Functionalized Aminothiazoles

Abstract

The present invention is 2B Novel antagonists of adenosine receptors and pharmaceutical compositions containing said antagonists, as well as 2B The present invention relates to the use of compounds of formula I for the treatment and prevention of disorders known to be susceptible to amelioration by receptor antagonism, such as asthma, chronic obstructive pulmonary disorder (COPD), pulmonary fibrosis, vascular disease, allergic disease, hypertension, retinopathy, diabetes mellitus, inflammatory gastrointestinal disorders, inflammatory diseases, autoimmune diseases, renal diseases, neurological disorders and especially cancer. [Formula 1] JPEG2025503720000148.jpg4346 (In the formula, R 1 is H, halogen, -C1-C8 alkyl, -C3-C8 cycloalkyl, -O-C1-C8 alkyl, or -CN, and each alkyl, cycloalkyl, or -O-alkyl is selected from one or more R 2 R 2 is independently selected at each occurrence from halogen, -OH, and -OC1-C8 alkyl; R A is a 5-6 membered heteroaryl, the heteroaryl being selected from one or more R A1 R A1 is independently selected at each occurrence from halogen, -OH, oxo, cyano, -C1-C8 alkyl, -C3-C8 cycloalkyl, and -O-C1-C8 alkyl, and each alkyl, cycloalkyl, or -O-alkyl is selected from one or more R A2 R A2 is independently, at each occurrence, halogen, -OC1-C8 alkyl, or -OH; R B is phenyl or 5-6 membered heteroaryl, each phenyl or heteroaryl being selected from one or more R B1 R B1 is independently selected at each occurrence from halogen, -OH, cyano, -C1-C8 alkyl, and -O-C1-C8 alkyl, each alkyl, and -O-alkyl being selected from one or more R B2 RB2 is independently at each occurrence halogen, -OH, or -OC1-C8 alkyl) or a pharma- ceutically acceptable salt, solvate or hydrate thereof.

Description

[Technical field]

[0001] The present invention relates to adenosine receptor subtypes other than adenosine receptor subtypes, e.g., A 2A and / or A3) having selectivity over A 2B Antagonist and Double A 2B The compounds of the present invention are adenosine A1 and / or A1 antagonists. 2B Receptors (especially A 2B The compounds are useful in the treatment and prevention of disorders known to be treatable by antagonism of the agonist receptor, including asthma, chronic obstructive pulmonary disorder (COPD), pulmonary fibrosis, vascular disease, allergic disease, hypertension, retinopathy, diabetes mellitus, inflammatory gastrointestinal disorders, inflammatory diseases, autoimmune diseases, renal diseases, neurological disorders, otological disorders, and especially cancer. [Background technology]

[0002] Adenosine is an endogenous regulator of multiple physiological responses that play an important role in protecting tissues during injury and acute conditions, such as hypoxia, inflammation and ischemia. These responses include, for example, vasodilation, pain, anti-inflammation, wound healing and thermogenesis. In contrast to its beneficial effects during acute conditions, chronic exposure to adenosine and its associated physiological responses can be harmful and can cause or prolong diseases such as hypertension, pulmonary and renal fibrosis and cancer (Gessi et al., Expert Opin. Investig. Drugs, (2011) 20 (12): 1591-609). In the immune system, adenosine is a central mediator that affects most, if not all, immune cells and affects many aspects of the immune response. These immunomodulatory effects are mostly anti-inflammatory, contributing to the general tissue-protective effects of adenosine and its receptors. However, in some cases, the effects of adenosine on the immune system are detrimental, as prolonged signaling can impede antitumor and antibacterial immunity, thereby promoting cancer development and progression and sepsis, respectively. Adenosine's effects are mediated by G-coupled signaling receptors, which are expressed in normal tissues by four subtypes (A1, A2, A3, A4, A5, A6, A7, A8, A9, A10, A11, A12, A13, A14, A15, A16, A17, A18, A19, A21, A22, A23, A24, A25, A26, A27, A28, A29, A30, A31, A32, A33, A34, A35, A36, A37, A38, A39, A39, A40, A41, A42, A43, A44, A45, A46, A47, A48, A49, A49, A50, A51, A52, A53, A54, A55, A56, A57, A58, A59, A61, A62, A63, A64, A65, A66, A67, A68, A69, A69, A71, A72, A73, A74, A75, A75, A76, A77, A78, A79, A79, A79, A79, A71, A74, A75, A75, A76, A77, A78, A79 ... 2A , A 2B Adenosine receptors are widely expressed in the nervous system (brain, nervous system, and nervous system), and are transduced by adenosine receptors (A3) that are coupled to various types of G proteins and mediate various signal transduction pathways within the cell.

[0003] In particular, cancer therapy could benefit from compounds that selectively target adenosine-dependent pathways, as adenosine signaling plays a role in both cancer development and immune evasion (Ohta et al., Proc. Natl. Acad. Sci. USA, (2006) 103(35): 13132-7; Kasama et al., BMC Cancer, (2015) 15(563); Corona et al., J. Cancer Metastasis Treat. (2017) 3: 206-08; Allard et al., Immunol. Cell Biol. (2017) 95(4): 333-339). In cancer cells, adenosine signaling has been shown to regulate apoptosis, angiogenesis, and metastasis (Bahreyni et al., J. Cell Physiol. (2018) 233(3): 1836-1843). Furthermore, adenosine antagonism in vivo has been shown to reverse the immunosuppressive phenotype within the tumor microenvironment. Thus, adenosine is thought to be a negative immune checkpoint that can be deregulated in cancer, creating an immunosuppressive tumor microenvironment that contributes to cancer resistance and aggressiveness. Studies in mice have shown that antagonism of adenosine signaling can restore immune responses and result in sustained antitumor responses (Ohta et al., Proc. Natl. Acad. Sci. USA, (2006) 103(35):13132-7). Furthermore, the antitumor effect was shown to be primarily mediated by T cells, as shown by CXCR3- / - knockout mice that showed loss of sensitivity to adenosine antagonists (Cekic et al., J. Immunol. (2012) 188(1):198-205). Adenosine is thought to be a negative immune checkpoint that can be deregulated in cancer, creating an immunosuppressive tumor microenvironment that contributes to cancer resistance and aggressiveness. Studies in mice have shown that antagonism of adenosine signaling can restore immune responses and result in sustained antitumor responses (Ohta et al., Proc. Natl. Acad. Sci. USA, (2006) 103(35):13132-7). Furthermore, the antitumor effect was shown to be primarily mediated by T cells, as shown by CXCR3- / - knockout mice that showed loss of sensitivity to adenosine antagonists (Cekic et al., J. Immunol. (2012) 188(1):198-205). 2A Although inhibition of receptor subtypes has received the most attention to date, A 2ASignal transduction is known to have opposing effects on cell proliferation, as it can improve cell proliferation but also induce apoptosis and impair cell survival (Merighi et al., J. Invest. Dermatol. (2002) 119(4): 923-33; Wei et al., Purinergic Signal. (2013) 9(2): 271-80). 2A The route is blocked by A 2A In some cases, adenosine may be counterproductive, since it blocks apoptotic signals and increases cell proliferation. For example, in the Caco2 cancer cell line, adenosine at high doses reduced cell proliferation due to apoptotic mechanisms dominating over cell proliferation components, and this effect was consistent with A 2A The effect was reversed only by antagonists of the A subtypes, but not by antagonists of other subtypes (Yasuda et al., J. Gastroenterol. (2009) 56-65). This led some authors to conclude that 2A Subtypes and A 2B The dual compound strategy of targeting both subtypes is called a "double-edged sword" (Allard et al., Curr. Opin. Pharmacol. (2016) 29:7-16), and selective A 2B The need for alternatives such as inhibitors was confirmed. 2A - / - and A 2B In studies of - / - knockout mice, the nonselective compound theophylline inhibited A 2B It was suggested that A may have a beneficial effect on tumor growth in vivo through its antagonistic action. 2A In knockout mice, tumors grew faster than in wild-type mice (Cekic et al., J Immunol. (2012) 188(1):198-205), and A 2A Specific A in contrast to 2B A strong rationale for the development of selective antagonists has been provided.

[0004] Selectivity against A3 receptor subtype is another important feature of drugs used to target adenosine receptors. To date, several lines of evidence support the conclusion that activation of A3R signaling is important for cardioprotection during and after ischemia-reperfusion, and it has been proposed that a certain portion of the cardioprotective effect exerted by adenosine, once thought to be largely attributable to A1 receptors, may now be partially attributed to A3R activation (Headric and Peart, Vascul. Pharmacol. (2005) 42 (5-6): 271-9). A3 receptor antagonism is associated with potential adverse effects on tissue damage, motor function and pain threshold after ischemia in the CNS, heart, kidney, lung and eye (Gessi et al., Pharmacol Ther. (2008) 117 (1): 123-40).

[0005] Using antagonists A 2B There is a strong rationale for targeting the receptor, 2B The receptor is found on many different cell types, but is generally referred to as A1, A2, A3, A4, A5, A6, A7, A8, A9, A10, A11, A12, A13, A14, A15, A16, A17, A18, A19 ...20, A21, A22, A23, A24, A25, A30, 2A However, extracellular concentrations of adenosine are markedly increased in the hypoxic tumor microenvironment, and A 2B It is now known that this can result in the activation of the receptor (Kasama et al., BMC Cancer (2015) 15, 563). 2B A was linked to cancer and showed reduced tumor growth compared to its wild-type counterpart. 2B From knockout mice, A 2B A tumor-promoting activity of Aβ signaling could be estimated. This effect was due, in part, to a significant decrease in intratumoral levels of vascular endothelial growth factor (VEGF) (Rhzhov et al., Neoplasia. (2008) 10(9):987-95). In addition, Aβ 2BIt has been found to induce tumor growth in lung, colon and prostate cancer by producing basic fibroblast growth factor (bFGF) (Bahreyni et al., J. Cell Physiol. (2018) 233(3):1836-1843). 2B It has been shown that A plays a role in supporting invasion and metastatic spread through the accumulation of non-prenylated Rap 1B, a small GTPase that regulates cell adhesion (Ntanie et al., Sci. Signal. (2013) 6(277):ra39). 2B plays a central role in the inflammatory response to tumors, including the amount of tumor-infiltrating myeloid-derived suppressor cells (MDSCs) (Ryzhov et al., Neoplasia. (2008) 10(9):987-95). 2B A is important for tumor immune surveillance because it is involved in the differentiation and functional maturation of dendritic cells (DCs) and macrophages (Iannone et al., Neoplasia. (2013) 15(12):1400-9; Allard et al., Immunol. Cell Biol. (2017) 95(4):333-339). Therefore, A 2B The anticancer effects of antagonists are diverse and occur through both tumor-intrinsic and host-mediated pathways. 2B Expression is associated with poor prognosis in several cancers (Ihara et al., Oncogene. (2017) 36(14): 2023-2029) and has been found to be increased in a variety of human cancers, including ovarian, lung, liver, oral, colon and prostate cancers, compared to adjacent normal tissues (Zhou et al., Oncotarget. (2017) 8(30): 48755-48768). In oral squamous cell carcinoma, A 2B The receptor was overexpressed and its silencing inhibited proliferation (Kasama et al., BMC Cancer, (2015) 15 (563). Selective A 2B The agonist BAY 60-6583 enhanced melanoma progression in mice, whereas the selective A 2BThe antagonist PSB1115 suppressed melanoma growth (Iannone et al., Neoplasia. (2013) 15(12):1400-9). Furthermore, the combination of PSB1115 with other checkpoint inhibitors used in cancer immunotherapy, such as PD-1 inhibitors or CTLA-4 inhibitors, inhibited Aβ expression. 2B Antagonism was shown to exhibit strong synergy with these compounds in vivo, confirming that they occur via fundamentally different mechanisms (Mittal et al., Cancer Res. (2016) 76(15):4372-82). 2B Antagonists are currently in development, but none have yet received regulatory approval.

[0006] A1 receptor antagonism is also believed to show strong potential for cancer treatment. A1 receptors have been reported to be involved in the pathogenesis of various cancers, including breast cancer, colon cancer, astrocytoma, renal cancer and gastric cancer (Sai ​​et al., Neurotoxicology. (2006) 27(4): 458-67; Hosseinzadeh et al., Iran Biomed J. (2008) 12(4): 203-8; Saito et al., Cancer Lett. (2010) 28; 290(2): 211-5; Sheng et al., Front. Biosci. (Landmark Ed). (2014) 19: 854-61). A 2BSimilarly, the anticancer effects of A1 antagonists are diverse and occur through both tumor-intrinsic and host-mediated pathways. For example, the A1 receptor antagonist DPCPX was shown to inhibit tumor progression in renal cell carcinoma (Zhou et al., Cell Physiol. Biochem. (2017) 43(2):733-742). DPCPX also induced apoptosis in MCF-7 breast cancer cells (Dastjerdi et al., Bratisl. Lek. Listy. (2016) 117(4):242-6), and upregulation of p53. Consistent with this behavior, RNA silencing of A1 receptor in overexpressing breast cancer cells results in a decrease in cell proliferation rate and induction of apoptosis (Mirza et al., Cancer Biol. Ther. (2005) 4(12):1355-60).

[0007] Additional rationales for A1 receptor antagonism also exist at the host level, which is paramount for cancer immunotherapy. Studies have shown that pharmacological preconditioning with A1 agonists reduces A 2A This leads to upregulation of the A 2A It was found that A1 signaling can induce the immunosuppressive effects predicted for A1 signaling (Nakav et al., PLoS ONE 3(5):e2107); (Nakav et al., Nephrology Dialysis Transplantation, (2009) 24(8) 2392-2399); (Naamani et al., International Immunopharmacology, (2014) 20(1) 205-212). This effect was later reproduced in vivo and found to induce immunosuppression in an allograft model, resulting in improved graft survival (Naamani et al., Sci. Rep. (2020) 11;10(1):4464). In the case of cancer, targeting A1 signaling may be a promising strategy to prevent A1-mediated cell death. 2AIt may have a positive effect in the tumor microenvironment with high adenosine concentrations, where upregulation of the receptor leads to immune suppression and tumor evasion. Furthermore, A1 receptor antagonism is also being tested in the treatment of respiratory diseases, such as asthma and obstructive pulmonary disease (COPD), and may therefore be beneficial outside of cancer therapy.

[0008] A 2B Receptor antagonism can also be applied outside of immuno-oncology, particularly in the treatment of respiratory diseases, where A 2B Signaling mediates the production and release of proinflammatory mediators (e.g., IL-4, IL-8, IL-13, and histamine) from mast cells. 2B Mice treated with the receptor antagonist had less lung inflammation, less fibrosis, and greater enlargement of alveolar air spaces than untreated mice, demonstrating reduced lung inflammation in vivo. 2B The potential of antagonists has been demonstrated (Sun et al., J Clin Invest. (2006) 116(8):2173-2182). Other indications include pulmonary fibrosis, pulmonary hypertension (PH), COPD and asthma (Zablocki et al., Expert Opinion on Therapeutic Patents, (2006) 16:10, 1347-1357). 2B Consistent with its anti-inflammatory and immunosuppressive effects, A has been found to be involved in various aspects of glucose regulation. 2B The antagonist was found to reduce inflammatory responses and improve insulin resistance in diabetic mouse strains by attenuating the production of IL-6 and other cytokines that affect glucose and fat metabolism (Figler et al., Diabetes. (2011) 60(2) 669-79). In addition, A 2B The antagonist was shown to be able to prevent fatty liver formation after alcohol consumption in a mouse model (Peng et al., J Clin. Invest. (2009) 119(3):582-94). 2BIt has been shown that inhibition can prevent induced diabetic nephropathy and renal fibrosis. In addition, kidney biopsy samples obtained from patients, as well as genetic and pharmacological approaches, have also demonstrated a role for A in the treatment of chronic kidney disease (CKD) and renal ischemia. 2B (Sun and Huang, Front Chem. (2016) 24;4:37) support the potential role of A in the central nervous system. 2B The role of the antagonist is 2A It has received less attention than inhibition. 2B A shows a clear anti-Parkinsonian effect and is of great interest in Alzheimer's disease, cerebral ischemia, spinal cord injury, drug addiction and other pathologies. 2A It is closely related to the receptor. - / - In mice, A 2B They reported that specific antagonist treatment significantly improved hearing loss, nerve fiber density and myelin compaction in mice, and that A2B receptors are the underlying pathogenic factor for age-related sensorineural hearing loss (Manalo et al., FASEB J. (2020) 34 (12) 15771-15787). 2B The low affinity of the receptors means that they may be good therapeutic targets, as these receptors are only activated under pathological conditions when adenosine levels are elevated to micromolar concentrations (Popoli and Pepponi, CNS Neurol Disord Drug Targets. (2012) 11(6):664-74). Thus, ADP-1 is a promising candidate for treating a wide range of diseases and disorders, including cancer and inflammatory diseases. 2B There is a need for safe and selective ligands for the A1 receptor and / or the A1 receptor. Summary of the Invention

[0009] The present invention relates to adenosine receptor subtypes other than adenosine receptor subtypes, e.g., A 2A and A3) having selectivity over A 2B Antagonist and Double A 2BThe present invention relates to compounds of formula I or a pharma- ceutically acceptable salt or hydrate thereof and their use as therapeutically active substances for the treatment or prevention of a pathological condition, disorder or disease, in particular in the treatment or prevention of cancer.

[0010] More specifically, the present invention relates to the discovery of certain 2-aminothiazoles that have a triazole substituent at the 2-amino group. The compounds are A1 receptor antagonists and A 2B Receptor antagonists, especially A 2B The compounds of the present invention are useful as receptor antagonists and do not exhibit meaningful, e.g., medically important, A3 adenosine receptor antagonist activity. Thus, the compounds of the present invention are particularly suitable as new pharmaceutical agents for the treatment of diseases.

[0011] A1 receptors and A 2B The selectivity profile of the compounds of the present invention allows their use as new pharmaceuticals, especially for the treatment of cancer, since both receptors have been shown to constitute important regulators of cancer growth and immune cancer responses within the tumor microenvironment as described above. Furthermore, an important feature of the present invention is its high selectivity compared to A3 receptor antagonistic activity, which in preferred embodiments prevents the undesirable side effects of the compounds of the present invention caused by the antagonism of A3 receptor.

[0012] Additionally, the molecules of the invention contain a triazole substituent attached to the 2-amino group of the thiazole core, which further confers favorable properties for drug candidates, such as solubility, lipophilicity, and cell permeability. For example, the aminotriazole group of the compounds of formula I is hydrophilic, and in some preferred embodiments, the R A Substituents and R B Combining lipophilicity with the substituents results in compounds with improved cell membrane permeability. Furthermore, the aminotriazole group incorporates a polar NH group that can enhance solubility while maintaining acceptable cell permeability through the possible formation of intramolecular hydrogen bonds via the central thiazole nitrogen.

[0013] Therefore, the compounds of the present invention disclosed herein are particularly suitable as therapeutic agents. Additional features and advantages of the present technology will be apparent to those skilled in the art upon reading the following detailed description.

[0014] Thus, in a first aspect, the present invention provides a compound of formula I: [ka] (In the formula, R 1 is H, halogen, -C1-C8 alkyl, -C3-C8 cycloalkyl, -O-C1-C8 alkyl, or -CN, and each alkyl, cycloalkyl, or -O-alkyl is selected from one or more R 2 may be substituted by R 2 is independently selected at each occurrence from halogen, -OH, and -OC1-C8 alkyl; R A is a 5-6 membered heteroaryl, the heteroaryl being selected from one or more R A1 may be substituted by R A1 is independently selected at each occurrence from halogen, -OH, oxo, cyano, -C1-C8 alkyl, -C3-C8 cycloalkyl, and -O-C1-C8 alkyl, and each alkyl, cycloalkyl, or -O-alkyl is selected from one or more R A2 may be substituted by R A2 is independently at each occurrence halogen, -OC1-C8 alkyl, or -OH; R B is phenyl or 5-6 membered heteroaryl, each phenyl or heteroaryl being selected from one or more R B1 may be substituted by R B1 is independently selected at each occurrence from halogen, -OH, cyano, -C1-C8 alkyl, and -O-C1-C8 alkyl, each alkyl, and -O-alkyl being selected from one or more RB2 may be substituted by R B2 is independently at each occurrence halogen, -OH, or -OC1-C8 alkyl. or a pharma- ceutically acceptable salt, solvate or hydrate thereof.

[0015] In another aspect, the present invention provides a compound of the present invention of formula I for use as a medicament.

[0016] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention of formula I, optionally together with a pharma- ceutically acceptable diluent or carrier.

[0017] In a further aspect, the present invention relates to adenosine A 2B and / or A1 receptors, preferably A 2B There is provided a compound of the invention of formula I, or a pharmaceutical composition of the invention, for use in a method of treating a condition, disorder or disease mediated by receptor activation.

[0018] In a further aspect, the present invention relates to adenosine A 2B and / or A1 receptors, preferably A 2B There is provided a compound of the invention of formula I, or a pharmaceutical composition of the invention, for use in a method of treating a condition, disorder, or disease that is ameliorated by inhibition of a receptor.

[0019] In a further aspect, the present invention relates to adenosine A 2B and / or A1 receptors, preferably A 2B There is provided a compound of the invention of formula I, or a pharmaceutical composition of the invention, for use in a method of treating a condition or disease susceptible to amelioration by antagonism of the receptor.

[0020] In another aspect, the present invention provides adenosine A 2B and / or A1 receptors, preferably A 2BThere is provided the use of a compound of formula I according to the invention in the manufacture of a medicament for the treatment of a condition, disorder or disease mediated by receptor activation.

[0021] In another aspect, the present invention provides adenosine A 2B and / or A1 receptors, preferably A 2B There is provided the use of a compound of formula I according to the invention in the manufacture of a medicament for the treatment of a condition, disorder or disease ameliorated by inhibition of a receptor.

[0022] In another aspect, the present invention provides adenosine A 2B and / or A1 receptors, preferably A 2B There is provided the use of a compound of formula I according to the invention in the manufacture of a medicament for the treatment of a condition, disorder or disease susceptible to amelioration by antagonism of a receptor.

[0023] In another aspect, the present invention provides adenosine A 2B and / or A1 receptors, preferably A 2B Adenosine A 2B and / or A1 receptors, preferably A 2B A method for treating a condition, disorder or disease mediated by receptor activation is provided, comprising administering to a subject a therapeutically effective amount of a compound of formula I according to the present invention.

[0024] In another aspect, the present invention provides adenosine A 2B and / or A1 receptors, preferably A 2B Adenosine A in a subject in need of treatment for a condition, disorder, or disease that is ameliorated by inhibition of the receptor. 2B and / or A1 receptors, preferably A 2B A method for treating a condition, disorder or disease ameliorated by receptor inhibition is provided, comprising administering to a subject a therapeutically effective amount of a compound of formula I according to the present invention.

[0025] In another aspect, the present invention provides adenosine A2B and / or A1 receptors, preferably A 2B Adenosine A in a subject in need of treatment for a condition, disorder, or disease susceptible to amelioration by receptor antagonism. 2B and / or A1 receptors, preferably A 2B A method for treating a condition, disorder or disease susceptible to amelioration by antagonism of a receptor is provided, comprising administering to a subject a therapeutically effective amount of a compound of formula I according to the present invention.

[0026] In another aspect, the present invention provides a compound of formula I, or a pharmaceutical composition of the present invention, for use in a method for treating a condition, disorder or disease selected from a respiratory disease, an inflammatory obstructive airways disease, an inflammatory disease, a metabolic disease, a renal disease, a vascular disease, an allergic disease, an inflammatory gastrointestinal disorder, an autoimmune disease, a neurological disorder, an otolarynological disorder and cancer.

[0027] In another aspect, the present invention provides the use of a compound of formula I according to the present invention in the manufacture of a medicament for the treatment of a condition, disorder or disease selected from a respiratory disease, an inflammatory obstructive airways disease, an inflammatory disease, a metabolic disease, a renal disease, a vascular disease, an allergic disease, an inflammatory gastrointestinal disorder, an autoimmune disease, a neurological disorder, an otolaryngological disorder and cancer.

[0028] In another aspect, the present invention provides a method of treating a condition, disorder or disease selected from a respiratory disease, an inflammatory obstructive airway disease, an inflammatory disease, a metabolic disease, a renal disease, a vascular disease, an allergic disease, an inflammatory gastrointestinal disorder, an autoimmune disease, a neurological disorder, an otolaryngologic disorder and a cancer, comprising administering to a subject, particularly a human subject, in need of treatment for the condition, disorder or disease a therapeutically effective amount of a compound of the present invention of formula I or a pharma- ceutically acceptable salt or hydrate thereof.

[0029] The present invention further relates to processes for producing said compounds, intermediates, and pharmaceutical compositions and medicaments containing said compounds or pharma- ceutically acceptable salts or hydrates thereof, as well as to methods for treating A1 receptors, particularly adenosine A 2BThe use thereof for a method for the prevention or treatment of disorders and diseases mediated by receptor activation is provided.

[0030] Further aspects and embodiments of the invention will become apparent as this description continues. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0031] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention belongs. The definitions used below typically refer to fragments, e.g., "C1-C8-" fragments, by specifying the number of carbon atoms. Such usage is for the purpose of definition and is not intended to be limited to fragments having the specific number of carbon atoms described. The definitions for fragments with fewer or more carbon atoms, e.g., "C1-C4-" or "C1-C3-" analogs, should be interpreted as the same as the definition of the larger "C1-C8-" fragment, except for the number of carbon atoms.

[0032] As used herein, "C1-C8 alkyl" refers to a straight or branched saturated C1-C8 hydrocarbon, which may be, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, straight or branched pentyl, straight or branched hexyl, straight or branched heptyl, or straight or branched octyl. Preferably, the C1-C8 alkyl is a C1-C4 alkyl.

[0033] As used herein, "C1-C8 alkoxy" refers to a linear or branched saturated -O-C1-C8 hydrocarbon, which may be, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, linear or branched pentoxy, linear or branched hexyloxy, linear or branched heptyloxy, or linear or branched octyloxy. Preferably, the C1-C8 alkoxy is a C1-C4 alkoxy. The "C1-C8 alkoxy" group may also be represented as "-O-C1-C8 alkyl".

[0034] "Halogen" as used herein refers to fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine, more preferably fluorine or chlorine when incorporated into a compound of formula I. This also applies correspondingly to halogen in combination with other meanings such as haloalkyl.

[0035] As used herein, "C1-C8 haloalkyl" refers to C1-C8 alkyl as defined hereinabove, substituted with one or more halogen atoms, preferably 1, 2 or 3 halogen atoms, preferably fluorine or chlorine atoms.Preferably, C1-C8 haloalkyl is C1-C4 alkyl substituted with 1, 2 or 3 fluorine or chlorine atoms.Preferred examples include difluoromethyl, trifluoromethyl, chlorodifluoromethyl, and 2,2,2-trifluoroethyl.

[0036] As used herein, "C1-C8 hydroxyalkyl" refers to a C1-C8 alkyl as defined hereinabove, substituted with one or more hydroxyl (OH) groups, preferably one, two or three hydroxyl (OH) groups, most preferably one hydroxyl (OH) group.

[0037] The term "C3-C8 cycloalkyl" as used herein refers to a monocyclic or bicyclic saturated hydrocarbon ring, typically and preferably a monocyclic form, containing 3 to 8 carbon atoms, more preferably 3 to 7 carbon atoms. Specific and preferred examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl and cyclohexyl. The term "C3-C6 cycloalkyl" as used herein refers to a monocyclic form containing 3 to 6 carbon atoms, specifically cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0038] The term "phenyl" as used herein refers to a -C6 aromatic ring. An unsubstituted phenyl group has the formula -C6H5. A substituted phenyl group has one or more hydrogen atoms replaced by a substituent.

[0039] The term "heteroaryl" as used herein refers to a 5-6 membered ring system containing an aromatic ring and containing at least one heteroatom selected from O and N. Heteroaryls can be a single ring or two or more fused rings in which at least one ring contains a heteroatom. Examples of monocyclic heteroaryls include imidazolyl, triazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyridinyl, pyridazinyl, pyrimidinyl and pyrazinyl.

[0040] The term "cyano" refers to the group --CN.

[0041] The term "carbonyl" refers to a functional group consisting of a carbon atom double bonded to an oxygen atom, which may be abbreviated herein as "oxo," C(O), or C=O.

[0042] When a group is said to be "optionally substituted", preferably, there are 1 to 5 optional substituents, more preferably, 1 to 3 optional substituents, even more preferably, 1 or 2 optional substituents, and most preferably, 1 optional substituent. When a group is said to be optionally substituted and there are multiple substituents present for said optional substitution of said group, said multiple substituents may be the same or different.

[0043] As used herein, the terms "treating," "treatment," or "therapy" refer to a means of obtaining a desired physiological effect. The effect may be therapeutic in that it partially or completely cures the disease or condition and / or the symptoms caused by the disease or condition. The terms refer to inhibiting the disease or condition, i.e., halting its development, or ameliorating the disease or condition, i.e., causing regression of the disease or condition.

[0044] As used herein, the term "for use" used in "a composition for use in the treatment of a disease" is intended to also disclose the corresponding method of treatment and the corresponding use of the preparation for the manufacture of a medicament for the treatment of a disease.

[0045] A "therapeutically effective amount" is an amount of a compound or pharmaceutical composition according to the invention that elicits the biological or medical response in a subject, preferably a human subject, that is desired by a researcher, veterinarian, physician or other clinician. As used herein, the term "therapeutic administration" refers to the administration of a therapeutically effective amount.

[0046] Compounds of the Invention In a first aspect, the present invention provides a compound of formula I: [ka] (In the formula, R 1 is H, halogen, -C1-C8 alkyl, -C3-C8 cycloalkyl, -O-C1-C8 alkyl, or -CN, and each alkyl, cycloalkyl, or -O-alkyl is selected from one or more R 2 may be substituted by R 2 is independently selected at each occurrence from halogen, -OH, and -OC1-C8 alkyl; R Ais a 5-6 membered heteroaryl, the heteroaryl being selected from one or more R A1 may be substituted by R A1 is independently selected at each occurrence from halogen, -OH, oxo, cyano, -C1-C8 alkyl, -C3-C8 cycloalkyl, and -O-C1-C8 alkyl, and each alkyl, cycloalkyl, or -O-alkyl is selected from one or more R A2 may be substituted by R A2 is independently at each occurrence halogen, -OC1-C8 alkyl, or -OH; R B is phenyl or 5-6 membered heteroaryl, each phenyl or heteroaryl being selected from one or more R B1 may be substituted by R B1 is independently selected at each occurrence from halogen, -OH, cyano, -C1-C8 alkyl, and -O-C1-C8 alkyl, each alkyl, and -O-alkyl being selected from one or more R B2 may be substituted by R B2 is independently at each occurrence halogen, -OH, or -OC1-C8 alkyl. or a pharma- ceutically acceptable salt, solvate or hydrate thereof.

[0047] In some embodiments, R 1 is H, halogen, -C1-C8 alkyl, -C3-C8 cycloalkyl, or -O-C1-C8 alkyl, and each alkyl, cycloalkyl, or -O-alkyl is selected from one or more R 2 may be substituted by:

[0048] In a further preferred embodiment, R 1 is H, halogen, -C1-C8 alkyl, or -C3-C8 cycloalkyl, each alkyl or cycloalkyl being selected from one or more R 2 may be substituted by:

[0049] In a further preferred embodiment, R 1 is H, halogen, -C1-C4 alkyl, or -C3-C6 cycloalkyl, each alkyl or cycloalkyl being selected from one or more R 2 may be substituted by:

[0050] In a further preferred embodiment, R 1 is H, halogen, -C1-C2 alkyl, or -C3-C6 cycloalkyl, each alkyl or cycloalkyl being selected from one or more R 2 may be substituted by:

[0051] In a further preferred embodiment, R 1 is H, halogen, -C1-C2 alkyl, or -C3-C4 cycloalkyl, each alkyl or cycloalkyl being selected from one or more R 2 may be substituted by:

[0052] In a further preferred embodiment, R 1 is H, halogen, -C1 alkyl, or -C3-C4 cycloalkyl, each alkyl or cycloalkyl being selected from one or more R 2 may be substituted by:

[0053] In a further preferred embodiment, R 1 is H, fluoro, chloro, -C1-C2 alkyl, or -C3-C4 cycloalkyl, each alkyl or cycloalkyl being selected from one or two R 2 may be substituted by:

[0054] In a further preferred embodiment, R 1 is H, fluoro, chloro, -C1 alkyl, or -C3-C4 cycloalkyl, each alkyl or cycloalkyl being selected from one or two R 2 may be substituted by:

[0055] In a further preferred embodiment, R 1is H, fluoro, chloro, -C1-C2 alkyl, or -C3-C4 cycloalkyl, each alkyl or cycloalkyl being selected from one R 2 may be substituted by:

[0056] In a further preferred embodiment, R 1 is H, fluoro, chloro, -C1 alkyl, or -C3-C4 cycloalkyl, each alkyl or cycloalkyl being selected from one R 2 may be substituted by:

[0057] In a further preferred embodiment, R 1 is H, -C1-C2 alkyl, or -C3-C4 cycloalkyl, each alkyl being selected from one R 2 may be substituted by:

[0058] In a further preferred embodiment, R 1 is H, -C1 alkyl, or -C3-C4 cycloalkyl, each alkyl being selected from one R 2 may be substituted by:

[0059] In a further preferred embodiment, R 1 is H, -C1-C2 alkyl, or -C3-C4 cycloalkyl, each alkyl optionally substituted by one -OH.

[0060] In a further preferred embodiment, R 1 is H, -C1 alkyl, or -C3-C4 cycloalkyl, each alkyl optionally substituted by one -OH.

[0061] In a further preferred embodiment, R 1 is H, -CH3, -CH2CH3, -CH2OH, or -C3-C4 cycloalkyl.

[0062] In a further preferred embodiment, R 1 is H, -CHOH, or -C3-C4 cycloalkyl.

[0063] In a further preferred embodiment, R 1 is H. In a further preferred embodiment, R 1 is halogen. In a further preferred embodiment, R 1 is fluoro or chloro.

[0064] In a further preferred embodiment, R 1 is -CH3.

[0065] In a further preferred embodiment, R 1 is -CH2CH3.

[0066] In a further preferred embodiment, R 1 is -CHOH.

[0067] In a further preferred embodiment, R 1 is cyclopropane.

[0068] In a further preferred embodiment, R 1 is cyclobutane.

[0069] In some preferred embodiments, R 2 is -OH, halogen, or -OC1-C4 alkyl. In a further preferred embodiment, R 2 is -OH, halogen, or -OC1-C2 alkyl. In a further preferred embodiment, R 2 is -OH or halogen, said halogen being preferably fluoro or chloro. 2 is -OH. In a further preferred embodiment, R 2 is a halogen, said halogen being preferably fluoro or chloro.

[0070] In some preferred embodiments, R Ais imidazolyl, triazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl or pyridonyl, each imidazolyl, triazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl or pyridonyl being selected from the group consisting of one or more R A1 may be substituted by:

[0071] In some preferred embodiments, R A is imidazolyl, triazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl, each imidazolyl, triazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl being selected from the group consisting of one or more R A1 may be substituted by:

[0072] In a further preferred embodiment, R A is 1-imidazolyl, 1-(1,2,4)-triazolyl, 4-(1,2,4)-triazolyl, 4-isoxazolyl, 5-isoxazolyl, 5-oxazolyl, 4-pyrazolyl, 4-pyridinyl, 4-pyridazinyl, 4-pyrimidinyl, 2-pyrazinyl, or 5-(2-pyridonyl), and each imidazolyl, triazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, or pyridonyl is selected from the group consisting of one or more R A1 may be substituted by:

[0073] In a further preferred embodiment, R A is 1-imidazolyl, 1-(1,2,4)-triazolyl, 4-(1,2,4)-triazolyl, 4-isoxazolyl, 5-isoxazolyl, 5-oxazolyl, 4-pyrazolyl, 4-pyridinyl, 4-pyridazinyl, 4-pyrimidinyl, or 2-pyrazinyl, and each imidazolyl, triazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl may be selected from the group consisting of one or more RA1 may be substituted by:

[0074] In a further preferred embodiment, R A is imidazolyl, triazolyl, isoxazolyl, pyrazolyl, pyridinyl, pyridazinyl, pyrimidinyl or pyridonyl, each imidazolyl, triazolyl, isoxazolyl, pyrazolyl, pyridinyl, pyridazinyl, pyrimidinyl or pyridonyl being selected from the group consisting of one or more R A1 may be substituted by:

[0075] In a further preferred embodiment, R A is imidazolyl, triazolyl, isoxazolyl, pyrazolyl, pyridinyl, pyridazinyl or pyrimidinyl, each of which may be selected from the group consisting of one or more R A1 may be substituted by:

[0076] In a further preferred embodiment, R A is 1-imidazolyl, 1-(1,2,4)-triazolyl, 4-(1,2,4)-triazolyl, 4-isoxazolyl, 5-isoxazolyl, 4-pyrazolyl, 4-pyridinyl, 4-pyridazinyl, 4-pyrimidinyl, or 5-(2-pyridonyl), and each imidazolyl, triazolyl, isoxazolyl, pyrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyridonyl is selected from the group consisting of one or more R A1 may be substituted by:

[0077] In a further preferred embodiment, R A is 1-imidazolyl, 1-(1,2,4)-triazolyl, 4-(1,2,4)-triazolyl, 4-isoxazolyl, 5-isoxazolyl, 4-pyrazolyl, 4-pyridinyl, 4-pyridazinyl, or 4-pyrimidinyl, and each imidazolyl, triazolyl, isoxazolyl, pyrazolyl, pyridinyl, pyridazinyl, and pyrimidinyl may be selected from the group consisting of one or more R A1 may be substituted by:

[0078] In a further preferred embodiment, R A is 1-imidazolyl, 1-(1,2,4)-triazolyl, 4-(1,2,4)-triazolyl, 4-isoxazolyl, 5-isoxazolyl, 4-pyrazolyl, 4-pyridinyl, 4-pyridazinyl, 4-pyrimidinyl, or 5-(2-pyridonyl), and each imidazolyl, triazolyl, isoxazolyl, pyrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyridonyl is selected from the group consisting of one and two R A1 may be substituted by:

[0079] In a further preferred embodiment, R A is 1-imidazolyl, 1-(1,2,4)-triazolyl, 4-(1,2,4)-triazolyl, 4-isoxazolyl, 5-isoxazolyl, 4-pyrazolyl, 4-pyridinyl, 4-pyridazinyl, or 4-pyrimidinyl, and each imidazolyl, triazolyl, isoxazolyl, pyrazolyl, pyridinyl, pyridazinyl, and pyrimidinyl may be selected from one or two R A1 may be substituted by:

[0080] In a further preferred embodiment, R A is imidazolyl, triazolyl, pyridinyl, pyridazinyl, pyrimidinyl or pyridonyl, each of which may be selected from the group consisting of one or more R A1 may be substituted by:

[0081] In a further preferred embodiment, R A is imidazolyl, triazolyl, pyridinyl or pyridonyl, each of which may be selected from the group consisting of one or more R A1 may be substituted by:

[0082] In a further preferred embodiment, R Ais imidazolyl, triazolyl, or pyridinyl, each of which may be selected from the group consisting of one or more R A1 may be substituted by:

[0083] In a further preferred embodiment, R A is 1-imidazolyl, 1-(1,2,4)-triazolyl, 4-(1,2,4)-triazolyl, 4-pyridinyl, 4-pyridazinyl, 4-pyrimidinyl, or 5-(2-pyridonyl), and each imidazolyl, triazolyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyridonyl is selected from the group consisting of one or more R A1 may be substituted by:

[0084] In a further preferred embodiment, R A is 1-imidazolyl, 1-(1,2,4)-triazolyl, 4-pyridinyl, 4-pyridazinyl, 4-pyrimidinyl, or 5-(2-pyridonyl), and each imidazolyl, triazolyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyridonyl is selected from the group consisting of one or more R A1 may be substituted by:

[0085] In a further preferred embodiment, R A is 1-imidazolyl, 1-(1,2,4)-triazolyl, 4-(1,2,4)-triazolyl, 4-pyridinyl, or 5-(2-pyridonyl), each imidazolyl, triazolyl, pyridinyl, or pyridonyl being selected from one or more R A1 may be substituted by:

[0086] In a further preferred embodiment, R A is 1-imidazolyl, 1-(1,2,4)-triazolyl, 4-(1,2,4)-triazolyl, or 4-pyridinyl, and each imidazolyl, triazolyl, and pyridinyl may be selected from one or more R A1 may be substituted by:

[0087] In a further preferred embodiment, R Ais 1-imidazolyl, 1-(1,2,4)-triazolyl, 4-(1,2,4)-triazolyl, 4-pyridinyl, 4-pyridazinyl, 4-pyrimidinyl, or 5-(2-pyridonyl), each of which may be selected from one or two R A1 may be substituted by:

[0088] In a further preferred embodiment, R A is 1-imidazolyl, 1-(1,2,4)-triazolyl, 4-pyridinyl, 4-pyridazinyl, 4-pyrimidinyl, or 5-(2-pyridonyl), each of which is selected from the group consisting of one or two R A1 may be substituted by:

[0089] In a further preferred embodiment, R A is 1-imidazolyl, 1-(1,2,4)-triazolyl, 4-(1,2,4)-triazolyl, 4-pyridinyl, or 5-(2-pyridonyl), each imidazolyl, triazolyl, pyridinyl, or pyridonyl being selected from one or two R A1 may be substituted by:

[0090] In a further preferred embodiment, R A is 1-imidazolyl, 1-(1,2,4)-triazolyl, 4-(1,2,4)-triazolyl, or 4-pyridinyl, each of which may be one or two R A1 may be substituted by:

[0091] In a further preferred embodiment, R A is 1-imidazolyl, 1-(1,2,4)-triazolyl, 4-(1,2,4)-triazolyl, 4-pyridinyl, 4-pyridazinyl, 4-pyrimidinyl, or 5-(2-pyridonyl), where each imidazolyl, triazolyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyridonyl is unsubstituted.

[0092] In a further preferred embodiment, R A is 1-imidazolyl, 1-(1,2,4)-triazolyl, 4-(1,2,4)-triazolyl, or 4-pyridinyl, where each imidazolyl, triazolyl, and pyridinyl is unsubstituted.

[0093] In a further preferred embodiment, R A is 1-imidazolyl, each imidazolyl having one or two R A1 may be substituted by:

[0094] In a further preferred embodiment, R A is 1-imidazolyl, where each imidazolyl is unsubstituted.

[0095] In a further preferred embodiment, R A is 1-(1,2,4)-triazolyl, each triazolyl having one or two R A1 may be substituted by:

[0096] In a further preferred embodiment, R A is 1-(1,2,4)-triazolyl, where each triazolyl is unsubstituted.

[0097] In a further preferred embodiment, R A is 4-(1,2,4)-triazolyl, each triazolyl having one or two R A1 may be substituted by:

[0098] In a further preferred embodiment, R A is 4-(1,2,4)-triazolyl, where each triazolyl is unsubstituted.

[0099] In a further preferred embodiment, R A is 4-pyridinyl, each pyridinyl having one or two R A1 may be substituted by:

[0100] In a further preferred embodiment, R A is 4-pyridinyl, wherein each pyridinyl is unsubstituted.

[0101] In a further preferred embodiment, R A is 4-pyridazinyl, each pyridazinyl may have one or two R A1 may be substituted by:

[0102] In a further preferred embodiment, R A is 4-pyridazinyl, and each pyridazinyl is unsubstituted.

[0103] In a further preferred embodiment, R A is 4-pyrimidinyl, each pyrimidinyl being selected from one or two R A1 may be substituted by:

[0104] In a further preferred embodiment, R A is 4-pyrimidinyl, wherein each pyrimidinyl is unsubstituted.

[0105] In a further preferred embodiment, R A is 5-(2-pyridonyl), each pyridonyl may have one or two R A1 may be substituted by:

[0106] In a further preferred embodiment, R A is 5-(2-pyridonyl), where each pyridonyl is unsubstituted.

[0107] In some preferred embodiments, R A1 is independently halogen, -OH, oxo, -C1-C4 alkyl, or -C3-C6 cycloalkyl, each alkyl or cycloalkyl being optionally substituted by one or more halogen or -OH. A1is independently halogen, -OH, -C1-C4 alkyl, or -C3-C6 cycloalkyl, each alkyl or cycloalkyl being optionally substituted by one or more halogen or -OH. A1 is independently halogen, -OH, or -C1-C4 alkyl, each alkyl being optionally substituted by one or more halogens or -OH. A1 is independently halogen, or -C1-C4 alkyl, each alkyl being optionally substituted by one or more halogens or -OH. In a further preferred embodiment, R A1 is independently halogen, or -C1-C2 alkyl, each alkyl being optionally substituted by one or more halogens or -OH. A1 is independently fluorine, chlorine, or -C1-C2 alkyl, each alkyl being optionally substituted by one or more fluorine, chlorine, or -OH. A1 is independently fluorine, chlorine, or -C1-C2 alkyl, each alkyl being optionally substituted by one or more -OH. A1 is independently fluorine, chlorine, or -C1-C2 alkyl, each alkyl being optionally substituted by 1 or 2, preferably 1, -OH.

[0108] In some preferred embodiments, R A is the following: [ka] (In the formula, X is -CH- or N; R A3 are independently, at each occurrence, 1 to 3 identical or different substituents selected from hydrogen, halogen, -C1-C8 alkyl, -C1-C8 haloalkyl, -C1-C8 alkoxy, -C1-C8 hydroxyalkyl, and -C1-C8 alkoxyalkyl; R A4 is independently at each occurrence hydrogen, halogen, -C1-C8 alkyl, -C3-C8 cycloalkyl, -C1-C8 hydroxyalkyl, and -C1-C8 alkoxyalkyl; R A5 is independently, at each occurrence, hydrogen, or -C1-C8 alkyl. is selected from.

[0109] In some preferred embodiments, R A is the following: [ka] (In the formula, X is -CH- or N; R A3 are independently, at each occurrence, 1 to 3 identical or different substituents selected from hydrogen, halogen, -C1-C8 alkyl, -C1-C8 haloalkyl, -C1-C8 alkoxy, -C1-C8 hydroxyalkyl, and -C1-C8 alkoxyalkyl; R A4 is independently at each occurrence hydrogen, halogen, -C1-C8 alkyl, -C3-C8 cycloalkyl, -C1-C8 hydroxyalkyl, and -C1-C8 alkoxyalkyl. is selected from.

[0110] In a further preferred embodiment, R A3 represents one or two substituents, preferably one substituent.

[0111] In a further preferred embodiment, R A is the following: [ka] is selected from.

[0112] In a further preferred embodiment, R A is the following: [ka] is selected from.

[0113] In a further preferred embodiment, R A is the following: [ka] is selected from.

[0114] In a further preferred embodiment, R A is the following: [ka] is selected from.

[0115] In some preferred embodiments, R B is selected from phenyl, oxazolyl, pyridinyl, pyrimidinyl, pyridazinyl, and pyrazinyl, each of which is selected from one or more of R B1 In a further preferred embodiment, R B is selected from phenyl, 2-oxazolyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 4-pyridazinyl, and 2-pyrazinyl, and each phenyl, oxazolyl, pyridinyl, pyrimidinyl, pyridazinyl, and pyrazinyl is selected from one or more R B1 In a further preferred embodiment, R B is selected from phenyl, 2-oxazolyl, 2-pyridinyl, 3-pyridinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 4-pyridazinyl, and 2-pyrazinyl, each of phenyl, oxazolyl, pyridinyl, pyrimidinyl, and pyrazinyl having one or two, preferably one, R B1 In a further preferred embodiment, RB is selected from phenyl, oxazolyl, pyridinyl and pyridinyl, each of which is selected from one or two, preferably one, R B1 In a further preferred embodiment, R B is selected from phenyl, 2-oxazolyl, 2-pyridinyl, and 3-pyridinyl, each of which is selected from one or two, preferably one, R B1 may be substituted by:

[0116] In a further preferred embodiment, R B is selected from phenyl, pyridinyl, pyrimidinyl, pyridazinyl, and pyrazinyl, each of which is selected from one or more R B1 may be substituted by:

[0117] In a further preferred embodiment, R B is selected from phenyl, 2-pyridinyl, 3-pyridinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 4-pyridazinyl, and 2-pyrazinyl, each of which is selected from one or more of R B1 may be substituted by:

[0118] In a further preferred embodiment, R B is derived from a phenyl, which is joined to another R B1 In a further preferred embodiment, R B is derived from phenyl, said phenyl having one or two, preferably one, R B1 may be substituted by:

[0119] In some preferred embodiments, R B1is selected from halogen, -OH, cyano, -C1-C4 alkyl, and -C1-C4 alkoxy, each alkyl and alkoxy being independently substituted with one or more halogen, -OH, or -C1-C4 alkoxy. B1 is selected from halogen, -OH, cyano, and -C1-C4 alkyl, said alkyl being independently substituted with one or more halogen, -OH, or -C1-C4 alkoxy. B1 is selected from halogen, -OH, cyano, and -C1-C4 alkyl, said alkyl being independently substituted by one or more halogen or -OH. B1 is selected from halogen, -OH, cyano, and -C1-C2 alkyl, said alkyl being independently substituted with one or more halogen or -OH. B1 is selected from halogen, -OH, and cyano. In a further preferred embodiment, R B1 is selected from halogen and cyano. In a further preferred embodiment, R B1 is selected from fluorine, chlorine and cyano. In a further preferred embodiment, R B1 is selected from fluorine and cyano. B1 is fluorine. In a further preferred embodiment, R B1 is cyano.

[0120] In some preferred embodiments, R B is the following: [ka] (In the formula, R B3is independently selected at each occurrence from hydrogen, halogen, -C1-C8 alkyl, -C1-C8 haloalkyl, -C1-C8 alkoxy, -C1-C8 hydroxyalkyl, -C1-C8 alkoxyalkyl, and -CN. In a further preferred embodiment, R B3 represents 1 to 3 identical or different substituents for b1 and b2, and represents 1 to 2 identical or different substituents for b3. B3 represents 1 to 2 identical or different substituents, preferably 1 substituent. In a further preferred embodiment, R B is the following: [ka] is selected from.

[0121] In a further preferred embodiment, R B is as follows: [ka] is selected from.

[0122] In a further preferred embodiment, R B is as follows: [ka] is selected from.

[0123] In some preferred embodiments, R B 1 or 2 R B1 is phenyl substituted by R B1 is independently at each occurrence cyano or fluoro. In a further preferred embodiment, R B is 2-fluorophenyl, 3-cyanophenyl, or 2-fluoro-5-cyanophenyl. B is 2-fluorophenyl. In a further preferred embodiment, R Bis 3-cyanophenyl. In a further preferred embodiment, R B is 2-fluoro-5-cyanophenyl.

[0124] In some embodiments, the present invention provides a compound of formula I: [ka] (In the formula, R 1 is H, halogen, -C1-C2 alkyl, or -C3-C4 cycloalkyl, each alkyl or cycloalkyl being selected from one or more R 2 may be substituted by R 2 is independently selected at each occurrence from halogen, -OH, and -OC1-C2 alkyl; R A is imidazolyl, triazolyl, pyridinyl, pyridazinyl, pyrimidinyl or pyridonyl, each of which may be selected from the group consisting of one or more R A1 may be substituted by R A1 is independently halogen, -OH, -C1-C4 alkyl, or -C3-C6 cycloalkyl, each alkyl or cycloalkyl being optionally substituted by one or more halogen or -OH; R B is selected from phenyl, pyridinyl, pyrimidinyl, pyridazinyl, and pyrazinyl, each of which is selected from one or more R B1 may be substituted by R B1 is independently selected at each occurrence from halogen and cyano. or a pharma- ceutically acceptable salt, solvate or hydrate thereof.

[0125] In some embodiments, the present invention provides a compound of formula I: [ka] (In the formula, R 1 is H, halogen, -C1-C8 alkyl, -C3-C8 cycloalkyl, -O-C1-C8 alkyl, or -CN, and each alkyl, cycloalkyl, or -O-alkyl is selected from one or more R 2 may be substituted by R 2 is independently selected at each occurrence from halogen, -OH, and -OC1-C8 alkyl; R A is a 5-6 membered heteroaryl, the heteroaryl being selected from one or more R A1 may be substituted by R A1 is independently selected at each occurrence from halogen, -OH, oxo, cyano, -C1-C8 alkyl, -C3-C8 cycloalkyl, and -O-C1-C8 alkyl, and each alkyl, cycloalkyl, or -O-alkyl is selected from one or more R A2 may be substituted by R A2 is independently at each occurrence halogen, -OC1-C8 alkyl, or -OH; R B is phenyl, said phenyl being selected from one or more R B1 may be substituted by R B1 is independently selected at each occurrence from halogen, -OH, cyano, -C1-C8 alkyl, and -O-C1-C8 alkyl, each alkyl, and -O-alkyl being selected from one or more R B2 may be substituted by R B2 is independently at each occurrence halogen, -OH, or -OC1-C8 alkyl. or a pharma- ceutically acceptable salt, solvate or hydrate thereof.

[0126] In some embodiments, the present invention provides a compound of formula I: [ka] (In the formula, R 1 is H, halogen, -C1-C2 alkyl, or -C3-C4 cycloalkyl, each alkyl or cycloalkyl being selected from one or more R 2 may be substituted by R 2 is independently selected at each occurrence from halogen, -OH, and -OC1-C2 alkyl; R A is imidazolyl, triazolyl, pyridinyl, pyridazinyl, pyrimidinyl or pyridonyl, each of which may be selected from the group consisting of one or more R A1 may be substituted by R A1 is independently halogen, -OH, -C1-C4 alkyl, or -C3-C6 cycloalkyl, each alkyl or cycloalkyl being optionally substituted by one or more halogen or -OH; R B is phenyl, said phenyl being selected from one or more R B1 may be substituted by R B1 is independently selected at each occurrence from halogen and cyano. or a pharma- ceutically acceptable salt, solvate or hydrate thereof.

[0127] In some embodiments, the present invention provides a compound of formula I: [ka] (In the formula, R 1 is H, -C1-C2 alkyl, or -C3-C4 cycloalkyl, each alkyl being selected from one R 2 may be substituted by R 2is independently selected at each occurrence from fluoro, chloro, or -OH, preferably R 2 is OH, R A is 1-imidazolyl, 1-(1,2,4)-triazolyl, 4-pyridinyl, 4-pyridazinyl, 4-pyrimidinyl, or 5-(2-pyridonyl), and each imidazolyl, triazolyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyridonyl is selected from the group consisting of one or more R A1 may be substituted by R A1 is independently fluorine, chlorine, or -C1-C2 alkyl, each alkyl being optionally substituted by one or more fluorine, chlorine, or -OH, preferably each alkyl being optionally substituted by one or more -OH; R B is phenyl, said phenyl being selected from one or more R B1 may be substituted by R B1 is independently selected at each occurrence from halogen and cyano. or a pharma- ceutically acceptable salt, solvate or hydrate thereof.

[0128] In some preferred embodiments, the compound has formula Ia1b: [ka] (In the formula, R 1 , R B , R A3 and R A4 is as defined in any of the above embodiments) It is of the following.

[0129] In some preferred embodiments, the compound has formula Ia2b: [ka] (In the formula, R 1 , R B , RA4 and X is as defined in any of the above embodiments. It is of the following.

[0130] In some preferred embodiments, the compound has formula Ia3b: [ka] (In the formula, R 1 , R B and R A3 is as defined in any of the above embodiments, and Y is independently, at each occurrence, -CH-, or N, and at least one of the Y's is -CH-. It is of the following.

[0131] In some preferred embodiments, the compound has formula Ia1b or Ia2b: [ka] (In the formula, R 1 , R B , R A3 , R A4 and X is as defined in any of the above embodiments, preferably R 1 is H, halogen, -C1-C8 alkyl, -C3-C8 cycloalkyl, -O-C1-C8 alkyl, or -CN, and each alkyl, cycloalkyl, or -O-alkyl is selected from one or more R 2 may be substituted by R 2 is independently selected at each occurrence from halogen, -OH, and -OC1-C8 alkyl; X is -CH- or N; R A3 are independently, at each occurrence, 1 to 3 identical or different substituents selected from hydrogen, halogen, -C1-C8 alkyl, -C1-C8 haloalkyl, -C1-C8 alkoxy, -C1-C8 hydroxyalkyl, and -C1-C8 alkoxyalkyl; R A4 is independently at each occurrence hydrogen, halogen, -C1-C8 alkyl, -C3-C8 cycloalkyl, -C1-C8 hydroxyalkyl, and -C1-C8 alkoxyalkyl; R B is phenyl or 5-6 membered heteroaryl, each phenyl or heteroaryl being selected from one or more R B1 may be substituted by R B1 is independently selected at each occurrence from halogen, -OH, cyano, -C1-C8 alkyl, and -O-C1-C8 alkyl, each alkyl, and -O-alkyl being selected from one or more R B2 may be substituted by R B2 is independently at each occurrence halogen, -OH, or -OC1-C8 alkyl. It is of the following.

[0132] In some preferred embodiments, the compound has formula Ia3b or Ia2b: [ka] (In the formula, R 1 , R B , R A3 , R A4 X and Y are as defined in any of the above embodiments, preferably R 1 is H, halogen, -C1-C8 alkyl, -C3-C8 cycloalkyl, -O-C1-C8 alkyl, or -CN, and each alkyl, cycloalkyl, or -O-alkyl is selected from one or more R 2 may be substituted by R 2 is independently selected at each occurrence from halogen, -OH, and -OC1-C8 alkyl; X is -CH- or N; Y, at each occurrence, is independently -CH-, or N, and at least one Y is -CH-; R A3 are independently, at each occurrence, 1 to 3 identical or different substituents selected from hydrogen, halogen, -C1-C8 alkyl, -C1-C8 haloalkyl, -C1-C8 alkoxy, -C1-C8 hydroxyalkyl, and -C1-C8 alkoxyalkyl; R A4 is independently at each occurrence hydrogen, halogen, -C1-C8 alkyl, -C3-C8 cycloalkyl, -C1-C8 hydroxyalkyl, and -C1-C8 alkoxyalkyl; R B is phenyl or 5-6 membered heteroaryl, each phenyl or heteroaryl being selected from one or more R B1 may be substituted by R B1 is independently selected at each occurrence from halogen, -OH, cyano, -C1-C8 alkyl, and -O-C1-C8 alkyl, each alkyl, and -O-alkyl being selected from one or more R B2 may be substituted by R B2 is independently at each occurrence halogen, -OH, or -OC1-C8 alkyl. It is of the following.

[0133] In some preferred embodiments, the compound has formula Ia1b1, Ia1b2, Ia1b3, Ia2b1, Ia2b2, Ia2b3, Ia3b1, Ia3b2, or Ia3b3: [ka] (In the formula, R 1 , R B3 , R A3 , R A4 and X is as defined in any of the above embodiments, preferably R 1 is H, halogen, -C1-C8 alkyl, -C3-C8 cycloalkyl, -O-C1-C8 alkyl, or -CN, and each alkyl, cycloalkyl, or -O-alkyl is selected from one or more R 2may be substituted by R 2 is independently selected at each occurrence from halogen, -OH, and -OC1-C8 alkyl; X is -CH- or N; Y, at each occurrence, is independently -CH-, or N, and at least one Y is -CH-; R A3 are independently, at each occurrence, 1 to 3 identical or different substituents selected from hydrogen, halogen, -C1-C8 alkyl, -C1-C8 haloalkyl, -C1-C8 alkoxy, -C1-C8 hydroxyalkyl, and -C1-C8 alkoxyalkyl; R A4 is independently at each occurrence hydrogen, halogen, -C1-C8 alkyl, -C3-C8 cycloalkyl, -C1-C8 hydroxyalkyl, and -C1-C8 alkoxyalkyl; R B3 is independently selected at each occurrence from hydrogen, halogen, -C1-C8 alkyl, -C1-C8 haloalkyl, -C1-C8 alkoxy, -C1-C8 hydroxyalkyl, -C1-C8 alkoxyalkyl, and -CN. It is of the following.

[0134] In a further preferred embodiment, the compound is B3 one R selected from cyano and fluoro; B3 and R 1 In some preferred embodiments, the compound is a compound of formula Ia1b1, wherein R B3 one R selected from cyano or fluoro; B3 and R 1 In some preferred embodiments, the compound is a compound of formula Ia2b1, wherein R B3 is 3-cyano, and R 1 In some preferred embodiments, the compound is of formula Ia1b1, where R B3 is 2-fluoro, and R1 In some preferred embodiments, the compound is of formula 1a1b1, where R B3 is 2-fluoro, and R 1 In some preferred embodiments, the compound is of formula Ia2b1, where R B3 is 3-cyano, and R 1 is a compound of formula Ia2b1, wherein

[0135] In a preferred embodiment, R A 1 or 2 R A1 is a pyridine optionally substituted by R A1 is independently at each occurrence fluoro, chloro, or methyl; R B is 3-cyanophenyl.

[0136] In a preferred embodiment, R A 1 or 2 R A1 1-imidazole optionally substituted by R A1 is independently at each occurrence methyl, ethyl, or hydroxymethyl; R B is 3-cyanophenyl.

[0137] In a preferred embodiment, R 1 is H and R A 1 or 2 R A1 1-imidazole optionally substituted by R A1 is independently at each occurrence methyl, ethyl, or hydroxymethyl; R B is 3-cyanophenyl.

[0138] In a preferred embodiment, R A is R A1 1-imidazole optionally substituted once at the 2-position by R A1 is independently at each occurrence methyl, ethyl, or hydroxymethyl; R B is 3-cyanophenyl.

[0139] In a preferred embodiment, R A is R A1 1-imidazole optionally substituted once at the 2-position by R A1 is methyl, R B is 3-cyanophenyl.

[0140] In a preferred embodiment, R A is a triazole, R B is 3-cyanophenyl.

[0141] In some preferred embodiments, the compound is: 5-Cyclobutyl-N-[4-(2-fluorophenyl)-5-(3-fluoropyridin-4-yl)-1,3-thiazol-2-yl]-1H-1,2,4-triazol-3-amine; 3-[5-(3-chloropyridin-4-yl)-2-[(5-cyclopropyl-1H-1,2,4-triazol-3-yl)amino]-1,3-thiazol-4-yl]benzonitrile; 3-{2-[(5-cyclopropyl-1H-1,2,4-triazol-3-yl)amino]-5-(3-fluoropyridin-4-yl)-1,3-thiazol-4-yl}benzonitrile; 3-{2-[(5-cyclopropyl-1H-1,2,4-triazol-3-yl)amino]-5-(2,5-dimethylpyridin-4-yl)-1,3-thiazol-4-yl}benzonitrile; 3-{2-[(5-cyclopropyl-1H-1,2,4-triazol-3-yl)amino]-5-(3-methylpyridin-4-yl)-1,3-thiazol-4-yl}benzonitrile; 3-{2-[(5-cyclopropyl-1H-1,2,4-triazol-3-yl)amino]-5-(2,3-dimethylpyridin-4-yl)-1,3-thiazol-4-yl}benzonitrile; 3-{2-[(5-cyclopropyl-1H-1,2,4-triazol-3-yl)amino]-5-(2-methyl-1H-imidazol-1-yl)-1,3-thiazol-4-yl}benzonitrile; 3-{2-[(5-cyclopropyl-1H-1,2,4-triazol-3-yl)amino]-5-(2-methylpyridin-4-yl)-1,3-thiazol-4-yl}benzonitrile; 3-[5-(2-methyl-1H-imidazol-1-yl)-2-[(1H-1,2,4-triazol-3-yl)amino]-1,3-thiazol-4-yl]benzonitrile; 3-{2-[(5-methyl-1H-1,2,4-triazol-3-yl)amino]-5-(2-methyl-1H-imidazol-1-yl)-1,3-thiazol-4-yl}benzonitrile; 3-(2-{[5-(hydroxymethyl)-1H-1,2,4-triazol-3-yl]amino}-5-(2-methyl-1H-imidazol-1-yl)-1,3-thiazol-4-yl)benzonitrile; 3-[5-(2,5-dimethylpyridin-4-yl)-2-[(1H-1,2,4-triazol-3-yl)amino]-1,3-thiazol-4-yl]benzonitrile; 3-[5-(2,5-dimethylpyridin-4-yl)-2-[(5-methyl-1H-1,2,4-triazol-3-yl)amino]-1,3-thiazol-4-yl]benzonitrile; 3-[5-(2,5-dimethylpyridin-4-yl)-2-{[5-(hydroxymethyl)-1H-1,2,4-triazol-3-yl]amino}-1,3-thiazol-4-yl]benzonitrile; 3-{2-[(5-cyclopropyl-1H-1,2,4-triazol-3-yl)amino]-5-(1H-1,2,4-triazol-1-yl)-1,3-thiazol-4-yl}benzonitrile; 3-[5-(2-ethyl-1H-imidazol-1-yl)-2-[(5-methyl-1H-1,2,4-triazol-3-yl)amino]-1,3-thiazol-4-yl]benzonitrile; 3-{2-[(5-cyclopropyl-1H-1,2,4-triazol-3-yl)amino]-5-[2-(hydroxymethyl)-1H-imidazol-1-yl]-1,3-thiazol-4-yl}benzonitrile; 3-{2-[(5-cyclopropyl-1H-1,2,4-triazol-3-yl)amino]-5-(2-methyl-1H-imidazol-1-yl)-1,3-thiazol-4-yl}-4-fluorobenzonitrile; 3-{5-[2-(hydroxymethyl)-1H-imidazol-1-yl)-2-[(1H-1,2,4-triazol-3-yl)amino]-1,3-thiazol-4-yl}benzonitrile; 3-{2-[(5-ethyl-1H-1,2,4-triazol-3-yl)amino]-5-[2-(hydroxymethyl)-1H-imidazol-1-yl]-1,3-thiazol-4-yl}benzonitrile; 3-{5-[2-(hydroxymethyl)-1H-imidazol-1-yl]-2-[(5-methyl-1H-1,2,4-triazol-3-yl)amino]-1,3-thiazol-4-yl}benzonitrile; 3-[5-(3-methylpyridin-4-yl)-2-[(1H-1,2,4-triazol-3-yl)amino]-1,3-thiazol-4-yl]benzonitrile; 3-{2-[(5-cyclopropyl-1H-1,2,4-triazol-3-yl)amino]-5-(5-methylpyridazin-4-yl)-1,3-thiazol-4-yl}benzonitrile; 3-{2-[(5-cyclopropyl-1H-1,2,4-triazol-3-yl)amino]-5-(pyrimidin-4-yl)-1,3-thiazol-4-yl}benzonitrile; 3-{2-[(5-cyclopropyl-1H-1,2,4-triazol-3-yl)amino]-5-(pyridazin-4-yl)-1,3-thiazol-4-yl}benzonitrile; 3-{2-[(5-cyclopropyl-1H-1,2,4-triazol-3-yl)amino]-5-(pyridin-4-yl)-1,3-thiazol-4-yl}benzonitrile; 3-{2-[(5-cyclopropyl-1H-1,2,4-triazol-3-yl)amino]-5-(5-methylpyrimidin-4-yl)-1,3-thiazol-4-yl}benzonitrile; m-[2-(5-cyclopropyl-1H-1,2,4-triazol-3-ylamino)-5-(2-ethyl-1-imidazolyl)-1,3-thiazol-4-yl]benzonitrile; and 3-{2-[(5-cyclopropyl-1H-1,2,4-triazol-3-yl)amino]-5-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1,3-thiazol-4-yl}benzonitrile is selected from.

[0142] In a preferred embodiment, the compound is 5-cyclobutyl-N-[4-(2-fluorophenyl)-5-(3-fluoropyridin-4-yl)-1,3-thiazol-2-yl]-1H-1,2,4-triazol-3-amine.

[0143] In some preferred embodiments, the compound is 3-[5-(3-chloropyridin-4-yl)-2-[(5-cyclopropyl-1H-1,2,4-triazol-3-yl)amino]-1,3-thiazol-4-yl]benzonitrile.

[0144] In some preferred embodiments, the compound is 3-{2-[(5-cyclopropyl-1H-1,2,4-triazol-3-yl)amino]-5-(3-fluoropyridin-4-yl)-1,3-thiazol-4-yl}benzonitrile.

[0145] In a preferred embodiment, the compound is 3-{2-[(5-cyclopropyl-1H-1,2,4-triazol-3-yl)amino]-5-(2,5-dimethylpyridin-4-yl)-1,3-thiazol-4-yl}benzonitrile.

[0146] In a preferred embodiment, the compound is 3-{2-[(5-cyclopropyl-1H-1,2,4-triazol-3-yl)amino]-5-(3-methylpyridin-4-yl)-1,3-thiazol-4-yl}benzonitrile.

[0147] In a preferred embodiment, the compound is 3-{2-[(5-cyclopropyl-1H-1,2,4-triazol-3-yl)amino]-5-(2,3-dimethylpyridin-4-yl)-1,3-thiazol-4-yl}benzonitrile.

[0148] In a preferred embodiment, the compound is 3-{2-[(5-cyclopropyl-1H-1,2,4-triazol-3-yl)amino]-5-(2-methyl-1H-imidazol-1-yl)-1,3-thiazol-4-yl}benzonitrile.

[0149] In a preferred embodiment, the compound is 3-{2-[(5-cyclopropyl-1H-1,2,4-triazol-3-yl)amino]-5-(2-methylpyridin-4-yl)-1,3-thiazol-4-yl}benzonitrile.

[0150] In a preferred embodiment, the compound is 3-[5-(2-methyl-1H-imidazol-1-yl)-2-[(1H-1,2,4-triazol-3-yl)amino]-1,3-thiazol-4-yl]benzonitrile.

[0151] In a preferred embodiment, the compound is 3-{2-[(5-methyl-1H-1,2,4-triazol-3-yl)amino]-5-(2-methyl-1H-imidazol-1-yl)-1,3-thiazol-4-yl}benzonitrile.

[0152] In a preferred embodiment, the compound is 3-(2-{[5-(hydroxymethyl)-1H-1,2,4-triazol-3-yl]amino}-5-(2-methyl-1H-imidazol-1-yl)-1,3-thiazol-4-yl)benzonitrile.

[0153] In a preferred embodiment, the compound is 3-[5-(2,5-dimethylpyridin-4-yl)-2-[(1H-1,2,4-triazol-3-yl)amino]-1,3-thiazol-4-yl]benzonitrile.

[0154] In a preferred embodiment, the compound is 3-[5-(2,5-dimethylpyridin-4-yl)-2-[(5-methyl-1H-1,2,4-triazol-3-yl)amino]-1,3-thiazol-4-yl]benzonitrile.

[0155] In a preferred embodiment, the compound is 3-[5-(2,5-dimethylpyridin-4-yl)-2-{[5-(hydroxymethyl)-1H-1,2,4-triazol-3-yl]amino}-1,3-thiazol-4-yl]benzonitrile.

[0156] In a preferred embodiment, the compound is 3-{2-[(5-cyclopropyl-1H-1,2,4-triazol-3-yl)amino]-5-(1H-1,2,4-triazol-1-yl)-1,3-thiazol-4-yl}benzonitrile.

[0157] In a preferred embodiment, the compound is 3-[5-(2-ethyl-1H-imidazol-1-yl)-2-[(5-methyl-1H-1,2,4-triazol-3-yl)amino]-1,3-thiazol-4-yl]benzonitrile.

[0158] In a preferred embodiment, the compound is 3-{2-[(5-cyclopropyl-1H-1,2,4-triazol-3-yl)amino]-5-[2-(hydroxymethyl)-1H-imidazol-1-yl]-1,3-thiazol-4-yl}benzonitrile.

[0159] In a preferred embodiment, the compound is 3-{2-[(5-cyclopropyl-1H-1,2,4-triazol-3-yl)amino]-5-(2-methyl-1H-imidazol-1-yl)-1,3-thiazol-4-yl}-4-fluorobenzonitrile.

[0160] In a preferred embodiment, the compound is 3-{5-[2-(hydroxymethyl)-1H-imidazol-1-yl)-2-[(1H-1,2,4-triazol-3-yl)amino]-1,3-thiazol-4-yl}benzonitrile.

[0161] In a preferred embodiment, the compound is 3-{2-[(5-ethyl-1H-1,2,4-triazol-3-yl)amino]-5-[2-(hydroxymethyl)-1H-imidazol-1-yl]-1,3-thiazol-4-yl}benzonitrile.

[0162] In a preferred embodiment, the compound is 3-{5-[2-(hydroxymethyl)-1H-imidazol-1-yl]-2-[(5-methyl-1H-1,2,4-triazol-3-yl)amino]-1,3-thiazol-4-yl}benzonitrile.

[0163] In a preferred embodiment, the compound is 3-[5-(3-methylpyridin-4-yl)-2-[(1H-1,2,4-triazol-3-yl)amino]-1,3-thiazol-4-yl]benzonitrile.

[0164] In a preferred embodiment, the compound is 3-{2-[(5-cyclopropyl-1H-1,2,4-triazol-3-yl)amino]-5-(5-methylpyridazin-4-yl)-1,3-thiazol-4-yl}benzonitrile.

[0165] In a preferred embodiment, the compound is 3-{2-[(5-cyclopropyl-1H-1,2,4-triazol-3-yl)amino]-5-(pyrimidin-4-yl)-1,3-thiazol-4-yl}benzonitrile.

[0166] In a preferred embodiment, the compound is 3-{2-[(5-cyclopropyl-1H-1,2,4-triazol-3-yl)amino]-5-(pyridazin-4-yl)-1,3-thiazol-4-yl}benzonitrile.

[0167] In a preferred embodiment, the compound is 3-{2-[(5-cyclopropyl-1H-1,2,4-triazol-3-yl)amino]-5-(pyridin-4-yl)-1,3-thiazol-4-yl}benzonitrile.

[0168] In a preferred embodiment, the compound is 3-{2-[(5-cyclopropyl-1H-1,2,4-triazol-3-yl)amino]-5-(5-methylpyrimidin-4-yl)-1,3-thiazol-4-yl}benzonitrile.

[0169] In a preferred embodiment, the compound is m-[2-(5-cyclopropyl-1H-1,2,4-triazol-3-ylamino)-5-(2-ethyl-1-imidazolyl)-1,3-thiazol-4-yl]benzonitrile.

[0170] In a preferred embodiment, the compound is 3-{2-[(5-cyclopropyl-1H-1,2,4-triazol-3-yl)amino]-5-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1,3-thiazol-4-yl}benzonitrile.

[0171] Many of the compounds of the present invention of formula I can form acid addition salts, particularly pharmaceutically acceptable acid addition salts.The pharmaceutically acceptable acid addition salts of the compounds of formula I include inorganic acids, such as hydrohalic acids, such as hydrofluoric acid, hydrochloric acid, hydrobromic acid or hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid; and organic acids, such as aliphatic monocarboxylic acids, such as formic acid, acetic acid, trifluoroacetic acid, propionic acid and butyric acid, aliphatic hydroxy acids, such as lactic acid, citric acid, tartaric acid or malic acid, dicarboxylic acids, such as maleic acid or succinic acid, aromatic carboxylic acids, such as benzoic acid, p-chlorobenzoic acid, diphenylacetic acid or triphenylacetic acid, aromatic hydroxy acids, such as o-hydroxybenzoic acid, parahydroxybenzoic acid, 1-hydroxynaphthalene-2-carboxylic acid or 3-hydroxynaphthalene-2-carboxylic acid, and sulfonic acids, such as methanesulfonic acid or benzenesulfonic acid. These salts may be prepared from compounds of formula I by known salt-forming procedures.

[0172] "Hydrate" refers to an association or complex of one or more water molecules with the compound of the present invention. Hydrate can be stoichiometric or non-stoichiometric. Particularly preferred examples of hydrate include hemihydrate, monohydrate and dihydrate.

[0173] Treatment method As shown in Examples 30-32 and Tables 1 and 2 below, the compounds of the invention disclosed herein inhibit adenosine A1 and A2. 2B , especially A 2B In particular, the compounds of the present invention selectively inhibit the A3 and / or A 2A A than receptor 2B and / or A1 receptors. Thus, in a preferred embodiment, the compounds of the present invention selectively inhibit adenosine A 2B It is used to treat a condition, disease or disorder mediated by activation of the receptor.

[0174] For example, Examples 30 and 31 and Table 1 show that compounds of the invention generally have EC 50 Value: A 2B In contrast, Table 1 demonstrates that the compounds of the present invention selectively inhibit the human A3 receptor and the human A1 receptor. 2A This indicates that it is largely inactive at the receptor.

[0175] Furthermore, Example 32 shows that the compound of the present invention is A 2A Receptor compared to human A 2B As shown in Example 32 and Table 2, the compounds of the present invention selectively bind to the human A receptor. 2B Selectively stabilizes receptors, increases melting points, and decreases ΔT m In contrast, the compounds of the present invention can increase human A 2A Receptor ΔT m has a much smaller effect on A 2A Weak receptor binding has been demonstrated.

[0176] The compounds of formula I according to the invention and their pharma- ceutically acceptable salts or hydrates are capable of inhibiting adenosine A1 and / or A2 2B Adenosine A1 and / or A2 due to their ability to inhibit receptor activation 2B The compounds and pharmaceutical compositions of the present invention are useful for treating or preventing pathologies, disorders and diseases mediated by the activation of receptors.These pathologies, disorders and diseases are selected from respiratory diseases, inflammatory obstructive airway diseases, inflammatory diseases, metabolic diseases, renal diseases, vascular diseases, allergic diseases, inflammatory gastrointestinal disorders, autoimmune diseases, neurological disorders, otolarynological disorders and cancer.In some embodiments, the compounds and pharmaceutical compositions of the present invention are useful for treating cancer, particularly ovarian cancer, including melanoma and squamous cell carcinoma, lung cancer, liver cancer, oral cancer, colon cancer, skin cancer and prostate cancer.In some embodiments, the compounds and pharmaceutical compositions of the present invention are useful for treating otolarynological disorders, preferably hearing loss.

[0177] In one aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention of formula I, optionally together with a pharma- ceutically acceptable diluent or carrier.

[0178] Thus, in one aspect, the present invention provides adenosine A1 and / or A 2B There is provided a compound of the invention of formula I, or a pharmaceutical composition of the invention, for use in a method of treating a condition, disorder or disease mediated by receptor activation.

[0179] In one aspect, the present invention relates to adenosine A1 and / or A 2B There is provided the use of a compound of formula I according to the invention in the manufacture of a medicament for the treatment of a condition, disorder or disease mediated by receptor activation.

[0180] In one aspect, the present invention provides a method for administering adenosine A1 and / or A2 to a subject in need thereof. 2B A method for treating a condition, disorder or disease mediated by receptor activation is provided, comprising administering to a subject a therapeutically effective amount of a compound of formula I according to the present invention.

[0181] In a further aspect, the present invention relates to adenosine A 2B There is provided a compound of the invention of formula I, or a pharmaceutical composition of the invention, for use in a method of treating a condition, disorder or disease mediated by receptor activation.

[0182] In a further aspect, the present invention relates to adenosine A 2B There is provided a compound of the invention of formula I, or a pharmaceutical composition of the invention, for use in a method of treating a condition, disorder, or disease that is ameliorated by inhibition of a receptor.

[0183] In a further aspect, the present invention relates to adenosine A 2B There is provided a compound of the invention of formula I, or a pharmaceutical composition of the invention, for use in a method of treating a condition or disease susceptible to amelioration by antagonism of the receptor.

[0184] In another aspect, the present invention provides adenosine A 2B There is provided the use of a compound of formula I according to the invention in the manufacture of a medicament for the treatment of a condition, disorder or disease mediated by receptor activation.

[0185] In another aspect, the present invention provides a method for administering adenosine A 2B A method for treating a condition, disorder or disease mediated by receptor activation is provided, comprising administering to a subject a therapeutically effective amount of a compound of formula I according to the present invention.

[0186] In another aspect, the present invention provides a compound of formula I, or a pharmaceutical composition of the present invention, for use in a method for treating a condition, disorder or disease selected from a respiratory disease, an inflammatory obstructive airways disease, an inflammatory disease, a metabolic disease, a renal disease, a vascular disease, an allergic disease, an inflammatory gastrointestinal disorder, an autoimmune disease, a neurological disorder, an otolarynological disorder and cancer.

[0187] In another aspect, the present invention provides the use of a compound of formula I according to the present invention in the manufacture of a medicament for the treatment of a condition, disorder or disease selected from a respiratory disease, an inflammatory obstructive airways disease, an inflammatory disease, a metabolic disease, a renal disease, a vascular disease, an allergic disease, an inflammatory gastrointestinal disorder, an autoimmune disease, a neurological disorder, an otolaryngological disorder and cancer.

[0188] In another aspect, the present invention provides a method of treating a condition, disorder or disease selected from a respiratory disease, an inflammatory obstructive airway disease, an inflammatory disease, a metabolic disease, a renal disease, a vascular disease, an allergic disease, an inflammatory gastrointestinal disorder, an autoimmune disease, a neurological disorder, an otolaryngologic disorder and cancer in a subject in need thereof, comprising administering to the subject, particularly a human subject, a therapeutically effective amount of a compound of the present invention of formula I or a pharmaceutically acceptable salt or hydrate thereof.

[0189] In a highly preferred embodiment, the respiratory disease, inflammatory obstructive airway disease, inflammatory disease, metabolic disease, renal disease, vascular disease, allergic disease, inflammatory gastrointestinal disorder, autoimmune disease, neurological disorder, otorhinolaryngological disorder or the cancer is selected from the group consisting of pulmonary fibrosis, pulmonary hypertension (PH), chronic obstructive pulmonary disease (COPD), asthma, acute lung injury (ALI), adult respiratory distress syndrome (ARDS), bronchitis, pneumoconiosis, psoriasis, contact dermatitis, atopic dermatitis, conjunctivitis, allergies, The cancer is selected from: allergic rhinitis, intestinal disease, multiple sclerosis, diabetes, juvenile diabetes, diabetes mellitus, diabetic nephropathy, renal fibrosis, chronic kidney disease (CKD), renal ischemia, hypertension, retinopathy, Parkinson's disease, Alzheimer's disease, Huntington's disease, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), hearing loss, ovarian cancer including melanoma and squamous cell carcinoma, lung cancer, liver cancer, kidney cancer, rectal cancer, oral cancer, breast cancer, bladder cancer, colon cancer, skin cancer and prostate cancer.

[0190] Therefore, the compounds and pharmaceutical compositions of the present invention are useful for treating inflammatory or obstructive airway diseases, for example, by reducing bronchial hyperresponsiveness, remodeling or disease progression.The inflammatory or obstructive airway diseases to which the compounds and pharmaceutical compositions of the present invention are applicable include any type or origin of asthma, including both intrinsic (non-allergic) asthma and extrinsic (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchial asthma, exercise-induced asthma, occupational asthma, and asthma induced after bacterial infection.The prophylactic efficacy in treating asthma is demonstrated by reducing the frequency or severity of symptomatic attacks, improving lung function, or by reducing the need for other symptomatic therapies, for example, anti-inflammatory therapy (e.g., corticosteroids) or bronchodilator therapy. Further inflammatory or obstructive airways diseases and conditions for which the compounds and pharmaceutical compositions of the invention are useful include acute lung injury (ALI), adult respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease, chronic obstructive airways disease or chronic obstructive lung disease (COPD, COAD or COLD), as well as bronchitis and pneumoconiosis.

[0191] Additionally, the compounds and pharmaceutical compositions of the invention are useful in the treatment of inflammatory or allergic conditions of the skin, such as psoriasis, contact dermatitis and atopic dermatitis, as well as inflammatory diseases or conditions of the eye, such as conjunctivitis, or diseases affecting the nose, including allergic rhinitis.

[0192] Additionally, the compounds and pharmaceutical compositions of the present invention are useful in treating inflammatory diseases involving an autoimmune response or having an autoimmune component, including autoimmune inflammatory bowel disease, multiple sclerosis, diabetes and juvenile onset diabetes mellitus (type I diabetes mellitus).

[0193] Additionally, the compounds and pharmaceutical compositions of the present invention are useful for treating otolaryngological disorders, such as hearing loss.

[0194] The compounds and pharmaceutical compositions of the present invention may be administered by any suitable route, for example orally (as syrups, tablets, capsules, lozenges, controlled release preparations, fast dissolving preparations, lozenges, etc.), topically (as creams, ointments, lotions, nasal sprays or aerosols, etc.), by injection (subcutaneously, intradermally, intramuscularly, intravenously, etc.), or by inhalation (as dry powders, solutions, dispersions, etc.), depending on the nature of the disorder to be treated.

[0195] Detailed Description of the Preparation Process of Compounds of Formula I The preparation of the compounds of formula I of the present invention can be carried out in sequential or convergent synthetic routes. The synthesis of the compounds of the present invention is shown in the following scheme. The skills required to carry out the reactions and purification of the products obtained are known to those skilled in the art. The substituents and indicators used in the following description of the process have the significance indicated herein, unless otherwise indicated. More specifically, the compounds of formula I can be prepared by the methods shown below, by the methods shown in the examples, or by similar methods. The reaction conditions suitable for the individual reaction steps are known to those skilled in the art. The reaction sequence is not limited to that shown in the scheme, but the order of the reaction steps can be freely changed depending on the starting materials and their respective reactivity. The starting materials are commercially available or can be prepared by methods similar to those shown below, by the methods described in the examples, or by methods known in the art.

[0196] The compounds of formula I of the present invention may be prepared according to the following Schemes 1-6.

[0197] Scheme 1. Synthesis of aminothiazoles from α-haloketones and thiourea triazoles [ka] The compound of formula I of the present invention can be prepared by reacting an α-haloketone of formula II with a thiourea triazole of formula III in a suitable solvent, such as acetonitrile, in the presence of a base, preferably a nitrogen base, such as triethylamine, preferably at elevated temperature. In scheme 1 above, the "Hal" substituent of formula II can be any halogen, preferably iodine or bromine, more preferably bromine. The condensation reaction produces a compound of formula I, which can be directly precipitated from the reaction mixture and purified by a suitable procedure, preferably by washing.

[0198] Scheme 2. Synthesis of aminothiazoles from ketones and thiourea triazoles [ka] As shown in Scheme 2 above, compounds of formula I can be prepared in a one-pot reaction from a ketone of formula IV and a thiourea triazole of formula III by in situ halogenation of the ketone of formula IV with a suitable halogenating reagent, preferably bromine or iodine, in a suitable solvent, such as dioxane or pyridine. The one-pot halogenation condensation reaction can proceed at room temperature or at elevated temperatures.

[0199] Scheme 3. Preparation of α-haloketones from ketones of formula IV [ka] As shown in Scheme 3, the α-haloketone of formula II can be obtained, for example, by halogenation of the ketone of formula IV with a suitable halogenating reagent in a suitable solvent. In a preferred embodiment, the halogenating reagent is bromine, the solvent is acetic acid, and the reaction is carried out at room temperature. In another preferred embodiment, the halogenating reagent is iodine, and the solvent is pyridine or dioxane.

[0200] Scheme 4. Preparation of six-membered heteroaryl ketones from esters [ka] As shown in Scheme 4, the α-(6-membered) heteroaryl ketones of formulae IV-a1, IV-a3 and IV-a4 can be prepared by the reaction of formula V(a1:Z 1 =Z 2 =CH;a3:Z 1 =N,Z 2 =CH;a4:Z 1 =CH,Z 2═N) and a heteroaryl carboxylate ester of formula VI. The 4-methylheteroaryl ring can be deprotonated with a suitable base (e.g., lithium bis(trimethylsilyl)amide; LiHMDS) in a suitable solvent (e.g., THF) and reacted with a carboxylate of formula VI in an acylation reaction to provide compounds of formula IV-a1, IV-a3, and IV-a4. In a preferred embodiment, Z 1 and Z 2 are each independently N or CH, and preferably the heteroaryl ring of formulas V and IV is 4-pyridinyl, 4-pyridazinyl, or 4-pyrimidinyl (i.e., the heteroaryl R of formula V is A The ring is one of rings a1, a3 or a4).

[0201] Scheme 5. Preparation of five-membered heteroaryl ketones from α-haloketones [ka] As shown in Scheme 5, α-(5-membered) heteroaryl ketones of formula IV-a2 (X=CH, N) can be prepared by reacting an α-haloketone (e.g., an α-bromoketone) of formula VII with the corresponding substituted imidazole or triazole of formula VIII in a suitable solvent (e.g., acetonitrile). The substitution reaction is carried out in the presence of an α-haloketone where X is CH or N (i.e., R A The ring is a 5-membered heteroaryl ring of formula a2) resulting in a compound of formula IV.

[0202] Scheme 6. Preparation of triazolothioureas [ka] As shown in Scheme 6, triazole-thioureas of formula III can be prepared in two steps. In the first step, an aminotriazole of formula IX is reacted with benzoyl isothiocyanate in a suitable solvent (e.g., acetone) to give the benzoyl-modified triazole-thiourea. In the second step, the benzoyl group is removed by treatment with a suitable base (e.g., KOH) in a suitable solvent (e.g., methanol) preferably at elevated temperature (e.g., 60° C. or higher) to give the triazole-thiourea of ​​formula III.

[0203] example The present disclosure is further described by the following examples, which should not be interpreted as limiting the scope or spirit of the present disclosure to the specific procedures described herein. It should be understood that the examples are provided to illustrate specific embodiments, and are not intended to limit the scope of the present disclosure. It should be further understood that various other embodiments, modifications and equivalents thereof that may be suggested to those skilled in the art can be taken without departing from the spirit of the present disclosure and / or the scope of the appended claims.

[0204] Abbreviations used in the following examples and elsewhere in this specification are as follows: [Table 1]

[0205] Preparation Example 1: Preparation of 2-bromo-1-(2-fluorophenyl)-2-(3-fluoropyridin-4-yl)ethan-1-one hydrobromide (Intermediate II-1) [ka] Step 1: Synthesis of methyl 2-fluorobenzoate: [ka] To a stirred suspension of 2-fluorobenzoic acid (30.0 g, 0.214 mol) and K2CO3 (32.5 g, 0.235 mol) in N,N-dimethylformamide (150 ml) was added iodomethane (45.6 g, 0.321 mol) and the reaction mixture was stirred at room temperature overnight. After completion, the mixture was poured into water and extracted with 2-methoxy-2-methylpropane. The organic layer was washed with water and brine, dried and evaporated in vacuum to give 31.5 g of methyl 2-fluorobenzoate (0.203 mol, 95% yield).

[0206] Step 2: Synthesis of 1-(2-fluorophenyl)-2-(3-fluoropyridin-4-yl)ethan-1-one (Intermediate IV-1): [ka] To a mixture of 3-fluoro-4-methylpyridine (21.4 g, 0.193 mol) and methyl 2-fluorobenzoate (31.2 g, 0.203 mol) in tetrahydrofuran (200 mL) was added lithium bis(trimethylsilyl)amide (168 g, 23% in tetrahydrofuran / ethylbenzene, 0.232 mol) dropwise at 0° C. After stirring for 1 h, the reaction mixture was warmed to room temperature and stirred for 16 h, then triturated with hexane and filtered. The solid was dissolved in 3N HCl (300 mL). The solution was neutralized with saturated aqueous NaHCO3 and extracted with ethyl acetate. The combined organic layers were washed with water, followed by brine, dried with Na2SO4, and evaporated to give 1-(2-fluorophenyl)-2-(3-fluoropyridin-4-yl)ethan-1-one (Intermediate IV-1) (33.6 g, 75% yield) as a pale yellow solid.

[0207] Step 3: Synthesis of 2-bromo-1-(2-fluorophenyl)-2-(3-fluoropyridin-4-yl)ethan-1-one hydrobromide (Intermediate II-1): [ka] Bromine (5.5 g, 0.034 mol) was added to a solution of 1-(2-fluorophenyl)-2-(3-fluoropyridin-4-yl)ethan-1-one (8.0 g, 0.034 mol) in acetic acid (50 mL), and the mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with 2-methoxy-2-methylpropane, and the solid was filtered. The filter cake was washed with 2-methoxy-2-methylpropane and dried. The resulting 2-bromo-1-(2-fluorophenyl)-2-(3-fluoropyridin-4-yl)ethan-1-one hydrobromide (intermediate II-1) was used in the next step without purification (11.2 g, 83% yield).

[0208] Preparation Example 2: Preparation of N-(5-cyclobutyl-1H-1,2,4-triazol-3-yl)thiourea (Intermediate III-1) [ka] To a suspension of 5-cyclobutyl-1H-1,2,4-triazol-3-amine (1.37 g, 0.01 mol) in chloroform (50 mL) at 0° C., benzoyl isothiocyanate (2.44 g, 0.0149 mol) was added slowly. The mixture was warmed to room temperature and stirred for 8 h. The solid was collected (0.61 g, crude), washed with acetonitrile, dried, and then dissolved in methanol (20 mL). A solution of NaOH (0.243 g, 0.0061 mol) in water (5 mL) was added to the solution, and the mixture was stirred at 50° C. for another 2 h. The methanol was then removed under reduced pressure, and the residue was purified by preparative HPLC to give N-(5-cyclobutyl-1H-1,2,4-triazol-3-yl)thiourea (intermediate III-1) (0.075 g, 2.5% yield).

[0209] Preparation Example 3: Preparation of N-(5-cyclopropyl-1H-1,2,4-triazol-3-yl)thiourea (Intermediate III-2) [ka] Step 1: Synthesis of N-[(5-cyclopropyl-1H-1,2,4-triazol-3-yl)carbamothioyl]benzamide: [ka] To a stirred mixture of 5-cyclopropyl-1H-1,2,4-triazol-3-amine (12.1 g, 97 mmol) in 200 mL of acetone was added benzoyl isothiocyanate (19.1 g, 116 mmol) at room temperature. After addition, the mixture was heated to reflux and stirred overnight. The resulting mixture was cooled to room temperature. The precipitated solid was collected, washed with water and acetone, and dried to give N-[(5-cyclopropyl-1H-1,2,4-triazol-3-yl)carbamothioyl]-benzamide (11 g, 39%). [M+H]+: 288.08, found: 288.0.

[0210] Step 2: Synthesis of N-(5-cyclopropyl-1H-1,2,4-triazol-3-yl)thiourea (Intermediate III-2): [ka] To a suspension of N-[(5-cyclopropyl-1H-1,2,4-triazol-3-yl)carbamothioyl]benzamide in MeOH (200 mL) was added a solution of KOH (4.7 g, 84 mmol in 50 mL water). The mixture was stirred at 60° C. for 16 h, cooled to room temperature and concentrated under reduced pressure. The residue was diluted with water and EtOAc (100 / 100 mL) and acidified to pH=3 with concentrated HCl. The precipitated solid was collected, washed with water, MeCN and dried to give N-(5-cyclopropyl-1H-1,2,4-triazol-3-yl)thiourea (Intermediate III-2) (4.5 g, 64%). [M+H]+: 184.06, found: 184.0.

[0211] Preparation Example 4: Preparation of 3-[(3-fluoropyridin-4-yl)acetyl]benzonitrile (Intermediate IV-2) [ka] To a solution of methyl 3-cyanobenzoate (0.67 g, 4.1 mmol) and 3-fluoro-4-methylpyridine (0.55 g, 5.0 mmol) in THF (20 mL) was added LiHMDS (7 mL, 9.1 mmol, 20% solution in THF / ethylbenzene) at 0° C. under argon atmosphere. The reaction mixture was warmed to room temperature and stirred overnight. The mixture was then diluted with MTBE. The precipitated solid was collected and washed with MTBE. The filter cake was dissolved in 1N HCl, basified with saturated NaHCO3, and extracted with EtOAc. The organic layer was washed with brine, dried, and evaporated in vacuo to give 3-[(3-fluoropyridin-4-yl)acetyl]benzonitrile (Intermediate IV-2) (0.63 g, 63%). [M+H]+: 241.07, found: 240.8

[0212] Preparation Example 5: Preparation of 3-[(3-methylpyridin-4-yl)acetyl]benzonitrile (Intermediate IV-3) [ka] To a solution of methyl 3-cyanobenzoate (0.34 g, 2.1 mmol) and 3,4-dimethylpyridine (0.27 g, 2.5 mmol) in THF (10 mL) was added LiHMDS (4 mL, 5.2 mmol, 20% solution in THF / ethylbenzene) at 0° C. under an argon atmosphere. The reaction mixture was warmed to room temperature and stirred overnight. The mixture was then diluted with MTBE. The precipitated solid was collected and washed with MTBE. The filter cake was dissolved in 1N HCl, basified with saturated NaHCO3, and extracted with EtOAc. The organic layer was washed with brine, dried, and evaporated in vacuo to give 3-[(3-methylpyridin-4-yl)acetyl]benzonitrile (Intermediate IV-3) (0.23 g, 46%). [M+H] + :236.09;Actual value:236.0.

[0213] Preparation Example 6: Preparation of 3-[(2,5-dimethylpyridin-4-yl)acetyl]benzonitrile (Intermediate IV-4) [ka] To a solution of methyl 3-cyanobenzoate (0.53 g, 4.4 mmol) in THF (15 mL) was added LiHMDS (7 mL, 9.1 mmol, 20% solution in THF / ethylbenzene) at 0° C. under argon atmosphere. After stirring at the same temperature for 30 min, a solution of 2,4,5-trimethylpyridine (0.64 g, 4.4 mmol) in THF (2 mL) was added dropwise. The reaction mixture was warmed to room temperature and stirred overnight. The mixture was then quenched with MeOH and concentrated under reduced pressure. The residue was taken up in MeOH and filtered. The filtrate was evaporated under reduced pressure and purified by preparative HPLC to give compound 3-[(2,5-dimethylpyridin-4-yl)acetyl]benzonitrile (intermediate IV-4) (0.099 g, 10%). [M+H] + :251.13;Actual value:251.0.

[0214] Preparation Example 7: Preparation of 3-[(3-chloropyridin-4-yl)acetyl]benzonitrile (Intermediate IV-5) [ka] To a solution of methyl 3-cyanobenzoate (0.31 g, 2.3 mmol) and 3-chloro-4-methylpyridine (0.32 g, 2.5 mmol) in THF (10 mL) was added LiHMDS (3.3 mL, 4.3 mmol, 20% solution in THF / ethylbenzene) at 0° C. under an argon atmosphere. The reaction mixture was warmed to room temperature and stirred overnight. The mixture was then diluted with MTBE. The precipitated solid was collected and washed with MTBE. The filter cake was dissolved in 1N HCl, basified with saturated NaHCO3, and extracted with EtOAc. The organic layer was washed with brine, dried, and evaporated in vacuo to give 3-[(3-chloropyridin-4-yl)acetyl]benzonitrile (Intermediate IV-5) (0.45 g, 88%).

[0215] Preparation Example 8: Preparation of 3-[(2,3-dimethylpyridin-4-yl)acetyl]benzonitrile (Intermediate IV-6) [ka] Step 1: Synthesis of 4-bromo-2,3-dimethylpyridine: [ka] A mixture of 2,3-dimethylpyridin-4-ol (3.3 g 27 mmol) and phosphorus tribromide oxide (19.3 g, 67 mmol) was stirred at 130° C. for 4 h under argon atmosphere. The reaction mixture was poured onto ice, basified with aqueous NaOH, diluted with water and extracted with diethyl ether. The organic layer was washed with brine, dried and evaporated in vacuo to give 4-bromo-2,3-dimethylpyridine (3.4 g, 68%). [M+H] + : 124.08, actual value: 122.0.

[0216] Step 2: Synthesis of 2,3,4-trimethylpyridine: [ka] A mixture of 4-bromo-2,3-dimethylpyridine (1.54 g, 8.3 mmol), MeB(OH)2 (1.977 g, 33 mmol), and Na2CO3 (2.62 g, 27.7 mmol) in dioxane / water (20 / 5 mL) was sparged with argon for 5 min, and then Pd(PPh3)4 (0.48 g) was added. The mixture was heated to 95 °C for 72 h. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between MTBE and water. The organic layer was washed with water and brine, dried, and evaporated in vacuum to give a crude residue, which was purified by flash column chromatography to give 2,3,4-trimethylpyridine (0.49 g, 49%). [M+H] +:122.09;Actual value:120.0.

[0217] Step 3: Synthesis of 3-[(2,3-dimethylpyridin-4-yl)acetyl]benzonitrile (Intermediate IV-6): [ka] To a solution of 2,3,4-trimethylpyridine (0.46 g, 3.8 mmol) in THF (15 mL) was added LiHMDS (6.4 mL, 8.3 mmol, 20% solution in THF / ethylbenzene) at 0° C. under argon atmosphere. After stirring at the same temperature for 30 min, a solution of methyl 3-cyanobenzoate (0.61 g, 3.8 mmol) in THF (3 mL) was added dropwise. The reaction mixture was warmed to room temperature and stirred overnight. The mixture was then quenched with MeOH and concentrated under reduced pressure. The residue was taken up in MeOH and filtered. The filtrate was evaporated under reduced pressure and purified by preparative HPLC to give 3-[(2,3-dimethylpyridin-4-yl)acetyl]benzonitrile (intermediate IV-6) (0.055 g, 5.5%). [M+H] + : 251.13, actual value: 251.2.

[0218] Preparation Example 9: Preparation of 3-[(2-methylpyridin-4-yl)acetyl]benzonitrile (Intermediate IV-7) [ka] To a solution of 2,4-dimethylpyridine (1.02 g, 9.5 mmol) in THF (20 mL) was added LiHMDS (14.5 mL, 19 mmol, 20% solution in THF / ethylbenzene) at 0° C. under argon atmosphere. After stirring at 0° C. for 30 min, a solution of methyl 3-cyanobenzoate (1.02 g, 6.3 mmol) in THF (3 mL) was added dropwise. The reaction mixture was warmed to room temperature and stirred overnight. The mixture was then quenched with MeOH and concentrated. The residue was taken up in MeOH and filtered. The filtrate was evaporated under reduced pressure and purified by preparative HPLC to give 3-[(2-methylpyridin-4-yl)acetyl]benzonitrile (intermediate IV-7) (0.255 g, 17%). [M+H] + : 237.11, actual value: 237.2.

[0219] Preparation Example 10: Preparation of 3-[(2-methyl-1H-imidazol-1-yl)acetyl]benzonitrile (Intermediate IV-8) [ka] To a solution of 2-methyl-1H-imidazole (0.911 g, 211 mmol) in MeCN (10 mL) in an ice / water bath was added 3-(bromoacetyl)benzonitrile (0.995 g, 4.4 mmol). The mixture was stirred at room temperature overnight and the precipitate was filtered off. The filtrate was evaporated under reduced pressure. The residue was triturated with water and dried to give 3-[(2-methyl-1H-imidazol-1-yl)acetyl]benzonitrile (Intermediate IV-8) (0.62 g, 62%).

[0220] Preparation Example 11: Preparation of N-1H-1,2,4-triazol-3-ylthiourea (Intermediate III-3) [ka] Step 1: Synthesis of N-[(1H-1,2,4-triazol-3-yl)carbamothioyl]benzamide: [ka] To a stirred mixture of 1H-1,2,4-triazol-3-amine (3.4 g, 40 mmol) in acetone (100 mL) was added benzoyl isothiocyanate (7.9 g, 48 mmol) at room temperature. The mixture was heated to reflux and stirred overnight. The resulting mixture was then cooled to room temperature. The precipitated solid was collected, washed with water and acetone, and dried to give N-[(1H-1,2,4-triazol-3-yl)carbamothioyl]benzamide (2.9 g, 29%).

[0221] Step 2: Synthesis of N-1H-1,2,4-triazol-3-ylthiourea (Intermediate III-3): [ka] To a suspension of N-[(1H-1,2,4-triazol-3-yl)carbamothioyl]benzamide (2.9 g, 11.8 mmol) in MeOH (50 mL) was added a solution of KOH (2.7 g, 47.5 mmol in 30 mL water). The reaction mixture was stirred at 60° C. for 16 h, cooled to room temperature, and concentrated under reduced pressure. The residue was diluted with water and EtOAc (100 / 100 mL) and acidified to pH=3 with concentrated HCl. The precipitated solid was collected, washed with water and MeCN, and dried to give N-1H-1,2,4-triazol-3-ylthiourea (intermediate III-3) (1.2 g, 70%), which was used in the next step without purification.

[0222] Preparation Example 12: Preparation of N-(5-methyl-1H-1,2,4-triazol-3-yl)thiourea (Intermediate III-4) [ka] Step 1: Synthesis of N-[(5-methyl-1H-1,2,4-triazol-3-yl)carbamothioyl]benzamide: [ka] To a stirred mixture of 5-methyl-1H-1,2,4-triazol-3-amine (3.7 g, 38 mmol) in acetone (100 mL) was added benzoyl isothiocyanate (9.37 g, 57 mmol) at room temperature. The mixture was heated to reflux and stirred overnight. The resulting mixture was then cooled to room temperature. The precipitated solid was collected, washed with water and acetone, and dried to give N-[(5-methyl-1H-1,2,4-triazol-3-yl)carbamothioyl]benzamide (4.9 g, 49%). [M+H] + : 262.07, actual value: 262.0.

[0223] Step 2: Synthesis of N-(5-methyl-1H-1,2,4-triazol-3-yl)thiourea (Intermediate III-4): [ka] To a suspension of N-[(5-methyl-1H-1,2,4-triazol-3-yl)carbamothioyl]benzamide (4.9 g, 19 mmol) in MeOH (100 mL) was added a solution of KOH (4.3 g, 76 mmol in 50 mL water). The reaction mixture was stirred at 60° C. for 16 h, cooled to room temperature, and concentrated under reduced pressure. The residue was diluted with water and EtOAc (100 / 100 mL) and acidified to pH=3 with concentrated HCl. The precipitated solid was collected, washed with water and MeCN, and dried to give N-(5-methyl-1H-1,2,4-triazol-3-yl)thiourea (intermediate III-4) (2.1 g, 70%), which was used in the next step without purification.

[0224] Preparation Example 13: Preparation of N-[5-(hydroxymethyl)-1H-1,2,4-triazol-3-yl]thiourea (Intermediate III-5) [ka] Step 1: Synthesis of N-{[5-(hydroxymethyl)-1H-1,2,4-triazol-3-yl]carbamothioyl}benzamide: [ka] To a stirred mixture of (3-amino-1H-1,2,4-triazol-5-yl)methanol (1.65 g, 14.5 mmol) in acetone (70 mL) was added benzoyl isothiocyanate (3.53 g, 21.7 mmol) at room temperature. The mixture was then heated to reflux and stirred overnight. The resulting mixture was then cooled to room temperature. The precipitated solid was collected, washed with water and acetone, and dried to give N-{[5-(hydroxymethyl)-1H-1,2,4-triazol-3-yl]carbamothioyl}benzamide (3.2 g, 67%). [M+H] + : 278.06, actual value: 277.0.

[0225] Step 2: Synthesis of N-[5-(hydroxymethyl)-1H-1,2,4-triazol-3-yl]thiourea (Intermediate III-5): [ka] To a suspension of N-{[5-(hydroxymethyl)-1H-1,2,4-triazol-3-yl]carbamothioyl}benzamide (3.2 g, 11.5 mmol) in MeOH (40 mL) was added a solution of KOH (2.6 g, 46 mmol in 20 mL water). The reaction mixture was stirred at 60° C. for 16 h, cooled to room temperature, and concentrated under reduced pressure. The residue was diluted with water and EtOAc (50 / 50 mL) and acidified to pH=3 with concentrated HCl. The precipitated solid was collected, washed with water and MeCN, and dried to give N-[5-(hydroxymethyl)-1H-1,2,4-triazol-3-yl]thiourea (intermediate III-5) (0.9 g, 45%), which was used in the next step without purification.

[0226] Preparation Example 14: Preparation of 3-[(1H-1,2,4-triazol-1-yl)acetyl]benzonitrile (Intermediate IV-9) [ka] To a suspension of 1,2,4-triazole (0.366 g, 5.3 mmol) and K2CO3 (0.798 g, 5.8 mmol) in an ice / water bath was added a solution of 3-(bromoacetyl)benzonitrile (1.055 g, 4.7 mmol) in MeCN (10 mL). The reaction mixture was stirred at room temperature overnight. The precipitate was filtered. The filtrate was evaporated under reduced pressure. The residue was triturated with water and dried to give 3-[(1H-1,2,4-triazol-1-yl)acetyl]benzonitrile (intermediate IV-9) (0.61 g, 61%), which was used in the next step without purification.

[0227] Preparation Example 15: Preparation of 3-[(2-ethyl-1H-imidazol-1-yl)acetyl]benzonitrile (Intermediate IV-10) [ka] To a suspension of 2-ethyl-1H-imidazole (0.482 g, 5 mmol) and K2CO3 (0.798 g, 5.8 mmol) in an ice / water bath was added a solution of 3-(bromoacetyl)benzonitrile (0.936 g, 4.2 mmol) in MeCN (10 mL). The reaction mixture was stirred at room temperature overnight. The precipitate was filtered. The filtrate was evaporated under reduced pressure. The residue was triturated with water and dried to give 3-[(2-ethyl-1H-imidazol-1-yl)acetyl]benzonitrile (Intermediate IV-10) (0.62 g, 62%), which was used in the next step without purification.

[0228] Preparation Example 16: Preparation of 3-{[2-(hydroxymethyl)-1H-imidazol-1-yl]acetyl}benzonitrile (Intermediate IV-11) [ka] To a suspension of (1H-imidazol-2-yl)methanol (0.488 g, 5 mmol) and K2CO3 (0.745 g, 5.4 mmol) in ice / water bath was added a solution of 3-(bromoacetyl)benzonitrile (0.929 g, 4.1 mmol) in MeCN (10 mL). The reaction mixture was stirred at room temperature overnight. The precipitate was filtered. The filtrate was evaporated under reduced pressure, diluted with water and extracted with EtOAc. The organic layer was washed with water and brine, dried and evaporated in vacuum to give crude 3-{[2-(hydroxymethyl)-1H-imidazol-1-yl]acetyl}benzonitrile (intermediate IV-11) (0.62 g, 62%), which was used in the next step without purification.

[0229] Preparation Example 17: Preparation of 4-fluoro-3-[(2-methyl-1H-imidazol-1-yl)acetyl]benzonitrile (Intermediate IV-12) [ka] Step 1: Synthesis of 3-acetyl-4-fluorobenzonitrile: [ka] A mixture of 1-(5-bromo-2-fluorophenyl)ethan-1-one (3.06 g, 14 mmol), Zn(CN)2 (2.48 g, 21 mmol) in DMF (15 mL) was degassed and Pd(PPh3)4 was added. The mixture was heated to 90° C. overnight. The resulting mixture was cooled to room temperature, poured into water, and extracted with MTBE. The organic layer was washed with water and brine, dried, and evaporated in vacuo. The residue was purified by flash column chromatography to give 3-acetyl-4-fluorobenzonitrile (1.15 g, 50%).

[0230] Step 2: Synthesis of 3-(bromoacetyl)-4-fluorobenzonitrile: [ka] 3-Acetyl-4-fluorobenzonitrile (0.674 g, 4.1 mmol) was dissolved in CHCl3 (20 mL). To this solution was added Br2 (0.759 g, 4.7 mmol). The mixture was stirred at room temperature for 2 h and diluted with saturated NaHCO3 solution. The organic layer was separated, washed with water and brine, dried and evaporated in vacuo to give 3-(bromoacetyl)-4-fluorobenzonitrile (0.89 g, 89%). [M+H] + : 241.95, actual value: 242.0.

[0231] Step 3: 4-Fluoro-3-[(2-methyl-1H-imidazol-1-yl)acetyl]benzonitrile (Intermediate IV-12): [ka] To a suspension of 2-methyl-1H-imidazole (0.456 g, 5.5 mmol) and K2CO3 (0.818 g, 5.9 mmol) in ice / water bath was added a solution of 3-(bromoacetyl)-4-fluorobenzonitrile (0.896 g, 3.7 mmol) in MeCN (10 mL). The reaction mixture was stirred at room temperature overnight. The precipitate was filtered. The filtrate was evaporated under reduced pressure, diluted with water and extracted with EtOAc. The organic layer was washed with water and brine, dried and evaporated in vacuum to give crude 4-fluoro-3-[(2-methyl-1H-imidazol-1-yl)acetyl]benzonitrile (Intermediate IV-12) (0.54 g, 60%), which was used in the next step without purification.

[0232] Preparation Example 18: Preparation of 3-[(5-methylpyridazin-4-yl)acetyl]benzonitrile (Intermediate IV-13) [ka] Step 1: Synthesis of 4,5-dimethylpyridazine [ka] To a solution of compound 3,6-dichloro-4,5-dimethylpyridazine (3.3 g, 18.5 mmol) in THF (50 mL) was added DIEA (5.26 g, 40.7 mmol) and Pd / C (10%, 0.98 g, 9.2 mmol). The reaction mixture was degassed, charged with hydrogen, and then stirred at room temperature under hydrogen atmosphere until the starting material was completely consumed. After completion, the Pd / C catalyst was removed by filtration and the filtrate was evaporated under reduced pressure. The residue was taken up in DCM (100 mL) and washed with 5% NH4OH (50 mL). The organic layer was dried over Na2SO4 and evaporated to dryness to give 4,5-dimethylpyridazine (1.4 g, 70% yield).

[0233] Step 2: Preparation of 3-[(5-methylpyridazin-4-yl)acetyl]benzonitrile (Intermediate IV-13) [ka] To a solution of 4,5-dimethylpyridazine (501 mg, 4.6 mmol) in THF (15 mL) was added LiHMDS (4.2 mL, 5.0 mmol, 20% solution in THF / ethylbenzene) under argon atmosphere at 0° C. After stirring at 0° C. for 30 min, a solution of methyl 3-cyanobenzoate (679 mg, 4.2 mmol) in THF (2 mL) was added dropwise. The reaction mixture was warmed to room temperature and stirred overnight. The mixture was diluted with hexane. The resulting solid was collected and dissolved in 1N HCl. The aqueous layer was washed with MTBE, basified with NaHCO3, and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and evaporated in vacuum to give 3-[(5-methylpyridazin-4-yl)acetyl]benzonitrile (Intermediate IV-13) (0.3 g, 30% yield). [M+H] + : 238.09, actual value: 238.4.

[0234] Preparation Example 19: Preparation of 3-[(pyrimidin-4-yl)acetyl]benzonitrile (Intermediate IV-14) [ka] To a solution of 4-methylpyrimidine (464 mg, 4.93 mmol) in THF (15 mL) was added LiHMDS (5.6 mL, 6.72 mmol, 20% solution in THF / ethylbenzene) under argon atmosphere at 0° C. After stirring at 0° C. for 30 min, a solution of methyl 3-cyanobenzoate (682 mg, 4.23 mmol) in THF (2 mL) was added dropwise. The reaction mixture was warmed to room temperature and stirred overnight. The mixture was diluted with hexane. The solid was collected, taken up in EtOAc, washed with 1N HCl and brine, then dried over Na2SO4 and evaporated in vacuo to give 3-[(pyrimidin-4-yl)acetyl]benzonitrile (Intermediate IV-14) (0.2 g, 20% yield). [M+H] + : 223.07, actual value: 223.09.

[0235] Preparation Example 20: Preparation of 3-[(pyridazin-4-yl)acetyl]benzonitrile (Intermediate IV-15) [ka] To a solution of 4-methylpyridazine (464 mg, 4.93 mmol) in THF (15 mL) was added LiHMDS (5.6 mL, 6.72 mmol, 20% solution in THF / ethylbenzene) under argon atmosphere at 0° C. After stirring at 0° C. for 30 min, a solution of methyl 3-cyanobenzoate (722 mg, 4.5 mmol) in THF (2 mL) was added dropwise. The reaction mixture was warmed to room temperature and stirred overnight. The mixture was diluted with hexane. The solid was collected and dissolved in 1N HCl. The aqueous layer was washed with MTBE, basified with NaHCO3, and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and evaporated in vacuo to give 3-[(pyridazin-4-yl)acetyl]benzonitrile (Intermediate IV-15) (0.34 g, 34% yield). [M+H] + : 224.08, actual value: 224.0.

[0236] Preparation Example 21: Preparation of 3-[(pyridin-4-yl)acetyl]benzonitrile (Intermediate IV-16) [ka] To a solution of 4-methylpyridine (461 mg, 4.95 mmol) in THF (15 mL) was added LiHMDS (4.9 mL, 5.85 mmol, 20% solution in THF / ethylbenzene) under argon atmosphere at 0° C. After stirring at 0° C. for 30 min, a solution of methyl 3-cyanobenzoate (725 mg, 4.5 mmol) in THF (2 mL) was added dropwise. The reaction mixture was warmed to room temperature and stirred overnight. The mixture was diluted with hexane. The solid was collected and dissolved in 1N HCl. The aqueous layer was washed with MTBE, basified with NaHCO3, and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and evaporated in vacuo to give 3-[(pyridin-4-yl)acetyl]benzonitrile (Intermediate IV-16) (0.6 g, 60% yield). [M+H] + : 223.08, actual value: 223.02.

[0237] Preparation Example 22: Preparation of 3-[(5-methylpyrimidin-4-yl)acetyl]benzonitrile (Intermediate IV-17) [ka] To a solution of 4,5-dimethylpyrimidine (410 mg, 3.8 mmol) in THF (15 mL) was added LiHMDS (3.8 mL, 4.55 mmol, 20% solution in THF / ethylbenzene) under argon atmosphere at 0° C. After stirring at 0° C. for 30 min, a solution of methyl 3-cyanobenzoate (611 mg, 3.8 mmol) in THF (2 mL) was added dropwise. The reaction mixture was warmed to room temperature and stirred overnight. The mixture was diluted with hexane. The solid was collected, taken up in EtOAc, washed with 1N HCl and brine, then dried over Na2SO4 and evaporated in vacuo to give 3-[(5-methylpyrimidin-4-yl)acetyl]benzonitrile (Intermediate IV-17) (0.15 g, 17% yield). [M+H] + : 238.09, actual value: 238.0.

[0238] Preparation Example 23: Preparation of 3-[(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)acetyl]benzonitrile (Intermediate IV-18) [ka] Step 1: Preparation of dimethyl[(3-cyanophenyl)(hydroxy)methyl]phosphonate [ka] 3-Formylbenzonitrile (1.09 g, 8.29 mmol) was dissolved in ethyl acetate (15 mL). Triethylamine (1.26 g, 12.4 mmol) was then added followed by dimethyl phosphite (1.19 g, 10.8 mmol) and the reaction mixture was stirred at room temperature for 2 h, then diluted with ethyl acetate (350 mL) and washed with saturated aqueous NH4Cl (2 x 30 mL). The organic layer was dried over Na2SO4 and evaporated under reduced pressure to give 1.7 g of dimethyl[(3-cyanophenyl)(hydroxy)methyl]phosphonate (85% yield). [M+H] + : 241.05, actual value: 242.2.

[0239] Step 2: Preparation of dimethyl{(3-cyanophenyl)[(oxan-2-yl)oxy]methyl}phosphonate [ka] To a solution of dimethyl[(3-cyanophenyl)(hydroxy)methyl]phosphonate (1.7 g, 7.07 mmol) in dry toluene (30 mL) was added 3,4-dihydro-2H-pyran (1.25 g, 14.8 mmol) and p-toluenesulfonic acid (37 mg, 0.2 mmol), and the reaction mixture was stirred at 50° C. under nitrogen atmosphere for 3 h. The solvent was then removed under vacuum and the residue was taken up with MTBE. The organic layer was washed with saturated NaHCO3 solution and brine, then dried over Na2SO4. The filtrate was evaporated to dryness to give dimethyl{(3-cyanophenyl)[(oxan-2-yl)oxy]methyl}phosphonate (2.2 g, 96% yield). [M+H] + : 325.11, actual value: 324.9.

[0240] Step 3: Preparation of 3-[(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)acetyl]benzonitrile (Intermediate IV-18) [ka] To a solution of dimethyl{(3-cyanophenyl)[(oxan-2-yl)oxy]methyl}phosphonate (967 mg, 3.0 mmol) in dry THF (20 mL) was added sodium hydride (187 mg, 4.46 mmol) and the mixture was stirred at room temperature for 15 min. Then 1-methyl-6-oxo-1,6-dihydropyridine-3-carbaldehyde (489 mg, 3.5 mmol) was added and the reaction mixture was stirred at 50° C. under nitrogen atmosphere for 3 h. The resulting mixture was cooled to room temperature, distilled water was added slowly and the solvent was removed under reduced pressure. The aqueous layer was extracted with MTBE and the organic layer was washed with water and brine, dried over Na2SO4 and filtered. The filtrate was evaporated to dryness to give the crude THP-protected intermediate, which was taken up in ether (10 mL), saturated ethereal HCl was added (5 mL) and the resulting mixture was stirred at ambient temperature for 1 h. The precipitated solid was collected and dried to give 3-[(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)acetyl]benzonitrile (0.35 g, 47% yield). [M+H] +: 252.09, actual value: 252.1.

[0241] Preparation Example 24: Preparation of N-(5-ethyl-1H-1,2,4-triazol-3-yl)thiourea (Intermediate III-6) [ka] Step 1: N-[(5-ethyl-1H-1,2,4-triazol-3-yl)carbamothioyl]benzamide [ka] To a stirred mixture of 5-ethyl-1H-1,2,4-triazol-3-amine (1.2 g, 10.9 mmol) in acetone (30 mL) was added benzoyl isothiocyanate (2.67 g, 16.3 mmol) at room temperature. After addition, the mixture was heated to reflux and stirred overnight. The reaction mixture was cooled to room temperature and evaporated under reduced pressure to give crude N-[(5-ethyl-1H-1,2,4-triazol-3-yl)carbamothioyl]benzamide (3.2 g), which was used in the next step without purification.

[0242] Step 2: Preparation of N-(5-ethyl-1H-1,2,4-triazol-3-yl)thiourea (Intermediate III-6) [ka] To a suspension of N-[(5-ethyl-1H-1,2,4-triazol-3-yl)carbamothioyl]benzamide (3.2 g, 11 mmol) in MeOH (40 mL) was added a solution of KOH (1.97 g, 35 mmol in 15 mL water). The reaction mixture was stirred at 60° C. for 16 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with water and EtOAc (50 / 50 mL) and acidified to pH=3 with concentrated HCl. The layers were separated. The organic layer was dried over Na2SO4, evaporated under reduced pressure, and triturated with IPA / Hex to give N-(5-ethyl-1H-1,2,4-triazol-3-yl)thiourea (Intermediate III-6) (0.2 g, 10% yield for two steps). [M+H]+: 172.06, found 172.1

[0243] Preparation Example 25: Preparation of compounds of formula I from intermediates II and III [ka] A mixture of the haloketone intermediate of formula II (0.144 g, 0.0004 mol; 1 eq.), the thiourea triazole intermediate of formula III (0.072 g, 0.0004 mol; 1 eq.), and triethylamine (0.111 g, 0.0011 mol; 2.75 eq.) in acetonitrile (2 ml) was heated to 60° C. and stirred overnight. The precipitated solid was collected, washed with water and acetonitrile, and dried to give the target compound of formula I.

[0244] Preparation Example 26: Preparation of compounds of formula I from intermediates III and IV via in situ halogenation and precipitation [ka] The ketone intermediate of formula IV (0.63 g, 2.6 mmol; 1 equiv.) was dissolved in dioxane (10 mL), followed by the addition of Br2 (0.42 g, 2.6 mmol; 1 equiv.) at room temperature. The mixture was stirred at room temperature overnight, and the thiourea triazole intermediate of formula III (0.48 g, 2.6 mmol; 1 equiv.) and EtOH (10 mL) were added. The resulting mixture was stirred overnight. The precipitated solid was collected, washed with saturated NaHCO3, water, cold MeCN, and dried to give the target compound of formula I. No further purification was required.

[0245] Preparation Example 27: Preparation of compounds of formula I from intermediates III and IV via in situ halogenation and chromatography [ka] The ketone intermediate of formula IV (0.091 g, 0.36 mmol; 1 equiv.) was dissolved in dioxane (2 mL), followed by the addition of Br2 (0.070 g, 0.44 mmol; 1.2 equiv.) at room temperature. The mixture was stirred at room temperature overnight, and the thiourea triazole intermediate of formula III (0.066 g, 0.36 mmol; 1 equiv.) and EtOH (2 mL) were added. The resulting mixture was stirred overnight. After the reaction was complete, the solution was basified with NH4OH and purified by preparative HPLC to obtain the target compound of formula I.

[0246] Preparation example 28:R A Preparation of compounds of formula I from intermediates IV and III when is A2 [ka] A mixture of ketone intermediate of formula IV (0.174 g, 0.77 mmol; 1 eq.), where A=a2, and thiourea triazole intermediate of formula III (0.142 g, 0.77 mmol; 1 eq.), iodine (0.196 g, 0.77 mmol; 1 eq.) and pyridine (2 mL) was stirred at room temperature overnight. The resulting mixture was diluted with water (50 mL). The resulting solid was filtered, stirred in water (50 mL) for 30 min and filtered again. The crude product was purified by preparative HPLC to give the title compound I, where A=a2.

[0247] Example 1: Preparation of 5-cyclobutyl-N-[4-(2-fluorophenyl)-5-(3-fluoropyridin-4-yl)-1,3-thiazol-2-yl]-1H-1,2,4-triazol-3-amine (Compound 1) [ka] Compound 1 was prepared from 2-bromo-1-(2-fluorophenyl)-2-(3-fluoropyridin-4-yl)ethan-1-one hydrobromide (intermediate II-1) and N-(5-cyclobutyl-1H-1,2,4-triazol-3-yl)thiourea (intermediate III-1) according to Preparation 25. Scale: 0.4 mmol.

[0248] Specifically, to a solution of triethylamine (0.111 g; 1.1 mmol) in acetonitrile (2 mL), 2-bromo-1-(2-fluorophenyl)-2-(3-fluoropyridin-4-yl)ethan-1-one hydrobromide (0.124 g; 0.4 mmol) and N-(5-cyclobutyl-1H-1,2,4-triazol-3-yl)thiourea (79 mg; 0.4 mmol) were added. The mixture was heated to 60° C. and stirred overnight. The precipitated solid was collected, washed with water and acetonitrile, and dried under vacuum to give compound 1 (5-cyclobutyl-N-[4-(2-fluorophenyl)-5-(3-fluoropyridin-4-yl)-1,3-thiazol-2-yl]-1H-1,2,4-triazol-3-amine; 0.046 g; 31% yield).

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[0249] Example 2: Preparation of 3-{2-[(5-cyclopropyl-1H-1,2,4-triazol-3-yl)amino]-5-(3-fluoropyridin-4-yl)-1,3-thiazol-4-yl}benzonitrile (compound 2) [ka] Compound 2 was prepared from 3-[(3-fluoropyridin-4-yl)acetyl]benzonitrile (Intermediate IV-2), Br2, and N-(5-cyclopropyl-1H-1,2,4-triazol-3-yl)thiourea (Intermediate III-2) according to Preparation 26. Scale: 2.6 mmol.

[0250] Specifically, 3-[(3-fluoropyridin-4-yl)acetyl]benzonitrile (0.63 g, 2.6 mmol) was dissolved in dioxane (10 mL), followed by the addition of Br2 (0.42 g, 2.6 mmol) at room temperature. The mixture was stirred overnight at room temperature, and N-(5-cyclopropyl-1H-1,2,4-triazol-3-yl)thiourea (0.48 g, 2.6 mmol) and EtOH (10 mL) were added. The resulting mixture was stirred overnight. The precipitated solid was collected, washed with saturated NaHCO3, water, cold MeCN, and dried under vacuum to give compound 2 (3-{2-[(5-cyclopropyl-1H-1,2,4-triazol-3-yl)amino]-5-(3-fluoropyridin-4-yl)-1,3-thiazol-4-yl}benzonitrile; 0.32 g; 30% yield).

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[0251] Example 3: Preparation of 3-{2-[(5-cyclopropyl-1H-1,2,4-triazol-3-yl)amino]-5-(3-methylpyridin-4-yl)-1,3-thiazol-4-yl}benzonitrile (compound 3) [ka] Compound 3 was prepared from 3-[(3-methylpyridin-4-yl)acetyl]benzonitrile (Intermediate IV-3), Br2, and N-(5-cyclopropyl-1H-1,2,4-triazol-3-yl)thiourea (Intermediate III-2) according to Preparation 26. Scale: 1 mmol. 0.09 g; yield 23%.

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[0252] Example 4: Preparation of 3-{2-[(5-cyclopropyl-1H-1,2,4-triazol-3-yl)amino]-5-(2,5-dimethylpyridin-4-yl)-1,3-thiazol-4-yl}benzonitrile (compound 4) [ka] Compound 4 was prepared from 3-[(2,5-dimethylpyridin-4-yl)acetyl]benzonitrile (Intermediate IV-4)Br2 and N-(5-cyclopropyl-1H-1,2,4-triazol-3-yl)thiourea (Intermediate III-2) according to Preparation 27. Scale: 0.36 mmol.

[0253] Specifically, 3-[(2,5-dimethylpyridin-4-yl)acetyl]benzonitrile (0.091 g, 0.36 mmol) was dissolved in dioxane (2 mL), followed by the addition of Br2 (0.070 g, 0.44 mmol) at room temperature. The mixture was stirred overnight at room temperature, and N-(5-cyclopropyl-1H-1,2,4-triazol-3-yl)thiourea (0.066 g, 0.36 mmol) and EtOH (2 mL) were added. The resulting mixture was stirred overnight. After the reaction was complete, the solution was quenched with NH4OH and purified by preparative HPLC to give compound 4 (0.022 g; yield 15%).

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[0254] Example 5: Preparation of 3-[5-(3-chloropyridin-4-yl)-2-[(5-cyclopropyl-1H-1,2,4-triazol-3-yl)amino]-1,3-thiazol-4-yl]benzonitrile (compound 5) [ka] Compound 5 was prepared from 3-[(3-chloropyridin-4-yl)acetyl]benzonitrile (Intermediate IV-5), Br2, and N-(5-cyclopropyl-1H-1,2,4-triazol-3-yl)thiourea (Intermediate III-2) according to Preparation 26. Scale: 1.8 mmol; 0.32 g; yield 43%.

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[0255] Example 6: Preparation of 3-{2-[(5-cyclopropyl-1H-1,2,4-triazol-3-yl)amino]-5-(2,3-dimethylpyridin-4-yl)-1,3-thiazol-4-yl}benzonitrile (compound 6) [ka] Compound 6 was prepared from 3-[(2,3-dimethylpyridin-4-yl)acetyl]benzonitrile (Intermediate IV-6), Br2, and N-(5-cyclopropyl-1H-1,2,4-triazol-3-yl)thiourea (Intermediate III-2) according to Preparation 27. Scale: 0.22 mmol; 0.023 g; yield 25%.

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[0256] Example 7: Preparation of 3-{2-[(5-cyclopropyl-1H-1,2,4-triazol-3-yl)amino]-5-(2-methylpyridin-4-yl)-1,3-thiazol-4-yl}benzonitrile (compound 7) [ka] Compound 7 was prepared from 3-[(2-methylpyridin-4-yl)acetyl]benzonitrile (Intermediate IV-7), Br2, and N-(5-cyclopropyl-1H-1,2,4-triazol-3-yl)thiourea (Intermediate III-2) according to Preparation 27. Scale: 0.45 mmol; 0.027 g; yield 15%.

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[0257] Example 8: Preparation of 3-{2-[(5-cyclopropyl-1H-1,2,4-triazol-3-yl)amino]-5-(2-methyl-1H-imidazol-1-yl)-1,3-thiazol-4-yl}benzonitrile (compound 8) [ka] Compound 8 was prepared from 3-[(2-methyl-1H-imidazol-1-yl)acetyl]benzonitrile (Intermediate IV-8), I2, and N-(5-cyclopropyl-1H-1,2,4-triazol-3-yl)thiourea (Intermediate III-2) according to Preparation 28. Scale: 0.77 mmol.

[0258] Specifically, a mixture of 3-[(2-methyl-1H-imidazol-1-yl)acetyl]benzonitrile (0.174 g, 0.77 mmol), N-(5-cyclopropyl-1H-1,2,4-triazol-3-yl)thiourea (0.142 g, 0.77 mmol), iodine (0.196 g, 0.77 mmol), and pyridine (2 mL) was stirred at room temperature overnight. The resulting mixture was diluted with water (50 mL). The resulting solid was filtered, stirred in water (50 mL) for 30 min, and filtered again. The crude product was purified by preparative HPLC to give compound 8 (0.022 g, 7.3% yield).

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[0259] Example 9: Preparation of 3-[5-(2-methyl-1H-imidazol-1-yl)-2-[(1H-1,2,4-triazol-3-yl)amino]-1,3-thiazol-4-yl]benzonitrile (Compound 9) [ka] Compound 9 was prepared from 3-[(2-methyl-1H-imidazol-1-yl)acetyl]benzonitrile (Intermediate IV-8), I2, and N-1H-1,2,4-triazol-3-ylthiourea (Intermediate III-3) according to Preparation Example 28. Scale: 0.57 mmol; 0.047 g, yield 23%.

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[0260] Example 10: Preparation of 3-{2-[(5-methyl-1H-1,2,4-triazol-3-yl)amino]-5-(2-methyl-1H-imidazol-1-yl)-1,3-thiazol-4-yl}benzonitrile (compound 10) [ka] Compound 10 was prepared from 3-[(2-methyl-1H-imidazol-1-yl)acetyl]benzonitrile (Intermediate IV-8), I2, and N-(5-methyl-1H-1,2,4-triazol-3-yl)thiourea (Intermediate III-4) according to Preparation Example 28. Scale: 0.55 mmol; 0.046 g, yield 23%.

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[0261] Example 11: Preparation of 3-(2-{[5-(hydroxymethyl)-1H-1,2,4-triazol-3-yl]amino}-5-(2-methyl-1H-imidazol-1-yl)-1,3-thiazol-4-yl)benzonitrile (compound 11) [ka] Compound 11 was prepared from 3-[(2-methyl-1H-imidazol-1-yl)acetyl]benzonitrile (Intermediate IV-8), I2, and N-[5-(hydroxymethyl)-1H-1,2,4-triazol-3-yl]thiourea (Intermediate III-5) according to Preparation Example 28. Scale: 0.55 mmol; 0.069 g, yield 34%.

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[0262] Example 12: Preparation of 3-[5-(2,5-dimethylpyridin-4-yl)-2-[(1H-1,2,4-triazol-3-yl)amino]-1,3-thiazol-4-yl]benzonitrile (compound 12) [ka] Compound 12 was prepared from 3-[(2,5-dimethylpyridin-4-yl)acetyl]benzonitrile (Intermediate IV-4), Br2, and N-1H-1,2,4-triazol-3-ylthiourea (Intermediate III-3) according to Preparation Example 27. Scale 0.27 mmol; 0.039 g; Yield 39%.

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[0263] Example 13: Preparation of 3-[5-(2,5-dimethylpyridin-4-yl)-2-[(5-methyl-1H-1,2,4-triazol-3-yl)amino]-1,3-thiazol-4-yl]benzonitrile (compound 13) [ka] Compound 13 was prepared from 3-[(2,5-dimethylpyridin-4-yl)acetyl]benzonitrile (Intermediate IV-4), Br2, and N-(5-methyl-1H-1,2,4-triazol-3-yl)thiourea (Intermediate III-4) according to Preparation 27. Scale: 0.26 mmol; 0.013 g; Yield 13%.

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[0264] Example 14: Preparation of 3-[5-(2,5-dimethylpyridin-4-yl)-2-{[5-(hydroxymethyl)-1H-1,2,4-triazol-3-yl]amino}-1,3-thiazol-4-yl]benzonitrile (compound 14) [ka] Compound 14 was prepared from 3-[(2,5-dimethylpyridin-4-yl)acetyl]benzonitrile (Intermediate IV-4), Br2, and N-[5-(hydroxymethyl)-1H-1,2,4-triazol-3-yl]thiourea (Intermediate III-5) according to Preparation Example 27. Scale: 0.25 mmol; 0.041 g; Yield 41%.

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[0265] Example 15: Preparation of 3-{2-[(5-cyclopropyl-1H-1,2,4-triazol-3-yl)amino]-5-(1H-1,2,4-triazol-1-yl)-1,3-thiazol-4-yl}benzonitrile (compound 15) [ka] Compound 15 was prepared from 3-[(1H-1,2,4-triazol-1-yl)acetyl]benzonitrile (Intermediate IV-9), I2, and N-(5-cyclopropyl-1H-1,2,4-triazol-3-yl)thiourea (Intermediate III-2) according to Preparation 28. Scale: 0.4 mmol; 0.013 g, yield 9%.

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[0266] Example 16: Preparation of 3-[5-(2-ethyl-1H-imidazol-1-yl)-2-[(5-methyl-1H-1,2,4-triazol-3-yl)amino]-1,3-thiazol-4-yl]benzonitrile (compound 16) [ka] Compound 16 was prepared from 3-[(2-ethyl-1H-imidazol-1-yl)acetyl]benzonitrile (Intermediate IV-10), I2, and N-(5-methyl-1H-1,2,4-triazol-3-yl)thiourea (Intermediate III-4) according to Preparation Example 28. Scale: 0.53 mmol; 0.038 g, yield 19%.

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[0267] Example 17: Preparation of 3-{2-[(5-cyclopropyl-1H-1,2,4-triazol-3-yl)amino]-5-[2-(hydroxymethyl)-1H-imidazol-1-yl]-1,3-thiazol-4-yl}benzonitrile (compound 17) [ka] Compound 17 was prepared from 3-{[2-(hydroxymethyl)-1H-imidazol-1-yl]acetyl}benzonitrile (Intermediate IV-11), I2, and N-(5-cyclopropyl-1H-1,2,4-triazol-3-yl)thiourea (Intermediate III-2) according to Preparation Example 28. Scale: 0.5 mmol; 0.041 g, yield 20%.

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[0268] Example 18: Preparation of 3-{2-[(5-cyclopropyl-1H-1,2,4-triazol-3-yl)amino]-5-(2-methyl-1H-imidazol-1-yl)-1,3-thiazol-4-yl}-4-fluorobenzonitrile (compound 18) [ka] Compound 18 was prepared from 4-fluoro-3-[(2-methyl-1H-imidazol-1-yl)acetyl]benzonitrile (Intermediate IV-12), I2, and N-(5-cyclopropyl-1H-1,2,4-triazol-3-yl)thiourea (Intermediate III-2) according to Preparation 28. Scale: 1.1 mmol; 0.022 g, yield 7.3%.

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[0269] Example 19: Preparation of 3-{5-[2-(hydroxymethyl)-1H-imidazol-1-yl)-2-[(1H-1,2,4-triazol-3-yl)amino]-1,3-thiazol-4-yl}benzonitrile (compound 19) [ka] Compound 19 was prepared from 3-{[2-(hydroxymethyl)-1H-imidazol-1-yl]acetyl}benzonitrile (Intermediate IV-11), I2, and N-1H-1,2,4-triazol-3-ylthiourea (Intermediate III-3) according to Preparation Example 28. Scale: 0.41 mmol; 0.025 g, 17% yield.

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[0270] Example 20: Preparation of 3-{2-[(5-ethyl-1H-1,2,4-triazol-3-yl)amino]-5-[2-(hydroxymethyl)-1H-imidazol-1-yl]-1,3-thiazol-4-yl}benzonitrile (Compound 20) [ka] Compound 20 was prepared from 3-{[2-(hydroxymethyl)-1H-imidazol-1-yl]acetyl}benzonitrile (Intermediate IV-11), I2, and N-(5-ethyl-1H-1,2,4-triazol-3-yl)thiourea (Intermediate III-6) according to Preparation Example 28. Scale: 0.51 mmol; 0.045 g, yield 22%.

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[0271] Example 21: Preparation of 3-{5-[2-(hydroxymethyl)-1H-imidazol-1-yl]-2-[(5-methyl-1H-1,2,4-triazol-3-yl)amino]-1,3-thiazol-4-yl}benzonitrile (compound 21) [ka] Compound 21 was prepared from 3-{[2-(hydroxymethyl)-1H-imidazol-1-yl]acetyl}benzonitrile (Intermediate IV-11), I2, and N-(5-methyl-1H-1,2,4-triazol-3-yl)thiourea (Intermediate III-4) according to Preparation Example 28. Scale: 0.4 mmol; 0.015 g, yield 10%.

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[0272] Example 22: Preparation of 3-{5-(3-methylpyridin-4-yl)-2-[(1H-1,2,4-triazol-3-yl)amino]-1,3-thiazol-4-yl}benzonitrile (Compound 22) [ka] Compound 22 was prepared from 3-[(3-methylpyridin-4-yl)acetyl]benzonitrile (intermediate IV-3)Br2 and N-1H-1,2,4-triazol-3-ylthiourea (intermediate III-3) according to Preparation 27. Scale: 0.84 mmol; 0.035 g, yield 12%.

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[0273] Example 23: Preparation of 3-{2-[(5-cyclopropyl-1H-1,2,4-triazol-3-yl)amino]-5-(5-methylpyridazin-4-yl)-1,3-thiazol-4-yl}benzonitrile (compound 23) [ka] Compound 23 was prepared from 3-[(5-methylpyridazin-4-yl)acetyl]benzonitrile (Intermediate IV-13), Br2, and N-(5-cyclopropyl-1H-1,2,4-triazol-3-yl)thiourea (Intermediate III-2) according to Preparation 27. Scale: 0.62 mmol; 0.058 g, yield 23%.

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[0274] Example 24: Preparation of 3-{2-[(5-cyclopropyl-1H-1,2,4-triazol-3-yl)amino]-5-(pyrimidin-4-yl)-1,3-thiazol-4-yl}benzonitrile (Compound 24) [ka] Compound 24 was prepared from 3-[(pyrimidin-4-yl)acetyl]benzonitrile (intermediate IV-14), Br2, and N-(5-cyclopropyl-1H-1,2,4-triazol-3-yl)thiourea (intermediate III-2) according to Preparation Example 27. Scale: 0.78 mmol; 0.045 g, yield 15%.

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[0275] Example 25: Preparation of 3-{2-[(5-cyclopropyl-1H-1,2,4-triazol-3-yl)amino]-5-(pyridazin-4-yl)-1,3-thiazol-4-yl}benzonitrile (Compound 25) [ka] Compound 25 was prepared from 3-[(pyridazin-4-yl)acetyl]benzonitrile (intermediate IV-15), Br2, and N-(5-cyclopropyl-1H-1,2,4-triazol-3-yl)thiourea (intermediate III-2) according to Preparation 27. Scale: 0.78 mmol; 0.039 g, yield 13%.

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[0276] Example 26: Preparation of 3-{2-[(5-cyclopropyl-1H-1,2,4-triazol-3-yl)amino]-5-(pyridin-4-yl)-1,3-thiazol-4-yl}benzonitrile (compound 26) [ka] Compound 26 was prepared from 3-[(pyridin-4-yl)acetyl]benzonitrile (intermediate IV-16), Br2, and N-(5-cyclopropyl-1H-1,2,4-triazol-3-yl)thiourea (intermediate III-2) according to Preparation 27. Scale: 0.9 mmol; 0.075 g, yield 25%.

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[0277] Example 27: Preparation of 3-{2-[(5-cyclopropyl-1H-1,2,4-triazol-3-yl)amino]-5-(5-methylpyrimidin-4-yl)-1,3-thiazol-4-yl}benzonitrile (compound 27) [ka] Compound 27 was prepared from 3-[(5-methylpyrimidin-4-yl)acetyl]benzonitrile (Intermediate IV-17), Br2, and N-(5-cyclopropyl-1H-1,2,4-triazol-3-yl)thiourea (Intermediate III-2) according to Preparation 27. Scale: 0.62 mmol; 0.033 g, yield 13%.

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[0278] Example 28: Preparation of 3-{2-[(5-cyclopropyl-1H-1,2,4-triazol-3-yl)amino]-5-(2-ethyl-1H-imidazol-1-yl)-1,3-thiazol-4-yl}benzonitrile (compound 28) [ka] Compound 28 was prepared from 3-[(2-ethyl-1H-imidazol-1-yl)acetyl]benzonitrile (Intermediate IV-10), I2, and N-(5-cyclopropyl-1H-1,2,4-triazol-3-yl)thiourea (Intermediate III-2) according to Preparation 28. Scale: 0.4 mmol; 0.015 g, yield 10%.

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[0279] Example 29: Preparation of 3-{2-[(5-cyclopropyl-1H-1,2,4-triazol-3-yl)amino]-5-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1,3-thiazol-4-yl}benzonitrile (compound 29) [ka] Compound 29 was prepared from 3-[(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)acetyl]benzonitrile (Intermediate IV-18), I2, and N-(5-cyclopropyl-1H-1,2,4-triazol-3-yl)thiourea (Intermediate III-2) according to Preparation 28. Scale: 0.24 mmol; 0.017 g, 17% yield.

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[0280] Example 30: Intracellular cAMP functional assay of compounds of formula I Human adenosine receptor A was assayed in this functional cell assay using the HTRF kit (Perkin Elmer). 2A , A 2BCompound activity in A1 and A3 was measured. Prior to testing, HEK293 cells expressing recombinant human adenosine receptors were grown in antibiotic-free medium, detached by gentle flushing with PBS-EDTA (5 mM EDTA), harvested by centrifugation, and resuspended in assay buffer (KRH: supplemented with 5 mM KCl, 1.25 mM MgSO4, 124 mM NaCl, 25 mM HEPES, 13.3 mM glucose, 1.25 mM KH2PO4, 1.45 mM CaCl2, 0.5 g / l BSA, 1 mM IBMX or 25 μM Rolipram). Dose-response curves were performed in parallel with reference compounds. A 2A , A 2B The reference compounds used for A1, A2 and A3 were NECA, ZM241385, DPCPX, and MRS, respectively. 12 μl of cells were mixed with 6 μl of test compounds at increasing concentrations and then incubated for 10 min. After that, 6 μl of reference agonist was added to the historical EC 80 (historical EC 80 ) at a final concentration corresponding to the adenosine receptor. The plate was then incubated at room temperature for 30 minutes. After addition of lysis buffer and incubation for 1 hour, cAMP concentrations were estimated using an HTRF kit according to the manufacturer's specifications. Results showing the functional activity of the embodied compounds on adenosine receptors are shown in Table 1 below.

[0281] Example 31: Radioligand binding assay Adenosine receptor A1, A 2A , A 2BFiltration binding assays were performed for A and A3. Radioligand binding competition assays were performed in duplicate in wells of a 96-well plate (Master Block, Greiner, 786201) containing binding buffer, receptor membrane extract, a fixed concentration of tracer, and increasing concentrations of test compound. To eliminate the influence of buffer components, the binding buffer was the same for all four receptors and contained 50 mM Tris-HCl pH 7.4, 5 mM MgCl, 1 mM EDTA, 150 mM NaCl, 0.1% Na-azide, and 5 U / ml adenosine-deaminase. Nonspecific binding was minimized by co-incubation with a 200-fold excess of cold competitor. For all radioligand binding experiments, samples were incubated in a final volume of 0.1 ml of binding buffer for 60 min at 25°C and then filtered through Unifilter plates (Perkin Elmer) that had been pretreated for 2 h to limit tracer nonspecific binding. Filters were washed five times with 0.5 ml of ice-cold wash buffer (50 mM Tris-HCl pH 7.4, 5 mM MgCl, 1 mM EDTA) and 50 μL of Microscint 20 (Perkin Elmer) was added to each filter. Plates were incubated for 15 minutes at room temperature on an orbital shaker and then counted for 1 minute / well using a TopCount™.

[0282] For the A1 receptor, assays were performed using [3H]-DPCPX and membranes from CHO-K1 cells transfected with the human A1 receptor (Euroscreen FAST-001B).

[0283] A 2A The receptors were [3H-NECA and human A 2A The assay was performed using membranes from receptor-transfected HEK293 cells (Euroscreen FAST-002B).

[0284] A 2B The receptors were [3H]-DPCPX and human A 2BThe assay was performed using membranes prepared from receptor-transfected HEK293 cells (Euroscreen FAST-003B).

[0285] For the A3 receptor, assays were performed using [125IJ-MECA and membranes from CHO-K1 cells transfected with the human A3 receptor (Euroscreen FAST-004B).

[0286] Table 1 shows the in vitro cAMP binding activity of embodied compounds as measured by a functional cAMP accumulation assay in HEK293 cells (Example 30) and a radioligand binding assay (Example 31). Table 1 also shows the binding affinity of embodied compounds to the human A1 receptor versus the human A3 receptor. 2B The results showed that the A receptor is more potent than the A3 receptor. 2B (and A1) receptors. [Table 2]

[0287] Example 32: CPM Thermostability Assay Using the CPM thermostability assay (A.I. Alexandrov et al., 2008, Structure 16, 351-359), 2B / A 2A Compounds of the present invention were screened for receptor binding and stabilization. Protein concentration in the reaction was 1 μM, while compound concentration for the data shown was 10 μM. The final concentration of CPM dye (Invitrogen D346) in the reaction was 7.5 μg / ml. 2B The reaction buffer was 40 mM Tris-HCl pH 7.4, 200 mM NaCl, 0.05% DDM, and 0.005% CHS. 2AThe reaction buffer for was 40 mM Tris-HCl pH 7.4, 200 mM NaCl, and 0.15% DDM. Compounds were incubated with purified receptor for 30 min on ice to allow binding, after which CPM dye was added. Measurements were performed using a Rotor-Gene Q qPCR instrument (QIAGEN). Temperature was ramped from 25°C to 90°C with an increase of 6°C per minute. Gain was set to the first sample in the run, which was always the protein without ligand, used as the reference. CPM dye binding was monitored using 365 nm excitation and 460 nm emission. Data was analyzed using the instrument software and melting temperatures were calculated as the average of each replicate (replicates did not differ by more than 0.5°C on average). Melting temperatures (ΔT m The increase in the thermal shift of each compound was calculated. The results are shown in Table 2 below. [Table 3]

Claims

1. Compounds of Formula I: 【Chemistry 1】 (In the formula, R １ is H, halogen, -C １ -C ８ Alkyl, -C ３ -C ８ Cycloalkyl, —O—C １ -C ８ alkyl, or -CN, each alkyl, cycloalkyl, or -O-alkyl being selected from one or more R ２ may be substituted by R ２ represents independently at each occurrence a halogen, —OH, and —OC １ -C ８ alkyl, R Ａ is a 5-6 membered heteroaryl, said heteroaryl being selected from one or more R Ａ１ may be substituted by R Ａ１ is independently, at each occurrence, halogen, —OH, oxo, cyano, —C １ -C ８ Alkyl, -C ３ -C ８ Cycloalkyl, and —O—C １ -C ８ alkyl, each alkyl, cycloalkyl, or -O-alkyl is selected from one or more R Ａ２ may be substituted by R Ａ２ represents independently at each occurrence a halogen, -OC １ -C ８ alkyl, or -OH; R Ｂ is phenyl or 5-6 membered heteroaryl, each phenyl or heteroaryl being selected from one or more R Ｂ１ may be substituted by R Ｂ１ is independently, at each occurrence, a halogen, —OH, cyano, —C １ -C ８ Alkyl, and —O—C １ -C ８ alkyl, each alkyl, and —O-alkyl being selected from one or more R Ｂ２ may be substituted by R Ｂ２ is independently at each occurrence a halogen, —OH, or —OC １ -C ８ is alkyl) or a pharma- ceutically acceptable salt, solvate or hydrate thereof.

2. R １ H, halogen, -C １ -C ８ Alkyl, -C ３ -C ８ Cycloalkyl, or -OC １ -C ８ alkyl, each alkyl, cycloalkyl, or -O-alkyl is selected from one or more R ２ The compound of claim 1, optionally substituted by:

3. R ２ is -OH, halogen, or -OC １ -C ４ The compound according to any one of claims 1 to 2, which is alkyl.

4. R Ａ is imidazolyl, triazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl, each imidazolyl, triazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl being selected from the group consisting of one or more R Ａ１ The compound according to any one of claims 1 to 3, optionally substituted by:

5. R Ａ１ are independently halogen, —OH, —C １ -C ４ Alkyl, or -C ３ -C ６ The compound according to any one of claims 1 to 4, wherein each alkyl or cycloalkyl is optionally substituted by one or more halogens or -OH.

6. R Ａ but the following: 【Chemistry 2】 (In the formula, X is -CH- or N; R Ａ３ is independently, at each occurrence, hydrogen, halogen, -C １ -C ８ Alkyl, -C １ -C ８ Haloalkyl, -C １ -C ８ Alkoxy, -C １ -C ８ Hydroxyalkyl, and -C １ -C ８ 1 to 3 identical or different substituents selected from alkoxyalkyl; R Ａ４ is independently, at each occurrence, hydrogen, halogen, -C １ -C ８ Alkyl, -C ３ -C ８ Cycloalkyl, -C １ -C ８ Hydroxyalkyl, and -C １ -C ８ is an alkoxyalkyl group. The compound according to any one of claims 1 to 5, selected from:

7. R Ｂ is selected from phenyl, oxazolyl, pyridinyl, pyrimidinyl, pyridazinyl, and pyrazinyl, each of which is selected from one or more of R Ｂ１ The compound according to any one of claims 1 to 6, optionally substituted by:

8. R Ｂ１ is halogen, -OH, cyano, -C １ -C ４ Alkyl, and -C １ -C ４ alkoxy, each alkyl and alkoxy being selected from one or more of halogen, —OH, or —OC １ -C ４ The compound of any one of claims 1 to 7, independently substituted with alkoxy.

9. R Ｂ but the following: 【Chemistry 3】 (In the formula, R Ｂ３ independently at each occurrence, hydrogen, halogen, -C １ -C ８ Alkyl, -C １ -C ８ Haloalkyl, -C １ -C ８ Alkoxy, -C １ -C ８ Hydroxyalkyl, -C １ -C ８ -alkoxyalkyl, and -CN. The compound according to any one of claims 1 to 8, selected from:

10. R Ｂ But one or two R Ｂ１ phenyl substituted by R Ｂ１ The compound of any one of claims 1 to 9, wherein, independently at each occurrence, is cyano or fluoro.

11. Formula Ia3b or Ia2b: 【Chemistry 4】 (In the formula, R １ H, halogen, -C １ -C ８ Alkyl, -C ３ -C ８ Cycloalkyl, —O—C １ -C ８ alkyl, or -CN, each alkyl, cycloalkyl, or -O-alkyl being selected from one or more R ２ may be substituted by R ２ independently at each occurrence, halogen, —OH, and —OC １ -C ８ alkyl, X is -CH- or N; Y is independently at each occurrence -CH- or N, and at least one of the Y's is -CH-; R Ａ３ independently at each occurrence, hydrogen, halogen, -C １ -C ８ Alkyl, -C １ -C ８ Haloalkyl, -C １ -C ８ Alkoxy, -C １ -C ８ Hydroxyalkyl, and -C １ -C ８ 1 to 3 identical or different substituents selected from alkoxyalkyl; R Ａ４ independently at each occurrence, hydrogen, halogen, -C １ -C ８ Alkyl, -C ３ -C ８ Cycloalkyl, -C １ -C ８ Hydroxyalkyl, and -C １ -C ８ is an alkoxyalkyl; R Ｂ is phenyl or 5-6 membered heteroaryl, each phenyl or heteroaryl being selected from one or more R Ｂ１ may be substituted by R Ｂ１ independently at each occurrence, halogen, —OH, cyano, —C １ -C ８ Alkyl, and —O—C １ -C ８ alkyl, each alkyl, and —O-alkyl being selected from one or more R Ｂ２ may be substituted by R Ｂ２ is independently at each occurrence a halogen, —OH, or —OC １ -C ８ is alkyl) The compound according to any one of claims 1 to 10,

12. Formula Ia1b1, Ia1b2, Ia1b3, Ia2b1, Ia2b2, Ia2b3, Ia3b1, Ia3b2 or Ia3b3: 【Chemistry 5】 (In the formula, R １ H, halogen, -C １ -C ８ Alkyl, -C ３ -C ８ Cycloalkyl, —O—C １ -C ８ alkyl, or -CN, each alkyl, cycloalkyl, or -O-alkyl being selected from one or more R ２ may be substituted by R ２ independently at each occurrence, halogen, —OH, and —OC １ -C ８ alkyl, X is -CH- or N; Y is independently at each occurrence -CH- or N, and at least one of the Y's is -CH-; R Ａ３ independently at each occurrence, hydrogen, halogen, -C １ -C ８ Alkyl, -C １ -C ８ Haloalkyl, -C １ -C ８ Alkoxy, -C １ -C ８ Hydroxyalkyl, and -C １ -C ８ 1 to 3 identical or different substituents selected from alkoxyalkyl; R Ａ４ independently at each occurrence, hydrogen, halogen, -C １ -C ８ Alkyl, -C ３ -C ８ Cycloalkyl, -C １ -C ８ Hydroxyalkyl, and -C １ -C ８ is an alkoxyalkyl; R Ｂ３ independently at each occurrence, hydrogen, halogen, -C １ -C ８ Alkyl, -C １ -C ８ Haloalkyl, -C １ -C ８ Alkoxy, -C １ -C ８ Hydroxyalkyl, -C １ -C ８ -alkoxyalkyl, and -CN. The compound according to any one of claims 1 to 11,

13. below: 5-cyclobutyl-N-[4-(2-fluorophenyl)-5-(3-fluoropyridin-4-yl)-1,3-thiazol-2-yl]-1H-1,2,4-triazol-3-amine; 3-[5-(3-chloropyridin-4-yl)-2-[(5-cyclopropyl-1H-1,2,4-triazol-3-yl)amino]-1,3-thiazol-4-yl]benzonitrile; 3-{2-[(5-cyclopropyl-1H-1,2,4-triazol-3-yl)amino]-5-(3-fluoropyridin-4-yl)-1,3-thiazol-4-yl}benzonitrile; 3-{2-[(5-cyclopropyl-1H-1,2,4-triazol-3-yl)amino]-5-(2,5-dimethylpyridin-4-yl)-1,3-thiazol-4-yl}benzonitrile; 3-{2-[(5-cyclopropyl-1H-1,2,4-triazol-3-yl)amino]-5-(3-methylpyridin-4-yl)-1,3-thiazol-4-yl}benzonitrile; 3-{2-[(5-cyclopropyl-1H-1,2,4-triazol-3-yl)amino]-5-(2,3-dimethylpyridin-4-yl)-1,3-thiazol-4-yl}benzonitrile; 3-{2-[(5-cyclopropyl-1H-1,2,4-triazol-3-yl)amino]-5-(2-methyl-1H-imidazol-1-yl)-1,3-thiazol-4-yl}benzonitrile; 3-{2-[(5-cyclopropyl-1H-1,2,4-triazol-3-yl)amino]-5-(2-methylpyridin-4-yl)-1,3-thiazol-4-yl}benzonitrile; 3-[5-(2-methyl-1H-imidazol-1-yl)-2-[(1H-1,2,4-triazol-3-yl)amino]-1,3-thiazol-4-yl]benzonitrile; 3-{2-[(5-methyl-1H-1,2,4-triazol-3-yl)amino]-5-(2-methyl-1H-imidazol-1-yl)-1,3-thiazol-4-yl}benzonitrile; 3-(2-{[5-(hydroxymethyl)-1H-1,2,4-triazol-3-yl]amino}-5-(2-methyl-1H-imidazol-1-yl)-1,3-thiazol-4-yl)benzonitrile; 3-[5-(2,5-dimethylpyridin-4-yl)-2-[(1H-1,2,4-triazol-3-yl)amino]-1,3-thiazol-4-yl]benzonitrile; 3-[5-(2,5-dimethylpyridin-4-yl)-2-[(5-methyl-1H-1,2,4-triazol-3-yl)amino]-1,3-thiazol-4-yl]benzonitrile; 3-[5-(2,5-dimethylpyridin-4-yl)-2-{[5-(hydroxymethyl)-1H-1,2,4-triazol-3-yl]amino}-1,3-thiazol-4-yl]benzonitrile; 3-{2-[(5-cyclopropyl-1H-1,2,4-triazol-3-yl)amino]-5-(1H-1,2,4-triazol-1-yl)-1,3-thiazol-4-yl}benzonitrile; 3-[5-(2-ethyl-1H-imidazol-1-yl)-2-[(5-methyl-1H-1,2,4-triazol-3-yl)amino]-1,3-thiazol-4-yl]benzonitrile; 3-{2-[(5-cyclopropyl-1H-1,2,4-triazol-3-yl)amino]-5-[2-(hydroxymethyl)-1H-imidazol-1-yl]-1,3-thiazol-4-yl}benzonitrile; 3-{2-[(5-cyclopropyl-1H-1,2,4-triazol-3-yl)amino]-5-(2-methyl-1H-imidazol-1-yl)-1,3-thiazol-4-yl}-4-fluorobenzonitrile; 3-{5-[2-(hydroxymethyl)-1H-imidazol-1-yl)-2-[(1H-1,2,4-triazol-3-yl)amino]-1,3-thiazol-4-yl}benzonitrile; 3-{2-[(5-ethyl-1H-1,2,4-triazol-3-yl)amino]-5-[2-(hydroxymethyl)-1H-imidazol-1-yl]-1,3-thiazol-4-yl}benzonitrile; 3-{5-[2-(hydroxymethyl)-1H-imidazol-1-yl]-2-[(5-methyl-1H-1,2,4-triazol-3-yl)amino]-1,3-thiazol-4-yl}benzonitrile; 3-[5-(3-methylpyridin-4-yl)-2-[(1H-1,2,4-triazol-3-yl)amino]-1,3-thiazol-4-yl]benzonitrile; 3-{2-[(5-cyclopropyl-1H-1,2,4-triazol-3-yl)amino]-5-(5-methylpyridazin-4-yl)-1,3-thiazol-4-yl}benzonitrile; 3-{2-[(5-cyclopropyl-1H-1,2,4-triazol-3-yl)amino]-5-(pyrimidin-4-yl)-1,3-thiazol-4-yl}benzonitrile; 3-{2-[(5-cyclopropyl-1H-1,2,4-triazol-3-yl)amino]-5-(pyridazin-4-yl)-1,3-thiazol-4-yl}benzonitrile; 3-{2-[(5-cyclopropyl-1H-1,2,4-triazol-3-yl)amino]-5-(pyridin-4-yl)-1,3-thiazol-4-yl}benzonitrile; 3-{2-[(5-cyclopropyl-1H-1,2,4-triazol-3-yl)amino]-5-(5-methylpyrimidin-4-yl)-1,3-thiazol-4-yl}benzonitrile; m-[2-(5-cyclopropyl-1H-1,2,4-triazol-3-ylamino)-5-(2-ethyl-1-imidazolyl)-1,3-thiazol-4-yl]benzonitrile; and 3-{2-[(5-cyclopropyl-1H-1,2,4-triazol-3-yl)amino]-5-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1,3-thiazol-4-yl}benzonitrile 2. The compound of claim 1 , selected from:

14. A pharmaceutical composition comprising a compound according to any one of claims 1 to 13 and a pharma- ceutically acceptable diluent or carrier.

15. Preferably adenosine A for use as a medicine ２Ｂ A compound according to any one of claims 1 to 13, or a pharmaceutical composition according to claim 14, for use in a method for the treatment of a condition, disorder or disease mediated by receptor activation.

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