Pyrazoleamide derivatives and their preparation methods and applications

Abstract

A compound of chemical formula (I), a preparation method and use thereof, a pharmaceutical composition comprising the compound as an active ingredient or a pharmaceutically acceptable salt thereof, and further relates to the use of the compound of formula (I) in treating and preventing EP4-mediated diseases.

Description

Technical Field

[0001] The present invention belongs to the field of medicine and specifically relates to a class of heterocyclic amide derivatives and pharmaceutically acceptable salts thereof that serve as EP4 receptor antagonists, and pharmaceutical compositions containing the same as active ingredients. The present invention also provides methods for preparing the compounds and their use as medicaments for treating prostaglandin E-mediated diseases. Background Art

[0002] After encountering antigen, original CD4+T helper cell precursor (Thp) cell differentiation is divided into two different hypotypes, i.e. type 1 T helper cell (Th1) and type 2 T helper cell (Th2). In recent years, novel T cell subtypes, i.e. Th17 cells, have also been identified and characterized. The Th cells of these differentiations are determined by their different functions and unique cytokine signatures. In contrast, known Th2 cells produce IL-4, IL-5, IL-6, IL-9, IL-10 and IL-13, which are responsible for the generation of strong antibodies, eosinophil activation and the suppression of several macrophage functions, thereby providing the protection response of phagocyte-independent. Th17 cells mainly produce IL-17A, IL-17F, IL-21, IL-22 and TNF, and are necessary for the defense of host antagonism extracellular pathogens, and are key mediators of autoimmunity. Therefore, Th1, Th2 and Th17 cells are relevant with different immunopathological responses.

[0003] Prostaglandin receptors and their most commonly used selective agonists and antagonists have been extensively studied for their characteristics and therapeutic utility.

[0004] Prostaglandins are mediators of pain, fever, and other symptoms associated with inflammation. Prostaglandin E2 (PGE2) is the primary metabolite of eicosanoids associated with inflammation. Furthermore, PGE2 is involved in various physiological and / or pathological symptoms, such as hyperalgesia, uterine contractions, gastrointestinal motility, arousal, inhibition of gastric acid secretion, blood pressure, platelet function, bone metabolism, and angiogenesis. The four subtypes of PGE2 receptors (EP1, EP2, EP3, and EP4) exhibit distinct pharmacological properties.

[0005] The EP4 receptor is characterized by having the longest intracellular C-terminal loop compared to other prostanoid receptors. The EP4 receptor is G-protein coupled and mediates elevated cyclic adenosine monophosphate concentrations. EP4 receptor expression is controlled by various physiological and pathophysiological processes, as it is involved in ovulation and fertilization, inducing bone formation, T-cell factor signaling, preventing inflammatory bowel disease, promoting Langerhans cell migration and maturation, and mediating joint inflammation in collagen-induced arthritis models, among other processes.

[0006] Studies have shown that prostaglandins can regulate the different stages of immune response. PGE2 stimulation via PGE2 receptor EP4 hypotype can also have opposite effect, i.e. promote Th1 differentiation and activated CD4+ cells to produce IL-17. Simultaneously, the antagonism of EP4 and novel selectivity EP4 antagonists or PGE2-neutralizing antibodies can suppress the IL-23 secretion of Th1 differentiation, Th17 breeding and activated dendritic cells. PGE2 is mediated by PI3K signaling to the induction of Th1 differentiation, and the stimulation that IL-17 produces needs cAMP signaling. In addition, administration of an EP4 antagonist to DBA / 1 or C57BL / 6 mice suppressed innate and adaptive immune responses and inhibited disease in collagen-induced arthritis (CIA) and experimental autoimmune encephalomyelitis (EAE) models, indicating that PGE2 / EP4 signaling is critically involved in autoimmune pathology and suggesting that inhibition of PGE2 / EP4 signaling may have therapeutic value in ameliorating inflammatory autoimmune diseases such as rheumatoid arthritis and multiple sclerosis.

[0007] Therefore, the compounds disclosed herein are expected to be useful in treating diseases or conditions mediated by the EP4 receptor in mammals, including humans, including but not limited to rheumatoid arthritis and multiple sclerosis.

[0008] There remains a need in the art for new compounds that can effectively and reliably inhibit EP4 both in vitro and in vivo. Summary of the Invention

[0009] The object of the present invention is to provide a new class of novel compounds having EP4 receptor inhibitory activity and / or having good pharmacodynamics / pharmacokinetic properties and their use in treating or alleviating prostaglandin E-mediated diseases.

[0010] The first aspect of the present invention provides a compound of formula I or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, isotope compound or prodrug thereof;

[0011]

[0012] in,

[0013] R1 and R2 are each independently selected from the group consisting of H, unsubstituted or halogen-substituted C1-C4 alkyl;

[0014] or R1 and R2 together with the carbon atom to which they are attached form a C3-C6 cycloalkyl group;

[0015] R3 is an unsubstituted or halogen-substituted C1-C4 alkyl group;

[0016] R4 is an unsubstituted or halogen-substituted C1-C4 alkyl group;

[0017] R5 is selected from the group consisting of hydrogen, halogen, C1-C4 alkyl, or C1-C4 alkoxy; and

[0018] R6 is none or selected from the following groups: halogen, unsubstituted or halogen-substituted C1-C4 alkyl, unsubstituted or halogen-substituted C1-C4 alkoxy.

[0019] In another preferred embodiment, one of R1 and R2 is H, and the other is an unsubstituted or halogen-substituted C1-C4 alkyl group.

[0020] In another preferred embodiment, one of R1 and R2 is H, and the other is CH3.

[0021] In another preferred embodiment, R3 is methyl, monofluoromethyl, difluoromethyl or trifluoromethyl.

[0022] In another preferred embodiment, R4 is methyl.

[0023] In another preferred embodiment, R5 is hydrogen.

[0024] In another preferred embodiment, R6 is anhydrous, chloro, fluoro, methyl, monofluoromethyl, difluoromethyl, trifluoromethyl or methoxy.

[0025] In another preferred embodiment, the prodrug is an ester formed by the compound of formula I and a C1-C4 alkyl-OH group.

[0026] In another preferred embodiment, R1, R2, R3, R4, R5 and R6 are each independently a corresponding group in compounds 1-3 of the present invention.

[0027] In another preferred embodiment, the compound of formula I is selected from the following group:

[0028]

[0029] In a second aspect, the present invention provides a pharmaceutical composition comprising the compound described in the first aspect or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, isotope compound or prodrug thereof and a pharmaceutically acceptable carrier or diluent.

[0030] In a third aspect, the present invention provides a use of the compound described in the first aspect or its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, isotope compound or prodrug, or the pharmaceutical composition described in the second aspect, in the preparation of a drug for inhibiting EP4 receptor activity in a cell or a subject.

[0031] In a fourth aspect, the present invention provides a use of the compound described in the first aspect or its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, isotope compound or prodrug, or the pharmaceutical composition described in the second aspect, in the preparation of a medicament for preventing and / or treating diseases associated with the EP4 receptor.

[0032] In another preferred embodiment, the EP4 receptor-related disease is selected from the group consisting of acute and chronic pain, osteoarthritis, rheumatoid arthritis and cancer.

[0033] On the other hand, a method for treating EP4 receptor-related diseases is provided, which comprises administering to a subject in need thereof a therapeutically effective amount of the compound as described above or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, isotope compound or prodrug thereof, or the pharmaceutical composition as described above.

[0034] In another preferred embodiment, the subject is identified or diagnosed as having an EP4 receptor-related disease.

[0035] In another preferred embodiment, the cells are mammalian cells.

[0036] In another preferred embodiment, the subject is a mammal, preferably a human, a mouse, or a rat.

[0037] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features described in detail below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be listed here one by one. DETAILED DESCRIPTION

[0038] After extensive and intensive research, and through extensive screening and testing, the present inventors have discovered a class of compounds with EP4 receptor inhibitory activity. Furthermore, the compounds of the present invention exhibit good pharmacodynamic and pharmacokinetic properties. Based on this, the present invention was completed.

[0039] the term

[0040] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0041] As used herein, the terms "comprising" or "including" may be open, semi-closed, or closed. In other words, the terms also include "consisting essentially of" or "consisting of."

[0042] When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents that would result if the formula were written from right to left. For example, -CH2O- is equivalent to -OCH2-.

[0043] The term "alkyl" by itself or as part of another substituent refers to a straight or branched chain hydrocarbon radical having the specified number of carbon atoms (i.e., C1-C6 refers to one to six carbon atoms). Examples of alkyl radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, and the like. One or more positions of an alkyl radical may be substituted, particularly 1 to 4 substituents, and substitutions may be made at any position.

[0044] The term "haloalkyl" refers to a group including branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms substituted with one or more halogen atoms. Examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl. Examples of haloalkyl groups also include "fluoroalkyl" groups including branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms substituted with one or more fluorine atoms.

[0045] The term "fluoroalkyl" refers to an alkyl group as defined above wherein one or more hydrogen atoms are replaced by fluorine atoms.

[0046] The term "alkoxy" refers to -O-alkyl, including linear, branched or cyclic alkoxy groups, representative examples of which include (but are not limited to): methoxy, ethoxy, propoxy, isopropoxy and butoxy, etc. Preferably, it is C1-C3 alkoxy.

[0047] The term "fluoroalkoxy" refers to an alkoxy group as defined above wherein one or more hydrogen atoms are replaced by fluorine atoms.

[0048] The term "haloalkoxy" refers to -O-haloalkyl, including linear, branched or cyclic haloalkoxy groups. Representative examples include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, trichloromethoxy, pentafluoroethoxy and pentachloroethoxy.

[0049] The term "cycloalkyl" refers to saturated monocyclic, bicyclic or polycyclic cyclic alkyl groups, such as C3-C8 or C3-C 12 Cycloalkyl. C3-C8 cycloalkyl refers to C3, C4, C5, C6, C7, or C8 cycloalkyl. Representative cycloalkyl groups of the present invention include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and norbornyl.

[0050] The term "halo" or "halogen" includes fluorine, chlorine, bromine and iodine.

[0051] Unless otherwise stated, any heteroatom with insufficient valence is assumed to have sufficient hydrogen atoms to complete the valence.

[0052] When a substituent is non-terminal, it is a substituent of the corresponding group, for example, alkyl for alkylene, cycloalkyl for cycloalkylene, heterocyclyl for heterocyclylene, alkoxy for alkyleneoxy, and the like.

[0053] The term "EP4 antagonist" refers to a compound that inhibits or blocks cell signal transduction triggered by the interaction of PGE2 with the EP4 receptor, including but not limited to the compound represented by formula (I) described herein.

[0054] Active ingredient

[0055] As used herein, the terms "compound of the present invention" or "active ingredient of the present invention" are used interchangeably to refer to a compound of Formula I, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, isotopic compound (e.g., deuterated compound), or prodrug thereof. The term also includes racemates and optical isomers.

[0056] The compound of the present invention has the structure shown in formula I

[0057]

[0058] wherein R1, R2, R3, R4, R5 and R6 are as defined above.

[0059] The salts that may be formed by the compounds of the present invention also fall within the scope of the present invention. Unless otherwise indicated, the compounds of the present invention are understood to include their salts. The term "salt" as used herein refers to acidic or basic salts formed with inorganic or organic acids and bases. In addition, when the compound of the present invention contains a basic fragment, it includes but is not limited to pyridine or imidazole, and contains an acidic fragment, including but not limited to carboxylic acid, the zwitterions ("inner salts") that may be formed are included within the scope of the term "salt". Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful, for example, in separation or purification steps during the preparation process. The compounds of the present invention may form salts, for example, compound I reacts with a certain amount, such as an equivalent amount, of an acid or base, salts out in a medium, or is obtained by freeze-drying in an aqueous solution.

[0060] The compounds of the present invention contain basic moieties, including but not limited to amines or pyridine or imidazole rings, which may form salts with organic or inorganic acids. Typical acids that can form salts include acetates (e.g., acetic acid or trihaloacetic acid, such as trifluoroacetic acid), adipates, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphor, camphorsulfonate, cyclopentanepropionate, diglycolate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide,

[0014] Examples of the present invention include, for example, hydroxyethylsulfonates, lactates, maleates, methanesulfonates, naphthalenesulfonates (e.g., 2-naphthalenesulfonate), nicotinates, nitrates, oxalates, pectinates, persulfates, phenylpropionates (e.g., 3-phenylpropionate), phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates (e.g., with sulfuric acid), sulfonates, tartrates, thiocyanates, toluenesulfonates such as p-toluenesulfonate, dodecanoates, and the like.

[0061] Certain compounds of the present invention may contain acidic moieties, including but not limited to carboxylic acids, which may form salts with various organic or inorganic bases. Typical base-forming salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, and salts formed with organic bases (e.g., organic amines), such as benzathine, dicyclohexylamine, hepamine (salt formed with N,N-di(dehydroabietyl)ethylenediamine), N-methyl-D-glucamine, N-methyl-D-glucamide, tert-butylamine, and salts formed with amino acids such as arginine, lysine, and the like. Basic nitrogen-containing groups can react with halide quaternary ammonium salts, such as small molecular alkyl halides (such as chlorides, bromides and iodides of methyl, ethyl, propyl and butyl), dialkyl sulfates (such as dimethyl sulfate, diethyl sulfate, dibutyl sulfate and dipentyl sulfate), long chain halides (such as chlorides, bromides and iodides of decyl, dodecyl, tetradecyl and tetradecyl), aralkyl halides (such as benzyl and phenyl bromide), etc.

[0062] Prodrugs and solvates of the compounds of the present invention are also encompassed. The term "prodrug" herein refers to a compound that undergoes chemical transformation via metabolic or chemical processes to produce a compound, salt, or solvate of the present invention when used to treat a relevant disease. The compounds of the present invention include solvates, such as hydrates.

[0063] As used herein, the term "solvate" refers to a complex in which the compound of the present invention is coordinated with solvent molecules to form a specific ratio.

[0064] As used herein, the term "hydrate" refers to a complex formed by coordination of a compound of the present invention with water, such as a monohydrate.

[0065] The compounds, salts or solvates of the present invention may exist in tautomeric forms (such as amides and imino ethers). All such tautomers are part of the present invention.

[0066] All stereoisomers of the compounds (e.g., those that may exist due to asymmetric carbon atoms for various substitutions), including enantiomeric and diastereomeric forms, are contemplated by the present invention. Individual stereoisomers of the compounds of the present invention may not exist with other isomers (e.g., as a pure or substantially pure optical isomer having a particular activity), or may be mixtures, such as racemates, or mixtures with all other stereoisomers or portions thereof. The chiral centers of the present invention have either S or R configurations, as defined by the 1974 recommendations of the International Union of Pure and Applied Chemistry (IUPAC). Racemic forms can be resolved by physical methods, such as fractional crystallization, or by crystallization of diastereomers derived from them, or by separation by chiral column chromatography. Individual optical isomers can be obtained from the racemate by suitable methods, including but not limited to conventional methods, such as salt formation with an optically active acid followed by recrystallization.

[0067] The compounds of the present invention, obtained by sequential preparation, isolation, and purification, are described in the text to a concentration of 90% or greater by weight, for example, 95% or greater, or 99% or greater ("very pure" compounds). Such "very pure" compounds of the present invention are also considered part of the present invention.

[0068] All configurational isomers of the compounds of the present invention are encompassed, whether in mixture, pure or very pure form. The definition of the compounds of the present invention includes both cis (Z) and trans (E) olefin isomers, as well as cis and trans isomers of carbocyclic and heterocyclic rings.

[0069] Throughout the specification, groups and substituents may be chosen to provide stable fragments and compounds.

[0070] Specific functional groups and chemical term definitions are detailed below. For the purposes of this invention, chemical elements are referred to in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th The definitions of specific functional groups are consistent with those in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito, 1999, which is incorporated by reference in its entirety.

[0071] Certain compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention encompasses all compounds, including their cis and trans isomers, R and S enantiomers, diastereomers, (D) isomers, (L) isomers, racemic mixtures, and other mixtures. Additionally, asymmetric carbon atoms may represent substituents, such as alkyl groups. All isomers and mixtures thereof are encompassed by the present invention.

[0072] According to the present invention, mixtures of isomers can contain various ratios of isomers. For example, mixtures containing only two isomers can have the following ratios: 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0. All ratios of isomers are within the scope of the present invention. Similar ratios, as well as ratios for more complex mixtures of isomers, are readily understood by those skilled in the art and are also within the scope of the present invention.

[0073] The present invention also includes isotopically labeled compounds that are equivalent to the original compounds disclosed herein. However, in practice, it is common for one or more atoms to be replaced by atoms having a different atomic mass or mass number. Examples of isotopes of the compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine isotopes, such as 2 H. 3 H. 13 C. 11 C. 14 C. 15 N. 18 O. 17 O. 31 P. 32 P. 35 S. 18 F and 36 The compounds of the present invention, or enantiomers, diastereomers, isomers, or pharmaceutically acceptable salts or solvates thereof, which contain isotopes or other isotopic atoms of the above compounds are within the scope of the present invention. Certain isotopically labeled compounds of the present invention, such as 3 H and 14 Radioisotopes of C are also included and are useful in tissue distribution experiments of drugs and substrates. 3 H and carbon-14, i.e. 14 C, their preparation and detection are relatively easy. It is the first choice among isotopes. In addition, heavier isotope substitutions such as deuterium, i.e. 2H, due to its excellent metabolic stability, has advantages in certain therapeutics, such as increasing half-life in vivo or reducing dosage, and therefore, may be preferred in some cases. Isotopically labeled compounds can be prepared using conventional methods by replacing readily available isotopically labeled reagents with non-isotopic reagents using the protocols disclosed in the examples.

[0074] If a synthesis of a specific enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, followed by separation of the resulting diastereomeric mixture and removal of the chiral auxiliary to obtain the pure enantiomer. Alternatively, if the molecule contains a basic functional group, such as an amino acid, or an acidic functional group, such as a carboxyl group, diastereomeric salts can be formed with a suitable optically active acid or base, followed by separation by conventional means such as fractional crystallization or chromatography to obtain the pure enantiomer.

[0075] As described herein, the compounds of the present invention may be substituted with any number of substituents or functional groups to expand their scope. Generally, the term "substituted," whether preceded or followed by the term "optionally," in formulas of the present invention including substituents, refers to the replacement of a hydrogen radical with a substituent of the specified structure. When multiple positions in a particular structure are substituted with multiple substituents of the specified structure, the substituents may be the same or different at each position. As used herein, the term "substituted" includes all permissible substitutions in organic compounds. Broadly speaking, permissible substituents include acyclic, cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic organic compounds. For example, heteroatoms of nitrogen may be substituted with hydrogen or any of the permissible organic compounds described above to supplement their valences. Furthermore, the present invention is not intended to limit the permissible substitutions in any way to organic compounds. The present invention recognizes that combinations of substituents and variables are advantageous for providing stable compounds for the treatment of diseases. As used herein, the term "stable" refers to compounds that are stable and maintain the structural integrity of the compound over a period of time sufficient to be detected, preferably over a period of time sufficient to be effective, as used herein for the purposes described above.

[0076] The metabolites of the compounds and pharmaceutically acceptable salts thereof involved in the present application, as well as prodrugs that can be converted into the structures of the compounds and pharmaceutically acceptable salts involved in the present application and in vivo, are also included in the claims of the present application.

[0077] Preparation method

[0078] The preparation method of the compound of formula (I) of the present invention is described in more detail below, but these specific methods do not constitute any limitation to the present invention. The compounds of the present invention can also be prepared by combining various synthetic methods described in this specification or known in the art, and such combinations can be easily carried out by those skilled in the art.

[0079] Typically, in the preparation process, each reaction is usually carried out under inert gas protection in a suitable solvent at room temperature to 90° C., and the reaction time is usually 2-24 hours.

[0080] Method 1:

[0081]

[0082] In method 1, R1, R2, R3, R4, R5, and R6 have the definitions described in the present invention. The method comprises the following steps:

[0083] (i) In an inert solvent under alkaline conditions, compound 1-1 reacts with an o-pentafluorosulfanylphenol derivative to produce compound 1-2;

[0084] (ii) Compound 1-2 reacts with 2-methyl-2-butene, sodium chlorite, and sodium dihydrogen phosphate in a polar solvent to produce compound 1-3;

[0085] (iii) condensing the carboxylic acid in compound 1-3 with methyl 4-aminomethylbenzoate in an inert solvent to form compound 1-4;

[0086] (iv) in a mixed solvent of methanol and tetrahydrofuran under alkaline conditions, the carboxylic acid methyl ester in compound 1-4 is hydrolyzed to carboxylic acid to produce compound 1-5;

[0087] In the above reaction steps, the reaction solvent, reaction temperature, reaction time, catalyst, etc. can be selected according to the specific reactants.

[0088] Pharmaceutical compositions and methods of administration

[0089] The compounds of the present invention are antagonists of the EP4 receptor and are therefore expected to be beneficial in the treatment of EP4 receptor-mediated diseases. The pharmaceutical compositions of the present invention are used to prevent and / or treat the following diseases: multiple sclerosis or rheumatoid arthritis, systemic lupus erythematosus, type 1 diabetes, psoriasis, atherosclerosis, Crohn's disease, inflammatory pain, neuropathic pain, migraine-related pain, spondyloarthritis, skin cancer, breast cancer, colorectal cancer, prostate cancer, kidney cancer, cervical cancer, ovarian cancer, endometrial cancer, glioblastoma, head and neck cancer, medulloblastoma, lung cancer, urethral cancer, and the like.

[0090] In certain embodiments, the compounds of the present invention are used as analgesics. For example, they are useful in the treatment of multiple sclerosis, chronic joint pain (e.g., rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, gouty arthritis, and juvenile arthritis), musculoskeletal pain; lower back and neck pain; sprains and strains; neuropathic pain; sympathetically maintained pain; pain associated with cancer and fibromyalgia; pain associated with migraines; pain associated with influenza or other viral infections such as the common cold; rheumatic fever; pain associated with functional bowel disorders such as non-ulcer dyspepsia, non-cardiac chest pain, and irritable bowel syndrome; pain associated with myocardial ischemia; postoperative pain; headache; dental pain; and dysmenorrhea.

[0091] The compounds of general formula (I) can be used in combination with other drugs known to treat or improve similar conditions. When administered in combination, the original drug's administration method and dosage can remain unchanged, while the compound of formula I is taken simultaneously or subsequently. When the compound of formula I is taken simultaneously with one or more other drugs, a pharmaceutical composition containing one or more known drugs and the compound of formula I can be preferably used. Drug combination also includes taking the compound of formula I and one or more other known drugs during overlapping time periods. When the compound of formula I is used in combination with one or more other drugs, the dosage of the compound of formula I or the known drug may be lower than the dosage of each drug taken alone.

[0092] "Pharmaceutically acceptable excipients" and "pharmaceutically acceptable carriers" refer to substances that aid in the formulation and / or administration and / or absorption of an active agent by an individual and can be included in the compositions of the present disclosure without causing significant adverse toxicological effects on the individual. Non-limiting examples of pharmaceutically acceptable carriers and excipients include water, NaCl, physiological saline solutions, lactated Ringer's solution, regular sucrose, regular glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (e.g., Ringer's solution), alcohols, oils, gelatin, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethylcellulose, polyvinylpyrrolidine, and pigments. Such preparations can be sterilized and, if necessary, mixed with adjuvants such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts that affect osmotic pressure, buffers, colorants, and / or aromatic substances that do not react harmfully with the compounds provided herein or interfere with the activity of the compounds provided herein. One of ordinary skill in the art will recognize that other pharmaceutical carriers and excipients are suitable for use with the disclosed compounds.

[0093] In certain embodiments, the pharmaceutical compositions of the present invention may be in solid or liquid form.

[0094] The active ingredient (i.e., the compound of Formula I) can be in a suitable oral dosage form, such as a tablet, troche, lozenge, aqueous or oily suspension, dispersed latex powder or granules, emulsion, hard or soft capsule, or syrup or elixir. Oral medications can be prepared according to known processes of the pharmaceutical ingredient manufacturer. These compositions may include one or more of the following agents, such as sweeteners, flavorings, colorants, and preservatives, to provide an elegant and palatable pharmaceutical formulation. Tablets contain the active ingredient mixed with non-toxic pharmaceutically acceptable excipients suitable for tablet production. Examples of such excipients include inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating agents such as corn starch or alginic acid; binders such as starch, gelatin, or gum arabic; and lubricants such as magnesium stearate, stearic acid, or talc. The tablets may be uncoated or coated to delay degradation and absorption in the gastrointestinal tract, thereby maintaining activity over a longer period of time.

[0095] The active compound can be administered to the subject by any suitable route, including orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the composition is administered orally, intraperitoneally or intravenously.

[0096] Pharmaceutical compositions of the present invention suitable for oral administration will typically be discrete units in solid form, e.g., tablets, capsules, cachets, powders, granules, lozenges, patches, suppositories, pills, or in liquid form, e.g., liquids, injectable or infusible solutions or suspensions.

[0097] The precise amount of the compound providing a therapeutically effective amount to an individual will depend on the mode of administration, the type and severity of the disease and / or illness, and the characteristics of the individual, such as general health, age, sex, weight, and tolerance to the drug. One of ordinary skill in the art will be able to determine a suitable dosage based on these and other factors. When administered in combination with other therapeutic agents, the "therapeutically effective amount" of any other therapeutic agent will depend on the type of drug used. Suitable dosages are known for approved therapeutic agents and can be adjusted by one of ordinary skill in the art based on the individual's condition, the type of illness being treated, and the amount of the compound of the present invention used below, for example, as reported in the literature and recommended in the Physician's Desk Reference (57th edition, 2003). Preferably, the composition should be formulated so that an inhibitor dose of 0.01-100 mg / kg body weight / day can be administered to patients receiving these compositions. In certain embodiments, the compositions of the present invention provide a dosage of 0.01 mg to 50 mg. In other embodiments, a dosage of 0.1 mg-25 mg or 5 mg-40 mg is provided.

[0098] Examples of subjects to whom the pharmaceutical composition or therapeutic agent of the present invention can be administered include mammals (eg, humans, mice, rats, hamsters, rabbits, cats, dogs, cows, sheep, monkeys, etc.).

[0099] The present invention also provides a method for preparing a pharmaceutical composition, comprising the steps of: mixing a pharmaceutically acceptable carrier with the compound of general formula (I) of the present invention or its crystal form, pharmaceutically acceptable salt, hydrate or solvate, thereby forming a pharmaceutical composition.

[0100] The present invention also provides a treatment method, which comprises the steps of administering to a subject in need of treatment the compound of general formula (I) of the present invention, or a crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, or administering the pharmaceutical composition of the present invention, for selectively inhibiting the EP4 receptor.

[0101] The present invention has the following main advantages:

[0102] (1) The compounds of the present invention have better inhibitory activity and selectivity against EP4 receptors.

[0103] (2) The compounds of the present invention have relatively low toxic side effects.

[0104] (3) The compounds of the present invention have better pharmacodynamics, pharmacokinetic properties and drugability.

[0105] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the invention. The experimental methods in the following examples, for which specific conditions are not specified, are generally based on conventional conditions such as those described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or according to the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0106] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those familiar to those skilled in the art. Furthermore, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0107] The structures of the compounds of the present invention are confirmed by nuclear magnetic resonance (NMR) and liquid chromatography-mass spectrometry (LC-MS).

[0108] NMR was measured using a Bruker AVANCE-400 and Bruker AVANCE-500 nuclear magnetic spectrometer. The measurement solvents included deuterated dimethyl sulfoxide (DMSO-d6), deuterated acetone (CD3COCD3), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). Tetramethylsilane (TMS) was used as the internal standard, and chemical shifts were measured in parts per million (ppm).

[0109] Liquid chromatography-mass spectrometry (LC-MS) was performed using an Agilent 1260 mass spectrometer. HPLC analysis was performed using an Agilent 1100 high pressure chromatograph (Microsorb 5 micron C18 100 x 3.0 mm column).

[0110] TLC silica gel plates used were Qingdao GF254 silica gel plates, with a diameter of 0.15-0.20 mm for TLC and 0.4-0.5 mm for preparative thin layer chromatography. Column chromatography generally used Qingdao 200-300 mesh silica gel as a carrier.

[0111] The starting materials in the examples of the present invention are all known and commercially available, or can be synthesized using or according to literature data reported in the art.

[0112] Unless otherwise specified, all reactions of the present invention are carried out under the protection of dry inert gas (such as nitrogen or argon) with continuous magnetic stirring, and the reaction temperatures are all degrees Celsius.

[0113] The following abbreviations are used throughout this invention:

[0114] THF: Tetrahydrofuran

[0115] MeOH: methanol

[0116] HCl: hydrochloric acid

[0117] Pd(PPh3)4: Tetrakistriphenylphosphine palladium

[0118] K2CO3: Potassium carbonate

[0119] AcOK: Potassium acetate

[0120] NaOH: sodium hydroxide

[0121] H2O: water

[0122] TEA: triethylamine

[0123] DIEA: N,N-diisopropylethylamine

[0124] DMF: N,N-dimethylformamide

[0125] DMA: N,N-dimethylacetamide

[0126] Py:pyridine

[0127] DCE: 1,2-dichloroethane

[0128] DMSO: dimethyl sulfoxide

[0129] TFA: trifluoroacetic acid

[0130] NaBH(AcO)3: Sodium triacetylborohydride

[0131] Sn2(Bu-n)6: Hexahexylditin

[0132] AlCl3: aluminum chloride

[0133] CuI: Cuprous iodide

[0134] DPPA: diphenylphosphoryl azide

[0135] BuOH: tert-butyl alcohol

[0136] Cs2CO3: cesium carbonate

[0137] K3PO4: Potassium phosphate

[0138] BnBr: benzyl bromide

[0139] Pd2(dba)3: tris(dibenzylideneacetone)dipalladium

[0140] X-Phos: 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl

[0141] EA: ethyl acetate

[0142] NaHCO3: sodium bicarbonate

[0143] DIPEA: N,N-diisopropylethylamine

[0144] HBr: Hydrogen bromide

[0145] Example 1 Synthesis of Compound 1

[0146]

[0147] Step 1: Synthesis of 3-(difluoromethyl)-1-methyl-5-(-(pentafluorosulfanyl)phenoxy)-1H-pyrazole-4-carbaldehyde

[0148] 3-(Pentafluorosulfanyl)phenol (0.85 g, 3.85 mmol) was dissolved in dry DMF (5 mL), followed by the addition of potassium hydroxide (0.29 g, 5.14 mmol). The reaction mixture was allowed to react at room temperature for 20 min. 5-Chloro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbaldehyde (0.50 g, 2.57 mmol) was then added and the mixture was heated to 40°C and stirred for 2 h. After monitoring for reaction completion, the reaction mixture was poured into an appropriate amount of ice water and stirred to precipitate a white solid. The solid was filtered, dissolved in EA, and dried to dryness to yield 0.84 g of 3-(difluoromethyl)-1-methyl-5-(3-(pentafluorosulfanyl)phenoxy)-1H-pyrazole-4-carbaldehyde. MS m / z (ESI): 379.3 [M+H]. + .

[0149] Step 2: Synthesis of 3-(difluoromethyl)-1-methyl-5-(3-(pentafluorosulfanyl)phenoxy)-1H-pyrazole-4-carboxylic acid

[0150] 3-(Difluoromethyl)-1-methyl-5-(3-(pentafluorosulfanyl)phenoxy)-1H-pyrazole-4-carboxaldehyde (0.84 g, 2.21 mmol) and 2-methyl-2-butene (0.25 g, 3.54 mmol) were dissolved in tert-butanol (6 mL). Sodium chlorite (0.40 g, 4.43 mmol) and sodium dihydrogen phosphate (0.58 g, 4.87 mmol) dissolved in water were then added. The reaction mixture was allowed to react at room temperature for 12 h. After TLC monitoring of the reaction, the solvent was evaporated to dryness, and the crude product was dissolved in EA. The organic phase was washed with water, dried, and then pumped for 10 min using an oil pump to obtain 0.83 g of pure 3-(difluoromethyl)-1-methyl-5-(3-(pentafluorosulfanyl)phenoxy)-1H-pyrazole-4-carboxylic acid. MS m / z (ESI): 395.3 [M+H] + .

[0151] Step 3: Synthesis of methyl 4-(1-(3-(difluoromethyl)-1-methyl-5-(3-(pentafluorosulfanyl)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoate

[0152] 3-(Difluoromethyl)-1-methyl-5-(3-(pentafluorosulfanyl)phenoxy)-1H-pyrazole-4-carboxylic acid (0.83 g, 2.11 mmol) was dissolved in dry DMF (6 mL). HATU (0.96 g, 2.53 mmol) was added under ice-cooling, followed by DIEA (0.82 g, 6.33 mmol). After stirring at room temperature for 10-30 min, (S)-methyl 4-(1-aminoethyl)benzoate (0.42 g, 2.32 mmol) was added. After reacting at room temperature for 1 h, the reaction progress was monitored by TLC. After completion of the reaction, the system was poured into ice water to precipitate a solid, which was dissolved in EA and dried by spin drying. The crude product was purified by silica gel column chromatography using EA / PE = 1:3 to obtain 1.04 g of pure product, methyl 4-(1-(3-(difluoromethyl)-1-methyl-5-(3-(pentafluorosulfanyl)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoate. MS m / z (ESI): 556.5 [M+H] + .

[0153] Step 4: Synthesis of 4-(1-(3-(difluoromethyl)-1-methyl-5-(3-(pentafluorosulfanyl)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid

[0154] Methyl 4-(1-(3-(difluoromethyl)-1-methyl-5-(3-(pentafluorosulfanyl)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoate (1.04 g, 1.87 mmol) was dissolved in THF / H₂O (3:1, 12 mL). Lithium hydroxide (0.09 g, 3.74 mmol) was added and stirred at 35°C for 16 h. The reaction progress was monitored by TLC. After the reaction was complete, the solvent was evaporated, water was added, and the pH was adjusted to approximately 2-3 with dilute hydrochloric acid. A white solid precipitated during the reaction, which was filtered and dissolved in EA. The aqueous phase was extracted twice with EA, and the combined organic phases were dried and evaporated. The crude product was purified by silica gel column chromatography using EA / PE = 1:5 to obtain 0.55 g of pure product 4-(1-(3-(difluoromethyl)-1-methyl-5-(3-(pentafluorosulfanyl)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound 1). MS m / z (ESI): 542.4 [M+H] + .

[0155] 1H NMR (500MHz, DMSO) δ12.79 (s, 1H), 8.16 (d, J = 7.4Hz, 1H), 7.75 (d, J = 1.8Hz, 2H), 7.70 (d, J = 2.2Hz 2H), 7.62 (t, J = 8.3Hz 1H),7.22(m,1H),7.12(m,1H),7.11(m,1H),7.09(m,1H),4.97(m,1H),3.77(s,3H),1.17(m,3H).

[0156] Example 2

[0157] Using a method similar to that of Example 1, compound 2 was prepared.

[0158]

[0159] Example 3

[0160] Using a method similar to that of Example 1, compound 3 was prepared.

[0161]

[0162] Biological activity test

[0163] (a) Radioligand EP4 receptor binding assay:

[0164] Experimental Methods: 8,000 Flpin-CHO-EP4 cells / well were seeded into 384-well plates (6007680-50, PE) in assay buffer (1X HBSS + 20 mM HEPES + 0.1% BSA + 500 μM IBMX). An 8X compound working solution was prepared in assay buffer. According to the plate map, 2.5 μL of the 8X compound working solution was added to each well of the plate and incubated at 37°C for 10 min. 8X PGE2 (400 nM) was prepared in assay buffer. 2.5 μL of 8X PGE2 was added to each well of the plate and incubated at 37°C for 30 min. Eu-cAMP tracer was diluted (1 / 50) in lysis buffer and 10 μL was added to each well of the plate. Ulight-anti-cAMP was diluted (1 / 150) in lysis buffer and 10 μL was added to each well of the plate. Incubation was carried out at room temperature for 1 h. The signal values ​​at wavelengths of 665 nm and 615 nm were read on an Envision 2105 plate reader. The results are shown in Table 1.

[0165] Table 1

[0166]

[0167]

[0168] The test showed that the compounds of the examples of the present invention have excellent EP4 inhibitory activity.

[0169] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. A compound or a pharmaceutically acceptable salt thereof, characterized in that: The compound is selected from the group consisting of:

2. A pharmaceutical composition, characterized in that The invention comprises the compound according to claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.

3. Use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 2, in the preparation of a medicament for inhibiting EP4 receptor activity in a cell or a subject.

4. Use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 2, in the preparation of a medicament for preventing and / or treating diseases associated with EP4 receptors.

5. The use according to claim 4, characterized in that The EP4 receptor-related disease is selected from the group consisting of acute and chronic pain, osteoarthritis, rheumatoid arthritis and cancer.

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