TW200538180A - New compounds - Google Patents

Abstract

The present invention is directed to novel compounds, to a process for their preparation, their use in therapy and pharmaceutical compositions comprising the novel compounds.

Description

200538180 IX. Description of the invention: [Examination of the household chair collar 3] The present invention relates to several novel compounds, their preparation methods, their use in facial treatment, and pharmaceutical compositions containing these compounds. 5 chairs] Metabolic nutritional glutamate receptor (mGhiR) is a G-protein binding receptor, which is involved in the regulation and activity of many synapses located in the central nervous system (CNS). Eight metabolic nutrient glutamate receptor subtypes have been identified and subdivided into three groups based on sequence similarity. The first group consists of mGluRl and mGluR5. These receptors activate the conversion of acid-lipid to C and increase neuronal stress. The second group consisting of mGluR2 and mGluR3 and the third group consisting of mGluR4, mGluR6, mGluR7 and mGluR8 have the ability to inhibit adenylate cyclase activity and reduce synaptic message transmission. Several of these receptors have also undergone alternative splicing and various isoforms have appeared 15

(Chen, CY et al., Journal of Physiology (2002), 538.3, ρ 773-786; Pin, JP et al., European Journal of Pharmacology (1999), 375, pp. 277-294; Brauner-Osborne, H et al. Journal of Medicinal Chemistry (2000), 43, pp · 2609-2645; Schoepp, DD, Jane DE Monn JA Neuropharmacology (1999), 38, pp.1431-1476) 〇20 Lower esophageal sphincter (LES) is often Relax intermittently. At this time, because the mechanical barrier is temporarily disabled, as a result, the fluid of the stomach can enter the esophagus. This kind of event mentioned below is called "countercurrent". Gastro-esophageal reflux disease (GERD) is the most common upper gastrointestinal disease. Current medications aim to reduce gastric acid secretion or neutralize acidity in the esophagus. The main mechanism behind countercurrent dorsal 5 200538180 is generally thought to be caused by a hypotonic lower esophageal sphincter. However, for example, Holloway & Dent (1990) Gastroenterol. Clin · N · Amer. 79, pp. 577-535. States that most cases of countercurrent occur during transient lower esophageal sphincter relaxations (TLESRs). In other words, sphincter relaxation is not caused by Choking trigger. It has also been reported that gastric acid secretion in patients with GERD is usually normal. The problem faced by the present invention is to find new compounds that are effective in treating GERD. [Summary] The present invention relates to several novel compounds according to general formula I:

10 wherein R1, R2, R3 and R4 are each independently selected from H, CKC4 alkyl, halogen, CN and N02;

R5 and R6 are each independently selected from fluorene, halogen, CN, and N02; Q is aryl or heteroaryl, and fluorene, CKC4 alkyl, C2-C4 alkenyl, halogen, alk 15oxy, CH2F, CHF2, CF3, NH2, NHAc, OH, OAc, or carboxy esters are optionally substituted, wherein one or more of these substituents may form part of a ring. In one embodiment, Q is selected from 6 200538180

Where X is selected from C, N, S, and 0; where R7, R8, R9, R10, R11, R12, R13, R] 4, R15, R16, R17, R18, and R19 are each independently selected from h, ckc4 Alkyl, c2-c4 alkenyl, halogen,

Alkoxy, CH2F, CHF2, CF3, NH2, NHAc, OH, OAc and carboxy esters, and among them R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18 and R19 One or more may form part of a ring. The general terms used to define the general formula I are as follows: Halogen means gas, fluorine, hydrogen, or Angstrom. 10 C ^ -C ^ alkyl refers to a straight-chain or branched alkyl group, each independently containing 1, 2, 3, or 4 carbon atoms, such as methyl, ethyl, η-propyl, isopropylalkyl, or n -Butyl. The alkyl group may contain one or more heteroatoms selected from 0, N and S. In other words, one or more carbon atoms on the carbon chain may be replaced by one heteroatom as described above. Examples of such groups are methyl ether, methyl ethylamine and dimethyl sulfide. 15 C2_C4 dilute groups refer to straight or branched almond groups, each independently containing 2, 3 or 4 carbon atoms, such as vinyl, isopropenyl and butenyl. An alkenyl group may contain one or more heteroatoms selected from O, N and S. In other words, one or more carbon atoms on the carbon chain may be replaced by one of the above heteroatoms. Examples of such groups are 3-acrylic acid and 3-methylsulfanyl-propenyl. 20 The term "aryl" as used herein means an aromatic ring ' having 6 to 14 carbon atoms and comprising monocyclic and polycyclic compounds, such as phenyl, benzyl or naphthyl. 7 200538180 The term "heteroaryl" as used herein means a heteroaromatic ring having 孓 14 carbon atoms, in which-or more ring atoms are oxygen, nitrogen or sulfur, and compounds containing monocyclic and polycyclic rings, For example imidazopyridine, furyl or thiophenyl. The pharmaceutically acceptable salts of the compounds of formula I and their isomers and isoforms 5 (lsoforms) also fall within the scope of the invention. It is generally understood that Certain compounds may exist in solvates, such as hydrates, as well as unsolvated forms. It is understood that the present invention encompasses all solvated forms. The pharmaceutically acceptable salts of the formulating persons also fall within the scope of the present invention. These salts are salts formed by inorganic acids such as the salt SiL salt; metal 10 salts such as sodium or potassium salts; or alkaline earth metal salts such as calcium or magnesium salts. Novel compounds according to the present invention For therapeutic use. In a bear-like form of the present invention, these compounds can be used to inhibit transient lower esophageal sphincter relaxations (TLESRs) and therefore can be used to treat or prevent gastric and esophageal reflux disease. In embodiments, the compounds according to the present invention can be used for the prevention of reflux, 15 treatment or prevention of nausea, treatment or prevention of asthma, treatment or prevention of laryngitis, treatment or prevention of lung diseases, and management from illness to health. Another aspect is the use of a compound of formula I for the manufacture of a medicament for the inhibition of transient lower esophageal sphincter relaxation, treatment or prevention of sunburn, prevention of reflux, treatment or prevention of nausea, treatment or prevention of asthma, treatment or prevention of throat 2 〇Inflammation, treatment or prevention of lung diseases and management from illness to health. Also known as a method for treating any of the aforementioned conditions, a pharmacologically effective amount of a compound of formula I is administered to a patient suffering from any of the aforementioned conditions. In one aspect of the invention, compounds of formula I are useful for the treatment and / or prevention of neurological and mental disorders, anxiety, chronic and acute pain in the heart and kn. In another aspect, the compounds are useful for the prevention and / or treatment of migraine-related pain, Uϋ pain, neuralgia such as diabetic neuropathy, arthritis, acrotalgia, lower pain, postoperative pain, and the following Many symptoms are associated with pain, including cancer, ~ streak, kidney or biliary colic, menstruation, migraine, and gout. Another aspect of the present invention is the use of a compound according to formula I for the manufacture of a medicament for the treatment or prevention of gastrointestinal disorders such as indigestion (FD). Another aspect of the present invention is the use of a compound according to formula J to manufacture a medicament for treating or preventing irritable bowel complications (IBS), such as constipation-type IBS, diarrhea-type iBS, or alternating Defecation IBS. The term "isomer," as used herein, is defined as the difference between several compounds of formula I in the functional group position and / or directionality. "Directivity," the term means stereoisomers, diastereomers Isomers, regioisomers and enantiomers. 15

The term "isoforms" as used herein is defined as the difference between several compounds of formula I in their crystalline lattices, such as crystalline compounds and amorphous compounds. The term "temporal lower esophageal sphincter relaxation (TLESR)" is defined herein based on "Mittal, RK ·, Holloway, RH ·, Penagini, R ·, Blackshaw, 20 LA ·, Dent, J., 1995; Transient lower esophageal sphincter relaxation · Gastroenterology 109, pp · 601-610 · ”o The term“ countercurrent ”is defined herein as the temporary failure of a mechanical barrier that allows fluid from the stomach to enter the esophagus. The term "gastric-esophageal reflux disease (GERD)" is defined herein based on "wm 9 200538180

Heerwarden, Μ · Α ·, Smout AJPM ·, 2000; Diagnosis of reflux disease · BailliSre's Clin · Gastroenterol. 14, pp · 759-774 · ″ o: Embodiment 3 Preparation Method 5 The compound of formula I can be obtained from the corresponding 4- Chloro-2-oxin-2-yl-pyrimidine (A) is synthesized by reacting a monothiol nucleophile in the presence or absence of a base such as sodium hydride (route 1).

10

1230-1241), 4-Chloro-2-pyridin-2-yl-pyrimidine (A) can be dissolved in phosphorus oxychloride by boiling at a high temperature in the range of 35-140 ° C. Synthesized from the corresponding 2-pyridin-2-yl-3H-pyrimidin-4-one (B) (route 2).

Path 2 冏 可 而 '2- ° than the bite-2-yl-3 kiss σ fixed -4- S with (B) can be determined by the corresponding ° ratio ° -2- A 10 15 200538 180 pulse (C) and 3- The sodium salt of ethyl-propionate was synthesized by refluxing in ethanol (pathway 3) ° This method has been described in js Moffat c / ^ m · * Soc. 1950, 1603) and such as ①) The synthesis of other compounds is described in 3 Gabriel

The compound (C) containing a fluorene functional group is usually synthesized by converting a nitrile group. Several methods are available to those skilled in the art, and typically involve the conversion of nitrile functionality to an imide or thioimide, followed by conversion to ammonia or other suitable solvents in methyl / ethanol or other suitable solvents. Ammonium or ammonium acetate equivalents, such as "Medwid ei (2 / ·, / · MM. CTzem. 1990, 33, pp 1230-1241 or Barber & Slack, 乂 Am. CTim. 5W · 1944, ρ · 1607 or Wendt α / ·, / · C / ^ m · 2004, 47, ρρ · 303-324 ·, where 0 is used to generate a formula such as, but not limited to, R] = Me or R2 = F (E) For compounds, it is advantageous from the standpoint of cleaner conversion and smaller amount of by-products to replace the acidity with the formation of imide using basic conditions. This method can expand the use of microwave technology to shorten the reaction time. By first using a catalyst amount of sodium alkoxide (such as but not limited to sodium methoxide and sodium glycolate) in a corresponding alcohol (such as but not limited to methanol or ethanol, respectively) at a temperature of up to 220 ° C at Once the microwave is sealed, the microwave is as short as 2-5 minutes, and then ammonium vaporized is added. Reaction was carried out at a temperature up to 220 ° C lower member, short duration to 112005381802-5 minutes.

Optional preparation method The compound of formula (I) can also be used in this process.

10 The formula ^^ substituted with 2-halogen | thio group is known from the corresponding and substituted or unsubstituted and can be chlorine, mo, or moth at 2 • 7), ... A suitable leaving pyrimidine (path 5) is prepared via a coupling reaction induced by a transition metal] and then coupled. For example, 2-bromopyrimidine can be sequentially treated with butyl but then with arsenic and zinc. The resulting organic zinc compound can then be coupled with rhenium in the presence of a catalyst (Negishi conditions) such as "SL Hargreaves Hit β / (M Le " 2000, 41, 1653-1656). Optionally, a 2-tin-based ° ratio. Stille reaction can be used

Conditional conformation (P. Gros and Y. Fort, 1999, 5, 754-756). Furthermore, a 2-tinylpyridine can be optionally prepared in situ from the corresponding 2-bromopyrimidine using hexamethyldistannane and 15 typical palladium catalysts such as pd (pph3) 4. The transformation reaction can also be completed by Suzuki reaction, using 2-boric acid- or boronic ester pyridine and palladium catalyst under heat or microwave heating conditions, such as "K · DeshayeS et al (Λ C / ^ m · 1991,56, 6787- 6795) ". hai

(Ο 12 200538180

Ar can be aryl or heteroaryl Hal = Cl, Br, I Path 5 Compounds of formula (F) can be reacted with a Sexually obtained pyrimidines substituted with 2-amino-4-thio groups (G. Luo et al Tet. Lett. 2002, 43, 5739-5742 and GA Breault et al. 13, 2961-2966) (route 6), for example, using sodium hydride as a test in a solvent such as DMF.

10

Ar may be an aryl group or a heteroaryl group. The six groups mentioned above are 1, 2, 3, 4, 5 and 6, and R1, R2, R3, R4, r5, r6, and Q are as defined in the above formula I.

Pharmaceutical Formula 15 For clinical use, the compound of Formula I is suitably formulated as a pharmaceutical formulation for oral administration according to the present invention. For those skilled in pharmaceutical technology, rectal, parenteral, or other routes of administration can also be considered. Therefore, the VII compounds are formulated with at least one pharmaceutically and pharmacologically acceptable carrier or adjuvant. The carrier may be in the form of a solid, semi-solid or liquid diluent. 20 In preparing an oral pharmaceutical formulation according to the present invention, the formulated person of formula J is mixed with solid and powdery ingredients such as lactose, sucrose, sorbitol, 13 200538180 ligitol, starch, amylopectin, Cellulose derivatives, gels, or other suitable ingredients, as well as disintegrating agents and lubricants such as magnesium stearate, calcium stearate, sodium organic pyrophosphate stearate, and polyethylene glycol paraffin. The mixture is then processed into small granules or compressed into tablets. 5 Soft gelatin capsules can be prepared as capsules containing a mixture of the active compounds of the present invention, vegetable oils, fats or other carriers suitable for soft gelatin capsules. Hard gelatin capsules can contain active compounds in combination with solid and powdery ingredients, such as lactose, sucrose, sorbitol, ligitol, tapioca powder, corn starch, amylopectin, cellulose derivatives, or gelatin gum. 10 The dosage for rectal administration may be in the form of a postal formulation containing a mixture of a neutral fatty salt base and the active substance; (ii) a rectal gel containing a vegetable oil, paraffin oil or other suitable vehicle and the active substance Capsule form; (iii) in the form of ready-made micro-enema or (iv) in the form of dehydrated micro-enema, add appropriate solvents before use to reconstitute. 15 Liquid oral medications can be prepared in the form of syrups or suspensions. For example, syrups or suspensions contain active compounds and formula residues consisting of bran or sugar alcohol, mixed with ethanol, water, glycerin, propylene glycol, and polyethylene glycol. . If necessary, the formulation may contain stains, seasonings, saccharin, carboxymethyl cellulose or other thickeners. Liquid oral medicines can also be prepared in the form of a dry powder and reconstituted by adding an appropriate solvent before use. The parenteral solution can be prepared by dissolving the compound of the present invention in a pharmaceutically acceptable solvent to form a solution. These solutions may also contain stability ingredients and / or buffer ingredients and are formulated as unit doses in the form of ampoule or vial. Preparation of non-oral medicated bath liquid can also be made into a dehydrated formula. Add appropriate 14 200538180 > cereal before use. In one aspect of the invention, the compound of formula j is taken once or twice daily, depending on the severity of the patient's condition.

5 weight patients, but there are still many influencing factors such as the route of administration, the age and weight of the patient, and the severity of the patient's condition. Examples The present invention will be described in more detail using the following examples. Preparation of intermediates 10 Bipyridin-2-a-3 //-pyrimidine-4- 翮

Pyridine-2 · fluorene hydrochloride (1 · 0 g, 6.5 mmoles), sodium (1 -3 -ethoxy-3-p-acetone-1-phenyl- 丨 -acid (3 · 5 grams, 25 millimoles) and sodium ethoxy compounds (0.45 grams, 6.5 millimoles) were added to ethanol (50 mL, 99 5%), and the reaction mixture was refluxed under a nitrogen atmosphere for 8 hours. , Hot filtered and concentrated. The filter residue was dissolved in water (20 ml), neutralized with hydrochloric acid (1M) and purified by reverse preparative high performance liquid chromatography. This method gave the title compound 0.68 g (60%).] H NMR (400 MHz, dmso-d6) (5 12.07 (br s, l H), 8.73 (m, 1 H), 8.29 (m, 1 H), 8.06-7.97 (m, 2 H), 7.63 (m, l H), 6.34 (d, 7 = 6.8 20 Hz, 1 H) 〇4-chloro-2pyridine-2-pico-pyrimidine

15 200538180 2-pyridin-2-yl-3 //-pyrimidin_4_one (0.945 g, 5.45 mmol) in two-gas methylbenzene (25 ml) and phosphorus oxide (10 ml, 107 mmol) A) Stir at 80 ° C ϊ Xiaori. One form of formazan and lin oxygenates were removed by vacuuming. Crushed ice (50 ml) was added to the reaction mixture followed by K2CO3 (1M, aqueous solution) until the pH reached 7. It was extracted with ethyl acetate (3 times in 50 ml) and dehydrated (MgS04). The solvent was evaporated to give the title compound (0 975 g, 93%). H NMR (400 MHz, dmso-d6) 5 7.6 (t, /=5.5 Hz, 1 H) 7.8 (d, ^ = 5.1 Hz, 1 H) 8.0 (td, 7 = 7.8, 1.2 Hz, 1 H) 8.4 (d, /=7.7 Hz, 1 H) 8.8 (m, 1 H) 8.9 (d, «7 = 5.0 Hz, 1 H). 10 HA pyridine-2-methyl hiding mm 礴

6-methyl-2-cyanopyridine (252.7 mg, 2.13 mmol) and sodium methoxide (25 ·;! Mg, 0.46 mmol) were dissolved in methanol (5 ml). The mixture was subjected to single-wave continuous microwave irradiation at 245 ° C for 625 seconds at 10000 ° C. After the addition of ammonium vapor (150.0 mg, 2.14 15 mmol), microwave irradiation was performed at 80 ° C for 720 seconds. Methanol (5 liters) was added under reduced pressure, followed by simple heating to reflux, then cooled to room temperature, and filtered and evaporated under reduced pressure. The solid was dissolved in water and washed with dichloromethane. The aqueous layer was freeze-dried to give the title compound (286.6 mg, 78%). lfi NMR (400 MHz, dmso-d6) d 9.22 (s br, 3 H), 8.07 (s, 1 H), 20 8 · 02 (t, i H), 2.59 (s, 3 H). Pyridin-2-yl) pyrimidine

16 200538180 6-fluorenyl. Bipyridin-2-hydrazone hydrochloride (0285 g, 66 quinones, mothur), sodium (1 £) -3-ethoxy-3-p-propane-phenylphenyl small acid (〇 • 872 g, 6.31 oz. • Zircon) and sodium ethoxide (0.114 g, 1.66 mol) were added to ethanol (15 ml, 99). The reaction mixture was refluxed under nitrogen for 19 hours. The residue was dissolved after evaporation of the solvent. 5 Neutralize in water with hydrochloric acid (1M). Extract the aqueous layer with EtOAc (3 times). Combine the organic layers and wash with concentrated brine, dehydrate (MgSOd, filter and evaporate the solvent to obtain the title compound 0.254 g (82%). No additional purification required in the next step

LC-MS (API-ES) m / z 188 (M ++ l) ° 4-gas-2- (6-fluorenyl ° than 0-determined 2-yl) p

The preparation procedure was as described for 4-Azine-2pyridin-2-yl-pyrimidine. 2- (6-Methyl, pyridin-2-yl) pyrimidin-4 (3 //)-one (0.099 g, 0.53 mmol) was started from dichloroethane and replaced with digas methane to obtain 0.095 g ( 87%) of the title compound. LC-MS (API-ES) m / z 206 (M ++ 1). 15 2-chloro-4- (3,4-digas-benzylsulfanyl) -pyrimidin

〇] \ ^ (60 ml) of 3,4-dichloro-thiophenol (3.0 g, 16.2 mmoles) was added to a mixture of NaH (452 mg, Π · 9 mmoles) in DMF (60 Ml) at ° C nitrogen. After 10 minutes, 2,4-diaziridine (2.66 g, 17.9 mmol) was added. 20 After 30 minutes, the reaction mixture was diluted with ethyl acetate. The solution was washed with 1M sodium hydroxide, water and concentrated brine, dried (Na2SO4) and concentrated. Recrystallization from ethyl acetate / heptane 17 200538180 alkane gave 3.3 g (70%) of the title compound. ] H NMR (400 MHz, CDC13): 5 6.79 (d, 1 Η) 7.45 (m, 1 Η) 7.59 (d, 1 Η) 7.72 (d, 1 Η) 8.28 (d9 1 H) MS (API-ES ) m / z 293 (M ++ l). 5 Preparation of final compounds

Method A 4- (3-Ranthylphenylsulfanyl) -2-heptyl-2-yl- ° D

4-Gas-2pyridin-2-yl-pyrimidine (0.04 g, 0.24 mmol) and 3-Ga-phenylthio 10 phenol (0.07 g, 0.47 mmol) in difluorenylamine (0.5 Ml) was stirred at room temperature overnight. After solvent evaporation, the reaction mixture was purified by high-performance liquid chromatography: Waters Fraction-Lynxsystem with UV, ELSD and MS; Column: Ace C8 5 // 100mm x 21, 2 mm id to obtain the title compound (0.042 g, yield 58%). NMR (400 MHz, dmso-d6) δ 7.0 (d, 7 = 5.2 Hz, 1 H) 7.5-7.6 (m, 15 2 H) 7.7 (t, 7 = 7.5 Hz, 2 H) 7.9 (t, 7 = 2.0 Hz, 1 H) 8.0 (m, 1 H) 8.7 (d, /=4.0 Hz, 1 H) 8.7 (m, 2 H). 4-"(4-pyridine, l-pyridin-2-yl-pyrimidine

Using Method A, starting with 'chloro-2pyridin-2-yl-pyrimidine (0.050 g, 0.26 20 mmol) and 4-chlorothiophenol (0.050 g, 0.35 mmol), isolated 0.0072005 200538 180 g (90% yield) of the title compound. lE NMR (400 MHz, dmso-d6) δ 8.71 (d, 7 = 4.2 Hz, 1 Η), 8.63 (d, /=5.4 Hz, 1 H), 8.19 (d, /=7.9 Hz, 1 H), 7.92 (dt, /=7.8, 1.6 Hz, 1 H), 7.74-7.60 (m, 4 H), 7.50 (m, 1 H), 6.92 (d, 7 = 5.4 Hz, 1 H ). 5 4 :: (3-Bromo-benzylthiomethyl) -2-pyrimidin-2-yl-p

Using method A, starting with 4-chloro-2pyridin-2-yl-pyrimidine (0.048 g, 0.25 mmol) and 3-bromo-thiophenol (0.071 g, 0.375 mmol), isolated 0.067 g (52% yield) of the title compound was obtained. 10 lE NMR (500 MHz, dmso ^ d6) 5 7.1 (d, /=5.5 Hz, 1 H) 7.5 (m, 2 H) 7.7 (d, 7 = 7.7 Hz, 1 H) 7.8 (d, /=8.1 Hz, 1 H) 7.9 (t, /=7.7 Hz, 1 H) 8.0 (t, 7 = 1.7 Hz, 1 H) 8.2 (d, J = 7.9 Hz, 1 H) 8.7 (d, 7 = 5.5 Hz, 1 Η) 8 · 7 (d, J = 4.9 Hz, 1 H). 2-2-yl-4- (3-trifluoromethyl-benzylsulfanyl) -pyrimidine

Using Method A, starting with 4-chloro-2pyridin-2-yl-pyrimidine (0.048 g, 0.25 mmol) and 3-trifluoromethylthiophenol (0.067 g, 0.375 mmol) were isolated. · 61 g (49% yield) of the title compound. lE NMR (500 MHz, dmso-d6) 5 7.2 (d, J = 5.5 Hz, 1 H) 7.5 (m9 1 20 H) 7.8 (t, J = 7.8 Hz, 1 H) 7.9 (td, 7 = 7.7, 1.8 Hz, 1 H) 8.0 (d, /=8.5 Hz, 1 H) 8.0 (d, 7 = 7.8 Hz, 1 H) 8.2 (d, /=9.0 Hz, 2 H) 8.7 19 200538 180 (d, ϋ · 4 Hz, 1 Η) 8.7 (d, /=4.6 Hz, 1 Η). Fixed fluoromethyl-loaded with a pinane) _Pyrimidine

5 10 Method A starts with 4-chloro · 2pyridin-2-yl-pyrimidine (0.020 g, 0.104 mmol) and 'trifluoromethyl-thiophenol (0.032 g, 0.209 mmol) ), 002 g (68% yield) of the title compound was isolated. 'Η NMR (400 MHz, CDC13): 5 7.1 (d, 7 = 5.3 Hz, 1 Η) 7.5 (m, 1 Η) 7.9 (m, 5 Η) 8.2 (dt, /=7.9, 0.9 Hz, 1 H ) 8.7 (d, /=5.4 Hz, 1 H) 8.7 (d, /=4.7 Hz, 1 H). Soil: (3,4-a random-base radical scorch base ratio p-determined 2-base-determined

Using Method A, starting with 4-chloro-2pyridin-2-yl-pyrimidine (0.020 g, 0.104 mmol) and 3,4-digas-thiophenol (0.045 g, 0.25 mmol), isolated 0.019 g (48% yield) of the title compound. 15] H NMR (400 MHz, dmso-d6) 5 7.0 (d, /=5.4 Hz, 1 H) 7.5 (m, 1 H) 7.7 (dd, 7 = 8.4, 2.1 Hz, 1 H) 7.8 (d, /=8.4 Hz, 1 H) 7.9 (dt, /=7.7, 1.8 Hz, 1 H) 8.1 (d, /=2.1 Hz, 1 H) 8.2 (d, 7 = 7.8 Hz, 1 H) 8.7 (d, /=5.4 Hz, 1 H) 8.7 (m, 1 H). 4- (3-methylamino-benzylsulfanyl) -2-pyridin-2-yl-pyrimidine 20 200538180

Using Method A, starting with 4-chloro-2pyridin-2-yl-pyrimidine (0.048 g, 0.25 mmol) and 3-methoxy-thiophenol (0.053 g, 0.375 mmol), isolated 0.048 g (43% yield) of the title compound was obtained.

5 JH NMR (500 MHz, dmso-d6) δ 3.8 (s, 3 Η) 6.9 (d, /=5.5 Hz, 1 Η) 7.2 (ddd, /=8.3, 2.4, 0.6 Hz, 1 Η) 7.3 (m , 2 H) 7.5 (m, 2 Η) 8.0 (dt, /=7.8, 1.8 Hz, 1 H) 8.3 (d, /=7.9 Hz, 1 H) 8.6 (d, 7 = 5.5 Hz, 1 H) 8.7 (m, 1 H) 〇Specific 2-yl-4-m-methythiothio-pyrimidine

10 Using method A, starting from 4-gas-2pyridin-2-yl-pyrimidine (0.048 g, 0.25 mmol) and 3-methoxy · thiophenol (0.047 g, 0.375 mmol), isolated 0.043 g (41% yield) of the title compound. ] H NMR (500 MHz, dmso-d6) δ 2.4 (s, 3 Η) 6.9 (d, 7 = 5.5 Hz, 1 H) 15 7.4 (m, 1 H) 7.5 (m, 4 H) 8.0 (td, 7 = 7.6, 1.7 Hz, 1 H) 8.3 (dt, /=7.9, 1.1 Hz, 1 H) 8.6 (d, J = 5.4 Hz, 1 H) 8.7 (m, 1 H). jbis (4-Gas-phenylsulfane) -2-pyridine-2-some-pyrimidine

F Method A starts with 4-chloro-2pyridin-2-yl-pyrimidine (0.020 g, 0.104 21 200538180 亳 mol) and 4-fluoro-thiophenol (0.032 g, 0.209 mmol). 0.018 g (59% yield) of the title compound was isolated. lR NMR (500 MHz, dmso-d6) δ 6.9 (d, /=5.4 Hz, 1 Η) 7 4 (m 2 Η) 7.5 (m, 1 Η) 7 · 8 (m, 2 Η) 8.0 (td, /=7.6, 1.8 Hz, 1 Η) 8.2 (dt,, 5 /=7.9, 1 · 1 ， ζ, 1 Η) 8.6 (d, / = 5.5 Ηζ, 1 Η) 8.7 (m, 1 Η). • 乂 [4- (2-pyridin-2-yl-pyrimidin-4-ylsulfanyl) -benzyl acetamidine

Method A starts with 4-Gas-2pyridin-2-yl-pyrimidine (0.020 g, 0.104 mol) and (4-thiol-phenyl) -acetamide (0.034 g, 0.203) Mmol), 10 isolated 0.010 g (19% yield) of the title compound. lH NMR (500 MHz, dmso-d6) d 2.1 (m, 3 H) 6.8 (d, /=5.4 Hz, 1 H) 7.5 (m, 1 H) 7.6 (d, /=8.7 Hz, 2 H) 7.8 (d, 7 = 8.5 Hz, 2 H) 8.0 (td, 7 = 7.8, 1.7 Hz, 1 H) 8.3 (d, 7 = 7.8 Hz, 1 H) 8.6 (d, /=5.5 Hz, 1 H) 8.7 (m, 1 H) 10.3 (m, 1 H). 15 iii3,4-dimethoxy-benzylsulfanyl) -2-pyridin-2-yl-pyrimidine

Method A starts with 4-Gas-2pyridin-2-yl- ° dense bite (0.020 g, 0.104 mmol) and 3,4-dimethoxy · thiophenol (0.039 g, 0.1 23 mmol), and 0.018 g (34% yield) of the title compound was isolated. 20 H NMR (500 MHz, dmso-d6) δ 3.8 (m, 3 Η) 3.9 (m, 3 Η) 6.8 (d, 22 200538180 7 = 5.5 Hz, 1 Η) 7.2 (m, j H) 7 3 ( m, 2 Η) 7.5 (m, 1 Η) 8.0 (td, /=7.8, 1.8 Hz, 1 H) 8.3 (dt, /=7.9, 1.0 Hz, 1 H) 8.6 (d, /=5.4 Hz, 1 H) 8.7 (m, 1 H) 〇t formamidine-6_ (2_ ° than -pyrimidin-4-ylsulfane)

Method A starts with 4-chloro_2pyridin-2-yl-methylpyridine (0.020 g, 0.14 mmol) and 6-thiol-4-methyl_σg Keto-2-one (0.040 g, 0.21 mole), 0.026 g (13% yield) of the title compound was isolated. H NMR (500 MHz, dmso-d6) 5 2.5 (s, overlapped by dmso-d6, 3 10 Η) 6.5 (d, 7 = 1.2 Hz, 1 Η) 7.1 (d, 7 = 5.5 Hz, 1 H) 7.5 (m, 1 H) 7.7 (m, 1 H) 7.8 (d, 7 = 1.7 Hz, 1 H) 8.0 (m, 2 H) 8.3 (d, /=7.9 Hz, 1 H) 8.7 (d, / = 5.4 Hz, 1 H) 8.7 (m, 1 H). 14- (2-sound bite-2-some-pyrimidine-4 · some serylphenyl-acetic acid

15 Using Method A, starting with 4-chloro-2pyridin-2-yl-pyrimidine (0.020 g, 0.104 mmol) and 4-thiol-phenyl-acetic acid (0.038 g, 0.22 mmol), isolated 0.033 g (78% yield) of the title compound was obtained. ] H NMR (500 MHz, dmso-d6) δ 3.7 (s, 3Η) 6.9 (d, 7 = 5.4 Hz, 1 H) 7.5 (d, /=8.3 Hz, 2 H) 7.5 (m? 1 H) 7.7 (d? / = 8.2 Hz, 2 H) 7.9 (td, 20 /=7.7, 7.8 Hz, 1 H) 8.2 (d, /=7.9 Hz, 1 H) 8.6 (d, 7 = 5.5 Hz, 1 H) 23 200538180 8.7 (dd, 7 = 4.7, 0.9 Hz, 1 H) 〇2- ° Specific-2-yl-4- (r--2-ylsulfanyl) -p

Using method A, starting from 4-chloro-2pyridin-2-yl-pyrimidine (0.020 g, 0104 5 mol) and 2-σ ratio thiothio (0.032 g, 0.209 mmol), isolated 0.018 g (64% yield) of the title compound was obtained.

! H NMR (400 MHz, dmso-d6) δ 7.3 (d, /=5.4 Hz, 1 Η) 7.5 (m, 2 Η) 7.9 (d, 7 = 7.9 Hz, 1 H) 7.9 (tt, J = 7.7 , 2.0 Hz, 2 H) 8.2 (d, /=7.9 Hz, 1 H) 8.7 (dt, /=4.8, 0.9 Hz, 1 H) 8.7 (d, 7 = 5.4 Hz, 1 H) 10 8.7 (m, 1 H) 〇2 ~ ° than p-Ding-2-yl-4- (° Sial-2-ylthioalkyl) -p dense p-Ding

Use Method A starting with 4-chloro-2pyridin-2-yl-pyrimidine (0.020 g, 0.104

Mmol) and thiazole-2-thioxo (0.032 g, 0.209 mmol), and 0.016 g (54% yield) of the title compound was isolated. 4 NMR (400 MHz, dmso-d6) 5 7.3 (d, · 7 = 5 · 4 Ηζ, 1 Η) 7.5 (ddd, ^ = 7.5, 4.7, 1.1 Hz, 1 Η) 8.0 (td, J = 7.7, 1.8 Hz, 1 H) 8.1 (d, 3.4 Hz, 1 H) 8.1 (d, 3.4 Hz, 1 H) 8.3 (d, 7 = 7.9 Hz, 1 H) 8.7 (ddd, ^ = 4.8, 1.6, 0.9 Hz , 1 H) 8.8 (d, 7 = 5.3 Hz, 1 H) ° difluorophenyl) thio 1-2-pyrimidine-2-its-pyrimidine 24 20 200538180

F F

4-Gas-2 Methyl-2-yl-pyrimidine (0.054 g, 0.28 mmol) and 3,4-difluorothiophenyl (32 ml, 0.28 mmol) Add 0 ° C NaH (95%, 0.009 g, 0.28 mmol) to the solution of dehydrated DMF. Stir for 5 hours at 0 ° C for 1 hour and 15 minutes. Sodium hydroxide (1M) and EtOAc were added and the layers were separated. The aqueous layer was extracted with EtOAc (3 times). The combined organic layer was washed (water and concentrated brine), dehydrated (MgS04), filtered and evaporated under reduced pressure, and then purified by high performance liquid chromatography to obtain 0.045 g (53%) of the title compound. lH NMR (400 MHz, DMSO-d6): 5 7.06 (d, 1H), 7.53 (m, 1H), 10 7.64 (m, 2H), 7.95 (m, 2H), 8.21 (d, 1H), 8.66 ( d, 1H), 8.73 (m, 1H), LC-MS (API-ES) m々302 (M ++ 1). 4-Γ (3,4-Diammonyl) thio 1- (6-methylpyridin-2-yl) pyrimidine

CI CI

Prepared according to Method B, using 4-gas-2- (6-methylpyridin-2-yl) pyrimidine (0.090 g, 0.44 mmol) and 3,4-dichloro · thiophenol (53 μl, 0.42 Millimolar) to produce 0.059 g (39%) of the title compound. ] H NMR (400 MHz, DMS0-d6): 5 2.56 (s, 3H), 7.16 (dd, 1H), 7.39 (d, 1H), 7.71 (m, 1H), 7.82 (m, 2H), 8.01 ( d, 1H), 8.10 (d, 1H), 8.66 (m, 1H); LC-MS (API-ES) m々348 (M ++ 1).

Method C 4- (3,4-Difluorobenzyl stone pentane) -2- (5-fluoro-pyridine-2-some V dense 25 20 200538180

2-bromo-5-fluoro, pyridine (352 mg, 2.0 mmoles), hexamethylditin (76 mg, 2.31 mmoles) and tetrakis (triphenyl) palladium phosphonium (92 mg) (0,08 mol) in degassed toluene, heated to 80 ° c overnight under nitrogen. Next, 5 2-gas-4_ (3,4-dichlorophenylsulfanyl) -pyrimidine (525 mg, 1.8 mmol) and tetrakis (diphenyl; μ 粦 Ιε (〇) (92 μg) were added. , 0.08 mmol), and the mixture was heated to 110 C for 3 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. Reflection chromatography (100% heptane to 100% ethyl acetate) provided 30 mg of the title Compound: lH NMR (400 MHz, CDC13): δ ppm 6.89 (d, 1 Η) 7.48-7.52 (m, 1 10 Η) 7.54 (m, 1 Η) 7.60 (d, 1 Η) 7.81 (d, 1 Η) ) 8.35 (m, 1 Η) 8.60 (d, 1 Η) 8.66 (d, 1 Η) Experimental details

° Bite bite-2-methyl vein is commercially available from Avocado (Avocado Research, Shore Road, Port of Heysham Industrial Park, Heysham, Lancashire LA3 2XY, United Kingdom) ° Unless otherwise specified, the chemicals used are all available Commercially available, the drug is well known to the public and does not require additional purification when used. Biological evaluation The function evaluation of mGluR5 antagonist cell line to express mGluR5D 20 The properties of the compounds of the present invention can be analyzed for pharmaceutical activity using standard assays. Examples of glutamate receptor analysis are well-known techniques. For example, Aramori a /., 8: 757 (1992)-Tanabe et alf Neuron 8: 169 (1992)-Miller et al.y J. 26 200538180 ⑼ce 15: 6103 (1995) and Balazs, d α / ..., 69: 151 (1997). The teaching methods described in these publications are incorporated herein as reference materials. The compounds of the present invention can be easily studied by the FLIPR analysis method, which measures intracellular calcium mobility, [Ca2 +] i shows 5 mGluR5 in the cell, or other analysis such as IP3 as a measurement of the amount of squamyl inositol . FL1PR Assay described in WO97 / 05252. Cells expressing human mGluR5D were seeded at a density of 100,000 cells per well in a 96-well black-edge black-plated plate covered with collagen and clean at the bottom. The experiment was completed within 24 hours after seeding. All analyses were completed in 10 buffers containing 127 mM NaC, 5 mM KC1, 2 mM MgCl2, 0.7 mM NaH2P04, 2 mM CaCl2, 0.422 mg / ml NaHC03, 2.4 mg / ml HEPES, 1.8 mg / ml glucose and 1 mg / ml BSA Fraction IV (pH 7.4). Cells were injected into a 96-well culture plate and cultured for 00 minutes in the above buffer solution containing 4 // M ethoxymethylethyl-type fluorescent calcium indicator 15 fluo_3 (Molecular Probes, Eugene, Oregon) at 0.01% polyoxygen Ethylene / polyoxypropylene polyacid (patented nonionic polyalcohol surfactant-CAS number 9003-11-6). After the incubation period, the fluO-3 buffer was removed and replaced with fresh analysis buffer. FLIPR experiments were performed using a CCD camera with a 0.800 watt laser and a shutter of 0.4 seconds. The excitation and emission wavelengths were 488 nm and 562 20 nm, respectively. Each assay starts in a cell culture plate with 160 // 1 buffer per well. «Without a few tablets add 40 and then add from the collaborative tablet. The interval between antagonistic and synergistic addition was 90 seconds. Immediately after the two additions, the fluorescence signal was sampled 50 times at intervals of 1 shift, and then 3 times every 5 seconds. The measured response is expressed as the difference in background glory signal from the response peak minus the sampling period. The decision 27 200538180 will use a linear least squares adaptation procedure. ΓΡ3 Assay Another mGluR5d functional assay described in WO97 / 05252 is based on the phospholipids inositol conversion number. Receptor activation stimulates phospholipase C production and leads to increased production of 5 inositol 1,4,5 triphosphate (IP3). GHEK stably expressing human mGluR5d was inoculated into a 24-well culture plate covered with poly-L·lysine, and the inoculation amount was 40 X 104 cells per well in the medium containing 1 // Ci / well [3H] inositol. Cells were cultured overnight (16 hours), then washed three times and incubated at 37 ° C for 1 hour in HEPES buffer solution (146 mM NaCl, 4.2 mM 10 Kα, 0.5 mM MgCl2, 0.1% glucose, 20 mM HEPES, pH 7.4) Supplement 1 unit / ml glutamate pyruvate transaminase and 2 mM pyruvate. The cells were washed again with a HEPES buffer solution and pre-cultured in a HEPES buffer solution containing 10 mM LiCl for 10 minutes. The compound was repeatedly cultured at 37 ° C for 15 minutes, followed by addition of glutamic acid (80 // · M) or DHPG (30 // M), respectively, followed by further incubation for 15 minutes. Add 0.5 ml of iced peroxy acid (5%) and place at 4 ° C for at least 30 minutes to stop the reaction. Samples were collected in 15 ml polypropylene tubes and the inositol salt was separated using an ion exchange resin (Dowex AG, X8 formate form, 200-400 mesh, BIORAD) column. Separation of inositol discoate was performed in the first elution of glycerophospholipid and inositol with 8 ml of 30 mM ammonium ammonium. Then the 'total inositol phosphate 20 salt was washed with 8 ml of 700 mM ammonium formate / 100 mM formic acid and collected in a scintillation counting bottle. The eluate was then mixed in 8 ml scintillator and combined with [3H] inositol as determined by the scintillation count. The linear least squares adaptation program was used to plot the disintegration count per minute of the duplicate samples and determine the IC50. Abbreviation 28 200538180 BSA Bovine Serum Albumin CCD Charge Coupled Element CRC Concentration Response Curve DHPG 3,5-two Disintegration amount of phenylglycinate 5 DPM per minute EDTA ethylenediamine tetraacetic acid FLIPR fluorescence image disk reader GHEK Human embryo kidney with GLAST GLAST glutamic acid / aspartic acid transporter 10 HEPES 4- ( 2-Hydroxyethyl) -1-p-diazahexylethanesulfonic acid (buffer) In general, compounds with an IC5G value of less than 10,000 nM in the above analysis are effective. In one aspect of the present invention, the IC50 value is lower than 1 β Μ. Furthermore, the IC50 value of the present invention is lower than 100 nM. Screening for compounds with anti-TLESR activity 15 Adult labrador retrievers trained on Pavlov slings, regardless of gender, were used as experimental subjects. Dogs shaping the mucosa into the skin's artificial esophagus are allowed to recover completely before starting the experiment. Mobility measurement Jian Luzhi, after about 17 hours of fasting but unlimited water supply, a sleeve with more than 20 lumens / parts with perforations on the sides (Dentsleeve, Adelaide, South Australia) was introduced through the artificial esophagus to measure Pressure on the stomach, lower esophageal sphincter (LES), and esophagus. Fill the fitting with clean water using a low adaptive pressure gauge's perfusion pump (Demsleeve, Adelaide, South Australia). Measure the direction of the swallowed trachea through the mouth, and additionally monitor the acid test on the lower esophageal sphincter 29 200538180 square 3 cm. All signals were amplified and obtained at 10 Hz using a personal computer. When an undoped gastric / lower esophageal sphincter fasting phase III motor nerve activity baseline has been obtained, intravenous (i.v., 0.5 ml / kg) placebo (0.9% NaCl) or test compound is entered into the forelimb vein. 10 minutes after intravenous injection, 5 perfusion nutrition meals (10% peptone, 5% D-glucose, 5% intravenous fat emulsion, pH 3.0) enter the stomach through the central lumen of the accessory at a rate of 100 ml / min to the final volume 30 ml / kg. After the nutritional meal was injected, ventilation was continued at a rate of 500 ml / min until the pressure in the stomach reached 10 ± 1 mm Hg. The perfusion pump was then used to inflate or deflate the stomach to maintain the experimental pressure at this standard. The duration of experiment 10 was 45 minutes from the start of nutrition infusion to the end of insufflation. This procedure has been identified as a trusted method for triggering TLESRs. TLESRs are defined as a rate of reduction of lower esophageal sphincter pressure (reference to gastric pressure) greater than 1 mmHg / s. The relaxation should not be before the signal of the pharynx, 2 seconds before the beginning of the relaxation, and this case is classified as relaxation caused by swallowing. The pressure difference between the lower esophageal sphincter 15 and the stomach should be less than 2 mm Hg, and the period of complete relaxation lasts more than 1 second. [Brief description of the diagram] None [Description of the main component symbols] None 30

Claims (1)

200538180 10. Scope of patent application: 1. A compound having the following formula I R, R2, R3, and R4 are each independently selected from Η, (ν (: 4 alkyl, halogen, CN, and N02; R5 and R6 are each independently selected from Η, halogen, CN, and Ν02; Q is aryl Or heteroaryl, optionally carboxylated by H, CrC: 4 alkyl, C ^ C: 4 alkenyl, hydrogen, alkoxy, CH2F, CHF2, CF3, NH2, NHAc, OH, 〇Ac Substitution, wherein one or more of these substituents may form part of a ring; and pharmaceutically acceptable salts, hydrates, isoforms and / or optical isomers thereof. 2. If the compound in the scope of patent application No. 丨, its Q is selected from Where X is selected from C, N, S, and 0; wherein R7, R8, R9, R10, R11, R12, R13, R14, R15, RI6, 31 15 200538180 R17, R18, and R19 are each independently selected from Η, C] -C4 alkyl, C2-C4 alkenyl, halogen, alkoxy, CH2F, CHF2, CF3, NH2, NHAc, OH, OAc, and sulfonyl groups, and R7, R8, R9, R10, Rn One or more of R12, R13, R14, R15, R16, R17, R18 and R19 may form a part of the ring. 3. The compound according to item 1 or 2 of the scope of patent application, which is selected from the group consisting of: 4- (3-chloro-phenylsulfanyl) -2-arimidin-2-yl-pyrimidine; 4-[(4- Phenyl) thio] -2-caramidin-2-yl-pyrimidine; 4- (3-bromo-phenylsulfanyl) -2-pyridin-2-yl-pyrimidine; 2-pyridine-2 -Yl-4- (3-difluoromethyl-phenylsulfanyl) -orally determined σ, 2- ^ ratio ° -2 * • yl 10 -4- (4-difluoromethyl-phenyl Sulfuryl) -0 dense stilbene, 4- (3,4-Dioxanyl-phenylsulfanyl) -2-yl-. Stilbidine, 4 · (3-methyllactyl-benzylsulfanyl ) · 2-ϋίίσ 定 -2-yl_ο dense bite, 2- ° ratio σdent-2-yl-4-m-methylbenzylsulfanyl-codidine, 4- (4-gas-benzylsulfide Carbo) -2- ° Specific -2-ylidene, A ^-[4- (2-σ Ratio ° Dynyl-2-yl-0 Dense-4-ylsulfanyl) -phenyl]- Ethylamine, 4- (3,4-dioxo-1-yl-phenylsulfanyl)-2-15 0 than 0-2-yl-oral sigma, 4-methyl-6-(2- hydrazidine-2-yl-oxo-4-ylsulfanyl)-cremen-2-one; [4- (2-pyridin-2-yl-pyrimidin-4-ylsulfanyl) ) -Phenyl] -acetic acid; 2-〇 than 17-determin-2-yl-4- (10 than bite-2-ylsulfanyl) -11-deuterine 11-diene, 2-117 than deutero-2-yl- 4- (1? Oxazol-2-ylsulfanyl) -pyrimidine; 4- [(3,4-difluorophenyl) thio] -2-pyridine-2-yl-pyrimidine; 4-[(3,4-difluorophenyl) thio] -2- (6-methylpyridine -2-yl) pyrimidine and 20 4- (3,4-difluorophenylsulfanyl) -2- (5-fluoro-romidin-2-yl) pyrimidine. 4. As described in item 1 of the scope of patent application Compound for therapeutic use. 5. The compound according to item 4 of the patent application, wherein the treatment is to treat or prevent gastro-esophageal reflux disease. 6. A compound according to item 1 of the patent application or its pharmacy Acceptable 32 200538180 Use of salts or optical isomers thereof for the manufacture of a drug that inhibits transient lower esophageal sphincter relaxation. 5 10 7. One as described in the first patent application Use of a compound or a pharmaceutically acceptable salt thereof or an optical isomer thereof for the manufacture of a medicine for treating or preventing a gastro-esophageal reflux disease. 8. A pharmaceutical composition, It contains, as an active ingredient, a compound as described in the scope of patent application No. 1 and a pharmacologically and pharmaceutically acceptable carrier. 9. A method for preparing a compound of formula I Method, which includes the following steps: a) Synthesis of 2-pyridin-2-yl-3 //-pyrimidin-4-one, by the corresponding pyridine-2-formamidine and sodium 3-hydroxy-ethyl acrylate The salt is reacted; b) synthesizing 4-gas-2-carolin-2-yl-pyrimidine, which is performed by refluxing the 2-pyridin-2-yl- ° -determined 4- 3 with the same emulsion, c ) A compound of formula I is synthesized by reacting the 4-chloro-2-arimidin-2-yl-pyrimidine (A) with a thiol nucleophile. 15 33 200538180 VII. Designated Representative Map: (1) The designated representative map in this case is: (). (2) Brief description of the component symbols in this representative map: 8. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: 4