Heterocycle compounds as formyl peptide receptor modulators

Abstract

Disclosed are compounds of formula (I) below and tautomers, stereoisomers, isotopologues, solvates, polymorphs, or pharmaceutically acceptable salts thereof: in which each of variables R1, R2, R3, R4, R5, R6 and L is defined herein. Also disclosed are a method for treating disease or disorder mediated by formyl peptide receptor with the compound of formula (I) or a tautomer, stereoisomer, isotopologue, solvate, polymorph, or salt thereof, and a pharmaceutical composition containing same.

Description

HETEROCYCLE COMPOUNDS AS FORMYL PEPTIDE RECEPTOR MODULATORSFIELD OF THE INVENTION

[0001] The present invention relates generally to compounds formyl peptide receptor 1 (FPR1) modulators, and uses of the compounds in the treatment of diseases mediated by FPR1.BACKGROUND OF THE INVENTION

[0002] Formyl peptide receptor (FPR) belongs to the family of G-protein coupled receptors (GPCRs). The FPR family can be divided into three classes, FPR1 , FPR2 and FPR3. FPR2 and FPR3 are classified into FPR-like receptors, wherein FPR2 is also known as FPR-like receptor 1 (FPRL-1) and FPR3 is also known as FPR-like receptor 2 (FPRL-2). FPR1 is found in monocytes, polymorphonuclear leukocytes and immature dendritic cells, and FPR2 is found in liver cells, lung cells, spleen cells, T lymphocytes, monocytes and polymorphonuclear leukocytes. FPR1 and FPR2 are two members of the FPRs, which are found in human neutrophils. Formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP or fMLF) is a N-formyl peptide, which is a chemo-attractant bound to FPR1 and further to trigger a cell activating response to release toxic substances or proteases. The affinities of fMLF toward the three FPRs are different, and the affinity is higher for FPR1. The activation of FPR1 elicits multiple signaling pathways, such as calcium, phospholipase C, phosphatidylinositol 3-kinase (PI3K), mitogen-activated protein kinases (MAPKs), and protein tyrosine kinases (PTKs), which cause neutrophils activation for migration, respiratory burst, and degranulation. Thus some literature reported that inhibition of activation of neutrophils could be as target for treatment of inflammation induced by neutrophils, such as asthma, rheumatoid arthritis, psoriasis, sepsis, myocardial ischemia / reperfusion injury, acute respiratory distress syndrome, chronic obstructive pulmonary disease, etc. Recent studies indicated that FPR1 is not only involved in infection and the inflammatory process, but also playing a role in promoting tumor progression. In particular, FPR1 is able to interact with endogenous annexin A1, and then transactivate EGFR in glioblastoma cells to mediate cell migration and growth. Therefore, FPR1 also is a therapeutic target for treating human glioblastoma.

[0003] Based on the above, FPR1 antagonists can regulate innate immune cells and other type of cell which expressed FPR1 in inflammatory disease, cancers and various other diseases. There is no FPR1 antagonist or agonist is used clinically. For FPR1 antagonism, dramatically remission of activated neutrophil can confer the therapeutic efficacy in acute inflammatory disease. Growing evidence of FPR1 overexpression in cancer and tumor inhibition ability of FPR1 antagonist all indicate therapeutic potential in cancer. Therefore, the development of an FPR1 modulator is currently very important.SUMMARY OF THE INVENTION

[0004] The present disclosure relates to certain compounds as FPR1 modulators for treating diseases regulated by FPR1 and its signaling. Unexpectedly, these compounds produce higher efficacies in modulating FRP1, as compared to other known therapeutic agents.

[0005] In one aspect, the present disclosure provides a compound of formula (I):or a tautomer, stereoisomer, isotopologue, solvate, polymorph, or pharmaceutically acceptable salt thereof, whereinR1is H, OR7, CH2OR7, C(=O)R7, C(=O)OR7, C(=O)NR7R8, NR7R8, NR7C(=O)R8, NR7SO2R8, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, C3-8cycloalkyl, C3-8heterocyclyl, aryl, or heteroaryl;R2is OR7, C(-O)R7, C(-O)OR7, C(=O)NR7R8, NR7R8, NR7C(=O)R8, NR7SO2R8, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, C3-8heterocyclyl, aryl, heteroaryl or heteroarylalkyl;L is C1-6alkyl, C3-8cycloalkyl, C3-8heterocyclyl, aryl, or heteroaryl;R3is H or C1-6alkyl;R4is H or C1-6alkyl;R5and R6independently is H, CH2R7, C(=O)R7, C(=O)CH2R7, C(=O)OR7, C(=O)NR7R8, SO2R7, SO2NR7R8, SOR7, SR7, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, C3-8cycloalkyl, C3-8heterocyclyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl;R7and R8independently is H, C(=NR9)NR10R11, C1-8alkyl, C3-8cycloalkyl, C3-8heterocyclyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, or R7and R8together with the atom to which they are attached form C3-8cycloalkyl or C3-8heterocyclyl; each of the C1-8alkyl, C2-8alkenyl, C2-8alkynyl, C3-8cycloalkyl, C3-8heterocyclyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl of R1to R8is optionally substituted with one or more moieties selected from the group consisting of halogen, OR9, CN, N3, NO2, NR9R10, NR9C(=O)R10, C(=O)R9, C(=O)OR9, C(=O)NR9R10, SO2R9, SO2NR9R10, SOR9, SR9, NR9SO2R10, C1-8alkyl, C1-8alkoxyl, C2-8alkenyl, C2-8alkynyl, C3-8cycloalkyl, C3-8heterocyclyl, aryl, and heteroaryl; andR9, R10and R11independently is H, C1-8alkyl, C3-8cycloalkyl, C3-8heterocyclyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl.

[0006] In some embodiments of the present disclosure, the compound is of formula (II):or a tautomer, stereoisomer, isotopologue, solvate, polymorph, or pharmaceutically acceptable salt thereof.

[0007] In some embodiments of the present disclosure,R1is H, CH2OR7, C(=O)OR7, C(=O)NR7R8, or C1-8alkyl;R2is C(=O)NR7R8or NR7R8;L is C1-6alkyl;R3is H or C1-6alkyl;R4is H or C1-6alkyl;R5and R6independently is H, CH2R7, C(=O)R7, C(=O)CH2R7, C(=O)OR7, C(=O)NR7R8, SO2R7or C1-8alkyl;R7and R8independently is H, C(=NR9)NR10R11, C1-8alkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl; each of the C1-8alkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl is optionally substituted with one or more moieties selected from the group consisting of halogen, CN, C1-8alkyl, C1-8alkoxyl, NR9R10, and C(=O)NR9R10; andR9, R10and R11independently is H or C1-8alkyl.

[0008] In some embodiments of the present disclosure, R3is H or methyl.

[0009] In some embodiments of the present disclosure, R4is H or methyl.

[0010] In some embodiments of the present disclosure, L is methyl, ethyl or propyl.

[0011] In some embodiments of the present disclosure, the compound is selected from the group consisting of: methyl N2-(benzoyl-L-tryptophyl)-N4-trityl-L-asparaginate ; methyl benzoyl-L-tryptophyl-L-asparaginate; benzoyl-L-tryptophyl-L-asparagine;(S)-N1-(2-aminoethyl)-2-((S)-2-benzamido-3-(1H-indol-3-yl)propanamido)-N4- tritylsuccinamide;(S)-N-(3-(1H-indol-3-yl)-1-oxo-1-((3-oxo-3-(tritylamino)propyl)amino)propan-2- yl)benzamide;N2-(benzoyl-L-tryptophyl)-N4-trityl-L-asparagine; methyl benzoyl-L-tryptophyl-L-argininate ; methyl N2-(benzoyl-L-tryptophyl)-N4-benzyl-L-asparaginate;(S)-2-((S)-2-benzamido-3-(1H-indol-3-yl)propanamido)-N1-methyl-N4-tritylsuccinamide; methyl N4-benzhydryl-N2-(benzoyl-L-tryptophyl)-L-asparaginate ; methyl N2-(benzoyl-L-tryptophyl)-N4-((4-methoxyphenyl)diphenylmethyl)-L-asparaginate; methyl N4-((9H-fluoren-9-yl)methyl)-N2-(benzoyl-L-tryptophyl)-L-asparaginate;N2-(benzoyl-L-tryptophyl)-N4-((4-methoxyphenyl)diphenyhnethyl)-L-asparagine;N-((S)-3-(1H-indol-3-yl)-1-(((S)-1-methoxy-4-oxo-4-(tritylamino)butan-2-yl)amino)-1- oxopropan-2-yl)benzamide;N4-((9H-fluoren-9-yl)methyl)-N2-(benzoyl-L-tryptophyl)-L-asparagine; methyl N2-(benzoyl-L-tryptophyl)-N2-methyl-N4-trityl-L-asparaginate;N2-(acetyl-L-tryptophyl)-N4-trityl-L-asparagine;N2-(methyl-L-tryptophyl)-N4-trityl-L-asparagine;N2-(Na-benzoyl-1-methyl-L-tryptophyl)-N4-trityl-L-asparagine;N2-((2-phenylacetyl)-L-tryptophyl)-N4-trityl-L-asparagine;N2-(benzyl-L-tryptophyl)-N4-trityl-L-asparagine; methyl N2-(Na-(4-fhiorobenzoyl)-1-methyl-L-tryptophyl)-N4-trityl-L-asparaginate; methyl N2-((4-fluorobenzoyl)-L-tryptophyl)-N4-trityl-L-asparaginate;N2-(Nα-(4-fluorobenzoyl)-1-methyl-L-tryptophyl)-N4-trityl-L-asparagine;N2-((4-fluorobenzoyl)-L-tryptophyl)-N4-trityl-L-asparagine; methyl N2-(1-methyl-Nα-nicotinoyl-L-tryptophyl)-N4-trityl-L-asparaginate;N2-(1-methyl-Nα-nicotinoyl-L-tryptophyl)-N4-trityl-L-asparagine; methyl N2-(nicotinoyl-L-tryptophyl)-N4-trityl-L-asparaginate;N2-(nicotinoyl-L-tryptophyl)-N4-trityl-L-asparagine;N2-(benzoyl-D-tryptophyl)-N4-trityl-L-asparagine;N2-(picolinoyl-L-tryptophyl)-N4-trityl-L-asparagine;N2-(isonicotinoyl-L-tryptophyl)-N4-trityl-L-asparagine;N2-(1-methyl-Nα-(pyridin-2-ylmethyl)-L-tryptophyl)-N4-trityl-L-asparagine;N2-(1-methyl-Nα-picolinoyl-L-tryptophyl)-N4-trityl-L-asparagine;N2-(Nα-isonicotinoyl-1-methyl-L-tryptophyl)-N4-trityl-L-asparagine;N2-(benzoyl-L-tryptophyl)-N4-trityl-D-asparagine;N2-((pyridin-2-ylmethyl)-L-tryptophyl)-N4-trityl-L-asparagine;N2-(1-methyl-Nα-(1H-pyrrole-2-carbonyl)-L-tryptophyl)-N4-trityl-L-asparagine;N2-((1H-pyrrole-2-carbonyl)-L-tryptophyl)-N4-trityl-L-asparagine;N2-((6-fluoronicotinoyl)-L-tryptophyl)-N4-trityl-L-asparagine;N2-((5-fluoropicolinoyl)-L-tryptophyl)-N4-trityl-L-asparagine;N2-(Nα-(5-fluoropicolinoyl)-1-methyl-L-tryptophyl)-N4-trityl-L-asparagine;N2-((6-methoxynicotinoyl)-L-tryptophyl)-N4-trityl-L- asparagine;N2-((6-cyanonicotinoyl)-L-tryptophyl)-N4-trityl-L-asparagine;N2-(Nα-(6-methoxynicotinoyl)-1-methyl-L-tryptophyl)-N4-trityl-L- asparagine;N2-((6-carbamoylnicotinoyl)-L-tryptophyl)-N4-trityl-L-asparagine;N2-(Nα-(5-cyanopicolinoyl)-1-methyl-L-tryptophyl)-N4-trityl-L-asparagine;N2-(Nα-(6-cyanonicotinoyl)-1-methyl-L-tryptophyl)-N4-trityl-L-asparagine;N2-(Nα-(6-fluoronicotinoyl)-1-methyl-L-tryptophyl)-N4-trityl-L-asparagine;N2-(Nα-(5-methoxypicolinoyl)-1-methyl-L-tryptophyl)-N4-trityl-L-asparagine;N2-(Nα-(5-carbamoylpicolinoyl)-1-methyl-L-tryptophyl)-N4-trityl-L-asparagine;N2-(1-methyl-Nα-((1-methyl- 1H-pyrrol-2-yl)methyl)-L-tryptophyl)-N4-trityl-L-asparagine;N2-(((1-methyl-1H-pyrrol-2-yl)methyl)-L-tryptophyl)-N4-trityl-L-asparagine;N2-(1-methyl-Nα-(phenylcarbamoyl)-L-tryptophyl)-N4-trityl-L-asparagine;N2-(Nα-((4-cyanophenyl)carbamoyl)-1-methyl-L-tryptophyl)-N4-trityl-L-asparagine;N2-(Nα-benzoyl-1-methyl-L-tryptophyl)-N5-trityl-L-glutamine;N2-(Nα-((4-methoxyphenyl)carbamoyl)-1-methyl-L-tryptophyl)-N4-trityl-L-asparagine;N2-(1-methyl-Nα-(naphthalen-1-ylcarbamoyl)-L-tryptophyl)-N4-trityl-L-asparagine;N2-(Nα-((3,5-dimethylisoxazol-4-yl)carbamoyl)-1-methyl-L-tryptophyl)-N4-trityl-L- asparagine;N2-(Nα-((4-(dimethylamino)phenyl)carbamoyl)-1-methyl-L-tryptophyl)-N4-trityl-L- asparagine;(S)-2-((S)-2-benzamido-3-(1-methyl- 1H-indol-3-yl)propanamido)-5-(tritylamino)pentanoic acid;(S)-2-((S)-2-benzamido-3-(1-methyl- 1H-indol-3-yl)propanamido)-6-oxo-6- (tritylamino)hexanoic acid;N2-(Nα-(cyclohexanecarbonyl)-1-methyl-L-tryptophyl)-N4-trityl-L-asparagine;N2-(Nα-((benzyloxy)carbonyl)-1-methyl-L-tryptophyl)-N4-trityl-L-asparagine;N2-(1-methyl-Nα-(phenylsulfonyl)-L-tryptophyl)-N4-trityl-L- asparagine; or a tautomer, stereoisomer, isotopologue, solvate, polymorph, or pharmaceutically acceptable salt thereof.

[0012] In an additional aspect, the present disclosure provides a pharmaceutical composition comprising an effective amount of the compound, or a tautomer, stereoisomer, isotopologue, solvate, polymorph, or pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable diluent or carrier.

[0013] In another aspect, the present disclosure provides the present disclosure, the pharmaceutical composition for use in preventing, ameliorating and / or treating a disease or disorder mediated by formyl peptide receptor 1 (FPR1).

[0014] In another aspect, the present disclosure provides a method for preventing, ameliorating and / or treating a disease or disorder mediated by FPR1 in a subject in need thereof, comprising administering to the subject in need thereof the pharmaceutical composition of claim 8.

[0015] In some embodiments of the present disclosure, the disease or disorder is inflammation and / or cancer.

[0016] In some embodiments of the present disclosure, the inflammation is a neutrophil inflammatory disorder.

[0017] In some embodiments of the present disclosure, the neutrophil inflammatory disorder is selected from the group consisting of lung injury, chronic obstructive pulmonary disease, acute respiratory distress syndrome, asthma, ischemic reperfusing injury, arthritis and septicemia.

[0018] In some embodiments of the present disclosure, the cancer exhibits FPR1 expression.

[0019] In some embodiments of the present disclosure, the cancer is selected from the group consisting of glioblastoma, lung cancer, colon cancer, colorectal cancer, breast cancer, prostate cancer, and leukemia.DETAILED DESCRIPTION OF THE INVENTION

[0020] In order for the present disclosure to be fully understood, the following detailed description is set forth. In the description, the following terms are employed:

[0021] It must be noted that, as used herein, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, unless otherwise required by context, singular terms shall include the plural and plural terms shall include the singular.

[0022] The term “and / or” is used to refer to both things or either one of the two mentioned.

[0023] The terms “treatment,” “treating,” and “treat” generally refer to obtaining a desired pharmacological and / or physiological effect. The effect maybe preventive in terms of completely or partially preventing a disease, disorder, or symptom thereof, and may be therapeutic in terms of a partial or complete cure for a disease, disorder, and / or symptoms attributed thereto. “Treatment” used herein covers any treatment of a disease in a mammal, preferably a human, and includes (1) suppressing development of a disease, disorder, or symptom thereof in a subject or (2) relieving or ameliorating the disease, disorder, or symptom thereof in a subject.

[0024] The term “preventing” or “prevention” is recognized in the art, and when used in relation to a condition, it includes administering, prior to onset of the condition, an agent to reduce the frequency orseverity of or delay the onset of symptoms of a medical condition in a subject relative to a subject which does not receive the agent.

[0025] The terms “individual,” “subject,” and “patient” herein are used interchangeably and refer to any mammalian subject for whom diagnosis, treatment, or therapy is desired.

[0026] The term “effective amount” of an active ingredient as provided herein means a sufficient amount of the ingredient to provide the desired regulation of a desired function. As will be pointed out below, the exact amount required will vary from subject to subject, depending on the disease state, physical conditions, age, sex, species and weight of the subject, the specific identity and formulation of the composition, etc. Dosage regimens may be adjusted to induce the optimum therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation. Thus, it is not possible to specify an exact “effective amount.” However, an appropriate effective amount can be determined by one of ordinary skill in the art using only routine experimentation.

[0027] Disclosed in detail below are the compounds of formula (I), as well as tautomers, stereoisomers, isotopologues, solvate, polymorph, or pharmaceutically acceptable salts thereof:or a tautomer, stereoisomer, isotopologue, solvate, polymorph, or pharmaceutically acceptable salt thereof, whereinR1is H, OR7, CH2OR7, C(=O)R7, C(=O)OR7, C(=O)NR7R8, NR7R8, NR7C(=O)R8, SO2R7, SO2NR7R8, SOR7, SR7, NR7SO2R8, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, C3-8cycloalkyl, C3-8heterocyclyl, aryl, or heteroaryl;R2is OR7, C(=O)R7, C(=O)OR7, C(=O)NR7R8, NR7R8, NR7C(=O)R8, SO2R7, SO2NR7R8, SOR7, SR7, NR7SO2R8, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, C3-8heterocyclyl, , arylalkyl, heteroaryl or heteroarylalkyl;L is C1-6alkyl, C3-8cycloalkyl, C3-8heterocyclyl, aryl, or heteroaryl;R3is H or C1-6alkyl;R4is H or C1-6alkyl;R5and R6independently is H, CH2R7, C(=O)R7, C(=O)CH2R7, C(=O)OR7, C(=O)NR7R8, SO2R7, SO2NR7R8, SOR7, SR7, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, C3-8cycloalkyl, C3-8heterocyclyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl;R7and R8independently is H, C(=NR9)NR10R11, C1-8alkyl, C3-8cycloalkyl, C3-8heterocyclyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, or R7and R8together with the atom to which they are attached form C3-8cycloalkyl or C3-8heterocyclyl; each of the C1-8alkyl, C2-8alkenyl, C2-8alkynyl, C3-8cycloalkyl, C3-8heterocyclyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl of R1to R8is optionally substituted with one or more moieties selected from the group consisting of halogen, OR9, CN, N3, NO2, NR9R10, NR9C(=O)R10, C(=O)R9, C(=O)OR9, C(=O)NR9R10, SO2R9, SO2NR9R10, SOR9, SR9, NR9SO2R10, C1-8alkyl, C1-8alkoxyl, C2-8alkenyl, C2-8alkynyl, C3-8cycloalkyl, C3-8heterocyclyl, aryl, and heteroaryl; andR9, R10and R11independently is H, C1-8alkyl, C3-8cycloalkyl, C3-8heterocyclyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl.

[0028] The term “alkyl” herein refers to a straight or branched hydrocarbon group, containing 1-20 (including any number between 1 and 20 carbons, such as 1-10 and 1-6) carbon atoms. Examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, and t-butyl.

[0029] The term “alkenyl” refers to a linear or branched hydrocarbon moiety, having 2-20 carbons, that contains at least one double bond, such as -CH=CH-CH3.

[0030] The term “alkynyl” refers to a linear or branched hydrocarbon moiety, having 2-20 carbons, that contains at least one triple bond, such as -C≡C-CH3.

[0031] The term “cycloalkyl” refers to a saturated and partially unsaturated monocyclic, bicyclic, tricyclic, or tetracyclic hydrocarbon group having 3-12 (including any number between 3 and 12 carbons, such as 3-10 and 3-8) carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.

[0032] The term “heterocycloalkyl” refers to a nonaromatic 5—8 membered monocyclic, 8-12 membered bicyclic, or 11—14 membered tricyclic ring system having one or more heteroatoms (e.g., O, N, P, and S). Examples include piperazinyl, imidazolidinyl, azepanyl, pyrrolidinyl, dihydrothiadiazolyl, dioxanyl, morpholinyl, tetrahydropuranyl, and tetrahydrofuranyl.

[0033] The term “halogen” refers to a fluoro, chloro, bromo, or iodo radical.

[0034] The term “amino” refers to a radical derived from amine, which is unsubstituted or mono- / di- substituted with alkyl, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl.

[0035] The term “aryl” refers to a functional group derived from an aromatic compound, which may contain one or more 6-carbon monocyclic, 10-carbon bicyclic, and / or 14-carbon tricyclic aromatic ring systems. Examples of aryl groups include phenyl, naphthyl, fluorenyl and anthracenyl.

[0036] The term “arylalkyl” refers to a functional group containing both aryl and alkyl, and the alkyl group in which one or more hydrogen atoms are replaced by aryl groups. The arylalkyl group may be unsubstituted or mono- / di / tri-substituted with halogen, alkyl or alkoxyl. In some embodiments, examples of the arylalkyl of R7and R8include trityl (triphenylmethyl), benzyl, benzhydryl, 4- methoxyphenyl (4-methoxytriphenylmethyl) or methylfluorenyl.

[0037] The term “heteroaryl” refers to an aromatic 5—8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having one or more heteroatoms (e.g., O, N, P, and S). Examples include triazolyl, oxazolyl, thiadiazolyl, tetrazolyl, pyrazolyl, pyridyl, furyl, imidazolyl, benzimidazolyl, pyrimidinyl, thienyl, quinolinyl, indolyl, thiazolyl, and benzothiazolyl.

[0038] Alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl mentioned herein include both substituted and unsubstituted moieties. Possible substituents on alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl include, but are not limited to, C1-C10alkyl, C2-C10alkenyl, C2-C10alkynyl, C3-C20cycloalkyl, C3-C20cycloalkenyl, C1-C20heterocycloalkyl, C1-C20heterocycloalkenyl, C1-C10alkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, amino, C1-C10alkylamino, C1-C20dialkylamino, arylamino, diarylamino, C1-C10alkylsulfonamino, arylsulfonamino, C1-C10alkylimino, arylimino, C1-C10alkylsulfonimino, arylsulfonimino, hydroxyl, halogen, thio, C1-C10alkylthio, arylthio, C1-C10alkylsulfonyl, arylsulfonyl, acylamino, aminoacyl, aminothioacyl, amido, amidino, guanidine, ureido, thioureido, cyano, nitro, nitroso, azido, acyl, thioacyl, acyloxy, carboxyl, and carboxylic ester. On the other hand, possible substituents on alkyl include all the above-recited substituents except C1-C10alkyl. Cycloalkyl, heterocycloalkyl, aryl, and heteroaryl can also be fused with each other.

[0039] In some embodiments of the disclosure, referring to formula (I) above, while R3is H or methyl, and R4is H or methyl.

[0040] One set of compounds of formula (I) have R5or R6being aryl, arylalkyl, heteroaryl or heteroarylalkyl substituted with one to three moieties selected from halogen; R1being C1-8alkyl optionally substituted with C1-8alkoxyl, C3-8cycloalkyl, C3-8heterocyclyl, or heteroaryl.

[0041] In some embodiments of the present disclosure, the compound is of formula (II):or a tautomer, stereoisomer, isotopologue, solvate, polymorph, or pharmaceutically acceptable salt thereof.

[0042] In some embodiments of the present disclosure,R1is H, CH2OR7, C(=O)OR7, C(=O)NR7R8, or alkyl;R2is C(=O)NR7R8or NR7R8;L is C1-6alkyl;R3is H or C1-6alkyl;R4is H or C1-6alkyl;R5and R6independently is H, CH2R7, C(=O)R7, C(=O)CH2R7, C(=O)OR7, C(=O)NR7R8, SO2R7or C1-8alkyl;R7and R8independently is H, C(=NR9)NR10R11, C1-8alkyl, aryl, arylalkyl, heteroaryl, or heteroaiylalkyl; each of the C1-8alkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl is optionally substituted with one or more moieties selected from the group consisting of halogen, CN, C1-8alkyl, C1-8alkoxyl, NR9R10, and C(=O)NR9R10; andR9, R10and R11independently is H or C1-8alkyl.

[0043] In some embodiments of the present disclosure, R3is H or methyl.

[0044] In some embodiments of the present disclosure, R4is H or methyl.

[0045] In some embodiments of the present disclosure, L is methyl, ethyl or propyl.

[0046] Referring to variables R1, R2, R3, R4, R5, R6and L in formula (I), each of these variables can have a stereoisomeric configuration of R or S, and such compounds can have an enantiomeric excess of 90% or higher (e.g., ≥ 95% or ≥ 99%).

[0047] As used herein, the phrase “substituted or unsubstituted” means that substitution is optional. In the event a substitution is desired, then such substitution means that any number of hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the normal valence of the designated atom is not exceeded, and that the substitution results in a stable compound. For example, when a substituent is keto (i.e., =0), then 2 hydrogens on the atom are replaced. Examples of substituents for a “substituted” group are those found in the exemplary compounds and embodiments disclosed herein and can include, for example, haloide, -OH, -CF3, -CN, -NO2, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, haloalkyl, alkylamino, aminoalkyl, dialkylamino, hydroxylalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkoxy, aminoalkoxy, alkylaminoalkoxy, alkylaminoalkyl, and aryl, and the like.

[0048] The compounds of the disclosure can exist as solvates. As used herein and unless otherwise indicated, the term “solvate” means a compound of formula (I), or a pharmaceutically acceptable salt thereof, that further includes a stoichiometric or non-stoichiometric amount of a solvent bound by non- covalent intermolecular forces. If the solvent is water, the solvate may be conveniently referred to as a“hydrate,” for example, a hemi-hydrate, a mono-hydrate, a sesqui-hydrate, a di-hydrate, a tri-hydrate, etc.

[0049] The term “tautomer” as used herein refers to compounds whose structures differ markedly in the arrangement of atoms, but which exist in easy and rapid equilibrium, and it is to be understood that compounds provided herein may be depicted as different tautomers, and when compounds have tautomeric forms, all tautomeric forms are intended to be within the scope of the invention, and the naming of the compounds does not exclude any tautomer. Exemplary tautomerizations include, but are not limited to, amide-to-imide; enamine-to-imine; enamine-to-(a different) enamine tautomerizations; and keto-to-enol.

[0050] The term “stereoisomers” refer to compounds that have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space. Stereoisomers include diastereomers, enantiomers, conformers and the like.

[0051] The term “polymorph” refers to a crystalline form of a compound (or a salt, hydrate, or solvate thereof). All polymorphs have the same elemental composition. Different crystalline forms usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Recrystallization solvent, rate of crystallization, storage temperature, and other factors may cause one crystal form to dominate. Various polymorphs of a compound can be prepared by crystallization under different conditions.

[0052] As used herein, “isotopologue” refers to a compound containing at least one atom having an isotopic composition other than the natural isotopic composition of that atom. “Isotopic enrichment” can be expressed in terms of the percentage of incorporation of an amount of a specific isotope at a given atom in a molecule in the place of the atom's natural isotopic abundance.

[0053] The term “pharmaceutically acceptable salts” as used herein refers to compounds according to the disclosure used in the form of salts derived from inorganic or organic acids and bases. Included among acid salts, for example, are the following: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, flucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2- hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectianate, persulfate, phenylproprionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate and undecanoate. Salts derived from appropriate bases include alkali metal (e.g. sodium), alkaline earth metal (e.g., magnesium), ammonium and NW4+(wherein W is C1-4alkyl).

[0054] In an additional aspect, the present disclosure provides a pharmaceutical composition comprising an effective amount of the compound, or a tautomer, stereoisomer, isotopologue, solvate,polymorph, or pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable diluent or carrier.

[0055] In another aspect, the present disclosure provides the present disclosure, the pharmaceutical composition for use in preventing, ameliorating and / or treating a disease or disorder mediated by formyl peptide receptor 1 (FPR1).

[0056] In another aspect, the present disclosure provides a method for preventing, ameliorating and / or treating a disease or disorder mediated by FPR1 in a subject in need thereof, comprising administering to the subject in need thereof the pharmaceutical composition of claim 8.

[0057] In some embodiments of the present disclosure, the disease or disorder is inflammation and / or cancer.

[0058] In some embodiments of the present disclosure, the inflammation is a neutrophil inflammatory disorder.

[0059] In some embodiments of the present disclosure, the neutrophil inflammatory disorder is selected from the group consisting of lung injury, chronic obstructive pulmonary disease, acute respiratory distress syndrome, asthma, ischemic reperfusing injury, arthritis and septicemia.

[0060] In some embodiments of the present disclosure, the cancer exhibits FPR1 expression.

[0061] In some embodiments of the present disclosure, the cancer is selected from the group consisting of glioblastoma, lung cancer, colon cancer, colorectal cancer, breast cancer, prostate cancer, and leukemia.

[0062] The pharmaceutical compositions can be administered in a variety of dosage forms including, but not limited to, a solid dosage form or a liquid dosage form, an oral dosage form, a parenteral dosage form, an intranasal dosage form, a suppository, a lozenge, a troche, buccal, a controlled release dosage form, a pulsed release dosage form, an immediate release dosage form, an intravenous solution, a suspension or combinations thereof. The pharmaceutical compositions can be administered, for example, by oral or parenteral routes, including intravenous, intramuscular, intraperitoneal, subcutaneous, transdermal, airway (aerosol), rectal, vaginal and topical (including buccal and sublingual) administration.

[0063] A composition for oral administration can be any orally acceptable dosage form including capsules, tablets, emulsions and aqueous suspensions, dispersions, and solutions. In the case of tablets, commonly used carriers include lactose and com starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried com starch. When aqueous suspensions or emulsions are administered orally, the active ingredient can be suspended or dissolved in an oily phase combined with emulsifying or suspending agents. If desired, certain sweetening, flavoring, or coloring agents can be added. Oral solid dosage forms can beprepared by spray dried techniques; hot melt extrusion strategy, micronization, and nano milling technologies.

[0064] A nasal aerosol or inhalation composition can be prepared according to techniques well known in the art of pharmaceutical formulation. For example, such a composition can be prepared as a solution in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters, fluorocarbons, and / or other solubilizing or dispersing agents known in the art. A composition having an active compound can also be administered in the form of suppositories for rectal administration.

[0065] The carrier in the pharmaceutical composition must be “acceptable” in the sense that it is compatible with the active ingredient of the composition (and preferably, capable of stabilizing the active ingredient) and not deleterious to the subject to be treated. One or more solubilizing agents can be utilized as pharmaceutical excipients for delivery of an active compound. Examples of other carriers include colloidal silicon oxide, magnesium stearate, cellulose, sodium lauryl sulfate, and D&C Yellow #10.

[0066] The above-described compounds or a pharmaceutical composition containing one or more of them can be administered to a subject orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, or via an implanted reservoir. The term “parenteral” as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrastemal, intrathecal, intralesional, and intracranial injection or infusion techniques.

[0067] An “excipient” generally refers to a substance, often an inert substance, added to a pharmacological composition or otherwise used as a vehicle to further facilitate administration of a compound. Examples of excipients include, but are not limited to, inert diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavoring agents, coloring agents, preservatives, effervescent mixtures, and adsorbents. Suitable inert diluents include, but are not limited to, sodium and calcium carbonate, sodium and calcium phosphate, lactose, and the like. Suitable disintegrating agents include, but are not limited to, starches, such as com starch, cross-linked polyvinyl pyrrolidone, agar, alginic acid, or a salt thereof, such as sodium alginate, and the like. Binding agents may include, but are not limited to, magnesium aluminum silicate, starches such as com, wheat or rice starch, gelatin, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, and the like. A lubricating agent, if present, will generally be magnesium stearate and calcium stearate, stearic acid, talc, or hydrogenated vegetable oils. If desired, the tablet may be coated with a material such as glyceryl monostearate or glyceryl distearate, to delay absorption in the gastrointestinal tract. The compositions can also be formulated as chewable tablets, for example, by using substances such as mannitol in the formulation.

[0068] FPR1 belongs to chemoattractant receptor family. FPR1 antagonism can be conducted through direct occupation of ligand binding pocket or indirect interfere of FPR function. For a FPR1 directantagonist, the ligand competition and diminished down stream signal are obviously. Reduction of superoxide production and elastase release by neutrophil, are physiological outcome of FPR1 antagonism.

[0069] The details of one or more embodiments of the invention are set forth in the description below. Other features, objects, and advantages of the invention will be apparent from the description and from the claims.

[0070] Reactions applied in synthesizing the compounds of formula (I) are well known in the art. See, for example, R. Larock, Comprehensive Organic Transformations (2ndEd., VCH Publishers 1999); P. G. M. Wuts and T. W. Greene, Greene’s Protective Groups in Organic Synthesis (4thEd., John Wiley and Sons 2007); L. Fieser and M. Fieser, Fieser and Fieser’s Reagents for Organic Synthesis (John Wiley and Sons 1994); L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis (2nded., John Wiley and Sons 2009); and Tsong-Long Hwang, Pei-Wen Hsieh, Yin-Ting Huang, Chih-Hao Hung, “FPR1 antagonist derivatives and use thereof’ US9593144B2.

[0071] In some embodiments of the disclosure, the compounds of formula (I) thus prepared can be further screened using in vitro assays, e.g., Neutrophil elastase release assay and Superoxide anion generation assay, both described in EXAMPLE 2 below, for their potency in inhibiting FPRs. They can be subsequently evaluated using in vivo assays known in the field. The selected compounds can be further tested to verify their efficacy in both disease-related efficacy models and adverse effect models. Based on the results, an appropriate dosage range and administration route can be determined.

[0072] Without further elaboration, it is believed that one skilled in the art can, based on the above description, utilize the present disclosure to its fullest extent. The following specific examples, i.e., EXAMPLES 1-2, are therefore to be construed as merely illustrative, and not limitative of the scope of the invention. All publications cited herein are incorporated by reference in their entirety.

[0073] Among the specific examples, EXAMPLE 1 sets forth the procedures for preparing certain intermediates and 62 exemplary compounds of formula (1), as well as the analytical data for the compounds thus prepared; and EXAMPLES 2 set forth the protocols for testing these compounds.

[0074] Shown in Table 1 below are the structures and analytical data of 62 exemplary compounds of formula (1).

[0075] Table 1

[0076] Described below are the procedures used to synthesize the above-described 62 exemplary compounds.

[0077] Unless otherwise stated, all starting materials used were commercially available and used as supplied. Reactions requiring anhydrous conditions were performed in flame-dried glassware and cooled under an argon or nitrogen atmosphere. Unless otherwise stated, reactions were carried out under argon or nitrogen and monitored by analytical thin-layer chromatography performed on glass-backed plates (5 cm x 10 cm) precoated with silica gel 60 F254 as supplied by Merck. Visualization of the resulting chromatograms was done by looking under an ultraviolet lamp (λ=254 nm), followed by dipping in an nBuOH solution of Ninhydrin (0.3% w / v) containing acetic acid (3% v / v) or ethanol solution of phosphomolybdic acid (2.5% w / v) and charring by heat gun. Solvents for reactions were dried under an argon or nitrogen atmosphere prior to use as follows: THF, Toluene, and DCM were dried by the column of Dried molecular Sieve 5 A (LC technology solution Inc.) and DMF was dried using calcium hydride or obtained commercially. Flash chromatography was used routinely for purification and separation of product mixtures using RediSep Rf Silica Gel Disposable Flash Columns, Gold®20-40 / 40-60 microns silica gel and Reusable RediSep Rf Gold®C18 Reversed Phase columns, 20-40 microns supplied by RediSep. Eluent systems are given in volume / volume concentrations.13C and1H NMR spectra were recorded on Broker A VIII (400 MHz). Chloroform-d or dimethyl sulfoxided6and CD3OD was used as the solvent mid TMS (δ 0.00 ppm) as an internal standard. Chemical shift values are reported in ppm relative to the TMS in delta (δ) units. Multiplicities are recorded as s (singlet),br s (broad singlet), d (doublet), t (triplet), q (quartet), dd (doublet of doublet), dt (doublet of triplet), m (multiplet), Coupling constants (J) are expressed in Hz. Electrospray mass spectra (ESMS) were recorded using a Thermo LTQ XL mass spectrometer. Spectral data were recorded as m / z values.

[0078] Shown below is the synthetic scheme followed for synthesizing the compounds of formula (I).

[0079] EXAMPLE 1: Synthesis of the compounds of formula (I)

[0080] The following scheme was followed for synthesizing Compound 3. The other exemplary compounds of formula (I) were prepared in a similar manner.

[0081] Step 1: synthesis of Methyl N2-(benzoyl-L-tryptophyl)-N4-trityl-L-asparaginate

[0082] To a solution of L-tryptophan (1 g, 4.90 mmol) in 2N NaOH(aq) (4.9 ml) was added benzoyl chloride (626 μl, 5.39 mmol) and stirred for 3h at room temperature. After the reaction was completely, IN HCl(aq) was added into the solution and extracted with DCM (3 x 10 ml). The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. It was recrystallizes from DCM to give the product (96 mg, 6%).

[0083] To a solution of SM (96 mg, 0.31 mmol), Asp(Trt)-OMe (100 mg, 0.26 mmol), HBTU (117 mg, 0.31 mmol) in DCM (1.3 ml) was added DIPEA (112 μl, 0.65 mmol) at 0°C. The mixture was stirred for Ih at room temperature. After the reaction was completely, H2O was added into the mixture and extracted with DCM (3 x 10 ml). The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give the product (96.7 mg, 55%). 1H NMR (600 MHz, DMSO) δ 10.77 (dd, J = 10.2, 1.9 Hz, 1H), 8.77 (d, J= 14.2 Hz, 1H), 8.62 (dd, J = 49.9, 7.9 Hz, 1H), 8.49 (dd, J = 23.2, 8.3 Hz, 1H), 7.80 - 7.76 (m, 2H), 7.70 (dd, J = 17.8, 7.9 Hz, 1H), 7.52 - 7.47 (m, 1H), 7.41 (ddd, J = 7.5, 5.8, 1.8 Hz, 2H), 7.32 - 7.19 (m, 9H), 7.16 (ddt, J = 6.8, 2.6, 1.4 Hz, 9H), 7.07 - 7.01 (m, 1H), 6.96 (td, J = 7.7, 0.8 Hz, 1H), 4.85 - 4.78 (m, 1H), 4.62 (ddd, J = 40.5, 14.4, 6.8 Hz, 1H), 3.59 (s, 3H), 3.22 (ddd, J = 32.3, 16.0, 11.9 Hz, 1H), 3.18 - 3.11 (m, 1H), 2.80 (ddd, J = 48.1, 21.1, 12.8 Hz, 2H).

[0084] Step 2: synthesis of Methylbenzoyl-L-tryptophyl-L-asparaginate

[0085] To a solution of the SM (200 mg, 0.29 mmol) in DCM (2 ml) was added TFA (2 ml) and few drops of TIPS. After 2 hours at RT, the mixture was concentrated in vacuo. It was purified by column chromatography on silica gel to give the product (59 mg, 46%) as white solid. 1H NMR (600 MHz, DMSO) δ 10.80 - 10.73 (m, 1H), 8.54 (dd, J = 28.3, 7.9 Hz, 2H), 7.80 - 7.76 (m, 2H), 7.70 (d, J = 7.9 Hz, 1H), 7.53 - 7.48 (m, 1H), 7.48 - 7.40 (m, 3H), 7.30 (dd, J = 8.1, 3.0 Hz, 1H), 7.21 (s, 1H), 7.05 (ddd, J = 8.3, 2.4, 1.2 Hz, 1H), 7.00 - 6.95 (m, 2H), 4.77 (td, J = 10.5, 4.2 Hz, 1H), 4.72 - 4.60 (m, 1H), 3.61 (d, J = 3.3 Hz, 3H), 3.26 - 3.18 (m, 1H), 3.13 (dd, J = 14.7, 10.5 Hz, 1H), 2.61 (td, J = 15.5, 6.0 Hz, 1H), 2.55 (dd, J = 15.9, 6.4 Hz, 1H).

[0086] Step 3: synthesis of Benzoyl-L-tryptophyl-L-asparagine

[0087] To a solution of the SM (200 mg, 0.30 mmol) in MeOH (2 ml) was added IN NaOH(aq) (2 ml) at 40°C. After 2 hours, the mixture was concentrated in vacuo. It was purified by column chromatography on silica gel to give the product (67 mg, 79%). 1H NMR (600 MHz, DMSO) δ 10.76 (s, 1H), 8.50 (d, J = 8.3 Hz, 1H), 8.40 (d, J = 7.7 Hz, 1H), 7.77 (dd, J = 10.4, 3.3 Hz, 2H), 7.69 (d, J = 7.9 Hz, 1H), 7.50 (t, J = 7.4 Hz, 1H), 7.45 - 7.40 (m, 2H), 7.30 (d, J = 8.1 Hz, 1H), 7.22 (d, J = 17.6 Hz, 2H), 7.04 (t, J = 7.5 Hz, 1H), 6.99 - 6.91 (m, 2H), 6.68 (s, 1H), 4.76 (s, 1H), 4.60 - 4.52 (m, 1H), 3.23 - 3.21 (m, 1H), 3.19 - 3.15 (m, 1H), 3.12 (dd, J = 14.9, 10.7 Hz, 2H).

[0088] EXAMPLE 2: Evaluation of inhibition activity of compounds of formula (I) in in vitro assays

[0089] The compounds prepared in EXAMPLE 1 were tested in the in vitro assays described below.

[0090] Receptor Binding Assay (FNLFNYK Competitive Binding Assay)

[0091] Certain compounds of formula (I) were tested for their potency in a cell based FPR1 binding assay. Standard assay conditions included human FPR1 overexpressed human embryonic kidney 293 cell (HEK293), at a concentration of 1 x 106cells / mL, were treated with CPDs for 5 minutes. Subsequently, N-formyl-Nle-Leu-Phe-Nle-Tyr-Lys-fluorescein (fNLFNYK, 2 nM) was added and incubated for 30 minutes at 4°C. The fluorescence of fNLFNYK was then analyzed using BD Accuri C6 flow cytometry (BD Biosciences, San Jose, CA).

[0092] Calcium Flux Assay

[0093] Certain compounds of formula (I) were tested for their potency in a cell based calcium flux assay. Assay were conducted with human lymphoma cell line HL-60 (CCL-240, ATCC, Manassas, VA), which were performed differentiation with 1.3% v / v DMSO 5% FBS for 7 days with changing media per 2-3 day. Phenotype of Granulocyte was revealed in differentiated HL-60 cell. Differentiated HL-60 cells were incubated with diluted Calcium 6 assay reagent for 2 hours at 37°C. Calcium flux were detected with FlexStation 3 Multi-Mode Microplate Reader (Molecular Devices).

[0094] Human Neutrophil Isolation

[0095] Human neutrophils were sourced from healthy donors aged between 20-35 years. Each participant provided informed consent and had not taken any medication in the preceding two weeks. Blood samples were collected using vacutainer tubes containing heparin. Erythrocyte sedimentationwas achieved with 3% (w / v) dextran. The neutrophils were then isolated via Ficoll-Paque (GE Healthcare) gradient centrifugation followed by a hypotonic lysis process, achieving a purity of over 98% (as determined via CD66b staining). The isolated neutrophils were resuspended in calcium-free Hank’s balanced salt solution (HBSS). All procedures adhered to the guidelines and received approval from the Institutional Review Board of Chang Gun Memorial Hospital.

[0096] Neutrophil Elastase Release Assay

[0097] Certain compounds of formula (I) were tested for their potency in inhibiting Neutrophil elastase release. Standard assay conditions included Human neutrophils, at a concentration of 6 x 105cells / mL, were co-incubated with methoxysuccinyl-Ala-Ala-Pro-Val-p-nitroanilide (0.1 mM) and subjected to CPDs treatment for 10 minutes. Following this, cytochalasin B (0.5 μg / mL) was introduced for 3 minutes, Next, either fMLF (30 nM) or MMK1 (100 nM) was introduced for 10 minutes to activate the neutrophils. The release of elastase was then continuously monitored using a U-3010 spectrophotometer (Hitachi, TYO, JP) by observing the changes in absorbance at 405 nm.

[0098] Superoxide Anion Generation Assay

[0099] Certain compounds of formula (I) were tested for their potency in inhibiting Superoxide anion generation. Standard assay conditions included Human neutrophils, at a concentration of 6 x 105cells / mL, were co-incubated with ferricytochrome c (0.6 mg / mL) and subjected to CPDs treatment for 10 minutes. Following this, cytochalasin B (1 μg / mL) was introduced for 3 minutes, Next, either N- formylmethionyl-leucyl-phenylalanine (fMLF, 30 nM) or MMK1 (100 nM) was introduced for 10 minutes to activate the neutrophils. The release of superoxide anion was then continuously monitored using a U-3010 spectrophotometer (Hitachi, TYO, JP) by observing the changes in absorbance at 550 nm.

[0100] Results

[0101] The test compounds were found to preferentially inhibit the activities of receptor binding - neutrophil elastase release and superoxide anion generation to various degrees as indicated by their IC50values (IC50being the concentration of an inhibitor where the response or binding is reduced by half). See Table 2 below.

[0102] More specifically, 17 of 62 compounds show the IC50values below 400 nM for neutrophil elastase release and 30 of 62 compounds show the IC50values below 100 nM for superoxide anion generation. As indicated in Tables 2 and 3, IC50values below 40 nM are represented by activity level “A”, IC50values between 40 nM and 100 nM are represented by activity level “B”, IC50values between 100 nM and 400 nM are represented by activity level “C”, IC50values between 400 nM and 1 μM are represented by activity level “D”, and IC50values > 1 μM are represented by activity level “E”.

[0103] Table 2. In vitro Potency of FPR1 Antagonists Activity, Potency of FPR1 Antagonists in Neutrophil elastase and Superoxide anion, and Inducing elastase release and superoxide anion generation in the presence of CB

[0104] These results show that compounds of formula (I) are selective and exhibit high potencies in inhibiting the activities of neutrophil elastase release and superoxide anion generation. The selectivities of compounds of formula (I) for FPR1 are unexpected and would make these compounds useful therapeutics for FPRl-associated diseases.

Claims

CLAIMSWhat is claimed is:

1. A compound of formula (I):or a tautomer, stereoisomer, isotopologue, solvate, polymorph, or pharmaceutically acceptable salt thereof, whereinR1is H, OR7, CH2OR7, C(=O)R7, C(=O)OR7, C(=O)NR7R8, NR7R8, NR7C(=O)R8, NR7SO2R8, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, C3-8cycloalkyl, C3-8heterocyclyl, aryl, or heteroaryl;R2is OR7, C(=O)R7, C(=O)OR7, C(=O)NR7R8, NR7R8, NR7C(=O)R8, NR7SO2R8, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, C3-8heterocyclyl, aryl, heteroaryl or heteroarylalkyl;L is C1-6alkyl, C3-8cycloalkyl, C3-8heterocyclyl, aryl, or heteroaryl;R3is H or C1-6alkyl;R4is H or C1-6alkyl;R5and R6independently is H, CH2R7, C(=O)R7, C(=O)CH2R7, C(=O)OR7, C(=O)NR7R8, SO2R7, SO2NR7R8, SOR7, SR7, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, C3-8cycloalkyl, C3-8heterocyclyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl;R7and R8independently is H, C(=NR9)NR10R11, C1-8alkyl, C3-8cycloalkyl, C3-8heterocyclyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, or R7and R8together with the atom to which they are attached form C3-8cycloalkyl or C3-8heterocyclyl; each of the C1-8alkyl, C2-8alkenyl, C2-8alkynyl, C3-8cycloalkyl, C3-8heterocyclyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl of R1to R8is optionally substituted with one or more moieties selected from the group consisting of halogen, OR9, CN, N3, NO2, NR9R10, NR9C(=O)R10, C(=O)R9, C(=O)OR9, C(=O)NR9R10, SO2R9, SO2NR9R10, SOR9, SR9, NR9SO2R10, C1-8alkyl, C1-8alkoxyl, C2-8alkenyl, C2-8alkynyl, C3-8cycloalkyl, C3-8heterocyclyl, aryl, and heteroaryl; andR9, R10and R11independently is H, C1-8alkyl, C3-8cycloalkyl, C3-8heterocyclyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl.

2. The compound of claim 1, which is of formula (II):or a tautomer, stereoisomer, isotopologue, solvate, polymorph, or pharmaceutically acceptable salt thereof.

3. The compound of claim 1, or a tautomer, stereoisomer, isotopologue, solvate, polymorph, or pharmaceutically acceptable salt thereof, whereinR1is H, CH2OR7, C(=O)OR7, C(=O)NR7R8, or C1-8alkyl;R2is C(=O)NR7R8or NR7R8;L is C1-6alkyl;R3is H or C1-6alkyl;R4is H or C1-6alkyl;R5and R6independently is H, CH2R7, C(=O)R7, C(=O)CH2R7, C(=O)OR7, C(=O)NR7R8, SO2R7or C1-8alkyl;R7and R8independently is H, C(=NR9)NR10R11, C1-8alkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl; each of the C1-8alkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl is optionally substituted with one or more moieties selected from the group consisting of halogen, CN, C1-8alkyl, C1-8alkoxyl, NR9R10, and C(=O)NR9R10; andR9, R10and R11independently is H or C1-8alkyl.

4. The compound of claim 1, or a tautomer, stereoisomer, isotopologue, solvate, polymorph, or pharmaceutically acceptable salt thereof, wherein R3is H or methyl.

5. The compound of claim 1, or a tautomer, stereoisomer, isotopologue, solvate, polymorph, or pharmaceutically acceptable salt thereof, wherein R4is H or methyl.

6. The compound of claim 1, or a tautomer, stereoisomer, isotopologue, solvate, polymorph, or pharmaceutically acceptable salt thereof, wherein L is methyl, ethyl or propyl.

7. The compound of claim 1, or a tautomer, stereoisomer, isotopologue, solvate, polymorph, or pharmaceutically acceptable salt thereof, wherein the arylalkyl of R7and R8is trityl, benzyl, benzhydryl, 4-methoxyphenyl or methylfluorenyl.

8. The compound of claim 1, which is selected from the group consisting of: methyl N2-(benzoyl-L-tryptophyl)-N4-trityl-L-asparaginate ; methyl benzoyl-L-tryptophyl-L-asparaginate; benzoyl-L-tryptophyl-L-asparagine;(S)-N 1 -(2-aminoethyl)-2-((S)-2-benzamido-3-( 1H-indol-3-yl)propanamido)-N4- tritylsuccinamide;(S)-N-(3-(1H-indol-3-yl)-1-oxo-1-((3-oxo-3-(tritylamino)propyl)amino)propan-2- yl)benzamide;N2-(benzoyl-L-tryptophyl)-N4-trityl-L-asparagine; methyl benzoyl-L-tryptophyl-L-argininate; methyl N2-(benzoyl-L-tryptophyl)-N4-benzyl-L-asparaginate;(S)-2-((S)-2-benzamido-3-(1H-indol-3-yl)propanamido)-N1-methyl-N4-tritylsuccinamide; methyl N4-benzhydryl-N2-(benzoyl-L-tryptophyl)-L-asparaginate ; methyl N2-(benzoyl-L-tryptophyl)-N4-((4-methoxyphenyl)diphenylmethyl)-L-asparaginate; methyl N4-((9H-fhioren-9-yl)methyl)-N2-(benzoyl-L-tryptophyl)-L-asparaginate;N2-(benzoyl-L-tryptophyl)-N4-((4-methoxyphenyl)diphenylmethyl)-L-asparagine;N-((S)-3-(1H-indol-3-yl)-1-(((S)-1-methoxy-4-oxo-4-(tritylamino)butan-2-yl)amino)-1- oxopropan-2-yl)benzamide;N4-((9H-fluoren-9-yl)methyl)-N2-(benzoyl-L-tryptophyl)-L-asparagine; methyl N2-(benzoyl-L-tryptophyl)-N2-methyl-N4-trityl-L-asparaginate;N2-(acetyl-L-tryptophyl)-N4-trityl-L-asparagine;N2-(methyl-L-tryptophyl)-N4-trityl-L-asparagine;N2-(Na-benzoyl-1-methyl-L-tryptophyl)-N4-trityl-L-asparagine ;N2-((2-phenylacetyl)-L-tryptophyl)-N4-trityl-L-asparagine;N2-(benzyl-L-tryptophyl)-N4-trityl-L-asparagine; methyl N2-(Na-(4-fluorobenzoyl)-1-methyl-L-tryptophyl)-N4-trityl-L-asparaginate; methyl N2-((4-fluorobenzoyl)-L-tryptophyl)-N4-trityl-L-asparaginate;N2-(Nα-(4-fluorobenzoyl)-1-methyl-L-tryptophyl)-N4-trityl-L-asparagine;N2-((4-fhiorobenzoyl)-L-tryptophyl)-N4-trityl-L-asparagine; methyl N2-(1-methyl-Nα-nicotinoyl-L-tryptophyl)-N4-trityl-L-asparaginate;N2-(1-methyl-Nα-nicotinoyl-L-tryptophyl)-N4-trityl-L-asparagine; methyl N2-(nicotinoyl-L-tryptophyl)-N4-trityl-L-asparaginate;N2-(nicotinoyl-L-tryptophyl)-N4-trityl-L-asparagine;N2-(benzoyl-D-tryptophyl)-N4-trityl-L-asparagine;N2-(picolinoyl-L-tryptophyl)-N4-trityl-L-asparagine;N2-(isonicotinoyl-L-tryptophyl)-N4-trityl-L-asparagine;N2-(1-methyl-Nα-(pyridin-2-ylmethyl)-L-tryptophyl)-N4-trityl-L-asparagine;N2-(1-methyl-Nα-picolinoyl-L-tryptophyl)-N4-trityl-L-asparagine;N2-(Nα-isonicotinoyl-1-methyl-L-tryptophyl)-N4-trityl-L-asparagine;N2-(benzoyl-L-tryptophyl)-N4-trityl-D-asparagine;N2-((pyridin-2-ylmethyl)-L-tryptophyl)-N4-trityl-L-asparagine;N2-(1-methyl-Nα-(1H-pyrrole-2-carbonyl)-L-tryptophyl)-N4-trityl-L-asparagine;N2-((1H-pyrrole-2-carbonyl)-L-tryptophyl)-N4-trityl-L-asparagine;N2-((6-fluoronicotinoyl)-L-tryptophyl)-N4-trityl-L-asparagine;N2-((5-fluoropicolinoyl)-L-tryptophyl)-N4-trityl-L-asparagine;N2-(Nα-(5-fluoropicolinoyl)-1-methyl-L-tryptophyl)-N4-trityl-L-asparagine;N2-((6-methoxynicotinoyl)-L-tryptophyl)-N4-trityl-L-asparagine;N2-((6-cyanonicotinoyl)-L-tryptophyl)-N4-trityl-L-asparagine;N2-(Nα-(6-methoxynicotinoyl)-1-methyl-L-tryptophyl)-N4-trityl-L-asparagine;N2-((6-carbamoylnicotinoyl)-L-tryptophyl)-N4-trityl-L-asparagine;N2-(Nα-(5-cyanopicolinoyl)-1-methyl-L-tryptophyl)-N4-trityl-L-asparagine;N2-(Nα-(6-cyanonicotinoyl)-1-methyl-L-tryptophyl)-N4-trityl-L-asparagine;N2-(Nα-(6-fluoronicotinoyl)-1-methyl-L-tryptophyl)-N4-trityl-L-asparagine;N2-(Nα-(5-methoxypicolinoyl)-1-methyl-L-tryptophyl)-N4-trityl-L-asparagine;N2-(Nα-(5-carbamoylpicolinoyl)-1-methyl-L-tryptophyl)-N4-trityl-L-asparagine;N2-(1-methyl-Nα-((1-methyl- 1H-pyrrol-2-yl)methyl)-L-tryptophyl)-N4-trityl-L-asparagine;N2-(((1-methyl-1H-pyrrol-2-yl)methyl)-L-tryptophyl)-N4-trityl-L-asparagine;N2-(1-methyl-Nα-(phenylcarbamoyl)-L-tryptophyl)-N4-trityl-L-asparagine;N2-(Nα-((4-cyanophenyl)carbamoyl)-1-methyl-L-tryptophyl)-N4-trityl-L-asparagine;N2-(Nα-benzoyl-1-methyl-L-tryptophyl)-N5-trityl-L-glutamine;N2-(Nα-((4-methoxyphenyl)carbamoyl)-1-methyl-L-tryptophyl)-N4-trityl-L-asparagine;N2-(1-methyl-Nα-(naphthalen-1-ylcarbamoyl)-L-tryptophyl)-N4-trityl-L-asparagine;N2-(Nα-((3,5-dimethylisoxazol-4-yl)carbamoyl)-1-methyl-L-tryptophyl)-N4-trityl-L- asparagine;N2-(Nα-((4-(dimethylamino)phenyl)carbamoyl)-1-methyl-L-tryptophyl)-N4-trityl-L- asparagine;(S)-2-((S)-2-benzamido-3-(1-methyl- 1H-indol-3-yl)propanamido)-5-(tritylamino)pentanoic acid;(S)-2-((S)-2-benzamido-3-(1-methyl- 1H-indol-3-yl)propanamido)-6-oxo-6- (tritylamino)hexanoic acid;N2-(Nα-(cyclohexanecarbonyl)-1-methyl-L-tryptophyl)-N4-trityl-L-asparagine;N2-(Nα-((benzyloxy)carbonyl)-1-methyl-L-tryptophyl)-N4-trityl-L-asparagine;N2-(1-methyl- Nα-(phenylsulfonyl)-L-tryptophyl)-N4-trityl-L-asparagine; or a tautomer, stereoisomer, isotopologue, solvate, polymorph, or pharmaceutically acceptable salt thereof.

9. A pharmaceutical composition comprising an effective amount of the compound of any one of claims 1 to 8, or a tautomer, stereoisomer, isotopologue, solvate, polymorph, or pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable diluent or carrier.

10. The pharmaceutical composition of claim 9 for use in preventing, ameliorating and / or treating a disease or disorder mediated by formyl peptide receptor 1 (FPR1).

11. The pharmaceutical composition for use of claim 10, wherein the disease or disorder is inflammation and / or cancer.

12. The pharmaceutical composition for use of claim 11, wherein the inflammation is a neutrophil inflammatory disorder.

13. The pharmaceutical composition for use of claim 11, wherein the neutrophil inflammatory disorder is selected from the group consisting of lung injury, chronic obstructive pulmonary disease, acute respiratory distress syndrome, asthma, ischemic reperfusing injury, arthritis and septicemia.

14. The pharmaceutical composition for use according to claim 11, wherein the cancer exhibits FPR1 expression.

15. The pharmaceutical composition for use according to claim 11, wherein the cancer is selected from the group consisting of glioblastoma, lung cancer, colon cancer, colorectal cancer, breast cancer, prostate cancer, and leukemia.

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