CN107098871A - Phenylpropionyl amine derivant, its preparation method and its in application pharmaceutically - Google Patents

Phenylpropionyl amine derivant, its preparation method and its in application pharmaceutically Download PDF

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Publication number
CN107098871A
CN107098871A CN201710095021.XA CN201710095021A CN107098871A CN 107098871 A CN107098871 A CN 107098871A CN 201710095021 A CN201710095021 A CN 201710095021A CN 107098871 A CN107098871 A CN 107098871A
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amino
alkyl
heterocyclic radical
compound
cycloalkyl
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CN107098871B (en
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李心
何威
刘涛
贺峰
陶维康
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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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/192—Radicals derived from carboxylic acids from aromatic carboxylic acids
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to phenylpropionyl amine derivant, its preparation method and its in application pharmaceutically.Especially, pharmaceutical composition the present invention relates to the phenylpropionyl amine derivant shown in logical formula (I), its preparation method and containing the derivative, and it is as the purposes of kappa opioid nonopioid receptors (KOR acceptors) activator, and its purposes in the medicine for the treatment of and/or pre- pain and pain related disorders is prepared.Each substituent of its formula of (I) is identical with the definition in specification.

Description

Phenylpropionyl amine derivant, its preparation method and its in application pharmaceutically
Technical field
The invention belongs to field of medicaments, it is related to a kind of phenylpropionyl amine derivant, its preparation method and its pharmaceutically Application.Especially, spread out the present invention relates to the phenylpropionyl amine derivant shown in logical formula (I), its preparation method and containing this Biological pharmaceutical composition, and its as the purposes of kappa opioid nonopioid receptors (KOR acceptors) activator and its treat preparing And/or the purposes in the medicine of pre- pain and pain related disorders.
Background technology
Opiate receptor is the important g protein coupled receptor of a class, is the target that endogenous opiatepeptide and opioid drug are combined Point, immune to nervous system after opiate receptor activation and internal system has adjustment effect, and opioid drug is most strong at present And conventional central analgesia medicine.Endogenous opiatepeptide is the opioid activity material naturally occurred in mammal body, at present The endogenous opiatepeptide known is roughly divided into enkephalins, endorphin, dynorphin and several classes of new deltorphin delta (Pharmacol Rev 2007； 59:88-123), there is its corresponding opiate receptor, i.e. μ, δ, kappa receptor etc. in central nervous system.
Kappa opioid receptor (κ-opioid receptor, KOR) is made up of 380 amino acid, and dynorphin is that its endogenous is matched somebody with somebody Body.There is expression in sensory neuron, Dorsal Root Ganglion Neurons and primary afferent neuron tip, participate in the pain sensation, nerve interior The important physiological activities such as secretion, affective behavior and cognition.People KOR is currently known by OPRK1 gene codes, chromosome is positioned at 8q11-12 sites (Simonin F, Gaveriaux Ruff C, Kieffer BL, et al.Proc Natl Acad Sci USA 1995,92(15):7006-10).KOR is activated and G-protein Gi/G0Coupling, adds phosphodiesterase activity, suppresses gland sweet The activity of cyclase of acid, reduces intracellular cAMP levels, so as to produce the inhibitory action to neuron.KOR activator repeated actions Acceptor has desensitization effect, and the inhibitory action to gland sweet acid cyclase activity reduces (Raynor K, Kong H, Hines J, et al.J Pharmacol Exp Ther,1994,270:1381-6).KOR is also logical with inward rectifyimg potassium channel and N-type calcium ion Road is coupled (Henry DJ, Grandy DK, Lester HA, Davidson N, Chavkin C (Mar 1995) Molecular Pharmacology 47(3):551–7).KOR activators can suppress the injury of (calcium ion dependence) peripheral sensory nerve endings The release of Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2 before preceding and inflammation, this is probably the reason for it has anti-nociceptive effects and antiinflammatory action.Except dynorphin, respectively Planting the part of natural alkaloid and synthesis can also be combined with KOR.KOR provide natural habituation controlling mechanism, therefore, as by The medicine of body activator has the potentiality of drug-addiction treatment.
Effect of the KOR activators Asimadoline (asimadoline) in rodent diabetes DPN (Jolivalt et al.Diabetologia 2006,49(11):2775-85；Epub Aug.19) and KOR activators U- 50488 effect and opioid antagonists in repressive damage (CCI) model of rat chronic of neuropathic pain receives Lip river Blocking (Bileviciute-Ljungar et al.Eur.J.Pharm 2004.494 of the ketone (naloxone) to its effect: 139-46), these observation results are supported to be used to KOR activators treat the neuropathic pain that diabetes, virus and chemotherapy trigger. KOR activators are used to treat or prevent including such as the splanchnodynia including the gynecological diseases such as dysmenorrhoea spasm and endometriosis Using also be evaluated (Riviere, Br.J.Pharmacol 2004.141:1331-4).
Kappa opioid material activator increase water renal excretion and reduce natruresis (i.e. produce optional water diuresis, also by Referred to as promote water excretion), many researchers think that this effect is due to suppress pituitary antidiuretic hormone.Compare maincenter work With property and it is said that the research institute of the selective kappa opioid material of periphery property is concluded that KOR in blood-brain barrier is responsible for Mediate this effect.There is researcher to propose to act on the plain peptide of nociception or powered peptide of the plain acceptor of nociception in periphery Conjugate treats hyponatremia, described injury experience peptide acceptor and KOR about but it is different (D.R.Kapusta, Life Sci., 60:15-21,1997)。
Presently disclosed KOR activators patent application include WO20071398, WO2008060552, WO09932510, WO2013184794, WO2014089019, WO2014184356 and WO2015065867.
Kappa opioid nonopioid receptors (KOR acceptors) activator has a good application prospect as medicine in pharmaceuticals industry, is The purpose of more preferable therapeutic effect is reached, the market demand is better met, inventor wishes to develop the efficient of a new generation The KOR activators of low toxicity.The present invention will provide a kind of new kappa opioid nonopioid receptors (KOR acceptors) agonist compound, suchization Compound astoundingly shows excellent effect and effect.
The content of the invention
It is an object of the invention to provide the compound shown in a kind of logical formula (I)：
Or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its mixture shape Formula, or its pharmaceutically useful salt,
Wherein：
G is C=O or O=S=O；
R1Selected from hydrogen atom, alkyl, alkoxy, haloalkyl, halogen, amino, nitro, hydroxyl, cyano group, cycloalkyl, miscellaneous Ring group, aryl, heteroaryl ,-OR3、-C(O)R3、-C(O)OR3、-S(O)mR3With-NR4R5, wherein described alkyl, alkyl halide Base, cycloalkyl, heterocyclic radical, aryl and heteroaryl are optionally selected from alkyl, haloalkyl, halogen, amino, nitro, cyano group, hydroxyl Base, alkoxy, halogenated alkoxy, hydroxyalkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl and NR6R7One or more of substitution Base is replaced；
R2Selected from hydrogen atom, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-OR3、-C(O) R3With-C (O) OR3, wherein described alkyl, haloalkyl, cycloalkyl, heterocyclic radical, aryl and heteroaryl be optionally selected from alkyl, Haloalkyl, halogen, amino, nitro, cyano group, hydroxyl, alkoxy, halogenated alkoxy, hydroxyalkyl, cycloalkyl, heterocyclic radical, aryl Replaced with one or more of heteroaryl substituent；
R3Selected from hydrogen atom, alkyl, amino, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclic radical, aryl and heteroaryl, wherein Described alkyl, cycloalkyl, heterocyclic radical, aryl and heteroaryl be optionally selected from alkyl, halogen, hydroxyl, amino, nitro, cyano group, One or more of alkoxy, hydroxyalkyl, cycloalkyl, heterocyclic radical, aryl and heteroaryl substituent is replaced；
R4And R5It is each independently selected from hydrogen atom, alkyl, alkoxy, hydroxyalkyl, hydroxyl, amino, carboxylic acid ester groups, cycloalkanes Base, heterocyclic radical, aryl and heteroaryl, wherein described alkyl, cycloalkyl, heterocyclic radical, aryl and heteroaryl are optionally selected from alkane Base, halogen, hydroxyl, amino, carboxylic acid ester groups, nitro, cyano group, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclic radical, aryl and heteroaryl One or more of substituent replaced；
R6For hydrogen atom or W；
R7Selected from hydrogen atom, alkyl, C (O) R8、C(O)OR8、C(O)NR9R10Or W, wherein described alkyl is optionally selected from One or more of alkoxy, hydroxyalkyl, cycloalkyl, heterocyclic radical, carboxylic acid group and carboxylic acid ester groups substituent is replaced；
R8Selected from hydrogen atom, alkyl, alkoxy, amino, cycloalkyl and heterocyclic radical, wherein described heterocyclic radical is optionally chosen Taken from one or more of alkyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclic radical, carboxylic acid group and carboxylic acid ester groups substituent Generation；
R9And R10It is each independently selected from hydrogen atom, alkyl or haloalkyl；Wherein described alkyl is optionally selected from carboxylic One or many in acidic group, alkoxy, amino, cyano group, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic radical, aryl and heteroaryl Individual substituent is replaced；
Or, R9And R10Heterocyclic radical is formed together with the nitrogen-atoms being connected, wherein containing 1~2 in described heterocyclic radical The individual identical or different hetero atom selected from N, O and S, and described heterocyclic radical is optionally selected from alkyl, alkoxy, halogen, ammonia One in base, cyano group, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic radical, carboxylic acid group, carboxylic acid ester groups, aryl and heteroaryl or Multiple substituents are replaced；
W is amino protecting group；And
M is 0,1 or 2.
In yet other embodiments, the compound shown in described logical formula (I) is shown in logical formula (II) Compound：
Or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its mixture shape Formula, or its officinal salt,
Wherein：
R1And R2As defined in logical formula (I).
In yet other embodiments, the compound shown in described logical formula (I), wherein R1For alkyl or OR3, wherein described alkyl is optionally by NR6R7Substituent is replaced；
R3Selected from alkyl or heterocyclic radical, wherein described alkyl is optionally selected from cycloalkyl, heterocyclic radical, aryl and heteroaryl One or more of substituent replaced；
R6For hydrogen atom；
R7Selected from hydrogen atom, alkyl, C (O) OR8Or C (O) NR9R10, wherein described alkyl is optionally selected from alkoxy, hydroxyl One or more of alkyl, carboxylic acid group and carboxylic acid ester groups substituent is replaced；
R8For hydrogen atom or alkyl；
R9And R10It is each independently hydrogen atom or alkyl；
Or, R9And R10Heterocyclic radical is formed together with the nitrogen-atoms being connected, wherein containing 1~2 in described heterocyclic radical The individual identical or different hetero atom selected from N, O and S, and described heterocyclic radical is optionally selected from alkyl, alkoxy, halogen, ammonia One or more of base, carboxylic acid group and carboxylic acid ester groups substituent is replaced.
In yet other embodiments, the compound shown in described logical formula (I) is shown in logical formula (III) Compound：
Or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its mixture shape Formula, or its officinal salt,
Wherein：
G、R6~R7And R2As defined in logical formula (I).
In yet other embodiments, the compound shown in described logical formula (I)~logical formula (III), its Middle R2Selected from hydrogen atom, alkyl, cycloalkyl and aryl；Preferably hydrogen atom, methyl, ethyl, cyclopropyl or phenyl.
The typical compound of logical formula (I), includes but is not limited to：
Or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its mixture shape Formula, or its officinal salt.
The present invention additionally provides a kind of logical formula (I) compound or its salt, wherein described salt is logical formula (I) and trifluoroacetic acid The addition salts of formation.
The present invention additionally provides the compound shown in a kind of logical formula (IV), the intermediate for synthesizing logical formula (I)：
Or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its mixture shape Formula or its pharmaceutically useful salt,
Wherein：
W is amino protecting group；
G and R1~R2As defined in logical formula (I).
The typical compound of logical formula (IV), includes but is not limited to：
Or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its mixture shape Formula, or its officinal salt.
Prepared the present invention additionally provides one kind according to logical formula (I) compound or its dynamic isomer, mesomer, racemic Body, enantiomter, diastereoisomer or its form of mixtures or the method for its officinal salt, this method include：
Formula (I-5) compound is reacted with formula (I-6) compound, obtains logical formula (IV) compound；Obtained formula (IV) compound further sloughs protection group, obtains logical formula (I) compound；
Wherein：
W is amino protecting group；
G、R1And R2As defined in logical formula (I).
Another aspect of the present invention is related to a kind of pharmaceutical composition, its contain treatment effective dose above-mentioned logical formula (I), (II) compound, shown in (III) or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereo-isomerism Body or its form of mixtures or pharmaceutically useful salt, and one or more pharmaceutically acceptable carriers, diluent or figuration Agent.The invention further relates to a kind of method for preparing aforementioned pharmaceutical compositions, it is included shown in logical formula (I), (II), (III) Compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its mixture shape Formula or its pharmaceutically useful salt are mixed with pharmaceutically acceptable carrier, diluent or excipient.
In one embodiment, pharmaceutical composition of the invention further comprises one or more kinds of following compounds： Opioid, cannboid, antidepressant, anticonvulsant, tranquilizer, corticosteroid, ion channel blocking agent or non-steroidal are anti- Scorching medicine (NSAID).
The invention further relates to the compound shown in logical formula (I), (II), (III) or its dynamic isomer, meso Body, racemic modification, enantiomter, diastereoisomer or its form of mixtures or its officinal salt, or the medicine comprising it Composition purposes in the medicine of excitement or antagonism kappa opioid nonopioid receptors (KOR acceptors) is prepared.
The invention further relates to the compound shown in logical formula (I), (II), (III) or its dynamic isomer, meso Body, racemic modification, enantiomter, diastereoisomer or its form of mixtures or its officinal salt, or the medicine comprising it Composition is in the medicine for preparing the relevant disease for preventing and/or treating the mediation of kappa opioid nonopioid receptors (KOR acceptors) activator Purposes in thing, the relevant disease of kappa opioid nonopioid receptors (KOR acceptors) receptor stimulating agent mediation be preferably selected from pain, Inflammation, itch, oedema, hyponatremia, hypopotassaemia, intestinal obstruction, cough and glaucoma, more preferably pain.
The invention further relates to the compound shown in logical formula (I), (II), (III) or its dynamic isomer, meso Body, racemic modification, enantiomter, diastereoisomer or its form of mixtures or its officinal salt, or the medicine comprising it Composition is being prepared for preventing and/or treating mammal (for example：People) pain and pain related disorders medicine in use On the way, wherein described pain can be postoperative pain, pain, neuropathic pain, treatment of traumatic pain and inflammation caused by cancer draw Pain risen etc..
The invention further relates to a kind of excitement or the method for antagonism kappa opioid nonopioid receptors (KOR acceptors), this method bag Include to need the logical formula (I) of the invention of its patient therapeuticallv's effective dose, (II), the compound shown in (III) or its Dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures or its is pharmaceutically acceptable Salt.
, should the invention further relates to a kind of method for the relevant disease for preventing and/or treating the mediation of KOR agonist receptors Method includes the chemical combination shown in the logical formula (I) of the invention of its patient therapeuticallv's effective dose of needs, (II), (III) Thing or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures or its Officinal salt.This method shows prominent curative effect and less side effect.Wherein described kappa opioid nonopioid receptors (KOR by Body) agonist receptor mediation relevant disease be selected from pain, inflammation, itch, oedema, hyponatremia, hypopotassaemia, intestinal obstruction, Cough and glaucoma, preferably pain.
The invention further relates to the compound shown in a kind of logical formula (I) as medicine, (II), (III) or its change Isomers, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures or its officinal salt.
The invention further relates to the compound shown in logical formula (I), (II), (III) or its dynamic isomer, meso Body, racemic modification, enantiomter, diastereoisomer or its form of mixtures or its officinal salt, it is used for exciting or short of money Anti- kappa opioid nonopioid receptors (KOR acceptors).
The invention further relates to the compound shown in logical formula (I), (II), (III) or its dynamic isomer, meso Body, racemic modification, enantiomter, diastereoisomer or its form of mixtures or its officinal salt, its be used for prevent and/ Or the relevant disease for the treatment of KOR receptor stimulating agent mediations.
The invention further relates to the compound shown in logical formula (I), (II), (III) or its dynamic isomer, meso Body, racemic modification, enantiomter, diastereoisomer or its form of mixtures or its officinal salt, its be used for prevent and/ Or treatment mammal is (for example：People) pain and pain related disorders.Kappa opioid nonopioid receptors (KOR acceptors) activator The relevant disease of mediation, the disorderly or patient's condition can be the correlations of any kappa opioid nonopioid receptors (KOR acceptors) activator mediation The patient's condition, including but not limited to acute or chronic pain, inflammation, itch, hyponatremia, oedema, intestinal obstruction, cough and green light Eye.For example, the related pain of kappa opioid nonopioid receptors (KOR acceptors) can be neuropathic pain, somatalgia, splanchnodynia or skin Skin pain.Some diseases, disorder or the patient's condition are relevant with more than one pain form.For example, postoperative pain can be nerve pain Bitterly, any of somatalgia, splanchnodynia or dermatalgia factor or all, this depend on used surgical operation type and Degree.
The related inflammation of kappa opioid nonopioid receptors (KOR acceptors) of the present invention can be any inflammatory disease or disease Condition, including but not limited to sinusitis, rheumatoid arthritis tenosynovitis, bursal synovitis, tendonitis, external humeral epicondylitis, sticky capsulitis, bone Marrow inflammation, osteoarthritic inflammation, inflammatory bowel disease (IBD), IBS (IBS), inflammation of eye section, ear inflammation or autoimmunity are scorching Disease.
The related itch of kappa opioid nonopioid receptors (KOR acceptors) of the present invention can be any pruritic condition and disease The related ocular pruritis of condition, such as ocular pruritis such as conjunctivitis, itch, itch (many of which patient relevant with latter stage nephropathy Receive Rend dialysis) and other forms cholestasis, it is including Primary biliary cirrhosis, intrahepatic cholestasis of pregnancy, chronic Cholesterol hepatopathy, uremia, pernicious cholestasis, jaundice and skin conditions, such as eczema (dermatitis) include atopic dermatitis Or contact dermatitis, skin tinea, polycythemia, lichen planus, lichen simplex chronicus, pediculosis, thyrotoxicosis, tinea pedis, Nettle rash, scabies, vaginitis, hemorrhoid related pruritus ani and insect bite itch and drug-induced itch, such as mu opioid Itch caused by material.
The related oedema of kappa opioid nonopioid receptors (KOR acceptors) of the present invention can be any edema disease or Oedema caused by the patient's condition, such as congestive heart disease or antidiuretic hormone (ADH) secrete oedema caused by improper syndrome.
The related intestinal obstruction of kappa opioid nonopioid receptors (KOR acceptors) of the present invention can be any intestinal obstruction disease Or the patient's condition, bowel dysfunction including but not limited to caused by post operative ileus or opioid.
The related neuropathic pain of kappa opioid nonopioid receptors (KOR acceptors) of the present invention can be any nerve Pain, for example, the related pain of pain such as herpes zoster, chemotherapy trigger caused by trigeminal neuralgia, diabetic pain, virus Pain, the metastatic cancer pain of invasion and attack nerve, the wound neuropathic pain related to surgical operation and various be considered as having There is the headache variant such as migraines of europathology factor.
The related pain of kappa opioid nonopioid receptors (KOR acceptors) of the present invention is coughed including ocular pain, for example, bending Eye pain after photosensitiveness cornea ablation art (PRK), eye tear, eyeground fracture, chemical burn, abrasio corneae or stimulation etc. Bitterly, or with conjunctivitis, ulcer of the cornea, sclerotitis, episcleritis, sclerokerratitis, herpes zoster ophthalmicus, chromic fibrous cornea Inflammation, acute iritis, keratoconjunctivitis sicca, orbital cell ulitis, orbital pseudotumor, pemphigus, trachoma or uveitis are related Ocular pain.
The related pain of kappa opioid nonopioid receptors (KOR acceptors) of the present invention is also wrapped work and had a sore throat, especially with inflammation Symptom condition, such as allergic rhinitis, acute bronchitis, common cold, contact ulcer, herpes simplex virus damage, infection Property monocytosis,mononucleosis, influenza, laryngocarcinoma, acute laryngitis, acute necrotizing ulcer gingivitis, tonsil abscess, pharynx Portion is burnt, pharyngitis, reflux sphagitis, acute sinusitis is related to tonsillitis has a sore throat.
The related pain of kappa opioid nonopioid receptors (KOR acceptors) of the present invention can be arthritis ache, kidney knot Stone, lithangiuria and calculus of bile duct pain, hysterotrismus, dysmenorrhoea, endometriosis, mastitis, indigestion, surgery hand Postoperative pain (for example appendectomy, open colorectal resection, hernia reparation, prostatectomy, colon enucleation, Gastrectomy, splenectomy, colectomy, colostomy, pelvis abdominoscopy book, tubal ligation, uterectomy, Postoperative pain caused by vasectoray or cholecystectomy), pain (such as colonoscopy, bladder after medical treatment Pain after spectroscopy, hysteroscopy or uterine neck or endometrial biopsy), otitis pain, explosive cancer Pain and the pain related to GI disorders, GI the disorder such as IBD or IBS or other inflammatory conditions, especially encelitis Disease is (for example, GORD, pancreatitis, acute pyelonephritis, ulcerative colitis, cholecystitis, hepatic sclerosis, hepatic pouch Swollen, hepatitis, duodenal ulcer or gastric ulcer, esophagitis, gastritis, gastroenteritis, colitis, diverticulitis, intestinal obstruction, ovarian bursa Swollen, pelvic inflammatory disease, perforated ulcer, peritonitis, prostatitis, interstitial cystitis) related pain, or connect with toxic agent Touch the pain that (medicine such as insect toxins or such as salicylate (salt) or NSAID) is brought.
The related hyponatremia of kappa opioid nonopioid receptors (KOR acceptors) of the present invention can the presence of hyponatremia Any disease or the patient's condition of (the low sodium patient's condition),, extremely can be with when na concn is less than 135mmol/l in blood plasma for example, in people Individually occur, or more insights are as the complication of other medical conditions or as using can cause the medicine of sodium deficiency As a result occur, wherein the disease related to hyponatremia includes but is not limited to：Cause the tumour of excessive ADH secretion because Element, including lung, duodenum, pancreas, ovary, cancer, thymoma, celiothelioma, bronchial adenoma, the class cancer of bladder and ureter Knurl, gangliocytoma and Ewing's sarcoma, infection；Such as pneumonia (bacillary or viral), abscess (lung or brain), sky Bubble forms (aspergillosis), tuberculosis (lung or brain), meningitis (bacillary or viral), encephalitis and AIDS；Vascular factor example Such as：Cerebral infarction or hemorrhage and cavernous sinus thrombosis；Neural factors are for example：Guillan-Barre syndromes, multiple sclerosis, Delirium tremens, ALS, hydrocephalus, mental disease, peripheral neurophaty, head trauma (closed and penetrability), Cns tumor or infection and the CNS infringements for influenceing hypothalamus osmoreceptor；Congenital abnormality bag is lived：Corpus callosum is developed not Entirely, harelip and line defect in other；Metabolic factor is for example：Acute intermittent porphyria, asthma, pneumothorax and positive pressure respiration；Medicine Thing is for example：Thiazide diuretic, paracetamol, barbiturate, cholinergic agent, estrogen, oral hypoglycemic, pitressin are gone Ammonia pitressin, high dose oxytocins chlorpropamide, vincristine, carbamazepine, nicotine, phenthazine, endoxan, three rings resist Down, MAOI and serotonin reuptake inhibitor；For example during hospitalization, surgical operation or physical culture (that is, related hyponatremia, which is moved, during or after activity) applies excessive hypotonic fluid, and using low in older individuals Sodium nutrition replenishers, other patient's condition related to hyponatremia include renal failure, nephrotic syndrome (model nephrosis and minute lesion disease Disease), pernicious matter, malnutrition, rhabdomyolysis, surgery processing, selective cardiac catheterization, lose blood and hypercalcinemia, low Potassium mass formed by blood stasis and result are the hyperglycemias for the glycosuria that can cause osmotic diuresis.
Another aspect of the present invention is related to a kind of be used as and prevented and/or treatment kappa opioid nonopioid receptors (KOR acceptors) activator The method of the relevant disease of mediation, disorderly or patient's condition relevant disease, this method, which includes its patient therapeuticallv to needs, to be had Each formula of the invention of dosage is imitated, particularly leads to compound or its dynamic isomer, mesomer shown in formula (I), disappear outside Revolve body, enantiomter, diastereoisomer or its form of mixtures or its officinal salt；This method shows the treatment of protrusion Effect and less side effect, wherein the relevant disease of described kappa opioid nonopioid receptors (KOR acceptors) activator mediation include but It is not limited to acute or chronic pain, inflammation, itch, hyponatremia, oedema, intestinal obstruction, cough and glaucoma.
Another aspect of the present invention is related to a kind of method prevented and/or treat mammalian pain and pain related disorders, This method is included to its mammal of needs using shown in the logical formula (I) of the invention for the treatment of effective dose, (II), (III) Compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its mixture shape Formula or its officinal salt；This method shows prominent curative effect and less side effect, wherein described pain can be postoperative Ache caused by pain, neuropathic pain, treatment of traumatic pain somatalgia, splanchnodynia, dermatalgia and inflammation caused by pain, cancer Bitterly, for example, postoperative pain can be any of neuropathic pain, somatalgia, splanchnodynia or dermatalgia factor or whole, this Depending on the type and extent of the surgical operation used；Described cancer can be selected from breast cancer, carcinoma of endometrium, uterine neck Cancer, cutaneum carcinoma, prostate cancer, oophoroma, fallopian tube cneoplasms, ovarioncus, hemophilia and leukaemia etc..
Pharmaceutical composition containing active component can apply to oral form, such as tablet, dragee, lozenge, water Or oil suspension, dispersible powder or particle, emulsion, hard or soft capsule, or syrup or elixir.Can be any according to this area Know that the method for preparing Pharmaceutical composition prepares Orally administered composition, such composition can containing it is one or more selected from it is following into Point：Sweetener, flavouring, colouring agent and preservative, to provide pleasing and tasty pharmaceutical formulation.Tablet contain active component and The suitable nontoxic pharmaceutically useful 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 disintegrant, 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 medicine or in intestines and stomach Middle delay disintegration and absorption, thus the known technology of offer slow releasing function is coated in a long time.For example, water can be used Dissolubility taste masked material, such as hydroxypropyl methyl cellulose or hydroxypropyl cellulose, or extension time material such as ethyl are fine Dimension element, acetylbutyrylcellulose.
What also available wherein active component was mixed with inert solid diluent such as calcium carbonate, calcium phosphate or kaolin is hard bright Glue capsule, or wherein active component 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 formulations.
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；Dispersant or wetting agent can be naturally-produced phosphatide such as lecithin, or alkylene oxide and aliphatic acid contracting Close product such as Myrj 45, or oxirane and long-chain fatty alcohol condensation product, such as 17 carbon ethylidene Epoxide cetanol, or oxirane with as derived from aliphatic acid and hexitol part ester condensation product, such as PEO Sorbitol monooleate, or oxirane with as derived from aliphatic acid and hexitan partial ester condensation product, such as polycyclic oxygen Ethane Arlacel-80.Aqueous suspension can also contain one or more preservative such as ethylparabens or Ni Bo Nintaus's propyl ester, one or more colouring agent, one or more flavourings and one or more sweeteners, such as sucrose, saccharin or Aspartame.
Oil suspension can by making active component 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.Can Above-mentioned sweetener and flavouring is added, to provide tasty preparation.Can by add antioxidant such as Butylated Hydroxyanisole or α- These compositions of fertility phenol preservation.
The dispersible powder and particle being suspended also by adding water to make suitable for preparing water provide active component and are used for The dispersant or wetting agent of mixing, suspending agent or one or more preservatives.Suitable dispersant or wetting agent and suspending agent can Illustrate above-mentioned example.Also other excipient such as sweetener, flavouring and colouring agent can be added.By adding antioxidant example As ascorbic acid preserves these compositions.
The pharmaceutical composition of the present invention can also be the form of oil in water emulsion.Oil phase can be vegetable oil such as olive oil Or peanut oil, or mineral oil such as atoleine or its mixture.Suitable emulsifying agent can be naturally-produced phosphatide, for example Soybean lecithin and ester or partial ester such as sorbitan monooleate as derived from aliphatic acid and hexitan, and the partial ester and ring The condensation product of oxidative ethane, such as polyoxyethylene sorbitol monoleate.Emulsion can also contain sweetener, flavouring, prevent Rotten agent and antioxidant.Syrup and elixir can be prepared with Sweetening agents such as glycerine, propane diols, sorbierite or sucrose.Such preparation Moderator, preservative, colouring agent and antioxidant can be contained.
The pharmaceutical composition of the present invention can be sterile injectable aqueous form.The acceptable solvent or molten that can be used Agent has water, ringer's solution and isotonic sodium chlorrde solution.Aseptic injection preparation can be that wherein active component is dissolved in the sterile of oil phase Inject oil-in-water microemulsion.For example active component is dissolved in the mixture of soybean oil and lecithin.Then oil solution is added into water Micro emulsion is formed with processing in the mixture of glycerine.Parenteral solution or micro emulsion can be injected to the blood flow of patient by local a large amount of injections In.Or, preferably give solution and micro emulsion in the way of it can keep the compounds of this invention constant circulating concentration.To keep this perseverance Determine concentration, continuous intravenous delivery device can be used.The example of this device is that Deltec CADD-PLUS.TM.5400 types are quiet Arteries and veins syringe pump.
The pharmaceutical composition of the present invention can be aseptic injection water or the shape of oil suspension for intramuscular and subcutaneous administration Formula.By known technology the suspension can be prepared with the suitable dispersant of those described above or wetting agent and suspending agent.Aseptic injection system Agent can also be the aseptic injectable solution or suspension prepared in the acceptable non-toxic diluent of parenteral or solvent, such as 1, The solution prepared in 3- butanediols.In addition, it is convenient to be used as solvent or suspension media with sterile fixed oil.For this purpose, can Use any mediation fixing oil including synthetic glycerine list or diester.In addition, aliphatic acid such as oleic acid can also prepare note Penetrate agent.
The compounds of this invention can be given by the suppository form for rectally.Can be by by medicine and at normal temperatures For solid but be liquid in the rectum, thus the suitable nonirritant excipient mixing of medicine can be dissolved and discharged in the rectum To prepare these pharmaceutical compositions.Such material includes cocoa butter, glycerin gelatine, hydrogenated vegetable oil, the poly- second of various molecular weight The mixture of the fatty acid ester of glycol and polyethylene glycol.
As it is well known to the skilled in the art, the dosage of medicine depends on many factors, including it is but and non-limiting In following factor：The activity of particular compound used, the age of patient, the body weight of patient, the health status of patient, the row of patient Quilt, the diet of patient, administration time, administering mode, speed, the combination of medicine of excretion etc.；In addition, optimal therapeutic modality is such as The species of the pattern for the treatment of, the consumption per day of general formula compound (I) or pharmaceutically useful salt can be tested according to traditional therapeutic scheme Card.
Detailed description of the invention
Unless stated to the contrary, the term used in the specification and in the claims has following implications.
Term " alkyl " refers to saturated aliphatic hydrocarbons group, and it is the straight or branched group for including 1 to 20 carbon atom, excellent Select the alkyl containing 1 to 12 carbon atom, the alkyl of further preferably 1 to 6 carbon atom.Non-limiting examples include methyl, Ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, sec-butyl, n-pentyl, 1,1- dimethyl propyls, 1,2- diformazans Base propyl group, 2,2- dimethyl propyls, 1- ethyl propyls, 2- methyl butyls, 3- methyl butyls, n-hexyl, 1- Ethyl-2-Methyls third Base, 1,1,2- thmethylpropyls, 1,1- dimethylbutyls, 1,2- dimethylbutyls, 2,2- dimethylbutyls, 1,3- dimethyl butyrates Base, 2- ethyl-butyls, 2- methyl amyls, 3- methyl amyls, 4- methyl amyls, 2,3- dimethylbutyls, n-heptyl, 2- methyl oneself Base, 3- methylhexyls, 4- methylhexyls, 5- methylhexyls, 2,3- dimethyl amyl groups, 2,4- dimethyl amyl groups, 2,2- dimethyl Amyl group, 3,3- dimethyl amyl groups, 2- ethyl pentyl groups, 3- ethyl pentyl groups, n-octyl, 2,3- dimethylhexanyls, 2,4- dimethyl oneself Base, 2,5- dimethylhexanyls, 2,2- dimethylhexanyls, 3,3- dimethylhexanyls, 4,4- dimethylhexanyls, 2- ethylhexyls, 3- Ethylhexyl, 4- ethylhexyls, 2- methyl -2- ethyl pentyl groups, 2- methyl -3- ethyl pentyl groups, n-nonyl, 2- methyl -2- ethyls Hexyl, 2- methyl -3- ethylhexyls, 2,2- diethyl amyl groups, positive decyl, 3,3- diethylhexyls, 2,2- diethylhexyls, and Its various branched chain isomer etc..Low alkyl group more preferably containing 1 to 6 carbon atom, non-limiting example includes first Base, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, sec-butyl, n-pentyl, 1,1- dimethyl propyls, 1,2- Dimethyl propyl, 2,2- dimethyl propyls, 1- ethyl propyls, 2- methyl butyls, 3- methyl butyls, n-hexyl, 1- ethyl -2- first Base propyl group, 1,1,2- thmethylpropyls, 1,1- dimethylbutyls, 1,2- dimethylbutyls, 2,2- dimethylbutyls, 1,3- diformazans Base butyl, 2- ethyl-butyls, 2- methyl amyls, 3- methyl amyls, 4- methyl amyls, 2,3- dimethylbutyls etc..Alkyl can be with It is substitution or non-substituted, when substituted, substituent can be substituted on any workable tie point, the substitution Base is preferably one or more following groups, its independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, Halogen, sulfydryl, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkanes Sulfenyl, heterocycle alkylthio group, oxo base, carboxyl or carboxylic acid ester groups.
Term " cycloalkyl " refers to saturation or part is unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, cycloalkyl ring comprising 3 to 20 carbon atoms, preferably comprise 3 to 12 carbon atoms, more preferably comprising 3 to 6 carbon atoms, most preferably comprise 5 to 6 carbon originals Son.The non-limiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopenta, cyclopentenyl, cyclohexyl, cyclohexenyl group, Cyclohexadienyl, suberyl, cycloheptatriene base, cyclooctyl etc.；Polycyclic naphthene base includes the cycloalkyl of loop coil, condensed ring and bridged ring.
Term " spiro cycloalkyl group " refers to the polycyclic moiety that a carbon atom (title spiro-atom) is shared between 5 to 20 yuan monocyclic, It can contain one or more double bonds, but neither one ring has the pi-electron system of total conjugated.Preferably 6 to 14 yuan, more Preferably 7 to 10 yuan.Spiro cycloalkyl group is divided into by single spiro cycloalkyl group, double spirocyclanes according to the number of shared spiro-atom between ring and ring Base or many spiro cycloalkyl groups, are 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 examples of spiro cycloalkyl group include：
Term " cycloalkyl " refers to each ring in 5 to 20 yuan, system and shared a pair adjoined of other rings in system The full carbon polycyclic moiety of carbon atom, wherein one or more rings can contain one or more double bonds, but neither one ring has The pi-electron system of total conjugated.Preferably 6 to 14 yuan, more preferably 7 to 10 yuan.It can be divided into according to the number of composition ring double Ring, three rings, Fourth Ring or polycyclic fused ring alkyl, preferably bicyclic or three rings, more preferably 5 yuan/5 yuan or 5 yuan/6 membered bicyclic alkyl. The non-limiting examples of cycloalkyl include：
Term " bridge ring alkyl " refers to 5 to 20 yuan, and the full carbon that any two ring shares two carbon atoms being not directly connected is more Cyclic group, it can contain one or more double bonds, but neither one ring has the pi-electron system of total conjugated.Preferably 6 to 14 yuan, more preferably 7 to 10 yuan.Bicyclic, three rings, Fourth Ring or polycyclic bridge ring alkyl can be divided into according to the number of composition ring, it is excellent Elect bicyclic, three rings or Fourth Ring, more preferably bicyclic or three rings as.The non-limiting examples of bridge ring alkyl include：
The cycloalkyl ring can be condensed on aryl, heteroaryl or heterocycloalkyl ring, wherein being connected to precursor structure Ring together is cycloalkyl, and non-limiting examples include indanyl, tetralyl, benzocyclohepta alkyl etc.；It is preferred that phenyl and ring Amyl group, tetralyl.Cycloalkyl can be it is optionally substituted or non-substituted, when substituted, substituent be preferably one or Multiple following groups, it is independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, sulfydryl, hydroxyl Base, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkane Sulfenyl, oxo base, carboxyl or carboxylic acid ester groups.
Term " heterocyclic radical " refers to the unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent of saturation or part, and it includes 3 to 20 rings Atom, wherein one or more annular atoms are selected from nitrogen, oxygen or S (O)mThe hetero atom of (wherein m is integer 0 to 2), but do not wrap - O-O- ,-O-S- or-S-S- loop section are included, remaining annular atom is carbon.3 to 12 annular atoms are preferably comprised, wherein 1~4 It is hetero atom；3 to 8 annular atoms are most preferably comprised, wherein 1~3 is hetero atom；5 to 6 annular atoms are most preferably comprised, its In 1~2 or 1~3 be hetero atom.The non-limiting examples of monocyclic heterocycles base include pyrrolidinyl, imidazolidinyl, tetrahydrofuran Base, THP trtrahydropyranyl, tetrahydro-thienyl, glyoxalidine base, dihydrofuran base, pyrazoline base, pyrrolin base, piperidyl, Piperazinyl, morpholinyl, thio-morpholinyl, homopiperazine base etc., preferably THP trtrahydropyranyl, piperidyl, pyrrolidinyl.Multiring heterocyclic Include the heterocyclic radical of loop coil, condensed ring and bridged ring.
Term " spiro heterocyclic radical " refers to the multiring heterocyclic that an atom (title spiro-atom) is shared between 5 to 20 yuan monocyclic Group, 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 For carbon.It can contain one or more double bonds, but neither one ring has the pi-electron system of total conjugated.Preferably 6 to 14 Member, more preferably 7 to 10 yuan.Spiro heterocyclic radical is divided into single spiro heterocyclic radical by the number according to spiro-atom is shared between ring and ring, double Spiro heterocyclic radical or many spiro heterocyclic radicals, are preferably single spiro heterocyclic radical and double spiro heterocyclic radicals.More preferably 4 yuan/4 yuan, 4 yuan/5 yuan, 4 Member/6 yuan, 5 yuan/5 yuan or 5 yuan/6 yuan single spiro heterocyclic radicals.The non-limiting examples of spiro heterocyclic radical include：
Term " condensed hetero ring base " refers to each ring in 5 to 20 yuan, system and shared a pair adjoined of other rings in system The polycyclic heterocyclic group of atom, one or more rings can contain one or more double bonds, but neither one ring is with completely common The pi-electron system of yoke, wherein one or more annular atoms are selected from nitrogen, oxygen or S (O)mThe miscellaneous original of (wherein m is integer 0 to 2) Son, remaining annular atom is carbon.Preferably 6 to 14 yuan, more preferably 7 to 10 yuan.According to composition ring number can be divided into it is bicyclic, Three rings, Fourth Ring or polycyclic condensed hetero ring base, preferably bicyclic or three rings, more preferably 5 yuan/5 yuan or 5 yuan/6 membered bicyclic condensed hetero rings Base.The non-limiting examples of condensed hetero ring base include：
Term " bridge heterocyclic radical " refers to 5 to 14 yuan, and any two ring shares the polycyclic heterocycle of two atoms being not directly connected Group, it can contain one or more double bonds, but neither one ring has the pi-electron system of total conjugated, one of them or Multiple annular atoms are selected from nitrogen, oxygen or S (O)mThe hetero atom of (wherein m is integer 0 to 2), remaining annular atom is carbon.Preferably 6 To 14 yuan, more preferably 7 to 10 yuan.Bicyclic, three rings, Fourth Ring or polycyclic bridge heterocyclic radical can be divided into according to the number of composition ring, Preferably bicyclic, three rings or Fourth Ring, more preferably bicyclic or three rings.The non-limiting examples of bridge heterocyclic radical include：
The heterocyclic ring can be condensed on aryl, heteroaryl or cycloalkyl ring, wherein being connected to one with precursor structure The ring risen is heterocyclic radical, and its non-limiting examples includes：
Deng.
Heterocyclic radical can be it is optionally substituted or non-substituted, when substituted, substituent be preferably it is one or more with Lower group, its independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, sulfydryl, hydroxyl, nitro, Cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, oxo Base, carboxyl or carboxylic acid ester groups.
Term " aryl ", which refers to, has 6 to 14 yuan of full carbon of the pi-electron system being conjugated monocyclic or fused polycycle (is namely shared The ring of adjacent carbon atoms pair) group, preferably 6 to 10 yuan, more preferably 5 to 6 yuan, such as phenyl and naphthyl.The aryl rings can To condense on heteroaryl, heterocyclic radical or cycloalkyl ring, wherein being aryl rings, its non-limit with the ring that precursor structure links together Property example processed includes：
Aryl can be substitution or non-substituted, and when substituted, substituent is preferably one or more following groups, It is independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, sulfydryl, hydroxyl, nitro, cyano group, ring Alkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, carboxyl or carboxylic acid Ester group.
Term " heteroaryl " refers to the heteroaromatic system comprising 1 to 4 hetero atom, 5 to 14 annular atoms, and wherein hetero atom is selected From oxygen, sulphur and nitrogen.Heteroaryl is preferably 5 to 10 yuan, containing 1 to 3 hetero atom；More preferably 5 yuan or 6 yuan, containing 1 to 2 miscellaneous original Son；It is preferred that such as imidazole radicals, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrole radicals, tetrazole radical, pyridine radicals, phonetic Piperidinyl, thiadiazoles, pyrazinyl etc., preferably imidazole radicals, pyrazolyl or pyrimidine radicals, thiazolyl；More preferably pyrazolyl.The heteroaryl Basic ring can be condensed on aryl, heterocyclic radical or cycloalkyl ring, wherein be heteroaryl ring with the ring that precursor structure links together, Its non-limiting examples includes：
Heteroaryl can be it is optionally substituted or non-substituted, when substituted, substituent be preferably it is one or more with Lower group, its independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, sulfydryl, hydroxyl, nitro, Cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, carboxyl Or carboxylic acid ester groups.
Term " alkoxy " refers to-O- (alkyl) and-O- (non-substituted cycloalkyl), wherein alkyl as defined above.Alcoxyl The non-limiting examples of base include：Methoxyl group, ethyoxyl, propoxyl group, butoxy, ring propoxyl group, cyclobutoxy group, cyclopentyloxy, Cyclohexyloxy.Alkoxy can be it is optionally substituted or non-substituted, when substituted, substituent be preferably it is one or more with Lower group, its independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, sulfydryl, hydroxyl, nitro, Cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, carboxyl Or carboxylic acid ester groups.
Term " amino protecting group " refers to suitable for the group that chemically reacts of protection (prevention) amino, but it molecule its His position needs the chemical reaction carried out to be easily removed after terminating.The Typical Representative of these groups has unsubstituted or substituted Acyl group, unsubstituted or substituted pi-allyl, aryl, Aralkoxymethyl, aralkyl form heterocyclic radical together with nitrogen-atoms And salt.Non-limiting example includes tertbutyloxycarbonyl (Boc), benzyloxycarbonyl, isobutoxy carbonyl, fluorenylmethyloxycarbonyl (Fmoc), benzoyl, the benzoyl of substitution, bytyry, acetyl group, trifluoroacetyl group, adjacent this dicarboximide base (Pht), succinimide base, Maleimido, benzyl, allyloxycarbonyl and to methoxy-benzyl etc..These groups can appoint Selection of land is selected from the substituted benzyl such as halogen, alkyl, alkoxy, hydroxyl, nitro, acyl amino, acyl group, adjacent methyl-benzyl, three One or more substituents of benzyl and benzhydryl are replaced.The amino protecting group is preferably tertbutyloxycarbonyl and fluorenes first Oxygen carbonyl (Fmoc).
Term " hydroxyalkyl " refers to the alkyl being optionally substituted by a hydroxyl group, wherein alkyl as defined above.
Term " haloalkyl " refers to alkyl and replaced by one or more halogens, and wherein alkyl is as defined above.
Term " hydroxyl " refers to-OH groups.
Term " halogen " refers to fluorine, chlorine, bromine or iodine.
Term " amino " refers to-NH2。
Term " cyano group " refers to-CN.
Term " nitro " refers to-NO2。
Term " carboxylic acid group " refers to-C (O) OH.
Term " carboxylic acid ester groups " refers to-C (O) O (alkyl) or-C (O) O (cycloalkyl), and wherein alkyl, cycloalkyl is as above determined Justice.
Term " carboxylic acid halides " refers to the compound of the group containing-C (O)-halogen.
" X is selected from A, B or C ", " X is selected from A, B and C ", " X is A, B or C ", " X is that the different terms such as A, B and C " are expressed Identical meaning, that is, it can be any one or a few in A, B, C to represent X.
" optional " or " optionally " mean event described later or environment can with but need not occur, the explanation includes The occasion that the event or environment occur or do not occurred.For example, " optionally by alkyl-substituted heterocyclic group " means that alkyl can be with But necessarily exist, the explanation includes heterocyclic group by alkyl-substituted situation and heterocyclic group not by alkyl-substituted situation.
" substituted " refers to one or more of group hydrogen atom, preferably at most 5, more preferably 1~3 hydrogen atom Replaced independently of one another by the substituent of respective number.Self-evident, substituent is only in their possible chemical position, this Art personnel can determine that (by experiment or theoretical) may or impossible take in the case where not paying excessive make great efforts Generation.For example, amino or hydroxyl with free hydrogen are probably unstable when being combined with the carbon atom with unsaturated (such as olefinic) key Fixed.
" pharmaceutical composition " represent containing one or more compounds described herein or its physiologically/pharmaceutically useful salt or Pro-drug and the mixture of other chemical constituents, and other components such as physiology/pharmaceutically useful carrier and excipient.Medicine The purpose of compositions is to promote the administration to organism, the absorption beneficial to active component and then performance bioactivity.
" officinal salt " refers to the salt of the compounds of this invention, and this kind of salt has security and had when being used in mammal body Effect property, and with due bioactivity.
The synthetic method of the compounds of this invention
In order to complete the purpose of the present invention, the present invention is adopted the following technical scheme that：
Compound or its dynamic isomer, mesomer, racemic modification, enantiomter shown in the logical formula (I) of the present invention, Diastereoisomer or its form of mixtures or its pharmaceutically useful salt production process, comprise the following steps：
Formula (I-1) compound is deprotected in acid condition obtains formula (I-2) compound or its salt, obtained formula (I-2) compound or its salt reacts in the basic conditions with formula (I-3) compound, obtains formula (I-4) compound, obtains Formula (I-4) compound sloughs the protection group on amino in the basic conditions, obtains formula (I-5) compound；Obtained formula (I-5) with formula (I-6) compound condensation reaction occurs in the basic conditions for compound, obtains logical formula (IV) compound；Obtain Logical formula (IV) further slough protection group in acid condition, obtain logical formula (I) compound or its salt.
There is provided the reagent of alkalescence condition includes organic base and inorganic base, and described organic bases include but is not limited to pyrrole Pyridine, hexahydropyridine, triethylamine, N, N- diisopropylethylamine, n-BuLi, lithium diisopropylamine, potassium acetate, sodium tert-butoxide or Potassium tert-butoxide, described inorganic base includes but is not limited to sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, hydroxide Sodium and lithium hydroxide, preferably pyridine.
There is provided acid condition reagent include but is not limited to hydrogen chloride, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid and Methanesulfonic acid, preferably hydrogen chloride or trifluoroacetic acid.
Condensing agent includes but is not limited to 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides, N, the hexamethylenes of N'- bis- Base carbodiimides, N, N'- diisopropylcarbodiimides, O- BTAs-N, N, N', N'- tetramethylurea tetrafluoro boric acid Ester, I-hydroxybenzotriazole, 1- hydroxyl -7- azos BTA, O- BTAs-N, N, N', N'- tetramethylurea (TMU) hexafluoro phosphorus Acid esters, 2- (7- oxidation BTA -1- bases)-N, N, N', N'- tetramethylurea hexafluorophosphoric acids ester, the 2- (nitrogen of 7- azos benzo three Azoles)-N, N, N', N'- tetramethylurea hexafluorophosphoric acids ester, (dimethylamino) phosphorus hexafluoro phosphorus of BTA -1- bases epoxide three Hydrochlorate or hexafluorophosphoric acid BTA -1- bases-epoxide tripyrrole alkyl phosphorus, preferably 2- (7- aoxidizes BTA)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester.
Above-mentioned reaction is preferably carried out in a solvent, and solvent for use includes but is not limited to：Acetic acid, methanol, ethanol, toluene, four Hydrogen furans, dichloromethane, dimethyl sulfoxide (DMSO), 1,4- dioxane, water, N,N-dimethylformamide and its mixture.
Wherein：
W is amino protecting group；
G、R1And R2As defined in logical formula (I).
Embodiment
The present invention is further described with reference to embodiments, but these embodiments not limit the scope of the present invention.
Embodiment
The structure of compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrum (MS).NMR displacements (δ) are with 10-6 (ppm) unit is provided.NMR measure is to use Bruker AVANCE-400 nuclear magnetic resonance spectrometers, and measure solvent is deuterated dimethyl sulfoxide (DMSO-d6), deuterochloroform (CDCl3), deuterated methanol (CD3), OD inside it is designated as tetramethylsilane (TMS).
MS measure is with FINNIGAN LCQAd (ESI) mass spectrograph (manufacturer:Thermo, model：Finnigan LCQ advantage MAX)。
HPLC measure uses Agilent 1200DAD high pressure liquid chromatographs (Sunfire C18 150 × 4.6mm chromatograms Post) and Waters 2695-2996 high pressure liquid chromatographs (Gimini 150 × 4.6mm of C18 chromatographic columns).
Kinases average inhibition and IC50The measure of value is with NovoStar ELIASAs (German BMG companies).
Tlc silica gel plate uses Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica gel plates, and thin-layered chromatography (TLC) makes The specification that silica gel plate is used is 0.15mm~0.2mm, the specification that thin-layer chromatography isolates and purifies product use be 0.4mm~ 0.5mm。
Column chromatography is carrier typically using the mesh silica gel of Yantai Huanghai Sea silica gel 200~300.
The known initiation material of the present invention can be used or synthesized according to methods known in the art, or can purchase certainly ABCR GmbH＆Co.KG, Acros Organics, Aldrich Chemical Company, splendid remote chemical science and technology (Accela ChemBio Inc), up to companies such as auspicious chemicals.
Without specified otherwise in embodiment, reaction can be carried out under argon atmospher or blanket of nitrogen.
Argon atmospher or blanket of nitrogen refer to that reaction bulb connects the argon gas or nitrogen balloon of an about 1L volume.
Nitrogen atmosphere refers to that reaction bulb connects the hydrogen balloon of an about 1L volume.
Pressure hydration reaction uses Parr 3916EKX types hydrogenation instrument and clear indigo plant QL-500 types hydrogen generator or HC2-SS Type hydrogenates instrument.
Hydrogenation is generally vacuumized, and is filled with hydrogen, is operated 3 times repeatedly.
Microwave reaction uses the type microwave reactors of CEM Discover-S 908860.
Without specified otherwise in embodiment, solution refers to the aqueous solution.
Without specified otherwise in embodiment, the temperature of reaction is room temperature, is 20 DEG C~30 DEG C.
The monitoring of reaction process in embodiment uses thin-layered chromatography (TLC), the system of solvent used in reaction Have：A：Dichloromethane and methanol system, B：N-hexane and ethyl acetate system, C：Petroleum ether and ethyl acetate system, D：Acetone, The volume ratio of solvent is adjusted according to the polarity difference of compound.The body of the eluant, eluent for the column chromatography that purifying compound is used The solvent system of system and thin-layered chromatography includes：A：Dichloromethane and methanol system, B：N-hexane and ethyl acetate system, C： Dichloromethane and acetone system, the volume ratio of solvent are adjusted according to the polarity difference of compound, can also add a small amount of Triethylamine and the alkalescence such as acetic acid or acid reagent be adjusted.
Embodiment 1
(R)-N- ((R) -6- amino -1- (4- (3- methyl urea groups) piperidin-1-yl) -1- oxohexane -2- bases) -2- ((R) -2- ((R) -2- amino -3- phenylpropionyls amido) -3- phenylpropionyls amido) -4- methylpentanamides 1
The first step
4- ((phenyloxycarbonyl) amino) piperidines -1- t-butyl formates 1b
By 4- amino piperidine -1- t-butyl formates 1a (0.5g, 2.5mmol), pyridine (0.22g, 2.75mmol) is dissolved in In 15mL tetrahydrofurans, phenyl chloroformate (0.43g, 2.75mmol) is added dropwise at 0 DEG C, reaction solution is warmed to room temperature, and stirring reaction 2 is small When.Reaction solution is concentrated under reduced pressure, and residue adds ethyl acetate dissolving, is washed with water, anhydrous sodium sulfate drying, filters, and filtrate subtracts Pressure concentration, obtains crude title product 1b (0.9g), the not purified direct carry out the next step of product.
Second step
4- (3- methyl urea groups) piperidines -1- t-butyl formates 1c
Crude product 1b (0.9g, 2.5mmol) is dissolved in 20mL methanol, the tetrahydrofuran for adding 1.3mL 2M methylamines is molten Liquid, stirring reaction 12 hours at 50 DEG C.Reaction solution is cooled to room temperature, is concentrated under reduced pressure, pure with solvent system A with thin-layered chromatography Change gained residue, obtain title product 1c (0.35g, yield：55%).
MS m/z(ESI):256.1[M-1]
3rd step
1- methyl -3- (piperidin-4-yl) urea hydrochloride 1d
1c (0.35g, 1.36mmol) is dissolved in 5mL dichloromethane, Isosorbide-5-Nitrae-dioxy six of 1mL 4M hydrogen chloride is added Ring solution, stirring reaction 2 hours.Reaction solution is concentrated under reduced pressure, and obtains crude title product 1d (0.3g), and product is not purified directly Carry out next step reaction.
4th step
(R)-(9H- fluorenes -9- bases) methyl tertbutyl (6- (4- (3- methyl urea groups) piperidin-1-yl) -6- oxohexane -1, 5- diyls) diurethane 1f
By crude product 1d (0.3g, 1.36mmol), (R) -2- ((((9H- fluorenes -9- bases) methoxyl group) carbonyl) amino) -6- ((uncles Butoxy carbonyl) amino) caproic acid 1e (and 637mg, 1.36mmol, using known method " Tetrahedron, 2002,58 (27), 5427-5439 " is prepared) it is dissolved in 5mL DMFs, add 2- (7- azo phenylpropyl alcohol triazoles -1- Base)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid esters (0.775g, 2.04mmol), triethylamine (0.38mL, 2.72mmol) stirs Mix reaction 12 hours.Reaction solution is concentrated under reduced pressure, with thin-layered chromatography with solvent system A purify gained residue, obtain title Product 1f (390mg, yield：47%).
MS m/z(ESI):608.2[M+1]
5th step
(R)-(5- amino -6- (4- (3- methyl urea groups) piperidin-1-yl) -6- oxo-hexyls) t-butyl carbamate 1g
1f (120mg, 0.197mmol) is dissolved in 5mL dichloromethane, 1mL hexahydropyridines are added, stirring reaction 12 is small When.Reaction solution is concentrated under reduced pressure, with thin-layered chromatography with solvent system A purify gained residue, obtain 1g (76mg, yield： 100%).
MS m/z(ESI):386.2[M+1]
6th step
N- [(5R) -5- [(2R) -2- [(2R) -2- [(2R) -2- { [(tert-butoxy) carbonyl] amino } -3- Phenylpropionamides Base] -3- phenylpropionyls amido] -4- methyl valeryls amido] -6- { 4- [(methylcarbamoyl) amino] piperidin-1-yl } -6- Oxo-hexyl] t-butyl carbamate 1i
By 1g (76mg, 0.197mmol), (6R, 9R, 12R) -6,9- dibenzyl -12- isobutyl group -2,2- dimethyl -4,7, 10- trioxy- -3- oxa-s -5,8,11- tri- azepine tridecane -13- carboxylics 1h (104mg, 0.197mmol, using patent application Method disclosed in " US20110212882 " is prepared), 2- (7- azo phenylpropyl alcohol triazole -1- bases)-N, N, N', N'- tetramethyls Urea hexafluorophosphoric acid ester (112mg, 0.296mmol) and triethylamine (0.055mL, 0.394mmol) are dissolved in 5mL N, N- dimethyl In formamide, stirring reaction 12 hours.Reaction solution is concentrated under reduced pressure, and it is remaining with solvent system A to purify gained with thin-layered chromatography Thing, obtains title product 1i (100mg, yield：57%).
MS m/z(ESI):894.5[M+1]
7th step
(R)-N- ((R) -6- amino -1- (4- (3- methyl urea groups) piperidin-1-yl) -1- oxohexane -2- bases) -2- ((R) -2- ((R) -2- amino -3- phenylpropionyls amido) -3- phenylpropionyls amido) -4- methylpentanamides 1
1i (100mg, 0.112mmol) is dissolved in 5mL dichloromethane, 0.5mL trifluoroacetic acids, stirring reaction 2 is added Hour.Reaction solution is concentrated under reduced pressure, with high performance liquid chromatography purify gained residue, obtain title product 1 (10mg, yield： 14%).
MS m/z(ESI):693.7[M+1]
1H NMR(400MHz,DMSO-d6):δ8.42(d,1H),8.19(d,1H),7.39-7.29(m,10H),7.22(d, 1H),6.10(s,1H),5.12(s,4H),4.73(d,1H),4.41-4.37(m,2H),4.09(d,1H),3.74(d,1H), 3.27-3.24(m,3H),3.02-2.96(m,4H),2.70(s,3H),2.16-1.90(m,2H),1.85-1.55(m,9H), 1.51-1.25(m,6H),1.00(d,3H),0.96(d,3H).
Embodiment 2
(R)-N- ((R) -6- amino -1- oxos -1- (4- (3- phenyl urea groups) piperidin-1-yl) hexane -2- bases) -2- ((R) -2- ((R) -2- amino -3- phenylpropionyls amido) -3- phenylpropionyls amido) -4- methylpentanamides 2
The first step
(R)-(9H- fluorenes -9- bases) methyl tertbutyl (6- oxos -6- (4- (3- phenyl urea groups) piperidin-1-yl) hexane -1, 5- diyls) diurethane 2b
By 1e (3.1g, 6.5mmol), 1- phenyl -3- (piperidin-4-yl) ureas 2a (1.44g, 6.5mmol, using patent Shen Please method disclosed in " EP628310 " is prepared) it is dissolved in 50mL DMFs, add 2- (7- azobenzenes Third triazole -1- bases)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid esters (3.77g, 9.9mmol), triethylamine (2g, 20mmol), Stirring reaction 12 hours.Reaction solution is concentrated under reduced pressure, and obtains crude title product 2b (4.43g), and product is not purified directly to be carried out The next step.
Second step
(R)-(5- amino -6- oxos -6- (4- (3- phenyl urea groups) piperidin-1-yl) hexyl) t-butyl carbamate 2c
Crude product 2b (4.43g, 6.5mmol) is dissolved in 20mL dichloromethane, 6mL hexahydropyridines, stirring reaction 2 is added Hour.Reaction solution is concentrated under reduced pressure, with silica gel column chromatography method with eluant, eluent system A purify gained residue, obtain 2c (2.96g, Yield：100%).
3rd step
N- [(5R) -5- [(2R) -2- [(2R) -2- [(2R) -2- { [(tert-butoxy) carbonyl] amino } -3- Phenylpropionamides Base] -3- phenylpropionyls amido] -4- methyl valeryls amido] -6- oxos -6- { 4- [(phenylcarbamoyl) amino] piperidines -1- Base } hexyl] t-butyl carbamate 2d
By 2c (200mg, 0.44mmol), 1h (235mg, 0.44mmol), 2- (7- azo phenylpropyl alcohol triazole -1- bases)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester (255mg, 0.67mmol) and triethylamine (135mg, 1.3mmol) are dissolved in 10mL In DMF, stirring reaction 12 hours.Reaction solution is concentrated under reduced pressure, and obtains crude title product 2d (427mg), production The not purified direct carry out the next step of product.
MS m/z(ESI):955.7[M+1]
4th step
(R)-N- ((R) -6- amino -1- oxos -1- (4- (3- phenyl urea groups) piperidin-1-yl) hexane -2- bases) -2- ((R) -2- ((R) -2- amino -3- phenylpropionyls amido) -3- phenylpropionyls amido) -4- methylpentanamides 2
Crude product 2d (427mg, 0.44mmol) is dissolved in 10mL dichloromethane, 2mL trifluoroacetic acids, stirring reaction is added 2 hours.Reaction solution is concentrated under reduced pressure, with high performance liquid chromatography purify gained residue, obtain title product 2 (15mg, yield 4.5%).
MS m/z(ESI):755.4[M+1]
1H NMR(400MHz,CD3OD)δ7.34-7.21(m,13H),7.18-6.96(m,2H),4.68-4.61(m,2H), 4.38-4.25(m,3H),4.08-4.00(m,1H),3.83-3.71(m,2H),3.70-3.55(m,2H),3.21-3.07(m, 3H),3.06-2.63(m,6H),2.75-2.56(m,2H),1.82-1.73(m,2H),1.72-1.56(m,6H),1.52-1.38 (m,4H),1.32-1.25(m,2H),0.98-0.91(m,6H),0.75-0.67(m,2H).
Embodiment 3
(R)-N- ((R) -6- amino -1- (4- (N- Methylsulfamoyls amino) piperidin-1-yl) -1- oxohexanes -2- Base) -2- ((R) -2- ((R) -2- amino -3- phenylpropionyls amido) -3- phenylpropionyls amido) -4- methylpentanamides 3
The first step
4- ((N- Methylsulfamoyls) amino) piperidines -1- t-butyl formates 3a
By 1a (113mg, 0.56mmol), pyridine (66mg, 0.84mmol) is dissolved in 5mL dichloromethane, is added dropwise at 0 DEG C The dichloromethane solution of 5mL meth vlsulfonamides chlorine (80mg, 0.62mmol), reaction solution is warmed to room temperature, stirring reaction 12 hours.Instead Answer liquid to add dichloromethane, be washed with water, anhydrous sodium sulfate drying, filter, filtrate decompression concentration obtains crude title product 3a (164mg), the not purified direct carry out the next step of product.
Second step
Methyl [(piperidin-4-yl) sulfamoyl] amine hydrochlorate 3b
Crude product 3a (164mg, 0.559mmol) is dissolved in 5mL dichloromethane, the Isosorbide-5-Nitrae-two of 1mL 4M hydrogen chloride is added The ring solution of oxygen six, stirring reaction 2 hours.Reaction solution is concentrated under reduced pressure, and obtains crude title product 3b (128mg), product is without pure Change and directly carry out the next step.
3rd step
(R)-(5- amino -6- (4- ((N- Methylsulfamoyls) amino) piperidin-1-yl) -6- oxo-hexyls) carbamic acid Tert-butyl ester 3c
By crude product 3b (120mg, 0.559mmol), 1e (290mg, 0.62mmol) is dissolved in 20mL N, N- dimethyl formyls In amine, addition 2- (7- azo phenylpropyl alcohol triazole -1- bases)-N, N, N', N'- tetramethylurea hexafluorophosphoric acids ester (343mg, 0.9mmol) with 3mL triethylamines, stirring reaction 12 hours.Reaction solution is concentrated under reduced pressure, and residue adds ethyl acetate, and washing has Machine mutually uses anhydrous sodium sulfate drying, and filtering, filtrate decompression concentration obtains crude title product 3c (261mg), product is not purified Directly carry out the next step.
4th step
N- [(5R) -5- [(2R) -2- [(2R) -2- [(2R) -2- { [(tert-butoxy) carbonyl] amino } -3- Phenylpropionamides Base] -3- phenylpropionyls amido] -4- methyl valeryls amido] -6- { 4- [(Methylsulfamoyl) amino] piperidin-1-yl } -6- oxygen For hexyl] t-butyl carbamate 3d
By crude product 3c (261mg, 0.559mmol), 1h (325mg, 0.62mmol), 2- (7- azo phenylpropyl alcohol triazoles -1- Base)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid esters (342mg, 0.9mmol) and triethylamine (1mL, 1.24mmol) are dissolved in In 20mL DMFs, stirring reaction 12 hours.Reaction solution is concentrated under reduced pressure, with thin-layered chromatography with solvent body It is A purifying gained residues, obtains title product 3d (300mg, yield：55.4%).
MS m/z(ESI):929.5[M+1]
5th step
(R)-N- ((R) -6- amino -1- (4- (N- Methylsulfamoyls amino) piperidin-1-yl) -1- oxohexanes -2- Base) -2- ((R) -2- ((R) -2- amino -3- phenylpropionyls amido) -3- phenylpropionyls amido) -4- methylpentanamides 3
3d (300mg, 0.323mmol) is dissolved in 10mL dichloromethane, Isosorbide-5-Nitrae-dioxy of 1mL 4M hydrogen chloride is added Six ring solution, stirring reaction 1 hour.Reaction solution is concentrated under reduced pressure, with high performance liquid chromatography purify gained residue, obtain title Product 3 (20mg, yield：9%).
MS m/z(ESI):729.4[M+1]
1H NMR(400MHz,CD3OD)δ8.46(s,1H),8.21(s,1H),7.33-7.24(m,10H),4.73-4.46 (m, 4H), 4.12-3.75 (m, 4H), 3.75-3.71 (m, 1H), 3.24-2.95 (m, 9H), 2.67-2.56 (m, 3H), 1.99- 1.81(m,3H),1.71-1.45(m,7H),1.39-1.33(m,7H),0.99(d,6H).
Embodiment 4
(R) -2- ((R) -2- ((R) -2- amino -3- phenylpropionyls amido) -3- phenylpropionyls amido) -4- methyl-N- ((R) -1- (4- (3- methyl urea groups) piperidin-1-yl) -1- oxos -3- (piperidin-4-yl epoxide) propane -2- bases) pentanamide 4
The first step
(R) -4- (2- (tertbutyloxycarbonylamino) -3- methoxyl group -3- oxopropoxies) piperidines -1- benzyl formates 4c
By 4- hydroxy piperidine -1- benzyl formates 4b (1.31g, 5.57mmol, using known method " Heterocycles, 2009,77 (1), 417-432 " is prepared) it is dissolved in 30mL dichloromethane, 0 DEG C is cooled to, BFEE is added (97 μ L, 0.77mmol), stirring reaction 10 minutes.Add 5mL (S) -1- tert-butyl group 2- methyl-aziridinyl propyl group -1,2- diformazans Acid esters 4a (773mg, 3.85mmol, using known method " OrganicLetters, 11 (23), 5558-5561；2009 " systems It is standby and obtain) dichloromethane solution, stirring reaction 1 hour.It is warmed to room temperature, stirring reaction 15 hours.Add 1M sodium hydroxides molten Liquid, is extracted with dichloromethane, anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, with silica gel column chromatography with eluant, eluent system A purifying gained residues, obtain title product 4c (0.63g, yield 38%).
MS m/z(ESI):337.2[M-100]
Second step
(R) -3- (1- (benzyloxycarbonyl) piperidin-4-yls epoxide) -2- (tertbutyloxycarbonylamino) propionic acid 4d
4c (1.39g, 3.18mmol) is dissolved in 20mL tetrahydrofurans, first alcohol and water (V:V:V=4:4:1) mixing is molten In agent, lithium hydroxide (670mg, 15.9mmol), stirring reaction 15 hours are added.The hydrochloric acid regulation reaction solution pH that 2M is added dropwise is 2, It is extracted with ethyl acetate (15mL × 3), saturated nacl aqueous solution (15mL × 3) washing, anhydrous sodium sulfate drying, filtering, filtrate It is concentrated under reduced pressure, obtains crude title product 4d (1.05g, yield 78%).
MS m/z(ESI):413.2[M+1]
3rd step
1- methyl -3- (piperidin-4-yl) urea 2,2,2- trifluoroacetates 4e
1c (0.15g, 0.584mmol) is dissolved in 5mL dichloromethane, 1mL trifluoroacetic acids are added, stirring reaction 2 is small When.Reaction solution is concentrated under reduced pressure, and obtains crude title product 4e (0.158g), and product is not purified directly to carry out next step reaction.
4th step
(R) -4- (2- ((tert-butoxycarbonyl) amino) -3- (4- (3- methyl urea groups) piperidin-1-yl) third oxygen of -3- oxos Base) piperidines -1- benzyl formates 4f
Crude product 4d (247mg, 0.58mmol) and crude product 4e (158mg, 0.58mmol) are dissolved in 5mL N, N- dimethyl In formamide, addition 2- (7- azo phenylpropyl alcohol triazole -1- bases)-N, N, N', N'- tetramethylurea hexafluorophosphoric acids ester (332mg, 0.876mmol), triethylamine (0.16mL, 1.17mmol), stirring reaction 12 hours.Reaction solution is concentrated under reduced pressure, and residue adds second Acetoacetic ester, washing, anhydrous sodium sulfate drying, filtering, filtrate decompression concentration purifies institute with thin-layered chromatography with solvent system A Residue is obtained, title product 4f (185mg, yield is obtained：56%).
5th step
(R) -4- (2- amino -3- (4- (3- methyl urea groups) piperidin-1-yl) -3- oxopropoxies) piperidines -1- formic acid benzyls Ester 2,2,2- trifluoroacetates 4g
4f (185mg, 0.329mmol) is dissolved in 5mL dichloromethane, 1mL trifluoroacetic acids are added, stirring reaction 2 is small When.Reaction solution is concentrated under reduced pressure, and obtains crude title product 4g (189mg), the not purified direct carry out the next step of product
6th step
4- (((6R, 9R, 12R, 15R) -6,9- dibenzyl -12- isobutyl group -2,2- dimethyl -15- (4- (3- MUs Base) piperidines -1- carbonyls) four oxo -3- oxa-s -5,8,11,14- of -4,7,10,13-, four azepine hexadecane -16- bases) epoxide) piperazine Pyridine -1- benzyl formates 4h
By crude product 4g (189mg, 0.329mmol), 1h (173mg, 0.329mmol), 2- (7- azo phenylpropyl alcohol triazoles -1- Base)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid esters (188mg, 0.494mmol) and triethylamine (0.092mL, 0.658mmol) It is dissolved in 5mL DMFs, stirring reaction 12 hours.Reaction solution is concentrated under reduced pressure, and residue adds acetic acid second Ester, washing, anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, with thin-layered chromatography with solvent system A purify obtained by it is residual Excess, obtains title product 4h (146mg, yield：46%).
MS m/z(ESI):969.6[M+1]
7th step
((R) -1- (((R) -1- (((R) -4- methyl isophthalic acids-(((R) -1- (4- (3- methyl urea groups) piperidin-1-yl) -1- oxygen Generation -3- (piperidin-4-yl epoxide) propane -2- bases) amino) -1- oxo-pentane -2- bases) amino) -1- oxo -3- phenyl-propanes - 2- yls) amino) -1- oxo -3- phenyl-propane -2- bases) t-butyl carbamate 4i
4h (146mg, 0.151mmol) is dissolved in 15mL methanol, palladium/carbon (20mg, 10%), hydrogen displacement three is added It is secondary, stirring reaction 12 hours.Reacting liquid filtering, filtrate decompression concentration, obtains crude title product 4i (126mg), product without Purifying directly carries out the next step
MS m/z(ESI):935.6[M+1]
8th step
(R) -2- ((R) -2- ((R) -2- amino -3- phenylpropionyls amido) -3- phenylpropionyls amido) -4- methyl-N- ((R) -1- (4- (3- methyl urea groups) piperidin-1-yl) -1- oxos -3- (piperidin-4-yl epoxide) propane -2- bases) pentanamide 4
Crude product 4i (126mg, 0.151mmol) is dissolved in 5mL dichloromethane, 1mL trifluoroacetic acids, stirring reaction is added 2 hours.Reaction solution is concentrated under reduced pressure, with high performance liquid chromatography purify gained residue, obtain title product 4 (45mg, yield 40%).
MS m/z(ESI):735.4[M+1]
1H NMR(400MHz,DMSO-d6):δ8.40(d,1H),8.36(d,1H),8.03(s,3H),7.21-7.40(m, 10H),5.10-5.16(m,2H),4.70-4.75(m,1H),4.38-4.51(m,2H),4.07-4.10(m,2H),3.85- 3.95(m,2H),3.71-3.78(m,4H),3.20-3.33(m,5H),3.05-3.15(m,2H),2.85-3.04(m,4H), 2.67(d,3H),1.82-2.05(m,6H),1.55-1.77(m,4H),1.00(d,3H),0.95(d,3H).
Embodiment 5
(R) -2- ((R) -2- ((R) -2- amino -3- phenylpropionyls amino) -3- phenylpropionyls amino) -4- methyl-N- ((R) -1- (4- (3- methyl urea groups) piperidin-1-yl) -1- oxos -3- ((S)-nafoxidine -2- ylmethoxies) propane -2- bases) Pentanamide 5
The first step
(S) -2- (((R) -2- ((tert-butoxycarbonyl) amino) -3- methoxyl group -3- oxopropoxies) methyl) pyrrolidines - 1- benzyl formates 5c
By (S) -2- (hydroxymethyl) pyrrolidines -1- benzyl carboxylates 5b (0.88g, 3.73mmol, using known method " Synthesis, 2013,45 (17), 2458-2468 " is prepared) it is dissolved in 10mL dichloromethane, it is cooled to 0 DEG C, addition Boron trifluoride ether solution (63 μ L, 498 μm of ol), stirring reaction 10 minutes adds 10mL (S) -1- tert-butyl group 2- methyl ring second Imines -1,2- dicarboxylic ester 5a (0.5g, 2.49mmol, using known method " Organic Letters, 2009,11 (23), 5558-5561 " is prepared) dichloromethane solution, 0 DEG C of stirring reaction 1 hour is warming up to room temperature, stirring reaction 16 hours. 20mL 1M sodium hydroxide solutions are added in reaction solution, are stirred 15 minutes, stratification, organic phase, aqueous phase ethyl acetate is separated Extraction, merges organic phase, and anhydrous slufuric acid is dried, filtering, and filtrate decompression concentration is purified with silica gel column chromatography with eluent system A Gained residue, obtains title product 5c (0.61g, yield：56%).
Second step
(R) -3- (((S) -1- ((benzyloxy) carbonyl) nafoxidine -2- bases) methoxyl group) -2- ((tert-butoxycarbonyl) ammonia Base) propionic acid 5d
5c (0.61g, 1.4mmol) is dissolved in 18mL tetrahydrofurans, first alcohol and water (V/V/V=4:4:1) mixed solvent In, a hydronium(ion) lithia (11.7mg, 2.8mmol) is added, reaction 16 hours is stirred at room temperature.Reaction solution pressurization concentration, It is 2 that 1M hydrochloric acid is added dropwise in residue to pH, and ethyl acetate extraction, organic phase anhydrous sodium sulfate drying, filtering, filtrate decompression is dense Contracting, obtains crude title product 5d (0.6g), and product is not purified directly to carry out next step reaction.
3rd step
(S) -2- (((R) -2- ((tert-butoxycarbonyl) amino) -3- (4- (3- methyl urea groups) piperidin-1-yl) -3- oxos Propoxyl group) methyl) pyrrolidines -1- benzyl formates 5e
By crude product 5d (0.1g, 237 μm of ol), crude product 4e (70mg, 253 μm of ol), 2- (7- azo phenylpropyl alcohol triazoles -1- Base)-N, N, N', N'- tetramethylurea hexafluorophosphoric acids ester (135mg, 356 μm of ol), triethylamine (66 μ L) and 3mLN, N- dimethyl methyl Acid amides is added in reaction bulb, and reaction 16 hours is stirred at room temperature.Reaction solution is concentrated under reduced pressure, with silica gel column chromatography with eluent system A purifying gained residues, obtain title product 5e (150mg, yield：100%).
4th step
(S) -2- (((R) -2- amino -3- (4- (3- methyl urea groups) piperidin-1-yl) -3- oxopropoxies) methyl) pyrroles Alkane -1- benzyl formate trifluoroacetates 5f
5e (150mg, 237 μm of ol), 1mL trifluoroacetic acids are dissolved in 5mL dichloromethane, reaction 2 hours is stirred at room temperature.Instead Answer liquid to be concentrated under reduced pressure, obtain crude title product 5f (140mg), product is not purified directly to carry out next step reaction.
5th step
(S) -2- ((4R, 7R, 10R, 13R) -10,13- dibenzyl -7- isobutyl group -17,17- dimethyl -4- (4- (3- first Base urea groups) piperidines -1- carbonyls) four oxo -2,16- dioxas -5,8,11,14- of -6,9,12,15-, four azepine octadecyls) pyrrole Cough up alkane -1- benzyl formates 5g
By crude product 5f (140mg, 0.237mmol), 1h (124mg, 0.237mmol), 2- (7- azo phenylpropyl alcohol triazoles -1- Base)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid esters (135mg, 0.356mmol) and triethylamine (66 μ L, 0.474mmol) dissolve In 5mL DMFs, stirring reaction 12 hours.Reaction solution is concentrated under reduced pressure, with thin-layered chromatography with solvent body It is A purifying gained residues, obtains title product 5g (240mg, yield：100%).
6th step
((4R, 7R, 10R, 13R) -10- benzyl -7- isobutyl groups -4- (4- (3- methyl urea groups) piperidines -1- carbonyls) -6,9, The azepine tetradecane -13- the bases of 12- trioxy- -14- phenyl -1- ((S)-nafoxidine -2- bases) -2- oxa-s -5,8,11- three) amino T-butyl formate 5h
5g (240mg, 0.237mmol) is dissolved in 15mL methanol, palladium carbon (30mg, 10%) is added, hydrogen is replaced three times, Stirring reaction 4 hours.Reacting liquid filtering, filtrate decompression concentration, obtains crude title product 5h (220mg), product is not purified Directly carry out next step reaction.
MS m/z(ESI):835.4[M+1]
7th step
(R) -2- ((R) -2- ((R) -2- amino -3- phenylpropionyls amino) -3- phenylpropionyls amino) -4- methyl-N- ((R) -1- (4- (3- methyl urea groups) piperidin-1-yl) -1- oxos -3- ((S)-nafoxidine -2- ylmethoxies) propane -2- bases) Pentanamide 5
Crude product 5h (220mg, 0.237mmol) is dissolved in 5mL dichloromethane, 1mL trifluoroacetic acids, stirring reaction 2 is added Hour.Reaction solution is concentrated under reduced pressure, with high performance liquid chromatography purify gained residue, obtain title product 5 (30mg, yield： 17%).
MS m/z(ESI):735.4[M+1]
1H NMR(400MHz,DMSO-d6):δ8.46(d,2H),8.30(t,3H),7.22-7.41(m,12H),5.05- 5.20(m,1H),4.72-4.76(m,1H),4.39-4.46(m,1H),4.05-4.11(m,1H),3.58-3.85(m,8H), 3.19-3.31(m,5H),2.93-3.04(m,3H),2.70(s,3H),1.85-2.18(m,6H),1.55-1.84(m,4H), 1.22-1.50(m,2H),1.01(d,3H),0.97(d,3H).
Embodiment 6
(R)-N- ((R) -6- amino -1- oxos -1- (4- (aminosulfonylamino) piperidin-1-yl) hexane -2- bases) -2- ((R) -2- ((R) -2- amino -3- phenylpropionyls amino) -3- phenylpropionyls amino) -4- methylpentanamides 6
The first step
(R)-(9H- fluorenes -9- bases) methyl tertbutyl (6- oxos -6- (4- (aminosulfonylamino) piperidin-1-yl) oneself Alkane -1,5- diyls) diurethane 6b
By N- (piperidin-4-yl) sulfamides 6a (1g, 3mmol, using known method " Bioorganic＆ Medicinal Chemistry Letters, 2009,19 (12), 3339-3343 " are prepared), 1e (1.4g, 3mmol) is molten Solution adds 2- (7- azo phenylpropyl alcohol triazole -1- bases)-N, N, N', N'- tetramethylureas in 20mL DMFs Hexafluorophosphoric acid ester (2.3g, 6mmol) and triethylamine (600mg, 6mmol), stirring reaction 12 hours.Reaction solution is concentrated under reduced pressure, plus Enter 10mL citric acids saturated solution and 100mL water, be extracted with ethyl acetate, organic phase anhydrous sodium sulfate drying, filtering, filtrate Be concentrated under reduced pressure, with thin-layered chromatography with solvent system A purify gained residue, obtain title product 6b (630mg, yield： 100%).
Second step
(R)-(5- amino -6- oxos -6- (4- (aminosulfonylamino) piperidin-1-yl) hexyl) t-butyl carbamate 6c
6b (630mg, 1mmol) is dissolved in 1mL DMFs, 3mL triethylamines, stirring reaction is added 12 hours.Reaction solution is concentrated under reduced pressure, and obtains crude title product 6c (407mg), and the not purified directly progress next step of product is anti- Should.
3rd step
N- [(5R) -5- [(2R) -2- [(2R) -2- [(2R) -2- { [(tert-butoxy) carbonyl] amino } -3- phenylpropionyl ammonia Base] -3- phenylpropionyls amino] -4- methylpentanoylaminos] and -6- oxos -6- (4- (aminosulfonylamino) piperidin-1-yl) oneself Base) t-butyl carbamate 6d
By crude product 6c (420mg, 1mmol), 1h (530mg, 1mmol), 2- (7- azo phenylpropyl alcohol triazole -1- bases)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester (760mg, 2mmol) are dissolved in 5mL DMFs, stirring reaction 12 Hour.Reaction solution is concentrated under reduced pressure, and adds 10mL citric acids saturated solution and 100mL water, is extracted with ethyl acetate, organic phase is successively With saturated sodium bicarbonate solution, saturated nacl aqueous solution washing, anhydrous sodium sulfate drying, filtering, filtrate decompression concentration obtains thick Product title product 6d (460mg), product is not purified directly to carry out next step reaction.
MS m/z(ESI):915.6[M+1]
4th step
(R)-N- ((R) -6- amino -1- oxos -1- (4- (aminosulfonylamino) piperidin-1-yl) hexane -2- bases) -2- ((R) -2- ((R) -2- amino -3- phenylpropionyls amino) -3- phenylpropionyls amino) -4- methylpentanamide trifluoroacetates 6e
Crude product 6d (460mg, 0.5mmol) is dissolved in 10mL dichloromethane, 4mL trifluoroacetic acids, stirring reaction 3 is added Hour.Reaction solution is concentrated under reduced pressure, with high performance liquid chromatography purify gained residue, obtain title product 6e (40mg, yield： 15%).
MS m/z(ESI):715.2[M+1]
1H NMR(400MHz,DMSO-d6)δ8.50-8.47(m,2H),8.44-8.40(m,2H),7.46-7.23(m, 10H),6.01-5.95(m,5H),5.11-5.07(m,2H),4.74-4.72(m,1H),4.37-4.30(m,2H),4.05- 3.99(m,2H),3.83-3.79(m,1H),3.28-2.92(m,8H),2.20-1.75(m,13H),0.99-0.95(m,6H).
5th step
(R)-N- ((R) -6- amino -1- oxos -1- (4- (aminosulfonylamino) piperidin-1-yl) hexane -2- bases) -2- ((R) -2- ((R) -2- amino -3- phenylpropionyls amino) -3- phenylpropionyls amino) -4- methylpentanamides 6
6e (40mg, 0.042mmol) is dissolved in 2mL dichloromethane and methanol (V:V=10:1) mixed solution dissolved clarification, Saturated aqueous sodium carbonate regulation pH to 7 or so is added dropwise, stirring reaction 30 minutes, static layering, collect organic phase, nothing at room temperature Water magnesium sulfate is dried, filtering, filtrate decompression concentration, obtains title product 6 (30mg, yield：99%).
MS m/z(ESI):715.2[M+1]
Embodiment 7
(R)-N- ((R) -6- amino -1- oxos -1- (4- Ureidopiperidine -1- bases) hexane -2- bases) -2- ((R) -2- ((R) - 2- amino -3- phenylpropionyls amino) -3- phenylpropionyls amino) -4- methylpentanamides 7
The first step
(R)-(9H- fluorenes -9- bases) methyl tertbutyl (6- oxos -6- (4- Ureidopiperidine -1- bases) hexane -1,5- diyls) two Carbamate 7b
By 1e (637mg, 1.36mmol), 1- (piperidin-4-yl) urea 7a (441mg, 2.04mmol, using patent application Method disclosed in " DE2609289 " is prepared) it is dissolved in 15mL DMFs, add 2- (7- azobenzenes third Triazole -1- bases)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid esters (775.2mg, 2.04mmol) and DIPEA (0.7mL, 4.08mmol), stirring reaction 12 hours.Reaction solution is concentrated under reduced pressure, and is purified with thin-layered chromatography with solvent system A Gained residue, obtains title product 7b (500mg, yield：62%).
Second step
(R)-(5- amino -6- oxos -6- (4- Ureidopiperidine -1- bases) hexyl) t-butyl carbamate 7c
7b (500mg, 0.84mmol) is dissolved in 5mL dichloromethane, 5mL hexahydropyridines are added, stirring reaction 12 is small When.Reaction solution is concentrated under reduced pressure, with thin-layered chromatography with solvent system A purify gained residue, obtain title product 7c (300mg, yield：96%).
3rd step
N- [(5R) -5- [(2R) -2- [(2R) -2- [(2R) -2- { [(tert-butoxy) carbonyl] amino } -3- phenylpropionyl ammonia Base] -3- phenylpropionyls amino] -4- methylpentanoylaminos] -6- [4- (carbamoylamino) piperidin-1-yl] -6- oxo-hexyls] T-butyl carbamate 7d
By 7c (300mg, 0.81mmol), 1h (424mg, 0.81mmol), 2- (7- azo phenylpropyl alcohol triazole -1- bases)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester (462mg, 1.2mmol) and DIPEA (0.3mL, 1.62mmol) are molten Solution is in 10mL DMFs, stirring reaction 12 hours.Reaction solution is concentrated under reduced pressure, with thin-layered chromatography method to open up Agent system A purifying gained residues are opened, title product 7d (300mg, yield is obtained：42%).
MS m/z(ESI):879.6[M+1]
4th step
(R)-N- ((R) -6- amino -1- oxos -1- (4- Ureidopiperidine -1- bases) hexane -2- bases) -2- ((R) -2- ((R) - 2- amino -3- phenylpropionyls amino) -3- phenylpropionyls amino) -4- methylpentanamide trifluoroacetates 7e
7d (300mg, 0.34mmol) is dissolved in 5mL dichloromethane, 5mL trifluoroacetic acids are added, stirring reaction 3 is small When.Reaction solution is concentrated under reduced pressure, with high performance liquid chromatography purify gained residue, obtain title product 7e (120mg, yield： 52%).
MS m/z(ESI):679.6[M+1]
1H NMR(400MHz,DMSO-d6)δ7.39-7.22(m,10H),4.88-4.87(m,1H),4.73-4.71(m, 1H),4.43-4.359(m,2H),4.12-4.10(m,1H),4.05-3.90(m,1H),3.81-3.78(m,1H),3.77- 3.76(m,2H),3.28-3.21(m,3H),3.00-2.95(m,5H),2.46-2.44(m,1H),2.04-1.90(m,2H), 1.72-1.47(m,12H),1.00-0.95(m,6H),0.98-0.96(m,6H).
5th step
(R)-N- ((R) -6- amino -1- oxos -1- (4- Ureidopiperidine -1- bases) hexane -2- bases) -2- ((R) -2- ((R) - 2- amino -3- phenylpropionyls amino) -3- phenylpropionyls amino) -4- methylpentanamides 7
7e (120mg, 0.132mmol) is dissolved in 5mL dichloromethane and methanol (V:V=10:1) mixed solution is molten Clearly, saturated aqueous sodium carbonate regulation pH to 7 or so is added dropwise, stirring reaction 30 minutes, static layering, are collected organic at room temperature Phase, anhydrous magnesium sulfate is dried, filtering, filtrate decompression concentration, obtains title product 7 (90mg, yield：100%).
MS m/z(ESI):679.6[M+1]
Embodiment 8
((R) -5- ((R) -2- ((R) -2- ((R) -2- amino -3- phenylpropionyls amino) -3- phenylpropionyls amino) -4- first Base valeryl amino) -6- (4- (3- methyl urea groups) piperidin-1-yl) -6- oxo-hexyls) methyl carbamate 8
The first step
(R)-benzyl tert-butyl group (6- (4- (3- methyl urea groups) piperidin-1-yl) -6- oxohexane -1,5- diyls) diaminourea Formic acid esters 8b
By crude product 1d (350mg, 1.31mmol), (R) -2- (((benzyloxy) carbonyl) amino) -6- ((tertbutyloxycarbonyl) ammonia Base) caproic acid 8a (500mg, 1.31mmol are prepared using method disclosed in patent application " WO2009018549 ") is dissolved in In 6mL DMFs, 2- (7- azo phenylpropyl alcohol triazole -1- bases)-N, N, N', N'- tetramethylurea hexafluoro phosphorus is added Acid esters (0.74g, 1.965mmol) and DIPEA (0.685mL, 3.93mmol), stirring reaction 15 hours.Reaction 50mL ethyl acetate, successively with saturated ammonium chloride solution (20mL × 3), saturated sodium bicarbonate solution (20mL × 3) are added in liquid With saturated nacl aqueous solution (20mL × 3) washing, anhydrous sodium sulfate drying, filtering, filtrate decompression concentration obtains crude title production Thing 8b (1.05g), product is not purified directly to carry out next step reaction.
Second step
(R)-(6- amino -1- (4- (3- methyl urea groups) piperidin-1-yl) -1- oxohexane -2- bases) benzyq carbamate Hydrochloride 8c
Crude product 8b (680mg, 1.31mmol) is dissolved in 7mL dichloromethane, add 3.25mL 4M hydrogen chloride Isosorbide-5-Nitrae- Dioxane solution, stirring reaction 3 hours.Reaction solution is concentrated under reduced pressure, and obtains crude title product 8c (1g), product is not purified Directly carry out next step reaction.
3rd step
(R)-benzyl methyl (6- (4- (3- methyl urea groups) piperidin-1-yl) -6- oxohexane -1,5- diyls) diaminourea first Acid esters 8d
Crude product 8c (137mg, 0.327mmol) is dissolved in 10mL dichloromethane, addition methylchloroformate (46mg, 0.49mmol) with triethylamine (110mg, 0.972mmol), stirring reaction 1 hour.30mL dichloromethane is added in reaction solution, according to Secondary use saturated ammonium chloride solution (20mL × 3), saturated sodium bicarbonate solution (20mL × 3) and saturated nacl aqueous solution (20mL × 3) wash, anhydrous sodium sulfate drying, filtering, filtrate decompression concentration obtains crude title product 8d (160mg), product is without pure Change and directly carry out next step reaction.
4th step
(R)-(5- amino -6- (4- (3- methyl urea groups) piperidin-1-yl) -6- oxohexanes) methyl carbamate 8e
Crude product 8d (160mg, 0.327mmol) is dissolved in 5mL methanol, palladium carbon (40mg, 10%), hydrogen displacement three is added It is secondary, stirring reaction 48 hours.Reacting liquid filtering, filtrate decompression concentration, obtains crude title product 8e (76mg), product is without pure Change and directly carry out next step reaction.
5th step
N- [(5R) -5- [(2R) -2- [(2R) -2- [(2R) -2- { [(tert-butoxy) carbonyl] amino } -3- phenylpropionyl ammonia Base] -3- phenylpropionyls amino] -4- methylpentanoylaminos) -6- { 4- [(methylcarbamoyl) amino] piperidin-1-yl } -6- oxygen For hexyl] methyl carbamate 8f
By crude product 8e (77mg, 0.22mmol), 1h (110mg, 0.22mmol) is dissolved in 5mL DMFs In, add 2- (7- azo phenylpropyl alcohol triazole -1- bases)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid esters (125mg, 0.33mmol) With DIPEA (85mg, 0.66mmol), stirring reaction 15 hours.50mL ethyl acetate is added in reaction solution, according to Secondary use saturated ammonium chloride solution (20mL × 3), saturated sodium bicarbonate solution (20mL × 3) and saturated nacl aqueous solution (20mL × 3) wash, anhydrous sodium sulfate drying, filtering, filtrate decompression concentration obtains crude title product 8f (187mg), product is without pure Change and directly carry out next step reaction.
MS m/z(ESI):851.4[M+1]
6th step
((R) -5- ((R) -2- ((R) -2- ((R) -2- amino -3- phenylpropionyls amino) -3- phenylpropionyls amino) -4- first Base valeryl amino) -6- (4- (3- methyl urea groups) piperidin-1-yl) -6- oxo-hexyls) methyl carbamate 8
Crude product 8f (187mg, 0.22mmol) is dissolved in 3mL dichloromethane, 1.5mL trifluoroacetic acids are added, stirring is anti- Answer 1 hour.Reaction solution is concentrated under reduced pressure, with high performance liquid chromatography purify gained residue, obtain title product 8 (20mg, production Rate：12%).
MS m/z(ESI):751.5[M+1]
1H NMR(400MHz,DMSO-d6)δ7.35-7.26(m,8H),7.22-7.18(m,2H),4.83(br,1H), 4.72(br,1H),4.41-4.36(m,2H),4.08-4.02(m,2H),3.76(br,1H),3.68(s,6H),3.60(br, 2H),3.27-3.22(m,6H),3.09(br,1H),3.01-2.98(m,2H),2.96-2.92(m,1H),2.73(d,3H), 1.98-1.92(m,2H),1.68-1.62(m,5H),1.46-1.42(m,7H),0.98(dd,6H).
Embodiment 9
(R) -2- ((R) -2- ((R) -2- amino -3- phenylpropionyls amino) -3- phenylpropionyls amino)-N- ((R) -6- ((2- methoxy ethyls) amino) -1- (4- (3- methyl urea groups) piperidin-1-yl) -1- oxohexane -2- bases) -4- methyl valeryls Amine 9
The first step
(R)-(6- ((2- methoxy ethyls) amino) -1- (4- (3- methyl urea groups) piperidin-1-yl) -1- oxohexanes -2- Base) benzyq carbamate 9b
Crude product 8c (330mg, 0.788mmol) is dissolved in 6mL DMFs, the bromo- 2- methoxyl groups of 1- are added Ethane 9a (164mg, 1.182mmol) and potassium carbonate (230mg, 1.67mmol), are warming up to 90 DEG C of stirring reactions 5 hours.Reaction Liquid is cooled to room temperature, adds 30mL ethyl acetate, is washed with saturated nacl aqueous solution (20mL × 3), anhydrous sodium sulfate drying, mistake Filter, filtrate decompression concentration obtains crude title product 9b (376mg), and product is not purified directly to carry out next step reaction.
Second step
(R)-(5- (((benzyloxy) carbonyl) amino) -6- (4- (3- methyl urea groups) piperidin-1-yl) -6- oxo-hexyls) (2- methoxy ethyls) t-butyl carbamate 9c
Crude product 9b (500mg, 0.75mmol) is dissolved in 15mL dichloromethane, di-tert-butyl dicarbonate is added (330mg, 1.5mmol) and triethylamine (227mg, 2.25mmol), stirring reaction 2.5 hours.30mL dichloros are added in reaction solution Methane, successively with saturated ammonium chloride solution (20mL × 3), saturated sodium bicarbonate solution (20mL × 3) and saturated nacl aqueous solution (20mL × 3) are washed, anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, are purified with thin-layered chromatography with solvent system A Gained residue, obtains title product 9c (190mg, yield：44%).
3rd step
(R)-(5- amino -6- (4- (3- methyl urea groups) piperidin-1-yl) -6- oxo-hexyls) (2- methoxy ethyls) amino T-butyl formate 9d
9c (160mg, 0.328mmol) is dissolved in 5mL methanol, palladium carbon (50mg, 10%) is added, hydrogen is replaced three times, Stirring reaction 15 hours.Reacting liquid filtering, filtrate decompression concentration, obtains crude title product 9d (120mg), product is not purified Directly carry out next step reaction.
4th step
((6R, 9R, 12R, 15R) -6,9- dibenzyl -12- isobutyl group -2,2- dimethyl -15- (4- (3- methyl urea groups) piperazines Pyridine -1- carbonyls) four oxo -3- oxa-s -5,8,11,14- of -4,7,10,13-, four azepine nonadecane -19- bases) (2- methoxyl group second Base) t-butyl carbamate 9e
By crude product 9d (120mg, 0.27mmol), 1h (145mg, 0.27mmol) is dissolved in 5mL DMFs In, addition 2- (7- azo phenylpropyl alcohol triazole -1- bases)-N, N, N', N'- tetramethylurea hexafluorophosphoric acids ester (150mg, 0.405mmol) with DIPEA (104mg, 0.81mmol), stirring reaction 15 hours.50mL is added in reaction solution Ethyl acetate, successively with saturated ammonium chloride solution (20mL × 3), saturated sodium bicarbonate solution (20mL × 3) and saturated sodium-chloride Solution (20mL × 3) is washed, anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, obtains crude title product 9e (250mg), Product is not purified directly to carry out next step reaction.MS m/z(ESI):951.6[M+1]
5th step
(R) -2- ((R) -2- ((R) -2- amino -3- phenylpropionyls amino) -3- phenylpropionyls amino)-N- ((R) -6- ((2- methoxy ethyls) amino) -1- (4- (3- methyl urea groups) piperidin-1-yl) -1- oxohexane -2- bases) -4- methyl valeryls Amine 9
Crude product 9e (250mg, 0.263mmol) is dissolved in 3mL dichloromethane, 1.5mL trifluoroacetic acids are added, stirring is anti- Answer 1.5 hours.Reaction solution is concentrated under reduced pressure, with high performance liquid chromatography purify gained residue, obtain title product 9 (20mg, production Rate：10%).
MS m/z(ESI):751.5[M+1]
1H NMR(400MHz,DMSO-d6)δ7.37-7.23(m,8H),7.21(br,1H),4.86-4.82(m,1H), 4.70-4.66(m,1H),4.39-4.36(m,2H),4.12-4.08(m,1H),3.75-3.72(m,6H),3.65-3.60(m, 4H),3.41(s,3H),3.20-3.15(m,4H),3.01-2.95(m,5H),2.94(d,3H),2.75-2.73(m,3H), 1.92-1.89(m,2H),1.67-1.62(m,7H),1.45-1.42(m,5H),0.98(dd,6H).
Embodiment 10
1- (((R) -5- ((R) -2- ((R) -2- ((R) -2- amino -3- phenylpropionyls amino) -3- phenylpropionyls amino) - 4- methylpentanoylaminos) -6- (4- (3- methyl urea groups) piperidin-1-yl) -6- oxo-hexyls) carbamoyl) piperidines -4- carboxylic acids 10
The first step
(R) -1- ((5- (((benzyloxy) carbonyl) amino) -6- (4- (3- methyl urea groups) piperidin-1-yl) -6- oxos oneself Base) carbamoyl) piperidines -4- carboxylic acid, ethyl esters 10b
Crude product 8c (124mg, 0.273mmol) and triethylamine (95 μ L, 0.681mmol) are dissolved in 20mL dichloromethane, Add 1- (chlorocarbonyl) piperidines -4- carboxylic acid, ethyl esters 10a (50mg, 0.227mmol, using patent application " CN102108092 " disclosure Method be prepared), be warming up to 40 DEG C of stirring reactions 12 hours.Reaction solution is cooled to room temperature, is concentrated under reduced pressure, and uses thin-layer chromatography Method purifies gained residue with solvent system A, obtains title product 10b (50mg, yield：36%).
Second step
(R) -1- ((5- amino -6- (4- (3- methyl urea groups) piperidin-1-yl) -6- oxo-hexyls) carbamoyl) piperazine Pyridine -4- carboxylic acid, ethyl esters 10c
10b (50mg, 0.083mmol) is dissolved in 10mL methanol, palladium carbon (10mg, 10%) is added, hydrogen is replaced three times, Stirring reaction 12 hours.Reacting liquid filtering, filtrate decompression concentration, obtains crude title product 10c (45mg), product is not purified Directly carry out next step reaction.
3rd step
1- (((6R, 9R, 12R, 15R) -6,9- dibenzyl -12- isobutyl group -2,2- dimethyl -15- (4- (3- MUs Base) piperidines -1- carbonyls)) four oxo -3- oxa-s -5,8,11,14- of -4,7,10,13-, four azepine nonadecane -19- bases) amino first Acyl group) piperidines -4- carboxylic acid, ethyl esters 10d
By crude product 10c (45mg, 0.083mmol), 1h (43.6mg, 0.083mmol) is dissolved in 3mL N, N- dimethyl methyls In acid amides, addition 2- (7- azo phenylpropyl alcohol triazole -1- bases)-N, N, N', N'- tetramethylurea hexafluorophosphoric acids ester (47mg, 0.124mmol) with triethylamine (23 μ L, 0.166mmol), stirring reaction 3 hours.Reaction solution is concentrated under reduced pressure, and uses thin-layered chromatography Gained residue is purified with solvent system A, title product 10d (40mg, yield is obtained：51%).
4th step
1- (((6R, 9R, 12R, 15R) -6,9- dibenzyl -12- isobutyl group -2,2- dimethyl -15- (4- (3- MUs Base) piperidines -1- carbonyls)) four oxo -3- oxa-s -5,8,11,14- of -4,7,10,13-, four azepine nonadecane -19- bases) amino first Acyl group) piperidines -4- carboxylic acids 10e
10d (40mg, 0.041mmol) is dissolved in 9mL tetrahydrofurans, first alcohol and water (V/V/V=4:4:1) mixed solvent In, add a hydronium(ion) lithia (3.4mg, 0.082mmol), stirring reaction 1 hour.1M hydrochloric acid is added dropwise into reaction solution to pH For 2, it is concentrated under reduced pressure, obtains crude title product 10e (40mg), product is not purified directly carries out next step reaction.
MS m/z(ESI):948.6[M+1]
5th step
1- (((R) -5- ((R) -2- ((R) -2- ((R) -2- amino -3- phenylpropionyls amino) -3- phenylpropionyls amino) - 4- methylpentanoylaminos) -6- (4- (3- methyl urea groups) piperidin-1-yl) -6- oxo-hexyls) carbamoyl) piperidines -4- carboxylic acids Trifluoroacetate 10f
Crude product 10e (40mg, 0.041mmol) is dissolved in 5mL dichloromethane, 1mL trifluoroacetic acids, stirring reaction 2 is added Hour.Reaction solution is concentrated under reduced pressure, with high performance liquid chromatography purify gained residue, obtain title product 10f (5mg, yield： 13%).
MS m/z(ESI):849.1[M+1]
1H NMR(400MHz,DMSO-d6):δ10.61(s,1H),8.39(d,2H),8.16(t,3H),7.21-7.41(m, 13H),4.86(d,1H),4.73(d,1H),4.46(d,1H),4.05-4.11(m,1H),3.90-4.05(m,4H),3.70- 3.80(m,2H),3.15-3.31(m,4H),2.83-3.03(m,5H),2.71(s,3H),2.49-2.52(m,1H),1.84- 2.08(m,4H),1.49-1.82(m,8H),1.24-1.47(m,5H),1.00(d,3H),0.96(d,3H).
6th step
1- (((R) -5- ((R) -2- ((R) -2- ((R) -2- amino -3- phenylpropionyls amino) -3- phenylpropionyls amino) - 4- methylpentanoylaminos) -6- (4- (3- methyl urea groups) piperidin-1-yl) -6- oxo-hexyls) carbamoyl) piperidines -4- carboxylic acids 10
10f (5mg, 0.005mmol) is dissolved in 1mL dichloromethane and methanol (V:V=10:1) mixed solution dissolved clarification, Saturated aqueous sodium carbonate regulation pH to 7 or so is added dropwise, stirring reaction 30 minutes, static layering, collect organic phase, nothing at room temperature Water magnesium sulfate is dried, filtering, filtrate decompression concentration, obtains title product 10 (4.4mg, yield：100%).
MS m/z(ESI):849.1[M+1]
Embodiment 11
(R) -2- ((R) -2- ((R) -2- amino -3- phenylpropionyls amino) -3- phenylpropionyls amino) -4- methyl-N- ((R) -6- (3- methyl urea groups) -1- (4- (3- methyl urea groups) piperidin-1-yl) -1- oxohexane -2- bases) pentanamide 11
The first step
(R)-(6- amino -1- (4- (3- methyl urea groups) piperidin-1-yl) -1- oxohexane -2- bases) benzyq carbamate 11a
Crude product 8b (390mg, 0.751mmol) is dissolved in 5mL dichloromethane, 1mL trifluoroacetic acids, stirring reaction 1 is added Hour.Reaction solution is concentrated under reduced pressure, and obtains crude title product 11a (310mg), and the not purified directly progress next step of product is anti- Should.
Second step
(6- (3- methyl urea groups) -1- (4- (3- methyl urea groups) piperidin-1-yl) -1- oxohexane -2- bases) carbamic acid Benzyl ester 11b
Crude product 11a (310mg, 0.739mmol) and triethylamine (224mg, 2.218mmol) are dissolved in 5mL dichloromethane, 0 DEG C is cooled to, methyl amido formyl chloride (83mg, 0.888mmol), stirring reaction 2 hours is added.Reaction solution is concentrated under reduced pressure, and uses Silica gel column chromatography purifies gained residue with solvent system A, obtains title product 11b (230mg, yield：66%).
3rd step
1- { 1- [(2R) -2- amino -6- [(methylcarbamoyl) amino] caproyl] piperidin-4-yl } -3- MUs 11c
11b (230mg, 0.483mmol) is dissolved in 5mL methanol, palladium carbon (23mg, 10%) is added, hydrogen is replaced three times, Stirring reaction 12 hours.Reacting liquid filtering, filtrate decompression concentration, obtains crude title product 11c (160mg), product is without pure Change and directly carry out next step reaction.
4th step
((9R, 12R, 15R, 18R) -15- benzyl -12- isobutyl groups -9- (4- (3- methyl urea groups) piperidines -1- carbonyls)) -3, Oxo -19- phenyl -2,4,10,13,16- pentaaza nonadecane -18- the bases of 11,14,17- tetra-) t-butyl carbamate 11d
By crude product 11c (160mg, 0.467mmol), 1h (250mg, 0.476mmol) is dissolved in 3mL N, N- dimethyl methyls In acid amides, addition 2- (7- azo phenylpropyl alcohol triazole -1- bases)-N, N, N', N'- tetramethylurea hexafluorophosphoric acids ester (266mg, 0.7mmol) with DIPEA (180mg, 1.393mmol), stirring reaction 12 hours.Reaction solution is concentrated under reduced pressure, institute Residue in add 30mL ethyl acetate, filtering, collect filter cake, dry, obtain crude title product 11d (155mg), product It is not purified directly to carry out next step reaction.
MS m/z(ESI):850.7[M+1]
5th step
(R) -2- ((R) -2- ((R) -2- amino -3- phenylpropionyls amino) -3- phenylpropionyls amino) -4- methyl-N- ((R) -6- (3- methyl urea groups) -1- (4- (3- methyl urea groups) piperidin-1-yl) -1- oxohexane -2- bases) pentanamide trifluoro second Hydrochlorate 11e
Crude product 11d (150mg, 0.176mmol) is dissolved in 7.5mL dichloromethane, 1.5mL trifluoroacetic acids is added, stirs Mix reaction 1 hour.Reaction solution is concentrated under reduced pressure, with high performance liquid chromatography purify gained residue, obtain title product 11e (90mg, yield：69%).
MS m/z(ESI):750.3[M+1]
1H NMR(400MHz,DMSO-d6):δ8.45(d,2H),8.23(t,3H),7.22-7.40(m,14H),4.85- 4.87(m,1H),4.74-4.77(m,1H),4.31-4.42(m,2H),4.09-4.11(m,1H),3.98(t,1H),3.67- 3.73(m,1H),3.20-3.34(m,2H),3.05-3.16(m,2H),2.85-3.01(m,3H),2.71(s,3H),2.70(s, 3H),1.87-2.05(m,2H),1.25-1.83(m,12H),1.00(d,3H),0.96(d,3H).
6th step
(R) -2- ((R) -2- ((R) -2- amino -3- phenylpropionyls amino) -3- phenylpropionyls amino) -4- methyl-N- ((R) -6- (3- methyl urea groups) -1- (4- (3- methyl urea groups) piperidin-1-yl) -1- oxohexane -2- bases) pentanamide 11
11e (90mg, 0.104mmol) is dissolved in 5mL dichloromethane and methanol (V:V=10:1) mixed solution is molten Clearly, saturated aqueous sodium carbonate regulation pH to 7 or so is added dropwise, stirring reaction 30 minutes, static layering, are collected organic at room temperature Phase, anhydrous magnesium sulfate is dried, filtering, filtrate decompression concentration, obtains title product 11 (78mg, yield：100%).
MS m/z(ESI):750.3[M+1]
Embodiment 12
(R) -2- ((R) -2- ((R) -2- amino -3- phenylpropionyls amino) -3- phenylpropionyls amino) -4- methyl-N- ((R) -1- (4- (3- methyl urea groups) piperidin-1-yl) -1- oxo -6- urea groups hexane -2- bases) pentanamide 12
The first step
(R)-(1- (4- (3- methyl urea groups) piperidin-1-yl) -1- oxo -6- urea groups hexane -2- bases) benzyq carbamate 12b
Crude product 8c (200mg, 0.44mmol) is dissolved in 10mL dichloromethane, trimethyl silicane based isocyanate 12a is added (202mg, 1.76mmol) and triethylamine (178mg, 1.76mmol), stirring reaction 12 hours.Reaction solution is concentrated under reduced pressure, and obtains thick Product title product 12b (203mg), product is not purified directly to carry out next step reaction.
Second step
(R) -1- (1- (2- amino -- 6- urea groups caproyl) piperidin-4-yl) -3- MUs 12c
Crude product 12b (140mg, 0.303mmol) is dissolved in 5mL methanol, palladium carbon (40mg, 10%), hydrogen displacement is added Three times, stirring reaction 1 hour.Reacting liquid filtering, filtrate decompression concentration, obtains crude title product 12c (99mg), product without Purifying directly carries out next step reaction.
3rd step
((7R, 10R, 13R, 16R) -1- amino -13- benzyl -10- isobutyl groups -7- (4- (3- methyl urea groups) piperidines -1- carbonyls Base) four oxo -17- phenyl -2,8,11,14- of -1,9,12,15-, four azepine heptadecane -16- bases) t-butyl carbamate 12d
By crude product 12c (100mg, 0.3mmol), 1h (160mg, 0.31mmol) is dissolved in 3mL DMFs In, add 2- (7- azo phenylpropyl alcohol triazole -1- bases)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid esters (170mg, 0.45mmol) With triethylamine (60mg, 0.6mmol), stirring reaction 12 hours.Reaction solution is concentrated under reduced pressure, with thin-layered chromatography with solvent system A purifying gained residues, obtain title product 12d (200mg, yield：80%).
MS m/z(ESI):836.4[M+1]
4th step
(R) -2- ((R) -2- ((R) -2- amino -3- phenylpropionyls amino) -3- phenylpropionyls amino) -4- methyl-N- ((R) -1- (4- (3- methyl urea groups) piperidin-1-yl) -1- oxo -6- urea groups hexane -2- bases) pentanamide trifluoroacetate 12e
12d (200mg, 0.24mmol) is dissolved in 5mL dichloromethane, 3mL trifluoroacetic acids, stirring reaction 1 hour is added. Reaction solution is concentrated under reduced pressure, with high performance liquid chromatography purify gained residue, obtain title product 12e (20mg, yield： 11%).
MS m/z(ESI):736.2[M+1]
1H NMR(400MHz,DMSO-d6)δ8.46(br,3H),7.42-7.23(m,10H),6.01(br,5H),5.10 (br,2H),4.74-4.73(m,1H),4.35-4.31(m,2H),4.01-3.99(m,2H),3.80-3.76(m,1H),3.28- 2.92(m,8H),2.70(s,3H),2.20-1.78(m,14H),0.98-0.96(m,6H).
5th step
(R) -2- ((R) -2- ((R) -2- amino -3- phenylpropionyls amino) -3- phenylpropionyls amino) -4- methyl-N- ((R) -1- (4- (3- methyl urea groups) piperidin-1-yl) -1- oxo -6- urea groups hexane -2- bases) pentanamide 12
12e (20mg, 0.024mmol) is dissolved in 2mL dichloromethane and methanol (V:V=10:1) mixed solution is molten Clearly, saturated aqueous sodium carbonate regulation pH to 7 or so is added dropwise, stirring reaction 30 minutes, static layering, are collected organic at room temperature Phase, anhydrous magnesium sulfate is dried, filtering, filtrate decompression concentration, obtains title product 12 (17mg, yield：98%).
MS m/z(ESI):736.2[M+1]
Embodiment 13
(8R, 11R, 14R, 17R) -17- amino -14- benzyl -11- isobutyl groups -8- (4- (3- methyl urea groups) piperidines -1- carbonyls Base) four azepines of-10,13,16- trioxy--18- phenyl-3,9,12,15-, 18-1- acid 13
The first step
(R) -2- ((5- (((benzyloxy) carbonyl) amino) -6- (4- (3- methyl urea groups) piperidin-1-yl) -6- oxos oneself Base) amino) methyl acetate 13b
Crude product 11a (640mg, 1.4mmol) is dissolved in 10mL DMFs, 2- methyl chloroacetates are added 13a (122mg, 1.12mmol), KI (465mg, 2.8mmol) and potassium carbonate (773mg, 5.6mmol), are warming up to 60 DEG C and stir Mix reaction 1.5 hours.Reaction solution is cooled to room temperature, adds water, is extracted with ethyl acetate (20mL × 3), merges organic phase, with full With sodium chloride solution (20mL × 3) washing, anhydrous sodium sulfate drying, filtering, filtrate decompression concentration obtains crude title product 13b (700mg), product is not purified directly to carry out next step reaction.
Second step
(R) -2- ((5- (((benzyloxy) carbonyl) amino) -6- (4- (3- methyl urea groups) piperidin-1-yl) -6- oxos oneself Base) (tertbutyloxycarbonyl) amino) methyl acetate 13c
Crude product 13b (700mg, 1.4mmol) is dissolved in 20mL dichloromethane, di-tert-butyl dicarbonate is added (466mg, 2.1mmol) and triethylamine (283mg, 2.8mmol), stirring reaction 12 hours.Reaction solution is concentrated under reduced pressure, and uses thin layer color Spectrometry purifies gained residue with solvent system A, obtains title product 13c (200mg, yield：24%).
3rd step
(R) -2- ((5- amino -6- (4- (3- methyl urea groups) piperidin-1-yl) -6- oxo-hexyls) (tertbutyloxycarbonyl) ammonia Base) methyl acetate 13d
13c (200mg, 0.34mmol) is dissolved in 10mL methanol, palladium carbon (20mg, 10%) is added, hydrogen is replaced three times, Stirring reaction 12 hours.Reacting liquid filtering, filtrate decompression concentration, obtains crude title product 13d (150mg), product is without pure Change and directly carry out next step reaction.
4th step
(6R, 9R, 12R, 15R) -6,9- dibenzyl -20- (tertbutyloxycarbonyl) -12- isobutyl group -2,2- dimethyl -15- Oxo -3- oxa- -5,8,11,14,20- the pentaazas 20 of (4- (3- methyl urea groups) piperidines -1- carbonyls) -4,7,10,13- four Two -22- acid methyl esters 13e
By crude product 13d (150mg, 0.33mmol), 1h (172mg, 0.33mmol) is dissolved in 10mL N, N- dimethyl formyls In amine, addition 2- (7- azo phenylpropyl alcohol triazole -1- bases)-N, N, N', N'- tetramethylurea hexafluorophosphoric acids ester (188mg, 0.5mmol) with DIPEA (85mg, 0.66mmol), stirring reaction 12 hours.Reaction solution is concentrated under reduced pressure, with thin Layer chromatography purifies gained residue with solvent system A, obtains title product 13e (120mg, yield：38%).
5th step
(6R, 9R, 12R, 15R) -6,9- dibenzyl -20- (tertbutyloxycarbonyl) -12- isobutyl group -2,2- dimethyl -15- Oxo -3- oxa- -5,8,11,14,20- the pentaazas 20 of (4- (3- methyl urea groups) piperidines -1- carbonyls) -4,7,10,13- four Two -22- acid 13f
13e (80mg, 0.082mmol) is dissolved in 10mL tetrahydrofurans and water (V/V=5:1) in the mixed solvent, is added One hydronium(ion) lithia (14mg, 0.33mmol), stirring reaction 12 hours.It is 6 that 2M hydrochloric acid is added dropwise into reaction solution to pH, uses second Acetoacetic ester extracts (20mL × 3), merges organic phase, is washed with saturated nacl aqueous solution (20mL × 3), anhydrous sodium sulfate drying, Filtering, filtrate decompression concentration obtains crude title product 13f (70mg), and product is not purified directly to carry out next step reaction.
MS m/z(ESI):951.6[M+1]
6th step
(8R, 11R, 14R, 17R) -17- amino -14- benzyl -11- isobutyl groups -8- (4- (3- methyl urea groups) piperidines -1- carbonyls Base) four azepines of-10,13,16- trioxy--18- phenyl-3,9,12,15-, 18-1- acid 13
Crude product 13f (70mg, 0.0736mmol) is dissolved in 1mL dichloromethane, 1mL trifluoroacetic acids are added, stirring is anti- Answer 2 hours.Reaction solution is concentrated under reduced pressure, with high performance liquid chromatography purify gained residue, obtain title product 13 (50mg, production Rate：91%).
MS m/z(ESI):751.7[M+1]
1H NMR(400MHz,DMSO-d6)δ7.40-7.23(m,10H),4.74-4.75(m,1H),4.37-4.35(m, 1H),4.17-4.12(m,6H),3.85-3.82(m,1H),3.77-3.76(m,2H),3.74-3.69(m,4H),3.68-3.66 (m,1H),3.28-3.22(m,6H),3.20-3.03(m,4H),2.70(s,3H),1.75-1.70(m,6H),1.47-1.30 (m,7H),0.98-0.96(m,6H).
Embodiment 14
(R)-N- ((R) -6- amino -1- (4- (3- ethyls urea groups) piperidin-1-yl) -1- oxohexane -2- bases) -2- ((R) -2- ((R) -2- amino -3- phenylpropionyls amino) -3- phenylpropionyls amino) -4- methylpentanamides 14
The first step
4- (3- ethyls urea groups) piperidines -1- t-butyl formates 14a
Crude product 1b (0.15g, 0.469mmol) is dissolved in 10mL methanol, addition ethylamine hydrochloride (38mg, 0.469mmol) and sodium carbonate (50mg, 0.469mmol), 50 DEG C of stirring reactions are warming up to 12 hours.Reaction solution is cooled to room temperature, It is concentrated under reduced pressure, with dichloromethane and methanol (V/V=10:1) mixed solvent mashing, filtering is collected filter cake, dried, and obtains thick Product title product 14a (0.18g), product is not purified directly to carry out next step reaction.
Second step
1- ethyls -3- (piperidin-4-yl) urea trifluoroacetate 14b
Crude product 14a (0.18g, 0.469mmol) is dissolved in 5mL dichloromethane, 1mL trifluoroacetic acids are added, stirring is anti- Answer 2 hours.Reaction solution is concentrated under reduced pressure, and obtains crude title product 14b (0.15g), the not purified direct carry out next step of product Reaction.
3rd step
(R)-(9H- fluorenes -9- bases) methyl tertbutyl (6- (4- (3- ethyls urea groups) piperidin-1-yl) -6- oxohexane -1, 5- diyls) diurethane 14c
By crude product 14b (0.15g, 0.469mmol), 1e (220mg, 0.469mmol) is dissolved in 5mL N, N- dimethyl methyls In acid amides, addition 2- (7- azo phenylpropyl alcohol triazole -1- bases)-N, N, N', N'- tetramethylurea hexafluorophosphoric acids ester (0.267g, 0.704mmol) with triethylamine (0.23mL, 0.938mmol), stirring reaction 2 hours.Reaction solution is concentrated under reduced pressure, and uses thin-layer chromatography Method purifies gained residue with solvent system A, obtains title product 14c (360mg, yield：100%).
4th step
(R)-(5- amino -6- (4- (3- ethyls urea groups) piperidin-1-yl) -6- oxo-hexyls) t-butyl carbamate 14d
14c (360mg, 0.469mmol) is dissolved in 5mL dichloromethane, 2mL hexahydropyridines are added, stirring reaction 2 is small When.Reaction solution is concentrated under reduced pressure, and adds water, is extracted with ethyl acetate, organic phase anhydrous sodium sulfate drying, filters, filtrate decompression Concentration, obtains crude title product 14d (200mg), and product is not purified directly to carry out next step reaction.
5th step
N- [(5R) -5- [(2R) -2- [(2R) -2- [(2R) -2- { [(tert-butoxy) carbonyl] amino } -3- phenylpropionyl ammonia Base] -3- phenylpropionyls amino] -4- methylpentanoylaminos] -6- { 4- [(ethylaminocarbonyl) amino] piperidin-1-yl } -6- Oxo-hexyl] t-butyl carbamate 14e
By crude product 14d (200mg, 0.469mmol), 1h (246mg, 0.469mmol), 2- (7- azo phenylpropyl alcohol triazoles -1- Base)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid esters (267mg, 0.703mmol) and triethylamine (0.13mL, 0.938mmol) are molten Solution is in 5mL DMFs, stirring reaction 12 hours.Reaction solution is concentrated under reduced pressure, with thin-layered chromatography with solvent System A purifying gained residues, obtain title product 14e (120mg, yield：28%).
MS m/z(ESI):907.6[M+1]
6th step
(R)-N- ((R) -6- amino -1- (4- (3- ethyls urea groups) piperidin-1-yl) -1- oxohexane -2- bases) -2- ((R) -2- ((R) -2- amino -3- phenylpropionyls amino) -3- phenylpropionyls amino) -4- methylpentanamides 14
14e (120mg, 0.132mmol) is dissolved in 5mL dichloromethane, 1mL trifluoroacetic acids are added, stirring reaction 2 is small When.Reaction solution is concentrated under reduced pressure, with high performance liquid chromatography purify gained residue, obtain title product 14 (30mg, yield： 14%).
MS m/z(ESI):707.2[M+1]
1H NMR(400MHz,DMSO-d6):δ8.44(d,2H),8.22(t,3H),7.21-7.41(m,12H),4.75(d, 1H),4.41(d,2H),4.06-4.11(m,1H),3.74(s,1H),3.20-3.30(m,3H),3.10-3.19(m,3H), 2.90-3.03(m,6H),1.84-2.06(m,2H),1.56-1.85(m,7H),1.30-1.55(m,6H),1.10(t,3H), 1.01(d,3H),0.97(d,3H).
Embodiment 15
(R)-N- ((R) -6- amino -1- (4- (3- cyclopropylureidos) piperidin-1-yl) -1- oxohexane -2- bases) -2- ((R) -2- ((R) -2- amino -3- phenylpropionyls amino) -3- phenylpropionyls amino) -4- methylpentanamides 15
The first step
(R)-(9H- fluorenes -9- bases) methyl tertbutyl (6- (4- (3- cyclopropylureidos) piperidin-1-yl) -6- oxohexanes - 1,5- diyls) diurethane 15b
By 1- cyclopropyl -3- (piperidin-4-yl) ureas 15a (0.2g, 1mmol, using patent application " WO2016035814 " public affairs The method opened is prepared), 1e (500mg, 1mmol) is dissolved in 5mL DMFs, adds 2- (7- azobenzenes Third triazole -1- bases)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid esters (0.57g, 1.5mmol) and triethylamine (202mg, 2mmol), stirring reaction 48 hours.Reaction solution is concentrated under reduced pressure, with thin-layered chromatography with solvent system A purify gained residue, Obtain title product 15b (200mg, yield：100%).
Second step
(R)-(5- amino -6- (4- (3- cyclopropylureidos) piperidin-1-yl) -6- oxo-hexyls) t-butyl carbamate 15c
15b (700mg, 1.11mmol) is dissolved in 3mL dichloromethane, 3mL hexahydropyridines, stirring reaction 0.5 is added Hour.Reaction solution is concentrated under reduced pressure, and obtains crude title product 15c (455mg), and the not purified directly progress next step of product is anti- Should.
3rd step
N- [(5R) -5- [(2R) -2- [(2R) -2- [(2R) -2- { [(tert-butoxy) carbonyl] amino } -3- phenylpropionyl ammonia Base] -3- phenylpropionyls amino] -4- methylpentanoylaminos] -6- { 4- [(cyclopropylcarbamoyl) amino] piperidin-1-yl } - 6- oxo-hexyls] t-butyl carbamate 15d
By crude product 15c (411.28mg, 1mmol), 1h (525.64mg, 1mmol), 2- (7- azo phenylpropyl alcohol triazoles -1- Base)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid esters (570mg, 1.5mmol) and triethylamine (218mg, 2mmol) are dissolved in 5mL In DMF, stirring reaction 12 hours.Reaction solution is concentrated under reduced pressure, pure with solvent system A with thin-layered chromatography Change gained residue, obtain title product 15d (300mg, yield：32.7%).
MS m/z(ESI):919.5[M+1]
4th step
(R)-N- ((R) -6- amino -1- (4- (3- cyclopropylureidos) piperidin-1-yl) -1- oxohexane -2- bases) -2- ((R) -2- ((R) -2- amino -3- phenylpropionyls amino) -3- phenylpropionyls amino) -4- methylpentanamide trifluoroacetates 15e
15d (300mg, 0.33mmol) is dissolved in 6mL dichloromethane, 2mL trifluoroacetic acids are added, stirring reaction 2 is small When.Reaction solution is concentrated under reduced pressure, with high performance liquid chromatography purify gained residue, obtain title product 15e (40mg, yield： 17%).
MS m/z(ESI):719.2[M+1]
1H NMR(400MHz,DMSO-d6)δ8.46(br,3H),8.19(br,2H),7.42-7.23(m,10H),5.09 (br,4H),4.38-4.27(m,2H),4.19-4.16(m,2H),4.01-3.99(m,2H),3.80-3.76(m,1H),3.28- 2.92(m,8H),2.76-2.71(m,1H),2.20-1.78(m,13H),0.98-0.96(m,6H),0.82-0.57(m,4H).
5th step
(R)-N- ((R) -6- amino -1- (4- (3- cyclopropylureidos) piperidin-1-yl) -1- oxohexane -2- bases) -2- ((R) -2- ((R) -2- amino -3- phenylpropionyls amino) -3- phenylpropionyls amino) -4- methylpentanamides 15e
15e (40mg, 0.042mmol) is dissolved in 2mL dichloromethane and methanol (V:V=10:1) mixed solution is molten Clearly, saturated aqueous sodium carbonate regulation pH to 7 or so is added dropwise, stirring reaction 30 minutes, static layering, are collected organic at room temperature Phase, anhydrous magnesium sulfate is dried, filtering, filtrate decompression concentration, obtains title product 15 (30mg, yield：99%).
MS m/z(ESI):719.2[M+1]
Biological assessment
The explanation present invention is further described below in conjunction with test case, but these embodiments are not meant as the limitation present invention's Scope.
Test case 1
1st, experiment purpose
The purpose of this experiment is the agonism in order to test the compounds of this invention to KOR acceptors, according to EC50Size is evaluated The external activity of compound.
2nd, the test of KOR activity
2.1 experiment purpose
The compound of the present invention can activate KOR acceptors (KOR), so as to reduce intracellular cAMP level；Second messenger CAMP is combined into nucleus with DNA CRE, can start downstream luciferase (Luciferase) expression, luciferase Fluorescence can be sent with its substrate reactions, the agonist activity of compound is reflected by determining fluorescence signal.
2.2 experimental method
The activity of embodiment compound excitement KOR influence downstream cAMP levels changes is tested by following method.
2.2.1 experiment material and instrument
1) laboratory apparatus
Instrument title Supply of material company Model
ELIASA PE Vector3
96 hole round bottom plates costar 3795
White 96 hole flat undersides, clear bottom Corning 3903
2) experiment material
2.2.2 experimental procedure
1) acquisition of HEK293/KOR/CRE monoclonal cell strains
KOR/pcDNA3.1 (+) and CRE/pGL4.29 are transferred to HEK293 cell lines, by adding G418 in the medium With hygromycin (Hygromycin), and HEK293/KOR/CRE monoclonal cell strains are filtered out in 96 porocyte culture plates.
2) embodiment compound is tested to KOR agonisms
HEK293/KOR/CRE monoclonal cell strains DMEM/ high glucoses culture medium (10%FBS, 1mg/ml G418, 200ug/ml hygromycin, is mixed) middle culture, passage in every 3 days is once.Experimental day is produced cell with Fresh cell culture medium and hanged Liquid, 20,000 cells/wells spread 96 orifice plates (BD, #356692), the culture of 5% 37 DEG C of carbon dioxide.It is second day, first that compound is molten Solution concentration in pure DMSO is 20mM, then is configured to DMSO first concentration 200nM, and is diluted to 8 concentration successively with 3 times, The hole for being arranged to blank and control adds 90 μ l DMSO；With the DMEM/ high glucoses containing 10 μM of Forskolin (SH30243.01B, Hyclone) culture medium dilutes 20 times.The Tissue Culture Plate of inoculation in first day is taken out, 10 are separately added into per hole Medicine or control (0.5%DMSO) after μ l dilutions, gently vibration are mixed, and are placed 37 DEG C and are cultivated 4 hours.In 96 porocyte culture plates In, 100 μ l luciferases detection liquid (Promega, #E6110) is added per hole, room temperature is placed 5 minutes, using Victor3.0's Cold light pattern surveys absorption value.Compound is calculated with corresponding signal value according to each concentration of compound with Graphpad Prism softwares EC50Value.Emax is the ceiling effect that compound causes cAMP levels to change.
2.3 test result
The change of the compound excitement KOR influence downstream cAMP levels of the present invention is measured by the experiment of the above, is surveyed The EC obtained50Value is shown in Table 1.1.
The EC of the compounds of this invention of table 1.1 excitement KOR receptor influences cAMP levels50
Embodiment is numbered EC50(pM)
1 0.5
2 4.
3 1
4 9
6 1
7 0.7
8 0.2
9 4
11 2
12 3
13 1
14 3
15 1
Conclusion：The compounds of this invention has obvious agonism to KOR acceptors.
Pharmacokinetic Evaluation
The pharmacokinetics test of test case 2, compound of the embodiment of the present invention
1st, make a summary
Using SD rats as animal subject, determine SD rat intravenous injections using LC/MS/MS methods and give embodiment 1 and real Apply after the compound of example 7 drug concentration not in the same time in blood plasma.Medicine of the compounds of this invention in SD rat bodies is studied for power Scholarship and moral conduct is to evaluate its characteristics of pharmacokinetics.
2nd, testing program
2.1 test drug
Embodiment 1 and the compound of embodiment 7
2.2 experimental animal
SD rats 8, male and female half and half are divided into 2 groups, purchased from the western pul-Bi Kai experimental animals Co., Ltd in Shanghai, animal life Produce credit number：SCXK (Shanghai) 2008-0016.
2.3 medicines are prepared
Appropriate amount of sample is weighed, 5%DMSO+5%PEG400+90% physiological saline is added, sequentially adds in order.
2.4 administration
SD rats 8, male and female half and half are divided into 2 groups；Intravenous injection administration respectively, is administered 1mg/kg after the night of fasting one.
3rd, operate
Vein group 5min before being administered and after administration, 0.25,0.5,1.0,2.0,4.0,8.0,11.0,24.0h is by eye socket Take a blood sample 0.2ml, is placed in heparinised tubes, 3500rpm centrifugation 10min separated plasmas, in -20 DEG C of preservations.
The testing compound content after different compound intravenous injection administrations in SD rat plasmas is determined with LC/MS/MS methods.
4th, SD pharmacokinetics in rats parametric results
The pharmacokinetic parameter of compound of the embodiment of the present invention is as follows：
Conclusion：The medicine of the compounds of this invention is for well-behaved.

Claims (16)

1. the compound shown in a kind of logical formula (I)：
Or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures, or Its pharmaceutically useful salt,
Wherein：
G is C=O or O=S=O；
R1Selected from hydrogen atom, alkyl, alkoxy, haloalkyl, halogen, amino, nitro, hydroxyl, cyano group, cycloalkyl, heterocyclic radical, Aryl, heteroaryl ,-OR3、-C(O)R3、-C(O)OR3、-S(O)mR3With-NR4R5, wherein described alkyl, haloalkyl, cycloalkanes Base, heterocyclic radical, aryl and heteroaryl are optionally selected from alkyl, haloalkyl, halogen, amino, nitro, cyano group, hydroxyl, alcoxyl Base, halogenated alkoxy, hydroxyalkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl and NR6R7One or more of substituent taken Generation；
R2Selected from hydrogen atom, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-OR3、-C(O)R3 With-C (O) OR3, wherein described alkyl, haloalkyl, cycloalkyl, heterocyclic radical, aryl and heteroaryl be optionally selected from alkyl, Haloalkyl, halogen, amino, nitro, cyano group, hydroxyl, alkoxy, halogenated alkoxy, hydroxyalkyl, cycloalkyl, heterocyclic radical, aryl Replaced with one or more of heteroaryl substituent；
R3Selected from hydrogen atom, alkyl, amino, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclic radical, aryl and heteroaryl, wherein described Alkyl, cycloalkyl, heterocyclic radical, aryl and heteroaryl are optionally selected from alkyl, halogen, hydroxyl, amino, nitro, cyano group, alcoxyl One or more of base, hydroxyalkyl, cycloalkyl, heterocyclic radical, aryl and heteroaryl substituent is replaced；
R4And R5Be each independently selected from hydrogen atom, it is alkyl, alkoxy, hydroxyalkyl, hydroxyl, amino, carboxylic acid ester groups, cycloalkyl, miscellaneous Ring group, aryl and heteroaryl, wherein described alkyl, cycloalkyl, heterocyclic radical, aryl and heteroaryl are optionally selected from alkyl, halogen In element, hydroxyl, amino, carboxylic acid ester groups, nitro, cyano group, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclic radical, aryl and heteroaryl One or more substituents are replaced；
R6For hydrogen atom or W；
R7Selected from hydrogen atom, alkyl, C (O) R8、C(O)OR8、C(O)NR9R10Or W, wherein described alkyl is optionally selected from alcoxyl One or more of base, hydroxyalkyl, cycloalkyl, heterocyclic radical, carboxylic acid group and carboxylic acid ester groups substituent is replaced；
R8Selected from hydrogen atom, alkyl, alkoxy, amino, cycloalkyl and heterocyclic radical, wherein described heterocyclic radical is optionally selected from alkane One or more of base, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclic radical, carboxylic acid group and carboxylic acid ester groups substituent is replaced；
R9And R10It is each independently selected from hydrogen atom, alkyl or haloalkyl；Wherein described alkyl be optionally selected from carboxylic acid group, One or more of alkoxy, amino, cyano group, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic radical, aryl and heteroaryl take Replaced for base；
Or, R9And R10Heterocyclic radical is formed together with the nitrogen-atoms being connected, wherein containing 1~2 phase in described heterocyclic radical The same or different hetero atoms for being selected from N, O and S, and described heterocyclic radical is optionally selected from alkyl, alkoxy, halogen, amino, cyanogen One or more of base, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic radical, carboxylic acid group, carboxylic acid ester groups, aryl and heteroaryl Substituent is replaced；
W is amino protecting group；And
M is 0,1 or 2.
2. the compound shown in logical formula (I) according to claim 1, it is the compound shown in logical formula (II)：
Or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures, or Its officinal salt,
Wherein：
R1And R2As defined in claim 1.
3. the compound or its salt according to logical formula (I) according to any one of claims 1 to 2, wherein R1For alkyl or OR3, wherein described alkyl is optionally by NR6R7Substituent is replaced；
R3Selected from alkyl or heterocyclic radical, wherein described alkyl is optionally selected from cycloalkyl, heterocyclic radical, aryl and heteroaryl One or more substituents are replaced；
R6For hydrogen atom；
R7Selected from hydrogen atom, alkyl, C (O) OR8Or C (O) NR9R10, wherein described alkyl is optionally selected from alkoxy, hydroxyl alkane One or more of base, carboxylic acid group and carboxylic acid ester groups substituent is replaced；
R8For hydrogen atom or alkyl；
R9And R10It is each independently hydrogen atom or alkyl；
Or, R9And R10Heterocyclic radical is formed together with the nitrogen-atoms being connected, wherein containing 1~2 phase in described heterocyclic radical The same or different hetero atoms for being selected from N, O and S, and described heterocyclic radical is optionally selected from alkyl, alkoxy, halogen, amino, carboxylic One or more of acidic group and carboxylic acid ester groups substituent are replaced.
4. the compound according to logical formula (I) according to any one of claims 1 to 3, it is the change shown in logical formula (III) Compound：
Or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures, or Its officinal salt,
Wherein：
G、R6~R7And R2As defined in claim 1.
5. the compound shown in logical formula (I) according to any one of Claims 1 to 4, wherein R2Selected from hydrogen atom, alkyl, ring Alkyl and aryl, preferably hydrogen atom, methyl, ethyl, cyclopropyl or phenyl.
6. the compound according to logical formula (I) according to any one of claims 1 to 5, wherein the compound is selected from：
7. according to compound or its salt according to any one of claims 1 to 6, wherein described salt is logical formula (I) and trifluoro The addition salts of acetic acid formation.
8. the compound shown in a kind of logical formula (IV)：
Or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures or Its pharmaceutically useful salt,
Wherein：
W is amino protecting group；
G and R1~R2As defined in claim 1.
9. the compound shown in logical formula (IV) according to claim 8, it is selected from：
10. a kind of method for preparing the compound shown in logical formula (I) according to claim 1, this method includes：
Formula (I-5) compound is reacted with formula (I-6) compound, obtains logical formula (IV) compound；Obtained logical formula (IV) Compound further sloughs protection group, obtains logical formula (I) compound；
Wherein：
W is amino protecting group；
G、R1And R2As defined in claim 1.
11. a kind of pharmaceutical composition, it contains the logical formula (I) institute according to any one of claim 1~7 of therapeutically effective amount The compound shown, and one or more pharmaceutically acceptable carriers, diluent or excipient.
12. the compound or according to claim 11 shown in logical formula (I) according to any one of claim 1~7 Use of the pharmaceutical composition in the medicine of relevant disease of prevention and/or the activator mediation for the treatment of kappa opioid nonopioid receptors is prepared On the way.
13. purposes according to claim 12, wherein the relevant disease of described kappa opioid nonopioid receptors activator mediation Selected from pain, inflammation, itch, oedema, hyponatremia, hypopotassaemia, intestinal obstruction, cough and glaucoma, preferably pain.
14. the compound or pharmaceutical composition according to claim 11 according to any one of claim 1~7 are in system Purposes in the standby medicine for preventing and/or treating pain and pain related disorders.
15. purposes according to claim 14, wherein described pain is selected from neuropathic pain, trunk pain, splanchnodynia, skin Skin pain, arthritis ache, kidney stone pain, hysterotrismus, dysmenorrhoea, endometriosis, indigestion, surgical site infections pain Bitterly, pain, ocular pain, otitis pain, explosive cancer pain and the disorderly related pain of GI after medical treatment.
16. the compound or according to claim 11 shown in logical formula (I) according to any one of claim 1~7 Pharmaceutical composition purposes in the medicine for preparing exciting kappa opioid nonopioid receptors.
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