Azine-based compounds as par-2 inhibitors and therapeutic uses thereof

Abstract

The present invention provides compounds that can act as PAR-2 inhibitors / antagonists. These compounds are highly advantageous for use in therapy, particularly in the treatment or prevention of pain, an autoimmune disorder, an autoinflammatory disorder, an inflammatory disorder, a central nervous system disorder, spinal cord injury, a metabolic disorder, a gastrointestinal disorder, a cardiovascular disorder, a fibrotic disorder, a respiratory disorder, a skin disorder, an allergic disorder, or cancer.

Description

[0001] New PCT patent application

[0002] Domain Therapeutics

[0003] Vossius Ref.: AJ 1028 PCT / A BS

[0004] Azine-based compounds as PAR-2 inhibitors and therapeutic uses thereof

[0005] The present application claims the benefit of priority of the international patent application PCT / EP2025 / 057283 filed 5 on March 17, 2025, which is incorporated herein by reference in its entirety.

[0006] The present invention provides novel compounds of formula (I) and pharmaceutical compositions containing these compounds. The compounds of formula (I) can act as PAR-2 inhibitors / antagonists, which renders these compounds highly advantageous for use in therapy, particularly in the treatment or prevention of pain, an autoimmune disorder, an autoinfl ammatory disorder, an inflammatory disorder, a central nervous system disorder, spinal cord injury, a metabolic disorder, a gastrointestinal disorder, a cardiovascular disorder, a fibrotic disorder, a respiratory disorder, a skin disorder, an allergic disorder, or cancer.

[0007] The protease-activated receptors (PARs) family

[0008] 15 G Protein-Coupled Receptors (GPCRs) form the largest family of human membrane proteins (~ 800 members) and are involved in many physiological processes. Compounds targeting GPCRs also represent approximately 27% of the global market for therapeutic drugs (Hauser et al., Nat. Rev. Drug Discov., 2017, 16(12):829-842).

[0009] 2% of the human genome code for proteases (also called proteinases) which suggests their importance in the correct functioning of the body (Hollenberg et al., Br. J. Pharmacol., 2014, 171 (5): 1180-94). Indeed, it has been shown that 20 certain soluble and membrane-bound proteinases can regulate cell function by cleaving GPCRs at the cell surface to activate or inactivate receptors such as the Protease-Activated Receptors (PARs). The PARs family is composed of four members (PAR-1 , PAR-2, PAR-3 and PAR-4) and belongs to the class A GPCR-receptor sub-family (Marcfarlane et al., Pharmacological Reviews, 2001, 475(7357):519-23). They are expressed in widely diverse cells such as platelets, immune cells, endothelial cells, myocytes, astrocytes, neurons, epithelial cells and fibroblasts and involved 25 in a large set of physiological and pathophysiological functions (Ossovskaya et al., Physiol. Rev., 2004, 84(2):579- 621).

[0010] PAR-2: mechanism of action

[0011] Activation of PARs involves the cleavage of the extracellular N-terminal part of the receptor by proteases at a specific 30 site. This unmasks an amino-acid sequence in the amino terminus that folds back to act as a "tethered ligand” (TL):

[0012] it binds to a conserved region in the second extracellular loop of the cleaved receptor and triggers intra-cellular signalling (Ossovskaya et al., Physiol. Rev., 2004, 84(2):579-621; Hollenberg et al., Br. J. Pharmacol., 2014, 171 (5): 1180-94).

[0013] PAR-2 is activated by several host and pathogen-derived serine proteases such as trypsin, mast cell tryptase, kallikreins and members of the coagulation cascade TF-FVIla and FVa-FXa. These proteases cleave at R34J,S35LIGKV and unmask the tethered ligand SLIGKV in humans. Artificially, in vitro, synthetic peptides corresponding to the TL (SLIGKV) can activate the receptor without cleavage.

[0014] Activation of PAR-2 induces several signalling cascades involving a number of G proteins such as Gq, G, and G12 / 13. The pathway best described so far involves its interaction with Gqand the mobilization of intracellular calcium that 40 influences the function of several cell types. After repeated activations, PAR2 is rapidly desensitized via itsendocytosis by a p-arrestin-dependent mechanism and its targeting to the lysosomes (Ossovskaya et al., Physiol. Rev., 2004, 84(2):579-621 ).

[0015] PAR-2 in physiological conditions

[0016] PAR-2 has been shown to have a key function in multiple organs (Ossovskaya et al., Physiol. Rev., 2004, 84(2):579-621). PAR-2 is expressed in the brain within neurons and glial cells. It is also found in the periphery in spinal afferent neurons and nociceptive DRG neurons. PAR-2 signalling has been involved in the survival, sensitization of these cells and their signal transmission, thereby controlling neuronal damage, inflammation and pain.

[0017] PAR-2 is involved in the function of the cardiovascular system. Indeed, its activation can induce the relaxation or contraction of some vessels such as pulmonary arteries, coronary and intramyocardial arteries, therefore regulating the blood flow. It also controls inflammation and repair of the endothelium which influences vascular permeability. PAR-2 expression has been detected within the gastrointestinal system in the small intestine, colon, liver, pancreas and stomach. Its activation has been involved in the regulation of ion transport from the intestinal mucosa, contraction of gastric longitudinal muscle, pancreatic, salivary and gastric secretions, excitation of myenteric neurons, intestinal barrier integrity, release of prostaglandins from enterocytes. PAR-2 therefore plays a key role in controlling fluid secretion, intestinal inflammation, and gastro-intestinal hyperalgesia.

[0018] PAR-2 is involved in airways function since it is expressed by epithelial and endothelial cells in the lungs. Its activation has been shown to regulate bronchodilatation or bronchoconstriction (depending on the experimental system used), ion transport in the airway epithelium, proliferation and activation of airway smooth muscle cells and lung fibroblasts. PAR-2 can thus regulate airway resistance, lung inflammation and lung fibrosis.

[0019] In the skin, PAR-2 expression has been detected in keratinocytes, microvasculature and immune cells. Its activation has been involved in skin pigmentation, skin inflammation, and wound healing.

[0020] Finally, PAR-2 expression has been detected in immune cells such as macrophages where it influences cell maturation and cytokine secretion, thereby regulating inflammation.

[0021] PAR-2 in pathological conditions

[0022] Since PAR-2 regulates numerous and diverse biological processes, it is not surprising that its dysfunction is involved in as many pathological conditions.

[0023] PAR-2 is expressed in the brain, dorsal root ganglia, spinal afferent neurons and nociceptive DRG neurons. Its activation by proteases such as the tryptase released by mast cells leads to calcium and cAMP signalling (Steinhoff et al., Nat Med, 2000, 6(2): 151 -8; Zhao et al., J Biol Chem., 2015, 290(22): 13875-87). This promotes inflammation and hyperalgesia through the release of CGRP (calcitonine gene-related peptide) and SP (substance P) from spinal afferent neurons and the sensitization of Transient Receptors Potential Vanilloid (TRPV) TRPV1 and TRPV4 in sensory neurons (Vergnolle et al., Nat Med, 2001, 6(2):151-8; Steinhoff et al., Nat Med, 2000, 6(2):151-8; Amadesi et al., JNeurosci, 2004, 24(18):4300-12; Grant et al., J Physiol, 2007, 578 (Pt 3), 715-33; Jimenez Vargas et al., Proc Natl Acad Sci USA, 2018, 115(31 ): E7438-E7447). This is supported by the large amount of in vivo data available in the literature demonstrating that inhibition of PAR-2 reduces inflammatory pain, neuropathic pain, cancer pain and treatment-induced pain in animal models (Bao et al., Expert Opin Ther Targets, 2014; 18(1):15-27; Chen et al., Neuroscience, 2011, 193, 440-51). PAR-2 is therefore clearly involved in the generation and the transmission of the pain signal, neurogenic inflammation and nociception.The expression of PAR-2 and proteases is elevated in the spinal cord after a contusion-compression injury (Radulovic et al., Neurobiol Dis, 2015, 83, 75-89; Li et al, Physiol. Res., 2019, 68(2):305-316). Its activation can result in cAMP signalling in oligodendrocytes (Yoon et al., Glia, 2017, 65(12):2070-2086). Experiments in vitro and in vivo in rodents have shown that the inhibition of PAR-2 signalling during experimental spinal cord injury reduces inflammation, scar formation and mechanical and thermal hyperalgesia and improves remyelination of oligodendrocytes and locomotor recovery (Radulovic et al., Neurobiol Dis, 2015, 83, 75-89; Li et al, Physiol. Res., 2019, 68(2):305-316; Yoon et al., Glia, 2017, 65(12):2070-2086; Li et al, Physiol. Res., 2019, 68(2):305-316 ; Wei et al, Physiol. Res., 2016, 65(1 ): 145-53). PAR-2 inhibitors can thus improve recovery from spinal cord injuries.

[0024] Disorders of the immune system are at the basis of numerous diseases. In all cases, the immune system attacks the normal constituents of the organism considering them as foreign. It becomes pathogenic and induces lesions on a specific organ (e.g., type 1 diabetes in the pancreas or multiple sclerosis in the brain) or systemically (e.g., rheumatoid arthritis or systemic lupus erythematosus, SLE).

[0025] Cytokines are small proteins involved in cell signalling that orchestrate the immune response. Their dysregulation is at the basis of the pathogenesis of autoinflammatory diseases. These conditions are characterized by immune activation, infiltration and abnormal cytokine production. They include conditions such as: rheumatologic inflammatory diseases, skin inflammatory diseases, lung inflammatory diseases, muscle inflammatory diseases, bowel inflammatory diseases, brain inflammatory diseases and autoimmune diseases.

[0026] While autoinflammatory diseases evolve chronically, some conditions can lead to an acute immune disorder. Indeed, a sudden excessive and uncontrolled release of pro-inflammatory cytokines, also called cytokine storm, has been observed in graft-versus-host disease, multiple sclerosis, pancreatitis, multiple organ dysfunction syndrome, viral diseases, bacterial infections, hemophagocytic lymphohistiocytosis, and sepsis (Gerlach H, F1000Res, 2016, 5, 2909; Tisoncik JR et al., Microbiol Mol Biol Rev, 2012, 76(1):16-32). In these conditions, a dysregulated immune response and subsequent hyperinflammation may lead to multiple organ failure that can be fatal.

[0027] Because PAR-2 influences the production of inflammatory cytokines and the function of diverse organs, numerous studies have demonstrated that it is a promising therapeutic target for various autoinflammatory diseases.

[0028] The expression of proteinases and PAR-2 is significantly increased in organs directly involved in autoinflammatory diseases such as the coronary arteries of atherosclerotic patients (Jones et al., Arterioscler Thromb Vase Biol, 2018, 38(6): 1271 -1282), the skin of atopic dermatitis and psoriasis patients (Nattkemper et al., Journal of Investigative Dermatology, 2018, 138:1311-1317), the joints of rheumatoid arthritis and osteoarthritis patients (Tindell et al., Rheum Int, 2012, 32(10):3077-86), the colon of inflammatory bowel disease patients (Christerson et al., J Crohns Colitis, 2009, 3(1):15-24; Kim et al., Inflamm Bowel Dis., 2003, 9(4):224-9), the lungs of idiopathic pulmonary fibrosis patients (Bardou et al., Am J Respir Crit Care Med, 2016, 193(8):847-60), the liver of non-alcoholic steatohepatitis patients (Rana et al., Mol Metab, 2019, 29:99-113), the area of active demyelination in the brain of multiple sclerosis patients (Noorbakhsh et al., J Exp Med, 2006, 203(2):425-35).

[0029] There, PAR-2 activation leads to calcium signalling in several cells such as osteoblasts, fibroblasts, monocytes, keratinocytes (Abraham et al, Bone, 2000, 26(1 ):7-14; Lin et al., J. Cell. Mol. Med., 2015, 19(6): 1346-56; Johansson et al., Jleukoc Biol, 2005, 78(4):967-75; Joo et al., Bio Mol Ther, 2016, 24(5):529-535). This signalling is associated with cell maturation and / or migration, activation as well as the secretion of inflammatory cytokines such as IL-8, IL-6, TN Fa and IL-113 in various cell types such as vascular smooth muscle cells, synovial cells, monocytes, keratinocytes, astrocytes, chondrocytes, adipocytes and fibroblasts (Demetz et al., Atherosclerosis, 2010, 212:466-471; Kelso etal., Arthritis Rheum, 2007, 56(3):765-71 ; Johansson et al., J Leukoc Biol, 2005, 78(4):967-75; Steven et al., Innate Immun, 2013, 19(6):663-72; Kim et al., Bio Mol Ther, 2012, 20(5):463-9; Radulovic et al., Neurobiol Dis, 2015, 83, 75-89; Lin et al., J. Cell. Mol. Med., 2015, 19(6): 1346-56; Bagher et al., Cell Communi and Signal, 2018, 16(1), 59; Huang et al, Aging, 2019, 11 (24): 12532- 12545; Bandeanlou et al., Nat. Med, 2011, 17:1490-1497). PAR-2 signalling also influences tissue remodelling through its role in the survival of key cells such as neurons and chondrocytes in central nervous system disorders and rheumatologic inflammatory diseases respectively (Afkhami-Goli et al., J Immunol, 2007, 179(8):5493-503; Huang et al., Aging, 2019, 11 (24): 12532-12545), as well as the secretion of growth factors (e.g. CTGF) and extracellular components (e.g. collagen) (Lin et al., Mol. Med, 2015, 21 (1):576-83; Chung et al., J Biol Chem, 2013, 288(52):37319-31 ). It is important to note that other signalling pathways such as cyclic AMP in alveolar macrophages and Gi in hepatocytes seem important to regulate cytokine secretion and steatosis respectively (Rayees et al., Cell Rep, 2019, 27(3):793-805.e4; Rana et al., Mol Metab, 2019, 29, 99-113).

[0030] In vivo, it has clearly been shown that the inhibition of PAR-2 signaling, either pharmacologically or by genetic modification, significantly reduced the symptoms of atherosclerosis, idiopathic pulmonary fibrosis, atopic dermatitis, multiple sclerosis, arthritis, non-alcoholic steatohepatitis and inflammatory bowel disease in mouse models (Jones et al., Arterioscler Thromb Vase Biol, 2018, 38(6): 1271 -1282; Borensztajn et al., Am J Pathol, 2010, 177(6):2753-64; Moniaga et al., Am J Pathol, 2013, 182: 841e851; Noorbakhsh et al., J Exp Med, 2006, 203(2):425-35, Ferrell et al., J Clin Invest, 2003, 111 (1):35-41 ; Rana et al., Mol Metab, 2019, 29:99-113; Hyun et al., Gut, 2008, 57(9): 1222-9). PAR-2 therefore plays a key role in the molecular and cellular mechanisms underlying the pathogenesis of autoinfl ammatory diseases.

[0031] PAR-2-dependent inflammation can also impair cellular metabolism and promote insulin resistance which then leads to the pathogenesis of diabetes, obesity and metabolic syndrome. Indeed, PAR-2 expression in adipocyte tissues has been correlated with the increasing BMI of volunteer people and the inhibition of PAR-2 signaling attenuates the symptoms of metabolic disorders in mice (Lim et al., FASEB Journal, 2013, 27(12):4757-4767; Badeanlou et al., Nat. Med, 2011, 17(11): 1490-1497).

[0032] Many airborne allergens from house dust mite and cockroach allergens contain protease activity. This protease activity can activate PAR-2 expressed on human airway epithelial cells, endothelial cells as well as immune cells and induce calcium signalling. This ultimately leads to the release of inflammatory cytokines and angiogenic response at the basis of the pathogenesis of cockroach allergy and allergic asthma (Do et al., Allergy, 2016, 71 (4):463-74; Asosingh et al., J Clin Invest, 2018, 128(7):3116-3128). In vivo, functional blockade of PAR-2 in the airways during allergen challenge improves allergen-induced inflammation and airway hyperresponsiveness in mice (Asaduzzaman et al., Clin Exp Allergy, 2015, 45(12): 1844-55).

[0033] The expression of PAR-2 and proteases is also significantly increased in many cancer types such as cervical squamous cell carcinoma, endocervical adenocarcinoma, colon adenocarcinoma, esophageal carcinoma, glioblastoma multiforme, acute myeloid leukemia, lung adenocarcinoma, lung squamous cell carcinoma, ovarian serous cystadenocarcinoma, pancreatic adenocarcinoma, prostate adenocarcinoma, rectum adenocarcinoma, stomach adenocarcinoma, testicular germ cell tumors, uterine corpus endometrial carcinoma, uterine carcinosarcoma, hepatocellular carcinoma, and breast cancer, which can be associated to poor prognosis (Kaufmann et al., Carcinogenesis, 2009, 30(9): 1487-96; Su et al., Oncogene, 2009, 28(34):3047-57; Arakaki et al., Int. J. Mol. Sci. 2018, 19, 1886). The activation of this receptor in cancer cells can lead to several signalling cascades such as calcium, p-arrestin and Gi signalling (Kaufmann et al., J Cancer Res Clin Oncol, 2011, 137 (6): 965-73; Wu et al, MolMed Rep, 2014, 10(6):3021 -6; Ge et al., J Biol Chem, 2004, 279(53):55419-24). This ultimately controls cancer cell migration, proliferation, survival, and expression of inflammatory cytokines (Jiang et al., J Pharmacol Exp Ther, 2018, 364(2):246-257; Darmoul et al., British J Cancer, 2001, 85(5):772-9; Quan et al., Oncol Res., 2019, 27(7):779-788). The expression of PAR-2 on other cells of the tumor microenvironment, such as immune cells, fibroblasts, endothelial cells and DRG neurons, can also control the immune response to cancer cells, fibrosis, as well as angiogenesis and cancer-induced pain (Mubbach et al., Mol cancer, 2016, 15(1):54; Uusitalo-Jarvinen et al., Arieriocler Thromb Vase Biol, 2007, 27(6): 1456-62; D’Andrea et al, Am J Pathol, 2001, 158(6):2031-41; Graf et al, Sci Immunol, 2019, 4(39):eaaw8405; Qian at al., Oncol Lett, 2018, 16(2): 1513-20; Tu et al, JNeurosci, 2021, 41 (1): 193-210). In vivo, the inhibition of PAR-2 has been shown to be an efficient way of reducing tumor growth and increasing survival in mouse models of different cancers such as breast cancer, liver cancer and colon cancer (Versteeg et al., Cancer Res, 2008, 68(17)7219-27; Sun et al., World J Gastroenterol, 2018, 24(10):1120-1133; Quan et al., Oncol Res., 2019, 27(7)779-788). Importantly, inhibition of PAR2 or one of its ligands led to reduced infiltration of immune-supressive Tumor Associated Macrophages and regulatory T cells while increasing cytotoxic T cells in the tumor as well as increasing antigen presenting cells in the draining lymph nodes in several syngeneic mouse models; this unleashed the anti-tumoral immune response and increased the potency of immune-checkpoint inhibitors currently used in the clinic (Graf et al, Sci Immunol, 2019, 4(39):eaaw8405). PAR-2 therefore constitutes a promising therapeutic target in oncology and immune-oncology.

[0034] Considering the role of PAR-2 in several pathophysiological conditions, inhibitors of this receptor can have therapeutic applications in a wide variety of human diseases. This has drawn a great interest from pharmaceutical industry to develop such compounds. Various PAR-2 inhibitors and therapeutic uses thereof have been proposed, for example, in: Yau et al., Expert Opin Ther Pat, 2016, 26(4):471-83; Jiang et al., J Pharmacol Exp Ther, 2018, 364(2):246-57; WO 2004 / 002418; WO 2005 / 030773; WO 2012 / 012843; WO 2012 / 026765; WO 2012 / 026766; WO 2012 / 101453; WO 2015 / 048245; WO 2016 / 154075; WO 2017 / 194716; WO 2017 / 197463; WO 2018 / 043461 (EP 3508487); WO 2018 / 057588; WO 2019 / 124567; WO 2019 / 163956 (EP 3 760631); WO 2019 / 199800; JP 2020 / 007262; WO 2021 / 106864; WO 2022 / 117882; WO 2022 / 255408; and WO 2023 / 233033. However, despite the efforts made, no PAR-2 inhibitor has reached the market yet (Yau et al., Expert Opin Ther Pat., 2016, 26 (4): 471-83). There is therefore still an unmet need for novel and / or improved PAR-2 inhibitors with high potency, selectivity and bioavailability.

[0035] The present invention addresses this need and solves the problem of providing novel and highly potent PAR-2 inhibitors / antagonists. In particular, it has surprisingly been found that the compounds of formula (I) as provided herein are potent and selective inhibitors of PAR-2 signalling, which renders these compounds advantageous for use in therapy, including in particular in the treatment or prevention of pain, an autoimmune disorder, an autoinflammatory disorder, an inflammatory disorder, a central nervous system disorder, spinal cord injury, a metabolic disorder, a gastrointestinal disorder, a cardiovascular disorder, a fibrotic disorder, a respiratory disorder, a skin disorder, an allergic disorder, or cancer.Accordingly, the present invention provides a compound of the following formula (I)

[0036]

[0037] wherein said compound is selected from the compounds of Examples 1 to 275 (as described herein below in the examples section) or a pharmaceutically acceptable salt or solvate thereof, preferably from the compounds of Examples 73 to 275 or a pharmaceutically acceptable salt or solvate thereof. These compounds share a common scaffold, as illustrated by formula (I) depicted above. The groups / variables in formula (I) are explained further below.

[0038] It is particularly preferred that the compound of formula (I) is any one of the compounds of Examples 75, 77, 79, 81, 83, 85, 89, 91, 93, 95, 97, 99, 101, 103, 105, 109, 117, 119, 121, 125, 127, 129, 131, 135, 137, 139, 145, 147, 149, 151, 153, 159, 167, 169, 171, 175, 177, 179, 181, 183, 185, 187, 193, 195, 197, 201, 203, 209, 211, 213, 215, 216, 222, 224, 226, 233, 234, 235, 236, 237, 239, 241, 243, 245, 247, 250, 254, 255, 256, 257, 259, 260, 261, 262, 263, 271 or 273, or a pharmaceutically acceptable salt or solvate thereof.

[0039] Accordingly, it is particularly preferred that the compound of formula (I) is selected from:

[0040] 6-(4-(5-((cyclopentylmethyl)amino)-6-isopropylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;

[0041] 6-(4-(5-(isopentylamino)-6-isopropylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid; 6-(4-(6-(cyclobutylmethyl)-5-((cyclohexylmethyl)amino)pyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;

[0042] 6-(4-(5-((4-chloro-3-fluorophenyl)amino)-6-ethylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;

[0043] 6-(4-(5-((4-chloro-3-fluorophenyl)amino)-6-cyclobutylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;

[0044] 6-(4-(5-((4-chloro-3-fluorophenyl)amino)-6-cyclopropylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;

[0045] 6-(4-(6-isopropyl-5-((4-(trifluoromethyl)benzyl)amino)pyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;

[0046] 6-(4-(6-(tert-butyl)-5-((4-chloro-3-fluorophenyl)amino)pyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;

[0047] 6-(4-(6-isopropyl-5-((4-(trifluoromethyl)phenethyl)amino)pyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;6-(4-(5-((2-cyclohexylethyl)amino)-6-isopropylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;

[0048] (R)-6-(4-(6-isopropyl-5-((1-phenylethyl)amino)pyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;

[0049] (R)-6-(4-(5-((2,3-dihydro-1 H-inden-1-yl)amino)-6-isopropylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;

[0050] 6-(4-(6-cyclobutyl-5-((cyclohexylmethyl)amino)pyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;

[0051] 6-(4-(6-cyclobutyl-5-(isopentylamino)pyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid; 6-(4-(6-cyclobutyl-5-((4-fluorobenzyl)amino)pyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;

[0052] 6-(4-(5-(isobutylamino)-6-isopropylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid; 6-(4-(5-((2,3-dihydro-1 H-inden-2-yl)amino)-6-isopropylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;

[0053] 6-(4-(5-((cyclopropylmethyl)amino)-6-isopropylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;

[0054] (R)-6-(4-(5-((cyclohexylmethyl)amino)-6-(1-methoxyethyl)pyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;

[0055] (R)-6-(4-(5-(isopentylamino)-6-(1-methoxyethyl)pyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;

[0056] (R)-6-(4-(5-((4-fluorobenzyl)amino)-6-(1-methoxyethyl)pyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;

[0057] 6-(4-(6-isopropyl-5-((2-(4-methoxycyclohexyl)ethyl)amino)pyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;

[0058] 6-(4-(5-(isopentylamino)-6-(tetrahydro-2H-pyran-4-yl)pyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;

[0059] 6-(4-(6-(cyclopropylmethyl)-5-(isopentylamino)pyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;

[0060] (S)-6-(4-(6-isopropyl-5-((2-phenylpropyl)amino)pyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;

[0061] 6-(4-(5-((cyclohexylmethyl)amino)-6-(cyclopropylmethyl)pyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;

[0062] 6-(4-(5-((cyclohexylmethyl)amino)-6-(tetrahydro-2H-pyran-4-yl)pyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;

[0063] 6-(4-(6-(cyclobutylmethyl)-5-((4-fluorobenzyl)amino)pyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;

[0064] 6-(4-(5-((2-cyclopropylethyl)amino)-6-isopropylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;

[0065] 6-(4-(6-(cyclobutylmethyl)-5-(isopentylamino)pyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;6-(4-(6-isopropyl-5-((2-(3-methoxybicyclo[1.1.1]pentan-1-yl)ethyl)amino)pyrazine-2-carbonyl)-3,3-dimethylpiperazin- 1 -y I )-2, 4-d i methy In i coti n i c acid;

[0066] 6-(4-(5-(butylamino)-6-isopropylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;

[0067] 6-(4-(5-((4-chloro-3-fluorobenzyl)amino)-6-isopropylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;

[0068] 6-(4-(5-((cyclobutylmethyl)amino)-6-isopropylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;

[0069] 6-(4-(6-isopropyl-5-(((1-methylcyclobutyl)methyl)amino)pyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;

[0070] 6-(4-(6-cyclopropyl-5-(isopentylamino)pyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid; 6-(4-(6-isopropyl-5-(neopentylamino)pyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid; 6-(4-(5-((2-cyclobutyl-2-methoxyethyl)amino)-6-isopropylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;

[0071] 6-(4-(6-cyclopropyl-5-((4-(trifluoromethyl)benzyl)amino)pyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;

[0072] 6-(4-(5-((cyclohexylmethyl)amino)-6-cyclopropylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;

[0073] 6-(4-(6-isopropyl-5-((4-methoxybenzyl)amino)pyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;

[0074] 6-(4-(5-((2-(1 ,3-dihydroisobenzofuran-5-yl)ethyl)amino)-6-isopropylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)- 2,4-dimethy Inicotinic acid;

[0075] 6-(4-(5-((3,3-dimethylbutyl)amino)-6-isopropylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;

[0076] 6-(4-(6-isopropyl-5-((2-(tetrahydro-2H-pyran-4-yl)ethyl)amino)pyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;

[0077] 6-(4-(5-(((2,3-dihydrobenzo[b][1 ,4]dioxin-2-yl)methyl)amino)-6-isopropylpyrazine-2-carbonyl)-3,3-dimethylpiperazin- 1 -y I )-2, 4-d i methy In i coti n i c acid;

[0078] 6-(4-(6-isopropyl-5-((pyrazin-2-ylmethyl)amino)pyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;

[0079] 6-(4-(5-((2,4-dichlorobenzyl)amino)-6-isopropylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;

[0080] 6-(4-(6-isopropyl-5-(((1-(methoxymethyl)cyclopentyl)methyl)amino)pyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)- 2,4-dimethy Inicotinic acid;

[0081] 6-(4-(6-isopropyl-5-(((1-methylcyclohexyl)methyl)amino)pyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;

[0082] 6-(4-(6-isopropyl-5-(((4-(trifluoromethyl)cyclohexyl)methyl)amino)pyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)- 2,4-dimethy Inicotinic acid;

[0083] 6-(4-(5-(((4,4-difluorocyclohexyl)methyl)amino)-6-isopropylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;

[0084] 4-(6-(cyclohex-1-en-1-yl)-5-((cyclohexylmethyl)amino)pyrazine-2-carbonyl)-3,3-dimethylpiperazin-2-one;6-(4-(6-isopropyl-5-(((4-methylcyclohexyl)methyl)amino)pyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;

[0085] 6-(4-(5-(((3,3-difluorocyclopentyl)methyl)amino)-6-isopropylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;

[0086] 6-(4-(5-(((3,3-difluorocyclohexyl)methyl)amino)-6-isopropylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;

[0087] 4-(5-(isopentylamino)-6-isopropylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-2-one;

[0088] 4-(6-(cyclobutylethynyl)-5-((cyclohexylmethyl)amino)pyrazine-2-carbonyl)-3,3-dimethylpiperazin-2-one;

[0089] 4-(5-((cyclopentylmethyl)amino)-6-isopropylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-2-one;

[0090] 4-(5-((cyclohexylmethyl)amino)-6-isopropylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-2-one;

[0091] 4-(6-isopropyl-5-((thiazol-2-ylmethyl)amino)pyrazine-2-carbonyl)-3,3-dimethylpiperazin-2-one;

[0092] 6-(4-(6-isopropyl-5-((thiophen-2-ylmethyl)amino)pyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;

[0093] 6-(4-(6-isopropyl-5-((thiophen-3-ylmethyl)amino)pyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;

[0094] 6-(4-(5-((cyclopentylmethyl)amino)-6-isopropylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-3-methylpicolinic acid;

[0095] 2-(4-(5-((cyclopentylmethyl)amino)-6-isopropylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-5-methylthiazole-4-carboxylic acid;

[0096] 2-(4-(5-((cyclopentylmethyl)amino)-6-isopropylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-4-methylthiazole-5-carboxylic acid;

[0097] 4-(5-((cyclopentylmethyl)amino)-6-((trimethylsilyl)ethynyl)pyrazine-2-carbonyl)-3,3-dimethylpiperazin-2-one; 6-(4-(5-(((3-fluorocyclopentyl)methyl)amino)-6-isopropylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;

[0098] 4-(6-isopropyl-5-((2-methoxybenzyl)amino)pyrazine-2-carbonyl)-3,3-dimethylpiperazin-2-one;

[0099] 2-(4-(5-((cyclopentylmethyl)amino)-6-isopropylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)thiazole-4-carboxamide;

[0100] 2-(4-(5-((cyclopentylmethyl)amino)-6-isopropylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-5-methylthiazole-4-carboxamide;

[0101] 2-(4-(5-((cyclopentylmethyl)amino)-6-isopropylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-4,6-dimethylpyrimidine-5-carboxylic acid;

[0102] (5-((cyclopentylmethyl)amino)-6-isopropylpyrazin-2-yl)(2,2-dimethylpiperidin-1-yl)methanone;

[0103] (5-((cyclopentylmethyl)amino)-6-isopropylpyrazin-2-yl)(3,3-dimethylmorpholino)methanone;

[0104] 4-(5-((4-chlorobenzyl)amino)-6-isopropylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-2-one;

[0105] 4-(5-((cyclopentylmethyl)amino)-6-ethynylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-2-one;

[0106] 6-(4-(5-((cyclopentylmethyl)amino)-6-isopropylpicolinoyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid; and 5-bromo-6-(4-(5-((cyclopentylmethyl)amino)-6-isopropylpicolinoyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;

[0107] or a pharmaceutically acceptable salt or solvate of any one of the aforementioned compounds.It will be understood that any reference in the present specification to a (or the) "compound of formula (I)” or to the "compounds of formula (I)” relates, in particular, to any of the compounds listed in the preceding paragraph.

[0108] Even more preferably, the compound of formula (I) is any one of the compounds of Examples 85, 149 or 167, or a pharmaceutically acceptable salt or solvate thereof:

[0109]

[0110] 6-(4-(5-(isopentylamino)-6-isopropylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid (compound of Example 85)

[0111]

[0112] 6-(4-(6-(cyclobutylmethyl)-5-((cyclohexylmethyl)amino)pyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4- dimethylnicotinic acid

[0113] (compound of Example 149)

[0114]

[0115] 6-(4-(5-((cyclopentylmethyl)amino)-6-isopropylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid

[0116] (compound of Example 167)

[0117] The present invention also relates to a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, in combination with a pharmaceutically acceptable excipient. Accordingly, the invention relates to a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising any of the aforementioned entities and a pharmaceutically acceptable excipient, for use as a medicament.The invention further relates to a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising any of the aforementioned entities and a pharmaceutically acceptable excipient, for use in the treatment or prevention of a PAR-2 mediated disease or disorder. Thus, the invention in particular provides a pharmaceutical composition comprising, as an active ingredient, a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, together with a pharmaceutically acceptable excipient, for use in the treatment or prevention of a PAR-2 mediated disease or disorder.

[0118] Moreover, the present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof in the preparation of a medicament for the treatment or prevention of a PAR-2 mediated disease or disorder.

[0119] The invention likewise relates to a method of treating or preventing a PAR-2 mediated disease or disorder, the method comprising administering a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising any of the aforementioned entities in combination with a pharmaceutically acceptable excipient, to a subject (preferably a human) in need thereof. It will be understood that a therapeutically effective amount of the compound of formula (I) or the pharmaceutically acceptable salt or solvate thereof (or of the pharmaceutical composition) is to be administered in accordance with this method.

[0120] As explained above, the disease or disorder to be treated or prevented with a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof (or a corresponding pharmaceutical composition) in accordance with the present invention includes any PAR-2 mediated disease or disorder. It is preferred that the disease / disorder to be treated or prevented in accordance with the invention is pain (e.g., chronic pain), an autoimmune disorder, an autoinfl ammatory disorder, an inflammatory disorder (e.g., a rheumatologic inflammatory disorder, a skin inflammatory disorder, a lung inflammatory disorder, a muscle inflammatory disorder, a bowel inflammatory disorder, or a brain inflammatory disorder), a central nervous system disorder, spinal cord injury, a metabolic disorder, a gastrointestinal disorder, a cardiovascular disorder, a fibrotic disorder, a respiratory disorder, a skin disorder, an allergic disorder, or cancer. More preferably, the disease / disorder to be treated or prevented in accordance with the present invention is selected from neuropathic pain, inflammatory pain, cancer pain, post-operative incision pain, fracture pain, osteoporotic fracture pain, gout joint pain, chronic pain, spinal cord injury, atopic dermatitis, contact dermatitis, dry skin dermatitis, seborrhoeic dermatitis, arthritis, rheumatoid arthritis, osteoarthritis, psoriasis, psoriatic arthritis, multiple sclerosis, non-alcoholic steatohepatitis (NASH), obesity (e.g., diet-induced obesity), diabetes (e.g., type 1 diabetes or type 2 diabetes), adipose inflammation, pancreatitis, metabolic syndrome, PAR-2 associated metabolic dysfunction, periodontitis, gingivitis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, peptic ulcer disease (e.g., gastric ulcer or duodenal ulcer), infectious enteritis, irritable bowel syndrome, atherosclerosis, asthma, interstitial lung disease, pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis), rheumatoid arthritis-associated interstitial lung disease, liver fibrosis, cystic fibrosis, renal fibrosis, peritoneal fibrosis, pancreatic fibrosis, intestinal fibrosis, cardiac fibrosis, skin fibrosis, systemic lupus erythematosus (SLE), scleroderma, skin eczema, acne, rosacea, post-inflammatory hyperpigmentation, lichen planus, pruritus, polymyositis, vasculitis, Wegener's granulomatosis (or granulomatosis with polyangiitis), Netherton syndrome, dermatomyositis, uveitis, liver cirrhosis,Alzheimer's disease, Parkinson's disease, dust mite allergy (e.g., house dust mite allergy), cockroach allergy, allergic asthma, colorectal cancer (e.g., colorectal carcinoma), colon cancer (e.g., colon adenocarcinoma), gastrointestinal cancer, gastric cancer (or stomach cancer; e.g., stomach adenocarcinoma), rectal cancer (e.g., rectum adenocarcinoma), anal cancer, liver cancer (e.g., hepatocellular carcinoma), breast cancer (e.g., triple-negative breast cancer, including in particular COX-2 expressing triple-negative breast cancer, or breast cancer having a BRCA1 and / or BRCA2 gene mutation), pancreatic cancer (e.g., pancreatic adenocarcinoma or pancreatic ductal adenocarcinoma), cervical cancer (e.g., cervical squamous cell carcinoma or endocervical adenocarcinoma), prostate cancer (e.g., prostate adenocarcinoma or hormone-refractory prostate cancer), ovarian cancer (e.g., ovarian carcinoma or ovarian serous cystadenocarcinoma), endometrial cancer (e.g., uterine corpus endometrial carcinoma), vaginal cancer, vulvar cancer, uterine cancer (e.g., uterine corpus cancer, uterine sarcoma, or uterine carcinosarcoma), testicular cancer, germ cell cancer (e.g., testicular germ cell cancer), esophageal cancer, laryngeal cancer, mouth cancer, hematological cancer, leukemia (e.g., acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, or chronic lymphocytic leukemia), lymphoma (e.g., Hodgkin lymphoma or non-Hodgkin lymphoma, such as, e.g., follicular lymphoma, diffuse large B-cell lymphoma, or lymphoid neoplasm diffuse large B-cell lymphoma), multiple myeloma, lung cancer (e.g., non-small cell lung cancer (including, e.g., lung adenocarcinoma or lung squamous cell carcinoma), small cell lung cancer, large cell lung carcinoma, lung carcinoid tumor, adenoid cystic carcinoma of the lung, pulmonary lymphoma, or pulmonary sarcoma), adrenal gland cancer (e.g., adrenocortical carcinoma), biliary tract cancer, bile duct cancer (e.g., cholangiocarcinoma), hepatobiliary cancer, genitourinary cancer, urothelial cancer (e.g., urothelial carcinoma), bladder cancer (e.g., bladder urothelial carcinoma), gallbladder cancer (e.g., gallbladder carcinoma), head and / or neck cancer (e.g., head and neck cancer, or head and neck squamous cell carcinoma), kidney cancer (e.g., kidney chromophobe, kidney renal cell carcinoma, kidney renal clear cell carcinoma, or kidney renal papillary cell carcinoma), mesothelioma, sarcoma, skin cancer, melanoma (e.g., skin cutaneous melanoma, or uveal melanoma), Merkel-cell cancer (e.g., Merkel-cell carcinoma), epidermoid cancer, thyroid cancer (e.g., papillary thyroid cancer, follicular thyroid cancer, medullary thyroid cancer, anaplastic thyroid cancer, or thyroid carcinoma), thymus cancer (or thymic cancer; e.g., thymoma), squamous cell cancer (or squamous cell carcinoma; including, e.g., oral squamous cell carcinoma / squamous-cell mouth carcinoma, squamous-cell skin cancer, squamous-cell lung carcinoma, squamous-cell thyroid carcinoma, squamous-cell esophageal carcinoma, or squamous-cell vaginal carcinoma), goblet cell cancer (e.g., goblet cell carcinoid), spleen cancer, bone cancer (e.g., osteosarcoma or osteogenic sarcoma), fibrosarcoma, Ewing's sarcoma, Kaposi's sarcoma, neuroendocrine cancer (e.g., neuroendocrine carcinoma), neuroblastoma, or brain cancer (e.g., glioblastoma). The cancer to be treated may further be a carcinoma or a sarcoma. The cancer to be treated or prevented (including any one of the aforementioned specific types of cancer) may also be a relapsed or refractory cancer. Moreover, the cancer to be treated or prevented (including any one of the aforementioned specific types of cancer) may also be a metastatic cancer.

[0121] The treatment can be used as first, second or third line therapy against cancer. When used as first line therapy in resectable solid tumors, it can be administered in a neoadjuvant or adjuvant setting or both.

[0122] As explained above, the cancer to be treated in accordance with the present invention may also be a hematological cancer (e.g., a lymphoma or a leukemia). Thus, for example, the hematological cancer may be selected from: Hodgkin's lymphoma, including, e.g., nodular sclerosing subtype of Hodgkin's lymphoma, mixed-cellularity subtype of Hodgkin's lymphoma, lymphocyte-rich subtype of Hodgkin's lymphoma, or lymphocyte-depleted subtype ofHodgkin's lymphoma; non-Hodgkin's lymphoma, including, e.g., follicular non-Hodgkin's lymphoma, mantle cell lymphoma, or diffuse non-Hodgkin's lymphoma (e.g., diffuse large B-cell lymphoma or Burkitt's lymphoma); nodular lymphocyte predominant Hodgkin's lymphoma; peripheral / cutaneous T-cell lymphoma, including, e.g., mycosis fungoides, Sezary syndrome, T-zone lymphoma, lymphoepithelioid lymphoma (e.g., Lennert's lymphoma), or peripheral T-cell lymphoma; lymphosarcoma; a malignant immunoproliferative disorder, including, e.g., Waldenstrom's macroglobulinemia, alpha heavy chain disease, gamma heavy chain disease (e.g., Franklin's disease), or an immunoproliferative small intestinal disease (e.g., Mediterranean disease); multiple myeloma, including, e.g., Kahler's disease, or myelomatosis; plasma cell leukemia; lymphoid leukemia, including, e.g., acute lymphoblastic leukemia, chronic lymphocytic leukemia, subacute lymphocytic leukemia, prolymphocytic leukemia, hairy-cell leukemia (e.g., leukemic reticuloendotheliosis), or adult T-cell leukemia; myeloid leukemia, including, e.g., acute myeloid leukemia, chronic myeloid leukemia, subacute myeloid leukemia, myeloid sarcoma (e.g., chloroma, or granulocytic sarcoma), acute promyelocytic leukemia, or acute myelomonocytic leukemia; a myeloproliferative neoplastic disorder, including, e.g., polycythemia vera, essential thrombocythemia, or idiopathic myelofibrosis; monocytic leukemia; acute erythraemia or erythroleukemia, including, e.g., acute erythraemic myelosis, or Di Guglielmo's disease; chronic erythraemia, including, e.g., Heilmeyer-Schdner disease; acute megakaryoblastic leukemia; mast cell leukemia; acute panmyelosis; acute myelofibrosis; and Letterer-Siwe disease.

[0123] In particular, the disease / disorder to be treated or prevented in accordance with the present invention may be selected from neuropathic pain, inflammatory pain, cancer pain, post-operative incision pain, fracture pain, osteoporotic fracture pain, gout joint pain, chronic pain, spinal cord injury, atopic dermatitis, contact dermatitis, dry skin dermatitis, seborrhoeic dermatitis, arthritis, rheumatoid arthritis, osteoarthritis, psoriasis, psoriatic arthritis, multiple sclerosis, non-alcoholic steatohepatitis (NASH), obesity (e.g., diet-induced obesity), diabetes (e.g., type 1 diabetes or type 2 diabetes), adipose inflammation, pancreatitis, metabolic syndrome, PAR-2 associated metabolic dysfunction, periodontitis, gingivitis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, peptic ulcer disease (e.g., gastric ulcer or duodenal ulcer), infectious enteritis, irritable bowel syndrome, atherosclerosis, asthma, interstitial lung disease, pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis), rheumatoid arthritis-associated interstitial lung disease, liver fibrosis, cystic fibrosis, renal fibrosis, peritoneal fibrosis, pancreatic fibrosis, intestinal fibrosis, cardiac fibrosis, skin fibrosis, systemic lupus erythematosus (SLE), scleroderma, skin eczema, acne, rosacea, post-inflammatory hyperpigmentation, lichen planus, pruritus, polymyositis, vasculitis, Wegener's granulomatosis (or granulomatosis with polyangiitis), Netherton syndrome, dermatomyositis, uveitis, liver cirrhosis, Alzheimer's disease, Parkinson's disease, dust mite allergy (e.g., house dust mite allergy), cockroach allergy, allergic asthma, colorectal cancer, colon cancer (e.g., colon adenocarcinoma), gastric cancer (e.g., stomach adenocarcinoma), rectal cancer (e.g., rectum adenocarcinoma), liver cancer (e.g., hepatocellular carcinoma), breast cancer, pancreatic cancer (e.g., pancreatic adenocarcinoma or pancreatic ductal adenocarcinoma), cervical cancer (e.g., cervical squamous cell carcinoma or endocervical adenocarcinoma), prostate cancer (e.g., prostate adenocarcinoma), ovarian cancer (e.g., ovarian serous cystadenocarcinoma), endometrial cancer (e.g., uterine corpus endometrial carcinoma), uterine sarcoma (e.g., uterine carcinosarcoma), germ cell cancer (e.g., testicular germ cell cancer), esophageal cancer, leukemia (e.g., acute myeloid leukemia), lung cancer (e.g., non-small cell lung cancer (including, e.g., lung adenocarcinoma or lung squamous cell carcinoma), small cell lung cancer, large cell lung carcinoma, lung carcinoid tumor, adenoid cystic carcinoma of the lung, pulmonary lymphoma, or pulmonary sarcoma), adrenal gland cancer (e.g., adrenocortical carcinoma), bile duct cancer (e.g., cholangiocarcinoma), bladder cancer (e.g., bladder urothelialcarcinoma), head and neck cancer, kidney cancer (e.g., kidney chromophobe, kidney renal cell carcinoma, kidney renal clear cell carcinoma, or kidney renal papillary cell carcinoma), lymphoma (e.g., lymphoid neoplasm diffuse large B-cell lymphoma), mesothelioma, sarcoma, melanoma (e.g., skin cutaneous melanoma, or uveal melanoma), thyroid carcinoma, thymus cancer (e.g., thymoma), or glioblastoma.

[0124] Accordingly, the present invention particularly relates to a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising any of the aforementioned entities and a pharmaceutically acceptable excipient, for use in the treatment or prevention of neuropathic pain, inflammatory pain, cancer pain, post-operative incision pain, fracture pain, osteoporotic fracture pain, gout joint pain, chronic pain, spinal cord injury, atopic dermatitis, contact dermatitis, dry skin dermatitis, seborrhoeic dermatitis, arthritis, rheumatoid arthritis, osteoarthritis, psoriasis, psoriatic arthritis, multiple sclerosis, non-alcoholic steatohepatitis (NASH), obesity (e.g., diet-induced obesity), diabetes (e.g., type 1 diabetes or type 2 diabetes), adipose inflammation, pancreatitis, metabolic syndrome, PAR-2 associated metabolic dysfunction, periodontitis, gingivitis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, peptic ulcer disease (e.g., gastric ulcer or duodenal ulcer), infectious enteritis, irritable bowel syndrome, atherosclerosis, asthma, interstitial lung disease, pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis), rheumatoid arthritis-associated interstitial lung disease, liver fibrosis, cystic fibrosis, renal fibrosis, peritoneal fibrosis, pancreatic fibrosis, intestinal fibrosis, cardiac fibrosis, skin fibrosis, systemic lupus erythematosus (SLE), scleroderma, skin eczema, acne, rosacea, post-inflammatory hyperpigmentation, lichen planus, pruritus, polymyositis, vasculitis, Wegener's granulomatosis (or granulomatosis with polyangiitis), Netherton syndrome, dermatomyositis, uveitis, liver cirrhosis, Alzheimer's disease, Parkinson's disease, dust mite allergy (e.g., house dust mite allergy), cockroach allergy, allergic asthma, colorectal cancer (e.g., colorectal carcinoma), colon cancer (e.g., colon adenocarcinoma), gastrointestinal cancer, gastric cancer (or stomach cancer; e.g., stomach adenocarcinoma), rectal cancer (e.g., rectum adenocarcinoma), anal cancer, liver cancer (e.g., hepatocellular carcinoma), breast cancer (e.g., triple-negative breast cancer, including in particular COX-2 expressing triple-negative breast cancer, or breast cancer having a BRCA1 and / or BRCA2 gene mutation), pancreatic cancer (e.g., pancreatic adenocarcinoma or pancreatic ductal adenocarcinoma), cervical cancer (e.g., cervical squamous cell carcinoma or endocervical adenocarcinoma), prostate cancer (e.g., prostate adenocarcinoma or hormone-refractory prostate cancer), ovarian cancer (e.g., ovarian carcinoma or ovarian serous cystadenocarcinoma), endometrial cancer (e.g., uterine corpus endometrial carcinoma), vaginal cancer, vulvar cancer, uterine cancer (e.g., uterine corpus cancer, uterine sarcoma, or uterine carcinosarcoma), testicular cancer, germ cell cancer (e.g., testicular germ cell cancer), esophageal cancer, laryngeal cancer, mouth cancer, hematological cancer, leukemia (e.g., acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, or chronic lymphocytic leukemia), lymphoma (e.g., Hodgkin lymphoma or nonHodgkin lymphoma, such as, e.g., follicular lymphoma, diffuse large B-cell lymphoma, or lymphoid neoplasm diffuse large B-cell lymphoma), multiple myeloma, lung cancer (e.g., non-small cell lung cancer (including, e.g., lung adenocarcinoma or lung squamous cell carcinoma), small cell lung cancer, large cell lung carcinoma, lung carcinoid tumor, adenoid cystic carcinoma of the lung, pulmonary lymphoma, or pulmonary sarcoma), adrenal gland cancer (e.g., adrenocortical carcinoma), biliary tract cancer, bile duct cancer (e.g., cholangiocarcinoma), hepatobiliary cancer, genitourinary cancer, urothelial cancer (e.g., urothelial carcinoma), bladder cancer (e.g., bladder urothelial carcinoma), gallbladder cancer (e.g., gallbladder carcinoma), head and / or neck cancer (e.g., head and neck cancer, or head and neck squamous cell carcinoma), kidney cancer (e.g., kidney chromophobe, kidney renal cell carcinoma,kidney renal clear cell carcinoma, or kidney renal papillary cell carcinoma), mesothelioma, sarcoma, skin cancer, melanoma (e.g., skin cutaneous melanoma, or uveal melanoma), Merkel-cell cancer (e.g., Merkel-cell carcinoma), epidermoid cancer, thyroid cancer (e.g., papillary thyroid cancer, follicular thyroid cancer, medullary thyroid cancer, anaplastic thyroid cancer, or thyroid carcinoma), thymus cancer (or thymic cancer; e.g., thymoma), squamous cell cancer (or squamous cell carcinoma; including, e.g., oral squamous cell carcinoma / squamous-cell mouth carcinoma, squamous-cell skin cancer, squamous-cell lung carcinoma, squamous-cell thyroid carcinoma, squamous-cell esophageal carcinoma, or squamous-cell vaginal carcinoma), goblet cell cancer (e.g., goblet cell carcinoid), spleen cancer, bone cancer (e.g., osteosarcoma or osteogenic sarcoma), fibrosarcoma, Ewing's sarcoma, Kaposi's sarcoma, neuroendocrine cancer (e.g., neuroendocrine carcinoma), neuroblastoma, or brain cancer (e.g., glioblastoma).

[0125] The present invention further relates to a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising any of the aforementioned entities and a pharmaceutically acceptable excipient, for use in the treatment or prevention of neuropathic pain, inflammatory pain, cancer pain, postoperative incision pain, fracture pain, osteoporotic fracture pain, gout joint pain, chronic pain, spinal cord injury, atopic dermatitis, contact dermatitis, dry skin dermatitis, seborrhoeic dermatitis, arthritis, rheumatoid arthritis, osteoarthritis, psoriasis, psoriatic arthritis, multiple sclerosis, non-alcoholic steatohepatitis (NASH), obesity (e.g., diet-induced obesity), diabetes, adipose inflammation, pancreatitis, metabolic syndrome, PAR-2 associated metabolic dysfunction, periodontitis, gingivitis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, peptic ulcer disease (e.g., gastric ulcer or duodenal ulcer), infectious enteritis, irritable bowel syndrome, atherosclerosis, asthma, interstitial lung disease, pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis), rheumatoid arthritis-associated interstitial lung disease, liver fibrosis, cystic fibrosis, renal fibrosis, peritoneal fibrosis, pancreatic fibrosis, intestinal fibrosis, cardiac fibrosis, skin fibrosis, systemic lupus erythematosus (SLE), scleroderma, skin eczema, acne, rosacea, post-inflammatory hyperpigmentation, lichen planus, pruritus, polymyositis, vasculitis, Wegener's granulomatosis (or granulomatosis with polyangiitis), Netherton syndrome, dermatomyositis, uveitis, liver cirrhosis, Alzheimer's disease, Parkinson's disease, dust mite allergy (e.g., house dust mite allergy), cockroach allergy, allergic asthma, or cancer (e.g., colorectal cancer, colon cancer (e.g., colon adenocarcinoma), gastric cancer (e.g., stomach adenocarcinoma), rectal cancer (e.g., rectum adenocarcinoma), liver cancer (e.g., hepatocellular carcinoma), breast cancer, pancreatic cancer (e.g., pancreatic adenocarcinoma or pancreatic ductal adenocarcinoma), cervical cancer (e.g., cervical squamous cell carcinoma or endocervical adenocarcinoma), prostate cancer (e.g., prostate adenocarcinoma), ovarian cancer (e.g., ovarian serous cystadenocarcinoma), endometrial cancer (e.g., uterine corpus endometrial carcinoma), uterine sarcoma (e.g., uterine carcinosarcoma), germ cell cancer (e.g., testicular germ cell cancer), esophageal cancer, leukemia (e.g., acute myeloid leukemia), lung cancer (e.g., lung adenocarcinoma or lung squamous cell carcinoma), adrenal gland cancer (e.g., adrenocortical carcinoma), bile duct cancer (e.g., cholangio carcinoma), bladder cancer (e.g., bladder urothelial carcinoma), head and neck cancer, kidney cancer (e.g., kidney chromophobe, kidney renal cell carcinoma, kidney renal clear cell carcinoma, or kidney renal papillary cell carcinoma), lymphoma (e.g., lymphoid neoplasm diffuse large B-cell lymphoma), mesothelioma, sarcoma, melanoma (e.g., skin cutaneous melanoma, or uveal melanoma), thyroid carcinoma, thymus cancer (e.g., thymoma), or glioblastoma.The present invention also relates to a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein said compound is conjugated via a linker to a membrane anchor. The corresponding conjugate can be employed in place of the compound of formula (I) for any use or purpose described in the present specification, e.g., for use in the treatment or prevention of a PAR-2 mediated disease or disorder, including any of the diseases / disorders mentioned herein above. Such conjugates are advantageous in that they allow to tether the conjugated compound of formula (I) to a cell membrane in the proximity of PAR-2 and, thus, to facilitate its interaction with PAR-2.

[0126] The membrane anchor may be any moiety that is capable of inserting / partitioning into a lipid membrane (preferably a cell membrane), particularly a hydrophobic moiety or a lipid moiety; the conjugated compound of formula (I) is thereby "anchored” to the corresponding lipid membrane. For example, the membrane anchor may be a

[0127]

[0128] alkanoyl group (e.g., a hexadecanoyl group, -CO-(CH2)i4-CH3), cholesterol, cholestanol, a sphingolipid, or glycophosphatidylinositol (GPI). The membrane anchor may also be, e.g., a moiety of formula (II), (III), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV) or (XV) as described and defined in WO 2017 / 197463, particularly on pages 10 to 15 of WO 2017 / 197463 which is incorporated herein by reference. The membrane anchor may further be, e.g., a raftophile A or A', or a moiety of any one of the formulae 2, 200a to 200m, 3, 300a to 300g, 4a, 400aa to 400ap, 4b, 400ba, 5a, 500aa to 500ae, 5b, 500ba, 6, 600, 7, 700, 700a to 700c, 8a, 800a, 8b, 9, 900, 10, 1000, 11, 1100a, 1100b, 12, 1200a, 1200b, 13a, 1300aa to 1300ac, 13b, 1300b, 14a, 1400aa to 1400ae, 14b, 1400b, 14c, 15, 1500a, 16, 1600a, 18a, 1800a to 1800d, 18b, 19a, 1900a, 19b or 1900b, as described and defined in WO 2005 / 097199 which is incorporated herein by reference.

[0129] The linker is covalently bound to the membrane anchor and to the compound of formula (I) (or the pharmaceutically acceptable salt or solvate thereof). While the linker is not particularly limited, it preferably has a length of about 1 nm to about 50 nm, and / or it preferably provides a distance of at least 8 atoms between the compound of formula (I) and the membrane anchor. For example, the linker may comprise (or consist of) one or more polyethylene glycol (PEG) units, or may comprise (or consist of) a peptide (which may be composed of, e.g., 2 to 200 amino acid residues). The linker may also be, e.g., a moiety of formula (IV), (XX), (XXI) or (XXII) as described and defined in WO 2017 / 197463, particularly on pages 15 to 18 of WO 2017 / 197463 which is incorporated herein by reference. The linker may further be, e.g., a linker B or B', or a moiety of any one of the formulae 20, 2000, 2001, 21, 2100, 2101, 22, 23, 28 or 28a, as described and defined in WO 2005 / 097199 which is incorporated herein by reference. It will be understood that the linker may be attached to the membrane anchor via any suitable chemical linkage, e.g. via an amide linkage or via an ester linkage. Likewise, the linker may be attached to the compound of formula (I) (or the pharmaceutically acceptable salt or solvate thereof) via any suitable chemical linkage, e.g. via an amide linkage or via an ester linkage. While the linker may be attached at any position (or to any functional group) of the compound of formula (I) or the pharmaceutically acceptable salt or solvate thereof, it is preferred that the linker is attached to the moiety -N(-RA)-RB, particularly to one of the groups RAor RB, to the heterocyclyl formed from RAor RB, or to a substituent Rc.

[0130] Moreover, the linker and the membrane anchor may together form, e.g., any one of the moieties described to be attached to a PAR-2 inhibitor in WO 2017 / 197463 (which is incorporated herein by reference), or to a PAR-2 modulating compound in WO 2017 / 173347 (which is incorporated herein by reference), or to a pharmacophore inWO 2005 / 097199 (which is incorporated herein by reference). Suitable protocols for the preparation of corresponding linkers and membrane anchors are also described in these documents.

[0131] In particular, the invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein said compound is conjugated via a linker to a membrane anchor, wherein the membrane anchor is a C12-20 alkanoyl group (e.g., a hexadecanoyl group, -CO-(CH2)i4-CH3).

[0132] A corresponding exemplary conjugate may be prepared, e.g., by coupling a compound of formula (I) having a carboxylic acid group (wherein said a carboxylic acid group preferably forms part of the moiety -N(-RA)-RB), or a pharmaceutically acceptable salt or solvate thereof, with the compound N-(1-amino-26-methyl-12,25-dioxo-3,6,9,16,19,22-hexaoxa-13,26-diazaoctacosan-28-yl)-N-methylpalmitamide (e.g., analogously as described in Example 227 of WO 2022 / 117882 or in Example 261 of WO 2023 / 233033, both of which are incorporated herein by reference). The present invention thus provides a compound of formula (I) having a carboxylic acid group (preferably a carboxylic acid group which forms part of the moiety -N(-RA)-RB) (including, e.g., any one of the specific compounds of formula (I) having a carboxylic acid group which are described in the examples section herein below), or a pharmaceutically acceptable salt or solvate thereof, wherein the carboxylic acid group (-COOH) is replaced by the following group:

[0133]

[0134] The present invention furthermore relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof as an inhibitor of protease-activated receptor 2 (PAR-2) in research, particularly as a research tool compound for inhibiting PAR-2. Accordingly, the invention refers to the in vitro use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof as a PAR-2 inhibitor and, in particular, to the in vitro use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof as a research tool compound acting as a PAR-2 inhibitor. The invention likewise relates to a method, particularly an in vitro method, of inhibiting PAR-2, the method comprising the application of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof. The invention further relates to a method of inhibiting PAR-2, the method comprising applying a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof to a test sample (e.g., a biological sample) or a test animal (i.e., a non-human test animal). The invention also refers to a method, particularly an in vitro method, of inhibiting PAR-2 in a sample (e.g., a biological sample), the method comprising applying a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof to said sample. The present invention further provides a method of inhibiting PAR-2, the method comprising contacting a test sample (e.g., a biological sample) or a test animal (i.e., a non-human test animal) with a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof. The terms "sample”, "test sample” and "biological sample” include, without being limited thereto: a cell, a cell culture or a cellular or subcellular extract; biopsied material obtained from an animal (e.g., a human), or an extract thereof; or blood, serum, plasma, saliva, urine, feces, or any other body fluid, or an extract thereof. It is to be understood that the term “in vitro" is used in this specific context in the sense of "outside a living human or animal body”, which includes, in particular, experiments performed with cells, cellular or subcellular extracts, and / or biologicalmolecules in an artificial environment such as an aqueous solution or a culture medium which may be provided, e.g., in a flask, a test tube, a Petri dish, a microtiter plate, etc.

[0135] As explained above, the compounds according to the present invention share a common structural scaffold, which is illustrated by formula (I):

[0136]

[0137] In formula (I), the ring atom X is N or C(-R5).

[0138] R1is a group R11, and R2is a group -L2-R21; or alternatively, R1and R2are mutually joined to form, together with the nitrogen atom that they are attached to, a heterocyclyl which is optionally substituted with one or more groups R24.

[0139] R11is selected from hydrogen, C1-5 alkyl, C1-5 haloalkyl, and -CO(Ci-5 alkyl).

[0140] L2is selected from a bond, C1-8 alkylene, C2-8 alkenylene, and C2-8 alkynylene, wherein said alkylene, said alkenylene and said alkynylene are each optionally substituted with one or more groups R22, and wherein one or more -CH2-units comprised in said alkylene, said alkenylene or said alkynylene are each optionally replaced by a group independently selected from -CO-, -O-, -S-, -SO-, -SO2-, -NH- and -N(CI-5 alkyl)-.

[0141] R21is selected from carbocyclyl, heterocyclyl, C1-8 alkyl, and C1-8 haloalkyl, wherein said carbocyclyl and said heterocyclyl are each optionally substituted with one or more groups R23, and wherein one or more -CH2- units comprised in said alkyl or in said haloalkyl are each optionally replaced by -O-.

[0142] Each R22is independently selected from -OH, -O(Ci-5 alkyl), -O(Ci-5 alkylene)-OH, -O(Ci-5 alkylene)-O(Ci-5 alkyl), -SH, -S(Ci.5alkyl), -S(Ci.5alkylene)-SH, -S(Ci.5alkylene)-S(Ci.5alkyl), -NH2, -NH(CI.5alkyl), -N(CI.5alkyl)(Ci.5alkyl), -NH-OH, -N(CI.5alkyl)-OH, -NH-O(CI.5alkyl), -N(CI.5alkyl)-O(Ci.5alkyl), halogen, C1.5 haloalkyl, -O-(Ci.5haloalkyl), -ON, -SF5, -OHO, -CO-(Ci.5alkyl), -COOH, -CO-O-(Ci.5alkyl), -O-CO-(Ci.5alkyl), -CO-NH2, -CO-NH(CI.5alkyl), -CO-N(CI.5 alkyl)(Ci.5alkyl), -NH-CO-(CI.5alkyl), -N(CI.5alkyl)-CO-(Ci.5alkyl), -NH-COO(CI.5alkyl), -N(CI.5alkyl)-COO(Ci.5 alkyl), -O-CO-NH(CI.5alkyl), -O-CO-N(CI.5alkyl)(Ci.5alkyl), -SO2-NH2, -SO2-NH(CI.5alkyl), -SO2-N(CI.5 alkyl)(Ci.5 alkyl), -NH-SO2-(CI.5alkyl), -N(CI.5alkyl)-SO2-(Ci-5 alkyl), -SO-(Ci.5alkyl), -SO2-(Ci.5alkyl), carbocyclyl, heterocyclyl, and -Lz-Rz, wherein said carbocyclyl and said heterocyclyl are each optionally substituted with one or more groups RCyc.Each R23is independently selected from C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, -(C0-3 alkylene)-OH, -(C0-3 alkylene)-O(Ci-5 alkyl), -(C0-3 alkylene)-O(Ci-5 alkylene)-OH, -(C0-3 alkylene)-O(Ci-5 alkylene)-O(Ci-5 alkyl), -(C0-3 alkylene)-SH, -(C0-3 alkylene)-S(Ci-5 alkyl), -(C0-3 alkylene)-S(Ci-5 alkylene)-SH, -(C0-3 alkylene)-S(Ci-5 alkylene)-S(Ci-5 alkyl), -(C0-3 alkylene)-NH2, -(C0-3 alkylene)-NH(Ci-5 alkyl), -(C0-3 alkylene)-N(Ci-5 alkyl)(Ci-5 alkyl), -(C0-3 alkylene)-NH-OH, -(C0-3 alkylene)-N(Ci_5alkyl)-OH, -(C0-3 alkylene)-NH-O(Ci.5alkyl), -(C0-3 alkylene)-N(Ci-5 alkyl)-O(Ci-5 alkyl), -(C0-3 alkylene)-halogen, -(C0-3 alkylene)-(Ci-5 haloalkyl), -(C0-3 alkylene)-O-(Ci-5 haloalkyl), -(C0-3 alkylene)-CN, -(C0-3 alkylene)-SF5, -(C0-3 alkylene)-CHO, -(C0-3 alkylene)-CO-(Ci-5 alkyl), -(C0-3 alkylene)-COOH, -(C0-3 alkylene)-CO-O-(Ci-5 alkyl), -(C0-3 alkylene)-O-CO-(Ci-5 alkyl), -(C0-3 alkylene)-CO-NH2, -(C0-3 alkylene)-CO-NH(Ci-5 alkyl), -(C0-3 alkylene)-CO-N(Ci-5 alkyl)(Ci-5 alkyl), -(C0-3 alkylene)-NH-CO-(Ci-5 alkyl), -(C0-3 alkylene)-N(Ci-5 alkyl)-CO-(Ci-5 alkyl), -(C0-3 alkylene)-NH-COO(Ci-5 alkyl), -(C0-3 alkylene)-N(Ci-5 alkyl)-COO(Ci-5 alkyl), -(C0-3 alkylene)-O-CO-NH(Ci-5 alkyl), -(C0-3 alkylene)-O-CO-N(Ci-5 alkyl)(Ci-5 alkyl), -(C0-3 alkylene)-SO2-NH2, -(C0-3 alkylene)-SO2-NH(Ci-5 alkyl), -(C0-3 alkylene)-SO2-N(Ci-5 alkyl)(Ci-5 alkyl), -(C0-3 alkylene)-NH-SO2-(Ci-5 alkyl), -(C0-3 alkylene)-N(Ci-5 alkyl)-SO2-(Ci-5 alkyl), -(C0-3 alkylene)-SO-(Ci-5 alkyl), -(C0-3 alkylene)-SO2-(Ci-5 alkyl), -(C0-3 alkylene)-carbocyclyl, -(C0-3 alkylene)-heterocyclyl, and -Lz-Rz, wherein the carbocyclyl group in said -(C0-3 alkylene)-carbocyclyl and the heterocyclyl group in said -(C0-3 alkylene)-heterocyclyl are each optionally substituted with one or more groups RCyc.

[0143] Each R24is independently selected from C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, -(C0-3 alkylene)-OH, -(C0-3 alkylene)-O(Ci-5 alkyl), -(C0-3 alkylene)-O(Ci-5 alkylene)-OH, -(C0-3 alkylene)-O(Ci-5 alkylene)-O(Ci-5 alkyl), -(C0-3 alkylene)-SH, -(C0-3 alkylene)-S(Ci-5 alkyl), -(C0-3 alkylene)-S(Ci-5 alkylene)-SH, -(C0-3 alkylene)-S(Ci-5 alkylene)-S(Ci-5 alkyl), -(C0-3 alkylene)-NH2, -(C0-3 alkylene)-NH(Ci-5 alkyl), -(C0-3 alkylene)-N(Ci-5 alkyl)(Ci-5 alkyl), -(C0-3 alkylene)-NH-OH, -(C0-3 alkylene)-N(Ci.5alkyl)-OH, -(C0-3 alkylene)-NH-O(Ci.5alkyl), -(C0-3 alkylene)-N(Ci-5 alkyl)-O(Ci-5 alkyl), -(C0-3 alkylene)-halogen, -(C0-3 alkylene)-(Ci-5 haloalkyl), -(C0-3 alkylene)-O-(Ci-5 haloalkyl), -(C0-3 alkylene)-CN, -(C0-3 alkylene)-SF5, -(C0-3 alkylene)-CHO, -(C0-3 alkylene)-CO-(Ci-5 alkyl), -(C0-3 alkylene)-COOH, -(C0-3 alkylene)-CO-O-(Ci-5 alkyl), -(C0-3 alkylene)-O-CO-(Ci-5 alkyl), -(C0-3 alkylene)-CO-NH2, -(C0-3 alkylene)-CO-NH(Ci-5 alkyl), -(C0-3 alkylene)-CO-N(Ci-5 alkyl)(Ci-5 alkyl), -(C0-3 alkylene)-NH-CO-(Ci-5 alkyl), -(C0-3 alkylene)-N(Ci-5 alkyl)-CO-(Ci-5 alkyl), -(C0-3 alkylene)-NH-COO(Ci-5 alkyl), -(C0-3 alkylene)-N(Ci-5 alkyl)-COO(Ci-5 alkyl), -(C0-3 alkylene)-O-CO-NH(Ci-5 alkyl), -(C0-3 alkylene)-O-CO-N(Ci-5 alkyl)(Ci-5 alkyl), -(C0-3 alkylene)-SO2-NH2, -(C0-3 alkylene)-SO2-NH(Ci-5 alkyl), -(C0-3 alkylene)-SO2-N(Ci-5 alkyl)(Ci-5 alkyl), -(C0-3 alkylene)-NH-SO2-(Ci-5 alkyl), -(C0-3 alkylene)-N(Ci-5 alkyl)-SO2-(Ci-5 alkyl), -(C0-3 alkylene)-SO-(Ci-5 alkyl), -(C0-3 alkylene)-SO2-(Ci-5 alkyl), -(C0-3 alkylene)-carbocyclyl, -(C0-3 alkylene)-heterocyclyl, and -Lz-Rz, wherein the carbocyclyl group in said -(C0-3 alkylene)-carbocyclyl and the heterocyclyl group in said -(C0-3 alkylene)-heterocyclyl are each optionally substituted with one or more groups RCyc.

[0144] R3is selected from C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, -(C0-5 alkylene)-carbocyclyl, and -(C0-5 alkylene)-heterocyclyl, wherein said alkyl, said alkenyl, said alkynyl, the alkylene group in said -(C0-5 alkylene)-carbocyclyl, and the alkylene group in said -(C0-5 alkylene)-heterocyclyl are each optionally substituted with one or more groups R31, and wherein the carbocyclyl group in said -(C0-5 alkylene)-carbocyclyl and the heterocyclyl group in said -(C0-5 alkylene)-heterocyclyl are each optionally substituted with one or more groups R32.Each R31is independently selected from -OH, -O(Ci-5 alkyl), -O(Ci-5 alkylene)-OH, -O(Ci-5 alkylene)-O(Ci-5 alkyl), -SH, -S(Ci.5alkyl), -S(Ci.5alkylene)-SH, -S(Ci_5alkylene)-S(Ci_5alkyl), -NH2, -NH(Ci.5alkyl), -N(Ci_5alkyl)(Ci_5alkyl), -NH-OH, -N(Ci_5alkyl)-OH, -NH-O(CI.5alkyl), -N(CI.5alkyl)-O(Ci_5alkyl), -Si(Ci_5alkyl)(Ci_5alkyl)(Ci_5alkyl), halogen, C1-5 haloalkyl, -O-(Ci-5 haloalkyl), -ON, -SF5, -CHO, -CO-(Ci-5 alkyl), -COOH, -CO-O-(Ci-5 alkyl), -O-CO-(Ci-5 alkyl), -CO-NH2, -CO-NH(CI.5 alkyl), -CO-N(CI.5alkyl)(Ci_5alkyl), -NH-CO-(CI.5alkyl), -N(CI.5alkyl)-CO-(Ci.5alkyl), -NH-COO(CI.5 alkyl), -N(CI.5alkyl)-COO(Ci.5alkyl), -O-CO-NH(CI.5alkyl), -O-CO-N(CI.5alkyl)(Ci_5alkyl), -SO2-NH2, -SO2-NH(CI.5 alkyl), -SO2-N(CI.5alkyl)(Ci_5alkyl), -NH-SO2-(CI.5alkyl), -N(CI.5alkyl)-SO2-(Ci.5alkyl), -SO-(Ci-5 alkyl), -SO2-(Ci-5 alkyl), carbocyclyl, heterocyclyl, and -Lz-Rz, wherein said carbocyclyl and said heterocyclyl are each optionally substituted with one or more groups Rc c.

[0145] Each R32is independently selected from C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, -(C0-3 alkylene)-OH, -(C0-3 alkylene)-O(Ci-5 alkyl), -(C0-3 alkylene)-O(Ci-5 alkylene)-OH, -(C0-3 alkylene)-O(Ci-5 alkylene)-O(Ci-5 alkyl), -(C0-3 alkylene)-SH, -(C0-3 alkylene)-S(Ci-5 alkyl), -(C0-3 alkylene)-S(Ci-5 alkylene)-SH, -(C0-3 alkylene)-S(Ci-5 alkylene)-S(Ci-5 alkyl), -(C0-3 alkylene)-NH2, -(C0-3 alkylene)-NH(Ci-5 alkyl), -(C0-3 alkylene)-N(Ci-5 alkyl)(Ci-5 alkyl), -(C0-3 alkylene)-NH-OH, -(C0-3 alkylene)-N(Ci_5alkyl)-OH, -(C0-3 alkylene)-NH-O(Ci.5alkyl), -(C0-3 alkylene)-N(Ci-5 alkyl)-O(Ci-5 alkyl), -(C0-3 alkylene)-halogen, -(C0-3 alkylene)-(Ci-5 haloalkyl), -(C0-3 alkylene)-O-(Ci-5 haloalkyl), -(C0-3 alkylene)-CN, -(C0-3 alkylene)-SF5, -(C0-3 alkylene)-CHO, -(C0-3 alkylene)-CO-(Ci-5 alkyl), -(C0-3 alkylene)-COOH, -(C0-3 alkylene)-CO-O-(Ci-5 alkyl), -(C0-3 alkylene)-O-CO-(Ci-5 alkyl), -(C0-3 alkylene)-CO-NH2, -(C0-3 alkylene)-CO-NH(Ci-5 alkyl), -(C0-3 alkylene)-CO-N(Ci-5 alkyl)(Ci-5 alkyl), -(C0-3 alkylene)-NH-CO-(Ci-5 alkyl), -(C0-3 alkylene)-N(Ci-5 alkyl)-CO-(Ci-5 alkyl), -(C0-3 alkylene)-NH-COO(Ci-5 alkyl), -(C0-3 alkylene)-N(Ci-5 alkyl)-COO(Ci-5 alkyl), -(C0-3 alkylene)-O-CO-NH(Ci-5 alkyl), -(C0-3 alkylene)-O-CO-N(Ci-5 alkyl)(Ci-5 alkyl), -(C0-3 alkylene)-SO2-NH2, -(C0-3 alkylene)-SO2-NH(Ci-5 alkyl), -(C0-3 alkylene)-SO2-N(Ci-5 alkyl)(Ci-5 alkyl), -(C0-3 alkylene)-NH-SO2-(Ci-5 alkyl), -(C0-3 alkylene)-N(Ci-5 alkyl)-SO2-(Ci-5 alkyl), -(C0-3 alkylene)-SO-(Ci-5 alkyl), -(C0-3 alkylene)-SO2-(Ci-5 alkyl), -(C0-3 alkylene)-carbocyclyl, -(C0-3 alkylene)-heterocyclyl, and -Lz-Rz, wherein the carbocyclyl group in said -(C0-3 alkylene)-carbocyclyl and the heterocyclyl group in said -(C0-3 alkylene)-heterocyclyl are each optionally substituted with one or more groups Rc c.

[0146] R4and R5(if present) are each independently selected from hydrogen, C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, -(C0-3 alkylene)-OH, -(C0-3 alkylene)-O(Ci-5 alkyl), -(C0-3 alkylene)-O(Ci-5 alkylene)-OH, -(C0-3 alkylene)-O(Ci-5 alkylene)-O(Ci-5 alkyl), -(C0-3 alkylene)-SH, -(C0-3 alkylene)-S(Ci-5 alkyl), -(C0-3 alkylene)-S(Ci-5 alkylene)-SH, -(C0-3 alkylene)-S(Ci-5 alkylene)-S(Ci-5 alkyl), -(C0-3 alkylene)-NH2, -(C0-3 alkylene)-NH(Ci-5 alkyl), -(C0-3 alkylene)-N(Ci-5 alkyl)(Ci-5alkyl), -(C0-3 alkylene)-NH-OH, -(C0-3 alkylene)-N(Ci.5alkyl)-OH, -(C0-3 alkylene)-NH-O(Ci.5alkyl), -(C0-3 alkylene)-N(Ci-5 alkyl)-O(Ci-5 alkyl), -(C0-3 alkylene)-halogen, -(C0-3 alkylene)-(Ci-5 haloalkyl), -(C0-3 alkylene)-O-(Ci-5 haloalkyl), -(C0-3 alkylene)-CN, -(C0-3 alkylene)-SF5, -(C0-3 alkylene)-CHO, -(C0-3 alkylene)-CO-(Ci-5 alkyl), -(C0-3 alkylene)-COOH, -(C0-3 alkylene)-CO-O-(Ci-5 alkyl), -(C0-3 alkylene)-O-CO-(Ci-5 alkyl), -(C0-3 alkylene)-CO-NH2, -(C0-3 alkylene)-CO-NH(Ci-5 alkyl), -(C0-3 alkylene)-CO-N(Ci-5 alkyl)(Ci-5 alkyl), -(C0-3 alkylene)-NH-CO-(Ci-5 alkyl), -(C0-3 alkylene)-N(Ci-5 alkyl)-CO-(Ci-5 alkyl), -(C0-3 alkylene)-NH-COO(Ci-5 alkyl), -(C0-3 alkylene)-N(Ci-5 alkyl)-COO(Ci-5 alkyl), -(C0-3 alkylene)-O-CO-NH(Ci-5 alkyl), -(C0-3 alkylene)-O-CO-N(Ci-5 alkyl)(Ci-5 alkyl), -(C0-3 alkylene)-SO2-NH2, -(C0-3 alkylene)-SO2-NH(Ci-5 alkyl), -(C0-3 alkylene)-SO2-N(Ci-5 alkyl)(Ci-5 alkyl), -(C0-3 alkylene)-NH-SO2-(Ci-5 alkyl), -(C0-3 alkylene)-N(Ci-5 alkyl)-SO2-(Ci-5 alkyl), -(C0-3 alkylene)-SO-(Ci-5 alkyl), -(C0-3alkylene)-SC>2-(Ci-5 alkyl), -(C0-3 alkylene)-carbocyclyl, and -(C0-3 alkylene)-heterocyclyl, wherein the carbocyclyl group in said -(C0-3 alkylene)-carbocyclyl and the heterocyclyl group in said -(C0-3 alkylene)-heterocyclyl are each optionally substituted with one or more groups F .

[0147] RAand RBare each independently selected from hydrogen, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, -(Co-8 alkylene)-OH, -(Co-8 alkylene)-O(Ci-5 alkyl), -(Co-8 alkylene)-SH, -(Co-8 alkylene)-S(Ci-5 alkyl), -(C1-8 alkylene)-NH2, -(C1-8 alkylene)-NH(Ci-5 alkyl), -(C1-8 alkylene)-N(Ci-5 alkyl)(Ci-5 alkyl), -(C1-8 alkylene)-halogen, -(C1-8 alkylene)-Ci-5 haloalkyl, -(Co-8 alkylene)-O-(Ci-8 haloalkyl), -(Co-8 alkylene)-CN, -(Co-8 alkylene)-SF5, -(Co-8 alkylene)-CHO, -(Co-8 alkylene)-CO-(Ci-5 alkyl), -(Co-8 alkylene)-COOH, -(Co-8 alkylene)-CO-O-(Ci-5 alkyl), -(Co-8 alkylene)-O-CO-(Ci-5 alkyl), -(Co-8 alkylene)-CO-NH2, -(Co-8 alkylene)-CO-NH(Ci-5 alkyl), -(Co-8 alkylene)-CO-N(Ci-5 alkyl)(Ci-5 alkyl), -(C1-8 alkylene)-NH-CO-(Ci-5 alkyl), -(C1-8 alkylene)-N(Ci-5 alkyl)-CO-(Ci-5 alkyl), -(C1-8 alkylene)-NH-COO(Ci-5 alkyl), -(C1-8 alkylene)-N(Ci-5 alkyl)-COO(Ci-5 alkyl), -(Co-8 alkylene)-O-CO-NH(Ci-5 alkyl), -(Co-8 alkylene)-O-CO-N(Ci-5 alkyl)(Ci-5 alkyl), -(Co-8 alkylene)-SO2-NH2, -(Co-8 alkylene)-SO2-NH(Ci-5 alkyl), -(Co-8 alkylene)-SO2-N(Ci-5 alkyl)(Ci-5 alkyl), -(C1-8 alkylene)-NH-SO2-(Ci-5 alkyl), -(C1-8 alkylene)-N(Ci-5 alkyl)-SO2-(Ci-5 alkyl), -(Co-8 alkylene)-SO-(Ci-5 alkyl), -(Co-8 alkylene)-SO2-(Ci-5 alkyl), -(Co-8 alkylene)-carbocyclyl, -(Co-8 alkylene)-heterocyclyl, and -Lz-Rz, wherein one or more -CH2- units comprised in said C1-8 alkyl, said C2-8 alkenyl, said C2-8 alkynyl, and in any of the aforementioned Co-s alkylene and C1-8 alkylene groups are each optionally replaced by a group independently selected from -O-, -NH-, -N(CI-5 alkyl)-, -CO-, -S-, -SO-, and -SO2-, wherein the carbocyclyl group in said -(Co-s alkylene)-carbocyclyl and the heterocyclyl group in said -(Co-s alkylene)-heterocyclyl are each optionally substituted with one or more groups Rc c, and wherein at least one of the groups RAand RBis not hydrogen; or alternatively, RAand RBare mutually joined to form, together with the nitrogen atom that they are attached to, a heterocyclyl which is optionally substituted with one or more groups Rc.

[0148] Each Rcis independently selected from C1.5 alkyl, C2-5 alkenyl, C2-5 alkynyl, -(C0-3 alky lene)-0 H, -(C0-3 alky lene)-0 (C 1-5 alkyl), -(C0-3 alkylene)-O(Ci-5 alkylene)-OH, -(C0-3 alkylene)-O(Ci-5 alkylene)-O(Ci-5 alkyl), -(C0-3 alkylene)-SH, -(C0-3 alkylene)-S(Ci-5 alkyl), -(C0-3 alkylene)-S(Ci-5 alkylene)-SH, -(C0-3 alkylene)-S(Ci-5 alkylene)-S(Ci-5 alkyl), -(C0-3 alkylene)-NH2, -(C0-3 alkylene)-NH(Ci-5 alkyl), -(C0-3 alkylene)-N(Ci-5 alkyl)(Ci-5 alkyl), -(C0-3 alkylene)-NH-OH, -(C0-3 alkylene)-N(Ci-5 alkyl)-OH, -(C0-3 alkylene)-NH-O(Ci-5 alkyl), -(C0-3 alkylene)-N(Ci-5 alkyl)-O(Ci-5 alkyl), -(C0-3 alkylene)-halogen, -(C0-3 alkylene)-(Ci-5 haloalkyl), -(C0-3 alkylene)-O-(Ci-5 haloalkyl), -(C0-3 alkylene)-CN, -(C0-3 alkylenej-SFs, -(C0-3 alkylene)-CHO, -(C0-3 alkylene)-CO-(Ci-5 alkyl), -(C0-3 alkylene)-COOH, -(C0-3 alkylene)-CO-O-(Ci-5 alkyl), -(C0-3 alkylene)-O-CO-(Ci-5 alkyl), -(C0-3 alkylene)-CO-NH2, -(C0-3 alkylene)-CO-NH(Ci-5 alkyl), -(C0-3 alkylene)-CO-N(Ci-5 alkyl)(Ci-5 alkyl), -(C0-3 alkylene)-NH-CO-(Ci-5 alkyl), -(C0-3 alkylene)-N(Ci-5 alkyl)-CO-(Ci-5 alkyl), -(C0-3 alkylene)-NH-COO(Ci-5 alkyl), -(C0-3 alkylene)-N(Ci-5 alkyl)-COO(Ci-5 alkyl), -(C0-3 alkylene)-O-CO-NH(Ci-5 alkyl), -(C0-3 alkylene)-O-CO-N(Ci-5 alkyl)(Ci-5 alkyl), -(C0-3 alkylene)-SO2-NH2, -(C0-3 alkylene)-SO2-NH(Ci-5 alkyl), -(C0-3 alkylene)-SO2-N(Ci-5 alkyl)(Ci-5 alkyl), -(C0-3 alkylene)-NH-SO2-(Ci-5 alkyl), -(C0-3 alkylene)-N(Ci-5 alkyl)-SO2-(Ci-5 alkyl), -(C0-3 alkylene)-SO-(Ci-5 alkyl), -(C0-3 alkylene)-SO2-(Ci-5 alkyl), -(C0-3 alkylene)-carbocyclyl, -(C0-3 alkylene)-heterocyclyl, and -Lz-Rz, wherein the carbocyclyl group in said -(C0-3 alkylene)-carbocyclyl and the heterocyclyl group in said -(C0-3 alkylene)-heterocyclyl are each optionally substituted with one or more groups R°rc; and further wherein any two groups Rc, which are attached to the same ring carbon atom of the heterocyclyl formed from RAand RB, may also be mutually joined to form, together with said ring carbonatom that they are attached to, a cycloalkyl or a heterocycloalkyl, wherein said cycloalkyl or said heterocycloalkyl is optionally substituted with one or more groups F .

[0149] Each R°rcis independently selected from C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, -(C0-3 alkylene)-OH, -(C0-3 alkylene)-O(Ci-5 alkyl), -(C0-3 alkylene)-O(Ci-5 alkylene)-OH, -(C0-3 alkylene)-O(Ci-5 alkylene)-O(Ci-5 alkyl), -(C0-3 alkylene)-SH, -(C0-3 alkylene)-S(0i-5 alkyl), -(C0-3 alkylene)-S(Ci-5 alkylene)-SH, -(C0-3 alkylene)-S(Ci-5 alkylene)-S(Ci-5 alkyl), -(C0-3 alkylene)-NH2, -(C0-3 alkylene)-NH(Ci-5 alkyl), -(C0-3 alkylene)-N(Ci-5 alkyl)(Ci-5 alkyl), -(C0-3 alkylene)-NH-OH, -(C0-3 alkylene)-N(Ci.5alkyl)-OH, -(C0-3 alkylene)-NH-O(Ci.5alkyl), -(C0-3 alkylene)-N(Ci-5 alkyl)-O(Ci-5 alkyl), -(C0-3 alkylene)-halogen, -(C0-3 alkylene)-Ci-5 haloalkyl, -(C0-3 alkylene)-O-(Ci-5 haloalkyl), -(C0-3 alkylene)-CN, -(C0-3 alkylene)-SF5, -(C0-3 alkylene)-CHO, -(C0-3 alkylene)-CO(Ci-5 alkyl), -(C0-3 alkylene)-COOH, -(C0-3 alkylene)-COO(Ci-5 alkyl), -(C0-3 alkylene)-O-CO(Ci-5 alkyl), -(C0-3 alkylene)-CO-NH2, -(C0-3 alkylene)-CO-NH(Ci-5 alkyl), -(C0-3 alkylene)-CO-N(Ci-5 alkyl)(Ci-5 alkyl), -(C0-3 alkylene)-NH-CO(Ci-5 alkyl), -(C0-3 alkylene)-N(Ci-5 alkyl)-CO(Ci-5 alkyl), -(C0-3 alkylene)-NH-COO(Ci-5 alkyl), -(C0-3 alkylene)-N(Ci-5 alkyl)-COO(Ci-5 alkyl), -(C0-3 alkylene)-O-CO-NH(Ci-5 alkyl), -(C0-3 alkylene)-O-CO-N(Ci-5 alkyl)(Ci-5 alkyl), -(C0-3 alkylene)-SO2-NH2, -(C0-3 alkylene)-SO2-NH(Ci-5 alkyl), -(C0-3 alkylene)-SO2-N(Ci-5 alkyl)(Ci-5 alkyl), -(C0-3 alkylene)-NH-SO2-(Ci-5 alkyl), -(C0-3 alkylene)-N(Ci-5 alkyl)-SO2-(Ci-5 alkyl), -(C0-3 alkylene)-SO2-(Ci-5 alkyl), -(C0-3 alkylene)-SO-(Ci-5alkyl), -(C0-3 alkylene)-P(=O)(-OH)(-OH), -(C0-3 alkylene)-P(=O)(-OH)(-O-Ci.5alkyl), -(C0-3 alkylene)-P(=O)(-O-Ci-5 alkyl)(-O-Ci-5 alkyl), -(C0-3 alkylene)-cycloalkyl, -(C0-3 alkylene)-heterocycloalkyl, and -Lz-Rz.

[0150] Each Lzis independently selected from a covalent bond, C1-7 alkylene, C2-7 alkenylene, and C2-7 alkynylene, wherein said alkylene, said alkenylene and said alkynylene are each optionally substituted with one or more groups independently selected from halogen, C1-5 haloalkyl, -O-(Ci-5 haloalkyl), -CN, -SF5, -OH, -O(Ci-5 alkyl), -SH, -S(Ci-5 alkyl), -NH2, -NH(CI-5 alkyl), and -N(CI-5 alkyl)(Ci-5 alkyl), and further wherein one or more -CH2- units comprised in said alkylene, said alkenylene or said alkynylene are each optionally replaced by a group independently selected from -O-, -NH-, -N(CI-5 alkyl)-, -CO-, -S-, -SO-, and -SO2-.

[0151] Each Rzis independently selected from -OH, -O(Ci-5 alkyl), -O(Ci-5 alkylene)-OH, -O(Ci-5 alkylene)-O(Ci-5 alkyl), -SH, -S(Ci.5alkyl), -S(Ci.5alkylene)-SH, -S(Ci.5alkylene)-S(Ci.5alkyl), -NH2, -NH(CI.5alkyl), -N(CI.5alkyl)(Ci.5alkyl), -NH-OH, -N(CI.5alkyl)-OH, -NH-O(CI.5alkyl), -N(CI.5alkyl)-O(Ci.5alkyl), halogen, C1.5 haloalkyl, -O-(Ci.5haloalkyl), -CN, -SP5, -CHO, -CO(Ci.5alkyl), -COOH, -COO(Ci.5alkyl), -O-CO(Ci.5alkyl), -CO-NH2, -CO-NH(CI.5alkyl), -CO-N(CI-5alkyl)(Ci.5alkyl), -NH-CO(CI.5alkyl), -N(CI.5alkyl)-CO(Ci.5alkyl), -NH-COO(CI.5alkyl), -N(CI.5alkyl)-COO(Ci-5alkyl), -O-CO-NH(CI.5alkyl), -O-CO-N(CI.5alkyl)(Ci.5alkyl), -SO2-NH2, -SO2-NH(CI.5alkyl), -SO2-N(CI-5alkyl)(Ci-5alkyl), -NH-SO2-(CI.5alkyl), -N(CI.5alkyl)-SO2-(Ci.5alkyl), -SO2-(Ci.5alkyl), -SO-(Ci.5alkyl), aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, wherein said aryl, said heteroaryl, said cycloalkyl, and said heterocycloalkyl are each optionally substituted with one or more groups independently selected from C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, halogen, C1-5 haloalkyl, -O-(Ci-5 haloalkyl), -CN, -SF5, -OH, -O(Ci-5 alkyl), -SH, -S(0i-5 alkyl), -NH2, -NH(CI.5alkyl), -N(CI.5alkyl)(Ci.5alkyl), -CHO, -CO-(Ci.5alkyl), -COOH, -CO-O-(Ci.5alkyl), -O-CO-(Ci.5alkyl), -CO-NH2, -CO-NH(CI-5 alkyl), -CO-N(CI.5alkyl)(Ci.5alkyl), -NH-CO-(CI.5alkyl), -N(CI.5alkyl)-CO-(Ci.5alkyl), -NH-COO(CI-5 alkyl), -N(CI.5alkyl)-COO(Ci.5alkyl), -O-CO-NH(CI.5alkyl), -O-CO-N(CI.5alkyl)(Ci.5alkyl), -SO2-NH2, -SO2-NH(CI.5 alkyl), -SO2-N(CI.5alkyl)(Ci.5alkyl), -NH-SO2-(CI.5alkyl), -N(CI.5alkyl)-SO2-(Ci.5alkyl), -S0-(Ci-5 alkyl), -SO2-(Ci-5 alkyl), carbocyclyl, and heterocyclyl, wherein said carbocyclyl and said heterocyclyl are each optionally substituted with one or more groups independently selected from C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, halogen, C1-5 haloalkyl, -O-(Ci-5 haloalkyl), -CN, -SF5, -OH, -O(Ci-5 alkyl), -SH, -S(Ci-5 alkyl), -NH2, -NH(CI-5 alkyl), -N(CI.5 alkyl)(Ci.5alkyl), -CHO, -CO-(Ci.5alkyl), -COOH, -CO-O-(Ci.5alkyl), -O-CO-(Ci.5alkyl), -CO-NH2, -CO-NH(CI.5 alkyl), -CO-N(CI.5alkyl)(Ci.5alkyl), -NH-CO-(CI.5alkyl), -N(CI.5alkyl)-CO-(Ci.5alkyl), -NH-COO(CI.5 alkyl), -N(CI_5alkyl)-COO(Ci.5alkyl), -O-CO-NH(CI.5alkyl), -O-CO-N(CI.5alkyl)(Ci.5alkyl), -SO2-NH2, -SO2-NH(CI.5 alkyl), -SO2-N(CI.5alkyl)(Ci.5alkyl), -NH-SO2-(CI.5alkyl), -N(CI.5alkyl)-SO2-(Ci.5alkyl), -SO-(Ci-5 alkyl), and -SO2-(Ci-5 alkyl).

[0152] In formula (I), the following provisos apply:

[0153] If X is N, if R1is a group R11, and if R11is hydrogen, then R3is not a group -(C1-5 alkylene)-phenyl, wherein the alkylene group in said -(C1-5 alkylene)-phenyl is optionally substituted with one or more groups R31and wherein the phenyl group in said -(C1-5 alkylene)-phenyl is optionally substituted with one or more groups R32.

[0154] If X is N, if R1and R2are mutually joined to form, together with the nitrogen atom that they are attached to, a heterocyclyl which is optionally substituted with one or more groups R24, and if RAand RBare mutually joined to form, together with the nitrogen atom that they are attached to, a bicyclic fused heterocyclyl which is optionally substituted with one or more groups Rc, then the heterocyclyl formed from R1and R2is not a spirocyclic group which comprises a piperidine ring and is attached via the nitrogen ring atom of said piperidine ring.

[0155] If X is N, if one of RAand RBis hydrogen, and if R1and R2are mutually joined to form, together with the nitrogen atom that they are attached to, a heterocyclyl which is optionally substituted with one or more groups R24, then said heterocyclyl is not decahydroquinoxalin-1-yl or octahydro-1 H-cyclopenta[b]pyrazin-1-yl. If X is N and if one of RAand RBis hydrogen, then R3is not phenyl which is optionally substituted with one or more groups R32.

[0156] If X is C(-R5), if one of RAand RBis hydrogen, if R1and R2are mutually joined to form, together with the nitrogen atom that they are attached to, a heterocyclyl which is piperazin-1 -yl and which is optionally substituted with one or more groups R24, then said piperazin-1 -yl is not substituted with 1 H-quinoxalin-2-on- 7-ylmethyl, wherein the 1 H-quinoxalin-2-on-7-yl group in said 1 H-quinoxalin-2-on-7-ylmethyl is optionally substituted with one or more groups RCyc.

[0157] If R1and R2are mutually joined to form, together with the nitrogen atom that they are attached to, a heterocycloalkyl which is optionally substituted with one or more groups R24, if R3is C1-8 alkyl which is optionally substituted with one or more halogen atoms, and if one of RAand RBis hydrogen, then the other one of RAand RBis not methyl.

[0158] If X is N and if R3is phenyl which is substituted with one or more halogen atoms, then R1and R2are not mutually joined to form, together with the nitrogen atom that they are attached to, a group which is pyrrolidin- 1-yl or piperidin-1-yl.

[0159] If X is N, if R11is C1-5 alkyl, and if R21is C1-8 alkyl, wherein one or more -CH2- units comprised in said C1-8 alkyl are each optionally replaced by -O-, then R3is not a cyclic group selected from phenyl, azetidinyl,pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, and azepanyl, wherein said cyclic group is optionally substituted with one or more halogen atoms.

[0160] If X is N and if R21is Cvs alkyl, wherein one or more -CH2- units comprised in said C1-8 alkyl are each optionally replaced by -O-, then R3is not a heterocycloalkyl comprising one or two nitrogen ring atoms, wherein all remaining ring atoms in said heterocycloalkyl are carbon atoms, and wherein said heterocycloalkyl is substituted with one or more groups R32.

[0161] If R1and R2are mutually joined to form, together with the nitrogen atom that they are attached to, a heterocyclyl which is imidazol-1-yl or 1 ,2,4-triazol-1-yl and which is optionally substituted with one or more groups R24, then R3is not C1-6 alkyl or -CF3.

[0162] If X is C(-R5) and if one of RAand RBis hydrogen, then the other one of RAand RBis not -NH-carbocyclyl or -NH-heterocyclyl, wherein the carbocyclyl in said -NH-carbocyclyl and the heterocyclyl in said -NH- heterocyclyl are each optionally substituted with one or more groups Rc c.

[0163] If R1is a group R11and R11is hydrogen, then R2is not -CO-NH-(1 ,2,3,4-tetrahydronaphthalen-1-yl), -CO- NH-(3',4'-dihydro-2'H-spiro[cyclopropane-1,1'-naphthalene]-4'-yl), -CO-NH-(3’,4’-dihydro-2’H- spiro[cyclobutane-1,1'-naphthalene]-4'-yl), -CO-NH-(3,4-dihydro-2H-spiro[naphthalene-1,3'-oxetane]-4-yl), -CO-NH-(3,4-dihydro-2H-spiro[naphthalene-1 , 2'-oxetane]-4-y I) or -CO-N H-(3’ ,4'-di hy d ro-2' H- spiro[azetidine-3,1'-naphthalene]-4'-yl), wherein the 1 ,2,3,4-tetrahydronaphthalen-1-yl in said -CO-NH- (1 ,2,3,4-tetrahydronaphthalen-1-yl), the 3',4'-dihydro-2'H-spiro[cyclopropane-1,1'-naphthalene]-4'-yl in said -CO-NH-(3',4'-dihydro-2'H-spiro[cyclopropane-1,1'-naphthalene]-4'-yl), the 3’,4’-dihydro-2’H- spiro[cyclobutane-1,1'-naphthalene]-4'-yl in said -CO-NH-(3',4'-dihydro-2'H-spiro[cyclobutane-1 ,T- naphthalene]-4'-yl), the 3,4-dihydro-2H-spiro[naphthalene-1,3'-oxetane]-4-yl in said -CO-NH-(3,4-dihydro- 2H-spiro[naphthalene-1,3'-oxetane]-4-yl), the 3,4-dihydro-2H-spiro[naphthalene-1,2'-oxetane]-4-yl in said -CO-NH-(3,4-dihydro-2H-spiro[naphthalene-1 ,2'-oxetane]-4-yl) and the 3',4'-dihydro-2'H-spiro[azetidine- 3,1'-naphthalene]-4'-yl in said -CO-NH-(3',4'-dihydro-2'H-spiro[azetidine-3, 1'-naphthalene]-4'-yl) are each optionally substituted with one or more groups R23.

[0164] If R1is a group R11and if R11is hydrogen, then R2is not -CO-O-CH2-CCI3, -CO-O-phenyl, -CO-O-(4- methlyphenyl), -CO-O-(imidazol-l-yl), -CO-O-(pyrrolidin-2,5-dion-1-yl).

[0165] As explained above, the present invention relates to a compound of formula (I) which is any one of the specific compounds of Examples 1 to 275 described further below, either in non-salt form and / or non-solvated form, or as a pharmaceutically acceptable salt or solvate of the respective compound.

[0166] The present invention also relates to each of the intermediates described further below in the examples section of this specification, including any one of these intermediates in non-salt form and / or non-solvated form, or in the form of a salt or solvate (e.g., a pharmaceutically acceptable salt or solvate) of the respective compound. Such intermediates can be used, in particular, in the synthesis of the compounds of formula (I).

[0167] For a person skilled in the field of synthetic chemistry, various ways for the preparation of the compounds of formula (I) and their pharmaceutically acceptable salts and solvates will be readily apparent. For example, the compounds of the invention can be prepared in accordance with, or in analogy to, the synthetic routes described in detail in theexamples section. In particular, the compounds of formula (I) can be synthesized in accordance with the methods described in the following general schemes (general disconnections).

[0168] Schematic overview:

[0169]

[0170] Compounds of formula (I) can be obtained from a precursor (ll)-A according to the general disconnection A:

[0171]

[0172] R(ll)-AR(I)

[0173] With Z1being a hydroxy group (based on the work described in Org. Process Res. Dev. 2004, 8, 62-71 or Tet. Lett., 1992, 33, 1181-1184):

[0174] By a transformation or sequence known to the person skilled in the art of Z1into a hydrogen, a halogen or a pseudo-halogen, followed by a transformation or a sequence described below.

[0175] With Z1being a hydrogen atom (based on the work described in ARKIVOC 2013, 1, 154-174, ARKIVOC 2001, 1, 242-268, Synthesis 2011, 20, 3209-3219, Adv. Synth. Catal. 2021, 363, 2-39, Angew. Chem. 2020, 132, 2 - 26, or Chem. Rev. 2017, 117, 9302-9332):

[0176] By N-oxidation followed by a sequence leading to the conversion of Z1into a halogen or a pseudo-halogen, followed by a transformation or a sequence described below.

[0177] By carbon-hydrogen bond activation with a metal leading to the conversion of Z1into a halogen, a pseudohalogen, or an organometallic group, followed by a transformation or a sequence described below.

[0178] By a transformation or sequence known to the person skilled in the art of Z1into a halogen or pseudohalogen, followed by a transformation or a sequence described below.With Z1being a halogen or pseudo-halogen (based on the work described in Org. Biomol. Chem., 2013, 11, 3583-3602):

[0179] By a nucleophilic aromatic substitution with the appropriate organometallic partner.

[0180] By a metal catalyzed coupling with the appropriate organometallic or halogenated or pseudo-halogenated partner.

[0181] By halogen-metal exchange followed by the nucleophilic substitution with the appropriate electrophile, or by the metal catalyzed coupling with the appropriate organometallic or halogenated or pseudo-halogenated partner.

[0182] Compounds of formula (I) can be obtained from a precursor (ll)-B according to the general disconnection B:

[0183]

[0184] With Z2being a hydroxy group (based on the work described in Org. Process Res. Dev. 2004, 8, 62-71, Comprehensive Heterocyclic Chemistry II, Volume 6, 1996, Pages 233-278, or Tet. Lett., 1992, 33, 1181-1184):

[0185] By a transformation or sequence known to the person skilled in the art of Z2into a hydrogen, a halogen or a pseudo-halogen, followed by a transformation or a sequence described below.

[0186] With Z2being a hydrogen atom (based on the work described in ARKIVOC 2013, 1, 154-174, ARKIVOC 2001, 1, 242-268 or Synthesis 2011, 20, 3209-3219):

[0187] By N-oxidation followed by a sequence leading to the conversion of Z2into a halogen or a pseudo-halogen, followed by a transformation or a sequence described below.

[0188] By carbon-hydrogen bond activation with a metal leading to the conversion of Z2into a halogen, a pseudohalogen, or an organometallic group, followed by a transformation or a sequence described below.

[0189] With Z2being a halogen or pseudo-halogen (based on the worked described in Org. Biomol. Chem., 2013, 11, 3583-3602):

[0190] By a nucleophilic aromatic substitution with the appropriate amine or aniline partner.

[0191] By a metal catalyzed coupling with the appropriate amine or aniline.

[0192] By halogen-metal exchange followed by the nucleophilic substitution with the appropriate electrophile, or by the metal catalyzed coupling with the appropriate amine or aniline.

[0193] Compounds of formula (I) can be obtained from a precursor (ll)-C according to the general disconnection C:

[0194]

[0195] With a partner containing a carbonyl:

[0196] By a reductive amination reaction or amide synthesis known to the person skilled in the art.By a Petasis reaction (based on the works described in Chem. Rev. 2019, 119, 11245-11290, or RSC Adv., 2015, 5, 76337-76341).

[0197] With a partner containing a halogen or pseudo-halogen, or an organometallic group:

[0198] By a nucleophilic substitution known to the person skilled in the art.

[0199] By a metal catalyzed coupling reaction (based on the works described in Chem. Rev. 2016, 116, 19, 12564— 12649, Chem. Soc. Rev., 2014, 43, 3525-3550 or Chem. Rev. 2019, 119, 24, 12491-12523).

[0200] Compounds of formula (I) can be obtained from a precursor (ll)-D according to the general disconnection D:

[0201] N-RA

[0202] RB

[0203]

[0204] (ll)-D

[0205] With Z3being a hydrogen atom (based on the work described in ARKIVOC 2013, 1, 154-174, ARKIVOC 2001, 1, 242-268 or Synthesis 2011, 20, 3209-3219):

[0206] By N-oxidation followed by a sequence leading to the carboxylic acid, and subsequent amide synthesis with the appropriate amine.

[0207] By N-oxidation followed by a sequence leading to the conversion of Z3into a halogen or a pseudo-halogen, followed by a transformation or a sequence described below.

[0208] By carbon-hydrogen bond activation with a metal leading to the conversion of Z3into a halogen, a pseudohalogen, or an organometallic group, followed by a transformation or a sequence described below.

[0209] With Z3being a hydroxy group (based on the work described in Org. Process Res. Dev. 2004, 8, 62-71 or Tet. Lett., 1992, 33, 1181-1184):

[0210] By a transformation or sequence known to the person skilled in the art of Z3into a halogen or pseudohalogen, followed by a transformation or a sequence described below.

[0211] With Z3being a halogen or a pseudo-halogen, or an organometallic group (based on the worked described in Org. Biomol. Chem., 2013, 11, 3583-3602):

[0212] By a direct, metal catalyzed amino-carbonylation reaction with the appropriate amine (based on the work described in RSCAdv., 2014, 4, 10367-10389 or Synthesis, 2008, 311-312).

[0213] By a transformation or a sequence known to the person skilled in the art leading to a carboxylic, followed by amide, synthesis with the appropriate amine (based on the work described in J. Org. Chem., 2008, 73, 3967- 3969).

[0214] Compounds of formula (I) can be obtained from a precursor (ll)-E according to the general disconnection E:

[0215] J J I J J J

[0216]

[0217] With the link containing an unsaturation:

[0218] By oxidative cleavage of the double bond.

[0219] By reductive cleavage of the carbon nitrogen bond.

[0220] With the link containing a carbonyl:

[0221] By oxidation of the ketone to the ester (Baeyer-Villiger oxidation) and subsequent ester cleavage.

[0222] By acidic or basic hydrolysis of the amide generating the amino-acid, potentially followed by a decarboxylation.

[0223] Or the compounds of formula (I) can be obtained by any other disconnection reaction known to the person skilled in the art.

[0224] Using and combining the above-mentioned general disconnections A, B, C, D, E, and available literature, enables the synthesis of compounds of formula (I) from commercially available compounds or from compounds whose synthesis is already described in the literature or compounds which are accessible with a method known in the art.

[0225] The following definitions apply throughout the present specification and the claims, unless specifically indicated otherwise.

[0226] The term "hydrocarbon group” refers to a group consisting of carbon atoms and hydrogen atoms.

[0227] The term "alicyclic” is used in connection with cyclic groups and denotes that the corresponding cyclic group is non-aromatic.

[0228] As used herein, the term "alkyl” refers to a monovalent saturated acyclic (i.e., non-cyclic) hydrocarbon group which may be linear or branched. Accordingly, an "alkyl” group does not comprise any carbon-to-carbon double bond or any carbon-to-carbon triple bond. A“CI-5 alkyl” denotes an alkyl group having 1 to 5 carbon atoms. Preferred exemplary alkyl groups are methyl, ethyl, propyl (e.g., n-propyl or isopropyl), or butyl (e.g., n-butyl, isobutyl, sec-butyl, or tertbutyl). Unless defined otherwise, the term "alkyl” preferably refers to C1-4 alkyl, more preferably to methyl or ethyl, and even more preferably to methyl.

[0229] As used herein, the term "alkenyl” refers to a monovalent unsaturated acyclic hydrocarbon group which may be linear or branched and comprises one or more (e.g., one or two) carbon-to-carbon double bonds while it does not comprise any carbon-to-carbon triple bond. The term "C2-5 alkenyl” denotes an alkenyl group having 2 to 5 carbon atoms. Preferred exemplary alkenyl groups are ethenyl, propenyl (e.g., prop-1 -en-1-yl, prop-1 -en-2-yl, or prop-2-en-1-yl), butenyl, butadienyl (e.g., buta-1 ,3-dien-1-yl or buta-1 ,3-dien-2-yl), pentenyl, or pentadienyl (e.g., isoprenyl). Unless defined otherwise, the term "alkenyl” preferably refers to C2-4 alkenyl.

[0230] As used herein, the term “alky ny I” refers to a monovalent unsaturated acyclic hydrocarbon group which may be linear or branched and comprises one or more (e.g., one or two) carbon-to-carbon triple bonds and optionally one or more(e.g., one or two) carbon-to-carbon double bonds. The term "C2-5 alkynyl” denotes an alkynyl group having 2 to 5 carbon atoms. Preferred exemplary alkynyl groups are ethynyl, propynyl (e.g., propargyl), or butynyl. Unless defined otherwise, the term "alkynyl” preferably refers to C2-4 alkynyl.

[0231] As used herein, the term "alkylene” refers to an alkanediyl group, i.e. a divalent saturated acyclic hydrocarbon group which may be linear or branched. A “C1-5 alkylene” denotes an alkylene group having 1 to 5 carbon atoms, and the term "C0-3 alkylene” indicates that a covalent bond (corresponding to the option "Co alkylene”) or a C1-3 alkylene is present. Preferred exemplary alkylene groups are methylene (-CH2-), ethylene (e.g., -CH2-CH2- or -CH(-CH3)-), propylene (e.g., -CH2-CH2-CH2-, -CH(-CH2-CH3)-, -CH2-CH(-CH3)-, or -CH(-CH3)-CH2-), or butylene (e.g., -CH2-CH2-CH2-CH2-). Unless defined otherwise, the term "alkylene” preferably refers to C1-4 alkylene (including, in particular, linear C1-4 alkylene), more preferably to methylene or ethylene, and even more preferably to methylene.

[0232] As used herein, the term "alkenylene” refers to an alkenediyl group, i.e. a divalent unsaturated acyclic hydrocarbon group which may be linear or branched and comprises one or more (e.g., one or two) carbon-to-carbon double bonds while it does not comprise any carbon-to-carbon triple bond. A "C2-5 alkenylene” denotes an alkenylene group having 2 to 5 carbon atoms. Unless defined otherwise, the term "alkenylene” preferably refers to C2-4 alkenylene (including, in particular, linear C2-4 alkenylene).

[0233] As used herein, the term "alkynylene” refers to an alkynediyl group, i.e. a divalent unsaturated acyclic hydrocarbon group which may be linear or branched and comprises one or more (e.g., one or two) carbon-to-carbon triple bonds and optionally one or more (e.g., one or two) carbon-to-carbon double bonds. A "C2-5 alkynylene” denotes an alkynylene group having 2 to 5 carbon atoms. Unless defined otherwise, the term "alkynylene” preferably refers to C2-4 alkynylene (including, in particular, linear C2-4 alkynylene).

[0234] As used herein, the term "carbocyclyl” refers to a hydrocarbon ring group, including monocyclic rings as well as bridged ring, spiro ring and / or fused ring systems (which may be composed, e.g., of two or three rings), wherein said ring group may be saturated, partially unsaturated (i.e., unsaturated but not aromatic) or aromatic. Unless defined otherwise, "carbocyclyl” preferably refers to aryl, cycloalkyl or cycloalkenyl.

[0235] As used herein, the term “heterocyclyl” refers to a ring group, including monocyclic rings as well as bridged ring, spiro ring and / or fused ring systems (which may be composed, e.g., of two or three rings), wherein said ring group comprises one or more (such as, e.g., one, two, three, or four) ring heteroatoms independently selected from 0, S and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) may optionally be oxidized, wherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo group), and further wherein said ring group may be saturated, partially unsaturated (i.e., unsaturated but not aromatic) or aromatic. For example, each heteroatom-containing ring comprised in said ring group may contain one or two 0 atoms and / or one or two S atoms (which may optionally be oxidized) and / or one, two, three or four N atoms (which may optionally be oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and that there is at least one carbon ring atom (which mayoptionally be oxidized) in the corresponding heteroatom-containing ring. Unless defined otherwise, "heterocyclyl” preferably refers to heteroaryl, heterocycloalkyl or heterocycloalkenyl.

[0236] As used herein, the term "aryl” refers to an aromatic hydrocarbon ring group, including monocyclic aromatic rings as well as bridged ring and / or fused ring systems containing at least one aromatic ring (e.g., ring systems composed of two or three fused rings, wherein at least one of these fused rings is aromatic; or bridged ring systems composed of two or three rings, wherein at least one of these bridged rings is aromatic). If the aryl is a bridged and / or fused ring system which contains, besides one or more aromatic rings, at least one non-aromatic ring (e.g., a saturated ring or an unsaturated alicyclic ring), then one or more carbon ring atoms in each non-aromatic ring may optionally be oxidized (i.e., to form an oxo group). "Aryl” may, e.g., refer to phenyl, naphthyl, dialinyl (i.e., 1 ,2-dihydronaphthyl), tetralinyl (i.e., 1 ,2,3,4-tetrahydronaphthyl), indanyl, indenyl (e.g., 1H-indenyl), anthracenyl, phenanthrenyl, 9H-fluorenyl, or azulenyl. Unless defined otherwise, an "aryl” preferably has 6 to 14 ring atoms, more preferably 6 to 10 ring atoms, even more preferably refers to phenyl or naphthyl, and most preferably refers to phenyl.

[0237] As used herein, the term "heteroaryl” refers to an aromatic ring group, including monocyclic aromatic rings as well as bridged ring and / or fused ring systems containing at least one aromatic ring (e.g., ring systems composed of two or three fused rings, wherein at least one of these fused rings is aromatic; or bridged ring systems composed of two or three rings, wherein at least one of these bridged rings is aromatic), wherein said aromatic ring group comprises one or more (such as, e.g., one, two, three, or four) ring heteroatoms independently selected from 0, S and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) may optionally be oxidized, and further wherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo group). For example, each heteroatom-containing ring comprised in said aromatic ring group may contain one or two 0 atoms and / or one or two S atoms (which may optionally be oxidized) and / or one, two, three or four N atoms (which may optionally be oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and that there is at least one carbon ring atom (which may optionally be oxidized) in the corresponding heteroatom-containing ring. "Heteroaryl” may, e.g., refer to thienyl (i.e., thiophenyl), benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl (i.e., furanyl), benzofuranyl, isobenzofuranyl, chromanyl, chromenyl (e.g., 2H-1 -benzopyranyl or 4H-1 -benzopyranyl), isochromenyl (e.g., 1 H-2-benzopyranyl), chromonyl, xanthenyl, phenoxathiinyl, pyrrolyl (e.g., 1 H-pyrrolyl), imidazolyl, pyrazolyl, pyridyl (i.e., pyridinyl; e.g., 2-pyridyl, 3-pyridyl, or 4-pyridyl), pyrazinyl, pyrimidinyl, pyridazinyl, indolyl (e.g., 1H-indolyl), isoindolyl, indazolyl, indolizinyl, purinyl, quinolyl, isoquinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, cinnolinyl, pteridinyl, carbazolyl, p-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl (e.g., [1 ,10]phenanthrolinyl, [1,7]phenanthrolinyl, or [4,7]phenanthrolinyl), phenazinyl, thiazolyl, isothiazolyl, phenothiazinyl, oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1.2.4-oxadiazolyl, 1 ,2,5-oxadiazolyl (i.e., furazanyl), or 1 ,3,4-oxadiazolyl), thiadiazolyl (e.g., 1 ,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, or 1 ,3,4-thiadiazolyl), phenoxazinyl, pyrazolo[1,5-a]pyrimidinyl (e.g., pyrazolo[1 ,5-a]pyrimidin-3-yl), 1 ,2-benzoisoxazol-3-yl, benzothiazolyl, benzothiadiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzo[b]thiophenyl (i.e., benzothienyl), triazolyl (e.g., 1 H-1,2,3-triazolyl, 2H-1 ,2,3-triazolyl, 1 H-1 ,2,4-triazolyl, or 4H- 1.2.4-triazolyl), benzotriazolyl, 1 H-tetrazolyl, 2H-tetrazolyl, triazinyl (e.g., 1 ,2,3-triazinyl, 1 ,2,4-triazinyl, or 1,3,5-triazinyl), furo[2,3-c]pyridinyl, dihydrofuropyridinyl (e.g., 2,3-dihydrofuro[2,3-c]pyridinyl or 1 ,3-dihydrofuro[3,4-c]pyridinyl), imidazopyridinyl (e.g., imidazo[1 ,2-a]pyridinyl or imidazo[3,2-a]pyridinyl), quinazolinyl, thienopyridinyl,tetrahydrothienopyridinyl (e.g., 4,5,6,7-tetrahydrothieno[3,2-c]pyridinyl), dibenzofuranyl, 1 ,3-benzodioxolyl, benzodioxanyl (e.g., 1,3-benzodioxanyl or 1 ,4-benzodioxanyl), or coumarinyl. Unless defined otherwise, the term "heteroaryl” preferably refers to a 5 to 14 membered (more preferably 5 to 10 membered) monocyclic ring or fused ring system comprising one or more (e.g., one, two, three or four) ring heteroatoms independently selected from 0, S and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized; even more preferably, a "heteroaryl” refers to a 5 or 6 membered monocyclic ring comprising one or more (e.g., one, two or three) ring heteroatoms independently selected from 0, S and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized. Moreover, unless defined otherwise, particularly preferred examples of a "heteroaryl” include pyridinyl (e.g., 2-pyridyl, 3-pyridyl, or 4-pyridyl), imidazolyl, thiazolyl, 1 H-tetrazolyl, 2H-tetrazolyl, thienyl (i.e., thiophenyl), or pyrimidinyl.

[0238] As used herein, the term “cycloalky I” refers to a saturated hydrocarbon ring group, including monocyclic rings as well as bridged ring, spiro ring and / or fused ring systems (which may be composed, e.g., of two or three rings; such as, e.g., a fused ring system composed of two or three fused rings). "Cycloalkyl” may, e.g., refer to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, decalinyl (i.e., decahydronaphthyl), or adamantyl. Unless defined otherwise, "cycloalkyl” preferably refers to a C3-11 cycloalkyl, and more preferably refers to a C3-7 cycloalkyl. A particularly preferred "cycloalkyl” is a monocyclic saturated hydrocarbon ring having 3 to 7 ring members. Moreover, unless defined otherwise, particularly preferred examples of a "cycloalkyl” include cyclohexyl or cyclopropyl, particularly cyclohexyl.

[0239] As used herein, the term “heterocycloalkyl” refers to a saturated ring group, including monocyclic rings as well as bridged ring, spiro ring and / or fused ring systems (which may be composed, e.g., of two or three rings; such as, e.g., a fused ring system composed of two or three fused rings), wherein said ring group contains one or more (such as, e.g., one, two, three, or four) ring heteroatoms independently selected from 0, S and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) may optionally be oxidized, and further wherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo group). For example, each heteroatom-containing ring comprised in said saturated ring group may contain one or two 0 atoms and / or one or two S atoms (which may optionally be oxidized) and / or one, two, three or four N atoms (which may optionally be oxidized), provided that the total number of heteroatoms in the corresponding heteroatomcontaining ring is 1 to 4 and that there is at least one carbon ring atom (which may optionally be oxidized) in the corresponding heteroatom-containing ring. "Heterocycloalkyl” may, e.g., refer to aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, piperazinonyl (e.g., piperazin-2-on-1-yl or piperazin-3-on-1-yl), azepanyl, diazepanyl (e.g., 1 ,4-diazepanyl), oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, morpholinyl (e.g., morpholin-4-yl), thiomorpholinyl (e.g., thiomorpholin-4-yl), oxazepanyl, oxiranyl, oxetanyl, tetrahydrofuranyl, 1.3-dioxolanyl, tetrahydropyranyl, 1 ,4-dioxanyl, oxepanyl, thiiranyl, thietanyl, tetrahydrothiophenyl (i.e., thiolanyl), 1.3-dithiolanyl, thianyl, thiepanyl, decahydroquinolinyl, decahydroisoquinolinyl, or 2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl. Unless defined otherwise, "heterocycloalkyl” preferably refers to a 3 to 11 membered saturated ring group, which is a monocyclic ring or a fused ring system (e.g., a fused ring system composed of two fused rings), wherein said ring group contains one or more (e.g., one, two, three, or four) ring heteroatoms independently selected from 0, S and N,wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized; more preferably, “heterocycloalky I” refers to a 5 to 7 membered saturated monocyclic ring group containing one or more (e.g., one, two, or three) ring heteroatoms independently selected from 0, S and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized. Moreover, unless defined otherwise, particularly preferred examples of a “heterocycloalky I” include tetrahydropyranyl, piperidinyl, piperazinyl, piperazinonyl, morpholinyl, pyrrolidinyl, or tetrahydrofuranyl.

[0240] As used herein, the term "cycloalkenyl” refers to an unsaturated alicyclic (non-aromatic) hydrocarbon ring group, including monocyclic rings as well as bridged ring, spiro ring and / or fused ring systems (which may be composed, e.g., of two or three rings; such as, e.g., a fused ring system composed of two or three fused rings), wherein said hydrocarbon ring group comprises one or more (e.g., one or two) carbon-to-carbon double bonds and does not comprise any carbon-to-carbon triple bond. "Cycloalkenyl” may, e.g., refer to cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, or cycloheptadienyl. Unless defined otherwise, "cycloalkenyl” preferably refers to a C3-11 cycloalkenyl, and more preferably refers to a C3-7 cycloalkenyl. A particularly preferred "cycloalkenyl” is a monocyclic unsaturated alicyclic hydrocarbon ring having 3 to 7 ring members and containing one or more (e.g., one or two; preferably one) carbon-to-carbon double bonds.

[0241] As used herein, the term "heterocycloal keny I” refers to an unsaturated alicyclic (non-aromatic) ring group, including monocyclic rings as well as bridged ring, spiro ring and / or fused ring systems (which may be composed, e.g., of two or three rings; such as, e.g., a fused ring system composed of two or three fused rings), wherein said ring group contains one or more (such as, e.g., one, two, three, or four) ring heteroatoms independently selected from 0, S and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) may optionally be oxidized, wherein one or more carbon ring atoms may optionally be oxidized (I . e. , to form an oxo group), and further wherein said ring group comprises at least one double bond between adjacent ring atoms and does not comprise any triple bond between adjacent ring atoms. For example, each heteroatom-containing ring comprised in said unsaturated alicyclic ring group may contain one or two 0 atoms and / or one or two S atoms (which may optionally be oxidized) and / or one, two, three or four N atoms (which may optionally be oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and that there is at least one carbon ring atom (which may optionally be oxidized) in the corresponding heteroatomcontaining ring. “Heterocycloalkenyl” may, e.g., refer to imidazolinyl (e.g., 2-imidazolinyl (i.e., 4,5-dihydro-1H-imidazolyl), 3-imidazolinyl, or 4-imidazolinyl), tetrahydropyridinyl (e.g., 1 ,2,3,6-tetrahydropyridinyl), dihydropyridinyl (e.g., 1 ,2-dihydropyridinyl or 2,3-dihydropyridinyl), pyranyl (e.g., 2H-pyranyl or 4H-pyranyl), thiopyranyl (e.g., 2H-thiopyranyl or 4H-thiopyranyl), dihydropyranyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrazinyl, dihydroisoindolyl, octahydroquinolinyl (e.g., 1 ,2,3,4,4a,5,6,7-octahydroquinolinyl), or octahydroisoquinolinyl (e.g., 1 ,2,3,4,5,6,7,8-octahydroisoquinolinyl). Unless defined otherwise, "heterocycloalkenyl” preferably refers to a 3 to 11 membered unsaturated alicyclic ring group, which is a monocyclic ring or a fused ring system (e.g., a fused ring system composed of two fused rings), wherein said ring group contains one or more (e.g., one, two, three, or four) ring heteroatoms independently selected from 0, S and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, wherein one or more carbon ring atoms are optionallyoxidized, and wherein said ring group comprises at least one double bond between adjacent ring atoms and does not comprise any triple bond between adjacent ring atoms; more preferably, "heterocycloalkenyl” refers to a 5 to 7 membered monocyclic unsaturated non-aromatic ring group containing one or more (e.g., one, two, or three) ring heteroatoms independently selected from 0, S and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, wherein one or more carbon ring atoms are optionally oxidized, and wherein said ring group comprises at least one double bond between adjacent ring atoms and does not comprise any triple bond between adjacent ring atoms.

[0242] As used herein, the term "halogen” refers to fluoro (-F), chloro (-CI), bromo (-Br), or iodo (-1).

[0243] As used herein, the term “haloalkyl” refers to an alkyl group substituted with one or more (preferably 1 to 6, more preferably 1 to 3) halogen atoms which are selected independently from fluoro, chloro, bromo and iodo, and are preferably all fluoro atoms. It will be understood that the maximum number of halogen atoms is limited by the number of available attachment sites and, thus, depends on the number of carbon atoms comprised in the alkyl moiety of the haloalkyl group. "Haloalkyl” may, e.g., refer to -CF3, -CHF2, -CH2F, -CF2-CH3, -CH2-CF3, -CH2-CHF2, -CH2-CF2-CH3, -CH2-CF2-CF3, or -CH(CF3)2. A preferred "haloalkyl” group is fluoroalkyl. A particularly preferred "haloalkyl” group is -CF3.

[0244] As used herein, the term “fluoroalky I” refers to an alkyl group substituted with one or more (preferably 1 to 6, more preferably 1 to 3) fluoro atoms (-F). It will be understood that the maximum number of fluoro atoms is limited by the number of available attachment sites and, thus, depends on the number of carbon atoms comprised in the alkyl moiety of the fluoroalkyl group. “ Fluoroalky I” may, e.g., refer to -CF3, -CHF2, -CH2F, -CF2-CH3, -CH2-CF3, -CH2-CHF2, -CH2-CF2-CH3, -CH2-CF2-CF3, or -CH(CF3)2. A particularly preferred “fluoroalkyl” group is -CF3.

[0245] The terms "bond” and "covalent bond” are used herein synonymously, unless explicitly indicated otherwise or contradicted by context.

[0246] As used herein, the terms "optional”, "optionally” and "may” denote that the indicated feature may be present but can also be absent. Whenever the term "optional”, "optionally” or "may” is used, the present invention specifically relates to both possibilities, i.e., that the corresponding feature is present or, alternatively, that the corresponding feature is absent. For example, the expression "X is optionally substituted with Y” (or "X may be substituted with Y”) means that X is either substituted with Y or is unsubstituted. Likewise, if a component of a composition is indicated to be "optional”, the invention specifically relates to both possibilities, i.e., that the corresponding component is present (contained in the composition) or that the corresponding component is absent from the composition.

[0247] Various groups are referred to as being "optionally substituted” in this specification. Generally, these groups may carry one or more substituents, such as, e.g., one, two, three or four substituents. It will be understood that the maximum number of substituents is limited by the number of attachment sites available on the substituted moiety. Unless defined otherwise, the "optionally substituted” groups referred to in this specification carry preferably not morethan two substituents and may, in particular, carry only one substituent. Moreover, unless defined otherwise, it is preferred that the optional substituents are absent, i.e. that the corresponding groups are unsubstituted.

[0248] A skilled person will appreciate that the substituent groups comprised in the compounds of the present invention may be attached to the remainder of the respective compound via a number of different positions of the corresponding specific substituent group. Unless defined otherwise, the preferred attachment positions for the various specific substituent groups are as illustrated in the examples.

[0249] As used herein, unless explicitly indicated otherwise or contradicted by context, the terms "a”, "an” and "the” are used interchangeably with "one or more” and "at least one”. Thus, for example, a composition comprising "a” compound of formula (I) can be interpreted as referring to a composition comprising "one or more” compounds of formula (I).

[0250] It is to be understood that wherever numerical ranges are provided / disclosed herein, all values and subranges encompassed by the respective numerical range are meant to be encompassed within the scope of the invention. Accordingly, the present invention specifically and individually relates to each value that falls within a numerical range disclosed herein, as well as each subrange encompassed by a numerical range disclosed herein.

[0251] As used herein, the term "about” preferably refers to ±10% of the indicated numerical value, more preferably to ±5% of the indicated numerical value, and in particular to the exact numerical value indicated. If the term "about” is used in connection with the endpoints of a range, it preferably refers to the range from the lower endpoint -10% of its indicated numerical value to the upper endpoint +10% of its indicated numerical value, more preferably to the range from of the lower endpoint -5% to the upper endpoint +5%, and even more preferably to the range defined by the exact numerical values of the lower endpoint and the upper endpoint.

[0252] As used herein, the term "comprising” (or "comprise”, "comprises”, "contain”, "contains”, or "containing”), unless explicitly indicated otherwise or contradicted by context, has the meaning of "containing, inter alia”, i.e., "containing, among further optional elements, ...”. In addition thereto, this term also includes the narrower meanings of "consisting essentially of' and "consisting of”. For example, the term "A comprising B and C” has the meaning of "A containing, inter alia, B and C”, wherein A may contain further optional elements (e.g., "A containing B, C and D” would also be encompassed), but this term also includes the meaning of "A consisting essentially of B and C” and the meaning of "A consisting of B and C” (i.e., no other components than B and C are comprised in A).

[0253] The scope of the invention embraces all pharmaceutically acceptable salt forms of the compounds of formula (I) which may be formed, e.g., by protonation of an atom carrying an electron lone pair which is susceptible to protonation, such as an amino group, with an inorganic or organic acid, or as a salt of an acid group (such as a carboxylic acid group) with a physiologically acceptable cation. Exemplary base addition salts comprise, for example: alkali metal salts such as sodium or potassium salts; alkaline earth metal salts such as calcium or magnesium salts; zinc salts; ammonium salts; aliphatic amine salts such as trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, procaine salts, meglumine salts, ethylenediamine salts, or choline salts; aralkyl amine salts such as N, N-dibenzylethylenediamine salts, benzathine salts, benethamine salts; heterocyclic aromaticamine salts such as pyridine salts, picoline salts, quinoline salts or isoquinoline salts; quaternary ammonium salts such as tetramethylammonium salts, tetraethylammonium salts, benzyltrimethylammonium salts, benzyltriethylammonium salts, benzyltributylammonium salts, methyltrioctylammonium salts or tetrabutylammonium salts; and basic amino acid salts such as arginine salts, lysine salts, or histidine salts. Exemplary acid addition salts comprise, for example: mineral acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate salts (such as, e.g., sulfate or hydrogensulfate salts), nitrate salts, phosphate salts (such as, e.g., phosphate, hydrogenphosphate, or dihydrogenphosphate salts), carbonate salts, hydrogencarbonate salts, perchlorate salts, borate salts, or thiocyanate salts; organic acid salts such as acetate, propionate, butyrate, pentanoate, hexanoate, heptanoate, octanoate, cyclopentanepropionate, decanoate, undecanoate, oleate, stearate, lactate, maleate, oxalate, fumarate, tartrate, malate, citrate, succinate, adipate, gluconate, glycolate, nicotinate, benzoate, salicylate, ascorbate, pamoate (embonate), camphorate, glucoheptanoate, or pivalate salts; sulfonate salts such as methanesulfonate (mesylate), ethanesulfonate (esylate), 2-hydroxyethanesulfonate (isethionate), benzenesulfonate (besylate), p-toluenesulfonate (tosylate), 2-naphthalenesulfonate (napsylate), 3-phenylsulfonate, or camphorsulfonate salts; glycerophosphate salts; and acidic amino acid salts such as aspartate or glutamate salts. Further pharmaceutically acceptable salts are described in the literature, e.g., in Stahl PH & Wermuth CG (eds.), "Handbook of Pharmaceutical Salts: Properties, Selection, and Use”, Wiley-VCH, 2002 and in the references cited therein. Preferred pharmaceutically acceptable salts of the compounds of formula (I) include a hydrochloride salt, a hydrobromide salt, a mesylate salt, a sulfate salt, a tartrate salt, a fumarate salt, an acetate salt, a citrate salt, and a phosphate salt. A particularly preferred pharmaceutically acceptable salt of the compound of formula (I) is a hydrochloride salt. Accordingly, it is preferred that the compound of formula (I), including any one of the specific compounds of formula (I) described herein, is in the form of a hydrochloride salt, a hydrobromide salt, a mesylate salt, a sulfate salt, a tartrate salt, a fumarate salt, an acetate salt, a citrate salt, or a phosphate salt, and it is particularly preferred that the compound of formula (I) is in the form of a hydrochloride salt.

[0254] The present invention also specifically relates to the compound of formula (I), including any one of the specific compounds of formula (I) described herein, in non-salt form.

[0255] Moreover, the scope of the invention embraces the compounds of formula (I) in any solvated form, including, e.g., solvates with water (I ,e. , as a hydrate) or solvates with organic solvents such as, e.g., methanol, ethanol, isopropanol, acetic acid, ethyl acetate, ethanolamine, DMSO, or acetonitrile. All physical forms, including any amorphous or crystalline forms (i.e., polymorphs), of the compounds of formula (I) are also encompassed within the scope of the invention. It is to be understood that such solvates and physical forms of pharmaceutically acceptable salts of the compounds of the formula (I) are likewise embraced by the invention.

[0256] Furthermore, the compounds of formula (I) may exist in the form of different isomers, in particular stereoisomers (including, e.g., geometric isomers (or cis / trans isomers), enantiomers and diastereomers) or tautomers (including, in particular, prototropic tautomers, such as keto / enol tautomers or thione / thiol tautomers). All such isomers of the compounds of formula (I) are contemplated as being part of the present invention, either in admixture or in pure or substantially pure form. As for stereoisomers, the invention embraces the isolated optical isomers of the compounds according to the invention as well as any mixtures thereof (including, in particular, racemic mixtures / racemates). Theracemates can be resolved by physical methods, such as, e.g., fractional crystallization, separation or crystallization of diastereomeric derivatives, or separation by chiral column chromatography. The individual optical isomers can also be obtained from the racemates via salt formation with an optically active acid followed by crystallization. The present invention further encompasses any tautomers of the compounds of formula (I). It will be understood that some compounds may exhibit tautomerism. In such cases, the formulae provided herein expressly depict only one of the possible tautomeric forms. The formulae and chemical names as provided herein are intended to encompass any tautomeric form of the corresponding compound and not to be limited merely to the specific tautomeric form depicted by the drawing or identified by the name of the compound.

[0257] The scope of the invention also embraces compounds of formula (I), in which one or more atoms are replaced by a specific isotope of the corresponding atom. For example, the invention encompasses compounds of formula (I), in which one or more hydrogen atoms (or, e.g., all hydrogen atoms) are replaced by deuterium atoms (i.e.,2H; also referred to as “D”). Accordingly, the invention also embraces compounds of formula (I) which are enriched in deuterium. Naturally occurring hydrogen is an isotopic mixture comprising about 99.98 mol-% hydrogen-1 (1H) and about 0.0156 mol-% deuterium (2H or D). The content of deuterium in one or more hydrogen positions in the compounds of formula (I) can be increased using deuteration techniques known in the art. For example, a compound of formula (I) or a reactant or precursor to be used in the synthesis of the compound of formula (I) can be subjected to an H / D exchange reaction using, e.g., heavy water (D2O). Further suitable deuteration techniques are described in: Atzrodt J et al., Bioorg Med Chem, 20(18), 5658-5667, 2012; William JS et al., Journal of Labelled Compounds and Radiopharmaceuticals, 53(11-12), 635-644, 2010; Modvig A et al., J Org Chem, 79, 5861-5868, 2014. The content of deuterium can be determined, e.g., using mass spectrometry or NMR spectroscopy. Unless specifically indicated otherwise, it is preferred that the compound of formula (I) is not enriched in deuterium. Accordingly, the presence of naturally occurring hydrogen atoms or1H hydrogen atoms in the compounds of formula (I) is preferred.

[0258] The present invention also embraces compounds of formula (I), in which one or more atoms are replaced by a positron-emitting isotope of the corresponding atom, such as, e.g.,18F,11C,13N,150,76Br,77Br,120l and / or124l. Such compounds can be used as tracers, trackers or imaging probes in positron emission tomography (PET). The invention thus includes (i) compounds of formula (I), in which one or more fluorine atoms (or, e.g., all fluorine atoms) are replaced by18F atoms, (ii) compounds of formula (I), in which one or more carbon atoms (or, e.g., all carbon atoms) are replaced by11C atoms, (iii) compounds of formula (I), in which one or more nitrogen atoms (or, e.g., all nitrogen atoms) are replaced by13N atoms, (iv) compounds of formula (I), in which one or more oxygen atoms (or, e.g., all oxygen atoms) are replaced by15O atoms, (v) compounds of formula (I), in which one or more bromine atoms (or, e.g., all bromine atoms) are replaced by76Br atoms, (vi) compounds of formula (I), in which one or more bromine atoms (or, e.g., all bromine atoms) are replaced by77Br atoms, (vii) compounds of formula (I), in which one or more iodine atoms (or, e.g., all iodine atoms) are replaced by120l atoms, and (viii) compounds of formula (I), in which one or more iodine atoms (or, e.g., all iodine atoms) are replaced by124l atoms. In general, it is preferred that none of the atoms in the compounds of formula (I) are replaced by specific isotopes.

[0259] The compounds provided herein may be administered as compounds perse or may be formulated as medicaments. The medicaments / pharmaceutical compositions may optionally comprise one or more pharmaceutically acceptableexcipients, such as carriers, diluents, fillers, disintegrants, lubricating agents, binders, colorants, pigments, stabilizers, preservatives, antioxidants, and / or solubility enhancers.

[0260] The pharmaceutical compositions may comprise one or more solubility enhancers, such as, e.g., poly(ethylene glycol), including poly (ethylene glycol) having a molecular weight in the range of about 200 to about 5,000 Da (e.g., PEG 200, PEG 300, PEG 400, or PEG 600), ethylene glycol, propylene glycol, glycerol, a non-ionic surfactant, tyloxapol, polysorbate 80, macrogol-15-hydroxystearate (e.g., Kolliphor® HS 15, CAS 70142-34-6), a phospholipid, lecithin, dimyristoyl phosphatidylcholine, dipalmitoyl phosphatidylcholine, distearoyl phosphatidylcholine, a cyclodextrin, o-cyclodextrin, p-cyclodextrin, y-cyclodextrin, hydroxyethyl-p-cyclodextrin, hydroxypropyl-p-cyclodextrin, hydroxyethyl-y-cyclodextrin, hydroxypropyl-y-cyclodextrin, dihydroxypropyl-p-cyclodextrin, sulfobutylether-p-cyclodextrin, sulfobutylether-y-cyclodextrin, glucosyl-o-cyclodextrin, glucosyl-p-cyclodextrin, diglucosyl-p-cyclodextrin, maltosyl-o-cyclodextrin, maltosyl-p-cyclodextrin, maltosyl-y-cyclodextrin, maltotriosyl-p-cyclodextrin, maltotriosyl-y-cyclodextrin, dimaltosyl-p-cyclodextrin, methyl-p-cyclodextrin, a carboxyalkyl thioether, hydroxypropyl methylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, a vinyl acetate copolymer, vinyl pyrrolidone, sodium lauryl sulfate, dioctyl sodium sulfosuccinate, or any combination thereof.

[0261] The pharmaceutical compositions may also comprise one or more preservatives, particularly one or more antimicrobial preservatives, such as, e.g., benzyl alcohol, chlorobutanol, 2-ethoxyethanol, m-cresol, chlorocresol (e.g., 2-chloro-3-methyl-phenol or 4-chloro-3-methy l-phenol), benzalkonium chloride, benzethonium chloride, benzoic acid (or a pharmaceutically acceptable salt thereof), sorbic acid (or a pharmaceutically acceptable salt thereof), chlorhexidine, thimerosal, or any combination thereof.

[0262] The pharmaceutical compositions can be formulated by techniques known to the person skilled in the art, such as the techniques published in "Remington: The Science and Practice of Pharmacy”, Pharmaceutical Press, 22ndedition. The pharmaceutical compositions can be formulated as dosage forms for oral, parenteral, such as intramuscular, intravenous, subcutaneous, intradermal, intraarterial, intracardial, rectal, nasal, topical, aerosol or vaginal administration. Dosage forms for oral administration include coated and uncoated tablets, soft gelatin capsules, hard gelatin capsules, lozenges, troches, solutions, emulsions, suspensions, syrups, elixirs, powders and granules for reconstitution, dispersible powders and granules, medicated gums, chewing tablets and effervescent tablets. Dosage forms for parenteral administration include solutions, emulsions, suspensions, dispersions and powders and granules for reconstitution. Emulsions are a preferred dosage form for parenteral administration. Dosage forms for rectal and vaginal administration include suppositories and ovula. Dosage forms for nasal administration can be administered via inhalation and insufflation, for example by a metered inhaler. Dosage forms for topical administration include creams, gels, ointments, salves, patches and transdermal delivery systems.

[0263] The compounds of formula (I) or the pharmaceutically acceptable salts or solvates thereof, or the above described pharmaceutical compositions comprising any of the aforementioned entities, may be administered to a subject by any convenient route of administration, whether systemically / peri pherally or at the site of desired action, including but not limited to one or more of: oral (e.g., as a tablet, capsule, or as an ingestible solution), topical (e.g., transdermal, intranasal, ocular, buccal, and sublingual), parenteral (e.g., using injection techniques or infusion techniques, andincluding, for example, by injection, e.g., subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, or intrasternal by, e.g., implant of a depot, for example, subcutaneously or intramuscularly), pulmonary (e.g., by inhalation or insufflation therapy using, e.g., an aerosol, e.g., through mouth or nose), gastrointestinal, intrauterine, intraocular, subcutaneous, ophthalmic (including intravitreal or intracameral), rectal, or vaginal administration.

[0264] If said compounds or pharmaceutical compositions are administered parenterally, then examples of such administration include one or more of: intravenously, intraarterially, intraperitoneally, intrathecally, intraventricularly, intraurethrally, intrasternally, intracardially, intracranially, intramuscularly or subcutaneously administering the compounds or pharmaceutical compositions, and / or by using infusion techniques. For parenteral administration, the compounds are best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood. The aqueous solutions should be suitably buffered (preferably to a pH of from 3 to 9), if necessary. The preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.

[0265] Said compounds or pharmaceutical compositions can also be administered orally in the form of tablets, capsules, ovules, elixirs, solutions or suspensions, which may contain flavoring or coloring agents, for immediate-, delayed-, modified-, sustained-, pulsed- or controlled-release applications.

[0266] The tablets may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine, disintegrants such as starch (preferably corn, potato or tapioca starch), sodium starch glycolate, croscarmellose sodium and certain complex silicates, and granulation binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included. Solid compositions of a similar type may also be employed as fillers in gelatin capsules. Preferred excipients in this regard include lactose, starch, a cellulose, or high molecular weight polyethylene glycols. For aqueous suspensions and / or elixirs, the agent may be combined with various sweetening or flavoring agents, coloring matter or dyes, with emulsifying and / or suspending agents and with diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof.

[0267] For oral administration, the compounds or pharmaceutical compositions are preferably administered by oral ingestion, particularly by swallowing. The compounds or pharmaceutical compositions can thus be administered to pass through the mouth into the gastrointestinal tract, which can also be referred to as "oral-gastrointestinal” administration.

[0268] Alternatively, said compounds or pharmaceutical compositions can be administered in the form of a suppository or pessary, or may be applied topically in the form of a gel, hydrogel, lotion, solution, cream, ointment or dusting powder. The compounds of the present invention may also be dermally or transdermally administered, for example, by the use of a skin patch.Said compounds or pharmaceutical compositions may also be administered by sustained release systems. Suitable examples of sustained-release compositions include semi-permeable polymer matrices in the form of shaped articles, e.g., films, or microcapsules. Sustained-release matrices include, e.g., polylactides, copolymers of L-glutamic acid and gamma-ethyl-L-glutamate, poly(2-hydroxyethyl methacrylate), ethylene vinyl acetate, or poly-D-(— )-3-hydroxybutyric acid. Sustained-release pharmaceutical compositions also include I iposomally entrapped compounds. The present invention thus also relates to liposomes containing a compound of the invention.

[0269] Said compounds or pharmaceutical compositions may also be administered by the pulmonary route, rectal routes, or the ocular route. For ophthalmic use, they can be formulated as micronized suspensions in isotonic, pH adjusted, sterile saline, or, preferably, as solutions in isotonic, pH adjusted, sterile saline, optionally in combination with a preservative such as a benzalkonium chloride. Alternatively, they may be formulated in an ointment such as petrolatum.

[0270] It is also envisaged to prepare dry powder formulations of the compounds of formula (I) for pulmonary administration, particularly inhalation. Such dry powders may be prepared by spray drying under conditions which result in a substantially amorphous glassy or a substantially crystalline bioactive powder. Accordingly, dry powders of the compounds of the present invention can be made according to an emulsification / spray drying process.

[0271] For topical application to the skin, said compounds or pharmaceutical compositions can be formulated as a suitable ointment containing the active compound suspended or dissolved in, for example, a mixture with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, emulsifying wax and water. Alternatively, they can be formulated as a suitable lotion or cream, suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, a polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax, 2-octyldodecanol, benzyl alcohol and water.

[0272] The present invention thus relates to the compounds or the pharmaceutical compositions provided herein, wherein the corresponding compound or pharmaceutical composition is to be administered by any one of: an oral route; topical route, including by transdermal, intranasal, ocular, buccal, or sublingual route; parenteral route using injection techniques or infusion techniques, including by subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, intrasternal, intraventricular, intraurethral, or intracranial route; pulmonary route, including by inhalation or insufflation therapy; gastrointestinal route; intrauterine route; intraocular route; subcutaneous route; ophthalmic route, including by intravitreal, or intracameral route; rectal route; or vaginal route. Preferred routes of administration are oral administration or parenteral administration. For each of the compounds or pharmaceutical compositions provided herein, it is particularly preferred that the respective compound or pharmaceutical composition is to be administered orally (particularly by oral ingestion).

[0273] Typically, a physician will determine the actual dosage which will be most suitable for an individual subject. The specific dose level and frequency of dosage for any particular individual subject may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length ofaction of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the individual subject undergoing therapy.

[0274] A proposed, yet non-limiting dose of the compounds according to the invention for oral administration to a human (of approximately 70 kg body weight) may be 0.05 to 2000 mg, preferably 0.1 mg to 1000 mg, of the active ingredient per unit dose. The unit dose may be administered, e.g., 1 to 3 times per day. The unit dose may also be administered 1 to 7 times per week, e.g., with not more than one administration per day. It will be appreciated that it may be necessary to make routine variations to the dosage depending on the age and weight of the patient / subject as well as the severity of the condition to be treated. The precise dose and also the route of administration will ultimately be at the discretion of the attendant physician or veterinarian.

[0275] The compound of formula (I) or the pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising any of the aforementioned entities, can be administered in monotherapy (e.g., without concomitantly administering any further therapeutic agents, or without concomitantly administering any further therapeutic agents against the same disease that is to be treated or prevented with the compound of formula (I)). However, the compound of formula (I) or the pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising any of the aforementioned entities, can also be administered in combination with one or more further therapeutic agents. If the compound of formula (I) is used in combination with a second therapeutic agent active against the same disease or condition, the dose of each compound may differ from that when the corresponding compound is used alone, in particular, a lower dose of each compound may be used. The combination of the compound of formula (I) with one or more further therapeutic agents may comprise the simultaneous / concomitant administration of the compound of formula (I) and the further therapeutic agent(s) (either in a single pharmaceutical formulation or in separate pharmaceutical formulations), or the sequential / separate administration of the compound of formula (I) and the further therapeutic agent(s). If administration is sequential, either the compound of formula (I) according to the invention or the one or more further therapeutic agents may be administered first. If administration is simultaneous, the one or more further therapeutic agents may be included in the same pharmaceutical formulation as the compound of formula (I), or they may be administered in two or more different (separate) pharmaceutical formulations.

[0276] For the treatment or prevention of cancer, the one or more further therapeutic agents to be administered in combination with a compound of the present invention are preferably anticancer drugs. The anticancer drug(s) to be administered in combination with a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof may, e.g., be selected from: a tumor angiogenesis inhibitor (e.g., a protease inhibitor, an epidermal growth factor receptor kinase inhibitor, or a vascular endothelial growth factor receptor kinase inhibitor); a cytotoxic drug (e.g., an antimetabolite, such as purine and pyrimidine analog antimetabolites); an antimitotic agent (e.g., a microtubule stabilizing drug or an antimitotic alkaloid); a platinum coordination complex; an anti-tumor antibiotic; an alkylating agent (e.g., a nitrogen mustard or a nitrosourea); an endocrine agent (e.g., an adrenocorticosteroid, an androgen, an anti-androgen, an estrogen, an anti-estrogen, an aromatase inhibitor, a gonadotropin-releasing hormone agonist, or a somatostatin analog); a compound that targets an enzyme or receptor that is overexpressed and / or otherwise involved in a specific metabolic pathway that is deregulated (or misregulated) in the tumor cell (e.g., ATP and GTPphosphodiesterase inhibitors, histone deacetylase inhibitors, protein kinase inhibitors (such as serine, threonine and tyrosine kinase inhibitors, e.g., Abelson protein tyrosine kinase inhibitors) and the various growth factors, their receptors and corresponding kinase inhibitors (such as epidermal growth factor receptor kinase inhibitors, vascular endothelial growth factor receptor kinase inhibitors, fibroblast growth factor inhibitors, insulin-like growth factor receptor inhibitors and platelet-derived growth factor receptor kinase inhibitors)); methionine; an aminopeptidase inhibitor; a proteasome inhibitor; a cyclooxygenase inhibitor (e.g., a cyclooxygenase-1 inhibitor or a cyclooxygenase-2 inhibitor); a topoisomerase inhibitor (e.g., a topoisomerase I inhibitor or a topoisomerase II inhibitor); a poly ADP ribose polymerase inhibitor (PARP inhibitor); an epidermal growth factor receptor (EGFR) inhibitor / antagonist; an adenosine A2A receptor antagonist; an adenosine A2B receptor antagonist; a dual adenosine A2A / A2B receptor antagonist; and a prostaglandin E2 receptor 4 (EP4) antagonist.

[0277] An alkylating agent which can be used as an anticancer drug in combination with a compound of the present invention may be, for example, a nitrogen mustard (such as cyclophosphamide, mechlorethamine (chlormethine), uramustine, melphalan, chlorambucil, ifosfamide, bendamustine, or trofosfamide), a nitrosourea (such as carmustine, streptozocin, fotemustine, lomustine, nimustine, prednimustine, ranimustine, or semustine), an alkyl sulfonate (such as busulfan, mannosulfan, or treosulfan), an aziridine (such as hexamethylmelamine (altretamine), triethylenemelamine, ThioTEPA (N.N'N'-triethylenethiophosphoramide), carboquone, or triaziquone), a hydrazine (such as procarbazine), a triazene (such as dacarbazine), or an imidazotetrazine (such as temozolomide).

[0278] A platinum coordination complex which can be used as an anticancer drug in combination with a compound of the present invention may be, for example, cisplatin, carboplatin, nedaplatin, oxaliplatin, satraplatin, or triplatin tetranitrate.

[0279] A cytotoxic drug which can be used as an anticancer drug in combination with a compound of the present invention may be, for example, an anti metabolite, including folic acid analogue antimetabolites (such as aminopterin, methotrexate, pemetrexed, or raltitrexed), purine analogue anti metabolites (such as cladribine, clofarabine, fludarabine, 6-mercaptopurine (including its prodrug form azathioprine), pentostatin, or 6-thiog uan I ne), and pyrimidine analogue antimetabolites (such as cytarabine, decitabine, 5-fluorouraci I (including its prodrug forms capecitabine and tegafur), floxuridine, gemcitabine, enocitabine, or sapacitabine).

[0280] An antimitotic agent which can be used as an anticancer drug in combination with a compound of the present invention may be, for example, a taxane (such as docetaxel, larotaxel, ortataxel, paclitaxel / taxol, tesetaxel, or nab-paclitaxel (e.g., Abraxane®)), a Vinca alkaloid (such as vinblastine, vincristine, vinflunine, vindesine, or vinorelbine), an epothilone (such as epothilone A, epothilone B, epothilone C, epothilone D, epothilone E, or epothilone F) or an epothilone B analogue (such as ixabepilone / azaepothilone B).

[0281] An anti-tumor antibiotic which can be used as an anticancer drug in combination with a compound of the present invention may be, for example, an anthracycline (such as aclarubicin, daunorubicin, doxorubicin, epirubicin, idarubicin, amrubicin, pirarubicin, valrubicin, or zorubicin), an anthracenedione (such as mitoxantrone, or pixantrone) or an anti-tumor antibiotic isolated from Streptomyces (such as actinomycin (including actinomycin D), bleomycin, mitomycin (including mitomycin C), or plicamycin).

[0282] A tyrosine kinase inhibitor which can be used as an anticancer drug in combination with a compound of the present invention may be, for example, axitinib, bosutinib, cediranib, dasatinib, erlotinib, gefitinib, imatinib, lapatinib, lestaurtinib, nilotinib, semaxanib, sorafenib, sunitinib, axitinib, nintedanib, ponatinib, vandetanib, or vemurafenib.A topoisomerase inhibitor which can be used as an anticancer drug in combination with a compound of the present invention may be, for example, a topoisomerase I inhibitor (such as irinotecan, topotecan, camptothecin, belotecan, rubitecan, or lamellarin D) or a topoisomerase II inhibitor (such as amsacrine, etoposide, etoposide phosphate, teniposide, or doxorubicin).

[0283] A PARP inhibitor which can be used as an anticancer drug in combination with a compound of the present invention may be, for example, niraparib, olaparib, rucaparib, talazoparib, veliparib, pamiparib (BGB-290), BMN-673, CEP 9722, MK 4827, E7016, or 3-aminobenzamide.

[0284] An EGFR inhibitor / antagonist which can be used as an anticancer drug in combination with a compound of the present invention may be, for example, gefitinib, erlotinib, lapatinib, afatinib, neratinib, osimertinib, brigatinib, dacomitinib, vandetanib, pelitinib, canertinib, icotinib, poziotinib, ABT-414, AV-412, PD 153035, PKI-166, BMS-690514, CUDC-101, AP26113, XL647, cetuximab, panitumumab, zalutumumab, nimotuzumab, or matuzumab.

[0285] An adenosine A2A receptor antagonist which can be used as an anticancer drug in combination with a compound of the present invention may be, for example, ciforadenant, imaradenant, inupadenant, istradefyl line, preladenant, SCH-58261, SCH-442416, ST 1535, or ZM241385.

[0286] An adenosine A2B receptor antagonist which can be used as an anticancer drug in combination with a compound of the present invention may be, for example, LAS38096 or LAS101057.

[0287] A dual adenosine A2A / A2B receptor antagonist which can be used as an anticancer drug in combination with a compound of the present invention may be, for example, M1069, etrumadenant, or I NCB106385.

[0288] A prostaglandin E2 receptor 4 (EP4) antagonist which can be used as an anticancer drug in combination with a compound of the present invention may be, for example, DT-9081 , grapiprant, palupiprant, BAY-1316957, CJ-42794, ER-819762, GW627368, L-161982, MF498, MF-766, MK-2894, or ONO-AE3-208.

[0289] Further anticancer drugs may also be used in combination with a compound of the present invention. The anticancer drugs may comprise biological or chemical molecules, like TNF-related apoptosis-inducing ligand (TRAIL), tamoxifen, amsacrine, bexarotene, estramustine, irofulven, trabectedin, cetuximab, panitumumab, tositumomab, alemtuzumab, bevacizumab, edrecolomab, gemtuzumab, alvocidib, seliciclib, aminolevulinic acid, methyl aminolevulinate, efaproxiral, porfimer sodium, talaporfin, temoporfin, verteporfin, alitretinoin, tretinoin, anagrelide, arsenic trioxide, atrasentan, bortezomib, carmofur, celecoxib, demecolcine, elesclomol, elsamitrucin, etoglucid, lonidamine, lucanthone, masoprocol, mitobronitol, mitoguazone, mitotane, oblimersen, omacetaxine, sitimagene, ceradenovec, tegafur, testolactone, tiazofurine, tipifarnib, vorinostat, iniparib, or copanlisib.

[0290] Also biological drugs, like antibodies, antibody fragments, antibody constructs (for example, single-chain constructs), and / or modified antibodies (like CDR-grafted antibodies, humanized antibodies, "fully human” antibodies, etc.) directed against cancer or tumor markers / factors / cytokines involved in proliferative diseases can be employed in cotherapy approaches with the compounds of the invention. Examples of such biological molecules are anti-HER2 antibodies (e.g., trastuzumab), anti-CD20 antibodies (e.g., rituximab), anti-CD19 / CD3 constructs, and anti-TNF antibodies (see, e.g., Taylor PC, Curr Opin Pharmacol, 2003, 3(3):323-328).

[0291] An anticancer drug which can be used in combination with a compound of the present invention may be, in particular, an immunooncology therapeutic (such as an antibody (e.g., a monoclonal antibody or a polyclonal antibody), an antibody fragment, an antibody construct (e.g., a single-chain construct), or a modified antibody (e.g., a CDR-grafted antibody, a humanized antibody, or a "fully human” antibody) or a small molecule) targeting any one of CTLA-4, PD-1 , PD-L1, TIGIT, TIM3, VISTA, BTLA, CD47, LAG3, 0X40, ICOS, CSF1R, IDO, CD40, adenosine A2A receptor (A2A),adenosine A2B receptor (A2B), A2A / A2B, prostaglandin E2 receptor 4 (EP4), or chemokine (C-C motif) receptor 8 (CCR8). Such immunooncology therapeutics include, e.g., an anti-CTLA-4 antibody (e.g., ipilimumab or tremelimumab), an anti-PD-1 antibody (e.g., nivolumab, pembrolizumab, cemiplimab, spartalizumab, dostarlimab, camrelizumab, sintilimab, tislelizumab, toripalimab, zimberelimab, pidilizumab, penpulimab, cadonilimab, serplulimab, pucotenlimab, prolgolimab, retifanlimab, sintilimab, AMP-224, AMP-514, JTX-4014, or APE02058), an anti-PD-L1 antibody (e.g., atezolizumab, avelumab, durvalumab, envafolimab, adebrelimab, socazolimab, sugemalimab, CK-301, BMS-936559, MEDI4736, MPDL3280A, MDX-1105, MEDI6469, or bintrafusp alfa), an anti-TIGIT antibody (e.g., tiragolumab, vibostolimab, domvanalimab, etigilimab, BMS-986207, EOS-448, COM902, ASP8374, SEA-TGT, BGB-A1217, IBI-939, or M6223), an anti-TIM3 antibody (e.g., sabatolimab, cobolimab, lomvastomig, BGB-A425, BMS-986258, INCAGN02390, LY3321367, LY3415244, SHR-1702, Sym023, or TQB2618), an anti-VISTA antibody (e.g., onvatilimab, HMBD-002, KVA12123, W0180, IGN-381, PMC-309, or APX-201), an anti-BTLA antibody (e.g., tifcemalimab, icatolimab, ANB032, or HFB200603), an anti-CD47 antibody (e.g., magrolimab, lemzoparlimab, ligufalimab, CC-90002, IMM0306, TG-1801, or TI-061), an anti-LAG3 antibody (e.g., relatlimab, ieramilimab, encelimab, tebotelimab, REGN3767, FS118, IMP701, or IMP731), an anti-OX40 antibody (e.g., ivuxolimab, MEDI0562, MEDI6383, MEDI6469, INCAGN01949, ABBV-368, BAT6026, BGB-A445, YH-002, BMS 986178, 1 NBRX-106, IBI101 , or MOXR0916), an anti-ICOS antibody (e.g., alomfilimab, feladilimab, izuralimab, vopratelimab, BMS-986226, or MEDI-570), an anti-CSF1R antibody (e.g., IMC-CS4 or RG7155), an anti-IDO antibody, an anti-CD40 antibody (e.g., CP-870,893 or Chi Lob 7 / 4), or an anti-CCR8 antibody (e.g., DT-7012, BMS-986340, S-531011, BAY-3375968, GS-1811 (or JTX-1811), FPA157, SRF114, HBM1022, or LM-108). Further immunooncology therapeutics are known in the art and are described, e.g., in: Kyi C et al., FEBS Lett, 2014, 588(2):368-76; Intlekofer AM et al., J Leukoc Biol, 2013, 94(1):25-39; Callahan MK et al., J Leukoc Biol, 2013, 94(1):41-53; Ngiow SF et al., Cancer Res, 2011, 71 (21):6567-71; and Blattman JN et al., Science, 2004, 305(5681 ):200-5.

[0292] In particular, a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising any of the aforementioned entities, may be administered in combination with an immune checkpoint inhibitor, preferably an antibody (or an antigen-binding fragment thereof, or an antibody construct) directed against CTLA-4, PD-1, PD-L1, TIGIT, TIM3, VISTA, BTLA, CD47, LAG3, 0X40, or ICOS. Corresponding preferred examples include, but are not limited to, any one of the anti-CTLA-4 antibodies ipilimumab or tremelimumab, any one of the anti-PD-1 antibodies nivolumab, pembrolizumab, cemiplimab, spartalizumab, dostarlimab, camrelizumab, sintilimab, tislelizumab, toripalimab, zimberelimab, pidilizumab, penpulimab, cadonilimab, serplulimab, pucotenlimab, prolgolimab, retifanlimab, sintilimab, AMP-224, AMP-514, JTX-4014, or APE02058, any one of the anti-PD-L1 antibodies atezolizumab, avelumab, durvalumab, envafolimab, adebrelimab, socazolimab, sugemalimab, CK-301, BMS-936559, MEDI4736, MPDL3280A, MDX-1105, MEDI6469, or bintrafusp alfa, any one of the anti-TIGIT antibodies tiragolumab, vibostolimab, domvanalimab, etigilimab, BMS-986207, EOS-448, CCM902, ASP8374, SEA-TGT, BGB-A1217, IBI-939, or M6223, any one of the anti-TIM3 antibodies sabatolimab, cobolimab, lomvastomig, BGB-A425, BMS-986258, INCAGN02390, LY3321367, LY3415244, SHR-1702, Sym023, or TQB2618, any one of the anti-VISTA antibodies onvatilimab, HMBD-002, KVA12123, W0180, IGN-381, PMC-309, or APX-201, any one of the anti-BTLA antibodies tifcemalimab, icatolimab, ANB032, or HFB200603, any one of the anti-CD47 antibodies magrolimab, lemzoparlimab, ligufalimab, CC-90002, IMM0306, TG-1801, or TI-061, any one of the anti-LAG3 antibodies relatlimab, ieramilimab, encelimab, tebotelimab, REGN3767, FS118, IMP701, or IMP731, any one of theanti-OX40 antibodies ivuxolimab, MEDI0562, MEDI6383, MEDI6469, INCAGN01949, ABBV-368, BAT6026, BGB-A445, YH-002, BMS 986178, INBRX-106, IBI101, or MOXR0916, and / or any one of the anti-ICOS antibodies alomfilimab, feladilimab, izuralimab, vopratelimab, BMS-986226, or MEDI-570. The present invention thus relates to a compound of formula (I) or a pharmaceutically acceptable salt or solvates thereof, or a pharmaceutical composition comprising any of the aforementioned entities optionally in combination with a pharmaceutically acceptable excipient, for use in the treatment or prevention of cancer, wherein the compound or the pharmaceutical composition is to be administered in combination with one or more immune checkpoint inhibitors, wherein said one or more immune checkpoint inhibitors are preferably selected from anti-CTLA-4 antibodies, anti-PD-1 antibodies, anti-PD-L1 antibodies, anti-TIGIT antibodies, anti-TIM3 antibodies, anti-VISTA antibodies, anti-BTLA antibodies, anti-CD47 antibodies, anti-LAG3 antibodies, anti-OX40 antibodies, and / or anti-ICOS antibodies; more preferably, said one or more immune checkpoint inhibitors are selected from ipilimumab, tremelimumab, nivolumab, pembrolizumab, cemiplimab, spartalizumab, dostarlimab, camrelizumab, sintilimab, tislelizumab, toripalimab, zimberelimab, pidilizumab, penpulimab, cadonilimab, serplulimab, pucotenlimab, prolgolimab, retifanlimab, sintilimab, AMP-224, AMP-514, JTX-4014, APE02058, atezolizumab, avelumab, durvalumab, envafolimab, adebrelimab, socazolimab, sugemalimab, CK-301 , BMS-936559, MEDI4736, MPDL3280A, MDX-1105, MEDI6469, bintrafusp alfa, tiragolumab, vibostolimab, domvanalimab, etigilimab, BMS-986207, EOS-448, COM902, ASP8374, SEA-TGT, BGB-A1217, IBI-939, M6223, sabatolimab, cobolimab, lomvastomig, BGB-A425, BMS-986258, INCAGN02390, LY3321367, LY3415244, SHR-1702, Sym023, TQB2618, onvatilimab, HMBD-002, KVA12123, W0180, IGN-381, PMC-309, APX-201, tifcemalimab, icatolimab, ANB032, HFB200603, magrolimab, lemzoparlimab, ligufalimab, CC-90002, IMM0306, TG-1801, TI-061, relatlimab, ieramilimab, encelimab, tebotelimab, REGN3767, FS118, IMP701, IMP731 , ivuxolimab, MEDI0562, MEDI6383, MEDI6469, INCAGN01949, ABBV-368, BAT6026, BGB-A445, YH-002, BMS 986178, INBRX-106, IBI101, MOXR0916, alomfilimab, feladilimab, izuralimab, vopratelimab, BMS-986226, and MEDI-570. Moreover, a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising any of the aforementioned entities, may also be administered in combination with an anti-CCR8 antibody (particularly an antagonistic anti-CCR8 antibody), such as, e.g., DT-7012, BMS-986340, S-531011, BAY-3375968, GS-1811 (or JTX-1811), FPA157, SRF114, HBM1022, or LM-108. Accordingly, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt or solvates thereof, or a pharmaceutical composition comprising any of the aforementioned entities optionally in combination with a pharmaceutically acceptable excipient, for use in the treatment or prevention of cancer, wherein the compound or the pharmaceutical composition is to be administered in combination with one or more anti-CCR8 antibodies (which may be selected, e.g., from DT-7012, BMS-986340, S-531011, BAY-3375968, GS-1811 (or JTX-1811), FPA157, SRF114, HBM1022, and LM-108).

[0293] The present invention thus particularly relates to a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising any of the aforementioned entities optionally in combination with a pharmaceutically acceptable excipient, for use in the treatment or prevention of cancer, wherein the compound or the pharmaceutical composition is to be administered in combination with one or more anticancer drugs (including any one or more of the specific anticancer drugs described herein above).

[0294] The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation. The individual components of such combinations may be administered either sequentially orsimultaneously / concomitantly in separate or combined pharmaceutical formulations by any convenient route. When administration is sequential, either the compound of the present invention (i.e., the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof) or the further therapeutic agent(s) may be administered first. When administration is simultaneous, the combination may be administered either in the same pharmaceutical composition or in different pharmaceutical compositions. When combined in the same formulation, it will be appreciated that the two or more compounds must be stable and compatible with each other and the other components of the formulation. When formulated separately, they may be provided in any convenient formulation and may be administered by any convenient route. For the combinations described above, it is preferred that the individual components of such combinations are provided in separate pharmaceutical formulations.

[0295] The subject or patient to be treated in accordance with the present invention may be an animal (e.g., a non-human animal). Preferably, the subject / patient is a mammal. More preferably, the subject / patient is a human (e.g., a male human or a female human) or a non-human mammal (such as, e.g., a guinea pig, a hamster, a rat, a mouse, a rabbit, a dog, a cat, a horse, a monkey, an ape, a marmoset, a baboon, a gorilla, a chimpanzee, an orangutan, a gibbon, a sheep, cattle, or a pig). Most preferably, the subject / patient to be treated in accordance with the invention is a human.

[0296] The term "treatment” of a disorder or disease, as used herein, is well known in the art. "Treatment” of a disorder or disease implies that a disorder or disease is suspected or has been diagnosed in a patient / subject. A patient / subject suspected of suffering from a disorder or disease typically shows specific clinical and / or pathological symptoms which a skilled person can easily attribute to a specific pathological condition (i.e., diagnose a disorder or disease).

[0297] The "treatment” of a disorder or disease may, for example, lead to a halt in the progression of the disorder or disease (e.g., no deterioration of symptoms) or a delay in the progression of the disorder or disease (in case the halt in progression is of a transient nature only). The "treatment” of a disorder or disease may also lead to a partial response (e.g., amelioration of symptoms) or complete response (e.g., disappearance of symptoms) of the subject / patient suffering from the disorder or disease. Accordingly, the "treatment” of a disorder or disease may also refer to an amelioration of the disorder or disease, which may, e.g., lead to a halt in the progression of the disorder or disease or a delay in the progression of the disorder or disease. Such a partial or complete response may be followed by a relapse. It is to be understood that a subject / patient may experience a broad range of responses to a treatment (such as the exemplary responses as described herein above). The treatment of a disorder or disease may, inter alia, comprise curative treatment (preferably leading to a complete response and eventually to healing of the disorder or disease) and palliative treatment (including symptomatic relief).

[0298] The term "prevention” of a disorder or disease, as used herein, is also well known in the art. For example, a patient / subject suspected of being prone to suffer from a disorder or disease may particularly benefit from a prevention of the disorder or disease. The subject / patient may have a susceptibility or predisposition for a disorder or disease, including but not limited to hereditary predisposition. Such a predisposition can be determined by standard methods or assays, using, e.g., genetic markers or phenotypic indicators. It is to be understood that a disorder or disease to be prevented in accordance with the present invention has not been diagnosed or cannot be diagnosed in the patient / subject (for example, the patient / subject does not show any clinical or pathological symptoms). Thus, the term"prevention” comprises the use of a compound of the present invention before any clinical and / or pathological symptoms are diagnosed or determined or can be diagnosed or determined by the attending physician.

[0299] It is to be understood that the present invention specifically relates to each and every combination of features and embodiments described herein, including any combination of general and / or preferred features / embodiments. In particular, the invention specifically relates to each combination of meanings (including general and / or preferred meanings) for the various groups and variables comprised in formula (I).

[0300] In this specification, a number of documents including patent applications and scientific literature are cited. The disclosure of these documents, while not considered relevant for the patentability of this invention, is herewith incorporated by reference in its entirety. More specifically, all referenced documents are incorporated by reference to the same extent as if each individual document was specifically and individually indicated to be incorporated by reference.

[0301] The reference in this specification to any prior publication (or information derived therefrom) is not and should not be taken as an acknowledgment or admission or any form of suggestion that the corresponding prior publication (or the information derived therefrom) forms part of the common general knowledge in the technical field to which the present specification relates.

[0302] The present invention is also illustrated by the following figures:

[0303] Figure 1 illustrates the insurmountable property of a PAR-2 antagonist panel of the present invention for their potential to functionally inhibit calcium signaling pathway. Their insurmountable nature, in pre-incubation experiments, produces a clear-cut rightward shift and a maximal response decrease of the trypsin concentration-response curve. See Example 276.

[0304] Figure 2 shows the influence of an exemplary compound according to the invention (Example 167) on the anti-tumor efficacy of an anti-PD1 antibody. MC38 cells were subcutaneously injected into groups of 12 syngeneic C57BL / 6 mice. Anti-PD 1 antibody or isotype control were intraperitoneally injected at days 6, 9 and 12 post tumor inoculation. The PAR2 inhibitor Example 167 (167) or vehicle were given once a day by oral gavage at a 10mg / kg, 30mg / kg or 100mg / kg dose from day 2 post tumor inoculation to day 6. Anti-tumor efficacy was determined by assessing progression-free survival rate and tumor growth. (A) Progression-free survival. Fig. 2A is a diagram showing the progression free survival rate in MC38 bearing mice treated with vehicle, anti-PD1, or a combination of anti-PD 1 and Example 167. For the combination groups, doses of Example 167 used are indicated. Log-rank (Mantel-Cox) test with Bonferroni correction was used to compare the groups, p < 0.05: *, p < 0.01: **, p < 0.005: ***, p < 0.001: ****.

[0305] (B) Mean tumor growth. Fig. 2B is a diagram showing mean MC38 tumor volume changes in mice treated with vehicle, anti-PD1, or a combination of anti-PD1 and Example 167. For the combination groups, doses of Example 167 used are indicated. Average tumor volume (mm2) and SD bars were plotted for each group. Tukey's multiple comparisons test was used to compare the groups after a mixed effect model test, p < 0.05: *, p < 0.01 : **, p < 0.005: ***, p < 0.001 :

[0306] **** (C) Individual tumor growth. Fig. 2C is a set of diagrams showing MC38 tumor volume changes in mice treatedwith vehicle, anti-PD 1 , or a combination of anti-PD 1 and Example 167. For the combination groups, doses of Example 167 used are indicated. The rate of complete response (CR) is indicated when applicable. See Example 278.

[0307] The invention will now be described by reference to the following examples which are merely illustrative and are not to be construed as a limitation of the scope of the present invention.

[0308] The compounds of formula (I) described in the following examples section are defined by their chemical formulae and their corresponding chemical names. In case of conflict between any chemical formula and the corresponding chemical name indicated herein, the present invention relates to both the compound defined by the chemical formula and the compound defined by the chemical name, and particularly relates to the compound defined by the chemical formula.

[0309] EXAMPLES

[0310] General experimental procedures

[0311] General conditions

[0312] All reagents were commercial grade and used without further purification. Reactions were typically run using commercial anhydrous solvents under argon atmosphere.

[0313] Column chromatography was generally performed with a Biotage Isolera® Four apparatus using, unless stated otherwise, Interchim® PURIFLASH jumbo pack silica HP cartridges pre-filed with 50 m silica gel. Alternatively, Interchim® PURIFLASH jumbo pack silica SDT cartridges pre-filed with 20 pm silica gel (mentioned as 20 pm), or Biotage Star® KP-Amino D cartridges pre-filed with 50 pm silica gel (mentioned as KPNH) could be used when necessary.

[0314] Thin layer chromatography (TLC) was carried out using pre-coated silica gel F-254 plates or Biotage KP-NH TLC plates.

[0315] Releasing of free bases from the corresponding salts was carried out using Biotage ISOLUTE® SCX-2 cation exchange cartridges.

[0316] 1H-NMR spectra were recorded on a Bruker AV-300 spectrometer, on a Bruker AMX-400 spectrometer or on a Bruker Avance NEO 400 Nanobay spectrometer. Proton chemical shifts are listed relative to residual CD3OD (3.31 ppm), DMSO (2.50 ppm), D2O (4.78 ppm) or CDCI3 (7.26 ppm). Splitting patterns are designated as s (singlet), d (doublet), dd (doublet-doublet), t (triplet), tt (triplet-triplet), td (triplet-doublet), q (quartet), quint (quintuplet), sex (sextuplet), sept (septuplet), m (multiplet), bs (broad).UPLC-MS analyses were recorded with an UPLC Waters Aquity platform with a photodiode array detector (210-400 nm) using an Acquity CSH G 1.7 pm (2.1 x 30 mm) column. The mobile phase consisted in a gradient of water with 0.025% of trifluoroacetic acid (TFA) and acetonitrile with 0.025% of TFA. The flow rate was 0.8 mL per min. All analyses were performed at 55 °C. The UPLC system was coupled with a Waters SQD2 platform. All mass spectra were full-scan experiments (mass range 100-800 amu) and were obtained using electrospray ionization.

[0317] HPLC-MS were recorded using an HPLC Waters platform with a 2767 sample manager, a 2525 pump, a photodiode array detector (200-400 nm). This HPLC system was coupled with a Waters Acquity QDa detector. Mass spectra were full-scan experiments (mass range 110-850 amu) and were obtained using electro spray ionization. For analytical samples, the selected column was a XSelect CSH C 3.5 pm (2.1x30 mm) column. For preparative purifications, the selected column was, unless otherwise stated, an XSelect CSH prep C 5 pm (19 x 100 mm) column. The mobile phase consisted in an appropriate gradient of water with 0.1% of formic acid and acetonitrile with 0.1% of formic acid. The flow rate was 1 mL / min in analytical mode, and in preparative mode 25 mL / min.

[0318] Alternatively, HPLC-MS were recorded using a Thermo LC / MS-Ultimate 3000-lon Trap HCT Brucker. Mass spectra were performed on a Brucker Ion Trap and were obtained using electrospray ionization. For analytical samples, the selected column was a Nucleodur 3 pm 4.6 x 100 mm reverse-phase column. The mobile phase consisted in a linear gradient with a flow rate of 1.3 mL / min from 95% A and 5% B to 5% A and 95% B in 8.5 min (solvent A, H2O with 0.1% formic acid; solvent B, acetonitrile with 0.1% formic acid). Preparative purifications were performed on a Gilson PLC 2020 apparatus using a column C8 Princeton SPHER.60-10 pm, mentioned as Column B. The mobile phase consisted in a gradient of acetonitrile (5 to 100%) in water + 0.1% formic acid with a flow rate of 30 mL / min.

[0319] After preparative HPLC, the fractions were combined, eventually partially concentrated under reduced pressure, then freeze dried from a water acetonitrile mixture.

[0320] All HPLC-MS were performed at room temperature.

[0321] Melting points were measured on a Barnstead Electrothermal 9100 or an Electrothermal 1002 and are not corrected.

[0322] Unless mentioned otherwise all compounds isolated by filtration or centrifugation were dried overnight in high vacuum at 50-70 °C.

[0323] General procedures

[0324] General procedure (I): Ester hydrolysis

[0325] To a solution of methyl ester (1.0 eq) in THF (0.1 M) was added lithium hydroxide 1M aq. (1.5 eq). The reaction was stirred at 25 °C for 1 to 18 hours. The reaction mixture was acidified with HCI 1M aq. to pH = 1 then extracted with EtOAc. The organic layer was dried over magnesium sulfate and concentrated to dryness to afford the corresponding crude acid.

[0326] General procedure (II): Methyl ester cleavage

[0327] To a solution of methyl ester in ‘BuOH (0.05 M) was added Sodium ‘Butoxide (10 eq). The reaction was stirred at 60°C for 18 hours. The reaction mixture was diluted with water and acidified with HCI aq. 1 M to pH = 3 then extracted with EtOAc. The organic layer was dried over magnesium sulfate and concentrated to dryness to afford the corresponding crude acid.General procedure (III): Peptidic coupling

[0328] To a mixture of acid in DCM (0.1 M) was added ((1H-benzo[d][1,2,3]triazol-1-yl)oxy)tris(dimethylamino)phosphonium hexafluorophosphate(V) (1.3 eq), N,N-diisopropylethylamine (1.0 to 5.0 eq) and the amine (1.0 to 2.0 eq). The reaction mixture was stirred at 25 °C for 18 hours. The reaction mixture was hydrolyzed with NH4CI sat. aq. then extracted with EtOAc. The organic layer was washed with brine, dried over magnesium sulfate then concentrated to dryness to afford the corresponding crude amide.

[0329] General procedure (lllb): Peptidic coupling

[0330] A mixture of acid (1.0 eq) in DCM (0.1 M-0.2 M) were successively added 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1 , 1 ,3,3-tetramethylisouronium tetrafluoroborate (1.5 eq), N, N-diisopropy lethy I amine (1.0 to 5.0 eq) and the amine (1.0 to 2.0 eq). The mixture was stirred at 25 °C for 18 hours. The reaction mixture was quenched with water then extracted with DCM. The organic layer was washed with brine, dried over magnesium sulfate then concentrated to dryness to afford the corresponding crude amide.

[0331] General procedure (lllc): Peptidic coupling

[0332] To a mixture of acid (1.0 eq) in DCM (0.1 M-0.2 M) were successively added 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.5 eq), the appropriate amine (1.0 to 2.0 eq), 1 H-benzo[d][1 ,2,3]triazol-1-ol hydrate (0.5 eq) and finally N,N-diisopropylethylamine (1.0 to 5.0 eq). The mixture was stirred at 25 °C for 18 hours. The reaction mixture was quenched with NH4CI, then aqueous layer was extracted with DCM. The organic layer was washed with brine, dried over magnesium sulfate then concentrated to dryness to afford the corresponding crude amide.

[0333] General procedure (IV): Amine boc deprotection

[0334] A solution of boc protected amine in DCM (0.2 M, 1 V) was treated with TFA (1 V). The reaction mixture was stirred at 25°C for 1 hour then concentrated under reduced pressure to obtain the corresponding crude amine.

[0335] General procedure (Va): Aromatic bromination

[0336] To a solution of aromatic in EtOAc (0.1 M, 1 V) was added N-bromosuccinimide (1.0 eq) followed by acetic acid (1.0 eq). The reaction mixture was stirred at 25°C for 1 hour, then washed with K2CO3 (sat. aq., 1 V), with Brine (0.3 V), dried over MgSO4, and concentrated under reduced pressure to obtain the crude corresponding brominated aromatic.

[0337] General procedure (Vb): Aromatic bromination

[0338] To a solution of aromatic in DMF (0.1 M, 1 V) was added 1 ,3-Dibromo-5,5-dimethylhydantoin (0.5 eq) at 0°C. The reaction mixture was stirred at 25°C for 2 hours, then acidified with HCI (1 N aq. 1 V) and extracted with DCM (2*2 V), the organic layer was washed with NH4CI (half saturated aq., 2V), dried over MgSO4, and concentrated under reduced pressure to obtain the crude corresponding brominated aromatic.

[0339] General procedure (Via): aminocarbonylation

[0340] In the first chamber of a two-chamber reactor (2*20 mL) was prepared a solution of halide or pseudo-halide, amine (1.0 to 2.0 eq), and triethyl amine (3.0 to 5.0 eq) in the appropriate solvent (0.12 M, 1 V). In the second chamber a suspension of Mo(CO)e (1.5 eq) in the appropriate solvent (1 V) was prepared. Both chambers were sparged with argon for 10 minutes then XantPhos Pd G4 (0.10 eq) was added in the first chamber, and DBU (3.0 eq) was addedin the second chamber. The set up was crimped and heated at 110°C for 16 hours. The mixture in the first chamber was filtered over a Celite pad, rinsed with DCM (3 V), the filtrate was washed with HCI (1M aq., 2*4V), brine (4 V) then dried over magnesium sulfate and concentrated under reduced pressure to obtain crude aminocarbonylated product.

[0341] General procedure (Vlb): aminocarbonylation

[0342] In the first chamber of a two-chamber reactor (2*20 mL) was prepared a solution of halide or pseudo-halide, amine (1.0 to 2.0 eq), Xantphos (0.1 eq), Palladium Chloride (0.1 eq) and triethyl amine (3.0 to 5.0 eq) in the appropriate solvent (0.12 M, 1 V). In the second chamber a suspension of Zinc dust (1.0-3.0 eq) in the appropriate solvent (1 V) was prepared. Both chambers were sparged with argon for 10 minutes, and Oxalyl Chloride (1.5 eq) was added in the second chamber. The set up was crimped and heated at 100°C for 16 hours. The mixture in the first chamber was filtered over a Celite pad, rinsed with the appropriate solvent (1 V), the filtrate was concentrated under reduced pressure to obtain the crude aminocarbonylated product.

[0343] General procedure (VII): methoxycarbonylation

[0344] In the first chamber of a two-chamber reactor (2*20 mL) was prepared a solution of halide or pseudo-halide, and triethyl amine (2.0 eq) in a dioxane / methanol mixture (1:1 0.15 M, 1 V). In the second chamber a suspension of Mo(CO)e (0.5 eq) in the appropriate solvent (1 V) was prepared. Both chambers were sparged with argon for 10 minutes then XantPhos Pd G4 (0.10 eq) was added in the first chamber, and DBU (1.5 eq) was added in the second chamber. The set up was crimped and heated at 80°C for 40 hours. The mixture in the first chamber was filtered over a Celite pad and rinsed with EtOAc (10 V). The filtrate was washed with NH4CI (10V, sat.aq.), brine (10 V), dried over MgSO4 and concentrated under reduced pressure to obtain the crude corresponding methoxycarbonylated product.

[0345] General procedure (VIII): Carboxylation

[0346] In the first chamber of a two-chamber reactor (2*20 mL) was prepared a solution of halide or pseudo-halide, Xantphos (0.1 eq), Palladium Chloride (0.1 eq) and triethyl amine (2.0 eq) in a dioxane / water mixture (1:1 0.15 M, 1 V). In the second chamber a suspension of Zinc dust (3.0 eq) in the appropriate solvent (1 V) was prepared. Both chambers were sparged with argon for 10 minutes, and oxalyl chloride(1.5 eq) was added in the second chamber. The set up was crimped and heated at 80°C for 16 hours. The mixture in the first chamber was filtered over a Celite pad and rinsed with MeOH (3 V). The filtrate was partially concentrated under reduced pressure, then diluted with water (15 V), treated with K2CO3 (sat. aq. 5V) and washed with EtOAc (2*10 V). The aqueous was acidified with HCI (1 M aq.) to pH = 2, then extracted with EtOAc (3*15 V). The organic layers were concentrated under reduced pressure to obtain the crude corresponding carboxylated product.

[0347] General procedure (IX): Buchwald coupling

[0348] Under inert atmosphere, to a solution of amine (1.0 to 2.0 eq) and halide or pseudo halide (1.0 to 2.0 eq) in the appropriate solvent (0.1 M) was added a base (1.0 to 4.0 eq). The mixture was sparged with Argon for 10 min before addition of Palladium catalyst (0.05 to 0.20 eq). The reaction mixture was heated at 25°C to 120 °C for 4 to 20 hours. The reaction mixture was diluted with water, filtered through a pad of Celite, the pad was washed with EtOAc then the organic layer was washed with brine, dried over MgSO4 and concentrated under reduced pressure. The crude residue was purified by flash chromatography to afford the corresponding N-Ary lated amine.

[0349] General procedure (Xa): Nucleophilic aromatic substitutionTo a solution of 2, 3-dichloro-py razi ne (1.0 eq.) in MeTHF (0.2 M, 1 V) at 25°C, was added aniline (1.0 eq.) and Sodium tert-butoxide (2.3 eq). The reaction mixture was stirred at 25°C for 16 hours, then hydrolysed with NH4CI (sat. aq., 2V), diluted with water (2V) and extracted with ethyl acetate (EtOAc 2* 3V). The organic layer was washed with brine, dried over magnesium sulfate then concentrated to dryness to obtain the corresponding amino-pyrazine product.

[0350] General procedure (Xb): Nucleophilic aromatic substitution

[0351] To a solution of 2, 3-dichloro-py razine (1.0 eq) in THF (0.35 M, 1 V) at 25°C, was added amine (1.0 eq.) and DIPEA (1.5 eq.). The reaction mixture was heated at 50°C for 24 hours, then diluted with EtOAc (4V), washed with HOI (1M aq., 2*2V) then with brine (4V), dried over magnesium sulfate then concentrated to dryness to obtain the corresponding amino-pyrazine product.

[0352] General procedure (Xc): Nucleophilic aromatic substitution

[0353] To a solution of (pseudo)haloheteroaryl (1.0 eq) in NMP (0.1 M, 1V) was added the nucleophile (2.0 eq) and the mixture was heated at 150°C for 18 hours. The reaction mixture was diluted with water (4V) and HCI (01. M aq, 1 V), then extracted with EtOAc (3*2V). The organic layer was washed with brine (2*4V), dried over magnesium sulfate then concentrated to dryness to obtain the corresponding amino-pyrazine product.

[0354] General procedure (Xd): Nucleophilic aromatic substitution

[0355] To a solution of (pseudo)haloheteroaryl (1.0 eq) in MeTHF (0.1 M, 1V) was added the nucleophile (2.0 eq) and triethyl amine (2.0 eq) the mixture was heated at 60°C to 80°C for 18 hours. The reaction mixture was diluted with NH4CI (sat. aq. 10V) and extracted with MeTHF (3*10V). The organic layer was washed with brine (10V), dried over magnesium sulfate then concentrated to dryness to obtain the corresponding amino-pyrazine product.

[0356] General procedure (Xe): Nucleophilic aromatic substitution

[0357] To a solution of (pseudo)haloheteroaryl (1.0 eq) in NMP (0.1 M, 1V) was added the nucleophile (2.0-3.0 eq) with or without additional EtaN (2.0-4.0 eq). The mixture was heated at 150°C for 1-18h. The reaction mixture was diluted with NH4CI and was then extracted with EtOAc or MeTHF. The organic layer was washed with brine, dried over magnesium sulfate then concentrated to dryness to obtain the corresponding crude amino-pyrazine product.

[0358] General procedure (Xf): Nucleophilic aromatic substitution

[0359] To a solution of (pseudo)haloheteroaryl (1.0 eq) in ACN (0.1 M-0.2 M) was added the nucleophile (2.0-3.0 eq) with or without additional EtaN (2.0-4.0 eq). The mixture was heated at 50°C for 1-18h. The reaction mixture was diluted with NH4CI and was then extracted with EtOAc. The organic layer was washed with brine, dried over magnesium sulfate then concentrated to dryness to obtain the corresponding crude amino-pyrazine product.

[0360] General procedure (XI): Suzuki coupling

[0361] Under inert atmosphere, to a solution of halide or pseudo halide (1.0 to 2.0 eq) and boronic derivative (1.0 to 4.0 eq) in the appropriate solvent (0.1 M) was added Potassium Carbonate (1.0 to 3.0 eq, 1.2 M aq). The mixture was sparged with Argon for 10 min before addition of Palladium catalyst (0.05 to 0.2 eq). The reaction mixture was heated at 25°C to 120 °C for 4 to 20 hours. The reaction mixture was filtered through a pad of Celite, the pad was washed with EtOAc then the filtrate was concentrated to dryness. The crude residue was purified by flash chromatography to afford the corresponding coupled product.General procedure (Xlla): Negishi coupling

[0362] Under inert atmosphere, to a solution of halide or pseudo halide (1.0 to 2.0 eq) in THF (0.1 M) was added organozinc (2.0 to 5.0 eq, in solution in THF). The mixture was sparged with Argon for 10 min before addition of Pd(dppf)Cl2 (0.10 eq). The reaction mixture was heated at 80 °C for 16 hours. The reaction mixture was filtered through a pad of Celite, the pad was washed with EtOAc then the filtrate was concentrated to dryness. The crude residue was purified by flash chromatography to afford the corresponding coupled product.

[0363] General procedure (Xllb): Negishi coupling

[0364] Under inert atmosphere, to a solution of halide or pseudo halide (1.0 to 2.0 eq) in THF (0.1 M) was added organozinc (2.0 to 5.0 eq, in solution in THF). The mixture was sparged with Argon for 10 min before addition of Pd(dppf)Cl2 (0.10 eq). The reaction mixture was heated at 80 °C for 16 hours. The reaction mixture was quenched with acetic acid (1.0 to 5.0 eq), and directly purified by flash chromatography to afford the corresponding coupled product.

[0365] General procedure (Xllc): Negishi coupling

[0366] Under inert atmosphere, to a solution of halide or pseudo halide (1.0 eq) in THF (0.1 M, 1 V) was added 2-propylzinc bromide in THF (3.0 eq, 0.5 M in solution in THF). The mixture was sparged with Argon for 10 min before addition of Pd(dppf)Cl2 (0.10 eq). The reaction mixture was heated at 80 °C for 16 hours. The reaction mixture was quenched with water (20 vol), extracted with EtOAc (2 x 20 vol). The combined organic layers were washed with brine (10 vol), dried over magnesium sulfate and concentrated to dryness to furnish the crude product.

[0367] General procedure (XIII): Amino-ester synthesis

[0368] To a solution of amino acid (1.0 eq) in MeOH (1 M, 1V) at 0 °C was added of thionyl chloride (2.0 eq), the reaction was heated at 60°C for 18 hours then concentrated under reduced pressure, co-evaporated with toluene (2*1 V). The oily residue was taken up in minimal MeOH (~0.1V) and transferred into Et20 (5V). After vigorous stirring (~30 min) solid formed and was collected by filtration. The solid was washed with Et20 (1 V) and dried under reduced pressure to obtain the corresponding amino-ester (as HCI salt).

[0369] General procedure (XIV): Amino-amide synthesis

[0370] To the amino-ester (HCI salt) ) was added Ammonium hydroxide (30% aq., 50 Eq). The mixture was stirred at 25 °C for 48 hours. The mixture was concentrated under reduced pressure then co-evaporated with ethanol (2*4V) to obtain the corresponding amino-amide.

[0371] General procedure (XV): Hydroxy-pyrazine synthesis

[0372] To a cooled (-35°C) solution of amino-amide (1.0 eq.) in MeOH (0.5 M) was added glyoxal (40% in water, 1.2 eq.), then NaOH (12 M aq., 2.4 eq.) was added dropwise over 20 minutes. The mixture was stirred at -35 °C for 30 min then let warm up at 25 °C for 2 hours. The mixture was cooled at0°C then HCI (12 M aq., 2.4 eq) was added, followed by portion wise addition of sodium bicarbonate (2.4 eq.). The mixture was diluted with water until complete dissolution (~1 V), then partially concentrated under reduced pressure. The obtained solution was extracted with DCM (3*2V), the combined organic layers were dried over MgSO4, and concentrated under reduced pressure to obtain the corresponding hydroxy-pyrazine.

[0373] General procedure (XVI): Hydroxy-pyrazine triflate synthesisTo a suspension of hydroxy-pyrazine (1.0 eq) in DCM (0.2 M, 1V) was added Pyridine (1.2 eq) at 0°C. Trifluoromethanesulfonic anhydride (1.2 eq) was then added dropwise during 30min. The reaction was stirred at 0 °C for 30 min then at 25 °C for 1 hour. The reaction mixture was quenched with water (7V) then extracted with DCM (7V). The organic layer was dried over MgSO4 then concentrated to dryness to obtain the crude corresponding triflate.

[0374] General procedure (XVII): Reductive amination

[0375] To a solution of aldehyde in DCM (0.1 M, 1 V) at 25°C was added the amine (1.5 eq) and Sodium triacetoxyhydroborate (1.5 eq). The reaction mixture was stirred at 60°C for 18 hours, then quenched with NaHCOa (sat. Aq. 2 V) and extracted with DCM (2*8 V). The combined organic layers were washed with brine, dried over MgSO4, and concentrated under reduced pressure to obtain the crude corresponding aldehyde.

[0376] General procedure (XVI lb): Reductive amination

[0377] To a solution of the appropriate amine and cyclopentanecarbaldehyde (1.1 eq) in EtOAc (0.1-0.4 M, 1 V) at 0°C was added Sodium triacetoxyborohydride (2.0 eq) and then trifluoroacetic acid (2.0 eq). The reaction mixture was stirred at from 0°C to rt for 1 hour, then was quenched with NaHCOa (sat. Aq. 5 V) and extracted with EtOAc (2 x 20 vol). The combined organic layers were washed with brine, dried over MgSO4, and concentrated under reduced pressure to obtain the crude corresponding aldehyde.

[0378] General procedure (XVIII): hydrogenation

[0379] To a solution of substrate in EtOH (0.1 M) was added Pd / C (10%) or Pt / C (10%) (0.1 eq). The mixture was sparged with argon for 10 minutes then with Hydrogen for 5 minutes. The mixture was stirred under Hydrogen pressure (1 bar) for 18 hours at 20 °C, then filtered over Celite and the filtrate was concentrated under reduced pressure to obtain the corresponding crude product.

[0380] General procedure (XIX): Saponification of methyl ester

[0381] To a solution / suspension of methyl ester (1.0 eq) in MeTHF (30 V) was added dropwise a solution tetrabutylammonium hydroxide hydrate (40% w / w in water, 3.0 eq). The mixture was heated at 70°C for 20h then cooled to room temperature (rt) and neutralized with 1N HCI (3.0 eq). The mixture was extracted with EtOAc or MeTHF, organic layer was washed with water (2 x 10 vol), then dried over MgSO4, filtered and concentrated to obtain the corresponding crude acid.

[0382] General procedure (XX): Saponification of methyl or ethyl ester

[0383] To a solution / suspension of methyl or ethyl ester (1.0 eq) in THF / H2O (2 / 1, 0.2 M, 1 vol) was added in one portion lithium hydroxide monohydrate (2.0-3.0 eq). The mixture was stirred at 25°C for the appropriate time. The mixture was acidified with 1 N HCI solution to pH = 2 then was extracted with DCM (2 x 10 vol). Organic layer was dried over MgSO4, filtered and concentrated to obtain the corresponding crude acid.

[0384] The synthesis and characterization of various exemplary compounds of formula (I) as well as corresponding synthetic intermediates are described in the following (where they are referred to as "Examples” and "Compounds”, respectively).

[0385] Compound 1: 1-(3-bromo-6-chloropyridin-2-yl)cyclopentane-1 -carbonitrileTo a solution of 3-bromo-6-chloro-2-fluoropyridine (5.00 g) and cyclopentanecarbonitrile (1.0 eq) in toluene (125 mL) was added at 0°C, dropwise over 15 min, a solution of sodium bis(trimethylsilyl)amide (2M in THF, 1.0 eq). The solution was stirred at 0°C for 2 hours then quenched with NH4CI (sat. aq. 60 mL), the aqueous layer was extracted with EtOAc (2*50 mL). The combined organic layers were washed with brine, dried over MgSC , and concentrated under reduced pressure. The residue was purified by flash chromatography (CyHex / Et2O, 100:0 to 80:20) to obtain Compound 1 (5.57 g, 82%) as a white solid.

[0386] M / Z (M[35CI][81Br]+H)+: 287.0

[0387] Compound 2: 1-(3-bromo-6-chloropyridin-2-yl)cyclopentane-1 -carboxamide

[0388] To a solution of Compound 1 (5.57 g) in DMSO (100 mL) was added K2CO3 (2.0 eq) and H2O2 (30% in water, 3.0 eq). The mixture was stirred for 2 hours then another portion of H2O2 was added (3.0 eq). The mixture was stirred for 2 hours then another portion of H2O2 was added (3.0 eq). The mixture was diluted with water (100 mL) and extracted with EtOAc (3*50 mL). The combined organic layers were washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by flash chromatography (CyHex / EtOAc, 100:0 to 0:100) to obtain Compound 2 (5.96 g, quant.) as a white solid.

[0389] M / Z (M[35CI][81Br]+H)+: 305.0

[0390] Compound 3: 5'-chlorospiro[cyclopentane-1 ,3'-py rrolo[3,2-b]py rid i n]-2' (1 'H)-one

[0391] To a solution of Compound 2 (5.97 g) in ‘BuOH (400 mL) were added benzene-1,2-diamine (0.2 eq) and sodium 2-methylpropan-2-olate (3.0 eq). The mixture was sparged with Argon for 30 minutes, then copper(l) oxide (0.1 eq) was added. The vessel was sealed and heated at 100°C for 18 hours. The mixture was filtered over celite, the pad was rinced with EtOAc (250 mL) then with DCM (250 mL) and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (CyHex / EtOAc, 100:0 to 50:50) to obtain Compound 3 (3.37 g, 77%) as a beige solid.

[0392] M / Z (M[35CI]+H)+: 223.0

[0393] Compound 4: 2'-oxo- T,2'-di hydrospiro[cyclopentane-1 , 3'-py rrolo [3, 2-b] py ri d i ne] -5'-carbon i trile

[0394] To a solution of Compound 3 (200 mg) in DMA (6 mL) was added zinc(ll) cyanide (1.5 eq). The mixture was sparged with Argon for 30 minutes, then Bis[tris(tert-butyl)phosphine]palladium (0.1 eq) was added. The vessel was sealed and heated at 130°C for 18 hours. The mixture was filtered over celite, the pad was rinced with EtOAc (50 mL) and the filtrate was concentrated under reduced pressure. The residue was diluted with NH4CI (sat. aq., 100 mL) and extracted with EtOAc (3*50 mL). The combined organic layers were washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by flash chromatography (CyHex / EtOAc, 100:0 to 0:100) to obtain Compound 4 (184 mg, 96%) as a white solid.

[0395] M / Z (M+H)+: 214.1

[0396] Compound 5: 1 '-(4-ch I oro-3-f I uorophenyl)-2'-oxo- T, 2'-dihy d rospiro [cy clopentane-1 , 3'-py rrolo [3, 2-b] py ridine]-5'-carbonitrile

[0397] A solution of Compound 4 (184 mg), 4-bromo-1-chloro-2-fluorobenzene (1.1 eq), K2CO3 (3.0 eq), and Trans-N,N'-Dimethylcyclohexane-1,2-diamine (0.2 eq), in dioxane (10 mL) was sparged with Argon for 20 min, and copper(l) iodide (0.1 eq) was added. The vessel was sealed and heated at 100°C for 18 hours. The mixture was filtered over celite, the pad was rinced with EtOAc (50 mL) and the filtrate was concentrated under reduced pressure.The residue was purified by flash chromatography (CyHex / EtOAc, 100:0 to 50:50) to obtain Compound 5 (250 mg, 85%) as a beige solid.

[0398] M / Z (M[35CI]+H)+: 342.1

[0399] Compound 6: 1 '-(4-ch I oro-3-f I uorophenyl)-2'-oxo- T, 2'-dihy d rospiro [cy clopentane-1 , 3'-py rrolo [3, 2-b] py ridine]-5'-carboxamide

[0400] To a solution of Compound 5 (220 mg) in DMSO (5 mL) was added K2CO3 (2.0 eq) and H2O2 (30% in water, 3.0 eq). The mixture was stirred for 18 hours then was diluted with water (100 mL) and extracted with EtOAc (3*50 mL). The combined organic layers were washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by flash chromatography (CyHex / EtOAc, 100:0 to 0:100) to obtain Compound 6 (240 mg, quant.) as a white solid.

[0401] M / Z (M[35CI]+H)+: 360.2

[0402] Compound 7: methyl T-(4-chloro-3-fluorophenyl)-2'-oxo-T,2'-dihydrospiro[cyclopentane-1,3'-pyrrolo[3,2-b]pyridine]-5'-carboxylate

[0403] To a solution of Compound 6 (230 mg) in MeOH (10 mL) was added N,N-dimethylformamide dimethyl acetal (6.0 eq) and the mixture was heated at 65°C for 6 hours. The mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (CyHex / EtOAc, 100:0 to 50:50) to obtain Compound 7 (212 mg, 89%) as a white solid.

[0404] M / Z (M[35CI]+H)+: 375.2

[0405] Compound 8: 5-((4-chloro-3-fluorophenyl)amino)-6-cyclopentylpicolinic acid

[0406] Compound 8 was obtained according to general procedure (I), starting from Compound 7 (212 mg). The crude was purified by flash chromatography (DCM / MeOH, 100:0 to 80:20) then by preparative HPLC (H2O / MeCN + 0.05% HCOOH) to obtain Compound 8 (95 mg, 50%) as a yellow solid.

[0407] M / Z (M[35CI]+H)+: 335.2

[0408] Example 1: 4-(5-((4-chloro-3-fluorophenyl)amino)-6-cyclopentylpicolinoyl)-3,3-dimethylpiperazin-2-one

[0409]

[0410] Example 1 was obtained according to general procedure (III), starting from Compound 8 (95 mg), using 3,3-dimethylpiperazin-2-one (1.3 eq) and N,N-diisopropylethylamine (3.0 eq). The crude was purified by flash chromatography (CyHex / EtOAc, 100:0 to 0:100) then freeze dried from a MeOH / water mixture to obtain Example 1 (96 mg, 75%) as a white solid.

[0411] 1H-NMR (DMSO-de, 300 MHz) 5: 1.56-1.77 (m, 12H, 3 CH2, 2 CH3); 1.88-1.99 (m, 2H, CH2); 3.27-3.31 (m, 2H, CH2); 3.41-3.51 (m, 1H, CH); 3.52-3.57 (m, 2H, CH2); 6.88 (dd, J 12.0, J2.7 Hz, 1H, Ar); 6.79 (dd, J 8.7, J2.7 Hz, 1H, Ar); 7.37 (t, J 8.7 Hz, 1H, Ar); 7.42 (d, J 8.4 Hz, 1H, Ar); 7.63 (d, J 8.4 Hz, 1H, Ar); 8.06-8.09 (m, 1H, NHCO); 8.12 (s, 1H, NH).

[0412] M / Z (M[35CI]+H)+: 445.0Example 2: 4-(5-((4-chloro-3-fluorophenyl)(methyl)amino)-6-cyclopentylpicolinoyl)-1 ,3,3-trimethylpiperazin-2-one °YT°

[0413]

[0414] 6 4.

[0415] Under inert atmosphere, to a solution of Example 1 (25 mg) in THF (2 mL) was added Sodium Hydride (60% in oil, 2.0 eq) at 0°C. After 5 minutes lodomethane (3.0 eq) was added at 0°C, and the mixture was let warm up at 25°C for 8 hours. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (3*20 mL). The organic layer was washed with brine, dried over MgSC and concentrated under reduced pressure. The residue was purified by flash chromatography (CyHex / EtOAc, 100:0 to 50:50) then freeze dried from a MeOH / water mixture to obtain Example 2 (18 mg, 68%) as a white solid.

[0416] 1H-NMR (DMSO-de, 300 MHz) 5: 1.50-1.58 (m, 2H, CH2); 1.64-1.85 (m, 12H, 3 CH2, 2 CH3); 2.91 (s, 3H, CH3); 3.11-3.22 (m, 4H, CH, CH3); 3.42-3.48 (m, 2H, CH2); 3.58-3.63 (m, 2H, CH2); 6.24 (dd, J 2.7, J 9.0 Hz, 1H, Ar); 6.59 (dd, J 2.7, J 12.9 Hz, 1H, Ar); 7.28 (t, J 9.0 Hz, 1H, Ar); 7.55 (d, J 8.5 Hz, 1H, Ar); 7.71 (d, J 8.5 Hz, 1H, Ar).

[0417] M / Z (M[35CI]+H)+: 473.3

[0418] Compound 9: methyl 5-amino-6-bromopicolinate

[0419] To a solution of methyl 5-aminopicolinate (4.90 g) in DMSO (30 mL) was added portion wise TBABr3(1.03 eq). The reaction mixture was stirred at 25°C for 14 hours then quenched in Na2S2O3(3% aq, 300 mL) and extracted with EtOAc (2*100 mL). The combined organic layers were washed with brine (20 mL), dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (CyHex / EtOAc, 100:0 to 30:70) to obtain Compound 9 (2.02 g, 89%) as a yellow solid.

[0420] M / Z (M[79Br]+H)+: 231.3

[0421] Compound 10: ethyl 5-amino-6-bromopicolinate

[0422] To a solution of Compound 9 (1.15 g) in EtOH (40 mL) was added Sodium Ethoxide (1.1 eq) and the mixture was heated at 60°C for 18 hours. The reaction mixture was concentrated under reduced pressure then diluted in EtOAc (100 mL), washed with NaHCO3(sat. aq. 50 mL) and brine (100 mL), and dried over MgSO4 and concentrated under reduced pressure to obtain Compound 10 (0.61 g, 50%) as a yellow solid.

[0423] M / Z (M[79Br]+H)+: 245.0

[0424] Compound 11: ethyl 5-amino-6-methylpicolinate

[0425] To a solution of Compound 10 (380 mg) in THF (15 mL) was added Cesium fluoride (1.2 eq) and trimethyl boroxine (1.0 eq). The mixture was sparged with argon for 10 minutes then Pd(dppf)CI2.DCM (0.1 eq) was added and the mixture was heated at 100°C for 18 hours. The reaction mixture was quenched in water (50 mL) and extracted with EtOAc (50 mL). The organic layer was washed with brine (50 mL), dried over MgSO4, and concentrated under reduced pressure. The residue was purified by flash chromatography (CyHex / EtOAc, 80:20 to 0:100) to obtain Compound 11 (100 mg, 36%) as a brown solid.

[0426] M / Z (M+H)+: 181.0

[0427] Compound 12: 5-((4-chloro-3-fluorophenyl)amino)-6-methylpicolinic acidCompound 12 was obtained according to general procedure (IX) starting from Compound 11 (100 mg) in THF, with 4-bromo-1-chloro-2-fluorobenzene (1.2 eq) and NaO’Bu (2.0 eq), using BrettPhosPd G1 (0.1 eq) under microwave irradiation at 60°C for 90 minutes. The crude was purified by flash chromatography (DCM / (MeOH / AcOH, 9:1), 100:0 to 80:20) to obtain Compound 12 (20 mg, 13%) as a red oil.

[0428] M / Z (M[35CI]+H)+: 281.0

[0429] Example 3: 4-(5-((4-chloro-3-fluorophenyl)amino)-6-methylpicolinoyl)-3,3-dimethylpiperazin-2-one

[0430]

[0431] Example 3 was obtained according to general procedure (III), starting from Compound 12 (20 mg), using 3,3-dimethylpiperazin-2-one (1.3 eq) and N, N-diisopropylethylamine (3.0 eq). The crude was purified by preparative HPLC (Column B) then freeze dried from a MeOH / water mixture to obtain Example 3 (5 mg, 20%) as a white solid.

[0432] 1H-NMR (DMSO-de, 300 MHz) 5: 1.67 (s, 6H, 2 CH3); 2.43 (s, 3H, CH3); 3.22-3.29 (m, 2H, N-CH2); 3.45-3.52 (m, 2H, N-CH2); 6.85 (dd, J 8.8, 2.1 Hz, 1H, Ar); 6.85 (dd, J 11.8, 2.5 Hz, 1H, Ar); 7.35-7.43 (m, 2H, Ar), 7.63 (d, J 8.5 Hz, 1H, Ar); 8.07 (bs, 1H, NH), 8.12 (bs, 1H, NH)

[0433] M / Z (M[35CI]+H)+: 391.1

[0434] Compound 13: methyl 5-amino-6-iodopicolinate

[0435] To a solution of methyl 5-aminopicolinate (1.0 g) in DMF (10 mL) was added Iodine (1.0 eq) and NalO4 (0.5 eq) then the mixture was heated at 60°C for 20 hours. The mixture was quenched in Na2S2O3 (3% aq. 100 mL), the precipitate was recovered by filtration and dried under high vacuum to obtain Compound 13 (0.75 g, 50%) as a brown solid. M / Z (M+H)+: 279.0

[0436] Compound 14: methyl 5-(((benzyloxy)carbonyl)amino)-6-chloropicolinate

[0437] To a solution of Compound 13 (350 mg) in THF (10 mL) were added at 0°C, N, N-diisopropylethylamine (4.0 eq) and triphosgene (1.0 eq). The mixture was stirred at 0°C for 30 minutes then let warm up at 25°C for 1 hour. Phenylmethanol (2.0 eq) was added and the mixture was stirred for 18 hours at 25°C, then quenched with water (30 mL) and extracted with EtOAc (3*30 mL). The combined organic layers were washed with brine (20 mL), dried over MgSO4, and concentrated under reduced pressure. The residue was purified by flash chromatography (CyHex / EtOAc, 100:0 to 50:50) to obtain Compound 14 (255 mg, 49%) as an off white solid.

[0438] M / Z (M[35CI]+H)+: 321.1

[0439] Compound 15: methyl 5-(((benzyloxy)carbonyl)amino)-6-(prop-1-en-2-yl)picolinate

[0440] Compound 15 was obtained according to general procedure (XI) from Compound 14 (105 mg) in Dioxane with K2CO3 (2.0 eq) and 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1 ,3,2-dioxaborolane (1.5 eq), using Pd(PPhs)4 (0.2 eq) at 100°C for 18 hours. The crude was purified by flash chromatography (CyHex / EtOAc, 100:0 to 50:50) to obtain Compound 15 (52 mg, 49%) as a white solid.

[0441] M / Z (M+H)+: 327.1

[0442] Compound 16: 5-(((benzyloxy)carbonyl)amino)-6-(prop-1-en-2-yl)picolinic acidStarting from Compound 15 (140 mg) and following general procedure (I), Compound 16 (130 mg, 96%) was obtained as an off white solid.

[0443] M / Z (M+H)+: 313.2

[0444] Example 4: benzyl (6-(2,2-dimethyl-3-oxopiperazine-1-carbonyl)-2-(prop-1-en-2-yl)pyridin-3-yl)carbamate

[0445]

[0446] Example 4 was obtained according to general procedure (III), starting from Compound 16 (130 mg), using 3,3-dimethylpiperazin-2-one (1.3 eq) and N,N-diisopropylethylamine (3.0 eq). The crude was purified by flash chromatography (CyHex / EtOAc, 100:0 to 0:100) to obtain Example 4 (110 mg, 74%) as a white solid.

[0447] M / Z (M+H)+: 423.3

[0448] Compound 17: 4-(5-amino-6-isopropylpicolinoyl)-3,3-dimethylpiperazin-2-one

[0449] Starting from Example 4 (130 mg) and following general procedure (XVIII) with Pd / C, Compound 17 (75 mg, quant.) was obtained as a white solid.

[0450] M / Z (M+H)+: 291.2

[0451] Example 5: 1-(4-chloro-3-fluorophenyl)-4-(5-((4-chloro-3-fluorophenyl)amino)-6-isopropylpicolinoyl)-3,3-dimethylpiperazin-2-one

[0452]

[0453] ci

[0454] Example 5 was obtained according to general procedure (IX) starting from Compound 17 (75 mg) in Dioxane, with 4-bromo-1-chloro-2-fluorobenzene (1.5 eq) and NaO‘Bu (1.0 eq), using BrettPhosPd G1 (0.2 eq) at 100°C for 18 hours. The crude was purified by flash chromatography (Cyhex / EtOAc, 100:0 to 0:100), then by preparative HPLC (Column B) and freeze dried from water / MeOH to obtain Example 5 (26 mg, 18%) as a white solid.

[0455] 1H-NMR (DMSO-de , 300 MHz) 5: 1.18 (d, J6.6 Hz, 6H, 2 CH3); 1.60 (s, 6H, 2 CH3); 3.39 (sept., J 6.6 Hz, 1H, CH); 3.83-3.94 (m, 4H, 2 CH2); 6.80 (dd, J 8.7, 2.1 Hz, 1H, Ar); 6.90 (dd, J 12.0, 2.7 Hz, 1H, Ar); 7.28-7.35 (m, 1H, Ar); 7.38 (t, J 8.7 Hz, 1H, Ar); 7.49 (d, J 8.4 Hz, 1H, Ar); 7.57-7.66 (m, 3H, Ar); 8.17 (bs, 1H, NH).

[0456] (M[35CI]2+H)+: 547.4

[0457] Compound 18: 5-((4-chloro-3-fluorophenyl)amino)-6-methylpicolinic acid

[0458] Compound 18 was obtained according to general procedure (IX) starting from methyl 5-aminopicolinate (500 mg) in THF, with 4-bromo-1-chloro-2-fluorobenzene (1.2 eq) and CS2CO3 (2.0 eq), using BrettPhosPd G1 (0.1 eq) under microwave irradiation at 60°C for 60 minutes. The crude was purified by flash chromatography (CyHex / EtOAc , 100:0 to 0:100) to obtain Compound 18 (260 mg, 28%) as a yellow solid.M / Z (M[35CI]+H)+: 281.0

[0459] Compound 19: 5-((4-chloro-3-fluorophenyl)amino)picolinic acid

[0460] Starting from Compound 18 (260 mg) and following general procedure (I), Compound 19 (230 mg, 93%) was obtained as a yellow solid.

[0461] M / Z (M[35CI]+H)+: 267.0

[0462] Compound 20: 4-(5-((4-chloro-3-fluorophenyl)amino)picolinoyl)-3,3-dimethylpiperazin-2-one

[0463] Compound 20 was obtained according to general procedure (III), starting from Compound 16 (130 mg), using 3,3-dimethylpiperazin-2-one (1.1 eq) and N,N-diisopropylethylamine (2.0 eq). The crude was purified by flash chromatography (DCM / MeOH, 100:0 to 90:10) to obtain Compound 20 (110 mg, 71%) as a white solid.

[0464] M / Z (M[35CI]+H)+: 377.3

[0465] Example 6: 4-(5-((4-chloro-3-fluorophenyl)amino)-6-(difluoromethyl)picolinoyl)-3,3-dimethylpiperazin-2-one

[0466]

[0467] To a solution of Compound 20 (110 mg) in a DCM / water mixture (3:1, 8 mL) was added TFA (1.0 eq), TBHP (3.0 eq, 70% in water) and Zinc difluoromethylsulfinate (2.0 eq). The reaction mixture was stirred at 30°C for 18 hours, then quenched in Na2S2O3 (3% aq, 10 mL) and extracted with DCM (2 *5 mL). The combined organic layers were washed with brine (20 mL), dried over MgSO4, and concentrated under reduced pressure. The residue was purified by preparative HPLC (Column B) and freeze dried from water / MeOH to obtain Example 6 (20 mg, 16%) as a white solid.

[0468] 1H-NMR (DMSO-de , 300 MHz) 5: 1.68 (s, 6H, 2 CH3); 3.48-3.52 (m, 2H, N-CH2); 6.94 (dd, J 8.7, 2.1 Hz, 1H, Ar); 7.10 (dd, J 11.4, 2.1 Hz, 1H, Ar); 7.13 (t, J 53.7 Hz, 1H, CHF2); 7.45 (t, J 8.7 Hz, 1H, Ar); 7.68 (d, J 8.6 Hz, 1H, Ar); 7.85 (d, J 8.6 Hz, 1H, Ar); 8.07 (bs, 1H, NH); 8.46 (bs, 1H, NH). One CH2was not observed.

[0469] M / Z (M[35CI]+H)+: 427.2

[0470] Example 7: 4-(5-((4-chloro-3-fluorophenyl)amino)-6-isopropylpicolinoyl)-3,3-dimethylpiperazin-2-one

[0471] N X-y ,-0

[0472] L ^NH

[0473] F

[0474]

[0475] Example 7 was obtained according to general procedure (IX) starting from Compound 17 (270 mg) in Dioxane, with 4-bromo-1-chloro-2-fluorobenzene (1.5 eq) and CS2CO3 (3.0 eq), using BrettPhosPd G4 (0.1 eq) at80°Cfor 18 hours. The crude was purified by flash chromatography (Cyhex / EtOAc, 100:0 to 0:100), then by preparative HPLC (Column A) and freeze dried from water / MeOH to obtain Example 7 (60 mg, 27%) as a white solid.1H-NMR (DMSO-C / 6 , 300 MHz) 6: 1.16 (d, 6H, J6.6 Hz, 2 CH3); 1.68 (s, 6H, 2 CH3); 3.41 (sept., 1H, CH); 3.51-3.61 (m, 2H, CH2); 6.78 (dd, 1 H, J 11.4, 3.0 Hz, 1H, Ar); 6.88 (dd, 1H, J 11.4, 3.0 Hz, 1H, Ar); 7.37 (t, 1H, J 8.7 Hz, Ar); 7.44 (d, 1H, J 8.4 Hz, Ar); 7.65 (d, 1H, J 8.4 Hz, Ar); 8.09 (bs, 1H, NH); 8.14 (s, 1H, NH). One CH2was not observed. M / Z (M[35CI]+H)+: 419.2

[0476] Compound 21: methyl (E)-5-(((benzyloxy)carbonyl)amino)-6-(2-ethoxyvinyl)picolinate

[0477] Compound 21 was obtained according to general procedure (XI) starting from Compound 14 (595 mg) in Dioxane, with K2CO3(4.0 eq) and 2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (3.0 eq), using Pd(PPh3)4 (0.2 eq) at 100°C for 18 hours. The crude was purified by flash chromatography (CyHex / EtOAc, 100:0 to 50:50) to obtain Compound 20 (405 mg, 61%) as an off white solid.

[0478] M / Z (M+H)+: 357.3

[0479] Compound 22: 5-(((benzyloxy)carbonyl)amino)-6-(2-ethoxyvinyl)picolinic acid

[0480] Starting from Compound 21 (435 mg) and following general procedure (I), Compound 22 (335 mg, 80%) was obtained as an off white solid.

[0481] M / Z (M+H)+: 343.2

[0482] Example 8: benzyl (6-(2,2-dimethyl-3-oxopiperazine-1-carbonyl)-2-(2-ethoxyvinyl)pyridin-3-yl)carbamate

[0483]

[0484] Example 8 was obtained according to general procedure (III), starting from Compound 16 (130 mg), using 3,3-dimethylpiperazin-2-one (1.0 eq) and N,N-diisopropylethylamine (3.0 eq). The crude was purified by flash chromatography (CyHex / EtOAc, 100:0 to 0:100) to obtain Example 8 (455 mg, quant.) as a white solid.

[0485] M / Z (M+H)+: 453.4

[0486] Compound 23: 4-(5-amino-6-(2-ethoxyethyl)picolinoyl)-3,3-dimethylpiperazin-2-one

[0487] Compound 23 was obtained according to general procedure (XVIII) with Pd / C, starting from Example 8 (265 mg). The crude was purified by flash chromatography (DCM / MeOH, 100:0 to 80:20) to obtain Compound 23 (34 mg, 18%) as a beige solid.

[0488] M / Z (M+H)+: 321.2

[0489] Example 9: 4-(5-((4-chloro-3-fluorophenyl)amino)-6-(2-ethoxyethyl)picolinoyl)-3,3-dimethylpiperazin-2-one

[0490]

[0491] Example 9 was obtained according to general procedure (IX), starting from Compound 23 (80 mg) in Dioxane, with 4-bromo-1-chloro-2-fluorobenzene (1.0 eq) and CS2CO3 (3.2 eq), using BrettPhosPd G4 (0.1 eq) at 80°C for 18 hours. The crude was purified by flash chromatography (EtOAc / MeOH, 100:0 to 80:20), then by preparative HPLC (Column A) and freeze dried from water / MeCN to obtain Example 9 (27 mg, 25%) as a white solid.

[0492] 1H-NMR (DMSO-de , 300 MHz) 5: 1.06 (t, 3H, J 7.2, CH3); 1.67 (s, 6H, 2 CH3); 3.01 (t, 2H, J 6.9, CH2); 3.26-3.30 (m, 2H, CH2); 3.42 (q, 2H, J 7.2, OCH2); 3.51-3.57 (m, 2H, CH2); 3.75 (t, 2H, J6.9, OCH2); 6.82 (dd, 1H, J 8.7, 2.7 Hz, Ar); 6.92 (dd, 1H, J 11.7, 2.4 Hz, Ar); 7.38 (t, 1H, J 8.7 Hz, Ar); 7.44 (d, 1H, J 8.4 Hz, Ar); 7.66 (d, 1H, J 8.4 Hz, Ar); 8.07 (bs, 1H, NH); 8.18 (s, 1H, NH).

[0493] M / Z (M[35CI]+H)+: 449.3

[0494] Compound 24: 6-chloro-2-(prop-1 -en-2-yl)pyridin-3-amine

[0495] Compound 24 was obtained according to general procedure (XI) starting from 6-chloro-2-iodopyridin-3-amine (550 mg) in Dioxane, with 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (1.05 eq) and K2CO3 (2.0 eq), using Pd(PPh3)4 (0.1 eq) at 100°C for 16 hours. The crude was purified by flash chromatography (CyHex / EtOAc, 100:0 to 80:20) to obtain Compound 24 (195 mg, 54%) as a pink solid.

[0496] M / Z (M[35CI]+H)+: 169.0

[0497] Compound 25: methyl 2-(1-(5-amino-6-(prop-1-en-2-yl)picolinoyl)piperidin-4-yl)acetate

[0498] Compound 25 was obtained according to general procedure (Via) starting from Compound 24 (195 mg) in Dioxane, with methyl 2-(piperidin-4-yl)acetate (2.0 eq), Triethylamine (4.0 eq), at 110°C for 44 hours. The crude was purified by flash chromatography (DCM / MeOH, 100:0 to 95:05) to obtain Compound 25 (113 mg, 31%) as an orange oil. M / Z (M+H)+: 318.3

[0499] Compound 26: methyl 2-(1-(5-amino-6-isopropylpicolinoyl)piperidin-4-yl)acetate

[0500] Starting from Compound 25 (113 mg) and following general procedure (XVIII) with Pd / C, Compound 26 (106 mg, 93%) was obtained as a clear oil.

[0501] M / Z (M+H)+: 320.3

[0502] Example 10: methyl 2-(1-(5-((3,4-difluorophenyl)amino)-6-isopropylpicolinoyl)piperidin-4-yl)acetate

[0503]

[0504] FExample 10 was obtained according to general procedure (IX) starting from Compound 26 (106 mg) in Dioxane, with 4-bromo-1,2-difluorobenzene (1.2 eq) and CS2CO3 (3.0 eq), using BrettPhos Pd G4 (0.1 eq) at 100°C for 4 hours. The crude was purified by flash chromatography (CyHex / EtOAc, 100:0 to 50:50) to obtain Example 10 (96 mg, 67%) as a beige solid.

[0505] 1H-NMR (DMSO-d6, 300 MHz) 5: 1.09-1.37 (m, 2H, CH2); 1.17 (d, 6H, J 6.6 Hz, 2 CH3); 1.63-1.78 (m, 2H, CH2); 1.93-2.06 (m, 1H, CH); 2.72-2.81 (m, 1H, NCH); 2.99-3.08 (m, 1H, NCH); 3.39 (sept., 1H, J 6.6, CH); 3.59 (s, 3H, OCH3); 4.10-4.15 (m, 1H, NCH); 4.43-4.47 (m, 1H, NCH); 6.76-6.82 (m, 1H, 1H, Ar); 6.93-7.02 (m, 1H, Ar); 7.24-7.34 (m, 1H, Ar); 7.36 (d, 1H, J 8.4 Hz, Ar); 7.45 (d, 1H, J 8.4 Hz, Ar); 7.92 (s, 1H, NH).

[0506] M / Z (M+H)+: 432.4

[0507] Example 11: 2-(1-(5-((3,4-difluorophenyl)amino)-6-isopropylpicolinoyl)piperidin-4-yl)acetic acid

[0508] I 0

[0509] HN" -QH

[0510] di

[0511]

[0512] F

[0513] Example 11 was obtained according to general procedure (I), starting from Example 10 (96 mg). The crude was purified by preparative HPLC (Column A) and freeze dried from water to obtain Example 11 (67 mg, 72%) as a white solid.

[0514] 1H-NMR (DMSO-de , 300 MHz) 5: 1.18 (d, J 6.7 Hz, 6H, 2 CH3); 1.23-1.36 (m, 2H, CH2); 1.65-1.80 (m, 2H, CH2); 1.90-2.01 (m, 1H, CH); 2.20 (d, J 7.0 Hz, 2H, CH2-CO); 2.72-2.82 (m, 1H, NCH); 2.98-3.08 (m, 1H, NCH); 3.43 (sept., J 6.7 Hz, 1H, CH); 4.10-4.14 (m, 1H, NCH); 4.43-4.48 (m, 1H, NCH); 6.76-6.82 (m, 1H, Ar); 6.94-7.02 (m, 1H, Ar); 7.24-7.33 (m, 1H, Ar); 7.36 (d, J 8.4 Hz, 1H, Ar); 7.55 (d, J 8.4 Hz, 1H, Ar); 7.92 (s, 1H, NH); 12.11 (s, 1H, COCH).

[0515] M / Z (M+H)+: 418.3

[0516] Compound 27: methyl 5-amino-6-(prop-1 -en-2-yl)picolinate

[0517] Compound 27 was obtained according to general procedure (VII), starting from Compound 24 (500 mg). The crude was purified by flash chromatography (DCM / MeOH, 100:0 to 98:02) to obtain Compound 27 (284 mg, 50%) as a yellow oil.

[0518] M / Z (M+H)+: 193.1

[0519] Compound 28: methyl 5-amino-6-isopropylpicolinate

[0520] Starting from Compound 27 (284 mg) and following general procedure (XVIII) Compound 28 (294 mg, quant.) was obtained as a yellow oil.

[0521] M / Z (M+H)+: 195.1

[0522] Compound 29: methyl 5-((3,4-difluorophenyl)amino)-6-isopropylpicolinate

[0523] Compound 29 was obtained according to general procedure (IX), starting from Compound 28 (175 mg) in Dioxane, with 4-bromo-1,2-difluorobenzene (1.2 eq) and Cs2CO3 (3.0 eq), using BrettPhos Pd G4 (0.1 eq) at 100°C for 22hours. The crude was purified by flash chromatography (CyHex / EtOAc, 100:0 to 80:20) to obtain Compound 29 (232 mg, 84%) as a yellow oil.

[0524] M / Z (M+H)+: 307.2

[0525] Compound 30: 5-((3,4-difluorophenyl)amino)-6-isopropylpicolinic acid

[0526] Starting from Compound 29 (232 mg) and following general procedure (I) Compound 30 (187 mg, 85%) was obtained as a yellow solid.

[0527] M / Z (M+H)+: 293.2

[0528] Example 12: methyl 2-((3R,4S)-1-(5-((3,4-difluorophenyl)amino)-6-isopropylpicolinoyl)-3-methoxypiperidin-4-yl)acetate

[0529] HN

[0530]

[0531] Example 12 was obtained according to general procedure (III), starting from Compound 30 (62 mg), using methyl 2-((3R,4S)-3-methoxypiperidin-4-yl)acetate hydrochloride (1.1 eq) and N,N-diisopropylethylamine (4.0 eq). The crude was purified by flash chromatography (CyHex / EtOAc, 100:0 to 50:50) to obtain Example 12 (71 mg, 73%) as a yellow oil.

[0532] M / Z (M+H)+: 462.3.

[0533] Example 13: 2-((3R,4S)-1-(5-((3,4-difluorophenyl)amino)-6-isopropylpicolinoyl)-3-methoxypiperidin-4-yl)acetic acid

[0534] HN

[0535]

[0536] Example 13 was obtained according to general procedure (I), starting from Example 12 (71 mg). The crude was purified by preparative HPLC (Column A) then freeze dried from water to obtain Example 13 (50 mg, 73%) as a white solid.

[0537] 1H-NMR (DMSO-de , 300 MHz) 5: 1.15-1.23 (m, 6H, 2 CH3); 1.38-1.67 (m, 2H, CH2); 2.10-2.39 (m, 3H, CH2+CHaHb); 2.73-2.81 (m, 1H, NCH); 2.86-2.95 (m, 1H, NCH); 3.08-3.18 (m, 1H, MeO-CH); 3.29 (s, 3H, OCH3); 3.39-3.47 (m, 1H, CH); 4.14-4.19 (m, 0.5H, one rotamer of NCH); 4.30-4.34 (m, 0.5H, other rotamer of NCH); 4.43-4.48 (m, 0.5H, one rotamer of NCH); 4.67-4.71 (m, 0.5H, other rotamer of NCH); 6.73-6.82 (m, 1H, Ar); 6.90-7.02 (m, 1H, Ar); 7.24-7.34 (m, 1H, Ar); 7.38 (dd, J 8.4, 6.0 Hz, 1H, Ar); 7.56 (dd, J 8.4, 6.0 Hz, 1H, Ar); 7.92 (s, 1H, NH); 12.12 (s, 1H, COCH)

[0538] M / Z (M+H)+: 448.3.Example 14: methyl 6-(4-(5-((3,4-difluorophenyl)amino)-6-isopropylpicolinoyl)-3,3-dimethylpiperazm-1-yl)-2,4-dimethylnicotinate

[0539] o

[0540]

[0541] Example 14 was obtained according to general procedure (III), starting from Compound 30 (62 mg), using methyl 6-(3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinate hydrochloride (1.1 eq) and N,N-diisopropylethylamine (4.0 eq). The crude was purified by flash chromatography (CyHex / EtOAc, 100:0 to 70:30) to obtain Example 14 (79 mg, 68%) as a clear oil.

[0542] 1H-NMR (DMSO-d6, 300 MHz) 5: 1.20 (d, J 6.7 Hz, 6H, 2 CH3); 1.50 (s, 6H, 2 CH3); 2.24 (s, 3H, CH3); 2.35 (s, 3H, CH3); 3.35 (sept., J 6.7 Hz, 1H, CH); 3.54-3.59 (m, 2H, CH2); 3.78 (s, 3H, OCH3); 3.87-3.90 (m, 4H, 2 CH2); 6.35 (s, 1H Ar); 6.76-6.82 (m, 1H, Ar); 6.93-7.01 (m, 1H, Ar); 7.24-7.34 (m, 1H, Ar); 7.37 (d, J 8.4 Hz, 1H, Ar); 7.55 (d, J 8.4 Hz, 1H, Ar); 7.92 (s, 1H, NH).

[0543] M / Z (M+H)+: 552.4

[0544] Example 15: 6-(4-(5-((3,4-difluorophenyl)amino)-6-isopropylpicolinoyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid

[0545]

[0546] F

[0547] Example 15 was obtained according to general procedure (II), starting from Example 14 (79 mg). The crude was purified by preparative HPLC (Column A) then freeze dried from a water / MeCN mixture to obtain Example 15 (7 mg, 9%) as a pink solid.

[0548] 1H-NMR (DMSO-de , 300 MHz) 5: 1.21 (d, J 6.7 Hz, 6H, 2 CH3); 1.50 (s, 6H, 2 CH3); 2.27 (s, 3H, CH3); 2.38 (s, 3H, CH3); 3.39 (sept., J 6.7 Hz 1H, CH); 3.54-3.59 (m, 2H, CH2); 3.87-3.89 (m, 4H, 2 CH2); 6.33 (s, 1H Ar); 6.76-6.82 (m, 1H, Ar); 6.93-7.01 (m, 1H, Ar); 7.25-7.34 (m, 1H, Ar); 7.37 (d, J 8.4 Hz, 1H, Ar); 7.56 (d, J 8.4 Hz, 1H, Ar); 7.92 (s, 1H, NH); 12.67 (s, 1H, COCH).

[0549] M / Z (M+H)+: 538.4

[0550] Compound 31 : 3-chloro-N-(4-chloro-3-fluorophenyl)pyrazin-2-amine

[0551] Following general procedure (Xa) with 4-Chloro-3-fluoroaniline (489 mg), and after purification by flash chromatography (CyHex / DCM, 100:0 to 20:80) Compound 31 (650 mg, 75%) was obtained as a pink powder. M / Z (M[35CI]+H)+: 258.1

[0552] Compound 32: N-(4-chloro-3-fluorophenyl)-3-(prop-1-en-2-yl)pyrazin-2-amineCompound 32 was obtained according to general procedure (XI) starting from Compound 31 (467 mg) in Dioxane, with 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1 ,3,2-dioxaborolane (2.0 eq) and K2CO3 (3.0 eq), using Pd(dppf)Cl2 (0.1 eq) at 80°C for 5 hours. The crude was purified by flash chromatography (CyHex / EtOAc, 100:0 to 85:15) to obtain Compound 32 (393 mg, 82%) as a yellow solid.

[0553] M / Z (M[35CI]+H)+: 264.1

[0554] Compound 33: N-(4-chloro-3-fluorophenyl)-3-isopropylpyrazin-2-amine

[0555] Starting from Compound 32 (393 mg) and following general procedure (XVIII) Compound 33 (400 mg, quant.) was obtained as a clear oil.

[0556] M / Z (M[35CI]+H)+: 266.2

[0557] Compound 34: 5-bromo-N-(4-chloro-3-fluorophenyl)-3-isopropylpyrazin-2-amine

[0558] Compound 34 was obtained according to general procedure (Va), starting from Compound 33 (400 mg). The crude was purified by flash chromatography (CyHex / EtOAc, 100:0 to 90:10) to obtain Compound 34 (228 mg, 44%) as a pink solid.

[0559] M / Z (M[35CI][81Br]+H)+: 346.2

[0560] Compound 35: 5-((4-chloro-3-fluorophenyl)amino)-6-isopropylpyrazine-2-carboxylic acid

[0561] Compound 35 was obtained according to general procedure (VIII), starting from Compound 34 (220 mg). The crude was resuspended in EtOAc to obtain Compound 35 (145 mg, 73%) as an off white solid.

[0562] M / Z (M[35CI]+H)+: 310.0

[0563] Example 16: methyl 2-(6-(4-(5-((4-chloro-3-fluorophenyl)amino)-6-isopropylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)pyridin-3-yl)acetate

[0564]

[0565] ci

[0566] Example 16 was obtained according to general procedure (III), starting from Compound 35 (62 mg), using methyl 2-(6-(3,3-dimethylpiperazin-1-yl)pyridin-3-yl)acetate dihydrochloride (1.0 eq) and N,N-diisopropylethylamine (4.0 eq). The crude Example 16 (101 mg) was obtained as an orange oil and used in next step without further purification. M / Z (M[35CI]+H)+: 555.4

[0567] Example 17: 2-(6-(4-(5-((4-chloro-3-fluorophenyl)amino)-6-isopropylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-y l)py ridin-3-y l)acetic acid

[0568]

[0569] Example 17 was obtained according to general procedure (I), starting from Example 16 (100 mg). The crude was purified by preparative HPLC (Column A) then freeze dried from water to obtain Example 16 (16 mg, 9% over 2 steps) as a white solid.

[0570] 1H-NMR (DMSO-d6, 400 MHz) 5: 1.26 (d, J 7.6 Hz, 6H, 2 CH3); 1.55 (s, 6H, 2 CH2); 3.52-3.59 (m, 3H, NCH2, CH); 3.64-3.67 (m, 2H, NCH2); 3.92 (s, 2H, CH2); 3.97-4.01 (m, 2H, NCH2); 7.16 (bs, 1H, Ar); 7.49-7.54 (m, 1H, Ar); 7.59-7.62 (m, 1H, Ar); 7.82-7.96 (m, 3H, Ar); 8.32 (s, 1H, Ar); 8.95 (s, 1H, NH). CO2H was not observed.

[0571] M / Z (M[35CI]+H)+: 541.3

[0572] Example 18: 4-(5-((4-chloro-3-fluorophenyl)amino)-6-isopropylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-2-one

[0573]

[0574] Example 18 was obtained according to general procedure (III), starting from Compound 35 (67 mg), using 3,3-dimethylpiperazin-2-one (1.0 eq) and N,N-diisopropylethylamine (2.0 eq). The crude was purified by preparative HPLC (Column A) then freeze dried from a water / MeCN mixture to obtain Example 18 (32 mg, 35%) as a white solid.

[0575] 1H-NMR (DMSO-de , 400 MHz) 5: 1.23 (d, J 6.4 Hz, 6H, 2 CH3); 1.68 (s, 6H, 2 CH3); 3.52-3.58 (m, 3H, CH2, CH); 7.51 (t, J 8.8 Hz, 1H, Ar); 7.59 (m, 1H, Ar); 7.92 (m, 1H, Ar); 8.09 (bs, 1H, NH); 8.32 (s, 1H, Ar); 8.94 (s, 1H, NH). One CH2was not observed.

[0576] M / Z (M[35CI]+H)+: 420.2

[0577] Compound 36: N-(4-chloro-3-fluorophenyl)-3-cyclopentylpyrazin-2-amine

[0578] Compound 36 was obtained according to general procedure (XI la) starting from Compound 31 (500 mg), with cyclopentylzinc bromide (0.5 M in THF, 2.8 eq). The crude was purified by flash chromatography (CyHex / EtOAc, 100:0 to 75:25) to obtain Compound 36 (366 mg, 65%) as an orange oil.

[0579] M / Z (M[35CI]+H)+: 292.3

[0580] Compound 37: 5-bromo-N-(4-chloro-3-fluorophenyl)-3-cyclopentylpyrazin-2-amine

[0581] Compound 37 was obtained according to general procedure (Va), starting from Compound 36 (366 mg). The crude was purified by flash chromatography (CyHex / EtOAc, 100:0 to 90:10) to obtain Compound 37 (250 mg, 54%) as a yellow oil.

[0582] M / Z (M[35CI][81Br]+H)+: 372.1

[0583] Compound 38: 5-((4-chloro-3-fluorophenyl)amino)-6-cyclopentylpyrazine-2-carboxylic acid

[0584] Compound 38 was obtained according to general procedure (VIII), starting from Compound 37 (250 mg). The crude Compound 38 (240 mg) was obtained as a brown solid and used in next step without further purification.

[0585] M / Z (M[35CI]+H)+: 336.3

[0586] Example 19: 4-(5-((4-chloro-3-fluorophenyl)amino)-6-cyclopentylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-2-one / vno^ I?Nx vro

[0587] HN-V

[0588]

[0589] V Cl"F

[0590] Example 19 was obtained according to general procedure (III), starting from Compound 38 (113 mg), using 3,3-dimethylpiperazin-2-one (1.0 eq) and N,N-diisopropylethylamine (2.0 eq). The crude was purified by preparative HPLC (Column B) then freeze dried from a water / MeCN mixture to obtain Example 19 (49 mg, 33% over 2 steps) as a white solid.

[0591] 1H-NMR (DMSO-de , 400 MHz) 5: 1.67 (s, 6H, 2 CH3); 1.69-1.75 (m, 6H, 3 CH2); 2.04-2.06 (m, 2H, CH2); 3.27-3.31 (m, 2H, NCH2); 3.55-3.57 (m, 2H, NCH2); 3.60-3.62 (m, 1H, CH); 7.50 (t, J 8.7 Hz, 1H, Ar); 7.58 (dd, J 8.7, 2.0 Hz, 1H, Ar); 7.91 (dd, J 12.3, 2.3 Hz, 1H, Ar); 8.07 (bs, 1H, NH); 8.29 (s, 1H, Ar); 8.87 (s, 1H, NH).

[0592] M / Z (M[35CI]+H)+: 446.3.

[0593] Compound 39: 2-(3-chloropyrazin-2-yl)isoindoline

[0594] Following general procedure (Xb) with isoindoline (240 mg), crude Compound 39 (390 mg, 83%) was obtained as a grey solid.

[0595] M / Z (M[35CI]+H)+: 232.1

[0596] Compound 40: 2-(3-propylpyrazin-2-yl)isoindoline

[0597] Compound 40 was obtained according to general procedure (XI la) starting from Compound 39 (390 mg), with propylzinc bromide (0.5 M in THF, 3.0 eq). The crude was purified by flash chromatography (CyHex / EtOAc, 100:0 to 70:30) to obtain Compound 40 (230 mg, 57%) as a yellow solid.

[0598] M / Z (M+H)+: 240.3

[0599] Compound 41: 2-(5-bromo-3-propylpyrazin-2-yl)isoindoline

[0600] Compound 41 was obtained according to general procedure (Va), starting from Compound 40 (230 mg). The crude Compound 41 (248 mg, 81%) was obtained as a yellow solid.

[0601] M / Z (M[79Br]+H)+: 318.3

[0602] Compound 42: 5-(isoindolin-2-yl)-6-propylpyrazine-2-carboxylic acid

[0603] Compound 42 was obtained according to general procedure (VIII), starting from Compound 41 (248 mg). The crude was resuspended in water to obtain Compound 42 (80 mg, 29%) as a white solid.

[0604] M / Z (M+H)+: 284.3

[0605] Example 20: 4-(5-(isoindolin-2-yl)-6-propylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-2-one

[0606]

[0607] Example 20 was obtained according to general procedure (III), starting from Compound 42 (80 mg), using 3,3-dimethylpiperazin-2-one (1.0 eq) and N,N-diisopropylethylamine (2.0 eq). The crude was purified by preparative HPLC (Column B) then freeze dried from a water / MeCN mixture to obtain Example 20 (40 mg, 36%) as a white solid.

[0608] 1H-NMR (DMSO-de , 400 MHz) 5: 0.96 (t, J7.4Hz, 3H, CH3); 1.67-1.74 (m, 8H, 2 CH3+ CH2); 3.05 (t, J7.5Hz, 2H, NCH2); 3.59-3.62 (m, 2H, NCH2); 5.04 (s, 4H, 2 NCH2); 7.31-7.33 (m, 2H, 2 Ar); 7.40-7.42 (m, 2H, 2 Ar); 8.06 (bs, 1 H, Ar); 8.28 (s, 1 H, Ar). One CH2was not observed.

[0609] M / Z (M+H)+: 394.4.

[0610] Compound 43: 3-chloro-N-(4-(pentafluorosulfanyl)phenyl)pyrazin-2-amine

[0611] Following general procedure (Xa) with 4-(pentafluorosulfanyl)aniline (500 mg), and after purification by flash chromatography (CyHex / EtOAc, 100:0 to 80:20) Compound 43 (450 mg, 59%) was obtained as a yellow solid. M / Z (M[35CI]+H)+: 332.2

[0612] Compound 44: N-(4-(pentafluorosulfanyl)phenyl)-3-propylpyrazin-2-amine

[0613] Compound 44 was obtained according to general procedure (XI la) starting from Compound 43 (450 mg), with propylzinc bromide (0.5 M in THF, 3.0 eq). The crude was purified by flash chromatography (CyHex / EtOAc, 100:0 to 60:40) to obtain Compound 44 (368 mg, 80%) as a yellow solid.

[0614] M / Z (M+H)+: 340.3

[0615] Compound 45: 5-bromo-N-(4-(pentafluorosulfanyl)phenyl)-3-propylpyrazin-2-amine

[0616] Compound 45 was obtained according to general procedure (Va), starting from Compound 44 (368 mg). The crude was purified by flash chromatography (CyHex / EtOAc, 100:0 to 80:20) to obtain Compound 45 (432 mg, 80%) as a yellow oil.

[0617] M / Z (M[81Br]+H)+: 420.1

[0618] Compound 46: 5-((4-(pentafluorosulfanyl)phenyl)amino)-6-propylpyrazine-2-carboxylic acid

[0619] Compound 46 was obtained according to general procedure (VIII), starting from Compound 45 (430 mg). The crude Compound 46 (418 mg, ND) was obtained as a brown oil and used in next step without further purification.

[0620] M / Z (M+H)+: 384.2

[0621] Example 21 : methyl 6-(3,3-di methy l-4-(5-((4-(pentafl uorosu Ifany I) pheny I) ami no)-6-propy Ipy razine-2-carbonyl)piperazin-1-yl)-2,4-dimethylnicotinate

[0622]

[0623] Example 21 was obtained according to general procedure (III), starting from Compound 46 (540 pimol), using methyl 6-(3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinate (1.0 eq) and N,N-diisopropylethylamine (2.0 eq). The crude Example 21 (489 mg, ND) was obtained as a brown oil and directly used in the next step.M / Z (M+H)+: 643.4

[0624] Example 22: 6-(3,3-dimethyl-4-(5-((4-(pentafluorosulfanyl)phenyl)amino)-6-propylpyrazine-2-carbonyl)piperazin-1-yl)-2,4-dimethylnicotinic acid

[0625]

[0626] Example 22 was obtained according to general procedure (II), starting from Example 21 (540 pimol). The crude was purified by preparative HPLC (Column B) then freeze dried from a water / MeCN mixture to obtain Example 22 (30 mg, 9% over 3 steps) as a white solid.

[0627] 1H-NMR (DMSO-de , 400 MHz) 5: 1.01 (t, J 7.4 Hz, 3H, CH3); 1.49 (s, 6H, 2 CH3); 1.75-1.84 (m, 2H, CH2-CH3); 2.26 (s, 3H, CH3); 2.37 (s, 3H, CH3); 2.91 (t, J 7.4 Hz, 2H, Ar-CH2); 3.52-3.55 (m, 2H, N-CH2); 3.83-3.88 (m, 4H, 2 N-CH2); 6.32 (s, 1H, Ar); 7.83 (d, J 9.3 Hz, 2H, 2 Ar); 7.92 (d, J 9.3 Hz, 2H, 2 Ar); 8.27 (s, 1H, Ar); 9.01 (s, 1H, NH); 12.71 (bs, 1H, COCH).

[0628] M / Z (M+H)+: 629.4.

[0629] Compound 47: N-(4-chloro-3-fluorophenyl)-3-isobutylpyrazin-2-amine

[0630] Compound 47 was obtained according to general procedure (XI la) starting from Compound 31 (500 mg), with isobutylzinc bromide (0.5 M in THF, 3.0 eq). The crude was purified by flash chromatography (CyHex / EtOAc, 100:0 to 60:40) to obtain Compound 47 (320 mg, 59%) as an orange oil.

[0631] M / Z (M[35CI]+H)+: 280.3.

[0632] Compound 48: 5-bromo-N-(4-chloro-3-fluorophenyl)-3-isobutylpyrazin-2-amine

[0633] Compound 48 was obtained according to general procedure (Va), starting from Compound 47 (300 mg). The crude was purified by flash chromatography (CyHex / EtOAc, 100:0 to 90:10) to obtain Compound 48 (243 mg, 63%) as an orange oil.

[0634] M / Z (M[81Br][35CI]+H)+: 360.2.

[0635] Compound 49: 5-((4-chloro-3-fluorophenyl)amino)-6-isobutylpyrazine-2-carboxylic acid

[0636] Compound 49 was obtained according to general procedure (VIII), starting from Compound 48 (243 mg).

[0637] The crude Compound 49 (279 mg, ND) was obtained as an orange oil and used in next step without further purification.

[0638] M / Z (M[35CI]+H)+: 324.3.

[0639] Example 23: methyl 6-(4-(5-((4-chloro-3-fluorophenyl)amino)-6-isobutylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-1 -y I )-2, 4-d i methy In i coti n ateF ' '"y''

[0640]

[0641] Cl

[0642] Example 23 was obtained according to general procedure (III), starting from Compound 49 (339 pimol), using methyl 6-(3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinate (1.0 eq) and N,N-diisopropylethylamine (2.0 eq). The crude Example 23 (227 mg, ND) was obtained as a brown oil and directly used in the next step.

[0643] M / Z (M[35CI]+H)+: 583.5.

[0644] Example 24: 6-(4-(5-((4-chloro-3-fluorophenyl)amino)-6-isobutylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)- 2,4-dimethy Inicotinic acid

[0645]

[0646] Example 24 was obtained according to general procedure (II), starting from Example 23 (339 pimol). The crude was purified by preparative HPLC (Column B) then freeze dried from water to obtain Example 24 (26 mg, 14% over 3 steps) as a white solid.

[0647] 1H-NMR (DMSO-de , 400 MHz) 5: 0.96 (d, J 6.6 Hz, 6H, 2 CH3); 1.49 (s, 6H, 2 CH3); 2.21-2.30 (m, 4H, CH3+ CH); 2.37 (s, 3H, CH3); 2.80 (d, J 6.9 Hz, 2H, Ar-CH2); 3.52-3.55 (m, 2H, N-CH2); 3.80-3.88 (m, 4H, 2 N-CH2); 6.32 (s, 1H, Ar); 7.50 (t, J 8.8 Hz, 1H, Ar); 7.57 (dd, J 8.8, 2.3 Hz, 1H, Ar); 7.90 (dd, J 12.3, 2.3 Hz, 1H, Ar); 8.27 (s, 1H, Ar); 8.81 (s, 1H, NH); 12.68 (bs, 1H, COCH).

[0648] M / Z (M[35CI]+H)+: 569.5.

[0649] Example 25: methyl 6-(4-(5-((4-chloro-3-fluorophenyl)amino)-6-cyclopentylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinate

[0650]

[0651] Example 25 was obtained according to general procedure (III), starting from Compound 38 (113 mg), using methyl 6-(3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinate (1.0 eq) and N,N-diisopropylethylamine (2.0 eq). The crude Example 25 (203 mg, ND) was obtained as a brown oil and directly used in the next step.

[0652] M / Z (M[35CI]+H)+: 595.4.Example 26: 6-(4-(5-((4-chloro-3-fluorophenyl)amino)-6-cyclopentylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)- 2,4-dimethy Inicotinic acid

[0653]

[0654] Example 26 was obtained according to general procedure (II), starting from Example 25 (337 pimol). The crude was purified by preparative HPLC (Column B) then freeze dried from water to obtain Example 26 (12 mg, 6% over 3 steps) as a white solid.

[0655] 1H-NMR (DMSO-d6, 400 MHz) 5: 1.49 (s, 6H, 2 CH3); 1.66-1.83 (m, 6H, 3 CH2); 2.04-2.10 (m, 2H, CH2); 2.26 (s, 3H, CH3); 2.37 (s, 3H, CH3); 3.51-3.58 (m, 2H, N-CH2); 3.60-3.66 (m, 1H, CH-Ar); 3.82-3.88 (m, 4H, 2 N-CH2); 6.32 (s, 1H, Ar); 7.50 (t, J 8.8 Hz, 1H, Ar); 7.57 (dd, J 8.8, 2.3 Hz, 1H, Ar); 7.91 (dd, J 12.3, 2.3 Hz, 1H, Ar); 8.27 (s, 1H, Ar); 8.85 (s, 1H, NH); COCH signal was not observed.

[0656] M / Z (M[35CI]+H)+: 581.4.

[0657] Example 27: 4-(5-((4-chloro-3-fluorophenyl)amino)-6-isobutylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-2-one

[0658]

[0659] ci

[0660] Example 27 was obtained according to general procedure (III), starting from Compound 49 (110 mg), using 3,3-dimethylpiperazin-2-one (1.0 eq) and N,N-diisopropylethylamine (2.0 eq). The crude was purified by preparative HPLC (Column B) then freeze dried from a water / MeCN mixture to obtain Example 27 (46 mg, 31% over 2 steps) as a white solid.

[0661] 1H-NMR (DMSO-de , 400 MHz) 5: 0.95 (d, J 6.6Hz, 6H, 2 CH3); 1.67 (s, 6H, 2 CH3); 2.23 (m, 1H, CH); 2.78 (d, J 6.9 Hz, 2H, Ar-CH2); 3.27-3.31 (m, 2H, N-CH2); 3.54-3.56 (m, 2H, N-CH2); 7.50 (t, J 8.8 Hz, 1H, Ar); 7.57 (dd, J 8.8, 2.3 Hz, 1H, Ar); 7.90 (dd, J 12.3, 2.3 Hz, 1H, Ar); 8.07 (bs, 1H, NH); 8.29 (s, 1H, Ar); 8.84 (s, 1H, NH).

[0662] M / Z (M[35CI]+H)+: 434.2.

[0663] Example 28: 3,3-dimethyl-4-(5-((4-(pentafluorosulfanyl)phenyl)amino)-6-propylpyrazine-2-carbonyl)piperazin-2-one

[0664]

[0665] Example 28 was obtained according to general procedure (III), starting from Compound 46 (200 mg), using 3,3-dimethylpiperazin-2-one (1.0 eq) and N,N-diisopropylethylamine (2.0 eq). The crude was purified by preparative HPLC (Column B) then freeze dried from a water / MeCN mixture to obtain Example 28 (46 mg, 17%) as a white solid.

[0666] 1H-NMR (DMSO-de , 400 MHz) 5: 0.99 (t, J 7.4 Hz, 3H, CH3); 1.67 (s, 6H, 2 CH3); 1.76 (m, 2H, CH2); 2.89 (t, J 7.4 Hz, 2H, Ar-CH2); 3.28-3.30 (m, 2H, N-CH2); 3.54-3.57 (m, 2H, N-CH2); 7.83 (d, J 9.3 Hz, 2H, 2 Ar); 7.92 (d, J 9.3 Hz, 2H, 2 Ar); 8.07 (bs, 1H, NH); 8.30 (s, 1H, Ar); 9.02 (s, 1H, NH).

[0667] M / Z (M+H)+: 494.3.

[0668] Compound 50: N-(4-chloro-3-fluorophenyl)-3-propylpyrazin-2-amine

[0669] Compound 50 was obtained according to general procedure (XI la) starting from Compound 31 (500 mg), with propyllzinc bromide (0.5 M in THF, 2.8 eq). The crude was purified by flash chromatography (CyHex / EtOAc, 100:0 to 60:40) to obtain Compound 50 (345 mg, 67%) as an orange oil.

[0670] M / Z (M[35CI]+H)+: 266.2.

[0671] Compound 51 : 5-bromo-N-(4-chloro-3-fluorophenyl)-3-propylpyrazin-2-amine

[0672] Compound 51 was obtained according to general procedure (Va), starting from Compound 50 (330 mg). The crude was purified by flash chromatography (CyHex / EtOAc, 100:0 to 80:20) to obtain Compound 51 (282 mg, 66%) as an orange oil.

[0673] M / Z (M[81Br][35CI]+H)+: 346.2.

[0674] Compound 52: 5-((4-chloro-3-fluorophenyl)amino)-6-propylpyrazine-2-carboxylic acid

[0675] Compound 52 was obtained according to general procedure (VIII), starting from Compound 51 (282 mg). The crude Compound 52 (282 mg) was obtained as a brown oil and used in next step without further purification.

[0676] M / Z (M[35CI]+H)+: 310.3.

[0677] Example 29: 4-(5-((4-chloro-3-fluorophenyl)amino)-6-propylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-2-one

[0678]

[0679] Cl

[0680] Example 29 was obtained according to general procedure (III), starting from Compound 52 (409 pimol), using 3,3-dimethylpiperazin-2-one (1.0 eq) and N,N-diisopropylethylamine (2.0 eq). The crude was purified by preparative HPLC (Column B) then freeze dried from a water / MeCN mixture to obtain Example 29 (10 mg, 6% over 2 steps) as a white solid.

[0681] 1H-NMR (DMSO-de , 400 MHz) 5: 0.99 (t, J 7.4 Hz, 3H, CH3); 1.67 (s, 6H, 2 CH3); 1.73-1.78 (m, 2H, CH2); 2.85 (t, J 7.4 Hz, 2H, Ar-CH2); 3.54-3.56 (m, 2H, N-CH2); 7.50 (t, J 8.8 Hz, 1H, Ar); 7.59 (dd, J 8.8, 2.3 Hz, 1H, Ar); 7.92 (dd, J 12.3, 2.3 Hz, 1 H, Ar); 8.06 (bs, 1 H, NH); 8.29 (s, 1 H, Ar); 8.86 (s, 1 H, NH). One N-CH2signal was not observed. M / Z (M[35CI]+H)+: 420.3.Example 30: methyl 6-(4-(5-((4-chloro-3-fluorophenyl)amino)-6-propylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinate

[0682]

[0683] Example 30 was obtained according to general procedure (III), starting from Compound 52 (127 mg), using methyl 6-(3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinate (1.0 eq) and N,N-diisopropylethylamine (2.0 eq). The crude Example 30 (208 mg, ND) was obtained as an orange oil and directly used in the next step.

[0684] M / Z (M[35CI]+H)+: 569.5.

[0685] Example 31: 6-(4-(5-((4-chloro-3-fluorophenyl)amino)-6-propylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid

[0686]

[0687] Example 31 was obtained according to general procedure (II), starting from Example 30 (366 pimol). The crude was purified by preparative HPLC (Column B) then freeze dried from water to obtain Example 31 (12 mg, 5% over 3 steps) as a white solid.

[0688] 1H-NMR (DMSO-de , 400 MHz) 5: 1.01 (t, J 7.4 Hz, 3H, CH3); 1.49 (s, 6H, 2 CH3); 1.75-1.81 (m, 2H, CH2); 2.26 (s, 3H, CH3); 2.37 (s, 3H, CH3); 2.88 (t, J 7.4 Hz, 2H, Ar-CH2); 3.52-3.55 (m, 2H, N-CH2); 3-82-3.88 (m, 4H, 2 N-CH2); 6.32 (s, 1 H, Ar); 7.50 (t, J 8.8 Hz, 1 H, Ar); 7.59 (dd, J 8.8, 2.3 Hz, 1 H, Ar); 7.92 (dd, J 12.3, 2.3 Hz, 1 H, Ar); 8.26 (s, 1 H, Ar); 8.84 (s, 1 H, NH); COCH signal not observed.

[0689] M / Z (M[35CI]+H)+: 555.4.

[0690] Example 32: methyl 6-(4-(5-((4-chloro-3-fluorophenyl)amino)-6-isopropylpyrazine-2-carbonyl)-3,3-dimethylpiperazin- 1 -y I )-2, 4-d I methy In I coti n ate

[0691]

[0692] Cl Example 32 was obtained according to general procedure (III), starting from Compound 35 (190 mg), using methyl 6-(3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinate (1.0 eq) and N,N-diisopropylethylamine (2.0 eq). The crude Example 32 (404 mg, ND) was obtained as a brown oil and directly used in the next step.M / Z (M[35CI]+H)+: 569.5.

[0693] Example 33: 6-(4-(5-((4-chloro-3-fluorophenyl)amino)-6-isopropylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)- 2,4-dimethy Inicotinic acid

[0694]

[0695] Example 33 was obtained according to general procedure (II), starting from Example 32 (460 pimol). The crude was purified by preparative HPLC (Column B) then freeze dried from water to obtain Example 33 (17 mg, 7% over 3 steps) as a white solid.

[0696] 1H-NMR (DMSO-C / 6 , 400 MHz) 5: 1.25 (d, J 6.6 Hz, 6H, 2 CH3); 1.50 (s, 6H, 2 CH3); 2.27 (s, 3H, CH3); 2.38 (s, 3H, CH3); 3.54-3.58 (m, 3H, CH + N-CH2); 3.88 (m, 4H, 2 N-CH2); 6.33 (s, 1H, Ar); 7.50 (t, J 8.8 Hz, 1H, Ar); 7.59 (dd, J 8.8, 2.3 Hz, 1H, Ar); 7.92 (dd, J 12.3, 2.3 Hz, 1H, Ar); 8.29 (s, 1H, Ar); 8.91 (s, 1H, NH); COCH signal was not observed.

[0697] M / Z (M[35CI]+H)+: 555.4.

[0698] Compound 53: 3-chloro-N-(4-(methylsulfonyl)phenyl)pyrazin-2-amine

[0699] Following general procedure (Xa) with 4-(methylsulfonyl)aniline (391 mg), and after purification by flash chromatography (CyHex / EtOAc, 75:25 to 35:65) Compound 53 (323 mg, 50%) was obtained as a yellow solid. M / Z (M[35CI]+H)+: 284.1

[0700] Compound 54: N-(4-(methylsulfonyl)phenyl)-3-propylpyrazin-2-amine

[0701] Compound 54 was obtained according to general procedure (XI lb) starting from Compound 53 (320 mg), with propylzinc bromide (0.5 M in THF, 3.0 eq). The crude was purified by flash chromatography (CyHex / EtOAc, 100:0 to 10:90) to obtain Compound 54 (350 mg, 80%) as a yellow oil.

[0702] M / Z (M+H)+: 292.3

[0703] Compound 55: 5-bromo-N-(4-(methylsulfonyl)phenyl)-3-propylpyrazin-2-amine

[0704] Compound 55 was obtained according to general procedure (Va), starting from Compound 54 (350 mg). The crude was purified by flash chromatography (CyHex / EtOAc, 100:0 to 50:50) to obtain Compound 55 (210 mg, 35%) as a yellow solid.

[0705] M / Z (M[81Br]+H)+: 372.2

[0706] Compound 56: 5-((4-(methylsulfonyl)phenyl)amino)-6-propylpyrazine-2-carboxylic acid

[0707] Compound 56 was obtained according to general procedure (VIII), starting from Compound 55 (210 mg). The crude Compound 56 (145 mg, ND) was obtained as a brown oil and used in next step without further purification.

[0708] M / Z (M+H)+: 336.3.

[0709] Example 34: 3,3-dimethyl-4-(5-((4-(methylsulfonyl)phenyl)amino)-6-propylpyrazine-2-carbonyl)piperazin-2-one— s=o

[0710]

[0711] 6

[0712] Example 34 was obtained according to general procedure (III), starting from Compound 56 (409 pimol), using 3,3-dimethylpiperazin-2-one (1.0 eq) and N,N-diisopropylethylamine (2.0 eq). The crude was purified by preparative HPLC (Column B) then freeze dried from a water / MeCN mixture to obtain Example 34 (16 mg, 6% over 2 steps) as a white solid.

[0713] 1H-NMR (DMSO-de , 400 MHz) 5: 0.99 (t, J 7.4 Hz, 3H, CH3); 1.68 (s, 6H, 2 CH3); 1.74-1.80 (m, 2H, CH2); 2.90 (t, J 7.4 Hz, 2H, Ar-CH2); 3.16 (s, 3H, S-CH3); 3.55-3.57 (m, 2H, N-CH2); 7.84 (d, J 9.3 Hz, 2H, 2 Ar); 7.95 (d, J 9.3 Hz, 2H, 2 Ar); 8.08 (bs, 1 H, NH); 8.31 (s, 1 H, Ar); 9.04 (s, 1 H, NH); One N-CH2signal was not observed.

[0714] M / Z (M+H)+: 446.4.

[0715] Compound 57: 3-chloro-N-(4-chlorobenzyl)pyrazin-2-amine

[0716] Following general procedure (Xb) with (4-chlorophenyl)methanamine (285 mg). The crude was purified by flash chromatography (CyHex / EtOAc, 100:0 to 80:20) to obtain Compound 57 (120 mg, 23%) as a yellow oil.

[0717] M / Z (M[35CI2]+H)+: 254.1.

[0718] Compound 58: N-(4-chlorobenzyl)-3-propylpyrazin-2-amine

[0719] Compound 58 was obtained according to general procedure (XI lb) starting from Compound 57 (510 mg), with propylzinc bromide (0.5 M in THF, 3.0 eq). The crude was purified by flash chromatography (CyHex / EtOAc, 100:0 to 50:50) to obtain Compound 58 (490 mg, 95%) as a brown solid.

[0720] M / Z (M[35CI]+H)+: 262.2.

[0721] Compound 59: 5-bromo-N-(4-chlorobenzyl)-3-propylpyrazin-2-amine

[0722] Compound 59 was obtained according to general procedure (Va), starting from Compound 58 (490 mg). The crude was purified by flash chromatography (CyHex / EtOAc, 100:0 to 70:30) to obtain Compound 59 (140 mg, 20%) as a yellow solid.

[0723] M / Z (M[35CI81Br]+H)+: 342.2.

[0724] Compound 60: 5-((4-chlorobenzyl)amino)-6-propylpyrazine-2-carboxylic acid

[0725] Compound 60 was obtained according to general procedure (VIII), starting from Compound 59 (140 mg). The crude was resuspended in water to obtain Compound 60 (25 mg, 20%) as a beige solid.

[0726] M / Z (M[35CI]+H)+: 306.3.

[0727] Example 35: 4-(5-((4-chlorobenzyl)amino)-6-propylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-2-one

[0728]

[0729] Example 35 was obtained according to general procedure (III), starting from Compound 60 (25 mg), using 3,3-dimethylpiperazin-2-one (1.0 eq) and N,N-diisopropylethylamine (2.0 eq). The crude was purified by preparative HPLC (Column B) then freeze dried from water to obtain Example 60 (13 mg, 38%) as a white solid.

[0730] 1H-NMR (DMSO-de , 400 MHz) 5: 0.97 (t, J 7.4 Hz, 3H, CH3); 1.63 (s, 6H, 2 CH3); 1.69-1.74 (m, 2H, CH2); 2.66 (t, J 7.4 Hz, 2H, Ar-CH2); 3.27-3.30 (m, 2H, N-CH2); 3.54-3.56 (m, 2H, N-CH2); 4.58 (d, J 5.9 Hz, 2H, N-CH2-Ar); 7.30-7.36 (m, 4H, 4 Ar); 7.65 (t, J 5.9 Hz, 1H, NH); 8.02 (bs, 1H, NH); 8.10 (s, 1H, Ar).

[0731] M / Z (M[35CI]+H)+: 416.3.

[0732] Compound 61 : 3-benzyl-N-(4-chloro-3-fluorophenyl)pyrazin-2-amine

[0733] Compound 61 was obtained according to general procedure (XI) starting from Compound 31 (467 mg) in Dioxane, with 2-benzyl-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (2.0 eq) and K2CO3(3.0 eq), using Pd(dppf)CI2(0.1 eq) at 100°C for 18 hours. The crude was purified by flash chromatography (CyHex / EtOAc, 100:0 to 40:60) to obtain Compound 61 (250 mg, 82%) as a pink oil.

[0734] M / Z (M[35CI]+H)+: 314.2

[0735] Compound 62: 3-benzyl-5-bromo-N-(4-chloro-3-fluorophenyl)pyrazin-2-amine

[0736] Compound 62 was obtained according to general procedure (Va), starting from Compound 61 (250 mg). The crude was purified by flash chromatography (CyHex / EtOAc, 100:0 to 90:10) to obtain Compound 62 (135 mg, 41%) as a pink oil.

[0737] M / Z (M[35CI][81Br]+H)+: 394.1

[0738] Compound 63: 6-benzyl-5-((4-chloro-3-fluorophenyl)amino)pyrazine-2-carboxylic acid

[0739] Compound 63 was obtained according to general procedure (VIII), starting from Compound 62 (130 mg). The crude was purified by flash chromatography (CyHex / EtOAc, 100:0 to 0:100, then to EtOAc / MeOH 85:15) to obtain Compound 63 (75 mg, 63%) as a yellow solid.

[0740] M / Z (M[35CI]+H)+: 358.3

[0741] Example 36: 4-(6-benzyl-5-((4-chloro-3-fluorophenyl)amino)pyrazine-2-carbonyl)-3,3-dimethylpiperazin-2-one

[0742]

[0743] Example 36 was obtained according to general procedure (III), starting from Compound 63 (75 mg), using 3,3-dimethylpiperazin-2-one (1.2 eq) and N,N-diisopropylethylamine (2.0 eq). The crude was purified by flash chromatography (DCM / EtOAc, 100:0 to 50:50) then freeze dried from a water / MeOH mixture to obtain Example 36 (20 mg, 20%) as a white solid.

[0744] 1H-NMR (DMSO-de , 400 MHz) 5: 1.62 (s, 6H, (CH3)2); 2.90-2.94 (m, 2H, CH2); 3.40-3.44 (m, 2H, CH2); 4.31 (s, 2H, CH2); 7.21-7.24 (m, 1H, Ar); 7.27-7.34 (m, 4H, Ar); 7.50-7.60 (m, 2H, Ar); 7.92-7.96 (m, 1H, Ar); 7.98 (bs, 1H, NH); 8.35 (s, 1H, Ar); 9.06 (s, 1H, NH).M / Z (M[35CI]+H)+: 468.3

[0745] Compound 64: methyl 5-((4-chloro-3-fluorophenyl)amino)-6-isopropylpicolinate

[0746] Compound 64 was obtained according to general procedure (IX), starting from Compound 28 (175 mg) in Dioxane, with 4-bromo-1-chloro-2-fluorobenzene (1.2 eq) and CS2CO3 (3.0 eq), using BrettPhos Pd G4 (0.1 eq) at 100°C for 6 hours. The crude was purified by flash chromatography (CyHex / DCM, 100:0 to 0:100) to obtain Compound 64 (417 mg, 78%) as a white solid.

[0747] M / Z (M[35CI]+H)+: 323.3

[0748] Compound 65: 5-((4-chloro-3-fluorophenyl)amino)-6-isopropylpicolinic acid

[0749] Starting from Compound 64 (530 mg) and following general procedure (I) Compound 65 (481 mg, 95%) was obtained as a yellow solid.

[0750] M / Z (M+H)+: 309.3

[0751] Example 37: methyl 6-(4-(5-((4-chloro-3-fluorophenyl)amino)-6-isopropylpicolinoyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinate

[0752]

[0753] Cl

[0754] Example 37 was obtained according to general procedure (III), starting from Compound 65 (200 mg), using methyl 6-(3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinate hydrochloride (1.1 eq) and N,N-diisopropylethylamine (4.0 eq). The crude was purified by flash chromatography (CyHex / EtOAc, 100:0 to 70:30) to obtain Example 37 (311 mg, 85%) as a white solid.

[0755] 1H-NMR (DMSO-de , 400 MHz) 5: 1.19 (d, J 6.7 Hz, 6H, 2 CH3); 1.50 (s, 6H, 2 CH3); 2.24 (s, 3H, CH3); 2.35 (s, 3H, CH3); 3.35 (sept., J 6.7 Hz, 1H, CH); 3.54-3.59 (m, 2H, CH2); 3.78 (s, 3H, OCH3); 3.85-3.90 (m, 4H, 2 CH2); 6.35 (s, 1H Ar); 6.75-6.78 (m, 1H, Ar); 6.84-6.87 (m, 1H, Ar); 7.34-7.41 (m, 2H, Ar); 7.65 (d, J 8.4 Hz, 1H, Ar); 8.15 (s, 1H, NH).

[0756] M / Z (M[35CI]+H)+: 568.5.

[0757] Example 38: 6-(4-(5-((4-chloro-3-fluorophenyl)amino)-6-isopropylpicolinoyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid

[0758]

[0759] Example 38 was obtained according to general procedure (II), starting from Example 37 (305 mg). The crude was purified by preparative HPLC (Column A), recrystallized from DMSO / Water (1 :4) then freeze dried from a water / MeCN mixture to obtain Example 38 (65 mg, 22%) as a brown solid.

[0760] 1H-NMR (DMSO-d6, 300 MHz) 5: 1.19 (d, JQ.7 Hz, 6H, 2 CH3); 1.50 (s, 6H, 2 CH3); 2.27 (s, 3H, CH3); 2.37 (s, 3H, CH3); 3.39 (sept., J 6.7 Hz 1H, CH); 3.54-3.59 (m, 2H, CH2); 3.84-3.87 (m, 2H, CH2); 3.89 (s, 2H, CH2); 6.33 (s, 1H Ar); 6.76 (dd, J 8.7, 2.3 Hz, 1 H, Ar); 6.86 (dd, J 11.8, 2.5 Hz, 1 H, Ar); 7.36 (t, J 8.7 Hz, 1 H, Ar); 7.40 (d, J 8.3 Hz, 1 H, Ar); 7.64 (d, J 8.3 Hz, 1H, Ar); 8.14 (s, 1H, NH); 12.66 (s, 1H, CO2H)

[0761] M / Z (M[35CI]+H+): 554.5.

[0762] Compound 66: 4-(5-chloropyrazine-2-carbonyl)-3,3-dimethylpiperazin-2-one

[0763] To a solution of 5-hydroxypyrazine-2-carboxylic acid (2.0 g) in THF (10 mL) was added DMF (50 piL), and Thionyl chloride (4.8 eq), the mixture was heated at 80°C for 1 hour, then concentrated under reduced pressure. The residue was dissolved in THF (5 mL), cooled at 0°C and DIPEA (4 eq) was added dropwise, then a solution of 3,3-dimethylpiperazin-2-one (1.2 eq) in THF (5 mL) was added and the mixture was stirred at 25°C for 2 hours. The mixture was diluted with EtOAc (50 mL) and treated with NaHCO3(sat. aq. 50 mL). The aqueous layer was extracted with EtOAc (2*50 mL), the combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The residue was recrystallized from DCM / EtOAc to obtain Compound 66 (1.82 g, 47%) as a white solid. M / Z (M[35CI]+H)+: 268.9.

[0764] Compound 67: 4-(5-((4,4-difluorocyclohexyl)amino)pyrazine-2-carbonyl)-3,3-dimethylpiperazin-2-one

[0765] To a solution of compound 66 (100 mg) in DMF (2 mL) was added 4,4-difluorocyclohexan-1-amine hydrochloride (2.0 eq) and Cesium carbonate (4.0 eq). The mixture was heated at 80°C for 22 hours, then diluted in DCM (50 mL) and washed with NH4CI (sat. aq. 3*50 mL). The organic layer was dried over MgSO4 then concentrated under reduced pressure. The crude was purified by flash chromatography (EtOAc / MeOH, 100:0 to 80:20) to obtain Compound 67 (20 mg, 15%) as a white solid.

[0766] M / Z (M+H)+: 368.3.

[0767] Compound 68: 4-(6-bromo-5-((4,4-difluorocyclohexyl)amino)pyrazine-2-carbonyl)-3,3-dimethylpiperazin-2-one Compound 68 was obtained according to general procedure (Va), starting from Compound 67 (176 mg). The crude was purified by flash chromatography (EtOAc / MeOH, 100:0 to 80:20) to obtain Compound 68 (121 mg, 57%) as a white solid.

[0768] M / Z (M[81Br]+H)+: 448.0.

[0769] Example 39: 4-(5-((4,4-difluorocyclohexyl)amino)-6-propylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-2-one

[0770] o

[0771]

[0772] Example 39 was obtained according to general procedure (XI lb) starting from Compound 68 (121 mg), with propylzinc bromide (0.5 M in THF, 3.0 eq). The crude was purified by flash chromatography (CyHex / EtOAc, 100:0 to0:100), then by preparative HPLC (Column B), and freeze dried from a water / MeCN mixture to obtain Example 39 (15 mg, 13%) as a brown solid.

[0773] 1H-NMR (DMSO-d6, 400 MHz) 5: 0.94 (t, J 7.3 Hz, 3H, CH3); 1.63-1.73 (m, 10H, 2 CH3, 2 CH2); 1.85-1.98 (m, 3H); 1.98-2.12 (m, 3H); 2.61 (t, J 7.4 Hz, 2H, Ar-CH2); 3.25-3.30 (m, 2H, NCH2); 3.52-3.59 (m, 2H, N-CH2); 4.06-4.19 (m, 1H, NCH); 6.66 (d, J 7.6 Hz, 1H, ArNH); 8.00-8.05 (m, 1H, NH), 8.16 (s, 1H, Ar).

[0774] M / Z (M+H)+: 410.2.

[0775] Compound 69: 4-(5-(4,4-difluoropiperidin-1-yl)pyrazine-2-carbonyl)-3,3-dimethylpiperazin-2-one

[0776] To a solution of compound 66 (200 mg) in DMF (2 mL) was added 4,4-difluoropiperidine hydrochloride (2.0 eq) and Cesium carbonate (4.0 eq). The mixture was heated at 80°C for 22 hours, then diluted in DCM (50 mL) and washed with NH4CI (sat. aq. 3*50 mL). The organic layer was dried over MgSO4 then concentrated under reduced pressure. The crude was purified by flash chromatography (EtOAc / MeOH, 100:0 to 80:20) to obtain Compound 69 (117 mg, 44%) as a white solid.

[0777] M / Z (M+H)+: 354.2

[0778] Compound 70: 4-(6-bromo-5-(4,4-difluoropiperidin-1-yl)pyrazine-2-carbonyl)-3,3-dimethylpiperazin-2-one Compound 70 was obtained according to general procedure (Va), starting from Compound 69 (117 mg). The crude was purified by flash chromatography (CyHex / EtOAc, 0:100 to 100:0, then EtOAc / MeOH, 100:0 to 80:20) to obtain Compound 70 (61 mg, 43%) as a white solid.

[0779] M / Z (M[81Br]+H)+: 434.0.

[0780] Example 40: 4-(5-(4,4-difluoropiperidin-1-yl)-6-propylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-2-one

[0781] ov,

[0782]

[0783] Example 40 was obtained according to general procedure (Xllb) starting from Compound 70 (60 mg), with propylzinc bromide (0.5 M in THF, 3.0 eq). The crude was purified by flash chromatography (CyHex / EtOAc, 100:0 to 0:100), then by preparative HPLC (Column B), and freeze dried from a water / MeCN mixture to obtain Example 40 (10 mg, 18%) as a yellow solid.

[0784] 1H-NMR (DMSO-de , 400 MHz) 5: 0.91 (t, J7.3 Hz, 3H, CH3); 1.67 (s, 6H, 2 CH3); 1.69-1.79 (m, 2H, CH2); 2.04-2.19 (m, 4H, 2 CH2); 2.75 (t, J 7.4 Hz, 2H, ArCH2); 3.24-3.30 (m, 2H, NCH2); 3.48-3.56 (m, 2H, NCH2); 8.08 (bs, 1H, NH), 8.31 (s, 1 H, Ar). Two CH2signals were not observed.

[0785] M / Z (M+H)+: 396.2

[0786] Example 41 : tert-butyl 4-(5-((4-chloro-3-fluorophenyl)amino)-6-isopropylpyrazine-2-carbonyl)-3,3-dimethylpiperazine-1-carboxylate

[0787] F

[0788]

[0789] Example 41 was obtained according to general procedure (III), starting from Compound 35 (200 mg), using tert-butyl 3,3-dimethylpiperazine-1-carboxylate (1.1 eq) and N,N-diisopropylethylamine (2.0 eq). The crude was purified by flash chromatography (CyHex / EtOAc, 100:0 to 50:50) to obtain Example 41 (107 mg, 33%) as a yellow oil.

[0790] 1H-NMR (DMSO-d6, 400 MHz) 5: 1.22 (d, J 6.5 Hz, 6H, (CH3)2); 1.42 (s, 9H, (CH3)3); 1.46 (s, 6H, (CH3)2); 3.39-3.57 (m, 5H, CH2A0H2A0H); 3.64-3.68 (m, 2H, CH2); 7.50 (t, J 8.8 Hz, 1H, Ar); 7.56-7.59 (m, 1H, Ar); 7.90 (dd, J 12.4, 2.2 Hz, 1H, Ar); 8.26 (s, 1H, Ar); 8.90 (s, 1H, NH).

[0791] M / Z (M[35CI]+H)+: 506.1.

[0792] Example 42: (5-((4-chloro-3-fluorophenyl)amino)-6-isopropylpyrazin-2-yl)(2,2-dimethylpiperazin-1-yl)methanone

[0793]

[0794] Example 42 was obtained according to general procedure (IV), starting from Example 41 (100 mg). The crude was sonicated with Et2O and the solid was recovered by filtration to obtain Example 42 (75 mg, 92%) as a yellow solid.

[0795] 1H-NMR (DMSO-d6, 400 MHz) 5: 1.22 (d, J 6.5 Hz, 6H, (CH3)2); 1.43 (s, 6H, C(CH3)2); 2.68 (s, 2H, NCH2); 2.85-2.87 (m, 2H, NCH2); 3.39-3.41 (m, 2H, NCH2); 3.50-3.56 (sept., J 6.5 Hz, 1H, CH); 7.49 (t, J 8.6 Hz, 1H, Ar); 7.56-7.59 (m, 1H, Ar); 7.91 (dd, J 12.4, 2.4 Hz, 1H, Ar); 8.24 (s, 1H, Ar); 8.89 (s, 1H, NH). One NH signal not observed.

[0796] M / Z (M[35CI]+H)+: 406.1.

[0797] Example 43: 1-(4-(5-((4-chloro-3-fluorophenyl)amino)-6-isopropylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)ethan-1-one

[0798]

[0799] ci

[0800] To a solution of Example 42 (70 mg) in DCM (1.5 mL) was added Triethylamine (3.0 eq) then Acetyl Chloride (1.2 eq). The mixture was stirred at 25°C for 18 hours, then quenched with NH4CI (sat. aq. 50 mL). The mixture was extracted with DCM (3*15 mL). The combined organic layers were washed with brine, dried over MgSO4 and concentrated under reduced pressure. The crude was purified by flash chromatography (EtOAc / MeOH, 100:0 to 90:10) then by preparative HPLC (Column B), and freeze dried from a water / MeCN mixture to obtain Example 43 (20 mg, 26%) as a white solid.

[0801] 1H-NMR (DMSO-de , 400 MHz) 5: 1.21-1.24 (m, 6H, (CH3)2); 1.46 (s, 3H, one rotamer of C(CH3)2); 1.50 (s, 3H, other rotamer of C(CH3)2); 1.99 (s, 1.5H, one rotamer of COCH3); 2.03 (s, 1.5H, other rotamer of COCH3); 3.44-3.63 (m, 5H, CH2, CH2, CH); 3.70-3.79 (m, 2H, CH2); 7.49 (t, J 8.6 Hz, 1H, Ar); 7.56-7.59 (m, 1H, Ar); 7.90 (d, J 12.4 Hz, 1H, Ar); 8.26 s, 0.5H, one rotamer of Ar); 8.27 (s, 0.5H, other rotamer of Ar); 8.91 (s, 1 H, NH).

[0802] M / Z (M[35CI]+H)+: 448.1Example 44: ethyl 2-(1-(5-((4-chloro-3-fluorophenyl)amino)-6-isopropylpyrazine-2-carbonyl)-2,2-dimethylpiperidin-4-yl)acetate

[0803]

[0804] Example 44 was obtained according to general procedure (III), starting from Compound 35 (150 mg), using ethyl 2-(2,2-dimethylpiperidin-4-yl)acetate hydrochloride (1.1 eq) and N,N-diisopropylethylamine (3.0 eq). The crude was purified by flash chromatography (CyHex / EtOAc, 100:0 to 70:30) then freeze dried from a water / MeCN mixture to obtain Example 44 (138 mg, 58%) as an orange solid.

[0805] 1H-NMR (DMSO-de , 400 MHz) 5: 1.17-1.28 (m, 10H, (CH3)2, CH, CH3); 1.36-1.56 (m, 8H, C(CH3)2, CH2); 1.79-1.88 (m, 1H, CHaHb); 2.05-2.17 (m, 1H, CHaHb); 2.27 (d, J 7.0 Hz, 2H, CH2CO); 3.08-3.14 (m, 1H, NCHaHb); 3.54 (sept., J 6.7 Hz, 1H, CH); 3.60-3.69 (m, 1H, NCHaHb); 4.03-4.10 (m, 2H, OCH2); 7.49 (t, J 8.7 Hz, 1H, Ar); 7.58 (dd, J 8.7, 2.0 Hz, 1H, Ar); 7.91 (dd, J 12.4, 2.4 Hz, 1H, Ar); 8.24 (s, 1H, Ar); 8.89 (s, 1H, NH).

[0806] M / Z (M[35CI]+H)+: 491.1.

[0807] Example 45: 2-(1-(5-((4-chloro-3-fluorophenyl)amino)-6-isopropylpyrazine-2-carbonyl)-2,2-dimethylpiperidin-4-yl)acetic acid

[0808] Y F

[0809]

[0810] Cl

[0811] Example 45 was obtained according to general procedure (I), starting from Example 44 (130 mg). The crude was purified by preparative HPLC (Column B) then freeze dried from water to obtain Example 45 (100 mg, 82%) as a white solid.

[0812] 1H-NMR (DMSO-d6, 400 MHz) 5: 1.21-1.31 (m, 7H, (CH3)2, CH); 1.37-1.58 (m, 8H, C(CH3)2, CH2); 1.79-1.88 (m, 1H, CHaHb); 2.03-2.14 (m, 1H, CHaHb); 2.19 (d, J6.9 Hz, 2H, CH2-CO); 3.05-3.16 (m, 1H, NCHaHb); 3.54 (sept., J6.7 Hz, 1H, CH); 3.61-3.71 (m, 1H, NCHaHb); 7.49 (t, J8.7 Hz, 1H, Ar); 7.58 (dd, J 8.7, 2.4 Hz, 1H, Ar); 7.90 (dd, J 12.4, 2.4 Hz, 1H, Ar); 8.24 (s, 1H, Ar); 8.89 (s, 1H, NH); 12.09 (s, 1H, CO2H).

[0813] M / Z (M[35CI]+H)+: 463.0

[0814] Compound 71: tert-butyl 5-(2-ethoxy-2-oxoethylidene)-2-azabicyclo[2.2.1]heptane-2-carboxylate

[0815] To a solution of tert-butyl 5-oxo-2-azabicyclo[2.2.1]heptane-2-carboxylate (1.0 g) in THF (12 mL) was added at -78°C ButylLithium (2.5 M in hexane, 1.5 eq), after 45 minutes, ethyl 2-(diethoxyphosphoryl)acetate (1.6 eq, in THF 10 mL) was added and the mixture was let warm up at 25°C for 72 hours. The mixture was quenched with NH4CI (sat. aq.

[0816] 100 mL) then extracted with EtOAc (3*50 mL). The combined organic layers were washed with brine (50 mL), dried over MgSO4 and concentrated under reduced pressure. The crude was purified by flash chromatography (CyHex / EtOAc, 0:100 to 80:20) to obtain Compound 71 (1.3 g, 98%) as a clear oil.

[0817] M / Z (M-‘Bu+H)+: 226.0.Compound 72: tert-butyl 5-(2-ethoxy-2-oxoethyl)-2-azabicyclo[2.2.1]heptane-2-carboxylate

[0818] Compound 73: ethyl 2-(2-(((tert-butoxycarbonyl)amino)methyl)cyclopentyl)acetate

[0819] Compound 72 and Compound 73 were obtained in mixture as a clear oil (1.2 g, 92%, 8:2 ratio) following general procedure (XVIII) and starting from Compound 71.

[0820] Compound 72: M / Z (M-‘Bu+H)+: 228.1.

[0821] Compound 73: M / Z (M-‘Bu+H)+: 230.1.

[0822] Compound 74: ethyl 2-(2-azabicyclo[2.2.1]heptan-5-yl)acetate hydrochloride

[0823] Compound 75: ethyl 2-(2-(aminomethyl)cyclopentyl)acetate hydrochloride

[0824] A mixture of Compound 72 and Compound 73 (1.2 g, 8:2 ratio) was dissolved in DCM (15 mL) and treated with HCI (2M in Et20, 10 eq). The mixture was stirred for 3 hours at 25°C, then concentrated under reduced pressure to obtain Compound 74 and Compound 75 (1.1 g, n.d., 8:2 ratio) as a clear oil.

[0825] Compound 74: M / Z (M+H)+: 184.0.

[0826] Compound 75: M / Z (M+H)+: 186.0.

[0827] Example 46: ethyl 2-(2-(5-((4-chloro-3-fluorophenyl)amino)-6-isopropylpyrazine-2-carbonyl)-2-azabicyclo[2.2.1]heptan-5-yl)acetate

[0828]

[0829] Cl

[0830] Example 47: ethyl 2-(2-((5-((4-chloro-3-fluorophenyl)amino)-6-isopropylpyrazine-2-carboxamido)methyl)cyclopentyl)acetate

[0831]

[0832] Examples 46 and 47 were obtained according to general procedure (III), starting from Compound 35 (150 mg), using Compounds 74 and 75 as a mixture (1.1 eq, 8:2 ratio) and N,N-diisopropylethylamine (3.0 eq). The crude was purified by flash chromatography (CyHex / EtOAc, 100:0 to 50:50) then freeze dried from a water / MeCN mixture to obtain Example 46 (145 mg, 63%) as a yellow solid, and Example 47 (32 mg, 14%) as a yellow solid.

[0833] Example 46 (diastereoisomeric mixture, 1:2 ratio):1H-NMR (DMSO-de , 400 MHz) 5: 1.12-1.30 (m, 10H, (CH3)2, CH, CH3); 1.39-1.43 (m, 1H, CH); 1.58-1.74 (m, 2H, CH2); 1.91-2.11 (m, 1H, CHaHb); 2.32-2.41 (m, 3H, CHaHb, CH2C(O)); 3.33-3.41 (m, 1.32 H, other diastereoisomer of NCHaHb); 3.55 (sept., J 6.5 Hz, 1H, CH); 3.66-3.69 (m, 0.33H, one diastereoisomer NCHaHb) 3.90-3.93 (m, 0.33H, one diastereoisomer of NCHaHb); 4.02-4.09 (m, 2H, OCH2); 4.53 (s,0.33H, one diastereoisomer, NCH); 4.75 (s, 0.66H, other diastereoisomer, NCH); 7.50 (t, J 8.7 Hz, 1H, Ar); 7.59 (dd, J 8.9, 2.0 Hz, 1 H, Ar); 7.91 (dd, J 12.4, 2.4 Hz, 1 H, Ar); 8.44 (s, 0.66H, other diastereoisomer, Ar); and 8.48 (s, 0.33H, one diastereoisomer, Ar); 8.94 (s, 1H, NH).

[0834] M / Z (M[35CI]+H)+: 475.1

[0835] Example 47 (diastereoisomeric mixture, 1:3 ratio):1H-NMR (DMSO-de , 400 MHz) 5: 1.12-1.40 (m, 12H, (CHs)?, CH, CH2, CH3); 1.50-1.59 (m, 2H, CH2); 1.63-2.00 (m, 3.5H, CH, CH2, CH2-CO one diastereoisomer); 2.18-2.24 (m, 1.5 H, CH2-CO other diastereoisomer); 3.21-3.31 (m, 2H, NHCH2); 3.54 (sept., J 6.6 Hz, 1H, CH); 3.98-4.07 (m, 2H, OCH2); 7.51 (t, J8.7 Hz, 1H, Ar); 7.60 (dd, J8.9, 2.0 Hz, 1H, Ar); 7.93 (dd, J 12.4, 2.4 Hz, 1H, Ar); 8.19 (t, J 6.1 Hz, 0.25H, one diastereoisomer, NH); 8.28 (t, J 6.1 Hz, 0.75H, other diastereoisomer, NH); 8.55 (s, 1H, Ar); 8.99 (s, 1H, NH).

[0836] M / Z (M[35CI]+H)+: 477.0

[0837] Example 48: 2-(2-(5-((4-chloro-3-fluorophenyl)amino)-6-isopropylpyrazine-2-carbonyl)-2-azabicyclo[2.2.1]heptan-5-yl)acetic acid

[0838]

[0839] Example 48 was obtained according to general procedure (I), starting from Example 46 (135 mg). The crude was purified by preparative HPLC (Column B) then freeze dried from water to obtain Example 45 (115 mg, 91%) as a white solid.

[0840] diastereoisomeric mixture, 1:2 ratio :1H-NMR (DMSO-d6, 400 MHz) 5: 1.14-1.26 (m, 7H); 1.34-1.43 (m, 1H); 1.57-1.74 (m, 2H); 1.90-2.52 (m, 4H); 3.34-3.47 (m, 0.66H, other diastereoisomer NCHaHb); 3.55 (sept., J 6.5 Hz, 1H, ArCH); 3.66-3.72 (m, 0.33 H, one diastereoisomer NCHaHb); 3.84-3.90 (m, 0.33H, one diastereoisomer NCHaHb); 4.52 (s, 0.33H, one diastereoisomer, NCH); 4.76 (s, 0.66H, other diastereoisomer, NCH); 7.50 (t, J 8.7 Hz, 1H, Ar); 7.59 (dd, J 8.9, 2.0 Hz, 1H, Ar); 7.92 (dd, J 12.4, 2.3 Hz, 1H, Ar); 8.42-8.50 (m, 1H, Ar); 8.94 (s, 1H, NH); 12.09 (s, 1H, CO2H). One CHaHb not observed for other diastereoisomer.

[0841] M / Z (M[35CI]+H)+: 447.0

[0842] Example 49: 2-(2-((5-((4-chloro-3-fluorophenyl)amino)-6-isopropylpyrazine-2-carboxamido)methyl)cyclopentyl)acetic acid

[0843]

[0844] Example 49 was obtained according to general procedure (I), starting from Example 47 (30 mg). The crude was purified by preparative HPLC (Column B) then freeze dried from water to obtain Example 49 (15 mg, 53%) as a white solid.diastereoisomeric mixture, 1:3 ratio :1H-NMR (DMSO-de , 400 MHz) 5: 1.18-1.40 (m, 9H); 1.49-1.59 (m, 2H, CH2); 1.64-1.96 (m, 2H, CH2); 2.11-2.17 (m, 1H, CH); 2.31-2.48 (m, 1H, CH); 3.14-3.30 (m, 2H, CH2); 3.32-3.42 (m, 1H); 3.53 (sept., J 6.5 Hz, 1H, ArCH); 7.51 (t, J 8.7 Hz, 1H, Ar); 7.60 (dd, J 8.9, 2.0 Hz, 1H, Ar); 7.93 (dd, J 12.4, 2.3 Hz, 1H, Ar); 8.24-8.30 (m, 1H, NH); 8.54 (s, 1H, Ar); 8.99 (s, 1H, NH); 12.04 (s, 1H, CO2H)

[0845] M / Z (M[35CI]+H)+: 449.0

[0846] Compound 76: 4-(5-((4-chlorobenzyl)(methyl)amino)pyrazine-2-carbonyl)-3,3-dimethylpiperazin-2-one

[0847] To a solution of compound 66 (177 mg) in MeCN (4 mL) was added 1-(4-chlorophenyl)-N-methylmethanamine hydrochloride (3.0 eq) and Cesium carbonate (4.0 eq). The mixture was heated at 100°C for 23 hours, then diluted in EtO Ac (50 mL) and washed with NH4CI (sat. aq. 50 mL). The organic layer was dried over MgSO4 then concentrated under reduced pressure. The crude was purified by flash chromatography (EtOAc / MeOH, 100:0 to 80:20) to obtain Compound 76 (150 mg, 59%) as a yellow oil.

[0848] M / Z (M[35CI]+H)+: 388.2.

[0849] Compound 77: 4-(6-bromo-5-((4-chlorobenzyl)(methyl)amino)pyrazine-2-carbonyl)-3,3-dimethylpiperazin-2-one Compound 77 was obtained according to general procedure (Va), starting from Compound 76 (150 mg). The crude was purified by flash chromatography (EtOAc / MeOH, 100:0 to 80:20) to obtain Compound 77 (61 mg, 34%) as a yellow solid.

[0850] M / Z (M[81Br35CI]]+H)+: 467.9.

[0851] Example 50: 4-(5-((4-chlorobenzyl)(methyl)amino)-6-propylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-2-one

[0852]

[0853] Example 50 was obtained according to general procedure (Xllb) starting from Compound 77 (61 mg), with propylzinc bromide (0.5 M in THF, 5.0 eq). The crude was purified by flash chromatography (CyHex / EtOAc, 100:0 to 0:100), then by preparative HPLC (Column B), and freeze dried from a water / MeCN mixture to obtain Example 50 (13 mg, 61%) as a white solid.

[0854] 1H-NMR (DMSO-de , 400 MHz) 5: 0.86 (t, J 7.3 Hz, 3H, CH3); 1.66 (s, 6H, (CH3)2); 1.67-1.75 (m, 2H, CH2-CH3); 2.78 (t, J 7.5 Hz, 2H, Ar-CH2); 2.89 (s, 3H, NCH3); 3.26-3.30 (m, 2H, NCH2); 3.51-3.58 (m, 2H, NCH2); 4.54 (s, 2H, NCH2Ar); 7.31 (d, J 8.8 Hz, 2H, Ar); ; 7.41 (d, J 8.8 Hz, 2H, Ar); 8.07 (bs, 1H, NH), 8.25 (s, 1H, Ar).

[0855] M / Z (M[35CI]+H)+: 430.1.

[0856] Example 51: tert-butyl 4-(5-((4-chloro-3-fluorophenyl)amino)-6-isopropylpyrazine-2-carbonyl)-3,3-dimethylpiperazine-1-carboxylate

[0857]

[0858] Example 51 was obtained according to general procedure (III), starting from Compound 35 (270 mg), using tert-butyl 4-(methylamino)piperidine-1 -carboxylate (1.0 eq) and N, N-diisopropylethylamine (2.0 eq). The crude was purified by flash chromatography (CyHex / EtOAc, 100:0 to 40:60) to obtain Example 51 (312 mg, 71%) as a brown oil.

[0859] M / Z (M[35CI]+H)+: 506.0.

[0860] Example 52: 5-((4-chloro-3-fluorophenyl)amino)-6-isopropyl-N-methyl-N-(piperidin-4-yl)pyrazine-2-carboxamide

[0861]

[0862] Example 52 was obtained according to general procedure (IV), starting from Example 51 (312 mg). The crude was purified by preparative HPLC (Column B), and freeze dried from a HCI (in water) / MeCN mixture to obtain Example 52 hydrochloride (60 mg, 22%) as a yellow solid.

[0863] 1H-NMR (DMSO-de , 400 MHz, 80°C) 5: 1.26 (d, J6.6 Hz, 6H, (CH3)2); 1.90-1.93 (m, 2H, CH2); 2.02-2.23 (m, 2H, CH2); 2.82-2.96 (m, 5H, CH3, CH2); 3.59 (sept., J 6.6 Hz, 1H, CH); 4.25-4.44 (m, 1H, CH); 7.44 (t, J 8.7 Hz, 1H, Ar); 7.56-7.59 (m, 1 H, Ar); 7.86 (dd, J 12.4, 2.4 Hz, 1 H, Ar); 8.29 (s, 1 H, Ar); 8.46-8.67 (m, 3H, NH, NH2CI). One CH2was not observed.

[0864] M / Z (M[35CI]+H)+: 406.1.

[0865] Example 53: N-(1-acetylpiperidin-4-yl)-5-((4-chloro-3-fluorophenyl)amino)-6-isopropyl-N-methylpyrazine-2-carboxamide

[0866]

[0867] To a solution of Example 52 (30 mg) in DCM (1.5 mL) was added Triethylamine (3.0 eq) then Acetyl Chloride (1.2 eq). The mixture was stirred at 25°C for 18 hours, then quenched with NH4CI (sat. aq. 50 mL). The mixture was extracted with DCM (3*15 mL). The combined organic layers were washed with brine, dried over MgSO4 and concentrated under reduced pressure. The crude was purified by preparative HPLC (Column B), and freeze dried from a water / MeCN mixture to obtain Example 53 (32 mg, 97%) as a white solid.

[0868] 1H-NMR (DMSO-de , 400 MHz, 80°C) 5: 1.26 (d, J 6.6 Hz, 6H, (CH3)2); 1.62-1.84 (m, 4H, CH2, CH2); 2.00 (s, 3H, CH3); 2.92-2.94 (m, 6H, CH3,3 CHaHb); 3.57 (sept, J 6.6 Hz, 1H, CH); 4.17-4.46 (bs, 2H, 2 CHaHb); 7.44 (t, J 8.7 Hz, 1H, Ar); 7.55-7.58 (m, 1H, Ar); 7.84 (dd, J 12.4, 2.4 Hz, 1H, Ar); 8.28 (s, 1H, Ar); 8.62 (bs, 1H, NH).

[0869] M / Z (M[35CI]+H)+: 448.1

[0870] Compound 78: 3-chloro-N-(4-fluorobenzyl)pyrazin-2-amine

[0871] Following general procedure (Xb) with (4-fluorophenyl)methanamine (343 mg). The crude was purified by flash chromatography (CyHex / EtOAc, 100:0 to 85:15) to obtain Compound 78 (482 mg, 76%) as a yellow oil.

[0872] M / Z (M[35CI]+H)+: 238.0.Compound 79: N-(4-fluorobenzyl)-3-(prop-1-en-2-yl)pyrazin-2-amine

[0873] Compound 79 was obtained according to general procedure (XI) starting from Compound 78 (467 mg) in Dioxane, with 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1 ,3,2-dioxaborolane (2.0 eq) and K2CO3(3.0 eq), using Pd(dppf)CI2(0.1 eq) at 80°C for 5 hours. The crude was purified by flash chromatography (CyHex / EtOAc, 100:0 to 80:20) to obtain Compound 79 (457 mg, 93%) as a yellow oil.

[0874] M / Z (M+H)+: 244.0

[0875] Compound 80: N-(4-fluorobenzyl)-3-isopropylpyrazin-2-amine

[0876] Starting from Compound 79 (457 mg) and following general procedure (XVIII) with Pt / C Compound 80 (430 mg, 93%) was obtained as a clear oil.

[0877] M / Z (M+H)+: 246.2

[0878] Compound 81 : 5-bromo-N-(4-fluorobenzyl)-3-isopropylpyrazin-2-amine

[0879] Compound 81 was obtained according to general procedure (Va), starting from Compound 80 (430 mg). The crude was purified by flash chromatography (CyHex / EtOAc, 100:0 to 90:10) to obtain Compound 81 (459 mg, 80%) as a white solid.

[0880] M / Z (M[81Br]+H)+: 326.0.

[0881] Compound 82: 5-((4-fluorobenzyl)amino)-6-isopropylpyrazine-2-carboxylic acid

[0882] Compound 82 was obtained according to general procedure (VIII), starting from Compound 81 (459 mg). No further purification was needed to obtain Compound 82 (229 mg, 56%) as a beige solid.

[0883] M / Z (M+H)+: 290.1.

[0884] Example 54: 4-(5-((4-fluorobenzyl)amino)-6-isopropylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-2-one

[0885]

[0886] Example 54 was obtained according to general procedure (III), starting from Compound 82 (80 mg), using 3,3-dimethylpiperazin-2-one (1.0 eq) and N,N-diisopropylethylamine (3.0 eq). The crude was purified by flash chromatography (DCM / MeOH, 100:0 to 95:5) to obtain Example 54 (80 mg, 72%) as a white solid.

[0887] 1H-NMR (DMSO-de , 400 MHz) 5: 1.18 (d, J 6.6 Hz, 6H, CH(CH3)2); 1.64 (s, 6H, (CH3)2); 3.23 (sept., J6.6 Hz, 1H, CH); 3.33-3.38 (m, 2H, NCH2); 3.56-3.60 (m, 2H, NCH2); 4.59 (d, J 5.8 Hz, 2H, CH2); 7.11 (t, J 8.9 Hz, 2H, Ar); 7.33 (dd, J 8.6, 5.7 Hz, 2H, Ar); 7.72 (t, J 5.8 Hz, 1H, NH); 8.02 (bs, 1H, CONH); 8.13 (s, 1H, Ar).

[0888] M / Z (M+H)+: 400.2.

[0889] Example 55: methyl 6-(4-(5-((4-fluorobenzyl)amino)-6-isopropylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinate

[0890]

[0891] Example 55 was obtained according to general procedure (III), starting from Compound 82 (150 mg), using methyl 6-(3,3-dimethylpiperazin-1 -yl)-2,4-dimethylnicotinate (1.2 eq) and N, N-diisopropylethylamine (3.0 eq). The crude was purified by flash chromatography (CyHex / EtOAc, 100:0 to 60:40) to obtain Example 55 (268 mg, 94%) as a white solid.

[0892] 1H-NMR (DMSO-de , 400 MHz) 5: 1.203 (d, J 6.6 Hz, 6H, CH(CH3)2); 1.45 (s, 6H, (CH3)2); 2.22 (s, 3H, ArCH3); 2.33 (s, 3H, ArCH3); 3.24 (sept., J 6.6 Hz, 1H, ArCH); 3.54-3.59 (m, 2H, NCH2); 3.77 (s, 3H, OCH3); 3.85 (s, 2H, NCH2); 3.90-3.94 (m, 2H, NCH2); 4.58 (d, J 6.0 Hz, 2H, ArCH2); 6.33 (s, 1H, Ar); 7.09-7.13 (m, 2H, Ar); 7.31-7.35 (m, 2H); 7.65 (t, J 6.0 Hz, 1H, NH); 8.09 (s, 1H, Ar).

[0893] M / Z (M+H)+: 549.1.

[0894] Example 56: 6-(4-(5-((4-fluorobenzyl)amino)-6-isopropylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid

[0895]

[0896] Example 56 was obtained according to general procedure (II), starting from Example 55 (268 mg). The crude was purified by preparative HPLC (Column B), then triturated in EtOAc (3*5 mL) and freeze dried from a water / MeCN mixture to obtain Example 56 (73 mg, 28%) as a white solid.

[0897] 1H-NMR (DMSO-de , 400 MHz) 5: 1.22 (d, J 6.6 Hz, 6H, CH(CH3)2); 1.46 (s, 6H, (CH3)2); 2.26 (s, 3H, ArCH3); 2.37 (s, 3H, ArCH3); 3.25 (sept., J6.6 Hz, 1H, ArCH); 3.53-3.58 (m, 2H, NCH2); 3.85 (s, 2H, NCH2); 3.88-3.92 (m, 2H, NCH2); 4.59 (d, J6.0 Hz, 2H, ArCH2); 6.32 (s, 1H, Ar); 7.09-7.13 (m, 2H, Ar); 7.32-7.36 (m, 2H); 7.66 (t, J 6.0 Hz, 1H, NH); 8.10 (s, 1H, Ar), 12.65 (bs, 1H, COCH).

[0898] M / Z (M+H+): 535.1.

[0899] Compound 83: N-benzyl-3-chloropyrazin-2-amine

[0900] Following general procedure (Xb) with phenylmethanamine (293 mg). The crude was purified by flash chromatography (CyHex / EtOAc, 100:0 to 80:20) to obtain Compound 83 (495 mg, 84%) as a yellow oil.

[0901] M / Z (M[35CI]+H)+: 220.0.

[0902] Compound 84: N-benzyl-3-(prop-1-en-2-yl)pyrazin-2-amine

[0903] Compound 84 was obtained according to general procedure (XI) starting from Compound 83 (495 mg) in Dioxane, with 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1 ,3,2-dioxaborolane (2.0 eq) and K2CO3 (3.0 eq), using Pd(dppf)Cl2 (0.1 eq) at 80°C for 5 hours. The crude was purified by flash chromatography (CyHex / EtOAc, 100:0 to 85:15) to obtain Compound 84 (475 mg, 94%) as a yellow oil.

[0904] M / Z (M+H)+: 226.0Compound 85: N-benzyl-3-isopropylpyrazin-2-amine

[0905] Starting from Compound 84 (475 mg) and following general procedure (XVIII) with Pt / C Compound 85 (439 mg, 92%) was obtained as a yellow oil.

[0906] M / Z (M+H)+: 228.2

[0907] Compound 86: N-benzyl-5-bromo-3-isopropylpyrazin-2-amine

[0908] Compound 86 was obtained according to general procedure (Va), starting from Compound 85 (439 mg). The crude was purified by flash chromatography (CyHex / EtOAc, 100:0 to 90:10) to obtain Compound 86 (472 mg, 80%) as a white solid.

[0909] M / Z (M[81Br]+H)+: 308.0.

[0910] Compound 87: 5-(benzylamino)-6-isopropylpyrazine-2-carboxylic acid

[0911] Compound 87 was obtained according to general procedure (VIII), starting from Compound 86 (472 mg). No further purification was needed to obtain Compound 87 (243 mg, 58%) as a yellow solid.

[0912] M / Z (M+H)+: 272.0

[0913] Example 57: 4-(5-(benzylamino)-6-isopropylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-2-one

[0914]

[0915] Example 57 was obtained according to general procedure (III), starting from Compound 87 (90 mg), using 3,3-dimethylpiperazin-2-one (1.2 eq) and N,N-diisopropylethylamine (3.0 eq). The crude was purified by flash chromatography (DCM / MeOH, 100:0 to 95:5) then by preparative HPLC (Column B) and freeze dried from water to obtain Example 57 (60 mg, 47%) as a white solid.

[0916] 1H-NMR (DMSO-de , 400 MHz) 5: 1.19 (d, J 6.6 Hz, 6H, CH(CH3)2); 1.64 (s, 6H, (CH3)2); 3.25 (sept., J6.6 Hz, 1H, CH); 3.29-3.36 (m, 2H, NCH2); 3.56-3.60 (m, 2H, NCH2); 4.62 (d, J 6.0 Hz, 2H, CH2); 7.18-7.23 (m, 1H, Ar); 7.26-7.33 (m, 4H, Ar); 7.71 (t, J 6.0 Hz, 1H, NH); 8.03 (bs, 1H, CONH); 8.12 (s, 1H, Ar).

[0917] M / Z (M+H)+: 382.2.

[0918] Example 58: methyl 6-(4-(5-(benzylamino)-6-isopropylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinate

[0919]

[0920] Example 58 was obtained according to general procedure (III), starting from Compound 87 (150 mg), using methyl 6-(3,3-dimethylpiperazin-1 -yl)-2,4-dimethylnicotinate (1.2 eq) and N, N-diisopropylethylamine (3.0 eq). The crude was purified by flash chromatography (CyHex / EtOAc, 100:0 to 70:30) to obtain Example 58 (254 mg, 87%) as a white solid.1H-NMR (DMSO-C / 6 , 400 MHz) 5: 1.23 (d, J 6.6 Hz, 6H, CH(CH3)2); 1.46 (s, 6H, (CH3)2); 2.23 (s, 3H, ArCH3); 2.34 (s, 3H, ArCH3); 3.26 (sept., J 6.6 Hz, 1H, ArCH); 3.54-3.59 (m, 2H, NCH2); 3.78 (s, 3H, OCH3); 3.86 (s, 2H, NCH2); 3.90-3.94 (m, 2H, NCH2); 4.62 (d, J 6.0 Hz, 2H, ArCH2); 6.34 (s, 1H, Ar); 7.18-7.24 (m, 1H, Ar); 7.27-7.34 (m, 4H); 7.66 (t, J 6.0 Hz, 1H, NH); 8.10 (s, 1H, Ar)

[0921] M / Z (M+H)+: 531.1.

[0922] Example 59: 6-(4-(5-(benzylamino)-6-isopropylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid

[0923]

[0924] Example 59 was obtained according to general procedure (II), starting from Example 58 (254 mg). The crude was purified by preparative HPLC (Column B), then freeze dried from a water / MeCN mixture to obtain Example 59 (130 mg, 53%) as a white solid.

[0925] 1H-NMR (DMSO-d6, 400 MHz) 5: 1.23 (d, J 6.6 Hz, 6H, CH(CH3)2); 1.46 (s, 6H, (CH3)2); 2.26 (s, 3H, ArCH3); 2.37 (s, 3H, ArCH3); 3.26 (sept., J6.6 Hz, 1H, ArCH); 3.53-3.58 (m, 2H, NCH2); 3.85 (s, 2H, NCH2); 3.90-3.94 (m, 2H, NCH2); 4.62 (d, J6.0 Hz, 2H, ArCH2); 6.31 (s, 1H, Ar); 7.18-7.23 (m, 1H, Ar); 7.27-7.34 (m, 4H); 7.66 (t, J 6.0 Hz, 1H, NH); 8.09 (s, 1H, Ar); 12.68 (bs, 1H, COCH).

[0926] M / Z (M+H+): 517.1.

[0927] Example 60: N-(1-(5-((4-chloro-3-fluorophenyl)amino)-6-isopropylpyrazine-2-carbonyl)-2,2-dimethylpiperidin-4-yl)-N-methylacetamide

[0928]

[0929] Example 60 was obtained according to general procedure (III), starting from Compound 35 (120 mg), using methyl N-(2, 2-di methyl piperidi n-4-yl)-N-methylacetamide hydrochloride (1.4 eq) and N, N-di isopropylethyl amine (3.0 eq). The crude was purified by flash chromatography (CyHex / EtOAc, 100:0 to 0:100), then by preparative HPLC (Column B), then freeze dried from a water to obtain Example 60 (62 mg, 34%) as a white solid.

[0930] 1H-NMR (DMSO-de , 400 MHz, 80°C) 5: 1.20-1.27 (m, 6H, CH(CH3)2); 1.29-1.64 (m, 7H, (CH3)2, CHaHb); 1.64-1.92 (m, 2H, CH2); 1.98-2.12 (m, 4H, NC(O)CH3, CHaHb); 2.69-2.93 (m, 3H, NCH3); 3.25-3.37 (m, 1H, NCHaCHb); 3.53 (sept., J 6.6 Hz, 1H, ArCH); 3,65-3.76 (m, 1H, NCHaHb); 3.95-4.71 (m, 1H, NCH); 7.41-7.48 (m, 1H, Ar); 7.53-7.60 (m, 1H, Ar); 7.82-7.90 (m, 1H, Ar); 8.25 (s, 1H, Ar); 8.71 (bs, 1H, NH).

[0931] M / Z (M[35CI]+H)+: 476.1.

[0932] Compound 88: tert-butyl 2, 2-dimethyl-4-(2, 2, 2-trifluoro-N-methylacetamido)piperidine-1 -carboxylate

[0933] To a solution of tert-butyl 2,2-dimethyl-4-(methylamino)piperidine-1 -carboxylate (200 mg) and triethylamine (2.5 eq)in DCM (2 mL) was added dropwise at 0°C Trifluoroacetic anhydride (1.5 eq). The mixture was stirred at 25°C for 1 hour then diluted with DCM (30 mL) and quenched with NaHCO3(sat. aq., 30 mL). The aqueous layer was extracted with DCM (3*30 mL), the combined organic layers were dried over MgSO4, and concentrated under reduced pressure. The crude was purified by flash chromatography (CyHex / EtOAc, 100:0 to 0:100) to obtain Compound 88 (94 mg, 34%) as a clear oil.

[0934] M / Z (M+H)+: 339.2.

[0935] Compound 89: N-(2,2-dimethylpiperidin-4-yl)-2,2,2-trifluoro-N-methylacetamide

[0936] Compound 89 was obtained according to general procedure (IV), starting from Compound 88 (94 mg). The crude was freeze from a HCI (in water) / MeCN mixture to obtain Compound 89 hydrochloride (73 mg, 96%) as a white solid. M / Z (M+H)+: 239.0.

[0937] Example 61: N-(1-(5-((4-chloro-3-fluorophenyl)amino)-6-isopropylpyrazine-2-carbonyl)-2,2-dimethylpiperidin-4-yl)- 2,2,2-trifluoro-N-methylacetamide

[0938]

[0939] Example 61 was obtained according to general procedure (III), starting from Compound 35 (65 mg), using Compound 89 (1.3 eq) and N,N-diisopropylethylamine (3.0 eq). The crude was purified by flash chromatography (CyHex / EtOAc, 100:0 to 0:100), then by preparative HPLC (Column B), then freeze dried from a water to obtain Example 61 (79 mg, 71%) as a white solid.

[0940] 1H-NMR (DMSO-de , 400 MHz) 5: 1.20-1.27 (m, 6H, CH(CH3)2); 1.45-1.63 (m, 7H, (CH3)2, CHaHb); 1.81-1.94 (m, 2H, CH2); 2.03-2.10 (m, 1H, CHaHb); 2.93-3.07 (m, 3H, NCH3); 3.21-3.38 (m, 1H, NCHaCHb); 3.53 (sept, J 6.6 Hz, 1H, ArCH); 3,61-3.81 (m, 1H, NCHaHb); 4.05-4.61 (m, 1H, NCH); 7.47-7.52 (m, 1H, Ar); 7.57-7.62 (m, 1H, Ar); 7.89-7.93 (m, 1H, Ar); 8.28 (s, 1H, Ar); 8.91 (bs, 1H, NH).

[0941] M / Z (M[35CI]+H)+: 530.0.

[0942] Compound 90: tert-butyl 4-(2-(dimethylamino)-2-oxoethoxy)-2,2-dimethylpiperidine-1 -carboxylate

[0943] To a solution of tert-butyl 4-hydroxy-2,2-dimethylpiperidine-1-carboxylate (200 mg) in THF (2.5 mL), was added Sodium hydride (60% in mineral oil, 1.5 eq) at 0°C. After 10 minutes was added 2-Bromo-N,N-dimethyl-acetamide (2.0 eq) and the reaction mixture was let warm up at 25°C for 1 hour, then quenched in water (30 mL). The mixture was extracted with EtOAc (3*30 mL), the combined organic layers were dried over MgSO4, and concentrated under reduced pressure. The crude was purified by flash chromatography (CyHex / EtOAc, 100:0 to 0:100) to obtain Compound 90 (213 mg, 78%) as a clear oil.

[0944] M / Z (M+H)+: 315.2

[0945] Compound 91: 2-((2,2-dimethylpiperidin-4-yl)oxy)-N,N-dimethylacetamide

[0946] Compound 91 was obtained according to general procedure (IV), starting from Compound 90 (213 mg). The crude was freeze from a HCI (in water) / MeCN mixture to obtain Compound 91 hydrochloride (152 mg, 90%) as a clear oil.M / Z (M+H)+: 215.1.

[0947] Example 62: 2-((1-(5-((4-chloro-3-fluorophenyl)amino)-6-isopropylpyrazine-2-carbonyl)-2,2-dimethylpiperidin-4-yl)oxy)-N,N-dimethylacetamide

[0948]

[0949] Example 62 was obtained according to general procedure (III), starting from Compound 35 (67 mg), using Compound 91 (2 eq) and N, N-diisopropylethylamine (3.0 eq). The crude was purified by flash chromatography (CyHex / EtOAc, 100:0 to 0:100), then by preparative HPLC (Column B), then freeze dried from a water to obtain Example 62 (73 mg, 68%) as a white solid.

[0950] 1H-NMR (DMSO-de , 400 MHz) 6: 1.21-1.25 (m, 6H, 2 CH(CH3)2); 1.42 (s, 3H,C(CH3)a(CH3)b); 1.54 (s, 3H,C(CH3)a(CH3)b)); 1.55-1.59 (m, 1H, CHaHb); 1.59-1.66 (m, 1H, CHaHb); 1.88-1.94 (m, 1H, CHaHb); 2.02-2.12 (m, 1H, CHaHb); 2.81 (s, 3H, NCH3); 2.93 (s, 3H, NCH3); 3.13-3.22 (m, 1H, NCHaHb); 3.53 (sept., J 6.6 Hz, 1H, ArCH); 3.60-3.68 (m, 1H, NCHaHb); 3.68-3.76 (m, 1H, OCH); 4.14 (s, 2H, OCH2); 7.45-7.52 (m, 1H, Ar); 7.55-7.61 (m, 1H, Ar); 7.88-7.94 (m, 1H, Ar); 8.25 (s, 1H, Ar); 8.90 (bs, 1H, NH).

[0951] M / Z (M[35CI]+H)+: 506.0.

[0952] Compound 92: 3-isopropylpyrazin-2-ol

[0953] Compound 92 (2.93 g, 98%) was obtained as an off white solid, according to general procedure (XV), and starting from 2-amino-3-methylbutanamide hydrochloride (3.30 g).

[0954] M / Z (M+H)+: 138.9.

[0955] Compound 93: 3-isopropylpyrazin-2-yl trifluoromethanesulfonate

[0956] Compound 93 (4.1 g, quant.) was obtained as a clear oil, according to general procedure (XVI), and starting from Compound 92 (1.90 g).

[0957] M / Z (M+H)+: 270.9.

[0958] Compound 94: 2-(3-isopropy I py razi n-2-y l)-1 , 2, 3, 4-tetrahy d roisoq uinoli ne

[0959] Compound 93 was obtained according to general procedure (Xc), starting from Compound 93 (200 mg) and 1, 2,3,4-tetrahydroisoquinoline. The crude was purified by flash chromatography (CyHex / EtOAc, 100:0 to 80:20) to obtain Compound 94 (134 mg, 72%) as a yellow oil.

[0960] M / Z (M+H)+: 254.1.

[0961] Compound 95: 2-(5-bromo-3-isopropylpyrazin-2-yl)-1,2,3,4-tetrahydroisoquinoline

[0962] Compound 95 was obtained according to general procedure (Va), starting from Compound 94 (134 mg). The crude was purified by flash chromatography (CyHex / EtOAc, 100:0 to 90:10) to obtain Compound 95 (40 mg, 22%) as a yellow oil.

[0963] M / Z (M[81Br]+H)+: 332.0.Example 63: methyl 6-(4-(5-(3,4-di hydroisoqui noli n-2(1 H)-y l)-6-isopropyl py razi ne-2-carbony l)-3,3-dimethy Ipi perazi n-1 -y I )-2, 4-d i methy In i coti n ate

[0964]

[0965] Example 63 was obtained according to general procedure (Vlb) starting from Compound 95 (40 mg) in Me-THF, with methyl 6-(3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinate (1.0 eq), Triethylamine (3.0 eq), at 100°C for 18 hours. The crude Example 63 (90 mg, n.d.) was used without further purification as an orange oil.

[0966] M / Z (M+H)+: 557.5

[0967] Example 64: 6-(4-(5-(3,4-dihydroisoquinolin-2(1 H)-yl)-6-isopropylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)- 2,4-dimethy Inicotinic acid

[0968]

[0969] Example 64 was obtained according to general procedure (II), starting from Example 63 (67 mg). The crude was purified by preparative HPLC (Column B), then freeze dried from a water / MeCN mixture to obtain Example 64 (25 mg, 38% over 2 steps) as a white solid.

[0970] 1H-NMR (DMSO-de , 400 MHz) 5: 1.25 (d, J 6.5 Hz, 6H, (CH3)2); 1.49 (s, 6H, (CH3)2); 2.25 (s, 3H, CH3); 2.36 (s, 3H, CH3); 3.01 (m, 2H, NCH2CH2N); 3.49-3.56 (m, 4H, NCH2CH2Ar); 3.84 (m, 2H, NCH2CH2N); 3.88 (s, 2H, NCH2); 4.44 (s, 2H, NCH2Ar); 6.32 (s, 1H, Ar); 7.19-7.20 (m, 4H, Ar); 8.31 (s, 1H, Ar); 12.70 (bs, 1H, COCH). One CH signal not observed.

[0971] M / Z (M+H)+: 543.1.

[0972] Compound 96: tert-butyl 2, 2-dimethyl-4-(N-methylmethylsulfonamido)piperidine-1 -carboxylate

[0973] To a solution of tert-butyl 2,2-dimethyl-4-(methylamino)piperidine-1 -carboxylate (400 mg) in DCM (4 mL) at 0°C was added triethylamine (2.5 eq) and dropwise methanesulfonyl chloride (1.5 eq). The mixture was let warm up at 25°C for 2 hours, then diluted with DCM (30 mL), and quenched in NaHCO3(sat. aq. 30 mL). The aqueous layer was extracted with DCM (3*30 mL) the combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The crude was purified by flash chromatography (CyHex / EtOAc, 100:0 to 0:100) to obtain Compound 96 (189 mg, 36%) as a clear oil.

[0974] M / Z (M-tBu+H)+: 264.9.

[0975] Compound 97: N-(2,2-dimethylpiperidin-4-yl)-N-methylmethanesulfonamide

[0976] Compound 97 was obtained according to general procedure (IV), starting from Compound 96 (189 mg). The crude was freeze from a HCI (in water) / MeCN mixture to obtain Compound 97 hydrochloride (148 mg, 98%) as a white solid.M / Z (M+H)+: 221.1

[0977] Example 65: N-(1-(5-((4-chloro-3-fluorophenyl)amino)-6-isopropylpyrazine-2-carbonyl)-2,2-dimethylpiperidin-4-yl)-N-methylmethanesulfonamide

[0978]

[0979] Example 65 was obtained according to general procedure (III), starting from Compound 35 (120 mg), using Compound 97 (1.5 eq) and N,N-diisopropylethylamine (3.0 eq). The crude was purified by flash chromatography (CyHex / EtOAc, 100:0 to 0:100), then by preparative HPLC (Column B), then freeze dried from a water to obtain Example 65 (45 mg, 23%) as a white solid.

[0980] 1H-NMR (DMSO-de , 400 MHz) 5: 1.20-1.27 (m, 6H, CH(CH3)2); 1.45-1.64 (m, 7H, (CH3)2, CHaHb); 1.72-1.85 (m, 1H, CHaHb); 1.90-2.05 (m, 2H, CH2); 2.72 (s, 3H, NCH3); 2.92 (s, 3H, SO2CH3); 3.23-3.32 (m, 1H, NCHaCHb); 3.53 (sept., J 6.6 Hz, 1H, ArCH); 3.65-3.76 (m, 1H, NCHaHb); 3.98-4.06 (m, 1H, NCH); 7.47-7.52 (m, 1H, Ar); 7.57-7.60 (m, 1H, Ar); 7.89-7.93 (m, 1H, Ar); 8.27 (s, 1H, Ar); 8.91 (bs, 1H, NH).

[0981] M / Z (M[35CI]+H)+: 511.9.

[0982] Compound 98: 3-methylpyrazin-2-ol

[0983] Compound 98 (140 mg, 5%) was obtained as a yellow solid, according to general procedure (XV), and starting from 2-aminopropanamide (3.47 g).

[0984] Compound 99: 3-methylpyrazin-2-yl trifluoromethanesulfonate

[0985] Compound 99 (243 mg, 79%) was obtained as an orange oil, according to general procedure (XVI), and starting from Compound 98 (140 mg).

[0986] M / Z (M+H)+: 242.9.

[0987] Compound 100: N-(4-chloro-3-fluorophenyl)-3-methylpyrazin-2-amine

[0988] Compound 100 was obtained according to general procedure (IX) starting from Compound 99 (144 mg) in dioxane, with 4-chloro-3-fluoroaniline (1.0 eq) and DBU (3.0 eq), using BrettPhosPd G4 (0.1 eq) at 90°C for 16 hours. The crude was purified by flash chromatography (CyHex / AcOEt, 100:0 to 70:30) to obtain Compound 100 (92 mg, 39%) as a pink powder.

[0989] M / Z (M[35CI]+H)+: 238.0.

[0990] Compound 101: 5-bromo-N-(4-chloro-3-fluorophenyl)-3-methylpyrazin-2-amine

[0991] Compound 101 was obtained according to general procedure (Va), starting from Compound 100 (90 mg). The crude was purified by flash chromatography (CyHex / EtOAc, 100:0 to 80:20) to obtain Compound 101 (102 mg, 85%) as a yellow solid.

[0992] M / Z (M[81Br][35CI]+H)+: 317.9.Example 66: methyl 6-(4-(5-((4-chloro-3-fluorophenyl)amino)-6-methylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinate

[0993]

[0994] Example 66 was obtained according to general procedure (Via) starting from Compound 101 (105 mg) in dioxane, with methyl 6-(3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinate (1.5 eq), Triethylamine (4.0 eq), at 120°C for 18 hours. The crude was purified by flash chromatography (CyHex / AcOEt, 100:0 to 70:30) to obtain Example 66 (50 mg, n.d.) as a yellow solid.

[0995] M / Z (M[35CI]+H)+: 541.0

[0996] Example 67: 6-(4-(5-((4-chloro-3-fluorophenyl)amino)-6-methylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid

[0997] F

[0998]

[0999] Example 67 was obtained according to general procedure (II), starting from Example 66 (50 mg). The crude was purified by preparative HPLC (Column A), then freeze dried from a water / MeCN mixture to obtain Example 67 (13 mg, 7% over 2 steps) as a white solid.

[1000] 1H-NMR (DMSO-de , 400 MHz) 5: 1.50 (s, 6H, (CH3)2); 2.28 (s, 3H, CH3); 2.38 (s, 3H, CH3); 2.58 (s, 3H, CH3); 3.51-3.54 (m, 2H, CH2); 3.81-3.83 (m, 2H, CH2); 3.89 (s, 2H, CH2); 6.34 (s, 1H, Ar); 7.52 (t, J 8.7 Hz, 1H, Ar); 7.60-7.63 (m, 1H, Ar); 7.95 (dd, J 12.4, J2.4 Hz, 1H, Ar); 8.26 (s, 1H, Ar); 8.84 (s, 1H, NH); 12.68 (bs, 1H, CO2H).

[1001] M / Z (M[35CI]+H)+: 527.2

[1002] Compound 102: 3-(methoxymethyl)pyrazin-2-ol

[1003] Compound 102 (240 mg, 6%) was obtained as a yellow solid, according to general procedure (XV), and starting from 2-amino-3-methoxypropanamide hydrochloride (4.80 g).

[1004] M / Z (M+H)+: 173.0

[1005] Compound 103: 3-(methoxymethyl)pyrazin-2-yl trifluoromethanesulfonate

[1006] Compound 103 (365 mg, 78%) was obtained as a red oil, according to general procedure (XVI), and starting from Compound 102 (240 mg).

[1007] M / Z (M+H)+: 272.9.

[1008] Compound 104: N-(4-chloro-3-fluorophenyl)-3-(methoxymethyl)pyrazin-2-amineCompound 104 was obtained according to general procedure (IX) starting from Compound 103 (195 mg) in dioxane, with 4-chloro-3-fluoroaniline (1.0 eq) and DBU (3.0 eq), using BrettPhosPd G4 (0.1 eq) at 90°C for 16 hours. The crude was purified by flash chromatography (CyHex / AcOEt, 100:0 to 50:50) to obtain Compound 104 (250 mg, nd) as a pink powder.

[1009] M / Z (M[35CI]+H)+: 267.9.

[1010] Compound 105: 5-bromo-N-(4-chloro-3-fluorophenyl)-3-(methoxymethyl)pyrazin-2-amine

[1011] Compound 105 was obtained according to general procedure (Va), starting from Compound 104 (235 mg). The crude was purified by flash chromatography (CyHex / EtOAc, 100:0 to 70:30) to obtain Compound 105 (189 mg, 40% over 2 steps) as a yellow solid.

[1012] M / Z (M[81Br][35CI]+H)+: 348.0.

[1013] Example 68: methyl 6-(4-(5-((4-chloro-3-fluorophenyl)amino)-6-(methoxymethyl)pyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinate

[1014]

[1015] Example 68 was obtained according to general procedure (Via) starting from Compound 105 (189 mg) in dioxane, with methyl 6-(3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinate (1.2 eq), Triethylamine (4.0 eq), at 120°C for 18 hours. The crude was purified by flash chromatography (CyHex / AcOEt, 100:0 to 0:100) to obtain Example 68 (79 mg, n.d.) as a yellow solid.

[1016] M / Z (M[35CI]+H)+: 571.1.

[1017] Example 69: 6-(4-(5-((4-chloro-3-fluorophenyl)amino)-6-(methoxymethyl)pyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid

[1018]

[1019] Example 69 was obtained according to general procedure (II), starting from Example 68 (79 mg). The crude was purified by preparative HPLC (Column A), then freeze dried from a water / MeCN mixture to obtain Example 69 (34 mg, 11 % over 2 steps) as a white solid.

[1020] 1H-NMR (DMSO-de , 400 MHz) 5: 1.50 (s, 6H, (CH3)2); 2.28 (s, 3H, CH3); 2.39 (s, 3H, CH3); 3.39 (s, 3H, OCH3); 3.52-3.55 (m, 2H, CH2); 3.81-3.84 (m, 2H, CH2); 3.90 (s, 2H, CH2); 4.73 (s, 2H, OCH2); 6.35 (s, 1H, Ar); 7.51-7.58 (m, 2H, Ar); 7.95-7.99 (m, 1H, Ar); 8.41 (s, 1H, Ar); 8.85 (s, 1H, NH); 12.67 (bs, 1H, CO2H).

[1021] M / Z (M[35CI]+H)+: 557.2Compound 106: 5-bromo-3-isopropylpyrazm-2-ol

[1022] Compound 106 was obtained according to general procedure (Vb), starting from Compound 92 (200 mg). The crude was purified by flash chromatography (CyHex / EtOAc, 100:0 to 50:50) to obtain Compound 106 (240 mg, 74%) as an off white solid.

[1023] M / Z (M[81Br]+H)+: 218.9.

[1024] Compound 107: methyl 6-(4-(5-hydroxy-6-isopropylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinate

[1025] Compound 107 was obtained according to a deviation of general procedure (Vlb) starting from Compound 106 (105 mg) in Me-THF, with methyl 6-(3,3-dimethylpiperazin-1 -yl)-2,4-dimethylnicotinate (1.4 eq), Triethylamine (3.0 eq), at 100°C for 2 hours. Here, the reaction mixture was directly purified by flash chromatography (DCM / MeOH, 100:0 to 95:5) to obtain Compound 107 (710 mg, 70%) as an orange solid.

[1026] M / Z (M]+H)+: 442.2.

[1027] Compound 108: methyl 6-(4-(6-isopropyl-5-(((trifluoromethyl)sulfonyl)oxy)pyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinate

[1028] Compound 108 (570 mg, 88%) was obtained as a brown solid, according to general procedure (XVI), and starting from Compound 107 (500 mg).

[1029] M / Z (M+H)+: 574.1

[1030] Example 70: methyl 6-(4-(5-((cyclohexylmethyl)amino)-6-isopropylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinate

[1031]

[1032] Example 70 was obtained according to general procedure (Xd) starting from Compound 108 (100 mg) and cyclohexylmethanamine. The crude was purified by flash chromatography (CyHex / AcOEt, 100:0 to 20:80) to obtain Example 70 (40 mg, 43%) as a yellow oil.

[1033] M / Z (M+H)+: 537.1.

[1034] Example 71: 6-(4-(5-((cyclohexylmethyl)amino)-6-isopropylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid

[1035]

[1036] Example 71 was obtained according to general procedure (II), starting from Example 70 (39 mg). The crude was purified by preparative HPLC (Column A), then freeze dried from water to obtain Example 71 (24 mg, 63%) as a white solid.

[1037] 1H-NMR (DMSO-d6, 400 MHz) 5: 0.86-0.99 (m, 2H, CH2); 1.11-1.22 (m, 9H, CH2, CH, CH(CH3)2); 1.48 (s, 6H, C(CH3)2); 1.59-1.76 (m, 6H, 3 CH2); 2.27 (s, 3H, CH3); 2.38 (s, 3H, CH3); 3.17-3.24 (m, 3H, NCH2, ArCH); 3.55-3.58 (m, 2H, NCH2); 3.85 (s, 2H, NCH2); 3.90-3.94 (m, 2H, NCH2); 6.32 (bs, 1H, Ar); 7.03 (t, J 5.4 Hz, 1H, NH); 8.13 (s, 1H, Ar); 12.68 (bs, 1H, CO2H)

[1038] M / Z (M+H)+: 523.3.

[1039] Example 73: (5-((4-chloro-3-fluorophenyl)amino)-6-isopropylpyrazin-2-yl)(4-(2-(dimethylamino)ethoxy)-2,2-dimethylpiperidin-1-yl)methanone

[1040]

[1041] Cl

[1042] Example 73 was obtained according to general procedure (III), starting from Compound 35 (36 mg), using 2-((2,2-dimethylpiperidin-4-yl)oxy)-N,N-dimethylethan-1-amine (1.1 eq) and N,N-diisopropylethylamine (4.0 eq). The crude was purified by flash by preparative HPLC (Column B), then freeze dried to obtain Example 73 (12 mg, 20%) as a white solid.

[1043] 1H-NMR (DMSO-de , 400 MHz) 5: 1.22-1.25 (m, 6H, CH(CH3)2); 1.46 (s, 3H, CH3); 1.56-1.58 (m, 4H, CH3, CHaHb); 1.61-1.67 (m, 1H, CHcHd); 1.93 (dd, J 13.5, 4.4 Hz, 1H, CHaHb); 2.06-2.15 (m, 1H, CHcHd); 2.79-2.80 (m, 6H, 2 N-CH3); 3.18-3.24 (m, 1H, N-CHaHb); 3.25-3.28 (m, 2H, N-CH2); 3.52-3.60 (m, 1H, CH-CH3); 3.64-3.78 (m, 4H, N-CHaHb, O-CH2, CH-O); 7.50 (t, J 8.8 Hz, 1H, Ar); 7.59 (dd, J8.8, 2.2 Hz, 1H, Ar); 7.92 (dd, J 12.4, 2.2 Hz, 1H, Ar); 8.27 (s, 1H, Ar); 8.93 (s, 1H, NH); 9.37 (bs, 1H, HCI signal).

[1044] M / Z (M[35CI]+H)+: 492.3.

[1045] Compound 109: 3-ethylpyrazin-2-ol

[1046] Compound 109 (2.04 g, 55%) was obtained as a white solid, according to general procedure (XV), and starting from 2-aminobutanamide (4.11 g).

[1047] Compound 110: 3-ethylpyrazin-2-yl trifluoromethanesulfonate

[1048] Compound 110 (3.40 g, 81%) was obtained as an orange oil, according to general procedure (XVI), and starting from Compound 109 (2.04 g).

[1049] M / Z (M+H)+: 256.9.

[1050] Compound 111: N-(4-chloro-3-fluoropheny l)-3-ethy Ipy razin-2-am i ne

[1051] Compound 111 was obtained according to general procedure (IX) starting from Compound 110 (500 mg) in dioxane, with 4-chloro-3-fluoroaniline (1.0 eq) and DBU (3.0 eq), using BrettPhosPd G4 (0.1 eq) at 90°C for 16 hours. The crude was purified by flash chromatography (CyHex / AcOEt, 100:0 to 40:60) to obtain Compound 111 (396 mg, nd) as an impure orange solid.M / Z (M[35CI]+H)+: 251.9.

[1052] Compound 112: 5-bromo-N-(4-chloro-3-fluorophenyl)-3-ethylpyrazin-2-amine

[1053] Compound 112 was obtained according to general procedure (Va), starting from Compound 111 (358 mg). The crude was purified by flash chromatography (CyHex / EtOAc, 100:0 to 80:20) to obtain Compound 112 (235 mg, nd) as an impure orange solid.

[1054] M / Z (M[81Br][35CI]+H)+: 332.0.

[1055] Example 74: ethyl 6-(4-(5-((4-chloro-3-fluorophenyl)amino)-6-methylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinate

[1056]

[1057] Example 74 was obtained according to general procedure (Via) starting from Compound 112 (235 mg) in dioxane, with methyl 6-(3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinate (1.5 eq), Triethylamine (4.0 eq), at 120°C for 18 hours. The crude was purified by flash chromatography (CyHex / DCM, 100:0 to 0:100 then, DCM / EtOAc, 100:0 to 60:40) to obtain Example 74 (186 mg, nd) as a yellow resin.

[1058] M / Z (M[35CI]+H)+: 555.3.

[1059] Example 75: 6-(4-(5-((4-chloro-3-fluorophenyl)amino)-6-ethylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid

[1060]

[1061] Example 75 was obtained according to general procedure (II), starting from Example 74 (180 mg). The crude was purified by preparative HPLC (Column A), then freeze dried from a water / MeCN mixture to obtain Example 75 (11 mg, 1% over 4 steps).

[1062] 1H-NMR (DMSO-de , 400 MHz) 5: 1.30 (t, J 7.3 Hz, 3H, CH3); 1.50 (s, 6H, (CH3)2); 2.28 (s, 3H (CH3); 2.39 (s, 3H, CH3); 2.92 (q, J 7.3 Hz, 2H, CH2); 3.54-3.57 (m, 2H, CH2); 3.85-3.90 (m, 4H, CH2, CH2); 6.34 (bs, 1H, Ar); 7.51 (t, J 8.7 Hz, 1H, Ar); 7.60-7.63 (m, 1H, Ar); 7.95 (dd, J 12.4 Hz, J 2.4 Hz, 1H, Ar); 8.29 (s, 1H, Ar); 8.85 (bs, 1H, NH); 12.67 (bs, 1H, COCH).

[1063] M / Z (M[35CI]+H)+: 527.2.

[1064] Compound 113: 3-cyclobutylpyrazin-2-olCompound 113 (4.36 g, 77%) was obtained as a white solid, according to general procedure (XV), and starting from 2-amino-2-cyclobutylacetamide hydrochloride (6.23 g).

[1065] Compound 114: 3-cyclobutylpyrazin-2-yl trifluoromethanesulfonate

[1066] Compound 114 (891 mg, 95%) was obtained as an orange oil, according to general procedure (XVI), and starting from Compound 113 (500 mg).

[1067] M / Z (M+H)+: 283.1.

[1068] Compound 115: N-(4-chloro-3-fluorophenyl)-3-cyclobutylpyrazin-2-amine

[1069] Compound 115 was obtained according to general procedure (IX) starting from Compound 114 (500 mg) in dioxane, with 4-chloro-3-fluoroaniline (1.0 eq) and DBU (3.0 eq), using BrettPhosPd G4 (0.1 eq) at 90°C for 16 hours. The crude was purified by flash chromatography (CyHex / AcOEt, 100:0 to 80:20) to obtain Compound 115 (238 mg, 48%) as a colorless oil.

[1070] M / Z (M[35CI]+H)+: 278.1.

[1071] Compound 116: 5-bromo-N-(4-chloro-3-fluorophenyl)-3-cyclobutylpyrazin-2-amine

[1072] Compound 116 was obtained according to general procedure (Va), starting from Compound 115 (230 mg). The crude was purified by flash chromatography (CyHex / EtOAc, 100:0 to 80:20) to obtain Compound 116 (159 mg, 54%) as an impure orange solid.

[1073] M / Z (M[81Br][35CI]+H)+: 358.3.

[1074] Example 76: methyl 6-(4-(5-((4-chloro-3-fluorophenyl)amino)-6-cyclobutylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinate

[1075]

[1076] Example 76 was obtained according to general procedure (Via) starting from Compound 116 (159 mg) in dioxane, with methyl 6-(3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinate (1.5 eq), Triethylamine (4.0 eq), at 120°C for 18 hours. The crude was purified by flash chromatography (CyHex / DCM, 100:0 to 0:100 then, DCM / EtOAc, 100:0 to 60:40) to obtain Example 76 (118 mg, nd) as a yellow gum.

[1077] M / Z (M[35CI]+H)+: 581.1.

[1078] Example 77: 6-(4-(5-((4-chloro-3-fluorophenyl)amino)-6-cyclobutylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)- 2,4-dimethy Inicotinic acid

[1079]

[1080] Example 77 was obtained according to general procedure (II), starting from Example 76 (100 mg). The crude was purified by preparative HPLC (Column B), then freeze dried from a water / MeCN mixture to obtain Example 77 (30 mg, 12% over 2 steps) as a white solid.

[1081] 1H-NMR (DMSO-de , 400 MHz) 5: 1.51 (s, 6H, (CH3)2); 1.84-1.92 (m, 1H, CH); 2.02-2.12 (m, 1H, CH); 2.27 (s, 3H, CH3); 2.31-2.38 (m, 2H, CH2); 2.39-2.44 (m, 4H, CH2, CH3); 3.56-3.62 (m, 2H, CH2); 3.88-3.94 (m, 4H, CH2, CH2); 4.01-4.08 (m, 1H, CH); 6.33 (bs, 1H, Ar); 7.51 (t, J 8.8 Hz, 1H, Ar); 7.59 (dd, J 8.8 Hz, J 1.8 Hz, 1H, Ar); 7.93 (dd, J 12.4 Hz, J 2.4 Hz, 1H, Ar); 8.29 (s, 1H, Ar); 8.62 (bs, 1H, NH); 12.70 (bs, 1H, COCH).

[1082] M / Z (M[35CI]+H)+: 567.5.

[1083] Compound 117: 3-cyclopropylpyrazin-2-ol

[1084] Compound 117 (3.39 g, 57%) was obtained as a white solid, according to general procedure (XV), and starting from 2-amino-2-cyclobutylacetamide hydrochloride (6.63 g).

[1085] Compound 118: 3-cyclopropylpyrazin-2-yl trifluoromethanesulfonate

[1086] Compound 118 (983 mg, 99%) was obtained as an orange oil, according to general procedure (XVI), and starting from Compound 117 (500 mg).

[1087] M / Z (M+H)+: 269.0.

[1088] Compound 119: N-(4-chloro-3-fluorophenyl)-3-cyclopropylpyrazin-2-amine

[1089] Compound 119 was obtained according to general procedure (IX) starting from Compound 118 (500 mg) in dioxane, with 4-chloro-3-fluoroaniline (1.0 eq) and DBU (3.0 eq), using BrettPhosPd G4 (0.1 eq) at 90°C for 16 hours. The crude was purified by flash chromatography (CyHex / AcOEt, 100:0 to 90:10) to obtain Compound 119 (334 mg, nd) as a colorless oil.

[1090] M / Z (M[35CI]+H)+: 264.0.

[1091] Compound 120: 5-bromo-N-(4-chloro-3-fluorophenyl)-3-cyclopropylpyrazin-2-amine

[1092] Compound 120 was obtained according to general procedure (Va), starting from Compound 119 (334 mg). The crude was purified by flash chromatogr...

Claims

1. CLAIMS1. A compound selected from:6-(4-(5-((cyclopentylmethyl)amino)-6-isopropylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4- dimethylnicotinic acid;6-(4-(5-(isopentylamino)-6-isopropylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;6-(4-(6-(cyclobutylmethyl)-5-((cyclohexylmethyl)amino)pyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)- 2,4-dimethylnicotinic acid;6-(4-(5-((4-chloro-3-fluorophenyl)amino)-6-ethylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4- dimethylnicotinic acid;6-(4-(5-((4-chloro-3-fluorophenyl)amino)-6-cyclobutylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4- dimethylnicotinic acid;6-(4-(5-((4-chloro-3-fluorophenyl)amino)-6-cyclopropylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4- dimethylnicotinic acid;6-(4-(6-isopropyl-5-((4-(trifluoromethyl)benzyl)amino)pyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4- dimethylnicotinic acid;6-(4-(6-(tert-butyl)-5-((4-chloro-3-fluorophenyl)amino)pyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4- dimethylnicotinic acid;6-(4-(5-(isopentylamino)-6-isopropylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;6-(4-(6-isopropyl-5-((4-(trifluoromethyl)phenethyl)amino)pyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)- 2,4-dimethylnicotinic acid;6-(4-(5-((2-cyclohexylethyl)amino)-6-isopropylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4- dimethylnicotinic acid;(R)-6-(4-(6-isopropyl-5-((1-phenylethyl)amino)pyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4- dimethylnicotinic acid;(R)-6-(4-(5-((2,3-dihydro-1 H-inden-1-yl)amino)-6-isopropylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)- 2,4-dimethylnicotinic acid;6-(4-(6-cyclobutyl-5-((cyclohexylmethyl)amino)pyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4- dimethylnicotinic acid;6-(4-(6-cyclobutyl-5-(isopentylamino)pyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;6-(4-(6-cyclobutyl-5-((4-fluorobenzyl)amino)pyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4- dimethylnicotinic acid;6-(4-(5-(isobutylamino)-6-isopropylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;6-(4-(5-((2,3-dihydro-1 H-inden-2-yl)amino)-6-isopropylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4- dimethylnicotinic acid;6-(4-(5-((cyclopropylmethyl)amino)-6-isopropylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;(R)-6-(4-(5-((cyclohexylmethyl)amino)-6-(1-methoxyethyl)pyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)- 2,4-dimethylnicotinic acid;(R)-6-(4-(5-(isopentylamino)-6-(1-methoxyethyl)pyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;(R)-6-(4-(5-((4-fluorobenzyl)amino)-6-(1-methoxyethyl)pyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)- 2,4-dimethylnicotinic acid;6-(4-(6-isopropyl-5-((2-(4-methoxycyclohexyl)ethyl)amino)pyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)- 2,4-dimethylnicotinic acid;6-(4-(5-(isopentylamino)-6-(tetrahydro-2H-pyran-4-yl)pyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;6-(4-(6-(cyclopropylmethyl)-5-(isopentylamino)pyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;(S)-6-(4-(6-isopropyl-5-((2-phenylpropyl)amino)pyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;6-(4-(5-((cyclohexylmethyl)amino)-6-(cyclopropylmethyl)pyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)- 2,4-dimethylnicotinic acid;6-(4-(5-((cyclohexylmethyl)amino)-6-(tetrahydro-2H-pyran-4-yl)pyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;6-(4-(6-(cyclobutylmethyl)-5-((4-fluorobenzyl)amino)pyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;6-(4-(5-((2-cyclopropylethyl)amino)-6-isopropylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;6-(4-(6-(cyclobutylmethyl)-5-(isopentylamino)pyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;6-(4-(6-(cyclobutylmethyl)-5-((cyclohexylmethyl)amino)pyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)- 2,4-dimethylnicotinic acid;6-(4-(6-isopropyl-5-((2-(3-methoxybicyclo[1.1.1]pentan-1-yl)ethyl)amino)pyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;6-(4-(5-(butylamino)-6-isopropylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid; 6-(4-(5-((4-chloro-3-fluorobenzyl)amino)-6-isopropylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;6-(4-(5-((cyclopentylmethyl)amino)-6-isopropylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;6-(4-(5-((cyclobutylmethyl)amino)-6-isopropylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;6-(4-(6-isopropyl-5-(((1-methylcyclobutyl)methyl)amino)pyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)- 2,4-dimethylnicotinic acid;1996-(4-(6-cyclopropyl-5-(isopentylamino)pyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;6-(4-(6-isopropyl-5-(neopentylamino)pyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;6-(4-(5-((2-cyclobutyl-2-methoxyethyl)amino)-6-isopropylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)- 2,4-dimethylnicotinic acid;6-(4-(6-cyclopropyl-5-((4-(trifluoromethyl)benzyl)amino)pyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)- 2,4-dimethylnicotinic acid;6-(4-(5-((cyclohexylmethyl)amino)-6-cyclopropylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;6-(4-(6-isopropyl-5-((4-methoxybenzyl)amino)pyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;6-(4-(5-((2-(1 ,3-dihydroisobenzofuran-5-yl)ethyl)amino)-6-isopropylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;6-(4-(5-((3,3-dimethylbutyl)amino)-6-isopropylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;6-(4-(6-isopropyl-5-((2-(tetrahydro-2H-pyran-4-yl)ethyl)amino)pyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;6-(4-(5-(((2,3-dihydrobenzo[b][1 ,4]dioxin-2-yl)methyl)amino)-6-isopropylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;6-(4-(6-isopropyl-5-((pyrazin-2-ylmethyl)amino)pyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;6-(4-(5-((2,4-dichlorobenzyl)amino)-6-isopropylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;6-(4-(6-isopropyl-5-(((1-(methoxymethyl)cyclopentyl)methyl)amino)pyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;6-(4-(6-isopropyl-5-(((1-methylcyclohexyl)methyl)amino)pyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)- 2,4-dimethylnicotinic acid;6-(4-(6-isopropyl-5-(((4-(trifluoromethyl)cyclohexyl)methyl)amino)pyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;6-(4-(5-(((4,4-difluorocyclohexyl)methyl)amino)-6-isopropylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethy Inicotinic acid;4-(6-(cyclohex-1-en-1-yl)-5-((cyclohexylmethyl)amino)pyrazine-2-carbonyl)-3,3-dimethylpiperazin-2-one; 6-(4-(6-isopropyl-5-(((4-methylcyclohexyl)methyl)amino)pyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)- 2,4-dimethylnicotinic acid;6-(4-(5-(((3,3-difluorocyclopentyl)methyl)amino)-6-isopropylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethy Inicotinic acid;6-(4-(5-(((3,3-difluorocyclohexyl)methyl)amino)-6-isopropylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethy Inicotinic acid;4-(5-(isopentylamino)-6-isopropylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-2-one;2004-(6-(cyclobutylethynyl)-5-((cyclohexylmethyl)amino)pyrazine-2-carbonyl)-3,3-dimethylpiperazin-2-one; 4-(5-((cyclopentylmethyl)amino)-6-isopropylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-2-one;4-(5-((cyclohexylmethyl)amino)-6-isopropylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-2-one;4-(6-isopropyl-5-((thiazol-2-ylmethyl)amino)pyrazine-2-carbonyl)-3,3-dimethylpiperazin-2-one;6-(4-(6-isopropyl-5-((thiophen-2-ylmethyl)amino)pyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4- dimethylnicotinic acid;6-(4-(6-isopropyl-5-((thiophen-3-ylmethyl)amino)pyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4- dimethylnicotinic acid;6-(4-(5-((cyclopentylmethyl)amino)-6-isopropylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-3- methylpicolinic acid;2-(4-(5-((cyclopentylmethyl)amino)-6-isopropylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-5- methyl th I azol e-4-carboxy 11 c aci d ;2-(4-(5-((cyclopentylmethyl)amino)-6-isopropylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-4- methyl th I azol e-5-carboxy 11 c aci d ;4-(5-((cyclopentylmethyl)amino)-6-((trimethylsilyl)ethynyl)pyrazine-2-carbonyl)-3,3-dimethylpiperazin-2- one;6-(4-(5-(((3-fluorocyclopentyl)methyl)amino)-6-isopropylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)- 2,4-dimethylnicotinic acid;4-(6-isopropyl-5-((2-methoxybenzyl)amino)pyrazine-2-carbonyl)-3,3-dimethylpiperazin-2-one;2-(4-(5-((cyclopentylmethyl)amino)-6-isopropylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)thiazole-4- carboxamide;2-(4-(5-((cyclopentylmethyl)amino)-6-isopropylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-5- methylthiazole-4-carboxamide;2-(4-(5-((cyclopentylmethyl)amino)-6-isopropylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-4,6- dimethylpyrimidine-5-carboxylic acid;(5-((cyclopentylmethyl)amino)-6-isopropylpyrazin-2-yl)(2,2-dimethylpiperidin-1-yl)methanone;(5-((cyclopentylmethyl)amino)-6-isopropylpyrazin-2-yl)(3,3-dimethylmorpholino)methanone;4-(5-((4-chlorobenzyl)amino)-6-isopropylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-2-one;4-(5-((cyclopentylmethyl)amino)-6-ethynylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-2-one;6-(4-(5-((cyclopentylmethyl)amino)-6-isopropylpicolinoyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid; and5-bromo-6-(4-(5-((cyclopentylmethyl)amino)-6-isopropylpicolinoyl)-3,3-dimethylpiperazin-1-yl)-2,4- dimethylnicotinic acid;or a pharmaceutically acceptable salt or solvate thereof.

2. The compound of claim 1, wherein said compound is 6-(4-(5-((cyclopentylmethyl)amino)-6- isopropylpyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid:201or a pharmaceutically acceptable salt or solvate thereof.

3. The compound of claim 1, wherein said compound is 6-(4-(5-(isopentylamino)-6-isopropylpyrazine-2- carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid:or a pharmaceutically acceptable salt or solvate thereof.

4. The compound of claim 1, wherein said compound is 6-(4-(6-(cyclobutylmethyl)-5- ((cyclohexylmethyl)amino)pyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid:or a pharmaceutically acceptable salt or solvate thereof.

5. A pharmaceutical composition comprising the compound of any one of claims 1 to 4 and a pharmaceutically acceptable excipient.

6. The compound of any one of claims 1 to 4 or the pharmaceutical composition of claim 5 for use in the treatment or prevention of pain, an autoimmune disorder, an autoinflammatory disorder, an inflammatory disorder, a central nervous system disorder, spinal cord injury, a metabolic disorder, a gastrointestinal disorder, a cardiovascular disorder, a fibrotic disorder, a respiratory disorder, a skin disorder, an allergic disorder, or cancer.

7. The compound of any one of claims 1 to 4 or the pharmaceutical composition of claim 5 for use in the treatment or prevention of neuropathic pain, inflammatory pain, cancer pain, post-operative incision pain, fracture pain, osteoporotic fracture pain, gout joint pain, chronic pain, spinal cord injury, atopic dermatitis,202contact dermatitis, dry skin dermatitis, seborrhoeic dermatitis, arthritis, rheumatoid arthritis, osteoarthritis, psoriasis, psoriatic arthritis, multiple sclerosis, non-alcoholic steatohepatitis, obesity, diabetes, adipose inflammation, pancreatitis, metabolic syndrome, PAR-2 associated metabolic dysfunction, periodontitis, gingivitis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, peptic ulcer disease, infectious enteritis, irritable bowel syndrome, atherosclerosis, asthma, interstitial lung disease, pulmonary fibrosis, rheumatoid arthritis-associated interstitial lung disease, liver fibrosis, cystic fibrosis, renal fibrosis, peritoneal fibrosis, pancreatic fibrosis, intestinal fibrosis, cardiac fibrosis, skin fibrosis, systemic lupus erythematosus, scleroderma, skin eczema, acne, rosacea, post-inflammatory hyperpigmentation, lichen planus, pruritus, polymyositis, vasculitis, Wegener's granulomatosis, Netherton syndrome, dermatomyositis, uveitis, liver cirrhosis, Alzheimer's disease, Parkinson's disease, dust mite allergy, cockroach allergy, or allergic asthma.

8. The compound of any one of claims 1 to 4 or the pharmaceutical composition of claim 5 for use in the treatment or prevention of cancer.

9. The compound for use according to claim 8 or the pharmaceutical composition for use according to claim 8, wherein said cancer is selected from colorectal cancer, colon cancer, gastrointestinal cancer, gastric cancer, rectal cancer, anal cancer, liver cancer, breast cancer, pancreatic cancer, cervical cancer, prostate cancer, ovarian cancer, endometrial cancer, vaginal cancer, vulvar cancer, uterine cancer, testicular cancer, germ cell cancer, esophageal cancer, laryngeal cancer, mouth cancer, hematological cancer, leukemia, lymphoma, multiple myeloma, lung cancer, adrenal gland cancer, biliary tract cancer, bile duct cancer, hepatobiliary cancer, genitourinary cancer, urothelial cancer, bladder cancer, gallbladder cancer, head and / or neck cancer, kidney cancer, mesothelioma, sarcoma, skin cancer, melanoma, Merkel-cell cancer, epidermoid cancer, thyroid cancer, thymus cancer, squamous cell cancer, goblet cell cancer, spleen cancer, bone cancer, osteosarcoma, fibrosarcoma, Ewing's sarcoma, Kaposi's sarcoma, neuroendocrine cancer, neuroblastoma, brain cancer, and glioblastoma.

10. The compound for use according to claim 8 or 9 or the pharmaceutical composition for use according to claim 8 or 9, wherein said compound or said pharmaceutical composition is to be administered in combination with one or more anticancer drugs.

11. An anticancer drug for use in the treatment or prevention of cancer, wherein said anticancer drug is to be administered in combination with the compound of any one of claims 1 to 4 or the pharmaceutical composition of claim 5.

12. The compound for use according to claim 10 or the pharmaceutical composition for use according to claim 10 or the anticancer drug for use according to claim 11, wherein said anticancer drug(s) is / are selected from immune checkpoint inhibitors.

13. The compound for use according to claim 12 or the pharmaceutical composition for use according to claim 12 or the anticancer drug for use according to claim 12, wherein said immune checkpoint inhibitors are203selected from anti-CTLA-4 antibodies, anti-PD-1 antibodies, anti-PD-L1 antibodies, anti-TIGIT antibodies, anti-TIM3 antibodies, anti-VISTA antibodies, anti-BTLA antibodies, anti-CD47 antibodies, anti-LAG3 antibodies, anti-OX40 antibodies, and anti-ICOS antibodies.

14. The compound for use according to claim 12 or 13 or the pharmaceutical composition for use according to claim 12 or 13 or the anticancer drug for use according to claim 12 or 13, wherein said immune checkpoint inhibitors are selected from ipilimumab, tremelimumab, nivolumab, pembrolizumab, cemiplimab, spartalizumab, dostarlimab, camrelizumab, sintilimab, tislelizumab, toripalimab, zimberelimab, pidilizumab, penpulimab, cadonilimab, serplulimab, pucotenlimab, prolgolimab, retifanlimab, sintilimab, AMP-224, AMP- 514, JTX-4014, APE02058, atezolizumab, avelumab, durvalumab, envafolimab, adebrelimab, socazolimab, sugemalimab, CK-301, BMS-936559, MEDI4736, MPDL3280A, MDX-1105, MEDI6469, bintrafusp alfa, tiragolumab, vibostolimab, domvanalimab, etigilimab, BMS-986207, EOS-448, COM902, ASP8374, SEA- TGT, BGB-A1217, IBI-939, M6223, sabatolimab, cobolimab, lomvastomig, BGB-A425, BMS-986258, INCAGN02390, LY3321367, LY3415244, SHR-1702, Sym023, TQB2618, onvatilimab, HMBD-002, KVA12123, W0180, IGN-381, PMC-309, APX-201, tifcemalimab, icatolimab, ANB032, HFB200603, magrolimab, lemzoparlimab, ligufalimab, CC-90002, IMM0306, TG-1801, TI-061, relatlimab, ieramilimab, encelimab, tebotelimab, REGN3767, FS118, IMP701, IMP731, ivuxolimab, MEDI0562, MEDI6383, MEDI6469, INCAGN01949, ABBV-368, BAT6026, BGB-A445, YH-002, BMS 986178, INBRX-106, IBI101, MOXR0916, alomfilimab, feladilimab, izuralimab, vopratelimab, BMS-986226, and MEDI-570.

15. In vitro use of a compound as defined in any one of claims 1 to 4 as a PAR-2 inhibitor.

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