New compounds for the treatment of respiratory diseases

Abstract

The present invention relates to novel compounds for the prevention or treatment of 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 the preparation of these compounds and to compositions comprising the compounds. The present invention also relates to the use of the compounds and compositions comprising the compounds in the treatment or prevention of respiratory diseases, acute and chronic inflammatory conditions and fibrotic diseases or conditions in which fibrosis leads to the pathology of the condition.

Description

[0001] Related Applications

[0002] This application claims priority to AU2018904241 and AU2018904242 (each filed on 7 November 2018). The entire contents of each of AU2018904241 and AU2018904242 are incorporated herein by reference. Technical Field

[0003] The present invention provides imidazole-based compounds that have potential in treating respiratory diseases such as asthma and related disorders, acute and chronic inflammatory disorders, fibrotic diseases or disorders in which fibrosis contributes to the pathology of the disorder. Background Art

[0004] Asthma is a syndrome that encompasses a variety of different types of illness that vary in severity, causes, and triggers. Common features of the asthma syndrome are reversible airway obstruction, airway hyperresponsiveness, and airway inflammation, most notably the infiltration of the airway wall by eosinophils and T lymphocytes in addition to mast cell activation.

[0005] 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 also available. Short-acting and long-acting muscarinic receptor antagonists (SAMA and LAMA) are often used in combination with other bronchodilators and anti-inflammatory drugs (especially ICS) for some patients. Leukotriene receptor antagonists (LTRA) can also be added to different treatment regimens. Recently, mepolizumab, a monoclonal antibody that neutralizes the chemoattractant of eosinophils (interleukin-5), has been shown to have benefits beyond the combination of ICS and LABA in specific patients. However, especially for severe asthma, patients still have symptoms and have periodic exacerbations of the disease (called exacerbations). There is a considerable unmet need in the pharmacological treatment of severe asthma. In most cases, these asthma exacerbations are thought to be caused by respiratory viral infections of the lower respiratory tract. Viruses that cause these exacerbations include respiratory syncytial virus, influenza virus, and rhinovirus, which infect respiratory epithelial cells. Epithelial cells in asthmatic individuals are thought to be particularly susceptible to this infection and have been implicated in an exacerbated inflammatory response.

[0006] Studies have shown that TGF-β can impair the effectiveness of ICS. In addition, the inventors have demonstrated that viral infection of airway epithelial cells impairs ICS activity by inducing TGF-β activity. Drug targeting of TGF-β carries the risk of autoimmunity and mitral valve defects. The inventors unexpectedly identified casein kinase 1δ / ε as a mediator of TGF-β-induced ICS insensitivity using compound PF670462 (WO2016 / 149756) and demonstrated the use of this agent in reversing steroid insensitivity.

[0007] This would be beneficial in developing alternative compounds useful in preventing or treating one or more respiratory diseases, acute and chronic inflammatory conditions, and fibrotic diseases or conditions where fibrosis contributes to the pathology of the condition. Summary of the invention

[0008] Described herein are compounds of formula (II) or salts, solvates, N-oxides, tautomers, stereoisomers, polymorphs and / or prodrugs thereof:

[0009]

[0010] in:

[0011] R1 and R2 are each independently selected from H, C 1-3 Alkyl C 6-12 Aryl, C 1-3 Alkyl C 5-11 Heteroaryl, C 1-3 Alkyl C 3-6 Cycloalkyl and C 1-3 Alkyl C 3-6 A group consisting of heterocyclic groups;

[0012] R3 is selected from the group consisting of H, F, Cl and CH3;

[0013] R4 is selected from C 0-3 Alkyl C 3-12 Cycloalkyl and C 1-12 A group consisting of alkyl groups;

[0014] wherein each of R1, R2, R3 and R4 is optionally substituted.

[0015] In some embodiments, the compound of formula (II) is a compound of formula (I)

[0016]

[0017] in:

[0018] R 1 Selected from C 2-3 Alkyl C 6-12 Aryl, C1 alkyl10-12 Aryl, C 1-3 Alkyl C 5-11 Heteroaryl, C 1-3 Alkyl C 3-6 Cycloalkyl and C 1-3 Alkyl C 3-6 A group consisting of heterocyclic groups;

[0019] R 2 It is H;

[0020] R 3 Selected from the group consisting of H, F, Cl and CH3;

[0021] R 4 Selected from C 0-3 Alkyl C 3-12 Cycloalkyl and C 1-12 A group consisting of alkyl groups;

[0022] Where R 1 , R 2 , R 3 and R 4 Each of which is optionally substituted,

[0023] Provided that the compound is not selected from:

[0024]

[0025] In another aspect, 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 (II) or a salt, solvate, N-oxide, tautomer, stereoisomer, polymorph and / or prodrug thereof, thereby treating or preventing the respiratory disease in the subject.

[0026] Further provided is a compound of formula (I) or (II) or a salt, solvate, N-oxide, tautomer, stereoisomer, polymorph and / or prodrug thereof for use in treating or preventing a respiratory disease in a subject.

[0027] The respiratory disease may be selected from asthma, chronic obstructive pulmonary disease, interstitial lung disease (e.g. idiopathic pulmonary fibrosis) and other disorders associated with tissue remodeling, primary or secondary lung tumors, hay fever, chronic and acute sinusitis, and chronic and acute respiratory viral, fungal and bacterial infections.

[0028] In another aspect, a method for improving the respiratory function of 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 (II) or a salt, solvate, N-oxide, tautomer, stereoisomer, polymorph and / or prodrug thereof, thereby improving the respiratory function of the subject.

[0029] Further provided is a compound of formula (I) or (II) or a salt, solvate, N-oxide, tautomer, stereoisomer, polymorph and / or prodrug thereof for use in improving respiratory function in a subject.

[0030] 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 with which the respiratory system can stretch. 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. On the other hand, a composition is provided, comprising a compound of formula (I) or (II) or a salt thereof, a solvate, an N-oxide, a tautomer, a stereoisomer, a polymorph and / or a prodrug, and a pharmaceutically acceptable excipient.

[0031] The composition may be formulated for oral administration or for administration by inhalation or injection.

[0032] Also described is the use of a compound or composition of the invention in the preparation of a medicament for treating or preventing a respiratory disease in a subject.

[0033] As used herein, the term "comprise" and variations of the term, such as "comprising" and "comprising", are not intended to exclude further additives, components, integers or steps, unless the context requires otherwise.

[0034] The reference to any prior art in the specification is not an acknowledgement or implication that the prior art forms part of the common general knowledge in any jurisdiction, or that it could reasonably be expected that the prior art would be understood, considered relevant and / or combined with other pieces of prior art by a person skilled in the art.

[0035] Further aspects of the invention and further embodiments of the aspects described in the preceding paragraphs will become apparent from the following description, given by way of example and with reference to the accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] Figure 1 Many known compounds are defined.

[0037] Figure 2 Inhibition of TGF-β-induced IL-11 (interpolated from linear regression of log concentration of small molecule and IL-11 levels) P IC 50 Value (negative logarithm of the concentration that inhibits IL-11 levels by 50%). DETAILED DESCRIPTION

[0038] It will be understood that the invention disclosed and defined in this specification extends to all alternative combinations of two or more of the individual features mentioned in or evident from the text or drawings. All these different combinations constitute various alternative aspects of the invention.

[0039] Reference will now be made in detail to certain embodiments of the present invention. Although the present invention will be described in conjunction with the embodiments, it should be understood that it is not intended to limit the present invention to these embodiments. On the contrary, the present invention is intended to cover all substitutions, modifications and equivalents, which may be included within the scope of the present invention as defined by the claims.

[0040] Those skilled in the art will recognize that many methods and materials similar or equivalent to the methods and materials described herein can be used to implement the present invention. The present invention is in no way limited to the methods and materials described. It will be understood that the present invention disclosed and defined in this specification extends to all alternative combinations of two or more individual features mentioned in the text or drawings or becoming apparent from the text or drawings. All these different combinations constitute various alternative aspects of the present invention.

[0041] All patents and publications cited herein are hereby incorporated by reference in their entirety.

[0042] For the purpose of interpreting this specification, terms used in the singular form will also include the plural form and vice versa.

[0043] Described herein are compounds of formula (II) or salts, solvates, N-oxides, tautomers, stereoisomers, polymorphs and / or prodrugs thereof:

[0044]

[0045] in:

[0046] R1 and R2 are each independently selected from H, C 1-3 Alkyl C 6-12 Aryl, C 1-3 Alkyl C 5-11 Heteroaryl, C 1-3 Alkyl C 3-6 Cycloalkyl and C 1-3 Alkyl C 3-6 A group consisting of heterocyclic groups;

[0047] R3 is selected from the group consisting of H, F, Cl and CH3;

[0048] R4 is selected from C 0-3 Alkyl C 3-12 Cycloalkyl and C 1-12 A group consisting of alkyl groups;

[0049] wherein each of R1, R2, R3 and R4 is optionally substituted.

[0050] In some embodiments, the compound of formula (II) is provided by the compound of formula (I)

[0051]

[0052] in:

[0053] R 1 Selected from C 2-3 Alkyl C 6-12 Aryl, C1 alkyl 10-12 Aryl, C 1-3 Alkyl C 5-11 Heteroaryl, C 1-3 Alkyl C 3-6 Cycloalkyl and C 1-3 Alkyl C 3-6 A group consisting of heterocyclic groups;

[0054] R 2 It is H;

[0055] R 3 Selected from the group consisting of H, F, Cl and CH3;

[0056] R 4 Selected from C 0-3 Alkyl C 3-12 Cycloalkyl and C 1-12 A group consisting of alkyl groups;

[0057] Where R 1 , R 2 , R 3 and R 4 Each of which is optionally substituted,

[0058] Provided that the compound is not selected from:

[0059]

[0060] In any embodiment, the present invention provides a compound of formula (I) or (II), provided that the compound is not selected from Figure 1Various compounds are also described in Keenan et al., Frontiers in Pharmacology, 2018, Vol. 9, Item 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. In some embodiments, any specific compound described in one or more of these documents can be excluded by a proviso.

[0061] In any embodiment, the present invention provides a compound of formula (I), wherein R 2 For H.

[0062] In any embodiment, R 1 C 1-3 Alkyl C 6-12 Aryl. 1 Can be C 2-3 Alkyl C 6-12 Aryl or C 1-3 Alkyl C 10-12 In some embodiments, R 1 is an optionally substituted C 2-3 Alkyl C 6-12 Aryl or C 1-3 Alkyl C 10-12 Aryl (e.g. unsubstituted C 1-3 Alkyl C 10-12 In some embodiments, C 2-3 Alkyl C 6-12 Aryl is an optionally substituted C 2-3 Alkyl C6 aryl. One or more C 6-12 Aryl groups can be composed of two ring systems. 1-3 The ring to which the alkyl group is attached may have a second ring in any position (i.e., ortho, meta, or para). 1 It is C 1-3 Alkyl C 6-12 When the group is aromatic, R 2 It can be H.

[0063] In any embodiment, R 1 C 1-3 Alkyl C 5-11 Heteroaryl. 1 Can be C 1-2 Alkyl C5-11 Heteroaryl. 5-11 The heteroaryl group can be composed of two ring systems. 1-3 The ring to which the alkyl is attached may have a second ring in any position (i.e., ortho, meta, or para). The heteroaryl may be selected from an oxygen-containing heteroaryl, a nitrogen-containing heteroaryl, or a sulfur-containing heteroaryl, or a heteroaryl containing a combination of two or more oxygen, nitrogen, and sulfur atoms. Examples include furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, oxopyridyl, thiadiazolyl, isothiazolyl, pyridyl, pyridazyl, pyrazinyl, and pyrimidinyl. The heteroatoms may be at 1 to 500 ft relative to C. 1-3 The ortho and / or para positions of the alkyl group. 1 It is C 1-3 Alkyl C 5-11 When heteroaryl, R 2 It can be H.

[0064] In any embodiment, R 1 C 1-3 Alkyl C 3-6 Cycloalkyl. 1 Can be C 1-2 Alkyl C 3-6 Cycloalkyl. 3-6 The cycloalkyl group may be selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. 1 It is C 1-3 Alkyl C 3-6 When cycloalkyl, R 2 It can be H. When R 1 It is C 1-3 Alkyl C 3-6 When cycloalkyl, R 1 The substituent may be selected from C 1-3 alkyl.

[0065] In any embodiment, R 1 C 1-3 Alkyl C 3-6 Heterocyclic group. 1 Can be C 1-2 Alkyl C 3-6 Heterocyclic group. 1It may be selected from an oxygen-containing heterocyclic group, a nitrogen-containing heterocyclic group, or a sulfur-containing heterocyclic group, or a heterocyclic group containing a combination of two or more oxygen, nitrogen and sulfur atoms. Examples include oxetanyl, thietanyl, pyrrolidinyl, pyridyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, 1,3-dioxolanyl, tetrahydropyranyl, tetrahydrothipheneyl and 1,2- and 1,3-oxathiolanyl. When R 1 It is C 1-3 Alkyl C 3-6 When the heterocyclic group is 2 It can be H.

[0066] In any embodiment, R 1 Can be selected from any one of the following groups G1-G7:

[0067]

[0068] in,

[0069] Each R 5 is selected from any optional substituent described herein. 5 Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 3-7 Heterocyclic group, C 3-7 Cycloalkyl, C 2-6 Alkoxy, C 1-6 Alkylsulfanyl, C 1-6 Alkylsulfenyl, C 1-6 Alkylsulfonyl, C 1-6 alkylsulfonylamino, arylsulfonylamino, alkylcarboxy, alkylcarboxyamide, oxo, hydroxy, thiol, amino, acyl, carboxyl, carbamoyl, aryl, aryloxy, heteroaryl, aminosulfonyl, aroyl, aroylamino, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy, alkoxycarbonyl, nitro, cyano, fluoro, iodo, bromo, ureido or C 1-6 The group consisting of perfluoroalkyl groups, each of which may be optionally substituted;

[0070] R6 is an optionally substituted C 1-2 alkyl;

[0071] L is (CR 7 R 8 ) m ;

[0072] L1 is (CR 7 R 8 ) p Optionally substituted C 1-2 alkyl;

[0073] R 7 and R 8 are independently selected from H and optionally substituted C 1-6 alkyl;

[0074] n is selected from 0, 1, 2 and 3;

[0075] m is selected from 1, 2 and 3; and

[0076] p is selected from 1 and 2.

[0077] In any of the embodiments of Groups G1-G7, n may be 0, 1 or 2.

[0078] In any embodiment, R 5 It is fluorinated.

[0079] In any embodiment, n is 0, 1 or 2.

[0080] In any embodiment, R 1 Can be selected from G1 to G5.

[0081] In any embodiment, R 1 It can be G6. In some embodiments of G6, R 6 is an optionally substituted methyl group.

[0082] In any embodiment, R 1 is a group selected from G1 to G7, and R 4 Selected from C 3-12 Cycloalkyl, C 1-12 Alkyl and halogenated C 1-12 In some embodiments, R 4 In some embodiments, R 4 Optionally one or more selected from C 1-6 Alkyl and halo substituents are substituted.

[0083] In any embodiment, the present invention provides a compound of formula (I), wherein R 3 is CH3.3 It can be F or Cl. Preferably, R 3 It's F.

[0084] In any embodiment, the present invention provides a compound of formula (I), wherein R 4 C 0-3 Alkyl C 3-12 Cycloalkyl. 4 Can be C 0-3 Alkyl C 3-12 Cycloalkyl, wherein C 3-12 Cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. 4 It is C 3-12 More preferably, R 4 is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. 4 Can be C 1-2 Alkyl C 3-12 Cycloalkyl. 4 Can be C1 alkyl C 3-12 In some embodiments, R 4 Selected from C 0-3 Alkyl C 4-12 Cycloalkyl, C3 cycloalkyl and C 2-3 AlkylC3 cycloalkyl. 3-12 The cycloalkyl group may be selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. 4 It is C 0-3 Alkyl C 3-12 When cycloalkyl, R 4 Can be replaced. C 3-12 The cycloalkyl group may be substituted. The substituent may be selected from one or more C 1-6 In some embodiments, the substituents are selected from one or more C 1-6 Alkyl and one or more halo groups (eg, -F).

[0085] In any embodiment, the present invention provides a compound of formula (I), wherein R 4 C 1-12 Alkyl. 4 It can be methyl, ethyl, propyl or butyl. 4 Can be branched C 1-12 Alkyl, for example branched C3, C4 or C5 alkyl. 4 may be substituted with one or more groups selected from halo and OH. 4 It may be substituted by one, two or more halo groups.

[0086] In any embodiment, R4 Selected from C 5-6 Cycloalkyl and halogenated C 2-5 In some embodiments, R 4 Selected from cyclohexyl and trifluoroethyl (eg -CH2CF3).

[0087] In any embodiment, R 1 , R 2 , R 3 and R 4 Optionally, one or more selected from OH, C 1-6 Alkoxy, halo (e.g. fluoro), amino, mercapto and C 1-6 Alkyl radicals are substituted.

[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 of carbon atoms 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, and the like.

[0089] Preferred "C 1-3 Alkyl", "C 1-4 Alkyl" and "C 1-6 These groups refer to alkyl groups containing 1-3, 1-4 or 1-6 carbon atoms, or any range of carbon atoms therebetween (e.g., alkyl groups containing 2-5 carbon atoms (i.e., 2, 3, 4 or 5 carbon atoms) are also in the C 1-6 In the use of the term “C 0-2 In the case of "alkyl" etc., 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 used) 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 connected through two positions, i.e., divalent. Preferably, "C 2-4 "Alkenyl" and "C 2-3 The term "alkenyl" includes vinyl, propenyl and butenyl, with vinyl being 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- and 2-butynyl, 2-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl and 5-hexynyl, and the like. 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 "halo" refers to the halogen radicals fluoro (-F), chloro (-Cl), bromo (-Br) and iodo (-I). Preferably, "halo" is fluoro.

[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 from three to seven carbon atoms or any integer range therebetween. For example, C 3-7 Cycloalkyl also includes cycloalkyl 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" includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

[0094] The cycloalkyl group may be optionally fused to one or more heterocyclic rings or cycloalkyl rings.The cycloalkyl ring may be substituted at 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 group or a 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 heterocyclic ring 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 cyclic hydrocarbon ring having three to seven carbon atoms (i.e., 3, 4, 5, 6 or 7 carbon atoms) which contains one or more heteroatom substitutions as defined herein. The heterocyclic moiety may be substituted, with multiple degrees of substitution being permitted. 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 5-6 A heterocyclic group of carbon atoms. Preferably, the heterocyclic ring contains four to six carbon atoms and one or two heteroatoms. More preferably, the heterocyclic ring contains five carbon atoms and one heteroatom, or four carbon atoms and two heteroatoms are substituted, or five carbon atoms and one heteroatom. The heterocyclic group 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 case, 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 group" as used herein refers to a heterocyclic group having 3, 4, 5, 6, 7, 8, 9 or 10 ring atoms. Examples of heterocyclic groups include 5-6 membered monocyclic heterocyclic groups and 9-10 membered fused bicyclic heterocyclic groups. Therefore, the heterocyclic ring described herein can be optionally fused to one or more other "heterocyclic" rings, cycloalkyl rings, aromatic rings or heteroaromatic rings. Examples of "heterocyclic" 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 heterocyclyl group may be substituted at any carbon atom on the ring with another heterocyclyl or cycloalkyl moiety to form spirocycloalkyl or spiroheteroalkyl compounds.

[0098] Two non-adjacent atoms on the heterocyclic group can be further 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 The term "heterocyclic group" includes a heterocyclic group that does not contain an alkyl group as a linking group between the compound and the heterocyclic ring, or a heterocyclic group that contains an alkyl group containing 1 or 2 carbon atoms as a linking group between the compound and the heterocyclic ring (i.e., a heterocyclic ring, -CH 2- 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 to 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, aralkyl, aralkylhalo, arylhalo and aralkoxy.

[0102] As used herein, the term "heteroaryl" refers to a monocyclic five-, six- or seven-membered aromatic ring, or to a fused bicyclic or tricyclic aromatic ring system containing at least one monocyclic five-, six- or seven-membered aromatic ring. These heteroaromatic rings contain one or more nitrogen, sulfur and / or oxygen heteroatoms, and may optionally be substituted by up to three members. N-containing heteroaryl groups may be in the form of N-oxides, and S-containing heteroaryl groups may 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, oxopyridyl, thiadiazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, quinolyl, isoquinolyl, benzofuranyl, benzothienyl, indolyl, indazolyl, benzimidazolyl and substituted forms thereof.

[0103] The terms "hydroxy" and "hydroxyl" refer to the group -OH.

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

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

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

[0107] The term "halogenated C 1-6 Alkoxy" and "C 1-6 "Alkoxyhalo" refers to a C 1-6 Alkoxy. Preferably C1-3 Alkoxyhalo, for example -OCF3.

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

[0109] The term "ester" refers to a hydrogen atom replaced by a C 1-6 Alkyl-substituted carboxyl (“carboxyl C 1-6 alkyl" or "alkyl ester"), carboxyl groups in which hydrogen is replaced by aryl or aralkyl ("aryl ester" or "aralkyl ester"), etc. CO2C 1-3 Alkyl groups such as methyl ester (CO2Me), ethyl ester (CO2Et) and propyl ester (CO2Pr) and include reverse esters thereof (eg, -OC(O)Me, -OC(O)Et and -OC(O)Pr).

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

[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-substituted amino groups (“C 1-6 alkylamino”), an amino group in which hydrogen is replaced by an aryl or aralkyl group (“arylamino”, “aralkylamino”), etc. 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, for example, C 1-6 alkyl (which may be the same or different) replaced by an amino group ("dialkylamino"), an amino group in which two hydrogen atoms are replaced by an aryl group and an alkyl group ("aryl(alkyl)amino"), and the like. 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 a -C(=O)H group.

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

[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 further group, such as a C 1-6 Alkyl (“C 1-6 "alkyl acyl" or "alkyl ketone" or "ketoalkyl"), aryl ("aryl ketone"), aralkyl ("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 amide" or "substituted amide" refers to a group in which a hydrogen is replaced by a C 1-6 Alkyl-substituted amide groups (“C 1-6 Alkylamide" or "C 1-6 The amide groups are amide groups in which hydrogen is replaced by an aryl group ("arylamide"), amide groups in which hydrogen is replaced by an aralkyl group ("aralkylamide"), and the like. Preferably C 1-3 Alkylamide groups, such as formamide (-C(O)NHMe), acetamide (-C(O)NHEt), and propionamide (-C(O)NHPr), and include reverse amides thereof (eg, -NHMeC(O)-, -NHEtC(O)-, and -NHPrC(O)-).

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

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

[0123] The term "C 1-6 "Alkylthio" refers to a group in which hydrogen is replaced by C 1-6 Alkyl-substituted thiol group. Preferably C 1-3 Alkylthio groups, such as thiolmethyl, thiolethyl and thiolpropyl.

[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 sulfonyl radical replaced by a hydrogen such as C 1-6 Alkyl-substituted sulfinyl (“C 1-6 Alkylsulfinyl" or "C 1-6 alkylsulfoxide”), sulfinyl in which hydrogen is replaced by an aryl group (“arylsulfinyl”), sulfinyl in which hydrogen is replaced by an aralkyl group (“aralkylsulfinyl”), and the like. Preferably C 1-3 Alkylsulfinyl, for example -SOmethyl, -SOethyl and -SOpropyl.

[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-substituted sulfonyl (“sulfonyl C 1-6 alkyl”), sulfonyl in which hydrogen is replaced by an aryl group (“arylsulfonyl”), sulfonyl in which hydrogen is replaced by an aralkyl group (“aralkylsulfonyl”), and the like. Preferably, the sulfonyl group is C 1-3 Alkyl groups such as -SO2Me, -SO2Et and -SO2Pr.

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

[0130] The term "substituted sulfonylamino" or "substituted sulfonamide" refers to a group in which a hydrogen is replaced by a C 1-6 Alkyl-substituted sulfonylamino (“sulfonylamino C 1-6 alkyl”), sulfonylamino in which hydrogen is replaced by aryl (“arylsulfonamide”), sulfonylamino in which hydrogen is replaced by aralkyl (“aralkylsulfonamide”), and the like. Preferably, sulfonylamino C 1-3 Alkyl groups such as -SO2NHMe, -SO2NHEt and -SO2NHPr, and include reverse sulfonamides thereof (such as -NHSO2Me, -NHSO2Et and -NHSO2Pr).

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

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

[0133] The term "sulfonate" refers to the group SO3H, which includes a hydrogen replaced by a C 1-6 The preferred alkyl sulfonate is a substituted alkyl group ("alkyl sulfonate"), a substituted aryl group ("aryl sulfonate"), a substituted aryl group ("aralkyl sulfonate"), etc. 1-3 Sulfonates such as SO3Me, SO3Et and SO3Pr.

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

[0135] As used throughout the specification, the term "optionally substituted" or "may be substituted" etc. means that the group may or may not be further substituted by one or more non-hydrogen substituents, or may or may not be fused with one or more non-hydrogen substituents (to form a polycyclic system). Suitable chemically feasible substituents for a particular functional group are obvious 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, more preferably 1 or 2 groups.

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

[0137] C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-7 Heterocyclic group, C 3-7 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylsulfanyl, C1-6 Alkylsulfenyl, C 1-6 Alkylsulfonyl, C 1-6 Alkylsulfonylamino, arylsulfonylamino, alkylcarboxyl, alkylcarboxylamide, oxo, hydroxyl, thiol, amino, acyl, carboxyl, carbamoyl, aryl, aryloxy, heteroaryl, aminosulfonyl, aroyl, aroylamino, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy, alkoxycarbonyl, nitro, cyano, halo, urea, C 1-6 Perfluoroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 alkyloxyaryl, ester, substituted amino, disubstituted amino, acyl, ketone, substituted ketone, amide, aminoacyl, substituted amide, disubstituted amide, thiol, alkylthio, thio, sulfate, sulfonate, sulfinyl, 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 each alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heterocyclyl and groups containing them may be further optionally substituted. In some embodiments, the moiety may be optionally substituted with any subset of optional substituents selected from those described above.

[0138] Optional substituents in the case of N-containing heterocycles (heterocyclyl and heteroaryl) 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 The optional one or more substituents are preferably selected from halo, aryl, heterocyclic, C 3-8 Cycloalkyl, C 1-6 Alkoxy, hydroxy, oxo, aryloxy, halogenated C 1-6 Alkyl, halogenated C 1-6 In some embodiments, the optionally substituted "C 1-6 Alkyl", "C 2-6 "Alkenyl" and "C2-6 The "alkynyl" group may be optionally substituted with any subset of the optional substituents selected from those listed 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] Examples of compounds of the invention are given in Table 1 below.

[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]

[0164]

[0165] 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 these non-pharmaceutically acceptable salts may be useful as intermediates in the preparation of pharmaceutically acceptable salts.

[0166] 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 is capable of (directly or indirectly) providing a compound of formula (I), or an active metabolite or residue thereof, upon administration to a subject, and is generally not harmful to the subject.

[0167] Suitable pharmaceutically acceptable salts include, but are not limited to, salts of pharmaceutically acceptable inorganic acids or salts of pharmaceutically acceptable organic acids, wherein the inorganic acids are, for example, hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, carbonic acid, boric acid, sulfamic acid and hydrobromic acid, and the organic acids are, for example, acetic acid, propionic acid, butyric acid, tartaric acid, maleic acid, hydroxymaleic acid, fumaric acid, malic acid, citric acid, lactic acid, mucic acid, gluconic acid, benzoic acid, succinic acid, oxalic acid, phenylacetic acid, methanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, salicylic acid, sulphanilic acid, aspartic acid, glutamic acid, edetic acid, stearic acid, palmitic acid, oleic acid, lauric acid, pantothenic acid, tannic acid, ascorbic acid, valeric acid and xinafoic acid.

[0168] Basic salts include, but are not limited to, those formed with pharmaceutically acceptable cations such as sodium, potassium, lithium, calcium, magnesium, zinc, ammonium, alkylammonium (e.g., salts formed by triethylamine), alkoxyammonium (e.g., those formed with 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 as described in general texts such as "Handbook of Pharmaceutical Salts", PHStahl, CGWermuth, 1st edition, 2002, Wiley-VCH.

[0169] Basic nitrogen-containing groups may be quarternised using, for example, lower alkyl halides such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dialkyl sulphates such as dimethyl and diethyl sulphate; and others.

[0170] "Prodrugs" are compounds that may not fully meet the structural requirements of the compounds provided herein, but are modified in vivo to produce compounds of formula (I) provided herein after being administered to a subject or patient. For example, a prodrug may be an acylated derivative of a compound provided herein. Prodrugs include compounds in which a hydroxyl, carboxyl, amine or thiol group is combined with any group, and when administered to a mammalian subject, cleaves to form free hydroxyl, carboxyl, amino or thiol groups, respectively. Examples of prodrugs include, but are not limited to, acetate, formate, phosphate and benzoate derivatives of alcohol and amine functional groups within the compounds provided herein. Prodrugs of compounds provided herein can be prepared by modifying the functional groups present in the compound in such a way that the modifications are cleaved in vivo to produce the parent compound.

[0171] Prodrugs include compounds in which an amino acid residue or a polypeptide chain of two or more (e.g., two, three, or four) amino acid residues is covalently attached to the free amino group and / or amide group of a compound of formula (I). Amino acid residues include 20 naturally occurring amino acids, typically 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 attached to the substituents of the above-mentioned formula (I) via the carbonyl carbon of the prodrug side chain. Prodrugs may include covalent irreversible inhibitors and reversible inhibitors.

[0172] In the case where the compounds are solids, those skilled in the art will appreciate that the compounds, formulations 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 specific form.

[0173] 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 exhibit polymorphism, all polymorphs are within the scope of the present invention.

[0174] Where applicable, Formula (I) is intended to encompass both solvated and unsolvated forms of the compounds. Thus, Formula (I) includes compounds having the indicated structures in both hydrated or solvated forms, as well as unhydrated and unsolvated forms.

[0175] Formula (I) compound or its salt, tautomer, N-oxide, polymorph or prodrug can be provided in the form of solvate. Solvate comprises stoichiometric or non-stoichiometric solvent, and can be formed with pharmaceutically acceptable solvents such as water, alcohol (such as methanol, ethanol or isopropanol), DMSO, acetonitrile, dimethylformamide (DMF), acetic acid, etc. during crystallization, wherein the solvate forms a part of the lattice by non-covalent bonding or by occupying holes in the lattice. Hydrate is formed when the solvent is water, and alcoholate is formed when the solvent is alcohol. Solvate of the compounds of the present invention can be conveniently prepared or formed in the methods described herein. Generally, for the purposes of the present invention, the solvated form is considered to be equivalent to the non-solvated form.

[0176] The compound of formula (I) or its salt, tautomer, N-oxide, solvate and / or prodrug that forms a crystalline solid may exhibit polymorphism. All polymorphic forms of the compound, salt, tautomer, N-oxide, solvate and / or prodrug are within the scope of the present invention.

[0177] The compounds of formula (I) may exhibit tautomerism. Tautomers are two interchangeable forms of a molecule that usually exist in equilibrium. Any tautomers of the compounds of formula (I) are understood to be within the scope of the present invention.

[0178] 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 olephinic 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. The compound may be enriched in one stereoisomer by at least about 60%, 70%, 80%, 90%, 95%, 98% or 99% than in another stereoisomer.

[0179] The compound of formula (I) or its salt, tautomer, solvate, N-oxide and / or stereoisomer may be isotopically enriched with 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. An isotope is said to be enriched when its abundance is greater than its natural abundance.

[0180] In some embodiments, the pIC of a compound of Formula (I) or a salt, solvate, N-oxide, tautomer, stereoisomer, polymorph and / or prodrug thereof is 50 At least 7. Inhibitory activity can be determined using a kinase assay. Such assays are well known to those skilled in the art, and examples of suitable assays are described in the Examples.

[0181] In another aspect, a composition is provided, comprising a compound of formula (I) or a salt, solvate, N-oxide, tautomer, stereoisomer, polymorph and / or prodrug thereof, and a pharmaceutically acceptable excipient.

[0182] 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 tablets 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 for symptomatic adjustment of dosage to the patient to be treated. 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 dosage frequency for any particular patient may vary and will 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 present invention in the composition also depends on the specific compound in the composition.

[0183] In the case of an inhaled product, the typical inhaled dose is smaller than that of other forms, starting from 1 microgram and rising to 1000 micrograms for a single puff. In a preferred form, the dose is 25 micrograms to 250 micrograms per puff. In another preferred form, the dose is 500 micrograms to 1000 micrograms per puff. In another form, the dose 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 and including two of these values ​​per puff. The medication can be puffed once a day or increased to four times a day with two puffs each time.

[0184] The pharmaceutical composition may further comprise other therapeutically active compounds that are commonly used to treat the disclosed diseases or conditions. One of ordinary skill in the art can select suitable formulations for combined therapy based on conventional pharmacological principles. The combination of therapeutic agents can act synergistically to affect the treatment or prevention of various diseases or conditions disclosed herein. Using this approach, one can achieve therapeutic efficacy with lower doses of various formulations, thereby reducing potential adverse side effects.

[0185] The compounds and compositions of the present invention can be formulated for any suitable route of administration, including, for example, topical (e.g., transdermal or ocular) administration, pulmonary administration, oral administration, oral administration, nasal administration, vaginal administration, rectal administration or parenteral administration. The term parenteral as used herein includes subcutaneous injection, intradermal injection, intravascular injection (e.g., intravenous injection), intramuscular injection, spinal injection, intracranial injection, intrathecal injection, intraocular injection, periocular injection, intraorbital injection, synovial and intraperitoneal injection, and any similar injection or infusion technique. In certain embodiments, the composition is preferably suitable for oral use or parenteral use. Suitable oral forms include, for example, tablets, lozenges, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard capsules or soft capsules, or syrups or elixirs. In other embodiments, the composition provided herein can be formulated into a lyophilized product.

[0186] In a preferred form, the composition is suitable for administration to the respiratory tract. In another form, the composition is suitable for oral administration.

[0187] The various dosage units are each preferably provided as separate doses of tablets, capsules, lozenges, dragees, colloids or other types of solid preparations. Capsules can encapsulate powders, liquids or gels. Solid preparations can be swallowed, or can be inhalable or chewable types (fragile or colloid). The present invention contemplates dosage unit retaining devices other than blister packs, for example, packaging such as bottles, tubes, cans, packets. The dosage unit may further include conventional excipients known in pharmaceutical preparation practice, such as adhesives, gelling agents, fillers, tableting lubricants, disintegrants, surfactants and colorants; and for inhalable or chewable preparations.

[0188] The composition intended for oral use may further comprise one or more components, such as sweeteners, flavoring agents, coloring agents and / or preservatives, to provide an attractive and palatable preparation. Tablets include active ingredients mixed with physiologically acceptable excipients suitable for tablet manufacture. Such excipients include, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate, granulating agents and disintegrating agents such as corn starch or alginic acid, adhesives such as starch, gelatin or gum arabic, and lubricants such as magnesium stearate, stearic acid or talcum. Tablets may be uncoated, or they 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.

[0189] Preparations for oral use may also be presented 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 (for example peanut oil, liquid paraffin or olive oil).

[0190] Aqueous suspensions contain one or more active ingredients mixed with excipients suitable for preparing aqueous suspensions. Such excipients include suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinyl pyrrolidone, tragacanth and gum arabic, and dispersants or wetting agents, such as naturally occurring phospholipids (e.g., lecithin), condensation products of alkylene oxides with fatty acids (e.g., polyoxyethylene stearate), condensation products of ethylene oxide with long-chain aliphatic alcohols (e.g., heptadecaethyleneoxycetanol), condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol (e.g., polyoxyethylene sorbitol monooleate), or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides (e.g., polyethylene 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 (for example sucrose or saccharin).

[0191] Oily suspensions can be prepared by suspending the active ingredient in a vegetable oil (e.g., peanut oil, olive oil, sesame oil, or coconut oil) or a mineral oil (e.g., liquid paraffin). Oily suspensions can contain thickeners, such as beeswax, hard paraffin, or cetyl alcohol. Sweeteners and / or flavorings such as those described above can be added to provide a palatable oral formulation. Such suspensions can be preserved by adding an antioxidant such as ascorbic acid.

[0192] Dispersible powders and granules suitable for preparing an aqueous suspension by adding water provide the active ingredient in admixture 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. Additional excipients such as sweeteners, flavoring agents and coloring agents may also be present.

[0193] Pharmaceutical composition can also be in the form of water-in-oil emulsion.Oil phase can be vegetable oil (such as olive oil or peanut oil), mineral oil (such as liquid paraffin), or its mixture.Suitable emulsifier comprises naturally occurring colloid (such as gum arabic or tragacanth), naturally occurring phosphatide (such as soybean lecithin) and ester or partial ester (such as sorbitan monooleate) derived from fatty acid and hexitol, acid anhydride and condensation product (such as polyoxyethylene sorbitan monooleate) of partial ester and ethylene oxide derived from fatty acid and hexitol.Emulsion can also comprise one or more sweeteners and / or flavorings.

[0194] Syrups and elixirs may be formulated with sweeteners such as glycerol, propylene glycol, sorbitol or sucrose. Such preparations may also contain one or more demulcents, preservatives, flavorings and / or coloring agents.

[0195] The compositions of the present invention may be formulated for regional or local administration, such as topical administration 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.

[0196] Suitable topical carriers and additional components are well known in the art, and it is clear 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, aliphatic alcohols such as lanolin, and mixtures of water and organic solvents, and mixtures of organic solvents such as alcohols and glycerol, lipid-based materials such as fatty acids, acylglycerols containing oils such as mineral oil, and fats of natural or synthetic origin, phosphoglycerides, sphingolipids and waxes, protein-based materials such as collagen and gelatin, silicone-based materials (both non-volatile and volatile), and hydrocarbon-based materials such as microsponges and polymer matrices.

[0197] The composition may further include one or more components suitable for improving the stability or effectiveness of the applied preparation, such as stabilizers, suspending agents, emulsifiers, viscosity modifiers, gelling agents, preservatives, antioxidants, transdermal enhancers, humectants and sustained release materials. Examples of such components are described in Martindale-The Extra Pharmacopoeia (Pharmaceutical Press, London, 1993) and Martin (ed.), Remington's Pharmaceutical Sciences. The preparation may include microcapsules, such as hydroxymethylcellulose or gelatin microcapsules, liposomes, albumin microspheres, microemulsions, nanoparticles or nanocapsules.

[0198] 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 such forms 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 hard and non-pourable, and are usually formulated into strips or rods, or are in particle form. Solids can be opaque or transparent, and can optionally include solvents, emulsifiers, humectants, 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, mainly in that their viscosities are different. Creams and lotions can all be opaque, translucent or transparent, and usually include emulsifiers, solvents and viscosity modifiers and humectants, emollients, spices, dyes / colorants, preservatives and other active ingredients that increase or enhance the efficacy of the final product. Gels with a range of viscosities can be prepared, from thick or high viscosity to rare or low viscosity. These formulations, like lotions and creams, 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 typically 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.

[0199] 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, ceteareth 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 alcohol 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 glycyrrhizic acid. Suitable surfactants include but are not limited to nonionic, amphoteric, ionic 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-dimonium chloride, and ammonium laureth sulfate may be used in topical formulations.

[0200] Preservatives include, but are not limited to, antimicrobial agents, and physical stabilizers and antioxidants, such as methylparaben, propylparaben, sorbic acid, benzoic acid and formaldehyde, and 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 lubricants include lanolin alcohol, lanolin, lanolin derivatives, cholesterol, petrolatum, isostearyl neopentanoate and mineral oil. Suitable spices and pigments 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 (e.g., witch hazel), alcohols and herbal extracts (e.g., chamomile extracts), binders / excipients, buffers, chelating agents, film formers, conditioners, propellants, opacifiers, pH regulators and protective agents.

[0201] Typical delivery modes of topical compositions include application with fingers, application with a physical applicator (e.g., cloth, tissue, cotton swab, stick or brush), spraying (including mist, aerosol or foam spray), dropper application, sprinkling, soaking and rinsing. Controlled release carriers may also be used, and the composition may be formulated for transdermal administration (e.g., as a transdermal patch).

[0202] The pharmaceutical composition can be formulated into a sustained release formulation, such as a capsule that produces a slow release of the regulator after administration. Such formulations can be prepared using known techniques generally, and can be administered, for example, by oral, rectal or subcutaneous implantation or by implantation at 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 regulator release. The amount of regulator contained 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.

[0203] The pharmaceutical composition can be formulated into an inhalation formulation, including sprays, mists or aerosols. For example, for respiratory administration. This may be particularly preferred for the treatment of respiratory diseases, the treatment of fibrotic airways or lung conditions 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 dose 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 nebulizers. Aerosol formulations used for the subject method generally include propellants, surfactants and cosolvents, and can be filled into conventional aerosol containers closed by suitable metering valves. 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. Furthermore, methods of micronization and nanoparticle formation for preparing the compounds described herein for use in inhalers such as dry powder inhalers are also known to those skilled in the art.

[0204] Inhalation compositions may include liquid or powdered compositions comprising active ingredients suitable for atomization and intrabronchial use, or aerosol compositions for administration of metered doses distributed by an aerosol unit. Suitable liquid compositions include active ingredients in aqueous, pharmaceutically acceptable inhalation solvents (such as isotonic saline or antibacterial water). The solution is administered by means of a pump or extrusion-actuated atomizing spray dispenser or by any other conventional means to cause or cause the necessary 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 active ingredients. Examples of inhaled drug delivery devices are described in Ibraim et al., Medical Devices: Evidence and Research 2015: 8 131–139, and are contemplated for use in the present invention.

[0205] In another aspect, provided is 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) or a salt, solvate, N-oxide, tautomer, stereoisomer, polymorph and / or prodrug thereof, thereby treating or preventing the respiratory disease in the subject.

[0206] Further provided is a compound of formula (I) or a salt, solvate, N-oxide, tautomer, stereoisomer, polymorph and / or prodrug thereof for use in treating or preventing a respiratory disease in a subject in need thereof.

[0207] 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.

[0208] As used herein, "preventing" or "preventing" is intended to mean at least reducing the likelihood of acquiring the risk (or susceptibility) of a disease or condition (i.e., preventing the development of at least one clinical symptom of the disease in a patient who may be exposed to or susceptible to the disease but has not yet experienced or shown symptoms of the disease). Biological and physiological parameters for identifying such patients are provided herein and are also well known to physicians.

[0209] The term "treatment" or "treating" a subject includes applying or administering a compound of the invention to a subject (or to a cell or tissue from a subject) for the purpose of delaying, slowing, stabilizing, curing, healing, alleviating, relieving, altering, remedying, alleviating, worsening, improving, ameliorging, or affecting a disease or condition, a symptom of a disease or condition, or a risk (or susceptibility) for a disease or condition. The term "treat" refers to any indication of success in the treatment or improvement of 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 a subject; slowing the rate of degeneration or decline; making the endpoint of degeneration less debilitating; or improving the physical or mental health of a subject.

[0210] As used herein, the term "antagonize" means "reduce" or "decrease". A sufficient period of time may be one week, or 1 week to 1 month, or 1 month to 2 months, or 2 months or longer. For chronic conditions, the compounds of the invention may be advantageously administered during the life span.

[0211] The term "breathing" refers to the process of taking oxygen into the body and expelling carbon dioxide through the body system including the nose, throat, larynx, trachea, bronchi, and lungs.

[0212] The term "respiratory disease" or "respiratory disorder" refers to any of several ailments that may involve inflammation and / or tissue remodeling affecting components 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 ailments include pulmonary fibrosis (interstitial lung disease), sinusitis, influenza, sarcoidosis, bronchial cancer (including but not limited to non-small cell lung cancer and small cell lung cancer, and lung metastases from tumors of other organs), silicosis, pneumoconiosis, acute lung injury, ventilation-induced 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, such afflictions include: asthmatic conditions including hay fever, allergen-induced asthma, exercise-induced asthma, pollution-induced asthma, cold-induced asthma, stress-induced asthma, viral-induced asthma, obesity-related asthma, occupational asthma, storm-induced asthma, asthma-COPD overlap syndrome (ACOS); chronic obstructive pulmonary disease including chronic bronchitis with normal airflow, chronic bronchitis with airway obstruction (chronic obstructive bronchitis), emphysema, asthmatic bronchitis; and bullous diseases; and other lung diseases involving inflammation including cystic fibrosis, pigeon fancier's disease, disease), farmer's lung, acute respiratory distress syndrome, fungal pneumonia, viral pneumonia, bacterial pneumonia, mixed or unknown etiology, inspiration or aspiration injury, fat embolism in the lung, acidotic inflammation of the lung, acute pulmonary edema, acute mountain sickness, post-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 in the upper and lower respiratory tracts may be associated with or caused by viral infections 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.

[0213] Respiratory diseases or conditions may be associated with or caused by allergens, such as 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 the disease, such as exacerbations caused by viral infections, such as RSV infections.

[0214] Symptoms of respiratory diseases can include coughing, producing excessive sputum, dyspnea or chest tightness with audible wheezing. Exercise capacity may be quite limited. In asthma, FEV1.0 (forced expiratory volume in one second) accounts for a percentage of the prediction of the nomogram based on weight, height and age, which may decrease with the peak expiratory flow rate in forced exhalation. In COPD, FEV1.0 is the ratio of forced vital capacity (FVC) that is usually reduced to less than 0.7. In IPF, FVC gradually decreases. The impact of each of these conditions can also be measured by the number of days of absence from work / school, sleep disorders, the need for bronchodilators, and the need for glucocorticoids (including oral glucocorticoids). Further measurements of the impact of these conditions include validated health-related quality of life measurements. 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.

[0215] The presence, amelioration, treatment or prevention of respiratory disease can be measured by any clinical or biochemically relevant method of the subject or its biopsy. For example, the parameters measured can be the presence or degree of lung function, signs and symptoms of obstruction; exercise tolerance; nighttime awakenings; number of days missed from school or work; use of bronchodilators; ICS dosage; use of oral GCs; need for other medications; need for medical treatment; hospitalization.

[0216] As used herein, the term "asthma" refers to a respiratory disorder characterized by paroxysmal dyspnea caused by any one or combination of the following three main factors: 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 can be triggered by exposure to allergens or allergen combinations (i.e., dust mites and molds), 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. As used herein, the term "asthmatic condition" refers to the characteristics of an individual experiencing an asthma attack when exposed to any one or more asthma triggers for the individual. The characteristics of an individual can be experiencing, for example, allergen-induced asthma, exercise-induced asthma, pollution-induced asthma, virus-induced asthma, or cold-induced asthma.

[0217] 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 to asthma exacerbation, and increase in forced expiratory volume in one second (FEV1.0).

[0218] The terms "chronic obstructive pulmonary disease" and "COPD" used interchangeably herein refer to a chronic condition or combination of conditions characterized by a decrease in maximum expiratory flow and a slow forced emptying of the lungs, which does not change significantly over several months and is irreversible or only minimally reversible using conventional bronchodilators. Most commonly, COPD is a combination of chronic bronchitis, i.e., cough and sputum for more than three months for about two consecutive years, and emphysema, i.e., alveolar damage. However, COPD may involve chronic bronchitis with normal airflow, chronic bronchitis with airway obstruction (chronic obstructive bronchitis), emphysema, asthmatic bronchitis, and bullous diseases, and combinations thereof. Chronic obstructive pulmonary disease is a condition usually, but not exclusively, caused by chronic lung damage induced by exposure to tobacco smoke. Other harmful airborne pollutants such as indoor cooking exhaust and automobile exhaust may cause COPD or increase the risk of COPD in the long term, as does aging.

[0219] The phrase "a condition of the airways or lungs involving fibrosis" or "a condition of the airways or lungs having a fibrotic component" includes any disease or condition in which excess fibrous connective tissue (fibrosis) forms or develops in the airways or lungs, resulting in the development of scar (fibrotic) tissue. This includes interstitial lung diseases such as pulmonary fibrosis, lung 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 leads to hardening of the lungs, which then makes breathing increasingly difficult. Pulmonary fibrosis can be caused by radiation damage or exposure to therapeutic agents such as bleomycin.

[0220] "Idiopathic pulmonary fibrosis (IPF)" is a specific manifestation of idiopathic interstitial pneumonia (IIP), which is a type of interstitial lung disease. Interstitial lung disease, also known as diffuse parenchymal lung disease (DPLD), refers to a type of lung disease that affects the interstitium. Under a microscope, lung tissue from IPF patients shows a set of characteristics of histological features known as usual interstitial pneumonia (UIP). UIP is therefore a pathological manifestation of IPF.

[0221] The presence, improvement, treatment or prevention of airway or lung disorders related to fibrosis, particularly pulmonary fibrosis / pulmonary fibrosis or idiopathic pulmonary fibrosis can be carried out by any clinical or biochemical correlation method of the experimenter or its biopsy. For example, the rate of decline of FVC or the appearance of high-resolution computed tomography images of the lung can be used for diagnosing IPF. In addition, the parameter measured can be the presence or degree of fibrosis, the content of collagen, fibronectin or another extracellular matrix protein, the proliferation rate of any extracellular matrix component in the cell or cell, or the transdifferentiation of cells into myofibroblasts.

[0222] In one embodiment, the respiratory disease is selected from asthma, chronic obstructive pulmonary disease, interstitial lung disease (e.g., idiopathic pulmonary fibrosis) and other disorders associated with tissue remodeling, primary or secondary lung tumors, hay fever, chronic and acute sinusitis, and chronic and acute respiratory viral, fungal and bacterial infections.

[0223] In one embodiment, 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 the ease with which the respiratory system can be stretched. Preferably, the improvement is selected from the reduction of lung contraction level and the reduction of respiratory system elastic stiffness. On the other hand, a composition is provided, which comprises a compound according to formula (I) or its salt, solvate, N-oxide, tautomer, stereoisomer, polymorph and / or prodrug, and a pharmaceutically acceptable excipient.

[0224] The therapeutically effective amount of the preparation depends on the severity of the specific respiratory disease indication (e.g., severe chronic asthma), the patient's clinical history and reaction, and the judgment of the attending physician. The preparation can be applied to the patient once or through a series of treatments. The initial candidate dose can be applied to the patient, and the appropriate dosage and treatment regimen can be established by monitoring the progress of the patient using conventional techniques 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 to 10μM. However, it should be understood that delivery by inhalation may cause the cells in the airway to be exposed to a concentration exceeding the above concentration for a period of time in a short time, while the drug is diluted in the airway surface fluid and also absorbed from the airway and lung surface.

[0225] In one aspect, the treatment methods of the present invention further include administering a concomitant medication for the target disease indication. For example, concomitant asthma medications (for both chronic and acute) that can be used with the methods of the present invention include, but are not limited to: inhaled and oral steroids (e.g., beclomethasone, budesonide, flunisolide, fluticasone, triamcinolone, mometasone); systemic corticosteroids (e.g., methylprednisolone, prednisolone, prednisone, dexamethasone, and deflazacort); inhaled or oral β2-adrenergic receptor agonists (e.g., salmeterol, formoterol, bitolterol, pirbuterol, vilanterol, terbutaline, bambuterol, and salbutamol); cromoglycine and nedocrolate; antiallergic ophthalmic drugs (e.g., dexamethasone); agents that modulate the production and action of transforming growth factor-β, including pirfenidone and nintedanib; methylxanthines and other phosphodiesterase inhibitors (e.g., theophylline and mepyramine-theophyllineacetate, roflumilast); leukotriene modifiers (e.g., zafirlukast, zileuton, montekulast, and pranlukast); anticholinergics (e.g., ipratropium 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., chemical contaminant mimetic antibodies (anticalins)) or natural, engineered or synthetic peptides; thromboxane A2 synthetase inhibitors; thromboxane prostanoid receptor antagonists; other eicosanoid modulators (e.g., alprostadil relative to PGE1, dinoprostone relative to PGE2, epoprostenol relative to prostacyclin and PGI2 analogs (e.g., PG12 beraprost), serotonin, phosphodiesterase 4 isozyme inhibitors, thromboxane A2 synthetase inhibitors (e.g., ozmagrel, damegrelide, 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 (e.g., icatibant); agents that inhibit activated eosinophils and T-cell recruitment (e.g., ketotifen), IL-13 blockers (e.g., soluble IL-13 receptor fragments), IL-4 blockers (e.g., soluble IL-4 receptor fragments); and ligands that bind to and block the activity of IL-13 or IL-4, as well as xanthine derivatives (e.g., pentoxifylline); and chemokine receptor antagonists and CRTH2 receptor antagonists.

[0226] In certain embodiments, the treatment methods of the present invention include providing inhibitory RNA molecules (RNA interference molecules) to the subject concomitantly to reduce, inhibit or prevent the expression of genes encoding target proteins. For example, inhibitory RNA molecules 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 isoforms and other components of the CLOCK regulatory network (e.g., ARNT1, cycle 1-3) and other proteins that contribute to inflammatory responses in the respiratory system, such as interleukin-5 and NALP inflammasomes.

[0227] The skilled person is familiar with various methods of using inhibitory RNA molecules to interfere with gene expression in a subject. 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 directly applied to the subject in need of treatment (e.g., by inhalation, intratracheal, oral or nasal administration or by parenteral administration), or alternatively, after administering a polynucleotide (vector) construct encoding a double-stranded RNA (dsRNA) molecule (which is capable of forming an inhibitory RNA molecule), the inhibitory RNA molecule is formed in the subject receiving treatment. Those skilled in the art are also 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 indication, wherein either or both are administered by inhalation or formulated for oral administration.

[0228] Although the present invention is suitable for use in humans, the present invention may also be used for veterinary therapeutic purposes. The present invention is useful for livestock or farm animals, such as cattle, sheep, horses and poultry, for companion animals such as cats and dogs, and for animals in zoos.

[0229] As used herein, "subject" refers to an animal, such as a mammal or bird, including humans, apes, horses, cows, sheep, goats, dogs, cats, guinea pigs, rats, mice, chickens, etc.

[0230] CK1δ homologues are ubiquitous in nature, including in protozoa (such as malaria), fungi and bacteria. Therefore, it is expected that the compounds of the present invention can be used in any application where inhibition of CK1δ homologues is required. Such uses may include administering the compounds of the present invention to a subject suffering from a disease, disorder and / or condition associated with infection and / or protozoan, fungal and / or bacterial infection.

[0231] 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, N-oxide, tautomer, stereoisomer, polymorph and / or prodrug thereof.

[0232] Surprisingly, the compounds of the present invention, or salts, solvates, N-oxides, tautomers, stereoisomers, polymorphs and / or prodrugs thereof, can be used as selective inhibitors of CK1δ. Any disclosed form of the compounds of the present invention can selectively inhibit CK1δ compared to one or more other kinases, such as ALK5 / TGFBR1, ARK5 / NUAK1, casein kinase 1ε (CK1ε), p38a / MAPK14, etc. In some embodiments, the selectivity of the compounds of the present invention for CK1δ can exceed at least one kinase by at least about 1, 5, 10, or 100 times.

[0233] In another aspect, the present invention provides a kit or article of manufacture comprising a compound of formula (I) as described herein or a pharmaceutical composition comprising a compound of formula (I) as described herein.

[0234] In other embodiments, a kit for the therapeutic or prophylactic use mentioned 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.

[0235] The kit or "article of manufacture" may include a container and a label or package insert on or associated with the container. Suitable containers include, for example, bottles, vials, syringes, one or more blister packages, and the like. The container may be formed from a variety of materials, such as glass or plastic. The container contains a compound of formula (I) or a composition that is effective in treating a condition and may have a sterile access port (e.g., the container may be an intravenous solution bag or a vial with a stopper that can be inserted by a hypodermic needle). The label or package insert indicates that the composition is used to treat a 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 a disease described herein.

[0236] The kit may include (a) a therapeutic or prophylactic composition; (b) a second container containing a second active ingredient or component. The kit in this embodiment of the 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 as described herein. Alternatively or additionally, the kit may further include a second (or third) container containing 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 required from a commercial and user perspective, including other buffers, diluents, filters, needles, and syringes.

[0237] 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 requiring mixing or addition of other components.

[0238] Example

[0239] In vitro testing

[0240] Kinase inhibition assay

[0241] The test used was the HotSpot test (Reaction Biology).

[0242] The compound was given at a dose of 10 IC 50 The test was performed in 5% saturation water mode, starting from 10 μM and performing 3-fold serial dilutions. The control compound Staurosporine was tested at a dose of 10 IC 50 The assay was performed in the 4-fold serial dilution mode starting from 20 μM. Reactions were performed at 10 μM ATP.

[0243] Reagents

[0244] Alkaline 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.

[0245] *Required cofactors are added separately to each kinase reaction

[0246] Reaction Procedure

[0247] 1. The peptide substrate is freshly prepared in alkaline reaction buffer

[0248] 2. Any required cofactors are delivered to the substrate solution as above

[0249] 3. Deliver human recombinant casein kinase 1δ to the substrate solution and mix gently

[0250] 4. Deliver the compound in DMSO to the kinase reaction mixture by acoustic technology (Echo 550; nanoliter range) and incubate at room temperature for 20 minutes

[0251] 5. 33 P-ATP (specific activity 10 mCi / mL) was delivered to the reaction mixture along with ATP (10 μM).

[0252] 6. Incubate the kinase reaction at room temperature for 2 hours

[0253] 7. Spot the reaction mixture on P81 ion exchange paper

[0254] 8. Measure by using filter binding method 33 The kinase activity was detected by labeling the product peptide with P-ATP.

[0255] The test results (performed on casein kinase 1δ) are shown in Table 2 below (pIC 50 ) and Table 3 (IC 50 ) is given in .

[0256] Table 2. Inhibitory activity of some compounds of the present invention

[0257] Compound <![CDATA[pIC 50 ]]> ZH2-102 8.77 ZH2-130 8.71 ZH2-62 7.42 ZH2-66 5.86 ZH2-86 8.15 ZH2-98 7.91 ZH3-74 8.53 ZH3-90 6.57 ZH3-94 7.46 ZH3-98 8.59 D4476 6.67

[0258] Table 3. Casein kinase 1δ inhibitory activity of some compounds of the present invention

[0259]

[0260]

[0261] Human parenchymal fibroblasts test

[0262] Primary human parenchymal fibroblasts (pFb) were cultured from the parenchyma of lung resection specimens and non-transplanted lungs of donors without chronic respiratory diseases. pFb were passaged in Dulbecco's Modified Eagle's Medium (DMEM) containing 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.

[0263] Prior to the experiment, pFb were cultured in serum-free DMEM containing 0.25% bovine serum albumin (BSA) and insulin-transferrin-selenium supplements (Monomed A; CSL, Parkville, Melbourne, Australia). Cells were incubated with small molecule CK1δelta inhibitors (0.1 μM to 10 μM) for 30 minutes and then incubated with 100 pM TGF-β1 (R&D Systems, Minneapolis, MN) for 16 to 24 hours, and then supernatants were collected to detect immunoreactive IL-11. A 10 mM stock solution was made in 100% DMSO and diluted to the desired concentration (final concentration) in medium containing 0.1% DMSO.

[0264] The supernatant was collected and IL-11 was measured by ELISA according to the manufacturer's instructions (R&D DuoSet, DY218). Typically, the capture antibody was initially diluted to the recommended concentration using 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), followed by the addition of 200 μL of blocking solution (PBS containing 1% (v / v) BSA) for 1 hour to block nonspecific sites. The plate was then washed 3 times with wash buffer, and 50 μL of sample or standard was then added to the wells and incubated for 2 hours at room temperature. After incubation, the plate was washed 3 times with wash buffer, 50 μL of detection antibody was added to the wells and incubated for 2 hours at room temperature. The plates were then washed three times before adding streptavidin-conjugated horseradish peroxidase (at the recommended concentration) for 45 minutes. The plates were then washed five times with wash buffer and 100 μL of TMB substrate solution (A and B equal parts, 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 plate was analyzed using Multiskan The plate reader measures absorbance at 450 nm. 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 from linear regression of log concentration of small molecule on IL-11 levels (Table 4 and Figure 2).

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

[0267]

[0268]

[0269] *pIC values ​​for compounds that did not produce 50% or more inhibition at 100 mM 50 The value is specified as 4.00.

[0270] synthesis

[0271] General

[0272] Proton NMR spectra were obtained in deuterated solvents ( 1 H NMR, 400, 600 MHz) and proton decoupled carbon-13 NMR spectroscopy ( 13 C NMR, 100, 150 MHz) with residual protiated solvent as internal standard. Chemical shifts are followed by multiplicity, coupling constant (J, Hz), integration and possible assignment. According to Still et al. 1 The method uses an automated system for flash chromatography. Analytical thin layer chromatography (tlc) was performed on 2 mm thick silica gel 60GF backed with aluminum 254 The chromatograms were visualized under UV light. High-resolution mass spectra (HRMS) were obtained by ionizing the samples using electrospray ionization (ESI) and a time-of-flight mass analyzer. 2 Dry THF and CH2Cl2 were obtained by the method of . Petroleum spirit refers to petroleum ether with a boiling range of 40°C-60°C. All other commercially available reagents were used as received.

[0273] 1 WC Still, M. Kahn and AM Mitra, J. Org. Chem., 1978, 43, 2923.

[0274] 2 ABPangborn, MAGiardello, RHGrubbs, RKRosen and FJTimmers, Organometallics, 1996, 15, 1518.

[0275]

[0276] 2-(Methylthio)pyrimidine-4-carbaldehyde (1)

[0277] 4M aqueous HCl (13 mL) was added to a solution of 4-dimethoxymethyl-2-methylsulfanyl-pyrimidine (2.42 g, 12.1 mmol) 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. The crude material was used in the next step without purification (2.74 g, 87%). 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).

[0278] 4-((Cyclohexylimino)-methyl)-N-methylsulfanylpyrimidin-2-amine (12)

[0279] K2CO3 20% w / v (0.55 g, 0.39 mmol) in water 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.

[0280] 4-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-2-(methylsulfanyl)pyrimidine (13)

[0281] A mixture of α-(p-Toluenesulfonyl)-4-fluorobenzyl isocyanide (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 at room temperature overnight. The reaction mixture was diluted with CH2Cl2, washed with water, dried (MgSO4), filtered and concentrated. The residue was flash chromatographed (EtOAc / pet. spirits 1:1) to give a solid which was recrystallized from EtOAc / pet. spirits to give the sulfide as pale yellow crystals (2.32 g, 35%), mp 192-195°C. 1H-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; for C 20 H 22 HRMS (ESI) calculated for FN4S (M+H) + ) is 369.1549. The measured value is 369.1545.

[0282] 4-(1-Cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-2-methylsulfonylpyrimidin-2-amine (14)

[0283] 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, mp 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); 13C-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; for C 20 H 22 HRMS (ESI+) calculated for FN4O2S (M+H) 401.1447. Found 401.1444.

[0284] 4-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)pyrimidin-2-amine (15; ZH2-102)

[0285] 4-Aminomethyltetrahydropyran (95.0 μL, 0.776 mmol) was added to a solution of 14 (31.1 mg, 0.078 mmol) in THF (5 mL), and the mixture was stirred for 2 days at 40° C. The mixture was concentrated under vacuum and the residue was purified by flash chromatography (EtOAc / petroleum spirit 35% to 100%) to give a light yellow solid (24.4 mg, 72%). 1 H-NMR (400MHz; CDCl3): δ1.23-1.42(6H,m),1.60-1.75(5H,m),1.89(2H,m),2.17(2H,m),3.38(4H,m),3.99(2H,dd,J=3.7,11.3Hz),4 .54(1H,s),5.41(1H,s),6.40(1H,d,J=5.1Hz),6.98(2H,t,J=8.7Hz),7.44(2H,dd,J=5.6,8.5Hz),7.74(1H,s),8.13(1H,d,J=3.9Hz); 13 C-NMR (101MHz; CDCl3): δ25.4,26.1,31.0,34.6,35.3,47.5,55.6,67.8,112.0,115.2,115.4,125.2,130.0(d,J C-F =8.0Hz),130.72(d,J C-F =3.1Hz),135.8,141.5,158.2,159.0,162.4(d,J C-F =248Hz),162.7.

[0286] 4-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(pyridin-2-ylmethyl)pyrimidin-2-amine (2-methylpyridine) (19; ZH2-130)

[0287] 2-Aminomethylpyridine (74.0 μL, 0.724 mmol) was added to a solution of 14 (29.0 mg, 0.072 mmol) in THF (5 mL), and the mixture was stirred for 2 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 solid (30.9 mg, 99%). 1 H-NMR (500MHz; CDCl3): δ1.20-1.27(3H,m),1.58-1.68(3H,m),1.83-1.85(2H,m),2.14-2. 16(2H,m),4.56(1H,tt,J=12.0,3.6Hz),4.80(2H,d,J=5.5Hz),6.35(1H,m),6.44(1H,d,J= 5.1Hz),6.95-7.00(2H,m),7.19-7.21(1H,m),7.32(1H,d,J=7.8Hz),7.43-7.47(2H,m),7. 66(1H,td,J=1.8,7.7Hz),7.73(1H,s),8.18(1H,d,J=5.1Hz),8.58(1H,dt,J=0.7,4.9Hz). 13 C-NMR (126MHz; CDCl3): δ25.4,25.9,34.7,46.7,55.7,112.3,115.3,115.4,121.6,122.4,125.2,130.1(d,J C-F =8.0Hz),130.7(d,J C-F =3.2Hz),135.8,136.8,141.5,149.4,157.7,158.4,159.0,162.4(d,J C-F =247Hz),162.5.

[0288] N-([1,1'-biphenyl]-4-ylmethyl)-4-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)pyrimidin-2-amine (25; ZH2-66)

[0289] 4-Phenylbenzylamine (30.0 mg, 0.162 mmol) was added to a solution of 14 (32.6 mg, 0.081 mmol) in THF (5 mL), and the mixture was stirred at room temperature for 6 days. The mixture was concentrated under vacuum and the residue was purified by flash chromatography (EtOAc / petroleum spirit 50% to 100%), then recrystallized from PhMe / EtOAc to give light yellow crystals (20.9 mg, 51%). 1 H-NMR (400MHz; CDCl3): 1 H-NMR (400MHz; CDCl3): δ1.12-1.26(2H,m),1.56-1.62(2H,m),1.81(2H,m),1.8 9-1.96(2H,m),2.13(2H,d,J=12.0Hz),4.52-4.59(1H,m),4.77(2H,d,J=6.0Hz) ,5.66(1H,t,J=0.8Hz),6.46(1H,d,J=5.1Hz),7.00(2H,t,J=8.6Hz),7.35(1H,t ,J=7.2Hz),7.42-7.48(6H,m),7.59(4H,m),7.75(1H,s),8.18(1H,d,J=4.7Hz); 13 C-NMR (101MHz; CDCl3): δ25.4,25.8,34.7,45.2,55.6,112.5,115.3,115.5,127.2,127.5,127.6,127.7,129.0,130.2(d,J C-F =7.8Hz),130.6(d,J C-F =3.3Hz),135.9,138.2,140.6,158.4,159.1,162.5,162.5(d,J C-F =247Hz).

[0290] 4-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(cyclopentylmethyl)pyrimidin-2-amine (27; ZH2-86)

[0291] Cyclopentylmethylamine (96.0 μL, 0.973 mmol) was added to a solution of 14 (39.0 mg, 0.097 mmol) in THF (5 mL), and the mixture was stirred at 40° C. for 18 h. 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 solid (17.2 mg, 42%). 1H-NMR (400MHz; CDCl3): δ1.19-1.41(5H,m),1.53-1.90(11H,m),2.16-2.25(3H,m),3.38(2H,t,J=6.5Hz),4.57-4.59(1H,m),5. 28-5.33(1H,bs),6.38(1H,d,J=5.1Hz),6.98(2H,t,J=8.7Hz),7.45(2H,dd,J=5.6,8.5Hz),7.74(1H,s),8.12(1H,bs,J=0.6Hz); 13 C-NMR (101MHz; CDCl3): δ25.5,26.0,30.6,34.7,39.7,46.9,55.6,111.8,115.2,115.5,125.3,130.1(d,J C-F =8.0Hz),130.7(d,J C-F =3.0Hz),135.8(d,J C-F =8.0Hz),141.5,158.1,159.0,162.3,162.4(d,J C-F =248Hz).

[0292] 4-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(cyclohexylmethyl)pyrimidin-2-amine (28; ZH2-98)

[0293] Cyclohexylmethylamine (92.0 μL, 0.706 mmol) was added to a solution of 14 (28.3 mg, 0.071 mmol) in THF (5 mL), and the mixture was stirred at room temperature for 2 days. The mixture was concentrated under vacuum and the residue was purified by flash chromatography (EtOAc / petroleum spirit 40% to 70%) to give a light yellow solid (28.4 mg, 92%). 1 H-NMR (400MHz; CDCl3): δ0.93-1.03(2H,m),1.11-1.37(7H,m),1.54-1.89(10H,m),2.16(2H,d,J=11.2Hz),3.29(2H,t,J=6.4Hz) ,4.57(1H,bs),5.37(1H,bs),6.36(1H,d,J=5.1Hz),6.97(2H,t,J=8.7Hz),7.44(2H,dd,J=5.6,8.6Hz),7.72(1H,s),8.10(1H,s); 13C-NMR (101MHz; CDCl3): δ25.5,26.0,26.6,31.2,34.7,38.0,48.0,55.6,111.7,115.2,115.4,125.3,130.1(d,J C-F =8.0Hz),130.8(d,J C-F =3.1Hz),135.8,141.5,158.2,159.0,162.4(d,J C-F =247Hz),162.8.

[0294] 4-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-((4,4-difluorocyclohexyl)methyl)pyrimidin-2-amine (32; ZH3-74)

[0295] 4,4-Difluorocyclohexylmethylamine hydrochloride (96.0 mg, 0.519 mmol) and KCO (72.0 mg, 0.519 mmol) were added to a solution of 14 (52.0 mg, 0.130 mmol) in THF / H0 (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 20% to 70%) to give a light yellow solid (56.8 mg, 93%). 1 H-NMR (400MHz; CDCl3): δ1.61-1.9(10H,m),2.12(4H,dt,J=12.1,20.9Hz),3.38(2H,t,J=6.5Hz),4.51-4.56(1H,m),5 .59(1H,s),6.41(1H,d,J=5.1Hz),6.98(2H,t,J=8.6Hz),7.44(2H,dd,J=5.6,8.3Hz),7.76(1H,s),8.12-8.13(1H,m); 13 C-NMR (101MHz; CDCl3): δ25.4,26.1,26.9,27.0,33.0,33.3(2C),33.5,34.7, 36.2,46.5,55.7,112.0,115.3,115.5,121.2,123.6,125.2,126.0,130.1(d,J C-F =7.9Hz),130.6(d,J C-F =3.1Hz),135.9,141.6,158.0,159.1,161.4(d,J C-F =247Hz),162.6; for C 26 H 26F2N5[M+H] + Calculated HRMS (ESI + ) is 470.2532. The measured value is 470.2524.

[0296] (S)-4-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(1-cyclohexylethyl)pyrimidin-2-amine (34; ZH3-90)

[0297] (S)-Cyclohexylethylamine (61.0 μL, 0.479 mmol) was added to a solution of 14 (24.0 mg, 0.060 mmol) in THF (4 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 light yellow oil (24.6 mg, 91%), [α] D 24 -9.3°(c 0.24,CH2Cl2). 1 H-NMR (400MHz; CDCl3): δ0.85-2.36(24H,m),3.98-4.05(1H,m),4.62-4.65(1H,m),5.99-6.00(1H,m),6.36(1 H,d,J=5.0Hz),7.02(2H,t,J=8.5Hz),7.47(2H,dd,J=5.7,8.1Hz),7.84(1H,d,J=14.5Hz),8.02-8.12(1H,m); 13 C-NMR (101MHz; CDCl3): δ18.2,25.4-26.6(m),29.1-29.8(m),34.5,34.7,43.4,51.2,55.6,111.3,115.3,115.6,125.3,130.2(d,J C-F =7.9Hz),130.3,135.9,159.3,161.9,162.5(d,J C-F =248Hz); for C 27 H 35 FN5[M+H] + Calculated HRMS (ESI + ) is 448.2876. The measured value is 448.2856.

[0298] (R)-4-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(1-cyclohexylethyl)pyrimidin-2-amine (35; ZH3-94)

[0299] (R)-Cyclohexylethylamine (56.0 μL, 0.437 mmol) was added to a solution of 14 (21.9 mg, 0.055 mmol) in THF (4 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 light yellow oil (24.1 mg, 99%), [α] D 24 +8.7(c 0.22,CH2Cl2). 1 H-NMR (400MHz; CDCl3): δ1.01-2.17(24H,m),3.98(1H,td,J=6.6,7.7Hz),4.59(1H,bs),6.31 (1H,d,J=5.0Hz),6.98(2H,t,J=8.6Hz),7.43(2H,s,J=5.6,8.1Hz),7.78(1H,s),8.04(1H,s); 13 C-NMR (101MHz; CDCl3): δ18.2,21.5,25.5-26.6(m),29.1,29.6,34.5,34.7,43.4,51.2,55.6,111.3,115.3,115.5,125.3,130.1(d,J C-F =8.0Hz),130.4(d,J C-F =2.8Hz),135.9,159.3,162.0,162.4(d,J C-F =248Hz); for C 27 H 35 FN5[M+H] + Calculated HRMS (ESI + ) is 448.2876. The measured value is 448.2864.

[0300] 4-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-phenylpropyl)pyrimidin-2-amine (36; ZH3-98)

[0301] 3-Amphetamine (60.0 μ L, 0.439 mmol) is added to a solution of 14 (22.0 mg, 0.055 mmol) in THF (5 mL), and the mixture is stirred for 3 days at 40 ° C. The mixture is concentrated under vacuum and purified by flash chromatography (EtOAc / petroleum spirit 50% to 70%) to obtain a light yellow oil (22.1 mg, 88%). 1H-NMR (500MHz; CDCl3): δ1.22-1.34(3H,m),1.60-1.73(3H,m),1.86-1.89(2H,m),2.0 1(2H,dt,J=7.4,15Hz),2.16(2H,d,J=11Hz),2.76(2H,t,J=7.7Hz),3.50(2H,q,J=6.6 Hz),4.57(1H,s),5.49(1H,s),6.41(1H,d,J=5.0Hz),7.00(2H,t,J=8.6Hz),7.21(3H, t,J=7.9Hz),7.27-7.31(2H,m),7.47(2H,dd,J=5.6,8.2Hz),7.77(1H,s),8.14(1H,s); 13 C-NMR (126MHz; CDCl3): δ25.7,26.2,31.6,33.6,34.9,41.5,55.9,112.1,115.6,115.7,125.5,126.4,126.4,128.7,128.8,130.4(d,J C-F =8.0Hz),130.9(d,J C-F =2.5Hz),136.1,141.8,158.2,159.4,162.7,162.7(d,J C-F =247Hz).

[0302] With the above R 4 =cyclohexyl compounds can be prepared as described in the following exemplary synthesis wherein R 4 =2,2,2-trifluoroethyl compound.

[0303] 1-(2-Methylthio)pyrimidin-4-yl)-N-(2,2,2-trifluoroethyl)methanimine

[0304] 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.

[0305] 4-(4-(4-fluorophenyl)-1-(2,2,2-trifluoroethyl)-1H-imidazol-5-yl)-2-(methylthio)pyrimidine

[0306] A mixture of α-(p-toluenesulfonyl)-4-fluorobenzyl isocyanide (3.33 g, 11.5 mmol), 1-(2-(methylthio)pyrimidin-4-yl)-N-(2,2,2-trifluoroethyl)formaniline (2.26 g, 9.60 mmol) and 20% aqueous KCO (8.00 mL, 11.5 mmol) in CHCl (20 mL) was stirred at room temperature for 5 days. The reaction mixture was diluted with CHCl, washed with water, dried (MgSO), filtered and concentrated. Flash chromatography of the residue (EtOAc / petroleum spirit 10% to 50%) provided a mixture of inseparable products (3.04 g crude).

[0307] 4-(4-(4-fluorophenyl)-1-(2,2,2-trifluoroethyl)-1H-imidazol-5-yl)-2-(methylsulfonyl)pyrimidine

[0308] mCPBA (57-86%) (4.27 g, 24.7 mmol) was added portionwise 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 in vacuo. The residue was purified by flash chromatography (EtOAc / petroleum spirit 50%) and concentrated to provide 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).

[0309] 4-(4-(4-fluorophenyl)-1-(2,2,2-trifluoroethyl)-1H-imidazol-5-yl)-N-(3-phenylpropyl)pyrimidin-2-amine (123; ZH4-166)

[0310] 3-phenylpropylamine (30.0 μ L, 0.211mmol) is added to 4-(4-(4-fluorophenyl)-1-(2,2,2-trifluoroethyl)-1H-imidazoles-5-yl)-2-(methylsulfonyl) pyrimidine (21.1mg, 0.053mmol) in THF (5mL) mixture, and the mixture is stirred at 40 ℃ for 72 hours.Mixture is concentrated under vacuum and by flash chromatography (EtOAc / petroleum spirit 20%) purification of compound to obtain light yellow oil (11.0mg, 46%). 1 H-NMR (400MHz; CDCl3): δ2.00(2H,m),2.75(2H,t,J=7.5Hz),3.48(2H,q,J=6.7Hz),5.12(2H,q,J=8.6Hz),5.24(1H,bs),6.41(1H,d,J=5.1Hz ),7.04(2H,t,J=8.6Hz),7.22(3H,d,J=6.0Hz),7.29(2H,dd,J=7.4,14.4Hz),7.50(2H,dd,J=5.5,8.5Hz),7.68(1H,s),8.13(1H,d,J=4.6Hz); 13 C-NMR (101MHz; CDCl3): δ31.3,33.4,41.2,46.7(q,J C-F =35.6Hz),111.1,115.5,115.8,124.5,125.1,126.2,128.6,130.1(d,J C-F =2.7Hz),130.5(d,J C-F =8.3Hz),140.1,141.5,143.3,157.6,158.7,162.3,162.8(d,J C-F =248Hz). 24 H 22 HRMS (ESI) calculated for F4N5 (M+H) + ) is 456.1811. The measured value is 456.1808.

[0311] Other compounds described herein can be prepared by methods analogous to those described above.

[0312] The following implementations are also described here:

[0313] 1. A compound of formula (II) or a salt, solvate, N-oxide, tautomer, stereoisomer, polymorph and / or prodrug thereof:

[0314]

[0315] in:

[0316] R 1 and R 2 Each independently selected from H, C 1-3 Alkyl C 6-12 Aryl, C 1-3 Alkyl C 5-11 Heteroaryl, C 1-3 Alkyl C 3-6 Cycloalkyl and C 1-3 Alkyl C 3-6 A group consisting of heterocyclic groups;

[0317] R 3 Selected from the group consisting of H, F, Cl and CH3;

[0318] R 4 Selected from C 0-3 Alkyl C 3-12 Cycloalkyl and C 1-12 A group consisting of alkyl groups;

[0319] Where R 1 , R 2 , R 3 and R 4 Each of is optionally substituted.

[0320] 2. The compound according to Embodiment 1, wherein the compound is not selected from the list of compounds in FIG. 8 .

[0321] 3. The compound according to embodiment 1, wherein R 1 C 1-3 Alkyl C 6-12 Aryl.

[0322] 4. The compound according to embodiment 3, wherein R 1 C 1-2 Alkyl C 6-12 Aryl.

[0323] 5. The compound according to embodiment 3 or embodiment 4, wherein C 6-12 The aryl group consists of two ring systems.

[0324] 6. The compound according to embodiment 1, wherein R 1 C 1-3 Alkyl C 5-11 Heteroaryl.

[0325] 7. The compound according to embodiment 6, wherein R 1 C 1-2 Alkyl C 5-11 Heteroaryl.

[0326] 8. A compound according to Embodiment 6 or Embodiment 7, wherein C 5-11 Heteroaryl groups consist of two ring systems.

[0327] 9. The compound according to embodiment 6 or embodiment 7, wherein C 5-11 The heteroatom of the heteroaryl group is located relative to the C 1-3 The ortho or para position of the alkyl group.

[0328] 10. A compound according to any one of embodiments 6 to 9, wherein C 5-11 Heteroaryl is a nitrogen-containing heteroaryl.

[0329] 11. The compound according to embodiment 1, wherein R 1 C 1-3 Alkyl C 3-6 Cycloalkyl.

[0330] 12. The compound according to embodiment 11, wherein R 1 C 2-3 Alkyl C 3-6 Cycloalkyl.

[0331] 13. The compound according to embodiment 11 or embodiment 12, wherein R 1 was replaced.

[0332] 14. The compound according to embodiment 13, wherein R 1 C 1-3 The alkyl group is substituted.

[0333] 15. A compound according to embodiment 13 or embodiment 14, wherein the substituent is C 1-3 alkyl.

[0334] 16. The compound according to embodiment 1, wherein R 1 C 1-3 Alkyl C 3-6 Heterocyclic group.

[0335] 17. The compound according to embodiment 16, wherein R 1 C 1-2 Alkyl C 3-6 Heterocyclic group.

[0336] 18. The compound according to embodiment 16 or embodiment 17, wherein C 3-6 The heterocyclic group is an oxygen-containing heterocyclic group.

[0337] 19. A compound according to any one of the preceding embodiments, wherein R 2 It's H.

[0338] 20. A compound according to any one of the preceding embodiments, wherein R 3 It is CH3.

[0339] 21. A compound according to any one of embodiments 1 to 19, wherein R 3 It is F or Cl.

[0340] 22. A compound according to any one of the preceding embodiments, wherein R 4 It is C 0-3 Alkyl C 3-12 Cycloalkyl.

[0341] 23. The compound according to embodiment 22, wherein R 4 C1 alkyl 3-12 Cycloalkyl.

[0342] 24. The compound according to embodiment 22, wherein R 4 C 3-12 Cycloalkyl.

[0343] 25. A compound according to any one of embodiments 22 to 24, wherein C 3-12 The cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

[0344] 26. A compound according to any one of embodiments 22 to 25, wherein R 4 was replaced.

[0345] 27. The compound according to embodiment 26, wherein the C 3-12 The cycloalkyl group is substituted.

[0346] 28. A compound according to embodiment 26 or embodiment 27, wherein the substituent is selected from one or more C 1-6 An alkyl group, one or more halo groups and one or more OH groups.

[0347] 29. A compound according to any one of embodiments 1 to 21, wherein R 4 C 1-12 alkyl.

[0348] 30. The compound according to embodiment 29, wherein R 4 It is methyl, ethyl, propyl or butyl.

[0349] 31. A compound according to embodiment 29 or embodiment 30, wherein R 4 It is a branched chain alkyl.

[0350] 32. A compound according to any one of embodiments 29 to 31, wherein R4 was replaced.

[0351] 33. A compound according to embodiment 32, wherein the substituents are selected from one or more OH groups and / or one or more halo groups.

[0352] 34. 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 (II) according to any one of Embodiments 1 to 33, thereby treating or preventing the respiratory disease in the subject.

[0353] 35. A compound of formula (II) according to any one of embodiments 1 to 33 for use in treating or preventing a respiratory disease in a subject.

[0354] 36. A composition comprising a compound of formula (II) according to any one of embodiments 1 to 33 and a pharmaceutically acceptable excipient.

[0355] 37. Use of a compound according to any one of embodiments 1 to 33 or a composition according to embodiment 36 in 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 thereof: in: R 1 It is -C1 alkyl C 3-6 Cycloalkyl; R 2 It is H; R 3 Selected from -F or -Cl; R 4 Selected from -C6 cycloalkyl or -C 1-6 alkyl; Where R 1 and R 4 Each of is optionally substituted with a halo group.

2. The compound or salt thereof according to claim 1, wherein R 1 Selected from the following groups: in, Each R 5 is selected from halogenated groups; n is selected from 0, 1, 2 or 3.

3. The compound or salt thereof according to claim 2, wherein n is 0, 1 or 2.

4. The compound or salt thereof according to claim 2, wherein R 1 It's G4.

5. The compound or salt thereof according to claim 2, wherein R 1 It's G3.

6. The compound or salt thereof according to claim 1, wherein R 1 Substituted with a halo group.

7. The compound or salt thereof according to claim 1, wherein R 3 It's F.

8. The compound or salt thereof according to claim 1, wherein R 4 For -C 1-6 alkyl.

9. The compound or salt thereof according to claim 1, wherein R 4 For -C 1-3 alkyl.

10. The compound or salt thereof according to claim 8, wherein R 4 is -methyl, -ethyl, -propyl or -butyl.

11. The compound or salt thereof according to claim 8, wherein R 4 Substituted with a halo group. 12 . The compound or a salt thereof according to claim 1 , wherein the halo group is -F.

13. A compound selected from the group consisting of:

14. The compound according to claim 13, or a pharmaceutically acceptable salt thereof, wherein the compound is:

15. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 14, and a pharmaceutically acceptable excipient.

16. Use of a compound or a salt thereof according to any one of claims 1 to 14 in the preparation of a medicament for treating or preventing a respiratory disease in a subject.

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