CN105658635B - Thieno naphthenic base or thieno heterocycle analog derivative, preparation method and its application in medicine - Google Patents

Thieno naphthenic base or thieno heterocycle analog derivative, preparation method and its application in medicine Download PDF

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CN105658635B
CN105658635B CN201580002261.XA CN201580002261A CN105658635B CN 105658635 B CN105658635 B CN 105658635B CN 201580002261 A CN201580002261 A CN 201580002261A CN 105658635 B CN105658635 B CN 105658635B
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alkyl
methyl
phenyl
ring
base
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CN105658635A (en
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应永铖
杨方龙
王伟民
李言华
陈刚
董庆
孙飘扬
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Jiangsu Hengrui Medicine Co Ltd
Shanghai Hengrui Pharmaceutical Co Ltd
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Jiangsu Hengrui Medicine Co Ltd
Shanghai Hengrui Pharmaceutical Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D333/70—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

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 naphthenic base or thieno heterocycle analog derivative, preparation method and its Application pharmaceutically
Technical field
The present invention relates to a kind of novel thiophene and naphthenic base or thieno heterocycle analog derivative, preparation method and contain The pharmaceutical composition as well as therapeutic agent of the derivative are especially as intestines 2B type sodium phosphate cotransporter (Npt2b) purposes of inhibitor and the use in the drug of the diseases such as preparation treatment and/or prevention hyperphospheremia or illness On the way.
Background technique
Inorganic phosphate (Pi) is the necessary component of bone mineral, extracellular base of the adult phosphatic about 80% outside mine In matter (such as bone and tooth), 18% in the cell, and 2% in extracellular fluid.Under normal physiological conditions, small intestine absorbs excessive phosphoric acid Salt, phosphatic homeostasis depend on excretion and the reabsorption function of kidney to adjust.Internal phosphate is excessive or very few equal Lead to body function disorder and cause a disease: as too low, leading to hypophosphatemia, osteomalacia, rickets and cardiac disorder； It is excessively high, induce hyperphospheremia, soft tissue and angiosteosis and renal dysfunction.Excessively high phosphate is cardiovascular disease An important factor for increasing with the death rate of chronic kidney disease (CKD) patient.The treatment of hyperphosphatemia at present mainly include diet limit phosphorus, The application and the excision of parathyroid gland when necessary of dialysis treatment, phosphate binder.There are 90~95% End-stage Renal Disease Patients needs Take phosphate binder treatment hyperphosphatemia.
Small intestine is to phosphatic absorption mainly by two kinds of approach, and passive transport and active transport, wherein active transport is just It is to cotransport what channel protein carried out by the sodium/phosphorus of Na-dependent.It has recently been demonstrated that sodium phosphate cotransporter 2B It (Npt2b) is important target spot (the J Pharm Sci.2011 Sep 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 family (Npt2a, Npt2b, Npt2c) is mainly expressed in kidney (Npt2c), lung, in intestines and testis (Npt2a, Npt2b)；3 Type family (Pit1, Pit2), is generally expressed in each organ.Wherein Npt2b has expression in entire upper digestive tract, mediates half Phosphatic absorption in the food of left and right, for maintaining phosphatic homeostasis.Npt2b also has table in its hetero-organization It reaches, it is necessary to keep the characteristic of nonabsorable and (Current the characteristics of can keep in enteric cavity for Npt2b inhibitor Pharmaceutical Design, 2012,18,1434-1445).The study found that Npt2b caused by Npt2b is mutated inactivates meeting Lead to the generation of the micro- calculus of autosomal recessive hereditary diseases alveolar (PAM), hint Npt2b is that removal is more in the major function of alveolar Remaining phosphate.In cancerous lung tissue slice, discovery Npt2b high expression, small interference siRNA experiment discovery reduces Npt2b expression It can inhibit the generation of lung cancer.It the exclusive use of non-absorbing Npt2b inhibitor (Ardelyx) of another research and establishment and is applied in combination Two animal models of (being combined with phosphate binder) find that the CKD rat model induced in adenine, NTX1942 can drop Low 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, rat shows renal function exacerbation delay and survival rate is significant The characterization of raising.As clinical dosage, the dosage of Npt2b inhibitor be hopeful it is lower than phosphate binder, more for more, range Phosphate needed for CKD patient provides before wide dialysis inhibits.
Hormone such as female hormone, glucocorticoid, fibroblast growth factor 23 (FGF23), 1,25 (OH) vitamins D3(1,25 (OH)2D3) and diet intake phosphate influences intestinal brush border film phosphorus absorb or Npt2b expression.Small intestine The reduction that the missing of interior Npt2b also causes FGF23 to express.The major function of FGF23 is by reducing phosphate co-transporter Expression and promote 1,25 (OH)2D3Synthesis adjust the phosphatic excretion of kidney, Npt2b is as phosphate sensor, regulation The balance of hormone in vivo maintains the balance of whole body system.
Disclose the patent application of a series of Npt2b inhibitor 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 there is still a need for Exploitation it is new with better drug effect, do not absorb or absorb less in blood, the compound small to physical toxicity effect, process It is continually striving to, present invention design has the compound of structure shown in logical formula (I), and is found to have the compound table of this class formation Revealing has excellent effect and effect in colon and jejunum position.
Summary of the invention
The purpose of the present invention is to provide a kind of logical formula (I) compound represented or its tautomers, mesomer, outer Raceme, enantiomter, diastereoisomer, or mixtures thereof form or its officinal salt:
Wherein:
X is selected from C (Ra)2, O, S or NRa；
Y is selected from-C (O)-or-NRbC(O)-；
RaIt is identical or different, it is each independently selected from hydrogen atom, alkyl, naphthenic base, heterocycle, aryl, heteroaryl ,-C (O)OR5、-C(O)R5、-C(O)NR6R7Or-S (O)pR5, wherein alkyl, naphthenic base, heterocycle, aryl or the heteroaryl are appointed Choosing is further selected from halogen, hydroxyl, alkoxy, cyano, nitro, alkyl, halogenated alkyl, hydroxyalkyl, cycloalkanes by one or more Base, heterocycle, 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 group replaced；
RbSelected from hydrogen atom or alkyl, wherein the alkyl optionally further by one or more selected from halogen, hydroxyl, Replaced the substituent group of alkoxy, cyano or nitro；
Ring A is selected from naphthenic base, heterocycle, aryl or heteroaryl；
Ring B is selected from aryl or heteroaryl；
Ring C is selected from naphthenic base, heterocycle, aryl or heteroaryl, wherein naphthenic base, heterocycle, aryl or the heteroaryl Base optionally further by one or more selected from halogen, hydroxyl, alkoxy, cyano, nitro, alkyl, halogenated alkyl, hydroxyalkyl, Naphthenic base, heterocycle, 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 group replaced；
R1Selected from alkyl, wherein the alkyl is further by one or more selected from naphthenic base, heterocycle, aryl or miscellaneous Replaced the substituent group of aryl, wherein naphthenic base, heterocycle, aryl or the heteroaryl is optionally further one or more Selected from halogen, hydroxyl, alkoxy, cyano, nitro, alkyl, halogenated alkyl, hydroxyalkyl, naphthenic base, heterocycle, aryl, heteroaryl Base ,-C (O) OR5、-OC(O)R5、-NHS(O)pR5、-C(O)R5、-NHC(O)R5、-NHC(O)OR5、-NR6R7、-OC(O)NR6R7 Or-C (O) NR6R7Substituent group replaced；
R2Selected from hydrogen atom, halogen, alkoxy, cyano, nitro or alkyl, wherein the alkyl or alkoxy optionally into One step is selected from halogen, hydroxyl, alkoxy, cyano, nitro, naphthenic base, heterocycle, aryl, heteroaryl ,-C by one or more (O)OR5、-OC(O)R5、-NHS(O)pR5、-C(O)R5、-NHC(O)R5、-NHC(O)OR5、-NR6R7、-OC(O)NR6R7Or-C (O) NR6R7Substituent group replaced；
R3Selected from hydrogen atom, halogen, alkoxy, cyano, nitro or alkyl, wherein the alkyl or alkoxy optionally into One step is selected from halogen, hydroxyl, alkoxy, cyano, nitro, naphthenic base, heterocycle, aryl, heteroaryl ,-C by one or more (O)OR5、-OC(O)R5、-NHS(O)pR5、-C(O)R5、-NHC(O)R5、-NHC(O)OR5、-NR6R7、-OC(O)NR6R7Or-C (O) NR6R7Substituent group replaced；
R4Selected from hydrogen atom or alkyl, wherein the alkyl optionally further by one or more selected from halogen, hydroxyl, Alkoxy, cyano, nitro, naphthenic base, heterocycle, 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 group replaced；
R5Selected from hydrogen atom, alkyl, naphthenic base, heterocycle, aryl or heteroaryl, wherein the alkyl, naphthenic base, virtue Base or heteroaryl are optionally further selected from alkyl, halogen, hydroxyl, hydroxyalkyl, alkoxy, naphthenic base, heterocycle by one or more Base, aryl, heteroaryl, carboxylic acid or carboxylate substituent group replaced；
R6Or R7It is each independently selected from hydrogen atom, alkyl, alkoxy, naphthenic base, heterocycle, aryl or heteroaryl, wherein Alkyl, alkoxy, naphthenic base, heterocycle, aryl or the heteroaryl is optionally further one or more each independently Substitution selected from alkyl, halogen, hydroxyl, hydroxyalkyl, alkoxy, naphthenic base, heterocycle, aryl, heteroaryl, carboxylic acid or carboxylate Replaced base；
Alternatively, R6Or R7Be formed together heterocycle with the nitrogen-atoms being connected, wherein in the heterocycle containing one or Multiple N, O or S (O)pHetero atom, and the heterocycle optionally further by one or more selected from alkyl, halogen, hydroxyl, Alkoxy, hydroxyalkyl, naphthenic base, heterocycle, aryl, heteroaryl, carboxylic acid or carboxylate substituent group replaced；
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, a kind of logical formula (I) compound represented or its tautomer, meso Body, racemic modification, enantiomter, diastereoisomer, or mixtures thereof form or its pharmaceutical salt, middle ring B be benzene Base or pyridyl group.
In a preferred embodiment of the invention, a kind of logical formula (I) compound represented or its tautomer, meso Body, racemic modification, enantiomter, diastereoisomer, or mixtures thereof form or its pharmaceutical salt, be general formula (II) compound represented or its tautomer, mesomer, racemic modification, enantiomter, diastereoisomer or its Form of mixtures or its pharmaceutical salt:
Wherein:
R1~R4, X, Y, m, n, ring A and ring C definition as described in logical formula (I).
In presently preferred scheme, a kind of logical formula (I) compound represented or its tautomer, meso Body, racemic modification, enantiomter, diastereoisomer, or mixtures thereof form or its pharmaceutical salt, middle ring A be selected from Heterocycle or aryl, preferably phenyl or morpholinyl.
In presently preferred scheme, a kind of logical formula (I) compound represented or its tautomer, meso Body, racemic modification, enantiomter, diastereoisomer, or mixtures thereof form or its pharmaceutical salt, be general formula (III) compound represented or its tautomer, mesomer, racemic modification, enantiomter, diastereoisomer or Its form of mixtures or its pharmaceutical salt:
Wherein:
R1~R4, X, Y, m, n and ring C definition as described in logical formula (I).
In presently preferred scheme, a kind of logical formula (I) compound represented or its tautomer, meso Body, racemic modification, enantiomter, diastereoisomer, or mixtures thereof form or its pharmaceutical salt, middle ring C be it is miscellaneous Ring group, preferably morpholine base or piperazinyl.
In another preferred embodiment of the invention, a kind of logical formula (I) compound represented or its tautomer, meso Body, racemic modification, enantiomter, diastereoisomer, or mixtures thereof form or its pharmaceutical salt, wherein R1Selected from- (CH2)r-Rc；
RcSelected from naphthenic base, heterocycle, aryl or heteroaryl, wherein naphthenic base, heterocycle, aryl or the heteroaryl Halogen, hydroxyl, alkoxy, cyano, nitro, alkyl, halogenated alkyl, hydroxyalkyl, ring are further optionally selected from by one or more Alkyl, heterocycle, 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 group 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, a kind of logical formula (I) compound represented or its tautomer, meso Body, racemic modification, enantiomter, diastereoisomer, or mixtures thereof form or its pharmaceutical salt, wherein R2It is selected from Hydrogen atom or alkyl, preferably methyl.
In presently preferred scheme, a kind of logical formula (I) compound represented or its tautomer, meso Body, racemic modification, enantiomter, diastereoisomer, or mixtures thereof form or its pharmaceutical salt, wherein R3It is selected from Hydrogen atom or alkyl, preferably methyl.
The typical compound of the present invention includes, but are not limited to:
Or its tautomer, mesomer, racemic modification, enantiomter, diastereoisomer, or mixtures thereof shape Formula or its officinal salt.
Logical formula (I) compound represented or its tautomer, mesomer, racemic are prepared the present invention also provides a kind of Body, enantiomter, diastereoisomer, or mixtures thereof form or its pharmaceutical salt method, this method comprises:
Under alkaline condition, general formula (IA) compound or its salt is reacted with general formula (IB) compound, optionally further hydrolysis And/or it is 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 present invention also provides a kind of general formula (IA) compound represented or its tautomer, mesomer, racemic modification, Enantiomter, diastereoisomer, or mixtures thereof form or its pharmaceutical salt:
Wherein:
X is selected from C (Ra)2, O, S or NRa；
RaIt is identical or different, it is each independently selected from hydrogen atom, alkyl, naphthenic base, heterocycle, aryl, heteroaryl ,-C (O)OR5、-C(O)R5、-C(O)NR6R7Or-S (O)pR5, wherein alkyl, naphthenic base, heterocycle, aryl or the heteroaryl are appointed Choosing is further selected from halogen, hydroxyl, alkoxy, cyano, nitro, alkyl, halogenated alkyl, hydroxyalkyl, cycloalkanes by one or more Base, heterocycle, 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 group replaced；
Condition is when X is selected from C (Ra)2When, RaIt is not selected from hydrogen atom；
Ring A is selected from naphthenic base, heterocycle, aryl or heteroaryl, preferably phenyl；
R1Selected from alkyl, wherein the alkyl is further by one or more selected from naphthenic base, heterocycle, aryl or miscellaneous Replaced the substituent group of aryl, wherein naphthenic base, heterocycle, aryl or the heteroaryl is optionally further one or more Selected from halogen, hydroxyl, alkoxy, cyano, nitro, alkyl, halogenated alkyl, hydroxyalkyl, naphthenic base, heterocycle, aryl, heteroaryl Base ,-C (O) OR5、-OC(O)R5、-NHS(O)pR5、-C(O)R5、-NHC(O)R5、-NHC(O)OR5、-NR6R7、-OC(O)NR6R7 Or-C (O) NR6R7Substituent group replaced；
R2Selected from hydrogen atom, halogen, alkoxy, cyano, nitro or alkyl, wherein the alkyl or alkoxy optionally into One step is selected from halogen, hydroxyl, alkoxy, cyano, nitro, naphthenic base, heterocycle, aryl, heteroaryl ,-C by one or more (O)OR5、-OC(O)R5、-NHS(O)pR5、-C(O)R5、-NHC(O)R5、-NHC(O)OR5、-NR6R7、-OC(O)NR6R7Or-C (O) NR6R7Substituent group replaced；
R5Selected from hydrogen atom, alkyl, naphthenic base, heterocycle, aryl or heteroaryl, wherein the alkyl, naphthenic base, virtue Base or heteroaryl are optionally further selected from alkyl, halogen, hydroxyl, hydroxyalkyl, alkoxy, naphthenic base, heterocycle by one or more Base, aryl, heteroaryl, carboxylic acid or carboxylate substituent group replaced；
R6Or R7It is each independently selected from hydrogen atom, alkyl, alkoxy, naphthenic base, heterocycle, aryl or heteroaryl, wherein Alkyl, alkoxy, naphthenic base, heterocycle, aryl or the heteroaryl is optionally further one or more each independently Substitution selected from alkyl, halogen, hydroxyl, hydroxyalkyl, alkoxy, naphthenic base, heterocycle, aryl, heteroaryl, carboxylic acid or carboxylate Replaced base；
Alternatively, R6Or R7Be formed together heterocycle with the nitrogen-atoms being connected, wherein in the heterocycle containing one or Multiple N, O or S (O)pHetero atom, and the heterocycle optionally further by one or more selected from alkyl, halogen, hydroxyl, Alkoxy, hydroxyalkyl, naphthenic base, heterocycle, aryl, heteroaryl, carboxylic acid or carboxylate substituent group replaced；
M is 0,1,2,3 or 4；And
P is 0,1 or 2.
The typical compound of general formula (IA) compound includes, but are not limited to:
Or its tautomer, mesomer, racemic modification, enantiomter, diastereoisomer, or mixtures thereof shape Formula or its officinal salt.
The invention further relates to a kind of pharmaceutical composition, described pharmaceutical composition contain therapeutically effective amount such as general formula (I) compound represented or its tautomer, mesomer, racemic modification, enantiomter, diastereoisomer or its Form of mixtures or its pharmaceutical salt and pharmaceutically acceptable carrier, diluent or excipient.Described pharmaceutical composition Further contain another or a variety of phosphate binders, the phosphate binder is preferably sevelamer.
The invention further relates to logical formula (I) compound represented or its tautomer, mesomer, racemic modification, Enantiomter, diastereoisomer, or mixtures thereof form or its pharmaceutical salt, or exist comprising its pharmaceutical composition Prepare the purposes in intestines 2B sodium phosphate cotransporter inhibitor.
The invention further relates to logical formula (I) compound represented or its tautomer, mesomer, racemic modification, Enantiomter, diastereoisomer, or mixtures thereof form or its pharmaceutical salt, or exist comprising its pharmaceutical composition Preparation treats or prevents the purposes in the drug of hyperphosphatemia.
The invention further relates to logical formula (I) compound represented or its tautomer, mesomer, racemic modification, Enantiomter, diastereoisomer, or mixtures thereof form or its pharmaceutical salt, or exist comprising its pharmaceutical composition Treat or prevent sodium phosphate transport protein mediate disease drug in purposes, the disease include but is not limited to nephrosis, The activated vitamin D or hyperthyroidism of high concentration caused by the calcification of inner membrance local vascular, hyperphosphatemia, it is described Nephrosis is preferably chronic nephrosis or end-stage renal disease.
The invention further relates to logical formula (I) compound represented or its tautomer, mesomer, racemic modification, mappings Isomers, diastereoisomer, or mixtures thereof form or its pharmaceutical salt, or comprising its pharmaceutical composition, be used as Intestines 2B type sodium phosphate cotransporter (Npt2b) inhibitor.
The invention further relates to logical formula (I) compound represented or its tautomer, mesomer, racemic modification, mappings Isomers, diastereoisomer, or mixtures thereof form or its pharmaceutical salt, or comprising its pharmaceutical composition, be used for Treat or prevent hyperphosphatemia.
The invention further relates to logical formula (I) compound represented or its tautomer, mesomer, racemic modification, mappings Isomers, diastereoisomer, or mixtures thereof form or its pharmaceutical salt, or comprising its pharmaceutical composition, be used for Treat or prevent sodium phosphate transport protein mediate disease, the disease be preferably selected from nephrosis, inner membrance local vascular calcification, Activated vitamin D, the hyperthyroidism of high concentration caused by hyperphosphatemia, the nephrosis are preferably chronic nephrosis Or end-stage renal disease.
The invention further relates to a kind of methods for inhibiting intestines 2B type sodium phosphate cotransporter comprising gives required patient It is the logical formula (I) compound represented of therapeutically effective amount or its tautomer, mesomer, racemic modification, enantiomter, non- Enantiomter, or mixtures thereof form or its pharmaceutical salt, or the pharmaceutical composition comprising it.
The invention further relates to a kind of methods for treating or preventing hyperphosphatemia comprising gives required bacterium Logical formula (I) compound represented or its tautomer, mesomer, racemic modification, enantiomter, diastereo-isomerism Body, or mixtures thereof form or its pharmaceutical salt, or the pharmaceutical composition comprising it.
The present invention relates to a kind of method of disease or illness that treatment or prevention sodium phosphate cotransporter mediates, packets Include the logical formula (I) compound represented or its tautomer, mesomer, racemic for giving required bacterium Body, enantiomter, diastereoisomer, or mixtures thereof form or its pharmaceutical salt, or the pharmaceutical composition comprising it Object, method described therein includes:
(a) method of hyperphosphatemia is treated；
(b) method of nephrosis is treated；
(c) delay the method for Rend dialysis time；
(d) weaken the method for inner membrance local vascular calcification；
(e) method of activated vitamin D caused by hyperphosphatemia is reduced；
(f) method of FGF23 is reduced；
(g) weaken the method for hyperthyroidism；
(h) improve the method for blood vessel endothelium exception by concentration phosphatic in post-prandial serum；
(i) method of urine phosphorus is reduced；
(j) make the method for phosphorus level standard in serum；
(k) method for the treatment of albumen urine；
(l) method of parathormone and phosphate concn in serum is reduced；
Wherein the nephrosis is chronic kidney disease or end-stage renal disease.
Pharmaceutical composition containing active constituent, which can be, is suitable for oral form, such as tablet, dragee, pastille, water Or oil suspension, dispersible powder or particle, lotion, hard or soft capsule or syrup or elixir.It can be any according to this field Know that the method for preparing Pharmaceutical composition prepares Orally administered composition, such composition can containing it is one or more it is selected from the following at Point: sweetener, corrigent, colorant and preservative, to provide pleasing and palatable pharmaceutical formulation.Tablet contain active constituent and The suitable nontoxic pharmaceutical excipient for preparing tablet for mixing.These excipient can be inert excipient, such as carbon Sour calcium, sodium carbonate, lactose, calcium phosphate or sodium phosphate；Granulating agent and disintegrating agent, such as microcrystalline cellulose, cross-linked carboxymethyl fiber Plain sodium, cornstarch or alginic acid；Adhesive, such as starch, gelatin, polyvinylpyrrolidone or Arabic gum and lubricant, example Such as magnesium stearate, stearic acid or talcum powder.These tablets can not be coated or can be by covering the taste of drug or in gastrointestinal tract Middle delay disintegration and absorption, thus the known technology for providing slow releasing function in a long time is coated.For example, water can be used Dissolubility taste masked substance, such as hydroxypropyl methyl cellulose or hydroxypropyl cellulose, or extend time substance such as ethyl fibre Dimension element, acetylbutyrylcellulose.
Also available wherein active constituent mixes hard bright with inert solid diluent such as calcium carbonate, calcium phosphate or kaolin Glue capsule or in which active constituent and water-solubility carrier such as polyethylene glycol or oily solvent such as peanut oil, atoleine or olive The Perle of olive oil mixing provides oral preparation.
Water slurry contains active material and the suitable excipient for preparing water slurry for mixing.Such excipient is Suspending agent, such as sodium carboxy methyl cellulose, methylcellulose, hydroxypropyl methyl cellulose, mosanom, polyvinylpyrrolidone And Arabic gum；Dispersing agent or wetting agent can be the contracting of naturally-produced phosphatide such as lecithin or alkylene oxide and fatty acid Close the condensation product of product such as Myrj 45 or ethylene oxide and long-chain fatty alcohol, such as 17 carbon ethylidene Oxygroup cetanol (heptadecaethyleneoxy cetanol) or ethylene oxide and the portion as derived from fatty acid and hexitol The condensation product of ester, such as polyoxyethylene sorbitol monoleate or ethylene oxide is divided to spread out with by fatty acid and hexitan The condensation product of raw partial ester, such as polyethylene oxide Sorbitan Monooleate.Aqueous suspension can also containing a kind of or Determination of Preservatives such as ethylparaben or nipalgin n-propyl, one or more colorants, one or more corrigents and one Kind or a variety of sweeteners, such as sucrose, saccharin or aspartame.
Oil suspension can by making active constituent be suspended in vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil, or It is formulated in mineral oil such as atoleine.Oil suspension can contain thickener, such as beeswax, hard paraffin or cetanol.It can Above-mentioned sweetener and corrigent is added, to provide palatable preparation.It can be by the way that antioxidant such as Butylated Hydroxyanisole or α-be added Give birth to these compositions of phenol preservation.
It can make to be suitable for preparing that water is suspended dispersible powder also and particle provides active constituent and is used for by the way that water is added Mixed dispersing agent or wetting agent, suspending agent or one or more preservatives.Suitable dispersing agent or wetting agent and suspending agent can Illustrate above-mentioned example.Other excipient such as sweetener, corrigent and colorant can also be added.By the way that antioxidant example is added As ascorbic acid saves these compositions.
Pharmaceutical composition of the invention is also possible to the form of oil in water emulsion.Oil mutually can be vegetable oil such as olive oil Or or mixtures thereof peanut oil or mineral oil such as atoleine.Suitable emulsifier can be naturally-produced phosphatide, such as Soybean lecithin and the ester as derived from fatty acid and hexitan or partial ester such as sorbitan monooleate and the partial ester and ring The condensation product of oxidative ethane, such as polyoxyethylene sorbitol monoleate.Emulsion can also contain sweetener, corrigent, prevent Rotten agent and antioxidant.Syrup and elixir can be prepared with Sweetening agents such as glycerol, propylene glycol, sorbierite or sucrose.Such preparation Moderator, preservative, colorant and antioxidant can be contained.
Pharmaceutical composition can be sterile injectable aqueous form.Can have in the acceptable solvent and solvent used Water, ringer's solution and isotonic sodium chlorrde solution.Aseptic injection preparation can be the aseptic injection that wherein active constituent is dissolved in oily phase Oil-in-water microemulsion.Such as active constituent is dissolved in the mixture of soybean oil and lecithin.Then water and sweet is added in oil solution Processing forms micro emulsion in the mixture of oil.Can be by a large amount of injections in part, it will be in injection or the blood flow of micro emulsion injection patient.Or Person preferably gives solution and micro emulsion in the way of it can keep the compounds of this invention constant circulating concentration.To keep this constant dense Degree, can be used continuous intravenous delivery device.The example of this device is Deltec CADD-PLUS.TM.5400 type vein note Penetrate pump.
Pharmaceutical composition can be for intramuscular and the aseptic injection water of subcutaneous administration or the form of oil suspension.It can be by Know technology, the dispersing agent or wetting agent and suspending agent for being suitable for those described above prepare the suspension.Aseptic injection preparation can also be with It is the aseptic injectable solution or suspension prepared in the acceptable diluent of nontoxic parenteral or solvent, such as 1,3-BDO The solution of middle preparation.Furthermore, it is convenient to use sterile fixed oil as solvent or suspension media.For this purpose, usable include Any reconciliation fixing oil including synthetic glycerine list or diester.In addition, fatty acid such as oleic acid can also prepare injection.
The compounds of this invention can be given by the suppository form for rectally.It can be by by drug and at normal temperatures For solid but in the rectum it is liquid, thus can dissolves and discharge the suitable nonirritant excipient mixing of drug in the rectum To prepare these pharmaceutical compositions.Substance of this kind includes the poly- second of cocoa butter, glycerin gelatine, hydrogenated vegetable oil, various molecular weight The mixture of the aliphatic ester of two pure and mild polyethylene glycol.
Well-known to those skilled in the art, the dosage of drug depends on many factors, including but and it is non-limiting with Lower factor: the activity of specific compound used, the age of patient, the weight of patient, the health status of patient, patient row by, Diet, administration time, administration mode, the rate of excretion, combination of drug of patient etc.；In addition, optimal therapeutic modality is such as controlled The type of the mode for the treatment of, the consumption per day of general formula compound (I) or pharmaceutical salt can be verified according to traditional therapeutic scheme.
Detailed description of the invention
Unless stated to the contrary, otherwise following that there are following meanings with term in the specification and in the claims.
" alkyl " refers to the aliphatic hydrocarbon group of saturation, straight chain and branched group including 1 to 20 carbon atom.Preferably comprise 1 To the alkyl of 10 carbon atoms, the alkyl of further preferably 1 to 6 carbon atom.Non-limiting embodiment include methyl, ethyl, N-propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl, sec-butyl, n-pentyl, 1,1- dimethyl propyl, 1,2- dimethyl propylene Base, 2,2- dimethyl propyl, 1- ethyl propyl, 2- methyl butyl, 3- methyl butyl, n-hexyl, 1- Ethyl-2-Methyl propyl, 1,1,2- thmethylpropyl, 1,1- dimethylbutyl, 1,2- dimethylbutyl, 2,2- dimethylbutyl, 1,3- dimethylbutyl, 2- ethyl-butyl, 2- methyl amyl, 3- methyl amyl, 4- methyl amyl, 2,3- dimethylbutyl, n-heptyl, 2- methylhexyl, 3- methylhexyl, 4- methylhexyl, 5- methylhexyl, 2,3- dimethyl amyl group, 2,4- dimethyl amyl group, 2,2- dimethyl-penten Base, 3,3- dimethyl amyl group, 2- ethylpentyl, 3- ethylpentyl, n-octyl, 2,3- dimethylhexanyl, 2,4- dimethylhexanyl, 2,5- dimethylhexanyls, 2,2- dimethylhexanyl, 3,3- dimethylhexanyl, 4,4- dimethylhexanyl, 2- ethylhexyl, 3- ethyl Hexyl, 4- ethylhexyl, 2- methyl -2- ethylpentyl, 2- methyl -3- ethylpentyl, n-nonyl, 2- methyl -2- ethylhexyl, 2- methyl -3- ethylhexyl, 2,2- diethyl amyl group, positive decyl, 3,3- diethylhexyl, 2,2- diethylhexyl, and its it is each Kind branched isomer etc..Low alkyl group more preferably containing 1 to 6 carbon atom, non-limiting embodiment include methyl, second Base, n-propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl, sec-butyl, n-pentyl, 1,1- dimethyl propyl, 1,2- dimethyl Propyl, 2,2- dimethyl propyl, 1- ethyl propyl, 2- methyl butyl, 3- methyl butyl, n-hexyl, 1- Ethyl-2-Methyl third Base, 1,1,2- thmethylpropyl, 1,1- dimethylbutyl, 1,2- dimethylbutyl, 2,2- dimethylbutyl, 1,3- dimethyl butyrate Base, 2- ethyl-butyl, 2- methyl amyl, 3- methyl amyl, 4- methyl amyl, 2,3- dimethylbutyl etc..Alkyl, which can be, to be taken Generation or unsubstituted, when substituted, substituent group can be substituted on any workable tie point, preferably one or Multiple following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, sulfydryl, hydroxyl, Nitro, cyano, naphthenic base, heterocycle, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, Oxo base, amino, halogenated alkyl, hydroxyalkyl, carboxyl, carboxylate ,-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 alkane as defined above by being at least made of two carbon atoms and at least one carbon-to-carbon double bond Base, such as vinyl, 1- acrylic, 2- acrylic, 1-, 2- or 3- cyclobutenyl etc..It is preferred that C2-10Alkenyl, more preferable C2-6Alkenyl, Most preferably C2-4Alkenyl.Alkenyl can be it is substituted or non-substituted, when substituted, substituent group be preferably it is one or more with Lower group, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, sulfydryl, hydroxyl, nitro, Cyano, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, oxo Base, amino, halogenated alkyl, hydroxyalkyl, carboxylic acid group, carboxylate ,-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 alkane as defined above being at least made of two carbon atoms and at least one carbon-carbon triple bond Base, such as acetenyl, 1- propinyl, 2-propynyl, 1-, 2- or 3- butynyl etc..It is preferred that C2-10Alkynyl, more preferable C2-6Alkynyl, Most preferably C2-4Alkynyl.Alkynyl can be it is substituted or non-substituted, when substituted, substituent group be preferably it is one or more with Lower group, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, sulfydryl, hydroxyl, nitro, Cyano, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, oxo Base, amino, halogenated alkyl, hydroxyalkyl, carboxylic acid group, carboxylate ,-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。
" naphthenic base " refers to the unsaturated monocycle of saturation or part or polycyclic cyclic hydrocarbon substituent comprising 3 to 20 carbon atoms, 3 to 12 carbon atoms are preferably included, more preferable cycloalkyl ring includes 3 to 10 carbon atoms, and most preferably cycloalkyl ring includes 3 to 6 A carbon atom.The non-limiting embodiment of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopenta, cyclopentenyl, cyclohexyl, Cyclohexenyl group, cyclohexadienyl, suberyl, cycloheptatriene base, cyclooctyl etc., preferably cyclopropyl, cyclohexenyl group.Polycyclic naphthene base Naphthenic base including loop coil, condensed ring and bridged ring.
" spiro cycloalkyl group " refers to 5 to 20 yuan, the polycyclic moiety of a carbon atom (claiming spiro-atom) is shared between monocycle, these can To contain one or more double bonds, but none ring has the pi-electron system of total conjugated.Preferably 6 to 14 yuan, more preferably It is 7 to 10 yuan.Spiro cycloalkyl group is divided into single spiro cycloalkyl group, double spiro cycloalkyl group bases according to the number for sharing spiro-atom between ring and ring Or more spiro cycloalkyl groups, 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 Member/5 yuan or 5 yuan/6 yuan single spiro cycloalkyl groups.The non-limiting embodiment of spiro cycloalkyl group includes
" cycloalkyl " refers to 5 to 20 yuan, and each ring in system and shared a pair of of the carbon adjoined of other rings in system are former The full carbon polycyclic moiety of son, wherein one or more rings can be containing one or more double bonds, but none ring has completely The pi-electron system of conjugation.Preferably 6 to 14 yuan, more preferably 7 to 10 yuan.According to a group cyclic number can be divided into it is bicyclic, three Ring, Fourth Ring or polycyclic fused ring alkyl, preferably bicyclic or tricyclic, more preferably 5 yuan/5 yuan or 5 yuan/6 membered bicyclic alkyl.Condensed ring The non-limiting embodiment of alkyl includes
" bridge ring alkyl " refers to 5 to 20 yuan, and any two ring shares the full carbon polycyclic group of two carbon atoms being not directly connected Group, these can be containing one or more double bonds, but none ring has the pi-electron system of total conjugated.Preferably 6 to 14 Member, more preferably 7 to 10 yuan.Bicyclic, tricyclic, Fourth Ring or polycyclic bridge ring alkyl can be divided into according to a group cyclic number, preferably For bicyclic, tricyclic or Fourth Ring, it is more selected as bicyclic or tricyclic.The non-limiting embodiment of bridge ring alkyl includes
The cycloalkyl ring can be condensed on aryl, heteroaryl or heterocyclic ring, wherein being connected to one with precursor structure The ring risen is naphthenic base, and non-limiting embodiment includes indanyl, tetralyl, benzocyclohepta alkyl etc..Naphthenic base can be Optionally substituted or unsubstituted, when substituted, substituent group is preferably one or more following groups, independently selected from alkane Base, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, sulfydryl, hydroxyl, nitro, cyano, naphthenic base, heterocycle, virtue Base, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, oxo base, amino, halogenated alkyl, hydroxyl alkane Base, carboxyl, carboxylate ,-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。
" heterocycle " refers to the unsaturated monocycle of saturation or part or polycyclic cyclic hydrocarbon substituent comprising 3 to 20 annular atoms, Wherein one or more annular atoms are selected from nitrogen, oxygen or S (O)m(wherein m be 0 to 2 integer) hetero atom, but do not include-O- The loop section of O- ,-O-S- or-S-S-, remaining annular atom are carbon.3 to 12 annular atoms are preferably included, wherein 1~4 is miscellaneous original Son；More preferable heterocyclic ring includes 3 to 10 annular atoms, wherein 1~3 is hetero atom；More preferable heterocyclic ring includes 5 to 6 A annular atom, wherein 1~2 is hetero atom.The non-limiting embodiment of monocyclic heterocycles base includes pyrrolidinyl, piperidyl, piperazine Piperazine base, morpholinyl, thio-morpholinyl, high piperazine base, pyranose, tetrahydrofuran base etc..Multiring heterocyclic include loop coil, condensed ring and The heterocycle of bridged ring.
" spiro heterocyclic radical " refers to 5 to 20 yuan, and the polycyclic heterocyclic group of an atom (claiming spiro-atom) is shared between monocycle, 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 are carbon.These Can be containing one or more double bonds, but none ring has the pi-electron system of total conjugated.It is preferably 6 to 14 yuan, more excellent It is selected as 7 to 10 yuan.Spiro cycloalkyl group is divided into single spiro heterocyclic radical, double spiro heterocyclic radicals according to the number for sharing spiro-atom between ring and ring Or more spiro heterocyclic radicals, 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 Member/5 yuan or 5 yuan/6 yuan single spiro heterocyclic radicals.The non-limiting embodiment of spiro heterocyclic radical includes
" condensed hetero ring base " refers to 5 to 20 yuan, each ring in system and shared a pair of of the atom adjoined of other rings in system Polycyclic heterocyclic group, one or more rings can be containing one or more double bonds, but none ring has the π of total conjugated Electronic system, 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 ring Atom is carbon.Preferably 6 to 14 yuan, more preferably 7 to 10 yuan.Bicyclic, tricyclic, Fourth Ring can be divided into according to a group cyclic number Or polycyclic condensed hetero ring base, preferably bicyclic or tricyclic, more preferably 5 yuan/5 yuan or 5 yuan/6 membered bicyclic condensed hetero ring bases.Condensed hetero ring base Non-limiting embodiment include
" bridge heterocycle " refers to 5 to 14 yuan, and any two ring shares the polycyclic heterocyclic group of two atoms being not directly connected, These can be containing one or more double bonds, but none ring has the pi-electron system of total conjugated, wherein one or more Annular atom is selected from nitrogen, oxygen or S (O)mThe hetero atom of (wherein m is integer 0 to 2), remaining annular atom are carbon.Preferably 6 to 14 yuan, More preferably 7 to 10 yuan.Bicyclic, tricyclic, Fourth Ring or polycyclic bridge heterocycle can be divided into according to a group cyclic number, it is preferably double Bicyclic or tricyclic is more selected as at ring, tricyclic or Fourth Ring.The non-limiting embodiment of bridge heterocycle includes:
The heterocyclic ring can be condensed on aryl, heteroaryl or cycloalkyl ring, wherein being connected to one with precursor structure The ring risen is heterocycle, and non-limiting embodiment includes:
Deng.
Heterocycle can be it is optionally substituted or unsubstituted, when substituted, substituent group be preferably it is one or more with Lower group, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, sulfydryl, hydroxyl, nitro, cyanogen Base, naphthenic base, heterocycle, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, oxo base, Amino, halogenated alkyl, hydroxyalkyl, carboxyl, carboxylate ,-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 " refers to that 6 to 14 yuan of full carbon monocycles of the pi-electron system with conjugation or fused polycycle are (namely shared to adjoin The ring of carbon atom pair) group, preferably 6 to 10 yuan, more preferable phenyl and naphthalene, most preferably phenyl.The aryl rings can be thick Together on heteroaryl, heterocycle or cycloalkyl ring, wherein being aryl rings, non-limiting reality with the ring that precursor structure links together Applying example includes:
Aryl can be substituted or unsubstituted, and when substituted, substituent group is preferably one or more following groups, Independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, sulfydryl, hydroxyl, nitro, cyano, cycloalkanes Base, heterocycle, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, amino, halogenated alkyl, Hydroxyalkyl, carboxyl, carboxylate ,-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 that with 1 to 4 hetero atom, as annular atom, remaining annular atom is 5 to 14 yuan of aryl of carbon, Middle hetero atom includes oxygen, sulphur and nitrogen.Preferably 5 to 10 yuan.Heteroaryl preferably be it is 5- or 6-membered, such as furyl, thienyl, Pyridyl group, pyrrole radicals, N- alkyl pyrrole radicals, pyrimidine radicals, pyrazinyl, imidazole radicals, tetrazole radical etc..The heteroaryl ring can condense In on aryl, heterocycle or cycloalkyl ring, wherein being heteroaryl ring, non-limiting implementation with the ring that precursor structure links together Example includes:
Heteroaryl can be it is optionally substituted or unsubstituted, when substituted, substituent group be preferably it is one or more with Lower group, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, sulfydryl, hydroxyl, nitro, cyanogen Base, naphthenic base, heterocycle, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, amino, halogen Substituted alkyl, hydroxyalkyl, carboxyl, carboxylate ,-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 naphthenic base), and wherein alkyl is as defined above.Non- limit Property embodiment processed includes methoxyl group, ethyoxyl, propoxyl group, butoxy, cyclopropyl oxygroup, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy Deng.Alkoxy can be optionally substituted or unsubstituted, and when substituted, substituent group is preferably one or more following bases Group, independently selected from for alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, sulfydryl, hydroxyl, nitro, cyanogen Base, naphthenic base, heterocycle, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, amino, halogen Substituted alkyl, hydroxyalkyl, carboxyl, carboxylate ,-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。
" halogenated alkyl " refers to that alkyl is replaced by one or more halogens, and wherein alkyl is as defined above.
" hydroxyl " refers to-OH group.
" 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 " refers to-CN.
" nitro " refers to-NO2。
" benzyl " refers to-CH2Phenyl.
" oxo base " refers to=O.
" carboxyl " refers to-C (O) OH.
" carboxylate " refers to-C (O) O (alkyl) or (naphthenic base), and wherein alkyl, naphthenic base are as defined above.
" optional " or " optionally " mean ground described later event or environment can with but need not occur, which includes The event or environment generation or not spot occasion.For example, meaning that alkyl can be with " optionally by alkyl-substituted heterocyclic group " 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 hydrogen atoms in group, preferably at most 5, more preferably 1~3 hydrogen atom Replaced independently of one another by the substituent group of respective number.Self-evident, substituent group is only in their possible chemical position, this Field technical staff, which can determine in the case where not paying excessive make great efforts and (pass through experiment or theoretical), may or impossible take Generation.It may be unstable when for example, amino or hydroxyl with free hydrogen are in conjunction with the carbon atom with unsaturated (such as olefinic) key Fixed.
" pharmaceutical composition " indicate containing one or more compounds described herein or its physiologically pharmaceutical salt or The mixture and the pharmaceutical carrier of other components such as physiology and excipient of pro-drug and other chemical constituents.Medicine The purpose of compositions is the administration promoted to organism, plays bioactivity in turn conducive to the absorption of active constituent.
p、R5~R7Definition as described in logical formula (I) compound.
Synthetic method of the invention
In order to complete synthesis purpose of the invention, the present invention uses following synthetic technology scheme:
The present invention lead to compound or its tautomer described in formula (I), mesomer, racemic modification, enantiomter, Diastereoisomer, or mixtures thereof form or its officinal salt preparation method, method includes the following steps:
Under condition of ice bath, general formula (Ia) compound and 2- cyanoacetic acid carry out condensation reaction in the presence of condensing agent, obtain To general formula (Ib) compound；General formula (Ib) compound and general formula (Ic) compound are reacted under the conditions of existing for the morpholine, Obtain general formula (Id) compound；General formula (Id) compound and sulphur are reacted under the conditions of existing for the morpholine, and it is logical to obtain general formula Formula (IA) compound；Under alkaline condition, general formula (IA) compound or its salt and general formula (IB) compound are in the presence of condensing agent Condensation reaction is carried out, logical formula (I) compound is optionally further hydrolyzed and/or be condensed to yield；
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, the reagent for providing alkaline condition includes organic base and inorganic base, and described is organic Bases includes but is not limited to triethylamine, morpholine, n,N-diisopropylethylamine, pyridine, sodium hexamethyldisilazide, normal-butyl Lithium, potassium tert-butoxide or tetrabutylammonium bromide, the inorganic base include but is not limited to lithium hydroxide, sodium hydroxide, hydroxide Potassium, sodium hydride, sodium carbonate, sodium bicarbonate, potassium carbonate, saleratus or cesium carbonate, preferably triethylamine.
Condensing agent includes but is not limited to 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride, N,-two hexamethylene of N ' Base carbodiimides, N, N '-diisopropylcarbodiimide, O- benzotriazole-N, N, N ', N '-tetramethylurea tetrafluoro boric acid Ester, I-hydroxybenzotriazole, 1- hydroxyl -7- azo benzotriazole, O- benzotriazole-N, N, N ', N '-tetramethylurea (TMU) hexafluoro phosphorus Acid esters, 2- (7- azo benzotriazole)-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester, benzotriazole -1- base oxygroup three (dimethylamino) phosphorus hexafluorophosphate or hexafluorophosphoric acid benzotriazole -1- base-oxygroup tripyrrole alkyl phosphorus.
Detailed description of the invention
Fig. 1: Npt2b three day averages influenced on rat phosphuresis, ratio are to reduce degree of convergence.
Specific embodiment
The present invention is further described with reference to embodiments, but these embodiments are not intended to limit the scope of the invention.
Test method without specific conditions in the embodiment of the present invention, usually according to normal condition, or according to raw material or Condition proposed by commodity manufacturer.The reagent in specific source is not specified, for the conventional reagent of market purchase.
Embodiment
The structure of compound is by nuclear magnetic resonance (NMR) or mass spectrum (MS) come what is determined.The measurement of NMR is to use Bruker AVANCE-400 nuclear magnetic resonance spectrometer, measurement solvent are deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), it is inside designated as tetramethylsilane (TMS), chemical shift is with 10-6(ppm) it is provided as unit.
The measurement of MS is with FINNIGAN LCQAd (ESI) mass spectrograph (manufacturer: Thermo, model: Finnigan LCQ advantage MAX)。
The measurement of HPLC uses Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18 150 × 4.6mm chromatography Column) and Waters 2695-2996 high pressure liquid chromatograph (Gimini 150 × 4.6mm of C18 chromatographic column).
Kinases average inhibition and IC50The measurement of value is with NovoStar microplate reader (German BMG company).
Tlc silica gel plate uses Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica gel plate, and thin-layered chromatography (TLC) makes The specification that silica gel plate uses is 0.15mm~0.2mm, thin-layer chromatography isolate and purify product use specification be 0.4mm~ 0.5mm silica gel plate.
Column chromatography is generally carrier using 200~300 mesh silica gel of the Yantai Huanghai Sea.
Known starting material of the invention can be used or be synthesized according to methods known in the art, or can purchase certainly ABCR GmbH&Co.KG, Acros Organnics, Aldrich Chemical Company, splendid remote chemical science and technology (Accela ChemBio Inc), up to the companies such as auspicious chemicals.
In embodiment unless otherwise specified, reaction carries out under argon atmospher or nitrogen atmosphere.
Argon atmospher or nitrogen atmosphere refer to that reaction flask connects the argon gas or nitrogen balloon of an about 1L volume.
Nitrogen atmosphere refers to that reaction flask connects the hydrogen balloon of an about 1L volume.
Pressure hydration reaction uses Parr 3916EKX type hydrogenation instrument and clear indigo plant QL-500 type hydrogen generator or HC2-SS Type hydrogenates instrument.
Hydrogenation usually vacuumizes, and is filled with hydrogen, operates 3 times repeatedly.
Microwave reaction uses 908860 type microwave reactor of CEM Discover-S.
In embodiment unless otherwise specified, the solution in reaction refers to 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), reacts the system of used solvent Have: A: methylene chloride 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 different according to the polarity of compound and is adjusted.
The system of the solvent of the system and thin-layered chromatography of the eluant, eluent for the column chromatography that purifying compound uses includes: A: Methylene chloride and methanol system, B: n-hexane and ethyl acetate system, C: n-hexane and acetone system, D: n-hexane, E: acetic acid The volume ratio of ethyl ester, solvent is different according to the polarity of compound and is adjusted, and a small amount of triethylamine and acidity can also be added Or alkaline reagent etc. is adjusted.
Embodiment 1
4- (3- (4- (2- (3- (methyl (2- morpholine ethyl) carbamyl) benzamido) -4,5,6,7- tetrahydro benzene And [b] thiophene -3- formamido) phenyl) propyl) benzoic acid
The first step
4- (3- (4- (2- (3- (methyl (2- morpholine ethyl) carbamyl) benzamido) -4,5,6,7- tetrahydro benzene And [b] thiophene -3- formamido) phenyl) propyl) methyl benzoate
By 4- (3- (4- (2- amino -4,5,6,7- tetrahydro benzos [b] thiophene -3- formamido) phenyl) propyl) benzoic acid Methyl esters 1a (149mg, 0.33mmol are prepared using method disclosed in patent application " WO2011136269 ") is dissolved in 5mL It in methylene chloride, is added triethylamine (101mg, 1mmol), 5mL 3- (methyl (2- morpholine ethyl) carbamyl) then is added The dichloro of chlorobenzoyl chloride 1b (124mg, 0.40mmol are prepared using method disclosed in patent application " WO2012006477 ") Dichloromethane is stirred to react 3 hours.20mL water is added, is extracted with dichloromethane (50mL × 3), merges organic phase, successively uses water (50mL × 1), saturated sodium chloride solution (50mL × 1) washing, anhydrous sodium sulfate dry, filter, and filtrate decompression concentration obtains thick Product title product 4- (3- (4- (2- (3- (methyl (2- morpholine ethyl) carbamyl) benzamido) -4,5,6,7- tetrahydros Benzo [b] thiophene -3- formamido) phenyl) propyl) methyl benzoate 1c (238mg, yellow solid), product is straight without further purification Row is tapped into react in next step.
MS m/z (ESI): 723.2 [M+1]
1H NMR (400MHz, DMSO-d6) δ 11.59 (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- morpholine ethyl) carbamyl) benzamido) -4,5,6,7- tetrahydro benzene And [b] thiophene -3- formamido) phenyl) propyl) benzoic acid
By crude product 4- (3- (4- (2- (3- (methyl (2- morpholine ethyl) carbamyl) benzamido) -4,5,6,7- Tetrahydro benzo [b] thiophene -3- formamido) phenyl) propyl) methyl benzoate 1c (238mg, 0.33mmol) is dissolved in 10mL tetra- In hydrogen furans, 3mL 2M sodium hydroxide solution is added, is stirred to react 2 hours.30mL water is added, with n-hexane and ethyl acetate (V : V=1: 1) mixed solution extracts (20mL × 2), merges water phase, and it is 2~3 that 2M hydrochloric acid, which is added dropwise, to water phase pH, and solid is precipitated.It crosses Filter, filter cake drying, with HPLC preparative separation method purify obtained by residue, obtain title product 4- (3- (4- (2- (3- (methyl (2- Morpholine ethyl) carbamyl) benzamido) -4,5,6,7- tetrahydro benzos [b] thiophene -3- formamido) phenyl) propyl) Benzoic acid 1 (160mg, white solid), yield: 68.7%.
MS m/z (ESI): 709.2 [M+1]
1H NMR (400MHz, DMSO-d6): δ 12.77 (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- morpholine ethyl) urea groups) benzamido) -4,5,6,7- tetrahydro benzos [b] thiophene -3- formamido) phenethyl) benzoic acid
The first step
3- (3- methyl -3- (2- morpholine ethyl) urea groups) chlorobenzoyl chloride
By 3- (3- methyl -3- (2- morpholine ethyl) urea groups) benzoic acid 2a (150mg, 0.50mmol, using patent application Method disclosed in " WO2012054110 " is prepared) it is dissolved in 60mL methylene chloride, it is cooled to 0 DEG C, thionyl chloride is added (177mg, 1.50mmol) is warming up to reflux, is stirred to react 2 hours.Reaction solution is concentrated under reduced pressure, and obtains crude title product 3- (3- methyl -3- (2- morpholine ethyl) urea groups) chlorobenzoyl chloride 2b (163mg, white solid), product directly carry out without further purification It reacts in next step.
Second step
4- (4- (2- (3- (3- methyl -3- (2- morpholine ethyl) urea groups) benzamido) -4,5,6,7- tetrahydro benzos [b] thiophene -3- formamido) phenethyl) methyl benzoate
By 4- (4- (2- amino -4,5,6,7- tetrahydro benzos [b] thiophene -3- formamido) phenethyl) methyl benzoate 2c (144mg, 0.33mmol are prepared using method disclosed in patent application " WO2011136269 ") is dissolved in tri- chloromethane of 5mL It in alkane, is added triethylamine (101mg, 1mmol), is cooled to 0 DEG C, crude product 3- (3- methyl -3- (2- morpholine ethyl) urea is added Base) chlorobenzoyl chloride 2b (163mg, 0.50mmol) dichloromethane solution, be warmed to room temperature, be stirred to react 12 hours.50mL is added Water is extracted with dichloromethane (50mL × 3), merges organic phase, successively uses water (50mL × 1), saturated sodium chloride solution (50mL × 1) wash, anhydrous sodium sulfate dries, filters, filtrate decompression concentration, with silica gel column chromatography with eluant, eluent system B purify obtained by it is residual Excess obtains title product 4- (4- (2- (3- (3- methyl -3- (2- morpholine ethyl) urea groups) benzamido) -4,5,6,7- Tetrahydro benzo [b] thiophene -3- formamido) phenethyl) methyl benzoate 2d (136mg, faint yellow solid), yield: 57.1%.
MS m/z (ESI): 724.2 [M+1]
1H NMR (400MHz, DMSO-d6): δ 13.44 (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)
Third step
4- (4- (2- (3- (3- methyl -3- (2- morpholine ethyl) urea groups) benzamido) -4,5,6,7- tetrahydro benzos [b] thiophene -3- formamido) phenethyl) benzoic acid
By 4- (4- (2- (3- (3- methyl -3- (2- morpholine ethyl) urea groups) benzamido) -4,5,6,7- tetrahydro benzene And [b] thiophene -3- formamido) phenethyl) methyl benzoate 2d (136mg, 0.19mmol) be dissolved in 4.5mL tetrahydrofuran and In the mixed solution of ethyl alcohol (V: V=2: 1), 1.1mL 2M sodium hydroxide solution is added, is warming up to 25 DEG C, it is small to be stirred to react 12 When.Reaction solution be concentrated under reduced pressure, with HPLC preparative separation method purify obtained by residue, obtain title product 4- (4- (2- (3- (3- first Base -3- (2- morpholine ethyl) urea groups) benzamido) -4,5,6,7- tetrahydro benzos [b] thiophene -3- formamido) benzene second Base) benzoic acid 2 (15mg, white solid), yield: 11.3%.
MS m/z (ESI): 710.2 [M+1]
1H NMR (400MHz, DMSO-d6): δ 8.71 (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- morpholine ethyl) carbamyl) benzamido) -6- ((tetrahydro -2H- pyrrole Mutter -4- base) methyl) -4,5,6,7- thiophanes simultaneously [2,3-c] pyridine-3-carboxamide base) phenyl) propyl) benzoic acid
The first step
2- amino -3- (4- (3- (4- (methoxycarbonyl) phenyl) propyl) anilinocarbonyl) -4,5- dihydro-thiophene simultaneously [2, 3-c] pyridine -6 (7H)-t-butyl formate
Sulphur (71mg, 2.23mmol) is dissolved in 20mL ethyl alcohol, 4- (3- (4- (2- cyano-acetamide amido) is sequentially added Phenyl) propyl) methyl benzoate 3a (750mg, 2.23mmol, using method system disclosed in patent application " WO2013062065 " It is standby and obtain), 4- carbonyl piperidines -1- t-butyl formate (443mg, 4.97mmol) and morpholine (213mg, 2.45mmol), heating rise Temperature is stirred to react 12 hours to 90 DEG C.60mL saturated sodium chloride solution is added, (50mL × 3) are extracted with ethyl acetate, are associated with Machine phase washs (50mL × 1) with saturated sodium chloride solution, and anhydrous sodium sulfate dries, filters, and silicagel column is used in filtrate decompression concentration Chromatography purifies gained residue with eluant, eluent system A, obtains title product 2- amino -3- (4- (3- (4- (methoxycarbonyl) Phenyl) propyl) anilinocarbonyl) -4,5- dihydro-thiophene 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) anilinocarbonyl) -2- (3- (methyl (2- morpholine ethyl) Carbamyl) benzamido) -4,5- dihydro-thiophene simultaneously [2,3-c] pyridine -6 (7H)-t-butyl formate
By 3- (methyl (2- morpholine ethyl) carbamyl) benzoic acid 3c (85mg, 0.30mmol, using patent application Method disclosed in " W02012006477 " is prepared) and 2- amino -3- (4- (3- (4- (methoxycarbonyl) phenyl) propyl) benzene Amino carbonyl) simultaneously [2,3-c] pyridine -6 (7H)-t-butyl formate 3b (100mg, 0.18mmol) is dissolved in -4,5- dihydro-thiophene In 10mL methylene chloride, 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride (52mg, 0.27mmol) is sequentially added With 4-dimethylaminopyridine (33mg, 0.27mmol), it is stirred to react 24 hours.50mL water is added, (50mL is extracted with ethyl acetate × 3), merge organic phase, wash (50mL × 1) with saturated sodium chloride solution, anhydrous sodium sulfate dries, filters, and filtrate decompression is dense Contracting, with silica gel column chromatography with eluant, eluent system A purify obtained by residue, obtain title product 3- (4- (3- (4- (methoxyl group carbonyl Base) phenyl) propyl) anilinocarbonyl) -2- (3- (methyl (2- morpholine ethyl) carbamyl) benzamido) -4,5- bis- Hydrogen thieno [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): δ 11.66 (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)
Third step
4- (3- (4- (2- (3- (methyl (2- morpholine ethyl) carbamyl) benzamido) -4,5,6,7- tetrahydro thiophenes Pheno simultaneously [2,3-c] pyridine-3-carboxamide base) phenyl) propyl) methyl benzoate
By 3- (4- (3- (4- (methoxycarbonyl) phenyl) propyl) anilinocarbonyl) -2- (3- (methyl (2- morpholine second Base) carbamyl) benzamido) and -4,5- dihydro-thiophene simultaneously [2,3-c] pyridine -6 (7H)-t-butyl formate 3d (100mg, It 0.10mmol) is dissolved in 3mL methylene chloride, is cooled to 0 DEG C, 0.5mL trifluoroacetic acid is added, is stirred to react 30 minutes.It is added dropwise Saturated sodium carbonate is 9~10 to reaction solution pH, is extracted with dichloromethane (50mL × 3), and organic phase is merged, molten with saturated sodium-chloride Liquid washs (50mL × 1), and anhydrous sodium sulfate dries, filters, and filtrate decompression concentration obtains crude title product 4- (3- (4- (2- (3- (methyl (2- morpholine ethyl) carbamyl) benzamido) -4,5,6,7- thiophanes simultaneously [2,3-c] pyridine -3- first Amide groups) phenyl) propyl) methyl benzoate 3e (50mg, yellow solid), product is directly entered without further purification to react in next step.
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- morpholine ethyl) carbamyl) benzamido) -6- ((tetrahydro -2H- pyrrole Mutter -4- base) methyl) -4,5,6,7- thiophanes simultaneously [2,3-c] pyridine-3-carboxamide base) phenyl) propyl) methyl benzoate
By crude product 4- (3- (4- (2- (3- (methyl (2- morpholine ethyl) carbamyl) benzamido) -4,5,6,7- Thiophane simultaneously [2,3-c] pyridine-3-carboxamide base) phenyl) propyl) methyl benzoate 3e (100mg, 0.14mmol) is dissolved in 5mLN in dinethylformamide, sequentially adds potassium carbonate (57mg, 0.41mmol) and 4- toluenesulfonic acid (tetrahydro -2H- pyrrole Mutter -4- base) methyl ester (56mg, 0.21mmol, using well known method document " Bioorganic&Medicinal Chemistry Letters, 21 (8), 2541-2546 " are prepared), 70 DEG C are heated to, is stirred to react 12 hours.It is added 30mL water is extracted with ethyl acetate (30mL × 3), merges organic phase, is washed (30mL × 1) with saturated sodium chloride solution, anhydrous Sodium sulphate dries, filters, filtrate decompression concentration, with silica gel column chromatography with eluant, eluent system A purify obtained by residue, marked Inscribe product 4- (3- (4- (2- (3- (methyl (2- morpholine ethyl) carbamyl) benzamido) -6- ((tetrahydro -2H- pyrans - 4- yl) methyl) -4,5,6,7- thiophanes simultaneously [2,3-c] pyridine-3-carboxamide base) phenyl) propyl) 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- morpholine ethyl) carbamyl) benzamido) -6- ((tetrahydro -2H- pyrrole Mutter -4- base) methyl) -4,5,6,7- thiophanes simultaneously [2,3-c] pyridine-3-carboxamide base) phenyl) propyl) benzoic acid
By 4- (3- (4- (2- (3- (methyl (2- morpholine ethyl) carbamyl) benzamido) -6- ((tetrahydro -2H- Pyrans -4- base) methyl) -4,5,6,7- thiophanes simultaneously [2,3-c] pyridine-3-carboxamide base) phenyl) propyl) methyl benzoate 3f (31mg, 0.04mmol) is dissolved in 5mL methanol, and 5mL 2M sodium hydroxide solution is added, is warming up to 50 DEG C, is stirred to react 1 Hour.It is 2~3 that 3M hydrochloric acid, which is added dropwise, to water phase pH, and solid is precipitated.Filtering, filter cake drying, purify with HPLC preparative separation method obtained by Residue obtains title product 4- (3- (4- (2- (3- (methyl (2- morpholine ethyl) carbamyl) benzamido) -6- ((tetrahydro -2H- pyrans -4- base) methyl) -4,5,6,7- thiophanes simultaneously [2,3-c] pyridine-3-carboxamide base) phenyl) propyl) Benzoic acid 3 (20mg, white solid), yield: 66.7%.
MS m/z (ESI): 808.4 [M+1]
1H NMR (400MHz, CD3OD): δ 8.08-8.15 (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-yl) ethyl) carbamyl) benzamido) -4,5,6, 7- tetrahydro benzo [b] thiophene -3- formamido) phenethyl) benzoic acid
The first step
3- (methyl (2- (4- methylpiperazine-1-yl) ethyl) carbamyl) methyl benzoate
By N- methyl -2- (4- methylpiperazine-1-yl) ethamine 4b (1.73g, 11.01mmol, using patent application Method disclosed in " WO2013014448 " is prepared) it is dissolved in 35mL methylene chloride, addition triethylamine (2.22g, 22.02mmol), it is cooled to 0 DEG C, 5mL3- (chloroformyl) methyl benzoate 4a (56mg, 0.21mmol, using well known is added Method document " Journal of the American Chemical Society, 135 (45), 16841-16844；2013 " systems It is standby and obtain) dichloromethane solution, be warmed to room temperature, be stirred to react 2 hours.Reaction solution be concentrated under reduced pressure, with silica gel column chromatography with Eluant, eluent system A purifying gained residue, obtains title product 3- (methyl (2- (4- methylpiperazine-1-yl) ethyl) carbamyl Base) 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-yl) ethyl) carbamyl) benzoic acid
By 3- (methyl (2- (4- methylpiperazine-1-yl) ethyl) carbamyl) methyl benzoate 4c (530mg, 1.66mmol), lithium hydroxide (209mg, 4.98mmol) is dissolved in 14mL tetrahydrofuran, and water and methanol (V: V: V=5: 4: 5) are mixed In bonding solvent, it is stirred to react 1 hour.Reaction solution be concentrated under reduced pressure, with silica gel chromatograph preparative separation method purify obtained by residue, obtain Title product 3- (methyl (2- (4- methylpiperazine-1-yl) ethyl) carbamyl) benzoic acid 4d (507mg, white solid) is produced Rate: 100%.
MS m/z (ESI): 306.2 [M+1]
Third step
4- (4- (2- (3- (methyl (2- (4- methylpiperazine-1-yl) ethyl) carbamyl) benzamido) -4,5,6, 7- tetrahydro benzo [b] thiophene -3- formamido) phenethyl) methyl benzoate
By 4- (4- (2- amino -4,5,6,7- tetrahydro benzos [b] thiophene -3- formamido) phenethyl) methyl benzoate 2c (70mg, 0.16mmol), 3- (methyl (2- (4- methylpiperazine-1-yl) ethyl) carbamyl) benzoic acid 4d (98mg, 0.32mmol), 2- (7- azo benzotriazole)-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester (122mg, 0.32mmol) and N,N-diisopropylethylamine (80 μ L, 0.48mmol) is dissolved in 5mL dimethylformamide, is warming up to 50 DEG C, is stirred to react 12 Hour.10mL saturated sodium bicarbonate solution is added, is extracted with dichloromethane (30mL × 3), merges organic phase, successively uses water (50mL × 1), saturated sodium chloride solution (50mL × 1) washing, anhydrous sodium sulfate dry, filter, and silica gel is used in filtrate decompression concentration Column chromatography purifies gained residue with eluant, eluent system B, obtains title product 4- (4- (2- (3- (methyl (2- (4- methyl piperazine Piperazine -1- base) ethyl) carbamyl) benzamido) -4,5,6,7- tetrahydro benzos [b] thiophene -3- formamido) 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-yl) ethyl) carbamyl) benzamido) -4,5,6, 7- tetrahydro benzo [b] thiophene -3- formamido) phenethyl) benzoic acid
By 4- (4- (2- (3- (methyl (2- (4- methylpiperazine-1-yl) ethyl) carbamyl) benzamido) -4,5, 6,7- tetrahydro benzos [b] thiophene -3- formamido) phenethyl) methyl benzoate 4e (71mg, 0.098mmol) is dissolved in 5mL first In alcohol, 1mL 2M sodium hydroxide solution is added, is warming up to 50 DEG C, is stirred to react 1 hour.Reaction solution is concentrated under reduced pressure, and 3M salt is added dropwise Acid is 2~3 to water phase pH, and solid is precipitated.Filtering, filter cake drying, with HPLC preparative separation method purify obtained by residue, marked Inscribe product 4- (4- (2- (3- (methyl (2- (4- methylpiperazine-1-yl) ethyl) carbamyl) benzamido) -4,5,6,7- Tetrahydro benzo [b] thiophene -3- formamido) phenethyl) benzoic acid 4 (9mg, faint yellow solid), yield: 12.9%.
MS m/z (ESI): 708.2 [M+1]
1H NMR (400MHz, CD3OD): δ 7.98-8.10 (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
(((((1,1,1- tri- is fluoro- by -6- by 2- (3- (methyl (2- morpholine ethyl) carbamyl) benzamido) by 4- by 3- by 4- 2- methyl-propyl -2- base oxo) carbonyl) -4,5,6,7- thiophanes simultaneously [2,3-c] pyridine-3-carboxamide base) phenyl) propyl) Benzoic acid
The first step
(((((1,1,1- tri- is fluoro- by -6- by 2- (3- (methyl (2- morpholine ethyl) carbamyl) benzamido) by 4- by 3- by 4- 2- methyl-propyl -2- base oxo) carbonyl) -4,5,6,7- thiophanes simultaneously [2,3-c] pyridine-3-carboxamide base) phenyl) propyl) Methyl benzoate
By 4- (3- (4- (2- (3- (methyl (2- morpholine ethyl) carbamyl) benzamido) -4,5,6,7- tetrahydros Thieno [2,3-c] pyridine-3-carboxamide base) phenyl) propyl) methyl benzoate 3e (50mg, 0.07mmol) is dissolved in 5mL tri- In chloromethanes, it is cooled to 0 DEG C, sequentially adding triethylamine (14mg, 0.14mmol) and 1mL 3- methyl-1-, ((1,1,1- tri- is fluoro- 2- methyl-propyl -2- base oxo) carbonyl) -1H- iodonium imidazolide salts 5a (25mg, 0.07mmol, using patent application Method disclosed in " WO2011142359 " is prepared) chloroform soln, be warmed to room temperature, be stirred to react 1 hour.It is added 50mL water is extracted with dichloromethane (50mL × 3), merges organic phase, is washed (30mL × 1) with saturated sodium chloride solution, anhydrous Sodium sulphate dries, filters, filtrate decompression concentration, with silica gel column chromatography with eluant, eluent system A purify obtained by residue, marked Inscribe product 4- (3- (4- (2- (3- (methyl (2- morpholine ethyl) carbamyl) benzamido) -6- ((1,1,1- tri- fluoro- 2- Methyl-propyl -2- base oxo) carbonyl) -4,5,6,7- thiophanes simultaneously [2,3-c] pyridine-3-carboxamide base) phenyl) propyl) benzene Methyl formate 5b (40mg, yellow oily liquid), yield: 66.1%.
MS m/z (ESI): 878.4 [M+1]
Second step
(((((1,1,1- tri- is fluoro- by -6- by 2- (3- (methyl (2- morpholine ethyl) carbamyl) benzamido) by 4- by 3- by 4- 2- methyl-propyl -2- base oxo) carbonyl) -4,5,6,7- thiophanes simultaneously [2,3-c] pyridine-3-carboxamide base) phenyl) propyl) Benzoic acid
By 4- (3- (4- (2- (3- (methyl (2- morpholine ethyl) carbamyl) benzamido) -6- ((1,1,1- tri- Fluoro- 2- methyl-propyl -2- base oxo) carbonyl) -4,5,6,7- thiophanes simultaneously [2,3-c] pyridine-3-carboxamide base) phenyl) third Base) methyl benzoate 5b (40mg, 0.65mmol) is dissolved in the mixed solution of 3mL tetrahydrofuran and methanol (V: V=2: 1), 1mL 1M sodium hydroxide solution is added, is warming up to 30 DEG C, is stirred to react 4 hours.Reaction solution is concentrated under reduced pressure, and 1M hydrochloric acid is added dropwise to anti- Answering liquid pH is 6, and solid is precipitated.Filtering, filtrate decompression concentration, with HPLC preparative separation method purify obtained by residue, obtain title Product 4- (3- (4- (2- (3- (methyl (2- morpholine ethyl) carbamyl) benzamido) -6- ((1,1,1- tri- fluoro- 2- first Base propyl -2- base oxo) carbonyl) -4,5,6,7- thiophanes simultaneously [2,3-c] pyridine-3-carboxamide base) phenyl) propyl) benzene first Sour 5 (6mg, white solids), yield: 15.4%.
MS m/z (ESI): 864.4 [M+1]
1H NMR (400MHz, DMSO-d6): δ 11.69 (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 -2- base carbamoyl) phenethyl) phenylamino Base formoxyl) -4,5,6,7- tetrahydro benzos [b] thiophene -2- base)-N3Methyl-N3(2- morpholine ethyl) isophtalamide
The first step
4- (4- (2- (3- (methyl (2- morpholine ethyl) carbamoyl) benzamido) -4,5,6,7- tetrahydro benzos [b] thiophene -3- formamido) phenethyl) methyl benzoate
By 3- (methyl (2- morpholine ethyl) carbamyl) benzoic acid 3c (315mg, 1.08mmol) and 4- (4- (2- ammonia Base -4,5,6,7- tetrahydro benzos [b] thiophene -3- formamido) phenethyl) methyl benzoate 2c (360mg, 0.83mmol), 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride (255mg, 1.33mmol) and 4-dimethylaminopyridine (162mg, It 1.33mmol) is dissolved in 5mL dimethylformamide, is stirred to react 24 hours.50mL water is added, is extracted with dichloromethane (20mL × 3) merge organic phase, wash (50mL × 1) with saturated sodium chloride solution, anhydrous sodium sulfate dries, filters, and filtrate subtracts Pressure concentration, with silica gel column chromatography with eluant, eluent system A purify obtained by residue, obtain title product 4- (4- (2- (3- (methyl (2- morpholine ethyl) carbamoyl) benzamido) -4,5,6,7- tetrahydro benzos [b] thiophene -3- formamido) benzene second Base) 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- morpholine ethyl) carbamoyl) benzamido) -4,5,6,7- tetrahydro benzos [b] thiophene -3- formamido) phenethyl) benzoic acid
By 4- (4- (2- (3- (methyl (2- morpholine ethyl) carbamoyl) benzamido) -4,5,6,7- tetrahydro benzene And [b] thiophene -3- formamido) phenethyl) methyl benzoate 6a (400mg, 0.56mmol) is dissolved in 9mL tetrahydrofuran and first In the mixed solution of alcohol (V: V=2: 1), 2.3mL 1M sodium hydroxide solution is added, is warming up to 30 DEG C, is stirred to react 12 hours. Reaction solution is concentrated under reduced pressure, and 10mL water is added, and it is 6~7 that 1M hydrochloric acid, which is added dropwise, to reaction solution pH, and (20mL × 3) are extracted with dichloromethane, Merge organic phase, wash (50mL × 1) with saturated sodium chloride solution, anhydrous sodium sulfate dries, filters, and filtrate decompression concentration obtains To crude title product 4- (4- (2- (3- (methyl (2- morpholine ethyl) carbamoyl) benzamido) -4,5,6,7- tetra- Hydrogen benzo [b] thiophene -3- formamido) phenethyl) benzoic acid 6b (352mg, yellow solid), product directly carries out without further purification It reacts in next step.
MS m/z (ESI): 695.3 [M+1]
1H NMR (400MHz, DMSO-d6): δ 11.59 (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)
Third step
N1(3- (4- (4- (1,3- dihydroxy -2- (hydroxymethyl) propyl -2- base carbamoyl) phenethyl) phenylamino Base formoxyl) -4,5,6,7- tetrahydro benzos [b] thiophene -2- base)-N3Methyl-N3(2- morpholine ethyl) isophtalamide
By crude product 4- (4- (2- (3- (methyl (2- morpholine ethyl) carbamoyl) benzamido) -4,5,6,7- tetra- Hydrogen benzo [b] thiophene -3- formamido) phenethyl) benzoic acid 6b (170mg, 0.25mmol) and 2- amino -2- (hydroxymethyl) Propane -1,3- glycol (60mg, 0.49mmol) is dissolved in 5mL dimethylformamide, sequentially adds 1- (3- dimethylamino third Base) -3- ethyl-carbodiimide hydrochloride (94mg, 0.49mmol), I-hydroxybenzotriazole (67mg, 0.49mmol) and N, N- bis- Wopropyl ethyl amine (64mg, 0.49mmol) is stirred to react 12 hours.Reaction solution is concentrated under reduced pressure, and is purified with HPLC preparative separation method Gained residue obtains title product N1(3- (4- (4- (1,3- dihydroxy -2- (hydroxymethyl) propyl -2- base carbamyl Base) phenethyl) phenylcarbamoyl) -4,5,6,7- tetrahydro benzos [b] thiophene -2- base)-N3Methyl-N3(2- morpholine second Base) isophtalamide 6 (110mg, faint yellow solid), yield: 56.4%.
MS m/z (ESI): 798.4 [M+1]
1H NMR (400MHz, DMSO-d6): δ 11.59 (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
N1Methyl-N1(2- morpholine ethyl)-N3(3- (4- phenethyl phenylcarbamoyl) -4,5,6,7- tetrahydros Benzo [b] thiophene -2- base) isophtalamide
The first step
2- cyano-N- (4- phenethyl phenyl) acetamide
By 4- phenethyl aniline 7a (2.15g, 10.91mmol, using well known method document " Journal of Medicinal Chemistry, 56 (5), 2139-2149；2013 " are prepared) and 2- cyanoacetic acid (1.39g, It 16.37mmol) is dissolved in 5mL dimethylformamide, is cooled to 0 DEG C, 1- (3- dimethylamino-propyl) -3- ethyl carbon two is added Inferior amine salt hydrochlorate (3.14g, 16.37mmol), is warmed to room temperature, and is stirred to react 2 hours.10mL water is added, stirs 30 minutes, solid It is precipitated, filtering, filter cake drying, obtains crude title product 2- cyano-N- (4- phenethyl phenyl) acetamide 7b (2.68g, white Solid), product directly carries out next step reaction without further purification.
MS m/z (ESI): 263.3 [M-1]
Second step
2- cyano -2- cyclohexylidene-N- (4- phenethyl phenyl) acetamide
By crude product 2- cyano-N- (4- phenethyl phenyl) acetamide 7b (2.68g, 10.13mmol) and cyclohexanone (2.88g, It 29.38mmol) is dissolved in 6mL toluene, is added morpholine (900mg, 10.33mmol), is warming up to 120 DEG C, it is small to be stirred to react 2 When.Reaction solution is concentrated under reduced pressure, and with ether and petroleum ether mashing purifying gained residue, obtains the Asia title product 2- cyano -2- ring Hexyl-N- (4- phenethyl phenyl) acetamide 7c (2.52g, brown solid), yield: 72.2%.
MS m/z (ESI): 345.2 [M+1]
Third step
2- amino-N- (4- phenethyl phenyl) -4,5,6,7- tetrahydro benzos [b] thiophene -3- formamide
By 2- cyano -2- cyclohexylidene-N- (4- phenethyl phenyl) acetamide 7c (2.52g, 7.32mmol) and sulphur (246mg, 7.68mmol) is dissolved in 10mL dimethylformamide, is added morpholine (670mg, 7.68mmol), is warming up to 50 DEG C, it is stirred to react 2 hours.50mL saturated sodium chloride solution is added, is extracted with ethyl acetate (20mL × 3), merges organic phase, uses Saturated sodium chloride solution washs (50mL × 1), and anhydrous sodium sulfate dries, filters, and filtrate decompression concentration is beaten with isopropanol and is purified Gained residue obtains title product 2- amino-N- (4- phenethyl phenyl) -4,5,6,7- tetrahydro benzos [b] thiophene -3- formyl Amine 7d (1.69g, yellow solid), yield: 61.2%.
MS m/z (ESI): 377.2 [M+1]
4th step
N1Methyl-N1(2- morpholine ethyl)-N3(3- (4- phenethyl phenylcarbamoyl) -4,5,6,7- tetrahydros Benzo [b] thiophene -2- base) isophtalamide
By 2- amino-N- (4- phenethyl phenyl) -4,5,6,7- tetrahydro benzos [b] thiophene -3- formamide 7d (200mg, 0.53mmol) and 3- (methyl (2- morpholine ethyl) carbamyl) benzoic acid 3c (292mg, 1mmol), 1- (3- dimethylamino Propyl) -3- ethyl-carbodiimide hydrochloride (153mg, 0.80mmol) and 4-dimethylaminopyridine (97mg, 0.80mmol) dissolution In 5mL dimethylformamide, 30 DEG C are warming up to, is stirred to react 12 hours.30mL water is added, (30mL is extracted with ethyl acetate × 3), merge organic phase, wash (50mL × 1) with saturated sodium chloride solution, anhydrous sodium sulfate dries, filters, and filtrate decompression is dense Contracting, with silica gel column chromatography with eluant, eluent system A purify obtained by residue, obtain title product N1Methyl-N1(2- morpholine Ethyl)-N3Phenyl-diformyl between (3- (4- phenethyl phenylcarbamoyl) -4,5,6,7- tetrahydro benzos [b] thiophene -2- base) Amine 7 (174mg, yellow solid), yield: 50.3%.
MS m/z (ESI): 651.5 [M+1]
1H NMR (400MHz, CDCl3): δ 7.99-8.10 (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- phenethyl phenylcarbamoyl) -4,5,6,7- tetrahydro benzos [b] thiophene Pheno -2- base)-N3Methyl-N3(2- morpholine ethyl) isophtalamide
The first step
3- methyl -4- phenethyl aniline
By (E) -2- methyl -4- nitro -1- styryl benzene 8a (40mg, 0.28mmol, using well known method document " Journal of Physical Chemistry A, 113 (17), 4868-4877；2009 " are prepared) it is dissolved in 75.4mL Methanol and methylene chloride (V: V=2: 1) in the mixed solvent are added palladium/carbon (280mg, 20%), and three times, stirring is anti-for replacing hydrogen It answers 3 hours.Filtering washs filter cake with methylene chloride, and filtrate decompression concentration is purified with silica gel column chromatography with eluant, eluent system A Gained residue obtains title product 3- methyl -4- phenethyl aniline 8b (1.20g, light yellow oil), yield: 97.6%.
MS m/z (ESI): 212.3 [M+1]
Second step
2- cyano-N- (3- methyl -4- phenethyl phenyl) acetamide
3- methyl -4- phenethyl aniline 8b (1.20g, 5.68mmol) and cyanoacetic acid (722mg, 8.50mmol) are dissolved In 10mL dimethylformamide, it is cooled to 0 DEG C, 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride is added (1.62g, 8.50mmol), is warmed to room temperature, and is stirred to react 1 hour.30mL ice water is added, it is rear that 50mL water, filtering, filter cake baking is added It is dry, crude title product 2- cyano-N- (3- methyl -4- phenethyl phenyl) acetamide 8c (1.39g, white solid) is obtained, is produced Rate: 88.0%.
MS m/z (ESI): 279.2 [M+1]
Third step
2- cyano -2- (4,4- dimethylcyclohexy-lene)-N- (3- methyl -4- phenethyl phenyl) acetamide
By crude product 2- cyano-N- (3- methyl -4- phenethyl phenyl) acetamide 8c (700mg, 2.52mmol), 4,4- diformazans Pentylcyclohexanone (921mg, 7.29mmol) and morpholine (224mg, 2.57mmol) are dissolved in 12mL toluene, are warming up to 120 DEG C, It is stirred to react 3 hours.Reaction solution be concentrated under reduced pressure, with silica gel column chromatography with eluant, eluent system A purify obtained by residue, marked Topic product 2- cyano -2- (4,4- dimethylcyclohexy-lene)-N- (3- methyl -4- phenethyl phenyl) acetamide 8d (852mg, it is light Yellow oil), yield: 87.6%.
MS m/z (ESI): 385.5 [M-1]
4th step
2- amino -6,6- dimethyl-N-(3- methyl -4- phenethyl phenyl) -4,5,6,7- tetrahydro benzos [b] thiophene -3- Formamide
By 2- cyano -2- (4,4- dimethylcyclohexy-lene)-N- (3- methyl -4- phenethyl phenyl) acetamide 8d (853mg, 2.20mmol), sulphur (75mg, 2.31mmol) and morpholine (202mg, 2.31mmol) are dissolved in 8mL dimethyl formyl In amine, 50 DEG C are warming up to, is stirred to react 12 hours.50mL water is added, is extracted with dichloromethane (50mL × 3), merges organic phase, (50mL × 1) is washed with saturated sodium chloride solution, anhydrous sodium sulfate dries, filters, and silica gel column chromatography is used in filtrate decompression concentration Gained residue is purified with eluant, eluent system A, obtains title product 2- amino -6,6- dimethyl-N-(3- methyl -4- phenethyl 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- phenethyl phenylcarbamoyl) -4,5,6,7- tetrahydro benzos [b] thiophene Pheno -2- base)-N3Methyl-N3(2- morpholine ethyl) isophtalamide
By 2- amino -6,6- dimethyl-N-(3- methyl -4- phenethyl phenyl) -4,5,6,7- tetrahydro benzos [b] thiophene - 3- formamide 8e (419mg, 1mmol) and 3- (methyl (2- morpholine ethyl) carbamyl) benzoic acid 3c (381mg, It 1.30mmol) is dissolved in 8mL dimethylformamide, 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride is added (307mg, 1.60mmol) and 4-dimethylaminopyridine (196mg, 1.60mmol), is stirred to react 12 hours.It pours into 30mL water, Filtering, 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- phenethyl phenylcarbamoyl) -4,5,6,7- tetrahydro benzos [b] thiophene -2- base)-N3Methyl- N3(2- morpholine ethyl) isophtalamide 8 (520mg, yellow solid), yield: 75.1%.
MS m/z (ESI): 693.3 [M+1]
1H NMR (400MHz, DMSO-d6): δ 11.68 (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- hydroxyethyl) carbamyls) phenyl) propyl) phenylcarbamoyl) -4,5,6, 7- tetrahydro benzo [b] thiophene -2- base)-N3Methyl-N3(2- morpholine ethyl) isophtalamide
By 4- (3- (4- (2- (3- (methyl (2- morpholine ethyl) carbamyl) benzamido) -4,5,6,7- tetrahydros Benzo [b] thiophene -3- formamido) phenyl) propyl) benzoic acid 1 (250mg, 0.35mmol) and 2,2 '-diethanol amine (75mg, 0.71mmol), 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride (136mg, 0.71mmol), 1- hydroxy benzo Triazole (96mg, 0.71mmol) and n,N-diisopropylethylamine (92mg, 0.71mmol) are dissolved in 5mL dimethylformamide, 25 DEG C are warming up to, is stirred to react 12 hours.Reaction solution is poured into 20mL ice water, is extracted with dichloromethane (30mL × 3), is merged Organic phase washs (50mL × 1) with saturated sodium chloride solution, and anhydrous sodium sulfate dries, filters, and silica gel is used in filtrate decompression concentration Column chromatography purifies gained residue with eluant, eluent system A, obtains title product N1(3- (4- (3- (4- (two (2- hydroxyl second Base) carbamyl) phenyl) propyl) phenylcarbamoyl) -4,5,6,7- tetrahydro benzos [b] thiophene -2- base)-N3Methyl-N3- (2- morpholine ethyl) isophtalamide 9 (120mg, yellow solid), yield: 42.7%.
MS m/z (ESI): 796.3 [M+1]
1H NMR (400MHz, DMSO-d6): δ 11.60 (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- morpholine ethyl) carbamyl) benzamido) -4,5,6,7- tetra- Hydrogen benzo [b] thiophene -3- formamido) phenethyl) benzoic acid
The first step
2- methyl -4- nitrobenzylphosphonic acid diethylester
By 1- (bromomethyl) -2- methyl -4- nitrobenzene 10a (2g, 8.69mmol, using well known method document " Journal of Physical Chemistry, 90 (1), 168-73；1986 " are prepared) and triethyl phosphite (2.04g, 12.26mmol) is added in bottle, is warming up to 160 DEG C, is stirred to react 2 hours.Reaction solution is concentrated under reduced pressure, and obtains crude product mark It inscribes product 2- methyl -4- nitrobenzylphosphonic acid diethylester 10b (2.50g, dark brown liquid), product directly carries out down without further purification One step.
Second step
4- (2- methyl -4- nitrostyrolene base) methyl benzoate
Crude product 2- methyl -4- nitrobenzylphosphonic acid diethylester 10b (2.50g, 8.69mmol) is dissolved in 20mL methanol, It is cooled to 0 DEG C, the methanol solution of 50% sodium methoxide (939mg, 17.38mmol) is added dropwise, is stirred to react 30 minutes, 10mL is added The methanol solution of 4- acyl radical methyl benzoate (1.44g, 8.78mmol), is warmed to room temperature, and is stirred to react 12 hours.Filtering, filter Liquid is concentrated under reduced pressure, and obtains crude title product 4- (2- methyl -4- nitrostyrolene base) methyl benzoate 10c (1.83g, yellow Solid), product directly carries out in next step without further purification.
Third step
4- (2- methyl -4- aminophenethyl) methyl benzoate
Crude product 4- (2- methyl -4- nitrostyrolene base) methyl benzoate 10c (1.83g, 6.16mmol) is dissolved in 100.5mL first alcohol and water (V: V=100: 0.5) in the mixed solvent is added palladium/carbon (366mg, 10%), and replacing hydrogen three times, stirs Mix reaction 24 hours.Filtering, filtrate decompression concentration, obtains crude title product 4- (2- methyl -4- aminophenethyl) benzoic acid Methyl esters 10d (1.41g, yellow solid), product directly carry out in next step without further purification.
MS m/z (ESI): 270.2 [M+1]
4th step
4- (4- (2- cyano-acetamide amido) -2- methylphenethyl) methyl benzoate
By crude product 4- (2- methyl -4- aminophenethyl) methyl benzoate 10d (1.41g, 5.25mmol) and cyanoacetic acid (670mg, 7.87mmol) is dissolved in 20mL dimethylformamide, is cooled to 0 DEG C, and 1- (3- dimethylamino-propyl) -3- is added Ethyl-carbodiimide hydrochloride (1.51g, 7.87mmol), is warmed to room temperature, and is stirred to react 40 minutes.Reaction solution is poured into 100mL It in ice water, stirs 30 minutes, filtering, filter cake drying obtains crude title product 4- (4- (2- cyano-acetamide amido) -2- methyl Phenethyl) methyl benzoate 10e (1.71g, pale solid), product without further purification directly carry out in next step.
MS m/z (ESI): 335.1 [M-1]
5th step
4- (4- (2- cyano -2- cyclohexylidene acetamido) -2- methylphenethyl) methyl benzoate
By crude product 4- (4- (2- cyano-acetamide amido) -2- methylphenethyl) methyl benzoate 10e (1.69g, 5.25mmol) it is dissolved in 26mL toluene with cyclohexanone (1.50g, 15.23mmol), addition morpholine (467mg, 5.36mmol), 120 DEG C are warming up to, is stirred to react 4 hours.Reaction solution is concentrated under reduced pressure, with petroleum ether and ethyl acetate mashing purifying Gained residue obtains title product 4- (4- (2- cyano -2- cyclohexylidene acetamido) -2- methylphenethyl) benzoic acid first Ester 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- formamido) -2- methylphenethyl) benzoic acid Methyl esters
By 4- (4- (2- cyano -2- cyclohexylidene acetamido) -2- methylphenethyl) methyl benzoate 10f (2g, 4.80mmol) it is dissolved in 5mL dimethylformamide with sulphur (161mg, 5.04mmol), addition morpholine (439mg, 5.04mmol), 50 DEG C are warming up to, is stirred to react 1 hour.50mL water is added, (50mL × 3) are extracted with ethyl acetate, are associated with Machine phase washs (50mL × 1) with saturated sodium chloride solution, and anhydrous sodium sulfate dries, filters, and isopropanol is used in filtrate decompression concentration Mashing purifying gained residue, obtains title product 4- (4- (2- amino -4,5,6,7- tetrahydro benzos [b] thiophene -3- formamide Base) -2- methylphenethyl) 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- morpholine ethyl) carbamyl) benzamido) -4,5,6,7- tetra- Hydrogen benzo [b] thiophene -3- formamido) phenethyl) methyl benzoate
By 4- (4- (2- amino -4,5,6,7- tetrahydro benzos [b] thiophene -3- formamido) -2- methylphenethyl) benzene first Sour methyl esters 10g (307mg, 0.68mmol) and 3- (methyl (2- morpholine ethyl) carbamyl) benzoic acid 3c (300mg, 1.03mmol), 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride (197mg, 1.03mmol) and 4- dimethylamino Pyridine (125mg, 1.03mmol) is dissolved in 5mL dimethylformamide, is warming up to 30 DEG C, is stirred to react 12 hours.It is added 30mL water is extracted with ethyl acetate (30mL × 3), merges organic phase, is washed (50mL × 1) with saturated sodium chloride solution, anhydrous Sodium sulphate dries, filters, filtrate decompression concentration, with silica gel column chromatography with eluant, eluent system A purify obtained by residue, marked Inscribe product 4- (2- methyl -4- (2- (3- (methyl (2- morpholine ethyl) carbamyl) benzamido) -4,5,6,7- tetrahydros Benzo [b] thiophene -3- formamido) phenethyl) methyl benzoate 10h (387mg, faint yellow solid), yield: 78.3%.
MS m/z (ESI): 723.5 [M+1]
1H NMR (400MHz, CDCl3): δ 8.04-8.12 (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- morpholine ethyl) carbamyl) benzamido) -4,5,6,7- tetra- Hydrogen benzo [b] thiophene -3- formamido) phenethyl) benzoic acid
By 4- (2- methyl -4- (2- (3- (methyl (2- morpholine ethyl) carbamyl) benzamido) -4,5,6,7- Tetrahydro benzo [b] thiophene -3- formamido) phenethyl) methyl benzoate 10h (250mg, 0.35mmol) is dissolved in 10mL methanol In, 1mL 2M sodium hydroxide solution is added, is stirred to react 12 hours.Reaction solution is concentrated under reduced pressure, and dropwise addition 1M hydrochloric acid to water phase pH is 4 ~5, it is extracted with dichloromethane (30mL × 3), merges organic phase, wash (50mL × 1), anhydrous slufuric acid with saturated sodium chloride solution Sodium dries, filters, and filtrate decompression concentration obtains title product 4- (2- methyl -4- (2- (3- (methyl (2- morpholine ethyl) ammonia Formoxyl) benzamido) -4,5,6,7- tetrahydro benzos [b] thiophene -3- formamido) phenethyl) benzoic acid 10 (233mg, Faint yellow solid), yield: 95.1%.
MS m/z (ESI): 709.4 [M+1]
1H NMR (400MHz, CDCl3): δ 7.93-8.13 (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- hydroxyethyl) carbamyls) phenylethyl) -3- aminomethyl phenyl carbamyl) -4, 5,6,7- tetrahydro benzos [b] thiophene -2- base)-N3Methyl-N3(2- morpholine ethyl) isophtalamide
By 4- (2- methyl -4- (2- (3- (methyl (2- morpholine ethyl) carbamyl) benzamido) -4,5,6,7- Tetrahydro benzo [b] thiophene -3- formamido) phenethyl) benzoic acid 10 (120mg, 0.17mmol) and 2,2 '-diethanol amine (36mg, 0.34mmol), 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride (65mg, 0.34mmol), 1- hydroxyl Benzotriazole (46mg, 0.34mmol) and n,N-diisopropylethylamine (66mg, 0.51mmol) are dissolved in 5mL dimethylformamide In, 30 DEG C are warming up to, is stirred to react 12 hours.Reaction solution is poured into 30mL ice water, (50mL × 3) are extracted with dichloromethane, Merge organic phase, wash (50mL × 1) with saturated sodium chloride solution, anhydrous sodium sulfate dries, filters, and filtrate decompression concentration is used Silica gel column chromatography purifies gained residue with eluant, eluent system A, obtains title product N1(3- (4- (4- (two (2- hydroxyl second Base) carbamyl) phenylethyl) -3- aminomethyl phenyl carbamyl) -4,5,6,7- tetrahydro benzos [b] thiophene -2- base)-N3First Base-N3(2- morpholine ethyl) isophtalamide 11 (50mg, faint yellow solid), yield: 37.0%.
MS m/z (ESI): 796.3 [M+1]
1H NMR (400MHz, CD3OD): δ 8.05-8.12 (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
N1Methyl-N1(2- morpholine ethyl)-N3(3- (4- (3- phenylpropyl) phenylcarbamoyl) -5,7- dihydro - 4H- thieno [2,3-c] pyrans -2- base) isophtalamide
The first step
2- cyano-N- (4- phenylpropyl phenyl) acetamide
By 4- phenylpropyl aniline 12a (10.30g, 48.74mmol, using well known method document " Bioorganic& Medicinal Chemistry Letters, 19 (3), 654-657；2009 " are prepared) it is dissolved in 100mL dimethyl formyl In amine, 2- cyanoacetic acid (6.22g, 73.12mmol) and 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride is added (14g, 73.12mmol) is stirred to react 12 hours.It pours into 300mL ice water, stirs 30 minutes, solid is precipitated, filtering, filter cake Drying, obtains crude title product 2- cyano-N- (4- phenylpropyl phenyl) acetamide 12b (12.2g, gray solid), product is not It is purified directly to carry out in next step.
MS m/z (ESI): 277.2 [M-1]
Second step
2- amino-N- (4- (3- phenylpropyl) phenyl) -3- carbamyl -5,7- dihydro -4H- thieno [2,3-c] pyrans
By crude product 2- cyano-N- (4- phenylpropyl phenyl) acetamide 12b (279mg, 1mmol), dihydro -2H- pyrans -4 (3H) -one (106mg, 1.05mmol), morpholine (92mg, 1.05mmol) and sulphur (50mg, 1.50mmol) are dissolved in 15mL second In alcohol, 90 DEG C are warming up to, is stirred to react 12 hours.Reaction solution is concentrated under reduced pressure, with ethyl acetate and petroleum ether mashing purifying gained Residue obtains title product 2- amino-N- (4- (3- phenylpropyl) phenyl) -3- carbamyl -5,7- dihydro -4H- thieno [2,3-c] pyrans 12c (1.13g, yellow oil), yield: 87.9%.
MS m/z (ESI): 393.2 [M+1]
Third step
N1Methyl-N1(2- morpholine ethyl)-N3(3- (4- (3- phenylpropyl) phenylcarbamoyl) -5,7- dihydro - 4H- thieno [2,3-c] pyrans -2- base) isophtalamide
By 2- amino-N- (4- (3- phenylpropyl) phenyl) -3- carbamyl -5,7- dihydro -4H- thieno [2,3-c] pyrrole Mutter 12c (255mg, 0.65mmol) and 3- (methyl (2- morpholine ethyl) carbamyl) benzoic acid 3c (246mg, 0.84mmol), 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride (200mg, 1.04mmol) and 4- dimethylamino Pyridine (128mg, 1.04mmol) is dissolved in 10mL dimethylformamide, is stirred to react 12 hours.It pours into 30mL ice water, uses Ethyl acetate extracts (30mL × 3), merges organic phase, is washed (50mL × 1) with saturated sodium chloride solution, and anhydrous sodium sulfate is dry It is dry, filtering, filtrate decompression concentration, with silica gel column chromatography with eluant, eluent system A purify obtained by residue, obtain title product N1Methyl-N1(2- morpholine ethyl)-N3(3- (4- (3- phenylpropyl) phenylcarbamoyl) -5,7- dihydro -4H- thieno [2,3-c] pyrans -2- base) isophtalamide 12 (235mg, yellow solid), yield: 54.2%.
MS m/z (ESI): 667.2 [M+1]
1H NMR (400MHz, DMSO-d6): δ 11.73 (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
N1Methyl-N1(2- morpholine ethyl)-N3(3- (4- phenylpropyl phenylcarbamoyl) -4,5,6,7- tetrahydros Benzo [b] thiophene -2- base) isophtalamide
The first step
2- cyano -2- cyclohexylidene-N- (4- phenylpropyl phenyl) acetamide
By crude product 2- cyano-N- (4- phenylpropyl phenyl) acetamide 12b (1g, 3.59mmol) and cyclohexanone (1.02g, It 10.41mmol) is dissolved in 20mL toluene, is added morpholine (319mg, 3.66mmol), is warming up to 130 DEG C, it is small to be stirred to react 2 When.Reaction solution is concentrated under reduced pressure, and with ethyl acetate and petroleum ether mashing purifying gained residue, obtains title product 2- cyano -2- Cyclohexylidene-N- (4- phenylpropyl phenyl) acetamide 13a (1.13g, yellow oil), yield: 87.9%.
MS m/z (ESI): 357.2 [M+1]
Second step
2- amino-N- (4- phenylpropyl phenyl) -4,5,6,7- tetrahydro benzos [b] thiophene -3- formamide
By 2- cyano -2- cyclohexylidene-N- (4- phenylpropyl phenyl) acetamide 13a (1.13g, 3.16mmol) and sulphur (106mg, 3.32mmol) is dissolved in 5mL dimethylformamide, is added morpholine (289mg, 3.32mmol), is warming up to 50 DEG C, it is stirred to react 1 hour.50mL water is added, is extracted with ethyl acetate (20mL × 3), merges organic phase, it is molten with saturated sodium-chloride Liquid washs (50mL × 1), and anhydrous sodium sulfate dries, filters, filtrate decompression concentration, is beaten purifying gained residue with isopropanol, Obtain title product 2- amino-N- (4- phenylpropyl phenyl) -4,5,6,7- tetrahydro benzos [b] thiophene -3- formamide 13b (1.12g, yellow solid), yield: 90.3%.
MS m/z (ESI): 391.2 [M+1]
Third step
N1Methyl-N1(2- morpholine ethyl)-N3(3- (4- phenylpropyl) phenylcarbamoyl) -4,5,6,7- tetrahydro benzene And [b] thiophene -2- base) isophtalamide
By 2- amino-N- (4- phenylpropyl phenyl) -4,5,6,7- tetrahydro benzos [b] thiophene -3- formamide 13b (1.12g, 2.87mmol) and 3- (methyl (2- morpholine ethyl) carbamyl) benzoic acid 3c (1.25g, 4.28mmol), 1- (3- diformazan ammonia Base propyl) -3- ethyl-carbodiimide hydrochloride (821mg, 4.28mmol) and 4-dimethylaminopyridine (523mg, 4.28mmol) It is dissolved in 5mL dimethylformamide, is warming up to 30 DEG C, be stirred to react 12 hours.30mL water is added, is extracted with ethyl acetate (30mL × 3) merge organic phase, wash (50mL × 1) with saturated sodium chloride solution, anhydrous sodium sulfate dries, filters, and filtrate subtracts Pressure concentration, with silica gel column chromatography with eluant, eluent system A purify obtained by residue, obtain title product N1Methyl-N1(2- Coffee quinoline ethyl)-N3(3- (4- phenylpropyl) phenylcarbamoyl) -4,5,6,7- tetrahydro benzos [b] thiophene -2- base) isophthalic diformazan Amide 13 (1.05g, faint yellow solid), yield: 40.2%.
MS m/z (ESI): 665.3 [M+1]
1H NMR (400MHz, CDCl3): δ 8.03-8.12 (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- morpholine ethyl) carbamyl) benzamido) -3- (4- (3- phenylpropyl) phenylamino first Acyl group) -4,5- dihydro-thiophene simultaneously [2,3-c] pyridine -6 (7H)-t-butyl formate
The first step
2- amino -3- (4- (3- phenylpropyl) phenylcarbamoyl) -4,5- dihydro-thiophene simultaneously [2,3-c] pyridine -6 (7H) - T-butyl formate
By crude product 2- cyano-N- (4- phenylpropyl phenyl) acetamide 12b (900mg, 3.23mmol), 4- carbonyl piperidines -1- T-butyl formate (677mg, 3.40mmol), morpholine (297mg, 3.40mmol) and sulphur (155mg, 4.85mmol) are dissolved in In 20mL ethyl alcohol, 90 DEG C are warming up to, is stirred to react 12 hours.Reaction solution is concentrated under reduced pressure, pure with ethyl acetate and petroleum ether mashing Change gained residue, obtaining title product 2- amino -3- (4- (3- phenylpropyl) phenylcarbamoyl), -4,5- dihydro-thiophene is 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- morpholine ethyl) carbamyl) benzamido) -3- (4- (3- phenylpropyl) phenylamino first Acyl group) -4,5- dihydro-thiophene simultaneously [2,3-c] pyridine -6 (7H)-t-butyl formate
By 2- amino -3- (4- (3- phenylpropyl) phenylcarbamoyl) -4,5- dihydro-thiophene simultaneously [2,3-c] pyridine -6 (7H)-t-butyl formate 14a (1.02g, 2.07mmol) and 3- (methyl (2- morpholine ethyl) carbamyl) benzoic acid 3c (789mg, 2.70mmol), 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride (635mg, 3.31mmol) and 4- Dimethylamino naphthyridine (405mg, 3.31mmol) is dissolved in 15mL dimethylformamide, is stirred to react 12 hours.Pour into 30mL It in ice water, is extracted with ethyl acetate (30mL × 3), merges organic phase, washed (50mL × 1) with saturated sodium chloride solution, it is anhydrous Sodium sulphate dries, filters, filtrate decompression concentration, with silica gel column chromatography with eluant, eluent system A purify obtained by residue, marked Inscribe product 2- (3- (methyl (2- morpholine ethyl) carbamyl) benzamido) -3- (4- (3- phenylpropyl) phenyl carbamyl Base) -4,5- dihydro-thiophene simultaneously [2,3-c] pyridine -6 (7H)-t-butyl formate 14 (1.10g, yellow solid), yield: 69.6%.
MS m/z (ESI): 766.4 [M+1]
1H NMR (400MHz, CD3OD): δ 11.67 (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- morpholine ethyl) carbamyl) pyridine -2- formamido group) -4,5,6,7- tetra- Hydrogen benzo [b] thiophene -3- formamido) phenyl) propyl) methyl benzoate
The first step
6- (methyl (2- morpholine ethyl) carbamyl) -2- pyridine carboxylic acid
Pyridine -2,6- dioctyl phthalate (500mg, 3mmol) is dissolved in 20mL methylene chloride, 2- (7- azo benzo is added Triazole)-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester (1.30g, 3.60mmol) and n,N-diisopropylethylamine (580mg, 4.50mmol), it stirs 10 minutes, N- methyl -2- morpholine ethamine 15a (432mg, 3mmol, using well known method text is added Offer " Journal of Combinatorial Chemistry, 8 (6), 834-840；2006 " are prepared), it is small to be stirred to react 4 When.Reaction solution be concentrated under reduced pressure, with silica gel column chromatography with eluant, eluent system A purify obtained by residue, obtain title product 6- (first Base (2- morpholine ethyl) carbamyl) -2- pyridine carboxylic acid 15b (375mg, white solid), yield: 41.7%.
MS m/z (ESI): 294.2 [M+1]
Second step
4- (3- (4- (2- (6- (methyl (2- morpholine ethyl) carbamyl) pyridine acylamino-) -4,5,6,7- tetrahydro benzene And [b] thiophene -3- formamido) phenyl) propyl) methyl benzoate
By 4- (3- (4- (2- amino -4,5,6,7- tetrahydro benzos [b] thiophene -3- formamido) phenyl) propyl) benzoic acid Methyl esters 1a (450mg, 1.06mmol) and 6- (methyl (2- morpholine ethyl) carbamyl) -2- pyridine carboxylic acid 15b (375mg, It 1.27mmol) is dissolved in 10mL dimethylformamide, 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride is added (305mg, 1.60mmol) and 4-dimethylaminopyridine (195mg, 1.60mmol), is warming up to 25 DEG C, is stirred to react 12 hours.Add Enter 50mL water, be extracted with dichloromethane (50mL × 3), merges organic phase, wash (50mL × 1), nothing with saturated sodium chloride solution Aqueous sodium persulfate dries, filters, filtrate decompression concentration, with silica gel column chromatography with eluant, eluent system A purify obtained by residue, obtain Title product 4- (3- (4- (2- (6- (methyl (2- morpholine ethyl) carbamyl) pyridine -2- formamido group) -4,5,6,7- tetra- Hydrogen benzo [b] thiophene -3- formamido) phenyl) propyl) methyl benzoate 15 (250mg, faint yellow solid), yield: 32.6%.
MS m/z (ESI): 724.4 [M+1]
1H NMR (400MHz, DMSO-d6): δ 12.29 (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
N1Methyl-N1(2- morpholine ethyl)-N3(3- (4- (2- morpholine ethyl) phenylcarbamoyl) -4,5,6, 7- tetrahydro benzo [b] thiophene -2- base) isophtalamide
The first step
2- cyano-N- (4- (2- morpholine ethyl) phenyl) acetamide
By 4- (2- morpholine ethyl) aniline 16a (450mg, 2.18mmol, using well known method document " Bioorganic&Medicinal Chemistry Letters, 23 (23), 6363-6369；2013 " are prepared) and cyano Acetic acid (277mg, 3.27mmol) is dissolved in 5mL dimethylformamide, is cooled to 0 DEG C, is added 1- (3- dimethylamino-propyl)- 3- ethyl-carbodiimide hydrochloride (625mg, 3.27mmol), is warmed to room temperature, and is stirred to react 2 hours.30mL water is added and 5mL is full And sodium bicarbonate solution, it is extracted with dichloromethane (50mL × 3), merges organic phase, washed with saturated sodium chloride solution (50mL × 1), anhydrous sodium sulfate dries, filters, filtrate decompression concentration, with silica gel column chromatography with eluant, eluent system A purify gained remnants Object obtains title product 2- cyano-N- (4- (2- morpholine ethyl) phenyl) acetamide 16b (530mg, white solid), yield: 88.9%.
MS m/z (ESI): 449.3 [M+1]
Second step
2- cyano -2- cyclohexylidene-N- (4- (2- morpholine ethyl) phenyl) acetamide
2- cyano-N- (4- (2- morpholine ethyl) phenyl) acetamide 16b (530mg, 1.94mmol) is dissolved in 15mL In toluene, cyclohexanone (190mg, 1.94mmol) and morpholine (168mg, 1.94mmol) is added, is warming up to 130 DEG C, stirring is anti- It answers 2 hours.Reaction solution be concentrated under reduced pressure, with silica gel column chromatography with eluant, eluent system A purify obtained by residue, obtain title product 2- cyano -2- cyclohexylidene-N- (4- (2- morpholine ethyl) phenyl) acetamide 16c (462mg, colorless oil), yield: 67.5%.
MS m/z (ESI): 354.3 [M+1]
Third step
2- amino-N- (4- (2- morpholine ethyl) phenyl) -4,5,6,7- tetrahydro benzos [b] thiophene -3- formamide
By 2- cyano -2- cyclohexylidene-N- (4- (2- morpholine ethyl) phenyl) acetamide 16c (462mg, 1.36mmol) It is dissolved in 6mL dimethylformamide with sulphur (44mg, 1.37mmol), is added morpholine (119mg, 1.37mmol), is warming up to It 50 DEG C, is stirred to react 45 minutes.50mL water is added, is extracted with dichloromethane (50mL × 3), merges organic phase, with saturation chlorination Sodium solution washs (50mL × 1), and anhydrous sodium sulfate dries, filters, filtrate decompression concentration, with silica gel column chromatography with eluant, eluent body It is A purifying gained residue, obtains title product 2- amino-N- (4- (2- morpholine ethyl) phenyl) -4,5,6,7- tetrahydro benzene And [b] thiophene -3- formamide 16d (300mg, yellow oil), yield: 60%.
MS m/z (ESI): 386.3 [M+1]
4th step
N1Methyl-N1(2- morpholine ethyl)-N3(3- (4- (2- morpholine ethyl) phenylcarbamoyl) -4,5,6, 7- tetrahydro benzo [b] thiophene -2- base) isophtalamide
By 2- amino-N- (4- (2- morpholine ethyl) phenyl) -4,5,6,7- tetrahydro benzos [b] thiophene -3- formamide 16d (160mg, 0.38mmol) is dissolved in 6mL dimethylformamide, and 3- (methyl (2- morpholine ethyl) carbamyl) benzene is added Formic acid 3c (219mg, 0.75mmol), 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride (146mg, 0.76mmol) with 4-dimethylaminopyridine (72mg, 0.57mmol), 25 DEG C are warming up to, is stirred to react 12 hours.30mL is added Water is extracted with dichloromethane (30mL × 3), merges organic phase, washs (50mL × 1), anhydrous slufuric acid with saturated sodium chloride solution Sodium dries, filters, filtrate decompression concentration, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title produce Object N1Methyl-N1(2- morpholine ethyl)-N3(3- (4- (2- morpholine ethyl) phenylcarbamoyl) -4,5,6,7- tetrahydros Benzo [b] thiophene -2- base) isophtalamide 16 (82mg, faint yellow solid), yield: 33.6%.
MS m/z (ESI): 674.2 [M-1]
1H NMR (400MHz, CDCl3): δ 8.07 (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- base carbamyl) phenethyl) -3- methylbenzene Base carbamyl) -6,6- dimethyl -4,5,6,7- tetrahydro benzos [b] thiophene -2- base)-N3Methyl-N3(2- morpholine ethyl) Isophtalamide
The first step
4- (4- (2- cyano -2- (4,4- dimethylcyclohexy-lene) acetamido) -2- methylphenethyl) methyl benzoate
Crude product 4- (4- (2- cyano-acetamide amido) -2- methylphenethyl) methyl benzoate 10e (2g, 6mmol) is dissolved In 30mL toluene, 4,4- dimethylcyclohexanon (2.16g, 17.20mmol) and morpholine (522mg, 6mmol), heating is added To 140 DEG C, it is stirred to react 3 hours.Reaction solution be concentrated under reduced pressure, with silica gel column chromatography with eluant, eluent system B purify gained remnants Object obtains title product 4- (4- (2- cyano -2- (4,4- dimethylcyclohexy-lene) acetamido) -2- methylphenethyl) benzene first Sour methyl esters 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- formamido) -2- methylbenzene Ethyl) methyl benzoate
By 4- (4- (2- cyano -2- (4,4- dimethylcyclohexy-lene) acetamido) -2- methylphenethyl) benzoic acid first Ester 17a (2.56g, 5.76mmol) is dissolved in 10mL dimethylformamide, and sulphur (184mg, 5.79mmol) and morpholine is added (501mg, 5.76mmol) is warming up to 50 DEG C, is stirred to react 2 hours.50mL water is added, (50mL × 3) are extracted with ethyl acetate, Merge organic phase, wash (50mL × 1) with saturated sodium chloride solution, anhydrous sodium sulfate dries, filters, and filtrate decompression concentration is used Silica gel column chromatography purifies gained residue with eluant, eluent system B, obtains title product 4- (4- (2- amino -6,6- dimethyl - 4,5,6,7- tetrahydro benzos [b] thiophene -3- formamido) -2- methylphenethyl) (2.30g, yellow are solid by methyl benzoate 17b Body), yield: 83.9%.
MS m/z (ESI): 475.2 [M-1]
Third step
4- (4- (6,6- dimethyl -2- (3- (methyl (2- morpholine ethyl) carbamyl) benzamido) -4,5,6, 7- tetrahydro benzo [b] thiophene -3- formamido) -2- methylphenethyl) methyl benzoate
By 4- (4- (2- amino -6,6- dimethyl -4,5,6,7- tetrahydro benzos [b] thiophene -3- formamido) -2- methyl Phenethyl) methyl benzoate 17b (2.36g, 4.83mmol) is dissolved in 5mL dimethylformamide, 3- (methyl (2- is added Coffee quinoline ethyl) carbamyl) benzoic acid 3c (1.80g, 6.25mmol), 1- (3- dimethylamino-propyl) -3- ethyl carbodiimide Hydrochloride (1.38g, 7.24mmol) and 4-dimethylaminopyridine (883mg, 7.24mmol), are stirred to react 12 hours.It is added 30mL water is extracted with ethyl acetate (30mL × 3), merges organic phase, is washed (50mL × 1) with saturated sodium chloride solution, anhydrous Sodium sulphate dries, filters, filtrate decompression concentration, with silica gel column chromatography with eluant, eluent system A purify obtained by residue, marked Inscribe product 4- (4- (6,6- dimethyl -2- (3- (methyl (2- morpholine ethyl) carbamyl) benzamido) -4,5,6,7- Tetrahydro benzo [b] thiophene -3- formamido) -2- methylphenethyl) 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- morpholine ethyl) carbamyl) benzamido) -4,5,6, 7- tetrahydro benzo [b] thiophene -3- formamido) -2- methylphenethyl) benzoic acid
By 4- (4- (6,6- dimethyl -2- (3- (methyl (2- morpholine ethyl) carbamyl) benzamido) -4,5, 6,7- tetrahydro benzos [b] thiophene -3- formamido) -2- methylphenethyl) methyl benzoate 17c (2.65g, 3.46mmol) is molten Solution is added 10mL 2M sodium hydroxide solution, is stirred to react 12 in 44mL tetrahydrofuran and methanol (V: V=3: 1) in the mixed solvent Hour.30mL water is added, reaction solution is concentrated under reduced pressure, and it is 6 that 1M hydrochloric acid, which is added dropwise, to water phase pH, (30mL × 3) are extracted with dichloromethane, Merge organic phase, wash (50mL × 1) with saturated sodium chloride solution, anhydrous sodium sulfate dries, filters, and filtrate decompression concentration obtains To crude title product 4- (4- (6,6- dimethyl -2- (3- (methyl (2- morpholine ethyl) carbamyl) benzamido) - 4,5,6,7- tetrahydro benzos [b] thiophene -3- formamido) -2- methylphenethyl) benzoic acid 17d (1.69g, yellow solid), it produces Rate: 66.5%.
MS m/z (ESI): 737.5 [M+1]
1H NMR (400MHz, DMSO-d6): δ 11.66 (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- base carbamyl) phenethyl) -3- methylbenzene Base carbamyl) -6,6- dimethyl -4,5,6,7- tetrahydro benzos [b] thiophene -2- base)-N3Methyl-N3(2- morpholine ethyl) Isophtalamide
By crude product 4- (4- (6,6- dimethyl -2- (3- (methyl (2- morpholine ethyl) carbamyl) benzamido) - 4,5,6,7- tetrahydro benzos [b] thiophene -3- formamido) -2- methylphenethyl) benzoic acid 17d (850mg, 1.15mmol) is molten Solution is added 2- amino -2- (methylol) propane -1,3- glycol (278mg, 2.30mmol), 1- in 5mL dimethylformamide (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride (439mg, 2.30mmol), I-hydroxybenzotriazole (310mg, 2.30mmol) with n,N-diisopropylethylamine (445mg, 3.50mmol), it is stirred to react 12 hours.50mL water is added and 20mL is full And sodium bicarbonate solution, it is extracted with dichloromethane (50mL × 3), merges organic phase, washed with saturated sodium chloride solution (50mL × 1), anhydrous sodium sulfate dries, filters, filtrate decompression concentration, with silica gel column chromatography with eluant, eluent system A purify gained remnants Object obtains title product N1(3- (4- (4- (1,3- dihydroxy -2- (methylol) propane -2- base carbamyl) phenethyl) -3- Aminomethyl phenyl carbamyl) -6,6- dimethyl -4,5,6,7- tetrahydro benzos [b] thiophene -2- base)-N3Methyl-N3(2- morphine Quinoline ethyl) isophtalamide 17 (600mg, yellow solid), yield: 62.1%.
MS m/z (ESI): 841.8 [M+1]
1H NMR (400MHz, DMSO-d6): δ 11.65 (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
Test case 1, the compounds of this invention are to the inhibiting effect of source of people Npt2b/HEK293 cell traffic Phos.
Following methods are used to measure inhibition of the compound to source of people Npt2b/HEK293 cell traffic Phos in the present invention Effect.
One, experimental material and instrument
1, scintillation counter (PerkinElmer#1450)
2、BD BioCoatTMPoly-D-Lysine 48- orifice plate (BD, #356509)
3, Npt2b plasmid (Guangzhou reactivation #NM_006424)
4, -32 radionuclide of phosphorus (Phosphorus-32 Radionuclide), 1mCi (37MBq) (H3 32PO4) (PerkinElmer, #NEX053001MC)
5、Optiphase Supermix(PerkinElmer#1200-439 for 5L)
Two, experimental procedure
1, source of people Npt2b/HEK293 cell is obtained
By Npt2b plasmid by a certain percentage with LipofectamineTMLTX (Invitrogen#15338-100) mixing, After placing 30 minutes, said mixture is added drop-wise in the HEK293 cell (Chinese Academy of Sciences cell bank #GNHu43) of logarithmic phase growth, Side edged is mixed；After 24 hours, it is nearly long to cell to change culture medium (Enzo#ALX-380-013-G005) culture containing G418 into Full, bed board selects monoclonal cell, verifies its function, obtains monoclonal stable cell line.
2, compound tests the inhibiting effect of source of people Npt2b/HEK293 cell traffic Phos
The previous day is mentioned by stable cell line source of people Npt2b/HEK293 cell kind in 48 orifice plates, 37 DEG C of carbon dioxide cultures It is cultivated in case.Culture medium is discarded, washs primary (250 μ of cell with Choline uptake buffer (Choline uptake buffer) The hole L/).Take 10 μ L H3 32PO4It is diluted in 1000ml sodium intake buffer (Sodium uptake buffer).Every hole is added 80 μ L test the H after compound and 20 μ L dilution3 32PO4, it is incubated at room temperature about 20 minutes.Final compound concentration are as follows: 100 μM, 10 μM, 1 μM, 0.1 μM, 0.01 μM, 0.001 μM, final DMSO concentration are as follows: 0.5%, final H3 32PO4Concentration Are as follows: the hole 0.2uCi/；Discard above compound and H3 32PO4, then with ice-cold terminate liquid (Ice cold stop Solution) cell is washed twice (350 hole μ L/).Then 150 μ L 200mM NaOH are added in every hole, at room temperature upper vibration plate device shake Swing cracking about 5 minutes.120 μ L cell lysates are shifted in the hole 96- sample panel in every hole.100 μ L are added in sample panel every hole in the hole 96- Then Optiphase Supermix seals the hole 96- sample panel with RE-SEALABLE TAPE, shake about on vibration plate device at room temperature 5 minutes.Scintillation counter readings.
The compounds of this invention is measured the inhibiting effect of source of people Npt2b/HEK293 cell traffic Phos, measures IC50Value is shown in Table 1.
The IC that 1 the compounds of this invention of table inhibits source of people Npt2b/HEK293 cell traffic Phos50
Conclusion: the compound in the present invention has apparent inhibition effect to source of people Npt2b/HEK293 cell traffic Phos Fruit.
Test case 2, the compounds of this invention are to the inhibiting effect of source of mouse Npt2b/HEK293 cell traffic Phos.
Following methods are used to measure inhibition of the compound to source of mouse Npt2b/HEK293 cell traffic Phos in the present invention Effect.
One, experimental material and instrument
L, scintillation counter (PerkinElmer#1450)
2、BD BioCoatTMPoly-D-Lysine 48- orifice plate (BD, #356509)
3, -32 radionuclide of phosphorus (Phosphorus-32 Radionuclide), 1mCi (37MBq) (H332PO4) (PerkinElmer, #NEX053001MC)
4、Optiphase Supermix(PerkinElmer#1200-439 for 5L)
Two, experimental procedure
1, source of mouse Npt2b/HEK293 cell is obtained
By Npt2b plasmid by certain than column and LipofectamineTMLTX mixing, after placing 30 minutes, by above-mentioned mixing Object is added drop-wise in the HEK293 cell of logarithmic phase growth, and side edged is mixed；After 24 hours, the culture medium culture containing G418 is changed into thin Born of the same parents nearly cover with, and bed board selects monoclonal cell, verify its function, obtain monoclonal stable cell line.
2, compound tests the inhibiting effect of source of mouse Npt2b/HEK293 cell traffic Phos
The previous day is mentioned by stable cell line source of mouse Npt2b/HEK293 cell kind in 48 orifice plates, 37 DEG C of carbon dioxide cultures It is cultivated in case.Culture medium is discarded, washs primary (250 μ of cell with Choline uptake buffer (Choline uptake buffer) The hole L/).Take 10 μ L H3 32PO4It is diluted in 1000ml sodium intake buffer (Sodium uptake buffer).Every hole is added 80 μ L test the H after compound and 20 μ L dilution3 32PO4, it is incubated at room temperature about 20 minutes.Final compound concentration are as follows: 100 μM, 10 μM, 1 μM, 0.1 μM, 0.01 μM, 0.001 μM, final DMSO concentration are as follows: 0.5%, final H3 32PO4Concentration Are as follows: the hole 0.2uCi/；Discard above compound and H3 32PO4, then with ice-cold terminate liquid (Ice cold stop Solution cell (350 hole μ L/) twice) is washed.150 μ L 200mM NaOH are added in every hole, shake cracking on vibration plate device at room temperature About 5 minutes.120 μ L cell lysates are shifted in the hole 96- sample panel in every hole.100 μ L are added in sample panel every hole in the hole 96- Then Optiphase Supermix seals the hole 96- sample panel with RE-SEALABLE TAPE, shake about on vibration plate device at room temperature 5 minutes.Scintillation counter readings.
The compounds of this invention is measured the inhibiting effect of source of mouse Npt2b/HEK293 cell traffic Phos, measures IC50Value is shown in Table 2.
The IC that 2 the compounds of this invention of table inhibits source of mouse Npt2b/HEK293 cell traffic Phos50
Embodiment number IC50(nM)
1 82
6 109
7 210
8 33
9 474
10 53
11 309
13 169
14 257
Conclusion: the compound in the present invention has apparent inhibition effect to source of mouse Npt2b/HEK293 cell traffic Phos Fruit.
The pharmacokinetics test of test case 3, the compounds of this invention
1, it makes a summary
Using rat as animal subject, when determining rat oral gavage using LC/MS/MS method and giving different after embodiment compound Carve the drug concentration in blood plasma.The compound of the present invention is studied in the intracorporal pharmacokinetics behavior of rat, evaluates its pharmacokinetics Feature.
2, testing program
2.1 test drug
6~9 compound of embodiment, embodiment 11, embodiment 13, embodiment 14 and embodiment 17.
2.2 experimental animal
Healthy adult SD rat 32, half male and half female is divided into 8 groups, every group 4, it is real to be purchased from the western Poole-Bi Kai in Shanghai Company of Animals Ltd. is tested, animal productiong licensing number: SCXK (Shanghai) 2008-0016.
2.3 drugs are prepared
Appropriate amount of sample is weighed, 0.5%CMC-Na is added to final volume, 0.5mg/ml suspension is made in ultrasound.
2.4 administration
SD rat 32, half male and half female is divided into 8 groups, distinguishes gastric infusion, dosage 5.0mg/ after one night of fasting Kg, administered volume 10mL/kg.
3, it operates
0.5,1,2,4,6,8,11,24 hour blood sampling 0.1mL before administration and after administration, is placed in the anticoagulant test tube of EDTA, 3500rpm is centrifuged 5 minutes, separated plasma, is saved in -20 DEG C.It feeds within 2 hours after administration.
Untested compound content after measuring different compound gastric infusions with LC/MS/MS method in rat plasma.Analysis side The range of linearity of method is respectively 5.00-2000ng/mL and 1.00-500ng/mL, lower limit of quantitation be respectively 5.00ng/mL and 1.00ng/mL；Plasma sample is analyzed after protein precipitation pre-processes.
4, 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 lower, the suction in blood medicine It receives few.
Test case 4, the test of the compounds of this invention rat excrement rate of recovery
1, it makes a summary
Using rat as animal subject, rat oral gavage is determined using LC/MS/MS method and gives preferred embodiment of the present invention chemical combination Drug concentration after object in different moments blood plasma.The compound of the present invention is studied in the intracorporal pharmacokinetics behavior of rat, is commented Its excrement rate of recovery of valence.
2, testing program
2.1 test drug
Embodiment 6,7 and 17 compounds.
2.2 experimental animal
Healthy adult SD rat 12, half male and half female is divided into 3 groups, every group 4, it is real to be purchased from the western Poole-Bi Kai in Shanghai Company of Animals Ltd. is tested, animal productiong licensing number: SCXK (Shanghai) 2008-0016.
2.3 drugs are prepared
Appropriate amount of sample is weighed, 0.5%CMC-Na is added to final volume, 2.0mg/ml suspension is made in ultrasound.
2.4 administration
SD rat 12, half male and half female is divided into 3 groups, is put into metabolic cage, freely ingest and drink water, is collected simultaneously Blank excrement sample, one night of fasting before being administered.Animal distinguishes gastric infusion, and gastric infusion, dosage 20.0mg/ are distinguished after one night of fasting Kg, administered volume 10mL/kg.
3, it operates
0~8 hour after administration, 8~24 hours, 24~48 hours, 48~72 hours Fractional Collections excrement samples, and claim respectively Weight.After record, label, 20 DEG C of freezen protectives are posted.Plasma sample respectively at administration before and administration after 1,2,4 and 8 hour by eye Socket of the eye blood sampling 0.2mL, is placed in heparinised tubes, and 3500rpm is centrifuged separated plasma after ten minutes, saves in -20 DEG C；3 after administration Hour feed.
4, faecal excretion rate result is accumulated
The accumulation faecal excretion rate of the compounds of this invention is shown in Table 4:
Conclusion: after the compounds of this invention of 20mg/kg is given in stomach-filling, the degree of exposure in urine and blood is lower, drug Prototype and the excrement rate of recovery of metabolin are high, and discovery contains relatively in tissues such as the stomach of digestive system, colon, jejunum, duodenums Amount is higher, and wherein colon and jejunum are the main function positions of drug.
Test case 5, the compounds of this invention treatment rat hyperphosphatemia test
1, it makes a summary
Using rat as animal subject, the serum phosphate lowering drug effect of the compound of the present invention is evaluated
2, testing program
2.1 test drug
5,6,7 compound of embodiment and 11 compound of embodiment.
Low-phosphorous feed (containing 0.1% phosphorus and 0.6% calcium): it is provided by Shanghai Slac Experimental Animal Co., Ltd..
Sodium dihydrogen phosphate (NaH2PO4·H2O): lot number 201209I06 is purchased from Hunan Jiudian Pharmaceutical Co., Ltd.Face use Before be configured to 1mmol/ml (138mg/ml, 5ml/kg).
Sodium carboxymethylcellulose (CMC-Na): lot number F20090508, Sinopharm Chemical Reagent Co., Ltd..
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, half male and half female is divided into 6 groups, every group 10, is purchased from the western Poole-Bi Kai in Shanghai Experimental animal Co., Ltd, animal productiong licensing number: SCXK (Shanghai) 2013-0016.
3, it operates
Experimental method is carried out according to method in patent application (WO2012006473).Animal is adapted to after buying with normal diet Property feed (at least 3 days), then switch to low-phosphorous forage feed, the screening of serum serium inorganic phosphorus carried out to rat,
Rat by serium inorganic phosphorus lower than 2.3mmol/L is according to the random grouping of serium inorganic phosphorus height, in the 2nd day stomach-filling biphosphate of experiment Sodium (1mmol/1mL) establishes rat hyperphosphatemia model.6 groups are randomly divided into according to enrolled rat serium inorganic phosphorus value, blank control group Give the distilled water of same volume.Give within each treatment group rat 15 minutes before modeling single oral gavage administration (5mL/kg, 30mg/kg), model group gives corresponding 0.5%CMC.Respectively at 0 hour (blank serum), 0.5 hour and 2 hours after modeling Eye socket blood sampling detection serum serium inorganic phosphorus value is carried out to rat afterwards.
4, serum phosphate lowering value result
The effect of the serum phosphate lowering of the compounds of this invention is shown in Table 5:
Embodiment number Serum phosphate lowering ratio (30mg/kg) after 0.5 hour
5 27.4%
6 31.4%
7 26.2%
11 29.4%
Conclusion: rat is after the preferred compounds of the invention of oral administration gavage 30mg/kg dosage, and giving, microcosmic salt 0.5 is small The apparent serum phosphate lowering effect of Shi Houyou.
Test case 6, Npt2b inhibitor compound 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, the limited public affairs of the vast great chemical science and technology in Shanghai Department, Cat#:B12264) or 7 feeding rat of Npt2b inhibitor embodiment compound, content of inorganic phosphorus in rat urine is detected, is come Evaluate the rush phosphorus Excretion of test drug.
2. experimental method and experimental material
2.1. experimental animal, feed and rearing conditions
Experiment SD male rat, purchased from Shanghai Bi Kai experimental animal Co., Ltd (Chinese Shanghai, quality certification number 2008001644738, licensing SCXK (Shanghai) 2013-0016).After animal is bought, after carrying out 3 days adaptive feedings, start general Logical feed and chocolate feed two-wheeled metabolic cage screening (being eaten up with 15g/ feed pcs/day as standard), the selected rat of success is again Start to test.
Normal diet (0.6%P, 0.6%Ca) by that triumphant must provide, chocolate feed (chocolate content be 3%, 0.6%P, It 0.6%Ca) is synthesized by the processing of this Leco Corp., pharmaceutical feed is to be mixed into drug in chocolate feed (to answer Yongcheng by medicine portion There is provided) it is process, be specifically formulated as follows: every gram of feed is mixed into 1.3mg test-compound, and reaching mean dose is 100mg/ kg/day；Every gram of feed of sevelamer is mixed into 9.75mg test-compound, and reaching mean dose is 750mg/kg/day.
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 adaptive feeding and screening, it is grouped as follows:
Group number Grouping 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 group -200mg/kg 4
Administration 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 (15g/ days) Screening, the rat that feed is all eaten up carry out screening for chocolate feed (15g/ days) again, finally all eat up feed big Mouse grouping enters experiment, is grouped as follows (dosage is mg/kg/day): 1. normal blank group at random, 2. sevelamer -750mg/kg Group, 3. compound 7-100mg/kg group, 4. compound 7-100mg/kg combines sevelamer -200mg/kg group.Every group of rat 4-5 Only.Two-wheeled screens successful rat and starts to feed said medicine feed in metabolic cage, totally 4 days, observes daily body weights, feeding Expect Expenditure Levels, and collect 24-48h, 48-72h and 72-96h urine respectively, detects the content of Phos in urine.
3. results and discussion: the influence of 2-Propen-1-amine polymer with(chloromethyl)oxirane carbonate and compound 7 to rat phosphuresis
Its urine phosphorus content of normal blank group was 25-26mg at 24-48h, 48-72h and 72-96h tri- days, with normal blank Group compares, and 3 days urine phosphorus total amounts of administration group or 3 days average magnitudes are substantially reduced (P < 0.05), sevelamer -750mg/kg group, Compound 7-100mg/kg group, compound 7-100mg/kg+ sevelamer -200mg/kg organize its reduction amplitude and are respectively 30.2%, 27.9% and 44.2%, 6, Fig. 1 are shown in Table, ratio is reduction amplitude.
Three day averages that table 6:Npt2b influences rat phosphuresis
The results show that 750mg/kg sevelamer, 100mg/kg compound 7 and the two combination have the apparent phosphorus that promotees to drain work With, be applied alone sevelamer and 7 drug effect of compound suitable, and 750mg/kg sevelamer+200mg/kg compound 7 be combined after its urinate Phosphorus reduction amplitude is higher than the two and is applied alone.

Claims (17)

1. a kind of logical formula (I) compound represented or its pharmaceutical salt:
Wherein:
X is selected from C (Ra)2, O or NRa；
Y is-C (O)-；
RaIt is identical or different, it is each independently selected from hydrogen atom, C1-6Alkyl or-C (O) OR5, wherein the C1-6Alkyl is optional Halogen, C are further selected from by one or more1-6Alkyl, C1-6Halogenated alkyl, C1-6Hydroxyalkyl, C3-6Naphthenic base, heterocycle take Replaced Dai Ji；
Ring A is phenyl；
Ring B is selected from phenyl or pyridyl group；
Ring C is heterocycle, and the heterocycle is optionally further by one or more C1-6Replaced alkyl；
R1Selected from C1-6Alkyl, the C1-6Alkyl further replaced phenyl, the phenyl optionally further by one or It is multiple to be selected from halogen, hydroxyl, C1-6Alkoxy, C1-6Alkyl ,-C (O) OR5、-OC(O)R5Or-C (O) NR6R7Substituent group taken Generation；
R2Selected from hydrogen atom, halogen or C1-6Alkyl；
R3Selected from hydrogen atom or C1-6Alkyl；
R4Selected from hydrogen atom or C1-6Alkyl；
R5Selected from hydrogen atom or C1-6Alkyl, wherein the C1-6Alkyl is optionally further selected from halogen, hydroxyl by one or more Substituent group replaced；
R6Or R7It is each independently selected from hydrogen atom or C1-6Alkyl, wherein the C1-6Alkyl is optionally further by one or more Replaced a hydroxyl；
The heterocycle includes 5-6 annular atom, and wherein 1-2 are the hetero atom selected from N or O；
M is 0,1,2,3 or 4；
N is 0,1,2,3 or 4.
2. logical formula (I) compound represented according to claim 1 or its pharmaceutical salt, for shown in logical formula (II) Compound or its pharmaceutical salt:
Wherein:
R1~R4, X, Y, m, n, ring A and ring C definition as described in the appended claim 1.
3. logical formula (I) compound represented according to claim 1 or its pharmaceutical salt, for shown in logical formula (III) Compound or its pharmaceutical salt:
Wherein:
R1~R4, X, Y, m, n and ring C definition as described in the appended claim 1.
4. logical formula (I) compound represented according to claim 1 or its pharmaceutical salt, middle ring C is morpholine base Or piperazinyl.
5. logical formula (I) compound represented according to claim 1 or its pharmaceutical salt, wherein R1Selected from-(CH2)r- Rc；
RcFor phenyl, the phenyl is optionally further selected from halogen, hydroxyl, C by one or more1-6Alkoxy, C1-6Alkyl ,- C(O)OR5、-OC(O)R5Or-C (O) NR6R7Substituent group replaced；
R is selected from 1,2,3,4 or 5；And
R5、R6、R7Definition as described in the appended claim 1.
6. logical formula (I) compound represented according to claim 5 or its pharmaceutical salt, wherein r is 2 or 3.
7. logical formula (I) compound represented according to claim 1 or its pharmaceutical salt, wherein the compound selects From:
8. a kind of method for preparing logical formula (I) compound represented according to claim 1 or its pharmaceutical salt, the party Method includes:
General formula (IA) compound or its salt is reacted with general formula (IB) compound, optionally further hydrolyzes and/or be condensed to yield general 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 described in a kind of general formula (IA) or its pharmaceutical salt,
Wherein:
X is selected from C (Ra)2, O or NRa；
RaIt is identical or different, it is each independently selected from hydrogen atom, C1-6Alkyl or-C (O) OR5, wherein the C1-6Alkyl is optional Halogen, C are further selected from by one or more1-6Alkyl, C1-6Halogenated alkyl, C1-6Hydroxyalkyl, C3-6Naphthenic base, heterocycle take Replaced Dai Ji；
Condition is when X is selected from C (Ra)2When, RaIt is not selected from hydrogen atom；
Ring A is phenyl；
R1Selected from C1-6Alkyl, the C1-6Alkyl further replaced phenyl, the phenyl optionally further by one or It is multiple to be selected from halogen, hydroxyl, C1-6Alkoxy, C1-6Alkyl ,-C (O) OR5、-OC(O)R5Or-C (O) NR6R7Substituent group taken Generation；Condition is the R when X is selected from O1Selected from C1-6Alkyl, wherein the C1-6Alkyl is described further replaced phenyl Phenyl is optionally further selected from halogen, hydroxyl, C by one or more1-6Alkoxy or C1-6Replaced alkyl substituent；
R2Selected from hydrogen atom, halogen or C1-6Alkyl；
R5Selected from hydrogen atom or C1-6Alkyl, wherein the C1-6Alkyl is optionally further selected from halogen, hydroxyl by one or more Substituent group replaced；
R6Or R7It is each independently selected from hydrogen atom or C1-6Alkyl, wherein the C1-6Alkyl is optionally further by one or more Replaced a hydroxyl；
M is 0,1,2,3 or 4；Condition is when X is selected from C (Ra)2When, m 1,2,3 or 4.
10. general formula (IA) compound represented according to claim 9 or its pharmaceutical salt, wherein the compound selects From:
11. a kind of pharmaceutical composition, described pharmaceutical composition contains logical formula (I) described in any one according to claim 1~7 Compound represented or its pharmaceutical salt and pharmaceutically acceptable carrier, diluent or excipient.
12. pharmaceutical composition according to claim 11 further contains another or a variety of phosphate binders.
13. pharmaceutical composition according to claim 12, the phosphate binder is sevelamer.
14. logical formula (I) compound represented or its pharmaceutical salt described in any one according to claim 1~7, or according to Pharmaceutical composition described in any one of claim 11-13 is preparing intestines 2B type sodium phosphate cotransporter Npt2b inhibition Purposes in agent.
15. logical formula (I) compound represented or its pharmaceutical salt described in any one according to claim 1~7, or according to Purposes of the pharmaceutical composition described in any one of claim 11-13 in the drug that preparation treats or prevents hyperphosphatemia.
16. logical formula (I) compound represented or its officinal salt described in any one according to claim 1~7, or according to power Benefit requires pharmaceutical composition described in any one of 11-13 to treat or prevent the disease that sodium phosphate transport protein mediates in preparation Purposes in drug, the disease are selected from the activity of high concentration caused by nephrosis, the calcification of inner membrance local vascular, hyperphosphatemia Vitamin D, hyperthyroidism.
17. purposes according to claim 16, the nephrosis is chronic nephrosis or end-stage renal disease.
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