WO2021104416A1

WO2021104416A1 - Compounds and methods for treating inflammatory bowel disease

Info

Publication number: WO2021104416A1
Application number: PCT/CN2020/132048
Authority: WO
Inventors: Chun-Chieh Hsu; Hsi-Lin Chiu; Hsiao-Wen Wang; Yu-Shu Kuei; Shu-Hao Chang
Original assignee: Medical And Pharmaceutical Industry Technology And Development Center
Priority date: 2019-11-29
Filing date: 2020-11-27
Publication date: 2021-06-03
Also published as: TW202123931A; WO2021104034A1; TW202120074A

Abstract

Provided are compounds of formula (I), which can be used as a selective tyrosine kinase inhibitor(Syk) and for the treatment of inflammatory bowel disease(IBD).

Description

COMPOUNDS AND METHODS FOR TREATING INFLAMMATORY BOWEL DISEASE

CROSS-REFERENCES TO RELATED APPLICATIONS

This application claims priority and the benefit of U.S. Provisional Patent Application No. 62/941,884, filed November 29, 2019, the entireties of which is incorporated herein by reference.

BACKGROUND OF THE INVENTION

1. FIELD OF THE INVENTION

The present disclosure relates to treatment of inflammatory bowel disease (IBD) . More particularly, the disclosure invention relates to novel spleen tyrosine kinase (Syk) inhibitors and their uses in the treatment of IBD.

2. DESCRIPTION OF RELATED ART

Inflammatory bowel disease (IBD) is an umbrella term primarily used to describe two conditions: Crohn's disease and ulcerative colitis (UC) . Both diseases are characterized by recurrent intestinal inflammation and epithelial injury believed to be initiated by an inappropriate response to the gut microbiota. Current medications used for IBD may not be enough for remission, creating a need for more potent and reliable medications.

A selective spleen tyrosine kinase (Syk) inhibitor, fostamatinib, has been shown to decrease mucosal damage in a mouse acetic acid–induced colitis model (J Crohns Colitis. 2015 9 (10) : 907-917) . Accordingly, Syk may serve as a target for identifying potential candidate useful for the development of a medicament suitable for treating IBD.

Inventors of the present disclosure unexpectedly identify novel compounds that inhibit Syk activity, these compounds are therefore potential candidates for the development of medicaments suitable for treating IBD and/or disorders associated with inhibition of Syk.

SUMMARY

The present disclosure is based on the unexpected discoveries that the novel compounds of this application are effective in inhibiting the activity of spleen tyrosine kinase, and lipopolysaccharide (LPS) -induced nitric oxide (NO) production, therefore are useful for treating IBD and improving the IBD disease activation index (DAI) in a subject. As such, these novel compounds as described herein can be used in treating IBD, as well as other diseases associated with IBD.

In one aspect, the present disclosure provides compounds of formula (I)

or a pharmaceutical acceptable salt, or solvate thereof,

wherein,

R ^a and R ^b are independently selected from the group consisting of hydrogen, halogen, and alkyl; or R ^a and R ^b are taken together to form a heterocyclyl;

X is alkylene, or -C (=O) (CH ₂) _n-, in which n is 0, 1, or 2;

Y is selected from the group consisting of halogen, phenyl and heterocyclyl;

the heterocyclyl is selected from the group consisting of furanyl, thiopheneyl, dioxolanyl, pyrrolyl, pyridinyl, indolinyl, indazolyl, and benzimidazole;

each of the phenyl and the heterocyclyl are optionally substituted with one or more of halogen, alkyl, hydroxy, -NO ₂, -CN, -CF ₃, -CONR’R”, - (CH ₂) _aCOOR’, -SO ₂R’, -NR’R”, pyrazolyl, pyrrolidinyl, piperidinyl, morpholinyl, or piperazinyl;

a is 0 or 1;

R’ and R” are independently hydrogen, C _1-5 alkyl or -COR; and

R is hydrogen or alkyl.

According to some embodiments of the present disclosure, the compound of formula (I) may be any one of formulas (II) , (III) , or (IV) ,

wherein,

m is 1 or 2;

R ^a, R ^b, R ^c and R ^d are independently hydrogen, halogen or alkyl; and

R ₁, R ₂, R ₃, R ₄, and R ₅ are independently selected from the group consisting of hydrogen, halogen, -NO ₂, -CN, -CF ₃, -CONH ₂, -COOCH ₃, -SO ₂CH ₃, and -CH ₂COOCH ₃.

According to some preferred embodiments of the present disclosure, the compound of formula (II) may be any one of,

According to other preferred embodiments of the present disclosure, the compound of formula (III) may be any one of,

According to certain embodiment of the present disclosure, the compound of formula (IV) is

According to some embodiments of the present disclosure, the compound of formula (I) has the structure of formula (V)

wherein

m is an integral from 1 to 5; and

Y is halogen.

According to certain embodiment of the present disclosure, the compound of formula (V) is

According to some embodiments of the present disclosure, the compound of formula (I) has the structure of formula (VI)

wherein

n is 0, 1 or 2;

R ₁, R ₂, R ₃, R ₄, and R ₅ are independently selected from the group consisting of hydrogen, halogen, -NO ₂, -CN, -CF ₃, -COOH, -NR’R”, -CONR’R”, -COOR’, pyrazolyl, pyrrolidinyl, piperidinyl, morpholinyl, or piperazinyl;

R’ and R” are independently hydrogen, C _1-5 alkyl or -COR; and

R is hydrogen or alkyl.

According to some preferred embodiments of the present disclosure, the compound of formula (VI) may be any one of,

According to some embodiments of the present disclosure, the compound of formula (I) has the structure of formula (VII)

wherein

Y is the heterocyclyl selected from the group consisting of furanyl, thiopheneyl, dioxolanyl, pyrrolyl, pyridinyl, indolinyl, and benzimidazole; and

the heterocyclyl is optionally substituted with one or more of halogen, alkyl, and -CF ₃.

According to certain embodiment of the present disclosure, the compound of formula (VII) may be any one of,

In another aspect, the present disclosure is directed to a method for treating an inflammatory bowel disease (IBD) in a subject. The method includes the step of administering to the subject an effective amount of any one of the compound of the present disclosure, or any one of the compound of formula (II) to (VII) .

According to preferred embodiments of the present disclosure, the compound is any one of,

According to embodiments of the present disclosure, the compound is administered in the amount of 0.01 to 100 mg/Kg to the subject.

Examples of the subject suitable for receiving treatment of the present disclosure include, but are not limited to, mammals. Preferably, the subject is a human.

Also within the scope of the present disclosure is the use of any of the compounds described herein for the manufacture of a medicament for the treatment of any of the target diseases described herein.

Many of the attendant features and advantages of the present disclosure will becomes better understood with reference to the following detailed description considered in connection with the accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

The present description will be better understood from the following detailed description read in light of the accompanying drawings, where:

FIG 1A is a bar diagram depicting respective effects of the present compounds PDC-II-001, PDC-II-002, and PDC-1I-003 on wound healing in accordance with one embodiment of the present disclosure;

FIG 1B is a bar diagram depicting respective effects of the present compounds PDC-I-001, PDC-I-004, PDC-1-008, PDC-I-012, PDC-I-014, PDC-1-016 and PDC-1-017 on wound healing in accordance with one embodiment of the present disclosure;

FIG 1C is a bar diagram depicting respective effects of the present compounds PDC-1-003, PDC-1-013, PDC-1-015, PDC-1-018, PDC-1I-004, PDC-I1-010, and PDC-1I-040 on wound healing in accordance with one embodiment of the present disclosure;

FIG 1D is a bar diagram depicting respective effects of the present compounds PDC-1I-009, PDC-I1-023, and PDC-1I-039 on wound healing in accordance with one embodiment of the present disclosure;

FIG 1E is a bar diagram depicting the effect of the present compound PDC-1I-041 on wound healing in accordance with one embodiment of the present disclosure;

FIG 1F is a bar diagram depicting respective effects of the present compounds PDC-1I-016, PDC-1I-017, PDC-1I-027, PDC-1I-035, PDC-1I-037, and PDC-1I-038 on wound healing in accordance with one embodiment of the present disclosure;

FIG 1G is a bar diagram depicting respective effects of the present compounds PDC-1-007, PDC-1I-005, PDC-1I-007, PDC-1I-008, PDC-1I-031, and PDC-1I-034 on wound healing in accordance with one embodiment of the present disclosure;

FIG 1H is a bar diagram depicting respective effect of the present compound PDC-1-009, PDC-1I-011, PDC-1I-029, and PDC-1I-043 on wound healing in accordance with one embodiment of the present disclosure;

FIG 1I is a bar diagram depicting respective effects of the present compounds PDC-1I-033, and PDC-1I-041 on wound healing in accordance with one embodiment of the present disclosure;

FIG 1J is a bar diagram depicting respective effects of the present compounds PDC-1-004a, PDC-1-004b, PDC-1-004c, PDC-1-004d, PDC-1-011, and PDC-1-017a on wound healing in accordance with one embodiment of the present disclosure; and

FIG 1K is a bar diagram depicting respective effects of the present compounds PDC-1I-012, PDC-1I-014, PDC-1I-015, PDC-1I-018, PDC-1I-019, and PDC-1I-022 on wound healing in accordance with one embodiment of the present disclosure.

In accordance with common practice, the various described features/elements are not drawn to scale but instead are drawn to best illustrate specific features/elements relevant to the present invention. Also, like reference numerals and designations in the various drawings are used to indicate like elements/parts.

DESCRIPTION

The detailed description provided below in connection with the appended drawings is intended as a description of the present examples and is not intended to represent the only forms in which the present example may be constructed or utilized. The description sets forth the functions of the example and the sequence of steps for constructing and operating the example. However, the same or equivalent functions and sequences may be accomplished by different examples.

1. Definitions

For convenience, certain terms employed in the specification, examples and appended claims are collected here. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of the ordinary skill in the art to which this invention belongs.

The singular forms “a” , “and” , and “the” are used herein to include plural referents unless the context clearly dictates otherwise.

Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., enantiomers and/or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. The invention additionally encompasses compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

Unless otherwise indicated, the term “alkyl” means a straight chain, branched and/or cyclic ( “cycloalkyl” ) hydrocarbon having from 1 to 20 (e.g., 1 to 10, 1 to 9, 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, 1 to 3, 1 to 2, or 1) carbon atoms. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, 2-isopropyl-3-methyl butyl, pentyl, pentan-2-yl, hexyl, isohexyl, heptyl, heptan-2-yl, 4, 4-dimethylpentyl, octyl, 2, 2, 4-trimethylpentyl, nonyl, decyl, undecyl and dodecyl. Cycloalkyl moieties may be monocyclic or multicyclic, and examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Unless otherwise specified, each instance of an alkyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkyl” ) or substituted (a “substituted alkyl” ) with one or more substituents. In certain embodiments, the alkyl group is unsubstituted C _1–6 alkyl. In certain examples, the alkyl group is methyl.

“Halo” or “halogen” refers to fluorine (fluoro, –F) , chlorine (chloro, –Cl) , bromine (bromo, –Br) , or iodine (iodo, –I) .

The term “haloalkyl” denotes an alkyl group, as defined above, having one, two, three, four, five, six, or more halogen atoms attached thereto. Haloalkyl includes fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl. “Fluoroalkyl” refers to an alkyl group having one, two, three, four, five, six, or more fluorine atoms attached thereto. “Chloroalkyl” refers to an alkyl group having one, two, three, four, five, six, or more chlorine atoms attached thereto. “Bromoalkyl” refers to an alkyl group having one, two, three, four, five, six, or more bromine atoms attached thereto. “Iodoalkyl” refers to an alkyl group having one, two, three, four, five, six, or more iodine atoms attached thereto. A haloalkyl group may include more than one type of halogen atoms. For example, fluoroalkyl includes an alkyl group having one or more fluorine atoms and one or more chlorine atoms. A haloalkyl group may be substituted with one or more substituents that are not halogen atoms.

“Heterocyclyl, ” “heterocycle, ” or “heterocyclic” refers to a radical of a 3–to 10–membered non–aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, phosphorus, and silicon ( “3–10 membered heterocyclyl” ) . In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic ( “monocyclic heterocyclyl” ) or a fused, bridged, or spiro ring system, such as a bicyclic system ( “bicyclic heterocyclyl” ) , and can be saturated or can be partially unsaturated. Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings. Heterocyclyl includes heteroaryl. Heterocyclyl also includes ring systems wherein the heterocyclic ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclic ring, or ring systems wherein the heterocyclic ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclic ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclic ring system. Unless otherwise specified, each instance of heterocyclyl is independently optionally substituted, i.e., unsubstituted (an “unsubstituted heterocyclyl” ) or substituted (a “substituted heterocyclyl” ) with one or more substituents. In certain embodiments, the heterocyclyl group is unsubstituted 3–10 membered heterocyclyl. In certain embodiments, the heterocyclyl group is substituted 3–10 membered heterocyclyl. In some embodiments, a heterocyclyl group is a 5–10 membered non–aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ( “5–10 membered heterocyclyl” ) . In some embodiments, a heterocyclyl group is a 5–8 membered non–aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ( “5–8 membered heterocyclyl” ) . In some embodiments, a heterocyclyl group is a 5–6 membered non–aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ( “5–6 membered heterocyclyl” ) . In some embodiments, the 5–6 membered heterocyclyl has 1–3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5–6 membered heterocyclyl has 1–2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5–6 membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.

Exemplary 3–membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, thiorenyl. Exemplary 4–membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary 5–membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl–2, 5–dione. Exemplary 5–membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5–membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6–membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6–membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, dioxanyl. Exemplary 6–membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl. Exemplary 7–membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8–membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a C ₆ aryl ring (also referred to herein as a 5, 6-bicyclic heterocyclic ring) include, without limitation, benzimidazolyl, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6, 6-bicyclic heterocyclic ring) include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

The term “aminocarbonyl” refers to a moiety of the formula: –C (=O) N (R ^hh) ₂, wherein each instance of R ^hh is independently hydrogen, -OH, alkyl, and etc. In certain embodiments, the aminocarbonyl is unsubstituted aminocarbonyl (i.e., –C (=O) NH ₂) . In certain embodiments, the aminocarbonyl is a substituted aminocarbonyl group, wherein at least one instance of R ^hh is not hydrogen.

The term “amino” refers to a moiety of the formula: –N (R ⁱⁱ) ₂, wherein each instance of R ⁱⁱ is independently hydrogen, -OH, alkyl, and etc. In certain embodiments, the amino is unsubstituted amino (i.e., –NH ₂) . In certain embodiments, the amino is a substituted amino group, wherein at least one instance of R ⁱⁱ is not hydrogen.

The term “alkoxy” refers to a moiety of the formula: –OR ^jj, wherein R ^jj is an optionally substituted alkyl group described herein.

The term “substituted, ” when used to describe a chemical structure or moiety, refers to a derivative of that structure or moiety wherein one or more of its hydrogen atoms is substituted with one or more of: alkyl, alkoxy, alkylamino, dialkylamino, amino, aminocarbonyl, carbony alkoxy, cyano, halo, haloalkyl, hydroxyl, nitro and etc.

An atom, moiety, or group described herein may be unsubstituted or substituted, as valency permits, unless otherwise provided expressly. The term “optionally substituted” refers to substituted or unsubstituted.

In general, the term “substituted” , whether preceded by the term “optionally” or not, means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position. The term “substituted” is contemplated to include substitution with all permissible substituents of organic compounds, any of the substituents described herein that results in the formation of a stable compound. The present invention contemplates any and all such combinations in order to arrive at a stable compound. For purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and/or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety. In certain embodiments, the substituent is a carbon atom substituent. In certain embodiments, the substituent is a nitrogen atom substituent. In certain embodiments, the substituent is an oxygen atom substituent.

It should also be noted that if the stereochemistry of a structure or a portion of a structure is not indicated with, for example, bold or dashed lines, the structure or the portion of the structure is to be interpreted as encompassing all stereoisomers of it. Similarly, names of compounds having one or more chiral centers that do not specify the stereochemistry of those centers encompass pure stereoisomers and mixtures thereof. Specific enantiomers can be separated and collected by the techniques known in the art such as chromatography in chiral stationary phase or chiral salt formation followed by separation based on selective crystallization. By using a specific enantiomer as a starting substance, it is also possible to obtain a corresponding isomer as the final product.

Unless otherwise indicated, any atom shown in a drawing with unsatisfied valences is assumed to be attached to enough hydrogen atoms to satisfy the valences.

The term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2–hydroxy–ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2–naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3–phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N ⁺ (C _1–4 alkyl) ₄ ^- salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

The term “solvate” refers to forms of the compound that are associated with a solvent, usually by a solvolysis reaction. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. The compounds described herein may be prepared, e.g., in crystalline form, and may be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include both stoichiometric solvates and non-stoichiometric solvates. In certain instances, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated in the crystal lattice of a crystalline solid. “Solvate” encompasses both solution-phase and isolatable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

The term “administered” , “administering” or “administration” are used interchangeably herein to refer a mode of delivery, including, without limitation, intraveneously, intramuscularly, intraperitoneally, intraarterially, intracranially, or subcutaneously administering an agent (e.g., a compound or a composition) of the present invention. In some embodiments, the compound of the present disclosure or a salt, a solvate thereof is formulated into tablets for oral administration. In other embodiments, t the compound of the present disclosure or a salt, a solvate thereof is formulated into powders for mixed with suitable carrier (e.g., buffer solution) before use, such as intraveneous injection.

The term “an effective amount” as used herein refers to an amount effective, at dosages, and for periods of time necessary, to achieve the desired result with respect to the treatment of a disease. For example, in the treatment of cancer, an agent (i.e., the present compound) which decrease, prevents, delays or suppresses or arrests any symptoms of the cancer would be effective. An effective amount of an agent is not required to cure a disease or condition but will provide a treatment for a disease or condition such that the onset of the disease or condition is delayed, hindered or prevented, or the disease or condition symptoms are ameliorated. The effective amount may be divided into one, two or more doses in a suitable form to be administered at one, two or more times throughout a designated time period.

Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in the respective testing measurements. Also, as used herein, the term “about” generally means within 10%, 5%, 1%, or 0.5%of a given value or range. Alternatively, the term “about” means within an acceptable standard error of the mean when considered by one of ordinary skill in the art. Other than in the operating/working examples, or unless otherwise expressly specified, all of the numerical ranges, amounts, values and percentages such as those for quantities of materials, durations of times, temperatures, operating conditions, ratios of amounts, and the likes thereof disclosed herein should be understood as modified in all instances by the term “about. ” Accordingly, unless indicated to the contrary, the numerical parameters set forth in the present disclosure and attached claims are approximations that can vary as desired. At the very least, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.

2. The compound of the present invention

Described herein are compounds having the structures as set forth herein, and methods of using one or more of such compounds for treating inflammatory bowel disease (IBD) .

Accordingly, it is the first aspect of the present disclosure to provide a compound capable of suppressing inflammation via inhibiting the production of nitric oxide (NO) and/or the activity of spleen tyrosine kinase (Syk) , as well as improving would healing. The compound has the structure of formula (I) ,

or a pharmaceutical acceptable salt, or solvate thereof.

In the formula (I) , R ^a and R ^b are independently selected from the group consisting of hydrogen, halogen, and alkyl; or R ^a and R ^b are taken together to form a heterocyclyl.

X is alkylene, or -C (=O) (CH ₂) _n-, in which n is 0, 1, or 2.

Y is selected from the group consisting of halogen, phenyl and heterocyclyl. The heterocyclyl is selected from the group consisting of furanyl, thiopheneyl, dioxolanyl, pyrrolyl, pyridinyl, indolinyl, indazolyl, and benzimidazole.

Each of the phenyl and the heterocyclyl are optionally substituted with one or more of halogen, alkyl, hydroxy, -NO ₂, -CN, -CF ₃, -CONR’R”, - (CH ₂) _aCOOR’, -SO ₂R’, -NR’R”, pyrazolyl, pyrrolidinyl, piperidinyl, morpholinyl, or piperazinyl; in which a is 0 or 1; R’ and R” are independently hydrogen, C _1-5 alkyl or -COR; and R is hydrogen or alkyl.

wherein,

m is 1 or 2;

R ^a, R ^b, R ^c and R ^d are independently hydrogen, halogen or alkyl; and

Exemplary compound of formula (II) may be any one of,

Exemplary compound of formula (III) may be any one of,

Exemplary compound of formula (IV) may be

wherein

m is an integral from 1 to 5; and

Y is halogen.

Exemplary compound of formula (V) is

wherein

n is 0, 1 or 2;

R’ and R” are independently hydrogen, C _1-5 alkyl or -COR; and

R is hydrogen or alkyl.

Exemplary compound of formula (VI) may be any one of,

wherein

Y is the heterocyclyl selected from the group consisting of furanyl, thiopheneyl, dioxolanyl, pyrrolyl, pyridinyl, indolinyl , and benzimidazole; and

Exemplary compound of formula (VII) may be any one of,

3. Method of treatment

A further aspect of the present disclosure is directed to a method for treating an inflammatory bowel disease (IBD) in a subject. The method includes the step of administering to the subject an effective amount of any one of the compounds described above, that is, any one of the compound of formulas (I) to (VII) .

The compound may be administered to the subject in the amount of 0.01 to 100 mg/Kg, such as 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 9.0, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, and 100 mg/Kg; preferably, the compound is administered to the subject in the amount of 1 to 90 mg/Kg, such as 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 9.0, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, and 90 mg/Kg; more preferably, the compound is administered to the subject in the amount of 5 to 85 mg/Kg, such as 5.0, 6.0, 7.0, 8.0, 9.0, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, and 85 mg/Kg.

4. Formulations

A further aspect of the present disclosure is to provide formulations for use in the present method. In some embodiments, the afore-described compounds of formula (I) to (VII) are formulated into dosage forms for administering to the subject.

The present formulation comprises any one of the compounds of formulas (I) to (VII) ; and a pharmaceutically acceptable excipient. In some embodiments, the compound of formula (II) (e.g., PDC-I-004 or PDC-I-008) is mixed with pharmaceutically acceptable excipients to form a formulation for administering to the subject. In other embodiments, the compound of formula (VI) (e.g., PDC-II-001) is mixed with pharmaceutically acceptable excipients to form a formulation for administering to the subject.

The compound of any one of formulas (I) to (VII) may be present at a level of about 0.1%to 99%by weight, based on the total weight of the formulation. In some embodiments, the compound of any one of formulas (I) to (VII) is present at a level of at least 1%by weight, based on the total weight of the formulation. In certain embodiments, the compound of any one of formulas (I) to (VII) is present at a level of at least 5%by weight, based on the total weight of the formulation. In still other embodiments, the compound of any one of formulas (I) to (VII) is present at a level of at least 10%by weight, based on the total weight of the formulation. In still yet other embodiments, the compound of any one of formulas (I) to (VII) is present at a level of at least 25%by weight, based on the total weight of the formulation.

The formulation is prepared in accordance with acceptable pharmaceutical procedures, such as described in Remington’s Pharmaceutical Sciences, 17 ^th edition, ed. Alfonoso R. Gennaro, Mack Publishing Company, Easton, Pa (1985) . Pharmaceutically acceptable excipients are those that are compatible with other ingredients in the formulation and biologically acceptable.

The formulation is manufactured in accordance with the intended routes for its administration. For example, if the formulation is intended to be administered by oral ingestion, an enteric coating may be applied on the formulation so as to prevent the compound of the present invention from being degraded in the acidic environment or until it reaches the intestines of the subject. The formulation may further include additional components that help deliver the compound of the present invention to its intended target site. In some examples, the agents constituted the sensitizer is enclosed in a liposome to prevent it from enzymatic degradation, and to help transporting the agents through the circulation system of the subject, and/or across cell membrane to its intended cellular target site.

Further, the least soluble agent of the sensitizer may be formulated with additional agents, such as a solvating agent, an emulsifying agent and/or a surfactant, into a liquid formulation. Examples of the additional agent include, but are not limited to, cyclodextrin (e.g., α-cyclodextrin and β-cyclodextrin) , and non-aqueous solvents, which include but are not limited to, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyl glycol, 1, 3-butyl glycol, dimethyl formamide, dimethyl sulfoxide, biocompatible oils (e.g., cottonseed oil, peanut oil, corn oil, wheat germ oil, castor oil, olive oil, sesame oil, glycerol, tetrahydrogen furan, polyethylene glycol (PEG) , fatty acid esters of sorbitan, and a combination thereof) .

The amount of the compound of any one of formulas (I) to (VII) in the formulation varies with the route of administration. For example, formulations for acute treatment will contain larger amounts of the sensitizer, as compared to formulations that are for chronic treatment. Similarly, parental formulations will comprise less amounts of the present sensitizer, as compared to formulations that are for oral ingestion. Also within the scope of the present disclosure are formulations suitable for other administration routes.

Formulations may be in the form of liquids, solutions, suspensions, emulsions, elixirs, syrups, tablets, lozenges, granules, powders, capsules, cachets, pills, ampoules, suppositories, pessaries, ointments, gels, pastes, creams, sprays, mists, foams, lotions, oils, boluses, electuaries, or aerosols.

4.1 Formulation for Oral Ingestion

The compound of the present disclosure may be formulation into compositions suitable for oral ingestion. Formulations suitable for oral administration (e.g. by ingestion) may be presented as discrete units such as capsules, cachets or tablets, each containing a predetermined amount of the active compound; as a powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion; as a bolus; as an electuary; or as a paste.

A tablet may be made by conventional means, e.g., compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active compound in a free-flowing form such as a powder or granules, optionally mixed with one or more binders (e.g. povidone, gelatin, acacia, sorbitol, tragacanth, hydroxypropylmethyl cellulose) ; fillers or diluents (e.g. lactose, microcrystalline cellulose, calcium hydrogen phosphate) ; lubricants (e.g. magnesium stearate, talc, silica) ; disintegrants (e.g. sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose) ; surface-active or dispersing or wetting agents (e.g. sodium lauryl sulfate) ; and preservatives (e.g. methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, sorbic acid) . Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active compound therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach.

4.2 Formulation for Parental Administration

Formulations suitable for parenteral administration (e.g. by injection, including cutaneous, subcutaneous, intramuscular, intravenous and intradermal) , include aqueous and nonaqueous isotonic, pyrogen-free, sterile injection solutions which may contain antioxidants, buffers, preservatives, stabilizers, bacteriostats, and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents, and liposomes or other microparticulate systems which are designed to target the compound to blood components or one or more organs. Examples of suitable isotonic vehicles for use in such formulations include Sodium Chloride Injection, Ringer's Solution, or Lactated Ringer's Injection. The formulations may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets. Formulations may be in the form of liposomes or other nanoparticulate or microparticulate systems which are designed to target the active compound to blood components or one or more organs.

4.3 Transmembrane Formulation

Transmembrane formulations are those suitable for topical and tansmucosal uses, which include but are not limited to, ophthalmic solutions, sprays, aerosols, creams, lotions, ointments, gels, solutions, suspensions, skin patches and the like. The patches include reservoir type and matrix type skin patches, and may adhere onto the skin for a certain period of time to allow the active component to be adsorbed into the subject’s body.

For topical administration, a wide variety of dermatologically acceptable inert excipients well known to the art may be employed. Typical inert excipients may be, for example, water, ethyl alcohol, polyvinyl pyrrolidone, propylene glycol, mineral oil, stearyl alcohol and gel-producing substances. All of the above dosages forms and excipients are well known to the pharmaceutical art. The choice of the dosage form is not critical to the efficacy of the composition described herein.

For transmucosal administration, the compound of the present disclosure may also be formulated in a variety of dosage forms for mucosal application, such as buccal and/or sublingual drug dosage units for drug delivery through oral mucosal membranes. A wide variety of biodegradable polymeric excipients may be used that are pharmaceutically acceptable, provide both a suitable degree of adhesion and the desired drug release profile, and are compatible with the active agents to be administered and any other components that may be present in the buccal and/or sublingual drug dosage units. Generally, the polymeric excipient comprises hydrophilic polymers that adhere to the wet surface of the oral mucosa. Examples of polymeric excipients include, but are not limited to, acrylic acid polymers and copolymers; hydrolyzed polyvinyl alcohol; polyethylene oxides; polyacrylates; vinyl polymers and copolymers; polyvinylpyrrolidone; dextran; guar gum; pectins; starches; and cellulosic polymers.

The following examples illustrate the invention.

EXAMPLES

Materials and Methods

Cell Culture

RAW264.7 cells were grown in DMEM growth medium with 10%FBS, 4 mM l-glutamine, 1 mM pyruvate, and 100 U/ml penicillin-100 μg/ml streptomycin at 37℃ in the presence of 5%CO ₂ atmosphere.

LPS-induced inflammation and treatment of compound of formula (I)

RAW264.7 cells were seeded in 96-well culture plate at a density of 10 ⁵ cells/well, the cells were then cultivated at 37℃ for 24 hr, and subsequently in the serum free DMEM medium overnight. The cells were then challenged with lipopolysaccharide (LPS) (10 μg/mL) in the presence or absence of a test compound (i.e., the compound of formula (I) at 1, 3 or 10 μM) for another 24 hr. The culture medium in each well was collected for the measurement of nitric oxide (NO) released in response to LPS challenge and the treatment of the test compound; and the cells remained in each well were subjected to cell viability assay.

Measurement of NO

The level of NO was measured by quantitative determination of nitrite and nitrate in the sample using nitric oxide assay kit (Caymen Chemical, Ann Arbor, Michigan, USA) . In general, the kit uses the enzyme nitrate reductase to convert nitrate to nitrite. Nitrite is then detected as a colored azo dye product of the Griess reaction that absorbs visible light at 550 nm. The level of nitric oxide in a system is thus measured by the determination of both nitrate and nitrite concentrations in the sample. Briefly, 50 μL of the collected culture medium was mixed with 50 μL of Griess reagent nitrate to nitrite, and the total nitrite was then determined by measuring the absorbance of the reaction product at 550 nm.

Cell Viability Assay

Cell viability was determined using MTS assay kit, in which the detection is based on the reduction of the MTS tetrazolium compound by viable cells to generate a colored formazan dye that is soluble in cell culture media. This conversion is thought to be carried out by NAD (P) H-dependent dehydrogenase enzymes in metabolically active cells. The formazan dye is quantified by measuring the absorbance at 490-500 nm. Briefly, cells were washed by PBS solution, then 100 μL of MTS reagent was added to cell culture media, incubated for 0.5 -4 hours before being subjected to the measurement of absorbance at 490 nm.

In vitro scratch assay

This assay is a straightforward and economical method to study cell migration in vitro as an indication of healing ability of cells. The assay is based on the observation that, upon creation of a new artificial gap, so called “scratch” , on a confluent cell monolayer, the cells on the edge of the newly created gap will move toward the opening to close the “gap” or “scratch” until new cell–cell contacts are established again.

Briefly, Caco-2 cells were cultured at a density of 5 x 10 ⁵ cells/culture insert until they reached confluence. Then, the culture insert was removed thereby created a gap of 500 ± 100 μm. The images of the cultured cells were captured at the beginning and regular intervals during cell migration to close the scratch in the presence or absence of the compound of formula (I) at 1 μM for 48 hrs. The images were subsequently compared to determine the efficacy of the compound of formula (I) in improving the cell haling capability.

Measurement of spleen tyrosine kinase (Syk) activity

Syk activity was determined by Syk assay kit (BSP Bioscience, CA, USA) in accordance with the manufacturer’s protocol. Briefly, the test compound (e.g., the compound of formula (I) ) , ATP (500 μM) , Poly-Glu, Tyrosine (10 mg/mL) and Syk (1 ng/μL) were mixed and incubated at 30℃ for 45 minutes, then kinase-Glo Max reagent was added and reacted for another 45 minutes, and the luminescence was determined using

M3 Multi-Mode Microplate Reader (Molecular Devices LLC) . The luminescence was an indication of the remaining amount of the ATP, which in terms represented the ATP that was consumed by Syk.

Example 1 Preparation of the compound of formula (I)

General. Compounds of this invention were prepared in accordance with procedures described in schemes 1 to 3. All reactions were monitored for completion by thin layer chromatography. Visualization of the resulting chromatograms wasdetected visually under UV irradiation (254 nm) . ¹H NMR spectra were recorded on or Varian Mercury-400 spectrometers and the chemical shifts were recorded in parts per million (ppm, δ) . Electrospray mass spectra (ESMS) were recorded as m/z values using Waters mass spectrometer. Purity of the final compound was determined with Waters ACQUITY Arc system using C18 column (Waters XSelect HSS T3 5 μm, 4.6 mm × 250 mm) operating at 40 ℃. Elution was carried out using water containing 0.1%trifluoroacetic acid as mobile phase A and methanol as mobile phase B. Elution condition: at 0 min, phase A 90%+ phase B 10%; at 6 min, phase A 70%+ phase B 30%; at 12 min, phase A 50%+ phase B 50%; at 18 min, phase A 10%+ phase B 90%; at 23 min, phase A 90%+ phase B 10%; at 30 min, phase A 90%+ phase B 10%. The flow-rate of the mobile phase was 1 mL/min, and the injection volume of the sample was 5 μL. Peaks were detected at 210-400 nm. Purity of final compound was found to be >90%.

General Procedure for the Synthesis of 3a-3s (3a as an example)

Scheme 1

To a solution of compound 2 (200 mg, 0.43 mmol, ) , 1- (bromomethyl) -4-nitrobenzene (0.11 g, 0.52 mmol) , and K ₂CO ₃ (0.71 g, 0.52 mmol) in dimethyl formaldehyde (DMF) (5 mL) was added, and the mixture was stirred at rt for 5 hr. The reaction mixture was diluted with ethyl acetate (EA) (100 mL) , washed with water (50 mL) , brine (100 mL) , and dried over Na ₂SO ₄. The mixture was filtered and concentrated to dryness. The crude product was purified by column chromatography to give compound 3a (92 mg, 36%) as a yellow solid.

Table 1. Preparation of Compounds 3a-3s

a: Isolated yield.

General Procedure for the Synthesis of PDC-I-001 to PDC-I-010, and PDC-I-012 to PDC-I-020 (PDC-I-008 as an example)

Scheme 2

To a solution of compound 3a (90 mg) in AcOH (20 mL) /H2O (4 mL) was stirred at 120℃ for 15 h. The reaction mixture was diluted with EA (100 mL) , washed with water (50 mL) , sat. NaHCO ₃ (aq) , brine, and dried over Na ₂SO ₄. The mixture was filtered and concentrated to dryness. Dicholomethane (DCM) (20 mL) was added to the mixture. The resulting solid was filtered to give PDC-I-008 (35 mg, 53%) as a yellow solid.

PDC-I-008

¹H NMR (400 MHz, DMSO) δ 8.21 (dd, J = 6.8, 2.0 Hz, 2H) , 7.71 (d, J = 8.4 Hz, 2H) , 7.45 (d, J = 2.0 Hz, 1H) , 7.38 (dd, J = 7.6, 2.4 Hz, 1H) , 6.84 (d, J = 8.4 Hz, 1H) , 6.39 (s, 1H) , 6.18 (s, 1H) , 5.13 (s, 2H) .

PDC-I-001

¹H NMR (400 MHz, DMSO) δ 7.47-7.38 (m, 4H) , 7.15 (t, J = 9.2 Hz, 2H) , 6.82 (d, J = 8.4 Hz, 1H) , 6.38 (s, 1H) , 6.14 (s, 1H) , 4.97 (s, 2H) .

PDC-I-002

¹H NMR (400 MHz, DMSO) δ 7.48 (d, J = 1.2 Hz, 1H) , 7.40-7.35 (m, 2H) , 7.24-7.21 (m, 2H) , 7.17-7.11 (m, 1H) , 6.85 (d, J = 8.8 Hz, 1H) , 6.38 (d, J = 2.0 Hz, 1H) , 6.18 (d, J = 2.0 Hz, 1H) , 5.01 (s, 2H) .

PDC-I-003

¹H NMR (400 MHz, DMSO) δ 7.49-7.45 (m, 1H) , 7.40-7.34 (m, 3H) , 7.16-7.10 (m, 2H) , 6.76 (d, J = 8.4 Hz, 1H) , 6.31 (s, 1H) , 6.13 (s, 1H) , 5.07 (s, 2H) .

PDC-I-004

¹H NMR (400 MHz, DMSO) δ 7.49-7.44 (m, 1H) , 7.40-7.39 (m, 1H) , 7.37-7.32 (m, 1H) , 7.35-7.32 (m, 1H) , 6.75 (d, J = 8.4 Hz, 1H) , 6.14 (s, 1H) , 5.96 (s, 1H) , 4.94 (s, 2H) .

PDC-I-005

¹H NMR (400 MHz, DMSO) δ 7.39 (d, J = 2.4 Hz, 1H) , 7.34-7.27 (m, 2H) , 7.18 (td, J = 7.2, 2.0 Hz, 2H) , 6.79 (d, J = 8.4 Hz, 1H) , 6.36 (s, 1H) , 6.17 (s, 1H) , 5.05 (s, 2H) .

PDC-I-006

¹H NMR (400 MHz, DMSO) δ 7.35 (t, J = 8.4 Hz, 1H) , 7.27-7.22 (m, 2H) , 6.93 (t, J = 8.0 Hz, 2H) , 6.72-6.69 (m, 1H) , 6.33 (d, J = 15 Hz, 1H) , 6.16 (d, J = 14.8 Hz, 1H) , 5.11 (s, 2H) .

PDC-I-007

¹H NMR (400 MHz, DMSO) δ 7.56-7.42 (m, 2H) , 7.28-7.24 (m, 2H) , 6.65 (d, J = 8.8 Hz, 1H) , 6.02 (s, 1H) , 5.85 (d, J = 1.6 Hz, 1H) , 4.98 (s, 2H) .

PDC-I-009

¹H NMR (400 MHz, DMSO) δ 8.09 (dd, J = 8.4, 1.6 Hz, 1H) , 7.96 (d, J = 8.0 Hz, 1H) , 7.79 (td, J = 8.0, 1.6 Hz, 1H) , 7.59 (td, J = 8.0, 1.6 Hz, 1H) , 7.42 (d, J = 2.0 Hz, 1H) , 7.36 (dd, J = 8.0, 2.4 Hz, 1H) , 6.81 (d, J = 8.8 Hz, 1H) , 6.41 (d, J = 2.0 Hz, 1H) , 6.20 (s, 1H) , 5.36 (s, 2H) .

PDC-I-010

¹H NMR (400 MHz, DMSO) δ 8.75-8.70 (m, 3H) , 7.36-7.31 (m, 2H) , 6.81 (d, J = 8.4 Hz, 1H) , 6.40 (d, J = 2.0 Hz, 1H) , 6.20 (d, J = 2.0 Hz, 1H) , 5.24 (s, 2H) .

PDC-I-012

¹H NMR (400 MHz, DMSO) δ 7.71 (d, J = 8.0 Hz, 2H) , 7.65 (d, J = 8.4 Hz, 2H) , 7.47 (d, J = 2.0 Hz, 1H) , 7.39 (dd, J = 8.8, 2.0 Hz, 1H) , 6.84 (d, J = 8.4 Hz, 1H) , 6.37 (s, 1H) , 6.17 (s, 1H) , 5.08 (s, 2H) .

PDC-I-013

¹H NMR (400 MHz, DMSO) δ 7.91 (d, J = 8.0 Hz, 1H) , 7.72-7.67 (m, 2H) , 7.55-7.51 (m, 1H) , 7.41-7.34 (m, 2H) , 6.78 (d, J = 8.4 Hz, 1H) , 6.37 (s, 1H) , 6.17 (s, 1H) , 5.15 (s, 2H) .

PDC-I-014

¹H NMR (400 MHz, DMSO) δ 8.10 (s, 2H) , 8.02 (s, 1H) , 7.41 (d, J = 2.4 Hz, 1H) , 7.34 (dd, J = 8.8, 4.8 Hz, 1H) , 6.81 (d, J = 8.8 Hz, 1H) , 6.38 (d, J = 2.0 Hz, 1H) , 6.19 (d, J = 2.0 Hz, 1H) , 5.19 (s, 2H) .

PDC-I-015

¹H NMR (400 MHz, DMSO) δ 7.96 (br, 1H) , 7.84 (d, J = 8.4 Hz, 2H) , 7.51-7.46 (m, 3H) , 7.42-7.40 (m, 1H) , 7.35 (br, 1H) , 6.84 (d, J = 8.4 Hz, 1H) , 6.37 (s, 1H) , 6.17 (d, J = 1.6 Hz, 1H) , 5.05 (s, 2H) .

PDC-I-016

¹H NMR (400 MHz, DMSO) δ 7.93 (d, J = 8.4 Hz, 2H) , 7.56 (d, J = 8.0 Hz, 2H) , 7.48 (d, J = 2.0 Hz, 1H) , 7.40 (dd, J = 8.4, 1.6 Hz, 1H) , 6.85 (d, J = 8.8 Hz, 1H) , 6.39 (d, J = 2.0 Hz, 1H) , 6.19 (d, J = 2.0 Hz, 1H) , 5.08 (s, 2H) , 3.84 (s, 3H) .

PDC-I-017

¹H NMR (400 MHz, DMSO) δ 7.89 (d, J = 8.4 Hz, 2H) , 7.69 (d, J = 8.4 Hz, 2H) , 7.43 (d, J = 2.0 Hz, 1H) , 7.37 (dd, J = 8.0, 2.0 Hz, 1H) , 6.79 (d, J = 8.8 Hz, 1H) , 6.27 (s, 1H) , 6.01 (s, 1H) , 5.08 (s, 2H) , 3.21 (s, 3H) .

PDC-I-018

¹H NMR (400 MHz, CD ₃OD) δ 7.49 (d, J = 2.0 Hz, 1H) , 7.42 (dd, J = 8.4, 2.4 Hz, 1H) , 7.29 (d, J = 8.4 Hz, 2H) , 7.18 (d, J = 8.0 Hz, 2H) , 6.83 (d, J = 8.4 Hz, 1H) , 6.37 (d, J = 2.4 Hz, 1H) , 6.20 (d, J = 2.0 Hz, 1H) , 4.97 (s, 2H) , 3.67 (s, 3H) , 3.62 (s, 2H) .

PDC-I-019

¹H NMR (400 MHz, DMSO) δ 8.574-8.570 (m, 1H) , 8.50 (dd, J = 4.8, 1.6 Hz, 1H) , 7.81 (td, J = 4.0, 2.0 Hz, 1H) , 7.46 (d, J = 2.4 Hz, 1H) , 7.39-7.33 (m, 2H) , 6.83 (d, J = 8.4 Hz, 1H) , 6.34 (s, 1H) , 6.15 (s, 1H) , 5.04 (s, 2H) .

PDC-I-020

¹H NMR (400 MHz, CD ₃OD) δ 7.50 (d, J = 2.0 Hz, 1H) , 7.34 (dd, J = 8.4, 2.0 Hz, 1H) , 7.22 (dd, J = 8.4, 5.6 Hz, 2H) , 6.96 (t, J = 8.8 Hz, 2H) , 6.73 (d, J = 8.4 Hz, 1H) , 6.37 (d, J = 2.0 Hz, 1H) , 6.19 (d, J = 2.0 Hz, 1H) , 4.13 (t, J = 7.2 Hz, 2H) , 3.02 (t, J = 7.2 Hz, 2H) .

General Procedure for the Synthesis of 5a-5v (Synthesis of 5a as an example)

Scheme 3

To a solution of compound 4 (200 mg, 0.35 mmol) , 1H-imidazole-4-carboxylic acid (47 mg, 0.42 mmol) , 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDCI) (135 mg, 0.7 mmol) and 4-dimethylaminopyridine (DMAP) (21 mg, 0.18 mmol) in DCM (10 mL) were added, and the mixture was stirred at rt for 15 h. The reaction mixture was diluted with DCM (100 mL) , washed with water (100 mL) , brine (100 mL) , and dried over Na ₂SO ₄. The mixture was filtered and concentrated to dryness. The crude product was purified by column chromatography to give compound 5a (95 mg, 41%) as a yellow solid.

Table 2

General Procedure for the Synthesis of PDC-II-004 -006, 008-012, 014-023, 025-043 (PDC-II-042 as an example) .

Scheme 4

To a solution of compound 5a (95 mg) and 10%Pd/C (20 mg) in EtOH (10 mL) /EA (5 mL) was stirred at rt for 5 h. The reaction mixture was filtered through a Celite pad and the filtrate was concentrated to dryness. The crude product was purified by column chromatography to give PDC-II-042 (19 mg, 34%) as a yellow solid.

PDC-II-042

¹H NMR (400 MHz, CD ₃OD) δ 8.05 (s, 1H) , 7.89 (s, 1H) , 7.42-7.37 (m, 2H) , 6.83 (d, J = 8.4 Hz, 1H) , 6.47 (d, J = 2.0 Hz, 1H) , 6.25 (d, J = 2.4 Hz, 1H) .

PDC-II-004

¹H NMR (400 MHz, CD ₃OD) δ 7.90 (d, J = 7.6 Hz, 2H) , 7.39 (s, 1H) , 7.34 (d, J = 8.0 Hz, 1H) , 6.82 (d, J = 8.0 Hz, 1H) , 6.70 (d, J = 6.8 Hz, 2H) , 6.46 (s, 1H) , 6.24 (s, 1H) .

PDC-II-004 ¹H NMR (600 MHz, DMSO) δ 7.78 (d, J = 8.8 Hz, 2H) , 7.35 (d, J = 2.3 Hz, 1H) , 7.28 (dd, J = 8.4, 2.3 Hz, 1H) , 6.84 (d, J = 8.5 Hz, 1H) , 6.64 (d, J = 8.8 Hz, 2H) , 6.48 (d, J = 2.1 Hz, 1H) , 6.26 –6.21 (m, 3H) .

PDC-II-005

¹H NMR (600 MHz, DMSO) δ 8.26 –8.19 (m, 2H) , 7.46 (t, J = 8.8 Hz, 2H) , 7.35 (d, J = 2.3 Hz, 1H) , 7.30 (dd, J = 8.4, 2.3 Hz, 1H) , 6.86 (d, J = 8.4 Hz, 1H) , 6.51 (d, J = 2.1 Hz, 1H) , 6.27 (d, J = 2.1 Hz, 1H) .

PDC-II-006

¹H NMR (400 MHz, CD ₃OD) δ 8.14 (td, J = 7.6, 1.6 Hz, 1H) , 7.75-7.70 (m, 1H) , 7.39-7.29 (m, 4H) , 6.85 (d, J = 8.4 Hz, 1H) , 6.48-6.47 (m, 1H) , 6.26-6.25 (m, 1H) .

PDC-II-008

¹H NMR (500 MHz, DMSO) δ 8.12 –8.01 (m, 2H) , 7.89 –7.80 (m, 2H) , 7.34 (d, J = 2.3 Hz, 1H) , 7.29 (dd, J = 8.4, 2.3 Hz, 1H) , 6.86 (d, J = 8.4 Hz, 1H) , 6.51 (d, J = 2.0 Hz, 1H) , 6.27 (d, J = 2.1 Hz, 1H) .

PDC-II-009

¹H NMR (600 MHz, DMSO) δ 8.36 (d, J = 8.1 Hz, 2H) , 8.01 (d, J = 8.5 Hz, 2H) , 7.35 (d, J = 2.3 Hz, 1H) , 7.31 (dd, J = 8.4, 2.3 Hz, 1H) , 6.87 (d, J = 8.4 Hz, 1H) , 6.52 (d, J = 2.1 Hz, 1H) , 6.28 (d, J = 2.1 Hz, 1H) .

PDC-II-010

¹H NMR (600 MHz, DMSO) δ 8.47 –8.36 (m, 4H) , 7.35 (d, J = 2.3 Hz, 1H) , 7.31 (dd, J = 8.4, 2.3 Hz, 1H) , 6.86 (d, J = 8.4 Hz, 1H) , 6.52 (d, J = 2.0 Hz, 1H) , 6.28 (d, J = 2.0 Hz, 1H) .

PDC-II-011

¹H NMR (400 MHz, CD ₃OD) δ 8.08 (d, J = 8.4 Hz, 2H) , 7.40-7.37 (m, 2H) , 7.33 (dd, J = 8.0, 2.0 Hz, 1H) , 6.81 (d, J = 8.4 Hz, 1H) , 6.47 (s, 1H) , 6.25 (s, 1H) , 2.47 (s, 3H) .

PDC-II-012

¹H NMR (600 MHz, DMSO) δ 8.28 –8.22 (m, 2H) , 8.17 –8.10 (m, 2H) , 7.35 (d, J = 2.3 Hz, 1H) , 7.31 (dd, J = 8.4, 2.3 Hz, 1H) , 6.86 (d, J = 8.4 Hz, 1H) , 6.52 (d, J = 2.1 Hz, 1H) , 6.28 (d, J= 2.1 Hz, 1H) .

PDC-II-013

¹H NMR (600 MHz, DMSO) δ 7.84 (d, J = 8.8 Hz, 2H) , 7.33 (d, J = 2.4 Hz, 1H) , 7.27 (dd, J = 8.4, 2.0 Hz, 1H) , 6.83-6.79 (m, 2H) , 6.63 (d, J = 9.2 Hz, 2H) , 6.43 (s, 1H) , 6.20 (s, 1H) , 2.77 (d, J = 4.8 Hz, 3H) .

PDC-II-014

¹H NMR (400 MHz, CD ₃OD) δ 8.01 (d, J = 9.6 Hz, 2H) , 7.39 (d, J = 2.0 Hz, 1H) , 7.35 (dd, J = 8.8, 2.4 Hz, 1H) , 6.82-6.78 (m, 3H) , 6.46 (d, J = 1.6 Hz, 1H) , 6.24 (d, J = 2.4 Hz, 1H) , 3.10 (s, 6H) .

PDC-II-015

¹H NMR (400 MHz, CD ₃OD) δ 7.51-7.49 (m, 2H) , 7.40-7.33 (m, 3H) , 7.10-7.07 (m, 1H) , 6.82 (d, J = 8.8 Hz, 1H) , 6.46 (d, J = 2.0 Hz, 1H) , 6.25 (d, J = 2.4 Hz, 1H) , 3.01 (s, 6H) .

PDC-II-016

¹H NMR (400 MHz, CD ₃OD) δ 7.93 (dd, J = 7.2, 2.0 Hz, 2H) , 7.40 (d, J = 2.4 Hz, 1H) , 7.34 (dd, J = 8.8, 2.4 Hz, 1H) , 6.82 (d, J = 8.8 Hz, 1H) , 6.65 (dd, J = 7.2, 2.0 Hz, 2H) , 6.46 (d, J = 2.0 Hz, 1H) , 6.24 (d, J = 2.4 Hz, 1H) , 3.22 (q, J = 7.2, 2H) , 1.27 (t, J = 7.2 Hz, 3H) .

PDC-II-017

¹H NMR (400 MHz, DMSO) δ 10.4 (br, 1H) , 8.08 (d, J = 8.8 Hz, 2H) , 7.81 (d, J = 9.2 Hz, 2H) , 7.35 (d, J = 2.4 Hz, 1H) , 7.29 (dd, J = 8.4, 2.4 Hz, 1H) , 6.84 (d, J = 8.4 Hz, 1H) , 6.49 (d, J = 2.0 Hz, 1H) , 6.25 (d, J = 2.0 Hz, 1H) , 2.11 (s, 3H) .

PDC-II-018

¹H NMR (600 MHz, DMSO) δ 8.71 (d, J = 2.6 Hz, 1H) , 8.30 –8.23 (m, 2H) , 8.13 –8.08 (m, 2H) , 7.88 –7.84 (m, 1H) , 7.37 (d, J = 2.3 Hz, 1H) , 7.32 (dd, J = 8.4, 2.3 Hz, 1H) , 6.86 (d, J = 8.5 Hz, 1H) , 6.65 (dd, J = 2.6, 1.8 Hz, 1H) , 6.52 (d, J = 2.1 Hz, 1H) , 6.28 (d, J = 2.1 Hz, 1H) .

PDC-II-019

¹H NMR (400 MHz, CD ₃OD) δ 7.99 (d, J = 7.2 Hz, 2H) , 7.40 (s, 1H) , 7.35 (d, J = 7.6 Hz, 1H) , 6.81 (d, J = 8.0 Hz, 1H) , 6.64 (d, J = 7.6 Hz, 2H) , 6.46 (s, 1H) , 6.24 (s, 1H) , 3.41 (br, 4H) , 2.08 (br, 4H) .

PDC-II-020

¹H NMR (400 MHz, CD ₃OD) δ 8.00 (d, J = 7.2 Hz, 2H) , 7.39 (d, J = 2.4 Hz, 1H) , 7.35 (dd, J = 8.4, 2.4 Hz, 1H) , 6.99 (d, J = 8.8 Hz, 2H) , 6.81 (d, J = 7.6 Hz, 1H) , 6.46 (d, J = 2.4 Hz, 1H) , 6.24 (d, J = 1.6 Hz, 1H) , 3.44 (br, 4H) , 1.67 (br, 6H) .

PDC-II-021

¹H NMR (400 MHz, DMSO) δ 7.95 (d, J = 9.2 Hz, 2H) , 7.34 (d, J = 2.4 Hz, 1H) , 7.28 (dd, J = 8.4, 2.0 Hz, 1H) , 7.07 (d, J = 9.2 Hz, 2H) , 6.82 (d, J = 8.0 Hz, 1H) , 6.47 (s, 1H) , 6.23 (s, 1H) , 3.75 (t, J = 4.4 Hz, 4H) , 3.35 (t, J = 4.8 Hz, 4H) .

PDC-II-022

¹H NMR (400 MHz, CD ₃OD) δ 8.04 (d, J = 9.2 Hz, 2H) , 7.39 (d, J = 2.0 Hz, 1H) , 7.34 (dd, J = 8.4, 2.4 Hz, 1H) , 7.04 (d, J = 9.2 Hz, 2H) , 6.81 (d, J = 8.4 Hz, 1H) , 6.46 (d, J = 2.4 Hz, 1H) , 6.25 (d, J = 2.0 Hz, 1H) , 3.48-3.44 (m, 4H) , 2.65-2.62 (m, 4H) , 2.38 (s, 3H) .

PDC-II-023

¹H NMR (600 MHz, DMSO) δ 7.50 (dd, J = 8.3, 2.2 Hz, 1H) , 7.48 (d, J = 2.2 Hz, 1H) , 7.33 (d, J = 2.3 Hz, 1H) , 7.27 (dd, J = 8.4, 2.3 Hz, 1H) , 6.90 (d, J = 8.3 Hz, 1H) , 6.85 (d, J = 8.4 Hz, 1H) , 6.50 (d, J = 2.1 Hz, 1H) , 6.26 (d, J = 2.1 Hz, 1H) .

PDC-II-025

¹H NMR (600 MHz, DMSO) δ 9.92 (s, 1H) , 9.80 (s, 2H) , 9.44 (s, 1H) , 7.32 (d, J = 2.2 Hz, 1H) , 7.26 (dd, J = 8.4, 2.3 Hz, 1H) , 6.97 (d, J = 2.2 Hz, 2H) , 6.87 (d, J = 8.4 Hz, 1H) , 6.56 (t, J = 2.2 Hz, 1H) , 6.50 (d, J = 2.0 Hz, 1H) , 6.27 (d, J = 2.0 Hz, 1H) .

PDC-II-026

¹H NMR (500 MHz, DMSO) δ 9.14 (t, J = 2.1 Hz, 1H) , 9.09 (d, J = 2.1 Hz, 2H) , 7.36 –7.30 (m, 2H) , 6.86 (d, J = 8.6 Hz, 1H) , 6.54 (d, J = 2.0 Hz, 1H) , 6.29 (d, J = 2.0 Hz, 1H) .

PDC-II-027

¹H NMR (600 MHz, DMSO) δ 7.32 (d, J = 2.3 Hz, 1H) , 7.26 (dd, J = 8.4, 2.3 Hz, 1H) , 6.86 (d, J = 8.4 Hz, 1H) , 6.57 (d, J = 2.0 Hz, 2H) , 6.49 (d, J = 2.1 Hz, 1H) , 6.26 (d, J = 2.1 Hz, 1H) , 6.12 (t, J = 2.0 Hz, 1H) , 5.11 (s, 4H) .

PDC-II-028

¹H NMR (400 MHz, CD ₃OD) δ 8.69 (d, J = 1.2 Hz, 2H) , 8.38 (s, 1H) , 7.34-7.31 (m, 2H) , 6.85 (dd, J = 6.4, 2.0 Hz, 1H) , 6.49 (d, J = 2.4 Hz, 1H) , 6.27 (d, J = 2.0 Hz, 1H) .

PDC-II-028 ¹H NMR (600 MHz, DMSO) δ 9.91 (s, 1H) , 9.44 (s, 1H) , 8.68 (s, 2H) , 8.62 (s, 1H) , 7.39 –7.30 (m, 2H) , 6.91 –6.80 (m, 1H) , 6.53 (d, J = 2.1 Hz, 1H) , 6.28 (d, J = 2.1 Hz, 1H) .

PDC-II-029

¹H NMR (400 MHz, CD ₃OD) δ 7.86-7.82 (m, 1H) , 7.53-7.48 (m, 1H) , 7.39-7.34 (m, 3H) , 6.86 (d, J = 8.4 Hz, 1H) , 6.48-6.46 (m, 1H) , 6.26-6.25 (m, 1H) .

PDC-II-030

¹H NMR (600 MHz, DMSO) δ 8.30 –8.26 (m, 2H) , 8.19 –8.16 (m, 2H) , 7.35 (d, J = 2.3 Hz, 1H) , 7.30 (dd, J = 8.4, 2.3 Hz, 1H) , 6.86 (d, J = 8.4 Hz, 1H) , 6.52 (d, J = 2.1 Hz, 1H) , 6.28 (d, J = 2.1 Hz, 1H) , 3.92 (s, 3H) .

PDC-II-031

¹H NMR (600 MHz, DMSO) δ 8.47 (d, J = 1.4 Hz, 1H) , 7.85 (dd, J = 8.6, 1.7 Hz, 1H) , 7.56 (d, J = 8.6 Hz, 1H) , 7.54 (d, J = 3.1 Hz, 1H) , 7.40 (d, J = 2.3 Hz, 1H) , 7.33 (dd, J = 8.5, 2.2 Hz, 1H) , 6.84 (d, J = 8.5 Hz, 1H) , 6.67 (d, J = 3.0 Hz, 1H) , 6.52 (d, J = 2.1 Hz, 1H) , 6.27 (d, J = 2.0 Hz, 1H) .

PDC-II-032

¹H NMR (400 MHz, CD ₃OD) δ 8.54-8.52 (m, 1H) , 8.38 (s, 1H) , 8.12 (dd, J = 8.8, 2.0 Hz, 1H) , 7.77-7.74 (m, 1H) , 7.41 (d, J = 2.4 Hz, 1H) , 7.36 (dd, J = 8.4, 2.0 Hz, 1H) , 6.81 (d, J = 8.4 Hz, 1H) , 6.47 (d, J = 2.0 Hz, 1H) , 6.25 (d, J = 2.0 Hz, 1H)

PDC-II-033

¹H NMR (400 MHz, CD ₃OD) δ 8.52 (d, J = 1.6 Hz, 1H) , 7.94 (dd, J = 8.8, 2.0 Hz, 1H) , 7.51 (d, J = 9.2 Hz, 1H) , 7.43 (d, J = 2.4 Hz, 1H) , 7.41-7.38 (m, 2H) , 6.80 (d, J = 8.4 Hz, 1H) , 6.65 (dd, J = 2.8, 0.8 Hz, 1H) , 6.49-6.47 (m, 1H) , 6.25 (dd, J = 2.4, 0.8 Hz, 1H) .

PDC-II-034

¹H NMR (600 MHz, DMSO) δ 9.89 (s, 1H) , 9.44 (s, 1H) , 8.73 (s, 1H) , 8.34 (s, 1H) , 8.04 (dd, J = 8.8, 1.4 Hz, 1H) , 7.72 (d, J = 8.8 Hz, 1H) , 7.39 (d, J = 2.3 Hz, 1H) , 7.33 (dd, J = 8.5, 2.2 Hz, 1H) , 6.84 (d, J = 8.5 Hz, 1H) , 6.52 (d, J = 2.1 Hz, 1H) , 6.27 (d, J = 2.1 Hz, 1H) .

PDC-II-035

¹H NMR (400 MHz, CD ₃OD) δ 9.30 (t, J = 1.6 Hz, 1H) , 8.86-8.85 (m, 1H) , 8.58-8.55 (m, 1H) , 7.68-7.64 (m, 1H) , 7.36-7.32 (m, 3H) , 6.85 (d, J = 8.0 Hz, 1H) , 6.47 (d, J = 2.0 Hz, 1H) , 6.26 (d, J = 2.4 Hz, 1H) .

PDC-II-0036

¹H NMR (400 MHz, CD ₃OD) δ 9.16 (d, J = 2.0 Hz, 1H) , 8.43 (dd, J = 8.4, 2.0 Hz, 1H) , 7.52 (d, J = 8.4 Hz, 1H) , 7.36-7.31 (m, 2H) , 6.84 (d, J = 8.0 Hz, 1H) , 6.48 (q, J = 1.2 Hz, 1H) , 6.268-6.260 (m, 1H) , 2.67 (s, 3H) .

PDC-II-037

¹H NMR (400 MHz, CD ₃OD) δ 9.04 (d, J = 2.8 Hz, 1H) , 8.66 (td, J = 8.0, 2.4 Hz, 1H) , 7.36-7.27 (m, 3H) , 6.86 (d, J = 8.8 Hz, 1H) , 6.48 (d, J = 2.0 Hz, 1H) , 6.27 (d, J = 2.0 Hz, 1H) .

PDC-II-038

¹H NMR (400 MHz, DMSO) δ 9.48 (d, J = 2.0 Hz, 1H) , 8.79 (dd, J = 8.0, 2.0 Hz, 1H) , 8.19 (d, J = 8.4 Hz, 1H) , 7.37-7.34 (m, 2H) , 6.87 (d, J = 2.0 Hz, 1H) , 6.52 (d, J = 2.0 Hz, 1H) , 6.27 (d, J = 2.0 Hz, 1H) .

PDC-II-039

¹H NMR (600 MHz, DMSO) δ 8.15 (dd, J = 1.7, 0.8 Hz, 1H) , 7.68 (dd, J = 3.6, 0.8 Hz, 1H) , 7.34 (d, J = 2.3 Hz, 1H) , 7.30 (dd, J = 8.4, 2.3 Hz, 1H) , 6.87 (d, J = 8.4 Hz, 1H) , 6.84 (dd, J = 3.6, 1.8 Hz, 1H) , 6.50 (d, J = 2.0 Hz, 1H) , 6.26 (d, J = 2.0 Hz, 1H) .

PDC-II-040

¹H NMR (600 MHz, DMS O) δ 8.15 (dd, J = 5.0, 1.3 Hz, 1H) , 8.08 (dd, J = 3.8, 1.3 Hz, 1H) , 7.37 –7.33 (m, 2H) , 7.30 (dd, J = 8.4, 2.3 Hz, 1H) , 6.87 (d, J = 8.4 Hz, 1H) , 6.51 (d, J = 2.0 Hz, 1H) , 6.27 (d, J = 2.0 Hz, 1H) .

PDC-II-041

¹H NMR (400 MHz, CD ₃OD) δ 7.38-7.32 (m, 2H) , 7.18 (s, 1H) , 7.08 (d, J = 4.0 Hz, 1H) , 6.84 (d, J = 8.0 Hz, 1H) , 6.47 (d, J = 2.0 Hz, 1H) , 6.30-6.28 (m, 1H) , 6.24 (d, J = 2.0 Hz, 1H) .

PDC-II-043

¹H NMR (500 MHz, DMSO) δ 7.64 (d, J = 2.2 Hz, 1H) , 7.56 (d, J = 8.3 Hz, 1H) , 7.44 (dd, J = 8.3, 2.2 Hz, 1H) , 7.36 (d, J = 2.3 Hz, 1H) , 7.21 (dd, J = 8.4, 2.3 Hz, 1H) , 6.86 (d, J = 8.4 Hz, 1H) , 6.47 (d, J = 2.0 Hz, 1H) , 6.25 (d, J = 2.0 Hz, 1H) , 4.20 (s, 2H) .

Example 2 The compound of formula (I) suppresses cell propagation and LPS-induced nitric oxide release in macrophage-like cells

The effects of the compound of formula (I) (1 or 10 μM) on cell propagation and LPS-induced nitric oxide (NO) release in macrophage-like Raw264.7 cells were independently investigated by cell viability assay and NO measurement in accordance with procedures described in “Materials and Method” section. Results are summarized in Table 3.

Table 3 The compound of formula (I) suppresses cell propagation and LPS-induced nitric oxide release in macrophage-like cells

- :not determined.

As the data indicated, except PDC-I-009, PDC-I-010, PDC-I-014, PDC-I-016, PDC-I-017, PDC-I-019, PDC-I-022, PDC-I-029, and PDC-I-042, the rest of the compounds that were tested exhibited cytotoxicity (i.e., suppressing cell propagation) at the concentration of 10 μM.

Further, except PDC-I-001, PDC-I-006, PDC-I-008, PDC-I-012, PDC-I-014, PDC-I-022, PDC-I-029, PDC-I-035, PDC-I-041 and PDC-I-042, the rest of the compounds including PDC-I-002 to PDC-I-005, PDC-I-007, PDC-I-009 to PDC-I-011, PDC-I-013, PDC-I-015 to PDC-I-021, PDC-I-0023 to PDC-I-028, PDC-I-030 to PDC-I-034, PDC-I-036 to PDC-I-040, PDC-I-043, and PDC-I-044 were all capable of suppressing LPS-induced NO released at the concentration of 1 μM.

Example 3 The compound of formula (I) promotes wound healing in colorectal adenocarcinoma cells

The effects of the compound of formula (I) (1 μM) on closing the artificial gap (or “scratch” ) created on confluent colorectal adenocarcinoma Caco-2 cells were investigated by wound healing assay in accordance with procedures described in “Materials and Method” section. Results are illustrated in FIGs 1A to 1K.

It was found that among the test compounds, PDC-I-003, PDC-I-008, PDC-I-009, PDC-II-016, PDC-II-017, PDC-I-017a, PDC-II-027, PDC-II-029, PDC-II-040, PDC-II-041, and PDC-II-043 exhibited improved wound healing capability as compared with that of the control.

Example 4 The compound of formula (I) inhibits spleen tyrosine kinase (Syk) activity

In this example, the effect of the compound of formula (I) on Syk activity was investigated, in which the Syk activity was determined by use of Syk assay kit (BSP Bioscience, CA, USA) in accordance with the manufacturer’s protocol. Results are summarized in Table 4.

Table 4 The compound of formula (I) inhibits Syk activity

Compound #	IC ⁵⁰ (μM)	Compound #	IC ⁵⁰ (μM)
PDC-I-001	0.18μM	PDC-II-010	0.51 μM
PDC-I-002	1.97μM	PDC-II-011	0.62 μM
PDC-I-003	1.10 μM	PDC-II-012	2.95 μM
PDC-I-004	0.49 μM	PDC-II-013	1.09 μM

Compound #	IC ⁵⁰ (μM)	Compound #	IC ⁵⁰ (μM)
PDC-I-004a	5.04 μM	PDC-II-014	0.89 μM
PDC-I-004b	2.01 μM	PDC-II-015	1.55 μM
PDC-I-004c	2.38 μM	PDC-II-016	0.91 μM
PDC-I-004d	1.96 μM	PDC-II-017	1.71 μM
PDC-I-005	1.76μM	PDC-II-018	0.58 μM
PDC-I-006	2.16μM	PDC-II-019	0.82 μM
PDC-I-007	1.00 μM	PDC-II-020	1.07 μM
PDC-I-008	0.45 μM	PDC-II-021	0.97 μM
PDC-I-009	1.04 μM	PDC-II-022	0.27 μM
PDC-I-010	0.59 μM	PDC-II-023	0.16 μM
PDC-I-011	0.95 μM	PDC-II-024	>10.0 μM
PDC-I-012	1.00 μM	PDC-II-025	3.17 μM
PDC-I-013	4.49 μM	PDC-II-026	0.56 μM
PDC-I-014	7.28 μM	PDC-II-027	1.19μM
PDC-I-015	1.02μM	PDC-II-028	>10.0 μM
PDC-I-016	0.35 μM	PDC-II-029	0.44 μM
PDC-I-017	0.34μM	PDC-II-030	0.40μM
PDC-I-017a	>10.0 μM	PDC-II-031	>10.0 μM
PDC-I-018	0.48μM	PDC-II-032	0.44 μM
PDC-I-019	1.82μM	PDC-II-033	0.66 μM
PDC-I-020	2.36 μM	PDC-II-034	0.46 μM
PDC-I-021	1.53 μM	PDC-II-035	0.68μM
PDC-II-001	1.29 μM	PDC-II-036	2.91 μM
PDC-II-002	1.07 μM	PDC-II-037	1.39μM
PDC-II-003	1.0 μM	PDC-II-038	1.44 μM
PDC-II-004	1.37 μM	PDC-II-039	2.05 μM
PDC-II-005	0.76 μM	PDC-II-040	0.87 μM
PDC-II-006	0.96 μM	PDC-II-041	1.28 μM
PDC-II-007	6.05μM	PDC-II-042	1.98 μM
PDC-II-008	3.08 μM	PDC-II-043	4.70 μM
PDC-II-009	7.49 μM

It was found that most of the compounds of formula (I) may suppress Syk at an IC ₅₀ no more than 5 μM, more specifically no more than 1 μM, which suggested the compounds of formula (I) are potential candidates for the development of medicaments suitable for treating IBD and/or disorders associated with inhibition of Syk.

It will be understood that the above description of embodiments is given by way of example only and that various modifications may be made by those with ordinary skill in the art. The above specification, examples, and data provide a complete description of the structure and use of exemplary embodiments of the invention. Although various embodiments of the invention have been described above with a certain degree of particularity, or with reference to one or more individual embodiments, those with ordinary skill in the art could make numerous alterations to the disclosed embodiments without departing from the spirit or scope of this invention.

Claims

1. A compound of formula (I)

or a pharmaceutical acceptable salt, or solvate thereof,

wherein,

X is alkylene, or -C (=O) (CH ₂) _n-, in which n is 0, 1, or 2;

Y is selected from the group consisting of halogen, phenyl and heterocyclyl;

the heterocyclyl is selected from the group consisting of furanyl, thiopheneyl, dioxolanyl, pyrrolyl, pyridinyl, indolinyl , indazolyl, and benzimidazole;

a is 0 or 1;

R’ and R” are independently hydrogen, C _1-5 alkyl or -COR; and

R is hydrogen or alkyl.

The compound of claim 1, wherein the compound is any one of formulas (II) , (III) , or (IV) ,

wherein,

m is 1 or 2;

R ^a , R ^b , R ^c and R ^d are independently hydrogen, halogen or alkyl; and

The compound of claim 2, wherein the compound of formula (II) is any one of,

The compound of claim 2, wherein the compound of formula (III) is

The compound of claim 2, wherein the compound of formula (IV) is

The compound of claim 1, wherein the compound has the structure of formula (V)

wherein

m is an integral from 1 to 5; and

Y is halogen.

The compound of claim 6, wherein the compound of formula (V) is

The compound of claim 1, wherein the compound has the structure of formula (VI)

wherein

n is 0, 1 or 2;

R’ and R” are independently hydrogen, C _1-5 alkyl or -COR; and

R is hydrogen or alkyl.

The compound of claim 8, wherein the compound is any one of,

The compound of claim 1, wherein the compound has the structure of formula (VII)

wherein

The compound of claim 9, wherein the compound of formula (VII) is any one of,

A method for treating an inflammatory bowel disease (IBD) in a subject comprising administering to the subject an effective amount of the compound of any of claims 1 to 11.

The method of claim 12, wherein the compound is any one of,

The method of claim 13, wherein the compound is administered in the amount of 0.01 to 100 mg/Kg to the subject.

The method of claim 13, wherein the subject is a human.