WO2022161422A1 - 杂环酰胺衍生物及其制备方法和应用 - Google Patents

杂环酰胺衍生物及其制备方法和应用 Download PDF

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WO2022161422A1
WO2022161422A1 PCT/CN2022/074184 CN2022074184W WO2022161422A1 WO 2022161422 A1 WO2022161422 A1 WO 2022161422A1 CN 2022074184 W CN2022074184 W CN 2022074184W WO 2022161422 A1 WO2022161422 A1 WO 2022161422A1
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compound
group
substituted
unsubstituted
alkyl
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PCT/CN2022/074184
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English (en)
French (fr)
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程辉敏
温晓明
张佩宇
刘志强
罗岚
赖力鹏
马健
温书豪
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深圳晶泰科技有限公司
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Priority to EP22745295.0A priority Critical patent/EP4286390A1/en
Priority to CN202280012166.8A priority patent/CN116783201A/zh
Priority to US18/274,548 priority patent/US20230399339A1/en
Publication of WO2022161422A1 publication Critical patent/WO2022161422A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the invention belongs to the field of medicinal chemistry, and in particular relates to a heterocyclic amide derivative and a preparation method and application thereof.
  • Prostaglandins are mediators that trigger pain, fever, and other symptoms associated with inflammation.
  • Prostaglandin E 2 (PGE 2 ) is the major metabolite of arachidonic acid involved in inflammation.
  • prostaglandin E 2 is also 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, angiogenesis and so on.
  • the four subtypes of prostaglandin E2 receptors exhibit different pharmacological properties.
  • the EP 4 receptor is characterized by the longest intracellular C-terminal loop when compared to other prostanoid receptors. EP 4 receptors are coupled to G proteins and mediate increased cyclic adenosine monophosphate concentrations. The expression of the EP 4 receptor is controlled by various physiological and pathophysiological processes, as the receptor is involved in ovulation and fertilization, induction of bone formation, T cell factor signaling, prevention of inflammatory bowel disease, promotion of Langerhans cell migration and maturation, and mediates joint inflammation as well as other processes in a collagen-induced arthritis model.
  • the compounds disclosed herein are expected to be therapeutically useful in the treatment of EP4 receptor-mediated diseases or disorders in mammals, including humans, including acute and chronic pain, osteoarthritis, rheumatoid arthritis, and cancer.
  • the object of the present invention is to provide a new class of novel compounds with EP 4 receptor inhibitory activity and/or good pharmacodynamic/pharmacokinetic properties that can be used as EP 4 receptor antagonists and pharmaceutically acceptable salts thereof, and pharmaceutical compositions using them as active ingredients, and their use in the treatment or alleviation of EP 4 receptor related diseases such as prostaglandin EP 4 receptor mediated diseases.
  • the first aspect of the present invention provides a compound of formula I or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, isotopic compound or prodrug thereof;
  • R 1 is independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 3-6 cycloalkyl;
  • R 2 and R 3 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 3-6 cycloalkyl; alternatively, R 2 and R 3 and attached thereto
  • the carbon atoms together form a C 3-6 carbocyclic ring or a 3- to 6-membered heterocycle; the heterocycle contains one or two ring members each independently selected from S, O or NR b ; and, the C 3-6 carbon
  • the ring or 3- to 6-membered heterocycle is optionally substituted with one or more R1;
  • Each R b is independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted C 6- 10 aryl, substituted or unsubstituted 5- to 6-membered heteroaryl, -C(O)R c , -S(O) 2 R c ;
  • Each R c is independently selected from the group consisting of substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 3-6 carbocycle, substituted or unsubstituted 3- to 6-membered heterocycle, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl;
  • R 4 and R 5 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1-3 alkyl; alternatively, R 4 and R 5 and the carbon atom to which they are attached together constitute a substituted or unsubstituted C 3-6 Carbocycle (e.g. cyclopropyl);
  • R 6 represents none or a group selected from the group consisting of halogen, cyano, haloalkyl (eg trifluoromethyl);
  • substitution means that one or more (eg 1, 2 or 3) hydrogens in the group are replaced by a substituent selected from the group consisting of halogen (eg F), C 1-4 alkyl , C 1-4 haloalkyl.
  • the substituted or unsubstituted C 1-6 alkyl is C 1-6 alkyl or C 1-6 haloalkyl; preferably, it is C 1-6 alkyl or C 1-6 6 Fluoroalkyl.
  • the substituted or unsubstituted C 3-6 cycloalkyl is C 3-6 cycloalkyl or C 3-6 halogenated cycloalkyl; preferably, it is C 3-6 alkane or C 3-6 fluorocycloalkyl.
  • R 1 is independently selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 fluorocycloalkyl, C 1-6 fluoro alkyl;
  • R 2 and R 3 are each independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 fluorocycloalkyl, C 1-6 fluoroalkyl; alternatively, R 2 and R and the carbon atoms connected to it together form a C 3-6 carbocyclic ring or a 3- to 6-membered heterocyclic ring; wherein, the heterocyclic ring comprises one or two ring members independently selected from S, O or NR b ; And, the C 3-6 carbocyclic ring or 3- to 6-membered heterocyclic ring is also optionally substituted by R 1 ;
  • R b is selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 fluorocycloalkyl, C 1-6 fluoroalkyl, C 6-10 aryl, 5 to 10-membered heteroaryl, C(O)-C 1-6 alkyl, C(O)-C 6-10 aryl, S(O) 2 -C 1-6 alkyl, S(O) 2 -C 6-10 aryl;
  • R 4 and R 5 are each independently hydrogen or C 1-3 alkyl
  • R 6 represents none or a substituent selected from the group consisting of halogen, cyano, trifluoromethyl.
  • R 1 is selected from the following group: hydrogen, halogen, C 1-6 alkyl, C 3-6 cycloalkyl;
  • R 2 and R 3 are each independently selected from hydrogen, C 1-6 alkyl, or, R 2 and R 3 and the carbon atoms connected to them together form a cyclopropyl group.
  • R 4 and R 5 are each independently hydrogen or methyl.
  • R 6 when R 6 is not none, R 6 is located at the ortho or meta position of -SF 5 .
  • R 6 represents none or a substituent selected from the group consisting of halogen.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R b and R c are each independently corresponding to the example compounds (as listed in Table 1). the group.
  • the compound of formula I or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, isotopic compound or prodrug thereof is selected from the group consisting of:
  • a pharmaceutical composition comprising a compound of formula I as described in the first aspect or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, isotopic compound thereof or prodrug, and a pharmaceutically acceptable carrier or diluent.
  • a compound of formula I as described in the first aspect or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, isotopic compound or prodrug thereof, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, isotopic compound or prodrug thereof.
  • the pharmaceutical composition described in the second aspect is used in the preparation of (i) a medicament for inhibiting the activity of EP 4 receptors and/or (ii) a medicament for treating or preventing diseases related to EP 4 receptors and/or (iii) Use in EP 4 receptor antagonists.
  • the EP 4 receptor-related diseases include diseases mediated by prostaglandin E2 and/or prostaglandin EP 4 receptors.
  • the EP 4 receptor-related diseases include: acute and chronic pain, osteoarthritis, rheumatoid arthritis, cancer, or a combination thereof.
  • a method of treating or preventing EP 4 receptor related diseases comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I as described in the first aspect or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, isotopic compound or prodrug thereof, or a pharmaceutical composition as described in the second aspect.
  • the subject in need refers to a subject identified or diagnosed as having an EP 4 receptor-related disease.
  • a method for inhibiting EP4 receptor activity in a cell or a subject comprising contacting the cell or administering to the subject a first A compound of formula I or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, isotopic compound or prodrug thereof of the aspect or a pharmaceutical composition of the second aspect.
  • the cells are mammalian cells.
  • the method when the method is used to inhibit cells, the method is non-therapeutic in vitro.
  • the subject is a mammal, preferably a human.
  • the present inventors unexpectedly found a class of compounds with novel structures that have better EP 4 receptor inhibitory activity.
  • the inventors also found that these compounds with novel structures have good pharmacodynamic/pharmacokinetic properties. On this basis, the present invention has been completed.
  • substituents When substituents are described by conventional chemical formulae written from left to right, the substituents also include the chemically equivalent substituents obtained when the structural formula is written from right to left. For example, -CH2O- is equivalent to -OCH2- .
  • alkyl by itself or as part of another substituent refers to a straight or branched chain hydrocarbon group having the specified number of carbon atoms (ie, C1-6 refers to one to six carbon atoms) .
  • the alkyl group generally contains 1-6 carbon atoms, ie, a C1-6 alkyl group.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, and similar alkyl groups.
  • One or more (eg, 1-4) positions in the alkyl group can be optionally substituted, and such substitution can occur at any position in the group.
  • haloalkyl is meant to include branched and straight chain saturated aliphatic hydrocarbon groups having the indicated number of carbon atoms and substituted with one or more halogens.
  • haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoroethyl propyl and heptachloropropyl.
  • haloalkyl groups also include "fluoroalkyl groups” having branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms and substituted with one or more fluorine atoms.
  • fluoroalkyl or “fluoroalkyl” refers to an alkyl group as defined above wherein one or more hydrogen atoms are replaced by fluorine atoms.
  • alkoxy refers to a straight or branched chain or cyclic alkyl group linked through an ether oxygen from which the free valences originate. Representative examples include, but are not limited to: methoxy, ethoxy, propoxy, isopropoxy, butoxy, and the like. Preferably it is C 1-3 alkoxy.
  • fluoroalkoxy refers to an alkoxy group as defined above wherein one or more hydrogen atoms are replaced by fluorine atoms.
  • haloalkoxy refers to -O-haloalkyl, including straight or branched or cyclic haloalkoxy, representative examples include (but are not limited to): fluoromethoxy, difluoromethoxy, Trifluoromethoxy, trichloromethoxy, pentafluoroethoxy, pentachloroethoxy.
  • cycloalkyl or “carbocycle” is meant to include saturated monocyclic, bicyclic, or polycyclic cyclic alkyl groups, such as C3-8 or C3-12 cycloalkyl groups.
  • C 3-8 cycloalkyl is meant to include C 3 , C 4 , C 5 , C 6 , C 7 , or C 8 cycloalkyl.
  • Cycloalkyl groups may also include cycloalkyl groups with structures such as spiro, bridged, and paracyclic structures.
  • Representative cycloalkyl groups of the present invention include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and norbornyl.
  • C 5-12 fused bicyclic rings include C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , C 12 bicycloalkyl groups, including but not limited to: Wait.
  • C 5-12 spirobicyclic ring refers to include C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , C 12 bicycloalkyl, including but not limited to: Wait.
  • the cycloalkyl group is preferably a monocyclic cycloalkyl group containing 3 to 6 carbon atoms (ie, C 3-6 ), such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • aryl or “aryl”, alone or as part of a group such as “aralkyl”, “aralkoxy” or “aryloxyalkyl”, refers to groups having a total of 5 to 15 A monocyclic, bicyclic or tricyclic ring system (preferably a 6-10 membered aromatic ring) of ring members (or ring atoms), wherein at least one ring in the system is aromatic and wherein each ring in the system is aromatic A ring contains 3 to 7 ring members. "Aryl” may be substituted or unsubstituted.
  • aryl refers to an aromatic ring system including, but not limited to, phenyl, biphenyl, indanyl, 1-naphthyl, 2-naphthyl, and tetrahydronaphthalene base.
  • a fused aryl group can be attached to another group at a suitable position on the cycloalkyl or aromatic ring.
  • the connecting lines drawn from the ring system indicate that the bond may be attached to any suitable ring atom.
  • heteroaryl refers to a heteroaromatic system comprising 1-4 heteroatoms, 5-14 ring atoms, wherein the heteroatoms are selected from oxygen, nitrogen and sulfur.
  • Heteroaryl is preferably a 5- to 10-membered ring, more preferably 5- or 6-membered, such as pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl , furanyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl and tetrazolyl, etc.
  • Heteroaryl may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy , haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, halogen, amino, nitro, hydroxyl, mercapto, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkane Thio, oxo, carboxyl and carboxylate groups.
  • heterocycloalkyl or “heterocycle” refers to a cycloalkyl group containing one to five heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternary Ammonized.
  • Heterocycloalkyl can be a monocyclic, bicyclic or polycyclic ring system.
  • heterocycloalkyl examples include pyrrolidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyranone, tetrahydrofuran, tetrahydrothiophene, quinuclidine, etc.
  • a heterocycloalkyl group can be attached to the remainder of the molecule through a ring carbon or a heteroatom.
  • hydroxy refers to -OH.
  • nitro refers to -NO2 .
  • amino refers to -NH2 .
  • halo or halogen includes fluorine, chlorine, bromine and iodine.
  • cyano refers to -CN.
  • each of the above-mentioned alkyl groups, haloalkyl groups, aryl groups, heteroaryl groups, alkenyl groups, alkynyl groups and the like may be substituted or unsubstituted.
  • substituted refers to the replacement of one or more hydrogen atoms on a specified group with a specified substituent.
  • substituents are those described correspondingly in the preceding paragraphs, or the substituents appearing in the various examples.
  • a substituted group may have at any substitutable position of the group a substituent selected from a particular group, which may be the same or different at each position. It will be understood by those skilled in the art that combinations of substituents contemplated by the present invention are those that are stable or chemically achievable.
  • substituents such as alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring may be optionally substituted.
  • the substituents are for example (but not limited to): halogen, hydroxyl, cyano, carboxyl (-COOH), C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 Cycloalkyl, 3-12-membered heterocyclic group, aryl, heteroaryl, C 1-8 aldehyde group, C 2-10 acyl group, C 2-10 ester group, amine group, C 1-6 alkoxy group, C 1-10 sulfonyl group, C 1-6 ureido group and the like.
  • a substituent is a non-terminal substituent, it is a subgroup of the corresponding group, for example, alkyl corresponds to alkylene, cycloalkyl corresponds to cycloalkylene, heterocyclyl to heterocyclylene, alkoxy to Alkyleneoxy, etc.
  • EP4 antagonist refers to a compound that inhibits or blocks cellular signaling triggered by the interaction of PGE2 with the EP4 receptor , including but not limited to compounds of formula (I) described herein.
  • treatment refers to reducing, inhibiting and/or reversing the progression of cancer in a subject in need thereof.
  • treatment includes any indicator of successful treatment or amelioration of cancer, including any objective or subjective parameter, such as reduction; remission; alleviation of symptoms or making the subject more tolerant of injury, pathology, or condition; delaying or slowing the rate of progression, and the like.
  • Measures of treatment or improvement can be based, for example, on the results of physical, pathological, and/or diagnostic tests known in the art.
  • Treatment can also refer to reducing the occurrence or onset of cancer, or its recurrence (eg, prolongation of remission), compared to what would have occurred if no measures were taken.
  • cancer can include cancers that are the result of inherited mutations in genes.
  • examples of such cancers include, but are not limited to, breast cancer, cancers associated with Lee-Fraumeni syndrome, such as childhood sarcoma, leukemia, and brain cancer, cancers associated with Lynch syndrome, such as colon cancer, bile duct cancer, Brain, Endometrial, Kidney, Ovarian, Pancreatic, Small Intestine, Stomach and Ureteral, Lung, Melanoma, Prostate, Retinoblastoma, Thyroid, and Uterine Cancers.
  • cancer can be the result of acquired mutations, eg, mutations caused by diet, environment, and/or lifestyle, or somatic mutations.
  • cancers may include, but are not limited to, adrenal cancer, adrenocortical cancer, bladder cancer, brain cancer, primary brain cancer, glioma, glioblastoma, breast cancer, cervical cancer, colon cancer (non- Limiting examples include colorectal cancer such as colon adenocarcinoma and colon cancer), endometrial cancer, epidermal cancer, esophagus cancer, gallbladder cancer, genitourinary tract cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer (non-limiting examples include adenocarcinoma, small cell lung cancer and non-small cell lung cancer), lymphoma (non-limiting examples include B-cell lymphoma, T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma), melanoma, malignant Melanoma, malignant carcinoid, malignant pancreatic insulinoma, myeloma, multiple myeloma,
  • 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, isotope thereof Compounds (eg, deuterated compounds) or prodrugs. The term also includes racemates, optical isomers.
  • the compound of the present invention has the structure shown in formula I
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 6 , R b , R c are as defined above.
  • the salts that the compounds may form also belong to the scope of the present invention.
  • the compounds of the present invention are understood to include their salts.
  • the term “salt” refers to salts formed with inorganic or organic acids and bases in the acid or basic form.
  • a compound of the present invention contains a basic moiety, which includes, but is not limited to, pyridine or imidazole, and when it contains an acidic moiety, including, but is not limited to, a carboxylic acid
  • the zwitterion inner salt
  • compositions of the present invention may form salts, for example, by reacting Compound I with an amount, eg, an equivalent, of an acid or base, salting out in a medium, or lyophilizing in an aqueous solution.
  • the compounds of the present invention contain basic moieties or moieties, including but not limited to amines or pyridine or imidazole rings, that may form salts with organic or inorganic acids.
  • Typical acids that can form salts include acetates (eg with acetic acid or trihaloacetic acids such as trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates , benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentane propionate, diglycolate, lauryl sulfate, Ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, caproate, hydrochloride, hydrobromide, hydroiodate, isethionate (eg, 2-hydroxyethanesulfonate), lac
  • Certain compounds of the present invention may contain acidic moieties or moieties, including but not limited to carboxylic acids, which may form salts with various organic or inorganic bases.
  • Typical base-formed salts include ammonium salts, alkali metal salts such as sodium, lithium, potassium salts, alkaline earth metal salts such as calcium, magnesium salts, and salts formed from organic bases (eg, organic amines) such as benzathine, dicyclohexylamine , Hepamine (salt with N,N-bis(dehydroabietyl)ethylenediamine), N-methyl-D-glucosamine, N-methyl-D-glucosamide, tert-butyl Amines, and salts with amino acids such as arginine, lysine, and the like.
  • Basic nitrogen-containing groups can be combined with halide quaternary ammonium salts, such as small molecule alkyl halides (such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides), dialkyl sulfates (eg, dimethyl, diethyl, dibutyl, and dipentyl sulfate), long-chain halides (eg, decyl, dodecyl, tetradecyl, and tetradecyl chlorides, bromides) and iodides), aralkyl halides (such as benzyl and phenyl bromides), and the like.
  • small halides such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides
  • dialkyl sulfates eg, dimethyl, diethyl, dibutyl, and dipentyl sulfate
  • Prodrugs and solvates of the compounds of the present invention are also contemplated.
  • the term "prodrug” as used herein refers to a compound that undergoes chemical transformation through a metabolic or chemical process to yield the compound, salt, or solvate of the present invention in the treatment of a related disease.
  • the compounds of the present invention include solvates, such as hydrates.
  • solvate refers to a complex in which a compound of the present invention coordinates with solvent molecules to form a complex in specified proportions.
  • hydrate refers to a complex formed by the coordination of a compound of the present invention with water, such as a monohydrate.
  • the compounds, salts or solvates of the present invention may exist in tautomeric forms (eg amides and imine ethers). All of these tautomers are part of the present invention.
  • Stereoisomers of all compounds are contemplated by the present invention.
  • Individual stereoisomers of the compounds of the present invention may not exist concurrently with other isomers (eg, as a pure or substantially pure optical isomer with specific activity), or may be mixtures such as Racemates, or mixtures with all other stereoisomers or a part thereof.
  • the chiral center of the present invention has two configurations, S or R, as defined by the 1974 recommendation of the International Union of Theoretical and Applied Chemistry (IUPAC).
  • the racemic form can be resolved by physical methods, such as fractional crystallization, or by derivatization to diastereomer separation crystallization, or by chiral column chromatography.
  • the individual optical isomers can be obtained from the racemates by suitable methods, including but not limited to conventional methods, such as salt formation with an optically active acid followed by crystallization.
  • the compound in the present invention the compound obtained by successively preparing, isolating and purifying the compound whose weight content is equal to or greater than 90%, for example, equal to or greater than 95%, equal to or greater than 99% ("very pure” compound), is described in the text List. Herein such "very pure" compounds of the invention are also intended to be part of the invention.
  • Certain compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention covers all compounds including their cis and trans isomers, R and S enantiomers, diastereomers, (D) isomers, (L) isomers, Spin mixtures and other mixtures. Additionally asymmetric carbon atoms may represent substituents such as alkyl groups. All isomers, as well as mixtures thereof, are encompassed by the present invention.
  • a mixture of isomers may contain isomers in various ratios.
  • isomers in various ratios.
  • Similar ratios readily understood by those of ordinary skill in the art, as well as ratios that are mixtures of more complex isomers, are also within the scope of the invention.
  • the present invention also includes isotopically labeled compounds (also referred to as isotopic compounds), which are equivalent to the original compounds disclosed herein. In practice, however, it usually occurs that one or more atoms are replaced by atoms with different atomic weights or mass numbers.
  • isotopes that may be listed as 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, respectively , 17 O, 31 P, 32 P, 35 S, 18 F and 36 Cl.
  • Isotopically-labeled compounds can be prepared by conventional methods by substituting readily available isotopically-labeled reagents for non-isotopically labeled reagents using the protocols disclosed in the Examples.
  • a synthesis of a particular enantiomer of a compound of the present invention can be prepared by asymmetric synthesis, or by derivatization with a chiral auxiliary, separation of the resulting diastereomeric mixture, and removal of the chiral auxiliary to obtain pure enantiomer.
  • a suitable optically active acid or base can be used to form diastereomeric salts with it, and then the diastereomeric salts can be formed by separation crystallization or chromatography, etc. Separation by conventional means then yields the pure enantiomer.
  • the compounds of the present invention may be taken with any number of substituents or functional groups to extend their encompassing scope.
  • the general formula for including substituents in the formulations of the present invention refers to the replacement of a hydrogen radical with a specified structural substituent.
  • the substituents may be the same or different at each position.
  • substituted as used herein includes all permissible substitutions of organic compounds.
  • permissible substituents include acyclic, cyclic, branched unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic organic compounds.
  • heteroatom nitrogen may have hydrogen substituents or any permissible organic compound as described above to supplement its valence.
  • the present invention is not intended to limit in any way the permitted substituted organic compounds.
  • the present invention contemplates that the combination of substituents and variable groups is well suited for the treatment of diseases in the form of stable compounds.
  • the term "stable" refers to compounds that are stable enough to be detected for a sufficient period of time to maintain the structural integrity of the compound, preferably for a sufficient period of time, as used herein for the above-mentioned purposes.
  • 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 conveniently prepared by optionally 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 to which the present invention belongs.
  • each reaction is usually carried out at room temperature to 90° C. under the protection of inert gas and in a suitable solvent, and the reaction time is usually 2-24 hours.
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 6 have the definitions described in the present invention.
  • the method includes the following steps:
  • methyl azidoacetate reacts with the aldehyde group in compound 1-1 to form compound 1-2; preferably, the reaction is carried out in the presence of a base, more preferably, the base is NaOMe (sodium methoxide);
  • compound 1-6 is catalyzed by palladium to generate compound 1-7;
  • the palladium catalyst used is PdCl 2 dppf, and/or the temperature of the reaction is 75 ⁇ 5°C;
  • reaction solvent reaction temperature, reaction time, catalyst, etc.
  • reaction time reaction time, catalyst, etc.
  • compositions and methods of administration are provided.
  • the compound of the present invention is an excellent EP 4 receptor antagonist
  • the compound of the present invention and its various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates, solvates, stereoisomers, isotopes can be used for the treatment or prevention of EP 4 receptor-related diseases such as prostaglandin E 2 /EP 4 receptor-mediated diseases.
  • the present invention includes a method of treating inflammatory diseases susceptible to non-steroidal anti-inflammatory drugs, the method comprising administering to a patient in need of such treatment a non-toxic therapeutically effective amount of a compound of formula I. Included in this embodiment are the above methods wherein the patient is also at risk for thrombotic cardiovascular events and/or gastrointestinal ulcers/bleeding.
  • Another embodiment of the present invention includes a method of treating prostaglandin E2-mediated diseases that are advantageously treated by selectively antagonizing EP 4 activators rather than by inhibiting COX-1/COX-2 activators for treatment comprising administering to a patient in need of such treatment a non-toxic and effective amount of a compound of formula I. Included in this embodiment is the above method wherein the patient is also at risk for a thrombotic cardiovascular event.
  • the compounds described herein can be used in cancer immunotherapy targeting host immune suppressor cells in the tumor microenvironment, which may be myeloid or lymphoid.
  • the compounds described herein are useful in the treatment of patients with various tumor types, including those with high levels of myeloid infiltrates. This level of myeloid infiltration can be determined, for example, based on The Cancer Genome Atlas (TCGA) and other sources.
  • TCGA The Cancer Genome Atlas
  • Such tumor types can also be identified based on protein or gene (eg, mRNA) expression analysis.
  • Tumor types include but are not limited to pancreatic adenocarcinoma, renal clear cell carcinoma, squamous cell carcinoma of the head and neck (SCCHN), non-small cell lung cancer (NSCLC), colorectal cancer (CRC), hepatocellular carcinoma (HCC), serous Epithelial ovarian cancer, cervical cancer, transitional cell bladder cancer, skin cancer, glioblastoma, kidney cancer, prostate cancer. Pancreatic cancer and triple negative breast cancer (TNBC).
  • SCCHN head and neck
  • NSCLC non-small cell lung cancer
  • CRC colorectal cancer
  • HCC hepatocellular carcinoma
  • TNBC triple negative breast cancer
  • the compounds of the present invention can be used to treat or prevent tumor formation in a subject in need of such treatment or prevention.
  • Treatment includes partial or complete inhibition of tumor formation, spread or metastasis, and partial or complete destruction of tumor cells.
  • prevention includes the complete prevention of the onset of clinically apparent neoplasia or the prevention of the onset of the clinically apparent stage of neoplasia in at-risk individuals.
  • the definition is also intended to include preventing the initiation of malignant cells or arresting or reversing the progression of pre-malignant cells to malignant cells. This includes preventive treatment for people at risk of developing neoplasms.
  • subject for therapeutic purposes includes any human or mammalian subject with any known tumor, and preferably is a human subject.
  • the subject is any human or animal subject, and preferably a human subject at risk of developing a tumor. Subjects may be at risk due to exposure to carcinogens, genetic predisposition to tumors, etc.
  • the compounds of general formula (I) may be used in combination with other drugs known to treat or ameliorate similar conditions.
  • the mode and dosage of the original drug may remain unchanged, while the compound of formula I is administered concurrently or subsequently.
  • a pharmaceutical composition containing both one or more known drugs and the compound of formula I may preferably be used.
  • Drug combinations also include administration of a compound of formula I with one or more other known drugs at overlapping time periods.
  • the dose of the compound of formula I or known drugs may be lower than the doses of the compounds of formula I administered alone.
  • anti-CTLA4 cytotoxic T-lymphocyte antigen 4
  • anti-PDL1 antibodies to programmed death ligand 1
  • anti-PD1 programmed cell death Antibody to protein 1
  • anti-metabolites have been detected.
  • the present invention also includes a method of treating cancer with an effective amount of a compound of the present invention or treating cancer using an effective amount of a compound of the present invention in combination with an effective amount of radiation; an antibody against cytotoxic T-lymphocyte antigen 4 (anti- CTLA4); anti-programmed death ligand 1 antibody (anti-PDL1); anti-programmed cell death protein 1 antibody (anti-PD1); indoleamine-2,3-dioxygenase (IDO) inhibitor; amino acid-2,3-dioxygenase (TDO) inhibitor; and antimetabolite.
  • an antibody against cytotoxic T-lymphocyte antigen 4 anti-CTLA4
  • anti-PDL1 anti-programmed death ligand 1 antibody
  • anti-PD1 anti-programmed cell death protein 1 antibody
  • IDO indoleamine-2,3-dioxygenase
  • TDO amino acid-2,3-dioxygenase
  • These antibodies may be selected from but not limited to MDX-010 (ipilimumab, Bristol-Myers Squibb), CP-675,206 (tremelimumab, Pfizer), MPDL 3280 A (Roche), MDX-1106 (nivolumab, Bristol-Myers Squibb), labrolizumab (Merck ) and pembrolizumab (Merck).
  • “Pharmaceutically acceptable carrier” refers to one or more compatible solid or liquid filler or gelling substances which are suitable for human use and which must be of sufficient purity and sufficiently low toxicity. "Compatibility” as used herein means that the components of the composition can be admixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds.
  • Examples of pharmaceutically acceptable carrier moieties include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid) , magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavors, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • cellulose and its derivatives such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.
  • gelatin such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.
  • “Pharmaceutically acceptable excipient” and “pharmaceutically acceptable carrier” refer to substances that aid in the formulation and/or administration and/or absorption of an active agent by an individual, and may be included in the compositions of the present disclosure without causing significant adverse toxicological effects in the individual.
  • Non-limiting examples of pharmaceutically acceptable carriers and excipients include water, NaCl, physiological saline solution, lactated Ringer's, conventional sucrose, conventional dextrose, binders, fillers, disintegrants, lubricants, Coatings, sweeteners, flavors, saline solutions (eg Ringer's solution), alcohols, oils, gelatin, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethylcellulose, polyvinylpyrrole alkanes and pigments, etc.
  • Such formulations can be sterilized and, if desired, with adjuvants such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers that do not deleteriously react with or interfere with the activity of the compounds provided herein , a mixture of salts, buffers, colorants and/or fragrances that affect osmotic pressure.
  • adjuvants such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers that do not deleteriously react with or interfere with the activity of the compounds provided herein , a mixture of salts, buffers, colorants and/or fragrances that affect osmotic pressure.
  • compositions of the present invention may be in solid or liquid form.
  • the drug containing the active ingredient can be in a suitable oral dosage form, such as tablet, troche, lozenge, water-soluble or oily suspension, dispersible powder or granule, emulsion, hard or soft capsule or syrup or elixir.
  • Medicaments for oral use may be prepared according to the known procedures of the pharmaceutical ingredient manufacturers, and these compositions may include one or more of the following agents, such as sweetening, flavoring, coloring and protecting agents, in order to provide elegance and Delicious medicinal preparation.
  • Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients examples include, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating, disintegrating agents such as corn starch or alginic acid; binding agents such as starch, Gelatin or acacia, and lubricants such as magnesium stearate, stearic acid, or talc.
  • the tablet may be uncoated or coated to delay degradation and absorption in the gastrointestinal tract, thereby maintaining activity over a longer period of time.
  • compositions of the present invention can be administered by parenteral, oral, buccal, sublingual, nasal, rectal, topical, or transdermal administration.
  • Pharmaceutical compositions for oral administration are generally preferred.
  • compositions of the present invention suitable for oral administration will typically be discrete units in solid form, such as in the form of tablets, capsules, cachets, powders, granules, lozenges, patches, suppositories, pills, or In liquid form, eg, liquid preparations, injectable or infusible solutions or suspensions.
  • the precise amount of compound to provide a therapeutically effective amount of the compound to an individual will depend on the mode of administration, the type and severity of the disease and/or disorder, and the characteristics of the individual, such as general health, age, sex, weight, and tolerance to the drug . Those of ordinary skill in the art will be able to determine appropriate dosages 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.
  • Appropriate dosages are known for the approved therapeutic agents and can be adjusted by one of ordinary skill in the art according to the individual's condition, the type of disorder being treated, and the amount of the compound of the invention used, for example, as reported in the literature and in Dosage recommended in Physician's Desk Reference (57th ed., 2003).
  • the content of the active ingredient is usually 0.000001-1 wt %, preferably 0.00001-1 wt %, and most preferably 0.0001-0.1 wt %.
  • subjects to which the pharmaceutical composition or therapeutic agent of the present invention is administered include mammals (eg, humans, mice, rats, hamsters, rabbits, cats, dogs, cows, sheep, monkeys, etc.).
  • the present invention also provides a preparation method of a pharmaceutical composition, comprising the steps of: mixing a pharmaceutically acceptable carrier with the compound of general formula (I) or its crystal form, pharmaceutically acceptable salt, hydrate or The solvates are mixed to form the pharmaceutical composition.
  • the present invention also provides a method of treatment, which comprises the steps of: administering the compound of general formula (I), or a crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, as described in the present invention to a subject in need of treatment , or administer the pharmaceutical composition of the present invention for selectively inhibiting EP 4 receptors.
  • the compound of the present invention has excellent inhibitory activity on EP 4 receptor, and has better selective inhibitory activity on EP 4 receptor;
  • the compounds of the present invention have better pharmacodynamics, pharmacokinetic properties and druggability.
  • the structures of the compounds of the present invention were determined by nuclear magnetic resonance (NMR) and liquid chromatography-mass spectrometry (LC-MS).
  • NMR was detected using Bruker AVANCE-400 and Bruker AVANCE-500 NMR spectrometers, and the determination solvent contained deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated acetone (CD 3 COCD 3 ), deuterated chloroform (CDCl 3 ) And deuterated methanol (CD 3 OD), etc., the internal standard is tetramethylsilane (TMS), and the chemical shift is measured in units of one millionth (ppm).
  • DMSO-d 6 deuterated dimethyl sulfoxide
  • CD 3 COCD 3 deuterated acetone
  • CDCl 3 deuterated chloroform
  • CD 3 OD deuterated methanol
  • TMS tetramethylsilane
  • LC-MS Liquid chromatography-mass spectrometry
  • TLC silica gel plate uses Qingdao GF254 silica gel plate, TLC adopts 0.15-0.20mm, and preparative thin-layer chromatography adopts 0.4mm-0.5mm.
  • Column chromatography generally uses Qingdao silica gel 200-300 mesh silica gel as a carrier.
  • the starting materials in the examples of the present invention are all known and commercially available, or can be synthesized by adopting or according to the literature data reported in the field.
  • THF tetrahydrofuran
  • MeOH methanol
  • HCl hydrochloric acid
  • Pd(PPh 3 ) 4 palladium tetrakistriphenylphosphine
  • K 2 CO 3 potassium carbonate
  • AcOK potassium acetate
  • NaOH sodium hydroxide
  • H 2 O water
  • TEA triethylamine
  • DIEA N,N-diisopropylethylamine
  • DMF N,N-dimethylformamide
  • DMA N,N-dimethylacetamide
  • Py pyridine
  • DCE 1,2-Dichloroethane
  • DMSO dimethyl sulfoxide
  • TFA trifluoroacetic acid
  • NaBH(AcO) 3 sodium triacetylborohydride
  • Sn 2 (Bu-n) 6 hexahexylditin
  • AlCl 3 aluminum trichloride
  • CuI cuprous io
  • Step 1 Synthesis of methyl 2-azido-3-(4-bromo-5-methylthiophen-2-yl)acrylate
  • Methyl azide acetate (8.3 g, 72.8 mmol), 4-bromo-5-methylthiophene-2-carbaldehyde (5 g, 24 mmol) were dissolved in 50 mL of methanol, and at -25 °C, a methanol solution of NaOMe ( 13.5mL, 5.4M). Stir at 0 °C for 2 h, and add 50 mL of ice water. After stirring and filtering, the filter cake was washed with water and dried. Methyl 2-azido-3-(4-bromo-5-methylthiophen-2-yl)acrylate (3.6 g, 49%) was obtained and used in the next step without purification.
  • Step 2 Synthesis of methyl 3-bromo-2-methyl-4H-thiophene[3,2-b]pyrrole-5-carboxylate
  • Step 3 Synthesis of methyl 3-bromo-2-methyl-4-(4-(pentafluorothio)benzyl)-4H-thieno[3,2-b]pyrrole-5-carboxylate
  • Step 4 Synthesis of 3-bromo-2-methyl-4-(4-(pentafluorosulfanyl)benzyl)-4H-thieno[3,2-b]pyrrole-5-carboxylic acid
  • Step 6 Synthesis of methyl 2-methyl-4-(4-(pentafluorothio)benzyl)-4H-thiophene[3,2-b]pyrrole-3-carboxylate
  • Step 7 Synthesis of 2-methyl-4-(4-(pentafluorosulfanyl)benzyl)-4H-thiophene[3,2-b]pyrrole-3-carboxylic acid
  • Step 8 Synthesis of 4-(1- ⁇ [2-methyl-4-(4-(pentafluorosulfanyl)benzyl)-4H-thiophene[3,2-b]pyrrole-3-carbonyl]amino ⁇ - Cyclopropyl) methyl benzoate
  • Step 9 Synthesis of 4-(1- ⁇ [2-methyl-4-(4-(pentafluorosulfanyl)benzyl)-4H-thiophene[3,2-b]pyrrole-3-carbonyl]amino ⁇ - cyclopropyl)benzoic acid
  • Flpin-CHO-EP4 cells (8000 cells/well) were seeded into 384-well plates (6007680-50, PE) with assay buffer (1X HBSS+20mM HEPES+0.1%BSA+500 ⁇ M IBMX).
  • assay buffer (1X HBSS+20mM HEPES+0.1%BSA+500 ⁇ M IBMX).
  • 8X compound working solutions in assay buffer.
  • 8X PGE2 (400 nM) was prepared in assay buffer.
  • Add 2.5 ⁇ L of 8 X PGE2 to each well of the cell plate and incubate at 37°C for 30 minutes.
  • the Eu-cAMP tracer (1/50) was diluted with lysis buffer and 10 ⁇ l per well was added to the assay plate. Dilute Ulight-anti-cAMP (1/150) with lysis buffer and add 10 ⁇ l per well to the assay plate. Incubate for 1 h at room temperature. The 665nm and 615nm wavelength signal values were read on an Envision 2105 plate reader. The results are shown in Table 2.
  • the compounds of the present invention have excellent EP4 receptor binding activity and excellent EP4 receptor inhibitory ability.
  • the compound of the present invention has better pharmacodynamics and pharmacokinetics.

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Abstract

本发明涉及一种杂环酰胺衍生物及其制备方法和应用。具体地，涉及一种式I化合物及其制备方法和应用，包括所述化合物作为活性成分的药物组合物或其药学上可接受的盐。本发明进一步涉及式(I)化合物在用于治疗和预防EP4介导的疾病的用途。

Description

杂环酰胺衍生物及其制备方法和应用 技术领域
本发明属于医药化学领域，具体涉及一种杂环酰胺衍生物及其制备方法和应用。
背景技术
前列腺素受体及其最常用的选择性激动剂和拮抗剂的特征和治疗实用性已被广泛地研究。前列腺素是引发疼痛、发烧和其他与炎症相关症状的介质。前列腺素E 2(PGE 2)是与炎症有关的花生酸主要代谢产物。此外，前列腺素E 2还参与各种生理和/或病理症状，如痛觉过敏、子宫收缩、消化道蠕动、觉醒、胃酸分泌的抑制、血压、血小板功能、骨代谢、血管生成等等。前列腺素E 2受体四个亚型(EP 1，EP 2，EP 3和EP 4)表现出不同的药理学特性。
EP 4受体的特征在于与其他前列腺素类受体相比时具有最长的细胞内C末端环。EP 4受体与G蛋白耦联，并介导环状单磷酸腺苷浓度升高。EP 4受体的表达受各种生理性和病理生理性过程控制，因为该受体参与排卵与受精、诱导骨形成、T细胞因子信号传导、预防炎症性肠病、促进朗格汉斯细胞迁移与成熟，并且在胶原诱导的关节炎模型中介导关节炎症以及其他过程。
研究表明，EP 4受体介导的cAMP水平升高是导致免疫细胞免疫抑制的主要信号。在APCmin突变的背景下，与野生动物相比，小鼠中EP4的敲除显示可延迟肿瘤的发生，表明宿主免疫细胞中PGE 2-EP 4信号传导的促肿瘤活性。
因此，本发明公开的化合物预计对治疗包括人类的哺乳动物由EP 4受体介导的疾病或不适有治疗作用，包括急性和慢性疼痛、骨关节炎、类风湿关节炎和癌症。
综上所述，本领域仍然迫切需要能够在体外和体内均有效且可靠地抑制EP 4的新型化合物。
发明内容
本发明的目的是提供一类新型的具有EP 4受体抑制活性和/或具有良好药效学/药代动力学性能的可作为EP 4受体拮抗剂的新颖化合物及其可药用盐，和以它们作为活性成分的药物组合物，以及其在治疗或减轻EP 4受体相关疾病如前列腺素EP 4受体介导的疾病中的用途。
本发明的第一方面，提供了一种式I化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、同位素化合物或前药；
Figure PCTCN2022074184-appb-000001
其中，
R 1独立地选自下组：氢、卤素、取代或未取代的C 1-6烷基、取代或未取代的C 3-6环烷基；
R 2和R 3各自独立选自下组：氢、取代或未取代的C 1-6烷基、取代或未取代的C 3-6环烷基；或者，R 2和R 3以及与其相连的碳原子共同构成C 3-6碳环或3至6元杂环；所述杂环包含一个或两个各独立选自S、O或NR b的环成员；并且，所述C 3-6碳环或3至6元杂环任选地被一个或多个R 1取代；
R b各自独立地选自下组：氢、取代或未取代的C 1-6烷基、取代或未取代的取代或未取代的C 3-6环烷基、取代或未取代的C 6-10芳基、取代或未取代的5至6元杂芳基、-C(O)R c、-S(O) 2R c；
R c各自独立地选自下组：取代或未取代的C 1-6烷基、取代或未取代的C 3-6碳环、取代或未取代的3至6元杂环、取代或未取代的C 6-10芳基、取代或未取代的5至10元杂芳基；
R 4和R 5各自独立选自下组：氢、取代或未取代的C 1-3烷基；或者，R 4和R 5以及与其相连的碳原子共同构成取代或未取代的C 3-6碳环(如环丙基)；
R 6代表无或选自下组的基团：卤素、氰基、卤代烷基(如三氟甲基)；
除非特别说明，所述的取代是指基团中一个或多个(如1、2或3个)氢被选自下组的取代基所取代：卤素(如F)、C 1-4烷基、C 1-4卤代烷基。
在另一优选例中，所述取代或未取代的C 1-6烷基为C 1-6烷基或者C 1-6卤代烷基；较佳地，为C 1-6烷基或者C 1-6氟代烷基。
在另一优选例中，所述取代或未取代的C 3-6环烷基为C 3-6环烷基或者C 3-6卤代环烷基；较佳地，为C 3-6烷基或者C 3-6氟代环烷基。
在另一优选例中，R 1独立选自下组：氢、卤素、C 1-6烷基、C 3-6环烷基、C 3-6氟代环烷基、C 1-6氟代烷基；
R 2和R 3各自独立选自下组：氢、C 1-6烷基、C 3-6环烷基、C 3-6氟环烷基、C 1-6氟烷基；或者，R 2和R 3以及与其相连的碳原子共同构成C 3-6碳环或3至6元杂环；其中,所述杂环包含一个或两个各独立选自S、O或NR b的环成员；并且，所述C 3-6碳环或3至6元杂环还任选地被R 1取代；
R b选自下组：氢、C 1-6烷基、C 3-6环烷基、C 3-6氟环烷基、C 1-6氟烷基、C 6-10芳基、5至10元杂芳基、C(O)-C 1-6烷基、C(O)-C 6-10芳基、S(O) 2-C 1-6烷基、S(O) 2-C 6-10芳基；
R 4和R 5各自独立为氢或C 1-3烷基；
R 6代表无或选自下组的取代基：卤素、氰基、三氟甲基。
在另一优选例中，R 1选自下组：氢、卤素、C 1-6烷基、C 3-6环烷基；
在另一优选例中，R 2和R 3各自独立地选自氢、C 1-6烷基，或者，R 2和R 3以及与其相连的碳原子共同构成环丙基。
在另一优选例中，R 4和R 5各自独立地为氢或甲基。
在另一优选例中，R 6不为无时，R 6位于-SF 5的邻位或间位。
在另一优选例中，R 6代表无或选自下组的取代基：卤素。
在另一优选例中，R 1、R 2、R 3、R 4、R 5、R 6、R b和R c各自独立地为实施例化合物(如表1中所列出的化合物)中对应的基团。
在另一优选例中，所述的式I化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、同位素化合物或前药，所述化合物选自下组：
Figure PCTCN2022074184-appb-000002
在本发明的第二方面中，提供一种药物组合物，其包含如第一方面所述的式I化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、同位素化合物或前药，以及药学上可接受的载体或稀释剂。
在本发明的第三方面中，提供了一种如第一方面所述的式I化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、同位素化合物或前药或如第二方面所述的药物组合物在制备(i)用于抑制EP 4受体活性的药物和/或(ii)用于治 疗或预防与EP 4受体相关疾病的药物和/或(iii)EP 4受体拮抗剂中的用途。
在另一优选例中，所述EP 4受体相关疾病包括前列腺素E2和/或前列腺素EP 4受体介导的疾病。
在另一优选例中，所述EP 4受体相关疾病包括：急性和慢性疼痛、骨关节炎、类风湿关节炎、癌症，或其组合。
在本发明的第四方面中，提供了一种治疗或预防EP 4受体相关疾病的方法，所述方法包括给予有需要的受试者治疗有效量的如第一方面所述的式I化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、同位素化合物或前药，或如第二方面所述的药物组合物。
在另一优选例中，有需要的受试者是指被鉴定或诊断为具有EP 4受体相关疾病的受试者。
在本发明的第五方面中，提供了一种用于抑制细胞或受试者中的EP 4受体活性的方法，所述方法包括使所述细胞接触或向所述受试者施用第一方面所述的式I化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、同位素化合物或前药或第二方面所述的药物组合物的步骤。
在另一优选例中，所述细胞为哺乳动物细胞。
在另一优选例中，当所述方法用于抑制细胞时，所述方法是体外非治疗性的。
在另一优选例中，所述受试者为哺乳动物，优选为人。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
具体实施方式
本发明人经过广泛而深入的研究，意外地发现了一类具有较好的EP 4受体抑制活性的具有新颖结构的化合物。此外，发明人还发现这些具有新颖结构的化合物具有良好药效学/药代动力学性能。在此基础上，完成了本发明。
术语
在本发明中，除非特别指出，所用术语具有本领域技术人员公知的一般含义。
当通过从左向右书写的常规化学式描述取代基时，该取代基也同样包括从 右向左书写结构式时所得到的在化学上等同的取代基。举例而言，-CH 2O-等同于-OCH 2-。
如本文所用，术语“烷基”本身或作为另一取代基的一部分，是指具有指定的碳原子数的直链或支链烃基(即，C 1-6是指一个至六个碳原子)。优选地，烷基一般包含1-6个碳原子，即C 1- 6烷基。烷基的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、仲丁基、正戊基、正己基及其类似烷基。烷基中的一个或多个(如1-4个)位置可任选地被取代，所述的取代可在基团中的任何位置上进行。
如本文所用，术语“卤代烷基”指包括具有指定碳原子数且取代有1个或多个卤素的支链和直链饱和脂族烃基团。卤代烷基的实例包括但不限于氟甲基、二氟甲基、三氟甲基、三氯甲基、五氟乙基、五氯乙基、2,2,2-三氟乙基、七氟丙基和七氯丙基。卤代烷基的实例还包括具有指定碳原子数且取代有1个或多个氟原子的支链和直链饱和脂族烃基团的“氟烷基”。
术语“氟烷基”或“氟代烷基”是指上述定义的烷基，其中一个或多个氢原子被氟原子取代。
术语“烷氧基”是指通过醚氧连接的直链或支链或环状烷基，其游离价键来自该醚氧。代表性的例子包括(但并不限于)：甲氧基、乙氧基、丙氧基、异丙氧基和丁氧基等。优选为C 1-3烷氧基。
术语“氟烷氧基”或“氟代烷氧基”是指如上定义的烷氧基，其中一个或多个氢原子被氟原子取代。
术语“卤代烷氧基”是指-O-卤代烷基，包括直链或支链或环状卤代烷氧基，代表性的例子包括(但并不限于)：氟甲氧基、二氟甲氧基、三氟甲氧基、三氯甲氧基、五氟乙氧基、五氯乙氧基。
术语“环烷基”或“碳环”是指包括饱和单环、双环或多环的环状烷基，例如C 3-8或C 3-12环烷基。C 3-8环烷基指包括C 3、C 4、C 5、C 6、C 7、或C 8环烷基。环烷基还可包括螺环、桥环、并环等结构的环烷基。本发明的代表性的环烷基包括但不限于：环丙基、环丁基、环戊基、环己基和降莰烷基。应理解，取代或未取代的环烷基，例如支化环烷基(如1-甲基环丙基和2-甲基环丙基)，均包括在“环烷基”的定义中。C 5-12稠合双环指包括C 5、C 6、C 7、C 8、C 9、C 10、C 11、C 12双环烷基，其包括但不限于：
Figure PCTCN2022074184-appb-000003
等。C 5-12螺双环指包括C 5、 C 6、C 7、C 8、C 9、C 10、C 11、C 12双环烷基，其包括但不限于：
Figure PCTCN2022074184-appb-000004
Figure PCTCN2022074184-appb-000005
等。在本发明中，环烷基优选为含有3至6个碳原子(即C 3-6)的单环环烷基，如环丙基、环丁基、环戊基、或环己基。
术语“芳基”或“芳香基”，单独或作为诸如“芳烷基”、“芳烷氧基”或“芳基氧基烷基”基团中的部分，是指具有总计5至15个环成员(或环原子)的单环、二环或三环的环系统(优选6-10元芳环)，其中所述系统中的至少一个环为芳族的且其中所述系统中的每个环含有3至7个环成员。“芳基”可以是取代的或者未取代的。在本发明的某些实施方案中，“芳基”是指芳族环系统，其包括但不限于苯基、联苯基、茚满基、1-萘基、2-萘基和四氢萘基。稠合的芳基可在环烷基环或芳族环的合适位置上连接至另一基团。从环系统中画出的连接线表明键可连接至任意合适的环原子。
术语“杂芳基”或“杂环芳香基”是指包含1-4个杂原子、5-14个环原子的杂芳族体系，其中杂原子选自氧、氮和硫。杂芳基优选5至10元环，更优选为5元或6元，例如吡咯基、吡唑基、咪唑基、噁唑基、异噁唑基、噻唑基、噻二唑基、异噻唑基、呋喃基、吡啶基、吡嗪基、嘧啶基、哒嗪基、三氮嗪基、三氮唑基及四氮唑基等。“杂芳基”可以是取代的或者未取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、烯基、炔基、烷硫基、烷基氨基、卤素、氨基、硝基、羟基、巯基、氰基、环烷基、杂环基、芳基、杂芳基、环烷硫基、氧代基、羧基和羧酸酯基。
术语“杂环烷基”或“杂环”是指含有一至五个选自N、O和S的杂原子的环烷基，其中氮和硫原子任选被氧化，且氮原子任选被季铵化。杂环烷基可以是单环、双环或多环体系。杂环烷基的非限制性例子包括吡咯烷、咪唑烷、吡唑烷、丁内酰胺、戊内酰胺、咪唑烷酮、乙内酰脲、二氧戊环、苯邻二甲酰亚胺、哌啶、1,4-二噁烷、吗啉、硫代吗啉、硫代吗啉-S-氧化物、硫代吗啉-S,S-氧化物、哌嗪、吡喃、吡啶酮、3-吡咯啉、噻喃、吡喃酮、四氢呋喃、四氢噻吩、奎宁环等。杂环烷基可以经环碳或杂原子连接于分子的其余部分。
术语“羟基”指-OH。
术语“硝基”指-NO 2。
术语“氨基”指-NH 2。
术语“卤代”或“卤素”包括氟、氯、溴和碘。
术语“氰基”指-CN。
在本发明中，上述的烷基、卤代烷基、芳基、杂芳基、烯基、炔基等中各基团 可以是取代的或未取代的。
在本发明中，术语“取代”指特定的基团上的一个或多个氢原子被特定的取代基所取代。特定的取代基为在前文中相应描述的取代基，或各实施例中所出现的取代基。除非特别说明，某个取代的基团可以在该基团的任何可取代的位点上具有一个选自特定组的取代基，所述的取代基在各个位置上可以是相同或不同的。本领域技术人员应理解，本发明所预期的取代基的组合是那些稳定的或化学上可实现的组合。典型的取代包括但不限于一个或多个以下基团：如氢、氘、卤素(例如，单卤素取代基或多卤素取代基，后者如三氟甲基或包含Cl 3的烷基)、腈基、硝基、氧代(如＝O)、三氟甲基、三氟甲氧基、环烷基、烯基、炔基、杂环、芳环、OR a、SR a、S(＝O)R e、S(＝O) 2R e、P(＝O) 2R e、S(＝O) 2OR e，P(＝O) 2OR e、NR bR c、NR bS(＝O) 2R e、NR bP(＝O) 2R e、S(＝O) 2NR bR c、P(＝O) 2NR bR c、C(＝O)OR d、C(＝O)R a、C(＝O)NR bR c、OC(＝O)R a、OC(＝O)NR bR c、NR bC(＝O)OR e、NR dC(＝O)NR bR c、NR dS(＝O) 2NR bR c、NR dP(＝O) 2NR bR c、NR bC(＝O)R a、或NR bP(＝O) 2R e，其中，R a可以独立表示氢、氘、烷基、环烷基、烯基、炔基、杂环或芳环，R b、R c和R d可以独立表示氢、氘、烷基、环烷基、杂环或芳环，或者R b和R c与N原子一起可以形成杂环；R e可以独立表示氢、烷基、环烷基、烯基、炔基、杂环或芳环。上述典型的取代基，如烷基、环烷基、烯基、环烯基、炔基、杂环或芳环可以任选取代。所述取代基例如(但并不限于)：卤素、羟基、氰基、羧基(-COOH)、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、3-12元杂环基、芳基、杂芳基、C 1-8醛基、C 2-10酰基、C 2-10酯基、胺基、C 1-6烷氧基、C 1-10磺酰基、及C 1-6脲基等。
除非另外说明，假定任何不满价态的杂原子有足够的氢原子补充其价态。
当取代基为非末端取代基时，其为相应基团的亚基，例如烷基对应于亚烷基、环烷基对应亚环烷基、杂环基对亚杂环基、烷氧基对应亚烷氧基等。
术语“EP 4拮抗剂”是指抑制或阻断由PGE 2与EP 4受体的相互作用触发的细胞信号转导的化合物，包括但不限于本文所述的式(I)所示的化合物。
术语“治疗(treatment)”是指减轻，抑制和/或逆转需要其的受试者的癌症进展。术语“治疗”包括成功治疗或改善癌症的任何指标，包括任何客观或主观参数，例如减少；缓解；减轻症状或使受试者更耐受伤害、病理或病证；延缓或减缓进展速度等。治疗或改善的测量可以基于，例如，本领域已知的身体检查，病理学检查和/或诊断检查的结果。与在没有采取措施的情况下发生的情况相比，治疗还可以指减少癌症的发生或发作，或其复发(例如缓解时间的延长)。
术语“癌症”可以包括基因遗传突变的结果的癌症。这类癌症的例子包括但不限于乳腺癌，与李-弗劳梅尼综合症有关的癌症，例如儿童肉瘤，白血病和脑癌，与林奇综合症有关的癌症，例如结肠癌，胆管癌，脑癌，子宫内膜癌，肾癌，卵巢癌，胰腺癌，小肠癌，胃癌和输尿管癌，肺癌，黑素瘤，前列腺癌，成视网膜细胞瘤，甲状腺癌和子宫癌。此外，癌症可以是获得性突变的结果，例如，饮食，环境和/或生活方式引起的突变或体细胞突变。此类癌症的实例可包括但不限于肾上腺癌，肾上腺皮质癌，膀胱癌，脑癌，原发性脑癌，神经胶质瘤，成胶质细胞瘤，乳腺癌，宫颈癌，结肠癌(非限制性实例包括结直肠癌如结肠腺癌和结肠癌)，子宫内膜癌，表皮癌，食道癌，胆囊癌，泌尿生殖道癌，头颈癌，肾癌，肝癌，肺癌(非限制性例子包括腺癌，小细胞肺癌和非小细胞肺癌)，淋巴瘤(非限制性例子包括B细胞淋巴瘤，T细胞淋巴瘤，霍奇金淋巴瘤，非霍奇金淋巴瘤)，黑素瘤，恶性黑素瘤，恶性类癌，恶性胰腺胰岛素瘤，骨髓瘤，多发性骨髓瘤，卵巢癌，胰腺癌(例如外分泌胰腺癌)，前列腺癌，肾细胞癌，皮肤癌，例如，除前述的其它那些之外，鳞状细胞癌，胃癌，睾丸癌，甲状腺癌，甲状腺滤泡癌，威尔姆斯氏肿瘤，绒毛膜癌，霉菌病，恶性高钙血症，子宫颈增生，白血病，急性淋巴细胞性白血病，慢性淋巴细胞性白血病，毛细胞淋巴瘤，伯克氏淋巴瘤，急性粒细胞性白血病，慢性粒细胞性白血病，骨髓增生异常综合征，早幼粒细胞性白血病，慢性粒细胞白血病，急性粒细胞白血病，纤维肉瘤，横纹肌肉瘤(habdomyosarcoma)，星形细胞瘤，神经母细胞瘤，横纹肌肉瘤(rhabdomyosarcoma)，神经鞘瘤，卡波济肉瘤，多发性红细胞增多症，原发性血小板增多症，霍奇金病，非霍奇金淋巴瘤，软组织肉瘤，成骨肉瘤，原发性巨球蛋白血症，精原细胞瘤，畸胎瘤，骨肉瘤，异种皮色素瘤，角化角膜瘤和视网膜母细胞瘤。
活性成分
如本文所用，术语“本发明的化合物”或“本发明的活性成分”可互换使用，指式I化合物、或其药学上可接受的盐、水合物、溶剂化物、立体异构体、同位素化合物(如氘代化合物)或前药。该术语还包括外消旋体、光学异构体。
本发明化合物具有式I所示的结构
Figure PCTCN2022074184-appb-000006
其中，R 1、R 2、R 3、R 4、R 5和R 6、R b、R c如前定义。
本发明中，化合物可能形成的盐也是属于本发明的范围。除非另有说明，本发明的化合物被理解为包括其盐类。在此使用的术语“盐”，指用无机或有机酸和碱形成酸式或碱式的盐。此外，当本发明中的化合物含一个碱性片段时，它包括但不限于吡啶或咪唑，含一个酸性片段时，包括但不限于羧酸，可能形成的两性离子(“内盐”)包含在术语“盐”的范围内。药学上可接受的(即无毒，生理可接受的)盐是首选，虽然其他盐类也有用，例如可以用在制备过程中的分离或纯化步骤。本发明的化合物可能形成盐，例如，化合物I与一定量如等当量的酸或碱反应，在介质中盐析出来，或在水溶液中冷冻干燥得来。
本发明的化合物含有的碱性片段或部分，包括但不限于胺或吡啶或咪唑环，可能会和有机或无机酸形成盐。可以成盐的典型的酸包括醋酸盐(如用醋酸或三卤代醋酸，如三氟乙酸)、己二酸盐、藻朊酸盐、抗坏血酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、硼酸盐、丁酸盐、柠檬酸盐、樟脑盐、樟脑磺酸盐、环戊烷丙酸盐、二甘醇酸盐、十二烷基硫酸盐、乙烷磺酸盐、延胡索酸盐、葡庚糖酸盐、甘油磷酸盐、半硫酸盐、庚酸盐、己酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、羟基乙磺酸盐(如，2-羟基乙磺酸盐)、乳酸盐、马来酸盐、甲磺酸盐、萘磺酸盐(如，2-萘磺酸盐)、烟酸盐、硝酸盐、草酸盐、果胶酸盐、过硫酸盐、苯丙酸盐(如3-苯丙酸盐)、磷酸盐、苦味酸盐、新戊酸盐、丙酸盐，水杨酸盐、琥珀酸盐、硫酸盐(如与硫酸形成的)、磺酸盐、酒石酸盐、硫氰酸盐、甲苯磺酸盐如对甲苯磺酸盐、十二烷酸盐等等。
本发明的某些化合物可能含有的酸性片段或部分，包括但不限于羧酸，可能会和各种有机或无机碱形成盐。典型的碱形成的盐包括铵盐、碱金属盐如钠、锂、钾盐，碱土金属盐如钙、镁盐和有机碱形成的盐(如有机胺)，如苄星、二环已基胺、海巴胺(与N,N-二(去氢枞基)乙二胺形成的盐)、N-甲基-D-葡糖胺、N-甲基-D-葡糖酰胺、叔丁基胺，以及和氨基酸如精氨酸、赖氨酸等等形成的盐。碱性含氮基团可以与卤化物季铵盐，如小分子烷基卤化物(如甲基、乙基、丙基和丁基的氯化物、溴 化物及碘化物)，二烷基硫酸盐(如，硫酸二甲酯、二乙酯，二丁酯和二戊酯)，长链卤化物(如癸基、十二烷基、十四烷基和十四烷基的氯化物、溴化物及碘化物)，芳烷基卤化物(如苄基和苯基溴化物)等等。
本发明中化合物的前药及溶剂合物也在涵盖的范围之内。此处术语“前药”是指一种化合物，在治疗相关疾病时，经过代谢或化学过程的化学转化而产生本发明中的化合物、盐、或溶剂合物。本发明的化合物包括溶剂合物，如水合物。如本文所用，术语“溶剂合物”是指本发明化合物与溶剂分子配位形成特定比例的配合物。如本文所用，术语“水合物”是指本发明化合物与水进行配位形成的配合物，如一水合物。
本发明中的化合物、盐或溶剂合物，可能存在的互变异构形式(例如酰胺和亚胺醚)。所有这些互变异构体都是本发明的一部分。
所有化合物的立体异构体(例如，那些由于对各种取代可能存在的不对称碳原子)，包括其对映体形式和非对映形式，都属于本发明的设想范围。本发明中的化合物独立的立体异构体可能不与其他异构体同时存在(例如，作为一个纯的或者实质上是纯的光学异构体具有特殊的活性)，或者也可能是混合物，如消旋体，或与所有其他立体异构体或其中的一部分形成的混合物。本发明的手性中心有S或R两种构型，由理论与应用化学国际联合会(IUPAC)1974年建议定义。外消旋形式可通过物理方法解决，例如分步结晶，或通过衍生为非对映异构体分离结晶，或通过手性柱色谱法分离。单个的光学异构体可通过合适的方法由外消旋体得到，包括但不限于传统的方法，例如与光学活性酸成盐后再结晶。
本发明中的化合物，依次通过制备、分离纯化获得的该化合物其重量含量等于或大于90％，例如，等于或大于95％，等于或大于99％(“非常纯”的化合物)，在正文描述列出。此处这种“非常纯”本发明的化合物也作为本发明的一部分。
本发明的化合物所有的构型异构体都在涵盖的范围之内，无论是混合物、纯的或非常纯的形式。在本发明化合物的定义包含顺式(Z)和返式(E)两种烯烃异构体，以及碳环和杂环的顺式和反式异构体。
在整个说明书中，基团和取代基可以被选择以提供稳定的片段和化合物。
本发明的某些化合物可能存在于特定的几何或立体异构体形式。本发明涵盖所有的化合物，包括其顺式和反式异构体、R和S对映异构体、非对映体、(D)型异构体、(L)型异构体、外消旋混合物和其它混合物。另外不对称碳原子可表示取代基，如烷基。所有异构体以及它们的混合物，都包涵在本发明中。
按照本发明，同分异构体的混合物含有异构体的比率可以是多样的。例如，在只有两个异构体的混合物可以有以下组合：50:50，60:40，70:30，80:20，90:10，95:5，96:4，97:3，98:2，99:1，或100:0，异构体的所有比率都在本发明范围之内。本专业内一般技术人员容易理解的类似的比率，及为更复杂的异构体的混合物的比率也在本发明范围之内。
本发明还包括同位素标记的化合物(也称为同位素化合物)，等同于原始化合物在此公开。不过实际上对一个或更多的原子被与其原子量或质量序数不同的原子取代通常会出现。可以列为本发明的化合物同位素的例子包括氢，碳，氮，氧，磷，硫，氟和氯同位素，分别如 2H、 3H、 13C、 11C、 14C、 15N、 18O、 17O、 31P、 32P、 35S、 18F和 36Cl。本发明中的化合物，或对映体，非对映体，异构体，或药学上可接受的盐或溶剂化物，其中含有上述化合物的同位素或其他同位素原子都在本发明的范围之内。本发明中某些同位素标记化合物，例如 3H和 14C的放射性同位素也在其中，在药物和底物的组织分布实验中是有用的。氚，即 3H和碳-14，即 14C，它们的制备和检测比较容易。是同位素中的首选。此外，较重同位素取代如氘，即 2H，由于其很好的代谢稳定性在某些疗法中有优势，例如在体内增加半衰期或减少用量，因此，在某些情况下可以优先考虑。同位素标记的化合物可以用一般的方法，通过用易得的同位素标记试剂替换为非同位素的试剂，用批露在示例中的方案可以制备。
如果要设计一个本发明的化合物特定的对映体的合成，它可以不对称合成制备，或用手性辅剂衍生化，将所产生的非对映混合物分离，再除去手性辅剂而得到纯的对映体。另外，如果分子中含有一个碱性官能团，如氨基酸，或酸性官能团，如羧基，可以用合适的光学活性的酸或碱的与之形成非对映异构体盐，再通过分离结晶或色谱等常规手段分离，然后就得到了纯的对映体。
如本文所述，本发明中的化合物可与任何数量取代基或官能团取而扩大其包涵范围。通常，术语“取代”不论在术语“可选”前面或后面出现，在本发明配方中包括取代基的通式，是指用指定结构取代基，代替氢自由基。当特定结构中的多个在位置被多个特定的取代基取代时，取代基每一个位置可以是相同或不同。本文中所使用的术语“取代”包括所有允许有机化合物取代。从广义上讲，允许的取代基包括非环状的、环状的、支链的非支链的、碳环的和杂环的，芳环的和非芳环的有机化合物。在本发明中，如杂原子氮可以有氢取代基或任何允许的上文所述的有机化合物来补充其价态。此外，本发明是无意以任何方式 限制允许取代有机化合物。本发明认为取代基和可变基团的组合在以稳定化合物形式在疾病的治疗上是很好的。此处术语“稳定”是指具有稳定的化合物，在足够长的时间内检测足以维持化合物结构的完整性，最好是在足够长的时间内都在效，本文在此用于上述目的。
本申请所涉及的化合物及其药学可接受的盐的代谢产物，以及可以在体内转变为本申请所涉及的化合物及其药学可接受的盐的结构的前药，也包含在本申请的权利要求中。
制备方法
下面更具体地描述本发明式(I)结构化合物的制备方法，但这些具体方法不对本发明构成任何限制。本发明化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便的制得，这样的组合可由本发明所属领域的技术人员容易的进行。
通常，在制备流程中，各反应通常惰性气体保护下，适当溶剂中，在室温到90℃下进行，反应时间通常为2-24小时。
方法一:
Figure PCTCN2022074184-appb-000007
方法一中，R 1、R 2、R 3、R 4、R 5、R 6具有本发明所述的定义。所述方法包 括以下步骤：
(i)在有机溶剂如甲醇中，叠氮乙酸甲酯与化合物1-1中的醛基反应生成化合物1-2；优选地，所述反应在碱存在下进行，更优选地，所述碱为NaOMe(甲醇钠)；
(ii)化合物1-2在有机溶剂如二甲苯中回流生成化合物1-3；
(iii)在惰性溶剂(如DMF)中，碱性条件下，化合物1-3与苄溴衍生物生成化合物1-4；优选地，所述反应在CsCO 3的存在下进行；
(iv)在有机溶剂(如甲醇和四氢呋喃的混合溶剂)中，碱性条件下，化合物1-4中的羧酸甲酯水解成羧酸生成化合物1-5；优选地，在LiOH的存在下水解；(v)在喹啉中，化合物1-5在酸性条件下与铜粉反应生成化合物1-6；优选地，在催化剂(如Cu)的存在下反应；
(vi)在有机溶剂(如DMSO和甲醇的混合溶剂)中，在碱性条件和一氧化碳的气氛下，化合物1-6经由钯催化生成化合物1-7；优选地，所用的钯催化剂为PdCl 2dppf，和/或反应的温度为75±5℃；
(vii)在有机溶剂(如甲醇和四氢呋喃的混合溶剂)中，碱性条件下，化合物7中的羧酸甲酯水解成羧酸生成化合物1-8；优选地，在LiOH的存在下水解；
(viii)在惰性溶剂(如DMF)中，化合物1-8与苄胺缩合生成化合物1-9；优选地，在HATU和DIEA的存在下缩合；
(ix)在惰性溶剂(如甲醇和四氢呋喃的混合溶剂)中，在碱性条件下，化合物1-9中的羧酸甲酯水解成羧酸生成化合物1-10；优选地，在LiOH的存在下水解。
以上反应步骤中，反应溶剂、反应温度、反应时间、催化剂等可以根据具体的反应物进行选择。
药物组合物和施用方法
由于本发明的化合物是优异的EP 4受体的拮抗剂，因此本发明化合物及其各种晶型，药学上可接受的无机或有机盐，水合物、溶剂合物、立体异构体、同位素化合物或前药等以及本发明所述的药物组合物可用于EP 4受体相关的疾病如前列腺素E 2/EP 4受体介导疾病的治疗或预防。本发明所述的药物组合物用于预防和/或治疗以下疾病：急性和慢性疼痛、炎性疼痛、与炎症相关联的疾患、骨关节炎和类风湿性关节炎、癌症的治疗中的用途。
本发明包括一种治疗对非甾体抗炎药敏感的炎性疾病的方法，该方法包括向需要这种治疗的患者施用无毒的治疗有效量的式I所示化合物。在该实施方案中包括以上方法，其中患者还处于血栓性心血管事件和/或胃肠道溃疡/出血的风险中。
本发明的另一个实施方案包括治疗前列腺素E2介导的疾病的方法，所述疾病有利地通过选择性拮抗EP 4的活性剂来治疗，而不是通过抑制COX-1/COX-2的活性剂来治疗，所述方法包括对需要这种治疗的患者施用无毒的有效量的式I所示化合物。在该实施方案中包括以上方法，其中患者也处于血栓性心血管事件的风险中。
举例来说，但不限于，本文所述的化合物可用于靶向肿瘤微环境中的宿主免疫抑制细胞的癌症免疫疗法，所述肿瘤微环境可以是髓系或淋巴系。在一个实施方案中，本文所述的化合物可用于治疗具有各种肿瘤类型的患者，包括那些具有高水平髓样浸润物的患者。可以例如基于癌症基因组图谱(TCGA)和其他来源来确定这种髓系浸润水平。还可以基于蛋白质或基因(例如，mRNA)表达分析来鉴定此类肿瘤类型。
肿瘤类型包括但不限于胰腺腺癌，肾透明细胞癌，头颈部鳞状细胞癌(SCCHN)，非小细胞肺癌(NSCLC)，结直肠癌(CRC)，肝细胞癌(HCC)，浆液性上皮性卵巢癌，宫颈癌，移行细胞膀胱癌，皮肤癌，成胶质细胞瘤，肾癌，前列腺癌。胰腺癌和三阴性乳腺癌(TNBC)。
本发明的化合物可用于在需要这种治疗或预防的受试者中治疗或预防肿瘤形成。治疗包括部分或全部抑制肿瘤形成，扩散或转移，以及部分或全部破坏肿瘤细胞。术语“预防”包括完全预防临床上明显的瘤形成的发作或预防处于危险中的个体的临床上明显的瘤形成阶段的发作。该定义还意图包括预防恶性细胞的起始或阻止或逆转恶性前细胞向恶性细胞的发展。这包括对有发生赘生物危险的人的预防性治疗。用于治疗目的的术语“受试者”包括患有任何一种已知肿瘤的任何人类或哺乳动物受试者，并且优选是人类受试者。对于预防方法，该受试者是任何人类或动物受试者，并且优选有患上肿瘤风险的人类受试者。受试者可能由于暴露于致癌剂，遗传易患肿瘤等，而处于危险中。
通式(I)所述化合物可以与已知的治疗或改进相似病状的其他药物联用。联合给药时，原来药物的给药方式和剂量可以保持不变，而同时或随后服用式I的化合物。当式I化合物与其它一种或几种药物同时服用时，可以优选使用同时 含有一种或几种已知药物和式I化合物的药用组合物。药物联用也包括在重叠的时间段服用式I化合物与其它一种或几种已知药物。当式I化合物与其它一种或几种药物进行药物联用时，式I化合物或已知药物的剂量可能比它们单独用药的剂量低。EP 4拮抗剂与以下药物的各种组合的抗肿瘤活性：辐射；细胞毒性t淋巴细胞抗原4的抗体(抗CTLA4)；程序性死亡配体1的抗体(抗-PDL1)；程序性细胞死亡蛋白1的抗体(抗PD1)；并且已经检测到抗代谢物。本发明还包括一种用有效量的本发明化合物治疗癌症或使用有效量的本发明化合物与有效量的下述物质组合治疗癌症的方法：放射线；抗细胞毒性t淋巴细胞抗原4的抗体(抗CTLA4)；抗程序性死亡配体1的抗体(抗PDL1)；抗程序性细胞死亡蛋白1的抗体(抗PD1)；吲哚胺-2,3-二加氧酶(IDO)抑制剂；色氨酸-2,3-双加氧酶(TDO)抑制剂；和抗代谢物。这些抗体可以选自但不限于MDX-010(ipilimumab，Bristol-Myers Squibb)，CP-675,206(tremelimumab，Pfizer)，MPDL 3280 A(Roche)，MDX-1106(nivolumab，Bristol-MyersSquibb)，labrolizumab(Merck)和pembrolizumab(Merck)。
“药学上可以接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺和，而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如
Figure PCTCN2022074184-appb-000008
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
“药学上可接受的赋形剂”和“药学上可接受的载体”是指有助于活性剂的配制和/或施用和/或被个体吸收的物质，并且可以包含在本公开的组合物中而不引起对该个体的显著不利的毒理作用。药学上可接受的载体和赋形剂的非限制性实例包括水、NaCl、生理盐水溶液、乳酸林格氏液、常规蔗糖、常规葡萄糖、粘合剂、填充剂、崩解剂、润滑剂、包衣、甜味剂、风味剂、盐溶液(例如林格溶液)、醇、油、明胶、碳水化合物，诸如乳糖、直链淀粉或淀粉、脂肪酸酯、羟甲基纤维素、聚乙烯吡咯烷和颜料等。这样的制剂可以被灭菌，并且如果需要，与不会有害地与本文提供的化合物反应或干扰本文提供的化合物的活性的 辅助剂例如润滑剂、防腐剂、稳定剂、润湿剂、乳化剂、影响渗透压的盐、缓冲剂、着色剂和/或芳香物质等混合。本领域普通技术人员将认识到其他药物载体和赋形剂适用于公开的化合物。
在某些实施例中，本发明的药物组合物可以以固体或液体形式。
含有活性成分的药物(即式I所示化合物)可以是适宜的口服剂型，例如片剂，药片，含片，水溶性或油性悬液，分散乳胶粉或颗粒，乳剂，硬或软胶囊或糖浆或酏剂。口服使用的药物可根据药物成分制造商的已知工艺方法来制备，这些组合物可包括下述一种或多种药剂，例如甜味剂，调味剂，着色剂和保护剂，以便提供优雅和美味的药品制剂。药片含有与非毒性药学上可接受的赋形剂混合的活性成分，这些赋形剂适合于生产片剂。这些赋形剂的例子有，惰性稀释剂，例如碳酸钙、碳酸钠、乳糖、钙磷酸盐或磷酸钠；制粒，崩解剂，例如，玉米淀粉或褐藻酸；结合剂，例如如淀粉、明胶或阿拉伯胶，以及润滑剂，例如硬脂酸镁、硬脂酸或滑石粉。该药片可无涂层，也可有涂层，以延迟在胃肠道的降解和吸收，从而在较长时期内维持活性。
本发明的药物组合物可以通过胃肠外的、口服的、颊的、舌下的、鼻的、直肠的、局部的、或经皮的施用被施用。用于口服施用的药物组合物通常是优选的。
适合于口服施用的本发明的药物组合物典型地将是以固体形式的离散单元，例如以片剂、胶囊、扁囊剂、粉末、颗粒、锭剂、贴片、栓剂、丸剂的形式，或以液体形式，例如液体制剂、可注射的或可输注的溶液或悬浮液。
向个体提供治疗有效量的化合物的精确量将取决于给药方式、疾病和/或病症的类型和严重程度以及个体的特征，例如一般健康状况、年龄、性别、体重和对药物的耐受性。本领域普通技术人员将能够根据这些和其他因素确定合适的剂量。当与其他治疗剂组合施用时，任何其他治疗剂的“治疗有效量”将取决于所用药物的类型。合适的剂量对于批准的治疗剂是已知的，并且可以由本领域普通技术人员根据个体的状况、治疗的病症类型和通过以下使用的本发明化合物的量进行调整，例如，在文献中报道和在Physician’s Desk Reference(第57版，2003)中推荐的剂量。
本发明的药物组合物中，活性成分的含量通常为0.000001-1wt％，优选为0.00001-1wt％，最优选为0.0001-0.1wt％。
本发明的药物组合物或治疗剂的给药对象的实例包括哺乳动物(例如，人、 小鼠、大鼠、仓鼠、兔、猫、狗、牛、绵羊、猴等)。
本发明还提供了一种药物组合物的制备方法，包括步骤：将药学上可接受的载体与本发明所述通式(I)化合物或其晶型、药学上可接受的盐、水合物或溶剂合物进行混合，从而形成药物组合物。
本发明还提供了一种治疗方法，它包括步骤：给需要治疗的对象施用本发明中所述通式(I)化合物，或其晶型、药学上可接受的盐、水合物或溶剂合物，或施用本发明所述的药物组合物，用于选择性地抑制EP 4受体。
本发明具有以下主要优点：
(1)本发明化合物对EP 4受体具有优良的抑制活性，且对EP 4受体具有更好的选择抑制活性；
(2)本发明化合物具有更低的毒副作用；
(3)本发明化合物具有更好的药效学、药代动力学性能及成药性。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件如Sambrook等人，分子克隆：实验室手册(New York:Cold Spring Harbor Laboratory Press，1989)中所述的条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
除非另行定义，文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。
本发明的化合物结构是通过核磁共振(NMR)和液质联用色谱(LC-MS)来确定的。
NMR是使用Bruker AVANCE-400和Bruker AVANCE-500核磁仪检测的，测定溶剂包含氘代二甲亚砜(DMSO-d 6)、氘代丙酮(CD 3COCD 3)、氘代氯仿(CDCl 3)及氘代甲醇(CD 3OD)等，内标采用四甲基硅烷(TMS)，化学位移以百万分之一(ppm)的单位计量。
液质联用色谱(LC-MS)是使用Agilent 1260质谱仪检测的。HPLC的测定使用Agilent 1100高压色谱仪(Microsorb 5micron C18 100x3.0mm色谱柱)。
薄层层析硅胶板使用青岛GF254硅胶板，TLC采用的是0.15-0.20mm，制备薄 层色谱采用的是0.4mm-0.5mm。柱层析一般使用青岛硅胶200-300目硅胶作为载体。
本发明实施例中的起始原料都是已知并有市售的，或者可以采用或按照本领域已报道的文献资料合成的。
除特殊说明外，本发明所有反应均在干燥的惰性气体(如氮气或氩气)保护下通过连续磁力搅拌进行，反应温度均为摄氏度。
下列简写词的使用贯穿本发明
THF：四氢呋喃；MeOH：甲醇；HCl：盐酸；Pd(PPh 3) 4：四三苯基膦钯；K 2CO 3：碳酸钾；AcOK：醋酸钾；NaOH：氢氧化钠；H 2O：水；TEA：三乙胺；DIEA：N,N-二异丙基乙胺；DMF：N,N-二甲基甲酰胺；DMA：N,N-二甲基乙酰胺；Py：吡啶；DCE：1,2-二氯乙烷；DMSO：二甲基亚砜；TFA：三氟乙酸；NaBH(AcO) 3：三乙酰基硼氢化钠；Sn 2(Bu-n) 6：六己基二锡；AlCl 3：三氯化铝；CuI：碘化亚铜；DPPA：叠氮磷酸二苯酯；BuOH：叔丁醇；Cs 2CO 3：碳酸铯；K 3PO 4：磷酸钾；BnBr：苄溴；Pd 2(dba) 3：三(二亚苄基丙酮)二钯；X-Phos：2-二环己基磷-2,4,6-三异丙基联苯；EA：乙酸乙酯；NaHCO 3：碳酸氢钠；DIPEA：N，N-二异丙基乙胺；HBr：溴化氢；
实施例
实施例1 化合物1的合成
Figure PCTCN2022074184-appb-000009
步骤1:合成2-叠氮-3-(4-溴-5-甲基噻吩-2-基)丙烯酸甲酯
将叠氮醋酸甲酯(8.3g,72.8mmol)，4-溴-5-甲基噻吩-2-甲醛(5g,24mmol)溶于50mL甲醇，在-25℃下，滴加NaOMe的甲醇溶液(13.5mL,5.4M)。在0℃搅拌2h，加入50mL冰水。搅拌过滤，滤饼经水洗涤，干燥。得2-叠氮-3-(4-溴-5-甲基噻吩-2-基)丙烯酸甲酯(3.6g，49％)，不需纯化并可用于下一步。
步骤2:合成3-溴-2-甲基-4H-噻吩[3,2-b]吡咯-5-羧酸甲酯
10分钟内，向回流二甲苯(40mL)中滴加溶于二甲苯(50mL)溶解的上一步粗产物(3.6g)。回流20分钟后，冷却到室温，浓缩移除溶剂得到固体粗产物。固体经溶解，萃取，干燥，浓缩得3-溴-2-甲基-4H-噻吩[3,2-b]吡咯-5-羧酸甲酯(3.2g,98％)，MS：m/z(ESI)：273.95[M+H] +。
步骤3:合成3-溴-2-甲基-4-(4-(五氟硫基)苄基)-4H-噻吩并[3,2-b]吡咯-5-羧酸甲酯
将3-溴-2-甲基-4H-噻吩[3,2-b]吡咯-5-羧酸甲酯(2.5g,9.1mmol)、4-(五氟硫基)苄基溴(3.0g,10.1mmol)、碳酸铯(9.0g,27.5mmol)溶解在DMF(20mL)中，在室温搅拌4小时。反应完全后加水淬灭，分离有机相，水洗，干燥，经柱层析(PE:EA＝5:1)得到3-溴-2-甲基-4-(4-(五氟硫基)苄基)-4H-噻吩并[3,2-b]吡咯-5-羧酸甲酯(3.0g,90％)黄色固体。MS：m/z(ESI):489.95[M+H] +。
步骤4:合成3-溴-2-甲基-4-(4-(五氟硫基)苄基)-4H-噻吩并[3,2-b]吡咯-5-羧酸
室温下，将3-溴-2-甲基-4-(4-(五氟硫基)苄基)-4H-噻吩并[3,2-b]吡咯-5-羧酸甲酯(3.0g,6.1mmol)溶于1:1的MeOH/THF的(40mL),然后加入H 2O(20mL),氢氧化锂(404mg,18.4mmol),55℃搅拌反应2小时，浓缩移除有机溶剂，柠檬酸水溶液调节PH＝4-5，固体过滤，洗涤干燥得3-溴-2-甲基-4-(4-(五氟硫基)苄基)-4H-噻吩[3,2-b]吡咯-5-羧酸(3.0g)黄色固体。MS：m/z(ESI):475.93[M+H] +。
步骤5:合成3-溴-2-甲基-4-(4-(五氟硫基)苄基)-4H-噻吩[3,2-b]吡咯
将3-溴-2-甲基-4-(4-(五氟硫基)苄基)-4H-噻吩[3,2-b]吡咯-5-羧酸(3.0g,6.3mmol)溶于30mL喹啉，然后加入2.0g铜粉，140℃反应16小时。冷却到室温，加入6N盐酸酸化至酸性，经萃取，水洗，干燥，柱层析(PE)得到3-溴-2-甲基-4-(4-(五氟硫基)苄基)-4H-噻吩[3,2-b]吡咯(1.21g,44％)浅黄色固体。MS m/z(ESI):431.94[M+H] +。
步骤6:合成2-甲基-4-(4-(五氟硫基)苄基)-4H-噻吩[3,2-b]吡咯-3-羧酸甲酯
室温下，将3-溴-2-甲基-4-(4-(五氟硫基)苄基)-4H-噻吩[3,2-b]吡咯(0.7g,1.85mmol)、PdCl 2dppf.CH 2Cl 2(680mg,0.83mmol)、三乙胺(374mg,3.70mmol)溶于20毫升1:1的二甲基亚砜/甲醇，在CO(气球压力)中，75℃下加热过夜。反应完全后加水淬灭、萃取、水洗、干燥，柱层析(PE:EA＝2:1)得到2-甲基-4-(4-(五氟硫基)苄基)-4H-噻吩[3,2-b]吡咯-3-羧酸甲酯(0.4g,52％)黄色固体。MS m/z(ESI):412.04[M+H] +。
步骤7:合成2-甲基-4-(4-(五氟硫基)苄基)-4H-噻吩[3,2-b]吡咯-3-羧酸
室温下，将2-甲基-4-(4-(五氟硫基)苄基)-4H-噻吩[3,2-b]吡咯-3-羧酸甲酯(0.4g,0.97mmol)溶于1:2的MeOH/THF的(15mL),然后加入H 2O(5mL),氢氧化锂(116mg,0.85mmol),55℃搅拌反应2小时，浓缩移除有机溶剂，柠檬酸水溶液调节PH＝4-5,固体过滤，洗涤干燥得2-甲基-4-(4-(五氟硫基)苄基)-4H-噻吩[3,2-b]吡咯-3-羧酸(340mg,85％)黄色固体。MS m/z(ESI):398.1[M+H] +。
步骤8:合成4-(1-{[2-甲基-4-(4-(五氟硫基)苄基)-4H-噻吩[3,2-b]吡咯-3-羰基]氨基}-环丙基)苯甲酸甲酯
室温下,将2-甲基-4-(4-(五氟硫基)苄基)-4H-噻吩[3,2-b]吡咯-3-羧酸(340mg,0.85mmol)，4-(1-氨基环丙基)-苯甲酸甲酯(245mg,1.28mmol)、HATU(486mg,1.28mmol)和DIEA(220mg,1.7mmol)溶于DMF(10mL)，室温下搅拌16小时。反应完全加水淬灭、萃取、水洗、干燥，柱层析(DCM:MeOH＝20:1)得到4-(1-{[2-甲基-4-(4-(五氟硫基)苄基)-4H-噻吩[3,2-b]吡咯-3-羰基]氨基}-环丙基)苯甲酸甲酯(0.45g,92％)黄色固体。MS m/z(ESI):571.1[M+H] +。
步骤9:合成4-(1-{[2-甲基-4-(4-(五氟硫基)苄基)-4H-噻吩[3,2-b]吡咯-3-羰基]氨基}-环丙基)苯甲酸
室温下，4-(1-{[2-甲基-4-(4-(五氟硫基)苄基)-4H-噻吩[3,2-b]吡咯-3-羰基]氨基}-环丙基)苯甲酸甲酯(0.45g,0.79mmol)溶于1:2的MeOH/THF的(30mL)，然后加入H 2O(5mL)，氢氧化锂(190mg,7.91mmol)，55℃搅拌反应2小时，浓缩移除有机溶剂，柠檬酸水溶液调节pH 4-5，固体过滤，洗涤干燥得粗品，粗品用乙醚(10mL)打浆得4-(1-{[2-甲基-4-(4-(五氟硫基)苄基)-4H-噻吩[3,2-b]吡咯-3-羰基]氨基}-环丙基)苯甲酸(化合物1)(340mg,85％)黄色固体。MS m/z(ESI):557.1[M+H] +。
1H NMR(400MHz):δ11.12(s,1H)，8.98(s,1H)，7.69-7.74(m,4H)，7.14(d,2H),7.06(s,1H)，6.97(d,2H)，6.38(s,2H)，5.43(s,2H)，2.48(s,3H)，1.17(m,2H)， 0.96(m,2H)。
实施例2
以与实施例1类似的方法制备表1中的其他化合物。
Figure PCTCN2022074184-appb-000010
生物活性测试例1：
(a)放射性配体EP4受体结合测定：
实验方法：用试验缓冲液(1X HBSS+20mM HEPES+0.1％BSA+500μM IBMX)将Flpin-CHO-EP4细胞(8000个/孔)种入384孔板(6007680-50,PE)。用试验缓冲液配制8X化合物工作液。按照plate map在细胞板中每孔加入2.5μL 8×化合物工作液，37℃孵育10min。用试验缓冲液制备8X PGE2(400nM)。在细胞板中每孔加入2.5μL 8 X PGE2，37℃孵育30分钟。用裂解缓冲液稀释Eu-cAMP示踪剂(1/50)，每孔加入10μl至检测板。用裂解缓冲液稀释Ulight-anti-cAMP(1/150)，每孔加入10μl至检测板。室温孵育1h。在Envision 2105读板器上读取665nm和615nm波长信号值。结果如表2.
表2：
Figure PCTCN2022074184-appb-000011
Figure PCTCN2022074184-appb-000012
经测试，本发明的化合物具有优异的EP4受体的结合活性，具有优异的EP 4受体抑制能力。
(b)本发明化合物的PK的确定：
在雄性Han Wistar大鼠中研究化合物的药物动力学。使用静脉内注射以及口服的方式给药(对于每个剂量途径n＝3)，在给药后的多个时间点进行取样。使用特异性的并且灵敏的LC-MS/MS生物分析方法定量地分析血浆抽出物。
经测试，本发明的化合物具有较好的药效学、药代动力学性能。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (10)

  1. 一种式I化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、同位素化合物或前药；
    Figure PCTCN2022074184-appb-100001
    其中，
    R 1独立地选自下组：氢、卤素、取代或未取代的C 1-6烷基、取代或未取代的C 3-6环烷基；
    R 2和R 3各自独立选自下组：氢、取代或未取代的C 1-6烷基、取代或未取代的C 3-6环烷基；或者，R 2和R 3以及与其相连的碳原子共同构成C 3-6碳环或3至6元杂环；所述杂环包含一个或两个各独立选自S、O或NR b的环成员；并且，所述C 3-6碳环或3至6元杂环任选地被一个或多个R 1取代；
    R b各自独立地选自下组：氢、取代或未取代的C 1-6烷基、取代或未取代的C 3-6环烷基、取代或未取代的C 6-10芳基、取代或未取代的5至6元杂芳基、-C(O)R c、-S(O) 2R c；
    R c各自独立地选自下组：取代或未取代的C 1-6烷基、取代或未取代的C 3-6碳环、取代或未取代的3至6元杂环、取代或未取代的C 6-10芳基、取代或未取代的5至10元杂芳基；
    R 4和R 5各自独立选自下组：氢、取代或未取代的C 1-3烷基；或者，R 4和R 5以及与其相连的碳原子共同构成取代或未取代的C 3-6碳环；
    R 6代表无或选自下组的基团：卤素、氰基、卤代烷基；
    除非特别说明，所述的取代是指基团中一个或多个氢被选自下组的取代基所取代：卤素、C 1-4烷基、C 1-4卤代烷基。
  2. 如权利要求1所述的式I化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、同位素化合物或前药，其特征在于，
    R 1独立地选自下组：氢、卤素、C 1-6烷基、C 3-6环烷基、C 3-6氟代环烷基、C 1-6氟代烷基；
    R 2和R 3各自独立选自下组：氢、C 1-6烷基、C 3-6环烷基、C 3-6氟代环烷基、C 1-6氟代烷基；或者，R 2和R 3以及与其相连的碳原子一起共同构成C 3-6元碳环或3至6元杂环；其中，所述杂环包含一个或两个各独立选自S、O或NR b的环成员；并且，所述C 3-6碳环或3至6元杂环还任选地被R 1取代；
    R b选自下组：氢、C 1-6烷基、C 3-6环烷基、C 3-6氟代环烷基、C 1-6氟代烷基、C 6-10芳基、5至10元杂芳基、C(O)-C 1-6烷基、C(O)-C 6-10芳基、S(O) 2-C 1-6烷基、S(O) 2-C 6-10芳基；
    R 4和R 5各自独立为氢或C 1-3烷基；
    R 6代表无或选自下组的取代基：卤素、氰基、三氟甲基。
  3. 如权利要求1或2所述的式I化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、同位素化合物或前药，其特征在于，R 1选自下组：氢、卤素、C 1-6烷基、C 3-6环烷基。
  4. 如权利要求1或2所述的式I化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、同位素化合物或前药，其特征在于，R 2和R 3各自独立地选自氢、C 1-6烷基；或者，R 2和R 3以及与其相连的碳原子共同构成环丙基。
  5. 如权利要求1或2所述的式I化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、同位素化合物或前药，其特征在于，R 4和R 5各自独立地为氢或甲基。
  6. 如权利要求1或2所述的式I化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、同位素化合物或前药，其特征在于，R 6代表无或卤素。
  7. 如权利要求1或2所述的式I化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、同位素化合物或前药，其特征在于，所述化合物选自下组：
    Figure PCTCN2022074184-appb-100002
  8. 一种药物组合物，其包含如权利要求1-7任一所述的式I化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、同位素化合物或前药，以及药学上可 接受的载体或稀释剂。
  9. 一种如权利要求1至7中任一所述的式I化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、同位素化合物或前药或如权利要求8所述的药物组合物在制备(i)用于抑制EP 4受体的药物和/或(ii)用于治疗或预防与EP 4受体相关疾病的药物和/或(iii)EP 4受体拮抗剂中的用途。
  10. 如权利要求9所述的用途，其特征在于，所述EP 4受体相关疾病包括：急性和慢性疼痛、骨关节炎、类风湿关节炎、癌症，或其组合。
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