Substituted imidazo [1, 2-a] pyridine compounds and their use in treatment and prophylaxis of fibrosis

Abstract

Provided are a class of substituted imidazo [1, 2-a] pyridine compounds, pharmaceutical compositions containing the compounds, and uses of the compounds in the treatment and prevention of fibrosis.

Description

Technical Field

[0001] The present disclosure generally relates to a class of substituted imidazo[1,2-a]pyridine compounds, compositions containing the compounds, and therapeutic uses of the compounds in the treatment and prevention of fibrosis. Background Art

[0002] Fibrosis is the development of fibrous connective tissue as a reparative response to injury or damage. Pulmonary fibrosis refers to a series of conditions that lead to interstitial lung damage, followed by fibrosis and ultimately loss of lung elasticity. These conditions lead to symptoms such as persistent cough, chest pain, dyspnea and fatigue. The average life expectancy of patients with pulmonary fibrosis is 3 to 5 years after diagnosis. Therefore, early detection and treatment are key to slowing progression and extending life.

[0003] In 2019, reports of severe acute respiratory illness caused by severe acute respiratory syndrome coronavirus 2 emerged. The virus has been named "Covid-19". As of July 2020, more than 20 million people have been infected with Covid-19 worldwide, with more than 750,000 deaths.

[0004] Recent reports indicate that a wide range of fibrotic lung disease patterns have occurred in subjects diagnosed with Covid-19, ranging from pneumonia-associated fibrosis to severe acute lung injury, where a wide range of fibrotic changes are present. It has also been observed that in fatal cases of Covid-19, pulmonary fibrosis is often present at autopsy, with anecdotal reports of severe fibrotic organizing pneumonia. Previous coronavirus outbreaks, such as severe acute respiratory syndrome (SARS) in 2003 and Middle East respiratory syndrome (MERS), have been associated with severe post-viral fibrosis and physiological impairment. Given the massive scale of the current Covid-19 pandemic, the burden of fibrotic lung disease is likely to increase dramatically and remain a significant problem for many years to come. The risk of future viral outbreaks caused by other respiratory viruses, such as those of avian and swine origin, has the potential to further increase this burden.

[0005] Therefore, there is an urgent need for new therapeutic and preventive options for the treatment and prevention of fibrosis, especially fibrosis associated with Covid-19. Summary of the invention

[0006] In a first aspect, a method of treating fibrosis in a subject in need thereof is provided, the method comprising administering to the subject a therapeutically effective amount of a compound having the following formula (I) or a pharmaceutically acceptable salt or prodrug thereof:

[0007]

[0008] in:

[0009] R1 is selected from: C 6-10 aryl, heteroaryl having 5 to 10 ring atoms wherein one or more ring atoms are selected from nitrogen, sulfur and oxygen, C 3-10 Cycloalkyl and heterocyclyl having 5 to 10 ring atoms wherein one or more ring atoms are selected from nitrogen, sulfur and oxygen, each of which is optionally substituted by one or more of the following groups: C 1-6 Alkoxy, C 1-6 Alkyl, CN, halogen and C 3-10 Cycloalkyl;

[0010] R2 is selected from:

[0011] (i)C 6-10 aryl, heteroaryl with 5 to 10 ring atoms wherein one or more ring atoms are selected from nitrogen, sulfur and oxygen, and heterocyclyl with 5 to 10 ring atoms wherein one or more ring atoms are selected from nitrogen, sulfur and oxygen, each of which is optionally substituted by one or more of the following groups: NR5R6, C 1-6 Alkyl, C 1-6 Alkoxy and halogen; and

[0012] (ii) -XY,

[0013] wherein X is selected from: a heterocyclic group having 5 to 10 ring atoms wherein one or more ring atoms are selected from nitrogen, sulfur and oxygen, C 6-10 aryl and heteroaryl having 5 to 10 ring atoms wherein one or more ring atoms are selected from nitrogen, sulfur and oxygen; and Y is selected from: C 6-10 aryl and heteroaryl having 5 to 10 ring atoms wherein one or more ring atoms are selected from nitrogen, sulfur and oxygen, and wherein the C of Y 6-10 Aryl and heteroaryl are optionally substituted by one or more of the following groups: NR5R6, C 1-6 Alkyl, C 1-6 Alkoxy and halogen;

[0014] R3 is selected from: halogen, C 1-6 Alkoxy, OH, CN, NO2, -OC(O)R4, -C(O)R4, -C(O)NR5R6, -C(O)OR4, -OS(O)2R4, NR5R6, SR4, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 6-10 aryl and heteroaryl having 5 to 10 ring atoms wherein one or more ring atoms are selected from nitrogen, sulfur and oxygen;

[0015] R4 is selected from H and C 1-6alkyl;

[0016] R5 and R6 are independently selected from H and C 1-6 alkyl;

[0017] n is 1 or 2; and

[0018] m is an integer between 0 and 4.

[0019] The fibrosis may be pulmonary fibrosis. In one embodiment, the fibrosis is idiopathic pulmonary fibrosis.

[0020] The method can reduce fibrotic damage.

[0021] The fibrosis may be caused by, associated with, or otherwise related to a coronavirus infection in the subject.

[0022] The subject may have a coronavirus infection, or the subject may have recovered from a coronavirus infection.

[0023] The coronavirus may be severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), such as Covid-19.

[0024] The compounds of formula (I) may be administered together with one or more anti-inflammatory compounds.

[0025] The compounds of formula (I) may be administered together with one or more antiviral compounds.

[0026] In a second aspect, the present invention provides a method for preventing or minimizing fibrosis in a subject, wherein the subject is infected with a coronavirus or is at risk of becoming infected with a coronavirus, the method comprising administering to the subject an effective amount of a compound of formula (I) as defined in the first aspect.

[0027] The subject may be suffering from pneumonia and / or acute respiratory distress syndrome (ARDS).

[0028] The compound of formula (I) may be administered within one week after the subject is diagnosed with the coronavirus.

[0029] The compound of formula (I) may be administered within one week after the onset of ARDS in the subject.

[0030] The coronavirus may be Covid-19.

[0031] The methods can prevent or minimize fibrotic damage.

[0032] The compounds of formula (I) may be administered together with one or more anti-inflammatory compounds.

[0033] The compounds of formula (I) may be administered together with one or more antiviral compounds.

[0034] In a third aspect, the present invention provides a method for preventing or minimizing lung injury or damage in a subject, wherein the subject is infected with a coronavirus or is at risk of becoming infected with a coronavirus, the method comprising administering to the subject an effective amount of a compound of formula (I) as defined in the first aspect.

[0035] The coronavirus may be Covid-19.

[0036] The lung injury or damage may be caused by, associated with, or otherwise related to fibrosis.

[0037] The compounds of formula (I) may be administered together with one or more anti-inflammatory compounds.

[0038] The compounds of formula (I) may be administered together with one or more antiviral compounds.

[0039] In a fourth aspect, the present invention provides a method for minimizing the severity of coronavirus infection in a subject, the method comprising administering to the subject an effective amount of a compound of formula (I) as defined in the first aspect.

[0040] The coronavirus may be Covid-19.

[0041] The compounds of formula (I) may be administered together with one or more anti-inflammatory compounds.

[0042] The compounds of formula (I) may be administered together with one or more antiviral compounds.

[0043] In a fifth aspect, a compound of formula (II) or a pharmaceutically acceptable salt or prodrug thereof is provided:

[0044]

[0045] in:

[0046] R7 is selected from: halogen, OC 1-6 Alkyl, OH, CN, NO2, -OC(O)R4, -C(O)R4, -C(O)NR5R6, -C(O)OR4, -OS(O)2R4, NR5R6, SR4, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 6-10aryl and heteroaryl having 5 to 10 ring atoms wherein one or more ring atoms are selected from nitrogen, sulfur and oxygen;

[0047] Z1 is a heterocyclyl group having 5 to 10 ring atoms wherein one or more ring atoms are selected from nitrogen, sulfur and oxygen;

[0048] Z2 is selected from: phenyl, heteroaryl with 5 to 10 ring atoms, wherein one or more ring atoms are selected from nitrogen, sulfur and oxygen, and heterocyclyl with 5 to 10 ring atoms, wherein one or more ring atoms are selected from nitrogen, sulfur and oxygen, each of which is optionally substituted by one or more of the following groups: NR5R6, C 1-6 Alkyl, OC 1-6 Alkyl and halogen;

[0049] p is 1 or 2; and

[0050] o is an integer between 0 and 4,

[0051] And wherein R4 to R6 are as defined in the first aspect.

[0052] In a sixth aspect, a pharmaceutical composition is provided, comprising a compound of formula (II) according to the fifth aspect and a pharmaceutically acceptable carrier, diluent or excipient.

[0053] In a seventh aspect, there is provided the use of a compound of formula (I) as defined in the first aspect for preparing a medicament for treating fibrosis.

[0054] In an eighth aspect, there is provided the use of a compound of formula (I) as defined in the first aspect for the preparation of a medicament for preventing or minimizing fibrosis in a subject, wherein the subject is infected with a coronavirus or is at risk of becoming infected with a coronavirus.

[0055] In a ninth aspect, there is provided the use of a compound of formula (I) as defined in the first aspect for the preparation of a medicament for preventing or minimizing lung injury or damage in a subject, wherein the subject is infected with a coronavirus or is at risk of becoming infected with a coronavirus.

[0056] In a tenth aspect, there is provided the use of a compound of formula (I) as defined in the first aspect for the preparation of a medicament for minimizing the severity of coronavirus infection.

[0057] In an eleventh aspect, there is provided a compound of formula (I) as defined in the first aspect for use in a method for treating fibrosis.

[0058] In a twelfth aspect, a compound of formula (I) as defined in the first aspect is provided for use in a method of preventing or minimizing fibrosis in a subject, wherein the subject is infected with a coronavirus or is at risk of becoming infected with a coronavirus.

[0059] In a thirteenth aspect, a compound of formula (I) as defined in the first aspect is provided for use in a method of preventing or minimizing lung injury or damage in a subject, wherein the subject is infected with a coronavirus or is at risk of becoming infected with a coronavirus.

[0060] In a fourteenth aspect, there is provided a compound of formula (I) as defined in the first aspect for use in a method for minimizing the severity of a coronavirus infection. DETAILED DESCRIPTION

[0061] definition

[0062] Below are some definitions that may be helpful in understanding the description of the present disclosure. They are intended as general definitions and should by no means limit the scope of the present disclosure to only these terms, but are provided for a better understanding of the following description.

[0063] Throughout this specification, unless the context requires otherwise, the word "comprise" or variations thereof, will be understood to imply the inclusion of a stated element, integer or step or group of elements, integers or steps but not the exclusion of any other element, integer or step or group of elements, integers or steps.

[0064] References without a specific number are used herein to refer to one or more than one (ie, at least one) of the referenced item. For example, "an element" means one element or more than one element.

[0065] In the context of this specification, the term "alkyl" means a straight or branched monovalent saturated hydrocarbon group having the stated number of carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, 1-propyl, isopropyl, 1-butyl, 2-butyl, isobutyl, tert-butyl, pentyl, 1,2-dimethylpropyl, 1,1-dimethylpropyl, pentyl, isopentyl, hexyl, 4-methylpentyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,2-dimethylbutyl and 1,3-dimethylbutyl, etc.

[0066] In the context of this specification, the term "alkenyl" means a straight or branched monovalent hydrocarbon radical having the recited number of carbon atoms and at least one carbon-carbon double bond, such as ethenyl, propenyl, 2-methyl-2-propenyl, butenyl, etc. The radical may contain multiple double bonds, and the geometry around each double bond is independently cis or trans, E or Z.

[0067] In the context of this specification, the term "alkynyl" means a straight or branched monovalent hydrocarbon radical having the stated number of carbon atoms and at least one carbon-carbon triple bond, for example ethynyl, propargyl, etc. The radical may contain multiple triple bonds.

[0068] In the context of this specification, the term "alkoxy" means O-alkyl, wherein alkyl is as defined herein. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, sec-butoxy and tert-butoxy.

[0069] In the context of this specification, the terms "halo" and "halogen" are used interchangeably and refer to fluorine, chlorine, bromine and iodine.

[0070] In the context of this specification, the term "aryl" means a monovalent aromatic hydrocarbon group having the stated number of ring carbon atoms. The aryl group may have a single ring or multiple rings. "Aryl" also includes a bicyclic group containing an aromatic ring fused to a saturated or partially unsaturated carbocyclic ring. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, phenanthrenyl, azulenyl, anthracenyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, etc.

[0071] In the context of this specification, the term "heteroaryl" refers to a monocyclic, bicyclic or tricyclic aromatic ring system having the recited total number of ring atoms, wherein the ring system contains at least one nitrogen, sulfur or oxygen atom, and the remaining ring atoms are carbon. Examples of heteroaryl include, but are not limited to, pyridyl, pyrrolyl, indolyl, quinolyl, furanyl, thienyl, Azolyl, thiazolyl, etc.

[0072] In the context of this specification, the term "heterocyclyl" refers to a non-aromatic, saturated or partially unsaturated ring system having the recited total number of ring atoms, wherein the ring system contains at least one nitrogen, sulfur or oxygen atom, and the remaining ring atoms are carbon. The term also includes substituents in which the heterocyclyl is fused to an aromatic ring. Examples of heterocyclyl include, but are not limited to, pyrrolidinyl, piperazinyl, 2,3-dihydroindolinyl, piperidinyl, azetidinyl, pyrazolinyl, morpholinyl, dihydroquinolinyl, and the like.

[0073] In the context of this specification, the term "cycloalkyl" means a monovalent saturated carbocyclic ring having the stated number of ring carbon atoms. The ring may be monocyclic or bicyclic. Bicyclic carbocyclic rings may be arranged, for example, as bicyclo[4,5], [5,5], [5,6] or [6,6] or as a bridged system such as bicyclo[2.2.1]heptane. Examples of carbocyclic radicals include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, cyclodecyl, etc.

[0074] In the context of the present specification, the term "prodrug" means a compound that can be converted into a compound of formula (I) or (II) in vivo by metabolic means (for example by hydrolysis, reduction or oxidation).

[0075] In the context of this specification, the term "effective amount" includes a non-toxic amount of the active compound but sufficient to provide the stated effect. Those skilled in the art will appreciate that the exact amount of the compound required will vary according to many factors, so it is not possible to specify an exact "effective amount". However, for any given situation, a suitable "effective amount" can be determined by a person of ordinary skill in the art.

[0076] In the context of this specification, the term "therapeutically effective amount" includes a non-toxic amount of an active compound that is sufficient to provide the desired therapeutic effect. Those skilled in the art will appreciate that the exact amount of the compound required will vary according to many factors, and therefore it is not possible to specify an exact "therapeutically effective amount". However, for any particular case, a suitable "therapeutically effective amount" can be determined by a person of ordinary skill in the art.

[0077] In the context of this specification, the terms "treatment" and "prevention" refer to any and all uses of remedying a disease state or its symptoms, preventing the establishment of a disease state, or otherwise preventing, hindering, delaying or reversing the progression of a disease or other adverse symptoms in any way. Therefore, the terms "treatment" and "prevention" and the like should be considered in their broadest context. For example, treatment does not necessarily imply that the subject is treated to complete recovery.

[0078] In the context of this specification, the term "subject" includes humans and non-human animals. Therefore, in addition to being useful for treating humans, the compounds of the present disclosure can also be used to treat non-human animals, such as mammals, such as companion animals and farm animals. Non-limiting examples of companion animals and farm animals include dogs, cats, horses, cows, sheep and pigs. Preferably, the subject is a human.

[0079] In the context of this specification, the term "administering" and variations thereof include contacting, applying, delivering or providing a compound or composition to an organism by any appropriate means.

[0080] Detailed Description

[0081] A new class of substituted imidazo[1,2-a]pyridine compounds is described in detail, which show promise in treating and preventing fibrosis and related lung disorders associated with Covid-19.

[0082] In one aspect, a method of treating fibrosis in a subject in need thereof is provided, the method comprising administering to the subject a therapeutically effective amount of a compound having the following formula (I) or a pharmaceutically acceptable salt or prodrug thereof:

[0083]

[0084] in:

[0085] R1 is selected from: C 6-10 aryl, heteroaryl having 5 to 10 ring atoms wherein one or more ring atoms are selected from nitrogen, sulfur and oxygen, C 3-10 Cycloalkyl and heterocyclyl having 5 to 10 ring atoms wherein one or more ring atoms are selected from nitrogen, sulfur and oxygen, each of which is optionally substituted by one or more of the following groups: C 1-6 Alkoxy, C 1-6 Alkyl, CN, halogen and C 3-10 Cycloalkyl;

[0086] R2 is selected from:

[0087] (i)C 6-10 aryl, heteroaryl with 5 to 10 ring atoms wherein one or more ring atoms are selected from nitrogen, sulfur and oxygen, and heterocyclyl with 5 to 10 ring atoms wherein one or more ring atoms are selected from nitrogen, sulfur and oxygen, each of which is optionally substituted by one or more of the following groups: NR5R6, C 1-6 Alkyl, C 1-6 Alkoxy and halogen; and

[0088] (ii) -XY,

[0089] wherein X is selected from: a heterocyclic group having 5 to 10 ring atoms wherein one or more ring atoms are selected from nitrogen, sulfur and oxygen, C 6-10 aryl and heteroaryl having 5 to 10 ring atoms wherein one or more ring atoms are selected from nitrogen, sulfur and oxygen; and Y is selected from: C 6-10 aryl and heteroaryl having 5 to 10 ring atoms wherein one or more ring atoms are selected from nitrogen, sulfur and oxygen, and wherein the C of Y 6-10 Aryl and heteroaryl are optionally substituted by one or more of the following groups: NR5R6, C 1-6 Alkyl, C 1-6 Alkoxy and halogen;

[0090] R3 is selected from: halogen, C 1-6 Alkoxy, OH, CN, NO2, -OC(O)R4, -C(O)R4, -C(O)NR5R6, -C(O)OR4, -OS(O)2R4, NR5R6, SR4, C 1-10 Alkyl, C2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 6-10 aryl and heteroaryl having 5 to 10 ring atoms wherein one or more ring atoms are selected from nitrogen, sulfur and oxygen;

[0091] R4 is selected from H and C 1-6 alkyl;

[0092] R5 and R6 are independently selected from H and C 1-6 alkyl;

[0093] n is 1 or 2; and

[0094] m is an integer between 0 and 4.

[0095] In another embodiment, R1 is selected from: C 6-10 aryl, heteroaryl having 5 to 10 ring atoms wherein one or more ring atoms are selected from nitrogen, sulfur and oxygen, C 3-10 Cycloalkyl and heterocyclyl having 5 to 10 ring atoms wherein one or more ring atoms are selected from nitrogen, sulfur and oxygen, each of which is optionally substituted by one or more of the following groups: C 1-4 Alkoxy, C 1-4 Alkyl, CN, halogen and C 3-6 Cycloalkyl.

[0096] In another embodiment, R1 is selected from: C 6-10 aryl, heteroaryl having 5 to 10 ring atoms wherein one or more ring atoms are selected from nitrogen, sulfur and oxygen, C 3-6 Cycloalkyl and heterocyclyl having 5 to 10 ring atoms wherein one or more ring atoms are selected from nitrogen, sulfur and oxygen, each of which is optionally substituted by one or more of the following groups: C 1-4 Alkoxy, C 1-4 Alkyl, halogen and C 3-6 Cycloalkyl.

[0097] In yet another embodiment, R1 is selected from: C 6-10 Aryl, heteroaryl having 5 to 10 ring atoms wherein one or more ring atoms are selected from nitrogen, sulfur and oxygen, and heterocyclyl having 5 to 10 ring atoms wherein one or more ring atoms are selected from nitrogen, sulfur and oxygen, each of which is optionally substituted by one or more of the following groups: C 1-4 Alkyl, halogen and C 3-6 Cycloalkyl.

[0098] In yet another embodiment, R1 is selected from: C 6-10Aryl, heteroaryl with 5 or 6 ring atoms wherein one or more ring atoms are selected from nitrogen, sulfur and oxygen, and heterocyclyl with 5 or 6 ring atoms wherein one or more ring atoms are selected from nitrogen, sulfur and oxygen, each of which is optionally substituted by one or more of the following groups: C 1-4 Alkyl, halogen and C 3-6 Cycloalkyl.

[0099] In another embodiment, R1 is selected from: phenyl, heteroaryl with 5 or 6 ring atoms wherein one or more ring atoms are selected from nitrogen, sulfur and oxygen, and heterocyclyl with 5 or 6 ring atoms wherein one or more ring atoms are selected from nitrogen, sulfur and oxygen, each of which is optionally substituted by one or more of the following groups: C 1-4 Alkyl, halogen and C 3-4 Cycloalkyl.

[0100] In yet another embodiment, R1 is selected from: phenyl, heteroaryl with 5 or 6 ring atoms wherein one or more ring atoms are selected from nitrogen, sulfur and oxygen, and heterocyclyl with 5 or 6 ring atoms wherein one or more ring atoms are selected from nitrogen, sulfur and oxygen, each of which is optionally substituted by one or more of the following groups: C 1-3 Alkyl, halogen and cyclopropyl.

[0101] In yet another embodiment, R1 is selected from: phenyl, heteroaryl with 5 or 6 ring atoms wherein 1 to 3 ring atoms are selected from nitrogen, sulfur and oxygen, and heterocyclyl with 5 or 6 ring atoms wherein 1 or 2 ring atoms are selected from nitrogen, sulfur and oxygen, each of which is optionally substituted by one or more of the following groups: C 1-3 Alkyl, halogen and cyclopropyl.

[0102] In another embodiment, R1 is selected from: phenyl, heteroaryl with 5 or 6 ring atoms wherein 1 to 3 ring atoms are selected from nitrogen, sulfur and oxygen, and heterocyclyl with 5 or 6 ring atoms wherein 1 or 2 ring atoms are selected from nitrogen and oxygen, each of which is optionally substituted by one or more of the following groups: C 1-3 Alkyl, halogen and cyclopropyl.

[0103] In another embodiment, R1 is selected from: phenyl, heteroaryl with 5 or 6 ring atoms wherein 1 to 3 ring atoms are selected from nitrogen, sulfur and oxygen, and heterocyclyl with 5 or 6 ring atoms wherein 1 or 2 ring atoms are selected from nitrogen and oxygen, each of which is optionally substituted by one or more of the following groups: methyl, chloro, fluoro and cyclopropyl.

[0104] In yet another embodiment, R1 is selected from: phenyl, heteroaryl with 5 or 6 ring atoms wherein 1 to 3 ring atoms are selected from nitrogen, sulfur and oxygen, and heterocyclyl with 6 ring atoms wherein 1 or 2 ring atoms are selected from nitrogen and oxygen, each of which is optionally substituted by one or both of the following groups: methyl, chloro, fluoro and cyclopropyl.

[0105] In another embodiment, R1 is selected from: phenyl, heteroaryl with 5 or 6 ring atoms wherein 1 to 3 ring atoms are selected from nitrogen, sulfur and oxygen, and heterocyclyl with 6 ring atoms wherein 1 or 2 ring atoms are selected from nitrogen and oxygen, each of which is optionally substituted by one of the following groups: methyl, chloro, fluoro and cyclopropyl.

[0106] In yet another embodiment, R1 is selected from:

[0107]

[0108] In one embodiment, R2 is selected from:

[0109] (i)C 6-10 aryl, heteroaryl with 5 to 10 ring atoms wherein one or more ring atoms is nitrogen, heterocyclyl with 5 to 10 ring atoms wherein one or more ring atoms is nitrogen or oxygen, each of which is optionally substituted by one or more of the following groups: NR5R6, C 1-6 Alkyl, C 1-6 Alkoxy and halogen; and

[0110] (ii) -XY,

[0111] wherein X is selected from: a heterocyclic group having 5 to 10 ring atoms in which one or more ring atoms are nitrogen or oxygen, C 6-10 aryl and heteroaryl having 5 to 10 ring atoms wherein one or more ring atoms are selected from nitrogen, sulfur and oxygen; and Y is selected from: C 6-10 aryl and heteroaryl having 5 to 10 ring atoms wherein one or more ring atoms is nitrogen and wherein the C 6-10 Aryl and heteroaryl are optionally substituted by one or more of the following groups: NR5R6, C 1-6 Alkyl, C 1-6 Alkoxy and halogen.

[0112] In another embodiment, R2 is selected from:

[0113] (i) phenyl, heteroaryl with 5 to 10 ring atoms wherein one or more ring atoms is nitrogen, heterocyclyl with 5 to 10 ring atoms wherein one or more ring atoms is nitrogen or oxygen, each of which is optionally substituted by one or more of the following groups: NR5R6, C 1-6 Alkyl, C1-6 Alkoxy and halogen; and

[0114] (ii) -XY,

[0115] wherein X is selected from the group consisting of: a heterocyclic group having 5 to 10 ring atoms, wherein one or more ring atoms are nitrogen, a phenyl group, and a heteroaryl group having 5 or 6 ring atoms, wherein one or more ring atoms are nitrogen; and Y is selected from the group consisting of: a phenyl group, and a heteroaryl group having 5 or 6 ring atoms, wherein one or more ring atoms are nitrogen, and wherein the phenyl and heteroaryl groups of Y are optionally substituted by one or more of the following groups: NR5R6, C 1-6 Alkyl, C 1-6 Alkoxy and halogen.

[0116] In another embodiment, R2 is selected from:

[0117] (i) heteroaryl with 5 to 10 ring atoms, wherein one or more ring atoms are nitrogen, heterocyclyl with 5 to 10 ring atoms, wherein one or more ring atoms are nitrogen or oxygen, each of which is optionally substituted by one or more of the following groups: NR5R6, C 1-6 Alkyl, C 1-6 Alkoxy and halogen; and

[0118] (ii) -XY,

[0119] wherein X is selected from: a heterocyclic group having 5 to 10 ring atoms, wherein one or more ring atoms are nitrogen, a phenyl group; and Y is selected from: a phenyl group and a heteroaryl group having 5 or 6 ring atoms, wherein one or more ring atoms are nitrogen, and wherein the phenyl and heteroaryl groups of Y are optionally substituted by one or more of the following groups: NR5R6, C 1-6 Alkyl, C 1-6 Alkoxy and halogen.

[0120] In yet another embodiment, R2 is selected from:

[0121] (i) a heterocyclic group having 5 to 10 ring atoms in which one or more ring atoms are nitrogen or oxygen, each of which is optionally substituted by one or more of the following groups: NR5R6, C 1-6 Alkyl, C 1-6 Alkoxy and halogen; and

[0122] (ii) -XY,

[0123] wherein X is selected from: a heterocyclic group having 5 or 6 ring atoms in which one or more ring atoms are nitrogen; and Y is selected from: a phenyl group and a heteroaryl group having 5 or 6 ring atoms in which one or more ring atoms are nitrogen, and wherein the phenyl and heteroaryl groups of Y are optionally substituted by one or more of the following groups: NR5R6, C1-6 Alkyl, C 1-6 Alkoxy and halogen.

[0124] In yet another embodiment, R2 is selected from:

[0125] (i) a heterocyclic group having 5 to 10 ring atoms, wherein 1 to 4 ring atoms are nitrogen or oxygen, each of which is optionally substituted by one or more of the following groups: NR5R6, C 1-6 Alkyl, C 1-6 Alkoxy and halogen; and

[0126] (ii) -XY,

[0127] wherein X is selected from: a heterocyclic group having 5 or 6 ring atoms in which one or more ring atoms are nitrogen; and Y is selected from: a phenyl group and a heteroaryl group having 5 or 6 ring atoms in which one or more ring atoms are nitrogen, and wherein the phenyl and heteroaryl groups of Y are optionally substituted by one or more of the following groups: NH2, N(Me)2, C 1-6 Alkyl, methoxy, ethoxy and halogen.

[0128] In another embodiment, R2 is selected from:

[0129] (i) a heterocyclic group having 5 to 10 ring atoms in which 1 to 4 ring atoms are nitrogen or oxygen, each of which is optionally substituted by one or more of the following groups: NH2, NMe2, C 1-6 Alkyl, methoxy, ethoxy and halogen; and

[0130] (ii) -XY,

[0131] wherein X is selected from: a heterocyclic group having 5 or 6 ring atoms in which one or more ring atoms are nitrogen; and Y is selected from: a phenyl group and a heteroaryl group having 5 or 6 ring atoms in which one or more ring atoms are nitrogen, and wherein the phenyl group and the heteroaryl group of Y are optionally substituted by one or more of the following groups: C 1-6 Alkyl, methoxy, ethoxy and halogen.

[0132] In yet another embodiment, R2 is selected from:

[0133] (i) a heterocyclyl group having 5 to 10 ring atoms in which 1 to 4 ring atoms are nitrogen or oxygen, each of which is optionally substituted by one or more of the following groups: NH2, N(Me)2, methyl, methoxy and halogen; and

[0134] (ii) -XY,

[0135] wherein X is selected from: a heterocyclyl group having 5 or 6 ring atoms in which one or more ring atoms is nitrogen; and Y is selected from: a phenyl group and a heteroaryl group having 5 or 6 ring atoms in which one or more ring atoms is nitrogen, and wherein the phenyl and heteroaryl groups of Y are optionally substituted by one to three of the following groups: methyl, methoxy and halogen.

[0136] In yet another embodiment, R2 is selected from:

[0137] (i) a heterocyclic group having 5 to 10 ring atoms in which 1 to 4 ring atoms are nitrogen or oxygen, each of which is optionally substituted by one to three of the following groups: NH2, N(Me)2, methyl and methoxy, and

[0138] (ii) -XY,

[0139] wherein X is selected from: a heterocyclyl group having 5 or 6 ring atoms in which one or two ring atoms are nitrogen; and Y is selected from: a phenyl group and a heteroaryl group having 5 or 6 ring atoms in which 1 to 3 ring atoms are nitrogen, and wherein the phenyl and heteroaryl groups of Y are optionally substituted by one or both of the following groups: methyl, methoxy, fluorine and chlorine.

[0140] In yet another embodiment, R2 is selected from:

[0141] (i) a heterocyclic group having 5 to 10 ring atoms in which 1 to 4 ring atoms are nitrogen or oxygen, each of which is optionally substituted by one to three of the following groups: NH2, N(Me)2, methyl and methoxy, and

[0142] (ii) -XY,

[0143] wherein X is selected from: a heterocyclyl group having 6 ring atoms, one or two of which are nitrogen; and Y is selected from: a phenyl group and a heteroaryl group having 5 or 6 ring atoms, one or two of which are nitrogen, and wherein the phenyl and heteroaryl groups of Y are optionally substituted by one or both of the following groups: methyl, methoxy, fluorine and chlorine.

[0144] In yet another embodiment, R2 may be selected from:

[0145]

[0146] In one embodiment, R3 is selected from: halogen, C 1-6 Alkoxy, OH, CN, -OC(O)R4, -C(O)R4, -C(O)NR5R6, -C(O)OR4, NR5R6, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C6-10 Aryl and heteroaryl having 5 to 10 ring atoms wherein one or more ring atoms are selected from nitrogen, sulfur and oxygen.

[0147] In another embodiment, R3 is selected from: halogen, C 1-6 Alkoxy, OH, CN, -C(O)R4, -C(O)NR5R6, -C(O)OR4, NR5R6, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl and heteroaryl having 5 or 6 ring atoms wherein one or more ring atoms are selected from nitrogen, sulfur and oxygen.

[0148] In another embodiment, R3 is selected from: halogen, C 1-6 Alkoxy, OH, CN, NR5R6, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 6-10 Aryl and heteroaryl having 5 or 6 ring atoms wherein one or more ring atoms are selected from nitrogen, sulfur and oxygen.

[0149] In yet another embodiment, R3 is selected from: halogen, C 1-4 Alkoxy, OH, CN, NR5R6, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 6-10 Aryl and heteroaryl having 5 or 6 ring atoms wherein one or more ring atoms are selected from nitrogen, sulfur and oxygen.

[0150] In yet another embodiment, R3 is selected from: halogen, C 1-4 Alkoxy, OH, CN, NR5R6, C 1-4 Alkyl, C 3-6 Cycloalkyl, phenyl and heteroaryl having 5 or 6 ring atoms wherein one or more ring atoms are selected from nitrogen, sulfur and oxygen.

[0151] In yet another embodiment, R3 is selected from: halogen, C 1-4 Alkoxy, OH, CN, C 1-4 Alkyl, phenyl and heteroaryl having 5 or 6 ring atoms wherein one or more ring atoms are selected from nitrogen, sulfur and oxygen.

[0152] In another embodiment, R3 is selected from: halogen, C 1-4 Alkoxy, OH, CN, C 1-4 Alkyl and phenyl.

[0153] In yet another embodiment, R3 is selected from: halogen, C 1-4 Alkoxy, CN and C 1-4 alkyl.

[0154] In yet another embodiment, R3 is selected from: halogen, C 1-4 Alkoxy, CN, C 1-4 Alkyl and phenyl.

[0155] In yet another embodiment, R3 is selected from the group consisting of: chloro, fluoro, methoxy, ethoxy, and CN.

[0156] In another embodiment, R3 is selected from the group consisting of: fluoro, methoxy, ethoxy, and CN.

[0157] In another embodiment, R3 is selected from the group consisting of: fluoro, methoxy, and CN.

[0158] In one embodiment, R4 is H or CH3.

[0159] In one embodiment, R5 and R6 are independently selected from H and CH3.

[0160] In one embodiment, n is 1.

[0161] In one embodiment, m is 0, 1 or 2. In another embodiment, m is 0 or 1.

[0162] In another aspect, a compound of formula (II) or a pharmaceutically acceptable salt or prodrug thereof is provided:

[0163]

[0164] in:

[0165] R7 is selected from: halogen, OC 1-6 Alkyl, OH, CN, NO2, -OC(O)R4, -C(O)R4, -C(O)NR5R6, -C(O)OR4, -OS(O)2R4, NR5R6, SR4, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 6-10 aryl and heteroaryl having 5 to 10 ring atoms wherein one or more ring atoms are selected from nitrogen, sulfur and oxygen;

[0166] Z1 is a heterocyclyl group having 5 to 10 ring atoms wherein one or more ring atoms are selected from nitrogen, sulfur and oxygen;

[0167] Z2 is selected from: phenyl, heteroaryl with 5 to 10 ring atoms, wherein one or more ring atoms are selected from nitrogen, sulfur and oxygen, and heterocyclyl with 5 to 10 ring atoms, wherein one or more ring atoms are selected from nitrogen, sulfur and oxygen, each of which is optionally substituted by one or more of the following groups: NR5R6, C 1-6 Alkyl, OC 1-6 Alkyl and halogen;

[0168] p is 1 or 2; and

[0169] o is an integer between 0 and 4,

[0170] And wherein R4 to R6 are as defined in the first aspect.

[0171] In some embodiments, R7 is selected from the group consisting of: halogen, methoxy, OH, CN, NR5R6, and methyl.

[0172] In one embodiment, Z1 is a heterocyclyl having 5 or 6 ring atoms wherein one or more ring atoms is nitrogen, oxygen or sulfur.

[0173] In another embodiment, Z1 is a heterocyclyl having 5 or 6 ring atoms wherein one or two of the ring atoms are nitrogen, oxygen or sulfur.

[0174] In another embodiment, Z1 is a heterocyclyl having 5 or 6 ring atoms in which one or two ring atoms are nitrogen.

[0175] In another embodiment, Z1 is a heterocyclyl having 6 ring atoms wherein one or two ring atoms are nitrogen.

[0176] In yet another embodiment, Z1 is:

[0177]

[0178] In another embodiment, Z2 is selected from: phenyl and heteroaryl with 5 or 6 ring atoms in which 1 to 3 ring atoms are nitrogen, and wherein the phenyl and heteroaryl are optionally substituted with one to three of the following groups: NH2, N(Me)2, methyl, methoxy and halogen.

[0179] In yet another embodiment, Z2 is selected from: phenyl and heteroaryl with 5 or 6 ring atoms in which 1 to 3 ring atoms are nitrogen, and wherein the phenyl and heteroaryl are optionally substituted with one or both of the following groups: NH2, N(Me)2, methyl, methoxy, fluoro and chloro.

[0180] In yet another embodiment, Z2 is selected from: phenyl and heteroaryl with 5 or 6 ring atoms in which one or two ring atoms are nitrogen, and wherein the phenyl and heteroaryl are optionally substituted with one or both of the following groups: NH2, N(Me)2, methyl, methoxy, fluoro and chloro.

[0181] In one embodiment, o is 0 or 1. In another embodiment, o is 0.

[0182] In one embodiment, p is 1.

[0183] Exemplary compounds according to formula (I) and (II) include:

[0184]

[0185]

[0186]

[0187]

[0188]

[0189]

[0190]

[0191]

[0192]

[0193]

[0194]

[0195]

[0196]

[0197]

[0198] In one embodiment, the compound of formula (I) is selected from any one or more of the above compounds 1 to 59.

[0199] In another embodiment, the compound of formula (II) is selected from any one or more of the above compounds 40 to 58.

[0200] The compound of formula (II) may also be used in any one of the first to fourth and seventh to tenth aspects.

[0201] The compounds of formula (I) and (II) include a carbon-carbon double bond connecting the carbonyl group to the imidazo[1,2-a]pyridine ring. The present disclosure extends to all geometric isomers, i.e. both cis and trans isomers. The compounds of formula (I) and (II) may exist as tautomers. The present disclosure extends to all tautomers.

[0202] Compounds of formula (I) and (II) also include hydrates and solvates. Solvates are complexes formed by the association of solvent molecules with compounds of formula (I) or (II). Where compounds of formula (I) and (II) are solids, those skilled in the art will appreciate that such compounds may exist in different crystalline or polymorphic forms, all of which are intended to be within the scope of the present disclosure.

[0203] The compounds of formula (I) and (II) can take the form of pharmaceutically acceptable salts. Such salts are well known to those skilled in the art. SMBerge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19. Pharmaceutically acceptable salts can be prepared in situ during the final separation and purification of the compounds of formula (I) and (II), or prepared separately by reacting the free base compound with a suitable organic acid. Suitable pharmaceutically acceptable acid addition salts of the compounds of the present disclosure can be prepared from inorganic or organic acids. Examples of such inorganic acids are hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, sulfuric acid and phosphoric acid. Suitable organic acid can be selected from aliphatic, alicyclic, aromatic, heterocyclic carboxylic acid and sulfonic acid classes of organic acid, examples of which are formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, fumaric acid, maleic acid, pyruvic acid, alkylsulfonic acid, arylsulfonic acid, aspartic acid, glutamic acid, benzoic acid, anthranilic acid, methanesulfonic acid, salicylic acid, p-hydroxybenzoic acid, phenylacetic acid, pamoic acid, pantothenic acid, sulfanilic acid, cyclohexylaminosulfonic acid, stearic acid, alginic acid, beta-hydroxybutyric acid and galacturonic acid. Suitable pharmaceutically acceptable base addition salts of compounds of the present disclosure include metal salts made from lithium, sodium, potassium, magnesium, calcium, aluminum and zinc, and organic salts made from organic bases such as choline, diethanolamine and morpholine. Alternatively, organic salts made from N,N'-dibenzhydrylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), procaine, ammonium salts, quaternary ammonium salts such as tetramethylammonium salts, amino acid addition salts such as glycine and arginine salts.

[0204] The compounds of formula (I) and (II) also extend to include all derivatives such as prodrugs having a physiologically cleavable leaving group which can be cleaved in vivo to provide the compounds of formula (I) and (II).

[0205] Compounds of formula (I) can be synthesized as described in Scheme 1 below.

[0206]

[0207] Reaction Scheme 1: Synthesis of compounds of formula (I)

[0208] Imidazolo[1,2-a]pyridine derivatives (III) wherein Q is a leaving group such as a halide can be reacted with an α,β-unsaturated ketone (IV) to give compounds of formula (I). With this synthetic procedure and common knowledge, one skilled in the art will be able to easily prepare all compounds covered by formula (I) and (II).

[0209] Compounds of formula (I) and (II) can be used to treat fibrosis. Fibrosis may occur in many tissues in the body, usually as a result of inflammation or injury, and the present disclosure contemplates the treatment of any and all types of fibrosis occurring in any part of the body. In some embodiments, the fibrosis occurs in the lungs, such as pulmonary fibrosis (including idiopathic pulmonary fibrosis), cystic fibrosis, or fibrosis caused by radiation (e.g., radiotherapy). In other embodiments, the fibrosis may be renal fibrosis, cardiac fibrosis, liver fibrosis, such as cirrhosis or bridging fibrosis. In optional embodiments, the fibrosis may be arthrofibrosis, nephrogenic systemic fibrosis, retroperitoneal fibrosis, scleroderma / systemic sclerosis, myelofibrosis, or mediastinal fibrosis. In other embodiments, the fibrosis may be associated with arterial stiffness, Crohn's disease, Dupuytren's contracture, keloids, Peyronie's disease, or adhesive capsulitis.

[0210] The compounds of formula (I) and (II) can also be used to treat fibrosis associated with coronavirus. Coronavirus is a group of related RNA viruses that cause diseases and various complications in mammals and birds. In some embodiments, the coronavirus is MERS coronavirus, SARS coronavirus or SARS coronavirus-2 (commonly referred to as "Covid-19"). It has been reported that in subjects diagnosed with Covid-19, pulmonary fibrosis diseases frequently occur, ranging from fibrosis associated with pneumonia to severe acute lung injury in which there are extensive fibrotic changes. Therefore, in some embodiments, the fibrosis is caused by, associated with, or otherwise related to coronavirus infection in the subject. In this case, the term "associated with or otherwise related to" means that pulmonary fibrosis or its symptoms have at least some direct or indirect connection with coronavirus infection in the subject.

[0211] In subjects recovering from Covid-19, progressive fibrotic irreversible interstitial lung disease (characterized by decreased lung function, increased fibrosis on CT, worsening symptoms and quality of life, and early death) may occur with varying frequencies. In this regard, eliminating the cause of lung damage does not exclude the development of progressive fibrotic irreversible interstitial lung disease. In addition, in elderly patient populations with COVID-19 (many of whom also have pre-existing lung conditions), non-progressive fibrosis may also lead to considerable morbidity and mortality, even if the residual degree is relatively small. Therefore, in some embodiments, the subject may have a coronavirus infection, or the subject may have recovered from a coronavirus infection, but may still suffer from pulmonary fibrosis or fibrotic damage or its symptoms, despite no longer having the virus. In the treatment of fibrosis, compounds of formula (I) or (II) can be used to reduce fibrotic damage in the subject.

[0212] In some embodiments, the compound of formula (I) or (II) can be used together with one or more anti-inflammatory compounds. Anti-inflammatory compounds are well known to those skilled in the art. Suitable anti-inflammatory compounds include steroids and non-steroidal compounds. Suitable non-steroidal anti-inflammatory compounds include but are not limited to indomethacin, diclofenac, aceclofenac, sulindac, phenylbutazone, valdecoxib, rofecoxib, celecoxib, tenoxicam, piroxicam, ketoprofen, naproxen, ibuprofen, flurbiprofen and nabumetone. Suitable steroidal anti-inflammatory compounds include but are not limited to hydrocortisone, cortisone, tixocortolone pivalate, prednisolone, methylprednisolone, prednisone, budesonide, desonide, amcinonide, fluocinolone acetate, fluocinocide, halcinonide, triamcinolone acetate, beclomethasone, dexamethasone, fluocortolone, halometasone and mometasone.

[0213] In some embodiments, the compound of formula (I) or (II) can be administered with one or more antiviral compounds. Antiviral compounds are well known to those skilled in the art. Suitable antiviral compounds include, but are not limited to, remdesivir, acyclovir, boceprevir, darunavir, entecavir, nelfinavir, penciclovir, praconaril, rilpivirine, simeprevir, etc.

[0214] In addition to treatment, the compound of formula (I) or (II) can be used to prevent or minimize fibrosis, lung injury and / or damage in subjects infected with coronavirus or subjects at risk of becoming infected by coronavirus. Such uses can substantially reduce the burden of pulmonary fibrosis by preventing the onset of pulmonary fibrosis or otherwise minimizing its harmful effects on the lungs. In some embodiments, the compound of formula (I) or (II) is administered within one week after the subject is diagnosed with coronavirus. In other embodiments, the compound of formula (I) or (II) can be administered within one week after the onset of ARDS in the subject. Administration within one week after the onset of ARDS may optimize effectiveness. In preventing or minimizing fibrosis, the compound of formula (I) or (II) can be used to prevent or minimize fibrotic damage in the subject.

[0215] Due to their anti-fibrotic effects, compounds of Formula (I) or (II) may also be used to minimize the severity of coronavirus infection by treating, preventing or otherwise reducing the severity of lung injury or damage.

[0216] Those skilled in the art will recognize that the compounds and pharmaceutical compositions of the present disclosure can be administered by any route that delivers an effective amount of the compound to the tissue or site to be treated. In general, the compounds and compositions can be administered parenterally (e.g., intravenously, intraspinal, subcutaneously or intramuscularly), orally, by rectal, by inhalation, or by topical routes. Administration can be systemic, regional, or local.

[0217] The specific route of administration to be used in any given case will depend on a variety of factors, including the nature of the fibrotic disorder to be treated, the severity and extent of the fibrotic disorder, the desired dose of the particular compound to be delivered, and the potential side effects of the compound.

[0218] In general, suitable compositions can be prepared according to methods known to those of ordinary skill in the art, and may include pharmaceutically acceptable carriers, diluents and / or excipients. The carriers, diluents and excipients must be "acceptable" in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient thereof.

[0219] Examples of pharmaceutically acceptable carriers or diluents are desalted or distilled water; physiological saline; vegetable oils, such as peanut oil, safflower oil, olive oil, cottonseed oil, corn oil or coconut oil; silicone oils, including polysiloxanes, such as methylpolysiloxane, phenylpolysiloxane and methylphenylpolysiloxane: volatile silicones; mineral oils, such as liquid paraffin, soft paraffin or squalane; cellulose derivatives, such as methylcellulose, ethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose or hydroxypropylmethylcellulose; Cyclodextrin; lower alcohols such as ethanol or isopropanol; lower polyalkylene glycols or lower alkylene glycols such as polyethylene glycol, polypropylene glycol, ethylene glycol, propylene glycol, 1,3-butylene glycol or glycerol; fatty acid esters such as isopropyl palmitate, isopropyl myristate or ethyl oleate; polyvinyl pyrrolidone; agar; carrageenan; tragacanth gum or gum arabic and vaseline. Typically, the one or more carriers will constitute about 10% to about 99.9% by weight of the composition.

[0220] The pharmaceutical composition may be in a form suitable for administration by injection, in the form of a formulation suitable for oral ingestion (e.g., capsules, tablets, caplets, elixirs), in the form of an ointment, cream or lotion suitable for topical application, in a form suitable for delivery as eye drops, in the form of an aerosol suitable for administration by inhalation (e.g., by intranasal inhalation or oral inhalation), in a form suitable for parenteral administration (i.e., subcutaneous, intramuscular or intravenous injection).

[0221] For administration as an injectable solution or suspension, non-toxic parenterally acceptable diluents or carriers may include cyclodextrins (e.g. Ringer's solution, isotonic saline, phosphate buffered saline, ethanol and 1,2-propylene glycol. To aid injection and delivery, the compounds can also be added to PEGylated and non-PEGylated liposomes or micelles, where the PEG portion is attached with a specific targeting tag, such as RGD peptide or glutathione, to help cross the blood-brain barrier.

[0222] Some examples of suitable carriers, diluents, excipients and adjuvants for oral use include cyclodextrins, Peanut oil, liquid paraffin, sodium carboxymethylcellulose, methylcellulose, sodium alginate, gum arabic, tragacanth, glucose, sucrose, sorbitol, mannitol, gelatin and lecithin. In addition, these oral preparations can contain suitable flavorings and coloring agents. When used in capsule form, the capsule can be coated with a compound that delays disintegration, such as glyceryl monostearate or glyceryl distearate.

[0223] Adjuvants typically include emollients, emulsifiers, thickeners, preservatives, bactericides and buffers.

[0224] Solid forms for oral administration can contain acceptable binders, sweeteners, disintegrants, diluents, flavoring agents, coating agents, preservatives, lubricants and / or time delay agents in human and veterinary pharmaceutical practices. Suitable binders include gum arabic, gelatin, corn starch, tragacanth gum, sodium alginate, carboxymethyl cellulose or polyethylene glycol. Suitable sweeteners include sucrose, lactose, glucose, aspartame or saccharin. Suitable disintegrants include corn starch, methylcellulose, polyvinyl pyrrolidone, guar gum, xanthan gum, bentonite, alginic acid or agar. Suitable diluents include lactose, sorbitol, mannitol, glucose, kaolin, cellulose, calcium carbonate, calcium silicate or dicalcium phosphate. Suitable flavoring agents include peppermint oil, wintergreen oil, cherry, orange or raspberry flavoring. Suitable coating agents include polymers or copolymers of acrylic acid and / or methacrylic acid and / or its esters, waxes, fatty alcohols, zein, shellac or gluten. Suitable preservatives include sodium benzoate, vitamin E, alpha-tocopherol, ascorbic acid, methylparaben, propylparaben or sodium bisulfite. Suitable lubricants include magnesium stearate, stearic acid, sodium oleate, sodium chloride or talc. Suitable delay agents include glyceryl monostearate or glyceryl distearate.

[0225] In addition to the above-mentioned agents, liquid forms suitable for oral administration can also contain a liquid carrier. Suitable liquid carriers include water, oil (e.g., olive oil, peanut oil, sesame oil, sunflower seed oil, safflower oil, coconut oil), liquid paraffin, ethylene glycol, propylene glycol, polyethylene glycol, ethanol, propanol, isopropanol, glycerol, fatty alcohol, triglyceride or a mixture thereof.

[0226] Suspensions for oral administration may further comprise dispersants and / or suspending agents.Suitable suspending agents include sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, sodium alginate or cetyl alcohol.Suitable dispersants include lecithin, fatty acids such as stearic polyoxyethylene esters, polyoxyethylene sorbitan monooleate or dioleate, stearate or laurate, polyoxyethylene sorbitan monooleate or dioleate, stearate or laurate, etc.

[0227] Emulsions for oral administration may further comprise one or more emulsifiers. Suitable emulsifiers include the dispersants exemplified above or natural gums such as guar gum, gum arabic or gum tragacanth.

[0228] Methods for preparing parenterally administrable compositions will be apparent to those skilled in the art, and are described in more detail in, for example, Remington's Pharmaceutical Science, 15th ed., Mack Publishing Company, Easton, PA, the entire contents of which are incorporated herein by reference.

[0229] Topical formulations may comprise the active ingredient and one or more acceptable carriers, and optionally any other therapeutic ingredients. Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the area in need of treatment, such as liniments, lotions, creams, ointments or pastes, and drops suitable for application to the eyes, ears or nose.

[0230] Drops can comprise sterile aqueous or oily solutions or suspensions. They can be prepared by dissolving active ingredients in an aqueous solution of bactericide and / or fungicide and / or any other applicable preservative, and optionally comprise a surfactant. Then, the solution obtained can be clarified by filtration, transferred to a suitable container and sterilized. Sterilization can be achieved by autoclaving or by keeping half an hour at 90 ℃ to 100 ℃ or by filtering, then transferred to a container by aseptic technique. Examples of bactericides and fungicides suitable for inclusion in drops are phenylmercuric nitrate or phenylmercuric acetate (0.002%), benzalkonium chloride (0.01%) and chlorhexidine acetate (0.01%). Suitable solvents for the preparation of oily solutions include glycerol, dilute alcohol and propylene glycol.

[0231] Lotions include those suitable for application to the skin or eyes. Eye lotions may comprise sterile aqueous solutions optionally containing bactericides and may be prepared by methods similar to those described above for the preparation of drops. Lotions or liniments for application to the skin may also include agents (e.g., alcohol or acetone) and / or moisturizers (e.g., glycerol) or oils (e.g., olive oil) that accelerate drying and cool the skin.

[0232] Creams, ointments or pastes are semisolid preparations of active ingredients for external use generally. They can be made by mixing with oily or non-oily base materials individually or in the form of solutions or suspensions in aqueous or non-aqueous fluids by subdividing or powdered active ingredients. The base material can include hydrocarbons such as hard, soft or liquid paraffin, glycerine, beeswax, metal soaps, mucus, oils of natural origin such as almond oil, corn oil, peanut oil, castor oil or olive oil, lanolin or its derivatives, or fatty acids such as stearic acid or oleic acid and alcohol such as propylene glycol or polyethylene glycol.

[0233] The composition may incorporate any suitable surfactant, for example anionic, cationic or nonionic surfactants, for example sorbitan esters or polyoxyethylene derivatives thereof. It may also include suspending agents such as natural gums, cellulose derivatives or inorganic materials such as siliceous silica, and other ingredients such as lanolin.

[0234] In some embodiments, the composition is applied in the form of a suppository suitable for rectal administration of a compound of formula (I) or (II). These compositions are prepared by mixing a compound of formula (I) or (II) with a suitable non-irritating excipient, which is solid at room temperature but liquid at rectal temperature and will therefore melt in the rectum to release the compound of formula (I) or (II). Such materials include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights, and fatty acid esters of polyethylene glycol.

[0235] The composition can also be applied or delivered to the target cell in the form of liposomes.Liposomes are generally derived from phospholipids or other lipid substances, and are formed by a monolayer or multilayer hydrated liquid crystal dispersed in an aqueous medium.The specific example of the liposome used to apply or deliver the composition to the target cell is synthetic cholesterol (Sigma), phospholipid 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC, Avanti Polar Lipids), PEG lipid 3-N-[(-methoxypolyethylene glycol 2000) carbamoyl]-1,2-dimyristyloxy-propylamine (PEG-cDMA) and cationic lipid 1,2-bis-octadecene-3-(N,N-dimethyl) aminopropane (DODMA) or 1,2-dilinoleyloxy-3-(N,N-dimethyl) aminopropane (DLinDMA) (molar ratio is respectively 55:20:10:15 or 48:20:2:30), PEG-cDMA, DODMA and DLinDMA. The liposomes can be constructed from 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (DSPE PEG2000) and phosphatidylcholine derived from soybeans and hydrogenated 50-100%, such as soybean PC-75 or soybean PC-100. PEG of different molecular weights can be used and covalently bound to various specific targeting agents such as glutathione, RGD peptide or other recognized liposome targeting agents. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The composition in the form of liposomes can contain stabilizers, preservatives, excipients, etc. Preferred lipids are natural and synthetic phospholipids and phosphatidylcholine (lecithin). Methods for forming liposomes are known in the art, with specific reference being made to: Prescott, ed., Methods in Cell Biology, Vol. XIV, Academic Press, New York, N.Y. (1976), pp. 33 et seq., the contents of which are incorporated herein by reference.

[0236] The composition can also be administered in the form of microparticles or nanoparticles. Biodegradable microparticles formed by polylactide (PLA), polylactide-co-glycolide (PLGA) and ε-caprolactone have been widely used as drug carriers to increase plasma half-life and thus prolong the therapeutic effect (R. Kumar, M. 2000. J. Pharm. Pharmaceut. Sci. 3 (2) 234-258). Microparticles have been formulated for delivering a series of drug candidates, including vaccines, antibiotics and DNA. In addition, these preparations have been developed for various delivery routes, including parenteral subcutaneous injection, intravenous injection and inhalation.

[0237] The composition can be incorporated into a controlled release matrix consisting of sucrose acetate isobutyrate (SAIB) and an organic solvent or an organic solvent mixture. Polymer additives can be added to the medium as a release modifier to further increase viscosity and slow down the release rate. SAIB is a well-known food additive. It is a very hydrophobic, fully esterified sucrose derivative with a nominal ratio of six isobutyrates to two acetate groups. As a mixed ester, SAIB does not crystallize, but exists as a transparent viscous liquid. SAIB is mixed with a pharmaceutically acceptable organic solvent (such as ethanol or benzyl alcohol) to fully reduce the viscosity of the mixture, thereby allowing injection. Active pharmaceutical ingredients can be added to the SAIB delivery medium to form a SAIB solution or suspension formulation. When the preparation is injected subcutaneously, the solvent is different from the matrix, allowing SAIB-drug or SAIB-drug-polymer mixture to be established as a reservoir formed in situ.

[0238] For administration by inhalation, the compound of formula (I) or (II) can be provided in the form of dry powder and delivered by dry powder inhaler (DPI). The dry powder can contain an extender such as lactose. DPI is well known to those skilled in the art. The compound of formula (I) or (II) can be optionally delivered in the form of an aerosol. For example, a mixture of the compound of formula (I) or (II) and a lubricant can be dispersed in a propellant and placed in a suitable metered dose inhaler for intranasal or oral inhalation delivery. When the compound of formula (I) or (II) is administered by inhalation, the method of the present invention may further include administering a bronchodilator to increase the airflow into the lungs of the subject. Non-limiting examples of bronchodilators include salbutamol, pirbuterol, terbutaline, clenbuterol, salmeterol, bambuterol and indacaterol. When the compound of formula (I) or (II) is administered together with a bronchodilator, each component can be administered simultaneously or sequentially in any order, or at different times to provide the desired effect. Alternatively, the components may be formulated together into a single dosage unit.

[0239] For the purposes of this disclosure, compounds and compositions can be administered to a subject therapeutically or prophylactically. In therapeutic applications, the composition is administered to a patient already suffering from fibrosis or a fibrotic disorder in an amount sufficient to cure or at least partially prevent fibrosis or a fibrotic disorder and its complications. The composition should provide the compound in an amount sufficient to effectively treat the subject.

[0240] The therapeutically effective amount for any particular subject will depend on a variety of factors, including: the fibrosis or fibrotic disorder being treated and its severity; the activity of the compound being administered; the composition in which the compound is present; the age, weight, general health, sex, and diet of the subject; the time of administration; the route of administration; the sequestration rate of the compound; the duration of treatment; drugs used in combination or concomitantly with the compound, and other relevant factors well known in medicine.

[0241] Those skilled in the art will be able to determine by routine experimentation the effective, non-toxic amount of the compound necessary to achieve the desired result.

[0242] Generally, an effective dose is expected to be in the range of about 0.0001 mg to about 1000 mg / kg body weight / 24 hours, typically about 0.001 mg to about 750 mg / kg body weight / 24 hours, about 0.01 mg to about 500 mg / kg body weight / 24 hours, about 0.1 mg to about 500 mg / kg body weight / 24 hours, about 0.1 mg to about 250 mg / kg body weight / 24 hours, about 1.0 mg to about 250 mg / kg body weight / 24 hours. More generally, it is expected that the effective dosage range will be from about 1.0 mg to about 200 mg / kg body weight / 24 hours, about 1.0 mg to about 100 mg / kg body weight / 24 hours, about 1.0 mg to about 50 mg / kg body weight / 24 hours, about 1.0 mg to about 25 mg / kg body weight / 24 hours, about 5.0 mg to about 50 mg / kg body weight / 24 hours, about 5.0 mg to about 20 mg / kg body weight / 24 hours, about 5.0 mg to about 15 mg / kg body weight / 24 hours.

[0243] Alternatively, effective doses may be up to about 500 mg / m 2 Generally, it is expected that effective doses will be in the range of about 25 to about 500 mg / m 2 , preferably about 25 to about 350 mg / m 2 , more preferably about 25 to about 300 mg / m 2 , more preferably about 25 to about 250 mg / m 2 , even more preferably about 50 to about 250 mg / m 2 , even more preferably about 75 to about 150 mg / m 2 within the range.

[0244] It will be apparent to one of ordinary skill in the art that the optimal amount and interval of the individual doses will be determined by the nature and extent of the fibrotic disorder being treated, the form, route and site of administration, and the nature of the specific individual being treated. In addition, such optimal conditions can be determined by conventional techniques.

[0245] The compounds of formula (I) may be used alone to treat fibrotic disorders, or in combination therapy with other therapeutic agents, such as anti-inflammatory compounds.

[0246] The term "combination therapy" is intended to include administration of multiple therapeutic agents in a sequential manner, in a regimen that will provide a beneficial effect, and is intended to include administration of these agents in a single or separate formulation.

[0247] In each case, combination therapy may involve administering the active agents together, sequentially or with appropriate intervals. Combinations of active agents, including compounds of the present disclosure, may be synergistic.

[0248] The combination of a compound of formula (I) or (II) with other therapeutic agents can be achieved by the compound of formula (I) or (II) and other therapeutic agents being in the same unit dosage form, or the compound of formula (I) or (II) and other therapeutic agents can be present in separate and discrete unit dosage forms, which are administered sequentially, simultaneously or at close times. Sequential administration can be in any order desired, and it may be necessary that the sustained physiological effects of the first or initial agent remain when the second or subsequent agent is administered, especially in the case where a cumulative or synergistic effect is desired. When administered separately, it may be preferred that the compound of formula (I) or (II) and other agents be administered by the same route of administration, although this is not required.

[0249] According to various embodiments of the present disclosure, one or more compounds of Formula (I) or (II) may be included in combination therapy with surgery.

[0250] Example

[0251] The present disclosure is further described below with reference to the following non-limiting examples.

[0252] Example 1 - Synthesis of compounds

[0253] Compound 7 was prepared according to reaction scheme 2:

[0254]

[0255] Reaction Scheme 2: Synthesis of Compound 7

[0256] Step 1:

[0257] To a solution of 2-amino-5-fluoropyridine (1.0 g, 8.9 mmol) in EtOH (8 ml) was added 2-bromo-1-phenyl-ethanone (1.5 g, 7.6 mmol) and NaHCO3 (0.97 g. 11.6 mmol), the resulting mixture was warmed to 60 ° C and stirred overnight. After cooling to room temperature, the reaction mixture was diluted with water. The resulting solid was collected by filtration to give 1.4 g (88%) of 6-fluoro-2-phenylimidazo[1,2-a]pyridine. LCMS (MSMS): m / z: 212.8.

[0258] Step 2:

[0259] To a solution of 6-fluoro-2-phenylimidazo[1,2-a]pyridine (0.39 g, 1.8 mmol) in DMF (4 ml) was added N-iodosuccinimide (0.50 g, 2.2 mmol) at room temperature. After 4 hours, the reaction mixture was diluted with water. The resulting solid was collected by filtration to give 0.59 g of crude product, which was rinsed through a silica gel pad with dichloromethane. The eluent was concentrated to give 6-fluoro-3-iodo-2-phenylimidazo[1,2-a]pyridine, which was used without further purification.

[0260] Step 3:

[0261] To a solution of 6-fluoro-3-iodo-2-phenylimidazo[1,2-a]pyridine (96 mg, 0.3 mmol) and 1-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)prop-2-en-1-one (84 mg, 0.4 mmol) in DMF (1.5 ml) was added tetrabutylammonium chloride (94 mg, 0.4 mmol), K2CO3 (78 mg, 0.6 mmol) and Pd(OAc)2 (20 mg) at room temperature. The resulting mixture was warmed to 100°C and stirred overnight. After cooling to room temperature, the reaction mixture was diluted with water and ethyl acetate. The layers were separated and the aqueous phase was extracted with ethyl acetate (2x). The combined organic phases were dehydrated (MgSO4), filtered and concentrated to give the crude product. Purification by silica gel flash column chromatography (5-100% ethyl acetate / hexanes) gave (2E)-1-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-3-{6-fluoro-2-phenylimidazo[1,2-a]pyridin-3-yl}prop-2-en-1-one as a yellow solid. LCMS (MSMS): m / z: 458.0.

[0262] The following compounds were prepared in a similar manner using appropriate intermediates:

[0263] (2E)-1-(6,7-Dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-3-{8-fluoro-2-phenylimidazo[1,2-a]pyridin-3-yl}prop-2-en-1-one (Compound 4); LCMS (MSMS): m / z: 458.0.

[0264] (2E)-1-(4-methoxypiperidin-1-yl)-3-{2-phenylimidazo[1,2-a]pyridin-3-yl}prop-2-en-1-one (Compound 3); LCMS (MSMS): m / z: 361.3.

[0265] (2E)-1-(1,3-dihydroisoindol-2-yl)-3-{2-phenylimidazo[1,2-a]pyridin-3-yl}prop-2-en-1-one (Compound 2); LCMS (MSMS): m / z: 365.3.

[0266] 2E)-3-[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]-1-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)prop-2-en-1-one (Compound 6); LCMS (MSMS): m / z: 473.8.

[0267] (2E)-1-(6,7-Dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-3-[2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]prop-2-en-1-one (Compound 5); LCMS (MSMS): m / z: 458.0.

[0268] The precursor compound in Reaction Scheme 2 can be synthesized as follows.

[0269]

[0270] 1-(1,3-Dihydroisoindol-2-yl)prop-2-en-1-one

[0271] To a mixture of isoindoline (0.50 g, 4.2 mmol) in DCM (20 ml) at -78°C was added triethylamine (25.2 mmol, 3.5 ml). After 10 minutes, a solution of acryloyl chloride (0.46 g, 5.0 mmol) in DCM (1 ml) was added dropwise. After 0.5 h, the reaction was concentrated and diluted with DCM and water. The layers were separated and the aqueous phase was extracted with DCM (2x). The combined organic phases were washed with brine and dried (MgSO4). Filtration and concentration gave the crude product which was purified by flash column chromatography (0-10% ethyl acetate / DCM) to give the desired product as a light orange solid.

[0272]

[0273] 1-(4-Methoxypiperidin-1-yl)prop-2-en-1-one

[0274] The mixture of 4-methoxypiperidine (0.50g, 4.3mmol) and triethylamine (0.84ml, 6.1mmol) in DCM (5ml) is cooled to -10 ℃. Acryloyl chloride (0.47g, 5.2mmol) as DCM solution (1ml) is added dropwise. After 10 minutes, the cooling bath is removed, and the reaction is stirred for 2 hours at ambient temperature. The reaction is poured into water and DCM, and the layers are separated. The aqueous phase is extracted with DCM (2x). The organic phase merged is washed with salt water, dehydrated (MgSO ), filtered and concentrated to give a crude product. Purification is carried out by rapid column chromatography (0-20% ethyl acetate / DCM) to give the desired product.

[0275]

[0276] 1-(6,7-Dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)prop-2-en-1-one

[0277] To a solution of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (1 g, 5 mmol) in THF (10 ml) was added K2CO3 (1.4 g, 10 mmol) and acryloyl chloride (540 mg, 6 mmol) at room temperature. The mixture was heated at 50 ° C for 3 hours. The mixture was cooled and water (15 ml) was added. The mixture was extracted with ethyl acetate (15 mL x 3) and the combined organic layers were dehydrated (MgSO4). The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography using 20% ​​ethyl acetate in hexane as the mobile phase to give 1-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)prop-2-en-1-one (1.17 g, 95%) as a white solid. LCMS (ESMS): m / z: 248.3 (M + +1).

[0278] Example 2 - Assay

[0279] Transforming TGF-β regulates the proliferation and differentiation of fibroblasts, the major constituent cells of fibrous tissue. Therefore, representative compounds of the present disclosure were tested for their ability to inhibit TGF-β.

[0280] Material

[0281] 1. TGFβ / SMAD signaling pathway SBE reporter-HEK293 cell line (BPS Bioscience catalog number: 60653)

[0282] 2. Human TGFβ1 (BPS Bioscience#90900-1)

[0283] 3. SIS3 (Sigma #S0447): Inhibitor of TGFβ pathway. Prepare stock solution in DMSO.

[0284] 4. Growth medium: MEM medium (Invitrogen#11095-080) + 10% FBS (ATCC#30-2020) + 1% non-essential amino acids (Lonza#13-114E) + 1 mM sodium pyruvate (Lonza#13-115E) + 1% penicillin / streptomycin (ATCC#30-2300) + 400 μg / ml geneticin (Invitrogen#11811-031).

[0285] 5. Assay culture medium: MEM medium + 0.5% FBS + 1% non-essential amino acids + 1mM sodium pyruvate + 1% penicillin / streptomycin

[0286] 6. 96-well tissue culture treated white clear bottom assay plate (Corning #3610)

[0287] 7.ONE-Step TM Luciferase Assay System (BPS, catalog number 60690)

[0288] method

[0289] SBE reporter HEK293 cells were harvested from cultures in growth medium and seeded into 100 μl of assay medium in a white clear bottom 96-well microplate at a density of ~10,000 cells per well. The plates containing the cells were incubated at 37°C in a CO2 incubator. 24 hours after seeding, the cells were washed with 100 μL of assay buffer and treated with three-fold serial dilutions of the compound in 50 μl of assay medium. The cells were incubated at 37°C in a CO2 incubator for 4 hours. 50 μl of assay medium without inhibitor was added to the control wells. Each treatment was performed in triplicate. After 4 hours of incubation, 5 μl of human TGFβ1 in assay medium was added to the cells (final concentration of TGFβ1 = 20 ng / ml). 5 μl of assay medium (for determination of basal activity) was added to the unstimulated control wells. The plates with cells were incubated overnight (~18 hours) at 37°C in a CO2 incubator. After 18 hours of incubation, ONE-Step TM Luciferase Assay System, perform luciferase assay according to the provided protocol: add 50 μl ONE-Step TMLuciferase reagent and shake at room temperature for ~10 minutes. Luminescence is measured using a luminometer.

[0290] result

[0291] The results are shown in Table 1 below.

[0292] Compound <![CDATA[IC 50 (μm)]]> <![CDATA[SIS3 ＊ ]]> 2.651 6 5.445 8 3.716 9 6.114 10 4.319 11 3.515

[0293] ＊ Comparative compounds

[0294] Compounds 6, 8, 9, 10 and 11 all showed inhibitory activity against TGF-β.

[0295] The citation of any reference in this article should not be construed as an admission that such reference is available as prior art for the present application. In addition, references to any prior publication (or information derived therefrom) or any known matter in this specification are not, and should not be construed as, an acknowledgement or admission or any form of suggestion that the prior publication (or information derived therefrom) or known matter constitutes part of the common general knowledge in the field to which this specification relates.

[0296] Those skilled in the art will recognize that the disclosure described herein is susceptible to variations and modifications other than those specifically described. It should be understood that the disclosure includes all such variations and modifications. The disclosure also includes all steps, features, compositions and compounds mentioned or indicated in this specification, either individually or collectively, and any and all combinations of two or more of the steps, features, compositions and compounds.

Claims

1. A method for treating fibrosis in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound having the following formula (I) or a pharmaceutically acceptable salt or prodrug thereof: (I) in: R1 is selected from: C 6-10 aryl, heteroaryl having 5 to 10 ring atoms wherein one or more ring atoms are selected from nitrogen, sulfur and oxygen, C 3-10 Cycloalkyl and heterocyclyl having 5 to 10 ring atoms wherein one or more ring atoms are selected from nitrogen, sulfur and oxygen, each of which is optionally substituted by one or more of the following groups: C 1-6 Alkoxy, C 1-6 Alkyl, CN, halogen and C 3-10 Cycloalkyl; R2 is selected from: (i) C 6-10 aryl, heteroaryl with 5 to 10 ring atoms wherein one or more ring atoms are selected from nitrogen, sulfur and oxygen, and heterocyclyl with 5 to 10 ring atoms wherein one or more ring atoms are selected from nitrogen, sulfur and oxygen, each of which is optionally substituted by one or more of the following groups: NR5R6, C 1-6 Alkyl, C 1-6 Alkoxy and halogen; and (ii) -XY, wherein X is selected from: a heterocyclic group having 5 to 10 ring atoms wherein one or more ring atoms are selected from nitrogen, sulfur and oxygen, C 6-10 aryl and heteroaryl having 5 to 10 ring atoms wherein one or more ring atoms are selected from nitrogen, sulfur and oxygen; and Y is selected from: C 6-10 aryl and heteroaryl having 5 to 10 ring atoms wherein one or more ring atoms are selected from nitrogen, sulfur and oxygen, and wherein the C of Y 6-10 Aryl and heteroaryl are optionally substituted by one or more of the following groups: NR5R6, C 1-6 Alkyl, C 1-6 Alkoxy and halogen; R3 is selected from: halogen, C 1-6 Alkoxy, OH, CN, NO2, -OC(O)R4, -C(O)R4, -C(O)NR5R6, -C(O)OR4, -OS(O)2R4, NR5R6, SR4, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 6-10 aryl and heteroaryl having 5 to 10 ring atoms wherein one or more ring atoms are selected from nitrogen, sulfur and oxygen; R4 is selected from H and C 1-6 alkyl; R5 and R6 are independently selected from H and C 1-6 alkyl; n is 1 or 2; and m is an integer between 0 and 4.

2. The method according to claim 1, wherein R1 is selected from: C 6-10 aryl, heteroaryl having 5 to 10 ring atoms wherein one or more ring atoms are selected from nitrogen, sulfur and oxygen, C 3-10 Cycloalkyl and heterocyclyl having 5 to 10 ring atoms wherein one or more ring atoms are selected from nitrogen, sulfur and oxygen, each of which is optionally substituted by one or more of the following groups: C 1-4 Alkoxy, C 1-4 Alkyl, CN, halogen and C 3-6 Cycloalkyl.

3. The method according to claim 1 or claim 2, wherein R1 is selected from: C 6-10 aryl, heteroaryl having 5 to 10 ring atoms wherein one or more ring atoms are selected from nitrogen, sulfur and oxygen, C 3-6 Cycloalkyl and heterocyclyl having 5 to 10 ring atoms wherein one or more ring atoms are selected from nitrogen, sulfur and oxygen, each of which is optionally substituted by one or more of the following groups: C 1-4 Alkoxy, C 1-4 Alkyl, halogen and C 3-6 Cycloalkyl.

4. The method according to any one of claims 1 to 3, wherein R1 is selected from: C 6-10 Aryl, heteroaryl having 5 to 10 ring atoms wherein one or more ring atoms are selected from nitrogen, sulfur and oxygen, and heterocyclyl having 5 to 10 ring atoms wherein one or more ring atoms are selected from nitrogen, sulfur and oxygen, each of which is optionally substituted by one or more of the following groups: C 1-4 Alkyl, halogen and C 3-6 Cycloalkyl.

5. The method according to any one of claims 1 to 4, wherein R1 is selected from: C 6-10 Aryl, heteroaryl with 5 or 6 ring atoms wherein one or more ring atoms are selected from nitrogen, sulfur and oxygen, and heterocyclyl with 5 or 6 ring atoms wherein one or more ring atoms are selected from nitrogen, sulfur and oxygen, each of which is optionally substituted by one or more of the following groups: C 1-4 Alkyl, halogen and C 3-6 Cycloalkyl.

6. The method according to any one of claims 1 to 5, wherein R1 is selected from: phenyl, heteroaryl with 5 or 6 ring atoms wherein one or more ring atoms are selected from nitrogen, sulfur and oxygen, and heterocyclyl with 5 or 6 ring atoms wherein one or more ring atoms are selected from nitrogen, sulfur and oxygen, each of which is optionally substituted by one or more of the following groups: C 1-4 Alkyl, halogen and C 3-4 Cycloalkyl.

7. The method according to any one of claims 1 to 6, wherein R1 is selected from: phenyl, heteroaryl with 5 or 6 ring atoms wherein one or more ring atoms are selected from nitrogen, sulfur and oxygen, and heterocyclyl with 5 or 6 ring atoms wherein one or more ring atoms are selected from nitrogen, sulfur and oxygen, each of which is optionally substituted by one or more of the following groups: C 1-3 Alkyl, halogen and cyclopropyl.

8. The method according to any one of claims 1 to 7, wherein R1 is selected from: phenyl, heteroaryl with 5 or 6 ring atoms wherein 1 to 3 ring atoms are selected from nitrogen, sulfur and oxygen, and heterocyclyl with 5 or 6 ring atoms wherein 1 or 2 ring atoms are selected from nitrogen, sulfur and oxygen, each of which is optionally substituted by one or more of the following groups: C 1-3 Alkyl, halogen and cyclopropyl.

9. The method according to any one of claims 1 to 8, wherein R1 is selected from: phenyl, heteroaryl with 5 or 6 ring atoms wherein 1 to 3 ring atoms are selected from nitrogen, sulfur and oxygen, and heterocyclyl with 5 or 6 ring atoms wherein 1 or 2 ring atoms are selected from nitrogen and oxygen, each of which is optionally substituted by one or more of the following groups: C 1-3 Alkyl, halogen and cyclopropyl.

10. The method according to any one of claims 1 to 9, wherein R1 is selected from: phenyl, heteroaryl with 5 or 6 ring atoms wherein 1 to 3 ring atoms are selected from nitrogen, sulfur and oxygen, and heterocyclyl with 5 or 6 ring atoms wherein 1 or 2 ring atoms are selected from nitrogen and oxygen, each of which is optionally substituted by one or more of the following groups: methyl, chloro, fluoro and cyclopropyl.

11. The method according to any one of claims 1 to 10, wherein R1 is selected from: phenyl, heteroaryl with 5 or 6 ring atoms wherein 1 to 3 ring atoms are selected from nitrogen, sulfur and oxygen, and heterocyclyl with 6 ring atoms wherein 1 or 2 ring atoms are selected from nitrogen and oxygen, each of which is optionally substituted by one or both of the following groups: methyl, chloro, fluoro and cyclopropyl.

12. The method according to any one of claims 1 to 11, wherein R1 is selected from: phenyl, heteroaryl with 5 or 6 ring atoms wherein 1 to 3 ring atoms are selected from nitrogen, sulfur and oxygen, and heterocyclyl with 6 ring atoms wherein 1 or 2 ring atoms are selected from nitrogen and oxygen, each of which is optionally substituted by one of the following groups: methyl, chloro, fluoro and cyclopropyl.

13. The method according to any one of claims 1 to 12, wherein R1 is selected from: 。 14. The method according to any one of claims 1 to 13, wherein R2 is selected from: (i) C 6-10 aryl, heteroaryl with 5 to 10 ring atoms wherein one or more ring atoms is nitrogen, heterocyclyl with 5 to 10 ring atoms wherein one or more ring atoms is nitrogen or oxygen, each of which is optionally substituted by one or more of the following groups: NR5R6, C 1-6 Alkyl, C 1-6 Alkoxy and halogen; and (ii) -XY, wherein X is selected from: a heterocyclic group having 5 to 10 ring atoms in which one or more ring atoms are nitrogen or oxygen, C 6-10 aryl and heteroaryl having 5 to 10 ring atoms wherein one or more ring atoms are selected from nitrogen, sulfur and oxygen; and Y is selected from: C 6-10 aryl and heteroaryl having 5 to 10 ring atoms wherein one or more ring atoms is nitrogen and wherein the C 6-10 Aryl and heteroaryl are optionally substituted by one or more of the following groups: NR5R6, C 1-6 Alkyl, C 1-6 Alkoxy and halogen.

15. The method according to any one of claims 1 to 14, wherein R2 is selected from: (i) phenyl, heteroaryl with 5 to 10 ring atoms wherein one or more ring atoms is nitrogen, heterocyclyl with 5 to 10 ring atoms wherein one or more ring atoms is nitrogen or oxygen, each of which is optionally substituted by one or more of the following groups: NR5R6, C 1-6 Alkyl, C 1-6 Alkoxy and halogen; and (ii) -XY, wherein X is selected from the group consisting of: a heterocyclic group having 5 to 10 ring atoms, wherein one or more ring atoms are nitrogen, a phenyl group, and a heteroaryl group having 5 or 6 ring atoms, wherein one or more ring atoms are nitrogen; and Y is selected from the group consisting of: a phenyl group, and a heteroaryl group having 5 or 6 ring atoms, wherein one or more ring atoms are nitrogen, and wherein the phenyl and heteroaryl groups of Y are optionally substituted by one or more of the following groups: NR5R6, C 1-6 Alkyl, C 1-6 Alkoxy and halogen.

16. The method according to any one of claims 1 to 15, wherein R2 is selected from: (i) heteroaryl with 5 to 10 ring atoms, wherein one or more ring atoms is nitrogen, heterocyclyl with 5 to 10 ring atoms, wherein one or more ring atoms is nitrogen or oxygen, each of which is optionally substituted by one or more of the following groups: NR5R6, C 1-6 Alkyl, C 1-6 Alkoxy and halogen; and (ii) -XY, wherein X is selected from: a heterocyclic group having 5 to 10 ring atoms, wherein one or more ring atoms are nitrogen, a phenyl group; and Y is selected from: a phenyl group and a heteroaryl group having 5 or 6 ring atoms, wherein one or more ring atoms are nitrogen, and wherein the phenyl and heteroaryl groups of Y are optionally substituted by one or more of the following groups: NR5R6, C 1-6 Alkyl, C 1-6 Alkoxy and halogen.

17. The method according to any one of claims 1 to 16, wherein R2 is selected from: (i) a heterocyclic group having 5 to 10 ring atoms in which one or more ring atoms are nitrogen or oxygen, each of which is optionally substituted by one or more of the following groups: NR5R6, C 1-6 Alkyl, C 1-6 Alkoxy and halogen; and (ii) -XY, wherein X is selected from: a heterocyclic group having 5 or 6 ring atoms in which one or more ring atoms are nitrogen; and Y is selected from: a phenyl group and a heteroaryl group having 5 or 6 ring atoms in which one or more ring atoms are nitrogen, and wherein the phenyl and heteroaryl groups of Y are optionally substituted by one or more of the following groups: NR5R6, C 1-6 Alkyl, C 1-6 Alkoxy and halogen.

18. The method according to any one of claims 1 to 17, wherein R2 is selected from: (i) a heterocyclic group having 5 to 10 ring atoms, wherein 1 to 4 ring atoms are nitrogen or oxygen, each of which is optionally substituted by one or more of the following groups: NR5R6, C 1-6 Alkyl, C 1-6 Alkoxy and halogen; and (ii) -XY, wherein X is selected from: a heterocyclic group having 5 or 6 ring atoms in which one or more ring atoms are nitrogen; and Y is selected from: a phenyl group and a heteroaryl group having 5 or 6 ring atoms in which one or more ring atoms are nitrogen, and wherein the phenyl and heteroaryl groups of Y are optionally substituted by one or more of the following groups: NH2, N(Me)2, C 1-6 Alkyl, methoxy, ethoxy and halogen.

19. The method according to any one of claims 1 to 18, wherein R2 is selected from: (i) a heterocyclic group having 5 to 10 ring atoms in which 1 to 4 ring atoms are nitrogen or oxygen, each of which is optionally substituted by one or more of the following groups: NH2, NMe2, C 1-6 Alkyl, methoxy, ethoxy and halogen; and (ii) -XY, wherein X is selected from: a heterocyclic group having 5 or 6 ring atoms in which one or more ring atoms are nitrogen; and Y is selected from: a phenyl group and a heteroaryl group having 5 or 6 ring atoms in which one or more ring atoms are nitrogen, and wherein the phenyl group and the heteroaryl group of Y are optionally substituted by one or more of the following groups: C 1-6 Alkyl, methoxy, ethoxy and halogen.

20. The method according to any one of claims 1 to 19, wherein R2 is selected from: (i) heterocyclyl having 5 to 10 ring atoms wherein 1 to 4 ring atoms are nitrogen or oxygen, each of which is optionally substituted by one or more of the following: NH2, N(Me)2, methyl, methoxy and halogen; and (ii) -XY, wherein X is selected from: a heterocyclyl group having 5 or 6 ring atoms in which one or more ring atoms is nitrogen; and Y is selected from: a phenyl group and a heteroaryl group having 5 or 6 ring atoms in which one or more ring atoms is nitrogen, and wherein the phenyl and heteroaryl groups of Y are optionally substituted by one to three of the following groups: methyl, methoxy and halogen.

21. The method according to any one of claims 1 to 20, wherein R2 is selected from: (i) a heterocyclyl group having 5 to 10 ring atoms in which 1 to 4 ring atoms are nitrogen or oxygen, each of which is optionally substituted by one to three of the following groups: NH2, N(Me)2, methyl and methoxy; and (ii) -XY, wherein X is selected from: a heterocyclyl group having 5 or 6 ring atoms in which one or two ring atoms are nitrogen; and Y is selected from: a phenyl group and a heteroaryl group having 5 or 6 ring atoms in which 1 to 3 ring atoms are nitrogen, and wherein the phenyl and heteroaryl groups of Y are optionally substituted by one or both of the following groups: methyl, methoxy, fluorine and chlorine.

22. The method according to any one of claims 1 to 21, wherein R2 is selected from: (i) a heterocyclyl group having 5 to 10 ring atoms in which 1 to 4 ring atoms are nitrogen or oxygen, each of which is optionally substituted by one to three of the following groups: NH2, N(Me)2, methyl and methoxy; and (ii) -XY, wherein X is selected from: a heterocyclyl group having 6 ring atoms, one or two of which are nitrogen; and Y is selected from: a phenyl group and a heteroaryl group having 5 or 6 ring atoms, one or two of which are nitrogen, and wherein the phenyl and heteroaryl groups of Y are optionally substituted by one or both of the following groups: methyl, methoxy, fluorine and chlorine.

23. The method according to any one of claims 1 to 22, wherein R2 is selected from: 。 24. The method according to any one of claims 1 to 23, wherein R3 is selected from: halogen, C 1-6 Alkoxy, OH, CN, -OC(O)R4, -C(O)R4, -C(O)NR5R6, -C(O)OR4, NR5R6, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl and heteroaryl having 5 to 10 ring atoms wherein one or more ring atoms are selected from nitrogen, sulfur and oxygen.

25. The method according to any one of claims 1 to 24, wherein R3 is selected from: halogen, C 1-6 Alkoxy, OH, CN, -C(O)R4, -C(O)NR5R6, -C(O)OR4, NR5R6, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl and heteroaryl having 5 or 6 ring atoms wherein one or more ring atoms are selected from nitrogen, sulfur and oxygen.

26. The method according to any one of claims 1 to 25, wherein R3 is selected from: halogen, C 1-6 Alkoxy, OH, CN, NR5R6, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 6-10 Aryl and heteroaryl having 5 or 6 ring atoms wherein one or more ring atoms are selected from nitrogen, sulfur and oxygen.

27. The method according to any one of claims 1 to 26, wherein R3 is selected from: halogen, C 1-4 Alkoxy, OH, CN, NR5R6, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 6-10 Aryl and heteroaryl having 5 or 6 ring atoms wherein one or more ring atoms are selected from nitrogen, sulfur and oxygen.

28. The method according to any one of claims 1 to 27, wherein R3 is selected from: halogen, C 1-4 Alkoxy, OH, CN, NR5R6, C 1-4 Alkyl, C 3-6 Cycloalkyl, phenyl and heteroaryl having 5 or 6 ring atoms wherein one or more ring atoms are selected from nitrogen, sulfur and oxygen.

29. The method according to any one of claims 1 to 28, wherein R3 is selected from: halogen, C 1-4 Alkoxy, OH, CN, C 1-4 Alkyl, phenyl and heteroaryl having 5 or 6 ring atoms wherein one or more ring atoms are selected from nitrogen, sulfur and oxygen.

30. The method according to any one of claims 1 to 29, wherein R3 is selected from: halogen, C 1-4 Alkoxy, OH, CN, C 1-4 Alkyl and phenyl.

31. The method according to any one of claims 1 to 30, wherein R3 is selected from: halogen, C 1-4 Alkoxy, CN and C 1-4 alkyl.

32. The method according to any one of claims 1 to 31, wherein R3 is selected from: halogen, C 1-4 Alkoxy, CN, C 1-4 Alkyl and phenyl.

33. The method according to any one of claims 1 to 32, wherein R3 is selected from the group consisting of: chloro, fluoro, methoxy, ethoxy and CN.

34. The method according to any one of claims 1 to 33, wherein R3 is selected from the group consisting of: fluoro, methoxy, ethoxy and CN.

35. The method according to any one of claims 1 to 34, wherein R3 is selected from: fluoro, methoxy and CN.

36. The method of any one of claims 1 to 35, wherein R4 is H or CH3.

37. The method according to any one of claims 1 to 36, wherein R5 and R6 are independently selected from H and CH3.

38. The method of any one of claims 1 to 37, wherein n is 1.

39. The method according to any one of claims 1 to 38, wherein m is 0, 1 or 2.

40. The method of any one of claims 1 to 39, wherein m is 0 or 1.

41. The method according to claim 1, wherein the compound of formula (I) is selected from: 。 42. The method of any one of claims 1 to 41, wherein the fibrosis is pulmonary fibrosis, fibrosis caused by radiation, renal fibrosis, cardiac fibrosis, hepatic fibrosis, arthrofibrosis, nephrogenic systemic fibrosis, retroperitoneal fibrosis, scleroderma / systemic sclerosis, myelofibrosis, or mediastinal fibrosis, or the fibrosis is associated with arterial stiffness, Crohn's disease, Dupuytren's contracture, keloids, Peyronie's disease, or adhesive capsulitis.

43. The method of claim 42, wherein the fibrosis is pulmonary fibrosis.

44. The method of claim 43, wherein the fibrosis is idiopathic pulmonary fibrosis.

45. The method of any one of claims 1 to 44, wherein the compound of formula (I) reduces fibrotic damage.

46. ​​The method of any one of claims 1 to 45, wherein the fibrosis is caused by, associated with, or otherwise related to a coronavirus infection in the subject.

47. The method of claim 46, wherein the subject is suffering from a coronavirus infection, or the subject has recovered from a coronavirus infection.

48. The method of claim 46 or claim 47, wherein the coronavirus is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

49. The method of any one of claims 1 to 48, wherein the compound of formula (I) is administered with one or more anti-inflammatory compounds.

50. The method of any one of claims 1 to 49, wherein the compound of formula (I) is administered with one or more antiviral compounds.

51. A method for preventing or minimizing fibrosis in a subject, wherein the subject is infected with a coronavirus or is at risk of becoming infected with a coronavirus, the method comprising administering to the subject an effective amount of a compound of formula (I) as defined in claim 1.

52. The method of claim 51, wherein the subject suffers from pneumonia and / or acute respiratory distress syndrome (ARDS).

53. The method of claim 51 or claim 52, wherein the compound of formula (I) is administered within one week of the subject being diagnosed with coronavirus.

54. The method of claim 51 or claim 52, wherein the compound of formula (I) is administered to the subject within one week after the onset of ARDS.

55. The method of any one of claims 51 to 54, wherein the coronavirus is SARS-CoV-2.

56. The method of any one of claims 51 to 55, wherein the compound of formula (I) prevents or minimizes fibrotic damage.

57. The method of any one of claims 51 to 56, wherein the compound of formula (I) is administered with one or more anti-inflammatory compounds.

58. The method of any one of claims 51 to 57, wherein the compound of formula (I) is administered with one or more antiviral compounds.

59. A method for preventing or minimizing lung injury or damage in a subject, wherein the subject is infected with or is at risk of becoming infected with a coronavirus, the method comprising administering to the subject an effective amount of a compound of formula (I) as defined in claim 1.

60. The method of claim 59, wherein the coronavirus is SARS-CoV-2.

61. The method of claim 59 or claim 60, wherein the lung injury or damage is caused by, associated with, or otherwise related to fibrosis.

62. The method of any one of claims 59 to 61, wherein the compound of formula (I) is administered with one or more anti-inflammatory compounds.

63. The method of any one of claims 59 to 62, wherein the compound of formula (I) is administered with one or more antiviral compounds.

64. A method for minimizing the severity of a coronavirus infection in a subject, the method comprising administering to the subject an effective amount of a compound of formula (I) as defined in claim 1.

65. The method of claim 64, wherein the coronavirus is SARS-CoV-2.

66. The method of claim 64 or claim 65, wherein the compound of formula (I) is administered with one or more anti-inflammatory compounds.

67. The method of any one of claims 64 to 66, wherein the compound of formula (I) is administered with one or more antiviral compounds.

68. A compound of formula (II) or a pharmaceutically acceptable salt or prodrug thereof: (II) in: R7 is selected from: halogen, OC 1-6 Alkyl, OH, CN, NO2, -OC(O)R4, -C(O)R4, -C(O)NR5R6, -C(O)OR4, -OS(O)2R4, NR5R6, SR4, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 6-10 aryl and heteroaryl having 5 to 10 ring atoms wherein one or more ring atoms are selected from nitrogen, sulfur and oxygen; Z1 is a heterocyclyl group having 5 to 10 ring atoms wherein one or more ring atoms are selected from nitrogen, sulfur and oxygen; Z2 is selected from: phenyl, heteroaryl with 5 to 10 ring atoms, wherein one or more ring atoms are selected from nitrogen, sulfur and oxygen, and heterocyclyl with 5 to 10 ring atoms, wherein one or more ring atoms are selected from nitrogen, sulfur and oxygen, each of which is optionally substituted by one or more of the following groups: NR5R6, C 1-6 Alkyl, OC 1-6 Alkyl and halogen; p is 1 or 2; and o is an integer between 0 and 4, And wherein R4 to R6 are as defined in claim 1.

69. The compound of claim 68, wherein R7 is selected from the group consisting of halogen, methoxy, OH, CN, NR5R6 and methyl.

70. A compound according to claim 68 or claim 69, wherein Z1 is a heterocyclyl having 5 or 6 ring atoms wherein one or more ring atoms are nitrogen, oxygen or sulfur.

71. according to the compound described in any one of claim 68 to 70, wherein Z1 is a heterocyclic radical with 5 or 6 ring atoms in which one or two ring atoms are nitrogen, oxygen or sulfur.

72. according to the compound described in any one of claim 68 to 71, wherein Z1 is a heterocyclic radical with 5 or 6 ring atoms in which one or two ring atoms are nitrogen.

73. according to the compound described in any one of claim 68 to 72, wherein Z1 is a heterocyclic radical with 6 ring atoms in which one or two ring atoms are nitrogen.

74. according to the compound described in any one of claim 68 to 73, wherein Z1 is 。 75. according to the compound described in any one in claim 68 to 74, wherein Z2 is selected from: phenyl and wherein 1 to 3 ring atoms are nitrogen heteroaryl with 5 or 6 ring atoms, and wherein said phenyl and heteroaryl are optionally substituted by one to three of the following groups: NH2, N (Me)2, methyl, methoxyl and halogen.

76. according to the compound described in any one in claim 68 to 75, wherein Z2 is selected from: phenyl and wherein 1 to 3 ring atoms are nitrogen heteroaryl with 5 or 6 ring atoms, and wherein said phenyl and heteroaryl are optionally substituted by one or both of the following groups: NH2, N (Me)2, methyl, methoxyl, fluorine and chlorine.

77. according to the compound described in any one in claim 68 to 75, wherein Z2 is selected from: phenyl and one or two ring atoms are nitrogen heteroaryl with 5 or 6 ring atoms, and wherein said phenyl and heteroaryl are optionally replaced by one or both of the following groups: NH2, N (Me)2, methyl, methoxyl, fluorine and chlorine.

78. A compound according to any one of claims 68 to 77, wherein o is 0 or 1.

79. The compound of claim 78, wherein o is 0.

80. A compound according to any one of claims 68 to 79, wherein p is 1.

81. A pharmaceutical composition comprising a compound of formula (II) according to any one of claims 68 to 80 and a pharmaceutically acceptable carrier, diluent or excipient.

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