CN103183660A - Chromane derivative used as TRPV3 (transient receptor potential vanilloid 3) conditioning agent - Google Patents

Chromane derivative used as TRPV3 (transient receptor potential vanilloid 3) conditioning agent Download PDF

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CN103183660A
CN103183660A CN 201110459248 CN201110459248A CN103183660A CN 103183660 A CN103183660 A CN 103183660A CN 201110459248 CN201110459248 CN 201110459248 CN 201110459248 A CN201110459248 A CN 201110459248A CN 103183660 A CN103183660 A CN 103183660A
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chromene
ring
unsubstituted
spiral shell
chloro
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Inventor
维·萨·普拉萨达奥·林加姆
亚伯拉罕·托马斯
拉克西米·阿特马兰·加拉塔
迪伊帕克·维特塔尔·乌基德
尚塔拉姆·卡希纳特·帕唐加尔
阿吉塔·尚卡尔·明德
尼利马·坎拉特卡-乔希
维迪亚·加纳帕蒂·卡蒂格
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Ichnos Sciences SA
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Glenmark Pharmaceuticals SA
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Abstract

The invention provides a TRPV conditioning agent, and particularly a compound provided by the invention can be used for treating or preventing diseases, symptoms and/or disorder regulated by TRPV 3. Meanwhile, the invention further provides a method for preparing the compound, an intermediate used in synthesis of the compound, a pharmaceutical compound and a method for treating or preventing diseases, symptoms and/or disorder regulated by TRPV 3.

Description

Chromanane derivative as the TRPV3 conditioning agent
Technical field
Present patent application relates to chromanane (chromane) derivative with transient receptor potential vanilla element 3 (TRPV3) activity.
Background technology
Ion moves through cytolemma and realizes by special albumen.The TRP passage is the extended familys of a non-selective cationic channel, plays the effect of assisting regulation and control ionic current and membrane potential.The TRP passage is divided into 6 subfamilies that comprise TRPV family.TRPV3 is the member of the TRPV class of TRP passage.
TRPV3 is the passage of calcium permeability, particularly is the non-selective cationic channel of calcium permeability.Except calcium ion, the TRPV3 passage is permeability for other positively charged ions, as sodium ion.Therefore, the TRPV3 passage is regulated membrane potential by regulating positively charged ion (as calcium ion and sodium ion) stream.The TRPV3 acceptor is different from valtage-gated calcium channel in mechanism.Usually, valtage-gated calcium channel to film depolarize reply, and open passage and flow into from extracellular matrix to allow calcium ion, thereby cause the increase of cellular calcium level or concentration.On the contrary, L type (long-lasting) TRP passage as non-selective cationic channel is producing more lasting variation aspect the ionic concn, and this passage is part gate (regulating by chemical reagent such as 2-amino ethoxy phenylbenzene boric acid ester [2-APB], heat and vanilla element (vanilloid)).Difference on these mechanism is accompanied by the difference on voltage-gated channel and the TRP channel architecture.Therefore, although replying in various kinds of cell type neutralization has a lot of different passages to play the effect of regulating ionic current and membrane potential aspect numerous stimulations, recognize between different types of ionic channel that the significant difference aspect structural, function and mechanism of is very important.
TRPV3 albumen be skin cells (Peier etc., Science (2002), 296,2046-2049) and dorsal root ganglion, gasserian ganglion, spinal cord and brain (Xu etc., Nature (2002), 418,181-185; Smith etc., Nature (2002), 418,186-188) middle temperature-sensitive passage of expressing.TRPV3 also expresses at the skin camber.In keratinocyte system, the stimulation of TRPV3 cause inflammation amboceptor, as the release of interleukin 1.Therefore, TRPV3 also can play a significant role in pain that the release of regulating by inflammatory stimulus causes and inflammation.As described herein, especially TRPV3 albumen can be used to the screening analysis, to differentiate the compound that the function of TRPV3 (including but not limited to people TRPV3, mouse TRPV3, rat TRPV3 and fruit bat TRPV3) is regulated.US2004/0009537 (' 537 application) discloses the sequence corresponding to people TRPV3, mouse TRPV3 and fruit bat TRPV3.For example, ' 537 Shen Qing sequence numbering 106 and 107 corresponds respectively to people's nucleotide sequence and aminoacid sequence.The sequence numbering 108 and 109 of ' 537 applications corresponds respectively to nucleotide sequence and the aminoacid sequence of mouse.
The function of TRPV3 involves reception and the transduction of pain basically.Therefore, the compound of one or more functions that can regulate TRPV3 is differentiated and is made in expectation.
WO 2007/056124 and WO 2006/017995 disclose TRPV3 conditioning agent, the especially antagonist of the multiple disease that is used for the treatment of the TRPV3 mediation.
WO 2006/065686 and WO 2007/042906 disclose 1-benzopyran derivatives.
Find in the process of better anodyne being devoted to, still need disease, illness (conditions) and/or the obstacle (disorders) regulated by TRPV3 are carried out therapeutic treatment.
Summary of the invention
Present patent application is regulated active chromanane compound at having TRP passages regulate activity, particularly TRPV3.Present patent application relates to the compound of formula (I):
Figure BDA0000127889200000021
Wherein,
R 1Be selected from and replace or unsubstituted aryl, replacement or unsubstituted heteroaryl, replacement or unsubstituted heterocyclic group or replacement or unsubstituted cycloalkyl; Wherein, aryl, heteroaryl and heterocyclic ring are monocycle, dicyclo or three rings, and all or part of be aromatics;
Wherein, aryl, heteroaryl, substituting group on heterocyclic ring and the cycloalkyl is independently selected from the group of being made up of following radicals: halogen, hydroxyl, nitro, cyano group, replace or unsubstituted amino, replace or unsubstituted alkyl, the straight or branched alkyl, the straight or branched alkoxyl group, replace or unsubstituted thiazolinyl, replace or unsubstituted alkoxyl group, replace or unsubstituted haloalkyl, the haloalkyl of all or part of replacement, replace or unsubstituted halogenated alkoxy, the halogenated alkoxy of all or part of replacement, replace or unsubstituted cycloalkyl, replace or unsubstituted cycloalkyloxy, replace or unsubstituted cycloalkylalkyl, replace or unsubstituted cycloalkyl alkoxy, replace or unsubstituted aryl, replace or unsubstituted aryloxy, replace or unsubstituted arylalkyl, replace or unsubstituted alkoxy aryl, replace or unsubstituted heterocyclic group, replace or unsubstituted heteroaryl,-S (O) pR a,-NHS (O) pR a,-O (CH 2) mNR aR b,-C (O)-R aOr-C (O) NR aR b
R 2Be selected from the group of being formed by following radicals: hydrogen, replacement or unsubstituted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted aryl, replacement or unsubstituted arylalkyl, replacement or unsubstituted heteroaryl or replacement or unsubstituted heterocyclic group;
R a, R b, R cAnd R dBe independently selected from hydrogen, nitro, cyano group, halogen ,-OR e, replacement or unsubstituted alkyl, replacement or unsubstituted thiazolinyl, replacement or unsubstituted alkynyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted cycloalkenyl group, replacement or unsubstituted aryl, replacement or unsubstituted heteroaryl, replacement or unsubstituted heterocyclic group;
R eBe selected from the group of being formed by following radicals: hydrogen, replacement or unsubstituted alkyl, replacement or unsubstituted thiazolinyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted aryl, replacement or unsubstituted heteroaryl or replacement or unsubstituted heterocyclic group;
R 3And R 4Be independently selected from hydrogen, halogen, replace or unsubstituted amino, replace or unsubstituted alkyl, the straight or branched alkyl, the straight or branched alkoxyl group, replace or unsubstituted thiazolinyl, replace or unsubstituted alkoxyl group, replace or unsubstituted haloalkyl, the haloalkyl of all or part of replacement, replace or unsubstituted halogenated alkoxy, the halogenated alkoxy of all or part of replacement, replace or unsubstituted cycloalkyl, replace or unsubstituted cycloalkyloxy, replace or unsubstituted cycloalkylalkyl, replace or unsubstituted cycloalkyl alkoxy, replace or unsubstituted aryl;
' m ' is for being selected from the integer of 1-4;
' n ' is for being selected from the integer of 0-3;
' p ' is for being selected from the integer of 0-2;
But R bNot for being selected from-OR e,-NR aR bOr C (O) NR aR bGroup.
Should be understood that formula (I) has structurally contained all steric isomers, enantiomer and diastereomer and the pharmacy acceptable salt that can be considered by the chemical structure of kind described herein.
According to an embodiment of the invention, ' n ' is integer 1.
According to another implementation of the invention, ' n ' is integer 2.
According to another implementation of the invention, ' n ' is integer 3.
According to another implementation of the invention, R 1For replacing or unsubstituted monocyclic aryl, be preferably phenyl.In this embodiment, substituting group is one or more, and (for example be independently selected from halogen, F, Cl or Br), hydroxyl, alkyl (for example, methyl), alkoxyl group (for example, methoxyl group, oxyethyl group, positive propoxy, n-butoxy, isopropoxy), cycloalkyloxy (for example, cyclopentyloxy), and ' m ' is 1,2 or 3, is preferably 2.
According to another implementation of the invention, R bBe halogen (for example, F, Cl or Br).
According to another implementation of the invention, R a, R cAnd R dBe independently selected from hydrogen or hydroxyl.
According to another implementation of the invention, R 3And R 4Be hydrogen.
Another preferred embodiment is the compound of formula (II) for the present invention:
Figure BDA0000127889200000041
Wherein,
R 1Be selected from and replace or unsubstituted aryl, replacement or unsubstituted heteroaryl, replacement or unsubstituted heterocyclic group or replacement or unsubstituted cycloalkyl; Wherein aryl, heteroaryl and heterocyclic ring are monocycle, dicyclo or three rings, and all or part of be aromatics;
Wherein, aryl, heteroaryl, substituting group on heterocyclic ring and the cycloalkyl is independently selected from the group of being made up of following radicals: halogen, hydroxyl, nitro, cyano group, amino, replace or unsubstituted alkyl, the straight or branched alkyl, the straight or branched alkoxyl group, replace or unsubstituted thiazolinyl, replace or unsubstituted alkoxyl group, replace or unsubstituted haloalkyl, the haloalkyl of all or part of replacement, replace or unsubstituted halogenated alkoxy, the halogenated alkoxy of all or part of replacement, replace or unsubstituted cycloalkyl, replace or unsubstituted cycloalkyloxy, replace or unsubstituted cycloalkylalkyl, replace or unsubstituted cycloalkyl alkoxy, replace or unsubstituted aryl, replace or unsubstituted aryloxy, replace or unsubstituted arylalkyl, replace or unsubstituted alkoxy aryl, replace or unsubstituted heterocyclic group, replace or unsubstituted heteroaryl,-S (O) pR a,-NHS (O) pR a,-O (CH 2) mNR aR b,-C (O)-R aOr-C (O) NR aR b
R a, R b, R cWith Rd be independently selected from hydrogen, nitro, cyano group, halogen ,-OR e, replacement or unsubstituted alkyl, replacement or unsubstituted thiazolinyl, replacement or unsubstituted alkynyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted cycloalkenyl group, replacement or unsubstituted aryl, replacement or unsubstituted heteroaryl, replacement or unsubstituted heterocyclic group;
R eBe selected from the group of being formed by following radicals: hydrogen, replacement or unsubstituted alkyl, replacement or unsubstituted thiazolinyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted aryl, replacement or unsubstituted heteroaryl or replacement or unsubstituted heterocyclic group;
R 3And R 4Be independently selected from hydrogen, halogen, replace or unsubstituted amino, replace or unsubstituted alkyl, the straight or branched alkyl, the straight or branched alkoxyl group, replace or unsubstituted thiazolinyl, replace or unsubstituted alkoxyl group, replace or unsubstituted haloalkyl, the haloalkyl of all or part of replacement, replace or unsubstituted halogenated alkoxy, the halogenated alkoxy of all or part of replacement, replace or unsubstituted cycloalkyl, replace or unsubstituted cycloalkyloxy, replace or unsubstituted cycloalkylalkyl, replace or unsubstituted cycloalkyl alkoxy, replace or unsubstituted aryl;
' m ' is for being selected from the integer of 1-4;
' n ' is for being selected from the integer of 0-3;
' p ' is for being selected from the integer of 0-2;
But R bNot for being selected from-OR e,-NR aR bOr C (O) NR aR bGroup.
Should be understood that formula (II) has structurally contained all steric isomers, enantiomer and diastereomer and the pharmacy acceptable salt that can be considered by the chemical structure of kind described herein.
According to an embodiment of the invention, ' n ' is integer 1.
According to an embodiment of the invention, R 1For replacing or unsubstituted aryl, wherein aryl is monocycle, dicyclo or three ring ring systems, is preferably monocycle ring or dicyclo ring.In this embodiment, ' m ' is 1,2 or 3.
According to another implementation of the invention, R 1For replacing or unsubstituted monocyclic aryl, be preferably phenyl.In this embodiment, one or more substituting groups (for example are independently selected from halogen, F, Cl or Br), hydroxyl, alkyl (for example, methyl), alkoxyl group (for example, methoxyl group, oxyethyl group, positive propoxy, n-butoxy, isopropoxy), cycloalkyloxy (for example, cyclopentyloxy), cycloalkyl alkoxy (for example, cyclo propyl methoxy), alkyl sulfonyl amino (for example ,-NHS (O) 2CH 3,-NHS (O) 2CH (CH 3) 2), the alkylamino alkoxyl group (for example ,-OCH 2CH 2N (CH 3) 2), alkoxy aryl (for example, benzyloxy) or heteroaryl (for example, pyridine or pyrimidine); And ' m ' is 1,2 or 3.
According to another implementation of the invention, R 1For replacing or unsubstituted bicyclic aryl, be preferably naphthyl.In this embodiment, one or more substituting groups are independently selected from the halogenated alkoxy (OCHF of alkoxyl group (for example, methoxyl group, oxyethyl group or isopropoxy) or all or part of replacement 2); And ' m ' is 1,2 or 3.
According to another implementation of the invention, R 1For replacing or unsubstituted bicyclic aryl.In this embodiment, aryl is the part aromatic ring, is preferably tetraline; And ' m ' is 1,2 or 3.
Another embodiment according to the present invention, R 1Be to replace or unsubstituted heterocyclic group, wherein heterocyclic group is monocycle, dicyclo or three-ring system, and all or part of be aromatics.
According to another implementation of the invention, R 1For replacing or unsubstituted heteroaryl, wherein heteroaryl is monocycle, dicyclo or three ring ring systems.In this embodiment, ' m ' is 1,2 or 3.
According to another implementation of the invention, R 1For replacing or unsubstituted bicyclic heteroaryl, be preferably pyridine.In this embodiment, ' m ' is 1,2 or 3.
According to another implementation of the invention, R 1For replacing or unsubstituted bicyclic heteroaryl, be preferably indoles, benzo dioxole, benzoisoxazole, cumarone, quinoline or Ben Bing dioxin.In this embodiment, one or more substituting groups are independently selected from halogen (for example, F, Cl or Br), alkyl (for example, methyl) or alkoxyl group (for example, methoxyl group, oxyethyl group, positive propoxy, n-butoxy, isopropoxy); And ' m ' is 1,2 or 3.
According to another implementation of the invention, R 1For replacing or unsubstituted tricyclic heteroaryl preferred diphenylene-oxide.In this embodiment, ' m ' is 1,2 or 3.
According to another implementation of the invention, R bBe selected from hydrogen or halogen (for example, fluorine, chlorine or bromine).
According to another implementation of the invention, R a, R cAnd R dBe independently selected from hydrogen, halogen (for example, fluorine, chlorine or bromine), replacement or unsubstituted alkyl (for example, methyl).
According to another implementation of the invention, R a, R cAnd R dBe independently selected from hydrogen or-OR e, R wherein eBe hydrogen, replacement or unsubstituted alkyl (for example, methyl) or replacement or unsubstituted aryl (for example, phenyl) or replacement or unsubstituted arylalkyl (for example, benzyl).
According to another implementation of the invention, R 3And R 4Be hydrogen, hydroxyl or alkyl (methyl) independently.In this embodiment, ' m ' is 1,2 or 3.
Following is representative compounds, in fact only is illustrative, is not intended to limit scope of the present invention.
N-(8-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-2-phenyl-acetamides (compound number 1);
N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-2-(2-p-methoxy-phenyl) ethanamide (compound number 2);
N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-the 2-{2-[(methyl sulphonyl) amino] phenyl } ethanamide (compound number 3);
N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-2-(2-(cyclopentyloxy)-3-p-methoxy-phenyl) ethanamide (compound number 4);
N-[(4R)-8-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl]-2-(2-cyclopentyloxy-3-methoxyl group) phenyl-acetamides (compound number 5);
N-[(4S)-8-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl]-2-(2-cyclopentyloxy-3-methoxyl group) phenyl-acetamides (compound number 6);
N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-2-(3,4-Dimethoxyphenyl) ethanamide (compound number 7);
N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-2-pyridine-2-yl acetamide (compound number 8);
N-(3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-2-(1-naphthyl) ethanamide (compound number 9);
N-(the 6-fluoro-(3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-2-(1-naphthyl) ethanamide (compound number 10);
N-[(4R)-6,8-two fluoro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl]-2-(1-naphthyl) ethanamide (compound number 11);
N-[(4R)-6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl]-2-(1-naphthyl) ethanamide (compound number 12);
N-[(4S)-6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl]-2-(1-naphthyl) ethanamide (compound number 13);
N-(7-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-2-(1-naphthyl) ethanamide (compound number 14);
N-[(4R)-8-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl]-2-(1-naphthyl) ethanamide (compound number 15);
N-[(4S)-8-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl]-2-(1-naphthyl) ethanamide (compound number 16);
N-(5-hydroxyl-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-2-(1-naphthyl) ethanamide (compound number 17);
N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-2-(2-naphthyl) ethanamide (compound number 18);
(2S)-N-[(4R)-6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl]-2-(6-methoxyl group-2-naphthyl) propionic acid amide (compound number 19);
(2S)-N-[(4S)-6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl]-2-(6-methoxyl group-2-naphthyl) propionic acid amide (compound number 20);
N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-2-(1,2,3,4-tetralin-1-yl) ethanamide (compound number 21);
N-[(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)]-2-(1,2,3,4-tetralin-2-yl) ethanamide (compound number 22);
2-(1,3-benzo dioxole-5-yl)-N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl) ethanamide (compound number 23);
N-(6-fluoro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-2-(5-fluoro-3-Methyl-1H-indole-2-yl) ethanamide (compound number 24);
N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-2-(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanamide (compound number 25);
2-(1,2-benzoisoxazole-3-yl)-N-[(4R)-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl) ethanamide (compound number 26);
2-(1,2-benzoisoxazole-3-yl)-N-[(4S)-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl) ethanamide (compound number 27);
N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(2-cyclopentyloxy phenyl) propionic acid amide (compound number 28);
N-[(4R)-6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl]-3-(3-cyclopentyloxy) Phenylpropionamide (compound number 29);
N-[(4S)-6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl]-3-(3-cyclopentyloxy) Phenylpropionamide (compound number 30);
N-[(4R)-(8-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-[2-(cyclopentyloxy) phenyl] propionic acid amide (compound number 31);
N-[(4S)-8-chloro-3,4-dihydro spiral shell [chromene-2,1 '-ring fourth-4-yl]-3-[2-(cyclopentyloxy) phenyl] propionic acid amide (compound number 32);
7-benzyloxy-N-(3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(2-cyclopentyloxy phenyl) propionic acid amide (compound number 33);
N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-{2-[(sec.-propyl alkylsulfonyl) amino] phenyl } propionic acid amide (compound number 34);
N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(2-pyridine-2-base phenyl) propionic acid amide (compound number 35);
N-(6,8-, two chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(2-pyridin-3-yl phenyl) propionic acid amide (compound number 36);
N-(3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(2-cyclopentyloxy-3-methoxyl group) Phenylpropionamide (compound number 37);
N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(2,3-dimethoxy) Phenylpropionamide (compound number 38);
N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(2-isopropoxy-3-methoxyl group) Phenylpropionamide (compound number 39);
N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(3-chloro-4-methoxyl group) Phenylpropionamide (compound number 40);
N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(2-cyclo propyl methoxy-3-methoxyl group) Phenylpropionamide (compound number 41);
N-[(4R)-6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)]-3-(2-cyclopentyloxy-3-methoxyl group) Phenylpropionamide (compound number 42);
N-[(4S)-6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)]-3-(2-cyclopentyloxy-3-methoxyl group) Phenylpropionamide (compound number 43);
N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(2-cyclopentyloxy-3-oxyethyl group) Phenylpropionamide (compound number 44);
N-(7-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(2-cyclopentyloxy-3-methoxyl group) Phenylpropionamide (compound number 45);
N-(8-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(2-oxyethyl group-3-methoxyl group) Phenylpropionamide (compound number 46);
N-[(4R)-8-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)]-3-(2-cyclopentyloxy-3-methoxyl group) Phenylpropionamide (compound number 47);
N-[(4S)-(8-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(2-cyclopentyloxy-3-methoxyl group) Phenylpropionamide (compound number 48);
N-(6-chloro-7-methyl-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(2-cyclopentyloxy-3-methoxyl group) Phenylpropionamide (compound number 49);
N-(5-benzyloxy-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(2-cyclopentyloxy-3-methoxyl group) Phenylpropionamide (compound number 50);
N-(5-hydroxyl-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(2-cyclopentyloxy-3-methoxyl group) Phenylpropionamide (compound number 51);
N-(3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-5-methoxyl group-4-yl)-3-(2-cyclopentyloxy-3-methoxyl group) Phenylpropionamide (compound number 52);
(4R)-6-chloro-N-(3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(2-cyclopentyloxy-3-methyl) Phenylpropionamide (compound number 53);
(4S)-6-chloro-N-(3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(2-cyclopentyloxy-3-methyl) Phenylpropionamide (compound number 54);
N-6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-4-base-3-(2-hydroxy 3-methoxybenzene base) propionic acid amide (compound number 55);
N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(2-benzyloxy-3-methoxyl group) Phenylpropionamide (compound number 56);
N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-{2-isopropoxy-3-[(methyl sulphonyl) amino] phenyl } propionic acid amide (compound number 57);
N-(8-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-{2-isopropoxy-3-[(methyl sulphonyl) amino] phenyl } propionic acid amide (compound number 58);
N-(6,8-, two chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(2-cyclopentyloxy-3-methoxyl group) Phenylpropionamide (compound number 59);
N-(6,8-, two chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-{[2-(dimethylamino) oxyethyl group-3-methoxyl group] phenyl } propionic acid amide (compound number 60);
N-(6,8-, two chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-{2-propoxy--3-[(methyl sulphonyl) amino] phenyl } propionic acid amide (compound number 61);
N-(6,8-, two chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-{2-isopropoxy-5-[(methyl sulphonyl) amino] phenyl } propionic acid amide (compound number 62);
N-(6,8-, two chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-{2-butoxy-3-[(methyl sulphonyl) amino] phenyl } propionic acid amide (compound number 63);
N-(6,8-, two chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-{2-(cyclo propyl methoxy)-3-[(methyl sulphonyl) amino] phenyl } propionic acid amide (compound number 64);
N-(6,8-, two chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-{2-isopropoxy-3-[(methyl sulphonyl) amino] phenyl } propionic acid amide (compound number 65);
N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(1-naphthyl) propionic acid amide (compound number 66);
N-[4 (S)-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(2-methoxyl group-1-naphthyl) propionic acid amide (compound number 67);
N-[4S-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(2-methoxyl group-1-naphthyl) propionic acid amide (compound number 68);
N-[(4R)-6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(4-methoxyl group-1-naphthyl) propionic acid amide (compound number 69);
N-[(4S)-6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(4-methoxyl group-1-naphthyl) propionic acid amide (compound number 70);
(4R)-6-chloro-N-(3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(4-difluoro-methoxy-1-naphthyl) propionic acid amide (compound number 71);
(4S)-6-chloro-N-(3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(4-difluoro-methoxy-1-naphthyl) propionic acid amide (compound number 72);
N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(2-naphthyl) propionic acid amide (compound number 73);
N-[4R-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(6-methoxyl group-2-naphthyl) propionic acid amide (compound number 74);
N-[4S-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(6-methoxyl group-2-naphthyl) propionic acid amide (compound number 75);
N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(quinoline-2-yl) propionic acid amide (compound number 76);
N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(1H-indol-3-yl) propionic acid amide (compound number 77);
N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(2-methyl-7-methoxyl group-1-cumarone-4-yl) propionic acid amide (compound number 78);
N-[(4R)-6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl]-3-(7-methoxyl group-2-methyl isophthalic acid-cumarone-5-yl) propionic acid amide (compound number 79);
N-[(4S)-6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl]-3-(7-methoxyl group-2-methyl isophthalic acid-cumarone-5-yl) propionic acid amide (compound number 80);
3-(1,4-Ben Bing dioxin-6-yl)-N-(6-fluoro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl) propionic acid amide (compound number 81);
3-(1,3-benzo dioxole-4-yl)-N-[6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl] propionic acid amide (compound number 82);
3-(1,3-benzo dioxole-4-yl)-N-(8-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl) propionic acid amide (compound number 83);
3-(1,4-Ben Bing dioxin-5-yl)-N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl) propionic acid amide (compound number 84);
N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(dibenzo [b, d] furans-4-yl) propionic acid amide (compound number 85);
N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-ring penta]-the 4-yl)-3-(2-cyclopentyloxy-3-methoxyl group) propionic acid amide (compound number 86);
N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-hexamethylene]-the 4-yl)-3-(2-cyclopentyloxy-3-methoxyl group) Phenylpropionamide (compound number 87);
N-(2,2-dimethyl-3,4-dihydro-2H-chromene-4-yl)-3-(2-cyclopentyloxy-3-methoxyl group) Phenylpropionamide (compound number 88);
N-(6-chloro-3,4-dihydro-2H-sulfo-chromene-4-yl)-3-(2-cyclopentyloxy-3-p-methoxy-phenyl) propionic acid amide (compound number 89);
N-(6-chloro-3,4-dihydro-2H-sulfo-chromene-4-yl)-3-(2-methoxyl group-1-naphthyl) propionic acid amide (compound number 90);
N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-4-(2-cyclopentyloxy phenyl) butyramide (compound number 91);
N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-4-[2-(cyclopentyloxy)-3-p-methoxy-phenyl] butyramide (compound number 92);
N-(4R)-6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-4-base-4-(2-cyclopentyloxy-3-p-methoxy-phenyl) butyramide (compound number 93);
N-{ (4S)-6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl }-4-[(2-(cyclopentyloxy)-3-p-methoxy-phenyl] butyramide (compound number 94);
(4R)-N-(8-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-4-(2-cyclopentyloxy-3-p-methoxy-phenyl) butyramide (compound number 95);
(4S)-N-(8-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-4-(2-cyclopentyloxy-3-p-methoxy-phenyl) butyramide (compound number 96);
N-(8-chloro-6-fluoro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-4-(2-cyclopentyloxy-3-p-methoxy-phenyl) butyramide (compound number 97);
N-(6,8-, two chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-4-(2-cyclopentyloxy-3-p-methoxy-phenyl) butyramide (compound number 98);
N-(7-benzyloxy-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-4-(2-cyclopentyloxy-3-p-methoxy-phenyl) butyramide (compound number 99);
N-(7-hydroxyl-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-4-(2-cyclopentyloxy-3-p-methoxy-phenyl) butyramide (compound number 100);
N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-4-oxo-4-(4-methoxyl group naphthyl) butyramide (compound number 101);
N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-4-hydroxyl-4-(4-methoxyl group naphthyl) butyramide (compound number 102);
N-(6-chloro-2,2-dimethyl-3,4-dihydro-2H-chromene-4-yl)-4-(2-cyclopentyloxy-3-methoxyl group) phenylbutanamides (compound number 103);
N-(6-chloro-3,4-dihydro-2H-sulfo-chromene-4-yl)-4-(2-cyclopentyloxy-3-p-methoxy-phenyl) butyramide (compound number 104); And
The steric isomer of compound 1-104, enantiomer, diastereomer and pharmacy acceptable salt are also at the row of consideration.
Present patent application also provides a kind of pharmaceutical composition, and it contains at least a compound as herein described and at least a pharmaceutically acceptable vehicle (as pharmaceutically acceptable carrier or thinner).Preferably, described pharmaceutical composition contains the compound at least a as herein described for the treatment of significant quantity.Compound of the present invention can be with pharmaceutically acceptable vehicle (as carrier or thinner) but in conjunction with or the suppressed by vector dilution, or be encapsulated in the carrier of capsule, anther sac, paper or other vessel forms.
Compound as herein described and pharmaceutical composition can be used for treating disease, illness and/or the obstacle of being regulated by the TRPV3 acceptor.
One or more compounds described herein that the present invention further provides the amount by will effectively suppressing the TRPV3 acceptor give experimenter that it is had needs, treat the method for disease, illness and/or the obstacle regulated by the TRPV3 acceptor in this subject.
This paper also provides the method for preparing compound described herein.
Embodiment
Present patent application provides the chromanane derivative that can be used as the TRPV3 conditioning agent and the method for synthesizing these compounds.Also provide and had pharmacy acceptable salts similar activity, these compounds, enantiomer and diastereomer.Further provide to comprise described compound together with the pharmaceutical composition of pharmaceutically acceptable carrier, vehicle or thinner, this pharmaceutical composition can be used for treating disease, illness and/or the obstacle by the TRPV3 mediation.
Following definition is applicable to term as used herein:
Term " halogen " or " halo " comprise fluorine, chlorine, bromine or iodine.
Term " alkyl " refer to have 1-8 carbon atom, only formed and do not have the straight or branched hydrocarbon chain group of degree of unsaturation by carbon and hydrogen atom, and be connected with the rest part of molecule by singly-bound, for example: methyl, ethyl, n-propyl, 1-methylethyl (sec.-propyl), normal-butyl, n-pentyl and 1,1-dimethyl ethyl (tertiary butyl).Term " C 1-6Alkyl " refer to have the alkyl chain of 1-6 carbon atom.
Term " thiazolinyl " refers to the straight or branched aliphatic hydrocarbon group that comprises 2-10 carbon atom and contain at least one carbon-to-carbon double bond.The limiting examples of alkenyl group comprises vinyl, 1-propenyl, 2-propenyl (allyl group), pseudoallyl, 2-methyl isophthalic acid-propenyl, 1-butylene base and crotyl.
Term " alkynyl " refers to have 2 to about 12 carbon atoms and has chain alkylene group at least one carbon-to-carbon triple bond, straight or branched (group with about 10 carbon atoms of 2-is preferred), for example ethynyl, proyl and butynyl.
The logical peroxide bridge of term " alkoxyl group " expression is connected to the alkyl group of molecule rest part.The representative example of this class group is-OCH 3With-OC 2H 5
Term " cycloalkyl " expression 3 is to the non-fragrant monocycle of about 12 carbon atoms or encircle ring system more, as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.Polycyclic naphthene base examples of groups includes but not limited to perhydro-naphthyl, adamantyl and norcamphyl group, bridged ring group or spiral shell bicyclic radicals (for example, spiral shell (4,4) ninth of the ten Heavenly Stems-2-yl).
Term " cycloalkylalkyl " refer to have 3 to about 8 carbon atoms, be directly connected to the group that contains cyclic rings on the alkyl group.The cycloalkylalkyl group can be connected to main structure in any carbon atom place in alkyl, thereby produces stable structure.The limiting examples of this class group comprises cyclopropyl methyl, cyclobutyl ethyl and cyclopentyl ethyl.
Term " cycloalkenyl group " refers to have 3 to the group that contains cyclic rings about 8 carbon atoms, that have at least one carbon-to-carbon double bond, as cyclopropenyl radical, cyclobutene base and cyclopentenyl.
Term " aryl " refers to have the aromatic group of 6-14 carbon atom, as phenyl, naphthyl, tetraline, indanyl and xenyl.
Term " arylalkyl " refers to directly be combined in the aromatic yl group as defined above on the alkyl as defined above, for example-and CH 2C 6H 5Or-C 2H 4C 6H 5
Term " heterocyclic radical " and " heterocyclic ring " refer to the cyclic group by carbon atom and 1-5 the heteroatoms that is selected from nitrogen, phosphorus, oxygen and sulphur 3-15 that form, stable unit.For the present invention, the heterocyclic ring group can be monocycle, dicyclo or three ring ring systems, can comprise to condense ring system, bridge joint ring system or spiro system, and the nitrogen in the heterocyclic ring group, phosphorus, carbon, oxygen or sulphur atom optionally is oxidized to various oxidation state.In addition, nitrogen-atoms is optionally by quaternized; And described cyclic group can be fractional saturation or all saturated (that is, heterocycle or heteroaryl).This class heterocyclic ring examples of groups includes but not limited to: azetidine base (azetidinyl), acridyl, benzo dioxolyl, benzo dioxacyclohexyl (benzodioxanyl), benzofuryl, carbazyl, cinnolines base, dioxolanyl, indolizinyl, naphthyridinyl, perhydro-azepine
Figure BDA0000127889200000161
Base, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pyridyl, pteridyl, purine radicals, quinazolyl, quinoxalinyl, quinolyl, isoquinolyl, tetrazyl, imidazolyl, tetrahydro isoquinolyl, piperidyl, piperazinyl, 2-oxo piperazinyl, 2-oxo-piperidine base, 2-oxo-pyrrolidine base, 2-oxo azepine
Figure BDA0000127889200000162
Base, azepine
Figure BDA0000127889200000163
Base, pyrryl, the 4-piperidone base, pyrrolidyl, pyrazinyl, pyrimidyl, pyridazinyl oxazolyl oxazolinyl oxazolidinyl (oxazolidinyl), triazolyl, indanyl isoxazolyl isoxazole alkyl, morpholinyl, thiazolyl, thiazolinyl, thiazolidyl, isothiazolyl, quinuclidinyl, the isothiazole alkyl, indyl, pseudoindoyl, the indoline base, the isoindoline base, the octahydro indyl, the octahydro pseudoindoyl, quinolyl (quinolyl), isoquinolyl, the Decahydroisoquinolinpreparation base, benzimidazolyl-, thiadiazolyl group, benzopyranyl, benzothiazolyl benzoxazolyl, furyl, tetrahydrofuran base, THP trtrahydropyranyl, thienyl, benzothienyl, thio-morpholinyl, the thio-morpholinyl sulfoxide, the thio-morpholinyl sulfone, dioxy phosphorus heterocycle amyl group oxadiazole base, chromanyl and isochroman base.Described heterocyclic ring group can be connected to main structure in any heteroatom or carbon atom place, thereby produces stable structure.
Term " heterocyclic radical alkyl " refers to be directly connected to the heterocyclic ring group on the alkyl group.The heterocyclic radical alkyl can be connected to main structure in any carbon atom place in alkyl group, thereby produces stable structure.
Term " heteroaryl " refers to the heteroaromatic cyclic group.The heteroaryl cyclic group can be connected to main structure in any heteroatom or carbon atom place, thereby produces stable structure.
Term " heteroarylalkyl " refers to be directly connected to the hetero-aromatic ring group on the alkyl group.The heteroarylalkyl group can be connected to main structure in any carbon atom place in alkyl group, thereby produces stable structure.
Unless otherwise prescribed, term used herein " replacement " refers to one or more substituting groups, and described substituting group comprises: hydroxyl, halogen, carboxyl, cyano group, nitro, oxo (=O), sulfo-(=S), replace or unsubstituted alkyl, replace or unsubstituted alkoxyl group, replace or unsubstituted thiazolinyl, replace or unsubstituted alkynyl, replace or unsubstituted aryl, replace or unsubstituted arylalkyl, replace or unsubstituted cycloalkyl, replace or unsubstituted cycloalkenyl alkyl, replace or unsubstituted cycloalkenyl group, replace or unsubstituted amino, replace or unsubstituted aryl, replace or unsubstituted heteroaryl, replace or unsubstituted heterocyclic alkyl ring, replace or unsubstituted heteroarylalkyl, replace or unsubstituted heterocyclic ring, replace or unsubstituted guanidine,-COOR x,-C (O) R x,-C (S) R x,-C (O) NR xR y,-C (O) ONR xR y,-NR xCONR yR z,-N (R x) SOR y,-N (R x) SO 2R y,-(=N-N (R x) R y) ,-NR xC (O) OR y,-NR xR y,-NR xC (O) R y,-NR xC (S) R y,-NR xC (S) NR yR z,-SONR xR y,-SO 2NR xR y,-OR x,-OR xC (O) NR yR z,-OR xC (O) OR y,-OC (O) R x,-OC (O) NR xR y,-R xNR yC (O) R z,-R xOR y,-R xC (O) OR y,-R xC (O) NR yR z,-R xC (O) R y,-R xOC (O) R y,-SR x,-SOR x,-SO 2R xWith-ONO 2, R wherein x, R yAnd R zBe independently selected from hydrogen, replace or unsubstituted alkyl, replace or unsubstituted alkoxyl group, replace or unsubstituted thiazolinyl, replace or unsubstituted alkynyl, replace or unsubstituted aryl, replace or unsubstituted arylalkyl, replace or unsubstituted cycloalkyl, replace or unsubstituted cycloalkenyl group, replace or unsubstituted amino, replace or unsubstituted aryl, replace or unsubstituted heteroaryl, the heterocyclic radical alkyl ring that replaces, replace or unsubstituted heteroarylalkyl, perhaps replace or unsubstituted heterocyclic ring.Substituting group in the group of above-mentioned " replacement " can not further be replaced.For example, when the substituting group on " substituted alkyl " was " substituted aryl ", the substituting group on " substituted aryl " can not be " substituted alkenyl ".
Term " treatment " state, obstacle or illness comprise:
(1) appearance of the clinical symptom of prevention or suspension status, obstacle or illness, described state, obstacle or illness develop in the experimenter who suffers from or easily suffer from described state, obstacle or illness but do not experience or demonstrate the clinical or inferior clinical symptom of described state, obstacle or illness as yet;
(2) suppress described state, obstacle or illness, that is, stop or palliate a disease or the development of its at least a clinical or inferior clinical symptom; Or
(3) eliminate a disease, that is, cause at least a clinical or inferior clinical symptom of described state, obstacle or illness or its to disappear.
The benefit of bringing for the experimenter who is treated is remarkable statistically, or is appreciable for experimenter or doctor at least.
Term " experimenter " comprises Mammals (especially human) and other animals, as domestic animal (for example household pet comprises cat, dog) and non-domestic animal (as wildlife).
" treatment significant quantity " refer to when giving when needing the experimenter of therapeutic state, obstacle or illness, is enough to the amount of compound that this treatment is told on." treatment significant quantity " is along with compound, disease, its severity and experimenter's to be treated age, body weight, physical appearance and responsiveness (responsiveness) and change.
The compound of describing in the present patent application can form salt.The limiting examples that constitutes the pharmacy acceptable salt of a present patent application part comprises salt, the salt of organic bases, the salt of chiral base, the salt of natural amino acid and the salt of alpha-non-natural amino acid that mineral alkali is derived.Some compound of present patent application can exist with the form of steric isomer (for example, diastereomer and enantiomer).With regard to the described whole compounds of formula (I), present patent application is prolonged and stereoisomeric forms in any ratio and its mixture.As long as prior art has been instructed the synthetic of specific steric isomer or has been separated, the various stereoisomer forms of present patent application can be separated from each other by methods known in the art, perhaps can obtain given isomer by stereospecificity or asymmetric synthesis.The tautomeric form of compound described herein and mixture are also at the row of consideration.
Pharmaceutical composition
The pharmaceutical composition of present patent application contains at least a compound as herein described and at least a pharmaceutically acceptable vehicle (as pharmaceutically acceptable carrier or thinner).Preferably, the pharmaceutical composition of considering contains compound as herein described with the amount that is enough to suppress the TRPV3 acceptor in the subject.
The experimenter who considers for example comprises: viable cell and the Mammals that comprises the people Mammals.Compound of the present invention can dilute with pharmaceutically acceptable vehicle (as carrier or thinner) combination or by carrier, or is encapsulated in the carrier of capsule, anther sac (sachet), paper or other vessel forms.
The example of suitable carriers includes but not limited to: water, salts solution, alcohol, polyoxyethylene glycol, the Viscotrol C of poly-hydroxy ethoxylation, peanut oil, sweet oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesiumcarbonate, sugar, cyclodextrin, amylose starch, Magnesium Stearate, talcum, gelatin, agar, pectin, gum arabic, stearic acid or Mierocrystalline cellulose hang down alkyl oxide, silicic acid, lipid acid, fatty acid amine, glycerine monofatty ester and two glyceryl ester, the sour ether of tetramethylolmethane fat, polyoxyethylene, Walocel MT 20.000PV and polyvinylpyrrolidone.
Described carrier and thinner can comprise slow-release material, as glyceryl monostearate or distearin (use separately or mix with paraffin).
This pharmaceutical composition also can comprise one or more pharmaceutically acceptable auxiliarys, wetting agent, emulsifying agent, suspension agent, sanitas, the salt that influences osmotic pressure, buffer reagent, sweeting agent, correctives, tinting material or above-mentioned any combination.Also can carry out preparation to pharmaceutical composition of the present invention, thus by program known in the art after experimenter's administration, provide activeconstituents fast, the release that continues or postpone.
Pharmaceutical composition as herein described can for example be recorded in Remington:The Science and Practice of Pharmacy by routine techniques preparation known in the art, and the 20th edition, 2003 (Lippincott Williams ﹠amp; Wilkins) technology in.For example, active compound can mix with carrier or be diluted by carrier, or is encapsulated in the carrier of ampoule, capsule, anther sac, paper or other vessel forms.When carrier when the thinner, it can be solid, semisolid or the fluent material of auxiliary material, vehicle or the medium effect of playing active compound.Active compound can be adsorbed on the granular solids container, for example in anther sac.
Pharmaceutical composition can be conventional form, for example product of capsule, tablet, aerosol, solution, suspension or topical application.
Route of administration can be transports active compound of the present invention effectively to any approach of action site suitable or expectation.Suitable route of administration includes but not limited to: administration in (subcutaneous) administration under oral administration, nasal administration, pulmonary administration, buccal administration, subcutaneous (subdermal) administration, intradermal administration, percutaneous dosing, parenteral admin, rectal administration, reservoir type administration, the skin, intravenous administration, the urethra, intramuscular administration, intranasal administration, dosing eyes (as using ophthalmic solution) or topical (as using topical ointment).The preferred oral route of administration.
The solid orally ingestible form includes but are not limited to: tablet, capsule (soft gelatin or glutoid), drageeing (activeconstituents that contains powder or ball shape form), lozenge (troches and lozenges).Tablet, drageeing or capsule with talcum and/or carbohydrate carrier or binding agent etc. are particularly suitable for oral application.Liquid preparation includes but not limited to syrup, emulsion, soft gelatin and aseptic injectable liquids, as water-based or nonaqueous liquid suspension or solution.Use outward for gi tract, injectable solution or suspension preparation are especially suitable.
Typical tablet by conventional pressed disc technique preparation can comprise: (1) core: active compound (as free compound or its salt), 250mg colloid silica
Figure BDA0000127889200000201
1.5mg Microcrystalline Cellulose
Figure BDA0000127889200000202
70mg modified cellulose gum (Ac-Di-
Figure BDA0000127889200000203
) and the 7.5mg Magnesium Stearate; (2) dressing: HPMC, approximately the Mywacett 9-40T of 9mg and approximately 0.9mg acidylate direactive glyceride.
Liquid preparation includes but not limited to syrup, emulsion, soft gelatin and aseptic injectable liquids, as water-based or nonaqueous liquid suspension or solution.
Use outward for gi tract, injectable solution or suspension preparation are especially suitable, preferably have the aqueous solution of the active compound that is dissolved in polyhydroxylated Viscotrol C.
Methods for the treatment of
The invention provides the compound and the pharmaceutical preparation thereof that are used for the treatment of disease, illness and/or the obstacle regulated by TRPV3.Result for the treatment of and the contact between the inhibition of TRPV3 for example is recorded in: WO2007/056124; Wissenbach, U. etc., Biology of the cell (2004), 96, 47-54; Nilius, B. etc., Physiol Rev (2007), 87, 165-217; Okuhara, D.Y. etc., Expert Opinion on Therapeutic Targets (2007), 11, 391-401; Hu, H.Z. etc., Journal of Cellular Physiology, (2006), 208,201-212; In the reference of quoting with this paper; The mode that All Files is quoted by integral body is incorporated this paper into and is used for described purpose.
Present patent application further provides by the compound of the present invention for the treatment of significant quantity or pharmaceutical composition in the method for being tried disease, illness and/or obstacle that the body interior therapeutic regulated by TRPV3 that needs is arranged.
It is believed that disease, illness and/or the obstacle regulated by TRPV3 include but not limited to: that migraine, arthrodynia, ischemic myocardium cause is pained, acute pain, chronic pain, neuropathic pain, post-operative pain, the pain (for example, postherpetic neuralgia or trigeminal neuralgia) that causes because of neurodynia, pain, toothache and the cancer pain, the inflammatory pain illness (for example sacroiliitis and osteoarthritis) that cause because of diabetic neuropathy.
It is believed that disease, illness and/or the obstacle regulated by TRPV3 include but not limited to: pain, nociceptive pain, toothache, it is pained that ischemic myocardium causes, the pain that causes because of migraine, arthrodynia, DPN, nerve degenerative diseases, retinopathy, the nervosa skin barrier, apoplexy, irritable bladder disease, the urinary incontinence, vulvodynia (vulvodynia), gastrointestinal disorders such as irritable bowel syndrome, stomach-esophageal reflux disease, enteritis, ileitis, gastroduodenal ulcer, inflammatory bowel, Crohn disease, celiac disease (celiacdisease); Inflammatory diseases is as pancreatitis; Dyspnoea is as supersensitivity and non-allergic rhinitis, asthma or chronic obstructive pulmonary disease; The stimulation of skin, eye or mucous membrane; Dermatitis; Pruritus is as uremic pruritus; Heating; Muscle spasm; Vomiting; Dyskinesia; Dysthymia disorders; Huntington's chorea; Hypomnesis; Brain function is limited; Amyotrophic lateral sclerosis (ALS); Dull-witted; Sacroiliitis, osteoarthritis; Diabetes; Obesity; Urticaria; Actinic keratosis; Keratoacanthoma (keratocanthoma); Alopecia (alopecia); Meniere; Tinnitus; Hyperacusis (hyperacusis); Anxiety disorder; And benign prostatic hyperplasia.
General preparation method
Use the known technology of those of ordinary skills to prepare compound described herein (comprising general formula (I) and general formula (II) and concrete example).Reaction sequence by describing in following scheme 1 and the scheme 2 prepares compound described herein.Can infer, all possible isomer also within the scope of the invention.
The starting raw material that is used for following reaction scheme is available commercially, and maybe can be prepared by method known to those skilled in the art.Usually, compound of the present invention can reaction scheme as follows be prepared, and wherein all symbols as hereinbefore defined.
Compound (wherein, the R of general formula (I) 1, R 3, R 4, R a, R b, R c, Rd, n, m as hereinbefore defined, and R 2Be H) can be prepared according to synthetic schemes 1.Therefore, the aryl substituted carboxylic acid generation linked reaction of the volution amine of formula (1) and formula (2), the acid amides of production (I).According to known reaction conditions, in the presence of activator (for example I-hydroxybenzotriazole (HOBt)) and alkali, in the solvent that is fit to, use suitable coupling agents (for example, dicyclohexylcarbodiimide (DCC) or 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCI)) to realize the formation of amido linkage.
Synthetic schemes 1
Figure BDA0000127889200000221
Perhaps, compound (wherein, the R of general formula (I) 1, R 3, R 4, R a, R b, R c, R d, n, m as hereinbefore defined, and R 2Be H) can be by the volution amine of formula (1) and the carboxylic acid halides of formula (3) (wherein X is halogen) in the presence of the alkali (for example triethylamine) that is fit to, in suitable solvent (for example tetrahydrofuran (THF)), be prepared the compound of production (I).
Synthetic schemes 2
Starting raw material 3,4-dihydro spiral shell [chromene-2,1 '-ring fourth]-4-ketone is available commercially, or by 2-hydroxy acetophenone and the cyclic ketones of suitable replacement in the presence of alkali, react (as Kabbe, people Angewandte Chemie (1982) such as H-J., 94, described in the 254-262) be prepared.All do not replace and replace 3,4-dihydro spiral shell [chromene-2,1 '-ring fourth]-4-amine is by 3,4-dihydro spiral shell [chromene-2,1 '-ring fourth]-4-ketone by its oxime intermediate with two the step prepare, as Ram, people such as P., Indian J.Chem.Sec B, (1981), described in 12, the 1063-1067.By using suitable chiral acid as resolution reagent corresponding amine to be split, prepare 3 of optical purity or enrichment, 4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-amine isomer.When using optically pure N-tosyl group proline(Pro) as resolution reagent, obtained best result.Two enantiomorphs of N-tosyl group proline(Pro) are all as Izumiya, people such as N., and Bull.Chem.Soc.Japan. (1953), 26, be prepared described in the 53-56.
Some phenyl acetic acid derivatives that is used for this research is available commercially.The derivative that can't be purchased is prepared by suitable phenyl aldehyde carburetting reaction (homologation).Tetraline acetic acid by corresponding Tetralone an intermediate of Sertraline by Wittig-Horner reaction, carry out shortening subsequently and the ester hydrolysis prepares.Indole-3-acetic acid is prepared by the Fischer indole synthesis described in the following document by the phenyl hydrazine and the γ-ketone acid that replace: Fox, S.S. wait the people, J.Am.Chem.Soc. (1951), 73, people such as 756-2758 and Jackson, Canadian J.Res.Sec.B, (1935), 13,170-172.Benzoisoxazole acetic acid by 4 hydroxy coumarin according to Casini, people J.Heterocyclic Chemistry such as G., (1969), the record among 6, the 279-283 is prepared.
Arylpropionic acid is prepared as committed step by using Knoevenagel condensation reaction (as people such as Rubenstein, J.Chem.Soc., (1926) are described in 650) by aromatic aldehyde and propanedioic acid.The dibenzyl propionic acid prepares by following step: make 2-formyl radical boric acid and aryl halide generation formyl Suzuki linked reaction; Make the aldehyde that obtains carry out the carburetting reaction by the propanedioic acid condensation then.
All aryl butyric acids prepare by the Wittig homlolgation that aromatic aldehyde passes through successively.Therefore, use methoxyl group methylene radical (triphenyl) chlorination phosphorane to make the phenyl aldehyde of replacement increase carbon reaction, obtain corresponding phenylacetic aldehyde derivative, re-use (triphenyl phosphoranediyl) methyl acetate and make this derivative further increase the reaction of two carbon, generate the phenylbutenic acid methyl esters that replaces.The phenylbutenic acid methyl esters of this replacement carries out hydrolysis again behind the shortening, obtains required arylbutyric acid derivatives.
Experimental procedure
3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-4-ketone:
All make by following reaction for the synthesis of needed all the starting raw material spiral shell chromene-4-ketone of 3,4-dihydro spiral shell chromene-4-amine: with the 2-hydroxy acetophenone (1 equivalent) that is commercially available and naphthenone (1 equivalent) in the presence of the excess of triethylamine (2-3 equivalent), in the methyl alcohol that refluxes, react.
3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-4-amine:
Figure BDA0000127889200000242
In the presence of the NaOH aqueous solution (3 equivalent), make and be in 3 in the ethanol (10V), 4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-4 (3H)-ketone (1.0 equivalent) and hydroxylamine hydrochloride (1.5 equivalent) react, generate (4E)-6-chlorine spiral shell [chromene-2,1 '-ring fourth]-4 (3H)-ketoximes with good productive rate.Gained oxime intermediate (1.0 equivalent) by zinc powder (2-3 equivalent) reduction, generates unhindered amina in Glacial acetic acid (10 volume).The amino chromene intermediates of all 4-(table 1) that make by this method all characterize by spectroscopic analysis methods.
The general step for preparing left-handed amine:
With (±) 3, the solution backflow of 4-dihydro spiral shell [chromene-2,1 '-ring fourth]-after 4-sulfonamide derivatives (1.0 equivalent) stirs in Virahol (10-12ml) 10 minutes, formation clear solution.Added the L-proline(Pro) tosylate (0.5 equivalent) that is in the Virahol (10ml) with 15 minutes then, further stirred 30 minutes at uniform temp again.Make the gained mixture be cooled to room temperature, by filtering the diastereomeric salt that collecting precipitation goes out.Under refluxing, make the gained resolution of precipitate in Virahol (10 volume), and slowly cool to room temperature.The mixture that obtains is further stirred 18h.By filtering the salt that collecting precipitation goes out.The suspension of gained salt in water is passed through to add K 2CO 3The aqueous solution alkalizes to pH 8.0.With ethyl acetate (3 * 50ml) extraction gained solution.Organic extract after the merging passes through K 2CO 3Drying is also evaporated under vacuum, obtains the pure enantiomer of 30-38%.Use normal hexane: Virahol: diethylamine (98: 2: 0.1) is analyzed the enantiomeric purity of gained material by the CHIRALPAK-IA post of 250 * 4.6mm as moving phase.
The general step of preparation dextrorotation amine:
As indicated above, to (±) 3,4-dihydro spiral shell [chromene-2,1 '-ring fourth]-4-sulfonamide derivatives (1.0 equivalent) carries out optical resolution with D-proline(Pro) tosylate (0.5 equivalent), obtains dextrorotation amine with the isolated yield of 30-38%.Use normal hexane: Virahol: diethylamine (98: 2: 0.1) is measured the enantiomeric purity of gained material by the CHIRALPAK-I A post of 250 * 4.6mm as moving phase.
The intermediate that the ownership system gets all characterizes by spectroscopic analysis methods before for the preparation of compound of the present invention.Structural details and the selected physical chemistry details of 3,4-dihydro spiral shell [chromene-2,1 '-ring fourth]-4-amine have been provided in the table 1.
Table 1:3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-4-amine
Figure BDA0000127889200000251
Figure BDA0000127889200000261
Provided the selected spectral analysis data of 3,4-dihydro spiral shell [chromene-2,1 '-ring fourth]-4-amine below.
Intermediate 1
8-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-4-amine:
1H?NMR(300MHz，CDCl 3)δ1.68-1.77(m，4H)，1.74-1.82(m，1H)，1.88-1.93(m，3H)，2.35-2.57(m，2H)，3.99-4.04(m，1H)，6.69(d，J＝7.2Hz，1H)，7.04(dd?J＝2.4，6.3Hz，1H)，7.36(s，1H)。
Intermediate 2
6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-4-amine:
1H?NMR(300MHz，CDCl 3)δ1.68-1.77(m，4H)，1.85-1.94(m，1H)，2.10-2.20(m，3H)，2.35-2.45(m，2H)，3.93-3.99(m，1H)，6.69(d，J＝7.5Hz，1H)，7.04(dd?J＝2.4，6.9Hz，1H)，7.36(s，1H)。
Intermediate 3
(4R)-8-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-4-amine:
1H NMR (300MHz, CDCl 3) δ 1.68-1.77 (m, 2H), 1.74-1.82 (m, 2H), 1.88-1.93 (m, 2H), and 1.97-2.05 (m, 1H), 2.10-2.19 (m, 1H), and 2.23-2.39 (m, 1H), 2.35-2.57 (m, 1H), and 3.99-4.04 (m, 1H), 6.80 (t, J=7.2Hz, 1H), 7.18 (d, J=7.8Hz, 1H), 7.28 (d, J=7.8Hz, 1H); HPLC: the retention time of advantage enantiomer: 26.23 minutes; Ee=96.06%; Specific rotatory power: [α] D=-6.63 °, c=1% is in methyl alcohol.
Intermediate 4
(4S)-8-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-4-amine:
1H NMR (300MHz, CDCl 3) δ 1.68-1.77 (m, 2H), 1.74-1.82 (m, 2H), 1.88-1.93 (m, 2H), and 1.97-2.05 (m, 1H), 2.10-2.19 (m, 1H), and 2.23-2.39 (m, 1H), 2.35-2.57 (m, 1H), and 3.99-4.04 (m, 1H), 6.80 (t, J=7.2Hz, 1H), 7.18 (d, J=7.8Hz, 1H), 7.28 (d, J=7.8Hz, 1H); HPLC: the retention time of advantage enantiomer: 30.57 minutes; Ee=97.14%; Specific rotatory power: [α] D=+6.30 °, c=1% is in methyl alcohol.
Intermediate 5
3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-4-amine:
1H?NMR(300MHz，CDCl 3)δ1.65-1.75(m，3H)，1.90-2.00(m，3H)，2.30-2.36(m，2H)，3.94-4.05(m，1H)，5.60-5.66(m，2H)，6.80-6.90(m，2H)，7.08-7.25(m，2H)。
Intermediate 6
6-fluoro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-4-amine:
1H?NMR(300MHz，CDCl 3)δ1.67-1.76(m，2H)，1.90-2.00(m，2H)，2.10-2.20(m，2H)，2.28-2.39(m，2H)，3.90-4.00(m，1H)，5.70-5.76(m，1H)，6.70-6.99(m，3H)，7.08(dd，J＝2.4，9.0Hz，1H)。
Intermediate 7
6,8-, two fluoro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-4-amine:
1H?NMR(300MHz，CDCl 3)δ1.69-1.82(m，5H)，2.05-2.22(m，3H)，2.36-2.55(m，2H)，3.99-4.06(m，1H)，6.69-6.76(m，1H)，6.96(d，J＝9.0Hz，1H)。
Intermediate 8
(4R)-6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-4-amine:
1H NMR (300MHz, CDCl 3) δ 1.68-1.77 (m, 4H), 1.74-1.82 (m, 1H), 1.88-1.93 (m, 3H), 2.35-2.57 (m, 2H), 3.99-4.04 (m, 1H), 6.69 (d, J=7.2Hz, 1H), 7.04 (dd J=2.4,6.3Hz, 1H), 7.36 (s, 1H); HPLC: the retention time of advantage enantiomer: 26.57 minutes; Ee=98.03%; Specific rotatory power: [α] D=+8.64 °, c=1% is in methyl alcohol.
Intermediate 9
(4S)-6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-4-amine:
1H NMR (300MHz, CDCl 3) δ 1.68-1.77 (m, 4H), 1.74-1.82 (m, 1H), 1.88-1.93 (m, 3H), 2.35-2.57 (m, 2H), 3.99-4.04 (m, 1H), 6.69 (d, J=7.2Hz, 1H), 7.04 (dd J=2.4,6.3Hz, 1H), 7.36 (s, 1H); HPLC: the retention time of advantage enantiomer: 27.26min; Ee=99.88%; Specific rotatory power: [α] D=-8.19 °, c=1% is in methyl alcohol.
Intermediate 10
7-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-4-amine:
1H?NMR(300MHz，CDCl 3)δ1.59-1.78(m，2H)，1.85-1.95(m，2H)，2.00-2.10(m，2H)，2.16-2.26(m，2H)，2.33-2.40(m，1H)，2.47-2.57(m，1H)，3.99-4.05(m，1H)，6.80(t，J＝7.8Hz，1H)，7.19(d，J＝7.8Hz，1H)，7.28(d，J＝7.8Hz，1H)。
Intermediate 11
5-benzyloxy-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-4-amine:
1H?NMR(300MHz，CDCl 3)δ2.00-2.14(m，6H)，2.25-2.40(m，2H)，3.73(br?s，2H)，4.29(t，J＝6.9Hz，1H)，5.03-5.12(m，2H)，6.50(dd，J＝2.4，8.4Hz，2H)，7.07(t，J＝8.4Hz，1H)，7.33-7.40(m，5H)。
Intermediate 12
7-(benzyloxy)-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-4-amine:
1H?NMR(300MHz，CDCl 3)δ1.64-1.71(m，1H)，1.84-1.91(m，3H)，2.10-2.18(m，2H)，2.26-2.34(m，1H)，4.45(br?s，1H)，5.07(s，2H)，6.45(s，1H)，6.62(d，J＝7.8Hz，1H)，7.09(s，1H)，7.26-7.37(m，5H)，8.69(br?s，3H)。
Intermediate 13
(6,8-dichloro)-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-4-amine:
IR(KBr)3426，2920，1519，1458，1243，1153，865cm -1； 1H?NMR(300MHz，CD 3OD)δ1.74-1.90(m，3H)，2.14-2.30(m，3H)，2.50-2.57(m，2H)，2.62-2.69(m，1H)，4.65-4.71(m，1H)，6.90-6.96(m，1H)，7.43(s，2H)；ESI-MS(m/z)258.20(M+H) +。
Intermediate 14
(6-chloro-7-methyl)-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-4-amine:
1H NMR (300MHz, CDCl 3) δ 1.85-1.93 (and m, 4H), 2.05-2.19 (m, 4H), 2.72 (s, 3H), 4.15-4.22 (m, 1H), 4.76 (br s, 2H, can with D 2O exchanges), 6.67 (s, 1H), 7.45 (s, 1H).
Intermediate 15
5-methoxyl group-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-4-amine:
1H NMR (300MHz, CDCl 3) δ 1.65-1.80 (and m, 1H), 1.90-2.08 (m, 3H), 2.20-2.30 (m, 4H), 2.36 (br s, 2H, can with D 2O exchanges), 3.83 (s, 3H), 4.15 (t, J=6.3Hz, 1H), 6.41 (d, J=8.1Hz, 1H), 6.47 (d, J=8.1Hz, 1H), 7.06 (t, J=8.4Hz, 1H).
Intermediate 16
6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-pentamethylene]-4-amine:
1H?NMR(300MHz，CDCl 3)δ1.30-1.45(m，4H)，1.68-1.78(m，4H)，2.05-2.12(m，2H)，3.90-4.01(m，1H)，6.76(d，J＝8.4Hz，1H)，7.02(dd，J＝2.4，8.4Hz，1H)，7.35(s，1H)。
Intermediate 17
6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-hexanaphthene]-4-amine:
1H?NMR(300MHz，CDCl 3)δ1.35-1.55(m，7H)，1.70-1.78(m，3H)，2.07-2.17(m，2H)，3.93-3.98(s，1H)，6.71(d，J＝8.7Hz，1H)，7.04(dd，J＝2.4，8.7Hz，1H)，7.38(s，1H)。
Intermediate 18
2,2-dimethyl chromanane-4-amine:
1H?NMR(300MHz，DMSO-d 6)δ1.23(s，3H)，1.34(s，3H)，1.48-1.56(m，1H)，1.97-2.03(m，3H)，3.80-3.86(m，1H)，6.64(d，J＝6.9Hz，1H)，6.83(t，J＝7.5Hz，1H)，7.05(t，J＝6.9Hz，1H)，7.53(d，J＝7.8Hz，1H)。
Intermediate 19
6-chlorothio chromanane-4-amine:
1H?NMR(300MHz，CD 3OD)δ2.20-2.26(m，1H)，2.32-2.40(m，1H)，3.00-3.10(m，2H)，4.51(br?s，1H)，7.07(d，J＝8.4Hz，1H)，7.17(dd，J＝2.4，9.0Hz，1H)，7.34(s，1H)。
Intermediate 20
(8-chloro-6-fluorine)-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-4-amine:
1H?NMR(300MHz，CDCl 3)δ1.74-1.86(m，1H)，1.92-2.05(m，2H)，2.15-2.29(m，3H)，2.45-2.55(m，1H)，2.63-2.69(m，1H)，4.66-4.72(m，1H)，7.17-7.26(m，2H)。
Intermediate 21
(6-chlorine)-2,2-dimethyl chromanane-4-amine:
IR(KBr)2977，2924，1522，1482，1223，1150，815cm -1； 1H?NMR(300MHz，CDCl 3)δ1.29(s，3H)，1.48(s，3H)，1.84-1.92(m，1H)，2.31-2.37(m，1H)，4.57-4.64(m，1H)，6.82(d，J＝8.7Hz，1H)，7.23(dd?J＝2.1，8.4Hz，1H)，7.47(s，1H)。
Embodiment
Further illustrate the present invention by the following example, described embodiment should not be considered as disclosed scope is limited by any way, and only is intended to illustrative purpose.
Embodiment 1
N-(8-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-the 2-phenyl-acetamides:
Figure BDA0000127889200000311
At room temperature, to intermediate 1 (200mg, 0.898mmol) add EDCIHCl (258mg in the solution after in methylene dichloride (10ml), fully stirring, 1.348mmol), HOBt (206mg, 1.348mmol), toluylic acid (183mg, 1.348mmol) and triethylamine (375 μ l, 2.696mmol).At room temperature, the gained reaction mixture is stirred 16h under nitrogen.Water (10ml) diluted reaction mixture also separates each layer.Water layer with chloroform (2 * 10ml) extractions, the organic layer water after the merging (2 * 30ml), salt solution (30ml) washing, and pass through Na 2SO 4Dry.Use is in 10% acetone in the sherwood oil, and the crude product that obtains behind the pressure reducing and steaming solvent is carried out purifying by silica gel column chromatography, obtains the greyish white solid product of 210mg; IR (KBr) 3294,2943,1647,1448,1243,704cm -1 1H NMR (300MHz, CDCl 3) δ 1.63-1.77 (m, 2H), 1.88-1.92 (m, 1H), 2.01-2.08 (m, 1H), and 2.17-2.28 (m, 2H), 2.34-2.41 (m, 2H), 3.64 (s, 2H), 5.26 (q, J=9.3Hz, 1H), 5.48 (d, J=9.0Hz, 1H), 6.72 (t, J=7.8Hz, 1H), 6.89 (d, J=7.8Hz, 1H), 7.27-7.35 (m, 6H); ESI-MS (m/z) 342.50 (M+H) +
Embodiment 2
N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-2-(2-p-methoxy-phenyl) ethanamide:
Figure BDA0000127889200000321
As described in example 1 above, title compound is by intermediate 2 (200mg, 0.763mmol) and 2-methoxyphenylacetic acid (190mg, 1.148mmol) at EDCIHCl (219mg, 1.148mmol), HOBt (175mg, 1.148mmol) and triethylamine (318 μ l, 2.289mmol) existence was descended, is prepared in methylene dichloride (10ml), obtained the 206mg white solid product through 6 hours; IR (KBr) 3272,2979,1634,1475,1248,753cm -1 1HNMR (300MHz, CDCl 3) δ 1.65-1.74 (m, 2H), 1.85-2.04 (m, 2H), 2.12-2.20 (m, 2H), and 2.24-2.38 (m, 2H), 3.62 (q, J=14.7Hz, 2H), 3.85 (s, 3H), 5.19 (q, J=9.3Hz, 1H), 5.78 (d, J=8.4Hz, 1H), 6.67 (d, J=8.7Hz, 1H), 6.87-6.94 (m, 3H), 7.02 (d, J=8.4Hz, 1H), 7.26-7.30 (m, 2H); ESI-MS (m/z) 372.50 (M+H) +
Embodiment 3
N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-the 2-{2-[(methyl sulphonyl) amino] phenyl } ethanamide:
Figure BDA0000127889200000322
Step 1:N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-2-(2-nitrophenyl) ethanamide: as described in example 1 above, this compound is by intermediate 2 (500mg, 1.923mmol) and 2-nitrophenyl-acetic acid (348mg, 1.923mmol) at EDCIHCl (191mg, 1.789mmol), HOBt (153mg, 1.789mmol) and triethylamine (802 μ l, 2.289mmol) exist down, in methylene dichloride (10ml), be prepared, obtained the 550mg white solid product through 6 hours; 1H NMR (300MHz, CDCl 3) δ 1.67-1.84 (m, 5H), 2.10-2.18 (m, 2H), 2.32-2.43 (m, 2H), 3.91 (s, 2H), 5.19-5.27 (m, 1H), and 5.92-5.98 (m, 1H), 6.71 (d, J=9.3Hz, 1H), 7.00-7.08 (m, 1H), 7.45-7.53 (m, 2H), 7.64 (d, J=7.5Hz, 1H), 8.05 (d, J=8.9Hz, 1H).
Step 2:2-(2-aminophenyl)-N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl) ethanamide: at room temperature, (200mg 0.512mmol) adds the NH that is in the water (3ml) in the solution after abundant the stirring in ethanol (5ml) to step 1 intermediate 4Cl (276mg, 5.102mmol).Under uniform temp, the gained reaction mixture was stirred 15 minutes, be heated to 80 ℃ with 15 minutes then.Under uniform temp, add iron (86mg, 1.552mmol).With the gained reaction mixture 2h that further refluxes.(2 * 50ml) extract with chloroform with boiling off the resistates that obtains behind the solvent.Chloroform layer is passed through diatomite.Separate each layer.The organic layer water (2 * 30ml), salt solution (30ml) washing, and pass through Na 2SO 4Dry.Boil off solvent and obtain the 150mg product.
Step 3:N-(6-chloro-3; 4-dihydro spiral shell [chromene-2; 1 '-cyclopropane]-the 4-yl)-the 2-{2-[(methyl sulphonyl) amino] phenyl } ethanamide: under 0 ℃; (150mg 0.420mmol) adds pyridine (1ml) in the solution after abundant the stirring in methylene dichloride (5ml) to step 2 intermediate.Under uniform temp, drip methylsulfonyl chloride (52mg, 0.462mmol).At room temperature, the gained reaction mixture is stirred under nitrogen spend the night.Water (20ml) diluted reaction mixture also separates each layer.Water layer with chloroform (2 * 20ml) extractions, the organic layer water after the merging (2 * 30ml), salt solution (30ml) washing, and pass through Na 2SO 4Dry.Use is in 10% acetone in the sherwood oil, and the crude product that obtains behind the pressure reducing and steaming solvent is carried out purifying by silica gel column chromatography, obtains the greyish white solid product of 210mg; IR (KBr) 3348,3299,2937,1646,1477,1153,976cm -1 1H NMR (300MHz, CDCl 3) δ 1.67-1.79 (m, 3H), 2.10-2.18 (m, 3H), 2.34-2.40 (m, 2H), 3.10 (s, 3H), 3.66 (d, J=6.0Hz, 2H), 5.16 (q, J=6.9Hz, 1H), 6.10 (d, J=9.0Hz, 1H), 6.72 (d, J=8.7Hz, 1H), 6.97 (s, 1H), 7.06 (d, J=9.0Hz, 1H), 7.17 (d, J=7.5Hz, 1H), 7.20 (s, 1H), 7.31 (t, J=6.6Hz, 1H), 7.49 (d, J=8.4Hz, 1H), 9.09 (s, 1H); ESI-MS (m/z) 433.38 (M-H) -
Embodiment 4
N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-2-(2-(cyclopentyloxy)-3-p-methoxy-phenyl) ethanamide:
Figure BDA0000127889200000341
As described in example 1 above, title compound is by the intermediate 2 (200mg that are in the methylene dichloride (10ml), 0.763mmol) and [2-(cyclopentyloxy)-3-p-methoxy-phenyl] acetic acid (283mg, 1.153mmol) at EDCIHCl (221mg, 1.153mmol), HOBt (178mg, 1.153mmol) and triethylamine (321 μ l 2.307mmol) exist down and are prepared, and life obtains the 236mg white solid product; IR (KBr) 3311,2963,1653,1529,1476,1266,813cm -1 1H NMR (300MHz, CDCl 3) δ 1.58-1.64 (m, 6H), 1.70-1.80 (m, 6H), 1.97-2.04 (m, 1H), 2.13 (t, J=7.8Hz, 2H), 2.26-2.33 (m, 2H), 3.58 (q, J=14.4Hz, 2H), 3.81 (s, 3H), 4.99 (br s, 1H), 5.09-5.17 (m, 1H), 6.31 (d, J=8.1Hz, 1H), 6.66 (t, J=8.4Hz, 1H), 6.81-7.02 (m, 4H).
Embodiment 5
N-[(4R)-8-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl]-2-(2-cyclopentyloxy-3-methoxyl group) phenyl-acetamides:
Figure BDA0000127889200000342
As described in example 1 above, title compound is by intermediate 3 (150mg, 0.675mmol) and 2-(2-cyclopentyloxy-3-p-methoxy-phenyl) acetic acid (167mg, 0.675mmol) at EDCIHCl (192mg, 1.047mmol), HOBt (154mg, 1.047mmol) and triethylamine (275 μ l, 2.008mmol) existence is descended, is prepared in methylene dichloride (10ml), obtains the 181mg white solid product through 5h; IR (KBr) 3309,2934,1654,1451,1074,968cm -1 1H NMR (300MHz, CDCl 3) δ 1.60-1.74 (m, 11H), 1.84-1.95 (m, 1H), 2.04-2.10 (m, 1H), 2.16-2.24 (m, 2H), 2.31-2.44 (m, 2H), 3.62 (d, J=7.8Hz, 2H), 3.80 (s, 3H), 4.96 (br s, 1H), 5.18 (d, J=8.7Hz, 1H), 6.28 (d, J=8.7Hz, 1H), 6.68 (t, J=7.8Hz, 1H), 6.79-6.88 (m, 2H), 6.96 (t, J=7.8Hz, 1H), 7.15 (d, J=7.8Hz, 1H); APCI-MS (m/z) 454.72 (M-H) -
Embodiment 6
N-[(4S)-8-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl]-2-(2-cyclopentyloxy-3-methoxyl group) phenylacetamide:
Figure BDA0000127889200000351
As described in example 1 above, title compound is by intermediate 4 (150mg, 0.675mmol) and 2-(2-cyclopentyloxy-3-p-methoxy-phenyl) acetic acid (167mg, 0.675mmol) at EDCIHCl (192mg, 1.047mmol), HOBt (154mg, 1.047mmol) and triethylamine (275 μ l, 2.008mmol) existence is descended, is prepared in methylene dichloride (10ml), obtains the 200mg white solid product; IR (KBr) 3308,2934,1654,1527,1451,1074,968cm -1 1H NMR (300MHz, CDCl 3) δ 1.60-1.74 (m, 11H), 1.83-1.93 (m, 1H), 2.00-2.10 (m, 1H), 2.16-2.24 (m, 2H), 2.31-2.44 (m, 2H), 3.62 (d, J=7.8Hz, 2H), 3.79 (s, 3H), 4.96 (br s, 1H), 5.18 (d, J=8.7Hz, 1H), 6.28 (d, J=8.7Hz, 1H), 6.68 (t, J=7.8Hz, 1H), 6.79-6.88 (m, 2H), 6.97 (t, J=7.8Hz, 1H), 7.16 (d, J=7.8Hz, 1H); APCI-MS (m/z) 454.72 (M-H) -
Embodiment 7
N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-2-(3,4-Dimethoxyphenyl) ethanamide:
Figure BDA0000127889200000352
As described in example 1 above, title compound is by intermediate 2 (200mg, 0.763mmol) with 3,4-dimethoxyphenylacetic acid (224mg, 1.145mmol) EDCIHCl (219mg, 1.145mmol), HOBt (175mg, 1.145mmol) and triethylamine (425 μ l, 3.053mmol) exist down, in methylene dichloride (10ml), be prepared, obtain the 217mg white solid product; IR (KBr) 3232,2938,1634,1478,1241,813cm -1 1H NMR (300MHz, CDCl 3) δ 1.62-1.70 (m, 2H), 1.87-1.90 (m, 2H), 1.99-2.15 (m, 2H), and 2.18-2.37 (m, 2H), 3.60 (q, J=16.2Hz, 2H), 3.85 (s, 6H), 5.23 (q, J=9.6Hz, 1H), 5.48 (d, J=9.0Hz, 1H), 6.68 (d, J=9.0Hz, 1H), 6.77-6.84 (m, 3H), 6.96 (s, 1H), 7.04 (d, J=8.4Hz, 1H); ESI-MS (m/z) 401.27 (100%).
Embodiment 8
N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-2-pyridine-2-yl acetamide:
Figure BDA0000127889200000361
As described in example 1 above, title compound is by intermediate 2 (200mg, 0.898mmol) and 2-pyridyl acetic acid (234mg, 1.348mmol) at EDCIHCl (258mg, 1.348mmol), HOBt (206mg, 1.348mmol) and triethylamine (375 μ l, 2.696mmol) existence is descended, is prepared in methylene dichloride (10ml), obtains the 151mg white solid product; IR (KBr) 3272,2936,1644,1477,1265,812cm -1 1H NMR (300MHz, DMSO-d 6) δ 1.65-1.88 (m, 3H), 2.02-2.20 (m, 3H), 2.25-2.35 (m, 2H), 3.71 (q, J=12.0Hz, 2H), 5.00-5.15 (m, 1H), 6.73 (t, J=7.8Hz, 1H), 6.76 (d, J=8.4Hz, 1H), 7.10-7.20 (m, 2H), 7.22-7.30 (m, 1H), and 7.70-7.80 (m, 1H), 8.49 (s, 1H), 8.62 (d, J=8.4Hz, 1H); ESI-MS (m/z) 343.21 (M+H) +
Embodiment 9
N-(3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-2-(1-naphthyl) ethanamide:
Figure BDA0000127889200000362
As described in example 1 above, title compound is by intermediate 5 (150mg, 0.806mmol) and 1-naphthyl acetic acid (150mg, 0.806mmol) at EDCIHCl (230mg, 1.209mmol), HOBt (185mg, 1.209mmol) and triethylamine (336 μ l, 2.418mmol) existence is descended, is prepared in methylene dichloride (10ml), obtains the 151mg white solid product through 3h; IR (KBr) 3278,2932,1635,1551,1229,771cm -1 1HNMR (300MHz, CDCl 3) δ 1.50-1.60 (m, 2H), 1.70-1.80 (m, 2H), 2.05-2.13 (m, 3H), 2.25 (dd, J=5.7,13.5Hz, 1H), 4.10 (s, 2H), 5.18-5.24 (m, 1H), 5.35-5.42 (m, 1H), 6.58-6.70 (s, 3H), 7.00 (t, J=7.8Hz, 1H), 7.30-7.39 (m, 2H), 7.48-7.59 (m, 2H), 7.70-7.77 (m, 1H), 7.84 (d, J=8.4Hz, 1H), 8.00 (d, J=7.8Hz, 1H); APCI-MS (m/z) 358.36 (M+H) +
Embodiment 10
N-(the 6-fluoro-(3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-2-(1-naphthyl) ethanamide:
As described in example 1 above, title compound is by intermediate 6 (300mg, 1.611mmol) and 1-naphthyl acetic acid (400mg, 1.933mmol) at EDCIHCl (463mg, 2.455mmol), HOBt (246mg, 1.611mmol) and triethylamine (926 μ l, 4.835mmol) existence is descended, is prepared in methylene dichloride (10ml), obtains the 310mg white solid product; IR (KBr) 3280,2933,1643,1485,1202,795cm -1 1H NMR (300MHz, CDCl 3) δ 1.44-1.54 (m, 2H), 1.75-1.80 (m, 2H), 2.02-2.10 (m, 3H), 2.13-2.26 (m, 1H), 4.11 (q, J=16.5Hz, 2H), 5.19 (q, J=9.0Hz, 1H), 5.32 (d, J=8.4Hz, 1H), 6.42 (dd, J=3.0,6.3Hz, 1H), 6.60-6.68 (m, 1H), 6.69-6.73 (m, 1H), and 7.39-7.50 (m, 2H), 7.52-7.61 (m, 2H), 7.77-7.87 (m, 2H), 7.99 (d, J=8.1Hz, 1H); ESI-MS (m/z) 376.32 (M+H) +
Embodiment 11
N-[(4R)-6,8-two fluoro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl]-2-(1-naphthyl) ethanamide:
Figure BDA0000127889200000372
As described in example 1 above, title compound is by intermediate 7 (95mg, 0.421mmol) and 1-naphthyl acetic acid (117mg, 0.632mmol) at EDCIHCl (121mg, 0.632mmol), HOBt (96mg, 0.632mmol) and triethylamine (176 μ l, 1.265mmol) existence is descended, is prepared in methylene dichloride (10ml), obtains 91mg pale solid product; IR (KBr) 3272,2936,1645,1565,1484,1226,794cm -1 1H NMR (300MHz, CDCl 3) δ 1.59-1.61 (m, 2H), 1.77-1.87 (m, 2H), 2.10-2.18 (m, 2H), 2.24-2.30 (m, 2H), 4.12 (q, J=16.5Hz, 2H), 5.16-5.24 (m, 1H), 5.30-5.36 (m, 1H), 6.22 (d, J=8.7Hz, 1H), 6.55-6.62 (m, 1H), 7.39-7.44 (m, 2H), 7.54-7.61 (m, 2H), 7.79 (d, J=6.9Hz, 1H), 7.85 (d, J=8.1Hz, 1H), 7.98 (d, J=7.8Hz, 1H); ESI-MS (m/z) 409.19 (M) +
Embodiment 12
N-[(4R)-6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl]-2-(1-naphthyl) ethanamide:
Figure BDA0000127889200000381
As described in example 1 above, title compound is by intermediate 8 (150mg, 0.674mmol) and 1-naphthyl acetic acid (188mg, 1.011mmol) at EDCIHCl (193mg, 1.011mmol), HOBt (154mg, 1.011mmol) and triethylamine (281 μ l, 2.022mmol) existence is descended, is prepared in methylene dichloride (10ml), obtains the 123mg white solid product; IR (KBr) 3277,2952,1640,1478,1236,751cm -1 1H NMR (300MHz, CDCl 3) δ 1.46-1.53 (m, 2H), 1.75-1.81 (m, 2H), 2.07-2.16 (m, 3H), 2.22-2.39 (m, 1H), 4.12 (q, J=16.5Hz, 2H), 5.19 (q, J=9.6Hz, 1H), 5.33 (d, J=8.4Hz, 1H), 6.58 (d, J=8.7Hz, 1H), 6.66 (s, 1H), 6.93 (d, J=7.2Hz, 1H), 7.23-7.42 (m, 2H), 7.54 (t, J=14.1Hz, 1H), 7.62 (t, J=7.5Hz, 1H), 7.82 (dd, J=8.4,10.2Hz, 2H), 7.99 (d, J=8.7Hz, 1H); ESI-MS (m/z) 392.49 (M+H) +
Embodiment 13
N-[(4S)-6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl]-2-(1-naphthyl) ethanamide:
Figure BDA0000127889200000382
As described in example 1 above, title compound is by intermediate 9 (200mg, 0.896mmol) and 1-naphthyl acetic acid (200mg, 1.076mmol) at EDCIHCl (257mg, 1.345mmol), HOBt (206mg, 1.341mmol) and triethylamine (374 μ l, 2.696mmol) existence is descended, is prepared in methylene dichloride (10ml), obtains the 169mg white solid product; IR (KBr) 3272,2942,1642,1473,1266,776cm -1 1H NMR (300MHz, CDCl 3) δ 1.45-1.53 (m, 2H), 1.74-1.82 (m, 2H), 2.06-2.12 (m, 3H), and 2.14-2.28 (m, 1H), 4.11 (q, J=16.5Hz, 2H), 5.19 (q, J=9.6Hz, 1H), 5.33 (d, J=9.0Hz, 1H), 6.57 (d, J=8.7Hz, 1H), 6.66 (s, 1H), 6.93 (d, J=6.3Hz, 1H), 7.39-7.43 (m, 2H), 7.51 (t, J=6.9Hz, 1H), 7.61 (t, J=6.9Hz, 1H), 7.70 (dd, J=1.8,5.1Hz, 1H), 7.85 (d, J=7.8Hz, 1H), 7.99 (d, J=8.1Hz, 1H); ESI-MS (m/z) 392.45 (M+H) +
Embodiment 14
N-(7-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-2-(1-naphthyl) ethanamide:
Figure BDA0000127889200000391
As described in example 1 above, title compound is by intermediate 10 (200mg, 0.761mmol) and 1-naphthyl acetic acid (171mg, 0.913mmol) at EDCIHCl (221mg, 1.141mmol), HOBt (176mg, 1.141mmol) and triethylamine (317 μ l, 2.283mmol) existence is descended, is prepared in THF (5ml), obtains the 250mg white solid product; IR (KBr) 3236,2945,1638,1412,1223,788cm -1 1H NMR (300MHz, CDCl 3) δ 1.47-1.55 (m, 2H), 1.72-1.78 (m, 2H), 2.09 (t, J=7.8Hz, 3H), 2.16-2.26 (m, 1H), 4.09 (q, J=6.9Hz, 2H), 5.11-5.19 (m, 1H), 5.29 (d, J=8.4Hz, 1H), 6.55 (s, 2H), 6.66 (s, 1H), 7.35-7.42 (m, 2H), 7.49-7.59 (m, 2H), 7.77 (d, J=7.2Hz, 1H), 7.82 (d, J=7.8Hz, 1H), 7.98 (d, J=7.8Hz, 1H); APCI-MS (m/z) 392.12 (M+H) +
Embodiment 15
N-[(4R)-8-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl]-2-(1-naphthyl) ethanamide:
Figure BDA0000127889200000401
As described in example 1 above, title compound is by intermediate 3 (100mg, 0.448mmol) and 1-naphthyl acetic acid (99mg, 0.531mmol) at EDCIHCl (128mg, 0.672mmol), HOBt (102mg, 0.672mmol) and triethylamine (185 μ l, 2.022mmol) existence is descended, is prepared in methylene dichloride (10ml), obtains the 100mg white solid product; IR (KBr) 3271,2938,1636,1449,1244,778cm -1 1H NMR (300MHz, CDCl 3) δ 1.62-1.78 (m, 5H), 2.11-2.30 (m, 3H), 4.09 (q, J=16.8Hz, 2H), 5.23 (q, J=9.3Hz, 1H), 5.46 (d, J=7.8Hz, 1H), 6.52 (t, J=7.2Hz, 1H), 6.60 (d, J=7.2Hz, 1H), 7.07 (d, J=7.8Hz, 1H), 7.37-7.42 (m, 2H), 7.48-7.59 (m, 2H), 7.77 (t, J=6.3Hz, 1H), 7.84 (d, J=7.8Hz, 1H), 7.99 (d, J=8.1Hz, 1H); ESI-MS (m/z) 392.59 (M+H) +
Embodiment 16
N-[(4S)-8-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl]-2-(1-naphthyl) ethanamide:
Figure BDA0000127889200000402
As described in example 1 above, title compound is by intermediate 4 (150mg, 0.668mmol) and 1-naphthyl acetic acid (149mg, 0.801mmol) at EDCIHCl (193mg, 1.008mmol), HOBt (154mg, 1.008mmol) and triethylamine (279 μ l, 2.004mmol) existence is descended, is prepared in methylene dichloride (10ml), obtains 150mg pale solid product; IR (KBr) 3275,2939,1636,1244,778cm -1 1H NMR (300MHz, CDCl 3) δ 1.61-1.79 (m, 5H), 2.10-2.30 (m, 3H), 4.08 (q, J=16.5Hz, 2H), 5.22 (q, J=8.7Hz, 1H), 5.43 (d, J=8.1Hz, 1H), 6.52 (t, J=7.2Hz, 1H), 6.60 (d, J=7.2Hz, 1H), 7.07 (d, J=7.8Hz, 1H), 7.35-7.42 (m, 2H), 7.48-7.60 (m, 2H), 7.77 (t, J=6.3Hz, 1H), 7.84 (d, J=7.8Hz, 1H), 7.98 (d, J=8.1Hz, 1H); ESI-MS (m/z) 392.63 (M+H) +
Embodiment 17
N-(5-hydroxyl-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-2-(1-naphthyl) ethanamide:
Figure BDA0000127889200000411
Step 1:N-(5-benzyloxy-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-2-(1-naphthyl) ethanamide: as described in example 1 above, title compound by intermediate 11 (872mg, 2.954mmol) (500mg is 2.685mmol) at EDCIHCl (772mg with the 1-naphthyl acetic acid, 4.027mmol), HOBt (411mg, 2.685mmol) and triethylamine (1.123ml, 2.274mmol) existence is descended, is prepared in methylene dichloride (10ml), obtains the 420mg white solid product; IR (KBr) 3293,2929,1638,1466,1120,778cm -1 1H NMR (300MHz, CDCl 3) δ 1.25-1.35 (m, 2H), 1.45-1.52 (m, 1H), 1.58-1.64 (m, 1H), and 1.94-2.00 (m, 2H), 2.15-2.25 (m, 2H), 3.64-3.70 (m, 1H), 3.98-4.04 (m, 1H), 4.87-5.02 (m, 2H), and 5.23-5.30 (m, 2H), 6.34-6.40 (m, 2H), 7.00-7.07 (m, 3H), 7.28-7.39 (m, 7H), 7.67-7.75 (m, 2H), 7.85-7.91 (m, 1H); APCI-MS (m/z) 464.5 (M+H) +
Step 2:N-(5-hydroxyl-3; 4-dihydro spiral shell [chromene-2; 1 '-the ring fourth]-the 4-yl)-2-(1-naphthyl) ethanamide: in the Paar instrument; under 65psi pressure; use is in 50%Pd/C (80mg) in the methyl alcohol (70ml) through 8h completing steps 1 intermediate (400mg, deprotection 0.863mmol).Reaction mixture is filtered by bed of diatomaceous earth.Concentrating under reduced pressure filtrate obtains rough resistates, by silica gel column chromatography this resistates is carried out purifying, obtains the 115mg white solid product; IR (KBr) 3293,2972,1608,1469,1120,775cm -1 1H NMR (300MHz, CDCl 3) δ 1.26-1.35 (m, 1H), 1.89-1.96 (m, 2H), 2.12-2.22 (m, 2H), and 3.64-3.70 (m, 1H), 3.98-4.04 (m, 1H), 4.85-4.91 (m, 1H), 5.00-5.08 (m, 1H), 5.20-2.30 (m, 2H), and 6.33-6.42 (m, 2H), 6.99-7.07 (m, 2H), 7.28-7.42 (m, 5H), 7.68 (d, J=7.5Hz, 1H), and 7.75-7.86 (m, 1H), 10.02 (br s 1H); ESI-MS (m/z) 374.37 (M+H) +
Embodiment 18
N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-2-(2-naphthyl) ethanamide:
Figure BDA0000127889200000421
As described in example 1 above, title compound is by intermediate 2 (200mg, 0.764mmol) and 2-naphthyl acetic acid (213mg, 1.141mmol) at EDCIHCl (213mg, 1.145mmol), HOBt (176mg, 1.145mmol) and triethylamine (425 μ l, 3.052mmol) existence is descended, is prepared in methylene dichloride (10ml), obtains the 193mg white solid product; IR (KBr) 3262,2933,1643,1474,1230,816cm -1 1H NMR (300MHz, CDCl 3) δ 1.63-1.77 (m, 2H), 1.84-1.92 (m, 2H), 1.95-2.02 (m, 2H), 2.16-2.36 (m, 2H), 3.82 (s, 2H), 5.24 (q, J=9.6Hz, 1H), 5.50 (d, J=8.7Hz, 1H), 6.65 (d, J=8.4Hz, 1H), 7.00 (d, J=9.3Hz, 2H), 7.39 (d, J=8.4Hz, 1H), 7.45-7.50 (m, 2H), 7.73 (s, 1H), 7.78-7.86 (m, 3H); ESI-MS (m/z) 392.58 (M+H) +
Embodiment 19
(2S)-N-[(4R)-6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl]-2-(6-methoxyl group-2-naphthyl) propionic acid amide:
Figure BDA0000127889200000422
As described in example 1 above, title compound is by intermediate 8 (200mg, 0.769mmol) and (2S)-2-(6-methoxyl group-2-naphthyl) propionic acid (213mg, 0.923mmol) at EDCIHCl (221mg, 1.153mmol), HOBt (176mg, 1.153mmol) and triethylamine (321 μ l, 2.307mmol) existence is descended, is prepared in methylene dichloride (10ml), obtains the 112mg white solid product; IR (KBr) 3351,2938,1652,1518,1482,1261,857cm -1 1H NMR (300MHz, CDCl 3) δ 1.64 (s, 3H), 1.66 (s, 2H), 1.80-1.90 (m, 2H), 2.08-2.14 (m, 3H), 2.21-2.27 (m, 1H), 3.76 (q, J=6.9Hz, 1H), 3.89 (s, 3H), 5.16-5.24 (m, 1H), 5.47 (d, J=8.4Hz, 1H), 6.60-6.67 (m, 1H), 6.94-7.02 (m, 1H), 7.10-7.16 (m, 3H), 7.36 (dd, J=1.5Hz, 1.5Hz, 1H), 7.64-7.72 (m, 3H); APCI-MS (m/z) 436.29 (M+H) +
Embodiment 20
(2S)-N-[(4S)-6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl]-2-(6-methoxyl group-2-naphthyl) propionic acid amide:
Figure BDA0000127889200000431
As described in example 1 above, title compound is by intermediate 9 (200mg, 0.769mmol) and (2S)-2-(6-methoxyl group-2-naphthyl) propionic acid (213mg, 0.923mmol) at EDCIHCl (221mg, 1.153mmol), HOBt (176mg, 1.153mmol) and triethylamine (321 μ l, 2.307mmol) existence is descended, is prepared in methylene dichloride (10ml), obtains the 103mg white solid product; IR (KBr) 3267,2932,1638,1477,1263,814cm -1 1H NMR (300MHz, DMSO-d 6) δ 1.65 (s, 3H), 1.68-1.74 (m, 2H), 1.84-1.90 (m, 1H), 2.13 (t, J=7.8Hz, 3H), 2.27-2.37 (m, 2H), 3.74 (q, J=6.9Hz, 1H), 3.89 (s, 3H), 5.22 (d, J=9.9Hz, 1H), 5.50 (d, J=8.4Hz, 1H), 6.60 (d, J=9.0Hz, 1H), 6.70-6.76 (m, 1H), 6.94 (dd, J=1.8,2.1Hz, 1H), 7.10-7.16 (m, 2H), 7.39 (d, J=8.7Hz, 1H), 7.67-7.76 (m, 3H); APCI-MS (m/z) 436.37 (M+H) +
Embodiment 21
N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-2-(1,2,3,4-tetralin-1-yl) ethanamide:
Figure BDA0000127889200000432
As described in example 1 above, title compound is by intermediate 2 (212mg, 0.951mmol) with 5,6,7,8-tetraline-1-guanidine-acetic acid (150mg, 0.791mmol) EDCIHCl (227mg, 1.663mmol), HOBt (121mg, 0.791mmol) and triethylamine (330 μ l, 2.371mmol) exist down, in methylene dichloride (10ml), be prepared, obtain the 154mg white solid product; IR (KBr) 3278,2935,1637,1474,1263,818cm -1 1H NMR (300MHz, CDCl 3) δ 1.70-1.87 (m, 6H), 2.03-2.18 (m, 3H), 2.20-2.46 (m, 3H), 2.60-2.70 (m, 1H), 2.77 (br s, 2H), 3.47 (br s, 2H), 5.27 (q, J=9.3Hz, 1H), 5.45 (d, J=7.8Hz, 1H), 6.70 (d, J=8.7Hz, 1H), and 7.05-7.18 (m, 6H); ESI-MS (m/z) 394.76 (M-H) -
Embodiment 22
N-[(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)]-2-(1,2,3,4-tetralin-2-yl) ethanamide:
Figure BDA0000127889200000441
As described in example 1 above, title compound is by intermediate 2 (218mg, 1.053mmol) with 1,2,3,4-tetraline-2-guanidine-acetic acid (200mg, 1.053mmol) EDCIHCl (302mg, 1.585mmol), HOBt (241mg, 1.585mmol) and triethylamine (439 μ l, 3.165mmol) exist down, in methylene dichloride (10ml), be prepared, obtain the 40mg white solid product; IR (KBr) 3250,2931,2343,1635,1474,1232,738cm -1 1HNMR (300MHz, CDCl 3) δ 1.67-1.82 (m, 3H), 1.83-1.95 (m, 2H), 2.21-2.29 (m, 3H), and 2.30-2.39 (m, 4H), 2.48-2.59 (m, 1H), 2.85-2.96 (m, 3H), 5.32 (q, J=7.8Hz, 1H), 5.59 (d, J=7.8Hz, 1H), 6.73 (d, J=8.4Hz, 1H), 6.73 (d, J=8.4Hz, 1H), 7.08-7.14 (m, 6H); ESI-MS (m/z) 396.95 (M+H) +
Embodiment 23
2-(1,3-benzo dioxole-5-yl)-N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl) ethanamide:
Figure BDA0000127889200000442
As described in example 1 above, title compound is by intermediate 2 (200mg, 0.892mmol) with 1,3-benzo dioxole-4-guanidine-acetic acid (161mg, 0.881mmol) EDCIHCl (256mg, 1.343mmol), HOBt (205mg, 1.343mmol) and triethylamine (366 μ l, 2.683mmol) exist down, in methylene dichloride (10ml), be prepared, obtain the 125mg white solid product; IR (KBr) 3059,2941,1634,1488,1243,1045cm -1 1H NMR (300MHz, CDCl 3) δ 1.63-1.72 (m, 2H), 1.83-1.89 (m, 1H), 2.00-2.07 (m, 1H), and 2.12-2.18 (m, 2H), 2.25-2.38 (m, 2H), 3.55 (d, J=2.4Hz, 2H), 5.21 (q, J=9.9Hz, 1H), 5.49 (d, J=8.1Hz, 1H), 5.94 (s, 2H), 6.68-6.76 (m, 4H), 6.93 (s, 1H), 7.04 (dd, J=2.4,6.3Hz, 1H); ESI-MS (m/z) 384.16 (M-H) -
Embodiment 24
N-(6-fluoro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-2-(5-fluoro-3-Methyl-1H-indole-2-yl) ethanamide:
As described in example 1 above, title compound is by intermediate 6 (200mg, 0.963mmol) and (5-fluoro-3-Methyl-1H-indole-2-yl) acetic acid (200mg, 0.963mmol) at EDCIHCl (276mg, 1.145mmo), HOBt (221mg, 1.145mmol) and triethylamine (401 μ l, 3.003mmol) existence is descended, is prepared in methylene dichloride (10ml), obtains the 18mg white solid product; 1H NMR (300MHz, DMSO-d 6) δ 1.52-1.74 (m, 4H), 1.88-1.95 (m, 2H), 2.08-2.25 (m, 2H), 2.40 (s, 3H), 3.70 (s, 2H), 5.23 (q, J=8.7Hz, 1H), 5.68 (d, J=9.0Hz, 1H), 6.61-6.66 (m, 2H), 6.72-6.89 (m, 2H), 7.07-7.18 (m, 2H), 8.01 (s, 1H); ESI-MS (m/z) 397.33 (M+H) +
Embodiment 25
N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-2-(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanamide:
As described in example 1 above, title compound is by intermediate 2 (200mg, 0.896mmol) and (5-methoxyl group-2-Methyl-1H-indole-3-yl) acetic acid (195mg, 0.896mmol) at EDCIHCl (256mg, 1.345mmol), HOBt (205mg, 1.345mmol) and triethylamine (374 μ l, 3.003mmol) existence is descended, is prepared in methylene dichloride (10ml), obtains the 35mg white solid product; IR (KBr) 3383,2934,2343,1648,1475,1217,820cm -1 1H NMR (300MHz, CDCl 3) δ 1.50-1.65 (m, 5H), 1.83-1.95 (m, 3H), 2.40 (s, 3H), 3.73 (s, 3H), 3.82 (s, 2H), 5.23 (q, J=9.6Hz, 1H), 5.76 (d, J=8.7Hz, 1H), 6.62 (d, J=8.4Hz, 1H), 6.77 (dd, J=2.4,6.6Hz, 1H), 6.82-6.89 (m, 2H), 6.98 (dd, J=2.1,6.3Hz, 1H), 7.14 (d, J=8.4Hz, 1H), 7.84 (s, 1H); ESI-MS (m/z) 423.58 (M-H) -
Embodiment 26
2-(1,2-benzoisoxazole-3-yl)-N-[(4R)-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl) ethanamide:
Figure BDA0000127889200000461
As described in example 1 above, title compound is by intermediate 8 (200mg, 0.763mmol) with 1,2-benzoisoxazole-3-guanidine-acetic acid (148mg, 0.839mmol) EDCIHCl (219mg, 1.145mmol), HOBt (175mg, 1.145mmol) and triethylamine (425 μ l, 3.053mmol) exist down, in methylene dichloride (10ml), be prepared, obtain the 176mg white solid product; IR (KBr) 3314,2940,1654,1533,1235,749cm -1 1H NMR (300MHz, CDCl 3) δ 1.61-1.68 (m, 1H), 1.77-1.87 (m, 2H), 2.03-2.14 (m, 3H), 2.29-2.38 (m, 2H), 4.06 (s, 2H), 5.24 (q, J=7.2Hz, 1H), 6.34 (d, J=8.7Hz, 1H), 6.68 (d, J=8.4Hz, 1H), 6.92 (s, 1H), 7.02 (d, J=9.0Hz, 1H), 7.28-7.38 (m, 1H), 7.57 (s, 2H), 7.80 (d, J=7.8Hz, 1H); ESI-MS (m/z) 383.50 (M+H) +
Embodiment 27
2-(1,2-benzoisoxazole-3-yl)-N-[(4S)-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl) ethanamide:
Figure BDA0000127889200000462
As described in example 1 above, title compound is by intermediate 9 (200mg, 0.763mmol) with 1,2-benzoisoxazole-3-guanidine-acetic acid (148mg, 0.839mmol) EDCIHCl (219mg, 1.145mmol), HOBt (175mg, 1.145mmol) and triethylamine (425 μ l, 3.053mmol) exist down, in methylene dichloride (10ml), be prepared, obtain the 176mg white solid product; IR (KBr) 3314,2940,1654,1533,1235,749cm -1 1H NMR (300MHz, CDCl 3) δ 1.60-1.67 (m, 1H), 1.79-1.87 (m, 2H), 2.05-2.18 (m, 3H), 2.29-2.38 (m, 2H), 4.05 (s, 2H), 5.24 (q, J=7.2Hz, 1H), 6.34 (d, J=8.7Hz, 1H), 6.68 (d, J=8.4Hz, 1H), 6.92 (s, 1H), 7.02 (d, J=9.0Hz, 1H), 7.28-7.38 (m, 1H), 7.57 (s, 2H), 7.80 (d, J=7.8Hz, 1H); ESI-MS (m/z) 383.50 (M+H) +
Embodiment 28
N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(2-cyclopentyloxy phenyl) propionic acid amide:
As described in example 1 above, title compound is by intermediate 2 (200mg, 0.779mmol) and 3-(2-cyclopentyloxy phenyl) propionic acid (181mg, 0.779mmol) at EDCIHCl (222mg, 1.152mmol), HOBt (177mg, 1.152mmol) and triethylamine (427 μ l, 3.116mmol) existence is descended, is prepared in methylene dichloride (10ml), obtains the 150mg white solid product; IR (KBr) 3316,2952,1651,1488,749cm -1 1H NMR (300MHz, CDCl 3) δ 1.58-1.65 (m, 3H), 1.72-1.87 (m, 8H), 2.02-2.12 (m, 3H), 2.26-2.36 (m, 2H), 2.56 (t, J=6.9Hz, 2H), 2.95 (t, J=7.5Hz, 2H), 4.72 (brs, 1H), 5.15 (q, J=8.7Hz, 1H), 5.59 (d, J=7.8Hz, 1H), 6.69 (d, J=8.4Hz, 1H), and 6.80-6.88 (m, 3H), 7.04 (dd, J=2.4,5.7Hz, 1H), 7.14 (d, J=7.5Hz, 2H); ESI-MS (m/z) 440.34 (M) +
Embodiment 29
N-[(4R)-6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl]-3-(3-cyclopentyloxy) Phenylpropionamide:
Figure BDA0000127889200000481
As described in example 1 above, title compound is by intermediate 8 (100mg, 0.448mmol) and 3-(3-cyclopentyloxy phenyl) propionic acid (105mg, 0.448mmol) at EDCIHCl (128mg, 0.672mmol), HOBt (102mg, 0.672mmol) and triethylamine (187 μ l, 1.344mmol) existence is descended, is prepared in methylene dichloride (10ml), obtains the 105mg white solid product; IR (KBr) 3019,2400,2973,1663,1215,761cm -1 1H NMR (300MHz, CDCl 3) δ 1.64-1.70 (m, 4H), 1.80-1.88 (m, 7H), 2.00-2.08 (m, 1H), 2.15 (t, J=8.1Hz, 2H), 2.25-2.32 (m, 2H), 2.55 (q, J=6.9Hz, 2H), 2.97 (t, J=6.6Hz, 2H), 4.72 (br s, 1H), 5.17 (q, J=4.2Hz, 1H), 5.40 (d, J=7.8Hz, 1H), 6.68-6.78 (m, 4H), 6.93 (s, 1H), 7.05 (d, J=6.6Hz, 1H), 7.18 (t, J=7.8Hz, 1H); ESI-MS (m/z) 440.54 (M+H) +
Embodiment 30
N-[(4S)-6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl]-3-(3-cyclopentyloxy) Phenylpropionamide:
Figure BDA0000127889200000482
As described in example 1 above, title compound is by intermediate 9 (104mg, 0.444mmol) and 3-(3-cyclopentyloxy phenyl) propionic acid (100mg, 0.444mmol) at EDCIHCl (128mg, 0.672mmol), HOBt (102mg, 0.672mmol) and triethylamine (186 μ l, 1.344mmol) existence is descended, is prepared in methylene dichloride (10ml), obtains the 100mg white solid product; IR (KBr) 3293,2934,1694,1532,1216,756cm -1 1H NMR (300MHz, CDCl 3) δ 1.62-1.70 (m, 6H), 1.78-1.85 (m, 5H), 2.04-2.16 (m, 3H), and 2.28-2.32 (m, 2H), 2.54 (d, J=6.9Hz, 2H), 2.90-2.99 (m, 2H), 4.72 (brs, 1H), 5.18 (q, J=5.7Hz, 1H), 5.37 (d, J=7.5Hz, 1H), 6.71-6.77 (m, 3H), 6.92 (s, 1H), 7.04 (d, J=7.8Hz, 1H), 7.10-7.18 (m, 2H); ESI-MS (m/z) 440.55 (M+H) +
Embodiment 31
N-[(4R)-(8-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-[2-(cyclopentyloxy)-1-phenyl] propionic acid amide:
Figure BDA0000127889200000491
As described in example 1 above, title compound is by intermediate 3 (100mg, 0.448mmol) and 3-(2-cyclopentyloxy phenyl) propionic acid (125mg, 0.536mmol) at EDCIHCl (128mg, 0.672mmol), HOBt (102mg, 0.672mmol) and triethylamine (186 μ l, 1.344mmol) existence is descended, is prepared in methylene dichloride (10ml), obtains the 142mg white solid product; IR (KBr) 3321,2950,1646,1453,1239,989cm -1 1H NMR (300MHz, CDCl 3) δ 1.68-1.75 (m, 11H), 2.05-2.17 (m, 3H), 2.36-2.46 (m, 2H), 2.56 (t, J=7.2Hz, 2H), 2.96 (t, J=6.6Hz, 2H), 4.72 (br s, 1H), 5.22 (q, J=8.7Hz, 1H), 5.55 (d, J=8.7Hz, 1H), 6.69 (s, 2H), 6.78-6.88 (m, 2H), 7.14-7.19 (m, 3H); ESI-MS (m/z) 440.34 (M+H) +
Embodiment 32
N-[(4S)-8-chloro-3,4-dihydro spiral shell [chromene-2,1 '-ring fourth-4-yl]-3-[2-(cyclopentyloxy) phenyl] propionic acid amide:
Figure BDA0000127889200000492
As described in example 1 above, title compound is by intermediate 4 (100mg, 0.448mmol) and 3-(2-cyclopentyloxy phenyl]) propionic acid (115mg, 0.494mmol) at EDCIHCl (129mg, 0.674mmol), HOBt (103mg, 0.674mmol) and triethylamine (187 μ l, 1.348mmol) existence is descended, is prepared in methylene dichloride (10ml), obtains the 211mg white solid product; IR (KBr) 3321,2950,1646,1453,1239,989cm -1 1H NMR (300MHz, CDCl 3) δ 1.68-1.75 (m, 11H), 2.05-2.17 (m, 3H), 2.36-2.46 (m, 2H), 2.56 (t, J=7.2Hz, 2H), 2.96 (t, J=6.6Hz, 2H), 4.72 (br s, 1H), 5.22 (q, J=8.7Hz, 1H), 5.55 (d, J=8.7Hz, 1H), 6.69 (s, 2H), 6.78-6.88 (m, 2H), 7.14-7.19 (m, 3H); ESI-MS (m/z) 440.34 (M+H) +
Embodiment 33
7-benzyloxy-N-(3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(2-cyclopentyloxy phenyl) propionic acid amide:
Figure BDA0000127889200000501
As described in example 1 above, title compound is by intermediate 12 (200mg, 0.603mmol) and 3-(2-cyclopentyloxy phenyl) propionic acid (169mg, 0.723mmol) at EDCIHCl (173mg, 0.904mmol), HOBt (138mg, 0.904mmol) and triethylamine (335 μ l, 2.413mmol) existence is descended, is prepared in methylene dichloride (10ml), obtains the 163mg white solid product; IR (KBr) 3324,2954,1647,1239,1171,745cm -1 1H NMR (300MHz, CDCl 3) δ 1.66-1.79 (m, 11H), 2.04-2.12 (m, 4H), 2.25-2.32 (m, 2H), 2.52 (t, J=7.2Hz, 2H), 2.94 (t, J=7.5Hz, 2H), 4.69 (br s, 1H), 4.98 (s, 2H), 5.17 (q, J=5.7Hz, 1H), 5.48 (d, J=9.3Hz, 1H), 6.39-6.46 (m, 2H), 6.67 (d, J=8.7Hz, 1H), 6.75-6.85 (m, 2H), and 7.10-7.16 (m, 2H), 7.29-7.37 (m, 4H); ESI-MS (m/z) 510.34 (M+H) +
Embodiment 34
N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-{2-[(sec.-propyl alkylsulfonyl) amino] phenyl } propionic acid amide:
Step 1:(2E)-N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-{2-[(sec.-propyl alkylsulfonyl) amino] phenyl } acrylamide: as described in example 1 above, this compound is by intermediate 2 (150mg, 0.576mmol) and (2E)-3-{2-[(2-sec.-propyl alkylsulfonyl) amino] phenyl } vinylformic acid (186mg, 0.692mmol) at EDCIHCl (165mg, 0.865mmol), HOBt (132mg, 0.865mmol) and triethylamine (240 μ l, 1.732mmol) exist down, in methylene dichloride (10ml), be prepared, obtain the 125mg white solid product; 1H NMR (300MHz, CDCl 3) δ 0.82-0.90 (m, 2H), 1.20-1.26 (m, 4H), 1.74-1.85 (m, 3H), 2.10-2.20 (m, 3H), 2.46-2.52 (m, 2H), 3.29 (t, J=6.3Hz, 1H), 3.34-3.40 (m, 1H), 6.00-6.06 (m, 1H), 6.40 (d, J=15.6Hz, 1H), 6.72 ((d, J=8.4Hz, 1H), 7.05-7.18 (m, 3H), 7.33 (d, J=7.8Hz, 2H), 7.49 (d, J=7.5Hz, 1H), 7.57 (d, J=7.8Hz, 1H), 8.08 (d, J=15.9Hz, 1H).
Step 2:N-(6-chloro-3; 4-dihydro spiral shell [chromene-2; 1 '-ring fourth]-the 4-yl)-3-{2-[(sec.-propyl alkylsulfonyl) amino] phenyl propionic acid amide: in the Paar instrument under 30psi pressure; use is in the 5%Pd/C (30mg) in the ethyl acetate; with step 1 intermediate (110mg, 0.232mmol) reduction 1.5h.Reaction mixture is filtered by diatomite, and concentrating under reduced pressure filtrate obtains crude compound; Use is in 13% acetone in the sherwood oil, and this compound is carried out purifying by silica gel column chromatography, obtains the 51mg white solid product; IR (Neat) 3343,2936,1651,1537,1475,1320,1102,756cm -1 1H NMR (300MHz, CDCl 3) δ 1.40-1.50 (m, 5H), 1.56-1.62 (m, 2H), 1.65-1.71 (m, 2H), 1.85-1.91 (m, 1H), 2.10-2.20 (m, 3H), 2.27-2.33 (m, 2H), 2.60-2.68 (m, 2H), 3.04-3.12 (m, 2H), 3.32-3.38 (m, 1H), 5.15 (br s, 1H), 5.60 (br s, 1H), 6.66-6.72 (m, 2H), 7.03 (d, J=6.9Hz, 1H), 7.12-7.20 (m, 2H), 7.47 (d, J=7.8Hz, 1H), 8.22 (s, 1H); ESI-MS (m/z) 477.95 (M) +
Embodiment 35
N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(2-pyridine-2-base phenyl) propionic acid amide:
Figure BDA0000127889200000511
Step 1:(2E)-N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(2-pyridine-2-base phenyl) acrylamide: as described in example 1 above, title compound is by intermediate 2 (300mg, 1.153mmol) and (2E)-3-(2-pyridine-2-base phenyl) vinylformic acid (260mg, 1.153mmol) at EDCIHCl (332mg, 1.730mmol), HOBt (177mg, 1.153mmol) and triethylamine (402 μ l, 2.884mmol) exist down, in methylene dichloride (10ml), be prepared, obtain the 400mg white solid product; IR (Neat) 3228,2935,1651,1540,1475,1264,759cm -1 1H NMR (300MHz, CDCl 3) δ 1.80-1.90 (m, 2H), 2.08-2.20 (m, 4H), 2.35-2.49 (m, 2H), 3.46 (q, J=7.2Hz, 1H), 5.34 (q, J=9.3Hz, 1H), 5.84 (d, J=8.7Hz, 1H), 6.37 (d, J=15.0Hz, 1H), 6.73 (d, J=8.1Hz, 1H), 7.08 (d, J=8.4Hz, 1H), 7.14 (s, 1H), 7.33-7.43 (m, 4H), and 7.61-7.70 (m, 3H), 8.55-8.61 (m, 2H); ESI-MS (m/z) 431.24 (M+H) +
Step 2:N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(2-pyridine-2-base phenyl) propionic acid amide: in the Paar instrument, under 40psi pressure, use the Pd/C (50mg) that is in the methyl alcohol with step 1 intermediate (300mg, 0.696mmol) reduction 3h.Reaction mixture is filtered by bed of diatomaceous earth, and concentrating under reduced pressure filtrate obtains crude compound; Use is in 25% ethyl acetate in the sherwood oil, and this compound is carried out purifying by silica gel column chromatography, obtains the 231mg white solid product; IR (KBr) 3270,2972,1674,1635,1449,775cm -1 1H NMR (300MHz, CDCl 3) δ 1.65-1.71 (m, 2H), 1.81-1.89 (m, 1H), 1.92-2.04 (m, 3H), 2.07-2.14 (m, 4H), 3.01 (q, J=4.2Hz, 2H), 5.13 (q, J=9.3Hz, 1H), 5.39 (d, J=7.8Hz, 1H), 6.70 (d, J=8.7Hz, 1H), 6.85 (s, 1H), 7.05 (d, J=9.0Hz, 1H), 7.20 (d, J=7.2Hz, 1H), 7.30-7.37 (m, 4H), 7.67 (d, J=7.8Hz, 1H), 8.55 (s, 2H); ESI-MS (m/z) 433.48 (M+H) +
Embodiment 36
N-(6,8-, two chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(2-pyridin-3-yl phenyl) propionic acid amide:
Figure BDA0000127889200000521
As described in example 1 above, title compound is by intermediate 13 (100mg, 0.340mmol) and 3-(2-pyridine-2-base phenyl) propionic acid (85mg, 0.374mmol) at EDCIHCl (97mg, 0.509mmol), HOBt (78mg, 0.511mmol) and triethylamine (142 μ l, 2.884mmol) existence is descended, is prepared in methylene dichloride (5ml), obtains the 59mg white solid product; 1H NMR (300MHz, CDCl 3) δ 1.71-1.79 (m, 4H), 1.98-2.07 (m, 2H), 2.22-2.39 (m, 4H), 2.76-2.84 (m, 2H), 4.90-5.05 (m, 1H), 6.83 (br s, 1H), 7.29-7.49 (m, 5H), 7.78 (d, J=7.2Hz, 1H), 8.28 (s, 2H), 8.50-8.58 (m, 2H).
Embodiment 37
N-(3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(2-cyclopentyloxy-3-methoxyl group) Phenylpropionamide:
Figure BDA0000127889200000531
As described in example 1 above, title compound is by intermediate 5 (113mg, 0.604mmol) and 3-[2-(cyclopentyloxy-3-methoxyl group) phenyl] propionic acid (150mg, 0.604mmol) at EDCIHCl (172mg, 0.906mmol), HOBt (137mg, 0.906mmol) and triethylamine (249 μ l, 1.835mmol) existence is descended, is prepared in methylene dichloride (10ml), obtains the 125mg white solid product; IR (KBr) 3282,2949,1640,1454,1232,753cm -1 1H NMR (300MHz, CDCl 3) δ 1.68-1.78 (m, 11H), 2.05-2.15 (m, 3H), 2.28-2.39 (m, 2H), 2.55 (t, J=6.6Hz, 2H), 2.98 (t, J=6.6Hz, 2H), 3.79 (s, 3H), 4.85 (br s, 1H), 5.19 (q, J=6.9Hz, 1H), 5.64 (d, J=7.8Hz, 1H), 6.73-6.80 (m, 5H), 6.95 (t, J=7.8Hz, 1H), 7.08 (t, J=7.5Hz, 1H); ESI-MS (m/z) 433.30 (M-H) -
Embodiment 38
N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(2,3-dimethoxy) Phenylpropionamide:
Figure BDA0000127889200000532
As described in example 1 above, title compound is by intermediate 2 (200mg, 0.898mmol) and 3-(2, the 3-Dimethoxyphenyl) propionic acid (207mg, 0.988mmol) EDCIHCl (258mg, 1.348mmol), HOBt (206mg, 1.348mmol) and triethylamine (372 μ l, 2.695mmol) exist down, in methylene dichloride (10ml), be prepared, obtain the 246mg white solid product; IR (KBr) 3051,2942,1642,1475,1263,750cm -1 1H NMR (300MHz, CDCl 3) δ 1.62-1.69 (m, 2H), 1.82-1.89 (m, 1H), 2.09-2.17 (m, 3H), and 2.25-2.36 (m, 2H), 2.57 (t, J=6.9Hz, 2H), 3.00 (t, J=6.9Hz, 2H), 3.81 (s, 6H), 5.16 (q, J=8.7Hz, 1H), 5.62 (d, J=7.8Hz, 1H), 6.68 (d, J=9.0Hz, 1H), 6.79-6.86 (m, 3H), 7.00 (q, J=7.2Hz, 2H); ESI-MS (m/z) 416.16 (M+H) +
Embodiment 39
N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(2-isopropoxy-3-methoxyl group) Phenylpropionamide:
Figure BDA0000127889200000541
As described in example 1 above, title compound is by intermediate 2 (200mg, 0.898mmol) and 3-(2-isopropoxy-3-p-methoxy-phenyl) propionic acid (235mg, 0.988mmol) at EDCIHCl (258mg, 1348mmol), HOBt (206mg, 1.348mmol) and triethylamine (372 μ l, 2.695mmol) existence is descended, is prepared in methylene dichloride (10ml), obtains the 157mg white solid product; 1H NMR (300MHz, CDCl 3) δ 1.23 (s, 6H), 1.87 (br s, 2H), 2.13-2.26 (m, 6H), 2.58 (br s, 2H), 3.01 (br s, 2H), 3.79 (s, 3H), 4.49 (br s, 1H), 5.15 (br s, 1H), 5.84 (br s, 1H), 6.67 (d, J=7.8Hz, 1H), 6.79-6.86 (m, 3H), 6.97-7.04 (m, 2H).
Embodiment 40
N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(3-chloro-4-methoxyl group) Phenylpropionamide:
Figure BDA0000127889200000542
As described in example 1 above, title compound is by intermediate 2 (200mg, 0.763mmol) and 3-(3-chloro-4-p-methoxy-phenyl) propionic acid (198mg, 0.923mmol) at EDCIHCl (221mg, 1.153mmol), HOBt (175mg, 1.153mmol) and triethylamine (321 μ l, 2.307mmol) existence is descended, is prepared in methylene dichloride (10ml), obtains the 136mg white solid product; IR (KBr) 3272,2972,1645,1484,1226,794cm -1 1H NMR (300MHz, CDCl 3) δ 1.60-1.73 (m, 1H), 1.85-1.91 (m, 1H), 2.03-2.17 (m, 3H), and 2.22-2.32 (m, 2H), 2.44-2.56 (m, 2H), 2.91-2.96 (m, 2H), 3.86 (s, 3H), 5.22 (q, J=8.4Hz, 1H), 5.49 (d, J=8.4Hz, 1H), 6.69 (d, J=8.7Hz, 1H), 6.83-6.90 (m, 2H), 7.05 (t, J=7.8Hz, 2H), 7.21 (s, 1H); ESI-MS (m/z) 456.38 (M+H) +
Embodiment 41
N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(2-cyclo propyl methoxy-3-methoxyl group) Phenylpropionamide:
Figure BDA0000127889200000551
As described in example 1 above, title compound is by intermediate 2 (200mg, 0.769mmol) and 3-(2-cyclo propyl methoxy-3-p-methoxy-phenyl) propionic acid (232mg, 0.923mmol) at EDCIHCl (221mg, 1.153mmol), HOBt (176mg, 1.153mmol) and triethylamine (321 μ l, 2.307mmol) existence is descended, is prepared in methylene dichloride (10ml), obtains the 134mg white solid product; IR (KBr) 3262,2938,1641,1476,1263,1082,820cm -1 1H NMR (300MHz, CDCl 3) δ 0.26 (d, J=4.8Hz, 2H), 0.51-0.57 (m, 2H), 1.16-1.23 (m, 1H), 1.63-1.71 (m, 4H), 1.85-1.89 (m, 1H), 2.01-2.16 (m, 1H), 2.23-2.36 (m, 2H), 2.61 (t, J=7.2Hz, 2H), 3.03 (t, J=7.5Hz, 2H), 3.76 (s, 3H), 3.80 (s, 2H), 5.15 (q, J=12.0Hz, 1H), 5.77 (d, J=8.7Hz, 1H), 6.67 (d, J=8.7Hz, 1H), 6.77-6.83 (m, 3H), 6.95-7.04 (m, 2H); ESI-MS (m/z) 456.38 (M+H) +
Embodiment 42
N-[(4R)-6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl]-3-(2-cyclopentyloxy-3-methoxyl group) Phenylpropionamide:
Figure BDA0000127889200000561
As described in example 1 above, title compound is by intermediate 8 (150mg, 0.674mmol) and 3-(2-cyclopentyloxy-3-p-methoxy-phenyl) propionic acid (213mg, 0.674mmol) at EDCIHCl (193mg, 1.011mmol), HOBt (154mg, 1.011mmol) and triethylamine (281 μ l, 2.021mmol) existence is descended, is prepared in methylene dichloride (10ml), obtains the 167mg white solid product; IR (KBr) 3274,2956,1643,1475,1263,1079cm -1 1H NMR (300MHz, CDCl 3) δ 1.71-1.78 (m, 8H), 2.04-2.16 (m, 6H), 2.22-2.39 (m, 2H), and 2.54-2.59 (m, 2H), 2.97 (t, J=6.6Hz, 2H), 3.79 (s, 3H), 4.85 (br s, 1H), 5.14 (q, J=8.7Hz, 1H), 5.78 (d, J=8.4Hz, 1H), 6.67 (d, J=8.4Hz, 1H), 6.77-6.84 (m, 3H), 6.94-7.00 (m, 2H); ESI-MS (m/z) 392.35 (M+H) +.
Embodiment 43
N-[(4S)-6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl]-3-(2-cyclopentyloxy-3-methoxyl group) Phenylpropionamide:
Figure BDA0000127889200000562
As described in example 1 above, title compound is by intermediate 9 (150mg, 0.674mmol) and 3-(2-cyclopentyloxy-3-p-methoxy-phenyl) propionic acid (195mg, 0.741mmol) at EDCIHCl (193mg, 1.011mmol), HOBt (154mg, 1.011mmol) and triethylamine (281 μ l, 2.022mmol) existence is descended, is prepared in methylene dichloride (10ml), obtains the 113mg white solid product; IR (KBr) 3316,2955,1650,1477,1264,1078cm -1 1H NMR (300MHz, CDCl 3) δ 1.68-1.72 (m, 8H), 1.74-1.82 (m, 6H), 2.22-2.39 (m, 2H), and 2.54-2.59 (m, 2H), 2.97 (t, J=7.5Hz, 2H), 3.80 (s, 3H), 4.85 (br s, 1H), 5.14 (q, J=6.3Hz, 1H), 5.76 (d, J=8.4Hz, 1H), 6.67 (d, J=8.4Hz, 1H), 6.77-6.84 (m, 3H), 6.94-7.00 (m, 2H); ESI-MS (m/z) 470.42 (M) +
Embodiment 44
N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(2-cyclopentyloxy-3-oxyethyl group) Phenylpropionamide:
Figure BDA0000127889200000571
As described in example 1 above, title compound is by intermediate 2 (150mg, 0.571mmol) and 3-(2-cyclopentyloxy-3-ethoxyl phenenyl) propionic acid (177mg, 0.631mmol) at EDCIHCl (166mg, 0.863mmol), HOBt (133mg, 0.863mmol) and triethylamine (241 μ l, 1.734mmol) existence is descended, is prepared in methylene dichloride (10ml), obtains the 180mg white solid product; IR (KBr) 3327,2953,1646,1476,1263,1071cm -1 1H NMR (300MHz, CDCl 3) δ 1.39-1.46 (m, 4H), 1.64-1.81 (m, 10H), 2.06-2.16 (m, 3H), and 2.22-2.32 (m, 2H), 2.57 (t, J=7.2Hz, 2H), 2.97 (t, J=7.5Hz, 2H), 3.99 (q, J=6.3Hz, 2H), 4.84 (br s, 1H), 5.14 (q, J=5.4Hz, 1H), 5.76 (d, J=9.3Hz, 1H), 6.66-6.91 (m, 4H), 7.01 (d, J=8.4Hz, 2H); ESI-MS (m/z) 484.28 (M) +
Embodiment 45
N-(7-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(2-cyclopentyloxy-3-methoxyl group) Phenylpropionamide:
Figure BDA0000127889200000572
As described in example 1 above, title compound is by intermediate 10 (200mg, 0.769mmol) and 3-(2-cyclopentyloxy-3-p-methoxy-phenyl) propionic acid (243mg, 0.923mmol) at EDCIHCl (221mg, 1.543mmol), HOBt (176mg, 1.543mmol) and triethylamine (321 μ l, 2.307mmol) existence is descended, is prepared in methylene dichloride (10ml), obtains the 121mg white solid product; IR (KBr) 3263,2938,1641,1480,1270,1081,966cm -1 1H NMR (300MHz, CDCl 3) δ 1.59-1.77 (m, 10H), 2.13-2.27 (m, 5H), 2.57 (br s, 2H), 2.97 (br s, 2H), 3.47 (s, 1H), 3.79 (s, 3H), 4.85 (br s, 1H), 5.12-5.19 (m, 1H), 5.69-5.77 (m, 1H), 6.60-6.66 (m, 2H), 6.74-6.79 (m, 3H), 6.89-6.95 (m, 1H); ESI-MS (m/z) 470.23 (M) +
Embodiment 46
N-(8-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(2-oxyethyl group-3-methoxyl group) Phenylpropionamide:
Figure BDA0000127889200000581
As described in example 1 above, title compound is by intermediate 1 (200mg, 0.893mmol) and 3-(2-oxyethyl group-3-p-methoxy-phenyl) propionic acid (240mg, 1.074mmol) at EDCIHCl (257mg, 1.346mmol), HOBt (205mg, 1.346mmol) and triethylamine (497 μ l, 3.563mmol) existence is descended, is prepared in methylene dichloride (10ml), obtains the 132mg white solid product; IR (KBr) 3263,2936,1649,1451,1243,749cm -1 1H NMR (300MHz, CDCl 3) δ 1.33 (t, J=6.9Hz, 3H), 1.63-1.74 (m, 2H), 1.85-1.91 (m, 1H), and 2.03-2.17 (m, 3H), 2.22-2.32 (m, 2H), 2.40-2.50 (m, 2H), 3.00 (t, J=6.6Hz, 2H), 3.80 (s, 3H), 4.00 (q, J=6.9Hz, 2H), 5.21 (q, J=8.7Hz, 1H), 5.65 (d, J=8.1Hz, 1H), 6.63-6.70 (m, 2H), 6.77-6.84 (m, 2H), and 6.88-6.97 (m, 1H), 6.99-7.17 (m, 1H); ESI-MS (m/z) 430.31 (M+H) +
Embodiment 47
N-[(4R)-8-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)]-3-(2-cyclopentyloxy-3-methoxyl group) Phenylpropionamide:
Figure BDA0000127889200000582
As described in example 1 above, title compound is by intermediate 3 (150mg, 0.674mmol) and 3-(2-cyclopentyloxy-3-p-methoxy-phenyl) propionic acid (213mg, 0.824mmol) at EDCIHCl (193mg, 1.511mmol), HOBt (154mg, 1.511mmol) and triethylamine (279 μ l, 2.001mmol) existence is descended, is prepared in THF (10ml), obtains the 207mg white solid product; IR (KBr) 3247,2960,1634,1450,1276,1084,746cm -1 1H NMR (300MHz, CDCl 3) δ 1.22-1.27 (m, 1H), 1.68-1.91 (m, 9H), 2.08-2.31 (m, 4H), 2.40-2.48 (m, 2H), 2.57 (t, J=6.9Hz, 2H), 2.95 (t, J=6.9Hz, 2H), 3.79 (s, 3H), 4.85 (br s, 1H), 5.20-5.30 (m, 1H), 5.72 (d, J=8.1Hz, 1H), 6.62-6.70 (m, 2H), 6.78-6.85 (m, 2H), 6.95 (t, J=7.8Hz, 1H), 7.16 (d, J=6.3Hz, 1H); ESI-MS (m/z) 470.58 (M) +
Embodiment 48
N-[(4S)-(8-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(2-cyclopentyloxy-3-methoxyl group) Phenylpropionamide:
As described in example 1 above, title compound is by intermediate 4 (150mg, 0.676mmol) and 3-(2-cyclopentyloxy-3-p-methoxy-phenyl) propionic acid (212mg, 0.892mmol) at EDCIHCl (193mg, 1.013mmol), HOBt (154mg, 1.013mmol) and triethylamine (203 μ l, 2.107mmol) existence is descended, is prepared in methylene dichloride (10ml), obtains the 141mg white solid product; 1H NMR (300MHz, CDCl 3) δ 1.22-1.27 (m, 1H), 1.68-1.91 (m, 9H), 2.08-2.31 (m, 4H), 2.40-2.48 (m, 2H), 2.57 (t, J=6.9Hz, 2H), 2.95 (t, J=6.9Hz, 2H), 3.79 (s, 3H), 4.85 (br s, 1H), 5.20-5.30 (m, 1H), 5.72 (d, J=8.1Hz, 1H), 6.62-6.70 (m, 2H), 6.78-6.85 (m, 2H), 6.95 (t, J=7.8Hz, 1H), 7.16 (d, J=6.3Hz, 1H); ESI-MS (m/z) 470.68 (M) +
Embodiment 49
N-(6-chloro-7-methyl-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(2-cyclopentyloxy-3-methoxyl group) Phenylpropionamide:
Figure BDA0000127889200000592
As described in example 1 above, title compound is by intermediate 14 (200mg, 0.841mmol) and 3-(2-cyclopentyloxy-3-p-methoxy-phenyl) propionic acid (222mg, 0.841mmol) at EDCIHCl (242mg, 1.262mmol), HOBt (129mg, 0.841mmol) and triethylamine (351 μ l, 2.524mmol) existence is descended, is prepared in methylene dichloride (10ml), obtains the 72mg white solid product; IR (KBr) 3060,2939,1643,1475,1158,1080,882cm -1 1H NMR (300MHz, DMSO-d 6) δ 1.63-1.78 (m, 12H), 2.03-2.25 (m, 3H), 2.20-2.25 (m, 4H), 2.55 (t, J=7.2Hz, 2H), 2.97 (t, J=7.5Hz, 2H), 3.79 (s, 3H), 4.85 (br s, 1H), 5.14 (q, J=9.3Hz, 1H), 5.70 (d, J=8.4Hz, 1H), 6.63 (s, 1H), 6.78 (d, J=7.8Hz, 2H), 6.85 (s, 1H), 6.96 (d, J=7.8Hz, 1H); ESI-MS (m/z) 484.61 (M) +
Embodiment 50
N-(5-benzyloxy-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(2-cyclopentyloxy-3-methoxyl group) Phenylpropionamide:
Figure BDA0000127889200000601
As described in example 1 above, title compound is by intermediate 11 (246mg, 0.833mmol) and 3-(2-cyclopentyloxy-3-p-methoxy-phenyl) propionic acid (200mg, 0.758mmol) at EDCIHCl (218mg, 1.137mmol), HOBt (116mg, 0.756mmol) and triethylamine (316 μ l, 2.274mmol) existence is descended, is prepared in methylene dichloride (10ml), obtains the 170mg white solid product; IR (KBr) 3293,2956,1631,1465,1120,776cm -1 1H NMR (300MHz, CDCl 3) δ 1.59-1.70 (m, 4H), 1.88-1.92 (m, 5H), 2.00-2.06 (m, 5H), 2.23-2.36 (m, 4H), 2.78-2.84 (m, 2H), 3.75 (s, 3H), 4.77 (br s, 1H), 4.99 (s, 2H), 5.20 (q, J=3.0Hz, 1H), 5.63 (d, J=6.0Hz, 1H), 6.43-6.50 (m, 2H), 6.67 (d, J=7.8Hz, 2H), 6.83-6.89 (m, 1H), and 7.07-7.13 (m, 2H), 7.25-7.31 (m, 4H); ESI-MS (m/z) 542.38 (M+H) +
Embodiment 51
N-(5-hydroxyl-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(2-cyclopentyloxy-3-methoxyl group) Phenylpropionamide:
Figure BDA0000127889200000611
Under 45psi pressure, use the Pd/C (28mg) be in the methyl alcohol in the Paar instrument, (140mg 0.258mmol) carries out the deprotection of 4h under nitrogen to embodiment 50.Reaction mixture is filtered by bed of diatomaceous earth.Concentrating under reduced pressure filtrate obtains crude compound; Use is in 25% ethyl acetate in the sherwood oil, and this compound is carried out purifying by silica gel column chromatography, obtains the 51mg white solid product; IR (KBr) 3275,2955,1638,1463,1117,783cm -1 1H NMR (300MHz, CDCl 3) δ 1.20-1.30 (m, 4H), 1.76-1.88 (m, 5H), 2.05-2.17 (m, 5H), 2.50-2.56 (m, 4H), 2.92 (t, J=6.6Hz, 2H), 3.80 (s, 3H), 4.87 (br s, 1H), 5.02-5.10 (m, 1H), 5.96 (d, J=8.7Hz, 1H), 6.33 (d, J=7.8Hz, 1H), 6.41 (d, J=8.4Hz, 1H), 6.68-6.74 (m, 2H), 6.86 (t, J=7.8Hz, 1H), 7.00 (t, J=8.4Hz, 1H), 10.02 (br s, 1H, can with D 2O exchanges); ESI-MS (m/z) 452.51 (M+H) +
Embodiment 52
N-(3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-5-methoxyl group-4-yl)-3-(2-cyclopentyloxy-3-methoxyl group) Phenylpropionamide:
As described in example 1 above, title compound is by intermediate 15 (165mg, 0.757mmol) and 3-(2-cyclopentyloxy-3-p-methoxy-phenyl) propionic acid (200mg, 0.757mmol) at EDCIHCl (218mg, 1.137mmol), HOBt (116mg, 0.757mmol) and triethylamine (317 μ l, 2.273mmol) existence is descended, is prepared in methylene dichloride (10ml), obtains the 80mg white solid product; IR (KBr) 3286,2957,1632,1471,1122,775cm -1 1H NMR (300MHz, DMSO-d 6) δ 1.64-1.89 (m, 8H), 1.98-2.09 (m, 6H), 2.22-2.32 (m, 2H), 2.41-2.46 (m, 2H), 2.93 (t, J=7.8Hz, 2H), 3.70 (s, 3H), 3.78 (s, 3H), 4.81 (br s, 1H), 5.14 (q, J=3.6Hz, 1H), 5.54 (d, J=6.3Hz, 1H), 6.36 (d, J=7.8Hz, 1H), 6.46 (d, J=8.1Hz, 1H), 6.70-6.80 (m, 2H), 6.91 (t, J=7.8Hz, 1H), 7.11 (t, J=8.4Hz, 1H); ESI-MS (m/z) 466.17 (M+H) +
Embodiment 53
(4R)-6-chloro-N-(3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(2-cyclopentyloxy-3-methyl) Phenylpropionamide:
Figure BDA0000127889200000621
As described in example 1 above, title compound is by intermediate 8 (100mg, 0.449mmol) and 3-(2-cyclopentyloxy-3-aminomethyl phenyl) propionic acid (122mg, 0.491mmol) at EDCIHCl (129mg, 0.675mmol), HOBt (103mg, 0.673mmol) and triethylamine (187 μ l, 1.346mmol) existence is descended, is prepared in methylene dichloride (10ml), obtains the 126mg white solid product; 1H NMR (300MHz, CDCl 3) δ 1.70-1.81 (m, 8H), 2.06-2.33 (m, 11H), 2.64 (d, J=6.0Hz, 2H), 3.03 (t, J=6.3Hz, 2H), 4.74 (br s, 1H), 5.18 (q, J=6.0Hz, 1H), 5.99 (d, J=7.8Hz, 1H), 6.72 (d, J=8.7Hz, 1H), 6.87 (s, 1H), 6.97-7.05 (m, 4H).
Embodiment 54
(4S)-6-chloro-N-(3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(2-cyclopentyloxy-3-methyl) Phenylpropionamide:
As described in example 1 above, title compound is by intermediate 9 (100mg, 0.449mmol) and 3-(2-cyclopentyloxy-3-aminomethyl phenyl) propionic acid (122mg, 0.491mmol) at EDCIHCl (129mg, 0.675mmol), HOBt (103mg, 0.673mmol) and triethylamine (187 μ l, 1.346mmol) existence is descended, is prepared in methylene dichloride (10ml), obtains the 89mg white solid product; 1H NMR (300MHz, CDCl 3) δ 1.70-1.81 (m, 8H), 2.06-2.33 (m, 11H), 2.64 (d, J=6.0Hz, 2H), 3.03 (t, J=6.3Hz, 2H), 4.74 (br s, 1H), 5.18 (q, J=6.0Hz, 1H), 5.99 (d, J=7.8Hz, 1H), 6.72 (d, J=8.7Hz, 1H), 6.87 (s, 1H), 6.97-7.05 (m, 4H).
Embodiment 55
N-6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-4-base-3-(2-hydroxy 3-methoxybenzene base) propionic acid amide:
Figure BDA0000127889200000631
Step 1:(2E)-N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(2-benzyloxy-3-p-methoxy-phenyl) acrylamide: as described in example 1 above, this compound is by intermediate 2 (500mg, 1.938mmol) and (2E)-3-[2-(benzyloxy)-3-p-methoxy-phenyl] vinylformic acid (575mg, 2.023mmol) at EDCIHCl (555mg, 2.897mmol), HOBt (443mg, 2.897mmol) and triethylamine (806 μ l, 5.791mmol) exist down, in methylene dichloride (15ml), be prepared, obtain the 633mg white solid product; 1H NMR (300MHz, CDCl 3) δ 1.70-1.84 (m, 3H), 2.11-2.22 (m, 3H), 2.35-2.47 (m, 2H), 3.89 (s, 3H), 5.02 (q, J=11.4Hz, 2H), 5.34 (q, J=9.9Hz, 1H), 5.44 (d, J=8.4Hz, 1H), 6.59 (d, J=15.6Hz, 1H), 6.75 (d, J=8.4Hz, 1H), 6.92-6.96 (m, 1H), and 7.04-7.10 (m, 4H), 7.19-7.29 (m, 3H), 7.41 (d, J=6.6Hz, 2H), 7.69 (d, J=16.2Hz, 1H).
Step 2:N-6-chloro-3; 4-dihydro spiral shell [chromene-2; 1 '-ring fourth]-4-base-3-(2-hydroxy 3-methoxybenzene base) propionic acid amide: in the Paar instrument under 45psi pressure; use is in the 5%Pd/C (50mg) in the ethyl acetate (20ml); (200mg 0.408mmol) carries out deprotection and the reduction of 4h under nitrogen with step 1 intermediate.Reaction mixture is filtered by bed of diatomaceous earth.Concentrating under reduced pressure filtrate obtains crude compound; Use is in 1% methyl alcohol in the chloroform, and this compound is carried out purifying by silica gel column chromatography, obtains the 121mg white solid product; 1H NMR (300MHz, CDCl 3) δ 1.57-1.69 (m, 2H), 1.83-1.88 (m, 1H), 2.11-2.17 (m, 3H), 2.26-2.36 (m, 2H), 2.62 (t, J=6.9Hz, 2H), 3.02 (t, J=6.6Hz, 2H), 3.85 (s, 3H), 5.17 (q, J=9.9Hz, 1H), 5.60 (d, J=7.8Hz, 1H), 6.07 (s, 1H), 6.67-6.76 (m, 4H), 6.82-6.86 (m, 1H), 7.04 (dd, J=6.3,1.8Hz, 1H).
Embodiment 56
N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(2-benzyloxy-3-methoxyl group) Phenylpropionamide:
Figure BDA0000127889200000641
At room temperature, to embodiment 55N-6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-4-base-3-(2-hydroxy 3-methoxybenzene base) propionic acid amide (150mg, 0.371mmol) drip K2CO3 and cylite (70mg in the solution after in dimethyl formamide (5ml), stirring, 0.411mmol), and stir at uniform temp and to spend the night.The gained reaction mixture is filtered, and filtrate is used ethyl acetate extraction.The ethyl acetate layer water (2 * 20ml), salt solution (20ml) washing, pass through Na 2SO 4Dry and concentrated.Use is in 10% acetone in the sherwood oil, and the crude product that obtains is carried out purifying by silica gel column chromatography, obtains the 130mg white solid product; IR (KBr) 3283,2939,1644,1476,1263,1082,820cm -1 1H NMR (300MHz, CDCl 3) δ 1.63-1.86 (m, 2H), 2.02 (br s, 1H), 2.11-2.36 (m, 5H), 2.41 (t, J=7.2Hz, 2H), 2.88 (t, J=7.8Hz, 2H), 3.86 (s, 3H), 4.99 (s, 2H), 5.06 (q, J=6.0Hz, 1H), 5.40 (d, J=7.8Hz, 1H), and 6.67-6.83 (m, 4H), 6.95-7.04 (m, 2H), 7.21-7.30 (m, 3H), 7.35 (d, J=7.2Hz, 2H); ESI-MS (m/z) 492.14 (M) +
Embodiment 57
N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-{2-isopropoxy-3-[(methyl sulphonyl) amino] phenyl } propionic acid amide:
Figure BDA0000127889200000642
As described in example 1 above, title compound is by intermediate 2 (100mg, 0.384mmol) and 3-{2-isopropoxy-3-[(methyl sulphonyl) amino] phenyl propionic acid (116mg, 0.384mmol) at EDCIHCl (111mg, 0.576mmol), HOBt (59mg, 0.384mmol) and triethylamine (134 μ l, 0.961mmol) existence is descended, is prepared in methylene dichloride (5ml), obtains the 122mg white solid product; IR (KBr) 3331,2950,1645,1473,1140,984cm -1 1H NMR (300MHz, CDCl 3) δ 1.35 (d, J=4.8Hz, 6H), 1.65-1.72 (m, 2H), 1.89-1.95 (m, 1H), 2.10-2.18 (m, 3H), 2.31-2.38 (m, 2H), 2.59 (t, J=7.5Hz, 2H), 3.00 (s, 5H), 4.22-4.28 (m, 1H), 5.21 (q, J=6.3Hz, 1H), 5.60 (d, J=8.7Hz, 1H), 6.71 (d, J=9.0Hz, 1H), 6.86 (s, 1H), 6.95 (d, J=9.3Hz, 2H), 7.01-7.08 (m, 2H), 7.37 (d, J=7.2Hz, 1H); ESI-MS (m/z) 507.39 (M+H) +
Embodiment 58
N-(8-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-{2-isopropoxy-3-[(methyl sulphonyl) amino] phenyl } propionic acid amide:
Figure BDA0000127889200000651
As described in example 1 above, title compound is by intermediate 1 (100mg, 0.384mmol) and 3-{2-isopropoxy-3-[(methyl sulphonyl) amino] phenyl) propionic acid (116mg, 0.384mmol) at EDCIHCl (111mg, 0.576mmol), HOBt (59mg, 0.384mmol) and triethylamine (134 μ l, 0.961mmol) existence is descended, is prepared in methylene dichloride (5ml), obtains the 121mg white solid product; IR (KBr) 3302,2937,1643,1449,1151,978cm -1 1H NMR (300MHz, CDCl 3) δ 1.34 (d, J=3.9Hz, 6H), 1.68-1.79 (m, 2H), 1.89-1.95 (m, 1H), 2.18-2.25 (m, 3H), 2.36-2.46 (m, 2H), 2.58 (t, J=7.2Hz, 2H), 2.99 (s, 5H), 4.23-4.29 (m, 1H), 5.25 (q, J=6.9Hz, 1H), 5.58 (d, J=9.0Hz, 1H), 6.72-6.78 (m, 2H), 6.85 (s, 1H), 6.96 (d, J=6.6Hz, 1H), 7.04 (t, J=8.1Hz, 1H), 7.19 (s, 1H), 7.37 (d, J=7.8Hz, 1H); ESI-MS (m/z) 507.46 (M+H) +
Embodiment 59
N-(6,8-, two chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(2-cyclopentyloxy-3-methoxyl group) Phenylpropionamide:
Figure BDA0000127889200000661
As described in example 1 above, title compound is by intermediate 13 (150mg, 0.511mmol) and 3-[2-(cyclopentyloxy-3-methoxyl group) phenyl] propionic acid (127mg, 0.511mmol) at EDCIHCl (147mg, 0.766mmol), HOBt (78mg, 0.511mmol) and triethylamine (249 μ l, 1.788mmol) existence is descended, is prepared in methylene dichloride (10ml), obtains the 85mg white solid product; IR (KBr) 3277,2956,1644,1451,1246,1080,970cm -1 1H NMR (300MHz, CDCl 3) δ 1.62-1.68 (m, 3H), 1.74-1.88 (m, 8H), 2.04-2.27 (m, 4H), and 2.58-2.61 (m, 3H), 2.96 (d, J=6.9Hz, 2H), 3.79 (s, 3H), 4.85 (br s, 1H), 5.17 (q, J=9.3Hz, 1H), 5.81 (d, J=8.1Hz, 1H), 6.77 (d, J=8.4Hz, 3H), 6.96 (t, J=7.8Hz, 1H), 7.17 (s, 1H); ESI-MS (m/z) 504.16 (M) +
Embodiment 60
N-(6,8-, two chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-{[2-(dimethylamino) oxyethyl group-3-methoxyl group] phenyl } propionic acid amide:
As described in example 1 above, title compound is by intermediate 13 (100mg, 0.339mmol) and 3-{2-[2-(dimethylamino) oxyethyl group]-the 3-p-methoxy-phenyl } propionic acid (102mg, 0.407mmol) at EDCIHCl (97mg, 0.509mmol), HOBt (78mg, 0.509mmol) and triethylamine (141 μ l, 1.017mmol) existence is descended, is prepared in methylene dichloride (10ml), obtains the 57mg white solid product; IR (KBr) 3273,2938,1651,1539,1454,1268,1247,1081,957cm -1 1H NMR (300MHz, CDCl 3) δ 1.17-1.25 (m, 3H), 1.63-1.74 (m, 2H), 1.91 (br s, 1H), 2.14-2.22 (m, 2H), 2.27 (s, 6H), 2.30-2.36 (m, 2H), 2.44-2.51 (m, 1H), 2.60-2.71 (m, 4H), 2.95-3.02 (m, 2H), 3.81 (s, 1H), 4.05-4.11 (m, 2H), 5.17-5.26 (m, 1H), 6.63 (d, J=7.8Hz, 1H), 6.79 (d, J=7.5Hz, 2H), 6.97 (t, J=7.8Hz, 1H), 7.16 (s, 1H); APCI-MS (m/z) 507.81 (M+H) +
Embodiment 61
N-(6,8-, two chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-{2-propoxy--3-[(methyl sulphonyl) amino] phenyl } propionic acid amide:
Figure BDA0000127889200000671
As described in example 1 above, title compound is by intermediate 13 (100mg, 0.339mmol) and the 3-{3-[(methyl sulphonyl) amino]-2-propoxy-phenyl } propionic acid (103mg, 0.339mmol) at EDCIHCl (98mg, 0.509mmol), HOBt (52mg, 0.339mmol) and triethylamine (119 μ l, 0.848mmol) existence is descended, is prepared in methylene dichloride (10ml), obtains the 119mg white solid product; IR (KBr) 3305,2937,1644,1451,1141,986cm -1 1H NMR (300MHz, CDCl 3) δ 1.08 (t, J=7.5Hz, 3H), 1.68-1.75 (m, 2H), 1.82-1.89 (m, 3H), 2.14-2.20 (m, 3H), 2.32-2.38 (m, 1H), and 2.42-2.50 (m, 1H), 2.60 (t, J=7.5Hz, 2H), 3.04 (s, 5H), 3.81 (t, J=6.9Hz, 2H), 5.24 (q, J=6.3Hz, 1H), 5.62 (d, J=8.7Hz, 1H), 6.81 (s, 1H), 6.86 (s, 1H), 6.97 (d, J=7.8Hz, 1H), 7.07 (t, J=7.8Hz, 1H), 7.20 (s, 1H), 7.38 (d, J=7.5Hz, 1H); ESI-MS (m/z) 541.67 (M) +
Embodiment 62
N-(6,8-, two chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-{2-isopropoxy-5-[(methyl sulphonyl) amino] phenyl } propionic acid amide:
Figure BDA0000127889200000672
As described in example 1 above, title compound is by intermediate 13 (100mg, 0.339mmol) and 3-{2-isopropoxy-5-[(methyl sulphonyl) amino] phenyl) propionic acid (112mg, 0.372mmol) at EDCIHCl (98mg, 0.509mmol), HOBt (78mg, 0.509mmol) and triethylamine (142 μ l, 1.017mmol) existence is descended, is prepared in methylene dichloride (5ml), obtains the 90mg white solid product; IR (KBr) 3275,2935,1648,1497,1152,960cm -1 1H NMR (300MHz, CDCl 3) δ 1.30 (s, 6H), 1.58-1.64 (m, 2H), 1.70-1.76 (m, 2H), and 2.10-2.17 (m, 2H), 2.38-2.45 (m, 2H), 2.58-2.65 (m, 2H), 2.90-3.02 (m, 4H), 4.49 (br s, 1H), 5.21 (br s, 1H), 5.74 (br s, 1H), 6.50-6.55 (m, 1H), 6.73-6.79 (m, 2H), 6.98-7.08 (m, 2H), 7.22 (d, J=15.6Hz, 2H); APCI-MS (m/z) 541.60 (M+H) +
Embodiment 63
N-(6,8-, two chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-{2-butoxy-3-[(methyl sulphonyl) amino] phenyl } propionic acid amide:
Figure BDA0000127889200000681
As described in example 1 above, title compound is by intermediate 13 (100mg, 0.339mmol) and 3-{2-butoxy-3-[(methyl sulphonyl) amino] phenyl) propionic acid (107mg, 0.339mmol) at EDCIHCl (98mg, 0.509mmol), HOBt (52mg, 0.339mmol) and triethylamine (119 μ l, 0.848mmol) existence is descended, is prepared in methylene dichloride (10ml), obtains the 107mg white solid product through 3h; IR (KBr) 3289,2935,1647,1451,1156,979cm -1 1H NMR (300MHz, CDCl 3) δ 0.99 (t, J=7.2Hz, 3H), 1.47-1.54 (m, 2H), 1.68-1.80 (m, 4H), 1.83-1.98 (m, 1H), 2.04-2.16 (m, 3H), and 2.32-2.45 (m, 2H), 2.60 (t, J=6.9Hz, 2H), 3.04 (s, 4H), 3.84 (t, J=6.3Hz, 2H), 5.24 (q, J=6.6Hz, 1H), 5.62 (d, J=9.3Hz, 1H), 6.80 (s, 1H), 6.85 (s, 1H), 6.97 (d, J=7.8Hz, 1H), 7.07 (t, J=7.8Hz, 1H), 7.20 (s, 1H), 7.37 (d, J=7.8Hz, 1H); ESI-MS (m/z) 555.32 (M) +
Embodiment 64
N-(6,8-, two chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-{2-(cyclo propyl methoxy)-3-[(methyl sulphonyl) amino] phenyl } propionic acid amide:
Figure BDA0000127889200000691
As described in example 1 above, title compound is by intermediate 13 (100mg, 0.339mmol) and 3-{2-(cyclo propyl methoxy)-3-[(methyl sulphonyl) amino] phenyl propionic acid (107mg, 0.339mmol) at EDCIHCl (98mg, 0.509mmol), HOBt (52mg, 0.339mmol) and triethylamine (119 μ l, 0.848mmol) existence is descended, is prepared in methylene dichloride (10ml), obtains the 140mg white solid product; IR (KBr) 3303,2934,1644,1451,1140,982cm -1 1H NMR (300MHz, CDCl 3) δ 0.35 (d, J=6.9Hz, 2H), 0.69 (d, J=5.4Hz, 2H), 1.22-1.26 (m, 2H), and 1.68-1.80 (m, 2H), 1.83-1.98 (m, 1H), 2.12-2.20 (m, 3H), 2.32-2.45 (m, 2H), 2.60 (t, J=7.2Hz, 2H), 3.03 (s, 4H), 3.73 (d, J=6.9Hz, 2H), 5.24 (q, J=5.7Hz, 1H), 5.62 (d, J=8.4Hz, 1H), 6.87 (s, 1H), 6.97-7.07 (m, 3H), 7.20 (s, 1H), 7.37 (d, J=7.2Hz, 1H); ESI-MS (m/z) 553.60 (M) +
Embodiment 65
N-(6,8-, two chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-{2-isopropoxy-3-[(methyl sulphonyl) amino] phenyl } propionic acid amide:
Figure BDA0000127889200000692
As described in example 1 above, title compound is by intermediate 13 (100mg, 0.339mmol) and 3-{2-isopropoxy-3-[(methyl sulphonyl) amino] phenyl) propionic acid (103mg, 0.339mmol) at EDCIHCl (98mg, 0.509mmol), HOBt (52mg, 0.339mmol) and triethylamine (119 μ l, 0.848mmol) existence is descended, is prepared in methylene dichloride (10ml), obtains the 85mg white solid product through 3h; IR (KBr) 3292,2935,1648,1451,1155,979cm -1 1H NMR (300MHz, CDCl 3) δ 1.35 (d, J=5.7Hz, 6H), 1.71 (t, J=3.4Hz, 2H), 1.82-1.90 (m, 1H), and 2.12-2.20 (m, 3H), 2.32-2.39 (m, 1H), 2.40-2.48 (m, 1H), 2.60 (t, J=7.5Hz, 2H), 3.01 (s, 5H), 4.22-4.28 (m, 1H), 5.19 (q, J=9.0Hz, 1H), 5.61 (d, J=9.0Hz, 1H), 6.86 (s, 2H), 6.96 (d, J=7.8Hz, 1H), 7.06 (t, J=8.4Hz, 1H), 7.20 (s, 1H), 7.36 (d, J=8.1Hz, 1H); ESI-MS (m/z) 540.86 (M) +
Embodiment 66
N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(1-naphthyl) propionic acid amide:
Figure BDA0000127889200000701
As described in example 1 above, title compound is by intermediate 2 (200mg, 0.896mmol) and 1-naphthyl propionic acid (178mg, 0.896mmol) at EDCIHCl (256mg, 1.345mmol), HOBt (205mg, 1.345mmol) and triethylamine (371 μ l, 2.690mmol) existence is descended, is prepared in methylene dichloride (10ml), obtains the 160mg white solid product; 1H NMR (300MHz, CDCl 3) δ 1.43-1.51 (m, 1H), 1.63-1.69 (m, 1H), 1.81-1.97 (m, 2H), 2.09-2.26 (m, 4H), 2.64-2.70 (m, 2H), 3.50 (t, J=7.2Hz, 2H), 5.14 (q, J=9.9Hz, 1H), 5.26 (d, J=8.4Hz, 1H), 6.65 (d, J=8.7Hz, 1H), 6.82 (s, 1H), 7.01 (dd, J=2.4,8.7Hz, 1H), 7.35-7.54 (m, 4H), 7.73 (d, J=6.9Hz, 1H), 7.84 (d, J=7.5Hz, 1H), 8.04 (d, J=8.1Hz, 1H); ESI-MS (m/z) 406.34 (M+H) +
Embodiment 67
N-[4R-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(2-methoxyl group-1-naphthyl) propionic acid amide:
Figure BDA0000127889200000702
As described in example 1 above, title compound is by intermediate 8 (100mg, 0.449mmol) and 3-(2-methoxyl group-1-naphthyl) propionic acid (113mg, 0.494mmol) at EDCIHCl (129mg, 0.677mmol), HOBt (103mg, 0.677mmol) and triethylamine (187 μ l, 1.348mmol) existence is descended, is prepared in methylene dichloride (10ml), obtains the 91mg white solid product; 1H NMR (300MHz, CDCl 3) δ 1.38-1.50 (m, 1H), 1.62-1.69 (m, 1H), 1.89-2.10 (m, 5H), and 2.20-2.30 (m, 1H), 2.65 (t, J=7.2Hz, 2H), and 3.43-3.49 (m, 2H), 3.83 (s, 3H), 5.08 (q, J=9.3Hz, 1H), 5.76 (d, J=8.1Hz, 1H), 6.67 (d, J=8.7Hz, 1H), 6.83 (s, 1H), 7.03 (dd, J=2.4,6.3Hz, 1H), 7.30 (s, 1H), 7.33-7.37 (m, 1H), 7.47-7.52 (m, 1H), 7.76 (t, J=8.4Hz, 2H), 7.98 (d, J=8.4Hz, 1H).
Embodiment 68
N-[4S-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(2-methoxyl group-1-naphthyl) propionic acid amide:
Figure BDA0000127889200000711
As described in example 1 above, title compound is by intermediate 9 (100mg, 0.449mmol) and 3-(2-methoxyl group-1-naphthyl) propionic acid (113mg, 0.494mmol) at EDCIHCl (129mg, 0.677mmol), HOBt (103mg, 0.677mmol) and triethylamine (187 μ l, 1.348mmol) existence is descended, is prepared in methylene dichloride (10ml), obtains the 117mg white solid product; 1H NMR (300MHz, CDCl 3) δ 1.38-1.50 (m, 1H), 1.62-1.69 (m, 1H), 1.89-2.10 (m, 5H), and 2.20-2.30 (m, 1H), 2.65 (t, J=7.2Hz, 2H), and 3.43-3.49 (m, 2H), 3.83 (s, 3H), 5.08 (q, J=9.3Hz, 1H), 5.76 (d, J=8.1Hz, 1H), 6.67 (d, J=8.7Hz, 1H), 6.83 (s, 1H), 7.03 (dd, J=2.4,6.3Hz, 1H), 7.30 (s, 1H), 7.33-7.37 (m, 1H), 7.47-7.52 (m, 1H), 7.76 (t, J=8.4Hz, 2H), 7.98 (d, J=8.4Hz, 1H).
Embodiment 69
N-[(4R)-6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(4-methoxyl group-1-naphthyl) propionic acid amide:
Figure BDA0000127889200000712
As described in example 1 above, title compound is by intermediate 8 (100mg, 0.449mmol) and 3-(4-methoxyl group-1-naphthyl) propionic acid (102mg, 0.449mmol) at EDCIHCl (129mg, 0.677mmol), HOBt (103mg, 0.677mmol) and triethylamine (187 μ l, 1.348mmol) existence is descended, is prepared in methylene dichloride (10ml), obtains the 110mg white solid product through 4h; 1H NMR (300MHz, CDCl 3) δ 1.62-1.69 (m, 1H), 1.89-1.95 (m, 2H), 2.09-2.26 (m, 5H), 2.64 (t, J=5.4Hz, 2H), 3.41 (t, J=7.5Hz, 2H), 3.96 (s, 3H), 5.14 (q, J=8.1Hz, 1H), 5.26 (d, J=8.7Hz, 1H), 6.65 (d, J=8.7Hz, 1H), 6.73 (d, J=7.8Hz, 1H), 6.84 (s, 1H), 7.00 (d, J=9.0Hz, 1H), 7.26-7.30 (m, 1H), 7.43-7.55 (m, 2H), 7.95 (d, J=8.1Hz, 1H), 8.28 (d, J=8.1Hz, 1H).
Embodiment 70
N-[(4S)-6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(4-methoxyl group-1-naphthyl) propionic acid amide:
As described in example 1 above, title compound is by intermediate 9 (100mg, 0.449mmol) and 3-(4-methoxyl group-1-naphthyl) propionic acid (102mg, 0.449mmol) at EDCIHCl (129mg, 0.677mmol), HOBt (103mg, 0.677mmol) and triethylamine (187 μ l, 1.348mmol) existence is descended, is prepared in methylene dichloride (10ml), obtains the 100mg white solid product through 4h; 1H NMR (300MHz, CDCl 3) δ 1.62-1.69 (m, 1H), 1.89-1.95 (m, 2H), 2.09-2.26 (m, 5H), 2.64 (t, J=5.4Hz, 2H), 3.41 (t, J=7.5Hz, 2H), 3.96 (s, 3H), 5.14 (q, J=8.1Hz, 1H), 5.26 (d, J=8.7Hz, 1H), 6.65 (d, J=8.7Hz, 1H), 6.73 (d, J=7.8Hz, 1H), 6.84 (s, 1H), 7.00 (d, J=9.0Hz, 1H), 7.26-7.30 (m, 1H), 7.43-7.55 (m, 2H), 7.95 (d, J=8.1Hz, 1H), 8.28 (d, J=8.1Hz, 1H).
Embodiment 71
(4R)-6-chloro-N-(3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(4-difluoro-methoxy-1-naphthyl) propionic acid amide:
Figure BDA0000127889200000722
As described in example 1 above, title compound is by intermediate 8 (100mg, 0.447mmol) and 3-(4-difluoro-methoxy-1-naphthyl) propionic acid (142mg, 0.536mmol) at EDCIHCl (128mg, 0.671mmol), HOBt (102mg, 0.671mmol) and triethylamine (124 μ l, 0.894mmol) existence is descended, is prepared in methylene dichloride (10ml), obtains the 89mg white solid product; 1H NMR (300MHz, CDCl 3) δ 1.53-1.64 (m, 2H), 1.88-1.97 (m, 2H), 2.13-2.25 (m, 5H), 2.63-2.69 (m, 2H), 3.47 (t, J=7.5Hz, 2H), 5.17 (q, J=5.7Hz, 1H), 5.32 (d, J=6.3Hz, 1H), 6.65 (t, J=8.7Hz, 1H), 6.86 (d, J=6.6Hz, 1H), 7.02 (d, J=8.4Hz, 1H), 7.11 (d, J=7.8Hz, 1H), 7.31 (d, J=7.2Hz, 1H), 7.55-7.60 (m, 2H), 8.03 (d, J=7.5Hz, 1H), 8.21 (d, J=7.5Hz, 1H).
Embodiment 72
(4S)-6-chloro-N-(3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(4-difluoro-methoxy-1-naphthyl) propionic acid amide:
Figure BDA0000127889200000731
As described in example 1 above, title compound is by intermediate 9 (100mg, 0.449mmol) and 3-(4-difluoro-methoxy-1-naphthyl) propionic acid (142mg, 0.536mmol) at EDCIHCl (128mg, 0.671mmol), HOBt (102mg, 0.671mmol) and triethylamine (124 μ l, 0.894mmol) existence is descended, is prepared in methylene dichloride (10ml), obtains the 62mg white solid product; 1H NMR (300MHz, CDCl 3) δ 1.53-1.64 (m, 2H), 1.88-1.97 (m, 2H), 2.13-2.25 (m, 5H), 2.63-2.69 (m, 2H), 3.47 (t, J=7.5Hz, 2H), 5.17 (q, J=5.7Hz, 1H), 5.32 (d, J=6.3Hz, 1H), 6.65 (t, J=8.7Hz, 1H), 6.86 (d, J=6.6Hz, 1H), 7.02 (d, J=8.4Hz, 1H), 7.11 (d, J=7.8Hz, 1H), 7.31 (d, J=7.2Hz, 1H), 7.55-7.60 (m, 2H), 8.03 (d, J=7.5Hz, 1H), 8.21 (d, J=7.5Hz, 1H).
Embodiment 73
N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(2-naphthyl) propionic acid amide:
Figure BDA0000127889200000741
As described in example 1 above, title compound is by intermediate 2 (100mg, 0.506mmol) and 3-(2-naphthyl) propionic acid (103mg, 0.506mmol) at EDCIHCl (143mg, 0.751mmol), HOBt (114mg, 0.751mmol) and triethylamine (209 μ l, 1.518mmol) existence is descended, is prepared in methylene dichloride (10ml), obtains the 101mg white solid product through 3h; IR (KBr) 3287,2937,1645,1475,1234,817cm -1 1H NMR (300MHz, CDCl 3) δ 1.41-1.48 (m, 1H), 1.80-1.86 (m, 2H), 2.06-2.26 (m, 4H), 2.56-2.68 (m, 2H), 3.19 (t, J=7.2Hz, 2H), 3.47 (s, 1H), 5.17 (q, J=9.0Hz, 1H), 5.35 (d, J=7.8Hz, 1H), 6.65 (d, J=8.7Hz, 1H), 6.91 (s, 1H), 7.01 (d, J=8.4Hz, 1H), 7.33-7.42 (m, 3H), 7.65 (s, 1H), 7.77 (d, J=8.1Hz, 3H); ESI-MS (m/z) 406.56 (M+H) +
Embodiment 74
N-[4R-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(6-methoxyl group-2-naphthyl) propionic acid amide:
Figure BDA0000127889200000742
As described in example 1 above, title compound is by intermediate 8 (150mg, 0.674mmol) and 3-(6-methoxyl group-2-naphthyl) propionic acid (170mg, 0.741mmol) at EDCIHCl (193mg, 1.017mmol), HOBt (154mg, 1.011mmol) and triethylamine (281 μ l, 2.022mmol) existence is descended, is prepared in methylene dichloride (10ml), obtains the 190mg white solid product; 1H NMR (300MHz, CDCl 3) δ 1.42-1.50 (m, 1H), 1.80-1.86 (m, 2H), 2.06-2.20 (m, 4H), 2.54-2.68 (m, 2H), 3.15 (t, J=6.6Hz, 2H), 3.89 (s, 3H), 5.15 (q, J=6.0Hz, 1H), 5.35 (d, J=7.8Hz, 1H), 6.65 (d, J=7.8Hz, 1H), 6.89 (s, 1H), 7.05 (d, J=7.8Hz, 1H), 7.09 (d, J=8.4Hz, 2H), 7.29 (d, J=8.4Hz, 1H), 7.57 (s, 1H), 7.65 (d, J=7.8Hz, 2H).
Embodiment 75
N-[4S-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(6-methoxyl group-2-naphthyl) propionic acid amide:
Figure BDA0000127889200000751
As described in example 1 above, title compound is by intermediate 9 (150mg, 0.674mmol) and 3-(6-methoxyl group-2-naphthyl) propionic acid (170mg, 0.741mmol) at EDCIHCl (193mg, 1.017mmol), HOBt (154mg, 1.011mmol) and triethylamine (281 μ l, 2.022mmol) existence is descended, is prepared in methylene dichloride (10ml), obtains the 127mg white solid product; IR (KBr) 3293,2956,1631,1465,1120,776cm -1 1H NMR (300MHz, CDCl 3) δ 1.42-1.50 (m, 1H), 1.80-1.86 (m, 2H), 2.06-2.20 (m, 4H), 2.54-2.68 (m, 2H), 3.15 (t, J=6.6Hz, 2H), 3.89 (s, 3H), 5.15 (q, J=6.0Hz, 1H), 5.35 (d, J=7.8Hz, 1H), 6.65 (d, J=7.8Hz, 1H), 6.89 (s, 1H), 7.05 (d, J=7.8Hz, 1H), 7.09 (d, J=8.4Hz, 2H), 7.29 (d, J=8.4Hz, 1H), 7.57 (s, 1H), 7.65 (d, J=7.8Hz, 2H); ESI-MS (m/z) 542.38 (M+H) +
Embodiment 76
N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(quinoline-2-yl) propionic acid amide:
Figure BDA0000127889200000752
Step 1:(2E)-N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-quinoline-2-base acrylamide: as described in example 1 above, this compound is by intermediate 2 (200mg, 0.894mmol) and (2E)-3-quinoline-2-base vinylformic acid (213mg, 1.073mmol) at EDCIHCl (257mg, 1.342mmol), HOBt (205mg, 1.342mmol) and triethylamine (248 μ l, 2.684mmol) exist down, in methylene dichloride (10ml), be prepared, obtain the 167mg white solid product; 1H NMR (300MHz, DMSO-d 6) δ 1.69-1.92 (m, 3H), 2.04-2.16 (m, 3H), 2.27-2.41 (m, 2H), 5.20 (q, J=10.2Hz, 1H), 6.81 (d, J=9.0Hz, 1H), 7.10-7.20 (m, 2H), 7.27 (d, J=15.6Hz, 1H), 7.60 (t, J=7.8Hz, 1H), 7.73-7.77 (m, 2H), 7.92-7.99 (m, 2H), 8.29 (s, 1H), 8.40 (d, J=8.1Hz, 1H), 8.88 (d, J=8.4Hz, 1H).
Step 2:N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-ring fourth]-the 4-yl)-3-(quinoline-2-yl) propionic acid amide: in the Paar instrument under 50psi pressure, use is in the 10%Pd/C (50mg) in the ethyl acetate (25ml), (150mg 0.388mmol) carries out the reduction of 2h under nitrogen to step 1 intermediate.Reaction mixture is filtered by bed of diatomaceous earth, and concentrating under reduced pressure filtrate obtains crude compound; Use is in 1% methyl alcohol in the chloroform, and this compound is carried out purifying by silica gel column chromatography, obtains the 121mg white solid product; 1H NMR (300MHz, DMSO-d 6) δ 1.64-1.77 (m, 3H), 2.00-2.07 (m, 3H), 2.19-2.28 (m, 2H), 2.67-2.82 (m, 2H), 3.17-3.26 (m, 2H), 5.02 (br s, 1H), 6.72 (d, J=9.0Hz, 1H), 6.94 (s, 1H), 7.10 (d, J=8.4Hz, 1H), 7.44-7.54 (m, 2H), 7.69 (t, J=7.5Hz, 1H), 7.91 (d, J=7.2Hz, 2H), 8.25 (d, J=8.1Hz, 1H), 8.40 (d, J=8.4Hz, 1H).
Embodiment 77
N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(1H-indol-3-yl) propionic acid amide:
Figure BDA0000127889200000761
As described in example 1 above, title compound is by intermediate 2 (200mg, 0.894mmol) and 3-(1H-indol-3-yl) propionic acid (187mg, 0.988mmol) at EDCIHCl (258mg, 1.345mmol), HOBt (206mg, 1.345mmol) and triethylamine (375 μ l, 2.684mmol) existence is descended, is prepared in methylene dichloride (10ml), obtains the 121mg white solid product; IR (KBr) 3395,2926,1642,1474,1234,748cm -1 1H NMR (300MHz, CDCl 3) δ 1.78-1.96 (m, 2H), 2.09-2.26 (m, 6H), 2.63 (t, J=6.3Hz, 2H), 3.17-3.21 (m, 2H), 5.15 (q, J=9.6Hz, 1H), 5.34 (d, J=8.4Hz, 1H), 6.65 (d, J=8.7Hz, 1H), 6.77 (s, 1H), 6.99-7.14 (m, 4H), 7.35 (d, J=7.8Hz, 1H), 7.59 (d, J=7.8Hz, 1H), 8.05 (s, 1H); ESI-MS (m/z) 395.63 (M+H) +
Embodiment 78
N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(2-methyl-7-methoxyl group-1-cumarone-4-yl) propionic acid amide:
Figure BDA0000127889200000771
As described in example 1 above, title compound is by intermediate 2 (200mg, 0.896mmol) and 3-(2-methyl-7-methoxyl group-1-cumarone-4-yl) propionic acid (209mg, 0.896mmol) at EDCIHCl (256mg, 1.345mmol), HOBt (205mg, 1.345mmol) and triethylamine (371 μ l, 2.690mmol) existence is descended, is prepared in methylene dichloride (10ml), obtains the 60mg white solid product through 4h; IR (KBr) 3395,2972,1642,1515,1423,1235,775cm -1 1H NMR (300MHz, CDCl 3) δ 1.41-1.61 (m, 4H), 1.90-1.98 (m, 4H), 2.46 (s, 3H), 2.55-2.62 (m, 2H), 3.96 (s, 3H), 5.10-5.16 (m, 1H), 5.26 (d, J=8.4Hz, 2H), 6.40-6.46 (m, 1H), 6.60-6.70 (m, 3H), 6.83 (s, 1H), 6.91 (d, J=7.8Hz, 1H), 7.02 (d, J=7.5Hz, 1H); ESI-MS (m/z) 395.63 (M+H) +
Embodiment 79
N-[(4R)-6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl]-3-(7-methoxyl group-2-methyl isophthalic acid-cumarone-5-yl) propionic acid amide:
Figure BDA0000127889200000772
As described in example 1 above, title compound is by intermediate 8 (200mg, 0.894mmol) and 3-(7-methoxyl group-2-methyl isophthalic acid-cumarone-4-yl) propionic acid (252mg, 1.078mmol) at EDCIHCl (258mg, 1.345mmol), HOBt (206mg, 1.345mmol) and triethylamine (375 μ l, 2.684mmol) existence is descended, is prepared in methylene dichloride (10ml), obtains the 231mg white solid product; 1H NMR (300MHz, CDCl 3) δ 1.47-1.55 (m, 1H), 1.63-1.74 (m, 2H), 1.84-1.99 (m, 5H), 2.09-2.18 (s, 3H), 2.52-2.57 (m, 2H), 3.11-3.16 (m, 2H), 3.95 (s, 3H), 5.14 (q, J=9.3Hz, 1H), 5.30 (d, J=7.8Hz, 1H), 6.42 (s, 1H), 6.64-6.68 (m, 2H), 6.83 (s, 1H), 6.91 (d, J=7.8Hz, 1H), 7.02 (dd, J=2.4,6.9Hz, 1H).
Embodiment 80
N-[(4S)-6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl]-3-(7-methoxyl group-2-methyl isophthalic acid-cumarone-5-yl) propionic acid amide:
As described in example 1 above, title compound is by intermediate 9 (200mg, 0.898mmol) and 3-(7-methoxyl group-2-methyl isophthalic acid-cumarone-5-yl) propionic acid (252mg, 1.078mmol) at EDCIHCl (258mg, 1.347mmol), HOBt (206mg, 1.347mmol) and triethylamine (375 μ l, 2.698mmol) existence is descended, is prepared in methylene dichloride (10ml), obtains the 199mg white solid product; 1H NMR (300MHz, CDCl 3) δ 1.47-1.55 (m, 1H), 1.63-1.74 (m, 2H), 1.84-1.99 (m, 5H), 2.09-2.18 (s, 3H), 2.52-2.57 (m, 2H), 3.11-3.16 (m, 2H), 3.95 (s, 3H), 5.14 (q, J=9.3Hz, 1H), 5.30 (d, J=7.8Hz, 1H), 6.42 (s, 1H), 6.64-6.68 (m, 2H), 6.83 (s, 1H), 6.91 (d, J=7.8Hz, 1H), 7.02 (dd, J=2.4,6.9Hz, 1H).
Embodiment 81
3-(1,4-Ben Bing dioxin-6-yl)-N-(6-fluoro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl) propionic acid amide:
Figure BDA0000127889200000782
As described in example 1 above, title compound is by intermediate 6 (200mg, 0.963mmol) and 3-(2,3-dihydro-1,4-Ben Bing dioxin-6-yl) (187mg is 0.963mmol) at EDCIHCl (276mg for propionic acid, 1.441mmol), HOBt (221mg, 1.441mmol) and triethylamine (403 μ l, 2.891mmol) existence is descended, is prepared in methylene dichloride (10ml), obtains the 16mg white solid product; IR (KBr) 3307,2951,1869,1643,1508,1257,1071,817cm -1 1H NMR (300MHz, DMSO-d 6) δ 1.13-1.23 (m, 1H), 1.66-1.78 (m, 3H), 2.04-2.13 (m, 3H), and 2.18-2.27 (m, 2H), 2.42-2.49 (m, 1H), 2.72-2.79 (m, 2H), 4.17 (s, 4H), 5.01 (br s, 1H), 6.54 (d, J=11.1Hz, 1H), 6.38-6.74 (m, 4H), 6.93 (t, J=8.1Hz, 1H), 8.25 (d, J=8.4Hz, 1H); ESI-MS (m/z) 396.66 (M-H) -
Embodiment 82
3-(1,3-benzo dioxole-4-yl)-N-[6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl] propionic acid amide:
Figure BDA0000127889200000791
As described in example 1 above, title compound is by intermediate 2 (150mg, 0.679mmol) and 3-(1,3-benzo dioxole-4-yl) propionic acid (169mg, 0.892mmol) EDCIHCl (192mg, 1.005mmol), HOBt (154mg, 1.005mmol) and triethylamine (135 μ l, 1.341mmol) exist down, in methylene dichloride (10ml), be prepared, obtain the 137mg white solid product; IR (KBr) 3314,2940,1640,1456,1243,1064cm -1 1H NMR (300MHz, CDCl 3) δ 1.63-1.72 (m, 2H), 1.85-1.89 (m, 1H), 2.04-2.17 (m, 3H), and 2.27-2.37 (m, 2H), 2.58 (t, J=6.9Hz, 2H), and 2.96-3.02 (m, 2H), 5.20 (q, J=9.3Hz, 1H), 5.54 (d, J=8.7Hz, 1H), 5.87 (d, J=8.7Hz, 2H), 6.69-6.80 (m, 4H), 6.92 (s, 1H), 7.05 (d, J=8.7Hz, 1H).
Embodiment 83
3-(1,3-benzo dioxole-4-yl)-N-(8-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl) propionic acid amide:
Figure BDA0000127889200000792
As described in example 1 above, title compound is by intermediate 1 (150mg, 0.679mmol) and 3-(1,3-benzo dioxole-4-yl) propionic acid (169mg, 0.892mmol) EDCIHCl (192mg, 1.005mmol), HOBt (154mg, 1.005mmol) and triethylamine (135 μ l, 1.341mmol) exist down, in methylene dichloride (10ml), be prepared, obtain the 56mg white solid product; IR (KBr) 3371,2940,1651,1461,1245,1064,934cm -1 1H NMR (300MHz, CDCl 3) δ 1.67-1.77 (m, 2H), 1.90-1.95 (m, 1H), 2.06-2.20 (m, 3H), and 2.32-2.47 (m, 2H), 2.58 (t, J=7.5Hz, 2H), and 2.96-3.02 (m, 2H), 5.26 (q, J=9.3Hz, 1H), 5.55 (d, J=8.7Hz, 1H), 5.85 (d, J=13.8Hz, 2H), 6.66-6.80 (m, 5H), 7.18 (d, J=6.9Hz, 1H); ESI-MS (m/z) 400.58 (M+H) +
Embodiment 84
3-(1,4-Ben Bing dioxin-5-yl)-N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl) propionic acid amide:
Figure BDA0000127889200000801
As described in example 1 above, title compound is by intermediate 2 (200mg, 0.769mmol) and 3-(2,3-dihydro-1,4-Ben Bing dioxin-5-yl) (191mg is 0.923mmol) at EDCIHCl (221mg for propionic acid, 1.153mmol), HOBt (176mg, 1.153mmol) and triethylamine (321 μ l, 2.307mmol) existence is descended, is prepared in methylene dichloride (10ml), obtains the 141mg white solid product; IR (KBr) 3276,2935,1639,1474,1262,1094cm -1 1H NMR (300MHz, CDCl 3) δ 1.63-1.71 (m, 3H), 1.89 (br s, 1H), 2.13-2.27 (m, 2H), and 2.33-2.37 (m, 2H), 2.57 (t, J=7.5Hz, 2H), 2.96 (t, J=6.9Hz, 2H), 4.19 (d, J=6.3Hz, 4H), 5.19 (q, J=8.7Hz, 1H), 5.62 (d, J=8.1Hz, 1H), 6.69-6.74 (m, 4H), 6.95 (s, 1H), 7.05 (d, J=8.1Hz, 1H); ESI-MS (m/z) 414.47 (M+H) +
Embodiment 85
N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(dibenzo [b, d] furans-4-yl) propionic acid amide:
Figure BDA0000127889200000802
As described in example 1 above, title compound is by intermediate 2 (200mg, 0.896mmol) and 3-dibenzo [b, d] furans-4-base propionic acid (214mg, 0.896mmol) EDCIHCl (256mg, 1.345mmol), HOBt (205mg, 1.345mmol) and triethylamine (371 μ l, 2.690mmol) exist down, in methylene dichloride (10ml), be prepared, obtain the 215mg white solid product through 4h; 1H NMR (300MHz, CDCl 3) δ 1.81-1.91 (m, 3H), 2.08-2.13 (m, 3H), 2.17-2.26 (m, 2H), 2.72-2.79 (m, 2H), 3.35-3.41 (m, 2H), 5.16 (q, J=9.3Hz, 1H), 5.44 (d, J=8.7Hz, 1H), 6.63 (d, J=8.7Hz, 1H), 6.82 (s, 1H), 6.99 (dd, J=6.3,1.8Hz, 1H), 7.28-7.33 (m, 3H), 7.42 (t, J=6.9Hz, 1H), 7.53 (d, J=8.7Hz, 1H), 7.82 (d, J=6.3Hz, 1H), 7.91 (d, J=8.7Hz, 1H); ESI-MS (m/z) 446.29 (M+H) +
Embodiment 86
N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-ring penta]-the 4-yl)-3-(2-cyclopentyloxy-3-methoxyl group) propionic acid amide:
Figure BDA0000127889200000811
As described in example 1 above, title compound is by intermediate 16 (200mg, 0.841mmol) and 3-(2-cyclopentyloxy-3-p-methoxy-phenyl) propionic acid (266mg, 1.009mmol) at EDCIHCl (241mg, 1.261mmol), HOBt (193mg, 1.261mmol) and triethylamine (351 μ l, 2.504mmol) existence is descended, is prepared in methylene dichloride (10ml), obtains the 197mg white solid product; IR (Neat) 3276,2959,1642,1475,1262,1082cm -1 1H NMR (300MHz, CDCl 3) δ 1.74-2.05 (m, 18H), 2.56 (t, J=6.3Hz, 2H), 2.96 (t, J=6.3Hz, 2H), 3.79 (s, 3H), 4.58 (br s, 1H), 5.14 (q, J=9.0Hz, 1H), 5.73 (d, J=8.4Hz, 1H), 6.63 (d, J=8.7Hz, 1H), 6.77 (d, J=7.8Hz, 2H), 6.95-7.00 (m, 3H); ESI-MS (m/z) 484.64 (M) +
Embodiment 87
N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-hexamethylene]-the 4-yl)-3-(2-cyclopentyloxy-3-methoxyl group) Phenylpropionamide:
Figure BDA0000127889200000812
As described in example 1 above, title compound is by intermediate 17 (209mg, 0.833mmol) and 3-(2-cyclopentyloxy-3-p-methoxy-phenyl) propionic acid (200mg, 0.758mmol) at EDCIHCl (116mg, 0.756mmol), HOBt (218mg, 1.137mmol) and triethylamine (316 μ l, 2.274mmol) existence is descended, is prepared in methylene dichloride (10ml), obtains the 250mg white solid product; IR (KBr) 3269,2935,1644,1475,1261,1080,970cm -1 1H NMR (300MHz, CDCl 3) δ 1.29-1.51 (m, 5H), 1.70-1.78 (m, 8H), 2.02-2.08 (m, 5H), and 2.56-2.62 (m, 4H), 2.96 (t, J=6.0Hz, 2H), 3.79 (s, 3H), 4.85 (br s, 1H), 5.14 (q, J=9.9Hz, 1H), 5.71 (d, J=9.0Hz, 1H), 6.69 (d, J=8.7Hz, 1H), 6.77 (d, J=7.8Hz, 2H), 6.93-7.04 (m, 3H); ESI-MS (m/z) 498.06 (M) +
Embodiment 88
N-(2,2-dimethyl-3,4-dihydro-2H-chromene-4-yl)-3-(2-cyclopentyloxy-3-methoxyl group) Phenylpropionamide:
As described in example 1 above, title compound is by intermediate 18 (200mg, 1.129mmol) and 3-(2-cyclopentyloxy-3-p-methoxy-phenyl) propionic acid (328mg, 1.242mmol) at EDCIHCl (324mg, 1.671mmol), HOBt (259mg, 1.671mmol) and triethylamine (471 μ l, 3.383mmol) existence is descended, is prepared in methylene dichloride (10ml), obtains the 187mg white solid product; 1H NMR (300MHz, CDCl 3) δ 1.27 (s, 3H), 1.36 (s, 3H), 1.48-1.79 (m, 8H), 2.02-2.10 (m, 1H), 2.55 (t, J=7.5Hz, 2H), 2.92-2.99 (s, 2H), 3.80 (s, 3H), 4.80 (br s, 1H), 5.18 (q, J=9.9Hz, 1H), 5.67 (d, J=8.7Hz, 1H), 6.70-6.80 (m, 5H), 6.94 (t, J=8.1Hz, 1H), 7.08 (t, J=7.2Hz, 1H).
Embodiment 89
N-(6-chloro-3,4-dihydro-2H-sulfo-chromene-4-yl)-3-(2-cyclopentyloxy-3-p-methoxy-phenyl) propionic acid amide:
Figure BDA0000127889200000822
As described in example 1 above, title compound is by intermediate 19 (100mg, 0.423mmol) and the 3-[2-[(cyclopentyloxy)-the 3-p-methoxy-phenyl] propionic acid (134mg, 0.508mmol) at EDCIHCl (121mg, 0.635mmol), HOBt (97mg, 0.635mmol) and triethylamine (176 μ l, 1.270mmol) existence is descended, is prepared in methylene dichloride (10ml), obtains the 113mg white solid product; 1H NMR (300MHz, CDCl 3) δ 1.57-1.80 (m, 8H), 1.90-1.96 (m, 1H), 2.12-2.18 (m, 1H), and 2.50-2.56 (m, 2H), 2.75-2.85 (m, 2H), 2.90-2.98 (m, 2H), 3.79 (s, 3H), 4.82 (br s, 1H), 5.02 (br s, 1H), 5.92 (br s, 1H), 6.72-6.80 (m, 2H), 6.91-6.98 (m, 3H), 7.03-7.10 (m, 1H).
Embodiment 90
N-(6-chloro-3,4-dihydro-2H-sulfo-chromene-4-yl)-3-(2-methoxyl group-1-naphthyl) propionic acid amide:
Figure BDA0000127889200000831
As described in example 1 above, title compound is by intermediate 19 (100mg, 0.423mmol) and 3-(2-methoxyl group-1-naphthyl) propionic acid (146mg, 0.508mmol) at EDCIHCl (121mg, 0.635mmol), HOBt (97mg, 0.635mmol) and triethylamine (176 μ l, 1.270mmol) existence is descended, is prepared in methylene dichloride (10ml), obtains the 67mg white solid product; 1H NMR (300MHz, CDCl 3) δ 1.79-1.87 (m, 1H), 2.07-2.14 (m, 1H), 2.52-2.70 (m, 4H), 3.38-3.45 (m, 2H), 3.80 (s, 3H), 4.97 (br s, 1H), 5.95 (d, J=6.9Hz, 1H), 6.92-6.98 (m, 2H), 7.04-7.10 (m, 1H), and 7.16-7.21 (m, 1H), 7.33 (t, J=7.5Hz, 1H), 7.48 (t, J=8.4Hz, 1H), 7.75 (t, J=9.3Hz, 2H), 7.95 (d, J=8.4Hz, 1H).
Embodiment 91
N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-4-(2-cyclopentyloxy phenyl) butyramide:
Figure BDA0000127889200000832
As described in example 1 above, title compound is by intermediate 2 (150mg, 0.579mmol) and 4-(2-cyclopentyloxy phenyl) butyric acid (158mg, 0.639mmol) at EDCIHCl (166mg, 0.863mmol), HOBt (133mg, 0.863mmol) and triethylamine (241 μ l, 2.043mmol) existence is descended, is prepared in methylene dichloride (5ml), obtains the 153mg white solid product; IR (KBr) 3300,2943,1646,1474,1238,749cm -1 1H NMR (300MHz, CDCl 3) δ 1.70-2.00 (m, 12H), 2.24-2.41 (m, 7H), 2.64-2.70 (m, 2H), 3.47 (s, 1H), 4.75 (br s, 1H), 5.25 (d, J=6.0Hz, 1H), 5.50 (d, J=6.9Hz, 1H), 6.71 (d, J=8.4Hz, 1H), 6.79-6.85 (m, 2H), and 7.05-7.12 (m, 4H); ESI-MS (m/z) 454.30 (M) +
Embodiment 92
N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-4-[2-(cyclopentyloxy)-3-p-methoxy-phenyl] butyramide:
Figure BDA0000127889200000841
As described in example 1 above, title compound is by intermediate 2 (200mg, 0.772mmol) and 4-(2-cyclopentyloxy-3-p-methoxy-phenyl) butyric acid (214mg, 0.772mmol) at EDCIHCl (222mg, 1.158mmol), HOBt (118mg, 0.772mmol) and triethylamine (273 μ l, 2.702mmol) existence is descended, is prepared in methylene dichloride (10ml), obtains the 210mg white solid product; IR (KBr) 3019,2970,1665,1475,1215,769cm -1 1H NMR (300MHz, CDCl 3) δ 1.70-1.80 (m, 11H), 1.97-2.04 (m, 2H), 2.14-2.20 (m, 5H), and 2.30-2.42 (m, 2H), 2.71 (t, J=6.9Hz, 2H), 3.81 (s, 3H), 4.80 (br s, 1H), 5.24 (br s, 1H), 5.55 (d, J=8.7Hz, 1H), 6.70-6.77 (m, 3H), 6.94 (t, J=7.2Hz, 1H), 7.06 (d, J=9.9Hz, 2H); ESI-MS (m/z) 482.44 (M-H) -.
Embodiment 93
N-(4R)-6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-4-base-4-(2-cyclopentyloxy-3-p-methoxy-phenyl) butyramide:
Figure BDA0000127889200000851
As described in example 1 above, title compound is by intermediate 8 (100mg, 0.449mmol) and 4-(2-cyclopentyloxy-3-p-methoxy-phenyl) butyric acid (124mg, 0.449mmol) at EDCIHCl (129mg, 0.672mmol), HOBt (69mg, 0.450mmol) and triethylamine (157 μ l, 1.123mmol) existence is descended, is prepared in methylene dichloride (10ml), obtains the 105mg white solid product; IR (KBr) 3019,2970,1665,1475,1215,769cm -1 1H NMR (300MHz, CDCl 3) δ 1.70-1.80 (m, 11H), 1.97-2.04 (m, 2H), 2.14-2.20 (m, 5H), and 2.30-2.42 (m, 2H), 2.71 (t, J=6.9Hz, 2H), 3.81 (s, 3H), 4.80 (br s, 1H), 5.24 (br s, 1H), 5.55 (d, J=8.7Hz, 1H), 6.70-6.77 (m, 3H), 6.94 (t, J=7.2Hz, 1H), 7.06 (d, J=9.9Hz, 2H); ESI-MS (m/z) 482.44 (M-H) -
Embodiment 94
N-{ (4S)-6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl }-4-[(2-(cyclopentyloxy)-3-p-methoxy-phenyl] butyramide:
Figure BDA0000127889200000852
As described in example 1 above, title compound is by intermediate (100mg, 0.449mmol) and 4-(2-cyclopentyloxy-3-p-methoxy-phenyl) butyric acid (132mg, 0.474mmol) at EDCIHCl (129mg, 0.672mmol), HOBt (69mg, 0.450mmol) and triethylamine (157 μ l, 1.123mmol) existence is descended, is prepared in methylene dichloride (10ml), obtains the 140mg white solid product; IR (KBr) 3019,2970,1665,1475,1215,769cm -1 1H NMR (300MHz, CDCl 3) δ 1.70-1.80 (m, 11H), 1.97-2.04 (m, 2H), 2.14-2.20 (m, 5H), and 2.30-2.42 (m, 2H), 2.71 (t, J=6.9Hz, 2H), 3.81 (s, 3H), 4.80 (br s, 1H), 5.24 (br s, 1H), 5.55 (d, J=8.7Hz, 1H), 6.70-6.77 (m, 3H), 6.94 (t, J=7.2Hz, 1H), 7.06 (d, J=9.9Hz, 2H); ESI-MS (m/z) 482.44 (M-H) -.
Embodiment 95
(4R)-N-(8-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-4-(2-cyclopentyloxy-3-p-methoxy-phenyl) butyramide:
Figure BDA0000127889200000861
As described in example 1 above, title compound is by intermediate 3 (150mg, 0.619mmol) and 4-(2-cyclopentyloxy-3-p-methoxy-phenyl) butyric acid (205mg, 0.739mmol) at EDCIHCl (193mg, 1.012mmol), HOBt (154mg, 1.012mmol) and triethylamine (279 μ l, 2.043mmol) existence is descended, is prepared in methylene dichloride (10ml), obtains the 149mg white solid product; IR (KBr) 3315,2945,1642,1438,1244,1040cm -1 1H NMR (300MHz, CDCl 3) δ 1.57-1.70 (m, 10H), 1.97-2.04 (m, 4H), 2.14-2.20 (m, 4H), and 2.40-2.47 (m, 2H), 2.66-2.72 (m, 2H), 3.80 (s, 3H), 4.79 (br s, 1H), 5.28 (d, J=6.3Hz, 1H), 5.56 (d, J=8.4Hz, 1H), 6.66-6.77 (m, 3H), 6.90-7.04 (m, 2H), 7.14-7.20 (m, 1H); ESI-MS (m/z) 484.26 (M) +
Embodiment 96
(4S)-N-(8-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-4-(2-cyclopentyloxy-3-p-methoxy-phenyl) butyramide:
Figure BDA0000127889200000862
As described in example 1 above, title compound is by intermediate 4 (150mg, 0.619mmol) and 4-(2-cyclopentyloxy-3-p-methoxy-phenyl) butyric acid (205mg, 0.739mmol) at EDCIHCl (193mg, 1.012mmol), HOBt (154mg, 1.012mmol) and triethylamine (279 μ l, 2.043mmol) existence is descended, is prepared in methylene dichloride (10ml), obtains the 153mg white solid product; IR (KBr) 3316,2946,1642,1538,1451,1084cm -1 1H NMR (300MHz, CDCl 3) δ 1.70-1.80 (m, 10H), 1.97-2.04 (m, 4H), 2.05-2.12 (m, 4H), and 2.39-2.49 (m, 2H), 2.70 (t, J=7.2Hz, 2H), 3.81 (s, 3H), 4.80 (br s, 1H), 5.29 (q, J=6.3Hz, 1H), 5.55 (d, J=7.5Hz, 1H), 6.76-6.79 (m, 3H), 6.91-7.05 (m, 4H), 7.20 (s, 1H); ESI-MS (m/z) 484.21 (M) +
Embodiment 97
N-(8-chloro-6-fluoro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-4-(2-cyclopentyloxy-3-p-methoxy-phenyl) butyramide:
Figure BDA0000127889200000871
As described in example 1 above, title compound is by intermediate 20 (200mg, 0.719mmol) and 4-(2-cyclopentyloxy-3-p-methoxy-phenyl) butyric acid (200mg, 0.719mmol) at EDCIHCl (207mg, 1.079mmol), HOBt (110mg, 0.719mmol) and triethylamine (250 μ l, 1.798mmol) existence is descended, is prepared in methylene dichloride (10ml), obtains the 105mg white solid product; IR (KBr) 3313,2956,1645,1463,1214,1083,742cm -1 1H NMR (300MHz, CDCl 3) δ 1.65-1.79 (m, 9H), 1.99-2.05 (m, 4H), 2.08-2.18 (m, 5H), and 2.38-2.43 (m, 2H), 2.71 (t, J=6.3Hz, 2H), 3.81 (s, 3H), 4.80 (br s, 1H), 5.27 (q, J=6.6Hz, 1H), 5.54 (d, J=7.8Hz, 1H), 6.66-6.75 (m, 3H), 6.91-6.96 (m, 2H); ESI-MS (m/z) 500.38 (M-H) -
Embodiment 98
N-(6,8-, two chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-4-(2-cyclopentyloxy-3-p-methoxy-phenyl) butyramide:
As described in example 1 above, title compound is by intermediate 13 (150mg, 0.511mmol) and 4-(2-cyclopentyloxy-3-p-methoxy-phenyl) butyric acid (142mg, 0.511mmol) at EDCIHCl (147mg, 0.766mmol), HOBt (78mg, 0.511mmol) and triethylamine (178 μ l, 1.277mmol) existence is descended, is prepared in methylene dichloride (10ml), obtains the 105mg white solid product; IR (KBr) 3283,2954,1644,1451,1220,1083cm -1 1HNMR (300MHz, CDCl 3) δ 1.72-1.82 (m, 10H), 1.97-2.01 (m, 3H), 2.12-2.20 (m, 5H), and 2.36-2.42 (m, 2H), 2.71 (t, J=6.6Hz, 2H), 3.80 (s, 3H), 4.80 (br s, 1H), 5.24 (q, J=6.3Hz, 1H), 5.53 (d, J=7.8Hz, 1H), and 6.72-6.78 (m, 2H), 6.91-6.96 (m, 1H), 7.01 (s, 1H), 7.20 (s, 1H); ESI-MS (m/z) 518.17 (M) +
Embodiment 99
N-(7-benzyloxy-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-4-(2-cyclopentyloxy-3-p-methoxy-phenyl) butyramide:
Figure BDA0000127889200000881
As described in example 1 above, title compound is by intermediate 12 (200mg, 0.603mmol) and 3-[(2-cyclopentyloxy-3-p-methoxy-phenyl) butyric acid (167mg, 0.603mmol) at EDCIHCl (173mg, 0.904mmol), HOBt (138mg, 0.904mmol) and triethylamine (335 μ l, 2.413mmol) existence is descended, is prepared in methylene dichloride (10ml), obtains the 156mg white solid product; IR (KBr) 3254,2960,1639,1269,1134,1019cm -1 1H NMR (300MHz, CDCl 3) δ 1.68-1.81 (m, 11H), 1.97-2.02 (m, 4H), 2.18-2.25 (m, 4H), 2.32-2.37 (m, 2H), 2.69 (t, J=7.2Hz, 2H), 3.81 (s, 3H), 4.79 (br s, 1H), 4.99 (s, 2H), 5.17 (q, J=6.0Hz, 1H), 5.49 (d, J=8.1Hz, 1H), 6.41 (s, 1H), 6.50 (d, J=8.7Hz, 1H), 6.62-6.74 (m, 2H), and 6.96-7.04 (m, 2H), 7.29-7.37 (m, 4H); ESI-MS (m/z) 554.40 (M-H) -
Embodiment 100
N-(7-hydroxyl-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-4-(2-cyclopentyloxy-3-p-methoxy-phenyl) butyramide:
Figure BDA0000127889200000882
As described in embodiment 17 steps 2, title compound is by under 50psi pressure, (100mg 0.181mmol) finished debenzylation and is prepared under nitrogen, obtain the 53mg white solid product to embodiment 99 through 2 hours by being in 10%Pd/C (30mg) in the methyl alcohol (10ml); IR (KBr) 3254,2960,1639,1474,1134,1019cm -1 1H NMR (300MHz, CDCl 3) δ 1.25-1.32 (m, 3H), 1.62-1.72 (m, 4H), 1.78-1.85 (m, 5H), 1.94-1.99 (m, 2H), 2.12-2.17 (m, 4H), 2.26-2.35 (m, 2H), 2.69 (t, J=6.9Hz, 2H), 3.81 (s, 3H), 4.79 (br s, 1H), 5.15 (q, J=5.7Hz, 1H), 5.52 (d, J=8.4Hz, 2H), 6.26-6.34 (m, 2H), and 6.72-6.76 (m, 2H), 6.91-6.96 (m, 2H); ESI-MS (m/z) 554.40 (M-H) -
Embodiment 101
N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-4-oxo-4-(4-methoxyl group naphthyl) butyramide:
Figure BDA0000127889200000891
As described in example 1 above, title compound is by intermediate 2 (250mg, 0.965mmol) and 4-(4-methoxyl group-1-naphthyl)-4-ketobutyric acid (274mg, 1.062mmol) at EDCIHCl (277mg, 1.451mmol), HOBt (221mg, 1.459mmol) and triethylamine (403 μ l, 2.905mmol) existence is descended, is prepared in methylene dichloride (10ml), obtains the 311mg white solid product; IR (KBr) 3204,2972,1632,1523,1230,757cm -1 1H NMR (300MHz, CDCl 3) δ 1.67-1.73 (m, 2H), 2.06-2.31 (m, 6H), 2.66-2.71 (m, 2H), 3.31-3.39 (m, 2H), 4.05 (s, 3H), 5.05 (br s, 1H), 6.77 (d, J=9.0Hz, 1H), 7.03 (d, J=8.4Hz, 1H), 7.14 (d, J=8.4Hz, 1H), 7.20 (s, 1H), 7.53-7.61 (m, 2H), 8.20-8.28 (m, 2H), 8.43 (d, J=8.4Hz, 1H), 8.86 (d, J=8.7Hz, 1H); ESI-MS (m/z) 464.17 (M+H) +
Embodiment 102
N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-4-hydroxyl-4-(4-methoxyl group naphthyl) butyramide:
Figure BDA0000127889200000892
Under 0 ℃, (932mg, 0.864mmol) (200mg, 0.431mmol) reduction 3h prepares title compound with embodiment 101 to use the sodium borohydride that is in tetrahydrofuran (THF) (10ml) and the methyl alcohol (5ml).Reaction mixture is heated to room temperature and concentrated, obtains the 31mg white solid product; 1H NMR (300MHz, CDCl 3) δ 1.67-1.76 (m, 3H), 2.02-2.09 (m, 3H), 2.25-2.42 (m, 7H), 3.35 (br s, 1H), 3.89 (s, 3H), 5.14 (br s, 1H), 5.36 (br s, 1H), 6.61-6.73 (m, 2H), and 6.96-7.05 (m, 2H), 7.34-7.41 (m, 2H), and 7.42-7.55 (m, 1H), 7.96 (br s, 1H), 8.17 (d, J=8.7Hz, 1H).
Embodiment 103
N-(6-chloro-2,2-dimethyl-3,4-dihydro-2H-chromene-4-yl)-4-(2-cyclopentyloxy-3-methoxyl group) phenylbutanamides:
Figure BDA0000127889200000901
As described in example 1 above, title compound is by intermediate 21 (200mg, 0.941mmol) and 4-(2-cyclopentyloxy-3-p-methoxy-phenyl) butyric acid (261mg, 0.941mmol) at EDCIHCl (270mg, 1.411mmol), HOBt (144mg, 0.941mmol) and triethylamine (328 μ l, 2.352mmol) existence is descended, is prepared in methylene dichloride (10ml), obtains the 173mg white solid product; IR (KBr) 3302,2958,1645,1475,1261,1085cm -1 1H NMR (300MHz, CDCl 3) δ 1.29 (s, 3H), 1.39 (s, 3H), 1.71-1.79 (m, 8H), and 1.95-2.02 (m, 2H), 2.12-2.20 (m, 3H), 2.70 (t, J=6.6Hz, 3H), 3.81 (s, 3H), 4.80 (br s, 1H), 5.25 (q, J=6.3Hz, 1H), 5.51 (d, J=7.8Hz, 1H), 6.67-6.77 (m, 3H), 6.90-6.97 (m, 1H), 7.05-7.13 (m, 2H); ESI-MS (m/z) 472.32 (M+H) +
Embodiment 104
N-(6-chloro-3,4-dihydro-2H-sulfo-chromene-4-yl)-4-(2-cyclopentyloxy-3-p-methoxy-phenyl) butyramide:
Figure BDA0000127889200000902
As described in example 1 above, title compound is by intermediate 19 (100mg, 0.423mmol) and 4-(2-cyclopentyloxy-3-p-methoxy-phenyl) butyric acid (141mg, 0.508mmol) at EDCIHCl (121mg, 0.635mmol), HOBt (97mg, 0.635mmol) and triethylamine (176 μ l, 1.270mmol) existence is descended, is prepared in methylene dichloride (10ml), obtains the 87mg white solid product; 1H NMR (300MHz, CDCl 3) δ 1.58-1.68 (m, 4H), 1.75-1.85 (m, 4H), 1.90-2.00 (m, 2H), and 2.10-2.20 (m, 4H), 2.63-2.70 (m, 2H), 2.95-3.01 (m, 2H), 3.81 (s, 3H), 4.79 (br s, 1H), 5.13 (br s, 1H), 5.60-5.66 (m, 1H), 6.72 (d, J=7.2Hz, 2H), 6.92 (t, J=7.8Hz, 1H), 7.00-7.09 (m, 2H), 7.17 (s, 1H).
Pharmacologically active
According to (a) T ó th, people such as A., Life Sciences, the development of putting down in writing among 2003,73, the 487-498 is screened the TRPV3 activity of exemplary embodiment of the present invention.Can carry out the screening of compound by additive method well known by persons skilled in the art and process.This class screening is found in following document: Hu, and H-Z. waits the people, J.Biol.Chem. (2004), 279, 35741-35748; Smith, people .Nature (2002) such as G.D, 418, 186-190 and Peier, A.M. waits the people, Science (2002), 296, 2046-2049.
Use 45Calcium absorption Analysis and Screening TRPV3 antagonist
The inhibition of TRPV3 receptor activation is investigated in the inhibition that the cell of inducing with the 2-APB to radiocalcium absorbs.Test compounds is dissolved among the DMSO, and the stoste (stocksolution) of preparation 20mM is used then and is contained 0.1%BSA and 1.8mM CaCl 2Basic medium (plain medium) dilution, obtain desired concn.DMSO final concentration in the reaction is 0.5% (v/v).The people TRPV3 that expresses Chinese hamster ovary celI grows in the F-12DMEM substratum that contains 10%FBS, 1% penicillin-Streptomycin sulphate solution and 400 μ g/ml G-418.24h before analyzing in 96 orifice plates, makes cell inoculation in～50,000 cells/well of experiment acquisition on the same day.With test compounds cell was handled 10 minutes, adding final concentration with 4 minutes then is 2-APB and the 5 μ Ci/ml of 500 μ M 45Ca + 2Use contains damping fluid washing and the lysing cell of 1%Triton X-100,0.1% deoxycholate salt and 0.1%SDS.After adding liquid scintillator (scintillant), in Packardt Top count, measure the radioactivity in the lysate.
Draw the concentration-response curve, as lacking the peak response % that obtains under the test antagonist.Use GraphPad PRISM software, by nonlinear regression analysis, can calculate IC from the concentration-response opisometer 50Value.
Use each compound of above-mentioned analytic process test preparation, acquisition the results are shown in table 2.For selected embodiment, concentration is that inhibition % under 1.0 μ M and the 10.0 μ M is together with IC 50(nM) value is shown in the table.
The IC of compound 50(nM) value is shown in table 2, and wherein " A " refers to IC 50Value is less than 500nM, and " B " refers to IC 50Value is 500.0-1000.0nM, and " C " refers to IC 50Value is 1000.01-2000.0nM." D " refers to IC 50Value is greater than 2000.0nM.
Table 2: the in-vitro screening result of The compounds of this invention:
Figure BDA0000127889200000921
Figure BDA0000127889200000931
Figure BDA0000127889200000941
Figure BDA0000127889200000951

Claims (10)

1. the described compound of formula (I):
Figure FDA0000127889190000011
Or its analogue, tautomer, regional isomer, steric isomer, enantiomer, diastereomer or pharmacy acceptable salt,
Wherein,
R 1Be selected from and replace or unsubstituted aryl, replacement or unsubstituted heteroaryl, replacement or unsubstituted heterocyclic group or replacement or unsubstituted cycloalkyl; Wherein aryl, heteroaryl and heterocyclic ring are monocycle, dicyclo or three rings, and all or part of be aromatics;
Wherein, aryl, heteroaryl, substituting group on heterocyclic ring and the cycloalkyl is independently selected from the group of being made up of following radicals: halogen, hydroxyl, nitro, cyano group, replace or unsubstituted amino, replace or unsubstituted alkyl, the straight or branched alkyl, the straight or branched alkoxyl group, replace or unsubstituted thiazolinyl, replace or unsubstituted alkoxyl group, replace or unsubstituted haloalkyl, the haloalkyl of all or part of replacement, replace or unsubstituted halogenated alkoxy, the halogenated alkoxy of all or part of replacement, replace or unsubstituted cycloalkyl, replace or unsubstituted cycloalkyloxy, replace or unsubstituted cycloalkylalkyl, replace or unsubstituted cycloalkyl alkoxy, replace or unsubstituted aryl, replace or unsubstituted aryloxy, replace or unsubstituted arylalkyl, replace or unsubstituted alkoxy aryl, replace or unsubstituted heterocyclic group, replace or unsubstituted heteroaryl,-S (O) pR a,-NHS (O) pR a,-O (CH 2) mNR aR b,-C (O)-R aOr-C (O) NR aR b
R 2Be selected from the group of being formed by following radicals: hydrogen, replacement or unsubstituted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted aryl, replacement or unsubstituted arylalkyl, replacement or unsubstituted heteroaryl or replacement or unsubstituted heterocyclic group;
R a, R b, R cAnd R dBe independently selected from hydrogen, nitro, cyano group, halogen ,-OR e, replacement or unsubstituted alkyl, replacement or unsubstituted thiazolinyl, replacement or unsubstituted alkynyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted cycloalkenyl group, replacement or unsubstituted aryl, replacement or unsubstituted heteroaryl, replacement or unsubstituted heterocyclic group;
R eBe selected from the group of being formed by following radicals: hydrogen, replacement or unsubstituted alkyl, replacement or unsubstituted thiazolinyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted aryl, replacement or unsubstituted heteroaryl or replacement or unsubstituted heterocyclic group;
R 3And R 4Be independently selected from hydrogen, halogen, replace or unsubstituted amino, replace or unsubstituted alkyl, the straight or branched alkyl, the straight or branched alkoxyl group, replace or unsubstituted thiazolinyl, replace or unsubstituted alkoxyl group, replace or unsubstituted haloalkyl, the haloalkyl of all or part of replacement, replace or unsubstituted halogenated alkoxy, the halogenated alkoxy of all or part of replacement, replace or unsubstituted cycloalkyl, replace or unsubstituted cycloalkyloxy, replace or unsubstituted cycloalkylalkyl, replace or unsubstituted cycloalkyl alkoxy, replace or unsubstituted aryl;
' m ' is for being selected from the integer of 1-4;
' n ' is for being selected from the integer of 0-3;
' p ' is for being selected from the integer of 0-2;
But R bNot for being selected from-OR e,-NR 3R 4Or C (O) NR 3R 4Group;
Wherein:
Preferred R 3And R 4Be hydrogen; Perhaps R 3And R 4In one of be hydrogen, another is hydroxyl or alkyl (methyl);
Preferred R a, R b, R cAnd R dIn any is hydrogen or halogen, wherein halogen is fluorine or chlorine;
Preferred R a, R cAnd R dIn any is hydrogen, hydroxyl, alkyl (methyl), alkoxyl group (methoxyl group) or alkoxy aryl (benzyloxy);
Preferred R 1Be phenyl, phenyl, replacement or unsubstituted naphthyl, tetraline, pyridine, indoles, benzo dioxole, benzoisoxazole, cumarone, quinoline, Ben Bing dioxin or the diphenylene-oxide that replaces, wherein substituting group comprises hydroxyl, halogen (F, Cl, Br or I), alkyl (methyl), alkoxyl group (methoxyl group, oxyethyl group, positive propoxy, n-butoxy or isopropoxy), halogenated alkoxy (all or part of replacement, preferred OCHF 2), cycloalkyloxy (cyclopentyloxy), cycloalkyl alkoxy (cyclo propyl methoxy), alkoxy aryl (benzyloxy), alkyl sulfonyl amino (NHS (O) 2CH 3Or NHS (O) 2CH (CH 3) 2), alkylamino alkoxyl group (OCH 2CH 2N (CH 3) 2) or heteroaryl (pyridine).
2. compound as claimed in claim 1, described compound are the compound by formula (II) expression:
Or its analogue, tautomer, regional isomer, steric isomer, enantiomer, diastereomer or pharmacy acceptable salt,
Wherein,
R 1Be selected from and replace or unsubstituted aryl, replacement or unsubstituted heteroaryl, replacement or unsubstituted heterocyclic group or replacement or unsubstituted cycloalkyl; Wherein aryl, heteroaryl and heterocyclic ring are monocycle, dicyclo or three rings, and partly or entirely are aromatics;
Wherein, aryl, heteroaryl, substituting group on heterocyclic ring and the cycloalkyl is independently selected from the group of being made up of following radicals: halogen, hydroxyl, nitro, cyano group, amino, replace or unsubstituted alkyl, the straight or branched alkyl, the straight or branched alkoxyl group, replace or unsubstituted thiazolinyl, replace or unsubstituted alkoxyl group, replace or unsubstituted haloalkyl, the haloalkyl of all or part of replacement, replace or unsubstituted halogenated alkoxy, the halogenated alkoxy of all or part of replacement, replace or unsubstituted cycloalkyl, replace or unsubstituted cycloalkyloxy, replace or unsubstituted cycloalkylalkyl, replace or unsubstituted cycloalkyl alkoxy, replace or unsubstituted aryl, replace or unsubstituted aryloxy, replace or unsubstituted arylalkyl, replace or unsubstituted alkoxy aryl, replace or unsubstituted heterocyclic group, replace or unsubstituted heteroaryl,-S (O) pR a,-NHS (O) pR a,-O (CH 2) mNR aR b,-C (O)-R aOr-C (O) NR aR b
R a, R b, R cAnd R dBe independently selected from hydrogen, nitro, cyano group, halogen ,-OR e, replacement or unsubstituted alkyl, replacement or unsubstituted thiazolinyl, replacement or unsubstituted alkynyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted cycloalkenyl group, replacement or unsubstituted aryl, replacement or unsubstituted heteroaryl, replacement or unsubstituted heterocyclic group;
R eBe selected from the group of being formed by following radicals: hydrogen, replacement or unsubstituted alkyl, replacement or unsubstituted thiazolinyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted aryl, replacement or unsubstituted heteroaryl or replacement or unsubstituted heterocyclic group;
R 3And R 4Be independently selected from hydrogen, halogen, replace or unsubstituted amino, replace or unsubstituted alkyl, the straight or branched alkyl, the straight or branched alkoxyl group, replace or unsubstituted thiazolinyl, replace or unsubstituted alkoxyl group, replace or unsubstituted haloalkyl, the haloalkyl of all or part of replacement, replace or unsubstituted halogenated alkoxy, the halogenated alkoxy of all or part of replacement, replace or unsubstituted cycloalkyl, replace or unsubstituted cycloalkyloxy, replace or unsubstituted cycloalkylalkyl, replace or unsubstituted cycloalkyl alkoxy, replace or unsubstituted aryl;
' m ' is for being selected from the integer of 1-4;
' n ' is for being selected from the integer of 0-3;
' p ' is for being selected from the integer of 0-2;
But R bFor or not be selected from-OR e,-NR 3R 4Or C (O) NR 3R 4Group.
3. compound as claimed in claim 1 or 2, described compound is selected from the group of being made up of following compounds:
N-(8-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-2-phenyl-acetamides (compound number 1);
N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-2-(2-p-methoxy-phenyl) ethanamide (compound number 2);
N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-the 2-{2-[(methylsulfonyl) amino] phenyl } ethanamide (compound number 3);
N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-2-(2-(cyclopentyloxy)-3-p-methoxy-phenyl) ethanamide (compound number 4);
N-[(4R)-8-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl]-2-(2-cyclopentyloxy-3-methoxyl group) phenyl-acetamides (compound number 5);
N-[(4S)-8-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl]-2-(2-cyclopentyloxy-3-methoxyl group) phenyl-acetamides (compound number 6);
N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-2-(3,4-Dimethoxyphenyl) ethanamide (compound number 7);
N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-2-pyridine-2-yl acetamide (compound number 8);
N-(3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-2-(1-naphthyl) ethanamide (compound number 9);
N-(the 6-fluoro-(3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-2-(1-naphthyl) ethanamide (compound number 10);
N-[(4R)-6,8-two fluoro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl]-2-(1-naphthyl) ethanamide (compound number 11);
N-[(4R)-6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl]-2-(1-naphthyl) ethanamide (compound number 12);
N-[(4S)-6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl]-2-(1-naphthyl) ethanamide (compound number 13);
N-(7-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-2-(1-naphthyl) ethanamide (compound number 14);
N-[(4R)-8-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl]-2-(1-naphthyl) ethanamide (compound number 15);
N-[(4S)-8-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl]-2-(1-naphthyl) ethanamide (compound number 16);
N-(5-hydroxyl-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-2-(1-naphthyl) ethanamide (compound number 17);
N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-2-(2-naphthyl) ethanamide (compound number 18);
(2S)-N-[(4R)-6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl]-2-(6-methoxyl group-2-naphthyl) propionic acid amide (compound number 19);
(2S)-N-[(4S)-6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl]-2-(6-methoxyl group-2-naphthyl) propionic acid amide (compound number 20);
N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-2-(1,2,3,4-tetralin-1-yl) ethanamide (compound number 21);
N-[(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)]-2-(1,2,3,4-tetralin-2-yl) ethanamide (compound number 22);
2-(1,3-benzo dioxole-5-yl)-N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl) ethanamide (compound number 23);
N-(6-fluoro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-2-(5-fluoro-3-Methyl-1H-indole-2-yl) ethanamide (compound number 24);
N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-2-(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanamide (compound number 25);
2-(1,2-benzoisoxazole-3-yl)-N-[(4R)-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl) ethanamide (compound number 26);
2-(1,2-benzoisoxazole-3-yl)-N-[(4S)-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl) ethanamide (compound number 27);
N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(2-cyclopentyloxy phenyl) propionic acid amide (compound number 28);
N-[(4R)-6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl]-3-(3-cyclopentyloxy) Phenylpropionamide (compound number 29);
N-[(4S)-6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl]-3-(3-cyclopentyloxy) Phenylpropionamide (compound number 30);
N-[(4R)-(8-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-[2-(cyclopentyloxy) phenyl] propionic acid amide (compound number 31);
N-[(4S)-8-chloro-3,4-dihydro spiral shell [chromene-2,1 '-ring fourth-4-yl]-3-[2-(cyclopentyloxy) phenyl] propionic acid amide (compound number 32);
7-benzyloxy-N-(3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(2-cyclopentyloxy phenyl) propionic acid amide (compound number 33);
N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-{2-[(sec.-propyl alkylsulfonyl) amino] phenyl } propionic acid amide (compound number 34);
N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(2-pyridine-2-base phenyl) propionic acid amide (compound number 35);
N-(6,8-, two chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(2-pyridin-3-yl phenyl) propionic acid amide (compound number 36);
N-(3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(2-cyclopentyloxy-3-methoxyl group) Phenylpropionamide (compound number 37);
N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(2,3-dimethoxy) Phenylpropionamide (compound number 38);
N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(2-isopropoxy-3-methoxyl group) Phenylpropionamide (compound number 39);
N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(3-chloro-4-methoxyl group) Phenylpropionamide (compound number 40);
N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(2-cyclo propyl methoxy-3-methoxyl group) Phenylpropionamide (compound number 41);
N-[(4R)-6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)]-3-(2-cyclopentyloxy-3-methoxyl group) Phenylpropionamide (compound number 42);
N-[(4S)-6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)]-3-(2-cyclopentyloxy-3-methoxyl group) Phenylpropionamide (compound number 43);
N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(2-cyclopentyloxy-3-oxyethyl group) Phenylpropionamide (compound number 44);
N-(7-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(2-cyclopentyloxy-3-methoxyl group) Phenylpropionamide (compound number 45);
N-(8-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(2-oxyethyl group-3-methoxyl group) Phenylpropionamide (compound number 46);
N-[(4R)-8-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)]-3-(2-cyclopentyloxy-3-methoxyl group) Phenylpropionamide (compound number 47);
N-[(4S)-(8-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(2-cyclopentyloxy-3-methoxyl group) Phenylpropionamide (compound number 48);
N-(6-chloro-7-methyl-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(2-cyclopentyloxy-3-methoxyl group) Phenylpropionamide (compound number 49);
N-(5-benzyloxy-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(2-cyclopentyloxy-3-methoxyl group) Phenylpropionamide (compound number 50);
N-(5-hydroxyl-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(2-cyclopentyloxy-3-methoxyl group) Phenylpropionamide (compound number 51);
N-(3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-5-methoxyl group-4-yl)-3-(2-cyclopentyloxy-3-methoxyl group) Phenylpropionamide (compound number 52);
(4R)-6-chloro-N-(3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(2-cyclopentyloxy-3-methyl) Phenylpropionamide (compound number 53);
(4S)-6-chloro-N-(3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(2-cyclopentyloxy-3-methyl) Phenylpropionamide (compound number 54);
N-6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-4-base-3-(2-hydroxy 3-methoxybenzene base) propionic acid amide (compound number 55);
N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(2-benzyloxy-3-methoxyl group) Phenylpropionamide (compound number 56);
N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-{2-isopropoxy-3-[(methyl sulphonyl) amino] phenyl } propionic acid amide (compound number 57);
N-(8-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-{2-isopropoxy-3-[(methyl sulphonyl) amino] phenyl } propionic acid amide (compound number 58);
N-(6,8-, two chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(2-cyclopentyloxy-3-methoxyl group) Phenylpropionamide (compound number 59);
N-(6,8-, two chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-{[2-(dimethylamino) oxyethyl group-3-methoxyl group] phenyl } propionic acid amide (compound number 60);
N-(6,8-, two chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-{2-propoxy--3-[(methyl sulphonyl) amino] phenyl } propionic acid amide (compound number 61);
N-(6,8-, two chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-{2-isopropoxy-5-[(methyl sulphonyl) amino] phenyl } propionic acid amide (compound number 62);
N-(6,8-, two chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-{2-butoxy-3-[(methyl sulphonyl) amino] phenyl } propionic acid amide (compound number 63);
N-(6,8-, two chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-{2-(cyclo propyl methoxy)-3-[(methyl sulphonyl) amino] phenyl } propionic acid amide (compound number 64);
N-(6,8-, two chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-{2-isopropoxy-3-[(methyl sulphonyl) amino] phenyl } propionic acid amide (compound number 65);
N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(1-naphthyl) propionic acid amide (compound number 66);
N-[4 (S)-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(2-methoxyl group-1-naphthyl) propionic acid amide (compound number 67);
N-[4S-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(2-methoxyl group-1-naphthyl) propionic acid amide (compound number 68);
N-[(4R)-6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(4-methoxyl group-1-naphthyl) propionic acid amide (compound number 69);
N-[(4S)-6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(4-methoxyl group-1-naphthyl) propionic acid amide (compound number 70);
(4R)-6-chloro-N-(3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(4-difluoro-methoxy-1-naphthyl) propionic acid amide (compound number 71);
(4S)-6-chloro-N-(3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(4-difluoro-methoxy-1-naphthyl) propionic acid amide (compound number 72);
N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(2-naphthyl) propionic acid amide (compound number 73);
N-[4R-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(6-methoxyl group-2-naphthyl) propionic acid amide (compound number 74);
N-[4S-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(6-methoxyl group-2-naphthyl) propionic acid amide (compound number 75);
N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(quinoline-2-yl) propionic acid amide (compound number 76);
N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(1H-indol-3-yl) propionic acid amide (compound number 77);
N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(2-methyl-7-methoxyl group-1-cumarone-4-yl) propionic acid amide (compound number 78);
N-[(4R)-6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl]-3-(7-methoxyl group-2-methyl isophthalic acid-cumarone-5-yl) propionic acid amide (compound number 79);
N-[(4S)-6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl]-3-(7-methoxyl group-2-methyl isophthalic acid-cumarone-5-yl) propionic acid amide (compound number 80);
3-(1,4-Ben Bing dioxin-6-yl)-N-(6-fluoro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl) propionic acid amide (compound number 81);
3-(1,3-benzo dioxole-4-yl)-N-[6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl] propionic acid amide (compound number 82);
3-(1,3-benzo dioxole-4-yl)-N-(8-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl) propionic acid amide (compound number 83);
3-(1,4-Ben Bing dioxin-5-yl)-N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl) propionic acid amide (compound number 84);
N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-3-(dibenzo [b, d] furans-4-yl) propionic acid amide (compound number 85);
N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-ring penta]-the 4-yl)-3-(2-cyclopentyloxy-3-methoxyl group) propionic acid amide (compound number 86);
N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-hexamethylene]-the 4-yl)-3-(2-cyclopentyloxy-3-methoxyl group) Phenylpropionamide (compound number 87);
N-(2,2-dimethyl-3,4-dihydro-2H-chromene-4-yl)-3-(2-cyclopentyloxy-3-methoxyl group) Phenylpropionamide (compound number 88);
N-(6-chloro-3,4-dihydro-2H-sulfo-chromene-4-yl)-3-(2-cyclopentyloxy-3-p-methoxy-phenyl) propionic acid amide (compound number 89);
N-(6-chloro-3,4-dihydro-2H-sulfo-chromene-4-yl)-3-(2-methoxyl group-1-naphthyl) propionic acid amide (compound number 90);
N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-4-(2-cyclopentyloxy phenyl) butyramide (compound number 91);
N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-4-[2-(cyclopentyloxy)-3-p-methoxy-phenyl] butyramide (compound number 92);
N-(4R)-6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-4-base-4-(2-cyclopentyloxy-3-p-methoxy-phenyl) butyramide (compound number 93);
N-{ (4S)-6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl }-4-[(2-(cyclopentyloxy)-3-p-methoxy-phenyl] butyramide (compound number 94);
(4R)-N-(8-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-4-(2-cyclopentyloxy-3-p-methoxy-phenyl) butyramide (compound number 95);
(4S)-N-(8-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-4-(2-cyclopentyloxy-3-p-methoxy-phenyl) butyramide (compound number 96);
N-(8-chloro-6-fluoro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-4-(2-cyclopentyloxy-3-p-methoxy-phenyl) butyramide (compound number 97);
N-(6,8-, two chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-4-(2-cyclopentyloxy-3-p-methoxy-phenyl) butyramide (compound number 98);
N-(7-benzyloxy-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-4-(2-cyclopentyloxy-3-p-methoxy-phenyl) butyramide (compound number 99);
N-(7-hydroxyl-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-4-(2-cyclopentyloxy-3-p-methoxy-phenyl) butyramide (compound number 100);
N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-4-oxygen-4-(4-methoxyl group naphthyl) butyramide (compound number 101);
N-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-4-hydroxyl-4-(4-methoxyl group naphthyl) butyramide (compound number 102);
N-(6-chloro-2,2-dimethyl-3,4-dihydro-2H-chromene-4-yl)-4-(2-cyclopentyloxy-3-methoxyl group) phenylbutanamides (compound number 103); With
N-(6-chloro-3,4-dihydro-2H-sulfo-chromene-4-yl)-4-(2-cyclopentyloxy-3-p-methoxy-phenyl) butyramide (compound number 104); Or
The analogue of above-claimed cpd, tautomer, geometrical isomer, steric isomer, enantiomer, diastereomer or pharmacy acceptable salt.
4. comprise the pharmaceutical composition as each described compound of claim 1-3 and pharmaceutically acceptable vehicle, described compound is as the form of free alkali or pharmacy acceptable salt; Wherein preferred described pharmaceutically acceptable vehicle is carrier or thinner.
5. prevention in the subject that needs is arranged, improve or disease, obstacle or the syndromic method for the treatment of novel vanilloid receptor mediation, described method comprise give described experimenter treat significant quantity as each described compound of claim 1-3.
6. method as claimed in claim 5, disease, obstacle or the syndrome of wherein said novel vanilloid receptor mediation be pain or inflammatory diseases, obstacle or the syndrome that is mediated by TRPV3.
7. method as claimed in claim 5, wherein said symptom with TRPV3 function diseases associated, obstacle, syndrome or illness is selected from the group of being made up of following symptom: pain; Acute pain; Chronic pain; Nociceptive pain; Neuropathic pain; Post-operative pain; Toothache; Cancer pain; It is pained that ischemic myocardium causes; The pain that causes because of migraine; Arthrodynia; DPN; Neurodynia; Trigeminal neuralgia; Nerve injury; Diabetic neuropathy; Nerve degenerative diseases; Retinopathy; The nervosa skin barrier; Apoplexy; Irritable bladder disease; The urinary incontinence; Vulvodynia; Gastrointestinal disorders is as irritable bowel syndrome, stomach-esophageal reflux disease, enteritis, ileitis, gastroduodenal ulcer, inflammatory bowel, Crohn disease, celiac disease; Inflammatory diseases is as pancreatitis; Dyspnoea is as supersensitivity and non-allergic rhinitis, asthma or chronic obstructive pulmonary disease; The stimulation of skin, eye or mucous membrane; Dermatitis; Pruritus is as uremic pruritus; Heating; Muscle spasm; Vomiting; Dyskinesia; Dysthymia disorders; Huntington's chorea; Hypomnesis; Brain function is limited; Amyotrophic lateral sclerosis (ALS); Dull-witted; Sacroiliitis; Osteoarthritis; Diabetes; Obesity; Urticaria; Actinic keratosis; Keratoacanthoma; Alopecia; Meniere; Tinnitus; Hyperacusis; Anxiety disorder; And benign prostatic hyperplasia.
8. in the method that the subject internal therapy pain that needs is arranged, described method comprise give described experimenter treat significant quantity as each described compound of claim 1-3, preferred described pain is acute pain, chronic pain or post-operative pain.
9. the subject internal therapy neuropathic pain that needs or the method for inflammation are being arranged, described method comprise give described experimenter treat significant quantity as each described compound of claim 1-3.
10. the method for the compound of preparation formula (I):
Figure FDA0000127889190000121
Wherein,
R 1Be selected from and replace or unsubstituted aryl, replacement or unsubstituted heteroaryl, replacement or unsubstituted heterocyclic group or replacement or unsubstituted cycloalkyl; Wherein aryl, heteroaryl and heterocyclic ring are monocycle, dicyclo or three rings, and all or part of be aromatics;
Wherein, aryl, heteroaryl, substituting group on heterocyclic ring and the cycloalkyl is independently selected from the group of being made up of following radicals: halogen, hydroxyl, nitro, cyano group, replace or unsubstituted amino, replace or unsubstituted alkyl, the straight or branched alkyl, the straight or branched alkoxyl group, replace or unsubstituted thiazolinyl, replace or unsubstituted alkoxyl group, replace or unsubstituted haloalkyl, the haloalkyl of all or part of replacement, replace or unsubstituted halogenated alkoxy, the halogenated alkoxy of all or part of replacement, replace or unsubstituted cycloalkyl, replace or unsubstituted cycloalkyloxy, replace or unsubstituted cycloalkylalkyl, replace or unsubstituted cycloalkyl alkoxy, replace or unsubstituted aryl, replace or unsubstituted aryloxy, replace or unsubstituted arylalkyl, replace or unsubstituted alkoxy aryl, replace or unsubstituted heterocyclic group, replace or unsubstituted heteroaryl,-S (O) pR a,-NHS (O) pR a,-O (CH 2) mNR aR b,-C (O)-R aOr-C (O) NR aR b
R 2Be hydrogen;
R a, R b, R cAnd R dBe independently selected from hydrogen, nitro, cyano group, halogen ,-OR e, replacement or unsubstituted alkyl, replacement or unsubstituted thiazolinyl, replacement or unsubstituted alkynyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted cycloalkenyl group, replacement or unsubstituted aryl, replacement or unsubstituted heteroaryl, replacement or unsubstituted heterocyclic group;
R eBe selected from the group of being formed by following radicals: hydrogen, replacement or unsubstituted alkyl, replacement or unsubstituted thiazolinyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted aryl, replacement or unsubstituted heteroaryl or replacement or unsubstituted heterocyclic group;
R 3And R 4Be independently selected from hydrogen, halogen, replace or unsubstituted amino, replace or unsubstituted alkyl, the straight or branched alkyl, the straight or branched alkoxyl group, replace or unsubstituted thiazolinyl, replace or unsubstituted alkoxyl group, replace or unsubstituted haloalkyl, the haloalkyl of all or part of replacement, replace or unsubstituted halogenated alkoxy, the halogenated alkoxy of all or part of replacement, replace or unsubstituted cycloalkyl, replace or unsubstituted cycloalkyloxy, replace or unsubstituted cycloalkylalkyl, replace or unsubstituted cycloalkyl alkoxy, replace or unsubstituted aryl;
' m ' is for being selected from the integer of 1-4;
' n ' is for being selected from the integer of 0-3;
' p ' is for being selected from the integer of 0-2;
But R bNot for being selected from-OR e,-NR 3R 4Or C (O) NR 3R 4Group;
Described method comprises the steps:
In the presence of the coupling agent combination that is fit to and the solvent that is fit to, by with the compound of formula (1) and the compound coupling of formula (2), the compound that obtains formula (I) (is worked as R 2During for H):
Figure FDA0000127889190000131
Wherein,
Preferred coupling agent combination is selected from down group: I-hydroxybenzotriazole (HOBt), 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCI) and triethylamine;
The preferred solvent that is fit to is methylene dichloride;
Preferred bases is triethylamine.
CN 201110459248 2011-12-31 2011-12-31 Chromane derivative used as TRPV3 (transient receptor potential vanilloid 3) conditioning agent Pending CN103183660A (en)

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