CN105658635A - Thienocycloalkyl or thienoheterocyclic derivatives, preparation method thereof and use thereof in medicine - Google Patents

Abstract

The present invention relates to thieno naphthenic base or thieno heterocycle analog derivative, preparation method and its applications in medicine. Specifically, the present invention relates to thieno naphthenic base shown in a kind of logical formula (I) or thieno heterocycle analog derivative, preparation method and contain the pharmaceutical composition of the derivative, as well as therapeutic agent, purposes in the drug of hyperphosphatemia is treated and/or prevents in preparation with it especially as the purposes of intestines 2B type sodium phosphate cotransporter (Npt2b) inhibitor, definition is the same as that in the specification for each substituent group in formula of (I).

Description

Thieno cycloalkyl or thieno heterocyclic radical analog derivative, its preparation method and its in application pharmaceutically Technical field

Pharmaceutical composition the present invention relates to a class novel thiophene and cycloalkyl or thieno heterocyclic radical analog derivative, its preparation method and containing the derivative, and its purposes as therapeutic agent especially as the purposes of intestines 2B types sodium phosphate cotransporter (Npt2b) inhibitor and in the medicine of the disease such as treatment and/or prevention hyperphospheremia or illness is prepared.

Background technology

During inorganic phosphate (Pi) is the necessary component of bone mineral, extracellular matrix (such as bone and tooth) of the adult phosphatic about 80% outside ore deposit, 18% in the cell, and 2% in extracellular fluid.Under normal physiological conditions, small intestine intake excessive phosphate, excretion and reabsorption function of the phosphatic homeostasis dependent on kidney is adjusted.Internal phosphate is excessive or very few cause body function disorderly and causes a disease：As too low, cause hypophosphatemia, osteomalacia, rickets and cardiac disorder；It is too high then to induce hyperphospheremia, soft tissue and angiosteosis and renal dysfunction.It is the key factor that increases of the death rate of angiocardiopathy and chronic kidney disease (CKD) patient that phosphate is too high.The treatment of current hyperphosphatemia mainly includes diet limit phosphorus, dialysis treatment, the application of phosphate binder and the excision of parathyroid gland if necessary.There are 90~95% End-stage Renal Disease Patients to need to take phosphate binder treatment hyperphosphatemia.

Small intestine absorbs main by two kinds of approach to phosphatic, and passive transport and active transport, wherein active transport are carried out by the sodium/phosphorus of the Na-dependent channel protein that cotransports.It has recently been demonstrated that sodium phosphate cotransporter 2B (Npt2b) is important target spot (the J Pharm Sci.2011Sep for treating hyperphospheremia in chronic kidney disease (CKD)；100(9):3719-30).Sodium phosphate cotransporter includes 1 type family (Npt1, Npt3, Npt4), is mainly expressed in kidney；2 type families (Npt2a, Npt2b, Npt2c), are mainly expressed in kidney (Npt2c), lung, intestines and testis (Npt2a, Npt2b)；3 type families (Pit1, Pit2), are generally expressed in each organ.Wherein Npt2b has expression in whole upper digestive tract, absorption phosphatic in the food of half or so is mediated, for maintaining phosphatic homeostasis.Npt2b also has an expression in its hetero-organization, the characteristics of Npt2b inhibitor is necessary to keep the characteristic of nonabsorable and can keep in enteric cavity (Current Pharmaceutical Design, 2012,18,1434-1445).Research finds that Npt2b inactivations can cause the generation of the micro- calculus of autosomal recessive hereditary diseases alveolar (PAM) caused by Npt2b mutation, and it is to remove unnecessary phosphate in the major function of alveolar to imply Npt2b.In cancerous lung tissue section, Npt2b height expression is found, small interference siRNA experiments find that reduction Npt2b expression can suppress the generation of lung cancer.The exclusive use of non-absorbing Npt2b inhibitor (Ardelyx) of another research and establishment and two animal models for being applied in combination and (being combined with phosphate binder), it was found that the CKD rat models induced in adenine, NTX1942 can reduce uremia biomarker (serum-concentration of phosphorus, kreatinin and BUN), thyroid hormone and FGF-23 blood plasma level；And in the rat model of 5/6 nephrectomy, after 50 days drug treatments, the sign that rat performance renal function exacerbation delay and survival rate are significantly improved.As clinical dosage, The dosage of Npt2b inhibitor be hopeful it is lower than phosphate binder, for before the wider array of dialysis of more, scope CKD patient provide needed for phosphate suppression.

Hormone such as female hormone, glucocorticoid, fibroblast growth factor 23 (FGF23), 1,25 (OH) vitamin Ds₃(1,25(OH)₂D₃) and diet intake phosphate influence intestinal brush border film phosphorus absorb or Npt2b expression.Small enteral Npt2b missing also causes the reduction that FGF23 is expressed.FGF23 major function is 1,25 (OH) of expression and promotion by reducing phosphate co-transporter₂D₃Synthesis adjust the phosphatic excretion of kidney, Npt2b is used as phosphate sensor, regulates and controls the balance of hormone in vivo, maintain the balance of whole body system.

The patent application of a series of Npt2b inhibitor is disclosed at present, including 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 still need exploitation it is new there is more preferable drug effect, do not absorb or absorb in blood few, small compound is acted on physical toxicity, by being continually striving to, compound of the present invention design with the structure shown in logical formula (I), and find that the compound with this class formation shows to have excellent effect and effect in colon and jejunum position.

The content of the invention

It is an object of the invention to provide the compound shown in a kind of logical formula (I) or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures, or its officinal salt：

Wherein：

X is selected from C (R^a)₂, O, S or NR^a；

Y is selected from-C (O)-or-NR^bC(O)-；

R^aIt is identical or different, it is each independently selected from hydrogen atom, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (O) OR⁵、-C(O)R⁵、-C(O)NR⁶R⁷Or-S (O)_pR⁵, wherein described alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl are optionally further selected from halogen, hydroxyl, alkoxy, cyano group, nitro, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (O) OR by one or more⁵、 -OC(O)R⁵、-NHS(O)_pR⁵、-C(O)R⁵、-NHC(O)R⁵、-NHC(O)OR⁵、-NR⁶R⁷、-OC(O)NR⁶R⁷Or-C (O) NR⁶R⁷Substituent replaced；

R^bSelected from hydrogen atom or alkyl, wherein described alkyl is optionally further replaced by one or more substituents selected from halogen, hydroxyl, alkoxy, cyano group or nitro；

Ring A is selected from cycloalkyl, heterocyclic radical, aryl or heteroaryl；

Ring B is selected from aryl or heteroaryl；

Ring C is selected from cycloalkyl, heterocyclic radical, aryl or heteroaryl, wherein described cycloalkyl, heterocyclic radical, aryl or heteroaryl are optionally further selected from halogen, hydroxyl, alkoxy, cyano group, nitro, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (O) OR by one or more⁵、-OC(O)R⁵、-NHS(O)_pR⁵、-C(O)R⁵、-NHC(O)R⁵、-NHC(O)OR⁵、-NR⁶R⁷、-OC(O)NR⁶R⁷Or-C (O) NR⁶R⁷Substituent replaced；

R¹Selected from alkyl, wherein described alkyl is further replaced by one or more substituents selected from cycloalkyl, heterocyclic radical, aryl or heteroaryl, wherein described cycloalkyl, heterocyclic radical, aryl or heteroaryl are optionally further selected from halogen, hydroxyl, alkoxy, cyano group, nitro, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (O) OR by one or more⁵、-OC(O)R⁵、-NHS(O)_pR⁵、-C(O)R⁵、-NHC(O)R⁵、-NHC(O)OR⁵、-NR⁶R⁷、-OC(O)NR⁶R⁷Or-C (O) NR⁶R⁷Substituent replaced；

R²Selected from hydrogen atom, halogen, alkoxy, cyano group, nitro or alkyl, wherein described alkyl or alkoxy are optionally further selected from halogen, hydroxyl, alkoxy, cyano group, nitro, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (O) OR by one or more⁵、-OC(O)R⁵、-NHS(O)_pR⁵、-C(O)R⁵、-NHC(O)R⁵、-NHC(O)OR⁵、-NR⁶R⁷、-OC(O)NR⁶R⁷Or-C (O) NR⁶R⁷Substituent replaced；

R³Selected from hydrogen atom, halogen, alkoxy, cyano group, nitro or alkyl, wherein described alkyl or alkoxy are optionally further selected from halogen, hydroxyl, alkoxy, cyano group, nitro, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (O) OR by one or more⁵、-OC(O)R⁵、-NHS(O)_pR⁵、-C(O)R⁵、-NHC(O)R⁵、-NHC(O)OR⁵、-NR⁶R⁷、-OC(O)NR⁶R⁷Or-C (O) NR⁶R⁷Substituent replaced；

R⁴Selected from hydrogen atom or alkyl, wherein described alkyl is optionally further selected from halogen, hydroxyl, alkoxy, cyano group, nitro, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (O) OR by one or more⁵、-OC(O)R⁵、-NHS(O)_pR⁵、-C(O)R⁵、-NHC(O)R⁵、-NHC(O)OR⁵、-NR⁶R⁷、-OC(O)NR⁶R⁷Or-C (O) NR⁶R⁷Substituent replaced；

R⁵Selected from hydrogen atom, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl, wherein described alkyl, cycloalkyl, aryl or heteroaryl are optionally further replaced by one or more substituents selected from alkyl, halogen, hydroxyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclic radical, aryl, heteroaryl, carboxylic acid or carboxylate；

R⁶Or R⁷Hydrogen atom, alkyl, alkoxy, cycloalkyl, heterocyclic radical, aryl or heteroaryl are each independently selected from, wherein described alkyl, alkoxy, cycloalkyl, heterocyclic radical, aryl or heteroaryl are optionally further replaced by one or more substituents selected from alkyl, halogen, hydroxyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclic radical, aryl, heteroaryl, carboxylic acid or carboxylate independently of one another；

Or, R⁶Or R⁷Heterocyclic radical is formed together with the nitrogen-atoms being connected, wherein containing in described heterocyclic radical One or more N, O or S (O)_pHetero atom, and the heterocyclic radical optionally further replaces by one or more substituents selected from alkyl, halogen, hydroxyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, carboxylic acid or carboxylate；

M is 0,1,2,3 or 4；

N is 0,1,2,3 or 4；And

P is 0,1 or 2.

In presently preferred scheme, compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures shown in a kind of logical formula (I), or its pharmaceutically useful salt, its middle ring B is phenyl or pyridine radicals.

In a preferred scheme of the invention, compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures shown in a kind of logical formula (I), or its pharmaceutically useful salt, it is to lead to the compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures shown in formula (II), or its pharmaceutically useful salt：

Wherein：

R¹~R⁴, X, Y, m, n, ring A and ring C definition as described in logical formula (I).

In presently preferred scheme, compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures shown in a kind of logical formula (I), or its pharmaceutically useful salt, its middle ring A is selected from heterocyclic radical or aryl, preferably phenyl or morpholinyl.

In presently preferred scheme, compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures shown in a kind of logical formula (I), or its pharmaceutically useful salt, it is to lead to the compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures shown in formula (III), or its pharmaceutically useful salt：

Wherein：

R¹~R⁴, X, Y, m, n and ring C definition as described in logical formula (I).

In presently preferred scheme, compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures shown in a kind of logical formula (I), or its pharmaceutically useful salt, its middle ring C is heterocyclic radical, preferably morpholine base or piperazinyl.

In another preferred scheme of the present invention, compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures shown in a kind of logical formula (I), or its pharmaceutically useful salt, wherein R¹Selected from-(CH₂)_r-R^c；

R^cSelected from cycloalkyl, heterocyclic radical, aryl or heteroaryl, wherein described cycloalkyl, heterocyclic radical, aryl or heteroaryl are optionally further selected from halogen, hydroxyl, alkoxy, cyano group, nitro, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (O) OR by one or more⁵、-OC(O)R⁵、-NHS(O)_pR⁵、-C(O)R⁵、-NHC(O)R⁵、-NHC(O)OR⁵、-NR⁶R⁷、-OC(O)NR⁶R⁷Or-C (O) NR⁶R⁷Substituent replaced；

R is selected from 1,2,3,4 or 5, preferably 2 or 3；And

R⁵、R⁶、R⁷, p definition as described in logical formula (I).

In presently preferred scheme, compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures shown in a kind of logical formula (I), or its pharmaceutically useful salt, wherein R²Selected from hydrogen atom or alkyl, preferably methyl.

In presently preferred scheme, compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures shown in a kind of logical formula (I), or its pharmaceutically useful salt, wherein R³Selected from hydrogen atom or alkyl, preferably methyl.

Typical compound of the invention includes, but are not limited to：

Or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures, or its officinal salt.

The present invention also provides a kind of compound prepared shown in logical formula (I) or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures, or its pharmaceutically useful salt method, this method includes：

In the basic conditions, formula (IA) compound or its salt reacts with formula (IB) compound, optionally further hydrolyzes and/or be condensed to yield logical formula (I) compound；

Wherein：

Z is selected from hydroxyl or halogen；

R¹~R⁴, X, Y, m, n, ring A, ring B and ring C definition as described in formula (I).

The compound or its dynamic isomer of the invention also provided shown in a kind of formula (IA), mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures, or its pharmaceutically useful salt：

Wherein：

X is selected from C (R^a)₂, O, S or NR^a；

R^aIt is identical or different, it is each independently selected from hydrogen atom, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (O) OR⁵、-C(O)R⁵、-C(O)NR⁶R⁷Or-S (O)_pR⁵, wherein described alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl are optionally further selected from halogen, hydroxyl, alkoxy, cyano group, nitro, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (O) OR by one or more⁵、-OC(O)R⁵、-NHS(O)_pR⁵、-C(O)R⁵、-NHC(O)R⁵、-NHC(O)OR⁵、-NR⁶R⁷、-OC(O)NR⁶R⁷Or-C (O) NR⁶R⁷Substituent replaced；

Condition is when X is selected from C (R^a)₂When, R^aIt is not selected from hydrogen atom；

Ring A is selected from cycloalkyl, heterocyclic radical, aryl or heteroaryl, preferably phenyl；

R¹Selected from alkyl, wherein described alkyl is further replaced by one or more substituents selected from cycloalkyl, heterocyclic radical, aryl or heteroaryl, wherein described cycloalkyl, heterocyclic radical, aryl or heteroaryl are optionally further selected from halogen, hydroxyl, alkoxy, cyano group, nitro, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (O) OR by one or more⁵、-OC(O)R⁵、-NHS(O)_pR⁵、-C(O)R⁵、-NHC(O)R⁵、-NHC(O)OR⁵、-NR⁶R⁷、-OC(O)NR⁶R⁷Or-C (O) NR⁶R⁷Substituent replaced；

R²Selected from hydrogen atom, halogen, alkoxy, cyano group, nitro or alkyl, wherein described alkyl or alkoxy optionally further by it is one or more selected from halogen, it is hydroxyl, alkoxy, cyano group, nitro, cycloalkyl, miscellaneous Ring group, aryl, heteroaryl ,-C (O) OR⁵、-OC(O)R⁵、-NHS(O)_pR⁵、-C(O)R⁵、-NHC(O)R⁵、-NHC(O)OR⁵、-NR⁶R⁷、-OC(O)NR⁶R⁷Or-C (O) NR⁶R⁷Substituent replaced；

R⁵Selected from hydrogen atom, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl, wherein described alkyl, cycloalkyl, aryl or heteroaryl are optionally further replaced by one or more substituents selected from alkyl, halogen, hydroxyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclic radical, aryl, heteroaryl, carboxylic acid or carboxylate；

R⁶Or R⁷Hydrogen atom, alkyl, alkoxy, cycloalkyl, heterocyclic radical, aryl or heteroaryl are each independently selected from, wherein described alkyl, alkoxy, cycloalkyl, heterocyclic radical, aryl or heteroaryl are optionally further replaced by one or more substituents selected from alkyl, halogen, hydroxyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclic radical, aryl, heteroaryl, carboxylic acid or carboxylate independently of one another；

Or, R⁶Or R⁷Heterocyclic radical is formed together with the nitrogen-atoms being connected, wherein containing one or more N, O or S (O) in described heterocyclic radical_pHetero atom, and the heterocyclic radical optionally further replaces by one or more substituents selected from alkyl, halogen, hydroxyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, carboxylic acid or carboxylate；

M is 0,1,2,3 or 4；And

P is 0,1 or 2.

The typical compound of formula (IA) compound includes, but are not limited to：

Or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures, or its officinal salt.

The invention further relates to a kind of pharmaceutical composition, described pharmaceutical composition contains the compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures as shown in logical formula (I) of therapeutically effective amount, or its pharmaceutically useful salt and pharmaceutically acceptable carrier, diluent or excipient.Described pharmaceutical composition further contains another or a variety of phosphate binders, and described phosphate binder is preferably sevelamer.

The invention further relates to lead to compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures shown in formula (I), or its pharmaceutically useful salt, or purposes of the pharmaceutical composition comprising it in intestines 2B sodium phosphate cotransporter inhibitor is prepared.

The invention further relates to lead to compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures shown in formula (I), or its pharmaceutically useful salt, or purposes of the pharmaceutical composition comprising it in the medicine for treating or preventing hyperphosphatemia is prepared.

The invention further relates to lead to compound or its dynamic isomer, mesomer, racemic shown in formula (I) Body, enantiomter, diastereoisomer or its form of mixtures, or its pharmaceutically useful salt, or purposes of the pharmaceutical composition comprising it in the medicine of disease of sodium phosphate transport protein mediation is treated or prevented, described disease includes but is not limited to nephrosis, the calcification of inner membrance local vascular, the activated vitamin D or hyperthyroidism of high concentration caused by hyperphosphatemia, and described nephrosis is preferably chronic nephrosis or ESRD.

The invention further relates to lead to compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures shown in formula (I), or its pharmaceutically useful salt, or the pharmaceutical composition comprising it, it is used as intestines 2B types sodium phosphate cotransporter (Npt2b) inhibitor.

The invention further relates to lead to compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures shown in formula (I), or its pharmaceutically useful salt, or the pharmaceutical composition comprising it, it is used to treat or prevent hyperphosphatemia.

The invention further relates to lead to compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures shown in formula (I), or its pharmaceutically useful salt, or the pharmaceutical composition comprising it, it is used for the disease for treating or preventing the mediation of sodium phosphate transport protein, described disease is preferably selected from nephrosis, the calcification of inner membrance local vascular, activated vitamin D, the hyperthyroidism of high concentration caused by hyperphosphatemia, and described nephrosis is preferably chronic nephrosis or ESRD.

The invention further relates to a kind of method for suppressing intestines 2B type sodium phosphate cotransporters, it includes the compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures shown in the logical formula (I) of bacterium needed for giving, or its pharmaceutically useful salt, or the pharmaceutical composition comprising it.

The invention further relates to a kind of method for treating or preventing hyperphosphatemia, it includes the compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures shown in the logical formula (I) of bacterium needed for giving, or its pharmaceutically useful salt, or the pharmaceutical composition comprising it.

The present invention relates to a kind of method for the disease or illness for treating or preventing sodium phosphate cotransporter mediation, it includes the compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures shown in the logical formula (I) of bacterium needed for giving, or its pharmaceutically useful salt, or the pharmaceutical composition comprising it, wherein described method includes：

(a) method for treating hyperphosphatemia；

(b) method for treating nephrosis；

(c) method of Rend dialysis time is delayed；

(d) method of inner membrance local vascular calcification is weakened；

(e) method for reducing activated vitamin D caused by hyperphosphatemia；

(f) method for reducing FGF23；

(g) method of hyperthyroidism is weakened；

(h) the abnormal method of blood vessel endothelium is improved by phosphatic concentration in post-prandial serum；

(i) method for reducing urine phosphorus；

(j) method of phosphorus level standard in serum is made；

(k) method for the treatment of albumen urine；

(l) method for reducing parathormone and phosphate concn in serum；

Wherein described nephrosis is chronic kidney disease or ESRD.

Pharmaceutical composition containing active component can apply to oral form, such as tablet, dragee, lozenge, water or oil suspension, dispersible powder or particle, emulsion, hard or soft capsule, or syrup or elixir.Orally administered composition can be prepared according to any known method for preparing Pharmaceutical composition in this area, such composition can be selected from following composition containing one or more：Sweetener, flavouring, colouring agent and preservative, to provide pleasing and tasty pharmaceutical formulation.Tablet contains active component and the suitable nontoxic pharmaceutically useful excipient for preparing tablet for mixing.These excipient can be inert excipient, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate；Granulating agent and disintegrant, such as microcrystalline cellulose, Ac-Di-Sol, cornstarch or alginic acid；Adhesive, such as starch, gelatin, polyvinylpyrrolidone or Arabic gum and lubricant, such as magnesium stearate, stearic acid or talcum powder.These tablets can not be coated or can be coated by covering the taste of medicine or delay disintegration and absorption in the gastrointestinal tract, thus providing the known technology of slow releasing function in a long time.For example, water soluble taste can be used to shelter material, such as hydroxypropyl methyl cellulose or hydroxypropyl cellulose, or extension time material such as ethyl cellulose, acetylbutyrylcellulose.

Also wherein active component and the inert solid diluent hard gelatin capsule that for example calcium carbonate, calcium phosphate or kaolin are mixed are can use, or wherein active component provides oral formulations with water-solubility carrier such as polyethylene glycol or the oily solvent Perle that for example peanut oil, atoleine or olive oil are mixed.

Water slurry contains active material and the suitable excipient for preparing water slurry for mixing.Such excipient is suspending agent, for example sodium carboxy methyl cellulose, methylcellulose, hydroxypropyl methyl cellulose, mosanom, polyvinylpyrrolidone and Arabic gum；Dispersant or wetting agent can be naturally-produced phosphatide such as lecithin, or the condensation product of alkylene oxide and aliphatic acid such as Myrj 45, or the condensation product of oxirane and long-chain fatty alcohol, such as 17 carbon ethyleneoxy group cetanols (heptadecaethyleneoxy cetanol), or the condensation product of oxirane and the part ester as derived from aliphatic acid and hexitol, such as polyoxyethylene sorbitol monoleate, or the condensation product of oxirane and the partial ester as derived from aliphatic acid and hexitan, such as PEO Arlacel-80.Aqueous suspension can also contain one or more preservatives such as ethylparaben or nipalgin n-propyl, one or more colouring agents, one or more flavourings and one or more sweeteners, such as sucrose, saccharin or aspartame.

Oil suspension can be formulated by making active component be suspended in vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil, or in mineral oil such as atoleine.Oil suspension can contain thickener, such as beeswax, hard paraffin or cetanol.Above-mentioned sweetener and flavouring can be added, to provide tasty preparation.These compositions can be preserved by adding antioxidant such as Butylated Hydroxyanisole or alpha-tocopherol.

It can make to be applied to prepare dispersible powder and particle offer active component and dispersant or wetting agent for mixing, suspending agent or one or more preservatives that water is suspended also by adding water.Above-mentioned example can be explained in suitable dispersant or wetting agent and suspending agent.Also other excipient such as sweetener, flavouring and colouring agent can be added.These compositions are preserved by adding antioxidant such as ascorbic acid.

The pharmaceutical composition of the present invention can also be the form of oil in water emulsion.Oil phase can be vegetable oil such as olive oil or peanut oil, or mineral oil such as atoleine or its mixture.Suitable emulsifying agent can be naturally-produced phosphatide, such as soybean lecithin and ester or partial ester such as sorbitan monooleate as derived from aliphatic acid and hexitan, and the partial ester and oxirane condensation product, such as polyoxyethylene sorbitol monoleate.Emulsion can also contain sweetener, flavouring, preservative and antioxidant.Syrup and elixir can be prepared with Sweetening agents such as glycerine, propane diols, sorbierite or sucrose.Such preparation can also contain moderator, preservative, colouring agent and antioxidant.

Pharmaceutical composition can be sterile injectable aqueous form.Can there are water, ringer's solution and isotonic sodium chlorrde solution in the acceptable solvent and solvent used.Aseptic injection preparation can be the aseptic injection oil-in-water microemulsion that wherein active component is dissolved in oil phase.For example active component is dissolved in the mixture of soybean oil and lecithin.Then oil solution is added to processing in the mixture of water and glycerine and forms micro emulsion.Parenteral solution or micro emulsion can be injected in the blood flow of patient by local a large amount of injections.Or, preferably give solution and micro emulsion in the way of it can keep the compounds of this invention constant circulating concentration.To keep this constant density, continuous intravenous delivery device can be used.The example of this device is Deltec CADD-PLUS.TM.5400 type Iv pumps.

Pharmaceutical composition can be aseptic injection water or the form of oil suspension for intramuscular and subcutaneous administration.By known technology the suspension can be prepared with the suitable dispersant of those described above or wetting agent and suspending agent.Aseptic injection preparation can also be the solution prepared in the aseptic injectable solution or suspension prepared in the acceptable diluent of nontoxic parenteral or solvent, such as 1,3-BDO.In addition, it is convenient to be used as solvent or suspension media with sterile fixed oil.For this purpose, any mediation fixing oil including synthetic glycerine list or diester can be used.In addition, aliphatic acid such as oleic acid can also prepare injection.

The compounds of this invention can be given by the suppository form for rectally.Can be by the way that by medicine, with being at normal temperatures solid but being liquid in the rectum, thus the suitable nonirritant excipient that can be dissolved in the rectum and discharge medicine mixes to prepare these pharmaceutical compositions.Such material includes the mixture of the fatty acid ester of cocoa butter, glycerin gelatine, hydrogenated vegetable oil, the polyethylene glycol of various molecular weight and polyethylene glycol.

Well-known to those skilled in the art, the dosage of medicine depends on many factors, including but and non-limiting following factor：The activity of specific compound used, the age of patient, the body weight of patient, the health status of patient, the row quilt of patient, the diet of patient, administration time, administering mode, speed, the combination of medicine of excretion etc.；In addition, optimal therapeutic modality can be verified such as the species of the pattern treated, the consumption per day of general formula compound (I) or pharmaceutically useful salt according to traditional therapeutic scheme.

Detailed description of the invention

Unless stated to the contrary, it is otherwise following that there are following implications with term in the specification and in the claims.

" alkyl " refers to the aliphatic hydrocarbon group of saturation, includes the straight chain and branched group of 1 to 20 carbon atom.Preferably comprise the alkyl of 1 to 10 carbon atom, the alkyl of further preferably 1 to 6 carbon atom.Non-limiting example includes methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, sec-butyl, n-pentyl, 1,1- dimethyl propyls, 1,2- dimethyl propyls, 2,2- dimethyl propyls, 1- ethyl propyls, 2- methyl butyls, 3- methyl butyls, n-hexyl, 1- Ethyl-2-Methyls propyl group, 1,1,2- thmethylpropyls, 1,1- dimethylbutyls, 1, 2- dimethylbutyls, 2, 2- dimethylbutyls, 1, 3- dimethylbutyls, 2- ethyl-butyls, 2- methyl amyls, 3- methyl amyls, 4- methyl amyls, 2, 3- dimethylbutyls, n-heptyl, 2- methylhexyls, 3- methylhexyls, 4- methylhexyls, 5- methylhexyls, 2, 3- dimethyl amyl groups, 2, 4- dimethyl amyl groups, 2, 2- dimethyl amyl groups, 3, 3- dimethyl amyl groups, 2- ethyl pentyl groups, 3- ethyl pentyl groups, n-octyl, 2, 3- dimethylhexanyls, 2, 4- dimethylhexanyls, 2, 5- dimethylhexanyls, 2, 2- dimethylhexanyls, 3, 3- dimethylhexanyls, 4, 4- dimethylhexanyls, 2- ethylhexyls, 3- ethylhexyls, 4- ethylhexyls, 2- methyl -2- ethyl pentyl groups, 2- methyl -3- ethyl pentyl groups, n-nonyl, 2- methyl -2- ethylhexyls, 2- methyl -3- ethylhexyls, 2, 2- diethyl amyl groups, positive decyl, 3, 3- diethylhexyls, 2, 2- diethylhexyls, and its various branched chain isomers etc..Low alkyl group more preferably containing 1 to 6 carbon atom, non-limiting example includes methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, sec-butyl, n-pentyl, 1, 1- dimethyl propyls, 1, 2- dimethyl propyls, 2, 2- dimethyl propyls, 1- ethyl propyls, 2- methyl butyls, 3- methyl butyls, n-hexyl, 1- Ethyl-2-Methyl propyl group, 1, 1, 2- thmethylpropyls, 1, 1- dimethylbutyls, 1, 2- dimethylbutyls, 2, 2- dimethylbutyls, 1, 3- dimethylbutyls, 2- ethyl-butyls, 2- methyl amyls, 3- methyl amyls, 4- methyl amyls, 2, 3- dimethylbutyls etc..Alkyl can be substituted or unsubstituted, when substituted, substituent can be substituted on any workable tie point, preferably one or more following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, sulfydryl, hydroxyl, nitro, cyano group, cycloalkyl, heterocyclic radical, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, oxo base, amino, haloalkyl, hydroxyalkyl, carboxyl, carboxylic acid ester groups ,-C (O) OR⁵、-OC(O)R⁵、-NHS(O)_pR⁵、-C(O)R⁵、-NHC(O)R⁵、-NHC(O)OR⁵、-NR⁶R⁷、-OC(O)NR⁶R⁷Or-C (O) NR⁶R⁷。

Term " alkenyl " refers to the alkyl as defined above by being at least made up of two carbon atoms and at least one carbon-to-carbon double bond, such as vinyl, 1- acrylic, 2- acrylic, 1-, 2- or 3- cyclobutenyl.It is preferred that C_2-10Alkenyl, more preferably C_2-6Alkenyl, most preferably C_2-4Alkenyl.Alkenyl can be substitution or non-substituted, when substituted, substituent is preferably one or more following groups, and it is independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, sulfydryl, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, oxo base, amino, haloalkyl, hydroxyalkyl, carboxylic acid group, carboxylic acid ester groups ,-C (O) OR⁵、-OC(O)R⁵、-NHS(O)_pR⁵、-C(O)R⁵、-NHC(O)R⁵、-NHC(O)OR⁵、-NR⁶R⁷、-OC(O)NR⁶R⁷Or-C (O) NR⁶R⁷。

Term " alkynyl " refers to the alkyl as defined above being at least made up of two carbon atoms and at least one carbon-to-carbon triple bond, such as acetenyl, 1- propinyls, 2-propynyl, 1-, 2- or 3- butynyl.It is preferred that C_2-10Alkynyl, more preferably C_2-6Alkynyl, most preferably C_2-4Alkynyl.Alkynyl can be substitution or non-substituted, when substituted, substituent is preferably one or more following groups, and it is independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, sulfydryl, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, oxo base, amino, haloalkyl, hydroxyalkyl, carboxylic acid group, carboxylic acid ester groups ,-C (O) OR⁵、-OC(O)R⁵、-NHS(O)_pR⁵、-C(O)R⁵、-NHC(O)R⁵、-NHC(O)OR⁵、-NR⁶R⁷、-OC(O)NR⁶R⁷Or-C (O) NR⁶R⁷。

" cycloalkyl " refers to the unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent of saturation or part, and it includes 3 to 20 Individual carbon atom, preferably includes 3 to 12 carbon atoms, and more preferably cycloalkyl ring includes 3 to 10 carbon atoms, and most preferably cycloalkyl ring includes 3 to 6 carbon atoms.The non-limiting example of monocyclic cycloalkyl includes cyclopropyl, cyclobutyl, cyclopenta, cyclopentenyl, cyclohexyl, cyclohexenyl group, cyclohexadienyl, suberyl, cycloheptatriene base, cyclooctyl etc., preferably cyclopropyl, cyclohexenyl group.Polycyclic naphthene base includes the cycloalkyl of loop coil, condensed ring and bridged ring.

" spiro cycloalkyl group " refers to 5 to 20 yuan, it is monocyclic between share the polycyclic moiety of a carbon atom (title spiro-atom), these can contain one or more double bonds, but neither one ring has the pi-electron system of total conjugated.Preferably 6 to 14 yuan, more preferably 7 to 10 yuan.Spiro cycloalkyl group is divided into by single spiro cycloalkyl group, double spiro cycloalkyl group bases or many spiro cycloalkyl groups according to the number of shared spiro-atom between ring and ring, is preferably single spiro cycloalkyl group and double spiro cycloalkyl groups.More preferably 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/5 yuan or 5 yuan/6 yuan single spiro cycloalkyl groups.The non-limiting example of spiro cycloalkyl group is included

" cycloalkyl " refers to 5 to 20 yuan, the full carbon polycyclic moiety of each ring and shared a pair of the carbon atoms adjoined of other rings in system in system, wherein one or more rings can contain one or more double bonds, but neither one ring has the pi-electron system of total conjugated.Preferably 6 to 14 yuan, more preferably 7 to 10 yuan.Bicyclic, three rings, Fourth Ring or polycyclic fused ring alkyl, preferably bicyclic or three rings, more preferably 5 yuan/5 yuan or 5 yuan/6 membered bicyclic alkyl can be divided into according to the number of composition ring.The non-limiting example of cycloalkyl is included

" bridge ring alkyl " refers to 5 to 20 yuan, and any two ring shares the full carbon polycyclic moiety of two carbon atoms being not directly connected, and these can contain one or more double bonds, but neither one ring has the pi-electron system of total conjugated.Preferably 6 to 14 yuan, more preferably 7 to 10 yuan.Bicyclic, three rings, Fourth Ring or polycyclic bridge ring alkyl, preferably bicyclic, three rings or Fourth Ring can be divided into according to the number of composition ring, bicyclic or three rings are more elected as.The non-limiting example of bridge ring alkyl is included

The cycloalkyl ring can be condensed on aryl, heteroaryl or heterocyclic ring, wherein being cycloalkyl with the ring that precursor structure links together, non-limiting example includes indanyl, tetralyl, benzocyclohepta alkyl etc.. Cycloalkyl can be optionally substituted or unsubstituted, when substituted, substituent is preferably one or more following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, sulfydryl, hydroxyl, nitro, cyano group, cycloalkyl, heterocyclic radical, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, oxo base, amino, haloalkyl, hydroxyalkyl, carboxyl, carboxylic acid ester groups ,-C (O) OR⁵、-OC(O)R⁵、-NHS(O)_pR⁵、-C(O)R⁵、-NHC(O)R⁵、-NHC(O)OR⁵、-NR⁶R⁷、-OC(O)NR⁶R⁷Or-C (O) NR⁶R⁷。

" heterocyclic radical " refers to the unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent of saturation or part, and it includes 3 to 20 annular atoms, and wherein one or more annular atoms are selected from nitrogen, oxygen or S (O)_mThe hetero atom of (wherein m is 0 to 2 integer), but do not include-O-O- ,-O-S- or-S-S- loop section, remaining annular atom is carbon.3 to 12 annular atoms are preferably included, wherein 1~4 is hetero atom；More preferably heterocyclic ring includes 3 to 10 annular atoms, wherein 1~3 is hetero atom；More preferably heterocyclic ring includes 5 to 6 annular atoms, wherein 1~2 is hetero atom.The non-limiting example of monocyclic heterocycles base includes pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, thio-morpholinyl, homopiperazine base, pyranose, tetrahydrofuran base etc..Multiring heterocyclic includes the heterocyclic radical of loop coil, condensed ring and bridged ring.

" spiro heterocyclic radical " refers to 5 to 20 yuan, it is monocyclic between share the polycyclic heterocyclic group of an atom (title spiro-atom), wherein one or more annular atoms are selected from nitrogen, oxygen or S (O)_mThe hetero atom of (wherein m is integer 0 to 2), remaining annular atom is carbon.These can contain one or more double bonds, but neither one ring has the pi-electron system of total conjugated.Preferably 6 to 14 yuan, more preferably 7 to 10 yuan.Spiro cycloalkyl group is divided into by single spiro heterocyclic radical, double spiro heterocyclic radicals or many spiro heterocyclic radicals according to the number of shared spiro-atom between ring and ring, is preferably single spiro heterocyclic radical and double spiro heterocyclic radicals.More preferably 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/5 yuan or 5 yuan/6 yuan single spiro heterocyclic radicals.The non-limiting example of spiro heterocyclic radical is included

" condensed hetero ring base " refers to 5 to 20 yuan, the polycyclic heterocyclic group of each ring and shared a pair of the atoms adjoined of other rings in system in system, one or more rings can contain one or more double bonds, but neither one ring has the pi-electron system of total conjugated, wherein one or more annular atoms are selected from nitrogen, oxygen or S (O)_mThe hetero atom of (wherein m is integer 0 to 2), remaining annular atom is carbon.Preferably 6 to 14 yuan, more preferably 7 to 10 yuan.Bicyclic, three rings, Fourth Ring or polycyclic condensed hetero ring base, preferably bicyclic or three rings, more preferably 5 yuan/5 yuan or 5 yuan/6 membered bicyclic condensed hetero ring bases can be divided into according to the number of composition ring.The non-limiting example of condensed hetero ring base is included

" bridge heterocyclic radical " refers to 5 to 14 yuan, any two ring shares the polycyclic heterocyclic group of two atoms being not directly connected, these can contain one or more double bonds, but neither one ring has the pi-electron system of total conjugated, and wherein one or more annular atoms are selected from nitrogen, oxygen or S (O)_mThe hetero atom of (wherein m is integer 0 to 2), remaining annular atom is carbon.Preferably 6 to 14 yuan, more preferably 7 to 10 yuan.Bicyclic, three rings, Fourth Ring or polycyclic bridge heterocyclic radical, preferably bicyclic, three rings or Fourth Ring can be divided into according to the number of composition ring, bicyclic or three rings are more elected as.The non-limiting example of bridge heterocyclic radical is included：

The heterocyclic ring can be condensed on aryl, heteroaryl or cycloalkyl ring, wherein the ring linked together with precursor structure is heterocyclic radical, non-limiting example is included：

Heterocyclic radical can be optionally substituted or unsubstituted, when substituted, substituent is preferably one or more following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, sulfydryl, hydroxyl, nitro, cyano group, cycloalkyl, heterocyclic radical, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, oxo base, amino, haloalkyl, hydroxyalkyl, carboxyl, carboxylic acid ester groups ,-C (O) OR⁵、-OC(O)R⁵、-NHS(O)_pR⁵、-C(O)R⁵、-NHC(O)R⁵、-NHC(O)OR⁵、-NR⁶R⁷、-OC(O)NR⁶R⁷Or-C (O) NR⁶R⁷。

" aryl ", which refers to, has 6 to 14 yuan of full carbon of the pi-electron system being conjugated monocyclic or fused polycycle (rings for namely sharing adjacent carbon atoms pair) group, more preferably preferably 6 to 10 yuan, most preferably phenyl and naphthyl, phenyl.The aryl rings can be condensed on heteroaryl, heterocyclic radical or cycloalkyl ring, wherein the ring linked together with precursor structure is aryl rings, non-limiting example is included：

Aryl can be substituted or unsubstituted, when substituted, substituent is preferably one or more following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, sulfydryl, hydroxyl, nitro, cyano group, cycloalkyl, heterocyclic radical, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, Cycloalkylthio, heterocycle alkylthio group, amino, haloalkyl, hydroxyalkyl, carboxyl, carboxylic acid ester groups ,-C (O) OR⁵、-OC(O)R⁵、-NHS(O)_pR⁵、-C(O)R⁵、-NHC(O)R⁵、-NHC(O)OR⁵、-NR⁶R⁷、-OC(O)NR⁶R⁷Or-C (O) NR⁶R⁷。

" heteroaryl " refers to 1 to 4 hetero atom as annular atom, and remaining annular atom is 5 to 14 yuan of aryl of carbon, and wherein hetero atom includes oxygen, sulphur and nitrogen.Preferably 5 to 10 yuan.It is 5 yuan or 6 yuan that heteroaryl, which is preferably, such as furyl, thienyl, pyridine radicals, pyrrole radicals, N- alkyl pyrrole radicals, pyrimidine radicals, pyrazinyl, imidazole radicals, tetrazole radical.The heteroaryl ring can be condensed on aryl, heterocyclic radical or cycloalkyl ring, wherein the ring linked together with precursor structure is heteroaryl ring, non-limiting example is included：

Heteroaryl can be optionally substituted or unsubstituted, when substituted, substituent is preferably one or more following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, sulfydryl, hydroxyl, nitro, cyano group, cycloalkyl, heterocyclic radical, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, amino, haloalkyl, hydroxyalkyl, carboxyl, carboxylic acid ester groups ,-C (O) OR⁵、-OC(O)R⁵、-NHS(O)_pR⁵、-C(O)R⁵、-NHC(O)R⁵、-NHC(O)OR⁵、-NR⁶R⁷、-OC(O)NR⁶R⁷Or-C (O) NR⁶R⁷。

" alkoxy " refers to-O- (alkyl) and-O- (unsubstituted cycloalkyl), and wherein alkyl is as defined above.Non-limiting example includes methoxyl group, ethyoxyl, propoxyl group, butoxy, ring propoxyl group, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy etc..Alkoxy can be optionally substituted or unsubstituted, when substituted, substituent is preferably one or more following groups, independently selected from for alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, sulfydryl, hydroxyl, nitro, cyano group, cycloalkyl, heterocyclic radical, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, amino, haloalkyl, hydroxyalkyl, carboxyl, carboxylic acid ester groups ,-C (O) OR⁵、-OC(O)R⁵、-NHS(O)_pR⁵、-C(O)R⁵、-NHC(O)R⁵、-NHC(O)OR⁵、-NR⁶R⁷、-OC(O)NR⁶R⁷Or-C (O) NR⁶R⁷。

" haloalkyl " refers to alkyl and replaced by one or more halogens, and wherein alkyl is as defined above.

" hydroxyl " refers to-OH groups.

" hydroxyalkyl " refers to the alkyl being optionally substituted by a hydroxyl group, and wherein alkyl is as defined above.

" halogen " refers to fluorine, chlorine, bromine or iodine.

" amino " refers to-NH₂。

" cyano group " refers to-CN.

" nitro " refers to-NO₂。

" benzyl " refers to-CH₂- phenyl.

" oxo base " refers to=O.

" carboxyl " refers to-C (O) OH.

" carboxylic acid ester groups " refers to-C (O) O (alkyl) or (cycloalkyl), and wherein alkyl, cycloalkyl is as defined above.

" optional " or " optionally " mean ground described later event or environment can with but need not occur, the explanation includes the event or environment occurs or not spot occasion.For example, " optionally by alkyl-substituted heterocyclic group " mean alkyl can with but necessarily exist, the explanation include heterocyclic group by alkyl-substituted situation and heterocyclic group not by alkyl-substituted situation.

" substituted " refers to one or more of group hydrogen atom, and preferably at most 5, more preferably 1~3 hydrogen atom is replaced by the substituent of respective number independently of one another.Self-evident, substituent is only in their possible chemical position, and those skilled in the art can determine (by experiment or theoretical) possible or impossible substitution in the case where not paying excessively effort.For example, amino or hydroxyl with free hydrogen are probably unstable when being combined with the carbon atom with unsaturated (such as olefinic) key.

" pharmaceutical composition " is represented containing one or more compounds described herein or its physiologically pharmaceutically useful salt or pro-drug and mixture of other chemical constituents, and the pharmaceutically useful carrier of other components such as physiology and excipient.The purpose of pharmaceutical composition is to promote the administration to organism, the absorption beneficial to active component and then performance bioactivity.

p、R⁵~R⁷Definition as described in logical formula (I) compound.

The synthetic method of the present invention

In order to complete the synthesis purpose of the present invention, the present invention uses following synthetic technology scheme：

Compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures described in the logical formula (I) of the present invention, or its officinal salt preparation method, this method comprises the following steps：

Under condition of ice bath, formula (Ia) compound carries out condensation reaction with 2- cyanoacetic acids in the presence of condensing agent, obtains formula (Ib) compound；Formula (Ib) compound and formula (Ic) compound, are reacted under conditions of morpholine presence, obtain formula (Id) compound；Formula (Id) compound and sulphur, are carried out under conditions of morpholine presence Reaction, obtains formula (IA) compound；In the basic conditions, formula (IA) compound or its salt carries out condensation reaction with formula (IB) compound in the presence of condensing agent, optionally further hydrolyzes and/or be condensed to yield logical formula (I) compound；

Wherein：

Z is selected from hydroxyl or halogen；

R¹~R⁴, X, Y, m, n, ring A, ring B and ring C definition as described in formula (I).

In above-mentioned synthetic technology scheme, there is provided the reagent of alkalescence condition includes organic base and inorganic base, described organic bases include but is not limited to triethylamine, morpholine, N, N- diisopropylethylamine, pyridine, sodium hexamethyldisilazide, n-BuLi, potassium tert-butoxide or TBAB, described inorganic base includes but is not limited to lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium hydride, sodium carbonate, sodium acid carbonate, potassium carbonate, saleratus or cesium carbonate, preferably triethylamine.

Condensing agent includes but is not limited to 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides, N, N'- dicyclohexyl carbodiimides, N, N'- diisopropylcarbodiimides, O- BTAs-N, N, N', N'- tetramethylurea tetrafluoro boric acid esters, I-hydroxybenzotriazole, 1- hydroxyl -7- azo BTAs, O- BTAs-N, N, N', N'- tetramethylurea (TMU) hexafluorophosphoric acid esters, 2- (7- azos BTA)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid esters, (dimethylamino) the phosphorus hexafluorophosphate of BTA -1- bases epoxide three or hexafluorophosphoric acid BTA -1- bases-epoxide tripyrrole alkyl phosphorus.

Brief description of the drawings

Fig. 1:Three day averages that Npt2b influences on rat phosphuresis, ratio is reduction degree of convergence.

Embodiment

The present invention is further described with reference to embodiments, but these embodiments are not intended to limit the scope of the invention.

The experimental method of unreceipted actual conditions in the embodiment of the present invention, generally according to normal condition, or according to the condition proposed by raw material or commodity manufacturer.The unreceipted reagent specifically originated, is the conventional reagent of market purchase.

Embodiment

The structure of compound is determined by nuclear magnetic resonance (NMR) or mass spectrum (MS).NMR measure is to use Bruker AVANCE-400 nuclear magnetic resonance spectrometers, and measure solvent is deuterated dimethyl sulfoxide (DMSO-d₆), deuterochloroform (CDCl₃), deuterated methanol (CD₃OD), tetramethylsilane (TMS) is inside designated as, chemical shift is with 10^-6(ppm) provided as unit.

MS measure is with FINNIGAN LCQAd (ESI) mass spectrograph (manufacturer：Thermo, model：Finnigan LCQ advantage MAX).

HPLC measure uses Agilent 1200DAD high pressure liquid chromatographs (Sunfire C18150 × 4.6mm chromatographic columns) and Waters 2695-2996 high pressure liquid chromatographs (Gimini C18150 × 4.6mm chromatographic columns).

Kinases average inhibition and IC₅₀The measure of value is with NovoStar ELIASAs (German BMG companies).

Tlc silica gel plate uses Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica gel plates, the specification that the silica gel plate that thin-layered chromatography (TLC) is used is used is 0.15mm~0.2mm, and the specification that thin-layer chromatography isolates and purifies product use is 0.4mm~0.5mm silica gel plates.

Column chromatography is carrier typically using the mesh silica gel of the Yantai Huanghai Sea 200~300.

The known initiation material of the present invention can be used or synthesized according to methods known in the art, or it is commercially available from ABCR GmbH＆Co.KG, Acros Organnics, Aldrich Chemical Company, splendid remote chemistry scientific and technological (Accela ChemBio Inc), up to companies such as auspicious chemicals.

In embodiment unless otherwise specified, reaction is carried out under argon atmospher or blanket of nitrogen.

Argon atmospher or blanket of nitrogen refer to that reaction bulb connects the argon gas or nitrogen balloon of an about 1L volume.

Nitrogen atmosphere refers to that reaction bulb connects the hydrogen balloon of an about 1L volume.

Pressure hydration reaction uses Parr 3916EKX types hydrogenation instrument and clear indigo plant QL-500 types hydrogen generator or HC2-SS types hydrogenation instrument.

Hydrogenation is generally vacuumized, and is filled with hydrogen, is operated 3 times repeatedly.

Microwave reaction uses the type microwave reactors of CEM Discover-S 908860.

In embodiment unless otherwise specified, the solution in reaction refers to the aqueous solution.

In embodiment unless otherwise specified, the temperature of reaction is room temperature.

Room temperature is optimum reaction temperature, and temperature range is 20 DEG C~30 DEG C.

The monitoring of reaction process in embodiment uses thin-layered chromatography (TLC), there is the system of solvent used in reaction：A：Dichloromethane and methanol system, B：N-hexane and ethyl acetate system, C：Petroleum ether and ethyl acetate system, D：Acetone, the volume ratio of solvent is adjusted according to the polarity difference of compound.

The system of the eluant, eluent for the column chromatography that purifying compound is used and the system of the solvent of thin-layered chromatography include：A：Dichloromethane and methanol system, B：N-hexane and ethyl acetate system, C：N-hexane and acetone system, D：N-hexane, E：Ethyl acetate, the volume ratio of solvent is adjusted according to the polarity difference of compound, can also add a small amount of triethylamine and acid or alkaline reagent etc. and be adjusted.

Embodiment 1

4- (3- (4- (2- (3- (methyl (2- morpholines ethyl) carbamyl) benzamido) -4; 5; 6,7- tetrahydro benzos [b] thiophene -3- formamidos) phenyl) propyl group) benzoic acid

The first step

4- (3- (4- (2- (3- (methyl (2- morpholines ethyl) carbamyl) benzamido) -4; 5; 6,7- tetrahydro benzos [b] thiophene -3- formamidos) phenyl) propyl group) methyl benzoate

By 4- (3- (4- (2- amino -4, 5, 6, 7- tetrahydro benzos [b] thiophene -3- formamidos) phenyl) propyl group) methyl benzoate 1a (149mg, 0.33mmol, it is prepared using method disclosed in patent application " WO2011136269 ") it is dissolved in 5mL dichloromethane, add triethylamine (101mg, 1mmol), then 5mL 3- (methyl (2- morpholines ethyl) carbamyl) chlorobenzoyl chloride 1b (124mg are added, 0.40mmol, be prepared using method disclosed in patent application " WO2012006477 ") dichloromethane solution, stirring reaction 3 hours.Add 20mL water, extracted with dichloromethane (50mL × 3), merge organic phase, water (50mL × 1) is used successively, saturated nacl aqueous solution (50mL × 1) is washed, anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, obtain crude title product 4- (3- (4- (2- (3- (methyl (2- morpholines ethyl) carbamyl) benzamido) -4, 5, 6, 7- tetrahydro benzos [b] thiophene -3- formamidos) phenyl) propyl group) methyl benzoate 1c (238mg, yellow solid), product is not purified directly to carry out next step reaction.

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)

Second step

4- (3- (4- (2- (3- (methyl (2- morpholines ethyl) carbamyl) benzamido) -4; 5; 6,7- tetrahydro benzos [b] thiophene -3- formamidos) phenyl) propyl group) benzoic acid

By crude product 4- (3- (4- (2- (3- (methyl (2- morpholines ethyl) carbamyl) benzamido) -4; 5; 6; 7- tetrahydro benzos [b] thiophene -3- formamidos) phenyl) propyl group) methyl benzoate 1c (238mg; 0.33mmol) it is dissolved in 10mL tetrahydrofurans; add 3mL 2M sodium hydroxide solutions, stirring reaction 2 hours.30mL water is added, is used N-hexane and ethyl acetate (V:V=1:1) mixed solution extraction (20mL × 2), merges aqueous phase, and it is 2~3 that 2M hydrochloric acid, which is added dropwise, to aqueous phase pH, and solid is separated out.Filtering; filter cake is dried; with HPLC preparative separation methods purify gained residue; obtain title product 4- (3- (4- (2- (3- (methyl (2- morpholines ethyl) carbamyl) benzamido) -4; 5,6,7- tetrahydro benzos [b] thiophene -3- formamidos) phenyl) propyl group) 1 (160mg of benzoic acid; white solid), yield：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)

Embodiment 2

4- (4- (2- (3- (3- methyl -3- (2- morpholines ethyl) urea groups) benzamido) -4,5,6,7- tetrahydro benzos [b] thiophene -3- formamidos) phenethyl) benzoic acid

The first step

3- (3- methyl -3- (2- morpholines ethyl) urea groups) chlorobenzoyl chloride

By 3- (3- methyl -3- (2- morpholines ethyl) urea groups) benzoic acid 2a (150mg, 0.50mmol, it is prepared using method disclosed in patent application " WO2012054110 ") it is dissolved in 60mL dichloromethane, it is cooled to 0 DEG C, add thionyl chloride (177mg, 1.50mmol), backflow, stirring reaction 2 hours are warming up to.Reaction solution is concentrated under reduced pressure, and obtains crude title product 3- (3- methyl -3- (2- morpholines ethyl) urea groups) chlorobenzoyl chloride 2b (163mg, white solid), and product is not purified directly to carry out next step reaction.

Second step

4- (4- (2- (3- (3- methyl -3- (2- morpholines ethyl) urea groups) benzamido) -4,5,6,7- tetrahydro benzos [b] thiophene -3- formamidos) phenethyl) methyl benzoate

By 4- (4- (2- amino -4,5,6,7- tetrahydro benzos [b] thiophene -3- formamidos) phenethyl) methyl benzoate 2c (144mg, 0.33mmol, it is prepared using method disclosed in patent application " WO2011136269 ") it is dissolved in 5mL chloroforms, add triethylamine (101mg, 1mmol), 0 DEG C is cooled to, crude product 3- (3- methyl -3- (2- morpholines ethyl) urea groups) chlorobenzoyl chloride 2b (163mg, 0.50mmol) dichloromethane solution is added, it is warmed to room temperature, stirring reaction 12 hours.Add 50mL water, extracted with dichloromethane (50mL × 3), merge organic phase, water (50mL × 1) is used successively, saturated nacl aqueous solution (50mL × 1) is washed, anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product 4- (4- (2- (3- (3- methyl -3- (2- morpholines ethyl) urea groups) benzamido) -4, 5, 6, 7- tetrahydro benzos [b] thiophene -3- formamidos) phenethyl) methyl benzoate 2d (136mg, faint yellow solid), yield：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)

3rd step

4- (4- (2- (3- (3- methyl -3- (2- morpholines ethyl) urea groups) benzamido) -4,5,6,7- tetrahydro benzos [b] thiophene -3- formamidos) phenethyl) benzoic acid

By 4- (4- (2- (3- (3- methyl -3- (2- morpholines ethyl) urea groups) benzamido) -4,5,6,7- tetrahydro benzos [b] thiophene -3- formamidos) phenethyl) methyl benzoate 2d (136mg, 0.19mmol) is dissolved in 4.5mL tetrahydrofurans and ethanol (V:V=2:1) in mixed solution, 1.1mL 2M sodium hydroxide solutions is added, 25 DEG C, stirring reaction 12 hours are warming up to.Reaction solution is concentrated under reduced pressure, with HPLC preparative separation methods purify gained residue, obtain title product 4- (4- (2- (3- (3- methyl -3- (2- morpholines ethyl) urea groups) benzamido) -4,5,6,7- tetrahydro benzos [b] thiophene -3- formamidos) phenethyl) benzoic acid 2 (15mg, white solid), yield：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)

Embodiment 3

4- (3- (4- (2- (3- (methyl (2- morpholines ethyl) carbamyl) benzamido) -6- ((tetrahydrochysene -2H- pyrans -4- bases) methyl) -4; 5; 6; 7- thiophanes simultaneously [2,3-c] pyridine-3-carboxamide base) phenyl) propyl group) benzoic acid

The first step

2- amino -3- (4- (3- (4- (methoxycarbonyl) phenyl) propyl group) anilinocarbonyl) -4,5- dihydro-thiophenes simultaneously [2,3-c] pyridine -6 (7H)-t-butyl formate

By sulphur (71mg, 2.23mmol) it is dissolved in 20mL ethanol, sequentially add 4- (3- (4- (2- cyano-acetamides amido) phenyl) propyl group) methyl benzoate 3a (750mg, 2.23mmol, it is prepared using method disclosed in patent application " WO2013062065 "), 4- carbonyl piperidines -1- t-butyl formates (443mg, 4.97mmol) with morpholine (213mg, 2.45mmol), it is heated to 90 DEG C, stirring reaction 12 hours.Add 60mL saturated nacl aqueous solutions, it is extracted with ethyl acetate (50mL × 3), merge organic phase, washed with saturated nacl aqueous solution (50mL × 1), anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product 2- amino -3- (4- (3- (4- (methoxycarbonyl) phenyl) propyl group) anilinocarbonyl) -4,5- dihydro-thiophenes simultaneously [2,3-c] pyridine -6 (7H)-t-butyl formate 3b (600mg, yellow solid), yield： 49.0%.

MS m/z(ESI):550.2[M+1]

Second step

3- (4- (3- (4- (methoxycarbonyl) phenyl) propyl group) anilinocarbonyl) -2- (3- (methyl (2- morpholines ethyl) carbamyl) benzamido) -4; 5- dihydro-thiophenes simultaneously [2,3-c] pyridine -6 (7H)-t-butyl formate

By 3- (methyl (2- morpholines ethyl) carbamyl) benzoic acid 3c (85mg, 0.30mmol, it is prepared using method disclosed in patent application " WO2012006477 ") and 2- amino -3- (4- (3- (4- (methoxycarbonyl) phenyl) propyl group) anilinocarbonyl) -4, 5- dihydro-thiophenes simultaneously [2, 3-c] pyridine -6 (7H)-t-butyl formate 3b (100mg, 0.18mmol) it is dissolved in 10mL dichloromethane, sequentially add 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (52mg, 0.27mmol) with DMAP (33mg, 0.27mmol), stirring reaction 24 hours.Add 50mL water, it is extracted with ethyl acetate (50mL × 3), merge organic phase, washed with saturated nacl aqueous solution (50mL × 1), anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product 3- (4- (3- (4- (methoxycarbonyl) phenyl) propyl group) anilinocarbonyl) -2- (3- (methyl (2- morpholines ethyl) carbamyl) benzamido) -4, 5- dihydro-thiophenes simultaneously [2, 3-c] pyridine -6 (7H)-t-butyl formate 3d (50mg, yellow solid), yield：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)

3rd step

4- (3- (4- (2- (3- (methyl (2- morpholines ethyl) carbamyl) benzamido) -4; 5; 6,7- thiophanes simultaneously [2,3-c] pyridine-3-carboxamide base) phenyl) propyl group) methyl benzoate

By 3- (4- (3- (4- (methoxycarbonyl) phenyl) propyl group) anilinocarbonyl) -2- (3- (methyl (2- morpholines ethyl) carbamyl) benzamido) -4; 5- dihydro-thiophenes simultaneously [2; 3-c] pyridine -6 (7H)-t-butyl formate 3d (100mg; 0.10mmol) it is dissolved in 3mL dichloromethane; it is cooled to 0 DEG C; add 0.5mL trifluoroacetic acids, stirring reaction 30 minutes.Be added dropwise saturated sodium carbonate to reaction solution pH be 9~10, extracted with dichloromethane (50mL × 3), merge organic phase, washed with saturated nacl aqueous solution (50mL × 1), anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, obtain crude title product 4- (3- (4- (2- (3- (methyl (2- morpholines ethyl) carbamyl) benzamido) -4, 5, 6, 7- thiophanes simultaneously [2, 3-c] pyridine-3-carboxamide base) phenyl) propyl group) methyl benzoate 3e (50mg, yellow solid), product is not purified to be directly entered next step reaction.

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)

4th step

4- (3- (4- (2- (3- (methyl (2- morpholines ethyl) carbamyl) benzamido) -6- ((tetrahydrochysene -2H- pyrans -4- bases) methyl) -4; 5; 6; 7- thiophanes simultaneously [2,3-c] pyridine-3-carboxamide base) phenyl) propyl group) methyl benzoate

By crude product 4- (3- (4- (2- (3- (methyl (2- morpholines ethyl) carbamyl) benzamido) -4, 5, 6, 7- thiophanes simultaneously [2, 3-c] pyridine-3-carboxamide base) phenyl) propyl group) methyl benzoate 3e (100mg, 0.14mmol) it is dissolved in 5mLN, in dinethylformamide, sequentially add potassium carbonate (57mg, 0.41mmol) with 4- toluene sulfonic acides (tetrahydrochysene -2H- pyrans -4- bases) methyl ester (56mg, 0.21mmol, using known method document " Bioorganic＆Medicinal Chemistry Letters, 21 (8), 2541-2546 " is prepared), it is heated to 70 DEG C, stirring reaction 12 hours.Add 30mL water, it is extracted with ethyl acetate (30mL × 3), merge organic phase, washed with saturated nacl aqueous solution (30mL × 1), anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product 4- (3- (4- (2- (3- (methyl (2- morpholines ethyl) carbamyl) benzamido) -6- ((tetrahydrochysene -2H- pyrans -4- bases) methyl) -4, 5, 6, 7- thiophanes simultaneously [2, 3-c] pyridine-3-carboxamide base) phenyl) propyl group) methyl benzoate 3f (31mg, faint yellow solid), yield：27.4%.

MS m/z(ESI):822.4[M+1]

5th step

4- (3- (4- (2- (3- (methyl (2- morpholines ethyl) carbamyl) benzamido) -6- ((tetrahydrochysene -2H- pyrans -4- bases) methyl) -4; 5; 6; 7- thiophanes simultaneously [2,3-c] pyridine-3-carboxamide base) phenyl) propyl group) benzoic acid

By 4- (3- (4- (2- (3- (methyl (2- morpholines ethyl) carbamyl) benzamido) -6- ((tetrahydrochysene -2H- pyrans -4- bases) methyl) -4; 5; 6; 7- thiophanes simultaneously [2; 3-c] pyridine-3-carboxamide base) phenyl) propyl group) methyl benzoate 3f (31mg; 0.04mmol) it is dissolved in 5mL methanol; add 5mL 2M sodium hydroxide solutions; it is warming up to 50 DEG C, stirring reaction 1 hour.It is 2~3 that 3M hydrochloric acid, which is added dropwise, to aqueous phase pH, and solid is separated out.Filtering; filter cake is dried; with HPLC preparative separation methods purify gained residue; obtain title product 4- (3- (4- (2- (3- (methyl (2- morpholines ethyl) carbamyl) benzamido) -6- ((tetrahydrochysene -2H- pyrans -4- bases) methyl) -4; 5; 6; 7- thiophanes simultaneously [2; 3-c] pyridine-3-carboxamide base) phenyl) propyl group) 3 (20mg of benzoic acid; white solid), yield：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)

Embodiment 4

4- (4- (2- (3- (methyl (2- (4- methylpiperazine-1-yls) ethyl) carbamyl) benzamido) -4; 5; 6,7- tetrahydro benzos [b] thiophene -3- formamidos) phenethyl) benzoic acid

The first step

3- (methyl (2- (4- methylpiperazine-1-yls) ethyl) carbamyl) methyl benzoate

By N- methyl -2- (4- methylpiperazine-1-yls) ethamine 4b (1.73g; 11.01mmol; it is prepared using method disclosed in patent application " WO2013014448 ") it is dissolved in 35mL dichloromethane; add triethylamine (2.22g; 22.02mmol); it is cooled to 0 DEG C; add 5mL3- (chloroformyl) methyl benzoate 4a (56mg; 0.21mmol; using known method document " Journal of the American Chemical Society; 135 (45), 16841-16844；2013 " are prepared) dichloromethane solution, be warmed to room temperature, stirring reaction 2 hours.Reaction solution is concentrated under reduced pressure; with silica gel column chromatography with eluant, eluent system A purify gained residue; obtain title product 3- (methyl (2- (4- methylpiperazine-1-yls) ethyl) carbamyl) methyl benzoate 4c (2.40g; brown oil liquid), yield：75%.

MS m/z(ESI):320.3[M+1]

Second step

3- (methyl (2- (4- methylpiperazine-1-yls) ethyl) carbamyl) benzoic acid

By 3- (methyl (2- (4- methylpiperazine-1-yls) ethyl) carbamyl) methyl benzoate 4c (530mg; 1.66mmol); lithium hydroxide (209mg, 4.98mmol) is dissolved in 14mL tetrahydrofurans, water and methanol (V:V:V=5:4:5) in the mixed solvent, stirring reaction 1 hour.Reaction solution is concentrated under reduced pressure; with silica gel chromatograph preparative separation method purify gained residue; obtain title product 3- (methyl (2- (4- methylpiperazine-1-yls) ethyl) carbamyl) benzoic acid 4d (507mg, white solid), yield：100%.

MS m/z(ESI):306.2[M+1]

3rd step

4- (4- (2- (3- (methyl (2- (4- methylpiperazine-1-yls) ethyl) carbamyl) benzamido) -4; 5; 6,7- tetrahydro benzos [b] thiophene -3- formamidos) phenethyl) methyl benzoate

By 4- (4- (2- amino -4, 5, 6, 7- tetrahydro benzos [b] thiophene -3- formamidos) phenethyl) methyl benzoate 2c (70mg, 0.16mmol), 3- (methyl (2- (4- methylpiperazine-1-yls) ethyl) carbamyl) benzoic acid 4d (98mg, 0.32mmol), 2- (7- azos BTA)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid esters (122mg, 0.32mmol) and N, N- diisopropylethylamine (80 μ L, 0.48mmol) it is dissolved in 5mL dimethylformamides, it is warming up to 50 DEG C, stirring reaction 12 hours.Add 10mL saturated sodium bicarbonate solutions, extracted with dichloromethane (30mL × 3), merge organic phase, water (50mL × 1) is used successively, saturated nacl aqueous solution (50mL × 1) is washed, anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product 4- (4- (2- (3- (methyl (2- (4- methylpiperazine-1-yls) ethyl) carbamyl) benzamido) -4, 5, 6, 7- tetrahydro benzos [b] thiophene -3- formamidos) phenethyl) methyl benzoate 4e (71mg, yellow solid), yield：30.6%.MS m/z(ESI):722.4[M+1]

4th step

4- (4- (2- (3- (methyl (2- (4- methylpiperazine-1-yls) ethyl) carbamyl) benzamido) -4; 5; 6,7- tetrahydro benzos [b] thiophene -3- formamidos) phenethyl) benzoic acid

By 4- (4- (2- (3- (methyl (2- (4- methylpiperazine-1-yls) ethyl) carbamyl) benzamido) -4; 5; 6; 7- tetrahydro benzos [b] thiophene -3- formamidos) phenethyl) methyl benzoate 4e (71mg; 0.098mmol) it is dissolved in 5mL methanol; 1mL 2M sodium hydroxide solutions are added, 50 DEG C, stirring reaction 1 hour are warming up to.Reaction solution is concentrated under reduced pressure, and it is 2~3 that 3M hydrochloric acid, which is added dropwise, to aqueous phase pH, and solid is separated out.Filtering; filter cake is dried; with HPLC preparative separation methods purify gained residue; obtain title product 4- (4- (2- (3- (methyl (2- (4- methylpiperazine-1-yls) ethyl) carbamyl) benzamido) -4; 5,6,7- tetrahydro benzos [b] thiophene -3- formamidos) phenethyl) 4 (9mg of benzoic acid; faint yellow solid), yield：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)

Embodiment 5

4- (3- (4- (2- (3- (methyl (2- morpholines ethyl) carbamyl) benzamido) -6- ((1; 1; the fluoro- 2- methyl-propyls -2- bases oxos of 1- tri-) carbonyl) -4; 5; 6; 7- thiophanes simultaneously [2,3-c] pyridine-3-carboxamide base) phenyl) propyl group) benzoic acid

The first step

4- (3- (4- (2- (3- (methyl (2- morpholines ethyl) carbamyl) benzamido) -6- ((1; 1; the fluoro- 2- methyl-propyls -2- bases oxos of 1- tri-) carbonyl) -4; 5; 6; 7- thiophanes simultaneously [2,3-c] pyridine-3-carboxamide base) phenyl) propyl group) methyl benzoate

By 4- (3- (4- (2- (3- (methyl (2- morpholines ethyl) carbamyl) benzamido) -4, 5, 6, 7- thiophanes simultaneously [2, 3-c] pyridine-3-carboxamide base) phenyl) propyl group) methyl benzoate 3e (50mg, 0.07mmol) it is dissolved in 5mL chloroforms, it is cooled to 0 DEG C, sequentially add triethylamine (14mg, 0.14mmol) with 1mL 3- methyl isophthalic acids-((1, 1, the fluoro- 2- methyl-propyls -2- bases oxos of 1- tri-) carbonyl) -1H- iodonium imidazolide salts 5a (25mg, 0.07mmol, be prepared using method disclosed in patent application " WO2011142359 ") chloroform soln, it is warmed to room temperature, stirring reaction 1 hour.Add 50mL water, extracted with dichloromethane (50mL × 3), merge organic phase, washed with saturated nacl aqueous solution (30mL × 1), anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product 4- (3- (4- (2- (3- (methyl (2- morpholines ethyl) carbamyl) benzamido) -6- ((1, 1, the fluoro- 2- methyl-propyls -2- bases oxos of 1- tri-) carbonyl) -4, 5, 6, 7- thiophanes simultaneously [2, 3-c] pyridine-3-carboxamide base) phenyl) propyl group) methyl benzoate 5b (40mg, yellow oily liquid), yield：66.1%.

MS m/z(ESI):878.4[M+1]

Second step

4- (3- (4- (2- (3- (methyl (2- morpholines ethyl) carbamyl) benzamido) -6- ((1; 1; the fluoro- 2- methyl-propyls -2- bases oxos of 1- tri-) carbonyl) -4; 5; 6; 7- thiophanes simultaneously [2,3-c] pyridine-3-carboxamide base) phenyl) propyl group) benzoic acid

By 4- (3- (4- (2- (3- (methyl (2- morpholines ethyl) carbamyl) benzamido) -6- ((fluoro- 2- first of 1,1,1- tri- Base propyl group -2- bases oxo) carbonyl) -4,5,6,7- thiophanes simultaneously [2,3-c] pyridine-3-carboxamide base) phenyl) propyl group) methyl benzoate 5b (40mg, 0.65mmol) is dissolved in 3mL tetrahydrofurans and methanol (V:V=2:1) in mixed solution, 1mL 1M sodium hydroxide solutions is added, 30 DEG C, stirring reaction 4 hours are warming up to.Reaction solution is concentrated under reduced pressure, and it is 6 that 1M hydrochloric acid, which is added dropwise, to reaction solution pH, and solid is separated out.Filtering; filtrate decompression is concentrated; with HPLC preparative separation methods purify gained residue; obtain title product 4- (3- (4- (2- (3- (methyl (2- morpholines ethyl) carbamyl) benzamido) -6- ((1; 1; the fluoro- 2- methyl-propyls -2- bases oxos of 1- tri-) carbonyl) -4; 5; 6; 7- thiophanes simultaneously [2; 3-c] pyridine-3-carboxamide base) phenyl) propyl group) benzoic acid 5 (6mg, white solid), yield：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)

Embodiment 6

N¹- (3- (4- (4- (1,3- dihydroxy -2- (hydroxymethyl) propyl group -2- bases carbamoyl) phenethyl) phenylcarbamoyl) -4,5,6,7- tetrahydro benzos [b] thiophene -2- bases)-N³- methyl-N³- (2- morpholines ethyl) isophtalamide

The first step

4- (4- (2- (3- (methyl (2- morpholines ethyl) carbamoyl) benzamido) -4,5,6,7- tetrahydro benzos [b] thiophene -3- formamidos) phenethyl) methyl benzoate

By 3- (methyl (2- morpholines ethyl) carbamyl) benzoic acid 3c (315mg; 1.08mmol) with 4- (4- (2- amino -4; 5; 6; 7- tetrahydro benzos [b] thiophene -3- formamidos) phenethyl) methyl benzoate 2c (360mg; 0.83mmol); 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (255mg; 1.33mmol) with DMAP (162mg; 1.33mmol) be dissolved in 5mL dimethylformamides, stirring reaction 24 hours.Add 50mL water; extracted with dichloromethane (20mL × 3); merge organic phase; washed with saturated nacl aqueous solution (50mL × 1); anhydrous sodium sulfate drying; filtering; filtrate decompression is concentrated; with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product 4- (4- (2- (3- (methyl (2- morpholines ethyl) carbamoyl) benzamido) -4,5; 6; 7- tetrahydro benzos [b] thiophene -3- formamidos) phenethyl) methyl benzoate 6a (400mg, yellow solid), yield：68.1%.

MS m/z(ESI):709.3[M+1]

Second step

4- (4- (2- (3- (methyl (2- morpholines ethyl) carbamoyl) benzamido) -4,5,6,7- tetrahydro benzos [b] thiophene -3- formamidos) phenethyl) benzoic acid

By 4- (4- (2- (3- (methyl (2- morpholines ethyl) carbamoyl) benzamido) -4; 5; 6; 7- tetrahydro benzos [b] thiophene -3- formamidos) phenethyl) methyl benzoate 6a (400mg, 0.56mmol) is dissolved in 9mL tetrahydrofurans and methanol (V:V=2:1) in mixed solution, 2.3mL 1M sodium hydroxide solutions is added, 30 DEG C, stirring reaction 12 hours are warming up to.Reaction solution is concentrated under reduced pressure, add 10mL water, be added dropwise 1M hydrochloric acid to reaction solution pH be 6~7, extracted with dichloromethane (20mL × 3), merge organic phase, washed with saturated nacl aqueous solution (50mL × 1), anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, obtain crude title product 4- (4- (2- (3- (methyl (2- morpholines ethyl) carbamoyl) benzamido) -4, 5, 6, 7- tetrahydro benzos [b] thiophene -3- formamidos) phenethyl) benzoic acid 6b (352mg, yellow solid), product is not purified directly to carry out next step reaction.

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)

3rd step

N¹- (3- (4- (4- (1,3- dihydroxy -2- (hydroxymethyl) propyl group -2- bases carbamoyl) phenethyl) phenylcarbamoyl) -4,5,6,7- tetrahydro benzos [b] thiophene -2- bases)-N³- methyl-N³- (2- morpholines ethyl) isophtalamide

By crude product 4- (4- (2- (3- (methyl (2- morpholines ethyl) carbamoyl) benzamido) -4; 5; 6; 7- tetrahydro benzos [b] thiophene -3- formamidos) phenethyl) benzoic acid 6b (170mg; 0.25mmol) with 2- amino -2- (hydroxymethyl) propane -1; 3- glycol (60mg; 0.49mmol) it is dissolved in 5mL dimethylformamides; sequentially add 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (94mg; 0.49mmol); I-hydroxybenzotriazole (67mg 0.49mmol) with DIPEA (64mg, 0.49mmol), stirring reaction 12 hours.Reaction solution is concentrated under reduced pressure, with HPLC preparative separation methods purify gained residue, obtain title product N¹- (3- (4- (4- (1,3- dihydroxy -2- (hydroxymethyl) propyl group -2- bases carbamoyl) phenethyl) phenylcarbamoyl) -4,5,6,7- tetrahydro benzos [b] thiophene -2- bases)-N³- methyl-N³- (2- morpholines ethyl) isophtalamide 6 (110mg, faint yellow solid), yield：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)

Embodiment 7

N¹- methyl-N¹- (2- morpholines ethyl)-N³- (3- (4- phenethyls phenylcarbamoyl) -4,5,6,7- tetrahydro benzos [b] thiophene -2- bases) isophtalamide

The first step

2- cyano group-N- (4- phenethyls phenyl) acetamide

By 4- phenethyl aniline 7a (2.15g, 10.91mmol, using known method document " Journal of Medicinal Chemistry, 56 (5), 2139-2149；2013 " are prepared) and 2- cyanoacetic acids (1.39g; 16.37mmol) be dissolved in 5mL dimethylformamides; be cooled to 0 DEG C; add 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (3.14g; 16.37mmol); be warmed to room temperature, stirring reaction 2 hours.10mL water is added, is stirred 30 minutes, solid is separated out, filtering, filter cake drying obtains crude title product 2- cyano group-N- (4- phenethyls phenyl) acetamide 7b (2.68g, white solid), and product is not purified directly to carry out next step reaction.

MS m/z(ESI):263.3[M-1]

Second step

2- cyano group -2- cyclohexylidenes-N- (4- phenethyls phenyl) acetamide

By crude product 2- cyano group-N- (4- phenethyls phenyl) acetamide 7b (2.68g, 10.13mmol) with cyclohexanone (2.88g, 29.38mmol) it is dissolved in 6mL toluene, add morpholine (900mg, 10.33mmol), it is warming up to 120 DEG C, stirring reaction 2 hours.Reaction solution is concentrated under reduced pressure, and with ether and petroleum ether mashing purifying gained residue, obtains title product 2- cyano group -2- cyclohexylidenes-N- (4- phenethyls phenyl) acetamide 7c (2.52g, brown solid), yield：72.2%.

MS m/z(ESI):345.2[M+1]

3rd step

2- amino-N- (4- phenethyls phenyl) -4,5,6,7- tetrahydro benzos [b] thiophene -3- formamides

By 2- cyano group -2- cyclohexylidenes-N- (4- phenethyls phenyl) acetamide 7c (2.52g, 7.32mmol) with sulphur (246mg, 7.68mmol) it is dissolved in 10mL dimethylformamides, add morpholine (670mg, 7.68mmol), it is warming up to 50 DEG C, stirring reaction 2 hours.50mL saturated nacl aqueous solutions are added, are extracted with ethyl acetate (20mL × 3), merge organic phase, washed (50mL × 1), anhydrous sodium sulfate drying, filtered with saturated nacl aqueous solution, filtrate decompression is concentrated, with isopropanol mashing purifying gained residue, title product 2- amino-N- (4- phenethyls phenyl) -4,5 is obtained, 6,7- tetrahydro benzos [b] thiophene -3- formamides 7d (1.69g, yellow solid), yield：61.2%.

MS m/z(ESI):377.2[M+1]

4th step

N¹- methyl-N¹- (2- morpholines ethyl)-N³- (3- (4- phenethyls phenylcarbamoyl) -4,5,6,7- tetrahydro benzos [b] thiophene -2- bases) isophtalamide

By 2- amino-N- (4- phenethyls phenyl) -4; 5; 6; 7- tetrahydro benzos [b] thiophene -3- formamide 7d (200mg; 0.53mmol) with 3- (methyl (2- morpholines ethyl) carbamyl) benzoic acid 3c (292mg; 1mmol); 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (153mg; 0.80mmol) with DMAP (97mg; 0.80mmol) it is dissolved in 5mL dimethylformamides; it is warming up to 30 DEG C, stirring reaction 12 hours.Add 30mL water, it is extracted with ethyl acetate (30mL × 3), merge organic phase, washed with saturated nacl aqueous solution (50mL × 1), anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product N¹- methyl-N¹- (2- morpholines ethyl)-N³- (3- (4- phenethyls phenylcarbamoyl) -4,5,6,7- tetrahydro benzos [b] thiophene -2- bases) isophtalamide 7 (174mg, yellow solid), yield：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)

Embodiment 8

N¹- (6,6- dimethyl -3- (3- methyl -4- phenethyls phenylcarbamoyl) -4,5,6,7- tetrahydro benzos [b] thiophene -2- bases)-N³- methyl-N³- (2- morpholines ethyl) isophtalamide

The first step

3- methyl -4- phenethyl aniline

By (E) -2- methyl -4- nitro -1- styryl benzene 8a (40mg, 0.28mmol, using known method document " Journal of Physical Chemistry A, 113 (17), 4868-4877；2009 " are prepared) it is dissolved in 75.4mL methanol and dichloromethane (V:V=2:1) in the mixed solvent, adds palladium/carbon (280mg, 20%), replacing hydrogen three times, stirring reaction 3 hours.Filtering, wash filter cake with dichloromethane, filtrate decompression concentration, with silica gel column chromatography with eluant, eluent system A purify obtained by residue, obtain title product 3- methyl -4- phenethyl aniline 8b (1.20g, pale yellow oil), yield：97.6%.

MS m/z(ESI):212.3[M+1]

Second step

2- cyano group-N- (3- methyl -4- phenethyls phenyl) acetamide

By 3- methyl -4- phenethyl aniline 8b (1.20g, 5.68mmol) with cyanoacetic acid (722mg, 8.50mmol) it is dissolved in 10mL dimethylformamides, it is cooled to 0 DEG C, add 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (1.62g, 8.50mmol), it is warmed to room temperature, stirring reaction 1 hour.30mL frozen water is added, rear to add 50mL water, filtering, filter cake drying obtains crude title product 2- cyano group-N- (3- methyl -4- phenethyls phenyl) acetamide 8c (1.39g, white solid), yield：88.0%.

MS m/z(ESI):279.2[M+1]

3rd step

2- cyano group -2- (4,4- dimethylcyclohexy-lenes)-N- (3- methyl -4- phenethyls phenyl) acetamide

By crude product 2- cyano group-N- (3- methyl -4- phenethyls phenyl) acetamide 8c (700mg, 2.52mmol), 4,4- dimethylcyclohexanons (921mg, 7.29mmol) with morpholine (224mg, 2.57mmol) it is dissolved in 12mL toluene, is warming up to 120 DEG C, stirring reaction 3 hours.Reaction solution is concentrated under reduced pressure, with silica gel column chromatography to elute Agent system A purifying gained residues, obtain title product 2- cyano group -2- (4,4- dimethylcyclohexy-lene)-N- (3- methyl -4- phenethyls phenyl) acetamide 8d (852mg, pale yellow oil), yield：87.6%.

MS m/z(ESI):385.5[M-1]

4th step

2- amino -6,6- dimethyl-N -s (3- methyl -4- phenethyls phenyl) -4,5,6,7- tetrahydro benzos [b] thiophene -3- formamides

By 2- cyano group -2- (4,4- dimethylcyclohexy-lenes)-N- (3- methyl -4- phenethyls phenyl) acetamide 8d (853mg, 2.20mmol), sulphur (75mg, 2.31mmol) with morpholine (202mg, 2.31mmol) it is dissolved in 8mL dimethylformamides, is warming up to 50 DEG C, stirring reaction 12 hours.Add 50mL water, extracted with dichloromethane (50mL × 3), merge organic phase, washed with saturated nacl aqueous solution (50mL × 1), anhydrous sodium sulfate drying, filtering, filtrate decompression concentrate, with silica gel column chromatography with eluant, eluent system A purify obtained by residue, obtain title product 2- amino -6,6- dimethyl-N -s (3- methyl -4- phenethyls phenyl) -4,5,6,7- tetrahydro benzos [b] thiophene -3- formamide 8e (720mg, pink solid), yield：78.2%.

MS m/z(ESI):417.5[M-1]

5th step

N¹- (6,6- dimethyl -3- (3- methyl -4- phenethyls phenylcarbamoyl) -4,5,6,7- tetrahydro benzos [b] thiophene -2- bases)-N³- methyl-N³- (2- morpholines ethyl) isophtalamide

By 2- amino -6; 6- dimethyl-N -s (3- methyl -4- phenethyls phenyl) -4; 5; 6; 7- tetrahydro benzos [b] thiophene -3- formamide 8e (419mg; 1mmol) with 3- (methyl (2- morpholines ethyl) carbamyl) benzoic acid 3c (381mg; 1.30mmol) it is dissolved in 8mL dimethylformamides; add 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (307mg; 1.60mmol) with DMAP (196mg; 1.60mmol), stirring reaction 12 hours.Pour into 30mL water, filter, filter cake drying, with silica gel column chromatography with eluant, eluent system A purify obtained by residue, obtain title product N¹- (6,6- dimethyl -3- (3- methyl -4- phenethyls phenylcarbamoyl) -4,5,6,7- tetrahydro benzos [b] thiophene -2- bases)-N³- methyl-N³- (2- morpholines ethyl) isophtalamide 8 (520mg, yellow solid), yield：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)

Embodiment 9

N¹- (3- (4- (3- (4- (two (2- hydroxyethyls) carbamyls) phenyl) propyl group) phenylcarbamoyl) -4,5,6,7- tetrahydro benzos [b] thiophene -2- bases)-N³- methyl-N³- (2- morpholines ethyl) isophtalamide

By 4- (3- (4- (2- (3- (methyl (2- morpholines ethyl) carbamyl) benzamido) -4, 5, 6, 7- tetrahydro benzos [b] thiophene -3- formamidos) phenyl) propyl group) 1 (250mg of benzoic acid, 0.35mmol) with 2, 2 '-diethanol amine (75mg, 0.71mmol), 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (136mg, 0.71mmol), I-hydroxybenzotriazole (96mg, 0.71mmol) and N, N- diisopropylethylamine (92mg, 0.71mmol) it is dissolved in 5mL dimethylformamides, it is warming up to 25 DEG C, stirring reaction 12 hours.Reaction solution is poured into 20mL frozen water, extracted with dichloromethane (30mL × 3), merge organic phase, washed with saturated nacl aqueous solution (50mL × 1), anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product N¹- (3- (4- (3- (4- (two (2- hydroxyethyls) carbamyls) phenyl) propyl group) phenylcarbamoyl) -4,5,6,7- tetrahydro benzos [b] thiophene -2- bases)-N³- methyl-N³- (2- morpholines ethyl) isophtalamide 9 (120mg, yellow solid), yield：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)

Embodiment 10

4- (2- methyl -4- (2- (3- (methyl (2- morpholines ethyl) carbamyl) benzamido) -4,5,6,7- tetrahydro benzos [b] thiophene -3- formamidos) phenethyl) benzoic acid

The first step

2- methyl -4- nitrobenzylphosphonic acid diethylesters

By 1- (bromomethyl) -2- methyl -4- nitrobenzene 10a (2g, 8.69mmol, using known method document " Journal of Physical Chemistry, 90 (1), 168-73；1986 " are prepared) and triethyl phosphite (2.04g, 12.26mmol) add bottle in, be warming up to 160 DEG C, stirring reaction 2 hours.Reaction solution is concentrated under reduced pressure, and obtains crude title product 2- methyl -4- nitrobenzylphosphonic acid diethylesters 10b (2.50g, dark brown liquid), the not purified direct carry out next step of product.

Second step

4- (2- methyl -4- nitrostyrolenes base) methyl benzoate

By crude product 2- methyl -4- nitrobenzylphosphonic acid diethylester 10b (2.50g; 8.69mmol) it is dissolved in 20mL methanol; it is cooled to 0 DEG C; 50% sodium methoxide (939mg, 17.38mmol) methanol solution, stirring reaction 30 minutes is added dropwise; add 10mL 4- acyl radical methyl benzoates (1.44g; methanol solution 8.78mmol), is warmed to room temperature, stirring reaction 12 hours.Filtering, filtrate decompression concentration, obtains crude title product 4- (2- methyl -4- nitrostyrolenes base) methyl benzoate 10c (1.83g, yellow solid), the not purified direct carry out next step of product.

3rd step

4- (2- methyl -4- aminophenethyls) methyl benzoate

Crude product 4- (2- methyl -4- nitrostyrolenes base) methyl benzoate 10c (1.83g, 6.16mmol) is dissolved in 100.5mL first alcohol and waters (V:V=100:0.5) in the mixed solvent, adds palladium/carbon (366mg, 10%), replacing hydrogen three times, stirring reaction 24 hours.Filtering, filtrate decompression concentration, obtains crude title product 4- (2- methyl -4- aminophenethyls) methyl benzoate 10d (1.41g, yellow solid), the not purified direct carry out next step of product.MS m/z(ESI):270.2[M+1]

4th step

4- (4- (2- cyano-acetamides amido) -2- methylphenethyls) methyl benzoate

By crude product 4- (2- methyl -4- aminophenethyls) methyl benzoate 10d (1.41g, 5.25mmol) with cyanoacetic acid (670mg, 7.87mmol) it is dissolved in 20mL dimethylformamides, it is cooled to 0 DEG C, add 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (1.51g, 7.87mmol), it is warmed to room temperature, stirring reaction 40 minutes.Reaction solution is poured into 100mL frozen water, stirring 30 minutes, filtering, filter cake is dried, obtain crude title product 4- (4- (2- cyano-acetamides amido) -2- methylphenethyls) methyl benzoate 10e (1.71g, pale solid), the not purified direct carry out next step of product.

MS m/z(ESI):335.1[M-1]

5th step

4- (4- (2- cyano group -2- cyclohexylidenes acetamido) -2- methylphenethyls) methyl benzoate

By crude product 4- (4- (2- cyano-acetamides amido) -2- methylphenethyls) methyl benzoate 10e (1.69g, 5.25mmol) with cyclohexanone (1.50g, 15.23mmol) it is dissolved in 26mL toluene, add morpholine (467mg, 5.36mmol), it is warming up to 120 DEG C, stirring reaction 4 hours.Reaction solution is concentrated under reduced pressure, with petroleum ether and ethyl acetate mashing purifying gained residue, obtain title product 4- (4- (2- cyano group -2- cyclohexylidenes acetamido) -2- methylphenethyls) methyl benzoate 10f (2.01g, light tan solid), yield：91.4%.

MS m/z(ESI):415.2[M-1]

6th step

4- (4- (2- amino -4,5,6,7- tetrahydro benzos [b] thiophene -3- formamidos) -2- methylphenethyls) methyl benzoate

By 4- (4- (2- cyano group -2- cyclohexylidenes acetamido) -2- methylphenethyls) methyl benzoate 10f (2g, 4.80mmol) with sulphur (161mg, 5.04mmol) it is dissolved in 5mL dimethylformamides, add morpholine (439mg, 5.04mmol), it is warming up to 50 DEG C, stirring reaction 1 hour.50mL water is added, is extracted with ethyl acetate (50mL × 3), merges organic phase, washed (50mL × 1), anhydrous sodium sulfate drying, filtered with saturated nacl aqueous solution, filtrate decompression is concentrated, with isopropanol mashing purifying gained residue, title product 4- (4- (2- amino -4,5 is obtained, 6,7- tetrahydro benzos [b] thiophene -3- formamidos) -2- methylphenethyls) methyl benzoate 10g (1.53g, yellow solid), yield：71.2%.

MS m/z(ESI):449.3[M+1]

7th step

4- (2- methyl -4- (2- (3- (methyl (2- morpholines ethyl) carbamyl) benzamido) -4,5,6,7- tetrahydro benzos [b] thiophene -3- formamidos) phenethyl) methyl benzoate

By 4- (4- (2- amino -4; 5; 6; 7- tetrahydro benzos [b] thiophene -3- formamidos) -2- methylphenethyls) methyl benzoate 10g (307mg; 0.68mmol) with 3- (methyl (2- morpholines ethyl) carbamyl) benzoic acid 3c (300mg; 1.03mmol); 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (197mg; 1.03mmol) with DMAP (125mg; 1.03mmol) it is dissolved in 5mL dimethylformamides; it is warming up to 30 DEG C, stirring reaction 12 hours.30mL water is added, is extracted with ethyl acetate (30mL × 3), merges organic phase, is washed with saturated nacl aqueous solution (50mL × 1), anhydrous sodium sulfate drying, is filtered, silicagel column color is used in filtrate decompression concentration Spectrometry purifies gained residue with eluant, eluent system A; obtain title product 4- (2- methyl -4- (2- (3- (methyl (2- morpholines ethyl) carbamyl) benzamido) -4; 5; 6; 7- tetrahydro benzos [b] thiophene -3- formamidos) phenethyl) methyl benzoate 10h (387mg; faint yellow solid), yield：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)

8th step

4- (2- methyl -4- (2- (3- (methyl (2- morpholines ethyl) carbamyl) benzamido) -4,5,6,7- tetrahydro benzos [b] thiophene -3- formamidos) phenethyl) benzoic acid

By 4- (2- methyl -4- (2- (3- (methyl (2- morpholines ethyl) carbamyl) benzamido) -4; 5; 6; 7- tetrahydro benzos [b] thiophene -3- formamidos) phenethyl) methyl benzoate 10h (250mg; 0.35mmol) it is dissolved in 10mL methanol; add 1mL 2M sodium hydroxide solutions, stirring reaction 12 hours.Reaction solution is concentrated under reduced pressure; be added dropwise 1M hydrochloric acid to aqueous phase pH be 4~5; extracted with dichloromethane (30mL × 3); merge organic phase; washed with saturated nacl aqueous solution (50mL × 1); anhydrous sodium sulfate drying; filtering; filtrate decompression is concentrated, and obtains title product 4- (2- methyl -4- (2- (3- (methyl (2- morpholines ethyl) carbamyl) benzamido) -4,5; 6; 7- tetrahydro benzos [b] thiophene -3- formamidos) phenethyl) benzoic acid 10 (233mg, faint yellow solid), yield：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)

Embodiment 11

N¹- (3- (4- (4- (two (2- hydroxyethyls) carbamyls) phenylethyl) -3- aminomethyl phenyls carbamyl) -4,5,6,7- tetrahydro benzos [b] thiophene -2- bases)-N³- methyl-N³- (2- morpholines ethyl) isophtalamide

By 4- (2- methyl -4- (2- (3- (methyl (2- morpholines ethyl) carbamyl) benzamido) -4, 5, 6, 7- tetrahydro benzos [b] thiophene -3- formamidos) phenethyl) 10 (120mg of benzoic acid, 0.17mmol) with 2, 2 '-diethanol amine (36mg, 0.34mmol), 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (65mg, 0.34mmol), I-hydroxybenzotriazole (46mg, 0.34mmol) and N, N- diisopropylethylamine (66mg, 0.51mmol) it is dissolved in 5mL dimethylformamides, it is warming up to 30 DEG C, stirring reaction 12 hours.Reaction solution is poured into 30mL frozen water, extracted with dichloromethane (50mL × 3), merge organic phase, washed with saturated nacl aqueous solution (50mL × 1), anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product N¹- (3- (4- (4- (two (2- hydroxyethyls) carbamyls) phenylethyl) -3- aminomethyl phenyls carbamyl) -4,5,6,7- tetrahydro benzos [b] thiophene -2- bases)-N³- methyl-N³- (2- morpholines ethyl) isophtalamide 11 (50mg, faint yellow solid), yield：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)

Embodiment 12

N¹- methyl-N¹- (2- morpholines ethyl)-N³- (3- (4- (3- phenylpropyls) phenylcarbamoyl) -5,7- dihydro -4H- thienos [2,3-c] pyrans -2- bases) isophtalamide

The first step

2- cyano group-N- (4- phenylpropyls phenyl) acetamide

By 4- phenylpropyl aniline 12a (10.30g, 48.74mmol, using known method document " Bioorganic＆Medicinal Chemistry Letters, 19 (3), 654-657；2009 " are prepared) it is dissolved in 100mL dimethylformamides; add 2- cyanoacetic acids (6.22g; 73.12mmol) and 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (14g, 73.12mmol), stirring reaction 12 hours.Pour into 300mL frozen water, stir 30 minutes, solid is separated out, filtering, filter cake drying obtains crude title product 2- cyano group-N- (4- phenylpropyls phenyl) acetamide 12b (12.2g, gray solid), the not purified direct carry out next step of product.

MS m/z(ESI):277.2[M-1]

Second step

2- amino-N- (4- (3- phenylpropyls) phenyl) -3- carbamyls -5,7- dihydro -4H- thienos [2,3-c] pyrans

By crude product 2- cyano group-N- (4- phenylpropyls phenyl) acetamide 12b (279mg, 1mmol), (3H) -one (106mg of dihydro -2H- pyrans -4,1.05mmol), morpholine (92mg, 1.05mmol) and sulphur (50mg, 1.50mmol) are dissolved in 15mL ethanol, it is warming up to 90 DEG C, stirring reaction 12 hours.Reaction solution is concentrated under reduced pressure; with ethyl acetate and petroleum ether mashing purifying gained residue; obtain title product 2- amino-N- (4- (3- phenylpropyls) phenyl) -3- carbamyls -5; 7- dihydro -4H- thienos [2; 3-c] pyrans 12c (1.13g; yellow oil), yield：87.9%.MS m/z(ESI):393.2[M+1]

3rd step

N¹- methyl-N¹- (2- morpholines ethyl)-N³- (3- (4- (3- phenylpropyls) phenylcarbamoyl) -5,7- dihydro -4H- thienos [2,3-c] pyrans -2- bases) isophtalamide

By 2- amino-N- (4- (3- phenylpropyls) phenyl) -3- carbamyls -5; 7- dihydro -4H- thienos [2; 3-c] pyrans 12c (255mg; 0.65mmol) with 3- (methyl (2- morpholines ethyl) carbamyl) benzoic acid 3c (246mg; 0.84mmol); 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (200mg; 1.04mmol) with DMAP (128mg; 1.04mmol) it is dissolved in 10mL dimethylformamides, stirring reaction 12 hours.Pour into 30mL frozen water, be extracted with ethyl acetate (30mL × 3), merge organic phase, use saturated nacl aqueous solution Wash (50mL × 1), anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, with silica gel column chromatography with eluant, eluent system A purify obtained by residue, obtain title product N¹- methyl-N¹- (2- morpholines ethyl)-N³- (3- (4- (3- phenylpropyls) phenylcarbamoyl) -5,7- dihydro -4H- thienos [2,3-c] pyrans -2- bases) isophtalamide 12 (235mg, yellow solid), yield：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)

Embodiment 13

N¹- methyl-N¹- (2- morpholines ethyl)-N³- (3- (4- phenylpropyls phenylcarbamoyl) -4,5,6,7- tetrahydro benzos [b] thiophene -2- bases) isophtalamide

The first step

2- cyano group -2- cyclohexylidenes-N- (4- phenylpropyls phenyl) acetamide

By crude product 2- cyano group-N- (4- phenylpropyls phenyl) acetamide 12b (1g, 3.59mmol) with cyclohexanone (1.02g, 10.41mmol) it is dissolved in 20mL toluene, add morpholine (319mg, 3.66mmol), it is warming up to 130 DEG C, stirring reaction 2 hours.Reaction solution is concentrated under reduced pressure, and with ethyl acetate and petroleum ether mashing purifying gained residue, obtains title product 2- cyano group -2- cyclohexylidenes-N- (4- phenylpropyls phenyl) acetamide 13a (1.13g, yellow oil), yield：87.9%.

MS m/z(ESI):357.2[M+1]

Second step

2- amino-N- (4- phenylpropyls phenyl) -4,5,6,7- tetrahydro benzos [b] thiophene -3- formamides

By 2- cyano group -2- cyclohexylidenes-N- (4- phenylpropyls phenyl) acetamide 13a (1.13g, 3.16mmol) with sulphur (106mg, 3.32mmol) it is dissolved in 5mL dimethylformamides, add morpholine (289mg, 3.32mmol), it is warming up to 50 DEG C, stirring reaction 1 hour.50mL water is added, is extracted with ethyl acetate (20mL × 3), merges organic phase, washed (50mL × 1), anhydrous sodium sulfate drying, filtered with saturated nacl aqueous solution, filtrate decompression is concentrated, with isopropanol mashing purifying gained residue, title product 2- amino-N- (4- phenylpropyls phenyl) -4,5 is obtained, 6,7- tetrahydro benzos [b] thiophene -3- formamides 13b (1.12g, yellow solid), yield：90.3%.

MS m/z(ESI):391.2[M+1]

3rd step

N¹- methyl-N¹- (2- morpholines ethyl)-N³- (3- (4- phenylpropyls) phenylcarbamoyl) -4,5,6,7- tetrahydro benzos [b] thiophene -2- bases) isophtalamide

By 2- amino-N- (4- phenylpropyls phenyl) -4; 5; 6; 7- tetrahydro benzos [b] thiophene -3- formamide 13b (1.12g; 2.87mmol) with 3- (methyl (2- morpholines ethyl) carbamyl) benzoic acid 3c (1.25g; 4.28mmol); 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (821mg; 4.28mmol) with DMAP (523mg; 4.28mmol) it is dissolved in 5mL dimethylformamides; it is warming up to 30 DEG C, stirring reaction 12 hours.Add 30mL water, it is extracted with ethyl acetate (30mL × 3), merge organic phase, washed with saturated nacl aqueous solution (50mL × 1), anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product N¹- methyl-N¹- (2- morpholines ethyl)-N³- (3- (4- phenylpropyls) phenylcarbamoyl) -4,5,6,7- tetrahydro benzos [b] thiophene -2- bases) isophtalamide 13 (1.05g, faint yellow solid), yield：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)

Embodiment 14

2- (3- (methyl (2- morpholines ethyl) carbamyl) benzamido) -3- (4- (3- phenylpropyls) phenylcarbamoyl) -4; 5- dihydro-thiophenes simultaneously [2,3-c] pyridine -6 (7H)-t-butyl formate

The first step

2- amino -3- (4- (3- phenylpropyls) phenylcarbamoyl) -4,5- dihydro-thiophenes simultaneously [2,3-c] pyridine -6 (7H)-t-butyl formate

By crude product 2- cyano group-N- (4- phenylpropyls phenyl) acetamide 12b (900mg, 3.23mmol), 4- carbonyl piperidines -1- t-butyl formates (677mg, 3.40mmol), morpholine (297mg, 3.40mmol) and sulphur (155mg, 4.85mmol) are dissolved in 20mL ethanol, it is warming up to 90 DEG C, stirring reaction 12 hours.Reaction solution is concentrated under reduced pressure; with ethyl acetate and petroleum ether mashing purifying gained residue; obtain title product 2- amino -3- (4- (3- phenylpropyls) phenylcarbamoyl) -4; 5- dihydro-thiophenes simultaneously [2; 3-c] pyridine -6 (7H)-t-butyl formate 14a (1.05g; yellow solid), yield：66.2%.

MS m/z(ESI):492.3[M+1]

Second step

2- (3- (methyl (2- morpholines ethyl) carbamyl) benzamido) -3- (4- (3- phenylpropyls) phenylcarbamoyl) -4; 5- dihydro-thiophenes simultaneously [2,3-c] pyridine -6 (7H)-t-butyl formate

By 2- amino -3- (4- (3- phenylpropyls) phenylcarbamoyl) -4; 5- dihydro-thiophenes simultaneously [2; 3-c] pyridine -6 (7H)-t-butyl formate 14a (1.02g; 2.07mmol) with 3- (methyl (2- morpholines ethyl) carbamyl) benzoic acid 3c (789mg; 2.70mmol); 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (635mg; 3.31mmol) with DMAP (405mg; 3.31mmol) it is dissolved in 15mL dimethylformamides, stirring reaction 12 hours.Pour into 30mL frozen water, it is extracted with ethyl acetate (30mL × 3), merge organic phase, washed with saturated nacl aqueous solution (50mL × 1), anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product 2- (3- (methyl (2- morpholines ethyl) carbamyl) benzamido) -3- (4- (3- phenylpropyls) phenylcarbamoyl) -4, 5- dihydro-thiophenes simultaneously [2, 3-c] pyridine -6 (7H)-(1.10g of t-butyl formate 14, yellow solid), yield：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)

Embodiment 15

4- (3- (4- (2- (6- (methyl (2- morpholines ethyl) carbamyl) pyridine -2- formamido groups) -4; 5; 6,7- tetrahydro benzos [b] thiophene -3- formamidos) phenyl) propyl group) methyl benzoate

The first step

6- (methyl (2- morpholines ethyl) carbamyl) -2- pyridine carboxylic acids

By pyridine -2,6- dioctyl phthalate (500mg, 3mmol) it is dissolved in 20mL dichloromethane, add 2- (7- azos BTA)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester (1.30g, 3.60mmol) and N, N- diisopropylethylamine (580mg, 4.50mmol), stir 10 minutes, add N- methyl -2- morpholine ethamine 15a (432mg, 3mmol, using known method document " Journal of Combinatorial Chemistry, 8 (6), 834-840；2006 " are prepared), stirring reaction 4 hours.Reaction solution is concentrated under reduced pressure; with silica gel column chromatography with eluant, eluent system A purify gained residue; obtain title product 6- (methyl (2- morpholines ethyl) carbamyl) -2- pyridine carboxylic acids 15b (375mg, white solid), yield：41.7%.

MS m/z(ESI):294.2[M+1]

Second step

4- (3- (4- (2- (6- (methyl (2- morpholines ethyl) carbamyl) pyridine acylamino-) -4; 5; 6,7- tetrahydro benzos [b] thiophene -3- formamidos) phenyl) propyl group) methyl benzoate

By 4- (3- (4- (2- amino -4; 5; 6; 7- tetrahydro benzos [b] thiophene -3- formamidos) phenyl) propyl group) methyl benzoate 1a (450mg; 1.06mmol) with 6- (methyl (2- morpholines ethyl) carbamyl) -2- pyridine carboxylic acid 15b (375mg; 1.27mmol) it is dissolved in 10mL dimethylformamides; add 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (305mg; 1.60mmol) with DMAP (195mg; 1.60mmol); it is warming up to 25 DEG C, stirring reaction 12 hours.Add 50mL water, extracted with dichloromethane (50mL × 3), merge organic phase, washed with saturated nacl aqueous solution (50mL × 1), anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product 4- (3- (4- (2- (6- (methyl (2- morpholines ethyl) carbamyl) pyridine -2- formamido groups) -4, 5, 6, 7- tetrahydro benzos [b] thiophene -3- formamidos) phenyl) propyl group) 15 (250mg of methyl benzoate, faint yellow solid), yield：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)

Embodiment 16

N¹- methyl-N¹- (2- morpholines ethyl)-N³- (3- (4- (2- morpholines ethyl) phenylcarbamoyl) -4,5,6,7- tetrahydro benzos [b] thiophene -2- bases) isophtalamide

The first step

2- cyano group-N- (4- (2- morpholines ethyl) phenyl) acetamide

By 4- (2- morpholines ethyl) aniline 16a (450mg, 2.18mmol, using known method document " Bioorganic＆Medicinal Chemistry Letters, 23 (23), 6363-6369；2013 " are prepared) and cyanoacetic acid (277mg; 3.27mmol) be dissolved in 5mL dimethylformamides; be cooled to 0 DEG C; add 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (625mg; 3.27mmol); be warmed to room temperature, stirring reaction 2 hours.Add 30mL water and 5mL saturated sodium bicarbonate solutions, extracted with dichloromethane (50mL × 3), merge organic phase, washed with saturated nacl aqueous solution (50mL × 1), anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product 2- cyano group - N- (4- (2- morpholines ethyl) phenyl) acetamide 16b (530mg, white solid), yield：88.9%.

MS m/z(ESI):449.3[M+1]

Second step

2- cyano group -2- cyclohexylidenes-N- (4- (2- morpholines ethyl) phenyl) acetamide

By 2- cyano group-N- (4- (2- morpholines ethyl) phenyl) acetamide 16b (530mg, 1.94mmol) it is dissolved in 15mL toluene, add cyclohexanone (190mg, 1.94mmol) with morpholine (168mg, 1.94mmol), it is warming up to 130 DEG C, stirring reaction 2 hours.Reaction solution is concentrated under reduced pressure, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product 2- cyano group -2- cyclohexylidenes-N- (4- (2- morpholines ethyl) phenyl) acetamide 16c (462mg, colorless oil), yield：67.5%.

MS m/z(ESI):354.3[M+1]

3rd step

2- amino-N- (4- (2- morpholines ethyl) phenyl) -4,5,6,7- tetrahydro benzos [b] thiophene -3- formamides

By 2- cyano group -2- cyclohexylidenes-N- (4- (2- morpholines ethyl) phenyl) acetamide 16c (462mg, 1.36mmol) with sulphur (44mg, 1.37mmol) it is dissolved in 6mL dimethylformamides, add morpholine (119mg, 1.37mmol), it is warming up to 50 DEG C, stirring reaction 45 minutes.Add 50mL water, extracted with dichloromethane (50mL × 3), merge organic phase, washed with saturated nacl aqueous solution (50mL × 1), anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product 2- amino-N- (4- (2- morpholines ethyl) phenyl) -4,5,6,7- tetrahydro benzos [b] thiophene -3- formamides 16d (300mg, yellow oil), yield：60%.

MS m/z(ESI):386.3[M+1]

4th step

N¹- methyl-N¹- (2- morpholines ethyl)-N³- (3- (4- (2- morpholines ethyl) phenylcarbamoyl) -4,5,6,7- tetrahydro benzos [b] thiophene -2- bases) isophtalamide

By 2- amino-N- (4- (2- morpholines ethyl) phenyl) -4; 5; 6; 7- tetrahydro benzos [b] thiophene -3- formamide 16d (160mg; 0.38mmol) it is dissolved in 6mL dimethylformamides; add 3- (methyl (2- morpholines ethyl) carbamyl) benzoic acid 3c (219mg; 0.75mmol); 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (146mg; 0.76mmol) with DMAP (72mg; 0.57mmol), 25 DEG C, stirring reaction 12 hours are warming up to.Add 30mL water, extracted with dichloromethane (30mL × 3), merge organic phase, washed with saturated nacl aqueous solution (50mL × 1), anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product N¹- methyl-N¹- (2- morpholines ethyl)-N³- (3- (4- (2- morpholines ethyl) phenylcarbamoyl) -4,5,6,7- tetrahydro benzos [b] thiophene -2- bases) isophtalamide 16 (82mg, faint yellow solid), yield：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)

Embodiment 17

N¹- (3- (4- (4- (1; 3- dihydroxy -2- (methylol) propane -2- bases carbamyl) phenethyl) -3- aminomethyl phenyls carbamyl) -6,6- dimethyl -4,5; 6,7- tetrahydro benzos [b] thiophene -2- bases)-N³- methyl-N³- (2- morpholines ethyl) isophtalamide

The first step

4- (4- (2- cyano group -2- (4,4- dimethylcyclohexy-lenes) acetamido) -2- methylphenethyls) methyl benzoate

By crude product 4- (4- (2- cyano-acetamides amido) -2- methylphenethyls) methyl benzoate 10e (2g, 6mmol) dissolvings In 30mL toluene, 4,4- dimethylcyclohexanons (2.16g, 17.20mmol) and morpholine (522mg, 6mmol) are added, 140 DEG C, stirring reaction 3 hours are warming up to.Reaction solution is concentrated under reduced pressure, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product 4- (4- (2- cyano group -2- (4,4- dimethylcyclohexy-lenes) acetamido) -2- methylphenethyls) methyl benzoate 17a (2.56g, light yellow oil), yield：95.9%.

MS m/z(ESI):443.3[M-1]

Second step

4- (4- (2- amino -6,6- dimethyl -4,5,6,7- tetrahydro benzos [b] thiophene -3- formamidos) -2- methylphenethyls) methyl benzoate

By 4- (4- (2- cyano group -2- (4,4- dimethylcyclohexy-lenes) acetamido) -2- methylphenethyls) methyl benzoate 17a (2.56g, 5.76mmol) it is dissolved in 10mL dimethylformamides, add sulphur (184mg, 5.79mmol) with morpholine (501mg, 5.76mmol), 50 DEG C, stirring reaction 2 hours are warming up to.Add 50mL water, it is extracted with ethyl acetate (50mL × 3), merge organic phase, washed with saturated nacl aqueous solution (50mL × 1), anhydrous sodium sulfate drying, filtering, filtrate decompression concentrate, with silica gel column chromatography with eluant, eluent system B purify obtained by residue, obtain title product 4- (4- (2- amino -6,6- dimethyl -4,5,6,7- tetrahydro benzos [b] thiophene -3- formamidos) -2- methylphenethyls) methyl benzoate 17b (2.30g, yellow solid), yield：83.9%.

MS m/z(ESI):475.2[M-1]

3rd step

4- (4- (6; 6- dimethyl -2- (3- (methyl (2- morpholines ethyl) carbamyl) benzamido) -4; 5,6,7- tetrahydro benzos [b] thiophene -3- formamidos) -2- methylphenethyls) methyl benzoate

By 4- (4- (2- amino -6; 6- dimethyl -4; 5; 6; 7- tetrahydro benzos [b] thiophene -3- formamidos) -2- methylphenethyls) methyl benzoate 17b (2.36g; 4.83mmol) it is dissolved in 5mL dimethylformamides; add 3- (methyl (2- morpholines ethyl) carbamyl) benzoic acid 3c (1.80g; 6.25mmol); 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (1.38g; 7.24mmol) with DMAP (883mg, 7.24mmol), stirring reaction 12 hours.Add 30mL water, it is extracted with ethyl acetate (30mL × 3), merge organic phase, washed with saturated nacl aqueous solution (50mL × 1), anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product 4- (4- (6, 6- dimethyl -2- (3- (methyl (2- morpholines ethyl) carbamyl) benzamido) -4, 5, 6, 7- tetrahydro benzos [b] thiophene -3- formamidos) -2- methylphenethyls) methyl benzoate 17c (2.60g, yellow solid), yield：72.2%.

MS m/z(ESI):751.5[M+1]

4th step

4- (4- (6; 6- dimethyl -2- (3- (methyl (2- morpholines ethyl) carbamyl) benzamido) -4; 5,6,7- tetrahydro benzos [b] thiophene -3- formamidos) -2- methylphenethyls) benzoic acid

By 4- (4- (6; 6- dimethyl -2- (3- (methyl (2- morpholines ethyl) carbamyl) benzamido) -4; 5; 6; 7- tetrahydro benzos [b] thiophene -3- formamidos) -2- methylphenethyls) methyl benzoate 17c (2.65g, 3.46mmol) is dissolved in 44mL tetrahydrofurans and methanol (V:V=3:1) in the mixed solvent, adds 10mL 2M sodium hydroxide solutions, stirring reaction 12 hours.30mL water is added, reaction solution is concentrated under reduced pressure, dropwise addition 1M hydrochloric acid to aqueous phase pH is 6; extracted with dichloromethane (30mL × 3); merge organic phase; washed with saturated nacl aqueous solution (50mL × 1); anhydrous sodium sulfate drying; filtering; filtrate decompression is concentrated; obtain crude title product 4- (4- (6,6- dimethyl -2- (3- (methyl (2- morpholines ethyl) carbamyl) benzamido) -4,5; 6; 7- tetrahydro benzos [b] thiophene -3- formamidos) -2- methylphenethyls) benzoic acid 17d (1.69g, yellow solid), yield：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)

5th step

N¹- (3- (4- (4- (1; 3- dihydroxy -2- (methylol) propane -2- bases carbamyl) phenethyl) -3- aminomethyl phenyls carbamyl) -6,6- dimethyl -4,5; 6,7- tetrahydro benzos [b] thiophene -2- bases)-N³- methyl-N³- (2- morpholines ethyl) isophtalamide

By crude product 4- (4- (6, 6- dimethyl -2- (3- (methyl (2- morpholines ethyl) carbamyl) benzamido) -4, 5, 6, 7- tetrahydro benzos [b] thiophene -3- formamidos) -2- methylphenethyls) benzoic acid 17d (850mg, 1.15mmol) it is dissolved in 5mL dimethylformamides, add 2- amino -2- (methylol) propane -1, 3- glycol (278mg, 2.30mmol), 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (439mg, 2.30mmol), I-hydroxybenzotriazole (310mg, 2.30mmol) and N, N- diisopropylethylamine (445mg, 3.50mmol), stirring reaction 12 hours.Add 50mL water and 20mL saturated sodium bicarbonate solutions, extracted with dichloromethane (50mL × 3), merge organic phase, washed with saturated nacl aqueous solution (50mL × 1), anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product N¹- (3- (4- (4- (1; 3- dihydroxy -2- (methylol) propane -2- bases carbamyl) phenethyl) -3- aminomethyl phenyls carbamyl) -6,6- dimethyl -4,5; 6,7- tetrahydro benzos [b] thiophene -2- bases)-N³- methyl-N³- (2- morpholines ethyl) isophtalamide 17 (600mg, yellow solid), yield：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).

Test case：

Biological assessment

The inhibitory action of test case 1, the compounds of this invention to people source Npt2b/HEK293 cell traffic Phos.

Following methods are used for determining inhibitory action of the compound to people source Npt2b/HEK293 cell traffic Phos in the present invention.

First, experiment material and instrument

1st, scintillation counter (PerkinElmer#1450)

2、BD BioCoat^TMPoly-D-Lysine 48- orifice plates (BD, #356509)

3rd, Npt2b plasmids (Guangzhou reactivation #NM_006424)

4th, the radionuclide of phosphorus -32 (Phosphorus-32Radionuclide), 1mCi (37MBq) (H₃ ³²PO₄)(PerkinElmer,#NEX053001MC)

5、Optiphase Supermix(PerkinElmer#1200-439for 5L)

2nd, experimental procedure

1st, people source Npt2b/HEK293 cells are obtained

By Npt2b plasmids by a certain percentage with Lipofectamine^TMLTX (Invitrogen#15338-100) is mixed, after placing 30 minutes, in the HEK293 cells (Chinese Academy of Sciences cell bank #GNHu43) that said mixture is added drop-wise to logarithmic phase growth, and side edged is mixed；After 24 hours, change the culture of the culture medium (Enzo#ALX-380-013-G005) containing G418 into and nearly covered with to cell, bed board selects monoclonal cell, verifies its function, obtains monoclonal stable cell line.

2nd, compound is tested to the inhibitory action of people source Npt2b/HEK293 cell traffic Phos

The previous day is carried by stable cell line people source Npt2b/HEK293 cells kind in 48 orifice plates, is cultivated in 37 DEG C of CO2gas incubators.Culture medium is discarded, cell once (250 μ L/ holes) is washed with Choline uptake buffer solution (Choline uptake buffer).Take 10 μ L H₃ ³²PO₄It is diluted in 1000ml sodium intake buffer solution (Sodium uptake buffer).The H added per hole after 80 μ L test compounds and 20 μ L dilutions₃ ³²PO₄, it is incubated at room temperature about 20 minutes.Final compound concentration is：100 μM, 10 μM, 1 μM, 0.1 μM, 0.01 μM, 0.001 μM, final DMSO concentration is：0.5%, final H₃ ³²PO₄Concentration is：0.2uCi/ holes；Discard above-claimed cpd and H₃ ³²PO₄, then wash cell (350 μ L/ holes) twice with ice-cold terminate liquid (Ice cold stop solution).Then 150 μ L 200mM NaOH are added per hole, at room temperature upper vibration plate device concussion cracking about 5 minutes.120 μ L cell lysates are shifted per hole in 96- holes sample panel.96- holes sample panel adds 100 μ L Optiphase Supermix per hole, and 96- holes sample panel is then sealed with RE-SEALABLE TAPE, is shaken at room temperature on vibration plate device about 5 minutes.Scintillation counter readings.

The compounds of this invention is measured to the inhibitory action of people source Npt2b/HEK293 cell traffic Phos, the IC measured₅₀Value is shown in Table 1.

The IC that the compounds of this invention of table 1 suppresses to people source Npt2b/HEK293 cell traffics Phos₅₀

Embodiment is numbered	IC<sub>50</sub>(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

Conclusion：Compound in the present invention has obvious inhibition to people source Npt2b/HEK293 cell traffic Phos.

The inhibitory action of test case 2, the compounds of this invention to mouse source Npt2b/HEK293 cell traffic Phos.

Following methods are used for determining inhibitory action of the compound to mouse source Npt2b/HEK293 cell traffic Phos in the present invention.

First, experiment material and instrument

1st, scintillation counter (PerkinElmer#1450)

2、BD BioCoat^TMPoly-D-Lysine 48- orifice plates (BD, #356509)

3rd, the radionuclide of phosphorus -32 (Phosphorus-32Radionuclide), 1mCi (37MBq) (H332PO4) (PerkinElmer, #NEX053001MC)

4、Optiphase Supermix(PerkinElmer#1200-439for 5L)

2nd, experimental procedure

1st, mouse source Npt2b/HEK293 cells are obtained

By Npt2b plasmids by certain than row and Lipofectamine^TMLTX is mixed, after placing 30 minutes, in the HEK293 cells that said mixture is added drop-wise to logarithmic phase growth, and side edged is mixed；After 24 hours, change the medium culture containing G418 into and nearly covered with to cell, bed board selects monoclonal cell, verify its function, obtain monoclonal stable cell line.

2nd, compound is tested to the inhibitory action of mouse source Npt2b/HEK293 cell traffic Phos

The previous day is carried by stable cell line mouse source Npt2b/HEK293 cells kind in 48 orifice plates, is cultivated in 37 DEG C of CO2gas incubators.Culture medium is discarded, cell once (250 μ L/ holes) is washed with Choline uptake buffer solution (Choline uptake buffer).Take 10 μ L H₃ ³²PO₄It is diluted in 1000ml sodium intake buffer solution (Sodium uptake buffer).The H added per hole after 80 μ L test compounds and 20 μ L dilutions₃ ³²PO₄, it is incubated at room temperature about 20 minutes.Final compound concentration is：100 μM, 10 μM, 1 μM, 0.1 μM, 0.01 μM, 0.001 μM, final DMSO concentration is：0.5%, final H₃ ³²PO₄Concentration is：0.2uCi/ holes；Discard above-claimed cpd and H₃ ³²PO₄, then wash cell (350 μ L/ holes) twice with ice-cold terminate liquid (Ice cold stop solution).150 μ L 200mM NaOH are added per hole, at room temperature concussion cracking about 5 minutes on vibration plate device.120 μ L cell lysates are shifted per hole in 96- holes sample panel.96- holes sample panel adds 100 μ L Optiphase Supermix per hole, 96- holes sample panel is then sealed with RE-SEALABLE TAPE, at room temperature vibration plate Shaken on device about 5 minutes.Scintillation counter readings.

The compounds of this invention is measured to the inhibitory action of mouse source Npt2b/HEK293 cell traffic Phos, the IC measured₅₀Value is shown in Table 2.

The IC that the compounds of this invention of table 2 suppresses to mouse source Npt2b/HEK293 cell traffics Phos₅₀

Embodiment is numbered	IC<sub>50</sub>(nM)
		1	82
6	109
		7	210
8	33
		9	474
10	53
		11	309
13	169
		14	257

Conclusion：Compound in the present invention has obvious inhibition to mouse source Npt2b/HEK293 cell traffic Phos.

The pharmacokinetics test of test case 3, the compounds of this invention

1st, make a summary

Using rat as animal subject, determine rat oral gavage using LC/MS/MS methods and give after embodiment compound not drug concentration in blood plasma in the same time.Pharmacokinetics behavior of the compound of the present invention in rat body is studied, its characteristics of pharmacokinetics is evaluated.

2nd, testing program

2.1 test drug

The compound of embodiment 6~9, embodiment 11, embodiment 13, embodiment 14 and embodiment 17.

2.2 experimental animal

Healthy adult SD rat 32, male and female half and half are divided into 8 groups, every group 4, purchased from the western pul-Bi Kai experimental animals Co., Ltd in Shanghai, animal productiong licensing number：SCXK (Shanghai) 2008-0016.

2.3 medicines are prepared

Appropriate amount of sample is weighed, 0.5%CMC-Na is added to final volume, 0.5mg/ml suspensions are made in ultrasound.

2.4 administration

SD rats 32, male and female half and half are divided into after 8 groups, the night of fasting one and distinguish gastric infusion, dosage is 5.0mg/kg, administered volume 10mL/kg.

3rd, operate

In before administration and 0.5 after administration, 1,2,4,6,8,11,24 hours blood sampling 0.1mL, be placed in EDTA anti-freezing test tubes, 3500rpm is centrifuged 5 minutes, separated plasma, in -20 DEG C of preservations.Feed within 2 hours after administration.

The testing compound content after different compound gastric infusions in rat plasma is determined with LC/MS/MS methods.The range of linearity of analysis method is respectively 5.00-2000ng/mL and 1.00-500ng/mL, and lower limit of quantitation is respectively 5.00ng/mL and 1.00ng/mL；Plasma sample is analyzed after being pre-processed through protein precipitation.

4th, pharmacokinetic parameter result

The pharmacokinetic parameter of the compounds of this invention is shown in Table 3：

Conclusion：The Pharmacokinetic Characteristics of the compounds of this invention are that its concentration in blood plasma is relatively low, and the absorption in blood medicine is few.

Test case 4, the test of the compounds of this invention rat excrement rate of recovery

1st, make a summary

Using rat as animal subject, determine rat oral gavage using LC/MS/MS methods and give after preferred embodiment of the present invention compound not drug concentration in blood plasma in the same time.Pharmacokinetics behavior of the compound of the present invention in rat body is studied, its excrement rate of recovery is evaluated.

2nd, testing program

2.1 test drug

Embodiment 6,7 and 17 compounds.

2.2 experimental animal

Healthy adult SD rat 12, male and female half and half are divided into 3 groups, every group 4, purchased from the western pul-Bi Kai experimental animals Co., Ltd in Shanghai, animal productiong licensing number：SCXK (Shanghai) 2008-0016.

2.3 medicines are prepared

Appropriate amount of sample is weighed, 0.5%CMC-Na is added to final volume, 2.0mg/ml suspensions are made in ultrasound.

2.4 administration

SD rats 12, male and female half and half are divided into 3 groups, are put into metabolic cage, freely ingest and drink water, while blank excrement sample is collected, the night of fasting one before administration.Animal distinguishes gastric infusion, gastric infusion is distinguished after the night of fasting one, dosage is 20.0mg/kg, administered volume 10mL/kg.

3rd, operate

In 0~8 hour after administration, 8~24 hours, 24~48 hours, 48~72 hours Fractional Collections excrement samples, and weigh respectively.After record, label, 20 DEG C of freezen protectives are posted.Plasma sample respectively at before administration and 1 after administration, 2,4 and 8 hours taken a blood sample 0.2mL by eye socket, be placed in heparinised tubes, separated plasma after 3500rpm is centrifuged 10 minutes, in -20 DEG C of preservations；Feed within 3 hours after administration.

4th, accumulation faecal excretion rate result

The accumulation faecal excretion rate of the compounds of this invention is shown in Table 4：

Conclusion：Gavage is given after 20mg/kg the compounds of this invention, degree of exposure in urine and blood is relatively low, medicine prototype and the excrement rate of recovery of metabolin are high, it was found that higher in the tissue relative amount such as the stomach of digestive system, colon, jejunum, duodenum, wherein colon and jejunum are the main function positions of medicine.

Test case 5, the compounds of this invention treatment rat hyperphosphatemia test

1st, make a summary

Using rat as animal subject, the serum phosphate lowering drug effect of the compound of the present invention is evaluated

2nd, testing program

2.1 test drug

The compound of embodiment 5,6,7 and the compound of embodiment 11.

Low-phosphorous feed (containing 0.1% phosphorus and 0.6% calcium)：There is provided by Shanghai Slac Experimental Animal Co., Ltd..

Sodium dihydrogen phosphate (NaH₂PO₄·H₂O)：Lot number is 201209I06, purchased from Hunan Jiudian Pharmaceutical Co., Ltd.Prepared before use is into 1mmol/ml (138mg/ml, 5ml/kg).

Sodium carboxymethylcellulose (CMC-Na)：Lot number is F20090508, Chemical Reagent Co., Ltd., Sinopharm Group.

Serium inorganic phosphorus detection kit：Lot number 20130905, builds up biotech firm by Nanjing and provides.

2.2 experimental animal

Healthy adult SD rat 60, male and female half and half are divided into 6 groups, every group 10, purchased from the western pul-Bi Kai experimental animals Co., Ltd in Shanghai, animal productiong licensing number：SCXK (Shanghai) 2013-0016.

3rd, operate

Experimental method is carried out according to method in patent application (WO2012006473).Animal feeds (at least 3 days) after buying with normal diet adaptability, then switchs to low-phosphorous forage feed, and serum serium inorganic phosphorus screening is carried out to rat,

By rat of the serium inorganic phosphorus less than 2.3mmol/L according to the random packet of serium inorganic phosphorus height, rat hyperphosphatemia model is set up in the gavage sodium dihydrogen phosphate of experiment the 2nd day (1mmol/1mL).6 groups are randomly divided into according to enrolled rat serium inorganic phosphorus value, blank control group gives the distilled water of same volume.Each treatment group rat gave single oral gavage administration (5mL/kg, 30mg/kg) respectively at 15 minutes before modeling, and model group gives corresponding 0.5%CMC.Respectively at detection serum serium inorganic phosphorus value of being taken a blood sample behind 0 hour (blank serum), 0.5 hour and 2 hours to rat progress eye socket after modeling.

4th, serum phosphate lowering value result

The effect of the serum phosphate lowering of the compounds of this invention is shown in Table 5：

Embodiment is numbered	Serum phosphate lowering ratio (30mg/kg) after 0.5 hour
		5	27.4%
6	31.4%
		7	26.2%
11	29.4%

Conclusion：Rat has obvious serum phosphate lowering to act on after the preferred compounds of the invention of oral administration gavage 30mg/kg dosage after microcosmic salt is given 0.5 hour.

Test case 6, Npt2b inhibitor compounds 7 and 2-Propen-1-amine polymer with(chloromethyl)oxirane carbonate forage feed rat its phosphorus metabolism laboratory report

1. experiment purpose

This experiment in feed by mixing sevelamer (i.e. 2-Propen-1-amine polymer with(chloromethyl)oxirane carbonate, Shanghai Hanhong Chemical Industry Co., Ltd., Cat#：B12264) or the feeding rat of Npt2b inhibitor embodiments compound 7, content of inorganic phosphorus in detection rat urine, to evaluate the rush phosphorus Excretion of by reagent.

2. experimental method and experiment material

2.1. experimental animal, feed and rearing conditions

SD male rats are used in experiment, purchased from Shanghai Bi Kai experimental animals Co., Ltd (Chinese Shanghai, quality certification numbering 2008001644738, licensing SCXK (Shanghai) 2013-0016).After animal is bought, carry out after adaptability raising in 3 days, start normal diet and chocolate feed two-wheeled metabolic cage screening (being eaten up with 15g/ feeds pcs/day as standard), the selected rat of success starts to test again.

Normal diet (0.6%P, 0.6%Ca) is by that triumphant must provide, and chocolate feed (chocolate content is 3%, 0.6%P, 0.6%Ca) is synthesized by the processing of this Leco Corp., and pharmaceutical feed is to be mixed into medicine in chocolate feed (answering Yongcheng to provide by medicine portion) processes, and is specifically formulated as follows：Every gram of feed is mixed into 1.3mg test-compounds, and it is 100mg/kg/day to reach mean dose；Every gram of feed of sevelamer is mixed into 9.75mg test-compounds, and it is 750mg/kg/day to reach mean dose.

2.2. experiment reagent

Phosphorus detection kit：Lot number 20140808, builds up biotech firm by Nanjing and provides.

2.3. experimental design and experimental method

2.3.1. animal packet：

After rat adaptability is raised and screened, it is grouped as follows：

Group number	Packet	n
			①	Normal blank group	5
②	Sevelamer group (750mg/kg)	5
			③	7 groups of compound (100mg/kg)	5
④	Compound 7-100mg/kg+ sevelamer groups -200mg/kg	4

Administering mode：Metabolic cage ad lib feed

2.3.2. experimental method：

Experimental method is carried out according to method in patent (WO2012006473).Rat is first passed through into chow diet screening in (15g/ days), the rat that feed is all eaten up carries out the screening in (15g/ days) of chocolate feed again, the rat packet that finally feed is all eaten up enters experiment, is grouped as follows at random (dosage is mg/kg/day)：1. normal blank group, 2. sevelamer -750mg/kg groups, 3. compound 7-100mg/kg groups, 4. compound 7-100mg/kg combine sevelamer -200mg/kg groups.Every group of rat 4-5 is only.Two-wheeled screens successful rat and starts to feed said medicine feed in metabolic cage, totally 4 days, observes daily body weights, food consumption situation, and collect the content of Phos in 24-48h, 48-72h and 72-96h urine, detection urine respectively.

3. result is with discussing:The influence of 2-Propen-1-amine polymer with(chloromethyl)oxirane carbonate and compound 7 to rat phosphuresis

Normal blank group its urinate phosphorus content in 24-48h, 48-72h and 72-96h tri- days be 25-26mg, compared with normal blank group, 3 days of administration group urine phosphorus total amounts or 3 days average magnitudes substantially reduce (P<0.05) it is respectively 30.2%, 27.9% and 44.2% that, sevelamer -750mg/kg groups, compound 7-100mg/kg groups, compound 7-100mg/kg+ sevelamers -200mg/kg, which organize its reduction amplitude, is shown in Table 6, Fig. 1, ratio is reduction amplitude.Table 6:Three day averages that Npt2b influences on rat phosphuresis

Group number	Packet	Ratio
			②	Sevelamer group (750mg/kg)	30.2%

③	7 groups of compound (100mg/kg)	27.9%
			④	Compound 7-100mg/kg+ sevelamer groups -200mg/kg	44.2%

As a result prove, 750mg/kg sevelamers, 100mg/kg compounds 7 and both combinations have obvious rush phosphorus Excretion, alone sevelamer and the drug effect of compound 7 quite, and 750mg/kg sevelamer+200mg/kg compounds 7 be combined after its urinate phosphorus reduction amplitude to be higher than both alone.

Claims (15)

1. Compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures shown in a kind of logical formula (I), or its pharmaceutically useful salt：

   Wherein：

   X is selected from C (R^a)₂, O, S or NR^a；

   Y is selected from-C (O)-or-NR^bC(O)-；

   R^aIt is identical or different, it is each independently selected from hydrogen atom, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (O) OR⁵、-C(O)R⁵、-C(O)NR⁶R⁷Or-S (O)_pR⁵, wherein described alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl are optionally further selected from halogen, hydroxyl, alkoxy, cyano group, nitro, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (O) OR by one or more⁵、-OC(O)R⁵、-NHS(O)_pR⁵、-C(O)R⁵、-NHC(O)R⁵、-NHC(O)OR⁵、-NR⁶R⁷、-OC(O)NR⁶R⁷Or-C (O) NR⁶R⁷Substituent replaced；

   R^bSelected from hydrogen atom or alkyl, wherein described alkyl is optionally further replaced by one or more substituents selected from halogen, hydroxyl, alkoxy, cyano group or nitro；

   Ring A is selected from cycloalkyl, heterocyclic radical, aryl or heteroaryl；

   Ring B is selected from aryl or heteroaryl；

   Ring C is selected from cycloalkyl, heterocyclic radical, aryl or heteroaryl, wherein described cycloalkyl, heterocyclic radical, aryl or heteroaryl are optionally further selected from halogen, hydroxyl, alkoxy, cyano group, nitro, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (O) OR by one or more⁵、-OC(O)R⁵、-NHS(O)_pR⁵、-C(O)R⁵、-NHC(O)R⁵、-NHC(O)OR⁵、-NR⁶R⁷、-OC(O)NR⁶R⁷Or-C (O) NR⁶R⁷Substituent replaced；

   R¹Selected from alkyl, wherein described alkyl is further replaced by one or more substituents selected from cycloalkyl, heterocyclic radical, aryl or heteroaryl, wherein described cycloalkyl, heterocyclic radical, aryl or heteroaryl are optionally further selected from halogen, hydroxyl, alkoxy, cyano group, nitro, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (O) OR by one or more⁵、-OC(O)R⁵、-NHS(O)_pR⁵、-C(O)R⁵、-NHC(O)R⁵、-NHC(O)OR⁵、-NR⁶R⁷、-OC(O)NR⁶R⁷Or-C (O) NR⁶R⁷Substituent replaced；

   R²Selected from hydrogen atom, halogen, alkoxy, cyano group, nitro or alkyl, wherein described alkyl or alkoxy optionally further by it is one or more selected from halogen, it is hydroxyl, alkoxy, cyano group, nitro, cycloalkyl, miscellaneous Ring group, aryl, heteroaryl ,-C (O) OR⁵、-OC(O)R⁵、-NHS(O)_pR⁵、-C(O)R⁵、-NHC(O)R⁵、-NHC(O)OR⁵、-NR⁶R⁷、-OC(O)NR⁶R⁷Or-C (O) NR⁶R⁷Substituent replaced；

   R³Selected from hydrogen atom, halogen, alkoxy, cyano group, nitro or alkyl, wherein described alkyl or alkoxy are optionally further selected from halogen, hydroxyl, alkoxy, cyano group, nitro, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (O) OR by one or more⁵、-OC(O)R⁵、-NHS(O)_pR⁵、-C(O)R⁵、-NHC(O)R⁵、-NHC(O)OR⁵、-NR⁶R⁷、-OC(O)NR⁶R⁷Or-C (O) NR⁶R⁷Substituent replaced；

   R⁴Selected from hydrogen atom or alkyl, wherein described alkyl is optionally further selected from halogen, hydroxyl, alkoxy, cyano group, nitro, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (O) OR by one or more⁵、-OC(O)R⁵、-NHS(O)_pR⁵、-C(O)R⁵、-NHC(O)R⁵、-NHC(O)OR⁵、-NR⁶R⁷、-OC(O)NR⁶R⁷Or-C (O) NR⁶R⁷Substituent replaced；

   R⁵Selected from hydrogen atom, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl, wherein described alkyl, cycloalkyl, aryl or heteroaryl are optionally further replaced by one or more substituents selected from alkyl, halogen, hydroxyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclic radical, aryl, heteroaryl, carboxylic acid or carboxylate；

   R⁶Or R⁷Hydrogen atom, alkyl, alkoxy, cycloalkyl, heterocyclic radical, aryl or heteroaryl are each independently selected from, wherein described alkyl, alkoxy, cycloalkyl, heterocyclic radical, aryl or heteroaryl are optionally further replaced by one or more substituents selected from alkyl, halogen, hydroxyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclic radical, aryl, heteroaryl, carboxylic acid or carboxylate independently of one another；

   Or, R⁶Or R⁷Heterocyclic radical is formed together with the nitrogen-atoms being connected, wherein containing one or more N, O or S (O) in described heterocyclic radical_pHetero atom, and the heterocyclic radical optionally further replaces by one or more substituents selected from alkyl, halogen, hydroxyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, carboxylic acid or carboxylate；

   M is 0,1,2,3 or 4；

   N is 0,1,2,3 or 4；And

   P is 0,1 or 2.
2. Compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures shown in logical formula (I) according to claim 1, or its pharmaceutically useful salt, it is to lead to the compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures shown in formula (II), or its pharmaceutically useful salt：

   Wherein：

   R¹~R⁴, X, Y, m, n, ring A and ring C definition as described in the appended claim 1.
3. The compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures shown in logical formula (I) according to claim 1~2 any one, or its pharmaceutically useful salt, its middle ring A is selected from heterocyclic radical or aryl, preferably phenyl or morpholinyl.
4. Compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures shown in logical formula (I) according to claim 1, or its pharmaceutically useful salt, it is to lead to the compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures shown in formula (III), or its pharmaceutically useful salt：

   Wherein：

   R¹~R⁴, X, Y, m, n and ring C definition as described in the appended claim 1.
5. The compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures shown in logical formula (I) according to Claims 1 to 4 any one, or its pharmaceutically useful salt, its middle ring C is heterocyclic radical, preferably morpholine base or piperazinyl.
6. The compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures shown in logical formula (I) according to Claims 1 to 5 any one, or its pharmaceutically useful salt, wherein R¹Selected from-(CH₂)_r-R^c；

   R^cSelected from cycloalkyl, heterocyclic radical, aryl or heteroaryl, wherein described cycloalkyl, heterocyclic radical, aryl or heteroaryl are optionally further selected from halogen, hydroxyl, alkoxy, cyano group, nitro, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (O) OR by one or more⁵、-OC(O)R⁵、-NHS(O)_pR⁵、-C(O)R⁵、-NHC(O)R⁵、-NHC(O)OR⁵、-NR⁶R⁷、-OC(O)NR⁶R⁷Or-C (O) NR⁶R⁷Substituent replaced；

   R is selected from 1,2,3,4 or 5, preferably 2 or 3；And

   R⁵、R⁶、R⁷, p definition as described in the appended claim 1.
7. The compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures shown in logical formula (I) according to claim 1~6 any one, or it can medicine Salt, wherein the compound is selected from：
8. A kind of compound or its dynamic isomer prepared shown in logical formula (I) according to claim 1, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures, or the method for its pharmaceutically useful salt, this method includes：

   Formula (IA) compound or its salt reacts with formula (IB) compound, optionally further hydrolyzes and/or be condensed to yield logical formula (I) compound；

   Wherein：

   Z is selected from hydroxyl or halogen；

   R¹~R⁴, X, Y, m, n, ring A, ring B and ring C definition as described in the appended claim 1.
9. Compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures or its pharmaceutically useful salt described in a kind of formula (IA),

   Wherein：

   X is selected from C (R^a)₂, O, S or NR^a；

   R^aIt is identical or different, it is each independently selected from hydrogen atom, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (O) OR⁵、-C(O)R⁵、-C(O)NR⁶R⁷Or-S (O)_pR⁵, wherein described alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl are optionally further selected from halogen, hydroxyl, alkoxy, cyano group, nitro, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (O) OR by one or more⁵、-OC(O)R⁵、-NHS(O)_pR⁵、-C(O)R⁵、-NHC(O)R⁵、-NHC(O)OR⁵、-NR⁶R⁷、-OC(O)NR⁶R⁷Or-C (O) NR⁶R⁷Substituent replaced；

   Condition is when X is selected from C (R^a)₂When, R^aIt is not selected from hydrogen atom；

   Ring A is selected from cycloalkyl, heterocyclic radical, aryl or heteroaryl, preferably phenyl；

   R¹Selected from alkyl, wherein described alkyl is further replaced by one or more substituents selected from cycloalkyl, heterocyclic radical, aryl or heteroaryl, wherein described cycloalkyl, heterocyclic radical, aryl or heteroaryl are optionally further selected from halogen, hydroxyl, alkoxy, cyano group, nitro, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (O) OR by one or more⁵、-OC(O)R⁵、-NHS(O)_pR⁵、-C(O)R⁵、-NHC(O)R⁵、-NHC(O)OR⁵、-NR⁶R⁷、-OC(O)NR⁶R⁷Or-C (O) NR⁶R⁷Substituent replaced；

   R²Selected from hydrogen atom, halogen, alkoxy, cyano group, nitro or alkyl, wherein described alkyl or alkoxy are optionally further selected from halogen, hydroxyl, alkoxy, cyano group, nitro, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (O) OR by one or more⁵、-OC(O)R⁵、-NHS(O)_pR⁵、-C(O)R⁵、-NHC(O)R⁵、-NHC(O)OR⁵、-NR⁶R⁷、-OC(O)NR⁶R⁷Or-C (O) NR⁶R⁷Substituent replaced；

   R⁵Selected from hydrogen atom, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl, wherein described alkyl, cycloalkyl, aryl or heteroaryl are optionally further replaced by one or more substituents selected from alkyl, halogen, hydroxyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclic radical, aryl, heteroaryl, carboxylic acid or carboxylate；

   R⁶Or R⁷Hydrogen atom, alkyl, alkoxy, cycloalkyl, heterocyclic radical, aryl or heteroaryl are each independently selected from, wherein described alkyl, alkoxy, cycloalkyl, heterocyclic radical, aryl or heteroaryl are optionally further replaced by one or more substituents selected from alkyl, halogen, hydroxyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclic radical, aryl, heteroaryl, carboxylic acid or carboxylate independently of one another；

   Or, R⁶Or R⁷Heterocyclic radical is formed together with the nitrogen-atoms being connected, wherein containing one or more N, O or S (O) in described heterocyclic radical_pHetero atom, and the heterocyclic radical is optionally further selected from by one or more Alkyl, halogen, hydroxyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, the substituent of carboxylic acid or carboxylate are replaced；

   M is 0,1,2,3 or 4；And

   P is 0,1 or 2.
10. Compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures shown in formula (IA) according to claim 9, or its pharmaceutically useful salt, wherein the compound is selected from：
11. A kind of pharmaceutical composition, described pharmaceutical composition contains compound or its dynamic isomer shown in the logical formula (I) according to claim 1~7 any one of therapeutically effective amount, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures or its pharmaceutically useful salt and pharmaceutically acceptable carrier, diluent or excipient.
12. Pharmaceutical composition according to claim 11, it further contains another or a variety of phosphate binders, and described phosphate binder is preferably sevelamer.
13. The compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures shown in logical formula (I) according to claim 1~7 any one, or its pharmaceutically useful salt, or purposes of the pharmaceutical composition in intestines 2B types sodium phosphate cotransporter (Npt2b) inhibitor is prepared according to claim 11 or 12.
14. The compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures shown in logical formula (I) according to claim 1~7 any one, or its pharmaceutically useful salt, or purposes of the pharmaceutical composition in the medicine for treating or preventing hyperphosphatemia is prepared according to claim 11 or 12.
15. Compound shown in logical formula (I) or its dynamic isomer according to claim 1~7 any one, mesomer, racemic modification, enantiomter, diastereoisomer, or its form of mixtures, or its officinal salt, or purposes of the pharmaceutical composition according to claim 11 or 12 in the medicine of disease of sodium phosphate transport protein mediation is treated or prevented, described disease is preferably selected from nephrosis, the calcification of inner membrance local vascular, the activated vitamin D of high concentration caused by hyperphosphatemia, hyperthyroidism, described nephrosis is preferably chronic nephrosis or ESRD.