CN118574828A

CN118574828A - Functionalized aminothiazoles

Info

Publication number: CN118574828A
Application number: CN202380017453.2A
Authority: CN
Inventors: W·奈德哈特; D·巴克尔
Original assignee: Reed Explo Inc
Current assignee: Reed Explo Inc
Priority date: 2022-01-19
Filing date: 2023-01-18
Publication date: 2024-08-30

Abstract

The present invention relates to novel a _2B adenosine receptor antagonists and pharmaceutical compositions containing them and their use for the treatment and prevention of disorders known to be susceptible to amelioration by antagonism of the a _2B receptor, such as asthma, chronic Obstructive Pulmonary Disease (COPD), pulmonary fibrosis, vascular disease, allergic disease, hypertension, retinopathy, diabetes mellitus, inflammatory gastrointestinal disorders, inflammatory diseases, autoimmune diseases, kidney disease, neurological disorders and in particular cancer. In particular, the present invention relates to compounds of formula I or a pharmaceutically acceptable salt, solvate or hydrate thereof,Wherein R ¹ is H, halogen, -C ₁-C₈ alkyl, -C ₃-C₈ cycloalkyl, -O-C ₁-C₈ alkyl or-CN, Wherein each alkyl, cycloalkyl or-O-alkyl is optionally substituted with one or more R ²; R ² is independently selected at each occurrence from halogen, -OH and-OC ₁-C₈ alkyl; r ^A is a five to six membered ring heteroaryl, wherein the heteroaryl is optionally substituted with one or more R ^A1; R ^A1 is independently at each occurrence selected from halogen, -OH, oxo, cyano, -C ₁-C₈ alkyl, -C ₃-C₈ cycloalkyl and-O-C ₁-C₈ alkyl, Wherein each alkyl, cycloalkyl or-O-alkyl is optionally substituted with one or more R ^A2; R ^A2 is independently at each occurrence halogen, -OC ₁-C₈ alkyl or-OH; r ^B is phenyl or heteroaryl of a five-to six-membered ring, wherein each phenyl or heteroaryl is optionally substituted with one or more R ^B1; R ^B1 is independently at each occurrence selected from halogen, -OH, cyano, -C ₁-C₈ alkyl, and-O-C ₁-C₈ alkyl, wherein each alkyl and-O-alkyl is optionally substituted with one or more R ^B2; And R ^B2 is independently at each occurrence halogen, -OH or-OC ₁-C₈ alkyl.

Description

Functionalized aminothiazoles

Technical Field

The present invention relates to selective a _2B antagonists and dual a _2B and a ₁ antagonists which are more selective than other adenosine receptor subtypes (e.g., a _2A and/or a ₃). The compounds of the invention are useful in the treatment and prevention of disorders that are known to be treatable by antagonizing the adenosine a ₁ and/or a _2B receptor, particularly the a _2B receptor. Such disorders include asthma, chronic Obstructive Pulmonary Disease (COPD), pulmonary fibrosis, vascular disease, allergic diseases, hypertension, retinopathy, diabetes mellitus, inflammatory gastrointestinal tract disorders, inflammatory diseases, autoimmune diseases, kidney diseases, neurological disorders, otologic disorders and in particular cancer.

Background

Adenosine is an endogenous regulator of a variety of physiological responses, which plays an important role in protecting tissues during injury and acute states such as hypoxia, inflammation and ischemia. These reactions include, for example, vasodilation, pain, anti-inflammatory, wound healing and thermogenesis. In contrast to its beneficial effects during acute states, chronic exposure to adenosine and its associated physiological responses can be detrimental, triggering or prolonging diseases such as hypertension, pulmonary and renal fibrosis, and cancer (Gessi et al., expert opin. Invest. Drugs, (2011) 20 (12): 1591-609). In the immune system, adenosine is a core mediator that affects most, if not all, immune cells and affects many aspects of the immune response. These immunomodulatory effects (primarily anti-inflammatory) contribute to the general tissue protective effects of adenosine and its receptors. However, in some cases, the effect of adenosine on the immune system is detrimental, as prolonged signaling can block anti-tumor and antibacterial immunity, thereby promoting cancer progression and sepsis, respectively. The role of adenosine is transmitted by adenosine receptors, which are G-coupled signaling receptors, and is widely expressed in normal tissues of the 4 subtypes (a ₁、A_2A、A_2B、A₃). Adenosine receptors couple to different types of G proteins and mediate various signaling pathways in cells.

In particular, cancer treatment may benefit from compounds that selectively target an adenosine dependent pathway, as adenosine signaling has been shown to regulate apoptosis, angiogenesis and metastasis in cancer cells, (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)., which play a role in both cancer progression and immune evasion (Bahreyni et al., j. Cell physiol. (2018) 233 (3): 1836-1843). Further, antagonism of adenosine in vivo has been shown to reverse immunosuppressive phenotypes in tumor microenvironment. Thus, adenosine is considered a negative immune checkpoint that can be deregulated in cancer and create an immunosuppressive tumor microenvironment responsible for cancer resistance and invasiveness. Mouse studies have shown that antagonism of adenosine signaling can restore immune responses and lead to a sustained anti-tumor response (Ohta et al, proc.Natl. Acad. Sci. USA, (2006) 103 (35): 13132-7). Further, the anti-tumor effect was shown to be largely mediated by T cells, as shown by CXCR 3-/-knockout mice that show a loss of sensitivity to adenosine antagonists (Cekic et al, J.Immunol. (2012) 188 (1): 198-205). Although inhibition of the A _2A receptor subtype has been of great interest to date, it is known that A _2A signalling shows a conflicting effect on cell growth, as it can improve cell proliferation, but can 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). for this reason, The blocking of the a _2A pathway may in some cases be of opposite effect, as it blocks a _2A apoptosis signal that leads to increased cell proliferation. for example, in caco cancer cell lines, adenosine reduces cell proliferation at high doses, due to the apoptotic mechanisms that predominate in the cell growth component, and this effect is reversed only by a _2A antagonists and not by any other subtype antagonists (Yasuda et al, j. Gasmotertol. (2009) 56-65). This has led some authors to label the strategy of targeting dual compounds of both subtypes a _2A and a _2B as "double sword" (Allard et al., curr. Opin. Pharmacol. (2016) 29:7-16), which supports the need for alternatives such as selective a _2B inhibitors. Indeed, studies in A _2A -/-and A _2B -/-knockout mice indicate that the non-selective compound theophylline has a beneficial effect on tumor growth in vivo via A _2B antagonism. In contrast, tumors grew faster in a _2A knockout than in wild-type mice (Cekic et al., J immunol. (2012) 188 (1): 198-205), which provides a powerful theoretical basis for developing a _2B -selective antagonist specific for a _2A.

Selectivity over the a ₃ receptor subtype is another important feature of drugs for targeting adenosine receptors. To date, several lines of evidence support the following conclusions: activation of a ₃ R signaling is critical for cardioprotection during and after ischemia reperfusion, and a consistent portion of the cardioprotection by adenosine has been proposed, once primarily due to the a ₁ receptor, and now possibly in part due to a ₃ R activation (HEADRIC AND PEART, VASCUL.PHARMACOL. (2005) 42 (5-6): 271-9). The a ₃ receptor antagonism is associated with tissue damage following ischemia in the CNS, heart, kidney, lung, eye, potential deleterious effects on motor function, and pain threshold (Gessi et al, pharmacol ter (2008) 117 (1): 123-40).

Although there is a strong theoretical basis for targeting the a _2B receptor with antagonists and the a _2B receptor is found in many different cell types, it has traditionally attracted less attention than the a ₁、A_2A and a ₃ subtypes due to its lower affinity for adenosine. However, it is now known that a significant increase in extracellular concentration of adenosine in hypoxic tumor microenvironment can lead to activation of the a _2B receptor (Kasama et al, BMC Cancer (2015) 15,563). In recent years, the association between a _2B and cancer has emerged, and the tumor promoting activity of a _2B signaling can be deduced from mice lacking a _2B, wherein the tumor growth of these mice is reduced compared to the corresponding wild type mice. This effect is due in part to a significant reduction in intratumoral Vascular Endothelial Growth Factor (VEGF) levels (Rhzhov et al., neoplasia (2008) 10 (9): 987-95). In addition, A _2B was found to induce tumor growth by the production of basic fibroblast growth factor (bFGF) in lung, colon and prostate cancers (Bahreyni et al., J.cell Physiol. (2018) 233 (3): 1836-1843). A _2B was shown to play a role in supporting invasion and metastatic spread by accumulation of non-prenylated Rap 1B, a small GTPase that controls cell adhesion (Ntanie et al., sci.Signal. (2013) 6 (277): ra 39). In addition, A _2B plays a central role in the inflammatory response to tumors, such as the amount of tumor-infiltrating myeloid-derived suppressor cells (MDSCs) (Ryzhov et al., neoplasia (2008) 10 (9): 987-95). Further, A _2B is involved in the maturation of Dendritic Cells (DCs) and differentiation and function of macrophages and is therefore critical for tumor immunomonitoring (Iannone et al, neoplasia (2013) 15 (12): 1400-9; allard et al, immunol. Cell biol (2017) 95 (4): 333-339). Thus, the anti-cancer benefits of a _2B antagonists are diverse and achieved by both tumor-intrinsic and host-mediated pathways. High expression of a _2B is associated with poor prognosis of many cancers (Ihara et al, oncogene et al (2017) 36 (14): 2023-2029), and it was found that in a variety of human cancers including ovarian, lung, liver, oral, colon and prostate cancers, expression of a _2B was increased compared to adjacent normal tissues (methou et al, oncotarget et al (2017) 8 (30): 48755-48768). In oral squamous cell carcinoma, A _2B receptor is overexpressed and its silencing inhibits growth (Kasama et al., BMC Cancer, (2015) 15 (563). Use of the selective A _2B agonist BAY 60-6583 increases melanoma progression in mice, while the selective A _2B antagonist PSB1115 inhibits melanoma growth (Iannone et al., neoplasia (2013) 15 (12): 1400-9). further, the combination of PSB1115 with other checkpoint inhibitors (such as PD-1 or CTLA-4 inhibitors) for Cancer immunotherapy suggests that A _2B antagonists show strong synergism with these compounds in vivo, confirming that they do so by entirely different mechanisms (Mittal et al, cancer Res. (2016) 76 (15): 4372-82). A variety of a _2B antagonists are currently being developed, but have not been approved by regulatory authorities.

A ₁ receptor antagonism is also believed to show strong potential for cancer treatment. The a ₁ receptor has been reported to be involved in the pathogenesis of a variety of cancers, including breast, colon, astrocytomas, renal and gastric cancers (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). as well as a _2B, the anti-cancer benefits of a ₁ antagonists are diverse and function through both tumor intrinsic and host mediated pathways. For example, the A ₁ receptor antagonist DPCPX has been shown to inhibit tumor progression in renal Cell carcinoma (Zhou et al, cell Physiol.biochem. (2017) 43 (2): 733-742). DPCPX also induced apoptosis (Dastjerdi et al., bradsl. Lek. List. (2016) 117 (4): 242-6) and up-regulation of p53 in MCF-7 breast cancer cells. Consistent with this behavior, RNA silencing of the A ₁ receptor in overexpressed breast Cancer cells resulted in a decrease in the rate of cell proliferation and induction of apoptosis (Mirza et al, cancer biol. Ther. (2005) 4 (12): 1355-60).

Additional theoretical grounds for A1 receptor antagonism also exist at the host level, which is most relevant for cancer immunotherapy. Pharmacological pre-modulation with a ₁ agonist was found to lead to upregulation of the a _2A receptor and trigger the immunosuppression (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); expected for a _2A signalling, which was subsequently replicated in vivo and found to induce immunosuppression leading to improved graft survival in allograft models (NAAMANI ET al., sci.rep. (2020) 11;10 (1): 4464). For cancer, targeting a ₁ signaling may have a positive effect on high adenosine concentrations in the tumor microenvironment, where upregulation of the a _2A receptor would lead to immunosuppression and tumor evasion. Further, a ₁ receptor antagonism is potentially beneficial beyond cancer treatment, as it has also been studied in the treatment of, for example, respiratory diseases such as asthma and obstructive pulmonary disease (COPD).

A _2B receptor antagonism may also be useful in fields other than immunooncology, particularly for the treatment of respiratory diseases, where A _2B signaling mediates the production and release of pro-inflammatory mediators from mast cells (e.g., IL-4, IL-8, IL-13, and histamine). Mice treated with the a _2B receptor antagonists had less lung inflammation, less fibrosis, and greater alveolar air space enlargement than untreated mice, demonstrating the potential of a _2B antagonists to reduce lung inflammation in vivo (Sun et al, JClin invest (2006) 116 (8): 2173-2182). Other indications include pulmonary fibrosis, pulmonary arterial hypertension (PH), COPD and asthma (Zablocki et al, expert Opinion on Therapeutic Patents, (2006) 16:10, 1347-1357). Consistent with its anti-inflammatory and immunosuppressive effects, a _2B has been found to be involved in different aspects of glucose regulation. The a _2B antagonists were found to reduce the inflammatory response of diabetic mouse strains and improve insulin resistance 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 antagonists have been shown to prevent fatty liver formation following alcohol consumption in a mouse model (Peng et al, J Clin. Invest. (2009) 119 (3): 582-94). Studies in a mouse model have shown that a _2B inhibitor can prevent induced diabetic nephropathy and renal fibrosis. In addition, kidney biopsy samples from patients and genetic and pharmacological approaches also support the potential role of a _2B inhibitor in the treatment of Chronic Kidney Disease (CKD) and renal ischemia (Sun and Huang, front chem (2016) 24; 4:37). The role of a _2B antagonists in the central nervous system is less of a concern than a _2A inhibitors. However, a _2B is closely related to the a _2A receptor, the a _2A receptor has shown a pronounced antiparkinsonian effect and is of great interest in alzheimer's disease, cerebral ischemia, spinal cord injury, drug addiction and other disorders. Manalo reports that treatment of Ada ^-/- mice with a _2B -specific antagonist significantly improves the hearing loss, nerve fiber density and myelin compression of the mice, and that the a _2B receptor is a causative agent of age-related sensorineural hearing loss (Manalo et al., FASEB j. (2020) 34 (12) 15771-15787). The low affinity of the a _2B receptors for adenosine suggests that they may represent a good therapeutic target, since these receptors are activated only under pathological conditions where adenosine levels are elevated to micromolar concentrations (Popoli and Pepponi, CNS Neurol Disord Drug targets (2012) 11 (6): 664-74). Thus, there is a need for safe and selective ligands for the a _2B receptor and/or the a ₁ receptor for use in the treatment of a wide range of diseases and disorders, including cancer and inflammatory diseases.

Disclosure of Invention

The present invention provides selective a _2B antagonists and dual a _2B and a ₁ antagonists that are more selective than other adenosine receptor subtypes (e.g., a _2A and a ₃). The present invention relates to compounds of formula I or pharmaceutically acceptable salts or hydrates thereof, and their use as therapeutically active substances for the treatment or prophylaxis of conditions, disorders or diseases, in particular for the treatment or prophylaxis of cancer.

More specifically, the present invention relates to the following findings: specific 2-aminothiazoles having a triazole substituent on the 2-amino group. The compounds are useful as a ₁ and a _2B receptor antagonists, particularly as a _2B receptor antagonists, and do not exhibit significant, e.g., medically relevant, a ₃ adenosine receptor antagonistic activity. The compounds of the invention are therefore particularly suitable as novel medicaments for the treatment of diseases.

The selective nature of the compounds of the invention makes them useful as new drugs, particularly for the treatment of cancer, since as mentioned above, both the a ₁ and a _2B receptors have been shown to be important modulators of cancer progression and immune cancer response in the tumor microenvironment. Further, an important feature of the present invention is the high selectivity compared to the A ₃ receptor antagonistic activity, which in a preferred embodiment prevents the adverse side effects of the compounds of the invention caused by antagonism of the A ₃ receptor.

Further, the molecules of the invention contain triazole substituents bonded to the 2-amino group of the thiazole core, which further impart advantageous properties to the drug candidate, such as solubility, lipophilicity, and cell permeability. For example, the aminotriazole group of the compound of formula I is hydrophilic, and in some preferred embodiments, balances the lipophilicity of the thiazole group and the related R ^A and R ^B substituents to obtain compounds with improved cell membrane permeability. Further, the aminotriazole groups contain polar NH groups that can increase solubility while maintaining acceptable cell permeability through intramolecular hydrogen bonds that may be formed through the nitrogen of the central thiazole.

Thus, the compounds of the 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.

Accordingly, in a first aspect, the present invention provides a compound of formula I, or a pharmaceutically acceptable salt, solvate or hydrate thereof,

Wherein,

R ¹ is H, halogen, -C ₁-C₈ alkyl, -C ₃-C₈ cycloalkyl, -O-C ₁-C₈ alkyl or-CN, wherein each alkyl, cycloalkyl or-O-alkyl is optionally substituted with one or more R ²;

R ² is independently selected at each occurrence from halogen, -OH and-OC ₁-C₈ alkyl;

R ^A is a five to six membered ring heteroaryl, wherein the heteroaryl is optionally substituted with one or more R ^A1;

R ^A1 is independently at each occurrence selected from halogen, -OH, oxy, cyano, -C ₁-C₈ alkyl, -C ₃-C₈ cycloalkyl, and-O-C ₁-C₈ alkyl, wherein each alkyl, cycloalkyl, or-O-alkyl is optionally substituted with one or more R ^A2;

R ^A2 is independently at each occurrence halogen, -OC ₁-C₈ alkyl or-OH;

R ^B is phenyl or heteroaryl of a five-to six-membered ring, wherein each phenyl or heteroaryl is optionally substituted with one or more R ^B1;

R ^B1 is independently at each occurrence selected from halogen, -OH, cyano, -C ₁-C₈ alkyl, and-O-C ₁-C₈ alkyl, wherein each alkyl and-O-alkyl is optionally substituted with one or more R ^B2; and

R ^B2 is independently at each occurrence halogen, -OH or-OC ₁-C₈ alkyl.

In a further aspect, the present invention provides the use of a compound of formula I of the present invention as a medicament.

In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula I of the present invention, optionally together with a pharmaceutically acceptable diluent or carrier.

In a further aspect, the invention provides a compound of formula I of the invention or a pharmaceutical composition of the invention for use in a method of treatment of a condition, disorder or disease mediated by the activation of adenosine a _2B and/or a ₁ receptor (preferably the a _2B receptor).

In a further aspect, the invention provides a compound of formula I of the invention or a pharmaceutical composition of the invention for use in a method of treatment of a condition, disorder or disease ameliorated by the inhibition of adenosine a _2B and/or a ₁ receptor, preferably the a _2B receptor.

In a further aspect, the invention provides a compound of formula I of the invention or a pharmaceutical composition of the invention for use in a method of treatment of a disorder or disease susceptible to alleviation by antagonism of the adenosine a _2B and/or a ₁ receptor, preferably the a _2B receptor.

In a further aspect, the invention provides the use of a compound of formula I of the invention in the manufacture of a medicament for the treatment of a condition, disorder or disease mediated by the activation of the adenosine a _2B and/or a ₁ receptor (preferably the a _2B receptor).

In another aspect, the invention provides the use of a compound of formula I of the invention in the manufacture of a medicament for the treatment of a condition, disorder or disease ameliorated by the inhibition of adenosine a _2B and/or a ₁ receptors, preferably a _2B receptor.

In another aspect, the invention provides the use of a compound of formula I of the invention in the manufacture of a medicament for the treatment of a condition, disorder or disease susceptible to alleviation by antagonism of the adenosine a _2B and/or a ₁ receptor, preferably the a _2B receptor.

In another aspect, the invention provides a method of treating a condition, disorder or disease mediated by the activation of adenosine a _2B and/or a ₁ receptor (preferably a _2B receptor) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula I of the invention.

In another aspect, the invention provides a method of treating a condition, disorder or disease in a subject in need thereof, which condition, disorder or disease is alleviated by inhibition of adenosine a _2B and/or a ₁ receptor (preferably a _2B receptor), which method comprises administering to the subject a therapeutically effective amount of a compound of formula I of the invention.

In another aspect, the invention provides a method of treating a condition, disorder or disease in a subject in need thereof, which condition, disorder or disease is susceptible to alleviation by antagonism of the adenosine a _2B and/or a ₁ receptor (preferably the a _2B receptor), which method comprises administering to the subject a therapeutically effective amount of a compound of formula I of the invention.

In another aspect, the invention provides a compound of formula I of the invention or a pharmaceutical composition of the invention for use in a method of treating a condition, disorder or disease selected from respiratory diseases, inflammatory obstructive airways diseases, inflammatory diseases, metabolic diseases, kidney diseases, vascular diseases, allergic diseases, inflammatory gastrointestinal disorders, autoimmune diseases, neurological disorders, otologic disorders and cancer.

In another aspect, the invention provides the use of a compound of formula I of the invention in the manufacture of a medicament for the treatment of a condition, disorder or disease selected from the group consisting of respiratory diseases, inflammatory obstructive airways diseases, inflammatory diseases, metabolic diseases, kidney diseases, vascular diseases, allergic diseases, inflammatory gastrointestinal disorders, autoimmune diseases, neurological disorders, otologic disorders and cancer.

In another aspect, the present invention provides a method of treating a condition, disorder or disease selected from the group consisting of respiratory diseases, inflammatory obstructive airways diseases, inflammatory diseases, metabolic diseases, kidney diseases, vascular diseases, allergic diseases, inflammatory gastrointestinal tract disorders, autoimmune diseases, neurological disorders, otologic disorders and cancer, wherein the method comprises administering to a subject (particularly a human subject) in need thereof a therapeutically effective amount of a compound of formula I of the present invention or a pharmaceutically acceptable salt or hydrate thereof.

Further, the present invention provides processes for preparing said compounds, intermediates and pharmaceutical compositions and medicaments comprising said compounds or pharmaceutically acceptable salts or hydrates thereof, as well as their use for preventing or treating disorders and diseases mediated by the activation of a ₁ and especially adenosine a _2B receptors.

Further aspects and embodiments of the present invention will become apparent as the description proceeds.

Detailed Description

Definition of the definition

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The definitions used below generally refer to fragments, such as the "C ₁-C₈ -" fragment, 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 specified number of carbon atoms as illustrated. The definition of a fragment having a lower or higher number of carbon atoms (e.g. "C ₁-C₄ -" or "C ₁-C₃ -" analogue) should be interpreted as the same as the definition of a larger "C ₁-C₈ -" fragment, except for the number of carbon atoms.

As used herein, "C ₁-C₈ alkyl" refers to a linear or branched saturated C ₁-C₈ hydrocarbon which may be, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, linear or branched pentyl, linear or branched hexyl, linear or branched heptyl, or linear or branched octyl. Preferably, the C ₁-C₈ alkyl is a C ₁-C₄ alkyl.

As used herein, "C ₁-C₈ alkoxy" refers to a linear or branched saturated-O-C ₁-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 hexoxy, linear or branched heptoxy, or linear or branched octoxy. Preferably, the C ₁-C₈ alkoxy group is a C ₁-C₄ alkoxy group. "C ₁-C₈ alkoxy" may also be represented as "-O-C ₁-C₈ alkyl".

As used herein, "halogen" refers to fluorine, chlorine, bromine or iodine; preferably it is fluorine or chlorine, more preferably it is fluorine or chlorine when included in the compound of formula I. Accordingly, this also applies to the combination of halogen with other meanings (such as haloalkyl).

As used herein, "C ₁-C₈ haloalkyl" refers to a C ₁-C₈ alkyl group as defined above, substituted with one or more halogen atoms (preferably one, two or three halogen atoms, preferably fluorine or chlorine atoms). Preferably, the C ₁-C₈ haloalkyl is a C ₁-C₄ alkyl substituted with one, two or three fluorine or chlorine atoms. Preferred examples include difluoromethyl, trifluoromethyl, chlorodifluoromethyl and 2, 2-trifluoro-ethyl.

As used herein, "C ₁-C₈ hydroxyalkyl" refers to a C ₁-C₈ alkyl group as defined above that is substituted with one or more hydroxyl (OH) groups, preferably one, two or three hydroxyl (OH) groups, most preferably One Hydroxyl (OH) group.

As used herein, the term "C ₃-C₈ cycloalkyl" refers to a monocyclic or bicyclic saturated hydrocarbon ring, typically and preferably in the form of a single ring, containing from 3 to 8 carbon atoms, more preferably from 3 to 7 carbon atoms. Specific and preferred examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, and cyclohexyl. As used herein, the term "C ₃-C₆ cycloalkyl" refers to a monocyclic form containing 3 to 6 carbon atoms, specifically cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

As used herein, the term "phenyl" refers to the-C ₆ aromatic ring. Unsubstituted phenyl has the formula-C ₆H₅. One or more hydrogen atoms of the substituted phenyl group are substituted with a substituent.

As used herein, the term "heteroaryl" refers to a ring system containing an aromatic ring and containing five to six membered rings of at least one heteroatom selected from O and N. Heteroaryl groups may be monocyclic or two or more fused rings, at least one of which contains heteroatoms. Examples of monocyclic heteroaryl groups include imidazolyl, triazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl.

The term "cyano" refers to the group-CN.

The term "carbonyl" refers to a functional group comprising a carbon atom double bonded to an oxygen atom. Which may be abbreviated herein as "oxo", C (O) or C ═ O.

In the case where the group is said to be "optionally substituted", there are preferably 1 to 5 substituents, more preferably 1 to 3 substituents, still more preferably 1 or 2 substituents, and most preferably 1 substituent. Where a group is said to be optionally substituted and where the optional substituent of the group has more than one substituent, the more than one substituents may be the same or different.

As used herein, the term "treatment" or "therapy" refers to a means of achieving a desired physiological effect. The effect may be therapeutic in terms of a partial or complete cure of the disease or disorder and/or symptoms due to the disease or disorder. The term refers to inhibiting a disease or disorder, i.e., arresting its development, or alleviating a disease or disorder, i.e., causing regression of a disease or disorder.

As used herein, the term "for" as used in "composition for treating a disease" will also disclose a corresponding method of treatment and corresponding use of a formulation for preparing a medicament for treating a disease.

A "therapeutically effective amount" is an amount of a compound or pharmaceutical composition of the present invention that will elicit the biological or medical response of a subject (preferably a human subject) that is being sought by a researcher, veterinarian, medical doctor or other clinician. As used herein, the term "therapeutic administration" refers to administration of a therapeutically effective amount.

Compounds of the invention

In a first aspect, the present invention provides a compound of formula I, or a pharmaceutically acceptable salt, solvate or hydrate thereof,

Wherein,

R ^A2 is independently at each occurrence halogen, -OC ₁-C₈ alkyl or-OH;

R ^B1 is independently at each occurrence selected from halogen, -OH, cyano, -C ₁-C₈ alkyl, and-O-C ₁-C₈ alkyl, wherein each alkyl and-O-alkyl is optionally substituted with one or more R ^B2;

r ^B2 is independently at each occurrence halogen, -OH or-OC ₁-C₈ alkyl.

In some embodiments, R ¹ is H, halo, -C ₁-C₈ alkyl, -C ₃-C₈ cycloalkyl, or-OC ₁-C₈ alkyl, wherein each alkyl, cycloalkyl, or-O-alkyl is optionally substituted with one or more R ².

In further preferred embodiments, R ¹ is H, halogen, -C ₁-C₈ alkyl, or-C ₃-C₈ cycloalkyl, wherein each alkyl or cycloalkyl is optionally substituted with one or more R ².

In further preferred embodiments, R ¹ is H, halogen, -C ₁-C₄ alkyl, or-C ₃-C₆ cycloalkyl, wherein each alkyl or cycloalkyl is optionally substituted with one or more R ².

In further preferred embodiments, R ¹ is H, halogen, -C ₁-C₂ alkyl, or-C ₃-C₆ cycloalkyl, wherein each alkyl or cycloalkyl is optionally substituted with one or more R ².

In further preferred embodiments, R ¹ is H, halogen, -C ₁-C₂ alkyl, or-C ₃-C₄ cycloalkyl, wherein each alkyl or cycloalkyl is optionally substituted with one or more R ².

In further preferred embodiments, R ¹ is H, halogen, -C ₁ alkyl, or-C ₃-C₄ cycloalkyl, wherein each alkyl or cycloalkyl is optionally substituted with one or more R ².

In further preferred embodiments, R ¹ is H, fluoro, chloro, -C ₁-C₂ alkyl, or-C ₃-C₄ cycloalkyl, wherein each alkyl or cycloalkyl is optionally substituted with one or two R ².

In further preferred embodiments, R ¹ is H, fluoro, chloro, -C ₁ alkyl, or-C ₃-C₄ cycloalkyl, wherein each alkyl or cycloalkyl is optionally substituted with one or two R ².

In a further preferred embodiment, R ¹ is H, fluoro, chloro, -C ₁-C₂ alkyl or-C ₃-C₄ cycloalkyl, wherein each alkyl or cycloalkyl is optionally substituted with one R ².

In a further preferred embodiment, R ¹ is H, fluoro, chloro, -C ₁ alkyl or-C ₃-C₄ cycloalkyl, wherein each alkyl or cycloalkyl is optionally substituted with one R ².

In a further preferred embodiment, R ¹ is H, -C ₁-C₂ alkyl or-C ₃-C₄ cycloalkyl, wherein each alkyl is optionally substituted with one R ².

In a further preferred embodiment, R ¹ is H, -C ₁ alkyl or-C ₃-C₄ cycloalkyl, wherein each alkyl is optionally substituted with one R ².

In a further preferred embodiment, R ¹ is H, -C ₁-C₂ alkyl or-C ₃-C₄ cycloalkyl, wherein each alkyl is optionally substituted with one-OH.

In a further preferred embodiment, R ¹ is H, -C ₁ alkyl or-C ₃-C₄ cycloalkyl, wherein each alkyl is optionally substituted with one-OH.

In a further preferred embodiment, R ¹ is H, -CH ₃、-CH₂CH₃、-CH₂ OH or-C ₃-C₄ cycloalkyl.

In a further preferred embodiment, R ¹ is H, -CH ₂ OH or-C ₃-C₄ cycloalkyl.

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.

In a further preferred embodiment, R ¹ is-CH ₃.

In a further preferred embodiment, R ¹ is-CH ₂CH₃.

In a further preferred embodiment, R ¹ is-CH ₂ OH.

In a further preferred embodiment, R ¹ is cyclopropane.

In a further preferred embodiment, R ¹ is cyclobutane.

In some preferred embodiments, R ² is-OH, halogen, or-OC ₁-C₄ alkyl. In a further preferred embodiment, R ² is-OH, halogen or-OC ₁-C₂ alkyl. In a further preferred embodiment, R ² is —oh or halogen, wherein the halogen is preferably fluorine or chlorine. In a further preferred embodiment, R ² is-OH. In a further preferred embodiment, R ² is halogen, wherein the halogen is preferably fluorine or chlorine.

In some preferred embodiments, R ^A is imidazolyl, triazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, or pyridonyl; wherein each imidazolyl, triazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or pyridonyl is optionally substituted with one or more R ^A1.

In some preferred embodiments, R ^A is imidazolyl, triazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, or pyrazinyl; wherein each imidazolyl, triazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl is optionally substituted with one or more R ^A1.

In a further preferred embodiment, R ^A is 1-imidazolyl, 1- (1, 2, 4) -triazolyl, 4-isoxazolyl, 5-oxazolyl, 4-pyrazolyl, 4-pyridyl, 4-pyridazinyl, 4-pyrimidinyl, 2-pyrazinyl or 5- (2-pyridonyl); wherein each imidazolyl, triazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or pyridonyl is optionally substituted with one or more R ^A1.

In a further preferred embodiment, R ^A is 1-imidazolyl, 1- (1, 2, 4) -triazolyl, 4-isoxazolyl, 5-oxazolyl, 4-pyrazolyl, 4-pyridyl, 4-pyridazinyl, 4-pyrimidinyl or 2-pyrazinyl; wherein each imidazolyl, triazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl is optionally substituted with one or more R ^A1.

In further preferred embodiments, R ^A is imidazolyl, triazolyl, isoxazolyl, pyrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyridonyl; wherein each imidazolyl, triazolyl, isoxazolyl, pyrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyridonyl is optionally substituted with one or more R ^A1.

In further preferred embodiments, R ^A is imidazolyl, triazolyl, isoxazolyl, pyrazolyl, pyridinyl, pyridazinyl, or pyrimidinyl; wherein each imidazolyl, triazolyl, isoxazolyl, pyrazolyl, pyridyl, pyridazinyl or pyrimidinyl is optionally substituted with one or more R ^A1.

In a further preferred embodiment, R ^A is 1-imidazolyl, 1- (1, 2, 4) -triazolyl, 4-isoxazolyl, 5-isoxazolyl, 4-pyrazolyl, 4-pyridinyl, 4-pyridazinyl, 4-pyrimidinyl or 5- (2-pyridonyl); wherein each imidazolyl, triazolyl, isoxazolyl, pyrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyridonyl is optionally substituted with one or more R ^A1.

In a further preferred embodiment, R ^A is 1-imidazolyl, 1- (1, 2, 4) -triazolyl, 4-isoxazolyl, 5-isoxazolyl, 4-pyrazolyl, 4-pyridinyl, 4-pyridazinyl or 4-pyrimidinyl; wherein each imidazolyl, triazolyl, isoxazolyl, pyrazolyl, pyridyl, pyridazinyl and pyrimidinyl is optionally substituted with one or more R ^A1.

In a further preferred embodiment, R ^A is 1-imidazolyl, 1- (1, 2, 4) -triazolyl, 4-isoxazolyl, 5-isoxazolyl, 4-pyrazolyl, 4-pyridinyl, 4-pyridazinyl, 4-pyrimidinyl or 5- (2-pyridonyl); wherein each imidazolyl, triazolyl, isoxazolyl, pyrazolyl, pyridinyl, pyridazinyl, pyrimidinyl or pyridonyl is optionally substituted with one or two R ^A1.

In a further preferred embodiment, R ^A is 1-imidazolyl, 1- (1, 2, 4) -triazolyl, 4-isoxazolyl, 5-isoxazolyl, 4-pyrazolyl, 4-pyridinyl, 4-pyridazinyl or 4-pyrimidinyl; wherein each imidazolyl, triazolyl, isoxazolyl, pyrazolyl, pyridyl, pyridazinyl and pyrimidinyl is optionally substituted with one or two R ^A1.

In a further preferred embodiment, R ^A is imidazolyl, triazolyl, pyridyl, pyridazinyl, pyrimidinyl or pyridonyl; wherein each imidazolyl, triazolyl, pyridinyl, pyridazinyl, pyrimidinyl or pyridonyl is optionally substituted with one or more R ^A1.

In a further preferred embodiment, R ^A is imidazolyl, triazolyl, pyridinyl or pyridinyl; wherein each imidazolyl, triazolyl, pyridyl or pyridonyl is optionally substituted with one or more R ^A1.

In a further preferred embodiment, R ^A is imidazolyl, triazolyl or pyridinyl; wherein each imidazolyl, triazolyl, and pyridyl is optionally substituted with one or more R ^A1.

In further preferred embodiments, R ^A is 1-imidazolyl, 1- (1, 2, 4) -triazolyl, 4-pyridyl, 4-pyridazinyl, 4-pyrimidinyl or 5- (2-pyridonyl); wherein each imidazolyl, triazolyl, pyridinyl, pyridazinyl, pyrimidinyl or pyridonyl is optionally substituted with one or more R ^A1.

In a further preferred embodiment, R ^A is 1-imidazolyl, 1- (1, 2, 4) -triazolyl, 4-pyridyl, 4-pyridazinyl, 4-pyrimidinyl or 5- (2-pyridonyl); wherein each imidazolyl, triazolyl, pyridinyl, pyridazinyl, pyrimidinyl or pyridonyl is optionally substituted with one or more R ^A1.

In further preferred embodiments, R ^A is 1-imidazolyl, 1- (1, 2, 4) -triazolyl, 4-pyridyl or 5- (2-pyridonyl); wherein each imidazolyl, triazolyl, pyridyl or pyridonyl is optionally substituted with one or more R ^A1.

In further preferred embodiments, R ^A is 1-imidazolyl, 1- (1, 2, 4) -triazolyl, 4- (1, 2, 4) -triazolyl, or 4-pyridyl; wherein each imidazolyl, triazolyl, and pyridyl is optionally substituted with one or more R ^A1.

In further preferred embodiments, R ^A is 1-imidazolyl, 1- (1, 2, 4) -triazolyl, 4-pyridyl, 4-pyridazinyl, 4-pyrimidinyl or 5- (2-pyridonyl); wherein each imidazolyl, triazolyl, pyridinyl, pyridazinyl, pyrimidinyl or pyridonyl is optionally substituted with one or two R ^A1.

In a further preferred embodiment, R ^A is 1-imidazolyl, 1- (1, 2, 4) -triazolyl, 4-pyridyl, 4-pyridazinyl, 4-pyrimidinyl or 5- (2-pyridonyl); wherein each imidazolyl, triazolyl, pyridinyl, pyridazinyl, pyrimidinyl or pyridonyl is optionally substituted with one or two R ^A1.

In further preferred embodiments, R ^A is 1-imidazolyl, 1- (1, 2, 4) -triazolyl, 4-pyridyl or 5- (2-pyridonyl); wherein each imidazolyl, triazolyl, pyridyl or pyridonyl is optionally substituted with one or two R ^A1.

In further preferred embodiments, R ^A is 1-imidazolyl, 1- (1, 2, 4) -triazolyl, 4- (1, 2, 4) -triazolyl, or 4-pyridyl; wherein each imidazolyl, triazolyl, and pyridyl is optionally substituted with one or two R ^A1.

In further preferred embodiments, R ^A is 1-imidazolyl, 1- (1, 2, 4) -triazolyl, 4-pyridyl, 4-pyridazinyl, 4-pyrimidinyl or 5- (2-pyridonyl); wherein each imidazolyl, triazolyl, pyridyl, pyridazinyl, pyrimidinyl or pyridonyl group is unsubstituted.

In further preferred embodiments, R ^A is 1-imidazolyl, 1- (1, 2, 4) -triazolyl, 4- (1, 2, 4) -triazolyl, or 4-pyridyl; wherein each of the imidazolyl, triazolyl and pyridyl groups is unsubstituted.

In a further preferred embodiment, R ^A is 1-imidazolyl; wherein each imidazolyl is optionally substituted with one or two R ^A1.

In a further preferred embodiment, R ^A is 1-imidazolyl; wherein each imidazolyl group is unsubstituted.

In a further preferred embodiment, R ^A is 1- (1, 2, 4) -triazolyl; wherein each triazolyl is optionally substituted with one or two R ^A1.

In a further preferred embodiment, R ^A is 1- (1, 2, 4) -triazolyl; wherein each triazolyl is unsubstituted.

In a further preferred embodiment, R ^A is 4- (1, 2, 4) -triazolyl; wherein each triazolyl is optionally substituted with one or two R ^A1.

In a further preferred embodiment, R ^A is 4- (1, 2, 4) -triazolyl; wherein each triazolyl is unsubstituted.

In a further preferred embodiment, R ^A is 4-pyridinyl; wherein each pyridinyl is optionally substituted with one or two R ^A1.

In a further preferred embodiment, R ^A is 4-pyridinyl; wherein each pyridyl group is unsubstituted.

In a further preferred embodiment, R ^A is 4-pyridazinyl; wherein each pyridazinyl is optionally substituted with one or two R ^A1.

In a further preferred embodiment, R ^A is 4-pyridazinyl; wherein each pyridazinyl is unsubstituted.

In a further preferred embodiment, R ^A is 4-pyrimidinyl; wherein each pyrimidinyl is optionally substituted with one or two R ^A1.

In a further preferred embodiment, R ^A is 4-pyrimidinyl; wherein each pyrimidinyl group is unsubstituted.

In a further preferred embodiment, R ^A is 5- (2-pyridonyl); wherein each pyridonyl group is optionally substituted with one or two R ^A1.

In a further preferred embodiment, R ^A is 5- (2-pyridonyl); wherein each pyridonyl group is unsubstituted.

In some preferred embodiments, R ^A1 is independently halogen, -OH, oxy, -C ₁-C₄ alkyl, or-C ₃-C₆ cycloalkyl, wherein each alkyl or cycloalkyl is optionally substituted with one or more halogens or-OH. In a further preferred embodiment, R ^A1 is independently halogen, -OH, -C ₁-C₄ alkyl or-C ₃-C₆ cycloalkyl, wherein each alkyl or cycloalkyl is optionally substituted with one or more halogen or-OH. In a further preferred embodiment, R ^A1 is independently halogen, -OH or-C ₁-C₄ alkyl, wherein each alkyl is optionally substituted with one or more halogen or-OH. In a further preferred embodiment, R ^A1 is independently halogen or-C ₁-C₄ alkyl, wherein each alkyl is optionally substituted with one or more halogen or-OH. In a further preferred embodiment, R ^A1 is independently halogen or-C ₁-C₂ alkyl, wherein each alkyl is optionally substituted with one or more halogen or-OH. In a further preferred embodiment, R ^A1 is independently fluoro, chloro or-C ₁-C₂ alkyl, wherein each alkyl is optionally substituted with one or more fluoro, chloro or-OH. In a further preferred embodiment, R ^A1 is independently fluoro, chloro or-C ₁-C₂ alkyl, wherein each alkyl is optionally substituted with one or more-OH. In a further preferred embodiment, R ^A1 is independently fluoro, chloro or-C ₁-C₂ alkyl, wherein each alkyl is optionally substituted with one or two, preferably one-OH.

In some preferred embodiments, R ^A is selected from:

Wherein,

X is-CH-or N;

R ^A3 is independently at each occurrence 1 to 3 identical or different substituents selected from the group consisting of hydrogen, halogen, -C ₁-C₈ alkyl, -C ₁-C₈ haloalkyl, -C ₁-C₈ alkoxy, -C ₁-C₈ hydroxyalkyl and-C ₁-C₈ alkoxyalkyl;

R ^A4 is independently at each occurrence hydrogen, halogen, -C ₁-C₈ alkyl, -C ₃-C₈ cycloalkyl, -C ₁-C₈ hydroxyalkyl, and-C ₁-C₈ alkoxyalkyl; and

R ^A5 is independently at each occurrence hydrogen or-C ₁-C₈ alkyl.

In some preferred embodiments, R ^A is selected from:

Wherein,

X is-CH-or N;

R ^A3 is independently at each occurrence 1 to 3 identical or different substituents selected from the group consisting of hydrogen, halogen, -C ₁-C₈ alkyl, -C ₁-C₈ haloalkyl, -C ₁-C₈ alkoxy, -C ₁-C₈ hydroxyalkyl and-C ₁-C₈ alkoxyalkyl; and

R ^A4 is independently at each occurrence hydrogen, halogen, -C ₁-C₈ alkyl, -C ₃-C₈ cycloalkyl, -C ₁-C₈ hydroxyalkyl, and-C ₁-C₈ alkoxyalkyl.

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

In a further preferred embodiment, R ^A is selected from:

In some preferred embodiments, R ^B is selected from phenyl, oxazolyl, pyridinyl, pyrimidinyl, pyridazinyl, and pyrazinyl, wherein each phenyl, oxazolyl, pyridinyl, pyrimidinyl, pyridazinyl, and pyrazinyl is optionally substituted with one or more R ^B1. In a further preferred embodiment, R ^B is selected from phenyl, 2-oxazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 4-pyridazinyl and 2-pyrazinyl, wherein each phenyl, oxazolyl, pyridyl, pyrimidinyl, pyridazinyl and pyrazinyl is optionally substituted with one or more R ^B1. In a further preferred embodiment R ^B is selected from phenyl, 2-oxazolyl, 2-pyridyl, 3-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 4-pyridazinyl and 2-pyrazinyl, wherein each phenyl, oxazolyl, pyridyl, pyrimidinyl, pyridazinyl and pyrazinyl is optionally substituted with one or two, preferably one R ^B1. In a further preferred embodiment, R ^B is selected from phenyl, oxazolyl, pyridinyl and pyridinyl, wherein each phenyl, oxazolyl and pyridinyl is optionally substituted by one or two, preferably one R ^B1. In a further preferred embodiment, R ^B is selected from phenyl, 2-oxazolyl, 2-pyridyl and 3-pyridyl, wherein each phenyl, oxazolyl and pyridyl is optionally substituted with one or two, preferably one R ^B1.

In a further preferred embodiment, R ^B is selected from phenyl, pyridinyl, pyrimidinyl, pyridazinyl and pyrazinyl, wherein each phenyl, pyridinyl, pyrimidinyl, pyridazinyl and pyrazinyl is optionally substituted with one or more R ^B1.

In a further preferred embodiment, R ^B is selected from phenyl, 2-pyridyl, 3-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 4-pyridazinyl and 2-pyrazinyl, wherein each phenyl, pyridyl, pyrimidinyl, pyridazinyl and pyrazinyl is optionally substituted with one or more R ^B1.

In a further preferred embodiment, R ^B is selected from phenyl, wherein the phenyl is optionally substituted with one or more R ^B1. In a further preferred embodiment, R ^B is selected from phenyl, wherein said phenyl is optionally substituted with one or two, preferably one R ^B1.

In some preferred embodiments, R ^B1 is selected from halogen, -OH, cyano, -C ₁-C₄ alkyl, and-C ₁-C₄ alkoxy, wherein each alkyl and alkoxy is independently substituted with one or more halogen, -OH, or-C ₁-C₄ alkoxy groups. In a further preferred embodiment, R ^B1 is selected from halogen, -OH, cyano and-C ₁-C₄ alkyl, wherein the alkyl is independently substituted with one or more halogen, -OH or-C ₁-C₄ alkoxy groups. In a further preferred embodiment, R ^B1 is selected from halogen, -OH, cyano and-C ₁-C₄ alkyl, wherein the alkyl is independently substituted with one or more halogen or-OH. In a further preferred embodiment, R ^B1 is selected from halogen, -OH, cyano and-C ₁-C₂ alkyl, wherein the alkyl is independently substituted with one or more halogen or-OH. In a further preferred embodiment, R ^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 fluoro and cyano. In a further preferred embodiment, R ^B1 is fluoro. In a further preferred embodiment, R ^B1 is cyano.

In some preferred embodiments, R ^B is selected from:

Wherein the method comprises the steps of

R ^B3 is independently at each occurrence selected from hydrogen, halogen, -C ₁-C₈ alkyl, -C ₁-C₈ haloalkyl, -C ₁-C₈ alkoxy, -C ₁-C₈ hydroxyalkyl, -C ₁-C₈ alkoxyalkyl, and-CN. In a further preferred embodiment, in the case of b1 and b2, R ^B3 represents 1 to 3 identical or different substituents; in the case of b3, R ^B3 represents 1 to 2 identical or different substituents. In a further preferred embodiment, R ^B3 represents 1 to 2 identical or different substituents, preferably 1 substituent. In a further preferred embodiment, R ^B is selected from:

In a further preferred embodiment, R ^B is selected from:

in some preferred embodiments, R ^B is phenyl substituted with one or two R ^B1, wherein R ^B1 is independently cyano or fluoro at each occurrence. In a further preferred embodiment, R ^B is 2-fluorophenyl, 3-cyanophenyl or 2-fluoro-5-cyanophenyl. In a further preferred embodiment, R ^B is 2-fluorophenyl. In a further preferred embodiment, R ^B is 3-cyanophenyl. In a further preferred embodiment, R ^B is 2-fluoro-5-cyanophenyl.

In some embodiments, the invention provides a compound of formula I, or a pharmaceutically acceptable salt, solvate, or hydrate thereof,

Wherein,

R ¹ is H, halogen, -C ₁-C₂ alkyl, or-C ₃-C₄ cycloalkyl, wherein each alkyl or cycloalkyl is optionally substituted with one or more R ²;

R ² is independently selected at each occurrence from halogen, -OH and-OC ₁-C₂ alkyl;

R ^A is imidazolyl, triazolyl, pyridyl, pyridazinyl, pyrimidinyl or pyridonyl; wherein each imidazolyl, triazolyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyridonyl is optionally substituted with one or more R ^A1;

R ^A1 is independently halogen, -OH, -C ₁-C₄ alkyl or-C ₃-C₆ cycloalkyl, wherein each alkyl or cycloalkyl is optionally substituted with one or more halogen or-OH;

R ^B is selected from phenyl, pyridinyl, pyrimidinyl, pyridazinyl, and pyrazinyl, wherein each phenyl, pyridinyl, pyrimidinyl, pyridazinyl, and pyrazinyl is optionally substituted with one or more R ^B1;

r ^B1 is independently selected at each occurrence from halogen and cyano.

Wherein,

R ^A2 is independently at each occurrence halogen, -OC ₁-C₈ alkyl or-OH;

R ^B is phenyl, wherein the phenyl is optionally substituted with one or more R ^B1;

r ^B2 is independently at each occurrence halogen, -OH or-OC ₁-C₈ alkyl.

Wherein,

r ^B1 is independently selected at each occurrence from halogen and cyano.

Wherein,

R ¹ is H, -C ₁-C₂ alkyl or-C ₃-C₄ cycloalkyl, wherein each alkyl is optionally substituted with one R ²;

R ² is independently selected at each occurrence from fluorine, chlorine or-OH, with R ² preferably being OH;

r ^A is 1-imidazolyl, 1- (1, 2, 4) -triazolyl, 4-pyridyl, 4-pyridazinyl, 4-pyrimidinyl or 5- (2-pyridonyl); wherein each imidazolyl, triazolyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyridonyl is optionally substituted with one or more R ^A1;

R ^A1 is independently fluoro, chloro or-C ₁-C₂ alkyl, wherein each alkyl is optionally substituted with one or more fluoro, chloro or-OH, preferably wherein each alkyl is optionally substituted with one or more-OH;

r ^B1 is independently selected at each occurrence from halogen and cyano.

In some preferred embodiments, the compound is a compound of formula Ia1 b:

wherein R ¹、R^B、R^A3 and R ^A4 are as defined in any of the embodiments above.

In some preferred embodiments, the compound is a compound of formula Ia2 b:

Wherein R ¹、R^B、R^A4 and X are as defined in any of the embodiments above.

In some preferred embodiments, the compound is a compound of formula Ia3 b:

Wherein R ¹、R^B and R ^A3 are as defined in any of the embodiments above, Y is independently at each occurrence-CH-or N, wherein at least one Y is-CH-.

In some preferred embodiments, the compound is a compound of formula Ia1b or Ia2 b:

Wherein R ¹、R^B、R^A3、R^A4 and X are as defined in any of the embodiments above; preferably, among them, there is provided a method for manufacturing a semiconductor device,

x is-CH-or N;

r ^A4 is independently at each occurrence hydrogen, halogen, -C ₁-C₈ alkyl, -C ₃-C₈ cycloalkyl, -C ₁-C₈ hydroxyalkyl, and-C ₁-C₈ alkoxyalkyl;

r ^B2 is independently at each occurrence halogen, -OH or-OC ₁-C₈ alkyl.

In some preferred embodiments, the compound is a compound of formula Ia3b or Ia2 b:

Wherein R ¹、R^B、R^A3、R^A4, X and Y are as defined in any of the above embodiments; preferably, among them, there is provided a method for manufacturing a semiconductor device,

x is-CH-or N;

Y is independently at each occurrence-CH-or N, wherein at least one Y is-CH-;

r ^B2 is independently at each occurrence halogen, -OH or-OC ₁-C₈ alkyl.

In some preferred embodiments, the compound is a compound of formula Ia1b1, ia1b2, ia1b3, ia2b1, ia2b2, ia2b3, ia3b1, ia3b2, or Ia3b 3:

wherein R ¹、R^B3、R^A3、R^A4 and X are as defined in any of the embodiments above; preferably, among them, there is provided a method for manufacturing a semiconductor device,

x is-CH-or N;

Y is independently at each occurrence-CH-or N, wherein at least one Y is-CH-;

R ^B3 is independently at each occurrence selected from hydrogen, halogen, -C ₁-C₈ alkyl, -C ₁-C₈ haloalkyl, -C ₁-C₈ alkoxy, -C ₁-C₈ hydroxyalkyl, -C ₁-C₈ alkoxyalkyl, and-CN.

In a further preferred embodiment, the compound is a compound of formula Ia1b1, wherein R ^B3 is one R ^B3;R¹ selected from cyano and fluoro is selected from-C ₃-C₄ cycloalkyl. In some preferred embodiments, the compound is a compound of formula Ia2b1, wherein R ^B3 is one selected from cyano or fluoro, and R ^B3;R¹ is selected from-C ₃-C₄ cycloalkyl. In some preferred embodiments, the compound is a compound of formula Ia1b1, wherein R ^B3 is 3-cyano; r ¹ is-C ₃-C₄ cycloalkyl. In some preferred embodiments, the compound is a compound of formula 1a1b1, wherein R ^B3 is 2-fluoro; R ¹ is-C ₃-C₄ cycloalkyl. In some preferred embodiments, the compound is a compound of formula Ia2b1, wherein R ^B3 is 2-fluoro and R ¹ is-C ₃-C₄ cycloalkyl. In some preferred embodiments, the compound is a compound of formula Ia2b1, wherein R ^B3 is 3-cyano and R ¹ is-C ₃-C₄ cycloalkyl.

In a preferred embodiment, R ^A is pyridine optionally substituted with one or two R ^A1, wherein,

R ^A1 is independently at each occurrence fluorine, chlorine or methyl; and

R ^B is 3-cyanophenyl.

In a preferred embodiment, R ^A is 1-imidazole optionally substituted with one or two R ^A1, wherein,

R ^A1 is independently at each occurrence methyl, ethyl or hydroxymethyl; and

R ^B is 3-cyanophenyl.

In a preferred embodiment, R ¹ is H; r ^A is 1-imidazole optionally substituted with one or two R ^A1, wherein,

R ^A1 is independently at each occurrence methyl, ethyl or hydroxymethyl; and

R ^B is 3-cyanophenyl.

In a preferred embodiment, R ^A is 1-imidazole optionally substituted once at the 2-position by R ^A1, wherein,

R ^A1 is independently at each occurrence methyl, ethyl or hydroxymethyl; and

R ^B is 3-cyanophenyl.

R ^A1 is methyl; and

R ^B is 3-cyanophenyl.

In a preferred embodiment, R ^A is triazole; and

R ^B is 3-cyanophenyl.

In some preferred embodiments, the compound is selected from the group consisting of:

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.

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.

In certain 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.

In certain 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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Many of the compounds of formula I of the present invention are capable of forming acid addition salts, in particular pharmaceutically acceptable acid addition salts. Pharmaceutically acceptable acid addition salts of the compounds of formula I include acid addition salts of inorganic acids (e.g., hydrohalic acids such as hydrofluoric, hydrochloric, hydrobromic or hydroiodic, nitric, sulfuric, phosphoric acid); and acid addition salts of organic acids (e.g., 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, p-hydroxybenzoic acid, 1-hydroxynaphthalene-2-carboxylic acid or 3-hydroxynaphthalene-2-carboxylic acid, and sulfonic acids such as methanesulfonic acid or benzenesulfonic acid). These salts can be prepared from the compounds of formula I by known salt formation processes.

"Hydrate" refers to an association or complex of one or more water molecules with a compound of the invention. The hydrates may be stoichiometric or non-stoichiometric. Particularly preferred examples of hydrates include hemihydrate, monohydrate, and dihydrate.

Therapeutic method

As shown in examples 30-32 below and tables 1 and 2, the compounds of the invention disclosed herein selectively inhibit adenosine a ₁ and a _2B (particularly a _2B) receptors. In particular, the compounds of the invention selectively inhibit the a _2B and/or a ₁ receptor relative to the a ₃ and/or a _2A receptor. Accordingly, in a preferred embodiment, the compounds of the invention are used for the treatment of conditions, diseases or disorders mediated by the activation of the adenosine a _2B receptor.

For example, examples 30 and 31 and table 1 demonstrate that the compounds of the invention selectively inhibit the a _2B and a ₁ receptors with EC ₅₀ values typically in the low nanomolar range. In contrast, table 1 shows that the compounds of the present invention are substantially inactive against human a ₃ and a _2A receptors.

Further, example 32 teaches that the compounds of the invention bind selectively to the human a _2B receptor compared to the a _2A receptor. As shown in example 32 and table 2, the compounds of the present invention can selectively stabilize the human a _2B receptor, resulting in an increased melting point and higher Δt _m. In contrast, the compounds of the present invention had much less effect on Δt _m of the human a _2A receptor, indicating weaker binding to the a _2A receptor.

Because of their ability to inhibit the activation of adenosine a ₁ and/or a _2B receptors, the compounds of formula I of the present invention, and pharmaceutically acceptable salts or hydrates thereof, are useful in the treatment or prevention of conditions, disorders and diseases mediated by the activation of adenosine a ₁ and/or a _2B receptors. The conditions, disorders and diseases are in particular selected from respiratory diseases, inflammatory obstructive airways diseases, inflammatory diseases, metabolic diseases, kidney diseases, vascular diseases, allergic diseases, inflammatory gastrointestinal disorders, autoimmune diseases, neurological disorders, otological disorders and cancers. In some embodiments, the compounds and pharmaceutical compositions of the present invention are useful for treating cancers, particularly ovarian, lung, liver, oral, colon, skin and prostate cancers, including melanoma and squamous cell carcinoma. In some embodiments, the compounds and pharmaceutical compositions of the invention are useful for treating an otologic disorder, preferably hearing loss.

In one aspect, the present invention provides a pharmaceutical composition comprising a compound of formula I of the present invention, optionally together with a pharmaceutically acceptable diluent or carrier.

Accordingly, in one aspect, the present invention provides a compound of formula I of the present invention or a pharmaceutical composition of the present invention for use in a method of treatment of a condition, disorder or disease mediated by the activation of adenosine a ₁ and/or a _2B receptors.

In one aspect, the invention provides the use of a compound of formula I of the invention in the manufacture of a medicament for the treatment of a condition, disorder or disease mediated by the activation of the adenosine a ₁ and/or a _2B receptor.

In one aspect, the invention provides a method of treating a condition, disorder or disease mediated by the activation of adenosine a ₁ and/or a _2B receptors in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula I of the invention.

In a further aspect, the invention provides a compound of formula I of the invention or a pharmaceutical composition of the invention for use in a method of treating a condition, disorder or disease mediated by the activation of the adenosine a _2B receptor.

In a further aspect, the invention provides a compound of formula I of the invention or a pharmaceutical composition of the invention for use in a method of treating a condition, disorder or disease ameliorated by the inhibition of the adenosine a _2B receptor.

In a further aspect, the invention provides a compound of formula I of the invention or a pharmaceutical composition of the invention for use in a method of treating a disorder or disease susceptible to alleviation by antagonism of the adenosine a _2B receptor.

In another aspect, the invention provides the use of a compound of formula I of the invention in the manufacture of a medicament for the treatment of a condition, disorder or disease mediated by the activation of the adenosine a _2B receptor.

In another aspect, the invention provides a method of treating a condition, disorder or disease mediated by activation of the adenosine a _2B receptor in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula I of the invention.

In another aspect, the present invention provides a method of treating a condition, disorder or disease selected from the group consisting of respiratory diseases, inflammatory obstructive airways diseases, inflammatory diseases, metabolic diseases, kidney diseases, vascular diseases, allergic diseases, inflammatory gastrointestinal tract disorders, autoimmune diseases, neurological disorders, otologic disorders and cancer in a subject in need thereof, wherein the method comprises administering to the subject (particularly a human subject) a therapeutically effective amount of a compound of formula I of the present invention or a pharmaceutically acceptable salt or hydrate thereof.

In a very preferred embodiment, the respiratory disease, inflammatory obstructive airways disease, inflammatory disease, metabolic disease, kidney disease, vascular disease, allergic disease, inflammatory gastrointestinal disorder, autoimmune disease, neurological disorder, otologic disorder or the cancer is selected from pulmonary fibrosis, pulmonary arterial 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, allergic rhinitis, intestinal disease, multiple sclerosis, diabetes, juvenile diabetes, diabetes mellitus kidney disease, 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, lung cancer, liver cancer, kidney cancer, rectal cancer, mouth cancer, breast cancer, bladder cancer, colon cancer, skin cancer and prostate cancer, including squamous cell carcinoma and melanoma.

Thus, the compounds and pharmaceutical compositions of the invention are useful for treating inflammatory diseases or obstructive airways diseases, for example to reduce bronchial hyperresponsiveness, remodeling or disease progression. Inflammatory diseases or obstructive airways diseases to which the compounds and pharmaceutical compositions of the present invention are applicable include asthma of any type or genesis including intrinsic (non-allergic) asthma and extrinsic (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchial asthma, exercise-induced asthma, occupational asthma and asthma induced following bacterial infection. The prophylactic efficacy in treating asthma will be demonstrated by a reduction in the frequency or severity of symptomatic attacks, an improvement in pulmonary function, or by a reduction in the need for other symptomatic therapies such as anti-inflammatory (e.g., corticosteroids) or bronchodilatory therapies. Other inflammatory or obstructive airways diseases and conditions in which the compounds and pharmaceutical compositions of the present invention may be employed include Acute Lung Injury (ALI), adult Respiratory Distress Syndrome (ARDS), chronic obstructive pulmonary, airways or lung disease (COPD, COAD or COLD) as well as bronchitis and pneumoconiosis.

Further, the compounds and pharmaceutical compositions of the invention are useful for treating inflammatory or allergic conditions of the skin, such as psoriasis, contact dermatitis and atopic dermatitis, as well as for treating inflammatory diseases or conditions of the eye such as conjunctivitis or diseases affecting the nose including allergic rhinitis.

Further, the compounds and pharmaceutical compositions of the invention are useful for treating inflammatory diseases involving or having an autoimmune component, including autoimmune inflammatory bowel disease, multiple sclerosis, diabetes, and juvenile diabetes (type I diabetes).

Further, the compounds and pharmaceutical compositions of the invention are useful for treating otologic disorders, such as hearing loss.

The compounds and pharmaceutical compositions of the invention may be administered by any suitable route, depending on the nature of the disorder to be treated, for example oral administration (e.g., syrups, tablets, capsules, lozenges, controlled release formulations, fast-dissolving formulations, lozenges, etc.); topical application (e.g., creams, ointments, emulsions, nasal sprays or aerosols, etc.); administration by injection (subcutaneous, intradermal, intramuscular, intravenous, etc.) or administration by inhalation (e.g., dry powder, solution, dispersion, etc.).

Detailed description of the preparation process of the Compounds of formula I

The preparation of the compounds of formula I according to the invention can be carried out in sequential or convergent synthetic routes. The synthesis of the compounds of the invention is given in the schemes below. The skills required for carrying out the reaction and purifying the resulting product are known to the person skilled in the art. Substituents and labels (indice) used in the following process descriptions have the meanings given herein unless otherwise indicated. In more detail, the compounds of formula I may be prepared by the methods given below, by the methods given in the examples or by similar methods. Suitable reaction conditions for the individual reaction steps are known to the person skilled in the art. The reaction sequence is not limited to the sequence shown in the scheme, but the sequence of the reaction steps may be freely changed depending on the starting materials and their respective reactivities. The starting materials are commercially available or can also be prepared by methods analogous to those given below, by the methods described in the examples or by methods known in the art.

The compounds of formula I of the present invention can be prepared according to schemes 1-6 below.

Scheme 1 Synthesis of aminothiazoles from alpha-haloketones and thiourea triazoles

The compounds 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 (e.g. acetonitrile), preferably at elevated temperature, in the presence of a base (preferably a nitrogen-containing base such as triethylamine). In scheme 1 above, the "Hal" substituent of formula II may be any halogen, preferably iodine or bromine, more preferably bromine. The condensation reaction yields a compound of formula I, which can be precipitated directly from the reaction mixture and purified by a suitable procedure, preferably by washing.

Scheme 2 Synthesis of aminothiazoles from ketones and Thiourea triazoles

As shown in scheme 2 above, compounds of formula I can be prepared from ketones of formula IV and thiourea triazoles of formula III in a one-step reaction by in situ halogenation of ketones of formula IV with a suitable halogenating agent, preferably bromine or iodine, in a suitable solvent, such as dioxane or pyridine. The one-step halogenation-condensation reaction can be carried out at room temperature or at elevated temperature.

Scheme 3. Preparation of alpha-halo ketones from ketones of formula IV

As shown in scheme 3 above, the α -halo ketones of formula II can be obtained, for example, by halogenating ketones of formula IV with a suitable halogenating agent in a suitable solvent. In a preferred embodiment, the halogenating agent is bromine, the solvent is acetic acid, and the reaction is carried out at room temperature. In other preferred embodiments, the halogenating agent is iodine and the solvent is pyridine or dioxane.

Scheme 4. Preparation of six membered ring heteroaryl ketones from esters

As shown in scheme 4 above, α - (six membered ring) heteroaryl ketones of formulas IV-a1, IV-a3 and IV-a4 can be prepared from a 4-methyl substituted heteroaryl ring of formula V (a1:z ¹＝Z²＝CH;a3：Z¹＝N、Z²＝CH;a4：Z¹＝CH、Z² =n) and a heteroaryl carboxylate of formula VI. The 4-methylheteroaryl ring may be deprotonated with a suitable base (e.g., lithium bis (trimethylsilyl) amide; liHMDS) in a suitable solvent (e.g., tetrahydrofuran) and reacted with a carboxylate of formula VI in an acylation reaction to produce compounds of formulas IV-a1, IV-a3, and IV-a 4. In a preferred embodiment, Z ¹ and Z ² are each independently N or CH; preferably the heteroaryl ring of formulas V and IV is 4-pyridyl; 4-pyridazinyl; or 4-pyrimidinyl (i.e., wherein the heteroaryl R ^A ring of formula V is one of rings a1, a3, or a 4).

Scheme 5 preparation of five membered ring heteroaryl ketones from alpha-halo ketones

As shown in scheme 5 above, the α - (five membered ring) heteroaryl ketones of formula IV-a2 (x=ch, N) can be prepared by reacting an α -halo ketone of formula VII (e.g., α -bromoketone) with the corresponding substituted imidazole or triazole of formula VIII in a suitable solvent (e.g., acetonitrile). This substitution reaction yields a compound of formula IV wherein X is CH or N (i.e., wherein the R ^A ring is a heteroaryl ring of the five-membered ring of formula a 2).

Scheme 6 preparation of triazolothiouronium

As shown in scheme 6 above, triazole-thioureas of formula III can be prepared in two steps. In a first step, an aminotriazole of formula IX is reacted with benzoyl isothiocyanate in a suitable solvent (e.g., acetone) to form benzoyl-modified triazole-thiourea. In the second step, the triazole-thioureas of formula III are produced by removal of the benzoyl group by treatment with a suitable base (e.g. KOH) in a suitable solvent (e.g. methanol), preferably at elevated temperature (e.g. above 60 ℃).

Examples

The present disclosure is further illustrated by the following examples, which should not be construed as limiting the scope or spirit of the disclosure to the particular processes described herein. It should be understood that the examples are provided to illustrate particular embodiments and are thus not intended to limit the scope of the disclosure. It is to be further understood that various other embodiments, modifications, and equivalents thereof which may occur to persons skilled in the art may be employed without departing from the spirit of the present disclosure and/or the scope of the appended claims.

Abbreviations used in the following examples and elsewhere herein are:

conc. concentrating

EtOAc ethyl acetate

H hours

HPLC high pressure liquid chromatography

MeCN acetonitrile

MeOH methanol

MTBE methyl tert-butyl ether

R.t. room temperature

THF tetrahydrofuran

Preparation example 1: preparation of 2-bromo-1- (2-fluorophenyl) -2- (3-fluoropyridin-4-yl) ethan-1-one hydrobromide salt (intermediate II-1)

Step 1: synthesis of methyl 2-fluorobenzoate:

To a stirred suspension of 2-fluorobenzoic acid (30.0 g,0.214 mol) and K ₂CO₃ (32.5 g,0.235 mol) in N, N-dimethylformamide (150 ml) was added methyl iodide (45.6 g,0.321 mol) and the reaction mixture was stirred at room temperature (r.t.) 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 vacuo to give 31.5g of methyl 2-fluorobenzoate (0.203 mol, 95% yield).

Step 2: synthesis of 1- (2-fluorophenyl) -2- (3-fluoropyridin-4-yl) ethan-1-one (intermediate IV-1):

Lithium bis (trimethylsilyl) amide (168 g, 23% in tetrahydrofuran/ethylbenzene, 0.232 mol) was added dropwise 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) at 0deg.C. After stirring for 1 hour, the reaction mixture was warmed to room temperature and stirred for 16 hours, then triturated with hexane and filtered. The solid was dissolved in 3N HCl (300 mL). The solution was neutralized with saturated aqueous NaHCO ₃ and extracted with ethyl acetate. The combined organic layers were washed with water and then brine, dried over Na ₂SO₄ 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.

Step 3: synthesis of 2-bromo-1- (2-fluorophenyl) -2- (3-fluoropyridin-4-yl) ethan-1-one hydrobromide (intermediate II-1):

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 hour. 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 obtained 2-bromo-1- (2-fluorophenyl) -2- (3-fluoropyridin-4-yl) ethan-1-one hydrobromide salt (intermediate II-1) was used in the next step (11.2 g,83% yield) without purification.

Preparation example 2: preparation of N- (5-cyclobutyl-1H-1, 2, 4-triazol-3-yl) thiourea (intermediate III-1)

To a suspension of 5-cyclobutyl-1H-1, 2, 4-triazol-3-amine (1.37 g,0.01 mol) in chloroform (50 mL) was slowly added benzoyl isothiocyanate (2.44 g,0.0149 mol) at 0deg.C. The mixture was warmed to room temperature and stirred for 8 hours. The solid (0.61 g, crude) was collected, washed with acetonitrile, dried, and then dissolved in methanol (20 mL). An aqueous solution (5 mL) of NaOH (0.243 g,0.0061 mol) was added to the solution, and the mixture was stirred at 50deg.C for an additional 2 hours. Next, methanol was 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).

Preparation example 3: preparation of N- (5-cyclopropyl-1H-1, 2, 4-triazol-3-yl) thiourea (intermediate III-2)

Step 1: synthesis of N- [ (5-cyclopropyl-1H-1, 2, 4-triazol-3-yl) thiocarbamoyl ] benzamide:

To a stirred mixture of 5-cyclopropyl-1H-1, 2, 4-triazol-3-amine (12.1 g,97 mmol) in 200mL of acetone at room temperature was added benzoyl isothiocyanate (19.1 g,116 mmol). 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) thiocarbamoyl ] -benzamide (11 g, 39%). [ M+H ] +:288.08, found: 288.0.

Step 2: synthesis of N- (5-cyclopropyl-1H-1, 2, 4-triazol-3-yl) thiourea (intermediate III-2):

To a suspension of N- [ (5-cyclopropyl-1H-1, 2, 4-triazol-3-yl) thiocarbamoyl ] benzamide in methanol (MeOH) (200 mL) was added a solution of KOH (4.7 g,84mmol in 50mL of water). The mixture was stirred at 60 ℃ for 16 hours, cooled to room temperature and concentrated under reduced pressure. The residue was diluted with water and ethyl acetate (EtOAc) (100/100 mL) and acidified with concentrated HCl to ph=3. The precipitated solid was collected, washed with water and acetonitrile (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.

Preparation example 4: preparation of 3- [ (3-fluoropyridin-4-yl) acetyl ] benzonitrile (intermediate IV-2)

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 Tetrahydrofuran (THF) (20 mL) was added LiHMDS (7 mL,9.1mmol, 20% in tetrahydrofuran/ethylbenzene) at 0 ℃ under an argon atmosphere. The reaction mixture was warmed to room temperature and stirred overnight. The mixture was then diluted with methyl tert-butyl ether (MTBE). The precipitated solid was collected and washed with methyl tert-butyl ether. The filter cake was dissolved in 1N HCl, basified with saturated NaHCO ₃ and extracted with ethyl acetate. 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.

Preparation example 5: preparation of 3- [ (3-methylpyridin-4-yl) acetyl ] benzonitrile (intermediate IV-3)

To a solution of methyl 3-cyanobenzoate (0.34 g,2.1 mmol) and 3, 4-lutidine (0.27 g,2.5 mmol) in tetrahydrofuran (10 mL) was added LiHMDS (4 mL,5.2mmol, 20% in tetrahydrofuran/ethylbenzene) at 0deg.C under an argon atmosphere. The reaction mixture was warmed to room temperature and stirred overnight. The mixture was then diluted with methyl tert-butyl ether. The precipitated solid was collected and washed with methyl tert-butyl ether. The filter cake was dissolved in 1N HCl, basified with saturated NaHCO ₃ and extracted with ethyl acetate. 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, found: 236.0.

Preparation example 6: preparation of 3- [ (2, 5-dimethylpyridin-4-yl) acetyl ] benzonitrile (intermediate IV-4)

To a solution of methyl 3-cyanobenzoate (0.53 g,4.4 mmol) in tetrahydrofuran (15 mL) was added LiHMDS (7 mL,9.1mmol, 20% in tetrahydrofuran/ethylbenzene) at 0deg.C under an argon atmosphere. After stirring at this temperature for 30 minutes, a solution of 2,4, 5-trimethylpyridine (0.64 g,4.4 mmol) in tetrahydrofuran (2 mL) was added dropwise. The reaction mixture was warmed to room temperature and stirred overnight. Next, the mixture was quenched with methanol and concentrated under reduced pressure. The residue was dissolved in methanol and filtered. The filtrate was evaporated under reduced pressure and purified by preparative HPLC to give the compound 3- [ (2, 5-dimethylpyridin-4-yl) acetyl ] benzonitrile (intermediate IV-4) (0.099 g, 10%). [ M+H ] ⁺: 251.13; actual measurement value: 251.0.

Preparation example 7: preparation of 3- [ (3-chloropyridin-4-yl) acetyl ] benzonitrile (intermediate IV-5)

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 tetrahydrofuran (10 mL) was added LiHMDS (3.3 mL,4.3mmol, 20% in tetrahydrofuran/ethylbenzene) at 0deg.C under an argon atmosphere. The reaction mixture was warmed to room temperature and stirred overnight. The mixture was then diluted with methyl tert-butyl ether. The precipitated solid was collected and washed with methyl tert-butyl ether. The filter cake was dissolved in 1N HCl, basified with saturated NaHCO ₃ and extracted with ethyl acetate. 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%).

Preparation example 8: preparation of 3- [ (2, 3-dimethylpyridin-4-yl) acetyl ] benzonitrile (intermediate IV-6)

Step 1: synthesis of 4-bromo-2, 3-lutidine:

A mixture of 2, 3-dimethylpyridine-4-ol (3.3 g,27 mmol) and phosphorus tribromooxide (19.3 g,67 mmol) was stirred at 130℃under an argon atmosphere for 4 hours. 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-lutidine (3.4 g, 68%). [ M+H ] ⁺: 124.08, found: 122.0.

Step 2: synthesis of 2,3, 4-trimethylpyridine:

A mixture of 4-bromo-2, 3-lutidine (1.54 g,8.3 mmol), meB (OH) ₂(1.977g,33mmol)、Na₂CO₃ (2.62 g,27.7 mmol) in dioxane/water (20/5 mL) was bubbled with argon for 5min, then Pd (PPh ₃)₄ (0.48 g)) was added the mixture was heated to 95℃for 72H after the reaction was complete, the mixture was cooled to room temperature and concentrated under reduced pressure the residue was partitioned between methyl tert-butyl ether and water, the organic layer was washed with water and brine, dried and evaporated in vacuo 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; found 120.0.

Step 3: synthesis of 3- [ (2, 3-dimethylpyridin-4-yl) acetyl ] benzonitrile (intermediate IV-6):

LiHMDS (6.4 mL,8.3mmol, 20% in tetrahydrofuran/ethylbenzene) was added to a solution of 2,3, 4-trimethylpyridine (0.46 g,3.8 mmol) in tetrahydrofuran (15 mL) at 0deg.C and under an argon atmosphere. After stirring at this temperature for 30 minutes, a solution of methyl 3-cyanobenzoate (0.61 g,3.8 mmol) in tetrahydrofuran (3 mL) was added dropwise. The reaction mixture was warmed to room temperature and stirred overnight. Next, the mixture was quenched with methanol and concentrated under reduced pressure. The residue was dissolved in methanol 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, found: 251.2.

Preparation example 9: preparation of 3- [ (2-methylpyridin-4-yl) acetyl ] benzonitrile (intermediate IV-7)

LiHMDS (14.5 mL,19mmol, 20% in tetrahydrofuran/ethylbenzene) was added to a solution of 2, 4-lutidine (1.02 g,9.5 mmol) in tetrahydrofuran (20 mL) at 0deg.C under an argon atmosphere. After stirring at 0deg.C for 30 min, a solution of methyl 3-cyanobenzoate (1.02 g,6.3 mmol) in tetrahydrofuran (3 mL) was added dropwise. The reaction mixture was warmed to room temperature and stirred overnight. The mixture was then quenched with methanol and concentrated. The residue was dissolved in methanol 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, found: 237.2.

Preparation example 10: preparation of 3- [ (2-methyl-1H-imidazol-1-yl) acetyl ] benzonitrile (intermediate IV-8)

To a solution of 2-methyl-1H-imidazole (0.911 g,211 mmol) in acetonitrile (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. 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%).

Preparation example 11: preparation of N-1H-1,2, 4-triazol-3-yl-thiourea (intermediate III-3)

Step 1: synthesis of N- [ (1H-1, 2, 4-triazol-3-yl) thiocarbamoyl ] benzamide:

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. Then, the resulting mixture was cooled to room temperature. The precipitated solid was collected, washed with water and acetone, and dried to obtain N- [ (1H-1, 2, 4-triazol-3-yl) thiocarbamoyl ] benzamide (2.9 g, 29%).

Step 2: synthesis of N-1H-1,2, 4-triazol-3-yl-thiourea (intermediate III-3):

A solution of KOH (2.7 g,47.5mmol in 30mL of water) was added to a suspension of N- [ (1H-1, 2, 4-triazol-3-yl) thiocarbamoyl ] benzamide (2.9 g,11.8 mmol) in methanol (50 mL). The reaction mixture was stirred at 60 ℃ for 16 hours, cooled to room temperature, and concentrated under reduced pressure. The residue was diluted with water and ethyl acetate (100/100 mL) and acidified with concentrated HCl to ph=3. The precipitated solid was collected, washed with water and acetonitrile, and dried to give N-1H-1,2, 4-triazol-3-yl thiourea (intermediate III-3) (1.2 g, 70%) which was used in the next step without purification.

Preparation example 12: preparation of N- (5-methyl-1H-1, 2, 4-triazol-3-yl) thiourea (intermediate III-4)

Step 1: synthesis of N- [ (5-methyl-1H-1, 2, 4-triazol-3-yl) thiocarbamoyl ] benzamide:

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. Then, the resulting mixture was cooled to room temperature. The precipitated solid was collected, washed with water and acetone, and dried to obtain N- [ (5-methyl-1H-1, 2, 4-triazol-3-yl) thiocarbamoyl ] benzamide (4.9 g, 49%). [ M+H ] ⁺: 262.07, found: 262.0.

Step 2: synthesis of N- (5-methyl-1H-1, 2, 4-triazol-3-yl) thiourea (intermediate III-4):

A solution of KOH (4.3 g,76mmol in 50mL of water) was added to a suspension of N- [ (5-methyl-1H-1, 2, 4-triazol-3-yl) thiocarbamoyl ] benzamide (4.9 g,19 mmol) in methanol (100 mL). The reaction mixture was stirred at 60 ℃ for 16 hours, cooled to room temperature, and concentrated under reduced pressure. The residue was diluted with water and ethyl acetate (100/100 mL) and acidified with concentrated HCl to ph=3. The precipitated solid was collected, washed with water and acetonitrile, and dried to obtain 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.

Preparation example 13: preparation of N- [5- (hydroxymethyl) -1H-1,2, 4-triazol-3-yl ] thiourea (intermediate III-5)

Step 1: synthesis of N- { [5- (hydroxymethyl) -1H-1,2, 4-triazol-3-yl ] thiocarbamoyl } benzamide:

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. Then, the resulting mixture was 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 ] thiocarbamoyl } benzamide (3.2 g, 67%). [ M+H ] ⁺: 278.06, found: 277.0.

Step 2: synthesis of N- [5- (hydroxymethyl) -1H-1,2, 4-triazol-3-yl ] thiourea (intermediate III-5):

A solution of KOH (2.6 g,46mmol in 20mL of water) was added to a suspension of N- { [5- (hydroxymethyl) -1H-1,2, 4-triazol-3-yl ] thiocarbamoyl } benzamide (3.2 g,11.5 mmol) in methanol (40 mL). The reaction mixture was stirred at 60 ℃ for 16 hours, cooled to room temperature and concentrated under reduced pressure. The residue was diluted with water and ethyl acetate (50/50 mL) and acidified with concentrated HCl to ph=3. The precipitated solid was collected, washed with water and acetonitrile, and dried to obtain 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.

Preparation example 14: preparation of 3- [ (1H-1, 2, 4-triazol-1-yl) acetyl ] benzonitrile (intermediate IV-9)

To a suspension of 1,2, 4-triazole (0.366 g,5.3 mmol) and K ₂CO₃ (0.798 g,5.8 mmol) in an ice/water bath was added 3- (bromoacetyl) benzonitrile (1.055 g,4.7 mmol) in acetonitrile (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.

Preparation example 15: preparation of 3- [ (2-ethyl-1H-imidazol-1-yl) acetyl ] benzonitrile (intermediate IV-10)

To a suspension of 2-ethyl-1H-imidazole (0.482 g,5 mmol) and K ₂CO₃ (0.798 g,5.8 mmol) in ice/water bath was added 3- (bromoacetyl) benzonitrile (0.936 g,4.2 mmol) in acetonitrile (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.

Preparation example 16: preparation of 3- { [2- (hydroxymethyl) -1H-imidazol-1-yl ] acetyl } benzonitrile (intermediate IV-11)

To a suspension of (1H-imidazol-2-yl) methanol (0.488 g,5 mmol) and K ₂CO₃ (0.745 g,5.4 mmol) in ice/water bath was added 3- (bromoacetyl) benzonitrile (0.929 g,4.1 mmol) in acetonitrile (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 ethyl acetate. The organic layer was washed with water and brine, dried and evaporated in vacuo 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.

Preparation example 17: preparation of 4-fluoro-3- [ (2-methyl-1H-imidazol-1-yl) acetyl ] benzonitrile (intermediate IV-12)

Step 1: synthesis of 3-acetyl-4-fluorobenzonitrile:

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 (PPh ₃)₄. The mixture was heated to 90 ℃ C. Overnight. The resulting mixture was cooled to room temperature, poured into water and extracted with methyl tert-butyl ether. 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%).

Step 2: synthesis of 3- (bromoacetyl) -4-fluorobenzonitrile:

3-acetyl-4-fluorobenzonitrile (0.674 g,4.1 mmol) was dissolved in CHCl ₃ (20 mL). To this solution was added Br ₂ (0.759 g,4.7 mmol). The mixture was stirred at room temperature for 2 hours and diluted with saturated NaHCO ₃ 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, found: 242.0.

Step 3: 4-fluoro-3- [ (2-methyl-1H-imidazol-1-yl) acetyl ] benzonitrile (intermediate IV-12):

To a suspension of 2-methyl-1H-imidazole (0.458 g,5.5 mmol) and K ₂CO₃ (0.818 g,5.9 mmol) in acetonitrile (10 mL) was added 3- (bromoacetyl) -4-fluorobenzonitrile (0.896 g,3.7 mmol) in an ice/water bath. 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 ethyl acetate. The organic layer was washed with water and brine, dried and evaporated in vacuo 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.

Preparation example 18: preparation of 3- [ (5-methylpyridazin-4-yl) acetyl ] benzonitrile (intermediate IV-13)

Step 1: synthesis of 4, 5-dimethylpyridazine

To a solution of 3, 6-dichloro-4, 5-dimethylpyridazine (3.3 g,18.5 mmol) in tetrahydrofuran (50 mL) was added DIEA (5.26 g,40.7 mmol) and Pd/C (10%, 0.98g,9.2 mmol). The reaction mixture was degassed and backfilled with hydrogen, followed by stirring at room temperature and under a hydrogen atmosphere until complete consumption of starting material. After completion, the Pd/C catalyst was removed by filtration, and the filtrate was evaporated under reduced pressure. The residue was dissolved in DCM (100 mL) and washed with 5% NH ₄ OH (50 mL). The organic layer was dried over Na ₂SO₄ and evaporated to dryness to give 4, 5-dimethylpyridazine (1.4 g,70% yield).

Step 2: preparation of 3- [ (5-methylpyridazin-4-yl) acetyl ] benzonitrile (intermediate IV-13)

To a solution of 4, 5-dimethylpyridazine (501 mg,4.6 mmol) in tetrahydrofuran (15 mL) was added LiHMDS (4.2 mL,5.0mmol, 20% solution in tetrahydrofuran/ethylbenzene) at 0deg.C and under argon atmosphere. After stirring at 0deg.C for 30 min, a solution of methyl 3-cyanobenzoate (679 mg,4.2 mmol) in tetrahydrofuran (2 mL) was added dropwise. The reaction mixture was warmed to room temperature and stirred overnight. The mixture was diluted with hexane. The solid obtained was collected and dissolved in 1N HCl. The aqueous layer was washed with methyl tert-butyl ether, basified with NaHCO ₃ and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na ₂SO₄ and evaporated in vacuo to give 3- [ (5-methylpyridazin-4-yl) acetyl ] benzonitrile (intermediate IV-13) (0.3 g,30% yield). [ M+H ] ⁺: 238.09, found: 238.4.

Preparation example 19: preparation of 3- [ (pyrimidin-4-yl) acetyl ] benzonitrile (intermediate IV-14)

To a solution of 4-methylpyrimidine (460 mg,4.93 mmol) in tetrahydrofuran (15 mL) was added LiHMDS (5.6 mL,6.72mmol, 20% solution in tetrahydrofuran/ethylbenzene) at 0deg.C and under an argon atmosphere. After stirring at 0deg.C for 30min, a solution of methyl 3-cyanobenzoate (682 mg,4.23 mmol) in tetrahydrofuran (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, dissolved in ethyl acetate and washed with 1N HCl and brine, then dried over Na ₂SO₄ and evaporated in vacuo to give 3- [ (pyrimidin-4-yl) acetyl ] benzonitrile (intermediate IV-14) (0.2 g,20% yield). [ M+H ] ⁺: 223.07, found: 223.09.

Preparation example 20: preparation of 3- [ (pyridazin-4-yl) acetyl ] benzonitrile (intermediate IV-15)

LiHMDS (5.6 mL,6.72mmol, 20% in tetrahydrofuran/ethylbenzene) was added to a solution of 4-methylpyridazine (460 mg,4.93 mmol) in tetrahydrofuran (15 mL) at 0deg.C under an argon atmosphere. After stirring at 0deg.C for 30 min, a solution of methyl 3-cyanobenzoate (720 mg,4.5 mmol) in tetrahydrofuran (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 methyl tert-butyl ether, basified with NaHCO ₃ and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na ₂SO₄ and evaporated in vacuo to give 3- [ (pyridazin-4-yl) acetyl ] benzonitrile (intermediate IV-15) (0.34 g,34% yield). [ M+H ] ⁺: 224.08, found: 224.0.

Preparation example 21: preparation of 3- [ (pyridin-4-yl) acetyl ] benzonitrile (intermediate IV-16)

LiHMDS (4.9 mL,5.85mmol, 20% in tetrahydrofuran/ethylbenzene) was added to a solution of 4-methylpyridine (4631 mg,4.95 mmol) in tetrahydrofuran (15 mL) at 0deg.C and under an argon atmosphere. After stirring at 0deg.C for 30 min, a solution of methyl 3-cyanobenzoate (725 mg,4.5 mmol) in tetrahydrofuran (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 methyl tert-butyl ether, basified with NaHCO ₃ and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na ₂SO₄ and evaporated in vacuo to give 3- [ (pyridin-4-yl) acetyl ] benzonitrile (intermediate IV-16) (0.6 g,60% yield). [ M+H ] ⁺: 223.08, found: 223.02.

Preparation example 22: preparation of 3- [ (5-methylpyrimidin-4-yl) acetyl ] benzonitrile (intermediate IV-17)

To a solution of 4, 5-dimethylpyrimidine (410 mg,3.8 mmol) in tetrahydrofuran (15 mL) was added LiHMDS (3.8 mL,4.55mmol, 20% in tetrahydrofuran/ethylbenzene) at 0deg.C and under an argon atmosphere. After stirring at 0deg.C for 30min, a solution of methyl 3-cyanobenzoate (611 mg,3.8 mmol) in tetrahydrofuran (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, dissolved in ethyl acetate and washed with 1NHCl and brine, then dried over Na ₂SO₄ 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, found: 238.0.

Preparation example 23: preparation of 3- [ (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) acetyl ] benzonitrile (intermediate IV-18)

Step 1: preparation of [ (3-cyanophenyl) (hydroxy) methyl ] phosphonic acid dimethyl ester

3-Formyl-benzonitrile (1.09 g,8.29 mmol) was dissolved in ethyl acetate (15 mL). Then triethylamine (1.26 g,12.4 mmol) was added followed by dimethyl phosphite (1.19 g,10.8 mmol) and the reaction mixture was stirred at room temperature for 2 hours, then diluted with ethyl acetate (350 mL) and washed with saturated aqueous NH ₄ Cl (2 x 30 mL). The organic layer was dried over Na ₂SO₄ and evaporated under reduced pressure to give 1.7g of dimethyl [ (3-cyanophenyl) (hydroxy) methyl ] phosphonate (85% yield). [ M+H ] ⁺: 241.05, found: 242.2.

Step 2: preparation of { (3-cyanophenyl) [ (Oxohexan-2-yl) oxy ] methyl } phosphoric acid dimethyl ester

3, 4-Dihydro-2H-pyran (1.25 g,14.8 mmol) and p-toluenesulfonic acid (37 mg,0.2 mmol) were added to a solution of dimethyl [ (3-cyanophenyl) (hydroxy) methyl ] phosphonate (1.7 g,7.07 mmol) in dry toluene (30 mL) and the reaction mixture was stirred at 50℃under nitrogen atmosphere for 3 hours. Next, the solvent was removed under vacuum and the residue was dissolved with methyl tert-butyl ether. The organic layer was washed with saturated NaHCO ₃ solution and brine, then dried over Na ₂SO₄. The filtrate was evaporated to dryness to obtain dimethyl { (3-cyanophenyl) [ (oxetan-2-yl) oxy ] methyl } phosphate (2.2 g,96% yield). [ M+H ] ⁺: 325.11, found: 324.9.

Step 3: preparation of 3- [ (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) acetyl ] benzonitrile (intermediate IV-18)

Sodium hydride (187 mg,4.46 mmol) was added to a solution of dimethyl { (3-cyanophenyl) [ (oxetan-2-yl) oxy ] methyl } phosphate (967 mg,3.0 mmol) in dry tetrahydrofuran (20 mL) and the mixture was stirred at room temperature for 15 min. Next, 1-methyl-6-oxo-1, 6-dihydropyridine-3-carbaldehyde (489 mg,3.5 mmol) was added and the reaction mixture was stirred at 50℃under nitrogen for 3 hours. The resulting mixture was cooled to room temperature, distilled water was slowly added, and the solvent was removed under reduced pressure. The aqueous layer was extracted with methyl tert-butyl ether and the organic layer was washed with water and brine, dried over Na ₂SO₄ and filtered. The filtrate was evaporated to dryness to give the crude THP-protected intermediate, which was dissolved in ether (10 mL), HCl saturated with ether (sat. Ethereal HCl) (5 mL) was added and the resulting mixture was stirred at ambient temperature for 1 hour. 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, found: 252.1.

Preparation example 24: preparation of N- (5-ethyl-1H-1, 2, 4-triazol-3-yl) thiourea (intermediate III-6)

Step 1: n- [ (5-ethyl-1H-1, 2, 4-triazol-3-yl) thiocarbamoyl ] benzamide

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) thiocarbamoyl ] benzamide (3.2 g) which was used in the next step without purification.

Step 2: preparation of N- (5-ethyl-1H-1, 2, 4-triazol-3-yl) thiourea (intermediate III-6)

A solution of KOH (1.97 g,35mmol in 15mL of water) was added to a suspension of N- [ (5-ethyl-1H-1, 2, 4-triazol-3-yl) thiocarbamoyl ] benzamide (3.2 g,11 mmol) in methanol (40 mL). The reaction mixture was stirred at 60 ℃ for 16 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with water and ethyl acetate (50/50 mL) and acidified with concentrated HCl to ph=3. The layers were separated. The organic layer was dried over Na ₂SO₄, 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, yield 10% in two steps). [ M+H ] +:172.06, found: 172.1.

Preparation example 25: preparation of Compounds of formula I from intermediates II and III

A mixture of the haloketone intermediate of formula II (0.144 g,0.0004mol;1 eq), the thiourea triazole intermediate of formula III (0.072 g,0.0004mol;1 eq) and triethylamine (0.111 g,0.0011mol;2.75 eq) in acetonitrile (2 ml) was heated to 60℃and stirred overnight. The precipitated solid was collected, washed with water and acetonitrile, and dried to obtain the target compound of formula I.

Preparation example 26: preparation of Compounds of formula I from intermediates III and IV via in situ halogenation and precipitation

The ketone intermediate of formula IV (0.63 g,2.6mmol;1 eq.) is dissolved in dioxane (10 mL) at room temperature, followed by the addition of Br ₂ (0.42 g,2.6mmol;1 eq.). The mixture was stirred at room temperature overnight, and thiourea triazole intermediate of formula III (0.48 g,2.6mmol;1 eq.) and EtOH (10 mL) were added. The resulting mixture was stirred overnight. The precipitated solid was collected, washed with saturated NaHCO ₃, water, cold acetonitrile and dried to obtain the target compound of formula I. No additional purification is required.

Preparation example 27: preparation of Compounds of formula I from intermediates III and IV via in situ halogenation and chromatography

The ketone intermediate of formula IV (0.091 g,0.36mmol;1 eq.) is dissolved in dioxane (2 mL) at room temperature followed by Br ₂ (0.070 g,0.44mmol;1.2 eq.) added. The mixture was stirred at room temperature overnight, and thiourea triazole intermediate of formula III (0.066 g,0.36mmol;1 eq.) and EtOH (2 mL) were added. The resulting mixture was stirred overnight. After completion of the reaction, the solution is basified with NH ₄ OH and purified by preparative HPLC to give the desired compound of formula I.

Preparation example 28: when R ^A is a2, compounds of formula I are prepared from intermediates IV and III

A mixture of the ketone intermediate of formula IV (0.174 g,0.77mmol;1 eq.) of formula A=a2, the thiourea triazole intermediate of formula III (0.142 g,0.77mmol;1 eq.), iodine (0.196 g,0.77mmol;1 eq.) and pyridine (2 mL) was stirred overnight at room temperature. The resulting mixture was diluted with water (50 mL). The solid obtained was filtered, stirred in water (50 mL) for 30 minutes and filtered again. The crude product was purified by prep HPLC to give the title compound I with a=a2.

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)

Compound 1 was prepared according to preparation 25 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). Scale of: 0.4mmol.

Specifically, 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 to a solution of triethylamine (0.111 g;1.1 mmol) in acetonitrile (2 mL). The mixture was heated to 60 ℃ 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; 0.046g;31% yield) ).LCMS[M+H]⁺：411.2.¹H NMR(DMSO-d₆,500MHz):δ(ppm)1.90(m,1H),2.03(m,1H),2.29(m,4H),3.59(m,1H),7.18(m,2H),7.26(t,1H),7.43(m,1H),7.52(m,1H),8.27(s,1H),8.54(s,1H),11.61(s,1H),13.36(s,1H).

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)

Compound 2 was prepared according to preparation 26 from 3- [ (3-fluoropyridin-4-yl) acetyl ] benzonitrile (intermediate IV-2), br ₂ and N- (5-cyclopropyl-1H-1, 2, 4-triazol-3-yl) thiourea (intermediate III-2). Scale of: 2.6mmol.

Specifically, 3- [ (3-fluoropyridin-4-yl) acetyl ] benzonitrile (0.63 g,2.6 mmol) was dissolved in dioxane (10 mL) at room temperature, followed by the addition of Br ₂ (0.42 g,2.6 mmol). The mixture was stirred at room temperature overnight 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 NaHCO ₃, water, cold acetonitrile and dried under vacuum to give the 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; 0.32g;30% yield ).LCMS[M+H]⁺：404.2.¹H NMR(500MHz,DMSO-d₆):δ(ppm)0.91(m,2H),1.03(m,2H),2.00(m,1H),7.37(t,1H),7.53(t,1H),7.66(d,1H),7.79(d,1H),7.82(s,1H),8.38(d,1H),8.58(s,1H),11.55(s,1H),13.33(s,1H).

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)

Compound 3 was prepared according to preparation 26 from 3- [ (3-methylpyridin-4-yl) acetyl ] benzonitrile (intermediate IV-3), br ₂ and N- (5-cyclopropyl-1H-1, 2, 4-triazol-3-yl) thiourea (intermediate III-2). Scale of: 1mmol.0.09g; yield of 23% .[M+H]⁺：400.0.¹H NMR(400MHz,DMSO-d₆):δ(ppm)0.91(m,2H),1.03(m,2H),1.98(m,1H),2.00(s,3H),7.32(d,1H),7.47(t,1H),7.53(d,1H),7.72(m,2H),8.44(d,1H),8.52(s,1H),11.41(s,1H),13.31(s,1H).

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)

Compound 4 was prepared according to preparation 27 from 3- [ (2, 5-dimethylpyridin-4-yl) acetyl ] benzonitrile (intermediate IV-4), br ₂ and N- (5-cyclopropyl-1H-1, 2, 4-triazol-3-yl) thiourea (intermediate III-2). Scale of: 0.36mmol.

Specifically, 3- [ (2, 5-dimethylpyridin-4-yl) acetyl ] benzonitrile (0.091 g,0.36 mmol) was dissolved in dioxane (2 mL) at room temperature, followed by the addition of Br ₂ (0.070 g,0.44 mmol). The mixture was stirred at room temperature overnight 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 completion of the reaction, the solution was quenched with NH ₄ OH and purified by preparative HPLC to give compound 4 (0.022 g, 15% yield ).[M+H]⁺：414.2.¹H NMR(500MHz,DMSO-d₆):δ(ppm)0.89(m,2H),1.02(m,2H),1.89(s,3H),1.98(m,1H),2.42(s,3H),7.22(s,1H),7.46(t,1H),7.52(d,1H),7.72(d,1H),7.75(s,1H),8.36(s,1H),11.37(s,1H),13.29(s,1H).

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)

Compound 5 was prepared according to preparation 26 from 3- [ (3-chloropyridin-4-yl) acetyl ] benzonitrile (intermediate IV-5), br ₂ and N- (5-cyclopropyl-1H-1, 2, 4-triazol-3-yl) thiourea (intermediate III-2). Scale of: 1.8mmol;0.32g; yield of 43% .[M+H]⁺：420.0.¹H NMR(400MHz,DMSO-d₆):δ(ppm)0.91(m,2H),1.04(m,2H),2.00(m,1H),7.53(m,3H),7.76(s,2H),8.53(s,1H),8.73(s,1H),11.55(s,1H),13.35(s,1H).

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)

Compound 6 was prepared according to preparation 27 from 3- [ (2, 3-dimethylpyridin-4-yl) acetyl ] benzonitrile (intermediate IV-6), br ₂ and N- (5-cyclopropyl-1H-1, 2, 4-triazol-3-yl) thiourea (intermediate III-2). Scale of: 0.22mmol;0.023g; yield of 25% .[M+H]⁺：414.2.¹H NMR(500MHz,DMSO-d₆):δ(ppm)0.92(m,2H),1.04(m,2H),2.00(s,3H),2.02(m,1H),2.48(s,3H),7.18(d,1H),7.48(t,1H),7.54(d,1H),7.73(d,1H),7.78(s,1H),8.32(d,1H),11.37(s,1H),13.29(s,1H).

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)

Compound 7 was prepared according to preparation 27 from 3- [ (2-methylpyridin-4-yl) acetyl ] benzonitrile (intermediate IV-7), br ₂ and N- (5-cyclopropyl-1H-1, 2, 4-triazol-3-yl) thiourea (intermediate III-2). Scale of: 0.45mmol;0.027g;15% yield .[M+H]⁺：400.0.¹H NMR(500MHz,DMSO-d₆):δ(ppm)0.92(m,2H),1.05(m,2H),2.02(m,1H),2.54(s,3H),7.22(d,1H),7.55(s,1H),7.61(t,1H),7.77(d,1H),7.89(d,1H),7.92(s,1H),8.42(d,1H),11.82(s,1H),13.41(s,1H).

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)

Compound 8 was prepared according to preparation 28 from 3- [ (2-methyl-1H-imidazol-1-yl) acetyl ] benzonitrile (intermediate IV-8), I ₂ and N- (5-cyclopropyl-1H-1, 2, 4-triazol-3-yl) thiourea (intermediate III-2). Scale of: 0.77mmol.

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 solid obtained was filtered, stirred in water (50 mL) for 30 minutes and filtered again. The crude product was purified by preparative HPLC to give compound 8 (0.022 g,7.3% yield ).[M+H]⁺：389.0.¹H NMR(500MHz,DMSO-d₆):δ(ppm)0.90(m,2H),1.03(m,2H),1.96(m,1H),2.01(s,3H),7.03(s,1H),7.35(s,1H),7.39(d,1H),7.48(s,1H),7.54(t,1H),7.76(d,1H),11.57(s,1H),13.37(s,1H).

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)

Compound 9 was prepared according to preparation 28 from 3- [ (2-methyl-1H-imidazol-1-yl) acetyl ] benzonitrile (intermediate IV-8), I ₂ and N-1H-1,2, 4-triazol-3-yl thiourea (intermediate III-3). Scale of: 0.57mmol;0.047g,23% yield .[M+H]⁺：349.2.¹H NMR(DMSO-d₆,400MHz):δ(ppm)2.04(s,3H),7.05(s,1H),7.36(s,1H),7.42(d,1H),7.48–7.62(m,2H),7.79(d,1H),8.48(s,1H),11.76(s,1H),13.79(s,1H).

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)

Compound 10 was prepared according to preparation 28 from 3- [ (2-methyl-1H-imidazol-1-yl) acetyl ] benzonitrile (intermediate IV-8), I ₂ and N- (5-methyl-1H-1, 2, 4-triazol-3-yl) thiourea (intermediate III-4). Scale of: 0.55mmol;0.046g,23% yield .[M+H]⁺：363.2.¹H NMR(DMSO-d₆ 400MHz):δ(ppm)2.03(s,3H),2.34(s,3H),7.05(s,1H),7.36(s,1H),7.42(d,1H),7.51(s,1H),7.56(t,1H),7.79(d,1H),11.62(s,1H),13.35(s,1H).

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)

Compound 11 was prepared according to preparation 28 from 3- [ (2-methyl-1H-imidazol-1-yl) acetyl ] benzonitrile (intermediate IV-8), I ₂ and N- [5- (hydroxymethyl) -1H-1,2, 4-triazol-3-yl ] thiourea (intermediate III-5). Scale of: 0.55mmol;0.069g,34% yield .[M+H]⁺：379.0.¹H NMR(DMSO-d₆,400MHz):δ(ppm)2.04(s,3H),4.56(d,2H),5.72(s,1H),7.05(d,1H),7.36(d,1H),7.42(d,1H),7.49–7.60(m,2H),7.78(d,1H),11.67(s,1H),13.61(s,1H).

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)

Compound 12 was prepared according to preparation 27 from 3- [ (2, 5-dimethylpyridin-4-yl) acetyl ] benzonitrile (intermediate IV-4), br ₂ and N-1H-1,2, 4-triazol-3-yl thiourea (intermediate III-3). Scale 0.27mmol;0.039g; yield of 39% .[M+H]⁺：374.4.¹H NMR(DMSO-d₆,400MHz):δ(ppm)1.93(s,3H),2.44(s,3H),7.24(s,1H),7.49(t,1H),7.55(d,1H),7.74(d,1H),7.81(s,1H),8.19–8.57(m,2H),11.37–12.19(m,1H),13.66(s,1H).

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)

Compound 13 was prepared according to preparation 27 from 3- [ (2, 5-dimethylpyridin-4-yl) acetyl ] benzonitrile (intermediate IV-4), br ₂ and N- (5-methyl-1H-1, 2, 4-triazol-3-yl) thiourea (intermediate III-4). Scale of: 0.26mmol;0.013g;13% yield .[M+H]⁺：388.2.¹H NMR(DMSO-d₆,400MHz):δ(ppm)1.91(s,3H),2.32(s,3H),2.44(s,3H),7.24(s,1H),7.49(t,1H),7.55(d,1H),7.74(d,1H),7.79(s,1H),8.37(s,1H),11.41(s,1H),13.24(s,1H).

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)

Compound 14 was prepared according to preparation 27 from 3- [ (2, 5-dimethylpyridin-4-yl) acetyl ] benzonitrile (intermediate IV-4), br ₂ and N- [5- (hydroxymethyl) -1H-1,2, 4-triazol-3-yl ] thiourea (intermediate III-5). Scale of: 0.25mmol;0.041g; yield of 41% .[M+H]⁺：404.2.¹H NMR(DMSO-d₆,400MHz):δ(ppm)1.91(s,3H),2.44(s,3H),4.55(d,2H),5.57–5.75(m,1H),7.25(s,1H),7.49(t,1H),7.55(d,1H),7.74(d,1H),7.80(s,1H),8.37(s,1H),11.58(s,1H),13.39(s,1H).

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)

Compound 15 was prepared according to preparation 28 from 3- [ (1H-1, 2, 4-triazol-1-yl) acetyl ] benzonitrile (intermediate IV-9), I ₂ and N- (5-cyclopropyl-1H-1, 2, 4-triazol-3-yl) thiourea (intermediate III-2). Scale of: 0.4mmol;0.013g,9% yield .[M+H]⁺：376.2.¹H NMR(DMSO-d₆,400MHz):δ(ppm)0.89–0.96(m,2H),1.03–1.07(m,2H),1.95–2.05(m,1H),7.46(d,1H),7.54–7.61(m,2H),7.81(d,1H),8.37(s,1H),8.86(s,1H),11.73(s,1H),13.44(s,1H).

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)

Compound 16 was prepared according to preparation 28 from 3- [ (2-ethyl-1H-imidazol-1-yl) acetyl ] benzonitrile (intermediate IV-10), I ₂ and N- (5-methyl-1H-1, 2, 4-triazol-3-yl) thiourea (intermediate III-4). Scale of: 0.53mmol;0.038g,19% yield .[M+H]⁺：377.0.¹H NMR(DMSO-d₆,400MHz):δ(ppm)0.99(t,3H),2.29–2.38(m,5H),7.08(d,1H),7.37(d,1H),7.40(d,1H),7.49–7.59(m,2H),7.78(d,1H),11.59(s,1H),13.33(s,1H).

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)

Compound 17 was prepared according to preparation 28 from 3- { [2- (hydroxymethyl) -1H-imidazol-1-yl ] acetyl } benzonitrile (intermediate IV-11), I ₂ and N- (5-cyclopropyl-1H-1, 2, 4-triazol-3-yl) thiourea (intermediate III-2). Scale of: 0.5mmol;0.041g,20% yield .[M+H]⁺：405.2.¹H NMR(DMSO-d₆,400MHz):δ(ppm)0.83–0.95(m,2H),0.96–1.10(m,2H),1.94–2.04(m,1H),4.28(d,2H),5.28(t,1H),7.09(s,1H),7.32(s,1H),7.44–7.56(m,3H),7.75(d,1H),11.53(s,1H),13.37(s,1H).

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)

Compound 18 was prepared according to preparation 28 from 4-fluoro-3- [ (2-methyl-1H-imidazol-1-yl) acetyl ] benzonitrile (intermediate IV-12), I ₂ and N- (5-cyclopropyl-1H-1, 2, 4-triazol-3-yl) thiourea (intermediate III-2). Scale of: 1.1mmol;0.022g,7.3% yield .[M+H]⁺：407.0.¹H NMR(DMSO-d₆,400MHz):δ(ppm)0.88–0.94(m,2H),1.01–1.07(m,2H),1.95–2.03(m,1H),2.05(s,3H),6.84(d,1H),7.17(d,1H),7.46(t,1H),7.91–7.97(m,2H),11.59(s,1H),13.39(s,1H).

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)

Compound 19 was prepared according to preparation 28 from 3- { [2- (hydroxymethyl) -1H-imidazol-1-yl ] acetyl } benzonitrile (intermediate IV-11), I ₂ and N-1H-1,2, 4-triazol-3-ylthiourea (intermediate III-3). Scale of: 0.41mmol;0.025g,17% yield .[M+H]⁺：365.08.¹H NMR(DMSO-d₆,500MHz):δ(ppm)2.29(s,3H),4.26(d,J＝5.1Hz,2H),5.24(t,J＝5.3,5.3Hz,1H),7.06(s,1H),7.27(s,1H),7.42–7.55(m,3H),7.72(d,J＝7.4Hz,1H),11.61(s,1H),13.21(s,1H).

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)

Compound 20 was prepared according to preparation 28 from 3- { [2- (hydroxymethyl) -1H-imidazol-1-yl ] acetyl } benzonitrile (intermediate IV-11), I ₂ and N- (5-ethyl-1H-1, 2, 4-triazol-3-yl) thiourea (intermediate III-6). Scale of: 0.51mmol;0.045g,22% yield .[M+H]⁺：393.12.¹H NMR(DMSO-d₆,500MHz):δ(ppm)1.22(t,J＝7.6,7.6Hz,3H),2.67(q,J＝7.6,7.6,7.6Hz,2H),4.27(d,J＝5.4Hz,2H),5.26(t,J＝5.6,5.6Hz,1H),7.07(d,J＝1.4Hz,1H),7.30(d,J＝1.4Hz,1H),7.46(dt,J＝8.1,1.5,1.5Hz,1H),7.49–7.55(m,2H),7.73(dt,J＝7.5,1.5,1.5Hz,1H),11.55(s,1H),13.32(s,1H).

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)

Compound 21 was prepared according to preparation 28 from 3- { [2- (hydroxymethyl) -1H-imidazol-1-yl ] acetyl } benzonitrile (intermediate IV-11), I ₂ and N- (5-methyl-1H-1, 2, 4-triazol-3-yl) thiourea (intermediate III-4). Scale of: 0.4mmol;0.015g,10% yield .[M+H]⁺：379.1.¹H NMR(DMSO-d₆,500MHz):δ(ppm)2.29(s,3H),4.26(d,J＝5.1Hz,2H),5.24(t,J＝5.3,5.3Hz,1H),7.06(s,1H),7.27(s,1H),7.42–7.55(m,3H),7.72(d,J＝7.4Hz,1H),11.61(s,1H),13.21(s,1H).

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)

Compound 22 was prepared according to preparation 27 from 3- [ (3-methylpyridin-4-yl) acetyl ] benzonitrile (intermediate IV-3), br ₂ and N-1H-1,2, 4-triazol-3-ylthiourea (intermediate III-3). Scale of: 0.84mmol;0.035g,12% yield .[M+H]⁺：360.1.¹H NMR(DMSO-d₆,400MHz):δ(ppm)2.03(s,3H),7.33(d,1H),7.49(t,1H),7.55(m,1H),7.74(d,1H),7.78(s,1H),8.38(s,1H),8.45(d,1H),8.53(s,1H),11.69(s,1H),13.66(s,1H).

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)

Compound 23 was prepared according to preparation 27 from 3- [ (5-methylpyridazin-4-yl) acetyl ] benzonitrile (intermediate IV-13)), br ₂ and N- (5-cyclopropyl-1H-1, 2, 4-triazol-3-yl) thiourea (intermediate III-2). Scale of: 0.62mmol;0.058g,23% yield .[M+H]⁺：401.13.¹H NMR(DMSO-d₆,400MHz):δ(ppm)0.91(m,2H),1.03(m,2H),2.00(tt,1H),2.10(s,3H),7.51(m,2H),7.78(m,2H),8.95(s,1H),9.16(s,1H),11.59(s,1H),13.34(s,1H).

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)

Compound 24 was prepared according to preparation 27 from 3- [ (pyrimidin-4-yl) acetyl ] benzonitrile (intermediate IV-14)), br ₂ and N- (5-cyclopropyl-1H-1, 2, 4-triazol-3-yl) thiourea (intermediate III-2). Scale of: 0.78mmol;0.045g,15% yield .[M+H]⁺：387.1.¹H NMR(DMSO-d₆,400MHz):δ(ppm)0.94(m,2H),1.05(m,2H),2.04(tt,1H),6.97(dd,1H),7.68(t,1H),7.88(d,1H),7.95(d,1H),8.02(s,1H),8.49(d,1H),9.04(d,1H),11.63(s,1H),13.37(s,1H).

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)

Compound 25 was prepared according to preparation 27 from 3- [ (pyridazin-4-yl) acetyl ] benzonitrile (intermediate IV-15), br ₂ and N- (5-cyclopropyl-1H-1, 2, 4-triazol-3-yl) thiourea (intermediate III-2). Scale of: 0.78mmol;0.039g,13% yield .[M+H]⁺：387.11.¹H NMR(DMSO-d₆,400MHz):δ(ppm)0.94(m,2H),1.05(m,2H),2.02(m,1H),7.51(dd,1H),7.60(t,1H),7.74(d,1H),7.87(d,1H),7.91(s,1H),8.97(s,1H),9.11(d,1H),11.61(s,1H),13.33(s,1H).

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)

Compound 26 was prepared according to preparation 27 from 3- [ (pyridin-4-yl) acetyl ] benzonitrile (intermediate IV-16), br ₂ and N- (5-cyclopropyl-1H-1, 2, 4-triazol-3-yl) thiourea (intermediate III-2). Scale of: 0.9mmol;0.075g,25% yield .[M+H]+：386.12.¹H NMR(DMSO-d₆,400MHz):δ(ppm)0.92(m,2H),1.04(m,2H),2.00(m,1H),7.22(m,2H),7.57(t,1H),7.71(d,1H),7.83(d,1H),7.87(s,1H),8.49(m,2H),11.53(s,1H),13.33(s,1H).

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)

Compound 27 was prepared according to preparation 27 from 3- [ (5-methylpyrimidin-4-yl) acetyl ] benzonitrile (intermediate IV-17), br ₂, and N- (5-cyclopropyl-1H-1, 2, 4-triazol-3-yl) thiourea (intermediate III-2). Scale of: 0.62mmol;0.033g,13% yield .[M+H]⁺：401.13.¹H NMR(DMSO-d₆,400MHz):δ(ppm)0.91(m,2H),1.03(m,2H),1.82(s,3H),2.00(tt,1H),7.53(m,2H),7.80(m,2H),8.66(s,1H),9.05(s,1H),11.56(s,1H),13.33(s,1H).

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)

Compound 28 was prepared according to preparation 28 from 3- [ (2-ethyl-1H-imidazol-1-yl) acetyl ] benzonitrile (intermediate IV-10), I ₂ and N- (5-cyclopropyl-1H-1, 2, 4-triazol-3-yl) thiourea (intermediate III-2). Scale of: 0.4mmol;0.015g,10% yield .[M+H]⁺：403.2.¹H NMR(DMSO-d₆,400MHz):δ(ppm)0.92(m,2H),0.99(t,3H),1.04(m,2H),2.00(m,1H),2.36(q,2H),7.10(s,1H),7.39(m,2H),7.51(s,1H),7.56(t,1H),7.78(d,1H),11.59(s,1H),13.39(s,1H).

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)

Compound 29 was prepared according to preparation 28 from 3- [ (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) acetyl ] benzonitrile (intermediate IV-18), I ₂ and N- (5-cyclopropyl-1H-1, 2, 4-triazol-3-yl) thiourea (intermediate III-2). Scale of: 0.24mmol;0.017g,17% yield .[M+H]⁺：416.2.¹H NMR(DMSO-d₆,500MHz):δ(ppm)0.89(m,2H),1.01(m,2H),1.97(m,1H),3.43(s,3H),6.35(d,1H),7.17(dd,1H),7.53(t,1H),7.74(d,1H),7.77(m,1H),7.90(s,2H),11.23(s,1H),13.23(s,1H).

Example 30: intracellular cAMP functional assay of Compounds of formula I

In this functional cell assay, the activity of compounds in human adenosine receptors a _2A、A_2B、A₁ and a ₃ was determined using HTRF kit (perkin elmer). HEK293 cells expressing recombinant human adenosine receptors were grown in antibiotic-free medium, isolated by gentle washing with PBS-EDTA (5 mM EDTA), recovered by centrifugation, and resuspended in assay buffer (KRH: 5mM KCl, 1.25mM MgSO ₄, 124mM NaCl, 25mM HEPES, 13.3mM glucose, 1.25mM KH ₂PO₄、1.45mM CaCl₂, 0.5g/l BSA, supplemented with 1mM IBMX or 25. Mu.M rolipram) prior to testing. Dose response curves were performed in parallel with the reference compound. The reference compounds for a _2A、A_2B、A₁ and a ₃ are NECA, ZM241385, DPCPX, MRS, respectively. Mu.l of cells were mixed with 6. Mu.l of test compound at increasing concentrations followed by incubation for 10 minutes. Thereafter, 6 μl of the reference agonist was added at a final concentration corresponding to historical EC ₈₀. Next, the plates were incubated at room temperature for 30 minutes. After addition of lysis buffer and incubation for 1 hour, cAMP concentrations were estimated using HTRF kit according to manufacturer's instructions. Table 1 below shows the results of the functional activity of specific compounds on adenosine receptors.

Example 31: radioligand binding assay

The adenosine receptors a _l、A_2A、A_2B and a ₃ were subjected to a filter binding assay. Radioligand binding competition assays were performed in duplicate in wells of 96-well plates (Master Block, greine, 786201) containing binding buffer, receptor membrane extract, immobilized concentration of tracer, and increasing concentration of test compound. To eliminate the effect of the buffer composition, the binding buffers for the 4 receptors were identical, containing 50mM tris-HCl pH 7.4, 5mM MgCl, 1mM EDTA, 150mM NaCl, 0.1% sodium azide and 5U/ml adenosine deaminase. Nonspecific binding was minimized by co-incubation with a 200-fold excess of cold competitor. In all radioligand binding experiments, samples were incubated at 25 ℃ for 60 minutes in a final volume of 0.1ml of binding buffer, followed by filtration on a Unifilter plate (perkin elmer) that had been pre-treated for 2 hours to limit non-specific binding of the tracer. Filters were washed 5 times with 0.5ml ice-cold wash buffer (50 mM tris-HCl pH 7.4, 5mM MgCl, 1mM EDTA) and 50. Mu.L Microscint 20 (Perkin Elmer) was added to each filter. Plates were incubated for 15 min at room temperature on an orbital shaker, followed by counting with TopCount ^TM for 1 min/well.

For the A _l receptor, experiments were performed with [3H ] -DPCPX and membranes from CHO-Kl cells transfected with human A _l receptor (Eurocreen FAST-001B).

For the A _2A receptor, experiments were performed with [3H-NECA and membranes from HEK293 cells transfected with human A _2A receptor (Eurocreen FAST-002B).

For the A _2B receptor, experiments were performed with [3H ] -DPCPX and membranes prepared from HEK293 cells transfected with human A _2B receptor (Euros Green FAST-003B).

For the A ₃ receptor, experiments were performed with [125IJ-MECA and membranes from CHO-Kl cells transfected with human A ₃ receptor (Euros Green FAST-004B).

Table 1 shows the in vitro cAMP binding activity of specific compounds as measured by a functional cAMP accumulation assay (example 30) and a radioligand binding assay (example 31) in HEK293 cells. Table 1 shows the affinity of specific compounds for human a _2B and binding affinity for human a ₁ and a ₃ receptors. The results indicate a higher selectivity for the a _2B (and a ₁) receptor than for the a ₃ receptor.

Table 1: binding affinity of selected compounds as measured by intracellular assays and radioligand binding

^* As measured by radioligand binding.

Example 32: CPM thermal stability test

Compounds of the invention were screened for a _2B/A_2A receptor binding and stability using a CPM thermal stability assay (a.i. alexandrov et al 2008,Structure 16,351-359). The protein concentration in the reaction was 1 μΜ, while the compound concentration of the data shown was 10 μΜ. The final concentration of CPM dye (Invitrogen D346) in the reaction was 7.5. Mu.g/ml. The reaction buffer of A _2B was 40mM tris-HCl pH 7.4, 200mM NaCl, 0.05% DDM and 0.005% CHS. The reaction buffer of A _2A was 40mM tris-HCl pH 7.4, 200mM NaCl and 0.15% DDM. To achieve binding, the compounds were incubated with purified receptors for 30 minutes on ice prior to addition of CPM dye. The measurement was performed using a Rotor-GENE Q QPCR Instrument (QIAGEN). The temperature was increased from 25 ℃ to 90 ℃ at a rate of 6 ℃ increase per minute. Gain (gain) was set as the first sample in operation, which was always ligand-free protein used as reference. CPM dye binding was monitored using 365nm excitation and 460nm emission. The data were analyzed using instrument software and the melting temperature was calculated as the average of each repetition (the average of the repetitions differ by no more than 0.5 ℃). The increase in melting temperature (Δt _m), i.e. the thermal shift value, of each compound is calculated by subtracting the melting temperature of the apolipoprotein receptor from the melting temperature of the receptor bound to the corresponding compound. The results are shown in Table 2 below.

Table 2: cAMP binding affinity of selected compounds as measured by thermal stability assay

Claims

1.A compound of formula I, or a pharmaceutically acceptable salt, solvate or hydrate thereof,

Wherein,

R ^A2 is independently at each occurrence halogen, -OC ₁-C₈ alkyl or-OH;

R ^B2 is independently at each occurrence halogen, -OH or-OC ₁-C₈ alkyl.

2. The compound of claim 1, wherein R ¹ is H, halo, -C ₁-C₈ alkyl, -C ₃-C₈ cycloalkyl, or-OC ₁-C₈ alkyl, wherein each alkyl, cycloalkyl, or-O-alkyl is optionally substituted with one or more R ².

3. The compound of claim 1 or 2, wherein R ² is-OH, halogen, or-OC ₁-C₄ alkyl.

4. A compound according to any one of the preceding claims, wherein R ^A is imidazolyl, triazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl; wherein each imidazolyl, triazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl is optionally substituted with one or more R ^A1.

5. A compound according to any one of the preceding claims, wherein R ^A1 is independently halogen, -OH, -C ₁-C₄ alkyl or-C ₃-C₆ cycloalkyl, wherein each alkyl or cycloalkyl is optionally substituted by one or more halogen or-OH.

6. A compound according to any one of the preceding claims, wherein R ^A is selected from:

Wherein,

X is-CH-or N;

7. A compound according to any one of the preceding claims wherein R ^B is selected from phenyl, oxazolyl, pyridinyl, pyrimidinyl, pyridazinyl and pyrazinyl, wherein each phenyl, oxazolyl, pyridinyl, pyrimidinyl, pyridazinyl and pyrazinyl is optionally substituted with one or more R ^B1.

8. A compound according to any one of the preceding claims, wherein R ^B1 is selected from halogen, -OH, cyano, -C ₁-C₄ alkyl and-C ₁-C₄ alkoxy, wherein each alkyl and alkoxy is independently substituted with one or more halogen, -OH or-OC ₁-C₄ alkoxy groups.

9. A compound according to any one of the preceding claims, wherein R ^B is selected from:

Wherein R ^B3 is independently at each occurrence selected from hydrogen, halogen, -C ₁-C₈ alkyl, -C ₁-C₈ haloalkyl, -C ₁-C₈ alkoxy, -C ₁-C₈ hydroxyalkyl, -C ₁-C₈ alkoxyalkyl, and-CN.

10. A compound according to any one of the preceding claims, wherein R ^B is phenyl substituted with one or two R ^B1, wherein R ^B1 is independently at each occurrence cyano or fluoro.

11. A compound according to any one of the preceding claims, wherein the compound is a compound of formula Ia3b or Ia2 b:

Wherein,

x is-CH-or N;

Y is independently at each occurrence-CH-or N, wherein at least one Y is-CH-;

R ^B2 is independently at each occurrence halogen, -OH or-OC ₁-C₈ alkyl.

12. A compound according to any one of the preceding claims, wherein the compound is of formula Ia1b1, ia1b2, ia1b3, ia2b1, ia2b2, ia2b3, ia3b1, ia3b2 or Ia3b 3:

Wherein,

x is-CH-or N;

Y is independently at each occurrence-CH-or N, wherein at least one Y is-CH-;

13. The compound of claim 1, wherein the compound is selected from the group consisting of:

14. A pharmaceutical composition comprising a compound according to any one of the preceding claims and a pharmaceutically acceptable diluent or carrier.

15. A compound according to any one of claims 1 to 13 or a pharmaceutical composition according to claim 14 for use as a medicament, preferably in a method of treatment of a condition, disorder or disease mediated by the activation of the adenosine a _2B receptor.