WO2016023459A1 - 吡咯磺酰类衍生物、其制备方法及其在医药上的应用 - Google Patents

吡咯磺酰类衍生物、其制备方法及其在医药上的应用 Download PDF

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WO2016023459A1
WO2016023459A1 PCT/CN2015/086603 CN2015086603W WO2016023459A1 WO 2016023459 A1 WO2016023459 A1 WO 2016023459A1 CN 2015086603 W CN2015086603 W CN 2015086603W WO 2016023459 A1 WO2016023459 A1 WO 2016023459A1
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group
aryl
alkyl
heteroaryl
preparation
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PCT/CN2015/086603
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French (fr)
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秦引林
金秋
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江苏柯菲平医药股份有限公司
南京柯菲平盛辉制药有限公司
南京柯菲平制药有限公司
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Publication of WO2016023459A1 publication Critical patent/WO2016023459A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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 present invention relates to a novel class of pyrrolesulfonyl derivatives, a process for the preparation thereof, and a pharmaceutical combination containing the same, and as a therapeutic agent, particularly as a gastric acid secretion inhibitor and a potassium ion competitive acid blocker (P-CABs) )the use of.
  • a novel class of pyrrolesulfonyl derivatives a process for the preparation thereof, and a pharmaceutical combination containing the same, and as a therapeutic agent, particularly as a gastric acid secretion inhibitor and a potassium ion competitive acid blocker (P-CABs) )the use of.
  • P-CABs potassium ion competitive acid blocker
  • proton pump inhibitors represented by omeprazole have been widely used clinically by inhibiting gastric acid secretion for the treatment of peptic ulcer, reflux esophagitis and Zhuo-Ai syndrome.
  • Long-term clinical applications have found that existing proton pump inhibitors have limitations in pharmacokinetics and pharmacodynamics. For example, the effect of administration time on the efficacy of the drug; slow acid onset at night; unstable under acidic conditions (need to be formulated into intestinal preparations); dependence on CYP450 enzyme (resulting in significant individual differences).
  • Potassium competitive acid blocker (Potassium-Competitive Acid Blockers, P -CABs) is generated by direct action, reversible processes competitively inhibiting H + / K + -ATP enzyme of K +.
  • P-CABs are characterized by lipophilicity, weak basicity, high dissociation constant and stability under low pH conditions.
  • P-CABs bind to H + /K + -ATPase in an ionized form, preventing H + transport and acid secretion into the gastric cavity, and rapidly increasing the pH in the stomach.
  • Animal experiments and clinical studies have shown that P-CABs have rapid onset of action and can achieve maximum therapeutic effect within one hour; blood concentration is linearly related to oral dose, and it is easier to achieve the best acid suppression effect.
  • the structure provided by the present application is a compound represented by formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, Or a pharmaceutically acceptable salt:
  • X is selected from CR 4 or N.
  • Y is selected from O or NR 5 .
  • R 1 is selected from an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocycloalkyl group, aryl group or heteroaryl group is optionally one or more Selected from hydrogen, halogen, cyano, nitro, hydroxy, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -OR 6 , -NR 6 R 7 , Substituted by a substituent of -C(O)NR 6 R 7 , -S(O) m R 6 , -C(O)R 6 , -O C(O)R 6 or -C(O)O R 6 .
  • R 2 is hydrogen, halogen, alkyl, cyano, nitro, hydroxy, aryl, or ester.
  • R 3 is hydrogen, halogen, alkyl, cyano, nitro, hydroxy, aryl, or ester.
  • R 4 is hydrogen, halogen, alkyl, cyano, nitro, or hydroxy.
  • R 5 is hydrogen, an alkyl group, or an aryl group.
  • R 6 or R 7 are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocycloalkyl group, aryl group or Any one or more heteroaryl groups selected from the group consisting of halogen, cyano, hydroxy, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Substituted by a substituent of a carboxyl group, an amide group or a carboxylate group.
  • n is selected from 0, 1, or 2.
  • R 1 is selected from an aryl group or a heteroaryl group, wherein the aryl group or heteroaryl group is optionally selected from one or more selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, alkyl, Haloalkyl, hydroxyalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -OR 6 , -NR 6 R 7 , -C(O)NR 6 R 7 , -S(O) m R 6, -C (O) R 6 , -O C (O) R 6 or -C (O) O R 6 is substituted with a substituent.
  • R 6 or R 7 are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocycloalkyl group, aryl group or Any one or more heteroaryl groups selected from the group consisting of halogen, cyano, hydroxy, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Substituted by a substituent of a carboxyl group, an amide group or a carboxylate group.
  • n is selected from 0, 1, or 2.
  • R 1 is selected from the group consisting of one living substituent:
  • the substituent is halogen, cyano, nitro, hydroxy, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocycloalkyl, -OR 6 , -NR 6 R 7 , -C(O)NR Substituents of 6 R 7 , -S(O) m R 6 , -C(O)R 6 , -O C(O)R 6 or -C(O)OR 6 are substituted.
  • R 6 or R 7 are each independently selected from a hydrogen atom, an alkyl group, wherein the alkylaryl group is optionally one or more selected from the group consisting of halogen, cyano, hydroxy, amino, alkyl, haloalkyl, hydroxyalkyl, alkane Substituents of an oxy group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, a carboxyl group, an amide group or a carboxylate group are substituted.
  • n is selected from 0, 1, or 2.
  • the present invention provides a compound of the formula (I) selected from the group consisting of:
  • the invention further relates to a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer thereof A conformation, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt and a pharmaceutically acceptable carrier, excipient or diluent.
  • the present invention also relates to a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or Use of a pharmaceutically acceptable salt or a pharmaceutical composition comprising the same for the preparation of a gastric acid secretion inhibitor.
  • Another aspect of the invention relates to a method for inhibiting gastric acid secretion comprising administering to a patient in need of treatment an effective amount of a compound of the formula (I) or a tautomer thereof, a mesogen, a racemic thereof , enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts Or a pharmaceutical composition comprising the same.
  • Another aspect of the invention relates to a compound represented by (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or Use of a pharmaceutically acceptable salt or a pharmaceutical composition comprising the same for the preparation of an H + /K + - adenosine triphosphatase (H + /K + -ATPase) inhibitor.
  • H + /K + - adenosine triphosphatase H + /K + -ATPase
  • Another aspect of the invention relates to a compound represented by (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or Use of a pharmaceutically acceptable salt or a pharmaceutical composition comprising the same in the preparation of potassium ion competitive acid blockers (P-CABs).
  • P-CABs potassium ion competitive acid blockers
  • the invention provides for treating or preventing peptic ulcer, Zhuo-Ai syndrome, gastritis, erosive esophagitis, reflux esophagitis, symptomatic gastroesophageal reflux disease, Barrett's esophagitis, functional dyspepsia, Use of Helicobacter pylori infection, gastric cancer, gastric MALT lymphoma, ulcers caused by non-steroidal anti-inflammatory drugs or drugs for hyperacidity or ulceration caused by post-operative stress; or in the preparation of inhibition for peptic ulcer, acute A method of stress ulcers, hemorrhagic gastritis, or drugs for upper gastrointestinal bleeding caused by invasive stress.
  • the peptic ulcer is selected from the group consisting of a gastric ulcer, a duodenal ulcer or an anastomotic ulcer; and the symptomatic gastroesophageal reflux disease is selected from a non-erosive reflux disease or a gastroesophageal reflux disease without esophagitis. method.
  • Alkyl means a saturated aliphatic hydrocarbon group. A straight or branched chain group of 1 to 20 carbon atoms is included. Preference is given to medium-sized alkyl groups having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl, pentyl and the like. More preferred are lower alkyl groups having 1 to 4 carbon atoms such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl or t-butyl groups and the like.
  • the alkyl group may be substituted or unsubstituted, and when substituted, preferred groups are: halogen, C 2 -C 6 alkenyl, C 6 -C 10 aryl, C 5 -C 10 heteroaryl, halogen C 1 -C 6 alkyl, 4 to 8 membered heteroalicyclic, hydroxy, C 1 -C 6 alkoxy, C 6 -C 10 aryloxy.
  • Cycloalkyl means a 3 to 8 membered all-carbon monocyclic, all-carbon 5/6 or 6/6-membered fused or polycyclic fused ring ("thickened” ring means each in the system The ring shares an adjacent pair of carbon atoms) groups with other rings in the system, wherein one or more of the rings have a fully linked pi-electron system, and examples of cycloalkyl groups (not limited to) are cyclopropane, cyclobutane, Cyclopentane, cyclopentene, cyclohexane, adamantane, cyclohexadiene, cycloheptane and cycloheptatriene.
  • Cycloalkyl groups are substitutable and substituted.
  • the substituent is preferably one or more groups each selected from the group consisting of: hydrogen, hydroxy, thiol, oxo, lower alkyl, lower alkoxy, lower cycloalkyl, lower heteroalicyclic , lower haloalkoxy, alkylthio, halogen, lower haloalkyl, lower hydroxyalkyl, lower cycloalkylalkylene, lower heteroalicyclic alkylene, aryl, heteroaryl, alkoxycarbonyl, Amino, alkylamino, alkylsulfonyl, arylsulfonyl, alkylaminosulfonyl, arylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, alkylaminocarbonyl, arylaminocarbonyl, Alkylcarbonylamino, arylcarbonylamino,
  • Aryl means an all-carbon monocyclic or fused polycyclic group of 6 to 14 carbon atoms having a fully conjugated pi-electron system. “Aryl” includes:
  • a six-membered carbon aromatic ring such as benzene
  • a bicyclic ring in which at least one ring is a carbon aromatic ring such as naphthalene, anthracene and 1,2,3,4-tetrahydroquinoline;
  • an aryl group includes a six-membered carbon aromatic ring and a six-membered heterocyclic ring containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. It is the connection point on the carbon aromatic ring.
  • the aryl group does not contain, nor does it overlap in any way with the heterocyclic aryl groups respectively defined below.
  • the resulting ring system is a heteroaryl group rather than an aryl group.
  • Non-limiting examples of aryl groups are phenyl, naphthyl.
  • the aryl group can be substituted or unsubstituted.
  • preferred groups are: hydrogen, hydroxy, nitro, cyano, oxo, lower alkyl, lower alkoxy, lower cycloalkyl, lower heteroalicyclic, lower haloalkoxy, alkane Thio group, halogen, lower haloalkyl group, lower hydroxyalkyl group, lower cycloalkylalkylene group, lower heteroalicyclic alkylene group, aryl group, heteroaryl group, alkoxycarbonyl group, amino group, alkylamino group, alkyl group Sulfonyl, arylsulfonyl, alkylaminosulfonyl, arylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, alkylaminocarbonyl, arylaminocarbonyl, alkylcarbonylamino, arylcarbonyl Amino group.
  • Heteroaryl means a monocyclic or fused ring radical of 5 to 14 ring atoms containing one, two, three or four ring heteroatoms selected from N, O or S, the remaining ring atoms being C In addition, it has a fully conjugated ⁇ -electron system. Heteroaryl refers to:
  • N N
  • O organic radical
  • S sulfur
  • a heteroaryl group includes a 5-6 membered heteroaromatic ring and a 5-6 membered cycloalkyl group.
  • one of the rings contains one or more heteroatoms and the attachment sites are on the heteroaromatic ring.
  • the total number of sulfur and oxygen atoms on the heteroaryl group exceeds 1, these heteroatoms are not adjacent one another. In some embodiments, the total number of sulfur and oxygen atoms in the heteroaryl group does not exceed two. In some embodiments, the total number of sulfur and oxygen atoms in the heteroaryl group does not exceed one.
  • heteroaryl groups include, but are not limited to, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, triazole, pyrimidine, pyridine, pyridone, imidate, pyrazine, pyridazine, anthracene, Azaindene, benzimidazole, benzotriazole, porphyrin, anthrone, quinoline, isoquinoline, quinazoline, thienopyridine, thienopyrimidine, and the like.
  • Preferred examples of such groups are pyrrolyl, pyrazolyl, imidazolyl, triazolyl, furyl, oxazolyl, thienyl, thiazolyl, benzimidazolyl, benzotriazole.
  • One or all of the hydrogen atoms in the heteroaryl group may be substituted with hydrogen, hydroxy, nitro, cyano, oxo, lower alkyl, lower alkoxy, lower cycloalkyl, lower heteroalicyclic, Lower haloalkoxy, alkylthio, halogen, lower haloalkyl, lower hydroxyalkyl, lower cycloalkylalkylene, lower heteroalicyclic alkylene, aryl, heteroaryl, alkoxycarbonyl, amino, Alkylamino, alkylsulfonyl, arylsulfonyl, alkylaminosulfonyl, arylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, alkylaminocarbonyl, arylaminocarbonyl, alkyl Carbonylamino, arylcarbonylamino.
  • Heterocycloalkyl means a monocyclic or fused ring radical having from 5 to 9 ring atoms in the ring wherein one or both of the ring atoms are selected from N, O or S(O) p (where p is A hetero atom of 0 to 2 integers, and the remaining ring atoms are C. These rings may have one or more double bonds, but these rings do not have a fully conjugated pi-electron system.
  • Non-limiting examples of unsubstituted heteroalicyclic groups are pyrrolidinyl, piperidino, piperazino, morpholino, thiomorpholino, homopiperazino and the like.
  • the heteroalicyclic group can be substituted or unsubstituted.
  • the substituent is preferably one or more, more preferably one, two or three, and even more preferably one or two, said substituent being selected from the group consisting of hydrogen, hydroxy, thiol, oxygen a lower alkyl group, a lower alkoxy group, a lower cycloalkyl group, a lower heteroalicyclic group, a lower haloalkoxy group, an alkylthio group, a halogen, a lower haloalkyl group, a lower hydroxyalkyl group, a lower cycloalkylalkylene group, Lower heteroalicyclic alkylene, aryl, heteroaryl, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, arylsulfonyl, alkylaminosulfonyl, arylaminosulfonyl, alkyl Sulfonylamino, arylsulfonylamino, alkylaminocarbony
  • heteroalicyclic groups include, but are not limited to, morpholinyl, piperazinyl, piperidinyl, azetidinyl, pyrrolidinyl, hexahydroazepine, oxetanyl, tetrahydrofuranyl , tetrahydrothiophenyl, oxazolidinyl, thiazolidinyl, isoxazolidinyl, tetrahydropyranyl, thiomorphinyl, quinuclidinyl and imidazolinyl, each group as described above, Examples may also be bicyclic, such as, for example, 3,8-diaza-bicyclo[3.2.1]octane, 2,5-diazabicyclo[2.2.2]octane or octahydro-pyrazine. [2,1-c][1,4]oxazine. Its heteroalicyclic group (and derivatives).
  • Alkoxy means -O-(unsubstituted alkyl) and -O (unsubstituted cycloalkyl). Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and the like.
  • Haldroxy means an -OH group.
  • Halogen means fluoro, chloro, bromo or iodo, preferably fluoro or chloro.
  • Haloalkyl means an alkyl group, preferably a lower alkyl group as defined above, which is substituted by one or more of the same or different halogen atoms, for example -CH 2 Cl, -CF 3 , -CCl 3 , -CH 2 CF 3 , -CH 2 CCl 3 and the like.
  • Cyano means a -CN group.
  • Amino means a -NH 2 group.
  • substituted by one or more groups means that one, two, three or four hydrogen atoms in a given atom or group are each selected from a specified range of groups. Replace the same or different groups.
  • “Pharmaceutically acceptable salt” means those salts which retain the biological effectiveness and properties of the parent compound. Such salts include:
  • a salt with an acid obtained by a reaction of a free base of a parent compound with an inorganic or organic acid includes hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, metaphosphoric acid, sulfuric acid, sulfurous acid, perchloric acid, etc.
  • Organic acids include acetic acid, propionic acid, acrylic acid, oxalic acid, (D) or (L) malic acid, fumaric acid, maleic acid, hydroxybenzoic acid, ⁇ -hydroxybutyric acid, methoxybenzoic acid, ortho-benzene Formic acid, methanesulfonic acid, ethanesulfonic acid, naphthalene-1-sulfonic acid, naphthalene-2-sulfonic acid, p-toluenesulfonic acid, salicylic acid, tartaric acid, citric acid, lactic acid, mandelic acid, succinic acid or malonic acid .
  • an organic base such as ethanolamine, diethanolamine, or the like. Ethanolamine, tromethamine, N-methylglucamine, and the like.
  • “Pharmaceutical composition” means that one or more of the compounds of the invention, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, is mixed with another chemical component, such as a pharmaceutically acceptable carrier. .
  • the purpose of the pharmaceutical composition is to facilitate the administration to the animal.
  • “Pharmaceutically acceptable carrier” refers to an inactive ingredient in a pharmaceutical composition that does not cause significant irritation to the organism and does not interfere with the biological activity and properties of the administered compound, such as, but not limited to, calcium carbonate, calcium phosphate, various Sugar (eg lactose, mannitol, etc.), starch, cyclodextrin, magnesium stearate, fiber , magnesium carbonate, acrylic polymer or methacrylic acid polymer, gel, water, polyethylene glycol, propylene glycol, ethylene glycol, castor oil or hydrogenated castor oil or polyethoxy hydrogenated castor oil, sesame oil, corn oil , peanut oil, etc.
  • the aforementioned pharmaceutical composition may include, in addition to a pharmaceutically acceptable carrier, an adjuvant which is commonly used in medicine, for example, an antibacterial agent, an antifungal agent, an antimicrobial agent, a quality agent, a tone.
  • an adjuvant which is commonly used in medicine, for example, an antibacterial agent, an antifungal agent, an antimicrobial agent, a quality agent, a tone.
  • Example 7 1-(5-(2-carboxylic acid ethyl ester-1H-indol-5-yl)-1-(pyridin-3-yl-sulfonyl)-1H-pyrrol-3-yl)-N- Preparation of methylmethylamine (CMP 7)
  • Example 8 1-(5-(2-Phenyl-1H-indol-5-yl)-1-(pyridin-3-yl-sulfonyl)-1H-pyrrol-3-yl)-N-A Preparation of methylamine (CMP 8)
  • Example 9 1-(5-(1-ethyl acetate-1H-indol-5-yl)-1-(pyridin-3-yl-sulfonyl)-1H-pyrrol-3-yl)-N- Preparation of methylmethylamine (CMP 9)
  • Example 13 1-(5-(1H-indol-5-yl)-1-((5,6,7,8-tetrahydronaphthalen-2-yl)sulfonyl)-1H-pyrrole-3- Preparation of )-N-methylmethylamine (CMP13)
  • Example 14 CMP 14 a solid CMP20 60 mg, 38% was obtained.
  • HPLC 98.69%
  • MS 440 [M+H] +
  • 1 H-NMR 400 MHz, DMSO-d6): ⁇ 11.31 (s, 1H), 7.61 (s, 1H), 7.39 to 7.44 (m, 3H) ), 7.30 (s, 1H), 6.93 (t, 1H), 6.47 (s, 1H), 6.40 (d, 1H), 4.03 (s, 2H), 2.58 (s, 3H) ppm.
  • Example 23 1-(5-(1H-indol-5-yl)-1-((2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-) Of sulfoyl)-1H-pyrrol-3-yl)-N-methylmethylamine (CMP23)
  • Example 40 1-(5-(1H-indol-5-yl)-1-((3-fluoro-6-methylphenyl)sulfonyl)-1H-pyrrol-3-yl)-N- Preparation of methylmethylamine (CMP40)
  • Example 14 CMP 14 60 mg of solid CMP44 was obtained in a yield of 82%.
  • HPLC 98.48%, MS: 367 [M+H] + , 1 H-NMR (400 MHz, DMSO-d6): ⁇ 11.22 (s, 1H), 8.32 (s, 1H), 7.61 to 7.75 (m, 3H) ), 7.38 to 7.46 (m, 1H), 7.35 to 7.37 (m, 1H), 7.21 to 7.23 (m, 1H), 7.09 to 7.12 (m, 1H), 6.84 (d, 1H), 6.53 (d, 1H) ), 5.80 (s, 1H), 3.97 (s, 2H), 2.49 (d, 3H) ppm.
  • Rabbit gastric mucosa microsomes (rich in H+/K+-ATPase), the extraction method is sucrose gradient centrifugation: the rabbit stomach is washed with tap water, 3M NaCl solution, and then the surface water is removed by filter paper. Pre-cooled homogenization buffer (4 ml/g tissue) was added and homogenized in a tissue homogenizer for 2-5 min.
  • the present invention provides a half-inhibitory concentration (IC 50 ) of a compound of formula I for H + /K + -ATPase activity.
  • +++ means IC 50 ⁇ 100nM; ++ means range 0.1 ⁇ 1 ⁇ M; + means range 1 ⁇ 5 ⁇ M

Abstract

本发明涉及一类新的吡咯磺酰类衍生物、其制备方法及在医药上的应用。具体而言，本发明涉及一种化学结构式（I）所示的吡咯磺酰类衍生物、其制备方法及含有该衍生物的药物组合以及作为治疗剂，特别是作为胃酸分泌抑制剂和钾离子竞争性酸阻滞剂（P-CABs）的用途，其通式（I）的各取代基与说明书中的定义相同。

Description

吡咯磺酰类衍生物、其制备方法及其在医药上的应用 技术领域
本发明涉及一类新的吡咯磺酰类衍生物、其制备方法及含有该衍生物的药物组合以及其作为治疗剂特别是作为胃酸分泌抑制剂和钾离子竞争性酸阻滞剂(P-CABs)的用途。
背景技术
自1988年以来，以奥美拉唑为代表的质子泵抑制剂通过抑制胃酸分泌以治疗消化性溃疡、反流性食管炎和卓-艾综合症等在临床上得到广泛应用。长期的临床应用发现，现有质子泵抑制剂在药代动力学、药效学方面还有局限性。如：给药时间对药效的影响；夜间酸突破起效慢；酸性条件下不稳定(需要配制成肠制剂)；对CYP450酶的依赖性(导致个体差异显著)等。
钾竞争性酸阻滞剂(Potassium-Competitive Acid Blockers，P-CABs)通过直接、可逆性的过程竞争性地抑制H+/K+-ATP酶中的K+而产生作用。与传统质子泵抑制剂相比，P-CABs具有亲脂性、弱碱性、解离常数高和在低pH条件下稳定的特点。在酸性环境下，P-CABs以离子化形式与H+/K+-ATP酶结合，阻止H+运送及酸分泌到胃腔中，迅速升高胃中pH值。动物实验和临床研究表明：P-CABs具备起效迅速，在1小时内就能达到最大治疗效果；血药浓度与口服给药剂量线性相关，比较容易达到最佳抑酸效果的优势。
尽管目前已公开了一系列钾竞争性酸阻滞剂，但仍需要开发结构类型更丰富，新的可能具有更好的成药性质的化合物，经过不断努力，本发明设计具有通式(I)所示的结构的化合物，并发现具有此类结构的化合物表现出优异的效果和作用。
发明内容
本申请提供的结构如式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或药学上可接受的盐：
Figure PCTCN2015086603-appb-000001
式中:
X选自CR4或N。
Y选自O或NR5。
R1选自烷基、环烷基、杂环烷基、芳基或杂芳基，其中所述烷基、环烷基、杂环烷基、芳基或杂芳基任意被一个或多个选自氢、卤素、氰基、硝基、羟基、烷基、卤代烷基、羟烷基、环烷基、杂环烷基、芳基、杂芳基、-OR6、-NR6R7、-C(O)NR6R7、-S(O)mR6、-C(O)R6、-O C(O)R6或-C(O)O R6的取代基所取代。
R2为氢、卤素、烷基、氰基、硝基、羟基、芳基、或酯基。
R3为氢、卤素、烷基、氰基、硝基、羟基、芳基、或酯基。
R4为氢、卤素、烷基、氰基、硝基、或羟基。
R5为氢、烷基、或芳基。
R6或R7各自独立地选自氢原子、烷基、环烷基、杂环烷基、芳基或杂芳基，其中所述烷基、环烷基、杂环烷基、芳基或杂芳基任意被一个或多个选自卤素、氰基、羟基、氨基、烷基、卤代烷基、羟烷基、烷氧基、环烷基、杂环烷基、芳基、杂芳基、羧基、酰胺基或羧酸酯基的取代基所取代。
m选自0、1或2。
进一步的式(I)中R1选自芳基或杂芳基，其中所述芳基或杂芳基任意被一个或多个选自氢、卤素、氰基、硝基、羟基、烷基、卤代烷基、羟烷基、环烷基、杂环烷基、芳基、杂芳基、-OR6、-NR6R7、-C(O)NR6R7、-S(O)mR6、-C(O)R6、-O C(O)R6或-C(O)O R6的取代基所取代。
R6或R7各自独立地选自氢原子、烷基、环烷基、杂环烷基、芳基或杂芳基，其中所述烷基、环烷基、杂环烷基、芳基或杂芳基任意被一个或多个选自卤素、氰基、羟基、氨基、烷基、卤代烷基、羟烷基、烷氧基、环烷基、杂环烷基、芳基、杂芳基、羧基、酰胺基或羧酸酯基的取代基所取代。
m选自0、1或2。
更进一步的R1选自被一个活多个取代基取代的：
Figure PCTCN2015086603-appb-000002
所述取代基为卤素、氰基、硝基、羟基、烷基、卤代烷基、羟烷基、环烷基、杂环烷基、-OR6、-NR6R7、-C(O)NR6R7、-S(O)mR6、-C(O)R6、-O C(O)R6或-C(O)OR6的取代基所取代。
R6或R7各自独立地选自氢原子、烷基其中所述烷基芳基任意被一个或多个选自卤素、氰基、羟基、氨基、烷基、卤代烷基、羟烷基、烷氧基、环烷基、杂环烷基、芳基、杂芳基、羧基、酰胺基或羧酸酯基的取代基所取代。
m选自0、1或2。
更进一步地，本发明提供了结构如式(I)所示化合物选自：
Figure PCTCN2015086603-appb-000003
Figure PCTCN2015086603-appb-000004
本发明还涉及一种药用组合物，所述药物组合物含有有效量的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或药学上可接受的盐和药物可接受的载体、赋形剂或稀释剂。
本发明还涉及通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或药学上可接受的盐或包含其的药物组合物在制备胃酸分泌抑制剂中的用途。
本发明另一方面涉及一种抑制胃酸分泌的方法，该方法包括给予需要治疗的患者有效剂量的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或药学上可接受的盐 或包含其的药物组合物。
本发明另一方面涉及(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或药学上可接受的盐或包含其的药物组合物在制备H+/K+-腺苷三磷酸酶(H+/K+-ATPase)抑制剂中的用途。
本发明另一方面涉及(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或药学上可接受的盐或包含其的药物组合物在制备钾离子竞争性酸阻滞剂(P-CABs)中的用途。
本发明提供用于治疗或预防消化性溃疡，卓-艾综合症、胃炎、糜烂性食管炎、反流性食管炎、症状性胃食管反流疾病、巴雷特食管炎、功能性消化不良、幽门螺旋杆菌感染、胃癌、胃MALT淋巴瘤、非甾体抗炎药引起的溃疡或手术后应激导致的胃酸过多或溃疡的药物中的用途；或者在制备抑制用于消化性溃疡、急性应激性溃疡、出血性胃炎或侵入性应激造成的上消化道出血的药物中的方法。其中消化性溃疡选自胃溃疡、十二指肠溃疡或吻合口溃疡；所述的症状性胃食管反流疾病选自非糜烂性的反流性疾病或无食管炎的胃食管反流疾病的方法。
发明的详细说明
除非有相反陈述，下列用在说明书和权利要求中的术语具有下述含义。
“烷基”指饱和的脂族烃基团。包括1至20个碳原子的直链或支链基团。优选含有1至6个碳原子的中等大小烷基，例如甲基、乙基、丙基、2-丙基、正丁基、异丁基、叔丁基、戊基等。更优选的是含有1至4个碳原子的低级烷基，例如甲基、乙基、丙基、2-丙基、正丁基、异丁基或叔丁基等。烷基可以是取代的或未取代的，当被取代时，优选的基团为：卤素、C2-C6烯基、C6-C10芳基、C5-C10杂芳基、卤代C1-C6烷基、4至8元杂脂环基、羟基、C1-C6烷氧基、C6-C10芳氧基。
“环烷基”指3至8元全碳单环、全碳5元/6元或6元/6元稠和环或多环稠和环(“稠和”环意味着系统中的每个环与系统中的其它环共享毗邻的一对碳原子)基团，其中一个或多个环具有完全连接的π电子系统，环烷基的实例(不局限于)为环丙烷、环丁烷、环戊烷、环戊烯、环己烷、金刚烷、环己二烯、环庚烷和环庚三烯。环烷基为可取代的和为取代的。当被取代时，取代基优选为一个或多个各自选自以下的基团，包括：氢、羟基、巯基、氧代、低级烷基、低级烷氧基、低级环烷基、低级杂脂环基、低级卤代烷氧基、烷硫基、卤素、低级卤代烷基、低级羟烷基、低级环烷基亚烷基、低级杂脂环基亚烷、芳基、杂芳基、烷氧基羰基、氨基、烷基氨基、烷基磺酰基、芳基磺酰基、烷基氨基磺酰基、芳基氨基磺酰基、烷基磺酰基氨基、芳基磺酰基氨基、烷基氨基羰基、芳基氨基羰基、烷基羰基氨基、芳基羰基氨基。
“芳基”表示6至14个碳原子的全碳单环或稠合多环基团，具有完全共轭的π电子系统。“芳基”包括：
六元的碳芳香环，如，苯；
双环，其中至少有一个环是碳芳香环，如，萘，茚和1,2,3,4-四氢喹啉；以及
三环，其中至少有一个环是碳芳香环，如，芴。
例如，芳基包括含六元的碳芳香环并一个六元杂环，这个杂环包含一个或多个选自氮、氧和硫的杂原子，条件 是连接点在碳芳香环上。但是，芳基不包含、也不通过任何方式与下面分别定义的杂环芳基重叠。因此，在此定义，如果一个或多个碳芳香环与一个杂芳香环并环，由此产生的环系统是杂芳基，而不是芳基。芳基的非限制性实例有苯基、萘基。芳基可以是取代的或未取代的。当被取代时，优选的基团为：氢、羟基、硝基、氰基、氧代、低级烷基、低级烷氧基、低级环烷基、低级杂脂环基、低级卤代烷氧基、烷硫基、卤素、低级卤代烷基、低级羟烷基、低级环烷基亚烷基、低级杂脂环基亚烷、芳基、杂芳基、烷氧基羰基、氨基、烷基氨基、烷基磺酰基、芳基磺酰基、烷基氨基磺酰基、芳基氨基磺酰基、烷基磺酰基氨基、芳基磺酰基氨基、烷基氨基羰基、芳基氨基羰基、烷基羰基氨基、芳基羰基氨基。
“杂芳基”表示5至14个环原子的单环或稠合环基团，含有一个、两个、三个或四个选自N、O或S的环杂原子，其余环原子是C，另外具有完全共轭的π电子系统。杂芳基指的是：
5-8元的单环芳烃，含一个或多个选自N、O和S的杂原子，如1-4个杂原子，在一些实施方案中，1-3个杂原子，环上其他原子是碳原子；
8-12元的双环芳烃，含一个或多个选自N、O和S的杂原子，如1-4个杂原子，在一些实施方案中，1-3个杂原子，环上其他原子是碳原子；其中至少有一个环是芳香环；以及
11-14元的三环芳烃，含一个或多个选自N、O和S的杂原子，如1-4个杂原子，在一些实施方案中，1-3个杂原子，环上其他原子是碳原子；其中至少有一个环是芳香环。
例如，杂芳基包括一个5-6元的杂芳香环并一个5-6元的环烷基。对于这样的双环并起来的杂芳基，其中只有一个环含有一个或多个杂原子，连接位点在杂芳香环上。
当杂芳基上的硫原子和氧原子总数超过1时，这些杂原子不会一一相邻。在一些实施方案中，硫原子和氧原子在杂芳基中的总数不超过2。在一些实施方案中，硫原子和氧原子在杂芳基中的总数不超过1。
杂芳基的例子，包括但不限于，吡咯、呋喃、噻吩、咪唑、噁唑、噻唑、吡唑、三氮唑、嘧啶、吡啶、吡啶酮、咪啶、吡嗪、哒嗪、吲哚、氮杂吲哚、苯并咪唑、苯并三氮唑、吲哚啉、吲哚酮、喹啉、异喹啉、喹唑啉、噻吩并吡啶、噻吩并嘧啶等。此类基团的优选实施例为吡咯基、吡唑基、咪唑基、三氮唑基、呋喃基、噁唑基、噻吩基、噻唑基、苯并咪唑基、苯并三氮唑。杂芳基中的一个或全部氢原子可被下列基团取代：氢、羟基、硝基、氰基、氧代、低级烷基、低级烷氧基、低级环烷基、低级杂脂环基、低级卤代烷氧基、烷硫基、卤素、低级卤代烷基、低级羟烷基、低级环烷基亚烷基、低级杂脂环基亚烷、芳基、杂芳基、烷氧基羰基、氨基、烷基氨基、烷基磺酰基、芳基磺酰基、烷基氨基磺酰基、芳基氨基磺酰基、烷基磺酰基氨基、芳基磺酰基氨基、烷基氨基羰基、芳基氨基羰基、烷基羰基氨基、芳基羰基氨基。
“杂环烷基”表示单环或稠和环基团，在环中具有5到9个环原子，其中一个或两个环原子是选自N、O或S(O)p(其中p是0至2的整数)的杂原子，其余环原子是C。这些环可以具有一条或多条双键，但这些环不具有完全共轭的π电子系统。未取代的杂脂环基的非限制性实例有吡咯烷基、哌啶子基、哌嗪子基、吗啉代基、硫代吗啉代基、高哌嗪子基等。杂脂环基可以是取代的或未取代的。当被取代时，取代基优选为一个或多个，更为优选为一个、两 个或三个，进而更优选为一个或两个，所述的取代基选自:氢、羟基、巯基、氧代、低级烷基、低级烷氧基、低级环烷基、低级杂脂环基、低级卤代烷氧基、烷硫基、卤素、低级卤代烷基、低级羟烷基、低级环烷基亚烷基、低级杂脂环基亚烷、芳基、杂芳基、烷氧基羰基、氨基、烷基氨基、烷基磺酰基、芳基磺酰基、烷基氨基磺酰基、芳基氨基磺酰基、烷基磺酰基氨基、芳基磺酰基氨基、烷基氨基羰基、芳基氨基羰基、烷基羰基氨基、芳基羰基氨基。除非另外指出。杂脂环基的实例包括但不限于，吗啉基，哌嗪基，哌啶基，氮杂环丁烷基，吡咯烷基，六氢氮杂□基，氧杂环丁烷基，四氢呋喃基，四氢噻吩基，噁唑烷基，噻唑烷基，异噁唑烷基，四氢吡喃基，硫代吗琳基，奎宁环基和咪唑啉基，各基团如前所述，实例还可以是双环的，诸如，例如，3，8-二氮杂-双环[3.2.1]辛烷、2，5-二氮杂双环[2.2.2]辛烷或八氢-吡嗪并[2，1-c][1,4]噁嗪。其杂脂环基(和衍生物)包括其离子形式。
“烷氧基”表示-O-(未取代的烷基)和-O(未取代的环烷基)。代表性的实例包括但不限于甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基等。
“羟基”表示-OH基团。
“卤素”表示氟、氯、溴或碘，优选为氟或氯。
“卤代烷基”表示烷基，优选如上所定义的低级烷基，它被一个或多个相同或不同的卤原子取代，例如-CH2Cl、-CF3、-CCl3、-CH2CF3、-CH2CCl3等。
“氰基”表示-CN基团。
“氨基”表示-NH2基团。
所谓“任意地”的意思是指后续描述的事件或情形可能会也可能不会发生，并且该描述包括事物或情形可能会也可能不会发生，并且该描述包括事物或情形发生和不发生两种情况。
在一些实施方案中，“被一个或多个基团取代”是指在指定的原子或基团中的一个、两个、三个或四个氢原子分别被指定范围的基团中选出的相同或不同的基团替换。
“药学上可接受的盐”表示保留母体化合物的生物有效性和性质的那些盐。这类盐包括：
(1)与酸成盐，通过母体化合物的游离碱与无机酸或有机酸的反应而得，无机酸包括盐酸、氢溴酸、硝酸、磷酸、偏磷酸、硫酸、亚硫酸和高氯酸等，有机酸包括乙酸、丙酸、丙烯酸、草酸、(D)或(L)苹果酸、富马酸、马来酸、羟基苯甲酸、γ-羟基丁酸、甲氧基苯甲酸、邻苯二甲酸、甲磺酸、乙磺酸、萘-1-磺酸、萘-2-磺酸、对甲苯磺酸、水杨酸、酒石酸、柠檬酸、乳酸、扁桃酸、琥珀酸或丙二酸等。
(2)存在于母体化合物中的酸性质子被金属离子代替或者与有机碱配位化合所生成的盐，金属例子例如碱金属离子、碱土金属离子或铝离子，有机碱例如乙醇胺、二乙醇胺、三乙醇胺、氨丁三醇、N-甲基葡糖胺等。
“药物组合物”指将本发明中的化合物中的一个或多个或其药学上可接受的盐、溶剂化物、水合物或前药与别的化学成分，例如药学上可接受的载体，混合。药物组合物的目的是促进给药给动物的过程。
“药用载体”指的是对有机体不引起明显的刺激性和不干扰所给予化合物的生物活性和性质的药物组合物中的非活性成分，例如但不限于：碳酸钙、磷酸钙、各种糖(例如乳糖、甘露醇等)、淀粉、环糊精、硬脂酸镁、纤维 素、碳酸镁、丙烯酸聚合物或甲基丙烯酸聚合物、凝胶、水、聚乙二醇、丙二醇、乙二醇、蓖麻油或氢化蓖麻油或多乙氧基氢化蓖麻油、芝麻油、玉米油、花生油等。
前述的药物组合物中，除了包括药学上可接受的载体外，还可以包括在药(剂)学上常用的辅剂，例如：抗细菌剂、抗真菌剂、抗微生物剂、保质剂、调色剂、增溶剂、增稠剂、表面活性剂、络合剂、蛋白质、氨基酸、脂肪、糖类、维生素、矿物质、微量元素、甜味剂、色素、香精或它们的结合等。
具体实施方式
以下结合实施例用于进一步描述本发明，但这些实施例并非限制着本发明的范围。
实施例1：1-(5-(苯并[d][1,3]二氧杂环戊烯-5-基)-1-(吡啶-3-基-磺酰基)-1H-吡咯-3-基)-N-甲基甲胺(化合物1)的制备
Figure PCTCN2015086603-appb-000005
1)将5-溴-1H-吡咯-3-甲醛(1-1,0.25g,1.45mmol)，苯并[d][1,3]二氧杂环戊烯-5-基硼酸(化合物1-2,0.3g,1.81mmol)，Pd(PPh3)4(0.12g,0.10mmol)，Na2CO3(367mg,3.46mmol)，DME(5mL)，水(2mL)加到25mL茄型瓶中，搅拌，升温至回流，反应2h。停止反应，自然冷却到室温，倾入冰水(50mL)，EA(50mL*3)萃取。合并有机相干燥，浓缩，柱层析(石油醚：乙酸乙酯＝2:1)得类白色固体1-3(38mg,12.23％)，MS(ESI)m/z:[M+H]+＝216.1.
2)将5-(苯并[d][1,3]二氧杂环戊烯-5-基)-1H-吡咯-3-甲醛(1-3，38mg,0.17mmol)，THF(2mL)配成溶液，在0℃滴加到t-BuOK(61mg,0.544mmol)，THF(2mL)的溶液中，滴加结束后继续反应0.5h。随后滴加吡啶-3-磺酰氯(1-4,47.5mg,0.267mmol)，15-crown-5(59mg,0.268mmol)的混合溶液。滴加结束，自然升温至25℃反应0.5h。反应结束后加入冰水20mL，乙酸乙酯(20mL*3)萃取。合并有机相干燥，浓缩，柱层析(石油醚：乙酸乙酯＝1:1)得黄色固体1-5(40mg,收率63.5％)，MS(ESI)m/z:[M+H]+＝357.1.
3)将甲胺醇溶液(96mg)，1-5(60mg,0.1685mmol)，醋酸(0.5mL)，甲醇(2mL)加到25mL茄型瓶中，25℃搅拌反应1h。降温至0℃，缓慢加入NaBH3CN(20mg,0.337)。加料结束后继续反应0.5h。将反应液倒入10mL冰水中，乙酸乙酯(20mLx3)萃取。合并有机相干燥，浓缩，柱层析(石油醚：乙酸乙酯＝1:1)得白色固体CMP 1(15mg,24％)
HPLC:95.3％；MS(ESI)m/z:[M+H]+＝372.2；1H-NMR(400MHz,MeOD)δ:8.77(s,1H),8.50(s,1H),7.81(d,1H),7.72(s,1H),7.51(t,1H),6.78(d,1H),6.58(m,2H),6.30(d,1H),6.02(s,2H),4.07(s,2H),2.70(s,3H)ppm。
实施例2：1-(5-(1H-吲哚-5-基)-1-(吡啶-3-基-磺酰基)-1H-吡咯-3-基)-N-甲基甲胺(CMP2)的制备
Figure PCTCN2015086603-appb-000006
参照实施例1CMP 1的制备方法，获得白色固体CMP 2，收率30％。HPLC:98.1％；MS(ESI)m/z:[M+H]+＝367.0；1H-NMR(400MHz,DMSO-d6)δ:11.21(s,1H),8.78(d,1H),8.39(s,1H),7.72(d,1H),7.51(m,1H),7.39(m,3H),7.34(m,1H),6.87(d,1H),6.43(s,1H),6.20(s,1H),3.45(s,2H),2.32(s,3H)ppm。
实施例3：1-(5-(2,3-二氢苯并呋喃-5-基)-1-(吡啶-3-基-磺酰基)-1H-吡咯-3-基)-N-甲基甲胺(CPM 3)的制备
Figure PCTCN2015086603-appb-000007
参照实施例1CMP 1的制备方法，获得白色固体CMP 3，收率28％。HPLC:96.8％；MS(ESI)m/z:[M+H]+＝370.0；1H-NMR(400MHz,DMSO-d6)δ:8.82(d,1H),8.47(d,1H),7.76(d,1H),7.57(d,1H),7.35(s,1H),6.97(s,1H),6.87(d,1H),6.74(d,1H),6.19(s,1H),4.58(t,2H),3.45(s,2H),3.16(t,2H),2.21(s,3H)ppm。
实施例4：1-(5-(苯并呋喃-5-基)-1-(吡啶-3-基-磺酰基)-1H-吡咯-3-基)-N-甲基甲胺(CMP 4)的制备
Figure PCTCN2015086603-appb-000008
1)将化合物4-1(2.0g,10mmol)和双联频哪醇硼酸酯(5.08g,20mmol)，乙酸钾(2.94g,30mmol)，Pd(dppf)Cl2(200mg)溶于DMF(20mL)中，氮气置换空气，加热回流过夜，用乙酸乙酯(150mL x3)萃取。合并有机相干燥，浓缩，过柱(PE:EA＝10:1)得黄色固体4-2(1.5g,收率：61％).
2)将化合物4-2(400mg,1.64mmol)和化合物4-4(516mg,1.639mmol)，碳酸氢钠(344mg,4.097mmol)，四三苯基磷钯(100mg)溶于DME(5mL)和水(1mL)中，氮气置换空气，加热回流过夜，用乙酸乙酯(150mL x3)萃取。合并有机相干燥，浓缩，过柱(PE:EA＝5:1)得黄色固体4-3(300mg,收率：52％).
3)将4-3(250mg,0.71mmol),乙酸(0.3mL),甲胺醇溶液(0.5mL)溶于3mL甲醇中，室温搅拌4hr。加NaBH3CN(209mg,3.55mmol)。搅拌50min。加水(20mL)淬灭，用乙酸乙酯(50mLx3)萃取。合并有机相干燥，浓缩，制备得白色固体CMP 4(100mg,38％)。HPLC:99.63％,MS:368[M+H]+,1H-NMR(400MHz,DMSO-d6): δ8.78～8.79(m,1H),8.41(d,1H),8.03(d,1H),7.53～7.57(m,1H),7.44(d,2H),7.39(m,2H),7.08～7.11(m,1H),6.96～6.97(m,1H),6.29(d,1H),3.43(d,2H),2.19(s,3H)ppm。
实施例5：1-(5-(1H-吡咯[2,3-b]吡啶-5-基)-1-(吡啶-3-基-磺酰基)-1H-吡咯-3-基)-N-甲基甲胺(CMP 5)的制备
Figure PCTCN2015086603-appb-000009
参照实施例4CMP 4的制备方法，获得白色固体CMP 5 30mg，收率11％。HPLC:99.58％,MS:368[M+H]+,1H-NMR(400MHz,DMSO-d6):δ8.81～8.82(m,1H),7.42(d,1H),7.94(d,1H),7.74～7.78(m,2H),7.53～7.56(m,2H),7.43(s,1H),6.47(d,1H),6.33(d,1H),3.47(s,2H),2.23(s,3H)ppm。
实施例6：1-(5-(2,3-二甲基-1H-吲哚-5-基)-1-(吡啶-3-基-磺酰基)-1H-吡咯-3-基)-N-甲基甲胺(CMP 6)的制备
Figure PCTCN2015086603-appb-000010
参照实施例4CMP 4的制备方法，获得固体CMP6 35mg，收率21％。HPLC:96.52％,MS:395[M+H]+,1H-NMR(400MHz,DMSO-d6):δ10.81(s,1H),8.79-8.80(m,1H),8.37(d,1H),7.71(s,1H),7.52(d,1H),7.37(s,1H),7.15～7.17(m,1H),7.01(s,1H),6.77～6.80(m,1H),6.19(d,1H),3.49(s,2H),2.32(s,3H),2.25(s,3H),2.08(s,3H)ppm。
实施例7：1-(5-(2-甲酸乙酯-1H-吲哚-5-基)-1-(吡啶-3-基-磺酰基)-1H-吡咯-3-基)-N-甲基甲胺(CMP 7)的制备
Figure PCTCN2015086603-appb-000011
参照实施例4CMP 4的制备方法，获得固体CMP 780mg，收率30.7％。HPLC:93.86％,MS:439[M+H]+,1H-NMR(400MHz,DMSO-d6):δ12.19(s,1H),8.83～8.84(m,1H),8.41(d,1H),7.73～7.75(m,1H),7.54～7.55(m,2H),7.37～7.44(m,2H),7.05～7.17(m,1H),7.03～7.05(m,1H),6.40(d,1H),4.36～4.38(m,2H),4.01～4.04(m,2H),2.51～2.58(m,3H),1.34(t,3H)ppm。
实施例8：1-(5-(2-苯基-1H-吲哚-5-基)-1-(吡啶-3-基-磺酰基)-1H-吡咯-3-基)-N-甲基甲胺(CMP 8)的制备
Figure PCTCN2015086603-appb-000012
参照实施例4CMP 4的制备方法，获得固体CMP830mg，18％。HPLC:98.02％,MS:443[M+H]+,1H-NMR(400MHz,DMSO-d6):δ11.69(s,1H),8.79～8.81(m,1H),8.42(d,1H),7.75～7.77(m,2H),7.74(m,1H),7.46～7.54(m,3H),7.32～7.38(m,4H),6.90(t,2H),6.25(d,1H),3.49(s,2H),2.24(s,3H)ppm。
实施例9：1-(5-(1-乙酸乙酯-1H-吲哚-5-基)-1-(吡啶-3-基-磺酰基)-1H-吡咯-3-基)-N-甲基甲胺(CMP 9)的制备
Figure PCTCN2015086603-appb-000013
参照实施例4CMP 4的制备方法，获得黄色固体CMP 9 42mg，收率13％。HPLC:92.36％,MS:453[M+H]+,1H-NMR(400MHz,CDCl3):δ8.53(s,1H),7.37～7.45(m,4H),7.10～7.19(m,5H),6.52(d,1H),6.20(d,1H),4.89(d,2H),3.79(s,2H),3.49(s,2H),2.43(s,3H),1.22～1.28(m,3H)ppm。
实施例10：1-(5-(1H-吲哚-5-基)-1-(苯并呋喃-2-磺酰基)-1H-吡咯-3-基)-N-甲基甲胺(CMP10)的制备
Figure PCTCN2015086603-appb-000014
参照实施例4CMP 4的制备方法，获得固体CMP 1029.3mg，收率31.8％。HPLC:98.05％,MS:406[M+H]+,1H-NMR(400MHz,CD3OD):δ7.71(d,1H),7.45～7.51(m,3H),7.29(d,1H),7.26(m,3H),6.86～6.88(m,1H),6.82(s,1H),6.33(d,1H),6.28(d,1H),4.11(s,2H),2.73(s,3H)ppm。
实施例11：1-(5-(1H-吲哚-5-基)-1-苯磺酰基-1H-吡咯-3-基)-N-甲基甲胺(CMP11)的制备
Figure PCTCN2015086603-appb-000015
参照实施例4CMP 4的制备方法，获得固体CMP11 45.9mg，23.8％。HPLC:96.32％,MS:366[M+H]+,1H-NMR(400MHz,CD3OD):δ7.68(d,1H),7.53(s,1H),7.24～7.31(m,7H),6.87(dd,1H),6.39(d,1H), 6.25(d,1H),4.07(s,2H),2.693(s,3H)ppm。
实施例12：1-(5-(1H-吲哚-5-基)-1-(噻吩-3-磺酰基)-1H-吡咯-3-基)-N-甲基甲胺(CMP12)的制备
Figure PCTCN2015086603-appb-000016
参照实施例4CMP 4的制备方法，获得固体CMP12 30mg,收率72％。HPLC:97.05％,MS:372[M+H]+,1H-NMR(400MHz,DMSO-d6):δ11.27(s,1H),7.88(m,1H),7.69～7.88(m,1H),7.61(d,1H),7.31～7.39(m,3H),6.43～6.96(m,2H),6.37～6.38(m,2H),3.92(s,2H),2.46(s,3H)ppm。
实施例13：1-(5-(1H-吲哚-5-基)-1-((5,6,7,8-四氢萘-2-基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺(CMP13)的制备
Figure PCTCN2015086603-appb-000017
参照实施例4CMP 4的制备方法，获得固体CMP13 60mg,58.3％。HPLC:95.40％,MS:420[M+H]+,1H-NMR(400MHz,MeOD):δ7.46(s,1H),6.91-7.30(m,6H),6.68(s,1H),6.38～6.39(m,1H),6.16(d,1H),3.713(d,2H),2.69(t,2H),2.47(d,3H),2.23(t,2H),1.63～1.72(m,4H)ppm。
实施例14：1-(5-(1H-吲哚-5-基)-1-((4-三氟甲基苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺(CMP14)的制备
Figure PCTCN2015086603-appb-000018
1)将14-1(400m g,2.31mmol)溶于干燥的THF(10ml)中，在0℃下加入叔丁醇钾(776mg，6.93mmol)，搅拌5min，再加入14-2(846mg，3.468mmol)，在室温下搅拌10min，LC-MS检测反应完全。加入氯化铵溶液淬灭反应，加水，用EA萃取，蒸干有机层，过柱分离得产品14-3(300mg，收率34％)。
2)将14-4(164mg,1.02mmol)、14-3(300m g，0.787mmol)、Pd(PPh3)4(45.5mg,0.039mmol),NaHCO3(198m g,2.36mmol)加入到DME(6ml)和H2O(1ml)中，混合物在氮气下于70℃搅拌1h，LC-MS检测反应完全。降温，向反应瓶中加入水，EA萃取，有机层蒸干，过柱纯化得14-5(250mg，收率75％)
3)将14-5(250m g,0.598mmol)溶于甲醇(8ml)，加入甲胺醇溶液(1.5ml)，在0℃用乙酸调节pH到6并搅拌 1h，加入氰基硼氢化钠(341mg，5.98mmol)，继续搅拌1h，LC-MS检测反应完全，加入碳酸氢钠水溶液，用EA萃取，有机层蒸干，制备得CMP14(180mg，69％)。HPLC:99.17％,MS:434[M+H]+,1H-NMR(400MHz,CDCl3):δ8.26(s,1H),7.47～7.49(m,2H),7.39～7.41(m,2H),7.26～7.34(m,3H),7.06～7.09(m,1H),6.51(s,1H),6.16(d,1H),3.63(s,2H),2.47(s,3H)ppm。
实施例15：1-(5-(1H-吲哚-5-基)-1-((1-甲基-1H-吡唑-4-基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺(CMP15)的制备
Figure PCTCN2015086603-appb-000019
参照实施例14CMP 14的制备方法，获得固体CMP15 24mg,29.38％。HPLC:95.89％,MS:370[M+H]+,1H-NMR(400MHz,MeOD):δ7.35～7.40(m,4H),7.30(d,2H),7.00～7.03(m,1H),6.45(d,1H),6.20(d,1H),3.69(s,2H),3.58(s,3H),2.47(s,3H)ppm。
实施例16：1-(5-(1H-吲哚-5-基)-1-((2-三氟甲氧基苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺(CMP16)的制备
Figure PCTCN2015086603-appb-000020
参照实施例14CMP 14的制备方法，获得固体CMP16 180mg，60％。HPLC:97.86％,MS:450[M+H]+,1H-NMR(400MHz,CDCl3):δ8.18(s,1H),7.42～7.46(m,2H),7.26(s,1H),7.15～7.20(m,3H),7.06～7.08(m,1H),6.91～6.93(m,1H),6.77(t,1H),6.39(s,1H),6.189(d,1H),3.69(s,2H),2.51(s,3H)ppm。
实施例17：1-(5-(1H-吲哚-5-基)-1-((4-叔丁基苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺(CMP17)的制备
Figure PCTCN2015086603-appb-000021
参照实施例14CMP 14的制备方法，获得固体CMP17 160mg，39％。HPLC:97.98％,MS:422[M+H]+,1H-NMR(400MHz,CDCl3):δ8.48(s,1H),7.37(d,1H),7.26～7.31(m,2H),7.21～7.25(m,5H),7.10～7.13(m,1H),6.46～6.47(m,1H),6.15(d,1H),3.65(s,2H),2.47(s,3H),1.26(s,9H)ppm。
实施例18：1-(5-(1H-吲哚-5-基)-1-((3-氰基苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺(CMP18)的制备
Figure PCTCN2015086603-appb-000022
参照实施例14CMP 14的制备方法，获得固体CMP18 15mg，收率30％。HPLC:98.06％,MS:391[M+H]+,1H-NMR(400MHz,CDCl3):δ8.24(s,1H),7.67(d,1H),7.54(d,1H),7.33～7.41(m,5H),7.25～7.30(m,1H),7.00-7.03(m,1H),6.53(s,1H),6.17(d,1H),3.63(s,2H),2.48(s,3H)ppm。
实施例19：1-(5-(1H-吲哚-5-基)-1-((3-氟-4甲基苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺(CMP19)的制备
Figure PCTCN2015086603-appb-000023
参照实施例14CMP 14的制备方法，获得固体CMP19 30mg，收率28.8％。HPLC:99.75％,MS:398[M+H]+,1H-NMR(400MHz,CD3OD):δ7.67(d,1H),7.30～7.32(m,2H),7.24(s,1H),7.17(s,1H),6.97～7.00(m,1H),6.84～6.91(m,2H),6.40(d,1H),6.27(d,1H),4.08(s,2H),2.72(s,3H),2.24(d,3H)ppm。
实施例20：1-(5-(1H-吲哚-5-基)-1-((4,5-二氯噻吩-2-基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺(CMP20)的制备
Figure PCTCN2015086603-appb-000024
参照实施例14CMP 14的制备方法，获得固体CMP20 60mg,38％。HPLC:98.69％,MS:440[M+H]+,1H-NMR(400MHz,DMSO-d6):δ11.31(s,1H),7.61(s,1H),7.39～7.44(m,3H),7.30(s,1H),6.93(t,1H),6.47(s,1H),6.40(d,1H),4.03(s,2H),2.58(s,3H)ppm。
实施例21：1-(5-(1H-吲哚-5-基)-1-((4-硝基苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺(CMP21)的制备
Figure PCTCN2015086603-appb-000025
参照实施例14CMP 14的制备方法，获得固体CMP21 65mg,76％。HPLC:96.71％,MS:411[M+H]+,1H-NMR(400MHz,CDCl3):δ8.29(s,1H),8.04(d,2H),7.44(d,2H),7.32～7.36(m,3H),7.26～7.28(m,1H),7.05(d,1H), 6.52(s,1H),6.18(d,1H),3.64(s,2H),2.478(s,3H)ppm。
实施例22：1-(5-(1H-吲哚-5-基)-1-((3-甲酸甲酯基苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺(CMP22)的制备
Figure PCTCN2015086603-appb-000026
参照实施例14CMP 14的制备方法，获得固体CMP22 16mg，收率10％。HPLC:98.13％,MS:424[M+H]+,1H-NMR(400MHz,CDCl3):δ8.26(s,1H),8.10(d,1H),7.89(t,1H),7.31～7.49(m,5H),7.23～7.26(m,1H),7.09～7.12(m,1H),6.48(t,1H),6.14(d,1H),3.807(s,3H),3.62(s,2H),2.46(s,3H)ppm。
实施例23：1-(5-(1H-吲哚-5-基)-1-((2,2,4,6,7-五甲基-2,3-二氢苯并呋喃-5-基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺(CMP23)的制备
Figure PCTCN2015086603-appb-000027
参照实施例14CMP 14的制备方法，获得固体CMP23 30mg,收率29％。HPLC:99.38％,MS:478[M+H]+,1HNMR(400MHz,DMSO):δ7.30～7.37(m,2H),7.03～7.08(m,2H),6.55～6.58(m,1H),6.26(s,1H),6.05(d,1H),4.00(s,2H),2.50(d,2H),2.30(d,3H),1.92(s,3H),1.82(s,3H),1.74(s,3H),1.34(s,6H)ppm。
实施例24：1-(5-(1H-吲哚-5-基)-1-((4-甲氧基苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺(CMP24)的制备
Figure PCTCN2015086603-appb-000028
参照实施例14CMP 14的制备方法，获得固体CMP24 60mg,收率:42％。HPLC:98.97％,MS:396[M+H]+,1H-NMR(400MHz,MeOD):δ7.51(d,1H),7.16～7.51(m,5H),6.92～6.95(m,1H),6.73(d,2H),6.40(d,1H),6.18(d,1H),3.82(s,2H),3.77(s,3H),2.54(s,3H)ppm。
实施例25：1-(5-(1H-吲哚-5-基)-1-((1-甲基-1H-吡唑-3-基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺(CMP25)的制备
Figure PCTCN2015086603-appb-000029
参照实施例14CMP 14的制备方法，获得固体CMP25 24mg,29.38％。HPLC:95.89％,MS:370[M+H]+,1H-NMR(400MHz,MeOD):δ7.35～7.39(m,4H),7.30(d,2H),7.00～7.03(m,1H),6.45(d,1H),6.20(d,1H),3.696(s,2H),3.69(s,2H),3.58(s,3H),2.47(s,3H)ppm。
实施例26：1-(5-(1H-吲哚-5-基)-1-((1-甲基-1H-咪唑-4-基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺(CMP26)的制备
Figure PCTCN2015086603-appb-000030
参照实施例14CMP 14的制备方法，获得固体CMP26 13mg,收率11.7％。HPLC:99.26％,MS:370[M+H]+,1H-NMR(400MHz,MeOD):δ7.60～7.64(m,2H),7.31～7.34(m,2H),7.16(s,1H),6.93(dd,1H),6.57(s,1H),6.42(d,1H),6.24(d,1H),4.08(s,2H),3.24(s,3H),2.73(s,3H)ppm。
实施例27：1-(5-(1H-吲哚-5-基)-1-((4-氰基苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺(CMP27)的制备
Figure PCTCN2015086603-appb-000031
参照实施例14CMP 14的制备方法，获得固体CMP27 40mg，收率38％。HPLC:93.59％,MS:391[M+H]+,1H-NMR(400MHz,CDCl3):δ8.22(s,1H),7.42～7.44(m,2H),7.24～7.30(m,5H),7.19～7.21(m,1H),6.97～6.99(m,1H),6.46(s,1H),6.11(d,1H),3.58(s,2H),2.41(s,3H)ppm。
实施例28：1-(5-(1H-吲哚-5-基)-1-((2,6-二氟苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺(CMP28)的制备
Figure PCTCN2015086603-appb-000032
参照实施例14CMP 14的制备方法，获得固体CMP28 100mg,收率32％。HPLC:92.91％,MS:402[M+H]+,1H-NMR(400MHz,DMSO-d6):δ11.19(s,1H),7.70～7.76(m,2H),7.37～7.38(m,1H),7.22～7.24(m,1H),7.09～7.13(m,3H), 6.72～6.74(m,1H),6.32～6.35(m,2H),4.05(t,2H),2.54(s,3H)ppm。
实施例29：1-(5-(1H-吲哚-5-基)-1-((2-氟苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺(CMP29)的制备
Figure PCTCN2015086603-appb-000033
参照实施例14CMP 14的制备方法，获得固体CMP29 130mg,收率42％。HPLC:97.23％,MS:384[M+H]+,1H-NMR(400MHz,DMSO-d6):δ11.16(s,1H),7.69(d,1H),7.22(d,3H),7.16(s,2H),7.03～7.10(m,1H),6.75～6.78(m,1H),6.34(s,1H),6.19(d,1H),3.50(s,2H),2.27(s,3H)ppm。
实施例30：1-(5-(1H-吲哚-5-基)-1-((4-氟苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺(CMP30)的制备
Figure PCTCN2015086603-appb-000034
参照实施例14CMP 14的制备方法，获得固体CMP30 14mg,收率：26.92％。HPLC:93.46％,MS:384[M+H]+,1H-NMR(400MHz,MeOD):δ7.27～7.41(m,7H),6.93～7.02(m,3H),6.41(d,1H),6.17(d,1H),3.61(s,2H),2.39(s,3H)ppm。
实施例31：1-(5-(1H-吡咯[2,3-b]吡啶-5-基)-1-((3-甲氧基苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺(CMP 31)的制备
Figure PCTCN2015086603-appb-000035
参照实施例14CMP 14的制备方法，获得固体CMP31 42mg，收率：36.5％。HPLC:95.97％,MS:397[M+H]+,1H-NMR(400MHz,MeOD):δ8.02(t,2H),7.80(d,1H),7.60(d,1H),7.30(t,1H),7.13～7.15(m,1H),6.96(d,1H),6.66(d,2H),6.47(d,1H),4.13(s,2H),3.54(s,3H),2.73(s,3H)ppm。
实施例32：1-(5-(1H-吲哚-5-基)-1-((3-(3-甲氧基丙氧基)苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺(CMP32)的制备
Figure PCTCN2015086603-appb-000036
参照实施例14CMP 14的制备方法，获得固体CMP32 54mg，收率：38.4％。HPLC:93.87％,MS:454[M+H]+。
实施例33：1-(5-(1H-吲哚-5-基)-1-((4-胺基乙酰基苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺(CMP32)的制备
Figure PCTCN2015086603-appb-000037
参照实施例14CMP 14的制备方法，获得固体CMP33 35mg，收率：18.2％。HPLC:93.17％,MS:423[M+H]+。
实施例34：1-(5-(1H-吲哚-5-基)-1-((4-甲基酰胺基苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺(CMP34)的制备
Figure PCTCN2015086603-appb-000038
参照实施例14CMP 14的制备方法，获得固体CMP34 15mg，收率：8.2％。HPLC:91.27％,MS:423[M+H]+。
实施例35：1-(5-(1H-吲哚-5-基)-1-((4-丁基苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺(CMP35)的制备
Figure PCTCN2015086603-appb-000039
参照实施例14CMP 14的制备方法，获得固体CMP35 60mg,收率45％。HPLC:97.60％,MS:422[M+H]+,1H-NMR(400MHz,CDCl3):δ8.27(s,1H),7.23～7.36(m,3H),7.12～7.19(m,3H),7.03～7.09(m,1H),6.99～7.01(m,2H),6.48(s,1H),6.14(d,1H),3.64(s,2H),2.55～2.59(m,2H),2.46(s,3H),1.49～1.57(m,2H),1.25～1.35(m,3H),0.88～0.93(m,2H)ppm。
实施例36：1-(5-(1H-吲哚-5-基)-1-((4-溴苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺(CMP36)的制备
Figure PCTCN2015086603-appb-000040
参照实施例14CMP 14的制备方法，获得固体CMP36 5mg，收率10％。HPLC:90.85％,MS:446[M+H]+,1HNMR(400MHz,MeOD):δ7.68(s,1H),7.43(d,2H),7.31(d,2H),7.23(s,1H),7.11(d,2H),6.88(t,1H),6.42(s,1H),6.27(d,1H),4.09(s,2H),2.72(s,3H)ppm。
实施例37：1-(5-(1H-吲哚-5-基)-1-((3-氟苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺(CMP37)的制备
Figure PCTCN2015086603-appb-000041
参照实施例14CMP 14的制备方法，获得固体CMP37 15mg，收率16％。HPLC:95.46％,MS:383[M+H]+,1H-NMR(400MHz,DMSO-d6):δ8.70(s,1H),7.69(s,1H),7.55～7.58(m,2H),7.42(t,1H),7.356(d,1H),7.22～7.27(m,2H),7.03(d,1H),6.82～6.84(m,1H),6.43(s,1H),6.33(d,1H),4.02(s,2H),2.57(s,3H)ppm。
实施例38：1-(5-(1H-吲哚-5-基)-1-((2,4,6-三甲基苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺(CMP38)的制备
Figure PCTCN2015086603-appb-000042
参照实施例14CMP 14的制备方法，获得固体CMP38 110mg，42％。HPLC:97.84％,MS:408[M+H]+,1HNMR(400MHz,CDCl3):δ8.15(s,1H),7.48(s,1H),7.17～7.18(m,1H),7.11(d,1H),6.99(s,1H),6.82～6.85(m,1H),6.58(s,2H),6.30(s,1H),6.15(d,1H),3.71(s,2H),2.52(s,3H),2.18(s,3H),2.02(s,6H)ppm。
实施例39：1-(5-(1H-吲哚-5-基)-1-((2-溴-4,6-二氟苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺(CMP39)的制备
Figure PCTCN2015086603-appb-000043
参照实施例14CMP 14的制备方法，获得固体CMP39 32mg，收率12％。
实施例40：1-(5-(1H-吲哚-5-基)-1-((3-氟-6-甲基苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺(CMP40)的制备
Figure PCTCN2015086603-appb-000044
参照实施例14CMP 14的制备方法，获得固体CMP40 70mg,收率75％。HPLC:98.05％,MS:398[M+H]+,1HNMR(400MHz,CDCl3):δ8.23(s,1H),7.56(s,1H),7.10～7.26(m,3H),7.05～7.07(m,1H),6.87～6.91(m,2H),6.67～6.69(m,1H),6.40(s,1H),6.21(s,1H),3.69(s,2H),2.51(s,3H),2.24(s,3H)ppm。
实施例41：1-(5-(1H-吲哚-5-基)-1-((2,4-二甲基噻唑-5-基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺(CMP41)的制备
Figure PCTCN2015086603-appb-000045
参照实施例14CMP 14的制备方法，获得固体CMP41 24mg,收率29.38％。HPLC:97.19％,MS:401[M+H]+,1H-NMR(400MHz,MeOD):δ7.42(d,1H),7.27～7.30(m,3H),6.94(t,1H),6.41(d,1H),6.24(d,1H),3.64(s,2H),2.41(s,6H),1.95(s,3H)ppm。
实施例42：1-(5-(苯并呋喃-5-基)-1-(3-甲氧基苯基磺酰基)-1H-吡咯-3-基)-N-甲基甲胺(CMP 42)的制备
Figure PCTCN2015086603-appb-000046
参照实施例14CMP 14的制备方法，获得固体CMP42 100mg，收率31％。HPLC:93.79％,MS:397[M+H]+,1H-NMR(400MHz,DMSO):δ8.79(s,2H),8.08(d,1H),7.73(d,1H),7.58(d,1H),7.39～7.46(m,2H),7.23～7.26(m,1H),7.02～7.09(m,1H),6.97～6.99(m,2H),6.68～6.69(m,1H),6.39(d,1H),4.01(d,2H),3.58(d,3H),2.54～2.57(m,3H)ppm。
实施例43：1-(5-(1H-吲哚-7-基)-1-(吡啶-3-基-磺酰基)-1H-吡咯-3-基)-N-甲基甲胺(CMP43)的制备
Figure PCTCN2015086603-appb-000047
参照实施例14CMP 14的制备方法，获得固体CMP43 30mg,收率48％。HPLC:96.68％,MS:367[M+H]+,1H-NMR(400MHz,DMSO-d6):δ10.61(s,1H),8.98(s,1H),8.71(d,1H),8.38(s,1H),7.83(s,1H),7.54～7.62(m,2H),7.34～7.37(m,1H),7.15(s,1H),6.97(t,1H),6.73(d,1H),6.57(s,1H),6.43(s,1H),4.01(s,2H),2.51(d,3H)ppm。
实施例44：1-(5-(1H-吲哚-4-基)-1-(吡啶-3-基-磺酰基)-1H-吡咯-3-基)-N-甲基甲胺(CMP44)的制备
Figure PCTCN2015086603-appb-000048
参照实施例14CMP 14的制备方法，获得固体CMP44 60mg,收率82％。HPLC:98.48％,MS:367[M+H]+,1H-NMR(400MHz,DMSO-d6):δ11.22(s,1H),8.32(s,1H),7.61～7.75(m,3H),7.38～7.46(m,1H),7.35～7.37(m,1H),7.21～7.23(m,1H),7.09～7.12(m,1H),6.84(d,1H),6.53(d,1H),5.80(s,1H),3.97(s,2H),2.49(d,3H)ppm。
实施例45：1-(5-(1H-吲哚-6-基)-1-(吡啶-3-基-磺酰基)-1H-吡咯-3-基)-N-甲基甲胺(CMP45)的制备
Figure PCTCN2015086603-appb-000049
参照实施例14CMP 14的制备方法，获得固体CMP45 65mg，收率35％。HPLC:98.85％,MS:367[M+H]+,1H-NMR(400MHz,CDCl3):δ8.66(d,1H),8.51(s,1H),8.28(s,1H),7.48～7.54(m,2H),7.36(s,2H),7.14～7.18(m,1H),6.87～6.88(m,1H),6.58(s,1H),6.19(s,1H),3.62(d,2H),2.45(d,3H)ppm。
实施例46：1-(5-(咪唑[1,2-a]吡啶-6-基)-1-(吡啶-3-基-磺酰基)-1H-吡咯-3-基)-N-甲基甲胺(CMP46)的制备
Figure PCTCN2015086603-appb-000050
参照实施例14CMP 14的制备方法，获得固体CMP46 40mg,收率：63.6％。HPLC:98.50％,MS:368[M+H]+,1HNMR(400MHz,MeOD):δ8.68～8.89(m,3H),8.22(d,1H),8.11(d,1H),7.87(m,4H),7.54～7.57(m,1H),6.65(d,1H),4.11(s,2H),2.71(s,3H)ppm。
实施例47：1-(1H-苯并[d]咪唑-6-基)-1-(吡啶-3-基-磺酰基)-1H-吡咯-3-基)-N-甲基甲胺(CMP47)的制备
Figure PCTCN2015086603-appb-000051
参照实施例14CMP 14的制备方法，获得固体CMP47 12mg，收率21％。HPLC:93.56％,MS:368[M+H]+,1H-NMR(400MHz,MeOD):δ9.28(s,1H),8.75(d,1H),8.37(d,1H),7.78～7.83(m,3H),7.67(s,1H),7.37～7.49(m,2H),6.50(d,1H),4.12(s,2H),2.72(s,3H)ppm。
测试例：
H+/K+-ATPase生物学评价
下面的体外筛选试验是用来评价本发明化合物对于H+/K+-ATPase酶活性抑制作用的。
实验材料和仪器：
1)兔胃粘膜微粒体(富含H+/K+-ATPase，自提)
2)5-三磷酸腺苷ATP(Sigma-Aldrich，货号：A2383)
3)孔雀石绿(百灵威化学技术有限公司，货号：913120)
4)钼酸铵(百灵威化学技术有限公司，货号：128321)
5)缬氨霉素(百灵威化学技术有限公司，货号：227304)
实验步骤：
试剂准备：
1)化合物用DMSO溶解配制成合适的浓度；
2)缓冲液:50mmol/L HEPEs-Tris，pH＝6.5，5mmol/L氯化镁，10μmol/L缬氨霉素；
3)缓冲液:50mmol/L HEPEs-Tris，pH＝6.5，5mmol/L氯化镁，10μmol/L缬氨霉素，5mmol/L氯化钾；
4)ATP：用缓冲液1稀释ATP至5mM；
5)孔雀石绿溶液：0.12％孔雀石绿溶于2.5mol/L硫酸，7.5％(V/V)钼酸铵和11％Tween 20(V/V)使用时按100:25:2比例混合；
6)兔胃黏膜微粒体(富含H+/K+-ATPase)，提取方法为蔗糖梯度离心：把兔胃用分别自来水，3M NaCl溶液洗净，然后用滤纸除去表面水分。加入预冷的匀浆缓冲液(4ml/g组织)，于组织匀浆机中匀浆2-5min。匀浆后，如果有较大的组织颗粒，可离心(600g,10min)去除，然后将上清移至干净的离心管中20000g离心30min后，然后将上清移至干净的离心管中，进一步离心，100000g离心90min，收集沉淀；利用匀浆液悬浮沉淀，吹散均匀，利用Bradford法测蛋白浓度，调整浓度为10mg/ml；等比例加入7.5％Ficoll分层液，100000g离心60min后，将中层(H+/K+-ATPaseenriched gastric membranes)收集于洁净离心管中，利用匀浆液4-5倍稀释，继续100000g离心90min，收集沉淀；利用匀浆液悬浮沉淀，玻璃匀浆器匀浆均匀，利用Bradford法测蛋白浓度，调整浓度22.5mg/ml。冻于-80℃备用。
实验过程：
向45μL缓冲液2中加入5μL的胃粘膜微粒体(H+/K+-ATPase)，再加入5μL的化合物溶液，然后加入5μL 5mM的ATP启动反应，在37℃预反应30min。加入15μL孔雀石绿溶液终止反应，室温平衡20min，在620nm处读吸 收光值。
同时，进行相同体积，不加氯化钾的反应作为背景，在计算酶活性时减去。
化合物IC50值通过不同浓度下的抑制率计算得到。
实验结果：化合物IC50值。
本发明提供结构如式I所示化合物对H+/K+-ATPase活性的半数抑制浓度(IC50)
TAK-438 CMP1 CMP2 CMP3 CMP4 CMP5 CMP6 CMP7 CMP8 CMP9
+++ ++ +++ ++ +++ ++ + + + ++
CMP10 CMP11 CMP12 CMP13 CMP14 CMP15 CMP16 CMP17 CMP18 CMP19
+ ++ ++ +++ +++ + + + +++ +++
CMP20 CMP21 CMP22 CMP23 CMP24 CMP25 CMP26 CMP27 CMP28 CMP29
+++ +++ +++ + +++ + + +++ ++ +++
CMP30 CMP31 CMP32 CMP33 CMP34 CMP35 CMP36 CMP37 CMP38 CMP39
+++ ++ ND ++ ++ + +++ ++ + ND
CMP40 CMP41 CMP42 CMP43 CMP44 CMP45 CMP46 CMP47    
++ ND ++ + ++ ++ + +    
+++表示IC50<100nM；++表示范围0.1～1μM；+表示范围1～5μM
己经通过举例说明和实施例的方式比较详细地描述了上述发明，以用于阐述和理解的目的。对于本领域技术人员显而易见的是，可以在后附权利要求的范围内进行改变和改进。因此，应该理解上述说明意在是举例说明性的而不是限制性的。因此，本发明的范围不应该参考上述说明书而确定，而应该参考下列后附的权利要求以及由权利要求授权的等价物的全部范围而确定。

Claims (10)

  1. 一种如化学结构式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或药学上可接受的盐：
    Figure PCTCN2015086603-appb-100001
    式中:
    X选自CR4或N。
    Y选自O或NR5。
    R1选自烷基、环烷基、杂环烷基、芳基或杂芳基，其中所述烷基、环烷基、杂环烷基、芳基或杂芳基任意被一个或多个选自氢、卤素、氰基、硝基、羟基、烷基、卤代烷基、羟烷基、环烷基、杂环烷基、芳基、杂芳基、-OR6、-NR6R7、-C(O)NR6R7、-S(O)mR6、-C(O)R6、-OC(O)R6或-C(O)OR6的取代基所取代。
    R2为氢、卤素、烷基、氰基、硝基、羟基、芳基、或者酯基。
    R3为氢、卤素、烷基、氰基、硝基、羟基、芳基、或者酯基。
    R4为氢、卤素、烷基、氰基、硝基、或者羟基。
    R5为氢、烷基、或者芳基。
    R6或R7各自独立地选自氢原子、烷基、环烷基、杂环烷基、芳基或杂芳基，其中所述烷基、环烷基、杂环烷基、芳基或杂芳基任意被一个或多个选自卤素、氰基、羟基、氨基、烷基、卤代烷基、羟烷基、烷氧基、环烷基、杂环烷基、芳基、杂芳基、羧基、酰胺基或羧酸酯基的取代基所取代。
    m选自0、1或2。
  2. 根据权利要求1的化学结构式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或药学上可接受的盐，其中R1选自芳基或杂芳基，其中所述芳基或杂芳基任意被一个或多个选自氢、卤素、氰基、硝基、羟基、烷基、卤代烷基、羟烷基、环烷基、杂环烷基、芳基、杂芳基、-OR6、-NR6R7、-C(O)NR6R7、-S(O)mR6、-C(O)R6、-OC(O)R6或-C(O)OR6的取代基所取代。
    R6或R7各自独立地选自氢原子、烷基、环烷基、杂环烷基、芳基或杂芳基，其中所述烷基、环烷基、杂环烷基、芳基或杂芳基任意被一个或多个选自卤素、氰基、羟基、氨基、烷基、卤代烷基、羟烷基、烷氧基、环烷基、杂环烷基、芳基、杂芳基、羧基、酰胺基或羧酸酯基的取代基所取代。
    m选自0、1或2。
  3. 根据权利要求2所示，R1选自被一个活多个取代基取代的：
    Figure PCTCN2015086603-appb-100002
    所述取代基为卤素、氰基、硝基、羟基、烷基、卤代烷基、羟烷基、环烷基、杂环烷基、-OR6、-NR6R7、-C(O)NR6R7、-S(O)mR6、-C(O)R6、-OC(O)R6或-C(O)OR6的取代基所取代。
    R6或R7各自独立地选自氢原子、烷基其中所述烷基芳基任意被一个或多个选自卤素、氰基、羟基、氨基、烷基、卤代烷基、羟烷基、烷氧基、环烷基、杂环烷基、芳基、杂芳基、羧基、酰胺基或羧酸酯基的取代基所取代。
    m选自0、1或2。
  4. 根据权利要求3所述化合物，其特征为选自以下任意一个化合物：
    Figure PCTCN2015086603-appb-100003
    Figure PCTCN2015086603-appb-100004
  5. 一种药用组合物，所述药物组合物含有有效量的权利要求1～4任意一项所述的化学结构式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或药学上可接受的盐和药物可接受的载体、赋形剂或稀释剂。
  6. 权利要求1～4的药物组合物，其特征为其为胃酸分泌抑制剂。
  7. 权利要求6的药物组合物在制备H+/K+-ATPase抑制剂药物中的用途。
  8. 权利要求7的药物组合物在制备钾离子竞争性酸阻滞剂(P-CABs)药物中的用途。
  9. 根据权利要求7的药物组合物在制备治疗或预防消化性溃疡、卓-艾综合症、胃炎、糜烂性食管炎、反流性食管炎、症状性胃食管反流疾病、巴雷特食管炎、功能性消化不良、幽门螺旋杆菌感染、胃癌、胃MALT淋巴瘤、非甾体抗炎药引起的溃疡或手术后应激导致的胃酸过多或溃疡的药物中的用途；或者在制备抑制用于消化性溃疡、急性应激性溃疡、出血性胃炎或侵入性应激造成的上消化道出血的药物中的用途。
  10. 根据权利要求9所述的用途，其中所述的消化性溃疡包括胃溃疡、十二指肠溃疡或吻合口溃疡；所述的症状性胃食管反流疾病包括非糜烂性的反流性疾病或无食管炎的胃食管反流疾病。
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