CN116082259B - Carbamate or carbamoyl substituted 5-HT2B antagonists - Google Patents

Carbamate or carbamoyl substituted 5-HT2B antagonists Download PDF

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CN116082259B
CN116082259B CN202211734967.3A CN202211734967A CN116082259B CN 116082259 B CN116082259 B CN 116082259B CN 202211734967 A CN202211734967 A CN 202211734967A CN 116082259 B CN116082259 B CN 116082259B
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pharmaceutically acceptable
compound
acceptable salt
ht2b
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CN116082259A (en
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李伟
李杨
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Beijing Ruipuxin Biotechnology Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
    • C07D251/72—Heterocyclic compounds containing 1,3,5-triazine rings condensed with carbocyclic rings or ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P1/12—Antidiarrhoeals
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    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Abstract

Disclosed herein are carbamate or carbamoyl substituted 5-HT2B antagonist compounds, which have been found to have increased binding activity to the 5-HT2B receptor due to the substitution of carbamate or carbamoyl groups, particularly carbamate groups, and methods of using the compounds in the treatment or prevention of disorders mediated by 5-HT 2B.

Description

Carbamate or carbamoyl substituted 5-HT2B antagonists
Technical Field
Disclosed herein are carbamate or carbamoyl substituted 5-HT2B antagonist compounds, which have been found to have increased binding activity to the 5-HT2B receptor due to the substitution of carbamate or carbamoyl groups, particularly carbamate groups, and methods of using the compounds in the treatment or prevention of disorders mediated by 5-HT 2B.
Background
G protein-coupled receptors (GPCRs) are involved in a variety of physiological processes and are the main drug targets in drug development. Over 40% of the drugs on the market act by modulating GPCRs. Previously, the discovery of GPCR drugs was based mainly on traditional pharmaceutical chemistry methods, which constrain GPCR drugs to a limited backbone space. Recently, molecular docking screening for GPCR crystal structures has been successfully applied to the discovery of novel highly potent ligands.
5-HT2B is one of three subtypes of the 5-HT2 family consisting of 5-HT2A, 5-HT2B and 5-HT 2C. The 5-HT2B receptor has been found to play a role in a number of medical disorders, indicating that 5-HT2B receptor antagonists are likely to have beneficial effects in patients suffering from these disorders. In general, 5-HT2B receptor antagonists may have been found useful in the prevention or treatment of a variety of disorders including, but not limited to, cardiovascular disorders, chronic lower back pain, constipation, diarrhea, fibromyalgia, fibrosis, functional gastrointestinal disorders, gastrointestinal (GI) tract disorders, gastroesophageal reflux disease (GERD), hepatocellular carcinoma, inflammatory pain, irritable Bowel Syndrome (IBS), migraine, nociceptive pain, pulmonary Arterial Hypertension (PAH), small intestine neuroendocrine tumors, visceral pain, and the like. The 5-HT2B receptor is reported to modulate smooth muscle contraction to mediate GI movement, and its inhibition shows benefits for dysuria.
WO2015158214A1 or its national stage CN106660972a discloses a range of 5-HT2B antagonist compounds that are useful for treating disorders characterized by enhanced, or undesired, 5-HT2B receptor signaling. However, there remains a desire for 5-HT2B antagonists that provide improved activity or performance.
Disclosure of Invention
The inventors of the present invention have previously thought that the activity is mainly derived from other moieties based on 5-HT2B antagonist compounds of WO2015158214A1, particularly compounds having spiro groups therein, and that there is no significant interaction on the six-membered spiro ring, but unexpectedly found that substitution of the six-membered spiro ring with a carbamate group or a carbamoyl group could further enhance the activity, and have achieved the present invention.
In a first aspect, the present invention relates to compounds of formula (I)
Or a pharmaceutically acceptable salt, enantiomer or solvate thereof,
wherein the method comprises the steps of
R is halogen, alkyl, haloalkyl, alkoxy or alkoxycarbonyl
X is a bond, CH 2 NH or O;
R 1 and R is 2 Each independently is hydrogen, alkyl, haloalkyl, hydroxyalkyl, or phenyl.
In one embodiment, R is halogen or alkoxycarbonyl; preferably fluorine, chlorine, bromine, propoxycarbonyl, isopropoxycarbonyl, ethoxycarbonyl, methoxycarbonyl; more preferably chlorine, bromine, ethoxycarbonyl or methoxycarbonyl.
In one embodiment, R 1 And R is 2 Each independently is hydrogen or C 1-4 An alkyl group. In one embodiment, R 1 And R is 2 Are all hydrogen. In one embodiment, R 1 And R is 2 Are all C 1-4 Alkyl is preferably methyl, ethyl, propyl or butyl. In one embodiment, R 1 Is hydrogen and R 2 Is C 1-4 Alkyl is preferably methyl, ethyl, propyl or butyl.
In one embodiment, X is a bond. In one embodiment, X is CH 2 . In one embodiment, X is NH. In one embodiment, X is O.
In one embodiment, R is halogen or alkoxycarbonyl; preferably fluorine, chlorine, bromine, propoxycarbonyl, isopropoxycarbonyl, ethoxycarbonyl, methoxycarbonyl; more preferably chlorine, bromine, ethoxycarbonyl or methoxycarbonyl; x is O; r is R 1 And R is 2 Each independently is hydrogen or alkyl.
In one embodiment, the compound is
In a second aspect, the present invention relates to a pharmaceutical composition comprising a compound of the invention or a pharmaceutically acceptable salt, enantiomer or solvate thereof, and a pharmaceutically acceptable excipient.
In a third aspect, the present invention relates to a method of treating a 5-HT2B mediated disorder comprising administering to a subject in need thereof a compound of the present invention or a pharmaceutically acceptable salt, enantiomer or solvate thereof. In one embodiment, the 5-HT2B mediated disorder is selected from cardiovascular disorders, chronic low back pain, constipation, diarrhea, fibromyalgia, fibrosis, functional gastrointestinal disorders, gastrointestinal (GI) tract disorders, gastroesophageal reflux disease (GERD), hepatocellular carcinoma, inflammatory pain, irritable Bowel Syndrome (IBS), migraine, nociceptive pain, pulmonary Arterial Hypertension (PAH), small intestine neuroendocrine tumor, or visceral pain. In a preferred embodiment, the 5-HT2B mediated disorder is irritable bowel syndrome. In a more preferred embodiment, the 5-HT2B mediated disorder is diarrhea predominant irritable bowel syndrome.
Detailed Description
The following terms have the indicated meanings throughout the specification:
as used in this application, including the claims that follow, unless the context clearly dictates otherwise, terms in the singular, such as "a" and "an" and "the" include their corresponding plural referents.
The term "or" is used to mean, and is used interchangeably with, the term "and/or" unless the context clearly indicates otherwise.
The term "halogen" in this application refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).
The term "alkyl" includes hydrocarbon groups selected from straight and branched chain saturated hydrocarbon groups comprising from 1 to 18, for example from 1 to 12, further for example from 1 to 10, still further for example from 1 to 8, or from 1 to 6, or from 1 to 4 carbon atoms. Examples of alkyl groups containing from 1 to 6 carbon atoms (i.e., C1-6 alkyl) include, but are not limited to: methyl, ethyl, 1-propyl or n-propyl ("n-Pr"), 2-propyl or isopropyl ("i-Pr"), 1-butyl or n-butyl ("n-Bu"), 2-methyl-1-propyl or isobutyl ("i-Bu"), 1-methylpropyl or sec-butyl ("s-Bu"), 1-dimethylethyl or tert-butyl ("t-Bu"), 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2, 3-dimethyl-2-butyl and 3, 3-dimethyl-2-butyl groups.
The term "haloalkyl" includes alkyl groups in which one or more hydrogens are replaced with one or more halogen atoms (e.g., fluorine, chlorine, bromine, and iodine). Examples of haloalkyl include halogenated C1-8 alkyl, halogenated C1-6 alkyl or halogenated C1-4 alkyl, but are not limited to-CF 3, -CH2Cl, -CH2CF3, -CHCl2, -CF3, and the like.
The compounds disclosed herein may contain asymmetric centers and thus may exist as enantiomers. "enantiomer" refers to two stereoisomers of a compound that are non-superimposable mirror images of each other. When the compounds disclosed herein have two or more chiral centers, they may additionally exist as diastereomers. Enantiomers and diastereomers belong to a broader class of stereoisomers. It is intended to include all possible stereoisomers, such as substantially pure resolved enantiomers, racemic mixtures thereof and mixtures of diastereomers. It is intended to include all stereoisomers of the compounds disclosed herein and/or pharmaceutically acceptable salts thereof. Unless specifically stated otherwise, references to one isomer apply to any possible isomer. Whenever the composition of an isomer is not specified, all possible isomers are included.
It may be advantageous to separate the reaction products from each other and/or from the starting materials. The desired product of each step or series of steps is isolated and/or purified (hereinafter referred to as "isolated") to a desired degree of uniformity by one of ordinary skill in the art. Typically, such separations involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography may involve a number of methods including, for example: reversed and normal phases; size exclusion; ion exchange; high, medium and low pressure liquid chromatography methods and apparatus; small-scale analysis; simulated moving bed ("SMB") and preparative thin-layer or thick-layer chromatography, and small-scale thin-layer and flash chromatography techniques. Those skilled in the art can select and apply the techniques most likely to achieve the desired separation.
"diastereoisomers" refers to stereoisomers of a compound having two or more chiral centers, but which are not mirror images of each other. The diastereomeric mixture may be separated into its individual diastereomers by methods known to those skilled in the art, such as chromatography and/or fractional crystallization, based on their physicochemical differences. Enantiomers may be separated as follows: the enantiomeric mixture is converted to a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), the diastereomers are separated, and the individual diastereomers are converted (e.g., hydrolyzed) to the corresponding pure enantiomers. Enantiomers can also be separated using chiral HPLC columns.
Single stereoisomers (e.g., substantially pure enantiomers) may be obtained by resolution of the racemic mixture using the following method: diastereoisomers (Eliel, e. And Wilen, S) are formed, for example, using optically active resolving agents.
Stereochemistry of Organic Compounds [ stereochemistry of organic Compounds ] New York: john Wiley & Sons, inc. [ New York: john wili parent-child publishing company ],1994; lochmuller, C.H. et al, "Chromatographic resolution of enantiomers: selective review @ [ chromatographic resolution of enantiomers: selectivity overview "J.chromatogrJ. [ J.chromatography ],113 (3) (1975): pages 283-302). The racemic mixture of the chiral compounds of the present invention may be separated and separated by any suitable method including: (1) Forming ionic diastereomeric salts with chiral compounds and separating by fractional crystallization or other methods; (2) Forming a diastereomeric compound with a chiral derivatizing reagent, separating the diastereomers and converting to pure stereoisomers; and (3) isolating the substantially pure or enriched stereoisomer directly under chiral conditions. See: wainer, irving w.edit Drug Stereochemistry: analytical Methods and Pharmacology [ drug stereochemistry: analytical methods and pharmacology New York: marcel Dekker, inc. [ New York: marseil Corp. ],1993.
By "pharmaceutically acceptable salts" is meant those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts can be prepared in situ during the final isolation and purification of the compounds disclosed herein, or separately by reacting the free base functionality with a suitable organic acid or by reacting the acidic group with a suitable base.
The term "administering" or "treatment" when applied to an animal, human, experimental subject, cell, tissue, organ or biological fluid means the contact of an exogenous agent, therapeutic, diagnostic agent or composition with the animal, human, subject, cell, tissue, organ or biological fluid. Treatment of a cell encompasses contact of an agent with the cell, as well as contact of an agent with a fluid, wherein the fluid is in contact with the cell. The terms "administering" and "treatment" also mean in vitro and ex vivo treatment of, for example, a cell by an agent, a diagnostic agent, a binding compound, or by another cell. The term "subject" in this application includes any organism, preferably an animal, more preferably a mammal (e.g., rat, mouse, dog, cat, and rabbit) and most preferably a human.
The term "effective amount" or "therapeutically effective amount" refers to an amount of an active ingredient (such as a compound) that is sufficient to affect such treatment of a disease or at least one clinical symptom of the disease or disorder when administered to a subject. The "therapeutically effective amount" may vary with the compound, the disease, disorder, and/or symptoms of the disease or disorder, the severity of the disease, disorder, and/or symptoms of the disease or disorder, the age of the subject to be treated, and/or the weight of the subject to be treated. In any given case, the appropriate amount may be apparent to those skilled in the art, or may be determined by routine experimentation. In some embodiments, a "therapeutically effective amount" is an amount of at least one compound disclosed herein and/or at least one stereoisomer thereof, and/or at least one pharmaceutically acceptable salt thereof, effective to "treat" (as defined above) a disease or disorder in a subject. In the case of combination therapies, "therapeutically effective amount" refers to the total amount of the combination subject used to effectively treat a disease, disorder, or condition.
Pharmaceutical compositions comprising the compounds disclosed herein may be administered to a subject in need thereof via oral, inhalation, rectal, parenteral or topical administration. For oral administration, the pharmaceutical composition may be a conventional solid formulation such as a tablet, powder, granule, capsule, etc., a liquid formulation such as an aqueous or oily suspension, or other liquid formulation such as syrup, solution, suspension, etc.; for parenteral administration, the pharmaceutical compositions may be in solution, aqueous solution, oil suspension concentrate, lyophilized powder, and the like. Preferably, the formulation of the pharmaceutical composition is selected from the group consisting of tablets, coated tablets, capsules, suppositories, nasal sprays or injections, more preferably tablets or capsules. The pharmaceutical composition may be a single unit administration with an accurate dosage. In addition, the pharmaceutical composition may further comprise additional active ingredients.
All formulations of the pharmaceutical compositions disclosed herein can be produced by conventional methods in the pharmaceutical arts. For example, the active ingredient may be mixed with one or more excipients and then the desired formulation is prepared. "pharmaceutically acceptable excipient" refers to conventional pharmaceutical carriers suitable for use in a desired pharmaceutical formulation, such as, for example: diluents, vehicles (such as water, various organic solvents, etc.), fillers (such as starch, sucrose, etc.), binders (such as cellulose derivatives, alginates, gelatin, and polyvinylpyrrolidone (PVP)); humectants, such as glycerol; disintegrants such as agar-agar, calcium carbonate and sodium bicarbonate; absorption enhancers such as quaternary ammonium compounds; surfactants such as cetyl alcohol; absorption carriers such as kaolin and bentonite; lubricants such as talc, calcium stearate, magnesium stearate, polyethylene glycol, and the like. In addition, the pharmaceutical composition may further comprise other pharmaceutically acceptable excipients, such as dispersing agents, stabilizers, thickeners, complexing agents, buffers, permeation enhancers, polymers, fragrances, sweeteners and dyes.
Unless defined otherwise herein, all other 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.
Examples
The compounds disclosed herein (including salts thereof) may be prepared using known organic synthesis techniques and may be synthesized according to any of numerous possible synthetic pathways.
The reactions for preparing the compounds disclosed herein can be carried out in suitable solvents that can be readily selected by those skilled in the art of organic synthesis. Suitable solvents may be substantially unreactive with the starting materials, intermediates, or products at the temperature at which the reaction is carried out (e.g., temperatures ranging from the boiling temperature of the solvent). The given reaction may be carried out in one solvent or a mixture of solvents.
The selection of the appropriate protecting group can be readily determined by one skilled in the art.
The reaction may be monitored according to any suitable method known in the art (e.g., NMR, UV, HPLC, LC-MS and TLC). The compounds may be purified by a variety of methods including HPLC, column chromatography and thin layer chromatography plates.
The following examples are intended to be purely exemplary and should not be taken as limiting in any way. Unless otherwise indicated, the experimental methods in the examples below are conventional. Reagents and materials are commercially available unless otherwise indicated. All solvents and chemicals used were analytical grade or chemical purity. The solvent was totally redistilled before use. The anhydrous solvents were prepared according to standard or reference methods.
Example 1
The compound of example 1 was synthesized from methylcarbamoyl chloride (methylcarbamoyl chloride) according to the following procedure:
step 1: methyl carbamic acid 2-amino-4- ((3-bromophenyl) amino) -1,3, 5-triazaspiro [5.5] undec-1, 3-dien-9-yl ester (example 1)
2-amino-4- ((3-bromophenyl) amino) -1,3,5-Triazaspiro [5.5]]A mixture of undec-1, 3-dien-9-ol (200 mg,0.57 mmol) in THF (10 mL) was stirred at 0deg.C and NaH (46 mg,1.14 mmol) was added. The mixture was stirred at 0℃for 1 hour. A solution of methylcarbamoyl chloride (79 mg,0.85 mmol) in THF (5 mL) was added to the above mixture, and the reaction mixture was warmed to room temperature overnight. The mixture was extracted 3 times with EA (50 mL). The extract was dried over anhydrous sodium sulfate and filtered. The filtrate was purified by preparative HPLC to give the product (21.2 mg, 9%). MS [ M+H ]] + C 16 H 21 BrN 6 O 2 Calculated 409.09, found 408.9. 1 H NMR(400MHz,DMSO)δ＝9.93(d,J＝63.9Hz,1H),8.93(d,J＝13.9Hz,2H),8.04(s,1H),7.79(d,J＝14.8Hz,1H),7.51(s,1H),7.38–7.17(m,2H),6.94(s,1H),4.58(s,1H),2.57(d,J＝4.0Hz,3H),2.11–1.48(m,8H)。
Example 2
Example 2 was prepared from 4-hydroxycyclohexane-1-one in three synthetic steps according to the following presence:
step 1:2, 4-diamino-5- (3-bromophenyl) -1,3, 5-triazaspiro [5.5]]Synthesis of undec-1, 3-dien-9-ol (2) A mixture of 4-hydroxycyclohexane-1-one (3 g,26.28 mmol), cyanoguanidine (2.43 g,28.91 mmol), concentrated hydrochloric acid (2.18 mL) and 3-bromoaniline (4.52 g,26.28 mmol) in ethanol (30 mL) was heated to reflux. After the reaction was completed, the solution was concentrated in vacuo to give a crude product. The residue was purified by column chromatography (silica gel, DCM/meoh=30/1) to give the desired product (4.24 g, 45%). MS [ MH] + C 14 H 18 BrN 5 O calculated values 352, 354, measured values 352, 354.
Step 2: synthesis of 2-amino-4- ((3-bromophenyl) amino) -1,3, 5-triazaspiro [5.5] undeca-1, 3-dien-9-ol (3)
2, 4-diamino-5- (3-bromophenyl) -1,3, 5-triazaspiro [5.5]]Undec-1, 3-dien-9-ol (4.24 g,12.04 mmol) was dissolved in pyridine (16 mL) and EtOH (24 mL) and the mixture was heated to 120℃overnight. Then vacuum concentrating to dry. Further purification was performed on column chromatography (silica gel, DCM/meoh=10/1) to give the desired product (3 g, 70%). MS [ MH] + C 14 H 18 BrN 5 O calculated values 352, 354, measured values 352, 354.
Step 3: synthesis of 2-amino-4- ((3-bromophenyl) amino) -1,3, 5-triazaspiro [5.5] undec-1, 3-dien-9-ylcarbamate (example 2)
Chlorosulfonyl isocyanate (200 mg,1.41 mmol) was added to 2-amino-4- ((3-bromophenyl) amino) -1,3, 5-triazaspiro [5.5]]In an acetone (4 mL) solution of undecan-1, 3-diene-9-ol (150 mg,0.42 mmol). The mixture was stirred at 0deg.C for 30 min, then H was added at 0deg.C 2 O (0.18 mL). The mixture was warmed to room temperature and stirred for 16 hours. The pH of the solution was adjusted to 7.9 and concentrated in vacuo. Further purification by preparative HPLC gave a white solid (8 mg,5% yield). MS [ MH] + C 15 H 19 BrN 6 O 2 Calculated values 395, 397, measured values 395, 397. 1 H NMR(400MHz,DMSO)δ11.05(s,1H),9.40(s,1H),8.44(s,1H),7.86(s,1H),7.65(t,J＝15.0Hz,2H),7.21(m,2H),6.46(s,2H),4.50(s,1H),1.88(m,4H),1.70(d,J＝6.8Hz,4H)。
Example 3
Example 3 was prepared from 4-hydroxycyclohexane-1-one in four synthetic steps according to the following procedure:
step 1: synthesis of ethyl 3- (2, 4-diamino-9-hydroxy-1, 3, 5-triazaspiro [5.5] undec-2, 4-dien-1-yl) benzoate (2)
A mixture of ethyl 3-aminobenzoate (3.58 g,21.67 mmol), 4-hydroxycyclohexane-1-one (2.47 g,21.67 mmol), dicyandiamide (2 g,23.84 mmol) and concentrated hydrochloric acid (1.8 mL) in EtOH (30 mL) was heated to reflux. After the reaction was completed, the mixture was filtered to give the desired solid (7.05 g, 94%). MS [ MH] + C 17 H 23 N 5 O 3 Calculated value 346, measured value 346.
Step 2: synthesis of ethyl 3- ((4-amino-9-hydroxy-1, 3, 5-triazaspiro [5.5] undec-2, 4-dien-2-yl) amino) benzoate (3)
3- (2, 4-diamino-9-hydroxy-1, 3, 5-triazaspiro [5.5]]Ethyl undec-2, 4-dien-1-yl benzoate (7 g,20.27 mmol) was dissolved in pyridine (20 mL) and EtOH (30 mL), and the mixture was then heated to 120℃overnight. The solution was concentrated to dryness in vacuo. Further purification was performed on column chromatography (silica gel, DCM/meoh=30/1) to give the desired product (3.14 g, 45%). MS [ MH] + C 17 H 23 N 5 O 3 Calculated value 346, measured value 346.
Step 3: synthesis of ethyl 3- ((4- ((tert-butoxycarbonyl) amino) -9-hydroxy-1, 3, 5-triazaspiro [5.5] undec-2, 4-dien-2-yl) amino) benzoate (4)
DMAP (53 mg,0.43 mmol) was added to 3- ((4-amino-9-hydroxy-1, 3, 5-triazaspiro [ 5.5)]Ethyl undec-2, 4-dien-2-yl) amino benzoate (1.5 g,4.34 mmol) and di-tert-butyl dicarbonate (8.68 g,8.68 mmol) in DCM (30 mL) and the mixture stirred overnight. The solution was concentrated to dryness in vacuo. Further purification was performed on column chromatography (silica gel, DCM/meoh=50/1) to give the desired product (700 mg, 36%). There is no nmr data. MS [ MH] + C 22 H 31 N 5 O 5 Calculated 446, measured 446.
Step 4: synthesis of ethyl 3- ((4-amino-9- (carbamoyloxy) -1,3, 5-triazaspiro [5.5] undec-2, 4-dien-2-yl) amino) benzoate (example 3)
3- ((4- ((tert-Butoxycarbonyl) amino) -9-hydroxy-1, 3, 5-triazaspiro [ 5.5)]To a solution of ethyl undec-2, 4-dien-2-yl) amino benzoate (600 mg,1.35 mmol) in water (0.24 mL) and acetone (20 mL) was added chlorosulfonyl isocyanate (629 mg,4.44 mmol), and the mixture was stirred overnight. The solution was adjusted to pH 8 with ammonium hydroxide and then concentrated to dryness in vacuo. Further purification by preparative HPLC gave a white solid (15 mg,3% yield). MS [ MH] + C 18 H 24 N 6 O 4 Calculated 389, measured 389. 1 H NMR(400MHz,DMSO)δ9.82(s,1H),8.87(s,1H),7.96(d,J＝8.3Hz,1H),7.90(s,1H),7.71(d,J＝7.8Hz,1H),7.50(t,J＝7.9Hz,1H),7.24(s,2H),6.49(s,2H),4.54(s,1H),4.33(q,J＝7.1Hz,2H),1.92(m,4H),1.73(m,4H),1.33(t,J＝7.1Hz,3H)。
Example 4
Example 4 was prepared from 4-hydroxycyclohexane-1-one in five synthetic steps according to the following procedure:
step 1: synthesis of propyl 3- (2, 4-diamino-9-hydroxy-1, 3, 5-triazaspiro [5.5] undec-2, 4-dien-1-yl) benzoate (2)
A mixture of propyl 3-aminobenzoate (2.01 g,11.22 mmol), 4-hydroxycyclohexane-1-one (1.28 g,11.22 mmol), dicyandiamide (1.04 g,12.34 mmol) and concentrated hydrochloric acid (0.94 mL) in ethanol (20 mL) was heated to reflux. After the reaction was completed, the mixture was filtered to give the desired solid (3.08 g, 76%). MS [ MH] + C 18 H 25 N 5 O 3 Calculated value 360, measured value 360.
Step 2: synthesis of propyl 3- ((4-amino-9-hydroxy-1, 3, 5-triazaspiro [5.5] undec-2, 4-dien-2-yl) amino) benzoate (3)
3- (2, 4-diamino-9-hydroxy-1, 3, 5-triazaspiro [5.5]]Propyl undec-2, 4-dien-1-yl benzoate (3.09 g,8.60 mmol) was dissolved in pyridine (18 mL) and EtOH (27 mL), and the mixture was then heated to 120℃overnight. The mixture was concentrated to dryness in vacuo. Further purification was performed on column chromatography (silica gel, DCM/meoh=20/1) to give the desired product (1.8 g, 58%). MS [ MH] + C 18 H 25 N 5 O 3 Calculated value 360, measured value 360.
Step 3: synthesis of propyl 3- ((4- ((tert-butoxycarbonyl) amino) -9-hydroxy-1, 3, 5-triazaspiro [5.5] undec-2, 4-dien-2-yl) amino) benzoate (4)
DMAP (400 mg,2.78 mmol) was added to 3- ((4-amino-9-hydroxy-1, 3, 5-triazaspiro [ 5.5)]Undec-2, 4-dien-2-yl) amino-benzoic acid propyl ester (1 g,2.78 mmol) and di-tert-butyl dicarbonate2.43g,11.13 mmol) in DCM (30 mL). The mixture was stirred overnight. The solution was concentrated to dryness in vacuo. Further purification was performed on column chromatography (silica gel, DCM/meoh=50/1) to give the desired product (1.4 g, crude). There is no nmr data. MS [ MH] + C 23 H 33 N 5 O 5 Calculated value 460, measured value 460.
Step 4: synthesis of propyl 3- ((4- ((tert-butoxycarbonyl) amino) -9- (carbamoyloxy) -1,3, 5-triazaspiro [5.5] undec-2, 4-dien-2-yl) amino) benzoate (5)
3- ((4- ((tert-Butoxycarbonyl) amino) -9-hydroxy-1, 3, 5-triazaspiro [ 5.5)]To a solution of propyl undec-2, 4-dien-2-yl amino) benzoate (1.092 g,2.38 mmol) in water (0.34 mL) and acetone (10 mL) was added chlorosulfonyl isocyanate (1.11 g,7.84 mmol), and the mixture was stirred overnight. The solution was adjusted to pH 8 with ammonium hydroxide and then concentrated to dryness in vacuo. Further purification was performed on column chromatography (silica gel, DCM/meoh=8/1) to give the desired product (700 mg, 56%). MS [ MH] + C 24 H 34 N 6 O 6 Calculated value 503, measured value 503.
Step 5: synthesis of propyl 3- ((4-amino-9- (carbamoyloxy) -1,3, 5-triazaspiro [5.5] undec-2, 4-dien-2-yl) amino) benzoate (example 4)
HCl/dioxane (10 mL) was added to 3- ((4- ((tert-butoxycarbonyl) amino) -9- (carbamoyloxy) -1,3, 5-triazaspiro [ 5.5)]Propyl undec-2, 4-dien-2-yl) amino benzoate (700 mg,1.39 mmol) and the mixture was stirred for 3 hours. The solution was adjusted to pH 8 with ammonium hydroxide and then concentrated to dryness in vacuo. Further purification by preparative HPLC gave a white solid (5 mg,0.9% yield). MS [ MH] + C 19 H 26 N 6 O 4 Calculated value is 403, and measured value is 403. 1 H NMR(400MHz,DMSO)δ11.74(s,1H),10.82(s,2H),9.23(s,1H),8.46(s,1H),7.97(s,1H),7.57(s,1H),7.40(d,J＝10.1Hz,1H),6.44(s,2H),4.54(s,1H),4.22(t,J＝6.5Hz,2H),1.78(m,10H),0.98(t,J＝7.4Hz,3H)。
Example 5
Example 5 was prepared from 4-hydroxycyclohexane-1-one in three synthetic steps according to the following procedure:
step 1: synthesis of 4-oxo-cyclohexyl dimethylcarbamate (2)
A mixture of 4-hydroxycyclohexane-1-one (2.0 g,17.54 mmol) in THF (20 mL) was stirred at 0deg.C and NaH (1.403 g,35.08 mmol) was added. The mixture was stirred at 0℃for 1 hour. A solution of dimethylcarbamoyl chloride (1.894 g,17.54 mmol) in THF (5 mL) was then added to the mixture and the reaction mixture was warmed to room temperature overnight. The mixture was extracted 3 times with EA (50 mL). The combined extracts were dried over anhydrous sodium sulfate and filtered. The filtrate was purified by silica gel chromatography (PE/ea=1:1) to give the crude product (1.0 g). MS [ M+H ]] + C 11 H 19 NO 4 Calculated 229.13, found 229.9.
Step 2: synthesis of 2, 4-diamino-5- (3-bromophenyl) -1,3, 5-triazaspiro [5.5] undec-1, 3-dien-9-yl dimethylcarbamate (3)
A mixture of 4-oxocyclohexyl dimethylcarbamate (1.0 g,5.41 mmol), cyanoguanidine (499 mg,5.95 mmol), concentrated hydrochloric acid (0.8 mL) and 3-bromoaniline (931 mg,5.41 mmol) in ethanol (15 mL) was heated to reflux. After completion of the reaction, the mixture was concentrated in vacuo and the residue was purified by silica gel chromatography (DCM: meoh=20:1) to give the crude product (1.40 g). MS [ M+H ]] + C 17 H 23 BrN 6 O 2 Calculated 422.11, found 422.9.
Step 3: synthesis of 2-amino-4- ((3-bromophenyl) amino) -1,3, 5-triazaspiro [5.5] undec-1, 3-dien-9-yl dimethylcarbamate (example 5)
2, 4-diamino-5- (3-bromophenyl) -1,3, 5-triazaspiro [5.5]]Undec-1, 3-dien-9-yl dimethylcarbamate (1.40 g,3.30 mmol) was dissolved in pyridine (4 mL) and EtOH (6 mL) and the mixture was heated to 120 ℃ overnight. And then concentrated to dryness in vacuo. Further purification by preparative HPLC gave a white solid (113.8mg, yield 8% and 148.9mg, yield 11%). MS [ M+H ]] + C 17 H 23 BrN 6 O 2 Calculated 422.9, found 422.9. 1 H NMR(400MHz,DMSO)δ10.50(s,1H),9.16(s,1H),8.96(s,1H),8.05(s,1H),7.81(s,1H),7.55(s,1H),7.28(d,J＝4.9Hz,2H),7.04(d,J＝4.0Hz,1H),4.56(s,1H),2.56(d,J＝4.5Hz,3H),1.89(d,J＝12.4Hz,3H),1.76(t,J＝8.5Hz,3H),1.24(s,2H)。
Example 6
Example 6 was prepared from 1, 4-dioxaspiro [4.5] decan-8-one in seven synthetic steps according to the following procedure:
step 1: synthesis of ethyl 2- (1, 4-dioxaspiro [4.5] decan-8-ylidene) acetate (2)
1, 4-dioxaspiro [4.5]]A mixture of decan-8-one (2.086 g,13.38 mmol) and ethyl 2- (triphenyl-l 5-phosphino) acetate (5.12 g,14.71 mmol) in toluene (20 mL) was heated to 112℃overnight. After completion of the reaction, the mixture was concentrated in vacuo and the residue was purified by silica gel chromatography (PE: ea=5:1) to give the crude product (2.064 g). MS [ M+H ]] +
C 12 H 18 O 4 Calculated 226.12, measured 227.
Step 2: synthesis of ethyl 2- (1, 4-dioxaspiro [4.5] decan-8-yl) acetate (3)
2- (1, 4-dioxaspiro [4.5]]A mixture of Ethyl decane-8-ylidene acetate (2.064 g,9.13 mmol) and Pd/C (1.032 g) in MeOH (20 mL) at room temperature in H 2 Stir overnight under an atmosphere. After the reaction was completed, the mixture was concentrated in vacuo. The crude product was used in the next step without purification. MS [ M+H ]] + C 12 H 20 O 4 Calculated 228.14, found 229.
Step 3: synthesis of ethyl 2- (4-oxocyclohexyl) acetate (4)
2- (1, 4-dioxaspiro [4.5]]A mixture of ethyl acetate (2.225 g,9.76 mmol) and 3N HCl (33 mL) in THF (20 mL) was stirred at room temperature overnight. After completion of the reaction, the mixture was concentrated in vacuo and the residue was purified by silica gel chromatography (DCM: meoh=100:1) to give the crude product (1.582 g). MS [ M+H ]] + C 10 H 16 O 3 Calculated 184.11, found 185.
Step 4: synthesis of ethyl 2- (2, 4-diamino-5- (3-bromophenyl) -1,3, 5-triazaspiro [5.5] undec-1, 3-dien-9-yl) acetate (5)
A mixture of ethyl 2- (4-oxocyclohexyl) acetate (1.528 g,8.59 mmol), cyanoguanidine (794 mg,9.46 mmol), concentrated hydrochloric acid (0.5 mL) and 3-bromoaniline (1.477 g,8.59 mmol) in ethanol (10 mL) was heated to reflux. After completion of the reaction, the mixture was concentrated in vacuo and the residue was purified by silica gel chromatography (DCM: meoh=30:1) to give the crude product (380 mg). MS [ M+H ]] + C 18 H 24 BrN 5 O 2 Calculated 421.11, measured 422.
Step 5: synthesis of ethyl 2- (2-amino-4- ((3-bromophenyl) amino) -1,3, 5-triazaspiro [5.5] undec-1, 3-dien-9-yl) acetate (6)
2- (2, 4-diamino-5- (3-bromophenyl) -1,3, 5-triazaspiro [5.5]]Ethyl undec-1, 3-dien-9-yl acetate (380 mg,0.90 mmol) was dissolved in pyridine (2 mL) and EtOH (3 mL) and the mixture was heated to 120℃overnight. And then concentrated to dryness in vacuo. Further purification by preparative HPLC gave the crude product (247 mg). MS [ M+H ]] +
C 18 H 24 BrN 5 O 2 Calculated 421.11, measured 422.
Step 6: synthesis of 2- (2-amino-4- ((3-bromophenyl) amino) -1,3, 5-triazaspiro [5.5] undec-1, 3-dien-9-yl) acetic acid (7)
2- (2-amino-4- ((3-bromophenyl) amino) -1,3, 5-triazaspiro [5.5]Ethyl undec-1, 3-dien-9-yl acetate (247 mg,0.65 mmol) was dissolved in THF (10 mL) and H 2 To O (10 mL) was added NaOH (104 mg,2.60 mmol). The mixture was stirred at room temperature overnight. The mixture was acidified with concentrated HCl to pH 3 and then filtered to give the crude product (100 mg). MS [ M+H ]] + C 16 H 20 BrN 5 O 2 Calculated 393.08, found 394.
Step 7: synthesis of 2- (2-amino-4- ((3-bromophenyl) amino) -1,3, 5-triazaspiro [5.5] undec-1, 3-dien-9-yl) -N, N-dimethylacetamide (example 6)
2- (2-amino-4- ((3-bromophenyl) amino) -1,3, 5-triazaspiro [5.5]Undec-1, 3-dien-9-yl) acetic acid (57 mg,0.14 mmol), dimethylamine (18 mg,0.22 mmol), HATU (106 mg,028 mmol) and DIPEA (90 mg,042 mmol) were stirred in DCM (15 mL) for 2 h at room temperature. After the reaction was completed, the mixture was concentrated in vacuo. The residue was purified by preparative HPLC to give a white solid (2.5 mg,4.3% yield). [ M+H ]] + C 18 H 25 BrN 6 O calculated 421, found 421. 1 H NMR(400MHz,DMSO)δ8.74(s,2H),7.84(s,1H),7.52(s,1H),7.38–7.11(m,3H),2.97(s,3H),2.82(s,3H),2.23(d,J＝6.7Hz,2H),2.00–1.88(m,2H),1.80–1.54(m,4H),1.24(s,3H)。
Example 7
Example 7 was prepared from methyl 4-oxocyclohexane-1-carboxylate in four synthetic steps according to the following procedure:
step 1: synthesis of methyl 2, 4-diamino-5- (3-bromophenyl) -1,3, 5-triazaspiro [5.5] undecane-1, 3-diene-9-carboxylate (2)
A mixture of methyl 4-oxocyclohexane-1-carboxylate (2.5 g,16.03 mmol), cyanoguanidine (1.48 g,17.63 mmol), concentrated hydrochloric acid (1.0 mL), and 3-bromoaniline (2.8 g,16.03 mmol) in ethanol (20 mL) was heated to reflux. After completion of the reaction, the mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography (DCM: meoh=20:1) to give crude product (1.50 g). MS [ M+H ]] + C 16 H 20 BrN 5 O 2 Calculated 393.08, found 394.
Step 2: synthesis of methyl 2-amino-4- ((3-bromophenyl) amino) -1,3, 5-triazaspiro [5.5] undecane-1, 3-diene-9-carboxylate (3)
2, 4-diamino-5- (3-bromophenyl) -1,3, 5-triazaspiro [5.5]]Undecane-1, 3-diene-9-carboxylic acid methyl ester (1.50 g,3.81 mmol) was dissolved inPyridine (4 mL) and EtOH (6 mL) and the mixture was heated to 120℃overnight. And then concentrated to dryness in vacuo. Further purification by preparative HPLC gave the crude product (1.052 mg, 70%). MS [ M+H ]] +
C 16 H 20 BrN 5 O 2 Calculated 393.08, found 394.
Step 3: synthesis of 2-amino-4- ((3-bromophenyl) amino) -1,3, 5-triazaspiro [5.5] undecane-1, 3-diene-9-carboxylic acid (4)
2-amino-4- ((3-bromophenyl) amino) -1,3, 5-triazaspiro [5.5]Undecane-1, 3-diene-9-carboxylic acid methyl ester (400 mg,1.02 mmol) was dissolved in THF (10 mL) and H 2 To O (10 mL) was added NaOH (81 mg,2.03 mmol). The mixture was stirred at room temperature overnight. The mixture was acidified with concentrated HCl to pH 3 and filtered to give the crude product (163 mg, 42%). MS [ M+H ]] + C 15 H 18 BrN 5 O 2 Calculated 379.06, found 380.
Step 4: synthesis of 2-amino-4- ((3-bromophenyl) amino) -N, N-dimethyl-1, 3, 5-triazaspiro [5.5] undecane-1, 3-diene-9-carboxamide (example 7)
2-amino-4- ((3-bromophenyl) amino) -1,3, 5-triazaspiro [5.5]Undecane-1, 3-diene-9-carboxylic acid (80 mg,0.21 mmol), dimethylamine (25 mg,0.32 mmol), HATU (160 mg,1.42 mmol) and DIPEA (135 mg,1.05 mmol) were stirred in DCM (15 mL) for 2 h at room temperature. After completion of the reaction, the mixture was concentrated in vacuo and the residue was purified by preparative HPLC to give a white solid (7.00 mg,17.5% yield). MS [ M+H ]] + C 17 H 23 BrN 6 O calculated 407, found 407. 1 H NMR(400MHz,DMSO)δ8.62(s,1H),8.02(s,1H),7.75(s,1H),7.52(s,1H),7.30(d,J＝5.0Hz,2H),6.83(s,1H),3.04(s,3H),2.83(s,3H),2.68(d,J＝5.2Hz,1H),1.96(d,J＝11.3Hz,2H),1.75–1.58(m,6H)。
Example 8
Example 8 was prepared from 1, 4-dioxaspiro [4.5] decan-8-one in five synthetic steps according to the following procedure:
step 1: synthesis of N-methyl-1, 4-dioxaspiro [4.5] decan-8-amine (2)
At 0 ℃, meNH 2 (17.22 mL,34.44 mmol) was added to 1, 4-dioxaspiro [4.5]]ClCH of decan-8-one (3.58 g,22.96 mmol) 2 CH 2 To a solution of Cl (45 mL), na (AcO) was added 3 BH (7.3 g,34.44 mmol). The solution was stirred at room temperature overnight. The reaction was quenched with water. The mixture was extracted with DCM and filtered. The filtrate was concentrated in vacuo to give the crude product (3.7 g). MS [ MH] + C 9 H 17 NO 2 Calculated value 172, measured value 172.
Step 2: synthesis of 1-methyl-1- (1, 4-dioxaspiro [4.5] decan-8-yl) urea (3)
Sodium cyanate (12.11 g,105.11 mmol) was added to N-methyl-1, 4-dioxaspiro [4.5]]A solution of decan-8-amine (3.6 g,21.02 mmol) in DCM (40 mL). The solution was stirred at room temperature for 16 hours. The reaction was quenched with water and the mixture extracted with EA (3X 30 mL). The combined organic layers were treated with Na 2 SO 4 Drying and filtering. Evaporation of the solvent gave the crude product, and the residue was purified by column chromatography (silica gel, DCM/MeOH=10/1) to give the desired product (2.75 g, 61%). MS [ MH] +
C 10 H 18 N 2 O 3 Calculated 215, measured 215.
Step 3: synthesis of 1-methyl-1- (4-oxocyclohexyl) urea (4)
HCl/H 2 O (47 mL,139.1mmol,3 mol/L) was added to 1-methyl-1- (1, 4-dioxaspiro [ 4.5)]Decane-8-yl) urea (2.98 g,13.91 mmol) in THF (21 mL) was stirred at room temperature overnight. The solution was concentrated in vacuo to give the crude product, which was purified by column chromatography (silica gel, DCM/meoh=10/1) to give the desired product (600 mg, 25%). MS [ MH] + C 8 H 14 N 2 O 2 Calculated 171, measured 171.
Step 4: synthesis of 1- (2, 4-diamino-5- (3-bromophenyl) -1,3, 5-triazaspiro [5.5] undec-1, 3-dien-9-yl) -1-methylurea (5)
1-methyl-1- (4-oxo-ring)A mixture of hexyl) urea (660 mg,3.58 mmol), cyanoguanidine (331 mg,3.94 mmol), concentrated HCl (0.6 mL), and 3-bromoaniline (616 mg,3.58 mmol) in ethanol (12 mL) was heated to reflux. After completion of the reaction, the solution was concentrated in vacuo to give the crude product, and the residue was purified on column chromatography (silica gel, DCM/meoh=5/1) to give the desired product (300 mg, 20%). MS [ MH] + C 16 H 22 BrN 7 O calculated values 408, 410, measured values 408, 410.
Step 5: synthesis of 1- (2-amino-4- ((3-bromophenyl) amino) -1,3, 5-triazaspiro [5.5] undec-1, 3-dien-9-yl) -1-methylurea (example 8)
1- (2, 4-diamino-5- (3-bromophenyl) -1,3, 5-triazaspiro [5.5]]Undec-1, 3-dien-9-yl) -1-methylurea (200 mg,0.49 mmol) was dissolved in pyridine (2 mL) and EtOH (3 mL). The mixture was heated to 80 ℃ for 10 hours, then warmed to 100 ℃ for 6 hours. The mixture was concentrated to dryness in vacuo. Further purification by preparative HPLC gave a white solid (5 mg,3% yield). MS [ MH] + Calculated values 408, 410 for C16H22BrN7O, measured values 408, 410. 1 H NMR(400MHz,DMSO)δ9.79(s,1H),9.00(s,1H),8.77(s,1H),8.02(s,1H),7.73(s,1H),7.49(d,J＝7.2Hz,1H),7.31(d,J＝7.2Hz,2H),5.84(s,2H),3.97(s,1H),2.70(s,3H),1.99(d,J＝8.1Hz,2H),1.74(d,J＝8.9Hz,4H),1.48(s,2H)。
Antagonistic Activity assay
A stable cell line CHO-K1/5-HT2B for use in cell screening of compounds that exhibit significant activity in 5-HT2B antagonist assays using the FLIPR method. Briefly, CHO-K1 cells expressing the 5-HT2B receptor were seeded at a density of 20,000 cells/well 18 hours prior to the day of the experiment in black, bottom-plated 384-well plates with 20. Mu.L of medium (10% dialyzed fetal bovine serum+90% F12) added to each well, and maintained at 37℃C.5% CO 2. mu.L of loading buffer and 10. Mu.L of test compound solution (5 times the final test concentration) were added to each well of cells. The cell plates were then placed in a 37℃incubator for 1 hour, followed by 15 minutes at ambient temperature. Finally, 12.5 μl of control agonist (5 times the EC80 concentration) was added. Control agonist is added to the reader plate at 20 seconds and then the fluorescent signal is monitored for an additional 100 seconds (21 seconds to 120 seconds). In the screening, cells stimulated with assay buffer (HBSS-HEPES) containing 0.1% dmso were selected as background; cells stimulated with 12nM (EC 80 value of cell line) of 5-HT were selected as agonist controls; cells treated with SB206553 were selected as positive controls for the screen.
Data were collected and analyzed using the ScreenWorks (version 3.1) software. The average value of fluorescence intensity in 1-20 seconds was calculated as the base value reading. Relative fluorescence units (Δrfu) were calculated as the average of the maximum fluorescence units (21 seconds to 120 seconds) minus the baseline reading. The inhibition rate of the test article was calculated using the following formula:
% inhibition= [1- (Δrfu) Compounds of formula (I) -ΔRFU Background )/(ΔRFU Agonist control -ΔRFU Background )]*100
The test results are shown in Table 1.
Table 1:5-HT2B receptor antagonistic Activity
It should be understood that if any prior art publication is referred to in this application, this reference does not constitute an admission that the publication forms a part of the common general knowledge in the art in any country.
The disclosures of all publications, patents, patent applications, and published patent applications mentioned in this application by reference are hereby incorporated by reference in their entirety.
Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be apparent to those skilled in the art that certain minor changes and modifications may be practiced. Accordingly, the description and examples should not be construed as limiting the scope of the invention.

Claims (21)

1. A compound of formula (I):
wherein the method comprises the steps of
R is halogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl, propoxycarbonyl, isopropoxycarbonyl, ethoxycarbonyl or methoxycarbonyl;
x is O;
R 1 and R is 2 Each independently is hydrogen, C 1-4 Alkyl or halo C 1-4 An alkyl group.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R is halo, propoxycarbonyl, isopropoxycarbonyl, ethoxycarbonyl, or methoxycarbonyl.
3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R is fluoro, chloro, bromo, propoxycarbonyl, isopropoxycarbonyl, ethoxycarbonyl, or methoxycarbonyl.
4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R is chloro, bromo, ethoxycarbonyl, or methoxycarbonyl.
5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 1 And R is 2 Each independently is hydrogen or C 1-4 An alkyl group.
6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 1 And R is 2 Are all hydrogen.
7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 1 And R is 2 Are all C 1-4 An alkyl group.
8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 1 And R is 2 Each independently is methyl, ethyl, propyl or butyl.
9. The compound of claim 1An agent or a pharmaceutically acceptable salt thereof, wherein R 1 Is hydrogen and R 2 Is C 1-4 An alkyl group.
10. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein R 2 Methyl, ethyl, propyl or butyl.
11. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R is halo, propoxycarbonyl, isopropoxycarbonyl, ethoxycarbonyl, or methoxycarbonyl; x is O; r is as follows 1 And R is 2 Each independently is hydrogen or C 1-4 An alkyl group.
12. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R is fluoro, chloro, bromo, propoxycarbonyl, isopropoxycarbonyl, ethoxycarbonyl, or methoxycarbonyl; x is O; r is as follows 1 And R is 2 Each independently is hydrogen or C 1-4 An alkyl group.
13. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R is chloro, bromo, ethoxycarbonyl, or methoxycarbonyl; x is O; r is as follows 1 And R is 2 Each independently is hydrogen or C 1-4 An alkyl group.
14. The compound of claim 1, or a pharmaceutically acceptable salt thereof, which is
15. A pharmaceutical composition comprising a compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
16. Use of a compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of 5-HT2B mediated disorders.
17. The use of claim 16, wherein the 5-HT2B mediated disorder is selected from the group consisting of cardiovascular disorders, chronic lower back pain, fibromyalgia, fibrosis, functional gastrointestinal disorders, gastroesophageal reflux disease, hepatocellular carcinoma, inflammatory pain, migraine, nociceptive pain, pulmonary arterial hypertension, small intestine neuroendocrine tumor, or visceral pain.
18. The use of claim 16, wherein the 5-HT2B mediated disorder is constipation.
19. The use according to claim 16, wherein the 5-HT2B mediated disorder is diarrhea.
20. The use according to claim 16, wherein the 5-HT2B mediated disorder is a gastrointestinal disorder.
21. The use according to claim 16, wherein the 5-HT2B mediated disorder is irritable bowel syndrome.
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