Substituted imidazo[1,2-a]pyridine compounds and their use in the treatment and prevention of fibrotic diseases

Abstract

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

Description

[Technical Field]

[0001] Technical Field FIELD OF THE DISCLOSURE

[0001] This disclosure relates generally to a class of substituted imidazo[1,2-a]pyridine compounds, compositions containing same, and therapeutic uses of the compounds in the treatment and prevention of fibrotic diseases. [Background technology]

[0002] Background technology

[0002] Fibrosis is the development of fibrous connective tissue as a repair response to injury or damage. Pulmonary fibrosis refers to several pathologies that cause interstitial lung injury, subsequent fibrosis, and ultimately a loss of lung elasticity. These pathologies result in 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 essential methods for slowing progression and prolonging life.

[0003]

[0003] In December 2019, reports of a severe acute respiratory illness caused by severe acute respiratory syndrome coronavirus 2 emerged. The virus was named "Covid-19." By the end of July 2020, over 20 million people worldwide had been infected with Covid-19, and over 750,000 had died.

[0004] Recent reports have described numerous instances of pulmonary fibrotic disease in subjects diagnosed with Covid-19, with a wide range of fibrotic changes occurring, ranging from pneumonia-associated fibrosis to severe acute lung injury. In fatal Covid-19 cases, pulmonary fibrosis has also been reported to be typically present at autopsy, with anecdotal reports of severe fibrotic organizing pneumonia. Previous coronavirus pandemics, such as severe acute respiratory syndrome (SARS) in 2003 and Middle East respiratory syndrome (MERS), have been associated with significant postviral fibrosis and physiological impairment. Given the magnitude of the current Covid-19 pandemic, it is likely that the burden of fibrotic lung disease will increase dramatically and remain a significant problem for many years to come. The risk of future viral outbreaks caused by other respiratory viruses (e.g., of avian and swine origin) has the potential to further increase the burden. Summary of the Invention [Problem to be solved by the invention]

[0005]

[0005] Therefore, new therapeutic and preventive options are urgently needed to treat and prevent fibrosis, particularly fibrosis associated with Covid-19. [Means for solving the problem]

[0006] Summary of the Invention In a first aspect, there is provided a method of treating fibrosis in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of the following formula (I): [ka] (In the ceremony R1 is each one of the following groups: C 1~6 Alkoxy, C 1~6 Alkyl, CN, halo and C 3~10 C optionally substituted with one or more cycloalkyl 6~10 aryl, heteroaryl groups having 5 to 10 ring atoms, one or more of which are selected from nitrogen, sulfur and oxygen; C3~10 selected from the group consisting of cycloalkyl and heterocyclyl groups having 5 to 10 ring atoms, wherein one or more of the ring atoms is selected from nitrogen, sulfur, and oxygen; R2 is (i) each of the following groups: NR5R6, C 1~6 Alkyl, C 1~6 C optionally substituted with one or more of alkoxy and halo; 6~10 aryl, heteroaryl groups having 5 to 10 ring atoms, one or more of which is selected from nitrogen, sulfur, and oxygen, and heterocyclyl groups having 5 to 10 ring atoms, one or more of which is selected from nitrogen, sulfur, and oxygen, and (ii)-XY wherein X is a heterocyclyl group having 5 to 10 ring atoms, one or more of the ring atoms being selected from nitrogen, sulfur, and oxygen; 6~10 and Y is selected from the group consisting of aryl and heteroaryl groups having 5 to 10 ring atoms, one or more of the ring atoms being selected from nitrogen, sulfur, and oxygen; 6~10 aryl and heteroaryl groups having 5 to 10 ring atoms, one or more of the ring atoms being selected from nitrogen, sulfur, and oxygen; 6~10 The aryl and heteroaryl groups include the following groups: NR5R6, C 1~6 Alkyl, C 1~6 optionally substituted with one or more of alkoxy and halo is selected from the group consisting of R3 is Halo, C 1~6 Alkoxy, OH, CN, NO2, -OC(O)R4, -C(O)R4 are -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 6~10selected from the group consisting of aryl and heteroaryl groups having 5 to 10 ring atoms, wherein one or more of the ring atoms is selected from nitrogen, sulfur, and oxygen; R4 is H and C 1~6 alkyl, R5 and R6 are H and C 1~6 alkyl; n is 1 or 2, and m is an integer from 0 to 4. or a pharmaceutically acceptable salt or prodrug thereof, is provided.

[0007]

[0007] The fibrosis can be pulmonary fibrosis. In one embodiment, the fibrosis is idiopathic pulmonary fibrosis.

[0008]

[0008] The method may reduce fibrotic injury.

[0009]

[0009] Fibrosis may be caused by, accompanied by, or otherwise associated with a coronavirus infection in a subject.

[0010]

[0010] The subject may be suffering from a coronavirus infection, or the subject may have recovered from a coronavirus infection.

[0011]

[0011] The coronavirus may be, for example, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), such as Covid-19.

[0012] The compounds of formula (I) may be administered in combination with one or more anti-inflammatory compounds.

[0013] The compounds of formula (I) may be administered in combination with one or more antiviral compounds.

[0014]

[0014] In a second aspect, the present invention provides a method for preventing or minimizing fibrosis in a subject infected with or at risk of being 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.

[0015] The subject may be suffering from pneumonia and / or acute respiratory distress syndrome (ARDS).

[0016] The compound of formula (I) may be administered within one week of the subject being diagnosed with coronavirus.

[0017] The compound of formula (I) may be administered within one week of the onset of ARDS in the subject.

[0018]

[0018] The coronavirus may be Covid-19.

[0019]

[0019] The method may prevent or minimize fibrotic injury.

[0020] The compounds of formula (I) may be administered in combination with one or more anti-inflammatory compounds.

[0021] The compounds of formula (I) may be administered in combination with one or more antiviral compounds.

[0022]

[0022] In a third aspect, the present invention provides a method for preventing or minimizing lung damage or injury in a subject infected with or at risk of being 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.

[0023]

[0023] The coronavirus may be Covid-19.

[0024]

[0024] Lung injury or damage may be caused by, accompanied by, or otherwise associated with fibrosis.

[0025] The compounds of formula (I) may be administered in combination with one or more anti-inflammatory compounds.

[0026] The compounds of formula (I) may be administered in combination with one or more antiviral compounds.

[0027]

[0027] In a fourth aspect, the present invention provides 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 the first aspect.

[0028]

[0028] The coronavirus may be Covid-19.

[0029] The compounds of formula (I) may be administered in combination with one or more anti-inflammatory compounds.

[0030] The compounds of formula (I) may be administered in combination with one or more antiviral compounds.

[0031] In a fifth aspect, a compound of formula (II): [ka] (In the formula, R7, Halo, 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 6~10selected from the group consisting of aryl and heteroaryl groups having 5 to 10 ring atoms, wherein one or more of the ring atoms is selected from nitrogen, sulfur, and oxygen; Z1 is a heterocyclyl group having 5 to 10 ring atoms, one or more of the ring atoms being selected from nitrogen, sulfur, and oxygen; Z2 is each one of the following groups: NR5R6, C 1~6 Alkyl, OC 1~6 selected from phenyl, heteroaryl groups having 5 to 10 ring atoms, wherein one or more of the ring atoms is selected from nitrogen, sulfur, and oxygen, and heterocyclyl groups having 5 to 10 ring atoms, wherein one or more of the ring atoms is selected from nitrogen, sulfur, and oxygen, optionally substituted with one or more of alkyl and halo; p is 1 or 2, and o is an integer from 0 to 4, R4 to R6 are as defined in the first aspect. or a pharmaceutically acceptable salt or prodrug thereof.

[0032] In a sixth aspect, there is provided a pharmaceutical composition comprising a compound of formula (II) according to the fifth aspect, together with a pharmaceutically acceptable carrier, diluent or excipient.

[0033] In a seventh aspect, there is provided the use of a compound of formula (I) as defined in the first aspect in the manufacture of a medicament for the treatment of fibrotic disease.

[0034]

[0034] In an eighth aspect, there is provided the use of a compound of formula (I) as defined in the first aspect in the manufacture of a medicament for preventing or minimizing fibrosis in a subject infected with or at risk of being infected with a coronavirus.

[0035]

[0035] In a ninth aspect, there is provided the use of a compound of formula (I) as defined in the first aspect in the manufacture of a medicament for preventing or minimizing lung damage or injury in a subject infected with or at risk of being infected with a coronavirus.

[0036] In a tenth aspect, there is provided the use of a compound of formula (I) as defined in the first aspect in the manufacture of a medicament for minimising the severity of coronavirus infection.

[0037] In an eleventh aspect, there is provided a compound of formula (I) as defined in the first aspect for use in a method of treatment of fibrosis.

[0038]

[0038] In a twelfth aspect, there is provided a compound of formula (I) as defined in the first aspect for use in a method for preventing or minimizing fibrosis in a subject infected with or at risk of being infected with a coronavirus.

[0039]

[0039] In a thirteenth aspect, there is provided a compound of formula (I) as defined in the first aspect for use in a method for preventing or minimizing lung injury or damage in a subject infected with or at risk of being infected with a coronavirus.

[0040] In a fourteenth aspect, there is provided a compound of formula (I) as defined in the first aspect for use in a method of minimising the severity of a coronavirus infection.

[0041] definition

[0041] Below are some definitions that may be useful in understanding the description of the present disclosure. These are intended to be general definitions, and should in no way limit the scope of the present disclosure to only these terms, but are set forth for a better understanding of the following description.

[0042]

[0042] Throughout this specification, unless the context requires otherwise, the term "comprise" or variations such as "comprises" or "comprising" 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 other elements, integers or steps or groups of elements, integers or steps.

[0043] The terms "a" and "an" are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0044] In the context of this specification, the term "alkyl" is understood to mean a straight or branched chain monovalent saturated hydrocarbon radical having the recited number of carbon atoms. Examples of alkyl radicals include, but are not limited to, methyl, ethyl, 1-propyl, isopropyl, 1-butyl, 2-butyl, isobutyl, tert-butyl, amyl, 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, 1,3-dimethylbutyl, etc.

[0045] In the context of this specification, the term "alkenyl" is understood to mean a straight or branched chain monovalent hydrocarbon radical having the recited number of carbon atoms and at least one carbon-carbon double bond, such as vinyl, propenyl, 2-methyl-2-propenyl, butenyl, etc. The radical may contain multiple double bonds, and the configuration around each double bond is independently cis or trans, E or Z.

[0046] In the context of this specification, the term "alkynyl" is understood to mean a straight- or branched-chain monovalent hydrocarbon radical having the recited number of carbon atoms and at least one carbon-carbon triple bond, such as ethynyl, propargyl, etc. The radical may contain multiple triple bonds.

[0047] In the context of this specification, the term "alkoxy" is understood to mean an O-alkyl group, wherein alkyl is as defined herein. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, sec-butoxy and tert-butoxy.

[0048]

[0048] In the context of this specification, the terms "halo" and "halogen" are used interchangeably and refer to fluorine, chlorine, bromine and iodine.

[0049] In the context of this specification, the term "aryl" is understood to mean a monovalent aromatic hydrocarbon group having the recited number of ring carbon atoms. An aryl group may have a single ring or multiple rings. "Aryl" also includes bicyclic groups 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.

[0050]

[0050] 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, containing at least one nitrogen, sulfur, or oxygen atom, with the remaining ring atoms being carbon. Examples of heteroaryl include, but are not limited to, pyridyl, pyrrolyl, indolyl, quinolinyl, furanyl, thienyl, oxazolyl, thiazolyl, and the like.

[0051]

[0051] 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, containing at least one nitrogen, sulfur, or oxygen atom, with the remaining ring atoms being carbon. The term also includes substituents in which the heterocyclyl group is fused to an aromatic ring. Examples of heterocyclyl include, but are not limited to, pyrrolidinyl, piperazinyl, 2,3-dihydroindolyl, piperidinyl, azetidinyl, pyrazolinyl, morpholinyl, dihydroquinolinyl, and the like.

[0052] In the context of this specification, the term "cycloalkyl" is understood to mean a monovalent saturated carbocyclic ring having the recited number of ring carbon atoms. The ring may be monocyclic or bicyclic. Bicyclic carbocyclic rings may be arranged as bridged systems, for example, bicyclo[4,5], [5,5], [5,6] or [6,6] or bicyclo[2.2.1]heptane. Examples of carbocyclyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, cyclodecyl, etc.

[0053] In the context of this specification, the term "prodrug" means a compound that is convertible in vivo by metabolic means (eg hydrolysis, reduction or oxidation) to a compound of formula (I) or (II).

[0054]

[0054] In the context of this specification, the term "effective amount" includes a non-toxic but sufficient amount of active compound to provide the stated effect. Those skilled in the art will recognize that the exact amount of compound required will vary based on several factors, and therefore it is not possible to specify an exact "effective amount." However, an appropriate "effective amount" can be determined by those skilled in the art in any event.

[0055]

[0055] In the context of this specification, the term "therapeutically effective amount" includes a non-toxic but sufficient amount of active compound to provide the desired therapeutic effect. Those skilled in the art will recognize that the exact amount of compound required will vary based on several factors, and therefore it is not possible to specify an exact "therapeutically effective amount." However, an appropriate "therapeutically effective amount" can be determined by those skilled in the art in any event.

[0056]

[0056] In the context of this specification, the terms "treat," "treatment," "prevent," and "prevention" refer to any use that ameliorates a pathological condition or its symptoms, prevents the establishment of a pathological condition, or otherwise prevents, hinders, slows, or reverses the progression of a disease or other undesirable condition, regardless of the manner. As such, the terms "treat," "treatment," "prevent," and "prevention," etc., are intended to be considered in their broadest context. For example, treatment does not necessarily mean that a subject is treated until complete recovery.

[0057]

[0057] In the context of this specification, the term "subject" includes humans and non-human animals. Thus, in addition to being useful in treating humans, the compounds of the present disclosure have application in treating non-human animals, e.g., mammals such as companion animals and livestock. Non-limiting examples of companion animals and livestock include dogs, cats, horses, cows, sheep, and pigs. Preferably, the subject is a human.

[0058]

[0058] In the context of this specification, the term "administering" and variations thereof, including "administer" and "administration," include contacting, applying, delivering or providing a compound or composition to an organism by any suitable means. DETAILED DESCRIPTION OF THE INVENTION

[0059] Detailed Description

[0059] A new class of substituted imidazo[1,2-a]pyridine compounds that show promise in the treatment and prevention of fibrosis and related pulmonary pathologies associated with Covid-19 are described in detail.

[0060] In one aspect, a method of treating fibrosis in a subject in need thereof comprises administering a therapeutically effective amount of a compound of formula (I): [ka] (In the formula, R1 is each one of the following groups: C 1~6 Alkoxy, C 1~6 Alkyl, CN, halo and C 3~10 C optionally substituted with one or more cycloalkyl 6~10 aryl, heteroaryl groups having 5 to 10 ring atoms, one or more of which are selected from nitrogen, sulfur and oxygen; C 3~10 selected from the group consisting of cycloalkyl and heterocyclyl groups having 5 to 10 ring atoms, wherein one or more of the ring atoms is selected from nitrogen, sulfur, and oxygen; R2 is (i) each of the following groups: NR5R6, C 1~6 Alkyl, C 1~6 C optionally substituted with one or more of alkoxy and halo; 6~10 aryl, heteroaryl groups having 5 to 10 ring atoms, one or more of which is selected from nitrogen, sulfur, and oxygen, and heterocyclyl groups having 5 to 10 ring atoms, one or more of which is selected from nitrogen, sulfur, and oxygen, and (ii)-XY wherein X is a heterocyclyl group having 5 to 10 ring atoms, one or more of the ring atoms being selected from nitrogen, sulfur, and oxygen; 6~10 and Y is selected from the group consisting of aryl and heteroaryl groups having 5 to 10 ring atoms, one or more of the ring atoms being selected from nitrogen, sulfur, and oxygen; 6~10aryl and heteroaryl groups having 5 to 10 ring atoms, one or more of the ring atoms being selected from nitrogen, sulfur, and oxygen; 6~10 The aryl and heteroaryl groups include the following groups: NR5R6, C 1~6 Alkyl, C 1~6 optionally substituted with one or more of alkoxy and halo is selected from the group consisting of R3 is Halo, 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 selected from the group consisting of aryl and heteroaryl groups having 5 to 10 ring atoms, wherein one or more of the ring atoms is selected from nitrogen, sulfur, and oxygen; R4 is H and C 1~6 alkyl, R5 and R6 are H and C 1~6 alkyl; n is 1 or 2, and m is an integer from 0 to 4. or a pharmaceutically acceptable salt or prodrug thereof, is provided.

[0061] In another embodiment, R1 is selected from the following groups: C 1~4 Alkoxy, C 1~4 Alkyl, CN, halo and C 3~6 C optionally substituted with one or more cycloalkyl 6~10 aryl, heteroaryl groups having 5 to 10 ring atoms, one or more of which are selected from nitrogen, sulfur and oxygen; C 3~10Selected from the group consisting of cycloalkyl and heterocyclyl groups having 5 to 10 ring atoms, wherein one or more of the ring atoms is selected from nitrogen, sulfur, and oxygen.

[0062] In further embodiments, R1 is each independently selected from the following groups: C 1~4 Alkoxy, C 1~4 Alkyl, halo and C 3~6 C optionally substituted with one or more cycloalkyl 6~10 aryl, heteroaryl groups having 5 to 10 ring atoms, one or more of which are selected from nitrogen, sulfur and oxygen; C 3~6 Selected from the group consisting of cycloalkyl and heterocyclyl groups having 5 to 10 ring atoms, wherein one or more of the ring atoms is selected from nitrogen, sulfur, and oxygen.

[0063] In yet another embodiment, R1 is selected from the following groups: C 1~4 Alkyl, halo and C 3~6 C optionally substituted with one or more cycloalkyl 6~10 Selected from the group consisting of aryl, heteroaryl groups having 5 to 10 ring atoms, one or more of which are selected from nitrogen, sulfur, and oxygen, and heterocyclyl groups having 5 to 10 ring atoms, one or more of which are selected from nitrogen, sulfur, and oxygen.

[0064] In still further embodiments, R1 is selected from the following groups: C 1~4 Alkyl, halo and C 3~6 C optionally substituted with one or more cycloalkyl 6~10Selected from the group consisting of aryl, heteroaryl groups having 5 or 6 ring atoms, one or more of which is selected from nitrogen, sulfur, and oxygen, and heterocyclyl groups having 5 or 6 ring atoms, one or more of which is selected from nitrogen, sulfur, and oxygen.

[0065] In another embodiment, R1 is selected from the following groups: C 1~4 Alkyl, halo and C 3~4 phenyl, optionally substituted with one or more cycloalkyl; heteroaryl groups having 5 or 6 ring atoms, wherein one or more of the ring atoms is selected from nitrogen, sulfur, and oxygen; and heterocyclyl groups having 5 or 6 ring atoms, wherein one or more of the ring atoms is selected from nitrogen, sulfur, and oxygen.

[0066] In still further embodiments, R1 is selected from the following groups: C 1~3 Selected from the group consisting of phenyl, heteroaryl groups having 5 or 6 ring atoms, wherein one or more of the ring atoms is selected from nitrogen, sulfur, and oxygen, optionally substituted with one or more of alkyl, halo, and cyclopropyl; and heterocyclyl groups having 5 or 6 ring atoms, wherein one or more of the ring atoms is selected from nitrogen, sulfur, and oxygen.

[0067] In yet another embodiment, R1 is selected from the following groups: C 1~3 Selected from the group consisting of phenyl, heteroaryl groups having 5 or 6 ring atoms, wherein 1 to 3 of the ring atoms are selected from nitrogen, sulfur, and oxygen, and heterocyclyl groups having 5 or 6 ring atoms, wherein 1 or 2 of the ring atoms are selected from nitrogen, sulfur, and oxygen, optionally substituted with one or more of alkyl, halo, and cyclopropyl.

[0068] In further embodiments, R1 each independently represents one of the following groups: C 1~3 Selected from the group consisting of phenyl, heteroaryl groups having 5 or 6 ring atoms, wherein 1 to 3 of the ring atoms are selected from nitrogen, sulfur, and oxygen, and heterocyclyl groups having 5 or 6 ring atoms, wherein 1 or 2 of the ring atoms are selected from nitrogen and oxygen, optionally substituted with one or more of alkyl, halo, and cyclopropyl.

[0069]

[0069] In another embodiment, R1 is selected from the group consisting of phenyl, heteroaryl groups having 5 or 6 ring atoms, wherein 1 to 3 of the ring atoms are selected from nitrogen, sulfur, and oxygen, each of which is optionally substituted with one or more of the following groups: methyl, chloro, fluoro, and cyclopropyl, and heterocyclyl groups having 5 or 6 ring atoms, wherein 1 or 2 of the ring atoms are selected from nitrogen and oxygen.

[0070]

[0070] In still further embodiments, R1 is selected from the group consisting of phenyl, heteroaryl groups having 5 or 6 ring atoms, wherein 1 to 3 of the ring atoms are selected from nitrogen, sulfur, and oxygen, each of which is optionally substituted with one or two of the following groups: methyl, chloro, fluoro, and cyclopropyl, and heterocyclyl groups having 6 ring atoms, wherein 1 or 2 of the ring atoms are selected from nitrogen and oxygen.

[0071]

[0071] In further embodiments, R1 is selected from the group consisting of phenyl, heteroaryl groups having 5 or 6 ring atoms, wherein 1 to 3 of the ring atoms are selected from nitrogen, sulfur, and oxygen, each of which is optionally substituted with one of the following groups: methyl, chloro, fluoro, and cyclopropyl, and heterocyclyl groups having 6 ring atoms, wherein 1 or 2 of the ring atoms are selected from nitrogen and oxygen.

[0072] In yet another embodiment, R1 is [ka] is selected from the group consisting of:

[0073] In one embodiment, R2 is (i) each of the following groups: NR5R6, C 1~6 Alkyl, C 1~6 C optionally substituted with one or more of alkoxy and halo; 6~10 aryl, heteroaryl groups having 5 to 10 ring atoms, one or more of which is nitrogen; heterocyclyl groups having 5 to 10 ring atoms, one or more of which is nitrogen or oxygen; and (ii)-XY wherein X is a heterocyclyl group having 5 to 10 ring atoms, one or more of the ring atoms being nitrogen or oxygen; 6~10 and Y is selected from the group consisting of aryl and heteroaryl groups having 5 to 10 ring atoms, one or more of the ring atoms being selected from nitrogen, sulfur, and oxygen; 6~10 aryl and heteroaryl groups having 5 to 10 ring atoms, one or more of the ring atoms being nitrogen; 6~10 The aryl and heteroaryl groups include the following groups: NR5R6, C 1~6 Alkyl, C 1~6 optionally substituted with one or more of alkoxy and halo is selected from the group consisting of:

[0074] In another embodiment, R2 is (i) each of the following groups: NR5R6, C 1~6 Alkyl, C 1~6phenyl, heteroaryl groups having 5 to 10 ring atoms, one or more of which is nitrogen, heterocyclyl groups having 5 to 10 ring atoms, one or more of which is nitrogen or oxygen, optionally substituted with one or more of alkoxy and halo; (ii)-XY wherein X is selected from the group consisting of heterocyclyl groups having 5 to 10 ring atoms, one or more of the ring atoms being nitrogen, phenyl and heteroaryl groups having 5 or 6 ring atoms, one or more of the ring atoms being nitrogen, and Y is selected from the group consisting of phenyl and heteroaryl groups having 5 or 6 ring atoms, one or more of the ring atoms being nitrogen, and the phenyl and heteroaryl groups of Y are selected from the group consisting of the following groups: NR5R6, C 1~6 Alkyl, C 1~6 optionally substituted with one or more of alkoxy and halo is selected from the group consisting of:

[0075] In a further embodiment, R2 is (i) each of the following groups: NR5R6, C 1~6 Alkyl, C 1~6 Heteroaryl groups having 5 to 10 ring atoms, wherein one or more of the ring atoms is nitrogen, optionally substituted with one or more of alkoxy and halo; heterocyclyl groups having 5 to 10 ring atoms, wherein one or more of the ring atoms is nitrogen or oxygen; and (ii)-XY wherein X is selected from the group consisting of phenyl, a heterocyclyl group having 5 to 10 ring atoms, one or more of the ring atoms being nitrogen, and Y is selected from the group consisting of phenyl and a heteroaryl group having 5 or 6 ring atoms, one or more of the ring atoms being nitrogen, and the phenyl and heteroaryl groups of Y are selected from the group consisting of the following groups: NR5R6, C 1~6 Alkyl, C 1~6optionally substituted with one or more of alkoxy and halo is selected from the group consisting of:

[0076] In yet another embodiment, R2 is (i) each of the following groups: NR5R6, C 1~6 Alkyl, C 1~6 heterocyclyl groups having 5 to 10 ring atoms optionally substituted with one or more of alkoxy and halo, wherein one or more of the ring atoms is nitrogen or oxygen; and (ii)-XY wherein X is selected from the group consisting of heterocyclyl groups having 5 or 6 ring atoms, one or more of the ring atoms being nitrogen, and Y is selected from the group consisting of phenyl and heteroaryl groups having 5 or 6 ring atoms, one or more of the ring atoms being nitrogen, and the phenyl and heteroaryl groups of Y are selected from the group consisting of the following groups: NR5R6, C 1~6 Alkyl, C 1~6 optionally substituted with one or more of alkoxy and halo is selected from the group consisting of:

[0077] In still further embodiments, R2 is (i) each of the following groups: NR5R6, C 1~6 Alkyl, C 1~6 Heterocyclyl groups having 5 to 10 ring atoms, wherein 1 to 4 of the ring atoms are nitrogen or oxygen, optionally substituted by one or more of alkoxy and halo, and (ii)-XY wherein X is selected from the group consisting of heterocyclyl groups having 5 or 6 ring atoms, one or more of the ring atoms being nitrogen, and Y is selected from the group consisting of phenyl and heteroaryl groups having 5 or 6 ring atoms, one or more of the ring atoms being nitrogen, and the phenyl and heteroaryl groups of Y are selected from the group consisting of the following groups: NH, N(Me), C 1~6optionally substituted with one or more of alkyl, methoxy, ethoxy and halo is selected from the group consisting of:

[0078] In another embodiment, R2 is (i) Each of the following groups: NH2, NMe2, C 1~6 Heterocyclyl groups having 5 to 10 ring atoms, optionally substituted by one or more of alkyl, methoxy, ethoxy, and halo, wherein 1 to 4 of the ring atoms are nitrogen or oxygen; and (ii)-XY wherein X is selected from the group consisting of heterocyclyl groups having 5 or 6 ring atoms, one or more of the ring atoms being nitrogen, and Y is selected from the group consisting of phenyl and heteroaryl groups having 5 or 6 ring atoms, one or more of the ring atoms being nitrogen, and the phenyl and heteroaryl groups of Y are selected from the group consisting of the following groups: C 1~6 optionally substituted with one or more of alkyl, methoxy, ethoxy and halo is selected from the group consisting of:

[0079] In yet another embodiment, R2 is (i) heterocyclyl groups having 5 to 10 ring atoms, wherein 1 to 4 of the ring atoms are nitrogen or oxygen, each of which is optionally substituted with one or more of the following groups: NH, N(Me), methyl, methoxy, and halo; and (ii)-XY wherein X is selected from the group consisting of heterocyclyl groups having 5 or 6 ring atoms, one or more of the ring atoms being nitrogen, and Y is selected from the group consisting of phenyl and heteroaryl groups having 5 or 6 ring atoms, one or more of the ring atoms being nitrogen, the phenyl and heteroaryl groups of Y being optionally substituted with one to three of the following groups: methyl, methoxy, and halo. is selected from the group consisting of:

[0080] In still further embodiments, R2 is (i) heterocyclyl groups having 5 to 10 ring atoms, each of which is optionally substituted with 1 to 3 of the following groups: NH, N(Me), methyl, and methoxy, and 1 to 4 of the ring atoms are nitrogen or oxygen; and (ii)-XY wherein X is selected from the group consisting of heterocyclyl groups having 5 or 6 ring atoms, wherein one or two of the ring atoms is nitrogen, and Y is selected from the group consisting of phenyl and heteroaryl groups having 5 or 6 ring atoms, wherein one to three of the ring atoms is nitrogen, and the phenyl and heteroaryl groups of Y are optionally substituted with one or two of the following groups: methyl, methoxy, fluoro, and chloro. is selected from the group consisting of:

[0081] In still further embodiments, R2 is (i) heterocyclyl groups having 5 to 10 ring atoms, each of which is optionally substituted with 1 to 3 of the following groups: NH, N(Me), methyl, and methoxy, and 1 to 4 of the ring atoms are nitrogen or oxygen; and (ii)-XY wherein X is selected from the group consisting of heterocyclyl groups having 6 ring atoms, one or two of which are nitrogen, and Y is selected from the group consisting of phenyl and heteroaryl groups having 5 or 6 ring atoms, one or two of which are nitrogen, and the phenyl and heteroaryl groups of Y are optionally substituted with one or two of the following groups: methyl, methoxy, fluoro, and chloro. is selected from the group consisting of:

[0082] In yet another embodiment, R2 is [ka] may be selected from the group consisting of:

[0083] In one embodiment, R3 is halo, 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 Selected from the group consisting of aryl and heteroaryl groups having 5 to 10 ring atoms, wherein one or more of the ring atoms is selected from nitrogen, sulfur, and oxygen.

[0084] In another embodiment, R3 is halo, 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 Selected from the group consisting of aryl and heteroaryl groups having 5 or 6 ring atoms, where one or more of the ring atoms is selected from nitrogen, sulfur, and oxygen.

[0085] In a further embodiment, R3 is halo, 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 Selected from the group consisting of aryl and heteroaryl groups having 5 or 6 ring atoms, where one or more of the ring atoms is selected from nitrogen, sulfur, and oxygen.

[0086] In yet another embodiment, R3 is halo, C1~4 Alkoxy, OH, CN, NR5R6, C 1~4 Alkyl, C 3~6 Cycloalkyl, C 6~10 Selected from the group consisting of aryl and heteroaryl groups having 5 or 6 ring atoms, where one or more of the ring atoms is selected from nitrogen, sulfur, and oxygen.

[0087] In still further embodiments, R3 is halo, C 1~4 Alkoxy, OH, CN, NR5R6, C 1~4 Alkyl, C 3~6 Selected from the group consisting of cycloalkyl, phenyl, and heteroaryl groups having 5 or 6 ring atoms, where one or more of the ring atoms is selected from nitrogen, sulfur, and oxygen.

[0088] In yet another embodiment, R3 is halo, C 1~4 Alkoxy, OH, CN, C 1~4 Selected from the group consisting of alkyl, phenyl, and heteroaryl groups having 5 or 6 ring atoms, where one or more of the ring atoms is selected from nitrogen, sulfur, and oxygen.

[0089] In a further embodiment, R3 is halo, C 1~4 Alkoxy, OH, CN, C 1~4 It is selected from the group consisting of alkyl and phenyl.

[0090] In still further embodiments, R3 is halo, C 1~4 Alkoxy, CN and C 1~4 alkyl.

[0091] In yet another embodiment, R3 is halo, C 1~4 Alkoxy, CN, C 1~4 It is selected from the group consisting of alkyl and phenyl.

[0092] In still further embodiments, R3 is selected from the group consisting of chloro, fluoro, methoxy, ethoxy, and CN.

[0093] In another embodiment, R3 is selected from the group consisting of fluoro, methoxy, ethoxy, and CN.

[0094] In another embodiment, R3 is selected from the group consisting of fluoro, methoxy, and CN.

[0095] In one embodiment, R4 is H or CH3.

[0096] In one embodiment, R5 and R6 are independently selected from H and CH3.

[0097] In one embodiment, n is 1.

[0098] In one embodiment, m is 0, 1, or 2. In another embodiment, m is 0 or 1.

[0099] In another embodiment, a compound of formula (II): [ka] (In the formula, R7, Halo, 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 selected from the group consisting of aryl and heteroaryl groups having 5 to 10 ring atoms, wherein one or more of the ring atoms is selected from nitrogen, sulfur, and oxygen; Z1 is a heterocyclyl group having 5 to 10 ring atoms, one or more of the ring atoms being selected from nitrogen, sulfur, and oxygen; Z2 is each one of the following groups: NR5R6, C 1~6 Alkyl, OC 1~6 selected from phenyl, heteroaryl groups having 5 to 10 ring atoms, wherein one or more of the ring atoms is selected from nitrogen, sulfur, and oxygen, and heterocyclyl groups having 5 to 10 ring atoms, wherein one or more of the ring atoms is selected from nitrogen, sulfur, and oxygen, optionally substituted with one or more of alkyl and halo; p is 1 or 2, and o is an integer from 0 to 4, R4 to R6 are as defined in the first aspect. or a pharmaceutically acceptable salt or prodrug thereof.

[0100] In some embodiments, R7 is selected from the group consisting of halo, methoxy, OH, CN, NR5R6, and methyl.

[0101] In one embodiment, Z1 is a heterocyclyl group having 5 or 6 ring atoms, wherein one or more of the ring atoms is nitrogen, oxygen, or sulfur.

[0102] In another embodiment, Z1 is a heterocyclyl group having 5 or 6 ring atoms, one or two of the ring atoms being nitrogen, oxygen, or sulfur.

[0103] In further embodiments, Z1 is a heterocyclyl group having 5 or 6 ring atoms, one or two of the ring atoms being nitrogen.

[0104] In a further embodiment, Z1 is a heterocyclyl group having 6 ring atoms, one or two of the ring atoms being nitrogen.

[0105] In yet another embodiment, Z1 is [ka] is.

[0106]

[0106] In a further embodiment, Z2 is selected from the group consisting of phenyl and heteroaryl groups having 5 or 6 ring atoms, 1 to 3 of which are nitrogen, and the phenyl and heteroaryl groups are optionally substituted with 1 to 3 of the following groups: NH2, N(Me)2, methyl, methoxy, and halo.

[0107]

[0107] In yet another embodiment, Z2 is selected from the group consisting of phenyl and heteroaryl groups having 5 or 6 ring atoms, wherein 1 to 3 of the ring atoms are nitrogen, and the phenyl and heteroaryl groups are optionally substituted with one or two of the following groups: NH2, N(Me)2, methyl, methoxy, fluoro, and chloro.

[0108]

[0108] In still further embodiments, Z2 is selected from the group consisting of phenyl and heteroaryl groups having 5 or 6 ring atoms, one or two of which are nitrogen, and the phenyl and heteroaryl groups are optionally substituted with one or two of the following groups: NH2, N(Me)2, methyl, methoxy, fluoro, and chloro.

[0109] In one embodiment, o is 0 or 1. In another embodiment, o is 0.

[0110] In one embodiment, p is 1.

[0111] Exemplary compounds according to formula (I) and (II) include: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] There is.

[0112] In one embodiment, the compound of formula (I) is selected from any one or more of compounds 1-59 above in any combination.

[0113] In another embodiment, the compound of formula (II) is selected from any one or more of compounds 40-58 above in any combination.

[0114]

[0114] The compound of formula (II) can be used in any of the first to fourth and seventh to tenth aspects.

[0115]

[0115] The compounds of formula (I) and (II) contain a carbon-carbon double bond connecting the carbonyl group to the imidazo[1,2-a]pyridine ring. The present disclosure covers all geometric isomers, both cis and trans isomers. The compounds of formula (I) and (II) can exist as tautomers. The present disclosure covers all tautomers.

[0116]

[0116] Compounds of formula (I) and (II) are understood to include hydrates and solvates. A solvate is a complex formed by the association of molecules of a solvent with a compound of formula (I) or (II). In the case of compounds of formula (I) and (II) that are solids, it will be understood by those skilled in the art 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.

[0117]

[0117] The compounds of formula (I) and (II) can be in the form of pharmaceutically acceptable salts. Such salts are well known to those skilled in the art. SM Berge 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 isolation and purification of the compounds of formula (I) and (II) or 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 acids may be selected from aliphatic, alicyclic, aromatic, heterocyclic carboxylic and sulfonic acid classes, examples of which include 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, mesylic acid, salicylic acid, p-hydroxybenzoic acid, phenylacetic acid, pamoic acid, pantothenic acid, sulfanilic acid, cyclohexylaminosulfonic acid, stearic acid, alginic acid, β-hydroxybutyric acid, and galacturonic acid. Suitable pharmaceutically acceptable base addition salts of the 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'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), procaine, ammonium salts, quaternary salts such as tetramethylammonium salts, amino acid addition salts such as salts with glycine and arginine.

[0118]

[0118] The compounds of formula (I) and (II) are also extended to include all derivatives such as prodrugs having a physiologically cleavable leaving group that can be cleaved in vivo to give compounds of formula (I) and (II).

[0119] Compounds of formula (I) may be synthesized as described below in Scheme 1. [ka]

[0120]

[0120] Imidazo[1,2-a]pyridine derivatives (III), where Q is a leaving group such as a halide, can be reacted with α,β-unsaturated ketones (IV) to give compounds of formula (I). Armed with this synthetic procedure and common general knowledge, one skilled in the art will be able to easily prepare all compounds encompassed by formulas (I) and (II).

[0121] The compounds of Formula (I) and (II) find use in the treatment of fibrosis. Fibrosis can occur in many tissues in the body, typically as a result of inflammation or injury, and the present disclosure contemplates the treatment of any type of fibrosis occurring in any part of the body. In some embodiments, the fibrosis is in the lung, e.g., pulmonary fibrosis (including idiopathic pulmonary fibrosis), cystic fibrosis, or fibrosis resulting from radiation, e.g., radiation therapy. In other embodiments, the fibrosis can be renal fibrosis, cardiac fibrosis, or hepatic fibrosis, e.g., cirrhosis or bridging fibrosis. In alternative embodiments, the fibrosis can be arthrofibrosis, nephrogenic systemic fibrosis, retroperitoneal fibrosis, scleroderma / systemic sclerosis, myelofibrosis, or mediastinal fibrosis. In other embodiments, the fibrosis can be associated with arterial sclerosis, Crohn's disease, Dupuytren's contracture, keloids, Peyronie's disease, or adhesive capsulitis.

[0122] Compounds of Formula (I) and (II) also find use in the treatment of coronavirus-associated fibrosis. Coronaviruses are a group of related RNA viruses that cause disease 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"). Reports of pulmonary fibrotic disease, with a wide range of fibrotic changes ranging from pneumonia-associated fibrosis to severe acute lung injury, have occurred periodically in subjects diagnosed with Covid-19. Thus, in some embodiments, the fibrosis is pulmonary fibrosis caused by, associated with, or otherwise associated with coronavirus infection in a subject. In this context, the term "associated with or otherwise associated with" means that the pulmonary fibrosis or a symptom thereof has at least some association, whether direct or indirect, with coronavirus infection in a subject.

[0123] In subjects who have recovered from COVID-19, progressive fibrotic irreversible interstitial lung disease (characterized by declining lung function, increasing fibrosis on CT scans, worsening symptoms and quality of life, and premature death) can occur with varying frequency. In this regard, eliminating the cause of lung injury does not eliminate the development of progressive fibrotic irreversible interstitial lung disease. Furthermore, even relatively low levels of residual, non-progressive fibrosis can result in significant morbidity and mortality in elderly COVID-19 patient populations, many of whom may also have pre-existing lung pathologies. Thus, in some embodiments, the subject may have a coronavirus infection, or alternatively, the subject may have recovered from a coronavirus infection but may still be affected by pulmonary fibrosis or fibrotic injury or its symptoms, despite no longer having the virus. In treating fibrosis, the compounds of Formula (I) or (II) can act to reduce fibrotic injury in the subject.

[0124] In some embodiments, a compound of Formula (I) or (II) may be administered with one or more anti-inflammatory compounds. Anti-inflammatory compounds will be well known to those skilled in the art. Suitable anti-inflammatory compounds include both steroidal and non-steroidal anti-inflammatory 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, tixocortol pivalate, prednisolone, methylprednisolone, prednisone, budesonide, desonide, amcinonide, fluocinolone acetonide, fluocinonide, halcinonide, triamcinolone acetonide, beclomethasone, dexamethasone, fluocortolone, halometasone, and mometasone.

[0125] In some embodiments, a compound of Formula (I) or (II) may be administered with one or more antiviral compounds. Antiviral compounds will be known to those skilled in the art. Suitable antiviral compounds include, but are not limited to, remdesivir, acyclovir, boceprevir, darunavir, entecavir, nelfinavir, penciclovir, pleconaril, rilpivirine, and simeprevir.

[0126] In addition to treatment, compounds of Formula (I) and (II) can be used to prevent or minimize fibrosis, lung injury, and / or damage in subjects infected with or at risk of coronavirus infection. Such use can significantly reduce the burden of pulmonary fibrosis by preventing the onset of pulmonary fibrosis or otherwise minimizing its deleterious effects on the lungs. In some embodiments, compounds of Formula (I) or (II) are administered within one week of a subject being diagnosed with coronavirus. In other embodiments, compounds of Formula (I) or (II) can be administered within one week of the onset of ARDS in a subject. Administration within one week of the onset of ARDS is likely to optimize efficacy. In preventing or minimizing fibrosis, compounds of Formula (I) or (II) can also act to prevent or minimize fibrotic injury in a subject.

[0127]

[0127] Due to their anti-fibrotic effects, the compounds of formula (I) and (II) may also find use in minimizing the severity of coronavirus infection by treating, preventing or otherwise reducing the severity of lung injury or damage.

[0128] 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. Generally, the compounds and compositions can be administered parenterally (e.g., intravenously, intrathecally, subcutaneously, or intramuscularly), orally, rectally, by inhalation, or topically. Administration can be systemic, local, or topical.

[0129]

[0129] The particular route of administration used in a given situation will depend on several factors, including the nature of the fibrotic disorder being treated, the severity and extent of the fibrotic disorder, the required dose of the particular compound being delivered, and the potential side effects of the compound.

[0130] In general, suitable compositions may be prepared according to methods known to those skilled 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.

[0131]

[0131] Examples of pharmaceutically acceptable carriers or diluents are deionized or distilled water; saline solution; vegetable oils such as peanut oil, safflower oil, olive oil, cottonseed oil, maize oil or coconut oil; silicone oils such as polysiloxanes, such as methylpolysiloxane, phenylpolysiloxane and methylphenylpolysiloxane; volatile silicones; mineral oils such as liquid paraffin, petrolatum or squalane; cellulose derivatives such as methylcellulose, ethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose or hydroxypropylmethylcellulose; Cremophor®; cyclodextrin; lower alcohols such as ethanol or i-propanol; lower polyalkylene glycols or lower alkylene glycols such as polyethylene glycol, polypropylene glycol, ethylene glycol, propylene glycol, 1,3-butylene glycol or glycerin; fatty acid esters such as isopropyl palmitate, isopropyl myristate or ethyl oleate; polyvinylpyrrolidone; agar; carrageenan; gum tragacanth or gum arabic and petrolatum. Typically, the carrier or carriers will form from about 10% to about 99.9% by weight of the composition.

[0132]

[0132] 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, etc.), in the form of an ointment, cream or lotion suitable for topical administration, in a form suitable for delivery as eye drops, in an aerosol form suitable for administration by inhalation, such as intranasal or oral inhalation, or in a form suitable for parenteral administration, i.e., subcutaneous, intramuscular or intravenous injection.

[0133] For administration as an injectable solution or suspension, non-toxic parenterally acceptable diluents or carriers may include cyclodextrins (e.g., Captisol®), Cremophor®, Ringer's solution, isotonic saline, phosphate buffered saline, ethanol, and 1,2 propylene glycol. To facilitate injection and delivery, the compounds may also be added to PEG and non-PEGylated liposomes or micelles, etc., having specific targeting tags attached to the PEG moiety, such as RGD peptides or glutathione, to assist transport across the blood-brain barrier.

[0134]

[0134] Some examples of suitable carriers, diluents, excipients and adjuvants for oral use include cyclodextrin, Cremophor®, peanut oil, liquid paraffin, sodium carboxymethylcellulose, methylcellulose, sodium alginate, gum arabic, gum tragacanth, dextrose, sucrose, sorbitol, mannitol, gelatin and lecithin.In addition, these oral preparations can contain suitable flavorings and colorings.When used in capsule form, the capsule can be coated with a compound such as glyceryl stearate or glyceryl distearate to delay disintegration.

[0135]

[0135] Adjuvants typically include emollients, emulsifiers, thickeners, preservatives, bactericides and buffers.

[0136]

[0136] Solid forms for oral administration may contain binders, sweeteners, disintegrants, diluents, flavorings, coatings, preservatives, lubricants, and / or time-delay agents acceptable to human and veterinary medicine. Suitable binders include gum arabic, gelatin, corn starch, tragacanth, sodium alginate, carboxymethylcellulose, or polyethylene glycol. Suitable sweeteners include sucrose, lactose, glucose, aspartame, or saccharin. Suitable disintegrants include corn starch, methylcellulose, polyvinylpyrrolidone, guar gum, xanthan gum, bentonite, alginic acid, or agar. Suitable diluents include lactose, sorbitol, mannitol, dextrose, kaolin, cellulose, calcium carbonate, calcium silicate, or dicalcium phosphate. Suitable flavoring agents include peppermint oil, oil of wintergreen, cherry, orange, or raspberry flavoring. Suitable coating agents include polymers or copolymers of acrylic acid and / or methacrylic acid and / or their esters, waxes, fatty alcohols, zein, shellac, or gluten. Suitable preservatives include sodium benzoate, vitamin E, α-tocopherol, ascorbic acid, methylparaben, propylparaben, or sodium bisulfite. Suitable lubricants include magnesium stearate, stearic acid, sodium oleate, sodium chloride, or talc. Suitable time delay agents include glyceryl stearate or glyceryl distearate.

[0137]

[0137] Liquid forms suitable for oral administration may contain, in addition to the above active ingredients, a liquid carrier. Suitable liquid carriers include water, oils such as olive oil, peanut oil, sesame oil, sunflower oil, safflower oil, coconut oil, liquid paraffin, ethylene glycol, propylene glycol, polyethylene glycol, ethanol, propanol, isopropanol, glycerol, aliphatic alcohols, triglycerides, or mixtures thereof.

[0138]

[0138] Suspensions for oral administration may further comprise a dispersing agent and / or a suspending agent. Suitable suspending agents include sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, sodium alginate, or cetyl alcohol. Suitable dispersing agents include lecithin, polyoxyethylene esters of fatty acids such as stearic acid, polyoxyethylene sorbitol mono- or di-oleate, stearate, or laurate, polyoxyethylene sorbitan mono- or di-oleate, stearate, or laurate, etc.

[0139]

[0139] Emulsions for oral administration may further comprise one or more emulsifying agents. Suitable emulsifying agents include dispersing agents as exemplified above or natural gums such as guar gum, gum acacia, or gum tragacanth.

[0140]

[0140] Methods for preparing parenterally administrable compositions will be apparent to those skilled in the art and are described in detail, for example, in Remington's Pharmaceutical Science, 15th ed., Mack Publishing Company, Easton, PA, the entire contents of which are incorporated herein by reference.

[0141]

[0141] Topical formulations may contain the active ingredient together with one or more acceptable carriers and, optionally, other therapeutic ingredients. Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the area where treatment is required, such as rennets, lotions, creams, ointments, or pastes, and drops suitable for administration to the eye, ear, or nose.

[0142] Drops may comprise sterile aqueous or oily solutions or suspensions. These may be prepared by dissolving the active ingredient in an aqueous solution of a bactericide and / or fungicide and / or any other suitable preservative, optionally including a surfactant. The resulting solution may then be clarified by filtration, transferred to a suitable container, and sterilized. Sterilization may be accomplished by autoclaving, maintaining at 90°C to 100°C for 30 minutes, or by filtration, followed by transfer to a container using aseptic techniques. Examples of bactericides and fungicides suitable for inclusion in drops are phenylmercuric nitrate or acetate (0.002%), benzalkonium chloride (0.01%), and chlorhexidine acetate (0.01%). Suitable solvents for preparing oily solutions include glycerol, diluted alcohol, and propylene glycol.

[0143] Lotions include those suitable for application to the skin or eyes. Eye drops may comprise a sterile aqueous solution, optionally containing a bactericide, and may be prepared by methods similar to those described above in connection with the preparation of drops. Lotions or irrigants for application to the skin may also contain agents that speed drying and cool the skin, such as alcohol or acetone, and / or moisturizing agents, such as glycerol or an oil, such as olive oil.

[0144] Creams, ointments, or pastes are typically semi-solid preparations of the active ingredient for external application. They can be prepared by mixing the active ingredient, alone or in finely divided or powdered form dissolved or suspended in an aqueous or non-aqueous fluid, with an oily or non-greasy base. The base may contain hydrocarbons such as solid paraffin, soft paraffin, or liquid paraffin, glycerol, beeswax, metallic soaps; mucilage; naturally occurring oils such as almond, corn, peanut, castor, or olive oil; wool fat or its derivatives, or alcohols such as propylene glycol or macrogol together with fatty acids such as stearic acid or oleic acid.

[0145]

[0145] The composition may incorporate any suitable surfactant, such as an anionic, cationic or nonionic surfactant, for example, a sorbitan ester or a polyoxyethylene derivative thereof. Suspending agents such as natural gums, cellulose derivatives or inorganic materials such as quartz silica, and other ingredients such as lanolin may also be included.

[0146] In some embodiments, the compositions are administered in the form of suppositories 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 that is solid at ordinary temperature but liquid at rectal temperature and therefore melts 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.

[0147] The composition may also be administered or delivered to target cells in the form of liposomes. Liposomes are generally derived from phospholipids or other lipid substances and are formed by mono- or multi-lamellar hydrated liquid crystals dispersed in an aqueous medium. Specific examples of liposomes used in administering or delivering the composition to target cells include those containing synthetic cholesterol (Sigma), the phospholipid 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC, Avanti Polar). Lipids), the PEG lipid 3-N-[(-methoxypoly(ethylene glycol)2000)carbamoyl]-1,2-dimyristyloxy-propylamine (PEG-cDMA), and the cationic lipid 1,2-di-o-octadecenyl-3-(N,N-dimethyl)aminopropane (DODMA) or 1,2-dilinoleyloxy-3-(N,N-dimethylaminopropane (DLinDMA) in a molar ratio of 55:20:10:15 or 48:20:2:30, respectively. The liposomes were prepared using 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (DSPE PEG2000) and 50-100% hydrogenated phosphatidylcholine derived from soybean, such as Soy PC-75 or Soy PC-75. The lipid may be composed of PC-100. PEGs of different MW may be used and may be covalently linked 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 may be used. The liposome-formed composition may contain stabilizers, preservatives, excipients, etc. Preferred lipids are phospholipids and phosphatidylcholines (lecithins), both natural and synthetic. Methods for forming liposomes are known in the art, and in this regard, specific reference is made to Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, NY (1976), p. 33 (see below), the contents of which are incorporated herein by reference.

[0148]

[0148] The composition can also be administered in the form of microparticles or nanoparticles. Biodegradable microparticles formed from polylactide (PLA), polylactide-co-glycolide (PLGA), and epsilon-caprolactone (ε-caprolactone) have been extensively used as drug carriers to increase plasma half-life and thereby prolong efficacy (R. Kumar, M. 2000. J. Pharm. Pharmaceut. Sci. 3 (2) 234-258). Microparticles have been formulated for the delivery of various drug candidates, including vaccines, antibiotics, and DNA. Furthermore, these formulations have been developed for various delivery routes, including parenteral subcutaneous injection, intravenous injection, and inhalation.

[0149] The composition may incorporate a controlled-release matrix composed of sucrose acetate isobutyrate (SAIB) and an organic solvent or organic solvent mixture. A polymer additive may be added to the vehicle as a release modifier to further increase viscosity and slow the release rate. SAIB is a well-known food additive. It is a highly hydrophobic, fully esterified sucrose derivative with a nominal ratio of six isobutyric acid groups to two acetate groups. As a mixed ester, SAIB does not crystallize and exists as a clear, viscous liquid. Mixing SAIB with a pharmaceutically acceptable organic solvent, such as ethanol or benzyl alcohol, reduces the viscosity of the mixture sufficiently to allow injection. An active pharmaceutical ingredient may be added to the SAIB delivery vehicle to form a SAIB solution or suspension formulation. When the formulation is to be injected subcutaneously, the solvent may be different from the matrix, allowing the SAIB-drug or SAIB-drug-polymer mixture to be prepared as an in situ-forming depot.

[0150] For administration by inhalation, the compound of Formula (I) or (II) can be provided in the form of a dry powder and delivered by a dry powder inhaler (DPI). The dry powder can include a bulking agent, such as lactose. DPIs are well known to those skilled in the art. The compound of Formula (I) or (II) can alternatively be 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 metered-dose inhaler suitable for delivery by intranasal or oral inhalation. When the compound of Formula (I) or (II) is administered by inhalation, the method of the present invention can further include administration of a bronchodilator to increase airflow to the subject's lungs. Non-limiting examples of bronchodilators include salbutamol, pirbuterol, terbutaline, clenbuterol, salmeterol, bambuterol, and indacaterol. When a compound of Formula (I) or (II) is administered with a bronchodilator, the components can be administered simultaneously, sequentially in any order, or at different times to provide the desired effect. Alternatively, the components can be formulated together in a single dosage unit.

[0151] For purposes of this disclosure, the compounds and compositions can be administered to a subject either therapeutically or prophylactically. In therapeutic applications, the compositions are administered to a patient already suffering from fibrosis or a fibrotic disorder in an amount sufficient to cure or at least partially halt the fibrosis or fibrotic disorder and its complications. The composition should provide a sufficient amount of the compound to effectively treat the subject.

[0152]

[0152] The therapeutically effective amount for a 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 rate of sequestration of the compound; the duration of treatment; drugs used in combination or concomitantly with the compound, along with other relevant factors well known in medicine.

[0153]

[0153] One skilled in the art would be able, by routine experimentation, to determine an effective, non-toxic amount of the compound required to achieve the desired outcome.

[0154]

[0154] In general, effective doses are expected to be in the range of about 0.0001 mg to about 1000 mg per kg body weight per 24 hours; typically about 0.001 mg to about 750 mg per kg body weight per 24 hours; about 0.01 mg to about 500 mg per kg body weight per 24 hours; about 0.1 mg to about 500 mg per kg body weight per 24 hours; about 0.1 mg to about 250 mg per kg body weight per 24 hours, or about 1.0 mg to about 250 mg per kg body weight per 24 hours. More typically, effective dosage ranges are expected to be in the ranges of about 1.0 mg to about 200 mg per kg body weight per 24 hours; about 1.0 mg to about 100 mg per kg body weight per 24 hours; about 1.0 mg to about 50 mg per kg body weight per 24 hours; about 1.0 mg to about 25 mg per kg body weight per 24 hours; about 5.0 mg to about 50 mg per kg body weight per 24 hours; about 5.0 mg to about 20 mg per kg body weight per 24 hours; and about 5.0 mg to about 15 mg per kg body weight per 24 hours.

[0155] Alternatively, the effective dose may be up to about 500 mg / m 2 Generally, an effective dose is 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 , and even more preferably about 25 to about 250 mg / m 2 , and even more preferably about 50 to about 250 mg / m 2 , and even more preferably about 75 to about 150 mg / m 2 It is assumed that the range is

[0156]

[0156] It will be apparent to those skilled in the art that the optimal amount and interval of 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 particular individual being treated. Such optimal conditions can also be determined by conventional techniques.

[0157] The compounds of formula (I) may be used alone in the treatment of fibrotic disorders or alternatively in combination therapy with other therapeutic agents, such as anti-inflammatory compounds.

[0158]

[0158] The term "combination therapy" is intended to encompass the sequential administration of multiple therapeutic agents in a regimen that provides a beneficial effect, and includes the administration of these agents in a single formulation or in separate formulations.

[0159]

[0159] Combination therapy may involve administering active agents together, sequentially or with intervals in each case as needed. Combinations of active agents, including compounds of the present disclosure, may be synergistic.

[0160] Co-administration of the compounds of Formula (I) and (II) with the other therapeutic agent can be accomplished by the compound of Formula (I) or (II) being in the same dosage unit form as the other therapeutic agent, or the compound of Formula (I) or (II) and the other therapeutic agent can be in separate, separate unit dosage forms that are administered sequentially, simultaneously, or at similar times. Sequential administration can be in any order as needed, and may require that an ongoing physiological effect of the first or earlier agent be ongoing when the second or later agent is administered, particularly when a cumulative or synergistic effect is desired. When administered separately, it may be preferred, but not required, that the compound of Formula (I) or (II) and the other agent be administered by the same route of administration.

[0161]

[0161] According to various embodiments of the present disclosure, one or more compounds of formula (I) or (II) may be included in a combination therapy with surgery. [Example]

[0162]

[0162] The present disclosure is further described below with reference to the following non-limiting examples.

[0163] Example 1 – Compound Synthesis Compound 7 was prepared according to Scheme 2. [ka]

[0164] Step 1: To a solution of 2-amino-5-fluoropyridine (1.0 g, 8.9 mmol) in EtOH (8 ml) were added 2-bromo-1-phenyl-ethanone (1.5 g, 7.6 mmol) and NaHCO (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.

[0165] Step 2: 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 eluted through a pad of silica gel using dichloromethane. Concentration of the eluent gave 6-fluoro-3-iodo-2-phenylimidazo[1,2-a]pyridine, which was used without further purification.

[0166] Step 3: 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 solution was dried (MgSO4), filtered, and concentrated to give the crude product. Purification by silica gel flash column chromatography (5-100% ethyl acetate / hexanes) afforded (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.

[0167] The following compounds were prepared in a similar manner using the appropriate intermediates: (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. (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. (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. 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. (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.

[0168] The precursor compounds in Scheme 2 can be synthesized as follows. [ka]

[0169] 1-(1,3-Dihydroisoindol-2-yl)prop-2-en-1-one To a mixture of isoindoline (0.50 g, 4.2 mmol) in DCM (20 ml) is added triethylamine (25.2 mmol, 3.5 ml) at −78° C. After 10 min, a solution of acryloyl chloride (0.46 g, 5.0 mmol) in DCM (1 ml) is added dropwise. After 0.5 h, the reaction is concentrated and diluted with DCM and water. The layers are separated and the aqueous phase is extracted with DCM (2×). The combined organics are washed with brine and dried (MgSO4). Filtration and concentration give the crude product, which is purified by flash column chromatography (0-10% ethyl acetate / DCM) to give the desired product as a pale orange solid. [ka]

[0170] 1-(4-Methoxypiperidin-1-yl)prop-2-en-1-one A mixture of 4-methoxypiperidine (0.50 g, 4.3 mmol) and triethylamine (0.84 ml, 6.1 mmol) in DCM (5 ml) is cooled to −10° C. Acryloyl chloride (0.47 g, 5.2 mmol) is added dropwise as a solution in DCM (1 ml). After 10 minutes, the cooling bath is removed and the reaction is stirred at ambient temperature for 2 hours. The reaction is poured into water and DCM and the layers are separated. The aqueous phase is extracted with DCM (2×). The combined organics are washed with brine, dried (MgSO4), filtered, and concentrated to give the crude product. Purification by flash column chromatography (0-20% ethyl acetate / DCM) gives the desired product. [ka]

[0171] 1-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)prop-2-en-1-one 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 h. 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 dried (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 a mobile phase to give 1-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)prop-2-en-1-one as a white solid (1.17 g, 95%). LCMS (ESMS): m / z: 248.3 (M + +1).

[0172] Example 2 - Assay

[0171] TGF-β transformation regulates the proliferation and differentiation of fibroblasts, the primary constituent cells of fibrous tissue, and therefore representative compounds of the present disclosure were tested for their ability to inhibit TGF-β.

[0173] material 1. TGFβ / SMAD Signaling Pathway SBE Reporter - HEK293 Cell Line BPS Bioscience Catalog No.: 60653 2. Human TGFβ1 (BPS Bioscience #90900-1) 3. SIS3 (Sigma #S0447): Inhibitor of the TGFβ pathway. Prepare a stock solution in DMSO. 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). 5. Assay medium: MEM medium + 0.5% FBS + 1% non-essential amino acids + 1 mM Na-pyruvate + 1% Pen / Strep 6. 96-well tissue culture-treated white clear-bottom assay plates (Corning #3610) 7. ONE-Step™ Luciferase Assay System (BPS, Cat. No. 60690)

[0174] method SBE reporter-HEK293 cells were harvested from culture in growth medium and seeded in 100 μl of assay medium in white, clear-bottom 96-well microplates at a density of approximately 10,000 cells per well. The plate containing the cells was incubated in a CO2 incubator at 37°C. 24 hours after seeding, the cells were washed with 100 μL of assay buffer and treated with 3-fold serial dilutions of compounds in 50 μL of assay medium. The cells were incubated for 4 hours in a CO2 incubator at 37°C. To control wells, 50 μL of assay medium was added without inhibitor. 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 TGFβ1 concentration = 20 ng / ml). 5 μl of assay medium was added to unstimulated control wells (to determine basal activity). The plate with the cells was incubated overnight (approximately 18 hours) in a CO2 incubator at 37°C. After 18 hours of incubation, luciferase assays were performed using the ONE-Step™ Luciferase Assay System according to the provided protocol: 50 μl of ONE-Step™ Luciferase Reagent was added per well and shaken for approximately 10 minutes at room temperature. Luminescence was measured using a luminometer.

[0175] result The results are shown in Table 1 below.

[0176] [Table 1]

[0177] Compounds 6, 8, 9, 10 and 11 all exhibited inhibitory activity against TGF-β.

[0178] The citation of any reference herein should not be construed as an admission that such reference is available as prior art prior to the present application. Furthermore, reference herein to a prior publication (or information derived therefrom) or known matter is not, and should not be construed as, an acknowledgement or acknowledgment, or any form of suggestion that the prior publication (or information derived therefrom) or known matter forms part of the common general knowledge in the field of endeavor to which this specification pertains.

[0179]

[0173] Those skilled in the art will recognize that the present disclosure described herein is capable of variations and modifications other than those specifically described. It is to be understood that the present disclosure includes all such variations and modifications. The present disclosure also includes, individually or collectively, all of the steps, features, compositions and compounds referred to or shown in this specification, as well as any combination of two or more of said steps, features, compositions and compounds.

Claims

1. A method of treating fibrosis in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of formula (I): 【Chemical 1】 (In the formula, R １ are each the following groups: C １～６ Alkoxy, C １～６ Alkyl, CN, halo and C ３～１０ C optionally substituted with one or more cycloalkyl ６～１０ aryl, heteroaryl groups having 5 to 10 ring atoms, one or more of which are selected from nitrogen, sulfur and oxygen; C ３～１０ selected from the group consisting of cycloalkyl and heterocyclyl groups having 5 to 10 ring atoms, wherein one or more of the ring atoms is selected from nitrogen, sulfur, and oxygen; R ２ teeth, (i) each of the following groups: NR ５ R ６ , C １～６ Alkyl, C １～６ C optionally substituted with one or more of alkoxy and halo; ６～１０ aryl, heteroaryl groups having 5 to 10 ring atoms, one or more of which is selected from nitrogen, sulfur, and oxygen, and heterocyclyl groups having 5 to 10 ring atoms, one or more of which is selected from nitrogen, sulfur, and oxygen, and (ii) -X-Y wherein X is a heterocyclyl group having 5 to 10 ring atoms, one or more of which are selected from nitrogen, sulfur, and oxygen; ６～１０ selected from the group consisting of aryl and heteroaryl groups having 5 to 10 ring atoms, wherein one or more of the ring atoms is selected from nitrogen, sulfur, and oxygen; and Y is C ６～１０ aryl and heteroaryl groups having 5 to 10 ring atoms, wherein one or more of the ring atoms are selected from nitrogen, sulfur, and oxygen; ６～１０ The aryl and heteroaryl groups include the following groups: NR ５ R ６ , C １～６ Alkyl, C １～６ optionally substituted with one or more of alkoxy and halo is selected from the group consisting of R ３ Ha, Halo, C １～６ Alkoxy, OH, CN, NO ２ , -OC(O)R ４ , -C(O)R ４ , —C(O)NR ５ R ６ , -C(O)OR ４ , -OS(O) ２ R ４ , N.R. ５ R ６ , S.R. ４ , C １～１０ Alkyl, C ２～１０ Alkenyl, C ２～１０ Alkynyl, C ３～１０ Cycloalkyl, C ６～１０ selected from the group consisting of aryl and heteroaryl groups having 5 to 10 ring atoms, wherein one or more of the ring atoms is selected from nitrogen, sulfur, and oxygen; R ４ is H and C １～６ alkyl, R ５ and R ６ is H and C １～６ alkyl; n is 1 or 2, and m is an integer from 0 to 4. or a pharmaceutically acceptable salt or prodrug thereof.

2. R １ are each the following groups: C １～４ Alkoxy, C １～４ Alkyl, CN, halo and C ３～６ C optionally substituted with one or more cycloalkyl ６～１０ aryl, heteroaryl groups having 5 to 10 ring atoms, one or more of which are selected from nitrogen, sulfur and oxygen; C ３～１０ 2. The method of claim 1, wherein the heterocyclyl group is selected from the group consisting of cycloalkyl and heterocyclyl groups having 5 to 10 ring atoms, wherein one or more of the ring atoms is selected from nitrogen, sulfur, and oxygen.

3. R １ are each the following groups: C １～４ Alkoxy, C １～４ Alkyl, halo and C ３～６ C optionally substituted with one or more cycloalkyl ６～１０ aryl, heteroaryl groups having 5 to 10 ring atoms, one or more of which are selected from nitrogen, sulfur and oxygen; C ３～６ 3. The method of claim 1 or 2, wherein the heterocyclyl group is selected from the group consisting of cycloalkyl and heterocyclyl groups having 5 to 10 ring atoms, wherein one or more of the ring atoms is selected from nitrogen, sulfur, and oxygen.

4. R １ are each the following groups: C １～４ Alkyl, halo and C ３～６ C optionally substituted with one or more cycloalkyl ６～１０ 4. The method of any one of claims 1 to 3, wherein the heteroaryl group is selected from the group consisting of aryl, heteroaryl groups having 5 to 10 ring atoms, wherein one or more of the ring atoms is selected from nitrogen, sulfur, and oxygen, and heterocyclyl groups having 5 to 10 ring atoms, wherein one or more of the ring atoms is selected from nitrogen, sulfur, and oxygen.

5. R １ are each the following groups: C １～４ Alkyl, halo and C ３～６ C optionally substituted with one or more cycloalkyl ６～１０ 5. The method of any one of claims 1 to 4, wherein the heteroaryl group is selected from the group consisting of aryl, heteroaryl groups having 5 or 6 ring atoms, one or more of which are selected from nitrogen, sulfur, and oxygen, and heterocyclyl groups having 5 or 6 ring atoms, one or more of which are selected from nitrogen, sulfur, and oxygen.

6. R １ are each the following groups: C １～４ Alkyl, halo and C ３～４ 6. The method of any one of claims 1 to 5, wherein the heteroaryl group has 5 or 6 ring atoms, and wherein one or more of the ring atoms is selected from nitrogen, sulfur, and oxygen, and wherein the heterocyclyl group has 5 or 6 ring atoms, and wherein one or more of the ring atoms is selected from nitrogen, sulfur, and oxygen, optionally substituted with one or more of the cycloalkyl groups.

7. R １ are each the following groups: C １～３ 7. The method of any one of claims 1 to 6, wherein the heteroaryl group is selected from the group consisting of phenyl, heteroaryl groups having 5 or 6 ring atoms, wherein one or more of the ring atoms is selected from nitrogen, sulfur, and oxygen, optionally substituted with one or more of alkyl, halo, and cyclopropyl, and heterocyclyl groups having 5 or 6 ring atoms, wherein one or more of the ring atoms is selected from nitrogen, sulfur, and oxygen.

8. R １ are each the following groups: C １～３ 8. The method of any one of claims 1 to 7, wherein the heteroaryl group is selected from the group consisting of phenyl, heteroaryl groups having 5 or 6 ring atoms, wherein one to three of the ring atoms are selected from nitrogen, sulfur, and oxygen, and heterocyclyl groups having 5 or 6 ring atoms, wherein one or two of the ring atoms are selected from nitrogen, sulfur, and oxygen, optionally substituted with one or more of alkyl, halo, and cyclopropyl.

9. R １ are each the following groups: C １～３ 9. The method of any one of claims 1 to 8, wherein the heteroaryl group is selected from the group consisting of phenyl, heteroaryl groups having 5 or 6 ring atoms, wherein one to three of the ring atoms are selected from nitrogen, sulfur, and oxygen, optionally substituted with one or more of alkyl, halo, and cyclopropyl, and heterocyclyl groups having 5 or 6 ring atoms, wherein one or two of the ring atoms are selected from nitrogen and oxygen.

10. R １ is selected from the group consisting of phenyl, heteroaryl groups having 5 or 6 ring atoms, wherein one to three of the ring atoms are selected from nitrogen, sulfur, and oxygen, each of which is optionally substituted with one or more of the following groups: methyl, chloro, fluoro, and cyclopropyl; and heterocyclyl groups having 5 or 6 ring atoms, wherein one or two of the ring atoms are selected from nitrogen and oxygen.

11. R １ is selected from the group consisting of phenyl, heteroaryl groups having 5 or 6 ring atoms, wherein 1 to 3 of the ring atoms are selected from nitrogen, sulfur, and oxygen, each of which is optionally substituted with one or two of the following groups: methyl, chloro, fluoro, and cyclopropyl; and heterocyclyl groups having 6 ring atoms, wherein 1 or 2 of the ring atoms are selected from nitrogen and oxygen.

12. R １ is selected from the group consisting of phenyl, heteroaryl groups having 5 or 6 ring atoms, wherein 1 to 3 of the ring atoms are selected from nitrogen, sulfur, and oxygen, each of which is optionally substituted with one of the following groups: methyl, chloro, fluoro, and cyclopropyl; and heterocyclyl groups having 6 ring atoms, wherein 1 or 2 of the ring atoms are selected from nitrogen and oxygen.

13. R １ teeth, 【Chemistry 2】 The method of any one of claims 1 to 12, selected from the group consisting of:

14. R ２ teeth, (i) each of the following groups: NR ５ R ６ , C １～６ Alkyl, C １～６ C optionally substituted with one or more of alkoxy and halo; ６～１０ aryl, heteroaryl groups having 5 to 10 ring atoms, one or more of which is nitrogen; heterocyclyl groups having 5 to 10 ring atoms, one or more of which is nitrogen or oxygen; and (ii) -X-Y wherein X is a heterocyclyl group having 5 to 10 ring atoms, one or more of the ring atoms being nitrogen or oxygen; ６～１０ selected from the group consisting of aryl and heteroaryl groups having 5 to 10 ring atoms, wherein one or more of the ring atoms is selected from nitrogen, sulfur, and oxygen; and Y is C ６～１０ aryl and heteroaryl groups having 5 to 10 ring atoms, one or more of said ring atoms being nitrogen; ６～１０ The aryl and heteroaryl groups include the following groups: NR ５ R ６ , C １～６ Alkyl, C １～６ optionally substituted with one or more of alkoxy and halo The method of any one of claims 1 to 13, selected from the group consisting of:

15. R ２ teeth, (i) each of the following groups: NR ５ R ６ , C １～６ Alkyl, C １～６ phenyl, heteroaryl groups having 5 to 10 ring atoms, wherein one or more of the ring atoms is nitrogen, heterocyclyl groups having 5 to 10 ring atoms, wherein one or more of the ring atoms is nitrogen or oxygen, optionally substituted with one or more of alkoxy and halo; and (ii) -X-Y wherein X is selected from the group consisting of heterocyclyl groups having 5 to 10 ring atoms, one or more of the ring atoms being nitrogen, phenyl, and heteroaryl groups having 5 or 6 ring atoms, one or more of the ring atoms being nitrogen; and Y is selected from the group consisting of phenyl and heteroaryl groups having 5 or 6 ring atoms, one or more of said ring atoms being nitrogen, and said phenyl and heteroaryl groups of Y are selected from the group: NR ５ R ６ , C １～６ Alkyl, C １～６ optionally substituted with one or more of alkoxy and halo The method of any one of claims 1 to 14, selected from the group consisting of:

16. R ２ teeth, (i) each of the following groups: NR ５ R ６ , C １～６ Alkyl, C １～６ Heteroaryl groups having 5 to 10 ring atoms, optionally substituted with one or more of alkoxy and halo, wherein one or more of the ring atoms is nitrogen; heterocyclyl groups having 5 to 10 ring atoms, wherein one or more of the ring atoms is nitrogen or oxygen; and (ii) -X-Y wherein X is selected from the group consisting of a heterocyclyl group having 5 to 10 ring atoms, one or more of said ring atoms being nitrogen, phenyl, and Y is selected from the group consisting of phenyl and heteroaryl groups having 5 or 6 ring atoms, one or more of said ring atoms being nitrogen, and said phenyl and heteroaryl groups of Y are selected from the group: NR ５ R ６ , C １～６ Alkyl, C １～６ optionally substituted with one or more of alkoxy and halo The method of any one of claims 1 to 15, selected from the group consisting of:

17. R ２ teeth, (i) each of the following groups: NR ５ R ６ , C １～６ Alkyl, C １～６ heterocyclyl groups having 5 to 10 ring atoms optionally substituted with one or more of alkoxy and halo, wherein one or more of the ring atoms is nitrogen or oxygen; and (ii) -X-Y wherein X is selected from the group consisting of heterocyclyl groups having 5 or 6 ring atoms, one or more of said ring atoms being nitrogen; and Y is selected from the group consisting of phenyl and heteroaryl groups having 5 or 6 ring atoms, one or more of said ring atoms being nitrogen, and said phenyl and heteroaryl groups of Y are selected from the group: NR ５ R ６ , C １～６ Alkyl, C １～６ optionally substituted with one or more of alkoxy and halo The method of any one of claims 1 to 16, selected from the group consisting of:

18. R ２ teeth, (i) each of the following groups: NR ５ R ６ , C １～６ Alkyl, C １～６ heterocyclyl groups having 5 to 10 ring atoms, optionally substituted with one or more of alkoxy and halo, wherein 1 to 4 of the ring atoms are nitrogen or oxygen; and (ii) -X-Y wherein X is selected from the group consisting of heterocyclyl groups having 5 or 6 ring atoms, one or more of said ring atoms being nitrogen; and Y is selected from the group consisting of phenyl and heteroaryl groups having 5 or 6 ring atoms, one or more of said ring atoms being nitrogen, and said phenyl and heteroaryl groups of Y are selected from the group: NH ２ , N(Me) ２ , C １～６ optionally substituted with one or more of alkyl, methoxy, ethoxy and halo The method of any one of claims 1 to 17, selected from the group consisting of:

19. R ２ teeth, (i) each of the following groups: NH ２ , NMe ２ , C １～６ Heterocyclyl groups having 5 to 10 ring atoms, optionally substituted with one or more of alkyl, methoxy, ethoxy, and halo, wherein 1 to 4 of the ring atoms are nitrogen or oxygen; and (ii) -X-Y wherein X is selected from the group consisting of heterocyclyl groups having 5 or 6 ring atoms, one or more of said ring atoms being nitrogen; and Y is selected from the group consisting of phenyl and heteroaryl groups having 5 or 6 ring atoms, one or more of said ring atoms being nitrogen, and said phenyl and heteroaryl groups of Y are selected from the group consisting of: １～６ optionally substituted with one or more of alkyl, methoxy, ethoxy and halo The method of any one of claims 1 to 18, selected from the group consisting of:

20. R ２ teeth, (i) each of the following groups: NH ２ , N(Me) ２ heterocyclyl groups having 5 to 10 ring atoms optionally substituted with one or more of methyl, methoxy, and halo, wherein 1 to 4 of the ring atoms are nitrogen or oxygen; and (ii) -X-Y wherein X is selected from the group consisting of heterocyclyl groups having 5 or 6 ring atoms, one or more of said ring atoms being nitrogen; and Y is selected from the group consisting of phenyl and heteroaryl groups having 5 or 6 ring atoms, one or more of said ring atoms being nitrogen, and said phenyl and heteroaryl groups of Y are optionally substituted with one to three of the following groups: methyl, methoxy, and halo. The method of any one of claims 1 to 19, selected from the group consisting of:

21. R ２ teeth, (i) each of the following groups: NH ２ , N(Me) ２ heterocyclyl groups having 5 to 10 ring atoms, optionally substituted with 1 to 3 of methyl and methoxy, wherein 1 to 4 of the ring atoms are nitrogen or oxygen; and (ii) -X-Y wherein X is selected from the group consisting of heterocyclyl groups having 5 or 6 ring atoms, one or two of said ring atoms being nitrogen; and Y is selected from the group consisting of phenyl and heteroaryl groups having 5 or 6 ring atoms, wherein 1 to 3 of the ring atoms are nitrogen, and the phenyl and heteroaryl groups of Y are optionally substituted with one or two of the following groups: methyl, methoxy, fluoro, and chloro. The method of any one of claims 1 to 20, selected from the group consisting of:

22. R ２ teeth, (i) each of the following groups: NH ２ , N(Me) ２ heterocyclyl groups having 5 to 10 ring atoms, optionally substituted with 1 to 3 of methyl and methoxy, wherein 1 to 4 of the ring atoms are nitrogen or oxygen; and (ii) -X-Y wherein X is selected from the group consisting of heterocyclyl groups having 6 ring atoms, one or two of said ring atoms being nitrogen; and Y is selected from the group consisting of phenyl and heteroaryl groups having 5 or 6 ring atoms, one or two of said ring atoms being nitrogen, said phenyl and heteroaryl groups of Y being optionally substituted with one or two of the following groups: methyl, methoxy, fluoro, and chloro. The method of any one of claims 1 to 21, selected from the group consisting of:

23. R ２ teeth, 【Chemistry 3】 The method of any one of claims 1 to 22, selected from the group consisting of:

24. R ３ Ha, Halo, C １～６ Alkoxy, OH, CN, —OC(O)R ４ , -C(O)R ４ , —C(O)NR ５ R ６ , -C(O)OR ４ , N.R. ５ R ６ , C １～１０ Alkyl, C ２～１０ Alkenyl, C ２～１０ Alkynyl, C ３～１０ Cycloalkyl, C ６～１０ 24. The method of any one of claims 1 to 23, wherein the heteroaryl group is selected from the group consisting of aryl and heteroaryl groups having 5 to 10 ring atoms, wherein one or more of the ring atoms is selected from nitrogen, sulfur, and oxygen.

25. R ３ Ha, Halo, C １～６ Alkoxy, OH, CN, —C(O)R ４ , —C(O)NR ５ R ６ , -C(O)OR ４ , N.R. ５ R ６ , C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C ３～１０ Cycloalkyl, C ６～１０ 25. The method of any one of claims 1 to 24, wherein the heteroaryl group is selected from the group consisting of aryl and heteroaryl groups having 5 or 6 ring atoms, wherein one or more of the ring atoms is selected from nitrogen, sulfur, and oxygen.

26. R ３ Ha, Halo, C １～６ Alkoxy, OH, CN, NR ５ R ６ , C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C ３～６ Cycloalkyl, C ６～１０ 26. The method of any one of claims 1 to 25, wherein the heteroaryl group is selected from the group consisting of aryl and heteroaryl groups having 5 or 6 ring atoms, wherein one or more of the ring atoms is selected from nitrogen, sulfur, and oxygen.

27. R ３ Ha, Halo, C １～４ Alkoxy, OH, CN, NR ５ R ６ , C １～４ Alkyl, C ３～６ Cycloalkyl, C ６～１０ 27. The method of any one of claims 1 to 26, wherein the heteroaryl group is selected from the group consisting of aryl and heteroaryl groups having 5 or 6 ring atoms, wherein one or more of the ring atoms is selected from nitrogen, sulfur, and oxygen.

28. R ３ Ha, Halo, C １～４ Alkoxy, OH, CN, NR ５ R ６ , C １～４ Alkyl, C ３～６ 28. The method of any one of claims 1 to 27, wherein the heteroaryl group is selected from the group consisting of cycloalkyl, phenyl, and heteroaryl groups having 5 or 6 ring atoms, wherein one or more of the ring atoms is selected from nitrogen, sulfur, and oxygen.

29. R ３ Ha, Halo, C １～４ Alkoxy, OH, CN, C １～４ 29. The method of any one of claims 1 to 28, wherein the heteroaryl group is selected from the group consisting of alkyl, phenyl, and heteroaryl groups having 5 or 6 ring atoms, wherein one or more of the ring atoms is selected from nitrogen, sulfur, and oxygen.

30. R ３ Ha, Halo, C １～４ Alkoxy, OH, CN, C １～４ 30. The method of any one of claims 1 to 29, wherein the alkyl group is selected from the group consisting of alkyl and phenyl.

31. R ３ Ha, Halo, C １～４ Alkoxy, CN and C １～４ The method of any one of claims 1 to 30, wherein the alkyl is selected from the group consisting of alkyl.

32. R ３ Ha, Halo, C １～４ Alkoxy, CN, C １～４ 32. The method of any one of claims 1 to 31, wherein the alkyl group is selected from the group consisting of alkyl and phenyl.

33. R ３ The method of any one of claims 1 to 32, wherein is selected from the group consisting of chloro, fluoro, methoxy, ethoxy and CN.

34. R ３ The method of any one of claims 1 to 33, wherein is selected from the group consisting of fluoro, methoxy, ethoxy and CN.

35. R ３ The method of any one of claims 1 to 34, wherein is selected from the group consisting of fluoro, methoxy and CN.

36. R ４ is H or CH ３ The method according to any one of claims 1 to 35, wherein

37. R ５ and R ６ is H and CH ３ 37. The method of any one of claims 1 to 36, wherein the

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

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

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

41. The compound of formula (I) is 【Chemistry 4】 【Chemistry 5】 【Chemistry 6】 【Chemistry 7】 【Chemistry 8】 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】 【Chemistry 16】 【Chemistry 17】 【Chemistry 18】 2. The method of claim 1, wherein the compound is selected from the group consisting of:

42. 42. The method of any one of claims 1 to 41, wherein the fibrosis is pulmonary fibrosis, radiation-induced fibrosis, 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 sclerosis, Crohn's disease, Dupuytren's contracture, keloids, Peyronie's disease or adhesive capsulitis.

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

44. 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 injury.

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

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

48. 48. The method of claim 46 or 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 in combination with one or more anti-inflammatory compounds.

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

51. 10. A method of preventing or minimizing fibrosis in a subject infected with or at risk of being infected with coronavirus, comprising administering to the subject an effective amount of a compound of formula (I) according to claim 1.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

68. Formula (II): 【Chemistry 19】 (In the formula, R ７ Ha, Hello, OC １～６ Alkyl, OH, CN, NO ２ , -OC(O)R ４ , -C(O)R ４ , —C(O)NR ５ R ６ , -C(O)OR ４ , -OS(O) ２ R ４ , N.R. ５ R ６ , S.R. ４ , C １～１０ Alkyl, C ２～１０ Alkenyl, C ２～１０ Alkynyl, C ３～１０ Cycloalkyl, C ６～１０ selected from the group consisting of aryl and heteroaryl groups having 5 to 10 ring atoms, wherein one or more of the ring atoms is selected from nitrogen, sulfur, and oxygen; Z １ is a heterocyclyl group having 5 to 10 ring atoms, one or more of which is selected from nitrogen, sulfur, and oxygen; Z ２ are each the following groups: NR ５ R ６ , C １～６ Alkyl, OC １～６ optionally substituted with one or more of alkyl and halo; phenyl; heteroaryl groups having 5 to 10 ring atoms, wherein one or more of the ring atoms is selected from nitrogen, sulfur, and oxygen; and heterocyclyl groups having 5 to 10 ring atoms, wherein one or more of the ring atoms is selected from nitrogen, sulfur, and oxygen; p is 1 or 2, and o is an integer from 0 to 4; R ４ ~R ６ is as defined in claim 1) or a pharmaceutically acceptable salt or prodrug thereof.

69. R ７ is halo, methoxy, OH, CN, NR ５ R ６ and methyl.

70. Z １ 70. The compound of claim 68 or 69, wherein is a heterocyclyl group having 5 or 6 ring atoms, one or more of the ring atoms being nitrogen, oxygen, or sulfur.

71. Z １ 71. The compound of any one of claims 68 to 70, wherein is a heterocyclyl group having 5 or 6 ring atoms, one or two of which are nitrogen, oxygen, or sulfur.

72. Z １ 72. The compound of any one of claims 68 to 71, wherein is a heterocyclyl group having 5 or 6 ring atoms, one or two of which are nitrogen.

73. Z １ 73. The compound of any one of claims 68 to 72, wherein is a heterocyclyl group having six ring atoms, one or two of which are nitrogen.

74. Z １ teeth, 【Chemistry 20】 The compound according to any one of claims 68 to 73, wherein

75. Z ２ is selected from the group consisting of phenyl and heteroaryl groups having 5 or 6 ring atoms, 1 to 3 of which are nitrogen, and the phenyl and heteroaryl groups are selected from the group: NH ２ , N(Me) ２ 75. The compound of any one of claims 68 to 74, optionally substituted with one to three of: methyl, methoxy and halo.

76. Z ２ is selected from the group consisting of phenyl and heteroaryl groups having 5 or 6 ring atoms, 1 to 3 of which are nitrogen, and the phenyl and heteroaryl groups are selected from the group: NH ２ , N(Me) ２ 76. The compound of any one of claims 68 to 75, optionally substituted with one or two of: methyl, methoxy, fluoro and chloro.

77. Z ２ is selected from the group consisting of phenyl and heteroaryl groups having 5 or 6 ring atoms, one or two of said ring atoms being nitrogen, said phenyl and heteroaryl groups being selected from the group: NH ２ , N(Me) ２ 76. The compound of any one of claims 68 to 75, optionally substituted with one or two of: methyl, methoxy, fluoro and chloro.

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

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

80. 80. The compound of 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, together with a pharmaceutically acceptable carrier, diluent or excipient.

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