl)quinolin-6-yl)-4-oxohexanamide (Example 124)

[0831]

[0832] To a stirred solution of 4-oxohexanoic acid (56.2 mg, 0.432 mmol) in DMF (2 mL) was added DIPEA (0.103 mL, 0.602 mmol) and HATU (171.68 mg, 0.452 mmol). Stirring was continued for 10 min., and then 2,3-bis(2-fluorophenyl)quinoline-6-amine (preparation 7-step 5) (100 mg, 0.301 mmol) was added. The whole was stirred at room temperature for 2 h. The reaction progress was confirmed by TLC / LCMS, and after completion, the reaction mixture was diluted with water and extracted with MTBE, washed with brine, and filtered through anhydrous Na 2 SO 4 Dry and evaporate in vacuo to give a crude product, which was purified by preparative HPLC to afford the title compound as a white solid (39 mg, 29% yield). LCMS m / z: 445.2 [M+H]; purity 98.04%; 1 H NMR (500 MHz; DMSO-d 6 ): δ0.96(t,J=7.3Hz,3H)2.52(t,J=7.35Hz,2H),2.66(t,J=6.65Hz,2H),2.79(t,J=6.6Hz,2H),7.03-7.21(m,4H),7.31-7.39(m,3H), 7.45 (t, J = 7.55Hz, 1H), 7.89 (dd, J' = 2.1Hz, J” = 9.15Hz, 1H), 8.04 (d, J = 9.1Hz, 1H), 8.37 (s, 1H), 8.45 (d, J = 1.85Hz, 1H), 10.41 (s, 1H).

[0833] Preparation 16: N-(2,3-bis(2-fluorophenyl)quinolin-6-yl)-4-hydroxyhexanamide (Example 128)

[0834]

[0835] To a stirred solution of N-(2,3-bis(2-fluorophenyl)quinolin-6-yl)-4-oxohexanamide (Preparation 15) (50 mg, 0.113 mmol) in MeOH (2 mL) was added NaBH at 0-5 °C. 4 (4.26 mg, 0.113 mmol) and stirred at the same temperature for 1 h. After the reaction was completed (monitored by TLC and LCMS), the reaction mixture was quenched with water and extracted with EtOAc, washed with brine, and washed with anhydrous Na 2 SO 4 Dry and evaporate in vacuo to give a crude product, which was purified by preparative HPLC to afford the title compound as a white solid (15 mg, 29.8% yield). LCMS m / z: 447.22 [M+H]; purity 98.69%; 1 H NMR (500 MHz; DMSO-d 6 ): δ0.89(t,J=7.35Hz,3H),1.23(s,1H),1.36-1.45(m,2H),1.60-1.63(m,1H),1.7 8-1.81(m,1H),2.46-2.48(m,1H),3.39(d,J=3.75Hz,1H),4.49(d,J=5.3Hz,1H),7 .05(t,J=9.4Hz,1H),7.10-7.21(m,3H),7.31-7.37(m,3H),7.45(t,J=7.25Hz,1H) ,7.90(t,J=7.15Hz,1H),7.92-7.05(m,1H),8.38(s,1H),8.49(s,1H),10.34(s,1H)

[0836]

[0837]

[0838]

[0839]

[0840]

[0841]

[0842] Biological analysis

[0843] ACSS 2 Enzyme analysis

[0844] In humans ACSS 2Screening for novel compounds in enzyme assays. Briefly, ACSS is monitored by directly measuring acetyl-CoA formation. 2 Enzyme reaction. Cytosolic fraction of BT474 cells was used as ACSS 2 Sources of Enzymes. A brief protocol for this assay is provided below.

[0845] Preparation of cytosolic fraction from BT474 cells

[0846] 9 × 10 were harvested by trypsinization and subsequent centrifugation. 6 The cell pellet was washed with PBS and dissolved in 500 μl STM buffer (50 mM Tris-HCl (pH 7.4), 250 mM sucrose, 5 mM MgCl 2 The supernatant was collected by centrifugation at 800 g for 15 min at 4 °C. The cytoplasmic fraction was prepared by further centrifugation of the supernatant at 12000 g for 15 min at 4 °C. The total protein content of the cytoplasmic fraction was estimated and the cytoplasmic fraction was quantified in storage buffer (25 mM Tris-HCl (pH 7.4), 1 mM MgCl 2 , 1 mM DTT and 10% glycerol) to a concentration of 1 mg / ml and stored at -80°C for further use.

[0847] Analysis plan

[0848] 100 ng was dissolved in a buffer solution consisting of 25 mM Tris-HCl (pH 7.4), 1 mM MgCl 2 , 1mM DTT and 0.05% Tween20) in the cytoplasmic fraction with the desired concentration of novel compounds pre-incubated for 5 min. and maintained at 1% DMSO. The reaction was started by adding a substrate mixture (100 μM acetate, CoA and ATP) and incubated at 500 rpm for 2 h at 25 ° C and constant shaking. After incubation, the reaction was terminated by adding 10% TCA and then diluted 5 times in water. The reaction mixture was centrifuged at 800g for 10 min. at room temperature and acetyl CoA in the supernatant was detected by LC-MS / MS (QTrap5500 ABSCIEX).

[0849] Cell-based 14 C] Acetate was included in the analysis

[0850] In cell analysis, targeting macromolecules [ 14 C] Acetate inclusion to screen ACSS 2 Inhibitor. 4×10 4BT474 cells were plated in 96-well plates in growth medium (consisting of DMEM and 10% FBS) and incubated at 37°C, 5% CO 2 Incubate overnight in an incubator. The next day, wash cells in HBSS and perform assays in 100 μl HBSS. Add 50 μl of 4x compound in 4% DMSO to cells and pre-incubate at 37°C for 10 min. Add 50 μl of acetate solution (0.1 μCi 14 C-Acetate + 10 μM 12 C acetate) was added to each well and incubated at 37°C, 5% CO 2 After incubation, cells were harvested on GF / C filter pads pre-soaked with polyethyleneimine (PEI) using water, air-dried and radioactivity counts were recorded in a Trilux microbeta liquid scintillation counter (PerkinElmer).

[0851] In the following table, the IC values ​​of exemplary compounds are given: 50 Value range. IC less than 100nM 50 The value range is indicated as "A", values ​​less than or equal to 1 μM are indicated as "B", values ​​less than or equal to 10 μM are indicated as "C", and values ​​greater than 10 μM are indicated as "D".

[0852] ACSS 2 active

[0853]

[0854]

[0855]

[0856]

Claims

1. A compound of formula (I), ， Where X is CR 3 ; Y is CR 4 ; Z is CR 5 or N; R is selected from the group consisting of: H, an optionally substituted monocyclic or bicyclic C6-C 12 wherein R is an optionally substituted 5- or 6-membered heteroaryl, an optionally substituted C1-C6 alkyl, a monocyclic or bicyclic C3-C6 cycloalkyl, an optionally substituted C2-C6 alkenyl, and an optionally substituted C2-C6 alkynyl; 12 When the aryl group is aryl, the aryl group is unsubstituted or substituted by one or more of the following groups: halogen, OH, C1-C6 alkyl, C1-C6 alkoxy, NR 9 R 10 、C(O)R 9 NR 9 C(O)R 10 , CN or C6-C 12 aryl; when R is an optionally substituted 5- or 6-membered heteroaryl, the heteroaryl is unsubstituted or substituted with one or more of the following groups: halogen, OH, oxo, C1-C6 alkyl, or C1-C6 alkoxy; and when R is an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, or an optionally substituted C2-C6 alkynyl, the alkyl, alkenyl, or alkynyl is unsubstituted or substituted with one or more of the following groups: halogen or C6-C 12 Aryl; R 1 is selected from the group consisting of an optionally substituted monocyclic or bicyclic C6-C 12 aryl, optionally substituted 5- or 6-membered heteroaryl and C1-C6 alkyl, wherein in R 1 is an optionally substituted monocyclic or bicyclic C6-C 12 When aryl is present, the aryl group is unsubstituted or substituted by one or more of the following groups: halogen, OH, C1-C6 alkoxy, C(O)R 9 or C1-C6 alkyl; and in R 1 When is an optionally substituted 5- or 6-membered heteroaryl, the heteroaryl is unsubstituted or substituted with one or more of the following groups: halogen, OH, oxo, C1-C6 alkoxy, C(O)R 9 or C1-C6 alkyl; R 2 It is H, COOR 9 、CN、CONR 9 R 10 NR 9 R 10 NR 9 S02R 10 NR 9 COR 10 , C1-C6 alkyl, C1-C6 alkoxy, monocyclic or bicyclic C6-C 12 Aryl or 5- or 6-membered heteroaryl; R 3 is H, halogen, C1-C6 alkyl, monocyclic or bicyclic C3-C6 cycloalkyl or optionally substituted 5- or 6-membered heteroaryl, wherein R 3 When is an optionally substituted 5- or 6-membered heteroaryl, the heteroaryl is unsubstituted or substituted with one or more of the following groups: oxo, OH, C1-C6 alkoxy or C1-C6 alkyl; R 4 and R 5 are each independently selected from the group consisting of H and halogen; R 6 It is H; L is NR 8 And R 7 is an optionally substituted C3-C6 alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted monocyclic or bicyclic C6-C 12 aryl, optionally substituted 5 or 6 membered heteroaryl, optionally substituted monocyclic or bicyclic C3-C6 cycloalkyl or optionally substituted 3 to 6 membered heterocycle; wherein L is NR 8 And R 7 When it is an optionally substituted C3-C6 alkyl, an optionally substituted C2-C6 alkenyl or an optionally substituted C2-C6 alkynyl, the alkyl, alkenyl or alkynyl is unsubstituted or substituted with one or more of the following groups: OH, halogen, C1-C6 alkoxy, OPO(OH)2 or NR 9 COR 10 ; and L is NR 8 And R 7 is an optionally substituted monocyclic or bicyclic C6-C 12 aryl, optionally substituted 5- or 6-membered heteroaryl, optionally substituted monocyclic or bicyclic C3-C6 cycloalkyl, or optionally substituted 3- to 6-membered heterocycle, said aryl, heteroaryl, cycloalkyl, or heterocycle is unsubstituted or substituted with one or more of the following: C1-C6 alkyl or OH; or L does not exist and R 7 is an optionally substituted C3-C6 alkyl or an optionally substituted 3 to 6 membered heterocycle; wherein In the absence of L and R 7 is an optionally substituted C3-C6 alkyl, the alkyl is unsubstituted or substituted with one or more of the following: OH, oxo or halogen; and L is absent and R 7 When it is an optionally substituted 3- to 6-membered heterocyclic ring, the heterocyclic ring is unsubstituted or substituted with one or more of the following groups: C1-C6 alkyl, C1-C6 alkoxy or COR 9 ; R 8 is H; and wherein R is a monocyclic or bicyclic C6-C 12 Aryl and the aryl is NR 9 R 10 、C(O)R 9 and / or NR 9 C(O)R 10 When replaced, then R 9 and R 10 Each is independently selected from the group consisting of: H and C1-C6 alkyl; In R 1 Is a monocyclic or bicyclic C6-C 12 Aryl and the aryl is C(O)R 9 When replaced, then R 9 Selected from the group consisting of: H and C1-C6 alkyl; In R 1 is an optionally substituted 5- or 6-membered heteroaryl and the heteroaryl is C(O)R 9 When replaced, then R 9 Selected from the group consisting of: H and C1-C6 alkyl; In R 2 It is COOR 9 ,CONR 9 R 10 NR 9 R 10 NR 9 S02R 10 or NR 9 COR 10 When R 9 and R 10 are each independently selected from the group consisting of: H, an optionally substituted monocyclic or bicyclic C6-C 12 aryl, optionally substituted 5- or 6-membered heteroaryl, optionally substituted C1-C6 alkyl or monocyclic or bicyclic C3-C6 cycloalkyl; wherein in R 9 and / or R 10 is an optionally substituted 5- or 6-membered heteroaryl or an optionally substituted monocyclic or bicyclic C6-C 12 When the heteroaryl or aryl group is aryl, the heteroaryl or aryl group is unsubstituted or substituted with one or more C1-C6 alkyl groups; and in R 9 and / or R 10 When it is an optionally substituted C1-C6 alkyl group, the alkyl group is unsubstituted or substituted with one or more of the following groups: a 5- or 6-membered heteroaryl group optionally substituted with a C1-C6 alkyl group, or a C6-C6 alkyl group optionally substituted with a C1-C6 alkyl group. 12 Aryl; In L is NR 8 And R 7 is a C3-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl group and the alkyl, alkenyl or alkynyl group is NR 9 COR 10 When replaced, then R 9 and R 10 Each is independently selected from the group consisting of: H and C1-C6 alkyl; In the absence of L and R 7 is a 3- to 6-membered heterocyclic ring and the heterocyclic ring is COR 9 When replaced, then R 9 and R 10 Each is independently selected from the group consisting of: H and C1-C6 alkyl; or a pharmaceutically acceptable salt thereof, in: The heterocyclic ring comprises at least one ring atom which is a heteroatom, and the or each heteroatom is independently selected from the group consisting of oxygen, sulfur and nitrogen; The heteroaryl group comprises at least one ring atom which is a heteroatom, and the or each heteroatom is independently selected from the group consisting of oxygen, sulfur and nitrogen; and Wherein the compound is not:

2. The compound according to claim 1, wherein R 1 is selected from an optionally substituted benzene ring, an optionally substituted C1-C6 alkyl group or an optionally substituted 5- or 6-membered heteroaryl group.

3. The compound of claim 1, wherein R is selected from an optionally substituted phenyl ring, an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, or an optionally substituted 5- or 6-membered heteroaryl.

4. The compound according to claim 1, wherein R and R 1 Each is an optionally substituted benzene ring or a methyl group.

5. The compound according to any one of claims 1 to 4, wherein X is CR 3 , Y is CR 4 and Z is CR 5 .

6. The compound according to any one of claims 1 to 4, wherein X is CR 3 , Y is CR 4 And Z is N.

7. The compound according to any one of claims 1 to 4, wherein R 3 is H, CN, F, Br, cyclopropyl or an optionally substituted 5- or 6-membered heteroaryl.

8. The compound according to claim 7, wherein R 3 It's H.

9. The compound according to any one of claims 1 to 4, wherein R 4 and / or R 5 is halogen, and the halogen is F.

10. The compound according to any one of claims 1 to 4, wherein R 4 and R 5 It's H.

11. The compound according to any one of claims 1 to 4, wherein L is NR 8 .

12. The compound according to claim 11, wherein R 7 Is butyl, pentyl, cyclohexyl, 13. The compound according to any one of claims 1 to 4, wherein L is absent and R 7 yes 14. A compound, wherein the compound is: 1-(2,3-diphenylquinolin-6-yl)-3-(2-hydroxybutyl)urea; (R)-1-(2,3-diphenylquinolin-6-yl)-3-(2-hydroxybutyl)urea; 1-Butyl-3-(2,3-diphenylquinolin-6-yl)urea; 1-(2,3-bis(2-fluorophenyl)quinolin-6-yl)-3-(2-hydroxybutyl)urea; 1-Butyl-3-(5-(2-hydroxypyridin-3-yl)-2,3-diphenylquinolin-6-yl)urea; 1-(2,3-bis(2-methoxyphenyl)quinolin-6-yl)-3-(2-hydroxybutyl)urea; 1-(3-(2-fluorophenyl)-2-phenylquinolin-6-yl)-3-(2-hydroxybutyl)urea; 1-(2-(2-fluorophenyl)-3-phenylquinolin-6-yl)-3-(2-hydroxybutyl)urea; 1-(2,3-bis(2-methoxypyridin-4-yl)quinolin-6-yl)-3-(2-hydroxybutyl)urea; 1-(2-Hydroxybutyl)-3-(3-(2-methoxyphenyl)-2-phenylquinolin-6-yl)urea; 1-(2,3-bis(6-methoxypyridin-3-yl)quinolin-6-yl)-3-(2-hydroxybutyl)urea; 1-(2-Hydroxybutyl)-3-(2-(2-methoxyphenyl)-3-phenylquinolin-6-yl)urea; 1-(2,3-bis(2-methoxypyridin-3-yl)quinolin-6-yl)-3-(2-hydroxybutyl)urea; 1-(2,3-bis(2-fluorophenyl)quinolin-6-yl)-3-butylurea; (R)-1-(3-(2-fluorophenyl)-2-phenylquinolin-6-yl)-3-(2-hydroxybutyl)urea; 1-Butyl-3-(3-(2-fluorophenyl)-2-phenylquinolin-6-yl)urea; 1-(2,3-bis(4-fluorophenyl)quinolin-6-yl)-3-(2-hydroxybutyl)urea; 1-(3-(2-fluorophenyl)-2-(2-methoxyphenyl)quinolin-6-yl)-3-(2-hydroxybutyl)urea; 1-(2,3-di(pyridin-3-yl)quinolin-6-yl)-3-(2-hydroxybutyl)urea; (R)-1-(2,3-bis(2-fluorophenyl)quinolin-6-yl)-3-(2-hydroxybutyl)urea; 1-(2,3-bis(3-acetylphenyl)quinolin-6-yl)-3-(2-hydroxybutyl)urea; 1-(2,3-Bis(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; 6-(3-(2-hydroxybutyl)ureido)-2,3-diphenylquinoline-4-carboxylic acid methyl ester; 6-(3-(2-hydroxybutyl)ureido)-2,3-diphenylquinoline-4-carboxamide; (E)-1-(2-hydroxybutyl)-3-(3-phenyl-2-phenylvinylquinolin-6-yl)urea; N-(2-(3-(2-fluorophenyl)-6-(3-(2-hydroxybutyl)ureido)quinolin-2-yl)phenyl)acetamide; 1-(2-hydroxybutyl)-3-(2-methyl-3-phenylquinolin-6-yl)urea; 1-(2-(2-cyanophenyl)-3-(2-fluorophenyl)quinolin-6-yl)-3-(2-hydroxybutyl)urea; 1-(2-(2-aminophenyl)-3-(2-fluorophenyl)quinolin-6-yl)-3-(2-hydroxybutyl)urea; 1-(2-([1,1'-biphenyl]-4-yl)-3-phenylquinolin-6-yl)-3-(2-hydroxybutyl)urea; 1-(2-Hydroxybutyl)-3-(2-phenethyl-3-phenylquinolin-6-yl)urea; (R)-6-(3-(2-hydroxybutyl)ureido)-2,3-diphenylquinoline-4-carboxamide; 1-(2-(2-ethoxyphenyl)-3-phenylquinolin-6-yl)-3-(2-hydroxybutyl)urea; 1-(2-Hydroxybutyl)-3-(2-(2-isobutoxyphenyl)-3-phenylquinolin-6-yl)urea; 1-(2-ethynyl-3-phenylquinolin-6-yl)-3-(2-hydroxybutyl)urea; 1-(2-ethyl-3-phenylquinolin-6-yl)-3-(2-hydroxybutyl)urea; 6-(3-(2-hydroxybutyl)ureido)-N-methyl-2,3-diphenylquinoline-4-carboxamide; 6-(3-(2-hydroxybutyl)ureido)-N,N-dimethyl-2,3-diphenylquinoline-4-carboxamide; N-cyclopropyl-6-(3-(2-hydroxybutyl)ureido)-2,3-diphenylquinoline-4-carboxamide; 6-(3-(2-hydroxybutyl)ureido)-2,3-diphenylquinoline-4-carboxylic acid; 6-(3-(2-hydroxybutyl)ureido)-2-methyl-3-phenylquinoline-4-carboxamide; (S)-1-(3-(2-fluorophenyl)-2-phenylquinolin-6-yl)-3-(2-hydroxybutyl)urea; (S)-1-(2,3-diphenylquinolin-6-yl)-3-(2-hydroxybutyl)urea; 6-(3-(2-hydroxybutyl)ureido)-2,3-dimethylquinoline-4-carboxamide; 1-(4-cyano-2,3-diphenylquinolin-6-yl)-3-(2-hydroxybutyl)urea; 6-(3-(2-hydroxybutyl)ureido)-3-phenylquinoline-4-carboxamide; (R)-1-(2-hydroxybutyl)-3-(2-methyl-3-phenylquinolin-6-yl)urea; 3-(2-Fluorophenyl)-6-(3-(2-hydroxybutyl)ureido)-2-methylquinoline-4-carboxamide; 1-(3-(2-fluorophenyl)-2-methylquinolin-6-yl)-3-(2-hydroxybutyl)urea; 1-Butyl-3-(2-methyl-3-phenylquinolin-6-yl)urea; 1-(2-methoxybutyl)-3-(2-methyl-3-phenylquinolin-6-yl)urea; 1-(2-methoxyethyl)-3-(2-methyl-3-phenylquinolin-6-yl)urea; 1-(2-Hydroxybutyl)-3-(2-methyl-3-(pyridin-3-yl)quinolin-6-yl)urea; 1-(2-Hydroxybutyl)-3-(2-methyl-3-(o-tolyl)quinolin-6-yl)urea; 1-(3-(2-chlorophenyl)-2-methylquinolin-6-yl)-3-(2-hydroxybutyl)urea; 1-(2-Hydroxybutyl)-3-(2-methyl-3-(1-methyl-1H-pyrazol-4-yl)quinolin-6-yl)urea; (R)-1-(2-hydroxybutyl)-3-(2-methyl-3-(o-tolyl)quinolin-6-yl)urea; N-(6-(3-(2-hydroxybutyl)ureido)-2,3-diphenylquinolin-4-yl)acetamide; 1-(2,5-dimethyl-3-phenylquinolin-6-yl)-3-(2-hydroxybutyl)urea; 1-(5-cyclopropyl-2-methyl-3-phenylquinolin-6-yl)-3-(2-hydroxybutyl)urea; 1-(5-Bromo-2-methyl-3-phenylquinolin-6-yl)-3-(2-hydroxybutyl)urea; 1-(2-Hydroxybutyl)-3-(3-phenyl-2-(trifluoromethyl)quinolin-6-yl)urea; (S)-1-(2-hydroxybutyl)-3-(2-methyl-3-phenylquinolin-6-yl)urea; (R)-1-(7-fluoro-2,3-diphenylquinolin-6-yl)-3-(2-hydroxybutyl)urea; 1-(4-(dimethylamino)-2,3-diphenylquinolin-6-yl)-3-(2-hydroxybutyl)urea; (R)-N-(6-(3-(2-hydroxybutyl)ureido)-2,3-diphenylquinolin-4-yl)cyclopropanecarboxamide; N-(6-(3-(2-hydroxybutyl)ureido)-2-methyl-3-phenylquinolin-4-yl)acetamide; N-(6-(3-(2-hydroxybutyl)ureido)-2,3-diphenylquinolin-4-yl)methanesulfonamide; 1-(4-amino-2,3-diphenylquinolin-6-yl)-3-(2-hydroxybutyl)urea; (R)-1-(2-hydroxybutyl)-3-(2-methyl-5-(1-methyl-1H-pyrazol-4-yl)-3-phenylquinolin-6-yl)urea; 1-(2-Hydroxybutyl)-3-(4-(oxazol-2-yl)-2,3-diphenylquinolin-6-yl)urea; 1-(4-cyano-2-methyl-3-phenylquinolin-6-yl)-3-(2-hydroxybutyl)urea; N-(1-(3-(2-methyl-3-phenylquinolin-6-yl)ureido)butan-2-yl)acetamide; (R)-1-(3-(2-fluorophenyl)-2-methylquinolin-6-yl)-3-(2-hydroxybutyl)urea; (R)-1-(2-hydroxybutyl)-3-(4-methoxy-2,3-diphenylquinolin-6-yl)urea; (R)-1-(2-hydroxybutyl)-3-(4-methoxy-2-methyl-3-phenylquinolin-6-yl)urea; (R)-1-(2-hydroxybutyl)-3-(4-methyl-2,3-diphenylquinolin-6-yl)urea; (R)-N-Benzyl-6-(3-(2-hydroxybutyl)ureido)-3-methyl-2-phenylquinoline-4-carboxamide; 1-(2,2-difluorobutyl)-3-(2-methyl-3-phenylquinolin-6-yl)urea; 6-(3-(2,2-difluorobutyl)ureido)-2,3-diphenylquinoline-4-carboxamide; 1-(2,2-difluorobutyl)-3-(2,3-diphenylquinolin-6-yl)urea; (R)-6-(3-(2-hydroxybutyl)ureido)-N,3-dimethyl-2-phenylquinoline-4-carboxamide; (R)-6-(3-(2-hydroxybutyl)ureido)-3-methyl-2-phenylquinoline-4-carboxamide; 1-(2,2-difluorobutyl)-3-(3-(2-fluorophenyl)-2-methylquinolin-6-yl)urea; (R)-1-(3-(2-fluorophenyl)-2-methyl-5-(2-oxo-1,2-dihydropyridin-3-yl)quinolin-6-yl)-3-(2-hydroxybutyl)urea; (R)-6-(3-(2-hydroxybutyl)ureido)-N-(1-methyl-1H-pyrazol-3-yl)-2,3-diphenylquinoline-4-carboxamide; (R)-1-(2,4-dimethyl-3-phenylquinolin-6-yl)-3-(2-hydroxybutyl)urea; (R)-6-(3-(2-hydroxybutyl)ureido)-3-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-2-phenylquinoline-4-carboxamide; (R)-6-(3-(2-hydroxybutyl)ureido)-3-methyl-N-(1-methyl-1H-pyrazol-3-yl)-2-phenylquinoline-4-carboxamide; 1-(3-(2-Fluorophenyl)-2-methylquinolin-6-yl)-3-(2-methoxyethyl)urea; (R)-1-(3-(3-(2-fluorophenyl)-2-phenylquinolin-6-yl)ureido)butan-2-yl dihydrogen phosphate; N-(2,3-diphenylquinolin-6-yl)hexanamide; N-(2,3-bis(2-methoxyphenyl)quinolin-6-yl)hexanamide; N-(2-(2-methoxyphenyl)-3-phenylquinolin-6-yl)-4-oxohexanamide; N-(2,3-bis(2-fluorophenyl)quinolin-6-yl)hexanamide; N-(2,3-diphenylquinolin-6-yl)-2,2-difluorohexanamide; N-(2-(2-fluorophenyl)-3-phenylquinolin-6-yl)-4-oxohexanamide; N-(2,3-bis(2-fluorophenyl)quinolin-6-yl)-4-oxohexanamide; N-(2,3-diphenylquinolin-6-yl)-4-oxohexanamide; N-(3-(2-fluorophenyl)-2-(2-methoxyphenyl)quinolin-6-yl)-4-oxohexanamide; N-(2,3-diphenylquinolin-6-yl)-4-hydroxyhexanamide; N-(2,3-bis(2-fluorophenyl)quinolin-6-yl)-4-hydroxyhexanamide; N-(3-(2-Fluorophenyl)-2-methylquinolin-6-yl)-4-hydroxyhexanamide; 4-Hydroxy-N-(2-methyl-3-phenylquinolin-6-yl)hexanamide; 1-cyclohexyl-3-(2,3-diphenylquinolin-6-yl)urea; N-(2,3-diphenylquinolin-6-yl)-4-methylpiperazine-1-carboxamide; 4-Acetyl-N-(2,3-diphenylquinolin-6-yl)piperazine-1-carboxamide; 1-allyl-3-(2,3-diphenylquinolin-6-yl)urea; 1-(2,3-diphenylquinolin-6-yl)-3-(prop-2-yn-1-yl)urea; 1-(2,3-diphenylquinolin-6-yl)-3-(2-hydroxycyclopentyl)urea; 1-(2,3-diphenylquinolin-6-yl)-3-(tetrahydro-2H-pyran-4-yl)urea; N-(2,3-diphenylquinolin-6-yl)-3-methoxypyrrolidine-1-carboxamide; 1-(2,3-diphenylquinolin-6-yl)-3-(pyridin-2-yl)urea; 1-(2,3-diphenylquinolin-6-yl)-3-phenylurea; 1-(2,3-diphenylquinolin-6-yl)-3-(1-methylpyrrolidin-3-yl)urea; 1-(2,3-diphenylquinolin-6-yl)-3-(pyridin-4-yl)urea; 1-(2,3-diphenylquinolin-6-yl)-3-(1-(hydroxymethyl)cyclopentyl)urea; 1-(2,3-diphenylquinolin-6-yl)-3-(1-methyl-1H-pyrazol-4-yl)urea; 1-(6,7-diphenyl-1,8-naphthyridin-3-yl)-3-(2-hydroxybutyl)urea; (R)-1-(6,7-diphenyl-1,8-naphthyridin-3-yl)-3-(2-hydroxybutyl)urea; or N-(6,7-diphenyl-1,8-naphthyridin-3-yl)-3-methoxypyrrolidine-1-carboxamide.

15. A pharmaceutical composition comprising a compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable vehicle.

16. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable vehicle in the preparation of a medicament for regulating acetyl-CoA synthetase short chain 2 (ACSS2) protein and thereby treating, ameliorating or preventing a disease selected from the group consisting of cancer, bacterial infection, viral infection, parasitic infection, fungal infection, neurological disorders, cerebrovascular disease, cardiovascular disease, non-alcoholic fatty liver disease and obesity; Wherein the compound of formula (I) is: ， Where X is CR 3 ; Y is CR 4 ; Z is CR 5 or N; R is selected from the group consisting of: H, an optionally substituted monocyclic or bicyclic C6-C 12 wherein R is an optionally substituted 5- or 6-membered heteroaryl, an optionally substituted C1-C6 alkyl, a monocyclic or bicyclic C3-C6 cycloalkyl, an optionally substituted C2-C6 alkenyl, and an optionally substituted C2-C6 alkynyl; 12 When the aryl group is aryl, the aryl group is unsubstituted or substituted by one or more of the following groups: halogen, OH, C1-C6 alkyl, C1-C6 alkoxy, NR 9 R 10 、C(O)R 9 NR 9 C(O)R 10 , CN or C6-C 12 aryl; when R is an optionally substituted 5- or 6-membered heteroaryl, the heteroaryl is unsubstituted or substituted with one or more of the following groups: halogen, OH, oxo, C1-C6 alkyl, or C1-C6 alkoxy; and when R is an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, or an optionally substituted C2-C6 alkynyl, the alkyl, alkenyl, or alkynyl is unsubstituted or substituted with one or more of the following groups: halogen or C6-C 12 Aryl; R 1 is selected from the group consisting of an optionally substituted monocyclic or bicyclic C6-C 12 aryl, optionally substituted 5- or 6-membered heteroaryl and C1-C6 alkyl, wherein in R 1 is an optionally substituted monocyclic or bicyclic C6-C 12 When aryl is present, the aryl group is unsubstituted or substituted by one or more of the following groups: halogen, OH, C1-C6 alkoxy, C(O)R 9 or C1-C6 alkyl; and in R 1 When is an optionally substituted 5- or 6-membered heteroaryl, the heteroaryl is unsubstituted or substituted with one or more of the following groups: halogen, OH, oxo, C1-C6 alkoxy, C(O)R 9 or C1-C6 alkyl; R 2 It is H, COOR 9 、CN、CONR 9 R 10 NR 9 R 10 NR 9 S02R 10 NR 9 COR 10 , C1-C6 alkyl, C1-C6 alkoxy, monocyclic or bicyclic C6-C 12 Aryl or 5- or 6-membered heteroaryl; R 3 is H, halogen, C1-C6 alkyl, monocyclic or bicyclic C3-C6 cycloalkyl or optionally substituted 5- or 6-membered heteroaryl, wherein R 3 When is an optionally substituted 5- or 6-membered heteroaryl, the heteroaryl is unsubstituted or substituted with one or more of the following groups: oxo, OH, C1-C6 alkoxy or C1-C6 alkyl; R 4 and R 5 are each independently selected from the group consisting of H and halogen; R 6 It is H; L is NR 8 And R 7 is an optionally substituted C3-C6 alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted monocyclic or bicyclic C6-C 12 aryl, optionally substituted 5 or 6 membered heteroaryl, optionally substituted monocyclic or bicyclic C3-C6 cycloalkyl or optionally substituted 3 to 6 membered heterocycle; wherein L is NR 8 And R 7 When it is an optionally substituted C3-C6 alkyl, an optionally substituted C2-C6 alkenyl or an optionally substituted C2-C6 alkynyl, the alkyl, alkenyl or alkynyl is unsubstituted or substituted with one or more of the following groups: OH, halogen, C1-C6 alkoxy, OPO(OH)2 or NR 9 COR 10 ; and L is NR 8 And R 7 is an optionally substituted monocyclic or bicyclic C6-C 12 aryl, optionally substituted 5- or 6-membered heteroaryl, optionally substituted monocyclic or bicyclic C3-C6 cycloalkyl, or optionally substituted 3- to 6-membered heterocycle, said aryl, heteroaryl, cycloalkyl, or heterocycle is unsubstituted or substituted with one or more of the following groups: OH or C1-C6 alkyl optionally substituted with OH; or L is absent and R 7 is an optionally substituted C3-C6 alkyl or an optionally substituted 3- to 6-membered heterocycle; wherein L is absent and R 7 is an optionally substituted C3-C6 alkyl, the alkyl is unsubstituted or substituted with one or more of the following: OH, oxo or halogen; and L is absent and R 7 When it is an optionally substituted 3- to 6-membered heterocyclic ring, the heterocyclic ring is unsubstituted or substituted with one or more of the following groups: C1-C6 alkyl, C1-C6 alkoxy or COR 9 ; R 8 is H; and wherein R is a monocyclic or bicyclic C6-C 12 Aryl and the aryl is NR 9 R 10 、C(O)R 9 and / or NR 9 C(O)R 10 When replaced, then R 9 and R 10 Each is independently selected from the group consisting of: H and C1-C6 alkyl; In R 1 Is a monocyclic or bicyclic C6-C 12 Aryl and the aryl is C(O)R 9 When replaced, then R 9 Selected from the group consisting of: H and C1-C6 alkyl; In R 1 is an optionally substituted 5- or 6-membered heteroaryl and the heteroaryl is C(O)R 9 When replaced, then R 9 Selected from the group consisting of: H and C1-C6 alkyl; In R 2 It is COOR 9 ,CONR 9 R 10 NR 9 R 10 NR 9 S02R 10 or NR 9 COR 10 When R 9 and R 10 are each independently selected from the group consisting of: H, an optionally substituted monocyclic or bicyclic C6-C 12 aryl, optionally substituted 5- or 6-membered heteroaryl, optionally substituted C1-C6 alkyl or monocyclic or bicyclic C3-C6 cycloalkyl; wherein in R 9 and / or R 10 is an optionally substituted 5- or 6-membered heteroaryl or an optionally substituted monocyclic or bicyclic C6-C 12 When the heteroaryl or aryl group is aryl, the heteroaryl or aryl group is unsubstituted or substituted with one or more C1-C6 alkyl groups; and in R 9 and / or R 10 When it is an optionally substituted C1-C6 alkyl group, the alkyl group is unsubstituted or substituted with one or more of the following groups: a 5- or 6-membered heteroaryl group optionally substituted with a C1-C6 alkyl group, or a C6-C6 alkyl group optionally substituted with a C1-C6 alkyl group. 12 Aryl; In L is NR 8 And R 7 is a C3-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl group and the alkyl, alkenyl or alkynyl group is NR 9 COR 10 When replaced, then R 9 and R 10 Each is independently selected from the group consisting of: H and C1-C6 alkyl; In the absence of L and R 7 is a 3- to 6-membered heterocyclic ring and the heterocyclic ring is COR 9 When replaced, then R 9 and R 10 Each is independently selected from the group consisting of: H and C1-C6 alkyl; in: The heterocyclic ring comprises at least one ring atom which is a heteroatom, and the or each heteroatom is independently selected from the group consisting of oxygen, sulfur and nitrogen; A heteroaryl group includes at least one ring atom which is a heteroatom, and the or each heteroatom is independently selected from the group consisting of oxygen, sulfur and nitrogen.

17. The use according to claim 16, wherein the disease is cancer, and the cancer is selected from the group consisting of: colorectal cancer, aerodigestive tract squamous cell carcinoma, gastrointestinal stromal tumors, lung cancer, brain cancer, neuroblastoma, 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 kidney cancer.

18. The use according to claim 16, wherein the disease is a viral infection, and the viral infection is hepatitis C virus (HCV) infection or human cytomegalovirus (HCMV) infection.

19. The use according to claim 16, wherein the neurological disorder is a neurodegenerative disease.

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