WO2016026372A1 - 噻吩并环烷基或噻吩并杂环基类衍生物、其制备方法及其在医药上的应用 - Google Patents

噻吩并环烷基或噻吩并杂环基类衍生物、其制备方法及其在医药上的应用 Download PDF

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WO2016026372A1
WO2016026372A1 PCT/CN2015/085385 CN2015085385W WO2016026372A1 WO 2016026372 A1 WO2016026372 A1 WO 2016026372A1 CN 2015085385 W CN2015085385 W CN 2015085385W WO 2016026372 A1 WO2016026372 A1 WO 2016026372A1
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group
aryl
cycloalkyl
heteroaryl
alkyl
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PCT/CN2015/085385
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English (en)
French (fr)
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应永铖
杨方龙
王伟民
李言华
陈刚
董庆
孙飘扬
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江苏恒瑞医药股份有限公司
上海恒瑞医药有限公司
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Priority to CN201580002261.XA priority Critical patent/CN105658635B/zh
Publication of WO2016026372A1 publication Critical patent/WO2016026372A1/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
    • A61K31/495—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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D333/70—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 2
    • 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 thienocycloalkyl or thienoheterocyclyl derivatives, a process for the preparation thereof, and a pharmaceutical composition containing the same, and as a therapeutic agent, particularly as a intestinal type 2B sodium phosphate cotransporter Use of (Npt2b) inhibitors and in the manufacture of a medicament for the treatment and/or prevention of diseases or conditions such as hyperphosphatemia.
  • Inorganic phosphate is an essential component of bone minerals. About 80% of adult phosphate is in extracellular matrix (such as bone and teeth), 18% in cells, and 2% in extracellular fluid. . Under normal physiological conditions, the small intestine takes up excess phosphate, and the homeostasis of phosphate is regulated by the excretion and reabsorption of the kidney. Excessive or too little phosphate in the body causes dysfunction of the body and causes disease: if it is too low, it leads to hypophosphatemia, rickets, rickets and cardiac dysfunction; if it is too high, it induces hyperphosphatemia, soft tissue and blood vessels. Calcification and renal dysfunction.
  • Hyperphosphate is an important factor in the mortality of patients with cardiovascular disease and chronic kidney disease (CKD).
  • the treatment of hyperphosphatemia mainly includes dietary phosphorus limitation, dialysis treatment, application of phosphorus binder and resection of parathyroid glands when necessary. 90 to 95% of patients with end-stage renal disease need to take phosphorus binders to treat hyperphosphatemia.
  • Npt2b sodium phosphate cotransporter 2B
  • CKD chronic kidney disease
  • the sodium phosphate cotransporter includes a type 1 family (Npt1, Npt3, Npt4), which is mainly expressed in the kidney; a type 2 family (Npt2a, Npt2b, Npt2c), mainly expressed in the kidney (Npt2c), lung, intestine and testis (Npt2a, In Npt2b); the type 3 family (Pit1, Pit2) is ubiquitously expressed in various organs. Among them, Npt2b is expressed in the entire upper digestive tract, mediating the absorption of phosphate in about half of the food, and is used to maintain the homeostasis of phosphate.
  • Npt2b is expressed in the entire upper digestive tract, mediating the absorption of phosphate in about half of the food, and is used to maintain the homeostasis of phosphate.
  • Npt2b is also expressed in other tissues, and it is necessary for Npt2b inhibitors to maintain non-absorbable properties and maintain characteristics in the intestinal lumen (Current Pharmaceutical Design, 2012, 18, 1434-1445).
  • PAM autosomal recessive alveolar microcalculus
  • lung cancer tissue sections high expression of Npt2b was found, and small interfering siRNA experiments showed that decreasing Npt2b expression inhibited lung cancer.
  • Npt2b inhibitors used alone or in combination (in combination with phosphate binders) and found that NTX1942 reduces uremia in adenine-induced CKD rat models.
  • Plasma biomarkers serum concentrations of phosphorus, creatinine and BUN
  • thyroid hormones plasma levels of FGF-23
  • rats were treated after 50 days of treatment Characterization of delayed renal function deterioration and significantly improved survival.
  • the dose of Npt2b inhibitors is expected to be lower than that of phosphate binders, providing more and a wider range of pre-dialysis CKD patients with the required phosphate inhibition.
  • Hormones such as estrogen, glucocorticoids, fibroblast growth factor 23 (FGF23), 1,25 (OH) vitamin D 3 (1,25(OH) 2 D 3 ) and dietary intake of phosphate all affect the small intestine brush Phosphorus uptake or expression of Npt2b. Deletion of Npt2b in the small intestine also results in a decrease in FGF23 expression.
  • the main function of FGF23 is to regulate the excretion of renal phosphate by reducing the expression of phosphate co-transporter and promoting the synthesis of 1,25(OH) 2 D 3 .
  • Npt2b regulates the balance of hormones in the body and maintains the systemic system. Balance.
  • Npt2b inhibitors include WO2004085382, WO2013082751, WO2001005398, WO2001082924, WO2003057225, WO2001087294, WO2014003153, WO2012006473, WO2012006474, WO2012006475, WO2012006477, WO2012054110, WO2002028353, WO2013062065, WO2013082756, WO2013082751, WO2013129435, WO2014142273 WO 2011136269, WO2009079373, and WO2013082756, etc., but there is still a need to develop new compounds having better pharmacological effects, which do not absorb or absorb less in the blood and have less toxicity to the body, and the design of the present invention has a general formula through continuous efforts.
  • the compound of the structure shown in (I) and it was found that the compound having such a structure exhibited excellent effects and effects in the colon and jejunum.
  • the object of the present invention is to provide a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer thereof, or In the form of a mixture, or a pharmaceutically acceptable salt thereof:
  • X is selected from C(R a ) 2 , O, S or NR a ;
  • Y is selected from -C(O)- or -NR b C(O)-;
  • R a are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -C(O)OR 5 , -C(O)R 5 , -C (O)NR 6 R 7 or -S(O) p R 5 , wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group is further further selected from one or more selected from the group consisting of halogens, Hydroxy, alkoxy, cyano, nitro, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)OR 5 , -OC(O) R 5 , -NHS(O) p R 5 , -C(O)R 5 , -NHC(O)R 5 , -NH
  • R b is selected from a hydrogen atom or an alkyl group, wherein the alkyl group is optionally further substituted with one or more substituents selected from halogen, hydroxy, alkoxy, cyano or nitro;
  • Ring A is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl;
  • Ring B is selected from aryl or heteroaryl
  • Ring C is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further selected from one or more selected from the group consisting of halogen and hydroxy.
  • R 1 is selected from the group consisting of an alkyl group, wherein the alkyl group is further substituted with one or more substituents selected from the group consisting of a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the cycloalkyl group is hetero
  • the cyclo, aryl or heteroaryl group is further optionally further selected from one or more selected from the group consisting of halogen, hydroxy, alkoxy, cyano, nitro, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl , aryl, heteroaryl, -C(O)OR 5 , -OC(O)R 5 , -NHS(O) p R 5 , -C(O)R 5 , -NHC(O)R 5 ,- Substituted by a substituent of NHC(O)OR 5 , -NR 6 R 7 ,
  • R 2 is selected from a hydrogen atom, a halogen, an alkoxy group, a cyano group, a nitro group or an alkyl group, wherein the alkyl group or alkoxy group is further optionally further selected from one or more selected from the group consisting of halogen, hydroxy, alkoxy, Cyano, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)OR 5 , -OC(O)R 5 , -NHS(O) p R 5 , -C(O Substituting for a substituent of R 5 , -NHC(O)R 5 , -NHC(O)OR 5 , -NR 6 R 7 , -OC(O)NR 6 R 7 or -C(O)NR 6 R 7 ;
  • R 3 is selected from a hydrogen atom, a halogen, an alkoxy group, a cyano group, a nitro group or an alkyl group, wherein the alkyl group or alkoxy group is further optionally further selected from one or more selected from the group consisting of halogen, hydroxy, alkoxy, Cyano, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)OR 5 , -OC(O)R 5 , -NHS(O) p R 5 , -C(O Substituting for a substituent of R 5 , -NHC(O)R 5 , -NHC(O)OR 5 , -NR 6 R 7 , -OC(O)NR 6 R 7 or -C(O)NR 6 R 7 ;
  • R 4 is selected from a hydrogen atom or an alkyl group, wherein the alkyl group is optionally further one or more selected from the group consisting of halogen, hydroxy, alkoxy, cyano, nitro, cycloalkyl, heterocyclic, aryl , heteroaryl, -C(O)OR 5 , -OC(O)R 5 , -NHS(O) p R 5 , -C(O)R 5 , -NHC(O)R 5 , -NHC(O) Substituting a substituent of OR 5 , -NR 6 R 7 , -OC(O)NR 6 R 7 or -C(O)NR 6 R 7 ;
  • R 5 is selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, cycloalkyl group, aryl group or heteroaryl group is optionally further one or more Substituted with a substituent selected from an alkyl group, a halogen, a hydroxyl group, a hydroxyalkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, a carboxylic acid or a carboxylic acid ester;
  • R 6 or R 7 are each independently selected from a hydrogen atom, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the alkoxy group, the cycloalkyl group,
  • the heterocyclyl, aryl or heteroaryl are each independently optionally further selected from one or more selected from the group consisting of alkyl, halo, hydroxy, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, hetero Substituted by a substituent of an aryl group, a carboxylic acid or a carboxylic acid ester;
  • R 6 or R 7 together with a nitrogen atom to which they are bonded form a heterocyclic group, wherein said heterocyclic group contains one or more N, O or S(O) p heteroatoms, and said heterocyclic group Optionally further substituted by one or more substituents selected from the group consisting of alkyl, halo, hydroxy, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxylic acid or carboxylic acid esters Replace
  • n 0, 1, 2, 3 or 4;
  • n 0, 1, 2, 3 or 4;
  • p 0, 1, or 2.
  • a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer thereof, Or a mixture thereof, or a pharmaceutically acceptable salt thereof which is a compound of the formula (II) or a tautomer, a mesogen, a racemate, an enantiomer, a non-pair Or a mixture thereof, or a pharmaceutically acceptable salt thereof:
  • R 1 to R 4 , X, Y, m, n, ring A and ring C are as defined in the formula (I).
  • a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof which is a compound of the formula (III) or a tautomer, a mesogen, a racemate, an enantiomer, or a non- Enantiomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof:
  • R 1 to R 4 , X, Y, m, n and ring C are as defined in the formula (I).
  • a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer or a diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof wherein R 1 is selected from -(CH 2 ) r -R c ;
  • R c is selected from a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the cycloalkyl group, heterocyclic group, aryl group or heteroaryl group is further optionally further selected from one or more selected from the group consisting of halogen and hydroxyl groups.
  • r is selected from 1, 2, 3, 4 or 5, preferably 2 or 3;
  • R 5 , R 6 , R 7 , p are as defined in the formula (I).
  • Typical compounds of the invention include, but are not limited to:
  • a tautomer a meso form, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • the present invention also provides a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer, or a mixture thereof. a method of form, or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound of the formula (IA) or a salt thereof is reacted with a compound of the formula (IB) under basic conditions, optionally further hydrolyzed and/or condensed to give a compound of the formula (I);
  • Z is selected from a hydroxyl group or a halogen
  • R 1 to R 4 , X, Y, m, n, ring A, ring B and ring C are as defined in formula (I).
  • the present invention also provides a compound of the formula (IA) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer, or a mixture thereof. , or a pharmaceutically acceptable salt thereof:
  • X is selected from C(R a ) 2 , O, S or NR a ;
  • R a are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -C(O)OR 5 , -C(O)R 5 , -C (O)NR 6 R 7 or -S(O) p R 5 , wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group is further further selected from one or more selected from the group consisting of halogens, Hydroxy, alkoxy, cyano, nitro, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)OR 5 , -OC(O) R 5 , -NHS(O) p R 5 , -C(O)R 5 , -NHC(O)R 5 , -NH
  • R a is not selected from a hydrogen atom
  • Ring A is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, preferably phenyl;
  • R 1 is selected from the group consisting of an alkyl group, wherein the alkyl group is further substituted with one or more substituents selected from the group consisting of a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the cycloalkyl group is hetero
  • the cyclo, aryl or heteroaryl group is further optionally further selected from one or more selected from the group consisting of halogen, hydroxy, alkoxy, cyano, nitro, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl , aryl, heteroaryl, -C(O)OR 5 , -OC(O)R 5 , -NHS(O) p R 5 , -C(O)R 5 , -NHC(O)R 5 ,- Substituted by a substituent of NHC(O)OR 5 , -NR 6 R 7 ,
  • R 2 is selected from a hydrogen atom, a halogen, an alkoxy group, a cyano group, a nitro group or an alkyl group, wherein the alkyl group or alkoxy group is further optionally further selected from one or more selected from the group consisting of halogen, hydroxy, alkoxy, Cyano, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)OR 5 , -OC(O)R 5 , -NHS(O) p R 5 , -C(O Substituting for a substituent of R 5 , -NHC(O)R 5 , -NHC(O)OR 5 , -NR 6 R 7 , -OC(O)NR 6 R 7 or -C(O)NR 6 R 7 ;
  • R 5 is selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, cycloalkyl group, aryl group or heteroaryl group is optionally further one or more Substituted with a substituent selected from an alkyl group, a halogen, a hydroxyl group, a hydroxyalkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, a carboxylic acid or a carboxylic acid ester;
  • R 6 or R 7 are each independently selected from a hydrogen atom, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the alkoxy group, the cycloalkyl group,
  • the heterocyclyl, aryl or heteroaryl are each independently optionally further selected from one or more selected from the group consisting of alkyl, halo, hydroxy, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, hetero Substituted by a substituent of an aryl group, a carboxylic acid or a carboxylic acid ester;
  • R 6 or R 7 together with the nitrogen atom to which they are attached form a heterocyclic group wherein the heterocyclic group contains one or more N, O or S(O) p heteroatoms, and the heterocyclic group Optionally further substituted by one or more substituents selected from the group consisting of alkyl, halo, hydroxy, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxylic acid or carboxylic acid esters Replace
  • n 0, 1, 2, 3 or 4;
  • p 0, 1, or 2.
  • Typical compounds of the compounds of formula (IA) include, but are not limited to:
  • a tautomer a meso form, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • the invention further relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of the formula (I) or a tautomer thereof, a mesogen, a racemate, an enantiomer Isomers, diastereomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.
  • the pharmaceutical composition further contains another one or more phosphorus binders, preferably sevelamer.
  • the invention further relates to a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or Use of a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the preparation of a intestinal 2B sodium phosphate cotransporter inhibitor.
  • the invention further relates to a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or Use of a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the preparation of a medicament for treating or preventing hyperphosphatemia.
  • the invention further relates to a compound of the formula (I) or a tautomer thereof, a mesogen, a racemic form , a substance, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in a medicament for treating or preventing a sodium phosphate transporter-mediated disease
  • the use of the disease includes, but is not limited to, kidney disease, calcification of endometrial local blood vessels, high concentration of active vitamin D or hyperthyroidism caused by hyperphosphatemia, and the renal disease is
  • 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 A pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used as an inhibitor of intestinal type 2B sodium phosphate cotransporter (Npt2b).
  • 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 A pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in the treatment or prevention of hyperphosphatemia.
  • 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 A pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in the treatment or prevention of a sodium phosphate transporter-mediated disease, preferably selected from the group consisting of nephropathy, calcification of endometrial local blood vessels, hyperphosphatemia The resulting high concentration of active vitamin D, hyperthyroidism, which is preferably chronic kidney disease or end stage renal disease.
  • the invention also relates to a method of inhibiting intestinal type 2B sodium phosphate cotransporter comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a tautomer thereof, a mesogen thereof, A racemic form, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
  • the present invention also relates to a method for treating or preventing hyperphosphatemia comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the formula (I) or a tautomer thereof, a mesogen, a foreign body.
  • the present invention relates to a method for treating or preventing a sodium phosphate cotransporter mediated disease or condition comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the formula (I) or a tautomer thereof, a racemate, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, wherein the method comprises:
  • the kidney disease described therein is chronic kidney disease or end stage renal disease.
  • the active ingredient-containing pharmaceutical composition may be in a form suitable for oral administration, such as tablets, dragees, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or Tincture.
  • Oral compositions can be prepared according to any method known in the art for preparing pharmaceutical compositions, such compositions may contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, coloring agents, and preservatives, To provide a pleasing and tasty pharmaceutical preparation. Tablets contain the active ingredient and non-toxic pharmaceutically acceptable excipients suitable for the preparation of a tablet for admixture.
  • excipients may be inert excipients such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating agents and disintegrating agents such as microcrystalline cellulose, croscarmellose sodium, corn Starch or alginic acid; a binder such as starch, gelatin, polyvinylpyrrolidone or gum arabic and a lubricant such as magnesium stearate, stearic acid or talc.
  • These tablets may be uncoated or may be coated by masking the taste of the drug or delaying disintegration and absorption in the gastrointestinal tract, thus providing a sustained release effect over a longer period of time.
  • water-soluble taste masking materials such as hydroxypropylmethylcellulose or hydroxypropylcellulose, or extended-time materials such as ethylcellulose, cellulose acetate butyrate may be used.
  • hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or in which the active ingredient is mixed with a water-soluble carrier such as polyethylene glycol or an oil vehicle such as peanut oil, liquid paraffin or olive oil.
  • Soft gelatin capsules provide oral preparations.
  • the aqueous suspension contains the active substance and excipients suitable for the preparation of the aqueous suspension for mixing.
  • excipients are suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone and acacia; dispersing or wetting agents may be naturally occurring a phospholipid such as lecithin, or a condensation product of an alkylene oxide with a fatty acid such as polyoxyethylene stearate, or a condensation product of ethylene oxide with a long chain fatty alcohol, such as heptadecylethyleneoxy cetyl alcohol (heptadecaethyleneoxy cetanol), or a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol, such as polyethylene oxide sorbitol monooleate, or ethylene oxide with derivatives derived from fatty acids and hexitols
  • the aqueous suspensions may also contain one or more preservatives such as ethylparaben or n-propylparaben, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents.
  • preservatives such as ethylparaben or n-propylparaben
  • coloring agents such as ethylparaben or n-propylparaben
  • flavoring agents such as sucrose, saccharin or aspartame.
  • the oil suspension can be formulated by suspending the active ingredient in a vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil, or a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol.
  • the above sweeteners and flavoring agents may be added to provide a palatable preparation.
  • These compositions can be preserved by the addition of an anti-oxidant such as butylated hydroxyanisole or alpha-tocopherol.
  • the dispersible powders and granules suitable for the preparation of aqueous suspensions can be provided by the addition of water to provide the active ingredient and dispersing or wetting agents, suspending agents or one or more preservatives. Suitable dispersing or wetting agents and suspending agents can be used to illustrate the above examples. Other excipients such as sweetening, flavoring, and coloring agents may also be added. These compositions are preserved by the addition of an anti-oxidant such as ascorbic acid.
  • the pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsion.
  • the oil phase may be a vegetable oil such as olive oil or peanut oil, or a mineral oil such as liquid paraffin or a mixture thereof.
  • Suitable emulsifiers may be naturally occurring phospholipids, such as soy lecithin and esters or partial esters derived from fatty acids and hexitol anhydrides such as sorbitan monooleate, and condensation products of the partial esters and ethylene oxide, For example, polyethylene oxide sorbitol monooleate.
  • the emulsions may also contain sweeteners, flavoring agents, preservatives, and antioxidants.
  • Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a colorant, and an antioxidant.
  • sweetening agents such as glycerol, propylene glycol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, a preservative, a colorant, and an antioxidant.
  • the pharmaceutical composition may be in the form of a sterile injectable aqueous solution.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution.
  • the sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oily phase.
  • the active ingredient is dissolved in a mixture of soybean oil and lecithin.
  • the oil solution is then added to a mixture of water and glycerin to form a microemulsion.
  • the injection or microemulsion can be injected into the bloodstream of the patient by a local injection.
  • the solution and microemulsion are preferably administered in a manner that maintains a constant circulating concentration of the compound of the invention.
  • a continuous intravenous delivery device can be used.
  • An example of such a device is the Deltec CADD-PLUS.TM.5400 intravenous pump.
  • the pharmaceutical composition may be in the form of a sterile injectable aqueous or oily suspension for intramuscular and subcutaneous administration.
  • the suspension may be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension, such as a solution prepared in 1,3-butanediol, in a non-toxic parenterally acceptable diluent or solvent.
  • sterile fixed oils may conveniently be employed as a solvent or suspension medium. For this purpose, any blended fixed oil including synthetic mono- or diglycerides can be used.
  • fatty acids such as oleic acid can also be prepared as an injection.
  • the compounds of the invention may be administered in the form of a suppository for rectal administration.
  • These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and thus dissolves in the rectum to release the drug.
  • suitable non-irritating excipient include a mixture of cocoa butter, glycerin gelatin, hydrogenated vegetable oil, polyethylene glycols of various molecular weights, and fatty acid esters of polyethylene glycol.
  • the dosage of the drug to be administered depends on a variety of factors including, but not limited to, the activity of the particular compound used, the age of the patient, the weight of the patient, the health of the patient, the conduct of the patient, The patient's diet, time of administration, mode of administration, rate of excretion, combination of drugs, etc.; additionally, the preferred mode of treatment, such as the mode of treatment, the daily dose of the compound of formula (I) or the type of pharmaceutically acceptable salt It can be verified according to traditional treatment options.
  • Alkyl means a saturated aliphatic hydrocarbon group, including straight chain and branched chain groups of 1 to 20 carbon atoms. An alkyl group having 1 to 10 carbon atoms is preferred, and an alkyl group having 1 to 6 carbon atoms is more preferred.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2 -methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl,
  • lower alkyl groups having from 1 to 6 carbon atoms, non-limiting examples including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl Base, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl Base, 2,3-dimethylbutyl and the like.
  • the alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from alkyl, alkenyl, Alkynyl, alkoxy, alkylthio, alkylamino, halogen, decyl, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkane Oxyl, cycloalkylthio, heterocycloalkylthio, oxo, amino, haloalkyl, hydroxyalkyl, carboxyl, carboxylate, -C(O)OR 5 , -OC(O)R 5 , -NHS(O) p R 5 , -C(O)R 5 , -NHC(O)R 5 , -NHC(O)OR 5 , -NR 6 R 7
  • alkenyl refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as ethenyl, 1-propenyl, 2-propenyl, 1-, 2- or -butenyl and the like.
  • a C 2-10 alkenyl group is preferred, a C 2-6 alkenyl group is more preferred, and a C 2-4 alkenyl group is most preferred.
  • the alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio, oxo, amino, haloalkyl, hydroxyalkyl, carboxylic acid, carboxylate, -C(O)OR 5 , -OC(O)R 5 , -NHS(O) p R 5 , -C(O)R 5 , -NHC(O)R 5 , -NHC(O)OR 5 , -NR 6 R 7 , -OC(
  • alkynyl refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, such as ethynyl, 1-propynyl, 2-propynyl, 1-, 2- Or 3-butynyl and the like.
  • a C 2-10 alkynyl group is preferred, a C 2-6 alkynyl group is more preferred, and a C 2-4 alkynyl group is most preferred.
  • the alkynyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio, oxo, amino, haloalkyl, hydroxyalkyl, carboxylic acid, carboxylate, -C(O)OR 5 , -OC(O)R 5 , -NHS(O) p R 5 , -C(O)R 5 , -NHC(O)R 5 , -NHC(O)OR 5 , -NR 6 R 7 , -OC
  • Cycloalkyl means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent which includes from 3 to 20
  • the carbon atoms preferably comprise from 3 to 12 carbon atoms, more preferably the cycloalkyl ring contains from 3 to 10 carbon atoms, and most preferably the cycloalkyl ring contains from 3 to 6 carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptene
  • the alkenyl group, the cyclooctyl group and the like are preferably a cyclopropyl group or a cyclohexenyl group.
  • Polycyclic cycloalkyl groups include spiro, fused, and bridged cycloalkyl groups.
  • Spirocycloalkyl means a polycyclic group of 5 to 20 members which shares a carbon atom (referred to as a spiro atom) between the monocyclic rings. These may contain one or more double bonds, but none of the rings are fully conjugated. ⁇ electronic system. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • the spirocycloalkyl group is classified into a monospirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group, preferably a monospirocycloalkyl group and a bispirocycloalkyl group, depending on the number of common spiro atoms between the ring and the ring.
  • spirocycloalkyl groups include
  • fused cycloalkyl means 5 to 20 members, each ring of the system sharing an adjacent carbon atomous all-carbon polycyclic group with other rings in the system, wherein one or more rings may contain one or more Two double bonds, but none of the rings have a fully conjugated ⁇ -electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyl group, preferably a bicyclic or tricyclic ring, more preferably a 5-membered/5-membered or 5-membered/6-membered bicycloalkyl group.
  • fused cycloalkyl groups include
  • Bridge cycloalkyl means 5 to 20 members, any two rings sharing two carbon-free all-carbon polycyclic groups, which may contain one or more double bonds, but none of the rings have a total The ⁇ -electron system of the yoke. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl group, preferably a bicyclic ring, a tricyclic ring or a tetracyclic ring, and more preferably a bicyclic ring or a tricyclic ring.
  • bridged cycloalkyl groups include
  • the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocyclyl ring, wherein the ring to which the parent structure is attached is a cycloalkyl group, non-limiting examples include indanyl, tetrahydronaphthalene Base, benzocycloheptyl and the like.
  • the cycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkanethio Base, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, hetero Cycloalkylthio, oxo, amino, haloalkyl, hydroxyalkyl, carboxyl, carboxylate, -C(O)OR 5 , -OC(O)R 5 , -NHS(O) p R 5 , -C(O)R 5 , -NHC(O)R 5 , -NHC(O)OR 5 , -NR 6 R 7 , -
  • Heterocyclyl means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising from 3 to 20 ring atoms wherein one or more of the ring atoms are selected from nitrogen, oxygen or S(O) m ( Wherein m is a hetero atom of 0 to 2, but does not include a ring moiety of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon.
  • the heterocyclic ring comprises 3 to 12 ring atoms, wherein 1 to 4 are hetero atoms; more preferably, the heterocyclic ring contains 3 to 10 ring atoms, of which 1 to 3 are hetero atoms; more preferably, the heterocyclic ring contains 5 to 6 ring atoms, of which 1 to 2 are heteroatoms.
  • monocyclic heterocyclic groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, tetrahydrofuranyl and the like.
  • Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups.
  • “Spiroheterocyclyl” means a polycyclic heterocyclic group of 5 to 20 members in which one atom (referred to as a spiro atom) is shared between monocyclic rings, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) m
  • the hetero atom (where m is an integer from 0 to 2) and the remaining ring atoms are carbon. These may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • the spirocycloalkyl group is classified into a monospiroheterocyclic group, a dispiroheterocyclic group or a polyspirocyclic group according to the number of common spiro atoms between the ring and the ring, and is preferably a monospiroheterocyclic group and a dispiroheterocyclic group. More preferably, it is 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6-membered monospiroheterocyclic group.
  • Non-limiting examples of spiroheterocyclyl groups include
  • “Fused heterocyclyl” refers to 5 to 20 members, each ring of the system sharing an adjacent pair of atoms of a polycyclic heterocyclic group with other rings in the system, and one or more rings may contain one or more a bond, but none of the rings have a fully conjugated ⁇ -electron system in which one or more ring atoms are selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2), and the remaining ring atoms are carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group preferably a bicyclic or tricyclic ring, more preferably a 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group.
  • fused heterocyclic groups include
  • “Bridge heterocyclyl” refers to a polycyclic heterocyclic group of 5 to 14 members, any two rings sharing two atoms which are not directly bonded, these may contain one or more double bonds, but none of the rings have a complete conjugation A ⁇ -electron system in which one or more ring atoms are selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2), and the remaining ring atoms are carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • bridged heterocyclic groups include:
  • the heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring wherein the ring to which the parent structure is attached is a heterocyclic group, non-limiting examples comprising:
  • the heterocyclic group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkanethio Base, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, hetero Cycloalkylthio, oxo, amino, haloalkyl, hydroxyalkyl, carboxyl, carboxylate, -C(O)OR 5 , -OC(O)R 5 , -NHS(O) p R 5 , -C(O)R 5 , -NHC(O)R 5 , -NHC(O)OR 5 , -NR 6 R 7 , -OC(O
  • Aryl means a 6 to 14 membered all-carbon monocyclic or fused polycyclic ring (i.e., a ring that shares a pair of adjacent carbon atoms) having a conjugated ⁇ -electron system, preferably 6 to 10 members, more preferably benzene.
  • the base and naphthyl are most preferably phenyl.
  • the aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring wherein the ring to which the parent structure is attached is an aryl ring, non-limiting examples comprising:
  • the aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkane.
  • Base amino, haloalkyl, hydroxyalkyl, carboxyl, carboxylate, -C(O)OR 5 , -OC(O)R 5 , -NHS(O) p R 5 , -C(O)R 5 , -NHC(O)R 5 , -NHC(O)OR 5 , -NR 6 R 7 , -OC(O)NR 6 R 7 or -C(O)NR 6 R 7 .
  • Heteroaryl refers to a 5 to 14 membered aryl group having from 1 to 4 heteroatoms as ring atoms, the remaining ring atoms being carbon, wherein the heteroatoms include oxygen, sulfur and nitrogen. It is preferably 5 to 10 yuan.
  • the heteroaryl group is preferably 5- or 6-membered, such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like.
  • the heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring wherein the ring to which the parent structure is attached is a heteroaryl ring, non-limiting examples comprising:
  • the heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkanethio Base, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, hetero Cycloalkylthio, amino, haloalkyl, hydroxyalkyl, carboxy, carboxylate, -C(O)OR 5 , -OC(O)R 5 , -NHS(O) p R 5 , -C(O R 5 , -NHC(O)R 5 , -NHC(O)OR 5 , -NR 6 R 7 , -OC(O)NR 6 R 7 or
  • Alkoxy means -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples include methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and the like.
  • the alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, and an alkane group.
  • Haloalkyl means that the alkyl group is substituted by one or more halogens, wherein the alkyl group is as defined above.
  • Hydrophilicity refers to an -OH group.
  • Hydroalkyl means an alkyl group substituted by a hydroxy group, wherein the alkyl group is as defined above.
  • Halogen means fluoro, chloro, bromo or iodo.
  • Amino means -NH 2 .
  • Niro means -NO 2 .
  • Benzyl refers to -CH 2 - phenyl.
  • Carboxy refers to -C(O)OH.
  • Carboxylic acid ester group means -C(O)O(alkyl) or (cycloalkyl) wherein alkyl, cycloalkyl are as defined above.
  • heterocyclic group optionally substituted by an alkyl group means that an alkyl group may be, but not necessarily, present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group.
  • Substituted refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3, hydrogen atoms, independently of each other, substituted by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art will be able to determine (by experiment or theory) substitutions that may or may not be possible without undue effort. For example, an amino group or a hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.
  • “Pharmaceutical composition” means a mixture comprising one or more of the compounds described herein, or a physiologically pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiologically pharmaceutically acceptable carriers and Shape agent.
  • the purpose of the pharmaceutical composition is to promote the administration of the organism, which facilitates the absorption of the active ingredient and thereby exerts biological activity.
  • the compound of the formula (Ia) is subjected to a condensation reaction with 2-cyanoacetic acid in the presence of a condensing agent under ice-cooling conditions to obtain a compound of the formula (Ib); a compound of the formula (Ib) and a compound of the formula (Ic),
  • the reaction is carried out in the presence of morpholine to obtain a compound of the formula (Id); the compound of the formula (Id) and sulfur are carried out in the presence of morpholine.
  • reaction gives a compound of the formula (IA); under basic conditions, the compound of the formula (IA) or a salt thereof is subjected to a condensation reaction with a compound of the formula (IB) in the presence of a condensing agent, optionally further hydrolyzed and/or Condensation to give a compound of the formula (I);
  • Z is selected from a hydroxyl group or a halogen
  • R 1 to R 4 , X, Y, m, n, ring A, ring B and ring C are as defined in formula (I).
  • the reagent for providing basic conditions includes an organic base and an inorganic base
  • the organic base includes, but not limited to, triethylamine, morphin, N,N-diisopropylethylamine, pyridine, Sodium hexamethyldisilazide, n-butyllithium, potassium t-butoxide or tetrabutylammonium bromide
  • said inorganic bases including but not limited to lithium hydroxide, sodium hydroxide, potassium hydroxide, hydrogenation Sodium, sodium carbonate, sodium hydrogencarbonate, potassium carbonate, potassium hydrogencarbonate or cesium carbonate, preferably triethylamine.
  • Condensing agents include, but are not limited to, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, N,N'-di Propylcarbodiimide, O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate, 1-hydroxybenzotriazole, 1-hydroxy-7- Azobenzotriazole, O-benzotriazole-N,N,N',N'-tetramethyluron hexafluorophosphate, 2-(7-azobenzotriazole)-N, N,N',N'-tetramethylurea hexafluorophosphate, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate or benzotriazole hexafluorophosphate- 1-yl
  • Figure 1 Three-day average of the effect of Npt2b on urinary phosphorus excretion in rats, with a ratio of reduced amplitude.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS).
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • the NMR was measured by a Bruker AVANCE-400 nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), and the internal standard was four.
  • DMSO-d 6 dimethyl sulfoxide
  • CDCl 3 deuterated chloroform
  • CD 3 OD deuterated methanol
  • TMS Methylsilane
  • chemical shifts are given in units of 10 -6 (ppm).
  • the measurement of the MS was carried out using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).
  • ESI FINNIGAN LCQAd
  • the HPLC was measured using an Agilent 1200 DAD high pressure liquid chromatograph (Sunfire C18 150 x 4.6 mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150 x 4.6 mm column).
  • Thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate.
  • the specification of silica gel plate used for thin layer chromatography (TLC) is 0.15mm ⁇ 0.2mm.
  • the specification for thin layer chromatography separation and purification is 0.4mm. ⁇ 0.5mm silica gel plate.
  • the known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from ABCR GmbH & Co. KG, Acros Organnics, Aldrich Chemical Company, Accela ChemBio Inc, Dari Companies such as chemicals.
  • An argon atmosphere or a nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon having a volume of about 1 L.
  • the hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume.
  • the pressurized hydrogenation reaction was carried out using a Parr Model 3916EKX hydrogenation apparatus and a clear blue QL-500 type hydrogen generator or a HC2-SS type hydrogenation apparatus.
  • the hydrogenation reaction is usually evacuated, charged with hydrogen, and operated three times.
  • the microwave reaction used a CEM Discover-S Model 908860 microwave reactor.
  • the solution in the reaction means an aqueous solution unless otherwise specified.
  • the temperature of the reaction was room temperature unless otherwise specified.
  • Room temperature is the most suitable reaction temperature, and the temperature range is from 20 ° C to 30 ° C.
  • the progress of the reaction in the examples was monitored by thin layer chromatography (TLC).
  • TLC thin layer chromatography
  • the system used for the reaction was: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: petroleum ether And the ethyl acetate system, D: acetone, the volume ratio of the solvent is adjusted depending on the polarity of the compound.
  • the system for the eluent of the column chromatography and the system for the thin layer chromatography of the developer used for the purification of the compound include: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: n-hexane and acetone
  • the volume ratio of the solvent is adjusted depending on the polarity of the compound, and may be adjusted by adding a small amount of triethylamine and an acidic or alkaline reagent.
  • N-Methyl-2-(4-methylpiperazin-1-yl)ethylamine 4b (1.73 g, 11.01 mmol, prepared by the method disclosed in the patent application "WO2013014448”) was dissolved in 35 mL of dichloromethane
  • Triethylamine (2.22 g, 22.02 mmol)
  • cool to 0 ° C and add 5 mL of methyl 3-(chloroformyl)benzoate 4a (56 mg, 0.21 mmol, using the well-known method "Journal of the American Chemical Society,"
  • a solution of 135 (45), 16841-16844; 2013 "prepared” in dichloromethane was allowed to warm to room temperature and the reaction was stirred for 2 hours.
  • the reaction mixture was concentrated under reduced pressure.
  • mjjjjjjjjjj Methyl benzoate 4c (2.40 g, brown oily liquid), yield: 75%.
  • reaction solution was concentrated under reduced pressure, and 10 mL of water was added, and 1 M hydrochloric acid was added dropwise to pH 6 to 7 and extracted with dichloromethane (20 mL ⁇ 3).
  • organic phase was combined and washed with saturated sodium chloride solution (50 mL ⁇ 1) Drying with anhydrous sodium sulfate, filtration, and EtOAcqqqqqqqq 4,5,6,7-Tetrahydrobenzo[b]thiophene-3-carboxamido)phenethyl)benzoic acid 6b (352 mg, yellow solid).
  • 3-Methyl-4-phenylethylaniline 8b (1.20g, 5.68mmol) and cyanoacetic acid (722mg, 8.50mmol) were dissolved in 10mL dimethylformamide, cooled to 0 ° C, added 1- (3) -Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.62 g, 8.50 mmol), warmed to room temperature and stirred for 1 hour.
  • reaction liquid was poured into 100 mL of ice water, stirred for 30 minutes, filtered, and the filter cake was dried to give the crude title product 4-(4-(2-cyanoacetamido)-2-methylphenethyl)benzoic acid Ester 10e (1.71 g, off white solid).
  • 4-Phenylpropylaniline 12a (10.30 g, 48.74 mmol, prepared by the well-known method literature "Bioorganic & Medicinal Chemistry Letters, 19 (3), 654-657; 2009" was dissolved in 100 mL of dimethylformamide.
  • 2-Cyanoacetic acid (6.22 g, 73.12 mmol)
  • 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride 14 g, 73.12 mmol
  • Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (305 mg, 1.60 mmol) and 4-dimethylaminopyridine (195 mg, 1.60 mmol) were warmed to 25 ° C and stirred for 12 hours.
  • the organic phase is combined, washed with a saturated sodium chloride solution (50 mL ⁇ 1), dried over anhydrous sodium sulfate, filtered and evaporated.
  • Test Example 1 Inhibition of the transport of inorganic phosphorus by human Npt2b/HEK293 cells by the compounds of the present invention.
  • the following method was used to determine the inhibitory effect of the compounds of the present invention on the transport of inorganic phosphorus by human Npt2b/HEK293 cells.
  • Npt2b plasmid and Lipofectamine TM LTX were mixed for 30 minutes, the mixture was added dropwise to HEK293 cells in logarithmic growth phase (cell bank CAS # GNHu43), the plus side mix After 24 hours, the medium was replaced with G418-containing medium (Enzo#ALX-380-013-G005) until the cells were nearly full, and the monoclonal cells were plated to verify their functions, and a monoclonal stable cell line was obtained.
  • Stable cell line human Npt2b/HEK293 cells were seeded in 48-well plates one day in advance and cultured in a 37 ° C carbon dioxide incubator. The medium was discarded and the cells were washed once with a Choline uptake buffer (250 ⁇ L/well). 10 ⁇ L of H 3 32 PO 4 was diluted in 1000 ml of sodium uptake buffer. 80 ⁇ L of the test compound and 20 ⁇ L of the diluted H 3 32 PO 4 were added to each well and incubated at room temperature for about 20 minutes.
  • the final compound concentrations were: 100 ⁇ M, 10 ⁇ M, 1 ⁇ M, 0.1 ⁇ M, 0.01 ⁇ M, 0.001 ⁇ M, final DMSO concentration: 0.5%, final H 3 32 PO 4 concentration: 0.2 uCi/well; discard the above compounds and H 3 32 PO 4 , then the cells were washed twice with ice cold stop solution (350 ⁇ L/well). Then 150 ⁇ L of 200 mM NaOH was added to each well, and the upper plate was shaken and lysed for about 5 minutes at room temperature. 120 ⁇ L of cell lysate was transferred to each well to a 96-well sample plate.
  • the 96-well sample plate was filled with 100 ⁇ L of Optiphase Supermix per well, and then the 96-well sample plate was sealed with RE-SEALABLE TAPE, and shaken on the plate shaker at room temperature for about 5 minutes. The flashing illuminometer reads the value.
  • Table 1 IC 50 of the compounds of the invention inhibiting the transport of inorganic phosphorus by human Npt2b/HEK293 cells
  • Example number IC 50 (nM) 1 twenty two 5 100 6 15 7 44 8 9 9 114
  • the compounds of the present invention have a significant inhibitory effect on the transport of inorganic phosphorus by human Npt2b/HEK293 cells.
  • Test Example 2 Inhibition of transport of inorganic phosphorus by murine Npt2b/HEK293 cells by the compounds of the present invention.
  • the following method was used to determine the inhibitory effect of the compounds of the present invention on the transport of inorganic phosphorus by murine Npt2b/HEK293 cells.
  • Stable cell line mouse Npt2b/HEK293 cells were seeded in 48-well plates one day in advance and cultured in a 37 ° C carbon dioxide incubator. The medium was discarded and the cells were washed once with a Choline uptake buffer (250 ⁇ L/well). 10 ⁇ L of H 3 32 PO 4 was diluted in 1000 ml of sodium uptake buffer. 80 ⁇ L of the test compound and 20 ⁇ L of the diluted H 3 32 PO 4 were added to each well and incubated at room temperature for about 20 minutes.
  • the final compound concentrations were: 100 ⁇ M, 10 ⁇ M, 1 ⁇ M, 0.1 ⁇ M, 0.01 ⁇ M, 0.001 ⁇ M, final DMSO concentration: 0.5%, final H 3 32 PO 4 concentration: 0.2 uCi/well; discard the above compounds and H 3 32 PO 4 , then the cells were washed twice with ice cold stop solution (350 ⁇ L/well). 150 ⁇ L of 200 mM NaOH was added to each well, and the plate was shaken and lysed for about 5 minutes at room temperature. 120 ⁇ L of cell lysate was transferred to each well to a 96-well sample plate.
  • the 96-well sample plate was filled with 100 ⁇ L of Optiphase Supermix per well, and then the 96-well sample plate was sealed with RE-SEALABLE TAPE, and shaken on the plate for about 5 minutes at room temperature. The flashing illuminometer reads the value.
  • the compounds of the present invention have a significant inhibitory effect on the transport of inorganic phosphorus by murine Npt2b/HEK293 cells.
  • Rats were used as test animals, and the concentration of the drug in plasma at different times after administration of the compound of the example by intragastric administration was determined by LC/MS/MS method.
  • the pharmacokinetic behavior of the compounds of the invention in rats was investigated and their pharmacokinetic characteristics were evaluated.
  • 0.1 mL of blood was collected before administration and 0.5, 1, 2, 4, 6, 8, 11, and 24 hours after administration, placed in an EDTA anticoagulation tube, centrifuged at 3500 rpm for 5 minutes, and plasma was separated and stored at -20 °C. Eat 2 hours after administration.
  • the content of the test compound in the plasma of rats after intragastric administration of different compounds was determined by LC/MS/MS method.
  • the linear range of the analytical method was 5.00-2000 ng/mL and 1.00-500 ng/mL, respectively, and the lower limit of quantification was 5.00 ng/mL and 1.00 ng/mL, respectively; the plasma samples were analyzed by pretreatment with precipitated proteins.
  • the pharmacokinetic profile of the compounds of the invention is that their concentration in plasma is low and absorption in blood is low.
  • Rats were used as test animals, and the concentration of the drug in plasma at different times after administration of the compound of the preferred embodiment of the present invention by intragastric administration was determined by LC/MS/MS method. The pharmacokinetic behavior of the compounds of the invention in rats was investigated and their fecal recovery was evaluated.
  • Fecal samples were collected from 0 to 8 hours, 8 to 24 hours, 24 to 48 hours, and 48 to 72 hours after administration, and weighed separately. After recording, the label was attached and stored frozen at 20 °C.
  • the plasma samples were collected from the eyelids at 0.2 mL before and 2, 4, and 8 hours after administration, placed in heparinized tubes, centrifuged at 3500 rpm for 10 minutes, and the plasma was separated and stored at -20 ° C; Eat for hours.
  • Test Example 5 the compound of the present invention is used to treat hyperphosphatemia test in rats
  • Low-phosphorus feed (containing 0.1% phosphorus and 0.6% calcium): supplied by Shanghai Slack Laboratory Animal Co., Ltd.
  • Sodium dihydrogen phosphate NaH 2 PO 4 ⁇ H 2 O: batch number 201209I06, purchased from Hunan Jiudian Pharmaceutical Co., Ltd. 1 mmol/ml (138 mg/ml, 5 ml/kg) was prepared before use.
  • CMC-Na Sodium Carboxymethyl Cellulose
  • the experimental method was carried out in accordance with the method of the patent application (WO2012006473). After the animals were purchased, they were fed with normal feed (at least 3 days), then converted to low-phosphorus feed, and the rats were screened for serum phosphorus.
  • Rats with blood phosphorus below 2.3 mmol/L were randomly divided into groups according to the level of blood phosphorus.
  • Rat model of hyperphosphatemia was established by intragastric administration of sodium dihydrogen phosphate (1 mmol/1 mL) on the second day of the experiment.
  • the blood phosphorus values of the rats in the group were randomly divided into 6 groups, and the blank control group was given the same volume of distilled water.
  • Rats in each treatment group were given a single intragastric administration (5 mL/kg, 30 mg/kg) 15 minutes before modeling, and the model group was given corresponding 0.5% CMC. After the model was established, the rats were subjected to eyelid blood sampling for blood phosphorus levels at 0 hours (blank serum), 0.5 hours, and 2 hours, respectively.
  • the rats After oral administration of a preferred compound of the present invention at a dose of 30 mg/kg, the rats have a significant hypophosphatemic effect after 0.5 hours of administration of the phosphorus salt.
  • mice were fed with sevelamer (ie, sevelamer carbonate, Shanghai Qihong Chemical Technology Co., Ltd., Cat#: B12264) or Npt2b inhibitor example compound 7 to test rats' urine.
  • sevelamer ie, sevelamer carbonate, Shanghai Qihong Chemical Technology Co., Ltd., Cat#: B12264
  • Npt2b inhibitor example compound 7 to test rats' urine.
  • the inorganic phosphorus content is used to evaluate the phosphorus-promoting effect of the test drug.
  • SD male rats were purchased from Shanghai Bikai Experimental Animal Co., Ltd. (Shanghai, China, certificate number 2008001644738, license SCXK (Shanghai) 2013-0016). After the animals were purchased, after three days of adaptive feeding, two rounds of metabolic cage screening of normal feed and chocolate feed (15 g/feed/day-to-day consumption) were started, and the successfully selected rats were restarted.
  • Phosphorus Detection Kit Lot No. 20140808, provided by Nanjing Jiancheng Biological Company.
  • the experimental method was carried out in accordance with the method of the patent (WO2012006473).
  • the rats were first screened through normal feed (15 g/day), and the rats that had eaten all the feed were further screened for chocolate feed (15 g/day). Finally, the rats that had all the feeds were grouped into the experiment, randomly grouped as follows ( The dose is mg/kg/day): 1 normal blank group, 2 sevelam-750 mg/kg group, 3 compound 7-100 mg/kg group, 4 compound 7-100 mg/kg combined with sevelam-200 mg/kg group. 4-5 rats per group. Two rounds of successfully selected rats were fed the above-mentioned drug feed in a metabolic cage for 4 days. The daily body weight and feed consumption were observed, and urine was collected for 24-48h, 48-72h and 72-96h respectively. The content of inorganic phosphorus in the liquid.
  • the urinary phosphorus content was 25-26 mg in the four days of 24-48 h, 48-72 h and 72-96 h.
  • the total amount of urinary phosphorus or the average of 3 days in the drug-administered group was significant.
  • the decrease was (P ⁇ 0.05), the reduction of the Sevelam-750mg/kg group, the compound 7-100mg/kg group, the compound 7-100mg/kg+Sevelamer-200mg/kg group were 30.2%, 27.9, respectively. % and 44.2%, see Table 6, Figure 1, the ratio is the reduction.
  • Table 6 Three-day average of the effect of Npt2b on urinary phosphorus excretion in rats

Abstract

本发明涉及噻吩并环烷基或噻吩并杂环基类衍生物、其制备方法及其在医药上的应用。具体而言，本发明涉及一种通式（I）所示噻吩并环烷基或噻吩并杂环基类衍生物、其制备方法及含有该衍生物的药物组合物，以及其作为治疗剂，特别是作为肠2B型磷酸钠协同转运蛋白（Npt2b）抑制剂的用途和其在制备治疗和/或预防高磷血症的药物中的用途，其中通式（I）中的各取代基的定义与说明书中的定义相同。

Description

噻吩并环烷基或噻吩并杂环基类衍生物、其制备方法及其在医药上的应用 技术领域
本发明涉及一类新型噻吩并环烷基或噻吩并杂环基类衍生物、其制备方法及含有该衍生物的药物组合物，以及其作为治疗剂特别是作为肠2B型磷酸钠协同转运蛋白(Npt2b)抑制剂的用途和在制备治疗和/或预防高磷酸盐血症等疾病或病症的药物中的用途。
背景技术
无机磷酸盐(Pi)是骨矿物质的必要组分，成体磷酸盐的大约80％在矿外的胞外基质(如骨和牙)中，18％在细胞内，2％在细胞外液中。正常生理条件下，小肠摄取过量的磷酸盐，磷酸盐的体内平衡依赖于肾脏的排泄和重吸收功能来调节。体内磷酸盐过多或过少均导致机体功能紊乱而致病：如过低则导致低磷酸盐血症、软骨病、佝偻病和心脏功能紊乱；过高则诱发高磷酸盐血症、软组织和血管钙化以及肾功能障碍。磷酸盐过高是心血管疾病和慢性肾病(CKD)患者的死亡率增高的重要因素。目前高磷血症的治疗主要包括饮食限磷、透析治疗、磷结合剂的应用及必要时甲状旁腺的切除。有90～95％的终末期肾病患者需要服用磷结合剂治疗高磷血症。
小肠对磷酸盐的吸收主要通过两种途径，被动运输和主动运输，其中主动运输就是通过钠依赖型的钠/磷共转运通道蛋白进行的。最近的研究表明，磷酸钠协同转运蛋白2B(Npt2b)是治疗慢性肾病(CKD)中高磷酸盐血症的重要靶点(J Pharm Sci.2011Sep；100(9):3719-30)。磷酸钠协同转运蛋白包括1型家族(Npt1,Npt3,Npt4)，主要表达于肾脏中；2型家族(Npt2a,Npt2b,Npt2c)，主要表达于肾脏(Npt2c)，肺，肠及睾丸(Npt2a,Npt2b)中；3型家族(Pit1，Pit2)，普遍表达于各器官中。其中Npt2b在整个上消化道均有表达，介导一半左右的食物中磷酸盐的的吸收，用于维持磷酸盐的体内平衡。Npt2b在其他组织中也有表达，Npt2b抑制剂有必要保持不可吸收的特性和能在肠腔内保持的特点(Current Pharmaceutical Design,2012,18,1434-1445)。研究发现，Npt2b突变引起的Npt2b失活会导致常染色体隐性遗传病肺泡微结石(PAM)的发生，暗示Npt2b在肺泡的主要功能是移除多余的磷酸盐。在肺癌组织切片中，发现Npt2b高表达，小干扰siRNA实验发现降低Npt2b表达可抑制肺癌的发生。另一研究构建了非吸收Npt2b抑制剂(Ardelyx)的单独使用和组合使用(与磷酸盐粘合剂联用)的两个动物模型，发现在腺嘌呤诱导的CKD大鼠模型，NTX1942可降低尿毒症生物标志物(磷、肌酸酐和BUN的血清浓度)、甲状腺激素和FGF-23的血浆水平；而在5/6肾切除的大鼠模型中，经过50天给药治疗后，大鼠表现肾功能恶化延迟和存活率显著提高的表征。作为临床剂量， Npt2b抑制剂的剂量有希望比磷酸盐粘合剂低，为更多、范围更广的透析前CKD患者提供所需的磷酸盐抑制。
激素如雌性激素、糖皮质激素、成纤维细胞生长因子23(FGF23)、1,25(OH)维他命D3(1,25(OH)2D3)和饮食摄入的磷酸盐均影响小肠刷状缘膜的磷摄取或Npt2b的表达。小肠内Npt2b的缺失也导致FGF23表达的减少。FGF23的主要功能是通过降低磷酸盐共转运蛋白的表达和促进1,25(OH)2D3的合成来调节肾脏磷酸盐的排泄，Npt2b作为磷酸盐传感器，调控体内激素的平衡，维持全身系统的平衡。
目前公开了一系列的Npt2b抑制剂的专利申请，其中包括WO2004085382、WO2013082751、WO2001005398、WO2001082924、WO2003057225、WO2001087294、WO2014003153、WO2012006473、WO2012006474、WO2012006475、WO2012006477、WO2012054110、WO2002028353、WO2013062065、WO2013082756、WO2013082751、WO2013129435、WO2014142273、WO 2011136269、WO2009079373和WO2013082756等，但仍需要开发新的具有更好的药效的、在血液中不吸收或吸收少、对机体毒性作用小的化合物，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在结肠和空肠部位有优异的效果和作用。
发明内容
本发明的目的在于提供一种通式(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，或其可药用盐：
Figure PCTCN2015085385-appb-000001
其中：
X选自C(Ra)2、O、S或NRa；
Y选自-C(O)-或-NRbC(O)-；
Ra相同或不同，各自独立地选自氢原子、烷基、环烷基、杂环基、芳基、杂芳基、-C(O)OR5、-C(O)R5、-C(O)NR6R7或-S(O)pR5，其中所述的烷基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自卤素、羟基、烷氧基、氰基、硝基、烷基、卤代烷基、羟烷基、环烷基、杂环基、芳基、杂芳基、-C(O)OR5、 -OC(O)R5、-NHS(O)pR5、-C(O)R5、-NHC(O)R5、-NHC(O)OR5、-NR6R7、-OC(O)NR6R7或-C(O)NR6R7的取代基所取代；
Rb选自氢原子或烷基，其中所述的烷基任选进一步被一个或多个选自卤素、羟基、烷氧基、氰基或硝基的取代基所取代；
环A选自环烷基、杂环基、芳基或杂芳基；
环B选自芳基或杂芳基；
环C选自环烷基、杂环基、芳基或杂芳基，其中所述的环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自卤素、羟基、烷氧基、氰基、硝基、烷基、卤代烷基、羟烷基、环烷基、杂环基、芳基、杂芳基、-C(O)OR5、-OC(O)R5、-NHS(O)pR5、-C(O)R5、-NHC(O)R5、-NHC(O)OR5、-NR6R7、-OC(O)NR6R7或-C(O)NR6R7的取代基所取代；
R1选自烷基，其中所述的烷基进一步被一个或多个选自环烷基、杂环基、芳基或杂芳基的取代基所取代，其中所述的环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自卤素、羟基、烷氧基、氰基、硝基、烷基、卤代烷基、羟烷基、环烷基、杂环基、芳基、杂芳基、-C(O)OR5、-OC(O)R5、-NHS(O)pR5、-C(O)R5、-NHC(O)R5、-NHC(O)OR5、-NR6R7、-OC(O)NR6R7或-C(O)NR6R7的取代基所取代；
R2选自氢原子、卤素、烷氧基、氰基、硝基或烷基，其中所述的烷基或烷氧基任选进一步被一个或多个选自卤素、羟基、烷氧基、氰基、硝基、环烷基、杂环基、芳基、杂芳基、-C(O)OR5、-OC(O)R5、-NHS(O)pR5、-C(O)R5、-NHC(O)R5、-NHC(O)OR5、-NR6R7、-OC(O)NR6R7或-C(O)NR6R7的取代基所取代；
R3选自氢原子、卤素、烷氧基、氰基、硝基或烷基，其中所述的烷基或烷氧基任选进一步被一个或多个选自卤素、羟基、烷氧基、氰基、硝基、环烷基、杂环基、芳基、杂芳基、-C(O)OR5、-OC(O)R5、-NHS(O)pR5、-C(O)R5、-NHC(O)R5、-NHC(O)OR5、-NR6R7、-OC(O)NR6R7或-C(O)NR6R7的取代基所取代；
R4选自氢原子或烷基，其中所述的烷基任选进一步被一个或多个选自卤素、羟基、烷氧基、氰基、硝基、环烷基、杂环基、芳基、杂芳基、-C(O)OR5、-OC(O)R5、-NHS(O)pR5、-C(O)R5、-NHC(O)R5、-NHC(O)OR5、-NR6R7、-OC(O)NR6R7或-C(O)NR6R7的取代基所取代；
R5选自氢原子、烷基、环烷基、杂环基、芳基或杂芳基，其中所述的烷基、环烷基、芳基或杂芳基任选进一步被一个或多个选自烷基、卤素、羟基、羟烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、羧酸或羧酸酯的取代基所取代；
R6或R7各自独立地选自氢原子、烷基、烷氧基、环烷基、杂环基、芳基或杂芳基，其中所述的烷基、烷氧基、环烷基、杂环基、芳基或杂芳基各自独立地任选进一步被一个或多个选自烷基、卤素、羟基、羟烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、羧酸或羧酸酯的取代基所取代；
或者，R6或R7与相连接的氮原子一起形成杂环基，其中所述的杂环基内含有 一个或多个N、O或S(O)p杂原子，并且所述杂环基任选进一步被一个或多个选自烷基、卤素、羟基、烷氧基、羟烷基、环烷基、杂环基、芳基、杂芳基、羧酸或羧酸酯的取代基所取代；
m为0、1、2、3或4；
n为0、1、2、3或4；且
p为0、1或2。
在本发明另一个优选方案中，一种通式(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，或其可药用的盐，其中环B为苯基或吡啶基。
在本发明一个优选方案中，一种通式(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，或其可药用的盐，其为通式(II)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，或其可药用的盐：
Figure PCTCN2015085385-appb-000002
其中：
R1～R4、X、Y、m、n、环A和环C的定义如通式(I)中所述。
在本发明另一个优选方案中，一种通式(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，或其可药用的盐，其中环A选自杂环基或芳基，优选为苯基或吗啉基。
在本发明另一个优选方案中，一种通式(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，或其可药用的盐，其为通式(III)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，或其可药用的盐：
Figure PCTCN2015085385-appb-000003
其中：
R1～R4、X、Y、m、n和环C的定义如通式(I)中所述。
在本发明另一个优选方案中，一种通式(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，或其可药用的盐，其中环C为杂环基，优选为吗啡啉基或哌嗪基。
在本发明的另一个优选方案，一种通式(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，或其可药用的盐，其中R1选自-(CH2)r-Rc；
Rc选自环烷基、杂环基、芳基或杂芳基，其中所述的环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自卤素、羟基、烷氧基、氰基、硝基、烷基、卤代烷基、羟烷基、环烷基、杂环基、芳基、杂芳基、-C(O)OR5、-OC(O)R5、-NHS(O)pR5、-C(O)R5、-NHC(O)R5、-NHC(O)OR5、-NR6R7、-OC(O)NR6R7或-C(O)NR6R7的取代基所取代；
r选自1、2、3、4或5，优选为2或3；且
R5、R6、R7、p的定义如通式(I)中所述。
在本发明另一个优选方案中，一种通式(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，或其可药用的盐，其中R2选自氢原子或烷基，优选为甲基。
在本发明另一个优选方案中，一种通式(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，或其可药用的盐，其中R3选自氢原子或烷基，优选为甲基。
本发明典型的化合物包括，但不限于：
Figure PCTCN2015085385-appb-000004
Figure PCTCN2015085385-appb-000005
Figure PCTCN2015085385-appb-000006
Figure PCTCN2015085385-appb-000007
Figure PCTCN2015085385-appb-000008
Figure PCTCN2015085385-appb-000009
Figure PCTCN2015085385-appb-000010
Figure PCTCN2015085385-appb-000011
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，或其可药用盐。
本发明还提供一种制备通式(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，或其可药用的盐的方法，该方法包括：
Figure PCTCN2015085385-appb-000012
在碱性条件下，通式(IA)化合物或其盐与通式(IB)化合物反应，任选进一步水解和/或缩合得到通式(I)化合物；
其中：
Z选自羟基或卤素；
R1～R4、X、Y、m、n、环A、环B和环C的定义如式(I)中所述。
本发明还提供一种通式(IA)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，或其可药用的盐：
Figure PCTCN2015085385-appb-000013
其中：
X选自C(Ra)2、O、S或NRa；
Ra相同或不同，各自独立地选自氢原子、烷基、环烷基、杂环基、芳基、杂芳基、-C(O)OR5、-C(O)R5、-C(O)NR6R7或-S(O)pR5，其中所述的烷基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自卤素、羟基、烷氧基、氰基、硝基、烷基、卤代烷基、羟烷基、环烷基、杂环基、芳基、杂芳基、-C(O)OR5、-OC(O)R5、-NHS(O)pR5、-C(O)R5、-NHC(O)R5、-NHC(O)OR5、-NR6R7、-OC(O)NR6R7或-C(O)NR6R7的取代基所取代；
条件是当X选自C(Ra)2时，Ra不选自氢原子；
环A选自环烷基、杂环基、芳基或杂芳基，优选为苯基；
R1选自烷基，其中所述的烷基进一步被一个或多个选自环烷基、杂环基、芳基或杂芳基的取代基所取代，其中所述的环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自卤素、羟基、烷氧基、氰基、硝基、烷基、卤代烷基、羟烷基、环烷基、杂环基、芳基、杂芳基、-C(O)OR5、-OC(O)R5、-NHS(O)pR5、-C(O)R5、-NHC(O)R5、-NHC(O)OR5、-NR6R7、-OC(O)NR6R7或-C(O)NR6R7的取代基所取代；
R2选自氢原子、卤素、烷氧基、氰基、硝基或烷基，其中所述的烷基或烷氧基任选进一步被一个或多个选自卤素、羟基、烷氧基、氰基、硝基、环烷基、杂 环基、芳基、杂芳基、-C(O)OR5、-OC(O)R5、-NHS(O)pR5、-C(O)R5、-NHC(O)R5、-NHC(O)OR5、-NR6R7、-OC(O)NR6R7或-C(O)NR6R7的取代基所取代；
R5选自氢原子、烷基、环烷基、杂环基、芳基或杂芳基，其中所述的烷基、环烷基、芳基或杂芳基任选进一步被一个或多个选自烷基、卤素、羟基、羟烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、羧酸或羧酸酯的取代基所取代；
R6或R7各自独立地选自氢原子、烷基、烷氧基、环烷基、杂环基、芳基或杂芳基，其中所述的烷基、烷氧基、环烷基、杂环基、芳基或杂芳基各自独立地任选进一步被一个或多个选自烷基、卤素、羟基、羟烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、羧酸或羧酸酯的取代基所取代；
或者，R6或R7与相连接的氮原子一起形成杂环基，其中所述的杂环基内含有一个或多个N、O或S(O)p杂原子，并且所述杂环基任选进一步被一个或多个选自烷基、卤素、羟基、烷氧基、羟烷基、环烷基、杂环基、芳基、杂芳基、羧酸或羧酸酯的取代基所取代；
m为0、1、2、3或4；且
p为0、1或2。
通式(IA)化合物的典型的化合物包括，但不限于：
Figure PCTCN2015085385-appb-000014
Figure PCTCN2015085385-appb-000015
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，或其可药用盐。
本发明进一步涉及一种药物组合物，所述药物组合物含有治疗有效量的如通式(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，或其可药用的盐以及药学上可接受的载体、稀释剂或赋形剂。所述药物组合物进一步含有另外一种或多种磷结合剂，所述的磷结合剂优选为司维拉姆。
本发明进一步涉及通式(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，或其可药用的盐，或包含其的药物组合物在制备肠2B磷酸钠协同转运蛋白抑制剂中的用途。
本发明进一步涉及通式(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，或其可药用的盐，或包含其的药物组合物在制备治疗或预防高磷血症的药物中的用途。
本发明进一步涉及通式(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，或其可药用的盐，或包含其的药物组合物在治疗或预防磷酸钠转运蛋白介导的疾病的药物中的用途，所述的疾病包括但不限于肾病、内膜局部血管的钙化、高磷血症引起的高浓度的活性维生素D或甲状腺功能亢进症，所述的肾病优选为慢性的肾病或终末期肾病。
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，或其可药用的盐，或包含其的药物组合物，其用作肠2B型磷酸钠协同转运蛋白(Npt2b)抑制剂。
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，或其可药用的盐，或包含其的药物组合物，其用于治疗或预防高磷血症。
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，或其可药用的盐，或包含其的药物组合物，其用于治疗或预防磷酸钠转运蛋白介导的疾病，所述的疾病优选选自肾病、内膜局部血管的钙化、高磷血症引起的高浓度的活性维生素D、甲状腺功能亢进症，所述的肾病优选为慢性的肾病或终末期肾病。
本发明还涉及一种抑制肠2B型磷酸钠协同转运蛋白的方法，其包括给予所需患者治疗有效量的通式(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，或其可药用的盐，或包含其的药物组合物。
本发明还涉及一种治疗或预防高磷血症的方法，其包括给予所需患者治疗有效量的通式(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，或其可药用的盐，或包含其的药物组合物。
本发明涉及一种治疗或预防磷酸钠协同转运蛋白介导的疾病或病症的方法，其包括给予所需患者治疗有效量的通式(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，或其可药用的盐，或包含其的药物组合物，其中所述的方法包括：
(a)治疗高磷血症的方法；
(b)治疗肾病的方法；
(c)延缓肾透析时间的方法；
(d)减弱内膜局部血管钙化的方法；
(e)减少高磷血症引起的活性维生素D的方法；
(f)减少FGF23的方法；
(g)减弱甲状腺功能亢进症的方法；
(h)通过餐后血清中磷酸盐的浓度来改善血管内皮异常的方法；
(i)减少尿磷的方法；
(j)使血清中磷水平标准化的方法；
(k)治疗蛋白尿的方法；
(l)减少血清中甲状旁腺素和磷酸盐浓度的方法；
其中所述的肾病为慢性肾病或终末期肾病。
含活性成分的药物组合物可以是适用于口服的形式，例如片剂、糖锭剂、锭剂、水或油混悬液、可分散粉末或颗粒、乳液、硬或软胶囊，或糖浆剂或酏剂。可按照本领域任何已知制备药用组合物的方法制备口服组合物，此类组合物可含有一种或多种选自以下的成分：甜味剂、矫味剂、着色剂和防腐剂，以提供悦目和可口的药用制剂。片剂含有活性成分和用于混合的适宜制备片剂的无毒的可药用的赋形剂。这些赋形剂可以是惰性赋形剂，如碳酸钙、碳酸钠、乳糖、磷酸钙或磷酸钠；造粒剂和崩解剂，例如微晶纤维素、交联羧甲基纤维素钠、玉米淀粉或藻酸；粘合剂，例如淀粉、明胶、聚乙烯吡咯烷酮或阿拉伯胶和润滑剂，例如硬脂酸镁、硬脂酸或滑石粉。这些片剂可以不包衣或可通过掩盖药物的味道或在胃肠道中延迟崩解和吸收，因而在较长时间内提供缓释作用的已知技术将其包衣。例如，可使用水溶性味道掩蔽物质，例如羟丙基甲基纤维素或羟丙基纤维素，或延长时间物质例如乙基纤维素、醋酸丁酸纤维素。
也可用其中活性成分与惰性固体稀释剂例如碳酸钙、磷酸钙或高岭土混合的硬明胶胶囊，或其中活性成分与水溶性载体例如聚乙二醇或油溶媒例如花生油、液体石蜡或橄榄油混合的软明胶胶囊提供口服制剂。
水悬浮液含有活性物质和用于混合的适宜制备水悬浮液的赋形剂。此类赋形剂是悬浮剂，例如羧基甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、藻酸钠、聚乙烯吡咯烷酮和阿拉伯胶；分散剂或湿润剂可以是天然产生的磷脂例如卵磷脂，或烯化氧与脂肪酸的缩合产物例如聚氧乙烯硬脂酸酯，或环氧乙烷与长链脂肪醇的缩合产物，例如十七碳亚乙基氧基鲸蜡醇(heptadecaethyleneoxy cetanol)，或环氧乙烷与由脂肪酸和己糖醇衍生的部分酯的缩合产物，例如聚环氧乙烷山梨醇单油酸酯，或环氧乙烷与由脂肪酸和己糖醇酐衍生的偏酯的缩合产物，例如聚环氧乙烷脱水山梨醇单油酸酯。水混悬液也可以含有一种或多种防腐剂例如尼泊金乙酯或尼泊金正丙酯、一种或多种着色剂、一种或多种矫味剂和一种或多种甜味剂，例如蔗糖、糖精或阿司帕坦。
油混悬液可通过使活性成分悬浮于植物油如花生油、橄榄油、芝麻油或椰子油，或矿物油例如液体石蜡中配制而成。油悬浮液可含有增稠剂，例如蜂蜡、硬石蜡或鲸蜡醇。可加入上述的甜味剂和矫味剂，以提供可口的制剂。可通过加入抗氧化剂例如丁羟茴醚或α-生育酚保存这些组合物。
通过加入水可使适用于制备水混悬也的可分散粉末和颗粒提供活性成分和用于混合的分散剂或湿润剂、悬浮剂或一种或多种防腐剂。适宜的分散剂或湿润剂和悬浮剂可说明上述的例子。也可加入其他赋形剂例如甜味剂、矫味剂和着色剂。通过加入抗氧化剂例如抗坏血酸保存这些组合物。
本发明的药物组合物也可以是水包油乳剂的形式。油相可以是植物油例如橄榄油或花生油，或矿物油例如液体石蜡或其混合物。适宜的乳化剂可以是天然产生的磷脂，例如大豆卵磷脂和由脂肪酸和己糖醇酐衍生的酯或偏酯例如山梨坦单油酸酯，和所述偏酯和环氧乙烷的缩合产物，例如聚环氧乙烷山梨醇单油酸酯。乳剂也可以含有甜味剂、矫味剂、防腐剂和抗氧剂。可用甜味剂例如甘油、丙二醇、山梨醇或蔗糖配制糖浆和酏剂。此类制剂也可含有缓和剂、防腐剂、着色剂和抗氧剂。
药物组合物可以是无菌注射水溶液形式。可在使用的可接受的溶媒和溶剂中有水、林格氏液和等渗氯化钠溶液。无菌注射制剂可以是其中活性成分溶于油相的无菌注射水包油微乳。例如将活性成分溶于大豆油和卵磷脂的混合物中。然后将油溶液加入水和甘油的混合物中处理形成微乳。可通过局部大量注射，将注射液或微乳注入患者的血流中。或者，最好按可保持本发明化合物恒定循环浓度的方式给予溶液和微乳。为保持这种恒定浓度，可使用连续静脉内递药装置。这种装置的实例是Deltec CADD-PLUS.TM.5400型静脉注射泵。
药物组合物可以是用于肌内和皮下给药的无菌注射水或油混悬液的形式。可按已知技术，用上述那些适宜的分散剂或湿润剂和悬浮剂配制该混悬液。无菌注射制剂也可以是在无毒肠胃外可接受的稀释剂或溶剂中制备的无菌注射溶液或混悬液，例如1,3-丁二醇中制备的溶液。此外，可方便地用无菌固定油作为溶剂或悬浮介质。为此目的，可使用包括合成甘油单或二酯在内的任何调和固定油。此外，脂肪酸例如油酸也可以制备注射剂。
可按用于直肠给药的栓剂形式给予本发明化合物。可通过将药物与在普通温度下为固体但在直肠中为液体，因而在直肠中会溶化而释放药物的适宜的无刺激性赋形剂混合来制备这些药物组合物。此类物质包括可可脂、甘油明胶、氢化植物油、各种分子量的聚乙二醇和聚乙二醇的脂肪酸酯的混合物。
本领域技术人员所熟知的，药物的给药剂量依赖于多种因素，包括但并非限定以下因素：所用特定化合物的活性、病人的年龄、病人的体重、病人的健康状况、病人的行被、病人的饮食、给药时间、给药方式、排泄的速率、药物的组合等；另外，最佳的治疗方式如治疗的模式、通式化合物(I)的日用量或可药用的盐的种类可以根据传统的治疗方案来验证。
发明详述
除非有相反陈述，否则下列用在说明书和权利要求书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个碳原子的直链和支链基团。优选含有1至10个碳原子的烷基，更优选含有1至6个碳原子的烷基。非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、 1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基，及其各种支链异构体等。更优选的是含有1至6个碳原子的低级烷基，非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以是取代的或未取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，优选为一个或多个以下基团，独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、氨基、卤代烷基、羟烷基、羧基、羧酸酯基、-C(O)OR5、-OC(O)R5、-NHS(O)pR5、-C(O)R5、-NHC(O)R5、-NHC(O)OR5、-NR6R7、-OC(O)NR6R7或-C(O)NR6R7。
术语“烯基”指由至少由两个碳原子和至少一个碳-碳双键组成的如上定义的烷基，例如乙烯基、1-丙烯基、2-丙烯基、1-、2-或3-丁烯基等。优选C2-10烯基，更优选C2-6烯基，最优选C2-4烯基。烯基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、氨基、卤代烷基、羟烷基、羧酸基、羧酸酯基、-C(O)OR5、-OC(O)R5、-NHS(O)pR5、-C(O)R5、-NHC(O)R5、-NHC(O)OR5、-NR6R7、-OC(O)NR6R7或-C(O)NR6R7。
术语“炔基”指至少由两个碳原子和至少一个碳-碳三键组成的如上所定义的烷基，例如乙炔基、1-丙炔基、2-丙炔基、1-、2-或3-丁炔基等。优选C2-10炔基，更优选C2-6炔基，最优选C2-4炔基。炔基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、氨基、卤代烷基、羟烷基、羧酸基、羧酸酯基、-C(O)OR5、-OC(O)R5、-NHS(O)pR5、-C(O)R5、-NHC(O)R5、-NHC(O)OR5、-NR6R7、-OC(O)NR6R7或-C(O)NR6R7。
“环烷基”指饱和或部分不饱和单环或多环环状烃取代基，其包括3至20 个碳原子，优选包括3至12个碳原子，更优选环烷基环包含3至10个碳原子，最优选环烷基环包含3至6个碳原子。单环环烷基的非限制性实施例包含环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等，优选环丙基、环己烯基。多环环烷基包括螺环、稠环和桥环的环烷基。
“螺环烷基”指5至20元，单环之间共用一个碳原子(称螺原子)的多环基团，这些可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基基或多螺环烷基，优选为单螺环烷基和双螺环烷基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺环烷基。螺环烷基的非限制性实施例包含
Figure PCTCN2015085385-appb-000016
“稠环烷基”指5至20元，系统中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳多环基团，其中一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠环烷基，优选为双环或三环，更优选为5元/5元或5元/6元双环烷基。稠环烷基的非限制性实施例包含
Figure PCTCN2015085385-appb-000017
“桥环烷基”指5至20元，任意两个环共用两个不直接连接的碳原子的全碳多环基团，这些可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基，优选为双环、三环或四环，更有选为双环或三环。桥环烷基的非限制性实施例包含
Figure PCTCN2015085385-appb-000018
所述环烷基环可以稠合于芳基、杂芳基或杂环基环上，其中与母体结构连接在一起的环为环烷基，非限制性实施例包括茚满基、四氢萘基、苯并环庚烷基等。 环烷基可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个以下基团，独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、氨基、卤代烷基、羟烷基、羧基、羧酸酯基、-C(O)OR5、-OC(O)R5、-NHS(O)pR5、-C(O)R5、-NHC(O)R5、-NHC(O)OR5、-NR6R7、-OC(O)NR6R7或-C(O)NR6R7。
“杂环基”指饱和或部分不饱和单环或多环环状烃取代基，其包括3至20个环原子，其中一个或多个环原子选自氮、氧或S(O)m(其中m是0至2的整数)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。优选包括3至12个环原子，其中1～4个是杂原子；更优选杂环基环包含3至10个环原子，其中1～3个是杂原子；更优选杂环基环包含5至6个环原子，其中1～2个是杂原子。单环杂环基的非限制性实施例包含吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基、吡喃基、四氢呋喃基等。多环杂环基包括螺环、稠环和桥环的杂环基。
“螺杂环基”指5至20元，单环之间共用一个原子(称螺原子)的多环杂环基团，其中一个或多个环原子选自氮、氧或S(O)m(其中m是整数0至2)的杂原子，其余环原子为碳。这些可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺环烷基分为单螺杂环基、双螺杂环基或多螺杂环基，优选为单螺杂环基和双螺杂环基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺杂环基。螺杂环基的非限制性实施例包含
Figure PCTCN2015085385-appb-000019
“稠杂环基”指5至20元，系统中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环基团，一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统，其中一个或多个环原子选自氮、氧或S(O)m(其中m是整数0至2)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠杂环基，优选为双环或三环，更优选为5元/5元或5元/6元双环稠杂环基。稠杂环基的非限制性实施例包含
Figure PCTCN2015085385-appb-000020
Figure PCTCN2015085385-appb-000021
“桥杂环基”指5至14元，任意两个环共用两个不直接连接的原子的多环杂环基团，这些可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统，其中一个或多个环原子选自氮、氧或S(O)m(其中m是整数0至2)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥杂环基，优选为双环、三环或四环，更有选为双环或三环。桥杂环基的非限制性实施例包含：
Figure PCTCN2015085385-appb-000022
所述杂环基环可以稠合于芳基、杂芳基或环烷基环上，其中与母体结构连接在一起的环为杂环基，非限制性实施例包含：
Figure PCTCN2015085385-appb-000023
杂环基可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个以下基团，独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、氨基、卤代烷基、羟烷基、羧基、羧酸酯基、-C(O)OR5、-OC(O)R5、-NHS(O)pR5、-C(O)R5、-NHC(O)R5、-NHC(O)OR5、-NR6R7、-OC(O)NR6R7或-C(O)NR6R7。
“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，优选为6至10元，更优选苯基和萘基，最优选苯基。所述芳基环可以稠合于杂芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为芳基环，非限制性实施例包含：
Figure PCTCN2015085385-appb-000024
芳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以下基团，独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环基、芳基、杂芳基、环烷氧基、杂环烷氧基、 环烷硫基、杂环烷硫基、氨基、卤代烷基、羟烷基、羧基、羧酸酯基、-C(O)OR5、-OC(O)R5、-NHS(O)pR5、-C(O)R5、-NHC(O)R5、-NHC(O)OR5、-NR6R7、-OC(O)NR6R7或-C(O)NR6R7。
“杂芳基”指具有1至4个杂原子作为环原子，其余的环原子为碳的5至14元芳基，其中杂原子包括氧、硫和氮。优选为5至10元。杂芳基优选为是5元或6元，例如呋喃基、噻吩基、吡啶基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、咪唑基、四唑基等。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，非限制性实施例包含：
Figure PCTCN2015085385-appb-000025
杂芳基可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个以下基团，独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氨基、卤代烷基、羟烷基、羧基、羧酸酯基、-C(O)OR5、-OC(O)R5、-NHS(O)pR5、-C(O)R5、-NHC(O)R5、-NHC(O)OR5、-NR6R7、-OC(O)NR6R7或-C(O)NR6R7。
“烷氧基”指-O-(烷基)和-O-(未取代的环烷基)，其中烷基的定义如上所述。非限制性实施例包含甲氧基、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。烷氧基可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个以下基团，独立地选自为烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氨基、卤代烷基、羟烷基、羧基、羧酸酯基、-C(O)OR5、-OC(O)R5、-NHS(O)pR5、-C(O)R5、-NHC(O)R5、-NHC(O)OR5、-NR6R7、-OC(O)NR6R7或-C(O)NR6R7。
“卤代烷基”指烷基被一个或多个卤素取代，其中烷基的定义如上所述。
“羟基”指-OH基团。
“羟烷基”指被羟基取代的烷基，其中烷基的定义如上所述。
“卤素”指氟、氯、溴或碘。
“氨基”指-NH2。
“氰基”指-CN。
“硝基”指-NO2。
“苄基”指-CH2-苯基。
“氧代基”指＝O。
“羧基”指-C(O)OH。
“羧酸酯基”指-C(O)O(烷基)或(环烷基)，其中烷基、环烷基的定义如上所述。
“任选”或“任选地”意味着随后所描述地事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生地场合。例如，“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在，该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。
“取代的”指基团中的一个或多个氢原子，优选为最多5个，更优选为1～3个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。
p、R5～R7的定义如通式(I)化合物中所述。
本发明的合成方法
为了完成本发明的合成目的，本发明采用如下的合成技术方案：
本发明通式(I)所述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，或其可药用盐的制备方法，该方法包括以下步骤：
Figure PCTCN2015085385-appb-000026
在冰浴条件下，通式(Ia)化合物与2-氰基乙酸在缩合剂存在下进行缩合反应，得到通式(Ib)化合物；通式(Ib)化合物与通式(Ic)化合物，在吗啡啉存在的条件下进行反应，得到通式(Id)化合物；通式(Id)化合物与硫，在吗啡啉存在的条件下进行 反应，得到通式通式(IA)化合物；在碱性条件下，通式(IA)化合物或其盐与通式(IB)化合物在缩合剂存在下进行缩合反应，任选进一步水解和/或缩合得到通式(I)化合物；
其中：
Z选自羟基或卤素；
R1～R4、X、Y、m、n、环A、环B和环C的定义如式(I)中所述。
上述合成技术方案中，提供碱性条件的试剂包括有机碱和无机碱类，所述的有机碱类包括但不限于三乙胺、吗啡啉、N,N-二异丙基乙胺、吡啶、六甲基二硅基胺基钠，正丁基锂、叔丁醇钾或四丁基溴化铵，所述的无机碱类包括但不限于氢氧化锂、氢氧化钠、氢氧化钾、氢化钠、碳酸钠、碳酸氢钠、碳酸钾、碳酸氢钾或碳酸铯，优选为三乙胺。
缩合剂包括但不限于1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐、N,N'-二环己基碳化二亚胺、N,N'-二异丙基碳二酰亚胺、O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸酯、1-羟基苯并三唑、1-羟基-7-偶氮苯并三氮唑、O-苯并三氮唑-N,N,N',N'-四甲脲六氟磷酸酯、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯、苯并三氮唑-1-基氧基三(二甲基氨基)磷鎓六氟磷酸盐或六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷。
附图说明
图1:Npt2b对大鼠尿磷排泄影响的三天平均值,比率为降低辐度。
具体实施方式
以下结合实施例进一步描述本发明，但这些实施例并非限制本发明的范围。
本发明实施例中未注明具体条件的实验方法，通常按照常规条件，或按照原料或商品制造厂商所建议的条件。未注明具体来源的试剂，为市场购买的常规试剂。
实施例
化合物的结构是通过核磁共振(NMR)或质谱(MS)来确定的。NMR的测定是用Bruker AVANCE-400核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d6)、氘代氯仿(CDCl3)、氘代甲醇(CD3OD)，内标为四甲基硅烷(TMS)，化学位移是以10-6(ppm)作为单位给出。
MS的测定用FINNIGAN LCQAd(ESI)质谱仪(生产商：Thermo,型号：Finnigan LCQ advantage MAX)。
HPLC的测定使用安捷伦1200DAD高压液相色谱仪(Sunfire C18150×4.6mm色谱柱)和Waters 2695-2996高压液相色谱仪(Gimini C18150×4.6mm色谱柱)。
激酶平均抑制率及IC50值的测定用NovoStar酶标仪(德国BMG公司)。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm～0.2mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm硅胶板。
柱层析一般使用烟台黄海200～300目硅胶为载体。
本发明的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买自ABCR GmbH&Co.KG，Acros Organnics，Aldrich Chemical Company，韶远化学科技(Accela ChemBio Inc)、达瑞化学品等公司。
实施例中如无特殊说明，反应均在氩气氛或氮气氛下进行。
氩气氛或氮气氛是指反应瓶连接一个约1L容积的氩气或氮气气球。
氢气氛是指反应瓶连接一个约1L容积的氢气气球。
加压氢化反应使用Parr 3916EKX型氢化仪和清蓝QL-500型氢气发生器或HC2-SS型氢化仪。
氢化反应通常抽真空，充入氢气，反复操作3次。
微波反应使用CEM Discover-S 908860型微波反应器。
实施例中如无特殊说明，反应中的溶液是指水溶液。
实施例中如无特殊说明，反应的温度为室温。
室温为最适宜的反应温度，温度范围是20℃～30℃。
实施例中的反应进程的监测采用薄层色谱法(TLC)，反应所使用的展开剂的体系有：A：二氯甲烷和甲醇体系，B：正己烷和乙酸乙酯体系，C：石油醚和乙酸乙酯体系，D：丙酮，溶剂的体积比根据化合物的极性不同而进行调节。
纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂的体系包括：A：二氯甲烷和甲醇体系，B：正己烷和乙酸乙酯体系，C：正己烷和丙酮体系，D：正己烷，E：乙酸乙酯，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺和酸性或碱性试剂等进行调节。
实施例1
4-(3-(4-(2-(3-(甲基(2-吗啡啉乙基)氨甲酰基)苯甲酰胺基)-4,5,6,7-四氢苯并[b]噻吩-3-甲酰胺基)苯基)丙基)苯甲酸
Figure PCTCN2015085385-appb-000027
Figure PCTCN2015085385-appb-000028
第一步
4-(3-(4-(2-(3-(甲基(2-吗啡啉乙基)氨甲酰基)苯甲酰胺基)-4,5,6,7-四氢苯并[b]噻吩-3-甲酰胺基)苯基)丙基)苯甲酸甲酯
将4-(3-(4-(2-氨基-4,5,6,7-四氢苯并[b]噻吩-3-甲酰胺基)苯基)丙基)苯甲酸甲酯1a(149mg，0.33mmol，采用专利申请“WO2011136269”公开的方法制备而得)溶解于5mL二氯甲烷中，加入三乙胺(101mg，1mmol)，然后加入5mL 3-(甲基(2-吗啡啉乙基)氨甲酰基)苯甲酰氯1b(124mg，0.40mmol，采用专利申请“WO2012006477”公开的方法制备而得)的二氯甲烷溶液，搅拌反应3小时。加入20mL水，用二氯甲烷萃取(50mL×3)，合并有机相，依次用水(50mL×1)，饱和氯化钠溶液(50mL×1)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题产物4-(3-(4-(2-(3-(甲基(2-吗啡啉乙基)氨甲酰基)苯甲酰胺基)-4,5,6,7-四氢苯并[b]噻吩-3-甲酰胺基)苯基)丙基)苯甲酸甲酯1c(238mg，黄色固体)，产物不经纯化直接进行下一步反应。
MS m/z(ESI):723.2[M+1]
1H NMR(400MHz,DMSO-d6)δ11.59(s,1H),9.68(s,1H),7.85-7.93(m,4H),7.62-7.64(d,4H),7.37(d,2H),7.18(d,2H),3.84(s,3H),3.41-3.56(m,5H),3.32(s,3H),2.88-2.96(m,3H),2.58-2.74(m,8H),2.37-2.42(m,2H),2.09(s,2H),1.75-1.93(m,6H)
第二步
4-(3-(4-(2-(3-(甲基(2-吗啡啉乙基)氨甲酰基)苯甲酰胺基)-4,5,6,7-四氢苯并[b]噻吩-3-甲酰胺基)苯基)丙基)苯甲酸
将粗品4-(3-(4-(2-(3-(甲基(2-吗啡啉乙基)氨甲酰基)苯甲酰胺基)-4,5,6,7-四氢苯并[b]噻吩-3-甲酰胺基)苯基)丙基)苯甲酸甲酯1c(238mg，0.33mmol)溶解于10mL四氢呋喃中，加入3mL 2M氢氧化钠溶液，搅拌反应2小时。加入30mL水，用 正己烷和乙酸乙酯(V:V＝1:1)的混合溶液萃取(20mL×2)，合并水相，滴加2M盐酸至水相pH为2～3，固体析出。过滤，滤饼烘干，用HPLC制备分离法纯化所得残余物，得到标题产物4-(3-(4-(2-(3-(甲基(2-吗啡啉乙基)氨甲酰基)苯甲酰胺基)-4,5,6,7-四氢苯并[b]噻吩-3-甲酰胺基)苯基)丙基)苯甲酸1(160mg，白色固体)，产率：68.7％。
MS m/z(ESI):709.2[M+1]
1H NMR(400MHz,DMSO-d6):δ12.77(s,1H),11.59(s,1H),9.65(s,1H),7.92(s,1H),7.85-7.87(m,3H),7.62(d,4H),7.33(d,2H),7.17(d,2H),3.88-3.96(m,3H),3.41-3.55(m,5H),2.88-2.96(d,3H),2.65-2.74(m,6H),2.56-2.60(m,2H),2.40(s,2H),2.10(s,2H).,1.6-1.93(m,2H),1.75-1.81(m,4H)
实施例2
4-(4-(2-(3-(3-甲基-3-(2-吗啡啉乙基)脲基)苯甲酰胺基)-4,5,6,7-四氢苯并[b]噻吩-3-甲酰胺基)苯乙基)苯甲酸
Figure PCTCN2015085385-appb-000029
第一步
3-(3-甲基-3-(2-吗啡啉乙基)脲基)苯甲酰氯
将3-(3-甲基-3-(2-吗啡啉乙基)脲基)苯甲酸2a(150mg，0.50mmol，采用专利申请“WO2012054110”公开的方法制备而得)溶解于60mL二氯甲烷中，降温至0℃，加入氯化亚砜(177mg，1.50mmol)，升温至回流，搅拌反应2小时。反应液减压浓缩，得到粗品标题产物3-(3-甲基-3-(2-吗啡啉乙基)脲基)苯甲酰氯2b(163mg，白色固体)，产物不经纯化直接进行下一步反应。
第二步
4-(4-(2-(3-(3-甲基-3-(2-吗啡啉乙基)脲基)苯甲酰胺基)-4,5,6,7-四氢苯并[b]噻吩-3-甲酰胺基)苯乙基)苯甲酸甲酯
将4-(4-(2-氨基-4,5,6,7-四氢苯并[b]噻吩-3-甲酰胺基)苯乙基)苯甲酸甲酯2c(144mg，0.33mmol，采用专利申请“WO2011136269”公开的方法制备而得)溶解于5mL三氯甲烷中，加入三乙胺(101mg，1mmol)，降温至0℃，加入粗品3-(3-甲基-3-(2-吗啡啉乙基)脲基)苯甲酰氯2b(163mg，0.50mmol)的二氯甲烷溶液，升至室温，搅拌反应12小时。加入50mL水，用二氯甲烷萃取(50mL×3)，合并有机相，依次用水(50mL×1)，饱和氯化钠溶液(50mL×1)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物4-(4-(2-(3-(3-甲基-3-(2-吗啡啉乙基)脲基)苯甲酰胺基)-4,5,6,7-四氢苯并[b]噻吩-3-甲酰胺基)苯乙基)苯甲酸甲酯2d(136mg，淡黄色固体)，产率：57.1％。
MS m/z(ESI):724.2[M+1]
1H NMR(400MHz,DMSO-d6):δ13.44(s,1H),9.26(s,1H),8.16-8.07(m,2H),7.88(d,2H),7.64(d,2H),7.51-7.44(m,2H),7.36(d,2H),7.12(d,2H),4.15(s,2H),3.83(s,3H),3.55-3.51(m,3H),3.33-3.30(m,6H),3.20(s,2H),2.98-2.89(m,3H),2.68(t,2H),2.56(t,2H),2.36-2.30(m,3H),2.03(s,2H),1.91-1.87(m,2H)
第三步
4-(4-(2-(3-(3-甲基-3-(2-吗啡啉乙基)脲基)苯甲酰胺基)-4,5,6,7-四氢苯并[b]噻吩-3-甲酰胺基)苯乙基)苯甲酸
将4-(4-(2-(3-(3-甲基-3-(2-吗啡啉乙基)脲基)苯甲酰胺基)-4,5,6,7-四氢苯并[b]噻吩-3-甲酰胺基)苯乙基)苯甲酸甲酯2d(136mg，0.19mmol)溶解于4.5mL四氢呋喃和乙醇(V:V＝2:1)的混合溶液中，加入1.1mL 2M氢氧化钠溶液，升温至25℃，搅拌反应12小时。反应液减压浓缩，用HPLC制备分离法纯化所得残余物，得到标题产物4-(4-(2-(3-(3-甲基-3-(2-吗啡啉乙基)脲基)苯甲酰胺基)-4,5,6,7-四氢苯并[b]噻吩-3-甲酰胺基)苯乙基)苯甲酸2(15mg，白色固体)，产率：11.3％。
MS m/z(ESI):710.2[M+1]
1H NMR(400MHz,DMSO-d6):δ8.71(s,1H),8.03(s,1H),7.85-7.75(d,2H),7.71(d,1H),7.60-7.59(m,2H),7.48-7.37(m,2H),7.36-7.30(m,2H),7.18-7.16(m,2H),3.54(t,4H),3.44(t,2H),3.01-2.92(m,4H),2.91-2.84(m,2H),2.79(s.,2H),2.68(s,2H),2.54(s,1H),2.49-2.37(m,6H),1.85-1.55(m,4H)
实施例3
4-(3-(4-(2-(3-(甲基(2-吗啡啉乙基)氨甲酰基)苯甲酰胺基)-6-((四氢-2H-吡喃-4-基)甲基)-4,5,6,7-四氢噻吩并[2,3-c]吡啶-3-甲酰胺基)苯基)丙基)苯甲酸
Figure PCTCN2015085385-appb-000030
第一步
2-氨基-3-(4-(3-(4-(甲氧基羰基)苯基)丙基)苯氨基羰基)-4,5-二氢噻吩并[2,3-c]吡啶-6(7H)-甲酸叔丁酯
将硫(71mg，2.23mmol)溶解于20mL乙醇中，依次加入4-(3-(4-(2-氰基乙酰胺基)苯基)丙基)苯甲酸甲酯3a(750mg，2.23mmol，采用专利申请“WO2013062065”公开的方法制备而得)，4-羰基哌啶-1-甲酸叔丁酯(443mg，4.97mmol)和吗啉(213mg，2.45mmol)，加热升温至90℃，搅拌反应12小时。加入60mL饱和氯化钠溶液，用乙酸乙酯萃取(50mL×3)，合并有机相，用饱和氯化钠溶液洗涤(50mL×1)，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题产物2-氨基-3-(4-(3-(4-(甲氧基羰基)苯基)丙基)苯氨基羰基)-4,5-二氢噻吩并[2,3-c]吡啶-6(7H)-甲酸叔丁酯3b(600mg，黄色固体)，产率： 49.0％。
MS m/z(ESI):550.2[M+1]
第二步
3-(4-(3-(4-(甲氧基羰基)苯基)丙基)苯氨基羰基)-2-(3-(甲基(2-吗啡啉乙基)氨甲酰基)苯甲酰胺基)-4,5-二氢噻吩并[2,3-c]吡啶-6(7H)-甲酸叔丁酯
将3-(甲基(2-吗啡啉乙基)氨甲酰基)苯甲酸3c(85mg，0.30mmol，采用专利申请“WO2012006477”公开的方法制备而得)和2-氨基-3-(4-(3-(4-(甲氧基羰基)苯基)丙基)苯氨基羰基)-4,5-二氢噻吩并[2,3-c]吡啶-6(7H)-甲酸叔丁酯3b(100mg，0.18mmol)溶解于10mL二氯甲烷中，依次加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(52mg，0.27mmol)和4-二甲氨基吡啶(33mg，0.27mmol)，搅拌反应24小时。加入50mL水，用乙酸乙酯萃取(50mL×3)，合并有机相，用饱和氯化钠溶液洗涤(50mL×1)，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题产物3-(4-(3-(4-(甲氧基羰基)苯基)丙基)苯氨基羰基)-2-(3-(甲基(2-吗啡啉乙基)氨甲酰基)苯甲酰胺基)-4,5-二氢噻吩并[2,3-c]吡啶-6(7H)-甲酸叔丁酯3d(50mg，黄色固体)，产率：33.8％。
MS m/z(ESI):824.4[M+1]
1H NMR(400MHz,DMSO-d6):δ11.66(s,1H),9.55(s,1H),7.95-7.92(m,1H),7.90-7.86(m,3H),7.63-7.61(m,4H),7.37-7.35(d,2H),7.19-7.17(d,2H),4.54(s,2H),3.87(s,3H),3.58-3.57(m,5H),3.41-3.30(m,2H),3.30-3.25(m,2H),2.96-2.83(m,5H),2.69-2.66(t,2H),2.60-2.58(t,2H),2.40-2.30(m,3H),2.15-2.05(m,2H),1.91-1.87(m,2H),1.44(s,9H)
第三步
4-(3-(4-(2-(3-(甲基(2-吗啡啉乙基)氨甲酰基)苯甲酰胺基)-4,5,6,7-四氢噻吩并[2,3-c]吡啶-3-甲酰胺基)苯基)丙基)苯甲酸甲酯
将3-(4-(3-(4-(甲氧基羰基)苯基)丙基)苯氨基羰基)-2-(3-(甲基(2-吗啡啉乙基)氨甲酰基)苯甲酰胺基)-4,5-二氢噻吩并[2,3-c]吡啶-6(7H)-甲酸叔丁酯3d(100mg，0.10mmol)溶解于3mL二氯甲烷中，降温至0℃，加入0.5mL三氟乙酸，搅拌反应30分钟。滴加饱和碳酸钠至反应液pH为9～10，用二氯甲烷萃取(50mL×3)，合并有机相，用饱和氯化钠溶液洗涤(50mL×1)，无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题产物4-(3-(4-(2-(3-(甲基(2-吗啡啉乙基)氨甲酰基)苯甲酰胺基)-4,5,6,7-四氢噻吩并[2,3-c]吡啶-3-甲酰胺基)苯基)丙基)苯甲酸甲酯3e(50mg，黄色固体)，产物不经纯化直接进入下一步反应。
MS m/z(ESI):724.2[M+1]
1H NMR(400MHz,DMSO-d6):7.92(s,1H),7.87(d,3H),7.67(d,1H),7.57-7.64(m,3H),7.34-7.40(m,2H),7.18(d,2H),3.83(s,3H),3.58(s,3H),3.43(d,2H),3.27(s,1H),2.84-3.02(m,10H),2.60-2.81(m,5H),2.55(s,1H),2.43(s,3H),2.06-2.18(m,2H)
第四步
4-(3-(4-(2-(3-(甲基(2-吗啡啉乙基)氨甲酰基)苯甲酰胺基)-6-((四氢-2H-吡喃-4-基)甲基)-4,5,6,7-四氢噻吩并[2,3-c]吡啶-3-甲酰胺基)苯基)丙基)苯甲酸甲酯
将粗品4-(3-(4-(2-(3-(甲基(2-吗啡啉乙基)氨甲酰基)苯甲酰胺基)-4,5,6,7-四氢噻吩并[2,3-c]吡啶-3-甲酰胺基)苯基)丙基)苯甲酸甲酯3e(100mg，0.14mmol)溶解于5mLN,N-二甲基甲酰胺中，依次加入碳酸钾(57mg，0.41mmol)和4-甲基苯磺酸(四氢-2H-吡喃-4-基)甲基酯(56mg，0.21mmol，采用公知的方法文献“Bioorganic&Medicinal Chemistry Letters,21(8),2541-2546”制备而得)，加热至70℃，搅拌反应12小时。加入30mL水，用乙酸乙酯萃取(30mL×3)，合并有机相，用饱和氯化钠溶液洗涤(30mL×1)，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题产物4-(3-(4-(2-(3-(甲基(2-吗啡啉乙基)氨甲酰基)苯甲酰胺基)-6-((四氢-2H-吡喃-4-基)甲基)-4,5,6,7-四氢噻吩并[2,3-c]吡啶-3-甲酰胺基)苯基)丙基)苯甲酸甲酯3f(31mg，淡黄色固体)，产率：27.4％。
MS m/z(ESI):822.4[M+1]
第五步
4-(3-(4-(2-(3-(甲基(2-吗啡啉乙基)氨甲酰基)苯甲酰胺基)-6-((四氢-2H-吡喃-4-基)甲基)-4,5,6,7-四氢噻吩并[2,3-c]吡啶-3-甲酰胺基)苯基)丙基)苯甲酸
将4-(3-(4-(2-(3-(甲基(2-吗啡啉乙基)氨甲酰基)苯甲酰胺基)-6-((四氢-2H-吡喃-4-基)甲基)-4,5,6,7-四氢噻吩并[2,3-c]吡啶-3-甲酰胺基)苯基)丙基)苯甲酸甲酯3f(31mg，0.04mmol)溶解于5mL甲醇中，加入5mL 2M氢氧化钠溶液，升温至50℃，搅拌反应1小时。滴加3M盐酸至水相pH为2～3，固体析出。过滤，滤饼烘干，用HPLC制备分离法纯化所得残余物，得到标题产物4-(3-(4-(2-(3-(甲基(2-吗啡啉乙基)氨甲酰基)苯甲酰胺基)-6-((四氢-2H-吡喃-4-基)甲基)-4,5,6,7-四氢噻吩并[2,3-c]吡啶-3-甲酰胺基)苯基)丙基)苯甲酸3(20mg，白色固体)，产率：66.7％。
MS m/z(ESI):808.4[M+1]
1H NMR(400MHz,CD3OD):δ8.08-8.15(m,2H),7.96(d,2H),7.81(d,1H),7.70(t,1H),7.58(d,2H),7.32(d,2H),7.26(d,2H),4.08(s,1H),3.92-4.06(m,5H),3.76-3.95(m,5H),3.44-3.62(m,5H),3.30(d,4H),3.09(s,3H),2.65-2.78(m,4H),2.28(d,1H),1.95-2.05(m,2H),1.79(d,2H),1.45-1.55(m,2H),1.27-1.38(m,3H),0.91-0.95(m,1H)
实施例4
4-(4-(2-(3-(甲基(2-(4-甲基哌嗪-1-基)乙基)氨甲酰基)苯甲酰胺基)-4,5,6,7-四氢苯并[b]噻吩-3-甲酰胺基)苯乙基)苯甲酸
Figure PCTCN2015085385-appb-000031
第一步
3-(甲基(2-(4-甲基哌嗪-1-基)乙基)氨甲酰基)苯甲酸甲酯
将N-甲基-2-(4-甲基哌嗪-1-基)乙胺4b(1.73g，11.01mmol，采用专利申请“WO2013014448”公开的方法制备而得)溶解于35mL二氯甲烷中，加入三乙胺(2.22g，22.02mmol)，冷却至0℃，加入5mL3-(氯甲酰基)苯甲酸甲酯4a(56mg，0.21mmol，采用公知的方法文献“Journal of the American Chemical Society,135(45),16841-16844；2013”制备而得)的二氯甲烷溶液，升至室温，搅拌反应2小时。反应液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题产物3-(甲基(2-(4-甲基哌嗪-1-基)乙基)氨甲酰基)苯甲酸甲酯4c(2.40g，棕色油状液体)，产率：75％。
MS m/z(ESI):320.3[M+1]
第二步
3-(甲基(2-(4-甲基哌嗪-1-基)乙基)氨甲酰基)苯甲酸
将3-(甲基(2-(4-甲基哌嗪-1-基)乙基)氨甲酰基)苯甲酸甲酯4c(530mg，1.66mmol)，氢氧化锂(209mg，4.98mmol)溶解于14mL四氢呋喃，水和甲醇(V:V:V＝5:4:5)混合溶剂中，搅拌反应1小时。反应液减压浓缩，用硅胶色谱制备分离法纯化所得残余物，得到标题产物3-(甲基(2-(4-甲基哌嗪-1-基)乙基)氨甲酰基)苯甲酸4d(507mg，白色固体)，产率：100％。
MS m/z(ESI):306.2[M+1]
第三步
4-(4-(2-(3-(甲基(2-(4-甲基哌嗪-1-基)乙基)氨甲酰基)苯甲酰胺基)-4,5,6,7-四氢苯并[b]噻吩-3-甲酰胺基)苯乙基)苯甲酸甲酯
将4-(4-(2-氨基-4,5,6,7-四氢苯并[b]噻吩-3-甲酰胺基)苯乙基)苯甲酸甲酯2c(70mg，0.16mmol)，3-(甲基(2-(4-甲基哌嗪-1-基)乙基)氨甲酰基)苯甲酸4d(98mg，0.32mmol)，2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(122mg，0.32mmol)和N,N-二异丙基乙胺(80μL，0.48mmol)溶解于5mL二甲基甲酰胺中，升温至50℃，搅拌反应12小时。加入10mL饱和碳酸氢钠溶液，用二氯甲烷萃取(30mL×3)，合并有机相，依次用水(50mL×1)，饱和氯化钠溶液(50mL×1)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物4-(4-(2-(3-(甲基(2-(4-甲基哌嗪-1-基)乙基)氨甲酰基)苯甲酰胺基)-4,5,6,7-四氢苯并[b]噻吩-3-甲酰胺基)苯乙基)苯甲酸甲酯4e(71mg，黄色固体)，产率：30.6％。MS m/z(ESI):722.4[M+1]
第四步
4-(4-(2-(3-(甲基(2-(4-甲基哌嗪-1-基)乙基)氨甲酰基)苯甲酰胺基)-4,5,6,7-四氢苯并[b]噻吩-3-甲酰胺基)苯乙基)苯甲酸
将4-(4-(2-(3-(甲基(2-(4-甲基哌嗪-1-基)乙基)氨甲酰基)苯甲酰胺基)-4,5,6,7-四氢苯并[b]噻吩-3-甲酰胺基)苯乙基)苯甲酸甲酯4e(71mg，0.098mmol)溶解于5mL甲醇中，加入1mL 2M氢氧化钠溶液，升温至50℃，搅拌反应1小时。反应液减压浓缩，滴加3M盐酸至水相pH为2～3，固体析出。过滤，滤饼烘干，用HPLC制备分离法纯化所得残余物，得到标题产物4-(4-(2-(3-(甲基(2-(4-甲基哌嗪-1-基)乙基)氨甲酰基)苯甲酰胺基)-4,5,6,7-四氢苯并[b]噻吩-3-甲酰胺基)苯乙基)苯甲酸4(9mg，淡黄色固体)，产率：12.9％。
MS m/z(ESI):708.2[M+1]
1H NMR(400MHz,CD3OD):δ7.98-8.10(m,2H),7.90-7.97(m,2H),7.64-7.77(m,2H),7.44-7.60(m,2H),7.29(d,2H),7.11-7.24(m,2H),3.78(s,1H),3.48(s,1H),3.21-3.31(m,2H),3.14(s,2H),2.92-3.12(m,8H),2.86(s,6H),2.76(s,2H),2.65(d,2H),1.72-1.98(m,4H),1.27-1.39(m,2H)
实施例5
4-(3-(4-(2-(3-(甲基(2-吗啡啉乙基)氨甲酰基)苯甲酰胺基)-6-((1,1,1-三氟-2-甲基丙基-2-基氧代)羰基)-4,5,6,7-四氢噻吩并[2,3-c]吡啶-3-甲酰胺基)苯基)丙基)苯甲酸
Figure PCTCN2015085385-appb-000032
第一步
4-(3-(4-(2-(3-(甲基(2-吗啡啉乙基)氨甲酰基)苯甲酰胺基)-6-((1,1,1-三氟-2-甲基丙基-2-基氧代)羰基)-4,5,6,7-四氢噻吩并[2,3-c]吡啶-3-甲酰胺基)苯基)丙基)苯甲酸甲酯
将4-(3-(4-(2-(3-(甲基(2-吗啡啉乙基)氨甲酰基)苯甲酰胺基)-4,5,6,7-四氢噻吩并[2,3-c]吡啶-3-甲酰胺基)苯基)丙基)苯甲酸甲酯3e(50mg，0.07mmol)溶解于5mL三氯甲烷中，冷却至0℃，依次加入三乙胺(14mg，0.14mmol)和1mL 3-甲基-1-((1,1,1-三氟-2-甲基丙基-2-基氧代)羰基)-1H-咪唑碘盐5a(25mg，0.07mmol，采用专利申请“WO2011142359”公开的方法制备而得)的三氯甲烷溶液，升至室温，搅拌反应1小时。加入50mL水，用二氯甲烷萃取(50mL×3)，合并有机相，用饱和氯化钠溶液洗涤(30mL×1)，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题产物4-(3-(4-(2-(3-(甲基(2-吗啡啉乙基)氨甲酰基)苯甲酰胺基)-6-((1,1,1-三氟-2-甲基丙基-2-基氧代)羰基)-4,5,6,7-四氢噻吩并[2,3-c]吡啶-3-甲酰胺基)苯基)丙基)苯甲酸甲酯5b(40mg，黄色油状液体)，产率：66.1％。
MS m/z(ESI):878.4[M+1]
第二步
4-(3-(4-(2-(3-(甲基(2-吗啡啉乙基)氨甲酰基)苯甲酰胺基)-6-((1,1,1-三氟-2-甲基丙基-2-基氧代)羰基)-4,5,6,7-四氢噻吩并[2,3-c]吡啶-3-甲酰胺基)苯基)丙基)苯甲酸
将4-(3-(4-(2-(3-(甲基(2-吗啡啉乙基)氨甲酰基)苯甲酰胺基)-6-((1,1,1-三氟-2-甲 基丙基-2-基氧代)羰基)-4,5,6,7-四氢噻吩并[2,3-c]吡啶-3-甲酰胺基)苯基)丙基)苯甲酸甲酯5b(40mg，0.65mmol)溶解于3mL四氢呋喃和甲醇(V:V＝2:1)的混合溶液中，加入1mL 1M氢氧化钠溶液，升温至30℃，搅拌反应4小时。反应液减压浓缩，滴加1M盐酸至反应液pH为6，固体析出。过滤，滤液减压浓缩，用HPLC制备分离法纯化所得残余物，得到标题产物4-(3-(4-(2-(3-(甲基(2-吗啡啉乙基)氨甲酰基)苯甲酰胺基)-6-((1,1,1-三氟-2-甲基丙基-2-基氧代)羰基)-4,5,6,7-四氢噻吩并[2,3-c]吡啶-3-甲酰胺基)苯基)丙基)苯甲酸5(6mg，白色固体)，产率：15.4％。
MS m/z(ESI):864.4[M+1]
1H NMR(400MHz,DMSO-d6):δ11.69(s,1H),9.71(s,1H),8.15-7.95(m,2H),7.87(d,2H),7.73(d,1H),7.67(t,1H),7.61(d,2H),7.33(d,2H),7.19(d,2H),4.58(s,2H),4.01(s,4H),3.83(s,5H),3.62(s,4H),3.18(s,2H),2.94(s,2H),2.89(s,2H),2.67(t,2H),2.59(t,2H),1.95-1.85(m,2H),1.68(s,6H)
实施例6
N1-(3-(4-(4-(1,3-二羟基-2-(羟基甲基)丙基-2-基氨基甲酰基)苯乙基)苯基氨基甲酰基)-4,5,6,7-四氢苯并[b]噻吩-2-基)-N3-甲基-N3-(2-吗啡啉乙基)间苯二甲酰胺
Figure PCTCN2015085385-appb-000033
第一步
4-(4-(2-(3-(甲基(2-吗啡啉乙基)氨基甲酰基)苯甲酰胺基)-4,5,6,7-四氢苯并[b]噻吩-3-甲酰胺基)苯乙基)苯甲酸甲酯
将3-(甲基(2-吗啡啉乙基)氨甲酰基)苯甲酸3c(315mg，1.08mmol)和4-(4-(2-氨基-4,5,6,7-四氢苯并[b]噻吩-3-甲酰胺基)苯乙基)苯甲酸甲酯2c(360mg，0.83mmol)，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(255mg，1.33mmol)和4-二甲氨基吡啶(162mg，1.33mmol)溶解于5mL二甲基甲酰胺中，搅拌反应24小时。加入50mL水，用二氯甲烷萃取(20mL×3)，合并有机相，用饱和氯化钠溶液洗涤(50mL×1)，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题产物4-(4-(2-(3-(甲基(2-吗啡啉乙基)氨基甲酰基)苯甲酰胺基)-4,5,6,7-四氢苯并[b]噻吩-3-甲酰胺基)苯乙基)苯甲酸甲酯6a(400mg，黄色固体)，产率：68.1％。
MS m/z(ESI):709.3[M+1]
第二步
4-(4-(2-(3-(甲基(2-吗啡啉乙基)氨基甲酰基)苯甲酰胺基)-4,5,6,7-四氢苯并[b]噻吩-3-甲酰胺基)苯乙基)苯甲酸
将4-(4-(2-(3-(甲基(2-吗啡啉乙基)氨基甲酰基)苯甲酰胺基)-4,5,6,7-四氢苯并[b]噻吩-3-甲酰胺基)苯乙基)苯甲酸甲酯6a(400mg，0.56mmol)溶解于9mL四氢呋喃和甲醇(V:V＝2:1)的混合溶液中，加入2.3mL 1M氢氧化钠溶液，升温至30℃，搅拌反应12小时。反应液减压浓缩，加入10mL水，滴加1M盐酸至反应液pH为6～7，用二氯甲烷萃取(20mL×3)，合并有机相，用饱和氯化钠溶液洗涤(50mL×1)，无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题产物4-(4-(2-(3-(甲基(2-吗啡啉乙基)氨基甲酰基)苯甲酰胺基)-4,5,6,7-四氢苯并[b]噻吩-3-甲酰胺基)苯乙基)苯甲酸6b(352mg，黄色固体)，产物不经纯化直接进行下一步反应。
MS m/z(ESI):695.3[M+1]
1H NMR(400MHz,DMSO-d6):δ11.59(s,1H),9.67(s,1H),7.95-7.92(m,1H),7.86-7.84(m,3H),7.62-7.59(m,4H),7.36-7.34(d,2H),7.19-7.17(d,2H),3.60-3.50(m,4H),3.35-3.25(m,3H),2.97-2.93(m,4H),2.90-2.88(m,4H),2.73-2.69(m,4H),2.55-2.45(m,1H),2.40-2.35(m,1H),2.15-2.05(m,2H),1.81-1.79(m,2H),1.75-1.73(m,2H)
第三步
N1-(3-(4-(4-(1,3-二羟基-2-(羟基甲基)丙基-2-基氨基甲酰基)苯乙基)苯基氨基甲酰基)-4,5,6,7-四氢苯并[b]噻吩-2-基)-N3-甲基-N3-(2-吗啡啉乙基)间苯二甲酰胺
将粗品4-(4-(2-(3-(甲基(2-吗啡啉乙基)氨基甲酰基)苯甲酰胺基)-4,5,6,7-四氢苯并[b]噻吩-3-甲酰胺基)苯乙基)苯甲酸6b(170mg，0.25mmol)和2-氨基-2-(羟基甲基)丙烷-1,3-二醇(60mg，0.49mmol)溶解于5mL二甲基甲酰胺中，依次加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(94mg，0.49mmol)，1-羟基苯并三唑(67mg， 0.49mmol)和N,N-二异丙基乙胺(64mg，0.49mmol)，搅拌反应12小时。反应液减压浓缩，用HPLC制备分离法纯化所得残余物，得到标题产物N1-(3-(4-(4-(1,3-二羟基-2-(羟基甲基)丙基-2-基氨基甲酰基)苯乙基)苯基氨基甲酰基)-4,5,6,7-四氢苯并[b]噻吩-2-基)-N3-甲基-N3-(2-吗啡啉乙基)间苯二甲酰胺6(110mg，淡黄色固体)，产率：56.4％。
MS m/z(ESI):798.4[M+1]
1H NMR(400MHz,DMSO-d6):δ11.59(s,1H),9.63(s,1H),7.89(d,2H),7.71(d,2H),7.67-7.58(m,4H),7.30(d,2H),7.23(s,1H),7.17(d,2H),4.78(t,3H),3.67(d,6H),3.56-3.23(m,6H),3.04-2.88(m,7H),2.71(d,4H),2.57-2.33(m,4H),2.10(s,2H),1.79-1.75(m,4H)
实施例7
N1-甲基-N1-(2-吗啡啉乙基)-N3-(3-(4-苯乙基苯基氨基甲酰基)-4,5,6,7-四氢苯并[b]噻吩-2-基)间苯二甲酰胺
Figure PCTCN2015085385-appb-000034
第一步
2-氰基-N-(4-苯乙基苯基)乙酰胺
将4-苯乙基苯胺7a(2.15g，10.91mmol，采用公知的方法文献“Journal of Medicinal Chemistry,56(5),2139-2149；2013”制备而得)和2-氰基乙酸(1.39g，16.37mmol)溶解于5mL二甲基甲酰胺中，降温至0℃，加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(3.14g，16.37mmol)，升至室温，搅拌反应2小时。加入10mL水，搅拌30分钟，固体析出，过滤，滤饼烘干，得到粗品标题产物2-氰基-N-(4-苯乙基苯基)乙酰胺7b(2.68g，白色固体)，产物不经纯化直接进行下一步反应。
MS m/z(ESI):263.3[M-1]
第二步
2-氰基-2-亚环己基-N-(4-苯乙基苯基)乙酰胺
将粗品2-氰基-N-(4-苯乙基苯基)乙酰胺7b(2.68g，10.13mmol)和环己酮(2.88g，29.38mmol)溶解于6mL甲苯中，加入吗啡啉(900mg，10.33mmol)，升温至120℃，搅拌反应2小时。反应液减压浓缩，用乙醚和石油醚打浆纯化所得残余物，得到标题产物2-氰基-2-亚环己基-N-(4-苯乙基苯基)乙酰胺7c(2.52g，浅褐色固体)，产率：72.2％。
MS m/z(ESI):345.2[M+1]
第三步
2-氨基-N-(4-苯乙基苯基)-4,5,6,7-四氢苯并[b]噻吩-3-甲酰胺
将2-氰基-2-亚环己基-N-(4-苯乙基苯基)乙酰胺7c(2.52g，7.32mmol)和硫(246mg，7.68mmol)溶解于10mL二甲基甲酰胺中，加入吗啡啉(670mg，7.68mmol)，升温至50℃，搅拌反应2小时。加入50mL饱和氯化钠溶液，用乙酸乙酯萃取(20mL×3)，合并有机相，用饱和氯化钠溶液洗涤(50mL×1)，无水硫酸钠干燥，过滤，滤液减压浓缩，用异丙醇打浆纯化所得残余物，得到标题产物2-氨基-N-(4-苯乙基苯基)-4,5,6,7-四氢苯并[b]噻吩-3-甲酰胺7d(1.69g，黄色固体)，产率：61.2％。
MS m/z(ESI):377.2[M+1]
第四步
N1-甲基-N1-(2-吗啡啉乙基)-N3-(3-(4-苯乙基苯基氨基甲酰基)-4,5,6,7-四氢苯并[b]噻吩-2-基)间苯二甲酰胺
将2-氨基-N-(4-苯乙基苯基)-4,5,6,7-四氢苯并[b]噻吩-3-甲酰胺7d(200mg，0.53mmol)和3-(甲基(2-吗啡啉乙基)氨甲酰基)苯甲酸3c(292mg，1mmol)，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(153mg，0.80mmol)和4-二甲氨基吡啶(97mg，0.80mmol)溶解于5mL二甲基甲酰胺中，升温至30℃，搅拌反应12小时。加入30mL水，用乙酸乙酯萃取(30mL×3)，合并有机相，用饱和氯化钠溶液洗涤(50mL×1)，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题产物N1-甲基-N1-(2-吗啡啉乙基)-N3-(3-(4-苯乙基苯基氨基甲酰基)-4,5,6,7-四氢苯并[b]噻吩-2-基)间苯二甲酰胺7(174mg，黄色固体)，产率：50.3％。MS m/z(ESI):651.5[M+1]
1H NMR(400MHz,CDCl3):δ7.99-8.10(m,2H),7.59-7.77(m,2H),7.50-7.59(m,1H),7.46(d,2H),7.27-7.32(m,1H),7.04-7.23(m,5H),3.91(s,1H),3.76(s,3H),3.58(s,2H),3.39(s,1H),3.04(s,4H),2.88(s,3H),2.74(s,5H),2.50(s,2H),2.24(s,2H),1.90(s,4H)
实施例8
N1-(6,6-二甲基-3-(3-甲基-4-苯乙基苯基氨甲酰基)-4,5,6,7-四氢苯并[b]噻吩-2-基)-N3-甲基-N3-(2-吗啡啉乙基)间苯二甲酰胺
Figure PCTCN2015085385-appb-000035
第一步
3-甲基-4-苯乙基苯胺
将(E)-2-甲基-4-硝基-1-苯乙烯基苯8a(40mg，0.28mmol，采用公知的方法文献“Journal of Physical Chemistry A,113(17),4868-4877；2009”制备而得)溶解于75.4mL甲醇和二氯甲烷(V:V＝2:1)混合溶剂中，加入钯/碳(280mg，20％)，置换氢气三次，搅拌反应3小时。过滤，用二氯甲烷洗涤滤饼，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题产物3-甲基-4-苯乙基苯胺8b(1.20g，淡黄色油状物)，产率：97.6％。
MS m/z(ESI):212.3[M+1]
第二步
2-氰基-N-(3-甲基-4-苯乙基苯基)乙酰胺
将3-甲基-4-苯乙基苯胺8b(1.20g，5.68mmol)和氰基乙酸(722mg，8.50mmol)溶解于10mL二甲基甲酰胺中，降温至0℃，加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(1.62g，8.50mmol)，升至室温，搅拌反应1小时。加入30mL冰水，后加入50mL水，过滤，滤饼烘干，得到粗品标题产物2-氰基-N-(3-甲基-4-苯乙基苯基)乙酰胺8c(1.39g，白色固体)，产率：88.0％。
MS m/z(ESI):279.2[M+1]
第三步
2-氰基-2-(4,4-二甲基亚环己基)-N-(3-甲基-4-苯乙基苯基)乙酰胺
将粗品2-氰基-N-(3-甲基-4-苯乙基苯基)乙酰胺8c(700mg，2.52mmol)，4,4-二甲基环己酮(921mg，7.29mmol)和吗啡啉(224mg，2.57mmol)溶解于12mL甲苯中，升温至120℃，搅拌反应3小时。反应液减压浓缩，用硅胶柱色谱法以洗脱 剂体系A纯化所得残余物，得到标题产物2-氰基-2-(4,4-二甲基亚环己基)-N-(3-甲基-4-苯乙基苯基)乙酰胺8d(852mg，淡黄色油状物)，产率：87.6％。
MS m/z(ESI):385.5[M-1]
第四步
2-氨基-6,6-二甲基-N-(3-甲基-4-苯乙基苯基)-4,5,6,7-四氢苯并[b]噻吩-3-甲酰胺
将2-氰基-2-(4,4-二甲基亚环己基)-N-(3-甲基-4-苯乙基苯基)乙酰胺8d(853mg，2.20mmol)，硫(75mg，2.31mmol)和吗啡啉(202mg，2.31mmol)溶解于8mL二甲基甲酰胺中，升温至50℃，搅拌反应12小时。加入50mL水，用二氯甲烷萃取(50mL×3)，合并有机相，用饱和氯化钠溶液洗涤(50mL×1)，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题产物2-氨基-6,6-二甲基-N-(3-甲基-4-苯乙基苯基)-4,5,6,7-四氢苯并[b]噻吩-3-甲酰胺8e(720mg，粉色固体)，产率：78.2％。
MS m/z(ESI):417.5[M-1]
第五步
N1-(6,6-二甲基-3-(3-甲基-4-苯乙基苯基氨甲酰基)-4,5,6,7-四氢苯并[b]噻吩-2-基)-N3-甲基-N3-(2-吗啡啉乙基)间苯二甲酰胺
将2-氨基-6,6-二甲基-N-(3-甲基-4-苯乙基苯基)-4,5,6,7-四氢苯并[b]噻吩-3-甲酰胺8e(419mg，1mmol)和3-(甲基(2-吗啡啉乙基)氨甲酰基)苯甲酸3c(381mg，1.30mmol)溶解于8mL二甲基甲酰胺中，加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(307mg，1.60mmol)和4-二甲氨基吡啶(196mg，1.60mmol)，搅拌反应12小时。倒入30mL水中，过滤，滤饼烘干，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题产物N1-(6,6-二甲基-3-(3-甲基-4-苯乙基苯基氨甲酰基)-4,5,6,7-四氢苯并[b]噻吩-2-基)-N3-甲基-N3-(2-吗啡啉乙基)间苯二甲酰胺8(520mg，黄色固体)，产率：75.1％。
MS m/z(ESI):693.3[M+1]
1H NMR(400MHz,DMSO-d6):δ11.68(s,1H),9.54(s,1H),7.93(s,1H),7.86(s,1H),7.64-7.60(m,2H),7.48-7.45(m,2H),7.31-7.23(m,4H),7.21-7.17(m,1H),7.12(d,1H),3.59-3.42(m,5H),3.32-3.29(m,2H),2.98-2.90(m,3H),2.81-2.76(m,6H),2.55-2.41(m,5H),2.25(s,3H),2.11(s,2H),1.52(t,2H),1.02(s,6H)
实施例9
N1-(3-(4-(3-(4-(二(2-羟基乙基)氨甲酰基)苯基)丙基)苯基氨甲酰基)-4,5,6,7-四氢苯并[b]噻吩-2-基)-N3-甲基-N3-(2-吗啡啉乙基)间苯二甲酰胺
Figure PCTCN2015085385-appb-000036
将4-(3-(4-(2-(3-(甲基(2-吗啡啉乙基)氨甲酰基)苯甲酰胺基)-4,5,6,7-四氢苯并[b]噻吩-3-甲酰胺基)苯基)丙基)苯甲酸1(250mg，0.35mmol)和2,2’-二乙醇胺(75mg，0.71mmol)，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(136mg，0.71mmol)，1-羟基苯并三唑(96mg，0.71mmol)和N,N-二异丙基乙胺(92mg，0.71mmol)溶解于5mL二甲基甲酰胺中，升温至25℃，搅拌反应12小时。将反应液倒入20mL冰水中，用二氯甲烷萃取(30mL×3)，合并有机相，用饱和氯化钠溶液洗涤(50mL×1)，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题产物N1-(3-(4-(3-(4-(二(2-羟基乙基)氨甲酰基)苯基)丙基)苯基氨甲酰基)-4,5,6,7-四氢苯并[b]噻吩-2-基)-N3-甲基-N3-(2-吗啡啉乙基)间苯二甲酰胺9(120mg，黄色固体)，产率：42.7％。
MS m/z(ESI):796.3[M+1]
1H NMR(400MHz,DMSO-d6):δ11.60(s,1H),9.65(s,1H),7.92(s,1H),7.85(s,1H),7.62(d,4H),7.31(d,2H),7.25(d,2H),7.18(d,2H),4.78(s,2H),3.59-3.27(m,14H),2.92(d,3H),2.72(d,4H),2.65-2.57(m,4H),2.54-2.33(m,4H),2.10(s,2H),1.93-1.85(m,2H),1.81-1.75(m,4H)
实施例10
4-(2-甲基-4-(2-(3-(甲基(2-吗啡啉乙基)氨甲酰基)苯甲酰胺基)-4,5,6,7-四氢苯并[b]噻吩-3-甲酰胺基)苯乙基)苯甲酸
Figure PCTCN2015085385-appb-000037
Figure PCTCN2015085385-appb-000038
第一步
2-甲基-4-硝基苄基膦酸二乙酯
将1-(溴甲基)-2-甲基-4-硝基苯10a(2g，8.69mmol，采用公知的方法文献“Journal of Physical Chemistry,90(1),168-73；1986”制备而得)和亚磷酸三乙酯(2.04g，12.26mmol)加入瓶中，升温至160℃，搅拌反应2小时。反应液减压浓缩，得到粗品标题产物2-甲基-4-硝基苄基膦酸二乙酯10b(2.50g，黑棕色液体)，产物不经纯化直接进行下一步。
第二步
4-(2-甲基-4-硝基苯乙烯基)苯甲酸甲酯
将粗品2-甲基-4-硝基苄基膦酸二乙酯10b(2.50g，8.69mmol)溶解于20mL甲醇中，降温至0℃，滴加50％甲醇钠(939mg，17.38mmol)的甲醇溶液，搅拌反应30分钟，加入10mL 4-甲酰基苯甲酸甲酯(1.44g，8.78mmol)的甲醇溶液，升至室温，搅拌反应12小时。过滤，滤液减压浓缩，得到粗品标题产物4-(2-甲基-4-硝基苯乙烯基)苯甲酸甲酯10c(1.83g，黄色固体)，产物不经纯化直接进行下一步。
第三步
4-(2-甲基-4-氨基苯乙基)苯甲酸甲酯
将粗品4-(2-甲基-4-硝基苯乙烯基)苯甲酸甲酯10c(1.83g，6.16mmol)溶解于100.5mL甲醇和水(V:V＝100:0.5)混合溶剂中，加入钯/碳(366mg，10％)，置换氢气三次，搅拌反应24小时。过滤，滤液减压浓缩，得到粗品标题产物4-(2-甲基-4-氨基苯乙基)苯甲酸甲酯10d(1.41g，黄色固体)，产物不经纯化直接进行下一步。MS m/z(ESI):270.2[M+1]
第四步
4-(4-(2-氰基乙酰胺基)-2-甲基苯乙基)苯甲酸甲酯
将粗品4-(2-甲基-4-氨基苯乙基)苯甲酸甲酯10d(1.41g，5.25mmol)和氰基乙酸(670mg，7.87mmol)溶解于20mL二甲基甲酰胺中，降温至0℃，加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(1.51g，7.87mmol)，升至室温，搅拌反应40分钟。将反应液倒入100mL冰水中，搅拌30分钟，过滤，滤饼烘干，得到粗品标题产物4-(4-(2-氰基乙酰胺基)-2-甲基苯乙基)苯甲酸甲酯10e(1.71g，灰白色固体)，产物不经纯化直接进行下一步。
MS m/z(ESI):335.1[M-1]
第五步
4-(4-(2-氰基-2-亚环己基乙酰胺基)-2-甲基苯乙基)苯甲酸甲酯
将粗品4-(4-(2-氰基乙酰胺基)-2-甲基苯乙基)苯甲酸甲酯10e(1.69g，5.25mmol)和环己酮(1.50g，15.23mmol)溶解于26mL甲苯中，加入吗啡啉(467mg，5.36mmol)，升温至120℃，搅拌反应4小时。反应液减压浓缩，用石油醚和乙酸乙酯打浆纯化所得残余物，得到标题产物4-(4-(2-氰基-2-亚环己基乙酰胺基)-2-甲基苯乙基)苯甲酸甲酯10f(2.01g，浅棕色固体)，产率：91.4％。
MS m/z(ESI):415.2[M-1]
第六步
4-(4-(2-氨基-4,5,6,7-四氢苯并[b]噻吩-3-甲酰胺基)-2-甲基苯乙基)苯甲酸甲酯
将4-(4-(2-氰基-2-亚环己基乙酰胺基)-2-甲基苯乙基)苯甲酸甲酯10f(2g，4.80mmol)和硫(161mg，5.04mmol)溶解于5mL二甲基甲酰胺中，加入吗啡啉(439mg，5.04mmol)，升温至50℃，搅拌反应1小时。加入50mL水，用乙酸乙酯萃取(50mL×3)，合并有机相，用饱和氯化钠溶液洗涤(50mL×1)，无水硫酸钠干燥，过滤，滤液减压浓缩，用异丙醇打浆纯化所得残余物，得到标题产物4-(4-(2-氨基-4,5,6,7-四氢苯并[b]噻吩-3-甲酰胺基)-2-甲基苯乙基)苯甲酸甲酯10g(1.53g，黄色固体)，产率：71.2％。
MS m/z(ESI):449.3[M+1]
第七步
4-(2-甲基-4-(2-(3-(甲基(2-吗啡啉乙基)氨甲酰基)苯甲酰胺基)-4,5,6,7-四氢苯并[b]噻吩-3-甲酰胺基)苯乙基)苯甲酸甲酯
将4-(4-(2-氨基-4,5,6,7-四氢苯并[b]噻吩-3-甲酰胺基)-2-甲基苯乙基)苯甲酸甲酯10g(307mg，0.68mmol)和3-(甲基(2-吗啡啉乙基)氨甲酰基)苯甲酸3c(300mg，1.03mmol)，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(197mg，1.03mmol)和4-二甲氨基吡啶(125mg，1.03mmol)溶解于5mL二甲基甲酰胺中，升温至30℃，搅拌反应12小时。加入30mL水，用乙酸乙酯萃取(30mL×3)，合并有机相，用饱和氯化钠溶液洗涤(50mL×1)，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色 谱法以洗脱剂体系A纯化所得残余物，得到标题产物4-(2-甲基-4-(2-(3-(甲基(2-吗啡啉乙基)氨甲酰基)苯甲酰胺基)-4,5,6,7-四氢苯并[b]噻吩-3-甲酰胺基)苯乙基)苯甲酸甲酯10h(387mg，淡黄色固体)，产率：78.3％。
MS m/z(ESI):723.5[M+1]
1H NMR(400MHz,CDCl3):δ8.04-8.12(m,2H),7.97(d,2H),7.65(s,1H),7.55-7.61(m,1H),7.31-7.38(m,2H),7.25(d,2H),7.11(d,1H),3.92(s,3H),3.86(s,3H),3.61(s,2H),3.30-3.52(s,1H),3.09(m,4H),2.85-2.97(m,7H),2.72-2.83(m,3H),2.48-2.61(s,1H),2.31(s,3H),2.29-2.21(s,1H),1.87-2.00(m,4H),1.74-1.60(s,1H)
第八步
4-(2-甲基-4-(2-(3-(甲基(2-吗啡啉乙基)氨甲酰基)苯甲酰胺基)-4,5,6,7-四氢苯并[b]噻吩-3-甲酰胺基)苯乙基)苯甲酸
将4-(2-甲基-4-(2-(3-(甲基(2-吗啡啉乙基)氨甲酰基)苯甲酰胺基)-4,5,6,7-四氢苯并[b]噻吩-3-甲酰胺基)苯乙基)苯甲酸甲酯10h(250mg，0.35mmol)溶解于10mL甲醇中，加入1mL 2M氢氧化钠溶液，搅拌反应12小时。反应液减压浓缩，滴加1M盐酸至水相pH为4～5，用二氯甲烷萃取(30mL×3)，合并有机相，用饱和氯化钠溶液洗涤(50mL×1)，无水硫酸钠干燥，过滤，滤液减压浓缩，得到标题产物4-(2-甲基-4-(2-(3-(甲基(2-吗啡啉乙基)氨甲酰基)苯甲酰胺基)-4,5,6,7-四氢苯并[b]噻吩-3-甲酰胺基)苯乙基)苯甲酸10(233mg，淡黄色固体)，产率：95.1％。
MS m/z(ESI):709.4[M+1]
1H NMR(400MHz,CDCl3):δ7.93-8.13(m,4H),7.73(d,1H),7.62-7.69(m,1H),7.54-7.61(m,1H),7.36(d,1H),7.14-7.23(m,2H),6.89(d,1H),3.89-4.08(m,4H),3.56-3.78(m,1H),3.11(s,6H),2.84-2.98(m,6H),2.76(s,2H),2.34-2.60(m,1H),2.21-2.33(m,3H),1.92(s,4H),1.22-1.30(m,3H)
实施例11
N1-(3-(4-(4-(二(2-羟基乙基)氨甲酰基)苯基乙基)-3-甲基苯基氨甲酰基)-4,5,6,7-四氢苯并[b]噻吩-2-基)-N3-甲基-N3-(2-吗啡啉乙基)间苯二甲酰胺
Figure PCTCN2015085385-appb-000039
Figure PCTCN2015085385-appb-000040
将4-(2-甲基-4-(2-(3-(甲基(2-吗啡啉乙基)氨甲酰基)苯甲酰胺基)-4,5,6,7-四氢苯并[b]噻吩-3-甲酰胺基)苯乙基)苯甲酸10(120mg，0.17mmol)和2,2’-二乙醇胺(36mg，0.34mmol)，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(65mg，0.34mmol)，1-羟基苯并三唑(46mg，0.34mmol)和N,N-二异丙基乙胺(66mg，0.51mmol)溶解于5mL二甲基甲酰胺中，升温至30℃，搅拌反应12小时。将反应液倒入30mL冰水中，用二氯甲烷萃取(50mL×3)，合并有机相，用饱和氯化钠溶液洗涤(50mL×1)，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题产物N1-(3-(4-(4-(二(2-羟基乙基)氨甲酰基)苯基乙基)-3-甲基苯基氨甲酰基)-4,5,6,7-四氢苯并[b]噻吩-2-基)-N3-甲基-N3-(2-吗啡啉乙基)间苯二甲酰胺11(50mg，淡黄色固体)，产率：37.0％。
MS m/z(ESI):796.3[M+1]
1H NMR(400MHz,CD3OD):δ8.05-8.12(m,2H),7.77(d,1H),7.68(t,1H),7.34-7.42(m,4H),7.24(d,2H),7.06(d,1H),4.07(s,2H),3.95(s,2H),3.83(d,4H),3.65-3.75(m,4H),3.58-3.64(m,2H),3.51(d,4H),3.25(s,1H),3.04-3.17(m,4H),2.92(s,4H),2.87(s,2H),2.75(s,2H),2.27(s,3H),1.89(d,4H)
实施例12
N1-甲基-N1-(2-吗啡啉乙基)-N3-(3-(4-(3-苯丙基)苯基氨甲酰基)-5,7-二氢-4H-噻吩并[2,3-c]吡喃-2-基)间苯二甲酰胺
Figure PCTCN2015085385-appb-000041
Figure PCTCN2015085385-appb-000042
第一步
2-氰基-N-(4-苯丙基苯基)乙酰胺
将4-苯丙基苯胺12a(10.30g，48.74mmol，采用公知的方法文献“Bioorganic&Medicinal Chemistry Letters,19(3),654-657；2009”制备而得)溶解于100mL二甲基甲酰胺中，加入2-氰基乙酸(6.22g，73.12mmol)和1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(14g，73.12mmol)，搅拌反应12小时。倒入300mL冰水中，搅拌30分钟，固体析出，过滤，滤饼烘干，得到粗品标题产物2-氰基-N-(4-苯丙基苯基)乙酰胺12b(12.2g，灰色固体)，产物不经纯化直接进行下一步。
MS m/z(ESI):277.2[M-1]
第二步
2-氨基-N-(4-(3-苯丙基)苯基)-3-氨甲酰基-5,7-二氢-4H-噻吩并[2,3-c]吡喃
将粗品2-氰基-N-(4-苯丙基苯基)乙酰胺12b(279mg，1mmol)，二氢-2H-吡喃-4(3H)-酮(106mg，1.05mmol)，吗啡啉(92mg，1.05mmol)和硫(50mg，1.50mmol)溶解于15mL乙醇中，升温至90℃，搅拌反应12小时。反应液减压浓缩，用乙酸乙酯和石油醚打浆纯化所得残余物，得到标题产物2-氨基-N-(4-(3-苯丙基)苯基)-3-氨甲酰基-5,7-二氢-4H-噻吩并[2,3-c]吡喃12c(1.13g，黄色油状物)，产率：87.9％。MS m/z(ESI):393.2[M+1]
第三步
N1-甲基-N1-(2-吗啡啉乙基)-N3-(3-(4-(3-苯丙基)苯基氨甲酰基)-5,7-二氢-4H-噻吩并[2,3-c]吡喃-2-基)间苯二甲酰胺
将2-氨基-N-(4-(3-苯丙基)苯基)-3-氨甲酰基-5,7-二氢-4H-噻吩并[2,3-c]吡喃12c(255mg，0.65mmol)和3-(甲基(2-吗啡啉乙基)氨甲酰基)苯甲酸3c(246mg，0.84mmol)，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(200mg，1.04mmol)和4-二甲氨基吡啶(128mg，1.04mmol)溶解于10mL二甲基甲酰胺中，搅拌反应12小时。倒入30mL冰水中，用乙酸乙酯萃取(30mL×3)，合并有机相，用饱和氯化钠溶液 洗涤(50mL×1)，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题产物N1-甲基-N1-(2-吗啡啉乙基)-N3-(3-(4-(3-苯丙基)苯基氨甲酰基)-5,7-二氢-4H-噻吩并[2,3-c]吡喃-2-基)间苯二甲酰胺12(235mg，黄色固体)，产率：54.2％。
MS m/z(ESI):667.2[M+1]
1H NMR(400MHz,DMSO-d6):δ11.73(s,1H),9.67(s,1H),7.94(s,1H),7.87(s,1H),7.62(d,4H),7.29(t,2H),7.21-7.16(m,5H),4.72(s,2H),3.88(t,2H),3.56-3.27(m,6H),2.97-2.88(m,5H),2.67-2.33(m,8H),2.10(s,2H),1.91-1.84(m,2H)
实施例13
N1-甲基-N1-(2-吗啡啉乙基)-N3-(3-(4-苯丙基苯基氨基甲酰基)-4,5,6,7-四氢苯并[b]噻吩-2-基)间苯二甲酰胺
Figure PCTCN2015085385-appb-000043
第一步
2-氰基-2-亚环己基-N-(4-苯丙基苯基)乙酰胺
将粗品2-氰基-N-(4-苯丙基苯基)乙酰胺12b(1g，3.59mmol)和环己酮(1.02g，10.41mmol)溶解于20mL甲苯中，加入吗啡啉(319mg，3.66mmol)，升温至130℃，搅拌反应2小时。反应液减压浓缩，用乙酸乙酯和石油醚打浆纯化所得残余物，得到标题产物2-氰基-2-亚环己基-N-(4-苯丙基苯基)乙酰胺13a(1.13g，黄色油状物)，产率：87.9％。
MS m/z(ESI):357.2[M+1]
第二步
2-氨基-N-(4-苯丙基苯基)-4,5,6,7-四氢苯并[b]噻吩-3-甲酰胺
将2-氰基-2-亚环己基-N-(4-苯丙基苯基)乙酰胺13a(1.13g，3.16mmol)和硫(106mg，3.32mmol)溶解于5mL二甲基甲酰胺中，加入吗啡啉(289mg，3.32mmol)，升温至50℃，搅拌反应1小时。加入50mL水，用乙酸乙酯萃取(20mL×3)，合并有机相，用饱和氯化钠溶液洗涤(50mL×1)，无水硫酸钠干燥，过滤，滤液减压浓缩，用异丙醇打浆纯化所得残余物，得到标题产物2-氨基-N-(4-苯丙基苯基)-4,5,6,7-四氢苯并[b]噻吩-3-甲酰胺13b(1.12g，黄色固体)，产率：90.3％。
MS m/z(ESI):391.2[M+1]
第三步
N1-甲基-N1-(2-吗啡啉乙基)-N3-(3-(4-苯丙基)苯基氨甲酰基)-4,5,6,7-四氢苯并[b]噻吩-2-基)间苯二甲酰胺
将2-氨基-N-(4-苯丙基苯基)-4,5,6,7-四氢苯并[b]噻吩-3-甲酰胺13b(1.12g，2.87mmol)和3-(甲基(2-吗啡啉乙基)氨甲酰基)苯甲酸3c(1.25g，4.28mmol)，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(821mg，4.28mmol)和4-二甲氨基吡啶(523mg，4.28mmol)溶解于5mL二甲基甲酰胺中，升温至30℃，搅拌反应12小时。加入30mL水，用乙酸乙酯萃取(30mL×3)，合并有机相，用饱和氯化钠溶液洗涤(50mL×1)，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题产物N1-甲基-N1-(2-吗啡啉乙基)-N3-(3-(4-苯丙基)苯基氨甲酰基)-4,5,6,7-四氢苯并[b]噻吩-2-基)间苯二甲酰胺13(1.05g，淡黄色固体)，产率：40.2％。
MS m/z(ESI):665.3[M+1]
1H NMR(400MHz,CDCl3):δ8.03-8.12(m,2H),7.63-7.72(m,2H),7.53-7.60(m,1H),7.49(d,2H),7.28-7.34(m,2H),7.15-7.23(m,3H),3.75(s,3H),3.60(s,2H),3.29-3.48(m,1H),3.02-3.16(m,3H),2.87-2.94(m,2H),2.77(t,2H),2.62-2.71(m,5H),2.38-2.62(m,3H),2.26(s,2H),1.86-2.02(m,6H)
实施例14
2-(3-(甲基(2-吗啡啉乙基)氨甲酰基)苯甲酰胺基)-3-(4-(3-苯丙基)苯基氨甲酰基)-4,5-二氢噻吩并[2,3-c]吡啶-6(7H)-甲酸叔丁酯
Figure PCTCN2015085385-appb-000044
Figure PCTCN2015085385-appb-000045
第一步
2-氨基-3-(4-(3-苯丙基)苯基氨甲酰基)-4,5-二氢噻吩并[2,3-c]吡啶-6(7H)-甲酸叔丁酯
将粗品2-氰基-N-(4-苯丙基苯基)乙酰胺12b(900mg，3.23mmol)，4-羰基哌啶-1-甲酸叔丁酯(677mg，3.40mmol)，吗啡啉(297mg，3.40mmol)和硫(155mg，4.85mmol)溶解于20mL乙醇中，升温至90℃，搅拌反应12小时。反应液减压浓缩，用乙酸乙酯和石油醚打浆纯化所得残余物，得到标题产物2-氨基-3-(4-(3-苯丙基)苯基氨甲酰基)-4,5-二氢噻吩并[2,3-c]吡啶-6(7H)-甲酸叔丁酯14a(1.05g，黄色固体)，产率：66.2％。
MS m/z(ESI):492.3[M+1]
第二步
2-(3-(甲基(2-吗啡啉乙基)氨甲酰基)苯甲酰胺基)-3-(4-(3-苯丙基)苯基氨甲酰基)-4,5-二氢噻吩并[2,3-c]吡啶-6(7H)-甲酸叔丁酯
将2-氨基-3-(4-(3-苯丙基)苯基氨甲酰基)-4,5-二氢噻吩并[2,3-c]吡啶-6(7H)-甲酸叔丁酯14a(1.02g，2.07mmol)和3-(甲基(2-吗啡啉乙基)氨甲酰基)苯甲酸3c(789mg，2.70mmol)，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(635mg，3.31mmol)和4-二甲氨基吡啶(405mg，3.31mmol)溶解于15mL二甲基甲酰胺中，搅拌反应12小时。倒入30mL冰水中，用乙酸乙酯萃取(30mL×3)，合并有机相，用饱和氯化钠溶液洗涤(50mL×1)，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题产物2-(3-(甲基(2-吗啡啉乙基)氨甲酰基)苯甲酰胺基)-3-(4-(3-苯丙基)苯基氨甲酰基)-4,5-二氢噻吩并[2,3-c]吡啶-6(7H)-甲酸叔丁酯14(1.10g，黄色固体)，产率：69.6％。
MS m/z(ESI):766.4[M+1]
1H NMR(400MHz,CD3OD):δ11.67(s,1H),9.70(s,1H),7.94(s,1H),7.86(s,1H),7.63-7.61(m,4H),7.30-7.27(m,2H),7.21-7.16(m,5H),4.55(s,2H),3.59-3.26(m,8H),2.97-2.84(m,5H),2.62-2.38(m,8H),2.10(s,2H),1.89-1.85(m,2H),1.44(s,9H)
实施例15
4-(3-(4-(2-(6-(甲基(2-吗啡啉乙基)氨甲酰基)吡啶-2-甲酰氨基)-4,5,6,7-四氢苯并[b]噻吩-3-甲酰胺基)苯基)丙基)苯甲酸甲酯
Figure PCTCN2015085385-appb-000046
第一步
6-(甲基(2-吗啡啉乙基)氨甲酰基)-2-吡啶甲酸
将吡啶-2,6-二甲酸(500mg，3mmol)溶解于20mL二氯甲烷中，加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(1.30g，3.60mmol)和N,N-二异丙基乙胺(580mg，4.50mmol)，搅拌10分钟，加入N-甲基-2-吗啡啉乙胺15a(432mg，3mmol，采用公知的方法文献“Journal of Combinatorial Chemistry,8(6),834-840；2006”制备而得)，搅拌反应4小时。反应液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题产物6-(甲基(2-吗啡啉乙基)氨甲酰基)-2-吡啶甲酸15b(375mg，白色固体)，产率：41.7％。
MS m/z(ESI):294.2[M+1]
第二步
4-(3-(4-(2-(6-(甲基(2-吗啡啉乙基)氨甲酰基)吡啶酰氨基)-4,5,6,7-四氢苯并[b]噻吩-3-甲酰胺基)苯基)丙基)苯甲酸甲酯
将4-(3-(4-(2-氨基-4,5,6,7-四氢苯并[b]噻吩-3-甲酰胺基)苯基)丙基)苯甲酸甲酯1a(450mg，1.06mmol)和6-(甲基(2-吗啡啉乙基)氨甲酰基)-2-吡啶甲酸15b(375mg，1.27mmol)溶解于10mL二甲基甲酰胺中，加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(305mg，1.60mmol)和4-二甲氨基吡啶(195mg，1.60mmol)，升温至25℃，搅拌反应12小时。加入50mL水，用二氯甲烷萃取(50mL×3)，合并有机相，用饱和氯化钠溶液洗涤(50mL×1)，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题产物4-(3-(4-(2-(6-(甲基(2-吗啡啉乙基)氨甲酰基)吡啶-2-甲酰氨基)-4,5,6,7-四氢苯并[b]噻吩-3-甲酰胺基)苯基)丙基)苯甲酸甲酯15(250mg，淡黄色固体)，产率：32.6％。
MS m/z(ESI):724.4[M+1]
1H NMR(400MHz,DMSO-d6):δ12.29(d,1H),9.62(d,1H),8.30-8.08(m,2H),7.98-7.75(m,3H),7.65(d,2H),7.36(d,2H),7.20(d,2H),3.83(s,3H),3.56-3.52(m,1H),3.51-3.41(m,2H),3.40(t,1H),3.30-3.20(m,2H),3.09-2.98(m,3H),2.85-2.80(m,2H),2.76-2.63(m,4H),2.59(t,2H),2.54-2.48(m,2H),2.44-2.33(m,2H),2.00-1.96(m,2H),1.94-1.86(m,2H),1.82(d,2H),1.79-1.68(m,2H)
实施例16
N1-甲基-N1-(2-吗啡啉乙基)-N3-(3-(4-(2-吗啡啉乙基)苯基氨甲酰基)-4,5,6,7-四氢苯并[b]噻吩-2-基)间苯二甲酰胺
Figure PCTCN2015085385-appb-000047
第一步
2-氰基-N-(4-(2-吗啡啉乙基)苯基)乙酰胺
将4-(2-吗啡啉乙基)苯胺16a(450mg，2.18mmol，采用公知的方法文献“Bioorganic&Medicinal Chemistry Letters,23(23),6363-6369；2013”制备而得)和氰基乙酸(277mg，3.27mmol)溶解于5mL二甲基甲酰胺中，降温至0℃，加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(625mg，3.27mmol)，升至室温，搅拌反应2小时。加入30mL水和5mL饱和碳酸氢钠溶液，用二氯甲烷萃取(50mL×3)，合并有机相，用饱和氯化钠溶液洗涤(50mL×1)，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题产物2-氰基 -N-(4-(2-吗啡啉乙基)苯基)乙酰胺16b(530mg，白色固体)，产率：88.9％。
MS m/z(ESI):449.3[M+1]
第二步
2-氰基-2-亚环己基-N-(4-(2-吗啡啉乙基)苯基)乙酰胺
将2-氰基-N-(4-(2-吗啡啉乙基)苯基)乙酰胺16b(530mg，1.94mmol)溶解于15mL甲苯中，加入环己酮(190mg，1.94mmol)和吗啡啉(168mg，1.94mmol)，升温至130℃，搅拌反应2小时。反应液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题产物2-氰基-2-亚环己基-N-(4-(2-吗啡啉乙基)苯基)乙酰胺16c(462mg，无色油状物)，产率：67.5％。
MS m/z(ESI):354.3[M+1]
第三步
2-氨基-N-(4-(2-吗啡啉乙基)苯基)-4,5,6,7-四氢苯并[b]噻吩-3-甲酰胺
将2-氰基-2-亚环己基-N-(4-(2-吗啡啉乙基)苯基)乙酰胺16c(462mg，1.36mmol)和硫(44mg，1.37mmol)溶解于6mL二甲基甲酰胺中，加入吗啡啉(119mg，1.37mmol)，升温至50℃，搅拌反应45分钟。加入50mL水，用二氯甲烷萃取(50mL×3)，合并有机相，用饱和氯化钠溶液洗涤(50mL×1)，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题产物2-氨基-N-(4-(2-吗啡啉乙基)苯基)-4,5,6,7-四氢苯并[b]噻吩-3-甲酰胺16d(300mg，黄色油状物)，产率：60％。
MS m/z(ESI):386.3[M+1]
第四步
N1-甲基-N1-(2-吗啡啉乙基)-N3-(3-(4-(2-吗啡啉乙基)苯基氨甲酰基)-4,5,6,7-四氢苯并[b]噻吩-2-基)间苯二甲酰胺
将2-氨基-N-(4-(2-吗啡啉乙基)苯基)-4,5,6,7-四氢苯并[b]噻吩-3-甲酰胺16d(160mg，0.38mmol)溶解于6mL二甲基甲酰胺中，加入3-(甲基(2-吗啡啉乙基)氨甲酰基)苯甲酸3c(219mg，0.75mmol)，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(146mg，0.76mmol)和4-二甲氨基吡啶(72mg，0.57mmol)，升温至25℃，搅拌反应12小时。加入30mL水，用二氯甲烷萃取(30mL×3)，合并有机相，用饱和氯化钠溶液洗涤(50mL×1)，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题产物N1-甲基-N1-(2-吗啡啉乙基)-N3-(3-(4-(2-吗啡啉乙基)苯基氨甲酰基)-4,5,6,7-四氢苯并[b]噻吩-2-基)间苯二甲酰胺16(82mg，淡黄色固体)，产率：33.6％。
MS m/z(ESI):674.2[M-1]
1H NMR(400MHz,CDCl3):δ8.07(s,2H),7.73(s,2H),7.53(d,2H),7.30(s.,2H),4.10-4.02(m,4H),3.85-3.80(m,4H),3.65-3.50(m,2H),3.40-3.35(m,1H),3.20-3.10(m,6H),3.04-2.95(m,8H),2.78-2.70(m,3H),2.55-2.45(m,1H),2.35-2.25(m,2H),2.00-1.93(m,4H)
实施例17
N1-(3-(4-(4-(1,3-二羟基-2-(羟甲基)丙烷-2-基氨甲酰基)苯乙基)-3-甲基苯基氨甲酰基)-6,6-二甲基-4,5,6,7-四氢苯并[b]噻吩-2-基)-N3-甲基-N3-(2-吗啡啉乙基)间苯二甲酰胺
Figure PCTCN2015085385-appb-000048
第一步
4-(4-(2-氰基-2-(4,4-二甲基亚环己基)乙酰胺基)-2-甲基苯乙基)苯甲酸甲酯
将粗品4-(4-(2-氰基乙酰胺基)-2-甲基苯乙基)苯甲酸甲酯10e(2g，6mmol)溶解 于30mL甲苯中，加入4,4-二甲基环己酮(2.16g，17.20mmol)和吗啡啉(522mg，6mmol)，升温至140℃，搅拌反应3小时。反应液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物4-(4-(2-氰基-2-(4,4-二甲基亚环己基)乙酰胺基)-2-甲基苯乙基)苯甲酸甲酯17a(2.56g，浅黄色油状物)，产率：95.9％。
MS m/z(ESI):443.3[M-1]
第二步
4-(4-(2-氨基-6,6-二甲基-4,5,6,7-四氢苯并[b]噻吩-3-甲酰胺基)-2-甲基苯乙基)苯甲酸甲酯
将4-(4-(2-氰基-2-(4,4-二甲基亚环己基)乙酰胺基)-2-甲基苯乙基)苯甲酸甲酯17a(2.56g，5.76mmol)溶解于10mL二甲基甲酰胺中，加入硫(184mg，5.79mmol)和吗啡啉(501mg，5.76mmol)，升温至50℃，搅拌反应2小时。加入50mL水，用乙酸乙酯萃取(50mL×3)，合并有机相，用饱和氯化钠溶液洗涤(50mL×1)，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物4-(4-(2-氨基-6,6-二甲基-4,5,6,7-四氢苯并[b]噻吩-3-甲酰胺基)-2-甲基苯乙基)苯甲酸甲酯17b(2.30g，黄色固体)，产率：83.9％。
MS m/z(ESI):475.2[M-1]
第三步
4-(4-(6,6-二甲基-2-(3-(甲基(2-吗啡啉乙基)氨甲酰基)苯甲酰胺基)-4,5,6,7-四氢苯并[b]噻吩-3-甲酰胺基)-2-甲基苯乙基)苯甲酸甲酯
将4-(4-(2-氨基-6,6-二甲基-4,5,6,7-四氢苯并[b]噻吩-3-甲酰胺基)-2-甲基苯乙基)苯甲酸甲酯17b(2.36g，4.83mmol)溶解于5mL二甲基甲酰胺中，加入3-(甲基(2-吗啡啉乙基)氨甲酰基)苯甲酸3c(1.80g，6.25mmol)，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(1.38g，7.24mmol)和4-二甲氨基吡啶(883mg，7.24mmol)，搅拌反应12小时。加入30mL水，用乙酸乙酯萃取(30mL×3)，合并有机相，用饱和氯化钠溶液洗涤(50mL×1)，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题产物4-(4-(6,6-二甲基-2-(3-(甲基(2-吗啡啉乙基)氨甲酰基)苯甲酰胺基)-4,5,6,7-四氢苯并[b]噻吩-3-甲酰胺基)-2-甲基苯乙基)苯甲酸甲酯17c(2.60g，黄色固体)，产率：72.2％。
MS m/z(ESI):751.5[M+1]
第四步
4-(4-(6,6-二甲基-2-(3-(甲基(2-吗啡啉乙基)氨甲酰基)苯甲酰胺基)-4,5,6,7-四氢苯并[b]噻吩-3-甲酰胺基)-2-甲基苯乙基)苯甲酸
将4-(4-(6,6-二甲基-2-(3-(甲基(2-吗啡啉乙基)氨甲酰基)苯甲酰胺基)-4,5,6,7-四氢苯并[b]噻吩-3-甲酰胺基)-2-甲基苯乙基)苯甲酸甲酯17c(2.65g，3.46mmol)溶解于44mL四氢呋喃和甲醇(V:V＝3:1)混合溶剂中，加入10mL 2M氢氧化钠溶液，搅拌反应12小时。加入30mL水，反应液减压浓缩，滴加1M盐酸至水相pH为 6，用二氯甲烷萃取(30mL×3)，合并有机相，用饱和氯化钠溶液洗涤(50mL×1)，无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题产物4-(4-(6,6-二甲基-2-(3-(甲基(2-吗啡啉乙基)氨甲酰基)苯甲酰胺基)-4,5,6,7-四氢苯并[b]噻吩-3-甲酰胺基)-2-甲基苯乙基)苯甲酸17d(1.69g，黄色固体)，产率：66.5％。
MS m/z(ESI):737.5[M+1]
1H NMR(400MHz,DMSO-d6):δ11.66(s,1H),9.55(s,1H),7.95-7.92(m,1H),7.87-7.85(m,3H),7.63-7.62(m,2H),7.48-7.45(m,2H),7.37-7.35(d,2H),7.12-7.10(d,1H),3.60-3.57(m,3H),3.42-3.30(m,5H),2.99-2.97(m,2H),2.91-2.87(m,5H),2.76-2.73(m,2H),2.54-2.41(m,4H),2.25(s,3H),2.11(m,2H),1.53-1.50(t,2H),1.02(s,6H)
第五步
N1-(3-(4-(4-(1,3-二羟基-2-(羟甲基)丙烷-2-基氨甲酰基)苯乙基)-3-甲基苯基氨甲酰基)-6,6-二甲基-4,5,6,7-四氢苯并[b]噻吩-2-基)-N3-甲基-N3-(2-吗啡啉乙基)间苯二甲酰胺
将粗品4-(4-(6,6-二甲基-2-(3-(甲基(2-吗啡啉乙基)氨甲酰基)苯甲酰胺基)-4,5,6,7-四氢苯并[b]噻吩-3-甲酰胺基)-2-甲基苯乙基)苯甲酸17d(850mg，1.15mmol)溶解于5mL二甲基甲酰胺中，加入2-氨基-2-(羟甲基)丙烷-1,3-二醇(278mg，2.30mmol)，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(439mg，2.30mmol)，1-羟基苯并三唑(310mg，2.30mmol)和N,N-二异丙基乙胺(445mg，3.50mmol)，搅拌反应12小时。加入50mL水和20mL饱和碳酸氢钠溶液，用二氯甲烷萃取(50mL×3)，合并有机相，用饱和氯化钠溶液洗涤(50mL×1)，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题产物N1-(3-(4-(4-(1,3-二羟基-2-(羟甲基)丙烷-2-基氨甲酰基)苯乙基)-3-甲基苯基氨甲酰基)-6,6-二甲基-4,5,6,7-四氢苯并[b]噻吩-2-基)-N3-甲基-N3-(2-吗啡啉乙基)间苯二甲酰胺17(600mg，黄色固体)，产率：62.1％。
MS m/z(ESI):841.8[M+1]
1H NMR(400MHz,DMSO-d6):δ11.65(s,1H),9.53(s,1H),7.91-7.90(d,1H),7.84(s,1H),7.73-7.71(d,2H),7.65-7.70(m,2H),7.47-7.43(m,2H),7.32-7.30(d,2H),7.23(s,1H),7.11-7.08(d,1H),4.79-4.76(t,3H),3.68-3.66(d,6H),3.58-3.52(m,3H),3.45-3.35(m,2H),3.30-3.25(m,4H),2.96-2.80(m,6H),2.75-2.65(m,2H),2.50-2.30(m,4H),2.25(s,3H),2.20-2.00(m,2H),1.53-1.50(t,2H),1.01(s,6H).
测试例：
生物学评价
测试例1、本发明化合物对人源Npt2b/HEK293细胞转运无机磷的抑制作用。
以下方法用来测定本发明中化合物对人源Npt2b/HEK293细胞转运无机磷的抑制作用。
一、实验材料及仪器
1、闪烁发光计数仪(PerkinElmer#1450)
2、BD BioCoatTM Poly-D-Lysine 48-孔板(BD，#356509)
3、Npt2b质粒(广州复能#NM_006424)
4、磷-32放射性核素(Phosphorus-32Radionuclide),1mCi(37MBq)(H3 32PO4)(PerkinElmer,#NEX053001MC)
5、Optiphase Supermix(PerkinElmer#1200-439for 5L)
二、实验步骤
1、获取人源Npt2b/HEK293细胞
将Npt2b质粒按一定比例与LipofectamineTM LTX(Invitrogen#15338-100)混合，放置30分钟后，将上述混合物滴加到对数期生长的HEK293细胞(中科院细胞库#GNHu43)中，边加边混；24小时后，换成含G418的培养基(Enzo#ALX-380-013-G005)培养至细胞将近长满，铺板挑选单克隆细胞，验证其功能，获得单克隆稳定细胞株。
2、化合物对人源Npt2b/HEK293细胞转运无机磷的抑制作用实验
提前一天将稳定细胞株人源Npt2b/HEK293细胞种于48孔板中，37℃二氧化碳培养箱中培养。弃去培养基，用胆碱摄取缓冲液(Choline uptake buffer)洗涤细胞一次(250μL/孔)。取10μL H3 32PO4稀释在1000ml钠摄取缓冲液(Sodium uptake buffer)中。每孔加入80μL测试化合物和20μL稀释后的H3 32PO4，于室温下孵育约20分钟。最终的化合物浓度为：100μM,10μM,1μM,0.1μM,0.01μM,0.001μM，最终的DMSO浓度为：0.5％，最终的H3 32PO4浓度为：0.2uCi/孔；弃去上述化合物和H3 32PO4，然后用冰冷的终止液(Ice cold stop solution)洗涤细胞两次(350μL/孔)。然后每孔加入150μL 200mM NaOH，室温下上振板器震荡裂解约5分钟。每孔转移120μL细胞裂解物于96-孔样品板。96-孔样品板每孔加入100μL Optiphase Supermix，然后用RE-SEALABLE TAPE封好96-孔样品板，室温下振板器上震荡约5分钟。闪烁发光计数仪读值。
本发明化合物对人源Npt2b/HEK293细胞转运无机磷的抑制作用进行测定，测得的IC50值见表1。
表1本发明化合物对人源Npt2b/HEK293细胞转运无机磷抑制的IC50
实施例编号 IC50(nM)
1 22
5 100
6 15
7 44
8 9
9 114
10 28
11 22
12 114
13 40
14 57
15 28
16 67
17 30
结论：本发明中的化合物对人源Npt2b/HEK293细胞转运无机磷具有明显的抑制效果。
测试例2、本发明化合物对鼠源Npt2b/HEK293细胞转运无机磷的抑制作用。
以下方法用来测定本发明中化合物对鼠源Npt2b/HEK293细胞转运无机磷的抑制作用。
一、实验材料及仪器
1、闪烁发光计数仪(PerkinElmer#1450)
2、BD BioCoatTM Poly-D-Lysine 48-孔板(BD，#356509)
3、磷-32放射性核素(Phosphorus-32Radionuclide),1mCi(37MBq)(H332PO4)(PerkinElmer,#NEX053001MC)
4、Optiphase Supermix(PerkinElmer#1200-439for 5L)
二、实验步骤
1、获取鼠源Npt2b/HEK293细胞
将Npt2b质粒按一定比列与LipofectamineTM LTX混合，放置30分钟后，将上述混合物滴加到对数期生长的HEK293细胞中，边加边混；24小时后，换成含G418的培养基培养至细胞将近长满，铺板挑选单克隆细胞，验证其功能，获得单克隆稳定细胞株。
2、化合物对鼠源Npt2b/HEK293细胞转运无机磷的抑制作用实验
提前一天将稳定细胞株鼠源Npt2b/HEK293细胞种于48孔板中，37℃二氧化碳培养箱中培养。弃去培养基，用胆碱摄取缓冲液(Choline uptake buffer)洗涤细胞一次(250μL/孔)。取10μL H3 32PO4稀释在1000ml钠摄取缓冲液(Sodium uptake buffer)中。每孔加入80μL测试化合物和20μL稀释后的H3 32PO4，于室温下孵育约20分钟。最终的化合物浓度为：100μM,10μM,1μM,0.1μM,0.01μM,0.001μM，最终的DMSO浓度为：0.5％，最终的H3 32PO4浓度为：0.2uCi/孔；弃去上述化合物和H3 32PO4，然后用冰冷的终止液(Ice cold stop solution)洗细胞两次(350μL/孔)。每孔加入150μL 200mM NaOH，室温下振板器上震荡裂解约5分钟。每孔转移120μL细胞裂解物于96-孔样品板。96-孔样品板每孔加入100μL Optiphase Supermix，然后用RE-SEALABLE TAPE封好96-孔样品板，室温下振板 器上震荡约5分钟。闪烁发光计数仪读值。
本发明化合物对鼠源Npt2b/HEK293细胞转运无机磷的抑制作用进行测定，测得的IC50值见表2。
表2本发明化合物对鼠源Npt2b/HEK293细胞转运无机磷抑制的IC50
实施例编号 IC50(nM)
1 82
6 109
7 210
8 33
9 474
10 53
11 309
13 169
14 257
结论：本发明中的化合物对鼠源Npt2b/HEK293细胞转运无机磷具有明显的抑制效果。
测试例3、本发明化合物的药代动力学测试
1、摘要
以大鼠为受试动物，应用LC/MS/MS法测定了大鼠灌胃给予实施例化合物后不同时刻血浆中的药物浓度。研究本发明的化合物在大鼠体内的药代动力学行为，评价其药动学特征。
2、试验方案
2.1试验药品
实施例6～9化合物、实施例11、实施例13、实施例14和实施例17。
2.2试验动物
健康成年SD大鼠32只，雌雄各半，平均分成8组，每组4只，购自上海西普尔-必凯实验动物有限公司，动物生产许可证号：SCXK(沪)2008-0016。
2.3药物配制
称取适量样品，加入0.5％CMC-Na至终体积，超声制成0.5mg/ml混悬液。
2.4给药
SD大鼠32只，雌雄各半，平均分成8组，禁食一夜后分别灌胃给药，剂量为5.0mg/kg，给药体积10mL/kg。
3、操作
于给药前及给药后0.5、1、2、4、6、8、11、24小时采血0.1mL，置于EDTA抗凝试管中，3500rpm离心5分钟，分离血浆，于-20℃保存。给药后2小时进食。
用LC/MS/MS法测定不同化合物灌胃给药后大鼠血浆中的待测化合物含量。分析方法的线性范围分别为5.00-2000ng/mL和1.00-500ng/mL，定量下限分别为5.00ng/mL和1.00ng/mL；血浆样品经沉淀蛋白预处理后进行分析。
4、药代动力学参数结果
本发明化合物的药代动力学参数见表3：
Figure PCTCN2015085385-appb-000049
结论：本发明化合物的药代动力学特征是其在血浆中的浓度较低，在血药中的吸收少。
测试例4、本发明化合物大鼠粪回收率测试
1、摘要
以大鼠为受试动物，应用LC/MS/MS法测定了大鼠灌胃给予本发明优选实施例化合物后不同时刻血浆中的药物浓度。研究本发明的化合物在大鼠体内的药代动力学行为，评价其粪回收率。
2、试验方案
2.1试验药品
实施例6、7和17化合物。
2.2试验动物
健康成年SD大鼠12只，雌雄各半，平均分成3组，每组4只，购自上海西普尔-必凯实验动物有限公司，动物生产许可证号：SCXK(沪)2008-0016。
2.3药物配制
称取适量样品，加入0.5％CMC-Na至终体积，超声制成2.0mg/ml混悬液。
2.4给药
SD大鼠12只，雌雄各半，平均分成3组，放入代谢笼中，自由摄食和饮水，同时收集空白粪样，给药前禁食一夜。动物分别灌胃给药，禁食一夜后分别灌胃给药，剂量为20.0mg/kg，给药体积10mL/kg。
3、操作
于给药后0～8小时,8～24小时,24～48小时,48～72小时分段收集粪样，并分别称重。记录后，贴好标签，20℃冷冻保存。血浆样品分别于给药前及给药后1、2、4和8小时由眼眶采血0.2mL，置于肝素化试管中，3500rpm离心10分钟后分离血浆，于-20℃保存；给药后3小时进食。
4、累积粪便排泄率结果
本发明化合物的累积粪便排泄率见表4：
Figure PCTCN2015085385-appb-000050
结论：灌胃给予20mg/kg的本发明化合物后，尿液和血液中的暴露程度较低，药物原型和代谢物的粪便回收率高，发现在消化系统的胃、结肠、空肠、十二指肠等组织相对含量较高，其中结肠和空肠是药物的主要作用部位。
测试例5、本发明化合物治疗大鼠高磷血症测试
1、摘要
以大鼠为受试动物，评价本发明的化合物的降血磷药效
2、试验方案
2.1试验药品
实施例5，6，7化合物和实施例11化合物。
低磷饲料(含0.1％磷和0.6％钙)：由上海斯莱克实验动物有限公司提供。
磷酸二氢钠(NaH2PO4·H2O)：批号为201209I06，购自湖南九典制药有限公司。临用前配制成1mmol/ml(138mg/ml，5ml/kg)。
羧甲基纤维素钠(CMC-Na)：批号为F20090508，国药集团化学试剂有限公司。
血磷检测试剂盒：批号20130905，由南京建成生物公司提供。
2.2试验动物
健康成年SD大鼠60只，雌雄各半，平均分成6组，每组10只，购自上海西普尔-必凯实验动物有限公司，动物生产许可证号：SCXK(沪)2013-0016。
3、操作
实验方法按照专利申请(WO2012006473)中方法进行。动物购进后用普通饲料适应性喂养(至少3天)，再转为低磷饲料喂养，对大鼠进行血清血磷筛选，
将血磷低于2.3mmol/L的大鼠按照血磷高低随机分组，于实验第2天灌胃磷酸二氢钠(1mmol/1mL)建立大鼠高磷血症模型。按照入组的大鼠血磷值随机分为6组，空白对照组给予相同容积的蒸馏水。各治疗组大鼠分别于造模前15分钟给予单次灌胃给药(5mL/kg，30mg/kg)，模型组给予相应的0.5％CMC。造模后分别于0小时(空白血清)、0.5小时和2小时后对大鼠进行眼眶采血检测血清血磷值。
4、降血磷值结果
本发明化合物的降血磷的效果见表5：
实施例编号 0.5小时后降血磷比率(30mg/kg)
5 27.4％
6 31.4％
7 26.2％
11 29.4％
结论：大鼠在口服灌胃30mg/kg剂量的本发明的优选化合物后，在给予磷盐0.5小时后有明显的降血磷作用。
测试例6、Npt2b抑制剂化合物7和碳酸司维拉姆饲料喂养大鼠其磷代谢实验报告
1.实验目的
本实验通过在饲料中掺入司维拉姆(即碳酸司维拉姆，上海瀚鸿化工科技有限公司，Cat#：B12264)或Npt2b抑制剂实施例化合物7喂食大鼠，检测大鼠尿液中无机磷含量，来评价受试药的促磷排泄作用。
2.实验方法和实验材料
2.1.实验动物、饲料和饲养条件
实验用SD雄性大鼠，购自上海必凯实验动物有限公司(中国上海，合格证编号2008001644738，许可证SCXK(沪)2013-0016)。动物购进后，进行3天适应性饲养后，开始普通饲料和巧克力饲料两轮代谢笼筛选(以15g/饲料只/天吃完为标准)，成功入选的大鼠再开始实验。
普通饲料(0.6％P，0.6％Ca)由必凯提供，巧克力饲料(巧克力含量为3％，0.6％P，0.6％Ca)由斯莱克公司加工合成，药物饲料是在巧克力饲料中混入药物 (由药化部应永城提供)加工而成，具体配制如下：每克饲料混入1.3mg受试化合物，达到平均剂量为100mg/kg/day；司维拉姆每克饲料混入9.75mg受试化合物，达到平均剂量为750mg/kg/day。
2.2.实验试剂
磷检测试剂盒：批号20140808，由南京建成生物公司提供。
2.3.实验设计和实验方法
2.3.1.动物分组：
大鼠适应性饲养和筛选后，分组如下：
组号 分组 n
① 正常空白组 5
② 司维拉姆组(750mg/kg) 5
③ 化合物7组(100mg/kg) 5
④ 化合物7-100mg/kg+司维拉姆组-200mg/kg 4
给药方式：代谢笼自由进食饲料
2.3.2.实验方法：
实验方法按照专利(WO2012006473)中方法进行。将大鼠先经过正常饲料(15g/天)筛选，将饲料全部吃完的大鼠再进行巧克力饲料(15g/天)筛选，最后将饲料全部吃完的大鼠分组进入实验，随机分组如下(剂量是mg/kg/day)：①正常空白组，②司维拉姆-750mg/kg组，③化合物7-100mg/kg组，④化合物7-100mg/kg联合司维拉姆-200mg/kg组。每组大鼠4-5只。两轮筛选成功的大鼠于代谢笼中开始喂养上述药物饲料，共4天，观察每日体重情况、饲料消耗情况，并分别收集24-48h、48-72h和72-96h尿液，检测尿液中无机磷的含量。
3.结果与讨论:碳酸司维拉姆和化合物7对大鼠尿磷排泄的影响
正常空白组其尿磷含量在24-48h、48-72h和72-96h三天均为25-26mg，与正常空白组比较，给药组的3天尿磷总量或3天平均量均明显降低(P<0.05)，司维拉姆-750mg/kg组、化合物7-100mg/kg组、化合物7-100mg/kg+司维拉姆-200mg/kg组其降低幅度均分别为30.2％、27.9％和44.2％，见表6,图1，比率为降低幅度。表6:Npt2b对大鼠尿磷排泄影响的三天平均值
组号 分组 比率
② 司维拉姆组(750mg/kg) 30.2％
③ 化合物7组(100mg/kg) 27.9％
④ 化合物7-100mg/kg+司维拉姆组-200mg/kg 44.2％
结果证明，750mg/kg司维拉姆、100mg/kg化合物7和两者联用有明显的促磷排泄作用，单用司维拉姆和化合物7药效相当，且750mg/kg司维拉姆+200mg/kg化合物7联用后其尿磷降低幅度要高于两者单用。

Claims (15)

  1. 一种通式(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，或其可药用的盐：
    Figure PCTCN2015085385-appb-100001
    其中：
    X选自C(Ra)2、O、S或NRa；
    Y选自-C(O)-或-NRbC(O)-；
    Ra相同或不同，各自独立地选自氢原子、烷基、环烷基、杂环基、芳基、杂芳基、-C(O)OR5、-C(O)R5、-C(O)NR6R7或-S(O)pR5，其中所述的烷基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自卤素、羟基、烷氧基、氰基、硝基、烷基、卤代烷基、羟烷基、环烷基、杂环基、芳基、杂芳基、-C(O)OR5、-OC(O)R5、-NHS(O)pR5、-C(O)R5、-NHC(O)R5、-NHC(O)OR5、-NR6R7、-OC(O)NR6R7或-C(O)NR6R7的取代基所取代；
    Rb选自氢原子或烷基，其中所述的烷基任选进一步被一个或多个选自卤素、羟基、烷氧基、氰基或硝基的取代基所取代；
    环A选自环烷基、杂环基、芳基或杂芳基；
    环B选自芳基或杂芳基；
    环C选自环烷基、杂环基、芳基或杂芳基，其中所述的环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自卤素、羟基、烷氧基、氰基、硝基、烷基、卤代烷基、羟烷基、环烷基、杂环基、芳基、杂芳基、-C(O)OR5、-OC(O)R5、-NHS(O)pR5、-C(O)R5、-NHC(O)R5、-NHC(O)OR5、-NR6R7、-OC(O)NR6R7或-C(O)NR6R7的取代基所取代；
    R1选自烷基，其中所述的烷基进一步被一个或多个选自环烷基、杂环基、芳基或杂芳基的取代基所取代，其中所述的环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自卤素、羟基、烷氧基、氰基、硝基、烷基、卤代烷基、羟烷基、环烷基、杂环基、芳基、杂芳基、-C(O)OR5、-OC(O)R5、-NHS(O)pR5、-C(O)R5、-NHC(O)R5、-NHC(O)OR5、-NR6R7、-OC(O)NR6R7或-C(O)NR6R7的取代基所取代；
    R2选自氢原子、卤素、烷氧基、氰基、硝基或烷基，其中所述的烷基或烷氧基任选进一步被一个或多个选自卤素、羟基、烷氧基、氰基、硝基、环烷基、杂 环基、芳基、杂芳基、-C(O)OR5、-OC(O)R5、-NHS(O)pR5、-C(O)R5、-NHC(O)R5、-NHC(O)OR5、-NR6R7、-OC(O)NR6R7或-C(O)NR6R7的取代基所取代；
    R3选自氢原子、卤素、烷氧基、氰基、硝基或烷基，其中所述的烷基或烷氧基任选进一步被一个或多个选自卤素、羟基、烷氧基、氰基、硝基、环烷基、杂环基、芳基、杂芳基、-C(O)OR5、-OC(O)R5、-NHS(O)pR5、-C(O)R5、-NHC(O)R5、-NHC(O)OR5、-NR6R7、-OC(O)NR6R7或-C(O)NR6R7的取代基所取代；
    R4选自氢原子或烷基，其中所述的烷基任选进一步被一个或多个选自卤素、羟基、烷氧基、氰基、硝基、环烷基、杂环基、芳基、杂芳基、-C(O)OR5、-OC(O)R5、-NHS(O)pR5、-C(O)R5、-NHC(O)R5、-NHC(O)OR5、-NR6R7、-OC(O)NR6R7或-C(O)NR6R7的取代基所取代；
    R5选自氢原子、烷基、环烷基、杂环基、芳基或杂芳基，其中所述的烷基、环烷基、芳基或杂芳基任选进一步被一个或多个选自烷基、卤素、羟基、羟烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、羧酸或羧酸酯的取代基所取代；
    R6或R7各自独立地选自氢原子、烷基、烷氧基、环烷基、杂环基、芳基或杂芳基，其中所述的烷基、烷氧基、环烷基、杂环基、芳基或杂芳基各自独立地任选进一步被一个或多个选自烷基、卤素、羟基、羟烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、羧酸或羧酸酯的取代基所取代；
    或者，R6或R7与相连接的氮原子一起形成杂环基，其中所述的杂环基内含有一个或多个N、O或S(O)p杂原子，并且所述杂环基任选进一步被一个或多个选自烷基、卤素、羟基、烷氧基、羟烷基、环烷基、杂环基、芳基、杂芳基、羧酸或羧酸酯的取代基所取代；
    m为0、1、2、3或4；
    n为0、1、2、3或4；且
    p为0、1或2。
  2. 根据权利要求1所述的通式(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，或其可药用的盐，其为通式(II)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，或其可药用的盐：
    Figure PCTCN2015085385-appb-100002
    其中：
    R1～R4、X、Y、m、n、环A和环C的定义如权利要求1中所述。
  3. 根据权利要求1～2任意一项所述的通式(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，或其可药用的盐，其中环A选自杂环基或芳基，优选为苯基或吗啉基。
  4. 根据权利要求1所述的通式(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，或其可药用的盐，其为通式(III)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，或其可药用的盐：
    Figure PCTCN2015085385-appb-100003
    其中：
    R1～R4、X、Y、m、n和环C的定义如权利要求1中所述。
  5. 根据权利要求1～4任意一项所述的通式(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，或其可药用的盐，其中环C为杂环基，优选为吗啡啉基或哌嗪基。
  6. 根据权利要求1～5任意一项所述的通式(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，或其可药用的盐，其中R1选自-(CH2)r-Rc；
    Rc选自环烷基、杂环基、芳基或杂芳基，其中所述的环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自卤素、羟基、烷氧基、氰基、硝基、烷基、卤代烷基、羟烷基、环烷基、杂环基、芳基、杂芳基、-C(O)OR5、-OC(O)R5、-NHS(O)pR5、-C(O)R5、-NHC(O)R5、-NHC(O)OR5、-NR6R7、-OC(O)NR6R7或-C(O)NR6R7的取代基所取代；
    r选自1、2、3、4或5，优选为2或3；且
    R5、R6、R7、p的定义如权利要求1中所述。
  7. 根据权利要求1～6任意一项所述的通式(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，或其可药 用的盐，其中所述化合物选自：
    Figure PCTCN2015085385-appb-100004
    Figure PCTCN2015085385-appb-100005
  8. 一种制备根据权利要求1所述的通式(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，或其可药用的盐的方法，该方法包括：
    Figure PCTCN2015085385-appb-100006
    通式(IA)化合物或其盐与通式(IB)化合物反应，任选进一步水解和/或缩合得到通式(I)化合物；
    其中：
    Z选自羟基或卤素；
    R1～R4、X、Y、m、n、环A、环B和环C的定义如权利要求1中所述。
  9. 一种通式(IA)所述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、或其可药用的盐，
    Figure PCTCN2015085385-appb-100007
    其中：
    X选自C(Ra)2、O、S或NRa；
    Ra相同或不同，各自独立地选自氢原子、烷基、环烷基、杂环基、芳基、杂芳基、-C(O)OR5、-C(O)R5、-C(O)NR6R7或-S(O)pR5，其中所述的烷基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自卤素、羟基、烷氧基、氰基、硝基、烷基、卤代烷基、羟烷基、环烷基、杂环基、芳基、杂芳基、-C(O)OR5、-OC(O)R5、-NHS(O)pR5、-C(O)R5、-NHC(O)R5、-NHC(O)OR5、-NR6R7、-OC(O)NR6R7或-C(O)NR6R7的取代基所取代；
    条件是当X选自C(Ra)2时，Ra不选自氢原子；
    环A选自环烷基、杂环基、芳基或杂芳基，优选为苯基；
    R1选自烷基，其中所述的烷基进一步被一个或多个选自环烷基、杂环基、芳基或杂芳基的取代基所取代，其中所述的环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自卤素、羟基、烷氧基、氰基、硝基、烷基、卤代烷基、羟烷基、环烷基、杂环基、芳基、杂芳基、-C(O)OR5、-OC(O)R5、-NHS(O)pR5、-C(O)R5、-NHC(O)R5、-NHC(O)OR5、-NR6R7、-OC(O)NR6R7或-C(O)NR6R7的取代基所取代；
    R2选自氢原子、卤素、烷氧基、氰基、硝基或烷基，其中所述的烷基或烷氧基任选进一步被一个或多个选自卤素、羟基、烷氧基、氰基、硝基、环烷基、杂环基、芳基、杂芳基、-C(O)OR5、-OC(O)R5、-NHS(O)pR5、-C(O)R5、-NHC(O)R5、-NHC(O)OR5、-NR6R7、-OC(O)NR6R7或-C(O)NR6R7的取代基所取代；
    R5选自氢原子、烷基、环烷基、杂环基、芳基或杂芳基，其中所述的烷基、环烷基、芳基或杂芳基任选进一步被一个或多个选自烷基、卤素、羟基、羟烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、羧酸或羧酸酯的取代基所取代；
    R6或R7各自独立地选自氢原子、烷基、烷氧基、环烷基、杂环基、芳基或杂芳基，其中所述的烷基、烷氧基、环烷基、杂环基、芳基或杂芳基各自独立地任选进一步被一个或多个选自烷基、卤素、羟基、羟烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、羧酸或羧酸酯的取代基所取代；
    或者，R6或R7与相连接的氮原子一起形成杂环基，其中所述的杂环基内含有一个或多个N、O或S(O)p杂原子，并且所述杂环基任选进一步被一个或多个选自 烷基、卤素、羟基、烷氧基、羟烷基、环烷基、杂环基、芳基、杂芳基、羧酸或羧酸酯的取代基所取代；
    m为0、1、2、3或4；且
    p为0、1或2。
  10. 根据权利要求9所述的通式(IA)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，或其可药用的盐，其中所述化合物选自：
    Figure PCTCN2015085385-appb-100008
  11. 一种药物组合物，所述药物组合物含有治疗有效量的根据权利要求1～7任意一项所述的通式(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、或其可药用的盐以及药学上可接受的载体、稀释剂或赋形剂。
  12. 根据权利要求11所述的药物组合物，其进一步含有另外一种或多种磷结合剂，所述的磷结合剂优选为司维拉姆。
  13. 根据权利要求1～7任意一项所述的通式(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，或其可药用的盐，或根据权利要求11或12所述的药物组合物在制备肠2B型磷酸钠协同转运蛋白(Npt2b)抑制剂中的用途。
  14. 根据权利要求1～7任意一项所述的通式(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，或其可药用的盐，或根据权利要求11或12所述的药物组合物在制备治疗或预防高磷血症的药物中的用途。
  15. 根据权利要求1～7任意一项所述的通式(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，或其可药用盐，或根据权利要求11或12所述的药物组合物在治疗或预防磷酸钠转运蛋白介导的疾病的药物中的用途，所述的疾病优选选自肾病、内膜局部血管的钙化、高磷血症引起的高浓度的活性维生素D、甲状腺功能亢进症，所述的肾病优选为慢性的肾病或终末期肾病。
PCT/CN2015/085385 2014-08-22 2015-07-29 噻吩并环烷基或噻吩并杂环基类衍生物、其制备方法及其在医药上的应用 WO2016026372A1 (zh)

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WO2018034883A1 (en) * 2016-08-15 2018-02-22 Eli Lilly And Company Condensed thiophene derivatives useful as napi-iib inhibitors
CN109422723A (zh) * 2017-08-25 2019-03-05 江苏恒瑞医药股份有限公司 一种肠2b型磷酸钠协同转运蛋白抑制剂的晶型及其制备方法

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CN107082773A (zh) * 2016-02-16 2017-08-22 江苏恒瑞医药股份有限公司 一种肠2b型磷酸钠协同转运蛋白抑制剂的硫酸盐及其结晶形式
WO2018034883A1 (en) * 2016-08-15 2018-02-22 Eli Lilly And Company Condensed thiophene derivatives useful as napi-iib inhibitors
KR20190026895A (ko) * 2016-08-15 2019-03-13 일라이 릴리 앤드 캄파니 NaPi-IIb 억제제로서 유용한 축합된 티오펜 유도체
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AU2017312783B2 (en) * 2016-08-15 2020-02-06 Eli Lilly And Company Condensed thiophene derivatives useful as NaPi-IIb inhibitors
CN109563070B (zh) * 2016-08-15 2021-02-26 伊莱利利公司 作为napi-iib抑制剂的稠合噻吩衍生物
US10934280B2 (en) 2016-08-15 2021-03-02 Eli Lilly And Company Condensed thiophene derivatives useful as NaPi-IIb inhibitors
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KR102266143B1 (ko) 2016-08-15 2021-06-17 일라이 릴리 앤드 캄파니 NaPi-IIb 억제제로서 유용한 축합된 티오펜 유도체
CN109422723A (zh) * 2017-08-25 2019-03-05 江苏恒瑞医药股份有限公司 一种肠2b型磷酸钠协同转运蛋白抑制剂的晶型及其制备方法

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