Compounds and compositions for treating respiratory diseases

Abstract

The present invention relates to a novel compound for preventing or treating respiratory diseases such as asthma, acute and chronic inflammatory conditions and fibrotic diseases or conditions in which fibrosis leads to the pathology of the condition. The present invention also relates to methods for preparing these compounds, and to compositions comprising these compounds. The present invention also relates to the use of the compounds and compositions comprising the compounds in treating or preventing respiratory diseases, acute and chronic inflammatory conditions and fibrotic diseases or conditions in which fibrosis leads to the pathology of the condition.

Description

[0001] This application claims priority to AU2018904241 and AU2018904242 (both filed on 7 November 2018). The entire contents of each of AU2018904241 and AU2018904242 are incorporated herein by reference. Technical Field

[0002] The present invention provides imidazole-based compounds that show potential in the treatment of respiratory diseases such as asthma and related disorders, acute and chronic inflammatory disorders, and fibrotic diseases or disorders in which fibrosis contributes to the pathology of the disorder. Background Art

[0003] Asthma is a syndrome that includes a variety of different types of diseases that vary in severity, causes, and inducing factors. The common features of the asthmatic syndrome are reversible airway obstruction, airway hyperresponsiveness, and airway inflammation, the most prominent feature of which is the infiltration of the airway wall by eosinophils and T lymphocytes, in addition to mast cell activation.

[0004] Current asthma medications include short-acting and long-acting β2-adrenergic receptor selective agonists (SABA and LABA) and inhaled corticosteroids (ICS). Ultra-LABA is now available on the market. Short-acting and long-acting muscarinic receptor antagonists (SAMA and LAMA) are used in some patients, usually in combination with other bronchodilators and anti-inflammatory drugs, especially ICS. Leukotriene receptor antagonists (LTRA) can also be added to different treatment regimens. Recently, the monoclonal antibody mepolizumab has shown additional benefits for the combination of ICS and LABA in selected patients, which neutralizes the eosinophil chemoattractant, interleukin-5. However, especially for severe asthma, patients still have symptoms and the disease periodically worsens, called exacerbations. There is a considerable unmet need for drug treatment of severe asthma. In most cases, these asthma exacerbations are believed to be caused by respiratory viral infections of the lower respiratory tract. The viruses that cause these exacerbations include respiratory syncytial virus, influenza virus and rhinovirus, which infect the respiratory epithelium. The epithelium of asthmatic individuals is thought to be particularly susceptible to such infections and is associated with an exacerbated inflammatory response.

[0005] Studies have shown that TGF-β can impair the effectiveness of ICS. In addition, the inventors have demonstrated that viral infection of the airway epithelium impairs ICS activity by inducing TGF-β activity. Drug targeting of TGF-β carries the risk of autoimmunity and mitral valve defects. The inventors surprisingly identified casein kinase 1δ / ε as a mediator of TGF-β-induced ICS insensitivity using compound PF670462 (WO2016 / 149756) and demonstrated the utility of this agent in reversing steroid insensitivity.

[0006] It would be useful to develop additional compounds that are capable of preventing or treating respiratory diseases, acute and chronic inflammatory disorders, and fibrotic diseases or disorders in which fibrosis contributes to the pathology of the disorder. Summary of the invention

[0007] Described herein are compounds of formula (I), or salts, solvates, N-oxides, tautomers, stereoisomers, polymorphs and / or prodrugs thereof:

[0008]

[0009] in:

[0010] R1 and R2 are each independently selected from H, C 1-6 Alkyl, C1 alkyl, C6 aryl, C 3-6 Cycloalkyl and C 3-6 Heterocyclic group;

[0011] R3 is selected from F, Cl and CH3;

[0012] R4 is selected from C 0-3 Alkyl C 3-12 Cycloalkyl and C 1-12 alkyl;

[0013] wherein R1, R2, R3 and R4 are each optionally substituted.

[0014] In some embodiments, the present invention provides a compound of formula (I) or a salt, solvate, nitrogen oxide, tautomer, stereoisomer, polymorph and / or prodrug thereof,

[0015] in,

[0016] R1 is selected from H, C 2-6 Alkyl, hydroxyl C 1-6 Alkyl, C1 alkyl C6 aryl, C1 alkyl C 12 Aryl, C1 alkyl C6 aryl halogen, C1 alkyl (C1 alkyl) C6 aryl, C 3-6 Cycloalkyl, halogen C 3-6 Cycloalkyl, hydroxyl C 3-6Cycloalkyl and C 3-5 Heterocyclic group;

[0017] R2 is H;

[0018] R3 is selected from F, Cl and CH3;

[0019] R4 is selected from C 0-3 Alkyl C 3-12 Cycloalkyl, C 0-3 Alkyl C 3-12 Cycloalkyl halogen, C 1-12 Alkyl and halogen C 1-12 alkyl;

[0020] wherein R1, R2, R3 and R4 are each optionally substituted; and

[0021] Among them, when R 1 When H, R 4 Selected from C 0-3 Alkyl C 4-12 Cycloalkyl and C 1-12 Alkyl, where R 4 When it is C6 cycloalkyl, R 4 Selected from C 1-6 Alkyl, C 1-6 halogenalkyl, aryl, heteroaryl and halogen substituted with one or more groups, and when R 4 C 1-3 When alkyl, R 4 is substituted with one or more halogen groups, and

[0022] When R 1 When it is C3 cycloalkyl, C1 alkyl C6 aryl or C1 alkyl (C1 alkyl) C6 aryl, R 4 Selected from halogen C 1-12 Alkyl, C 0-3 Alkyl C 3-12 Cycloalkyl and C 0-3 Alkyl C 3-12 Cycloalkyl halogen.

[0023] On the other hand, a method for treating or preventing a respiratory disease in a subject in need thereof is provided, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a salt, solvate, nitrogen oxide, tautomer, stereoisomer, polymorph and / or prodrug thereof, thereby treating or preventing the respiratory disease in the subject.

[0024] Also provided is a compound of formula (I) or a salt, solvate, nitrogen oxide, tautomer, stereoisomer, polymorph and / or prodrug thereof for use in treating or preventing a respiratory disease in a subject.

[0025] Respiratory diseases may be selected from asthma, chronic obstructive pulmonary disease, interstitial lung diseases (such as idiopathic pulmonary fibrosis) and other conditions associated with tissue remodeling, primary or secondary lung tumors, pollen allergies, chronic and acute sinusitis, and chronic and acute viral, fungal and bacterial infections of the respiratory tract.

[0026] On the other hand, a method for improving respiratory function in a subject in need thereof is provided, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a salt, solvate, nitrogen oxide, tautomer, stereoisomer, polymorph and / or prodrug thereof, thereby improving the subject's respiratory function.

[0027] Also provided is a compound of formula (I) or a salt, solvate, nitroxide, tautomer, stereoisomer, polymorph and / or prodrug thereof for use in improving respiratory function in a subject.

[0028] The improvement of respiratory function can be selected from the reduction of lung contraction level, the reduction of respiratory system elastic stiffness and / or the increase of respiratory system stretching ease. Preferably, the improvement is selected from the reduction of lung contraction level and the reduction of respiratory system elastic stiffness. In another aspect, a composition is provided, which comprises a compound according to formula (I) or a salt thereof, a solvate, a nitrogen oxide, a tautomer, a stereoisomer, a polymorph and / or a prodrug, and a pharmaceutically acceptable excipient.

[0029] The composition may be formulated for oral administration or for administration by inhalation or injection.

[0030] Also described is the use of a compound of the invention, or a salt, solvate, N-oxide, tautomer, stereoisomer, polymorph and / or prodrug thereof, in the preparation of a medicament for treating or preventing a respiratory disease in a subject.

[0031] As used herein, the term "comprise" and variations of the term, such as "comprising", "containing" and "having", are not intended to exclude additional additives, components, integers or steps, unless the context requires otherwise.

[0032] The reference to any prior art in the specification is not intended to be an acknowledgement or implication that the prior art forms part of the common general knowledge in any jurisdiction, or that the prior art could reasonably be expected to be understood by a person skilled in the art, to be relevant and / or to be combined with other prior art.

[0033] Further aspects of the invention and further embodiments of the aspects described in the preceding paragraphs will become apparent from the following description, which is given by way of example and with reference to the accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1Many known compounds are defined.

[0035] Figure 2 Inhibition of TGF-β-induced IL-11 P IC 50 Values ​​(negative logarithm of the concentration that inhibits IL-11 levels by 50%) (interpolated from linear regression of small molecule concentration versus logarithm of IL-11 levels).

[0036] Figure 3 Compounds disclosed in WO2018 / 201192 are defined.

[0037] Figure 4 Plasma concentrations over time following intravenous (IV) or oral administration of PF670462 (A) and ZH3-138 (B) to male C57BL / 6 mice.

[0038] Figure 5 Comparison of PF670462 and ZH3-138 inhibition of TGF-β-induced IL-11 levels (A - graph of IL-11 concentrations in supernatants from MRC5 cells after exposure to vehicle, 0.1 μM, 1 μM and 10 μM PF670462 and ZH3-138; B - graph of IL-11 concentrations in supernatants from A549 cells treated with various concentrations of PF670462 or ZH3-138 for 24 hours 30 minutes before TGF-β treatment).

[0039] Figure 6 Effects of 0.1 μM, 1 μM and 10 μM ZH3-126 on TGF-β-induced IL-11 concentrations in supernatants from MRC5 cells compared to vehicle.

[0040] Figure 7 Comparison of the effects of a range of concentrations of PF670462 and compounds of the invention (ZH3-126 and ZH3-138) on supernatant concentrations of various inflammatory biomarkers (A: IL-6; B: IL-8; C: GM-CSF). DETAILED DESCRIPTION

[0041] It should be understood that the invention disclosed and defined in the specification extends to all alternative combinations of two or more of the individual features mentioned or evident from the text or drawings. All these different combinations constitute various alternative aspects of the invention.

[0042] Now will be referred to in detail certain embodiments of the present invention. Although the present invention will be described in conjunction with the embodiments, it will be appreciated that the present invention is not limited to these embodiments. On the contrary, the present invention is intended to cover all replacements, modifications and equivalents, which may be included within the scope of the present invention as defined by the claims.

[0043] Those skilled in the art will recognize many methods and materials similar or equivalent to those described herein that can be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described. It should be understood that the present invention disclosed and defined in the specification extends to all optional combinations of two or more individual features mentioned or apparent from the text or drawings. All of these different combinations constitute various alternative aspects of the present invention.

[0044] All patents and publications cited herein are incorporated by reference in their entirety.

[0045] For the purpose of interpreting this specification, terms used in the singular form will also include the plural form and vice versa.

[0046] The present invention provides a compound of formula (I) or its salt, solvate, nitrogen oxide, tautomer, stereoisomer, polymorph and / or prodrug:

[0047]

[0048] in:

[0049] R1 and R2 are each independently selected from H, C 1-6 Alkyl, C1 alkyl, C6 aryl, C 3-6 Cycloalkyl and C 3-6 Heterocyclic group;

[0050] R3 is selected from F, Cl and CH3;

[0051] R4 is selected from C 0-3 Alkyl C 3-12 Cycloalkyl and C 1-12 alkyl;

[0052] wherein R1, R2, R3 and R4 are each optionally substituted.

[0053] In some embodiments, the present invention provides a compound of formula (I), wherein

[0054] R1 is selected from H, C 2-6 Alkyl, hydroxyl C 1-6 Alkyl, C1 alkyl C6 aryl, C1 alkyl C 12 Aryl, C1 alkyl C6 aryl halogen, C1 alkyl (C1 alkyl) C6 aryl, C 3-6 Cycloalkyl, halogen C 3-6 Cycloalkyl, hydroxyl C 3-6 Cycloalkyl and C 3-5 Heterocyclic group;

[0055] R2 is H;

[0056] R3 is selected from F, Cl and CH3;

[0057] R4 is selected from C 0-3 Alkyl C 3-12 Cycloalkyl, C 0-3 Alkyl C 3-12 Cycloalkyl halogen, C 1-12 Alkyl and halogen C 1-12 alkyl;

[0058] wherein R1, R2, R3 and R4 are each optionally substituted,

[0059] Among them, when R 1 When H, R 4 Selected from C 0-3 Alkyl C 4-12 Cycloalkyl and C 1-12 Alkyl, where R 4 When it is C6 cycloalkyl, R 4 Selected from C 1-6 Alkyl, C 1-6 halogenalkyl, aryl, heteroaryl and halogen substituted with one or more groups, and when R 4 C 1-3 When alkyl, R 4 is substituted with one or more halogens, and

[0060] When R 1 When it is C3 cycloalkyl, C1 alkyl C6 aryl or C1 alkyl (C1 alkyl) C6 aryl, R 4 Selected from halogen C 1-12 Alkyl and C 0-3 Alkyl C 3-12 Cycloalkyl.

[0061] The inventors of the present invention have discovered that compounds of formula (I) are inhibitors of CK1δ. Advantageously, at least preferred embodiments of these compounds are selective inhibitors of CK1δ compared to other kinases. Selective CK1δ inhibitors can avoid adverse effects associated with the activity of other kinases (i.e., the kinases that the CK1δ inhibitor selectively inhibits). Also advantageously, at least preferred embodiments provide lower clearance rates after administration (e.g., IV or oral) compared to known CK1δ inhibitors such as PF670462.

[0062] In any embodiment, the present invention provides a compound of formula (I), provided that the compound is not selected from Figure 1 and / or Figure 3A list of compounds in. Keenan et al. Frontiers in Pharmacology, 2018, Vol. 9, article 738; WO2016 / 149756A1; WO1996 / 021654A1; WO1999 / 032121A1; WO1997 / 035856A1; Kim, DK. et al., Bioorganic & Medicinal Chemistry Letters, 2008, 18, 4006-4010; WO1999 / 001136A1; US6369068B1; and WO2018 / 201192A1 also describe a variety of compounds. In some embodiments, any specific compound described in one or more of these documents can be excluded by a proviso.

[0063] In any embodiment, R1 is C 2-6 Alkyl, preferably C 2-3 Alkyl. When R1 is C 2-3 When the alkyl group is alkyl, R2 can be H. R1 can be C substituted by one or more hydroxyl groups. 1-3 alkyl.

[0064] In any embodiment, R1 can be a hydroxyl group C 1-6 In some embodiments, the hydroxyl group C 1-6 The alkyl group contains a hydroxy substituent.

[0065] In any embodiment, the present invention provides a compound of formula (I), wherein R2 is H.

[0066] In any embodiment, R1 is C 3-6 Cycloalkyl. R1 can be selected from cyclobutyl, cyclopentyl and cyclohexyl. When R1 is C 3-6 When R1 is C 3-6 When it is a cycloalkyl group, R2 may be H.

[0067] In any embodiment, R1 is halogen C 3-6 In these embodiments, R1 may contain 1 to 2 halogen groups which may be the same or different. In some embodiments, R1 contains 2 halogen groups which may be attached to the same carbon atom. In some embodiments, the halogen C 3-6 Cycloalkyl is fluorine C 3-6 Typically, the halogen group is located in the para position relative to the point of attachment of R1 to the pyrimidinylamine of formula (I).

[0068] In any embodiment, R1 is hydroxyl C 3-6 Cycloalkyl. In these embodiments, R1 may contain 1 hydroxyl group. Typically, the hydroxyl group is located in the para position relative to the point of attachment of the pyrimidinylamine of formula (I).

[0069] In any embodiment, R1 is C 3-6 Heterocyclyl. R1 can be selected from an oxygen-containing heterocyclyl, a nitrogen-containing heterocyclyl or a sulfur-containing heterocyclyl, or a heterocyclyl containing a combination of two or more oxygen, nitrogen and sulfur atoms. In some embodiments, R1 is an optionally substituted 4-7 membered heterocyclyl or 4-6 membered heterocyclyl. In some embodiments, R1 is selected from oxetane, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, 1,3-dioxolanyl, tetrahydropyranyl, tetrahydrothienyl and 1,2- and 1,3-oxathiolanyl groups. In one embodiment, when R1 is C 3-5 When it is a heterocyclic group, R2 is H.

[0070] In any embodiment, the present invention provides a compound of formula (I), wherein R1 and R2 are the same as each other. For example, R1 and R2 can both be H, or R1 and R2 can both be C 1-6 Alkyl (eg, methyl, ethyl, propyl or butyl).

[0071] In any embodiment, R1 is C1 alkyl C6 aryl. The C1 alkyl C6 aryl may be substituted. The substituent may be selected from one or more alkyl groups, one or more hydroxyl groups and one or more halogen groups. The aryl may be substituted. The alkyl may be substituted.

[0072] In any embodiment, R1 is C1 alkyl C 12 Typically, C 12 The aryl group is biphenyl. In some embodiments, the covalent bond between the benzene rings is para relative to the C1 alkyl moiety. Typically, the C1 alkyl C 12 The aryl group is linked to the pyrimidinylamine via the C1 alkyl moiety.

[0073] In any embodiment, R1 is C1 alkyl C6 aryl halogen. Typically, the halogen moiety is a substituent of a C6 aryl ring. The halogen group can be in any one or more positions of ortho, meta or para relative to the C1 alkyl moiety. Typically, the C1 alkyl C6 aryl halogen is a C1 alkyl C6 aryl fluoride. Typically, the C1 alkyl C6 aryl halogen is attached to the pyrimidinylamine via the C1 alkyl moiety.

[0074] In any embodiment, R1 is C1 alkyl (C1 alkyl) C6 aryl. Typically, the C1 alkyl (C1 alkyl) C6 aryl is attached to the pyrimidinylamine via the C1 alkyl moiety, which can be represented as -C1 alkyl (C1 alkyl) C6 aryl.

[0075] In any embodiment, R1 is selected from H, ethyl, hydroxyethyl, halobenzyl, hydroxypropyl, cyclopropyl, cyclobutyl, oxetanyl, halogencyclobutyl (such as difluorocyclobutyl), hydroxycyclobutyl, cyclopentyl, cyclohexyl, halogencyclohexyl (such as difluorocyclohexyl), pyranyl and S,S-dioxythienyl.

[0076] In any embodiment, R3 is CH3. In any embodiment, R3 is F or Cl. Preferably, R3 is F.

[0077] In any embodiment, R4 is C 0-3 Alkyl C 3-12 Cycloalkyl. R4 can be C 0-3 Alkyl C 3-12 Cycloalkyl, where C 3-12 The cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. In a preferred form, R4 is C 3-12 More preferably, R4 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

[0078] In any embodiment, R4 is C 1-2 Alkyl C 3-12 Cycloalkyl. R4 can be C1 alkyl C 3-12 Cycloalkyl. 3-12 The cycloalkyl group may be selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

[0079] In any embodiment, wherein R4 is C 0-3 Alkyl C 3-12 Cycloalkyl, R4 may be substituted. The substituent may be selected from one or more OH groups, one or more C 1-6 an alkyl group, and one or more halogen groups.

[0080] In any embodiment, R4 is selected from C 0-3 Alkyl C 4-12 Cycloalkyl and C3 cycloalkyl and C 2-3 AlkylC3cycloalkyl, which may each be optionally substituted.

[0081] In any embodiment, R4 is C 0-3 Alkyl C 3-12Cycloalkylhalogen. Typically, halogen is a substituent of the cycloalkyl moiety. The group may contain 1 or 2 halogen groups. In embodiments that include 2 halogen groups, they may be attached to the same carbon atom. Typically, the halogen substituent is attached to the C atom of the cycloalkyl group. 0-3 The para position of the alkyl moiety or the position of the point of attachment to the imidazole of formula (I). 0-3 Alkyl C 3-12 The C of the cycloalkyl halogen group 3-12 Cycloalkyl and / or C 0-3 The alkyl moiety may be any of the preferred C 0-3 Alkyl and / or C 3-12 Cycloalkyl groups. Preferred groups include dihalogen cyclobutyl (such as 3,3-difluorocyclobutyl-1-yl), dihalogen cyclobutylmethyl (such as 3,3-difluorocyclobutyl-1-methyl), dihalogen cyclohexyl (such as 4,4-difluorocyclohexyl-1-yl) and dihalogen cyclohexylmethyl (such as 4,4-difluorocyclohexyl-1-methyl). Preferably, halogen is fluorine. Typically, C 0-3 Alkyl C 3-12 Cycloalkyl halogens through C 0-3 The alkyl moiety (when present) is attached to the imidazole nitrogen and can be represented by -C 0-3 Alkyl C 3-12 Cycloalkyl.

[0082] In any embodiment, R4 is C 1-12 R4 can be methyl, ethyl, propyl or butyl. R4 can be a branched C 1-12 Alkyl, such as branched C3, C4 or C5 alkyl. R4 may be substituted by one or more groups selected from halogen and OH. For example, R4 may be substituted by one, two or more halogen groups.

[0083] In any embodiment, R4 is halogen C 1-12 In some embodiments, R4 is halogen. 1-6 Alkyl or halogen C 1-4Alkyl. This group can contain 1,2 or 3 halogen groups. In the embodiment comprising more than 2 halogen groups, they can be connected to the same carbon atom. Typically, the halogen group is connected to the carbon atom at the far end of the connection point of the imidazole part of formula (I). Preferably, the halogen is fluorine. In some embodiments, R4 is selected from trihalomethyl, trihaloethyl (e.g., 2,2,2-trifluoroeth-1-yl), dihalomethyl (e.g., difluoromethyl), halogenmethyl (e.g., fluoromethyl), dihaloethyl (e.g., 2,2-difluoroeth-1-yl), hexahalopropyl (e.g., 1,1,1,3,3,3-hexafluoroprop-2-yl), trihalopropyl (e.g., 3,3,3-trifluoroprop-1-yl and 1,1,1-trifluoroprop-2-yl), halogenpropyl (e.g., 2-fluoroprop-2-yl), dihalopropyl (e.g., 3,3-difluoroprop-1-yl), halogenethyl (e.g., 2-fluoroeth-1-yl).

[0084] In some embodiments, R4 is selected from ethyl, pentyl, cyclopentyl, cyclohexyl, halogen cyclohexyl methyl, halogen cyclohexyl and halogen ethyl. In some embodiments, R4 is selected from ethyl, pentyl, cyclopentyl, cyclohexyl, difluorocyclohexyl (e.g. 4,4-difluorocyclohexyl-1-yl), difluorocyclohexyl methyl (e.g. 4,4-difluorocyclohexyl-1-methyl) and trifluoroethyl (e.g. 2,2,2-trifluoroethyl-1-yl).

[0085] In any embodiment, when R 1 When H, R 4 Selected from C 0-3 Alkyl C 4-12 Cycloalkyl and C 1-12 In these embodiments, when R 4 When it is C6 cycloalkyl, R 4 Selected from C 1-6 Alkyl, C 1-6 halogenalkyl, aryl, heteroaryl and halogen, preferably halogen (such as fluorine) substituted with one or more groups; and when R 4 It is C 1-3 When alkyl, R 4 Substituted with one or more halogen groups.

[0086] In any embodiment, when R 1 When it is C3 cycloalkyl, C1 alkyl C6 aryl or C1 alkyl (C1 alkyl) C6 aryl, R 4 Selected from halogen C 1-12 Alkyl and C 0-3 Alkyl C 3-12 Cycloalkyl.

[0087] In any embodiment, R1, R2, R3 and R4 are optionally selected from OH, C 1-6Alkoxy, halogen, amino, mercapto and C 1-6 In some embodiments, R1, R2, R3 and R4 are unsubstituted.

[0088] As used herein, the term “C 1-12 "Alkyl" refers to a straight or branched hydrocarbon group having 1 to 12 carbon atoms or any range therebetween, i.e., it contains 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms. The alkyl group is optionally substituted with substituents, and multiple degrees of substitution are allowed. As used herein, "C 1-12 Examples of "alkyl" include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, and the like.

[0089] Preferred "C 1-3 Alkyl", "C 1-4 Alkyl" and "C 1-6 "Alkyl". These groups refer to alkyl groups containing 1-3, 1-4 or 1-6 carbon atoms, or any range therebetween (for example, alkyl groups containing 2-5 carbon atoms, i.e., alkyl groups containing 2, 3, 4 or 5 carbon atoms are also in the C 1-6 When using the term “C 0-2 When the term "alkyl" is used, there may be no alkyl group or an alkyl group containing 1 or 2 carbon atoms.

[0090] The term "C 2-6 "Alkenyl" refers to an optionally substituted straight or branched chain hydrocarbon radical having at least one double bond of E or Z stereochemistry (if applicable) and 2 to 6 carbon atoms. Examples include ethenyl, 1-propenyl, 1- and 2-butenyl, and 2-methyl-2-propenyl. Unless the context requires otherwise, the term "C 2-6 "Alkenyl" also includes alkenyl groups containing one less hydrogen atom, so that the group is attached through two positions, i.e., divalent. 2-4 Alkenyl" and "C 2-3 The "alkenyl group" preferably includes vinyl, propenyl and butenyl, and vinyl is particularly preferred.

[0091] The term "C 2-6 "Alkynyl" refers to an optionally substituted straight or branched chain hydrocarbon group having at least one triple bond and 2 to 6 carbon atoms. Examples include ethynyl, 1-propynyl, 1-butynyl, 2-butynyl, 2-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl and 5-hexynyl, etc. Unless the context indicates otherwise, the term "C 2-6 "Alkynyl" also includes alkynyl groups containing one less hydrogen atom, so that the group is connected through two positions, i.e., divalent. Preferably C 2-3 Alkynyl.

[0092] As used herein, the term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I), and the term "halogen group" refers to the halogen groups fluorine (-F), chlorine (-Cl), bromine (-Br) and iodine (-I). Preferably, the halogen group is fluorine.

[0093] As used herein, the term "cycloalkyl" refers to a non-aromatic cyclic hydrocarbon ring. 3-7 "Cycloalkyl" refers to a non-aromatic cyclic hydrocarbon ring having 3 to 7 carbon atoms or any integer range therebetween. For example, C 3-7 Cycloalkyl also includes cycloalkyl groups containing 4 to 6 (i.e., 4, 5, or 6) carbon atoms. Alkyl is as defined above and may be substituted. Exemplary "C 3-7 "Cycloalkyl" groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0094] The cycloalkyl group may be optionally fused to one or more heterocyclic or cycloalkyl rings. The cycloalkyl ring may be substituted on any carbon atom on the ring with another cycloalkyl or heterocyclic moiety to form a spirocycloalkyl or spiroheteroalkyl compound.

[0095] Two non-adjacent atoms on the cycloalkyl group can be bridged by an alkyl or heteroalkyl group to form a bridged system. Preferably, the length of the bridging group is 1-3 atoms.

[0096] As used herein, the term "heterocycle" or "heterocyclyl" refers to a non-aromatic heterocycle that is saturated or has one or more degrees of unsaturation and contains one or more heteroatoms selected from S, S(O), S(O)2, O or N. 3-7 "Heterocyclyl" refers to a non-aromatic hydrocarbon ring containing 3 to 7 carbon atoms (i.e., 3, 4, 5, 6 or 7 carbon atoms) which contains one or more heteroatom substitutions as described herein. The heterocyclic moiety may be substituted, with multiple degrees of substitution being allowed. The term "C 3-7 "Heterocyclic group" also includes 4-5 , C 5-7 , C 6-7 , C 4-7 , C 4-6 and C 5-6The heterocyclic ring is a ring group of 3 to 10 members. Preferably, the heterocyclic ring contains 4 to 6 carbon atoms and one or two heteroatoms. More preferably, the heterocyclic ring contains 5 carbon atoms and 1 heteroatom, or 4 carbon atoms and 2 heteroatoms are substituted, or 5 carbon atoms and 1 heteroatom. The heterocyclic ring can be a 3 to 10 membered ring system, which represents the total number of atoms (carbon atoms and heteroatoms) contained in the ring system. In this article, the prefix 3-, 4-, 5-, 6-, 7-, 8-, 9- and 10-members represent the number of ring atoms or the range of ring atoms, whether carbon atoms or heteroatoms. For example, the term "3-10 membered heterocyclic ring" used herein refers to a heterocyclic ring having 3, 4, 5, 6, 7, 8, 9 or 10 ring atoms. Examples of heterocyclic rings include 5-6 membered monocyclic heterocyclic rings and 9-10 membered fused bicyclic heterocyclic rings. Thus, a heterocyclyl, heterocyclyl ring may be optionally fused to one or more other "heterocycles", one or more cycloalkyl rings, one or more aryl rings or one or more heteroaryl rings. Examples of "heterocycle" moieties include, but are not limited to, tetrahydrofuran, pyran, oxetane, 1,4-dioxane, 1,3-dioxane, piperidine, piperazine, N-methylpiperazinyl, 2,4-piperazinedione, pyrrolidine, imidazolidine, pyrazolidine, morpholine, thiomorpholine, tetrahydrothiopyran, tetrahydrothiophene, and the like.

[0097] The heterocyclic group may be substituted at any carbon atom in the ring with another cycloalkyl or heterocyclic moiety to form a spirocycloalkyl or spiroheterocyclic compound.

[0098] Two non-adjacent atoms on the heterocyclyl group can be bridged by an alkyl or heteroalkyl group to form a bridged system. Preferably, the length of the bridging group is 1-3 atoms.

[0099] As an example of a substituted heterocyclic group, the term "C 0-2 Alkyl C 3-7 "Heterocyclic group" includes heterocyclic groups that either do not contain an alkyl group as a link between the compound and the heterocycle, or contain an alkyl group of 1 or 2 carbon atoms as a link between the compound and the heterocycle (i.e., heterocycle, -CH2-heterocycle or -CH2CH2-heterocycle). These heterocycles may be further substituted.

[0100] Substituted cycloalkyl and heterocyclyl groups may be substituted with any suitable substituents as described below.

[0101] As used herein, the term "aryl" refers to an optionally substituted benzene ring or an optionally substituted benzene ring system fused to one or more optionally substituted benzene rings to form, for example, an anthracene, phenanthrene or naphthalene ring system. Examples of "aryl" groups include, but are not limited to, phenyl, 2-naphthyl, 1-naphthyl, biphenyl and substituted derivatives thereof. Preferred substituted aryl groups include arylamino, arylalkyl, arylalkylhalogen, arylhalogen and aralkyloxy.

[0102] As used herein, the term "heteroaryl" refers to a monocyclic five-, six- or seven-membered aromatic ring, or a fused bicyclic or tricyclic aromatic ring system comprising at least one monocyclic five-, six- or seven-membered aromatic ring. These heteroaryl rings contain one or more nitrogen, sulfur and / or oxygen heteroatoms, and may be optionally substituted by up to three members. N-containing heteroaryl can be in the form of nitrogen oxides, and sulfur-containing heteroaryl can be in the form of sulfur oxides and sulfur dioxides. Examples of "heteroaryl" groups used herein include furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, oxo-pyridyl, thiadiazolyl, isothiazolyl, pyridyl, pyridazyl (pyridazyl), pyrazinyl, pyrimidinyl, quinolyl, isoquinolyl, benzofuranyl, benzothienyl, indolyl, indazolyl, benzimidazolyl and substituted forms thereof.

[0103] The term "hydroxy" refers to -OH.

[0104] The term "oxo" refers to the group =0.

[0105] The term "C 1-6 "Alkoxy" refers to an alkyl group containing 1 to 6 carbon atoms and covalently bonded to the above-defined alkyl group through an O link, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy and pentoxy. Preferably, "C 1-4 Alkoxy" and "C 1-3 The term "alkenyl" includes methoxy, ethoxy, propoxy and butoxy, with methoxy being particularly preferred.

[0106] The term "halogen C 1-6 Alkyl" and "C 1-6 "Alkylhalogen" refers to a C 1-6 Alkyl. Preferably halogen C 1-3 Alkyl groups, such as -CH2CF3 and -CF3.

[0107] The term "halogen C 1-6 Alkoxy" and "C 1-6 "Alkoxyhalogen" refers to a C 1-6 Alkoxy. Preferably C 1-3 Alkoxyhalogen groups, such as -OCF3.

[0108] The term "carboxylate" or "carboxyl" refers to -COO - Or a -COOH group.

[0109] The term "ester" refers to a hydrogen atom replaced by a C 1-6 Alkyl ("carboxyl C 1-6 alkyl" or "alkyl ester"), aryl or aralkyl ("aryl ester" or "aralkyl ester"), etc. substituted carboxyl. Preferably CO2C1-3 Alkyl esters, such as methyl ester (CO2Me), ethyl ester (CO2Et), and propyl ester (CO2Pr), and including their reverse esters (eg, -OC(O)Me, -OC(O)Et, and -OC(O)Pr).

[0110] The terms "cyano" and "nitrile" refer to the group -CN.

[0111] The term "nitro" refers to the group -NO2.

[0112] The term "amino" refers to the group -NH2.

[0113] The term "substituted amino" or "secondary amino" refers to a hydrogen replaced by a C 1-6 Alkyl (“C 1-6 An amino group substituted with an alkylamino group ("alkylamino"), an aryl group or an aralkyl group ("arylamino" or "aralkylamino"). Preferably C 1-3 Alkylamino groups, such as methylamino (NHMe), ethylamino (NHEt), and propylamino (NHPr).

[0114] The term "disubstituted amino" or "tertiary amino" refers to a group in which two hydrogen atoms are replaced by the same or different C 1-6 alkyl ("dialkylamino"), aryl and alkyl ("aryl (alkyl) amino"), etc. substituted amino. Preferably di (C 1-3 alkyl)amino, such as dimethylamino (NMe2), diethylamino (NEt2), dipropylamino (NPr2) and variants thereof (such as N(Me)(Et), etc.).

[0115] The term "aldehyde" refers to the group -C(=O)H.

[0116] The term "acyl" refers to the group -C(O)CH3.

[0117] The term "ketone" refers to a carbonyl group, which may be represented by -C(O)-.

[0118] The term "substituted ketone" refers to a ketone group covalently linked to at least one additional group, e.g., C 1-6 Alkyl groups (“C 1-6 alkyl acyl" or "alkyl ketone" or "ketoalkyl"), aryl group ("aryl ketone"), aralkyl group ("aralkyl ketone"), etc. Preferably C 1-3 Alkyl acyl.

[0119] The term "amido" or "amide" refers to the group -C(O)NH2.

[0120] The term "substituted acylamino" or "substituted amido" refers to a group in which a hydrogen is replaced by a C 1-6 Alkyl (“C 1-6Alkylamido" or "C 1-6 The acylamino group is preferably substituted with an aryl group ("aryl acylamino"), an aralkyl group ("aralkyl acylamino"), or the like. Preferably C 1-3 Alkylamide groups, such as methylamide (-C(O)NHMe), ethylamide (-C(O)NHEt), and propylamide (-C(O)NHPr), and include reversed amides thereof (e.g., -NHMeC(O)-, -NHEtC(O)-, and -NHPrC(O)-).

[0121] The term "disubstituted acylamino" or "disubstituted amido" refers to a group in which two hydrogen atoms are replaced by, for example, C 1-6 Alkyl ("di(C 1-6 Alkyl) acylamino" or "di(C 1-6 alkyl)amide group"), aryl and alkyl ("alkyl (arylalkyl) acylamino"), etc. substituted acylamino. Preferably di(C 1-3 alkyl) amide groups, such as dimethylamide (-C(O)NMe2), diethylamino (-C(O)NEt2) and dipropylamide (-C(O)NPr2) and variants thereof (e.g., -C(O)N(Me)Et, etc.), and including reverse amide groups thereof.

[0122] The term "mercapto" refers to the group -SH.

[0123] The term "C 1-6 "Alkylmercapto" refers to a hydrogen replaced by a C 1-6 Alkyl group substituted mercapto group. Preferably C 1-3 Alkylmercapto groups such as mercaptomethyl, mercaptoethyl and mercaptopropyl.

[0124] The term "thio" refers to the group =S.

[0125] The term "sulfinyl" refers to the group -S(=O)H.

[0126] The term "substituted sulfinyl" or "sulfoxide" refers to a substituted hydrogen group replaced by a C 1-6 Alkyl (“C 1-6 Alkylsulfinyl" or "C 1-6 Sulfinyl groups substituted with -SO-alkylsulfinyl groups, such as -SO-methyl, -SO-ethyl and -SO-propyl groups, are preferred.

[0127] The term "sulfonyl" refers to the group -SO2H.

[0128] The term "substituted sulfonyl" refers to a hydrogen atom replaced by a C 1-6 Alkyl groups ("sulfonyl C 1-6Sulfonyl groups substituted with alkyl, aryl ("arylsulfonyl"), aralkyl ("aralkylsulfonyl"), etc. are preferred. 1-3 Alkyl groups such as -SO2Me, -SO2Et and -SO2Pr.

[0129] The term "sulfonylamino" or "sulfonamido" refers to the group -SO2NH2.

[0130] The term "substituted sulfonylamino" refers to a hydrogen atom replaced by a C 1-6 Alkyl groups ("sulfonylamino" 1-6 The sulfonylamino group is preferably substituted with a sulfonylamino group such as an alkyl group, an aryl group ("arylsulfonylamide"), an aralkyl group ("aralkylsulfonylamide"), etc. 1-3 Alkyl groups such as -SO2NHMe, -SO2NHEt and -SO2NHPr, and include reversed sulfonamide groups thereof (such as -NHSO2Me, -NHSO2Et and -NHSO2Pr).

[0131] The term "disubstituted sulfonylamino" or "disubstituted sulfonamido" refers to a group in which the two hydrogen atoms are replaced by C 1-6 Alkyl groups ("sulfonylaminodi(C 1-6 alkyl)”), aralkyl and alkyl (“sulfonylamino (aralkyl) alkyl”) substituted sulfonylamino. Preferably sulfonylamino di (C 1-3 alkyl) groups, such as -SO2NMe2, -SO2NEt2 and -SO2NPr2 and variants thereof (e.g., -SO2N(Me)Et, etc.), and include reversed sulfonamide groups thereof (e.g., -N(Me)SO2Me, etc.).

[0132] The term "sulfate" refers to the group OS(O)2OH, as well as groups including those in which hydrogen is replaced by, for example, C 1-6 alkyl group ("alkyl sulfate group"), aryl group ("aryl sulfate group"), aralkyl group ("aralkyl sulfate group"), etc. substituted groups. Preferably C 1-3 Sulfate groups, such as OS(O)2OMe, OS(O)2OEt and OS(O)2OPr.

[0133] The term "substituted sulfonate" refers to the group SO3H and includes hydrogen replaced by, for example, C 1-6 Alkyl groups ("alkyl sulfonate groups", aryl groups ("aryl sulfonate groups"), aralkyl groups ("aralkyl sulfonate groups"), etc. substituted groups. Preferably C 1-3 Sulfonate groups, such as SO3Me, SO3Et and SO3Pr.

[0134] As used herein, "substituent" refers to a portion of a molecule that is covalently bonded to an atom within a molecule of interest. For example, a "ring substituent" can be a moiety covalently bonded to an atom (preferably a carbon or nitrogen atom) that is a member of a ring, such as a halogen, an alkyl group, or other substituents described herein. As used herein, the term "substituted" means that any one or more hydrogens on a designated atom are replaced by a substituent selected from a designated atom, as long as the normal valence of the designated atom is not exceeded, and the substitution results in a stable compound, i.e., a compound that can be isolated, characterized, and tested for biological activity.

[0135] The terms "optionally substituted" or "may be substituted" and the like used throughout the specification indicate that the group may or may not be further substituted by one or more non-hydrogen substituents or fused to one or more non-hydrogen substituents (to form a polycyclic system). Suitable chemically feasible substituents for a particular functional group will be apparent to those skilled in the art. In some embodiments, the optionally substituted portion may or may not be further substituted by 1, 2, 3, 4 or more groups, preferably 1, 2 or 3 groups, more preferably 1 or 2 groups.

[0136] Examples of substituents include, but are not limited to:

[0137] C 1-6 Alkyl, C 1-6 Halogen alkyl, C 1-6 Halogen alkoxy, C 1-6 Hydroxyalkyl, C 3-7 Heterocyclic group, C 3-7 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylsulfanyl, C 1-6 Alkylsulfinyl, C 1-6 Alkylsulfonyl, C 1-6 alkylsulfonylamino, arylsulfonylamino, alkylcarboxyl, alkylcarboxamide, oxo, hydroxyl, thiol, amino, acyl, carboxyl, carbamoyl, aryl, aryloxy, heteroaryl, aminosulfonyl, aroyl, aroylamino, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy, alkoxycarbonyl, nitro, cyano, halogen, urea, C 1-6 Perfluoroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6alkyloxyaryl, ester, substituted amino, disubstituted amino, acyl, keto, substituted keto, amide, aminoacyl, substituted amide, disubstituted amide, thiol, alkylthio, thio, sulfate, sulfonate, sulfonyl, substituted sulfinyl, sulfonyl, substituted sulfonyl, sulfonamide, substituted sulfonamide, disubstituted sulfonamide, aryl C 1-6 Alkyl, heterocyclic C 1-6 Alkyl and C 3-7 Cycloalkyl C 1-6 Alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heterocyclyl and groups containing them can each be substituted. In some embodiments, the moiety can be optionally substituted with any subset of optional substituents selected from those described above.

[0138] In the case of nitrogen-containing heterocycles (heterocyclyl and heteroaryl), optional substituents may also include, but are not limited to, C 1-6 Alkyl, i.e. NC 1-3 Alkyl, more preferably methyl, especially N-methyl.

[0139] In one embodiment, the cyclic or heterocyclic substituent may form a spirocycloalkyl or spiroheteroalkyl substituent with a carbon in the substituted portion of the cyclic or heterocyclic group. In another embodiment, the cyclic or heterocyclic substituent may be bridged.

[0140] For the optionally substituted "C 1-6 Alkyl", "C 2-6 Alkenyl" and "C 2-6 Alkynyl", optionally one or more substituents are preferably selected from halogen, aryl, heterocyclic, C 3-8 Cycloalkyl, C 1-6 Alkoxy, hydroxyl, oxo, aryloxy, halogen C 1-6 Alkyl, halogen C 1-6 In some embodiments, the optionally substituted "C 1-6 Alkyl", "C 2-6 Alkenyl" and "C 2-6 The "alkynyl" group may be optionally substituted with any subset of optional substituents selected from those described above.

[0141] Where appropriate, any of these groups may be further substituted by any of the above groups. For example, alkylamino or dialkylamino, C 1-6 Alkoxy, etc.

[0142] Table 1 below gives examples of compounds of the present invention.

[0143] Table 1 Examples of compounds of the present invention.

[0144]

[0145]

[0146]

[0147]

[0148]

[0149]

[0150]

[0151]

[0152]

[0153]

[0154]

[0155]

[0156]

[0157]

[0158]

[0159]

[0160]

[0161]

[0162]

[0163] The salts of the compounds of formula (I) are preferably pharmaceutically acceptable, but it will be appreciated that non-pharmaceutically acceptable salts also fall within the scope of the present disclosure since they may be useful as intermediates in the preparation of pharmaceutically acceptable salts.

[0164] The term "pharmaceutically acceptable" may be used to describe any pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, polymorph and / or prodrug, or any other compound that, upon administration to a subject, is capable of providing (directly or indirectly) a compound of Formula (I) or its active metabolite or residue, and which is generally not harmful to the subject.

[0165] Suitable pharmaceutically acceptable salts include, but are not limited to, pharmaceutically acceptable inorganic acid salts, such as hydrochlorides, sulfates, phosphates, nitrates, carbonates, borates, sulfamates, and hydrobromides, or pharmaceutically acceptable organic acid salts, such as acetates, propionates, butyrates, tartrates, maleates, hydroxymaleates, fumarates, malates, citrates, lactates, mucates, gluconates, benzoates, succinates, oxalates, phenylacetates, methanesulfonates, toluenesulfonates, benzenesulfonates, salicylates, sulfanilates, aspartates, glutamates, edetates, stearates, palmitates, oleates, laurates, pantothenates, tannates, ascorbates, valerates, and hydroxynaphthoates.

[0166] Basic salts include, but are not limited to, salts formed with pharmaceutically acceptable cations, such as sodium salts, potassium salts, lithium salts, calcium salts, magnesium salts, zinc salts, ammonium salts, alkylammonium salts (such as salts formed by triethylamine), alkoxyammonium salts (such as salts formed by ethanolamine and salts formed by ethylenediamine, choline or amino acids (such as arginine, lysine or histidine). General information about the types of pharmaceutically acceptable salts and their formation is known to those skilled in the art and is described in conventional texts such as "Handbook of Pharmaceutical salts" (PH Stahl, CG Wermuth, first edition, 2002, Wiley-VCH).

[0167] Basic nitrogen-containing groups can be quaternized with agents such as lower alkyl halides (such as methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides); dialkyl sulfates (such as dimethyl sulfate and diethyl sulfate); and others.

[0168] "Prodrug" is a compound that may not fully meet the structural requirements of the compounds provided herein, but is modified in vivo after administration to a subject or patient to produce a compound of formula (I) provided herein. For example, a prodrug may be an acylated derivative of a compound provided herein. Prodrugs include compounds in which a hydroxyl, carboxyl, amine or sulfhydryl group is bonded to any group that, when administered to a mammalian subject, cleaves to form free hydroxyl, carboxyl, amino or sulfhydryl groups, respectively. Examples of prodrugs include, but are not limited to, acetate, formate, phosphate and benzoate derivatives of alcohol and amine functional groups in the compounds provided herein. Prodrugs of compounds provided herein can be prepared by modifying the functional groups present in the compound in a manner that is cleaved in vivo to produce the parent compound.

[0169] Prodrugs include compounds in which a polypeptide chain of one amino acid residue or two or more (e.g., two, three, or four) amino acid residues is covalently attached to the free amino group and / or acylamino group of a compound of formula (I). Amino acid residues include 20 naturally occurring amino acids, usually represented by three letter symbols, and also include 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvaline, β-alanine, γ-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine, and methionine sulfone. Prodrugs also include compounds in which carbonates, carbamates, amides, and alkyl esters are covalently bonded to the above-mentioned substituents of formula (I) via a carbonyl carbon prodrug side chain. Prodrugs may include covalent irreversible and reversible inhibitors.

[0170] Where the compounds are solids, those skilled in the art will appreciate that the compounds, agents and salts of the invention may exist in different crystalline or polymorphic forms, all of which are intended to be within the scope of the invention and the particular chemical formula.

[0171] The present invention includes all crystalline forms of the compound of formula (I), including anhydrous crystalline forms, hydrates, solvates and mixed solvates. If any of these crystalline forms exhibits polymorphism, all polymorphs are within the scope of the present invention.

[0172] Formula (I) is intended to encompass, where applicable, both solvated and unsolvated forms of the compounds. Thus, Formula (I) includes compounds having the indicated structure in hydrated or solvated forms, as well as unhydrated and unsolvated forms.

[0173] Formula (I) compound or its salt, tautomer, nitrogen oxide, polymorph or prodrug can be provided in the form of solvate. Solvate comprises stoichiometric or non-stoichiometric solvent, and can be formed together with pharmaceutically acceptable solvent (such as water, alcohol (such as methanol, ethanol or isopropanol), DMSO, acetonitrile, dimethylformamide (DMF), acetic acid etc.) in crystallization process, wherein, by non-covalent bonding or by occupying the solvate forming part of the lattice of the hole formation in the lattice. When the solvent is water, hydrate is formed, and when the solvent is alcohol, alcoholate is formed. Solvate of the compounds of the present invention can be conveniently prepared or formed in the method described herein. In general, solvated form is considered to be equivalent to the unsolvated form for the purpose of the present invention.

[0174] Compounds of formula (I) or their salts, tautomers, nitroxides, solvates and / or prodrugs that form crystalline solids may exhibit polymorphism. All polymorphic forms of the compounds, salts, tautomers, nitroxides, solvates and / or prodrugs are within the scope of the present invention.

[0175] Compounds of formula (I) may exhibit tautomerism. Tautomers are two interchangeable forms of a molecule that generally exist in equilibrium. Any tautomers of compounds of formula (I) are understood to be within the scope of the present invention.

[0176] The compound of formula (I) may contain one or more stereocenters. All stereoisomers of the compound of formula (I) are within the scope of the present invention. Stereoisomers include enantiomers, diastereomers, geometric isomers (E and Z olefin forms and cis and trans substitution patterns) and atropisomers. In some embodiments, the compound is a stereoisomerically enriched form of the compound of formula (I) at any stereocenter. One stereoisomer of the compound is enriched at least about 60%, 70%, 80%, 90%, 95%, 98% or 99% more than another stereoisomer.

[0177] The compound of formula (I) or its salt, tautomer, solvate, nitrogen oxide and / or stereoisomer may be isotopically enriched with respect to one or more isotopes of the atoms present in the compound. For example, the compound may be enriched with one or more of the following minor isotopes: 2 H. 3 H. 13 C. 14 C. 15 N and / or 17 O. When the abundance of an isotope is greater than its natural abundance, it is considered enriched.

[0178] In some embodiments, the compound of formula (I) or its salt, solvate, N-oxide, tautomer, stereoisomer, polymorph and / or prodrug has a pIC of at least 7M. 50 Such assays are well known to those skilled in the art, and examples of suitable assays are described in the Examples.

[0179] In yet another aspect, there is provided a composition comprising a compound according to formula (I) or a salt, solvate, nitrogen oxide, tautomer, stereoisomer, polymorph and / or prodrug thereof, and a pharmaceutically acceptable excipient.

[0180] Suitable dosage levels are generally about 0.01 mg to 500 mg per kilogram of patient body weight per day, which can be administered in single or multiple doses. Preferably, the dosage level is about 0.1 mg / kg to about 250 mg / kg per day; more preferably about 0.5 mg / kg to about 100 mg / kg per day. Suitable dosage levels can be about 0.01 mg / kg to 250 mg / kg per day, about 0.05 mg / kg to 100 mg / kg per day, or about 0.1 mg / kg to 50 mg / kg per day. Within this range, the dosage can be 0.05 mg / kg to 0.5 mg / kg, 0.5 mg / kg to 5 mg / kg, or 5 mg / kg to 50 mg / kg per day. For oral administration, the composition is preferably provided in the form of a tablet containing 1.0 mg to 1000 mg of active ingredient, particularly 1.0 mg, 5.0 mg, 10.0 mg, 15.0 mg, 20.0 mg, 25.0 mg, 50.0 mg, 75.0 mg, 100.0 mg, 150.0 mg, 200.0 mg, 250.0 mg, 300.0 mg, 400.0 mg, 500.0 mg, 600.0 mg, 750.0 mg, 800.0 mg, 900.0 mg and 1000.0 mg of active ingredient, so that the dosage of the patient to be treated can be adjusted symptomatically. The compound can be administered in a regimen of 1 to 4 times a day, preferably once or twice a day. However, it should be understood that the specific dosage level and frequency of administration for any particular patient may vary and depend on a variety of factors, including the activity of the specific compound used, the metabolic stability and duration of action of the compound, age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, severity of the particular condition, and the host being treated. The amount of the compound of the invention in the composition will also depend on the specific compound in the composition.

[0181] In the case of inhaled products, the typical inhaled dose is less than other forms of administration, and a puff inhalation starts from 1 microgram and rises to 1000 micrograms. In a preferred form, the dosage range of each puff is from 25 micrograms to 250 micrograms. In another preferred form, the dosage range of each puff is from 500 micrograms to 1000 micrograms. In another form, the dosage of each puff is selected from 1 microgram, 2.5 micrograms, 10.0 micrograms, 25.0 micrograms, 50.0 micrograms, 75.0 micrograms, 100.0 micrograms, 150.0 micrograms, 200.0 micrograms, 250.0 micrograms, 300.0 micrograms, 400.0 micrograms, 500.0 micrograms, 600.0 micrograms, 750.0 micrograms, 800.0 micrograms, 900.0 micrograms and 1000.0 micrograms or any range between two of these values ​​and including these two values. The medication can be given as one puff per day or increased to four times per day with two puffs each time.

[0182] The pharmaceutical composition may further comprise other therapeutically active compounds commonly used to treat the disclosed diseases or conditions. One of ordinary skill in the art can select suitable agents for combined therapy according to conventional pharmaceutical principles. The combination of therapeutic agents can act synergistically to achieve the treatment or prevention of various diseases or conditions disclosed herein. Using this approach, a therapeutic effect can be achieved with a lower dose of each drug, thereby reducing potential side effects.

[0183] The compounds and compositions of the present invention can be formulated into any suitable route of administration, including, for example, topical (e.g., transdermal or ophthalmic) administration, pulmonary administration, oral administration, oral administration, nasal administration, vaginal administration, rectal or parenteral administration. The term parenteral as used herein includes subcutaneous injection, intradermal injection, intravascular (e.g., intravenous) injection, intramuscular injection, spinal injection, intracranial injection, intrathecal injection, intraocular injection, periocular injection, intraorbital injection, intrasynovial injection and intraperitoneal injection, and any similar injection or infusion technique. In certain embodiments, the composition is preferably suitable for oral or parenteral use. Suitable oral forms include, for example, tablets, lozenges, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. In other embodiments, the compositions provided herein can be formulated into lyophilized agents.

[0184] In a preferred form, the composition is suitable for administration to the respiratory tract. In another form, the composition is suitable for oral administration.

[0185] The various dosage units are each preferably provided in the form of discrete dose tablets, capsules, lozenges, dragees, gums or other types of solid preparations. Capsules can encapsulate powders, liquids or gels. Solid preparations can be swallowed, or can be of the inhalable or chewable type (fragile or gelatinous). The present invention contemplates dosage unit holding devices other than blister packs; for example, packaging such as bottles, tubes, cans, bags. The dosage unit may further include conventional excipients well known in pharmaceutical preparation practice, such as binders, gelling agents, fillers, tableting lubricants, disintegrants, surfactants and colorants; and for inhalable or chewable preparations.

[0186] Compositions for oral use may further comprise one or more components, such as sweeteners, flavoring agents, coloring agents and / or preservatives, so as to provide attractive and palatable preparations. Tablets contain active ingredients and physiologically acceptable excipients that are suitable for tablet production mixed therewith. These excipients include, for example, inert diluents (such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate), granulating agents and disintegrants (such as corn starch or alginic acid), adhesives (such as starch, gelatin or gum arabic), lubricants (such as magnesium stearate, stearic acid or talcum). Tablets may not be coated, or may be coated by known techniques, to delay disintegration and absorption in the gastrointestinal tract, thereby providing a longer sustained effect. For example, time-delay materials, such as glyceryl monostearate or glyceryl distearate, may be used.

[0187] Oral preparations can also be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent (such as calcium carbonate, calcium phosphate or kaolin), or in the form of soft gelatin capsules in which the active ingredient is mixed with water or an oil medium (such as peanut oil, liquid paraffin or olive oil).

[0188] Aqueous suspensions contain one or more active ingredients and excipients suitable for the manufacture of aqueous suspensions in admixture therewith. These excipients include suspending agents (such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum arabic), and dispersants or wetting agents (such as natural phospholipids (such as lecithin), condensation products of alkylene oxides with fatty acids (such as polyoxyethylene stearate), condensation products of ethylene oxide with long-chain fatty alcohols (such as heptadecenyloxycyclobutane alcohol), condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol (such as polyoxyethylene sorbitol monooleate), or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides (for example, polyoxyethylene sorbitan monooleate)). The aqueous suspension may also contain one or more preservatives, for example ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

[0189] Oily suspensions can be prepared by suspending the active ingredient in a vegetable oil (such as peanut oil, olive oil, sesame oil or coconut oil), or in a mineral oil (such as liquid paraffin). Oily suspensions can contain thickeners, such as beeswax, hard paraffin or hexadecanol. Sweeteners (such as those mentioned above) and / or flavorings can be added to provide a palatable oral preparation. Such suspensions can be preserved by adding an antioxidant (such as ascorbic acid).

[0190] Dispersible powders and granules suitable for preparing aqueous suspensions by adding water provide the active ingredient mixed with a dispersant or wetting agent, a suspending agent and one or more preservatives. Examples of suitable dispersants or wetting agents and suspending agents are those already mentioned above. Other excipients may also be present, such as sweeteners, flavorings and coloring agents.

[0191] Pharmaceutical composition can also be in the form of water-in-oil emulsion. The oil phase can be vegetable oil (such as olive oil or peanut oil), mineral oil (such as liquid paraffin), or their mixture. Suitable emulsifiers include natural gums (such as gum arabic or tragacanth), natural phospholipids (such as soybean lecithin), and esters or partial esters (such as sorbitan monooleate) derived from fatty acids and hexitol, acid anhydrides, and condensation products (such as polyoxyethylene sorbitan monooleate) derived from partial esters of fatty acids and hexitol and ethylene oxide. The emulsion can also include one or more sweeteners and / or flavorings.

[0192] Syrups and elixirs may be formulated with sweetening agents, such as glycerol, propylene glycol, sorbitol or sucrose. Such preparations may also contain one or more demulcents, preservatives, flavorings and / or coloring agents.

[0193] The compositions of the present invention may be formulated for topical or local administration, for example, for topical application to the skin. Formulations for topical administration generally comprise a topical carrier in combination with one or more active agents, with or without additional optional components.

[0194] Suitable topical carriers and additional components are well known in the art, and it is apparent that the choice of carrier will depend on the particular physical form and mode of delivery. Topical carriers include organic solvents (such as alcohols (e.g., ethanol, isopropanol or glycerol), glycols (such as butylene glycol, isopentyl glycol or propylene glycol), fatty alcohols (such as lanolin); mixtures of water and organic solvents; and mixtures of organic solvents (such as alcohols and glycerol); lipid-based materials (such as fatty acids); acylglycerols (which include oils (such as mineral oil) and fats of natural or synthetic origin, phosphoglycerides, sphingolipids and waxes); protein-based materials (such as collagen and gelatin); silicon-based materials (non-volatile and volatile) and hydrocarbon-based materials (such as microsponges and polymer matrices).

[0195] The composition may further include one or more components suitable for improving the stability or effectiveness of the administered formulation, such as stabilizers, suspending agents, emulsifiers, viscosity modifiers, gelling agents, preservatives, antioxidants, skin penetration enhancers, humectants and sustained release materials. Examples of these components are given in Martindale-The Extra Pharmacopoeia (Pharmaceutical Press, London 1993) and Martin (ed.), Remington's Pharmaceutical Sciences. The formulation may include microcapsules (e.g., hydroxymethylcellulose or gelatin microcapsules), liposomes, albumin microspheres, microemulsions, nanoparticles or nanocapsules.

[0196] Topical preparations can be prepared in a variety of physical forms, including, for example, solids, pastes, creams, foams, lotions, gels, powders, aqueous liquids, emulsions, sprays and skin patches. The physical appearance and viscosity of this form can be controlled by the presence and amount of one or more emulsifiers and one or more viscosity modifiers present in the preparation. Solids are usually firm and non-pourable, and are usually formulated into strips or rods, or granular forms. Solids can be opaque or transparent, and optionally can contain solvents, emulsifiers, moisturizers, emollients, spices, dyes / colorants, preservatives and other active ingredients that increase or enhance the efficacy of the final product. Creams and lotions are usually similar to each other, with the main difference being their viscosity. Lotions and creams can be opaque, translucent or transparent, and usually contain emulsifiers, solvents and viscosity modifiers, as well as moisturizers, emollients, spices, dyes / colorants, preservatives and other active ingredients that increase or enhance the efficacy of the final product. Gels can be prepared to have a range of viscosities, from thick or high viscosity to rare or low viscosity. Like lotions and creams, these formulations may also contain solvents, emulsifiers, moisturizers, emollients, fragrances, dyes / colorants, preservatives, and other active ingredients that increase or enhance the efficacy of the final product. Liquids are thinner than creams, lotions, or gels and usually do not contain emulsifiers. Liquid topical products typically contain solvents, emulsifiers, moisturizers, emollients, fragrances, dyes / colorants, preservatives, and other active ingredients that increase or enhance the efficacy of the final product.

[0197] Emulsifiers for topical preparations include, but are not limited to, ionic emulsifiers, cetearyl alcohol, nonionic emulsifiers (such as polyoxyethylene oleyl ether, PEG-40 stearate, ceteareth-12, ceteareth-20, ceteareth-30, cetearyl alcohol, PEG-100 stearate and glyceryl stearate). Suitable viscosity modifiers include, but are not limited to, protective colloids or nonionic glues, such as hydroxyethylcellulose, xanthan gum, magnesium aluminum silicate, silicon dioxide, microcrystalline wax, beeswax, paraffin and cetyl hexadecanoate. Gel compositions can be formed by adding gelling agents (such as chitosan, methylcellulose, ethylcellulose, polyvinyl alcohol, polyquaternium salt, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carbomer or ammoniated glycyrrhizinate). Suitable surfactants include, but are not limited to, nonionic surfactants, amphoteric surfactants, ionic surfactants and anionic surfactants. For example, one or more of dimethicone copolyol, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, lauramide DEA, cocamide DEA and cocamide MEA, oleyl betaine, cocamidopropyl phosphatidyl PG-diium chloride, and ammonium lauryl sulfate can be used in topical formulations.

[0198] Preservatives include, but are not limited to, antimicrobial agents (such as methylparaben, propylparaben, sorbic acid, benzoic acid, and formaldehyde), as well as physical stabilizers and antioxidants (such as vitamin E, sodium ascorbate / ascorbic acid, and propyl gallate). Suitable moisturizers include, but are not limited to, lactic acid and other hydroxy acids and their salts, glycerol, propylene glycol, and butylene glycol. Suitable emollients include lanolin alcohol, lanolin, lanolin derivatives, cholesterol, petrolatum, isostearyl neopentanoate, and mineral oil. Suitable fragrances and colorants include, but are not limited to, FD&C Red No.40 and FD&C Yellow No.5. Other suitable additional ingredients that may be included in topical preparations include, but are not limited to, abrasives, absorbents, anti-caking agents, defoamers, antistatic agents, astringents (such as witch hazel), alcohols and herbal extracts (such as chamomile extracts), binders / excipients, buffers, chelating agents, film formers, regulators, propellants, sunscreens, pH regulators, and protective agents.

[0199] Typical delivery methods for topical compositions include application with the fingers, application with a physical applicator (e.g., cloth, tissue, cotton swab, stick or brush), spraying (including spray, aerosol or foam spray), dropper application, sprinkling, soaking and rinsing. Controlled release carriers may also be used, and compositions for transdermal administration may be formulated (e.g., as a transdermal patch).

[0200] The pharmaceutical composition can be formulated into a sustained release formulation, such as a capsule that produces a slow release of the modulator after administration. Such formulations can be prepared using well-known techniques and are administered, for example, by oral, rectal or subcutaneous implantation, or by implantation in a desired target site. The carrier used in such formulations is biocompatible and can also be biodegradable. Preferably, the formulation provides a relatively constant level of modulator release. The amount of modulator included in the sustained release formulation depends on, for example, the implantation site, the rate of release and the expected duration and the nature of the disease to be treated or prevented.

[0201] The pharmaceutical composition can be formulated into an inhalation formulation, including a spray, mist or aerosol. For example, for respiratory administration. This may be particularly preferably used to treat respiratory diseases, such as the airway or lung diseases related to fibrosis as described herein. Inhalation formulations can be used for the upper respiratory tract (including the nasal cavity, pharynx and larynx) and the lower respiratory tract (including the trachea, bronchi and lungs). For inhalation formulations, the compositions or combinations provided herein can be delivered by any inhalation method known to those skilled in the art. Such inhalation methods and devices include, but are not limited to, metered inhalers with propellants (such as HFA or physiologically and environmentally acceptable propellants). Other suitable devices are breath-operated inhalers, multi-dose dry powder inhalers and aerosol sprayers. The aerosol formulation used in the present method generally includes propellants, surfactants and cosolvents, and can be filled into a conventional aerosol container closed by a suitable metering valve. Depending on the application to the upper respiratory tract (including the nasal cavity, pharynx and larynx) or the lower respiratory tract (including the trachea, bronchi and lungs), different devices and excipients can be used, and can be determined by those skilled in the art. Additionally, micronization and nanoparticle formation methods for preparing the compounds described herein for use in inhalers (eg, dry powder inhalers) are also known to those skilled in the art.

[0202] Inhalation compositions may include liquid or powder compositions containing active ingredients suitable for nebulization and intrabronchial use, or aerosol compositions administered by dispensing metered dose aerosol units. Suitable liquid compositions contain active ingredients in aqueous, pharmaceutically acceptable inhalation solvents (e.g., isotonic saline or bacteriostatic water). The solution is administered by means of a pump or extrusion-actuated spray dispenser, or by any other conventional means, to cause or allow the desired dose of the liquid composition to be inhaled into the patient's lungs. Suitable formulations for administration, wherein the carrier is a liquid, such as nasal sprays or nasal drops, include aqueous or oily solutions of the active ingredient. Ibrahim et al. (Medical Devices: Evidence and Research 2015: 8 131–139) describe examples of inhaled drug delivery devices envisioned for use in the present invention.

[0203] On the other hand, a method for treating or preventing a respiratory disease in a subject in need thereof is provided, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a salt, solvate, nitrogen oxide, tautomer, stereoisomer, polymorph and / or prodrug thereof, thereby treating or preventing the respiratory disease in the subject.

[0204] Also provided is a compound of formula (I) or a salt, solvate, nitrogen oxide, tautomer, stereoisomer, polymorph and / or prodrug thereof for use in treating or preventing a respiratory disease in a subject in need thereof.

[0205] Also described is the use of a compound of formula (I) or a salt, solvate, N-oxide, tautomer, stereoisomer, polymorph and / or prodrug thereof in the preparation of a medicament for treating or preventing a respiratory disease in a subject in need thereof.

[0206] As used herein, "prevent" or "preventing" is intended to mean at least reducing the likelihood of acquiring the risk (or susceptibility) of a disease or condition (i.e., causing a patient who may be exposed to or susceptible to the disease but has not yet experienced or manifested symptoms of the disease to not develop at least one clinical symptom of the disease). Biological and physiological parameters for identifying these patients are provided herein and are also well known to physicians.

[0207] The term "treatment" of a subject includes applying or administering a compound of the invention to a subject (or to a subject's cells or tissues) for the purpose of delaying, slowing, stabilizing, curing, rehabilitating, alleviating, altering, remedying, lessening worsening, improving, ameliorating, or affecting a disease or condition, a symptom of a disease or condition, or the risk (or susceptibility) of a disease or condition. The term "treating" refers to any sign of success in treating or ameliorating an injury, pathology, or condition, including any objective or subjective parameter, such as alleviation; remission; reducing the rate of worsening; reducing the severity of a disease; stabilizing, alleviating symptoms, or making an injury, pathology, or condition more tolerable to the subject; slowing the rate of degeneration or decline; making a degenerative endpoint less debilitating; or improving the physical or mental health of the subject.

[0208] The term "antagonize" as used herein means "lower" or "decrease". A sufficiently long period of time can be one week, or 1 week to 1 month, or 1 to 2 months, or 2 months or longer. For chronic diseases, the compounds of the present invention can be advantageously administered for life.

[0209] The term "breathing" refers to the process of taking oxygen into the body and expelling carbon dioxide through the body's systems, including the nose, throat, larynx, trachea, bronchi, and lungs.

[0210] The term "respiratory disease" or "respiratory disorder" refers to any of several diseases that may involve inflammation and / or tissue remodeling that affects a component of the respiratory system, including the upper respiratory tract (including the nasal cavity, pharynx, and larynx) and the lower respiratory tract (including the trachea, bronchi, and lungs). These diseases include pulmonary fibrosis (interstitial lung disease), sinusitis, influenza, sarcoidosis, bronchial cancer (including but not limited to non-small cell and small cell lung cancer, and lung metastases from tumors of other organs), silicosis, pneumoconiosis, acute lung injury, mechanical ventilation lung injury, congenital emphysema, bronchopulmonary dysplasia, bronchiectasis, atelectasis, nasal polyps, asbestosis, mesothelioma, pulmonary eosinophilia, diffuse pulmonary hemorrhagic syndrome, bronchiolitis obliterans, pulmonary alveolar proteinosis, collagen and vascular diseases affecting the lungs, and cough. Preferably, the respiratory disease is an obstructive airway disease, including: asthma conditions, including hay fever, allergen-induced asthma, exercise-induced asthma, pollution-induced asthma, cold-induced asthma, stress-induced asthma and virus-induced asthma, obesity-related asthma, occupational asthma, thunderstorm-induced asthma, asthma-COPD overlap syndrome (ACOS disease); chronic obstructive pulmonary disease, including chronic bronchitis with normal airflow, chronic bronchitis with airway obstruction (chronic obstructive bronchitis), emphysema, asthmatic bronchitis; Tracheitis and bullous diseases; and other lung diseases involving inflammation, including cystic fibrosis, pigeon breeder's disease, farmer's lung, acute respiratory distress syndrome, fungal pneumonia, viral pneumonia, bacterial pneumonia, mixed or unknown cause of pneumonia, inhalation injury or respiration injury, pulmonary fat embolism, pulmonary acidosis inflammation, acute pulmonary edema, acute altitude sickness, postoperative cardiac surgery, acute pulmonary hypertension, persistent pulmonary hypertension of the newborn, perinatal aspiration syndrome, hyaline membrane disease, acute pulmonary thromboembolism, heparin-protamine reaction, sepsis, status asthmaticus and hypoxia. Inflammation of the upper and lower respiratory tract may be associated with or caused by viral infection or allergens. It is expected that the anti-inflammatory activity of the compounds when administered alone or in combination with glucocorticoids will make them particularly suitable for treating these diseases or conditions.

[0211] Respiratory diseases or conditions may be associated with or caused by allergens such as house dust mites. Respiratory diseases or conditions may be the result of allergen-induced inflammation. The present invention is particularly applicable to allergic diseases of the airways or lungs and exacerbations of such diseases, such as exacerbations caused by viral infections (e.g. RSV infection).

[0212] Symptoms of respiratory disease may include cough, excessive sputum production, dyspnea, or chest tightness with audible wheezing. Exercise capacity may be quite limited. In asthma, FEV1.0 (forced expiratory volume in one second) as a percentage of the nomogram predicted value based on weight, height, and age may decrease with the maximum expiratory flow rate during forced expiration. In COPD, FEV1.0 as a ratio of forced vital capacity (FVC) usually decreases to less than 0.7. In IPF, FVC decreases progressively. The impact of each of these conditions can also be measured by the number of days missed from work / school, sleep disturbances, the need for bronchodilators, and the need for glucocorticoids (including oral glucocorticoids). Further measures of the impact of these conditions include valid health-related quality of life measures. Medical imaging procedures including, but not limited to, X-rays, high-resolution computed tomography, magnetic resonance imaging, positron emission tomography, ultrasound, optical coherence tomography, and fluoroscopy can also be used to evaluate disease and treatment response.

[0213] The presence, amelioration, treatment or prevention of respiratory diseases can be achieved by any clinical or biochemically relevant method of the subject or a biopsy thereof. For example, the parameters measured can be the presence or degree of lung function, signs and symptoms of obstruction; exercise tolerance; night awakenings; number of days missed from work or school; use of bronchodilators; ICS dosage; oral GC usage; need for other requirements; medical needs; hospital admissions.

[0214] As used herein, the term "asthma" refers to a breathing disorder characterized by intermittent dyspnea caused by any one or combination of three major factors, including: 1) bronchospasm (i.e., variable and reversible airway obstruction due to contraction of airway muscles), 2) inflammation of the airway lining, and 3) bronchial hyperresponsiveness resulting in excess mucus in the airways, which may be caused by exposure to allergens or combinations of allergens (i.e., dust mites and mold), viral or bacterial infections (i.e., common cold viruses), environmental pollutants (i.e., chemical fumes or smoke), physical exertion (i.e., during exercise), stress, or inhalation of cold air. The term "asthmatic condition" as used herein refers to the characteristics of an individual suffering from an asthma attack when exposed to any one or more asthma triggers for the individual. An individual may be presented as having, for example, allergen-induced asthma, exercise-induced asthma, pollution-induced asthma, viral-induced asthma, or cold-induced asthma.

[0215] The efficacy of asthma treatment can be measured by methods well known in the art, such as increase in lung function (spirometry), reduction in asthma exacerbations, increase in morning peak expiratory flow rate, reduction in rescue medication use, reduction in daytime and nighttime asthma symptoms, increase in asthma-free days, increase in time between asthma exacerbations, and increase in forced expiratory volume in one second (FEV1.0).

[0216] The terms "chronic obstructive pulmonary disease" and "COPD" are used interchangeably herein to refer to a chronic disease or combination of diseases characterized by a reduction in maximum expiratory flow and slow forced emptying of the lungs that does not change significantly over several months and is irreversible or only minimally reversible with conventional bronchodilators. Most commonly, COPD is a combination of chronic bronchitis (i.e., cough and sputum for more than three months for two consecutive years) and emphysema (i.e., alveolar damage). However, COPD can involve chronic bronchitis with normal airflow, chronic bronchitis with airway obstruction (chronic obstructive bronchitis), emphysema, asthmatic bronchitis, and bullous disease, and combinations thereof. Chronic obstructive pulmonary disease is a condition that is usually, but not exclusively, caused by chronic lung damage caused by exposure to tobacco smoke. As with aging, other harmful airborne pollutants, such as indoor fumes and automobile exhaust, may cause or increase the risk of chronic obstructive pulmonary disease over the long term, as does aging.

[0217] The phrases "conditions of the airways or lungs involving fibrosis" or "conditions of the airways or lungs with a fibrotic component" include any disease or condition in which there is formation or development of excess fibrous connective tissue (fibrosis) in the airways or lungs, resulting in the development of scar (fibrotic) tissue. This includes interstitial lung diseases such as pulmonary fibrosis, pulmonary fibrosis, or idiopathic pulmonary fibrosis (IPF). More precisely, pulmonary fibrosis is a chronic disease that causes swelling and scarring of the alveoli and interstitial tissue of the lungs. Scar tissue replaces healthy tissue and causes inflammation. This damage to the lung tissue can cause the lungs to stiffen, making it increasingly difficult to breathe. Pulmonary fibrosis can be caused by radiation damage or exposure to therapeutic agents such as bleomycin.

[0218] Idiopathic pulmonary fibrosis (IPF) is a special manifestation of idiopathic interstitial pneumonia (IIP), a type of interstitial lung disease. Interstitial lung disease, also known as diffuse parenchymal lung disease (DPLD), refers to a group of lung diseases that affect the interstitium. Under a microscope, the lung tissue of IPF patients shows a group of typical histological features called usual interstitial pneumonia (UIP). Therefore, UIP is a pathological manifestation of IPF.

[0219] The presence, improvement, treatment or prevention of airway or lung disorders involving fibrosis, particularly pulmonary interstitial fibrosis / pulmonary fibrosis or idiopathic pulmonary interstitial fibrosis can be achieved by any clinical or biochemically relevant method or biopsy of the subject. For example, the rate of decline of FVC or the appearance of high-resolution computed tomography images of the lungs may help diagnose IPF. In addition, the measured parameters may be the presence or extent of fibrosis; the content of collagen, fibronectin or another extracellular matrix protein; the proliferation rate of cells or any extracellular matrix component in cells or the transdifferentiation of cells to myofibroblasts.

[0220] In one embodiment, the respiratory disease is selected from asthma, chronic obstructive pulmonary disease, interstitial lung disease (such as idiopathic pulmonary fibrosis) and other diseases related to tissue remodeling, primary or secondary lung tumors, pollen allergies, chronic and acute sinusitis, and chronic and acute viral, fungal and bacterial infections of the respiratory tract.

[0221] In one embodiment, the improvement in respiratory function can be selected from a reduction in the level of lung contraction, a reduction in the elastic stiffness of the respiratory system, and / or an increase in the ease of stretching of the respiratory system. Preferably, the improvement is selected from a reduction in the level of lung contraction and a reduction in the elastic stiffness of the respiratory system. In another aspect, a composition is provided, comprising a compound according to formula (I) or a salt thereof, a solvate, a nitrogen oxide, a tautomer, a stereoisomer, a polymorph and / or a prodrug, and a pharmaceutically acceptable excipient.

[0222] The therapeutically effective amount of the preparation depends on the severity of the specific respiratory disease indication (such as severe chronic asthma), the patient's clinical history and reaction, and the judgment of the attending physician. The preparation can be administered to the patient once or through a series of treatments. The initial candidate dose can be administered to the patient, and a suitable dosage and treatment regimen can be established by monitoring the patient's progress using conventional techniques well known to those of ordinary skill in the art. Preferably, the therapeutically effective concentration of the active compound will be in the range of 0.1nM to 100μM. More preferably, the range is 0.1μM-10μM. However, it is understood that inhalation administration can cause cells in the airway to be exposed to concentrations exceeding the above concentrations for a short time, and over a period of time, the drug is diluted in the airway surface fluid and is also absorbed from the airway and lung surfaces.

[0223] In one aspect, the therapeutic method of the present invention further comprises administering a concomitant drug for the target disease indication. For example, concomitant asthma drugs (chronic and acute) that can be used in the method of the present invention include, but are not limited to: inhaled and oral steroids (such as beclomethasone, budesonide, flunisolide, fluticasone, triamcinolone, mometasone); systemic corticosteroids (such as methylprednisolone, prednisolone, prednisone, dexamethasone and deflazacort); inhaled or oral β2-adrenergic receptor agonists (such as salmeterol, formoterol, bitolterol, pirbuterol, vilanterol, terbutaline, bambuterol and salbutamol cromolyn and nedocromil; antiallergic ophthalmic drugs (such as dexamethasone); drugs that modulate the production and action of transforming growth factor-β, including pirfenidone and nintedanib; methylxanthines and other phosphodiesterase inhibitors (such as theophylline and mepyramine-theophylline acetate, roflumilast); leukotriene modifiers (such as zafirlukast, zileuton, montekulast, and pranlukast); anticholinergic drugs (such as ipratropium bromide); bromide); other therapeutic antibodies in any form (e.g., antibodies to interleukin 5, such as mepolizumab, or antibodies to IgE, such as omalizumab, those in monoclonal form, Fab, scFV, multivalent compositions, xenoantibodies, etc.), natural or engineered antibody mimetics (e.g., anticalins), or natural, engineered or synthetic peptides; thromboxane A2 synthetase inhibitors; thromboxane prostaglandin receptor antagonists; other eicosanoid modifiers (e.g., alprostadil vs. PGE1, dinoprostone vs. PGE2, epoprostenol vs. prostacyclin and PGI2 analogs (e.g., PG12 beraprost), serotonin, phosphodiesterase 4 isozyme inhibitors, thromboxane A2 synthetase inhibitors (e.g., ozmagrel, damegre or ozagrel); ditec (low-dose disodium cromoglycate and fenoterol); platelet-activating factor receptor antagonists; antihistamines or histamine antagonists: promethazine, chlorpheniramine, loratadine, cetirazine, azelastine; thromboxane A2 receptor antagonists; bradykinin receptor antagonists (such as icatibant); drugs that inhibit activated eosinophils and T-cell recruitment (such as ketotifen), IL-13 blockers (such as soluble IL-13 receptor fragments), IL-4 blockers (such as soluble IL-4 receptor fragments); ligands that bind to and block IL-13 or IL-4 activity, and xanthine derivatives (such as pentoxifylline); chemokine receptor antagonists and CRTH2 receptor antagonists.

[0224] In certain embodiments, the treatment method of the present invention includes providing an inhibitory RNA molecule (RNA interference molecule) to the subject at the same time, with the purpose of reducing, inhibiting or preventing the expression of the gene encoding the target protein. For example, the inhibitory RNA molecule can be used to reduce or inhibit the expression of one or more of the following: proteins associated with pathogens (viruses, bacteria, fungi) or mammalian cells, including but not limited to casein kinase 1 subtypes and other components of the CLOCK regulatory network (such as ARNT1, cycle 1-3) and other proteins that contribute to respiratory inflammatory responses, such as interleukin-5 and NALP inflammasomes.

[0225] Those skilled in the art will be familiar with various methods of interfering with gene expression in a subject using inhibitory RNA molecules. For example, the inhibitory RNA molecule can be any of the following: short interfering RNA (siRNA), microRNA mimics (miRNA), short hairpin RNA (shRNA) or long double-stranded RNA (long dsRNA) molecules. The inhibitory RNA molecule can be administered directly to the subject in need of treatment (e.g., by inhalation, intratracheal, oral or intranasal administration or by parenteral administration), or, after administering a polynucleotide (vector) construct encoding a double-stranded RNA (dsRNA) molecule capable of forming an inhibitory RNA molecule, it is formed in the subject being treated. Those skilled in the art will also be familiar with various methods known in the art for preparing inhibitory RNA molecules for administration (e.g., in liposomes, nanoparticles, etc.). The present invention also includes the administration of a casein kinase 1 inhibitor and a drug for the above-mentioned target disease indications, wherein one or both of the above are administered by inhalation or formulated for oral administration.

[0226] Although the present invention finds application in humans, the present invention may also be used for veterinary therapeutic purposes. The present invention may be used with livestock or farm animals, such as cattle, sheep, horses and poultry; companion animals such as cats and dogs; and zoo animals.

[0227] As used herein, "subject" refers to an animal, such as a mammal or a bird, including humans, apes, horses, cows, sheep, goats, dogs, cats, guinea pigs, rats, mice, chickens, and the like.

[0228] Ck1δ homologs are ubiquitous in nature, including in protozoa (such as malaria), in fungi and bacteria. Therefore, it is foreseeable that the compounds of the present invention can be used in any application requiring inhibition of CK1δ homologs. These uses may include administering the compounds of the present invention to a subject suffering from a disease, condition and / or disorder associated with a protozoan, fungal and / or bacterial infection and / or infestation.

[0229] In another aspect, the present invention provides a method for inhibiting casein kinase 1δ (CK1δ), comprising contacting a cell with an effective amount of a compound of formula (I) as defined herein, or a salt, solvate, nitrogen oxide, tautomer, stereoisomer, polymorph and / or prodrug thereof.

[0230] Surprisingly, the compounds of the present invention, or salts, solvates, nitrogen oxides, tautomers, stereoisomers, polymorphs and / or prodrugs thereof, can be used as selective inhibitors of CK1δ. The compounds of the present invention in any of their disclosed forms can selectively inhibit CK1δ compared to one or more other kinases such as ERBB4 / HER4, MINK / MINK1, etc. In some embodiments, the compounds of the present invention are at least about 1-fold, 5-fold, 10-fold, or 100-fold more selective for CK1δ than at least one kinase.

[0231] In another aspect, the present invention provides a kit or article of manufacture comprising a compound of formula (I) or a pharmaceutical composition comprising a compound of formula (I) as described herein.

[0232] In other embodiments, a kit for the therapeutic or prophylactic use described herein is provided, the kit comprising: a container containing a compound of Formula (I) or a pharmaceutical composition comprising a compound of Formula (I); and a label or package insert with instructions for use.

[0233] The kit or "article of manufacture" may include a container and a label or package inserted on or associated with the container. Suitable containers include, for example, bottles, medicine bottles, syringes, blister packs, etc. The container can be made of a variety of materials, such as glass or plastic. The container is filled with a compound of formula (I) or a composition effective for treating the condition and may have a sterile access port (for example, the container may be an intravenous fluid bag or a medicine bottle with a stopper that can be pierced by a hypodermic needle). The label or package insert indicates that the composition is used to treat the disease. In one embodiment, the label or package insert includes instructions for use and indicates that the therapeutic or preventive composition can be used to treat the disease described herein.

[0234] The kit may include (a) a therapeutic or preventive composition; and (b) a second container, which contains a second active substance or ingredient. The kit in an embodiment of the present invention may further include a package insert indicating that the composition and other active ingredients can be used to treat a disease or prevent complications caused by a disease described herein. Alternatively or additionally, the kit may further include a second (or third) container, which contains a pharmaceutically acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution, and dextrose solution. It may also include other materials desired from a commercial and user perspective, including other buffers, diluents, filters, needles, and syringes.

[0235] In certain embodiments, the therapeutic composition can be provided in the form of a disposable or reusable device, including a container for accommodating a compound of formula (I) or a therapeutic or preventive pharmaceutical composition comprising a compound of formula (I). In one embodiment, the device is a syringe. The therapeutic or preventive composition can be provided in the device in a ready-to-use state or in a state where it is necessary to mix or add other components.

[0236] Example

[0237] In vitro testing

[0238] Kinase inhibition assay

[0239] The assay used was the HotSpot assay (Reaction Biology).

[0240] Start with 10 μM and make a 3-fold serial dilution to get a dose of 10 IC 50 Model test compounds. Four-fold serial dilutions were performed starting from 20 μM to a dose of 10 IC 50 Model test control compound, D4476. Reactions were performed at 10 μM ATP.

[0241] Reagents

[0242] Base Reaction buffer: 20 mM Hepes (pH 7.5), 10 mM MgCl2, 1 mM EGTA, 0.02% Brij35, 0.02 mg / mL BSA, 0.1 mM Na3VO4, 2 mM DTT, 1% DMSO.

[0243] *Add required cofactors separately to each kinase reaction

[0244] Reaction Procedure

[0245] 1. Prepare peptide substrate freshly in basic reaction buffer

[0246] 2. Any required cofactors are delivered to the substrate solution above

[0247] 3. Deliver human recombinant casein kinase 1δ to the substrate solution and mix gently

[0248] 4. Deliver the compound in DMSO solution by acoustic technology (Echo550; nanoliter range) and incubate at room temperature for 20 minutes

[0249] 5. 33P-ATP (specific activity 10 mCi / mL) and ATP (10 μM) were delivered to the reaction mixture to initiate the reaction.

[0250] 6. Incubate the kinase reaction at room temperature for 2 hours

[0251] 7. The reaction mixture was spotted on P81 ion exchange paper

[0252] 8. Measure by using filter combination method 33 P-ATP-labeled product peptides to detect kinase activity

[0253] The results of the test (conducted on casein kinase 1δ) are shown in Table 2 (PIC 50 ) and Table 3 (IC 50 ) as shown.

[0254] Table 2 Inhibitory activity of the compounds of the present invention

[0255]

[0256]

[0257] Table 3 IC values ​​of various compounds for CK1δ, ERBB4 / HER4 and MINK / MINK1 50

[0258]

[0259]

[0260] Note: ^No inhibition or compound activity cannot be fitted to IC50 curve

[0261] Human parenchymal fibroblast assay

[0262] Primary human lung parenchymal fibroblasts (pFbs) were cultured from lung parenchyma of lung resection specimens and non-transplanted lungs of donors without chronic respiratory diseases. pFbs were passaged in Dulbecco's Modified Eagle's Media (DMEM), which contained 10% (v / v) heat-inactivated fetal calf serum (FCS), 15mM HEPES, 0.2% (v / v) sodium bicarbonate, 2mM L-glutamine, 1% (v / v) non-essential amino acids, 1% (v / v) sodium pyruvate, 2.5μg / mL amphotericin, 5IU / mL penicillin and 50μg / mL streptomycin. In some experiments, human lung fibroblast cell line MRC5 (derived from ATTC) was used as shown. The MRC5 cell line was maintained under the same conditions as pFb.

[0263] Before the experiment, pFb were incubated in serum-free DMEM (Monomed A; CSL, Parkville, Melbourne, Australia) containing 0.25% bovine serum albumin (BSA) and insulin-transferrin-selenium supplements. Cells were incubated with small molecule CK1δ inhibitors (0.1-10 μM) for 30 minutes before 100 pM TGF-β1 (R&D Systems, Minneapolis, Minnesota), and continued to incubate for 16-24 hours before harvesting supernatants for detection of immunoreactive IL-11. A 10 mM stock solution was prepared in 100% DMSO and diluted to the desired concentration (final concentration) in a culture medium containing 0.1% DMSO.

[0264] Supernatants were collected for measurement of IL-11 (R&D DuoSet, DY218) by ELISA according to the manufacturer's instructions. Typically, the capture antibody was initially diluted to the recommended concentration with PBS buffer and then used to coat the wells of a 96-well microplate (Greiner, #655061) by adding 50 μL / well and incubating overnight at room temperature. The next day, the solution was discarded and the wells were washed 3 times with wash buffer (PBS containing 0.1% (v / v) Tween-20) before adding 200 μL of blocking solution (PBS containing 1% (v / v) BSA) for 1 hour to block nonspecific sites. The microplate was then washed 3 times with wash buffer, and 50 μL of sample or standard was added to the well and incubated for 2 hours at room temperature. After incubation, the microplate was washed 3 times with wash buffer, 50 μL of detection antibody was added to the well, and incubated for 2 hours at room temperature. The microplate was then washed three times before the addition of streptavidin-conjugated horseradish peroxidase (recommended concentration) for 45 minutes. The microplate was then washed five times with wash buffer and 100 μL of TMB substrate solution (equal amounts of A and B, BD Biosciences) was added to each well until sufficient signal appeared. The reaction was inactivated by adding 100 μL of sulfuric acid (2M H2SO4). The absorbance is measured at 450 nm using a microplate reader. The absorbance of the cytokine standards is fit to a logistic equation, allowing the concentration of the cytokine in the sample to be determined.

[0265] Inhibition of TGF-β-induced IL-11 P IC 50 The values ​​(negative logarithm of the concentration that inhibits IL-11 levels by 50%) were interpolated by linear regression of the small molecule concentration against the logarithm of IL-11 levels (Table 4 and Figure 2 ).

[0266] Table 4 IL-11 inhibitory activity of the compounds of the present invention

[0267] Compound <![CDATA[pIC 50 IL-11 Inhibition]]> ZH3-114 4.98 ZH3-118 5.08 ZH3-122 6.75 ZH3-126 5.73 ZH2-114 4.00* ZH2-118 5.84 ZH2-122 5.61 ZH2-146 4.94 ZH2-38 4.00* ZH2-46 4.00* ZH2-54 5.36 ZH2-58 4.53 ZH2-78 6.53 ZH3-50 6.38 ZH3-62 6.00 ZH3-70 4.00* ZH3-86 6.47 ZH3-134 4.00* ZH3-58 6.26 ZH3-130 6.08 ZH3-138 4.70 ZH3-78 5.07

[0268] *Compounds that failed to cause more than 50% inhibition at 10 mM were assigned a pIC50 value of 4.00.

[0269] Cell-based assay (MRC5 and A549) for evaluating TGF-β-induced IL-11 levels following exposure to ZH3-138, ZH3-126, and PF670462

[0270] Another set of experiments was performed in MRC5 cells to determine the potential of ZH3-138 compared with PF670462 in modulating TGF-β-induced IL-11 levels. Figure 5 Shown in A are the mean and SEM of 3 replicates.

[0271] A549 cells were treated with different concentrations of PF670462 or ZH3-138 30 min before TGF-b (40 pM) for 24 h. Supernatants were collected for determination of IL-11 or PAI-1 by ELISA. Data are available at Figure 5 Mean ± SEM of three replicates are shown in B. A similar assay was also performed to assess the ability of ZH3-126 to affect IL-11 levels after administration. Data from this experiment are presented in Figure 6 Shown are the mean ± SEM of three replicates.

[0272] These examples demonstrate that inhibition of CK1δ by compounds of the invention can reduce the levels of inflammatory biomarkers.

[0273] Cellular Assay to Evaluate the Effects of ZH3-138, ZH3-126, and PF670462 on IL1α-Mediated Cytokine Production (A549 Human Lung Adenocarcinoma Cells)

[0274] In addition, the compounds of the present invention (such as ZH3-138 and ZH3-126) show the ability to reduce supernatant concentrations of other inflammatory biomarkers (such as interleukin-1α (IL1α) mediated cytokine production) in a dose-dependent manner. The anti-inflammatory potential of the selected compounds was tested by establishing the effect on interleukin-1α (Il1α) mediated cytokine production by the lung adenocarcinoma cell line A549. Serum-starved A549 cells were treated with different concentrations of relevant CK1δ inhibitors (PF670462, ZH3-126 and ZH3-138) for 24 hours 30 minutes before IL-1α (1ng / ml). The supernatant was collected and the concentrations of IL-6, IL-8 and GM-CSF were detected by ELISA. The data are in Figure 7 The data are shown as mean ± SEM of three replicates (A: IL-6; B: IL-8 and C: GM-CSF).

[0275] Human microsomal stability of the compounds of the present invention

[0276] In vitro metabolic stability

[0277] Incubation: Metabolic stability assays were performed by incubating each test compound in human liver microsomes at 37°C and a protein concentration of 0.4 mg / mL. The metabolic reaction was initiated by the addition of an NADPH-regenerating system and quenched at different time points during the 60-minute incubation period by the addition of acetonitrile containing diazepam as an internal standard. Control samples (without NADPH) were included (and quenched at 2, 30, and 60 minutes) to monitor potential degradation in the absence of cofactors. The human liver microsomes used in this experiment were provided by XenoTech, lot number 1410230. Microsome incubations were performed at a substrate concentration of 1 μM.

[0278] Data analysis: The species scaling factor in Ring et al. (2011) JPharmSci, 100:4090-4110 was used to convert in vitro CLint (μL / min / mg) to in vivo CLint (mL / min / kg). The “In vitro T 1 / 2 " method, hepatic blood clearance and the corresponding hepatic extraction efficiency (EH) were calculated using a well-stirred model of hepatic extraction for each species. Compounds were then classified using the EH as low (<0.3), medium (0.3-0.7), high (0.7-0.95), or very high (>0.95) extracted compounds. The values ​​of predicted in vivo clearance have not been corrected for microsomal or plasma protein binding. The species scaling calculations are based on two assumptions:

[0279] 1) NADPH-dependent oxidative metabolism is superior to other metabolic pathways (i.e., direct conjugation metabolism, reduction, hydrolysis, etc.), and;

[0280] 2) The rates and enzyme activities of in vitro metabolism truly reflect in vivo metabolism and enzyme activity. If significant non-NADPH-mediated degradation is observed in the microsomal control samples, then assumption (1) is invalid and therefore the predicted clearance parameters are not reported.

[0281] Table 5 Metabolic evaluation of the compounds of the present invention

[0282]

[0283] Notes: #The compound showed minimal degradation (<15%) during incubation in human microsomes; ^obtained by incubation at 1 μM in human or mouse liver microsomes.

[0284] Pharmacokinetics: PF670462 and compounds of the invention

[0285] PF670462 (2HCl 0.4 mol, isopropanol eq.) and ZH3-138 (unionised) were administered to male C57BL / 6 mice either IV (3 mg / kg) or orally (10 mg / kg). IV administration was achieved by bolus injection into the tail vein of the mice using a 1 mL syringe at a volume of 3 mL / kg with a 25G x 1" needle. Oral administration was achieved by gavage needle at a volume of 3 mL / kg.

[0286] Blood was collected from mice 15 minutes and 1 hour after each compound was administered for determination of the ratio of whole blood to plasma (B / P). The apparent whole blood plasma ratio (B / P) of PF670462 and ZH3-138 in mouse blood was 1.0 and 0.91, respectively, indicating that all compounds were effectively distributed into erythrocytes. No adverse reactions or compound-related side effects were observed in any mice during the 24-hour sampling period after administration of any compound. Plasma samples were also taken from 2 mice, which were not administered test compounds to be used as analytical tools.

[0287] The experimental scheme is summarized in Table 6 below

[0288] Table 6 Overview of pharmacokinetic study experimental plan

[0289]

[0290] PF670462 concentrations were measurable only 4 hours after administration and had a short apparent half-life (approximately 0.5 hours), which is consistent with previous literature (Neuropsychopharmacology 2012;37:2121–2131 and CPTPharmacometrics and Systems Pharmacology 2013;2:e57). The apparent blood volume distribution and blood clearance values ​​of Pf670462 were moderate.

[0291] The concentration-time curve of ZH3-138 is significantly different from that of PF670462 ( Figure 4). During the 24-hour sampling period, plasma concentrations remained above the lower limit of quantification (LLQ) and the apparent half-life was approximately 3 hours. In addition, the concentration-time curve showed a clear secondary peak 2 hours after dosing; this may be indicative of enterohepatic circulation, in which the compound is excreted in the bile (either unchanged or as conjugated metabolites) and then reabsorbed from the gastrointestinal tract into the systemic circulation. ZH3-138 has a moderate apparent blood volume distribution and a low apparent blood clearance. Given the possible contribution of enterohepatic circulation to plasma exposure, the calculated pharmacokinetic parameters of ZH3-138 should be considered as apparent values ​​only. In addition, it should be noted that although no secondary peaks were observed for PF670462, this does not rule out the potential sensitivity of these compounds to biliary excretion.

[0292] These apparent blood clearance values ​​are consistent with their relative metabolic stabilities in mouse liver microsomes, with an in vivo predicted liver extraction rate of 0.90 for PF670462 (0.88 for PF670462 in human microsomes and <0.22 for ZH3-138 in human microsomes) (see Table 5 above).

[0293] Preparation and analysis of formulations

[0294] Intravenous (IV) and oral formulations were prepared using the same method. On the day of administration, each solid compound was dissolved in DMSO, to which an aqueous solution containing 10% of Captisol was added. Hydrochloric acid (1M) was used to adjust the pH of the ZH3-138 formulation in order to dissolve the compound (see Part B for the final pH of each formulation). The formulation of each compound was thoroughly vortexed, and all three compounds produced a colorless solution.

[0295] The IV formulation was filtered through a 0.22 μm syringe filter before IV administration. For PF670462 and ZH3-138, the average measured concentrations of the compounds in the aliquots (n=2) of the filtered solutions were 0.806 mg / mL and 0.908 mg / mL, respectively. For oral formulations, for PF670462, the average measured concentration of the compounds in the aliquots (n=3) of the bulk formulation was 3.38 mg / mL (range 3.34 mg / mL-3.45 mg / mL), and for ZH3-138, the average measured concentration of the compounds in the aliquots (n=3) of the bulk formulation was 3.00 mg / mL (range 2.59 mg / mL-3.28 mg / mL).

[0296] Mouse Pharmacokinetics

[0297] All animal studies were performed using established procedures in accordance with the Australian Code of Practice for the Care and Use of Animals for Scientific Purposes, and study protocols were reviewed and approved by the Monash Institute of Pharmaceutical Sciences Animal Ethics Committee.

[0298] Systemic exposure to PF670462 and ZH3-138 was studied in fasted male C57BL / 6 mice weighing 19.8-26.8 g. Mice had ad libitum access to food and water throughout the pre-dose and post-dose sampling periods.

[0299] Compounds were injected into the lateral tail vein by bolus injection (3 mL / kg) for IV administration and by gavage (3 mL / kg) for oral administration. Blood samples were collected up to 24 hours after IV and oral administration (n=3 mice per time point), with a maximum of three samples collected per mouse. Samples were collected by submandibular bleeding (approximately 120 μL; conscious sampling). Urine samples were not collected because mice were kept in cages with beds.

[0300] Blood was collected into a mixture containing heparin as an anticoagulant and a stabilizing mixture (containing (a protease inhibitor cocktail) and potassium fluoride) in polypropylene Eppendorf tubes to minimize the potential for in vitro compound degradation in blood / plasma samples.

[0301] Once collected, blood samples were immediately centrifuged and the supernatant plasma was removed and stored at -80 °C until analysis by LC-MS.

[0302] Plasma samples were quantified against calibration standards, which were prepared by spiking blank mouse plasma (50 μL) with solution standards (10 μL), which were obtained by diluting the test compound stock solution (1 mg / mL in DMSO) with 50% acetonitrile in water. Diazepam (10 μL, 5 μg / mL in 50% acetonitrile / water) was added as an internal standard (IS) to all plasma calibration standards and samples. Extraction of test compounds and IS from plasma was performed by precipitating proteins with acetonitrile. Protein precipitation was performed by adding acetonitrile, followed by vortexing and centrifugation (10,000 rpm) for 3 minutes to obtain the supernatant for analysis using the LC-MS conditions described in Table 7.

[0303] Table 7 Overview of bioanalytical methods

[0304]

[0305] Analysis of B / P partition samples was performed in a similar manner and quantified against calibration standards prepared using a 1:1 v / v mixture of blank mouse blood and plasma. Matrix matched B / P partition samples and standards were processed using acetonitrile protein precipitation as described above.

[0306] Formulation aliquots were analyzed against standard samples prepared in 50% acetonitrile / water. Formulation aliquots (50 or 100 μL) were dissolved in DMSO (1 mL final volume) and diluted with 50% acetonitrile / water to within the calibration range.

[0307] The accuracy and precision of the test met the CDCO acceptance criteria and are summarized in Table 8.

[0308] Table 8 Repeat analysis and calibration

[0309]

[0310] In vivo determination of whole blood to plasma ratio

[0311] Blood was collected by cardiac puncture (under gaseous isoflurane anesthesia) into tubes containing heparin and stabilizing mixture. Hematocrit was determined by centrifugation (using Microhematocrit centrifuge and Plain Self-sealing Mylar Wrapped capillary tubes (13000 x g, 4 min), the values ​​were 38% to 40% for PF670462 and 38% to 44% for ZH3-138.

[0312] Blood aliquots (4×25 μL) were collected and matrix matched with an equal amount of blank plasma. The remaining blood samples were centrifuged, and 4×25 μL plasma aliquots were collected from each mouse and matrix matched with an equal amount of blank blood. The samples were frozen on dry ice and stored at -80°C until analyzed by LC-MS.

[0313] The B / P ratio was obtained by dividing the mean concentration measured in blood by the mean concentration measured in plasma after centrifugation of whole blood.

[0314] Table 9 Plasma concentrations of PF670462 in male C57BL / 6 mice after IV administration at 2.42 mg / kg

[0315]

[0316] aIncluded as a value in PK data analysis only slightly below LLQ

[0317] ND Not detected

[0318] Table 10 Plasma concentrations of PF670462 in male C57BL / 6 mice after oral administration at 10.1 mg / kg

[0319]

[0320] ND Not detected

[0321] Table 11 Plasma concentrations of ZH3-138 in male C57BL / 6 mice after IV administration at 2.69 mg / kg

[0322]

[0323] aThe actual sampling time is 0.10 hours

[0324] Table 12 Plasma concentrations of ZH3-138 in male C57BL / 6 mice after oral administration at 8.96 mg / kg

[0325]

[0326] synthesis

[0327] General Introduction

[0328] Proton NMR spectroscopy ( 1 H NMR, 400, 600 MHz) and proton decoupled carbon-13 NMR ( 13 C NMR, 100, 150 MHz) were obtained in deuterated solvents with the remaining protonated solvent as internal standard. Chemical shifts are followed by multiplicity, one or more coupling constants (J, Hz), integration and possible assignment. The automated system was used according to the procedure of Still et al. 1 Perform rapid chromatography analysis. 2 mm thick silica gel 60GF on aluminum back 254 Analytical thin layer chromatography (tlc) was performed on the chromatograms visible under UV light. High resolution mass spectra (HRMS) were obtained by ionizing samples using electrospray ionization (ESI) and a time-of-flight mass analyzer. Dry THF and CH2Cl2 were prepared by Pangborn et al. 2 Petroleum spirits refer to petroleum ether with a boiling range of 40-60°C. All other commercially available reagents were used directly.

[0329] 1 WCStill,M.Kahn and AMMitra,J.Org.Chem.,1978,43,2923.

[0330] 2 ABPangborn, MAGiardello, RHGrubbs, RKRosen and FJTimmers, Organometallics, 1996, 15, 1518.

[0331]

[0332] 2-(Methylthio)pyrimidine-4-carboxaldehyde (1)

[0333] To a solution of 4-dimethoxymethyl-2-methylsulfanyl-pyrimidine (4.10 g, 20.5 mmol) was added 4M aqueous HCl (13 mL) The resulting mixture was heated at 50° C. for 18 hours. 1 H NMR analysis indicated conversion to formaldehyde, so the mixture was cooled to room temperature. The reaction mixture was diluted with EtOAc and neutralized with K2CO3 solution. The aqueous phase was extracted with EtOAc, dried (MgSO4) and concentrated. The unpurified crude material (2.74 g, 87%) was used in the next step. 1 H NMR (CDCl3, 400MHz) δ2.64 (3H, s), 7.44 (1H, d, J = 4.8Hz), 8.77 (1H, d, J = 4.8Hz), 9.96 (1H, s).

[0334] N-ethyl-1-(2-(methylthio)pyrimidin-4-yl)methanimine (2)

[0335] 2.0 M ethylamine in THF (1.37 mL, 2.74 mmol) and 20% aqueous K2CO3 (0.230 g, 1.64 mmol) were added to a solution of the crude aldehyde (0.21 g, 1.37 mmol) in CH2Cl2 (5 mL). The reaction mixture was stirred at room temperature overnight. 1 H NMR analysis indicated complete consumption of the aldehyde. The reaction mixture containing the imine was used directly in the next step without isolation.

[0336] 4-(1-ethyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-2-(methylthio)pyrimidine (3)

[0337] A mixture of α-(p-toluenesulfonyl)-4-fluorobenzyl isonitrile (0.474 g, 1.64 mmol), 2 (0.248 g, 1.37 mmol) and K2CO3 20% w / v (1.13 mL, 1.64 mmol) in CH2Cl2 (5 ml) was stirred at room temperature for 5 days. The reaction mixture was diluted with CH2Cl2, washed with water, dried (MgSO4), filtered and concentrated. Flash chromatography of the residue (EtOAc / petroleum spirit 20% to 80%) gave a light orange oil (0.340 g, 79%). 1 H-NMR (400MHz; CDCl3): δ1.33(3H,t,J=7.2Hz), 2.53(3H,s,), 4.32(2H,q,J=7.2Hz), 6.75(1H,d, J=5.2Hz),6.97(2H,t,J=8.6Hz),7.40(2H,dd,J=5.8,7.9Hz),7.63(1H,s),8.27(1H,d,J=5.2Hz); 13 C-NMR (101MHz; CDCl3): δ14.1,16.7,42.0,115.4,115.6,116.2,130.2(d,J C-F =8.1Hz),130.4(d,J C-F =3.1Hz),139.3,143.8,156.9,157.7,162.5(d,J C-F =247Hz),172.8;HRMS(ESI + ) is calculated as C 16 H 16 FN4S[M+H] + 315.1080. Measured value is 315.1075.

[0338] 4-(1-ethyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-2-(methylsulfonyl)pyrimidine (4)

[0339] mCPBA (57-86%) (0.559 g, 3.24 mmol) was added portionwise to a mixture of the sulfide (0.340 g, 1.08 mmol) in CH2Cl2 (10 mL) and the mixture was stirred at room temperature overnight. TLC showed conversion to a more polar compound. The mixture was quenched with Na2CO3 10% aqueous solution (w / v), water, brine, dried (MgSO4), and concentrated in vacuo to give the sulfone (0.294 g, 79%) as a pale yellow oil. 1H-NMR (500MHz; CDCl3): δ0.97 (3H, t, J = 7.2Hz), 2.88 (3H, s), 3.99 (2H, q, J = 7.2Hz) ,6.59(2H,t,J=8.7Hz),6.81(1H,d,J=5.4Hz),6.96(3H,m),8.10(1H,d,J=5.4Hz); 13 C-NMR (126MHz; CDCl3): δ16.7,39.1,42.9,115.9,116.1,122.1,122.9,130.1(d,J C-F =3.4Hz),130.5(d,J C-F =8.2Hz),140.9,146.4,157.4,159.1,162.9(d,J C-F =248Hz),166.0;HRMS(ESI + ) is calculated as C 16 H 16 FN4O2S[M+H] + 347.0978. Actual value is 347.0970.

[0340] N-cyclobutyl-4-(1-ethyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)pyrimidin-2-amine (5; ZH3-122)

[0341] Cyclobutylamine (61.0 μL, 0.854 mmol) was added to a mixture of 4 (37.0 mg, 0.107 mmol) in THF (5 mL), and the mixture was stirred for 4 days at 40° C. The mixture was concentrated under vacuum and the residue was purified by flash chromatography (EtOAc / petroleum spirit 70%) to give a light orange solid (31.6 mg, 88%). 1 H-NMR (500MHz; CDCl3): δ1.38(3H,t,J=7.2Hz),1.71-1.82(2H,m),1.90-1.9(2H,m),2.42(2H,m),4.31-4.35(2H,m),4.44-4.52 (1H,m),5.46-5.50(1H,m),6.40(1H,d,J=5.1Hz),7.00(2H,t,J=8.7Hz),7.48(2H,dd,J=5.5,8.6Hz),7.63(1H,s),8.11(1H,m); 13 C-NMR (126MHz; CDCl3): δ15.2,16.8,31.7,41.8,46.7,111.3,115.3,115.5,125.2,130.20(d,J C-F=8.0Hz),130.8(d,J C-F =2.9Hz),138.6,142.6,158.0,158.7,162.4(d,J C-F =247 Hz); HRMS (ESI + ) is calculated as C 21 H 21 FN5[M+H] + 338.1781. Actual value is 338.1773.

[0342] 2-((4-(1-ethyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)ethan-1-ol (6; ZH3-126)

[0343] Ethanolamine (46.0 μL, 0.762 mmol) was added to a mixture of 4 (33.0 mg, 0.095 mmol) in THF (5 mL), and the mixture was stirred for 3 days at 40° C. The mixture was concentrated in vacuo and the residue was purified by flash chromatography (EtOAc 100% to MeOH / EtOAc 20%) to give a light orange oil (24.9 mg, 78%). 1 H-NMR (500MHz; CDCl3): δ1.36(3H,t,J=7.2Hz), 3.60(2H,m), 3.83(2H,m), 4.30(2H,q,J=7.2Hz), 5.90-5.97(1H,m) ,6.41(1H,d,J=5.2Hz),7.00(2H,m,J=4.8,8.7Hz),7.45(2H,m,J=4.9,5.3Hz),7.63(1H,s),8.09(1H,d,J=5.2Hz); 13 C-NMR (126MHz; CDCl3): δ16.8,41.8,45.9,58.4,111.4,115.4,115.6,125.0,130.2(d,J C-F =8.1Hz),130.6(d,J C-F =3.4Hz),138.7,142.6,158.8,162.5(d,J C-F =247Hz),162.8;HRMS(ESI + ) is calculated as C 17 H 19 FN5O[M+H] + 328.1574. Actual value is 328.1570.

[0344]

[0345] N-(Cyclohexylmethyl)-1-(2-(methylsulfanyl)pyrimidin-4-yl)methanimine (7)

[0346] Cyclohexylmethylamine (356 μL, 2.74 mmol) and K2CO3 (0.227 g, 1.64 mmol) were added to a solution of crude aldehyde 1 (0.211 g, 1.37 mmol) in CH2Cl2 (5 mL). The reaction mixture was stirred at room temperature overnight. 1 H NMR analysis indicated complete consumption of the aldehyde. The reaction mixture containing the imine was used directly in the next step without isolation.

[0347] 4-(1-(Cyclohexylmethyl)-4-(4-fluorophenyl)-1H-imidazol-5-yl)-2-(methylthio)pyrimidine (8)

[0348] A mixture of α-(p-toluenesulfonyl)-4-fluorobenzyl isonitrile (0.474 g, 1.64 mmol), 7 (0.342 g, 1.37 mmol) and K2CO3 20% w / v (1.13 mL, 1.64 mmol) in CH2Cl2 (5 ml) was stirred at room temperature for 5 days. The reaction mixture was diluted with CH2Cl2, washed with water, dried (MgSO4), filtered and concentrated. Flash chromatography of the residue (EtOAc / petroleum spirit 50%) gave a yellow oil (0.410 g, 78%). 1 H-NMR (400MHz; CDCl3): δ0.85 (2H, q, J = 10.8Hz), 1.09 (3H, d, J = 8.0Hz), 1.53-1.65 (6H, m), 2.55 (3H, s), 4.12 (2H, d, J = 6.7Hz), 6.75 (1H, d, J = 5.3Hz), 6.98 (2H, t, J = 8.6Hz), 7.42 (2H, dd, J = 5.5, 8.5Hz), 7.55 (1H, s), 8.28 (1H, d, J = 5.2Hz); 13 C-NMR (101MHz; CDCl3): δ14.1,25.6,26.1,30.5,38.7,53.1,115.4,115.6,116.3,124.2,130.3(d,J C-F =7.9Hz),130.4(d,J C-F =3.2Hz),140.6,143.7,156.9,157.82,162.5(d,J C-F =248Hz),172.8;HRMS(ESI+ ) is calculated as C 21 H 24 FN4S[M+H] + 383.1706. Actual value is 383.1698.

[0349] 4-(1-(Cyclohexylmethyl)-4-(4-fluorophenyl)-1H-imidazol-5-yl)-2-(methylsulfonyl)pyrimidine (9)

[0350] mCPBA (57-86% purity) (0.459 g, 2.66 mmol) was added portionwise to a mixture of the sulfide (0.339 g, 0.886 mmol) in CH2Cl2 (15 mL) and the mixture was stirred at room temperature overnight. The mixture was quenched with aqueous Na2CO3, water, brine, dried (MgSO4), and concentrated in vacuo to give the sulfone (0.308 g, 84%) as a pale yellow solid. 1 H-NMR (400MHz; CDCl3): δ0.88-0.96(2H,m),1.15(3H,m),1.67(6H,m),3.36(3H,s),4.28(2H,d,J=6.9Hz),7 .08(2H,t,J=8.6Hz),7.28(1H,d,J=5.4Hz),7.45(2H,dd,J=5.4,8.5Hz),7.68(1H,s),8.56(1H,d,J=5.4Hz); 13 C-NMR (101MHz; CDCl3): δ25.6,26.3,30.4,38.7,39.2,54.1,116.1,116.3,122.2,123.2,130.0(d,J C-F =3.0Hz),130.7(d,J C-F =8.1Hz),142.3,146.4,157.4,159.5,163.1(d,J C-F =249Hz),166.2;HRMS(ESI + ) is calculated as C 21 H 24 FN4O2S[M+H] + 415.1604. Actual value is 415.1597.

[0351] 4-(1-(Cyclohexylmethyl)-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(oxetan-3-yl)pyrimidin-2-amine (10; ZH3-114)

[0352] 3-Oxetaneamine (100 μL, 1.18 mmol) was added to a mixture of 9 (49.0 mg, 0.118 mmol) in THF (5 mL), and the mixture was stirred for 5 days at 40° C. The mixture was concentrated under vacuum and the residue was purified by flash chromatography (EtOAc / petroleum spirit (50% to 100%)) to give a light yellow oil (31.9 mg, 66%). 1 H-NMR (400MHz; CDCl3): δ0.85-1.69(11H,m),4.10(2H,d,J=6.8Hz), 4.63(2H,t,J=6.3Hz), 5.00(2H,t,J=6.9Hz), 5.15(1H,dt,J=6.8, 13.6Hz),6.08(1H,bs),6.47(1H,d,J=5.0Hz),6.99(2H,t,J=8.5Hz),7.45(2H,dd,J=5.6,8.3Hz),7.57(1H,s),8.15(1H,d,J=5.1Hz); 13 C-NMR (101MHz; CDCl3): δ25.7,26.2,30.7,38.9,46.6,52.8,79.2,112.4,115.4,115.6,125.0,130.2(d,J C-F =8.2Hz),130.5(d,J C-F =3.2Hz),140.0,142.7,158.2,159.1,161.3,162.5(d,J C-F =248Hz).

[0353] 2-((4-(1-(cyclohexylmethyl)-4-(4-fluorophenyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)ethan-1-ol (11; ZH3-118)

[0354] Ethanolamine (75.0 μL, 1.25 mmol) was added to a mixture of 9 (52.0 mg, 0.125 mmol) in THF (5 mL), and the mixture was stirred for 5 days at 40° C. The mixture was concentrated under vacuum and the residue was purified by flash chromatography (EtOAc / petroleum spirit 70% to 100%) to give a light yellow foam (41.7 mg, 85%). 1H-NMR (400MHz; CDCl3): δ0.84-1.67(10H,m),2.04(1H,d,J=8.3Hz), 3.61(2H,q,J=5.1Hz), 3.83(2H,t,J=4.9Hz), 4.09(3H,m,J=6. 6Hz), 5.93 (1H, bs), 6.41 (1H, d, J = 5.1Hz), 6.99 (2H, t, J = 8.6Hz), 7.45 (2H, dd, J = 5.6, 8.4Hz), 7.56 (1H, s), 8.10 (1H, d, J = 4.9Hz); 13 C-NMR (101MHz; CDCl3): δ25.7,26.2,30.7,38.8,44.4,52.8,62.7,111.6,115.3,115.6,125.2,130.2(d,J C-F =8.0Hz),130.5(d,J C-F =3.1Hz),140.0,142.5,157.8,159.1,162.5(d,J C-F =248Hz),162.7;HRMS(ESI + ) is calculated as C 22 H 27 FN5O[M+H] + 396.2200. Actual value is 396.2193.

[0355]

[0356] 4-((Cyclohexylimino)-methyl)-N-methylthiopyrimidin-2-amine (12)

[0357] K2CO3 20% w / v aqueous solution (0.55 g, 0.39 mmol) and cyclohexylamine (2.45 mL, 21.4 mmol) were added to a solution of the crude aldehyde (2.74 g, 17.8 mmol) in CH2Cl2 (15 mL). The reaction mixture was stirred at room temperature overnight. 1 H NMR analysis indicated complete consumption of the aldehyde. The reaction mixture containing the imine was used directly in the next step without isolation.

[0358] 4-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-2-(methylthio)pyrimidine (13)

[0359] A mixture of α-(p-toluenesulfonyl)-4-fluorobenzyl isonitrile (5.67 g, 19.6 mmol), 12 (2.74 g, 17.8 mmol) and K2CO3 (2.71 g, 19.6 mmol) in CH2Cl2 (15 ml) was stirred overnight at room temperature. The reaction mixture was diluted with CH2Cl2, washed with water, dried (MgSO4), filtered and concentrated. Flash chromatography (EtOAc / petroleum spirit 1:1) of the residue gave a solid which was recrystallized from EtOAc / petroleum spirit to give the sulfide as pale yellow crystals (2.32 g, 35%), m.p. 192-195°C. 1 H-NMR (400MHz; CDCl3): δ1.41-1.19(3H,m),1.75-1.59(3H,m),1.88(2H,d,J=13.3Hz),2.16(2H,d,J=11.3Hz),2.58(3H,s),4.62(1 H,tt,J=11.9,3.4Hz),6.76(1H,d,J=5.2Hz),6.99(2H,t,J=8.6Hz),7.40(2H,dd,J=8.5,5.5Hz),7.76(1H,s),8.31(1H,d,J=5.2Hz); 13 C-NMR (101MHz; CDCl3): δ14.2,25.4,26.0,34.7,55.9,115.5,115.71(s,1C),117.2,124.2,130.3(d,J C-F =8.0Hz),130.6(d,J C-F =3.2Hz),136.6,143.1,157.1,158.2,162.6(d,J C-F =247Hz),173.0;HRMS(ESI + ) is calculated as C 20 H 22 FN4S (M+H) 369.1549. Found 369.1545.

[0360] 4-(1-Cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-2-methylsulfonylpyrimidin-2-amine (14)

[0361] mCPBA (55-86%) (0.569 g, 3.30 mmol) was added portionwise to a mixture of 13 (0.404 g, 1.10 mmol) in CH2Cl2 (20 mL), and the mixture was stirred at room temperature overnight. The mixture was quenched with aqueous Na2CO3, water, brine, dried over Na2SO4, and concentrated in vacuo to give the sulfone (0.440 g, 87%) as a colorless solid. Melting point: 196-202°C. 1 H-NMR (400MHz; CDCl3): δ1.93-1.21(8H,m),2.23(2H,d,J=11.3Hz), 3.39(3H,s),4.85(1H,tt,J=11.8,3. 4Hz),7.08(2H,t,J=8.6Hz),7.27(1H,m),7.43(2H,dd,J=8.5,5.5Hz),7.86(1H,s),8.59(1H,d,J=5.4Hz); 13 C-NMR (101MHz; CDCl3): δ25.5,25.8,34.9,39.2,56.9,116.0,116.3,123.1,130.3(d,J C-F =3.6Hz,1C),130.7(d,J C-F =8.2Hz),138.2,146.0,157.5,159.8,163.1(d,J C-F =249Hz),166.3;HRMS(ESI + ) is calculated as C 20 H 22 FN4O2S(M+H)401.1447. Found:401.1444.

[0362] 4-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-fluorobenzyl)pyrimidin-2-amine (16; ZH2-114)

[0363] 3-Fluorobenzylamine (118 μL, 1.03 mmol) was added to a solution of 14 (41.3 mg, 0.103 mmol) in THF (5 mL), and the mixture was stirred at 40° C. for 5 days. The mixture was concentrated under vacuum and the residue was purified by flash chromatography (EtOAc / petroleum spirit 40% to 70%) to give a colorless solid (45.1 mg, 99%). 1H-NMR (500MHz; CDCl3): δ1.12-1.20(3H,m),1.55-1.65(3H,m),1.79-1.81(2H,m) ,2.09(2H,m,J=11.8Hz),4.47-4.52(1H,m),4.71(2H,d,J=6.2Hz),5.90(1H,s),6. 44(1H,d,J=5.1Hz),6.94-7.00(3H,m),7.06(1H,d,J=9.8Hz),7.13(1H,d,J=7.6Hz ),7.30(1H,td,J=6.0,7.9Hz),7.42-7.45(2H,m),7.71(1H,s),8.12-8.13(1H,m); 13 C-NMR (126MHz; CDCl3): δ25.4,25.7,34.6,44.8,55.5,112.6,113.9,114.1,114.1,114.3,115.3,115.4,122.7(d,J C-F =2.3Hz),125.0,130.1(d,J C-F =8.0Hz),130.3(d,J C-F =8.2Hz),130.7(d,J C-F =3.2Hz),135.9,141.7,142.0,142.1,158.4,159.2,162.4(d,J C-F =247Hz),162.5,163.2(d,J C-F =247 Hz); HRMS (ESI + ) is calculated as C 26 H 26 F2N5[M+H] + 446.2156. Actual value is 446.2148.

[0364] 4-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorobenzyl)pyrimidin-2-amine (17; ZH2-118)

[0365] 2-Fluorobenzylamine (87.0 μL, 0.759 mmol) was added to a solution of 14 (30.4 mg, 0.076 mmol) in THF (5 mL), and the mixture was stirred at 40° C. for 5 days. The mixture was concentrated under vacuum and the residue was purified by flash chromatography (EtOAc / petroleum spirit 40% to 70%) to give a colorless solid (33.2 mg, 98%). 1H-NMR (500MHz; CDCl3): δ1.22-2.14(10H,m),4.56(1H,ddd,J=3.3,8.7,11.7Hz),4.78(2H,d,J=6.2Hz),5.78(1H,s),6.45(1H ,d,J=5.1Hz),6.97-7.01(2H,m),7.06-7.14(2H,m),7.30-7.26(1H,m),7.39-7.47(3H,m),7.74(1H,s),8.14(1H,d,J=4.2Hz); 13 C-NMR (126MHz; CDCl3): δ25.4,25.8,34.7,39.5,55.6,112.5,115.3,115.4,115.5,115.7,124.3,124.4,125.1,126.1,126.2,129.2(d,J C-F =8.0Hz),129.4(d,J C-F =2.8Hz),130.1(d,J C-F =8.1Hz),130.8(d,J C-F =3.2Hz), 135.9, 141.7, 158.4, 159.1, 161.1 (d, J = 246Hz), 162.4 (d, J = 247Hz), 162.5; HRMS (ESI + ) is calculated as C 26 H 25 F2N5[M+H] + 446.2156. Actual value is 446.1195.

[0366] 4-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(4-fluorobenzyl)pyrimidin-2-amine (18; ZH2-122)

[0367] 4-Fluorobenzylamine (79.0 μL, 0.694 mmol) was added to a solution of 14 (27.8 mg, 0.069 mmol) in THF (5 mL), and the mixture was stirred at 40° C. for 5 days. The mixture was concentrated under vacuum and the residue was purified by flash chromatography (EtOAc / petroleum spirit 40% to 70%) to give a colorless solid (21.4 mg, 70%). 1H-NMR (400MHz; CDCl3): δ1.22(3H,m),1.63(3H,m),1.83(2H,m),2.12(2H,m) ,4.52(1H,tt,J=3.3,11.9,Hz),4.67(2H,d,J=6.0Hz),5.66(1H,dd,J=0.7,1 .4Hz),6.45(1H,d,J=5.1Hz),7.02(4H,dt,J=9.0,18.3,Hz),7.33(2H,dd,J= 5.5,8.2Hz),7.45(2H,dd,J=5.6,8.4Hz),7.76(1H,s),8.16(1H,d,J=4.7Hz); 13 C-NMR (101MHz; CDCl3): δ25.4,25.8,34.6,44.8,55.7,112.5,115.3,115.6(2C),115.8,125.1,128.9,129.0(d,J C-F =8.1Hz),130.1(d,J C-F =8.0Hz),130.4(d,J C-F =3.2Hz),134.8(d,J=3.0Hz,1C),135.8,141.5,158.3,159.0,162.3(d,J C-F =246Hz),162.4,162.5(d,J C-F =247 Hz); HRMS (ESI + ) is calculated as C 26 H 26 F2N5[M+H] + 446.2156. Actual value is 446.2147.

[0368] 4-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(4,4-difluorocyclohexyl)pyrimidin-2-amine (20; ZH2-146)

[0369] 4,4-Difluorocyclohexan-1-amine (67.0 mg, 0.499 mmol) was added to a solution of 14 (20.0 mg, 0.050 mmol) in THF (5 mL), and the mixture was stirred at 40° C. for 3 days. The mixture was concentrated under vacuum and the residue was purified by flash chromatography (EtOAc / petroleum spirit 70% to 100%) to give a light orange solid (22.2 mg, 98%). 1H-NMR (500MHz; CDCl3): δ1.27-1.34(2H,m),1.63-1.92(10H,m),2.12-2.17(6H,m),3.96-4.01(1H,m),4.48(1H,tt,J=3. 6,12.0Hz),5.21(1H,s),6.43(1H,d,J=5.1Hz),6.96-7.01(2H,m),7.41-7.45(2H,m),7.76(1H,s),8.15(1H,d,J=5.1Hz); 13 C-NMR (126MHz; CDCl3): δ25.4, 26.1, 28.9 (d, J = 9.9Hz), 32.3 (t, J = 24.8Hz), 3 4.7,47.9,55.6,112.4,115.3,115.5,120.8,122.7,124.6,125.2,130.1(d,J C-F =8.0Hz),130.6(d,J C-F =3.3Hz),135.9,141.5,158.4,160.0,161.9. 162.4(d,J C-F =247Hz).

[0370] 3-((4-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)propan-1-ol (21; ZH2-38)

[0371] 3-Amino-1-propanol (46.0 μL, 0.100 mmol) was added to a solution of 14 (45.0 mg, 0.600 mmol) in THF (5 mL), and the mixture was stirred at room temperature for 18 h. The mixture was concentrated under vacuum and the residue was purified by flash chromatography (EtOAc 100% to EtOAc / MeOH 90%) to give a light yellow oil (39.0 mg, 99%). 1 H-NMR (500MHz; CDCl3): δ1.29-1.39(2H,m),1.63-1.83(8H,m),2.15-2.17(2H,m),3.63(2H,q,J=6.2Hz), 3.71(2H,t,J=5.7Hz), 4.48-4.55(1H,m),5.43(1H,s),6.41(1H,d,J=5.1Hz),6.97-7.01(2H,m),7.42-7.46(2H,m),7.73(1H,s),8.14(1H,d,J=5.1Hz); 13C-NMR (126MHz; CDCl3): δ25.5,26.0,29.9,33.1,34.7,38.1,55.7,59.4,112.0,115.3,115.5,124.9,130.1(d,J C-F =8.0Hz),130.7(d,J C-F =3.4Hz),136.0,141.9,158.2,159.4,162.4(d,J C-F =247Hz),163.0;HRMS(ESI + ) is calculated as C 22 H 27 FN5O[M+H] + 396.2200. Measured value is 396.2191.

[0372] 4-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-cyclopentylpyrimidin-2-amine (22; ZH2-46)

[0373] Cyclopentylamine (110 μL, 1.12 mmol) was added to a solution of 14 (75.0 mg, 0.187 mmol) in THF (5 mL), and the mixture was stirred at 40° C. for 4 days. The mixture was concentrated under vacuum and the residue was purified by flash chromatography (EtOAc / petroleum spirit 50% to 70%) to give a colorless solid (75.0 mg, 99%). 1 H-NMR (500MHz; CDCl3): δ1.23-2.17(18H,m),4.32(1H,q,J=6.8Hz),4.61(1H,s),5.29(1H,s),6 .37(1H,d,J=5.1Hz),6.96-6.99(2H,m),7.44-7.47(2H,m),7.73(1H,s),8.12(1H,d,J=4.7Hz); 13 C-NMR (126MHz; CDCl3): δ23.6,25.2,25.7,33.4,34.4,52.8,55.2,111.5,115.0,115.1,125.1,129.8(d,J C-F =8.0Hz),130.59(d,J C-F =3.1Hz),135.5,141.2,157.9,158.8,162.1,162.1(d,J C-F =247 Hz); HRMS (ESI + ) is calculated as C 24 H 29 FN5[M+H] +406.2407. Actual value is 406.2403.

[0374] 4-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-amine (23; ZH2-54)

[0375] 4-Aminotetrahydropyran (67.0 μL, 0.649 mmol) was added to a solution of 14 (32.5 mg, 0.081 mmol) in THF (5 mL), and the mixture was stirred at 40° C. for 6 days. The mixture was concentrated under vacuum and the residue was purified by flash chromatography (EtOAc / petroleum spirit 50% to 100%) to give a colorless oil (30.9 mg, 91%). 1 H-NMR (400MHz; CDCl3): δ1.24-2.19(14H,m),3.52(2H,t,J=11.3Hz),4.01-4.15(3H,m),4.51(1H,ddd,J=3.4,8.6,12Hz),5 .29(1H,s),6.42(1HM,d,J=5.1Hz),6.99(2H,t,J=8.7Hz),7.44(2H,dd,J=5.5,8.6Hz),7.76(1H,s),8.15(1H,d,J=5.0Hz); 13 C-NMR (101MHz; CDCl3): δ25.4,26.1,33.5,34.7,47.4,55.6,67.0,112.2,115.3,115.5,125.2,130.1(d,J C-F =8.1Hz),130.6(d,J C-F =3.2Hz),135.8,141.5,158.4,159.0,161.8,162.4(d,J C-F =248Hz).

[0376] N-cyclohexyl-4-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)pyrimidin-2-amine (24; ZH2-58)

[0377] Cyclohexylamine (75.0 μL, 0.659 mmol) was added to a solution of 14 (33.0 mg, 0.082 mmol) in THF (5 mL), and the mixture was stirred at 40° C. for 6 days. The mixture was concentrated under vacuum and the residue was purified by flash chromatography (EtOAc / petroleum spirit 40% to 100%) to give a light yellow oil (32.7 mg, 95%). 1H-NMR (400MHz; CDCl3): δ1.19-1.43(6H,m),1.60-1.73(4H,m),1.73-1.8 0(4H,m),1.87-1.94(2H,m),2.05-2.22(4H,m),3.82-3.89(2H,m),4.54- 4.59(1H,m),5.25(1H,bs,J=0.5Hz),6.36(1H,d,J=5.1Hz),6.98(2H,t,J =8.6Hz),7.45(2H,dd,J=5.5,8.4Hz),7.74(1H,s),8.11(1H,d,J=4.9Hz); 13 C-NMR (101MHz; CDCl3): δ25.1,25.5,25.8,26.0,33.5,34.7,49.9,55.51,111.7,115.2,115.4,125.4,130.1(d,J C-F =8.2Hz),130.7(d,J C-F =3.1Hz),135.8,141.4,158.2,159.0,161.9,162.4(d,J C-F =247 Hz); HRMS (ESI + ) is calculated as C 25 H 31 FN5[M+H] + 420.2563. Actual value is 420.2553.

[0378] 4-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-ethylpyrimidin-2-amine (26; ZH2-78)

[0379] Ethylamine solution (2.0 M in THF) (377 μL, 0.754 mmol) was added to a solution of 14 (30.2 mg, 0.075 mmol) in THF (5 mL), and the mixture was stirred for 3 days at 40° C. The mixture was concentrated in vacuo and the residue was purified by flash chromatography (EtOAc / petroleum spirit 50%) to give a light yellow solid (29.1 mg, 98%). 1H-NMR (500MHz; CDCl3): δ1.32-2.19(13H,m),3.49(2H,qd,J=7.2,5.7Hz),4.59(1H,m),5.25(1H,t,J=0.6Hz),6. 39(1H,d,J=5.1Hz),6.96-7.00(2H,m),7.46(2H,ddd,J=2.7,5.4,9.3Hz),7.73(1H,s,1H),8.13(1H,d,J=4.8Hz); 13 C-NMR (126MHz; CDCl3): δ15.3,25.5,26.0,34.7,36.4,55.6,111.9,115.2,115.4,125.3,130.1(d,J C-F =8.0Hz),130.8(d,J C-F =3.2Hz),135.8,141.5,158.2,159.0,162.4(d,J C-F =247Hz),162.5;HRMS(ESI + ) is calculated as C 21 H 25 FN5[M+H] + 366.2094. Actual value is 366.2087.

[0380] trans-3-((4-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)cyclobutan-1-ol (29; ZH3-50)

[0381] Trans-3-aminocyclobutanol (29.0 mg, 0.328 mmol) was added to a solution of 14 (26.3 mg, 0.066 mmol) in THF (5 mL), and the mixture was stirred at room temperature for 5 days. The mixture was concentrated under vacuum and the residue was purified by flash chromatography (EtOAc / petroleum spirit 80% to 10%) to give a light yellow solid (26.5 mg, 99%). 1 H-NMR (400MHz; CDCl3): δ1.21-1.41(5H,m),1.59-1.75(3H,m),1.87-1.91(2H,m),2.31-2.45(4H,m),4.51-4.63(4 H,m),6.38(1H,d,J=5.1Hz),6.98(2H,t,J=8.6Hz),7.42(2H,dd,J=5.5,8.4Hz),7.80(1H,s),8.07(1H,d,J=4.5Hz); 13C-NMR (126MHz; CDCl3): δ25.4,26.0,34.6,40.5,42.9,55.9,65.2,112.1,115.5,115.7,125.1,129.9(d,J C-F =2.0Hz),130.3(d,J C-F =8.1Hz),135.9,157.2,159.2,161.4,162.7(d,J C-F =247Hz).

[0382] cis-3-((4-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)cyclobutan-1-ol (30; ZH3-62)

[0383] Cis-3-aminocyclobutanol (20.0 mg, 0.226 mmol) was added to a solution of 14 (22.7 mg, 0.057 mmol) in THF (4 mL), and the mixture was stirred at 40° C. for 7 days. The mixture was concentrated under vacuum and the residue was purified by flash chromatography (EtOAc / petroleum spirit 80% to 100%) to give a light yellow solid (26.5 mg, 91%). 1 H-NMR (400MHz; CD3OD): δ1.29-1.41(3H,m),1.76(3H,m),1.89-1.96(4H,m),2.12(2H,m),2.74-2.81(2H,m),4.01(2H,m),4.5 8-4.64(1H,m),6.36(1H,d,J=5.1Hz),7.06(2H,t,J=8.6Hz),7.39(2H,dd,J=5.5,8.4Hz),8.01(1H,s),8.13(1H,d,J=4.8Hz); 13 C-NMR (101MHz; CD3OD): δ26.3,26.9,35.3,38.9,42.1,57.0,61.5,112.6,116.1,116.4,131.3(d,J C-F =8.3Hz),131.6(d,J C-F =2.7Hz),137.4,159.5,163.2,163.8(d,J C-F =247 Hz); HRMS (ESI + ) is calculated as C 23 H 27 FN5O[M+H] + 408.2200. Actual value is 408.2187.

[0384] 4-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3,3-difluorocyclobutyl)pyrimidin-2-amine (31; ZH3-70)

[0385] 3,3-Difluorocyclobutane hydrochloride (67.0 mg, 0.469 mmol) and K2CO3 (65.0 mg, 0.469 mmol) were added to a solution of 14 (47.0 mg, 0.117 mmol) in THF / H2O (5:1, 6 mL), and the mixture was stirred at 40°C for 5 days. The mixture was concentrated under vacuum and the residue was purified by flash chromatography (EtOAc / petroleum spirit 30% to 100%) to give a colorless solid (32.2 mg, 64%). 1 H-NMR (500MHz; CDCl3): δ1.25-1.37(3H,m),1.62-1.78(3H,m),1.91-1.93( 2H,m),2.15-2.17(2H,m),2.51-2.61(2H,m),3.03-3.11(2H,m),4.35-4.41 (1H,m),4.52-4.57(1H,m),5.71(1H,bs),6.48(1H,d,J=5.1Hz),7.00(2H,t ,J=8.7Hz),7.43(2H,dd,J=5.5,8.6Hz),7.78(1H,s),8.16(1H,d,J=5.0Hz); 13 C-NMR (126MHz; CDCl3): δ22.8,25.4,26.0,29.4-29.8(m),32.1,34.7,36.5-36.7(m),4 3.6-43.9(m),55.7,113.0,115.4,115.5,116.7,118.9,118.9,121.1,125.0,130.2(d,J C-F =8.0Hz),130.5(d,J C-F =3.0Hz),136.0,141.8,158.2,159.2,161.8,162.5(d,J C-F =247 Hz); HRMS (ESI + ) is calculated as C 23 H 25 F3N5[M+H] + 428.2062. Actual value is 428.2056.

[0386] 4-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-cyclopropylpyrimidin-2-amine (33; ZH3-86)

[0387] Cyclopropylamine (34.0 mg, 0.599 mmol) was added to a solution of 14 (24.0 mg, 0.060 mmol) in THF (5 mL), and the mixture was stirred at 40° C. for 3 days. The mixture was concentrated under vacuum and the residue was purified by flash chromatography (EtOAc / petroleum spirit 50% to 80%) to give a light yellow solid (11.8 mg, 51%). 1 H-NMR (400MHz; CDCl3): δ0.59-0.63(2H,m),0.80-0.90(2H,m),1.19-1.41(3H,m ),1.59-1.75(3H,m),1.87-1.90(2H,m),2.16-2.19(2H,t,J=12.0Hz),2.82(1H,q d,J=3.5,6.5Hz),4.67-4.73(1H,m),5.58(1H,d,J=13.9Hz),6.45(1H,d,J=5.1H z),6.99(2H,t,J=8.6Hz),7.41-7.48(2H,m),7.78(1H,s),8.17(1H,d,J=3.9Hz); 13 C-NMR (101MHz; CDCl3): δ7.7,24.2,25.5,26.0,34.6,55.6,112.5,115.3,115.5,125.3,130.2(d,J C-F =8.0Hz),130.5(d,J C-F =2.2Hz),135.9,141.7,158.0,159.1,161.2,162.5(d,J C-F =248 Hz); HRMS (ESI + ) is calculated as C 22 H 25 FN5[M+H] + 378.2094. Actual value is 378.2086.

[0388] 4-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(tetrahydro-2H-thiopyran-4-yl)pyrimidin-2-amine (37; ZH2-142)

[0389] Tetrahydrothiopyran-4-ylamine (57.0 mg, 0.486 mmol) was added to a solution of 14 (29.9 mg, 0.075 mmol) in THF (5 mL), and the mixture was stirred for 3 days at 40° C. The mixture was concentrated under vacuum and the residue was purified by flash chromatography (EtOAc / petroleum spirit 50% to 70%) to give a light yellow solid (27.0 mg, 83%). 1H-NMR (500MHz; CDCl3): δ1.27-1.33(2H,m),1.62-1.76(6H,m),1.90-1.93(2H,m),2.15-2.18(2H,m),2.35-2.38(2H,m),2.69-2.79(4H,m),3.87 -3.90(1H,m),4.46-4.51(1H,m),5.29(1H,bs),6.41(1H,d,J=5.1Hz),6 .97-7.01(2H,m),7.42-7.45(2H,m),7.76(1H,s),8.14(1H,d,J=5.1Hz); 13 C-NMR (126MHz; CDCl3): δ25.4,26.1,28.0,34.5,34.7,49.3,55.6,112.2,115.3,115.5,125.2,130.1(d,J C-F =8.0Hz),130.5(d,J C-F =3.2Hz),135.8,141.5,158.3,159.1,161.6,162.4(d,J C-F =248 Hz); HRMS (ESI + )calcd for C 24 H 29 FN5[M+H] + HRMS(ESI + ) is calculated as C 27 H 35 FN5[M+H] + 438.2128. Actual value is 438.2119.

[0390]

[0391] 4-((4-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)tetrahydro-2H-thiopyran 1,1-dioxide (38; ZH3-134)

[0392] mCPBA (57-86%) (32.0 mg, 0.185 mmol) was added to a mixture of ZH2-142 (27.0 mg, 0.062 mmol) in CH2Cl2 (10 mL), and the mixture was stirred at room temperature overnight. The mixture was quenched with aqueous NaHCO3, water and brine and dried (MgSO4). The residue was purified by flash chromatography (EtOAc / petroleum spirit 50% to 100%) to give sulfone (12.0 mg, 41%) as a yellow oil. 1H-NMR (400MHz; CDCl3): δ1.24-1.31(3H,m),1.64-1.77(4H,m),1.93(2H,m),2.14-2.30-2.14(5H,m),2.44(2H,m),3.05-3.18(4H,m),4.13(1H,m) ),4.39-4.45(1H,m),5.40(1H,bs),6.50(1H,d,J=5.0Hz),6.99(2H,t,J= 8.5Hz),7.42(2H,dd,J=5.6,8.0Hz),7.81(1H,s),8.19(1H,d,J=4.9Hz); 13 C-NMR (101MHz; CDCl3): δ25.3,26.1,29.9,34.7,47.0,49.6,55.8,112.9,115.4,115.6,130.1(d,J C-F =8.0Hz),136.0,158.3,159.2,161.5,162.5(d,J C-F =248 Hz); HRMS (ESI + ) is calculated as C 24 H 29 FN5O2S[M+H] + 470.2026. Measured value is 470.2014.

[0393]

[0394] Benzyl 4-formylpyrimidin-2-ylcarbamate hydrochloride (39)

[0395] To a solution of dimethyl acetal (0.133 g, 0.438 mmol) in THF (1 mL) was added 4 M aqueous HCl (2 ml). The resulting mixture was heated to 40 °C overnight and then cooled to room temperature. The reaction mixture containing the hydrochloride salt of the acetal was used directly in the next step without isolation.

[0396] Benzyl (4-((cyclopentylimino)methyl)pyrimidin-2-yl)carbamate hydrochloride (40)

[0397] 45% aqueous KOH (0.449 g, 8.00 mmol) was added to an ice-cooled solution of crude aldehyde 39 (0.113 g, 0.438 mmol) in aqueous HCl (2 ml, 8.00 mmol) while keeping the temperature below 15°C. CH2Cl2 (5 ml) and K2CO3 (0.073 g, 0.523 mmol) were added to the neutralized solution followed by cyclopentylamine (87.0 μL, 0.877 mmol). The reaction mixture was gradually warmed to room temperature and stirring was continued for 18 hours. 1 H NMR analysis showed complete consumption of the aldehyde. The crude material was used directly in the next step without isolation.

[0398] Benzyl 4-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)pyrimidin-2-yl)carbamate (41)

[0399] A mixture of α-(p-toluenesulfonyl)-4-fluorobenzyl isonitrile (0.152 g, 0.526 mmol), 40 (0.142 g, 0.438 mmol) and KCO 20% w / v (0.365 mL, 0.526 mmol) in CH Cl (10 ml) was stirred at room temperature for 3 days. The reaction mixture was diluted with CH Cl, washed with water, dried (MgSO), filtered and concentrated. Flash chromatography of the residue (EtOAc / petroleum spirit 20% to 80%) gave a mixture of inseparable components (137 mg).

[0400] 4-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-pyrimidin-2-amine (42; ZH3-58)

[0401] 20wt% of Pd(OH)2 / C (33.0mg) was added to a solution of difluorocyclohexylcarbamate (25.0mg, 0.135mmol) in THF / MeOH 5:3 (8mL). The resulting mixture was stirred for 2 hours under a hydrogen atmosphere of 200psi. The mixture was filtered through diatomaceous earth, concentrated, and the residue was purified by flash chromatography (EtOAc / petroleum spirit 80% to 100%) to obtain a light yellow solid (29.8mg, 21% over 3 steps). 1H-NMR (500MHz; CDCl3): δ1.69-1.75(2H,m),1.82-1.89(4H,m),2.11-2.17(2H,m),4.98-5.04(1H,m),5.2 0(2H,s),6.52(1H,d,J=5.1Hz),6.98-7.02(2H,m),7.44-7.47(2H,m),7.81(1H,s),8.20(1H,d,J=5.1Hz); 13 C-NMR (126MHz; CDCl3): δ24.1,33.9,57.8,113.2,115.5,115.7,125.6,129.7(d,J C-F =1.4Hz),130.0(d,J C-F =8.2Hz),135.7,141.3,158.3,159.4,162.6(d,J C-F =248Hz),163.0;HRMS(ESI + ) is calculated as C 18 H 19 FN5[M+H] + 324.1624. The actual value is 324.1620.

[0402] Benzyl (4-(((4,4-difluorocyclohexyl)imino)methyl)pyrimidin-2-yl)carbamate (43)

[0403] 45% (w / v) aqueous KOH solution (0.449 g, 8.00 mmol) was added to an ice-cooled solution of crude aldehyde 39 (0.116 g, 0.451 mmol) in aqueous HCl (2 ml, 8.00 mmol) while keeping the temperature below 15°C. CH2Cl2 (5 ml) and K2CO3 (0.075 g, 0.541 mmol) were added to the neutralized solution followed by difluorocyclohexylamine (125 μL, 0.901 mmol). The reaction mixture was gradually warmed to room temperature and stirring was continued for 18 hours. 1 H NMR analysis showed complete consumption of the aldehyde. The crude material was used directly in the next step without isolation.

[0404] Benzyl (4-(1-(4,4-difluorocyclohexyl)-4-(4-fluorophenyl)-1H-imidazol-5-yl)pyrimidin-2-yl)carbamate (44)

[0405] A mixture of α-(p-toluenesulfonyl)-4-fluorobenzyl isonitrile (0.156 g, 0.541 mmol), 43 (0.142 g, 0.451 mmol) and KCO 20% (w / v) (0.374 mL, 0.541 mmol) in CH Cl (5 ml) was stirred at room temperature for 2 days. The reaction mixture was diluted with CH Cl, washed with water, dried (MgSO), filtered and concentrated. Flash chromatography of the residue (EtOAc / petroleum spirit 20% to 100%) followed by recrystallization from Et O / petroleum spirit afforded difluorocyclohexylcarbamate (30.4 mg, 13%) as colorless crystals, mp: 224-231 °C. 1 H-NMR (500MHz; CDCl3): δ1.98-2.20(8H,m),5.24(2H,s),5.87-5.90(1H,m),6.78(1H,d,J=5. 3Hz),7.06-7.09(2H,m),7.34-7.48(7H,m),7.99(1H,s),8.08(1H,s),8.29(1H,d,J=5.3Hz); 13 C-NMR (126MHz; CDCl3): δ30.1,30.2,32.7(m),53.4,67.8,116.1(m),124.1,128.8 ,128.9,130.9(d,J=8.3Hz),135.5,136.3,151.4,157.3,158.,163.2(d,J=248Hz).

[0406] 4-(1-(4,4-difluorocyclohexyl)-4-(4-fluorophenyl)-1H-imidazol-5-yl)-pyrimidin-2-amine (45; ZH3-138)

[0407] 20wt% of Pd(OH)2 / C (9.00mg) was added to a solution of difluorocyclohexylcarbamate 44 (25.0mg, 0.135mmol) in THF / MeOH 2:1 (6mL). The resulting mixture was stirred for 3 hours under a hydrogen atmosphere of 200psi. The mixture was filtered through diatomaceous earth, concentrated, and the residue was purified by flash chromatography (EtOAc / petroleum spirit 50% to 100%) to give a light yellow solid (29.8mg, 82%). 1H-NMR (500MHz; CDCl3): δ1.80-1.93(2H,m),2.00-2.07(2H,m),2.20-2.28(4H,m),4.68-4.74(1H,m),5.34 (2H,bs),6.48(1H,d,J=5.2Hz),6.99-7.02(2H,m),7.41-7.44(2H,m),7.78(1H,s),8.14(1H,d,J=5.2Hz); 13 C-NMR (126MHz; CDCl3): δ29.9,29.9,32.8-33.2(m),53.6,112.8,115.4,115.6,119.9,121.8,123.7,124.6,130.0(d,J C-F =3.1Hz),130.2(d,J C-F =8.1Hz),135.8,142.4,158.1,159.1,162.6(d,J C-F =248Hz),162.8;HRMS(ESI + ) is calculated as C 19 H 19 F3N5[M+H] + 374.1593. Actual value is 374.1587.

[0408] Benzyl (4-((((4,4-difluorocyclohexyl)methyl)imino)methyl)pyrimidin-2-yl)carbamate (46)

[0409] A 45% aqueous solution of KOH (0.449 g, 8.00 mmol) was added to an ice-cooled solution of crude aldehyde 39 (0.101 g, 0.393 mmol) in aqueous HCl (2 ml, 8.00 mmol) while keeping the temperature below 15°C. CH2Cl2 (5 ml) and K2CO3 (0.119 g, 0.786 mmol) were added to the neutralized solution followed by 4,4-difluorocyclohexylmethylamine hydrochloride (146 mg, 0.786 mmol). The reaction mixture was gradually warmed to room temperature and stirring was continued for 18 hours. 1 H NMR analysis showed complete consumption of the aldehyde. The crude material was used directly in the next step without isolation.

[0410] Benzyl (4-(1-((4,4-difluorocyclohexyl)methyl)-4-(4-fluorophenyl)-1H-imidazol-5-yl)pyrimidin-2-yl)carbamate (47)

[0411] A mixture of α-(p-toluenesulfonyl)-4-fluorobenzyl isonitrile (0.137 g, 0.472 mmol), 46 (0.153 g, 0.393 mmol) and 20% KCO (0.326 mL, 0.472 mmol) in CHCl (5 ml) was stirred at room temperature for 4 days. The reaction mixture was diluted with CHCl, washed with water, dried (MgSO), filtered and concentrated. Flash chromatography of the residue (EtOAc / petroleum spirit 30% to 100%) gave a mixture of inseparable components (97.2 mg) which was used in the next step.

[0412] 4-(1-((4,4-difluorocyclohexyl)methyl)-4-(4-fluorophenyl)-1H-imidazol-5-yl)-pyrimidin-2-amine (48; ZH3-130)

[0413] 20wt% of Pd(OH)2 / C (65.0mg) was added to a solution of difluorocyclohexylmethylcarbamate (90.0mg, 0.173mmol) in THF / MeOH 5:3 (8mL). The resulting mixture was stirred for 2 hours under a hydrogen atmosphere of 200psi. The mixture was filtered through diatomaceous earth, concentrated, and the residue was purified by flash chromatography (EtOAc / petroleum spirit 80% to 100%) to give a light yellow solid (45.3mg, 30% over 3 steps). 1H-NMR (400MHz; CD3OD): δ1.25-1.35(2H,m),1.59-1.71(4H,m),1.97-1.99(2H,m),4.33(2H,d,J=7.1 Hz), 6.40 (1H, d, J = 4.6Hz), 7.09 (2H, t, J = 8.4Hz), 7.44 (2H, t, J = 6.6Hz), 7.87 (1H, bs), 8.12 (1H, bs); 13C-NMR (126 MHz; CD3OD): δ 27.4, 27.5, 33.6-34.0 (m), 38.0, 52.3, 116.3, 116.5, 124.4, 131.5 (d, JC-F = 8.2 Hz), 159.3, 161.9, 164.0 (d, JC-F = 248 Hz), 164.9; HRMS (ESI+) calculated for C20H21F3N5 [M+H] + 388.1749. Found 388.1742.

[0414] Benzyl (4-((neopentylimino)methyl)pyrimidin-2-yl)carbamate (49)

[0415] A 45% aqueous solution of KOH (0.449 g, 8.00 mmol) was added to an ice-cooled solution of crude aldehyde 39 (0.155 g, 0.603 mmol) in aqueous HCl (2 ml, 8.00 mmol) while keeping the temperature below 15°C. CH2Cl2 (5 ml) and K2CO3 (0.100 g, 0.724 mmol) were added to the neutralized solution followed by neopentylamine (105 mg, 1.21 mmol). The reaction mixture was gradually warmed to room temperature and stirring was continued for 18 hours. 1 H NMR analysis showed complete consumption of the aldehyde. The crude material was used directly in the next step without isolation.

[0416] Benzyl (4-(4-(4-fluorophenyl)-1-neopentyl-1H-imidazol-5-yl)pyrimidin-2-yl)carbamate (50)

[0417] A mixture of α-(p-toluenesulfonyl)-4-fluorobenzyl isonitrile (0.209 g, 0.724 mmol), 49 (0.197 g, 0.603 mmol) and 20% KCO (0.500 mL, 0.724 mmol) aqueous solution in CHCl (5 ml) was stirred at room temperature for 3 days. The reaction mixture was diluted with CHCl, and washed with water, dried (MgSO), filtered and concentrated. Flash chromatography of the residue (EtOAc / petroleum spirit 30% to 100%) gave a mixture of inseparable components (185 mg) which was used in the next step.

[0418] 4-(4-(4-Fluorophenyl)-1-neopentyl-1H-imidazol-5-yl)-pyrimidin-2-amine (51; ZH3-78)

[0419] 20wt% Pd(OH)2 / C (52.0mg) was added to a solution of impure neopentylcarbamate (109mg) in THF / MeOH 5:1 (6mL). The resulting mixture was stirred for 18 hours under a hydrogen atmosphere of 200psi. The mixture was filtered through celite, concentrated, and the residue was purified by flash chromatography (EtOAc / petroleum spirit 50% to 100%), followed by recrystallization in toluene to give light yellow crystals (29.3mg, 15% over 3 steps). 1 H-NMR (400MHz; CDCl3): δ0.78(9H,s,)4.22(2H,s),5.32(2H,bs),6.48(1H,d,J=5.1Hz) ,6.99(2H,t,J=8.6Hz),7.45(2H,dd,J=5.6,8.4Hz),7.58(1H,s),8.15(1H,d,J=5.1Hz); 13C-NMR (101MHz; CDCl3): δ27.8,33.3,53.5,56.7,102.4,108.9,113.1,115.3,115.5,125.5,130.2(d,J C-F =8.2Hz),130.5(d,J C-F =3.2Hz),140.5,141.9,158.4,159.2,159.9,162.5(d,J C-F =248Hz),163.1;HRMS(ESI + ) is calculated as C 18 H 21 FN5[M+H] + 326.1781. Actual value is 326.1775.

[0420]

[0421] 2-(Methylthio)pyrimidine-4-carboxaldehyde (1)

[0422] To a solution of 4-dimethoxymethyl-2-methylsulfanyl-pyrimidine (2.42 g, 12.1 mmol) was added 4M aqueous HCl (13 mL) The resulting mixture was heated at 50° C. for 18 hours. 1 H NMR analysis indicated conversion to formaldehyde, so the mixture was cooled to room temperature. The reaction mixture was diluted with EtOAc and neutralized with 45% KOH solution. The aqueous phase was extracted with EtOAc, dried over MgSO4, and concentrated. Unpurified crude material (2.74 g, 87%) was used in the next step. 1 H NMR (CDCl3, 400MHz) δ2.64 (3H, s), 7.44 (1H, d, J = 4.8Hz), 8.77 (1H, d, J = 4.8Hz), 9.96 (1H, s).

[0423] 1-(2-(Methylthio)pyrimidin-4-yl)-N-(2,2,2-trifluoroethyl)methanimine (52)

[0424] 2,2,2-Trifluoroethylamine hydrochloride (1.96 g, 14.5 mmol) and K2CO3 (3.68 g, 26.6 mmol) were added to a solution of the crude aldehyde (1.87 g, 12.1 mmol) in CH2Cl2 (20 mL). The reaction mixture was stirred at room temperature overnight. 1 H NMR analysis indicated complete consumption of the aldehyde. The reaction mixture containing the imine was used directly in the next step without isolation.

[0425] 4-(4-(4-Fluorophenyl)-1-(2,2,2-trifluoroethyl)-1H-imidazol-5-yl)-2-(methylthio)pyrimidine (53)

[0426] A mixture of a-(p-toluenesulfonyl)-4-fluorobenzyl isonitrile (3.33 g, 11.5 mmol), 2 (2.26 g, 9.60 mmol) and 20% aqueous solution of K2CO3 (8.00 mL, 11.5 mmol) in CH2Cl2 (50 ml) was stirred at room temperature for 5 days. The reaction mixture was diluted with CH2Cl2, washed with water, dried (MgSO4), filtered and concentrated. Flash chromatography of the residue (EtOAc / petroleum spirit 10% to 50%) gave a mixture of inseparable products (3.04 g crude product).

[0427] 4-(4-(4-Fluorophenyl)-1-(2,2,2-trifluoroethyl)-1H-imidazol-5-yl)-2-(methylsulfonyl)pyrimidine (54)

[0428] mCPBA (57-86%) (4.27 g, 24.7 mmol) was added in portions to a mixture of the crude sulfide (3.04 g, 8.24 mmol) in CH2Cl2 (20 mL), and the mixture was stirred at room temperature overnight. The mixture was quenched with aqueous Na2CO3, water, brine, dried over MgSO4, and concentrated under vacuum. The residue was purified by flash chromatography (EtOAc / petroleum spirit 50%) and concentrated to give the sulfone (0.438 g, 9% over 4 steps) as a yellow solid. 1 H-NMR (400MHz; CDCl3): δ3.37(3H,s),5.41(2H,q,J=8.4Hz),7.13(2H,t,J=8.5Hz),7 .32(1H,d,J=5.4Hz), 7.49(2H,dd,J=8.4,5.4Hz), 7.87(1H,s), 8.65(1H,d,J=5.4Hz).

[0429] N-ethyl-4-(4-(4-fluorophenyl)-1-(2,2,2-trifluoroethyl)-1H-imidazol-5-yl)pyrimidin-2-amine (55; ZH4-186)

[0430] A solution of ethylamine (2.0 M) in THF (115 μL, 0.230 mmol) was added to a mixture of sulfone (22.5 mg, 0.057 mmol) in THF (5 mL), and the mixture was stirred at 40° C. for 24 hours. The mixture was concentrated under vacuum and the compound was purified by flash chromatography (EtOAc / petroleum spirit 30% to 50%) to give a light yellow solid (15.0 mg, 72%). 1H-NMR (400MHz; CDCl3): δ1.28(3H,t,J=7.2Hz), 3.48(2H,m), 5.22(2H,d,J=8.3Hz), 6.40(1H,d,J =5.1Hz),7.04(2H,t,J=8.7Hz),7.49(2H,dd,J=5.5,8.6Hz),7.70(1H,s),8.13(1H,d,J=4.9Hz); 13 C-NMR (101MHz; CDCl3): δ15.1,36.5,46.7(q,J C-F =35.4Hz),111.0,115.5,115.7,121.8,124.5,125.1,130.1(d,J C-F =3.0Hz),130.5(d,J C-F =8.2Hz),140.1,143.2,157.6,158.7,162.3,162.8(d,J C-F =248 Hz). HRMS (ESI + ) is calculated as C 17 H 16 F4N5(M+H)366.1342. Found: 366.1337.

[0431] 2-((4-(4-(4-fluorophenyl)-1-(2,2,2-trifluoroethyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)ethan-1-ol (56; ZH5-38)

[0432] Ethanolamine (8.00 μL, 0.130 mmol) was added to a mixture of sulfone (13.0 mg, 0.032 mmol) in THF (5 mL), and the mixture was stirred at room temperature for 48 hours. The mixture was concentrated under vacuum and the compound was purified by flash chromatography (EtOAc / petroleum spirit 50% to 100%) to give an oil (8.10 mg, 66%). 1 H-NMR (400MHz; CDCl3): δ3.66 (2H, q, J = 5.1Hz), 3.88 (2H, t, J = 4.9Hz), 5.20 (2H, q, J = 8.5Hz), 6.4 6(1H,d,J=5.3Hz), 7.05(2H,t,J=8.6Hz), 7.48(2H,dd,J=5.5,8.4Hz), 7.74(1H,s), 8.08(1H,s). HRMS(ESI + ) is calculated as C 17 H 16 F4N5O(M+H)382.1291. Found: 382.1284.

[0433] 3-((4-(4-(4-fluorophenyl)-1-(2,2,2-trifluoroethyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)propan-1-ol (57; ZH5-6)

[0434] 3-Amino-1-propanol (18.0 μL, 0.237 mmol) was added to a mixture of sulfone (23.7 mg, 0.059 mmol) in THF (5 mL), and the mixture was stirred at 40° C. for 48 hours. The mixture was concentrated under vacuum and the compound was purified by flash chromatography (EtOAc / petroleum spirit 20% to 100%) to give a light yellow oil (15.3 mg, 66%). 1 H-NMR (500MHz; CDCl3): δ1.81-1.86(2H,m),3.62(2H,q,J=6.2Hz), 3.73(2H,t,J=5.5Hz), 5.17(2H,q,J=8.5Hz) ,5.50(1H,s),6.41(1H,d,J=5.2Hz),7.02-7.06(2H,m),7.46-7.50(2H,m),7.70(1H,s),8.12(1H,d,J=5.2Hz); 13 C-NMR (126MHz; CDCl3): δ32.8,38.4,46.8(q,J C-F =35.4Hz),59.5,107.9,111.2,115.6,115.8,119.8,122.0,124.2,124.9,126.5,130.0(d,J C-F =3.3Hz),130.5(d,J C-F =8.0Hz),140.3,143.4,158.0,158.4,162.7,162.8(d,J C-F =248 Hz). HRMS (ESI + ) is calculated as C 18 H 18 F4N5O(M+H)396.1447. Found: 396.1443.

[0435] N-Cyclopropyl-4-(4-(4-fluorophenyl)-1-(2,2,2-trifluoroethyl)-1H-imidazol-5-yl)pyrimidin-2-amine (58; ZH4-154)

[0436] Cyclopropylamine (14.0 μL, 0.252 mmol) was added to a mixture of sulfone (25.2 mg, 0.063 mmol) in THF (5 mL), and the mixture was stirred at 50° C. for 48 hours. The mixture was concentrated under vacuum and the compound was purified by flash chromatography (EtOAc / petroleum spirit 30% to 40%) to give a light yellow solid (18.8 mg, 79%). 1 H-NMR (400MHz; CDCl3): δ0.58-0.62(2H,m),0.79-0.87(2H,m),2.78(1H,m),5.34-5.42(2H,m),5.57-5.62( 1H,m),6.46(1H,d,J=5.1Hz),7.05(2H,t,J=8.7Hz),7.47-7.52(2H,m),7.71(1H,s),8.13(1H,d,J=4.8Hz); 13 C-NMR (101MHz; CDCl3): δ7.47,24.1,46.8(q,J C-F =35.2Hz),111.2,115.6,115.8,121.9,122.1,124.6,124.9,130.2(d,J C-F =3.2Hz),130.7(d,J C-F =8.3Hz),140.5,143.7,157.7,158.4,162.9(d,J C-F =248 Hz), 163.2. HRMS (ESI + ) is calculated as C 18 H 16 F4N5 (M+H) 378.1342. Found 378.1336.

[0437] N-cyclobutyl-4-(4-(4-fluorophenyl)-1-(2,2,2-trifluoroethyl)-1H-imidazol-5-yl)pyrimidin-2-amine (59; ZH4-174)

[0438] Cyclobutylamine (20.0 μL, 0.236 mmol) was added to a mixture of sulfone (23.6 mg, 0.059 mmol) in THF (5 mL), and the mixture was stirred at 40° C. for 72 hours. The mixture was concentrated under vacuum and the compound was purified by flash chromatography (EtOAc / petroleum spirit 20% to 60%) to give a light yellow solid (17.3 mg, 75%). 1H-NMR (400MHz; CDCl3): δ1.76-1.88(2H,m),1.94-2.11(2H,m),2.43-2.49(2H,m),4.47(1H,q,J=7.8Hz),5.23-5.25(2H,m) ,5.59(1H,s),6.43(1H,d,J=5.1Hz),7.06(2H,t,J=8.6Hz),7.51(2H,dd,J=5.5,8.5Hz),7.73(1H,s),8.13(1H,d,J=4.6Hz); 13 C-NMR (101MHz; CDCl3): δ15.3,31.6,47.2-46.2,111.1,115.6,115.8,121.8,124.5,125.0,130.1(d,J C-F =3.5Hz),130.6(d,J C-F =8.3Hz),140.2,143.5,157.9,158.2,161.1,162.8(d,J C-F =248 Hz). HRMS (ESI + ) is calculated as C 19 H 18 F4N5 (M+H) 392.1498. Found 392.1493.

[0439] cis-3-((4-(4-(4-fluorophenyl)-1-(2,2,2-trifluoroethyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)cyclobutane-1-ol (60; ZH5-30)

[0440] Cis-3-aminocyclobutanol (17.0 μL, 0.190 mmol) was added to a mixture of sulfone (19.1 mg, 0.047 mmol) in THF (5 mL), and the mixture was stirred at 40° C. for 72 hours. The mixture was concentrated under vacuum and the compound was purified by flash chromatography (EtOAc / petroleum spirit 50% to 100%) to give a light yellow oil (15.8 mg, 83%). 1 H-NMR (500MHz; CDCl3): δ1.90-1.95(2H,m),2.87-2.93(2H,m),3.99-4.04(1H,m),4.15(1H,quintet,J=7.1Hz),5.16-5.19(2 H,m),5.38(1H,s),6.42(1H,d,J=5.1Hz),7.02-7.05(2H,m),7.48(2H,td,J=2.7,6.0Hz),7.70(1H,s),8.13(1H,d,J=5.1Hz); 13C-NMR (126MHz; CDCl3): δ38.0,42.1,46.7(q,J C-F =35.4Hz),61.3,111.5),115.6,115.8,119.8,122.0,124.2,125.0,126.5,130.0(d,J C-F =3.2Hz),130.5(d,J C-F =8.2Hz),140.1,143.3,157.7,158.7,161.5,162.8(d,J C-F =248 Hz). HRMS (ESI + ) is calculated as C 19 H 18 F4N5O(M+H)408.1447. Found:408.1442.

[0441] trans-3-((4-(4-(4-fluorophenyl)-1-(2,2,2-trifluoroethyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)cyclobutane-1-ol (61; ZH5-34)

[0442] Trans-3-aminocyclobutanol (19.0 μL, 0.214 mmol) was added to a mixture of sulfone (21.4 mg, 0.053 mmol) in THF (5 mL), and the mixture was stirred for 72 hours at 40° C. The mixture was concentrated under vacuum and the compound was purified by flash chromatography (EtOAc / petroleum spirit 50% to 100%) to give a light yellow oil (4.1 mg, 20%). 1 H-NMR (500MHz; CDCl3): δ2.32-2.36(2H,m),2.43-2.48(2H,m),4.51(1H,m),4.62(1H,m)),5.23(2H,m),5.40( 1H, bs), 6.44 (1H, d, J = 5.1Hz), 7.04 (2H, t, J = 8.8Hz), 7.47-7.50 (2H, m), 7.70 (1H, s), 8.13 (1H, dd, J = 4.8Hz); 13 C-NMR (126MHz; CDCl3): δ40.5,42.7,46.7(q,J C-F =35.3Hz),65.3,111.5,115.6,115.8,122.0,124.3,125.0,130.1(d,J C-F =2.9Hz),130.6(d,J C-F =8.2Hz),140.3,143.5,157.7,158.6,161.7,162.9(d,JC-F =248 Hz). HRMS (ESI + ) is calculated as C 19 H 18 F4N5O(M+H)408.1447. Found:408.1436.

[0443] N-(3,3-difluorocyclobutyl)-4-(4-(4-fluorophenyl)-1-(2,2,2-trifluoroethyl)-1H-imidazol-5-yl)pyrimidin-2-amine (62; ZH5-10)

[0444] 3.3-Difluorocyclobutylamine hydrochloride (30.0 mg, 0.206 mmol) was added to a mixture of sulfone (20.6 mg, 0.206 mmol) and 20% K2CO3 (140 μL, 0.206 mmol) aqueous solution in THF (5 mL), and the mixture was stirred at room temperature for 48 hours. The mixture was concentrated under vacuum and the compound was purified by flash chromatography (EtOAc / petroleum spirit 20% to 40%) to give a light yellow solid (11.2 mg, 51%). 1 H-NMR (400MHz; CDCl3): δ2.51-2.64(2H,m),3.09(2H,m),4.33-4.37(1H,m),5.18(2H,q,J=8.5Hz),6.49 (1H,d,J=5.2Hz),7.04(2H,t,J=8.6Hz),7.48(2H,dd,J=5.5,8.6Hz),7.73(1H,s),8.14(1H,d,J=5.1Hz). HRMS(ESI + ) is calculated as C 19 H 16 F6N5 (M+H) 428.1310. Found 428.1305.

[0445] N-Cyclopentyl-4-(4-(4-fluorophenyl)-1-(2,2,2-trifluoroethyl)-1H-imidazol-5-yl)pyrimidin-2-amine (63; ZH5-2)

[0446] Cyclopentylamine (24.0 μL, 0.242 mmol) was added to a mixture of sulfone (24.2 mg, 0.060 mmol) in THF (5 mL), and the mixture was stirred at room temperature for 48 hours. The mixture was concentrated under vacuum and the compound was purified by flash chromatography (EtOAc / petroleum spirit 10% to 50%) to give an oil (17.7 mg, 73%). 1H-NMR (400MHz; CDCl3): δ1.49-1.81(8H,m),2.06(2H,m),4.28(1H,dq,J=6.6,13Hz),5.23(3H,m),6.39( 1H,d,J=5.1Hz),7.04(2H,t,J=8.7Hz),7.50(2H,dd,J=8.6,5.5Hz),7.70(1H,s),8.12(1H,d,J=4.9Hz); 13 C-NMR (101MHz; CDCl3): δ23.9,33.6,46.7(q,J C-F =35.4Hz),53.1,110.9,115.5,115.7,119.0,121.8,124.6,125.1,127.3,130.2(d,J C-F =3.2Hz),130.5(d,J C-F =8.2Hz),140.1,143.2,157.6,158.7,162.0,162.8(d,J C-F =248 Hz). HRMS (ESI + ) is calculated as C 20 H 19 F4N5(M+H)406.1655. Found:406.1651.

[0447] 4-(4-(4-fluorophenyl)-1-(2,2,2-trifluoroethyl)-1H-imidazol-5-yl)-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-amine (64; ZH5-14)

[0448] 4-Aminotetrahydropyran (17 mg, 0.170 mmol) was added to a mixture of sulfone (17.8 mg, 0.042 mmol) in THF (5 mL), and the mixture was stirred at 40° C. for 48 hours. The mixture was concentrated under vacuum and the compound was purified by flash chromatography (EtOAc / petroleum spirit 50% to 70%) to give a light yellow oil (13.1 mg, 74%). 1 H-NMR (400MHz; CDCl3): δ1.59-1.67(2H,m),2.04(2H,d,J=11.0Hz),3.51-3.57(2H,m),4.04(3H,m),5.16(3H,dt,J=7.6 ,16.1Hz),6.43(1H,d,J=5.1Hz),7.04(2H,t,J=8.7Hz),7.49(2H,dd,J=5.5,8.6Hz),7.71(1H,s),8.14(1H,d,J=5.1Hz); 13C-NMR (101MHz; CDCl3): δ33.5,46.7(q,J C-F =35.4Hz),47.5,66.9,111.4,115.6,115.8,121.8,124.5,125.0,127.3,130.1(d,J C-F =3.5Hz),130.5(d,J C-F =8.0Hz),140.1,143.4,156.2,157.7,158.8,162.5(d,J C-F =248 Hz). HRMS (ESI + ) is calculated as C 20 H 20 F4N5O(M+H)422.1604. Found:422.1600.

[0449] N-(4,4-difluorocyclohexyl)-4-(4-(4-fluorophenyl)-1-(2,2,2-trifluoroethyl)-1H-imidazol-5-yl)pyrimidin-2-amine (65; ZH4-170)

[0450] 4,4-Difluorocyclohexylamine (40.0 μL, 0.301 mmol) was added to a mixture of sulfone (30.0 mg, 0.075 mmol) in THF (5 mL), and the mixture was stirred at 40° C. for 48 hours. The mixture was concentrated under vacuum and the compound was purified by flash chromatography (EtOAc / petroleum spirit 20% to 50%) to give a light yellow solid (27.4 mg, 80%). 1 H-NMR (400MHz; CDCl3): δ1.63-1.71(2H,m),1.83-1.99(2H,m),2.15(4H,m),3.94-4.01(1H,m),5.16(3H,m,J=8.5 Hz), 6.44 (1H, d, J = 5.1Hz), 7.04 (2H, t, J = 8.6Hz), 7.49 (2H, dd, J = 5.5, 8.5Hz), 7.71 (1H, s), 8.14 (1H, d, J = 5.1Hz); 13 C-NMR (101MHz; CDCl3): δ28.9(d,J C-F =9.9Hz),32.3(t,J C-F =24.9Hz),46.7(q,J C-F =35.3Hz),48.0,111.5,115.6,115.8,116.3,116.5,120.3,121.8,122.7,124.5,125.0,125.1,130.1(d,J C-F=3.2Hz),130.5(d,J C-F =8.1Hz),140.2,143.4,157.8,158.7,161.7,162.8(d,J C-F =248 Hz). HRMS (ESI + ) is calculated as C 21 H 20 F6N5(M+H)456.1623 measured as 456.1619.

[0451] N-(2-Fluorobenzyl)-4-(4-(4-fluorophenyl)-1-(2,2,2-trifluoroethyl)-1H-imidazol-5-yl)pyrimidin-2-amine (66; ZH4-146)

[0452] 2-Fluorobenzylamine (28.0 μL, 0.247 mmol) was added to a mixture of sulfone (24.7 mg, 0.062 mmol) in THF (5 mL), and the mixture was stirred at 40° C. for 48 hours. The mixture was concentrated under vacuum and the compound was purified by flash chromatography (EtOAc / petroleum spirit 10% to 80%) to give a light yellow oil (24.7 mg, 89%). 1 H-NMR (400MHz; CDCl3): δ4.74 (2H, d, J = 6.1Hz), 4.96 (2H, bs), 5.69 (1H, bs), 6.46 (1H, d, J = 5.1Hz), 7.01-7. 14(4H,m),7.26-7.29(1H,m),7.38(1H,t,J=7.3Hz),7.46-7.50(2H,m),7.66(1H,s),8.17(1H,d,J=5.1Hz). HRMS(ESI + ) is calculated as C 22 H 17 F5N5(M+H)446.1404. Found:446.1401.

[0453] N-(4-fluorobenzyl)-4-(4-(4-fluorophenyl)-1-(2,2,2-trifluoroethyl)-1H-imidazol-5-yl)pyrimidin-2-amine (67; ZH4-150)

[0454] 4-Fluorobenzylamine (28.0 μL, 0.244 mmol) was added to a mixture of sulfone (24.4 mg, 0.061 mmol) in THF (5 mL), and the mixture was stirred at 40° C. for 48 hours. The mixture was concentrated under vacuum and the compound was purified by flash chromatography (EtOAc / petroleum spirit 30% to 80%) to give a light yellow oil (24.4 mg, 90%). 1H-NMR (400MHz; CDCl3): δ4.64(2H,d,J=5.9Hz), 4.87(2H,s), 5.76(1H,s), 6.46(1H,d,J=5.1Hz), 7.04 (4H,m),7.33(2H,dd,J=5.4,8.2Hz),7.48(2H,dd,J=5.5,8.5Hz),7.64(1H,s),8.16(1H,d,J=5.0Hz); 13 C-NMR (101MHz; CDCl3): δ44.9,46.4(q,J C-F =35.9Hz),111.8,115.5,115.7,115.8,115.9,121.6,124.4,125.0,128.6,130.0(d,J C-F =3.2Hz),130.5(d,J C-F =8.0Hz),134.8(d,J C-F =3.2Hz),140.2,143.3,157.8,158.8,161.0,162.2,162.3(d,J C-F =247Hz),162.8(d,J C-F =249 Hz). HRMS (ESI + ) is calculated as C 22 H 17 F5N5(M+H)446.1404. Found:446.1397.

[0455] Other compounds described herein can be prepared by methods similar to those described above.

[0456] The following implementations are also described herein:

[0457] 1. A compound of formula (I) or its salt, solvate, nitrogen oxide, tautomer, stereoisomer, polymorph and / or prodrug:

[0458]

[0459] in:

[0460] R1 and R2 are each independently selected from H, C 1-6 Alkyl, C1 alkyl, C6 aryl, C 3-6 Cycloalkyl and C 3-5 Heterocyclic group;

[0461] R3 is selected from F, Cl and CH3;

[0462] R4 is selected from C 0-3 Alkyl C 3-12 Cycloalkyl and C1-12 alkyl;

[0463] wherein R1, R2, R3 and R4 are each optionally substituted.

[0464] 2. The compound according to embodiment 1, wherein the compound is not selected from Figure 1 in the list of compounds.

[0465] 3. A compound according to any one of the preceding embodiments, wherein R1 is C 1-3 alkyl.

[0466] 4. The compound according to embodiment 3, wherein R1 is substituted.

[0467] 5. The compound according to embodiment 4, wherein the substituent is selected from one or more hydroxyl groups.

[0468] 6. The compound according to embodiment 1, wherein R1 is C 3-6 Cycloalkyl.

[0469] 7. A compound according to embodiment 6, wherein R1 is selected from cyclobutyl, cyclopentyl and cyclohexyl.

[0470] 8. A compound according to embodiment 6 or embodiment 7, wherein R1 is substituted.

[0471] 9. The compound according to embodiment 8, wherein the substituent is selected from one or more OH groups and / or one or more halogen groups.

[0472] 10. The compound according to embodiment 1, wherein R1 is C 3-6 Heterocyclic group.

[0473] 11. A compound according to any one of embodiments 1 to 9, wherein R1 is C1 alkyl or C6 aryl.

[0474] 12. A compound according to embodiment 11, wherein the C1 alkyl group is substituted.

[0475] 13. A compound according to embodiment 12, wherein the substituent is selected from one or more alkyl groups, one or more hydroxyl groups and / or one or more halogen groups.

[0476] 14. A compound according to any one of embodiments 11 to 13, wherein the C6 aryl group is substituted.

[0477] 15. A compound according to embodiment 14, wherein the substituent is selected from one or more alkyl groups, one or more hydroxyl groups and / or one or more halogen groups.

[0478] 16. A compound according to any one of the preceding embodiments, wherein R2 is H.

[0479] 17. The compound according to embodiment 1, wherein R1 and R2 are the same as each other.

[0480] 18. A compound according to any one of the preceding embodiments, wherein R3 is CH3.

[0481] 19. A compound according to any one of embodiments 1 to 17, wherein R3 is F or Cl.

[0482] 20. A compound according to any one of the preceding embodiments, wherein R4 is C 0-3 Alkyl C 3-12 Cycloalkyl.

[0483] 21. The compound according to embodiment 20, wherein R4 is C 1-2 Alkyl C 3-12 Cycloalkyl.

[0484] 22. The compound according to embodiment 20, wherein R4 is C 3-12 Cycloalkyl.

[0485] 23. A compound according to any one of embodiments 20 to 22, wherein C 3-12 The cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

[0486] 24. A compound according to any one of embodiments 20 to 23, wherein R4 is 1-3 The alkyl group is substituted.

[0487] 25. A compound according to any one of embodiments 20 to 24, wherein R4 is 3-12 The cycloalkyl group is substituted.

[0488] 26. A compound according to embodiment 24 or embodiment 25, wherein the substituent is selected from one or more C 1-6 an alkyl group, one or more OH groups and one or more halogen groups.

[0489] 27. A compound according to any one of embodiments 1 to 19, wherein R4 is C 1-12 alkyl.

[0490] 28. A compound according to embodiment 27, wherein R4 is a methyl, ethyl, propyl or butyl group.

[0491] 29. The compound according to embodiment 27, wherein R4 is a branched alkyl group.

[0492] 30. A compound according to any one of embodiments 27 to 29, wherein R4 is substituted.

[0493] 31. A compound according to embodiment 30, wherein the substituent is selected from one or more OH groups and / or one or more halogen groups.

[0494] 32. A compound according to any one of the preceding embodiments, wherein R1, R2, R3 and R4 are optionally selected from OH, C 1-6 Alkoxy, halogen, amino, mercapto and C 1-6 One or more groups in the alkyl group are substituted.

[0495] 33. A method for treating or preventing a respiratory disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) according to any one of embodiments 1 to 32, thereby treating or preventing the respiratory disease in the subject.

[0496] 34. A compound of formula (I) according to any one of embodiments 1 to 32 for use in treating or preventing a respiratory disease in a subject.

[0497] 35. A composition comprising a compound of formula (I) according to any one of embodiments 1 to 32 and a pharmaceutically acceptable excipient.

[0498] 36. Use of a compound of formula (I) according to any one of embodiments 1 to 32 or a composition according to embodiment 35 for the preparation of a medicament for treating or preventing a respiratory disease in a subject.

Claims

1. A compound of formula (I) or a salt, tautomer and / or stereoisomer thereof: in: R1 is selected from H, C 2-6 Alkyl, hydroxyl C 1-6 Alkyl, C1 alkyl, C6 aryl halogen, C 3-6 Cycloalkyl, halogen C 3-6 Cycloalkyl, hydroxyl C 3-6 Cycloalkyl, or oxygen- or sulfur-containing C 3-6 Heterocyclic group; R2 is H; R3 is selected from F or Cl; R4 is selected from -C 0-3 Alkyl C 3-12 Cycloalkyl, or -C 0-3 Alkyl C 3-12 Cycloalkyl halogen; When R1 is H, R4 is C 0-3 Alkyl C 4-12 Cycloalkyl, wherein when R4 is C6 cycloalkyl, R4 is selected from C 1-6 Alkyl, C 1-6 halogenalkyl and halogen substituted with one or more groups, and When R1 is a C3 cycloalkyl group, R4 is selected from C 0-3 Alkyl C 3-12 Cycloalkyl.

2. The compound according to claim 1 or its salt, tautomer and / or stereoisomer, wherein: R1 is selected from C 2-6 Alkyl, hydroxyl C 1-6 Alkyl, C1 alkyl, C6 aryl halogen, C 3-6 Cycloalkyl, halogen C 3-6 Cycloalkyl, hydroxyl C 3-6 Cycloalkyl, or oxygen- or sulfur-containing C 3-5 Heterocyclic group.

3. The compound according to claim 1, or a salt, tautomer and / or stereoisomer thereof, wherein: R1 is C 2-3 alkyl.

4. The compound according to claim 1, or a salt, tautomer and / or stereoisomer thereof, wherein: R1 is hydroxyl C 2-3 alkyl.

5. The compound according to claim 1, or a salt, tautomer and / or stereoisomer thereof, wherein: R1 is C 3-6 Cycloalkyl.

6. The compound according to claim 1, or a salt, tautomer and / or stereoisomer thereof, wherein: R1 is selected from halogen C 3-6 Cycloalkyl and hydroxy C 3-6 Cycloalkyl.

7. The compound according to claim 5, or a salt, tautomer and / or stereoisomer thereof, wherein: R1 is selected from cyclobutyl, cyclopentyl and cyclohexyl, each of which is optionally substituted with one or more groups selected from hydroxy and halogen.

8. The compound according to claim 7, or a salt, tautomer and / or stereoisomer thereof, wherein: The one or more halogen groups are one or more fluorine groups.

9. The compound according to claim 1, or a salt, tautomer and / or stereoisomer thereof, wherein: R1 is an oxygen- or sulfur-containing C 3-6 Heterocyclic group.

10. The compound according to claim 1, or a salt, tautomer and / or stereoisomer thereof, wherein: R1 is selected from C2 alkyl or C1 alkyl C6 aryl halogen.

11. The compound according to claim 10, or a salt, tautomer and / or stereoisomer thereof, wherein: R1 is C1 alkyl, C6 aryl, halogen.

12. The compound according to claim 1, or a salt, tautomer and / or stereoisomer thereof, wherein: R1 is H.

13. The compound according to claim 1, or a salt, tautomer and / or stereoisomer thereof, wherein: R3 is F.

14. The compound according to claim 1, or a salt, tautomer and / or stereoisomer thereof, wherein: R4 is selected from C 1-2 Alkyl C 3-12 Cycloalkyl, or C 1-2 Alkyl C 3-12 Cycloalkyl halogen.

15. The compound according to claim 1, or a salt, tautomer and / or stereoisomer thereof, wherein: R4 is selected from C 3-12 Cycloalkyl, or C 3-12 Cycloalkyl halogen.

16. The compound according to claim 1, or a salt, tautomer and / or stereoisomer thereof, wherein: R4 is selected from C 0-3 Alkyl C 3-7 Cycloalkyl, or C 0-3 Alkyl C 3-7 Cycloalkyl halogen.

17. The compound according to claim 1, or a salt, tautomer and / or stereoisomer thereof, wherein: R4 is C 0-3 Alkyl C 3-7 Cycloalkyl halogen, and wherein C 3-7 The cycloalkyl moiety is substituted with one or more halogen groups.

18. A compound selected from the following or a pharmaceutically acceptable salt, tautomer and / or stereoisomer thereof 19. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 18 or a pharmaceutically acceptable salt, tautomer and / or stereoisomer thereof, and a pharmaceutically acceptable excipient.

20. Use of a compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt, tautomer and / or stereoisomer thereof in the preparation of a medicament for treating or preventing a respiratory disease in a subject.

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