CN1917921A - Calcitonin gene related peptide receptor antagonists - Google Patents

Calcitonin gene related peptide receptor antagonists Download PDF

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CN1917921A
CN1917921A CNA200380111030XA CN200380111030A CN1917921A CN 1917921 A CN1917921 A CN 1917921A CN A200380111030X A CNA200380111030X A CN A200380111030XA CN 200380111030 A CN200380111030 A CN 200380111030A CN 1917921 A CN1917921 A CN 1917921A
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oxo
piperidines
dihydro
quinazoline
indazole
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CN100558428C (en
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安德鲁·P·德格南
陈岭
丽塔·西维洛
吉恩·M·杜鲍奇克
韩晓军
西昂·J·J·姜
约翰·E·马科
乔治·托拉
罗光林
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Bristol Myers Squibb Co
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Abstract

The present invention relates to compounds of Formula (I) as antagonists of calcitonin gene-related peptide receptors ('CGRP-receptor'), pharmaceutical compositions comprising them, methods for identifying them, methods of treatment using them and their use in therapy for treatment of neurogenic vasodilation, neurogenic inflammation, migraine and other headaches, thermal injury, circulatory shock, flushing associated with menopause, airway inflammatory diseases, such as asthma and chronic obstructive pulmonary disease (COPD), and other conditions the treatment of which can be effected by the antagonism of CGRP-receptors.

Description

Calcitonin gene related peptide receptor antagonists
Invention field
The present invention relates to the micromolecule antagonist of novel calcitonin gene related peptide receptor (" CGRP-receptor "), the pharmaceutical composition that contains them, identify their method, use the method that they treat, and they are at treatment neurogenicity vasodilation (neurogenic vasodilation), neurogenic inflammation, migraine, cluster headache and other headache, thermal burn, cyclical shock (circulatory shock), the flushing relevant with climacteric, air flue inflammatory diseases (as asthma and chronic obstructive pulmonary disease (COPD)) and antagonism that can the CGRP-receptor are carried out the therapeutic use in other symptom of treatment.
Background of invention
Calcitonin-gene-related peptide (CGRP) is that (Science 1982,298,240-244) for Amara, S.G. etc. for a kind of naturally occurring 37-amino acid peptide of identifying first in nineteen eighty-two.This peptide is with two kinds of formal representations (α CGRP and β CGRP), and they have 1 and 3 amino acid whose differences respectively in rat and people.This peptide is distributed widely in peripheral nervous system (PNS) and central nervous system (CNS) among both, mainly concentrate on feel to import into axoneuron in, and show multiple biological effect, comprise vasorelaxation action.
When CGRP discharged from cell, CGRP was incorporated into specific cell surface G protein-coupled receptor, and mainly brings into play its biological action (Poyner, D.R. etc., Br J Pharmacol 1992,105,441-7 by adenyl cyclase in the active cell; Van Valen, F.et al, Neurosci Lett 1990,119,195-8.).Activate CGRP according to the antagonistic properties of described fragments of peptides CGRP (8-37) and the linear analog of CGRP 2The ability of receptor has proposed two class CGRP receptors, CGRP 1And CGRP 2(TiPS 2000,21,432-438) for Juaneda, C. etc.Yet, lack CGRP 2(TiPS 2002,23,51-53) for Brain, S.D. etc. for the molecular Evidence of receptor.Described CGRP 1Receptor has three kinds of compositions: (i) 7 stride film calcitonin receptor-sample receptor (CRLR); (ii) single transmembrane receptor activity modifying protein type 1 (RAMP1); And (iii) intracellular receptor composition albumen (receptor component protein) (RCP) (Evans B.N. etc., J BiolChem.2000,275,31438-43).RAMP1 is delivered to plasma membrane with CRLR and makes part that necessary (Nature 1998,393,333-339) for McLatchie, L.M. etc. in conjunction with the CGRP-receptor.RCP be signal transduction necessary (Evans B.N. etc., J Biol Chem.2000,275,31438-43).There is kind-specificity difference in combining of known small molecules antagonist and CGRP-receptor, can be observed usually the human receptor to be compared the antagonism that other species have bigger affinity (TiPS 2002,23,51-53) for Brain, S.D. etc.The aminoacid sequence of RAMP1 has determined option of species, particularly the phenotype of amino acid residue Trp74 director receptoroid (Mallee etc., J Biol Chem 2002,277,14294-8).
In the pathophysiology disease of supposition to the CGRP receptor excessive activation appearance therein of the inhibitor on the CGRP acceptor levels is favourable.Some such symptoms comprise neurogenicity vasodilation, neurogenic inflammation, migraine, cluster headache and other headache, thermal burn, cyclical shock, climacteric flushing, and asthma.Relevant (the Edvinsson L.CNS Drugs2001 of CGRP receptor activation with pathogenesis of migraine; 15 (10): 745-53; Williamson, D.J.Microsc.Res.Tech.2001,53,167-178.; Grant, A.D.Brit.J.Pharmacol.2002,135,356-362).The serum levels of CGPR during migraine, raise (Goadsby PJ etc., Ann Neurol 1990; 28:183-7), with the normal level that after anti--migraine agent treatment the CGRP level is returned to conform to the alleviation of having a headache (Gallai V. etc., Cephalalgia 1995; 15:384-90).Compare with the collator, the migraineur shows basic CGRP level (Ashina M. etc., the Pain.2000 of rising; 86 (1-2): 133-8.2000).In the migraineur, intravenous infusion CGRP causes persistent headache (Lassen LH etc., Cephalalgia.2002 Feb; 22 (1): 54-61).The preclinical study report that in Canis familiaris L. and rat, carries out, can not change tranquillization systemic blood flow kinetics with described peptide antagonists CGRP (8-37) blocking-up general CGRP (systemic CGRP blockade), can not change partial blood flow (Shen, Y-T. etc., J Pharmacol Exp Ther2001,298,551-8).Therefore, the CGRP-receptor antagonist can be represented a kind of migrainous new Therapeutic Method that is used for, and this method has been avoided and non-selective 5-HT 1B/1DAgonist " triptan (triptans) " (for example sumatriptan) is relevant enlivens vasoconstrictive cardiovascular liability.
In the document known have Nerve in Migraine Model in the various bodies (see De Vries, P etc., Eur J Pharmacol1999,375,61-74).Some models adopt electricity irritation trigeminal ganglion, measure dilating effect .Cephalalgia 1997 17:518-24 such as (for example) Williamson of the intracranial vessel that innervates then.Because facial tremulous pulse also is subjected to trifacial domination, so the inductive facial blood flow change of trifacial activations institute of other scale-model investigation electricity irritation .Brain Res 1995 669:93 such as (for example) Escott.In addition, other peripheral nervous (for example, saphenous (saphenous)) and vascular bed (for example, the blood flow of abdominal part) (for example .Br J Pharmacol 1,993 110,772-6 such as Escott have also been studied; ).Shown that all models all can pass through with described peptide antagonists CGRP (8-37), a kind of fragments of peptides that lacks in first section 7 residue perhaps carries out pretreatment by a kind of micromolecule CGRP-receptor antagonist and blocks.In some cases, exogenous CGRP has been used as a kind of stimulus object.Yet, these models are invasive limit approach (invasive terminal procedures), when using the post processing of CGRP-receptor antagonist, all do not demonstrate the influence of the important clinically disruptive that reverses abundant arteriectasia of proving conclusively or blood flow increase..Cephalalgia such as Williamson 1997 17:518-24, with Williamson etc., Cephalalgia.1997 17:525-31: this method is included on the skull cranium window (cranial window) that bores a thin hole and set up a closure to observe dural tremulous pulse, in the rat of pentobarbital sodium anesthesia, the process of ' live body ' of operating limit, particularly intravenous CGRP is as a kind of stimulus object, to increase intracranial cerebral dura mater artery diameter.Its effect is blocked by carrying out pretreatment with i.v.CGRP (8-37)..Brain Res 1995 669:93 such as Escott; Particularly on the rat skull, hole, and use brain electrode that trigeminal ganglion is carried out electricity irritation, in rat, adopt limit approach (comprising neuromuscular blockade, tracheal intubation and artificial ventilation) then, the facial blood flow of Laser Measurement doppler cabinet with pentobarbital sodium anesthesia.This effect is blocked by carrying out pretreatment with CGRP (8-37).Escott etc., Br J Pharmacol 19931l0,772-6: particularly use intradermal injection (i.d.) CGRP as stimulus object, the blood flow of the rat abdomen skin of the animal of increase pentobarbital sodium (sodium pentobarb) anesthesia (be equipped with and insert jugular sleeve pipe) so that anesthesia and administration.This effect is blocked by carrying out pretreatment with i.v.CGRP (8-37).Chu etc., Neurosci Lett 2,001 310,169-72 use particularly i.d.CGRP as stimulus object, adopt limit approach, use the animal of pentobarbital sodium anesthesia and tracheal intubation, the variation of measuring the laser-Doppler chamber blood flow of rat back skin; And show by the osmotic pumps of implanting from subcutaneous (s.c.) and discharge CGRP (8-37) pretreatment blocking-up continuously.Br J Pharmacol 1,995 114 such as Hall, Br such as 592-7 and Hall J Pharmacol 1,999 126, the local especially CGRP that uses of 280-4, to increase the arteriolar diameter of hamster cheek pouch, and use i.d.CGRP, with the blood flow of increase with the rat dorsal part skin of the animal (be equipped with and insert jugular sleeve pipe) of increase pentobarbital sodium anesthesia so that anesthesia and administration.This effect is blocked by carrying out pretreatment with i.v.CGRP (8-37)..Br J Pharmacol.2000 Feb such as Doods; 129 (3): 420-3 particularly holes on the skull of Adeps seu carnis Rhiopithecus roxellanae (new ape and monkey (new world monkey)), use brain electrode that trigeminal ganglion is produced electricity irritation then, and in the primate of pentobarbital sodium anesthesia, adopt invasive limit approach (comprising neuromuscular and artificial ventilation), measure facial blood flow.The increase of blood flow is blocked by the pretreatment of micromolecule CGRP antagonist.Also see WO 03/272252Isolated DNA Molecules Encoding Humanized Calcitonin Gene-Related PeptideReceptor, Related Non-Human Transgenis Animals and Assay Methods (dna molecular of separated coding hCGRP's receptor, relevant non--people transgenic animal and analytical method).Therefore, method of operating of the present invention, particularly in the non--invasive survival model in primate, measure the change of the inductive facial blood flow of exogenous CGRP-and confirm peptide and micromolecule CGRP antagonist sucks the pre-treatment and the post processing effect of the Adeps seu carnis Rhiopithecus roxellanae (it can recover clear-headed from operation, this provides important advantage) of isoflurane anesthesia to spontaneity.
Reported recently a large amount of non--the peptide class, micromolecule CGRP-receptor antagonist.WO 97/09046 and equivalent thereof disclose the particularly quinine chemical compound relevant with chinidine, and they are the part of CGRP-receptor, particularly antagonist.WO 98/09630 and WO 98/56779 and equivalent disclose the nitrobenzamide chemical compound as the various replacements of CGRP-receptor antagonist especially.WO 01/32649, WO 01/49676 disclose a series of as the 4-oxo butyramide of CGRP-receptor antagonist and relevant cyclopropane derivative with WO 01/32648 and equivalent especially.WO 00/18764, WO 98/11128 and WO 00/55154 and equivalent disclose the benzimidazoline phenylpiperidines as the CGRP-receptor antagonist especially.WO 99/52875 and WO 01/25228 and equivalent disclose irrelevant a series of somatostatin antagonists with CGRP.Also with reference to US 6,344,449, US 6,313,097, US 6,521,609, US 6,552,043, US 20030181462, US 20030191068 and WO 03/076432 and equivalent.Therefore, the novel C GRP-receptor antagonist of effectively treating neurogenic inflammation, migraine and other disease will be very useful.
Summary of the invention
Therefore first embodiment according to a first aspect of the invention provides formula (I) chemical compound and pharmaceutically acceptable salt and solvate,
Wherein
V is-N (R 1) (R 2) or OR 4
R 4Be H, C 1-6Alkyl, C 1-4Haloalkyl or (C 1-4Alkylene) 0-1R 4 '
R 4 'Be C 3-7Cycloalkyl, phenyl, adamantyl (adamantly), quininuclidinyl (quinuclidyl), azabicyclic (azabicyclo) [2.2.1] heptyl, azetidinyl, tetrahydrofuran base, furyl (furanyl), dioxolanyl (dioxolanyl), thienyl, tetrahydro-thienyl, pyrrole radicals, pyrrolinyl, pyrrolidinyl, imidazole radicals, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl,  azoles base, different  azoles base, thiazolyl, isothiazolyl, the  di azoly, thiadiazolyl group (thiadiazolyl), triazolyl, pyranose, pyridine radicals, pyrimidine radicals, pyrazinyl, pyridazinyl, triazine radical, piperidyl, piperazinyl, morpholino, tetrahydro-1,4-thiazine generation (thiomorpholino) or dioxolanyl; With
R 4 'Optional be selected from 1 or 2 following identical or different substituent group and replaced: halogen, cyano group, C 1-4Alkyl, C 1-4Haloalkyl, C 1-4Alkoxyl, hydroxyl, amino, C 3-7Cycloalkyl, C 1-3Alkyl amino, C 1-3Dialkyl amido, (C 1-3Alkyl) 0-2Urea groups, phenyl and benzyl; With
R 4 'Choose wantonly and contain 1 or 2 carbonyl, the carbon atom of wherein said carbonyl is R 4 'The member of ring structure;
R 1And R 2Be L independently of one another 1, L wherein 1Be selected from: H, C 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl ,-C 1-6Alkylene-amino (C 1-3Alkyl) 2, C 3-7Cycloalkyl, phenyl, azetidinyl, adamantyl, tetrahydrofuran base, furyl, dioxolanyl, thienyl, tetrahydro-thienyl, pyrrole radicals, pyrrolinyl, pyrrolidinyl, imidazole radicals, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl,  azoles base, different  azoles base, thiazolyl, isothiazolyl, the  di azoly, thiadiazolyl group, triazolyl, pyranose, pyridine radicals, pyrimidine radicals, pyrazinyl, pyridazinyl, triazine radical, piperidyl, piperazinyl, morpholino, tetrahydro-1,4-thiazine generation and dioxolanyl; With
R 1And R 2Choose wantonly separately and be selected from 1 or 2 following identical or different substituent group independently and replace: halogen, cyano group, C 1-4Alkyl, C 1-4Haloalkyl, C 1-4Alkoxyl, hydroxyl, amino, C 3-7Cycloalkyl, C 1-3Alkyl amino, C 1-3Dialkyl amido, (C 1-3Alkyl) 0-2Urea groups, phenyl and benzyl;
R 1And R 2Choose wantonly also and contain 1 or 2 carbonyl independently, the carbon atom of wherein said carbonyl is to comprise R 1And R 2Heterocyclic member;
L wherein 1Optional also independently by L 2The nitrogen that connects interrupts, wherein L 2Be C independently 1-3Alkylene or C 1-3Alkylidene; Or
R 1And R 2The nitrogen that connects with them forms X,
Wherein X is azetidinyl, pyrrole radicals, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, azepine  base (azepinyl), diaza  base, piperazinyl, piperidyl, morpholino or tetrahydro-1,4-thiazine generation;
Wherein X is optional is replaced by Y, and wherein Y is dioxolanyl, C 1-9Alkyl, C 2-9Alkenyl, C 2-9Alkynyl, C 1-4Alkyl amino, C 1-4Dialkyl amido, C 1-4Alkoxyl, C 3-7Cycloalkyl, phenyl, azetidinyl, furyl, thienyl, pyrrole radicals, pyrrolinyl, pyrrolidinyl, pyrrolidone-base (pyrrolidinonyl), imidazole radicals, imidazolinyl, imidazolidinyl, imidazolidinonyl (imidazolidinonyl), pyrazolyl, pyrazolinyl, pyrazolidinyl, azepine  base, diaza  base, pyridine radicals, pyrimidine radicals, dihydrobenzo imidazoline ketone group (benzimidazolonyl), piperazinyl, piperidyl, morpholino, benzothiazolyl, benzisothiazole base or tetrahydro-1,4-thiazine generation;
And X and Y are optional to be interrupted by Z, wherein Z be-NHC (O) O-,-NHC (O) NH-, NC (O) NH 2,-NH-,-C 1-3Alkylene-,-C 1-3Alkylene-,-C 1-3Alkylene (alkenylene)-NHC (O) O-C 1-3Alkylene-; And
X and Y choose wantonly and are selected from 1 or 2 following identical or different substituent group independently and replace: C 1-4Alkyl, amino, C 1-3Alkyl amino ,-C 1-6Alkylene-amino (C 1-3Alkyl) 2, (C 1-3Alkyl) 0-2Urea groups, phenyl and benzyl;
X and Y are optional and contain 1 or 2 carbonyl independently, and the carbon atom of wherein said carbonyl is the heterocyclic member of containing X and Y;
Condition is if X is replaced by Y, and if X and Y be not interrupted by Z, then X and Y are optional shares a carbon atom, and forms the volution part together;
Q is Q ' or Q ";
Wherein Q ' is (S y) sR 3And
Q " is NH (S y) sR 3, NHC (O) (S y) sR 3, NHC (O) O (S y) sR 3, NHC (O) NH (S y) sR 3, O (S y) sR 3, (S y) sNHR 3, (S y) sNHC (O) R 3, (S y) sNHC (O) OR 3, (S y) sNHC (O) NHR 3Or (S y) sOR 3
S wherein yBe C 1-3Alkylene or C 1-3Alkylidene, and s is 0 or 1;
U is CH 2Or NH;
Condition is if Q is Q ", U is CH so 2
R 3Be R 3aOr R 3b
R wherein 3aFor
(i) has the heterocycle that two fused rings and described ring contain 5-7 member separately, described heterocycle contains 1-5 identical or different hetero atom that is selected from O, N and S, and described heterocycle is optional to contain 1 or 2 carbonyl, and the carbon atom of wherein said carbonyl is the member of described fused rings;
(ii) contain 1-3 identical or different heteroatomic 4-6 element heterocycle that is selected from O, N and S, described heterocycle is optional to contain 1-2 carbonyl, and the carbon atom of wherein said carbonyl is the member of described 4-6 element heterocycle;
(iii) C 3-7Cycloalkyl;
(iv) carbazyl, fluorenyl, phenyl ,-the O-phenyl ,-O-C 1-4Alkylene-phenyl or naphthyl; Or
(v) C 1-8Alkyl, C 2-7Alkenyl ,-C (O) R 3 ', CHC (O) O-R 3 ', CH (CH 3) C (O) O-R 3 ',-C (O) O-R 3 'Or C 2-7Alkynyl; And
R wherein 3aOptional be selected from following 1-3 identical or different substituent group and replaced: benzyl, phenyl ,-the O-phenyl ,-O-C 1-3The alkylene phenyl ,-C 1-3Alkylene-OC (O)-phenyl, cyano group, amino, nitro, halogen, C 1-6Alkyl, C 1-3List-two-three-haloalkyl, C 1-3List-two-three-halogenated alkoxy, (C 1-3Alkyl) 1-2Amine ,-OR 3 ',-C (O) R 3 ',-C (O) O-R 3 ',-O-C (O) R 3 ',-N (R 3 ') 2,-C (O) N (R 3 ') 2,-N (R 3 ') C (O) (R 3 ') 2,-N (R 3 ') C (O) N (R 3 ') 2,-N (R 3 ') C (O) OR 3 ',-O-C (O) N (R 3 ') 2,-N (R 3 ') SO 2R 3 ',-SO 2N (R 3 ') 2With-SO 2R 3 '
R 3 'For H or-C 1-6Alkyl;
Condition is if R 3aFor-C (O) R 3 ', CHC (O) O-R 3 ', CH (CH 3) C (O) O-R 3 'Or-C (O) O-R 3 ', so described-C (O) R 3 ', CHC (O) O-R 3 ', CH (CH 3) C (O) O-R 3 'Or-C (O) O-R 3 'For unsubstituted;
R 3bBe R 3aBut not phenyl, 1-naphthyl, 2-naphthyl, 1,2,3,4-tetrahydrochysene-1-naphthyl, 1H-indol-3-yl, 1-Methyl-1H-indole-3-base, 1-formoxyl-1H-indol-3-yl, 1-(1,1-dimethyl ethoxy carbonyl)-1H-indol-3-yl, 4-imidazole radicals, 1-methyl-4-imidazole radicals, 2-thienyl, 3-thienyl, thiazolyl, 1H-indazole-3-base, 1-methyl isophthalic acid H-indazole-3-base, benzo [b] furan-3-base, benzo [b] thiene-3-yl-, pyridine radicals, quinolyl or isoquinolyl; Choose wantonly on carbon skeleton by fluorine, chlorine or bromine atom or be selected from following groups single-, two-or three replacements: the alkyl of side chain or straight chain, C 3-8-cycloalkyl, phenylalkyl, alkenyl, alkoxyl, phenyl, the phenyl alkoxyl, trifluoromethyl, alkoxy carbonyl alkyl, carboxyalkyl, alkoxy carbonyl, carboxyl, dialkyl aminoalkyl, the dialkyl amido alkoxyl, hydroxyl, nitro, amino, acetyl-amino, propiono amino, benzoyl, benzoyl-amido, the benzoyl methylamino, mesyl oxygen base, amino carbonyl, alkyl amino-carbonyl, dialkyl amino carbonyl, alkanoyl, cyano group, tetrazole radical, phenyl, pyridine radicals, thiazolyl, furyl, trifluoromethoxy, trifluoromethylthio, the trifluoromethyl sulphinyl base-or trifyl;
Wherein said substituent group can be identical or different, and above-mentioned benzoyl, benzoyl-amido-and the benzoyl methylamino can further be replaced by fluorine, chlorine or bromine atom successively at phenyl moiety, or further replaced by alkyl, trifluoromethyl, amino or acetyl-amino;
D is O, NCN or NSO 2C 1-3Alkyl;
A is C, N or CH;
M and n are 0,1 or 2 independently;
Condition is
If m and n are 0, then A is not N;
If m is 2, then n is not 2; Or
If n is 2, then m is not 2;
E is N, CH or C;
P is 0 or 1;
If p is 1, then G, J and E form A together xOr A y
A xContain 5-7 member's annelated heterocycles separately for having two fused rings and described ring, described heterocycle contains 1-4 identical or different hetero atom that is selected from O, N and S; And choose wantonly and contain 1 or 2 carbonyl, the carbon atom of wherein said carbonyl is the member of described annelated heterocycles;
A yFor containing 1-3 heteroatomic 4-6 element heterocycle that is selected from O, N and S; And described heterocycle is optional to contain 1-2 carbonyl, and the carbon atom of wherein said carbonyl is the member of described 4-6 element heterocycle;
A wherein xAnd A yOptional be selected from following group and replaced: C 1-4Alkyl, C 1-4Alkoxyl, C 1-4Haloalkyl, cyano group, C 3-7Cycloalkyl, phenyl, halogenophenyl, halogen, furyl, pyrrole radicals, pyrrolinyl, pyrrolidinyl, imidazole radicals, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, pyridine radicals, pyrimidine radicals, piperidyl, piperazinyl or morpholino; Or
If p 0 makes G link to each other with A separately with J, then A is C, and G, J and A form the volution ring system with the described ring that contains A together, and wherein G, J and A are GJA ' or GJA together ";
Wherein
GJA ' is A xOr A yWith
GJA " is A xOr A y
Condition is
A xNot 1,3-diaza-condensed heterocycle; With
A yNot 1,3-diaza-heterocycle;
And further condition is
If Q is Q ", R then 3Be R 3aWith
If Q be Q ' then
R 3Be R 3bOr
R 3Be R 3a, p be 0 and G, J and A form GJA together ".
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, and wherein Q is Q ' and R 3Be R 3b
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, and wherein Q is Q ', R 3Be R 3aAnd p is 0, makes G, J and A form GJA together ".
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, and wherein Q is that Q ' and Q ' are (S y) sR 3And s is 0.
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, and wherein Q is that Q ' and Q ' are (S y) sR 3, S yBe C 1-3Alkylene and s are 1.
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, and wherein Q is that Q ' and Q ' are (S y) sR 3, S yBe C 1-3Alkylidene and s are 1.
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, and wherein Q is that Q ' and U are CH 2
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, and wherein Q is Q ', and Q ' is (S y) sR 3, s be 0 and U be CH 2
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, and wherein Q is Q ', and Q ' is (S y) sR 3, S yBe C 1-3Alkylene, s be 1 and U be CH 2
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, and wherein Q is Q ', and Q ' is (S y) sR 3, S yBe C 1-3Alkylidene, s be 1 and U be CH 2
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, and wherein Q is that Q ' and U are NH.
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, and wherein Q is Q ', and Q ' is (S y) sR 3, s be 0 and U be NH.
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, and wherein Q is Q ', and Q ' is (S y) sR 3, S yBe C 1-3Alkylene, s be 1 and U be NH.
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, and wherein Q is Q ', and Q ' is (S y) sR 3, S yBe C 1-3Alkylidene, s be 1 and U be NH.
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, and wherein Q is Q ".
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, and wherein Q is that Q " and Q " is NH (S y) sR 3
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, and wherein Q is that Q " and Q " is NH (S y) sR 3And s is 0.
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, and wherein Q is that Q " and Q " is NH (S y) sR 3, S yBe C 1-3Alkylene and s are 1.
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, and wherein Q is that Q " and Q " is NH (S y) sR 3, S yBe C 1-3Alkylidene and s are 1.
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, and wherein Q is that Q " and Q " is NHC (O) (S y) sR 3
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, and wherein Q is that Q " and Q " is NHC (O) (S y) sR 3And s is 0.
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, and wherein Q is that Q " and Q " is NHC (O) (S y) sR 3, S yBe C 1-3Alkylene and s are 1.
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, and wherein Q is that Q " and Q " is NHC (O) (S y) sR 3, S yBe C 1-3Alkylidene and s are 1.
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, and wherein Q is that Q " and Q " is NHC (O) O (S y) sR 3
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, and wherein Q is that Q " and Q " is NHC (O) O (S y) sR 3And s is 0.
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, and wherein Q is that Q " and Q " is NHC (O) O (S y) sR 3, S yBe C 1-3Alkylene and s are 1.
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, and wherein Q is that Q " and Q " is NHC (O) O (S y) sR 3, S yBe C 1-3Alkylidene and s are 1.
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, and wherein Q is that Q " and Q " is NHC (O) NH (S y) sR 3
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, and wherein Q is that Q " and Q " is NHC (O) NH (S y) sR 3And s is 0.
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, and wherein Q is that Q " and Q " is NHC (O) NH (S y) sR 3, S yBe C 1-3Alkylene and s are 1.
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, and wherein Q is that Q " and Q " is NHC (O) NH (S y) sR 3, S yBe C 1-3Alkylidene and s are 1.
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, and wherein V is OR 4
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, and wherein V is OR 4And R 4Be C 1-6Alkyl.
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, and wherein V is-N (R 1) (R 2).
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, wherein
V is-N (R 1) (R 2) or OR 4
R 4Be H, C 1-6Alkyl, C 1-4Haloalkyl, (C 1-4Alkylene) 0-1R 4 '
R 4 'Be C 3-7Cycloalkyl, phenyl, adamantyl, quininuclidinyl, azabicyclic [2.2.1] heptyl, azetidinyl, tetrahydrofuran base, furyl, dioxolanyl, thienyl, tetrahydro-thienyl, pyrrole radicals, pyrrolinyl, pyrrolidinyl, imidazole radicals, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl,  azoles base, different  azoles base, thiazolyl, isothiazolyl, the  di azoly, thiadiazolyl group, triazolyl, pyranose, pyridine radicals, pyrimidine radicals, pyrazinyl, pyridazinyl, triazine radical, piperidyl, piperazinyl, morpholino, tetrahydro-1,4-thiazine generation or dioxolanyl; With
R 4 'Optional be selected from 1 or 2 following identical or different substituent group and replaced: halogen, cyano group, C 1-4Alkyl, C 1-4Haloalkyl, C 1-4Alkoxyl, hydroxyl, amino, C 3-7Cycloalkyl, C 1-3Alkyl amino, C 1-3Dialkyl amido, (C 1-3Alkyl) 0-2Urea groups, phenyl and benzyl;
R 4 'Choose wantonly and contain 1 or 2 carbonyl, the carbon atom of wherein said carbonyl is R 4 'The member of ring structure;
R 1And R 2Be L independently of one another 1, L wherein 1Be selected from: H, C 1-6Alkyl ,-C 1-6Alkylene-amino (C 1-3Alkyl) 2, C 3-7Cycloalkyl, phenyl, adamantyl, azetidinyl, tetrahydrofuran base, furyl, dioxolanyl, thienyl, tetrahydro-thienyl, pyrrole radicals, pyrrolinyl, pyrrolidinyl, imidazole radicals, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl,  azoles base, different  azoles base, thiazolyl, isothiazolyl, the  di azoly, thiadiazolyl group, triazolyl, pyranose, pyridine radicals, pyrimidine radicals, pyrazinyl, pyridazinyl, triazine radical, piperidyl, piperazinyl, morpholino, tetrahydro-1,4-thiazine generation and dioxolanyl; And
R 1And R 2Choose wantonly separately and be selected from 1 or 2 following identical or different substituent group independently and replace: halogen, cyano group, C 1-4Alkyl, C 1-4Haloalkyl, C 1-4Alkoxyl, hydroxyl, amino, C 3-7Cycloalkyl, C 1-3Alkyl amino, C 1-3Dialkyl amido, (C 1-3Alkyl) 0-2Urea groups, phenyl and benzyl;
R 1And R 2Choose wantonly also and contain 1 or 2 carbonyl independently, the carbon atom of wherein said carbonyl is for comprising R 1And R 2Heterocyclic member;
L wherein 1Optional by L 2The nitrogen that connects interrupts, wherein L 2Be C 1-3Alkylene; Or
R 1And R 2The nitrogen that connects with their forms X, and wherein X is azetidinyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, azepine  base, diaza  base, piperazinyl, piperidyl, morpholino or tetrahydro-1,4-thiazine generation;
Wherein X is optional is replaced by Y, and wherein Y is dioxolanyl, C 1-4Alkyl, C 1-4Alkyl amino, C 1-4Dialkyl amido, C 1-4Alkoxyl, C 3-7Cycloalkyl, phenyl, azetidinyl, pyrrole radicals, pyrrolinyl, pyrrolidinyl, pyrrolidone-base, imidazole radicals, imidazolinyl, imidazolidinyl, imidazolidinonyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, azepine  base, diaza  base, pyridine radicals, pyrimidine radicals, dihydrobenzo imidazoline ketone group, piperazinyl, piperidyl, morpholino, benzothiazolyl, benzisothiazole base or tetrahydro-1,4-thiazine generation;
Wherein X and Y
Optional be interrupted by Z, wherein Z be-NHC (O) O-,-NHC (O) NH-, NC (O) NH 2,-NH-,-C 1-3Alkylene-,-C 1-3Alkylene-NHC (O) O-C 1-3Alkylene-; And
Choose wantonly and be selected from 1 or 2 following identical or different substituent group independently and replace: C 1-4Alkyl, amino, C 1-3Alkyl amino ,-C 1-6Alkylene-amino (C 1-3Alkyl) 2, (C 1-3Alkyl) 0-2Urea groups, phenyl and benzyl;
X and Y are optional and contain 1 or 2 carbonyl independently, and the carbon atom of wherein said carbonyl is the heterocyclic member who comprises X and Y;
Condition is if X is replaced by Y, and if X and Y be not interrupted by Z, then X and Y are optional shares a carbon atom, and forms the volution part together.
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, wherein R 4Be H, C 1-6Alkyl, C 1-4Haloalkyl or (C 1-4Alkylene) 0-1R 4 'R 4 'Be C 3-7Cycloalkyl, phenyl, adamantyl, quininuclidinyl, azabicyclic [2.2.1] heptyl, azetidinyl, tetrahydrofuran base, furyl, dioxolanyl, thienyl, tetrahydro-thienyl, pyrrole radicals, pyrrolinyl, pyrrolidinyl, imidazole radicals, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl,  azoles base, different  azoles base, thiazolyl, isothiazolyl, the  di azoly, thiadiazolyl group, triazolyl, pyranose, pyridine radicals, pyrimidine radicals, pyrazinyl, pyridazinyl, triazine radical, piperidyl, piperazinyl, morpholino, tetrahydro-1,4-thiazine generation or dioxolanyl; And R 4 'Optional be selected from 1 or 2 following identical or different substituent group and replaced: halogen, cyano group, C 1-4Alkyl, C 1-4Haloalkyl, C 1-4Alkoxyl, hydroxyl, amino, C 3-7Cycloalkyl, C 1-3Alkyl amino, C 1-3Dialkyl amido, (C 1-3Alkyl) 0-2Urea groups, phenyl and benzyl.
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, wherein R 4Be H, C 1-6Alkyl, C 1-4Haloalkyl or (C 1-4Alkylene) 0-1R 4 'R 4 'Be C 3-7Cycloalkyl, phenyl, adamantyl, quininuclidinyl, azabicyclic [2.2.1] heptyl, azetidinyl, tetrahydrofuran base, furyl, dioxolanyl, thienyl, tetrahydro-thienyl, pyrrole radicals, pyrrolinyl, pyrrolidinyl, imidazole radicals, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl,  azoles base, different  azoles base, thiazolyl, isothiazolyl, the  di azoly, thiadiazolyl group, triazolyl, pyranose, pyridine radicals, pyrimidine radicals, pyrazinyl, pyridazinyl, triazine radical, piperidyl, piperazinyl, morpholino, tetrahydro-1,4-thiazine generation or dioxolanyl.
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, wherein R 4Be H, C 1-6Alkyl or (C 1-4Alkylene) 0-1R 4 'R 4 'Be C 3-7Cycloalkyl.
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, and wherein V is-N (R 1) (R 2) and
R 1And R 2Be L independently of one another 1, L wherein 1Be selected from: H, C 1-6Alkyl ,-C 1-6Alkylene-amino (C 1-3Alkyl) 2, C 3-7Cycloalkyl, phenyl, azetidinyl, adamantyl, tetrahydrofuran base, furyl, dioxolanyl, thienyl, tetrahydro-thienyl, pyrrole radicals, pyrrolinyl, pyrrolidinyl, imidazole radicals, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl,  azoles base, different  azoles base, thiazolyl, isothiazolyl, the  di azoly, thiadiazolyl group, triazolyl, pyranose, pyridine radicals, pyrimidine radicals, pyrazinyl, pyridazinyl, triazine radical, piperidyl, piperazinyl, morpholino, tetrahydro-1,4-thiazine generation and dioxolanyl; Or
R 1And R 2The nitrogen that connects with their forms X, and wherein X is azetidinyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, azepine  base, diaza  base, piperazinyl, piperidyl, morpholino or tetrahydro-1,4-thiazine generation; Wherein X is replaced by Y, and wherein Y is dioxolanyl, C 1-4Alkyl, C 1-4Alkoxyl, C 3-7Cycloalkyl, phenyl, azetidinyl, pyrrole radicals, pyrrolinyl, pyrrolidinyl, pyrrolidone-base, imidazole radicals, imidazolinyl, imidazolidinyl, imidazolidinonyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, azepine  base, diaza  base, pyridine radicals, pyrimidine radicals, dihydrobenzo imidazoline ketone group, piperazinyl, piperidyl, morpholino, benzothiazolyl, benzisothiazole base or tetrahydro-1,4-thiazine generation;
Wherein X and Y are optional shares a carbon atom, and forms the volution part together.
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, and wherein V is-N (R 1) (R 2), and
R 1And R 2Be L independently of one another 1, L wherein 1Be selected from: H, C 1-6Alkyl, or
R 1And R 2The nitrogen that connects with them forms X,
Wherein X is piperidyl or morpholino;
Wherein X is replaced by Y, and wherein Y is dioxolanyl, C 1-4Alkyl or piperidyl;
Wherein X and Y are optional shares a carbon atom, and forms the volution part together.
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, and wherein V is-N (R 1) (R 2), and R wherein 1And R 2Be L independently of one another 1, L wherein 1Be selected from: H, C 1-6Alkyl.
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, and wherein V is-N (R 1) (R 2), and R wherein 1And R 2The nitrogen that connects with them forms X, and wherein X is piperidyl or morpholino; Wherein X is replaced by Y, and wherein Y is dioxolanyl, C 1-4Alkyl or piperidyl; And wherein X and Y are optional shares a carbon atom, and forms the volution part together.
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, and wherein V is-N (R 1) (R 2), and R wherein 1And R 2The nitrogen that connects with them forms X, and wherein X is a piperidyl; Wherein X is replaced by Y, and wherein Y is a piperidyl.
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, and wherein V is-N (R 1) (R 2), and R wherein 1And R 2The nitrogen that connects with them forms X, and wherein X is a morpholino; Wherein X is replaced by Y, and wherein Y is C 1-4Alkyl.
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, and wherein V is-N (R 1) (R 2), and R wherein 1And R 2The nitrogen that connects with them forms X, and wherein X is a piperidyl; Wherein X is replaced by Y, and wherein Y is C 1-4Alkyl.
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, and wherein V is-N (R 1) (R 2), and R wherein 1And R 2The nitrogen that connects with them forms X, and wherein X is a piperidyl; Wherein X is replaced by Y, and wherein Y is a dioxolanyl; And wherein X and Y share a carbon atom, and form the volution part together.
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, and wherein X and Y are not interrupted by Z.
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, and wherein X and Y are not interrupted by Z; And X and Y share a carbon atom, and form the volution part together.
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, wherein R 3Be R 3a
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, wherein R 3Be R 3b
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, wherein R 3aContain 5-7 member's heterocycle separately for having two fused rings and described ring, described heterocycle contains 1-5 identical or different hetero atom that is selected from O, N and S.
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, wherein R 3aContain 5-7 member's heterocycle separately for having two fused rings and described ring, described heterocycle contains 1-5 identical or different hetero atom that is selected from O, N and S, and described heterocycle is optional to contain 1 or 2 carbonyl, and the carbon atom of wherein said carbonyl is the member of described fused rings.
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, wherein R 3aContain 5-7 member's heterocycle separately for having two fused rings and described ring, described heterocycle contains 1-5 identical or different hetero atom that is selected from O, N and S, and described heterocycle is optional to contain 1 or 2 carbonyl, and the carbon atom of wherein said carbonyl is the member of described fused rings; R wherein 3aOptional be selected from following 1-3 identical or different substituent group and replaced: benzyl, phenyl ,-the O-phenyl ,-O-C 1-3Alkyl phenyl ,-C 1-3Alkylene-OC (O)-phenyl, cyano group, amino, nitro, halogen, C 1-3List-two-three-haloalkyl, C 1-3List-two-three-halogenated alkoxy, C 1-6Alkoxyl, (C 1-3Alkyl) 1-2Amine ,-OR 3 ',-C (O) R 3 ',-C (O) O-R 3 ',-O-C (O) R 3 ',-N (R 3 ') 2,-C (O) N (R 3 ') 2,-N (R 3 ') C (O) (R 3 ') 2,-N (R 3 ') C (O) N (R 3 ') 2,-N (R 3 ') C (O) OR 3 ',-O-C (O) N (R 3 ') 2,-N (R 3 ') SO 2R 3 ',-SO 2N (R 3 ') 2With-SO 2R 3 'R 3 'For H or-C 1-6Alkyl.
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, wherein R 3aFor containing 1-3 identical or different heteroatomic 4-6 element heterocycle that is selected from O, N and S.
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, wherein R 3aFor containing the identical or different heteroatomic 4-6 element heterocycle that 1-3 is selected from O, N and S, and optionally contain 1-2 carbonyl, the carbon atom of wherein said carbonyl is the member of described 4-6 element heterocycle.
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, wherein R 3aFor containing the identical or different heteroatomic 4-6 element heterocycle that 1-3 is selected from O, N and S, and optionally contain 1-2 carbonyl, the carbon atom of wherein said carbonyl is the member of described 4-6 element heterocycle; R wherein 3aOptional be selected from following 1-3 identical or different substituent group and replaced: benzyl, phenyl ,-the O-phenyl ,-O-C 1-3Alkyl phenyl ,-C 1-3Alkylene-OC (O)-phenyl, cyano group, amino, nitro, halogen, C 1-3List-two-three-haloalkyl, C 1-3List-two-three-halogenated alkoxy, C 1-6Alkoxyl, (C 1-3Alkyl) 1-2Amine ,-OR 3 ',-C (O) R 3 ',-C (O) O-R 3 ',-O-C (O) R 3 ',-N (R 3 ') 2,-C (O) N (R 3 ') 2,-N (R 3 ') C (O) (R 3 ') 2,-N (R 3 ') C (O) N (R 3 ') 2,-N (R 3 ') C (O) OR 3 ',-O-C (O) N (R 3 ') 2,-N (R 3 ') SO 2R 3 ',-SO 2N (R 3 ') 2With-SO 2R 3 'R 3 'For H or-C 1-6Alkyl.
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, wherein R 3aBe C 3-7Cycloalkyl.
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, wherein R 3aBe C 3-7Cycloalkyl; R wherein 3aOptional be selected from following 1-3 identical or different substituent group and replaced: benzyl, phenyl ,-the O-phenyl ,-O-C 1-3Alkyl phenyl ,-C 1-3Alkylene-OC (O)-phenyl, cyano group, amino, nitro, halogen, C 1-3List-two-three-haloalkyl, C 1-3List-two-three-halogenated alkoxy, C 1-6Alkoxyl, (C 1-3Alkyl) 1-2Amine ,-OR 3 ',-C (O) R 3 ',-C (O) O-R 3 ',-O-C (O) R 3 ',-N (R 3 ') 2,-C (O) N (R 3 ') 2,-N (R 3 ') C (O) (R 3 ') 2,-N (R 3 ') C (O) N (R 3 ') 2,-N (R 3 ') C (O) OR 3 ',-O-C (O) N (R 3 ') 2,-N (R 3 ') SO 2R 3 ',-SO 2N (R 3 ') 2With-SO 2R 3 'R 3 'For H or-C 1-6Alkyl.
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, wherein R 3aFor carbazyl, fluorenyl, phenyl ,-the O-phenyl ,-O-C 1-4Alkylene (alklylene)-phenyl or naphthyl.
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, wherein R 3aFor carbazyl, fluorenyl, phenyl ,-the O-phenyl ,-O-C 1-4Alkylene (alklylene)-phenyl or naphthyl; R wherein 3aOptional be selected from following 1-3 identical or different substituent group and replaced: benzyl, phenyl ,-the O-phenyl ,-O-C 1-3Alkyl phenyl ,-C 1-3Alkylene-OC (O)-phenyl, cyano group, amino, nitro, halogen, C 1-3List-two-three-haloalkyl, C 1-3List-two-three-halogenated alkoxy, C 1-6Alkoxyl, (C 1-3Alkyl) 1-2Amine ,-OR 3 ',-C (O) R 3 ',-C (O) O-R 3 ',-O-C (O) R 3 ',-N (R 3 ') 2,-C (O) N (R 3 ') 2,-N (R 3 ') C (O) (R 3 ') 2,-N (R 3 ') C (O) N (R 3 ') 2,-N (R 3 ') C (O) OR 3 ',-O-C (O) N (R 3 ') 2,-N (R 3 ') SO 2R 3 ',-SO 2N (R 3 ') 2With-SO 2R 3 'R 3 'For H or-C 1-6Alkyl.
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, wherein R 3aBe C 1-8Alkyl, C 2-7Alkenyl ,-C (O) R 3 ',-C (O) O-R 3 'Or C 2-7Alkynyl.
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, wherein R 3aBe C 1-8Alkyl, C 2-7Alkenyl ,-C (O) R 3 ',-C (O) O-R 3 'Or C 2-7Alkynyl; R wherein 3aOptional be selected from following 1-3 identical or different substituent group and replaced: benzyl, phenyl ,-the O-phenyl ,-O-C 1-3Alkyl phenyl ,-C 1-3Alkylene-OC (O)-phenyl, cyano group, amino, nitro, halogen, C 1-3List-two-three-haloalkyl, C 1-3List-two-three-halogenated alkoxy, C 1-6Alkoxyl, (C 1-3Alkyl) 1-2Amine ,-OR 3 ',-C (O) R 3 ',-C (O) O-R 3 ',-O-C (O) R 3 ',-N (R 3 ') 2,-C (O) N (R 3 ') 2,-N (R 3 ') C (O) (R 3 ') 2,-N (R 3 ') C (O) N (R 3 ') 2,-N (R 3 ') C (O) OR 3 ',-O-C (O) N (R 3 ') 2,-N (R 3 ') SO 2R 3 ',-SO 2N (R 3 ') 2With-SO 2R 3 'R 3 'For H or-C 1-6Alkyl; Condition is if R 3aFor-C (O) R 3 ', CHC (O) O-R 3 ', CH (CH 3) C (O) O-R 3 'Or-C (O) O-R 3 ', then described-C (O) R 3 ', CHC (O) O-R 3 ', CH (CH 3) C (O) O-R 3 'Or-C (O) O-R 3 'For unsubstituted.
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, wherein R 3Be R 3a, and R 3aBe phenyl, hydroxy phenyl, azetidinyl, naphthyl, C 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl, dihydroquinoline ketone group (quinolinonyl), the hydrogenated quinoline ketone group, quinolyl, the dihydro-isoquinoline ketone group, the hydrogenated isoquinoline ketone group, isoquinolyl, dihydroquinazoline ketone group (quinazolinonyl), the hydrogenated quinazolines ketone group, quinazolyl, dihydro-quinoxaline ketone group (quinoxalinonyl), hydrogenation quinoxaline ketone group, quinoxalinyl, benzimidazolyl, indazolyl, dihydrobenzo imidazoline ketone group, hydrogenated benzimidazoles ketone group (hydrobenzimidazolonyl), the benzimidazoline base, dihydro-benzothiazole ketone group (benzthiazolonyl), hydrogenation benzothiazolone base, benzothiazolyl, dihydrobenzo  azoles base, the benzotriazole base, dihydrobenzo thiophene ketone group (benzothiophenonyl), hydrogenation of benzene bithiophene ketone group, benzothienyl, the Dihydrobenzofuranes ketone group, hydrogenation benzo furanonyl, benzofuranyl, the benzo dioxolanyl, the indoline ketone group, the hydrogenated indoles ketone group, indyl, the indolizine base, isoindolyl, indolinyl, indazolyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, furyl, thienyl, pyrrole radicals, pyrrolinyl, pyrrolidinyl, imidazole radicals, imidazolinyl, imidazolidinyl, pyridine radicals, purine radicals, carbazyl, pyrimidine radicals, piperidyl, triazolopyrimidinyl, tetrahydro-pyrazole and pyridine radicals, piperazinyl or morpholino; Its optional being substituted as defined in first embodiment of first aspect.
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, wherein R 3Be R 3aAnd R 3aBe phenyl, naphthyl, indazolyl, benzimidazoline base, dihydrobenzo  azoles base, benzotriazole base, benzothienyl, benzo dioxolanyl, indoline ketone group, indyl, furyl, thienyl, pyridine radicals, purine radicals, carbazyl, piperidyl, triazolopyrimidinyl, tetrahydro-pyrazole and pyridine radicals; Its optional being substituted as defined in first embodiment of first aspect.
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, wherein R 3Be R 3a, and R 3aBe dihydro-benzothiazole ketone group, hydrogenation benzothiazolone base, benzothiazolyl, dihydrobenzo thiophene ketone group, hydrogenation of benzene bithiophene ketone group, benzothienyl, Dihydrobenzofuranes ketone group, hydrogenation benzo furanonyl, benzofuranyl, indoline ketone group, hydrogenated indoles ketone group, indyl, indolizine base, isoindolyl, indolinyl or indazolyl; Its optional being substituted as defined in first embodiment of first aspect.
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, wherein R 3Be R 3a, and R 3aBe dihydrobenzo  azoles base, benzotriazole base, indyl, halogenated nitrobenzene base, halogenated pyrimidine, halo purine radicals, C 1-3Alkyl-nitro amino pyrimidine, triazolopyrimidinyl, pyridine radicals, indazolyl, phenyl or benzo dioxolanyl; Its optional being substituted as defined in first embodiment of first aspect.
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, wherein R 3Be R 3a, and R 3aBe naphthyl, phenyl-O-phenyl or thienyl; Its optional being substituted as defined in first embodiment of first aspect.
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, wherein R 3Be R 3b
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, wherein R 3Be R 3b, and R 3bFor
1H-indole-5-base
1H-indazole-5-base
1H-benzotriazole-5-base
Figure A20038011103000433
1,3-dihydro-indol-2-one-5-base
3H-benzoxazol-2-ketone-6-base
Figure A20038011103000441
1,3-dihydro-benzimidazolyl-2 radicals-ketone-5-base
Figure A20038011103000442
The 1-methyl isophthalic acid, 3-dihydro-benzimidazolyl-2 radicals-ketone-6-base
3,4-dihydro-1H-quinoline-2-one--6-base
1,4-dihydro-benzo [d] [1,3]  piperazine-2-ketone-6-base
Figure A20038011103000445
3,4-dihydro-1H-quinazoline-2-ketone-6-base
3-methyl-3,4-dihydro-1H-quinazoline-2-ketone-6-base
Or
4H-benzo [1,4]  piperazine-3-ketone-7-base
Figure A20038011103000452
T wherein yBe H, C 1-4Alkyl, F, Cl, Br or nitrile.
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, wherein R 3Be R 3b, and R 3bBe azetidinyl, C 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl, the dihydroquinoline ketone group, the hydrogenated quinoline ketone group, the dihydro-isoquinoline ketone group, the hydrogenated isoquinoline ketone group, the dihydroquinazoline ketone group, the hydrogenated quinazolines ketone group, quinazolyl, the dihydro-quinoxaline ketone group, hydrogenation quinoxaline ketone group, quinoxalinyl, benzimidazolyl, 1H-indazole-5-base, dihydrobenzo imidazoline ketone group, the hydrogenated benzimidazoles ketone group, the benzimidazoline base, dihydro-benzothiazole ketone group, hydrogenation benzothiazolone base, benzothiazolyl, dihydrobenzo thiophene ketone group, hydrogenation of benzene bithiophene ketone group, the Dihydrobenzofuranes ketone group, hydrogenation benzo furanonyl, the benzo dioxolanyl, dihydrobenzo  azoles base, the benzotriazole base, the indoline ketone group, the hydrogenated indoles ketone group, the indolizine base, isoindolyl, indolinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, furyl, pyrrole radicals, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, purine radicals, carbazyl, pyrimidine radicals, piperidyl, piperazinyl or morpholino; Its optional being substituted as defined in first embodiment of first aspect.
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, wherein R 3Be R 3b, and R 3bBe dihydrobenzo imidazoline ketone group, the hydrogenated benzimidazoles ketone group, the benzimidazoline base, dihydro-benzothiazole ketone group, hydrogenation benzothiazolone base, benzothiazolyl, dihydrobenzo thiophene ketone group, hydrogenation of benzene bithiophene ketone group, the Dihydrobenzofuranes ketone group, hydrogenation benzo furanonyl, 1H-indazole-5-base, the benzo dioxolanyl, dihydrobenzo  azoles base, the benzotriazole base, the indoline ketone group, the hydrogenated indoles ketone group, the indolizine base, isoindolyl, indolinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, furyl, pyrrole radicals, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, purine radicals, carbazyl, pyrimidine radicals, piperidyl, piperazinyl or morpholino; Its optional being substituted as defined in first embodiment of first aspect.
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, wherein R 3Be R 3b, and R 3bBe azetidinyl, C 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl, the dihydroquinoline ketone group, the hydrogenated quinoline ketone group, the dihydro-isoquinoline ketone group, the hydrogenated isoquinoline ketone group, the dihydroquinazoline ketone group, the hydrogenated quinazolines ketone group, quinazolyl, the dihydro-quinoxaline ketone group, hydrogenation quinoxaline ketone group, quinoxalinyl, benzimidazolyl, 1H-indazole-5-base, dihydrobenzo imidazoline ketone group, the hydrogenated benzimidazoles ketone group, the benzimidazoline base, dihydro-benzothiazole ketone group, hydrogenation benzothiazolone base, benzothiazolyl, dihydrobenzo thiophene ketone group, hydrogenation of benzene bithiophene ketone group, the Dihydrobenzofuranes ketone group, hydrogenation benzo furanonyl, the benzo dioxolanyl, dihydrobenzo  azoles base, the benzotriazole base, purine radicals, carbazyl, pyrimidine radicals, piperidyl, piperazinyl or morpholino; Its optional being substituted as defined in first embodiment of first aspect.
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, wherein R 3Be R 3b, and R 3bBe azetidinyl, C 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl, the dihydroquinoline ketone group, the hydrogenated quinoline ketone group, the dihydro-isoquinoline ketone group, the hydrogenated isoquinoline ketone group, the dihydroquinazoline ketone group, the hydrogenated quinazolines ketone group, quinazolyl, the dihydro-quinoxaline ketone group, hydrogenation quinoxaline ketone group, quinoxalinyl, benzimidazolyl, the benzo dioxolanyl, dihydrobenzo  azoles base, the benzotriazole base, the indoline ketone group, the hydrogenated indoles ketone group, 1H-indazole-5-base, the indolizine base, isoindolyl, indolinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, furyl, pyrrole radicals, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, purine radicals, carbazyl, pyrimidine radicals, piperidyl, piperazinyl or morpholino; Its optional being substituted as defined in first embodiment of first aspect.
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, wherein R 3Be R 3b, and R 3bBe benzo dioxolanyl, dihydrobenzo  azoles base, benzotriazole base, purine radicals, carbazyl; Its optional being substituted as defined in first embodiment of first aspect.
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, wherein R 3Be R 3b, and R 3bBe dihydrobenzo  azoles base, benzotriazole base, indyl, halogenated nitrobenzene base, halogenated pyrimidine base, halo purine radicals, C 1-3Alkyl-nitro amino pyrimidine radicals, triazolopyrimidinyl, pyridine radicals, 1H-indazole-5-base, phenyl or benzo dioxolanyl.
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, and wherein Q is Q ', and wherein said chemical compound has the absolute configuration of R.
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, and wherein Q is Q ', and wherein said chemical compound has the absolute configuration of S.
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, and wherein Q is Q ", and wherein said chemical compound has the absolute configuration of R.
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, and wherein Q is Q ", and wherein said chemical compound has the absolute configuration of S.
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, and wherein m and n respectively do for oneself 1.
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, and wherein D is O.
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, and wherein A is C.
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, and wherein A is CH.
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, and wherein A is N.
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, and wherein E is N.
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, and wherein E is CH.
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, and wherein E is C.
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, and wherein said compound exhibits goes out the CGRP that is lower than 10nM as described herein in conjunction with (Binding) IC 50
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, and wherein said compound exhibits goes out the CGRP that is lower than 100nM as described herein in conjunction with (Binding) IC 50
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, and the wherein said compound exhibits of wherein said chemical compound goes out the CGRP that is lower than 1000nM as described herein in conjunction with (Binding) IC 50
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, and wherein p is 1; And G, J and E form A together xOr A y
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, and wherein p is 1; And G, J and E form A together x
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, and wherein p is 1; And G, J and E form A together y
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, wherein A xContain 5-7 member's annelated heterocycles separately for having two fused rings and described ring, described heterocycle contains 1-4 identical or different hetero atom that is selected from O, N and S; And choose wantonly and contain 1 or 2 carbonyl, the carbon atom of wherein said carbonyl is the member of described annelated heterocycles.
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, wherein A xContain 5-7 member's annelated heterocycles separately for having two fused rings and described ring, described heterocycle contains 1-4 identical or different hetero atom that is selected from O, N and S.
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, wherein A xContain 5-7 member's annelated heterocycles separately for having two fused rings and described ring, described heterocycle contains 1-4 identical or different hetero atom that is selected from O, N and S, and A wherein xReplaced by phenyl.
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, wherein A xBe condensed heterocycle described herein.
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, wherein A yFor containing 1-3 heteroatomic 4-6 element heterocycle that is selected from O, N and S; And choose wantonly and contain 1-2 carbonyl, the carbon atom of wherein said carbonyl is the member of described 4-6 element heterocycle.
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, wherein A yFor containing 1-3 heteroatomic 4-6 element heterocycle that is selected from O, N and S.
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, wherein A yFor containing 1-3 heteroatomic 4-6 element heterocycle that is selected from O, N and S; And choose wantonly and contain 1-2 carbonyl, the carbon atom of wherein said carbonyl is the member of described 4-6 element heterocycle; And A wherein yReplaced by phenyl.
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, wherein A yBe 4-6 element heterocycle described herein.
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, wherein p is 0, make G link to each other with A separately with J, then G, J and A form the volution ring system of the described ring of the described system that contains A together, and wherein G, J and A are GJA ' or GJA together ".
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, wherein p is 0, make G link to each other with A separately with J, then G, J and A form the volution ring system of the described ring of the described system that contains A together, and wherein G, J and A are GJA ' together.
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, wherein p is 0, make G link to each other with A separately with J, then G, J and A form the volution ring system of the described ring of the described system that contains A together, and wherein G, J and A are GJA together ".
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, wherein p is 0, make G link to each other with A separately with J, then G, J and A form the volution ring system of the described ring of the described system that contains A together, and wherein G, J and A are GJA ' together, and GJA ' is A x
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, wherein p is 0, make G link to each other with A separately with J, then G, J and A form the volution ring system of the described ring of the described system that contains A together, and wherein G, J and A are GJA ' together, and GJA ' is A y
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, wherein p is 0, make G link to each other with A separately with J, then G, J and A form the volution ring system of the described ring of the described system that contains A together, and wherein G, J and A are GJA together ", and GJA " is A x
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, wherein p is 0, make G link to each other with A separately with J, then G, J and A form the volution ring system of the described ring of the described system that contains A together, and wherein G, J and A are GJA together ", and GJA " is A y
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, wherein p is 0, make G link to each other with A separately with J, G then, J and A form the volution ring system of the described ring of the described system that contains A together, and G wherein, J and A form together and are selected from following heterocycle: the imidazoline ketone group, imidazolidinonyl, the dihydroquinoline ketone group, the dihydro-isoquinoline ketone group, the dihydroquinazoline ketone group, the dihydro-quinoxaline ketone group, dihydrobenzo  piperazine base, the hydrogenation Benzoxazinyl, dihydrobenzo  piperazine ketone group, dihydrobenzo imidazoline ketone group, the dihydrobenzo imidazole radicals, dihydro-benzothiazole ketone group, the dihydro-benzothiazole base, dihydrobenzo thiophene ketone group, the Dihydrobenzofuranes ketone group, the indoline ketone group, indolinyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, piperidyl, piperazinyl and morpholino; Wherein said heterocycle is optional to be selected from following group and to be replaced: C 1-4Alkyl, C 1-4Alkoxyl, C 1-4Haloalkyl, cyano group, C 3-7Cycloalkyl, phenyl, halogenophenyl, furyl, pyrrole radicals, pyrrolinyl, pyrrolidinyl, imidazole radicals, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, pyridine radicals, pyrimidine radicals, piperidyl, piperazinyl or morpholino.
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, wherein p is 0, make G link to each other with A separately with J, G then, J and A form the volution ring system of the described ring of the described system that contains A together, and G wherein, J and A form together and are selected from following heterocycle: the imidazoline ketone group, imidazolidinonyl, the dihydroquinoline ketone group, the dihydro-isoquinoline ketone group, the dihydroquinazoline ketone group, the dihydro-quinoxaline ketone group, dihydrobenzo  piperazine base, the hydrogenation Benzoxazinyl, dihydrobenzo  piperazine ketone group, dihydrobenzo imidazoline ketone group, the dihydrobenzo imidazole radicals, dihydro-benzothiazole ketone group, the dihydro-benzothiazole base, dihydrobenzo thiophene ketone group, the Dihydrobenzofuranes ketone group, the indoline ketone group, indolinyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, piperidyl, piperazinyl and morpholino; Wherein said heterocycle is optional to be selected from following group and to be replaced: C 1-4Alkyl, C 1-4Alkoxyl, C 1-4Haloalkyl, cyano group, C 3-7Cycloalkyl, phenyl, halogenophenyl, furyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, pyridine radicals, pyrimidine radicals, piperidyl, piperazinyl or morpholino.
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, wherein p is 0, make G link to each other with A separately with J, G then, J and A form the volution ring system of the described ring of the described system that contains A together, and G wherein, J and A form together and are selected from following heterocycle: the imidazoline ketone group, imidazolidinonyl, the dihydroquinoline ketone group, the dihydro-isoquinoline ketone group, the dihydroquinazoline ketone group, the Dihydrobenzofuranes ketone group, the indoline ketone group, indolinyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, piperidyl, piperazinyl and morpholino; Wherein said heterocycle is optional to be selected from following group and to be replaced: C 1-4Alkyl, C 1-4Alkoxyl, C 1-4Haloalkyl, cyano group, C 3-7Cycloalkyl, phenyl, halogenophenyl, piperazinyl or morpholino.
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, wherein p is 0, make G link to each other with A separately with J, G then, J and A form the volution ring system of the described ring of the described system that contains A together, and G wherein, J and A form together and are selected from following heterocycle: the imidazoline ketone group, imidazolidinonyl, the dihydroquinoline ketone group, the dihydro-isoquinoline ketone group, the dihydroquinazoline ketone group, the dihydro-quinoxaline ketone group, dihydrobenzo  piperazine base, the hydrogenation Benzoxazinyl, dihydrobenzo  piperazine ketone group, dihydrobenzo imidazoline ketone group, the dihydrobenzo imidazole radicals, dihydro-benzothiazole ketone group, the dihydro-benzothiazole base, dihydrobenzo thiophene ketone group, the Dihydrobenzofuranes ketone group, the indoline ketone group, indolinyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, piperidyl, piperazinyl and morpholino.
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, wherein p is 0, make G link to each other with A separately with J, then G, J and A form the volution ring system of the described ring of the described system that contains A together, and wherein G, J and A form together and be selected from following heterocycle: imidazoline ketone group, imidazolidinonyl, dihydroquinoline ketone group, dihydro-isoquinoline ketone group, dihydroquinazoline ketone group, dihydro-quinoxaline ketone group, dihydrobenzo  piperazine base, hydrogenation Benzoxazinyl and dihydrobenzo  piperazine ketone group.
Another embodiment according to a first aspect of the invention provides the chemical compound of first embodiment according to a first aspect of the invention, wherein p is 0, make G link to each other with A separately with J, then G, J and A form the volution ring system of the described ring of the described system that contains A together, and wherein G, J and A form together and be selected from following heterocycle: imidazoline ketone group, imidazolidinonyl, dihydroquinoline ketone group, dihydro-isoquinoline ketone group, dihydroquinazoline ketone group, dihydro-quinoxaline ketone group and dihydrobenzo  piperazine base.
A plurality of embodiments according to a second aspect of the invention provide the pharmaceutical composition that contains defined formula (I) chemical compound in the literary composition.
According to a plurality of embodiments of third aspect of the present invention, provide the pharmaceutical composition that comprises formula (I) chemical compound of this paper definition by administration to treat inflammation (particularly neurogenic inflammation), headache (particularly migraine), pain, thermal burn, cyclical shock (circulatory shock), diabetes, Reynaud ' s syndrome, peripheral arterial deficiency (peripheral arterial insufficiency), under the arachnoidea/intracranial hemorrhage (cranial hemorrhage), tumor growth, the flushing relevant (flushing) with climacteric, and other can realize the method for other symptom of treatment by the antagonism of CGRP receptor.
A plurality of embodiments of the 4th aspect according to the present invention; the purposes of The compounds of this invention is provided; this purposes is selected from down group: (a) immunomodulating in intestinal mucosa; (b) protective effect of inhibition heart allergy damage; (c) bone resorption of stimulation or prevention il-1 b (IL-1b)-stimulation; (d) expression of adjusting NK1 receptor in spinal neuron and (e) air flue inflammatory diseases and chronic obstructive pulmonary disease comprise asthma.With reference to (a) Calcitonin Receptor-Like Receptor Is Expressed on GastrointestinalImmune Cells (calcitonin receptor sample expression of receptor is in the gastrointestinal immunocyte) .Hagner, Stefanie; Knauer, Jens; Haberberger, Rainer; Goeke, Burkhard; Voigt, Karlheinz; McGregor, Gerard Patrick.Institute of Physiology, Philipps University, Marburg, Germany.Digestion (2002), 66 (4), 197-203; (b) Protective effects of calcitoningene-related peptide-mediated evodiamine on guinea-pig cardiac anaphylaxis (the halogen nitrogen compound of calcitonin-gene-related peptide mediation is to the anaphylactoid protective effect of guinea pig heart) .Rang, Wei-Qing; Du, Yan-Hua; Hu, Chang-Ping; Ye, Feng; Tan, Gui-Shan; Deng, Han-Wu; Li, Yuan-Jian.School of Pharmaceutical Sciences, Department ofPharmacology, Central South University, Xiang-Ya Road 88, Changsha, Hunan, Naunyn-Schmiedeberg ' s Archives of Pharmacology (2003), 367 (3), 306-311; (c) The experimental study on the effect calcitonin gene-related peptide on boneresorption mediated by interleukin-1 (calcitonin-gene-related peptide is to the experimental study of the resorbent effect of the bone of il-1 mediation) .Lian, Kai; Du, Jingyuan; Rao, Zhenyu; Luo, Huaican.Department of Orthopedics, Xiehe Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Peop.Rep.China.Journal of Tongji Medical University (2001), 21 (4), 304-307, (d) Calcitoningene-related Peptide regulates expression of neurokininl receptors by rat spinalneurons (calcitonin-gene-related peptide is regulated rat spinal nerves unit neurokinin 1 receptor expression) .Seybold VS, McCarson KE, Mermelstein PG, Groth RD, Abrahams LG, J.Neurosci.200323 (5): 1816-1824.epartment of Neuroscience, University ofMinnesota, Minneapolis, Minnesota 55455, and Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160 (e) Attenuation of antigen-induced airway hyperresponsiveness inCGRP-deficient mice (weakening of the respiratory tract overresponse of the antigen induction of CGRP-deficient mice) .Aoki-Nagase, Tomoko; Nagase, Takahide; Oh-Hashi, Yoshio; Shindo, Takayuki; Kurihara, Yukiko; Yamaguchi, Yasuhiro; Yamamoto, Hiroshi; Tomita, Tetsuji; Ohga, Eijiro; Nagai, Ryozo; Kurihara, Hiroki; Ouchi, Yasuyoshi.Department ofGeriatric Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.American Journal of Physiology (2002), 283 (5, Pt.1), L963-L970; (f) Calcitonin gene-related peptide as inflammatory mediator (as the calcitonin-gene-related peptide of inflammatory mediator) .Springer, Jochen; Geppetti, Pierangelo; Fischer, Axel; Groneberg, David A.Charite Campus-Virchow, Department of PediatricPneumology and Immunology, Division of Allergy Research, Humboldt-University Berlin, Berlin, Germany.Pulmonary Pharmacology ﹠amp; Therapeutics (2003), 16 (3), 121-130; (g) Pharmacological targets for theinhibition of neurogenic inflammation (suppressing the drug targeting agent of neurogenic inflammation).Helyes, Zsuzsanna; Pinter, Erika; Nemeth, Jozsef; Szolcsauyi, Janos.Departmentof Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Pecs, Pecs, Hung.Current Medicinal Chemistry:Anti-Inflammatory ﹠amp; Anti-AllergyAgents (2003), 2 (2), 191-218 all is incorporated herein by reference.
A plurality of embodiments of the 5th aspect according to the present invention provide combination (combinations) that The compounds of this invention and one or more are selected from following medicine to be used for the treatment of migraine: cox 2 inhibitor, NSAIDS, aspirin, acetaminophen, triptan (triptans), Ergotamine and caffeine.
The 6th aspect according to the present invention provides body Nei Fei-limit (non-terminal) method of identifying anti--migraine compounds.
First embodiment of the 6th aspect according to the present invention, body Nei Fei-limit approach of identifying anti--migraine compounds is provided, described method comprises the CGRP-receptor stimulating agent is delivered medicine to mammal with the amount that can induce blood flow to increase, subsequently reversing the amount medicine-feeding test chemical compound that the inductive blood flow of described CGRP-increases, wherein said mammal be contain Trp74 people source RAMP1 transgene mammal or contain the mammal of the endogenous expression RAMP1 of Trp74.
Another embodiment according to a sixth aspect of the invention provides body Nei Fei-limit approach of identifying anti--migraine compounds, described method delivers medicine to mammal with test compound before being included in administration CGRP-receptor stimulating agent, wherein said CGRP-receptor stimulating agent is the amount administration can induce blood flow to increase, and wherein said test compound is suppressing the amount administration that the inductive blood flow of described CGRP-increases, wherein said mammal be contain Trp74 people source RAMP1 transgene mammal or contain the mammal of the endogenous expression RAMP1 of Trp74.
Another embodiment according to a sixth aspect of the invention provides body Nei Fei-limit approach of identifying anti--migraine compounds, described method comprises the CGRP-receptor stimulating agent is delivered medicine to mammal with the amount that can induce the peripheral arterial diameter to increase, subsequently reversing the amount medicine-feeding test chemical compound that the inductive peripheral arterial diameter of described CGRP-increases, wherein said mammal be contain Trp74 people source RAMP1 transgene mammal or contain the mammal of the endogenous expression RAMP1 of Trp74.
Another embodiment according to a sixth aspect of the invention provides body Nei Fei-limit approach of identifying anti--migraine compounds, described method delivers medicine to mammal with test compound before being included in administration CGRP-receptor stimulating agent, wherein said CGRP-receptor stimulating agent is the amount administration can induce the peripheral arterial diameter to increase, and wherein said test compound is suppressing the amount administration that the inductive peripheral arterial diameter of described CGRP-increases, wherein said mammal be contain Trp74 people source RAMP1 transgene mammal or contain the mammal of the endogenous expression RAMP1 of Trp74.
Other embodiment according to a sixth aspect of the invention provides body Nei Fei-limit approach of identifying the anti--migraine compounds described in the literary composition, and wherein said blood flow is facial blood flow.
Other embodiment according to a sixth aspect of the invention provides body Nei Fei-limit approach of identifying the anti--migraine compounds described in the literary composition, the wherein said mammal right and wrong-people primate that contains the endogenous expression RAMP1 of Trp74.
Other embodiment according to a sixth aspect of the invention provides body Nei Fei-limit approach of identifying the anti--migraine compounds described in the literary composition, and the mammal of the endogenous expression RAMP1 of the wherein said Trp74 of containing is the people.
Other embodiment according to a sixth aspect of the invention provides body Nei Fei-limit approach of identifying the anti--migraine compounds described in the literary composition, the wherein said mammal right and wrong-people primate that contains the endogenous expression RAMP1 of Trp74, and described non--the people primate is an Adeps seu carnis Rhiopithecus roxellanae.
Other embodiment according to a sixth aspect of the invention provides body Nei Fei-limit approach of identifying the anti--migraine compounds described in the literary composition, and wherein said resisting-migraine compounds is the CGRP-receptor antagonist.
Other embodiment of the present invention may comprise the suitable combination of disclosed two or more embodiments in the literary composition and/or aspect.
Other embodiment of the present invention also can comprise the suitable subclass of a kind of embodiment disclosed herein and/or aspect.
According to following explanation, other embodiment of the present invention and aspect also will be conspicuous.
Description of drawings
Fig. 1 .Schild analyzes
Increase progressively there be not (closed square) and exist under (other all figures), the dose response that the cAMP that CGRP stimulates produces of CGRP antagonist embodiment 2 of (from left to right) in concentration.Vignette is that log dosage ratio subtracts the Schild figure of 1 (Y-axle) to the log concentration (X-axle) of antagonist embodiment 2: slope=0.94, K b=0.16nM.
Fig. 2. as the direct checking of the alternate facial blood flow that the rat entocranial artery is expanded.
Intravenous transmits (i.v.) h α CGRP and induces that the comparable percentage ratio of meninges artery diameter and the facial blood flow of rat increases (100-120% of baseline) (being respectively the striped bar diagram (striped bars) on the left side and the right) in the rat.With peptide antagonists CGRP (8-37) pretreatment, i.v. gives h α CGRP subsequently, to carry out two kinds of measurements, has produced 50% inhibition (solid bar diagram).In every animal (n=5 rat), measure entocranial artery diameter and facial blood flow simultaneously.Data are mean value sem *P＜0.05, *P＜0.01, suitable with the corresponding h α of independent use CGRP.
The dose-response of Fig. 3 .h α CGRP in the facial blood flow of non--people-primate laser-Doppler.
Being delivered in of h α CGRP be non--and induce dosage-dependency of the facial blood flow of laser-Doppler to increase in the people primate (for example, common Adeps seu carnis Rhiopithecus roxellanae).With 30 minutes interval, make animal (n=6) accept to increase the h α CGRP of dosage.Data are to change with respect to the peak value % of baseline ± sem, and every animal is as the contrast of itself.
Fig. 4 .CGRP-inductive non--inhibition that the facial blood flow of people primate changes.
After transmitting new CGRP antagonist embodiment 2 (solid bar diagram), give h α CGRP (striped bar diagram), dosage-dependency ground suppresses the increase of the facial blood flow of the inductive laser-Doppler of CGRP-.Vehicle (hollow bar diagram) is invalid.Data are mean value sem (every group of n=5-6 primate). *P＜0.05 and gives CGRP separately and compares.
Fig. 5 .CGRP antagonist is to the effect of non--people primate blood pressure.
With the dosage-dependency rejection ratio of the facial blood flow of primate (seeing Fig. 4 .), 2 pairs of blood pressures of embodiment have negligible influence and (average research (parallelstudies) in the animal of separately (separate), n=6).With 20 minutes interval, make the repeated doses of animals received embodiment 2.The mean value sem 20 minute in of BP data for measuring by arm cuff.
Detailed Description Of The Invention
Should explain description of the present invention with the rules and the principle that meet chemical bonding in this article.For example, in order to provide substituent group on any given position, removing hydrogen atom does not need.
As used in this article, " heterocyclic " or " heterocycle " comprises the annulus that contains one or more hetero atoms (for example O, N or S).Except as otherwise noted, described heterocycle comprises that those heteroaromatics and those are not the heterocycles of aromatic series (i.e. " alicyclic ").
As used in this article, when being described to the condensed bicyclo-of the 5.6-system that for example contains 1 to 4 nitrogen-atoms, term " condensed bicyclo-system " comprises aromatic series and alicyclic system, for example indolizine, indole, iso-indoles, 3H-indole, indoline, indazole or benzimidazole.
If with generic (generically) name substituent group, aspect then of the present invention comprises any and all categories in this genus.For example, the substituent group (group of " pyrrolidone " promptly has the pyrroles of carbonyl) that generic name is called " pyrroles's ketone group " comprises pyrroles-2-ketone group (wherein said carbonyl and nitrogen in abutting connection with) and pyrroles-3-ketone group (wherein said carbonyl and nitrogen have insertion methylene therebetween).
Similarly, except as otherwise noted, the present invention includes the substituent group of any one and all suitable junction points that can be connected on the described substituent group.
Yet, it should also be understood that the included chemical compound of the present invention is those chemically stable chemical compounds, be that aliphatic heterocyclic substituent of the present invention should not be that the mode of the α position of junction point is connected with the hetero atom on the described aliphatic heterocyclic substituent, wherein this junction point also is a hetero atom.
Be subordinated to the embodiment or the aspect of another embodiment or aspect, have embodiment or the various numerical value of aspect or the variable of condition that is different from its subordinate only describing.For example, if the embodiment of subordinate has only been described R 2, then with R 2The variable and the restrictive condition of the embodiment that irrelevant variable and restrictive condition should reflect its subordinate.
If a variable represents that with numerical value 0 key that then connects described variable will no longer exist.
As used in this article, " alkylene (alkylene) " refers to bivalence alkane, promptly removes the alkane (when this alkane contains more than one carbon atom, then removing described hydrogen from two different carbon atoms) of two hydrogen atoms from this alkane, for example-and CH 2CH 2CH 2-.
As used in this article, " alkylidene (alkylidene) " refers to that a carbon atom from this alkane removes the alkane of two hydrogen atoms, for example
Should be appreciated that in formula (I) representedly 5, the name (designations) of the alternately two keys on the 6-person's ring in the condensed structure of 6-person is relative (relative), and represents the delocalization π orbital electron of this ring.
As used in this article, " aryl " or " virtue-" comprises phenyl or naphthyl.
As used in this article, " heterocyclic " or " heterocyclic radical " comprises heteroaryl and aliphatic heterocyclic radical.
As used in this article, " halo " or " halogen " comprises fluorine, chlorine, bromine and iodine, but also refer to can substituted one or more identical or different halogens on part separately.
Except as otherwise noted, acyclic hydrocarbons can be side chain or straight chain, as alkyl, alkoxyl, alkenyl and alkynyl.
Unless should be appreciated that this description specified otherwise is arranged in addition, the present invention can comprise any and all possible stereoisomer, geometric isomer, diastereomer, enantiomer, anomer and optical isomer.
As used in this article, " Trp74 " refers to that the 74th residue among the RAMP1 is that (J Biol Chem 2002,277 such as Mallee 14294-8), is hereby incorporated by tryptophan.
Comprise that as used in this article " anti--migraine compounds " any energy reverses (reversing) or alleviates the receptor-mediated vasodilative chemical compound of CGRP-, peptide or fragments of peptides (modification or unmodified) (for example CGRP-receptor antagonist).
Comprise any tested to determine whether to reverse or to alleviate the receptor-mediated vasodilative chemical compound of CGRP-, peptide or fragments of peptides (modification or unmodified) (the CGRP-receptor antagonist of for example inferring) as used in this article " test compound ".
As used in this article, " CGRP-receptor stimulating agent " comprises anyly can induce the receptor-mediated vasodilative chemical compound of CGRP-, peptide or fragments of peptides (modification or unmodified), particularly for example α CGRP or CGRP; Other member of calcitonin family, for example adrenomedullin; The terminal CGRP fragment of N-, for example CGRP (1-12) CGRP (1-15) and CGRP (1-22); C-terminal amide (NH2) variant of CGRP, for example CGRP (1-8+NH2), CGRP (1-13+NH2) or CGRP (1-14+NH2); With non--naturally occurring CGRP analog, for example [Ala 1ψ (CH2NH) Cys 2] hCGRP, it is at Ala 1And Cys 2Between contain false peptide bond.Referring to Maggi CA, Rovero P, Giuliani S, Evangelista S, Regoli D, Meli A.Biological activity of N-terminal fragments of calcitoningene-related peptide (biologic activity of the N-terminal fragment of calcitonin gene-related peptides).Eur JPharmacol.1990 Apr 10; 179 (1-2): 217-9; Qing X, Wimalawansa SJ, Keith IM.Specific N-terminal CGRP fragments mitigate chronic hypoxic pulmonaryhypertension in rats (the terminal CGRP fragment of specificity N-alleviates the Chronic hypoxia pulmonary hypertension of rat).Regul Pept.2003 Jan 31; 110 (2): 93-9; With Dennis T, Fournier A, St PierreS, Quirion R.structure-activity profile of calcitonin gene-related peptide inperipheral and brain tissues (structure-active pattern of calcitonin-gene-related peptide in peripheral nervous system and cerebral tissue).Evidence for receptor multiplicity.J Pharmacol Exp Ther.1989Nov; 251 (2): 718-25 is hereby incorporated by.
The compounds of this invention can pharmaceutically acceptable salt form exist.These salt can comprise with mineral acid (for example hydrochloric acid and sulphuric acid) and with the salt of organic acid (for example acetic acid, citric acid, methanesulfonic acid, toluenesulfonic acid, tartaric acid and maleic acid) addition.In addition, contain at chemical compound of the present invention under the situation of acidic-group, acidic-group can alkali metal salt (for example potassium salt and sodium salt); Alkali salt (for example magnesium salt and calcium salt); And the form of tool and the formed salt of organic base (for example triethylammonium salts and arginine salt) exists.Under the situation of sublingual formulation, saccharin salt or maleate may advantageous particularlies.Chemical compound of the present invention can be hydrate or non--hydrate.
Chemical compound of the present invention can give with peroral dosage form such as tablet, capsule (wherein comprise separately and continue to discharge or time release formulation), pill, powder, granule, elixir, tincture, suspensoid, syrup and Emulsion.Chemical compound of the present invention also can give through intravenous, intraperitoneal, subcutaneous or intramuscular injection, knows so the dosage form of all uses all is the pharmaceutical field technical staff.Described chemical compound can give separately, but gives with putting into practice selected pharmaceutical carrier according to the pharmacy of selected medicine-feeding way and standard usually.Chemical compound of the present invention also can give with form with intranasal with vehicle (vehicles) by the local intranasal that is fit to that uses, or gives by the percutaneous path of using the percutaneous patch.When transdermal administration chemical compound of the present invention, then during whole dosage regimen, continue to discharge dosage.
When design with chemical compound of the present invention during with 0.01mg/kg to 30mg/kg administration, then all must utilize rational professional judgement in all cases and consider receiver's age, body weight and symptom, administration path, and the character of disease symptoms and dosage and dosage and the administration arrangement that the order of severity is adjusted The compounds of this invention carefully.According to good clinical practice, preferably to produce effective beneficial effect and can not cause any concentration harmful or undesirable side effect to give chemical compound of the present invention.
Synthetic
Can synthesize chemical compound of the present invention according to the general approach that is hereinafter provided.The definition of the variable that provides in the scheme except as otherwise noted, is with described consistent to the following formula chemical compound.Chemical compound of the present invention also can be according to scheme 1 or scheme 2 preparations.It also is possible adopting the various variations of described flow process to prepare chemical compound of the present invention, and described variation is well-known to those skilled in the art.
Synthesizing of scheme 1. formula I chemical compounds
Figure A20038011103000591
Synthesizing described in the scheme 1 begun by formula II chemical compound, and this chemical compound is for having protected aminoterminal aminoacid.Common amino protecting group (PG) comprises BOC, CBZ and FMOC, and their adding and removal method are well known in the art.The peptide coupling reagent of use standard makes the carboxylic moiety and the formula HNR of formula II chemical compound 1R 2Amine carry out coupling, form the amide of formula III.Remove amino protecting group, obtain formula IV chemical compound.Then, make the amine (seeing below) of this chemical compound and formula V in the isostere reactant (isostere reaction) of blended urea or urea, carry out coupling, production I chemical compound.Use phosgene, two succinimidyl carbonates, carbonyl dimidazoles or other equivalent can form blended urea easily.The formation of the isostere of urea (as cyanoguanidines and sulfonylguanidine) is known in the document.
Synthesizing of scheme 2. formula I chemical compounds
Synthesizing described in the scheme 2 begun by formula V chemical compound, and this chemical compound is for having the terminal aminoacid of protected carboxylate (carboxylate).Described protecting group is generally methyl ester, but also can use other protecting group such as ethyl ester, the tert-butyl ester and benzyl ester.According to as above, make the amine (seeing below) of formula V chemical compound and formula VIII in the isostere reactant of blended urea or urea, carry out coupling, production VI chemical compound.Make this formula VI chemical compound be converted into the free acid chemical compound of formula VII, then should acid and formula HNR 1R 2Amine carry out coupling, production I chemical compound.
Synthesizing of scheme 3. formula I chemical compounds
Scheme 3 described synthetic formula VII chemical compounds by scheme 2 begin.Make formula V chemical compound and pure R 4-OH coupling.The reaction of this formation ester is well-known in the art, and can use for example carbodiimide coupling reagent such as N, and the N-dicyclohexylcarbodiimide carries out this reaction.In addition, it is favourable often to comprise the additive (as 4-dimethylaminopyridine) that can quicken acylation reaction, particularly for the ester of the secondary alcohol and the tertiary alcohol.
HNR 1R 2Preparation with formula VIII amine
Formula VIII and HNR 1R 2Amine can maybe can prepare by the method described in literature method or the literary composition through commercially available acquisition.
Figure A20038011103000611
The amino acid whose preparation of formula II and formula V
The aminoacid of formula II and formula V can commercially availablely be buied, or can be according to preparing described in the scheme 4.
Synthesizing of scheme 4. formula II and formula V chemical compound
Figure A20038011103000613
Synthetic described in the scheme 4 is that the aldehyde by formula IX begins, and the glycine phosphonate ester that makes this aldehyde and formula X is through the Wadsworth-Emmons coupling reaction.Make formula X chemical compound deprotonation with alkali such as diazabicylo endecatylene or tetramethyl guanidine or other organic or inorganic alkali well-known in the art.Two keys of the formula XI chemical compound that reduction generates obtain formula XII chemical compound.Carry out this reduction reaction, obtain racemic modification, or, obtain the enantiomer of formula XII by using stereoselective catalyst.This reduction can be by carrying out with the transfer hydrogenation of hydrogen donor (as formic acid or cyclohexadiene), or use Gaseous Hydrogen hydrogenation to carry out, and two kinds of hydrogenations are all carried out in the presence of appropriate catalyst.Formula II chemical compound prepares by the acid or the basic hydrolysis of described ester.By using methods known in the art to remove protecting group (PG), can prepare formula V chemical compound.
The amino acid derivativges of other of formula XII can be according to preparing shown in the scheme 5.
Scheme 5. formula XII's is synthetic
For implementation 5, formula XIV chemical compound is a nucleophilic compound, as amine or alcohol, and shown in these chemical compounds can participate in and Michael addition reaction formula XIII chemical compound.
Other formula I chemical compound can prepare according to scheme 6 or scheme 7.It also is possible adopting the various variations of described scheme to prepare chemical compound of the present invention, and described variation is well known to those of ordinary skill in the art.
Synthesizing of scheme 6. formula I chemical compounds
Synthetic described in the scheme 6 is to be begun by aldehyde commercially available acquisition or synthetic.The homogenization of described two carbon (homologation) and two key reduction are known in the document, obtain formula XV chemical compound.Some formula XV chemical compounds also are commercially available, and other can prepare by other method well-known in the art.As the substrate of Evans chirality asymmetric synthesis and the formula XVI of product and the preparation of XVII chemical compound is known in the document.Hydrolysis obtains formula XVIII chemical compound.Described according to the formula VII chemical compound in the scheme 2, adopt the amide coupling scheme of knowing, can make these carboxylic acids and formula R 1R 2The amine reaction of NH obtains formula XIX chemical compound.The hydrolysis tert-butyl ester obtains formula XX chemical compound, this chemical compound can with the further coupling of formula VIII chemical compound, obtain formula I chemical compound.
Synthesizing of scheme 7. formula I chemical compounds
Figure A20038011103000631
Scheme 7 is also begun by aldehyde that be commercially available or synthetic.In the presence of alkali, make the reaction of these aldehyde and dimethyl succinate, obtain formula XXI chemical compound.Two keys of reduction-type XXI chemical compound obtain formula XXII chemical compound.Can reduce and obtain racemic modification, or by using stereoselective catalyst to obtain the enantiomer of formula XXII.This reduction can be undertaken by the transfer hydrogenation of hydrogen donor (as formic acid or cyclohexadiene), or uses Gaseous Hydrogen hydrogenation to carry out, and two kinds of hydrogenations are all carried out in the presence of appropriate catalyst.The amide synthetic schemes that employing is known makes the amine coupling of amide and formula VIII, obtains formula XXIII chemical compound.The hydrolyzing methyl ester obtains formula XXIV chemical compound, this chemical compound further with various amine or pure coupling, obtain the amide of formula I and the ester of formula I respectively.
Formula I chemical compound also can be according to scheme 8 preparations.
Synthesizing of scheme 8. formula I chemical compounds
Figure A20038011103000641
Synthesizing described in the scheme 8 begun by the N-tert-butoxycarbonyl that is commercially available-L-aspartic acid benzyl ester.Also can use the aspartame of various different protections synthetic easily.The peptide coupling scheme of employing standard makes the amine coupling of β carboxyl and formula VIII.Remove the α-carboxy protective group of formula XXV chemical compound by hydrogenolysis, obtain formula XXVI chemical compound.Make these chemical compounds and formula HNR 1R 2The further coupling of amine, obtain formula XXVII chemical compound.In organic solvent,, remove the amido protecting group by with strong acid such as trifluoroacetic acid or hydrogen chloride processing.Make the formula XXVIII chemical compound and the reaction of various electrophilic reagent of generation then, production I chemical compound.For example, use known method, comprise heating at various temperatures or by with transition metal such as palladium or copper catalysis (using), also can make they and halo-aromatic compounds coupling with stoichiometric amount or as catalyst.Under the standard reductive alkylation condition of fully describing in this area, also can make they and the reaction of various aldehydes or ketones.They and isocyanates, acyl chlorides or carbamyl chloride are reacted, generate urea, amide or carbamate derivatives respectively.The order that should be appreciated that modification described above (modifications) can change according to the selection of blocking group and the order of removing them.
Formula I chemical compound also can prepare according to scheme 9.
Synthesizing of scheme 9. formula I chemical compounds
Figure A20038011103000651
Synthetic imines by formula XXIX described in the scheme 9 begins.This imines is by glyoxylic acid ethyl ester and formula R 3-NH 2The condensation prepared of amine.Make described imines and 2-tert-butoxy-2-oxoethyl zinc chloride reaction, obtain formula XXX chemical compound.Remove tert-butyl ester blocking group with strong acid treatment, obtain the free acid of formula XXXI, make the amine coupling of this free acid and formula VIII, obtain the chemical compound of formula XXXII.With the described ethyl ester of aqueous hydrolysis of metal alkoxide (metal hydroxide salt) or alkali, obtain α-free acid of formula XXXIII.Make these free acids and formula HNR then 1R 2The amine coupling, obtain formula I chemical compound.
Urea groups amide intermediate and embodiment
Universal method. on Bruker 500 or 300MHz instrument, carry out 1H-and 13The C-NMR spectroscopic measurement.Chemical shift with respect to tetramethylsilane (δ=0.0) with ppm (δ) record.All evaporations are all under reduced pressure carried out.Unless otherwise indicated, on the Shimadzu instrument, carry out LC/MS and analyze, use YMC C18 post (3 * 50 millimeters) to carry out 3 minutes, use 2 minutes 0% to 100% the linear gradient liquid of solvent B in A.For LC/MS and Shimadzu preparation HPLC system, solvent orange 2 A is 10% methanol/90% water/0.1% trifluoroacetic acid, and solvent B is 90% methanol/10% water/0.1% trifluoroacetic acid, and the UV detector is set at 220 nanometers.
1-benzyl-2 ', 3 '-dihydro-2 '-oxo spiral shell-[piperidines-4,4 ' (1 ' H)-quinazoline
Figure A20038011103000661
Polyphosphoric acid (113g) is heated to 100-110 ℃ and stir, add simultaneously 1-benzyl-piperidin-4-one-(9.27ml, 50mmol).Immediately afterwards, (9.55g 70.mmol) makes and is enough to avoid producing excessive foam to add phenylurea several times on a small quantity.With mixture 150-160 ℃ of following heated overnight.Then water (200mL) is slowly joined in the mixture, make it be cooled to 100-110 ℃ (at low temperatures, thickness can't stir to such an extent as to this mixture becomes too).The solution that generates is neutralized to pH with 10N NaOH is about 8, and use chloroform extraction then.Organic facies through dried over mgso, and is concentrated then, obtain crude product, it through silica gel flash column chromatography purification (6: 4 ethyl acetate/hexane), is obtained required product (9.0g, 58%).Mass spectrum: 308.25 (MH) +.
2 ', 3 '-dihydro-2 '-oxo spiral shell-[piperidines-4,4 ' (1 ' H)-quinazoline
Figure A20038011103000662
To 1-benzyl-2 ', 3 '-dihydro-2 '-the oxo spiral shell-[piperidines-4,4 ' (1 ' H)-quinazoline (1.00g) the degassing methanol (50ml) and the solution in the 6N hydrochloric acid (2.0ml) in the adding 10% palladium charcoal (150mg).Under the 60psi nitrogen atmosphere, with mixture shaken overnight on the Parr device.LC/MS shows that reaction not exclusively.Add the palladium charcoal (200mg) more than 10%, and vibrate mixture more than 2 days.At this moment, all starting materials exhaust.Filtering mixt, and concentrated filtrate obtain the required chemical compound (64%) of 531mg.Mass spectrum: 218.12 (MH) +.
4-amino-4-cyano group-piperidines-1-carboxylic acid tert-butyl ester
At room temperature, (9.0g, (2.66g 49.8mmol), and stirred 1 hour to add ammonium chloride in methanol solution 45.3mmol) to well-beaten 4-oxo-piperidines-1-carboxylic acid tert-butyl ester.(2.44g 49.8mmol), and continues to stir 16 hours again to add Cyanogran..With reactant mixture with 5% sodium bicarbonate aqueous solution (50mL) quencher, dilute with water, and remove methanol by rotary evaporation.(3 * 100mL) extractions through dried over sodium sulfate, and evaporating solvent, obtain the required oily compound of 91% productive rate with dichloromethane with cyano group amine.
1H-NMR(300MHz，CDCl 3)：δ3.95-3.90(m，1H)，3.80-3.71(m，1H)，3.42-3.06(m，2H)，2.04-1.94(m，1H)，1.71-1.50(m，3H)。Mass spectrum: 226 (MH) +
2-phenyl-1,3,8-three azepines-spiral shell [4.5] last of the ten Heavenly stems-1-alkene-4-ketone, hydrochlorate
To 4-amino-4-cyano group-piperidines-1-carboxylic acid tert-butyl ester (1.0g, add in dichloromethane 4.44mmol) (30mL) solution triethylamine (1.24mL, 8.88mol), add subsequently Benzenecarbonyl chloride. (936mg, 6.66mmol).After 30 minutes, (40mg 0.33mmol), and continues to stir 12 hours again to add 4-(dimethylamino) pyridine.With reactant mixture 1M sodium hydroxide (10mL) quencher,, and separate then with ethyl acetate (100mL) dilution.Use 1M sodium hydroxide (40mL), sodium bicarbonate aqueous solution (50mL) and saline (50mL) washing organic layer in turn, then through dried over sodium sulfate.Come crystallization by the hexane solution that uses 30% ethyl acetate as solvent, obtain the required product of 90% productive rate, 4-benzoyl-amido-4-cyano group-piperidines-1-carboxylic acid tert-butyl ester.
(1.3g adds 6M sodium hydroxide (1.5mL) in ethanol 4mmol) (10mL) solution, add 30% hydrogen peroxide subsequently to 4-benzoyl-amido-4-cyano group-piperidines-1-carboxylic acid tert-butyl ester.Then with reaction mixture refluxed 3 hours.Then reactant mixture water (30mL) is diluted, and remove ethanol.Residue is diluted with ethyl acetate (100mL).Organic facies is washed with saline (30mL), and through dried over sodium sulfate.Obtain the required product of 80% productive rate by the hexane solution crystallization of using 30% ethyl acetate, 4-oxo-2-phenyl-1,3,8-three azepines-spiral shell [4.5] last of the ten Heavenly stems-1-alkene-8-carboxylic acid tert-butyl ester.The tert-butyl ester is dissolved in the dichloromethane (5mL) then, and adds two  alkane solution (25mL) of saturated hydrogen chloride.After 2 hours, remove and to desolvate, obtain the white powder 2-phenyl-1,3 of 95% productive rate, 8-three azepines-spiral shell [4.5] last of the ten Heavenly stems-1-alkene-4-ketone, hydrochlorate.
1H-NMR(500MHz，CD 3OD)：δ8.23-8.21(m，2H)，7.96-7.92(m，1H)，7.79-7.76(m，2H)，3.68-3.64(m，3H)，3.31-3.30(m，1H)，2.47-2.44(m，4H)。Mass spectrum: 230 (MH) +
5-formoxyl-indazole-1-carboxylic acid tert-butyl ester
Figure A20038011103000681
At room temperature, with two carbonic acid, two-tert-butyl ester (388mg, 1.78mmol) dichloromethane (2mL) drips of solution be added to 1H-indazole-5-formaldehyde (273mg, 1.87mmol), 4-dimethylaminopyridine (114mg, 0.94mmol) and triethylamine (0.26mL is in dichloromethane 1.87mmol) (10mL) solution.The bright yellow solution that generates was at room temperature stirred 16 hours.Solvent removed in vacuo, and residue handled through flash chromatography on silica gel method (25g), and with the ethyl acetate/hexane that contains 1% triethylamine (1: 1) as eluent, obtain the title compound (414mg, 90%) of yellowish-brown liquid.
1H-NMR(CDCl 3，500MHz)δ10.08(s，1H)，8.38(s，1H)，8.34(s，1H)，8.25(d，J＝8.5Hz，1H)，8.04(d，J＝8.8Hz，1H)，1.71(s，9H)。 13CNMR(CDCl 3，125MHz)δ191.8，149.0，142.5，140.6，133.0，128.3，126.4，125.8，115.3，85.7，27.8。
5-(2-benzyloxycarbonyl amino-2-methoxycarbonyl-vinyl)-indazole-1-carboxylic acid tert-butyl ester
Figure A20038011103000682
Under-78 ℃, with N-(benzyloxycarbonyl)-α-phosphono glycine trimethyl (5.50g, 16.6mmol) and tetramethyl guanidine (1.99mL, anhydrous tetrahydro furan 15.9mmol) (50mL) solution stirring 20 minutes.With 10 minutes time, in this solution, add 5-formoxyl-indazole-1-carboxylic acid tert-butyl ester (3.72g, oxolane 15.1mmol) (25mL) solution at leisure by syringe.Reactant mixture was stirred 4 hours down at-78 ℃, and be warmed to ambient temperature overnight then.Evaporating solvent, and the residue that generates handled through silica gel flash column chromatography (1: 2 ethyl acetate/hexane), white foam shape title compound (5.77g, 85%) obtained.
1H-NMR(CDCl 3，500MHz)δ8.09(d，J＝9.0Hz，1H)，8.08(s，1H)，7.84(s，1H)，7.67(d，J＝9.0Hz，1H)，7.47(s，1H)，7.30(br s，5H)，6.43(br s，1H)，5.09(s，2H)，3.84(s，3H)，1.72(s，9H)。Mass spectrum: 452 (MH) +
(±)-5-(2-amino-2-methoxycarbonyl-ethyl)-indazole-1-carboxylic acid tert-butyl ester
Figure A20038011103000691
Use the Parr hydrogenator, (524mg 1.16mmol) vibrated 4.5 hours under 50psi hydrogen with the mixture of 10% palladium on carbon (60mg) in methanol (20mL) with 5-(2-benzyloxycarbonyl amino-2-methoxycarbonyl-vinyl)-indazole-1-carboxylic acid tert-butyl ester.With the reactant mixture aerofluxus, use purging with nitrogen gas.Then, reactant mixture is filtered by Celite pad (celite pad), and should fill up with several parts of methanol wash.With the evaporation of methanol filtrate, obtain title compound (351mg, 95%).
1H-NMR(CDCl 3，500MHz)δ8.12-8.10(m，2H)，7.55(br s，1H)，7.37(dd，J＝8.9，1.5Hz，1H)，3.77-3.75(m，1H)，3.70(s，3H)，3.19(dd，J＝13.7，5.5Hz，1H)，2.99(dd，J＝13.7，8.0Hz，1H)，1.72(s，9H)。Mass spectrum: 320 (MH) +
(±)-5-(2-methoxycarbonyl-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-ethyl)-indazole-1-carboxylic acid tert-butyl ester
Figure A20038011103000692
At room temperature, with 5-(2-amino-2-methoxycarbonyl-ethyl)-indazole-1-carboxylic acid tert-butyl ester (307mg, 0.96mmol), N, N-two succinimidyl carbonate (246mg, 0.961mmol) and N, (0.67mL, dichloromethane solution 3.84mmol) stirred 30 minutes the N-diisopropylethylamine.Add 3-piperidin-4-yl-3, (238mg 1.03mmol), and at room temperature stirred reactant mixture 16 hours 4-dihydro-1H-quinazoline-2-ketone.Evaporating solvent, and residue is passed through use methylene chloride/triethylamine (93: 5: 2) handle as the flash chromatography of eluent, product (259mg, 47%) obtained.
1H-NMR(CDCl 3，300MHz)δ8.13-8.10(m，2H)，7.48(br s，1H)，7.31(dd，J＝8.8，1.6Hz，1H)，7.16(t，J＝8.0Hz，1H)，7.05(d，J＝7.0Hz，1H)，6.94(t，J＝7.7Hz，1H)，6.82(s，1H)，6.66(d，J＝8.0Hz，1H)，4.98(d，J＝7.7Hz，1H)，4.87-4.81(m，1H)，4.58-4.49(m，1H)，4.26(s，2H)，4.05-3.97(m，2H)，3.74-3.67(m，4H)，3.29-3.23(m，2H)，2.93-2.84(m，2H)，1.76-1.62(m，1H)，1.70(s，9H)，1.48-1.42(m，1H)。Mass spectrum: 577 (MH) +
2-TMS-ethyl sulfonic chloride
At 0 ℃, in flame-dried (flame-dried) three-neck round-bottomed flask, (43ml, (129g was in the settled solution of dichloromethane 490mmol) (200mL) 539mmol) to join triphenylphosphine with sulfonic acid chloride with 3 minutes.In 0 ℃ stir 5 minutes after, remove deicing-water-bath, and with added in 10 minutes in batches 2-TMS ethyl sulfonic acid sodium (50g, 245mmol).The white suspension that generates was at room temperature stirred 16 hours, then it is filtered by Celite pad.Concentrated filtrate is to about 50mL, and the adding ethyl acetate/hexane (1: 3,1000mL) and kieselguhr (40g).Mixture was at room temperature stirred 15 minutes, and filter by Celite pad.Solvent removed in vacuo, and residue is filled on wetted in advance silica gel (300mL) post, use 1: 3 ethyl acetate/hexane as eluent.Remove and desolvate, and obtain the title compound (41.9g, 85%) of light brown liquid.If do not use immediately, end product should be stored under nitrogen in refrigerator (freezer) or the fridge (refrigerator) and decompose to reduce as far as possible.
1H-NMR(CDCl 3，500MHz)δ3.61-3.57(m，2H)，1.32-1.27(m，2H)，0.10(s，9H)。
1-(2-TMS-ethylsulfonyl)-1H-indole-5-carboxylic acid ethyl ester
Figure A20038011103000702
Under 0 ℃, (10.31g, dimethyl formamide 58.8mmol) (50mL) drips of solution is added to sodium hydride, and (1.83g is 76.4mmol) in the mixture in dimethyl formamide (150mL) with 1H-indole-5-carboxylic acid ethyl ester.The mixture that generates was stirred 30 minutes down at 0 ℃, and (17.7g, dimethyl formamide 88.2mmol) (100mL) solution slowly joins in the said mixture with 2-TMS-ethyl sulfonic chloride under 0 ℃ then.After 2 hours, add saturated aqueous ammonium chloride solution (200mL), and mixture is extracted with ethyl acetate (300mL).After the separation, (2 * 150mL) extract with ethyl acetate with water layer.(3 * 150mL) wash, and through anhydrous sodium sulfate drying with saline with the organic layer that merges.Solvent removed in vacuo, and on silica gel, use 1: 1.5 dichloromethane/hexane to handle the residue as the flash chromatography of eluent, obtain the title compound (15.8g, 79%) of white solid.
1H-NMR(CDCl 3，500MHz)δ8.36(d，J＝1.5Hz，1H)，8.03(dd，J＝9.0，2.0Hz，1H)，7.92(d，J＝8.5Hz，1H)，7.50(d，J＝3.5Hz，1H)，6.75(d，J＝3.5Hz，1H)，3.94(s，3H)，3.21-3.18(m，2H)，0.84-0.80(m，2H)，-0.06(s，9H)。 13C-NMR (CDCl 3, 125MHz) δ 167.3,137.7,130.3,128.3,125.9,125.5,124.0,112.8,108.3,52.2,51.2,10.1 ,-2.1. mass spectrum 354.12 (MH) +
Preparation similarly:
1-(2-TMS-ethylsulfonyl)-1H-indazole-5-carboxylic acid, ethyl ester
Figure A20038011103000711
1H-NMR(CDCl 3，500MHz)δ8.51(s，1H)，8.34(s，1H)，8.21(dd，J＝8.9，1.5Hz，1H)，8.12(d，J＝9.2Hz，1H)，3.96(s，3H)，3.42-3.39(m，2H)，0.86-0.82(m，2H)，-0.02(s，9H)。 13C-NMR (CDCl 3, 125MHz) δ 166.4,143.1,141.2,130.1,126.5,125.0,124.2,112.9,52.5,51.3,9.8 ,-2.1. mass spectrum 355.13 (MH) +
[1-(2-TMS-ethylsulfonyl)-1H-indole-5-yl]-methanol
Figure A20038011103000712
(82.9mmol) solution slowly joins 1-(2-TMS-ethylsulfonyl)-1H-indole-5-carboxylic acid ethyl ester (8.81g is in toluene 25.9mmol) (200mL) solution for 82.9mL, the toluene solution of 1M with diisobutyl aluminium hydride under 0 ℃.It, should be reacted by adding methanol (26mL), pulverous sodium sulfate decahydrate (194g) and kieselguhr (26mL) and came quencher after 45 minutes in 0 ℃ of stirring.In 1 hour, mixture is warmed to room temperature, and filters by Celite pad.Solvent removed in vacuo obtains the very title compound of thick liquid, and its cooling after fixing is white solid (8.08g, 100% productive rate).
1H-NMR(CDCl 3，500MHz)δ7.87(d，J＝8.5Hz，1H)，7.62(s，1H)，7.44(d，J＝3.7Hz，1H)，7.35(dd，J＝8.6，1.5Hz，1H)，6.66(d，J＝3.7Hz，1H)，4.79(s，2H)，3.18-3.14(m，2H)，1.73(s，1H)，0.85-0.82(m，2H)，-0.06(s，9H)。Mass spectrum 312.14 (MH) +
[1-(2-TMS-ethylsulfonyl)-1H-indazole-5-yl]-methanol
Under 0 ℃; with 1-(2-TMS-ethylsulfonyl)-1H-indazole-5-carboxylic acid, ethyl ester (with methylbenzene azeotropic drying (2x); 5.77g oxolane 16.9mmol) (50mL) solution joins lithium borohydride, and (3.68g is in oxolane 169mmol) (100mL) mixture.Mixture is warmed to room temperature, and stirred 14 hours.It is cooled to 0 ℃, and adds lithium borohydride (3.5g).Mixture is warmed to room temperature, and stirred 14 hours.It is cooled to 0 ℃ once more, and slowly adds saturated aqueous ammonium chloride solution (25mL).The white suspension that generates is filtered by Celite pad, remove and desolvate, and residue is contained the flash chromatography processing of ethyl acetate/hexane (1: the 1.5) eluting of 1% triethylamine by use, obtain the title compound (3.8g, 72%) of white solid.
1H-NMR(CD 3OD，500MHz)δ8.41(s，1H)，8.04(d，J＝8.5Hz，1H)，7.85(s，1H)，7.61(dd，J＝8.5，1.2Hz，1H)，4.76(s，2H)，3.49-3.46(m，2H)，0.76-0.72(m，2H)，-0.03(s，9H)； 13C-NMR(CD 3OD，125MHz)δ141.2，140.9，138.3，129.2，125.8，119.6，112.7，63.8，50.8，9.9，-3.2。Mass spectrum 313.12 (MH) +
1-(2-TMS-ethylsulfonyl)-1H-indole-5-formaldehyde (carbaldehyde)
Under 0 ℃; in the 500mL round-bottomed flask; with [1-(2-TMS-ethylsulfonyl)-1H-indole-5-yl]-methanol (2.1g; 6.74mmol) dichloromethane (30mL) solution join in the mixture of activatory manganese dioxide (22g is with methylbenzene azeotropic drying (2x)) and dichloromethane (70mL).Reactant mixture is stirred 30min down at 0 ℃, and filter by Celite pad.Solvent removed in vacuo obtains the title compound (1.8g, 80%) of white solid.
1H-NMR(CDCl 3，500MHz)δ10.06(s，1H)，8.15(s，1H)，8.01(d，J＝8.6Hz，1H)，7.87(dd，J＝8.6，1.5Hz，1H)，7.54(d，J＝3.4Hz，1H)，6.80(d，J＝3.6Hz，1H)，3.24-3.20(m，2H)，0.86-0.82(m，2H)，-0.06(s，9H)。 13C-NMR (CDCl 3, 125MHz) δ 191.9,138.5,132.3,130.7,128.8,125.3,125.1,1134.6,108.4,51.4,10.2 ,-2.1. mass spectrum 310.12 (MH) +
Preparation similarly:
1-(2-TMS-ethylsulfonyl)-1H-indazole-5-formaldehyde
Figure A20038011103000732
Mass spectrum 311.10 (MH) +.
2-benzyloxycarbonyl amino-3-[1-(2-TMS-ethylsulfonyl)-1H-indole-5-yl]-acrylic acid methyl ester.
Figure A20038011103000741
At room temperature, with 1,1,3, (0.68mL, (1.88g is in oxolane 5.69mmol) (40mL) solution 5.43mmol) to join N-(benzyloxycarbonyl)-α-phosphono (phophono) glycine trimethyl for the 3-tetramethyl guanidine.Mixture is at room temperature stirred 15min, and be cooled to-78 ℃, and slowly add 1-(2-TMS-ethylsulfonyl)-1H-indole-5-formaldehyde (1.6g, oxolane 5.17mmol) (15mL) solution.The reactant mixture that generates is stirred 2 hour down, and be warmed to room temperature then in 3 hours at-78 ℃.Solvent removed in vacuo, and residue handled through the flash chromatography on silica gel method, use the dichloromethane/hexane (1: 1.5) that contains 1% triethylamine as eluent, obtain title compound, be that 92: 8 Z/E mixture (pass through CO 2CH 3Integration (integration) determine that Z isomer is in 3.79ppm, and E isomer is in 3.65ppm).For Z isomer: 1H-NMR (CD 3CN, 500MHz) δ 7.96 (s, 1H), 7.91 (d, J=8.5Hz, 1H), 7.66 (d, J=8.5Hz, 1H), 7.56 (d, J=3.7Hz, 1H), 7.51 (s, 1H), 7.43-7.35 (m, 5H), 7.67 (d, J=3.7Hz, 1H), 5.16 (s, 2H), 3.79 (s, 3H), 3.42-3.38 (m, 2H), 0.87-0.83 (m, 2H) ,-0.04 (s, 9H).Mass spectrum 515.20 (MH) +
Preparation similarly:
2-benzyloxycarbonyl amino-3-[1-(2-TMS-ethylsulfonyl)-1H-indazole-5-yl]-acrylic acid methyl ester.
Figure A20038011103000742
Use contains the dichloromethane of 1% triethylamine as eluent, through the flash chromatography on silica gel method, obtains title compound, and the Z/E mixture that is 95: 5 is (by-CH=C (CO 2Me) integration (NHCBz) (integration) is determined, 3.72g, 92%).For Z isomer: 1H-NMR (CD 3CN, 500MHz) δ 8.39 (s, 1H), 8.12 (s, 1H), 8.03 (d, J=8.8Hz, 1H), 7.84 (dd, J=8.8,1.2Hz, 1H), 7.51 (s, 1H), 7.43-7.35 (m, 5H), 5.14 (s, 2H), 3.81 (s, 3H), 3.51-3.47 (m, 2H), 0.83-0.79 (m, 2H) ,-0.02 (s, 9H).Mass spectrum 516.18 (MH) +
(±)-2-amino-3-[1-(2-TMS-ethylsulfonyl)-1H-indole-5-yl]-methyl propionate
In the round-bottomed flask of flame-dried 500mL, add 2-benzyloxycarbonyl amino-3-[1-(2-TMS-ethylsulfonyl)-1H-indole-5-yl]-acrylic acid methyl ester. (2.24 hours, 4.36mmol), methanol (100mL) and 10% palladium charcoal (palladium on charcoal) (0.52g).With mixture with the hydrogen degassing with purge five times.It was at room temperature stirred 1 hour, and filter by Celite pad.Remove and desolvate, and residue is contained the flash chromatography processing of the ethyl acetate/hexane (1: 1 and 2: 1) of 1% triethylamine by use, obtain the title compound (1.27g, 76%) of colourless viscous solution, it cools off after fixing.
1H-NMR(CD 3CN，500MHz)δ7.82(d，J＝8.2Hz，1H)，7.51-7.49(m，2H)，7.22(dd，J＝8.6，1.5Hz，1H)，6.72(d，J＝3.7Hz，1H)，3.70(dd，J＝7.3，6.1Hz，1H)，3.65(s，3H)，3.38-3.34(m，2H)，3.08(dd，J＝13.4，5.8Hz，1H)，2.95(dd，J＝13.4，7.3Hz，1H)，0.82-0.79(m，2H)，-0.05(s，9H)。 13C-NMR(CDCl 3，125MHz)δ176.0，134.4，133.4，131.1，127.9，126.4，122.4，113.1，107.7，56.6，51.7，50.8，41.3，10.1，-2.7。Mass spectrum 383.16 (MH) +
Preparation similarly:
(±)-2-amino-3-[1-(2-TMS-ethylsulfonyl)-1H-indazole-5-yl]-methyl propionate
1H-NMR(CD 3CN，500MHz)δ8.34(s，1H)，7.98(d，J＝8.6Hz，1H)，7.69(s，1H)，7.46(dd，J＝8.6，1.5Hz，1H)，3.71(dd，J＝7.3，5.8Hz，1H)，3.65(s，3H)，3.48-3.44(m，2H)，3.12(dd，J＝13.7，5.8Hz，1H)，2.97(dd，J＝13.7，7.6Hz，1H)，0.83-0.79(m，2H)，-0.02(s，9H)。 13C-NMR (CDCl 3, 125MHz) δ 175.9,141.1,140.5,134.6,131.5,126.0,122.2,112.7,56.4,51.8,51.1,40.9,9.8 ,-2.6. mass spectrum 384.15 (MH) +
(R)-2-benzyloxycarbonyl amino-3-[1-(2-TMS-ethylsulfonyl)-1H-indazole-5-yl]-methyl propionate
In experience 3 vacuum purges (purge) circulation bag gloves (glove bag), to the AIRFREE that is equipped with splash bar with rubber diaphragm separator (rubber septum) sealing (Schlenk) pack (-)-1 in the reaction flask into, 2-pair ((2R, 5R)-2,5-diethyl phosphorus heterocycle amyl group (phospholano)) (123mg, 0.17mmol 5mol%), and remove from bag glove benzene (cyclo-octadiene) rhodium (I) fluoroform sulphonate.With 2-benzyloxycarbonyl amino-3-[1-(2-TMS-ethylsulfonyl)-1H-indazole-5-yl]-(1.75g's acrylic acid methyl ester. 3.40mmol) weighs, and joins second AIRFREE that is equipped with splash bar and seals with rubber diaphragm separator (Schlenk) in the reaction flask.After 3 vacuum purge circulations, make in its mixture that is dissolved in absolute methanol (75mL) and anhydrous methylene chloride (15mL).Make two kinds of solvent deoxidations, added nitrogen at least 1 hour by spraying then.In this solution, make this mixture experience 3 vacuum purge circulations once more.This dehydroamino acid solution is incorporated into the AIRFREE that contains catalyst by conduit (canula) (Schlenk) in the reaction flask.With 5 vacuum of this reactant mixture experience/hydrogen purge circulation, open flask subsequently and butt up against 1 atmospheric hydrogen (air bag (balloon)).After 16 hours, with 3 vacuum purge circulations of reactant mixture experience.Evaporating solvent, and residue carried out column chromatography (1: 4 ethyl acetate/hexane to 1 of gradient liquid: 2 ethyl acetate/hexane) handle, obtain the title compound of 1.5g (85%) white solid, through the HPLC assay determination, use Chirocel OD post, as eluent (retention time: for title compound 13.9min, for S-enantiomer 11.2min), is 98.4% enantiomeric excess (ee) with 80% hexane/20% ethanol.
1H-NMR(CDCl 3，300MHz)δ8.17(s，1H)，7.98(d，J＝8.8Hz，1H)，7.47(s，lH)，7.35-7.25(m，6H)，5.29-5.24(m，1H)，5.08(dd，J＝19.0，12.1Hz，2H)，4.73-4.67(m，1H)，3.73(s，3H)，3.38-3.32(m，2H)，3.29(dd，J＝14.2，5.6Hz，1H)，3.19(dd，J＝13.9，5.6Hz，1H)，0.91-0.85(m，2H)，-0.02(s，9H)。Mass spectrum: 518 (MH) +
(R)-2-amino-3-[1-(2-TMS-ethylsulfonyl)-1H-indazole-5-yl]-methyl propionate
Figure A20038011103000771
Use the Parr hydrogenator; under 50psi hydrogen; with (R)-2-benzyloxycarbonyl amino-3-[1-(2-TMS-ethylsulfonyl)-1H-indazole-5-yl]-methyl propionate (1.24g, 2.40mmol) and methanol (50mL) the mixture vigorous stirring of 10% palladium on carbon (124mg) 2 hours.3 vacuum purge circulations of reactant mixture experience are purged.Then reactant mixture is filtered by Celite pad, and should fill up with several parts of washed with methanol.Evaporate methanol filtrate, obtain the title compound of 879mg (96%) thickness jelly.
1H-NMR(CDCl 3，300MHz)δ8.21(s，1H)，8.02(d，J＝8.8Hz，1H)，7.59(s，1H)，7.38(d，J＝8.8Hz，1H)，3.72(s，3H)，3.38-3.32(m，2H)，3.21(dd，J＝13.9，5.1Hz，1H)，2.98(dd，J＝13.9，7.9Hz，1H)，0.91-0.85(m，2H)，-0.02(s，9H)。Mass spectrum: 384 (MH) +
7-methyl-2-(2-TMS-ethylsulfonyl)-2H-indazole-5-formaldehyde
(3.0g 18.7mmol) adds triethylamine (7.83mL, 56.2mL in the suspension in dichloromethane (150mL) to 7-methylindazole 5-formaldehyde (aldehyde), 3 equivalents), drip purified 2-TMS-ethyl sulfonic chloride (5.60g, 28.1mmol, 1.5 equivalents) subsequently.This mixture gradually becomes homogeneous phase, and at room temperature stirs 16 hours.Solution concentration to minimum dichloromethane, and then through silica gel flash column chromatography (1: 4 ethyl acetate/hexane), is obtained the product 4.7g (77%) of light yellow solid.
1H-NMR(CDCl 3，300MHz)δ9.98(s，1H)，8.77(s，1H)，8.09(s，1H)，7.64(s，1H)，3.64-3.58(m，2H)，2.65(s，3H)，0.88-0.82(m，2H)，0.01(s，9H)。
2-benzyloxycarbonyl amino-3-[7-methyl-2-(2-TMS-ethylsulfonyl)-2H-indazole-5-yl]-acrylic acid methyl ester.
In anhydrous tetrahydro furan (75mL) solution of N-(benzyloxycarbonyl)-α-phosphono glycine trimethyl (4.93g, 14.9mmol, 1.1 equivalents), add tetramethyl guanidine (1.78mL, 1.05 equivalents).Under nitrogen, at room temperature, mixture is stirred 5min, and is cooled to then-78 ℃.After stirring 15min under-78 ℃, add oxolane (25mL) solution of 7-methyl-2-(2-TMS-ethylsulfonyl)-2H-indazole-5-formaldehyde.Make reactant mixture be warmed to ambient temperature overnight at leisure.Even should react not exclusively evaporating solvent.The residue that generates is dissolved in the ethyl acetate, and washes with 1M sulphuric acid.Separate organic layer,, filter and evaporation through dried over mgso.By flash column chromatography (1: 4 ethyl acetate/hexane), obtain the glassy product of 2.66g (37%) white foam.
1H-NMR(CDCl 3，300MHz)δ8.48(s，1H)，7.62(s，1H)，7.38-7.25(m，7H)，6.48(bs，1H)，5.10(s，2H)，3.83(s，3H)，3.58-3.52(m，2H)，2.51(s，3H)，0.89-0.83(m，2H)，0.02(s，9H)。Mass spectrum: 530 (MH) +
(R)-2-benzyloxycarbonyl amino-3-[7-methyl-2-(2-TMS-ethylsulfonyl)-2H-indazole-5-yl]-methyl propionate
Figure A20038011103000791
In 3 vacuum purge circulation bag gloves of experience (glove bag), to the AIRFREE that is equipped with splash bar with rubber diaphragm separator (rubber septum) sealing (Schlenk) pack (-)-1 in the reaction flask into, 2-pair ((2R, 5R)-2,5-diethyl phosphorus heterocycle amyl group) (259mg, 0.36mmol 9mol-%), and remove from bag glove benzene (cyclo-octadiene) rhodium (I) fluoroform sulphonate.With 2-benzyloxycarbonyl amino-3-[7-methyl-2-(2-TMS-ethylsulfonyl)-2H-indazole-5-yl]-(2.03g's acrylic acid methyl ester. 3.83mmol) weighs, and joins second AIRFREE that is equipped with splash bar and seals with rubber diaphragm separator (Schlenk) in the reaction flask.After 3 vacuum purge circulations, it is dissolved in the absolute methanol (80mL, deoxidation added nitrogen 1 hour by spraying then) at least.In this solution, make this mixture experience 3 vacuum purge circulations once more.This dehydroamino acid solution is transferred to the AIRFREE that contains catalyst by conduit (Schlenk) in the reaction flask.With 5 vacuum of this reactant mixture experience/hydrogen purge circulation, open flask butt joint hydrogen capsule (1atm) subsequently.2.5 after hour, with 3 vacuum purge circulations of reactant mixture experience.Evaporating solvent, and residue is carried out column chromatography, and (1: 4 ethyl acetate/hexane to 1 of gradient liquid: 2 ethyl acetate/hexane) processing obtains 1.4g (68%; Ee=99.2%) title compound of white solid.
1H-NMR(CDCl 3，300MHz)δ8.43(s，1H)，7.34(s，5H)，7.19(s，1H)，6.87(s，1H)，5.24(d，J＝8.1Hz，1H)，5.08(dd，J＝18.3，12.1Hz，2H)，4.67(dd，J＝13.9，6.2Hz，1H)，3.73(s，3H)，3.57-3.51(m，2H)，3.16(dd，J＝14.0，5.9Hz，1H)。3.06(dd，J＝13.9，6.6Hz，1H)，2.55(s，3H)，0.89-0.83(m，2H)，0.01(s，9H)。 13C-NMR(CDCl 3，75MHz)δ172.0，155.7，151.7，136.2，132.2，129.8，129.5，128.6，128.4，128.2，125.1，121.1，118.1，67.1，54.7，52.5，51.1，38.6，17.1，9.7，-2.0。Mass spectrum: 532 (MH) +
(R)-2-amino-3-[7-methyl-2-(2-TMS-ethylsulfonyl)-2H-indazole-5-yl]-methyl propionate
Figure A20038011103000801
Use the Parr device; under 55psi hydrogen with 2-benzyloxycarbonyl amino-3-[7-methyl-2-(2-TMS-ethylsulfonyl)-2H-indazole-5-yl]-methyl propionate (1.35g, 2.54mmol) and 10% palladium on carbon (135mg) in methanol (40mL), vibrated 3.0 hours.3 vacuum purges of reactant mixture experience are circulated purge.Then reactant mixture is filtered by Celite pad, and should fill up with several parts of washed with methanol.Evaporate methanol filtrate, obtain the title compound (1.01g, quantitative yield) of thickness jelly.
1H-NMR(CDCl 3，300MHz)δ8.45(s，1H)，7.29(s，1H)，6.97(s，1H)，3.79-3.73(m，1H)，3.73(s，3H)，3.56-3.50(m，2H)，5.12(dd，J＝13.5，5.12Hz，1H)，4.85(dd，J＝13.5，8.1Hz，1H)，2.58(s，3H)，0.87-0.81(m，2H)，0.01(s，9H)。 13C-NMR(CDCl 3，75MHz)δ175.5，151.8，133.7，129.9，129.4，125.0，121.3，117.9，55.5，52.1，51.1，41.4，17.1，9.8，-2.1。Mass spectrum: 398 (MH) +
(R)-3-[7-methyl-2-(2-TMS-ethylsulfonyl)-2H-indazole-5-yl]-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-methyl propionate
At room temperature; with 2-amino-3-[7-methyl-2-(2-TMS-ethylsulfonyl)-2H-indazole-5-yl]-methyl propionate (500mg; 1.26mmol), N; N-diisopropylethylamine (0.66mL; 3.77mmol) and two succinimidyl carbonates (322mg, mixture 1.26mmol) stirs 30min together in dichloromethane (20mL).Then, add 3-piperidin-4-yl-3, (444mg 1.35mmol), and at room temperature stirs reactant mixture and to spend the night 4-dihydro-1H-quinazoline-2-ketone.Evaporating solvent, and residue is carried out flash column chromatography (1: 4 acetone/ethyl acetate) handle, the title compound of 490mg (60% productive rate) white solid obtained.
1H-NMR(CDCl 3，300MHz)δ8.47(s，1H)，7.23(s，1H)，7.19-7.14(m，1H)，7.04(d，J＝7.3Hz，1H)，6.97-6.93(m，2H)，6.77(s，1H)，6.65(d，J＝7.7Hz，1H)，4.99(d，J＝7.3Hz，1H)，4.81(dd，J＝13.5，6.2Hz，1H)，4.58-4.46(m，1H)，4.27(s，2H)，4.10-3.98(m，2H)，3.73(s，2H)，3.57-3.51(m，2H)，3.14-3.11(m，2H)，2.95-2.83(m，2H)，2.58(s，3H)，1.77-1.65(m，4H)，0.92-0.84(m，2H)，-0.01(s，9H)。Mass spectrum: 655 (MH) +
Preparation similarly:
(±)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-3-[1-(2-TMS-ethylsulfonyl)-1H-indole-5-yl]-methyl propionate
Figure A20038011103000811
1H-NMR (CD 3OD, 500MHz) δ 7.85 (d, J=8.2Hz, 1H), 7.55 (s, 1H), 7.51 (d, J=3.7Hz, 1H), 7.27 (dd, J=8.6,1.5Hz, 1H), 7.16 (t, J=7.6Hz, 1H), 7.10 (d, J=7.6Hz, 1H), 6.95 (t, J=7.6Hz, 1H), 6.79 (d, J=8.0Hz, 1H), 6.73 (d, J=3.7Hz, 1H), 4.44-4.38 (m, 1H), 4.26 (s, 2H), 4.13-4.08 (m, 2H), 3.73 (s, 3H), 3.34-3.29 (m, 4H), 3.13 (dd, J=13.5,9.4Hz, 1H), 2.89-2.79 (m, 2H), 1.76-1.70 (m, 1H), 1.63-1.59 (m, 3H), 0.76-0.72 (m, 2H) ,-0.07 (s, 9H); Mass spectrum: 640.40 (MH) +
(R)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-3-[1-(2-TMS-ethylsulfonyl)-1H-indazole-5-yl]-methyl propionate
Figure A20038011103000821
At room temperature; with (R)-2-amino-3-[1-(2-TMS-ethylsulfonyl)-1H-indazole-5-yl]-methyl propionate (764mg; 1.99mmol), N; N-diisopropylethylamine (1.10mL; 5.97mmol) and two succinimidyl carbonates (509mg, dichloromethane 1.99mmol) (20mL) solution stirring 40min.At room temperature add 3-piperidin-4-yl-3 then, (70% purity, 703mg 2.13mmol), and stir reactant mixture and spend the night 4-dihydro-1H-quinazoline-2-ketone.Vacuum evaporating solvent, and residue is carried out flash column chromatography (1: 4 acetone/ethyl acetate) handle, 1.15g (90%) title compound obtained.
1H-NMR(CDCl 3，300MHz)δ8.21(s，1H)，8.01(d，J＝8.5Hz，1H)，7.53(s，1H)，7.32(d，J＝8.5Hz，1H)，7.16(t，J＝7.8Hz，1H)，7.06(d，J＝7.6Hz，1H)，6.95(d，J＝7.6Hz，1H)1，6.76(s，1H)，6.65(d，J＝7.9Hz，1H)，5.01(d，J＝7.6Hz，1H)，4.84(dd，J＝13.1，6.0Hz，1H)，4.56-4.49(m，1H)，4.28(s，2H)，4.13-3.98(m，2H)，3.73(s，3H)，3.39-3.35(m，2H)，3.28(dd，J＝14.0，6.1Hz，1H)，3.24(dd，J＝13.7，5.8Hz，1H)，2.94-2.87(m，2H)，1.75-1.67(m，4H)，0.91-0.87(m，2H)，-0.02(s，9H)。Mass spectrum: 641 (MH) +
Preparation similarly:
(±)-2-{[4-(2-oxo-2,3-dihydro-benzimidazole-1-yl)-piperidines-1-carbonyl]-amino }-3-[1-(2-TMS-ethylsulfonyl)-1H-indole-5-yl]-methyl propionate
Figure A20038011103000831
1H-NMR(CD 3CN，500MHz)δ9.78(s，1H)，7.86(d，J＝8.5Hz，1H)，7.56(s，1H)，7.49(d，J＝3.7Hz，1H)，7.28(dd，J＝8.5，1.5Hz，1H)，7.10-7.08(m，1H)，7.05-7.03(m，1H)，6.99-6.97(m，2H)，6.70(d，J＝3.7Hz，1H)，5.91(d J＝7.9Hz，1H)，4.66(q，J＝8.2Hz，1H)，4.45-4.39(m，1H)，4.14(br s，1h)，3.68(s，3H)，3.36-3.32(m，2H)，3.27(dd，J＝14.0，5.5Hz，1H)，3.18(dd，J＝13.7，8.5Hz，1H)，2.90-2.84(m，2H)，2.55(br s，1H)，2.36-2.21(m，2H)，1.74-1.70(m，2H)，0.82-0.78(m，2H)，-0.09(s，9H)。Mass spectrum 626.26 (MH) +
(±)-2-{[4-(2-oxo-2,3-dihydro-benzimidazole-1-yl)-piperidines-1-carbonyl]-amino }-3-[1-(2-TMS-ethylsulfonyl)-1H-indazole-5-yl]-methyl propionate
Figure A20038011103000832
1H-NMR(CD 3CN，500MHz)δ9.61(br s，1H)，8.35(s，1H)，8.00(d，J＝8.5Hz，1H)，7.74(s，1H)，7.51(dd，J＝8.8，1.5Hz，1H)，7.10-7.06(m，1H)，7.05-7.02(m，1H)，7.00-6.97(m，2H)，5.90n(d，J＝7.9Hz，1H)，4.674.62(m，1H)，4.42-4.36(m，1H)，4.13-4.07(br s，1H)，3.68(s，3H)，3.45-3.42(m，2H)，3.30(dd，J＝14.0，5.8Hz，1H)，3.20(dd，J＝13.7，8.8Hz，1H)，2.89-2.84(m，2H)，2.52(br s，1H)，2.33-2.23(m，2H)，1.72-1.69(m，2H)，0.80-0.76(m，2H)，-0.07(s，9H)。Mass spectrum 627.25 (MH) +
(±)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-3-[1-(2-TMS-ethylsulfonyl)-1H-indole-5-yl]-methyl propionate
1H-NMR(CD 3OD，500MHz)δ7.85(d，J＝8.2Hz，1H)，7.55(s，1H)，7.51(d，J＝3.7Hz，1H)，7.27(dd，J＝8.6，1.5Hz，1H)，7.16(t，J＝7.6Hz，1H)，7.10(d，J＝7.6Hz，1H)，6.95(t，J＝7.6Hz，1H)，6.79(d，J＝8.0Hz，1H)，6.73(d，J＝3.7Hz，1H)，4.44-4.38(m，1H)，4.26(s，2H)，4.13-4.08(m，2H)，3.73(s，3H)，3.34-3.29(m，4H)，3.13(dd，J＝13.5，9.4Hz，1H)，2.89-2.79(m，2H)，1.76-1.70(m，1H)，1.63-1.59(m，3H)，0.76-0.72(m，2H)，-0.07(s，9H)。Mass spectrum 640.40 (MH) +
(±)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-3-[1-(2-TMS-ethylsulfonyl)-1H-indazole-5-yl]-methyl propionate
Figure A20038011103000842
1H-NMR(CD 3OD，500MHz)δ8.39(d，J＝0.5Hz，1H)，8.02(d，J＝8.5Hz，1H)，7.75(s，1H)，7.52(dd，J＝8.5，1.5Hz，1H)，7.14-7.10(m，2H)，6.94(t，J＝7.5Hz，1H)，6.78(d，J＝7.5Hz，1H)，4.63-4.60(m，1h)，4.43-4.37(m，1H)，4.27(s，2H)，4.11(br s，1H)，4.08(br s，1H)，3.71(s，3H)，3.47-3.43(m，2H)，3.37-3.33(m，1H)，3.18(dd，j＝13.5，10.0Hz，1H)，2.87-2.79(m，2H)，1.73-1.59(m，4H)，0.80-0.75(m，2H)，-0.05(s，9H)； 13C-NMR(CD 3OD，125MHz)δ173.7，155.5，158.1，141.0，140.6，137.2，134.4，131.3，128.2，126.1，125.8，122.2，121.9，118.3，113.4，112.6，55.9，52.1，51.7，50.8，48.9，48.6，48.4，48.2，48.0，47.9，47.7，47.5，43.8，43.7，43.1，37.2，28.5，9.8，-3.2。Mass spectrum: 641.40 (MH) +
Embodiment 1
(±)-3-(1H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-propanoic acid
To be dissolved in 5-(2-methoxycarbonyl-2-{[4-(the 2-oxo-1 in the oxolane (5mL), 4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-ethyl)-(168mg, 0.29mmol) solution is cooled to 0 ℃ to indazole-1-t-butyl formate in methanol (5mL).Add lithium hydroxide monohydrate (49mg, aqueous solution 2.04mmol) (5mL).Reactant mixture was stirred 6 hours down at 0 ℃, and placed refrigerator (freezer) then other 16 hours.Solvent removed in vacuo, and with in the residue water-soluble (15mL).The pH of aqueous solution is adjusted to about 1 with 1N hydrochloric acid.Filter the white solid that collecting precipitation obtains.This solid of vacuum drying obtains title compound (108mg, 80%).
1H-NMR(DMSO-d 6，300MHz)δ12.94(bs，1H)，9.19(s，1H)，8.01(s，1H)，7.61(s，1H)，7.46(d，J＝8.4Hz，1H)，7.28(dd，J＝8.5，1.5Hz，1H)，7.13-7.06(m，2H)，6.86(t，J＝7.0Hz，1H)，6.76-6.72(m，2H)，4.32-4.24(m，2H)，4.09-4.02(m，4H)，3.17-2.97(m，2H)，2.72-2.59(m，2H)，1.57-1.35(m，4H)。IR (KBr, cm-1) 3424,2963,2930,1660,1628,1505,1474,1446,753. mass spectrums: 463 (MH) +
(R)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-3-[1-(2-TMS-ethylsulfonyl)-1H-indazole-5-yl]-propanoic acid
Figure A20038011103000861
With (R)-2-{[4-(2-oxo-1; 4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-3-[1-(2-TMS-ethylsulfonyl)-1H-indazole-5-yl]-(775mg, 1.21mmol) solution in oxolane (9mL) and methanol (3mL) is cooled to 0 ℃ to methyl propionate.Add lithium hydroxide monohydrate (115mg, aqueous solution 4.84mmol) (3mL).Reactant mixture was stirred 2 hours down at 0 ℃, and place-15 ℃ refrigerator 16 hours then.When cooling off this reactant mixture, pH is increased to about 7 by adding 1N hydrochloric acid (3.8mL) with ice bath.Vacuum is removed organic solvent.After adding more 1N hydrochloric acid (0.5mL), with the aqueous solution ethyl acetate extraction that generates.The extract that merges through dried over mgso, is filtered also evaporation, obtain the title compound of 684mg (90%) white solid.
1H-NMR(DMSO-d 6，300MHz)δ9.21(s，1H)，8.58(s，1H)，7.90(d，J＝8.4Hz，1H)，7.78(s，1H)，7.56(d，J＝8.1Hz，1H)，7.13-7.09(m，2H)，6.88-6.83(m，1H)，6.76-6.74(m，2H)，4.33-4.27(m，2H)，4.18(s，2H)，4.09-3.96(m，3H)，3.57-3.51(m，2H)，3.25-3.04(m，2H)，2.74-2.60(m，2H)，1.54-1.43(m，4H)，0.70-0.64(m，2H)，-0.08(s，9H)。Mass spectrum: 627 (MH) +
Preparation similarly:
(±)-2-{[4-(2-oxo-2,3-dihydro-benzimidazole-1-yl)-piperidines-1-carbonyl]-amino }-3-[1-(2-TMS-ethylsulfonyl)-1H-indole-5-yl]-propanoic acid
Figure A20038011103000871
Mass spectrum 612.25 (MH) +
(±)-2-{[4-(2-oxo-2,3-dihydro-benzimidazole-1-yl)-piperidines-1-carbonyl]-amino }-3-[1-(2-TMS-ethylsulfonyl)-1H-indazole-5-yl]-propanoic acid
Figure A20038011103000872
Mass spectrum 613.26 (MH) +
(±)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-3-[1-(2-TMS-ethylsulfonyl)-1H-indazole-5-yl]-propanoic acid
1H-NMR(CD 3CN，500MHz)δ8.37(s，1H)，8.08(s，1H)，8.01(d，J＝8.5Hz，1H)，7.77(s，1H)，7.53(dd，J＝8.5，1.5Hz，1H)，7.19(t，J＝7.3Hz，1H)，7.14(d，J＝7.3Hz，1H)，6.98(td，j＝7.6，1.2Hz，1H)，6.79(d，j＝8.0Hz，1H)，6.28(br s，3H)，4.54-4.49(m，1H)，4.37-4.32(m，1H)，4.30(s，2H)，3.98-3.92(m，2H)，3.45-3.41(m，2H)，3.37(dd，j＝14.0，4.9Hz，1H)，3.20(dd，J＝14.0，9.7Hz，1H)，2.84-2.77(m，2H)，1.65-1.57(m，4H)，0.79-0.76(m，2H)，-0.05(s，9H)。Mass spectrum: 627.30 (MH) +
(R)-4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid 2-[1,4 '] connection piperidines-1 '-Ji-2-oxo-1-[1-(2-TMS-ethylsulfonyl)-1H-indazole-5-ylmethyl]-ethyl }-amide
To (R)-2-{[4-(2-oxo-1; 4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-3-[1-(2-TMS-ethylsulfonyl)-1H-indazole-5-yl]-propanoic acid (554mg; 0.88mmol) and N; N-diisopropylethylamine (0.62mL; 3.54mmol) dichloromethane (20mL) solution in add 4-piperidino (piperidino) piperidines (164mg, 0.97mmol) and PyBOP (460mg, dichloromethane 0.88mmol) (15mL) solution.Reactant mixture was at room temperature stirred 16 hours.Then it is concentrated into about 2mL, and carries out flash column chromatography and handle, use methylene chloride/triethylamine (94: 5: 1), obtain the title compound of 599mg (87%) white solid as eluent.
1H-NMR(CD 3CN，300MHz)δ8.37(s，0.5H)，8.36(s，0.5H)，8.02-7.96(m，1H)，7.74(s，0.5H)，7.71(s，0.5H)，7.55-7.46(m，1H)，7.21-7.12(m，2H)，6.97-6.92(m，1H)，6.79(d，J＝8.1Hz，1H)，5.71(t，J＝8.1Hz，1H)，5.00(dd，J＝15.0，8.1Hz，1H)，4.63-4.51(m，1H)，4.39-4.29(m，1H)，4.29(s，2H)，4.10-3.96(m，3H)，3.46-3.40(m，2H)，2.92-2.70(m，8H)，2.58-2.37(m，5H)，1.74-1.40(m，13H)，0.80-0.74(m，2H)，-0.04(s，9H)。Mass spectrum: 778 (MH) +
Preparation similarly:
(±)-4-(2-oxo-2; 3-dihydro-benzimidazole-1-yl)-piperidines-1-carboxylic acid (carboxylicacid) 2-[1,4 '] connection piperidines (bipiperidinyl)-1 '-Ji-2-oxo-1-[1-(2-TMS-ethylsulfonyl)-1H-indole-5-ylmethyl]-ethyl }-amide
Figure A20038011103000891
1H-NMR(CD 3CN，500MHz)δ9.42(br s，1H)，7.80(d，J＝8.5Hz，0.6H)，7.78(d，J＝8.2Hz，0.4H)，7.50(s，1H)，7.43(t，J＝3.0Hz，1H)，7.27(d，J＝8.5Hz，0.6H)，7.23(d，J＝8.5Hz，0.4H)，7.10-7.07(m，1H)，7.02-6.95(m，3H)，6.69(s，0.4H)，6.68(s，0.6H)，5.88(d，J＝8.5Hz，0.6H)，5.85(d，J＝8.4Hz，0.4H)，5.04-4.98(m，1H)，4.49(s，0.4H)，4.46(s，0.6H)，4.36-4.30(m，1H)，4.11-4.07(m，1H)，3.97-3.91(m，1H)，3.31-3.28(m，2H)，3.11-3.05(m，6H)，2.87-2.80(m，2H)，2.43-2.07(m，8H)，1.78-1.74(m，4H)，1.71-1.65(m，2H)，1.46-1.40(m，2H)，1.37-1.31(m，2H)，0.80-74(m，2H)，-0.10(s，9H)。LC/MS:t R=2.47 minutes, 762.37 (MH) +
(±)-4-(2-oxo-2,3-dihydro-benzimidazole-1-yl)-piperidines-1-carboxylic acid 2-[1,4 '] connection piperidines-1 '-Ji-2-oxo-1-[1-(2-TMS-ethylsulfonyl)-1H-indazole-5-ylmethyl]-ethyl }-amide
Figure A20038011103000892
1H-NMR(CD 3CN，500MHz)δ9.67(s，1H)，8.32(s，1H)，7.96(d，J＝8.7Hz，0.55H)，7.93(d，J＝8.6Hz，0.45H)，7.70(s，1H)，7.51(d，J＝8.6Hz，0.55H)，7.47(d，J＝8.8Hz，0.45H)，7.08-7.05(m，1H)，7.03-6.99(m，1H)，6.98-6.94(m，2H)，6.01(d，J＝7.9Hz，0.45H)，5.96(d，J＝7.9Hz，0.55h)，5.05-5.00(m，1H)，4.49-4.46(m，1H)，4.35-4.29(m，1H)，4.10-4.05(m，1H)，4.00-3.93(m，1H)，3.40-3.36(m，2H)，3.17-3.30(m，6H)，2.91-2.71(m，2H)，2.52-2.13(m，8H)，1.769br s，4H)，1.69-1.65(m，2H)，1.44-1.41(m，2H)，1.34-1.30(m，2H)，0.77-0.71(m，2H)，-0.08(s，9H)。LC/MS:t R=2.35 minutes, 763.35 (MH) +
(±)-4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid 2-[1,4 '] connection piperidines-1 '-Ji-2-oxo-1-[1-(2-TMS-ethylsulfonyl)-1H-indole-5-ylmethyl]-ethyl }-amide
1H-NMR(CD 3CN，500MHz)δ8.17(s，0.6H)，8.16(s，0.4H)，7.84(d，J＝8.5Hz，0.6H)，7.81(d，J＝8.5Hz，0.4H)，7.54(s，0.4H)，7.53(s，0.6H)，7.48(t，J＝4.1Hz，1H)，7.31(dd，J＝8.5，1.5Hz，0.6H)，7.28(dd，J＝8.5，1.5Hz，0.4H)，7.18(t，j＝7.4Hz，1H)，7.09-7.06(m，1H)，6.93(t，J＝7.3Hz，1H)，6.83(d，J＝7.9Hz，1H)，6.72(d，J＝3.6Hz，1H)，6.09(d，J＝8.2Hz，1H)，5.05-4.99(m，1H)，4.53-4.50(m，1H)，4.40-4.34(m，1H)，4.26(s，1.2H)＜4.24(s，0.8H)，3.99-3.94(m，1H)，3.35-3.30(m，2H)，3.15-3.07(m，3H)，3.08-3.03(m，1H)，2.81-2.73(m，3H)，2.55-2.37(m，6H)，2.21-2.16(m，1H)，2.13-2.08(m，1H)，1.69-1.57(m，4H)，1.51-1.45(m，4H)，1.41-1.35(m，4H)，0.83-0.74(m，2H)，-0.06(s，9H)。Mass spectrum: 776.44 (MH) +
(±)-4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid 2-[1,4 '] connection piperidines-1 '-Ji-2-oxo-1-[1-(2-TMS-ethylsulfonyl)-1H-indazole-5-ylmethyl]-ethyl }-amide
Figure A20038011103000911
By using dichloromethane: methanol/triethylamine (90: 10: 0.5) carries out purification as the silica gel chromatography of eluent. 1H-NMR(CD 3CN，500MHz)δ8.36(s，1H)，8.04(s，1H)，8.01(d，J＝8.8Hz，0.6H)，7.97(dd，J＝8.8Hz，0.4H)，7.74(s，1H)，7.54(dd，J＝8.5，1.5Hz，0.6H)，7.51(dd，J＝8.5，1.5Hz，0.4H)，7.18(t，J＝7.4Hz，1H)，7.11(t，J＝7.3Hz，1H)，6.94(t，J＝7.3Hz，1H)，6.83(d，J＝7.9Hz，1H)，6.05(d，J＝8.5Hz，0.4H)，6.02(d，J＝8.5Hz，0.6H)，5.06-5.01(m，1H)，4.52-4.50(m，1H)，4.39-4.34(m，1H)，4.27(s，1.2H)，4.25(s，0.8H)，4.00-3.97(m，2H)，3.45-3.40(m，2H)，3.20-3.08(m，2H)，2.81-2.74(m，2H)，2.56-2.39(m，8H)，2.27-2.24(m，1H)，2.20-2.16(m，1H)，1.68-1.57(m，4H)，1.52-1.45(m，4H)，1.41-1.34(m，4H)，1.06-1.01(m，1H)，0.80-0.75(m，2H)，-0.07(s，9H)。Mass spectrum: 777.40 (MH) +
(±)-4-(2-oxo-2,3-dihydro-benzimidazole-1-yl)-piperidines-1-carboxylic acid 2-(4-isobutyl group-piperazine-1-yl)-2-oxo-1-[1-(2-TMS-ethylsulfonyl)-1H-indole-5-ylmethyl]-ethyl }-amide
1H-NMR(CD 3CN，500MHz)δ9.75(s，1H)，7.82(d，J＝8.2Hz，1H)，7.54(s，1H)，7.48(d，J＝3.6Hz，1H)，7.28(d，J＝8.5Hz，1H)，7.12-7.09(m，1H)，7.04-7.02(m，1H)，7.00-6.97(m，2H)，6.72(d，J＝3.7Hz，1H)，5.97(d，J＝8.2Hz，1H)，5.01(dd，J＝14.6，7.2Hz，1H)，4.40-4.34(m，1H)，4.15-4.08(m，2H)，3.58-3.54(m，1H)，3.50-3.45(m，2H)，3.39-3.35(m，1H)，3.36-3.32(m，2H)，3.14-3.10(m，8H)，2.89-2.83(m，2H)，2.34-2.23(m，4H)，2.17-2.13(m，1H)，0.85(d，J＝6.7Hz，6H)，0.83-0.80(m，2H)，-0.06(s，9H)。Mass spectrum: 736.40 (MH) +
(±)-4-(2-oxo-2,3-dihydro-benzimidazole-1-yl)-piperidines-1-carboxylic acid 2-(1,4-two oxa-s-8-azepine-spiral shell [4.5] last of the ten Heavenly stems-8-yl)-2-oxo-1-[1-(2-TMS-ethylsulfonyl)-1H-indole-5-ylmethyl]-ethyl }-amide
1H-NMR(CD 3CN，500MHz)δ9.27(s，1H)，7.82(d，J＝8.5Hz，1H)，7.55(s，1H)，7.48(d，J＝3.6Hz，1H)，7.28(dd，J＝8.5，1.5Hz，1H)，7.13-7.10(m，1H)，7.06-7.03(m，1H)，7.01-6.98(m，2H)，6.72(d，J＝3.6Hz，1H)，5.95(d，J＝8.0Hz，1H)，5.05(dd，J＝15.0，7.3Hz，1H)，4.41-4.34(m，1H)，4.14-4.08(m，2H)，3.90-3.86(m，3H)，3.68-3.64(m，1H)，3.60-3.56(m，2H)，3.45-3.40(m，1H)，3.35-3.31(m，2H)，3.15(dd，J＝13.4，7.1Hz，1H)，3.05(dd，J＝13.4，7.0Hz，1H)，2.89-2.83(m，2H)，2.34-2.19(m，3H)，1.73-1.70(m，2H)，1.64-1.56(m，2H)，1.53-1.49(m，1H)，1.29-1.26(m，1H)，0.84-0.80(m，2H)，-0.05(s，9H)。Mass spectrum: 737.37 (MH) +
(±)-4-(2-oxo-2,3-dihydro-benzimidazole-1-yl)-piperidines-1-carboxylic acid 2-(4-isobutyl group-piperazine-1-yl)-2-oxo-1-[1-(2-TMS-ethylsulfonyl)-1H-indazole-5-ylmethyl]-ethyl }-amide
1H-NMR(CD 3CN，500MHz)δ9.84(s，1H)，8.37(s，1H)，7.98(d，J＝8.5Hz，1H)，7.74(s，1H)，7.52(dd，J＝8.8，1.5Hz，1H)，7.11-7.09(m，1H)，7.06-7.03(m，1H)，7.02-6.98(m，2H)，5.97(d，J＝8.2Hz，1H)，5.02(dd，J＝14.3，7.3hz，1H)，4.39-4.33(m，1H)，4.14-4.07(m，2H)，3.53-3.50(m，3H)，3.46-3.42(m，2H)，3.45-3.39(m，1H)，3.20-3.06(m，5H)，2.89-2.83(m，2H)，2.30-2.27(m，4H)，2.21-2.17(m，1H)，1.74-1.70(m，3H)，0.86(d，J＝6.7Hz，6H)，0.81-0.77(m，2H)，-0.04(s，9H)。Mass spectrum: 737.40 (MH) +
(±)-4-(2-oxo-2,3-dihydro-benzimidazole-1-yl)-piperidines-1-carboxylic acid 2-(1,4-two oxa-s-8-azepine-spiral shell [4.5] last of the ten Heavenly stems-8-yl)-2-oxo-1-[1-(2-TMS-ethylsulfonyl)-1H-indazole-5-ylmethyl]-ethyl }-amide
Figure A20038011103000932
1H-NMR(CD 3CN，500MHz)δ9.34(s，1H)，8.36(s，1H)，7.97(d，J＝8.5Hz，1H)，7.74(s，1H)，7.52(dd，J＝8.5，1.5Hz，1H)，7.11-7.08(m，1H)，7.06-7.03(m，1H)，7.02-6.98(m，2H)，5.98(d，J＝8.2Hz，1H)，5.06(dd，J＝14.6，7.3Hz，1H)，4.39-4.32(m，1H)，4.13-4.03(m，2H)，3.92-3.88(m，2H)，3.71-3.66(m，1H)，3.63-3.53(m，2H)，3.48-3.45(m，1H)，3.44-3.40(m，2H)，3.19(dd，j＝13.4，6.5Hz，1H)，3.08(dd，J＝13.7，7.3Hz，1H)，2.85(t，J＝12.8Hz，2H)，2.32-2.20(m，4H)，1.73-1.70(m，2H)，1.67-1.51(m，3H)，1.38-1.33(m，1H)，0.81-0.77(m，2H)，-0.04(s，9H)。Mass spectrum: 738.32 (MH) +
Embodiment 2
(R)-4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(1H-indazole-5-ylmethyl)-2-oxo-ethyl]-amide ()
With (R)-4-(2-oxo-1; 4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid { 2-[1; 4 '] connection piperidines-1 '-Ji-2-oxo-1-[1-(2-TMS-ethylsulfonyl)-1H-indazole-5-ylmethyl]-ethyl }-amide (568mg; 0.73mmol) and cesium fluoride (1.11g, acetonitrile 7.31mmol) (50mL) solution in 80 ℃ the heating 4.5 hours.Reactant mixture is concentrated, and residue carried out flash column chromatography (methylene chloride/triethylamine, 94: 5: 1) handle, obtain the title compound of 280mg (63% productive rate) white solid, determine to have 98.2%ee by the HPLC analysis of using Chirocel OD post, with 20%B (A=ethanol, the hexane solution of B=0.05% diethylamine) as eluent (retention time: for title compound 9.51min, and for S-enantiomer 15.9 minutes). 1H-NMR (CD 3OD, 500MHz) δ 8.04 (s, 0.75H), 8.03 (s, 0.25H), 7.67 (s, 0.75H), 7.65 (s, 0.25H), 7.56 (d, J=8.5Hz, 0.75H), 7.51 (d, J=8.5Hz, 0.25H), 7.41 (d, J=8.5Hz, 0.75H), 7.31 (d, J=8.5Hz, 0.25H), 7.19-7.12 (m, 2H), 6.97-6.94 (m, 1H), 6.80 (d, J=7.9Hz, 1H), 5.08-5.05 (m, 1H), 4.60-4.53 (m, 1H), 4.48-4.40 (m, 1H), 4.37 (s, 1.5H), 4.26 (s, 0.5H), 4.24-4.14 (m, 2H), 4.06-3.97 (m, 1H), 3.15 (d, J=7.9Hz, 1.5H), 3.12-3.05 (m, 0.5H), 2.94-2.86 (m, 3H), and 2.57-2.51 (m, 1.5H), 2.47-2.42 (m, 1H), and 2.37-2.33 (m, 0.75H), 2.03-2.02 (m, 1.5H), 1.87-1.75 (m, 3.75H), 1.73-1.68 (m, 2H), 1.67-1.54 (m, 3H), 1.53-1.44 (m, 4H), and 1.43-1.34 (m, 2H), 1.30-1.26 (m, 1H), 0.83-0.77 (m, 0.75H) ,-0.16 to-0.24 (m, 0.75H).Mass spectrum: 613 (MH) +
Preparation similarly:
Embodiment 3
(±)-4-(2-oxo-2,3-dihydro-benzimidazole-1-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(1H-indole-5-ylmethyl)-2-oxo-ethyl]-amide
Figure A20038011103000951
1H-NMR(DMSO-d 6，500MHz)δ10.99(s，0.6H)，10.96(s，0.4H)，10.85(s，1H)，7.41(s，0.4H)，7.36(s，0.6H)，7.33(d，J＝8.0Hz，0.6H)，7.29-7.26(m，1H)，7.16-7.14(m，1H)，7.10(d，J＝7.6Hz，0.4H)，7.02-6.96(m，4H)，6.81(br s，1H)，6.37-6.35(m，1H)，4.86(q，J＝8.0Hz，0.6H)，4.80(q，J＝7.5Hz，0.4H)，4.45(br s，1H)，4.38-4.32(m，1H)，4.21-4.16(m，1H)，3.98(br s，1H)，3.18(d，J＝5.2Hz，0.6H)，3.04-2.92(m，2.4H)，2.82-2.74(m，4H)，2.37-2.33(m，2H)，2.25-2.08(m，4H)，2.04-1.90(m，2H)，1.47-1.24(m，10H)，0.75-0.71(m，1H)。LC/MS:t R=1.90 minutes, 598.42 (MH) +
Embodiment 4
(±)-4-(2-oxo-2,3-dihydro-benzimidazole-1-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(1H-indazole-5-ylmethyl)-2-oxo-ethyl]-amide
Figure A20038011103000952
1H-NMR(DMSO-d 6，500MHz)δ10.70(s，1H)，8.22(d，J＝8.2Hz，0.6H)，8.11(s，0.4H)，8.00(s，0.6H)，7.89(d，J＝9.1Hz，0.4H)，7.62-7.57(m，1H)，7.50-7.43(m，1H)，7.30-7.26(m，1H)，7.14-7.08(m，1H)，6.99-6.95(m，2H)，6.85(br s，1H)，4.89-4.80(m，1H)，4.45-4.31(m，2H)，4.18-4.00(m，2H)，3.26-3.16(m，1H)，3.09-2.96(m，2H)，2.82-2.73(m，4H)，2.38-2.34(m，2H)，2.24-2.08(m，4H)，2.03-1.88(m，2H)，1.47-1.22(m，10H)，0.90-0.84(m，1H)。LC/MS:t R=1.73 minutes, 599.32 (MH) +
Embodiment 5
(±)-4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(1H-indole-5-ylmethyl)-2-oxo-ethyl]-amide
With 4-(2-oxo-1; 4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid { 2-[1; 4 '] connection piperidines-1 '-Ji-2-oxo-1-[1-(2-TMS-ethylsulfonyl)-1H-indole-5-ylmethyl]-ethyl }-amide (52mg; 0.067mmol), (51mg, 0.33mmol) mixture in acetonitrile (5mL) is 80 ℃ of down heating 4 hours for cesium fluoride.Solvent removed in vacuo, and on silica gel, use methylene chloride/triethylamine (93: 5: 2) to carry out chromatography as eluent residue and handle, obtain the title compound (70% productive rate) of white solid. 1H-NMR(CD 3CN，500MHz)δ9.30(s，1H)，7.48(s，1H)，7.42(s，1H)，7.39(d，J＝8.2Hz，0.6H)，7.36(d，J＝8.2Hz，0.4H)，7.24-7.21(m，1H)，7.19(t，J＝7.9Hz，1H)，7.12-7.09(m，1H)，7.06(d，J＝8.2Hz，0.6H)，7.02(d，J＝8.2Hz，0.4H)，6.95(t，J＝7.4Hz，1，4.04-3.93(m，1H)，3.07-3.02(m，1.6H)，2.95(dd，J＝13.7，7.1Hz，0.4H)，2.85-2.72(m，3H)，2.56-2.37(m，3H)，2.42-2.37(m，1H)，1.99-1.95(m，7H)，1.76-1.51(m，8H)，1.45-1.40(m，3H)。LC/MS:t R=1.91 minutes, 612.44 (MH) +
Embodiment 6
(±)-4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(1H-indazole-5-ylmethyl)-2-oxo-ethyl]-amide
Figure A20038011103000971
By using dichloromethane: methanol: triethylamine (93: 5: 2) obtains the title compound (90% productive rate) of white solid as the silica gel chromatography purification of eluent. 1H-NMR(CD 3OD，500MHz)δ8.04(s，0.7H)，8.02(s，0.3H)，7.67(s，0.7H)，7.65(s，0.3H)，7.56(d，J＝8.5Hz，0.7H)，7.51(d，J＝8.5Hz，0.3H)，7.40(d，J＝8.5Hz，0.7H)，7.33(d，J＝8.5Hz，0.3H)，7.19-7.12(m，2H)，6.97-6.94(m，1H)，6.80(d，J＝8.0Hz，1H)，5.08-5.05(m，1H)，4.59-4.54(m，1H)，4.48-4.42(m，1H)，4.37(s，1H)，4.27-4.20(m，2H)，4.04(d，J＝13.4Hz，0.3H)，3.99(d，J＝13.4Hz，0.7H)，3.19-3.08(m，2H)，2.94-2.86(m，3H)，2.57(br s，2H)，2.51-2.36(m，2H)，2.07-2.05(m 1H)，1.90-1.31(m，16H)。LC/MS:t R=1.85 minutes, 613.44 (MH) +Adopt following condition: Chiracel OD prep post, 50 * 500mm, 20um; A=EtOH, B=0.05% diethylamine/hexane; 20%B@65ml/min carried out 45 minutes; Retention time: (R)-enantiomer is 20.5 minutes, and the S enantiomer is 32.8 minutes, by the chiral separation racemic modification, obtains (R)-enantiomer, its discontinuous synthetic (embodiment 1) as mentioned above.
Embodiment 7
(±)-4-(2-oxo-2,3-dihydro-benzimidazole-1-yl)-piperidines-1-carboxylic acid [1-(1H-indole-5-ylmethyl)-2-(4-isobutyl group-piperazine-1-yl)-2-oxo-ethyl]-amide
LC/MS:t R=2.05 minutes, 572.31 (MH) +
Embodiment 8
(±)-4-(2-oxo-2,3-dihydro-benzimidazole-1-yl)-piperidines-1-carboxylic acid [2-(1,4-two oxa-s-8-azepine-spiral shell [4.5] last of the ten Heavenly stems-8-yl)-1-(1H-indole-5-ylmethyl)-2-oxo-ethyl]-amide
Figure A20038011103000981
LC/MS:t R=2.35 minutes, 573.26 (MH) +
Embodiment 9
(±)-4-(2-oxo-2,3-dihydro-benzimidazole-1-yl)-piperidines-1-carboxylic acid [1-(1H-indazole-5-ylmethyl)-2-(4-isobutyl group-piperazine-1-yl)-2-oxo-ethyl]-amide
Figure A20038011103000982
LC/MS:t R=1.86 minutes, 573.28 (MH) +
Embodiment 10
(±)-4-(2-oxo-2,3-dihydro-benzimidazole-1-yl)-piperidines-1-carboxylic acid [2-(1,4-two oxa-s-8-azepine-spiral shell [4.5] last of the ten Heavenly stems-8-yl)-1-(1H-indazole-5-ylmethyl)-2-oxo-ethyl]-amide
LC/MS:t R=2.18 minutes, 574.23 (MH) +
Embodiment 11
(±)-4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-(1,4-two oxa-s-8-azepine-spiral shell [4.5] last of the ten Heavenly stems-8-yl)-1-(1H-indazole-5-ylmethyl)-2-oxo-ethyl]-amide
To 3-(1H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-propanoic acid (95mg, 0.21mmol) and N, N-diisopropylethylamine (0.14mL, 0.82mmol) dimethyl formamide (5mL) solution in add 1,4-two oxa-s-8-azaspiro [4,5] decane (32mg, 0.23mmol) and PyBOP (107mg, dichloromethane 0.21mmol) (5mL) solution.Reactant mixture was at room temperature stirred 16 hours.Use fine vacuum to remove all solvents.Residue through flash column chromatography, with methylene chloride/triethylamine (93: 5: 2) eluting, is obtained the title compound (67mg, 56% productive rate) of white solid. 1H-NMR(CDCl 3，500MHz)δ10.52(s，1H)，7.97(s，1H)，7.54(s，1H)，7.37(d，J＝8.6Hz，1H)，7.20(d，J＝10.7Hz，1H)，7.16(t，J＝7.2Hz，1H)，7.04(d，J＝7.6Hz，1H)，7.01(s，1H)，6.94(t，J＝8.6Hz，1H)，6.67(d，J＝7.6Hz，1H)，5.64(d，J＝7.9Hz，1H)，5.16(dd，J＝15.0，6.7Hz，1H)，4.56-4.49(m，1H)，4.25(s，2H)，4.11(br t，J＝15.6Hz，2H)，3.92-3.84(m，4H)，3.73-3.69(m，1H)，3.60-3.56(m，1H)，3.48-3.43(m，1H)，3.22-3.17(m，1H)，3.11(d，J＝6.7Hz，2H)，2.90-2.85(m，2H)，2.68-2.60(m，4H)，1.67-1.61(m，2H)，1.54-1.49(m，2H)。Mass spectrum: 588 (MH) +
4-bromo-2,6-3,5-dimethylphenyl diazo-tert-butyl group thioether (sulfide)
Figure A20038011103001001
With 4-bromo-2, (20.00g 100mmol) is milled to powder with mortar and pestle to the 6-dimethylaniline, and is suspended in then in 24% hydrochloric acid (41mL).This stirred mixture is cooled to-20 ℃, and handles, make temperature keep below-5 ℃ simultaneously with the aqueous solution (16mL) that time of 40 minutes drips sodium nitrite (7.24g, 1.05 equivalents).After keeping 30 minutes again under-5 ℃ to-20 ℃, it is 5 that mixture is buffered to about pH with the solid sodium acetate.Under 0 ℃,, this mixture (being maintained at about under-10 ℃) is joined in the agitating solution of tert-butyl mercaptan (11.3mL, 1 equivalent) in ethanol (100mL) in batches with about 10 minutes time.After the adding, mixture was stirred 30 minutes down at 0 ℃, and add finely divided ice (about 150mL) then.This mixture preserved in fridge spend the night.The light brown solid that filter to collect generates washes with water, and under fine vacuum dry a few hours (26.90g, 89%).This chemical compound is stable during as solid, but when attempting to use ethyl alcohol recrystallization, tangible decomposition takes place then.
1H-NMR(CDCl 3，500MHz)δ1.58(9H，s)，1.99(6H，s)，7.21(2H，s)。Mass spectrum: 303.05 (MH) +
5-bromo-7-methylindazole
With 4-bromo-2,6-3,5-dimethylphenyl diazo-tert-butyl group thioether (12.50g, 41.5mmol) and potassium tert-butoxide (46.56g, 10 equivalents) in flame-dried (flame-dried) round-bottomed flask, mix.Add splash bar (stirring bar), and mixture is placed under the nitrogen.To wherein adding exsiccant DMSO (120mL).With mixture at room temperature vigorous stirring spend the night.Reactant mixture is poured into carefully in the mixture of finely divided ice (400mL) and 10% hydrochloric acid (200mL) then.The suspension that generates is spent the night in 4 ℃ of placements, and this solid filtering is collected, and wash with water.Thick solid is dissolved in 5: 1 methylene chloride, and with solution through dried over mgso, and evaporation obtains the product (7.60g, 87%) of pale solid.
1H-NMR(CDCl 3/CD 3OD，500MHz)δ2.51(3H，s)，7.22(1H，s)，7.69(1H，s)，7.94(1H，s)。Mass spectrum: 211.03 (MH) +
7-methylindazole-5-formaldehyde
With 5-bromo-7-methylindazole (6.10g, 28.9mmol) and sodium hydride (60% in mineral oil, 1.27g, 1.1 equivalents) weigh and join in flame-dried (flame-dried) round-bottomed flask that is equipped with the magnetic splash bar.Under blanket of nitrogen, at room temperature, add exsiccant oxolane (30mL).Mixture was at room temperature stirred 15 minutes, and this mixture becomes homogeneous phase during this period.This stirred mixture is cooled to-70 ℃, and with time of a few minutes, adds cyclohexane extraction (1.4M, 45mL, the 2.2 equivalents) solution of s-butyl lithium.At-70 ℃ after following 1 hour, add dimethyl formamide (10mL) with time of a few minutes.Mixture is warmed to room temperature, and stirs and spend the night.It is cooled to 0 ℃ then, and uses 1N hydrochloric acid (60mL) to handle carefully.After a few minutes, add solid sodium bicarbonate with this mixture is alkalized to pH be 9-10.Separate each layer, and water is washed twice with ethyl acetate.With organic facies 0.8M sodium bisulfate (3 * 125mL) extractions that merge.The water that merges is washed with ethyl acetate (100mL), and then with solid sodium hydroxide with pH regulator extremely about 10.With suspension ethyl acetate (3 * 150mL) extractions that generate.The organic facies that merges is washed with salt, and dry (magnesium sulfate) and evaporation obtain filbert solid product (3.01g, 65%). 1H-NMR(CDCl 3，500MHz)δ2.63(3H，s)，7.73(1H，s)，8.12(1H，s)，8.25(1H，s)，10.03(1H，s)。Mass spectrum: 161.06 (MH) +
2-benzyloxycarbonyl amino-3-(7-methyl isophthalic acid H-indazole-5-yl)-acrylic acid methyl ester.
At room temperature, the agitating solution of N-benzyloxycarbonyl-α-phosphono glycine trimethyl (5.51g, 1.2 equivalents) in oxolane (30mL) handled with tetramethyl guanidine (1.91mL, 1.1 equivalents).After 10 minutes, add 7-methylindazole-5-formaldehyde (2.22g, oxolane 13.86mmol) (20mL) solution.Disappearance by TLC and LC/MS monitoring starting material.After at room temperature 5 days, evaporating solvent, and residue is dissolved in the ethyl acetate.Solution is washed dry (magnesium sulfate) and evaporation with 2% phosphoric acid and salt.With residue through flash chromatography on silica gel method purification, with 1) 1: 1 and 2) 2: 1 ethyl acetate/hexane eluting, obtain the product (4.93g, 97%) of colourless foam shape.
1H-NMR(CDCl 3，500MHz)δ2.43(3H，s)，3.80(3H，s)，5.12(2H，s)，6.66(1H，s)，7.28(5H，brs)，7.33(1H，s)，7.47(1H，s)，7.74(1H，s)，7.96(1H，s)。Mass spectrum: 366.16 (MH) +
(±)-2-amino-3-(7-methyl isophthalic acid H-indazole-5-yl)-methyl propionate
Feed nitrogen 30min by bubbling, (4.93g, methanol 13.49mmol) (125mL) solution outgases, and adds 10% palladium charcoal (0.6g) then carefully to make 2-benzyloxycarbonyl amino-3-(7-methyl isophthalic acid H-indazole-5-yl)-acrylic acid methyl ester..Jolt in the device at the Parr of 40psi, mixture hydrogenation is spent the night.Catalyst is removed by filter by Celite pad, and vacuum concentrated filtrate, obtain the product (3.62g, quantitative) of colourless foam shape.
1H-NMR(CD 3OD，500MHz)δ2.45(3H，s)，2.99(1H，Abq)，3.22(1H，Abq)，3.74(3H，s)，3.89(1H，m)，6.91(1H，s)，7.31(1H，s)，7.73(1H，s)。Mass spectrum: 234.11 (MH) +
Embodiment 12
(±)-3-(7-methyl isophthalic acid H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-methyl propionate
Figure A20038011103001022
At room temperature, (162.9mg, 0.698mmol) agitating solution in dichloromethane (3mL) is handled with carbonyl dimidazoles (113.2mg, 1 equivalent) with (±)-2-amino-3-(7-methyl isophthalic acid H-indazole-5-yl)-methyl propionate.After at room temperature 1.5 hours, add 3-piperidin-4-yl-3,4-dihydro-1H-quinazoline-2-ketone (161.5mg, 1 equivalent).Mixture at room temperature stirred spend the night.Form white depositions, show that it is required product.Evaporating solvent, and residue ground with dichloromethane.Filter and collect product, wash with dichloromethane, and vacuum drying, white solid (241.5mg, 71%) obtained.Some products are still stayed in the mother solution.
1H-NMR (dimethyl formamide-d7,500MHz) δ 1.75 (4H, m), 2.78 (3H, s), 2.7-3.1 (4H, m), 3.35 (2H, m), 3.86 (3H, s), 4.44 (2H, s), 4.57 (1H, m), 4.72 (1H, m), 7.11 (3H, m), 7.31 (1H, s), 7.34 (2H, m), 7.72 (1H, s), 9.34 (1H, s).Mass spectrum: 491.13 (MH) +
Preparation similarly:
Embodiment 13
3-(7-methyl isophthalic acid H-indazole-5-yl)-2-[2 ', 3 '-dihydro-2 '-the oxo spiral shell-(piperidines-4,4 '-(1H)-and quinazoline) carbonylamino]-methyl propionate
Figure A20038011103001031
1H-NMR(DMSO-d 6)δ1.59(4H，m)，2.46(3H，s)，3.00-3.08(4H，m)，3.6(3H，s)，3.78-3.81(2H，m)，4.30-4.32(1H，m)，6.78-6.88(4H，m)，7.03(1H，s)，7.10(IH，m)，7.13(1H，s)，7.41(1H，s)，7.96(1H，s)，9.12(1H，s)。Mass spectrum: 477.11 (MH) +
Embodiment 14
3-(7-methyl isophthalic acid H-indazole-5-yl)-2-(1,2-dihydro-2-oxo-spiral shell-4H-3,1-dihydro-benzoxazine-4 ' 4-piperidines-carbonylamino)-methyl propionate
Mass spectrum: 478.15 (MH) +
3-(7-methyl isophthalic acid H-indazole-5-yl)-2{3 ', 4 '-dihydro-2 '-the oxo spiral shell-(piperidines-4,4 '-(1H)-the quinoline carbonylamino }-methyl propionate
1H-NMR(DMSO-d 6)δ1.42-1.56(4H，m)，2.47(3H，s)，2.50-2.54(1H，d)，2.60-2.64(1H，d)，2.98-3.06 4H，m)，3.60(3H，s)3.80(2H，m)，4.30(1H，m)，6.86(2H，d)，6.95(2H，m)，7.15(1H，m)，7.40(1H，s)，7.95(1H，s)，8.32(1H，s)，10.14(1H，s)，13.05(1H，s)。Mass spectrum: 476.17 (MH) +
3-(7-methyl isophthalic acid H-indazole-5-yl)-2-[2 '-phenyl-1 ', 3 ', 8 '-three azepines-spiral shell (4 ', 5 ') last of the ten Heavenly stems (deo)-1-alkene-8-carbonylamino]-methyl propionate
1H-NMR (DMSO-d 6) δ 1.50 (2H, m), 1.68 (2H, m), 2.46 (3H, s is covered by DMSO), 3.05 (2H, m), 3.30 (2H, m), 3.60 (3H, s), 3.86 (2H, m), 4.28 (1H, m), 6.98 (1H, d), 7.04 (1H, s), 7.40 (1H, s), 7.58 (2H, m), 7.65 (1H, m), 8.00 (1H, s), 8.04 (2H, m).Mass spectrum: 489.15 (MH) +
Embodiment 15
(±)-3-(7-methyl isophthalic acid H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-propanoic acid
At room temperature, with (±)-3-(7-methyl isophthalic acid H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-methyl propionate (240.0mg, 0.489mmol) suspension in 1: 1 oxolane/methanol (20mL) handles with the aqueous solution (10mL) of Lithium hydrate (140.5mg, 7 equivalents).In 1 minute, this mixture becomes homogeneous phase, and it is spent the night 4 ℃ of placements.At about 30 ℃ of following these solvents of evaporation, and with 1N hydrochloric acid with pH regulator extremely about 1.The white suspension that generates is stored a few hours down at 4 ℃, and filter and collect product, with a spot of as far as possible washing, and vacuum drying (169.0mg, 73%).Solid sodium chloride is joined in the filtrate, obtain being rich in the precipitation (5.2mg, gross production rate 75%) of product.
1H-NMR(CD 3OD，500MHz)δ1.2-1.7(4H，m)，2.58(3H，s)，2.5-3.2(4H，m)，3.35(2H，m)，4.15(2H，m)，4.36(1H，m)，4.60(1H，m)，6.79(1H，d)，6.96(1H，t)，7.18(3H，m)，7.49(1H，s)，8.00(1H，s)。Mass spectrum: 477.13 (MH) +
Preparation similarly:
3-(7-methyl isophthalic acid H-indazole-5-yl)-2-[2 ', 3 '-dihydro-2 '-the oxo spiral shell-(piperidines-4,4 '-(1H)-the quinazoline carbonylamino]-propanoic acid
Figure A20038011103001052
1H-NMR(DMSO-d 6)δ1.58(4H，m)，2.46(3H，s)，3.00-3.23(3H，m)，3.78-3.91(3H，m)，3.88(2H，m)4.28(1H，s)，6.70(1H，d)，6.75-6.85(3H，m)，7.04(1H，d)，7.11(1H，m)7.18(1H，s)，7.96(1H，s)，13.02(1H，m)。Mass spectrum: 463.09 (MH) +
3-(7-methyl isophthalic acid H-indazole-5-yl)-2-(1,2-dihydro-2-oxo-spiral shell-4H-3,1-dihydro-benzoxazine-4 ' 4-piperidines-carbonylamino)-methyl propionate
Figure A20038011103001061
1H-NMR (DMSO-d 6) δ 1.63-1.98 (4H, m), 2.46 (7-Me is covered by DMSO for 3H, s), 2.98-3.32 (4H, m), 3.90 (2H, m), 4.28 (1H, m), 6.78 (1H, d), 6.87 (2H, m), 6.96 (1H, m), 7.05 (1H, s), 7.24 (1H, m), 7.41 (1H, s), 7.96 (1H, s), 10.22 (1H, s) 12.42 (1H, and br.) 13.02 (1H, m).Mass spectrum: 464.07 (MH) +
3-(7-methyl isophthalic acid H-indazole-5-yl)-2{3 ', 4 '-dihydro-2 '-the oxo spiral shell-(piperidines-4,4 '-(1H)-quinoline-carbonylamino }-propanoic acid
Figure A20038011103001062
1H-NMR(DMSO-d 6)δ1.39-1.45(2H，m)，1.53-1.56(2H，m)，2.46(3H，s)，2.50-2.54(1H，d)，2.60-2.63(1H，d)，2.88-3.00(3H，m)，3.09-3.11(1H，m)，3.78-3.81(2H，m)，4.27(1H，m)，6.69-6.70(1H，d)，6.86-6.87(1H，d)，6.93-6.94(1H，m)6.99-7.00(1H，m)，7.05(1H，m)，7.41(1H，s)，7.95(1H，s)，10.13(1H，s)，12.50(1H，m)，13.03(1H，m)。Mass spectrum: 462 (MH) +
3-(7-methyl isophthalic acid H-indazole-5-yl)-2-[2 '-phenyl-1 ', 3 ', 8 '-three azepines-spiral shell (4 ', 5 ') last of the ten Heavenly stems-1-alkene-8-carbonylamino]-propanoic acid
1H-NMR (DMSO-d 6) δ 1.36 (2H, m), 1.63 (2H, m), 2.46 (3H, s is covered by DMSO), 2.98-3.03 (2H.m), 3.09-3.11 (2H, m), 3.86 (2H, m), 4.21 (1H, m), 6.69 (1H, m), 7.04 (1H, s), 7.40 (1H, s), 7.52-7.58 (3H, m), 7.99 (3H, m), 11.55 (1H, m), 13.00 (1H, m).Mass spectrum: 475.08 (MH) +
Embodiment 16
(±)-4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-2-oxo-ethyl]-amide
Under 0 ℃, with (±)-3-(7-methyl isophthalic acid H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-propanoic acid (65.7mg, 0.138mmol) agitating solution in 2: 1 dimethylformamide/dichloromethane (1.5mL) is with 4-(piperidino)-piperidines (46.5mg, 2 equivalents), diisopropylethylamine (0.048mL, 2 equivalents) and PyBOP (75.5mg, 1.05 equivalents) are handled.Make ice bath fusing, and mixture at room temperature stirred spend the night.Remove under the fine vacuum and desolvate, and with residue through flash chromatography on silica gel method purification, with 18: 1 methylene chloride eluting that contain 1% triethylamine, obtain the product (80.4mg, 93%) of light yellow solid.
1H-NMR (CD 3OD, 500MHz) δ-0.28 (1H, m), 0.75 (1H, m), 1.2-2.0 (12H, m), 2.08 (2H, m), 2.4-2.5 (3H, m), 2.59 (3H, s), 2.68 (2H, m), 2.90 (4H, m), 3.08 (4H, m), 3.9-5.1 (4H, some m), 6.81 (1H, d), 6.96 (1H, t), 7.16 (3H, m), 7.49 (1H, s), 8.03 (1H, s).Mass spectrum: 627.29 (MH) +
Preparation similarly:
Embodiment 17
(±)-4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [1-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-2-oxo-2-piperidines-1-base-ethyl]-amide
Figure A20038011103001081
1H-NMR(CD 3OD，500MHz)δ0.87(1H，m)，1.33(1H，m)，1.47(2H，m)，1.80(6H，m)，2.57(3H，s)，2.89(2H，m)，3.06(2H，m)，3.18(4H，m)，3.40(2H，m)，3.61(1H，m)，4.16(1H，m)，4.28(1H，Abq)，4.43(1H，m)，5.02(1H，m)，6.51(1H，d)，6.79(1H，d)，6.96(1H，t)，7.11(1H，d)，7.15(1H，t)，7.48(1H，s)，8.01(1H，s)。Mass spectrum: 544.24 (MH) +
Embodiment 18
(±)-4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [1-formyl-dimethylamino-2-(7-methyl isophthalic acid H-indazole-5-yl)-ethyl]-amide
1H-NMR(CD 3OD，500MHz)δ1.12(2H，d)，1.64(2H，m)，2.57(3H，s)，2.74(1H，m)，2.87(3H，s)，2.89(3H，s)，2.86(2H，m)，3.07(2H，m)，3.20(1H，m)，4.17(1H，m)，4.25(1H，Abq)，4.43(1H，m)，4.97(1H，m)，6.79(1H，d)，6.95(1H，t)，7.0-7.4(3H，m)，7.48(1H，d)，8.01(1H，s)。Mass spectrum: 504.15 (MH) +
Embodiment 19
(±)-4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [1-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-2-(4-methyl-piperazine-1-yl)-2-oxo-ethyl]-amide
1H-NMR(CD 3OD，500MHz)δ1.30(2H，m)，1.66(2H，m)，1.78(1H，m)，1.90(1H，m)，2.00(3H，s)，2.19(1H，m)，2.35(1H，m)，2.58(3H，s)，2.88(2H，m)，3.09(2H，d)，3.10-3.45(3H，m)，3.66(1H，m)，4.19(2H，d)，4.20(2H，s)，4.43(1H，m)，4.98(1H，t)，6.80(1H，d)，6.95(1H，t)，7.11(2H，m)，7.16(1H，t)，7.47(1H，s)，8.02(1H，s)。Mass spectrum: 559.23 (MH) +
Embodiment 20
(±)-4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [1-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-2-oxo-2-pyrrolidine-1-base-ethyl]-amide
Figure A20038011103001092
1H-NMR(CD 3OD，500MHz)δ1.40-1.90(5H，m)，2.02(3H，brs)，2.57(3H，s)，2.86(1H，m)，2.89(2H，q)，3.09(2H，m)，3.16(1H，m)，3.25(2H，m)，3.40(1H，m)，3.56(1H，m)，4.17(2H，d)，4.27(2H，s)，4.40(1H，m)，4.69(1H，t)，6.80(1H，d)，6.95(1H，t)，7.10(1H，s)，7.16(1H，m)，7.48(1H，s)，7.53(1H，m)，8.01(1H，s)。Mass spectrum: 530.19 (MH) +
Embodiment 21
(±)-4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [1-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-2-oxo-2-(4-pyridin-4-yl-piperazine-1-yl)-ethyl]-amide
Figure A20038011103001101
1H-NMR(CD 3OD，500MHz)δ1.38(1H，t)，1.68(2H，m)，1.81(1H，m)，2.30(1H，m)，2.53(3H，s)，2.95(4H，m)，3.13(2H，d)，3.22(1H，m)，3.35-3.65(4H，m)，3.79(1H，m)，4.18(2H，d)，4.31(2H，s)，4.42(1H，m)，4.99(1H，t)，6.64(2H，d)，6.80(1H，d)，6.89(1H，m)，6.96(1H，t)，7.14(3H，m)，7.51(1H，s)，7.99(1H，s)，8.10(2H，d)，8.16(1H，m)。Mass spectrum: 622.26 (MH) +
Embodiment 22
(±)-4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [1-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-2-oxo-2-(4-pyridine-2-base-piperazine-1-yl)-ethyl]-amide
Figure A20038011103001102
1H-NMR(CD 3OD，500MHz)δ1.27(1H，m)，1.38(1H，m)，1.67(2H，m)，1.84(1H，m)，2.54(3H，s)，2.65(1H，m)，2.88(2H，m)，3.15(4H，m)，3.35(1H，m)，3.58(3H，m)，3.77(1H，m)，4.18(2H，d)，4.30(2H，s)，4.42(1H，m)，5.01(1H，t)，6.62(1H，d)，6.70(1H，t)，6.80(1H，d)，6.95(1H，t)，7.103H，m)，7.50(1H，s)，7.54(1H，t)，7.99(1H，s)，8.05(1H，7)。Mass spectrum: 622.25 (MH) +
Embodiment 23
(±)-1-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-2-[1,4-joins piperidines]-1-base-2-oxoethyl]-2 ', 3 '-dihydro-2 '-the oxo spiral shell-[piperidines-4,4 '-(1H)-quinazoline]-the 1-Methanamide
Figure A20038011103001111
1H-NMR(DMSO-d 6，500MHz)δ1.2-1.73(14H，m)，2.46(3H，s)，2.75-3.24(12H，m)，3.87(2H，m)，4.45(1H，m)，4.78-4.85(1H，m)，6.80(1H，m)，6.86(1H，m)，7.05(1H，m)，7.12(1H，m)，7.21(1H，m)，7.27(2H，m)，7.98(1H，m)，9.23(1H，m)。Mass spectrum: 613.25 (MH) +
Embodiment 24
(±)-1-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-2-(piperidino)-2-oxoethyl]-2 ', 3 '-dihydro-2 '-the oxo spiral shell-[piperidines-4,4 '-(1H)-quinazoline]-the 1-Methanamide
1H-NMR(CD 3OD，500MHz)δ0.87(1H，m)，1.28-1.47(5H，m)，1.74-1.85(4H，m)，2.53(3H，s)，3.02-3.38(8H，m)，3.92(2H，m)，5.02(1H，m)，6.82(1H，d)，6.99(1H，d)，7.04-7.09(2H，m)，7.17(1H，m)，7.32(2H，s)，7.45(1H，s)，7.96(1H，s)。Mass spectrum: 530.17 (MH) +
Embodiment 25
(±)-1-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-2-[1,4-joins piperidines]-1-base-2-oxoethyl]-1 ', 2 '-dihydro-2 '-the oxo spiral shell-[4H-3 ', 1-benzoxazine-4,4 '-piperidines]-the 1-Methanamide
Figure A20038011103001121
1H-(DMSO-d 6，500MHz)δ1.88(14H，m)，2.64(3H，s)，2.78(12H，m)，4.0(2H，m)，4.4(1H，m)，4.85(1H，m)，6.80-6.88(2H，m)，7.03(2H，m)，7.11(1H，m)，7.23(1H，m)，7.36(2H，m)，7.97(1H，m)。Mass spectrum: 614.73 (MH) +
Embodiment 26
(±)-1-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-2-(piperidino)-2-oxoethyl]-1 ', 2 '-dihydro-2 '--the oxo spiral shell-[4H-3 ', 1-benzoxazine-4,4 '-piperidines]-the 1-Methanamide
Figure A20038011103001122
1H-NMR(DMSO-d 6，500MHz)δ1.15-1.91(10H，m)，2.47(3H，s)，2.95-3.05(6H，m)3.40(4H，m)3.95(2H，d)，4.81(1H，m)，6.81(1H，d)，6.88(1H，d)，6.94(1H，m)，6.99(1H，m)，7.04(1H，s)，7.24(1H，m)，7.37(1H，s)，7.96(1H，s)。Mass spectrum: 531.23 (MH) +
Embodiment 27
(±)-[1-formyl-dimethylamino-2-(7-methyl isophthalic acid H-indazole-5-yl)-ethyl]-1 ', 2 '-dihydro-2 '-the oxo spiral shell-[4H-3 ', 1-benzoxazine-4,4 '-piperidines]-the 1-Methanamide
1H-NMR(DMSO-d 6，500MHz)δ1.68-1.88(4H，m)，2.47(3H，m)，2.79(6H，s)，2.89-3.04(4H，m)，3.96(2H，d)，4.75(1H，m)，6.81(1H，d)，6.88(1H，m)，6.93(1H，m)，6.98(1H，m)，7.05(1H，s)，7.24(1H，m)，7.43(1H，s)，7.97(1H，m)，8.32(1H，s)。Mass spectrum: 491.14 (MH) +
Embodiment 28
(±)-[1-(2-adamantyl-carbamoyl)-2-(7-methyl isophthalic acid H-indazole-5-yl)-ethyl]-1 ', 2 '-dihydro-2 '-the oxo spiral shell-[4H-3 ', 1-benzoxazine-4,4 '-piperidines]-the 1-Methanamide
1H-NMR(DMSO-d 6，500MHz)δ1.40-1.95(15H，m)，2.46(3H，m)，2.89-3.07(4H，m)，3.81(1H，m)，3.90(2H，m)，4.48(1H，m)，6.74(2H，m)，6.86(1H，d)，6.97(1H，m)，7.11(1H，s)，7.24(1H，m)，7.36(1H，s)，7.44(1H，s)，7.96(1H，s)。Mass spectrum: 597.27 (MH) +
Embodiment 29
(±)-1 ', 2 '-dihydro-2 '-the oxo spiral shell-[4H-3 ', 1-benzoxazine-4,4 '-piperidines-1-carboxylic acid [1-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-2-oxo-2-(4-pyridin-4-yl-piperazine-1-yl)-ethyl]-amide
Figure A20038011103001132
LC/MS:t R=1.56 minutes, 609.14 (MH) +
Embodiment 30
(±)-1 ', 2 '-dihydro-2 '-the oxo spiral shell-[4H-3 ', 1-benzoxazine-4,4 '-piperidines-1-carboxylic acid 2-(7-methyl isophthalic acid H-indazole-5-yl)-1-[(pyridin-4-yl methyl)-carbamoyl]-ethyl }-amide
Figure A20038011103001141
LC/MS:t R=1.49 minutes, 553.12 (MH) +
Embodiment 31
(±)-1-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-2-[1,4-joins piperidines]-1-base-2-oxoethyl] 3 ', 4 '-dihydro-2 '-the oxo spiral shell-[piperidines-4,4 '-(1H)-quinoline]-the 1-Methanamide
Figure A20038011103001142
1H-NMR(DMSO-d 6，500MHz)δ1.20-2.00(14H，m)，2.46(3H，s)，2.38-3.03(12H，m)，3.87(2H，m)，4.34(1H，m)，4.76-4.87(1H，m)，6.65(1H，m)，6.82-7.64(3H，m)，7.13-7.23(2H，m)，7.36(3h，m)，7.96(1H，s)。Mass spectrum: 612.32 (MH) +
Embodiment 32
(±)-1-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-2-[1-piperidyl]-the 2-oxoethyl] 3 ', 4 '-dihydro-2 '-the oxo spiral shell-[piperidines-4,4 '-(1H)-quinoline]-the 1-Methanamide
Figure A20038011103001151
1H-NMR(DMSO-d 6，500MHz)δ1.10-1.68(10H，m)，2.46(3H，s)，2.50-2.60(2H，m)，2.82-2.97(4H，m)，3.39(2H，m)，3.85(2H，m)，4.80(1H，m)，6.68(1H，m)，6.87(1H，d)，6.94(1H，m)，7.03(1H，s)，7.06(1H，m)，7.15(1H，m)，7.37(1H，s)，7.40(1H，s)，7.96(1H，s)。Mass spectrum: 529.25 (MH) +
Embodiment 33
(±)-[1-formyl-dimethylamino-2-(7-methyl isophthalic acid H-indazole-5-yl)-ethyl]-3 ', 4 '-dihydro-2 '-the oxo spiral shell-[piperidines-4,4 '-(1H)-quinoline]-the 1-Methanamide
Figure A20038011103001152
1H-NMR(DMSO-d 6，500MHz)δ1.43(2H，m)，1.56(2H，m)，2.46(3H，s)，2.56(2H，m)，2.79(3H，s)，2.90(5H，m)，3.84(2H，m)，4.731H，m)，6.69(1H，d)，2.69(1H，d)，6.94(1H，m)，7.05(2H，m)，7.14(1H，m)，7.37(1H，s)，7.42(1H，s)，7.96(1H，s)。Mass spectrum: 489.2 (MH) +
Embodiment 34
(±)-4-oxo-2-phenyl-1,3,8-three azepines-spiral shell [4,5] last of the ten Heavenly stems-1-alkene-8-carboxylic acid 1-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-2-[1,4] connection piperidines-1 '-Ji-2-oxo-ethyl }-amide
1H-NMR (DMSO-d 6, 500MHz) δ 1.34-2.00 (14H, m), 2.48 (3H, s and DMSO are overlapping), 2.70-3.30 (12H, m), 3.90 (2H, m), 4.40 (1H, m), 4.82 (1H, m), 6.82 (1H, m), 7.04 (1H, s), 7.37 (2H, m), 7.56 (3H, m), 7.98 (3H, m).Mass spectrum: 625.29 (MH) +
Embodiment 35
(±)-4-oxo-2-phenyl-1,3,8-three azepines-spiral shell [4,5] last of the ten Heavenly stems-1-alkene-8-carboxylic acid 1-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-2-[1-piperidyl]-2-oxo-ethyl }-amide
1H-NMR(DMSO-d 6，500MHz)δ1.10-1.62(6H，m)，1.73(4H，m)，2.48(3H，s)，3.00(6H，m)，3.39(2H，m)，3.93(2H，m)，4.82(1H，m)，6.78(1H，m)，7.05(1H，s)，7.37(2H，s)，7.40(1H，s)，7.53(2H，m)，7.98(2H，m)。Mass spectrum: 543.26 (MH) +
Embodiment 36
(±)-4-oxo-2-phenyl-1,3,8-three azepines-spiral shell [4,5] last of the ten Heavenly stems-1-alkene-8-carboxylic acid [1-formyl-dimethylamino-2-(7-methyl isophthalic acid H-indazole-5-yl)-ethyl] amide
1H-NMR(DMSO-d 6，500MHz)δ1.28-1.61(4H，m)，2.78(4H，m)，2.90(6H，m)，3.94(2H，m)，4.74(1H，m)，6.77(1H，m)，7.05(1H，s)，7.37(4H，s)，7.42(1H，s)，7.52(2H，m)，7.98(2H，m)。Mass spectrum: 502.21 (MH) +
Embodiment 37
4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid 1-(1H-indazole-5-ylmethyl)-2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-yl]-ethyl }-amide
LC/MS:t R=1.51 minutes, 674 (MH) -
Embodiment 38
4-(3-(1H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-propiono)-piperazine-1-carboxylic acid benzyl ester
Figure A20038011103001172
LC/MS:t R=1.74 minutes, 665 (MH) +
Embodiment 39
4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [1-(1H-indazole-5-ylmethyl)-2-oxo-2-piperazine-1-base-ethyl]-amide
Figure A20038011103001181
To 4-(3-(1H-indazole-5-yl)-2-{[4-(2-oxo-1; 4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-propiono)-(280mg 0.42mmol) adds 10% palladium charcoal (50mg) to piperazine-1-carboxylic acid benzyl ester in the de gassed solution in methanol (50ml).Under the 50psi nitrogen atmosphere, mixture was vibrated 3 hours in the Parr device.Mixture is passed through diatomite filtration.Concentrating under reduced pressure filtrate obtains the required product of 91% productive rate.LC/MS:t R=1.22 minutes, 531 (MH) +
Embodiment 40a
4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid 1-(1H-indazole-5-ylmethyl)-2-[4-(2-methyl-butyl)-piperazine-1-yl]-2-oxo-ethyl }-amide
With 4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [1-(1H-indazole-5-ylmethyl)-2-oxo-2-piperazine-1-base-ethyl]-amide (100mg, 0.188mmol) (0.03ml 0.376mmol) handles with 2-methyl-butyraldehyde for agitating solution in methanol (25mL).After at room temperature 1 hour, and the adding sodium triacetoxy borohydride (80mg, 0.316mmol).The mixture stirring is spent the night.Solution is filtered by the SCX post.Post is at first used methanol-eluted fractions, and use the methanol solution eluting of 1M ammonia then.Solvent removed in vacuo obtains the required product of 50% productive rate.LC/MS:t R=1.31 minutes, 601 (MH) +
The general experimental technique of preparation embodiment 40b-40k
Suitable aldehyde (0.04mmol) is joined in methanol (2.0mL) solution of embodiment 39 piperazines (0.02mmol), and the solution that generates was at room temperature vibrated 1 hour.Add sodium triacetoxy borohydride (0.2mmol) then, and solution at room temperature stirred spend the night.Filter this solution by the SCX post then, and this post is washed with methanol and ammonia hydroxide/methanol.The vacuum concentration ammonia hydroxide/methanol, and with crude product by the preparation HPLC purification, obtain product listed in the table 1.
Table 1. embodiment 40b-40k
Figure A20038011103001191
Figure A20038011103001201
Embodiment 41a
3-(7-methyl isophthalic acid H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-cyclohexyl propionate
To (±)-2-amino-3-(7-methyl isophthalic acid H-indazole-5-yl)-propanoic acid (propinic acid) (20mg, 0.042mmoles), 4-(dimethylamino) pyridine (2.5mg, 0.02mmoles) and 1-[3-(dimethylamino) propyl group]-3-ethyl-carbodiimide hydrochloride (33mg, 0.17mmoles) add in the agitating solution in dichloromethane (2mL) and dimethyl formamide (1mL) Hexalin (13.3 μ L, 0.126mmoles).Reactant mixture was stirred 4 hours down at 50-55 ℃.Removal of solvent under reduced pressure, with residue on silica gel by preparation type TLC (9: 1 chloroform/methanol) purification, obtain the required product (9.4mg, 40%) of white solid.
1H-NMR(CD 3OD，500MHz)δ1.32-1.87(14H，m)，2.57(3H，s)，2.86(2H，m)，3.11-3.26(2H，m)，4.13-4.22(3H，m)，4.46(1H，m)，4.55(1H，m)，4.80(1H，m)，6.79(1H，d)，6.97(1H，m)，7.08-7.18(2H，m)，7.35(1H，s)，7.47(1H，s)，8.01-8.02(1H，m)。Mass spectrum: 559.22 (MH) +
Preparation similarly:
Embodiment 41b
3-(7-methyl isophthalic acid H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-propanoic acid 1-benzyl-piperidin-4-yl ester
LC/MS:t R=1.76 minutes, 650.30 (MH) +
Embodiment 41c
3-(7-methyl isophthalic acid H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-propanoic acid 1-methyl-piperidin-4-yl ester
Figure A20038011103001212
LC/MS:t R=1.59 minutes, 574.27 (MH) +
Embodiment 41d
3-(7-methyl isophthalic acid H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-propanoic acid 4-phenyl-cyclohexyl
Figure A20038011103001213
LC/MS:t R=2.69 minutes, 635.29 (MH) +
Embodiment 41e
3-(7-methyl isophthalic acid H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-propanoic acid (R)-1-pyridin-4-yl-ethyl ester
Figure A20038011103001221
LC/MS:t R=1.66 minutes, 582.22 (MH) +
Embodiment 41f
3-(7-methyl isophthalic acid H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-propanoic acid (S)-1-pyridin-4-yl-ethyl ester
Figure A20038011103001222
LC/MS:t R=1.65 minutes, 582.23 (MH) +
4-bromo-2-chloro-6-aminomethyl phenyl diazo-tert-butyl group thioether
Figure A20038011103001223
(4.0g 18.3mmol) is suspended in 24% hydrochloric acid (5mL) with 4-bromo-2-chloro-6-monomethylaniline..This stirred mixture is cooled to-20 ℃, and handles, make temperature keep below-5 ℃ simultaneously with the aqueous solution (2mL) that dripped sodium nitrite (1.32g, 1.05 equivalents) in 10 minutes.After keeping 30min again under-5 ℃ to-20 ℃, mixture is buffered to pH with the solid sodium acetate is about 5.Under 0 ℃,, this mixture (being maintained at about under-10 ℃) is joined in the agitating solution of tert-butyl mercaptan (2.06mL, 1 equivalent) in ethanol (18.5mL) in batches with about 10 minutes time.After the adding, mixture is stirred down 30min at 0 ℃, and add finely divided ice (about 50mL) then.Mixture preserved in fridge spend the night.The light brown solid that filter to collect generates washes with water, and under fine vacuum dry several hours (4.60g, 78%).Mass spectrum: 323.03 (MH) +
5-bromo-7-chlorine indazole
Figure A20038011103001231
With 4-bromo-2-chloro-6-aminomethyl phenyl diazo-tert-butyl group thioether (4.60g, 14.4mmol) and potassium tert-butoxide (16.1g, 10 equivalents) in flame-dried (flame-dried) round-bottomed flask, mix.Add splash bar, and mixture is placed under the nitrogen.In this mixture, add exsiccant DMSO (50mL).With mixture vigorous stirring 10min at room temperature.Reactant mixture is poured into carefully in the mixture of finely divided ice (150mL) and 10% hydrochloric acid (74mL) then.The suspension placement under 4 ℃ that generates is spent the night, and filter and collect this solid, and wash with water.Collect this solid, and vacuum drying, 2.86g (86%) beige solid obtained. 1H-NMR(CDCl 3，500MHz)δ7.52(d，J＝1.5，1H)，7.82(d，J＝1.5，1H)，8.08(s，1H)。Mass spectrum: 230.90 (MH) +
7-chlorine indazole-5-formaldehyde
Figure A20038011103001232
With 5-bromo-7-chlorine indazole (2.0g, 8.7mmol) and sodium hydride (221mg, 1.1 equivalents) weigh and join in flame-dried (flame-dried) round-bottomed flask that is equipped with the magnetic splash bar.Under blanket of nitrogen, at room temperature, add exsiccant oxolane (30mL).Mixture was at room temperature stirred 15 minutes, and this mixture becomes homogeneous phase during this period.Make this stirred mixture be cooled to-78 ℃, and add the pentane solution (1.7M, 10.5mL, 2.0 equivalents) of tert-butyl lithium with time of a few minutes.Behind-78 ℃ of following 30min, this reactant is warmed to-50 ℃ gradually, keep 15 minutes in the case, and be cooled to-78 ℃ once more.Slowly add dimethyl formamide (2.8mL), and mixture is warmed to-50 ℃.This solution is transferred in the separatory funnel that contains ether and water fast.Make this acidified aqueous solution by adding the 1M potassium acid sulfate, and by adding the sodium bicarbonate neutralization.This aqueous solution with extracted with diethyl ether (3x), then with the salt washing, through dried over mgso, and is concentrated its water, obtain the almost pure material of 1.7g (100%).Obtain analytically pure sample by recrystallization from the methanol of heat.
1H-NMR(CDCl 3，500MHz)δ7.97(s，1H)，8.20(s，1H)，8.30(s，1H)，10.02(s，1H)。Mass spectrum: 181.09 (MH) +.
2-benzyloxycarbonyl amino-3-(7-chloro-1H-indazole-5-yl)-acrylic acid methyl ester.
Figure A20038011103001241
The stirred suspension of potassium tert-butoxide (375mg, 1.2 equivalents) in dichloromethane (20mL) is cooled to-20 ℃, and with dichloromethane (5mL) solution-treated of N-benzyloxycarbonyl-α-phosphono glycine trimethyl (1.11g, 1.2 equivalents).After 10 minutes, add 7-chlorine indazole-5-formaldehyde (0.50g, dichloromethane 2.79mmol) (5mL) solution.Should react and be warmed to room temperature gradually, and stir 3 days.This reactant is poured in the separatory funnel of moisture and ether.Aqueous solution with extracted with diethyl ether (3x), is washed it with salt,, and concentrated through dried over mgso.Obtain 0.40g (37%) product and 0.20g (40%) starting material through column chromatography.
1H-NMR(CDCl 3，500MHz)δ3.64(s，3H)，5.11(s，2H)，6.44(bs，1H)，7.30(bs，5H)，7.43(s，1H)，7.62(s，1H)，7.80(s，1H)，8.07(s，1H)。Mass spectrum: 386.16 (MH) +
(±)-2-amino-3-(7-chloro-1H-indazole-5-yl)-methyl propionate
Figure A20038011103001242
Under competent nitrogen, (300mg, methanol 0.78mmol) (10mL) solution is handled with trifluoroacetic acid (0.2mL), uses 10% palladium charcoal (30mg) to handle then with 2-benzyloxycarbonyl amino-3-(7-chloro-1H-indazole-5-yl)-acrylic acid methyl ester..Be full of flask with hydrogen, under nitrogen atmosphere, stir then.After 4 days, all starting materials are all depleted.Should react and use nitrogen wash,, and concentrate by diatomite filtration.Through column chromatography, obtain 78mg (40%).
1H-NMR(CDCl 3，500MHz)δ1.31(bs，3H)，2.95(dd，J＝13.7，7.9，1H)，3.18(dd，J＝13.7，5.2，1H)，3.48(s，3H)，3.78(dd，J＝7.9，5.2，1H)，7.23(s，1H)，7.46(s，1H)，8.00(s，1H)。Mass spectrum: 254.06 (MH) +
Embodiment 42
(±)-3-(7-chloro-1H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-methyl propionate
Figure A20038011103001251
Under 0 ℃, (78mg, 0.31mmol) agitating solution in oxolane (2mL) is handled with carbonyl dimidazoles (50mg, 1 equivalent) with (±)-2-amino-3-(7-chloro-1H-indazole-5-yl)-methyl propionate.Should react and stir 5min, be warmed to room temperature, stir 10 minutes, and with 3-piperidin-4-yl-3,4-dihydro-1H-quinazoline-2-ketone (78mg, 1.1 equivalents) processing.Mixture at room temperature stirred spend the night.Evaporating solvent, and, obtain 148mg (94%) white powder by this residue of column chromatography purification.
1H-NMR(DMSO-d 6，500MHz)δ1.46(m，4H)，2.55-2.80(m，2H)，3.05(dd，J＝13.7，10.7，1H)，3.15(m，1H)，3.62(s，3H)，4.04(d，J＝13.4，2H)，4.11(s，2H)，4.22-4.39(m，2H)，6.76(d，J＝7.9，1H)，6.87(dd，J＝7.3，7.3，1H)，6.90(d，J＝8.2，1H)，7.08(d，J＝7.6，1H)，7.12(dd，J＝7.6，7.6，1H)，7.40(s，1H)，7.60(s，1H)，8.15(s，1H)，9.18(s，1H)，13.48(s，1H)。Mass spectrum: 511.18 (MH) +
Embodiment 43
(±)-4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(7-chloro-1H-indazole-5-ylmethyl)-2-oxo-ethyl]-amide
Figure A20038011103001261
At room temperature, with (±)-3-(7-chloro-1H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-methyl propionate (15mg, 0.029mmol) suspension in 1: 1 oxolane/methanol (1mL) is with Lithium hydrate (3.0mg, 2.5 aqueous solution equivalent) (0.25mL) is handled, and with the solution stirring that generates 1.5 hours.Solution is cooled to 0 ℃, handles, and concentrate, obtain crude acid, it need not directly be used by purification with 1M aqueous potassium hydrogen sulfate (60 μ L, 2.0 equivalents).This crude acid is dissolved in the dimethyl formamide (0.3mL), and uses dichloromethane (0.15mL), 4-piperidyl-piperidines (10.1mg, 2 equivalents), diisopropylethylamine (10 μ L, 2 equivalents) and PyBOP in turn (16.5mg, 1.1 equivalents) are handled.With solution stirring 30min and concentrated.Product by the column chromatography purification, is obtained 14.7mg (77%, 2 step).
1H-NMR(CDCl 3，500MHz)δ1.30-1.60(m，8H)，1.65-1.88(m，5H)，2.14(m，1H)，2.23(m，1H)，2.30-2.70(m，7H)，2.80-3.20(m，5H)，3.94(d，J＝13.4，13.1，1H)，4.10-4.30(m，4H)，4.55(m，1H)，4.62(dd，J＝13.1，12.8，1H)，5.19(m，1H)，5.91(dd，J＝30.2，22.3，1H)，6.70(d，J＝7.6，1H)，6.92(dd，J＝7.6，7.3，1H)，7.01(dd，J，7.9，7.6，1H)，7.13(s，0.4H)，7.15(dd，J＝7.9，7.6，1H)，7.24(s，0.6H)，7.33(s，0.4H)，7.43(s，0.6H)，7.49(bs，1H)，7.91(s，0.4H)，7.95(s，0.6H)，11.25(bd，J＝50.7，1H)。Mass spectrum: 647.37 (MH) +
4-bromo-2-ethyl-6-methyl-phenyl amine
(14mL 100mmol) is dissolved in concentrated hydrochloric acid (30mL) and the water (220mL), and is cooled to 0 ℃ with 2-ethyl-6-methyl-phenyl amine.To dripping bromine (5.1mL, 1 equivalent) wherein.Generate white depositions fast.Filter this precipitate, and wash with ether.This precipitate is suspended in water, and neutralize with wet chemical.The grease of this formation is extracted in the ether.This ether extract through the potassium carbonate drying, is filtered, and concentrate, obtain the purple grease of 7.0g (33%), need not purification and use with it.Mass spectrum: 214.01 (MH) +.
4-bromo-2-ethyl-6-aminomethyl phenyl diazo-tert-butyl group thioether
(7.0g 33mmol) is suspended in the 7.8M hydrochloric acid (30mL) with 4-bromo-2-ethyl-6-monomethylaniline..This stirred mixture is cooled to-20 ℃, and handles, make temperature keep below-5 ℃ simultaneously with the aqueous solution (5mL) that dripped sodium nitrite (2.27g, 1.05 equivalents) in 10 minutes.After keeping 30min again under-5 ℃ to-20 ℃, mixture is buffered to pH with the solid sodium acetate is about 5.Under 0 ℃,, this mixture (being maintained at about under-10 ℃) is joined in the agitating solution of tert-butyl mercaptan (3.7mL, 1 equivalent) in ethanol (50mL) in batches with about 10 minutes.After the adding, mixture is stirred down 30min at 0 ℃, and add finely divided ice (about 50mL) then.Mixture was preserved in fridge 2 hours.The light brown solid that filter to collect generates washes with water, and under fine vacuum dry several hours (9.47g, 92%).Mass spectrum: 315.05 (MH) +
5-bromo-7-ethyl-1H-indazole
Figure A20038011103001272
In the agitating solution of potassium tert-butoxide (33.6g, 10 equivalents) in DMSO (200mL), add 4-bromo-2-ethyl-6-aminomethyl phenyl diazo-tert-butyl group thioether (9.4g, DMSO 30mmol) (100mL) solution by conduit.With mixture vigorous stirring 1 hour.Reactant mixture is poured into carefully in the mixture of finely divided ice (500mL), concentrated hydrochloric acid (25mL) and water (100mL) then.Filter the precipitate that generates, wash with water, be dissolved in the methanol, and concentrate, obtain the yellowish-brown solid of 5.7g (85%).
1H-NMR(CDCl 3，500MHz)δ1.39(t，J＝7.6，3H)，2.92(q，J＝7.6，2H)，7.30(s，1H)，7.75(s，1H)，8.04(s，1H)。Mass spectrum: 225.00 (MH) +
7-ethyl-1H-indazole-5-formaldehyde
Figure A20038011103001281
With 5-bromo-7-ethyl-1H-indazole (2.0g, 8.9mmol) and sodium hydride (226mg, 1.1 equivalents) weigh and join in flame-dried (flame-dried) round-bottomed flask that is equipped with the magnetic splash bar.Under blanket of nitrogen, at room temperature, add exsiccant oxolane (60mL).Mixture was at room temperature stirred 15 minutes.This stirred mixture is cooled to-78 ℃, and adds the pentane solution (1.7M, 10.5mL, 2.0 equivalents) of tert-butyl lithium with time of a few minutes.Behind-78 ℃ of following 15min, should react and be warmed to-50 ℃ gradually, and be cooled to-78 ℃ once more.Add dimethyl formamide (2.8mL) at leisure, and mixture is warmed to-50 ℃.Solution is transferred to apace in the agitating solution of the water of 300mL and 1M potassium acid sulfate (25mL).With the suspension extracted with diethyl ether that generates, water, through dried over mgso and concentrates then with the salt washing.Obtain the white solid of 160mg (10%) through column chromatography.
1H-NMR(CD 3OD，500MHz)δ1.38(t，J＝7.6，3H)，2.98(q，J＝7.6，2H)，7.71(s，1H)，8.22(s，1H)，8.24(s，1H)，9.96(s，1H)。Mass spectrum: 175.08 (MH) +
2-benzyloxycarbonyl amino-3-(7-ethyl-1H-indazole-5-yl)-acrylic acid methyl ester.
Figure A20038011103001282
Under 0 ℃; to N-benzyloxycarbonyl-α-phosphono glycine trimethyl (0.61g; 2.0 equivalent) and 7-ethyl-1H-indazole-5-formaldehyde (160mg 0.92mmol) adds tetramethyl guanidine (0.22mL, 1.9 equivalents) in the agitating solution in oxolane (5mL).Should react and be warmed to ambient temperature overnight at leisure.Concentrate this reaction, be dissolved in the ether, water is washed with salt then, and dry (magnesium sulfate), and concentrate.Residue by the column chromatography purification, is obtained the grease of 333mg (95%).
1H-NMR(CDCl 3，500MHz)δ1.33(t，J＝7.6，3H)，2.86(q，J＝7.3，2H)，3.83(s，3H)，5.11(s，2H)，6.39(bs，1H)，7.29(bs，5H)，7.43(s，1H)，7.50(s，1H)，7.78(s，1H)，8.04(s，1H)。Mass spectrum: 380.17 (MH) +
(±)-2-amino-3-(7-ethyl-1H-indazole-5-yl)-methyl propionate
Figure A20038011103001291
Under nitrogen, to 2-benzyloxycarbonyl amino-3-(7-ethyl-1H-indazole-5-yl)-acrylic acid methyl ester. (330mg, add in methanol 0.78mmol) (5mL) solution palladium charcoal (10%, 33mg).Be full of flask with hydrogen, and under nitrogen atmosphere, stir and spend the night.Should react and use nitrogen wash,, and concentrate, obtain 210mg (98%) by diatomite filtration, need not purification and use with it.
1H-NMR(CDCl 3，500MHz)δ1.34(t，J＝7.6，3H)，2.85(q，J＝7.6，2H)，2.96(dd，J＝13.7，7.6，1H)，3.19(dd，J＝13.7，8.6，1H)，3.48(s，2H)，3.73(s，3H)，3.80(dd，J＝7.6，5.2，1H)，6.99(s，1H)，7.38(s，1H)，7.97(s，1H)。Mass spectrum: 248.15 (MH) +
Embodiment 44
(±)-3-(7-ethyl-1H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-methyl propionate
Under 0 ℃, (100mg, 0.41mmol) agitating solution in oxolane (2mL) is handled with carbonyl dimidazoles (66mg, 1 equivalent) with (±)-2-amino-3-(7-ethyl-1H-indazole-5-yl)-methyl propionate.Should react and stir 5 minutes, and be warmed to room temperature, and stir 15 minutes, and use 3-piperidin-4-yl-3 then, 4-dihydro-1H-quinazoline-2-ketone (103mg, 1.1 equivalents) is handled.Mixture at room temperature stirred spend the night.Evaporating solvent, and with residue by the column chromatography purification, obtain the white solid of 188mg (92%).
1H-NMR(CDCl 3，500MHz)δ1.36(t，J＝7.6，3H)，1.69(m，4H)，2.86(m，2H)，2.90(q，J＝7.6，2H)，3.22(dd，J＝5.5，4.9，2H)，3.75(s，3H)，4.03(dd，J＝44.0，13.7，2H)，4.26(s，2H)，4.51(m，1H)，4.84(m，1H)，5.02(m，1H)，6.70(d，J＝7.9，1H)，6.90-7.05(m，4H)，7.16(dd，J＝7.6，7.6，1H)，7.34(s，1H)，8.03(s，1H)。Mass spectrum: 505.29 (MH) +
Embodiment 45
(±)-4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(7-ethyl-1H-indazole-5-ylmethyl)-2-oxo-ethyl]-amide
To (±)-3-(7-ethyl-1H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-methyl propionate (15mg, 0.03mmol) methanol (0.6mL) solution in add lithium hydroxide monohydrate (3.0mg, 2.5 aqueous solution equivalent) (0.1mL), and with the solution stirring that generates 6 hours.Solution is cooled to 0 ℃, handles, and concentrate, obtain crude acid with 1M aqueous potassium hydrogen sulfate (60 μ L, 2.0 equivalents), need not purification and directly use with it.This crude acid is dissolved in the dimethyl formamide (0.4mL), is cooled to 0 ℃, and use dichloromethane (0.2mL), 4-piperidyl-piperidines (11mg, 2.2 equivalents), diisopropylethylamine (12 μ L, 2.3 equivalents) and PyBOP in turn (19mg, 1.2 equivalents) are handled.Solution is stirred 15min under 0C, be warmed to room temperature, stirred 1.5 hours, and concentrate.Product by the column chromatography purification, is obtained 14.5mg (76%, 2 step).
1H-NMR(CDCl 3，500MHz)δ1.28-1.48(m，10H)，1.52(m，2H)，1.60-1.82(m，6H)，1.95(m，1.4H)，2.06(m，1.6H)，2.20-2.50(m，5H)，2.77-2.93(m，5H)，2.96-3.17(m，2H)，3.76(d，J＝13.4，0.4H)，3.86(d，J＝13.7，0.6H)，4.10-4.20(m，2H)，4.26(s，2H)，4.57(m，2H)，5.10-5.24(m，1H)，5.67(d，J＝8.2，0.6H)，5.74(d，J＝7.9，0.4H)，6.67(d，J＝7.9，1H)，5.67(d，J＝8.2，0.6H)，5.74(d，J＝7.9，0.4H)，6.67(d，J＝7.9，1H)，6.93(dd，J＝7.6，7.3，1H)，6.96(s，0.4H)，7.03(dd，J＝7.0，6.7，1H)，7.09(m，1.6H)，7.15(dd，J＝7.0，6.7，1H)，7.31(s，0.4H)，7.38(s，0.6H)，7.94(s，0.4H)，7.95(s，0.6H)。Mass spectrum: 641.50 (MH) +
(3,4-dinitro-phenyl)-methanol
Figure A20038011103001311
At-20 ℃, with the time of 45min, (tetrahydrofuran solution of 1M, 800mL 800mmol) join 3, and (93.5g is in oxolane 441mmol) (300mL) solution for the 4-dinitrobenzoic acid with monoborane-tetrahydrofuran complex.The mixture that generates is stirred 1 hour down, and be warmed to room temperature then at-20 ℃, and stir and spend the night.It is come quencher by 1: 1 acetic acid/water that adds 32mL.Solvent removed in vacuo is poured into residue in the saturated sodium bicarbonate of the 1000mL of ice-cold, and vigorous stirring is 15 minutes simultaneously.(3 * 500mL) extract with ethyl acetate with mixture.The organic layer that merges is washed with saturated sodium bicarbonate, salt, and through dried over sodium sulfate.After the filtration, remove and desolvate, obtain the title compound (100%) of faint yellow solid.
1H-NMR(CDCl 3，500MHz)δ7.91(d，J＝8.0Hz，1H)，7.89(s，1H)，7.71(dd，J＝8.5，1.0Hz，1H)，4.87(s，2H)，2.30(s，1H)。
3,4-dinitro-benzaldehyde
Figure A20038011103001312
(95.3g, dichloromethane 481mmol) (500mL) solution all join pyridinium chlorochromate  at once, and (156g is 722mmo1) in the suspension in dichloromethane (900mL) with (3,4-dinitro-phenyl)-methanol.Mixture is at room temperature stirred 1.5 hours, and add ether (1500mL) then.Supernatant is slowly poured out from the black gum that generates, and with insoluble sludge dichloromethane (3 * 250mL) thorough washing.The organic solution that merges is filtered by the florisil pad, obtain light glassy yellow clear solutions.Solvent removed in vacuo, and with residue by using the silica gel chromatography purification of dichloromethane as eluent, obtain the title compound (71%) of yellow solid.
1H-NMR(CDCl 3，300MHz)δ8.45(d，J＝1.5Hz，1H)，8.28(dd，J＝8.1，1.5Hz，1H)，8.07(d，J＝8.1Hz，1H)。 13CNMR(CD 3OD，125MHz)δ187.7，139.2，134.2，126.2，125.7。
2-benzyloxycarbonyl amino-3-(3,4-dinitro-phenyl)-acrylic acid methyl ester.
Figure A20038011103001313
At room temperature, with 1,1,3, (41.2mL, (114.1g is in oxolane 344mmol) (800mL) solution 329mmol) to join N-(benzyloxycarbonyl)-α-phosphono glycine trimethyl for the 3-tetramethyl guanidine.Mixture is at room temperature stirred 15min, and be cooled to-78 ℃ then.Slowly add 3 by conduit, 4-dinitro-benzaldehyde (61.4g, oxolane 313mmol) (200mL) solution.The mixture that generates is stirred 2 hour down, and be warmed to ambient temperature overnight then at-78 ℃.Solvent removed in vacuo, and yellow residue is dissolved in the ethyl acetate of 4.5L.With 1N sulphuric acid, water (twice), the salt washing of solution with 1.5L, and through dried over sodium sulfate.After the filtration, solvent removed in vacuo, and with residue by crystallization in the ethyl acetate (20g crude product/100mL ethyl acetate).Collect this yellow crystal, and be further purified, use dichloromethane as eluent by silica gel chromatography.Obtain the title compound (77%) of yellow crystal.
1H-NMR(CDCl 3，500MHz)δ7.85(d，J＝1.5Hz，1H)，7.74(d，J＝8.0Hz，1H)，7.62(dd，J＝8.5，1.5Hz，1H)，7.35-7.34(m，3H)，7.34(br s，2H)，7.23(s，1H)，6.95(br s，1H)，5.07(s，2H)，3.90(s，3H)。
Preparation similarly:
2-benzyloxycarbonyl amino-3-(3-hydroxyl-4-nitro-phenyl)-acrylic acid methyl ester.
Figure A20038011103001321
1H-NMR(CDCl 3，500MHz)δ7.93(d，J＝9.0Hz，1H)，7.32(br s，sH)，7.28(brs，2H)，7.17(s，1H)，7.16(d，J＝2.0Hz，1H)，7.01(dd，J＝9.0，2.0Hz，1H)，6.74(brs，1H)，5.06(s，2H)，3.86(s，3H)。
(R)-2-benzyloxycarbonyl amino-3-(3,4-dinitro-phenyl)-methyl propionate
Figure A20038011103001322
The 500mL Shlenck flask of oven dry is put in the bag glove (glove-bag) that is full of nitrogen.After with the bag glove evacuation, be full of, seal this flask, and from bag glove, take out and weigh with nitrogen (3x).It is put back in the bag glove again, and evacuation also is full of nitrogen (3x), packs (-)-1 then into, 2-pair ((2R, 5R)-2,5-diethyl phosphorus heterocycle amyl group) benzene (cyclo-octadiene) rhodium (I) fluoroform sulphonate.Seal this flask, and from bag glove, take out and weigh (784mg, 1.08mmol).(8.72g 21.7mmol) joins in the Schlenck flask of another 500mL, and evacuation also is full of nitrogen (3x) with 2-benzyloxycarbonyl amino-3-(3,4-dinitro-phenyl)-acrylic acid methyl ester..Add dichloromethane (350mL was with the nitrogen degassing 2 hours), and the solution that generates is transferred in the catalyst flask by conduit.With hydrogen (4x) purge and be full of flask, this mixture was at room temperature stirred 4 hours.Solvent removed in vacuo, and with residue by using the silica gel chromatography purification of ethyl acetate/hexane (1: 1) as eluent, obtain the solid title compound of light brown gumminess (99% productive rate, through the HPLC assay determination is 99.2% enantiomer excessive (ee), use following condition: Chiral pak AD post (4.6 * 250mm, 10um; A=ethanol, the B=hexane; 40%B@1.0mL/min, 14min; Retention time: for the R enantiomer is 10.9min, and is 6.9min for the S enantiomer).
1H-NMR(CDCl 3，500MHz)δ7.80(d，J＝8.0Hz，1H)，7.63(s，1H)，7.45(d，J＝8.0Hz，1H)，7.38-7.31(m，5H)，5.37(d，J＝6.0Hz，1H)，5.13-5.05(m，2H)，4.68(d，J＝6.0Hz，1H)，3.71(s，3H)，3.36(dd，J＝13.5，5.0Hz，1H)，3.17(dd，J＝13.5，6.0Hz，1H)。
Preparation similarly:
(R)-2-benzyloxycarbonyl amino-3-(3-hydroxyl-4-nitro-phenyl)-methyl propionate
Figure A20038011103001331
1H-NMR(CDCl 3，500MHz)δ7.97(d，J＝9.0Hz，1H)，7.36-7.30(m，5H)，6.90(s，1H)，6.71(d，J＝8.5Hz，1H)，5.29(d，j＝7.0Hz，1H)，5.11(d，J＝12.5Hz，1H)，5.07(d，J＝12.0Hz，1H)，4.68(dd，j＝13.0，6.0Hz，1H)，3.74(s，3H)，3.20(dd，j＝13.5，5.0Hz，1H)，3.05(dd，J＝13.5，6.0Hz，1H)。
(R)-2-benzyloxycarbonyl amino-3-(3,4-diaminourea-phenyl)-methyl propionate
Under 0 ℃, (2.27g 36mmol) joins (R)-2-benzyloxycarbonyl amino-3-(3 in batches on a small quantity with the solid formic acid ammonium, 4-dinitro-phenyl)-methyl propionate (1.45g, 3.6mmol) and zinc powder (1.41g is in methanol 21.6mmol) (50mL was with the nitrogen degassing 2 hours) suspension.The mixture that generates at room temperature stirred spend the night.Solvent removed in vacuo, and add toluene (30mL, the degassing) and ethyl acetate (30mL, the degassing) then, add acetic acid (3mL) subsequently.The further dilution of mixture is all dissolved until all organic solid, then with its water, salt washing, and through dried over sodium sulfate.After the filtration, solvent removed in vacuo obtains containing the title compound of 1 equivalent acetic acid, is pale red gumminess solid (85%).Mass spectrum: 344.18 (MH) +
(R)-2-benzyloxycarbonyl amino-3-(2-methyl isophthalic acid H-benzimidazole-5-yl)-methyl propionate
Acetic acid (8mL) solution of (R)-2-benzyloxycarbonyl amino-3-(3,4-diaminourea-phenyl)-methyl propionate-acetic acid (640mg) was heated 4 hours down at 130 ℃.Then mixture is poured in the water, and is cooled to 0 ℃.By slowly adding solid sodium bicarbonate with pH regulator to 8.Then with mixture with ethyl acetate (3 * 100mL) extractions, and with the organic layer water, the salt washing that merge, and through dried over sodium sulfate.After the filtration, remove and desolvate, obtain the solid title compound of brown cystose (95%).
1H-NMR(CDCl 3，500MHz)δ7.39(d，J＝8.5Hz，1H)，7.35(s，1H)，7.26-7.22(m，5H)，7.06(d，J＝8.0Hz，1H)，5.03(d，J＝12.5Hz，1H)，4.99(d，J＝13.0hz，1H)，4.51(dd，J＝8.5，5.5Hz，1H)，3.70(s，3H)，3.27(dd，J＝13.5，5.0Hz，1H)，3.03(dd，J＝14.0，9.0Hz，1H)，2.55(s，3H)。Mass spectrum: 368.19 (MH) +
(R)-2-benzyloxycarbonyl amino-3-[2-methyl-3-(2-TMS-ethylsulfonyl)-3H-benzimidazole-5-yl]-methyl propionate
With
(R)-2-benzyloxycarbonyl amino-3-[2-methyl isophthalic acid-(2-TMS-ethylsulfonyl)-1H-benzimidazole-5-yl]-methyl propionate
With purified 2-TMS-ethyl sulfonic chloride all join immediately (R)-2-benzyloxycarbonyl amino-3-(2-methyl isophthalic acid H-benzimidazole-5-yl)-methyl propionate (533mg, 1.96mmol) and the suspension of sodium carbonate in acetonitrile (20mL) in.Mixture at room temperature stirred spend the night.Remove and to desolvate, and with residue through the silica gel chromatography purification, use ethyl acetate/hexane (1: 2) as eluent, obtain the solid title compound of ceraceous (1: 1 N1 and N3 mixture of isomers, 66%).
1H-NMR(CDCl 3，500MHz)δ7.68(d，J＝8.5hz，0.5H)，7.55(d，J＝8.5Hz，0.5H)，7.53(s，0.5H)，7.41(s，0.5H)，7.34-7.29(m，5H)，7.06-7.04(m，1H)，5.22(d，J＝8.0Hz，0.5H)，5.17(d，J＝7.5Hz，0.5H)，5.11-5.07(m，2H)，4.72-4.69(m，1H)，3.75(s，1.5H)，3.72(s，1.5H)，3.24-3.17(m，2H)，2.79(s，3H)，0.92-0.83(m，2H)，-0.02(s，4.5H)，-0.05(s，4.5H)。Mass spectrum: 532.26 (MH) +
(R)-2-amino-3-[2-methyl isophthalic acid-(2-TMS-ethylsulfonyl)-1H-benzimidazole-5-yl]-methyl propionate
With
(R)-2-amino-3-[2-methyl-3-(2-TMS-ethylsulfonyl)-3H-benzimidazole-5-yl]-methyl propionate
Figure A20038011103001351
At room temperature under 40psi hydrogen; with (R)-2-benzyloxycarbonyl amino-3-[2-methyl-3-(2-TMS-ethylsulfonyl)-3H-benzimidazole-5-yl]-methyl propionate and (R)-2-benzyloxycarbonyl amino-3-[2-methyl isophthalic acid-(2-TMS-ethylsulfonyl)-1H-benzimidazole-5-yl]-methyl propionate (1: 1 mixture, 600mg) and methanol (50mL) suspension shaken overnight in the Parr device of 10% palladium charcoal (180mg).After replacing hydrogen, mixture is filtered by Celite pad with nitrogen.Solvent removed in vacuo obtains the solid title compound of yellowish-brown (80%).
1H-NMR (CD 3OD, 500MHz) δ 7.81 (d, J=8.5,0.5Hz, 0.5H), 7.70 (s, 0.5H), 7.58 (d, J=8.5Hz, 0.5H), 7.49 (s, 0.5H), 7.25 (d, J=9.0Hz, 1H), 3.89 (dd, J=14.0,6.5Hz, 1H), 3.75 (s, 1.5H), 3.72 (s, 1.5H), 3.55-3.51 (m, 2H), 3.18 (d, J=6.0Hz, 1H), 3.22-3.18 (m, 0.5H), 3.14-3.09 (m, 0.5H), 2.81 (s, 1.5H), 2.80 (s, 1.5H), 0.92-0.88 (m, 2H), 0.02 (s, 4.5H), 0.01 (s, 4.5H); 13CNMR (CD 3OD, 125MHz) δ 174.3,174.1, and 153.5,153.3,141.7,140.6,133.9,133.82,133.78,132.7,126.5,126.3,119.7,119.0,114.1,113.4,55.6,51.8,51.7,51.6,40.2,39.8,15.83,15.77,9.9 ,-3.07 ,-3.11. mass spectrum: 398.20 (MH) +
(R)-3-[2-methyl isophthalic acid-(2-TMS-ethylsulfonyl)-1H-benzimidazole-5-yl]-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-methyl propionate
With
(R)-3-[2-methyl-3-(2-TMS-ethylsulfonyl)-3H-benzimidazole-5-yl]-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-methyl propionate
According to as above preparation (R)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-3-[1-(2-TMS-ethylsulfonyl)-1H-indazole-5-yl]-preparation of the method for methyl propionate.Contain the silica gel chromatography purification of the ethyl acetate of 1% triethylamine by use, obtain the title compound (87%) of pale solid as eluent.
1H-NMR(CD 3OD，500MHz)δ7.82(d，J＝8.5Hz，0.5H)，7.80(s，0.5H)，7.59(d，J＝8.0Hz，0.5H)，7.55(s，0.5H)，7.33-7.30(m，1H)，7.16(t，J＝8.0Hz，1H)，7.12(t，J＝7.5Hz，1H)，6.95(t，J＝7.5Hz，1H)，6.79(d，J＝7.5Hz，1H)，4.60-4.55(m，1H)，4.45-4.40(m，1H)，4.29-4.27(m，2H)，4.15-4.10(m，2H)，3.77(s，1.5H)，3.74(s，1.5H)，3.56-3.51(m，2H)，3.35-3.31(m，2H)，3.21-3.15(m，1H)，2.91-2.80(m，2H)，2.78(s，1.5H)，2.77(s，1.5H)，1.76-1.73(m，1H)，1.66-1.61(m，2H)，0.92-0.87(m，2H)，0.009(s，4.5H)，-0.007(s，4.5H)。 13CNMR (CD 3OD, 125MHz) 173.8,173.7,158.2,158.1,155.6,153.4,153.2,141.6,140.3,137.2,135.3,135.1,133.7,132.5,128.2,126.4,126.3,125.7,122.13,122.10,119.6,118.8,118.4,114.0,113.4,113.2,57.3,56.2,51.9,51.7,51.5,43.8,43.7,42.9,37.6,37.2,28.4,17.4,15.7,15.6,9.9 ,-3.1 ,-3.2. mass spectrum: 655.36 (MH) +
(R)-3-(2-methyl isophthalic acid H-benzimidazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-propanoic acid
Figure A20038011103001371
With (R)-3-[2-methyl isophthalic acid-(2-TMS-ethylsulfonyl)-1H-benzimidazole-5-yl]-2-{[4-(2-oxo-1; 4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-methyl propionate and (R)-3-[2-methyl-3-(2-TMS-ethylsulfonyl)-3H-benzimidazole-5-yl]-2-{[4-(2-oxo-1; 4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-1: 1 mixture of methyl propionate is according to above-mentioned processing (R)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-3-[1-(2-TMS-ethylsulfonyl)-1H-indazole-5-yl]-method of propanoic acid handles.(Lithium hydrate/methanol-oxolane-water (1: 1: 1) spends the night to use this hydrolysising condition down at-15 ℃.Obtain the title compound (25%) of white solid.Mass spectrum: 477.24 (MH) +
Embodiment 46
(R)-4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(2-methyl isophthalic acid H-benzimidazole-5-ylmethyl)-2-oxo-ethyl]-amide
Figure A20038011103001372
According to as above preparing (R)-4-(2-oxo-1; 4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid 2-[1,4 '] connection piperidines-1 '-Ji-2-oxo-1-[1-(2-TMS-ethylsulfonyl)-1H-indazole-5-ylmethyl]-ethyl }-preparation of the method for amide.By using dichloromethane: methanol: triethylamine (93: 5: 2) obtains white solid as the silica gel chromatography purification of eluent.It is dissolved in the ethyl acetate (60mL), and washes twice with 1: 1 saturated sodium bicarbonate/salt, and through dried over sodium sulfate.After the filtration, remove and desolvate, obtain the title compound (11% productive rate) of white solid.LC/MS:t R=1.59 minutes, 627.34 (MH) +
(R)-3-(4-amino-3-hydroxyl-phenyl)-2-benzyloxycarbonyl amino-methyl propionate hydrochlorate
Figure A20038011103001381
Under 0 ℃, with iron powder (3.7g, 66.4mmol) and ammonium chloride (5.9g, 111mmol) join (R)-2-benzyloxycarbonyl amino-3-(3-hydroxyl-4-nitro-phenyl)-methyl propionate (2.07g, 5.53mmol) the degassing 1: 1 methanol (400mL) in solution in.The mixture that generates was at room temperature stirred 48 hours.Add trifluoroacetic acid (7mL), and stir the mixture until the clarification dark red solution that it is become contain the suspension of unreacted iron powder.Filtering mixt, and vacuum concentrated filtrate.(2 * 150mL) extractions are washed the organic layer that merges with salt, and through dried over sodium sulfate with ethyl acetate with residue.After the filtration, add hydrochloric acid (4.2mL, the two  alkane solution of 4M).Solvent removed in vacuo obtains the solid title compound of yellowish-brown cystose (80%).
1H-NMR(CD 3OD，500MHz)δ7.34-7.28(m，5H)，7.20(d，J＝8.0hz，1H)，6.88(s，1H)，6.78(d，J＝7.5Hz，1H)，5.05-5.00(m，2H)，4.42(dd，J＝8.5，5.0Hz，1H)，3.70(s，3H)，3.65(s，1H)，3.33(br s，2H)，3.11(dd，J＝14.0，5.0hz，1H)，2.90(dd，J＝13.5，9.0Hz，1H)。 13CNMR(CD 3OD，125MHz)172.5，157.4，151.2，140.2，137.0，128.5，128.0，127.7，123.8，120.9，117.0，116.9，67.2，55.7，52.0，37.2。Mass spectrum: 345.20 (MH) +
(R)-2-benzyloxycarbonyl amino-3-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-methyl propionate
Figure A20038011103001382
Under 0 ℃, with carbonyl dimidazoles (498mg, 3.07mmol) dichloromethane (15mL) solution join (R)-3-(4-amino-3-hydroxyl-phenyl)-2-benzyloxycarbonyl amino-methyl propionate (1.17g, 3.07mmol), (1.60mL is 9.21mmol) and in the solution of dichloromethane (85mL) for diisopropylethylamine.Mixture was stirred 4 hours down at 0 ℃.Solvent removed in vacuo, and with residue by using the silica gel chromatography purification of ethyl acetate/hexane as eluent, obtain the title compound (51%) of white solid.
1H-NMR(CDCl 3，500MHz)δ9.07(s，1H)，7.37-7.29(m，5H)，6.96(s，1H)，6.90(d，J＝8.0Hz，1H)，6.87(d，J＝8.0Hz，1H)，5.36(d，J＝8.0Hz，1H)，5.11(d，J＝12.0Hz，1H)，5.07(d，J＝12.5Hz，1H)，4.65(dd，J＝13.5，5.5Hz，1H)，3.74(s，3H)，3.17(dd，J＝14.0，5.5Hz，1H)，3.07(dd，J＝14.0，6.0Hz，1H)。 13CNMR (CDCl 3, 125MHz) δ 171.9,155.7,155.5,144.1,136.2,130.8,128.6,128.42,128.38,128.2,125.1,111.1,109.8,67.2,55.1,52.6, the 38.3. mass spectrum: 371.18 (MH) +
(R)-2-amino-3-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-methyl propionate
By conduit with (R)-2-benzyloxycarbonyl amino-3-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-methyl propionate (310mg) is at the methanol (20ml of 4.4% formic acid, prepared fresh in the methanol of the degassing) solution in joins 10% palladium charcoal in the suspension in the methanol (20ml, prepared fresh in the methanol of the degassing) of 4.4% formic acid.The mixture that generates was at room temperature stirred 4 hours.After the Celite pad filtration, solvent removed in vacuo obtains the yellowish-brown solid.This solid is dissolved in the mixture of ethyl acetate (50mL), toluene (10mL) and ethanol (40ml), and adds solid sodium bicarbonate (3.1g).Mixture was at room temperature stirred 2 hours, and filter.Solvent removed in vacuo obtains title compound.
1H-NMR(CD 3OD，500MHz)δ8.41(br s，2H)，7.17(s，1H)，7.09(br s，2H)，4.32(s，1H)，3.83(s，3H)，3.33(s，1H)，3.30(s，1H)，3.22(s，1H)。Mass spectrum: 237.20 (MH) +
(R)-3-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-methyl propionate
Figure A20038011103001392
According to as above being used for preparation (R)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-3-[1-(2-TMS-ethylsulfonyl)-1H-indazole-5-yl]-preparation of the method for methyl propionate.By using dichloromethane: methanol: triethylamine (93: 5: 2) carries out purification as the silica gel chromatography of eluent, obtains the title compound (33%) of white solid.
1H-NMR(CD 3OD，500MHz)δ7.17-7.13(m，3H)，7.08(d，J＝7.9hz，1H)，7.03(d，J＝8.0Hz，1H)，6.95(t，J＝7.0Hz，1H)，6.79(d，J＝8.0Hz，1H)，4.55-4.51(m，1H)，4.44-4.41(m，1H)，4.33(s，2H)，4.14-4.10(m，2H)，3.74(s，3H)，3.33(br s，2H)，3.23(dd，j＝13.7，5.2Hz，1H)，3.03(dd，J＝14.0，9.7Hz，1H)，2.92-2.82(m，2H)，1.79-1.63(m，4H)。 13CNMR (CD 3OD, 125MHz) 173.8,158.2,156.2,155.6,144.4,137.1,132.7,129.3,128.2,125.7,125.0,122.2,118.4,113.4,110.6,109.6,56.2,52.0,51.7,43.8,42.9,37.3,28.4. mass spectrum: 494.30 (MH) +
(R)-3-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-propanoic acid
Figure A20038011103001401
According to as above being used for preparation (R)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-3-[1-(2-TMS-ethylsulfonyl)-1H-indazole-5-yl]-preparation of the method for propanoic acid.(Lithium hydrate/methanol-oxolane-water (1: 1: 1) spends the night under-15 ℃ to use this hydrolysising condition.Obtain the title compound (95%) of white solid.Mass spectrum: 480.30 (MH) +.
Embodiment 47
(R)-4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-2-oxo-1-(2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-ethyl]-amide
Figure A20038011103001411
According to as above being used for preparation (R)-4-(2-oxo-1; 4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid 2-[1,4 '] connection piperidines-1 '-Ji-2-oxo-1-[1-(2-TMS-ethylsulfonyl)-1H-indazole-5-ylmethyl]-ethyl }-preparation of the method for amide.By using dichloromethane: methanol: triethylamine (93: 5: 2) obtains white solid as this crude product of silica gel chromatography purification of eluent.It is dissolved in the ethyl acetate (60mL), and washes twice with saturated sodium bicarbonate/salt of 1: 1, and through dried over sodium sulfate.After the filtration, remove and desolvate, obtain the title compound (70%) of white solid.
1H-NMR(CD 3OD，500MHz)δ7.20-7.14(m 4H)，7.08(d，J＝9.0Hz，1H)，6.96(td，J＝7.5，1.0Hz，1H)，6.79(d，J＝8.0Hz，1H)，4.99-4.94(m，1H)，4.61-4.58(m，1H)，4.47-4.43(m，1H)，4.39(s，1H)，4.23-4.16(m，2H)，4.08-4.04(m，1H)，3.06-2.88(m，5H)，2.74-2.69(m，2H)，2.59-2.52(m，2H)，2.41-2.33(m，2H)，1.96-1.89(m，1H)，1.88-1.47(m，16H)。LC/MS:t R=1.86 minutes, 630.31 (MH) +
(R)-3-(1H-benzotriazole-5-yl)-2-benzyloxycarbonyl amino-methyl propionate
At room temperature, with time of a few minutes to (R)-2-benzyloxycarbonyl amino-3-(3,4-diaminourea-phenyl)-methyl propionate one acetate (2.68g, 6.65mmol) drip sodium nitrite (0.46g, aqueous solution 6.65mmol) (8mL) in the solution in acetic acid (30mL) and water (40mL).The mixture that generates was at room temperature stirred 20 minutes, be cooled to 0 ℃ then, add dense ammonium hydroxide and regulate pH to 11.In the presence of solid sodium chloride, with mixture with ethyl acetate extraction twice, and with organic layer through dried over sodium sulfate.After the filtration, solvent removed in vacuo, and with residue through the silica gel chromatography purification, use ethyl acetate/hexane (6: 4) as eluent, obtain the solid title compound of yellowish-brown (94% productive rate).
1H-NMR(CD 3OD，500MHz)δ7.75(d，J＝8.5Hz，1H)，7.58(s，1H)，7.31-7.25(m，5H)，7.18(d，J＝8.5Hz，1H)，5.39(d，J＝8.0Hz，1H)，5.10(d，J＝12.0Hz，1H)，5.05(d，J＝12.0Hz，1H)，4.74(dd，j＝13.5，6.0Hz，1H)，3.73(s，3H)，3.34(dd，J＝14.0，5.5Hz，1H)，3.22(dd，J＝13.5，6.0Hz，1H)。 13CNMR (CD 3OD, 125MHz) δ 172.1,156.0,136.1,128.6,128.3,128.1,67.2,55.2,52.7,38.5. mass spectrum 355.18 (MH) +
(R)-2-amino-3-(1H-benzotriazole-5-yl)-methyl propionate
According to the method preparation that as above is used for preparing (R)-2-amino-3-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-methyl propionate.
1H-NMR(CD 3OD，500MHz)δ8.38(br s，2H)，7.89(d，J＝7.5Hz，1H)，7.81(s，1H)，7.40(d，J＝7.5Hz，1H)，4.44(s，1H)，3.81(s，3H)，3.48-3.45(m，1H)，3.40-3.37(m，1H)，3.33(br s，1H)。 13CNMR (CD 3OD, 125MHz) δ 169.8,139.4,138.9,133.0,127.6,115.52,115.47,54.3,52.6,36.7. mass spectrum 221.15 (MH) +
Embodiment 48
(R)-3-(1H-benzotriazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-methyl propionate
According to as above being used for preparation (R)-2-{[4-(2-oxo-1; 4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-3-[1-(2-TMS-ethylsulfonyl)-1H-indazole-5-yl]-method of methyl propionate prepares; except using carbonyl dimidazoles to replace N, N-two succinimidyl carbonates (DSC).
1H-NMR(CD 3OD，300MHz)δ7.82(d，J＝8.4Hz，1H)，7.24(s，1H)，7.39(dd，J＝8.7，1.2Hz，1H)，7.15-7.08(m，2H)，6.94(td，J＝7.5，0.9Hz，1H)，6.75(d，J＝7.8Hz，1H)，4.67-4.60(m，1H)，4.39-4.31(m，1H)，4.15(s，2H)，4.08-4.03(m，2H)，3.72(s，3H)，3.38(dd，J＝13.9，5.5Hz，1H)，3.32-3.29(m，1H)，3.17(dd，J＝13.9，10.3Hz，1H)，2.87-2.71(m，2H)，1.64-1.48(m，4H)。Mass spectrum 478.30 (MH) +
Embodiment 49
(R)-4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [1-(1H-benzotriazole-5-ylmethyl)-2-[1,4 '] connection piperidines-1 '-Ji-2-oxo-ethyl]-amide
Figure A20038011103001431
According to as above being used for preparation (R)-4-(2-oxo-1; 4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid 2-[1,4 '] connection piperidines-1 '-Ji-2-oxo-1-[1-(2-TMS-ethylsulfonyl)-1H-indazole-5-ylmethyl]-ethyl }-preparation of the method for amide.By using the silica gel chromatography purification of methylene chloride/triethylamine (93: 5: 2) as eluent.
1H-NMR(CD 3OD，500MHz)δ7.83d，J＝8.2Hz，0.75H)，7.79(d，J＝8.5Hz，0.25H)，7.71(s，0.25H)，7.69(s，0.75H)，7.33(d，J＝9.2Hz，1H)，7.16-7.12(m，2H)，6.96-6.91(m，1H)，6.78(d，J＝8.0Hz，0.75H)，6.77(d，J＝8.0Hz，0.25H)，5.07-5.03(m，1H)，4.58-4.55(m，1H)，4.45-4.40(m，1H)，4.34(s，1.25H)，4.24(s，0.75H)，4.20-4.05(m，2.25H)，4.00-3.96(m，0.75H)，3.24-3.09(m，2H)，2.91-2.78(m，4H)，2.64-2.61(m，2H)，2.56-2.42(m，2H)，2.15-2.10(m，1.25H)，2.02-1.98(m，1.75H)，1.95-1.90(m，1H)，1.68-1.60(m，8H)，1.54-1.46(m，6H)。LC/MS:t R=1.86 minutes, 614.28 (MH) +
(R)-2-benzyloxycarbonyl amino-3-(2-oxo-2,3-dihydro-1H-indole-5-yl)-methyl propionate
Figure A20038011103001432
With 30 minutes time, with PyHBr 3(1.28g, 4.02mmol) gradation a small amount of (small portions) joins (R)-2-benzyloxycarbonyl amino-3-(1H-indole-5-yl)-methyl propionate (0.47g, 1.34mmol) the tert-butyl alcohol (10mL) solution in, this reaction temperature is remained under 25-30 ℃.The mixture that generates was at room temperature stirred 3.5 hours.Solvent removed in vacuo, and with residue ethyl acetate (2x) extraction.The organic facies that merges is washed with salt, and through dried over sodium sulfate.After the filtration, remove and desolvate, and with residue and dehydrated alcohol azeotropic drying.Residue is dissolved in the glacial acetic acid (10mL), and the adding zinc powder (0.88g, 13.4mmol).Mixture at room temperature stirred spend the night.After vacuum is removed acetic acid, residue through the silica gel chromatography purification, as eluent, is obtained the title compound (41%, 2 step) of white solid with ethyl acetate/hexane [earlier with (1: 3), and use then (3: 2)].
1H-NMR(CDCl 3，500MHz)δ8.03(s，1H)，7.36-7.31(m，5H)，6.94(s，1H)，6.91(d，J＝8.0Hz，1H)，6.73(d，J＝7.5Hz，1H)，5.26(d，J＝8.0Hz，1H)，5.11(d，J＝12.0Hz，1H)，5.05(d，j＝12.5Hz，1H)，4.61(dd，J＝13.5，6.0hz，1H)，3.72(s，3H)，3.45(s，2H)，3.10(dd，J＝14.0，5.5Hz，1H)，3.00(dd，J＝14.0，6.0Hz，1H)。 13CNMR(CDCl 3，125MHz)δ177.7，172.2，155.7，141.7，136.3，129.8，128.9，128.6，128.3，128.2，125.8，125.6，109.8，67.1，55.1，52.5，38.0，36。Mass spectrum 369.20 (MH) +
(R)-2-amino-3-(2-oxo-2,3-dihydro-1H-indole-5-yl)-methyl propionate
Figure A20038011103001441
According to the method preparation that as above is used for preparing (R)-2-amino-3-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-methyl propionate.
1H-NMR(CD 3OD，500MHz)δ8.48(br s，2H)，7.16(s，1H)，7.10(s，1H)，6.89(s，1H)，4.21(s，1H)，3.81(s，3H)，3.54(s，1H)，3.33(s，2H)，3.20(s，1H)，3.12(s，1H)。 13CNMR(CD 3OD，125MHz)δ178.9，170.7，143.3，129.0，128.6，126.9，125.6，110.0，57.3，54.6，52.3，37.0。Mass spectrum 235.30 (MH) +
(R)-3-(2-oxo-2,3-dihydro-1H-indole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-methyl propionate
Figure A20038011103001451
Toluene solution (2M with phosgene, 0.158mL, 0.30mmol) (70mg is 0.25mmol) in the mixture in dichloromethane (15mL) and saturated sodium bicarbonate (7.5mL) to join (R)-2-amino-3-(2-oxo-2,3-dihydro-1H-indole-5-yl)-methyl propionate of vigorous stirring.After mixture at room temperature stirred 30 minutes, add 3-piperidin-4-yl-3, and 4-dihydro-1H-quinazoline-2-ketone (58mg, 0.25mmol).The mixture that generates was at room temperature stirred 1.5 hours, and with the ethyl acetate dilution, and with the salt pickling of 0.25N, this hydrochloric acid has used solid sodium chloride saturated.With organic layer through dried over sodium sulfate.After the filtration, remove and desolvate, obtain the heavy-gravity oily title compound of yellowish-brown.LC/MS:t R=2.01 minutes, 492.10 (MH) +
Embodiment 50
(R)-4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-2-oxo-1-(2-oxo-2,3-dihydro-1H-indole-5-ylmethyl)-ethyl]-amide
Figure A20038011103001452
According to as above preparing (R)-4-(2-oxo-1; 4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid 2-[1,4 '] connection piperidines-1 '-Ji-2-oxo-1-[1-(2-TMS-ethylsulfonyl)-1H-indazole-5-ylmethyl]-ethyl }-method of amide prepares.Through flash chromatography on silica gel method purification, use methylene chloride/triethylamine (93: 5: 2) as eluent.
1H-NMR(CD 3OD，500MHz)δ7.20-7.09(m，4H)，6.97(t，J＝7.3Hz，1H)，6.88(d，J＝7.9Hz，0.65H)，6.84(d，J＝7.6Hz，0.35H)，6.80(d，J＝7.7Hz，1H)，5.51(s，0.65H)，5.23(s，0.35H)，4.99-4.95(m，0.65H)，4.92-4.88(m，0.35H)，4.60-4.56(m，1.65H)，4.46-4.41(m，1.35H)，4.39(s，1.3H)，4.36(s，0.7H)，4.24-4.17(m，2H)，4.05-4.02(m，1H)，3.65-3.61(m，2H)，3.52-3.47(m，1H)，3.20-3.16(m，1H)，3.00-2.88(m，2H)，2.70-2.64(m，2H)，2.53-2.46(m，2H)，2.40-2.34(m，2H)，1.94-1.46(m，15H)，1.39-1.36(m，2H)。LC/MS:t R=1.83 minutes, 628.40 (MH) +
2-(two-tert-butoxycarbonyl amino)-acrylic acid methyl ester.
At room temperature, (10.0g 39mmol) and in acetonitrile (40mL) solution of two dimethyl dicarbonate butyl esters (21.8g, 2.6 equivalents) adds 4-dimethylaminopyridine (0.48g, 0.1 equivalent) to 2-tert-butoxycarbonyl amino-3-hydroxyl-methyl propionate.Solution stirring spent the night and concentrate.Residue is dissolved in the ether, uses 1M potassium acid sulfate (2x), saturated sodium bicarbonate, salt to wash in turn,, and concentrate, obtain 15.6g (quantitative) grease through dried over mgso. 1H NMR detects the mixture that is shown as title compound and 2-(two-tert-butoxycarbonyl amino)-3-tert-butoxycarbonyl oxygen base-methyl propionate.Because finding afterwards that both and secondary amine react obtained identical product, thereby can not need separate and use this mixture.2-(two-tert-butoxycarbonyl amino)-acrylic acid methyl ester.: 1H-NMR (CDCl 3) δ 1.45 (s, 18H), 3.78 (s, 3H), 5.63 (s, 1H), 6.33 (s, 1H).Mass spectrum: 324.14 (M+Na) +2-(two-tert-butoxycarbonyl amino)-3-tert-butoxycarbonyl oxygen base-methyl propionate: 1H-NMR (CDCl 3, 500MHz) δ 1.46 (s, 9H), 1.49 (s, 18H), 3.72 (s, 3H), 4.42 (dd, J=11.6,9.2,1H), 4.75 (dd, J=11.3,4.6,1H), 5.30 (dd, J=9.2,4.6,1H).Mass spectrum: 442.21 (M+Na) +
(±)-3-(4-benzyloxy-2-oxo-2H-pyridine-1-yl)-2-(two-tert-butoxycarbonyl amino)-methyl propionate
Figure A20038011103001462
(900mg 3.0mmol) and in acetonitrile (2.5mL) solution of 4-benzyloxy-1H-pyridin-2-ones (630mg, 1.03 equivalents) adds cesium carbonate (100mg, 0.10 equivalent) to 2-(two-tert-butoxycarbonyl amino)-acrylic acid methyl ester..The suspension that generates was heated 2 hours in 80 ℃ by microwave.Should react concentrated, soluble in water, and extract with dichloromethane (3x).The organic facies that merges is washed with salt, through dried over mgso, and concentrate, obtain 1.47g (97%), it need not purification and use.Mass spectrum: 503.56 (MH) +
(±)-4-benzyloxy-1-[3-[1,4 '] connection piperidines-1 '-Ji-2-(two-tert-butoxycarbonyl amino)-3-oxo-propyl group]-the 1H-pyridin-2-ones
To 3-(4-benzyloxy-2-oxo-2H-pyridine-1-yl)-2-(two-tert-butoxycarbonyl amino)-methyl propionate (1.47g, 2.9mmol) add the aqueous solution (2.85mL) of lithium hydroxide monohydrate (0.50g, 4 equivalents) in the agitating solution in methanol (17mL).Reactant mixture was at room temperature stirred 3 hours, be cooled to 0 ℃, handle with concentrated hydrochloric acid (0.99mL), and concentrate, obtain crude acid, getting wherein, half is used for following step.This crude acid is dissolved in the dichloromethane (6mL), be cooled to 0 ℃, and use 4-piperidyl-piperidines (0.25g, 1 equivalent), triethylamine (0.31mL in turn, 2.5 equivalent) and two-2-oxo-3- oxazolidinyl) inferior phosphonic chloride (phoshinic chloride) (0.38g, 1 equivalent) handles.This reaction is warmed to room temperature, and stirs and spend the night.Should react concentrated, and, obtain 489mg (52%, 2 step) by the preparation HPLC purification.Mass spectrum: 639.41 (MH) +
Embodiment 51
(±)-4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [1-(4-benzyloxy-2-oxo-2H-pyridine-1-ylmethyl)-2-[1,4 '] connection piperidines-1 '-Ji-2-oxo-ethyl]-amide
Figure A20038011103001481
Under 0 ℃, to 4-benzyloxy-1-[3-[1,4 '] connection piperidines-1 '-Ji-2-(two-tert-butoxycarbonyl amino)-3-oxo-propyl group]-add trifluoroacetic acid (1mL) in the agitating solution in the dichloromethane (3mL) of 1H-pyridin-2-ones.After 2 hours, should react concentrated, obtain crude product amine (151mg, 97%) [mass spectrum: 439.61 (MH) into its trifluoroacetic acid salt form +], be divided into two parts, in following step, use half.Under 0 ℃, to crude product amine (75mg, 0.11mmol) and add in dichloromethane (3mL) solution of diisopropylethylamine (80 μ L, 4 equivalents) carbonyl dimidazoles (29mg, 1.6 equivalents, at twice).Stir after 10 minutes, with solution 3-piperidin-4-yl-3,4-dihydro-1H-quinazoline-2-acetic acid (40mg, 1.15 equivalents) is handled.This reaction is warmed to room temperature, and stirs and spend the night.Should react concentrated, and, obtain 40.8mg (53%) by preparation type TLC purification.
1H-NMR(CD 3OD，500MHz)δ1.25-1.56(m，4H)，1.56-1.84(m，9H)，1.90-2.08(m，2H)，2.60-2.95(m，8H)，3.11(dd，J＝24.1，12.8，1H)，3.89(ddd，J＝22.0，13.2，9.2，1H)，4.10(dd，J＝14.3，14.1，2H)，4.27-4.54(m，5H)，4.60(bd，J＝11.9，1H)，5.08(dd，J＝13.2，12.2，2H)，5.26(ddd，J＝9.4，9.4，4.8，1H)，6.05(dd，J＝13.7，2.7，1H)，6.16(m，1H)，6.77(d，J＝8.0，1H)，6.84(ddd，J＝7.6，7.6，2.1，1H)，7.04(d，J＝7.6，1H)，7.12(dd，J＝7.6，7.4，1H)，7.28-7.43(m，5H)，7.48(d，J＝7.6，1H)。Mass spectrum: 696.85 (MH) +
Embodiment 52
(±)-4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(4-hydroxyl-2-oxo-2H-pyridine-1-ylmethyl)-2-oxo-ethyl]-amide
With 4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [1-(4-benzyloxy-2-oxo-2H-pyridine-1-ylmethyl)-2-[1,4 '] connection piperidines-1 '-Ji-2-oxo-ethyl]-amide (29mg) and the agitating solution of 10% palladium charcoal (5mg) in methanol (1mL) place under the nitrogen atmosphere.After at room temperature 1 hour, should react and use nitrogen wash,, and concentrate, obtain product by diatomite filtration.
1H-NMR(CD 3OD，500MHz)δ1.40-1.85(m，12H)，2.04(dd，J＝27.4，17.0，2H)，2.66(dd，J＝21.1，11.0，1H)，2.80-3.19(m，8H)，3.95(ddd，J＝49.8，12.5，7.9，1H)，4.07-4.28(m，3H)，4.34(bs，2H)，4.36-4.59(m，2H)，4.63(bd，J＝12.8，1H)，5.20(m，1H)，5.75(dd，J＝7.3，2.1，1H)，5.97(dd，J＝8.9，7.6，1H)，6.78(d，J＝7.6，1H)，6.93(dd，J＝7.6，7.3，1H)，7.08-7.18(m，2H)，7.33(dd，J＝18.3，11.0，1H)。Mass spectrum: 606.32 (MH) +
(±)-2-(two-tert-butoxycarbonyl amino)-3-(4-hydroxy-piperdine-1-yl)-methyl propionate
(1.0g adds piperidines-4-alcohol (0.33g, 1.1 equivalents) in acetonitrile 3.0mmol) (10mL) solution to 2-(two-tert-butoxycarbonyl amino)-acrylic acid methyl ester..Nitrogen current is leniently fed reactant, stir simultaneously and spend the night.The crude product grease that generates is dissolved in the ethyl acetate, and water, then with the salt washing through dried over mgso, and concentrates, and obtains 1.38g (quantitative) grease, and it need not purification and use.Mass spectrum: 403.42 (MH) +
(±)-1-[1,4 '] connection piperidines-1 '-Ji-2-(two-tert-butoxycarbonyl amino)-3-(4-hydroxy-piperdine-1-yl)-third-1-ketone
Figure A20038011103001501
(1.0g adds the aqueous solution (1mL) of lithium hydroxide monohydrate (400mg, 3.9 equivalents) in methanol 2.5mmol) (6mL) solution to 2-(two-tert-butoxycarbonyl amino)-3-(4-hydroxy-piperdine-1-yl)-methyl propionate.This reactant was stirred 6 hours, be cooled to 0 ℃,, and concentrate with the concentrated hydrochloric acid neutralization.Need not purification and use this crude acid.This crude acid is suspended in the dichloromethane (25mL), handles to help this acid of dissolving, be cooled to 0 ℃ then with several methanol.The suspension that generates is used 4-piperidyl-piperidines (0.53g, 1.25 equivalents), triethylamine (0.70mL, 2. equivalent) and two-2-oxo-3- oxazolidinyl in turn) inferior phosphonic chloride (0.80g, 1.25 equivalents) processing.This reaction is warmed to ambient temperature overnight.Should react concentrated, and, obtain 310mg (23%, 2 step) then by the preparation HPLC purification.Mass spectrum: 539.49 (MH) +
(±)-2-amino-1-[1,4 '] connection piperidines-1 '-Ji-3-(4-hydroxy-piperdine-1-yl)-third-1-ketone
Figure A20038011103001502
Under 0 ℃, to 1-[1,4 '] connection piperidines-1 '-(310mg adds trifluoroacetic acid (2.0mL) in dichloromethane 0.58mmol) (5mL) solution to Ji-2-(two-tert-butoxycarbonyl amino)-3-(4-hydroxy-piperdine-1-yl)-third-1-ketone.Remove ice bath, and should react and stir 30 minutes.Should react and concentrate, and obtain required product, be that (400mg, quantitatively), it need not purification and use for its trifluoroacetic acid salt form.Mass spectrum: 339.46 (MH) +
(±)-[2-[1,4 '] connection piperidines-1 '-Ji-1-(4-hydroxy-piperdine-1-ylmethyl)-2-oxo-ethyl]-t-butyl carbamate
Figure A20038011103001503
To 2-amino-1-[1,4 '] connection piperidines-1 '-Ji-3-(4-hydroxy-piperdine-1-yl)-third-1-ketone (trifluoroacetate, 300mg, 0.58mmol) and diisopropylethylamine (0.30mL, 4 equivalents) add two dimethyl dicarbonate butyl esters (128mg, 1 equivalent) in oxolane (5mL) solution.The solution that generates was at room temperature stirred 1 hour, and concentrate.Residue is dissolved in the ethyl acetate, and water, then with salt washing through dried over mgso, and concentrates, and obtains 248mg (98%), and it need not purification and use.Mass spectrum: 439.65 (MH) +
(±)-[2-[1,4 '] connection piperidines-1 '-Ji-2-oxo-1-(4-oxo-piperidines-1-ylmethyl)-ethyl]-t-butyl carbamate
Figure A20038011103001511
To 1-[1,4 '] connection piperidines-1 '-Ji-2-(two-tert-butoxycarbonyl amino)-3-(4-hydroxy-piperdine-1-yl)-third-1-ketone (200mg, 0.37mmo1) dichloromethane (4mL) solution in add Dess-Martin with two batches and cross iodine alkane (periodinane) (316mg, 2 equivalents).After 1 hour, this reaction is come quencher by adding saturated sodium bicarbonate, and be extracted in the dichloromethane (3x).The organic facies that merges is washed with salt, through dried over mgso, and concentrate, obtain 187mg (94%), it need not purification and use.Mass spectrum: 437.63 (MH) +
(±)-1-(2-amino-3-[1,4 '] connection piperidines-1 '-Ji-3-oxo-propyl group)-piperidin-4-one-
Figure A20038011103001512
Under 0 ℃, to [2-[1,4 '] connection piperidines-1 '-Ji-2-oxo-1-(4-oxo-piperidines-1-ylmethyl)-ethyl]-(100mg adds trifluoroacetic acid in dichloromethane 0.23mmol) (5mL) solution to t-butyl carbamate.Remove ice bath, continue to stir 1 hour, and should react concentrated, obtain 150mg (96%), be its trifluoroacetate, it need not purification and use.Mass spectrum: 337.64 (MH) +.
Embodiment 53
(±)-4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(4-hydroxy-piperdine-1-ylmethyl)-2-oxo-ethyl]-amide
Figure A20038011103001521
Under 0 ℃, to 4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(4-hydroxy-piperdine-1-ylmethyl)-2-oxo-ethyl]-amide (3 trifluoroacetates, 200mg, 0.39mmol) dichloromethane (5mL) solution in add diisopropylethylamine (0.27mL, 3.9 equivalents) and carbonyl dimidazoles (63mg, 1 equivalent).Stir after 15 minutes, with solution 3-piperidin-4-yl-3,4-dihydro-1H-quinazoline-2-ketone (acetate, 142mg, 1.25 equivalents) is handled.Solution is warmed to room temperature, and stirs and spend the night.Should react concentrated, and, obtain 130mg (56%) grease by preparation type TLC purification.LC/MS:t R=1.17 minutes, 596.44 (MH) +
3-dimethylamino methylene-4-oxo-piperidines-1-carboxylic acid tert-butyl ester
With 4-oxo-piperidines-1-carboxylic acid tert-butyl ester (10g, 50mmol) be dissolved in dimethylformamide dimethyl acetal (dimethyl acetal) (50mL) in, and reflux 1.25 hours.Cool off this solution, concentrate, and, obtain 2.55g (19%) by purified by flash chromatography.Mass spectrum: 255.16 (MH) +
1,4,6,7-tetrahydrochysene-pyrazolo [4,3-c] pyridine-5-carboxylic acid tert-butyl ester
Figure A20038011103001523
(2.55g adds hydrazine hydrate (0.61mL, 1.25 equivalents) in methanol 10mmol) (50mL) solution to 3-dimethylamino methylene-4-oxo-piperidines-1-carboxylic acid tert-butyl ester.Solution is heated to backflow, is cooled to room temperature immediately, and concentrate, obtain 1.4g (63%), it need not purification and use.Mass spectrum: 224.11 (MH) +
4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine
Figure A20038011103001531
Under 0 ℃, with 1,4,6, (0.70g 3.1mmol) is dissolved in the trifluoroacetic acid (10mL) 7-tetrahydrochysene-pyrazolo [4,3-c] pyridine-5-carboxylic acid tert-butyl ester, stirs 1 hour, and concentrates.Residue is dissolved in the ethanol, and handles with concentrated hydrochloric acid (1mL).This pair-hydrochlorate is precipitated out with the form of white solid, with its filtration, obtains 510mg (83%).Pass through described salt soluble in waterly when needing, it is loaded in the SCX post, use washed with methanol, use the methanol solution eluting of 2M ammonia then, can prepare free alkali.
(±)-2-(two-tert-butoxycarbonyl amino)-3-(1,4,6,7-tetrahydrochysene-pyrazolo [4,3-c] pyridine-5-yl)-methyl propionate
To 4,5,6, add 2-(two-tert-butoxycarbonyl amino)-acrylic acid methyl ester. (400mg) in the 2.5mL methanol solution of 7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridines (160mg).By using gentle nitrogen current, this reaction is concentrated into about 1.5mL.This solution at room temperature stirred spend the night.Should react concentrated, be dissolved in the ethyl acetate,,, and concentrate through dried over mgso with the salt washing.The residue that obtains is enough pure, need not can use by purification.
1H-NMR(CDCl 3，500MHz)δ1.44(s，9H)，2.73(m，3H)，2.91(m，1H)，3.06(dd，J＝13.4，8.6，1H)，3.22(dd，J＝13.4，8.2，1H)，3.54(d，J＝13.4，1H)，3.63(d，J＝13.4，1H)，3.71(s，3H)，5.11(dd，J＝8.5，5.2，1H)，7.25(s，1H)。Mass spectrum: 425.23 (MH) +
(±)-2-amino-3-(1,4,6,7-tetrahydrochysene-pyrazolo [4,3-c] pyridine-5-yl)-methyl propionate
In dichloromethane (5mL, the 0 ℃) solution of 2-(two-tert-butoxycarbonyl amino)-3-(1,4,6,7-tetrahydrochysene-pyrazolo [4,3-c] pyridine-5-yl)-methyl propionate (0.55g, 1 equivalent), add trifluoroacetic acid (1.5mL).Remove ice bath, and continue to stir 2 hours.Concentrate this solution, be dissolved in the methanol again, and by the strong cation-exchanging resin post.After washed with methanol, remove product by methanol solution eluting from post with 2M ammonia, obtain product (275mg, 95%) into its free alkali form.
1H-NMR(CDCl 3，500MHz)δ2.71(dd，J＝12.8，8.6，1H)，2.74-2.91(m，6H)，3.48(s，2H)，3.54(d，J＝13.4，1H)，3.62(d，J＝13.4，1H)，3.69(dd，J＝8.2，4.9，1H)，3.73(s，3H)，7.27(s，1H)。Mass spectrum: 225.16 (MH) +
3,3-dimethyl-4-oxo-piperidines-1-carboxylic acid tert-butyl ester
Under 0 ℃, (16g adds sodium hydride (4.1g, 2.1 equivalents) with 4 batches in oxolane 80mmol) (400mL) solution to 4-oxo-piperidines-1-carboxylic acid tert-butyl ester.To wherein dripping iodomethane (12.5mL, 2.5 equivalents).Should react and be warmed to room temperature gradually, and stir and spend the night.Should react concentrated, be dissolved in the ether,,, and concentrate through dried over mgso with the salt washing.Product by crystallization in the pentane of heat (2X), is obtained 5.9g (32%).
1H-NMR(CDCl 3，500MHz)δ1.09(s，6H)，1.47(s，9H)，2.47(dd，J＝6.4，6.4，2H)，3.41(m，2H)，3.70(m，2H)。Mass spectrum: 250.12 (M+Na) +
5-dimethylamino methylene-3,3-dimethyl-4-oxo-piperidines-1-carboxylic acid tert-butyl ester
Figure A20038011103001543
With 3, (5g 22mmol) is dissolved in the dimethylformamide dimethyl acetal (25mL) 3-dimethyl-4-oxo-piperidines-1-carboxylic acid tert-butyl ester, and heats 2 hours under refluxing.Then with reactant mixture by microwave in 130 ℃ of heating 1 hour, and concentrate, obtain 6.43g (quantitative) grease, need not purification and use with it.
1H-NMR(CDCl 3，500MHz)δ1.07(s，6H)，1.45(s，9H)，3.06(s，6H)，3.37(m，2H)，4.57(m，2H)，7.41(bs，1H)。
7,7-dimethyl-1,4,6,7-tetrahydrochysene-pyrazolo [4,3-c] pyridine-5-carboxylic acid tert-butyl ester
To 5-dimethylamino methylene-3, (6.35g adds hydrazine hydrate (1.2mL, 1.1 equivalents) to 3-dimethyl-4-oxo-piperidines-1-carboxylic acid tert-butyl ester in methanol 22mmol) (15mL) solution.Solution at room temperature stirred spend the night, and concentrate, obtain 5.3g (94%), it need not purification and use.Mass spectrum: 252.19 (MH) +.
7,7-dimethyl-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine
Figure A20038011103001552
At 0 ℃, to 7,7-dimethyl-1,4,6, (5.3g adds trifluoroacetic acid (5mL) in dichloromethane 21mmol) (10mL) solution to 7-tetrahydrochysene-pyrazolo [4,3-c] pyridine-5-carboxylic acid tert-butyl ester.This reaction is warmed to room temperature, stirred 15 minutes, and handle with other trifluoroacetic acid (5mL).After 1 hour, should react concentrated, be dissolved in the ethanol (10mL), be cooled to 0 ℃, and handle with concentrated hydrochloric acid (3mL), and concentrate.The solid that generates is ground with ethanol, and filter, obtain the form of its pair-hydrochlorate of 3.02g (64%).Pass through described salt soluble in waterly when needing, it is loaded in the SCX post, use washed with methanol, use the methanol solution eluting of 2M ammonia then, can prepare free alkali.
1H-NMR(D 2O，500MHz)δ1.49(s，6H)，3.46(s，2H)，4.39(s，2H)，7.86(s，1H)。Mass spectrum: 152.14 (MH) +
(±)-2-(two-tert-butoxycarbonyl amino)-3-(7,7-dimethyl-1,4,6,7-tetrahydrochysene-pyrazolo [4,3-c] pyridine-5-yl)-methyl propionate
Figure A20038011103001561
To 7,7-dimethyl-4,5,6 adds 2-(two-tert-butoxycarbonyl amino)-acrylic acid methyl ester. (331mg) in methanol (3mL) solution of 7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridines (160mg).Use gentle nitrogen current, and should react to stir and spend the night.In second day morning, its volume significantly reduces.Remove the solvent of trace under the fine vacuum, obtain 490mg (quantitatively), it need not purification and use.
1H-NMR(CDCl 3，500MHz)δ1.24(s，3H)，1.26(s，3H)，1.38(s，18H)，2.33(d，J＝11.3，1H)，2.57(d，J＝11.3，1H)，3.09(dd，J＝13.1，5.5，1H)，3.15(dd，J＝13.4，9.5，1H)，3.35(d，J＝12.8，1H)，3.57(d，J＝12.8，1H)，3.68(s，3H)，5.13(dd，J＝9.5，3.7，1H)，7.16(s，1H)。Mass spectrum: 453.30 (MH) +
(±)-2-amino-3-(7,7-dimethyl-1,4,6,7-tetrahydrochysene-pyrazolo [4,3-c] pyridine-5-yl)-methyl propionate
Figure A20038011103001562
In dichloromethane (5mL, the 0 ℃) solution of 2-(two-tert-butoxycarbonyl amino)-3-(7,7-dimethyl-1,4,6,7-tetrahydrochysene-pyrazolo [4,3-c] pyridine-5-yl)-methyl propionate (0.49g, 1 equivalent), add trifluoroacetic acid (1.5mL).Remove ice bath, and continue to stir 2 hours.Concentrate this solution, make again to be dissolved in the methanol, and fill in the strong cation-exchanging resin post.After washed with methanol,, obtain product (250mg, 94%) into its free alkali form by with the methanol solution of 2M ammonia eluted product from the post.
1H-NMR(CDCl 3，500MHz)δ1.27(s，3H)，1.28(s，3H)，2.41(d，J＝11.3，1H)，2.50(d，J＝11.3，1H)，2.69(dd，J＝12.5，7.9，1H)，2.82(dd，J＝12.5，5.2，1H)，3.45(d，J＝12.8，1H)，3.52(d，J＝12.8，1H)，3.67(m，1H)，3.69(s，3H)，7.19(s，1H)。Mass spectrum: 253.16 (MH) +
(±)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-3-(1,4,6,7-tetrahydrochysene-pyrazolo [4,3-c] pyridine-5-yl)-methyl propionate
In dichloromethane (2mL, the 0 ℃) solution of 2-amino-3-(1,4,6,7-tetrahydrochysene-pyrazolo [4,3-c] pyridine-5-yl)-methyl propionate (260mg, 1 equivalent), add carbonyl dimidazoles (188mg, 1 equivalent).After 15 minutes, disposable adding 3-piperidin-4-yl-3,4-dihydro-1H-quinazoline-2-ketone (295mg, 1.1 equivalents).Remove ice bath, and continue to stir and spend the night.Should react concentrated, and, obtain 118mg (21%) by the column chromatography purification.
1H-NMR(CDCl 3，500MHz)δ1.60-1.80(m，4H)，2.70-3.05(m，8H)，3.45(s，2H)，3.56(d，J＝13.4，1H)，3.62(d，J＝13.4，1H)，3.75(s，3H)，4.02(d，J＝13.1，1H)，4.10(d，J＝12.5，1H)，4.24(s，2H)，4.45-4.57(m，2H)，5.79(bs，1H)，6.68(d，J＝7.94，1H)，6.90(dd，J＝7.3，7.3，1H)，7.00(d，J＝7.3，1H)，7.13(dd，J＝7.6，7.3，1H)，7.25(s，1H)，7.82(s，1H)。Mass spectrum: 482.27 (MH) +
Embodiment 54
(±)-4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-2-oxo-1-(1,4,6,7-tetrahydrochysene-pyrazolo [4,3-c] pyridine-5-ylmethyl)-ethyl]-amide
Figure A20038011103001572
To 2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-3-(1,4,6,7-tetrahydrochysene-pyrazolo [4,3-c] pyridine-5-yl)-add lithium hydroxide monohydrate (3mg in methanol (0.6mL) solution of methyl propionate (16mg, 1 equivalent), 2.2 aqueous solution equivalent) (0.1mL), and at room temperature stirred 4 hours.Solution is cooled to 0 ℃, handles, and concentrate, obtain crude acid with 1M aqueous potassium hydrogen sulfate (60 μ l, 1.8 equivalents), need not purification and directly use with it.This crude acid is dissolved in the dimethyl formamide (0.3mL), and uses dichloromethane (0.15mL), 4-piperidyl-piperidines (11mg, 2 equivalents), diisopropylethylamine (12 μ L, 2 equivalents) and PyBOP in turn (19mg, 1.1 equivalents) are handled.With solution stirring 30 minutes, and concentrate.Product by the column chromatography purification, is obtained 17.6mg (85%, 2 step).
1H-NMR(CDCl 3，500MHz)δ1.30-1.60(m，9H)，1.62-1.78(m，5H)，1.81(bd，J＝11.0，2H)，2.23-2.49(m，6H)，2.55-3.10(m，11H)，3.59(d，J＝7.3，2H)，4.00-4.20(m，3H)，4.23(s，2H)，4.50(m，1H)，4.63(m，1H)，5.03(m，1H)，5.71(d，J＝7.3，1H)，6.67(d，J＝7.9，1H)，6.91(dd，J＝7.6，7.3，1H)，7.02(dd，J＝7.9，7.3，1H)，7.14(dd，J＝7.6，7.6，1H)，7.24(s，1H)，7.39(s，1H)，10.76(bs，1H)。Mass spectrum: 618.34 (MH) +
Embodiment 55
(±)-3-(7,7-dimethyl-1,4,6,7-tetrahydrochysene-pyrazolo [4,3-c] pyridine-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-methyl propionate
In oxolane (4mL, the 0 ℃) solution of 2-amino-3-(7,7-dimethyl-1,4,6,7-tetrahydrochysene-pyrazolo [4,3-c] pyridine-5-yl)-methyl propionate (250mg, 1 equivalent), add carbonyl dimidazoles (162mg, 1 equivalent).After 5 minutes, remove ice bath, and should react and at room temperature stir 30 minutes.To disposable adding 3-piperidin-4-yl-3 wherein, 4-dihydro-1H-quinazoline-2-ketone (250mg, 1.1 equivalents), and this reactant stirred spend the night.Should react concentrated, and, obtain 228mg (45%) by the column chromatography purification.
1H-NMR(CDCl 3，500MHz)δ1.30(s，3H)，1.31(s，3H)，1.60-1.80(m，4H)，2.43(d，J＝11.6，1H)，2.53(d，J＝11.3，1H)，2.80-2.95(m，4H)，3.51(dd，J＝20.4，13.1，2H)，3.74(s，3H)，4.00(d，J＝13.7，1H)，4.10(d，J＝12.2，1H)，4.25(dd，J＝16.2，14.4，2H)，4.86(m，2H)，6.66(d，J＝7.6，1H)，6.92(dd，J＝7.6，7.3，1H)，7.02(d，J＝7.3，1H)，7.14(dd，J＝7.6，7.6，1H)，7.24(s，1H)。Mass spectrum: 510.27 (MH) +
Embodiment 56
(±)-4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(7,7-dimethyl-1,4,6,7-tetrahydrochysene-pyrazolo [4,3-c] pyridine-5-ylmethyl)-2-oxo-ethyl]-amide
To 3-(7,7-dimethyl-1,4,6,7-tetrahydrochysene-pyrazolo [4,3-c] pyridine-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino)-methyl propionate (20mg, 1.0 add the aqueous solution (0.1mL) of lithium hydroxide monohydrate (4mg, 2.2 equivalents) in methanol equivalent) (0.6mL) solution, and at room temperature stirred 4 hours.Solution is cooled to 0 ℃, handles, and concentrate, obtain crude acid with 1M aqueous potassium hydrogen sulfate (75 μ l, 1.8 equivalents), need not purification and directly use with it.This crude acid is dissolved in the dimethyl formamide (0.3mL), and uses dichloromethane (0.15mL), 4-piperidyl-piperidines (13mg, 2 equivalents), diisopropylethylamine (14 μ L, 2 equivalents) and PyBOP in turn (22mg, 1.1 equivalents) are handled.With solution stirring 1.5 hours and concentrated.Product by the column chromatography purification, is obtained polluting the product that HOBT is arranged.Make product remove HOBT, with the dichloromethane solution eluting of 10% methanol by the alkali alumina post.Concentrate, obtain 18.3mg (72%, 2 step).
1H-NMR(CDCl 3，500MHz)δ1.25-1.32(m，6H)，1.40(m，4H)，1.54(m，5H)，1.65(m，4H)，1.83(m，2H)，2.30-2.56(m，8H)，2.81(m，4H)，3.04(dt，J＝57.1，12.2，1H)，3.43-3.60(m，2H)，4.00-4.17(m，2H)，4.18-4.26(m，3H)，4.49(m，1H)，4.62(m，1H)，5.03(m，1H)，5.80(dd，J＝16.8，9.8，1H)，6.69(d，J＝7.9，1H)，6.90(dd，J＝7.3，7.3，1H)，6.99(dd，J＝7.6，7.3，1H)，7.13(dd，J＝7.6，7.6，1H)，7.19(s，1H)，7.66(bd，J＝12.8，1H)。Mass spectrum: 646.43 (MH) +
2-benzyloxycarbonyl amino-3-(6-methoxyl group-pyridin-3-yl)-acrylic acid methyl ester.
Dichloromethane (15mL) solution that in the suspension in the dichloromethane (70mL ,-20 ℃) of potassium tert-butoxide (1.23g, 1.5 equivalents), adds N-benzyloxycarbonyl-α-phosphono glycine trimethyl (3.63g, 1.5 equivalents).With the solution stirring that generates 5 minutes, and with 6-methoxyl group-pyridine-3-formaldehyde (1.0g, dichloromethane 7.3mmol) (15mL) solution-treated.Stir after 1.5 hours, make reactant be warmed to 0 ℃, and stirred 1 hour.This reactant is poured in the separatory funnel that contains ethyl acetate and water fast.Add saline to help to separate each layer.With ethyl acetate (3X) extraction, reuse salt washing through dried over mgso, and concentrates, and obtains 2.63g (quantitatively) with water layer, and it need not purification and use.Mass spectrum: 343.08 (MH) +
(±)-2-amino-3-(6-methoxyl group-pyridin-3-yl)-methyl propionate
Figure A20038011103001602
To contain 2-benzyloxycarbonyl amino-3-(6-methoxyl group-pyridin-3-yl)-acrylic acid methyl ester. (620mg), palladium charcoal (10%, 100mg), feed competent nitrogen in the flask of ethyl acetate (10mL) and methanol (20mL), feed hydrogen then, be connected in a hydrogen capsule at last.This reactant stirring is spent the night.With the flask nitrogen wash, by diatomite filtration, and concentrate, obtain 390mg (quantitatively), it need not purification and use.Mass spectrum: 211.11 (MH) +
(±)-3-(6-methoxyl group-pyridin-3-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-methyl propionate
Figure A20038011103001603
In dichloromethane (2mL, the 0 ℃) solution of 2-amino-3-(6-methoxyl group-pyridin-3-yl)-methyl propionate (130mg) and diisopropylethylamine (0.3mL), add N, N '-two succinimidyl carbonate (158mg).After 30 minutes, add 3-piperidin-4-yl-3, dichloromethane (1mL) solution of 4-dihydro-1H-quinazoline-2-ketone (120mg) by conduit.This reactant is warmed to room temperature, and stirs and spend the night.Should react concentrated, and, obtain 160mg (55%) by the preparation HPLC purification.Mass spectrum: 468.19 (MH) +
Embodiment 57
(±)-4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(6-methoxyl group-pyridin-3-yl methyl)-2-oxo-ethyl]-amide
Figure A20038011103001611
To 3-(6-methoxyl group-pyridin-3-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-add the aqueous solution (1mL) of lithium hydroxide monohydrate (29mg) in methanol (6mL) solution of methyl propionate (160mg).Should react and at room temperature stir 4 hours, and be cooled to 0 ℃.Should react with 1N hydrochloric acid (0.6mL) and handle, concentrate.The residue of gained is dissolved in the dichloromethane (5mL), and uses 4-piperidyl-piperidines (75mg), triethylamine (0.14mL) and two-2-oxo-3- oxazolidinyl in turn) inferior phosphonic chloride (104mg) processing.Should react to stir and spend the night, concentrate, and, obtain 94mg (45%) by preparation property HPLC purification.LC/MS:t R=1.86 minutes, 604.51 (MH) +
2-benzyloxycarbonyl amino-3-(2-methoxyl group-pyrimidine-5-yl)-acrylic acid methyl ester.
Dichloromethane (15mL) solution that in the suspension in the dichloromethane (70mL ,-30 ℃) of potassium tert-butoxide (1.23g), adds N-benzyloxycarbonyl-α-phosphono glycine trimethyl (3.63g).With the solution stirring that generates 5 minutes, and with dichloromethane (15mL) solution-treated of 2-methoxyl group-pyrimidine-5-formaldehyde (1.0g).Stir after 1.5 hours, this reaction is warmed to 0 ℃, and stirred 1 hour.This reaction is poured in the separatory funnel that contains ethyl acetate and water fast.Add saline, to help to separate each layer.Water layer is extracted with ethyl acetate (3X), and the washing of reuse salt through dried over mgso, and concentrates.With the recrystallizing methanol of crude product, obtain the pure material of 1.4g by heat.Mass spectrum: 344.10 (MH) +
(±)-2-amino-3-(2-methoxyl group-pyrimidine-5-yl)-methyl propionate
To contain amino ester (700mg), palladium charcoal (10%, 100mg) and feed competent nitrogen in the flask of methanol (20mL), feed hydrogen then, be connected in a hydrogen capsule at last.Should react to stir and spend the night.With the flask nitrogen wash, by diatomite filtration, and concentrate, obtain 379mg (88%), it need not purification and use.Mass spectrum: 212.08 (MH) +
(±)-3-(2-methoxyl group-pyrimidine-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-methyl propionate
Figure A20038011103001622
In the solution in the dichloromethane (2mL, 0 ℃), add N, N '-two succinimidyl carbonate (155mg) to 2-amino-3-(2-methoxyl group-pyrimidine-5-yl)-methyl propionate (125mg) and diisopropylethylamine (0.3mL).After 30 minutes, add 3-piperidin-4-yl-3, dichloromethane (2mL) solution of 4-dihydro-1H-quinazoline-2-ketone (120mg) by conduit.This reaction is warmed to room temperature, and stirs and spend the night.Should react concentrated, and, obtain 99mg (36%) by the preparation HPLC purification.Mass spectrum: 469.10 (MH) +
Embodiment 58
(±)-4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(2-methoxyl group-pyrimidine-5-ylmethyl)-2-oxo-ethyl]-amide
To 3-(2-methoxyl group-pyrimidine-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-add the aqueous solution (1mL) of lithium hydroxide monohydrate (18mg) in methanol (6mL) solution of methyl propionate (99mg).Should react and at room temperature stir 4 hours, and be cooled to 0 ℃.Should react with 1N hydrochloric acid (0.4mL) and handle, concentrate.The residue of gained is dissolved in the dichloromethane (3mL), and uses 4-piperidyl-piperidines (50mg), triethylamine (88 μ L) and two-2-oxo-3- oxazolidinyl in turn) inferior phosphonic chloride (71mg) processing.Should react to stir and spend the night, and concentrate, and, obtain 103mg (45%) by the preparation HPLC purification.LC/MS:t R=1.23 minutes, 605.54 (MH) +
2-benzyloxy-5-bromo-pyridine
In being equipped with the device of dean stark trap, with 2,5-dibromo pyridine (2.0g, 8.4mmol), dibenzo-18-is preced with-6 (0.14g, .05 benzyl alcohol (1.1mL equivalent),, 1.3 equivalent) and the heating 3 hours under refluxing of the suspension of potassium hydroxide (1.1g, 2.4 equivalents) in toluene (30mL).Cool off this suspension, concentrate, suspend in water then, and be extracted in the dichloromethane.With the organic facies water that merges, then with the salt washing, through dried over mgso, and concentrate, obtain 1.9g (85%), it need not purification and use.Mass spectrum: 264.25 (MH) +
6-benzyloxy-pyridine-3-formaldehyde
Figure A20038011103001633
(1.64g adds n-BuLi (hexane solution of 2.5M, 2.61mL, 1.05 equivalents) in oxolane 6.2mmol) (25mL ,-78 ℃) solution to 2-benzyloxy-5-bromo-pyridine.At-78 ℃ after following 1 hour, add dimethyl formamide (0.97mL, 2 equivalents), and mixture was stirred 30 minutes.This reactant is poured into fast in the agitating solution of 5% sodium bicarbonate aqueous solution (50mL), and extracts with ether (3x).This is contained ether (ethereal) solution wash with salt, through dried over mgso, and concentrate, obtain 1.16g (quantitatively), it need not purification and use.Mass spectrum: 186.34 (MH) +
2-benzyloxycarbonyl amino-3-(6-benzyloxy-pyridin-3-yl)-acrylic acid methyl ester.
Under-20 ℃, in the stirred suspension of potassium tert-butoxide (0.440g, 1.7 equivalents) in dichloromethane (25mL), add dichloromethane (5mL) solution of N-benzyloxycarbonyl-α-phosphono glycine trimethyl (1.3g, 1.7 equivalents).With the solution stirring that generates 5 minutes, and with 6-benzyloxy-pyridine-3-formaldehyde (0.49g, dichloromethane 2.28mmol) (5mL) solution-treated.This reactant was stirred 1 hour down at-20 ℃, be warmed to 0 ℃ gradually, and be poured in the separatory funnel of moisture and ether.This reactant with ether (2x) extraction, with the salt washing, through dried over mgso, and is concentrated, obtain 0.98g (quantitatively) grease, it need not purification and use.Mass spectrum: 419.32 (MH) +
(±)-2-benzyloxycarbonyl amino-3-(6-benzyloxy-pyridin-3-yl)-methyl propionate
Figure A20038011103001642
The 2-benzyloxycarbonyl of in flask, packing into amino-3-(6-benzyloxy-pyridin-3-yl)-acrylic acid methyl ester. (0.50g, 1.2mmol), Wilkinson ' s catalyst (200mg, 0.2 equivalent), methanol (5mL) and toluene (3mL).In this flask, feed competent nitrogen, feed hydrogen then, be heated to 35 ℃, and under nitrogen atmosphere, stirred 4 days.Should react and use nitrogen wash, and with the methanol dilution, filter, and concentrate, obtain crude product, it by the column chromatography purification, was obtained 145mg (29%).
(±)-2-amino-3-(6-benzyloxy-pyridin-3-yl)-methyl propionate
Figure A20038011103001651
(130mg 0.31mmol) adds TMS iodine (44 μ L, 1.0 equivalents) in the agitating solution in the dichloromethane (5mL, 0 ℃) to 2-benzyloxycarbonyl amino-3-(6-benzyloxy-pyridin-3-yl)-methyl propionate.Remove ice bath, and continue to stir 1 hour.This reactant is poured in the saturated sodium bicarbonate, with ethyl acetate (3x) extraction, with salt washing, through dried over mgso, and concentrates, obtain 81mg (91%), it need not purification and use.Mass spectrum: 287.37 (MH) +
(±)-3-(6-benzyloxy-pyridin-3-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-methyl propionate
Figure A20038011103001652
(60mg 0.21mmol) adds carbonyl dimidazoles (34mg, 1.0 equivalents) in the agitating solution in the dichloromethane (1mL, 0 ℃) to 2-amino-3-(6-benzyloxy-pyridin-3-yl)-methyl propionate.After 15 minutes, add 3-piperidin-4-yl-3, dichloromethane (0.5mL) solution of 4-dihydro-1H-quinazoline-2-ketone (58mg, 1.2 equivalents) by conduit.Remove ice bath, and continue to stir and spend the night.This reactant is concentrated, and, obtain 59mg (52%) by the column chromatography purification.Mass spectrum: 544.49 (MH) +
Embodiment 59
(±)-4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [1-(6-benzyloxy-pyridin-3-yl methyl)-2-[1,4 '] connection piperidines-1 '-Ji-2-oxo-ethyl]-amide
To 3-(6-benzyloxy-pyridin-3-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-methyl propionate (59mg, 0.11mmol) add the aqueous solution (0.5mL) of lithium hydroxide monohydrate (9.1mg, 2 equivalents) in the agitating solution in methanol (3mL).Should react and at room temperature stir 2 hours, be cooled to 0 ℃, and come quencher by adding 1N hydrochloric acid (0.15mL), and concentrate.Need not purification and use this crude product.This crude acid is dissolved in the dichloromethane (2mL, 0 ℃), and uses 4-piperidino-piperidines (34mg, 1.8 equivalents), triethylamine (35 μ L, 2.3 equivalents) and two-2-oxo-3- oxazolidinyl in turn) inferior phosphonic chloride (34mg, 1.2 equivalents) processing.Remove ice bath, and this reactant stirring is spent the night.Should react concentrated, and, obtain 30.3mg (41%) by preparation type TLC purification.LC/MS:t R=1.49 minutes, 680.29 (MH) +
Embodiment 60
(±)-4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-2-oxo-1-(6-oxo-1,6-dihydro-pyridin-3-yl methyl)-ethyl]-amide
Figure A20038011103001662
4-(the 2-oxo-1 of in flask, packing into, 4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [1-(6-benzyloxy-pyridin-3-yl methyl)-2-[1,4 '] connection piperidines-1 '-Ji-2-oxo-ethyl]-amide (27mg, 0.04mmol), palladium charcoal (10%, 4mg) and methanol (1mL).In this flask, feed competent nitrogen, feed hydrogen then, and under nitrogen atmosphere, stir and spend the night.With the flask nitrogen wash, and should react, obtain 22.1mg (94%) by diatomite filtration.LC/MS:t R=0.93 minute, 590.32 (MH) +
Piperidines-1,4-dicarboxylic acids 1-tert-butyl ester 4-ethyl ester
Figure A20038011103001671
Under 0 ℃, to 4-piperidine ethyl formate (ethyl isonipecotate) (5.00g, 0.032mol) and triethylamine (4.9mL slowly adds two carbonic acid, two-tert-butyl ester (7.2g, dichloromethane 0.033mol) (25mL) solution in dichloromethane 0.035mmol) (25mL) solution.Reactant mixture at room temperature stirred spend the night, give a baby a bath on the third day after its birth time with potassium acid sulfate then, and with the salt washing once.Organic extract through anhydrous sodium sulfate drying, is filtered and vacuum concentration, obtain the required product (8.23g, 100%) of colorless oil.
1H NMR(C 6D 6，500MHz)δ3.88(q，J＝7.5Hz，2H)，2.52(m，1H)，1.60-1.48(m，8H)，1.42(s，9H)，0.92(t，3H)。Mass spectrum: 280.44 (M+Na) +
4-(2-nitro-benzyl)-piperidines-1,4-dicarboxylic acids 1-tert-butyl ester 4-ethyl ester
Figure A20038011103001672
To piperidines-1, (8.23g slowly adds two (TMS) sodium amide (44mL, solution 0.044mol) to 4-dicarboxylic acids 1-tert-butyl ester 4-ethyl ester in oxolane 0.032mol) (85mL) solution.The mixture that generates after 1 hour, is added 2-nitrobenzyl bromine (8.21g, 0.038mol) solution in stirring under-78 ℃.Reactant mixture is warmed to room temperature, and stirs and spend the night.Then it is concentrated, and residue is distributed between water and ethyl acetate.Organic extract is washed with salt,, filtered through anhydrous magnesium sulfate drying, and vacuum concentration.End product by silica gel column chromatography (eluent-hexane-ethyl acetate 4: 1), by purification in blended (complex) reactant mixture, is obtained the required product (1.61g, 13%) of brown oil.Mass spectrum: 415.38 (M+Na) +
4-(2-amino-benzyl)-piperidines-1,4-dicarboxylic acids 1-tert-butyl ester 4-ethyl ester
Figure A20038011103001681
With 4-(2-nitro-benzyl)-piperidines-1, (the 1.61g's 4-dicarboxylic acids 1-tert-butyl ester 4-ethyl ester 4.102mmol) spends the night with the hydrogenation under 50psi hydrogen of the mixture of 10% palladium charcoal (0.10g) in ethanol (190mL).The mixture that generates is filtered by siliceous earth column (plug), and vacuum concentrated filtrate, obtain the required product (1.29g, 99%) of colorless oil.Mass spectrum: 363.45 (MH) +
4-(2-amino-benzyl)-piperidines-4-carboxylic acid, ethyl ester hydrochlorate
Figure A20038011103001682
To 4-(2-amino-benzyl)-piperidines-1,4-dicarboxylic acids 1-tert-butyl ester 4-ethyl ester (1.29g, two  alkane (5mL) solution of adding 4.0M hydrogen chloride in dichloromethane 4.102mmol) (15mL) solution.The solution that generates at room temperature stirred spend the night.This solution of vacuum concentration obtains the title compound (1.23g, 100%) of white solid, need not purification with it and use in next step.Mass spectrum: 263.40 (MH) +
3,4-benzo-2,9-diaza spiro [5.5] hendecane-1-ketone
Figure A20038011103001683
(1.23g, 4.102mmol) solution is dissolved in the methanol, and the solution that generates is at room temperature stirred spend the night with 4-(2-amino-benzyl)-piperidines-4-carboxylic acid, ethyl ester hydrochlorate.With one times of this solution with water dilution, and pass through AG The short column (shortplug) of the hydroxide form of 1-X2 ion exchange resin (100-200 sieve mesh), the methanol aqueous solution eluting with 50%.Evaporate the fraction of collecting (fractions), obtain the required product (0.89g, 100%) of white solid. 1H-NMR(CD 3OD，500MHz)δ7.23(m，2H)，7.05(d，J＝7.5Hz，1H)，6.89(d，J＝8.0Hz，1H)，3.46-3.41(m，2H)，3.34-3.30(m，2H)，2.14-2.09(m，2H)，1.73-1.67(m，4H)。Mass spectrum: 217.46 (MH) +
(R)-2-amino-3-benzo [b] thiene-3-yl--1-[1,4 '] connection piperidines-1 '-Ji-third-1-ketone, dihydrochloride
Figure A20038011103001691
At room temperature, to well-beaten 3-benzo [b] thiene-3-yl--(2R)-2-tert-butoxycarbonyl amino-propanoic acid (1.0g, 3.1mmol) add 4-piperidino piperidines (573mg in the solution in dichloromethane (30mL), 3.4mmol), triethylamine (1.3mL, 9.3mmol), add 3-(diethoxy phosphoryl oxy (phosphoryloxy))-1,2 subsequently, 3-phentriazine-4 (3H)-ketone (1.02g, 3.4mmol).After 3 hours, reactant mixture is handled with sodium bicarbonate aqueous solution (15mL), saline (20mL), and dry (sodium sulfate).The mixture that this is thick obtains (1R)-1-benzo [b] thiene-3-yl-methyl-2-[1 of 82% productive rate by the purified by flash chromatography of the dichloromethane solution of use 5% methanol, 4 '] connection piperidines-1 '-Ji-2-oxo-ethyl)-the carbamic acid tertiary butyl ester.With (1R)-1-benzo [b] thiene-3-yl-methyl-2-[1,4 '] connection piperidines-1 '-Ji-2-oxo-ethyl)-carbamic acid tertiary butyl ester (1.2g, 2.54mmol) dichloromethane (5mL) solution join in the two  alkane solution (20mL) of saturated hydrogen chloride, and stirred 2 hours.Remove and desolvate, obtain (2R)-2-amino-3-benzo [b] thiene-3-yl--1-[1 of 98% productive rate, 4 '] connection piperidines-1 '-Ji-third-1-ketone, dihydrochloride.
1H-NMR(500MHz，CD 3OD)：δ7.98-7.88(m，2H)，7.55-7.40(m，3H)，4.85-4.83(m，1H)，3.66-2.68(m，9H)，1.92-1.44(m，12H)。Mass spectrum: 372 (MH) +
Embodiment 61
(R)-and 1-oxo-3,4-benzo-2,9-diaza-spiro [5.5] hendecane-3-alkene-9-carboxylic acid (1-benzo [b] thiene-3-yl-methyl-2-[1,4 '] connection piperidines-1 '-Ji-2-oxo-ethyl)-amide
To 2-amino-3-benzo [b] thiene-3-yl--1-[1,4 '] connection piperidines-1 '-Ji-third-1-ketone (50.0mg, 0.135mmol) 1, add N in 2-dichloroethanes (1.5mL) solution, N '-two succinimidyl carbonate (34.6mg, 0.135mmol) and diisopropyl ethyl amine (0.09mL, 0.500mmol).With the solution stirring that generates 1 hour, add 3 at this moment, 4-benzo-2,9-diaza spiro [5.5] hendecane-1-ketone (30.4mg, 0.140mmol).Reactant mixture at room temperature stirred spend the night, and concentrate.Realize purification by anti-phase preparation HPLC, obtain the required product (75.5mg, 77%) of brown oil.
1H-NMR(CD 3OD，500MHz)δ7.92-7.85(m，2H)，7.44-7.34(m，3H)，7.21-7.16(m，2H)，7.00(t，J＝7.0Hz，1H)，6.86(t，J＝8.5Hz，1H)，5.15-5.02(m，1H)，4.72-4.45(m，1H)，3.95-3.20(m，8H)，3.18-2.92(m，4H)，2.92-2.75(m，2H)，2.75-2.63(m，1H)，2.40-2.30(m，1H)，2.08-1.64(m，8H)，1.58-1.20(m，6H)。Mass spectrum: 614.37 (MH) +
Embodiment 62
N-[(1R)-1-(benzo [b] thiene-3-yl-methyl)-2-[1,4-joins piperidines]-1-base-2-oxoethyl]-3 ', 4 '-dihydro-2-oxo-spiral shell-[piperidines-4,4 ' (1H)-quinoline]-1-Methanamide
According to described preparation (R)-1-oxo-3,4-benzo-2,9-diaza-spiro [5.5] hendecane-3-alkene-9-carboxylic acid (1-benzo [b] thiene-3-yl-methyl-2-[1,4 '] connection piperidines-1 '-Ji-2-oxo-ethyl)-method of amide, by 3 ', 4 '-dihydro-2-oxo-spiral shell-[piperidines-4,4 ' (1H)-quinoline] prepare (M.S.Chambers, etc., J.Med.Chem., 1992,35,2033-2039; WO-94/13696).
1H-NMR(CDCl 3，500MHz)δ-0.35(1H，m)，0.79(1H，m)，1.2-2.1(12H，m)，2.22(5H，m)，2.38(2H，m)，2.74(2H，ABq)，3.19(3H，m)，3.33(2H，m)，3.65(1H，d)，3.80(1H，m)，3.93(1H，t)，4.49(1H，d)，5.31(1H，t)，5.96(1H，t)，6.89(1H，d)，7.05(1H，t)，7.18(1H，d)，7.26(1H，m)，7.33(1H，m)，7.40(1H，m)，7.78(1H，m)，7.96(1H，Abq)，9.01(1H，brs)，9.17(1H，brs)。Mass spectrum: 614.36 (MH) +
Embodiment 63
N-[(1R)-1-(benzo [b] thiene-3-yl-methyl)-2-[1,4-joins piperidines]-1-base-2-oxoethyl]-2 ', 3 '-dihydro-1-oxo spiral shell-[piperidines-4,4 ' (1H)-isoquinolin]-1-Methanamide
Figure A20038011103001711
According to described preparation (R)-1-oxo-3,4-benzo-2,9-diaza-spiro [5.5] hendecane-3-alkene-9-carboxylic acid (1-benzo [b] thiene-3-yl-methyl-2-[1,4 '] connection piperidines-1 '-Ji-2-oxo-ethyl)-method of amide, by 2 ', 3 '-dihydro-1-oxo spiral shell-[piperidines-4,4 ' (1H)-isoquinolin] prepare (M.S.Chambers, etc., J.Med.Chem., 1992,35,2033-2039; WO-94/13696).
1H-NMR(CDCl 3，500MHz)δ0.01(1H，m)，0.78(1H，m)，1.1-2.0(12H，m)，2.15-2.30(5H，m)，2.74(1H，t)，3.0-3.6(9H)，3.89(2H，m)，4.46(1H，d)，5.29(1H，m)，5.62(1H，d)，6.47(1H，brs)，7.38(5H，m)，7.51(1H，m)，7.77(1H，m)，7.85(1H，m)，8.11(1H，d)。Mass spectrum: 614.42 (MH) +
Embodiment 64
N-[(1R)-1-(benzo [b] thiene-3-yl-methyl)-2-[1,4 '-the Lian piperidines]-1 '-Ji-2-oxoethyl]-1,2-dihydro-2-oxo-spiral shell-[4H-3,1-benzoxazine-4,4 '-piperidines]-1 '-Methanamide
According to preparation (R)-1-oxo-3,4-benzo-2,9-diaza-spiro [5.5] hendecane-3-alkene-9-carboxylic acid (1-benzo [b] thiene-3-yl-methyl-2-[1,4 '] connection piperidines-1 '-Ji-2-oxo-ethyl)-method of amide, by 1,2-dihydro-2-oxo-spiral shell-[4H-3,1-benzoxazine-4,4 '-piperidines] prepare (according to Takai, etc.; Chem.Pharm.Bull.1985,33, the preparation described in the 1129-1139), obtain title compound (76%).Mass spectrum: 616 (MH) +.R f=1.42.
Succinate intermediate and embodiment
3-benzo [b] thiene-3-yl--acrylic acid
With 1-benzothiophene-3-formaldehyde (4.9g, 0.03mol), malonic acid (6.6g, 0.06mol) and the suspension of piperidines (1mL) in the 100mL anhydrous pyridine 110 ℃ of following heated overnight.Reactant mixture is cooled to room temperature, and solvent removed in vacuo.Residue is dissolved in the water of 100mL, and adds 1N hydrochloric acid and this solution is adjusted to pH is about 3.Filter this suspension, collect xanchromatic solid, water (3 * 50mL) wash, and vacuum concentration, obtain having 95% purity shown in product (5.65g, 91%).
3-benzo [b] thiene-3-yl--propanoic acid
Figure A20038011103001722
With 3-benzo [b] thiene-3-yl--acrylic acid: (5.6g, 0.027mol) and the suspension of 10%Pd/C (600mg) in 1: 1 methanol/ethyl acetate (50mL) under the 50psi hydrogen in the Parr device hydrogenation spend the night.Filtering mixt also concentrates, and obtains crude product, need not be further purified (about 100% conversion ratio).Mass spectrum: 205 (MH) -
3-(3-benzo [b] thiene-3-yl--propiono)-4 (R)-benzyl- azoles alkane-2-ketone
Under 0 ℃, to 3-benzo [b] thiene-3-yl--propanoic acid (2.1g, 0.010mol), triethylamine (4.12g, add in anhydrous tetrahydro furan 0.040mol) (100mL) solution pivalyl chloride (1.38mL, 0.011mol).0 ℃ down stir 1.5 hours after, add lithium chloride (0.475g, 0.011mol) and (R)-4-benzyl-2- oxazolidone (oxazolidinoe) (1.988g, 0.011mol).Reactant mixture is warmed to room temperature, and stirs and spend the night.(3 * 150mL) wash with the mixture water then.Separate organic layer, drying, and evaporation obtain crude product.On silica gel,, obtain the title product (90%) of brown oil by flash chromatography with 100% dichloromethane eluting.This chemical compound is directly used in following step.
3 (S)-benzo [b] thiene-3-yl-methyl-4-(4-benzyl-2-oxo- azoles alkane-3-yl)-4-ketobutyric acid tert-butyl esters
Figure A20038011103001731
Under-78 ℃; to 3-(3-benzo [b] thiene-3-yl--propiono)-4-benzyl- azoles alkane-2-ketone (3.35g; 9.18mmol) the 100mL anhydrous tetrahydrofuran solution in add the oxolane (6.1mL of diisopropylaminoethyl lithium; 11.01mmol) solution, and reactant mixture stirred 30min.Under-78 ℃, add the monobromo-acetic acid tert-butyl ester (1.62mL, 11.01mmol) after, mixture stirred spends the night, simultaneously it is warmed to room temperature.Evaporating solvent, and residue diluted with ethyl acetate.(3 * 100mL) wash, and drying is filtered, and concentrates, and obtains crude product with the organic layer water.Filter by silicagel pad (pad of silica), obtain title product (49%) with the dichloromethane eluting.
2 (S)-benzo [b] thiene-3-yl-methyl-succinic acid, the 4-tert-butyl ester
Figure A20038011103001732
Under 0 ℃, to 3-benzo [b] thiene-3-yl-methyl-4-(4-benzyl-2-oxo- azoles alkane-3-yl)-4-ketobutyric acid tert-butyl ester (2.15g, 4.49mmol) add 30% aqueous hydrogen peroxide solution (1mL) in the agitating solution in oxolane (50mL) and water (30mL), add subsequently Lithium hydrate (0.2155g, 8.98mmol).The reactant mixture stirring is spent the night.Vacuum is removed oxolane, and with the solution that generates with 10% citric acid acidify, and with ethyl acetate (3 * 50mL) extract.Wash this organic layer with sodium sulfite solution, dry and concentrated, obtain title product.
3 (S)-benzo [b] thiene-3-yl-methyl-4-[1,4 '] connection piperidines-1 '-Ji-4-oxo-tert-butyl acetate
Figure A20038011103001741
With 2-benzo [b] thiene-3-yl-methyl-succinic acid 4-tert-butyl ester (1.8420g, 5.76mmol), piperidinyl piperidine (1.2240g, 7.28mmol) and triethylamine (0.7353g, 7.28mmol) the 100mL dichloromethane solution with 3-(diethoxy phosphoryl oxy)-1,2, (DEPBT, 1.8953g 6.34mmol) handle 3-phentriazine-4 (3H)-ketone.The mixture stirring is spent the night, and wash (3 * 40mL) then with water.Dry organic layer filters, and vacuum concentration, obtains crude product.It is further purified through the flash chromatography on silica gel method, uses the methanol solution/dichloromethane eluting of the 2M ammonia of 0-10%, obtain required product.Need not be further purified and use this product.
3 (S)-benzo [b] thiene-3-yl-methyl-4-[1,4 '] connection piperidines-1 '-Ji-4-oxo-butanoic acid
With 3-benzo [b] thiene-3-yl-methyl-4-[1,4 '] connection piperidines-1 '-the 15mL dichloromethane solution of Ji-4-oxo-tert-butyl acetate handles with trifluoroacetic acid (3mL), and at room temperature reactant mixture stirred and spend the night.Evaporating solvent obtains the corresponding trifluoroacetate (99%) of title product.
Embodiment 65
1-[1,4 '] connection piperidines-1 '-Ji-2-(3 (S)-benzo [b] thiene-3-yl-methyl)-4-[1 ', 2 '-dihydro-2 '-the oxo spiral shell-[4H-3 ', 1-benzoxazine-4,4 '-piperidyl]-butane-1, the 4-diketone
Figure A20038011103001751
At room temperature, with 3-benzo [b] thiene-3-yl-methyl-4-[1,4 '] connection piperidines-1 '-Ji-4-oxo-butanoic acid (25.0mg, 0.060mmol), 1,2-dihydro-2-oxo-spiral shell-4H-3,1-dihydro-benzoxazine-4 ' 4-piperidines (15.7mg, 0.072mmol) and triethylamine (7.3mg, 0.072mmol) solution in the 5mL dichloromethane is with 3-(diethoxy phosphoryl oxy)-1,2, (DEPBT, 21.5mg 0.072mmol) handle 3-phentriazine-4 (3H)-ketone.Solution stirring is spent the night, and then water (3 * 5mL) wash.Dry organic layer concentrates, and with crude product through flash chromatography on silica gel method purification, with the methanol solution/dichloromethane eluting of the 2M ammonia of 0-10%, obtain the required product of 60% productive rate.LC/MS:t R=1.34 minutes, 615.45 (MH) +
2-(7-methyl isophthalic acid H-indazole-5-methylene)-succinic acid 1-methyl ester
Figure A20038011103001752
To 7-methylindazole aldehyde (0.2619g, 1.64mmol) and DBE-4 dibasic ester (dimethyl succinate) (0.32mL, 2.45mmol) add in the mixture in the tert-butyl alcohol (20mL) potassium tert-butoxide (0.4036g, 3.60mmol).Under nitrogen, reactant mixture was heated 2 hours down at 50 ℃.At room temperature again after 16 hours, solvent removed in vacuo, and with in the residue water-soluble (100mL), and with ethyl acetate extraction (3 * 50mL).With water layer with the 1N hcl acidifying to pH be 3～4, and with ethyl acetate (3 * 50mL) extraction.The dry ethyl acetate solution that merges, and vacuum concentration obtain the crude product (99%, about 40: 60 suitable/trans isomer) of yellow solid.The mixture that this is thick need not be further purified and be used for next step.Mass spectrum: 275 (MH) +
(±)-2-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-succinic acid 1-methyl ester
Figure A20038011103001753
With 2-(7-methyl isophthalic acid H-indazole-5-methylene)-succinic acid 1-methyl ester (0.4440g, 1.62mmol) and the suspension of 10%Pd/C (0.04g) in ethyl acetate (15mL) and methanol (5mL) in the Parr device under 50psi hydrogen hydrogenation spend the night.Reactant mixture is filtered by Celite pad, and evaporated filtrate, obtain the required product (100%) of yellow solid.Mass spectrum: 277 (MH) +
Embodiment 66
(±)-2-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-4-oxo-4-[1 ', 2 '-dihydro-2 '-the oxo spiral shell-[4H-3 ', 1-benzoxazine-4,4 '-piperidyl]-methyl butyrate
Figure A20038011103001761
With 2-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-succinic acid 1-methyl ester (0.2253g, 0.82mmol), 1,2-dihydro-2-oxo-spiral shell-4H-3,1-dihydro-benzoxazine-4 ' 4-piperidines (0.1938g, 0.89mmol) and triethylamine (0.099g, dichloromethane 0.98mmol) (15mL) solution is with 3-(diethoxy phosphoryl oxy)-1,2, (DEPBT, 0.2685g 0.90mmol) handle 3-phentriazine-4 (3H)-ketone.Mixture stirred spends the night, and then water (3 * 5mL) wash.Dry organic layer, and vacuum concentration.Residue through flash chromatography on silica gel method purification, is used the methanol solution/dichloromethane eluting of the 2M ammonia of 0-10%, obtain required product (53%).LC/MS:t R=1.40 minutes, 477.28 (MH) +
Preparation similarly:
Embodiment 67
(±)-2-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-yl]-methyl butyrate
Figure A20038011103001762
1H-NMR(400MHz，CDCl 3)δ8.02(1H，s)，7.98(1H，m)，7，90(1H，m)，7.35-6.89(4H，m)，6.72(1H，m)，4.71(1H，m)，4.57(1H，m)，4.27(1H，s)，4.22(1H，m)，3.85(1H，m)，3.65(3H，m)，3.30(1H，m)，3.11(2H，m)，2.83(2H，m)，2.81-2.54(4H，m)，2.35(1H，m)，1.73-1.67(4H，m)。Mass spectrum: 490.32 (MH) +
(±)-2-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-4-oxo-4-[1 ', 2 '-dihydro-2 '-the oxo spiral shell-[4H-3 ', 1-benzoxazine-4,4 '-piperidyl]-butanoic acid
With 2-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-4-oxo-4-[1 ', 2 '-dihydro-2 '-the oxo spiral shell-[4H-3 ', 1-benzoxazine-4,4 '-piperidyl]-methyl butyrate (0.1911g, 0.40mmol) and Lithium hydrate (19.3mg, 0.80mmol) solution in oxolane (10mL) and water (8mL) at room temperature stirs and spends the night.Is 1 with the 1N hcl acidifying to about pH with reactant mixture, and vacuum concentration removes oxolane, obtains white solid precipitates, and it is filtered collection.With this solid with a spot of washing twice, and vacuum drying spend the night (100%).Mass spectrum: 477 (MH) +
Embodiment 68
(±)-1-[1,4 '] connection piperidines-1 '-Ji-2-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-4-[1 ', 2 '-dihydro-2 '-the oxo spiral shell-[4H-3 ', 1-benzoxazine-4,4 '-piperidyl]-butane-1, the 4-diketone
At room temperature, with 2-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-4-oxo-4-[1 ', 2 '-dihydro-2 '-the oxo spiral shell-[4H-3 ', 1-benzoxazine-4,4 '-piperidyl]-butanoic acid (0.020g, 0.04mmol), piperidinyl piperidine (0.0087g, 0.05mmol) and triethylamine (0.09g, dichloromethane 0.08mmol) (5mL) solution is with 3-(diethoxy phosphoryl oxy)-1,2, (DEPBT, 0.0155g 0.05mmol) handle 3-phentriazine-4 (3H)-ketone.Mixture stirred spends the night, and then water (3 * 5mL) wash.Dry organic layer, and solvent removed in vacuo.Crude product through preparation of silica gel type TLC (dichloromethane solution of 2M ammonium hydroxide/methanol of 10%) purification, is obtained required product (36%).LC/MS:t R=1.18 minutes, 613.47 (MH) +
Preparation similarly:
Embodiment 69
(±)-1-[1,4 '] connection piperidines-1 '-Ji-2-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-4-[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-yl]-butane-1, the 4-diketone
Figure A20038011103001781
1H-NMR(400MHz，CDCl 3)δ7.99(1H，m)，7.62(1H，m)，7.38(1H，m)，7.14(1H，m)，7.04-6.90(3H，m)，6.70(2H，d，J＝8.0Hz)，4.70-4.58(3H，m)，4.24(2H，m)，4.00(2H，m)，3.70(1H，m)，3.18-2.72(5H，m)，2.64-2.22(8H，m)，2.18-0.82(17H，m)。Mass spectrum: 626.34 (MH) +
Embodiment 70
(±)-1-(1,4-two oxa-s-8-azepine-spiral shell [4.5] last of the ten Heavenly stems-8-yl)-2-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-4-[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-yl]-butane-1, the 4-diketone
1H-NMR(400MHz，CDCl 3)δ8.06(1H，s)，7.75(1H，m)，7.36(1H，m)，7.14(1H，m)，7.01-6.79(3H，m)，6.70(1H，m)，4.70-4.49(2H，m)，4.23(2H，m)，3.98(1H，m)，3.87(3H，m)，3.65-3.44(4H，m)，3.26(1H，m)，3.10-2.88(3H，m)，2.75(1H，m)，2.51(3H，s)，2.35(1H，m)，2.00(1H，m)，1.70-1.00(9H，m)。Mass spectrum: 601.38 (MH) +
Embodiment 71
(±)-1-(1,4-two oxa-s-8-azepine-spiral shell [4.5] last of the ten Heavenly stems-8-yl)-2-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-4-[1 ', 2 '-dihydro-2 '-the oxo spiral shell-[4H-3 ', 1-benzoxazine-4,4 '-piperidyl]-butane-1, the 4-diketone
Figure A20038011103001792
1H-NMR(400MHz，CDCl 3)δ9.27(1H，m)，8.00(1H，s)，7.37(1H，m)，7.23(1H，m)，7.10-6.99(3H，m)，6.87(1H，m)，4.54(1H，m)，3.97-3.50(10H，m)，3.30(1H，m)，3.16-2.76(4H，m)，2.53(3H，s)，2.35(1H，m)，2.20-1.00(9H，m)。Mass spectrum: 588.36 (MH) +
Embodiment 72
(±)-N, N-dimethyl-2-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-yl]-butyramide
Figure A20038011103001801
LC/MS:t R=1.36 minutes, 525.35 (M+Na) +
Embodiment 73
(±)-1-(2,6-dimethyl-morpholine-4-yl)-2-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-4-[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-yl]-butane-1, the 4-diketone
LC/MS:t R=1.41 minutes, 573.39 (MH) +
Embodiment 74
(±)-2-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-1-(4-methyl-piperidines-1-yl)-4-[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-yl]-butane-1, the 4-diketone
Figure A20038011103001803
1H-NMR(400MHz，CDCl 3)δ8.06(1H，b)，7.60-6.73(7H，m)，4.71(1H，m)，4.54(2H，m)，4.26(2H，m)，4.05-3.89(2H，m)，3.65(1H，m)，3.09-2.81(4H，m)，2.61(3H，s)，2.41(2H，m)，1.76-0.51(15H，m)。Mass spectrum: 557.38 (MH) +
Embodiment 75
(±)-2-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-1-morpholine-4-base-4-[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-yl]-butane-1, the 4-diketone
LC/MS:t R=1.32 minutes, 545.42 (MH) +
Embodiment 76
(±)-N, N-dimethyl-2-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-4-oxo-4-[1 ', 2 '-dihydro-2 '-the oxo spiral shell-[4H-3 ', 1-benzoxazine-4,4 '-piperidyl]-butyramide
Figure A20038011103001812
LC/MS:t R=1.27 minutes, 512.30 (M+Na) +
Embodiment 77
(±)-2-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-1-(piperidines-1-yl)-4-[1 ', 2 '-dihydro-2 '-the oxo spiral shell-[4H-3 ', 1-benzoxazine-4,4 '-piperidyl]-butane-1, the 4-diketone
Figure A20038011103001821
1H-NMR(400MHz，CDCl 3)δ9.26-9.01(1H，m)，8.09(1H，s)，7.42-6.89(7H，m)，4.56(1H，m)，3.84(1H，m)，3.65(3H，m)，3.30(2H，m)，3.05(3H，m)，2.81(1H，m)，2.60(3H，s)，2.39(1H，m)，2.09(2H，m)，1.85(1H，m)，1.43-0.79(9H，m)。Mass spectrum: 530.34 (MH) +
Embodiment 78
(±)-2-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-4-[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-yl]-1-piperidines-1-base-butane-1, the 4-diketone
Figure A20038011103001822
1H-NMR(400MHz，CDCl 3)δ8.02(1H，s)，7.82(1H，m)，7.37(1H，m)，7.14(1H，m)，7.04-6.90(3H，m)，6.73(1H，d，J＝8.0Hz)，4.69(1H，m)，4.56(1H，m)，4.24(2H，d，J＝7.2Hz)，4.02(1H，m)，3.65(2H，m)，3.33(3H，m)，3.07(3H，m)，2.78(1H，m)，2.55(3H，s)，2.36(1H，m)，1.80-1.50(4H，m)，1.43(4H，b)，1.26(2H，b)，0.81(2H，b)。Mass spectrum: 543.40 (MH) +
Embodiment 79
(±)-1-[1,4 '] connection piperidines-1 '-Ji-2-(1H-indazole-5-ylmethyl)-4-[1 ', 2 '-dihydro-2 '-the oxo spiral shell-[4H-3 ', 1-benzoxazine-4,4 '-piperidyl]-butane-1, the 4-diketone
Figure A20038011103001831
1H-NMR(400MHz，CDCl 3)δ8.86(1H，m)，7.98(1H，s)，7.54-6.85(7H，m)，4.73-4.48(3H，m)，3.96-.80(3H，m)，3.73-3.58(3H，m)，3.17-2.78(5H，m)，2.55-2.24(5H，m)，2.02-1.79(6H，m)，1.70-0.79(7H，m)。Mass spectrum: 599.31 (M+Na) +
Embodiment 80
(±)-1-(1,4-two oxa-s-8-azepine-spiral shell [4.5] last of the ten Heavenly stems-8-yl)-2-(1H-indazole-5-ylmethyl)-4-[1 ', 2 '-dihydro-2 '-the oxo spiral shell-[4H-3 ', 1-benzoxazine-4,4 '-piperidyl]-butane-1, the 4-diketone
LC/MS:t R=1.25 minutes, 574.25 (MH) +
Embodiment 81
(±)-1-(1,4-two oxa-s-8-azepine-spiral shell [4.5] last of the ten Heavenly stems-8-yl)-2-(1H-indazole-5-ylmethyl)-4-[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-yl]-butane-1, the 4-diketone
LC/MS:t R=1.34 minutes, 587.38 (MH) +
Embodiment 82
(±)-2-(1H-indazole-5-ylmethyl)-N, N-dimethyl-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-yl]-butyramide
Figure A20038011103001842
LC/MS:t R=1.28 minutes, 489.33 (MH) +
Embodiment 83
(±)-5-{2-([1,4 '] connection piperidines-1 '-carbonyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-yl]-butyl }-indazole-1-carboxylic acid tert-butyl ester
LC/MS:t R=1.47 minutes, 742.55 (M+Na) +
Embodiment 84
(±)-2-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-yl]-N-Propargyl-butyramide
LC/MS:t R=1.33 minutes, 535.32 (M+Na) +
Aspartate intermediate and embodiment
(L)-2-tert-butoxycarbonyl amino-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-yl]-the butanoic acid benzyl ester
Figure A20038011103001852
To N-tert-butoxycarbonyl-L-aspartic acid-α-benzyl ester (1.4g, 4.33mmol) and 3,4-dihydro-3-(4-piperidyl-2 (1H)-quinazolinone (1.26g, 4.33mmol) disposable adding 3-(diethoxy phosphoryl oxy)-1,2 in the agitating solution in dichloromethane (12mL), 3-phentriazine-4 (3H)-ketone (DEPBT, 1.425g, 4.76mmol), drip subsequently triethylamine (0.724mL, 5.20mmol).The suspension that generates under agitation gradually becomes homogeneous phase, and at room temperature stirs spend the night (15 hours).Mixture is diluted with dichloromethane, and with sodium hydroxide (0.5N) and the washing.Separate each layer, and with the organic layer dried over sodium sulfate, and vacuum concentration, weak yellow foam obtained.This crude product by flash column chromatography (dichloromethane solution of 10% methanol) purification, is obtained colorless oil.Mass spectrum: 559 (M+Na) +
(L)-2-tert-butoxycarbonyl amino-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-yl]-butanoic acid
Figure A20038011103001861
In the Parr bottle to 2-tert-butoxycarbonyl amino-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-yl]-butanoic acid benzyl ester (1.48g, 2.76mmol) ethyl acetate/methanol (16mL, 1: 1) solution in disposable adding 10% palladium charcoal (150mg).Use the hydrogenation 1 hour under 52psi hydrogen of Parr device.TLC (dichloromethane solution of 10% methanol) shows Quantitative yield.Filtering mixt, and vacuum concentration obtain glass colorless solid (1.14g, 93%).
Embodiment 85
(L)-1-([1,4 '] connection piperidines-1 '-carbonyl)-3-oxo-3-[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-yl]-propyl group }-t-butyl carbamate
Figure A20038011103001862
To 2-tert-butoxycarbonyl amino-4-oxo-4-[4-(the 2-oxo-1 that stirs, 4-dihydro-2H-quinazoline-3-yl)-piperidines-1-yl]-butanoic acid (1.14g, 2.55mmol) and 4-piperidyl-piperidines (525mg, 2.81mmol) dichloromethane (20mL) solution in disposable adding 3-(diethoxy phosphoryl oxy)-1,2,3-phentriazine-4 (3H)-ketone (DEPBT, 840mg, 2.81mmol), drip subsequently triethylamine (0.427mL, 3.06mmol).The mixture that generates is at room temperature stirred spend the night (15 hours).Mixture is diluted with dichloromethane, and with sodium hydroxide solution (0.5N) and the washing.Separate each layer, and with the organic layer dried over sodium sulfate, and vacuum concentration, flaxen foam thing obtained.(10% (methanol solution of 1M ammonia (ammonia in methanol) is in dichloromethane) purification obtains colourless foam thing (1.08g, 71%) by flash column chromatography with this crude product.
1H-NMR(400MHz，CDCl 3)δ8.86-8.55(1H，br)，7.05(1H，br)，6.93(1H，br)，6.82(1H，br)，6.72(1H，d，J＝7.6Hz)，6.10-5.68(1H，br)，5.20(1H，m)，54.70-4.40(2H，br)，4.20(2H，br)，4.01-3.82(2H，br.)，3.10-2.88(3H，br)，2.99(3H，br)，2.53(6H，br)，1.90-1.10(23H，m)。Mass spectrum: 597 (MH) +
(L)-2-amino-1-[1,4 '] connection piperidines-1 '-Ji-4-[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-yl]-butane-1, the 4-diketone
Figure A20038011103001871
To stir { 1-([1,4 '] connection piperidines-1 '-carbonyl)-3-oxo-3-[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-yl]-propyl group }-(1.05g adds trifluoroacetic acid (2mL) in dichloromethane 1.76mmol) (12mL) solution to t-butyl carbamate.Mixture is at room temperature stirred until transforming (by LCMS monitoring, about 15 hours) fully.Then with the mixture dilute with water, and under agitation slowly add sodium hydroxide (1.5g).Separate each layer, and with the water layer dichloromethane extraction.Through dried over sodium sulfate, and vacuum concentration obtains weak yellow foam thing (860mg, 98%) with the organic layer that merges.Mass spectrum: 497 (MH) +
Embodiment 86
(L)-1-[1,4 '] connection piperidines-1 '-Ji-2-(1H-indole-5-base is amino)-4-[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-yl]-butane-1, the 4-diketone
Figure A20038011103001881
Under nitrogen, in 5mL rotary drum phial (drum vial), to 2-amino-1-[1,4 '] connection piperidines-1 '-Ji-4-[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-yl]-butane-1,4-diketone (52mg, 0.105mmol) and uncle N--BOC-5-bromo-indole (according to Tetrahedron 2000, preparation described in the pp 8473-8482) (31mg, 0.105mmol) oxolane (1mL) solution in add 2-dicyclohexyl phosphino--2 '-(N, N-dimethylamino)-biphenyl (4.1mg, 0.0105mmol), Pd2 (dba) 3 (4.8mg, 0.005mmol) and cesium carbonate (54.6mg, 0.168mmol).With phial teflon The pipe cap sealing of-lining.Under agitation, the reactant mixture with this darkorange heats down at 80 ℃.This is reflected at 80 ℃ continues down to react to spend the night.After 17 hours, conversion reaches about 50%.Solvent removed in vacuo, and residue is dissolved in the dichloromethane, and filter.Required product is carried out purification (dichloromethane solution of 10% methanol) by preparation type arative TLC, obtain the product (11mg, 15%) of tert-butoxycarbonyl-protection.Mass spectrum: 712 (MH) +(11mg) is dissolved in the 3mL dichloromethane with this intermediate, and handles with trifluoroacetic acid (1.5mL).This colourless solution overstrike at room temperature stirred 1.5 hours.Vacuum concentrated mixture, and dry under fine vacuum, obtain brown powder (15mg, 100%).Mass spectrum: 612 (MH) +
Embodiment 87
(L)-1-[1,4 '] connection piperidines-1 '-Ji-2-(5-chloro-2-nitro-phenyl amino)-4-[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-yl]-butane-1, the 4-diketone
Figure A20038011103001882
To the 2-amino-1-[1 that stirs, 4 '] connection piperidines-1 '-Ji-4-[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-yl]-butane-1,4-diketone (33.7mg, 0.068mmol) and 4-chloro-1, (16.8mg adds saturated sodium bicarbonate solution (4) to the 2-dinitro benzene in ethanol 0.075mmol) (0.5mL) solution.Mixture at room temperature stirred made about 60% to transform in 70 hours.Product by the preparation HPLC purification, is obtained yellow solid (17.7mg, 40%).Mass spectrum: 652 (MH) +
Embodiment 88
(L)-1-[1,4 '] connection piperidines-1 '-Ji-2-(6-chloro-pyrimidine-4-base is amino)-4-[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-yl]-butane-1, the 4-diketone
Under microwave radiation, in the microwave phial, with 2-amino-1-[1,4 '] connection piperidines-1 '-Ji-4-[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-yl]-butane-1, (22.3mg is 0.045mmol) with 4 for the 4-diketone, (16mg, 0.095mmol) mixture in 2-propanol (0.5mL) was in 130 ℃ of heating 40 minutes for the 6-dichloro pyrimidine.LC/MS shows that 90% transforms.Solvent removed in vacuo, and residue distributed between dichloromethane and 1N sodium hydroxide solution.Separate organic layer, through dried over sodium sulfate, and vacuum concentration.Residue by flash column chromatography (10% (methanol solution of 1N ammonia) is in dichloromethane) purification, is obtained white solid (23mg, 84%).
1H-NMR(400MHz，CDCl 3)δ8.36(1H，d，J＝12.8Hz)，8.04-7.81(1H，2s)，7.14(1H，t，J＝7.6Hz)，7.10-6.80(2H，m)，6.74(1H，t，J＝8.2Hz)，6.52-6.42(1H，m)，5.90-5.50(1H，br)，4.85-4.40(3H，m)，4.40-4.05(3H，m)，4.05-3.82(1H，m)，3.20-3.00(2H，m)，3.00-2.68(2H，m)，2.68-2.30(8H，m)，2.05-1.90(2H，m)，1.90-0.70(12H，m)。Mass spectrum: 609 (MH) +
Preparation similarly:
Embodiment 89
(L)-1-[1,4 '] connection piperidines-1 '-Ji-2-(2-chloro-9H-purine-6-base is amino)-4-[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-yl]-butane-1, the 4-diketone
LC/MS:t R=1.10 minutes, 649 (MH) +
Embodiment 90
(L)-2-(4-amino-6-methyl-5-nitro-pyrimidine-2--amino)-1-[1,4 '] connection piperidines-1 '-Ji-4-[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-yl]-butane-1, the 4-diketone
Figure A20038011103001902
LC/MS:t R=1.12 minutes, 649 (MH) +
Embodiment 91
(L)-1-[1,4 '] connection piperidines-1 '-Ji-2-(4,5-diaminourea-6-methyl-pyrimidine-2--amino)-4-[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-yl]-butane-1, the 4-diketone
In the Parr bottle, to 2-(4-amino-6-methyl-5-nitro-pyrimidine-2--amino)-1-[1,4 '] connection piperidines-1 '-Ji-4-[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-yl]-butane-1, add 10% palladium charcoal (60mg) in 2: 1 methanol/ethyl acetate (6mL) solution of 4-diketone.Mixture was vibrated 20 hours under the 55psi nitrogen atmosphere.Mixture is passed through diatomite filtration, and vacuum concentrated filtrate, colorless solid (41.2mg, 49.2%, two step) obtained.LC/MS:t R=0.86 minute, 619 (MH) +
Embodiment 92
(L)-1-[1,4 '] connection piperidines-1 '-Ji-2-(7-methyl isophthalic acid H-[1,2,3] triazol [4,5-d] pyrimidine-5-base amino)-4-[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-yl]-butane-1, the 4-diketone
Figure A20038011103001912
To the 1-[1 that stirs, 4 '] connection piperidines-1 '-Ji-2-(4,5-diaminourea-6-methyl-pyrimidine-2--amino)-4-[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-yl]-butane-1,4-diketone (10.6mg, 0.0125mmol) acetic acid (1.5mL) solution in add sodium nitrite (24mg), add several dripping subsequently.The yellow solution that generates was at room temperature stirred 6 hours.With reactant mixture water and methanol dilution, and, obtain colorless oil/solid (3.0mg, 28%) by the preparation HPLC purification.LC/MS:t R=1.07 minutes, 630 (MH) +
The synthetic logical method of embodiment 93-95:
With 2-amino-1-[1,4 '] connection piperidines-1 '-Ji-4-[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-yl]-butane-1, one of 4-diketone (0.014mmol), a series of aldehyde (0.07mmol, 5 equivalents) and solid water-free magnesium sulfate (0.031mmol, 2.2 equivalent) 1, the acetic acid treatment of catalytic amount of the mixture in the 2-dichloroethanes (3.0mL), and shaken overnight.Disposable then adding sodium cyanoborohydride (0.07mmol, 5 equivalents), and with suspension shaken overnight once more.By the filtration of SCX post or by the preparation HPLC purification.
Embodiment 93
(L)-1-[1,4 '] connection piperidines-1 '-Ji-2-((2 '-pyridine radicals)-methyl-amino)-4-[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-yl]-butane-1, the 4-diketone
Figure A20038011103001921
LC/MS:t R=0.87 minute, 588 (MH) +
Embodiment 94
(L)-1-[1,4 '] connection piperidines-1 '-Ji-2-((5 '-indazolyl)-methyl-amino)-4-[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-yl]-butane-1, the 4-diketone
Figure A20038011103001931
LC/MS:t R=0.92 minute, 626 (MH) +
Embodiment 95
(L)-1-[1,4 '] connection piperidines-1 '-Ji-2-((3 '-methyl-phenyl)-methyl-amino)-4-[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-yl]-butane-1, the 4-diketone
LC/MS:t R=1.08 minutes, 600 (MH) +
Embodiment 96
(L)-1-[1,4 '] connection piperidines-1 '-Ji-4-[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-yl]-2-(pyrimidine-4-base is amino)-butane-1, the 4-diketone
In the Parr bottle, with 1-[1,4 '] connection piperidines-1 '-Ji-2-(6-chloro-pyrimidine-4-base is amino)-4-[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-yl]-butane-1,4-diketone (21mg) solution is dissolved in the 4mL ethyl acetate/methanol (1: 1), adds 10% palladium charcoal (10mg).In the Parr device, hydrogenation is spent the night under 55psi hydrogen.Mixture with the degassing filters then, and vacuum concentration.Residue by the preparation HPLC purification, is obtained yellow solid (12.4mg, 45%).Mass spectrum: 575 (MH) +
Embodiment 97
(L)-1-[1,4 '] connection piperidines-1 '-Ji-2-(4-hydroxyl-cyclohexyl amino)-4-[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-yl]-butane-1, the 4-diketone
To 2-amino-1-[1,4 '] connection piperidines-1 '-Ji-4-[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-yl]-butane-1,4-diketone (47.9mg, 0.096mmol) and 4-hydroxyl-Ketohexamethylene (press Can.J.Chem.1994,72, report is synthetic among the 1699-1704) (11mg, 0.096mmol) add excessive zinc chloride in the stirring the mixture in methanol (1.0mL), add sodium cyanoborohydride (5 equivalent) subsequently.Suspension was at room temperature stirred 6 days.Vacuum is removed methanol, and residue is distributed between dichloromethane and 1N sodium hydroxide.Water layer is extracted with dichloromethane (3x).The dichloromethane solution that merges is passed through siliceous earth column, and vacuum concentration.Residue by preparation type TLC (10% (methanol solution of 1N ammonia) is in dichloromethane) purification, is obtained the required product (15.3mg, 27%) of white solid.Mass spectrum: 595 (MH) +
Embodiment 98
(L)-1-[1,4 '] connection piperidines-1 '-Ji-2-[(1H-imidazol-4 yl methyl)-amino]-4-[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-yl]-butane-1, the 4-diketone
To the 2-amino-1-[1 that stirs, 4 '] connection piperidines-1 '-Ji-4-[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-yl]-butane-1,4-diketone (20.6mg, 0.0415mmol) and 4-imidazole formaldehyde (carboxylaldehyde) (4mg, 0.0415mmol) dichloromethane (1.0mL) solution in disposable adding sodium cyanoborohydride (8.8mg, 0.0415mmol).Suspension is at room temperature stirred 2 days, and between dichloromethane and 1N sodium hydroxide, distribute then.Separate each layer, and with the water layer dichloromethane extraction.With the organic layer that merges through dried over sodium sulfate, and vacuum concentration.Residue by preparation type TLC (10% (methanol solution of 1N ammonia) is in dichloromethane) purification, is obtained the required product of colorless oil, and it leaves standstill after fixing (6.1mg, 26%).
1H-NMR(400MHz，CDCl 3)δ7.61(1H，d，J＝4.8Hz)，7.16(1H，t，J＝7.6Hz)，7.10-6.85(3H，m)，6.67(1H，d，J＝8.0Hz)，4.85-4.63(2H，m)，4.63-4.40(1H，m)，4.40-3.65(7H，m)，3.25-2.40(10H，m)，2.15-0.70(18H，m)。Mass spectrum: 577 (MH) +
Embodiment 99
(L)-N-{1-([1,4 '] connection piperidines-1 '-carbonyl)-3-oxo-3-[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-yl]-propyl group }-4-methoxyl group-Benzoylamide
Figure A20038011103001961
To 2-amino-1-[1,4 '] connection piperidines-1 '-Ji-4-[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-yl]-butane-1,4-diketone (91.5mg, 0.184mmol) and anisoyl chloride (34.6mg, 0.203mmol) middle two triethylamines (35 μ L) that add that stir the mixture in dichloromethane.Yellow solution is at room temperature stirred 2.5 hours to reach conversion completely.Reactant mixture is washed with sodium hydroxide (1N), and then with the water layer dichloromethane extraction.The organic layer that merges is passed through siliceous earth column, and vacuum concentration, vitreous solid obtained.Crude product by flash column chromatography (10% (methanol solution of 1N ammonia) is in dichloromethane) purification, is obtained vitreous solid (92.8mg, 80%).
1H-NMR(400MHz，CDCl 3)δ8.55-8.47(1H，d)，8.10-7.78(3H，m)，7.09(1H，t，J＝7.4Hz)，6.96-6.74(4H，m)，5.62-5.44(1H，br)，4.75-4.40(3H，m)，4.40-4.05(3H，m)，4.05-3.82(1H，br)，3.76(3H，s)，3.18-2.88(3H，m)，2.88-2.70(1H，m)，2.70-2.30(8H，m)，2.05-1.19(14H，m)。Mass spectrum: 631 (MH) +
Embodiment 100
(L)-N-{1-([1,4 '] connection piperidines-1 '-carbonyl)-3-oxo-3-[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-yl]-propyl group }-4-hydroxyl-Benzoylamide
At room temperature, (1M is in dichloromethane by dripping Boron tribromide, 0.6mL) N-{1-([1 that handle to stir, 4 '] connection piperidines-1 '-carbonyl)-3-oxo-3-[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-yl]-propyl group }-dichloromethane (69mg) solution of 4-methoxyl group-Benzoylamide.The suspension that generates is at room temperature stirred 7 hours, and will react with excessive triethylamine then, come quencher with methanol subsequently.Solvent removed in vacuo, and residue is dissolved in the methanol, and by the preparation HPLC purification.LC/MS:t R=1.03 minutes, 617 (MH) +
Embodiment 101
(L)-1H-pyrazoles-3-carboxylic acid 1-([1,4 '] connection piperidines-1 '-carbonyl)-3-oxo-3-[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-yl]-propyl group }-amide
To the pyrazoles-3-carboxylic acid (4mg that stirs, 0.036mmol) and 2-amino-1-[1,4 '] connection piperidines-1 '-Ji-4-[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-yl]-butane-1,4-diketone (13mg, 0.026mmol) dichloromethane (1mL) solution in disposable adding 3-(diethoxy phosphoryl oxy)-1,2,3-phentriazine-4 (3H)-ketone (DEPBT, 8.6mg, 0.036mmol), add a triethylamine subsequently.The mixture that generates is at room temperature stirred spend the night (15 hours).Then mixture is distributed between sodium hydroxide (0.5N) and dichloromethane.Separate each layer, and water layer is extracted with dichloromethane (3x).LCMS shows that product is retained in the water layer.Product by the preparation HPLC purification, is obtained yellow oil (17.2mg, 94%).Mass spectrum: 591 (MH) +
The universal method of synthetic embodiment 102-134:
Figure A20038011103001981
With raw material amine, 2-amino-1-[1,4 '] connection piperidines-1 '-Ji-4-[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-yl]-butane-1, the 4-diketone is distributed in the 1mL dichloroethanes of a 96-hole trace-Sptting plate (mini-reactor) (the about 10mg in every hole).Add different acyl chlorides (about 2 equivalents) respectively, add resin-bonded (resin-bound) solid phase piperidines alkali (4 equivalent) subsequently.With subregion Sptting plate (block) shaken overnight.About 4 normal HN-3 resins are joined in each hole, and trace-Sptting plate was vibrated 5 hours again.Filter reaction mixture, and by the preparation HPLC purification or by the filtration of SCX post or by both purification.HPLC retention time and the mass spectrometric data of each embodiment are listed in the table 2.
Table 2. amide and carbamate
Figure A20038011103001991
Figure A20038011103002041
Figure A20038011103002051
The universal method of synthetic embodiment 135-200:
Figure A20038011103002061
With raw material amine, 2-amino-1-[1,4 '] connection piperidines-1 '-Ji-4-[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-yl]-butane-1, the 4-diketone is distributed in the dichloroethanes (1mL) of (each hole 10mg) in the 96-hole trace-Sptting plate.Different isocyanates (about 2 equivalents) is joined in each hole.With this subregion Sptting plate vibration 2 days.About 4 normal HN-3 resins are joined in each hole, and trace-Sptting plate was vibrated two days again.Filter reaction mixture, and by the preparation HPLC purification or by the filtration of SCX post or by both purification.HPLC retention time and the mass spectrometric data of each embodiment are listed in the table 3.
Table 3. urea
Figure A20038011103002062
Figure A20038011103002071
Figure A20038011103002081
Figure A20038011103002101
Figure A20038011103002111
Figure A20038011103002121
Figure A20038011103002141
Figure A20038011103002161
Figure A20038011103002201
Figure A20038011103002221
2-(1H-indazole-5-base is amino)-succinic acid 4-tert-butyl ester 1-ethyl ester
(1.01g, disposable adding glyoxylic acid ethyl ester (ethyl glyoxlate) solution (about 50% toluene solution, 1.7mL, 1.1 equivalents) adds magnesium sulfate (4.6g) subsequently in oxolane 7.6mmol) (20mL) solution/suspension to the 5-Aminoindazole.Mixture is at room temperature stirred spend the night (23 hours), and filter then, and vacuum concentration.(1.3g is 6mmol) by coming dry, and further dry under fine vacuum with the anhydrous benzene azeotropic with the crude product imine intermediate that generates.Residue is dissolved in the oxolane (20mL) then, and 0 ℃ of cooling down.Slowly add 2-tert-butoxy-2-oxoethyl liquor zinci chloridi (diethyl ether solution of 0.5M, 24mL, 2 equivalents) then.After stirring 1 hour under 0 ℃, mixture preservation under 4 ℃ is spent the night.Then mixture is diluted with ethyl acetate, and, dissolve this precipitated solid with minimum 0.5N HCl simultaneously by with half saturated ammonium chloride solution quencher.Separate each layer, and with the water layer ethyl acetate extraction.The organic layer water of merging and saturated sodium bicarbonate solution are washed.With organic layer through dried over sodium sulfate, and vacuum concentration.Crude product through silica gel flash column chromatography purification, with the dichloromethane solution eluting of 10% methanol, is obtained the required product (1.3g, 65%) of brown oil.
1H-NMR(400MHz，CDCl 3)δ7.89(1H，s)，7.40-7.27(1H，m)，6.98-6.77(2H，m)，4.42-4.35(1H，m)，4.30-4.12(3H，m)，2.80(2H，d，J＝4.4Hz)，1.43(9H，s)，1.27-1.17(4H，m)。Mass spectrum: 356.24 (M+Na) +, 278.23 (M- tBu) +, t R=1.287 minutes.
2-(1H-indazole-5-base is amino)-succinic acid 1-ethyl ester
Figure A20038011103002232
(1H-indazole-5-base is amino)-(123.6mg, 0.37mmol) solution in dichloromethane (2mL) and trifluoroacetic acid (0.5mL) at room temperature stirs and spends the night succinic acid 4-tert-butyl ester 1-ethyl ester with the 2-that stirs.Then reactant mixture is diluted with ethyl acetate, and wash with saturated ammonium chloride solution, water and salt.Dry organic layer, and concentrate, bottle green grease: LC/MS:t obtained R=0.643 minute, 278.19 (MH) +
2-(1H-indazole-5-base is amino)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-yl]-ethyl n-butyrate.
To the 2-that stirs (1H-indazole-5-base is amino)-succinic acid 1-ethyl ester (84mg, 0.215mmol) dichloromethane (1mL) solution in add amine (99mg, 0.429mmol, 2 equivalents), add DEPBT (128mg, 0.43mmol, 2 equivalents) and triethylamine (70 μ L subsequently, 0.47mmol, 2.2 equivalents).The mixture stirring is spent the night, and dilute with ethyl acetate then, and wash with half saturated ammonium chloride solution, water and salt.Dry organic layer, and be condensed into brown oil.Crude product through silica gel flash column chromatography purification, with the dichloromethane solution eluting of 10% methanol, is obtained the required product (36.2mg, 34.5%, two step) of pale red grease.
1H-NMR(400MHz，CDCl 3)δ7.90(2H，d，J＝4.4Hz)，7.33(1H，d，J＝8.4Hz)，7.20-7.14(1H，m)，7.00-6.80(4H，m)，6.70(1H，t，J＝6.8Hz)，4.58-4.48(1H，m)，4.65-4.40(2H，m)，4.34-4.05(3H，m)，4.02-3.82(1H，m)，3.20-2.99(2H，m)，2.99-2.84(1H，m)，2.70-2.52(1H，m)，1.80-1.50(5H，m)，1.35-1.12(5H，m)。LC/MS:t R=1.130 minutes, 491.37 (MH) +
2-(1H-indazole-5-base is amino)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-yl]-butanoic acid
Figure A20038011103002242
(34mg adds the aqueous solution (1M, 280 μ L, 4 equivalents) of Lithium hydrate in oxolane 0.069mmol) (0.3mL) solution, and mixture was at room temperature stirred 17 hours to described ethyl ester.Dry this solution under nitrogen current.The oxolane and the 0.2mL anhydrous benzene that in residue, add 0.2mL, and suspension dried up once more with nitrogen current.LC/MS:t R=0.900 minute, 463.30 (MH) +
Embodiment 201
(±)-1-[1,4 '] connection piperidines-1 '-Ji-2-(1H-indazole-5-base is amino)-4-[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-yl]-butane-1, the 4-diketone
In the rotary drum phial of adding a cover (capped drum vial), to 2-(1H-indazole-5-base is amino)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-yl]-add piperidinyl piperidine (14.3mg in dimethyl formamide (0.5mL) solution of ethyl n-butyrate. (0.069mmol), 0.076mmol, 1.1 DEPBT (22.8mg equivalent),, 1.1 equivalent) and triethylamine (8, about 160 μ L).Mixture at room temperature stirred spend the night.End product by the preparation HPLC purification, is obtained the solid required product of yellowish-brown (15mg, 26%, two step).LC/MS:t R=0.917 minute, 613.54 (MH) +
Additional embodiments
(1-benzyl-piperidin-4-yl)-(2-nitro-benzyl)-amine
(1g, 6.61mmol) (1.35mL 6.61mmol) mixes in ethanol (20mL) with 4-amino-1-benzyl piepridine with the 2-nitrobenzaldehyde.The suspension that generates is at room temperature stirred 20min, use 10 minutes time subsequently, drip sodium borohydride (0.25g, ethanol 6.61mmol) (5mL) solution.After adding is finished, should react and stir 1 hour, be cooled to 0 ℃, dense ammonium chloride is joined in the reactant mixture does not have bubble to produce until observing.Vacuum evaporating solvent, and in thick mixture that will generate water-soluble (10mL) and the dichloromethane (10mL).Separate each layer, and organic layer water (2x) and saline (2x) are washed, through dried over sodium sulfate, filter, and concentrate, obtain the required product of 1.5g (70%).LC/MS:t R=0.7 minute, 326.18 (MH) +
(2-amino-benzyl)-(1-benzyl-piperidin-4-yl)-amine
Figure A20038011103002261
(1.2g 3.7mmol) and in the aqueous acetic acid (16mL) of zinc powder (1g, excessive) 75% mixes, and stirs 2 hours down at 60 ℃ with (1-benzyl-piperidin-4-yl)-(2-nitro-benzyl)-amine.After being cooled to room temperature, solvent removed in vacuo, and with in the crude product water-soluble (10mL) that generates, add ammonium hydroxide subsequently and reach 3 until pH.Solution is extracted with dichloromethane (3x).Organic layer is collected together, and water (2x), saline (2x) are washed, and through dried over sodium sulfate, filter, and concentrate, and obtain the required product of 0.8g (73%).
1H-NMR(CD 3OD)δ2.50(m，2H)，3.20(m，2H)，3.49(dd，J＝7.0，7.3，1H)，3.62(m，4H)，4.20(s，2H)，4.36(s，2H)，7.04(m，2H)，7.32(dd，J＝7.3，7.6，1H)，7.41(d，J＝7.9，1H)，7.50(m，5H)。Mass spectrum: 296.40 (MH) +
3-(1-benzyl-piperidin-4-yl)-3,4-dihydro-1H-benzo [1,2,6] thiadiazine-2,2-dioxide
Figure A20038011103002262
With (2-amino-benzyl)-(1-benzyl-piperidin-4-yl)-amine (1.0g, 3.39mmol) and sulfonamide (0.64g, the 6.78mmol) heating 14 hours under refluxing of the solution in pyridine.After being cooled to room temperature, evaporating solvent, and crude product is soluble in water.After being adjusted to pH with the 6N sodium hydroxide and being 9, with the mixture that generates with dichloromethane (2x) extraction.(2x) washes with the extract water, through dried over sodium sulfate, filters, and concentrates, and obtains buttery residue, and it is dissolved in the ethyl acetate (4mL).With 1 of this solution and 4N HCl, 4-two  alkane (2mL) solution mix, and add ether subsequently and are precipitated out until product.Obtain the required product of 0.7g (53%) by filtration.LC/MS:t R=0.96 minute, 358.16 (MH) +
3-piperidin-4-yl-3,4-dihydro-1H-benzo [1,2,6] thiadiazine-2,2-dioxide
Figure A20038011103002271
With 3-(1-benzyl-piperidin-4-yl)-3,4-dihydro-1H-benzo [1,2,6] thiadiazine-2, the 2-dioxide (0.46g, methanol 1.29mmol) (10mL) solution nitrogen wash, and with palladium charcoal (10%, 46mg) handle.Be full of flask with hydrogen, and under nitrogen atmosphere, stir and spend the night.Should react and be full of,, and concentrate by diatomite filtration with nitrogen.Through column chromatography, obtain the required material of 0.26g (75%).
1H-NMR(CD 3OD)δ1.53-1.61(m，2H)，1.80(m，2H)，2.55(m，2H)，2.95-3.05(m，2H)，3.30(m，2H)，3.70(m，2H)，4.65(s，2H)，6.70(d，J＝7.9，1H)，7.40(dd，J＝8.2，6.7，1H)，7.10(m，2H)。Mass spectrum: 268.10 (MH) +
6-bromo-3-piperidin-4-yl-3,4-dihydro-1H-quinazoline-2-ketone
With 3-piperidin-4-yl-3, (0.2g 0.87mmol) is dissolved in the acetic acid (2mL) 4-dihydro-1H-quinazoline-2-ketone.With 5 minutes time, dripping bromine in this solution (1.8mL, acetic acid 35.14mmol) (0.5mL) solution.After at room temperature stirring 1 hour, reactant mixture is diluted with dichloromethane, water (2x), saline (2x) are washed, and through dried over sodium sulfate, filter, and concentrate, and obtain 0.16g (59%), it need not be further purified and directly use.LC/MS:t R=0.91 minute, 310.15 (MH) +
2-oxo-3-piperidin-4-yl-1,2,3,4-tetrahydrochysene-quinazoline-6-nitrile
With 6-bromo-3-piperidin-4-yl-3,4-dihydro-1H-quinazoline-2-ketone (0.16g, 0.52mmol), zinc cyanide (37mg, 0.31mmol) and tetrakis triphenylphosphine palladium (0) (60mg 0.05mmol) mixes in dimethyl formamide (4mL).Reaction flask is connected to fine vacuum, and, under nitrogen, under agitation heated 1 hour down subsequently at 90 ℃ by the freezing-thawing method degassing (3x).After being cooled to room temperature, solution for vacuum is evaporated, and crude mixture is passed through the preparation HPLC purification, obtain the required nitrile of 50mg (38%).
1H-NMR(CD 3OD)δ1.99(m，2H)，2.08-2.23(m，2H)，3.15(m，2H)，3.50(bs，1H)，3.55(bs，1H)，4.40(m，1H)，4.47(s，2H)，6.93(d，J＝8.1，1H)，4.10(m，2H)。Mass spectrum: 257.13 (MH) +
N-(1-benzyl-piperidin-4-yl)-2-(2-nitro-phenyl)-acetamide
Figure A20038011103002281
With (2-nitro-phenyl)-acetic acid (2.0g, 11.04mmol), 4-amino-1-benzyl piepridine (2.25mL, 10.03mmol), I-hydroxybenzotriazole (1.49g, 11.04mmol) and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide (2.3g, 12.03mmol) mixing in ethyl acetate (25mL).In this solution, add triethylamine (4.2mL.30.1mmol), and reactant mixture was stirred 2 hours down at 40 ℃.After being cooled to room temperature, mixture is diluted with ethyl acetate, and water (2x), 5% sodium bicarbonate, saline (2x) wash,, and concentrate, obtain the required product of 3.5g (98%) through dried over sodium sulfate.LC/MS:t R=1.24 minutes, 354.30 (MH) +
[2-(2-amino-phenyl)-ethyl]-(1-benzyl-piperidin-4-yl)-amine
Figure A20038011103002282
With N-(1-benzyl-piperidin-4-yl)-2-(2-nitro-phenyl)-acetamide (3.2g, 9.06mmol) and lithium aluminium hydride reduction (1.0g 18.12mmol) mixes in flame-dried flask.Add 1,4-two  alkane (15mL), and mixture was slowly refluxed 1 hour, and reflux and stirred 16 hours.Reactant mixture is cooled to 0 ℃, and adds 20% potassium hydroxide subsequently carefully and destroy excessive lithium aluminium hydride reduction by dripping methanol.Filter this aluminum salt, concentrate this filtrate, and be used for following reaction.
3-(1-benzyl-piperidin-4-yl)-1,3,4,5-tetrahydrochysene-benzo [d] [1,3] diaza -2-ketone
Under 0 ℃, (0.44g, 1.42mmol) (0.23g 1.42mmol) handles the agitating solution in oxolane (5mL) with carbonyl dimidazoles with [2-(2-amino-phenyl)-ethyl]-(1-benzyl-piperidin-4-yl)-amine.This is reflected at 0 ℃ stirs 30min down, and refluxed 1 hour.After being cooled to room temperature, evaporating solvent, and with residue by the column chromatography purification, obtain the required product of 100mg (21%).LC/MS:t R=1.29 minutes, 336.34 (MH) +
3-piperidin-4-yl-1,3,4,5-tetrahydrochysene-benzo [d] [1,3] diaza -2-ketone
With 3-(1-benzyl-piperidin-4-yl) 1,3,4,5-tetrahydrochysene-benzo [d] [1,3] diaza -2-ketone (100mg, methanol 0.3mmol) (5mL) solution nitrogen wash, and with palladium charcoal (10%, 10mg) handle.Be full of flask with hydrogen, and under nitrogen atmosphere, stir and spend the night.Should react and be full of,, and concentrate by diatomite filtration with nitrogen.Through column chromatography, obtain the desired substance of 50mg (68%).LC/MS:t R=1.07 minutes, 246.26 (MH) +
3-[(1-benzyl-piperidin-4-yl-amino)-methyl]-4-nitro-phenol
Figure A20038011103002292
(5g, 29.9mmol) (5.6mL 29.9mmol) mixes in ethanol (30mL) with 4-amino-1-benzyl piepridine with 5-hydroxyl-2-nitro-benzaldehyde.The suspension that generates is at room temperature stirred 20min, use 10 minutes time subsequently, drip sodium borohydride (1.13g, ethanol 29.9mmol) (10mL) solution.After adding is finished, should react and at room temperature stir 1 hour, be cooled to 0 ℃, dense ammonium chloride is joined in the reactant mixture does not have bubble to produce until observing.Vacuum evaporating solvent, and in thick mixture that will generate water-soluble (30mL) and the dichloromethane (40mL).Separate each layer, and organic layer water (2x), saline (2x) are washed, through dried over sodium sulfate, filter, and concentrate, obtain the required product of 5.8g (57%).LC/MS:t R=0.95 minute, 342.27 (MH) +
4-amino-3-[(1-benzyl-piperidin-4-yl-amino)-methyl]-phenol
Figure A20038011103002293
(0.25g 0.7mmol) and in the aqueous acetic acid (8mL) of zinc powder (0.2g, excessive) 75% mixes, and stirs 2 hours down at 60 ℃ with (1-benzyl-piperidin-4-yl)-(2-nitro-benzyl)-amine.After being cooled to room temperature, solvent removed in vacuo, and in the thick mixture that will generate water-soluble (10mL), add ammonium hydroxide subsequently and reach 3 until pH.Solution is extracted with dichloromethane (3x).Organic layer is collected together, and water (2x), saline (2x) are washed, and through dried over sodium sulfate, filter, and concentrate, and obtain the required product of 0.18g (79%).
3-(1-benzyl-piperidin-4-yl)-6-hydroxyl-3,4-dihydro-1H-quinazoline-2-ketone
Under 0 ℃, with the 4-amino-3-[(1-benzyl-piperidin-4-yl-amino that stirs)-methyl]-(0.16g, (52mg 0.51mmol) handles oxolane 0.51mmol) (3mL) solution phenol with carbonyl dimidazoles.This is reflected at 0 ℃ stirs 30min down, and refluxed 1 hour.After being cooled to room temperature, evaporating solvent, and with residue by the column chromatography purification, obtain the required product of 100mg (57%).LC/MS:t R=1.09 minutes, 338.28 (MH) +
6-hydroxyl-3-piperidin-4-yl-3,4-dihydro-1H-quinazoline-2-ketone
With 3-(1-benzyl-piperidin-4-yl)-6-hydroxyl-3,4-dihydro-1H-quinazoline-2-ketone (100mg, methanol 0.3mmol) (5mL) solution nitrogen wash, and with palladium charcoal (10%, 10mg) handle.Be full of flask with hydrogen, and under nitrogen atmosphere, stir and spend the night.Should react and use nitrogen wash,, and concentrate by diatomite filtration.Through column chromatography, obtain the desired substance of 60mg (81%).LC/MS:t R=0.75 minute, 248.22 (MH) +
N-(1-benzyl-piperidin-4-yl)-2-methoxyl group-6-nitro-Benzoylamide
With 2-methoxyl group-6-nitro-benzoic acid (2.0g, 10.1mmol), 4-amino-1-benzyl piepridine (1.9mL, 10.1mmol), I-hydroxybenzotriazole (1.43g, 10.5mmol) and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide (1.9g, 10.1mmol) mixing in ethyl acetate (25mL).In this solution, add triethylamine (4.2mL.30.3mmol), and reactant mixture was stirred 2 hours down at 40 ℃.After being cooled to room temperature, mixture is diluted with ethyl acetate, and water (2x), 5% sodium bicarbonate, saline (2x) wash,, and concentrate, obtain the required product of 3.2g (86%) through dried over sodium sulfate.LC/MS:t R=1.10 minutes, 370.28 (MH) +
(2-amino-6-methoxyl group-benzyl)-(1-benzyl-piperidin-4-yl)-amine
Figure A20038011103002312
With N-(1-benzyl-piperidin-4-yl)-2-methoxyl group-6-nitro-Benzoylamide (1.0g, 2.8mmol) and lithium aluminium hydride reduction (0.31g 8.45mmol) mixes in flame-dried flask.In this mixture, add anhydrous 1,4-two  alkane (15mL).Mixture was slowly refluxed 1 hour, and reflux and stirred 16 hours.Reactant mixture is cooled to 0 ℃, and adds 20% potassium hydroxide subsequently carefully and destroy excessive lithium aluminium hydride reduction by dripping methanol.Filter this aluminum salt, concentrate this filtrate, and be used for following reaction.
3-(1-benzyl-piperidin-4-yl)-8-methoxyl group-3,4-dihydro-1H-quinazoline-2-ketone
Figure A20038011103002313
Under 0 ℃, with (2-amino-6-methoxyl group-benzyl)-(1-benzyl-piperidin-4-yl)-amine (0.2g, oxolane 0.62mmol) (3mL) solution carbonyl dimidazoles (99mg, 0.62mmol) processing of stirring.This is reflected at 0 ℃ stirs 30min down, and refluxed 1 hour.After being cooled to room temperature, evaporating solvent, and with residue by the column chromatography purification, obtain the required product of 150mg (68%).LC/MS:t R=1.41 minutes, 352.30 (MH) +
8-methoxyl group-3-piperidin-4-yl-3,4-dihydro-1H-quinazoline-2-ketone
Figure A20038011103002321
With 3-(1-benzyl-piperidin-4-yl)-8-methoxyl group-3,4-dihydro-1H-quinazoline-2-ketone (100mg, methanol 0.28mmol) (5mL) solution nitrogen wash, and with palladium charcoal (10%, 10mg) handle.Be full of flask with hydrogen, and under nitrogen atmosphere, stir and spend the night.Should react and use nitrogen wash,, and concentrate by diatomite filtration.Through column chromatography, obtain the desired substance of 68mg (93%).LC/MS:t R=1.11 minutes, 262.23 (MH) +
N-(1-benzyl-piperidin-4-yl)-2-chloro-6-nitro-Benzoylamide
Figure A20038011103002322
With 2-chloro-6-nitro-benzoic acid (1.2g, 5.97mmol), 4-amino-1-benzyl piepridine (1.1mL, 5.97mmol), I-hydroxybenzotriazole (0.84g, 1.05 equivalent) and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide (1.1g, 1.05 equivalents) in ethyl acetate (20mL), mix.In this solution, add triethylamine (2.5mL.3.0 equivalent), and this reactant mixture was stirred 2 hours down at 40 ℃.After being cooled to room temperature, mixture is diluted with ethyl acetate, and water (2x), 5% sodium bicarbonate, saline (2x) wash,, and concentrate, obtain the required product of 1.9g (85%) through dried over sodium sulfate.
(2-amino-6-chloro-benzyl)-(1-benzyl-piperidin-4-yl)-amine
Figure A20038011103002323
With N-(1-benzyl-piperidin-4-yl)-2-chloro-6-nitro-Benzoylamide (1.67g, 4.47mmol) and lithium aluminium hydride reduction (0.51g 13.43mmol) mixes in flame-dried flask.Anhydrous 1 to wherein adding, 4-two  alkane (15mL).Mixture is slowly refluxed, and stirred 16 hours.Reactant mixture is cooled to 0 ℃, and adds 20% potassium hydroxide subsequently carefully and destroy excessive lithium aluminium hydride reduction by dripping methanol.Filter this aluminum salt, concentrate this filtrate, and be used for following reaction.
3-(1-benzyl-piperidin-4-yl)-8-chloro-3,4-dihydro-1H-quinazoline-2-ketone
Figure A20038011103002331
Under 0 ℃, with (2-amino-6-chloro-benzyl)-(1-benzyl-piperidin-4-yl)-amine (0.66g, oxolane 2.0mmol) (8mL) solution carbonyl dimidazoles (0.36g, 2.05mmol) processing of stirring.This is reflected at 0 ℃ stirs 30min down, and refluxed 1 hour.After being cooled to room temperature, evaporating solvent, and with residue by the column chromatography purification, obtain the required product of 0.58g (82%).LC/MS:t R=1.40 minutes, 356.25 (MH) +
2-chloro-3-piperidin-4-yl-3,4-dihydro-1H-quinazoline-2-ketone
With 3-(1-benzyl-piperidin-4-yl)-8-chloro-3,4-dihydro-1H-quinazoline-2-ketone (0.17g, methanol 0.48mmol) (10mL) solution nitrogen wash, and with palladium charcoal (10%, 17mg) handle.Add trifluoroacetic acid (0.2mL), and, under nitrogen atmosphere, stir then and spend the night the mixture nitrogen wash.Should react and use nitrogen wash,, and concentrate by diatomite filtration.Through column chromatography, obtain the desired substance of 100mg (79%).LC/MS:t R=0.99 minute, 266.08 (MH) +
5-bromo-1H-indole-3-nitrile
With 5-bromo-indole-3-formaldehyde (5g, 22.3mmol), diammonium phosphate (15.6g, the 31.8mmol) heating 16 hours under refluxing of the mixture in 1-nitropropane (66mL) and acetic acid (22mL).After being cooled to room temperature, removal of solvent under reduced pressure, and water is joined in the residue of dark color.After short time, rapid precipitation goes out 5-bromo-1H-indole-3-nitrile.Filter this solid, wash with water several times, and dry several hours, obtain the required product of 4.3g (86%).
1H-NMR(CD 3OD)δ7.40(m，2H)，7.77(s，1H)，7.97(s，1H)。Mass spectrum: 222.95 (MH) +
5-formoxyl-1H-indole-3-nitrile
Figure A20038011103002341
With 5-bromo-1H-indole-3-nitrile (4.25g, 19.23mmol) and sodium hydride (0.51g 21.2mmol) weighs and joins in flame-dried (flame-dried) round-bottomed flask that is equipped with the magnetic splash bar.Under blanket of nitrogen, at room temperature, add exsiccant oxolane (24mL).Mixture was at room temperature stirred 15 minutes, and it becomes homogeneous phase during this period.This stirred mixture is cooled to-78 ℃, and with time of a few minutes, adds the cyclohexane solution (1.4M, 30.2mL, 2.2 equivalents) of s-butyl lithium.At-78 ℃ after following 1 hour, slowly add dimethyl formamide (6.0mL), and mixture is warmed to ambient temperature overnight.Solution is cooled to 0 ℃, and uses 1N hydrochloric acid (45mL) to handle carefully.After a few minutes, add solid sodium bicarbonate, reach 9-10 until pH.Separates two, and water washed twice with ethyl acetate.The organic layer water (2x), the saline (2x) that merge are washed,, and concentrated through dried over sodium sulfate.Through column chromatography, obtain the pure material of 2.4g (72%).LC/MS:t R=0.99 minute, 171.07 (MH) +
2-benzyloxycarbonyl amino-3-(3-cyano-1 H-indol--5-yl)-acrylic acid methyl ester.
At room temperature, (1.68g, 5.1mmol) agitating solution in oxolane (10mL) is handled with tetramethyl guanidine (0.6mL, 1.1 equivalents) with N-benzyloxycarbonyl-α-phosphono glycine trimethyl.After 10 minutes, and adding 5-formoxyl-1H-indole-3-nitrile (0.72g, 4.24mmol).After at room temperature stirring 3 days, evaporating solvent, and residue water (2x), saline (2x) washed, through dried over sodium sulfate, and concentrate.Through column chromatography, obtain the pure material of 1.3g (82%).LC/MS:t R=1.43 minutes, 376.22 (MH) +
(±)-2-amino-3-(3-cyano-1 H-indol--5-yl)-methyl propionate
With 2-benzyloxycarbonyl amino-3-(3-cyano-1 H-indol--5-yl)-acrylic acid methyl ester. (0.5g, methanol 1.3mmol) (8mL) solution nitrogen wash, and with palladium charcoal (10%, 50mg) handle.Be full of flask with hydrogen, and under nitrogen atmosphere, stir and spend the night.Should react and use nitrogen wash,, and concentrate by diatomite filtration.Through column chromatography, obtain the desired substance of 0.3g (92%).LC/MS:t R=0.80 minute, 244.20 (MH) +
Embodiment 202
(±)-3-(3-cyano-1 H-indol--5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-methyl propionate
Under 0 ℃, (25mg, 0.11mmol) agitating solution in oxolane (3mL) is handled with carbonyl dimidazoles (17.5mg, 1.1 equivalents) with 2-amino-3-(3-cyano-1 H-indol--5-yl)-methyl propionate.This is reflected at 0 ℃ stirred 5 minutes down, be warmed to room temperature, stirred 10 minutes, and with 3-piperidin-4-yl-3,4-dihydro-1H-quinazoline-2-ketone (25mg, 1.1 equivalents) processing.Mixture at room temperature stirred spend the night.Evaporating solvent, and with residue by the column chromatography purification, obtain the white powder of 40mg (75%).LC/MS:t R=1.37 minutes, 501.33 (MH) +
Embodiment 203
(±)-4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(3-cyano-1 H-indol--5-base-methyl)-2-oxo-ethyl]-amide
Figure A20038011103002361
At room temperature, with 3-(3-cyano-1 H-indol--5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-methyl propionate (15mg, 0.03mmol) methanol (0.6mL) solution with lithium hydroxide monohydrate (3.0mg, 2.5 equivalents) water (0.1mL) solution-treated.Solution was at room temperature stirred 2 hours.Solution is cooled to 0 ℃, and handles, and evaporating solvent, obtain crude acid with 1M aqueous potassium hydrogen sulfate (60 μ L, 2.0 equivalents), need not purification and directly use with it.This crude acid is dissolved in the dimethyl formamide (0.4mL), is cooled to 0 ℃, and use dichloromethane (0.2mL), 4-piperidyl-piperidines (11mg in turn, 2.2 N equivalent),, N-diisopropylethylamine (12 μ L, 2.3 equivalents) and PyBop (19mg, 1.2 equivalents) handle.Solution is stirred 15min down at 0 ℃, be warmed to room temperature, stirred 1.5 hours, and concentrate.Product by the column chromatography purification, is obtained 10.1mg (52%, 2 step).
1H-NMR(CD 3OD)δ1.60-2.10(m，14H)，2.53(d，J＝13.0，1H)，2.58(d，J＝12.2，1H)，2.65-3.00(m，7H)，3.12(d，J＝7.0，1H)，3.17(d，J＝7.0，1H)，3.84(s，1H)，3.46(bs，1H)，4.08-4.86(m，5H)，4.70(m，1H)，5.02(dd，J＝8.2，6.7，1H)，6.79(d，J＝7.6，1H)，6.9(m，1H)，7.10(dd，J＝7.3，7.9，1H)，9.18(s，1H)，7.15(dd，J＝7.3，7.6，1H)，7.30(m，1H)，7.50(m，1H)，8.00(s，1H)。Mass spectrum: 647.41 (MH) +
3-(4-bromo-2-methyl-phenyl amino)-2-methyl-ethyl acrylate
Figure A20038011103002362
Under ice-cooled, (7.0g, (2.74g, water 39.7mmol) (40mL) solution obtain diazol to add concentrated hydrochloric acid (15mL), water (40mL) and sodium nitrite in acetonitrile 37.8mmol) (80mL) solution in turn to 4-bromo-2-aminotoluene.Under 0 ℃, solution shifted being added drop-wise to 50% potassium hydroxide (16mL) and ethyl-2-methyl-acetoacetic ester (5.38mL is in ethanol 38mmol) (50mL) solution.After adding is finished, reactant mixture is poured in ice-water (150mL), and uses ethyl acetate extraction.With saline (2x) washing organic layer, through dried over sodium sulfate, filter, and concentrate, obtain the title compound of 7.5g (66%), need not purification and directly use with it.
1H-NMR(CD 3OD)δ1.80(t，J＝7.0，3H)，2.13(s，3H)，2.29(s，3H)，4.26(dd，J＝5.8，7.0，1H)，4.30(dd，J＝5.8，7.0，1H)，7.26(m，2H)，7.43(m，1H)。Mass spectrum: 323.07 (MNa) +
5-bromo-7-Methyl-1H-indole-2-carboxylic acid, ethyl ester
(4.26g, toluene 75mmol) (80mL) solution heated 1.5 hours under refluxing in Dean-Rodney Stark water separator with right-toluenesulfonic acid monohydrate.In this solution, add 5-bromo-7-Methyl-1H-indole-2-carboxylic acid, ethyl ester (7.5g, toluene 25.0mmol) (40mL) solution, and with reactant mixture heating 5 hours under refluxing.After being cooled to room temperature, reactant mixture is poured in ice-water (120mL), and with twice of ethyl acetate extraction.Organic layer is collected together, and washed, through dried over sodium sulfate, filter, and concentrate with sodium bicarbonate (2x), saline (2x).Through silica gel column chromatography, obtain the title compound of 5.5g (78%).
1H-NMR(CD 3OD)δ1.35(t，J＝7.0，3H)，2.52(s，3H)，4.36(q，J＝7.0，2H)，7.13(s，1H)，7.14(s，1H)，7.70(s，1H)，11.90(s，1H)。Mass spectrum: 284.09 (MH) +
5-bromo-7-Methyl-1H-indole
Figure A20038011103002372
(5.3g 18.7mmol) joins in 1: 1 water/alcohol mixture (20mL) of potassium hydroxide solution, and heats 12 hours under refluxing with 5-bromo-7-Methyl-1H-indole-2-carboxylic acid, ethyl ester.After being cooled to room temperature, solvent removed in vacuo, and the residue that generates transferred in the 6N hydrochloric acid solution (20mL).The white depositions that forms is filtered, wash with water several times, and dry several hours.Thick solid is dissolved in the quinoline (14mL), and under refluxing, heated 4 hours.After being cooled to room temperature, thick mixture is poured in the mixture of frozen water (100mL) and concentrated hydrochloric acid (16mL),,, and concentrates through dried over sodium sulfate with ethyl acetate (2x), saline (2x) extraction.When attempting, cause tangible decomposition by the required product of isopropyl alcohol recrystallization.Handle through the flash chromatography on silica gel method, obtain 1.5g title compound (38%, 2 step).LC/MS:t R=1.72 minutes, 210.05 (MH) +
5-bromo-7-Methyl-1H-indole-3-formaldehyde
With 5-bromo-7-Methyl-1H-indole (1.2g 5.71mmol) is dissolved in the acetonitrile (6mL), and-10 ℃ under 0 ℃, (1.36g is in acetonitrile 6.28mmol) (9mL) solution slowly to transfer to bromine methylene dimethyl ammonium bromide.This is reflected at 0 ℃ stirred 2 hours, and at room temperature stirred 30 minutes down.Evaporating solvent, and thick mixture is soluble in water, and under 50 ℃, stirred 4 hours.After being cooled to room temperature, thick mixture is extracted with ethyl acetate (2x).Organic layer is collected together, and washed, through dried over mgso, filter, and concentrate with saline (2x).Through flash chromatography on silica gel method purification, obtain the 0.7g required compound in (52%, 2 step).
1H-NMR(CD 3OD)δ2.50(s，3H)，7.24(s，1H)，8.34(m，1H)，9.93(s，1H)。Mass spectrum: 238.05 (MH) +
5-bromo-7-Methyl-1H-indole-3-nitrile
With 5-bromo-indole-3-formaldehyde (0.7g, 2.94mmol), diammonium phosphate (2.05g, the 15.5mmol) heating 16 hours under refluxing of the mixture in 1-nitropropane (9mL) and acetic acid (3mL).After being cooled to room temperature, removal of solvent under reduced pressure, and water joined in this dark color residue.After short time, 5-bromo-1H-indole-3-nitrile rapid precipitation is come out, and filters, and washes with water several times, and dry several hours, obtains the required nitrile of 0.6g (87%).LC/MS:t R=1.71 minutes, 235.01 (MH) +
5-formoxyl-7-Methyl-1H-indole-3-nitrile
Figure A20038011103002391
With 5-bromo-7-Methyl-1H-indole-3-nitrile (0.58g, 2.46mmol) and sodium hydride (68mg 2.7mmol) weighs and joins in flame-dried (flame-dried) round-bottomed flask that is equipped with the magnetic splash bar.Under blanket of nitrogen, at room temperature, add exsiccant oxolane (9mL).Mixture was at room temperature stirred 15 minutes, and it becomes homogeneous phase during this period.This stirred mixture is cooled to-78 ℃, and with time of a few minutes, adds the cyclohexane solution (1.4M, 3.8mL, 2.2 equivalents) of s-butyl lithium.At-78 ℃ after following 1 hour, slowly add dimethyl formamide (0.9mL), and mixture is warmed to ambient temperature overnight.Solution is cooled to 0 ℃, and uses the acid treatment of 1N salt carefully.After a few minutes, add solid sodium bicarbonate and reach 9-10 until pH.Separates two, and water washed twice with ethyl acetate.The organic layer water (2x), the saline (2x) that merge are washed,, and concentrated through dried over sodium sulfate.Through column chromatography, obtain required product and the unreacted starting material of 0.4g of 60mg (14%).LC/MS:t R=1.21 minutes, 185.10 (MH) +
2-benzyloxycarbonyl amino-3-(3-cyano group-7-Methyl-1H-indole-5-yl)-acrylic acid methyl ester.
At room temperature, (180mg, 0.54mmol) agitating solution in oxolane (3mL) is handled with tetramethyl guanidine (40 μ L, 1.1 equivalents) with N-benzyloxycarbonyl-α-phosphono glycine trimethyl.After 10 minutes, and adding 5-formoxyl-7-Methyl-1H-indole-3-nitrile (50mg, 0.27mmol).After at room temperature stirring 3 days, evaporating solvent, and residue water (2x), saline (2x) washed, through dried over sodium sulfate, and concentrate.Through column chromatography, obtain the pure material of 100mg (95%).LC/MS:t R=1.59 minutes, 390.24 (MH) +
(±)-2-amino-3-(3-cyano group-7-Methyl-1H-indole-5-yl)-methyl propionate
With 2-benzyloxycarbonyl amino-3-(3-cyano group-7-Methyl-1H-indole-5-yl)-acrylic acid methyl ester. (0.1g, 0.26mmol) the solution nitrogen wash in methanol (2.5mL), and with palladium charcoal (10%, 10mg) handle.Be full of flask with hydrogen, and under nitrogen atmosphere, stir and spend the night.Should react and use nitrogen wash,, and concentrate by diatomite filtration.By column chromatography, obtain the required material of 60mg (90%).LC/MS:t R=0.93 minute, 258.22 (MH) +
Embodiment 204
(±)-4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1 (3-cyano group-7-Methyl-1H-indole-5-base-methyl)-2-oxo-ethyl]-amide
Figure A20038011103002402
Method according to the foregoing description 203 prepares: 1H-NMR (CD 3OD) δ 1.55-2.10 (m, 16H), 2.50 (s, 3H), 2.80-3.20 (m, 9H), 4.10-4.40 (m, 7H), 4.90 (m, 3H), 6.72 (d, J=7.9,1H), 6.93 (dd, J=8.5,8.5,1H), 7.40 (s, 1H), 7.88 (s, 1H), 7.90 (s, 1H), 7.99 (s, 1H).Mass spectrum: 651.57 (MH) +
4-bromo-2-isopropyl-6-methyl-phenyl amine
(5g 33.5mmol) is dissolved in the acetic acid (20mL) with 2-isopropyl-6-methyl-phenyl amine.With 10 minutes time, dripping bromine in this solution (1.8mL, acetic acid 35.14mmol) (5mL) solution.After at room temperature stirring 1 hour, reactant mixture is diluted water (2x), saturated sodium thiosulfate (2x), saturated sodium bicarbonate (2x) and salt washing with dichloromethane.Organic facies through dried over sodium sulfate, is filtered, and concentrate.Through flash chromatography on silica gel method purification, obtain the required product of 7.6g (quantitatively).LC/MS:t R=1.37 minutes, 230.07 (MH) +
4-bromo-2-isopropyl-6-methyl-phenyl diazo-tert-butyl group thioether
Figure A20038011103002411
(7.6g 33.5mmol) is suspended in 24% hydrochloric acid (15mL) with 4-bromo-2-isopropyl-6-methyl-phenyl amine.This stirred mixture is cooled to-20 ℃, and handles, make temperature keep below-5 ℃ simultaneously with the aqueous solution (5mL) that time of 30min drips sodium nitrite (2.4g, 1.05 equivalents).After keeping 30min again under-5 ℃ to-20 ℃, mixture is buffered to pH with the solid sodium acetate is about 5.0 ℃ down with about 30 minutes time, this mixture (being maintained at about under-10 ℃) is joined in batches in ethanol (25mL) solution of tert-butyl mercaptan (3.77mL, 1.0 equivalents) of stirring.After the adding, mixture is stirred down 30min at 0 ℃, and add finely divided ice (about 50mL) then.The light brown solid that filter to collect generates washes with water, and under fine vacuum dry several hours, obtains the required product of 7.9g (72%).
1H-NMR(CDCl 3)δ1.15(t，J＝6.7，3H)，1.58(s，9H)，2.00(s，3H)，2.54(m，1H)，7.20(s，1H)，7.28(s，1H)。Mass spectrum: 331.08 (MNa) +
5-bromo-7-isopropyl-1H-indazole
The 4-bromo-2 of in flame-dried (flame-dried) round-bottomed flask, packing into, and 6-diethylbenzene basic weight nitrilo-tert-butyl group thioether (7.94g, 24mmol) and potassium tert-butoxide (27g, 10 equivalents).Add splash bar, and mixture is placed under the nitrogen.To wherein adding exsiccant dimethyl sulfoxine (70mL).With mixture at room temperature vigorous stirring spend the night.Reactant mixture is poured into carefully in the mixture of finely divided ice (250mL) and 10% hydrochloric acid (120mL).Filter and collect the suspension that generates, and wash with water several times.Collect this solid, and vacuum drying, obtain the required product of 4.2g (74%).LC/MS:t R=1.73 minutes, 241.06 (MH) +
7-isopropyl-1H-indazole-5-formaldehyde
With 5-bromo-7-isopropyl-1H-indazole (3.1g, 12.1mmol) and sodium hydride (0.34g, 1.1 equivalents) weigh and join in flame-dried (flame-dried) round-bottomed flask that is equipped with the magnetic splash bar.Under blanket of nitrogen, at room temperature, add exsiccant oxolane (18mL).Mixture was at room temperature stirred 15 minutes, and it becomes homogeneous phase during this period.This stirred mixture is cooled to-78 ℃, and with time of a few minutes, adds cyclohexane extraction (1.4M, 20mL, the 2.2 equivalents) solution of s-butyl lithium.At-78 ℃ after following 1 hour, slowly add dimethyl formamide (3.0mL), and mixture is warmed to ambient temperature overnight.Solution is cooled to 0 ℃, and handles carefully with 1N hydrochloric acid (35mL).After a few minutes, add solid sodium bicarbonate and reach 9-10 until pH.Separates two, and water washed twice with ethyl acetate.The organic layer water (2x), the saline (2x) that merge are washed,, and concentrated through dried over sodium sulfate.Through column chromatography, obtain the pure material of 2.1g (92%).LC/MS:t R=1.15 minutes, 189.12 (MH) +
2-benzyloxycarbonyl amino-3-(7-isopropyl-1H-indazole-5-yl) acrylic acid methyl ester.
Figure A20038011103002422
At room temperature, oxolane (5mL) solution of N-benzyloxycarbonyl-α-phosphono glycine trimethyl (0.39g, 1.2 equivalents) of stirring is handled with tetramethyl guanidine (0.16mL, 1.1 equivalents).After 10 minutes, and adding 7-isopropyl-1H-indazole-5-formaldehyde (0.2g, 1.06mmol).After at room temperature stirring 3 days, evaporating solvent, and with residue through flash chromatography on silica gel method purification, obtain the product of 0.35g (84%).LC/MS:t R=1.61 minutes, 394.16 (MH) +
(±)-2-amino-3-(7-isopropyl-1H-indazole-5-yl) methyl propionate
Figure A20038011103002431
With 2-benzyloxycarbonyl amino-3-(7-isopropyl-1H-indazole-5-yl) acrylic acid methyl ester. (0.35g, methanol 0.89mmol) (7mL) solution nitrogen wash, and with palladium charcoal (10%, 35mg) handle.Be full of flask with hydrogen, and under nitrogen atmosphere, stir and spend the night.Should react and use nitrogen wash,, and concentrate by diatomite filtration.By column chromatography, obtain the desired substance of 0.21g (90%).
Embodiment 205
(±)-3-(7-isopropyl-1H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-methyl propionate
Be used to prepare 3-(3-cyano-1 H-indol--5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl according to above-mentioned]-amino }-method of methyl propionate prepares.LC/MS:t R=1.49 minutes, 519.35 (MH) +
Embodiment 206
(±)-4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1 (7-isopropyl-1H-indazole-5-base-methyl)-2-oxo-ethyl]-amide
Figure A20038011103002433
Described according to top embodiment 203 by 3-(7-isopropyl-1H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-methyl propionate prepares:
1H-NMR(CD 3OD)δ1.45(m，6H)，1.60-2.05(m，14H)，2.20-2.50(m，4H)，2.73(d，J＝13.7，1H)，2.90(m，4H)，4.05(d，J＝14.0，1H)，4.20(m，2H)，4.35(s，1H)，4.65(dd，J＝12.2，14.3，1H)，4.95(m，2H)，6.79(d，J＝7.9，1H)，6.92(dd，J＝7.6，6.1，1H)，7.13(m，1H)，7.80(s，1H)，7.45(s，1H)，8.05(s，1H)。Mass spectrum: 655.40 (MH) +
4-bromo-2,6-diethylbenzene basic weight nitrilo-tert-butyl group thioether
Figure A20038011103002441
With 4-bromo-2, (6.3g 27.6mmol) is suspended in 24% hydrochloric acid (15mL) the 6-diethylaniline.This stirred mixture is cooled to-20 ℃, and handles, make temperature keep below-5 ℃ simultaneously with the aqueous solution (5mL) that time of 30min drips sodium nitrite (2.0g, 1.05 equivalents).After keeping 30min again under-5 ℃ to-20 ℃, it is 5 that mixture is buffered to about pH with the solid sodium acetate.Under 0 ℃, with about 30 minutes time this mixture (being maintained at about under-10 ℃) is joined in batches in ethanol (25mL) solution of tert-butyl mercaptan (3.15mL, 1.0 equivalents) of stirring.After the adding, mixture is stirred down 30min at 0 ℃, and add finely divided ice (about 50mL) then.The light brown solid that filter to collect generates washes with water, and under fine vacuum dry several hours, obtains the required product of 6.0g (66%).
1H-NMR(CDCl 3)δ1.15(t，J＝7.6，6H)，1.50(s，9H)，2.27(m，4H)，7.21(s，2H)。Mass spectrum: 331.08 (MH) +
5-bromo-7-ethyl-3-methylindazole
In flame-dried (flame-dried) round-bottomed flask, add 4-bromo-2, and 6-diethylbenzene basic weight nitrilo-tert-butyl group thioether (4.0g, 12.1mmol) and potassium tert-butoxide (13.2g, 10 equivalents).Add splash bar, and mixture is placed under the nitrogen.To wherein adding exsiccant dimethyl sulfoxine (35mL).With mixture at room temperature vigorous stirring spend the night.Reactant mixture is poured into carefully in the mixture of finely divided ice (130mL) and 10% hydrochloric acid (60mL).Filter and collect the suspension that generates, and wash with water several times.Collect this solid, and vacuum drying, obtain the beige solid of 2.85g (98%). 1H-NMR(CD 3OD)δ1.32(t，J＝7.6，3H)，2.50(s，3H)，2.88(m，2H)，7.25(s，1H)，7.68(s，1H)。Mass spectrum: 239.26 (MH) +
7-ethyl-3-methylindazole-5-formaldehyde
Figure A20038011103002451
With 5-bromo-7-ethyl-3-methylindazole (2.85g, 11.9mmol) and sodium hydride (0.31g, 1.1 equivalents) weigh and join in flame-dried (flame-dried) round-bottomed flask that is equipped with the magnetic splash bar.Under blanket of nitrogen, at room temperature, add exsiccant oxolane (15mL).Mixture was at room temperature stirred 15 minutes, and it becomes homogeneous phase during this period.This stirred mixture is cooled to-78 ℃, and adds pentane (1.4M, 18.7mL, the 2.0 equivalents) solution of tert-butyl lithium with time of a few minutes.At-78 ℃ after following 1 hour, slowly add dimethyl formamide (2.8mL), and mixture is warmed to ambient temperature overnight.Solution is cooled to 0 ℃, and uses 1N hydrochloric acid (30mL) to handle carefully.After a few minutes, add solid sodium bicarbonate and reach 9-10 until pH.Separates two, and water washed twice with ethyl acetate.The organic layer water (2x), the saline (2x) that merge are washed,, and concentrated through dried over sodium sulfate.Through column chromatography, obtain the pure material of 1.5g (67%).LC/MS:t R=1.15 minutes, 189.12 (MH) +
2-benzyloxycarbonyl amino-3-(7-ethyl-3-methyl isophthalic acid H-indazole-5-yl)-acrylic acid methyl ester.
Figure A20038011103002452
At room temperature, oxolane (15mL) solution of N-benzyloxycarbonyl-α-phosphono glycine trimethyl (3.17g, 9.57mmol, 1.2 equivalents) of stirring is handled with tetramethyl guanidine (1.1mL, 1.1 equivalents).After 10 minutes, and adding 7-ethyl-3-methylindazole-5-formaldehyde (1.5g, 7.98mmol).After at room temperature stirring 3 days, evaporating solvent, and with residue through flash chromatography on silica gel method purification, obtain the product of 2.5g (80%).LC/MS:t R=1.61 minutes, 394.16 (MH) +
(±)-2-amino-3-(7-ethyl-3-methyl isophthalic acid H-indazole-5-yl)-methyl propionate
Figure A20038011103002461
With 2-benzyloxycarbonyl amino-3-(7-ethyl-3-methyl isophthalic acid H-indazole-5-yl)-acrylic acid methyl ester. (1.0g, methanol 2.54mmol) (15mL) solution be with nitrogen wash (flushed), and with palladium charcoal (10%, 100mg) processing.Be full of flask with hydrogen, and under nitrogen atmosphere, stir and spend the night.Should react and use nitrogen wash,, and concentrate by diatomite filtration.Through column chromatography, obtain the desired substance of 0.6g (91%).
1H-NMR(CD 3OD)δ1.32(m，3H)，2.50(s，3H)，2.88(dd，J＝7.3，7.6，1H)，2.89(dd，J＝7.6，7.6，1H)，3.02(dd，J＝6.4，7.0，1H)，3.11(dd，J＝7.6，5.8，1H)，3.35(s，1H)，3.65(m，3H)，7.00(s，1H)，7.33(s，1H)。Mass spectrum: 262.24 (MH) +
Embodiment 207
(±)-4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1 (7-ethyl-1H-indazole-5-base-methyl)-2-oxo-ethyl]-amide
Prepare by (±)-2-amino-3-(7-ethyl-3 methyl isophthalic acid H-indazole-5-yl)-methyl propionate according to embodiment 203 is described.
1H-NMR(CD 3OD)δ1.35(m，3H)，1.85-2.20(m，4H)，2.50(s，1H)，2.70(m，2H)，2.85(s，3H)，2.88-3.25(m，7H)，3.35(s，1H)，3.47(dd，J＝7.3，7.3，1H)，4.00-4.40(m，7H)，4.70(m，1H)，5.00(m，3H)，6.79(d，J＝7.6，1H)，6.93(dd，J＝7.3，7.3，1H)，7.10(m，1H)，7.15(dd，J＝7.3，7.6，1H)，7.45(m，1H)。Mass spectrum: 655.50 (MH) +
Embodiment 208
(±)-4-(2,2-dioxo-1,4-dihydro-2H-2 λ 6-benzo [1,2,6] thiadiazine-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1 (7-methyl isophthalic acid H-indazole-5-base-methyl)-2-oxo-ethyl]-amide
Figure A20038011103002471
Described according to embodiment 203 by 3-piperidin-4-yl-3,4-dihydro-1H-benzo [1,2,6] thiadiazine-2, the 2-dioxide prepares:
1H-NMR(CD 3OD)δ1.20-2.10(m，12H)，2.20-2.60(m，6H)，2.90(m，6H)，3.78-4.11(m，4H)，4.60(s，3H)，4.90(m，1H)，6.70(d，J＝8.1，1H)，6.79(dd，J＝7.67，7.3，1H)，7.44(s，1H)，7.10(m，1H)，7.13(m，3H)，8.03(s，1H)。Mass spectrum: 663.60 (MH) +
Embodiment 209
(±)-4-(2,2-dioxo-1,4-dihydro-2H-2 λ 6-benzo [1,2,6] thiadiazine-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1 (7-ethyl-3-methyl isophthalic acid H-indazole-5-base-methyl)-2-oxo-ethyl]-amide
Figure A20038011103002472
Described according to embodiment 203 by 3-piperidin-4-yl-3,4-dihydro-1H-benzo [1,2,6] thiadiazine-2, the 2-dioxide prepares: 1H-NMR (CD 3OD) δ 1.35 (m, 3H), 1.42-2.05 (m, 10H), 2.40 (m, 3H), 2.55 (s, 3H), 2.67-3.12 (m, 7H), 3.85 (m, 1H), 3.97 (s, 1H), 4.03 (m, 3H), 4.65 (m, 4H), 4.95 (dd, J=4.9,5.8,1H), 6.73 (d, J=7.9,1H), 6.98 (dd, J=7.3,6.4,1H), 7.20 (m, 2H), 7.88 (s, 1H).Mass spectrum: 691.51 (MH) +
Embodiment 210
(±)-2-[4-(6-cyano group-2-oxo-1,4-dihydro-2H-quinazoline (qinazolin)-3-yl)-piperidines-1-carbonyl]-amino]-3-(7-methyl isophthalic acid H-indazole-5-yl)-methyl propionate
Be used to prepare 3-(3-cyano-1 H-indol--5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl according to above-mentioned]-amino }-method of methyl propionate prepares: LC/MS:t R=1.34 minutes, 516.40 (MH) +
Embodiment 211
(±)-4-(6-cyano group-2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid 2-[1,4 '] connection piperidines-1 '-Ji-1-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-2-oxo-ethyl }-amide
Described by 2-oxo-3-piperidin-4-yl-1,2,3 according to top embodiment 203,4-tetrahydrochysene-quinazoline-6-nitrile prepares: 1H-NMR (CD 3OD) δ 1.80 (m, 12H), 2.4 0 (m, 4H), 2.60 (s, 3H), 2.70-3.20 (m, 10H), 4.00-4.30 (m, 6H), 5.00 (m, 1H), 5.50 (s, 2H), 6.90 (d, J=7.8,1H), 7.21 (s, 1H), 7.50 (m, 4H), 8.05 (s, 1H).Mass spectrum: 652.64 (MH) +
Embodiment 212
(±)-4-(2-oxo-1,2,4,5-tetrahydrochysene-benzo [d] [1,3] diaza -3-base-1-carboxylic acid 2-[1,4 '] connection piperidines-1 '-Ji-1-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-2-oxo-ethyl }-amide
Figure A20038011103002491
Described by 3-piperidin-4-yl-1,3,4 according to top embodiment 203,5-tetrahydrochysene-benzo [d] [1,3] diaza -2-ketone prepares: 1H-NMR (CD 3OD) δ 1.40-2.00 (m, 12H), 2.30-2.60 (m, 8H), 2.70-3.20 (m, 10H), 3.70 (m, 2H), 3.60 (d, J=9.5,1H), 4.00-4.30 (m, 4H), 4.70 (m, 1H), 5.00 (m, 1H), 6.90 (m, 2H), 7.10 (m, 3H), 7.20 (s, 1H), 7.50 (s, 1H), 8.05 (s, 1H).Mass spectrum: 652.64 (MH) +
Embodiment 213
(±)-4-(6-hydroxyl-2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid 2-[1,4 '] connection piperidines-1 '-Ji-1-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-2-oxo-ethyl }-amide
Figure A20038011103002492
Described by 6-hydroxyl-3-piperidin-4-yl-3 according to top embodiment 203,4-dihydro-1H-quinazoline-2-ketone prepares: LC/MS:t R=1.24 minutes, 643.62 (MH) +
Embodiment 214
(±)-4-(8-methoxyl group-2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid 2-[1,4 '] connection piperidines-1 '-Ji-1-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-2-oxo-ethyl }-amide
Figure A20038011103002501
Described by 8-methoxyl group-3-piperidin-4-yl-3 according to top embodiment 203,4-dihydro-1H-quinazoline-2-ketone prepares: 1H-NMR (CD 3OD) δ 1.40-2.00 (m, 12H), 2.40 (m, 2H), 2.50 (s, 3H), 2.80 (m, 3H), 3.00-3.20 (m, 3H), 3.50 (m, 2H), 4.00-4.60 (m, 6H), 5.00 (m, 2H), 6.70 (dd, J=8.5,10.1,1H), 6.85 (m, 2H), 7.10 (m, 1H), 7.20 (s, 1H), 7.47 (s, 1H).Mass spectrum: 657.41 (MH) +
Embodiment 215
(±)-4-(8-chloro-2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid 2-[1,4 '] connection piperidines-1 '-Ji-1-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-2-oxo-ethyl }-amide
Figure A20038011103002502
Described by 2-chloro-3-piperidin-4-yl-3 according to top embodiment 203,4-dihydro-1H-quinazoline-2-ketone prepares: 1H-NMR (CD 3OD) δ 1.40-2.00 (m, 14H), 2.30-2.60 (m, 8H), 2.80 (m, 4H), 3.50 (m, 3H), 3.98 (s, 1H), 4.10 (m, 4H), 4.40 (m, 2H), 4.60 (m, 1H), 4.95 (m, 1H), 6.95 (dd, J=7.9,7.9,1H), 7.10 (m, 1H), 7.26 (dd, J=6.7,7.6,1H), 7.47 (m, 1H), 8.04 (s, 1H).Mass spectrum: 661.27 (MH) +
Embodiment 216
(±)-N-(3-(7-ethyl-3-methyl isophthalic acid H-indazole-5-yl)-1-oxo-1-(4-(piperidines-1-yl) piperidines-1-yl) third-2-yl)-2 ', 3 '-dihydro-2 '-the oxo spiral shell-(piperidines-4,4 '-quinazoline)-the 1-Methanamide
Prepare according to the method that is used to prepare embodiment 203: LC/MS:t R=1.51 minutes, 641.63 (MH) +
Embodiment 217
(±)-N-(3-(7-ethyl-3-methyl 1H-indazole-5-yl)-1-oxo-1-(4-(piperidines-1-yl) piperidines-1-yl) third-2-yl)-2,4-dihydro-2 '-the oxo spiral shell-(piperidines-4,4 '-1H-benzo [d] [1,3]  piperazine)-the 1-Methanamide
Figure A20038011103002512
Prepare according to the method that is used to prepare embodiment 203: LC/MS:t R=1.48 minutes, 642.61 (MH) +.
2-fluorophenyl t-butyl carbamate
Figure A20038011103002513
At room temperature, and adding 2-fluoroaniline in oxolane (210mL) solution of two carbonic acid, two-tert-butyl ester (45.2g, 207mmol, 1.0 equivalents) (20.0mL, 207mmol).This reaction is heated to backflow, and kept 6 hours.With its cooling, concentrate, be dissolved in the pentane, use 5% citric acid, use 1M potassium acid sulfate (2x) then, then water, then with 20% potassium hydroxide, then with salt washing, through dried over mgso, and concentrate, obtaining the faint yellow oily thing of 48.0g (quantitatively), it need not purification and use.
1H-NMR(CDCl 3，500MHz)δ1.52(s，9H)，6.68(bs，1H)，6.85-7.20(m，3H)，8.07(dd，J＝8.1，8.1，1H)。Mass spectrum: 234.18 (MNa) +
2-(tert-butoxycarbonyl amino)-3-fluoro-benzoic acid
Under-78 ℃, to 2-fluorophenyl t-butyl carbamate (44.0g, pentane (1.7M, 306mL, the 2.5 equivalents) solution of dropping tert-butyl lithium in oxolane 208mmol) (660mL) solution.After adding is finished, this is reflected at-78 ℃ and stirred 30 minutes down.Make solution reach-20 ℃ gradually, be cooled to-78 ℃ subsequently once more, and transfer to by conduit in the slurry of carbon dioxide (excessive) and oxolane (500mL).Solution slowly is warmed to room temperature.Reactant mixture is concentrated removing most oxolane, and be poured in the separatory funnel of moisture and ether.Separate each layer, and use extracted with diethyl ether more than twice water layer.Remove the ether extracting substance.Water layer with 5% citric acid acidify, is extracted with ether (3x).And with the ether extracting substance through dried over mgso, and concentrate, obtain the glassy yellow solid, with its toluene recrystallization, obtain the faint yellow solid of 37.1g (70%) by heat.
1H-NMR(CDCl 3，500MHz)δ1.50(s，9H)，6.25(bs，1H)，7.18(ddd，J＝7.9，7.9，4.9，1H)，7.33(dd，J＝9.5，9.2，1H)，7.79(d，J＝7.9，1H)，7.94(s，1H)。Mass spectrum: 278.21 (MNa) +
2-(1-benzyl piepridine-4-base carbamoyl)-6-fluorophenyl t-butyl carbamate
To 2-(tert-butoxycarbonyl amino)-3-fluoro-benzoic acid (37.1g, 145mmol), 4-amino-1-benzyl piepridine (35.6mL, 1.20 I-hydroxybenzotriazole (21.6g equivalent),, 1.1 equivalent) and triethylamine (44.1g, 3.0 disposable adding 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (30.7g, 1.1 equivalents) in ethyl acetate equivalent) (450mL) solution.At first, each is joined in the solution, but form precipitate very fast.Make this reaction that reflux condenser is installed, and under refluxing, heated 5 hours.Should react with ethyl acetate dilution, water (2x), then use 1N sodium hydroxide (2x), then with the salt washing, through dried over mgso, and concentrate, obtain the white solid of 67.0g (quantitatively), it need not purification and use.
1H-NMR(CDCl 3，500MHz)δ1.48(s，9H)，1.55(m，2H)，1.99(bd，J＝11.0，2H)，2.17(dd，J＝11.0，11.0，2H)，2.84(bd，J＝11.3，2H)，3.51(s，2H)，3.94(m，1H)，6.13(bd，J＝7.6，1H)，7.10-7.28(m，4H)，7.31(m，4H)，7.59(s，1H)。Mass spectrum: 428.41 (MH) +
2-amino-N-(1-benzyl piepridine-4-yl)-3-fluorobenzamide
Under 0 ℃, (1-benzyl piepridine-4-base carbamoyl)-(67.0g adds trifluoroacetic acid (100mL) in dichloromethane 157mmol) (700mL) solution to 6-fluorophenyl t-butyl carbamate to 2-.Remove ice bath, and should react at room temperature to stir and spend the night.Should react and concentrated, and between ethyl acetate and saturated sodium bicarbonate, distribute.The water-bearing layer with ethyl acetate (2x) extraction, with its water (3x), then with salt washing, through dried over mgso, and is concentrated, obtain the white solid of 47.6g (93%), it need not purification and use.Mass spectrum: 328.33 (MH) +
N-(2-amino-3-luorobenzyl)-1-benzyl piepridine-4-amine
Figure A20038011103002532
To the lithium aluminium hydride (16.1g that refluxes, 424mmol, 3.50 in two  alkane (800mL) suspensions equivalent), add 2-amino-N-(1-benzyl piepridine-4-yl)-3-fluorobenzamide (39.7g, two  alkane (250mL) solution 121mmol) under the speed of a permissible velocity gas being emitted be restricted to.Finish in case add, the suspension that generates was heated 4 hours under refluxing.This reaction is cooled to 0 ℃, and comes quencher by adding 20% potassium hydroxide carefully.In case form the filterable precipitate of white, this solid is filtered by one deck sintered glass funnel (course glass sintered funnel), and concentrate this eluent, obtain the glassy yellow grease of 36.3g (96%), it need not purification and use.Mass spectrum: 314.29 (MH) +
3-(1-benzyl piepridine-4-yl)-8-fluoro-3,4-dihydroquinazoline-2 (1H)-ketone
Figure A20038011103002541
At room temperature, to N-(2-amino-3-luorobenzyl)-1-benzyl piepridine-4-amine (36.3g, disposable adding carbonyl dimidazoles in oxolane 116mmol) (600mL) solution (20.7g, 1.10 equivalents).Should react and at room temperature stir 3 hours, heating is 30 minutes under refluxing, and concentrates.The solid that generates is dissolved in 1: 1 ether/ethyl acetate, and water (3x), then with the salt washing through dried over mgso, and concentrates the crude product of the yellow solid that obtains wetting.This solid is ground with ether, and filter, obtain the white powder of 30.0g (76%).
1H-NMR(CDCl 3，500MHz)δ1.68(m，2H)，1.86(dddd，J＝11.9，11.9，11.9，3.4，2H)，2.14(dd，J＝11.6，10.1，2H)，2.98(d，J＝11.6，2H)，3.51(s，2H)，4.34-4.44(m，3H)，6.71(bs，1H)，6.79-6.89(m，2H)，6.94(dd，J＝9.2，9.2，1H)，7.21-7.34(m，5H)。Mass spectrum: 340.30 (MH) +
8-fluoro-3,4-dihydro-3-(piperidin-4-yl) quinazoline-2 (1H)-ketone
Figure A20038011103002542
In the 250mL flask, add 3-(1-benzyl piepridine-4-yl)-8-fluoro-3, and 4-dihydroquinazoline-2 (1H)-ketone (1.40g, 4.12mmol) and methanol (25.0mL).Suspension is dissolved with help with heat gun (heat gun) heating.Flask is full of with nitrogen, handles with palladium charcoal (141mg, 0.032 equivalent), with nitrogen, then with the hydrogen flushing, and vigorous stirring is spent the night under nitrogen atmosphere.Should react and use nitrogen wash, and by diatomite filtration, and concentrate, and obtain the white solid of 0.99g (97%), it need not purification and use.
1H-NMR(CDCl 3，500MHz)δ1.71(m，4H)，2.75(m，2H)，3.16(m，2H)，4.38(s，2H)，4.46(m，1H)，6.77(bs，1H)，6.81-6.89(m，2H)，6.95(m，1H)。Mass spectrum: 250.22 (MH) +
3-(1-benzyl piepridine-4-yl)-8-Fluquinconazole quinoline-2,4 (1H, 3H)-diketone
Figure A20038011103002551
Under 0 ℃, (750mg adds the solution of triphosgene (227mg, 0.33 equivalent) in dichloromethane (5mL) in dichloromethane 2.29mmol) (30.0mL) solution to 2-amino-N-(1-benzyl piepridine-4-yl)-3-fluorobenzamide.Remove ice bath, and this is reflected at the heating down 6 hours that refluxes.Should react and concentrated, be dissolved in the ethyl acetate, with saturated sodium bicarbonate, then water, then with the salt washing, through dried over mgso, and concentrated, obtain the 700mg white solid.This crude product by purified by flash chromatography, is obtained 205mg (25%) white solid.Mass spectrum: 354.13 (MH) +
8-fluoro-3-(piperidin-4-yl) quinazoline-2,4 (1H, 3H)-diketone
Figure A20038011103002552
To contain 3-(1-benzyl piepridine-4-yl)-8-Fluquinconazole quinoline-2,4 (1H, 3H)-diketone (75.0mg, 0.21mmol) and the flask of methanol (3.00mL) solution of palladium charcoal (8.00mg, 0.035 equivalent) at first be full of, be full of with hydrogen then with nitrogen.This is reflected under the nitrogen atmosphere to stir spends the night.Should react and use nitrogen wash, and by diatomite filtration, and concentrate, and obtain the white solid of 53mg (95%), it need not purification and use.Mass spectrum: 264.25 (MH) +
8 '-fluoro-2 ', 3 '-dihydro-2 '-oxo spiral shell-(1-phenyl methyl piperidines)-4,4 '-quinazoline
In the 3-of 500mL neck flask, add polyphosphoric acid (110mL), and be equipped with agitator, nitrogen inlet and bubbler (bubbler) in the above.Flask is full of with nitrogen, and in oil bath, is heated to 105 ℃.To wherein add 1-benzyl-4-piperidones (21.0mL, 115mmol).With 2 hours time, add N-(2-fluorophenyl) urea (21.3g, 1.2 equivalents) on a small quantity to gradation wherein.This is reflected at is heated to 160 ℃ under the vigorous stirring.After 2 hours, should react by being poured into and stopped on finely divided ice, and neutralize with 20% potassium hydroxide.With the reactant mixture dichloromethane extraction, water, then with salt washing through dried over mgso, and concentrates.All the batch product obtains purer product by preparation HPLC (～130 injection (injections)) purification.Product is passed through flash chromatography purification once more, obtain solid, it is ground with ether, and filter, obtain the white solid of 275mg (0.7%).
1H-NMR(CDCl 3，500MHz)δ1.91(dd，J＝13.7，2.1，2H)，2.10(ddd，J＝13.1，13.1，4.3，2H)，2.27(ddd，J＝12.5，12.5，2.1，2H)，2.86(m，2H)，3.57(s，2H)，5.40(bs，1H)，6.90(bs，1H)，6.90-7.05(m，3H)，7.27(m，1H)，7.32(m，4H)。Mass spectrum: 326.13 (MH) +
8 '-fluoro-2 ', 3 '-dihydro-2 '-oxo spiro-piperidine-4,4 '-quinazoline
Figure A20038011103002561
To 8 '-fluoro-2 ', 3 '-dihydro-2 '-oxo spiral shell-(1-phenyl methyl piperidines)-4,4 '-(250mg adds palladium charcoal (30.0mg, 0.037 equivalent) to quinazoline in the solution of methanol 0.77mmol) (4mL) and dichloromethane (4mL).Should react with the hydrogen flushing, and under nitrogen atmosphere, stir and spend the night.Remove air bag (balloon), should react and use nitrogen wash, by diatomite filtration, wash with other methanol, and concentrate, obtain the white solid of 158mg (87%), it need not purification and use.
1H-NMR(CDCl 3/CD 3OD，500MHz)δ1.87(d，J＝12.8，2H)，2.15(ddd，J＝14.0，14.0，5.5，2H)，3.10(m，4H)，6.84(m，2H)，6.93(d，J＝7.0，1H)。Mass spectrum: 236.11 (MH) +
Embodiment 218
(±)-N-(3-(7-ethyl-1H-indazole-5-yl)-1-(6, the 7-dihydro-1 h-pyrazole is [4,3-c] pyridines-5 (4H)-yl)-1-oxo third-2-yl also)-4-(1,2-dihydro-2-oxo-quinazoline-3 (4H)-yl) piperidines-1-Methanamide
Prepare according to the method that is used to prepare embodiment 203: 1H-NMR (CD 3OD, 500MHz) δ 1.24 (m, 2H), 1.55-2.07 (m, 5H), 2.57 (m, 1H), 2.82 (m, 4H), 3.08 (m, 2H), 3.30 (m, 3H), 3.35 (m, 5H), 3.48 (m, 3H), 3.65 (m, 1H), 4.14 (m, 2H), 4.27 (m, 2H), 4.33-4.57 (m, 2H), 5.06 (dd, J=6.7,6.7,1H), 5.22 (d, J=1.8,2H), 6.78 (d, J=7.6,1H), 6.93 (m, 1H), 7.00-7.18 (m, 3.5H), 7.37 (d, J=9.8,1H), 7.46 (s, 0.5H), 7.91 (dd, J=10.1,1.8,1H).Mass spectrum: 596.43 (MH) +
Embodiment 219
(±)-N-(3-(7-ethyl-1H-indazole-5-yl)-1-(6,7-dihydro-7,7-dimethyl-1H-pyrazolo [4,3-c] pyridines-5 (4H)-yl)-1-oxo third-2-yl)-4-(1,2-dihydro-2-oxo-quinazoline-3 (4H)-yl) piperidines-1-Methanamide
Figure A20038011103002571
Prepare according to the method that is used to prepare embodiment 203: 1H-NMR (CD 3OD, 500MHz) δ 1.11 (m, 3H), 1.50-1.80 (m, 4H), 2.87 (m, 4H), 3.10 (m, 2H), 3.32 (m, 9H), 3.48 (m, 4H), 4.00-4.45 (m, 6H), 5.05-5.25 (m, 2H), 6.77 (d, J=6.1,1H), 6.93 (m, 1H), 7.13 (m, 3H), 7.30-7.60 (m, 2H), 7.95 (m, 1H).Mass spectrum: 624.49 (MH) +
Embodiment 220
(±)-methyl 2-(4-(8-fluoro-1,2-dihydro-2-oxo-quinazoline-3 (4H)-yl) piperidines-1-formamido (carboxamido))-3-(7-methyl isophthalic acid H-indazole-5-yl) propionic ester
According to as above being used to prepare 3-(3-cyano-1 H-indol--5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-method of methyl propionate prepares: 1H-NMR (CDCl 3, 500MHz) δ 1.53-1.68 (m, 4H), 2.48 (s, 3H), 2.82 (m, 2H), 3.05 (m, 6H), 3.09 (dd, J AB=13.7,6.1,1H), 3.14 (dd, J AB=14.0,6.1,1H), 3.35 (bs, 1H), 3.68 (s, 3H), 3.88-4.02 (m, 2H), 4.22 (d, J AB=15.6,1H), 4.25 (d, J AB=15.3,1H), 4.44 (m, 1H), 4.71 (dd, J=6.1,6.1,1H), 6.78 (d, J=7.3,1H), 6.84 (ddd, J=7.6,7.6,4.9,1H), 6.88-6.95 (m, 2H), 7.28 (s, 1H), 7.91 (s, 1H).Mass spectrum: 509.25 (MH) +
Embodiment 221
(±)-4-(8-fluoro-1,2-dihydro-2-oxo-quinazoline-3 (4H)-yl)-N-(3-(7-methyl isophthalic acid H-indazole-5-yl)-1-oxo-1-(4-(piperidines-1-yl) piperidines-1-yl) third-2-yl) piperidines-1-Methanamide
Prepare according to the method that is used to prepare embodiment 203: 1H-NMR (CD 3OD, 500MHz) δ-0.25 (m, 1H), 0.82 (m, 1H), 1.25-2.10 (m, 13H), 2.20-2.63 (m, 6H), 2.68-2.98 (m, 4H), 3.00-3.22 (m, 3H), 3.31 (m, 2H), 3.44 (bs, 1H), 4.00-4.50 (m, 6H), 4.64 (m, 1H), 4.96 (m, 1H), 6.85-7.05 (m, 3H), 7.08 (s, 0.4H), 7.20 (s, 0.6H), 7.46 (d, J=7.0,1H), 7.99 (s, 0.4H), 8.05 (d, J=2.4,0.6H).Mass spectrum: 645.58 (MH) +
Embodiment 222
(±)-4-(8-fluoro-1,2-dihydro-2-oxo-quinazoline-3 (4H)-yl)-N-(3-(7-methyl isophthalic acid H-indazole-5-yl)-1-oxo-1-(4-phenylpiperazine-1-yl) third-2-yl) piperidines-1-Methanamide
Figure A20038011103002582
Prepare according to the method that is used to prepare embodiment 203: 1H-NMR (CDCl 3, 500MHz) δ 1.73 (m, 4H), 2.49 (m, 4H), 2.80-3.26 (m, 7H), 3.43 (m, 2H), 3.65-3.95 (m, 3H), 4.14 (dd, J=21.7,14.3,2H), 4.32 (s, 2H), 4.51 (m, 1H), 5.15 (dd, J=7.9,6.4,1H), 5.90 (bs, 1H), 6.80 (d, J=7.3,1H), 6.83-7.01 (m, 4H), 7.06 (dd, J=7.6,7.3,1H), 7.10 (s, 1H), 7.26-7.33 (m, 2H), 7.44 (s, 1H), 7.87 (s, 1H), 8.06 (s, 1H).Mass spectrum: 639.36 (MH) +
Embodiment 223
(±)-4-(8-fluoro-1,2-dihydro-2-oxo-quinazoline-3 (4H)-yl)-N-(1-(4-(4-fluorophenyl) piperazine-1-yl)-3-(7-methyl isophthalic acid H-indazole-5-yl)-1-oxo third-2-yl) piperidines-1-Methanamide
Figure A20038011103002591
Prepare according to the method that is used to prepare embodiment 203: 1H-NMR (CDCl 3, 500MHz) δ 1.73 (m, 4H), 2.26 (dd, J=7.9,7.6,1H), 2.49 (s, 3H), 2.75-3.05 (m, 4H), 3.09 (m, 2H), 3.19-3.45 (m, 3H), 3.63 (m, 1H), 3.78 (m, 2H), 4.13 (dd, J=16.5,15.3,2H), 4.32 (s, 2H), 4.50 (m, 1H), 5.15 (dd, J=8.2,6.1,1H), 5.85 (bs, 1H), 6.70-6.84 (m, 3H), 6.85-7.02 (m, 5H), 7.09 (s, 1H), 7.43 (s, 1H), 7.78 (s, 1H), 8.06 (s, 1H).Mass spectrum: 657.35 (MH) +
Embodiment 224
(±)-4-(8-fluoro-1,2-dihydro-2-oxo-quinazoline-3 (4H)-yl)-N-(1-(4-(2-fluorophenyl) piperazine-1-yl)-3-(7-methyl isophthalic acid H-indazole-5-yl)-1-oxo third-2-yl) piperidines-1-Methanamide
Figure A20038011103002601
Prepare according to the method that is used to prepare embodiment 203: 1H-NMR (CDCl 3, 500MHz) δ 1.62-1.78 (m, 4H), 2.24 (dd, J=7.9,8.2,1H), 2.50 (s, 3H), 2.70-2.85 (m, 2H), 2.85-2.96 (m, 2H), 2.00 (m, 1H), 3.08 (dd, J AB=13.1,8.6,1H), 3.12 (m, 1H), 3.30 (m, 1H), 3.57 (m, 1H), 3.73 (m, 2H), 4.13 (dd, J=19.8,15.0,2H), 4.33 (s, 2H), 4.53 (m, 1H), 5.18 (dd, J=8.2,5.8,1H), 5.82 (bs, 1H), 6.58 (dd, J=8.2,8.2,1H), 6.81 (d, J=7.6,1H), 6.85-7.05 (m, 5H), 7.09 (s, 1H), 7.44 (s, 1H), 7.58 (s, 1H), 8.05 (s, 1H).Mass spectrum: 657.37 (MH) +
Embodiment 225
(±)-4-(8-fluoro-1,2-dihydro-2-oxo-quinazoline-3 (4H)-yl)-N-(3-(7-methyl isophthalic acid H-indazole-5-yl)-1-oxo-1-(4-o-tolyl piperazine-1-yl) third-2-yl) piperidines-1-Methanamide
Figure A20038011103002602
Prepare according to the method that is used to prepare embodiment 203: 1H-NMR (CDCl 3, 500MHz) δ 1.60-1.79 (m, 4H), 2.03 (dd, J=8.5,8.2,1H), 2.22 (s, 3H), 2.49 (s, 3H), 2.54 (dd, J=8.6,8.5,1H), 2.65 (m, 1H), 2.81 (m, 1H), and 2.85-2.97 (m, 2H), 3.05-3.22 (m, 3H), 3.38 (m, 1H), 3.50-3.65 (m, 2H), 3.83 (m, 1H), 4.15 (dd, J=15.9,15.3,2H), 4.31 (s, 2H), 4.53 (m, 1H), 5.19 (dd, J=7.9,5.8,1H), 5.84 (bs, 1H), 6.54 (d, J=7.6,1H), 6.81 (d, J=7.6,1H), 6.89 (ddd, J=7.6,7.6,5.2,1H), 6.96 (m, 2H), 7.00-7.23 (m, 4H), 7.39 (s, 1H), 7.43 (s, 1H), 8.04 (s, 1H).Mass spectrum: 653.38 (MH) +
Embodiment 226
(±)-methyl 2-(4-(8-fluoro-1,2-dihydro-2-oxo-quinazoline-3 (4H)-yl) piperidines-1-formamido)-3-(7-ethyl-3-methyl isophthalic acid H-indazole-5-yl) propionic ester
Figure A20038011103002611
Be used to prepare 3-(3-cyano-1 H-indol--5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl according to above-mentioned]-amino }-method of methyl propionate prepares:
1H-NMR(CD 3OD，500MHz)δ1.33(m，3H)，1.39-1.72(m，4H)，2.70-2.95(m，3H)，3.06(m，1H)，3.25(m，1H)，3.70(m，3H)，3.95-4.30(m 4H)，4.38(m，1H)，4.57(m，1H)，6.80-7.05(m，3H)，7.08(s，1H)，7.38(s，1H)。Mass spectrum: 537.47 (MH) +
Embodiment 227
(±)-N-(3-(7-ethyl-3-methyl isophthalic acid H-indazole-5-yl)-1-oxo-1-(4-(piperidines-1-yl) piperidines-1-yl) third-2-yl)-4-(8-fluoro-1,2-dihydro-2-oxo-quinazoline-3 (4H)-yl) piperidines-1-Methanamide
Prepare according to the method that is used to prepare embodiment 203: 1H-NMR (CD 3OD, 500MHz) δ-0.36 (m, 1H), 0.70 (m, 1H), 1.21 (bd, J=11.9,1H), 1.28-2.00 (m, 19H), 2.31 (dd, J=11.6,11.3,1H), 2.40 (dd, J=13.1,11.6,1H), 2.79-3.16 (m, 7H), 3.72 (m, 1H), and 3.85-4.03 (m, 1H), 4.10-4.48 (m, 5H), 4.53 (bd, J=11.0,1H), 5.05 (m, 1H), 6.85-7.03 (m, 3H), 7.08 (s, 0.2H), 7.18 (s, 0.8H), 7.37 (s, 1H).Mass spectrum: 673.42 (MH) +
Embodiment 228
(R)-N-((R)-3-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-1-oxo-1-(4-(piperidines-1-yl) piperidines-1-yl) third-2-yl)-4-(8-fluoro-1,2-dihydro-2-oxo-quinazoline-3 (4H)-yl) piperidines-1-Methanamide
Prepare according to the method that is used to prepare embodiment 203: 1H-NMR (CD 3OD, 500MHz) δ 0.71 (m, 1H), 1.26 (m, 1H), 1.40-2.15 (m, 13H), 2.50-3.29 (m, 9H), 3.32-3.64 (m, 3H), 4.14 (d, JAB=12.8,1H), 4.17 (d, JAB=11.6,1H), 4.32-4.45 (m, 3H), 4.68 (bd, J=13.4,1H), 4.92 (m, 1H), 6.87-7.22 (m, 6H).Mass spectrum: 648.47 (MH) +
Embodiment 229
(±)-N-(3-(7-methyl isophthalic acid H-indazole-5-yl)-1-oxo-1-(4-(piperidines-1-yl) piperidines-1-yl) third-2-yl)-8 '-fluoro-2 ', 3 '-dihydro-2 '-the oxo spiral shell-(piperidines-4,4 '-quinazoline)-the 1-Methanamide
Figure A20038011103002622
Prepare according to the method that is used to prepare embodiment 203: 1H-NMR (CD 3OD, 500MHz) δ-0.23 (m, 1H), 0.85 (m, 1H), 1.20-2.10 (m, 22H), 2.25-2.55 (m, 7H), 2.58 (s, 3H), 2.74 (d, J=11.3,1H), 2.94 (dd, J=12.5,12.2,2H), 3.00-3.20 (m, 5H), 3.40-3.65 (m, 2H), 3.80-4.15 (m, 4H), 4.55-4.73 (m, 2H), 4.96 (dd, J=7.9,7.6,1H), 5.01 (dd, J=10.4,5.8,1H), and 6.65-7.15 (m, 5H), 7.21 (s, 1H), 7.47 (s, 1H), 7.96 (m, 1H), 8.04 (s, 1H).Mass spectrum: 631.29 (MH) +
Embodiment 230
(±)-4-(8-fluoro-1,2-dihydro-2,4-dioxo quinazoline-3 (4H)-yl)-N-(3-(7-methyl isophthalic acid H-indazole-5-yl)-1-oxo-1-(4-(piperidines-1-yl) piperidines-1-yl) third-2-yl) piperidines-1-Methanamide
Prepare according to the method that is used to prepare embodiment 203: 1H-NMR (CD 3OD, 500MHz) δ-0.26 (m, 1H), 0.81 (m, 1H), 1.20-2.10 (m, 11H), 2.20-2.80 (m, 9H), 2.90 (m, 3H), 3.10 (m, 3H), 3.34 (m, 1H), 3.44 (m, 1H), 4.06 (bd, J=13.4,1H), 4.17 (d, JAB=15.9,1H), 4.22 (d, JAB=13.1,1H), 4.64 (dd, J=24.4,13.1,1H), and 4.91-5.13 (m, 2H), 7.00-7.25 (m, 2H), 7.44 (m, 2H), 7.81 (m, 1H), 7.92-8.08 (m, 1H).Mass spectrum: 659.59 (MH) +
(R)-methyl 2-amino-3-(2-(trifluoromethyl)-1H-benzo [d] imidazoles-5-yl) propionic ester
Figure A20038011103002632
With (R)-2-benzyloxycarbonyl amino-3-(3,4-diaminourea-phenyl)-methyl propionate (500mg, 1.20mmol) and the mixture of trifluoroacetic acid (6mL) 80 ℃ of down heating 16 hours.Reactant mixture is poured in the frozen water (75mL), and being neutralized to pH with saturated sodium bicarbonate aqueous solution is 7, and (2 * 250mL) extract with ethyl acetate.Organic extract through dried over sodium sulfate, is filtered and evaporation, obtain the title compound (459mg, 84% productive rate) of trifluoroacetic acid salt form. 1H-NMR(CDCl 3，300MHz)δ7.37(bs，1H)7.35(bs，1H)，7.17(d，J＝8.4Hz，1H)，4.70(s，2H)，3.85(dd，J＝8.4，4.8Hz，1H)，3.77(s，3H)，3.30(dd，J＝13.9，4.8Hz，1H)，2.97(dd，J＝13.5，8.4Hz，1H)。Mass spectrum: 288 (MH) +
(R)-methyl 2-(4-(1,2-dihydro-2-oxo-quinazoline-3 (4H)-yl) piperidines-1-formamido)-3-(2-(trifluoromethyl)-1H-benzo [d] imidazoles-5-yl) propionic ester
Figure A20038011103002641
With ammonia ester (R)-methyl 2-amino-3-(2-(trifluoromethyl)-1H-benzo [d] imidazoles-5-yl) propionic ester (230mg, 0.51mmol), diisopropylethylamine (262mg, 2.03mmol) and two succinimidyl carbonates (129mg, 0.51mmol) solution in the mixture (15: 1 ratios) of dichloromethane/dimethyl formamide at room temperature stirred 30 minutes.In solution, add 4-(2-ketone-1-benzimidazoline base) piperidines, and reactant mixture was at room temperature stirred 16 hours.Filter reaction mixture to be removing any solid, and then by flash column chromatography (95: 3: 2 methylene chloride/triethylamines) purification, obtains the solid title compound of yellowish-brown (215mg, 77% productive rate). 1H-NMR(CDCl 3，300MHz)δ7.67(d，J＝8.4Hz，1H)，7.39(s，1H)，7.21-7.16(m，1H)，7.05-6.94(m，3H)，6.70-6.68(m，2H)，5.11(d，J＝7.3Hz，1H)，4.78(dd，J＝12.1，5.5Hz，1H)，4.42(d，J＝4.4Hz，2H)，4.29(d，J＝12.1Hz，1H)，3.82-3.72(m，2H)，3.74(s，3H)，3.44(dd，J＝13.9，5.5Hz，1H)，3.22(dd，J＝13.9，5.5Hz)，2.95-2.83(m，3H)，2.18-2.03(m，2H)，1.79-1.68(m，2H)。Mass spectrum: 545 (MH) +
(R)-2-(4-(1,2-dihydro-2-oxo-quinazoline-3 (4H)-yl) piperidines-1-formamido)-3-(2-(trifluoromethyl)-1H-benzo [d] imidazoles-5-yl) propanoic acid
Under 0 ℃, (4-(1 to ester (R)-methyl 2-, 2-dihydro-2-oxo-quinazoline-3 (4H)-yl) piperidines-1-formamido)-3-(2-(trifluoromethyl)-1H-benzo [d] imidazoles-5-yl) propionic ester (220mg, 0.40mmol) at oxolane and methanol (1: 1 mixture, add Lithium hydrate (36mg, aqueous solution 1.51mmol) (10mL) in the solution 20mL).Mixture was stirred 2 hours down at 0 ℃, and preserved 16 hours down at-15 ℃ then.The evaporation organic solvent.With the aqueous solution ethyl acetate extraction, use the HCl (3mL) of 1N to regulate pH to 4 simultaneously.Organic extract through dried over sodium sulfate, is filtered, and evaporation, title compound (176mg, 82% productive rate) obtained.LC/MS:t R=2.01 minutes, 531 (MH) +
Embodiment 231
N-((R)-3-(2-(trifluoromethyl)-1H-benzo [d] imidazoles-5-yl)-1-oxo-1-(4-(piperidines-1-yl) piperidines-1-yl) third-2-yl)-4-(1,2-dihydro-2-oxo-quinazoline-3 (4H)-yl) piperidines-1-Methanamide
Figure A20038011103002651
(4-(1 to acid (the R)-2-that stirs, 2-dihydro-2-oxo-quinazoline-3 (4H)-yl) piperidines-1-formamido)-3-(2-(trifluoromethyl)-1H-benzo [d] imidazoles-5-yl) propanoic acid (33mg, 0.06mmol) and diisopropylethylamine (33mg, 0.25mmol) dichloromethane (2mL) solution in add PyBOP (33mg, 0.06mmol) and 4-piperidino piperidines (12mg, dichloromethane 0.07mmol) (1mL) solution.Reactant mixture was at room temperature stirred 16 hours, and carry out purification, obtain title compound (4.6mg, 12% productive rate) by preparative thin-layer chromatography method (methanol solution/dichloromethane of 1: 10 2M ammonia).
1H-NMR(CD 3OD，500MHz)δ7.73-7.71(m，1H)，7.62(bs，1H)，7.39-7.36(m，1H)，7.19-7.11(m，2H)，6.96(t，J＝7.2Hz，1H)，6.81(d，J＝7.9Hz，1H)，5.06-5.02(m，1H)，4.67-4.58(m，1H)，4.49-4.40(m，1H)，4.38(s，1H)，4.33(bs，1H)，4.25-4.16(m，2H)，4.10-4.03(m，1H)，3.22-3.14(m，3H)，3.04-2.87(m，4H)，2.79-2.71(m，1H)，2.58-2.48(m，1H)，2.44-2.33(m，1H)，2.31-2.22(m，1H)，2.04-1.92(m，1H)，1.86-1.43(m，11H)，1.33-1.29(m，1H)，0.94-0.84(m，1H)，-0.04--0.12(m，1H)。LC/MS:t R=1.97 minutes, 681 (MH) +
Embodiment 232
N-((R)-1-(formyl-dimethylamino)-2-(2-(trifluoromethyl)-1H-benzo [d] imidazoles-5-yl) ethyl)-4-(1,2-dihydro-2-oxo-quinazoline-3 (4H)-yl) piperidines-1-Methanamide
According to the as above preparation described in the embodiment 231.
1H-NMR(CD 3OD，300MHz)δ7.69-7.56(m，2H)，7.34(d，J＝7.7Hz，1H)，7.17-7.08(m，2H)，6.92(t，J＝7.7Hz，1H)，6.77(d，J＝8.4Hz，1H)，6.56(d，J＝7.7Hz，1H)，5.02-4.97(m，1H)，4.46-4.35(m，1H)，4.29(s，2H)，4.15(d，J＝12.8Hz，1H)，3.26-3.11(m，5H)，2.87(s，6H)，1.86-1.68(m，2H)，1.66-1.59(m，2H)。LC/MS:t R=2.37 minutes, 558 (MH) +
(R)-1-(methoxycarbonyl)-2-(2,3-dihydro-2-oxo--1H-benzo [d] imidazoles-6-yl) ethyl carbamic acid benzyl ester
Figure A20038011103002662
(600mg adds triethylamine (320mg in oxolane 1.44mmol) (125mL) solution to (R)-2-benzyloxycarbonyl amino-3-(3,4-diaminourea-phenyl)-methyl propionate that dilutes, 3.17mmol), add 1 subsequently, and 1 '-carbonyl dimidazoles (280mg, 1.73mmol).Reactant mixture is at room temperature stirred 16 hours, and solids removed by filtration then.Evaporated filtrate, and carry out flash column chromatography (1: 12 ethanol/methylene), obtain title compound (313mg, 59% productive rate).
1H-NMR(CD 3OD，300MHz)δ7.28-7.21(m，5H)，6.94-6.83(m，3H)，5.06-4.95(m，2H)，4.46-4.41(m，1H)，3.68(s，3H)，3.17-3.11(m，1H)，2.95-2.88(m，1H)。LC/MS:t R=2.11 minutes, 370 (MH) +
(R)-methyl 2-amino-3-(2,3-dihydro-2-oxo--1H-benzo [d] imidazoles-6-yl) propionic ester
Figure A20038011103002671
Under 50psi hydrogen, use the Parr device, with (R)-1-(methoxycarbonyl)-2-(2,3-dihydro-2-oxo--1H-benzo [d] imidazoles-6-yl) (265mg 0.72mmol) stirred 1.5 hours in methanol (15mL) with 10% palladium on carbon (30mg) ethyl carbamic acid benzyl ester.With 3 vacuum purge circulations of reactant mixture experience.Then reactant mixture is passed through Celite Pad filters, and should fill up with several parts of washed with methanol.Evaporation methanol filtrate obtains title compound (168mg, quantitative yield).
1H-NMR(CD 3OD，300MHz)δ6.97(d，J＝8.1Hz，1H)，6.87(s，1H)，6.86(d，J＝8.2Hz，1H)，3.71-3.64(m，1H)，3.67(s，3H)，3.04-2.89(m，2H)。LC/MS:t R=0.87 minute, 236 (MH) +
Embodiment 233
(R)-methyl 2-(4-(1,2-dihydro-2-oxo-quinazoline-3 (4H)-yl) piperidines-1-formamido)-3-(2,3-dihydro-2-oxo--1H-benzo [d] imidazoles-6-yl) propionic ester
(method of 4-(1,2-dihydro-2-oxo-quinazoline-3 (4H)-yl) piperidines-1-formamido)-3-(2-(trifluoromethyl)-1H-benzo [d] imidazoles-5-yl) propionic ester prepares according to preparing (R)-methyl 2-as mentioned above.
1H-NMR(CD 3OD，300MHz)δ7.16-7.08(m，2H)，6.98-6.90(m，4H)，6.76(d，J＝8.1Hz，1H)，4.52-4.47(m，1H)，4.39-4.35(m，1H)，4.27(s，2H)，4.13-4.05(m，2H)，3.70(s，3H)，3.21-3.14(m，1H)，3.04-2.96(m，1H)，2.89-2.74(m，2H)，1.78-1.59(m，4H)。LC/MS:t R=1.77 minutes, 493 (MH) +
(R)-2-(4-(1,2-dihydro-2-oxo-quinazoline-3 (4H)-yl) piperidines-1-formamido)-3-(2,3-dihydro-2-oxo--1H-benzo [d] imidazoles-6-yl) propanoic acid
(method of 4-(1,2-dihydro-2-oxo-quinazoline-3 (4H)-yl) piperidines-1-formamido)-3-(2-(trifluoromethyl)-1H-benzo [d] imidazoles-5-yl) propanoic acid prepares according to preparing (R)-2-as mentioned above.
1H-NMR(CD 3OD，300MHz)δ7.16-7.09(m，2H)，6.99-6.90(m，4H)，6.76(d，J＝7.3Hz，1H)，4.53-4.48(m，1H)，4.28(s，2H)，4.13-4.03(m，2H)，3.07-2.97(m，1H)，2.89-2.77(m，2H)，1.79-1.60(m，4H)，1.28-1.21(m，1H)。LC/MS:t R=1.83 minutes, 479 (MH) +
Embodiment 234
N-((R)-3-(2,3-dihydro-2-oxo--1H-benzo [d] imidazoles-6-yl)-1-oxo-1 (4-piperidines-1-yl) piperidines-1-yl) third-2-yl)-and 4-(1,2-dihydro-2-oxo-quinazoline-3 (4H)-yl) piperidines-1-Methanamide
According to the as above preparation described in the embodiment 231.
1H-NMR(CD 3OD，300MHz)δ7.17-7.10(m，2H)，7.01(s，1H)，6.95-6.90(m，3H)，6.78(d，J＝8.1Hz，1H)，4.98-4.93(m，1H)，4.62-4.55(m，1H)，4.41-4.33(m，2H)，4.20-4.16(m，2H)，4.04-3.96(m，1H)，3.05-2.85(m，7H)，2.71-2.57(m，1H)，2.53-2.32(m，1H)，1.86-1.76(m，2H)，1.70-1.61(m，8H)，1.50-1.41(m，2H)，1.03-0.89(m，1H)，0.10--0.02(m，1H)。Mass spectrum: 629.22 (MH) +
Embodiment 235
N-((R)-1-(formyl-dimethylamino)-2-(2,3-dihydro-2-oxo--1H-benzo [d] imidazoles-6-yl) ethyl)-4-(1,2-dihydro-2-oxo-quinazoline-3 (4H)-yl) piperidines-1-Methanamide
Figure A20038011103002691
According to the as above preparation described in the embodiment 231.LC/MS:t R=1.96 minutes, 506 (MH) +
(R)-and methyl 2-[2 ', 3 '-dihydro-2 '-oxo spiral shell-(piperidines-4,4 '-(1H)-quinazoline) carbonylamino]-3-2,3-dihydro-2-oxo--1H-benzo [d] imidazoles-6-yl) propionic ester
Figure A20038011103002692
(method of 4-(1,2-dihydro-2-oxo-quinazoline-3 (4H)-yl) piperidines-1-formamido)-3-(2-(trifluoromethyl)-1H-benzo [d] imidazoles-5-yl) propionic ester prepares according to preparing (R)-methyl 2-as mentioned above.
1H-NMR(DMSO-d 6，500MHz)δ10.54(s，1H)，10.50(s，1H)，9.22(s，1H)，7.21(s，1H)，7.13-7.10(m，1H)，6.96-6.79(m，7H)，4.29-4.25(m，1H)，3.82-3.78(m，2H)，3.60(s，3H)，3.32-3.23(m，1H)，3.16-3.14(m，1H)，3.00-2.90(m，2H)，2.08(s，1H)，1.67-1.55(m，4H)。LC/MS:t R=1.62 minutes, 479 (MH) +
(R)-and 2-[2 ', 3 '-dihydro-2 '-oxo spiral shell-(piperidines-4,4 '-(1H)-quinazoline) carbonylamino]-3-2,3-dihydro-2-oxo--1H-benzo [d] imidazoles-6-yl) propanoic acid
(method of 4-(1,2-dihydro-2-oxo-quinazoline-3 (4H)-yl) piperidines-1-formamido)-3-(2-(trifluoromethyl)-1H-benzo [d] imidazoles-5-yl) propanoic acid prepares according to preparing (R)-2-as mentioned above.
1H-NMR(CD 3OD，300MHz)δ7.19-7.14(m，1H)，7.05-6.95(m，5H)，6.81(d，J＝7.7Hz，1H)，5.04-4.90(m，1H)，4.57-4.52(m，1H)，3.96-3.84(m，2H)，3.24-3.14(m，2H)，3.07-2.95(m，1H)，1.94-1.73(m，4H)。LC/MS:t R=1.67 minutes, 465 (MH) +
Embodiment 236
N-((R)-3-(2,3-dihydro-2-oxo--1H-benzo [d] imidazoles-6-yl)-and 1-oxo-1 (4-piperidines-1-yl) piperidines-1-yl) third-2-yl)-4-(2 ', 3 '-dihydro-2 '-oxo spiral shell (piperidines-4,4 '-(1H)-quinazoline) Methanamide (carboxamide)
Figure A20038011103002701
According to the as above preparation described in the embodiment 231.LC/MS:t R=1.55 minutes, 615 (MH) +.
4-acetamido-3-ar-Toluic acid
To 4-amino-3-ar-Toluic acid (60g, add in dichloromethane 0.40mol) (800mL) suspension triethylamine (121g, 1.19mol).This solution becomes clarification.Then, (81g 0.79mol), and at room temperature stirred reactant mixture 60 hours to add acetic anhydride.Evaporating solvent.Residue water (400mL) is diluted, and (3 * 600mL) extract with ethyl acetate.The organic extract that merges through dried over mgso, is filtered also evaporation, obtain the solid title compound of yellowish-brown (43g, 56% productive rate).
1H-NMR(d 6-DMSO，300MHz)δ9.36(s，1H)，7.77(s，1H)，7.10(s，2H)，2.27(s，3H)，2.10(s，3H)。LC/MS:t R=1.22 minutes, 194 (MH) +
4-acetamido-3-methyl-5-nitro benzoic acid
With the time of 40min, acetamido-(43g 0.22mol), cools off with ice bath the 3-ar-Toluic acid gradation a small amount of (smallportions) adding 4-simultaneously in sulphuric acid (410mL) solution of 60% nitric acid.After all amide addings are finished, reactant mixture was stirred 1 hour down at 0 ℃, and be poured into 1500mL on ice then very slowly.Filter and collect this yellow solid, and wash, obtain title compound (38g, 72% productive rate) with icy water.
1H-NMR(CD 3OD，300MHz)δ8.29(s，1H)，8.18(s，1H)，2.39(s，3H)，2.16(s，3H)。Mass spectrum: 237 (MH) +
4-amino-3-methyl-5-nitro benzoic acid
(38g, 0.16mol) suspension in 3N hydrochloric acid (800mL) heated 8 hours under refluxing, and at room temperature stirred then 8 hours with 4-acetamido-3-methyl-5-nitro benzoic acid.This yellow solid is filtered collection, and transfer in the 2L flask that contains dichloromethane and carbinol mixture.Evaporating solvent under fine vacuum obtains title compound (23g, 74% productive rate).
1H-NMR(DMSO-d6，300MHz)δ12.79(bs，1H)，8.46(s，1H)，7.79(s，1H)，7.61(s，2H)，2.34(s，3H)。 13C-NMR (d 6-DMSO, 75MHz) δ 166.0,147.0,135.1,130.0,126.4,125.9,116.7,17.9.LC/MS:t R=1.23 minutes, 195 (MH) -
3-methyl-4, the 5-dinitrobenzoic acid
Figure A20038011103002713
To 4-amino-3-methyl-5-nitro benzoic acid (5.0g, add in trifluoroacetic acid 25.5mmol) (200mL) suspension hydrogen peroxide (50wt-%, 15mL).Reactant mixture was heated 2 hours down at 50 ℃, and this solution becomes light yellow clear solutions by the darkorange clear solutions at last.Reactant mixture slowly is poured in the frozen water (800mL).This solid is collected in filtration, and vacuum drying, obtains the title compound (4.0g, 70% productive rate) of pale solid.
1H-NMR(CD 3OD，300MHz)δ8.59(s，1H)，8.40(s，1H)，2.45(s，3H)。 13C-NMR (CD 3OD, 75MHz) δ 165.8,147.4,142.0,139.3,134.8,134.6,125.4, the 17.2. mass spectrum: 225.14 (MH) -
(3-methyl-4,5-dinitrophenyl) methanol
With 3-methyl-4, (4.0g, oxolane 17.7mmol) (200mL) solution is cooled to-70 ℃ with dry ice/acetone batch to the 5-dinitrobenzoic acid.In this solution, add monoborane-oxolane (tetrahydrofuran solution of 1M, 35.4mL).Make reactant mixture be warmed to room temperature at leisure, and stirred 16 hours.Reaction not exclusively and is cooled to-50 ℃ once more, and add other monoborane-oxolane (tetrahydrofuran solution of 1M, 35.4mL).Once more, make reactant mixture be warmed to ambient temperature overnight at leisure.This is reacted the mixture of using acetic acid and water, and (1: 1,30mL) quencher was simultaneously 0 ℃ of cooling down.Stir after 30 minutes, evaporate all organic solvents, and the hydrous matter gradation is poured in the ice-cold saturated sodium bicarbonate (350mL) on a small quantity neutralizes.With the water layer ethyl acetate extraction.Extract is washed with salt,, filtered and evaporation through dried over mgso.Residue is handled through flash column chromatography (1: 2 hexane/ethyl acetate), obtained title compound (3.2g, 86% productive rate).
1H-NMR(CDCl 3，300MHz)δ8.00(s，1H)，7.62(s，1H)，4.82(s，2H)，2.41(s，3H)。 13C-NMR(CDCl 3，75MHz)δ144.5，143.3，140.9，134.3，132.9，120.8，63.0，17.4。
3-methyl-4, the 5-dinitrobenzal-dehyde
Figure A20038011103002731
In flame-dried (flame-dried) flask, (36.0g is 414mmol) with the methylbenzene azeotropic drying with manganese oxide (IV).Then, (3.2g, chloroform 15mmol) (100mL) solution is transferred in the flask that contains manganese dioxide with (3-methyl-4,5-dinitrophenyl) methanol.Reactant mixture was under agitation heated 3 hours down at 50 ℃.When this reaction is finished, reactant mixture is passed through Celite Pad filters, and removes manganese dioxide, and kieselguhr is washed several times with chloroform.Evaporated filtrate obtains title compound (1.4g, 44% productive rate).
1H-NMR(CDCl 3，300MHz)δ10.09(s，1H)，8.51(s，1H)，8.16(s，1H)，2.51(s，3H)。
(Z)-1-(methoxycarbonyl)-2-(3-methyl-4,5-dinitrophenyl) vinyl benzyq carbamate
Figure A20038011103002732
Under-78 ℃, (2.4g adds 1,1,3 in oxolane 7.3mmol) (40mL) solution, and (729mg 6.33mmol), and down stirs mixture 1 hour at-78 ℃ the 3-tetramethyl guanidine to N-(benzyloxycarbonyl)-α-phosphono glycine trimethyl.In this mixture, add 3-methyl-4,5-dinitrobenzal-dehyde (1.4g, oxolane 6.7mmol) (15mL) solution.Make reactant mixture be warmed to room temperature at leisure, and at room temperature stir 16 hours then.Evaporating solvent, and residue is carried out flash column chromatography (gradient liquid, 1: 2 to 1: 1 ethyl acetate/hexane) handle.Then with product by ethyl acetate/hexane (1: 1) recrystallization, obtain title compound (1.7g, 62% productive rate).
1H-NMR(CDCl 3，300MHz)δ8.01(s，1H)，7.55(s，1H)，7.33-7.22(m，6H)，6.94(bs，1H)，5.06(s，2H)，3.89(s，3H)，2.29(s，3H)。 13C-NMR (CDCl 3, 75MHz) δ 164.7,152.5,143.1,140.6,137.7,137.0,135.3,132.5,128.8,128.7,128.6,127.1,123.5,123.2,68.3,53.5, the 17.4. mass spectrum: 414.20 (MH) -.
(R)-1-(methoxycarbonyl)-2-(3-methyl-4,5-dinitrophenyl) ethyl carbamic acid benzyl ester
Figure A20038011103002741
In experience 3 vacuum purges (purge) circulation bag gloves (glove bag), to the AIRFREE that splash bar is installed (Schlenk) pack (-)-1 in the reaction flask into, the two ((2R of 2-, 5R)-2,5-diethyl phosphorus heterocycle amyl group (phospholano)) benzene (cyclo-octadiene) rhodium (I) fluoroform sulphonate (125g, 0.173mmol, 4mol%), with rubber diaphragm separator (rubber septum) sealing, and from bag glove, remove.(1.65g 3.97mmol) weighs and joins second AIRFREE that splash bar is installed with (Z)-1-(methoxycarbonyl)-2-(3-methyl-4,5-dinitrophenyl) vinyl benzyq carbamate (Schlenk) in the reaction flask, and seal with rubber diaphragm separator.After 3 vacuum purge circulations, it is dissolved in the mixture of anhydrous methylene chloride (40mL).Behind spraying adding nitrogen, solvent is carried out deoxidation at least 1 hour.In this solution, mixture is experienced 3 vacuum purge circulations once more.This dehydroamino acid solution is incorporated into the AIRFREE that contains catalyst by conduit (canula) (Schlenk) in the reaction flask.With 5 vacuum of this reactant mixture experience/hydrogen purge circulation, subsequently this flask is opened the nitrogen atmosphere that butts up against latm.After 16 hours, with 3 vacuum purge circulations of reactant mixture experience.Evaporating solvent, and residue is carried out column chromatography (1: 1 ethyl acetate/hexane) handle, title compound (1.58g, 95%) obtained.
1H-NMR(CDCl 3，300MHz)δ7.75(s，1H)，7.39-7.33(m，6H)，5.37(d，J＝7.0Hz，1H)，5.15-5.04(m，2H)，4.70-4.46(m，1H)，3.77(s，3H)，3.30(dd，J＝13.9，5.5Hz，1H)，3.12(dd，J＝13.9，6.2Hz，1H)，2.33(s，3H)。LC/MS:t R=2.71 minutes, 418 (MH) +
(R)-1-(methoxycarbonyl)-2-(3,4-diaminourea-5-aminomethyl phenyl) ethyl carbamic acid benzyl ester
Figure A20038011103002751
Under 0 ℃, with solid formic acid ammonium (755mg, 11.9mmol) join (R)-1-(methoxycarbonyl)-2-(3-methyl-4 on a small quantity in batches, the 5-dinitrophenyl) ethyl carbamic acid benzyl ester (500mg, 1.20mmol) and zinc powder (470mg, 7.19mmol) in the suspension in the methanol (20mL was with the nitrogen degassing 2 hours).The mixture that generates was at room temperature stirred 60 hours.Reaction not exclusively.Reactant mixture is cooled to 0 ℃ once more, and add other zinc powder (470mg, 7.19mmol).Should react and stir 4 hours, react completely this moment.Reactant mixture is removed by filter zinc.Evaporated filtrate.Add the mixture of toluene and ethyl acetate (1: 1), add acetic acid (2mL) subsequently.Mixture is further diluted, all dissolve until all organic solid, then with its water, salt washing, through dried over sodium sulfate, and evaporation.Then residue is dissolved in the ethyl acetate again, and adds two  alkane solution (4mL) of 4N hydrogen chloride.Evaporating solvent obtains the title compound (515mg, quantitative yield) of dihydrochloride form.
1H-NMR(CD 3OD，300MHz)δ7.35-7.30(m，5H)，6.94-6.93(m，2H)，5.03(s，2H)，4.42-4.37(m，1H)，3.70(s，3H)，3.09-3.03(m，1H)，2.87-2.79(m，1H)，2.25(s，3H)。LC/MS:t R=1.79 minutes, 358 (MH) +
(R)-1-(methoxycarbonyl)-2-(7-methyl isophthalic acid H-benzo [d] [1,2,3] triazole-5-yl) ethyl carbamic acid benzyl ester
At room temperature, with time of a few minutes to (R)-1-(methoxycarbonyl)-2-(3,4-diaminourea-5-aminomethyl phenyl) ethyl carbamic acid benzyl ester (250mg, 0.58mmol) acetic acid (6mL) and the solution of water (10mL) in drip sodium nitrite (40mg, water 0.58mmol) (1mL) solution.The mixture that generates was at room temperature stirred 30 minutes, be cooled to 0 ℃ then.(1: 1, mixture 15mL) was regulated pH to 11 to add ammonium hydroxide and water.With twice of ethyl acetate extraction of mixture.Organic layer is washed with salt, and through dried over sodium sulfate.After the filtration, solvent removed in vacuo, and, obtain the solid title compound of yellowish-brown (155mg, 72% productive rate) through silica gel flash column chromatography (1: 1 ethyl acetate/hexane) purification residue.
1H-NMR(CDCl 3，300MHz)δ7.34(s，1H)，7.32-7.28(m，6H)，6.93(s，1H)，5.40(d，J＝8.1Hz，1H)，5.13-5.02(m，2H)，4.76-4.69(m，1H)，3.73(s，3H)，3.28(dd，J＝13.9，5.5Hz，1H)，3.16(dd，J＝13.9，6.2Hz，1H)，2.64(s，3H)。LC/MS:t R=2.30 minutes, 369 (MH) +
(R)-methyl 2-amino-3-(7-methyl isophthalic acid H-benzo [d] [1,2,3] triazole-5-yl) propionic ester
Figure A20038011103002761
(146mg 0.40mmol) is dissolved in the methanol solution of 4.4% formic acid of 12mL with (R)-1-(methoxycarbonyl)-2-(7-methyl isophthalic acid H-benzo [d] [1,2,3] triazole-5-yl) ethyl carbamic acid benzyl ester.The reaction flask that contains this solution is equipped with the magnetic splash bar, and uses nitrogen wash a few minutes then.In this solution, add palladium on carbon (10%, 200mg), and under blanket of nitrogen, at room temperature should react and stir 16 hours.Reactant mixture is passed through Celite Pad filters, and should fill up several times with methanol wash.Evaporated filtrate obtains title compound (quantitative yield).
1H-NMR(CDCl 3，300MHz)δ8.40(bs，1H)，7.55(s，1H)，7.14(s，1H)，4.29-4.24(m，1H)，3.78(s，3H)，3.39-3.19(m，2H)，2.69(s，3H)。LC/MS:t R=1.18 minutes, 235 (MH) +
(R)-methyl 2-(4-(1,2-dihydro-2-oxo-quinazoline-3 (4H)-yl) piperidines-1-formamido)-3-(7-methyl isophthalic acid H-benzo [d] [1,2,3] triazole-5-yl) propionic ester
(method of 4-(1,2-dihydro-2-oxo-quinazoline-3 (4H)-yl) piperidines-1-formamido)-3-(2-(trifluoromethyl)-1H-benzo [d] imidazoles-5-yl) propionic ester prepares according to preparing (R)-methyl 2-as mentioned above.LC/MS:t R=2.17 minutes, 492 (MH) +
(R)-2-(4-(1,2-dihydro-2,4-dioxo quinazoline-3 (4H)-yl) piperidines-1-formamido)-3-(7-methyl isophthalic acid H-benzo [d] [1,2,3] triazole-5-yl) propanoic acid
Figure A20038011103002771
(method of 4-(1,2-dihydro-2-oxo-quinazoline-3 (4H)-yl) piperidines-1-formamido)-3-(2-(trifluoromethyl)-1H-benzo [d] imidazoles-5-yl) propanoic acid prepares according to preparing (R)-2-as mentioned above.LC/MS:t R=2.11 minutes, 492 (MH) +
Embodiment 237
4-(1,2-dihydro-2,4-dioxo quinazoline-3 (4H)-yl)-N-((R)-3-(7-methyl isophthalic acid H-benzo [d] [1,2,3] triazole-5-yl)-1-oxo-1-(4-(piperidines-1-yl) piperidines-1-yl) third-2-yl) piperidines-1-Methanamide
Figure A20038011103002772
According to the as above preparation described in the embodiment 231.
1H-NMR(CD 3OD，300MHz)δ8.01(d，J＝8.1Hz，1H)，7.63(t，J＝7.5Hz，1H)，7.28-7.11(m，4H)，5.06-5.00(m，1H)，4.70-4.60(m，1H)，4.31-4.17(m，2H)，3.50-3.44(m，1H)，3.20-2.82(m，7H)，2.75-2.47(m，6H)，2.12-2.02(m，2H)，1.93-1.67(m，11H)，1.37-1.28(m，2H，0.97-0.79(m，2H)，0.23-0.09(m，1H)。Mass spectrum: 642 (MH) +
(R)-2-benzyloxycarbonyl amino-3-(4-chloro-2-oxo-2,3-dihydro-benzoxazol-6-yl)-methyl propionate
Figure A20038011103002781
With (R)-2-benzyloxycarbonyl amino-3-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-methyl propionate (373mg, 1.01mmol), N-chloro-succinimide (168mg, 1.26mmol), silica gel (EMScientific, the 230-400 sieve mesh, 3.73g) mixture in dichloroethanes (20mL) heated 16 hours down at 90 ℃.After being cooled to room temperature, solvent removed in vacuo.Residue is handled as the silica gel chromatography of eluent by using ethyl acetate/hexane (1: 2), obtain title compound (40mg, 9.8%) and 2-benzyloxycarbonyl amino-3-(5-chloro-2-oxo-2,3-dihydro-benzoxazol-6-yl)-methyl propionate (78mg, 19%).Compare to determine this structure by 2D NMR and by 2-benzyloxycarbonyl amino-3-(5-chloro-2-oxo-2,3-dihydro-benzoxazol-6-the yl)-methyl propionate that obtains with prepared in reaction as follows.
1H-NMR (CD 3COCD 3, 500MHz) δ 7.37-7.27 (m, 5H), 7.18 (d, J=1.0Hz, 1H), 7.16 (s, 1H), 6.76 (d, J=8.5hz, 1H), 5.06 (d, J=12.5Hz, 1H), 5.02 (d, J=12.5Hz, 1H), 4.55-4.51 (m, 1H), 3.72 (s, 3H), 3.26 (dd, J=14.0,5.0Hz, 1H), 3.04 (dd, J=14.0,9.5Hz, 1H); 13C-NMR (CD 3COCD 3, 125MHz) δ 172.2,156.4, and 154.0,144.8,137.6,133.3,128.7,128.2,128.0,127.9,125.0,66.3,55.9,52.0,37.3; Mass spectrum 405 (MH +).
(R)-2-benzyloxycarbonyl amino-3-(5-chloro-2-oxo-2,3-dihydro-benzoxazol-6-yl)-methyl propionate
Figure A20038011103002782
At room temperature, (315mg, (700mg is in acetic acid 1.89mmol) (50mL) solution 2.36mmol) to join (R)-2-benzyloxycarbonyl amino-3-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-methyl propionate with N-chloro-succinimide.Mixture was heated 16 hours down at 100 ℃.After it is cooled to room temperature, solvent removed in vacuo.With residue by use ethyl acetate/hexane (4: 6) then (1: 1) handle as the silica gel chromatography of eluent, obtain being bordering on the title compound (242mg, 32%) of yellow solid.Confirm the structure of product by 2D NMR.
1H-NMR (CD 3COCD 3, 500MHz) δ 10.47 (s, 1H), 7.36-7.28 (m, 6H), 7.20 (s, 1H), 6.80 (d, J=8.5Hz, 1H), 5.05 (d, J=12.5Hz, 1H), 5.00 (d, J=12.5Hz, 1H), 4.65-4.60 (m, 1H), 3.73 (s, 3H), 3.43 (dd, J=14.0,5.0Hz, 1H), 3.08 (dd, J=14.0,10.5Hz, 1H); 13C-NMR (CD 3COCD 3, 125MHz) δ 172.2,156.5, and 154.5,143.1,137.5,130.8,129.0,128.9,128.7,128.2,128.0,112.8,110.9,66.3,54.3,52.1,35.8; Mass spectrum 405 (MH +).
(R)-2-benzyloxycarbonyl amino-3-(4-bromo-2-oxo-2,3-dihydro-benzoxazol-6-yl)-methyl propionate
Figure A20038011103002791
With (R)-2-benzyloxycarbonyl amino-3-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-methyl propionate (418mg, 1.13mmol), N-bromine butanimide (221mg, 1.24mmol), silica gel (EMScientific, the 230-400 sieve mesh, 2.51g) and the mixture of dichloromethane (70mL) at room temperature stirred 16 hours.Solvent removed in vacuo, and residue handled as the silica gel chromatography of eluent by using ethyl acetate/hexane (2: 3), title compound obtained.
1H-NMR (CD 3COCD 3, 500MHz) δ 10.71 (s, 1H), 7.35-7.28 (m, 6H), 7.21 (s, 1H), 6.75 (d, J=7.5Hz, 1H), 5.06 (d, 12.5Hz, 1H), 5.02 (d, J=12.5Hz, 1H), 4.56-4.51 (m, 1H), 3.73 (s, 3H), 3.26 (dd, J=14.0,5.0Hz, 1H), 3.03 (dd, J=14.0,10.0Hz, 1H); 13C-NMR (CD 3COCD 3, 125MHz) δ 172.2,156.4, and 153.8,144.4,137.6,133.7,129.8,128.7,128.2,128.0,127.8,110.1,100.9,66.3,55.9,52.0,37.3; Mass spectrum 448.03 (MH +).
(R)-2-benzyloxycarbonyl amino-3-(5-bromo-2-oxo-2,3-dihydro-benzoxazol-6-yl)-methyl propionate
Figure A20038011103002801
With (R)-2-benzyloxycarbonyl amino-3-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-methyl propionate (1.07g, 2.89mmol), N-bromine butanimide (643mg, 3.61mmol) and the mixture of acetic acid (150mL) 105 ℃ of down heating 14 hours.After being cooled to room temperature, solvent removed in vacuo.With residue by use ethyl acetate/hexane (2: 3), then (1: 1) handle as the silica gel chromatography of eluent, obtain title compound (446mg, 34%).Confirm the structure of title compound by 2D NMR.
1H-NMR (CD 3COCD 3, 500MHz) δ 10.46 (s, 1H), 7.36-7.28 (m, 7H), 6.82 (d, J=8.5Hz, 1H), 5.05 (d, J=12.5Hz, 1H), 5.00 (d, J=12.5Hz, 1H), 4.67-4.62 (m, 1H), 3.73 (s, 3H), 3.43 (dd, J=14.0,5.0Hz, 1H), 3.10 (dd, J=14.0,10.5Hz, 1H); 13C-NMR (CD 3COCD 3, 125MHz) δ 172.2,156.4, and 154.2,143.7,137.6,131.1,130.6,128.7,128.2,128.0,118.2,113.9,112.9,66.2,54.3,52.1,38.3; Mass spectrum 448.03 (MH +).
(R)-2-benzyloxycarbonyl amino-3-(4-iodo-2-oxo-2,3-dihydro-benzoxazol-6-yl)-methyl propionate
With (R)-2-benzyloxycarbonyl amino-3-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-methyl propionate (324mg, 0.87mmol), I (PyH) 2BF 4(409mg, 1.08mmol), silica gel (EM Scientific, the 230-400 sieve mesh, 3.24g) and the mixture of dichloroethanes (20mL) 90 ℃ of down heating 6 hours.After being cooled to room temperature, solvent removed in vacuo.Use ethyl acetate/hexane (1: 2) to handle residue, obtain title compound (175mg, 40%) as the silica gel chromatography of eluent.Confirm the structure of title compound by 2D NMR.
1H-NMR (CD 3COCD 3, 500MHz) δ 10.47 (s, 1H), 7.46 (s, 1H), 7.37-7.29 (m, 5H), 7.22 (s, 1H), 6.74 (d, J=8.5Hz, 1H), 5.07 (d, J=12.5Hz, 1H), 5.02 (d, J=12.5Hz, 1H), 4.54-4.49 (m, 1H), 3.72 (s, 3H), 3.23 (dd, J=14.0,5.0Hz, 1H), 3.01 (dd, J=14.0,9.5Hz, 1H); 13C-NMR (CD 3COCD 3, 125MHz) δ 172.2,156.4, and 153.4,143.3,137.6,134.1,133.64,133.60,128.7,128.2,128.0,110.7,71.1,66.3,56.0,52.0,37.1; Mass spectrum 496.01 (MH +).
(R)-2-amino-3-(5-bromo-2-oxo-2,3-dihydro-benzoxazol-6-yl)-methyl propionate
At room temperature, with TMS iodine (73mL, 0.73mmol) join (R)-2-benzyloxycarbonyl amino-3-(5-bromo-2-oxo-2 of azeotropic drying, 3-dihydro-benzoxazol-6-yl)-methyl propionate (146mg, 0.33mmol) in the solution in acetonitrile (10mL), and the mixture that generates at room temperature stirred 2 hours.Add triethylamine (0.12mL), and mixture was at room temperature stirred 15 minutes.Solvent removed in vacuo, and with the residue ethyl acetate extraction.The Organic substance that merges is washed with sodium bicarbonate and salt, through dried over sodium sulfate and filtration.Remove and desolvate, and residue is directly used in next step.Mass spectrum 315.10 (MH) +
(R)-2-amino-3-(4-bromo-2-oxo-2,3-dihydro-benzoxazol-6-yl)-methyl propionate
Figure A20038011103002812
Prepare according to the method for preparing (R)-2-amino-3-(5-bromo-2-oxo-2,3-dihydro-benzoxazol-6-yl)-methyl propionate as mentioned above.Mass spectrum 315.06 (MH) +
(R)-2-amino-3-(5-chloro-2-oxo-2,3-dihydro-benzoxazol-6-yl)-methyl propionate
Prepare according to the method for preparing (R)-2-amino-3-(5-bromo-2-oxo-2,3-dihydro-benzoxazol-6-yl)-methyl propionate as mentioned above.Mass spectrum 271.10 (MH) +
(R)-2-amino-3-(4-chloro-2-oxo-2,3-dihydro-benzoxazol-6-yl)-methyl propionate
Figure A20038011103002814
Prepare according to the method for preparing (R)-2-amino-3-(5-bromo-2-oxo-2,3-dihydro-benzoxazol-6-yl)-methyl propionate as mentioned above.Mass spectrum 271.16 (MH) +
(R)-2-amino-3-(4-iodo-2-oxo-2,3-dihydro-benzoxazol-6-yl)-methyl propionate:
Figure A20038011103002821
Prepare according to the method for preparing (R)-2-amino-3-(5-bromo-2-oxo-2,3-dihydro-benzoxazol-6-yl)-methyl propionate as mentioned above.Mass spectrum 363.04 (MH) +
(R)-and 3-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-2-{[2,4-dihydro-2 '-the oxo spiral shell-(piperidines-4,4 '-1H-benzo [d] [1,3]  piperazine)-the 1-carbonyl]-amino }-methyl propionate
(method of 4-(1,2-dihydro-2-oxo-quinazoline-3 (4H)-yl) piperidines-1-formamido)-3-(2-(trifluoromethyl)-1H-benzo [d] imidazoles-5-yl) propionic ester prepares according to preparing (R)-methyl 2-as mentioned above.Mass spectrum 481.20 (MH) +
(R)-and 3-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-2-{[2,4-dihydro-2 '-the oxo spiral shell-(piperidines-4,4 '-the 1H-quinazoline)-the 1-carbonyl]-amino }-methyl propionate
Figure A20038011103002823
(method of 4-(1,2-dihydro-2-oxo-quinazoline-3 (4H)-yl) piperidines-1-formamido)-3-(2-(trifluoromethyl)-1H-benzo [d] imidazoles-5-yl) propionic ester prepares according to preparing (R)-methyl 2-as mentioned above.Mass spectrum 480.24 (MH) +
(R)-3-(4-chloro-2-oxo-2,3-dihydro-benzoxazol-6-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-methyl propionate
Figure A20038011103002831
(method of 4-(1,2-dihydro-2-oxo-quinazoline-3 (4H)-yl) piperidines-1-formamido)-3-(2-(trifluoromethyl)-1H-benzo [d] imidazoles-5-yl) propionic ester prepares according to preparing (R)-methyl 2-as mentioned above.Mass spectrum 528.16 (MH) +
(R)-3-(5-chloro-2-oxo-2,3-dihydro-benzoxazol-6-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-methyl propionate
Figure A20038011103002832
(method of 4-(1,2-dihydro-2-oxo-quinazoline-3 (4H)-yl) piperidines-1-formamido)-3-(2-(trifluoromethyl)-1H-benzo [d] imidazoles-5-yl) propionic ester prepares according to preparing (R)-methyl 2-as mentioned above.Mass spectrum 528.20 (MH) +
(R)-3-(4-bromo-2-oxo-2,3-dihydro-benzoxazol-6-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-methyl propionate
(method of 4-(1,2-dihydro-2-oxo-quinazoline-3 (4H)-yl) piperidines-1-formamido)-3-(2-(trifluoromethyl)-1H-benzo [d] imidazoles-5-yl) propionic ester prepares according to preparing (R)-methyl 2-as mentioned above.Mass spectrum 572.20 (MH) +
(R)-3-(5-bromo-2-oxo-2,3-dihydro-benzoxazol-6-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-methyl propionate
Figure A20038011103002842
(method of 4-(1,2-dihydro-2-oxo-quinazoline-3 (4H)-yl) piperidines-1-formamido)-3-(2-(trifluoromethyl)-1H-benzo [d] imidazoles-5-yl) propionic ester prepares according to preparing (R)-methyl 2-as mentioned above.Mass spectrum 572.15 (MH) +
(R)-3-(4-iodo-2-oxo-2,3-dihydro-benzoxazol-6-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-methyl propionate
Figure A20038011103002851
(method of 4-(1,2-dihydro-2-oxo-quinazoline-3 (4H)-yl) piperidines-1-formamido)-3-(2-(trifluoromethyl)-1H-benzo [d] imidazoles-5-yl) propionic ester prepares according to preparing (R)-methyl 2-as mentioned above.Mass spectrum 620.20 (MH) +
(R)-and 3-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-2-{[2,4-dihydro-2 '-the oxo spiral shell-(piperidines-4,4 '-1H-benzo [d] [1,3]  piperazine)-the 1-carbonyl]-amino }-propanoic acid
(method of 4-(1,2-dihydro-2-oxo-quinazoline-3 (4H)-yl) piperidines-1-formamido)-3-(2-(trifluoromethyl)-1H-benzo [d] imidazoles-5-yl) propanoic acid prepares according to preparing (R)-2-as mentioned above.Mass spectrum 467.18 (MH) +
(R)-and 3-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-2-{[2,4-dihydro-2 '-the oxo spiral shell-(piperidines-4,4 '-the 1H-quinazoline)-the 1-carbonyl]-amino }-propanoic acid
(method of 4-(1,2-dihydro-2-oxo-quinazoline-3 (4H)-yl) piperidines-1-formamido)-3-(2-(trifluoromethyl)-1H-benzo [d] imidazoles-5-yl) propanoic acid prepares according to preparing (R)-2-as mentioned above.Mass spectrum 466.20 (MH) +
(R)-3-(4-chloro-2-oxo-2,3-dihydro-benzoxazol-6-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-propanoic acid
(method of 4-(1,2-dihydro-2-oxo-quinazoline-3 (4H)-yl) piperidines-1-formamido)-3-(2-(trifluoromethyl)-1H-benzo [d] imidazoles-5-yl) propanoic acid prepares according to preparing (R)-2-as mentioned above.Mass spectrum 514.20 (MH) +
(R)-3-(5-chloro-2-oxo-2,3-dihydro-benzoxazol-6-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-propanoic acid
(method of 4-(1,2-dihydro-2-oxo-quinazoline-3 (4H)-yl) piperidines-1-formamido)-3-(2-(trifluoromethyl)-1H-benzo [d] imidazoles-5-yl) propanoic acid prepares according to preparing (R)-2-as mentioned above.Mass spectrum 514.24 (MH) +
(R)-3-(4-bromo-2-oxo-2,3-dihydro-benzoxazol-6-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-propanoic acid
Figure A20038011103002871
(method of 4-(1,2-dihydro-2-oxo-quinazoline-3 (4H)-yl) piperidines-1-formamido)-3-(2-(trifluoromethyl)-1H-benzo [d] imidazoles-5-yl) propanoic acid prepares according to preparing (R)-2-as mentioned above.Mass spectrum 558.30 (MH) +
(R)-3-(5-bromo-2-oxo-2,3-dihydro-benzoxazol-6-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-propanoic acid
(method of 4-(1,2-dihydro-2-oxo-quinazoline-3 (4H)-yl) piperidines-1-formamido)-3-(2-(trifluoromethyl)-1H-benzo [d] imidazoles-5-yl) propanoic acid prepares according to preparing (R)-2-as mentioned above.Mass spectrum 558.25 (MH) +
(R)-3-(4-iodo-2-oxo-2,3-dihydro-benzoxazol-6-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-propanoic acid
Figure A20038011103002881
(method of 4-(1,2-dihydro-2-oxo-quinazoline-3 (4H)-yl) piperidines-1-formamido)-3-(2-(trifluoromethyl)-1H-benzo [d] imidazoles-5-yl) propanoic acid prepares according to preparing (R)-2-as mentioned above.Mass spectrum 606.10 (MH) +
Embodiment 238
(R)-4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-(4-cyclohexyl-piperazine-1-yl)-2-oxo-1-(2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-ethyl]-amide
Figure A20038011103002882
According to the as above preparation described in the embodiment 231.LC/MS:t R=1.80 minutes, 630.37 (MH) +
Embodiment 239
(R)-4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-(4-isopropyl-piperazine-1-yl)-2-oxo-1-(2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-ethyl]-amide
Figure A20038011103002891
According to the as above preparation described in the embodiment 231.LC/MS:t R=1.71 minutes, 590.34 (MH) +
Embodiment 240
(R)-and N-((R)-3-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-1-oxo-1-(4-(piperidines-1-yl) piperidines-1-yl) third-2-yl)-2,4-dihydro-2 '-the oxo spiral shell-(piperidines-4,4 '-1H-benzo [d] [1,3]  piperazine)-the 1-Methanamide
Figure A20038011103002892
According to the as above preparation described in the embodiment 231.LC/MS:t R=1.64 minutes, 617.34 (MH) +
Embodiment 241
(R)-and N-((R)-3-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-1-oxo-1-(4-(hexamethylene-1-yl) piperazine-1-yl) third-2-yl)-2,4-dihydro-2 '-the oxo spiral shell-(piperidines-4,4 '-1H-benzo [d] [1,3]  piperazine)-the 1-Methanamide
Figure A20038011103002901
According to the as above preparation described in the embodiment 231.LC/MS:t R=1.69 minutes, 617.35 (MH) +
Embodiment 242
(R)-and N-((R)-3-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-1-oxo-1-(4-(third-2-yl) piperazine-1-yl) third-2-yl)-2,4-dihydro-2 '-the oxo spiral shell-(piperidines-4,4 '-1H-benzo [d] [1,3]  piperazine)-the 1-Methanamide
Figure A20038011103002902
According to the as above preparation described in the embodiment 231.LC/MS:t R=1.57 minutes, 577.32 (MH) +
Embodiment 243
(R)-and N-((R)-3-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-1-oxo-1-(4-(piperidines-1-yl) piperidines-1-yl) third-2-yl)-2,4-dihydro-2 '-the oxo spiral shell-(piperidines-4,4 '-the 1H-quinazoline)-the 1-Methanamide
According to the as above preparation described in the embodiment 231.LC/MS:t R=1.74 minutes, 616.37 (MH) +
Embodiment 244
(R)-and N-((R)-3-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-1-oxo-1-(4-(hexamethylene-1-yl) piperazine-1-yl) third-2-yl)-2,4-dihydro-2 '-the oxo spiral shell-(piperidines-4,4 '-the 1H-quinazoline)-the 1-Methanamide
Figure A20038011103002911
According to as above preparing.LC/MS:t R=1.79 minutes, 616.36 (MH) +
Embodiment 245
(R)-and N-((R)-3-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-1-oxo-1-(4-(third-2-yl) piperazine-1-yl) third-2-yl)-2,4-dihydro-2 '-the oxo spiral shell-(piperidines-4,4 '-the 1H-quinazoline)-the 1-Methanamide
According to the as above preparation described in the embodiment 231.LC/MS:t R=1.67 minutes, 576.34 (MH) +
Embodiment 246
(R)-4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(4-chloro-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-ethyl]-amide
Figure A20038011103002921
According to the as above preparation described in the embodiment 231.LC/MS:t R=1.91 minutes, 664.35 (MH) +
Embodiment 247
(R)-4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(5-chloro-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-ethyl]-amide
According to the as above preparation described in the embodiment 231.LC/MS:t R=1.91 minutes, 664.34 (MH) +
Embodiment 248
(R)-4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(4-bromo-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-ethyl]-amide
Figure A20038011103002931
According to the as above preparation described in the embodiment 231.LC/MS:t R=1.96 minutes, 708.31 (MH) +
Embodiment 249
(R)-4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(5-bromo-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-ethyl]-amide
Figure A20038011103002932
According to the as above preparation described in the embodiment 231.LC/MS:t R=1.96 minutes, 708.31 (MH) +
Embodiment 250
(R)-4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(4-iodo-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-ethyl]-amide
Figure A20038011103002941
According to the as above preparation described in the embodiment 231.LC/MS:t R=1.97 minutes, 756.36 (MH +).
Embodiment 251
(±)-N-(1-benzyl-2-hydroxyl-ethyl)-2-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-4-oxo-4-[1 ', 2 '-dihydro-2 '-the oxo spiral shell-[4H-3 ', 1-benzoxazine-4,4 '-piperidyl]-butyramide
Figure A20038011103002942
According to preparing (±)-1-[1 as mentioned above, 4 '] connection piperidines-1 '-Ji-2-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-4-[1 ', 2 '-dihydro-2 '-the oxo spiral shell-[4H-3 ', 1-benzoxazine-4,4 '-piperidyl]-butane-1, the method for 4-diketone prepares.LC/MS:t R=1.38 minutes, 596 (MH) +
Embodiment 252
(±)-N-(1-benzyl-2-hydroxyl-ethyl)-2-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-yl]-butyramide
Figure A20038011103002951
According to preparing (±)-1-[1 as mentioned above, 4 '] connection piperidines-1 '-Ji-2-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-4-[1 ', 2 '-dihydro-2 '-the oxo spiral shell-[4H-3 ', 1-benzoxazine-4,4 '-piperidyl]-butane-1, the method for 4-diketone prepares.LC/MS:t R=1.50 minutes, 609 (MH) +
1H NMR(400MHz，CD 3OD)δ7.90(1H，s)，7.64-7.84(1H，m)，6.71-7.42(11H，m)，4.58(1H，m)，3.82-4.50(6H，m)，2.21-3.52(13H，m)，1.42-1.87(4H，m)。
Embodiment 253
(±)-phenyl-acetic acid N '-2-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-yl]-bytyry }-hydrazides
Figure A20038011103002952
According to preparing (±)-1-[1 as mentioned above, 4 '] connection piperidines-1 '-Ji-2-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-4-[1 ', 2 '-dihydro-2 '-the oxo spiral shell-[4H-3 ', 1-benzoxazine-4,4 '-piperidyl]-butane-1, the method for 4-diketone prepares.LC/MS:t R=1.43 minutes, 630 (M+Na) +
Embodiment 254
(±)-1-[1,4 '] connection piperidines-1 '-Ji-4-[4-(8-fluoro-2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-yl]-2-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-butane-1, the 4-diketone
Figure A20038011103002961
According to preparing (±)-1-[1 as mentioned above, 4 '] connection piperidines-1 '-Ji-2-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-4-[1 ', 2 '-dihydro-2 '-the oxo spiral shell-[4H-3 ', 1-benzoxazine-4,4 '-piperidyl]-butane-1, the method for 4-diketone prepares.LC/MS:t R=1.18 minutes, 644 (MH) +
1H NMR(400MHz，CDCl 3)δ8.00(1H，s)，6.82-7.40(6H，m)，4.48-4.70(3H，m)，4.31(2H，s)，3.85-4.11(2H，m)，3.65(1H，m)，2.70-3.16(5H，m)，2.53(3H，s)，0.72-2.52(23H，m)。
Embodiment 255
(±)-1-[1,4 '] connection piperidines-1 '-Ji-2-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-4-[2 ', 3 '-dihydro-2 '-the oxo spiral shell-(piperidines-4,4 '-quinazoline]-butane-1, the 4-diketone
Figure A20038011103002962
According to preparing (±)-1-[1 as mentioned above, 4 '] connection piperidines-1 '-Ji-2-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-4-[1 ', 2 '-dihydro-2 '-the oxo spiral shell-[4H-3 ', 1-benzoxazine-4,4 '-piperidyl]-butane-1, the method for 4-diketone prepares.LC/MS:t R=1.09 minutes, 612 (MH) +
2-oxo-2,3-dihydro-benzoxazol-6-formaldehyde
Figure A20038011103002971
Under nitrogen, with 6-bromo-3H-benzoxazol-2-ketone (0.9236g, 4.31 the micromole) solution in anhydrous tetrahydro furan (25mL) and dimethyl formamide (3mL) is cooled to-78 ℃, is just adding subsequently-butyl lithium (hexane solution of 2.5M) (3.8mL, 2.2 equivalents).After stirring 10min under-78 ℃, add the s-butyl lithium (cyclohexane solution of 1.4M, 8 equivalents) of 24mL.Should react stirring, be warmed to-40 ℃ at leisure simultaneously.When reaching this temperature, should react by adding methanol and come quencher.With the reactant mixture vacuum concentration, and add entry.With water layer with 1N HCl (about pH is 5) acidify, and with ethyl acetate (3 * 50mL) extractions through dried over sodium sulfate, are filtered also and are concentrated, and obtain product, 0.6402g (91%).MS(ESI)164(MH) +。
1H NMR(400MHz，DMSO-d6)δ9.90(1H，s)，7.79(1H，d，J＝8.0Hz)，7.74(1H，s)，7.28(1H，d，J＝8.0Hz)。
3-(2-oxo-2,3-dihydro-benzoxazol-6-methylene)-monomethyl glutarate
Prepare (1.4g, 90% productive rate) according to the method that as above is used to prepare 2-(7-methyl isophthalic acid H-indazole-5-methylene)-succinic acid 1-methyl ester.MS(ESI)300(M+Na) +。
(±)-3-(2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-monomethyl glutarate
Figure A20038011103002973
Prepare (1.4g, 99% productive rate) according to the method that as above is used for preparing (±)-2-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-succinic acid 1-methyl ester.MS(ESI)302(M+Na) +。
(±)-4-oxo-2-(2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-4-[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-yl]-methyl butyrate
According to as above being used for preparation (±)-2-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-4-oxo-4-[1 ', 2 '-dihydro-2 '-the oxo spiral shell-[4H-3 ', 1-benzoxazine-4,4 '-piperidyl]-method of methyl butyrate prepares.MS(ESI)493(MH) +。
(±)-4-oxo-2-(2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-4-[2 ', 3 '-dihydro-2 '-the oxo spiral shell-(piperidines-4,4 '-quinazoline)]-methyl butyrate
According to as above being used for preparation (±)-2-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-4-oxo-4-[1 ', 2 '-dihydro-2 '-the oxo spiral shell-[4H-3 ', 1-benzoxazine-4,4 '-piperidyl]-method of methyl butyrate prepares.MS(ESI)479(MH) +。
(±)-4-oxo-2-(2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-4-[2 ', 3 '-dihydro-2 '-the oxo spiral shell-(piperidines-4,4 '-quinazoline)]-butanoic acid
According to as above being used for preparation (±)-2-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-4-oxo-4-[1 ', 2 '-dihydro-2 '-the oxo spiral shell-[4H-3 ', 1-benzoxazine-4,4 '-piperidyl]-butyro-method prepares.MS(ESI)465(MH) +。
(±)-4-oxo-2-(2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-4-[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-yl]-butanoic acid
Figure A20038011103002991
According to as above being used for preparation (±)-2-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-4-oxo-4-[1 ', 2 '-dihydro-2 '-the oxo spiral shell-[4H-3 ', 1-benzoxazine-4,4 '-piperidyl]-butyro-method prepares.MS(ESI)479(MH) +。
Embodiment 256
(±)-1-(4-cyclohexyl-piperazine-1-yl)-2-(2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-4-[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-yl]-butane-1, the 4-diketone
Figure A20038011103002992
According to as above being used for preparation (±)-1-[1,4 '] connection piperidines-1 '-Ji-2-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-4-[1 ', 2 '-dihydro-2 '-the oxo spiral shell-[4H-3 ', 1-benzoxazine-4,4 '-piperidyl]-butane-1, the method for 4-diketone prepares.LC/MS:t R=1.10 minutes, 629 (MH) +
Embodiment 257
(±)-1-[1,4 '] connection piperidines-1 '-Ji-2-(2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-4-[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-yl]-butane-1, the 4-diketone
According to as above being used for preparation (±)-1-[1,4 '] connection piperidines-1 '-Ji-2-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-4-[1 ', 2 '-dihydro-2 '-the oxo spiral shell-[4H-3 ', 1-benzoxazine-4,4 '-piperidyl]-butane-1, the method for 4-diketone prepares.LC/MS:t R=1.08 minutes, 629 (MH) +
1H NMR(400MHz，CDCl 3)δ9.89(1H，s)，8.28(1H，d，J＝11.2Hz)，6.90-7.25(5H，m)，6.75(1H，d，J＝8.0Hz)，4.40-4.79(3H，m)，4.35(2H，s)，2.27-3.98(19H，m)，1.46-2.10(9H，m)，1.36(1H，m)，1.08(1H，m)，0.12(1H，m)。
Embodiment 258
(±)-1-[1,4 '] connection piperidines-1 '-Ji-2-(2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-4-[2 ', 3 '-dihydro-2 '-the oxo spiral shell-(piperidines-4,4 '-quinazoline)]-butane-1, the 4-diketone
According to as above being used for preparation (±)-1-[1,4 '] connection piperidines-1 '-Ji-2-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-4-[1 ', 2 '-dihydro-2 '-the oxo spiral shell-[4H-3 ', 1-benzoxazine-4,4 '-piperidyl]-butane-1, the method for 4-diketone prepares.LC/MS:t R=1.02 minutes, 615 (MH) +
Embodiment 259
(±)-1-(4-cyclohexyl-piperazine-1-yl)-2-(2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-4-[2 ', 3 '-dihydro-2 '-the oxo spiral shell-(piperidines-4,4 '-quinazoline)]-butane-1, the 4-diketone
According to as above being used for preparation (±)-1-[1,4 '] connection piperidines-1 '-Ji-2-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-4-[1 ', 2 '-dihydro-2 '-the oxo spiral shell-[4H-3 ', 1-benzoxazine-4,4 '-piperidyl]-butane-1, the method for 4-diketone prepares.LC/MS:t R=1.04 minutes, 615 (MH) +
Embodiment 260
(±)-4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-(4-cyclohexyl-piperazine-1-yl)-1-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-2-oxo-ethyl]-amide
Prepare according to the above-mentioned method that is used to prepare embodiment 16.
1H-NMR(CD 3OD，500MHz)δ0.81(1H，m)，0.89(1H，m)，1.02(1H，m)，1.1-2.0(12H，m)，2.23(1H，d)，2.47(1H，d)，2.61(3H，s)，2.90(4H，t)，3.08(4H，m)，3.2-3.5(4H，m)，3.82(1H，m)，4.14(2H，d)，4.29(2H，s)，4.40(1H，t)，6.80(1H，d)，6.95(1H，t)，7.12(3H，m)，7.47(1H，s)，8.01(1H，s)。Mass spectrum: 627.47 (MH) +
Embodiment 261
(±)-4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[4-(4-fluoro-phenyl)-piperazine-1-yl]-1-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-2-oxo-ethyl]-amide
Figure A20038011103003021
Prepare according to the above-mentioned method that is used to prepare embodiment 16.LC/MS:t R=2.34 minutes, 621.42 (MH) +
Embodiment 262
(±)-3-(7-methyl isophthalic acid H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-the propanoic acid tert-butyl ester
With (±)-3-(7-methyl isophthalic acid H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-propanoic acid (50mg, 0.105mmol) and dicyclohexylcarbodiimide (25mg, 0.12mmol) dimethyl formamide solution at room temperature stirred 30 minutes, and add then Pentafluorophenol (26mg, 1.3mmol).At room temperature continue to stir and spend the night, and remove then and desolvate, with residue under fine vacuum dry 4 hours.The pentafluorophenyl group ester that this is thick need not be further purified and be directly used in next step.Under nitrogen, under-78 ℃, in the tetrahydrofuran solution of the tert-butyl alcohol (10 equivalent), add the cyclohexane extraction (10 equivalent) of 1.4M s-butyl lithium.After 10-15 minute, add the tetrahydrofuran solution of phenyl-pentafluoride phenolic ester (1 equivalent).Reactant mixture at room temperature stirred spend the night.Solvent removed in vacuo, and with residue by preparation type-HPLC purification, obtain required chemical compound.
1H-NMR(CD 3OD)δ1.40(s，9H)1.56(m，4H)，2.54(s，3H)2.85(m，2H)3.05(m，1H)3.19(m，1H)4.14(m，4H)4.44(m，2H)6.76(d，J＝7.68Hz，1H)6.93(t，J＝7.5Hz，1H)7.10(m，3H)7.14(s，1H)7.97(s，1H)。LC/MS:t R=2.19 minutes, 533.36 (MH) +
Embodiment 263
(±)-3-(7-methyl isophthalic acid H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-propanoic acid 1-methyl cyclohexane ester
According to as above being used for preparation (±)-3-(7-methyl isophthalic acid H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-method of the propanoic acid tert-butyl ester prepares.LC/MS:t R=2.47 minutes, 574.39 (MH) +
Embodiment 264
(±)-3-(7-methyl isophthalic acid H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-propanoic acid 1-aza-bicyclo [2.2.2] oct-3-yl ester
To (±)-3-(7-methyl isophthalic acid H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-propanoic acid (50mg, 0.105mmol), add aza-bicyclo [2.2.2] oct-3-yl alcohol (0.525mmol, 5 equivalents) in the dimethyl formamide solution of EDCI (100mg) and 4-dimethylaminopyridine (0.2 equivalent).Mixture at room temperature stirred spend the night.Solvent removed in vacuo, and residue is dissolved in the ethyl acetate, with the salt washing,, and, obtain required chemical compound by the preparation HPLC purification through dried over mgso.LC/MS:t R=1.62 minutes, 586.41 (MH) +
Embodiment 265
(±)-3-(7-methyl isophthalic acid H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-propanoic acid piperidin-4-yl ester
Figure A20038011103003041
According to as above being used for preparation (±)-3-(7-methyl isophthalic acid H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-method of propanoic acid 1-aza-bicyclo [2.2.2] oct-3-yl ester prepares.LC/MS:t R=1.58 minutes, 560.37 (MH) +
Embodiment 266
(±)-4-(3-(7-methyl isophthalic acid H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-propionyloxy)-piperidines-1-carboxylic acid tert-butyl ester
According to as above being used for preparation (±)-3-(7-methyl isophthalic acid H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-method of propanoic acid 1-aza-bicyclo [2.2.2] oct-3-yl ester prepares.LC/MS:t R=2.38 minutes, 660.42 (MH) +
Embodiment 267
(±)-3-(7-methyl isophthalic acid H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-propanoic acid 3,4,5,6-tetrahydrochysene-2H-[1,4 '] bipyridyl-4-base ester
According to as above being used for preparation (±)-3-(7-methyl isophthalic acid H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-method of propanoic acid 1-aza-bicyclo [2.2.2] oct-3-yl ester prepares.LC/MS:t R=1.67 minutes, 637.43 (MH) +
Embodiment 268
(±)-3-(7-methyl isophthalic acid H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-propanoic acid 1-diethylamino-1-methyl-ethyl ester
Figure A20038011103003051
According to as above being used for preparation (±)-3-(7-methyl isophthalic acid H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-method of propanoic acid 1-aza-bicyclo [2.2.2] oct-3-yl ester prepares.LC/MS:t R=1.66 minutes, 590.44 (MH) +
Embodiment 269
(±)-3-(7-methyl isophthalic acid H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-propanoic acid 1,1-dimethyl-2-phenyl-ethyl ester
Figure A20038011103003052
According to as above being used for preparation (±)-3-(7-methyl isophthalic acid H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-method of the propanoic acid tert-butyl ester prepares.LC/MS:t R=2.52 minutes, 609.46 (MH) +
Embodiment 270
(±)-3-(7-methyl isophthalic acid H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-propanoic acid 1,1-dimethyl-3-phenyl-propyl ester
Figure A20038011103003053
According to as above being used for preparation (±)-3-(7-methyl isophthalic acid H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-method of the propanoic acid tert-butyl ester prepares.LC/MS:t R=2.61 minutes, 623.48 (MH) +
Embodiment 271
(±)-3-(7-methyl isophthalic acid H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-ethyl propionate
According to as above being used for preparation (±)-3-(7-methyl isophthalic acid H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-method of the propanoic acid tert-butyl ester prepares.LC/MS:t R=1.98 minutes, 505.32 (MH) +
Embodiment 272
(±)-1-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-2-[1-pyridin-4-yl-methyl]-the 2-oxoethyl]-2 ', 3 '-dihydro-2 '-the oxo spiral shell-[piperidines-4,4 '-(1H)-quinazoline]-the 1-Methanamide
Figure A20038011103003062
Prepare according to the above-mentioned method that is used to prepare embodiment 16.LC/MS:t R=1.49 minutes, 553.12 (MH) +
Embodiment 273
(±)-1-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-2-[1-pyridin-4-yl-piperazinyl]-the 2-oxoethyl]-2 ', 3 '-dihydro-2 '-the oxo spiral shell-[piperidines-4,4 '-(1H)-quinazoline]-the 1-Methanamide
Prepare according to the above-mentioned method that is used to prepare embodiment 16.LC/MS:t R=1.56 minutes, 608.18 (MH) +
Embodiment 274
(±)-1-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-2-[(2-dimethylamino-ethyl-ethylamino formoxyl)-the 2-oxoethyl]-2 ', 3 '-dihydro-2 '-the oxo spiral shell-[piperidines-4,4 '-(1H)-quinazoline]-the 1-Methanamide
Prepare according to the above-mentioned method that is used to prepare embodiment 16.LC/MS:t R=1.58 minutes, 561.20 (MH) +
Embodiment 275
(±)-1-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-2-[1-pyridin-4-yl-piperazinyl]-the 2-oxoethyl]-1 ', 2 '-dihydro-2 '-the oxo spiral shell-[4H-3 ', 1-benzoxazine-4,4 '-piperidines]-the 1-Methanamide
Prepare according to the above-mentioned method that is used to prepare embodiment 16.LC/MS:t R=1.56 minutes, 609.14 (MH) +
Embodiment 276
(±)-1-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-2-[1-pyridine-2-base-piperazinyl]-the 2-oxoethyl]-1 ', 2 '-dihydro-2 '-the oxo spiral shell-[4H-3 ', 1-benzoxazine-4,4 '-piperidines]-the 1-Methanamide
Figure A20038011103003081
Prepare according to the above-mentioned method that is used to prepare embodiment 16.LC/MS:t R=1.57 minutes, 609.17 (MH) +
Embodiment 277
(R)-and 4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1d-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-2-oxo-ethyl] amide
Prepare according to the above-mentioned method that is used to prepare embodiment 16.
1H-NMR (CD 3OD, 500MHz) δ-0.27 (1H, m), 0.75 (1H, m), 1.1-2.0 (12H, m), 2.10 (2H, m), 2.4-2.5 (3H, m), 2.57 (3H, s), 2.68 (2H, m), 2.92 (4H, m), 3.10 (4H, m), 3.9-5.1 (4H, a plurality of m), 6.82 (1H, d), 6.96 (1H, t), 7.18 (3H, m), 7.50 (1H, s), 8.05 (1H, s).LC/MS:t R=1.68 minutes, 627.42 (MH) +
Embodiment 278
(R)-1-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-2-[1,4-joins piperidines]-1-base-2-oxoethyl]-2 ', 3 '-dihydro-2 '-the oxo spiral shell-[piperidines-4,4 '-(1H)-quinazoline]-the 1-Methanamide
Figure A20038011103003091
Prepare according to the above-mentioned method that is used to prepare embodiment 16.LC/MS:t R=1.63 minutes, 613.36 (MH) +
Embodiment design and that can comprise following expectation according to other chemical compound of description provided herein or method known to those skilled in the art preparation in the scope of the invention.
4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(7-bromo-1H-indazole-5-ylmethyl)-2-oxo-ethyl]-amide
Figure A20038011103003092
4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-oxo-1-(2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-(4-pyridin-4-yl-piperazine-1-yl)-ethyl]-amide
Figure A20038011103003101
4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-oxo-1-(2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-piperidines-1-base-ethyl]-amide
Figure A20038011103003102
4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-(4-methyl-piperazine-1-yl)-2-oxo-1-(2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-ethyl]-amide
4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(4-methyl-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-ethyl]-amide
Figure A20038011103003111
4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [1-(4-methyl-2-oxo-2,3-dioxy-benzoxazol-6-ylmethyl)-2-oxo-2-piperidines-1-base-ethyl]-amide
Figure A20038011103003112
4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [1-(4-chloro-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-2-piperidines-1-base-ethyl]-amide
Figure A20038011103003113
4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [1-formyl-dimethylamino-2-(4-methyl-2-oxo-2,3-dihydro-benzoxazol-6-yl)-ethyl]-amide
4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-(4-chloro-2-oxo-2,3-dihydro-benzoxazol-6-yl)-1-formyl-dimethylamino-ethyl]-amide
Figure A20038011103003122
4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [1-(4-methyl-2-oxo-2,3-dioxy-benzoxazol-6-ylmethyl)-2-oxo-2-(4-pyridin-4-yl-piperazine-1-yl)-ethyl]-amide
Figure A20038011103003123
4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [1-(4-chloro-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-2-(4-pyridin-4-yl-piperazine-1-yl)-ethyl]-amide
4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(4-ethyl-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-ethyl]-amide
4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(7-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-ylmethyl)-2-oxo-ethyl]-amide
4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(7-chloro-2-oxo-2,3-dihydro-1H-benzimidazole-5-ylmethyl)-2-oxo-ethyl]-amide
Figure A20038011103003141
4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(7-ethyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-ylmethyl)-2-oxo-ethyl]-amide
Figure A20038011103003142
4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-ylmethyl)-2-oxo-ethyl]-amide
4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(3,7-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-ylmethyl)-2-oxo-ethyl]-amide
4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(7-chloro-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-ylmethyl)-2-oxo-ethyl]-amide
Figure A20038011103003152
4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(7-ethyl-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-ylmethyl)-2-oxo-ethyl]-amide
Figure A20038011103003153
3-(7-methyl isophthalic acid H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-isopropyl propionate
3-(7-chloro-1H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-isopropyl propionate
3-(7-ethyl-1H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-isopropyl propionate
3-(7-chloro-1H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-the propanoic acid tert-butyl ester
Figure A20038011103003164
3-(7-ethyl-1H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-the propanoic acid tert-butyl ester
3-(7-chloro-1H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-cyclohexyl propionate
3-(7-ethyl-1H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-cyclohexyl propionate
3-(7-chloro-1H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-propanoic acid 1-methyl-piperidin-4-yl ester
Figure A20038011103003173
3-(7-ethyl-1H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-propanoic acid 1-methyl-piperidin-4-yl ester
3-(7-chloro-1H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-propanoic acid 1-methyl-cyclohexyl ester
Figure A20038011103003181
3-(7-ethyl-1H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-propanoic acid 1-methyl-cyclohexyl ester
Figure A20038011103003182
3-(7-chloro-1H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-propanoic acid 4-phenyl-cyclohexyl
Figure A20038011103003183
3-(7-ethyl-1H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-propanoic acid 4-phenyl-cyclohexyl
CGRP is in conjunction with test
Tissue culture.At 37 ℃ and 5%CO 2In the culture medium of forming by MEM that contains Earle ' s salt and L-glutaminate (Gibco) that adds 10% hyclone (Gibco), the SK-N-MC cell is grown with monolayer down.
Cell granulations.With cell with phosphate buffered saline (PBS) (155mM NaCl, 3.3mM Na 2HPO 4, 1.1mM KH 2PO 4, pH 7.4) and flushing twice, under 4 ℃, in the hypotonic cell lysis buffer solution that contains 10mM Tris (pH 7.4) and 5mM EDTA (hypotonic lysis buffer), hatched 5-10 minute then.Cell is transferred to the polypropylene test tube by plate (in 16 * 100mm), to be used polytron (homogenizer) then and makes it homogenize.With homogenate centrifugal 30 minutes with 32,000 * g.Granular precipitation (pellets) is suspended in cold containing in 0.1% mammalian protease inhibitor mixed agent (cocktail) the hypotonic cell lysis buffer solution (hypotonic lysis buffer) (Sigma) once more, measures protein concentration then.Then SK-N-MC homogenate is divided into equal portions, be stored in-80 ℃ stand-by.
Radioligand-binding assay.Make the The compounds of this invention dissolving and carry out serial dilution with 100%DMSO.With the serial dilution of the The compounds of this invention of equal portions further to measure buffer (50mMTris-Cl pH 7.5,5mM MgCl 2, 0.005% Triton X-100) and dilute 25 times, and shift (50 μ l amount) to 96 hole assay plate.Will [ 125I]-CGRP (Amersham Biosciences) is diluted to 60pM, and adds 50 μ l volumes in every hole in measuring buffer.The granular precipitation of SK-N-MC (pellets) is thawed, be diluted in contain fresh 0.1% mammalian protease inhibitor mixed agent (mammalian proteaseinhibitor cocktail, in mensuration buffer Sigma), homogenize once more.The SK-N-MC homogenate (5 μ g/ hole) that adds 100 μ l volumes.Then assay plate at room temperature is incubated two hours.(20mM Tris-Cl pH 7.5 0.1%BSA) stops measuring, and filters by the glass fiber filter (Whatman GF/B) that soaks in 0.5%PEI in advance immediately then by adding excessive cold lavation buffer solution.Define non-specific binding with 1 μ M β-CGRP.Use gamma or scintillation counter to measure protein bound radioactivity.With IC 50Be defined as displacement 50% radioligand in conjunction with required compound concentrations of the present invention.
In following table, ecbatic as follows: A≤10nM; 10nM＜B≤100nM; 100nM＜C≤1000nM; D＞1000nM.
Table 4.CGRP combination, cAMP function and external human arteriae cerebri data
Embodiment # The CGRP combination 1 IC 50(nM) The cAMP function 2 IC 50(nM) Arteriae cerebri 3 EC 50(nM)
1 C * *
2 A A A
3 B B B
4 B B *
5 A A *
6 A A A
7 C C *
8 C C *
9 B B *
10 C B *
11 B B *
12 B C *
13 C * *
14 D * *
15 C C *
16 A A A
17 A A A
18 A B A
19 A A A
20 A A A
21 A A A
22 A A *
23 A A A
24 B B *
25 A A A
Embodiment # The CGRP combination 1 IC 50(nM) The cAMP function 2 IC 50(nM) Arteriae cerebri 3 EC 50(nM)
26 B B *
27 B C *
28 C * *
29 A * *
30 B * *
31 A A *
32 C * *
33 C * *
34 A A *
35 B B *
36 B B *
37 A B *
38 B B *
39 C C *
40a A A *
40b B * *
40c D * *
40d C * *
40e D * *
40f D * *
40g D * *
40h D * *
40i B * *
40j D * *
40k D * *
41a B * *
41b A * *
41c A * *
Embodiment # The CGRP combination 1 IC 50(nM) The cAMP function 2 IC 50(nM) Arteriae cerebri 3 EC 50(nM)
41d B * *
41e A * *
41f B * *
42 C * *
43 A A A
44 C * *
45 A * *
46 B B *
47 A A A
48 D * *
49 A * *
50 A * *
51 D * *
52 D * *
53 D * *
54 B C A
55 C * *
56 A A *
57 C * *
58 D * *
59 C * *
60 C * *
61 C C *
62 B B *
63 C C *
64 B * B
65 A B B
66 C * *
Embodiment # The CGRP combination 1 IC 50(nM) The cAMP function 2 IC 50(nM) Arteriae cerebri 3 EC 50(nM)
67 B C B
68 A A A
69 A A A
70 A A A
71 A A A
72 A A A
73 B B *
74 A A A
75 A B *
76 B B A
77 B B *
78 A A *
79 B C *
80 C * *
81 B C *
82 B C *
83 B C *
84 B B *
85 C * *
86 C B C
87 B B *
88 C B *
89 C B *
90 B * *
91 C * *
92 B C *
93 C * *
94 C C *
Embodiment # The CGRP combination 1 IC 50(nM) The cAMP function 2 IC 50(nM) Arteriae cerebri 3 EC 50(nM)
95 C * *
96 D * *
97 D * *
98 D * *
99 D D *
100 C * *
101 D * *
102 C * *
103 C * *
104 C * *
105 C * *
106 C * *
107 C * *
108 C * *
109 C * *
110 C * *
111 C * *
112 C * *
113 C * *
114 C * *
115 C * *
116 C * *
117 C * *
118 C * *
119 C * *
120 C * *
121 C * *
122 C * *
Embodiment # The CGRP combination 1 IC 50(nM) The cAMP function 2 IC 50(nM) Arteriae cerebri 3 EC 50(nM)
123 B * *
124 C * *
125 C * *
126 C * *
127 C * *
128 C * *
129 C * *
130 C * *
131 C * *
132 C * *
133 C * *
134 C * *
135 C * *
136 C * *
137 C * *
138 C * *
139 C * *
140 B * *
141 C * *
142 C * *
143 C * *
144 C * *
145 C * *
146 B * *
147 C * *
148 B * *
149 B * *
150 B * *
Embodiment # The CGRP combination 1 IC 50(nM) The cAMP function 2 IC 50(nM) Arteriae cerebri 3 EC 50(nM)
151 C * *
152 C * *
153 C * *
154 C * *
155 C * *
156 C * *
157 C * *
158 B * *
159 B * *
160 C * *
161 B * *
162 C * *
163 C * *
164 C * *
165 C * *
166 C * *
167 C * *
168 C * *
169 C * *
170 C * *
171 B * *
172 B * *
173 C * *
174 C * *
175 C * *
176 B * *
177 B * *
178 B * *
Embodiment # The CGRP combination 1 IC 50(nM) The cAMP function 2 IC 50(nM) Arteriae cerebri 3 EC 50(nM)
179 C * *
180 C * *
181 C * *
182 C * *
183 C * *
184 B * *
185 C * *
186 C * *
187 C * *
188 C * *
189 C * *
190 C * *
191 C * *
192 C * *
193 B * *
194 C * *
195 C * *
196 B * *
197 C * *
198 C * *
199 B * *
200 B * *
201 C * *
Ring AMP test
Functional antagonism.Measure the antagonism of The compounds of this invention by the formation of measurement ring adenylic acid (3 ' 5-cyclic adenosine monophosphate) in the SK-N-MC cell of endogenous ground expressing human class CGRP receptor.Make CGRP receptor complex and Gs protein binding (couple), and CGRP therewith the combination of complex cause the activation of a kind of adenyl cyclase of relying on by Gs-to generate cyclic adenosine monophosphate (Juaneda C etc., TiPS, 2000; 21:432-438; Be hereby incorporated by).Therefore, the CGRP receptor antagonist suppresses generation (Doods H etc., the Br JPharmacol 2000 of the inductive cyclic adenosine monophosphate of CGRP-in the SK-N-MC cell; 129 (3): 420-423; Be hereby incorporated by).Be the measurement ring adenylic acid, with the SK-N-MC cell separately and 0.3nM CGRP or in the presence of the The compounds of this invention of variable concentrations, incubated at room 30 minutes.Before adding CGRP, with The compounds of this invention and SK-N-MC cell preincubation 15 minutes so that receptor occupy-place (receptor occupancy) (Edvinsson etc., Eur JPharmacol, 2001,415:39-44; Be hereby incorporated by).Use (cell) lytic reagent extraction cyclic adenosine monophosphate, adopt the direct screening reagent box of RPA559 cyclic adenosine monophosphate SPA (RPA559 cAMPSPA Direct Screening Assay Kit, Amersham Pharmacia Biotech) to measure its concentration then by radioimmunoassay.Use Excel fit and calculate the IC50 value.Because test compound of the present invention shows dosage-dependent inhibitory action to the cyclic adenosine monophosphate generation of CGRP-mediation, determine that test compound of the present invention is an antagonist.Overview is referring to table 3 as a result.
Schild analyzes.Can use Schild and analyze to the antagonism of The compounds of this invention qualitative, single use CGRP, or in the presence of the The compounds of this invention of variable concentrations, carry out the dose response of the cyclic adenosine monophosphate generation of CGRP stimulation.Antagonist dosage is made as X-axis, and corresponding with it, dosage rate (being defined as single IC50 that removes the agonist in the presence of chemical compound with the IC50 of agonist) deducts 1 and is Y-axis.Then X-axis and Y-axis all carried out linear regression to number conversion (log-transformed).There is not the slope of significant difference to be designated as emulative antagonism with condition (unity) (1).K bIt is the dissociation constant of antagonist.
Table 5.Schild analyzes
Embodiment # K b(nM) Slope
2 0.16 0.94
3 55 0.96
5 3 0.92
6 0.36 0.93
16 1.3
17 1.1 0.92
18 1 0.8
21 0.018 0.89
Embodiment # K b(nM) Slope
43 0.018 1.2
45 1.4
47 0.1 0.93
69 0.016 1
70 0.71
71 2 0.87
Analyze referring to Fig. 1 .Schild.
External human arteriae cerebri analysis
Ultimate principle and summary.Design a kind of analyzed in vitro method, used the ability of the expansion of the human brain blood vessel of thinking noval chemical compound reverse CGRP-mediation that direct evidence is provided.In brief, isolating vascular ring is placed in organizes in the bath, blood vessel with potassium chloride (KCl) preshrinking, and is expanded with hCGRP fully, and the CGRP-receptor antagonist that adds by accumulation is with this diastole (relaxation) reverse (whole particularss is as follows) then.
Tissue samples.Human artery's anatomical samples is from supplier (ABS Inc. or NDRI).All blood vessels are transported to ice-cold HEPES buffer, and (its composition (mM): NaCl 130, and KCl 4, KH 2PO 41.2, MgSO 41.2, CaCl 21.8, glucose 6, NaHCO 34, HEPES 10, and EDTA 0.025) in.After the reception, blood vessel is put into cold Kreb ' s buffer, and (its composition (mM): NaCl 118.4, and KCl 4.7, KH 2PO 41.2, MgSO 41.2, CaCl 21.8, glucose 10.1, NaHCO 325) in, this buffer carbogen (5%CO 2With 95% oxygen) make it saturated.
In vitro tissue is bathed (Isolated Tissue Baths).Remove the connective tissue on the blood vessel, be cut into the long cylindric sections of 4-5mm.In organizing bath blood vessel is placed between two rustless steel hooks, one of them is fixed, and another is connected on the tension force displacement transducer (force displacement transducer).Use data collecting system (Powerlab, ADInstruments, MountainView, CA) a continuous record antiotasis that is connected to pick off.Feed the temperature of organizing bath (37 ℃) and the pH (7.4) that carbogen control comprises the blood vessel of Krebs buffer and storing to continue bubbling.Tremulous pulse fragment balance about 30-45 minute is reached a stable resting tension (resting tone) until it.Before test, blood vessel with 100mM KCl pretreatment (primed) (adjusting (conditioned)), is washed then.Blood vessel with 10mM KCl preshrinking, is fully expanded with 1nM hCGRP then.By being the medicine that the accumulation of unit adds with the semilog, obtain the concentration-response curve of CGRP-receptor antagonist in the blood vessel of fully expansion.Under each concentration, the effect of medicine is expressed as the % reverse of the diastole of CGRP-mediation in the every blood vessel.Every blood vessel is individually carried out practical measurement and data analysis, concentration-response data is fitted to one four parameter logical equation, thereby infer the EC50 value by nonlinear regression analysis.Summary sees Table 3 as a result.
Non-limit approach (Non-Terminal Method) is to micromolecule CGRP-receptor antagonist in the mammal
The assessment of rendeing a service in the body
Summary.The someone proposes to block the arteriae cerebri expansion of calcitonin-gene-related peptide (CGRP) mediation as migrainous a kind of Therapeutic Method, yet, new micromolecule CGRP-receptor antagonist has shown kind-species diversity, low (the Mallee etc. of its relative activity in rodent, thereby need new model and render a service in the body J Biol Chem 2002277:14294), with assessment.Inhuman primates (for example Adeps seu carnis Rhiopithecus roxellanae) is known unique animal with the pharmacological action of humanized (humanized) CGRP receptor, be characterized as in its RAMP1 sequence and have the formation peculiar amino acid residue of human receptor's phenotype (Trp74) (Mallee etc., J Biol Chem 2002,277:14294).Because general Nerve in Migraine Model is mainly used rat (Escott etc., Brain Res 1995 669:93; Williamson etc., Cephalalgia1997 17:525), or be invasive terminal procedures (Doods etc. in primate, Br JPharmacol 2000 129:420), a kind of new Noninvasive in inhuman primates, be used to assess the Survival Models of rendeing a service in the body of CGRP-receptor antagonist, as described herein, be an important contribution.Although known stimulation nervi trigeminus can increase the blood flow of brain (Goadsby and Edvinsson, 1993) and facial (Doods etc., 2000), the evidence that finds expression in facial blood flow in the allogenic animal and the direct relation between the arteriae cerebri expansion is still unknown.Therefore, before the research of beginning in inhuman primates, it is arteriodilating alternative that the direct confirmation of elder generation facial blood flow of mensuration laser-Doppler in rat can be used as final research deutocerebrum, the described final arteriae cerebri diameter of research measurement in allogenic animal and the variation of facial blood flow (referring to Fig. 2. the alternate direct proof that the facial blood flow in rat is expanded as arteriae cerebri).In both measurements, inject CGRP by vein and mediate comparable growth, block with peptide antagonists h α CGRP (8-37) then.Thereafter, use h α CGRP (8-37) in the rat of propofol anesthesia, the method validation that vein is injected the facial blood flow change of CGRP mediation is a recovery model.In non-human primates, formulate the existence scheme thereafter, and finish with vein inject the dose-response research that the CGRP activity is a feature (referring to Fig. 3. the dose-response of the facial blood flow h of non-human primates laser-Doppler α CGRP).Use peptide and micromolecule CGRP-receptor antagonist checking non-human primates model.With micromolecule antagonist or h α CGRP (8-37) but pretreatment dosage-dependency ground suppresses the increase that vein injects the facial blood flow of primates that CGRP-stimulates (inhibition that changes referring to the facial blood flow of the non-human primates of Fig. 4 .CGRP-mediation), and do not change blood pressure (referring to of the influence of Fig. 5 .CGRP antagonist) to the non-human primates blood pressure.The facial blood flow that the post processing of antagonist also reverses the CGRP-mediation increases (not shown).These Survival Models provide a kind of restoration methods new, Noninvasive, in order to be evaluated in the non-human primates, or in the transgenic animal that humanized (humanized) RAMP1 (Trp74) (it has similar CGRP receptor pharmacological action) arranged the prevention of CGRP-receptor antagonist and the effect of termination, and as the surrogate markers of a cerebral blood vessel diameter.
Animal.Experimental subject is bull and female common Adeps seu carnis Rhiopithecus roxellanae (Callithrix jacchus), available from Harlan, and body weight 350-500g.Other endogenous expression have Trp 74 RAMP1 mammal or have humanized (humanized) to have the transgene mammal of the RAMP1 of Trp74 also to can be used for the method described in the literary composition.
Anesthesia and surgery are prepared.(4-5% sucks fast, and 1-2.5% keeps in an induction chamber (induction chamber); Solomon etc., 1999) by sucking isoflurane with Animal Anesthesia.Give constant gas supply by face shield or by intubate and ventilation (detecting): air in conjunction with vim and vigour: oxygen (50: 50) and isoflurane, to keep anesthesia.By keeping its body temperature on the temperature automatically controlled surface that is placed on outfit rectum spy (heat) pin is 38 ± 0.5 ℃.Use depilatory cream in facial one or both sides and remove and/or shave off the hair (about 1.5 square centimeters) of a small size.Prune operative region betadine preserved skin (Surgicalareas are clipped and prepared with betadine).Insert a vein circuit to give test compound and CGRP-receptor stimulating agent (agonist) in any enterable vein, if desired, take a blood sample (maximum 2.5mL, 10%) is to carry out courage and uprightness monitoring and content analysis.The glucose solution of venoclysis 5% is to keep blood sugar level.Use the arm cuff method (arm cuff method) and the pulse oximeter of Noninvasive, by measuring blood pressure and heart rate monitoring depth of anesthesia respectively.But vein injects and gives guanethidine 5-10mg/kg, and vein injects additional 5mg/kg changes visible facial blood flow with the blood flow of stablizing repetitive stimulation-mediation peak flow (Escott etc., 1999 more if needed; Be hereby incorporated by).By on skin of face, sticking the laser-Doppler flow probe monitoring microvascular blood flow of self-adhesion.
The compound administration test compound can be by following form administration: intravenous injection (0.01-5mg/kg), intramuscular injection (0.01-0.5ml/kg), subcutaneous injection (0.01-5ml/kg) or oral (0.1-10ml/kg) (Diehl etc., 2001; Be hereby incorporated by).The CGRP-receptor stimulating agent can be by intravenous injection (0.01-5ml/kg), intravenous drip (i.d.) (10-100 μ l/ position) or subcutaneous injection (10-100 μ l/ position) administration.
Laser Doppler flowmeter is by giving vasodilator such as CGRP (0.05-100 μ g/kg intravenous injection) or 2-20pmol/ position intravenous drip (i.d.)) or adrenomedullin (ADM, 0.05-5mg/kg intravenous injection or the intravenous drip of 10-100pmol/ position) cause that the controllability of facial blood flow increases.(pretreatment) or (post processing) administration afterwards before giving vasodilation continuously with test compound or carrier are to provide the ability of assessment prevention or therapeutical effect.Constantly monitor blood pressure to guarantee the appropriate anaesthetization degree of depth, regulate and anaesthetize with maintenance and the maintenance level that numerical value is complementary before handling.During gathering the laser-Doppler data on flows, owing to before the electrophysiologic studies of Adeps seu carnis Rhiopithecus roxellanae is found it to the isoflurane concentration sensitivity, so isoflurane can be reduced to 0.25-0.75% (Solomon, 1999; Be hereby incorporated by).For reducing the quantity of used animal, in single campaign, the effect of test compound to the blood flow change of intravenous injection vasodilation mediation can be repeated nearly 6 times.
Recover (Recovery) and send animal back to the transhipment cage, this cage places a controllable temperature surface, and is warm clear-headed fully and can walk about to it to keep animal.Can be after rest 7-14 days test animal once more, the health status of apparent motion thing can be 7-14 days interval retest animals.
Referring to Diehl KH, Hull R, Morton D, Pfister R, Rabemampianina Y, Smith D, Vidal JM, the administration that van de Vorstenbosch C. is good and take the operating guidance of blood sample comprises administration and sampling approach and capacity.(A good practice guide to the administration ofsubstances and removal of blood, including routes and volumes.) J Appl Toxicol.2001 Jan-Feb; 21 (1): 15-23; Doods H, Hallermayer G, Wu D, Entzeroth M, Rudolf K, Engel W, pharmacology's brief introduction of Eberlein W.BIBN4096BS-first micromolecule CGRP-receptor antagonist optionally.(Pharmacological profile of BIBN4096BS, thefirst selective small molecule CGRP-receptor antagonist.) Br J Pharmacol.2000Feb; 129 (3): 420-3; The pathophysiology of Edvinsson L. calcitonin-gene-related peptide (CGRP) and headache: the complication of treatment.(Calcitonin gene-related peptide (CGRP) and thepathophysiology of headache:therapeutic implications.) CNS Drugs 2001; 15 (10): 745-53; Escott KJ, Beattie DT, Connor HE, Brain SD. increases the skin of face blood flow at rat moderate stimulation trigeminal ganglion: a main effect of calcitonin-gene-related peptide.(Trigeminalganglion stimulation increases facial skin blood flow in the rat:a major role forcalcitonin gene-related peptide.) Brain Res.1995 Jan 9; 669 (1): 93-9; Goadsby PJ, Edvinsson L. nervi trigeminus vascular system and migraine: the The Characteristics of the change of cerebrovascular and neuropeptide in the mankind and the cat.(The trigeminovascular system and migraine:studiescharacterizing cerebrovascular and neuropeptide changes seen in humans andcats.) Ann Neurol.1993 Jan; 33 (1): 48-56; Lassen LH, Haderslev PA, JacobsenVB, Iversen HK, Sperling B, Olsen J.CGRP cause migrainous reason.(CGRP may play a causative role in migraine.) Cephalalgia, 2002,22,54-61; Mallee JJ, Salvatore CA, LeBourdelles B, Oliver KR, Longmore J, Koblan KS, Kane SA.RAMP1 determine the kind selectivity of non-peptide CGRP receptor antagonist.(RAMP1determiners the species selectivity of non-peptide CGRP receptor antagonists.) JBiol Chem.2002 Feb 14[waits to deliver]; Solomon SG, White AJ, temporary transient contrast sensitivity in the lateral geniculate nucleus of Martin PR. New World monkey Callithrix jacchus Adeps seu carnis Rhiopithecus roxellanae.(Temporalcontrast sensitivity in the lateral geniculate nucleus of a New World monkey, themarmoset Callithrix jacchus.) J Physiol.1999 Jun 15; 517 (Pt 3): 907-17; All documents are hereby incorporated by.
Difference with other Nerve in Migraine Model.The present invention proposes a new Nerve in Migraine Model, and is obviously different with other Nerve in Migraine Model.The tangible characteristics of some of the inventive method comprise: (i) the unique migraine life of which kind of apoplexy due to endogenous wind in office; (ii) prove the unique model of CGRP antagonist to termination (post processing) effect of activity mediation blood flow increase; (iii) in allogenic animal, carry out unique proof of the direct relation of facial blood flow and entocranial artery expansion; (iv) use the Noninvasive surgical technic, and do not require that conduit is inserted, unique model of intubate or neuromuscular blockade; (v) use exogenous CGRP passes through CGRP antagonist pretreatment retardance and CGRP antagonist post processing reverse as stimulus object and proof unique primates model; (vi) in the animal of spontaneous respiration, use unique Nerve in Migraine Model of isoflurane anesthesia.This model description is in Williamson etc., and sumatriptan is to the inhibitory action of the expansion of neuropathic pachymeninx blood vessel in the in vivo microscopic study of the rat of anesthesia.(Sumatriptan inhibits neurogenic vasodilationof dural blood vessels in the anaesthetized rat-intravital microscope studies.) Cephalalgia.1997 Jun; 17 (4): 525-31; Williamson DJ, Hargreaves RJ, Hill RG, Shepheard SL. neurokinin agonist and calcitonin-gene-related peptide in the rat of anesthesia to the in vivo microscopic study of the effect of the diameter of pachymeninx blood vessel.(Intravital microscope studieson the effects of neurokinin agonists and calcitonin gene-related peptide on duralvessel diameter in the anaesthetized rat.) Cephalalgia.1997 Jun; 17 (4): 518-24; Escott KJ etc., the nervi trigeminus knot stimulates in rat increases the skin of face blood flow: a main effect of calcitonin-gene-related peptide.(Trigeminal ganglion stimulation increases facial skin bloodflow in the rat:a major role for calcitonin gene-related peptide.) Brain Res.1995Jan 9; 669 (1): 93-9; Chu DQ etc., calcitonin-gene-related peptide (CGRP) antagonist CGRP (8-37) blocks the expansion at the rat skin medium vessels of inflammation: also relate to adrenomedullin except that CGRP.(Thecalcitonin gene-related peptide (CGRP) antagonist CGRP (8-37) blocksvasodilatation in inflamed rat skin:involvement of adrenomedullin in addition toCGRP.) Neurosci Lett.2001 Sep 14; 310 (2-3): 169-72; Escott KJ, Brain SD. calcitonin-gene-related peptide antagonist (CGRP8-37) is to the cutaneous vasodilation that causes by stimulation in rats saphena nerve and the effect of edema.(Effct of a calcitonin gene-related peptide antagonist (CGRP8-37) on skin vasodilatation and oedema induced by stimulation of the ratsaphenous nerve.) Br J Pharmacol.1993 Oct; 110 (2): 772-6; Hall JM, Siney L, Lippton H, Hyman A, Kang-Chang J, human adrenomedullin 13-53 of Brain SD. and the interaction of calcitonin gene related peptide receptor in the microvasculature of rat and hamster.(Interactionof human adrenomedullin 13-52 with calcitonin gene-related peptide receptors inthe microvasculature of the rat and hamster.) Br J Pharmacol.1995 Feb; 114 (3): 592-7; Hall JM, Brain SD.amylin and the calcitonin gene related peptide receptor intravital interaction in the microvasculature of hamster cheek pouch.(Interaction of amylin with calcitoningene-related peptide receptors in the microvasculature of the hamster cheekpouch in vivo.) Br J Pharmacol.1999 Jan; 126 (1): 280-4; And Doods H, Hallermayer G, Wu D, Entzeroth M, Rudolf K, Engel W, pharmacology's brief introduction of Eberlein W.BIBN4096BS: first is micromolecule CGRP-receptor antagonist (Pharmacological profile of BIBN4096BS, the first selective small moleculeCGRP-receptor antagonist.) Br J Pharmacol.2000 Feb optionally; 129 (3): 420-3, above document all fails to comprise the notable attribute of the inventive method.
In following table, the represented meaning of result is as follows: W≤25%; 25%＜X≤50%; 50%＜Y≤75%; Z＞75%.
The inhibition that the facial blood flow of laser-Doppler of table 6. CGRP-mediation in non--human primates (for example common Adeps seu carnis Rhiopithecus roxellanae) increases
The increase of the facial blood flow of laser-Doppler of non--human primates (suppressing %) CGRP-mediation (10 μ g/kg, intravenous injection)
Embodiment # 0.01mg/kg，iv 0.03mg/kg，iv 0.1mg/kg，iv 0.3mg/kg，iv 1mg/kg，iv
2 W X X Y Z
6 Z
16 Y
69 Y Z
hCGRP(8-37) Z
W≤25％；25％＜X≤50％；50％＜Y≤75％；Z＞75％.
Referring to of the effect of Fig. 5 .CGRP antagonist to non--human primates blood pressure.

Claims (6)

1. be selected from following chemical compound:
(±)-3-(3-cyano-1 H-indol--5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-methyl propionate;
(±)-4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(3-cyano-1 H-indol--5-base-methyl)-2-oxo-ethyl]-amide;
(±)-4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(3-cyano group-7-Methyl-1H-indole-5-base-methyl)-2-oxo-ethyl]-amide;
(±)-3-(7-isopropyl-1H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-methyl propionate;
(±)-4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(7-isopropyl-1H-indazole-5-base-methyl)-2-oxo-ethyl]-amide;
(±)-4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(7-ethyl-1H-indazole-5-base-methyl)-2-oxo-ethyl]-amide;
(±)-4-(2,2-dioxo-1,4-dihydro-2H-2 λ 6-benzo [1,2,6] thiadiazine-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(7-methyl isophthalic acid H-indazole-5-base-methyl)-2-oxo-ethyl]-amide;
(±)-4-(2,2-dioxo-1,4-dihydro-2H-2 λ 6-benzo [1,2,6] thiadiazine-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(7-ethyl-3-methyl isophthalic acid H-indazole-5-base-methyl)-2-oxo-ethyl]-amide;
(±)-2-[4-(6-cyano group-2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino]-3-(7-methyl isophthalic acid H-indazole-5-yl)-methyl propionate;
(±)-4-(6-cyano group-2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid 2-[1,4 '] connection piperidines-1 '-Ji-1-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-2-oxo-ethyl }-amide;
(±)-4-(2-oxo-1,2,4,5-tetrahydrochysene-benzo [d] [1,3] diaza -3-base-1-carboxylic acid 2-[1,4 '] connection piperidines-1 '-Ji-1-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-2-oxo-ethyl }-amide;
(±)-4-(6-hydroxyl-2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid 2-[1,4 '] connection piperidines-1 '-Ji-1-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-2-oxo-ethyl }-amide;
(±)-4-(8-methoxyl group-2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid 2-[1,4 '] connection piperidines-1 '-Ji-1-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-2-oxo-ethyl }-amide;
(±)-4-(8-chloro-2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid 2-[1,4 '] connection piperidines-1 '-Ji-1-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-2-oxo-ethyl }-amide;
(±)-N-(3-(7-ethyl-3-methyl isophthalic acid H-indazole-5-yl)-1-oxo-1-(4-(piperidines-1-yl) piperidines-1-yl) third-2-yl)-2 ', 3 '-dihydro-2 '-oxo spiral shell-(piperidines-4,4 '-quinazoline)-1-Methanamide;
(±)-N-(3-(7-ethyl-3-methyl 1H-indazole-5-yl)-1-oxo-1-(4-(piperidines-1-yl) piperidines-1-yl) third-2-yl)-2,4-dihydro-2 '-oxo spiral shell-(piperidines-4,4 '-1H-benzo [d] [1,3]  piperazine)-1-Methanamide;
(±)-N-(3-(7-ethyl-1H-indazole-5-yl)-1-(6, the 7-dihydro-1 h-pyrazole is [4,3-c] pyridines-5 (4H)-yl)-1-oxo third-2-yl also)-4-(1,2-dihydro-2-oxo-quinazoline-3 (4H)-yl) piperidines-1-Methanamide;
(±)-N-(3-(7-ethyl-1H-indazole-5-yl)-1-(6,7-dihydro-7,7-dimethyl-1H-pyrazolo [4,3-c] pyridines-5 (4H)-yl)-1-oxo third-2-yl)-4-(1,2-dihydro-2-oxo-quinazoline-3 (4H)-yl) piperidines-1-Methanamide;
(±)-methyl 2-(4-(8-fluoro-1,2-dihydro-2-oxo-quinazoline-3 (4H)-yl) piperidines-1-formamido)-3-(7-methyl isophthalic acid H-indazole-5-yl) propionic ester;
(±)-4-(8-fluoro-1,2-dihydro-2-oxo-quinazoline-3 (4H)-yl)-N-(3-(7-methyl isophthalic acid H-indazole-5-yl)-1-oxo-1-(4-(piperidines-1-yl) piperidines-1-yl) third-2-yl) piperidines-1-Methanamide;
(±)-4-(8-fluoro-1,2-dihydro-2-oxo-quinazoline-3 (4H)-yl)-N-(3-(7-methyl isophthalic acid H-indazole-5-yl)-1-oxo-1-(4-phenylpiperazine-1-yl) third-2-yl) piperidines-1-Methanamide;
(±)-4-(8-fluoro-1,2-dihydro-2-oxo-quinazoline-3 (4H)-yl)-N-(1-(4-(4-fluorophenyl) piperazine-1-yl)-3-(7-methyl isophthalic acid H-indazole-5-yl)-1-oxo third-2-yl) piperidines-1-Methanamide;
(±)-4-(8-fluoro-1,2-dihydro-2-oxo-quinazoline-3 (4H)-yl)-N-(1-(4-(2-fluorophenyl) piperazine-1-yl)-3-(7-methyl isophthalic acid H-indazole-5-yl)-1-oxo third-2-yl) piperidines-1-Methanamide;
(±)-4-(8-fluoro-1,2-dihydro-2-oxo-quinazoline-3 (4H)-yl)-N-(3-(7-methyl isophthalic acid H-indazole-5-yl)-1-oxo-1-(4-o-tolyl piperazine-1-yl) third-2-yl) piperidines-1-Methanamide;
(±)-methyl 2-(4-(8-fluoro-1,2-dihydro-2-oxo-quinazoline-3 (4H)-yl) piperidines-1-formamido)-3-(7-ethyl-3-methyl isophthalic acid H-indazole-5-yl) propionic ester;
(±)-N-(3-(7-ethyl-3-methyl isophthalic acid H-indazole-5-yl)-1-oxo-1-(4-(piperidines-1-yl) piperidines-1-yl) third-2-yl)-4-(8-fluoro-1,2-dihydro-2-oxo-quinazoline-3 (4H)-yl) piperidines-1-Methanamide;
(R)-N-((R)-3-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-1-oxo-1-(4-(piperidines-1-yl) piperidines-1-yl) third-2-yl)-4-(8-fluoro-1,2-dihydro-2-oxo-quinazoline-3 (4H)-yl) piperidines-1-Methanamide;
(±)-N-(3-(7-methyl isophthalic acid H-indazole-5-yl)-1-oxo-1-(4-(piperidines-1-yl) piperidines-1-yl) third-2-yl)-8 '-fluoro-2 ', 3 '-dihydro-2 '-oxo spiral shell-(piperidines-4,4 '-quinazoline)-1-Methanamide;
(±)-4-(8-fluoro-1,2-dihydro-2,4-dioxo quinazoline-3 (4H)-yl)-N-(3-(7-methyl isophthalic acid H-indazole-5-yl)-1-oxo-1-(4-(piperidines-1-yl) piperidines-1-yl) third-2-yl) piperidines-1-Methanamide;
N-((R)-3-(2-(trifluoromethyl)-1H-benzo [d] imidazoles-5-yl)-1-oxo-1-(4-(piperidines-1-yl) piperidines-1-yl) third-2-yl)-4-(1,2-dihydro-2-oxo-quinazoline-3 (4H)-yl) piperidines-1-Methanamide;
N-((R)-1-(formyl-dimethylamino)-2-(2-(trifluoromethyl)-1H-benzo [d] imidazoles-5-yl) ethyl)-4-(1,2-dihydro-2-oxo-quinazoline-3 (4H)-yl) piperidines-1-Methanamide;
(R)-methyl 2-(4-(1,2-dihydro-2-oxo-quinazoline-3 (4H)-yl) piperidines-1-formamido)-3-(2,3-dihydro-2-oxo--1H-benzo [d] imidazoles-6-yl) propionic ester;
N-((R)-3-(2,3-dihydro-2-oxo--1H-benzo [d] imidazoles-6-yl)-1-oxo-1-(4-piperidines-1-yl) piperidines-1-yl) third-2-yl)-and 4-(1,2-dihydro-2-oxo-quinazoline-3 (4H)-yl) piperidines-1-Methanamide;
N-((R)-1-(formyl-dimethylamino)-2-(2,3-dihydro-2-oxo--1H-benzo [d] imidazoles-6-yl) ethyl)-4-(1,2-dihydro-2-oxo-quinazoline-3 (4H)-yl) piperidines-1-Methanamide;
N-((R)-3-(2,3-dihydro-2-oxo--1H-benzo [d] imidazoles-6-yl)-1-oxo-1-(4-piperidines-1-yl) piperidines-1-yl) third-2-yl)-4-(2 ', 3 '-dihydro-2 '-oxo spiral shell (piperidines-4,4 '-(1H)-quinazoline) Methanamide;
4-(1,2-dihydro-2,4-dioxo quinazoline-3 (4H)-yl)-N-((R)-3-(7-methyl isophthalic acid H-benzo [d] [1,2,3] triazole-5-yl)-1-oxo-1-(4-(piperidines-1-yl) piperidines-1-yl) third-2-yl) piperidines-1-Methanamide;
(R)-4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-(4-cyclohexyl-piperazine-1-yl)-2-oxo-1-(2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-ethyl]-amide;
(R)-4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-(4-isopropyl-piperazine-1-yl)-2-oxo-1-(2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-ethyl]-amide;
(R)-and N-((R)-3-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-1-oxo-1-(4-(piperidines-1-yl) piperidines-1-yl) third-2-yl)-2,4-dihydro-2 '-oxo spiral shell-(piperidines-4,4 '-1H-benzo [d] [1,3]  piperazine)-1-Methanamide;
(R)-and N-((R)-3-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-1-oxo-1-(4-(hexamethylene-1-yl) piperazine-1-yl) third-2-yl)-2,4-dihydro-2 '-oxo spiral shell-(piperidines-4,4 '-1H-benzo [d] [1,3]  piperazine)-1-Methanamide;
(R)-and N-((R)-3-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-1-oxo-1-(4-(third-2-yl) piperazine-1-yl) third-2-yl)-2,4-dihydro-2 '-oxo spiral shell-(piperidines-4,4 '-1H-benzo [d] [1,3]  piperazine)-1-Methanamide;
(R)-and N-((R)-3-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-1-oxo-1-(4-(piperidines-1-yl) piperidines-1-yl) third-2-yl)-2,4-dihydro-2 '-oxo spiral shell-(piperidines-4,4 '-1H-quinazoline)-1-Methanamide;
(R)-and N-((R)-3-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-1-oxo-1-(4-(hexamethylene-1-yl) piperazine-1-yl) third-2-yl)-2,4-dihydro-2 '-oxo spiral shell-(piperidines-4,4 '-1H-quinazoline)-1-Methanamide;
(R)-and N-((R)-3-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-1-oxo-1-(4-(third-2-yl) piperazine-1-yl) third-2-yl)-2,4-dihydro-2 '-oxo spiral shell-(piperidines-4,4 '-1H-quinazoline)-1-Methanamide;
(R)-4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(4-chloro-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-ethyl]-amide;
(R)-4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(5-chloro-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-ethyl]-amide;
(R)-4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(4-bromo-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-ethyl]-amide;
(R)-4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(5-bromo-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-ethyl]-amide;
(R)-4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(4-iodo-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-ethyl]-amide;
(±)-N-(1-benzyl-2-hydroxyl-ethyl)-2-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-4-oxo 4-[1 ', 2 '-dihydro-2 '-oxo spiral shell-[4H-3 ', 1-benzoxazine-4,4 '-piperidyl]-butyramide;
(±)-N-(1-benzyl-2-hydroxyl-ethyl)-2-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-yl]-butyramide;
(±)-phenyl-acetic acid N '-2-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-yl]-bytyry }-hydrazides;
(±)-1-[1,4 '] connection piperidines-1 '-Ji-4-[4-(8-fluoro-2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-yl]-2-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-butane-1, the 4-diketone;
(±)-1-[1,4 '] connection piperidines-1 '-Ji-2-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-4-[2 ', 3 '-dihydro-2 '-oxo spiral shell-(piperidines-4,4 '-quinazoline]-butane-1, the 4-diketone;
(±)-1-(4-cyclohexyl-piperazine-1-yl)-2-(2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-4-[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-yl]-butane-1, the 4-diketone;
(±)-1-[1,4 '] connection piperidines-1 '-Ji-2-(2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-4-[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-yl]-butane-1, the 4-diketone;
(±)-1-[1,4 '] connection piperidines-1 '-Ji-2-(2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-4-[2 ', 3 '-dihydro-2 '-oxo spiral shell-(piperidines-4,4 '-quinazoline)]-butane-1, the 4-diketone;
(±)-1-(4-cyclohexyl-piperazine-1-yl)-2-(2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-4-[2 ', 3 '-dihydro-2 '-oxo spiral shell-(piperidines-4,4 '-quinazoline)]-butane-1, the 4-diketone;
(±)-4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-(4-cyclohexyl-piperazine-1-yl)-1-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-2-oxo-ethyl]-amide;
(±)-4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[4-(4-fluoro-phenyl)-piperazine-1-yl]-1-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-2-oxo-ethyl]-amide;
(±)-3-(7-methyl isophthalic acid H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-the propanoic acid tert-butyl ester;
(±)-3-(7-methyl isophthalic acid H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-propanoic acid 1-methyl cyclohexane ester;
(±)-3-(7-methyl isophthalic acid H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-propanoic acid 1-aza-bicyclo [2.2.2] oct-3-yl ester;
(±)-3-(7-methyl isophthalic acid H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-propanoic acid piperidin-4-yl ester;
(±)-4-(3-(7-methyl isophthalic acid H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-propionyloxy)-piperidines-1-carboxylic acid tert-butyl ester;
(±)-3-(7-methyl isophthalic acid H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-propanoic acid 3,4,5,6-tetrahydrochysene-2H-[1,4 '] bipyridyl-4-base ester;
(±)-3-(7-methyl isophthalic acid H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-propanoic acid 1-diethylamino-1-methyl-ethyl ester;
(±)-3-(7-methyl isophthalic acid H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-propanoic acid 1,1-dimethyl-2-phenyl-ethyl ester;
(±)-3-(7-methyl isophthalic acid H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-propanoic acid 1,1-dimethyl-3-phenyl-propyl ester;
(±)-3-(7-methyl isophthalic acid H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-ethyl propionate;
(±)-1-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-2-[1-pyridin-4-yl-methyl]-the 2-oxoethyl]-2 ', 3 '-dihydro-2 '-oxo spiral shell-[piperidines-4,4 '-(1H)-quinazoline]-1-Methanamide;
(±)-1-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-2-[1-pyridin-4-yl-piperazinyl]-the 2-oxoethyl]-2 ', 3 '-dihydro-2 '-oxo spiral shell-[piperidines-4,4 '-(1H)-quinazoline]-1-Methanamide;
(±)-1-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-2-[(2-dimethylamino-ethyl-ethylamino formoxyl)-and the 2-oxoethyl]-2 ', 3 '-dihydro-2 '-oxo spiral shell-[piperidines-4,4 '-(1H)-quinazoline]-1-Methanamide;
(±)-1-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-2-[1-pyridin-4-yl-piperazinyl]-the 2-oxoethyl]-1 ', 2 '-dihydro-2 '-oxo spiral shell-[4H-3 ', 1-benzoxazine-4,4 '-piperidines]-the 1-Methanamide;
(±)-1-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-2-[1-pyridine-2-base-piperazinyl]-the 2-oxoethyl]-1 ', 2 '-dihydro-2 '-oxo spiral shell-[4H-3 ', 1-benzoxazine-4,4 '-piperidines]-the 1-Methanamide;
(R)-and 4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1d-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-2-oxo-ethyl] amide; With
(R)-1-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-2-[1,4-joins piperidines]-1-base-2-oxoethyl]-2 ', 3 '-dihydro-2 '-oxo spiral shell-[piperidines-4,4 '-(1H)-quinazoline]-1-Methanamide;
Or its pharmaceutically acceptable salt or solvate.
2. be selected from following chemical compound:
4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(7-bromo-1H-indazole-5-ylmethyl)-2-oxo-ethyl]-amide;
4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-oxo-1-(2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-(4-pyridin-4-yl-piperazine-1-yl)-ethyl]-amide;
4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-oxo-1-(2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-piperidines-1-base-ethyl]-amide;
4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-(4-methyl-piperazine-1-yl)-2-oxo-1-(2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-ethyl]-amide;
4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(4-methyl-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-ethyl]-amide;
4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [1-(4-methyl-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-2-piperidines-1-base-ethyl]-amide;
4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [1-(4-chloro-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-2-piperidines-1-base-ethyl]-amide;
4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [1-formyl-dimethylamino-2-(4-methyl-2-oxo-2,3-dihydro-benzoxazol-6-yl)-ethyl]-amide;
4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-(4-chloro-2-oxo-2,3-dihydro-benzoxazol-6-yl)-1-formyl-dimethylamino-ethyl]-amide;
4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [1-(4-methyl-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-2-(4-pyridin-4-yl-piperazine-1-yl)-ethyl]-amide;
4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [1-(4-chloro-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-2-(4-pyridin-4-yl-piperazine-1-yl)-ethyl]-amide;
4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(4-ethyl-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-ethyl]-amide;
4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(7-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-ylmethyl)-2-oxo-ethyl]-amide;
4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(7-chloro-2-oxo-2,3-dihydro-1H-benzimidazole-5-ylmethyl)-2-oxo-ethyl]-amide;
4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(7-ethyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-ylmethyl)-2-oxo-ethyl]-amide;
4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-ylmethyl)-2-oxo-ethyl]-amide;
4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(3,7-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-ylmethyl)-2-oxo-ethyl]-amide;
4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(7-chloro-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-ylmethyl)-2-oxo-ethyl]-amide;
4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(7-ethyl-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-ylmethyl)-2-oxo-ethyl]-amide;
3-(7-methyl isophthalic acid H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-isopropyl propionate;
3-(7-chloro-1H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-isopropyl propionate;
3-(7-ethyl-1H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-isopropyl propionate;
3-(7-chloro-1H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-the propanoic acid tert-butyl ester;
3-(7-ethyl-1H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-the propanoic acid tert-butyl ester;
3-(7-chloro-1H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-cyclohexyl propionate;
3-(7-ethyl-1H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-cyclohexyl propionate;
3-(7-chloro-1H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-propanoic acid 1-methyl-piperidin-4-yl ester;
3-(7-ethyl-1H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-propanoic acid 1-methyl-piperidin-4-yl ester;
3-(7-chloro-1H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-propanoic acid 1-methyl-cyclohexyl ester;
3-(7-ethyl-1H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-propanoic acid 1-methyl-cyclohexyl ester;
3-(7-chloro-1H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-propanoic acid 4-phenyl-cyclohexyl; With
3-(7-ethyl-1H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-propanoic acid 4-phenyl-cyclohexyl;
Or its pharmaceutically acceptable salt or solvate.
3. pharmaceutical composition, it comprises and is selected from following chemical compound:
(±)-3-(3-cyano-1 H-indol--5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-methyl propionate;
(±)-4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(3-cyano-1 H-indol--5-base-methyl)-2-oxo-ethyl]-amide;
(±)-4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(3-cyano group-7-Methyl-1H-indole-5-base-methyl)-2-oxo-ethyl]-amide;
(±)-3-(7-isopropyl-1H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-methyl propionate;
(±)-4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(7-isopropyl-1H-indazole-5-base-methyl)-2-oxo-ethyl]-amide;
(±)-4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(7-ethyl-1H-indazole-5-base-methyl)-2-oxo-ethyl]-amide;
(±)-4-(2,2-dioxo-1,4-dihydro-2H-2 λ 6-benzo [1,2,6] thiadiazine-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(7-methyl isophthalic acid H-indazole-5-base-methyl)-2-oxo-ethyl]-amide;
(±)-4-(2,2-dioxo-1,4-dihydro-2H-2 λ 6-benzo [1,2,6] thiadiazine-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(7-ethyl-3-methyl isophthalic acid H-indazole-5-base-methyl)-2-oxo-ethyl]-amide;
(±)-2-[4-(6-cyano group-2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino]-3-(7-methyl isophthalic acid H-indazole-5-yl)-methyl propionate;
(±)-4-(6-cyano group-2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid 2-[1,4 '] connection piperidines-1 '-Ji-1-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-2-oxo-ethyl }-amide;
(±)-4-(2-oxo-1,2,4,5-tetrahydrochysene-benzo [d] [1,3] diaza -3-base-1-carboxylic acid 2-[1,4 '] connection piperidines-1 '-Ji-1-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-2-oxo-ethyl }-amide;
(±)-4-(6-hydroxyl-2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid 2-[1,4 '] connection piperidines-1 '-Ji-1-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-2-oxo-ethyl }-amide;
(±)-4-(8-methoxyl group-2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid 2-[1,4 '] connection piperidines-1 '-Ji-1-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-2-oxo-ethyl }-amide;
(±)-4-(8-chloro-2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid 2-[1,4 '] connection piperidines-1 '-Ji-1-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-2-oxo-ethyl }-amide;
(±)-N-(3-(7-ethyl-3-methyl isophthalic acid H-indazole-5-yl)-1-oxo-1-(4-(piperidines-1-yl) piperidines-1-yl) third-2-yl)-2 ', 3 '-dihydro-2 '-oxo spiral shell-(piperidines-4,4 '-quinazoline)-1-Methanamide;
(±)-N-(3-(7-ethyl-3-methyl 1H-indazole-5-yl)-1-oxo-1-(4-(piperidines-1-yl) piperidines-1-yl) third-2-yl)-2,4-dihydro-2 '-oxo spiral shell-(piperidines-4,4 '-1H-benzo [d] [1,3]  piperazine)-1-Methanamide;
(±)-N-(3-(7-ethyl-1H-indazole-5-yl)-1-(6, the 7-dihydro-1 h-pyrazole is [4,3-c] pyridines-5 (4H)-yl)-1-oxo third-2-yl also)-4-(1,2-dihydro-2-oxo-quinazoline-3 (4H)-yl) piperidines-1-Methanamide;
(±)-N-(3-(7-ethyl-1H-indazole-5-yl)-1-(6,7-dihydro-7,7-dimethyl-1H-pyrazolo [4,3-c] pyridines-5 (4H)-yl)-1-oxo third-2-yl)-4-(1,2-dihydro-2-oxo-quinazoline-3 (4H)-yl) piperidines-1-Methanamide;
(±)-methyl 2-(4-(8-fluoro-1,2-dihydro-2-oxo-quinazoline-3 (4H)-yl) piperidines-1-formamido)-3-(7-methyl isophthalic acid H-indazole-5-yl) propionic ester;
(±)-4-(8-fluoro-1,2-dihydro-2-oxo-quinazoline-3 (4H)-yl)-N-(3-(7-methyl isophthalic acid H-indazole-5-yl)-1-oxo-1-(4-(piperidines-1-yl) piperidines-1-yl) third-2-yl) piperidines-1-Methanamide;
(±)-4-(8-fluoro-1,2-dihydro-2-oxo-quinazoline-3 (4H)-yl)-N-(3-(7-methyl isophthalic acid H-indazole-5-yl)-1-oxo-1-(4-phenylpiperazine-1-yl) third-2-yl) piperidines-1-Methanamide;
(±)-4-(8-fluoro-1,2-dihydro-2-oxo-quinazoline-3 (4H)-yl)-N-(1-(4-(4-fluorophenyl) piperazine-1-yl)-3-(7-methyl isophthalic acid H-indazole-5-yl)-1-oxo third-2-yl) piperidines-1-Methanamide;
(±)-4-(8-fluoro-1,2-dihydro-2-oxo-quinazoline-3 (4H)-yl)-N-(1-(4-(2-fluorophenyl) piperazine-1-yl)-3-(7-methyl isophthalic acid H-indazole-5-yl)-1-oxo third-2-yl) piperidines-1-Methanamide;
(±)-4-(8-fluoro-1,2-dihydro-2-oxo-quinazoline-3 (4H)-yl)-N-(3-(7-methyl isophthalic acid H-indazole-5-yl)-1-oxo-1-(4-o-tolyl piperazine-1-yl) third-2-yl) piperidines-1-Methanamide;
(±)-methyl 2-(4-(8-fluoro-1,2-dihydro-2-oxo-quinazoline-3 (4H)-yl) piperidines-1-formamido)-3-(7-ethyl-3-methyl isophthalic acid H-indazole-5-yl) propionic ester;
(±)-N-(3-(7-ethyl-3-methyl isophthalic acid H-indazole-5-yl)-1-oxo-1-(4-(piperidines-1-yl) piperidines-1-yl) third-2-yl)-4-(8-fluoro-1,2-dihydro-2-oxo-quinazoline-3 (4H)-yl) piperidines-1-Methanamide;
(R)-N-((R)-3-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-1-oxo-1-(4-(piperidines-1-yl) piperidines-1-yl) third-2-yl)-4-(8-fluoro-1,2-dihydro-2-oxo-quinazoline-3 (4H)-yl) piperidines-1-Methanamide;
(±)-N-(3-(7-methyl isophthalic acid H-indazole-5-yl)-1-oxo-1-(4-(piperidines-1-yl) piperidines-1-yl) third-2-yl)-8 '-fluoro-2 ', 3 '-dihydro-2 '-oxo spiral shell-(piperidines-4,4 '-quinazoline)-1-Methanamide;
(±)-4-(8-fluoro-1,2-dihydro-2,4-dioxo quinazoline-3 (4H)-yl)-N-(3-(7-methyl isophthalic acid H-indazole-5-yl)-1-oxo-1-(4-(piperidines-1-yl) piperidines-1-yl) third-2-yl) piperidines-1-Methanamide;
N-((R)-3-(2-(trifluoromethyl)-1H-benzo [d] imidazoles-5-yl)-1-oxo-1-(4-(piperidines-1-yl) piperidines-1-yl) third-2-yl)-4-(1,2-dihydro-2-oxo-quinazoline-3 (4H)-yl) piperidines-1-Methanamide;
N-((R)-1-(formyl-dimethylamino)-2-(2-(trifluoromethyl)-1H-benzo [d] imidazoles-5-yl) ethyl)-4-(1,2-dihydro-2-oxo-quinazoline-3 (4H)-yl) piperidines-1-Methanamide;
(R)-methyl 2-(4-(1,2-dihydro-2-oxo-quinazoline-3 (4H)-yl) piperidines-1-formamido)-3-(2,3-dihydro-2-oxo--1H-benzo [d] imidazoles-6-yl) propionic ester;
N-((R)-3-(2,3-dihydro-2-oxo--1H-benzo [d] imidazoles-6-yl)-1-oxo-1-(4-piperidines-1-yl) piperidines-1-yl) third-2-yl)-and 4-(1,2-dihydro-2-oxo-quinazoline-3 (4H)-yl) piperidines-1-Methanamide;
N-((R)-1-(formyl-dimethylamino)-2-(2,3-dihydro-2-oxo--1H-benzo [d] imidazoles-6-yl) ethyl)-4-(1,2-dihydro-2-oxo-quinazoline-3 (4H)-yl) piperidines-1-Methanamide;
N-((R)-3-(2,3-dihydro-2-oxo--1H-benzo [d] imidazoles-6-yl)-1-oxo-1-(4-piperidines-1-yl) piperidines-1-yl) third-2-yl)-4-(2 ', 3 '-dihydro-2 '-oxo spiral shell (piperidines-4,4 '-(1H)-quinazoline) Methanamide;
4-(1,2-dihydro-2,4-dioxo quinazoline-3 (4H)-yl)-N-((R)-3-(7-methyl isophthalic acid H-benzo [d] [1,2,3] triazole-5-yl)-1-oxo-1-(4-(piperidines-1-yl) piperidines-1-yl) third-2-yl) piperidines-1-Methanamide;
(R)-4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-(4-cyclohexyl-piperazine-1-yl)-2-oxo-1-(2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-ethyl]-amide;
(R)-4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-(4-isopropyl-piperazine-1-yl)-2-oxo-1-(2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-ethyl]-amide;
(R)-and N-((R)-3-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-1-oxo-1-(4-(piperidines-1-yl) piperidines-1-yl) third-2-yl)-2,4-dihydro-2 '-oxo spiral shell-(piperidines-4,4 '-1H-benzo [d] [1,3]  piperazine)-1-Methanamide;
(R)-and N-((R)-3-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-1-oxo-1-(4-(hexamethylene-1-yl) piperazine-1-yl) third-2-yl)-2,4-dihydro-2 '-oxo spiral shell-(piperidines-4,4 '-1H-benzo [d] [1,3]  piperazine)-1-Methanamide;
(R)-and N-((R)-3-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-1-oxo-1-(4-(third-2-yl) piperazine-1-yl) third-2-yl)-2,4-dihydro-2 '-oxo spiral shell-(piperidines-4,4 '-1H-benzo [d] [1,3]  piperazine)-1-Methanamide;
(R)-and N-((R)-3-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-1-oxo-1-(4-(piperidines-1-yl) piperidines-1-yl) third-2-yl)-2,4-dihydro-2 '-oxo spiral shell-(piperidines-4,4 '-1H-quinazoline)-1-Methanamide;
(R)-and N-((R)-3-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-1-oxo-1-(4-(hexamethylene-1-yl) piperazine-1-yl) third-2-yl)-2,4-dihydro-2 '-oxo spiral shell-(piperidines-4,4 '-1H-quinazoline)-1-Methanamide;
(R)-and N-((R)-3-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-1-oxo-1-(4-(third-2-yl) piperazine-1-yl) third-2-yl)-2,4-dihydro-2 '-oxo spiral shell-(piperidines-4,4 '-1H-quinazoline)-1-Methanamide;
(R)-4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(4-chloro-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-ethyl]-amide;
(R)-4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(5-chloro-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-ethyl]-amide;
(R)-4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(4-bromo-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-ethyl]-amide;
(R)-4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(5-bromo-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-ethyl]-amide;
(R)-4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(4-iodo-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-ethyl]-amide;
(±)-N-(1-benzyl-2-hydroxyl-ethyl)-2-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-4-oxo-4-[1 ', 2 '-dihydro-2 '-oxo spiral shell-[4H-3 ', 1-benzoxazine-4,4 '-piperidyl]-butyramide;
(±)-N-(1-benzyl-2-hydroxyl-ethyl)-2-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-yl]-butyramide;
(±)-phenyl-acetic acid N '-2-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-yl]-bytyry }-hydrazides;
(±)-1-[1,4 '] connection piperidines-1 '-Ji-4-[4-(8-fluoro-2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-yl]-2-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-butane-1, the 4-diketone;
(±)-1-[1,4 '] connection piperidines-1 '-Ji-2-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-4-[2 ', 3 '-dihydro-2 '-oxo spiral shell-(piperidines-4,4 '-quinazoline]-butane-1, the 4-diketone;
(±)-1-(4-cyclohexyl-piperazine-1-yl)-2-(2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-4-[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-yl]-butane-1, the 4-diketone;
(±)-1-[1,4 '] connection piperidines-1 '-Ji-2-(2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-4-[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-yl]-butane-1, the 4-diketone;
(±)-1-[1,4 '] connection piperidines-1 '-Ji-2-(2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-4-[2 ', 3 '-dihydro-2 '-oxo spiral shell-(piperidines-4,4 '-quinazoline)]-butane-1, the 4-diketone;
(±)-1-(4-cyclohexyl-piperazine-1-yl)-2-(2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-4-[2 ', 3 '-dihydro-2 '-oxo spiral shell-(piperidines-4,4 '-quinazoline)]-butane-1, the 4-diketone;
(±)-4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-(4-cyclohexyl-piperazine-1-yl)-1-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-2-oxo-ethyl]-amide;
(±)-4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[4-(4-fluoro-phenyl)-piperazine-1-yl]-1-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-2-oxo-ethyl]-amide;
(±)-3-(7-methyl isophthalic acid H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-the propanoic acid tert-butyl ester;
(±)-3-(7-methyl isophthalic acid H-indazole-5-yl)-2-{[4-(2-oxo-1,4--hydrogen-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-propanoic acid 1-methyl cyclohexane ester;
(±)-3-(7-methyl isophthalic acid H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-propanoic acid 1-aza-bicyclo [2.2.2] oct-3-yl ester;
(±)-3-(7-methyl isophthalic acid H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-propanoic acid piperidin-4-yl ester;
(±)-4-(3-(7-methyl isophthalic acid H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-propionyloxy)-piperidines-1-carboxylic acid tert-butyl ester;
(±)-3-(7-methyl isophthalic acid H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-propanoic acid 3,4,5,6-tetrahydrochysene-2H-[1,4 '] bipyridyl-4-base ester;
(±)-3-(7-methyl isophthalic acid H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-propanoic acid 1-diethylamino-1-methyl-ethyl ester;
(±)-3-(7-methyl isophthalic acid H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-propanoic acid 1,1-dimethyl-2-phenyl-ethyl ester;
(±)-3-(7-methyl isophthalic acid H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-propanoic acid 1,1-dimethyl-3-phenyl-propyl ester;
(±)-3-(7-methyl isophthalic acid H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-ethyl propionate;
(±)-1-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-2-[1-pyridin-4-yl-methyl]-the 2-oxoethyl]-2 ', 3 '-dihydro-2 '-oxo spiral shell-[piperidines-4,4 '-(1H)-quinazoline]-1-Methanamide;
(±)-1-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-2-[1-pyridin-4-yl-piperazinyl]-the 2-oxoethyl]-2 ', 3 '-dihydro-2 '-oxo spiral shell-[piperidines-4,4 '-(1H)-quinazoline]-1-Methanamide;
(±)-1-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-2-[(2-dimethylamino-ethyl-ethylamino formoxyl)-and the 2-oxoethyl]-2 ', 3 '-dihydro-2 '-oxo spiral shell-[piperidines-4,4 '-(1H)-quinazoline]-1-Methanamide;
(±)-1-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-2-[1-pyridin-4-yl-piperazinyl]-the 2-oxoethyl]-1 ', 2 '-dihydro-2 '-oxo spiral shell-[4H-3 ', 1-benzoxazine-4,4 '-piperidines]-the 1-Methanamide;
(±)-1-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-2-[1-pyridine-2-base-piperazinyl]-the 2-oxoethyl]-1 ', 2 '-dihydro-2 '-oxo spiral shell-[4H-3 ', 1-benzoxazine-4,4 '-piperidines]-the 1-Methanamide;
(R)-and 4-(2-oxo-1,4-dihydro-2H-quinazoline-3 base)-piperidines-1d-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-2-oxo-ethyl] amide; With
(R)-1-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-2-[1,4-joins piperidines]-1-base-2-oxoethyl]-2 ', 3 '-dihydro-2 '-oxo spiral shell-[piperidines-4,4 '-(1H)-quinazoline]-1-Methanamide;
Or its pharmaceutically acceptable salt or solvate.
4. pharmaceutical composition, it comprises and is selected from following chemical compound:
4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(7-bromo-1H-indazole-5-ylmethyl)-2-oxo-ethyl]-amide;
4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-oxo-1-(2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-(4-pyridin-4-yl-piperazine-1-yl)-ethyl]-amide;
4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-oxo-1-(2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-piperidines-1-base-ethyl]-amide;
4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-(4-methyl-piperazine-1-yl)-2-oxo-1-(2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-ethyl]-amide;
4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(4-methyl-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-ethyl]-amide;
4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [1-(4-methyl-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-2-piperidines-1-base-ethyl]-amide;
4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [1-(4-chloro-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-2-piperidines-1-base-ethyl]-amide;
4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [1-formyl-dimethylamino-2-(4-methyl-2-oxo-2,3-dihydro-benzoxazol-6-yl)-ethyl]-amide;
4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-(4-chloro-2-oxo-2,3-dihydro-benzoxazol-6-yl)-1-formyl-dimethylamino-ethyl]-amide;
4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [1-(4-methyl-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-2-(4-pyridin-4-yl-piperazine-1-yl)-ethyl]-amide;
4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [1-(4-chloro-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-2-(4-pyridin-4-yl-piperazine-1-yl)-ethyl]-amide;
4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(4-ethyl-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-ethyl]-amide;
4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(7-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-ylmethyl)-2-oxo-ethyl]-amide;
4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(7-chloro-2-oxo-2,3-dihydro-1H-benzimidazole-5-ylmethyl)-2-oxo-ethyl]-amide;
4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(7-ethyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-ylmethyl)-2-oxo-ethyl]-amide;
4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-ylmethyl)-2-oxo-ethyl]-amide;
4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(3,7-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-ylmethyl)-2-oxo-ethyl]-amide;
4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(7-chloro-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-ylmethyl)-2-oxo-ethyl]-amide;
4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(7-ethyl-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-ylmethyl)-2-oxo-ethyl]-amide;
3-(7-methyl isophthalic acid H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-isopropyl propionate;
3-(7-chloro-1H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-isopropyl propionate;
3-(7-ethyl-1H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-isopropyl propionate;
3-(7-chloro-1H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-the propanoic acid tert-butyl ester;
3-(7-ethyl-1H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-the propanoic acid tert-butyl ester;
3-(7-chloro-1H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-cyclohexyl propionate;
3-(7-ethyl-1H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-cyclohexyl propionate;
3-(7-chloro-1H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-propanoic acid 1-methyl-piperidin-4-yl ester;
3-(7-ethyl-1H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-propanoic acid 1-methyl-piperidin-4-yl ester;
3-(7-chloro-1H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-propanoic acid 1-methyl-cyclohexyl ester;
3-(7-ethyl-1H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-propanoic acid 1-methyl-cyclohexyl ester;
3-(7-chloro-1H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-propanoic acid 4-phenyl-cyclohexyl; With
3-(7-ethyl-1H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-propanoic acid 4-phenyl-cyclohexyl;
Or its pharmaceutically acceptable salt or solvate.
5. be selected from following chemical compound, its pharmaceutically acceptable salt or solvate preparation be used for the treatment of or the medicine of prevention of migraine in purposes:
(±)-3-(3-cyano-1 H-indol--5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-methyl propionate;
(±)-4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(3-cyano-1 H-indol--5-base-methyl)-2-oxo-ethyl]-amide;
(±)-4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(3-cyano group-7-Methyl-1H-indole-5-base-methyl)-2-oxo-ethyl]-amide;
(±)-3-(7-isopropyl-1H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-methyl propionate;
(±)-4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(7-isopropyl-1H-indazole-5-base-methyl)-2-oxo-ethyl]-amide;
(±)-4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(7-ethyl-1H-indazole-5-base-methyl)-2-oxo-ethyl]-amide;
(±)-4-(2,2-dioxo-1,4-dihydro-2H-2 λ 6-benzo [1,2,6] thiadiazine-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(7-methyl isophthalic acid H-indazole-5-base-methyl)-2-oxo-ethyl]-amide;
(±)-4-(2,2-dioxo-1,4-dihydro-2H-2 λ 6-benzo [1,2,6] thiadiazine-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(7-ethyl-3-methyl isophthalic acid H-indazole-5-base-methyl)-2-oxo-ethyl]-amide;
(±)-2-[4-(6-cyano group-2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino]-3-(7-methyl isophthalic acid H-indazole-5-yl)-methyl propionate;
(±)-4-(6-cyano group-2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid 2-[1,4 '] connection piperidines-1 '-Ji-1-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-2-oxo-ethyl }-amide;
(±)-4-(2-oxo-1,2,4,5-tetrahydrochysene-benzo [d] [1,3] diaza -3-base-1-carboxylic acid 2-[1,4 '] connection piperidines-1 '-Ji-1-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-2-oxo-ethyl }-amide;
(±)-4-(6-hydroxyl-2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid 2-[1,4 '] connection piperidines-1 '-Ji-1-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-2-oxo-ethyl }-amide;
(±)-4-(8-methoxyl group-2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid 2-[1,4 '] connection piperidines-1 '-Ji-1-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-2-oxo-ethyl }-amide;
(±)-4-(8-chloro-2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid 2-[1,4 '] connection piperidines-1 '-Ji-1-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-2-oxo-ethyl }-amide;
(±)-N-(3-(7-ethyl-3-methyl isophthalic acid H-indazole-5-yl)-1-oxo-1-(4-(piperidines-1-yl) piperidines-1-yl) third-2-yl)-2 ', 3 '-dihydro-2 '-oxo spiral shell-(piperidines-4,4 '-quinazoline)-1-Methanamide;
(±)-N-(3-(7-ethyl-3-methyl 1H-indazole-5-yl)-1-oxo-1-(4-(piperidines-1-yl) piperidines-1-yl) third-2-yl)-2,4-dihydro-2 '-oxo spiral shell-(piperidines-4,4 '-1H-benzo [d] [1,3]  piperazine)-1-Methanamide;
(±)-N-(3-(7-ethyl-1H-indazole-5-yl)-1-(6, the 7-dihydro-1 h-pyrazole is [4,3-c] pyridines-5 (4H)-yl)-1-oxo third-2-yl also)-4-(1,2-dihydro-2-oxo-quinazoline-3 (4H)-yl) piperidines-1-Methanamide;
(±)-N-(3-(7-ethyl-1H-indazole-5-yl)-1-(6,7-dihydro-7,7-dimethyl-1H-pyrazolo [4,3-c] pyridines-5 (4H)-yl)-1-oxo third-2-yl)-4-(1,2-dihydro-2-oxo-quinazoline-3 (4H)-yl) piperidines-1-Methanamide;
(±)-methyl 2-(4-(8-fluoro-1,2-dihydro-2-oxo-quinazoline-3 (4H)-yl) piperidines-1-formamido)-3-(7-methyl isophthalic acid H-indazole-5-yl) propionic ester;
(±)-4-(8-fluoro-1,2-dihydro-2-oxo-quinazoline-3 (4H)-yl)-N-(3-(7-methyl isophthalic acid H-indazole-5-yl)-1-oxo-1-(4-(piperidines-1-yl) piperidines-1-yl) third-2-yl) piperidines-1-Methanamide;
(±)-4-(8-fluoro-1,2-dihydro-2-oxo-quinazoline-3 (4H)-yl)-N-(3-(7-methyl isophthalic acid H-indazole-5-yl)-1-oxo-1-(4-phenylpiperazine-1-yl) third-2-yl) piperidines-1-Methanamide;
(±)-4-(8-fluoro-1,2-dihydro-2-oxo-quinazoline-3 (4H)-yl)-N-(1-(4-(4-fluorophenyl) piperazine-1-yl)-3-(7-methyl isophthalic acid H-indazole-5-yl)-1-oxo third-2-yl) piperidines-1-Methanamide;
(±)-4-(8-fluoro-1,2-dihydro-2-oxo-quinazoline-3 (4H)-yl)-N-(1-(4-(2-fluorophenyl) piperazine-1-yl)-3-(7-methyl isophthalic acid H-indazole-5-yl)-1-oxo third-2-yl) piperidines-1-Methanamide;
(±)-4-(8-fluoro-1,2-dihydro-2-oxo-quinazoline-3 (4H)-yl)-N-(3-(7-methyl isophthalic acid H-indazole-5-yl)-1-oxo-1-(4-o-tolyl piperazine-1-yl) third-2-yl) piperidines-1-Methanamide;
(±)-methyl 2-(4-(8-fluoro-1,2-dihydro-2-oxo-quinazoline-3 (4H)-yl) piperidines-1-formamido)-3-(7-ethyl-3-methyl isophthalic acid H-indazole-5-yl) propionic ester;
(±)-N-(3-(7-ethyl-3-methyl isophthalic acid H-indazole-5-yl)-1-oxo-1-(4-(piperidines-1-yl) piperidines-1-yl) third-2-yl)-4-(8-fluoro-1,2-dihydro-2-oxo-quinazoline-3 (4H)-yl) piperidines-1-Methanamide;
(R)-N-((R)-3-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-1-oxo-1-(4-(piperidines-1-yl) piperidines-1-yl) third-2-yl)-4-(8-fluoro-1,2-dihydro-2-oxo-quinazoline-3 (4H)-yl) piperidines-1-Methanamide;
(±)-N-(3-(7-methyl isophthalic acid H-indazole-5-yl)-1-oxo-1-(4-(piperidines-1-yl) piperidines-1-yl) third-2-yl)-8 '-fluoro-2 ', 3 '-dihydro-2 '-oxo spiral shell-(piperidines-4,4 '-quinazoline)-1-Methanamide;
(±)-4-(8-fluoro-1,2-dihydro-2,4-dioxo quinazoline-3 (4H)-yl)-N-(3-(7-methyl isophthalic acid H-indazole-5-yl)-1-oxo-1-(4-(piperidines-1-yl) piperidines-1-yl) third-2-yl) piperidines-1-Methanamide;
N-((R)-3-(2-(trifluoromethyl)-1H-benzo [d] imidazoles-5-yl)-1-oxo-1-(4-(piperidines-1-yl) piperidines-1-yl) third-2-yl)-4-(1,2-dihydro-2-oxo-quinazoline-3 (4H)-yl) piperidines-1-Methanamide;
N-((R)-1-(formyl-dimethylamino)-2-(2-(trifluoromethyl)-1H-benzo [d] imidazoles-5-yl) ethyl)-4-(1,2-dihydro-2-oxo-quinazoline-3 (4H)-yl) piperidines-1-Methanamide;
(R)-methyl 2-(4-(1,2-dihydro-2-oxo-quinazoline-3 (4H)-yl) piperidines-1-formamido)-3-(2,3-dihydro-2-oxo--1H-benzo [d] imidazoles-6-yl) propionic ester;
N-((R)-3-(2,3-dihydro-2-oxo--1H-benzo [d] imidazoles-6-yl)-1-oxo-1-(4-piperidines-1-yl) piperidines-1-yl) third-2-yl)-and 4-(1,2-dihydro-2-oxo-quinazoline-3 (4H)-yl) piperidines-1-Methanamide;
N-((R)-1-(formyl-dimethylamino)-2-(2,3-dihydro-2-oxo--1H-benzo [d] imidazoles-6-yl) ethyl)-4-(1,2-dihydro-2-oxo-quinazoline-3 (4H)-yl) piperidines-1-Methanamide;
N-((R)-3-(2,3-dihydro-2-oxo--1H-benzo [d] imidazoles-6-yl)-1-oxo-1-(4-piperidines-1-yl) piperidines-1-yl) third-2-yl)-4-(2 ', 3 '-dihydro-2 '-oxo spiral shell (piperidines-4,4 '-(1H)-quinazoline) Methanamide;
4-(1,2-dihydro-2,4-dioxo quinazoline-3 (4H)-yl)-N-((R)-3-(7-methyl isophthalic acid H-benzo [d] [1,2,3] triazole-5-yl)-1-oxo-1-(4-(piperidines-1-yl) piperidines-1-yl) third-2-yl) piperidines-1-Methanamide;
(R)-4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-(4-cyclohexyl-piperazine-1-yl)-2-oxo-1-(2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-ethyl]-amide;
(R)-4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-(4-isopropyl-piperazine-1-yl)-2-oxo-1-(2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-ethyl]-amide;
(R)-and N-((R)-3-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-1-oxo-1-(4-(piperidines-1-yl) piperidines-1-yl) third-2-yl)-2,4-dihydro-2 '-oxo spiral shell-(piperidines-4,4 '-1H-benzo [d] [1,3]  piperazine)-1-Methanamide;
(R)-and N-((R)-3-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-1-oxo-1-(4-(hexamethylene-1-yl) piperazine-1-yl) third-2-yl)-2,4-dihydro-2 '-oxo spiral shell-(piperidines-4,4 '-1H-benzo [d] [1,3]  piperazine)-1-Methanamide;
(R)-and N-((R)-3-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-1-oxo-1-(4-(third-2-yl) piperazine-1-yl) third-2-yl)-2,4-dihydro-2 '-oxo spiral shell-(piperidines-4,4 '-1H-benzo [d] [1,3]  piperazine)-1-Methanamide;
(R)-and N-((R)-3-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-1-oxo-1-(4-(piperidines-1-yl) piperidines-1-yl) third-2-yl)-2,4-dihydro-2 '-oxo spiral shell-(piperidines-4,4 '-1H-quinazoline)-1-Methanamide;
(R)-and N-((R)-3-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-1-oxo-1-(4-(hexamethylene-1-yl) piperazine-1-yl) third-2-yl)-2,4-dihydro-2 '-oxo spiral shell-(piperidines-4,4 '-1H-quinazoline)-1-Methanamide;
(R)-and N-((R)-3-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-1-oxo-1-(4-(third-2-yl) piperazine-1-yl) third-2-yl)-2,4-dihydro-2 '-oxo spiral shell-(piperidines-4,4 '-1H-quinazoline)-1-Methanamide;
(R)-4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(4-chloro-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-ethyl]-amide;
(R)-4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(5-chloro-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-ethyl]-amide;
(R)-4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(4-bromo-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-ethyl]-amide;
(R)-4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(5-bromo-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-ethyl]-amide;
(R)-4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(4-iodo-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-ethyl]-amide;
(±)-N-(1-benzyl-2-hydroxyl-ethyl)-2-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-4-oxo-4-[1 ', 2 '-dihydro-2 '-oxo spiral shell-[4H-3 ', 1-benzoxazine-4,4 '-piperidyl]-butyramide;
(±)-N-(1-benzyl-2-hydroxyl-ethyl)-2-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-yl]-butyramide;
(±)-phenyl-acetic acid N '-2-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-yl]-bytyry }-hydrazides;
(±)-1-[1,4 '] connection piperidines-1 '-Ji-4-[4-(8-fluoro-2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-yl]-2-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-butane-1, the 4-diketone;
(±)-1-[1,4 '] connection piperidines-1 '-Ji-2-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-4-[2 ', 3 '-dihydro-2 '-oxo spiral shell-(piperidines-4,4 '-quinazoline]-butane-1, the 4-diketone;
(±)-1-(4-cyclohexyl-piperazine-1-yl)-2-(2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-4-[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-yl]-butane-1, the 4-diketone;
(±)-1-[1,4 '] connection piperidines-1 '-Ji-2-(2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-4-[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-yl]-butane-1, the 4-diketone;
(±)-1-[1,4 '] connection piperidines-1 '-Ji-2-(2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-4-[2 ', 3 '-dihydro-2 '-oxo spiral shell-(piperidines-4,4 '-quinazoline)]-butane-1, the 4-diketone;
(±)-1-(4-cyclohexyl-piperazine-1-yl)-2-(2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-4-[2 ', 3 '-dihydro-2 '-oxo spiral shell-(piperidines-4,4 '-quinazoline)]-butane-1, the 4-diketone;
(±)-4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-(4-cyclohexyl-piperazine-1-yl)-1-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-2-oxo-ethyl]-amide;
(±)-4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[4-(4-fluoro-phenyl)-piperazine-1-yl]-1-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-2-oxo-ethyl]-amide;
(±)-3-(7-methyl isophthalic acid H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-the propanoic acid tert-butyl ester;
(±)-3-(7-methyl isophthalic acid H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-propanoic acid 1-methyl cyclohexane ester;
(±)-3-(7-methyl isophthalic acid H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-propanoic acid 1-aza-bicyclo [2.2.2] oct-3-yl ester;
(±)-3-(7-methyl isophthalic acid H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-propanoic acid piperidin-4-yl ester;
(±)-4-(3-(7-methyl isophthalic acid H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-propionyloxy)-piperidines-1-carboxylic acid tert-butyl ester;
(±)-3-(7-methyl isophthalic acid H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-propanoic acid 3,4,5,6-tetrahydrochysene-2H-[1,4 '] bipyridyl-4-base ester;
(±)-3-(7-methyl isophthalic acid H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-propanoic acid 1-diethylamino-1-methyl-ethyl ester;
(±)-3-(7-methyl isophthalic acid H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-propanoic acid 1,1-dimethyl-2-phenyl-ethyl ester;
(±)-3-(7-methyl isophthalic acid H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-propanoic acid 1,1-dimethyl-3-phenyl-propyl ester;
(±)-3-(7-methyl isophthalic acid H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-ethyl propionate;
(±)-1-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-2-[1-pyridin-4-yl-methyl]-the 2-oxoethyl]-2 ', 3 '-dihydro-2 '-oxo spiral shell-[piperidines-4,4 '-(1H)-quinazoline]-1-Methanamide;
(±)-1-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-2-[1-pyridin-4-yl-piperazinyl]-the 2-oxoethyl]-2 ', 3 '-dihydro-2 '-oxo spiral shell-[piperidines-4,4 '-(1H)-quinazoline]-1-Methanamide;
(±)-1-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-2-[(2-dimethylamino-ethyl-ethylamino formoxyl)-and the 2-oxoethyl]-2 ', 3 '-dihydro-2 '-oxo spiral shell-[piperidines-4,4 '-(1H)-quinazoline]-1-Methanamide;
(±)-1-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-2-[1-pyridin-4-yl-piperazinyl]-the 2-oxoethyl]-1 ', 2 '-dihydro-2 '-oxo spiral shell-[4H-3 ', 1-benzoxazine-4,4 '-piperidines]-the 1-Methanamide;
(±)-1-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-2-[1-pyridine-2-base-piperazinyl]-the 2-oxoethyl]-1 ', 2 '-dihydro-2 '-oxo spiral shell-[4H-3 ', 1-benzoxazine-4,4 '-piperidines]-the 1-Methanamide;
(R)-and 4-(2-oxo-1,4-dihydro-2H-quinazoline-3 base)-piperidines-1d-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-2-oxo-ethyl] amide; With
(R)-1-(7-methyl isophthalic acid H-indazole-5-ylmethyl)-2-[1,4-joins piperidines]-1-base-2-oxoethyl]-2 ', 3 '-dihydro-2 '-oxo spiral shell-[piperidines-4,4 '-(1H)-quinazoline]-1-Methanamide.
6. be selected from following chemical compound, its pharmaceutically acceptable salt or solvate preparation be used for the treatment of or the medicine of prevention of migraine in purposes:
4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(7-bromo-1H-indazole-5-ylmethyl)-2-oxo-ethyl]-amide;
4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-oxo-1-(2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-(4-pyridin-4-yl-piperazine-1-yl)-ethyl]-amide;
4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-oxo-1-(2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-piperidines-1-base-ethyl]-amide;
4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-(4-methyl-piperazine-1-yl)-2-oxo-1-(2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-ethyl]-amide;
4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(4-methyl-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-ethyl]-amide;
4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [1-(4-methyl-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-2-piperidines-1-base-ethyl]-amide;
4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [1-(4-chloro-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-2-piperidines-1-base-ethyl]-amide;
4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [1-formyl-dimethylamino-2-(4-methyl-2-oxo-2,3-dihydro-benzoxazol-6-yl)-ethyl]-amide;
4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-(4-chloro-2-oxo-2,3-dihydro-benzoxazol-6-yl)-1-formyl-dimethylamino-ethyl]-amide;
4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [1-(4-methyl-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-2-(4-pyridin-4-yl-piperazine-1-yl)-ethyl]-amide;
4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [1-(4-chloro-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-2-(4-pyridin-4-yl-piperazine-1-yl)-ethyl]-amide;
4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(4-ethyl-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-ethyl]-amide;
4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(7-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-ylmethyl)-2-oxo-ethyl]-amide;
4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(7-chloro-2-oxo-2,3-dihydro-1H-benzimidazole-5-ylmethyl)-2-oxo-ethyl]-amide;
4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(7-ethyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-ylmethyl)-2-oxo-ethyl]-amide;
4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-ylmethyl)-2-oxo-ethyl]-amide;
4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(3,7-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-ylmethyl)-2-oxo-ethyl]-amide;
4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(7-chloro-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-ylmethyl)-2-oxo-ethyl]-amide;
4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carboxylic acid [2-[1,4 '] connection piperidines-1 '-Ji-1-(7-ethyl-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-ylmethyl)-2-oxo-ethyl]-amide;
3-(7-methyl isophthalic acid H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-isopropyl propionate;
3-(7-chloro-1H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-isopropyl propionate;
3-(7-ethyl-1H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-isopropyl propionate;
3-(7-chloro-1H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-the propanoic acid tert-butyl ester;
3-(7-ethyl-1H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-the propanoic acid tert-butyl ester;
3-(7-chloro-1H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-cyclohexyl propionate;
3-(7-ethyl-1H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-cyclohexyl propionate;
3-(7-chloro-1H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-propanoic acid 1-methyl-piperidin-4-yl ester;
3-(7-ethyl-1H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-propanoic acid 1-methyl-piperidin-4-yl ester;
3-(7-chloro-1H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-propanoic acid 1-methyl-cyclohexyl ester;
3-(7-ethyl-1H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-propanoic acid 1-methyl-cyclohexyl ester;
3-(7-chloro-1H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-propanoic acid 4-phenyl-cyclohexyl; With
3-(7-ethyl-1H-indazole-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3-yl)-piperidines-1-carbonyl]-amino }-propanoic acid 4-phenyl-cyclohexyl.
CNB200380111030XA 2003-12-05 2003-12-05 Calcitonin gene related peptide receptor antagonists Expired - Fee Related CN100558428C (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015158299A1 (en) * 2014-04-17 2015-10-22 沈华浩 Application of sulfonamides compound in chronic airway inflammatory disease
WO2024046223A1 (en) * 2022-08-30 2024-03-07 熙源安健医药（上海）有限公司 Indazole formamide derivatives, preparation method therefor, and use thereof

Families Citing this family (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7220862B2 (en) 2002-06-05 2007-05-22 Bristol-Myers Squibb Company Calcitonin gene related peptide receptor antagonists
US7842808B2 (en) 2002-06-05 2010-11-30 Bristol-Myers Squibb Company Anti-migraine spirocycles
AR046787A1 (en) 2003-12-05 2005-12-21 Bristol Myers Squibb Co HETEROCICLIC ANTIMIGRAN AGENTS
US7820673B2 (en) * 2003-12-17 2010-10-26 Takeda Pharmaceutical Company Limited Urea derivative, process for producing the same, and use
TW200533398A (en) 2004-03-29 2005-10-16 Bristol Myers Squibb Co Novel therapeutic agents for the treatment of migraine
US7786141B2 (en) 2004-08-19 2010-08-31 Vertex Pharmaceuticals Incorporated Dihydrospiroindene modulators of muscarinic receptors
MX2007002033A (en) 2004-08-19 2007-04-26 Vertex Pharma Modulators of muscarinic receptors.
US7384931B2 (en) 2004-11-03 2008-06-10 Bristol-Myers Squibb Company Constrained compounds as CGRP-receptor antagonists
US7384930B2 (en) 2004-11-03 2008-06-10 Bristol-Myers Squibb Company Constrained compounds as CGRP-receptor antagonists
US7449586B2 (en) 2004-12-03 2008-11-11 Bristol-Myers Squibb Company Processes for the preparation of CGRP-receptor antagonists and intermediates thereof
US7834007B2 (en) 2005-08-25 2010-11-16 Bristol-Myers Squibb Company CGRP antagonists
DE102005050892A1 (en) * 2005-10-21 2007-04-26 Boehringer Ingelheim Pharma Gmbh & Co. Kg Selected CGRP antagonists, process for their preparation and their use as pharmaceuticals
US8168592B2 (en) 2005-10-21 2012-05-01 Amgen Inc. CGRP peptide antagonists and conjugates
US7473778B2 (en) 2005-12-24 2009-01-06 Boehringer Ingelheim International Gmbh 3-(4-piperidinyl)-2,3,4,5-tetrahydro-1,3-benzodiazepin-2(1H)-one
JP2009527568A (en) 2006-02-22 2009-07-30 バーテックス ファーマシューティカルズ インコーポレイテッド Modulator of muscarinic receptor
EP2251338A3 (en) 2007-11-22 2011-06-08 Boehringer Ingelheim International GmbH Organic compounds
GB201519196D0 (en) 2015-10-30 2015-12-16 Heptares Therapeutics Ltd CGRP Receptor Antagonists
GB201519195D0 (en) 2015-10-30 2015-12-16 Heptares Therapeutics Ltd CGRP Receptor Antagonists
GB201519194D0 (en) 2015-10-30 2015-12-16 Heptares Therapeutics Ltd CGRP receptor antagonists
WO2023034466A1 (en) * 2021-09-02 2023-03-09 Pfizer Ireland Pharmaceuticals Cgrp antagonists for treating psoriasis

Family Cites Families (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0851759A4 (en) 1995-09-05 2000-12-06 Smithkline Beecham Corp Compounds and methods
GB2311523A (en) * 1996-03-25 1997-10-01 Merck & Co Inc Tryptophan urea tachykinin receptor antagonists
US5869489A (en) * 1996-03-25 1999-02-09 Merck & Co., Inc. Trypthophan ureas as neurokinnin antagonists
AU4261697A (en) 1996-09-09 1998-03-26 Smithkline Beecham Corporation Compounds and methods
EP0927192B1 (en) 1996-09-10 2004-05-12 Boehringer Ingelheim Pharma GmbH & Co.KG Modified aminoacids, pharmaceuticals containing these compounds and method for their production
US6063796A (en) * 1997-04-04 2000-05-16 Merck & Co., Inc. Somatostatin agonists
WO1998056779A1 (en) 1997-06-13 1998-12-17 Smithkline Beecham Corporation 4-sulfinyl benzamides as calcitonin gene-related peptide receptor antagonists
WO1999052875A1 (en) 1998-04-08 1999-10-21 Takeda Chemical Industries, Ltd. Amine compounds, their production and their use as somatostatin receptor antagonists or agonists
AU6211499A (en) * 1998-09-30 2000-04-17 Merck & Co., Inc. Benzimidazolinyl piperidines as cgrp ligands
DE19911039A1 (en) 1999-03-12 2000-09-14 Boehringer Ingelheim Pharma Modified amino acid amides, pharmaceutical compositions containing these compounds and process for their preparation
US6313097B1 (en) 1999-03-02 2001-11-06 Boehringer Ingelheim Pharma Kg Antagonists of calcitonin gene-related peptide
US6521609B1 (en) 1999-08-10 2003-02-18 Boehringer Ingelheim Pharma Kg Use of CGRP antagonists and CGRP release inhibitors for combating menopausal hot flushes
CA2386517A1 (en) 1999-10-07 2001-04-12 Takeda Chemical Industries, Ltd. Amine derivatives
DE19952147A1 (en) 1999-10-29 2001-05-03 Boehringer Ingelheim Pharma New cyclopropanes, pharmaceutical compositions containing these compounds and process for their preparation
DE19952146A1 (en) 1999-10-29 2001-06-07 Boehringer Ingelheim Pharma Arylalkanes, arylalkenes and aryl-azaalkanes, medicaments containing these compounds and process for their preparation
DE19963868A1 (en) 1999-12-30 2001-07-12 Boehringer Ingelheim Pharma New substituted piperidines, pharmaceutical compositions containing these compounds and process for their preparation
KR20030036724A (en) * 2000-09-14 2003-05-09 도레이 가부시끼가이샤 Urea derivative and adhesive-molecule inhibitor containing the same as active ingredient
US20030181462A1 (en) 2001-08-17 2003-09-25 Boehringer Ingelheim Pharma Kg Use of BIBN4096 in combination with other antimigraine drugs for the treatment of migraine
WO2003027252A2 (en) 2001-09-27 2003-04-03 Merck & Co., Inc. Isolated dna molecules encoding humanized calcitonin gene-related peptide receptor, related non-human transgenic animals and assay methods
US6900317B2 (en) 2002-02-19 2005-05-31 Boehringer Ingelheim Pharma Gmbh & Co. Kg Salts of the CGRP antagonist BIBN4096 and inhalable powdered medicaments containing them
DE10211770A1 (en) 2002-03-14 2003-10-02 Boehringer Ingelheim Pharma Novel substituted piperidines, pharmaceutical compositions containing them and processes for their preparation
MXPA04011960A (en) * 2002-06-05 2005-03-31 Squibb Bristol Myers Co Calcitonin gene related peptide receptor antagonists.
DE10300973A1 (en) * 2003-01-14 2004-07-22 Boehringer Ingelheim Pharma Gmbh & Co. Kg New carboxylic acids and their esters, medicaments containing these compounds and processes for their preparation

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015158299A1 (en) * 2014-04-17 2015-10-22 沈华浩 Application of sulfonamides compound in chronic airway inflammatory disease
CN105012318A (en) * 2014-04-17 2015-11-04 沈华浩 Application of sulfonamide compound in chronic airway inflammatory diseases
WO2024046223A1 (en) * 2022-08-30 2024-03-07 熙源安健医药（上海）有限公司 Indazole formamide derivatives, preparation method therefor, and use thereof

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