Heterocyclic compounds as modulators of formyl peptide receptors

Abstract

Disclosed are compounds of the following Formula (I) and tautomers, stereoisomers, isotopologues, solvates, polymorphs, or pharmaceutically acceptable salts thereof: Formula (I), wherein each of the variables R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and L are defined below. Also disclosed is a method of treating a disease or disorder mediated by Formyl Peptide Receptor 1 (FPR1) with a compound of Formula (I) or a tautomer, stereoisomer, isotopologue, solvate, polymorph, or pharmaceutically acceptable salt thereof, and pharmaceutical compositions comprising the same.

Description

Technical Field

[0001] This disclosure relates generally to compounds that act as formyl peptide receptor 1 (FPR1) modulators and the use of such compounds in the treatment of FPR1-mediated diseases. Background Technology

[0002] The formyl peptide receptor (FPR) belongs to the G protein-coupled receptor (GPCR) family. The FPR family can be divided into three classes: FPR1, FPR2, and FPR3. FPR2 and FPR3 are classified as FPR-like receptors, with FPR2 also known as FPR-like receptor 1 (FPRL-1) and FPR3 as FPR-like receptor 2 (FPRL-2). FPR1 is found in monocytes, polymorphonuclear leukocytes, and immature dendritic cells, while FPR2 is found in hepatocytes, lung cells, spleen cells, T lymphocytes, monocytes, and polymorphonuclear leukocytes. FPR1 and FPR2 are two members of the FPR family and are found in human neutrophils. Formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP or fMLF) is an N-formyl peptide that acts as a chemical inducer to bind to FPR1, thereby triggering cell activation and the release of toxic substances or proteases. fMLF exhibits varying affinities for the three FPRs, with a higher affinity for FPR1. Activation of FPR1 initiates multiple signaling pathways, including those involving calcium, phospholipase C, phosphatidylinositol 3-kinase (PI3K), mitogen-activated protein kinases (MAPK), and protein tyrosine kinases (PTK), leading to neutrophil activation for migration, respiratory burst, and degranulation. Therefore, some literature reports that inhibiting neutrophil activation can serve as a therapeutic target for neutrophil-induced inflammation, such as in asthma, rheumatoid arthritis, psoriasis, sepsis, myocardial ischemia / reperfusion injury, acute respiratory distress syndrome, and chronic obstructive pulmonary disease. Recent studies have shown that FPR1 not only participates in infection and inflammatory processes but also plays a role in promoting tumor progression. Specifically, FPR1 can interact with endogenous annexin A1, thereby transcribing and activating EGFR in glioblastoma cells, mediating cell migration and growth. Therefore, FPR1 is also a therapeutic target for human glioblastoma.

[0003] Based on the above, FPR1 antagonists can modulate innate immune cells and other cell types that express FPR1 in inflammatory diseases, cancer, and various other diseases. FPR1 antagonists or agonists are not currently used clinically. Significant relief of activated neutrophils in FPR1 antagonism can confer therapeutic efficacy in acute inflammatory diseases. Increasing evidence suggests that FPR1 overexpression in cancer and the tumor-suppressive capabilities of FPR1 antagonists demonstrate their therapeutic potential in cancer. Therefore, the development of FPR1 modulators is currently of great importance. Summary of the Invention

[0004] This disclosure relates to certain compounds as FPR1 modulators for the treatment of diseases regulated by FPR1 and its signaling pathways. Surprisingly, these compounds exhibit greater efficacy in modulating FPR1 compared to other known therapeutic agents.

[0005] In one state sample, this disclosure provides a compound of formula (I):

[0006] Formula (I),

[0007] Or its tautomers, stereoisomers, isotopes, solvates, polymorphs, or pharmaceutically acceptable salts.

[0008] in

[0009] R 1 For H, OR 7 CH2OR 7 C(=O)R 7 C(=O)OR 7 C(=O)NR 7 R 8 NR 7 R 8 NR 7 C(=O)R 8 NR 7 SO2R 8 C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 3-8 cycloalkyl, C 3-8 Heterocyclic, aryl, or heteroaryl groups;

[0010] R 2 OR 7 C(=O)R 7 C(=O)OR 7 C(=O)NR 7 R 8 NR 7 R 8NR 7 C(=O)R 8 NR 7 SO2R 8 C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 3-8 Heterocyclic, aryl, heteroaryl, or heteroarylalkyl;

[0011] L is C 1-6 Alkyl, C 3-8 cycloalkyl, C 3-8 Heterocyclic, aryl, or heteroaryl groups;

[0012] R 3 For H or C 1-6 alkyl;

[0013] R 4 It is H or C1-6 alkyl;

[0014] R 5 and R 6 Independently H, CH2R 7 C(=O)R 7 C(=O)CH2R 7 C(=O)OR 7 C(=O)NR 7 R 8 SO2R 7 SO2NR 7 R 8 SOR 7 SR 7 C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 3-8 cycloalkyl, C 3-8 Heterocyclic, aryl, aralkyl, heteroaryl or heteroarylalkyl;

[0015] R 7 and R 8 Independently for H, C (=NR) 9 )NR 10 R 11 C 1-8 Alkyl, C 3-8 cycloalkyl, C 3-8 Heterocyclic, aryl, aralkyl, heteroaryl or heteroarylalkyl, or R 7 and R 8 Together with the atoms it is attached to, they form C 3-8 cycloalkyl or C 3-8 Heterocyclic groups;

[0016] R1 To R 8 C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 3-8 cycloalkyl, C 3-8 Each of the heterocyclic, aryl, aralkyl, heteroaryl, and heteroarylalkyl groups may be partially substituted, as appropriate, by one or more of the following groups: halogens, OR 9 CN, N3, NO2, NR 9 R 10 NR 9 C(=O)R 10 C(=O)R 9 C(=O)OR 9 C(=O)NR 9 R 10 SO2R 9 SO2NR 9 R 10 SOR 9 SR 9 NR 9 SO2R 10 C 1-8 Alkyl, C 1-8 Alkoxy, C 2-8 alkenyl, C 2-8 alkynyl group, C 3-8 cycloalkyl, C 3-8 Heterocyclic, aryl, and heteroaryl groups; and

[0017] R 9 R 10 and R 11 H and C independently 1-8 Alkyl, C 3-8 cycloalkyl, C 3-8 Heterocyclic, aryl, aralkyl, heteroaryl or heteroarylalkyl.

[0018] In some embodiments disclosed herein, the compounds are of formula (II):

[0019] Equation (II),

[0020] Or its tautomers, stereoisomers, isotopes, solvates, polymorphs, or pharmaceutically acceptable salts.

[0021] In some embodiments disclosed herein,

[0022] R 1 H, CH2OR 7 C(=O)OR 7 C(=O)NR 7R 8 Or C 1-8 alkyl;

[0023] R 2 For C(=O)NR 7 R 8 or NR 7 R 8 ;

[0024] L is C 1-6 alkyl;

[0025] R 3 For H or C 1-6 alkyl;

[0026] R 4 It is H or C1-6 alkyl;

[0027] R 5 and R 6 Independently H, CH2R 7 C(=O)R 7 C(=O)CH2R 7 C(=O)OR 7 C(=O)NR 7 R 8 SO2R 7 Or C 1-8 alkyl;

[0028] R 7 and R 8 Independently for H, C (=NR) 9 )NR 10 R 11 C 1-8 Alkyl, aryl, aralkyl, heteroaryl, or heteroarylalkyl;

[0029] C 1-8 Each of the alkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl groups may be partially substituted, depending on the case, by one or more of the following groups: halogen, CN, C. 1-8 Alkyl, C 1-8 Alkoxy, NR 9 R 10 and C(=O)NR 9 R 10 ;and

[0030] R 9 R 10 and R 11 Independently H or C 1-8 alkyl.

[0031] In some embodiments disclosed herein, R 3 It is H or methyl.

[0032] In some embodiments disclosed herein, R 4 It is H or methyl.

[0033] In some embodiments disclosed herein, L is methyl, ethyl, or propyl.

[0034] In some embodiments disclosed herein, the compounds are selected from the group consisting of:

[0035] N2-(benzoyl-L-tryptophanyl)-N4-triphenylmethyl-L-aspartic acid methyl ester

[0036] Benzoyl-L-tryptophanyl-L-aspartic acid methyl ester

[0037] Benzoyl-L-tryptophanyl-L-aspartic acid,

[0038] (S)-N1-(2-aminoethyl)-2-((S)-2-benzoylamino-3-(1H-indol-3-yl)propionylamino)-N4-triphenylmethylsuccinylamino,

[0039] (S)-N-(3-(1H-indol-3-yl)-1-sideoxy-1-((3-sideoxy-3-(triphenylmethylamino)propyl)amino)propyl-2-yl)benzoylamine,

[0040] N2-(benzoyl-L-tryptophanyl)-N4-triphenylmethyl-L-aspartic acid,

[0041] Benzoyl-L-tryptophanyl-L-arginine methyl ester

[0042] N2-(benzoyl-L-tryptophanyl)-N4-benzyl-L-aspartic acid methyl ester

[0043] (S)-2-((S)-2-benzoylamino-3-(1H-indol-3-yl)propionylamino)-N1-methyl-N4-triphenylmethylsuccinylamino,

[0044] N4-Diphenylmethyl-N2-(benzoyl-L-tryptophanyl)-L-aspartic acid methyl ester

[0045] N2-(benzoyl-L-tryptophanyl)-N4-((4-methoxyphenyl)diphenylmethyl)-L-aspartic acid methyl ester

[0046] N4-((9H-furo-9-yl)methyl)-N2-(benzoyl-L-tryptophanyl)-L-aspartic acid methyl ester,

[0047] N2-(benzoyl-L-tryptophanyl)-N4-((4-methoxyphenyl)diphenylmethyl)-L-aspartic acid,

[0048] N-((S)-3-(1H-indol-3-yl)-1-(((S)-1-methoxy-4-sideoxy-4-(triphenylmethylamino)but-2-yl)amino)-1-sideoxypropyl-2-yl)benzoylamine,

[0049] N4-((9H-furo-9-yl)methyl)-N2-(benzoyl-L-tryptophanyl)-L-aspartic acid,

[0050] N2-(benzoyl-L-tryptophanyl)-N2-methyl-N4-triphenylmethyl-L-aspartic acid methyl ester

[0051] N2-(acetyl-L-tryptophanyl)-N4-triphenylmethyl-L-aspartic acid,

[0052] N2-(methyl-L-tryptophanyl)-N4-triphenylmethyl-L-aspartic acid,

[0053] N2-(Nα-benzoyl-1-methyl-L-tryptophanyl)-N4-triphenylmethyl-L-aspartic acid,

[0054] N2-((2-Phenylacetyl)-L-Tryptocyano)-N4-Triphenylmethyl-L-Aspartate,

[0055] N2-(phenylmethyl-L-tryptophanyl)-N4-triphenylmethyl-L-aspartic acid,

[0056] N2-(Nα-(4-fluorobenzoyl)-1-methyl-L-tryptophanyl)-N4-triphenylmethyl-L-aspartic acid methyl ester

[0057] N2-((4-fluorobenzoyl)-L-tryptophanyl)-N4-triphenylmethyl-L-aspartic acid methyl ester

[0058] N2-(Nα-(4-fluorobenzoyl)-1-methyl-L-tryptophanyl)-N4-triphenylmethyl-L-aspartic acid,

[0059] N2-((4-fluorobenzoyl)-L-tryptophanyl)-N4-triphenylmethyl-L-aspartic acid,

[0060] N2-(1-Methyl-Nα-nicotinyl-L-tryptophanyl)-N4-triphenylmethyl-L-aspartic acid methyl ester

[0061] N2-(1-Methyl-Nα-nicotinyl-L-tryptophanyl)-N4-triphenylmethyl-L-aspartic acid,

[0062] N2-(nicotinyl-L-tryptophanyl)-N4-triphenylmethyl-L-aspartic acid methyl ester

[0063] N2-(nicotinyl-L-tryptophanyl)-N4-triphenylmethyl-L-aspartic acid,

[0064] N2-(benzoyl-D-tryptophanyl)-N4-triphenylmethyl-L-aspartic acid,

[0065] N2-(pyridinyl-L-tryptophanyl)-N4-triphenylmethyl-L-aspartic acid,

[0066] N2-(isonicotinyl-L-tryptophanyl)-N4-triphenylmethyl-L-aspartic acid,

[0067] N2-(1-methyl-Nα-(pyridin-2-ylmethyl)-L-tryptophanyl)-N4-triphenylmethyl-L-aspartic acid,

[0068] N2-(1-Methyl-Nα-pyridinyl-L-tryptophanyl)-N4-triphenylmethyl-L-aspartic acid,

[0069] N2-(Nα-isonicotinyl-1-methyl-L-tryptophanyl)-N4-triphenylmethyl-L-aspartic acid

[0070] N2-(benzoyl-L-tryptophanyl)-N4-triphenylmethyl-D-aspartic acid,

[0071] N2-((pyridin-2-ylmethyl)-L-tryptophanyl)-N4-triphenylmethyl-L-aspartic acid,

[0072] N2-(1-methyl-Nα-(1H-pyrrolo-2-carbonyl)-L-tryptophanyl)-N4-triphenylmethyl-L-aspartic acid,

[0073] N2-((1H-pyrrolo-2-carbonyl)-L-tryptophanyl)-N4-triphenylmethyl-L-aspartic acid,

[0074] N2-((6-Fluoronicoyl)-L-Tryptoyl)-N4-Triphenylmethyl-L-Aspartic acid,

[0075] N2-((5-Fluoropyridinecarboxyl)-L-Tryptocyano)-N4-Triphenylmethyl-L-Aspartate,

[0076] N2-(Nα-(5-fluoropyridinyl)-1-methyl-L-tryptophanyl)-N4-triphenylmethyl-L-aspartic acid,

[0077] N2-((6-methoxynicotinyl)-L-tryptophanyl)-N4-triphenylmethyl-L-aspartic acid,

[0078] N2-((6-cyanoconicoyl)-L-tryptophanyl)-N4-triphenylmethyl-L-aspartic acid,

[0079] N2-(Nα-(6-methoxynicotinyl)-1-methyl-L-tryptophanyl)-N4-triphenylmethyl-L-aspartic acid,

[0080] N2-((6-carbamoylnicotinyl)-L-tryptophanyl)-N4-triphenylmethyl-L-aspartic acid,

[0081] N2-(Nα-(5-cyanopyridinyl)-1-methyl-L-tryptophanyl)-N4-triphenylmethyl-L-aspartic acid,

[0082] N2-(Nα-(6-cyanoconicoyl)-1-methyl-L-tryptophanyl)-N4-triphenylmethyl-L-aspartic acid,

[0083] N2-(Nα-(6-fluoronicotinyl)-1-methyl-L-tryptophanyl)-N4-triphenylmethyl-L-aspartic acid,

[0084] N2-(Nα-(5-methoxypyridinyl)-1-methyl-L-tryptophanyl)-N4-triphenylmethyl-L-aspartic acid,

[0085] N2-(Nα-(5-carbamoylpyridinyl)-1-methyl-L-tryptophanyl)-N4-triphenylmethyl-L-aspartic acid,

[0086] N2-(1-methyl-Nα-((1-methyl-1H-pyrrolo-2-yl)methyl)-L-tryptophanyl)-N4-triphenylmethyl-L-aspartic acid,

[0087] N2-(((1-Methyl-1H-pyrrolo-2-yl)methyl)-L-tryptophanyl)-N4-triphenylmethyl-L-aspartic acid,

[0088] N2-(1-Methyl-Nα-(phenylcarbamoyl)-L-tryptophanyl)-N4-triphenylmethyl-L-aspartic acid,

[0089] N2-(Nα-((4-cyanophenyl)carbamoyl)-1-methyl-L-tryptophanyl)-N4-triphenylmethyl-L-aspartic acid,

[0090] N2-(Nα-benzoyl-1-methyl-L-tryptophanyl)-N5-triphenylmethyl-L-glutamyl amino acid,

[0091] N2-(Nα-((4-methoxyphenyl)carbamoyl)-1-methyl-L-tryptophanyl)-N4-triphenylmethyl-L-aspartic acid,

[0092] N2-(1-methyl-Nα-(naphth-1-ylcarbamoyl)-L-tryptophanyl)-N4-triphenylmethyl-L-aspartic acid,

[0093] N2-(Nα-((3,5-dimethylisoazol-4-yl)carbamoyl)-1-methyl-L-tryptophanyl)-N4-triphenylmethyl-L-aspartic acid,

[0094] N2-(Nα-((4-(dimethylamino)phenyl)carbamoyl)-1-methyl-L-tryptophanyl)-N4-triphenylmethyl-L-aspartic acid,

[0095] (S)-2-((S)-2-benzoylamino-3-(1-methyl-1H-indol-3-yl)propionylamino)-5-(triphenylmethylamino)valeric acid,

[0096] (S)-2-((S)-2-benzoylamino-3-(1-methyl-1H-indol-3-yl)propionylamino)-6-sideoxy-6-(triphenylmethylamino)hexanoic acid,

[0097] N2-(Nα-(cyclohexanecarbonyl)-1-methyl-L-tryptophanyl)-N4-triphenylmethyl-L-aspartic acid,

[0098] N2-(Nα-((benzooxy)carbonyl)-1-methyl-L-tryptophanyl)-N4-triphenylmethyl-L-aspartic acid,

[0099] N2-(1-Methyl-Nα-(benzenesulfonyl)-L-tryptophanyl)-N4-triphenylmethyl-L-aspartic acid,

[0100] Or its tautomers, stereoisomers, isotopes, solvates, polymorphs, or pharmaceutically acceptable salts.

[0101] In one additional state, this disclosure provides a pharmaceutical composition comprising an effective amount of the compound, or its tautomers, stereoisomers, isotopes, solvates, polymorphs, or pharmaceutically acceptable salts thereof, and, where appropriate, pharmaceutically acceptable diluents or carriers.

[0102] In another embodiment, this disclosure provides pharmaceutical compositions for the prevention, improvement and / or treatment of diseases or conditions mediated by formyl peptide receptor 1 (FPR1).

[0103] In another embodiment, this disclosure provides a method for preventing, improving, and / or treating an individual in need of an FPR1-mediated disease or condition, comprising administering to the individual in need the pharmaceutical composition as described in claim 8.

[0104] In some embodiments disclosed herein, the disease or condition is inflammation and / or cancer.

[0105] In some embodiments disclosed herein, the inflammation is a neutrophilic inflammatory condition.

[0106] In some embodiments disclosed herein, the neutrophilic inflammatory condition is selected from the group consisting of: lung injury, chronic obstructive pulmonary disease, acute respiratory distress syndrome, asthma, ischemia-reperfusion injury, arthritis, and sepsis.

[0107] In some embodiments disclosed herein, the cancer exhibits FPR1 manifestation.

[0108] In some embodiments disclosed herein, the cancer is selected from the group consisting of: glioblastoma, lung cancer, colon cancer, colorectal cancer, breast cancer, prostate cancer, and leukemia. Detailed Implementation

[0109] To ensure a full understanding of this disclosure, the following embodiments are described. The following terms are used in this specification:

[0110] It must be noted that, unless the context explicitly indicates otherwise, as used herein, the singular forms “a,” “an,” and “the” include plural indicators. Therefore, unless the context requires otherwise, singular terms should include plural, and plural terms should include the singular.

[0111] The term "and / or" is used to refer to two things or either of the two things mentioned.

[0112] The terms “treatment,” “treating,” and “treat” generally refer to the attainment of a desired pharmacological and / or physiological effect. This effect may be preventative in terms of complete or partial prevention of a disease, condition, or its symptoms, and therapeutic in terms of partial or complete cure of a disease, condition, and / or symptoms attributable to it. As used herein, “treatment” encompasses any treatment of a disease in a mammal (preferably a human), including (1) the suppression of the development of an individual’s disease, condition, or its symptoms, or (2) the relief or improvement of an individual’s disease, condition, or its symptoms.

[0113] The term “preventing” or “prevention” is recognized in this technology and, when used in conjunction with a condition, includes administering a medication before the onset of the condition, which reduces the frequency or severity of symptoms of the individual’s medical condition or delays the onset of the condition compared to an individual who has not received the medication.

[0114] The terms “individual,” “subject,” and “patient” used in this article are used interchangeably and refer to any individual mammal in need of diagnosis, treatment, or therapy.

[0115] The term "effective amount" as used herein for active ingredients refers to the amount of the ingredient that is sufficient to provide the desired function. As will be noted below, the precise amount required will vary from person to person depending on individual disease condition, physical condition, age, sex, species and weight, the specific characteristics of the composition, and the formulation. Dosing regimens can be adjusted to induce an optimal therapeutic response. For example, several divided doses may be administered daily, or the dose may be reduced proportionally as indicated by the urgency of the treatment situation. Therefore, it is impossible to specify a precise "effective amount." However, an appropriate effective amount can usually be determined by a person skilled in the art using routine experiments.

[0116] The following details the compounds of formula (I), as well as their tautomers, stereoisomers, isotopes, solvates, polymorphs, or pharmaceutically acceptable salts:

[0117] Formula (I),

[0118] Or its tautomers, stereoisomers, isotopes, solvates, polymorphs, or pharmaceutically acceptable salts.

[0119] in

[0120] R 1 For H, OR 7 CH2OR 7 C(=O)R 7 C(=O)OR 7 C(=O)NR 7 R 8 NR 7 R 8 NR 7 C(=O)R 8 SO2R 7 SO2NR 7 R 8 SOR 7 SR 7 NR 7 SO2R 8C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 3-8 cycloalkyl, C 3-8 Heterocyclic, aryl, or heteroaryl groups;

[0121] R 2 OR 7 C(=O)R 7 C(=O)OR 7 C(=O)NR 7 R 8 NR 7 R 8 NR 7 C(=O)R 8 SO2R 7 SO2NR 7 R 8 SOR 7 SR 7 NR 7 SO2R 8 C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 3-8 Heterocyclic, aralkyl, heteroaryl, or heteroarylalkyl;

[0122] L is C 1-6 Alkyl, C 3-8 cycloalkyl, C 3-8 Heterocyclic, aryl, or heteroaryl groups;

[0123] R 3 For H or C 1-6 alkyl;

[0124] R 4 It is H or C1-6 alkyl;

[0125] R 5 and R 6 Independently H, CH2R 7 C(=O)R 7 C(=O)CH2R 7 C(=O)OR 7 C(=O)NR 7 R 8 SO2R 7 SO2NR 7 R 8 SOR 7 SR 7 C 1-8 Alkyl, C 2-8 alkenyl, C 2-8alkynyl group, C 3-8 cycloalkyl, C 3-8 Heterocyclic, aryl, aralkyl, heteroaryl or heteroarylalkyl;

[0126] R 7 and R 8 Independently for H, C (=NR) 9 )NR 10 R 11 C 1-8 Alkyl, C 3-8 cycloalkyl, C 3-8 Heterocyclic, aryl, aralkyl, heteroaryl or heteroarylalkyl, or R 7 and R 8 Together with the atoms it is attached to, they form C 3-8 cycloalkyl or C 3-8 Heterocyclic groups;

[0127] R 1 To R 8 C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 3-8 cycloalkyl, C 3-8 Each of the heterocyclic, aryl, aralkyl, heteroaryl, and heteroarylalkyl groups may be partially substituted, as appropriate, by one or more of the following groups: halogens, OR 9 CN, N3, NO2, NR 9 R 10 NR 9 C(=O)R 10 C(=O)R 9 C(=O)OR 9 C(=O)NR 9 R 10 SO2R 9 SO2NR 9 R 10 SOR 9 SR 9 NR 9 SO2R 10 C 1-8 Alkyl, C 1-8 Alkoxy, C 2-8 alkenyl, C 2-8 alkynyl group, C 3-8 cycloalkyl, C 3-8 Heterocyclic, aryl, and heteroaryl groups; and

[0128] R 9 R 10 and R 11 Independently for H and C 1-8 Alkyl, C3-8 cycloalkyl, C 3-8 Heterocyclic, aryl, aralkyl, heteroaryl or heteroarylalkyl.

[0129] The term "alkyl" in this document refers to a straight-chain or branched hydrocarbon group containing 1 to 20 carbon atoms (including any number between 1 and 20 carbon atoms, such as 1 to 10 and 1 to 6). Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl.

[0130] The term "alkenyl" refers to a straight-chain or branched-chain hydrocarbon moiety having 2 to 20 carbons and containing at least one double bond, such as -CH=CH-CH3.

[0131] The term "alkynyl" refers to a straight-chain or branched hydrocarbon moiety having 2 to 20 carbons and containing at least one paranegative bond, such as -C≡C-CH3.

[0132] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic, bicyclic, tricyclic, or tetracyclic hydrocarbon group having 3 to 12 carbon atoms (any number between 3 and 12, such as 3 to 10 and 3 to 8). Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.

[0133] The term "heterocyclic alkyl" refers to a non-aromatic 5- to 8-membered monocyclic, 8- to 12-membered bicyclic, or 11- to 14-membered tricyclic ring system having one or more heteroatoms (e.g., O, N, P, and S). Examples include piperidine, imidazolidinyl, azaheptanyl, pyrrolidinyl, dihydrothiadiazolyl, dialkyl, succinyl, tetrahydropuranyl, and tetrahydrofuranyl.

[0134] The term "halogen" refers to a fluorine group, a chlorine group, a bromine group, or an iodine group.

[0135] The term "amino" refers to a group derived from ammonia that is unsubstituted or mono- or disubstituted with alkyl, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl groups.

[0136] The term "aryl" refers to a functional group derived from aromatic compounds, which may contain one or more aromatic ring systems such as a 6-carbon monocyclic ring, a 10-carbon bicyclic ring, and / or a 14-carbon tricyclic ring. Examples of aryl groups include phenyl, naphthyl, tyrosyl, and anthracene.

[0137] The term "aralkyl" refers to an alkyl group containing both an aryl and an alkyl functional group, and wherein one or more hydrogen atoms are replaced by an aryl group. Aralkyl groups can be unsubstituted or mono-, di-, or tri-substituted with halogens, alkyl groups, or alkoxy groups. In some embodiments, R 7 and R 8Examples of aryl groups include triphenylmethyl, benzyl, diphenylmethyl, 4-methoxyphenyl, 4-methoxytriphenylmethyl or methyl fumonisinyl.

[0138] The term "heteroaryl" refers to aromatic cyclic systems having one or more heteroatoms (e.g., O, N, P, and S) such as 5- to 8-membered monocyclic, 8- to 12-membered bicyclic, or 11- to 14-membered tricyclic systems. Examples include triazolyl, acezolyl, thiadiazolyl, tetrazolyl, pyrazolyl, pyridinyl, furanyl, imidazolyl, benzimidazolyl, pyrimidinyl, thienyl, quinolinyl, indolyl, thiazolyl, and benzothiazolyl.

[0139] The terms alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as used in this article include both substituted and unsubstituted portions. Possible substituents on alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups include, but are not limited to, C0. l -C l0 Alkyl, C2-C l0 alkenyl, C2-C l0 alkynyl group, C3-C 20 cycloalkyl, C3-C 20 Cycloalkenyl, C l -C 20 Heterocyclic alkyl, C l -C 20 Heterocyclic alkenyl, C1-C 10 Alkyl, aryl, aryloxy, heteroaryl, heteroaryloxy, amino, C1-C 10 Alkylamino, C l -C 20 Dialkylamino, arylamino, diarylamino, C1-C 10 Alkylsulfonamide, arylsulfonamide, C1-C 10 Alkylimino, arylimino, C1-C 10 Alkylsulfonylimino, arylsulfonylimino, hydroxyl, halogen, thio group, C1-C 10 Alkylthio, Arylthio, C1-C 10 Alkyl sulfonyl, aryl sulfonyl, amide, amino acyl, aminothioyl, amide, formamidinyl, guanidine, ureido, thiourea, cyano, nitro, nitroso, azide, acyl, thioyl, acyloxy, carboxyl, and carboxylic acid esters. On the other hand, possible substituents on the alkyl group include those other than C. l -C l0 All of the above-mentioned substituents other than alkyl. Cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups may also be fused together.

[0140] In some embodiments of this disclosure, reference is made to formula (I) above, and R 3 It is H or methyl, and R 4It is H or methyl.

[0141] R of a group of compounds of formula (I) 5 or R 6 It is an aryl, arylalkyl, heteroaryl, or heteroarylalkyl group that has been partially substituted with one to three halogens; R 1 As per C 1-8 Alkoxy, C 3-8 cycloalkyl, C 3-8 C-substituted with heterocyclic or heteroaryl groups 1-8 alkyl.

[0142] In some embodiments disclosed herein, the compound is a compound of formula (II):

[0143] Equation (II),

[0144] Or its tautomers, stereoisomers, isotopes, solvates, polymorphs, or pharmaceutically acceptable salts.

[0145] In some embodiments disclosed herein,

[0146] R 1 H, CH2OR 7 C(=O)OR 7 C(=O)NR 7 R 8 Or C 1-8 alkyl;

[0147] R 2 For C(=O)NR 7 R 8 or NR 7 R 8 ;

[0148] L is C 1-6 alkyl;

[0149] R 3 For H or C 1-6 alkyl;

[0150] R 4 It is H or C1-6 alkyl;

[0151] R 5 and R 6 Independently H, CH2R 7 C(=O)R 7 C(=O)CH2R 7 C(=O)OR 7 C(=O)NR 7 R 8 SO2R 7 Or C1-8 alkyl;

[0152] R 7 and R 8 Independently for H, C (=NR) 9 )NR 10 R 11 C 1-8 Alkyl, aryl, aralkyl, heteroaryl, or heteroarylalkyl;

[0153] C 1-8 Each of the alkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl groups may be partially substituted, depending on the case, by one or more of the following groups: halogen, CN, C. 1-8 Alkyl, C 1-8 Alkoxy, NR 9 R 10 and C(=O)NR 9 R 10 ;and

[0154] R 9 R 10 and R 11 Independently H or C 1-8 alkyl.

[0155] In some embodiments disclosed herein, R 3 It is H or methyl.

[0156] In some embodiments disclosed herein, R 4 It is H or methyl.

[0157] In some embodiments disclosed herein, L is methyl, ethyl, or propyl.

[0158] Regarding the variable R in equation (I) 1 R 2 R 3 R 4 R 5 R 6 And L, each of these variables may have R or S The stereoisomer configuration, and such compounds may have a mirror-image isomer excess of 90% or higher (e.g., ≥95% or ≥99%).

[0159] As used herein, the phrase “substituted or unsubstituted” means substitution is chosen as appropriate. Where substitution is required, such substitution means that any number of hydrogen atoms on a specified atom are selectively replaced by a specified group, provided that the substitution does not exceed the normal valence of the specified atom and produces a stable compound. For example, when the substituent is a ketone group (i.e., =O), two hydrogen atoms on the atom are replaced. Examples of substituents for “substituted” groups are those seen in the exemplary compounds and examples disclosed herein, and may include, for example, halides, -OH, -CF3, -CN, -NO2, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, haloalkyl, alkylamino, aminoalkyl, dialkylamino, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkoxy, aminoalkoxy, alkylaminoalkoxy, alkylaminoalkyl, and aryl and similar groups.

[0160] The compounds disclosed herein may exist as solvates. As used herein and unless otherwise specified, the term “solvate” means that a compound of formula (I) or a pharmaceutically acceptable salt thereof further includes a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. If the solvent is water, the solvate may be referred to as a “hydrate,” such as a hemihydrate, monohydrate, sesquihydrate, dihydrate, trihydrate, etc.

[0161] As used herein, the term "tautomer" refers to a compound whose structure differs significantly in atomic arrangement but which readily and rapidly reaches equilibrium. It should be understood that the compounds described herein can be described as various tautomers, and when a compound has a tautomer form, all tautomer forms are intended to fall within the scope of this disclosure, and the naming of compounds does not exclude any tautomer. Exemplary tautomerizations include, but are not limited to, amide to imide; enyl to imide; enyl to (different) enyl tautomerizations; and keto to enol.

[0162] The term "stereoisomer" refers to compounds that have the same chemical composition but differ in the spatial arrangement of atoms or groups. Stereoisomers include non-mirror image isomers, mirror image isomers, configurational isomers, and the like.

[0163] The term "polymorph" refers to the crystalline form of a compound (or its salts, hydrates, or solvates). All polymorphs have the same elemental composition. Different crystalline forms typically exhibit different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shapes, optical and electrical properties, stability, and solubility. Recrystallization solvents, crystallization rates, storage temperatures, and other factors can cause one crystalline form to dominate. Various polymorphs of a compound can be prepared by crystallization under different conditions.

[0164] As used herein, "isotope" refers to a compound containing at least one atom having an isotopic composition other than that of the naturally occurring atom. "Isotopic enrichment" is expressed as a percentage of a specific isotope incorporated at a designated atom in the molecule, rather than as the natural isotopic abundance of that atom.

[0165] As used herein, the term "medically acceptable salt" refers to compounds according to this disclosure used in the form of salts derived from inorganic or organic acids and bases. Acid salts include, for example, the following: acetates, adipates, alginates, aspartates, benzoates, benzenesulfonates, hydrogen sulfates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, diglucose, dodecyl sulfates, ethanesulfonates, transbutenediacetes, fluoroheptates, glycerophosphates, hemisulfates, heptanates, hexanoates, hydrochlorides, hydrobromide, hydroiodates, 2-hydroxyethanesulfonate, lactates, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, dihydroxynaphthalate, pectate, persulfate, phenylpropionate, picrates, pentanoates, propionates, succinates, tartrates, thiocyanates, toluenesulfonates, and undecanoates. Salts derived from suitable bases include alkali metals (e.g., sodium), alkaline earth metals (e.g., magnesium), ammonium, and NW. 4+ (where W is C) 1-4 alkyl).

[0166] In another embodiment, this disclosure provides a pharmaceutical composition comprising an effective amount of the compound or its tautomers, stereoisomers, isotopes, solvates, polymorphs or pharmaceutically acceptable salts thereof, and, where appropriate, a pharmaceutically acceptable diluent or carrier.

[0167] In another embodiment, this disclosure provides pharmaceutical compositions disclosed herein for the prevention, improvement and / or treatment of diseases or conditions mediated by formyl peptide receptor 1 (FPR1).

[0168] In another embodiment, this disclosure provides a method for preventing, improving, and / or treating an individual in need of an FPR1-mediated disease or condition, comprising administering the pharmaceutical composition of claim 8 to the individual in need.

[0169] In some embodiments of this disclosure, the disease or condition is inflammation and / or cancer.

[0170] In some embodiments disclosed herein, the inflammation is a neutrophilic inflammatory condition.

[0171] In some embodiments disclosed herein, neutrophil inflammatory conditions are selected from the group consisting of: lung injury, chronic obstructive pulmonary disease, acute respiratory distress syndrome, asthma, ischemia-reperfusion injury, arthritis, and sepsis.

[0172] In some embodiments disclosed herein, the cancer exhibits FPR1 expression.

[0173] In some embodiments disclosed herein, cancer is selected from the group consisting of: glioblastoma, lung cancer, colon cancer, colorectal cancer, breast cancer, prostate cancer, and leukemia.

[0174] Pharmaceutical compositions can be administered in a variety of dosage forms, including (but not limited to) solid or liquid dosage forms, oral dosage forms, non-enteric dosage forms, intranasal dosage forms, suppositories, lozenges, sugar-coated lozenges, buccal lozenges, controlled-release dosage forms, pulsatile-release dosage forms, immediate-release dosage forms, intravenous solutions, suspensions, or combinations thereof. Pharmaceutical compositions can be administered, for example, via oral or non-enteric routes, including intravenous, intramuscular, intraperitoneal, subcutaneous, transdermal, respiratory (aerosol), rectal, vaginal, and topical administration (including buccal and sublingual).

[0175] Compositions intended for oral administration can be in any orally acceptable dosage form, including capsules, tablets, emulsions, and aqueous suspensions, dispersions, and solutions. In the case of tablets, common carriers include lactose and corn starch. Lubricants, such as magnesium stearate, are also typically added. For oral administration in capsule form, suitable diluents include lactose and dried corn starch. When administered orally in aqueous suspensions or emulsions, the active ingredient can be suspended or dissolved in the oil phase in combination with an emulsifier or suspending agent. Sweeteners, flavoring agents, or coloring agents may be added if necessary. Oral solid dosage forms can be prepared using spray drying technology; hot melt extrusion strategies; micronization; and nano-milling technology.

[0176] Nasal aerosol or inhalation compositions can be prepared according to techniques well known in pharmaceutical formulation. For example, such compositions can be prepared as a saline solution using benzyl alcohol or other suitable preservatives, absorption enhancers, fluorocarbons, and / or other solubilizers or dispersants known in this art. Compositions containing active compounds can also be administered rectally as suppositories.

[0177] The carrier in a pharmaceutical composition must be "acceptable," meaning it is compatible with the active ingredient of the composition (and preferably, can stabilize the active ingredient) and does not harm the individual being treated. One or more solubilizers may be used as pharmaceutical excipients to deliver the active compound. Other examples of carriers include colloidal silica, magnesium stearate, cellulose, sodium lauryl sulfate, and D&C Yellow #10.

[0178] The above-mentioned compounds, or pharmaceutical compositions containing one or more of them, may be administered to an individual orally, non-enterally, by inhalation spray, topically, rectally, nasally, buccally, or via an implantable reservoir. As used herein, the term "non-enteral" includes subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intra-articular, intrasynovial, intrasternal, intrathecal, intralesional, and intracranial injection or infusion techniques.

[0179] "Excipients" generally refer to substances added to a pharmacological composition or used as a mediator to further promote the delivery of the compound to it, and are often inert substances. Examples of excipients include (but are not limited to) inert diluents, disintegrants, binders, lubricants, sweeteners, flavorings, colorants, preservatives, foaming mixtures, and adsorbents. Suitable inert diluents include (but are not limited to) sodium carbonate and calcium carbonate, sodium phosphate and calcium phosphate, lactose, and the like. Suitable disintegrants include (but are not limited to) starch (such as corn starch), croscarmellose, agar, alginate or its salts (such as sodium alginate), and the like. Binders may include (but are not limited to) magnesium aluminum silicate, starch (such as corn, wheat, or rice starch), gelatin, methylcellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone, and the like. Lubricants, if present, are typically magnesium stearate and calcium stearate, stearic acid, talc, or hydrogenated vegetable oil. If necessary, the tablets can be coated with materials such as glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract. The composition can also be formulated into chewable tablets, for example, by using a substance such as mannitol in the formulation.

[0180] FPR1 belongs to the chemokine family. FPR1 antagonism can occur through direct occupation of the ligand-binding pocket or indirect interference with FPR function. For direct FPR1 antagonists, ligand competition and attenuated downstream signaling are evident. Reduced superoxide production and elastase release from neutrophils are physiological consequences of FPR1 antagonism.

[0181] One or more embodiments of this disclosure are set forth in detail in the following description. Other features, objectives, and advantages of this disclosure will be set forth in the description and claims.

[0182] The reactions used to synthesize compounds of formula (I) are well known in this art. See, for example, R. Larock, Comprehensive Organic Transformations (2nd ed., VCH Publishers 1999); PGMWuts and TW Greene, Greene's Protective Groups in Organic Synthesis (4th ed., 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 (2nd ed., John Wiley and Sons 2009); and Tsong-Long Hwang, Pei-Wen Hsieh, Yin-Ting Huang, Chih-Hao Hung, "FPR1antagonist derivatives and use thereof" US9593144B2.

[0183] In some embodiments disclosed herein, the compounds of formula (I) thus prepared can be further screened for their efficacy in inhibiting FPR using in vitro assays, such as neutrophil elastase release assays and superoxide anion production assays, both described in Example 2 below. They can then be evaluated using in vivo assays known in the art. The selected compounds can be further tested to validate their efficacy in both disease-related efficacy models and adverse reaction models. Based on these results, appropriate dosage ranges and routes of administration can be determined.

[0184] Without further detailed description, it is believed that those skilled in the art can make full use of this disclosure based on the above description. Therefore, the specific examples below, namely Examples 1-2, should be interpreted as illustrative only and do not limit the scope of this disclosure. All disclosures cited herein are incorporated herein by reference in their entirety.

[0185] In specific examples, Example 1 illustrates a method for preparing certain intermediates and 62 exemplary compounds of formula (I), and analytical data of the compounds prepared therefrom; and Example 2 illustrates a scheme for testing these compounds.

[0186] Table 1 below shows the structures and analytical data of 62 exemplary (I) compounds.

[0187] Table 1

[0188]

[0189]

[0190]

[0191]

[0192]

[0193]

[0194]

[0195]

[0196]

[0197]

[0198]

[0199]

[0200]

[0201]

[0202]

[0203]

[0204]

[0205]

[0206]

[0207]

[0208] The procedure for synthesizing the above 62 exemplary compounds is described below.

[0209] Unless otherwise specified, all starting materials used were commercially available and used as supplied. Reactions requiring anhydrous conditions were carried out in flame-dried glassware and cooled under an argon or nitrogen atmosphere. Unless otherwise specified, the reactions were carried out under argon or nitrogen atmosphere and monitored by analytical thin-layer chromatography on a glass backing plate (5 cm × 10 cm) pre-coated with Merck silica gel 60F254. Visualization of the resulting chromatograms was achieved by observation under a UV lamp (λ = 254 nm), followed by immersion in an nBuOH solution containing ninhydrin (0.3% w / v) of acetic acid (3% v / v) or an ethanol solution containing phosphomolybdic acid (2.5% w / v), and carbonization by a heat gun. Solvents used in the reaction were dried under an argon or nitrogen atmosphere as follows before use: THF, toluene, and DCM were dried using a drying molecular sieve 5A (LC technology solution Inc.) column, and DMF was dried using calcium hydride or obtained commercially. Rapid chromatography is routinely used for the purification and separation of product mixtures, employing a RediSep Rf silica disposable rapid chromatography column and Gold... ® 20-40 / 40-60 micron silica gel and reusable RediSep RfC18 reverse-phase columns, 20-40 microns. Solvent system is expressed as volume / volume concentration. 13 C and 1 ¹H NMR spectra were recorded on a Bruker AIII (400 MHz). Chloroform-d or dimethyl sulfoxide-d6 and CD3OD were used as solvents, and TMS (δ 0.00 ppm) was used as an internal standard. Chemical shift values ​​are reported in ppm relative to TMS, in δ (delta). Multiplicity was recorded as s (singleton), br s (broad singleton), d (doublet), t (triplet), q (quartet), dd (doublet), dt (doubletuplet), and m (multiplet). Coupling constants (J) are expressed in Hz. Electrospray ionization mass spectrometry (ESMS) was recorded using a Thermo LTQ XL mass spectrometer. Mass spectrometry data are recorded as m / z values.

[0210] The following describes the synthetic procedure followed for compound (I).

[0211]

[0212] Example 1: Synthesis of compound (I)

[0213] Compound 3 was synthesized following the procedure below. Other exemplary compounds of formula (I) were prepared in a similar manner.

[0214]

[0215] Step 1: Synthesis of N2-(benzoyl-L-tryptophanyl)-N4-triphenylmethyl-L-aspartic acid methyl ester

[0216]

[0217] Benzoyl chloride (626 μl, 5.39 mmol) was added to a solution of L-tryptophan (1 g, 4.90 mmol) in 2N NaOH (aqueous solution) (4.9 ml), and the mixture was stirred at room temperature for 3 h. After the reaction was complete, 1N HCl (aqueous solution) was added to the solution, and the mixture was extracted with DCM (3 × 10 ml). The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The product was recrystallized from DCM to give 96 mg, 6%.

[0218] DIPEA (112 μl, 0.65 mmol) was added to a solution of SM (96 mg, 0.31 mmol), Asp(Trt)-OMe (100 mg, 0.26 mmol), and HBTU (117 mg, 0.31 mmol) in DCM (1.3 ml) at 0 °C. The mixture was stirred at room temperature for 1 h. After the reaction was complete, H2O was added to the mixture and it was extracted with DCM (3 × 10 ml). The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography 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, 0.8Hz, 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).

[0219] Step 2: Synthesis of benzoyl-L-tryptophanyl-L-aspartic acid methyl ester

[0220]

[0221] 1N NaOH (aqueous solution) (2 ml) was added to a solution of SM (200 mg, 0.30 mmol) in MeOH (2 ml) at 40 °C. After 2 hours, the mixture was concentrated under vacuum. It was then purified by silica gel column chromatography 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 = 7.9Hz, 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).

[0222] Example 2: Evaluation of the inhibitory activity of compound (I) in in vitro assays

[0223] The compound prepared in Example 1 was tested in the in vitro analysis described below.

[0224] Receptor binding analysis (FNLFNYK competitive binding analysis)

[0225] The potency of certain formula (I) compounds was tested in a cell-based FPR1 binding assay. Standard analytical conditions included loading human FPR1-overexpressing human embryonic kidney 293 cells (HEK293) at 1 × 10⁻⁶. 6 Cells / mL were treated with CPD for 5 minutes. Then, N-formyl-Nle-Leu-Phe-Nle-Tyr-Lys-luciferin (fNLFNYK, 2 nM) was added and the cells were incubated at 4°C for 30 minutes. The fluorescence of fNLFNYK was then analyzed using BD Accuri C6 flow cytometry (BD Biosciences, San Jose, CA).

[0226] Calcium flux analysis

[0227] The potency of certain formula (I) compounds was tested in a cell-based calcium flux assay. The assay was performed using the human lymphoma cell line HL-60 (CCL-240, ATCC, Manassas, VA), which was differentiated for 7 days in 1.3% v / v DMSO and 5% FBS, with the medium changed every 2–3 days. A granular phenotype was observed in the differentiated HL-60 cells. The differentiated HL-60 cells were incubated at 37°C for 2 hours with a diluted calcium 6 assay reagent. Calcium flux was detected using a FlexStation 3 multimode microdisk reader (Molecular Devices).

[0228] Human neutrophil separation

[0229] Human neutrophils were obtained from healthy donors aged 20-35 years. All participants provided informed consent and had not taken any medications in the preceding two weeks. Blood samples were collected using vacuum blood collection tubes containing heparin. Red blood cells were precipitated with 3% (w / v) polydextrose. Neutrophils were then separated by Ficoll-Paque (GE Healthcare) gradient centrifugation, followed by a hypotonic dissolution process to achieve a purity of over 98% (as determined by CD66b staining). The separated neutrophils were resuspended in calcium-free Hank's balanced salt solution (HBSS). All procedures were performed in accordance with guidelines and were approved by the Institutional Review Board of Chang Gung Memorial Hospital.

[0230] Neutrophil elastase release analysis

[0231] The efficacy of certain compounds of formula (I) in inhibiting the release of neutrophil elastase was tested. Standard analytical conditions included setting a concentration of 6 × 10⁻⁶. 5 Human neutrophils at a density of 1 cell / mL were co-cultured with methoxysuccinyl-Ala-Ala-Pro-Val-p-nitrophenylamine (0.1 mM) and CPD-treated for 10 min. Subsequently, cytochalasin B (0.5 μg / mL) was introduced and maintained for 3 min, followed by the introduction of fMLF (30 nM) or MMK1 (100 nM) and maintenance for 10 min to activate the neutrophils. Elastase release was then continuously monitored by observing changes in absorbance at 405 nm using a U-3010 spectrophotometer (Hitachi, TYO, JP).

[0232] Analysis of superoxide anion generation

[0233] The efficacy of certain compounds of formula (I) in inhibiting superoxide anion production was tested. Standard analytical conditions included setting a concentration of 6 × 10⁻⁶. 5 Human neutrophils were co-cultured with methemoglobin c (0.6 mg / mL) at a concentration of 10 cells / mL and treated with CPD for 10 minutes. Subsequently, cytochalasin B (1 μg / mL) was introduced and maintained for 3 minutes, followed by the introduction of N-formylmethylthioyl-leucyl-phenylalanine (fMLF, 30 nM) or MMK1 (100 nM) and maintained for 10 minutes to activate the neutrophils. The release of superoxide anions was then continuously monitored by observing changes in absorbance at 550 nm using a U-3010 spectrophotometer (Hitachi, TYO, JP).

[0234] result

[0235] Analysis revealed that the tested compounds exhibited, to varying degrees, the desired inhibitory activities against receptor binding, neutrophil elastase release, and superoxide anion production, which are mediated by their IC50... 50 Value indicated (IC) 50 (The concentration of the inhibitor is halved when the reaction or binding is reduced). See Table 2 below.

[0236] More specifically, 17 of the 62 compounds showed an IC50 response rate of neutrophil elastase release. 50 Values ​​below 400 nM, and 30 out of 62 compounds exhibiting superoxide anion production IC50. 50 Values ​​below 100 nM. As indicated in Tables 2 and 3, activity level "A" represents an IC50 value below 40 nM. 50 Value, activity level "B" represents an IC50 value between 40 nM and 100 nM. 50 Value, activity level "C" represents the IC50 value between 100 nM and 400 nM. 50 Value, activity level "D" represents an IC50 value between 400 nM and 1 μM. 50 Value, and the activity level "E" represents an IC50 concentration > 1 μM. 50 value.

[0237] Table 2. In vitro potency of FPR1 antagonists, potency of FPR1 antagonists in neutrophil elastase and superoxide anion, and potency in inducing elastase release and superoxide anion production in the presence of CB.

[0238]

[0239]

[0240] fMLF / CB-induced cellular responses are represented as 100%.

[0241] These results demonstrate that compounds of formula (I) are selective and exhibit high efficacy in inhibiting the release of neutrophil elastase and the production of superoxide anions. The selectivity of compounds of formula (I) for FPR1 is unexpected and will make them suitable therapeutic agents for FPR1-related diseases.

Claims

1. A compound of formula (I): Equation (I), Or its tautomers, stereoisomers, isotopes, solvates, polymorphs, or pharmaceutically acceptable salts. in R 1 For H, OR 7 CH2OR 7 C(=O)R 7 C(=O)OR 7 C(=O)NR 7 R 8 NR 7 R 8 NR 7 C(=O)R 8 NR 7 SO2R 8 C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 3-8 cycloalkyl, C 3-8 Heterocyclic, aryl, or heteroaryl groups; R 2 OR 7 C(=O)R 7 C(=O)OR 7 C(=O)NR 7 R 8 NR 7 R 8 NR 7 C(=O)R 8 NR 7 SO2R 8 C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 3-8 Heterocyclic, aryl, heteroaryl, or heteroarylalkyl; L is C 1-6 Alkyl, C 3-8 cycloalkyl, C 3-8 Heterocyclic, aryl, or heteroaryl groups; R 3 For H or C 1-6 alkyl; R 4 It is H or C1-6 alkyl; R 5 and R 6 Independently H, CH2R 7 C(=O)R 7 C(=O)CH2R 7 C(=O)OR 7 C(=O)NR 7 R 8 SO2R 7 SO2NR 7 R 8 SOR 7 SR 7 C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 3-8 cycloalkyl, C 3-8 Heterocyclic, aryl, aralkyl, heteroaryl or heteroarylalkyl; R 7 and R 8 Independently for H, C (=NR) 9 )NR 10 R 11 C 1-8 Alkyl, C 3-8 cycloalkyl, C 3-8 Heterocyclic, aryl, aralkyl, heteroaryl or heteroarylalkyl, or R 7 and R 8 Together with the atoms it is attached to, they form C 3-8 cycloalkyl or C 3-8 Heterocyclic groups; R 1 To R 8 C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 3-8 cycloalkyl, C 3-8 Each of the heterocyclic, aryl, aralkyl, heteroaryl, and heteroarylalkyl groups may be partially substituted, as appropriate, by one or more of the following groups: halogens, OR 9 CN, N3, NO2, NR 9 R 10 NR 9 C(=O)R 10 C(=O)R 9 C(=O)OR 9 C(=O)NR 9 R 10 SO2R 9 SO2NR 9 R 10 SOR 9 SR 9 NR 9 SO2R 10 C 1-8 Alkyl, C 1-8 Alkoxy, C 2-8 alkenyl, C 2-8 alkynyl group, C 3-8 cycloalkyl, C 3-8 Heterocyclic, aryl, and heteroaryl groups; and R 9 R 10 and R 11 Independently for H and C 1-8 Alkyl, C 3-8 cycloalkyl, C 3-8 Heterocyclic, aryl, aralkyl, heteroaryl or heteroarylalkyl.

2. The compound according to claim 1, wherein it is a compound of formula (II): Equation (II), Or its tautomers, stereoisomers, isotopes, solvates, polymorphs, or pharmaceutically acceptable salts.

3. The compound of claim 1, or its tautomers, stereoisomers, isotopes, solvates, polymorphs, or pharmaceutically acceptable salts, wherein... R 1 H, CH2OR 7 C(=O)OR 7 C(=O)NR 7 R 8 Or C 1-8 alkyl; R 2 For C(=O)NR 7 R 8 or NR 7 R 8 ; L is C 1-6 alkyl; R 3 For H or C 1-6 alkyl; R 4 It is H or C1-6 alkyl; R 5 and R 6 Independently H, CH2R 7 C(=O)R 7 C(=O)CH2R 7 C(=O)OR 7 C(=O)NR 7 R 8 SO2R 7 Or C 1-8 alkyl; R 7 and R 8 Independently for H, C (=NR) 9 )NR 10 R 11 C 1-8 Alkyl, aryl, aralkyl, heteroaryl, or heteroarylalkyl; C 1-8 Each of the alkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl groups may be partially substituted, depending on the case, by one or more of the following groups: halogen, CN, C. 1-8 Alkyl, C 1-8 Alkoxy, NR 9 R 10 and C(=O)NR 9 R 10 ;and R 9 R 10 and R 11 Independently H or C 1-8 alkyl.

4. The compound of claim 1, or its tautomers, stereoisomers, isotopes, solvates, polymorphs, or pharmaceutically acceptable salts, wherein R 3 It is H or methyl.

5. The compound of claim 1, or its tautomers, stereoisomers, isotopes, solvates, polymorphs, or pharmaceutically acceptable salts, wherein R 4 It is H or methyl.

6. The compound of claim 1, or its tautomers, stereoisomers, isotopes, solvates, polymorphs, or pharmaceutically acceptable salts, wherein L is methyl, ethyl, or propyl.

7. The compound of claim 1, or its tautomers, stereoisomers, isotopes, solvates, polymorphs, or pharmaceutically acceptable salts, wherein R 7 and R 8 The aryl group is triphenylmethyl, benzyl, diphenylmethyl, 4-methoxyphenyl or methyl benzoyl.

8. The compound of claim 1, wherein the compound is selected from the group consisting of: N2-(benzoyl-L-tryptophanyl)-N4-triphenylmethyl-L-aspartic acid methyl ester Benzoyl-L-tryptophanyl-L-aspartic acid methyl ester Benzoyl-L-tryptophanyl-L-aspartic acid, (S)-N1-(2-aminoethyl)-2-((S)-2-benzoylamino-3-(1H-indol-3-yl)propionylamino)-N4-triphenylmethylsuccinylamino, (S)-N-(3-(1H-indol-3-yl)-1-sideoxy-1-((3-sideoxy-3-(triphenylmethylamino)propyl)amino)propyl-2-yl)benzoylamine, N2-(benzoyl-L-tryptophanyl)-N4-triphenylmethyl-L-aspartic acid, Benzoyl-L-tryptophanyl-L-arginine methyl ester N2-(benzoyl-L-tryptophanyl)-N4-benzyl-L-aspartic acid methyl ester (S)-2-((S)-2-benzoylamino-3-(1H-indol-3-yl)propionylamino)-N1-methyl-N4-triphenylmethylsuccinylamino, N4-Diphenylmethyl-N2-(benzoyl-L-tryptophanyl)-L-aspartic acid methyl ester N2-(benzoyl-L-tryptophanyl)-N4-((4-methoxyphenyl)diphenylmethyl)-L-aspartic acid methyl ester N4-((9H-furo-9-yl)methyl)-N2-(benzoyl-L-tryptophanyl)-L-aspartic acid methyl ester, N2-(benzoyl-L-tryptophanyl)-N4-((4-methoxyphenyl)diphenylmethyl)-L-aspartic acid, N-((S)-3-(1H-indol-3-yl)-1-(((S)-1-methoxy-4-sideoxy-4-(triphenylmethylamino)but-2-yl)amino)-1-sideoxypropyl-2-yl)benzoylamine, N4-((9H-furo-9-yl)methyl)-N2-(benzoyl-L-tryptophanyl)-L-aspartic acid, N2-(benzoyl-L-tryptophanyl)-N2-methyl-N4-triphenylmethyl-L-aspartic acid methyl ester N2-(acetyl-L-tryptophanyl)-N4-triphenylmethyl-L-aspartic acid, N2-(methyl-L-tryptophanyl)-N4-triphenylmethyl-L-aspartic acid, N2-(Nα-benzoyl-1-methyl-L-tryptophanyl)-N4-triphenylmethyl-L-aspartic acid, N2-((2-Phenylacetyl)-L-Tryptocyano)-N4-Triphenylmethyl-L-Aspartate, N2-(phenylmethyl-L-tryptophanyl)-N4-triphenylmethyl-L-aspartic acid, N2-(Nα-(4-fluorobenzoyl)-1-methyl-L-tryptophanyl)-N4-triphenylmethyl-L-aspartic acid methyl ester N2-((4-fluorobenzoyl)-L-tryptophanyl)-N4-triphenylmethyl-L-aspartic acid methyl ester N2-(Nα-(4-fluorobenzoyl)-1-methyl-L-tryptophanyl)-N4-triphenylmethyl-L-aspartic acid, N2-((4-fluorobenzoyl)-L-tryptophanyl)-N4-triphenylmethyl-L-aspartic acid, N2-(1-Methyl-Nα-nicotinyl-L-tryptophanyl)-N4-triphenylmethyl-L-aspartic acid methyl ester N2-(1-Methyl-Nα-nicotinyl-L-tryptophanyl)-N4-triphenylmethyl-L-aspartic acid, N2-(nicotinyl-L-tryptophanyl)-N4-triphenylmethyl-L-aspartic acid methyl ester N2-(nicotinyl-L-tryptophanyl)-N4-triphenylmethyl-L-aspartic acid, N2-(benzoyl-D-tryptophanyl)-N4-triphenylmethyl-L-aspartic acid, N2-(pyridinyl-L-tryptophanyl)-N4-triphenylmethyl-L-aspartic acid, N2-(isonicotinyl-L-tryptophanyl)-N4-triphenylmethyl-L-aspartic acid, N2-(1-methyl-Nα-(pyridin-2-ylmethyl)-L-tryptophanyl)-N4-triphenylmethyl-L-aspartic acid, N2-(1-Methyl-Nα-pyridinyl-L-tryptophanyl)-N4-triphenylmethyl-L-aspartic acid, N2-(Nα-isonicotinyl-1-methyl-L-tryptophanyl)-N4-triphenylmethyl-L-aspartic acid N2-(benzoyl-L-tryptophanyl)-N4-triphenylmethyl-D-aspartic acid, N2-((pyridin-2-ylmethyl)-L-tryptophanyl)-N4-triphenylmethyl-L-aspartic acid, N2-(1-methyl-Nα-(1H-pyrrolo-2-carbonyl)-L-tryptophanyl)-N4-triphenylmethyl-L-aspartic acid, N2-((1H-pyrrolo-2-carbonyl)-L-tryptophanyl)-N4-triphenylmethyl-L-aspartic acid, N2-((6-Fluoronicoyl)-L-Tryptoyl)-N4-Triphenylmethyl-L-Aspartic acid, N2-((5-Fluoropyridinecarboxyl)-L-Tryptocyano)-N4-Triphenylmethyl-L-Aspartate, N2-(Nα-(5-fluoropyridinyl)-1-methyl-L-tryptophanyl)-N4-triphenylmethyl-L-aspartic acid, N2-((6-methoxynicotinyl)-L-tryptophanyl)-N4-triphenylmethyl-L-aspartic acid, N2-((6-cyanoconicoyl)-L-tryptophanyl)-N4-triphenylmethyl-L-aspartic acid, N2-(Nα-(6-methoxynicotinyl)-1-methyl-L-tryptophanyl)-N4-triphenylmethyl-L-aspartic acid, N2-((6-aminoformylnicotinyl)-L-tryptophanyl)-N4-triphenylmethyl-L-aspartic acid, N2-(Nα-(5-cyanopyridinyl)-1-methyl-L-tryptophanyl)-N4-triphenylmethyl-L-aspartic acid, N2-(Nα-(6-cyanoconicoyl)-1-methyl-L-tryptophanyl)-N4-triphenylmethyl-L-aspartic acid, N2-(Nα-(6-fluoronicotinyl)-1-methyl-L-tryptophanyl)-N4-triphenylmethyl-L-aspartic acid, N2-(Nα-(5-methoxypyridinyl)-1-methyl-L-tryptophanyl)-N4-triphenylmethyl-L-aspartic acid, N2-(Nα-(5-aminocarbamoylpyridinyl)-1-methyl-L-tryptophanyl)-N4-triphenylmethyl-L-aspartic acid, N2-(1-methyl-Nα-((1-methyl-1H-pyrrolo-2-yl)methyl)-L-tryptophanyl)-N4-triphenylmethyl-L-aspartic acid, N2-(((1-Methyl-1H-pyrrolo-2-yl)methyl)-L-tryptophanyl)-N4-triphenylmethyl-L-aspartic acid, N2-(1-Methyl-Nα-(phenylaminoformyl)-L-tryptophanyl)-N4-triphenylmethyl-L-aspartic acid, N2-(Nα-((4-cyanophenyl)carbamoyl)-1-methyl-L-tryptophanyl)-N4-triphenylmethyl-L-aspartic acid, N2-(Nα-benzoyl-1-methyl-L-tryptophanyl)-N5-triphenylmethyl-L-glutamyl amino acid, N2-(Nα-((4-methoxyphenyl)carbamoyl)-1-methyl-L-tryptophanyl)-N4-triphenylmethyl-L-aspartic acid, N2-(1-methyl-Nα-(naphth-1-ylcarbamoyl)-L-tryptophanyl)-N4-triphenylmethyl-L-aspartic acid, N2-(Nα-((3,5-dimethylisoazol-4-yl)carbamoyl)-1-methyl-L-tryptophanyl)-N4-triphenylmethyl-L-aspartic acid, N2-(Nα-((4-(dimethylamino)phenyl)carbamoyl)-1-methyl-L-tryptophanyl)-N4-triphenylmethyl-L-aspartic acid, (S)-2-((S)-2-benzoylamino-3-(1-methyl-1H-indol-3-yl)propionylamino)-5-(triphenylmethylamino)valeric acid, (S)-2-((S)-2-benzoylamino-3-(1-methyl-1H-indol-3-yl)propionylamino)-6-sideoxy-6-(triphenylmethylamino)hexanoic acid, N2-(Nα-(cyclohexanecarbonyl)-1-methyl-L-tryptophanyl)-N4-triphenylmethyl-L-aspartic acid, N2-(Nα-((benzooxy)carbonyl)-1-methyl-L-tryptophanyl)-N4-triphenylmethyl-L-aspartic acid, N2-(1-Methyl-Nα-(benzenesulfonyl)-L-tryptophanyl)-N4-triphenylmethyl-L-aspartic acid, Or its tautomers, stereoisomers, isotopes, solvates, polymorphs, or pharmaceutically acceptable salts.

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

10. The pharmaceutical composition of claim 9, for the prevention, improvement and / or treatment of diseases or conditions mediated by formyl peptide receptor 1 (FPR1).

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

12. The pharmaceutical composition of claim 11, wherein the inflammation is a neutrophilic inflammatory condition.

13. The pharmaceutical composition of claim 11, wherein the neutrophilic inflammatory condition is selected from the group consisting of: lung injury, chronic obstructive pulmonary disease, acute respiratory distress syndrome, asthma, ischemia-reperfusion injury, arthritis, and sepsis.

14. The pharmaceutical composition of claim 11, wherein the cancer exhibits FPR1 expression.

15. The pharmaceutical composition of 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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