CN101605758A - The method of treatment hepatitis C - Google Patents

The method of treatment hepatitis C Download PDF

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Publication number
CN101605758A
CN101605758A CNA2007800089028A CN200780008902A CN101605758A CN 101605758 A CN101605758 A CN 101605758A CN A2007800089028 A CNA2007800089028 A CN A2007800089028A CN 200780008902 A CN200780008902 A CN 200780008902A CN 101605758 A CN101605758 A CN 101605758A
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alkyl
randomly
yuan
replaced
replaces
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G·M·卡普
A·阿福罗
任洪玉
A·A·图尔波夫
R·G·怀尔德
J·J·塔卡苏季
P·S·黄
陈光明
J·A·坎贝尔
张南京
张小燕
朱进
李春时
S·佩吉特
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PTC Therapeutics Inc
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PTC Therapeutics Inc
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Abstract

The invention provides these compounds of compound, pharmaceutical composition and use or composition is used for the treatment of virus infection or is used to influence the active method of viral IRES.

Description

The method of treatment hepatitis C
The cross reference related application
The application is the application 11/331 that January 13 submitted in 2006,180 part continuation application, it is the application 11/180 that July 14 submitted in 2005, the part continuation application of International Application PCT/US2005/024881 that 961 part continuation application and on July 14th, 2005 submit, the U.S. Provisional Application 60/587 that on July 14th, 2004 submitted is all advocated in these two applications, 487, the U.S. Provisional Application 60/634 that on December 13rd, 2004 submitted, 979, the U.S. Provisional Application 60/645 that on January 24th, 2005 submitted, 586, the U.S. Provisional Application 60/665 that on March 28th, 2005 submitted, the rights and interests of the U.S. Provisional Application 60/675,440 that on April 28th, 349 and 2005 submitted; The application also advocates the rights and interests of the U.S. Provisional Application 60/758,527 that on January 13rd, 2006 submitted.The full content of these applications mode by reference is incorporated into this.
Technical field
The invention provides these compounds of compound, pharmaceutical composition and use or composition is used for the treatment of virus infection or is used to influence the active method of viral IRES.
Background technology
It is reported that the whole world has 1.7 hundred million people to infect hepatitis C virus (HCV), the i.e. virulence factor of hepatitis C approximately.70% to 80% HCV infects and causes chronic liver to infect, and the latter may cause serious hepatic diseases conversely, comprises hepatic fibrosis, liver cirrhosis and hepatocellular carcinoma (115).
HCV belongs to flaviviridae Hepacivirus (106), contains the positive chain RNA genome of 9.6kb.The genomic characteristics of HCV comprise the 5 '-non-translational region (UTR) of coding internal ribosome entry site (IRES), and the translation of the single long open reading frame (ORF) of 3010 amino acid whose polyproteins of coding can be instructed in this site.Depend on the HCV varient, met 3 ' variable-UTR of a segment length behind the HCV ORF, its coding starts the synthetic required sequence (79) of anti-genome chain.
Required RNA structural region is translated and duplicated to the equal encoding gene group of HCV IRES and 3 '-UTR.The HCV polyprotein becomes at least 10 ripe viral proteins through the translation post-treatment, comprising structural protein core (inferring nucleocapsid (putativenucleocapsid)), E1 and E2 and non-structure (NS) albumen NS2 to NS5B.
Shown already that three kinds of different elements had participated in the translation of HCV IRES mediation: the integrally-built integrity of (1) HCV IRES, the genomic 3 '-stub area of (2) HCV; And the trans-acting cytokine (35) of (3) and interaction of HCV IRES element and supplementary translation startup.
The rule (61) of 5 ' cap-dependency, first AUG is mainly followed in the startup of eukaryotic protein synthesis.But, shown already that increasing virus (6,12,28,31a, 50,95,97,98,105,128) and cell mRNA (18,39,45,78,91,130) use IRES element instructed translation initiation.1992, it is reported that there is IRES element (129) in 5 ' UTR of HCV rna gene group, this shows that the synthetic of viral protein is not start to rely on the mode that adds cap.
Can use the bicistronic mRNA expression system to determine and estimate the function of IRES element.This detection system is carried two different reporter genes, wherein near 5 ' reporter gene of end expresses by adding the dependent translating mechanism of cap, and second reporter only just expressed when the upstream sequence of transcribed spacer contains the IRES sequential element between the gene being inserted into.Utilize this system, be positioned at the translational control (133) that IRES is confirmed to have participated in as IRES viral protein of inferring of HCV 5 ' UTR beyond all doubtly.External translation, RNA transfection and mutagenesis research provide further evidence, and promptly HCV 5 ' UTR contains IRES element (23,41,42,108,129,132,133,134).External and cell research proves that all HCVIRES guides to the site, inside (56,58,120) of viral RNA with the translation initiation factor of cell, thereby has confirmed the IRES activity of HCV from functional perspective.In a word, these results show that HCV 5 '-UTR contains the IRES element, and it has brought into play active and crucial effect in the internal start mechanism of HCV protein translation.
This IRES is one of the most conservative zone of HCV genome, and this has reflected that it is for virus replication and the synthetic indispensable character (13,118,122) of albumen.Although as if 5 ' and the 3 ' terminal sequence of IRES all participated in the regulation and control (42,109,110,113,136) of translation initiation, require to be located in zone (40) between the Nucleotide 44-354 for the lowest series of HCV IRES function.
Biochemical probe and microcomputer modelling show that HCV IRES and 5 ' terminal sequence thereof are folded into by four primary structure territories and the unique texture (11,42,122) that false knot is formed.As if structural domain I contains a little loop-stem structure, and it is not the funtion part of IRES element, and domain II, III and IV contain HCV IRES activity (43,111).Recently determined the relation (5,55,56,99,124) between HCV IRES secondary and tertiary structure and its function.Domain II and III form by a plurality of stems, ring and projection, and are important (23,40,51,52,54,56,64,74,75,93,107,108,110,124,127,131,139,141,142) for the IRES activity.Domain II can be induced the rrna conformational change, and they are relevant with decode procedure.Domain II I has the conservative degree of the highest structure between different HCV virus strain.It comprises the core of flavivirus IRES and has 6 subdomains (40).Various researchs had shown already that subdomain IIId formed complicated secondary/tertiary structure, and it is for initial activity most important (55,56,57,124,129).Structural domain IV has a stem ring across initiator codon, and this structural domain is HCV IRES peculiar (41,122), but still there is dispute (41,112) in the concrete effect of structural domain IV in the IRES activity.
The effect of HCV IRES is translating equipment is positioned near the internal start codon of virus mRNA.The translation initiation mechanism of HCV and other viral IRES obviously is different from 5 '-the dependent translation initiation mechanism of Jia cap (7,21,31,35,61,71,72,81,88,96,114,123).The mRNA that adds cap in the most cells uses the required many initiation factors (eIF) of translation initiation process.The initial step of this process need interact and the 40S ribosomal subunit be raised the albumen of mRNA cap near zone with 5 ' cap structure.3 ' end of this complex body scanning cap starts translation (21,114) until arrival AUG codon and at this place subsequently.But with regard to HCV, IRES has replaced 5 ' cap structure from function, makes 40S ribosomal subunit and eIF3 directly be attached on the RNA.The subdomain IIId of HCV IRES carries the binding site of 40S ribosomal subunit, and the required unique initiation factor of translation initiation is eIF2, eIF3 and eIF4E (15,58,94,100,120,124).
Polypyrimidine tract is conjugated protein, and (polypyrimidine track-binding protein is to be attached on the HCV IRES and the promotion active non-classical initiation factor of HCV IRES (1,2,3,4,5,30,48,49,53) with the La autoantigen PTB).PTB is one and participates in the 57kDa albumen that RNA shears that it also is essential (10,11,36,53,59,89,92) for effective translation initiation of the IRES mediation of picornavirus mRNA and some cell mRNA.The La autoantigen is the double-stranded RNA untwising protein of a 52kDa, and it also can increase the activity (38,85,86) of poliovirus and cell IRES.Other cytokines that participate in the translation initiation of HCV IRES mediation comprise proteasome-subunit PSMA7 (62), ribosome protein s 5 (26), ribosomal protein S9 (24,25,100) and hnRNPL (33).But, still do not know these the effect of albumen in the translation initiation of HCV IRES mediation in conjunction with RNA.Recently, it is reported that the activity that suppresses Interferon, rabbit (IFN) α that HCV duplicates may be by reducing the translation initiation (117) of La protein level target at HCV IRES mediation.It is reported that for example NS5A, core protein and NS4A/4B have also participated in the function (143-146) of HCV IRES to some HCV albumen.Therefore, interactional inhibitor may effectively suppress HCV and duplicates between blocking-up IRES and the non-classical factor, and does not have cytotoxicity.
At present, only there are IFN α and nucleotide analog 'Libaweilin ' to unite on the market and are used for the treatment that HCV infects.But these two kinds of medicines are immunomodulators, render a service limitedly, and toxicity is higher relatively, and (80,83,84,138) with high costs.Although six kinds of genotypic treatment result of main HCV are not quite similar, only have among all patients that receive treatment only about half of treatment to be responded, the protein product of this prompting encoding viral might directly or indirectly weaken the antivirus action of IFN.IFN is the natural product that virus infection is responded, and cellular exposure can cause the abduction delivering of the gene (ISG) that many IFN of being subjected to stimulate in IFN, and wherein many have an antiviral function.The ISG effect can be duplicated at a plurality of somes limiting virus of replicative cycle.
Still need to treat HCV infection patient's more efficiently method.Particularly, need with existing methods of treatment do not have crossed resistance and with other anti-HCV medicaments can synergistic novel antiviral medicine.
The All Files of this place reference all by reference mode is brought the application into, treats as in quoting in full at this paper.
Summary of the invention
The invention provides these compounds of compound, pharmaceutical composition and use or composition is used for the treatment of virus infection or is used to influence the active method of viral IRES.
Detailed Description Of The Invention
A. The compounds of this invention
In another embodiment, the present invention includes formula (I) compound
Figure A20078000890201071
Or the acceptable salt of their pharmacology,
Wherein:
X is:
-hydrogen;
-cyano group;
-nitro;
-formyl radical;
--the COOH base;
-COR xBase, wherein R xBe C 1To C 6Alkyl;
Figure A20078000890201081
Alkoxyl group;
Figure A20078000890201082
Randomly by one or more C 1To C 6The amino that alkyl replaces;
-halogen;
-the alkyl that randomly replaced by one or more halogens;
-randomly by C 1To C 6The alkynes that alkyl replaces, wherein C 1To C 6Alkyl is randomly replaced by one or more halogens of selecting independently or cyano group;
-oxime;
-SO 2R x；
-SO 2NH 2；
-SO 2NH(R x)；
-SO 2N(R x) 2；
-randomly by one or more C 1To C 6Alkyl or C 1To C 6The amino that alkyl-carbonyl replaces;
-randomly by one or more C that select independently 1To C 6The amide group that alkyl replaces;
-five yuan or hexa-member heterocycle;
-randomly by one or more C 1To C 6Five yuan or six membered heteroaryl that alkyl replaces, wherein said one or more C 1To C 6Alkyl is randomly replaced by one or more halogens;
-the C that randomly replaced by one or more following groups 6To C 8Aryl:
-the C that randomly replaced by one or more halogens 1To C 6Alkyl;
-halogen, or
-cyano group;
Y is:
-hydrogen;
-alkylhalide group;
-halogen;
-cumarone;
-thionaphthene;
-diphenylene-oxide;
-dibenzothiophene;
-the benzothiazole that randomly replaced by amino, wherein amino is randomly by one or more C 1To C 6Alkyl replaces;
-naphthalene;
-indoles, it is randomly by C 1To C 6Alkyl or-SO 2R xBase replaces at N atom place;
R wherein bBe hydrogen or C 1To C 6Alkyl, and n is 0 or 1;
Figure A20078000890201092
R wherein cBe hydrogen ,-CONHR x, R wherein xBe C 1To C 6Alkyl, or-SO 2R x,
R wherein xBe C 1To C 6Alkyl; Or
Figure A20078000890201093
R wherein dBe C 1To C 6Alkyl or C 6To C 8Aryl;
--NHCOR eBase, wherein R eBe:
-C 1To C 6Alkyl;
-C 6To C 8Aryl, it is randomly replaced by following groups:
-C 1To C 6Alkyl,
-alkoxyl group,
-cyano group,
-nitro, or
-halogen;
--NHCOOR xBase, wherein R xBe C 1To C 6Alkyl;
-NR gR hBase, wherein R gBe C 1To C 6Alkyl or hydrogen; R hBe hydrogen, C 1To C 6Alkyl or C 6To C 8Aryl, described C 1To C 6Alkyl or C 6To C 8Aryl randomly alkoxy replaces;
-C 1To C 6Alkyl;
-five yuan or six membered heteroaryl, it is randomly replaced by one or more following groups:
-C 1To C 6Alkyl, it is randomly by one or more halogens or C 6To C 8Aryl replaces,
-randomly by-COOR xThe C that replaces 6To C 8Aryl, wherein R xBe C 1To C 6Alkyl,
-amino, or
-from the substituting group of organizing A;
-five yuan or hexa-member heterocycle, it is randomly replaced by following groups:
-COOR xBase, wherein R xDefinition the same, or
-NHCOOR xBase, wherein R xDefinition the same;
-C 6To C 8Aryl, it is randomly replaced by one or more following groups:
-the alkoxyl group that randomly replaced by following groups:
-alkoxyl group,
-hydroxyl,
-one or more halogens,
-five yuan or hexa-member heterocycle, it is randomly replaced by following groups:
-C 1To C 6Alkyl, or
-hydroxyl,
-C 6To C 8Aryl, it is randomly replaced by one or more substituting groups that are independently selected from group A,
-five yuan or six membered heteroaryl, it is randomly replaced by one or more substituting groups that are independently selected from group A,
-randomly by one or more C 1To C 6The amino that alkyl replaces,
--NR iSO 2R xBase, wherein R xBe C 1To C 6Alkyl, R iBe:
-hydrogen,
-C 1To C 6Alkyl,
-COR xBase, wherein R xDefinition the same,
-alkylhalide group, or
-halogen alkoxyl group,
-NR jCOR kBase, wherein R kBe:
-C 1To C 6Alkyl,
-hydrogen, or
-randomly by one or more C 1To C 6The amino that alkyl replaces,
And R jBe:
-hydrogen,
-C 1To C 6Alkyl,
-COR xBase, wherein R xBe C 1To C 6Alkyl,
-alkylhalide group, or
-halogen alkoxyl group,
-N=N +=N -Base, or
-COR l, R wherein lBe five yuan or the hexa-member heterocycle that is randomly replaced by hydroxyl,
-amino,
-C 1To C 6Alkyl, it is randomly replaced by following groups:
-NHSO 2R xBase, wherein R xDefinition the same, or
-NR xSO 2R xBase, wherein R xDefinition the same,
-halogen alkoxyl group,
-halogen,
-hydroxyl,
-OC(O)NHR x，
-OC(O)N(R x) 2，
-OC(O)NH(OR x)，
-OC(O)NR x(OR x)，
-OC (O) R Ab, R wherein AbBe five yuan or hexa-member heterocycle group,
-COOR xBase, wherein R xBe C 1To C 6Alkyl,
-COR mBase, wherein R mBe:
-randomly by one or more C 1To C 6The amino that alkyl replaces, wherein C 1To C 6Alkyl is randomly replaced by following groups:
-hydroxyl,
-five or hexa-member heterocycle;
-randomly by one or more C 1To C 6The amino that alkyl replaces,
-alkoxyl group,
-ternary is to seven membered heterocyclic, and it is randomly by C 1To C 6Alkyl replaces, randomly replaced by dialkyl-7-amino,
-NHR nBase, wherein R nBe:
-CH 2CONH 2, or
-C 6To C 8Aryl, it is randomly replaced by following groups:
-alkyl,
-one or more halogens,
-nitro, or
-one or more alkoxyl groups,
-NR oCOR pBase, wherein R pBe:
-C 1To C 6Alkyl, it is randomly replaced by following groups:
-halogen,
-alkoxyl group, or
-C 6To C 8Aryl,
-five yuan or hexa-member heterocycle, it is randomly by one or more C 1To C 6Alkyl or C 6To C 8Aryl replaces,
-C 6To C 8Aryl, it is randomly replaced by halogen,
-five yuan or six membered heteroaryl, it is randomly by one or more C 1To C 6Alkyl replaces,
-hydrogen,
Figure A20078000890201121
And R wherein oBe:
-hydrogen,
-C 1To C 6Alkyl,
-COR xBase, wherein R xBe C 1To C 6Alkyl,
-alkylhalide group, or
-halogen alkoxyl group,
-NR qCONR qR rBase, wherein R qBe:
-hydrogen,
-C 1To C 6Alkyl,
-alkylhalide group,
-halogen alkoxyl group, or
-COR xBase, wherein R xDefinition the same,
And R wherein rBe:
-C 6To C 8Aryl, it is randomly replaced by following groups:
Figure A20078000890201131
-halogen,
-C 1To C 6Alkyl, it is randomly and independently by one or more C 6To C 8Aryl, halogen and/or C 1To C 6Alkoxyl group replaces,
-C 1To C 6Alkoxyl group,
-C 1To C 6The halogen alkoxyl group,
-OR sBase, wherein R sBe C 6To C 8Aryl, or
-COOR xBase, wherein R xDefinition the same,
-C 1To C 6Alkyl, it is randomly replaced by one or more following groups:
-halogen,
-hydroxyl,
-alkoxyl group,
-alkylidene group,
-five yuan or hexa-member heterocycle, it is randomly by one or more halogens, C 1To C 6Alkyl, C 1To C 6Alkylhalide group, C 1To C 6Alkoxyl group, C 1To C 6The halogen alkoxyl group replace,
-five yuan or six membered heteroaryl, it is randomly by one or more halogens, C 1To C 6Alkyl, C 1To C 6Alkylhalide group, C 1To C 6Alkoxyl group, C 1To C 6The halogen alkoxyl group replace,
-C 6To C 8Aryl, it is randomly by one or more halogens, C 1To C 6Alkyl, C 1To C 6Alkylhalide group, C 1To C 6Alkoxyl group, C 1To C 6The halogen alkoxyl group replace, or
-COOR xBase, wherein R xDefinition the same,
-C 2To C 6Alkylidene group,
-C 1To C 6Alkoxyl group,
-five yuan or hexa-member heterocycle group, it is randomly by one or more halogens, C 1To C 6Alkyl, C 1To C 6Alkylhalide group, C 1To C 6Alkoxyl group, C 1To C 6The halogen alkoxyl group replace,
-COOR xBase, wherein R xDefinition the same,
-NR tCOOR uBase, wherein R uBe:
-C 1To C 12Alkyl, it is randomly replaced by one or more groups that are independently selected from down group,
-C 6To C 8Aryl, it is randomly by one or more halogens, C 1To C 6Alkyl, C 1To C 6Alkylhalide group, C 1To C 6Alkoxyl group, C 1To C 6The halogen alkoxyl group replace,
-alkylidene group,
-alkoxyl group,
-alkynes,
-the alkoxyl group that randomly replaced by one or more alkoxyl groups,
-randomly by one or more C 1To C 6The amino that alkyl replaces,
-halogen, or
-five yuan or hexa-member heterocycle,
-five yuan or six membered heteroaryl,
-C 2To C 6Alkylidene group,
-C 6To C 8Aryl, it is randomly replaced by following groups:
-alkoxyl group,
-halogen, or
-C 1To C 6Alkyl, or
-five yuan or hexa-member heterocycle,
And R tBe:
-hydrogen,
-C 1To C 6Alkyl,
-COR xBase, wherein R xDefinition the same,
-alkylhalide group, or
-halogen alkoxyl group,
-NR vSO 2R wBase, wherein R vBe:
-hydrogen,
-COR x, R wherein xDefinition the same, or
-C 1To C 6Alkyl, it is randomly replaced by following groups:
-halogen,
-COR xBase, wherein R xDefinition the same,
-OCOR xBase, wherein R xDefinition the same,
-hydroxyl, or
-alkoxyl group,
And R wherein wBe:
-C 1To C 6Alkyl, it is randomly replaced by following groups:
-halogen,
-alkylhalide group,
-C 6To C 8Aryl, or
-five yuan or hexa-member heterocycle,
-C 2To C 6Alkylidene group,
-alkyl-amino or dialkyl-7-amino, it is randomly replaced by halogen,
-five yuan or hexa-member heterocycle, or
-five yuan or six membered heteroaryl, it is randomly replaced by one or more following groups:
-halogen,
-C 1To C 6Alkyl,
-C 1To C 6Alkylhalide group,
-C 1To C 6Alkoxyl group,
-C 1To C 6The halogen alkoxyl group,
-five yuan or hexa-member heterocycle, or
Figure A20078000890201161
Figure A20078000890201162
Replaced by Ry, wherein R yBe hydrogen, randomly by C 1To C 6The C that alkoxyl group replaces 1To C 6Alkyl, C 1To C 6Alkylhalide group, C 6To C 8Aryl, five yuan or six membered heteroaryl or five yuan or hexa-member heterocycle, wherein C 6To C 8Aryl, five yuan or six membered heteroaryl and five yuan or hexa-member heterocycle are separately randomly and independently by one or more halogens, C 1To C 6Alkyl, C 1To C 6Alkoxyl group, C 1To C 6Alkylhalide group, C 1To C 6The halogen alkoxyl group replace,
Figure A20078000890201163
Replaced by Ry, wherein R yDescription the same,
Figure A20078000890201164
R wherein yDescription the same, R zBe hydrogen or randomly by C 6To C 8The C that aryl replaces 1To C 6Alkyl,
Figure A20078000890201171
R wherein yDescription the same,
-SR xBase, wherein R xDefinition the same,
-SO 2R AaBase, wherein R AaBe:
-C 1To C 6Alkyl,
-amino,
-alkyl-amino or dialkyl-7-amino, its randomly by hydroxyl, five yuan or hexa-member heterocycle, five yuan or six membered heteroaryl or-COOR xBase replaces, wherein R xDefinition the same,
-five yuan or six membered heteroaryl,
-five yuan or hexa-member heterocycle, it is randomly by hydroxyl, C 1To C 6Alkoxyl group or C 1To C 6Alkyl replaces, and wherein said alkyl is randomly replaced by one or more hydroxyls,
-C 6To C 8Aryl, or
-NHR BbBase, wherein R BbBe:
Figure A20078000890201172
-C (=S) NH 2Base, or
-PO (OR x) 2, R wherein xDefinition the same;
Figure A20078000890201181
Base, wherein R CcBe:
-naphthalene,
-five yuan or six membered heteroaryl,
Figure A20078000890201182
-C 6To C 8Aryl, it is randomly replaced by one or more following groups:
-alkoxyl group,
-hydroxyl,
-halogen,
-C 1To C 6Alkyl, its optional by cyano replaces,
-randomly by one or more C 1To C 6The amino that alkyl replaces,
-NHPOR xR xBase, wherein R xDefinition the same,
-NR EeCONR FfR FfBase, wherein R EeBe hydrogen or the C that randomly replaced by halogen 1To C 6Alkyl, and R FfBe:
-hydrogen,
-alkylhalide group,
-halogen alkoxyl group,
-C 1To C 6Alkyl, or
-COR x, R wherein xDefinition the same,
-NR GgCOR HhBase, wherein R HhBe:
-hydrogen,
-C 1To C 6Alkyl, it is randomly replaced by following groups:
-alkoxyl group,
-halogen, or
-randomly by one or more C 1To C 6The amino that alkyl replaces,
-randomly by one or more C 1To C 6The amino that alkyl replaces, wherein said alkyl is randomly replaced by halogen,
-five yuan or hexa-member heterocycle,
-five yuan or six membered heteroaryl,
And R GgBe:
-hydrogen,
-C 1To C 6Alkyl,
-alkylhalide group,
-halogen alkoxyl group, or
-COR xBase, wherein R xDefinition the same,
-alkylhalide group,
-five yuan or hexa-member heterocycle,
-randomly by one or more C 1To C 6The amino that alkyl replaces,
-NR IiSO 2R xBase, wherein R xDefinition the same, and R IiBe
-hydrogen,
-C 1To C 6Alkyl,
-alkylhalide group,
-halogen alkoxyl group,
-COR xBase, wherein R xDefinition the same;
Z is:
-hydrogen;
-C 1To C 6Alkyl, it is randomly replaced by following groups:
-alkoxyl group,
-one or more halogens,
-five yuan or hexa-member heterocycle, or
-C 6To C 8Aryl;
-five yuan or hexa-member heterocycle;
-C 2To C 6Alkylidene group;
-C 6To C 8Aryl, it is alkoxy or one or more C randomly 1To C 6Alkyl replaces;
-COOR xBase, wherein R xDefinition the same; Or
Figure A20078000890201201
R is hydrogen, halogen or alkoxyl group;
R 1Be:
-hydrogen;
-hydroxyl;
-halogen;
-alkylhalide group;
-nitro;
-five yuan or six membered heteroaryl;
-five yuan or hexa-member heterocycle;
-the alkoxyl group that randomly replaced by following groups:
-one or more halogens,
-C 6To C 8Aryl, it is randomly by one or more halogens, C 1To C 6Alkyl, C 1To C 6Alkoxyl group, C 1To C 6Alkylhalide group, C 1To C 6Halogen alkoxyl group, C 1To C 6Hydroxyl and/or SO 2R xBase replaces,
-five yuan or hexa-member heterocycle, it is randomly by one or more halogens, C 1To C 6Alkyl, C 1To C 6Alkoxyl group, C 1To C 6Alkylhalide group, C 1To C 6Halogen alkoxyl group, C 1To C 6Hydroxyl and/or SO 2R xBase replaces,
-five yuan or six membered heteroaryl, it is randomly by one or more halogens, C 1To C 6Alkyl, C 1To C 6Alkoxyl group, C 1To C 6Alkylhalide group, C 1To C 6Halogen alkoxyl group, C 1To C 6Hydroxyl and/or SO 2R xBase replaces,
-randomly heterocyclically substituted amino;
-C 6To C 8Aryl, its randomly alkoxy replacement,
-COR xBase, wherein R xDefinition the same;
-C 1To C 6Alkyl, it is randomly by one or more dialkyl-7-aminos, C 6To C 8Aryl, five yuan or six membered heteroaryl and/or five yuan or hexa-member heterocycle replacement, wherein C 6To C 8In aryl, five yuan or six membered heteroaryl and five yuan or the hexa-member heterocycle each is randomly by one or more halogens, C 1To C 6Alkyl, C 1To C 6Alkoxyl group, C 1To C 6Alkylhalide group, C 1To C 6Halogen alkoxyl group, C 1To C 6Hydroxyl and/or SO 2R xBase replaces; Or
R 1With R 2Combine formation:
Figure A20078000890201211
R 2Be:
-nitro;
-hydrogen;
-halogen;
-hydroxyl;
-C 1To C 6Alkyl, it is randomly replaced by one or more following groups:
-halogen,
-five yuan or hexa-member heterocycle group, it is randomly by one or more halogens, C 1To C 6Alkyl, C 1To C 6Alkoxyl group, C 1To C 6Alkylhalide group, C 1To C 6Halogen alkoxyl group, C 1To C 6Hydroxyl and/or SO 2R xBase replaces,
-five yuan or six membered heteroaryl, it is randomly by one or more halogens, C 1To C 6Alkyl, C 1To C 6Alkoxyl group, C 1To C 6Alkylhalide group, C 1To C 6Halogen alkoxyl group, C 1To C 6Hydroxyl and/or SO 2R xBase replaces,
-C 6To C 8Aryl, it is randomly by one or more halogens, C 1To C 6Alkyl, C 1To C 6Alkoxyl group, C 1To C 6Alkylhalide group, C 1To C 6Halogen alkoxyl group, C 1To C 6Hydroxyl and/or SO 2R xBase replaces,
-amino, it is randomly replaced by one or more alkoxyl groups or alkyl, and it is randomly replaced by one or more alkoxyl groups,
-randomly by one or more C 1To C 6The amino that alkyl replaces,
-alkoxyl group, it is randomly replaced by one or more groups that are independently selected from down group:
-halogen,
-hydroxyl,
-the alkoxyl group that replaces of alkoxy randomly,
-OCOR xBase, wherein R xDefinition the same,
-amino, randomly by one or more five yuan or hexa-member heterocycle base or alkyl replacements, wherein said alkyl randomly and is independently replaced by one or more following groups for it:
-five yuan or hexa-member heterocycle, or
-the amino that randomly replaced by one or more alkyl;
-the dialkyl-7-amino that replaces of alkoxy randomly,
-quaternary is to the seven membered heterocyclic base, and it is randomly by one or more hydroxyl or C that select independently 1To C 6Alkyl replaces, wherein said C 1To C 6Alkyl is randomly by one or more C that select independently 1To C 6Alkoxyl group replaces,
-five yuan or six membered heteroaryl, it is randomly by one or more halogen, C that select independently 1To C 6Alkyl, C 1To C 6Alkoxyl group, C 1To C 6Alkylhalide group, C 1To C 6Halogen alkoxyl group, C 1To C 6Hydroxyl, and/or SO 2R xBase replaces,
-C 6To C 8Aryl, it is randomly by one or more halogen, C that select independently 1To C 6Alkyl, C 1To C 6Alkoxyl group, C 1To C 6Alkylhalide group, C 1To C 6Halogen alkoxyl group, C 1To C 6Hydroxyl, and/or SO 2R xBase replaces,
-C (O)-five yuan or hexa-member heterocycle, it is randomly by one or more C 6To C 8Aryl replaces;
--the COOH base;
-COOR xBase, wherein R xDefinition the same;
-alkylhalide group;
--C (O) NH 2, it is randomly replaced by one or more following groups:
-C 1To C 6Alkyl, it is randomly by one or more halogen, C that select independently 1To C 6Alkoxyl group, C 1To C 6Hydroxyl, five yuan or hexa-member heterocycle and/or five yuan or six membered heteroaryl replace,
-hydroxyl, or
-C 6To C 8Aryl;
-five yuan or hexa-member heterocycle, it is randomly replaced by one or more following groups:
-C 1To C 6Alkyl,
-SO 2R x，
-C (O)-C 6To C 8Aryl,
-C (O) OR xOr
-hydroxyl,
-five yuan or six membered heteroaryl, it is randomly by one or more halogen, C that select independently 1To C 6Alkyl, C 1To C 6Alkoxyl group, C 1To C 6Alkylhalide group, C 1To C 6Halogen alkoxyl group, C 1To C 6Hydroxyl, and/or SO 2R xBase replaces ,-OCOR xBase, wherein R xDefinition the same;
-NHCOR JjBase, wherein R JjBe:
-alkyl,
-C 6To C 8Aryl,
-alkoxyl group, or
-randomly by one or more C 1To C 6The amino that alkyl replaces;
-OR KkBase, wherein R KkBe:
-C 6To C 8Aryl, it is randomly by one or more halogen, C that select independently 1To C 6Alkyl, C 1To C 6Alkoxyl group, C 1To C 6Alkylhalide group, C 1To C 6Halogen alkoxyl group, C 1To C 6Hydroxyl, and/or SO 2R xBase replaces,
-five yuan to six membered heteroaryl, and it is randomly by halogen, C 1To C 6Alkyl, C 1To C 6Alkoxyl group, C 1To C 6Alkylhalide group, C 1To C 6Halogen alkoxyl group, C 1To C 6Hydroxyl, and/or SO 2R xBase replaces,
-five yuan to hexa-member heterocycle, and it is randomly by C 1To C 6Alkyl replaces, or randomly by C 6To C 8Aryl replaces, or
-Si(Rx) 3
-NHSO 2R xBase, wherein R xDefinition the same; Or
R 2With R 1Combine formation:
Figure A20078000890201231
R 3Be:
-hydrogen; Or
-CH 2OCOR x, R wherein xDefinition the same;
Group A is
-halogen,
-C 1To C 6Alkyl,
-C 1To C 6Alkoxyl group,
-C 1To C 6Alkylhalide group,
-C 1To C 6The halogen alkoxyl group,
-NR oCOR pBase, wherein R pBe:
-C 1To C 6Alkyl, it is randomly replaced by following groups:
-halogen,
-alkoxyl group, or
-C 6To C 8Aryl,
-five yuan or hexa-member heterocycle, it is randomly by one or more C 1To C 6Alkyl or C 6To C 8Aryl replaces,
-C 6To C 8Aryl, it is randomly replaced by halogen,
-five yuan or six membered heteroaryl, it is randomly by one or more C 1To C 6Alkyl replaces,
-hydrogen,
Figure A20078000890201241
And R wherein oBe:
-hydrogen,
-C 1To C 6Alkyl,
-COR xBase, wherein R xBe C 1To C 6Alkyl,
-alkylhalide group, or
-halogen alkoxyl group,
-NR qCONR qR rBase, wherein R qBe:
-hydrogen,
-C 1To C 6Alkyl,
-alkylhalide group,
-halogen alkoxyl group, or
-COR xBase, wherein R xDefinition the same,
And R wherein rBe:
-C 6To C 8Aryl, it is randomly replaced by following groups:
-halogen,
-C 1To C 6Alkyl, it is randomly and independently by one or more C 6To C 8Aryl, halogen and/or C 1To C 6Alkoxyl group replaces,
-C 1To C 6Alkoxyl group,
-C 1To C 6The halogen alkoxyl group,
-OR sBase, wherein R sBe C 6To C 8Aryl, or
-COOR xBase, wherein R xDefinition the same,
-C 1To C 6Alkyl, it is randomly replaced by one or more following groups:
-halogen,
-hydroxyl,
-alkoxyl group,
-alkylidene group,
-five yuan or hexa-member heterocycle, it is randomly by one or more halogens, C 1To C 6Alkyl, C 1To C 6Alkylhalide group, C 1To C 6Alkoxyl group, C 1To C 6The halogen alkoxyl group replace,
-five yuan or six membered heteroaryl, it is randomly by one or more halogens, C 1To C 6Alkyl, C 1To C 6Alkylhalide group, C 1To C 6Alkoxyl group, C 1To C 6The halogen alkoxyl group replace,
-C 6To C 8Aryl, it is randomly by one or more halogens, C 1To C 6Alkyl, C 1To C 6Alkylhalide group, C 1To C 6Alkoxyl group, C 1To C 6The halogen alkoxyl group replace, or
-COOR xBase, wherein R xDefinition the same,
-C 2To C 6Alkylidene group,
-C 1To C 6Alkoxyl group,
-five yuan or hexa-member heterocycle base, it is randomly by one or more halogens, C 1To C 6Alkyl, C 1To C 6Alkylhalide group, C 1To C 6Alkoxyl group, C 1To C 6The halogen alkoxyl group replace,
-COOR xBase, wherein R xDefinition the same,
-NR tCOOR uBase, wherein R uBe:
-C 1To C 12Alkyl, it is randomly replaced by one or more groups that are independently selected from down group,
-C 6To C 8Aryl, it is randomly by one or more halogens, C 1To C 6Alkyl, C 1To C 6Alkylhalide group, C 1To C 6Alkoxyl group, C 1To C 6The halogen alkoxyl group replace,
-alkylidene group,
-alkoxyl group,
-alkynes,
-the alkoxyl group that randomly replaced by one or more alkoxyl groups,
-randomly by one or more C 1To C 6The amino that alkyl replaces,
-halogen, or
-five yuan or hexa-member heterocycle,
-five yuan or six membered heteroaryl,
-C 2To C 6Alkylidene group,
-C 6To C 8Aryl, it is randomly replaced by following groups:
-alkoxyl group,
-halogen, or
-C 1To C 6Alkyl, or
-five yuan or hexa-member heterocycle,
And R tBe:
-hydrogen,
-C 1To C 6Alkyl,
-COR xBase, wherein R xDefinition the same,
-alkylhalide group, or
-halogen alkoxyl group,
-NR vSO 2R wBase, wherein R vBe:
-hydrogen,
-COR xBase, wherein R xDefinition the same, or
-C 1To C 6Alkyl, it is randomly replaced by following groups:
-halogen,
-COR xBase, wherein R xDefinition the same,
-OCOR xBase, wherein R xDefinition the same,
-hydroxyl, or
-alkoxyl group,
And R wherein wBe:
-C 1To C 6Alkyl, it is randomly replaced by following groups:
-halogen,
-alkylhalide group,
-C 6To C 8Aryl, or
-five yuan or hexa-member heterocycle,
-C 2To C 6Alkylidene group,
-alkyl-amino or dialkyl-7-amino, it is randomly replaced by halogen,
-five yuan or hexa-member heterocycle, or
-five yuan or six membered heteroaryl, it is randomly replaced by one or more following groups:
-halogen,
-C 1To C 6Alkyl,
-C 1To C 6Alkylhalide group,
-C 1To C 6Alkoxyl group,
-C 1To C 6The halogen alkoxyl group,
-five yuan or hexa-member heterocycle, or
Figure A20078000890201271
-SO 2R AaBase, wherein R AaBe:
-C 1To C 6Alkyl,
-amino,
-alkyl-amino or dialkyl-7-amino, its randomly by hydroxyl, five yuan or hexa-member heterocycle, five yuan or six membered heteroaryl or-COOR xBase replaces, wherein R xDefinition the same,
-five yuan or six membered heteroaryl,
-five yuan or hexa-member heterocycle, it is randomly by hydroxyl, C 1To C 6Alkoxyl group or C 1To C 6Alkyl replaces, and wherein said alkyl is randomly replaced by one or more hydroxyls,
-NHR BbBase, wherein R BbBe:
-C (=S) NH 2Base, or
-PO (OR x) 2, R wherein xDefinition the same;
-COR mBase, wherein R mBe:
-randomly by one or more C 1To C 6The amino that alkyl replaces, wherein said C 1To C 6Alkyl is randomly replaced by following groups:
-hydroxyl,
-five yuan or hexa-member heterocycle,
-randomly by one or more C 1To C 6The amino that alkyl replaces,
-alkoxyl group,
-ternary is to seven membered heterocyclic, and it is randomly by C 1To C 6Alkyl replaces, randomly replaced by dialkyl-7-amino,
-NHR nBase, wherein R nBe:
-CH 2CONH 2, or
-C 6To C 8Aryl, it is randomly replaced by following groups:
-alkyl,
-one or more halogens,
-nitro, or
-one or more alkoxyl groups;
And
L is direct key, C 1To C 12Alkylidene group, C 2To C 12Alkenylene or C 2To C 12Alkynylene, alkylidene group, alkenylene or alkynylene one or more-CH wherein 2-Ji randomly by-O-,-S-,-SO 2-and/or-NR Mm-replace, and alkylidene group, alkenylene or alkynylene are randomly by one or more ketonic oxygens, halogen and/or hydroxyl replacement, wherein R MmBe hydrogen or C 1To C 6Alkyl.
In another embodiment, the present invention includes formula I compound or the acceptable salt of their pharmacology, condition is Y, Z, R 1And R 2In have a following selection at least:
Y is:
-by the amino benzothiazole that replaces, wherein amino is randomly by one or more C 1To C 6Alkyl replaces;
-indoles, it is at the quilt-SO of nitrogen-atoms place 2R xBase replaces;
-C 6To C 8Aryl, it is replaced by one or more following groups:
-the amino that randomly replaced by one or more following groups:
-SO 2R x, or
-C 1To C 6Alkyl, it is replaced by one or more five yuan or six membered heteroaryl,
-OC(O)NHR x，
-OC(O)N(R x) 2，
-OC(O)NH(OR x)，
-OC(O)NR x(OR x)，
-OC(O)N(OR x) 2，
-OC (O) R Ab, R wherein AbBe five yuan or hexa-member heterocycle base,
-NR oCOR pBase, wherein R pBe:
-randomly by one or more C 1To C 6The amino that alkyl replaces, wherein said C 1To C 6Alkyl is randomly and independently by one or more C 6To C 8Aryl and/or alkoxyl group replace, or
-five yuan or hexa-member heterocycle, it is by one or more C 1To C 6Alkyl or C 6To C 8Aryl replaces ,-NR qCONR qR rBase, wherein R rBe:
-C 1To C 6Alkyl, it is replaced by one or more following groups:
-hydroxyl,
-alkoxyl group,
-five yuan or hexa-member heterocycle,
-five yuan or six membered heteroaryl, or
-C 6To C 8Aryl, it is randomly replaced by halogen,
-C 2To C 6Alkylidene group,
-C 1To C 6Alkoxyl group, or
-five yuan or hexa-member heterocycle base,
-NR tCOOR uBase, wherein R uBe:
-C 1To C 12Alkyl, it is replaced by one or more following groups:
-the alkoxyl group that replaced by one or more alkoxyl groups,
-randomly by one or more C 1To C 6The amino that alkyl replaces, or
-five yuan or six membered heteroaryl,
-C 2To C 6Alkylidene group, or
Figure A20078000890201301
Z is:
-C 1To C 6Alkyl, it is replaced by five yuan or hexa-member heterocycle, or
-five yuan or hexa-member heterocycle; Or
R 1By the alkoxyl group that amino replaces, wherein said amino is randomly by heterocyclic substituted;
R 2Be:
-C 1To C 6Alkyl, it is replaced by one or more following groups:
-five yuan or hexa-member heterocycle base, or
-amino, it is randomly replaced by one or more alkoxyl groups or alkyl, and it is randomly replaced by one or more alkoxyl groups,
-alkoxyl group, it is replaced by one or more groups that are independently selected from down group:
-hydroxyl,
-the alkoxyl group that replaces of alkoxy randomly,
-amino, it is by one or more five yuan or hexa-member heterocycle base or alkyl replacements, and wherein said alkyl randomly and is independently replaced by one or more following groups:
-five yuan or hexa-member heterocycle, or
-the amino that randomly replaced by one or more alkyl;
-seven membered heterocyclic group;
-five yuan to seven membered heterocyclic, and it is replaced by one or more hydroxyls of selecting independently or by one or more C that select independently 1To C 6Alkyl replaces, wherein C 1To C 6Alkyl is by C 1To C 6Alkoxyl group replaces, or
-five yuan or six membered heteroaryl, it is by one or more C 1To C 6Alkyl replaces;
-C (O)-five yuan or hexa-member heterocycle, it is randomly by one or more C 6To C 8Aryl replaces;
--the COOH base;
-by one or more C 1To C 6The amide group that alkyl replaces;
-five yuan or hexa-member heterocycle, it is randomly replaced by one or more following groups:
-C 1To C 6Alkyl,
-SO 2R x，
-C (O)-C 6To C 8Aryl, or
-C (O) OR xBase;
-OR KkBase, wherein R KkBe:
-five yuan to hexa-member heterocycle, and it is randomly by C 1To C 6Alkyl replaces, randomly by C 6To C 8Aryl replaces, or
-Si(Rx) 3。
Comprise formula I compound or the acceptable salt of their pharmacology in another embodiment, condition is X, Y, Z, R 1And R 2In have a following selection at least:
X is:
--the COOH base;
Figure A20078000890201311
To C 6Alkoxyl group,
Randomly by one or more C 1To C 6The amino that alkyl replaces;
-halogen;
-the alkyl that randomly replaced by one or more halogens;
-randomly by C 1To C 6The alkynes that alkyl replaces, wherein C 1To C 6Alkyl is randomly replaced by one or more halogens or cyano group;
-oxime;
-SO 2R x；
-SO 2NH 2；
-SO 2NH(R x)；
-SO 2N(Rx) 2；
-randomly by one or more C 1To C 6Alkyl or C (O)-C 1To C 6The amino that alkyl replaces;
-randomly by one or more C that select independently 1To C 6The amide group that alkyl replaces;
-five yuan or hexa-member heterocycle;
-five yuan or six membered heteroaryl, it is by one or more C 1To C 6Alkyl replaces, wherein one or more C 1To C 6Alkyl is replaced by one or more halogens; Or
-C 6To C 8Aryl, it is replaced by one or more following groups:
-the C that randomly replaced by one or more halogens 1To C 6Alkyl;
-halogen, or
-cyano group;
Y is:
-by the amino benzothiazole that replaces, wherein amino is randomly by one or more C 1To C 6Alkyl replaces;
-indoles, its at the nitrogen-atoms place by SO 2R xBase replaces;
-C 6To C 8Aryl, it is replaced by one or more following groups:
-the amino that randomly replaced by one or more following groups:
-SO 2R x, or
-C 1To C 6Alkyl, it is replaced by one or more five yuan or six membered heteroaryl,
-OC(O)NHR x，
-OC(O)N(R x) 2，
-OC(O)NH(OR x)，
-OC(O)NR x(OR x)，
-OC(O)N(OR x) 2，
-OC (O) R Ab, R wherein AbBe five yuan or hexa-member heterocycle base,
-NR oCOR pBase, wherein R pBe:
-randomly by one or more C 1To C 6The amino that alkyl replaces, wherein C 1To C 6Alkyl is randomly and independently by one or more C 6To C 8Aryl and/or alkoxyl group replace, or
-five yuan or hexa-member heterocycle, it is by one or more C 1To C 6Alkyl or C 6To C 8Aryl replaces,
-NR qCONR qR rBase, wherein R rBe:
-C 1To C 6Alkyl, it is replaced by one or more following groups:
-hydroxyl,
-alkoxyl group,
-five yuan or hexa-member heterocycle,
-five yuan or six membered heteroaryl, or
-C 6To C 8Aryl, it is replaced by halogen,
-C 2To C 6Alkylidene group,
-C 1To C 6Alkoxyl group,
-five yuan or hexa-member heterocycle base,
-NR tCOOR uBase, wherein R uBe:
-C 1To C 12Alkyl, it is independently selected from following group and replaces by one or more:
-the alkoxyl group that replaced by one or more alkoxyl groups,
-randomly by one or more C 1To C 6The amino that alkyl replaces, or
-five yuan or six membered heteroaryl,
-C 2To C 6Alkylidene group, or
Figure A20078000890201331
Z is:
-C 1To C 6Alkyl, it is replaced by five yuan or hexa-member heterocycle, or
-five yuan or hexa-member heterocycle;
R 1Be:
-C 1To C 6Alkyl, it is replaced by following groups:
-randomly by one or more C 1To C 6The acid amides that alkyl replaces, or
-five yuan or six membered heteroaryl;
-C 1To C 6Alkoxyl group, it is replaced by following groups:
-randomly heterocyclically substituted amino,
-randomly by C 1To C 6The acid amides that alkyl replaces,
-five yuan or hexa-member heterocycle, it is by C 1To C 6Alkyl replaces, or
-five yuan or six membered heteroaryl;
-(O)-five yuan or hexa-member heterocycle;
-(O)-five yuan or six membered heteroaryl;
-SO 2R xBase, it is randomly replaced by following groups:
-five yuan or hexa-member heterocycle,
-C 6To C 8Aryl,
-five yuan or six membered heteroaryl; Or
-alkylthio, it is randomly replaced by following groups:
-five yuan or hexa-member heterocycle,
-C 6To C 8Aryl,
-five yuan or six membered heteroaryl; Or
R 2Be:
-C 1To C 6Alkyl, it is replaced by one or more following groups:
-five yuan or hexa-member heterocycle base,
-five yuan or six membered heteroaryl,
-C 6To C 8Aryl,
-acid amides, it is randomly by one or more C 1To C 6Alkyl replaces, or
-amino, it is randomly replaced by one or more heterocycles, alkoxyl group or alkyl, and it is randomly replaced by one or more alkoxyl groups;
-alkylthio, it is randomly replaced by five yuan or six membered heteroaryl, and wherein five yuan or six membered heteroaryl are randomly replaced by alkyl;
-alkylthio, it is randomly by five yuan or hexa-member heterocycle replacement;
-alkylthio, it is randomly by C 6To C 8Aryl replaces;
-alkylthio, it is randomly by C 1To C 6Alkyl replaces;
-SO 2R xBase, it is randomly replaced by five yuan or six membered heteroaryl, and wherein five yuan or six membered heteroaryl are randomly by one or more C 1To C 6Alkyl replaces;
-SO 2R xBase, it is randomly by five yuan or hexa-member heterocycle replacement;
-SO 2R xBase, it is randomly by C 6To C 8Aryl replaces;
-SO 2R xBase, it is randomly by C 1To C 6Alkyl replaces;
-S (O) R xBase, it is randomly by five yuan or six membered heteroaryl replacement;
-S (O) R xBase, it is randomly by five yuan or hexa-member heterocycle replacement;
-S (O) R xBase, it is randomly by C 6To C 8Aryl replaces;
-S (O) R xBase, it is randomly by C 1To C 6Alkyl replaces;
-the alkoxyl group that replaces of alkoxy randomly,
-amino, it is replaced by one or more five yuan or six membered heteroaryl, five yuan or hexa-member heterocycle base or alkyl, and wherein said alkyl randomly and is independently replaced by one or more following groups:
-five yuan or hexa-member heterocycle, or
-the amino that randomly replaced by one or more alkyl;
-randomly by C 1To C 6The amide group that alkyl replaces,
Five yuan of-S-or hexa-member heterocycle,
Five yuan of-S-or six membered heteroaryl, it is randomly by C 1To C 6Alkyl replaces,
-S-C 1To C 6Alkyl,
-S-C 6To C 8Aryl,
-sulfinyl-five yuan or hexa-member heterocycle,
-sulfinyl-five yuan or six membered heteroaryl,
-sulfinyl-C 1To C 6Alkyl,
-sulfinyl-C 6To C 8Aryl,
-alkylsulfonyl-five yuan or hexa-member heterocycle,
-alkylsulfonyl-randomly by C 1To C 6Five yuan or six membered heteroaryl that alkyl replaces,
-alkylsulfonyl-C 1To C 6Alkyl,
-alkylsulfonyl-C 6To C 8Aryl,
-five yuan to seven membered heterocyclic, and it is replaced by one or more hydroxyls of selecting independently or by one or more C that select independently 1To C 6Alkyl replaces, wherein C 1To C 6Alkyl is by C 1To C 6Alkoxyl group replaces, or
-five yuan or six membered heteroaryl, it is by one or more C 1To C 6Alkyl replaces
-C 6To C 8Aryl;
-C (O)-five yuan or hexa-member heterocycle, it is randomly by one or more C 6To C 8Aryl replaces;
-C (O)-C 6To C 8Aryl;
--the COOH base;
-by one or more C 1To C 6The amide group that alkyl replaces, wherein one or more C 1To C 6Alkyl is randomly by one or more C 1To C 6Alkoxyl group replaces;
-five yuan or hexa-member heterocycle, it is replaced by one or more following groups:
-hydroxyl,
-C 1To C 6Alkyl,
-SO 2R xBase,
-C (O)-C 6To C 8Aryl, or
-C (O) OR xBase;
-OR KkBase, wherein R KkBe:
-C 6To C 8Aryl,
-five yuan to hexa-member heterocycle, and it is randomly by C 1To C 6Alkyl replaces, randomly by C 6To C 8Aryl replaces, or
-Si(Rx) 3；
-(O)-five yuan or hexa-member heterocycle; Or
-(O)-five yuan or six membered heteroaryl, it is randomly by one or more C that select independently 1To C 6Alkyl replaces.
The present invention includes formula I compound or the acceptable salt of their pharmacology in another embodiment, condition is Y, Z and R 2In have a following selection at least:
Y is:
-by the amino benzothiazole that replaces, wherein amino is randomly by one or more C 1To C 6Alkyl replaces;
-indyl, it is at the quilt-SO of nitrogen-atoms place 2R xBase replaces;
-C 6To C 8Aryl, it is replaced by one or more following groups:
-amino, it is randomly replaced by one or more following groups:
-SO 2R x, or
-C 1To C 6Alkyl, it is replaced by one or more five yuan or six membered heteroaryl,
-OC(O)NHR x，
-OC(O)N(R x) 2，
-OC(O)NH(OR x)，
-OC(O)NR x(OR x)，
-OC(O)N(OR x) 2，
-OC (O) R Ab, R wherein AbBe five yuan or hexa-member heterocycle,
-NR oCOR pBase, wherein R pBe:
-randomly by one or more C 1To C 6The amino that alkyl replaces, wherein C 1To C 6Alkyl is randomly and independently by one or more C 6To C 8Aryl and/or alkoxyl group replace,
-five yuan or hexa-member heterocycle, it is by one or more C 1To C 6Alkyl or C 6To C 8Aryl replaces,
-NR qCONR qR rBase, wherein R rBe:
-C 1To C 6Alkyl, it is replaced by one or more following groups:
-hydroxyl,
-alkoxyl group,
-five yuan or hexa-member heterocycle,
-five yuan or six membered heteroaryl, or
-C 6To C 8Aryl, it is replaced by halogen,
-C 2To C 6Alkylidene group,
-C 1To C 6Alkoxyl group,
-five yuan or hexa-member heterocycle,
-NR tCOOR uBase, wherein R uBe:
-C 1To C 12Alkyl, it is replaced by one or more groups that are independently selected from down group:
-the alkoxyl group that replaced by one or more alkoxyl groups,
-randomly by one or more C 1To C 6The amino that alkyl replaces, or
-five yuan or six membered heteroaryl,
-C 2To C 6Alkylidene group,
Figure A20078000890201371
Z is:
-C 1To C 6Alkyl, it is replaced by five yuan or hexa-member heterocycle, or
-five yuan or hexa-member heterocycle;
R 2Be:
-C 1To C 6Alkyl, it is replaced by one or more following groups:
-five yuan or hexa-member heterocycle,
-amino, it is randomly replaced by one or more alkoxyl groups or alkyl, and it is randomly replaced by one or more alkoxyl groups,
-alkoxyl group, it is replaced by one or more groups that are independently selected from down group:
-hydroxyl,
-the alkoxyl group that replaces of alkoxy randomly,
-amino, it is by one or more five yuan or hexa-member heterocycle base or alkyl replacements, and wherein said alkyl randomly and is independently replaced by one or more following groups:
-five yuan or hexa-member heterocycle, or
-the amino that randomly replaced by one or more alkyl;
-seven membered heterocyclic;
-five yuan to seven membered heterocyclic, and it is replaced by one or more hydroxyls of selecting independently or by one or more C that select independently 1To C 6Alkyl replaces, wherein C 1To C 6Alkyl is by C 1To C 6Alkoxyl group replaces, or
-five yuan or six membered heteroaryl, it is by one or more C 1To C 6Alkyl replaces;
-C (O)-five yuan or hexa-member heterocycle, it is randomly by one or more C 6To C 8Aryl replaces;
--the COOH base;
-by one or more C 1To C 6The amide group that alkyl replaces;
-five yuan or hexa-member heterocycle, it is randomly replaced by one or more following groups:
-C 1To C 6Alkyl,
-SO 2R xBase,
-C (O)-C 6To C 8Aryl, or
-C (O) OR xBase;
-OR KkBase, wherein R KkBe:
-five yuan to hexa-member heterocycle, and it is randomly by C 1To C 6Alkyl replaces, randomly by C 6To C 8Aryl replaces, or
-Si(Rx) 3。
Just as used herein, term " alkyl " generally means the saturated hydrocarbyl of the combination of straight chain, side chain or cyclic configuration or ring-type and side chain or straight chain, and it comprises methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, n-hexyl, cyclohexyl, n-heptyl, octyl group, n-octyl etc.In some embodiments, alkyl substituent can be C 1To C 12, or C 1To C 8Or C 1To C 6Alkyl.
Just as used herein, " alkylidene group " (alkylene) generally means straight chain, side chain or the ring-type thiazolinyl with one or more carbon-carbon double bonds, for example comprises the C of 3-propenyl 2To C 6Alkylidene group.
Just as used herein, " aryl " means the carbocyclic ring aromatic ring structure.Aromatic ring with 5 to 20 carbon atoms is included in the aryl groups range.Aromatic ring structure comprises the compound with one or more ring structures, for example single-, two-or tricyclic compound.The example of aryl comprises phenyl, tolyl, anthryl, fluorenyl, indenyl, Azulene base, phenanthryl (promptly luxuriant and rich with fragrance) and naphthyl (being naphthalene) ring structure.In some embodiments, described aryl can randomly be substituted.
Just as used herein, " heteroaryl " means the ring-type aromatic ring structure, wherein on the ring one or more heteroatomss except that carbon arranged.Heteroatoms is generally O, S or N atom.O, N and S are assorted, and aromatic ring structure is included in the heteroaryl category, and can select independently.Described ring structure can comprise the compound with one or more ring structures, for example single-, two-or tricyclic compound.In some embodiments, how heteroatomic described heteroaryl is optional from containing two or more heteroatomss, three or more heteroatoms or four or more heteroaryl.The heteroaryl ring structure is optional from containing five or more polyatom, six or more polyatom or eight or more polyatomic ring structure.The example of heteroaryl ring structure comprises: acridine, benzoglyoxaline, benzoxazole, benzodioxole, cumarone, 1,3-diazine, 1,2-diazine, 1,2-diazole, 1,4-naphthyridine, furans, furazan, imidazoles, indoles, isoxazole, isoquinoline 99.9, isothiazole, oxazole, purine, pyridazine, pyrazoles, pyridine, pyrazine, pyrimidine, pyrroles, quinoline, quinoxaline, thiazole, thiophene, 1,3,5-triazine, 1,2,4-triazine, 1,2,3-triazine, tetrazolium and quinazoline.
Just as used herein, " heterocycle " means ring texture, wherein on the ring one or more heteroatomss except that carbon arranged.Heteroatoms is generally O, S or N atom.O, N and S heterocycle structure are included in the heterocycle category, and can select independently.Described ring structure can comprise the compound with one or more ring structures, for example single-, two-or tricyclic compound.The example of heterocyclic radical comprises morpholinyl, pyrrolidone-base, pyrrolidyl, piperidyl, piperazinyl, glycolylurea base, Valerolactim base, Oxyranyle, oxa-cyclobutyl, tetrahydrofuran base, THP trtrahydropyranyl, tetrahydro pyridyl, tetrahydro-pyrimidine base, tetrahydro-thienyl or tetrahydro thiapyran base etc.In some embodiments, described heterocycle can randomly be substituted.
Just as used herein, " alkoxyl group " generally means to have-group of O-R structure, and wherein R is according to alkyl defined above.
For the present invention, halogenic substituent can be independently selected from halogen, for example fluorine, chlorine, bromine, iodine and astatine.The above defined alkyl that alkylhalide group is replaced by one or more halogens.The above defined alkoxyl group that the halogen alkoxyl group is replaced by one or more halogens.
For the present invention, wherein contain X, Y, Z, R, R 1, R 2And R 3One or more functional groups be incorporated in the compound of the present invention, appearing on the disclosed compound each functional group in any site can select independently, also can be substituted independently when suitable.And when having listed the more upper substituting group that is positioned on the molecule of the present invention optional position, being interpreted as the described bit substituent of going up can be replaced by substituting group more specifically, and formed molecule is still in the scope of molecule of the present invention.
Unless mean and specifically mention certain chemical group, then described specified substituent can be well known to a person skilled in the art that being suitable for mentioned substituent chemical group replaces so-called " being substituted " or " randomly being substituted ".
In another embodiment, the present invention includes formula (I-X) compound
Or the acceptable salt of their pharmacology,
Wherein:
X is:
-cyano group;
Y is:
-hydrogen;
-alkylhalide group;
-halogen;
-randomly by one or more C 1To C 6The amino that alkyl replaces;
-cumarone;
-thionaphthene;
-diphenylene-oxide;
-dibenzothiophene;
-the benzothiazole that randomly replaced by amino, wherein amino is randomly by one or more C 1To C 6Alkyl replaces;
-naphthalene;
-indoles, it is randomly by C 1To C 6Alkyl or-SO 2R xBase replaces at N atom place;
Figure A20078000890201402
R wherein bBe hydrogen or C 1To C 6Alkyl, and n is 0 or 1;
Figure A20078000890201412
R wherein cBe hydrogen ,-CONHR x, R wherein xBe C 1To C 6Alkyl or-SO 2R x, R wherein xBe C 1To C 6Alkyl; Or
Figure A20078000890201413
R wherein dBe C 1To C 6Alkyl or C 6To C 8Aryl;
--NHCOR eBase, wherein R eBe:
-C 1To C 6Alkyl;
-C 6To C 8Aryl, it is randomly replaced by following groups:
-C 1To C 6Alkyl,
-alkoxyl group,
-cyano group,
-nitro, or
-halogen;
--NHCOOR xBase, wherein R xBe C 1To C 6Alkyl;
-CH 2O-R fBase, wherein R fBe C 6To C 8Aryl;
-NR gR hBase, wherein R gBe C 1To C 6Alkyl or hydrogen, R hBe the C that replaces of alkoxy randomly 6To C 8Aryl;
-C 1To C 6Alkyl;
-five yuan or six membered heteroaryl, it is randomly replaced by following groups:
-C 1To C 6Alkyl, it is randomly by C 6To C 8Aryl replaces,
-C 6To C 8Aryl, it is randomly by-COOR xReplace, wherein R xBe C 1To C 6Alkyl, or
-amino;
-five yuan or hexa-member heterocycle, it is randomly replaced by following groups:
-COOR xBase, wherein R xDefinition the same, or
-NHCOOR xBase, wherein R xDefinition the same;
-C 6To C 8Aryl, it is randomly replaced by one or more following groups:
-the alkoxyl group that randomly replaced by following groups:
-alkoxyl group,
-hydroxyl,
-one or more halogens,
-five yuan or hexa-member heterocycle, it is randomly replaced by following groups:
-C 1To C 6Alkyl, or
-hydroxyl,
-randomly by one or more C 1To C 6The amino that alkyl replaces,
--NR iSO 2R xBase, wherein R xBe C 1To C 6Alkyl, R iBe
-hydrogen,
-C 1To C 6Alkyl,
-COR xBase, wherein R xDefinition the same,
-alkylhalide group, or
-halogen alkoxyl group,
-NR jCOR kBase, wherein R kBe:
-C 1To C 6Alkyl,
-hydrogen, or
-randomly by one or more C 1To C 6The amino that alkyl replaces,
And R jBe:
-hydrogen,
-C 1To C 6Alkyl,
-COR xBase, wherein R xBe C 1To C 6Alkyl,
-alkylhalide group, or
-halogen alkoxyl group,
-N=N +=N -, or
-COR 1, R wherein 1Be five yuan or the hexa-member heterocycle that is randomly replaced by hydroxyl,
-the amino that randomly replaced by one or more following groups:
-SO 2(R x), or
-C 1To C 6Alkyl, described C 1To C 6Alkyl is replaced by one or more five yuan or six membered heteroaryl randomly and independently,
-nitro,
-C 1To C 6Alkyl, it is randomly replaced by following groups:
-NHSO 2R xBase, wherein R xDefinition the same, or
-NR xSO 2R xBase, wherein R xDefinition the same,
-halogen alkoxyl group,
-halogen,
-hydroxyl,
-OC(O)NHR x，
-OC(O)N(R x) 2，
-OC(O)NH(OR x)，
-OC(O)NR x(OR x)，
-OC(O)N(OR x) 2，
-OC (O) R Ab, R wherein AbBe five yuan or hexa-member heterocycle,
-COOR xBase, wherein R xBe C 1To C 6Alkyl,
-COR mBase, wherein R mBe:
-randomly by one or more C 1To C 6The amino that alkyl replaces, wherein C 1To C 6Alkyl is randomly replaced by following groups:
-hydroxyl,
-five yuan or hexa-member heterocycle,
-randomly by one or more C 1To C 6The amino that alkyl replaces, or
-alkoxyl group,
-ternary is to seven membered heterocyclic, and it is randomly by C 1To C 6Alkyl replaces, randomly replaced by dialkyl-7-amino, or
-NHR nBase, wherein R nBe:
-CH 2CONH 2, or
-C 6To C 8Aryl, it is randomly replaced by following groups:
-alkyl,
-one or more halogens,
-nitro, or
-one or more alkoxyl groups,
-NR oCOR pBase, wherein R pBe:
-C 1To C 6Alkyl, it is randomly replaced by following groups:
-halogen,
-alkoxyl group, or
-C 6To C 8Aryl,
-randomly by one or more C 1To C 6The amino that alkyl replaces, wherein C 1To C 6Alkyl is randomly and independently by one or more C 6To C 8Aryl and/or alkoxyl group replace,
-five yuan or hexa-member heterocycle, it is randomly by one or more C 1To C 6Alkyl or C 6To C 8Aryl replaces,
-C 6To C 8Aryl, it is randomly replaced by halogen,
-five yuan or six membered heteroaryl, it is randomly by one or more C 1To C 6Alkyl replaces,
-hydrogen,
Figure A20078000890201441
And R wherein oBe:
-hydrogen,
-C 1To C 6Alkyl,
-COR xBase, wherein R xBe C 1To C 6Alkyl,
-alkylhalide group, or
-halogen alkoxyl group,
-NR qCONR qR rBase, wherein R qBe:
-hydrogen,
-C 1To C 6Alkyl,
-alkylhalide group,
-halogen alkoxyl group, or
-COR xBase, wherein R xDefinition the same,
And R wherein rBe:
-C 6To C 8Aryl, it is randomly replaced by following groups:
Figure A20078000890201451
-C 1To C 6Alkyl,
-alkylhalide group,
-OR sBase, wherein R sBe C 6To C 8Aryl, or
-COOR xBase, wherein R xDefinition the same,
-C 1To C 6Alkyl, it is randomly replaced by one or more following groups:
-halogen,
-hydroxyl,
-alkoxyl group,
-alkylidene group,
-five yuan or hexa-member heterocycle,
-five yuan or six membered heteroaryl,
-C 6To C 8Aryl, it is randomly replaced by halogen, or
-COOR xBase, wherein R xDefinition the same,
-C 2To C 6Alkylidene group,
-C 1To C 6Alkoxyl group,
-five yuan or hexa-member heterocycle, or
-COOR xBase, wherein R xDefinition the same,
-NR tCOOR uBase, wherein R uBe:
-C 1To C 12Alkyl, it is randomly replaced by one or more groups that are independently selected from down group,
-C 6To C 8Aryl, it is randomly by halogen, C 1To C 6Alkyl or alkoxyl group replace,
-alkylidene group,
-alkoxyl group,
-alkynes,
-the alkoxyl group that randomly replaced by one or more alkoxyl groups,
-randomly by one or more C 1To C 6The amino that alkyl replaces,
-halogen,
-five yuan or hexa-member heterocycle, or
-five yuan or six membered heteroaryl,
-C 2To C 6Alkylidene group,
-C 6To C 8Aryl, it is randomly replaced by following groups:
-alkoxyl group,
-halogen, or
-C 1To C 6Alkyl, or
-five yuan or hexa-member heterocycle,
And R tBe:
-hydrogen,
-C 1To C 6Alkyl,
-COR xBase, wherein R xDefinition the same,
-alkylhalide group, or
-halogen alkoxyl group,
-NR vSO 2R wBase, wherein R vBe:
-hydrogen,
-COR xBase, wherein R xDefinition the same, or
-C 1To C 6Alkyl, it is randomly replaced by following groups:
-halogen,
-COR xBase, wherein R xDefinition the same,
-OCOR xBase, wherein R xDefinition the same,
-hydroxyl, or
-alkoxyl group,
And R wherein wBe:
-C 1To C 6Alkyl, it is randomly replaced by following groups:
-halogen,
-alkylhalide group,
-C 6To C 8Aryl, or
-five yuan or hexa-member heterocycle,
-C 2To C 6Alkylidene group,
-alkyl-amino or dialkyl-7-amino, it is randomly replaced by halogen,
-five yuan or hexa-member heterocycle, or
-five yuan or six membered heteroaryl, it is randomly replaced by following groups:
-C 1To C 6Alkyl,
-five yuan or hexa-member heterocycle, or
Figure A20078000890201481
It is randomly by C 1To C 6Alkyl replaces, wherein R yBe C 1To C 6Alkyl or hydrogen,
Figure A20078000890201483
R wherein zBe hydrogen or C 1To C 6Alkyl, it is randomly by C 6To C 8Aryl replaces ,-SR xBase, wherein R xDefinition the same,
-SO 2R AaBase, wherein R AaBe:
-C 1To C 6Alkyl,
-amino,
-alkyl-amino or dialkyl-7-amino, its randomly replaced by hydroxyl or-COOR xBase, wherein R xDefinition the same, or
-five yuan or six membered heteroaryl,
-C 6To C 8Aryl, or
-NHR BbBase, wherein R BbBe:
-C (=S) NH 2Base, or
-PO (OR x) 2, R wherein xDefinition the same; Or
Figure A20078000890201491
Base, wherein R CcBe:
-naphthalene,
-five yuan or six membered heteroaryl,
Figure A20078000890201492
-C 6To C 8Aryl, it is randomly replaced by one or more following groups:
-alkoxyl group,
-hydroxyl,
-halogen,
-C 1To C 6Alkyl, its optional by cyano replaces,
-randomly by one or more C 1To C 6The amino that alkyl replaces,
-NHPOR xR xBase, wherein R xDefinition the same,
-NR EeCONR FfR FfBase, wherein R EeBe hydrogen or the C that randomly replaced by halogen 1To C 6Alkyl, and R FfBe:
-hydrogen,
-alkylhalide group,
-halogen alkoxyl group,
-C 1To C 6Alkyl, or
-COR x, R wherein xDefinition the same,
-NR GgCOR HhBase, wherein R HhBe:
-hydrogen,
-C 1To C 6Alkyl, it is randomly replaced by following groups:
-alkoxyl group,
-halogen, or
-randomly by one or more C 1To C 6The amino that alkyl replaces,
-randomly by one or more C 1To C 6The amino that alkyl replaces, wherein said alkyl is randomly replaced by halogen,
-five yuan or hexa-member heterocycle, or
-five yuan or six membered heteroaryl,
And R GgBe:
-hydrogen,
-C 1To C 6Alkyl,
-alkylhalide group,
-halogen alkoxyl group, or
-COR xBase, wherein R xDefinition the same,
-alkylhalide group,
-five yuan or hexa-member heterocycle,
-randomly by one or more C 1To C 6The amino that alkyl replaces, or
-NR IiSO 2R xBase, wherein R xDefinition the same, and R IiBe
-hydrogen,
-C 1To C 6Alkyl,
-alkylhalide group,
-halogen alkoxyl group, or
-COR xBase, wherein R xDefinition the same;
Z is:
-hydrogen;
-C 1To C 6Alkyl, it is randomly replaced by following groups:
-alkoxyl group,
-one or more halogens,
-five yuan or hexa-member heterocycle, or
-C 6To C 8Aryl;
-five yuan or hexa-member heterocycle;
-C 2To C 6Alkylidene group;
-C 6To C 8Aryl, it is alkoxy or one or more C randomly 1To C 6Alkyl replaces;
-COOR xBase, wherein R xDefinition the same; Or
Figure A20078000890201511
R is hydrogen, halogen or alkoxyl group;
R 1Be:
-hydrogen;
-hydroxyl;
-halogen;
-alkylhalide group;
-nitro;
-five yuan or six membered heteroaryl;
-five yuan or hexa-member heterocycle;
-the alkoxyl group that randomly replaced by following groups:
-one or more halogens,
-C 6To C 8Aryl,
-five yuan or hexa-member heterocycle, or
-randomly heterocyclically substituted amino;
-C 6To C 8Aryl, its randomly alkoxy replacement,
-COR xBase, wherein R xDefinition the same; Or
-C 1To C 6Alkyl, it is randomly by dialkyl-7-amino or five yuan or hexa-member heterocycle replacement; Or
R 1With R 2Combine formation:
Figure A20078000890201512
R 2Be:
-nitro;
-hydrogen;
-halogen;
-hydroxyl;
-C 1To C 6Alkyl, it is randomly replaced by one or more following groups:
-halogen,
-five yuan or hexa-member heterocycle, or
-amino, it is randomly replaced by one or more alkoxyl groups or alkyl, and it is randomly replaced by one or more alkoxyl groups,
-amino;
-alkoxyl group, it is randomly replaced by one or more groups that are independently selected from down group:
-halogen,
-hydroxyl,
-the alkoxyl group that replaces of alkoxy randomly,
-OCOR xBase, wherein R xDefinition the same, or
-amino, randomly by one or more five yuan or hexa-member heterocycle base or alkyl replacements, wherein said alkyl randomly and is independently replaced by one or more following groups for it:
-five yuan or hexa-member heterocycle, or
-the amino that randomly replaced by one or more alkyl;
-the dialkyl-7-amino that replaces of alkoxy randomly,
-five yuan to seven membered heterocyclic, and it is randomly by one or more hydroxyl or C that select independently 1To C 6Alkyl replaces, wherein said C 1To C 6Alkyl is randomly by one or more C that select independently 1To C 6Alkoxyl group replaces,
-five yuan or six membered heteroaryl, it is randomly by one or more C 1To C 6Alkyl replaces, or
-C 6To C 8Aryl;
-C (O)-five yuan or hexa-member heterocycle, it is randomly by one or more C 6To C 8Aryl replaces;
--the COOH base;
-COOR xBase, wherein R xDefinition the same;
-alkylhalide group;
-the amide group that randomly replaced by one or more following groups:
-C 1To C 6Alkyl,
-hydroxyl, or
-C 6To C 8Aryl;
-five yuan or hexa-member heterocycle, it is randomly replaced by one or more following groups:
-C 1To C 6Alkyl,
-SO 2R x，
-C (O)-C 6To C 8Aryl, or
-C (O) OR xBase;
-five yuan or six membered heteroaryl;
-OCOR xBase, wherein R xDefinition the same;
-NHCOR JjBase, wherein R JjBe:
-alkoxyl group, or
-randomly by one or more C 1To C 6The amino that alkyl replaces;
-OR KkBase, wherein R KkBe:
-five yuan to six membered heteroaryl,
-five yuan to hexa-member heterocycle, and it is randomly by C 1To C 6Alkyl replaces, randomly by C 6To C 8Aryl replaces, or
-Si (Rx) 3Or
-NHSO 2R xBase, wherein R xDefinition the same; Or
R 2With R 1Combine formation:
Figure A20078000890201531
R 3Be:
-hydrogen; Or
-CH 2OCOR x, R wherein xDefinition the same.
In another embodiment, the present invention includes formula (I-Xa) compound
Figure A20078000890201541
Or the acceptable salt of their pharmacology,
Wherein
X is:
-cyano group;
Y is:
-hydrogen;
-alkylhalide group;
-halogen;
-randomly by one or more C 1To C 6The amino that alkyl replaces;
-cumarone;
-thionaphthene;
-diphenylene-oxide;
-dibenzothiophene;
-the benzothiazole that randomly replaced by amino, wherein amino is randomly by one or more C 1To C 6Alkyl replaces;
-naphthalene;
-indoles, it is randomly by C 1To C 6Alkyl or-SO 2R xBase replaces at N atom place;
Figure A20078000890201542
Figure A20078000890201551
R wherein bBe hydrogen or C 1To C 6Alkyl, and n is 0 or 1;
Figure A20078000890201552
R wherein cBe hydrogen ,-CONHR x, R wherein xBe C 1To C 6Alkyl, or-SO 2R x, R wherein xBe C 1To C 6Alkyl; Or
R wherein dBe C 1To C 6Alkyl or C 6To C 8Aryl;
--NHCOR eBase, wherein R eBe:
-C 1To C 6Alkyl;
-C 6To C 8Aryl, it is randomly replaced by following groups:
-C 1To C 6Alkyl,
-alkoxyl group,
-cyano group,
-nitro, or
-halogen;
--NHCOOR xBase, wherein R xBe C 1To C 6Alkyl;
-CH 2O-R fBase, wherein R fBe C 6To C 8Aryl;
-NR gR hBase, wherein R gBe C 1To C 6Alkyl or hydrogen, R hBe the C that replaces of alkoxy randomly 6To C 8Aryl;
-C 1To C 6Alkyl;
-five yuan or six membered heteroaryl, it is randomly replaced by following groups:
-C 1To C 6Alkyl, it is randomly by C 6To C 8Aryl replaces,
-C 6To C 8Aryl, it is randomly by-COOR xReplace, wherein R xBe C 1To C 6Alkyl, or
-amino;
-five yuan or hexa-member heterocycle, it is randomly replaced by following groups:
-COOR xBase, wherein R xDefinition the same, or
-NHCOOR xBase, wherein R xDefinition the same;
-C 6To C 8Aryl, it is randomly replaced by one or more following groups:
-the alkoxyl group that randomly replaced by following groups:
-alkoxyl group,
-hydroxyl,
-one or more halogens,
-five yuan or hexa-member heterocycle, it is randomly replaced by following groups:
-C 1To C 6Alkyl, or
-hydroxyl,
-randomly by one or more C 1To C 6The amino that alkyl replaces,
--NR iSO 2R xBase, wherein R xBe C 1To C 6Alkyl, R iBe
-hydrogen,
-C 1To C 6Alkyl,
-COR xBase, wherein R xDefinition the same,
-alkylhalide group, or
-halogen alkoxyl group,
-NR jCOR kBase, wherein R kBe:
-C 1To C 6Alkyl,
-hydrogen, or
-randomly by one or more C 1To C 6The amino that alkyl replaces,
And R jBe:
-hydrogen,
-C 1To C 6Alkyl,
-COR xBase, wherein R xBe C 1To C 6Alkyl,
-alkylhalide group, or
-halogen alkoxyl group,
-N=N +=N -Base, or
-COR l, R wherein lBe five yuan or the hexa-member heterocycle that is randomly replaced by hydroxyl,
-the amino that randomly replaced by one or more following groups:
-SO 2(R x), or
-C 1To C 6Alkyl, described C 1To C 6Alkyl is replaced by one or more five yuan or six membered heteroaryl randomly and independently,
-nitro,
-C 1To C 6Alkyl, it is randomly replaced by following groups:
-NHSO 2R xBase, wherein R xDefinition the same, or
-NR xSO 2R xBase, wherein R xDefinition the same,
-halogen alkoxyl group,
-halogen,
-hydroxyl,
-OC(O)NHR x，
-OC(O)N(R x) 2，
-OC(O)NH(OR x)，
-OC(O)NR x(OR x)，
-OC(O)N(OR x) 2，
-OC (O) R Ab, R wherein AbBe five yuan or hexa-member heterocycle base,
-COOR xBase, wherein R xBe C 1To C 6Alkyl,
-COR mBase, wherein R mBe:
-randomly by one or more C 1To C 6The amino that alkyl replaces, wherein C 1To C 6Alkyl is randomly replaced by following groups:
-hydroxyl,
-five yuan or hexa-member heterocycle,
-randomly by one or more C 1To C 6The amino that alkyl replaces, or
-alkoxyl group,
-ternary is to seven membered heterocyclic, and it is randomly by C 1To C 6Alkyl replaces, randomly replaced by dialkyl-7-amino,
-NHR nBase, wherein R nBe:
-CH 2CONH 2, or
-C 6To C 8Aryl, it is randomly replaced by following groups:
-alkyl,
-one or more halogens,
-nitro, or
-one or more alkoxyl groups,
-NR oCOR pBase, wherein R pBe:
-C 1To C 6Alkyl, it is randomly replaced by following groups:
-halogen,
-alkoxyl group, or
-C 6To C 8Aryl,
-randomly by one or more C 1To C 6The amino that alkyl replaces, wherein C 1To C 6Alkyl is randomly and independently by one or more C 6To C 8Aryl and/or alkoxyl group replace,
-five yuan or hexa-member heterocycle, it is randomly by one or more C 1To C 6Alkyl or C 6To C 8Aryl replaces,
-C 6To C 8Aryl, it is randomly replaced by halogen,
-five yuan or six membered heteroaryl, it is randomly by one or more C 1To C 6Alkyl replaces,
-hydrogen,
Figure A20078000890201581
And R wherein oBe:
-hydrogen,
-C 1To C 6Alkyl,
-COR xBase, wherein R xBe C 1To C 6Alkyl,
-alkylhalide group, or
-halogen alkoxyl group,
-NR qCONR qR rBase, wherein R qBe:
-hydrogen,
-C 1To C 6Alkyl,
-alkylhalide group,
-halogen alkoxyl group, or
-COR xBase, wherein R xDefinition the same,
And R wherein rBe:
-C 6To C 8Aryl, it is randomly replaced by following groups:
Figure A20078000890201591
-C 1To C 6Alkyl,
-alkylhalide group,
-OR sBase, wherein R sBe C 6To C 8Aryl, or
-COOR xBase, wherein R xDefinition the same,
-C 1To C 6Alkyl, it is randomly replaced by one or more following groups:
-halogen,
-hydroxyl,
-alkoxyl group,
-alkylidene group,
-five yuan or hexa-member heterocycle,
-five yuan or six membered heteroaryl,
-C 6To C 8Aryl, it is randomly replaced by halogen, or
-COOR xBase, wherein R xDefinition the same,
-C 2To C 6Alkylidene group,
-C 1To C 6Alkoxyl group,
-five yuan or hexa-member heterocycle,
-COOR xBase, wherein R xDefinition the same,
-NR tCOOR uBase, wherein R uBe:
-C 1To C 12Alkyl, it is randomly replaced by one or more following groups:
-C 6To C 8Aryl, it is randomly by halogen, C 1To C 6Alkyl or alkoxyl group replace,
-alkylidene group,
-alkoxyl group,
-alkynes,
-the alkoxyl group that randomly replaced by one or more alkoxyl groups,
-randomly by one or more C 1To C 6The amino that alkyl replaces,
-halogen,
-five yuan or hexa-member heterocycle, or
-five yuan or six membered heteroaryl,
-C 2To C 6Alkylidene group,
-C 6To C 8Aryl, it is randomly replaced by following groups:
-alkoxyl group,
-halogen, or
-C 1To C 6Alkyl, or
-five yuan or hexa-member heterocycle,
And R tBe:
-hydrogen,
-C 1To C 6Alkyl,
-COR xBase, wherein R xDefinition the same,
-alkylhalide group, or
-halogen alkoxyl group,
-NR vSO 2R wBase, wherein R vBe:
-hydrogen,
-COR xBase, wherein R xDefinition the same, or
-C 1To C 6Alkyl, it is randomly replaced by following groups:
-halogen,
-COR xBase, wherein R xDefinition the same,
-OCOR xBase, wherein R xDefinition the same,
-hydroxyl, or
-alkoxyl group,
And R wherein wBe:
-C 1To C 6Alkyl, it is randomly replaced by following groups:
-halogen,
-alkylhalide group,
-C 6To C 8Aryl, or
-five yuan or hexa-member heterocycle,
-C 2To C 6Alkylidene group,
-alkyl-amino or dialkyl-7-amino, it is randomly replaced by halogen,
-five yuan or hexa-member heterocycle, or
-five yuan or six membered heteroaryl, it is randomly replaced by following groups:
-C 1To C 6Alkyl,
-five yuan or hexa-member heterocycle, or
Figure A20078000890201611
Figure A20078000890201621
It is randomly by C 1To C 6Alkyl replaces, wherein R yBe C 1To C 6Alkyl or hydrogen,
Figure A20078000890201622
R wherein zBe hydrogen or C 1To C 6Alkyl, it is randomly by C 6To C 8Aryl replaces ,-SR xBase, wherein R xDefinition the same,
-SO 2R AaBase, wherein R AaBe:
-C 1To C 6Alkyl,
-amino,
-alkyl-amino or dialkyl-7-amino, it is randomly replaced by hydroxyl
Or-COOR xBase, wherein R xDefinition the same, or
-five yuan or six membered heteroaryl,
-C 6To C 8Aryl, or
-NHR BbBase, wherein R BbBe:
-C (=S) NH 2Base, or
-PO (OR x) 2, R wherein xDefinition the same; Or
Base, wherein R CcBe:
-naphthalene,
-five yuan or six membered heteroaryl,
Figure A20078000890201633
-C 6To C 8Aryl, it is randomly replaced by one or more following groups:
-alkoxyl group,
-hydroxyl,
-halogen,
-C 1To C 6Alkyl, its optional by cyano replaces,
-randomly by one or more C 1To C 6The amino that alkyl replaces,
-NHPOR xR xBase, wherein R xDefinition the same,
-NR EeCONR FfR FfBase, wherein R EeBe hydrogen or the C that randomly replaced by halogen 1To C 6Alkyl, and
R FfBe:
-hydrogen,
-alkylhalide group,
-halogen alkoxyl group,
-C 1To C 6Alkyl, or
-COR x, R wherein xDefinition the same,
-NR GgCOR HhBase, wherein R HhBe:
-hydrogen,
-C 1To C 6Alkyl, it is randomly replaced by following groups:
-alkoxyl group,
-halogen, or
-randomly by one or more C 1To C 6The amino that alkyl replaces,
-randomly by one or more C 1To C 6The amino that alkyl replaces, wherein said alkyl is randomly replaced by halogen,
-five yuan or hexa-member heterocycle, or
-five yuan or six membered heteroaryl,
And R GgBe:
-hydrogen,
-C 1To C 6Alkyl,
-alkylhalide group,
-halogen alkoxyl group, or
-COR xBase, wherein R xDefinition the same,
-alkylhalide group,
-five yuan or hexa-member heterocycle,
-randomly by one or more C 1To C 6The amino that alkyl replaces, or
-NR IiSO 2R xBase, wherein R xDefinition the same, and R IiBe
-hydrogen,
-C 1To C 6Alkyl,
-alkylhalide group,
-halogen alkoxyl group, or
-COR xBase, wherein R xDefinition the same;
Z is:
-hydrogen;
-C 1To C 6Alkyl, it is randomly replaced by following groups:
-alkoxyl group,
-one or more halogens,
-five yuan or hexa-member heterocycle, or
-C 6To C 8Aryl;
-five yuan or hexa-member heterocycle;
-C 2To C 6Alkylidene group;
-C 6To C 8Aryl, it is alkoxy or one or more C randomly 1To C 6Alkyl replaces;
-COOR xBase, wherein R xDefinition the same; Or
R is hydrogen, halogen or alkoxyl group;
R 1Be:
-hydrogen;
-hydroxyl;
-halogen;
-alkylhalide group;
-nitro;
-five yuan or six membered heteroaryl;
-five yuan or hexa-member heterocycle;
-the alkoxyl group that randomly replaced by following groups:
-one or more halogens,
-C 6To C 8Aryl,
-five yuan or hexa-member heterocycle, or
-amino, it is randomly by five yuan or hexa-member heterocycle replacement;
-C 6To C 8Aryl, its randomly alkoxy replacement,
-COR xBase, wherein R xDefinition the same; Or
-C 1To C 6Alkyl, it is randomly by dialkyl-7-amino or five yuan or hexa-member heterocycle replacement; Or
R 1With R 2Combine formation:
R 2Be:
-nitro;
-hydrogen;
-halogen;
-hydroxyl;
-C 1To C 6Alkyl, it is randomly replaced by one or more following groups:
-halogen,
-five yuan or hexa-member heterocycle, or
-amino, it is randomly replaced by one or more alkoxyl groups or alkyl, and it is randomly replaced by one or more alkoxyl groups,
-amino;
-alkoxyl group, it is randomly replaced by one or more following groups:
-halogen,
-hydroxyl,
-the alkoxyl group that replaces of alkoxy randomly,
-OCOR xBase, wherein R xDefinition the same,
-amino, randomly by one or more five yuan or hexa-member heterocycle base or alkyl replacements, wherein said alkyl randomly and is independently replaced by one or more following groups for it:
-five yuan or hexa-member heterocycle, or
-the amino that randomly replaced by one or more alkyl;
-the dialkyl-7-amino that replaces of alkoxy randomly,
-five yuan to seven membered heterocyclic, and it is randomly by one or more hydroxyl or C that select independently 1To C 6Alkyl replaces, wherein said C 1To C 6Alkyl is randomly by one or more C that select independently 1To C 6Alkoxyl group replaces,
-five yuan or six membered heteroaryl, it is randomly by one or more C 1To C 6Alkyl replaces, or
-C 6To C 8Aryl;
-C (O)-five yuan or hexa-member heterocycle, it is randomly by one or more C 6To C 8Aryl replaces;
--the COOH base;
-COOR xBase, wherein R xDefinition the same;
-alkylhalide group;
-the amide group that randomly replaced by one or more following groups:
-C 1To C 6Alkyl,
-hydroxyl, or
-C 6To C 8Aryl;
-five yuan or hexa-member heterocycle, it is randomly replaced by one or more following groups:
-C 1To C 6Alkyl,
-SO 2R xBase,
-C (O)-C 6To C 8Aryl, or
-C (O) OR xBase;
-five yuan or six membered heteroaryl;
-OCOR xBase, wherein R xDefinition the same;
-NHCOR JjBase, wherein R JjBe:
-alkoxyl group, or
-randomly by one or more C 1To C 6The amino that alkyl replaces;
-OR KkBase, wherein R KkBe:
-five yuan to six membered heteroaryl,
-five yuan to hexa-member heterocycle, and it is randomly by C 1To C 6Alkyl replaces, randomly by C 6To C 8Aryl replaces, or
-Si(Rx) 3；
-NHSO 2R xBase, wherein R xDefinition the same; Or
R 2With R 1Combine formation:
Figure A20078000890201671
R 3Be:
-hydrogen; Or
-CH 2OCOR x, R wherein xDefinition the same;
Condition is Y, Z, R 1And R 2In have a following selection at least:
Y is:
-by the amino benzothiazole that replaces, wherein amino is randomly by one or more C 1To C 6Alkyl replaces;
-indoles, it is at the quilt-SO of nitrogen-atoms place 2R xBase replaces;
-the C that replaced by one or more following groups 6To C 8Aryl:
-the amino that randomly replaced by one or more following groups:
-SO 2R x, or
-C 1To C 6Alkyl, it is replaced by one or more five yuan or six membered heteroaryl,
-OC(O)NHR x，
-OC(O)N(R x) 2，
-OC(O)NH(OR x)，
-OC(O)NR x(OR x)，
-OC(O)N(OR x) 2，
-OC (O) R Ab, R wherein AbBe five yuan or hexa-member heterocycle,
-NR oCOR pBase, wherein R pBe:
-randomly by one or more C 1To C 6The amino that alkyl replaces, wherein C 1To C 6Alkyl is randomly and independently by one or more C 6To C 8Aryl and/or alkoxyl group replace, or
-five yuan or hexa-member heterocycle, it is by one or more C 1To C 6Alkyl or C 6To C 8Aryl replaces,
-NR qCONR qR rBase, wherein R rBe:
-C 1To C 6Alkyl, it is replaced by one or more following groups:
-hydroxyl,
-alkoxyl group,
-five yuan or hexa-member heterocycle,
-five yuan or six membered heteroaryl, or
-C 6To C 8Aryl, it is randomly replaced by halogen,
-C 2To C 6Alkylidene group,
-C 1To C 6Alkoxyl group, or
-five yuan or hexa-member heterocycle,
-NR tCOOR uBase, wherein R uBe:
-C 1To C 12Alkyl, it is replaced by one or more following groups:
-the alkoxyl group that replaced by one or more alkoxyl groups,
-randomly by one or more C 1To C 6The amino that alkyl replaces, or
-five yuan or six membered heteroaryl,
-C 2To C 6Alkylidene group, or
Figure A20078000890201691
Z is:
-C 1To C 6Alkyl, it is replaced by five yuan or hexa-member heterocycle, or
-five yuan or hexa-member heterocycle; Or
R 1By the alkoxyl group that amino replaces, wherein said amino is randomly by heterocyclic substituted;
R 2Be:
-C 1To C 6Alkyl, it is replaced by one or more following groups:
-five yuan or hexa-member heterocycle, or
-amino, it is randomly replaced by one or more alkoxyl groups or alkyl, and it is randomly replaced by one or more alkoxyl groups,
-alkoxyl group, it is replaced by one or more groups that are independently selected from down group:
-hydroxyl,
-the alkoxyl group that replaces of alkoxy randomly,
-amino, it is by one or more five yuan or hexa-member heterocycle base or alkyl replacements, and wherein said alkyl randomly and is independently replaced by one or more following groups:
-five yuan or hexa-member heterocycle, or
-the amino that randomly replaced by one or more alkyl;
-seven membered heterocyclic;
-five yuan to seven membered heterocyclic, and it is replaced by one or more hydroxyls of selecting independently or by one or more C that select independently 1To C 6Alkyl replaces, wherein C 1To C 6Alkyl is by C 1To C 6Alkoxyl group replaces, or
-five yuan or six membered heteroaryl, it is by one or more C 1To C 6Alkyl replaces;
-C (O)-five yuan or hexa-member heterocycle, it is randomly by one or more C 6To C 8Aryl replaces;
--the COOH base;
-by one or more C 1To C 6The amide group that alkyl replaces;
-five yuan or hexa-member heterocycle, it is randomly replaced by one or more following groups:
-C 1To C 6Alkyl,
-SO 2R x，
-C (O)-C 6To C 8Aryl, or
-C(O)OR x；
-OR KkBase, wherein R KkBe:
-five yuan to hexa-member heterocycle, and it is randomly by C 1To C 6Alkyl replaces, randomly by C 6To C 8Aryl replaces, or
-Si(Rx) 3。
In some embodiments, R is selected from the R substituting group of compound 1330-2128 and 2600-3348.
Compound is provided in some embodiments of the present invention, and wherein R is selected from following non-limiting substituting group:
Figure A20078000890201701
In other embodiments of the present invention, R is a hydrogen.
In some embodiments of the present invention, R 1Be selected from following non-limiting substituting group:
Figure A20078000890201702
In some embodiments of the present invention, R 2Be selected from following non-limiting substituting group:
Figure A20078000890201712
Figure A20078000890201721
In some embodiments, R 3Be selected from the R of compound 1330-2128 and 2600-3348 3Substituting group.
In some embodiments of the present invention, provide compound, wherein R 3Be selected from following non-limiting substituting group:
Figure A20078000890201732
In other embodiments of the present invention, provide compound, wherein R 3Be hydrogen.
In another embodiment, the present invention includes formula (I-XI) compound
Figure A20078000890201733
Or the acceptable salt of their pharmacology,
Wherein:
X is:
-hydrogen;
-cyano group;
-nitro;
-formyl radical;
--the COOH base;
-COR xBase, wherein R xBe C 1To C 6Alkyl;
Figure A20078000890201741
To C 6Alkoxyl group,
Randomly by one or more C 1To C 6The amino that alkyl replaces;
-halogen;
-the alkyl that randomly replaced by one or more halogens;
-randomly by C 1To C 6The alkynes that alkyl replaces, wherein C 1To C 6Alkyl is randomly replaced by one or more halogens of selecting independently or cyano group;
-oxime;
-SO 2R x；
-SO 2NH 2；
-SO 2NH(R x)；
-SO 2N(Rx) 2；
-randomly by one or more C 1To C 6Alkyl or C (O)-C 1To C 6The amino that alkyl replaces;
-randomly by one or more C that select independently 1To C 6The amide group that alkyl replaces;
-five yuan or hexa-member heterocycle;
-five yuan or six membered heteroaryl, it is randomly by one or more C 1To C 6Alkyl replaces, and described alkyl is randomly replaced by one or more halogens; Or
-C 6To C 8Aryl, it is randomly replaced by one or more following groups:
-C 1To C 6Alkyl, it is randomly replaced by one or more halogens;
-halogen, or
-cyano group;
Y is:
-the benzothiazole that randomly replaced by amino, wherein amino is randomly by one or more C 1To C 6Alkyl replaces;
-indoles, it is randomly at the quilt-SO of nitrogen-atoms place 2R xBase replaces; Or
-C 6To C 8Aryl, it is randomly replaced by one or more following groups:
-halogen;
-C 1To C 6Alkyl;
-alkoxyl group,
-the amino that randomly replaced by one or more following groups:
-SO 2R x，
-C 1To C 6Alkyl, described C 1To C 6Alkyl is replaced by one or more five yuan or six membered heteroaryl randomly and independently, or
-PO 2R x，
-OC(O)NHR x，
-OC(O)N(R x) 2，
-OC(O)NH(OR x)，
-OC(O)NR x(OR x)，
-OC(O)N(OR x) 2，
-OC (O) R Ab, R wherein AbBe five yuan or hexa-member heterocycle,
-NR oCOR pBase, wherein R pBe:
-C 1To C 6Alkyl,
-amino, it is randomly by one or more C 1To C 6Alkyl replaces, wherein C 1To C 6Alkyl is randomly and independently by one or more C 6To C 8Aryl and/or alkoxyl group replace, or
-five yuan or hexa-member heterocycle, it is randomly by one or more C 1To C 6Alkyl or C 6To C 8Aryl replaces,
And R wherein oBe:
-hydrogen, or
-C 1To C 6Alkyl,
-NR qCONR qR rBase, wherein R qBe hydrogen,
And R wherein rBe:
-C 1To C 6Alkyl, it is randomly replaced by one or more following groups:
-halogen,
-hydroxyl,
-alkoxyl group,
-five yuan or hexa-member heterocycle,
-five yuan or six membered heteroaryl, or
-C 6To C 8Aryl, it is randomly replaced by halogen,
-C 2To C 6Alkylidene group, it is randomly replaced by one or more halogens,
-C 1To C 6Alkoxyl group, or
-five yuan or hexa-member heterocycle,
-NR tCOOR uBase, wherein R uBe:
-C 1To C 12Alkyl, it is randomly replaced by one or more groups that are independently selected from down group,
-C 6To C 8Aryl, it is randomly replaced by halogen,
-the alkoxyl group that randomly replaced by one or more alkoxyl groups,
-randomly by one or more C 1To C 6The amino that alkyl replaces,
-halogen, or
-five yuan or six membered heteroaryl,
-C 2To C 6Alkylidene group, or
-C 6To C 8Aryl, it is randomly replaced by halogen,
And R tBe:
-hydrogen;
-NHR BbBase, wherein R BbBe:
-C (=S) NH 2Base, or
-PO (OR x) 2, R wherein xDefinition the same;
-NR vSO 2R wBase, wherein R vBe hydrogen, R wBe C 1To C 6Alkyl,
Figure A20078000890201761
Z is:
-C 1To C 6Alkyl, it is randomly replaced by five yuan or hexa-member heterocycle, or
-five yuan or hexa-member heterocycle;
R is a hydrogen;
R 1Be:
-hydrogen;
-C 1To C 6Alkyl, it is randomly replaced by following groups:
-randomly heterocyclically substituted amino,
-randomly by C 1To C 6The amide group that alkyl replaces,
-five yuan or hexa-member heterocycle, it is randomly by C 1To C 6Alkyl replaces,
-five yuan or six membered heteroaryl, or
-C 6To C 8Aryl;
-C 1To C 6Alkoxyl group, it is randomly replaced by following groups:
-randomly heterocyclically substituted amino,
-randomly by C 1To C 6The amide group that alkyl replaces,
-five yuan or hexa-member heterocycle, it is randomly by C 1To C 6Alkyl replaces,
-five yuan or six membered heteroaryl, or
-C 6To C 8Aryl;
-(O)-five yuan or hexa-member heterocycle;
-(O)-five yuan or six membered heteroaryl;
-SO 2R xBase, it is randomly replaced by following groups:
-five yuan or hexa-member heterocycle,
-C 6To C 8Aryl,
-five yuan or six membered heteroaryl; Or
-alkylthio, it is randomly replaced by following groups:
-five yuan or hexa-member heterocycle,
-C 6To C 8Aryl,
-five yuan or six membered heteroaryl;
R 2Be:
-C 1To C 6Alkyl, it is randomly replaced by one or more following groups:
-five yuan or hexa-member heterocycle,
-five yuan or six membered heteroaryl,
-C 6To C 8Aryl,
-randomly by C 1To C 6The amide group that alkyl replaces, or
-amino, it is randomly replaced by one or more heterocycles that randomly replaced by one or more alkoxyl groups, alkoxyl group or alkyl;
-alkylthio, it is randomly replaced by five yuan or six membered heteroaryl, and wherein five yuan or six membered heteroaryl are randomly replaced by alkyl;
-alkylthio, it is randomly by five yuan or hexa-member heterocycle replacement;
-alkylthio, it is randomly by C 6To C 8Aryl replaces;
-alkylthio, it is randomly by C 1To C 6Alkyl replaces;
-SO 2R xBase, it is randomly replaced by five yuan or six membered heteroaryl, and wherein five yuan or six membered heteroaryl are randomly by one or more C 1To C 6Alkyl replaces;
-SO 2R xBase, it is randomly by five yuan or hexa-member heterocycle replacement;
--SO 2R xBase, it is randomly by C 6To C 8Aryl replaces;
-SO 2R xBase, it is randomly by C 1To C 6Alkyl replaces;
-SO 2R xBase, it is randomly by five yuan or six membered heteroaryl replacement;
-SO 2R xBase, it is randomly by five yuan or hexa-member heterocycle replacement;
-S (O) R xBase, it is randomly by C 6To C 8Aryl replaces;
-S (O) R xBase, it is randomly by C 1To C 6Alkyl replaces;
-alkoxyl group, it is randomly replaced by one or more groups that are independently selected from down group:
-halogen,
-hydroxyl,
-the alkoxyl group that replaces of alkoxy randomly,
-amino, it is replaced by one or more five yuan or six membered heteroaryl, five yuan or hexa-member heterocycle base or alkyl, and wherein said alkyl is replaced independently by one or more following groups:
-five yuan or hexa-member heterocycle, or
-the amino that randomly replaced by one or more alkyl,
-randomly by C 1To C 6The amide group that alkyl replaces,
Five yuan of-S-or hexa-member heterocycle,
Five yuan of-S-or six membered heteroaryl, it is randomly by C 1To C 6Alkyl replaces,
-S-C 1To C 6Alkyl,
-S-C 6To C 8Aryl,
-sulfinyl-five yuan or hexa-member heterocycle,
-sulfinyl-five yuan or six membered heteroaryl,
-sulfinyl-C 1To C 6Alkyl,
-sulfinyl-C 6To C 8Aryl,
-alkylsulfonyl-five yuan or hexa-member heterocycle,
-alkylsulfonyl-randomly by C 1To C 6Five yuan or six membered heteroaryl that alkyl replaces,
-alkylsulfonyl-C 1To C 6Alkyl,
-alkylsulfonyl-C 6To C 8Aryl,
-five yuan to the seven membered heterocyclic base, and it is randomly by one or more hydroxyl or C that select independently 1To C 6Alkyl replaces, wherein said C 1To C 6Alkyl is randomly by one or more C that select independently 1To C 6Alkoxyl group replaces,
-five yuan or six membered heteroaryl, it is randomly by one or more C 1To C 6Alkyl replaces,
-C 6To C 8Aryl;
-C 6To C 8Aryl;
-(O)-five yuan or hexa-member heterocycle;
-(O)-five yuan or six membered heteroaryl, it is randomly by one or more C that select independently 1To C 6Alkyl replaces;
-C (O)-five yuan or hexa-member heterocycle, it is randomly by one or more C 6To C 8Aryl replaces;
-C (O)-five yuan or six membered heteroaryl;
-C (O)-C 6To C 8Aryl;
--the COOH base;
-randomly by one or more C 1To C 6The amide group that alkyl replaces, described alkyl is randomly by one or more C 1To C 6Alkoxyl group replaces;
-five yuan or hexa-member heterocycle, it is randomly replaced by one or more following groups:
-hydroxyl,
-C 1To C 6Alkyl,
-SO 2R x，
-C (O)-C 6To C 8Aryl, or
-C (O) OR xBase;
-OR KkBase, wherein R KkBe:
-C 6To C 8Aryl,
-five yuan to six membered heteroaryl,
-five yuan to hexa-member heterocycle, and it is randomly by C 1To C 6Alkyl replaces, randomly by C 6To C 8Aryl replaces, or
-Si (Rx) 3And
R 3Be hydrogen.
In another embodiment of the invention, compound of the present invention comprises formula (I-XIa) compound
Figure A20078000890201801
Or the acceptable salt of their pharmacology,
Wherein:
X is:
-hydrogen;
-cyano group;
-nitro;
-formyl radical;
--the COOH base;
-COR xBase, wherein R xBe C 1To C 6Alkyl;
Figure A20078000890201802
To C 6Alkoxyl group,
Figure A20078000890201803
Randomly by one or more C 1To C 6The amino that alkyl replaces;
-halogen;
-the alkyl that randomly replaced by one or more halogens;
-randomly by C 1To C 6The alkynes that alkyl replaces, wherein C 1To C 6Alkyl is randomly replaced by one or more halogens or cyano group;
-oxime;
-SO 2R x；
-SO 2NH 2；
-SO 2NH(R x)；
-SO 2N(Rx) 2；
-randomly by one or more C 1To C 6Alkyl or C (O)-C 1To C 6The amino that alkyl replaces;
-randomly by one or more C that select independently 1To C 6The amide group that alkyl replaces;
-five yuan or hexa-member heterocycle;
-five yuan or six membered heteroaryl, it is randomly by one or more C 1To C 6Alkyl replaces, and described alkyl is randomly replaced by one or more halogens; Or
-C 6To C 8Aryl, it is randomly replaced by one or more following groups:
-C 1To C 6Alkyl, it is randomly replaced by one or more halogens;
-halogen, or
-cyano group;
Y is:
-the benzothiazole that randomly replaced by amino, wherein amino is randomly by one or more C 1To C 6Alkyl replaces;
-indoles, it is randomly at the quilt-SO of nitrogen-atoms place 2R xBase replaces;
-C 6To C 8Aryl, it is randomly replaced by one or more following groups:
-halogen;
-C 1To C 6Alkyl;
-alkoxyl group,
-the amino that randomly replaced by one or more following groups
-SO 2R xBase,
-C 1To C 6Alkyl, described C 1To C 6Alkyl is replaced by one or more five yuan or six membered heteroaryl randomly and independently, or
-PO 2R xBase,
-OC(O)NHR x，
-OC(O)N(R x) 2，
-OC(O)NH(OR x)，
-OC(O)NR x(OR x)，
-OC(O)N(OR x) 2，
-OC (O) R Ab, R wherein AbBe five yuan or hexa-member heterocycle,
-NR oCOR pBase, wherein R pBe:
-C 1To C 6Alkyl,
-amino, it is randomly by one or more C 1To C 6Alkyl replaces, wherein C 1To C 6Alkyl is randomly and independently by one or more C 6To C 8Aryl and/or alkoxyl group replace,
-five yuan or hexa-member heterocycle, it is randomly by one or more C 1To C 6Alkyl or C 6To C 8Aryl replaces,
And R wherein oBe:
-hydrogen,
-C 1To C 6Alkyl,
-NR qCONR qR rBase, wherein R qBe hydrogen:
And R wherein rBe:
-C 1To C 6Alkyl, it is randomly replaced by one or more following groups:
-halogen,
-hydroxyl,
-alkoxyl group,
-five yuan or hexa-member heterocycle,
-five yuan or six membered heteroaryl, or
-C 6To C 8Aryl, it is randomly replaced by halogen,
-C 2To C 6Alkylidene group, it is randomly replaced by one or more halogens,
-C 1To C 6Alkoxyl group, or
-five yuan or hexa-member heterocycle base,
-NR tCOOR uBase, wherein R uBe:
-C 1To C 12Alkyl, it is randomly replaced by one or more groups that are independently selected from down group,
-C 6To C 8Aryl, it is randomly replaced by halogen,
-the alkoxyl group that randomly replaced by one or more alkoxyl groups,
-randomly by one or more C 1To C 6The amino that alkyl replaces,
-halogen, or
-five yuan or six membered heteroaryl,
-C 2To C 6Alkylidene group,
-C 6To C 8Aryl, it is randomly replaced by halogen,
And R tBe hydrogen;
-NHR BbBase, wherein R BbBe:
-C (=S) NH 2Base, or
-PO (OR x) 2, R wherein xDefinition the same;
-NR vSO 2R wBase, wherein R vBe hydrogen, R wBe C 1To C 6Alkyl,
Z is:
-C 1To C 6Alkyl, it is randomly replaced by five yuan or hexa-member heterocycle, or
-five yuan or hexa-member heterocycle;
R is a hydrogen;
R 1Be:
-hydrogen;
-C 1To C 6Alkyl, it is randomly replaced by following groups:
-randomly heterocyclically substituted amino,
-randomly by C 1To C 6The amide group that alkyl replaces,
-five yuan or hexa-member heterocycle, it is randomly by C 1To C 6Alkyl replaces,
-five yuan or six membered heteroaryl, or
-C 6To C 8Aryl;
-C 1To C 6Alkoxyl group, it is randomly replaced by following groups:
-randomly heterocyclically substituted amino,
-randomly by C 1To C 6The amide group that alkyl replaces,
-five yuan or hexa-member heterocycle, it is randomly by C 1To C 6Alkyl replaces,
-five yuan or six membered heteroaryl, or
-C 6To C 8Aryl;
-(O)-five yuan or hexa-member heterocycle;
-(O)-five yuan or six membered heteroaryl;
-SO 2R xBase, it is randomly replaced by following groups:
-five yuan or hexa-member heterocycle,
-C 6To C 8Aryl,
-five yuan or six membered heteroaryl; Or
-alkylthio, it is randomly replaced by following groups:
-five yuan or hexa-member heterocycle,
-C 6To C 8Aryl,
-five yuan or six membered heteroaryl;
R 2Be:
-C 1To C 6Alkyl, it is randomly replaced by one or more following groups:
-five yuan or hexa-member heterocycle,
-five yuan or six membered heteroaryl,
-C 6To C 8Aryl,
-randomly by one or more C 1To C 6The amide group that alkyl replaces, or
-amino, it is randomly replaced by one or more heterocycles that randomly replaced by one or more alkoxyl groups, alkoxyl group or alkyl;
-alkylthio, it is randomly replaced by five yuan or six membered heteroaryl, and wherein five yuan or six membered heteroaryl are randomly replaced by alkyl;
-alkylthio, it is randomly by five yuan or hexa-member heterocycle replacement;
-alkylthio, it is randomly by C 6To C 8Aryl replaces;
-alkylthio, it is randomly by C 1To C 6Alkyl replaces;
-SO 2R xBase, it is randomly replaced by five yuan or six membered heteroaryl, and wherein five yuan or six membered heteroaryl are randomly by one or more C 1To C 6Alkyl replaces;
-SO 2R xBase, it is randomly by five yuan or hexa-member heterocycle replacement;
--SO 2R xBase, it is randomly by C 6To C 8Aryl replaces;
-SO 2R xBase, it is randomly by C 1To C 6Alkyl replaces;
-S (O) R xBase, it is randomly by five yuan or six membered heteroaryl replacement;
-S (O) R xBase, it is randomly by five yuan or hexa-member heterocycle replacement;
-S (O) R xBase, it is randomly by C 6To C 8Aryl replaces;
-S (O) R xBase, it is randomly by C 1To C 6Alkyl replaces;
-alkoxyl group, it is randomly replaced by one or more groups that are independently selected from down group:
-halogen,
-hydroxyl,
-the alkoxyl group that replaces of alkoxy randomly,
-amino, it is replaced by one or more five yuan or six membered heteroaryl, five yuan or hexa-member heterocycle base or alkyl, and wherein said alkyl randomly and is independently replaced by one or more following groups:
-five yuan or hexa-member heterocycle, or
-the amino that randomly replaced by one or more alkyl,
-randomly by C 1To C 6The amide group that alkyl replaces,
Five yuan of-S-or hexa-member heterocycle,
Five yuan of-S-or six membered heteroaryl, it is by C 1To C 6Alkyl replaces,
-S-C 1To C 6Alkyl,
-S-C 6To C 8Aryl,
-sulfinyl-five yuan or hexa-member heterocycle,
-sulfinyl-five yuan or six membered heteroaryl,
-sulfinyl-C 1To C 6Alkyl,
-sulfinyl-C 6To C 8Aryl,
-alkylsulfonyl-five yuan or hexa-member heterocycle,
-alkylsulfonyl-randomly by C 1To C 6Five yuan or six membered heteroaryl that alkyl replaces,
-alkylsulfonyl-C 1To C 6Alkyl,
-alkylsulfonyl-C 6To C 8Aryl,
-five yuan to the seven membered heterocyclic base, and it is randomly by one or more hydroxyl or C that select independently 1To C 6Alkyl replaces, wherein said C 1To C 6Alkyl is randomly by one or more C that select independently 1To C 6Alkoxyl group replaces,
-five yuan or six membered heteroaryl, it is randomly by one or more C 1To C 6Alkyl replaces,
-C 6To C 8Aryl;
-C 6To C 8Aryl;
-(O)-five yuan or hexa-member heterocycle;
-(O)-five yuan or six membered heteroaryl, it is randomly by one or more C that select independently 1To C 6Alkyl replaces;
-C (O)-five yuan or hexa-member heterocycle, it is randomly by one or more C 6To C 8Aryl replaces;
-C (O)-five yuan or six membered heteroaryl;
-C (O)-C 6To C 8Aryl;
--the COOH base;
-the amide group that randomly replaced by one or more following groups:
-C 1To C 6Alkyl, it is randomly by one or more C 1To C 6Alkoxyl group replaces,
-five yuan or hexa-member heterocycle, it is randomly replaced by one or more following groups:
-hydroxyl,
-C 1To C 6Alkyl,
-SO 2R x，
-C (O)-C 6To C 8Aryl, or
-C (O) OR xBase;
-OR KkBase, wherein R KkBe:
-C 6To C 8Aryl,
-five yuan to six membered heteroaryl,
-five yuan to hexa-member heterocycle, and it is randomly by C 1To C 6Alkyl replaces, randomly by C 6To C 8Aryl replaces, or
-Si (Rx) 3And
R 3Be hydrogen;
Condition is X, Y, Z, R 1And R 2In have a following selection at least:
X is:
--the COOH base;
Figure A20078000890201871
To C 6Alkoxyl group,
Figure A20078000890201872
Randomly by one or more C 1To C 6The amino that alkyl replaces;
-halogen;
-the alkyl that randomly replaced by one or more halogens;
-randomly by C 1To C 6The alkynes that alkyl replaces, described alkyl are randomly replaced by one or more halogens or cyano group;
-oxime;
-SO 2R x；
-SO 2NH 2；
-SO 2NH(R x)；
-SO 2N(Rx) 2；
-randomly by one or more C 1To C 6Alkyl or C (O)-C 1To C 6The amino that alkyl replaces;
-randomly by one or more C that select independently 1To C 6The amide group that alkyl replaces;
-five yuan or hexa-member heterocycle;
-five yuan or six membered heteroaryl, it is by one or more C 1To C 6Alkyl replaces, and described alkyl is replaced by one or more halogens; Or
-C 6To C 8Aryl, it is replaced by one or more following groups:
-the C that randomly replaced by one or more halogens 1To C 6Alkyl;
-halogen, or
-cyano group;
Y is:
-by the amino benzothiazole that replaces, wherein amino is randomly by one or more C 1To C 6Alkyl replaces;
-indoles, its at the nitrogen-atoms place by SO 2R xBase replaces;
-C 6To C 8Aryl, it is replaced by one or more following groups:
-the amino that randomly replaced by one or more following groups:
-SO 2R x, or
-C 1To C 6Alkyl, it is replaced by one or more five yuan or six membered heteroaryl,
-OC(O)NHR x，
-OC(O)N(R x) 2，
-OC(O)NH(OR x)，
-OC(O)NR x(OR x)，
-OC(O)N(OR x) 2，
-OC (O) R Ab, R wherein AbBe five yuan or hexa-member heterocycle,
-NR oCOR pBase, wherein R pBe:
-amino, it is randomly by one or more C 1To C 6Alkyl replaces, wherein C 1To C 6Alkyl is randomly and independently by one or more C 6To C 8Aryl and/or alkoxyl group replace, or
-five yuan or hexa-member heterocycle, it is by one or more C 1To C 6Alkyl or C 6To C 8Aryl replaces ,-NR qCONR qR rBase, wherein R rBe:
-C 1To C 6Alkyl, it is replaced by one or more following groups:
-hydroxyl,
-alkoxyl group,
-five yuan or hexa-member heterocycle,
-five yuan or six membered heteroaryl, or
-C 6To C 8Aryl, it is randomly replaced by halogen,
-C 2To C 6Alkylidene group,
-C 1To C 6Alkoxyl group,
-five yuan or hexa-member heterocycle base,
-NR tCOOR uBase, wherein R uBe:
-C 1To C 12Alkyl, it is replaced by one or more following groups:
-the alkoxyl group that replaced by one or more alkoxyl groups,
-randomly by one or more C 1To C 6The amino that alkyl replaces, or
-five yuan or six membered heteroaryl,
-C 2To C 6Alkylidene group, or
Figure A20078000890201891
Z is:
-C 1To C 6Alkyl, it is replaced by five yuan or hexa-member heterocycle, or
-five yuan or hexa-member heterocycle;
R 1Be:
-C 1To C 6Alkyl, it is replaced by following groups:
-randomly by C 1To C 6The amide group that alkyl replaces, or
-five yuan or six membered heteroaryl;
-C 1To C 6Alkoxyl group, it is replaced by following groups:
-randomly heterocyclically substituted amino,
-randomly by C 1To C 6The amide group that alkyl replaces,
-five yuan or hexa-member heterocycle, it is by C 1To C 6Alkyl replaces, or
-five yuan or six membered heteroaryl;
-(O)-five yuan or hexa-member heterocycle;
-(O)-five yuan or six membered heteroaryl;
-SO 2R xBase, it is randomly replaced by following groups:
-five yuan or hexa-member heterocycle,
-C 6To C 8Aryl,
-five yuan or six membered heteroaryl; Or
-alkylthio, it is randomly replaced by following groups:
-five yuan or hexa-member heterocycle,
-C 6To C 8Aryl,
-five yuan or six membered heteroaryl; Or
R 2Be:
-C 1To C 6Alkyl, it is replaced by one or more following groups:
-five yuan or hexa-member heterocycle,
-five yuan or six membered heteroaryl,
-C 6To C 8Aryl,
-randomly by C 1To C 6The amide group that alkyl replaces, or
-amino, it is randomly replaced by one or more heterocycles that randomly replaced by one or more alkoxyl groups, alkoxyl group or alkyl;
-alkylthio, it is randomly replaced by five yuan or six membered heteroaryl, and wherein five yuan or six membered heteroaryl are randomly replaced by alkyl;
-alkylthio, it is randomly by five yuan or hexa-member heterocycle replacement;
-alkylthio, it is randomly by C 6To C 8Aryl replaces;
-alkylthio, it is randomly by C 1To C 6Alkyl replaces;
-SO 2R xBase, it is randomly replaced by five yuan or six membered heteroaryl, and wherein five yuan or six membered heteroaryl are randomly by one or more C 1To C 6Alkyl replaces;
-SO 2R xBase, it is randomly by five yuan or the replacement of hexa-member heterocycle base;
--SO 2R xBase, it is randomly by C 6To C 8Aryl replaces;
-SO 2R xBase, it is randomly by C 1To C 6Alkyl replaces;
-S (O) R xBase, it is randomly by five yuan or six membered heteroaryl replacement;
-S (O) R xBase, it is randomly by five yuan or hexa-member heterocycle replacement;
-S (O) R xBase, it is randomly by C 6To C 8Aryl replaces;
-S (O) R xBase, it is randomly by C 1To C 6Alkyl replaces;
-the alkoxyl group that replaces of alkoxy randomly,
-amino, it is replaced by one or more five yuan or six membered heteroaryl, five yuan or hexa-member heterocycle base or alkyl, and wherein said alkyl randomly and is independently replaced by one or more following groups:
-five yuan or hexa-member heterocycle, or
-the amino that randomly replaced by one or more alkyl;
-randomly by C 1To C 6The amide group that alkyl replaces,
Five yuan of-S-or hexa-member heterocycle,
Five yuan of-S-or six membered heteroaryl, it is randomly by C 1To C 6Alkyl replaces,
-S-C 1To C 6Alkyl,
-S-C 6To C 8Aryl,
-sulfinyl-five yuan or hexa-member heterocycle,
-sulfinyl-five yuan or six membered heteroaryl,
-sulfinyl-C 1To C 6Alkyl,
-sulfinyl-C 6To C 8Aryl,
-alkylsulfonyl-five yuan or hexa-member heterocycle,
-alkylsulfonyl-randomly by C 1To C 6Five yuan or six membered heteroaryl that alkyl replaces,
-alkylsulfonyl-C 1To C 6Alkyl,
-alkylsulfonyl-C 6To C 8Aryl,
-five yuan to seven membered heterocyclic, and it is replaced by one or more hydroxyls of selecting independently or by one or more C that select independently 1To C 6Alkyl replaces, wherein C 1To C 6Alkyl is by C 1To C 6Alkoxyl group replaces, or
-five yuan or six membered heteroaryl, it is by one or more C 1To C 6Alkyl replaces
-C 6To C 8Aryl;
-C (O)-five yuan or hexa-member heterocycle, it is randomly by one or more C 6To C 8Aryl replaces;
-C (O)-C 6To C 8Aryl;
--the COOH base;
-by one or more C 1To C 6The amide group that alkyl replaces, described alkyl is randomly by one or more C 1To C 6Alkoxyl group replaces;
-five yuan or hexa-member heterocycle, it is replaced by one or more following groups:
-hydroxyl,
-C 1To C 6Alkyl,
-SO 2R xBase,
-C (O)-C 6To C 8Aryl, or
-C (O) OR xBase;
-OR KkBase, wherein R KkBe:
-C 6To C 8Aryl,
-five yuan to hexa-member heterocycle, and it is randomly by C 1To C 6Alkyl replaces, randomly by C 6To C 8Aryl replaces, or
-Si(Rx) 3；
-(O)-five yuan or hexa-member heterocycle; Or
-(O)-five yuan or six membered heteroaryl, it is randomly by one or more C that select independently 1To C 6Alkyl replaces.
In another embodiment, formula I-XIb provides a kind of compound, and wherein the substituting group of all except that X is identical with formula I-XI, and X is an electron-withdrawing group.In another embodiment, formula I-XIc provides a kind of compound, and wherein the substituting group of all except that X is identical with formula I-XIa, and X is an electron-withdrawing group.For example, electron-withdrawing group comprises any electronegative element, and it can be connected on the aromatic ring or be adjacent with aromatic ring.As limiting examples, electron-withdrawing group can comprise cyano group, alkynyl, nitro, oxime, halogen, haloalkyl, carbonyl, alkylsulfonyl and heterocycle.In an embodiment of the invention, X is a cyano group.In another embodiment of formula I, I-XI, I-XIa, I-XIb, I-XIc, IIa, IIb, IIc, IId or IIe, X is a halogen.In the embodiment of formula I, I-XI, I-XIa, I-XIb, I-XIc, IIa, IIb, IIc, IId or IIe, X is fluorine, chlorine, bromine or iodine.In the embodiment of formula I, I-XI, I-XIa, I-XIb, I-XIc, IIa, IIb, IIc, IId or IIe, X is fluorine, bromine or iodine.In the embodiment of formula I, I-XI, I-XIa, I-XIb, I-XIc, IIa, IIb, IIc, IId or IIe, X is a fluorine or chlorine.In the embodiment of formula I, I-XI, I-XIa, I-XIb, I-XIc, IIa, IIb, IIc, IId or IIe, X is a fluorine.In the embodiment of formula I, I-XI, I-XIa, I-XIb, I-XIc, IIa, IIb, IIc, IId or IIe, X is a chlorine.In the embodiment of formula I, I-XI, I-XIa, I-XIb, I-XIc, IIa, IIb, IIc, IId or IIe, X is a bromine.In the embodiment of formula I, I-XI, I-XIa, I-XIb, I-XIc, IIa, IIb, IIc, IId or IIe, X is an iodine.In the another embodiment of formula I, I-XI, I-XIa, I-XIb, I-XIc, IIa, IIb, IIc, IId or IIe, the alkyl that X is replaced by one or more halogens.In another embodiment, X is a trifluoromethyl.
In some embodiments, X is selected from the X substituting group of compound 1330-2128 and 2600-3348.
In the embodiment of formula I, I-XI, I-XIa, I-XIb, I-XIc, IIa, IIb, IIc, IId or IIe, X is selected from down the group group:
Figure A20078000890201921
Figure A20078000890201941
In other limiting examples of formula I, I-XI, I-XIa, I-XIb, I-XIc, IIa, IIb, IIc or IIe, X is selected from down the group group:
Figure A20078000890201942
Figure A20078000890201951
In some embodiments, R 1Be selected from the R of compound 1330-2128 and 2600-3348 1Substituting group.
In the embodiment of formula I, I-XI, I-XIa, I-XIb, I-XIc, IIa, IIb, IIc, IId or IIe, R 1Be selected from down the group group:
In another embodiment, the present invention includes formula (I-XII) compound
Figure A20078000890201953
Figure A20078000890201961
Or the acceptable salt of their pharmacology,
Wherein:
X is:
-cyano group;
Y is:
-the benzothiazole that randomly replaced by amino, wherein amino is randomly by one or more C 1To C 6Alkyl replaces;
-indoles, its randomly at the nitrogen-atoms place by SO 2R xBase replaces;
-C 6To C 8Aryl, it is randomly replaced by one or more following groups:
-alkoxyl group,
-the amino that randomly replaced by one or more following groups:
-SO 2R xBase, or
-C 1To C 6Alkyl, described C 1To C 6Alkyl is replaced by one or more five yuan or six membered heteroaryl randomly and independently,
-OC(O)NHR x，
-OC(O)N(R x) 2，
-OC(O)NH(OR x)，
-OC(O)NR x(OR x)，
-OC(O)N(OR x) 2，
-OC (O) R Ab, R wherein AbBe five yuan or hexa-member heterocycle,
-NR oCOR pBase, wherein R pBe:
-C 1To C 6Alkyl,
-amino, it is randomly by one or more C 1To C 6Alkyl replaces, wherein C 1To C 6Alkyl is randomly and independently by one or more C 6To C 8Aryl and/or alkoxyl group replace,
-five yuan or hexa-member heterocycle, it is randomly by one or more C 1To C 6Alkyl or C 6To C 8Aryl replaces,
And R wherein oBe:
-hydrogen,
-C 1To C 6Alkyl,
-NR qCONR qR rBase, wherein R qBe hydrogen:
And R wherein rBe:
-C 1To C 6Alkyl, it is randomly replaced by one or more following groups:
-hydroxyl,
-alkoxyl group,
-five yuan or hexa-member heterocycle,
-five yuan or six membered heteroaryl, or
-C 6To C 8Aryl, it is randomly replaced by halogen,
-C 2To C 6Alkylidene group,
-C 1To C 6Alkoxyl group,
-five yuan or hexa-member heterocycle base,
-NR tCOOR uBase, wherein R uBe:
-C 1To C 12Alkyl, it is randomly replaced by one or more groups that are independently selected from down group,
-C 6To C 8Aryl, it is randomly replaced by halogen,
-the alkoxyl group that randomly replaced by one or more alkoxyl groups,
-randomly by one or more C 1To C 6The amino that alkyl replaces,
-halogen, or
-five yuan or six membered heteroaryl,
-C 2To C 6Alkylidene group,
-C 6To C 8Aryl, it is randomly replaced by halogen,
And R tBe:
-hydrogen;
-NHR BbBase, wherein R BbBe:
-C (=S) NH 2Base, or
-PO (OR x) 2, R wherein xDefinition the same;
-NR vSO 2R wBase, wherein R vBe hydrogen, R wBe C 1To C 6Alkyl,
Figure A20078000890201981
Z is:
-C 1To C 6Alkyl, it is randomly replaced by five yuan or hexa-member heterocycle, or
-five yuan or hexa-member heterocycle;
R is a hydrogen;
R 1Be hydrogen;
R 2Be:
-C 1To C 6Alkyl, it is randomly replaced by one or more following groups:
-five yuan or hexa-member heterocycle base,
-amino, it is randomly replaced by one or more alkoxyl group or alkyl that randomly replaced by one or more alkoxyl groups,
-alkoxyl group, it is randomly replaced by one or more groups that are independently selected from down group:
-halogen,
-hydroxyl,
-the alkoxyl group that replaces of alkoxy randomly,
-amino, randomly by one or more five yuan or hexa-member heterocycle base or alkyl replacements, wherein said alkyl randomly and is independently replaced by one or more following groups for it:
-five yuan or hexa-member heterocycle, or
-the amino that randomly replaced by one or more alkyl;
-five yuan to the seven membered heterocyclic base, and it is randomly by one or more hydroxyl or C that select independently 1To C 6Alkyl replaces, wherein said C 1To C 6Alkyl is randomly by one or more C that select independently 1To C 6Alkoxyl group replaces,
-five yuan or six membered heteroaryl, it is randomly by one or more C 1To C 6Alkyl replaces,
-C (O)-five yuan or hexa-member heterocycle, it is randomly by one or more C 6To C 8Aryl replaces;
--the COOH base;
-randomly by one or more C 1To C 6The amide group that alkyl replaces;
-five yuan or hexa-member heterocycle, it is randomly replaced by one or more following groups:
-C 1To C 6Alkyl,
-SO 2R x，
-C (O)-C 6To C 8Aryl, or
-C (O) OR xBase;
-OR KkBase, wherein R KkBe:
-five yuan to hexa-member heterocycle, and it is randomly by C 1To C 6Alkyl replaces, randomly by C 6To C 8Aryl replaces, or
-Si(Rx) 3；
R 3Be hydrogen.
In another embodiment, the present invention includes formula (I-XIIa) compound
Or the acceptable salt of their pharmacology,
Wherein:
X is:
-cyano group;
Y is:
-the benzothiazole that randomly replaced by amino, wherein amino is randomly by one or more C 1To C 6Alkyl replaces;
-indoles, its randomly at the nitrogen-atoms place by SO 2R xBase replaces;
-C 6To C 8Aryl, it is randomly replaced by one or more following groups:
-alkoxyl group,
-the amino that randomly replaced by one or more following groups:
-SO 2R x, or
-C 1To C 6Alkyl, described C 1To C 6Alkyl is replaced by one or more five yuan or six membered heteroaryl randomly and independently,
-OC(O)NHR x，
-OC(O)N(R x) 2，
-OC(O)NH(OR x)，
-OC(O)NR x(OR x)，
-OC(O)N(OR x) 2，
-OC (O) R Ab, R wherein AbBe five yuan or hexa-member heterocycle base,
-NR oCOR pBase, wherein R pBe:
-C 1To C 6Alkyl,
-amino, it is randomly by one or more C 1To C 6Alkyl replaces, wherein C 1To C 6Alkyl is randomly and independently by one or more C 6To C 8Aryl and/or alkoxyl group replace,
-five yuan or hexa-member heterocycle, it is randomly by one or more C 1To C 6Alkyl or C 6To C 8Aryl replaces,
And R wherein oBe:
-hydrogen,
-C 1To C 6Alkyl,
-NR qCONR qR rBase, wherein R qBe hydrogen:
And R wherein rBe:
-C 1To C 6Alkyl, it is randomly replaced by one or more following groups:
-hydroxyl,
-alkoxyl group,
-five yuan or hexa-member heterocycle,
-five yuan or six membered heteroaryl, or
-C 6To C 8Aryl, it is randomly replaced by halogen,
-C 2To C 6Alkylidene group,
-C 1To C 6Alkoxyl group,
-five yuan or hexa-member heterocycle base,
-NR tCOOR uBase, wherein R uBe:
-C 1To C 12Alkyl, it is randomly replaced by one or more groups that are independently selected from down group,
-C 6To C 8Aryl, it is randomly replaced by halogen,
-the alkoxyl group that randomly replaced by one or more alkoxyl groups,
-randomly by one or more C 1To C 6The amino that alkyl replaces,
-halogen, or
-five yuan or six membered heteroaryl,
-C 2To C 6Alkylidene group,
-C 6To C 8Aryl, it is randomly replaced by halogen,
And R tBe:
-hydrogen;
-NHR BbBase, wherein R BbBe:
-C (=S) NH 2Base, or
-PO (OR x) 2, R wherein xDefinition the same;
-NR vSO 2R wBase, wherein R vBe hydrogen, R wBe C 1To C 6Alkyl,
Figure A20078000890202011
Z is:
-C 1To C 6Alkyl, it is randomly replaced by following groups :-five yuan or hexa-member heterocycle, or
-five yuan or hexa-member heterocycle;
R is a hydrogen;
R 1Be hydrogen;
R 2Be:
-C 1To C 6Alkyl, it is randomly replaced by one or more following groups:
-five yuan or hexa-member heterocycle,
-amino, it is randomly replaced by one or more alkoxyl group or alkyl that randomly replaced by one or more alkoxyl groups,
-alkoxyl group, it is randomly replaced by one or more groups that are independently selected from down group:
-halogen,
-hydroxyl,
-the alkoxyl group that replaces of alkoxy randomly,
-amino, randomly by one or more five yuan or hexa-member heterocycle base or alkyl replacements, wherein said alkyl randomly and is independently replaced by one or more following groups for it:
-five yuan or hexa-member heterocycle, or
-the amino that randomly replaced by one or more alkyl;
-five yuan to the seven membered heterocyclic base, and it is randomly by one or more hydroxyl or C that select independently 1To C 6Alkyl replaces, wherein said C 1To C 6Alkyl is randomly by one or more C that select independently 1To C 6Alkoxyl group replaces,
-five yuan or six membered heteroaryl, it is randomly by one or more C 1To C 6Alkyl replaces,
-C (O)-five yuan or hexa-member heterocycle, it is randomly by one or more C 6To C 8Aryl replaces;
--the COOH base;
-randomly by one or more C 1To C 6The amide group that alkyl replaces;
-five yuan or hexa-member heterocycle, it is randomly replaced by one or more following groups:
-C 1To C 6Alkyl,
-SO 2R x，
-C (O)-C 6To C 8Aryl, or
-C(O)OR x；
-OR KkBase, wherein R KkBe:
-five yuan to hexa-member heterocycle, and it is randomly by C 1To C 6Alkyl replaces, randomly by C 6To C 8Aryl replaces, or
-Si(Rx) 3；
R 3Be hydrogen;
Condition is Y, Z, R 1And R 2In have a following selection at least:
Y is:
-by the amino benzothiazole that replaces, wherein amino is randomly by one or more C 1To C 6Alkyl replaces;
-indoles, it is at the quilt-SO of nitrogen-atoms place 2R xBase replaces;
-C 6To C 8Aryl, it is replaced by one or more following groups:
-the amino that randomly replaced by one or more following groups:
-SO 2R x, or
-C 1To C 6Alkyl, it is replaced by one or more five yuan or six membered heteroaryl,
-OC(O)NHR x，
-OC(O)N(R x) 2，
-OC(O)NH(OR x)，
-OC(O)NR x(OR x)，
-OC(O)N(OR x) 2，
-OC (O) R Ab, R wherein AbBe five yuan or hexa-member heterocycle base,
-NR oCOR pBase, wherein R pBe:
-amino, it is randomly by one or more C 1To C 6Alkyl replaces, wherein C 1To C 6Alkyl is randomly and independently by one or more C 6To C 8Aryl and/or alkoxyl group replace,
-five yuan or hexa-member heterocycle, it is by one or more C 1To C 6Alkyl or C 6To C 8Aryl replaces,
-NR qCONR qR rBase, wherein R rBe:
-C 1To C 6Alkyl, it is replaced by one or more following groups:
-hydroxyl,
-alkoxyl group,
-five yuan or hexa-member heterocycle,
-five yuan or six membered heteroaryl, or
-C 6To C 8Aryl, it is randomly replaced by halogen,
-C 2To C 6Alkylidene group,
-C 1To C 6Alkoxyl group,
-five yuan or hexa-member heterocycle base,
-NR tCOOR uBase, wherein R uBe:
-C 1To C 12Alkyl, it is replaced by one or more groups that are independently selected from following groups:
-the alkoxyl group that replaced by one or more alkoxyl groups,
-randomly by one or more C 1To C 6The amino that alkyl replaces, or
-five yuan or six membered heteroaryl,
-C 2To C 6Alkylidene group,
Figure A20078000890202041
Z is:
-C 1To C 6Alkyl, it is replaced by five yuan or hexa-member heterocycle, or
-five yuan or hexa-member heterocycle;
R 2Be:
-C 1To C 6Alkyl, it is replaced by one or more following groups:
-five yuan or hexa-member heterocycle base,
-amino, it is randomly replaced by one or more alkoxyl group or alkyl that randomly replaced by one or more alkoxyl groups,
-alkoxyl group, it is replaced by one or more groups that are independently selected from down group:
-hydroxyl,
-the alkoxyl group that replaces of alkoxy randomly,
-amino, it is by one or more five yuan or hexa-member heterocycle base or alkyl replacements, and wherein said alkyl randomly and is independently replaced by one or more following groups:
-five yuan or hexa-member heterocycle, or
-the amino that randomly replaced by one or more alkyl;
-seven membered heterocyclic base;
-five yuan to the seven membered heterocyclic base, and it is replaced by one or more hydroxyls of selecting independently or by one or more C that select independently 1To C 6Alkyl replaces, wherein C 1To C 6Alkyl is by C 1To C 6Alkoxyl group replaces, or
-five yuan or six membered heteroaryl, it is by one or more C 1To C 6Alkyl replaces;
-C (O)-five yuan or hexa-member heterocycle, it is randomly by one or more C 6To C 8Aryl replaces;
--the COOH base;
-by one or more C 1To C 6The amide group that alkyl replaces;
-five yuan or hexa-member heterocycle, it is randomly replaced by one or more following groups:
-C 1To C 6Alkyl,
-SO 2R xBase,
-C (O)-C 6To C 8Aryl, or
-C (O) OR xBase;
-OR KkBase, wherein R KkBe:
-five yuan to hexa-member heterocycle, and it is randomly by C 1To C 6Alkyl replaces, randomly by C 6To C 8Aryl replaces, or
-Si(Rx) 3。
In another embodiment, the present invention includes the compound of formula I, I-X, I-XI, I-XII, I-Xa, I-XIa, I-XIIa, I-XIb, I-XIc, IIa, IIb, IIc, IId or IIe, wherein Y is C 6To C 8Aryl, it is randomly replaced by one or more following groups:
-NR qCONR qR rBase, wherein R qBe hydrogen:
And R wherein rBe:
-C 1To C 6Alkyl, it is randomly replaced by one or more following groups:
-hydroxyl,
-alkoxyl group,
-five yuan or hexa-member heterocycle,
-five yuan or six membered heteroaryl, or
-C 6To C 8Aryl, it is randomly replaced by halogen,
-C 2To C 6Alkylidene group,
-C 1To C 6Alkoxyl group,
-five yuan or hexa-member heterocycle,
-NR tCOOR uBase, wherein R uBe:
-C 1To C 12Alkyl, it is randomly replaced by one or more groups that are independently selected from down group,
-C 6To C 8Aryl, it is randomly replaced by halogen,
-the alkoxyl group that randomly replaced by one or more alkoxyl groups,
-randomly by one or more C 1To C 6The amino that alkyl replaces,
-halogen, or
-five yuan or six membered heteroaryl,
-C 2To C 6Alkylidene group,
-C 6To C 8Aryl, it is randomly replaced by halogen,
And R tBe:
-hydrogen;
-NHR BbBase, wherein R BbBe:
-C (=S) NH 2Base, or
-PO (OR x) 2, R wherein xDefinition the same;
Or
-NR vSO 2R wBase, wherein R vBe hydrogen, R wBe C 1To C 6Alkyl.
In another embodiment, the present invention includes compound, wherein Y is C 6To C 8Aryl, it is randomly replaced by following groups:
-NR qCONR qR rBase, wherein R qBe hydrogen,
And R wherein rBe:
-C 1To C 6Alkyl, it is randomly replaced by one or more following groups:
-hydroxyl,
-alkoxyl group,
-five yuan or hexa-member heterocycle,
-five yuan or six membered heteroaryl, or
-C 6To C 8Aryl, it is randomly replaced by halogen,
-C 2To C 6Alkylidene group,
-C 1To C 6Alkoxyl group, or
-five yuan or hexa-member heterocycle base.
In another embodiment, the present invention includes compound, wherein Y is NR tCOOR uBase, wherein R uBe:
-C 1To C 12Alkyl, it is randomly replaced by one or more groups that are independently selected from down group,
-C 6To C 8Aryl, it is randomly replaced by halogen,
-the alkoxyl group that randomly replaced by one or more alkoxyl groups,
-randomly by one or more C 1To C 6The amino that alkyl replaces,
-halogen, or
-five yuan or six membered heteroaryl,
-C 2To C 6Alkylidene group,
-C 6To C 8Aryl, it is randomly replaced by halogen,
And R tBe:
-hydrogen.
In another embodiment, the present invention includes following compounds:
1. formula IIa compound
Figure A20078000890202071
Or the acceptable salt of their pharmacology, wherein:
X is:
-cyano group;
-nitro;
-formyl radical;
-COOH；
-COR x, R wherein xBe C 1To C 6Alkyl;
-CH=N-(C 1To C 6Alkoxyl group);
-CH=N-is (randomly by one or more C 1To C 6The amino that alkyl replaces);
-halogen;
-the alkyl that randomly replaced by one or more halogens;
-randomly by C 1To C 6The alkynyl that alkyl replaces, described alkyl are randomly replaced by one or more halogens and/or cyano group;
-oximido (oximyl);
-SO 2R x；
-SO 2NH 2；
-SO 2NH(R x)；
-SO 2N(R x) 2；
-randomly by one or more C 1To C 6Alkyl and/or C (O)-C 1To C 6The amino that alkyl replaces;
-randomly by one or more C that are independently selected from 1To C 6The amido that alkyl replaces;
-five yuan or hexa-member heterocycle;
-five yuan or six membered heteroaryl, it is randomly by one or more C 1To C 6Alkyl replaces, and described alkyl is randomly replaced by one or more halogens; Or
-C 6To C 8Aryl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-the C that randomly replaced by one or more halogens 1To C 6Alkyl;
-halogen; And
-cyano group;
Y is:
-the benzothiazolyl that randomly replaced by amino, described amino is randomly by one or more C 1To C 6Alkyl replaces;
-indyl, it is randomly at the quilt-SO of nitrogen-atoms place 2R xReplace;
-C 6To C 8Aryl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-halogen;
-C 1To C 6Alkyl;
-randomly by one or more alkoxyl groups that are independently selected from the substituting groups replacement of following groups:
-one or more halogens; And
-five yuan or hexa-member heterocycle;
-hydroxyl;
-randomly by one or more amino that are independently selected from the substituting groups replacement of following groups:
-SO 2R x；
-C 1To C 6Alkyl, it is replaced by one or more five yuan or six membered heteroaryl randomly and independently; And
-PO 2R x；
-OC(O)NHR x；
-OC(O)N(R x) 2；
-OC(O)NH(OR x)；
-OC(O)NR x(OR x)；
-OC(O)N(OR x) 2；
-OC (O) R Ab, R wherein AbBe five yuan or hexa-member heterocycle;
-NR oCOR p, R wherein pBe:
-C 1To C 6Alkyl;
-amino, it is randomly by one or more C 1To C 6Alkyl replaces, and described alkyl is randomly and independently by one or more C 6To C 8Aryl and/or alkoxyl group replace; Or
-five yuan or hexa-member heterocycle, it is randomly by one or more C 1To C 6Alkyl and/or C 6To C 8Aryl replaces;
And R wherein oBe:
-hydrogen; Or
-C 1To C 6Alkyl;
-NR qCONR qR r, R wherein qBe hydrogen;
And R wherein rBe:
-C 1To C 6Alkyl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-halogen;
-hydroxyl;
-alkoxyl group;
-five yuan or hexa-member heterocycle;
-five yuan or six membered heteroaryl; And
-the C that randomly replaced by one or more halogens 6To C 8Aryl;
-C 2To C 6Thiazolinyl, it is randomly replaced by one or more halogens;
-C 1To C 6Alkoxyl group; Or
-five yuan or hexa-member heterocycle;
-SO 2R Aa, R wherein AaBe:
-five yuan or hexa-member heterocycle, it is randomly replaced by hydroxyl;
-C 1To C 6Alkoxyl group; Or
-C 1To C 6Alkyl;
-COR m, R wherein mBe:
-randomly by one or more C 1To C 6The amino that alkyl replaces, wherein C 1To C 6Alkyl is randomly by five yuan or hexa-member heterocycle replacement; Or
-ternary is to seven membered heterocyclic, and it is randomly by C 1To C 6Alkyl replaces, and described alkyl is randomly replaced by dialkyl-7-amino;
-NR tCOOR u, R wherein tBe hydrogen, R uBe:
-C 1To C 12Alkyl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-randomly by the C of one or more halogens and/or alkylhalide group replacement 6To C 8Aryl;
-the alkoxyl group that randomly replaced by one or more alkoxyl groups;
-randomly by one or more C 1To C 6The amino that alkyl replaces;
-halogen;
-five yuan or six membered heteroaryl, and
-five yuan or hexa-member heterocycle;
-C 2To C 6Thiazolinyl; Or
-C 6To C 8Aryl, it is randomly replaced by halogen;
-NHR Bb, R wherein BbBe:
-C (=S) NH 2Or
-PO(OR x) 2；
-NR vSO 2R w, R wherein vBe hydrogen, R wBe:
-C 1To C 6Alkyl; Or
-alkyl-amino or dialkyl-7-amino, it is randomly replaced by halogen;
Figure A20078000890202101
Z is:
-C 1To C 6Alkyl, it is randomly by five yuan or hexa-member heterocycle replacement; Or
-five yuan or hexa-member heterocycle;
R is a hydrogen;
R 1Be:
-hydrogen;
-five yuan or hexa-member heterocycle;
-C 1To C 6Alkyl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-randomly heterocyclically substituted amino;
-randomly by C 1To C 6The amido that alkyl replaces;
-five yuan or hexa-member heterocycle, it is randomly by C 1To C 6Alkyl replaces;
-five yuan or six membered heteroaryl, and
-C 6To C 8Aryl;
-C 1To C 6Alkoxyl group, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-randomly heterocyclically substituted amino;
-randomly by C 1To C 6The amido that alkyl replaces;
-five yuan or hexa-member heterocycle, it is randomly by C 1To C 6Alkyl replaces;
-five yuan or six membered heteroaryl,
-C 6To C 8Aryl;
-(O)-five yuan or hexa-member heterocycle;
-(O)-five yuan or six membered heteroaryl;
-randomly by one or more SO that are independently selected from the substituting groups replacement of following groups 2R x:
-five yuan or hexa-member heterocycle;
-C 6To C 8Aryl; And
-five yuan or six membered heteroaryl; Or
-randomly by one or more alkylthios that are independently selected from the substituting groups replacement of following groups:
-five yuan or hexa-member heterocycle;
-C 6To C 8Aryl; And
-five yuan or six membered heteroaryl;
R 2Be:
-C 1To C 6Alkyl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or hexa-member heterocycle;
-five yuan or six membered heteroaryl;
-C 6To C 8Aryl;
-randomly by C 1To C 6The amido that alkyl replaces; And
-amino, it is randomly replaced by one or more substituting groups that are independently selected from heterocycle, alkoxyl group and alkyl, and described alkyl is randomly replaced by one or more alkoxyl groups;
-alkylthio, randomly by five yuan or six membered heteroaryl replacement, described heteroaryl is randomly replaced by alkyl for it;
-alkylthio, it is randomly by five yuan or hexa-member heterocycle replacement;
-alkylthio, it is randomly by C 6To C 8Aryl replaces;
-alkylthio, it is randomly by C 1To C 6Alkyl replaces;
-SO 2R x, randomly by five yuan or six membered heteroaryl replacement, described heteroaryl is randomly by one or more C for they 1To C 6Alkyl replaces;
-SO 2R x, it is randomly by five yuan or hexa-member heterocycle replacement;
-SO 2R x, it is randomly by C 6To C 8Aryl replaces;
-SO 2R x, it is randomly by C 1To C 6Alkyl replaces;
-S (O) R x, it is randomly by five yuan or six membered heteroaryl replacement;
-S (O) R x, it is randomly by five yuan or hexa-member heterocycle replacement;
-S (O) R x, it is randomly by C 6To C 8Aryl replaces;
-S (O) R x, it is randomly by C 1To C 6Alkyl replaces;
-randomly by one or more alkoxyl groups that are independently selected from the substituting groups replacement of following groups:
-halogen;
-hydroxyl;
-the alkoxyl group that replaces of alkoxy randomly;
-amino, it is randomly replaced by one or more substituting groups that are independently selected from five yuan or six membered heteroaryl, five yuan or hexa-member heterocycle and alkyl, and described alkyl is randomly replaced by one or more substituting groups that are selected from following groups:
-five yuan or hexa-member heterocycle; And
-the amino that randomly replaced by one or more alkyl;
-randomly by C 1To C 6The amido that alkyl replaces;
Five yuan of-S-or hexa-member heterocycle;
Five yuan of-S-or six membered heteroaryl, it is randomly by C 1To C 6Alkyl replaces;
-S-C 1To C 6Alkyl;
-S-C 6To C 8Aryl;
-sulfinyl-five yuan or hexa-member heterocycle;
-sulfinyl-five yuan or six membered heteroaryl;
-sulfinyl-C 1To C 6Alkyl;
-sulfinyl-C 6To C 8Aryl;
-alkylsulfonyl-five yuan or hexa-member heterocycle;
-alkylsulfonyl-randomly by C 1To C 6Five yuan or six membered heteroaryl that alkyl replaces;
-alkylsulfonyl-C 1To C 6Alkyl;
-alkylsulfonyl-C 6To C 8Aryl;
-five yuan to seven membered heterocyclic, and it is randomly by one or more hydroxyl and C of being independently selected from 1To C 6The substituting group of alkyl replaces, and described alkyl is randomly by one or more C 1To C 6Alkoxyl group replaces;
-five yuan or six membered heteroaryl, it is randomly by one or more C 1To C 6Alkyl replaces; And
-C 6To C 8Aryl;
-C 6To C 8Aryl;
-(O)-five yuan or six membered heteroaryl, it is randomly by one or more C that select independently 1To C 6Alkyl replaces;
-C (O)-five yuan or hexa-member heterocycle, it is randomly by one or more C 6To C 8Aryl replaces;
-C (O)-C 6To C 8Aryl;
-COOH；
-C (O) NH 2, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-C 1To C 6Alkyl, it is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-amido, it is randomly by one or more C 1To C 6Alkyl replaces, and described alkyl is randomly by one or more C 1To C 6Alkoxyl group replaces;
-five yuan or six membered heteroaryl, it is randomly replaced by one or more substituting groups that are independently selected from down group:
-C 1To C 6Alkyl; And
-five yuan or hexa-member heterocycle, it is randomly replaced by one or more substituting groups that are independently selected from down group:
-hydroxyl;
-C 1To C 6Alkyl;
-SO 2R x；
-C (O)-C 6To C 8Aryl; And
-C (O) OR xOr
-OR Kk, R wherein KkBe:
-C 6To C 8Aryl;
-five yuan or hexa-member heterocycle, it is randomly by C 1To C 6Alkyl replaces, and described alkyl is randomly by C 6To C 8Aryl replaces;
Five yuan or six membered heteroaryl, it is randomly by one or more halogen, C of being independently selected from 1To C 6Alkyl, C 1To C 6Alkoxyl group and C 1To C 6The substituting group of alkylhalide group replaces;
-SO 2R xOr
-Si (R x) 3And
R 3Be hydrogen;
Condition is X, Y, Z, R 1And R 2In have a following selection at least:
X is:
-COOH；
-CH=N-(C 1To C 6Alkoxyl group);
-CH=N-is (randomly by one or more C 1To C 6The amino that alkyl replaces);
-halogen;
-the alkyl that randomly replaced by one or more halogens;
-randomly by C 1To C 6The alkynyl that alkyl replaces, described alkyl are randomly replaced by one or more halogens and/or cyano group;
-oximido;
-SO 2R x；
-SO 2NH 2；
-SO 2NH(R x)；
-SO 2N(R x) 2；
-randomly by one or more C 1To C 6Alkyl and/or C (O)-C 1To C 6The amino that alkyl replaces;
-randomly by one or more C that are independently selected from 1To C 6The amido that alkyl replaces;
-five yuan or hexa-member heterocycle;
-five yuan or six membered heteroaryl, it is by one or more C 1To C 6Alkyl replaces, and described alkyl is replaced by one or more halogens; Or
-C 6To C 8Aryl, it is replaced by one or more substituting groups that are independently selected from following groups:
-the C that randomly replaced by one or more halogens 1To C 6Alkyl;
-halogen; And
-cyano group;
Y is:
-by the amino benzothiazolyl that replaces, described amino is randomly by one or more C 1To C 6Alkyl replaces;
-indyl, it is at the quilt-SO of nitrogen-atoms place 2R xReplace; Or
-C 6To C 8Aryl, it is replaced by one or more substituting groups that are independently selected from following groups:
-randomly by one or more amino that are independently selected from the substituting groups replacement of following groups:
-SO 2R x, and
-C 1To C 6Alkyl, it is by one or more five yuan or six membered heteroaryl replacements;
-OC(O)NHR x；
-OC(O)N(R x) 2；
-OC(O)NH(OR x)；
-OC(O)NR x(OR x)；
-OC(O)N(OR x) 2；
-OC (O) R Ab, R wherein AbBe five yuan or hexa-member heterocycle;
-NR oCOR p, R wherein pBe:
-amino, it is randomly by one or more C 1To C 6Alkyl replaces, and described alkyl is randomly and independently by one or more C 6To C 8Aryl and/or alkoxyl group replace; Or
-five yuan or hexa-member heterocycle, it is by one or more C 1To C 6Alkyl and/or C 6To C 8Aryl replaces;
-NR qCONR qR r, R wherein rBe:
-C 1To C 6Alkyl, it is replaced by one or more substituting groups that are independently selected from following groups:
-hydroxyl;
-alkoxyl group;
-five yuan or hexa-member heterocycle;
-five yuan or six membered heteroaryl, and
-C 6To C 8Aryl, it is replaced by one or more halogens;
-C 2To C 6Thiazolinyl;
-C 1To C 6Alkoxyl group; Or
-five yuan or hexa-member heterocycle;
-NR tCOOR u, R wherein uBe:
-C 1To C 12Alkyl, it is replaced by one or more substituting groups that are independently selected from following groups:
-the alkoxyl group that replaced by one or more alkoxyl groups;
-randomly by one or more C 1To C 6The amino that alkyl replaces; And
-five yuan or six membered heteroaryl; Or
-C 2To C 6Thiazolinyl; And
Figure A20078000890202161
Z is:
-C 1To C 6Alkyl, it is randomly by five yuan or hexa-member heterocycle replacement; Or
-five yuan or hexa-member heterocycle;
R 1Be:
-C 1To C 6Alkyl, it is replaced by following groups:
-randomly by C 1To C 6The amido that alkyl replaces; And/or
-five yuan or six membered heteroaryl;
-C 1To C 6Alkoxyl group, it is replaced by following groups:
-randomly heterocyclically substituted amino;
-randomly by C 1To C 6The amido that alkyl replaces;
-five yuan or hexa-member heterocycle, it is randomly by C 1To C 6Alkyl replaces; And/or
-five yuan or six membered heteroaryl;
-(O)-five yuan or hexa-member heterocycle;
-(O)-five yuan or six membered heteroaryl;
-SO 2R x, it is randomly replaced by following groups:
-five yuan or hexa-member heterocycle;
-C 6To C 8Aryl; And/or
-five yuan or six membered heteroaryl; Or
-alkylthio, it is randomly replaced by following groups:
-five yuan or hexa-member heterocycle;
-C 6To C 8Aryl; And/or
-five yuan or six membered heteroaryl;
R 2Be:
-C 1To C 6Alkyl, it is replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or hexa-member heterocycle;
-five yuan or six membered heteroaryl;
-C 6To C 8Aryl;
-randomly by C 1To C 6The amido that alkyl replaces; And
-amino, it is randomly replaced by one or more substituting groups that are independently selected from heterocycle, alkoxyl group and alkyl, and described alkyl is randomly replaced by one or more alkoxyl groups;
-alkylthio, randomly by five yuan or six membered heteroaryl replacement, described heteroaryl is randomly replaced by alkyl for it;
-alkylthio, it is randomly by five yuan or hexa-member heterocycle replacement;
-alkylthio, it is randomly by C 6To C 8Aryl replaces;
-alkylthio, it is randomly by C 1To C 6Alkyl replaces;
-SO 2R x, randomly by five yuan or six membered heteroaryl replacement, described heteroaryl is randomly by one or more C for they 1To C 6Alkyl replaces;
-SO 2R x, it is randomly by five yuan or hexa-member heterocycle replacement;
-SO 2R x, it is randomly by C 6To C 8Aryl replaces;
-SO 2R x, it is randomly by C 1To C 6Alkyl replaces;
-S (O) R x, it is randomly by five yuan or six membered heteroaryl replacement;
-S (O) R x, it is randomly by five yuan or hexa-member heterocycle replacement;
-S (O) R x, it is randomly by C 6To C 8Aryl replaces;
-S (O) R x, it is randomly by C 1To C 6Alkyl replaces;
-alkoxyl group, it is replaced by following groups:
-alkoxyl group;
-amino, it is replaced by one or more substituting groups that are independently selected from five yuan or six membered heteroaryl, five yuan or hexa-member heterocycle and alkyl, and described alkyl is randomly replaced by one or more substituting groups that are selected from following groups:
-five yuan or hexa-member heterocycle; And
-the amino that randomly replaced by one or more alkyl;
-randomly by C 1To C 6The amido that alkyl replaces;
Five yuan of-S-or hexa-member heterocycle;
Five yuan of-S-or hexa-member heterocycle, it is randomly by C 1To C 6Alkyl replaces;
-S-C 1To C 6Alkyl;
-S-C 6To C 8Aryl;
-sulfinyl-five yuan or hexa-member heterocycle;
-sulfinyl-five yuan or six membered heteroaryl;
-sulfinyl-C 1To C 6Alkyl;
-sulfinyl-C 6To C 8Aryl;
-alkylsulfonyl-five yuan or hexa-member heterocycle;
-alkylsulfonyl-randomly by C 1To C 6Five yuan or six membered heteroaryl that alkyl replaces;
-alkylsulfonyl-C 1To C 6Alkyl;
-alkylsulfonyl-C 6To C 8Aryl;
-five yuan to seven membered heterocyclic, and it is by one or more hydroxyl and C of being independently selected from 1To C 6The substituting group of alkyl replaces, and described alkyl is by one or more C 1To C 6Alkoxyl group replaces;
-five yuan or six membered heteroaryl, it is by one or more C 1To C 6Alkyl replaces; Or
-C 6To C 8Aryl;
-C (O)-five yuan or hexa-member heterocycle, it is randomly by one or more C 6To C 8Aryl replaces;
-C (O)-C 6To C 8Aryl;
-COOH；
-amido, it is by one or more C 1To C 6Alkyl replaces, and described alkyl is randomly by one or more C 1To C 6Alkoxyl group replaces;
-five yuan or hexa-member heterocycle, it is replaced by one or more substituting groups that are independently selected from down group:
-hydroxyl;
-C 1To C 6Alkyl;
-SO 2R x；
-C (O)-C 6To C 8Aryl; And
-C(O)OR x；
-OR Kk, R wherein KkBe:
-C 6To C 8Aryl;
-five yuan or hexa-member heterocycle, it is randomly by one or more C 1To C 6Alkyl and/or C 6To C 8Aryl replaces; Or
-Si(R x) 3；
-(O)-five yuan or hexa-member heterocycle, it is randomly by one or more C that select independently 1To C 6Alkyl replaces; Or
-(O)-five yuan or six membered heteroaryl, it is randomly by one or more C that select independently 1To C 6Alkyl replaces.
2. the compound of embodiment 1, wherein:
X is:
-COOH；
-CH=N-(C 1To C 6Alkoxyl group);
-CH=N-is (randomly by one or more C 1To C 6The amino that alkyl replaces);
-halogen;
-the alkyl that randomly replaced by one or more halogens;
-randomly by C 1To C 6The alkynyl that alkyl replaces, described alkyl are randomly replaced by one or more halogens and/or cyano group;
-oximido;
-SO 2R x；
-SO 2NH 2；
-SO 2NH(R x)；
-SO 2N(R x) 2；
-randomly by one or more C 1To C 6Alkyl and/or-C (O)-C 1To C 6The amino that alkyl replaces;
-randomly by one or more C that are independently selected from 1To C 6The amido that alkyl replaces;
-five yuan or hexa-member heterocycle;
-five yuan or six membered heteroaryl, it is by one or more C 1To C 6Alkyl replaces, and described alkyl is replaced by one or more halogens; Or
-C 6To C 8Aryl, it is replaced by one or more substituting groups that are independently selected from following groups:
-the C that randomly replaced by one or more halogens 1To C 6Alkyl;
-halogen; And
-cyano group.
3. the compound of embodiment 2, wherein X is cyano group, halogen or the alkyl that replaced by one or more halogens.
4. the compound of embodiment 3, wherein X is a cyano group.
5. the compound of embodiment 3, wherein X is fluorine, bromine, chlorine or iodine.
6. the compound of embodiment 3, wherein X is a trifluoromethyl.
7. the compound of embodiment 1, wherein:
The C that Y is replaced by one or more following groups 6To C 8Aryl:
-randomly by one or more amino that are independently selected from the substituting groups replacement of following groups:
-SO 2R xAnd
-C 1To C 6Alkyl, it is by one or more five yuan or six membered heteroaryl replacements;
-OC(O)NHR x；
-OC(O)N(R x) 2；
-OC(O)NH(OR x)；
-OC(O)NR x(OR x)；
-OC(O)N(OR x) 2；
-OC (O) R Ab, R wherein AbBe five yuan or hexa-member heterocycle;
-NR oCOR p, R wherein pBe:
-amino, it is randomly by one or more C 1To C 6Alkyl replaces, and described alkyl is randomly and independently by one or more C 6To C 8Aryl and/or alkoxyl group replace; Or
-five yuan or hexa-member heterocycle, it is by one or more C 1To C 6Alkyl and/or C 6To C 8Aryl replaces,
-NR qCONR qR r, R wherein rBe:
-C 1To C 6Alkyl, it is replaced by one or more substituting groups that are independently selected from following groups:
-hydroxyl;
-alkoxyl group;
-five yuan or hexa-member heterocycle;
-five yuan or six membered heteroaryl, and
-C 6To C 8Aryl, it is replaced by halogen,
-C 2To C 6Thiazolinyl;
-C 1To C 6Alkoxyl group; Or
-five yuan or hexa-member heterocycle;
-NR tCOOR u, R wherein uBe:
-C 1To C 12Alkyl, it is replaced by one or more substituting groups that are independently selected from following groups:
-the alkoxyl group that replaced by one or more alkoxyl groups;
-randomly by one or more C 1To C 6The amino that alkyl replaces; And
-five yuan or six membered heteroaryl;
-C 2To C 6Thiazolinyl, or
Figure A20078000890202211
8. the compound of embodiment 7, wherein C 6To C 8Aryl is a phenyl.
9. the compound of embodiment 8, wherein the contraposition of phenyl has at least one substituting group.
10. the compound of embodiment 1, wherein Z is:
-C 1To C 6Alkyl, it is by five yuan or hexa-member heterocycle replacement; Or
-five yuan or hexa-member heterocycle.
11. the compound of embodiment 1, wherein Z is C 1To C 6Alkyl.
12. the compound of embodiment 11, wherein Z is cyclobutyl, cyclopropyl, cyclopropyl methyl, ethyl or cyclopentyl.
13. the compound of embodiment 1, wherein:
R 1Be:
-C 1To C 6Alkyl, it is replaced by following groups:
-randomly by C 1To C 6The amido that alkyl replaces; And/or
-five yuan or six membered heteroaryl;
-C 1To C 6Alkoxyl group, it is replaced by following groups:
-randomly heterocyclically substituted amino;
-randomly by C 1To C 6The amido that alkyl replaces;
-five yuan or hexa-member heterocycle, it is by C 1To C 6Alkyl replaces; And/or
-five yuan or six membered heteroaryl;
-(O)-five yuan or hexa-member heterocycle;
-(O)-five yuan or six membered heteroaryl;
-SO 2R x, it is randomly replaced by following groups:
-five yuan or hexa-member heterocycle;
-C 6To C 8Aryl; And/or
-five yuan or six membered heteroaryl; Or
-alkylthio, it is randomly replaced by following groups:
-five yuan or hexa-member heterocycle;
-C 6To C 8Aryl; And/or
-five yuan or six membered heteroaryl;
14. the compound of embodiment 1, wherein:
R 2Be:
-C 1To C 6Alkyl, it is replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or hexa-member heterocycle;
-five yuan or six membered heteroaryl;
-C 6To C 8Aryl;
-randomly by C 1To C 6The amido that alkyl replaces; And
-amino, it is randomly replaced by one or more substituting groups that are independently selected from heterocycle, alkoxyl group and alkyl, and described alkyl is randomly replaced by one or more alkoxyl groups;
-alkylthio, randomly by five yuan or six membered heteroaryl replacement, described heteroaryl is randomly replaced by alkyl for it;
-alkylthio, it is randomly by five yuan or hexa-member heterocycle replacement;
-alkylthio, it is randomly by C 6To C 8Aryl replaces;
-alkylthio, it is randomly by C 1To C 6Alkyl replaces;
-SO 2R x, randomly by five yuan or six membered heteroaryl replacement, described heteroaryl is randomly by one or more C for they 1To C 6Alkyl replaces;
-SO 2R x, it is randomly by five yuan or hexa-member heterocycle replacement;
-SO 2R x, it is randomly by C 6To C 8Aryl replaces;
-SO 2R x, it is randomly by C 1To C 6Alkyl replaces;
-S (O) R x, it is randomly by five yuan or six membered heteroaryl replacement;
-S (O) R x, it is randomly by five yuan or hexa-member heterocycle replacement;
-S (O) R x, it is randomly by C 6To C 8Aryl replaces;
-S (O) R x, it is randomly by C 1To C 6Alkyl replaces;
-alkoxyl group, it is replaced by following groups:
-alkoxyl group;
-amino, it is replaced by one or more substituting groups that are independently selected from five yuan or six membered heteroaryl, five yuan or hexa-member heterocycle and alkyl, and described alkyl is randomly replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or hexa-member heterocycle; And
-the amino that randomly replaced by one or more alkyl;
-randomly by C 1To C 6The amido that alkyl replaces;
Five yuan of-S-or hexa-member heterocycle;
Five yuan of-S-or six membered heteroaryl, it is randomly by C 1To C 6Alkyl replaces;
-S-C 1To C 6Alkyl;
-S-C 6To C 8Aryl;
-sulfinyl-five yuan or hexa-member heterocycle;
-sulfinyl-five yuan or six membered heteroaryl;
-sulfinyl-C 1To C 6Alkyl;
-sulfinyl-C 6To C 8Aryl;
-alkylsulfonyl-five yuan or hexa-member heterocycle;
-alkylsulfonyl-randomly by C 1To C 6Five yuan or six membered heteroaryl that alkyl replaces;
-alkylsulfonyl-C 1To C 6Alkyl;
-alkylsulfonyl-C 6To C 8Aryl;
-five yuan to seven membered heterocyclic, and it is by one or more hydroxyl and C of being independently selected from 1To C 6The substituting group of alkyl replaces, and described alkyl is by C 1To C 6Alkoxyl group replaces;
-five yuan or six membered heteroaryl, it is by one or more C 1To C 6Alkyl replaces; Or
-C 6To C 8Aryl;
-C (O)-five yuan or hexa-member heterocycle, it is randomly by one or more C 6To C 8Aryl replaces;
-C (O)-C 6To C 8Aryl;
-COOH；
-amido, it is by one or more C 1To C 6Alkyl replaces, and described alkyl is randomly by one or more C 1To C 6Alkoxyl group replaces;
-five yuan or hexa-member heterocycle, it is replaced by one or more substituting groups that are independently selected from down group:
-hydroxyl;
-C 1To C 6Alkyl;
-SO 2R x；
-C (O)-C 6To C 8Aryl; And
-C(O)OR x；
-OR Kk, R wherein KkBe:
-C 6To C 8Aryl;
-five yuan or hexa-member heterocycle, it is randomly by one or more C 1To C 6Alkyl and/or C 6To C 8Aryl replaces; Or
-Si(Rx) 3；
-(O)-five yuan or hexa-member heterocycle; Or
-(O)-five yuan or six membered heteroaryl, it is randomly by one or more C that select independently 1To C 6Alkyl replaces.
15. the compound of embodiment 1, wherein:
X is:
-cyano group;
-halogen; Or
-alkynyl, it is randomly by C 1To C 6Alkyl replaces;
Y is:
-C 6To C 8Aryl, it is replaced by one or more substituting groups that are independently selected from following groups:
-halogen;
-hydroxyl;
-alkoxyl group, it is randomly replaced by following groups:
-one or more halogens; Or
-five yuan or hexa-member heterocycle;
-C 1To C 6Alkyl;
-randomly by one or more amino that are independently selected from the substituting groups replacement of following groups:
-SO 2R xAnd
-C 1To C 6Alkyl, it is replaced by one or more five yuan or six membered heteroaryl randomly and independently;
-OC(O)NHR x；
-NR oCOR p, R wherein pBe:
-C 1To C 6Alkyl; Or
-randomly by one or more C 1To C 6The amino that alkyl replaces;
And R wherein oBe hydrogen;
-NR qCONR qR r, R wherein qBe hydrogen, R rBe:
-the C that randomly replaced by one or more halogens 1To C 6Alkyl; Or
-C 6To C 8Aryl, it is randomly replaced by halogen;
-SO 2R Aa, R wherein AaBe:
-five yuan or hexa-member heterocycle, it is randomly replaced by hydroxyl;
-C 1To C 6Alkoxyl group; Or
-C 1To C 6Alkyl;
-COR m, R wherein mBe:
-amino, it is randomly by one or more C 1To C 6Alkyl replaces, wherein C 1To C 6Alkyl is randomly by five yuan or hexa-member heterocycle replacement; Or
-ternary is to seven membered heterocyclic, and it is randomly by C 1To C 6Alkyl replaces, and described alkyl is randomly replaced by dialkyl-7-amino;
-NR tCOOR u, R wherein tBe hydrogen, R uBe:
-C 1To C 12Alkyl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-randomly by the C of one or more halogens and/or alkylhalide group replacement 6To C 8Aryl;
-halogen; And
-five yuan or six membered heteroaryl;
-C 6To C 8Aryl, it is randomly replaced by halogen; Or
-five yuan or hexa-member heterocycle;
-NHR Bb, R wherein BbBe:
-C (=S) NH 2Or
-PO(OR x) 2；
-NR vSO 2R w, R wherein vBe hydrogen, R wBe:
-C 1To C 6Alkyl; Or
-alkyl-amino or dialkyl-7-amino, it is randomly replaced by halogen; Or
Figure A20078000890202261
Z is:
-C 1To C 6Alkyl; Or
-five yuan or hexa-member heterocycle;
R is a hydrogen;
R 1Be:
-hydrogen;
-C 1To C 6Alkoxyl group, it is replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or hexa-member heterocycle; And
-five yuan or six membered heteroaryl;
-(O)-five yuan or hexa-member heterocycle;
-(O)-five yuan or six membered heteroaryl; Or
-five yuan or hexa-member heterocycle;
R 2Be:
-the alkoxyl groups that replaced by one or more substituting groups that are independently selected from following groups:
-halogen;
-hydroxyl;
-the alkoxyl group that replaces of alkoxy randomly;
-amino, it is randomly replaced by one or more substituting groups that are independently selected from five yuan or six membered heteroaryl, five yuan or hexa-member heterocycle and alkyl, and described alkyl is randomly replaced by one or more substituting groups that are selected from following groups:
-five yuan or hexa-member heterocycle; And
-the amino that replaced by one or more alkyl;
-randomly by C 1To C 6The amido that alkyl replaces;
Five yuan of-S-or six membered heteroaryl, it is randomly by C 1To C 6Alkyl replaces;
-S-C 1To C 6Alkyl;
-sulfinyl-C 1To C 6Alkyl;
-alkylsulfonyl-C 1To C 6Alkyl;
-five yuan to seven membered heterocyclic, and it is randomly by one or more hydroxyl and C of being independently selected from 1To C 6The substituting group of alkyl replaces, and described alkyl is randomly by one or more C that select independently 1To C 6Alkoxyl group replaces; And
-five yuan or six membered heteroaryl, it is randomly by one or more C 1To C 6Alkyl replaces;
-SO 2R x, it is randomly by C 1To C 6Alkyl replaces;
-S (O) R x, it is randomly by C 1To C 6Alkyl replaces;
-(O)-five yuan or six membered heteroaryl, it is randomly by one or more C that select independently 1To C 6Alkyl replaces;
-C (O)-five yuan or hexa-member heterocycle, it is randomly by one or more C 6To C 8Aryl replaces;
-C (O)-C 6To C 8Aryl;
-COOH；
-C (O) NH 2, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-C 1To C 6Alkyl, it is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-five yuan or hexa-member heterocycle, it is randomly replaced by one or more substituting groups that are independently selected from down group:
-C 1To C 6Alkyl; And
-five yuan or hexa-member heterocycle, it is randomly replaced by one or more substituting groups that are independently selected from down group:
-one or more halogens;
-C 1To C 6Alkyl; And
-SO 2R x；
-amido, it is randomly by one or more C 1To C 6Alkyl replaces, and described alkyl is randomly by one or more C 1To C 6Alkoxyl group replaces; Or
-OR Kk, R wherein KkBe:
Five yuan or six membered heteroaryl, it is randomly by one or more halogen, C of being independently selected from 1To C 6Alkyl, C 1To C 6Alkoxyl group and C 1To C 6The substituting group of alkylhalide group replaces; Or
-five yuan or hexa-member heterocycle, it is randomly by C 1To C 6Alkyl replaces, and described alkyl is randomly by C 6To C 8Aryl replaces; And
R 3Be hydrogen.
16. the compound of embodiment 15, wherein:
X is:
-cyano group; Or
-halogen;
Y is:
-the phenyl that replaced by one or more substituting groups that are independently selected from following groups:
-halogen; And
-NR tCOOR u, R wherein tBe hydrogen, R uBe:
-C 1To C 12Alkyl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-the C that randomly replaced by one or more halogens 6To C 8Aryl;
-halogen; And
-five yuan or six membered heteroaryl;
-C 6To C 8Aryl, it is randomly replaced by halogen; Or
-five yuan or hexa-member heterocycle;
Z is C 1To C 6Alkyl;
R is a hydrogen;
R 1Be hydrogen;
R 2Be:
-the alkoxyl groups that replaced by one or more substituting groups that are independently selected from following groups:
-halogen; And
-the alkoxyl group that replaces of alkoxy randomly;
-(O)-five yuan or hexa-member heterocycle;
-amido, it is randomly by one or more C 1To C 6Alkyl replaces, and described alkyl is randomly by one or more C 1To C 6Alkoxyl group replaces;
-five yuan or hexa-member heterocycle, it is randomly replaced by one or more substituting groups that are independently selected from down group:
-one or more halogens;
-C 1To C 6Alkyl; And
-SO 2R xAnd
R 3Be hydrogen.
17. the compound of embodiment 15, wherein:
X is a cyano group;
Y is C 6To C 8Aryl, it is by one or more NR that are independently selected from tCOOR uSubstituting group replace, wherein be hydrogen, R uBe randomly by one or more C 6To C 8The C that aryl replaces 1To C 12Alkyl;
Z is five yuan or hexa-member heterocycle;
R is a hydrogen;
R 1Be hydrogen;
R 2It is alkoxyl group; And
R 3Be hydrogen.
18. the compound of embodiment 15, wherein:
X is a cyano group;
Y is C 6To C 8Aryl, it is replaced by one or more substituting groups that are independently selected from following groups:
-randomly by C 1To C 6The amino that alkyl replaces;
-NR qCONR qR r, R wherein qBe hydrogen, R rBe C 1To C 6Alkyl:
-COR m, R wherein mBe:
-randomly by one or more C 1To C 6The amino that alkyl replaces, wherein C 1To C 6Alkyl is randomly by five yuan or hexa-member heterocycle replacement; Or
-ternary is to seven membered heterocyclic; And
-NR tCOOR u, R wherein tBe hydrogen, R uBe:
-C 1To C 12Alkyl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-the C that randomly replaced by one or more alkylhalide groups 6To C 8Aryl; And
-halogen, or
-five yuan or hexa-member heterocycle;
Z is C 1To C 6Alkyl;
R is a hydrogen;
R 1Be hydrogen;
R 2It is the alkoxyl group that alkoxy replaces; And
R 3Be hydrogen.
19. the compound of embodiment 15, wherein:
X is a cyano group;
Y is C 6To C 8Aryl, it is replaced by one or more substituting groups that are independently selected from following groups:
-NR tCOOR u, R wherein tBe hydrogen, R uThe C that is replaced by one or more halogens 1To C 12Alkyl; And
-NR vSO 2R w, R wherein vBe hydrogen, R wBe C 1To C 6Alkyl;
Z is C 1To C 6Alkyl;
R is a hydrogen;
R 1Be hydrogen;
R 2Be amido, it is randomly by one or more C 1To C 6Alkyl replaces, and described alkyl is by one or more C 1To C 6Alkoxyl group replaces; And
R 3Be hydrogen.
20. the compound of embodiment 15, wherein:
X is a cyano group;
Y is C 6To C 8Aryl, it is replaced by one or more substituting groups that are independently selected from following groups:
-randomly by one or more C 1To C 6The amino that alkyl replaces;
-NR tCOOR u, R wherein tBe hydrogen, R uBe the C that is randomly replaced by one or more halogens 1To C 12Alkyl;
-NR vSO 2R w, R wherein vBe hydrogen, R wBe C 1To C 6Alkyl; And
Figure A20078000890202301
Z is C 1To C 6Alkyl;
R is a hydrogen;
R 1Be hydrogen;
R 2By alkylsulfonyl-C 1To C 6The alkoxyl group that alkyl replaces; And
R 3Be hydrogen.
21. the compound of embodiment 15, wherein Y is C 6To C 8Aryl, it is by one or more NR that are independently selected from tCOOR uSubstituting group replace R wherein tBe hydrogen, R uBe the C that is randomly replaced by one or more halogens 1To C 12Alkyl.
22. the compound of embodiment 15, wherein:
X is a cyano group;
Y is C 6To C 8Aryl, it is replaced by one or more substituting groups that are independently selected from following groups:
-C 1To C 6Alkyl;
-randomly by one or more C 1To C 6The amino that alkyl replaces;
-NR qCONR qR r, R wherein qBe hydrogen, R rBe C 1To C 6Alkyl:
-NR tCOOR u, R wherein tBe hydrogen, R uBe C 1To C 12Alkyl;
-NR vSO 2R w, R wherein vBe hydrogen, R wBe:
-C 1To C 6Alkyl; Or
-alkyl-amino or dialkyl-7-amino;
Z is C 1To C 6Alkyl;
R is a hydrogen;
R 1Be hydrogen;
R 2Be OR Kk, R wherein KkBe five yuan or six membered heteroaryl, it is by one or more halogen, C of being independently selected from 1To C 6Alkyl, C 1To C 6Alkoxyl group and C 1To C 6The substituting group of alkylhalide group replaces; And
R 3Be hydrogen.
23. the compound of embodiment 22, wherein:
X is a cyano group;
Y is C 6To C 8Aryl, it is replaced by one or more substituting groups that are independently selected from following groups:
-NR tCOOR u, R wherein tBe hydrogen, R uBe C 1To C 12Alkyl; And
-NR vSO 2R w, R wherein vBe hydrogen, R wBe:
-C 1To C 6Alkyl; Or
-alkyl-amino or dialkyl-7-amino;
Z is C 1To C 6Alkyl;
R is a hydrogen;
R 1Be hydrogen;
R 2Be OR Kk, R wherein KkBe five yuan or six membered heteroaryl, it is by one or more halogen, C of being independently selected from 1To C 6Alkyl, C 1To C 6Alkoxyl group and C 1To C 6The substituting group of alkylhalide group replaces; And
R 3Be hydrogen.
24. the compound of embodiment 22, wherein R 2Be OR Kk, R wherein KkBy one or more C 1To C 6Five yuan or six membered heteroaryl that alkylhalide group replaces.
25. the compound of embodiment 22, wherein R 2Be OR Kk, R wherein KkBy one or more C 1To C 6Five yuan or six membered heteroaryl that alkyl replaces.
26. the compound of embodiment 1, wherein:
X is a cyano group;
Y is C 6To C 8Aryl, it is replaced by one or more substituting groups that are independently selected from following groups:
-NR tCOOR u, R wherein tBe hydrogen, R uBe C 1To C 12Alkyl; And
-NR vSO 2R w, R wherein vBe hydrogen, R wBe C 1To C 6Alkyl;
Z is C 1To C 6Alkyl;
R is a hydrogen;
R 1Be hydrogen;
R 2Be C (O)-five yuan or hexa-member heterocycle; And
R 3Be hydrogen.
27. the compound of embodiment 1, wherein:
X is a halogen;
Y is C 6To C 8Aryl, it is replaced by one or more substituting groups that are independently selected from following groups:
-amino;
-NR qCONR qR r, R wherein qBe hydrogen, R rBe C 1To C 6Alkyl; And
-NR tCOOR u, R wherein tBe hydrogen, R uBe C 1To C 12Alkyl;
Z is C 1To C 6Alkyl;
R is a hydrogen;
R 1Be hydrogen;
R 2It is alkoxyl group; And
R 3Be hydrogen.
The compound of 28 embodiments 15, wherein:
X is a cyano group;
Y is C 6To C 8Aryl, it is replaced by one or more substituting groups that are independently selected from following groups:
-halogen;
-NR qCONR qR r, R wherein qBe hydrogen, R rBe C 1To C 6Alkyl:
-NR tCOOR u, R wherein tBe hydrogen, R uBe C 1To C 12Alkyl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-C 6To C 8Aryl, it is randomly replaced by one or more halogens; And
-halogen;
-NR vSO 2R w, R wherein vBe hydrogen, R wBe:
-C 1To C 6Alkyl; Or
-alkyl-amino or dialkyl-7-amino, it is randomly replaced by halogen; And
Figure A20078000890202331
Z is C 1To C 6Alkyl;
R is a hydrogen;
R 1Be hydrogen;
R 2Be five yuan or hexa-member heterocycle; And
R 3Be hydrogen.
29. the compound of embodiment 28, wherein Y is by NR vSO 2R wThe C that replaces 6To C 8Aryl, wherein R vBe hydrogen, R wBe C 1To C 6Alkyl.
30. the compound of embodiment 28, the wherein C that replaced by following formula of Y 6To C 8Aryl:
Figure A20078000890202332
31. the compound of embodiment 15, wherein:
X is a cyano group;
Y is C 6To C 8Aryl, it is replaced by one or more substituting groups that are independently selected from following groups:
-halogen;
-randomly by one or more C 1To C 6The amino that alkyl replaces;
-OC(O)NHR x；
-NR qCONR qR r, R wherein qBe hydrogen, R rBe C 1To C 6Alkyl:
-NR tCOOR u, R wherein tBe hydrogen, R uBe C 1To C 12Alkyl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-C 6To C 8Aryl, it is randomly replaced by one or more halogens and/or alkylhalide group; And
-halogen;
-NHR Bb, R wherein BbBe-C (=S) NH 2
-NR vSO 2R w, R wherein vBe hydrogen, R wBe:
-C 1To C 6Alkyl; Or
-alkyl-amino or dialkyl-7-amino, it is randomly replaced by halogen; And
Figure A20078000890202341
Z is C 1To C 6Alkyl;
R is a hydrogen;
R 1Be hydrogen;
R 2Be (O)-five yuan or hexa-member heterocycle; And
R 3Be hydrogen.
32. the compound of embodiment 31, wherein Y is by NR tCOOR uThe C that replaces 6To C 8Aryl, wherein R tBe hydrogen, R uBe randomly to be independently selected from randomly by the C of one or more halogens and/or alkylhalide group replacement by one or more 6To C 8The C that the substituting group of aryl replaces 1To C 12Alkyl.
33. the compound of embodiment 15, wherein:
X is a cyano group;
Y is C 6To C 8Aryl, it is by one or more NR that are independently selected from tCOOR uSubstituting group replace R wherein tBe hydrogen, R uThe C that is replaced by one or more halogens 1To C 12Alkyl;
Z is C 1To C 6Alkyl;
R is a hydrogen;
R 1Be
-hydrogen;
-(O)-five yuan or hexa-member heterocycle; Or
-five yuan or hexa-member heterocycle;
R 2Be:
-the alkoxyl groups that replaced by one or more substituting groups that are independently selected from following groups:
-halogen;
-alkoxyl group;
-alkylsulfonyl-C 1To C 6Alkyl;
-five yuan to seven membered heterocyclic;
-five yuan or six membered heteroaryl;
-(O)-five yuan or hexa-member heterocycle;
-(O)-five yuan or six membered heteroaryl;
-five yuan or six membered heteroaryl;
-five yuan or hexa-member heterocycle; Or
-OR Kk, R wherein KkBe randomly by one or more C 1To C 6Five yuan or six membered heteroaryl that alkoxyl group replaces; And
R 3Be hydrogen.
34. the compound of embodiment 33, wherein R 1Be hydrogen, R 2The alkoxyl group that is replaced by one or more halogens.
35. the compound of embodiment 33, wherein R 1Be hydrogen, R 2The alkoxyl group that is replaced by one or more alkoxyl groups.
36. the compound of embodiment 15, wherein:
X is a cyano group;
Y is C 6To C 8Aryl, it is replaced by one or more substituting groups that are independently selected from following groups:
-NR qCONR qR r, R wherein qBe hydrogen, R rThe C that is replaced by halogen 6To C 8Aryl; And
-NR tCOOR u, R wherein tBe hydrogen, R uBy C 6To C 8The C that aryl replaces 1To C 12Alkyl, described aryl is replaced by one or more halogens and/or alkylhalide group;
Z is C 1To C 6Alkyl;
R is a hydrogen;
R 1Be hydrogen;
R 2Be:
-the alkoxyl groups that replaced by one or more substituting groups that are independently selected from following groups:
-alkoxyl group; And
-five yuan or six membered heteroaryl;
-(O)-five yuan or hexa-member heterocycle; Or
-(O)-five yuan or six membered heteroaryl; And
R 3Be hydrogen.
37. the compound of embodiment 36, wherein Y is by NR qCONR qR rThe C that replaces 6To C 8Aryl, wherein R qBe hydrogen, R rThe C that is replaced by halogen 6To C 8Aryl.
38. the compound of embodiment 36, wherein Y is by one or more NR that are independently selected from tCOOR uThe C that replaces of substituting group 6To C 8Aryl, wherein R tBe hydrogen, R uBy C 6To C 8The C that aryl replaces 1To C 12Alkyl, described aryl is replaced by one or more halogens and/or alkylhalide group.
39. formula IIb compound
Figure A20078000890202361
Or the acceptable salt of their pharmacology, wherein:
X is a cyano group;
Y is C 6To C 8Aryl, it is replaced by one or more substituting groups that are independently selected from following groups:
-C 1To C 6Alkyl;
-by C 1To C 6The amino that alkyl replaces;
-NR tCOOR u, R wherein tBe hydrogen, R uBe the C that is randomly replaced by one or more halogens 1To C 12Alkyl;
-NR vSO 2R w, R wherein vBe hydrogen, R wBe C 1To C 6Alkyl;
Z is C 1To C 6Alkyl;
R is a hydrogen;
R 1Be hydrogen;
R 2Be:
-the alkoxyl group that replaced by one or more halogens;
-five yuan or hexa-member heterocycle;
-five yuan or six membered heteroaryl, it is randomly replaced by one or more substituting groups that are independently selected from down group:
-C 1To C 6Alkyl; And
-NO 2；
-C (O)-ternary to seven membered heterocyclic or-C (O)-5 yuan heterocycle; And
-OR Kk, R wherein KkBe:
-five yuan or six membered heteroaryl, it is randomly by one or more cyano group and C of being independently selected from 1To C 6Alkyl replaces; Or
-five yuan or hexa-member heterocycle, it is randomly replaced by one or more=O; And
R 3Be hydrogen.
40. the compound of embodiment 39, wherein:
X is a cyano group;
Y is C 6To C 8Aryl, it is by NR tCOOR uReplace, wherein R tBe hydrogen, R uThe C that is replaced by one or more halogens 1To C 12Alkyl;
Z is C 1To C 6Alkyl;
R is a hydrogen;
R 1Be hydrogen;
R 2The alkoxyl group that is replaced by one or more halogens; And
R 3Be hydrogen.
41. the compound of embodiment 40, wherein C 6To C 8Aryl is a phenyl.
42. the compound of embodiment 41, wherein said phenyl is substituted in contraposition.
43. the compound of embodiment 41, wherein R uThe C that is replaced by fluorine 1To C 12Alkyl.
44. the compound of embodiment 39, wherein:
X is a cyano group;
Y is C 6To C 8Aryl, it is replaced by one or more substituting groups that are independently selected from following groups:
-C 1To C 6Alkyl;
-by C 1To C 6The amino that alkyl replaces; And
-NR vSO 2R w, R wherein vBe hydrogen, R wBe C 1To C 6Alkyl;
Z is C 1To C 6Alkyl;
R is a hydrogen;
R 1Be hydrogen;
R 2Be OR Kk, R wherein KkFive yuan or six membered heteroaryl being replaced by cyano group; And
R 3Be hydrogen.
45. the compound of embodiment 44, wherein Y is by NR vSO 2R wC at para-orientation 6To C 8Aryl, wherein R vBe hydrogen, R wBe C 1To C 6Alkyl.
46. the compound of embodiment 44, wherein Y is by C 1To C 6Alkyl and NR vSO 2R wC at para-orientation 6To C 8Aryl, wherein R vBe hydrogen, R wBe C 1To C 6Alkyl.
47. the compound of embodiment 44, wherein Y is by the C of amino at para-orientation 6To C 8Aryl, wherein amino by C 1To C 6Alkyl replaces.
48. the compound of embodiment 44, wherein R 2Be OR Kk, R wherein KkBy five yuan or the six membered heteroaryl of cyano group in the ortho position replacement.
49. the compound of embodiment 39, wherein:
X is a cyano group;
Y is C 6To C 8Aryl, it is replaced by one or more substituting groups that are independently selected from following groups:
-NR tCOOR u, R wherein tBe hydrogen, R uBe C 1To C 12Alkyl; And
-NR vSO 2R w, R wherein vBe hydrogen, R wBe C 1To C 6Alkyl;
Z is C 1To C 6Alkyl;
R is a hydrogen;
R 1Be hydrogen;
R 2Be OR Kk, R wherein KkBy C 1To C 6Five yuan or six membered heteroaryl that alkyl replaces; And R 3Be hydrogen.
50. the compound of embodiment 49, wherein C 6To C 8Aryl is a phenyl.
51. the compound of embodiment 50, wherein Y is by NR vSO 2R wAt the phenyl of para-orientation, wherein R vBe hydrogen, R wBe C 1To C 6Alkyl.
52. the compound of embodiment 50, wherein Y is by NR tCOOR uAt the phenyl of para-orientation, wherein R tBe hydrogen, R uBe C 1To C 12Alkyl.
53. the compound of embodiment 39, wherein:
X is a cyano group;
Y is C 6To C 8Aryl, it is by NR tCOOR uReplace, wherein R tBe hydrogen, R uThe C that is replaced by one or more halogens 1To C 12Alkyl;
Z is C 1To C 6Alkyl;
R is a hydrogen;
R 1Be hydrogen;
R 2Be OR Kk, R wherein KkBe five yuan or six membered heteroaryl; And
R 3Be hydrogen.
54. the compound of embodiment 53, wherein C 6To C 8Aryl is a phenyl.
55. the compound of embodiment 54, wherein said phenyl is substituted in contraposition.
56. the compound of embodiment 55, wherein R uThe C that is replaced by fluorine 1To C 12Alkyl.
57. the compound of embodiment 39, wherein:
X is a cyano group;
Y is by NR tCOOR uThe C that replaces 6To C 8Aryl, wherein R tBe hydrogen, R uBe the C that is randomly replaced by one or more halogens 1To C 12Alkyl;
Z is C 1To C 6Alkyl;
R is a hydrogen;
R 1Be hydrogen;
R 2Be five yuan or six membered heteroaryl, it is randomly by C 1To C 6Alkyl replaces; And
R 3Be hydrogen.
58. the compound of embodiment 57, wherein C 6To C 8Aryl is a phenyl.
59. the compound of embodiment 58, wherein Y is by NR tCOOR uAt the phenyl of para-orientation, wherein R tBe hydrogen, R uBe C 1To C 12Alkyl.
60. the compound of embodiment 58, wherein Y is by NR tCOOR uAt the phenyl of para-orientation, wherein R tBe hydrogen, R uThe C that is replaced by one or more halogens 1To C 12Alkyl.
61. the compound of embodiment 60, wherein R uThe C that is replaced by fluorine 1To C 12Alkyl.
62. the compound of embodiment 39, wherein:
X is a cyano group;
Y is by NR tCOOR uThe C that replaces 6To C 8Aryl, wherein R tBe hydrogen, R uBe C 1To C 12Alkyl;
Z is C 1To C 6Alkyl;
R is a hydrogen;
R 1Be hydrogen;
R 2Be OR Kk, R wherein KkBe five yuan or hexa-member heterocycle; And
R 3Be hydrogen.
63. the compound of embodiment 62, wherein C 6To C 8Aryl is a phenyl.
64. the compound of embodiment 63, wherein said phenyl is substituted in contraposition.
65. the compound of embodiment 39, wherein:
X is a cyano group;
Y is by NR tCOOR uThe C that replaces 6To C 8Aryl, wherein R tBe hydrogen, R uBe C 1To C 12Alkyl;
Z is C 1To C 6Alkyl;
R is a hydrogen;
R 1Be hydrogen;
R 2Be five yuan or hexa-member heterocycle; And
R 3Be hydrogen.
66. the compound of embodiment 65, wherein C 6To C 8Aryl is a phenyl.
67. the compound of embodiment 66, wherein said phenyl is substituted in contraposition.
68. the compound of embodiment 39, wherein:
X is a cyano group;
Y is by NR tCOOR uThe C that replaces 6To C 8Aryl, wherein R tBe hydrogen, R uBe C 1To C 12Alkyl;
Z is C 1To C 6Alkyl;
R is a hydrogen;
R 1Be hydrogen;
R 2By NO 2Five yuan or six membered heteroaryl replacing; And
R 3Be hydrogen.
69. the compound of embodiment 68, wherein C 6To C 8Aryl is a phenyl.
70. the compound of embodiment 69, wherein said phenyl is substituted in contraposition.
71. the compound of embodiment 39, wherein:
X is a cyano group;
Y is by NR tCOOR uThe C that replaces 6To C 8Aryl, wherein R tBe hydrogen, R uBe C 1To C 12Alkyl;
Z is C 1To C 6Alkyl;
R is a hydrogen;
R 1Be hydrogen;
R 2Be-C (O)-ternary to seven membered heterocyclic or-C (O)-five-membered ring; And
R 3Be hydrogen.
72. the compound of embodiment 71, wherein C 6To C 8Aryl is a phenyl.
73. the compound of embodiment 72, wherein said phenyl is substituted in contraposition.
74. the compound of embodiment 39, wherein:
X is a cyano group;
Y is by NR tCOOR uThe C that replaces 6To C 8Aryl, wherein R tBe hydrogen, R uBe C 1To C 12Alkyl;
Z is C 1To C 6Alkyl;
R is a hydrogen;
R 1Be hydrogen;
R 2Be OR Kk, R wherein KkBy five yuan or hexa-member heterocycle of one or more=O replacement; And
R 3Be hydrogen.
75. the compound of embodiment 74, wherein C 6To C 8Aryl is a phenyl.
76. the compound of embodiment 75, wherein said phenyl is substituted in contraposition.
77. formula IIc compound
Figure A20078000890202421
Or the acceptable salt of their pharmacology, wherein:
X is a cyano group;
Y is C 6To C 8Aryl, it is replaced by one or more substituting groups that are independently selected from following groups:
-NR qCONR qR r, R wherein qBe hydrogen, R rBe C 1To C 6Alkyl:
-NR tCOOR u, R wherein tBe hydrogen, R uBe C 1To C 12Alkyl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-the C that randomly replaced by one or more halogens 6To C 8Aryl;
-halogen; And
-five yuan or six membered heteroaryl, and
-NR vSO 2R w, R wherein vBe hydrogen, R wBe C 1To C 6Alkyl;
Z is:
-C 1To C 6Alkyl; Or
-five yuan or hexa-member heterocycle;
R is a hydrogen;
R 1Be:
-C 1To C 6Alkoxyl group, it is replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or hexa-member heterocycle; And
-five yuan or six membered heteroaryl;
-(O)-five yuan or hexa-member heterocycle;
-(O)-five yuan or six membered heteroaryl; Or
-five yuan or hexa-member heterocycle;
R 2Be hydrogen; And
R 3Be hydrogen;
Condition is to work as R 1The C that is replaced by five yuan or hexa-member heterocycle 1To C 6Alkoxyl group or R 1When being five yuan or hexa-member heterocycle, Y is by NR tCOOR uThe C that replaces 6To C 8Aryl, wherein R tBe hydrogen, R uBe:
The C that is replaced by one or more halogens 1To C 12Alkyl; Or
The aryl that is replaced by one or more halogens;
78. the compound of embodiment 77, wherein:
Y is by NR tCOOR uThe C that replaces 6To C 8Aryl, wherein R tBe hydrogen, R uBe C 1To C 12Alkyl;
Z is C 1To C 6Alkyl; And
R 1The C that is replaced by five yuan or six membered heteroaryl 1To C 6Alkoxyl group.
79. the compound of embodiment 77, wherein R 1The C that is replaced by five yuan or six membered heteroaryl 1To C 6Alkoxyl group.
80. the compound of embodiment 77, wherein R 1Be (O)-five yuan or hexa-member heterocycle.
81. the compound of embodiment 77, wherein R 1Be (O)-five yuan or six membered heteroaryl.
82. the compound of embodiment 77, wherein Z is cyclobutyl, cyclopropyl, cyclopropyl methyl, ethyl or cyclopentyl.
83. formula IId compound
Figure A20078000890202431
Or the acceptable salt of their pharmacology, wherein:
X is a hydrogen;
Y is C 6To C 8Aryl, it is replaced by one or more substituting groups that are independently selected from following groups:
-NR qCONR qR r, R wherein qBe hydrogen, R rBe C 1To C 6Alkyl; And
-NR tCOOR u, R wherein tBe hydrogen, R uThe C that is replaced by one or more halogens 1To C 12Alkyl;
Z is C 1To C 6Alkyl;
R is a hydrogen;
R 1Be hydrogen;
R 2Be OR Kk, R wherein KkBe:
-five yuan or six membered heteroaryl;
-five yuan or hexa-member heterocycle; Or
-five yuan or six membered heteroaryl, it is randomly replaced by one or more halogens of selecting independently; And
R 3Be hydrogen.
84. the compound of embodiment 83, wherein:
X is a hydrogen;
Y is C 6To C 8Aryl, it is by NR tCOOR uReplace, wherein R tBe hydrogen, R uThe C that is replaced by one or more halogens 1To C 12Alkyl;
Z is C 1To C 6Alkyl;
R is a hydrogen;
R 1Be hydrogen;
R 2Be OR Kk, R wherein KkBe five yuan or six membered heteroaryl; And
R 3Be hydrogen.
85. the compound of embodiment 84, wherein C 6To C 8Aryl is a phenyl.
86. the compound of embodiment 84, wherein Y is by NR tCOOR uAt the phenyl of para-orientation, wherein R tBe hydrogen, R uThe C that is replaced by fluorine 1To C 12Alkyl.
87. the compound of embodiment 84, wherein Z is cyclobutyl, cyclopropyl, cyclopropyl methyl, ethyl or cyclopentyl.
88. the compound of embodiment 83, wherein R 2Be (O)-five yuan or hexa-member heterocycle.
89. formula IIe compound
Figure A20078000890202441
Or the acceptable salt of their pharmacology, wherein:
X is:
-hydrogen;
-cyano group;
-nitro;
-formyl radical;
-COOH；
-COR x, R wherein xBe C 1To C 6Alkyl;
-CH=N-(C 1To C 6Alkoxyl group);
-CH=N-is (randomly by one or more C 1To C 6The amino that alkyl replaces);
-halogen;
-the alkyl that randomly replaced by one or more halogens;
-randomly by C 1To C 6The alkynyl that alkyl replaces, described alkyl are randomly replaced by one or more halogens and/or cyano group;
-oximido;
-SO 2R x；
-SO 2NH 2；
-SO 2NH(R x)；
-SO 2N(R x) 2；
-randomly by one or more C that select independently 1To C 6Alkyl and/or-C (O)-C 1To C 6The amino that alkyl replaces;
-randomly by one or more C that select independently 1To C 6The amido that alkyl replaces;
-five yuan or hexa-member heterocycle;
-five yuan or six membered heteroaryl, it is randomly by one or more C 1To C 6Alkyl replaces, and described alkyl is randomly replaced by one or more halogens; Or
-C 6To C 8Aryl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-the C that randomly replaced by one or more halogens 1To C 6Alkyl;
-halogen; And
-cyano group;
Y is:
-the benzothiazolyl that randomly replaced by amino, described amino is randomly by one or more C 1To C 6Alkyl replaces;
-indyl, it is randomly at the quilt-SO of nitrogen-atoms place 2R xReplace;
-C 6To C 8Aryl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-halogen;
-C 1To C 6Alkyl;
-alkoxyl group, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-halogen;
-five yuan or hexa-member heterocycle;
-C (O) NH 2, it is randomly by C 6To C 8Alkyl replaces;
-C (O) NH-(C 1To C 6)-aryl;
-hydroxyl;
-alkylhalide group;
-cyano group;
-nitro;
-COOH；
-N＝CHN(R x) 2；
-randomly by one or more amino that are independently selected from the substituting groups replacement of following groups:
-SO 2R x；
-hexa-atomic to eight yuan of aryl, it is randomly by one or more alkyl, halogen, alkylhalide group, cyano group, alkoxyl group, COR of being independently selected from xReplace with the substituting group of halogen alkoxyl group;
-five yuan or six membered heteroaryl, it is randomly by one or more C that are independently selected from alkyl, halogen, alkylhalide group, cyano group, alkoxyl group, halogen alkoxyl group and randomly replaced by halogen 6To C 8The substituting group of aryl replaces;
-five yuan or hexa-member heterocycle, its randomly by one or more be independently selected from hydroxyl ,=substituting group of O, alkyl and alkylhalide group replaces;
-C 1To C 7Alkyl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or six membered heteroaryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, halogen and alkylhalide group;
-C 6To C 8Aryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, halogen and alkylhalide group;
-alkoxyl group; And
-halogen; And
-PO 2R x；
-OC (O) NHR x, R wherein xRandomly by vinyl substituted;
-OC (O) N (R u) 2, R wherein uBe alkyl or C 6To C 8Aryl, described alkyl or aryl is randomly replaced by dialkyl amido;
-OC (O) NH (OR Uu), R wherein UuBe the C that is randomly replaced by dialkyl amido 6To C 8Aryl;
-OC(O)NR x(OR x)；
-OC(O)N(OR x) 2；
-OC (O) R Ab, R wherein AbBe five yuan or the hexa-member heterocycle that is randomly replaced by heteroaryl, described heteroaryl is randomly replaced by alkyl or alkylhalide group;
-NR oC (O) R p, R wherein pBe:
-C 1To C 6Alkyl;
-randomly by one or more C 1To C 6The amino that alkyl replaces, described alkyl is randomly by one or more C that are independently selected from 6To C 8The substituting group of aryl and alkoxyl group replaces; Or
-five yuan or hexa-member heterocycle, it is randomly by one or more C that are independently selected from 1To C 6Alkyl and C 6To C 8Aryl replaces;
And R wherein oBe;
-hydrogen; Or
-C 1To C 6Alkyl;
-NR qCONR qR r, R wherein qBe hydrogen, R rBe:
-C 1To C 6Alkyl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-halogen;
-hydroxyl;
-alkoxyl group;
-five yuan or hexa-member heterocycle;
-five yuan or six membered heteroaryl, and
-C 6To C 8Aryl, it is randomly replaced by halogen;
-C 2To C 6Thiazolinyl, it is randomly replaced by one or more halogens;
-C 1To C 6Alkoxyl group;
-five yuan or hexa-member heterocycle; Or
-five yuan to six membered heteroaryl, and it is randomly replaced by alkyl;
-SO 2R Aa, R wherein AaBe:
-five yuan or hexa-member heterocycle, it is randomly replaced by one or more substituting groups that are independently selected from down group:
-hydroxyl;
-C 1To C 6Alkoxyl group; And
-C 1To C 6Alkyl;
-the amino that randomly replaced by alkyl, described alkyl are randomly replaced by one or more substituting groups that are independently selected from down group:
-alkoxyl group;
-hydroxyl;
-halogen;
-COR m, R wherein mBe:
-randomly by one or more C 1To C 6The amino that alkyl replaces, described alkyl is randomly by five yuan or hexa-member heterocycle or C 6To C 8Aryl replaces, and described heterocycle or aryl are randomly replaced by one or more substituting groups that are independently selected from halogen and alkoxyl group;
-the heterocycle that randomly replaced by hydroxyl;
-ternary is to seven membered heterocyclic, and it is randomly by C 1To C 6Alkyl replaces, and described alkyl is randomly replaced by dialkyl-7-amino;
-NR tCOOR u, R wherein tBe hydrogen, R uBe:
-C 1To C 12Alkyl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-randomly by the C of one or more halogens and/or alkylhalide group replacement 6To C 8Aryl;
-the alkoxyl group that randomly replaced by one or more alkoxyl groups;
-randomly by one or more C 1To C 6The amino that alkyl replaces;
-halogen;
-SO 2R w；
-SO 2R x；
-five yuan or six membered heteroaryl, and
-five yuan or hexa-member heterocycle;
-C 2To C 6Thiazolinyl;
-C 6To C 8Aryl, it is randomly replaced by halogen;
-quaternary is to seven membered heterocyclic, and it is randomly replaced by one or more substituting groups that are independently selected from down group:
＝O；
-SO 2R w；
-COR pAnd
-(CO) O-(C 1To C 4Alkyl)-O-(C 1To C 4Alkyl);
-NHR Bb, R wherein BbBe:
-C(＝S)NH 2；
-C(＝S)NHR x；
-C(＝S)NR xR x；；
-C (=N-CN) NHR xOr
-PO(OR x) 2；
-N(CONHR w) 2；
-NH(SOR w)；
-N(SO 2R w) 2；
-NR vSO 2R w, R wherein vBe hydrogen or the alkyl that randomly replaced by quaternary to seven membered heterocyclic;
And R wherein wBe:
-randomly by C 6To C 8The C that aryl replaces 1To C 6Alkyl, described aryl are randomly replaced by one or more substituting groups that are independently selected from alkylhalide group, halogen, alkoxyl group and alkyl;
-C 6To C 8Aryl;
-C 6To C 8Heteroaryl; Or
-randomly by the amino of heterocyclic radical or alkyl replacement, described heterocyclic radical or alkyl are randomly by one or more halogen, C of being independently selected from 1To C 6Alkoxyl group, carbalkoxy, (CO) O-(C 1To C 6) alkyl), the substituting group of hydroxyl, cyano group, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
Figure A20078000890202501
-five yuan to six membered heteroaryl, and it is randomly replaced by one or more substituting groups that are independently selected from down group:
-halogen;
-C 1To C 6Alkyl;
-randomly by one or more alkoxyl groups that are independently selected from the substituting groups replacement of following groups:
-halogen;
-five yuan or hexa-member heterocycle; And
-C (O) NH 2, it is randomly by C 6To C 8Alkyl replaces;
-hydroxyl;
-alkylhalide group;
-cyano group;
-nitro;
-COOH；
-randomly by one or more amino that are independently selected from the substituting groups replacement of following groups:
-SO 2R x；
-hexa-atomic to eight yuan of aryl, it is randomly by one or more alkyl, halogen, alkylhalide group, cyano group, alkoxyl group, COR of being independently selected from xReplace with the substituting group of halogen alkoxyl group;
-five yuan or six membered heteroaryl, it is randomly by one or more C that are independently selected from alkyl, halogen, alkylhalide group, cyano group, alkoxyl group, halogen alkoxyl group and randomly replaced by halogen 6To C 8The substituting group of aryl replaces;
-C 5To C 6Heterocycle, it is randomly replaced by one or more substituting groups that are independently selected from hydroxyl, alkyl and alkylhalide group; And
-C 1To C 7Alkyl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or six membered heteroaryl, it is randomly replaced by one or more alkyl, halogen and/or alkylhalide group;
-C 6To C 8Aryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, halogen and alkylhalide group;
-alkoxyl group; And
-halogen;
-NR oCOR p, R wherein pBe:
-C 1To C 6Alkyl;
-randomly by one or more C 1To C 6The amino that alkyl replaces, described alkyl are randomly and independently by one or more C 6To C 8Aryl and/or alkoxyl group replace; Or
-five yuan or hexa-member heterocycle, it is by one or more C 1To C 6Alkyl and/or C 6To C 8Aryl replaces;
And R wherein oBe:
-hydrogen; Or
-C 1To C 6Alkyl;
-NR qCONR qR r, R wherein qBe hydrogen, R rBe:
-C 1To C 6Alkyl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-halogen;
-hydroxyl;
-alkoxyl group;
-five yuan or hexa-member heterocycle;
-five yuan or six membered heteroaryl, and
-C 6To C 8Aryl, it is randomly replaced by halogen;
-C 2To C 6Thiazolinyl, it is randomly replaced by one or more halogens;
-C 1To C 6Alkoxyl group;
-five yuan or hexa-member heterocycle; Or
-five yuan to six membered heteroaryl, and it is randomly replaced by alkyl;
-NR tCOOR u, R wherein tBe hydrogen, R uBe:
-C 1To C 12Alkyl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-randomly by the C of one or more halogens and/or alkylhalide group replacement 6To C 8Aryl;
-the alkoxyl group that randomly replaced by one or more alkoxyl groups;
-randomly by one or more C 1To C 6The amino that alkyl replaces;
-halogen;
-SO 2R w；
-SO 2R x；
-five yuan or six membered heteroaryl, and
-five yuan or hexa-member heterocycle; And
-NR vSO 2R w, R wherein vBe hydrogen or the alkyl that randomly replaced by quaternary to seven membered heterocyclic;
And R wherein wBe:
-randomly by C 6To C 8The C that aryl replaces 1To C 6Alkyl, described aryl are randomly replaced by one or more substituting groups that are independently selected from alkylhalide group, halogen, alkoxyl group and alkyl;
-C 6To C 8Aryl;
-C 6To C 8Heteroaryl;
-randomly by the amino of heterocyclic radical or alkyl replacement, described heterocyclic radical or alkyl are randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, carbalkoxy, hydroxyl, cyano group, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
Figure A20078000890202531
Figure A20078000890202541
Z is:
-C 1To C 6Alkyl, it is randomly by five yuan or hexa-member heterocycle replacement; Or
-five yuan or hexa-member heterocycle;
R is a hydrogen;
R 1Be:
-hydrogen;
-five yuan or hexa-member heterocycle, it is randomly replaced by one or more substituting groups that are independently selected from down group:
-hydroxyl;
-C 1To C 6Alkyl;
-SO 2R x；
-C (O)-C 6To C 8Aryl;
-COR pAnd
-C (O) OR xOr
-five yuan or six membered heteroaryl, it is randomly replaced by one or more substituting groups that are independently selected from down group:
-C 1To C 6Alkyl, it is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-alkoxyl group;
-halogen;
-alkylthio;
-alkylhalide group;
-cyano group;
-the amino that randomly replaced by alkyl, described alkyl is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, cyano group, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-heterocycle;
-nitro;
-hydroxyl;
-COOH；
-CO 2R x；
-COR x；
-randomly by one or more C 1To C 6C (O) NH that alkyl replaces 2, described alkyl is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-amido, it is randomly by one or more halogen, C of being independently selected from 1To C 6Alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle, five yuan or six membered heteroaryl and C 1To C 6The substituting group of alkyl replaces, and described alkyl is randomly by one or more C 1To C 6Alkoxyl group replaces;
-C 1To C 6Alkyl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-amino, it is randomly replaced by one or more substituting groups that are independently selected from heterocycle, alkoxyl group and alkyl, and described alkyl is randomly replaced by one or more alkoxyl groups;
-randomly by C 1To C 6The amido that alkyl replaces;
-five yuan or hexa-member heterocycle, it is randomly by C 1To C 6Alkyl replaces;
-five yuan or six membered heteroaryl, and
-C 6To C 8Aryl;
-SO 2R x；
-C 2To C 6Thiazolinyl, it is randomly by SO 2R xReplace;
-C 1To C 6Alkoxyl group, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-halogen;
-hydroxyl;
-cyano group;
-the alkoxyl group that replaces of alkoxy randomly;
-amino, it is randomly replaced by one or more substituting groups that are independently selected from five yuan or six membered heteroaryl, five yuan or hexa-member heterocycle and alkyl, and described alkyl is randomly replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or hexa-member heterocycle; And
-the amino that randomly replaced by one or more alkyl;
-randomly heterocyclically substituted amino;
-randomly by C 1To C 6The amido that alkyl replaces;
-five yuan to seven membered heterocyclic, and it is randomly by one or more hydroxyl and C of being independently selected from 1To C 6Alkyl replaces, and described alkyl is randomly replaced by one or more substituting groups that are selected from following groups;
-C 1To C 6Alkoxyl group; And
-C 6To C 8Alryl;
-five yuan or six membered heteroaryl, it is randomly replaced by one or more substituting groups that are independently selected from down group:
-C 1To C 6Alkyl; And
-quaternary is to seven membered heterocyclic;
-alkoxyl group; And
-C 6To C 8Aryl;
-(O)-five yuan or hexa-member heterocycle, it is randomly replaced by one or more substituting groups that are independently selected from down group:
-hydroxyl;
-C 1To C 6Alkyl;
-SO 2R x；
-C (O)-C 6To C 8Aryl;
-COR pAnd
-C (O) OR xOr
-(O)-five yuan or six membered heteroaryl, it is randomly replaced by one or more substituting groups that are independently selected from down group:
-C 1To C 6Alkyl, it is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-alkoxyl group;
-halogen;
-alkylthio;
-alkylhalide group;
-cyano group;
-the amino that randomly replaced by alkyl, described alkyl is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, cyano group, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-heterocycle;
-nitro;
-hydroxyl;
-COOH；
-CO 2R x；
-COR x；
-C (O) NH 2, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-C 1To C 6Alkyl, it is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces; And
-amido, it is randomly by one or more halogen, C of being independently selected from 1To C 6Alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle, five yuan or six membered heteroaryl and C 1To C 6The substituting group of alkyl replaces, and described alkyl is randomly by one or more C 1To C 6Alkoxyl group replaces;
-randomly by one or more C 1To C 6C (O) NH that alkyl replaces 2, described alkyl is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-C (O)-ternary is to seven membered heterocyclic, and it is randomly replaced by one or more substituting groups that are independently selected from down group:
-C 6To C 8Aryl;
-five yuan or six membered heteroaryl, and
-C 1To C 6Alkyl, it is randomly further by one or more replacements that replaced by hydroxyl;
-SO 2R x, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or hexa-member heterocycle;
-C 6To C 8Aryl; And
-five yuan or six membered heteroaryl; Or
-alkylthio, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or hexa-member heterocycle;
-C 6To C 8Aryl; And
-five yuan or six membered heteroaryl;
-C 6To C 8Aryl;
-C (O)-five yuan or six membered heteroaryl;
-C (O)-C 6To C 8Aryl;
-COOH; Or
-OR Kk, R wherein KkBe:
C 6To C 8Aryl, it is randomly by one or more halogen, C of being independently selected from 1To C 6Alkyl, C 1To C 6Alkoxyl group and C 1To C 6The substituting group of alkylhalide group replaces;
R 2Be:
-C 1To C 6Alkyl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or hexa-member heterocycle;
-five yuan or six membered heteroaryl;
-C 6To C 8Aryl;
-randomly by C 1To C 6The amido that alkyl replaces; And
-amino, it is randomly replaced by one or more substituting groups that are independently selected from heterocycle, alkoxyl group and alkyl, and described alkyl is randomly replaced by one or more alkoxyl groups; And
-SO 2R x；
-C 2To C 6Thiazolinyl, it is randomly by SO 2R xReplace;
-alkylthio, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or six membered heteroaryl, it is randomly replaced by alkyl;
-five yuan or hexa-member heterocycle;
-C 6To C 8Aryl; And
-C 1To C 6Alkyl;
-SO 2R x, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or six membered heteroaryl, it is randomly by one or more C 1To C 6Alkyl replaces;
-five yuan or hexa-member heterocycle;
-C 6To C 8Aryl; And
-C 1To C 6Alkyl;
-S (O) R x, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or six membered heteroaryl;
-five yuan or hexa-member heterocycle;
-C 6To C 8Aryl; And
-C 1To C 6Alkyl;
-alkoxyl group, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-halogen;
-hydroxyl;
-cyano group;
-the alkoxyl group that replaces of alkoxy randomly;
-amino, it is randomly by one or more being independently selected from-SO 2-C 1To C 4The substituting group of alkyl, five yuan or six membered heteroaryl, five yuan or hexa-member heterocycle and alkyl replaces, and described alkyl is randomly replaced by one or more substituting groups that are selected from following groups:
-five yuan or hexa-member heterocycle; And
-the amino that randomly replaced by one or more alkyl;
-randomly by C 1To C 6The amido that alkyl replaces;
Five yuan of-S-or hexa-member heterocycle;
Five yuan of-S-or six membered heteroaryl, it is randomly by C 1To C 6Alkyl replaces;
-S-C 1To C 6Alkyl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-C 6To C 8Aryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, alkylhalide group and halogen; And
-C 5To C 6Heteroaryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, alkylhalide group and halogen;
-S-C 6To C 8Aryl;
-sulfinyl-five yuan or hexa-member heterocycle;
-sulfinyl-five yuan or six membered heteroaryl;
-sulfinyl-C 1To C 6Alkyl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-C 6To C 8Aryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, alkylhalide group and halogen; And
-C 5To C 6Heteroaryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, alkylhalide group and halogen;
-sulfinyl-C 6To C 8Aryl;
-alkylsulfonyl-five yuan or hexa-member heterocycle;
-alkylsulfonyl-randomly by C 1To C 6Five yuan or six membered heteroaryl that alkyl replaces;
-alkylsulfonyl-C 1To C 6Alkyl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-C 6To C 8Aryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, alkylhalide group and halogen; And
-C 5To C 6Heteroaryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, alkylhalide group and halogen;
-alkylsulfonyl-C 6To C 8Aryl;
-five yuan to seven membered heterocyclic, its randomly by one or more be independently selected from hydroxyl ,=O, heterocycle and C 1To C 6The substituting group of alkyl replaces, and described alkyl is randomly replaced by one or more substituting groups that are selected from following groups:
-C 1To C 6Alkoxyl group; And
-C 6To C 8Aryl;
-five yuan or six membered heteroaryl, it is randomly replaced by one or more substituting groups that are independently selected from down group:
-C 1To C 6Alkyl, it is randomly replaced by one or more alkoxyl groups;
-quaternary is to seven membered heterocyclic; And
-alkoxyl group; And
-C 6To C 8Aryl;
-C 6To C 8Aryl;
-(O)-five yuan or hexa-member heterocycle, it is randomly replaced by one or more substituting groups that are independently selected from down group:
-hydroxyl;
＝O；
-C 1To C 6Alkyl;
-SO 2R x；
-C (O)-C 6To C 8Aryl;
-COR pAnd
-C (O) OR xOr
-(O)-five yuan or six membered heteroaryl, it is randomly replaced by one or more substituting groups that are independently selected from down group:
-C 1To C 6Alkyl, it is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-alkoxyl group;
-halogen;
-alkylthio;
-alkylhalide group;
-cyano group;
-the amino that randomly replaced by alkyl, described alkyl is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, cyano group, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-heterocycle;
-nitro;
-hydroxyl;
-COOH；
-CO 2R x；
-COR x；
-randomly by one or more C 1To C 6C (O) NH that alkyl replaces 2, described alkyl is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-amido, it is randomly by one or more halogen, C of being independently selected from 1To C 6Alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle, five yuan or six membered heteroaryl and C 1To C 6The substituting group of alkyl replaces, and described alkyl is randomly by one or more C 1To C 6Alkoxyl group replaces;
-C (O)-ternary is to seven membered heterocyclic, and it is randomly replaced by one or more substituting groups that are independently selected from down group:
-C 6To C 8Aryl;
-five yuan or six membered heteroaryl, and
-C 1To C 6Alkyl, it is randomly replaced by one or more hydroxyls;
-C (O)-five yuan or six membered heteroaryl;
-C (O)-C 6To C 8Aryl;
-COOH；
-randomly by one or more C 1To C 6C (O) NH that alkyl replaces 2, described alkyl is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-amido, it is randomly by one or more C 1To C 6Alkyl replaces, and described alkyl is randomly by one or more C 1To C 6Alkoxyl group replaces;
-randomly by one or more amino that are independently selected from the substituting groups replacement of following groups:
-SO 2R x；
-hexa-atomic to eight yuan of aryl, it is randomly by one or more alkyl, halogen, alkylhalide group, cyano group, alkoxyl group, COR of being independently selected from xReplace with the substituting group of halogen alkoxyl group;
-five yuan or six membered heteroaryl, it is randomly by one or more C that are independently selected from alkyl, halogen, alkylhalide group, cyano group, alkoxyl group, halogen alkoxyl group and randomly replaced by halogen 6To C 8The substituting group of aryl replaces;
-C 5To C 6Heterocycle, it is randomly replaced by one or more substituting groups that are independently selected from hydroxyl, alkyl and alkylhalide group;
-C 1To C 7Alkyl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or six membered heteroaryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, halogen and alkylhalide group;
-C 6To C 8Aryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, halogen and alkylhalide group;
-alkoxyl group; And
-halogen;
-five yuan or six membered heteroaryl, it is randomly replaced by one or more substituting groups that are independently selected from down group:
-C 1To C 6Alkyl, it is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-alkoxyl group;
-halogen;
-alkylthio;
-alkylhalide group;
-cyano group;
-the amino that randomly replaced by one or more alkyl, described alkyl is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, cyano group, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-heterocycle;
-nitro;
-hydroxyl;
-COOH；
-CO 2R x；
-COR x；
-randomly by one or more C 1To C 6C (O) NH that alkyl replaces 2, described alkyl is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-amido, it is randomly by one or more halogen, C of being independently selected from 1To C 6Alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle, five yuan or six membered heteroaryl and C 1To C 6The substituting group of alkyl replaces, and described alkyl is randomly by one or more C 1To C 6Alkoxyl group replaces;
-five yuan or hexa-member heterocycle, it is randomly replaced by one or more substituting groups that are independently selected from down group:
-hydroxyl;
＝O；
-C 1To C 6Alkyl;
-SO 2R x；
-C (O)-C 6To C 8Aryl;
-COR pAnd
-C(O)OR x；
-OR Kk, R wherein KkBe:
-C 6To C 8Aryl, it is randomly by one or more halogen, C of being independently selected from 1To C 6Alkyl, C 1To C 6Alkoxyl group and C 1To C 6The substituting group of alkylhalide group replaces;
-five yuan to hexa-member heterocycle, and it is randomly by C 1To C 6Alkyl replaces, and described alkyl is randomly by C 6To C 8Aryl replaces; Or
-five yuan to six membered heteroaryl, and it is randomly by one or more halogen, C of being independently selected from 1To C 6Alkyl, C 1To C 6Alkoxyl group and C 1To C 6The substituting group of alkylhalide group replaces;
-SO 2R xOr
-Si(Rx) 3；
-OC (O) NHR x, R wherein xRandomly by C 6To C 8Aryl replaces;
-OC (O) N (R x) 2Or
Figure A20078000890202641
R 3Be hydrogen; Or nitro;
Condition is X, Y, Z, R 1, R 2And R 3In have a following selection at least:
X is:
-CH=N-(C 1To C 6Alkoxyl group);
-CH=N-is (randomly by one or more C 1To C 6The amino that alkyl replaces);
-halogen;
-the alkyl that randomly replaced by one or more halogens;
-randomly by C 1To C 6The alkynyl that alkyl replaces, described alkyl are randomly replaced by one or more halogens and/or cyano group;
-oximido;
-SO 2R x；
-SO 2NH 2；
-SO 2NH(R x)；
-SO 2N(R x) 2；
-amino, it is randomly by one or more C that select independently 1To C 6Alkyl and/or-C (O)-C 1To C 6Alkyl replaces;
-amido, it is randomly by one or more C that select independently 1To C 6Alkyl replaces;
-five yuan or hexa-member heterocycle;
-five yuan or six membered heteroaryl, it is by one or more C 1To C 6Alkyl replaces, and described alkyl is randomly replaced by one or more halogens; Or
-C 6To C 8Aryl, it is replaced by one or more substituting groups that are independently selected from following groups:
-the C that randomly replaced by one or more halogens 1To C 6Alkyl;
-halogen; And
-cyano group;
Y is:
-by the amino benzothiazolyl that replaces, described amino is randomly by one or more C 1To C 6Alkyl replaces;
-indyl, it is at the quilt-SO of nitrogen-atoms place 2R xReplace;
-C 6To C 8Aryl, it is replaced by one or more substituting groups that are independently selected from following groups:
-alkoxyl group, it is replaced by one or more substituting groups that are independently selected from following groups:
-C (O) NH 2, it is randomly by C 6To C 8Alkyl replaces; And
-C (O) NH-(C 1To C 6)-alkyl;
-alkylhalide group;
-cyano group;
-COOH；
-N＝CHN(R x) 2；
-amino, it is replaced by one or more substituting groups that are independently selected from following groups:
-SO 2R x；
-hexa-atomic to eight yuan of aryl, it is randomly by one or more alkyl, halogen, alkylhalide group, cyano group, alkoxyl group, COR of being independently selected from xReplace with the substituting group of halogen alkoxyl group;
-five yuan or six membered heteroaryl, it is randomly by one or more C that are independently selected from alkyl, halogen, alkylhalide group, cyano group, alkoxyl group, halogen alkoxyl group and randomly replaced by halogen 6To C 8The substituting group of aryl replaces;
-five yuan or hexa-member heterocycle, its randomly by one or more be independently selected from hydroxyl ,=substituting group of O, alkyl and alkylhalide group replaces;
-C 1To C 7Alkyl, it is replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or six membered heteroaryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, halogen and alkylhalide group;
-C 6To C 8Aryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, halogen and alkylhalide group;
-alkoxyl group; And
-halogen; And
-PO 2R x；
-OC (O) NHR x, R wherein xRandomly by vinyl substituted;
-OC (O) N (R u) 2, R wherein uBe alkyl or C 6To C 8Aryl, described alkyl or aryl is randomly replaced by dialkyl amido;
-OC (O) NH (OR Uu), R wherein UuBe the C that is randomly replaced by dialkyl amido 6To C 8Aryl;
-OC(O)NR x(OR x)；
-OC(O)N(OR x) 2；
-OC (O) R Ab, R wherein AbBe five yuan or the hexa-member heterocycle that is randomly replaced by heteroaryl, described heteroaryl is randomly replaced by alkyl or alkylhalide group;
-NR oC (O) R p, R wherein pBe:
-randomly by one or more C 1To C 6The amino that alkyl replaces, described alkyl is randomly by one or more C that are independently selected from 6To C 8The substituting group of aryl and alkoxyl group replaces; Or
-five yuan or hexa-member heterocycle, it is by one or more C that are independently selected from 1To C 6Alkyl and C 6To C 8Aryl replaces;
-NR qCONR qR r, R wherein rBe:
-C 1To C 6Alkyl, it is replaced by one or more substituting groups that are independently selected from following groups:
-hydroxyl;
-alkoxyl group;
-five yuan or hexa-member heterocycle;
-five yuan or six membered heteroaryl, and
-C 6To C 8Aryl, it is replaced by halogen,
-C 2To C 6Thiazolinyl, it is randomly replaced by one or more halogens;
-C 1To C 6Alkoxyl group;
-five yuan or hexa-member heterocycle; Or
-five yuan to six membered heteroaryl, and it is randomly replaced by alkyl;
-SO 2R Aa, R wherein AaBe:
-five yuan or hexa-member heterocycle, it is randomly replaced by one or more substituting groups that are independently selected from down group:
-hydroxyl;
-C 1To C 6Alkoxyl group; And
-C 1To C 6Alkyl;
-the amino that randomly replaced by alkyl, described alkyl are randomly replaced by one or more substituting groups that are independently selected from down group:
-alkoxyl group;
-hydroxyl;
-halogen;
-COR m, R wherein mBe:
-amino, it is by one or more C 1To C 6Alkyl replaces, and described alkyl is by five yuan or hexa-member heterocycle or C 6To C 8Aryl replaces, and described heterocycle is replaced by one or more halogens and/or alkoxyl group, and described aryl is randomly replaced by one or more halogens and/or alkoxyl group;
-the heterocycle that replaced by hydroxyl;
-NR tCOOR u, R wherein uBe:
-C 1To C 12Alkyl, it is replaced by one or more substituting groups that are independently selected from following groups:
-C 6To C 8Aryl, it is replaced by one or more halogens and/or alkylhalide group;
-alkoxyl group, it is replaced by one or more alkoxyl groups;
-amino, it is randomly by one or more C 1To C 6Alkyl replaces;
-SO 2R w；
-SO 2R xAnd
-five yuan or six membered heteroaryl;
-C 2To C 6Thiazolinyl;
-quaternary is to seven membered heterocyclic, and it is replaced by one or more substituting groups that are independently selected from down group:
＝O；
-SO 2R w；
-COR pAnd
-(CO) O-(C 1To C 4Alkyl)-O-(C 1To C 4Alkyl);
-quaternary or seven membered heterocyclic, it is randomly replaced by one or more substituting groups that are independently selected from down group:
＝O；
-SO 2R w；
-COR pAnd
-(CO) O-(C 1To C 4Alkyl)-O-(C 1To C 4Alkyl);
-NHR Bb, R wherein BbBe:
-C(＝S)NHR x；
-C (=S) NR xR xOr
-C(＝N-CN)NHR x；
-N(CONHR w) 2；
-NH(SOR w)；
-N(SO 2R w) 2；
-NR vSO 2R w, R wherein vBy the alkyl of quaternary or seven membered heterocyclic replacement;
Or R wherein wBe:
-randomly by C 6To C 8The C that aryl replaces 1To C 6Alkyl, described aryl is replaced by one or more substituting groups that are independently selected from alkylhalide group, halogen, alkoxyl group and alkyl;
-randomly by the amino of heterocyclic radical or alkyl replacement, described heterocyclic radical or alkyl are randomly by one or more halogen, C of being independently selected from 1To C 6Alkoxyl group, carbalkoxy, (CO) O-(C 1To C 6) alkyl), the substituting group of hydroxyl, cyano group, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
Figure A20078000890202691
-five yuan to six membered heteroaryl, and it is randomly replaced by one or more substituting groups that are independently selected from down group:
-halogen;
-C 1To C 6Alkyl;
-alkoxyl group, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-halogen;
-five yuan or hexa-member heterocycle; And
-C (O) NH 2, it is randomly by C 6To C 8Alkyl replaces;
-hydroxyl;
-alkylhalide group;
-cyano group;
-nitro;
-COOH；
-amino, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-SO 2R x；
-hexa-atomic to eight yuan of aryl, it is randomly by one or more alkyl, halogen, alkylhalide group, cyano group, alkoxyl group, COR of being independently selected from xReplace with the substituting group of halogen alkoxyl group;
-five yuan or six membered heteroaryl, it randomly is independently selected from alkyl, halogen, alkylhalide group, cyano group, alkoxyl group, halogen alkoxyl group and is randomly replaced C by halogen by one or more 6To C 8The substituting group of aryl replaces;
-C 5To C 6Heterocycle, it is randomly replaced by one or more substituting groups that are independently selected from hydroxyl, alkyl and alkylhalide group; And
-C 1To C 7Alkyl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or six membered heteroaryl, it is randomly replaced by one or more alkyl, halogen and/or alkylhalide group;
-C 6To C 8Aryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, halogen and alkylhalide group;
-alkoxyl group; And
-halogen;
-NR oCOR p, R wherein pBe:
-randomly by one or more C 1To C 6The amino that alkyl replaces, described alkyl are randomly and independently by one or more C 6To C 8Aryl and/or alkoxyl group replace; Or
-five yuan or hexa-member heterocycle, it is randomly by one or more C 1To C 6Alkyl and/or C 6To C 8Aryl replaces;
-NR qCONR qR r, R wherein rBe:
-C 1To C 6Alkyl, it is replaced by one or more substituting groups that are independently selected from following groups:
-hydroxyl;
-alkoxyl group;
-five yuan or hexa-member heterocycle;
-five yuan or six membered heteroaryl,
-C 6To C 8Aryl, it is replaced by halogen,
-C 2To C 6Thiazolinyl, it is randomly replaced by one or more halogens;
-C 1To C 6Alkoxyl group;
-five yuan or hexa-member heterocycle; Or
-five yuan to six membered heteroaryl, and it is randomly replaced by alkyl;
-NR tCOOR u, R wherein uBe:
-C 1To C 12Alkyl, it is replaced by one or more substituting groups that are independently selected from following groups:
-C 6To C 8Aryl, it is replaced by one or more halogens and/or alkylhalide group;
-alkoxyl group, it is replaced by one or more alkoxyl groups;
-randomly by one or more C 1To C 6The amino that alkyl replaces;
-SO 2R w；
-SO 2R xAnd
-five yuan or six membered heteroaryl;
-NR vSO 2R w, R wherein vBy the alkyl of quaternary to the seven membered heterocyclic replacement;
Or R wherein wBe:
-randomly by C 6To C 8The C that aryl replaces 1To C 6Alkyl, described aryl is replaced by one or more substituting groups that are independently selected from alkylhalide group, halogen, alkoxyl group and alkyl;
-C 6To C 8Aryl;
-by the amino of heterocyclic radical or alkyl replacement, described heterocycle is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, carbalkoxy, hydroxyl, cyano group, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces, and described alkyl is by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, carbalkoxy, hydroxyl, cyano group, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
Figure A20078000890202711
Z is:
-C 1To C 6Alkyl, it is by five yuan or hexa-member heterocycle replacement; Or
-five yuan or hexa-member heterocycle;
R 1Be:
-five yuan or hexa-member heterocycle, it is replaced by one or more substituting groups that are independently selected from down group:
-hydroxyl;
-C 1To C 6Alkyl;
-SO 2R x；
-C (O)-C 6To C 8Aryl;
-COR pAnd
-C (O) OR xOr
-five yuan or six membered heteroaryl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-C 1To C 6Alkyl, it is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-alkoxyl group;
-halogen;
-alkylthio;
-alkylhalide group;
-cyano group;
-the amino that randomly replaced by alkyl, described alkyl is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, cyano group, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-heterocycle;
-nitro;
-hydroxyl;
-COOH；
-CO 2R x；
-COR x；
-randomly by one or more C 1To C 6C (O) NH that alkyl replaces 2, described alkyl is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-amido, it is randomly by one or more halogen, C of being independently selected from 1To C 6Alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle, five yuan or six membered heteroaryl and C 1To C 6The substituting group of alkyl replaces, and described alkyl is randomly by one or more C 1To C 6Alkoxyl group replaces;
-C 1To C 6Alkyl, it is replaced by one or more substituting groups that are independently selected from following groups:
-amino, it is randomly replaced by one or more substituting groups that are independently selected from heterocycle, alkoxyl group and alkyl, and described alkyl is replaced by one or more alkoxyl groups;
-randomly by C 1To C 6The amido that alkyl replaces;
-five yuan or hexa-member heterocycle, it is by C 1To C 6Alkyl replaces;
-five yuan or six membered heteroaryl, and
-C 6To C 8Aryl;
-SO 2R x；
-C 2To C 6Thiazolinyl, it is randomly by SO 2R xReplace;
-C 1To C 6Alkoxyl group, it is replaced by one or more substituting groups that are independently selected from following groups:
-hydroxyl;
-cyano group;
-the alkoxyl group that replaces of alkoxy randomly;
-amino, it is randomly replaced by one or more substituting groups that are independently selected from five yuan or six membered heteroaryl, five yuan or hexa-member heterocycle and alkyl, and described alkyl is randomly replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or hexa-member heterocycle; And
-the amino that randomly replaced by one or more alkyl;
-randomly heterocyclically substituted amino;
-randomly by C 1To C 6The amido that alkyl replaces;
-five yuan to seven membered heterocyclic, and it is by one or more hydroxyl and C of being independently selected from 1To C 6The substituting group of alkyl replaces, and described alkyl is randomly replaced by one or more substituting groups that are independently selected from following groups;
-C 1To C 6Alkoxyl group; And
-C 6To C 8Aryl;
-five yuan or six membered heteroaryl, it is randomly replaced by one or more substituting groups that are independently selected from down group:
-C 1To C 6Alkyl; And
-quaternary is to seven membered heterocyclic; And
-alkoxyl group;
-(O)-five yuan or hexa-member heterocycle, it is randomly replaced by one or more substituting groups that are independently selected from down group:
-hydroxyl;
-C 1To C 6Alkyl;
-SO 2R x；
-C (O)-C 6To C 8Aryl;
-COR pAnd
-C (O) OR xOr
-(O)-five yuan or six membered heteroaryl, it is randomly replaced by one or more substituting groups that are independently selected from down group:
-C 1To C 6Alkyl, it is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-alkoxyl group;
-halogen;
-alkylthio;
-alkylhalide group;
-cyano group;
-the amino that randomly replaced by alkyl, described alkyl is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, cyano group, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-heterocycle;
-nitro;
-hydroxyl;
-COOH；
-CO 2R x；
-COR x；
-C (O) NH 2, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-C 1To C 6Alkyl, it is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces; And
-amido, it is randomly by one or more halogen, C of being independently selected from 1To C 6Alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle, five yuan or six membered heteroaryl and C 1To C 6The substituting group of alkyl replaces, and described alkyl is randomly by one or more C 1To C 6Alkoxyl group replaces;
-randomly by one or more C 1To C 6C (O) NH that alkyl replaces 2, described alkyl is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-C (O)-ternary is to seven membered heterocyclic, and it is randomly replaced by one or more substituting groups that are independently selected from down group:
-C 6To C 8Aryl;
-five yuan or six membered heteroaryl, and
-C 1To C 6Alkyl, it is randomly by one or more replacements that replaced by hydroxyl;
-SO 2R x, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or hexa-member heterocycle;
-C 6To C 8Aryl; And
-five yuan or six membered heteroaryl; Or
-alkylthio, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or hexa-member heterocycle;
-C 6To C 8Aryl; And
-five yuan or six membered heteroaryl;
-C (O)-five yuan or six membered heteroaryl;
-C (O)-C 6To C 8Aryl;
-COOH；
-OR Kk, R wherein KkBe:
C 6To C 8Aryl, it is randomly by one or more halogen, C of being independently selected from 1To C 6Alkyl, C 1To C 6Alkoxyl group and C 1To C 6The substituting group of alkylhalide group replaces;
R 2Be:
-C 1To C 6Alkyl, it is replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or hexa-member heterocycle;
-five yuan or six membered heteroaryl;
-C 6To C 8Aryl;
-amido, it is randomly by C 1To C 6Alkyl replaces; And
-amino, it is randomly replaced by one or more substituting groups that are independently selected from heterocycle, alkoxyl group and alkyl, and described alkyl is randomly replaced by one or more alkoxyl groups; And
-SO 2R x；
-C 2To C 6Thiazolinyl, it is randomly by SO 2R xReplace;
-alkylthio, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or six membered heteroaryl, it is randomly replaced by alkyl;
-five yuan or hexa-member heterocycle;
-C 6To C 8Aryl; And
-C 1To C 6Alkyl;
-SO 2R x, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or six membered heteroaryl, it is randomly by one or more C 1To C 6Alkyl replaces;
-five yuan or hexa-member heterocycle;
-C 6To C 8Aryl; And
-C 1To C 6Alkyl;
-S (O) R x, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or six membered heteroaryl;
-five yuan or hexa-member heterocycle;
-C 6To C 8Aryl; And
-C 1To C 6Alkyl;
-alkoxyl group, it is replaced by one or more substituting groups that are independently selected from following groups:
-halogen;
-hydroxyl;
-cyano group;
-the alkoxyl group that replaces of alkoxy randomly;
-amino, it is by one or more being independently selected from-SO 2-C 1To C 4The substituting group of alkyl and alkyl replaces, and described alkyl is replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or hexa-member heterocycle; And
-the amino that randomly replaced by one or more alkyl;
-by C 1To C 6The amido that alkyl replaces;
Five yuan of-S-or hexa-member heterocycle;
Five yuan of-S-or six membered heteroaryl, it is randomly by C 1To C 6Alkyl replaces;
-S-C 1To C 6Alkyl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-C 6To C 8Aryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, alkylhalide group and halogen; And
-C 5To C 6Heteroaryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, alkylhalide group and halogen;
-S-C 6To C 8Aryl;
-sulfinyl-five yuan or hexa-member heterocycle;
-sulfinyl-five yuan or six membered heteroaryl;
-sulfinyl-C 1To C 6Alkyl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-C 6To C 8Aryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, alkylhalide group and halogen; And
-C 5To C 6Heteroaryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, alkylhalide group and halogen;
-sulfinyl-C 6To C 8Aryl;
-alkylsulfonyl-five yuan or hexa-member heterocycle;
-alkylsulfonyl-randomly by C 1To C 6Five yuan or six membered heteroaryl that alkyl replaces;
-alkylsulfonyl-C 1To C 6Alkyl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-C 6To C 8Aryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, alkylhalide group and halogen; And
-C 5To C 6Heteroaryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, alkylhalide group and halogen;
-alkylsulfonyl-C 6To C 8Aryl;
-five yuan to seven membered heterocyclic, its randomly by one or more be independently selected from hydroxyl ,=O, heterocycle and C 1To C 6The substituting group of alkyl replaces, and described alkyl is randomly replaced by one or more substituting groups that are independently selected from following groups:
-C 1To C 6Alkoxyl group; And
-C 6To C 8Aryl;
-five yuan or six membered heteroaryl, it is randomly replaced by one or more substituting groups that are independently selected from down group:
-C 1To C 6Alkyl, it is randomly replaced by one or more alkoxyl groups;
-quaternary is to seven membered heterocyclic; And
-alkoxyl group; And
-C 6To C 8Aryl;
-C 6To C 8Aryl;
-(O)-five yuan or hexa-member heterocycle, it is replaced by one or more substituting groups that are independently selected from down group:
-hydroxyl;
＝O；
-C 1To C 6Alkyl;
-SO 2R x；
-C (O)-C 6To C 8Aryl;
-COR pAnd
-C (O) OR xOr
-(O)-five yuan or six membered heteroaryl, it is replaced by one or more substituting groups that are independently selected from down group:
-C 1To C 6Alkyl, it is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-alkoxyl group;
-halogen;
-alkylthio;
-alkylhalide group;
-cyano group;
-the amino that randomly replaced by alkyl, described alkyl is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, cyano group, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-heterocycle;
-nitro;
-hydroxyl;
-COOH；
-CO 2R x；
-COR x；
-randomly by one or more C 1To C 6C (O) NH that alkyl replaces 2, described alkyl is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-amido, it is randomly by one or more halogen, C of being independently selected from 1To C 6Alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle, five yuan or six membered heteroaryl and C 1To C 6The substituting group of alkyl replaces, and described alkyl is randomly by one or more C 1To C 6Alkoxyl group replaces;
-C (O)-ternary is to seven membered heterocyclic, and it is randomly replaced by one or more substituting groups that are independently selected from down group:
-C 6To C 8Aryl;
-five yuan or six membered heteroaryl, and
-C 1To C 6Alkyl, it is randomly replaced by one or more hydroxyls;
-C (O)-five yuan or six membered heteroaryl;
-C (O)-C 6To C 8Aryl;
-COOH；
-randomly by one or more C 1To C 6C (O) NH that alkyl replaces 2, described alkyl is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-amido, it is by one or more C 1To C 6Alkyl replaces, and described alkyl is randomly by one or more C 1To C 6Alkoxyl group replaces;
-amino, it is replaced by one or more substituting groups that are independently selected from following groups:
-SO 2R x；
-hexa-atomic to eight yuan of aryl, it is randomly by one or more alkyl, halogen, alkylhalide group, cyano group, alkoxyl group, COR of being independently selected from xReplace with the substituting group of halogen alkoxyl group;
-five yuan or six membered heteroaryl, it is randomly by one or more C that are independently selected from alkyl, halogen, alkylhalide group, cyano group, alkoxyl group, halogen alkoxyl group and randomly replaced by halogen 6To C 8The substituting group of aryl replaces;
-C 5To C 6Heterocycle, it is randomly replaced by one or more substituting groups that are independently selected from hydroxyl, alkyl and alkylhalide group;
-C 1To C 7Alkyl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or six membered heteroaryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, halogen and alkylhalide group;
-C 6To C 8Aryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, halogen and alkylhalide group;
-alkoxyl group; And
-halogen;
-five yuan or six membered heteroaryl, it is replaced by one or more substituting groups that are independently selected from down group:
-C 1To C 6Alkyl, it is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-alkoxyl group;
-halogen;
-alkylthio;
-alkylhalide group;
-cyano group;
-the amino that randomly replaced by one or more alkyl, described alkyl is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, cyano group, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-heterocycle;
-nitro;
-hydroxyl;
-COOH；
-CO 2R x；
-COR x；
-randomly by one or more C 1To C 6C (O) NH that alkyl replaces 2, described alkyl is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-amido, it is randomly by one or more halogen, C of being independently selected from 1To C 6Alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle, five yuan or six membered heteroaryl and C 1To C 6The substituting group of alkyl replaces, and described alkyl is randomly by one or more C 1To C 6Alkoxyl group replaces;
-five yuan or hexa-member heterocycle, it is randomly replaced by one or more substituting groups that are independently selected from down group:
-hydroxyl;
＝O；
-C 1To C 6Alkyl;
-SO 2R x；
-C (O)-C 6To C 8Aryl;
-COR pAnd
-C(O)OR x；
-OR Kk, R wherein KkBe:
C 6To C 8Aryl, it is randomly by one or more halogen, C of being independently selected from 1To C 6Alkyl, C 1To C 6Alkoxyl group and C 1To C 6The substituting group of alkylhalide group replaces;
-five yuan to hexa-member heterocycle, and it is randomly by C 1To C 6Alkyl replaces, and described alkyl is randomly by C 6To C 8Aryl replaces; Or
-five yuan to six membered heteroaryl, and it is by one or more halogen, C of being independently selected from 1To C 6Alkyl, C 1To C 6Alkoxyl group and C 1To C 6The substituting group of alkylhalide group replaces;
-SO 2R xOr
-Si(Rx) 3；
-OC (O) NHR x, R wherein xRandomly by C 6To C 8Aryl replaces;
-OC (O) N (R x) 2Or
Figure A20078000890202821
R 3It is nitro.
90. the compound of embodiment 89, wherein:
X is:
-CH=N-(C 1To C 6Alkoxyl group);
-CH=N-is (randomly by one or more C 1To C 6The amino that alkyl replaces);
-halogen;
-the alkyl that randomly replaced by one or more halogens;
-randomly by C 1To C 6The alkynyl that alkyl replaces, described alkyl are randomly replaced by one or more halogens and/or cyano group;
-oximido;
-SO 2R x；
-SO 2NH 2；
-SO 2NH(R x)；
-SO 2N(R x) 2；
-randomly by one or more C that select independently 1To C 6Alkyl and/or-C (O)-C 1To C 6The amino that alkyl replaces;
-randomly by one or more C that are independently selected from 1To C 6The amido that alkyl replaces;
-five yuan or hexa-member heterocycle;
-five yuan or six membered heteroaryl, it is by one or more C 1To C 6Alkyl replaces, and described alkyl is randomly replaced by one or more halogens; Or
-C 6To C 8Aryl, it is replaced by one or more substituting groups that are independently selected from following groups:
-C 1To C 6Alkyl, it is randomly replaced by one or more halogens;
-halogen; And
-cyano group.
91. the compound of embodiment 89, wherein:
Y is:
-by the amino benzothiazolyl that replaces, described amino is randomly by one or more C 1To C 6Alkyl replaces;
-indyl, it is at the quilt-SO of nitrogen-atoms place 2R xReplace; Or
-C 6To C 8Aryl, it is replaced by one or more substituting groups that are independently selected from following groups:
-alkoxyl group, it is replaced by one or more substituting groups that are independently selected from following groups:
-C (O) NH 2, it is randomly by C 6To C 8Alkyl replaces; And
-C (O) NH-(C 1To C 6)-alkyl;
-alkylhalide group;
-cyano group;
-COOH；
-N＝CHN(R x) 2；
-the amino that replaced by one or more substituting groups that are independently selected from following groups:
-SO 2R x；
-hexa-atomic to eight yuan of aryl, it is randomly by one or more alkyl, halogen, alkylhalide group, cyano group, alkoxyl group, COR of being independently selected from xReplace with the substituting group of halogen alkoxyl group;
-five yuan or six membered heteroaryl, it is randomly by one or more C that are independently selected from alkyl, halogen, alkylhalide group, cyano group, alkoxyl group, halogen alkoxyl group and randomly replaced by halogen 6To C 8The substituting group of aryl replaces;
-five yuan or hexa-member heterocycle, its randomly by one or more be independently selected from hydroxyl ,=substituting group of O, alkyl and alkylhalide group replaces;
-C 1To C 7Alkyl, it is replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or six membered heteroaryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, halogen and alkylhalide group;
-C 6To C 8Aryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, halogen and alkylhalide group;
-alkoxyl group; And
-halogen; And
-PO 2R x；
-OC (O) NHR x, R wherein xRandomly by vinyl substituted;
-OC (O) N (R u) 2, R wherein uBe alkyl or C 6To C 8Aryl, described alkyl or aryl is randomly replaced by dialkyl amido;
-OC (O) NH (OR Uu), R wherein UuBe the C that is randomly replaced by dialkyl amido 6To C 8Aryl;
-OC(O)NR x(OR x)；
-OC(O)N(OR x) 2；
-OC (O) R Ab, R wherein AbBe five yuan or the hexa-member heterocycle that is randomly replaced by heteroaryl, described heteroaryl is randomly replaced by alkyl or alkylhalide group;
-NR oC (O) R p, R wherein pBe:
-randomly by one or more C 1To C 6The amino that alkyl replaces, described alkyl is randomly by one or more C that are independently selected from 6To C 8The substituting group of aryl and alkoxyl group replaces; Or
-five yuan or hexa-member heterocycle, it is by one or more C that are independently selected from 1To C 6Alkyl and C 6To C 8Aryl replaces;
-NR qCONR qR r, R wherein rBe:
-C 1To C 6Alkyl, it is replaced by one or more substituting groups that are independently selected from following groups:
-hydroxyl;
-alkoxyl group;
-five yuan or hexa-member heterocycle;
-five yuan or six membered heteroaryl, and
-C 6To C 8Aryl, it is replaced by halogen,
-C 2To C 6Thiazolinyl, it is randomly replaced by one or more halogens;
-C 1To C 6Alkoxyl group;
-five yuan or hexa-member heterocycle; Or
-five yuan to six membered heteroaryl, and it is randomly replaced by alkyl;
-SO 2R Aa, R wherein AaBe:
-five yuan or hexa-member heterocycle, it is randomly replaced by one or more substituting groups that are independently selected from down group:
-hydroxyl;
-C 1To C 6Alkoxyl group; And
-C 1To C 6Alkyl;
-the amino that randomly replaced by alkyl, described alkyl are randomly replaced by one or more substituting groups that are independently selected from down group:
-alkoxyl group;
-hydroxyl;
-halogen;
-COR m, R wherein mBe:
-amino, it is by one or more C 1To C 6Alkyl replaces, and described alkyl is by five yuan or hexa-member heterocycle or C 6To C 8Aryl replaces, and described heterocycle is replaced by one or more halogens and/or alkoxyl group, and described aryl is randomly replaced by one or more halogens and/or alkoxyl group;
-the heterocycle that replaced by hydroxyl;
-NR tCOOR u, R wherein uBe:
-C 1To C 12Alkyl, it is replaced by one or more substituting groups that are independently selected from following groups:
-C 6To C 8Aryl, it is replaced by one or more halogens and/or alkylhalide group;
-the alkoxyl group that replaced by one or more alkoxyl groups;
-randomly by one or more C 1To C 6The amino that alkyl replaces;
-SO 2R w；
-SO 2R xAnd
-five yuan or six membered heteroaryl;
-C 2To C 6Thiazolinyl;
-quaternary is to seven membered heterocyclic, and it is replaced by one or more substituting groups that are independently selected from down group:
＝O；
-SO 2R w；
-COR pAnd
-(CO) O-(C 1To C 4Alkyl)-O-(C 1To C 4Alkyl);
-quaternary or seven membered heterocyclic, it is randomly replaced by one or more substituting groups that are independently selected from down group:
＝O；
-SO 2R w；
-COR pAnd
-(CO) O-(C 1To C 4Alkyl)-O-(C 1To C 4Alkyl);
-NHR Bb, R wherein BbBe:
-C(＝S)NHR x；
-C (=S) NR xR xOr
-C(＝N-CN)NHR x；
-N(CONHR w) 2；
-NH(SOR w)；
-N(SO 2R w) 2；
-NR vSO 2R w, R wherein vBy the alkyl of quaternary or seven membered heterocyclic replacement;
Or R wherein wBe:
-randomly by C 6To C 8The C that aryl replaces 1To C 6Alkyl, described aryl is replaced by one or more substituting groups that are independently selected from alkylhalide group, halogen, alkoxyl group and alkyl;
-randomly by the amino of heterocyclic radical or alkyl replacement, described heterocyclic radical or alkyl are randomly by one or more halogen, C of being independently selected from 1To C 6Alkoxyl group, carbalkoxy, (CO) O-(C 1To C 6) alkyl), the substituting group of hydroxyl, cyano group, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
Figure A20078000890202861
-five yuan to six membered heteroaryl, and it is randomly replaced by one or more substituting groups that are independently selected from down group:
-halogen;
-C 1To C 6Alkyl;
-alkoxyl group, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-halogen;
-five yuan or hexa-member heterocycle; And
-C (O) NH 2, it is randomly by C 6To C 8Alkyl replaces;
-hydroxyl;
-alkylhalide group;
-cyano group;
-nitro;
-COOH；
-randomly by one or more amino that are independently selected from the substituting groups replacement of following groups:
-SO 2R x；
-hexa-atomic to eight yuan of aryl, it is randomly by one or more alkyl, halogen, alkylhalide group, cyano group, alkoxyl group, COR of being independently selected from xReplace with the substituting group of halogen alkoxyl group;
-five yuan or six membered heteroaryl, it is randomly by one or more C that are independently selected from alkyl, halogen, alkylhalide group, cyano group, alkoxyl group, halogen alkoxyl group and randomly replaced by halogen 6To C 8The substituting group of aryl replaces;
-C 5To C 6Heterocycle, it is randomly replaced by one or more substituting groups that are independently selected from hydroxyl, alkyl and alkylhalide group; And
-C 1To C 7Alkyl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or six membered heteroaryl, it is randomly replaced by one or more alkyl, halogen and/or alkylhalide group;
-C 6To C 8Aryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, halogen and alkylhalide group;
-alkoxyl group; And
-halogen;
-NR oCOR p, R wherein pBe:
-randomly by one or more C 1To C 6The amino that alkyl replaces, described alkyl are randomly and independently by one or more C 6To C 8Aryl and/or alkoxyl group replace; Or
-five yuan or hexa-member heterocycle, it is by one or more C 1To C 6Alkyl and/or C 6To C 8Aryl replaces;
-NR qCONR qR r, R wherein rBe:
-C 1To C 6Alkyl, it is replaced by one or more substituting groups that are independently selected from following groups:
-hydroxyl;
-alkoxyl group;
-five yuan or hexa-member heterocycle;
-five yuan or six membered heteroaryl, and
-C 6To C 8Aryl, it is replaced by halogen,
-C 2To C 6Thiazolinyl, it is randomly replaced by one or more halogens;
-C 1To C 6Alkoxyl group;
-five yuan or hexa-member heterocycle; Or
-five yuan to six membered heteroaryl, and it is randomly replaced by alkyl;
-NR tCOOR u, R wherein uBe:
-C 1To C 12Alkyl, it is replaced by one or more substituting groups that are independently selected from following groups:
-C 6To C 8Aryl, it is replaced by one or more halogens and/or alkylhalide group;
-the alkoxyl group that replaced by one or more alkoxyl groups;
-randomly by one or more C 1To C 6The amino that alkyl replaces;
-SO 2R w；
-SO 2R xAnd
-five yuan or six membered heteroaryl, and
-NR vSO 2R w, R wherein vBy the alkyl of quaternary to the seven membered heterocyclic replacement;
Or R wherein wBe:
-by C 6To C 8The C that aryl replaces 1To C 6Alkyl, described aryl is replaced by one or more substituting groups that are independently selected from alkylhalide group, halogen, alkoxyl group and alkyl;
-C 6To C 8Aryl;
-by the amino of heterocyclic radical or alkyl replacement, described heterocycle is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, carbalkoxy, hydroxyl, cyano group, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces, and described alkyl is by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, carbalkoxy, hydroxyl, cyano group, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
Figure A20078000890202891
Figure A20078000890202901
92. the compound of embodiment 89, wherein:
Z is:
-C 1To C 6Alkyl, it is by five yuan or hexa-member heterocycle replacement; Or
-five yuan or hexa-member heterocycle.
93. the compound of embodiment 89, wherein:
R 1Be:
-five yuan or hexa-member heterocycle, it is replaced by one or more substituting groups that are independently selected from down group:
-hydroxyl;
-C 1To C 6Alkyl;
-SO 2R x；
-C (O)-C 6To C 8Aryl;
-COR pAnd
-C (O) OR xOr
-five yuan or six membered heteroaryl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-C 1To C 6Alkyl, it is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-alkoxyl group;
-halogen;
-alkylthio;
-alkylhalide group;
-cyano group;
-the amino that randomly replaced by alkyl, described alkyl is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, cyano group, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-heterocycle;
-nitro;
-hydroxyl;
-COOH；
-CO 2R x；
-COR x；
-randomly by one or more C 1To C 6C (O) NH that alkyl replaces 2, described alkyl is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-amido, it is randomly by one or more halogen, C of being independently selected from 1To C 6Alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle, five yuan or six membered heteroaryl and C 1To C 6The substituting group of alkyl replaces, and described alkyl is randomly by one or more C 1To C 6Alkoxyl group replaces;
-C 1To C 6Alkyl, it is replaced by one or more substituting groups that are independently selected from following groups:
-amino, it is randomly replaced by one or more substituting groups that are independently selected from heterocycle, alkoxyl group and alkyl, and described alkyl is replaced by one or more alkoxyl groups;
-randomly by C 1To C 6The amido that alkyl replaces;
-five yuan or hexa-member heterocycle, it is by C 1To C 6Alkyl replaces;
-five yuan or six membered heteroaryl, and
-C 6To C 8Aryl;
-SO 2R x；
-C 2To C 6Thiazolinyl, it is randomly by SO 2R xReplace;
-C 1To C 6Alkoxyl group, it is replaced by one or more substituting groups that are independently selected from following groups:
-hydroxyl;
-cyano group;
-the alkoxyl group that replaces of alkoxy randomly;
-amino, it is randomly replaced by one or more substituting groups that are independently selected from five yuan or six membered heteroaryl, five yuan or hexa-member heterocycle and alkyl, and described alkyl is randomly replaced by one or more substituting groups that randomly are selected from following groups:
-five yuan or hexa-member heterocycle; And
-the amino that randomly replaced by one or more alkyl;
-randomly heterocyclically substituted amino;
-randomly by C 1To C 6The amido that alkyl replaces;
-five yuan to seven membered heterocyclic, and it is by one or more hydroxyl and C of being independently selected from 1To C 6The substituting group of alkyl replaces, and described alkyl randomly is selected from independently by one or more that the substituting group of following groups replaces;
-C 1To C 6Alkoxyl group; And
-C 6To C 8Aryl;
-five yuan or six membered heteroaryl, it is randomly replaced by one or more substituting groups that are independently selected from down group:
-C 1To C 6Alkyl; And
-quaternary is to seven membered heterocyclic; And
-alkoxyl group;
-(O)-five yuan or hexa-member heterocycle, it is randomly replaced by one or more substituting groups that are independently selected from down group:
-hydroxyl;
-C 1To C 6Alkyl;
-SO 2R x；
-C (O)-C 6To C 8Aryl;
-COR pAnd
-C (O) OR xOr
-(O)-five yuan or six membered heteroaryl, it is randomly replaced by one or more substituting groups that are independently selected from down group:
-C 1To C 6Alkyl, it is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-alkoxyl group;
-halogen;
-alkylthio;
-alkylhalide group;
-cyano group;
-the amino that randomly replaced by alkyl, described alkyl is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, cyano group, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-heterocycle;
-nitro;
-hydroxyl;
-COOH；
-CO 2R x；
-COR x；
-C (O) NH 2, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-C 1To C 6Alkyl, it is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces; And
-amido, it is randomly by one or more halogen, C of being independently selected from 1To C 6Alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle, five yuan or six membered heteroaryl and C 1To C 6The substituting group of alkyl replaces, and described alkyl is randomly by one or more C 1To C 6Alkoxyl group replaces;
-randomly by one or more C 1To C 6C (O) NH that alkyl replaces 2, described alkyl is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-C (O)-ternary is to seven membered heterocyclic, and it is randomly replaced by one or more substituting groups that are independently selected from down group:
-C 6To C 8Aryl;
-five yuan or six membered heteroaryl, and
-C 1To C 6Alkyl, it is randomly by one or more replacements that replaced by hydroxyl;
-SO 2R x, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or hexa-member heterocycle;
-C 6To C 8Aryl; And
-five yuan or six membered heteroaryl; Or
-alkylthio, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or hexa-member heterocycle;
-C 6To C 8Aryl; And
-five yuan or six membered heteroaryl;
-C (O)-five yuan or six membered heteroaryl;
-C (O)-C 6To C 8Aryl;
-COOH; Or
-OR Kk, R wherein KkBe:
C 6To C 8Aryl, it is randomly by one or more halogen, C of being independently selected from 1To C 6Alkyl, C 1To C 6Alkoxyl group and C 1To C 6The substituting group of alkylhalide group replaces.
94. the compound of embodiment 89, wherein:
R 2Be:
-C 1To C 6Alkyl, it is replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or hexa-member heterocycle;
-five yuan or six membered heteroaryl;
-C 6To C 8Aryl;
-randomly by C 1To C 6The amido that alkyl replaces; And
-amino, it is randomly replaced by one or more substituting groups that are independently selected from heterocycle, alkoxyl group and alkyl, and described alkyl is randomly replaced by one or more alkoxyl groups;
-SO 2R x；
-C 2To C 6Thiazolinyl, it is randomly by SO 2R xReplace;
-alkylthio, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or six membered heteroaryl, it is randomly replaced by alkyl;
-five yuan or hexa-member heterocycle;
-C 6To C 8Aryl; And
-C 1To C 6Alkyl;
-SO 2R x, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or six membered heteroaryl, it is randomly by one or more C 1To C 6Alkyl replaces;
-five yuan or hexa-member heterocycle;
-C 6To C 8Aryl; And
-C 1To C 6Alkyl;
-S (O) R x, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or six membered heteroaryl;
-five yuan or hexa-member heterocycle;
-C 6To C 8Aryl; And
-C 1To C 6Alkyl;
-alkoxyl group, it is replaced by one or more substituting groups that are independently selected from following groups:
-halogen;
-hydroxyl;
-cyano group;
-the alkoxyl group that replaces of alkoxy randomly;
-amino, it is by one or more being independently selected from-SO 2-C 1To C 4The substituting group of alkyl and alkyl replaces, and described alkyl is replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or hexa-member heterocycle; And
-the amino that randomly replaced by one or more alkyl;
-by C 1To C 6The amido that alkyl replaces;
Five yuan of-S-or hexa-member heterocycle;
Five yuan of-S-or six membered heteroaryl, it is randomly by C 1To C 6Alkyl replaces;
-S-C 1To C 6Alkyl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-C 6To C 8Aryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, alkylhalide group and halogen; And
-C 5To C 6Heteroaryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, alkylhalide group and halogen;
-S-C 6To C 8Aryl;
-sulfinyl-five yuan or hexa-member heterocycle;
-sulfinyl-five yuan or six membered heteroaryl;
-sulfinyl-C 1To C 6Alkyl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-C 6To C 8Aryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, alkylhalide group and halogen; And
-C 5To C 6Heteroaryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, alkylhalide group and halogen;
-sulfinyl-C 6To C 8Aryl;
-alkylsulfonyl-five yuan or hexa-member heterocycle;
-alkylsulfonyl-randomly by C 1To C 6Five yuan or six membered heteroaryl that alkyl replaces;
-alkylsulfonyl-C 1To C 6Alkyl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-C 6To C 8Aryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, alkylhalide group and halogen; And
-C 5To C 6Heteroaryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, alkylhalide group and halogen;
-alkylsulfonyl-C 6To C 8Aryl;
-five yuan to seven membered heterocyclic, its randomly by one or more be independently selected from hydroxyl ,=O, heterocycle and C 1To C 6The substituting group of alkyl replaces, and described alkyl is randomly replaced by one or more substituting groups that are independently selected from following groups:
-C 1To C 6Alkoxyl group; And
-C 6To C 8Aryl;
-five yuan or six membered heteroaryl, it is randomly replaced by one or more substituting groups that are independently selected from down group:
-C 1To C 6Alkyl, it is randomly replaced by one or more alkoxyl groups;
-quaternary is to seven membered heterocyclic; And
-alkoxyl group; And
-C 6To C 8Aryl;
-C 6To C 8Aryl;
-(O)-five yuan or hexa-member heterocycle, it is replaced by one or more substituting groups that are independently selected from down group:
-hydroxyl;
＝O；
-C 1To C 6Alkyl;
-SO 2R x；
-C (O)-C 6To C 8Aryl;
-COR pAnd
-C (O) OR xOr
-(O)-five yuan or six membered heteroaryl, it is replaced by one or more substituting groups that are independently selected from down group:
-C 1To C 6Alkyl, it is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-alkoxyl group;
-halogen;
-alkylthio;
-alkylhalide group;
-cyano group;
-the amino that randomly replaced by alkyl, described alkyl is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, cyano group, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-heterocycle;
-nitro;
-hydroxyl;
-COOH；
-CO 2R x；
-COR x；
-randomly by one or more C 1To C 6C (O) NH that alkyl replaces 2, described alkyl is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-amido, it is randomly by one or more halogen, C of being independently selected from 1To C 6Alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle, five yuan or six membered heteroaryl and C 1To C 6The substituting group of alkyl replaces, and described alkyl is randomly by one or more C 1To C 6Alkoxyl group replaces;
-C (O)-ternary is to seven membered heterocyclic, and it is randomly replaced by one or more substituting groups that are independently selected from down group:
-C 6To C 8Aryl;
-five yuan or six membered heteroaryl, and
-C 1To C 6Alkyl, it is randomly replaced by one or more hydroxyls;
-C (O)-five yuan or six membered heteroaryl;
-C (O)-C 6To C 8Aryl;
-COOH；
-randomly by one or more C 1To C 6C (O) NH that alkyl replaces 2, described alkyl is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-amido, it is by one or more C 1To C 6Alkyl replaces, and described alkyl is randomly by one or more C 1To C 6Alkoxyl group replaces;
-the amino that replaced by one or more substituting groups that are independently selected from following groups:
-SO 2R x；
-hexa-atomic to eight yuan of aryl, it is randomly by one or more alkyl, halogen, alkylhalide group, cyano group, alkoxyl group, COR of being independently selected from xReplace with the substituting group of halogen alkoxyl group;
-five yuan or six membered heteroaryl, it is randomly by one or more C that are independently selected from alkyl, halogen, alkylhalide group, cyano group, alkoxyl group, halogen alkoxyl group and randomly replaced by halogen 6To C 8The substituting group of aryl replaces;
-C 5To C 6Heterocycle, it is randomly replaced by one or more substituting groups that are independently selected from hydroxyl, alkyl and alkylhalide group;
-C 1To C 7Alkyl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or six membered heteroaryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, halogen and alkylhalide group;
-C 6To C 8Aryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, halogen and alkylhalide group;
-alkoxyl group; And
-halogen;
-five yuan or six membered heteroaryl, it is replaced by one or more substituting groups that are independently selected from down group:
-C 1To C 6Alkyl, it is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-alkoxyl group;
-halogen;
-alkylthio;
-alkylhalide group;
-cyano group;
-the amino that randomly replaced by one or more alkyl, described alkyl is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, cyano group, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-heterocycle;
-nitro;
-hydroxyl;
-COOH；
-CO 2R x；
-COR x；
-randomly by one or more C 1To C 6C (O) NH that alkyl replaces 2, described alkyl is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-amido, it is randomly by one or more halogen, C of being independently selected from 1To C 6Alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle, five yuan or six membered heteroaryl and C 1To C 6The substituting group of alkyl replaces, and described alkyl is randomly by one or more C 1To C 6Alkoxyl group replaces;
-five yuan or hexa-member heterocycle, it is randomly replaced by one or more substituting groups that are independently selected from down group:
-hydroxyl;
＝O；
-C 1To C 6Alkyl;
-SO 2R x；
-C (O)-C 6To C 8Aryl;
-COR pAnd
-C(O)OR x；
-OR Kk, R wherein KkBe:
-C 6To C 8Aryl, it is randomly by one or more halogen, C of being independently selected from 1To C 6Alkyl, C 1To C 6Alkoxyl group and C 1To C 6The substituting group of alkylhalide group replaces;
-five yuan to hexa-member heterocycle, and it is randomly by C 1To C 6Alkyl replaces, and described alkyl is randomly by C 6To C 8Aryl replaces; Or
-five yuan to six membered heteroaryl, and it is by one or more halogen, C of being independently selected from 1To C 6Alkyl, C 1To C 6Alkoxyl group and C 1To C 6The substituting group of alkylhalide group replaces;
-SO 2R xOr
-Si(Rx) 3；
-OC (O) NHR x, R wherein xRandomly by C 6To C 8Aryl replaces;
-OC (O) N (R x) 2Or
Figure A20078000890203001
95. the compound of embodiment 89, wherein R 3It is nitro.
96. the compound of embodiment 89, wherein:
X is cyano group or hydrogen;
Y is:
-C 6To C 8Aryl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-halogen;
-C 1To C 6Alkyl;
-randomly by one or more amino that are independently selected from the substituting groups replacement of following groups:
-SO 2R x；
-five yuan or six membered heteroaryl, it is randomly replaced by one or more alkyl;
-C 1To C 7Alkyl;
-NR tCOOR u, R wherein tBe hydrogen, R uBe C 1To C 12Alkyl;
-NR vSO 2R w, R wherein vBe hydrogen, R wBe C 1To C 6Alkyl or the amino that is randomly replaced by alkyl;
Figure A20078000890203002
Z is C 1To C 6Alkyl;
R is a hydrogen;
R 1Be hydrogen;
R 2Replaced by cyano group-(O)-five yuan or six membered heteroaryl; And
R 3Be hydrogen.
97. the compound of embodiment 96, wherein C 6To C 8Aryl is a phenyl.
98. the compound of embodiment 97, wherein:
X is a cyano group;
Y is contraposition quilt-NR vSO 2R wThe phenyl that replaces, wherein R vBe hydrogen, R wBe C 1To C 6Alkyl; And
R 2Be the ortho position replaced by cyano group-(O)-five yuan or six membered heteroaryl.
99. the compound of embodiment 97, wherein:
X is a cyano group;
Y is by C 1To C 6Alkyl and NR vSO 2R wThe phenyl that replaces, wherein R vBe hydrogen, R wBe C 1To C 6Alkyl; And R 2Be the ortho position replaced by cyano group-(O)-five yuan or six membered heteroaryl.
100. the compound of embodiment 97, wherein:
X is a cyano group;
Y is by halogen and NR vSO 2R wThe phenyl that replaces, wherein R vBe hydrogen, R wBe C 1To C 6Alkyl; And
R 2Be the ortho position replaced by cyano group-(O)-five yuan or six membered heteroaryl.
101. the compound of embodiment 97, wherein:
X is a hydrogen;
Y is that contraposition is by NR tCOOR uThe phenyl that replaces, wherein R tBe hydrogen, R uBe C 1To C 12Alkyl;
Z is cyclobutyl, cyclopropyl, cyclopropyl methyl, ethyl or cyclopentyl; And
R 2Be the ortho position replaced by cyano group-(O)-five yuan or six membered heteroaryl.
102. the compound of embodiment 89, wherein:
X is a cyano group;
Y is:
-C 6To C 8Aryl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-NR tCOOR u, R wherein tBe hydrogen, R uThe C that is replaced by one or more halogens 1To C 12Alkyl; Or
-NR vSO 2R w, R wherein vBe hydrogen, R wBe C 1To C 6Alkyl;
Z is C 1To C 6Alkyl;
R is a hydrogen;
R 1Be hydrogen;
R 2Replaced by one or more=O-(O)-five yuan or hexa-member heterocycle; And
R 3Be hydrogen.
103. be selected from the compound of compound 1330-2128 and 2600-3348.
104. the compound of embodiment 103, it is selected from:
Figure A20078000890203031
105. composition that comprises embodiment 1 described compound and the acceptable vehicle of one or more pharmacology.
106. composition that comprises embodiment 39 described compounds and the acceptable vehicle of one or more pharmacology.
107. composition that comprises embodiment 77 described compounds and the acceptable vehicle of one or more pharmacology.
108. composition that comprises embodiment 83 described compounds and the acceptable vehicle of one or more pharmacology.
109. composition that comprises embodiment 89 described compounds and the acceptable vehicle of one or more pharmacology.
110. a method that is used for the treatment of the infection with hepatitis C virus in the individuality that these needs are arranged, this method comprise to one or more of described individual effective dosage as enforcement mode 1 described compound or comprise one or more pharmaceutical compositions as enforcement mode 1 described compound of significant quantity.
111. a method that is used for the treatment of the infection with hepatitis C virus in the individuality that these needs are arranged, this method comprise to one or more of described individual effective dosage as enforcement mode 39 described compounds or comprise one or more pharmaceutical compositions as enforcement mode 39 described compounds of significant quantity.
112. a method that is used for the treatment of the infection with hepatitis C virus in the individuality that these needs are arranged, this method comprise to one or more of described individual effective dosage as enforcement mode 77 described compounds or comprise one or more pharmaceutical compositions as enforcement mode 77 described compounds of significant quantity.
113. a method that is used for the treatment of the infection with hepatitis C virus in the individuality that these needs are arranged, this method comprise to one or more of described individual effective dosage as enforcement mode 83 described compounds or comprise one or more pharmaceutical compositions as enforcement mode 83 described compounds of significant quantity.
114. a method that is used for the treatment of the infection with hepatitis C virus in the individuality that these needs are arranged, this method comprise to one or more of described individual effective dosage as enforcement mode 89 described compounds or comprise one or more pharmaceutical compositions as enforcement mode 89 described compounds of significant quantity.
115. method that is used for the treatment of the virus infection in the individuality that these needs are arranged, wherein said virus comprises internal ribosome entry site, and this method comprises to one or more of described individual effective dosage as enforcement mode 1 described compound or comprise one or more pharmaceutical compositions as enforcement mode 1 described compound of significant quantity.
116. method that is used for the treatment of the virus infection in the individuality that these needs are arranged, wherein said virus comprises internal ribosome entry site, and this method comprises to one or more of described individual effective dosage as enforcement mode 39 described compounds or comprise one or more pharmaceutical compositions as enforcement mode 39 described compounds of significant quantity.
117. method that is used for the treatment of the virus infection in the individuality that these needs are arranged, wherein said virus comprises internal ribosome entry site, and this method comprises to one or more of described individual effective dosage as enforcement mode 77 described compounds or comprise one or more pharmaceutical compositions as enforcement mode 77 described compounds of significant quantity.
118. method that is used for the treatment of the virus infection in the individuality that these needs are arranged, wherein said virus comprises internal ribosome entry site, and this method comprises to one or more of described individual effective dosage as enforcement mode 83 described compounds or comprise one or more pharmaceutical compositions as enforcement mode 83 described compounds of significant quantity.
119. method that is used for the treatment of the virus infection in the individuality that these needs are arranged, wherein said virus comprises internal ribosome entry site, and this method comprises to one or more of described individual effective dosage as enforcement mode 89 described compounds or comprise one or more pharmaceutical compositions as enforcement mode 89 described compounds of significant quantity.
In another embodiment, the present invention includes formula I, I-X, I-XI, I-XII, I-Xa, I-XIa, I-XIIa, I-XIb, I-XIc, IIa, IIb, IIc, IId or IIe compound, wherein Y is NR tCOOR uBase, R uBe C 1To C 6Alkyl.Compound is provided in one embodiment, and wherein Y is NR tCOOR uBase, R uBe the C that is positioned at contraposition 1To C 6Alkyl.In another embodiment, the present invention includes formula I, I-X, I-XI, I-XII, I-Xa, I-XIa, I-XIIa, I-XIb, I-XIc, IIa, IIb, IIc, IId or IIe compound, wherein Y is NR tCOOR uBase, R uBe the C of side chain 1To C 6Alkyl.In the embodiment of formula I, I-X, I-XI, I-XII, I-Xa, I-XIa, I-XIIa, I-XIb, I-XIc, IIa, IIb, IIc, IId or IIe, Y is NR tCOOR uBase, R uBe the C that is positioned at the side chain of contraposition 1To C 6Alkyl.In another embodiment, the present invention includes formula I, I-X, I-XI, I-XII, I-Xa, I-XIa, I-XIIa, I-XIb, I-XIc, IIa, IIb, IIc, IId or IIe compound, wherein Y is NR tCOOR uBase, R uIt is sec.-propyl.In another embodiment, the present invention includes formula I-X, I-XI, I-XII, I-Xa, I-XIa, I-XIIa, I-XIb, I-XIc, IIa, IIb, IIc, IId or IIe compound, wherein Y is NR tCOOR uBase, R uIt is the methyl cyclopropyl.In another embodiment, the present invention includes formula I-X, I-XI, I-XII, I-Xa, I-XIa, I-XIIa, I-XIb, I-XIc, IIa, IIb, IIc, IId or IIe compound, wherein Y is NR tCOOR uBase, R uIt is the ethyl cyclopropyl.
In another embodiment, the present invention includes formula I-X, I-XI, I-XII, I-Xa, I-XIa, I-XIIa, I-XIb, I-XIc, IIa, IIb, IIc, IId or IIe compound, wherein Y is NR vSO 2R wBase, R vBe hydrogen, and R wBe C 1To C 6Alkyl.In another embodiment, the present invention includes compound, wherein Y is-NR vSO 2R wBase, R wIt is propyl group.
Compound is provided in an embodiment of the invention, and wherein Y is substituted C 6To C 8Aryl.Compound is provided in an embodiment of the invention, and wherein Y is substituted phenyl.Compound is provided in an embodiment of the invention, and wherein Y has 1,2,3 or 4 substituent C 6To C 8Aryl.In another embodiment of compound of the present invention, Y has 1,2 or 3 substituent C 6To C 8Aryl.In another embodiment, Y has 1 or 2 substituent C 6To C 8Aryl.In another embodiment, Y has 3 substituent C 6To C 8Aryl.In another embodiment, Y has 2 substituent C 6To C 8Aryl.In another embodiment, Y has 1 substituent C 6To C 8Aryl.
Compound is provided in another embodiment of the present invention, and wherein Y is the C with at least 1 ortho position, a position or para-orienting group 6To C 8Aryl.In another embodiment, Y is the C that has between 1 position or para-orienting group at least 6To C 8Aryl.In another embodiment, Y is the C with para-orienting group 6To C 8Aryl.
Compound is provided in an embodiment of the invention, and wherein Y is C 6To C 8Aryl, its randomly by one of following groups at para-orientation:
-alkoxyl group,
-the amino that randomly replaced by one or more following groups:
-SO 2R xBase, or
-C 1To C 6Alkyl, described C 1To C 6Alkyl is replaced by one or more five yuan or six membered heteroaryl randomly and independently,
-OC(O)NHR x，
-OC(O)N(R x) 2，
-OC(O)NH(OR x)，
-OC(O)NR x(OR x)，
-OC(O)N(OR x) 2，
-OC (O) R Ab, R wherein AbBe five yuan or hexa-member heterocycle base,
-NR oCOR pBase, wherein R pBe:
-C 1To C 6Alkyl,
-randomly by one or more C 1To C 6The amino that alkyl replaces, wherein C 1To C 6Alkyl is randomly and independently by one or more C 6To C 8Aryl and/or alkoxyl group replace,
-five yuan or hexa-member heterocycle, it is randomly by one or more C 1To C 6Alkyl or C 6To C 8Aryl replaces,
And R wherein oBe:
-hydrogen,
-C 1To C 6Alkyl,
-NR qCONR qR rBase, wherein R qBe hydrogen,
And R wherein rBe:
-C 1To C 6Alkyl, it is randomly replaced by one or more following groups:
-hydroxyl,
-alkoxyl group,
-five yuan or hexa-member heterocycle,
-five yuan or six membered heteroaryl, or
-C 6To C 8Aryl, it is randomly replaced by halogen,
-C 2To C 6Alkylidene group,
-C 1To C 6Alkoxyl group,
-five yuan or hexa-member heterocycle base,
-NR tCOOR uBase, wherein R uBe:
-C 1To C 12Alkyl, it is randomly replaced by one or more groups that are independently selected from down group,
-C 6To C 8Aryl, it is randomly replaced by halogen,
-the alkoxyl group that randomly replaced by one or more alkoxyl groups,
-randomly by one or more C 1To C 6The amino that alkyl replaces,
-halogen, or
-five yuan or six membered heteroaryl,
-C 2To C 6Alkylidene group,
-C 6To C 8Aryl, it is randomly replaced by halogen,
And R tBe:
-hydrogen;
-NHR BbBase, wherein R BbBe:
-C (=S) NH 2Base, or
-PO (OR x) 2, R wherein xDefinition the same;
-NR vSO 2R wBase, wherein R vBe hydrogen, R wBe C 1To C 6Alkyl,
Figure A20078000890203081
In some embodiments, Y is selected from the Y substituting group of compound 1330-2128 and 2600-3348.
Provide compound in other embodiments of the present invention, wherein Y is selected from following substituting group:
Figure A20078000890203082
Figure A20078000890203091
Figure A20078000890203101
Figure A20078000890203111
Figure A20078000890203121
Provide compound in other non-limiting embodiments of the present invention, wherein Y is selected from following groups:
Figure A20078000890203122
Figure A20078000890203131
Figure A20078000890203141
Figure A20078000890203161
Figure A20078000890203171
Figure A20078000890203191
Figure A20078000890203201
Figure A20078000890203211
Figure A20078000890203221
Figure A20078000890203231
Figure A20078000890203241
Figure A20078000890203251
Figure A20078000890203261
Figure A20078000890203271
Figure A20078000890203281
Figure A20078000890203301
Figure A20078000890203321
Figure A20078000890203331
In one embodiment, the present invention includes formula I, I-X, I-XI, I-XII, I-Xa, I-XIa, I-XIIa, I-XIb, I-XIc, IIa, IIb, IIc, IId or IIe compound, wherein Z is five yuan or hexa-member heterocycle.In another embodiment of formula I, I-X, I-XI, I-XII, I-Xa, I-XIa, I-XIIa, I-XIb, I-XIc, IIa, IIb, IIc, IId or IIe, Z is a five-membered ring.In the another embodiment of formula I, I-X, I-XI, I-XII, I-Xa, I-XIa, I-XIIa, I-XIb, I-XIc, IIa, IIb, IIc, IId or IIe, Z is a hexa-member heterocycle.In another embodiment, the present invention includes formula I, I-X, I-XI, I-XII, I-Xa, I-XIa, I-XIIa, I-XIb, I-XIc, IIa, IIb, IIc, IId or IIe compound, wherein Z is the C that is randomly replaced by five yuan or hexa-member heterocycle 1To C 6Alkyl.In another embodiment, the present invention includes compound, wherein Z is C 1To C 6Alkyl.In another embodiment, the present invention includes compound, wherein Z is C 1Alkyl.In another embodiment, the present invention includes compound, wherein Z is C 2Alkyl.In another embodiment, the present invention includes compound, wherein Z is C 3Alkyl.In another embodiment, the present invention includes compound, wherein Z is C 4Alkyl.In another embodiment, the present invention includes compound, wherein Z is C 5Alkyl.In another embodiment, the present invention includes compound, wherein Z is C 6Alkyl.
In another embodiment, the present invention includes compound, wherein Z is the C of straight chain 1To C 6Alkyl.In another embodiment, the present invention includes compound, wherein Z is C 1To C 6Cyclic alkyl.In another embodiment, the present invention includes compound, wherein Z is C 1To C 6Straight chain and the alkyl of ring-type combination.In another embodiment, the present invention includes compound, wherein Z is selected from cyclobutyl, cyclopropyl, cyclopropyl methyl, ethyl, cyclopentyl and sec.-propyl.In another embodiment, the present invention includes compound, wherein Z is cyclobutyl, cyclopropyl or ethyl.In another embodiment, the present invention includes compound, wherein Z is cyclobutyl, cyclopropyl or encircles third methyl.In another embodiment, the present invention includes compound, wherein Z is cyclobutyl or cyclopropyl.A kind of compound is provided in an embodiment of the invention, and wherein Z is a cyclobutyl.
In some embodiments, Z is selected from the Z substituting group of compound 1330-2128 and 2600-3348.
In the non-limiting embodiment of compound of the present invention, Z is selected from following groups:
Figure A20078000890203341
Provide compound in another non-limiting embodiment of the present invention, wherein Z is selected from following groups:
Figure A20078000890203342
In some embodiments, described Z substituting group is a hydrogen.In other embodiments, Z is the C that is randomly replaced by five-membered ring 1To C 6Alkyl.In other embodiments, Z is the C that is randomly replaced by hexa-member heterocycle 1To C 6Alkyl.Provide compound in an embodiment of the invention, wherein R 2It is alkoxyl group.In one embodiment, the invention provides compound, wherein R 2It is methoxy or ethoxy.In an embodiment of The compounds of this invention, R 2It is methoxyl group.In an embodiment of compound of the present invention, R 2It is oxyethyl group.In one embodiment, the invention provides compound, wherein R 2Be alkoxyl group, it is randomly replaced by one or more groups that are independently selected from following groups:
-five yuan to the seven membered heterocyclic base, and it is randomly by one or more C that select independently 1To C 6Alkyl, alkoxyl group or hydroxyl replace; Or
-five yuan or six membered heteroaryl, it is randomly by one or more C 1To C 6Alkyl replaces.
In one embodiment, the invention provides compound, wherein R 2By the alkoxyl group of imidazoles, triazole, thiazole replacement.In another embodiment, R 2By the alkoxyl group of hydroxyl and imidazoles, triazole or thiazole replacement.
In one embodiment, the invention provides compound, wherein R 2Be OR KkBase, wherein R KkBe five yuan to hexa-member heterocycle, it is randomly by C 1To C 6Alkyl replaces, randomly by C 6To C 8Aryl replaces.
Provide compound in an embodiment of the invention, wherein R 2Be C 1To C 6Alkyl, it is randomly by one or more five yuan or the replacements of hexa-member heterocycle base.In another embodiment of the invention, provide compound, wherein R 2Be-C (O)-five yuan or hexa-member heterocycle, it is randomly by one or more C 6To C 8Aryl replaces.
In some embodiments, R 2Be selected from the R of compound 1330-2128 and 2600-3348 2Substituting group.
Provide compound in an embodiment of the invention, wherein R 2Be selected from following substituting group:
Figure A20078000890203361
Figure A20078000890203371
Figure A20078000890203381
Provide compound of the present invention in another embodiment, wherein R 2Be selected from following substituting group:
Figure A20078000890203382
Figure A20078000890203391
Figure A20078000890203401
In an embodiment of the invention, Z is C 1To C 6Alkyl, Y are NR tCOOR uBase, wherein R uBe C 1To C 12Alkyl, R tBe hydrogen, and R 2Be:
-alkoxyl group, it is randomly replaced by one or more groups that are independently selected from down group:
-amino, randomly by one or more five yuan or hexa-member heterocycle base or alkyl replacements, described alkyl randomly for it
And independently by one or more five yuan or hexa-member heterocycle replacements,
-five yuan to the seven membered heterocyclic base, and it is randomly by one or more hydroxyl or C that select independently 1To C 6Alkyl is got
Generation, wherein said C 1To C 6Alkyl is randomly by one or more C that select independently 1To C 6Alkane
The oxygen base replaces,
-five yuan or six membered heteroaryl, it is randomly by one or more C 1To C 6Alkyl replaces ,-OR KkBase, wherein R KkBe five yuan to hexa-member heterocycle, it is randomly by C 1To C 6Alkyl replaces, randomly by C 6To C 8Aryl replaces.
In yet another embodiment of the present invention, Z is C 1To C 6Alkyl, Y are NR tCOOR uBase, wherein R uBe C 1To C 12Alkyl, R tBe hydrogen, and R 2Be:
-alkoxyl group, it is randomly replaced by one or more groups that are independently selected from down group:
-five yuan to the seven membered heterocyclic base, and it is randomly by one or more hydroxyl or C that select independently 1To C 6Alkyl replaces, wherein said C 1To C 6Alkyl is randomly by one or more C that select independently 1To C 6Alkoxyl group replaces,
-five yuan or six membered heteroaryl, it is randomly by one or more C 1To C 6Alkyl replaces ,-OR KkBase, wherein R KkBe five yuan to hexa-member heterocycle, it is randomly by C 1To C 6Alkyl replaces, randomly by C 6To C 8Aryl replaces.
In yet another embodiment of the present invention, Z is C 1To C 6Alkyl, Y are NR tCOOR uBase, wherein R uBe C 1To C 12Alkyl, R tBe hydrogen, and R 2Be:
-alkoxyl group, it is randomly replaced by one or more groups that are independently selected from down group:
-five yuan to the seven membered heterocyclic base, and it is randomly by one or more hydroxyl or C that select independently 1To C 6Alkyl replaces, wherein said C 1To C 6Alkyl is randomly by one or more C that select independently 1To C 6Alkoxyl group replaces,
-five yuan or six membered heteroaryl, it is randomly by one or more C 1To C 6Alkyl replaces.
In yet another embodiment of the present invention, Z is C 1To C 6Alkyl, Y are NR tCOOR uBase, wherein R uBe C 1To C 12Alkyl, R tBe hydrogen, and R 2Be:
-alkoxyl group, it is randomly replaced by one or more groups that are independently selected from down group:
-five yuan to the seven membered heterocyclic base, and it is randomly by one or more hydroxyl or C that select independently 1To C 6Alkyl replaces, wherein said C 1To C 6Alkyl is randomly by one or more C that select independently 1To C 6Alkoxyl group replaces.
In yet another embodiment of the present invention, Z is C 1To C 6Alkyl, Y are NR tCOOR uBase, wherein R uBe C 1To C 12Alkyl, R tBe hydrogen, and R 2Be:
-alkoxyl group, it is randomly replaced by one or more groups that are independently selected from down group:
Exemplary compounds comprises following compounds:
Figure A20078000890203421
Figure A20078000890203431
Figure A20078000890203441
Figure A20078000890203451
Figure A20078000890203471
Figure A20078000890203481
Figure A20078000890203491
Figure A20078000890203501
Figure A20078000890203511
Figure A20078000890203521
Figure A20078000890203531
Figure A20078000890203551
Figure A20078000890203561
Figure A20078000890203571
Figure A20078000890203581
Figure A20078000890203611
Figure A20078000890203621
Figure A20078000890203631
Figure A20078000890203641
Figure A20078000890203661
Figure A20078000890203671
Figure A20078000890203681
Figure A20078000890203691
Figure A20078000890203701
Figure A20078000890203711
Figure A20078000890203721
Figure A20078000890203731
Figure A20078000890203741
Figure A20078000890203751
Figure A20078000890203781
Figure A20078000890203801
Figure A20078000890203811
Figure A20078000890203821
Figure A20078000890203831
Figure A20078000890203841
Figure A20078000890203861
Figure A20078000890203871
Figure A20078000890203881
Figure A20078000890203891
Figure A20078000890203901
Figure A20078000890203911
Figure A20078000890203921
Figure A20078000890203931
Figure A20078000890203951
Figure A20078000890203961
Figure A20078000890203971
Figure A20078000890203981
Figure A20078000890204011
Figure A20078000890204031
Figure A20078000890204041
Figure A20078000890204051
Figure A20078000890204061
Figure A20078000890204071
Figure A20078000890204081
Figure A20078000890204091
Figure A20078000890204101
Figure A20078000890204111
Figure A20078000890204121
Figure A20078000890204131
Figure A20078000890204141
Figure A20078000890204161
Figure A20078000890204171
Figure A20078000890204181
Figure A20078000890204191
Figure A20078000890204201
Figure A20078000890204211
Figure A20078000890204221
Figure A20078000890204231
Exemplary compounds comprises following compounds:
Figure A20078000890204241
Figure A20078000890204251
Figure A20078000890204271
Figure A20078000890204281
Figure A20078000890204291
Figure A20078000890204301
Figure A20078000890204311
Figure A20078000890204321
Figure A20078000890204331
Figure A20078000890204341
Figure A20078000890204361
Figure A20078000890204371
Figure A20078000890204401
Figure A20078000890204421
Figure A20078000890204441
B. The preparation of The compounds of this invention
Benzazolyl compounds of the present invention can obtain by standard and the synthetic method of knowing.Many indoles raw materials can or can be prepared by those skilled in the art through route hereinafter described.
The formula I compound of structure I I representative can be prepared by the method that synthetic route A is hereinafter painted:
Use the activatory carboxylic acid derivative for example acylimidazole compound (imidazolide) the A1 negatively charged ion of handling Nitromethane 99Min. can derivation obtain α-nitroketone derivative A2, for example sodium tert-butoxide or potassium tert.-butoxide or sodium hydride are handled the negatively charged ion that Nitromethane 99Min. obtains Nitromethane 99Min. wherein to use alkali.Component A3 is mixed with A4, and for example heat in alcohol or the aprotic solvent, make sulfonamide derivatives A3 and α-nitroketone A2 reaction generate Nitroenamine A4 in The suitable solvent.Use quinone A5 for example near room temperature or room temperature, to handle Nitroenamine A4, production II compound in the acetate at polar aprotic solvent.
I. synthetic route A
The formula I compound of structure I I representative can be prepared by method shown in the synthetic route A hereinafter:
Use the alkaline purification Nitromethane 99Min., subsequently with the activating carboxy acid for example imidazolium compounds such as compd A 1 react, generate type A2 compound.The amine of utilization structure A3 is handled type A2 compound, generates compd A 4.Compd A 4 for example reacts the oxyindole of generating structure II with quinine (quinine) in the acetate in acid.
Figure A20078000890204451
The formula I compound of structure III representative can be prepared by method shown in the synthetic route B hereinafter:
Use contains reactive alkyl or aryl treatments B 1 in suitable solvent of leavings group L, simultaneously with or without alkali for example mineral alkali such as yellow soda ash or salt of wormwood or organic bases for example triethylamine in the presence of heat, but the compound of generating structure III.The example of leavings group includes but not limited to halogen (for example chlorine, bromine or iodine) or alkyl or aryl sulfonate.
II synthetic route B
Figure A20078000890204461
The formula I compound of structure I V representative can be prepared by method shown in the synthetic route C hereinafter:
Can be by the nitrated one-tenth of the indoles of structure C 1 3-nitroindoline C2 being obtained the compound of structure I V.For example nitric acid or Sodium Nitrite can carry out nitrated at solvent for example acetate, diacetyl oxide, sulfuric acid or containing organic solvent and for example handle C1 in the mixed solvent system of methylene dichloride by using nitrating agent.This reaction can be carried out under the temperature between-30 ℃ to+50 ℃.Use contains the reactive functional groups R of suitable leavings group L 9(C3) handle C2, but the compound of generating structure IV.Reactive functional groups can by but be not limited to form by alkyl and aralkyl.L can represent halogenide, especially chlorine, bromine or iodine or alkylsulfonate.Reaction between C2 and the C3 can be in The suitable solvent and mineral alkali for example salt of wormwood or sodium hydride or organic bases for example trialkylamine in the presence of carry out.Perhaps, radicals R 9Can represent aryl or heteroaryl, L can represent halogenide, especially chlorine, bromine or iodine.This reaction can be in polarity or non-polar solvent under the temperature range of room temperature to 200 ℃ and copper catalyst CuI, alkali Cs for example for example 2CO 3Or K 3PO 4With optional amine ligand for example 1, two (methylamino) ethane or 1 of 2-carry out under the existence of 2-cyclohexanediamine.
An other approach is with similar fashion mentioned above C1 to be converted into C4, carries out nitration reaction, the compound of generating structure IV subsequently.
III. synthetic route C
Figure A20078000890204471
The formula I compound of structure V representative can be prepared by method shown in the synthetic route D:
The 'beta '-ketoester that uses amine D2 Processing Structure D1 The suitable solvent for example in alcohol or the protonic solvent heating generate amino crotonate derivative D3.D3 and quinone D4 for example react in the acetate at polar aprotic solvent, the compound of generating structure V.
IV. synthetic route D
Figure A20078000890204472
The The compounds of this invention of structure VI compound representative can be prepared according to the described chemical reaction of synthetic route E hereinafter.
Use for example acid or alkali in water solvent or water-organic mixed solvent under room temperature or high temperature the compound of Processing Structure E1, or use nucleophilic reagent for example boron tribromide or Iodotrimethylsilane in suitable solvent, handle, Indole-3-Carboxylic Acid's ester E1 can be converted into Indole-3-Carboxylic Acid E2.Type E2 compound can be activated subsequently and handle with the amine of type E3, generates compd E 4.Can carry out the carboxylic acid activation by for example any standard method.For example; can use coupling agent for example EDCI or DCC (adding or do not add HOBt) activated acids E2 in the presence of amine E3; for example perhaps use thionyl chloride or oxalyl chloride to handle acid and described acid is activated be acyl chlorides, or successively use carbonyl dimidazoles and amine E3 to handle acid can to make acid activation be acylimidazole compound.Use contains the reactive functional groups R of above-mentioned suitable leavings group L 9(E5) handle E4, compd E 4 can be converted into the compound of structure VI.Perhaps, use E5 to handle the compound that the compound that can make type E1 is converted into structure E6.The nationality aforesaid method can make Indole-3-Carboxylic Acid's ester E6 be converted into Indole-3-Carboxylic Acid E7 subsequently.Make amine E3 activation and react according to aforesaid method, can carry out E7 to structure VI conversion of compounds with E7.
V. synthetic route E
Figure A20078000890204481
The The compounds of this invention of structure VII compound representative can be prepared according to the described chemical reaction of synthetic route F hereinafter.
Use reagent for example Phosphorus Oxychloride can make indoles F1 that formylation takes place in the presence of DMF, generates indole-3-formaldehyde F2.Use compound F 17-hydroxy-corticosterone 3 to handle F2 according to aforesaid method, can finish the conversion of compounds of structure VII.Perhaps, the compound of type F1 can at first be converted into F4, is turned to the compound of structure VII subsequently by formyl.
VI. synthetic route F
Figure A20078000890204491
The formula G compound of structure VIII representative can be prepared by method shown in the synthetic route G.
Use reagent for example potassium permanganate carries out oxidation in aqueous conditions, the indole-3-formaldehyde of structure G1 can be converted into Indole-3-Carboxylic Acid's derivative.
VII. synthetic route G
The formula H compound of structure I X representative can be prepared by method shown in the synthetic route H.
The indoles 3-formaldehyde of structure H1 can be converted into indoles-3-carbonitrile derivatives H2 by many methods.Use nitro-paraffin for example nitropropane the amine source for example diammonium hydrogen phosphate in the presence of handle H1, generate indoles-3-nitrile H2 derivative.Another approach that generates compound H 2 is by intermediate H3.H1 can carry out dehydrogenation after being converted into 9 oxime derivate H3, for example uses diacetyl oxide and alkaline purification oxime, or uses thionyl chloride and oxime reaction to generate H2.Compound H 2 subsequently can with the above-mentioned reactive functional groups R that contains suitable leavings group L 9(H4) reaction, the compound of generating structure IX.
Perhaps, H1 can with the reactive functional groups R that contains suitable leavings group L 9(H4) reaction generates intermediate H5, and it can react with above-mentioned nitro-paraffin, generates indoles-3-nitrile IX compound.Also can be by being converted into oxime H6 and obtaining Compound I X according to the dehydrogenation reaction of aforesaid method subsequently.
VIII. synthetic route H
The The compounds of this invention of structure X representative also can be prepared according to the described method of synthetic route I hereinafter.
Can use suitable cyanidization agent for example Sulfuryl chloride isocyanate (I2) or dialkyl group phosphinylidyne isocyanic ester at The suitable solvent or solvent mixture for example DMF, CH 3In the CN Huo diox indoles I1 is carried out cyaniding, the compound of generating structure I3.Subsequently Compound I 3 can with the aforementioned reactive functional groups R that contains suitable leavings group L 9(I4) reaction generates compounds X.
Perhaps, Compound I 1 subsequently can with the reactive functional groups R that contains suitable leavings group L 9Reaction, generating structure I5 compound, it subsequently can be by as above cyaniding, production X compound.
IX. synthetic route I
Figure A20078000890204511
The formula J compound of structure XI representative can be prepared by method shown in the synthetic route J.
Amino cronate (amino crotonate) J1 can generate J3 with amine J2 reaction.J3 and quinone for example react in the acetate at polar aprotic solvent, generating structure XI compound.
X. synthetic route J
Figure A20078000890204512
The The compounds of this invention of structure XII and XIII representative can be prepared according to the described method of synthetic route K hereinafter.
The aldehyde of structure K1 can with alkyl diazoimide acetic ester K2 suitable organic solvent for example in proton or the aprotic solvent and organic or inorganic alkali in the presence of heat, reaction generates α-nitrine acrylate K3.K3 suitable non-reacted organic solvent for example toluene or dimethylbenzene in the presence of heat, can generate 2-carbalkoxy indoles K4.Use suitable reductive agent for example lithium aluminum hydride can generate intermediate K5 in The suitable solvent ester reduction functional group among ether or the THF for example.Use the above-mentioned reactive functional groups R that contains suitable leavings group L 9(K6) with the K5 reaction, generate compound K 7.Use above-mentioned cyanidization agent for example Sulfuryl chloride isocyanate make the K7 cyaniding, can generate compounds X II.Perhaps, use Sulfuryl chloride isocyanate that K5 is carried out cyaniding and generate K8, its can with the above-mentioned reactive functional groups R that contains suitable leavings group L 9(K6) reaction generates compounds X II.
Hereinafter illustration the another kind of purposes of intermediate K4.The 2-carbalkoxy of indoles K4 can generate intermediate K9 through decarboxylation after hydrolysis under acidity or the alkaline condition.Decarboxylation can be undertaken by type of heating, promptly for example heats in toluene, dimethylbenzene or the quinoline in suitable solvent.Perhaps, can add the copper source for example bronze to promote decarboxylation.Use the above-mentioned reactive functional groups R that contains suitable leavings group L 9(K6) with the K9 reaction, can generate compound K 10.Use above-mentioned cyanidization agent for example Sulfuryl chloride isocyanate make the K10 cyaniding, can generate compounds X III.Perhaps, use Sulfuryl chloride isocyanate that K9 is carried out cyaniding and generate K11, its can with the above-mentioned reactive functional groups R that contains suitable leavings group L 9(K6) reaction generates compounds X III.
XI. synthetic route K
Figure A20078000890204521
The formula L compound of structure XIV representative can be prepared by method shown in the synthetic route L.
The 2-methyl of formula L1 compound can be generated 2-brooethyl or chloromethyl indoles L2 by halogenation.Can use reagent for example the N-bromo-or chlorosuccinimide carry out halogenating reaction.This reaction can for example be carried out among chloroform, tetracol phenixin or the THF in The suitable solvent, and can carry out in the scope between envrionment temperature and 80 ℃.Randomly, can add radical initiator, for example benzoyl peroxide or AIBN.Compound L 2 subsequently can with nucleophilic R 5-W (L3) reaction, the compound of generating structure XIV.This reaction can be at The suitable solvent for example THF, CH 2Cl 2Or in 0 ℃ to 120 ℃ temperature range, carry out among the DMF.For example mineral alkali such as salt of wormwood or organic bases such as trialkylamine remove the acid that forms in the dereaction can to use alkali.Group W can be N, O or S atom.
XII. synthetic route L
Figure A20078000890204531
The The compounds of this invention of structure XV representative can be prepared according to the described method of synthetic route M hereinafter.
The aniline of structure M1 can be by diazotization, and formed diazonium salt can be reduced into phenylhydrazine compound M2.Reaction between hydrazine M2 and the ketone M3 under acidic conditions can generate benzazolyl compounds M4.The condition of cyclization can be carried out under the representative condition that those skilled in the art use, and for example uses acid as Bronstead sour as acetate, hydrochloric acid or polyphosphoric acid or the Lewis acid acidic conditions of zinc chloride for example.This reaction can be at cosolvent CH for example 2Cl 2Or in 0 ℃ to 120 ℃ representative temperature scope, carry out under the existence of THF.Use the above-mentioned reactive functional groups R that contains suitable leavings group L 9(M5) with the M4 reaction, can generate compound M6.Use cyanidization agent for example Sulfuryl chloride isocyanate makes indoles M6 cyaniding, but the compound of generating structure XV.
Perhaps, indoles M4 can be the compound of structure M7 by cyaniding.Use the above-mentioned reactive functional groups R that contains suitable leavings group L 9(M5) with the M7 reaction, but the compound of generating structure XV.
XIII. synthetic route M
Figure A20078000890204541
The formula I compound of structure XVI representative can be prepared by method shown in the synthetic route N.
Formula N1 compound can with dialkylformamide dialkyl acetal N2, for example dimethylformamide dimethyl acetal optional suitable solvent for example DMF or diox in the presence of under the temperature range of envrionment temperature to 150 ℃, react the compound of generating structure N3.But the benzazolyl compounds of the reduction generating structure N4 of the nitro of type N3 compound under standard conditions.The hydrogenation catalyst that can use the substoichiometric amount for example platinum or palladium reduces through hydrogenation in proton or aprotic solvent in the presence of hydrogen source.This reduction can be carried out in the temperature range of envrionment temperature to 80 ℃.Perhaps, this reduction can be carried out through chemical reduction, is for example reducing under the temperature range of envrionment temperature to 100 ℃ in suitable solvent in the presence of the Fe of stoichiometry or the Sn compound.Subsequently compound N 4 can with the above-mentioned reactive functional groups R that contains suitable leavings group L 9(N5) reaction, the compound of generating structure N6.Use cyanidization agent for example Sulfuryl chloride isocyanate makes the N6 cyaniding in suitable solution, but the compound of generating structure XVI.
Perhaps, the compound of structure N4 can be become the compound of structure N7 by cyaniding.Use the above-mentioned reactive functional groups R that contains suitable leavings group L 9(N5) with the N7 reaction, but the compound of generating structure XVI.
XIV. synthetic route N
Figure A20078000890204551
The formula I compound of structure XVII representative can be prepared by method shown in the synthetic route O.
The compound of structure O1 can be converted into 2-iodo-or bromo indole O2.Generally speaking, use highly basic for example n-Butyl Lithium or s-butyl lithium or diisopropylamino lithium (lithium diisopropylamide) or hexamethyl two silica-based potassium amides (potassium hexamethyldisilazide) or hexamethyl two silica-based potassium amides at suitable non-reactive solvent for example ether or THF or contain in their solvent mixture and generate 2-indyl negatively charged ion.This reaction is generally carried out to the scope of envrionment temperature at-78 ℃.2-indyl negatively charged ion subsequently can be by the compound of the electric halogen source cancellation of parent generating structure O2, and wherein close electric halogen source includes but not limited to iodine, bromine or N-bromo-succinimide.2-iodo-or bromo indole O2 and acid reaction (be commonly referred to Suzuki reaction) or with trialkyltin (trialkyl stannane) reaction (being commonly referred to the Stille reaction) but the compound of generating structure XVII.But the method that linked reaction nationality those skilled in the art know is carried out, and it is included in catalyzer and for example carries out this reaction under the existence of the phosphine part of tetrakis triphenylphosphine palladium (0), two (triphenylphosphine) palladium chloride (II) or acid chloride and adding.This is reflected at The suitable solvent and for example carries out under the temperature range of envrionment temperature to 150 ℃ in DMF, toluene, the glycol dimethyl ether Huo diox.For the Suzuki reaction, add alkali usually.Alkali can be the aqueous solution for example yellow soda ash or sodium bicarbonate aqueous solution, and perhaps alkali can use for example cesium fluoride or Potassium monofluoride under anhydrous condition.For the Stille reaction, can add the copper co-catalyst, for example cuprous iodide.
Perhaps, above-mentioned 2-indyl negatively charged ion can be reacted with trialkylboron hydrochlorate or chloro trialkyltin respectively, make indoles O1 be converted into indoles-2-boric acid or indoles-2-trialkyltin derivative O3.The compound of type O3 can react under above-mentioned conditions of similarity with aryl and heteroaryl bromine and iodine, forms the compound of structure XVII.
XV. synthetic route O
The formula I compound of structure XVIII representative can be prepared by method shown in the synthetic route P.
Use aryl or heteroaryl halogen (P2) to handle P1 under organo-metallic catalysis, the compound of structure P1 can be converted into Compound P 3.This class catalyst combination can comprise palladium catalyst, for example acid chloride and Tong Yuan, for example cuprous iodide.This reaction can alkali for example cesium carbonate in the presence of carry out.This reaction can be carried out in the temperature range of envrionment temperature to 150 ℃.
XVI. synthetic route P
Figure A20078000890204562
The The compounds of this invention of structure XIX representative can be prepared according to the described method of synthetic route Q hereinafter.
Benzazolyl compounds by protection structure Q1 is N-Boc derivative Q2 for example, can prepare the compound of structure XIX.Perhaps, can use but other protecting group of being not limited thereto comprises benzyl, alkyl or aryl alkylsulfonyl or trialkylsilkl.Use highly basic for example diisopropylamino lithium is handled Q2 in aprotic solvent such as THF, subsequently with the cancellation of trialkylboron acid salt derivant, can generate indoles-2-boric acid Q3.With halogenated aryl hydrocarbon or heterocyclic arene Q4 palladium catalyst for example tetrakis triphenylphosphine palladium (0), two (triphenylphosphine) palladium chloride (II) or acid chloride and adding the phosphine part in the presence of reaction can generate compound Q 5.Remove protecting group and can obtain Q6.Use the above-mentioned reactive functional groups R that contains suitable leavings group L 9With the Q6 reaction, but the compound of generating structure Q7.But the compound of the cyaniding generating structure XIX of compound Q 7.
XVII. synthetic route Q
Figure A20078000890204571
The formula I compound of structure XX representative can be prepared by method shown in the synthetic route R.
By for example above-mentioned N-Boc derivative of the benzazolyl compounds R2 of protection structure R1, can prepare the compound of structure R1.The compound of structure R2 can be converted into 2-iodo-or bromo indole R3.Generally speaking, use highly basic for example n-Butyl Lithium or s-butyl lithium or diisopropylamino lithium or hexamethyl two silica-based Lithamides or hexamethyl two silica-based potassium amides at suitable non-reactive solvent for example ether or THF or contain in their solvent mixture and generate 2-indyl negatively charged ion.This reaction is generally carried out to the scope of envrionment temperature at-78 ℃.2-indyl negatively charged ion subsequently can be by the compound of the electric halogen source cancellation of parent generating structure R3, and wherein close electric halogen source includes but not limited to iodine, bromine or N-bromo-succinimide.After removing protecting group, the R4 compound can with aryl or heteroaryl boric acid or ester (R5) reaction (being commonly referred to the Suzuki reaction), the compound of generating structure R6.But the method that linked reaction nationality those skilled in the art know is carried out, and it is included in catalyzer and for example carries out this reaction under the existence of the phosphine part of tetrakis triphenylphosphine palladium (0), two (triphenylphosphine) palladium chloride (II) or acid chloride and adding.Use the above-mentioned reactive functional groups R that contains suitable leavings group L 9With the R6 reaction, but the compound of generating structure XX.
XVIII. synthetic route R
Figure A20078000890204581
The The compounds of this invention of structure XXI representative can be prepared according to the described method of synthetic route S hereinafter.
The 2-iodo-of structure S1 or bromo indole can react in the presence of palladium catalyst with alkene (being commonly referred to the Heck reaction), generate the compound of type XXI.But the method that linked reaction nationality those skilled in the art know is carried out.Catalyzer and choice of Solvent and aforementioned similar.
XIX. synthetic route S
Figure A20078000890204582
The formula I compound of structure XXII representative can be prepared by method shown in the synthetic route T.
The 2-iodo-of structure T1 or 2-bromo indole can react in the presence of palladium catalyst with acetylene (being commonly referred to the Sonagashira reaction), generate the compound of type XXII.But the method that linked reaction nationality those skilled in the art know is carried out.The typical reaction conditions of one cover comprises that the indoles of structure T1 and acetylide T2 react in the presence of palladium source, copper co-catalyst and amine source.This is reflected in the suitable non-reactive solvent and carries out, and carries out in the temperature range of envrionment temperature to 150 ℃.
XX. synthetic route T
Figure A20078000890204591
The formula I compound of structure XXIII representative can be prepared by method shown in the synthetic route U.
The compound of structure XXIII can obtain from the reduction of compounds X XI and XXII.Reductive condition can include but not limited to catalytic reduction, for example on platinum or palladium source and at suitable solvent CH for example 2Cl 2, carry out hydrogenation in ether, THF, methyl alcohol or the solvent combination.
XXI. synthetic route U
Figure A20078000890204592
The The compounds of this invention of structure XXIV representative can be prepared according to the described method of synthetic route V hereinafter.
The indoles of structure V1 can with suitable alkali for example diisopropylamino lithium or hexamethyl two silica-based potassium amides suitable non-reactive solvent for example ether or THF or contain in their the solvent combination react, generate 2-indyl negatively charged ion.This reaction is generally carried out to the scope of envrionment temperature at-78 ℃.2-indyl negatively charged ion subsequently can be by zinc halide source zinc halide metal or contain their solution cancellation, the organic zinc compound of generating structure V2 for example.V2 and fragrant halogen (V3) react in the presence of palladium catalyst (being commonly referred to the Negishi reaction), the compound of generating structure XXIV.Perhaps, 2-iodine or the bromo indole of the structure V4 that is prepared from from compound V1 according to aforesaid method can react the compound of generating structure XXIV with the organic zinc compound of structure V5 in the presence of suitable palladium catalyst.Organic zinc compound V5 can derive after alkylogen or thiazolinyl halogen are using activatory zinc to handle and obtain, or derives after aryl or heteroaryl lithium or magnesium compound are using zinc halide to handle and obtain.And, the reaction of V2 or V4 can the palladium source for example tetrakis triphenylphosphine palladium (0) or two (triphenylphosphine) palladium chloride (II) in the presence of in The suitable solvent, under the temperature range of envrionment temperature to 150 ℃, carry out.
XXII. synthetic route V
Figure A20078000890204601
The formula I compound of structure XXV-XXVIII representative can be prepared by method shown in the synthetic route W.
The 2-iodo-of structure W1 or bromo indole can react in the presence of palladium catalyst with the acetylene of structure W2 (being commonly referred to the Sonagashira reaction), generate the compound of type XXV.But the method that linked reaction nationality those skilled in the art know is carried out.The typical reaction conditions of one cover comprises that the indoles of structure W1 and acetylide W2 react in the presence of palladium source, optional copper co-catalyst and amine source.This is reflected in the suitable non-reactive solvent and carries out, and carries out in the temperature range of envrionment temperature to 150 ℃.Use the above-mentioned reactive functional groups R that contains suitable leavings group L 9With the XXV reaction, but the compound of generating structure XXVI.
The 2-iodo-of structure W1 or bromo indole also can react in the presence of palladium catalyst with alkene (being commonly referred to the Heck reaction), generate the compound of type XXVII.But the method that linked reaction nationality those skilled in the art know is carried out.Catalyzer and choice of Solvent and aforementioned similar.Use the above-mentioned reactive functional groups R that contains suitable leavings group L 9With the XXVII reaction, but the compound of generating structure XXVIII.
XXIII. synthetic route W
Figure A20078000890204611
The formula I compound of structure XXIX representative can be prepared by method shown in the synthetic route X.
The indoles of structure X1 can be carried out acidylate by the carboxylic acid halides of structure X2, the compound of generating structure XXIX.Can use Lewis acid to promote this reaction.Best Lewis acid can be selected from but be not limited to aluminum chloride, iron(ic) chloride, tin chloride or diethyl aluminum.This reaction generally comprises CH at suitable non-reactive solvent 2Cl 2, carry out in dithiocarbonic anhydride or the ethylene dichloride, and generally be in-20 ℃ to 80 ℃ temperature range, to carry out.
XXIV. synthetic route X
Figure A20078000890204612
Formula I compound by structure XXX representative can be prepared by method shown in the synthetic route Y.
The 3-cyanoindole of structure Y1 is handled the tetrazolium that can be converted into structure Y2 through for example sodiumazide.The mixture of heating Y2 and reagent Y3 can generate 3-(1,2, the 4-oxadiazole) benzazolyl compounds XXX.Reagent Y3 for example can be carboxylic acid halides or by reagent such as dicyclohexylcarbodiimide or DIC activatory acid derivative.This reaction can comprise in toluene, diox, pyridine and the ethylene dichloride at many solvents to be carried out, and can be undertaken by temperature range internal heating Y2 and the Y3 at 30 ° to 130 ℃.
XXV. synthetic route Y
Figure A20078000890204621
The formula I compound of structure XXXI representative can be prepared by method shown in the synthetic route Z.
But the 3-cyanoindole of structure Z1 is handled the hydroxyamidines compound of production Z2 through azanol.The reaction of the compound of the hydroxyamidines of structure Z2 and structure Z3 can generate O-acyl group hydroxyamidines Z4.But compound Z3 typical example such as carboxylic acid halides or by reagent for example dicyclohexylcarbodiimide or DIC activatory carboxylic acid.The compound of structure Z4 heats under 30 ℃ to 150 ℃ temperature range in non-reacted organic solvent such as toluene, ethylene dichloride Huo diox, but the compound of generating structure XXXI.
XXVI. synthetic route Z
The The compounds of this invention of structure XXXII representative can be prepared according to the described method of synthetic route AA hereinafter.
Heating ketone group indoles (ketoindole) and azanol (free alkali or acid salt (acid salt)) in suitable solvent, the oxyindole of type AA1 can be converted into the oxime of structure AA2.Use highly basic (for example n-Butyl Lithium or s-butyl lithium or tert-butyl lithium) that type AA2 compound is carried out two deprotonations, subsequently itself and DMF are reacted, but the compound of production XXXII.
XXVII. synthetic route AA
Figure A20078000890204631
The formula I compound of structure XXXIII representative can be prepared by method shown in the synthetic route AB.
The 3-ketone group indoles warp of structure AB1 and dialkyl amide dialkyl acetal AB2 reaction, but homology turns to the vinylogous amide (vinylogous amide) of structure AB3.Dialkyl amide can comprise for example low alkyl group acid amides such as methane amide, ethanamide and propionic acid amide.Example comprises dimethylformamide dimethyl acetal and dimethylacetamide dimethylacetal.AB1 and AB2 are reacted (adding or do not add additional solvent) under the temperature of envrionment temperature to 150 ℃, can carry out this reaction.Use azanol (free alkali or acid salt) but in suitable solvent, handle the compound of AB3 generating structure XXXIII.This reaction generally is to carry out in the temperature range of envrionment temperature to 120 ℃.
XXVIII. synthetic route AB
The formula I compound of structure XXXIV representative can be prepared by method shown in the synthetic route AC.
Use hydrazine AC2 in suitable organic solvent (DMF, alcohol or acetate) in the temperature range of envrionment temperature to 150 ℃ the vinylogous amide (as above prepared) of Processing Structure AC1, but the compound of generating structure XXXIV.
XXIX. synthetic route AC
Figure A20078000890204641
The The compounds of this invention of structure XXXV representative can be prepared according to the described method of synthetic route AD hereinafter.
The indole-3-formaldehyde of structure AD1 (synthetic route F is prepared) can with (tosyl group) methyl isocyanate (TOSMIC) is reacted the compound of generating structure XXXV in the presence of alkali.Alkali can comprise salt of wormwood or 1,8-diazabicylo [5.4.0] 11-7-alkene, and this reaction can be in The suitable solvent be carried out under envrionment temperature to 150 ℃.
XXX. synthetic route AD
Figure A20078000890204642
The formula I compound of structure XXXVI and XXXVII representative can be prepared by method shown in the synthetic route AE.
The 3-indole-carboxylic acid of structure AE1 (from synthetic route E) can be converted into the acid amides of structure AE2.The compound of structure AE2 can be activated by any standard method.For example, can use coupling agent for example EDCI or DCC (adding or do not add HOBt) activated acids AE1 in the presence of ammoniacal liquor.Perhaps, described acid can be activated into acyl chlorides or above-mentioned acylimidazole compound, subsequently with ammonia treatment.
The indoles of structure AE2-3-methane amide can with the replacement aldehydes or ketones (AE3) that contains suitable leavings group L in The suitable solvent under 200 ℃ temperature, reacting more than the envrionment temperature.When carrying out, this reaction can add or not add alkali, generating structure XXXVI De oxazole.
Use La Weisong reagent or thiophosphoric anhydride to handle primary amine in envrionment temperature or more than the envrionment temperature in suitable organic solvent, the indoles of structure AE2-3-methane amide also can be converted into the thioamides of structure AE4.Formed thioamides AE4 can with the replacement aldehydes or ketones (AE3) that contains suitable leavings group L in The suitable solvent under 200 ℃ temperature, reacting more than the envrionment temperature.When carrying out, this reaction can add or not add alkali, the thiazole of generating structure XXXVII.
XXXI. synthetic route AE
Figure A20078000890204651
The The compounds of this invention of structure XXXVIII and XXXIX representative can be prepared according to the described method of synthetic route AF hereinafter.
The 3-ketone group indoles of structure AF1 can be become the compound of structure AF3 by halogenation (as bromination).Suitable bromizating agent can include but not limited to phenyl trimethylammonium tribromide ammonium (AF2), N-bromo-succinimide or bromine, and can carry out in many organic solvents.
The acid amides of type of service AF4 in suitable solvent under the situation that is adding or do not adding alkali under 200 ℃ the temperature, handling compd A F3 more than the envrionment temperature, but generating structure XXXVIII De oxazole.
The thioamides of type of service AF5 in suitable solvent under the situation that is adding or do not adding alkali under 150 ℃ the temperature, handling compd A F3 more than the envrionment temperature, but the thiazole of generating structure XXXIX.
XXXII. synthetic route AF
Figure A20078000890204661
The formula I compound of structure XL representative can be prepared by method shown in the synthetic route AG.
The indoles of structure AG1 can be by bromination or iodate, the compound of generating structure AG2.Bromizating agent can include but not limited to bromine or N-bromo-succinimide, and iodinating agent can comprise iodine monochloride or two-trifluoroacetic acid iodobenzene.The reaction of 3-iodo-or bromo indole AG2 and boric acid AG3 (be commonly referred to Suzuki reaction) but the compound of generating structure XL.But the method that linked reaction nationality those skilled in the art know is carried out, and it is included in catalyzer and for example carries out this reaction under the existence of the phosphine part of tetrakis triphenylphosphine palladium (0), two (triphenylphosphine) palladium chloride (II) or acid chloride and adding.These are reflected at The suitable solvent and for example carry out under the temperature of envrionment temperature to 150 ℃ in DMP, toluene, the glycol dimethyl ether Huo diox.These reactions are generally carried out in the presence of alkali such as yellow soda ash or sodium bicarbonate aqueous solution, perhaps can use alkali for example cesium fluoride or Potassium monofluoride under anhydrous condition.
Perhaps, use strong organic bases (lithium alkylide or Grignard reagent) and 3-halogen indoles AG2 reaction, and make the negatively charged ion and the trialkylboron silicate reagent AG4 reaction of formation, indoles AG2 can be converted into indoles-3-boric acid derivatives AG5.The compound of type AG5 can react under above-mentioned conditions of similarity with aryl and heteroaryl bromine and iodine, forms the compound of structure XL.
XXXIII. synthetic route AG
Figure A20078000890204671
The The compounds of this invention of structure XLI representative can be prepared according to the described method of synthetic route AH hereinafter.
The 3-iodo-of structure AH1 or bromo indole can react in the presence of palladium catalyst with alkene AH2 (being commonly referred to the Heck reaction), generate the compound of type XLI.But the method that linked reaction nationality those skilled in the art know is carried out.Catalyzer and choice of Solvent and synthetic route AG are described similar.
XXXIV. synthetic route AH
The formula I compound of structure XLII representative can be prepared by method shown in the synthetic route AI.
The 3-iodo-of structure AI1 or bromo indole can react in the presence of palladium catalyst with acetylene AI2 (being commonly referred to the Sonagashira reaction), generate the compound of type XLII.But the method that linked reaction nationality those skilled in the art know is carried out.The typical reaction conditions of one cover comprises that the indoles of structure AI1 and acetylide AI2 react in the presence of palladium source, copper co-catalyst and amine source, and carries out this reaction under the temperature range of envrionment temperature to 150 ℃.
XXXV. synthetic route AI
Figure A20078000890204681
The The compounds of this invention of structure XLIII and XLIV representative can be prepared according to the described method of synthetic route AJ hereinafter.
Nitrile by utilization structure AJ2 carries out condensation and cyclization, and the N-methyl-p-nitroaniline of structure AJ1 can be converted into the indoles of structure XLIII.This reaction can for example be carried out in the DMF Huo diox at suitable organic solvent.Use the compound of alkaline purification structure XLIII, subsequently itself and the reactive functional groups R that contains suitable leavings group L 9Reaction, but the compound of production XLIV.
XXXVI. synthetic route AJ
Figure A20078000890204682
The formula I compound of structure XLV-XLVIII representative can be prepared by method shown in the synthetic route AK.
Can use the reactive functional groups R that contains suitable leavings group L 15Alkali for example sodium hydride or salt of wormwood in the presence of and the 2-amino indole generation alkylation that in suitable organic solvent, makes structure XLV, the compound of generating structure XLVI.Equally, use the reactive functional groups R ' that contains suitable leavings group L 15Carry out second alkylation, but the compound of generating structure XLVII.
But the acyl chlorides of utilization structure AK1 carries out the compound of the acidylate generating structure XLVIII of structure XLV compound.This reaction generally be organic bases for example trialkylamine or mineral alkali for example salt of wormwood in the presence of in suitable organic solvent, carry out.
XXXVII. synthetic route AK
Figure A20078000890204691
The The compounds of this invention of structure XLIX representative can be prepared according to the described method of synthetic route AL hereinafter.
The Indole-3-Carboxylic Acid of structure AL1 can be activated the compound that forms structure AL2.But the compound typical example of structure AL2 such as carboxylic acid halides or by reagent for example dicyclohexylcarbodiimide or DIC activatory carboxylic acid.The reaction of the hydroxyamidines of the chemical combination of structure AL2 and structure AL3 can generate O-acyl group hydroxyamidines AL4.Hydroxyamidines can be buied from the market or the nationality azanol is handled nitrile compound and obtained.The compound of structure AL4 for example heats under 30 ℃ to 150 ℃ temperature range in toluene, the ethylene dichloride Huo diox at non-reacted organic solvent, but the compound of generating structure XLIX.
XXXVIII. synthetic route AL
The formula I compound of structure L representative can be prepared by method shown in the synthetic route AM.
The 3-cyanoindole of structure AM1 is handled the tetrazolium that can be converted into structure AM2 through for example sodiumazide.The mixture of heating AM2 and reagent A M3 can generate 3-(1,2, the 4-oxadiazole) benzazolyl compounds L.Reagent A M3 for example can be carboxylic acid halides or by reagent for example dicyclohexylcarbodiimide or DIC institute activatory acid derivative.This reaction can for example be carried out in toluene, diox, pyridine and the ethylene dichloride at many solvents, and this reaction can be undertaken by temperature range internal heating AM2 and the AM3 at 30 ° to 130 ℃.
XXXIX. synthetic route AM
Figure A20078000890204701
The formula I compound of structure LI representative can be prepared by method shown in the synthetic route AN.
But the 3-cyanoindole of structure AN1 is handled the hydroxyamidines compound of production AN2 through azanol.The reaction of the compound of the hydroxyamidines of structure AN2 and structure AN3 can generate O-acyl group hydroxyamidines AN4.But compd A N3 typical example such as carboxylic acid halides or by reagent for example dicyclohexylcarbodiimide or DIC activatory carboxylic acid.The compound of structure AN4 for example heats under 30 ℃ to 150 ℃ temperature in toluene, the ethylene dichloride Huo diox at non-reacted organic solvent, but the compound of generating structure LI.
XL. synthetic route AN
Figure A20078000890204711
The The compounds of this invention of structure LII compound representative can be prepared according to the described method of synthetic route AO hereinafter.
By ketone group indoles and azanol (free alkali or acid salt) in the heating suitable solvent, the ketone group indoles of type AO1 can be converted into the oxime of structure AO2.Use highly basic (for example n-Butyl Lithium or s-butyl lithium or tert-butyl lithium) to carry out two deprotonations of type AO2 compound, subsequently itself and DMF are reacted, but the compound of production LII.
XLI. synthetic route AO
Figure A20078000890204712
The formula I compound of structure LIII representative can be prepared by method shown in the synthetic route AP.
The 3-ketone group indoles warp of structure AP1 and dialkyl amide dialkyl acetal AP2 reaction, but homology turns to the vinylogous amide of structure AP3.Dialkyl amide can comprise for example low alkyl group acid amides such as methane amide, ethanamide and propionic acid amide.Example comprises dimethylformamide dimethyl acetal and dimethylacetamide dimethylacetal.React by AP1 and AP2 under the temperature of envrionment temperature to 150 ℃ (adding or do not add additional solvent), can carry out this reaction.Use azanol (free alkali or acid salt) but in suitable solvent, handle the compound of AP3 generating structure LIII.This reaction generally is to carry out in the temperature range of envrionment temperature to 120 ℃.
XLII. synthetic route AP
Figure A20078000890204721
The formula I compound of structure LIV representative can be prepared by method shown in the synthetic route AQ.
Use hydrazine AQ2 in suitable organic solvent (DMF, alcohol or acetate) in the temperature range of envrionment temperature to 150 ℃ the vinylogous amide (as above prepared) of Processing Structure AQ1, but the compound of generating structure LIV.
XLIII. synthetic route AQ
Figure A20078000890204722
The The compounds of this invention of structure LV representative can be prepared according to the described method of synthetic route AR hereinafter.
The indole-3-formaldehyde of structure AR1 (synthetic route F is prepared) can be with (TOSMIC AR2) reacts in the presence of alkali, the compound of generating structure LV to (tosyl group) methyl isocyanate.Alkali can comprise salt of wormwood or 1,8-diazabicylo [5.4.0] 11-7-alkene, and this reaction can be in The suitable solvent be carried out under envrionment temperature to 150 ℃.
XLIV. synthetic route AR
Figure A20078000890204731
The formula I compound of structure LVI and LVII representative can be prepared by method shown in the synthetic route AS.
The 3-indole-carboxylic acid of structure AS1 (from synthetic route F) can be converted into the acid amides of structure AS2.The compound of structure AS1 can be activated by any standard method.For example, can use coupling agent for example EDCI or DCC (adding or do not add HOBt) activated acids AS1 in the presence of ammoniacal liquor.Perhaps, described acid can be activated into acyl chlorides or above-mentioned acylimidazole compound, subsequently with ammonia treatment.
The indoles of structure AS2-3-methane amide can with the replacement aldehydes or ketones (AS3) that contains suitable leavings group L in The suitable solvent under 200 ℃ temperature, reacting more than the envrionment temperature.When carrying out, this reaction can add or not add alkali, generating structure LVI De oxazole.
Use La Weisong reagent or thiophosphoric anhydride to handle primary amide in envrionment temperature or more than the envrionment temperature in suitable organic solvent, the indoles of structure AS2-3-methane amide also can be converted into the thioamides of structure AS4.Formed thioamides AS4 can with the replacement aldehydes or ketones (AS3) that contains suitable leavings group L in The suitable solvent under 150 ℃ temperature, reacting more than the envrionment temperature.When carrying out, this reaction can add or not add alkali, the thiazole of generating structure LVII.
XLV. synthetic route AS
Figure A20078000890204741
The The compounds of this invention of structure LVIII and LIX representative can be prepared according to the described method of synthetic route AT hereinafter.
The 3-ketone group indoles of structure AT1 can be become the compound of structure AT3 by halogenation (as bromination).Suitable bromizating agent can include but not limited to phenyl trimethylammonium tribromide ammonium (AT2), N-bromo-succinimide or bromine, can carry out in many organic solvents.
The acid amides of type of service AT4 in suitable solvent under the situation that is adding or do not adding alkali under 200 ℃ the temperature, handling compd A T3 more than the envrionment temperature, but generating structure LVIII De oxazole.
The thioamides of type of service AT5 in suitable solvent under the situation that is adding or do not adding alkali under 150 ℃ the temperature, handling compd A T3 more than the envrionment temperature, but the thiazole of generating structure LIX.
XLVI. synthetic route AT
Figure A20078000890204751
The The compounds of this invention of structure LX compound representative can be prepared according to the described method of synthetic route AU hereinafter.
The Indole-3-Carboxylic Acid of structure AU1 can be activated the compound into structure AU2.But the compound typical example of structure AU2 such as carboxylic acid halides or by reagent for example dicyclohexylcarbodiimide or DIC activatory carboxylic acid.The reaction of the hydroxyamidines of the chemical combination of structure AU2 and structure AU3 can generate O-acyl group hydroxyamidines AU4.Hydroxyamidines can be buied from the market or the nationality azanol is handled nitrile compound and obtained.The compound of structure AU4 for example heats under 30 ℃ to 150 ℃ temperature in toluene, the ethylene dichloride Huo diox at non-reacted organic solvent, but the compound of generating structure LX.
XLVII. synthetic route AU
Figure A20078000890204761
The formula I compound of structure LXI representative can be prepared by method shown in the synthetic route AV.
The reaction of 3-iodo-or bromo indole AV1 and boric acid AV2 (be commonly referred to Suzuki reaction) but the compound of generating structure LXI.But the method that linked reaction nationality those skilled in the art know is carried out, and it is included in catalyzer and for example carries out this reaction under the existence of the phosphine part of tetrakis triphenylphosphine palladium (0), two (triphenylphosphine) palladium chloride (II) or acid chloride and adding.These are reflected at The suitable solvent and for example carry out under the temperature of envrionment temperature to 150 ℃ in DMF, toluene, the glycol dimethyl ether Huo diox.These reactions are generally for example carried out in the presence of the aqueous solution of yellow soda ash or sodium bicarbonate at alkali, perhaps can use alkali for example cesium fluoride or Potassium monofluoride under anhydrous condition.
Perhaps, use strong organic bases (lithium alkylide or Grignard reagent) and 3-halogen indoles AV1 reaction, and make the negatively charged ion and the trialkylboron silicate reagent AV4 reaction of formation, indoles AV1 can be converted into indoles-3-boric acid derivatives AV3.The compound of type AV3 can react under above-mentioned conditions of similarity with aryl and heteroaryl bromine and iodine AV6, forms the compound of structure LXI.
XLVIII. synthetic route AV
Figure A20078000890204771
The formula I compound of structure LXII representative can be prepared by method shown in the synthetic route AW.
The compound of formula AW1 can with protecting group for example tert-Butyl dicarbonate reaction form the boc-protection indoles in the presence of suitable alkali and solvent under envrionment temperature, the compound of generating structure AW2.Use alkali in polar aprotic solvent at-78 ℃ of Processing Structure AW2 compounds to the envrionment temperature, add the trialkylboron hydrochlorate subsequently, after hydrolysis treatment, obtain the compound of type AW3.Reactive aryl halide or aryl trifluoromethane sulfonic acid ester (triflate, type AW4) and formula AW3 compound near the suitable solvent system of the palladium catalyst that is containing alkali and catalytic amount envrionment temperature or the envrionment temperature, react, but the compound of production AW5.Remove after the protecting group of structure AW5 compound (for example the Boc yl is removed in acid treatment) but the compound of generating structure AW6.Its indole nitrogen atom of the compound of type AW6 can be by alkylation, the compound of generating structure LXII.This alkylation can carried out production LXII compound in the presence of suitable alkylating agent and the alkali under the temperature between the envrionment temperature to 150 ℃ in polar solvent.
XLIX. synthetic route AW
Figure A20078000890204781
The formula I compound of structure LXIII representative can be prepared by method shown in the synthetic route AX.
3 of formula AX1 compound can by the electric fluorizating agent of parent for example N-fluoro collidine a tetrafluoro borate in suitable non-polar solvent, under the temperature between-78 ℃ to 100 ℃, fluoridize the compound of generating structure LXIII.
L. synthetic route AX
Figure A20078000890204782
The formula I compound of structure LIV representative can be prepared by method shown in the synthetic route AY.
3 of formula AY1 compound can be by for example N-chlorosuccinimide or the chlorine chlorination under the temperature between-78 ℃ to 100 ℃ in The suitable solvent of the electric chlorizating agent of parent, the product of generating structure LXIV.
LI. synthetic route AY
The formula I compound of structure LXV representative can be prepared by method shown in the synthetic route AZ.
3 of formula AZ1 compound can by the electric bromizating agent of parent for example N-bromo-succinimide or bromine in The suitable solvent under the temperature between-78 ℃ to 100 ℃ bromination, the product of generating structure LXV.
LII. synthetic route AZ
Figure A20078000890204791
The formula I compound of structure LXVI representative can be prepared by method shown in the synthetic route BA.
3 of formula BA1 compound can be by for example N-iodo succimide, (two-trifluoroacetic acid) iodobenzene or the ICl iodate under the temperature between-78 ℃ to 100 ℃ in The suitable solvent of the electric iodinating agent of parent, the product of generating structure LXVI.
LIII. synthetic route BA
Figure A20078000890204792
The formula I compound of structure LXVII representative can be prepared by method shown in the synthetic route BB.
The 3-iodo-of structure BB1 or bromo indole can react in the presence of palladium catalyst with acetylene BB2 (being commonly referred to the Sonagashira reaction), generate the compound of type LXVII.But the method that linked reaction nationality those skilled in the art know is carried out.The typical reaction conditions of one cover comprises that the indoles of structure BB1 and acetylide BB2 react in the presence of palladium source, copper co-catalyst and amine source, and carries out this reaction under the temperature range of envrionment temperature to 150 ℃.
LIV. synthetic route BB
Figure A20078000890204793
The formula I compound of structure LXVIII representative can be prepared by method shown in the synthetic route BC.
Formula BC1 compound can with POCl 3React under the temperature range of envrionment temperature to 140 ℃ with the mixture of DMF, after intermediate imonium salt (imminium salt) is by the NaOH aqueous hydrolysis, the 3-formaldehyde of generating structure LXVIII.
LV. synthetic route BC
Figure A20078000890204801
The formula I compound of structure LXIX representative can be prepared by method shown in the synthetic route BD.
The formaldehyde of formula BD1 can with fluorizating agent for example (diethyl ammonium sulfur trifluoride (diethylammonium sulfurtrifluoride)) in The suitable solvent, under 0 ℃ to 80 ℃ temperature range, handle the compound of production LXIX.
LVI. synthetic route BD
Figure A20078000890204802
The formula I compound of structure LXX representative can be prepared by method shown in the synthetic route BE.
The formaldehyde of formula BE1 can react production LXX compound in the presence of suitable polar solvent system and the alkali with the azanol of structure BE2 under the temperature range of envrionment temperature to 100 ℃.
LVII. synthetic route BE
The formula I compound of structure LXXI representative can be prepared by method shown in the synthetic route BF.
The formaldehyde of formula BF1 can react production LXXI compound in the presence of suitable solvent and the alkali with the hydrazine of structure BF2 under the temperature range of envrionment temperature to 100 ℃.
LVIII. synthetic route BF
Figure A20078000890204812
The formula I compound of structure LXXII representative can be prepared by method shown in the synthetic route BG.
The reagent that use those skilled in the art know is KMnO for example 4Or chromic acid, can make the indolecarboxaldehyde of formula BG1 be oxidized to the carboxylic acid of formula LXXII.This oxidation can be carried out in water or water/organic mixed solvent system usually.This oxidation also can be carried out under envrionment temperature or high temperature.
LIX. synthetic route BG
Figure A20078000890204813
The formula I compound of structure LXXIII representative can be prepared by method shown in the synthetic route BH.
Use suitable activator (thionyl chloride, oxalyl chloride or carbonyl dimidazoles) to handle carboxylic acid, use the amine of formula BH2 to handle subsequently, can make the carboxylic acid of formula BH1 be converted into acid amides.
LX. synthetic route BH
Figure A20078000890204821
The formula I compound of structure LXXIV representative can be prepared by method shown in the synthetic route BI.
Use suitable activator (thionyl chloride, oxalyl chloride or carbonyl dimidazoles) to handle carboxylic acid, use hydrazine and the alkoxylamine processing activatory carboxylic acid of formula BI2 to obtain the compound of formula LXXIV subsequently, thereby can make the carboxylic acid of formula BI1 be converted into hydrazides and N-alkoxyl group acid amides.
LXI. synthetic route BI
Figure A20078000890204822
The formula I compound of structure LXXV representative can be prepared by method shown in the synthetic route BJ.
The Grignard reagent of available suitable lithium alkylide or formula BJ2 is at-78 ℃ of formaldehyde of handling formula BJ1 to the envrionment temperature in suitable aprotic solvent, the secondary alcohol of production LXXV.Perhaps use suitable hydride reducer to envrionment temperature, to go back ortho-formaldehyde at-78 ℃, but the primary alconol of production LXXV.
LXII. synthetic route BJ
Figure A20078000890204823
The formula I compound of structure LXXVI representative can be prepared by method shown in the synthetic route BK.
3 of the compound of structure BK1 can be by sulphur trioxide or some similar sulfuric acid Equivalent sulfonation, the compound of production BK2.Available reagent is such as but not limited to POCl 3Under 50 ℃ to 100 ℃ temperature, handle the compound of formula BK2, make it be converted into the SULPHURYL CHLORIDE of formula BK3.Perhaps, use the reagent for example compound of chlorsulfonic acid Processing Structure BK1, the directly compound of generating structure BK3.Compd B K3 can react the sulphonamide of production LXXVI at ambient temperature with the amine of formula BK4 in the presence of suitable alkali and solvent.
LXIII. synthetic route BK
Figure A20078000890204831
The formula I compound of structure LXXVII representative can be prepared by method shown in the synthetic route BL.
Use suitable copper catalyst for example CuI and suitable mercaptan or disulphide, can make the iodide of structure BL1 or bromide be converted into 3-sulfane base indoles (3-thioalkyl indole).This reaction generally can be carried out the compound of generating structure BL2 under the temperature between envrionment temperature and 150 ℃.Use oxygenant such as but not limited to the chloroformic solution of m-CPBA under envrionment temperature or high temperature, can be with the sulfone of the compound oxidation accepted way of doing sth LXXVII of structure BL2.
LXIV. synthetic route BL
Figure A20078000890204841
The formula I compound of structure LXXVIII representative can be prepared by method shown in the synthetic route BM.
Use suitable copper catalyst for example CuI and suitable mercaptan or disulphide, can make the iodide of structure BM1 or bromide be converted into 3-alkylthio indoles.This reaction generally can be carried out the compound of generating structure BM2 under the temperature between envrionment temperature and 150 ℃.Use the oxygenant at ambient temperature can be with the sulfoxide of the compound selective oxidation accepted way of doing sth LXXVIII of structure BM2 such as but not limited to the methanol solution of sodium periodate.
LXV. synthetic route BM
The formula I compound of structure LXXIX representative can be prepared by method shown in the synthetic route BN.
The acyl chlorides of use formula BN2 is through Friedel-crafts reaction, can make the compound of structure BN1 be converted into the ketone of formula LXXIX.This reaction generally can be at non-polar solvent for example methylene dichloride or CS 2In at suitable Lewis acid AlCl for example 3Or FeCl 3Existence under carry out, also can under 0 ℃ to 100 ℃ temperature range, carry out.
LXVI. synthetic route BN
Figure A20078000890204851
The formula I compound of structure LXXX representative can be prepared by method shown in the synthetic route BO.
The nitric acid that uses stoichiometry under mild reaction conditions, can make 3 of structure BO1 compound nitrated by selectivity, the compound of production LXXX.These conditions can include but not limited to the solution of acetic anhydride that uses nitric acid to the temperature range of room temperature at-40 ℃.
LXVII. synthetic route BO
Figure A20078000890204852
The formula I compound of structure LXXXI representative can be prepared by method shown in the synthetic route BP.
Use the standard conditions as the known any number of this area chemist, for example hydrogenation or iron reduction can make the 3-nitroindoline of structure BP1 be reduced into the 3-amino indole of structure BP2.Use suitable alkylating agent, solvent and alkali under the temperature range of envrionment temperature to 150 ℃, can make the compound of formula BP2 through the list of amino-or dialkyl groupization further modified.
Perhaps, through using the condition of knowing as this area chemist, the 3-halogen indoles of structure BP3 can with the list of formula BP4-or dialkylamine Buchwald linked reaction, the compound of production LXXXI take place in the presence of copper or palladium catalyst.
LXVIII. synthetic route BP
Figure A20078000890204861
The formula I compound of structure LXXXII representative can be prepared by method shown in the synthetic route BQ.
The 3-amino indole of structure BQ1 can react the acid amides of generating structure LXXXII at ambient temperature with carboxylic acid halides or the acid anhydride of formula BQ2 in the presence of suitable alkali and solvent.
LXIX. synthetic route BQ
Figure A20078000890204862
The formula I compound of structure LXXXIII representative can be prepared by method shown in the synthetic route BR.
The 3-amino indole of structure BR1 can react the carbamate of generating structure LXXXIII with the chloro-formic ester of formula BR2 or carbonate or supercarbonate under envrionment temperature or high temperature in the presence of suitable alkali and solvent.Other alternative condition comprises reactive amino formyl intermediate synthetic of compd B R1, for example by using p-nitrophenyl chloro-formic ester or phosgene to handle amine BR1, in The suitable solvent, react under the temperature range of envrionment temperature to 100 ℃ with the alcohol of postactivated carbamyl intermediate and formula BR3, form the carbamate of formula LXXXIII.
LXX. synthetic route BR
Figure A20078000890204871
The formula I compound of structure LXXXIV representative can be prepared by method shown in the synthetic route BS.
The 3-amino indole of structure BS1 can react the urea of generating structure LXXXIV with the isocyanic ester of formula BS2 under envrionment temperature or high temperature in the presence of suitable alkali and solvent.Other alternative condition comprises reactive amino formyl intermediate synthetic of compd B S1, for example by using p-nitrophenyl chloro-formic ester or phosgene to handle amine BS1, alcohol with postactivated carbamyl intermediate and formula BS3 reacts at ambient temperature, forms the urea of formula LXXXIV.
LXXI. synthetic route BS
Figure A20078000890204872
The formula I compound of structure LXXXV representative can be prepared by method shown in the synthetic route BT.
The 3-amino indole of structure BT1 can react the sulphonamide of generating structure LXXXV with the SULPHURYL CHLORIDE of formula BT2 under-20 ℃ to 50 ℃ temperature range in the presence of suitable alkali and solvent.
LXXII. synthetic route BT
Figure A20078000890204881
The formula I compound of structure LXXXVI representative can be prepared by method shown in the synthetic route BU.
The 3-iodo-of structure BU1 or bromo indole can react in the presence of palladium catalyst with alkene BU2 (being commonly referred to the Heck reaction), the compound of generating structure LXXXVI.But the method that linked reaction nationality those skilled in the art know is carried out.Catalyzer and choice of Solvent and synthetic route AG are described similar.
LXXIII. synthetic route BU
Figure A20078000890204882
The formula I compound of structure LXXXVII representative can be prepared by method shown in the synthetic route BV.
The hydrazine of structure BV1 can be with 3,3, and 3-trifluoropropyl aldehyde reaction forms the hydrazone intermediate.The hydrazone intermediate heats under the temperature of envrionment temperature to 150 ℃ in The suitable solvent, can form the indoles of formula BV2.Generally speaking, use Lewis acid, for example AlCl 3, TiCl 4Or ZnCl 4The compound of formula BV2 can with for example tert-Butyl dicarbonate reaction of protecting group, be prepared into Boc derivative BV3.Use highly basic for example diisopropylamino lithium add the trialkylboron hydrochlorate subsequently at aprotic solvent such as THF or DME compound in-78 ℃ of Processing Structure BV3 to the envrionment temperature, after hydrolysis treatment, can generate compd B V4.Use reactive aryl halide or trifluoromethyl sulfonic acid for example BV5 in the suitable solvent system of the palladium catalyst that is containing alkali and substoichiometric amount under-20 ℃ to 100 ℃ the temperature range, react with compd B V4, but the compound of production BV6.But the compound of the protein cleavage generating structure BV7 of type B V6 compd B oc base.Indoles BV7 can be in the presence of suitable alkylating agent and alkali in The suitable solvent under 0 ℃ to 150 ℃ temperature range by alkylation, the indoles of production LXXXVII.
LXXIV. synthetic route BV
The formula I compound of structure LXXXVIII representative can be prepared by method shown in the synthetic route BW.
The compound of structure BW1 can buy from the market or but the nationality well-known process prepares, for example from the hydrolysis of benzyl cyanide.Can use peptide coupling agent activated b W1 subsequently, or make BW1 be converted into carboxylic acid halides, with amine (BW2) reaction, generate substituted ethanamide BW3 then.The compound of type B W3 can alkali for example salt of wormwood or sodium hydride and catalyzer for example CuI or CuBr in the presence of cyclisation takes place, form the compound of structure BW4.Use reductive agent for example DIBALH or lithium aluminium hydride reduction compd B W4, can generate the indoles of type B W5.Use subsequently reagent for example Sulfuryl chloride isocyanate (BW6) compound of type B W5 is carried out cyaniding, generate the compound of type B W7.Use alkali for example diisopropylamino lithium for example handle compd B W7 in THF or DME and the trialkylboron hydrochlorate at solvent, can generate 2-indoles boric acid intermediate.Use group L-R 12In the presence of palladium catalyst, react with 2-indoles boric acid intermediate, but the compound of generating structure LXXXVIII.
LXXV. synthetic route BW
The formula I compound of structure LXXXIX representative can be prepared by method shown in the synthetic route BX.
Can use suitable cyanidization agent for example Sulfuryl chloride isocyanate (BX2) or dialkyl group phosphinylidyne isocyanic ester at The suitable solvent or solvent mixture for example DMF, CH 3In the CN Huo diox indoles BX1 is carried out cyaniding, and carry out this reaction, the compound of generating structure BX3 in envrionment temperature or more than envrionment temperature.Use contains reactive functional groups Z (BX4) the treatments B X3 of suitable leavings group L, but generating structure BX5 compound.L can represent halogenide, especially chlorine, bromine or iodine or alkylsulfonate.Reaction between BX3 and the BX4 can be in The suitable solvent and mineral alkali for example salt of wormwood or sodium hydride or organic bases for example trialkylamine in the presence of carry out the compound of production BX5.
The compound of structure BX5 can be converted into indoles-2-boric acid BX6.Generally speaking, at suitable non-reactive solvent for example among ether or the THF or contain in their solvent mixture and use highly basic for example diisopropylamino lithium or hexamethyl two silica-based Lithamides or hexamethyl two silica-based potassium amides.This reaction is generally carried out to the scope of envrionment temperature at-78 ℃.Use the trialkylboron acid salt derivant to carry out cancellation and can generate indoles-2-boric acid BX6.Use aryl or heteroaryl halogen BX7 and indoles-2-boric acid BX6 to react (being commonly referred to the Suzuki reaction), but the compound of generating structure BX8.But the method that linked reaction nationality those skilled in the art know is carried out, and it is included in catalyzer and for example carries out this reaction under the existence of 1,1 '-two (diphenylphosphine) ferrocene palladium chloride (II) methylene dichloride complex compound.This is reflected at The suitable solvent and for example carries out in the presence of alkali under the temperature range of envrionment temperature to 150 ℃ in DMF, toluene, the glycol dimethyl ether Huo diox.Alkali can be the aqueous solution for example yellow soda ash or sodium bicarbonate aqueous solution, and perhaps alkali can use for example cesium fluoride or Potassium monofluoride under anhydrous condition.
Compd B X8 can be by demethylating, the compound of generating structure BX9.Suitable demethylation reagent can include but not limited at many organic solvents boron tribromide, boron trichloride or Iodotrimethylsilane in the methylene dichloride for example.The indoles of structure BX9 can be by the L (CH of parent's electricity 2) nOP (BX10) alkylation, the compound of generating structure BX11.L can represent halogenide, especially chlorine, bromine or iodine or alkylsulfonate.N can equal 2,3 or 4.P can represent the protecting group of any acid labile, for example t-butyldimethylsilyl, triethylsilyl or THP trtrahydropyranyl.This reaction can be at The suitable solvent for example THF, CH 2Cl 2Or DMF carries out in 20 ℃ to 100 ℃ temperature range.Can use alkali for example mineral alkali such as salt of wormwood or cesium carbonate or organic bases such as trialkylamine, to remove the acid that forms in the dereaction.Compd B X11 can be formed the compound of structure BX12 by deprotection.Suitable deprotection agent can include but not limited to any gentle organic acid for example tosic acid or pyridine tosilate or mineral acid such as acetate or the hydrochloric acid in many organic solvents such as methylene dichloride, THF or methyl alcohol.
For example potassium permanganate or pyridinium dichromate can make compd B X12 be oxidized to the carboxylic acid with structure BX13 to use various oxygenants.Can activate type B X13 compound subsequently and handle the compound of generating structure LXXXIX with the amine of type B X14.But the activation of carboxylic acid is carried out in any standard method of nationality.For example, can use coupling agent for example EDCI or DCC (adding or do not add HOBt) activated acids BX13 in the presence of amine BX14, for example perhaps using thionyl chloride or oxalyl chloride to handle acid can make this acid be activated to be acyl chlorides, or use carbonyl dimidazoles to handle acid, use amine BX14 to handle subsequently and can make acid activation be the carbonylic imidazole compound.
LXXVI. synthetic route BX
Figure A20078000890204921
The present invention of structure XC and XCI representative can be prepared by method shown in the synthetic route BY hereinafter, and wherein p is the integer between 2 and 6.
The compound of the agent treated formula BY1 of utilization structure BY2, wherein L and L ' represent leavings group (halogen, arylsulphonate etc.), and can be identical or different.If different, reactive between the two stronger will being replaced by the phenol Sauerstoffatom generates compd B Y3.The condition that is used for this reaction comprises solvent, such as but not limited to acetonitrile, acetone, 2-butanone or dimethyl formamide; Alkali is salt of wormwood, salt of wormwood, cesium carbonate, tertiary amine base or sodium hydride for example; With reflux temperature from envrionment temperature to selected solvent.Other leavings group of this molecule can be by formula R 18The reagent of SH (BY4) replaces the compound with generating structure XC, wherein R 18Can be alkyl, aryl or heteroaryl.The condition that is used for this reaction can be with to be used for BY1 similar to the condition of the conversion of BY3, but not necessarily just the same.
Use oxygenant for example metachloroperbenzoic acid, potassium permanganate, peroxidation sulfate mono potassium or dimethyldioxirane, its stoichiometry is through selecting to optimize the specific state of oxidation, and use solvent for example methylene dichloride, ethanol, methyl alcohol or acetone and under-30 ℃ to 120 ℃ temperature range, the oxide compound that can prepare formed thioether group among the compounds X C, the compound of generating structure XCI.
LXXVII. synthetic route BY
Figure A20078000890204931
The The compounds of this invention of structure XCII representative can be prepared through the method shown in the synthetic route BZ hereinafter, and wherein p is 1-6.
The compound of the agent treated formula BZ1 of utilization structure BZ2, wherein L and L ' represent leavings group (halogen, arylsulphonate etc.), and can be identical or different.Formed formula BZ3 compound can be by formula R 18R 19The amine of NH carries out alkylation, with the compound of preparation formula XCII.The condition that is used for this alkylated reaction can comprise solvent such as ethanol, tetrahydrofuran (THF) or dimethyl formamide.Can use alkaline reagents for example pyridine, diisopropylethylamine or salt of wormwood.
LXXVIII. synthetic route BZ
Figure A20078000890204941
The The compounds of this invention of structure XCIII representative can be prepared by method shown in the synthetic route CA hereinafter.
Oxybenzene compound CA1 can react with alkylating agent CA3, and wherein CA3 can be derived from the compound of structure C A2.R in the compound of structure C A2 19The carbon atom that carries hydroxyl that is connected with it is together represented four-seven-membered ring.This class atom can all be a carbon atom, but also can comprise and be selected from N, O, S or SO 2Two heteroatomss at the most.The reagent of formula CA2 can be buied from the source, market, or by the known method preparation of organic synthesis those skilled in the art, it is converted into the compound of structure C A3 subsequently, and wherein L represents leavings group.Use oxybenzene compound CA1 and compound to adopt common alkylation conditions CA3 discussed above to carry out the compound of alkylated reaction production XCIII subsequently.
LXXIX. synthetic route CA
Figure A20078000890204942
The The compounds of this invention of structure XCIV and XCV representative can be prepared by method shown in the synthetic route CB hereinafter.
Can use other local method of discussing of the present invention (introduce the Z base, introduce cyano group, and aryl reagent and indoles cross-coupling generate corresponding 2-aryl) to begin to prepare the compound of structure C B1 from the indoles of bromine replacement at the C-3 place of indole ring.Perhaps, for example bromine, N-bromo-succinimide or HOBr form bromide by the bromination indole ring in the later stage to use bromide reagent.Metal-halogen exchange reaction can take place in this bromide subsequently, generates to need not to separate and be directly used in the organometallic compound CB2 of subsequent reactions, and wherein M is for example magnesium or a lithium of atoms metal.Use MAGNESIUM METAL in the ether sample solvent that refluxes, to handle, or use other organomagnesium reagent for example isopropylmagnesium chloride handle, can prepare organomagnesium reagent from aryl bromide.Use metallic lithium in backflow reagent, to handle, or use other organolithium reagent for example s-butyl lithium or tert-butyl lithium handle, can prepare organolithium reagent from aryl bromide.Can use sulfuration reagent (thionatingagent) to handle metallized indoles in position subsequently, generate compound for example XCIV or CB3.If radicals R 18(CH 2) pSimple relatively, then prove utilization structure R 18-(CH 2) p-S-S-(CH 2) p-R 18Reagent be easily, it will directly generate sulfide XCIV.Otherwise Compound C B2 and reagent is atomic sulfur (S for example 8) reaction then be more efficiently, it will generate mercaptan compound CB3.This sulfydryl can be by the reagent alkylation of structure C B4, and wherein L represents suitable leavings group.The typical alkylation conditions that can use those skilled in the art to know.
Use oxygenant for example metachloroperbenzoic acid, potassium permanganate, peroxidation sulfate mono potassium or dimethyldioxirane, its stoichiometry is through selecting to optimize the required specific state of oxidation, and use solvent for example methylene dichloride, ethanol, methyl alcohol or acetone and under-30 ℃ to 120 ℃ temperature range, can prepare the oxide compound of formed thioether group among the compounds X CV.
LXXX. synthetic route CB
Figure A20078000890204961
The The compounds of this invention of structure XCVI and XCVII representative can be prepared by method shown in the synthetic route CC hereinafter.
The compound of formula CCl can be in indoles C-5 position by reagent for example concentrated nitric acid and optional solvent for example acetate or sulfuric acid are nitrated.Use reductive agent for example hydrogen (using catalyzer such as palladium carbon), tindichloride (in the presence of HCl), Sulfothiorine (in the presence of ammoniacal liquor) or iron powder, Compound C C2 can be gone up formed nitroreduction is the aminocompound of structure C C3.Can use amino and the hydroxyl of Compound C C3 to make up ring, for example phosgene, carbonyl dimidazoles or trichloromethyl chloro-formic ester carry out the cyclization of CC3, the compound of generating structure CC5 in the presence of alkaline reagents for example to use reagent C C4.Perhaps, the compound of compound generating structure CC7 in the presence of alkali of the compound of structure C C3 and structure C C6.Compound C C5 and CC7 can be by structure L-R 21Alkylation generates compounds X CVI and XCVII.
LXXXI. synthetic route CC
Figure A20078000890204971
The The compounds of this invention of structure C XVIII, XCIX and C representative can be prepared by method shown in the synthetic route CD hereinafter.
Can use that group P protection market buys 5, the phenylol of 6-dihydroxy indole generates Compound C D1.Suitable protecting group comprises for example t-butyldimethylsilyl, benzyl or THP trtrahydropyranyl, and their removal synthetic and subsequently is well known to those skilled in the art.The present invention had discussed in other place the indole nitrogen atom already through functionalized generation Compound C D2, CD2 generates CD3 and CD3 generates CD4 through the aryl cross-coupling through cyaniding subsequently.Can remove protecting group and the Sauerstoffatom that is used for various ring-closure reactions on the phenylol subsequently.For example, the reagent of utilization structure CD6 reacts in suitable alkali and can generate compounds X CIX De diox condensed member ring systems.Use phosgene or phosgene Equivalent (CD7) but the compound of processing CD5 generating structure XCVIII.The ketone of use formula CD8 or the ketal derivatives of ketone CD8 carry out the condensation of CD5, but the cyclic ketal compound of generating structure C.
LXXXII. synthetic route CD
Figure A20078000890204981
The formula I compound of structure C I representative can be prepared by method shown in the synthetic route CE hereinafter.
The reactive heteroaryl that use contains leavings group L is handled CE1 in suitable solvent, simultaneously with or without alkali for example mineral alkali such as yellow soda ash or salt of wormwood or organic bases for example trialkylamine in the presence of heat, but the compound of generating structure CI.Leavings group L can be halogenide, especially chlorine, bromine or iodine.R 18Can be alkyl, aryl or heteroaryl.
LXXXIII. synthetic route CE
Figure A20078000890204982
The formula I compound of structure C II representative can be prepared by method shown in the synthetic route CF hereinafter.
The Compound C F2 that use contains leavings group L and L ' handles CF1 in suitable solvent, simultaneously with or without alkali for example mineral alkali such as yellow soda ash or salt of wormwood or organic bases for example triethylamine in the presence of heat, but the compound of generating structure CF3.L and L ' represent leavings group separately, and it includes but not limited to halogen (for example chlorine, bromine or iodine) or alkyl or aryl sulfonate, and p is the integer between 1 and 6.Reactive heterocycle or heteroaryl compound CF4 can react in The suitable solvent with Compound C F3, simultaneously with or without alkali for example mineral alkali such as yellow soda ash or salt of wormwood or organic bases such as triethylamine, diisopropylamine in the presence of heat, but the compound of generating structure CII.
Perhaps, the available above-mentioned reactive compounds CF5 that contains suitable leavings group L handles Compound C F1, the compound of generating structure CII.
LXXXIV. synthetic route CF
Figure A20078000890204991
The formula I compound of structure C III representative can be prepared by method shown in the synthetic route CG hereinafter.
Can use suitable cyanidization agent for example Sulfuryl chloride isocyanate (CG2) or dialkyl group phosphinylidyne isocyanic ester at The suitable solvent or solvent mixture for example DMF, CH 3In the CN Huo diox indoles CG1 is carried out cyaniding, and under the temperature between-20 ℃ and 80 ℃, carry out this reaction, the compound of generating structure CG3.Compound C G3 can react with the above-mentioned reactive functional groups Z (CG4) that contains suitable leavings group L subsequently, generates Compound C G6.Perhaps, Compound C G1 can react with the reactive functional groups Z that contains suitable leavings group L subsequently, the compound of generating structure CG5, and it subsequently can be by as above cyaniding, production CG6 compound.
The compound of structure C G6 can be converted into indoles-2-boric acid CG7.Generally speaking, at suitable non-reactive solvent for example among ether or the THF or contain in their solvent mixture and use highly basic for example diisopropylamino lithium or hexamethyl two silica-based Lithamides or hexamethyl two silica-based potassium amides.This reaction is generally carried out to the scope of envrionment temperature at-78 ℃.Can generate indoles-2-boric acid CG7 with the cancellation of trialkylboron acid salt derivant.Use aryl or heteroaryl halogen CG8 and indoles-2-boric acid CG7 to react (being commonly referred to the Suzuki reaction), but the compound of generating structure CG9.But the method that linked reaction nationality those skilled in the art know is carried out, and it is included in catalyzer and for example carries out this reaction under the existence of 1,1 '-two (diphenylphosphine) ferrocene palladium chloride (II) methylene dichloride complex compound.This is reflected at The suitable solvent and for example carries out in the presence of alkali under the temperature range of envrionment temperature to 150 ℃ in DMF, toluene, the glycol dimethyl ether Huo diox.Alkali can be the aqueous solution for example yellow soda ash or sodium bicarbonate aqueous solution, and perhaps alkali can use for example cesium fluoride or Potassium monofluoride under anhydrous condition.
By using for example acid or alkali compound at water solvent or water-organic mixed solvent Processing Structure CG9 under room temperature or high temperature, or use nucleophilic reagent for example boron tribromide or Iodotrimethylsilane in suitable solvent, handle, indoles-carboxylicesters CG9 can be converted into indoles-carboxylic acid CG10.Can activate Type C G10 compound subsequently, and handle the compound of generating structure CIII with the amine of Type C G11.But the activation of carboxylic acid is carried out in any standard method of nationality.For example; can use coupling agent for example EDCI or DCC (adding or do not add HOBt) activated acids CG10 in the presence of amine CG11; for example perhaps using thionyl chloride or oxalyl chloride to handle acid can make this acid be activated to be acyl chlorides; or use carbonyl dimidazoles processing acid to make acid activation be acylimidazole compound, use amine CG11 to handle subsequently.
LXXXV. synthetic route CG
Figure A20078000890205011
The formula I compound of structure C IV representative can be prepared by method shown in the synthetic route CH.
The compound of formula CH1 can be reduced at its 6-ester group place, generates 6-skatoxyl CH2.Can use hydride reagent for example lithium borohydride for example to the temperature range of reflux temperature, carry out this reduction reaction in envrionment temperature among THF, ether or the DME at ether solvents, generate pure CH2.Use reagent for example thionyl chloride, phosphorus trichloride, thionyl bromide, methane sulfonyl chloride or toluene sulfonyl chloride at solvent such as but not limited to methylene dichloride, 1, handle in 2-ethylene dichloride or the chloroform, the benzylalcohol base of CH2 can be converted into leavings group L (halogen, arylsulphonate or alkylsulfonate).The leavings group L of formula CH3 compound can be by formula R 18The reagent of H replaces, production CIV compound, wherein R 18Can be by heterocycle or heteroaryl compound.The condition that is used for this reaction comprises solvent, such as but not limited to acetonitrile, tetrahydrofuran (THF), dimethyl formamide or methyl-sulphoxide; Alkali is salt of wormwood, cesium carbonate or sodium hydride for example; With the temperature range of envrionment temperature to reflux temperature.
LXXXVI. synthetic route CH
Figure A20078000890205021
The formula I compound of structure C V representative can be prepared by method shown in the synthetic route CI.
The compound of formula CI1 (wherein V represents bromide or iodide) can with alkyl vinyl ether for example ethyl vinyl ether react the adduct of production CI2 at solvent in such as but not limited to dimethyl formamide or glycol dimethyl ether at palladium catalyst in the presence of such as but not limited to acid chloride, palladium (four) triphenylphosphine.Use acid such as but not limited to hydrochloric acid, sulfuric acid or acetic acid water solution, can make the vinyl ether of formula CI2 be hydrolyzed to the aldehyde of formula CI3.Use hydride for example lithium borohydride or sodium borohydride for example in methyl alcohol or the tetrahydrofuran (THF), can make the compound of formula CI3 be reduced into alcohol at solvent, generate primary alconol CI4.
Use reagent for example thionyl chloride, phosphorus trichloride, thionyl bromide, methane sulfonyl chloride or toluene sulfonyl chloride at solvent such as but not limited to methylene dichloride, 1, handle in 2-ethylene dichloride or the chloroform, the alcohol radical of CI4 can be converted into leavings group L (halogen or arylsulphonate or alkylsulfonate).The leavings group L of formula CI5 compound can be by formula R 18The reagent of H replaces, production CV compound, wherein R 18Can be heterocycle or heteroaryl.The condition that is used for this reaction comprises the use solvent, such as but not limited to acetonitrile, tetrahydrofuran (THF), dimethyl formamide or methyl-sulphoxide; Alkali is salt of wormwood, cesium carbonate or sodium hydride for example; With the temperature range of envrionment temperature to reflux temperature.
LXXXVII. synthetic route CI
Figure A20078000890205031
The formula I compound of structure C VI representative can be prepared by method shown in the synthetic route CJ.
The compound of formula CJ1 (wherein V represents iodide or bromide) can react the compound of generating structure CJ2 at solvent in such as but not limited to dimethyl formamide or glycol dimethyl ether or toluene at palladium catalyst in the presence of such as but not limited to acid chloride, palladium (four) triphenylphosphine or (two)-triphenylphosphine palladium chloride and part such as triphenylphosphine or three-neighbour-toluene phosphine with acrylate.By catalyzer for example palladium or platinum in the presence of under 1-5 atmospheric pressure range, carry out hydrogenation at solvent in such as but not limited to methyl alcohol, ethanol or acetate, the hydrogenation of Type C J2 compound can generate the product of Type C J3.Can use for example reduction of lithium borohydride realization Compound C J3 ester group of hydride reagent, generate pure CJ4.Use reagent for example thionyl chloride, phosphorus trichloride, thionyl bromide, methane sulfonyl chloride or toluene sulfonyl chloride at solvent such as but not limited to methylene dichloride, 1, handle in 2-ethylene dichloride or the chloroform, can realize of the conversion of the alcohol of CJ4 to leavings group L (halogen, arylsulphonate or alkylsulfonate).The leavings group L of formula CJ5 compound can be by formula R 18The reagent of H replaces, production CVI compound, wherein R 18Can be heterocycle or heteroaryl.The condition that is used for this reaction comprises solvent, such as but not limited to acetonitrile, tetrahydrofuran (THF), dimethyl formamide or methyl-sulphoxide; Alkali is salt of wormwood, cesium carbonate or sodium hydride for example; With the temperature range of envrionment temperature to reflux temperature.
LXXXVIII. synthetic route CJ
Figure A20078000890205041
The formula I compound of structure C VII representative can be prepared by method shown in the synthetic route CK.
(wherein L is a leavings group to the compound of formula CK1, for example muriate, bromide, iodide or sulfonate, n is 0 or 1) can react under the temperature range in envrionment temperature to reflux temperature at solvent with triphenylphosphine such as but not limited to tetrahydrofuran (THF), toluene or methylene dichloride, give birth to into phosphonium salt CK2.Use alkali for example butyllithium, sodium hydride, sodium amide or potassium tert.-butoxide is for example handled among tetrahydrofuran (THF), ether or the DMF at solvent, adds aldehyde R in envrionment temperature to the temperature range of reflux temperature subsequently 18CHO (R wherein 18Be aryl, heterocycle or heteroaryl), can make microcosmic salt CK2 be converted into the olefin(e) compound of Type C K3.The hydrogenation of the compound of Type C K3 can catalyzer for example palladium or platinum in the presence of under the temperature range of envrionment temperature to 100 ℃, under nitrogen atmosphere, carry out the compound of production CVII such as but not limited to methyl alcohol, ethanol or acetate at solvent.
LXXXIX. synthetic route CK
Figure A20078000890205051
The formula I compound of structure C VIII representative can be prepared by method shown in the synthetic route CL.
The compound of formula CL1 (wherein L represents iodide, bromide or muriate or methane sulfonates) can with structure R 18B (OH) 2Boric acid (R wherein 18Be aryl or heteroaryl) palladium catalyst for example acid chloride, palladium (four) triphenylphosphine or palladium chloride and part such as triphenylphosphine or three-neighbour-toluene phosphine in the presence of react at solvent such as but not limited to acetone, dimethyl formamide or toluene, generate adduct CVIII.
XC. synthetic route CL
Figure A20078000890205052
The formula I compound of structure C IX representative can be prepared by method shown in the synthetic route CM.
The compound of formula CM1 (wherein L represents iodide, bromide or muriate or mesylate) can with metal-sulfinate (R wherein 18Be alkyl, aryl or heteroaryl) react to the temperature range of reflux temperature in envrionment temperature at solvent such as but not limited to acetone, dimethyl formamide or toluene, generate adduct CIX.
XCI. synthetic route CM
Figure A20078000890205061
The formula I compound of structure C X representative can be prepared by method shown in the synthetic route CN.
The compound of formula CL1 (R17 wherein defined above is 1-3 the substituting group that is positioned on the indole ring) is with for example processing such as potassium hydride KH, sodium hydride of alkali, subsequently with lithium alkylide for example tert-butyl lithium handle and form carbanion, itself and disulphide R 18SSR 18(R wherein 18Be alkyl, aryl or heteroaryl) react to the temperature of envrionment temperature at-78 ℃ at solvent such as but not limited to THF, ether or toluene, generate intermediate.Alkylation and the metal coupling of above having narrated cyaniding (CN3), indole nitrogen (CN4) form product C X.
XCII. synthetic route CN
Figure A20078000890205062
The formula I compound of structure C XI representative can be prepared by method shown in the synthetic route CO.The compound of formula CO1 (R wherein defined above 17Be 1-3 the substituting group that is positioned on the indoles) with alkali, cuprous iodide (I) and replacement amine (Z-NH 2, wherein the Z definition is the same) and handle the compound of production CO2.Use 2-chloroacetyl chloride and alkali for example triethylamine carry out acidylate in envrionment temperature such as but not limited to methylene dichloride, tetrahydrofuran (THF) or toluene at solvent to the temperature range of reflux temperature; generate intermediate CO3, use subsequently acid chloride (II) catalyzer, phosphine part and alkali for example triethylamine intermediate CO3 is cyclized into to the temperature of reflux temperature the compound of structure C O4 in envrionment temperature such as but not limited to tetrahydrofuran (THF), dimethyl formamide or toluene at solvent.Use hydride source for example DIBAL-H reduce and eliminate to the temperature that refluxes at 0 ℃ at solvent such as but not limited to methylene dichloride, tetrahydrofuran (THF) or toluene, generate intermediate CO5.Above narrated the subsequent step that generates product C XI.
XCIII. synthetic route CO
Figure A20078000890205071
The formula I compound of structure C XII representative can be prepared by method shown in the synthetic route CP.Use condition machining type CP1 compound mentioned above, generate CP3, through use metal for example palladium carbon and hydrogen source for example hydrogen or ammonium formiate CP3 is hydrogenated, generate aniline intermediate CP4.Use has the CP5 of 2 above-mentioned leavings groups (L), and (wherein X can be CH 2, S, SO, SO 2, O, C=O etc., n=0 to 3) and suitable alkali for example triethylamine or potassium hydroxide to the temperature of reflux temperature, carry out two alkylations in envrionment temperature such as but not limited to tetrahydrofuran (THF), dimethyl formamide or toluene at solvent, generate intermediate CP6.Use above-mentioned condition to generate product C XII subsequently.
XCIV. synthetic route CP
Figure A20078000890205072
The formula I compound of structure C XIII representative can be prepared by method shown in the synthetic route CQ.Can use above-mentioned condition to modify the compound of formula CQ1, generate product C XIII.
XCV. synthetic route CQ
Figure A20078000890205081
The formula I compound of structure C XIV representative can be prepared by method shown in the synthetic route CR.Can use above-mentioned condition to modify the compound of formula CR1, generate intermediate CR4.The use halogen source for example succimide of halogen replacement is handled indoles CR4 in envrionment temperature such as but not limited to tetrahydrofuran (THF), dimethyl formamide or toluene at solvent to the temperature of reflux temperature, generate the product C XIV that halogen replaces.
XCVI. synthetic route CR
Figure A20078000890205082
The formula I compound of structure C XV representative can be prepared by method shown in the synthetic route CS.The compound of formula CS1 can with the trifluoromethyl sulfonic acid source for example trifluoromethanesulfanhydride anhydride and alkali for example pyridine handle to the temperature of reflux temperature in envrionment temperature at solvent such as but not limited to tetrahydrofuran (THF), methylene dichloride or toluene, generate intermediate CS2.CS2 or can be directly and palladium (0) and R 12The trialkyl tin compound that replaces is reacting to the temperature of reflux temperature in envrionment temperature in such as but not limited to tetrahydrofuran (THF), dimethyl formamide or toluene at solvent in the presence of cesium fluoride and the cuprous iodide (I), generate product C XV, or carry out two the step linked reactions, wherein palladium (II) and alkali for example potassium acetate in the presence of to use pinacol borine source for example two pinacol diboron hexahydrides to carry out under the temperature in envrionment temperature to reflux temperature at solvent in such as but not limited to tetrahydrofuran (THF), diox or toluene coupled, use palladium (0), cesium chloride and suitable R subsequently 12The L compound carries out the palladium coupling second time at solvent under such as but not limited to tetrahydrofuran (THF), glycol dimethyl ether or the toluene temperature in envrionment temperature to reflux temperature, generates CXV.
XCVII. synthetic route CS
Figure A20078000890205091
C. The inventive method
The present invention relates to the method that a kind of hepatitis C virus (HCV) that is used for the treatment of the individuality that these needs are arranged infects on the other hand, this method comprises to one or more The compounds of this invention of described individual effective dosage or the acceptable salt of one or more its pharmacology, or comprises one or more The compounds of this invention of significant quantity or the pharmaceutical composition of the acceptable salt of one or more its pharmacology as mentioned above.
Just as used herein, term " treatment " means: (i) prevent from easily to suffer from this disease, obstacle and/or illness but the diagnosis individuality of suffering from it described disease, obstacle or illness take place; (ii) suppress disease, obstacle or illness, promptly stop its development; And/or (iii) alleviate disease, obstacle or illness, even described disease, obstacle or illness disappear.
Just as used herein, term " individuality " means to have sensation and autokinetic movement ability and need oxygen and animal or any biology that organic food is used to survive, and limiting examples comprises the mankind, equine, pig, Bovidae, Muridae, Canidae and feline species.In some embodiments, described individuality is Mammals or warm-blooded vertebrate.In other embodiments, described individuality is human.Just as used herein, term " patient " can exchange with " mankind " and use.
Be not subjected to any concrete theoretical restriction, it is believed that compound of the present invention passes through directly to disturb the IRES function and/or disturbs the interaction of IRES and cell and/or virokine to suppress startup, extension and the termination that IRES-mediates, be i.e. translation.Therefore, the present invention relates to the method that is used for the treatment of in the individuality that these needs are arranged the infection that the virus by wild-type virus or the existing antiviral of opposing causes on the other hand, wherein said wild-type or drug-resistant type (resistant) virus comprises internal ribosome entry site (IRES), this method comprises to one or more The compounds of this invention of described individual effective dosage or the acceptable salt of one or more its pharmacology, or comprises one or more The compounds of this invention of above-mentioned significant quantity or the pharmaceutical composition of the acceptable salt of one or more its pharmacology.The limiting examples of this viroid comprises that picornavirus belongs to the virus of (picornavirus genus), for example poliovirus, hepatitis A virus (HAV), Coxsackie virus and rhinovirus; The virus of coronavirus genus (coronaviridae genus), for example SARS; Arboviruses belongs to the virus of (arbovirus genus); The virus of Flavivirus (flavivirus genus), for example yellow fever virus, dengue fever virus and west Nile virus; Simplexvirus, for example hsv has the virus of similar replication mode with Kaposi sarcoma-relevant simplexvirus and other; And HIV, human leukovirus (HTLV) and other have the virus of similar interpretive scheme.
Another aspect of the present invention relates to a kind of startup of the individuality HCV IRES-mediation that is used for suppressing having these needs and/or the method for translation, this method comprises to one or more The compounds of this invention of described individual effective dosage or the acceptable salt of one or more its pharmacology, or comprises the pharmaceutical composition of above-mentioned one or more The compounds of this invention or the acceptable salt of one or more its pharmacology.
Just as used herein, term " significant quantity " means the amount that needs to produce required effect.For example, significant quantity can be at individuality or more specifically in the mankind, treatment hepatitis C virus (HCV) infects required amount, treatment comprises the required amount of virus infection of internal ribosome entry site (IRES), suppress the startup of HCV IRES-mediation and/or translate required amount, or suppress virus replication or infectious required amount.In some cases, by analyzing the existence of (1) HCV RNA; (2) existence of whose anti-HCV antibody; (3) level of serum alanine transaminase (ALT) and aspartate aminotransferase (AST) (ALT and AST raise long-term the infection in patient's body that HCV is arranged); (4) infect caused hepatocellular injury by HCV, comprise steatosis, fibrosis and liver cirrhosis; (5) by the caused hepatocellular carcinoma of chronic HCV infection; And (6) can measure required effect by HCV or other outer sequela (extrahepatic sequelae) (limiting examples comprises pruritus, encephalopathic, mental disorder for example anxiety or depression) of the caused liver of virus infection that contains the IRES element.Be used for individual significant quantity and depend on various factors, comprise body weight, the size and healthy of described individuality.Be used for the technical ability that the significant quantity of given individuality can be by being positioned at the clinician and judge with the normal experiment method determine.
For any compound, described significant quantity can for example be estimated in marmoset monkey and the Tamarin (tarmarin) in cell culture assays or in relevant animal models at first.Also can use described animal model to measure suitable concentration scope and route of administration.Can use this category information to measure useful dosage and the route of administration that is used for human body subsequently.Can in cell cultures or laboratory animal, measure treatment validity and toxicity, for example ED through the method for pharmacy of standard 50(dosage that colony 50% is had result of treatment) and LD 50(dosage fatal) to colony 50%.Dosage ratio between treatment effect and toxic effect is a therapeutic index, and it can be expressed as ED 50/ LD 50The ratio.In some embodiments, described significant quantity can realize big therapeutic index.In other embodiments, described dosage is positioned at the scope of circulation composition, and it comprises seldom or does not have a toxic ED 50Depend on formulation, patient's susceptibility and the route of administration of use, described dosage can change in this scope.
Particularly, using the viewed concentration of compound of the present invention-initial blood plasma target level scope of biological effect relation prompting is to about 25 μ g/mL from about 0.1 μ g/ml to about 100 μ g/mL, from about 1 μ g/mL to about 50 μ g/mL, from about 5 μ g/mL to about 50 μ g/mL or from about 10 μ g/mL.In order to realize these plasma concentrations, but the dosage of compound administration of the present invention is 0.1 μ g to 100,000mg, and this depends on route of administration.Document provides the guidance of given dose and medication, and this area insider generally can obtain these guidances.Generally speaking, be used for patient between the body weight about 40 to about 100kg (for the patient who is greater than or less than this weight range, especially body weight can be regulated these dosage less than the children of 40kg) the scope of single dose, fractionated dose or lasting dosage of described dosage be about 1mg/ days to about 10g/ days or about 0.1g to about 3g/ days or about 0.3g extremely about 3g/ days or about 0.5g extremely about 2g/ days.
Concrete dosage can be determined with reference to the factor relevant with individuality by the insider.Can regulate dosage and administration with active medicine that the capacity level is provided or keep required effect.The factor that need take in comprises the seriousness of morbid state, individual general health situation, age, body weight and individual sex, diet, administration time and frequency, drug regimen, reaction sensibility and the tolerance/response to treating.The transformation period and the clearance rate that depend on particular formulations can per 3 to 4 days, weekly or every administering long-lasting pharmaceutical composition biweekly.
But any route of administration that nationality this area is known is to described patient's administration compound of the present invention and composition.That limiting examples comprises is oral, in eye, rectum, oral cavity, part, nasal cavity, eye, subcutaneous, intramuscular, intravenously (injecting and infusion), the brain, through skin and pulmonary administration approach.
D. The metabolite of compound of the present invention
The interior metabolism product of compound described herein also is located within the scope of the present invention.This class product can be from the compound of for example institute's administration mainly by enzymatic oxidation, reduction, hydrolysis, amidation, esterification etc.Therefore, the present invention includes the compound that is produced by following method, this method comprises makes compound of the present invention contact one period that is enough to produce the meta-bolites of The compounds of this invention with mammalian tissues or Mammals.General by preparation radio-labeling of the present invention (C for example 14Or H 3) compound and give Mammals for example rat, mouse, cavy, monkey or people with detectable dosage (for example greater than about 0.5mg/kg) with its administration, allow time enough generation metabolism (general about 30 seconds to 30 hours), and from urine, blood or other biological sample, separate its converted product, thereby identify these products.Because they are labeled, these products separated easily (can separate other product in conjunction with the antibody of the epi-position that metabolite remained) by using.Through conventional mode for example MS or NMR assay determination metabolite structure.Generally speaking, can use the mode identical to carry out the analysis of metabolite with conventional medicine metabolism research well known to those skilled in the art.As long as converted product was not present in the body originally, even if they biologically active not itself, the diagnostic that also can be used for the therapeutic dose of compound of the present invention is measured.
E. Pharmaceutical composition of the present invention
Another aspect of the invention relates to a kind of pharmaceutical composition, it contains: (i) one or more The compounds of this invention of significant quantity or the acceptable salt of one or more its pharmacology, or a kind of one or more The compounds of this invention of above-mentioned significant quantity or pharmaceutical composition of the acceptable salt of one or more its pharmacology of comprising.
A kind of pharmaceutical composition of the present invention can realize being fit to the pH of physiological condition through preparation, and its scope is about 3 pH to about 11 pH.In some embodiments, described pharmaceutical composition can realize that through preparation about 3 pH arrives about 7 pH.In other embodiments, described pharmaceutical composition can realize that through preparation about 5 pH arrives about 8 pH.
Described pharmaceutical composition can comprise the combination of The compounds of this invention, second active ingredient that maybe can comprise the treatment that can be used for virus infection, for example antiviral includes but not limited to: the Interferon, rabbit of Pegylation comprises the alpha-interferon of limiting examples Pegylation; The Interferon, rabbit of Pegylation does not comprise the not alpha-interferon of Pegylation of limiting examples; Ribavirin or their prodrug or derivative; Glycosidase inhibitor; Proteinase inhibitor; AG14361; The p7 inhibitor; Entry inhibitor comprises for example Fuzeon of fusion inhibitor TM(Trimeris); The helicase inhibitor; Toll sample receptor stimulant, Caspase inhibitor, fibrosis medicine; The medicine of IMPDH target (inosine monophosphate dehydrogenase inhibitor), for example Merimepadib TM(Vertex Pharmaceuticals Inc.); Synthesizing thymosins alpha 1 (ZADAXIN TM, SciClone Pharmaceuticals Inc.); Glycosidase inhibitor; Therapeutic virus vaccine, for example vaccine produced of Chiron and Immunogenics; With immunomodulator histamine for example.
Term " the acceptable vehicle of pharmacology " means and is used for for example vehicle of compound of the present invention of administration medicine composition.This term does not have the acceptable vehicle of any pharmacology of excessive toxicity when meaning administration.Particular composition by institute's administration and ad hoc approach and/or formulation by administration can partly be determined the acceptable vehicle of pharmacology.The limiting examples of the acceptable vehicle of pharmacology comprises carrier, solvent, stablizer, adjuvant, thinner etc.Therefore, there is the several formulations (referring to for example Remington ' s PharmaceuticalSciences) that is fit to pharmaceutical composition of the present invention.
Suitable vehicle can be carrier molecule, and it comprises big metabolism macromole slowly, for example virion of protein, polysaccharide, poly(lactic acid), polyglycolic acid, polyamino acid, amino acid copolymer and deactivation.Other Exemplary excipients comprises antioxidant, for example xitix; Sequestrant is EDTA for example; Carbohydrate is dextrin, hydroxy alkyl cellulose, hydroxyalkyl methylcellulose gum, stearic acid for example; Liquid is oil, water, physiological saline, glycerine and ethanol for example; Wetting agent or emulsifying agent; PH buffer substance etc.Liposome is also included within the definition of the acceptable vehicle of pharmacology.
Pharmaceutical composition of the present invention can be formulated as any formulation that is fit to required medication.The suitable formulations that is used for oral administration comprises solid formulation, liquor, emulsion and suspensoid, and the suitable inhalative solution formulation that is used for pulmonary administration comprises liquid agent and pulvis.Other preparation comprises syrup, emulsifiable paste, ointment, tablet and lyophilized solid, and wherein available physiology solvent is rebuild before the lyophilized solid administration.For example need be used for when oral, can prepare tablet, lozenge (troches), dragee (lozenges), water or oil suspension, water-free solution, dispersible pulvis or granule (comprising micron particle or nanoparticle), emulsion, hard or soft capsule, syrup or elixir.Can prepare the composition that is used to orally use according to any method that is used to produce pharmaceutical composition known in the art, described composition can contain one or more materials, comprises sweeting agent, perfume compound, tinting material and sanitas, so that good to eat preparation to be provided.
Be fit to the acceptable vehicle of pharmacology with the tablet coupling and for example comprise for example for example croscarmellose sodium, polyvinylpolypyrrolidone, W-Gum or Lalgine of Mierocrystalline cellulose, lime carbonate or yellow soda ash, lactose, calcium phosphate or sodium phosphate, disintegrating agent of inert diluent; Tackiness agent is polyvidone, starch, gelatin or gum arabic for example; With lubricant for example Magnesium Stearate, stearic acid or talcum.Tablet can be the coated tablet of uncoated tablets or the preparation of nationality known technology, provides the micro encapsulation of long-time continuous action in GI disintegration and absorption thereby these technology comprise the delay tablet.For example, the serviceable time postpones glyceryl monostearate or the distearin that material for example adds or do not add wax.
The preparation that orally uses also can be rendered as hard gelatin capsule, wherein for example Mierocrystalline cellulose, lactose, calcium phosphate or kaolin mix activeconstituents with inert solid diluent, or be rendered as soft gelatin capsule, for example glycerine, propylene glycol, polyoxyethylene glycol, peanut oil, whiteruss or mixed with olive oil of activeconstituents and non-water or oily medium wherein.
In other embodiments, pharmaceutical composition of the present invention can be formulated as suspensoid, and it comprises one or more The compounds of this invention with the acceptable mixed with excipients of at least a pharmacology that is fit to the production suspensoid.In another embodiment, pharmaceutical composition of the present invention can be formulated as dispersible pulvis and granule, and they are suitable for preparing suspensoid through adding one or more vehicle.
The vehicle that suitable and suspensoid is united use comprises for example Xylo-Mucine of suspending agent, methylcellulose gum, HPMC, sodium alginate, polyvinylpyrrolidone, tragakanta, gum arabic, dispersion agent or wetting agent be natural phospholipid (as Yelkin TTS) for example, the condensation product of oxyalkylene and lipid acid (for example polyoxyethylene stearic acid ester), the condensation product of oxyethane and long chain aliphatic alcohol (for example 17 ethyleneoxy group hexadecanols (heptadecaethyleneoxycethanol)), oxyethane and condensation product (for example polyoxyethylene 20 sorbitan monooleate) derived from the partial ester of lipid acid and hexitan; With thickening material for example carbomer, beeswax, paraffinum durum or hexadecanol.Described suspensoid also can contain one or more sanitass, for example acetate, to hydroxy-benzoic acid methyl and/or n-propyl ester; One or more tinting materials; One or more flavouring agents; With one or more sweeting agents for example sucrose and asccharin.
Pharmaceutical composition of the present invention also can be the formulation of oil-in-water emulsion.Oil phase can be vegetables oil, for example sweet oil or peanut oil; Mineral oil, for example whiteruss; Or their mixture.Examples of suitable emulsifiers comprises natural natural gum, for example gum arabic and tragakanta; Natural phospholipid, for example soybean lecithin, derived from the ester or the partial ester of lipid acid and hexitan, for example sorbitan monooleate; With the condensation product of these partial esters and oxyethane, for example polyoxyethylene 20 sorbitan monooleate.Described emulsion also can comprise sweeting agent and flavouring agent.When preparing, syrup and tincture can add sweeting agent, for example glycerine, sorbyl alcohol or sucrose.Described preparation also can comprise wetting agent, sanitas, flavouring agent or tinting material.
In addition, pharmaceutical composition of the present invention can be the formulation of sterilization injection preparation, for example sterilized water for injection emulsion or oil suspension.Described emulsion or suspensoid can use suitable dispersion agent mentioned above or wetting agent and suspending agent to be prepared according to known technology.Described sterilization injection preparation also can be sterile solution for injection solution or the suspensoid that is dissolved in acceptable nontoxic thinner of parenteral or the solvent, and for example 1,2-third-glycol solution.Described sterile solution for injection preparation also can be prepared as lyophilized powder.In carrier and the solvent water, Ringer's solution and isotonic sodium chlorrde solution are arranged these spendable acceptance.In addition, can use the expressed oil of sterilization as solvent or suspension medium.With regard to this purpose, can use the expressed oil of any gentleness, it comprises synthetic list or two glyceryl ester.In addition, in injection preparation, also can use for example oleic acid of lipid acid equally.
Compound of the present invention can be water insoluble basically, is slightly soluble in acceptable protonic solvent of most drug and vegetables oil, but generally be dissolved in the propylene glycol ester of medium chain fatty acid (for example sad and capric acid) or triglyceride level and medium chain fatty acid.Therefore, what the present invention considered is by replacement or adding chemistry or the adorned compound of biochemical part, and these modifications make these compounds be more suitable for carrying (for example increasing solubleness, biological activity, palatability, reduction side reaction etc.) by for example esterification, glycosylation, Pegylation etc.
In some embodiments, compound of the present invention is prepared to the fat-based compositions that is used for oral administration, and these fat-based compositions are suitable for the compound of low solubility.The fat based formulation generally can strengthen the oral administration biaavailability of this compounds.Therefore, pharmaceutical composition of the present invention can comprise one or more present compositions of significant quantity and be selected from medium chain fatty acid or the acceptable vehicle of at least a pharmacology and the pharmacology acceptable surfactant of the propylene glycol ester of medium chain fatty acid (for example propylene glycol ester of edible fat acid as sad and capric acid), for example polyoxyethylene (40) hydrogenated castor oil.
In other embodiments, described pharmaceutical composition also can comprise one or more water solubility toughener, for example cyclodextrin.The limiting examples of cyclodextrin comprise α-, β-and the derivative of hydroxypropyl, hydroxyethyl, glucosyl, malt-base and the maltotriose glycosyl of γ-Huan Hujing and hydroxypropyl-beta-cyclodextrin (HPBC).In some embodiments, described pharmaceutical composition also can comprise about 0.1% to about 20% hydroxypropyl-beta-cyclodextrin, about 1% to about 15% hydroxypropyl-beta-cyclodextrin, or about 2.5% to about 10% hydroxypropyl-beta-cyclodextrin.The amount of employed solubility enhancing agent can be depending on the amount of compound of the present invention in described composition.
F. Combined therapy
Also might unite use any compound of the present invention and one or more other can be used for treating the single formulation of the active ingredient (containing compound) that HCV infects or formulation separately, to be used for simultaneously or successively to patient's administration of needs treatment.Successively during administration, described combination can be at twice or more times administration.In a substituting embodiment, might be with different approaches administration one or more compounds of the present invention and one or more additional active ingredients.
The technician will appreciate that many active ingredients can with compound Combined Preparation of the present invention, it can increase or collaborative increase the activity that composition of the present invention suppresses virus.This class active ingredient comprises anti-HCV agent.Anti-HCV agent comprises the material that target should virus and has the material of immunomodulatory effect.For example, anti-HCV agent includes but not limited to Interferon, rabbit (it comprises the α such as but not limited to IFN-), ribavirin or their prodrug or derivative, glucosidase inhibitor, proteinase inhibitor, polymer inhibitor, helicase inhibitor, Toll sample receptor stimulant, Caspase inhibitor and glycosidase inhibitor.And composition of the present invention also can influence the active compound Combined Preparation of IRES with other.
According to the method for the invention, the combination of active ingredient can be: (1) co-production and administration simultaneously or conveying in combination preparation; (2) alternately or carry simultaneously with independent preparation; Or any other combinational therapeutic methods of knowing of (3) nationality this area.When carrying in rotational therapy, the method for the invention can comprise administration successively or carry independent solution, emulsion, suspensoid, tablet, pill or the capsule of described active ingredient, or carry out different injections with independent syringe.Generally speaking, in rotational therapy, the effective dose of (promptly in turn) each active ingredient of administration successively, and in therapy synchronously, the effective dose of two or more active ingredients of administration simultaneously.Also can use the various orders of discontinuity conjoint therapy.
Understand the present invention for auxiliary, included the following example in.Relate to experiment of the present invention and undoubtedly should not be construed as concrete restriction the present invention, on the contrary, at present known and develop of the present invention various this type of that is positioned at those skilled in the art's limit of power that in the future and change and all be considered as being positioned at the scope of the invention described herein and that hereinafter advocated.
Those skilled in the art's easy to understand, the specific embodiment of the present invention may relate to one, some or all of above shown in aspect and others, and can comprise one, some or all of above shown in and hereinafter shown in embodiment and other embodiment.
Except in an embodiment or other have in addition under the occasion of explanation, be used in this specification sheets and claims represent that the numeral of component, reaction conditions equivalent is interpreted as being subjected to term " about " to modify.Therefore, unless indicate reverse situation is arranged, these numerals are approximations, the required character change that it can institute's phase obtains according to the present invention.Never and do not wish to limit range applications doctrine of equivalents yet, should understand each digital parameters with reference to the number and the routine method of rounding up of significant figure to claim.
Although stipulated that the numerical range of broad range of the present invention and parameter are approximation, as far as possible accurately write down listed in an embodiment numerical value.But any numerical value all contains inherently and is derived from its certain error of existing standard deviation during experimental measurement separately inevitably.
Embodiment
The present invention has carried out more detailed description with reference to following non-limiting examples, and these non-limiting examples are used for setting forth more fully the present invention, but unintelligible for limiting the scope of the invention.These embodiment have set forth the preparation of some compound of the present invention, and these compounds are in external or body or detection in vitro and in vivo.It will be understood by those skilled in the art that the described technology of these embodiment represents that the inventor is described can to bring into play the technology of good action in enforcement of the present invention, and itself constituted and implement optimal way of the present invention.What however, it should be understood that is, those skilled in the art it will be appreciated that and can make many changes and still can obtain same or similar result disclosed concrete grammar according to this specification sheets, and without departing from the spirit and scope of the present invention.
Embodiment 1: the preparation of The compounds of this invention
The preparation of embodiment 1A:1-ethyl-6-methoxyl group-1H-indoles-3-nitrile (compound 5)
Steps A: (10.0g, DMF 68.0mmol) (120mL) solution is cooled to 0 ℃, uses Sulfuryl chloride isocyanate (7.72mL, 88.4mmol) processing again with 6-methoxyl group indoles.After the adding, reaction mixture stirs 1h under room temperature.Pour dark solution into frozen water (600mL), collect the light brown solid after filtration, add H 2O washs, and obtains the light brown solid of 9.9g (85%) 6-methoxyl group-1H-indoles-3-nitrile after the drying.
Step B: to 6-methoxyl group-1H-indoles-3-nitrile (9.9g, DMF 57.6mmol) (150mL) solution add NaH (be dissolved in mineral oil, concentration 60%, 3.45g, 86.3mmol).Reaction mixture stirs 15min, and (5.53mL, 69.1mmol), mixture stirs under room temperature and spends the night to add iodoethane then.Use H then 2The O diluted reaction mixture, and extract with EtOAc (2X).Organic phase is with H 2O (3X) and saturated NaCl washing, drying is concentrated into semisolid.With CH 2Cl 2/ hexane (50-100%) is gone up purifying crude product through column chromatography at silica gel (200g) as eluent, obtains the brown solid of 6-methoxyl group-1-ethyl-1H-indoles-3-nitrile.
Use above-mentioned steps A to replace the generation following compounds: compound 43,45,51,52,108,109,115,118,120,123,126,179 and 714 with B and different indoles and halohydrocarbon.
The preparation of embodiment 1B:6-oxyethyl group-1-ethyl-1H-indoles-3-nitrile (compound 9).
Figure A20078000890205172
Steps A: 1-ethyl-6-methoxyl group-1H-indoles-3-nitrile (2.85g, CH 14.2mmol) that under 0 ℃, prepares to the step B of embodiment 1A 2Cl 2(40mL) add 1M BBr in the solution 3CH 2Cl 2(28.5mL, 28.5mmol) solution.Mixture is warming up to room temperature, and keeps 2.5h., adding the 1M NaOH of capacity with the black reaction mixture extremely on ice subsequently, is 8-9 until pH.Use CH 2Cl 2(3X) extraction product, and with saturated NaHCO 3, H 2The organic phase that O and saturated NaCl washing merge.MgSO 4After the drying, concentrated solution is through chromatography (EtOAc/CH 2Cl 2, 0-10%) purified product, the yellow solid of 6-hydroxyl-1-ethyl-1H-indoles-3-nitrile of generation 2.15g (82%).
Step B: (80mg, methylethylketone 0.43mmol) (5mL) solution adds anhydrous K to 6-hydroxyl-1 ethyl-1H-indoles-3-nitrile 2CO 3(71mg, 0.52mmol) and methyl iodide (0.05mL, 0.60mmol).After refluxed overnight stirred, reaction mixture was used H 2O dilutes, and extracts with EtOAc (3X).Dry and the concentrated organic phase that merges.Through flash chromatography (CH 2Cl 2) generate the white wax of 6-oxyethyl group-1-ethyl-1H-indoles-3-nitrile of 94mg (100%).
Adopt steps A and B also to prepare following compounds in a similar manner: compound 6,10,11,12 and 24.
Embodiment 1C:5-(4-p-methoxy-phenyl)-5H-[1,3] the also preparation of [4,5-f] indoles-7-nitrile (compound 44) of dioxane penta
With paraiodoanisole (85mg, 0.36mmol), anhydrous K 3PO 4(102mg, 0.48mmol), CuI (4.6mg, 0.024mmol) and N, N '-dimethyl cyclohexane-1, the 2-diamines (14mg, mixture 0.096mmol) join the 5H-[1 according to the preparation of the method for embodiment 1A steps A, 3] dioxane penta also [4,5-f] (45mg is in dry toluene 0.24mmol) (0.4mL) solution for indoles-7-nitrile.Behind the reflux 24h, evaporating solvent under the vacuum.Use CH 2Cl 2(5mL) dissolving resistates, filtering mixt.Concentrated filtrate generates crude product, with EtOAc/ sherwood oil (1: 4) as solvent through silica gel chromatography purifying crude product, generate 5-(4-p-methoxy-phenyl)-5H-[1,3] dioxane penta [4,5-f] indoles-7-nitrile also.
Use above-mentioned steps and replace different aryl iodides and generated following compounds: compound 4,8,102,103,111,112,117,119,124,125,127,154.
The preparation of embodiment 1D:1-ethyl-6-(pyrazine-2-base oxygen base)-1H-indoles-3-nitrile (compound 13)
Figure A20078000890205191
(60mg adds K in DMF 0.32mmol) (5mL) solution to the 1-ethyl-6-hydroxyl-1H-indoles-3-nitrile for preparing to foundation embodiment 1A steps A 2CO 3(55mg, 0.40mmol) and 2-chlorine pyridazine (45mg, 0.40mmol).Mixture heats 18h down in 110 ℃.After being cooled to room temperature, reaction mixture is with H 2O dilutes, and extracts with EtOAc (3X).The organic phase that merges is with H 2O and saturated NaCl washing are dried concentrated.Adopt chromatography (EtOAc/CH 2Cl 2, 1-3%) separated product on silica gel, the target compound of generation 76mg (96%), i.e. the off-white color solid of 1-ethyl-6-(pyrazine-2-base oxygen base)-1H-indoles-3-nitrile.
The preparation of embodiment 1E:3-cyano group-1-ethyl-1H-Indole-6-carboxylic acid benzamide (compound 15).
Figure A20078000890205192
Steps A: according to embodiment 1A institute described method, prepare 3-cyano group-1-ethyl-1H-indole-6-carboxylic methyl ester from the 1H-indole-6-carboxylic methyl ester, its (1.60g, 7.02mmol) THF (35mL) solution is with 1N NaOH (7.7mL, 7.7mmol) handle reflux 2.5h.After being cooled to room temperature, remove most of THF, solution dilutes with water, and extracts with ether (2X).Discard ethereal extract.Use 6N HCl to pH2, extracts aqueous phase as acidified then with EtOAc (3X).Merge the EtOAc layer, with saturated NaCl washing, drying generates 3-cyano group-1-ethyl-1H-Indole-6-carboxylic acid's of 1.43g (95%) white solid with concentrated.
Step B: with 3-cyano group-1-ethyl-1H-Indole-6-carboxylic acid (0.42g, CH 1.96mmol) 2Cl 2(15mL) suspension is cooled to 0 ℃.Use DMF (2) to handle this suspension, then with syringe in 2min, add oxalyl chloride (0.34mL, 3.92mmol).Remove ice bath afterwards, make reaction mixture be warming up to envrionment temperature in 1.5h, this moment, reactant became yellow solution.Concentrated solution under vacuum subsequently generates the yellow solid of 0.46g (quantitative yield) 3-cyano group-1-ethyl-1H-indoles-6-dicarbonyl chloride.
Step C: (70mg, THF 0.30mmol) (5mL) suspension is cooled to 0 ℃, and (0.08mL 0.90mmol) handles with aniline with 3-cyano group-1-ethyl-1H-indoles-6-dicarbonyl chloride.After adding aniline, reactant is heated to room temperature, stir 16 hours in addition after, reaction mixture is with H 2O dilutes, and extracts with EtOAc (2X).The organic phase that merges is washed with saturated NaCl, is dried and concentrates, and generates product.Through silica gel chromatography (EtOAc/CH 2Cl 2, 2/98) and obtain 3-cyano group-1-ethyl-1H-Indole-6-carboxylic acid benzamide of 44mg (51%).
Basically use above-mentioned steps to generate following compounds: compound 89.
Embodiment 1F:(3-cyano group-1-ethyl-1H-indoles-6-yl) preparation of t-butyl carbamate (compound 16).
Figure A20078000890205201
Use Et 3N (0.46mL, 3.36mmol) and diphenyl phosphate azide (0.73mL 3.36mmol) handles 3-cyano group-1-ethyl-1H-Indole-6-carboxylic acid from embodiment 1E steps A (0.60g, trimethyl carbinol 2.80mmol) (20mL) solution, and with its reflux 4h.After being cooled to room temperature, remove most trimethyl carbinols under the vacuum, generate oily matter, then oily matter is dissolved in EtOAc.Use H 2After the O washing, use EtOAc reversed phase extraction organic phase, merge organic phase, and with other H 2O, saturated NaHCO 3Wash organic phase successively with saturated NaCl.Dry and concentrated organic phase is with EtOAc/CH 2Cl 2(0-1%) through the formed crude product of silica gel chromatography purifying, generate the white solid of 0.52g (65%) (3-cyano group-1-ethyl-1H-indoles-6-yl)-t-butyl carbamate.
Prepare following compounds in a similar way: compound 90.
Embodiment 1Ga: prepare 2-(4-amino-benzene)-1-ethyl-6-methoxyl group-1H-indoles-3-nitrile (compound 55) through the Suzuki path
Steps A: (3.9mL, 7.8mmol) solution is dissolved in straight fiery exsiccant (flame-dried) flask with the THF/ hexane (Acros) of 2 M N-Lithiodiisopropylamides to use THF (5mL).After reactant is cooled to-30 ℃, in 10min, drip 1-ethyl-6-methoxyl group-1H-indoles-3-nitrile (1.30g, THF 6.5mmol) (10mL) solution, and temperature remained on-30 ℃.After stirring 30min under this temperature, in 10min, add iodine (2.31g, THF 9.1mmol) (5mL) solution.After this, reactant is warming up to room temperature in 1h.Reactant is subsequently with ice H 2O dilutes, and extracts with EtOAc (2X).The organic phase that merges is concentrated into brown solid subsequently with 1M Sulfothiorine and saturated NaCl washing.Through silica gel chromatography (CH 2Cl 2/ hexane, 1/1) obtains the off-white color solid of 1-ethyl-2-iodo-6-methoxyl group-1H-indoles-3-nitrile of 1.31g (62%).
Step B: with 1-ethyl-2-iodo-6-methoxyl group-1H-indoles-3-nitrile (1.25g, 3.83mmol), 4-(4,4,5, the 5-tetramethyl-)-1,3-2-two oxa-s borine-2-base-aniline (0.96g, 4.90mmol), CsF (1.46g, 9.58mmol) and be dissolved in the Pd (PPh of DME (20mL) 3) 2Cl 2(110mg, mixture 0.15mmol) joins in the flask, and exhaust and N hocket 2Flushing.Reactant is reflux 24h then, is cooled to room temperature then.Reaction mixture is subsequently with H 2O dilutes, and extracts with EtOAc (2X).The organic phase that merges is with H 2O and saturated NaCl washing, and with MgSO 4Drying concentrates.Crude product mixture is with EtOAc/CH 2Cl 2(5/95) as eluent on silica gel through purified by flash chromatography, generate the yellow solid of 2-(4-amino-benzene)-1-ethyl-6-methoxyl group-1H-indoles-3-nitrile of 765mg (69%).
Use with essentially identical step mentioned above and replace different boric acid and obtain following compounds: compound 19,20,21,22,53,63,70,71,74,76,77,79,80,100,110,229,239,240,247,250,254,255,256,257,258,259,260,281,282,283,284,286,335,336,337,338,339,347,348,426,427,428,429,476,543,578,758
Embodiment 1Gb: prepare 2-(4-amino-benzene)-1-butyl-6-methoxyl group-1H-indoles-3-nitrile through selectable Suzuki path
Figure A20078000890205221
To (i-Pr) that be cooled to-78 ℃ 2NH (1.35mL, THF 9.65mmol) (30mL) solution once add n-BuLi (3.7mL, the 2.5M solution in hexane, 9.21mmol).Acetone/the dry ice bath is changed to ice/water-bath, and solution further stirs 40min.This solution is cooled to-78 ℃, dropwise adds 1-butyl-6-methoxyl group-1H-indoles-3-nitrile (2.0g, THF 8.77mmol) (10mL) solution according to embodiment 1A preparation then.This solution stirs 15min down at-78 ℃, stirs 20min down at-20 ℃ subsequently.Add the trimethyl-boron hydrochlorate (1.0mL, 8.77mmol), this reaction mixture stirs 15min down at-20 ℃, remove cryostat after, this solution is restir 1h at room temperature further.Successively add K 3PO 4(11.7mL, the 3M aqueous solution, 35.1mmol) solution, 4-Iodoaniline (2.5g, 11.40mmol) solution and PdCl 2Dppf catalyzer (640mg, DMF 0.88mmol) (40mL, other adds 5mL and is used for flushing) solution.This reaction mixture stirs and spends the night (ca.18h), adds entry (80mL) then, uses EtOAc (3X50mL) extraction product.The organic phase that merges is with MgSO 4Drying, filtration under diminished pressure and concentrated.Use flash chromatography (5 → 60%EtOAc/ hexane is as eluent) purified product on silica gel, generate the brown solid (2.4g, yield 86%) of required 2-(4-amino-benzene)-1-butyl-6-methoxyl group-1H-indoles-3-nitrile
Use the bromide and the iodide of other indoles and aryl and heteroaryl to prepare following compounds in a similar way: compound 656,659,660,661,682,683,712,731,732,733,806,807,808,809,810,811,812,813,814,827.
Embodiment 1Gc: prepare 2-(4-amino-benzene)-6-methoxyl group-1-propyl group--1H-indoles-3-nitrile through the Negishi path
Figure A20078000890205222
Add exsiccant THF (all adding) (20mL) to the flask of being furnished with barrier film and nitrogen pin (having used nitrogen purging in advance) with syringe.(Aldrich Sure-Seal, 2.00mL 14.3mmol), are cooled to 0 ℃ with solution to add diisopropylamine.Slow adding n-Butyl Lithium (the 1.6M hexane solution of 8.50mL, 13.6mmol).Make flask temporarily be warming up to room temperature, be cooled to-78 ℃ then.Slowly add 6-methoxyl group-1-propyl group-1H-indoles-3-nitrile (2.77g, 12.9mmol; Similar with the preparation of the compound 5 of embodiment 1A) spissated THF solution, formed solution is kept 30min under-78 ℃.Then flask is transferred on the ice-water bath, returned to 0 ℃ in about 15 minutes.Once more solution is cooled to-78 ℃, slowly adds ZnCl 2(0.5M THF solution, 27.0mL, 13.5mmol).Observed precipitation this moment, and it might be two (indoles) zn cpds, but after adding whole liquor zinci chloridis, this solution becomes gets homogeneous.After about 10 minutes, this solution returns to room temperature, add this moment the 4-Iodoaniline (3.47g, 15.8mmol) and triphenylphosphine (338mg, THF solution (5mL) 1.29mmol).Remove barrier film, add Pd 2(dba) 3(295mg, 0.322mmol) solid.Load onto reflux exchanger to flask, by three successive vacuum exhaust/N 2Purging is removed the gas in the solution.The heated solution that spends the night then refluxes.After being cooled to room temperature,, add the ethyl acetate of 4 times of volumes again with the water of 4 times of volumes of solution impouring.Formed mixture is carried out 30 minutes vigorous stirring, filter by Celite (using the ethyl acetate washing) then, remove the solid matter that contains Zn and Pd.Separate each phase, and use more ethyl acetate extraction water.With saturated brine washing organic phase,,, filter and evaporation successively with anhydrous sodium sulfate drying with its merging.Form solid precipitation this moment, and it is enough pure product, grinds and filter its collection through ether.Use column chromatography (with 1: 2 ethyl acetate-hexane wash-out on silica gel 60) purifying resistates.The total recovery of product 2-(4-amino-phenyl)-6-methoxyl group-1-propyl group-1H-indoles-3-nitrile is 2.75g (8.99mmol, 70%).
Use the iodide or the bromide of essentially identical step and other aryl of replacement or heteroaryl to prepare following compounds: compound 393,408,430,431,436,437,438,459,460,461,462,483,484,632,633,634,635,636,650,651.
The preparation of embodiment 1Gd:1-ethyl-2-(3-hydroxyphenyl)-6-methoxyl group-1H indoles-3-nitrile (compound 288)
Figure A20078000890205231
Steps A: (5.5mL, solution 39mmol) are cooled to-78 ℃ with THF (60mL) and Diisopropylamine.In 5 minutes, dropwise add n-Butyl Lithium hexane solution (14.5mL, 2.5M, 36.2mmol).The LDA mixture stirred 10 minutes down at-78 ℃, stirred 20 minutes down at 0 ℃ then.Again solution is cooled to-78 ℃.(5.0g 25mmol) is absorbed in THF (30mL) to the 1-ethyl-6-methoxyl group-1H-indoles-3-nitrile that will prepare according to embodiment 1A, and it is dropwise joined in the LDA mixture, continues 15 minutes.Reactant stirred 10 minutes down at-78 ℃, stirred 30 minutes down at 0 ℃ then.Reaction mixture is cooled to-78 ℃ once more.Dropwise add the iodate tributyltin (10mL, 35mmol).Mixture stirred 15 minutes down at-78 ℃, stirred 30 minutes down at 0 ℃ then.Absorb and concentrated reaction mixture with silica gel.Through chromatography (CH 2Cl 2) purifying generation 1-ethyl-6-methoxyl group-2-tributyl tin alkyl-1H-indoles-3-nitrile (12.05g, 98%).
Step B: with the 1-ethyl-6-methoxyl group-2-tributyl tin alkyl-1H-indoles-3-nitrile of steps A preparation (1.0g, 2.05mmol) with the 3-iodophenol (474mg, 2.15mmol), Pd (PPh 3) 2Cl 2(67mg, 0.102mmol), CuI (75mg, 0.39mmol) and THF (4.0mL) merge.Mixture is in 65 ℃ of heated overnight.Reaction mixture dilutes with EtOAc, and filters with Celite.Concentrated filtrate, and the use silica gel chromatography (4: 1, CH 2Cl 2/ EtOAc) purifying resistates generates crude product.Grind the white-yellowish solid that generates 1-ethyl-2-(3-hydroxyl-phenyl)-6-methoxyl group-1H-indoles-3-nitrile (430mg, 72%) through ether.
Use other commercially available iodide and bromide or use and prepare following compounds: compound 275,276,277,278,331,363,364,373,374,375,474,475,678 with above-mentioned similar approach derived from iodobenzene SULPHURYL CHLORIDE one is gone on foot amidated iodide.
Embodiment 1Ge: prepare ethyl sulfonic acid [4-(3-cyano group-6-difluoro-methoxy-1-ethyl-1H-iodo-2-yl)-phenyl]-acid amides (compound 519) through the Heck path.
Figure A20078000890205241
Steps A: with 6-difluoro-methoxy-1-ethyl-1H-indoles (402.8mg, 2.04mmol) solution, ethyl sulfonic acid (4-iodo-phenyl)-acid amides (712.1mg, 2.29mmol), cesium carbonate (733.2mg, 3.82mmol), triphenylphosphine (33.1mg, 0.13mmol) and (5.7mg, 0.025mmol) solution is at 135 ℃ of following heating 48h to be dissolved in the acid chloride of DMA (5ml).Reaction mixture dilutes with water subsequently, and with EtOAc (2 * 10mL) extractions.The organic phase salt water washing that merges is with MgSO 4Drying concentrates then.With EtOAc/ hexane (10-20%) as eluent on silica gel (25g) through column chromatography purifying resistates, [4-(6-difluoro-methoxy-1-ethyl-1H-iodo-2-yl)-phenyl]-acid amides is the light brown solid of compound 516 to generate the ethyl sulfonic acid of 298.2mg (yield 37.1%).
Step B: adopt program 1A steps A, ethyl sulfonic acid [4-(6-difluoro-methoxy-1-ethyl-1H-iodo-2-yl)-phenyl]-acid amides is converted into ethyl sulfonic acid [4-(3-cyano group-6-difluoro-methoxy-1-ethyl-1H-indoles-2-yl)-phenyl]-acid amides, and promptly compound 519.
Adopt above steps A and B, prepare following compounds in a similar manner: compound 343,344,345,346,409,410,411,412,413,414,41 5,416,417,418,419,463,464,465,466,467,468,469,470,471,472,473,51 5,517,518,520,521,522,523,524,575,577,579,580,611,612,613,614.
The preparation of embodiment 1H:1-ethyl-2-(4-fluorophenyl ethynyl)-6-methoxyl group-1H-indoles-3-nitrile (compound 67)
Figure A20078000890205251
Will be according to the 1-ethyl-2-iodo-6-methoxyl group-1H-indoles-3-nitrile (150mg of embodiment 1Ga steps A preparation, 0.46mmol), 4-fluorophenyl acetylene (80mg, 0.0.69mmol), two (triphenylphosphine) palladium chloride (II) (6mg, 0.009mmol) and CuI (4mg, 0.018mmol) mixture join the sealing test tube in, exhaust and N hocket 2Flushing.Add DMF (4mL) and Et toward this test tube then 3(0.25mL, 1.84mmol), reactant heats 20h down at 80 ℃ to N, is cooled to room temperature then.Reaction mixture is then with H 2O dilutes, and extracts with EtOAc (2X).The organic phase that merges is with H 2MgSO is used in O (3X) and saturated NaCl washing subsequently 4Drying concentrates.Crude product mixture is absorbed in that silica gel (0.6g) is gone up and on silica gel with EtOAc/ hexane (10-20%) as the eluent chromatographic separation, generate the yellow solid of 1-ethyl-2-(4-fluorophenyl ethynyl)-6-methoxyl group-1H-indoles-3-nitrile of 120mg (82%).
Use basic with above describe identical step and replace different acetylene-derivative generation following compounds: compound 64,65,66,68,69,91,92,93,94,95,96,133,134,135,136,137,143,144,145,146,147,148,149,150,151,158,159,160,161,169,170,171,172,173,174,175,176,177,178,184,185,186,187,188,196,197,198,199,200,201,202,223,230,231,232,233,234,235,236,237,238.
The preparation of embodiment 1I:1-ethyl-3-(5-ethyl-[1,2,4] oxadiazole-3-yls)-6-methoxyl group-1H-indoles (compound 28)
Steps A: use azanol (0.38mL, 6.25mmol) aqueous solution processing 1-ethyl-6-methoxyl group-1H-indoles-3-nitrile (1.00g, MeOH 5.00mmol) (10mL) solution, reflux 18h of 50%.After being cooled to room temperature, filter inhomogenous mixture, generate the brown solid of the required product of 525mg.Filtrate is concentrated into oily matter, then it is dissolved in CH 2Cl 2, and use EtOAc/CH 2Cl 2(15-50%) generate the brown solid of 295mg product in addition through silica gel chromatography.The total recovery of 1-ethyl-N-hydroxyl-6-methoxyl group-1H-indoles-3-carbonamidine is 820mg (70%).
Step B: with top N-hydroxyl carbonamidine (50mg, 0.21mmol), polystyrene-diisopropyl ethyl amine (165mg, 3.90mmol/g load) and propionyl chloride (0.03mL, CH 0.32mmol) 2Cl 2(10mL) solution places test tube, rotates 22h under the room temperature.Subsequently, add Tutofusin tris resin (77mg, 2.71mmol/g load), this test tube at room temperature rotates 30min again.Cross filter solid, concentrated filtrate then, and with dilution with toluene (5mL), 110 ℃ of following heated overnight.Crude product mixture is through chromatography (EtOAc/CH 2Cl 2, 2/98) concentrate and purifying, generate the white solid of 1-ethyl-3-(5-ethyl-[1,2,4] oxadiazole-3-yls)-6-methoxyl group-1H-indoles of 27mg (46%).
Use the replacement of above-mentioned steps and suitable carboxylic acid halides to prepare following compounds: compound 29.
The preparation of embodiment 1J:1-ethyl-6-methoxyl group-3-(5-ethyl-[1,3,4] oxadiazole-2-yls)-1H-indoles (compound 54)
Figure A20078000890205262
Steps A: use triethylamine hydrochloric acid (1.03g, 7.50mmol) and sodiumazide (0.49g, 7.50mmol) handle 1-ethyl-6-methoxyl group-1H-indoles-3-nitrile (1.00g, 5.00mmol) and the mixture of toluene (30mL), and with its reflux 16h.After being cooled to room temperature, reaction mixture is with saturated NaHCO 3Dilute, and extract with EtOAc.Use NaHCO then 3(2X) washing organic layer.The organic phase that merges is acidified to pH 2 by 6N HCl.Use the formed dense throw out of hot EtOAc (3X) extraction, the organic phase that merges with saturated NaCl washing, and be dried concentratedly, generate the yellow solid of 1-ethyl-6-methoxyl group-3-(1H-tetrazolium-5-yl)-1H-indoles of 0.55g (45%).
Step B: tetrazolium that will be above (50mg, 0.21mmol) and propionyl chloride (0.03mL, the suspension returning of methylene dichloride 0.31mmol) (5mL) solution heats 21h.After reaction mixture was cooled to room temperature, (3.4meq/g), reactant at room temperature rotated 4h for polystyrene trisamine resin, 70mg to add polystyrene Tutofusin tris resin.After filtering resin and remove desolvates, absorb crude product with silica gel, with silica gel chromatography (EtOAc/CH 2Cl 2, 5-10%) separate this product, generate the brown solid of 1-ethyl-6-methoxyl group-3-(5-ethyl-[1,3,4] oxadiazole-2-yls)-1H-indoles of 30mg (53%).
The preparation of embodiment 1K:5-difluoro-methoxy-1-(4-p-methoxy-phenyl)-2-Methyl-1H-indole-3-carboxylic acid, ethyl ester (compound 49).
In 0 ℃ with freonll-11-22 (HCF 2Cl) gas feeds 5-hydroxyl-1-(4-p-methoxy-phenyl)-2-Methyl-1H-indole-3-carboxylic acid, ethyl ester (250mg, CH 0.77mmol) 2Cl 2(5mL) in the solution, wherein this solution contains a spot of Tetrabutyl amonium bromide as phase-transfer catalyst.Dropwise add 50%NaOH solution in 0 ℃.After the adding, mixture stirs 2h down in 0 ℃.Add H 2Behind the O, separate organic phase, with the salt water washing, again with Na 2SO 4Dry.Concentrated solvent then, with EtOAc/ sherwood oil (1/2) as eluent on silica gel through column chromatography purifying resistates, generate the purpose product, its yield is 40%.
Use the replacement of above-mentioned steps and suitable oxyindole to prepare following compounds: compound 18,46 and 50.
Embodiment 1L:1-[5-methoxyl group-1-(4-p-methoxy-phenyl)-1-H-indol-3-yl]-preparation of ethyl ketone (compound 42).
Figure A20078000890205281
(50mg 0.2mmol) is dissolved in 1mL CH in 0 ℃ of 5-methoxyl group-1-(4-p-methoxy-phenyl)-1-H-indoles that will prepare according to the method for embodiment 1C 2Cl 2Add Et then 2The hexane solution of AlCl (300 μ L, 1M, 0.3mmol).After stirring 30min under 0 ℃, dropwise add 1mL Acetyl Chloride 98Min. (22 μ L, CH 0.3mmol) 2Cl 2Solution.Mixture stirs 90min down in addition at 0 ℃.Reaction mixture is with H 2O cancellation (quench), and with CH 2Cl 2Extraction concentrates under vacuum then.Use EtOAc/CH 2Cl 2(5/95) carries out the silica gel column chromatography purifying, generate the white solid (42mg, 71%) of target compound.
Use with essentially identical step mentioned above and replace different acyl chlorides and prepare following compounds: compound 32,33,34,37,38,39,47,48.
The preparation of embodiment 1M:1-ethyl-3-isoxazole-3-base-6-methoxyl group-1-H-indoles (compound 57).
Figure A20078000890205282
Steps A: will be according to 1-(1-ethyl-6-methoxyl group-1-H-indol-3-yl) ethyl ketone (200mg of the described step of embodiment 1L from 1-ethyl-6-methoxyl group-1H-indoles preparation, 0.92mmol), oxammonium hydrochloride (128mg, 1.84mmol), NaOAc (151mg, 1.84mmol) and the mixture of EtOH (7mL) at 85 ℃ of following heating 4h.Reaction mixture is used H subsequently 2O and EtOAc distribute.The dry organic phase that concentrates under the vacuum.With EtOAc/CH 2Cl 2(1/9) generates the white solid (189mg, 92%) of 1-(1-ethyl-6-methoxyl group-1-H-indol-3-yl) ethyl ketone oxime through the column chromatography purifying.
Step B: (100mg 0.43mmol) is dissolved in THF (900 μ L) under 0 ℃ with 1-(1-ethyl-6-methoxyl group-1-H-indol-3-yl) ethyl ketone oxime.(450 μ L, 2.5M 1.12mol), form solid precipitation immediately dropwise to add the hexane solution of n-BuLi.DMF (70 μ L, 0.9mol) solution that dropwise add 260 μ L then.Mixture stirs 1h down at 0 ℃, at room temperature stirs 1h then.Reaction mixture transferred to contain 1mL H 2O, 1mL THF and the dense H of 100 μ L 2SO 4Mixture in.This mixture heats 1h down at 75 ℃, uses H then 2O and EtOAc distribute.Dry and concentrated organic phase.Through column chromatography (CH 2Cl 2) purifying generates the white solid (13mg, 12%) of 1-ethyl-3-isoxazole-3-base-6-methoxyl group-1-H-indoles product.
The preparation of embodiment 1N:1-ethyl-3-isoxazole-5-base-6-methoxyl group-1H-indoles (compound 58).
Figure A20078000890205291
Prepare 1-(1-ethyl-6-methoxyl group-1H-indol-3-yl) ethyl ketone (100mg according to the described step of embodiment from 1-ethyl-6-methoxyl group-1H-indoles, 0.46mmol), with itself and 1.5mL dimethylformamide dimethyl acetal and 100 μ L tetramethyleneimine 110 ℃ of following heated overnight.Under vacuum, concentrate dimethylformamide dimethyl acetal then.Resistates is dissolved in again EtOH and the 250 μ L H of 1.25mL 2O, and with oxammonium hydrochloride (66mg 0.95mmol) handles, in 80 ℃ of heating 2h down.Organic phase H 2O and EtOAc distribute, after dry the concentrating, through silica gel chromatography (EtOAc/CH 2Cl 2, 5/95) and purifying generates the white solid (72mg, 66%) of 1-ethyl-3-isoxazole-5-base-6-methoxyl group-1H-indoles.
Use with essentially identical step mentioned above and prepared following compounds: compound 60.
The preparation of embodiment 1O:1-ethyl-6-methoxyl group-3-(2H-pyrazole-3-yl)-1H-indoles (compound 59).
Figure A20078000890205292
Prepare 1-(1-ethyl-6-methoxyl group-1H-indol-3-yl) ethyl ketone (100mg according to the described step of embodiment 1L from 1-ethyl-6-methoxyl group-1H-indoles, 0.46mmol), with itself and 1.5mL dimethylformamide dimethyl acetal and 100 μ L tetramethyleneimine 110 ℃ of following heated overnight.Remove the DMF dimethylacetal under the vacuum.Resistates is dissolved in again in the acetate of 3mL, (70 μ L, 1.38mmol), this mixture heats 2h down at 100 ℃ to add hydrazine hydrate.Remove acetate under the vacuum, with EtOAc and saturated NaHCO 3Distribute resistates.The dry organic phase that concentrates through silica gel chromatography (EtOAc/Hex, 1/1) purified product, generates the colourless semisolid of 1-ethyl-6-methoxyl group-3-(2H-pyrazole-3-yl)-1H-indoles (54%) of 59mg.Through Et 2O grinds and generates white crystalline powder.
Use above-mentioned steps to prepare following compounds: compound 61.
Embodiment 1P:1-ethyl-3-oxazole-5-base-1H-indole-6-carboxylic methyl ester's (compound 72) preparation.
Figure A20078000890205301
Steps A: (900mg 4.45mmol) is dissolved among the DMF (3.3mL) with 1-ethyl-1H-indole-6-carboxylic methyl ester.It is dropwise joined ice-cold POCl 3(430 μ L are in DMF 4.5mmol) (1.5mL) solution.Reaction mixture at room temperature stirred 90 minutes.Use 6N NaOH (3.5ml) to handle this reaction mixture then.Reaction mixture is used H subsequently 2O and ethyl acetate are distributed.Through silica gel chromatography (5-10%EtOAc/CH 2Cl 2) purifying generates 1-ethyl-3-formyl radical-1H-indole-6-carboxylic methyl ester's (985mg, 96%) white solid.
Step B:1-ethyl-3-formyl radical-1H-indole-6-carboxylic methyl ester (100mg, 0.42mmol), TOSMIC (100mg, 0.52mmol), K 2CO 3(178mg, 1.29mmol) and MeOH (the 800 μ L) heating of under 80 ℃, spending the night.Reaction mixture is used H subsequently 2O and ether distribute.Organic phase dry and concentrate after, through silica gel chromatography (EtOAc/CH 2Cl 2, 10/90) and purified product, generation 1-ethyl-3-oxazole-5-base-1H-indole-6-carboxylic methyl ester's (26mg, 23%) off-white color solid.
Embodiment 1Q:1-ethyl-3-oxazole-2-base-1H-indole-6-carboxylic methyl ester's (compound 75) preparation.
Figure A20078000890205302
Steps A: (800mg 3.5mmol) is dissolved in acetone (98mL) to the 1-ethyl-3-formyl radical-1H-indole-6-carboxylic methyl ester that will prepare according to method shown in the embodiment 1P steps A.Add KMnO 4(655mg, H 4.15mmol) 2O (31mL) solution.Reaction mixture at room temperature stirred 90 minutes.Need add KMnO once more 4H (108mg) 2O (6mL) solution and stir once more subsequently 45 minutes with impel the reaction finish.Use 10%H then 2O 2(1.5mL) cancellation reaction mixture.Mixture filters with Celite.Remove filtrate under the vacuum, make its volume be roughly original 1/3.Resistates is with 6N HCl acidifying, and with ethyl acetate extraction.Grind the solid that separates from ethyl acetate layer with acetone, generate 1-ethyl-1H-indoles-3, the greenish orange yellow solid of 6-dicarboxylic acid 6-methyl ester (696mg, 79%).
Step B: with 1-ethyl-1H-indoles-3, (600mg 2.43mmol) is suspended in CH to 6-dicarboxylic acid 6-methyl ester 2Cl 2(27ml) and in the solution of DMF (20 μ L).(470 μ L, 5.38mmol), reaction mixture at room temperature stirred 1 hour to add oxalyl chloride.Then this mixture is slowly poured into the dense NH in the quick stirring 4In OH (10mL) solution.Then it is used H 2O and EtOAc distribute.Use the resistates of acetone grinding, generate the white solid of 6-methoxycarbonyl-1-ethyl-1H-indoles-3-methane amide (511mg, 85%) from ethyl acetate layer.
Step C: (430 μ L, mixture 3.7mmol) is at 125 ℃ of heating 2h down with diglyme (3.6mL) solution of 150mg (0.61mmol) 6-methoxycarbonyl-1-ethyl-1H-indoles-3-methane amide and bromoacetaldehyde dimethylacetal.Reaction mixture is used H 2O and EtOAc distribute.Dry and concentrated organic phase is through silica gel chromatography (EtOAc/CH 2Cl 25-10%) purified product.Merge and the concentrated product that contains each component, use the hexane abrasive solid, generate 1-ethyl-3-oxazole-2-base-1H-indole-6-carboxylic methyl ester's (75mg, 46%) yellow solid.
The preparation of embodiment 1R:1-ethyl-6-methoxyl group-3-thiazol-2-yl-1H-indoles (compound 73).
Figure A20078000890205311
Steps A: (900mg 5.14mmol) is dissolved in DMF (1.5mL) with 1-ethyl-6-methoxyl group-1H-indoles.It is dropwise joined ice-cold POCl 3(500 μ L are in DMF 5.2mmol) (1.75mL) solution.Stir under the room temperature after 90 minutes, reaction mixture on ice bath again, and with slowly cancellation reaction of 6N NaOH (4mL).Reaction mixture EtOAc and H 2O distributes.Through silica gel chromatography (EtOAc/CH 2Cl 2, 5/95) and purifying generates the yellow solid of 1-ethyl-6-methoxyl group-1H-indole-3-formaldehyde (849mg, 81%).
Step B: (600mg 2.95mmol) is dissolved in acetone (85mL) with 1-ethyl-6-methoxyl group-1H-indole-3-formaldehyde.Add KMnO 4(450mg, H 2.85mmol) 2O (28mL) solution.Stirred 5 hours under the room temperature.Add KMnO subsequently again 4(450mg, H 2.85mmol) 2O (25mL) solution.After stirring 1 hour once more under the room temperature, finish reaction.Reaction mixture is with 10%H 2O 2(1.5mL) cancellation reaction is filtered it then with Celite.Remove filtrate under the vacuum, make its volume be roughly original 1/3.Resistates is with 6N HCl acidifying, and with ethyl acetate extraction.Generate crude product through silicagel column (hexane/acetone/acetate, 70/30/1) purifying.Grind the yellow solid that obtains pure 1-ethyl-6-methoxyl group-1H-Indole-3-Carboxylic Acid (365mg, 56%) through ether.
Step C: (250mg 1.14mmol) is suspended in CH with 1-ethyl-6-methoxyl group-1H-Indole-3-Carboxylic Acid 2Cl 2(12.5mL) and in the solution of DMF (10 μ L).(230 μ L, 2.64mmol), reaction mixture at room temperature stirred 1 hour to add oxalyl chloride.Then mixture is slowly poured into the dense NH in the quick stirring 4In OH (5mL) solution.Use H then 2O and EtOAc distribute.Use the resistates of acetone grinding, generate the white solid of 1-ethyl-6-methoxyl group-1H-indoles-3-methane amide (134mg, 54%) from ethyl acetate layer.
Step D: with 1-ethyl-6-methoxyl group-1H-indoles-3-methane amide (120mg, 0.55mmol), La Weisong reagent (240mg, 0.6mmol) and toluene (2mL) at 90 ℃ of following heating 90min.Reaction mixture is through silica gel chromatography (EtOAc/CH 2Cl 2, 1/9) concentrate and purifying, generate the yellow solid of 1-ethyl-6-methoxyl group-1H-indoles-3-thioformamide (92mg, 71%).
Step e: with 1-ethyl-6-methoxyl group-1H-indoles-3-thioformamide (83mg, 0.36mmol), (220 μ L are 1.86mmol) at 80 ℃ of heating 16h for glyme (3.6mL) and bromoacetaldehyde dimethylacetal.Add more bromoacetaldehyde dimethylacetal (250 μ L).It is heated 2h down at 80 ℃.After adding 250 μ L bromoacetaldehyde dimethylacetals once more, heated again 2 hours.Reaction mixture is cooled to room temperature, with silica gel absorb and on silica gel with chromatography (hexane/EtOAc, 7/3) purification reaction mixture, generate the brown oil of 1-ethyl-6-methoxyl group-3-thiazol-2-yl-1H-indoles (44mg, 47%).
Prepare following compounds according to above-mentioned steps: compound 78,101,104,105 and 106.
Embodiment 1S:1-ethyl-6-methoxyl group-2-Phenoxymethyl-1H-indoles-3-nitrile compound 99) preparation.
Figure A20078000890205331
Steps A: in 0 ℃ to LiAlH 4(7.6g, 0.2mol) De diox (100mL) suspension dropwise adds 6-methoxyl group-1H-indole-2-carboxylic methyl ester (8.2g, 0.04mol) De diox (50mL) solution.After the adding, mixture at room temperature stirs 1h, then reflux 5h.After being cooled to 0 ℃, reaction is successively with water (dropping) and the cancellation of the 15%NaOH aqueous solution.After stirring 1h under the room temperature, mixture filters with Celite.With a large amount of EtOAc washing solids.Solvent is with salt water washing, Na 2SO 4After the drying, evaporate under the vacuum.Use EtOAc/ sherwood oil (1/5) as eluent on silica gel through the purified by flash chromatography product, generate 6-methoxyl group-2-Methyl-1H-indole of 61%.
Step B: (3.9g dropwise adds ClSO in solution 24mmol) to the 6-methoxyl group-2-Methyl-1H-indole in acetonitrile (200mL) and DMF (20mL) in 0 ℃ 2NCO (4mL, acetonitrile 1.3eq.) (31mL) solution.After the adding, mixture at room temperature stirs 3h.Be poured into frozen water then, add saturated NaHCO 3, become alkalescence until it.Water is with CH 2Cl 2Extract, subsequently evaporation.Use EtOAc/ sherwood oil (1/5) as eluent on silica gel through the purified by flash chromatography resistates, generate 6-methoxyl group-2-Methyl-1H-indole-3-nitrile of 81%.
Step C: under 0 ℃ to NaH (0.6g, DMF 2eq.) (7mL) suspension add 6-methoxyl group-2-Methyl-1H-indole-3-nitrile (1.3g, DMF 7.0mmol) (8mL) solution, add subsequently iodoethane (1.2mL, 2eq.).After stirring 1h, pour mixture into frozen water, with CH 2Cl 2Extract this mixture.Organic layer is with the salt water washing, and with Na 2SO 4Dry.Vacuum evaporating solvent, with EtOAc/ sherwood oil (1/5) as eluent on silica gel through purified by flash chromatography, generate 1-ethyl-6-methoxyl group-2-Methyl-1H-indole-3-nitrile of 92%.
Step D: to 1-ethyl-6-methoxyl group-2-Methyl-1H-indole-3-nitrile (1.38g, benzene 6.45mmol) (130mL) solution add Benzoyl Peroxide (226mg) and NBS (1.21g, 1.05eq.).Then with mixture reflux 3h.After cooling and the filtration, concentrated filtrate under the vacuum.Crude product 2-brooethyl-1-ethyl-6-methoxyl group-1H-indoles-3-nitrile (1.6g, 86%) need not be further purified when using.
Step e: to NaH (44mg, add in DMF 4eq.) (0.5mL) solution 2-brooethyl-1-ethyl-6-methoxyl group-1H-indoles-3-nitrile (80mg, 0.274mmol) and phenol (2eq.).After stirring 20h, pour mixture into frozen water, and with CH 2Cl 2Extraction.Organic layer is with the salt water washing, and with Na 2SO 4Dry.Evaporating solvent under the vacuum, with EtOAc/ sherwood oil (1/5) as eluent on silica gel through purified by flash chromatography, generate 1-ethyl-6-methoxyl group-2-Phenoxymethyl-1H-indoles-3-nitrile, promptly compound 99.
The preparation of embodiment 1T:6-nitro-2-pyrroles-1-base-1H-indoles-3-nitrile (compound 7).
Figure A20078000890205341
Steps A: use propane dinitrile (5.28 g, 80.0mmol) and salt of wormwood (11.05g, 80.0mmol) processing 2-fluoro-5-nitrophenyl hydrazine (11.7g, 74.9mmol) solution (the Modification ofChem.Heterocyclic Cpd. (Engl.Trans. of dimethyl formamide (120mL), 9 37(2001).Gentle reflux adds the heterogeneity mixture 3h of thermosetting, during cooling is fallen back (500mL).Collect the throw out that forms after filtration, absorb with ethyl acetate (300mL).This solution is through Na 2SO 4Drying is filtered, and the part evaporation generates throw out, and this throw out is collected after filtration.Evaporate once more and filtration obtains second batch of product (crop).Merge two batches of products, it is dry under vacuum, the orange powder of generation 2-amino-1-ethyl-6-nitro-1H-indoles-3-nitrile (7.90g, 52%).
Step B: use 2, (0.30mL, amino-(362mg, acetate 1.79mmol) (5mL) solution is with this solution reflux 14h for 6-nitro-1H-indoles-3-nitrile 2.27mmol) to handle 2-for the 5-dimethoxy-tetrahydrofuran.After being cooled to envrionment temperature, this solution is poured in the water (100mL), added sodium bicarbonate solid, until no longer producing CO 2(2 * 100mL) extractions, extraction liquid is with the salt water washing, after the merging, with MgSO with EtOAc for this mixture 4Drying is filtered and is concentrated.Separate residual substance through silica gel chromatography (EtOAc/ hexane, 1/4), generate the yellow solid of 6-nitro-2-pyrroles-1-base-1H-indoles-3-nitrile (232mg, 51%), promptly compound 5.
The preparation of embodiment 1U:N-(3-cyano group-1-ethyl-6-nitro-1H-indoles-2-yl) ethanamide (compound 25).
Steps A: with hexane wash sodium hydride (60%w/w is suspended in mineral oil for 42mg, 1.05mmol), and with methyl-sulphoxide (1mL) sodium hydride suspension.Methyl-sulphoxide (1mL) solution with syringe adding 2-amino-6-nitro-1H-indoles-3-nitrile (step 1T preparation) stirs 20min with the mixture that forms.Then, (77 μ L 0.96mmol), stir 14h with mixture to add iodoethane with syringe.Then reactant is poured among the EtOAc (50mL), this solution is with water (3 * 50mL) and saturated brine (40mL) washing.Use EtOAc back extraction water, merge organic phase, with Na 2SO 4Drying is filtered and evaporation.Separate residual substance through column chromatography (EtOAc/ hexane, 1/1) on silica gel, at first generate a spot of dialkyl group analogue, next is the purpose compound, being 2-amino-1-ethyl-6-nitro-1H-indoles-3-nitrile (114mg, 52%), is unreacted raw material at last.Separate the purpose product that obtains the orange powder shape.
Step B: use hexane wash sodium hydride (60%w/w is dissolved in mineral oil for 44mg, 1.10mmol), and with 1,4-diox (3mL) absorbs sodium hydride.(120mg, 0.521mmol) De diox (2mL) solution stirs 30min with the mixture that forms to the 2-amino-1-ethyl-6-nitro-1H-indoles-3-nitrile of adding above-mentioned steps B preparation.(45 μ L, 0.63mmol), this solution stirs 12h again then to add Acetyl Chloride 98Min. with syringe then.Reactant water and EtOAc (every part of 20mL) distribute, and organic phase is with the salt water washing.Use ethyl acetate back extraction water successively, merge organic phase, with Na 2SO 4Drying is filtered and evaporation.Use Et 2O grinds the solid that forms, and this solid is collected after filtration, vacuum-drying, and the off-white powder of generation N-(3-cyano group-1-ethyl-6-nitro-1H-indoles-2-yl)-ethanamide (100mg, 71%), promptly compound 25.
Use this step and replace suitable sour chlorine or chloro-formic ester generation following compounds: compound 23,26,35,36,203,204,214,215,216.
The preparation of embodiment 1V:N-ethyl-3-phenyl-5-nitroindoline (compound 41).
Figure A20078000890205361
Steps A: passing to nitrogen and carrying out under the condition of stirring, past-4 ℃ 5-nitroindoline (5.00g, 30.8mmol) pyridine (200mL) solution dropwise added pyridinium bromide hydrobromate (pyridinium bromide perbromide, 10.99g, pyridine 34.3mmol) (200mL) solution.After adding was finished, reaction mixture stirred 5min down at 0 ℃.This reaction mixture is with 0 ℃ of water (200mL) dilution, and with the Et of 200mL 2The O extraction.Organic phase is with 6M HCl (300mL), 5%NaHCO 3(300mL) and salt solution (300mL) washing.Organic phase is with MgSO 4Drying is removed and is desolvated, and generates 80% 3-bromo-5-nitroindoline yellow powder and 20%5-nitroindoline (6.80g, yield 74%).
Step B: remove from top 3-bromo-5-nitroindoline (625mg, 2.1mmol), phenylo boric acid (381mg, 3.13mmol), triphenylphosphine (109.3mg, the gas in glycol dimethyl ether 0.417mmol) (4.16mL) solution.Toward the yellow soda ash (6.25mL) of this mixture adding 2N, remove the gas of reaction mixture once more.To reactant add acid chloride (II) (23.4mg, 0.104mmol), and pass to nitrogen and in addition under the condition of stirring with reactant backflow 8 hours.Reaction mixture dilutes with 1M HCl (100mL) subsequently, and with ethyl acetate extraction (100mL).Organic phase is with water (100mL) and salt solution (100mL) washing.Organic phase is with MgSO 4Dry and concentrated under vacuum.Through silica gel (EtOAc/ hexane, 10/90) chromatography purification crude product, generate the orange powder of 3-phenyl-5-nitroindoline (45mg, yield 9%).
Step C: to the mineral oil of 60%NaH (8.7mg, 0.630mmol) and dropwise add 3-phenyl-5-nitroindoline (40.0mg, DMF 2.1mmol) (0.75mL) solution in DMF (1.0mL) mixture.Reaction mixture is at 0 ℃ and pass to N 2Under stir 20min.(14.8 μ L, 0.185mmol), reaction mixture stirred again 3 hours dropwise to add iodoethane.Reaction mixture dilutes with water (250mL) then, and extracts with EtOAc (30mL).Organic phase is with water (250mL) washing, then with MgSO 4Drying is removed under the vacuum and is desolvated.Obtain required N-ethyl-3-phenyl-5-nitroindoline yellow powder (40.0mg, yield 89.5%).
Prepare following compounds in a similar manner: compound 40.
Embodiment 1W:[3-cyano group-1-(4-p-methoxy-phenyl)-1H-indoles-6-yl]-preparation of carboxylamine propyl ester (compound 97).
Figure A20078000890205371
(30mg 0.12mmol) is suspended among the EtOH (300 μ L) with 6-amino-1-(4-p-methoxy-phenyl)-1H-indoles-3-nitrile.(168 μ L, 1.5mmol), this mixture at room temperature stirs and spends the night to add propyl chloroformate.Add triethylamine (300 μ L), at room temperature stirred once more 1 hour, finish reaction.Directly this reaction mixture is inserted silicagel column, with CH 2Cl 2Wash-out.Need fully purified product [3-cyano group-1-(4-methoxyl group-phenyl)-1H-indoles-6-yl]-carboxylamine propyl ester (19mg, 45%) of another root silicagel column (3/2, ether/hexane), obtain white solid.
Embodiment 1X:N-[4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indoles-2-ethyl-acetylene base)-phenyl]-preparation of sulfonyloxy methyl amine (compound 130).
Figure A20078000890205372
(50mg 0.16mmol) at room temperature is dissolved in the pyridine (550 μ L) 2-(4-aminophenyl the ethynyl)-1-ethyl-6-methoxyl group-1H-indoles-3-nitrile that will prepare according to the described method of embodiment 1H.Dropwise add methylsulfonyl chloride (17 μ L, 0.21mmol).It is at room temperature stirred spend the night.Then reaction mixture is absorbed in ethyl acetate, and successively with the HCl aqueous solution and salt water washing.Dry and concentrated organic layer.Through silica gel chromatography (9/1, CH 2Cl 2/ EtOAc) purifying generates N-[4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indoles-2-ethyl-acetylene base)-phenyl]-the off-white color solid of sulfonyloxy methyl amine (58mg, 92%).
Step shown in using above is substituted suitable amino-benzene Ethynylindole and SULPHURYL CHLORIDE and prepares following compounds: compound 131,132,208,209 and 210.
Embodiment 1Y:N-[4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indoles-2-yl)-phenyl]-preparation of sulfonyloxy methyl amine (compound 129).
Figure A20078000890205381
Will be according to 2-(4-the aminophenyl)-1-ethyl-6-methoxyl group-1H-indoles-3-nitrile (70mg of embodiment 1Ga step B preparation, 0.24mmol) THF (3mL) solution be cooled to 0 ℃, and with triethylamine (0.04mL, 0.31mmol) and methylsulfonyl chloride (0.02mL, 0.29mmol) handle and stir, spending the night is warming up to room temperature.Reaction mixture is used H subsequently 2O dilutes, and extracts with ethyl acetate (3X).Organic phase is with H 2O and saturated NaCl washing, after dry the concentrating, use EtOAc/ hexane (30-50%) through purified by flash chromatography, generate N-[4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indoles-2-yl)-phenyl of 60 mg (68%)]-the brown solid of sulfonyloxy methyl amine.
Use step same as described above substantially and replace suitable amino-benzene indoles and SULPHURYL CHLORIDE, or in the pyridine as alkali and solvent, react, generate following compounds: compound 83,85,86,87,88,243,251,252,272,273,287,289,365,366,367,368,369,370,371,394,439,440,448,449,451,452,477,487,488,495,505,510,548,549,550,551,552,562,563,598,599,601,602,608,609,610,615,616,617,621,622,623,629,630,631,639,655,657,658,662,669,670,671,674,675,701,702,703,706,707,708,709,710,711,713,715,720,789,790,791,850,851,867,868,890,891,912,919,920,921,922,923,924,932,933,934,935,941,953,968,982,988,990,995,996,997,998,1035,1038,1041,1103,1105,1115,1116,1117,1123,1140,1 141,1155,1160,1161,1170,1175,1181,1182,1188,1189,1228,1229,1230,1231,1280.
Embodiment 1Za:N-[4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indoles-2-ethyl-acetylene base)-phenyl]-preparation of ethanamide (compound 138).
Figure A20078000890205391
(95mg 0.29mmol) is dissolved among the THF (1.4mL) 2-(4-amino-benzene the ethynyl)-1-ethyl-6-methoxyl group-1H-indoles-3-nitrile that will prepare according to the described method of embodiment 1H.Add triethylamine (84 μ L, 0.6mmol), dropwise add subsequently Acetyl Chloride 98Min. (44 μ L, 0.5mmol).It is at room temperature stirred 1h.Reaction mixture EtOAc and H 2O distributes.Dry and concentrated organic layer.Through silica gel chromatography (9/1, CH 2Cl 2/ EtOAc) purifying generates N-[4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indoles-2-ethyl-acetylene base)-phenyl]-yellow solid of ethanamide (103mg, 96%).
Step shown in using above is substituted suitable amino-benzene Ethynylindole and acyl chlorides and prepares following compounds: compound 82,139,152,153,162,163,165,167,205,206,207,211,212,213,219,224,225,228.
Embodiment 1Zb:N-[4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indoles-2-ethyl-acetylene base)-phenyl]-preparation of methane amide (compound 241).
Diacetyl oxide (2.5mL) and 98% formic acid (1.0mL) were heated 1 hour down at 65 ℃.It is cooled to 0 ℃.(100mg 0.32mmol) is absorbed in THF (1.2mL), and joins in first and second acid anhydride mixtures 2-(4-amino-benzene the ethynyl)-1-ethyl-6-methoxyl group-1H-indoles-3-nitrile that will prepare according to embodiment 1H.It was stirred 30 minutes at 0 ℃.Reaction mixture is used H subsequently 2O and EtOAc distribute.Use saturated NaHCO successively 3With saturated brine washing EtOA layer.Dry and concentrated organic layer.Through silica gel chromatography (4/1, CH 2Cl 2/ EtOAc) purifying generates N-[4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indoles-2-ethyl-acetylene base)-phenyl]-yellow solid of methane amide (105mg, 96%).
Prepare following compounds according to method similar to the above: compound 218.
Embodiment 1AA:N-[4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indoles-2-yl)-phenyl]-preparation of ethanamide (compound 128).
Figure A20078000890205401
Will be according to 2-(4-the aminophenyl)-1-ethyl-6-methoxyl group-1H-indoles-3-nitrile (70mg of embodiment 1Ga step B preparation, 0.24mmol) THF (3mL) solution be cooled to 0 ℃, with triethylamine (0.04mL, 0.31mmol) and Acetyl Chloride 98Min. (0.02mL, 0.29mmol) handle and stir, spending the night is warming up to room temperature.Use H then 2The O diluted reaction mixture, and extract with ethyl acetate (3X).Organic phase is with H 2O and saturated NaCl washing after dry the concentrating, uses EtOAc/ hexane (30-50%) through purified by flash chromatography, generates N-[4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indoles-2-yl)-phenyl of 57mg (71%)]-the brown solid of ethanamide.
Use and above-mentioned essentially identical step and suitable amino-benzene indoles and the acyl chlorides of replacement, preparation following compounds: compound 81,242,244,324,325,326,327,328,329,330,383,420,421,422,423,424,425,544,558,559,560,561,565,566,567,644,645,646,755,756,757,759,760,761,762,763,764,765,766,798,799,801,802,803,804,854,855,856,857,858,859,895,896,897,898,899,900,901,913,914,915,916,983.
Embodiment 1AB:1-[3-(3-cyano group-1-ethyl-6-methoxyl group-1H indoles-2-ethyl-acetylene base) phenyl]-preparation of 3-ethyl urea (compound 220).
(100mg 0.32mmol) is dissolved in the pyridine (670 μ L) 2-(3-amino-benzene the ethynyl)-1-ethyl-6-methoxyl group-1H-indoles-3-nitrile that will prepare according to the described method of embodiment 1H.The adding ethyl isocyanate (62 μ L, 0.75mmol).Reaction mixture heats 2h down at 100 ℃ subsequently.Mixture dilutes with EtOAc subsequently, and successively with the HCl aqueous solution and salt water washing.Dry and concentrated organic layer.Earlier after silica gel chromatography (4/1, CH 2Cl 2/ EtOAc) purifying and grind through hexane/acetone (1/1) generates 1-[3-(3-cyano group-1-ethyl-6-methoxyl group-1H-indoles-2-ethyl-acetylene base)-phenyl]-white solid of 3-ethyl urea (44mg, 36%).
Embodiment 1AC:1-(2-chloroethyl)-3-[4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indoles-2-ethyl-acetylene base)-phenyl] preparation of urea (compound 156).
Figure A20078000890205411
(100mg 0.32mmol) is suspended in the toluene (600 μ L) 2-(4-amino-benzene the ethynyl)-1-ethyl-6-methoxyl group-1H-indoles-3-nitrile that will prepare according to the described method of embodiment 1H.(32 μ L, 0.37mmol), this mixture heats 5h down at 100 ℃ to add 2-isocyanic acid chloroethene ester.Reaction mixture then with acetone diluted, and absorbs with silica gel.Through the column chromatography (CH of 5-10%EtOAc 2Cl 2Solution) purifying generates 1-(2-chloro-ethyl)-3-[4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indoles-2-ethyl-acetylene base)-phenyl] yellow solid of urea (73mg, 54%).
Use above-mentioned steps to prepare following compounds: compound 221.
Embodiment 1AD: the preparation of ethyl sulfonic acid [4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indoles-2-ethyl-acetylene base)-phenyl] methane amide (compound 157).
Figure A20078000890205412
Will be according to N-[4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indoles-2-ethyl-acetylene base) phenyl of embodiment 1X preparation] and ethyl sulfonamide (70mg, 0.17mmol) and K 2CO 3(49mg, 0.35mmol) and DMF (1.0mL) mix.(16 μ L, 0.26mmol), reaction mixture at room temperature stirred 1 hour to add methyl iodide.Reaction mixture dilutes with EtOAc subsequently, and successively with H 2O and salt water washing.Dry and concentrated organic layer.Through silica gel chromatography (95/5, CH 2Cl 2/ EtOAc) purifying generates light brown brown solid.Obtain the orange white solid of ethyl sulfonic acid [4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indoles-2-ethyl-acetylene base)-phenyl] methane amide (61mg, 85%) through grinding.
Use above-mentioned steps to be substituted suitable sulphonamide and prepare following compounds: compound 182,652,840.
Embodiment 1AE:1-ethyl-5-methoxyl group-2-[4-(morpholine-4-carbonyl)-phenyl]-preparation of 1H-indoles-3-nitrile (compound 245)
Figure A20078000890205421
Steps A: will according to methyl 4-(3-cyano group-1-ethyl-5-methoxyl group-1H-indoles-2-yl)-benzoic ether of embodiment 1Ga step B preparation (350mg, 1.05mmol) with NaOH (40mg, 1mmol), H 2O (0.8mL) and THF (3.4mL) mix, and it was heated 1 hour down at 80 ℃.Reaction mixture is with H 2The O dilution is washed with ether then.Use HCl acidified aqueous solution aqueous phase layer, and aqueous phase layer is extracted to EtOAc.The organic layer drying obtains the pure white solid of 4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indoles-2-yl)-phenylformic acid (311mg, 92%) with concentrated.
Step B: (3-cyano group-1-ethyl-6-methoxyl group-1H-indoles-2-yl)-(50mg 0.16mmol) is suspended in CH to phenylformic acid with 4- 2Cl 2(2.2mL) and rise among the DMF (2 μ L) of katalysis.The adding oxalyl chloride (22 μ L, 0.25mmol).Reaction mixture at room temperature stirred 1 hour, and it is fully dissolved.Reaction mixture is dropwise joined the CH of the morpholine (1.0mL) that is in the vigorous stirring 2Cl 2(5ml) solution.After adding is finished, use HCl solution washing reaction mixture.Dry and concentrated organic layer.Through silicagel column (1: 1 CH 2Cl 2/ EtOAc) purifying generates 1-ethyl-6-methoxyl group-2-[4-(morpholine-4-carbonyl)-phenyl]-white solid of 1H-indoles-3-nitrile (56 mg, 90%).
Prepare following compounds according to method similar to the above: compound 113,114,246,270,271,290,291,292,323,377,378,379,380,381,382,384,385,386,387,388,389,390,391,392,432,433,564,568,569,570,571,572,573,647,648,853,860,861,862.
Embodiment 1AF: the preparation of cyclopropyl carboxylic acid [4-(3-cyano group-1-ethyl-6-hydroxyl-1H-indoles-2-ethyl-acetylene base)-phenyl] acid amides (compound 194).
Figure A20078000890205431
Will [4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indoles-2-ethyl-acetylene base)-phenyl]-(60mg be 0.16mmol) at BBr for acid amides according to the cyclopropyl carboxylic acid of embodiment 1Za preparation 3CH 2Cl 2(800 μ L, 1M stirred under room temperature 1 hour in 0.8mmol) solution.Reaction mixture is with H 2O cancellation reaction, and with CH 2Cl 2Extract.Dry and concentrated organic layer.Obtain impure product through silica gel chromatography (EtOAC) purifying.Use 1/1 hexane/acetone to grind this crude product, generate the off-white color solid of cyclopropyl carboxylic acid [4-(3-cyano group-1-ethyl-6-hydroxyl-1H-indoles-2-ethyl-acetylene base)-phenyl]-acid amides (32mg, 54%).
Use above-mentioned steps to be substituted suitable sulphonamide (from embodiment 1X) or acid amides (from embodiment 1Z) preparation following compounds: compound 164,168,183,193,195.
Embodiment 1AG:1-ethyl-6-methoxyl group-2-[4-(2-oxo-imidazolidine-1-yl)-phenylacetylene base]-preparation of 1H-indoles-3-nitrile (compound 166).
Will be according to 1-(2-chloroethyl)-3-[4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indoles-2-ethyl-acetylene the base)-phenyl of embodiment 1AC preparation] and urea (55 mg, 0.13mmol) and K 2CO 3(50mg, 0.36mmol) and DMF (550 μ L) mix.Mixture at room temperature stirred 3 hours.Reaction mixture dilutes with EtOAc, and successively with H 2O and salt water washing.Dry and concentrated organic layer.Through silicagel column (10-50%, EtOAc/CH 2Cl 2) purifying generates 1-ethyl-6-methoxyl group-2-[4-(2-oxo-imidazolidine-1-yl)-phenylacetylene base]-white solid of 1H-indoles-3-nitrile (47mg, 94%).
Use above-mentioned steps to be substituted suitable urea and prepare following compounds: compound 222.
Embodiment 1AH:N-[4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indoles-2-ethyl-acetylene base)-phenyl]-preparation of dimethyl time phosphamide (compound 227).
Figure A20078000890205441
(100mg 0.32mmol) is dissolved under 0 ℃ in the pyridine (300 μ L) 2-(3-aminophenyl the ethynyl)-1-ethyl-6-methoxyl group-1H-indoles-3-nitrile that will prepare according to the described method of embodiment 1H.Add dimethyl time phosphoryl chloride (60mg, THF 0.53mmol) (300 μ L) solution.Reactant at room temperature stirred 2 hours.Reaction mixture dilutes with EtOAc, and successively with the HCl aqueous solution and salt water washing.Dry and concentrated organic layer.Generate N-[4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indoles-2-ethyl-acetylene base)-phenyl through silica gel chromatography (acetone) purifying]-dimethyl time phosphamide (65mg, 52%), i.e. the pure white solid of compound 227.Use 9/1 CH then 2Cl 2/ MeOH washes silicagel column, obtains N-[4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indoles-2-ethyl-acetylene base)-phenyl of 9mg]-by product of two-(dimethyl time phosphorus) acid amides.
Embodiment 1AI:1-ethyl-6-methoxyl group-3-[5-(4-p-methoxy-phenyl)-isoxazole-3-bases]-preparation of 1H-indoles (compound 116)
Steps A: use N-chlorosuccinimide (0.12g, 0.92mmol) and pyridine (0.04mL, 0.46mmol) handle 1-ethyl-6-methoxyl group-1H-indole-3-carbaldehyde oxime (0.20g according to the aldehyde precursor preparation of embodiment 1R, 0.92mmol) the mixture of ethylene dichloride (3mL), stir 1h under the room temperature.Then reaction mixture is poured into H 2Among the O, and carrying out acidifying with 1NHCl, is 2 until pH.With EtOAc extraction mixture, organic phase is then with H 2O and saturated NaCl washing, the mixture of dry simmer down to chlorine oxime, the chlorine oxime need not purifying, can be directly used in subsequent step.
Step B: will be dissolved in CH according to the chlorine oxime of above preparation 2Cl 2(5mL), in this mixture, add under 0 ℃ 4-anisole acetylene (0.24g, 1.84mmol) and triethylamine (0.25mL 1.84mmol), then with the reactant stirred overnight, makes it be warming up to room temperature.Reactant is subsequently with H 2O dilutes, and extracts with EtOAc (3X).Organic phase is with H 2O and saturated NaCl washing, dry and concentrated.Through silica gel chromatography (the EtOAc/ hexane 10-20%) generates 1-ethyl-6-methoxyl group-3-[5-(4-methoxyl group-phenyl)-isoxazole-3-bases of 76mg (24%)]-the brown solid of 1H-indoles.
Embodiment 1AJ:[4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indoles-2-yl)-phenyl]-preparation of urethanum (compound 121).
Figure A20078000890205451
Prepare 2-(4-amino-phenyl)-1-ethyl-6-methoxyl group-1H-indoles-3-nitrile (70mg, 0.24mmol) (according to the step B preparation of embodiment 1Ga) and Vinyl chloroformate (0.03mL, EtOAc 0.29mmol) (3mL) and saturated NaHCO down at 0 ℃ 3(3mL) biphase mixture of solution makes it be warming up to room temperature, and stirs 24h.Reactant is subsequently with H 2O dilutes, and extracts with EtOAc (2X).Organic phase is with H 2O and saturated NaCl washing are dried then and concentrate.Generate the off-white color solid of [4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indoles-2-yl)-phenyl]-urethanum of 48mg (55%) through flash chromatography (EtOAc/ hexane 20-40%).
Prepare following compounds in a similar way: compound 122,293,294,296,297,298,299,300,301,302,303,304,305,306,307,308,309,310,311,312,313,314,315,316,317,318,319,320,321,349,350,351,352,353,354,355,356,357,358,359,360,361,372,434,435,450,453,454,455,457,485,486,489,490,500,501,502,503,506,507,508,509,545,546,547,553,554,555,556,557,581,582,583,584,585,585,586,587,588,589,590,591,592,593,594,595,596,597,603,604,605,606,607,618,619,624,625,637,640,641,664,665,676,677,721,722,723,734,735,736,737,738,739,744,745,746,747,787,788,792,793,794,795,796,797,819,822,823,824,825,826,849,925,926,945,946,947,948,949,950,951,970,971,972,973,974,975,976,977,978,979,981,984,985,986,991,992,993,1015,1020,1021,1022,1029,1030,1031,1032,1033,1034,1037,1040,1042,1044,1055,1056,1057,1058,1059,1062,1063,1064,1065,1071,1073,1074,1075,1077,1078,1079,1107,1109,1111,1112,1113,1114,1122,1127,1128,1129,1145,1148,1149,1150,1151,1152,1153,1154,1169,1174,1176,1177,1178,1179,1180,1186,1193,1194,1195,1196,1197,1198,1199,1200,1201,1202,1203,1204,1205,1206,1207,1211,1222,1232,1233,1300,1302.
The preparation of embodiment 1AK:1-ethyl-5-thiene-3-yl--1H-indoles-3-nitrile (compound 141).
Figure A20078000890205461
With 5-bromo-1-ethyl-1H-indoles-3-nitrile (100mg, 0.40mmol), thiophene-3-boric acid (72mg, 0.56mmol), PdCl 2(PPh 3) 2(11mg, 0.016mmol) and CsF (152mg 1mmol) joins in the same test tube, and the exhaust and fill nitrogen (3X) of hocketing then, and with glycol dimethyl ether (3mL) dilution is then at 90 ℃ of heating 19h down.After the cooling, crude product mixture is with saturated NaHCO 3Dilute, and extract with EtOAc (2X).The organic phase that merges is washed with saturated NaCl, and is dry and concentrated.Through silica gel (CH 2Cl 2/ hexane, 40/60) flash chromatography obtains the white solid of 1-ethyl-5-thiene-3-yl--1H-indoles-3-nitrile of 25mg (25%).
Prepare following compounds in a similar way: compound 140 and 142.
Embodiment 1AL:N-[4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indoles-2-yl)-phenyl]-preparation of N-methyl-sulfonyloxy methyl amine (compound 180).
Figure A20078000890205462
Use NaH (21mg 0.53mmol) handles N-[4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indoles-2-yl)-phenyl for preparing according to embodiment 1Y] (130mg, DMF 0.35mmol) (10mL) solution stirs 10min under the room temperature to sulfonyloxy methyl amine.(0.03mL, 0.53mmol), this mixture at room temperature stirs 18h to add methyl iodide.Use H then 2The O diluted reaction mixture, and extract with EtOAc (2X).Organic phase is with H 2O and saturated NaCl washing, dry then and concentrated.Through silica gel (EtOAc/CH 2Cl 2, 0-1%) purified by flash chromatography obtains N-[4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indoles-2-yl)-phenyl of 60mg (45%)]-white solid of N-methyl sulphonamide.
Prepare following compounds in a similar manner: compound 181,642,643,672,673,816,852,1002,1003,1004,1005,1006,1007.
Embodiment 1AM:N-[4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indoles-2-yl)-phenyl]-preparation of sulfonyloxy methyl amine (compound 189).
Figure A20078000890205471
With N-[4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indoles-2-yl)-phenyl] sulfonyloxy methyl amine (85mg, CH 0.23mmol) 2Cl 2(2mL) solution is cooled to-5 ℃.The CH that adds boron tribromide 2Cl 2(1.15mL, 1.15mmol 1M), make reaction mixture be warming up to 10 ℃ in 4h to solution.Pour reaction mixture into H 2Among the O, and extract with EtOAc (3X).The organic phase that merges is with H 2O and saturated NaCl washing, dry and concentrated.Through silica gel (EtOAc/CH 2Cl 2, 5-10%) purified by flash chromatography obtains N-[4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indoles-2-yl)-phenyl of 18mg (22%)]-the brown solid of sulfonyloxy methyl amine.
Prepare following compounds in a similar manner: compound 190,191,192.
The preparation of embodiment 1AN:3-[5-(3-cyano group-6-methoxyl group-1H-indoles-2-yl)-[1,2,4] oxadiazole-3-yl] methyl benzoate (compound 226).
Figure A20078000890205472
Steps A: to the 6-methoxyl group-1H-indoles-3-nitrile of foundation previous embodiment preparation (5.88g, 40mmol) and (Boc) 2O (9.59g, add in the mixture of DCM 44.0mmol) (50mL) solution DMAP (0.10g, 0.8mmol).Mixture at room temperature stirs 48h, handles with water (30mL) then, and with anhydrous Na 2SO 4Dry.Crude product separates (hexane/EtOAc, 7/1) through silica gel chromatography and generates required intermediate, i.e. 3-cyano group-6-methoxyl group indoles-1-carboxylic acid tert-butyl ester (8.48g, 86%).
Step B: with above-mentioned intermediate (2.72g 10.0mmol) is dissolved in anhydrous THF (20mL), is cooled to-78 ℃, add subsequently LDA (the single THF of 1.5M is dissolved in hexanaphthene, 10.0mL, 15mmol).After stirring 45min, feed the CO of 2h 2Gas.Make mixture return to room temperature then, remove under the vacuum and desolvate, resistates is with water treatment, and is acidified to pH=2 with 6N HCl.The collecting precipitation thing washes with water, and drying obtains acid intermediate 3-cyano group-6-methoxyl group-indoles-1, the 2-dicarboxylic acid 1-tert-butyl ester (2.40g, 73%).
Step C: Zhi Bei 3-cyano group-6-methoxyl group indoles-1 upward, the 2-dicarboxylic acid 1-tert-butyl ester (474mg, 1.5mmol) and HOBt (200mg, 1.5mmol) DCE/DMF (10mL/1mL) solution in add DCC (310mg successively, 1.5mmol) and 3-(N-hydroxy formamidine base) benzoic acid methyl ester (291mg, 1.5mmol).This mixture at room temperature stirred 2 hours, filtered then.Collect filtrate, use the chlorobenzene replace solvents, heat 48h down at 150 ℃ subsequently.After being cooled to room temperature, removing under the vacuum and desolvate, resistates is through silica gel chromatography (CH 2Cl 2/ EtOAc, 8/2) generate intermediate 3-cyano group-6-methoxyl group-2-[3-(3-methoxycarbonyl phenyl)-[1,2,4] oxadiazole-5-yl]-indoles-1-carboxylic acid tert-butyl ester, its DCM with 50%TFA (10.0mL) solution is at room temperature handled 1h.After removing volatile matter under the vacuum, resistates is suspended in water, and with K 2CO 3Neutralization generates purpose product 3-[5-(3-cyano group-6-methoxyl group-1H-indoles-2-base-) [1,2,4] oxadiazole-3-yl] methyl benzoate, i.e. compound 226 (350mg, 62%).
The preparation of embodiment 1AO:1-ethyl-2-(4-methylsulfonyl phenyl)-6-methoxyl group-1H-indoles-3-nitrile (compound 265)
Figure A20078000890205481
Use a metachloroperbenzoic acid (Aldrich,＜77%, 0.26g) handle 1-ethyl-6-methoxyl group-2-(4-methylthio group phenyl)-1H-indoles-3-nitrile (0.12g, CH 0.37mmol) 2Cl 2(5mL) solution, reactant at room temperature stir 10h.Reactant is subsequently with H 2O and saturated NaHCO 3Dilution, and with the EtOAc extracting twice.Organic phase NaHCO 3(3X) with saturated NaCl washing, drying is concentrated into black semisolid.Make crude product stream through being covered with the 5g silicagel column of 1g alkali alumina, carry out flash chromatography (EtOAc/CH2Cl2,0-3%) purifying, the off-white color solid of 1-ethyl-6-methoxyl group-2-(4-methylsulfonyl phenyl)-1H-indoles-3-nitrile of generation 72mg (55%).
Embodiment 1AP:N-{4-[3-cyano group-1-ethyl-6-(2-morpholine-4-base-oxyethyl group)-1H-indoles-2-yl]-phenyl } preparation of sulfonyloxy methyl amine (compound 478).
Figure A20078000890205491
With N-{4-[6-(2-chloroethoxy)-3-cyano group-1-ethyl-1H-indoles-2-yl]-phenyl } sulfonyloxy methyl amine (90mg, 0.21mmol), morpholine (0.06mL, 0.65mmol), NaI (32mg, 0.21mmol) and diisopropyl ethyl amine (0.06mL, CH 0.32mmol) 3CN (2mL) solution heats 25h down in 100 ℃ in sealed tube.After reaction mixture is cooled to room temperature, use H 2O dilutes, and extracts with EtOAc (3X).The organic phase that merges is washed with saturated NaCl, and is dry and concentrated.Thick solid grinds and filters through EtOAc, generates N-{4-[3-cyano group-1-ethyl-6-(2-morpholine-4-base-oxyethyl group)-1H-indoles-2-yl of 41mg (41%)]-phenyl } the brown solid of sulfonyloxy methyl amine.
Prepare following compounds in a similar manner: compound 479,480,481,482,496,497 and 498.
The preparation of embodiment 1AQ:2-morpholine-4-base-ethyl sulfonic acid [4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indoles-2-yl)-phenyl] acid amides (compound 653).
Figure A20078000890205492
Steps A: at room temperature dropwise add chloroethyl SULPHURYL CHLORIDE (0.38mL, 3.66mmol) handle 2-(4-aminophenyl)-1-ethyl-6-methoxyl group-1H-indoles-3-nitrile (0.82mg, pyridine 2.82mmol) (10mL) solution according to embodiment 1Ga step B preparation.After stirring 4h, use frozen water cancellation reaction mixture, add the 6N HCl of capacity, make pH drop to 2.With hot EtOAc (3X) extraction suspension.Organic phase is subsequently successively with 1N HCl, H 2O and saturated NaCl washing, dry and concentrate after, generate the greenish orange yellow solid of vinyl sulfonic acid [4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indoles-2-yl)-phenyl] acid amides, this product need not purifying can be directly used in subsequent step.
Step B: the vinyl sulfonic acid that will above prepare (ethenesulfonic acid) [4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indoles-2-yl)-phenyl] acid amides (70mg, 0.18mmol), morpholine (0.05mL, CH 0.55mmol) 3The suspension returning heating 1.5h of CN (1.5mL) solution.After being cooled to room temperature, the concentration response thing, through flash chromatography on silica gel method (acetone/EtOAc, 2/98) purifying resistates, generate the brown foam thing of 2-morpholine-4-base-ethyl sulfonic acid [4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indoles-2-yl)-phenyl] acid amides of 89mg (100%).
Prepare following compounds in a similar manner: compound 654.
The preparation of embodiment 1AR:2-morpholine-4-base-ethyl sulfonic acid [4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indoles-2-yl)-phenyl] methyl nitrosourea (compound 668).
Figure A20078000890205501
Use K 2CO 3(35mg, 0.26mmol) and methyl-iodide (0.02mL, 0.26mmol) 2-morpholine-4-base-ethyl sulfonic acid [4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indoles-2-yl)-phenyl] acid amides (60mg, DMF 0.13mmol) (3mL) solution of Processing Example 1AQ preparation.Stir 1.5h under the room temperature, reaction mixture is with H 2O dilutes, and extracts with EtOAc (2X).Organic phase H 2O (3X) and saturated NaCl washing are carried out drying subsequently and are concentrated the generation resistates.(acetone/EtOAc, 0-2%) flash chromatography generates the off-white color solid of 2-morpholine-4-base-ethyl sulfonic acid [4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indoles-2-yl)-phenyl] methyl nitrosourea of 31mg (50%) through silica gel.
Prepare following compounds in a similar manner: compound 684,685,686,687,688,689,690,691,692,693,694,695,696,697,698.
Embodiment 1AS:2-[4-(1,1-dioxo-1 6-isothiazolidine-2-yl) phenyl]-preparation of 1-ethyl-6-methoxyl group-1H-indoles-3-nitrile (compound 84).
Steps A: (1.45mL 11.9mmol) handles 2-(4-aminophenyl)-1-ethyl-6-methoxyl group-1H-indoles-3-nitrile (2.78g, pyridine 9.55mmol) (40mL) solution for preparing according to embodiment 1Ga step B dropwise to add 3-chlorine third SULPHURYL CHLORIDE.Reactant makes pH reduce to 2 with the 6N HCl dilution of water and capacity.Reaction mixture extracts with EtOAc (3X), the organic layer that merges is subsequently successively with 1N HCl, water and saturated NaCl washing, carry out drying and concentrated subsequently, generate the brown foam thing of 3-chloropropane-1-sulfonic acid [4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indoles-2-yl)-phenyl] acid amides of 3.9g (95%), it can be directly used in subsequent step.
Step B: use K 2CO 3(3.65g, DMF 2.33mmol) (100mL) solution heat 2h with it down at 70 ℃ to handle 3-chloropropane-1-sulfonic acid [4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indoles-2-yl)-phenyl] acid amides that above prepares.After being cooled to room temperature, reaction mixture is with H 2The O dilution, and with hot EtOAc extraction three times.The organic layer H of heat 2O (3X) and saturated NaCl washing, drying is concentrated into solid.Grind (CH 2Cl 2/ hexane) after, and the 2-[4-of generation 2.27g (68%) (1,1-dioxo-1 6-isothiazolidine-2-yl) phenyl]-the light brown solid of 1-ethyl-6-methoxyl group-1H-indoles-3-nitrile.
Prepare following compounds in a similar way: compound 649,775,809,969,980.
Embodiment 1AT:2-[4-(1,1-dioxo-1 6-isothiazolidine-2-yl) phenyl]-preparation of 1-ethyl-6-methoxyl group-1H-indoles-3-nitrile (compound 666).
Figure A20078000890205512
Steps A:, use 1M BBr according to the steps A of embodiment 1B 3CH 2Cl 2Solution-15 ℃ handle down 2-[4-(1,1-dioxo-1 6-isothiazolidine-2-yl) phenyl]-1-ethyl-6-methoxyl group-1H-indoles-3-nitrile, be poured into frozen water then, behind the filtration drying, obtain being close to quantitative yield 2-[4-(1,1-dioxo-1 6-isothiazolidine-2-yl) phenyl]-1-ethyl-6-hydroxyl-1H-indoles-3-nitrile.
Step B: according to the step B of embodiment 1B, reflux 2-[4-(1,1-dioxo-1 6-isothiazolidine-2-yl) phenyl]-1-ethyl-6-hydroxyl-1H-indoles-3-nitrile, K 2CO 3, 2-iodopropane and methyl ethyl ketone are through flash chromatography (EtOAc/CH 2Cl 2, 0-2%) after, generate 61% 2-[4-(1,1-dioxo-1 6-isothiazolidine-2-yl) phenyl]-the off-white color solid of 1-ethyl-6-isopropoxy-1H-indoles-3-nitrile.
Prepare following compounds in a similar manner: compound 667,699.
Embodiment 1AU:2-[4-(1,1-dioxo-1 6-isothiazolidine-2-yl) phenyl]-preparation of 1-ethyl-6-(2-morpholine-4-base-oxyethyl group)-1H-indoles-3-nitrile (compound 729).
Will according to the 2-[4-of the preparation of embodiment 1AT above (1, the 1-dioxo- 1 6-isothiazolidine-2-yl) phenyl]-1-ethyl-6-hydroxyl-1H-indoles-3-nitrile (70mg, 0.25mmol), K 2CO 3(75mg, 0.51mmol), sodium iodide (27mg, 0.18mmol), 4-(2-chloroethyl) alkylbenzyldimethylasaltsum saltsum acidulants (42mg, the mixture of methyl ethyl ketone 0.25mmol) (3mL) solution in sealed tube in 100 ℃ of down heating.After 13 hours, add DMF (3mL), reactant heats 6h again in addition.Afterwards, add 4-(2-chloroethyl) the alkylbenzyldimethylasaltsum saltsum acidulants of 42mg and the K of 135mg 2CO 3, reactant heats 6h again to finish reaction.After reaction mixture is cooled to room temperature, dilute with water, and extract with EtOAc (3X).The organic phase that merges is carried out drying and concentrated subsequently with water (2X) and saturated NaCl washing.Through flash chromatography (MeOH/CH 2Cl 2, 0-6%) obtain pure 2-[4-(1,1-dioxo-1 6-isothiazolidine-2-yl) phenyl]-the brown solid of 1-ethyl-6-(2-morpholine-4-base-oxyethyl group)-1H-indoles-3-nitrile (29mg, 34%).
Prepare following compounds in a similar manner: compound 728 and 730.
Embodiment 1AV:2-[4-(2,5-dioxo-imidazolidine-1-yl)-phenyl]-preparation of 6-oxyethyl group-1-ethyl-1H-indoles-3-nitrile (compound 779).
Figure A20078000890205531
Steps A: use isocyanide ethyl acetoacetic acid ethyl ester (0.25mL, 2.12mmol) handle 2-(4-aminophenyl)-6-oxyethyl group-1-ethyl-1H-indoles-3-nitrile (585mg, 1.92mmol) 1,4-diox (10 mL) solution, formed solution refluxed overnight heating.Cooling solution desolvates through revolving to steam to remove.Use ether grinding residues matter, collect the precipitation that forms after filtration, dry under vacuum, generate compound 773 (587mg, 1.35mmol, 70%).
Use similar step to prepare 2-{3-[4-(3-cyano group-6-oxyethyl group-1-ethyl-1H-indoles-2-yl)-phenyl]-urea groups }-3-phenyl-methyl propionate (compound 777).
Step B: the trimethyl carbinol (0.30mL that uses potassium tert.-butoxide, 1.0M, 0.30mmol) the solution-treated ethyl 3-[4-(3-cyano group-6-oxyethyl group-1-ethyl-1H-indoles-2-yl)-phenyl]-urea groups }-ethyl acetate (compound 773,101mg, 0.232mmol) THF (10mL) solution, the mixture that stirred overnight forms.Reactant water and ethyl acetate (every part of 50mL) are distributed, and organic phase is washed with saturated brine.Use more ethyl acetate extraction water, combining extraction liquid with anhydrous magnesium sulfate drying, filters and evaporation.Residual substance separates with column chromatography (2/1 ethyl acetate/hexane is wash-out on silica gel 60), obtain 2-[4-(2,5-dioxo-imidazolidine-1-yl)-phenyl]-6-oxyethyl group-1-ethyl-1H-indoles-3-nitrile, it is compound 779, be further purified compound 779 (76mg through ether grinding, filtration collection and high vacuum drying, 0.196mmol, 84%).
Embodiment 1AW:2-[4-(2,4-dioxo-imidazolidine-1-yl)-phenyl]-preparation of 6-oxyethyl group-1-ethyl-1H-indoles-3-nitrile (compound 776).
Figure A20078000890205532
Use chloroacetyl isocyanate (0.10mL, 1.17mmol) handle 2-(4-aminophenyl)-6-oxyethyl group-1-ethyl-1H-indoles-3-nitrile (319mg, 1.04mmol) 1, the heating of under 60 ℃, spending the night of 4-diox (3mL) solution, formed solution.Cooling solution, and adding DBU (0.20mL, 1.31mmol).Mixture is stirred overnight at ambient temperature, and water and ethyl acetate (every part of 50mL) are distributed then.Organic layer washs with saturated brine, then with anhydrous magnesium sulfate drying, filters and evaporation.Use ether grinding residues matter, collect the solid that forms after filtration, after the drying, generate target product (319mg, 0.821mmol, 79%) under the high vacuum.
Embodiment 1AX:N, N-dimethyl-2-[4-(3,4-dimethyl-2,5-dioxo-imidazolidine-1-yl)-phenyl]-6-oxyethyl group-1-ethyl-1H-indoles-3-methane amide (compound 780) and N, N-dimethyl-6-oxyethyl group-1-ethyl-2-[4-(3-methyl-2,5-dioxo-imidazolidine-1-yl)-phenyl]-preparation of 1H-indoles-3-methane amide (compound 781).
Figure A20078000890205541
Steps A.Use HCl (3mL, 6N) handle { 3-[4-(3-cyano group-6-oxyethyl group-1-ethyl-1H-indoles-2-yl)-phenyl]-urea groups } ethyl acetate (compound 773 according to the preparation of step 1AV steps A, 325mg, acetone 0.748mmol) (5mL) solution, refluxed overnight adds the solution of thermosetting.Reaction mixture is collected the throw out that forms after filtration, washs with ether, and dry down in high vacuum, generate product 6-oxyethyl group-1-ethyl-2-[4-(2,5-dioxo-imidazolidine-1-yl)-phenyl]-1H-indoles-3-methane amide (264mg, 0.650mmol, 87%).
Step B.Use mineral oil (75mg) dispersion liquid of a spot of hexane wash sodium hydride, remove hexane layer.Add 6-oxyethyl group-1-ethyl-2-[4-(2,5-dioxo-imidazolidine-1-yl)-phenyl]-(190mg, dimethyl formamide 0.468mmol) (2mL) solution stir this mixture 1 hour 1H-indoles-3-methane amide.Use then syringe add iodoethane (0.10mL, 1.61mmol).The mixture that forms stirs at ambient temperature and spends the night, and is poured into the ethyl acetate of 50 mL then.Organic phase with water (3 * 50mL) and saturated brine (20ml) washing, then with anhydrous magnesium sulfate drying, filter and evaporation.Separate residual substance through column chromatography (with 1/1 ethyl acetate/hexane wash-out on silica gel 60), generating target product is compound 780 and 781.
Embodiment 1AY:N-[4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indoles-2-yl)-phenyl]-preparation of N-(2-hydroxyethyl)-sulfonyloxy methyl amine (compound 828).
Figure A20078000890205551
Steps A: use mineral oil (108mg) dispersion liquid of a spot of hexane wash sodium hydride, remove hexane layer subsequently.Slowly add N-[4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indoles-2-yl)-phenyl]-sulfonyloxy methyl amine (compound 129,500mg, DMF 1.35mmol) (5mL) solution.After gas discharges fully, add the 2-ethyl bromoacetate (0.30mL, 2.64mmol) and sodium iodide (20mg).Mixture stirs at ambient temperature and spends the night, and pours the ethyl acetate of 50mL then into.With water (3 * 50mL) and saturated brine washing, then with anhydrous magnesium sulfate drying, filter and evaporation.Separate residual substance through column chromatography (1/1 ethyl acetate/hexane is wash-out on silica gel 60), generate compound 815 (364mg, 0.799mmol, 59%).
Step B: with N-(2-acetoxyl ethyl)-N-[4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indoles-2-yl)-phenyl] sulfonyloxy methyl amine (compound 815,164mg, 0.360mmol) and hydronium(ion) oxidation lithium (45mg, the heating of under 60 ℃, spending the night of 5mLTHF/1mL aqueous solution 1.07mmol).Cooling mixture is poured into (50mL) in the ethyl acetate.With water (50mL) and salt solution (20mL) washing, then with anhydrous magnesium sulfate drying, evaporation generates solid.Use the ether abrasive solid, collect after filtration, after the high vacuum drying, generate N-[4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indoles-2-yl)-phenyl]-N-(2-hydroxyethyl) sulfonyloxy methyl amine, i.e. compound 828 (137mg, 0.331mmol, 92%).
Embodiment 1AZ:1-ethyl-6-methoxyl group-2-[4-(2-methoxyethoxy)-phenyl]-preparation of 1H-indoles-3-nitrile (compound 248)
Will according to 1-ethyl-2-(4-hydroxyl-phenyl)-6-methoxyl group-1H-indoles-3-nitrile of embodiment 1Ga step B preparation (40mg, 0.14mmol) and K 2CO 3(77mg, 0.56mmol), the bromotrifluoromethane methyl ether (26 μ L, 0.28mmol) and DMF (450 μ L) mix.It was at room temperature stirred 1 hour, stirred 3 hours down at 75 ℃ then.Reaction mixture is used H subsequently 2O and EtOAc distribute.Dry and concentrated organic layer.Through silica gel chromatography (CH 2Cl 2, 0-5%EtOAc) purifying generates 1-ethyl-6-methoxyl group-2-[4-(2-methoxyethoxy)-phenyl]-white solid of 1H-indoles-3-nitrile (44mg, 90%).
Prepare following compounds according to method similar to the above: compound 249.
Embodiment 1BA:1-ethyl-6-methoxyl group-2-[4-(2-morpholine-4-base-oxyethyl group)-phenyl]-preparation of 1H-indoles-3-nitrile (compound 261)
Steps A: will be according to 1-ethyl-6-methoxyl group-2-[4-(2-the hydroxyl-oxethyl)-phenyl of embodiment 1AZ preparation]-1H-indoles-3-nitrile (450mg, 1.34mmol) and PPh 3(878mg, CH 3.35mmol) 2Cl 2(32mL) solution mixes under 0 ℃.Once add the N-bromo-succinimide (600mg, 3.37mmol).Reaction mixture at room temperature stirred 30 minutes.Reaction mixture is with NaHCO 3Solution washing.Dry and concentrated organic layer is through silica gel chromatography (CH 2Cl 2) behind the purifying, generate 2-[4-(2-bromine oxethyl)-phenyl]-1-ethyl-6-methoxyl group-1H-indoles-3-nitrile (506mg, 95%) is the white solid of compound 253.
Step B: will be according to 2-[4-(2-the bromine oxethyl)-phenyl of the preparation of steps A above]-1-ethyl-6-methoxyl group-1H-indoles-3-nitrile (40mg, 0.1mmol) with morpholine (50 μ L, 0.58mmol) and acetonitrile (1.0mL) mix.It is heated 2h down at 85 ℃.Reaction mixture is used CH subsequently 2Cl 2And H 2O distributes.Dry and concentrated organic layer.Generate 1-ethyl-6-methoxyl group-2-[4-(2-morpholine-4-base-oxyethyl group)-phenyl through silica gel chromatography (6/4, acetone/hexane) purifying]-white solid of 1H-indoles-3-nitrile (39mg, 96%).
Use different amine to prepare following compounds according to method similar to the above: compound 262,263,264.
Embodiment 1BB:N-{2-[4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indoles-2-yl)-phenoxy group]-ethyl } preparation of sulfonyloxy methyl amine (compound 268).
Figure A20078000890205571
Steps A: will be according to 2-[4-(2-the bromine oxethyl)-phenyl of embodiment 1BA steps A preparation]-1-ethyl-6-methoxyl group-1H-indoles-3-nitrile (258mg, 0.65mmol) and NaN 3(144mg, 2.2mmol) and MeOH (3.2mL) mix.With its heating of under 75 ℃, spending the night.Reaction mixture is used CH subsequently 2Cl 2And H 2O distributes.Dry and concentrated organic layer.Through silica gel chromatography (CH 2Cl 2) purifying generation 2-[4-(2-nitrine oxyethyl group) phenyl]-1-ethyl-6-methoxyl group-1H-indoles-3-nitrile (187mg, 80%) is the white solid of compound 266.
Step B: will be according to 2-[4-(the 2-nitrine oxyethyl group) phenyl of the preparation of steps A above]-(410mg 1.14mmol) is suspended in the solution of MeOH (20mL) and dense HCl (500 μ L) 1-ethyl-6-methoxyl group-1H-indoles-3-nitrile.Add Pd/C (150mg, 10%), this mixture is carried out the hydrogenation of 1h under 30p.s.i..With its filtration, concentrated filtrate.Filtrate residue is distributed with EtOAc and 0.5N NaOH.Dry and concentrated organic layer.Through silica gel chromatography (10-30%, MeOH/CH 2Cl 2) purifying generation 2-[4-(2-amino ethoxy) phenyl]-1-ethyl-6-methoxyl group-1H-indoles-3-nitrile (298mg, 78%) is the white solid of compound 267.
Step C: will be according to 2-[4-(2-amino ethoxy) phenyl of above-mentioned steps B preparation]-(30mg 0.09mmol) is dissolved in the pyridine (300 μ L) 1-ethyl-6-methoxyl group-1H-indoles-3-nitrile.The adding methylsulfonyl chloride (8 μ L, 0.1mmol).It was at room temperature stirred 45 minutes.Add again methylsulfonyl chloride (4 μ L, 0.05mmol).Continue to stir 1 hour.Reaction mixture distributes with the EtOAc and the HCl aqueous solution.Dry and concentrated organic layer.Through silica gel chromatography (1/1, CH 2Cl 2/ EtOAc) purifying generates N-{2-[4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indoles-2-yl) phenoxy group] ethyl } sulfonyloxy methyl amine (32mg, 86%) is the white solid of compound 268.
Prepare following compounds according to method similar to the above: compound 269.
Embodiment 1BC:N-{2-[4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indoles-2-yl)-phenoxy group]-ethyl } preparation of ethanamide (compound 274).
Will be according to 2-[4-(2-amino ethoxy) phenyl of embodiment 1BB step B preparation]-(30mg 0.09mmol) is dissolved in THF (400 μ L) and Et to 1-ethyl-6-methoxyl group-1H-indoles-3-nitrile 3N (24 μ L, 0.17mmol) in.(10 μ L, 0.14mmol), reaction mixture at room temperature stirs 2h to add Acetyl Chloride 98Min..Reaction mixture EtOAc and H 2O distributes.Dry and concentrated organic layer.Generate N-{2-[4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indoles-2-yl) phenoxy group through silica gel chromatography (EtOAc) purifying] ethyl } white solid of ethanamide (33mg, 97%).
Embodiment 1BD:1-{2-[4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indoles-2-yl)-phenoxy group] ethyl }-preparation of 3-ethyl-urea (compound 279).
Figure A20078000890205582
Will be according to 2-[4-(2-amino ethoxy) phenyl of embodiment 1BB preparation]-1-ethyl-6-methoxyl group-1H-indoles-3-nitrile (30mg, 0.09mmol) with ethyl isocyanate (18 μ L, 0.21mmol) and pyridine (300 μ L) mix.Mixture at room temperature stirred 90 minutes, distributed with the EtOAc and the HCl aqueous solution subsequently.Dry and concentrated organic layer.Generate 1-{2-[4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indoles-2-yl)-phenoxy group through silica gel chromatography (EtOAc) purifying]-ethyl }-white solid of 3-ethyl-urea (34mg, 93%).
Embodiment 1BE:N-{2-[4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indoles-2-yl)-phenoxy group]-ethyl } preparation of methane amide (compound 280).
The formic acid (280 μ L) of diacetyl oxide (700 μ L) and 98% is heated 1h down at 65 ℃.It is cooled to 0 ℃.Will be according to 2-[4-(2-amino ethoxy) phenyl of embodiment 1BB preparation]-(30mg 0.09mmol) is absorbed in THF (400 μ L) to 1-ethyl-6-methoxyl group-1H-indoles-3-nitrile, and it is joined in the mixed anhydride.It was stirred 45 minutes at 0 ℃.Reaction mixture is used EtOAc and NaHCO subsequently 3The aqueous solution distributes.Dry and concentrated organic layer.Through silica gel chromatography (4/1, CH 2Cl 2/ acetone) purifying generates N-{2-[4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indoles-2-yl) phenoxy group] ethyl } white solid of methane amide (28mg, 86%).
Embodiment 1BF:1-ethyl-2-{4-[2-(3-hydroxyl pyrrolidine-1-yl)-2-oxo-oxyethyl group] phenyl }-preparation of 6-methoxyl group-1H-indoles-3-nitrile (compound 285).
Steps A: utilize basic identical step to use 1-ethyl-2-(4-hydroxy phenyl)-6-methoxyl group-1H-indoles-3-nitrile (559mg with embodiment 1AZ, 1.91mmol) preparation [4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indoles-2-yl)-phenoxy group]-tert.-butyl acetate (780mg, 100%).
Step B: (745mg is 1.83mmol) at the CH of 20%TFA with [4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indoles-2-yl)-phenoxy group]-tert.-butyl acetate 2Cl 2Under room temperature, stirred 3 hours in the solution.It is concentrated resistates H 2O and EtOAc distribute.Dry and concentrated organic layer.Use CH 2Cl 2Grinding residues, the white solid of generation [4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indoles-2-yl)-phenoxy group]-acetate (634mg, 99%).
Step C: (40mg 0.12mmol) is suspended in CH with [4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indoles-2-yl)-phenoxy group]-acetate 2Cl 2(1.65mmol) and among the DMF (2 μ L).The adding oxalyl chloride (17 μ L, 0.19mmol).It was at room temperature stirred 30 minutes.Then the solution that forms is joined S-3-hydroxyl pyrrolidine (150 μ L) and the CH that is stirring 2Cl 2(3.0mL).Reaction mixture is with the HCl solution washing.Dry and concentrated organic layer.Through silica gel chromatography (3/2 CH 2Cl 2/ acetone) purifying generates 1-ethyl-2-{4-[2-(3-hydroxyl-tetramethyleneimine-1-yl)-2-oxo-oxyethyl group]-phenyl }-6-methoxyl group-1H-indoles-3-nitrile (40mg, 79%) is the white solid of compound 285.
The preparation of embodiment 1BG:1-ethyl-6-methoxyl group-2-(2-oxo-2,3-dihydro-benzoxazoles-5-yl)-1H-indoles-3-nitrile (compound 332).
Figure A20078000890205601
Steps A: (369mg 1.1mmol) mixes with EtOAc (20mL) and Pd/C (150mg, 10%) 1-ethyl-2-(4-hydroxyl-3-the nitrophenyl)-6-methoxyl group-1H-indoles-3-nitrile that will prepare according to embodiment 1Gd.With this mixture hydrogenation 1h under 30 p.s.i..Use Celite that it is filtered.Concentrated filtrate grinds with ether, and generating 2-(3-amino-4-hydroxy phenyl)-1-ethyl-6-methoxyl group-1H-indoles-3-nitrile (307mg, 91%) is the white solid of compound 322.
Step B: will according to 2-(3-amino-4-hydroxy the phenyl)-1-ethyl-6-methoxyl group-1H-indoles-3-nitrile of steps A preparation (100mg, 0.33mmol) with CDI (83mg, 0.51mmol) and THF (1.1mL) mixing.It was heated 1 hour down at 65 ℃.Reaction mixture distributes with the EtOAc and the HCl aqueous solution.Dry and concentrated organic layer.Through silica gel column chromatography (9/1, CH 2Cl 2/ EtOAc) purifying generates the white solid of 1-ethyl-6-methoxyl group-2-(2-oxo-2,3-dihydro-benzoxazoles-5-yl)-1H-indoles-3-nitrile (89mg, 81%).
The preparation of embodiment 1BH:1-ethyl-6-methoxyl group-2-(3-oxo-3,4-dihydro-2H-benzo [1,4] oxazine-6-yl)-1H-indoles-3-nitrile (compound 334).
Figure A20078000890205602
Steps A: with bromoacetic acid (52mg, 0.37mmol) with the EDCI hydrochloride (62mg, 0.4mmol) and acetonitrile (900 μ L) mix the formation uniform solution.Will according to embodiment 1BG step B preparation 2-(3-amino-4-hydroxy phenyl)-(100mg 0.33mmol) joins in this solution 1-ethyl-6-methoxyl group-1H-indoles-3-nitrile.The thick mashed prod of very fast formation.Add the 1.1mL acetonitrile again, then mixture was at room temperature stirred 2 hours.Reaction mixture is used H subsequently 2O and EtOAc distribute.Dry and concentrated organic layer.Through silica gel chromatography (4/1, CH 2Cl 2/ EtOAc) purifying generates 2-chloro-N-[5-(3-cyano group-1-ethyl-6-methoxyl group-1H-indoles-2-yl)-2-hydroxy phenyl] ethanamide (82mg, 60%) is the white solid of compound 333.
Step B: will be according to 2-chloro-N-[5-(3-cyano group-1-ethyl-6-methoxyl group-1H-indoles-2-yl)-2-hydroxyl-phenyl of steps A preparation] and ethanamide (57mg, 0.13mmol) and K 2CO 3(55mg, 0.4mmol) and DMF (400 μ L) mix.It was heated 1 hour down at 80 ℃.Reaction mixture is used H subsequently 2O and EtOAc distribute.Dry and concentrated organic layer.Through silica gel column chromatography (9/1, CH 2Cl 2/ EtOAc) purifying generates the white solid of 1-ethyl-6-methoxyl group-2-(3-oxo-3,4-dihydro-2H-benzo [1,4] oxazine-6-yl)-1H-indoles-3-nitrile (45mg, 90%).
The preparation of embodiment 1BI:1-ethyl-6-methoxyl group-2-(2-oxo-2,3-dihydro-benzoxazoles-6-yl)-1H-indoles-3-nitrile (compound 340).
Figure A20078000890205611
Steps A: with the 4-aminosallcylic acid (4.0g, 26mmol) at-5 ℃ of low suspensions in H 2SO 4(26mL, 2.7M).With Sodium Nitrite (1.8g, H 26.1mmol) 2O (6.5mL) solution is cooled to the ice bath temperature, dropwise adds aminosallcylic acid in 5 minutes.The suspension that forms stirred 15 minutes down at-5 ℃.With KI (6.8g, H 41mmol) 2SO 4(13mL, 1M) solution dropwise joins in the diazonium salt, and this process discharges a large amount of N 2Reaction mixture heated 20 minutes down at 70 ℃.Reaction mixture is used H subsequently 2O and EtOAc distribute.Dry and concentrated organic layer.Generate 4-iodo-salicylic acid (5.33g, 85-90% purity) through silica gel chromatography (7/3, hexane/acetone, 1% acetate) purifying.
Step B: (1.0g 3.8mmol) is dissolved in THF (28mL) and Et with thick 4-iodo-salicylic acid 3N (1.15mL, 8.2mmol) in.Adding DPPA (1.7mL, 7.8mmol).With it 70 ℃ of following heated overnight.Reaction mixture is used H subsequently 2O and EtOAc distribute.Dry and concentrated organic layer.Through silica gel chromatography (9/1, CH 2Cl 2/ EtOAc) purifying generates the thick intermediate of 472mg.Grind the white solid that generates 6-iodo-3H-benzoxazole-2-ketone (369mg, 37%) through ether.
Step C: utilize with the essentially identical step of embodiment 1Gd and use 6-iodo-3H-benzoxazole-2-ketone (118mg, 0.45mmol) preparation 1-ethyl-6-methoxyl group-2-(2-oxo-2,3-dihydro-benzoxazoles-6-yl)-1H-indoles-3-nitrile is compound 340 (75mg, 55%).
The preparation of embodiment 1BJ:1-ethyl-6-methoxyl group-2-(4-methyl-3-oxo-3,4 ,-dihydro-2H-benzo [1,4] oxazine-6-yl)-1H-indoles-3-nitrile (compound 339).
Figure A20078000890205621
Will according to the 1-ethyl-6-methoxyl group-2-of embodiment 1BH preparation (3-oxo-3,4-dihydro-2H-benzo [1,4] oxazine-6-yl)-1H-indoles-3-nitrile (20mg, 0.058mmol) with the oily suspension of NaH (14mg, 60%, 0.35mmol) mix.Add THF (300 μ L).It was at room temperature stirred 5 minutes.THF (the 100 μ L) solution that adds methyl-iodide (4.4 μ L).It was at room temperature stirred 1 hour.Reaction mixture distributes with the EtOAc and the HCl aqueous solution.Dry and concentrated organic layer.Through silica gel column chromatography (9/1, CH 2Cl 2/ EtOAc) purifying generates the white solid of 1-ethyl-6-methoxyl group-2-(4-methyl-3-oxo-3,4 ,-dihydro-2H-benzo [1,4] oxazine-6-yl)-1H-indoles-3-nitrile (16mg, 76%).
Prepare following compounds in a similar manner: compound 341.
The preparation of embodiment 1BK:1-ethyl-2-iodo-6-methoxyl group-5-nitro-1H-indoles-3-nitrile (compound 499)
Figure A20078000890205622
Will (50mg be 0.15mmol) at 0 ℃ of low suspension (620 μ L) in acetate according to the 1-ethyl-2-iodo-6-methoxyl group-1H-indoles-3-nitrile of embodiment 1Ga steps A preparation.The AcOH solution that adds nitric acid (4.25M).It was at room temperature stirred 2 hours.Reaction mixture is used CH subsequently 2Cl 2And H 2O distributes.Organic layer is with NaHCO 3Solution washing, dry then and concentrated.Through silica gel chromatography (6/4, CH 2Cl 2/ hexane) purifying and ether grind, and generate the yellow solid of 1-ethyl-2-iodo-6-methoxyl group-5-nitro-1H-indoles-3-nitrile (16mg, 29%).
Embodiment 1BL:1 '-second sulphonyl-1-ethyl-6-methoxyl group-2 ', 3 '-dihydro-1H, 1H '-[2,6 '] two indoles-3-nitrile (compound 753) preparation.
Steps A: (3.0g 18.3mmol) is dissolved in THF (45mL) and Et under 0 ℃ with 6-nitroindoline quinoline 3N (3.4mL, 24.4mmol).Dropwise add Acetyl Chloride 98Min. (1.5mL, 21mmol).Mixture at room temperature stirred 30 minutes.Mixture distributes with the EtOAc and the HCl aqueous solution.Dry and concentrated organic layer, the yellow solid of generation 1-ethanoyl-6-nitroindoline quinoline (3.8g, 100%).
Step B: (3.8g 18.3mmol) is suspended among the EtOAc (200mL) with 1-ethanoyl-6-nitroindoline quinoline.Add Pd/C (650mg, 10%), this mixture is carried out 2 hours hydrogenation under 40-55p.s.i..Then with the Celite filtering mixt.Concentrated filtrate uses the ether grinding residues, generates the orange solids of 1-ethanoyl-6-amino indole quinoline (3.18g, 99%).
Step C: utilize and the essentially identical step of embodiment 1BI steps A, use 1-ethanoyl-6-amino indole quinoline (1.5g, 8.5mmol) preparation 1-ethanoyl-6-iodo indoline (1.06g, 43%).
Step D: with 1-ethanoyl-6-iodo indoline (1.06g, 3.7mmol), NaOH (1.16g, 29mmol), EtOH (8mL) and H 2O (6mL) heating of under 90 ℃, spending the night.Reaction mixture is used H subsequently 2O and EtOAc distribute.Organic layer is extracted in the HCl aqueous solution.Use NaOH alkalization water layer conversely, extract with EtOAc.Dry and concentrated organic layer.Grind the brown solid that obtains 6-iodo indoline (577mg, 64%) through hexane.
Step e: utilize and the essentially identical step of embodiment 1Gd step B, use 1-iodo indoline (600mg, 2.45mmol) preparation 1-ethyl-6-methoxyl group-2 ', 3 '-dihydro-1H, 1H '-[2,6 '] two indoles-3-nitrile (535mg, 67%).
Step F: the step of utilizing embodiment 1Y, use 1-ethyl-6-methoxyl group-2 ', 3 '-dihydro-1H, 1H '-[2,6 '] two indoles-3-nitrile (30mg, 0.095mmol) preparation 1 '-second sulphonyl-1-ethyl-6-methoxyl group-2 ', 3 '-dihydro-1H, 1H '-[2,6 '] two indoles-3-nitrile (24mg, 62%).
Prepare following compounds according to method similar to the above: compound 752 and 754.
The preparation of embodiment 1BM:5-ethanoyl-1-ethyl-6-methoxyl group-2-(4-nitro-phenyl)-1H-indoles-3-nitrile (compound 844).
Figure A20078000890205641
The 1-ethyl that embodiment 1Gc method is prepared-6-methoxyl group-2-(4-nitrophenyl)-1H-indoles-3-nitrile (100mg, 0.3mmol) at 0 ℃ of low suspension in 1, in the 2-ethylene dichloride (500 μ L).(50 μ L 0.69mmol), once add AlCl subsequently to add Acetyl Chloride 98Min. 3(55mg, 0.4mmol).It was stirred 1 hour down at 0 ℃, stirred 4 hours under the room temperature, stir down at 45 ℃ again and spend the night.Reaction mixture is used CH subsequently 2Cl 2And H 2O distributes.Dry and concentrated organic layer.Through silica gel chromatography (195: 5 CH 2Cl 2/ EtOAc) purifying generates the orange solids of 5-ethanoyl-1-ethyl-6-methoxyl group-2-(4-nitro-phenyl)-1H-indoles-3-nitrile (33mg, 29%).
The preparation of embodiment 1BN:1-ethyl-6-methoxyl group-5-morpholine-4-ylmethyl-2-(4-nitro-phenyl)-1H-indoles-3-nitrile (compound 845).
Figure A20078000890205642
Steps A: the 1-ethyl that embodiment 1Ge method is prepared-6-methoxyl group-2-(4-nitrophenyl)-1H-indoles-3-nitrile (100mg, 0.3mmol) with 1,3, the 5-trioxane (64mg, 0.71mmol) and acetate (2.0mL) mixing.Acetate (2.0mL) solution that adds 33%HBr.It was at room temperature stirred 4 hours.Reaction mixture is used CH subsequently 2Cl 2And H 2O distributes.Organic layer is with NaHCO 3Solution washing carries out drying and concentrated subsequently.Thick material is carried out subsequent step.
Step B: with crude product 6-brooethyl-1-ethyl-6-methoxyl group-2-(4-nitro-phenyl)-1H-indoles-3-nitrile (0.3mmol) and morpholine (150 μ L, 1.75mmol) and DCE (1.0mL) heating of under 90 ℃, together spending the night.Reaction mixture is used H subsequently 2O and EtOAc distribute.Dry and concentrated organic layer.Through silica gel chromatography (50-100%, EtOAc/CH 2Cl 2) purifying and grind through 1/1 hexane/acetone, generate the yellow solid of 1-ethyl-6-methoxyl group-5-morpholine-4-ylmethyl-2-(4-nitrophenyl)-1H-indoles-3-nitrile (57 mg, total recovery 44%).
Embodiment 1BO:2-[4-(1,1-titanium dioxide isothiazolidine-2-yl) phenyl]-1-encircles the preparation of third methyl-6-methoxyl group-1H-indoles-3-nitrile (compound 716).
Figure A20078000890205651
Steps A: to 40 ℃ and be in 6-methoxyl group indoles in the stirring (5.88g, 40.0mmol) (9.59g adds DMAP (0.10g) in DCM 44.0mmol) (50mL) solution with the two carbonic acid tert-butyl esters.After stirring was spent the night, this mixture was successively with 0.1N HCl, water and salt water washing, and with anhydrous Na 2SO 4Dry.Evaporating solvent, resistates generate 6-methoxyl group-1H-indoles-1-carboxylic acid tert-butyl ester (8.48g, 86%) after chromatography (silica gel, EtOAc/ hexane, 1/7).
Step B: (3.08g, 12.5mmol) (4.83mL 21.9mmol) is dissolved in anhydrous THF (20mL), and this solution is cooled to 0 ℃ with the sec.-propyl borate with above-mentioned Boc-indoles.(12.5mL, 1.5M list-THF mixture is dissolved in hexanaphthene, 18.7mmol) dropwise to add LDA during stirring.Mixture stirs down 15min at 0 ℃, at room temperature stirs 0.5h then, on ice-water bath, add subsequently HCl (6N, 3.0mL, 18mmol).Remove organic solvent under the vacuum, resistates is suspended in H 2Among the O (100mL), be 4～5 with the pH acidifying with HCl (6N).The collecting precipitation thing with water and hexane wash, after the dry air, generates 1-Boc-6-methoxyl group indoles-2-boric acid (3.38g, 93%) after filtration.
Step C: under 0 ℃ to the 4-Iodoaniline (3.18g, pyridine 14.5mmol) (15mL) solution add 3-chlorine third SULPHURYL CHLORIDE (2.3mL, 18.9mmol).After the adding, mixture at room temperature stirs 2hr, pours frozen water (200mL) then into.Separate organic layer, use DCM (2 * 50mL) aqueous phase extracted layers.The organic phase that merges use successively HCl (2N, 2 * 15mL), water (2 * 50mL) and salt solution (20mL) wash, and with anhydrous Na 2SO 4Dry.Evaporation subsequently removes desolvates, and resistates generates 3-chloro-N-(4-iodophenyl) propane-1-sulphonamide (4.68g, 90%) after chromatography.Use K down at 50 ℃ subsequently 2CO 3(3.33g, chlorine sulphonamide (3.47g, 9.6mmol) the processing 2h of DMF 24.1mmol) (50mL) solution to obtaining.This mixture is poured in the frozen water (300mL), and the collecting precipitation thing after the dry air, obtains 2-(4-iodophenyl) isothiazolidine-1 of substantially pure, 1-dioxide (3.11g, 100%).
Step D: toward 1-Boc-6-methoxyl group indoles-2-boric acid of step B above (0.36g, 1.25mmol), 2-(4-iodophenyl) isothiazolidine-1, the 1-dioxide (0.32g, 1.0mmol) and PdCl 2(dppf) (0.037g adds K in the mixture of DMF 0.05mmol) (4.0mL) solution 2CO 3(1.5mL, 2.0M, aqueous solution 3.0mmol).Mixture at room temperature stirs and spends the night, and pours frozen water (100mL) then into.The collecting precipitation thing washes with water, behind flash column chromatography (silica gel, DCM/EtOAc, 9/1) purifying, generates 1-Boc-2-[4-(1,1-titanium dioxide isothiazolidine-2-yl) phenyl]-6-methoxyl group-1H-indoles (0.43g, 98%).
Prepare following compounds in a similar manner: compound 768.
Step e: DCM (25mL) solution that uses TFA (25mL) is at room temperature to 1-Boc-2-[4-(1,1-titanium dioxide isothiazolidine-2-yl) phenyl]-(1.63g 3.7mmol) handles 4h to 6-methoxyl group-1H-indoles.After removing volatile matter, use saturated NaHCO 3Resistates is carried out the careful stirring of 0.5h.Collecting precipitation thing after filtration, the water thorough washing obtains 1-H-2-[4-(1, the 1-titanium dioxide isothiazolidine-2-yl) phenyl of substantially pure after the drying]-6-methoxyl group indoles (1.17g, 92%).
In the time of 0 ℃ with 1-H-2-[4-(1,1-titanium dioxide isothiazolidine-2-yl) phenyl]-(0.95g 2.8mmol) is dissolved in DMF (10mL) to 6-methoxyl group indoles, and (0.36mL 4.2mmol) handles with Sulfuryl chloride isocyanate.Mixture at room temperature stirs subsequently and spends the night, and pours frozen water (150mL) into, continues to stir 0.5h.Collecting precipitation thing after filtration, the water thorough washing obtains 1-H-2-[4-(1, the 1-titanium dioxide isothiazolidine-2-yl) phenyl of substantially pure after the dry air]-6-methoxyl group indoles-3-nitrile (0.89g, 87%).
Prepare following compounds according to method same as described above: compound 829.
Step F: to 1-H-2-[4-(1,1-titanium dioxide isothiazolidine-2-yl) phenyl]-6-methoxyl group indoles-3-nitrile (73mg, 0.2mmol) and K 2CO 3(69mg, and the adding ring third methyl iodide in DMF 0.5mmol) (3.0mL) solution (0.029mL, 0.3mmol).Mixture stirs down at 50 ℃ and spends the night, and pours frozen water (10mL) then into.Collecting precipitation thing after filtration, the water thorough washing obtains 2-[4-(1,1-titanium dioxide isothiazolidine-2-yl) phenyl behind the column chromatography purifying]-to encircle third skatole-3-nitrile be compound 716 (73mg, 87%) to 6-methoxyl group-1-..
Prepare following compounds according to method same as described above: compound 717,71 8,719,782,783,784.
Embodiment 1BP:2-[4-(1,1 '-dioxo-1 λ 6-isothiazolidine-2-yl)-preparation of 6-methoxyl group-3-oxazole-5-base-1-propyl group-1H-indoles (compound 805).
Steps A: utilize and the essentially identical step of embodiment 1A step B, use the prepared 2-[4-of embodiment 1BO step D (1,1 '-dioxo-1 λ 6-isothiazolidine-2-yl)-6-methoxyl group-indoles (900mg, 2.62mmol) preparation 2-[4-(1,1 '-dioxo-1 λ 6-isothiazolidine-2-yl)-6-methoxyl group-1-propyl group-1H-indoles (608mg, 60%).
Step B: according to the testing program of embodiment 1P, use 2-[4-(1,1 '-dioxo-1 λ 6-isothiazolidine-2-yl)-6-methoxyl group-1-propyl group-1H-indoles (50mg, 0.13mmol) preparation 2-[4-(1,1 '-dioxo-1 λ 6-isothiazolidine-2-yl)-6-methoxyl group-3-oxazole-5-base-1-propyl group-1H-indoles (9mg, total recovery 15%).
Embodiment 1BQ:2-[4-(encircling third sulphonyl) piperazine-1-yl]-preparation of 1-ethyl-6-(trifluoromethyl)-1H-indoles-3-nitrile (compound 842).
Figure A20078000890205681
Steps A: (2.54g, anhydrous THF (20.0mL) solution 10.0mmol) dropwise adds LDA, and (8.3mL, 1.5M are dissolved in the list-THF of hexanaphthene, 12.5mmol) to prepared-78 ℃ 1-ethyl of step 1A method-6-trifluoro methyl indole-3-nitrile.Add the back and continue to mix 0.5hr, add hexachloroethane subsequently, make mixture slowly return to room temperature, stir 0.5hr simultaneously.Evaporation subsequently removes desolvates, and resistates is with water treatment.Organic phase is with dichloromethane extraction, and water and salt water washing are with anhydrous Na 2SO 4Dry.Remove and desolvate the back crude product that is obtained after chromatography (silica gel, dichloromethane/hexane, 3/2), obtain 2-chloro-1-ethyl-6-(trifluoromethyl)-1H-indoles-3-nitrile (1.75g, 64%).
Step B: the chloro-indole that will above obtain (0.27g, 1.0mmol), K 2CO 3(0.35g, 2.5mmol) (0.28g 1.5mmol) stirred 3 days down in 70 ℃ in DMF (5.0mL), poured into then in the water (50mL) with the N-Boc-piperazine.The collecting precipitation thing washes with water after filtration.4-(3-cyano group-1-ethyl-6-Trifluoromethyl-1 H-indoles-2-yl)-piperazine-1-carboxylic acid tert-butyl ester is compound 785 (0.30g, 71%) to this crude product through chromatography (silica gel, dichloromethane/ethyl acetate, 9/1) generation.
Prepare following compounds according to method same as described above through using other amine: compound 514,785,786.
Step C: methylene dichloride (5mL) solution that uses TFA (5mL) is at room temperature to 4-(3-cyano group-1-ethyl-6-Trifluoromethyl-1 H-indoles-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (0.26g, 6.1mmol) processing 1hr.After removing volatile matter, resistates is with saturated NaHCO 3Handle, collecting precipitation thing after filtration, the water thorough washing obtains 1-ethyl-2-piperazine-1-base-6-(the trifluoromethyl)-1H-indoles-3-nitrile (0.20g, 100%) of substantially pure after the dry air.
Step D: to 1-ethyl-2-piperazine-1-base-6-(trifluoromethyl)-1H-indoles-3-nitrile (32mg, 0.1mmol) and methylene dichloride (1.0mL) solution of piperidines (0.1mL) in add the ring third SULPHURYL CHLORIDE (28mg, 0.2mmol), this mixture at room temperature stirs and spends the night.It is diluted with methylene dichloride (5mL); and with HCl (2N; 2 * 2mL), water (2 * 5mL) and salt solution (5mL) washing; through silica gel chromatography (dichloromethane/ethyl acetate; 9/1) after; obtain 2-[4-(encircling third alkylsulfonyl) piperazine-1-yl]-1-ethyl-6-(trifluoromethyl)-1H-indoles-3-nitrile, i.e. compound 842 (30mg, 70%).
Prepare following compounds according to method same as described above through using other SULPHURYL CHLORIDE: compound 841,843.
Embodiment 1BR: ethyl sulfonic acid [3-cyano group-2-(4-ethoxyl phenenyl)-1-ethyl-1H-indoles-6-yl]-acid amides (compound 835)
Figure A20078000890205691
Steps A: (0.74g 2.0mmol) is compound 831 and K to 6-bromo-2-(4-the ethoxyl phenenyl)-1-ethyl-1H-indoles-3-nitrile that will prepare with the 6-bromo indole according to embodiment 1Gb 2CO 3(0.55g, 4.0mmol), CuI (0.02g, 0.1mmol), t-butyl carbamate (0.35g, 3.0mmol), N, N '-dimethyl cyclohexane-1,2-two amine ligands (0.028g, 0.2mmol) and dry toluene (5.0mL) in sealed tube, mix.This reaction system is with nitrogen wash, subsequently 110 ℃ of following stirred overnight.After the cooling, solvent is replaced by methylene dichloride, after chromatography (silica gel, methylene dichloride), generates [3-cyano group-2-(4-oxyethyl group-phenyl)-1-ethyl-1H-indoles-6-yl]-t-butyl carbamate (0.68g, 84%), and promptly compound 832.
Step B: at room temperature (0.63g 1.56mmol) handles 2h, removes volatile matter under vacuum to the prepared compound 832 of above-mentioned steps A to use TFA/DCM (7.5mL/7.5mL).Resistates is with saturated NaHCO 3Handle, collecting precipitation thing after filtration, the water thorough washing after the dry air, generates 6-amino-2-(4-ethoxyl phenenyl)-1-ethyl-1H-indoles-3-nitrile (0.45g, 96%), and promptly compound 833.
Step C: use ethyl sulfonyl chloride (19mg, 0.15mmol) pyridine (1.0mL) solution at room temperature spend the night and handle above-mentioned amine (31mg, 0.1mmol), behind the column chromatography purifying, [3-cyano group-2-(4-oxyethyl group-phenyl)-1-ethyl-1H-indoles-6-yl]-acid amides (83%) is a compound 835 to generate ethyl sulfonic acid.
Prepare following compounds according to method same as described above: compound 830,834,836 and 837.
Embodiment 1BS:[3-cyano group-2-(4-ethoxyl phenenyl)-1-ethyl-1H-indoles-6-yl]-preparation of urethanum (compound 838)
Figure A20078000890205701
Use Vinyl chloroformate (16mg, 0.15mmol) pyridine (1.0mL) solution at room temperature spend the night and handle according to prepared 6-amino-2-(4-the ethoxyl phenenyl)-1-ethyl-1H-indoles-3-nitrile (31mg of embodiment 1BR step B, 0.1mmol) be compound 833, behind the column chromatography purifying, generate [3-cyano group-2-(4-ethoxyl phenenyl)-1-ethyl-1H-indoles-6-yl]-urethanum (30mg, 79%).
Embodiment 1BT:1-[3-cyano group-2-(4-ethoxyl phenenyl)-1-ethyl-1H-indoles-6-yl]-preparation of 3-ethyl-urea (compound 839)
Figure A20078000890205702
Use ethyl isocyanate (14mg, methylene dichloride 0.2mmol) (1.0mL) solution under 40 ℃, spend the night handle 6-amino-2-(4-ethoxyl phenenyl)-1-ethyl-1H-indoles-3-nitrile (31mg, 0.1mmol).The collecting precipitation thing is used washed with dichloromethane after filtration, after the dry air, generates 1-[3-cyano group-2-(4-oxyethyl group-phenyl)-1-ethyl-1H-indoles-6-yl]-3-ethyl-urea (36mg, 95%).
Embodiment 1BU:1-(2-chloroethyl)-3-[4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indoles-2-yl)-phenyl]-preparation of urea (compound 442).
Figure A20078000890205703
Under the room temperature to 2-(4-aminophenyl)-1-ethyl-6-methoxyl group-1H-indoles-3-nitrile (50mg, add in THF 0.172mmol) (2mL) solution 2-chloroethyl isocyanate (22uL, 0.258mmol).After the stirring that refluxes was spent the night, reaction mixture concentrated under vacuum, and resistates dilutes with ethyl acetate.Grind the semisolid that forms with hexane, collecting precipitation thing after filtration is with the hexane solution thorough washing of 50% ethyl acetate, after the vacuum-drying, generate 1-(2-chloroethyl)-3-[4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indoles-2-yl)-phenyl]-urea (62mg, 91%).
Use essentially identical step to prepare following compounds: compound 295,362,395,396,397,398,399,400,401,402,403,404,405,406,407,443,444,445,446,511,512,513,600,620,626,627,628,679,680,681,740,741,742,743,748,749,750,751,774,817,818,846,847,848,954,955,956,957,958,987,999,1000,1001,1008,1009,1010,1011,1012,1013,1014,1016,1017,1018,1019,1023,1024,1027,1036,1039,1043,1045,1060,1061,1066,1067,1070,1080,1092,1094,1095,1096,1097,1098,1099,1100,1101,1102,1106,1108,1118,1120,1124,1125,1126,1136,1137,1138,1139,1143,1144,1156,1157,1162,1163,1164,1165,1171,1172,1173,1197,1190,1214,1221,1223,1224,1225,1225,1227,1256,1279,1301,1303,1304,1305.
Embodiment 1BV:1-ethyl-6-methoxyl group-2-[4-(2-oxo-imidazolidine-1-yl)-phenyl]-preparation of 1H-indoles-3-nitrile (compound 771).
Figure A20078000890205711
Toward 1-(2-chloroethyl)-3-[4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indoles-2-yl)-phenyl]-(100mg adds 1M KOH (504uL) aqueous solution to urea in MeOH 0.252mmol) (10mL) solution, stir 24h down at 49 ℃ then.Removal of solvent under reduced pressure.Resistates dilutes with ethyl acetate, washes with water then.Organic phase is with anhydrous MgSO 4Drying, filtration under diminished pressure concentrates.Resistates dilutes with ethyl acetate, grinds with hexane then, after filtration the collecting precipitation thing, hexane solution thorough washing with 50% ethyl acetate, after the vacuum-drying, generate 1-ethyl-6-methoxyl group-2-[4-(2-oxo-imidazolidine-1-yl)-phenyl]-1H-indoles-3-nitrile (56mg, 62%).
Use essentially identical step to prepare following compounds: compound 770,778.
Embodiment 1BW:1-ethyl-6-isopropoxy-2-[4-(2-oxo-oxazolidines-3-yl)-phenyl]-preparation of 1H-indoles-3-nitrile (compound 638).
Figure A20078000890205721
To [4-(3-cyano group-1-ethyl-6-isopropoxy-1H-indoles-2-yl)-phenyl]-(30mg adds K in DMF 0.07mmol) (1mL) solution to carboxylamine 2-chloro-ethyl ester 2CO 3(10mg) aqueous solution stirs 18h down at 50 ℃ then.Pour reaction mixture into cold water, the collecting precipitation thing with hexane wash, after the vacuum-drying, generates target compound (21mg, 81%) after filtration.
Prepare following compounds in a similar way: compound 820,821,863,864.
Embodiment 1BX:{3-[3-cyano group-1-ethyl-6-(3-tetramethyleneimine-1-base-propoxy-)-1H-indoles-2-yl]-phenyl }-preparation of urethanum (compound 530).
Figure A20078000890205722
Steps A: (1.65g adds 1M BBr in 20min in DCM 4.37mmol) (20mL) solution to [3-(3-cyano group-1-ethyl-6-methoxyl group-1H-indoles-2-yl)-phenyl]-urethanum 3DCM (13.12mL) solution.Reaction mixture at room temperature stirs 1h, removal of solvent under reduced pressure then again.Resistates is dissolved among the MeOH, pours cold water then into.The collecting precipitation thing with hexane wash, after the vacuum-drying, generates [3-(3-cyano group-1-ethyl-6-hydroxyl-1H-indoles-2-yl)-phenyl]-urethanum (1.5g, 98%) after filtration.
Step B: to [3-(3-cyano group-1-ethyl-6-hydroxyl-1H-indoles-2-yl)-phenyl]-(1.2g adds K in DMF 2.91mmol) (10mL) solution to urethanum 2CO 3(538mg, 3.9mmol) (383uL, 3.9mmol), reactant stirs down at 50 ℃ and spends the night with 3-bromo-n-propyl chloride.Pour reaction mixture into cold water then, the collecting precipitation thing with hexane wash, after the vacuum-drying, generates purpose product (1.1g, 89%) after filtration.
Step C: to 3-[3-cyano group-1-ethyl-6-(3-tetramethyleneimine-1-base-propoxy-)-1H-indoles-2-yl]-phenyl }-urethanum (50mg, CH 0.12mmol) 3Add in CN (2mL) solution DIEA (31uL, 0.18mmol), sodium iodide (20mg, 0.132mmol) and tetramethyleneimine (30uL, 0.36mmol).The mixture that forms at room temperature refluxes to stir and spends the night.Evaporation removes and desolvates, resistates dilutes with ethyl acetate, grind with hexane then, collecting precipitation thing after filtration, with the hexane solution thorough washing of 50% ethyl acetate, after the vacuum-drying, generate 1-ethyl-6-isopropoxy-2-[4-(2-oxo-oxazolidines-3-yl)-phenyl]-1H-indoles-3-nitrile (46mg, 85%) compound 638, i.e..
Adopt above-mentioned steps A-C to prepare following compounds in a similar manner: compound 441,447,491,492,493,504,525,526,527,528,529,531,532,533,534,535,536,537,538,539.
Embodiment 1BY:[3-(3-cyano group-1-ethyl-6-methoxyl group-1H-indoles-2-yl)-phenyl]-preparation of thiocarbamide (compound 767).
Figure A20078000890205731
Steps A: (187mg 0.642mmol) is dissolved in anhydrous propanone (3.0mL) with raw material 2-(3-amino-phenyl)-1-ethyl-6-methoxyl group-1H-indoles-3-nitrile.(107mg 0.656mmol), stirs 17h with this mixture, forms precipitation to add benzoyl isothiocyanate toward solution under the room temperature.Filtering precipitate is used washing with acetone, after the drying, obtains 1-benzoyl-3-[3-(3-cyano group-1-ethyl-6-methoxyl group-1H-indoles-2-yl)-phenyl of 264mg]-faint yellow solid of thiocarbamide (yield 90%).
Step B: add sodium hydroxide (31mg, 0.78mmol) time, stir 1-benzoyl-3-[3-(3-cyano group-1-ethyl-6-methoxyl group-1H-indoles-2-yl)-phenyl under the room temperature]-thiocarbamide (241mg, the suspension of methyl alcohol 0.530mmol) (2.0ml) and water (0.5mL).Reaction mixture heats 17h down at 50 ℃.Concentrated reaction mixture is to remove methyl alcohol.Water is joined in the mixture, and filtering precipitate washes with water, after the drying, obtain 179mg [3-(3-cyano group-1-ethyl-6-methoxyl group-1H-indoles-2-yl)-phenyl]-thiocarbamide is the white solid of compound 767 (yield 96%).
Embodiment 1BZ:1-ethyl-6-methoxyl group-2-[4-(2-phenylquinazoline-4-base amino)-phenyl]-preparation of 1H-indoles-3-nitrile (compound 458).
Backflow is spent the night and is heated 2-(4-aminophenyl)-1-ethyl-6-methoxyl group-1H-indoles-3-nitrile (100mg, 0.343mmol), 4-chloro-2-phenyl-quinazoline (83mg, 0.34mmol) and diisopropylethylamine (0.10mL, dehydrated alcohol 0.57mmol) (3mL) solution.Cooling and evaporating solns are absorbed in ethyl acetate (50mL) with resistates.With water and saturated brine (each 50mL) washing,, filter and evaporation then with anhydrous magnesium sulfate drying.Use ether to grind the solid that forms, after collection and the vacuum-drying, generate 1-ethyl-6-methoxyl group-2-[4-(2-phenylquinazoline-4-base is amino)-phenyl after filtration]-1H-indoles-3-nitrile (139mg, 0.280mmol, 82%).
Embodiment 1CA: the preparation of diethyl [4-(3-cyano group-6-oxyethyl group-1-ethyl-1H-indoles-2-yl)-phenyl]-phosphoramidate (compound 772).
With 2-(4-aminophenyl)-6-oxyethyl group-1-ethyl-1H-indoles-3-nitrile (148mg, 0.484mmol), diethyl chloro orthophosphate (0.086mL, 0.58mmol) and diisopropylethylamine (0.10mL, 0.57mmol) 1,4-diox (5mL) solution stirred 12 hours at ambient temperature, heated 24 hours down at 80 ℃ then.Cooling solution is poured the ethyl acetate of 50mL into.With water and saturated brine (each 50mL) washing,, filter and evaporation subsequently with anhydrous magnesium sulfate drying.Residual substance separates through flash chromatography (with 2/1 ethyl acetate/hexane wash-out on silica gel 60), the evaporation back generates diethyl [4-(3-cyano group-6-oxyethyl group-1-ethyl-1H-indoles-2-yl)-phenyl]-phosphoramidate (108mg, 0.245mmol, 51%) white powder.
Prepare following compounds in a similar way: compound 936,937,942,943,944,1081.
Embodiment 1CB:1-ethyl-6-methoxyl group-2-[4-(5-methyl isophthalic acid, 1-dioxo-16-[1,2,5] thiadiazoles-2-yl)-phenyl]-preparation of 1H-indoles-3-nitrile (compound 726).
Figure A20078000890205751
Steps A: past 2-(4-aminophenyl)-1-ethyl-6-methoxyl group-1H-indoles-3-nitrile (202mg, and adding N-β-(chlorethamin) SULPHURYL CHLORIDE in pyridine 0.693mmol) (2.0mL) solution (222mg, 1.39mmol).Mixture at room temperature stirs 17h, adds entry (12.0mL) then, and (3 * 2mL) extract this mixture with ethyl acetate.((2 * 2mL) washings are with MgSO for 2 * 2mL) aqueous solution, water with 10%HCl for extract 4Drying, and on rotary evaporator, concentrate.Through flash chromatography (0-5%, ethyl acetate/dichloromethane) purifying crude product, generate N-(2-chloro-ethyl)-N '-[4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indoles-2-yl) phenyl] sulphonamide (yield 75%), i.e. brown solid of compound 724 of 217mg.
Prepare following compounds in a similar manner: compound 540,541,542,574,576,704.
Step B: toward N-(2-chloro-ethyl)-N '-[4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indoles-2-yl) phenyl] sulphonamide (100mg, add in dry DMF 0.241mmol) (1.25mL) solution salt of wormwood (71.0mg, 0.514mmol).Mixture at room temperature stirs 17h, dilutes with water (7.5mL) then.(3 * 2mL) extractions, (2 * 2mL) washings are and with MgSO with water for extract with ethyl acetate for reaction mixture 4Drying, and generation 2-[4-after concentrating (1,1-dioxo-1 6-[1,2,5] thiadiazoles-2-yl) phenyl]-1-ethyl-6-methoxyl group-1H-indoles-3-nitrile (84mg, yield 88%) is the white solid of compound 725.
Prepare following compounds in a similar manner: compound: 705.
Step C: past 2-[4-(1,1-dioxo-1 6-[1,2,5] thiadiazoles-2-yl) phenyl]-1-ethyl-6-methoxyl group-1H-indoles-3-nitrile (34mg, add in dry DMF 0.086mmol) (1.0mL) solution salt of wormwood (25mg, 0.18mmol) and methyl iodide (20.4mg, 0.144mmol).Mixture at room temperature stirs 2h, with water (6.0mL) dilution, generates throw out then.Filtering precipitate washes with water, obtains 1-ethyl-6-methoxyl group-2-[4-(5-methyl isophthalic acid, 1-dioxo-1 after the drying 6-[1,2,5] thiadiazoles-2-yl)-phenyl]-1H-indoles-3-nitrile (35mg, yield 98%) is the white solid of compound 726.
Prepare following compounds in a similar manner: compound 727,1110.
EXAMPLE l CC:[4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indoles-2-yl)-phenyl]-preparation of carboxylamine propyl ester (compound 877).
Prepare 2-(4-amino-3-fluorophenyl)-1-ethyl-6-methoxyl group-1H-indoles-3-nitrile (74mg, 0.24mmol) (according to embodiment 1Ga preparation) and propyl chloroformate (0.033mL, (3mL) solution of EtOAc 0.29mmol) and saturated NaHCO down at 0 ℃ 3Biphase mixture (3mL) makes it be warming up to room temperature, stirs 24h.Reactant is subsequently with H 2O dilutes, and extracts with EtOAc (2X).Organic phase is with H 2O and saturated NaCl washing, dry then and concentrated.Generate the off-white color solid of [4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indoles-2-yl)-2-fluorophenyl]-carboxylamine propyl ester of 60mg (63%) through flash chromatography (EtOAc/ hexane 10-40%).
Prepare following compounds in a similar way: compound 875,876,878,879.By using 2-(4-amino-3-aminomethyl phenyl)-1-ethyl-6-methoxyl group-1H-indoles-3-nitrile, preparation following compounds: compound: 963,964,965.
Utilize described same materials of embodiment 1Y and step, preparation following compounds: compound 871,872,873,874.According to similar approach, by using 2-(4-amino-3-aminomethyl phenyl)-1-ethyl-6-methoxyl group-1H-indoles-3-nitrile, preparation following compounds: compound 959,960,961,962.
Utilize described same materials of embodiment 1BU and step, preparation following compounds: 909,910,911.According to similar approach, by using 2-(4-amino-3-aminomethyl phenyl)-1-ethyl-6-methoxyl group-1H-indoles-3-nitrile, preparation following compounds: compound: 966,967.
Embodiment C D: the preparation of cyclopropyl carboxylic acid { 4-[3-cyano group-1-ethyl-6-(2-imidazoles-1-base-oxyethyl group)-1H-indoles-2-yl]-phenyl }-acid amides (compound 118 3).
Figure A20078000890205771
Steps A: toward (3.66g, THF 12mmol) (20mL) solution adds Et according to the prepared compound 2-of embodiment 1Gb (4-aminophenyl)-6-oxyethyl group-1-ethyl-1H-indoles-3-nitrile 3N (3.37ml) and ring third carbonyl chloride (1.6mL, 18mmol).Mixture at room temperature stirs 3h.Add entry and ethyl acetate to reaction mixture then.Separate organic layer, with salt solution (2X) washing, and with anhydrous Na 2SO 4Filter and concentrate.Use ethyl acetate and hexane to make resistates crystallization again, obtain cyclopropyl carboxylic acid [4-(3-cyano group-6-oxyethyl group-1-ethyl-1H-indoles-2-yl)-phenyl]-acid amides of 99%.
Step B: past under 10 ℃ cyclopropyl carboxylic acid [4-(3-cyano group-6-oxyethyl group-1-ethyl-1H-indoles-2-yl)-phenyl]-(4.4g adds BBr in DCM 11.8mmol) (60mL) solution to acid amides 3(6.65mL, 70mmol).After the adding, this mixture stirs 3h down at 0 ℃.Carefully add NaHCO then to mixture 3The aqueous solution becomes alkalescence until mixture.Collect thick solid after filtration, generate cyclopropyl carboxylic acid [4-(3-cyano group-1-ethyl-6-hydroxyl-1H-indoles-2-yl)-phenyl]-acid amides of 91%, it need not to be further purified, and promptly can be used for subsequent step.
Step C: [4-(3-cyano group-1-ethyl-6-hydroxyl-1H-indoles-2-yl)-phenyl]-(4g adds K in MEK 11.6mmol) (15mL) solution to acid amides to cyclopropyl carboxylic acid 2CO 3(8g, 58mmol) and 1-bromo-2-chloro-ethane (6.7mL, 70mmol).This mixture of heating that spends the night subsequently refluxes.After being cooled to room temperature, add entry and ethyl acetate.Separate organic layer, with salt solution (2X) washing, and with anhydrous Na 2SO 4Drying, after filtering and concentrating, the cyclopropyl carboxylic acid of generation 81% 4-[6-(2-chloroethoxy)-3-cyano group-1-ethyl-1H-indoles-2-yl]-phenyl }-acid amides.
Step D: { 4-[6-(2-chloroethoxy)-3-cyano group-1-ethyl-1H-indoles-2-yl]-phenyl } in sealed tube-acid amides (102mg, acetonitrile 0.25mmol) (1.5mL) solution add NaI (46mg, 0.275mmol), K 2CO 3(138mg, 1mmol) and imidazoles (51mg, 0.75mmol).At 90 ℃ of following heated mixt, stirring is spent the night then.After being cooled to room temperature, add entry and ethyl acetate.Separate organic layer, with salt solution (2X) washing, and with anhydrous Na 2SO 4Drying is filtered and is concentrated.Crude compound is through preparation scale HPLC purifying, obtains 71% cyclopropyl carboxylic acid { 4-[3-cyano group-1-ethyl-6-(2-imidazoles-1-base-oxyethyl group)-1H-indoles-2-yl]-phenyl }-acid amides.
Use identical step and replace suitable nucleophilic reagent, generate following compounds: compound 952,1025,1054,1090,1091,1092,1093,1184,1394,1395,1413,1414.
Embodiment C E: the preparation of ethyl sulfonic acid [4-(3-cyano group-1-ethyl-6-trifluoromethoxy indoles-2-yl) phenyl] acid amides (compound 881).
Figure A20078000890205781
Steps A: to 61 ℃ and be in t-BuONO in the mild stirring (8.01mL, 67.5mmol) and CuCl 2(7.26g, and acetonitrile 54mmol) (50mL) suspension gradation adding 2-nitro-4-trifluoro-methoxyaniline (10.0g, 45.0mmol).After the adding, this mixture stirred 2 hours under this temperature.Remove on rotovap and desolvate, (6N 200mL) handles resistates, and (3 * 100mL) extract with methylene dichloride with HCl.Combining extraction liquid is with anhydrous Na 2SO 4Drying, and make its short silicagel pad of flowing through.Remove and to desolvate, with resistates join cyanoacetic acid benzyl ester (7.88g, 45mmol) and K 2CO 3(12.42g is in the solution of DMF 90mmol) (100mL).Mixture is poured frozen water (700mL) into 45 ℃ of following stirred overnight, and with methylene dichloride (3 * 100mL) extractions.Organic layer is with anhydrous Na 2SO 4Drying, the short silicagel pad of flowing through once more adopts eluent ethyl acetate simultaneously.Solvent is substituted by EtOH (160mL), acetate (16mL) and water (16mL) subsequently, with the reaction mixture hydrogenation of spending the night under 50psi and 5%Pd/C (2.80g).Use the Celite filtering mixt, remove volatile matter under the vacuum.Resistates is dissolved in the methylene dichloride (200mL), with Na 2CO 3(2M, 2 * 50mL), water (2 * 50mL) and salt solution (50mL) washing, and with anhydrous Na 2SO 4Dry.Remove crude product that the back of desolvating obtained through chromatography (silica gel, DCM/ hexane, 1/1), generate 6-trifluoromethoxy indoles (5.70g is 63% based on the yield of 2-nitro-4-trifluoro-methoxyaniline).
Step B: under 0 ℃ to 6-trifluoromethoxy indoles (2.68g, dry DMF 13.3mmol) (10mL) solution add Sulfuryl chloride isocyanate (2.35g, 1.44mL, 16.6mmol).Make mixture slowly return to room temperature, stir 1h.Mixture is poured in the frozen water (100mL), stirred 1h.Collecting precipitation thing after filtration, the water thorough washing after the vacuum-drying, is dissolved in DMF (15mL).In this solution, add K 2CO 3And EtI (16.6mmol), this mixture is 50 ℃ of following stirred overnight for 2.59g, 1.34mL.Be poured into frozen water (200mL) then.The collecting precipitation thing washes with water after filtration, through dry air and chromatography purification (silica gel, DCM) after, generate 1-ethyl-6-trifluoromethoxy indoles-3-nitrile (2.90g, 86%).
Step C: under-78 ℃ to the intermediate that above obtains (2.03g, 8.0mmol), the triisopropyl borate (2.16g, 2.65mL, 12.0mmol) anhydrous THF (15mL) solution add LDA (6.7mL, 1.5M, 10.0mmol).After the adding, this mixture stirs 15min down at-78 ℃, makes it slowly return to room temperature then, stirs 30min.Make it be cooled to-78 ℃ subsequently, add the 4-Iodoaniline (2.10g, 9.6mmol), PdCl 2(dppf) (0.29g, 0.4mmol), DMF (30mL) and K 2CO 3(12.0mL, 2.0M, 24.0mmol).Make this mixture slowly return to room temperature, stirring is spent the night, and is poured into frozen water (400mL) then.The collecting precipitation thing washes with water, chromatography (silica gel, EtOAc/DCM, 0.5/9.5) after, generate 2-(4-aminophenyl)-1-ethyl-6-trifluoromethoxy indoles-3-nitrile (1.99g, 72%).
Step D: to the resulting compound of step C (31mg, anhydrous pyridine 0.1mmol) (1.0mL) solution add ethyl sulfonyl chloride (14 μ L, 0.15mmol).This mixture at room temperature stirs and spends the night, and dilutes with water (5mL) then.Organic layer extracts with DCM (5mL), and with HCl (2N, 2 * 3mL), water (2 * 4mL) and salt solution (3mL) washing, chromatography (silica gel, EtOAc/DCM, 0.5/9.5) after obtain product, i.e. ethyl sulfonic acid [4-(3-cyano group-1-ethyl-6-trifluoromethoxy indoles-2-yl) phenyl] acid amides (33mg, 83%).
Utilize above-mentioned path to use suitable alkyl sulfonyl chloride (step 1Y) or chloro-formic ester (step 1AJ) preparation compound 882,883,884,885,886,887,888,889.
Embodiment 1CF:2-[4-(1,1-titanium dioxide isothiazolidine-2-yl) phenyl]-preparation of 1-ethyl-6-(trifluoromethoxy) indoles-3-nitrile (compound 903).
Figure A20078000890205801
Steps A: toward 40 ℃ and be in 6-trifluoromethoxy indoles in the stirring (3.01g, 15.0mmol) (3.59g adds DMAP (0.04g) in DCM 16.5mmol) (30mL) solution with the two carbonic acid tert-butyl esters.After stirring was spent the night, this mixture was successively with 0.1N HCl, water and salt water washing, and with anhydrous Na 2SO 4Dry.Evaporating solvent, resistates generate 6-trifluoromethoxy-1H-indoles-1-carboxylic acid tert-butyl ester through chromatography (silica gel, EtOAc/ hexane, 1/9).
Step B: (4.73g, 5.8mL 26.3mmol) are dissolved in anhydrous THF (20mL), and this solution is cooled to ℃ with above-mentioned Boc-indoles and triisopropyl borate.(15.0mL, the single THF mixture of 1.5M is dissolved in hexanaphthene, 22.5mmol) dropwise to add LDA during stirring.Mixture stirs down 15min at 0 ℃, at room temperature stirs 0.5h then, on ice-water bath, add subsequently HCl (6N, 3.75mL, 22.5mmol).Remove organic solvent under the vacuum, resistates is suspended in H 2Among the O (100mL), and be 4～5 with the pH acidifying with HCl (6N).The collecting precipitation thing with water and hexane wash, after the dry air, generates 1-Boc-6-trifluoromethoxy indoles-2-boric acid (2.56g, 49%) after filtration.
Step C: to above prepared 1-Boc-6-trifluoromethoxy indoles-2-boric acid (0.74g, 2.1mmol), 2-(4-iodophenyl) isothiazolidine-1, the 1-dioxide (0.76g, 2.4mmol) and PdCl 2(dppf) (0.08g adds K in the mixture of DMF 0.1mmol) (6.0mL) solution 2CO 3(3.2mL, 2.0M, aqueous solution 6.4mmol).Mixture at room temperature stirs and spends the night, and pours frozen water (100mL) then into.The collecting precipitation thing washes with water, through flash chromatography (silica gel, DCM/EtOAc, 9/1) behind the purifying, generates 1-Boc-2-[4-(1,1-titanium dioxide isothiazolidine-2-yl) phenyl]-6-methoxyl group indoles, this product is at room temperature handled 1h with DCM (15mL) solution of 50%TFA.After removing volatile matter, use saturated NaHCO 3Resistates is carried out the meticulous stirring of 0.5h.Collecting precipitation thing after filtration, the water thorough washing obtains 1-H-2-[4-(1, the 1-titanium dioxide isothiazolidine-2-yl) phenyl of substantially pure after the drying]-6-trifluoromethoxy indoles.
Step D: (0.38g, 0.23mL is 2.68mmol) at 0 ℃ of dry DMF (10mL) solution of handling the intermediate that above obtains down to use Sulfuryl chloride isocyanate.This mixture at room temperature stirs subsequently and spends the night, and pours frozen water (150mL) into, continues to stir 0.5h.Collecting precipitation thing after filtration, the water thorough washing obtains 1-H-2-[4-(1,1-titanium dioxide isothiazolidine-2-yl) phenyl after the dry air]-6-trifluoromethoxy indoles-3-nitrile (0.81g, 90%).
Step e: to 1-H-2-[4-(1,1-titanium dioxide isothiazolidine-2-yl) phenyl]-6-trifluoromethoxy indoles-3-nitrile (63mg, 0.15mmol) and K 2CO 3(62mg, add in DMF 0.45mmol) (2.0mL) solution iodoethane (36 μ L, 0.45mmol).Mixture stirs down at 50 ℃ and spends the night, and pours frozen water (10mL) then into.Collecting precipitation thing after filtration, the water thorough washing obtains 2-[4-(1,1-titanium dioxide isothiazolidine-2-yl) phenyl behind the column chromatography purifying]-6-trifluoromethoxy-1-ethylindole-3-nitrile (59mg, 88%).
Prepare following compounds according to method same as described above: compound 902,904,905,906.
Embodiment 1CG:[4-(3-cyano group-1-cyclopropyl-6-methoxyl group indoles-2-yl) phenyl] preparation of carbamic acid isopropyl ester (compound 1234).
Figure A20078000890205811
Steps A: to the 2-bromo-4-methoxyphenylacetic acid (24.5g that is stirring, DCM 100mmol) (100mL) suspension adding DMF (～10mL), disappear up to all solids, add DCC (22.66g subsequently, 110mmol) and HOBt (14.85g, 110mmol).Behind the stirring at room 10min, (150mmol), the mixture of formation at room temperature stirs 4h for 8.55g, 10.4mL to add cyclopropylamine toward mixture.Cross filter solid, with DCM (300mL) thorough washing.Filtrate is cooled to-10 ℃, gentle agitation 1h removes by filter extra urea by product once more.Make filtrate flow through silicagel pad, with DCM/EtOAc, 8/2) wash-out.Except that after desolvating, obtain encircling the white solid (28.34g, 100%) of propionic acid amide intermediate.
Step B: with above-mentioned acid amides (14.2g, 50.0mmol), K 2CO 3(13.8g, 100mmol), (0.74g, 5.0mmol) and N, (mixture of toluene 10.0mmol) (150mL) solution is at 110 ℃ and N for 1.42g, 1.57mL for N '-dimethyl cyclohexanediamine for Cul 2Stir 48h under the atmosphere.After being cooled to room temperature, mixture filters through Celite, and with the DCM thorough washing.Reduction vaporization filtrate is to doing, and resistates is through chromatography (DCM/EtOAc, 9.5/0.5) faint yellow solid of generation product 1-cyclopropyl-6-methoxyl group Oxoindole (4.30g, 42%).
Step C: (5.0g, anhydrous DCM (25mL) solution 24.6mmol) adds DIBAL-H (1.0M, 35.0mL, DCM solution 35.0mmol) to resulting Oxoindole above under 0 ℃.After the adding, mixture at room temperature stirs 4h, is cooled to 0 ℃ again, dropwise adds HCl (2N) subsequently.The DCM layer with HCl (2N, 10mL), water and salt water washing, with anhydrous Na 2SO 4Dry.Remove desolvate the resulting crude product in back through chromatography (hexane/EtOAc, 9.5/0.5) after, generate the colorless oil of 1-cyclopropyl-6-methoxyl group indoles (4.52g, 98%).
Step D: under 0 ℃ to 1-cyclopropyl-6-methoxyl group 1 indoles (3.29g, dry DMF 17.6mmol) (30mL) solution add Sulfuryl chloride isocyanate (3.11g, 1.91mL, 22.0mmol).After the adding, mixture at room temperature stirs 2h, carries out water treatment subsequently.Obtain 3-cyano group-1-cyclopropyl-6-methoxyl group indoles (3.05g, 82%) through chromatography (silica gel, hexane/EtOAc, 9/1).
Step e: under-78 ℃ to the intermediate that above obtains (2.65g, 12.5mmol) and the triisopropyl borate (3.38g, 4.14mL, 18.8mmol) anhydrous THF (18mL) solution add LDA (10mL, 1.5M, 15.0mmol).After the adding, this mixture stirs 15min down at-78 ℃, makes it slowly return to room temperature then, stirs 30min.Make it be cooled to-78 ℃ subsequently, add the 4-Iodoaniline (3.29g, 15.0mmol), PdCl 2(dppf) (0.46g, 0.6mmol), DMF (40mL) and K 2CO 3(18.8mL, 2.0M, 37.6mmol).Make this mixture slowly return to room temperature, stirring is spent the night, and is poured into frozen water (400mL) then.The collecting precipitation thing washes with water, dry and chromatography (silica gel, EtOAc/DCM, 0.5/9.5) after, generation 2-(4-aminophenyl)-1-cyclopropyl-6-methoxyl group indoles-3-nitrile (2.84g, 75%).
Step F: (61mg, anhydrous pyridine 0.2mmol) (2.0mL) solution adds isopropyl chlorocarbonate (0.3mL, 1.0M, toluene solution 0.3mmol) to the resulting compound of step e.Mixture at room temperature stirs and spends the night, and dilutes with water (10mL) then.Organic layer extracts with DCM (10mL), and with HCl (2N, 2 * 3mL), water (2 * 4mL) and salt solution (3mL) washing, chromatography (silica gel, EtOAc/DCM, 0.5/9.5) after obtain product, i.e. [4-(3-cyano group-1-cyclopropyl-6-methoxyl group indoles-2-yl) phenyl] carbamic acid isopropyl ester (66mg, 85%).
Use above-mentioned chemical reaction to prepare compound 1235 and 1236.
Embodiment 1CH:1-allyl group-6-methoxyl group-2-[4-(2-oxo-oxo-pyrrolidine-1-yl)-phenyl]-preparation of 1H-indoles-3-nitrile (compound 938).
Figure A20078000890205831
(92.3mg 0.43mmol) and 1-(4-iodophenyl)-pyrrolidin-2-one, generates the compound 938 of 99.0mg (yield 61.3%) to utilize the described method of embodiment 1Gb to be substituted 1-allyl group-6-methoxyl group-1H-indoles-3-nitrile.
Embodiment 1CI:6-encircles propoxy--2-[4-(1,1-dioxo-1 λ 6-isothiazolidine-2-yl)-phenyl]-preparation of 1-ethyl-1H-indoles-3-nitrile (compound 1046).
Figure A20078000890205832
Steps A: (503.9mg adds anhydrous K in DMF 2.70mmol) (5mL) solution to 6-hydroxyl-1-ethyl-1H-indoles-3-nitrile 2CO 3(1.12g, 8.12mmol) and 1-bromine 2-fluoroethane (413.7mg, 3.29mmol).The mixture that forms stirs down at 80 ℃, exhausts (measuring through TLC) fully until raw material.Reaction mixture, (THF solution 5.43mmol) continues stirring down at 80 ℃ and spends the night for 1M, 5.5ml to add potassium tert.-butoxide.This mixture distributes with EtOAc (30mL) and 1N HCl (20mL).Use saturated NaHCO 3With saturated NaCl washing organic phase, be dried and concentrate.Through silica gel chromatography (EtOAc/ hexane, 10-25%) separated product, the white solid of generation 430.2mg (74.9%) 1-ethyl-6-vinyloxy group-1H-indoles-3-nitrile.
Step B: use syringe in 10 minutes, zinc ethyl to be joined 1-ethyl-6-vinyloxy group-1H-indoles-3-nitrile (288.1mg, 1.36mmol), chloroiodomethane (268.9mg, 1.53mmol) and 5ml1, in the mixture of 2-ethylene dichloride, temperature remains on-10 ℃.This mixture heating up to 20-25 ℃ 20 minutes, be cooled to 0 ℃ then.Under this temperature, add saturated NH successively 4Cl (15mL), strong aqua (15mL) and ethyl acetate (15mL) stir 10min.Separate each mutually after, use ethyl acetate (10mL) back extraction water.The organic phase that merges is with saturated NH 4Cl (10mL) washing is with MgSO 4Drying, concentrated solution uses the 15-30% ethyl acetate/hexane through the chromatography purification product subsequently, generates the yellow solid of 6-ring propoxy--1-ethyl-1H-indoles-3-nitrile of 140.5mg (yield 45.7%).
Step C: use the method identical with embodiment 1Gb with 2-(4-iodo-phenyl)-isothiazolidine 1, the 1-dioxide replaces the 4-Iodoaniline, generates target compound.
According to above-mentioned steps A to C, also prepared compound 1047 in a similar manner.
Embodiment C J: the preparation of propane-1-sulfonic acid [4-(3-cyano group-6-difluoro-methoxy-1-ethyl-1H-indoles-2-yl)-phenyl]-acid amides (compound 928).
Figure A20078000890205841
Steps A: with 6-difluoro-methoxy-1-ethyl-1H-indoles-3-nitrile (316.3mg, 1.34mmol) and the triisopropyl borate (402.9mg, THF 2.14mmol) (15mL) solution is cooled to-78 ℃, and (1.5M list-THF is dissolved in hexanaphthene with LDA with it, 1.07mL, 1.61mmol) handle.After the adding, acetone/the dry ice bath changes ice bath into, and solution carries out 30min again and stirs.Solution is cooled to-78 ℃, adds 4-Iodoaniline (299.5mg, DMF 1.37mmol) (8mL) solution, K successively 2CO 3(2M, 2.01mL, 6.02mmol) and PdCl 2Dppf (51.3mg, 0.07mmol) solution.Continuous three vacuum exhaust/N 2Purging is removed the gas of mixture, stirs spend the night (ca.16h).Pour reaction mixture the water of 4 times of volumes into, add the ethyl acetate of 4 times of volumes.Separate each phase, and use more ethyl acetate extraction water.Organic phase is with water and saturated NaCl washing, then with anhydrous MgSO 4Drying, filtration and evaporation.Residual substance carries out the column chromatography purifying through 5-15% ethyl acetate/hexane wash-out on silica gel, generates the white solid of the aniline intermediate of 304.5mg (70%).
Step B: use the method identical to be substituted the n-propyl SULPHURYL CHLORIDE, generate target compound with embodiment 1Y.
Use essentially identical method and replace other SULPHURYL CHLORIDE, preparation following compounds: compound 929,930,931.
Embodiment 1CK:[4-(3-cyano group-6-difluoro-methoxy-1-ethyl-1H-indoles-2-yl)-phenyl]-preparation of Urethylane (compound 1130).
Figure A20078000890205851
Use 2M wet chemical (0.370mL, 0.74mmol) processing 2-(4-aminophenyl)-6-difluoro-methoxy-1-ethyl-1H-indoles-3-nitrile (200mg, 0.611mmol) and methyl-chloroformate (95 μ L, 1.23mmol) etheric acid (2mL) solution, the mixture vigorous stirring of formation is spent the night.Add saturated brine solution (1mL), mixture stirred 10 minutes.Remove organic layer,, filter and evaporation with anhydrous magnesium sulfate drying.Use 1/1 ether-hexane to grind the solid that forms, collect solid after filtration, after the vacuum-drying, generate the white solid of target product.
According to similar approach be: compound 1131,1132,1133,1134,1135 with the compound of suitable reagent preparation.
Embodiment 1CL:1-[4-(3-cyano group-6-difluoro-methoxy-1-ethyl-1H-indoles-2-yl)-phenyl]-preparation of 3-propyl group-urea (compound 893).
Figure A20078000890205852
Use the n-propyl isocyanic ester (115mL, 1.23mmol) and triethylamine (170mL, 1.22mmol) processing 2-(4-aminophenyl)-6-difluoro-methoxy-1-ethyl-1H-indoles-3-nitrile (200mg, 0.611mmol) 1,2-ethylene dichloride (2mL) solution.The solution that forms stirred 12 hours at ambient temperature, concentrated then.Separate residual substance through silica gel chromatography (1/2 ethyl acetate-hexane), generate the solid of target product.
According to similar approach be: compounds 892,894 with the compound of suitable reagent preparation.
Embodiment 1CM: the preparation of morpholine-4 carboxylic acid [4-(3-cyano group-1-cyclobutyl-6-oxyethyl group-1H-indoles-2-yl)-phenyl]-acid amides (compound 1166).
Figure A20078000890205861
Steps A: the 6-oxyethyl group-1H-indoles-3-nitrile that will prepare according to embodiment 1A (2.8g, 15mmol) and Cs 2CO 3(11.6g, 35.6mmol), (1.73mL 17.9mmol) mixes in sealed tube for DMF (21mL) and brominated butyl.Reaction mixture is heated 8h down at 80 ℃.Then with H 2O (200mL) cancellation, and extract with EtOAc.Successively with H 2O and salt solution backwash EtOAc layer.The dry organic phase that concentrates.Through silica gel chromatography (hexane/CH 2Cl 2.50-100%) purifying generates the white solid of 1-cyclobutyl-6-oxyethyl group-1H-indoles-3-nitrile (3.00g, 83%).
Step B: follow the described method of embodiment 1Gb substantially, with 1-cyclobutyl-6-oxyethyl group-1H-indoles-3-nitrile (3.0g, 12.4mmol) be converted into the off-white color solid of 2-(4-aminophenyl)-1-cyclobutyl 6-oxyethyl group-1H-indoles-3-nitrile (2.60g, 68%) through the Suzuki coupling.
Step C: with 2-(4-aminophenyl)-1-cyclobutyl-6-oxyethyl group-1H-indoles-3-nitrile (40mg, 0.12mmol), 4-oil of mirbane chlorocarbonate (60mg, 0.30mmol), CH 2Cl 2(25 μ L 0.31mmol) at room temperature stir 1 hour for (400 μ L) and pyridine.The adding morpholine (60 μ L, 0.70mmol).After stirring 30 minutes again under the room temperature, reaction mixture is with CH 2Cl 2Dilution, and the NaOH solution washing to dilute are to remove xanchromatic nitrophenols by product.Dry and concentrated organic layer.Through silica gel chromatography (CH 2Cl 2/ EtOAc, 7/3) purifying generates the white solid of morpholine-4-carboxylic acid [4-(3-cyano group-1-cyclobutyl-6-oxyethyl group-1H-indoles-2-yl)-phenyl]-acid amides (53mg, 100%).
In the end a step is used suitable amine in a similar way, preparation following compounds: compound 1087,1088,1089,1119,1159,1168,1191,1266,1288,1324,1325,1326.
Embodiment 1CN:rac-[4-(3-cyano group-1-cyclobutyl-6-oxyethyl group-1H-indoles-2-yl)-phenyl]-preparation of carboxylamine 1-cyclopropyl-ethyl ester (compound 1147).
Figure A20078000890205871
Will be according to prepared 2-(4-the aminophenyl)-1-cyclobutyl-6-oxyethyl group-1H-indoles-3-nitrile (50mg of embodiment 1CM step B, 0.15mmol) and 4-oil of mirbane chlorocarbonate (76mg, 0.38mmol), (30 μ L 0.37mmol) mix for DCE (0.5mL) and pyridine.Suspension at room temperature stirs 1h.Adding Rac-cyclopropyl carbinol methine (100 μ L, 0.98mmol).This mixture is 75 ℃ of following heated overnight.This reaction mixture is subsequently with CH 2Cl 2Dilution, and the NaOH solution washing to dilute are to remove xanchromatic nitrophenols by product.Dry and concentrated organic layer.Through silica gel chromatography (CH 2Cl 2) purifying generates rac-[4-(3-cyano group-1-cyclobutyl-6-oxyethyl group-1H-indoles-2-yl)-phenyl]-white solid of carboxylamine 1-cyclopropyl-ethyl ester (40mg, 60%).
Use suitable alcohol in a similar way, preparation following compounds: compound 1146,1158,1167,1192,1208,1209,1210,1215,1216,1240,1241,1242,1243,1244,1246,1247,1248,1249,1250,1264,1265,1267,1268,1281,1282,1283,1286,1287,1289,1290,1291,1292,1294,1295,1296,1297,1298,1299,1312,1313.
The preparation of embodiment 1CO:1-cyclobutyl-6-oxyethyl group-2-(4-ethylamino-phenyl)-1H-indoles-3-nitrile (compound 1239)
Figure A20078000890205881
Steps A: (600mg 1.81mmol) is suspended in CH to 2-(4-the aminophenyl)-1-cyclobutyl-6-oxyethyl group-1H-indoles-3-nitrile that will prepare according to embodiment 1CM step B 2Cl 2(18mL) and Et 3N (390 μ L, 2.7mmol) in.Dropwise add trifluoroacetic anhydride (310 μ L, 2.2mmol).Reaction mixture at room temperature stirred 30 minutes, and it is dissolved fully.Reaction mixture is with saturated NaHCO subsequently 3Solution washing.Dry and concentrated organic layer generates N-[4-(3-cyano group-1-cyclobutyl-6-oxyethyl group-1H-indoles-2-yl)-phenyl]-2,2, the yellow solid of 2-three fluoro-ethanamides (802mg, 100%).
Step B: with N-[4-(3-cyano group-1-cyclobutyl-6-oxyethyl group-1H-indoles-2-yl)-phenyl]-2,2, (800mg 1.8mmol) is dissolved in DMF (10mL) to 2-three fluoro-ethanamides.Add NaH (140mg, 60%, oily suspended substance 3.5mmol).Stirred for several minute under the room temperature, add subsequently iodoethane (176 μ L, 2.2mmol).Stir under the room temperature and spend the night, stir 6h down at 75 ℃ subsequently.Be necessary gradation add NaH (200mg, 5.0mmol) and iodoethane (200 μ L 2.5mmol) carry out with driving a reaction.It is heated down at 75 ℃.Add extra iodoethane (200 μ L, 2.5mmol).Heat 2h again.Reaction mixture is with H subsequently 2The O dilution extracts with EtOAc then.Dry and concentrated EtOAc layer.Through silica gel chromatography (CH 2Cl 2) obtain estimating product N-[4-(3-cyano group-1-cyclobutyl-6-oxyethyl group-1H-indoles-2-yl)-phenyl]-N-ethyl-2,2,2-three fluoro-ethanamides and hydrolysate 1-cyclobutyl-6-oxyethyl group-2-(4-ethylamino--phenyl)-1H-indoles-3-nitrile can't isolating mixture (384mg).
Step C: will be dissolved in methane (5mL) from the rapid crude mixture of previous step.(1.0mL 6mmol), heats 1h with this mixture down at 80 ℃ to add 6N NaOH.Reaction mixture is with H subsequently 2The O dilution is then with CH 2Cl 2Extraction.Dry and concentrated organic layer.Through silica gel chromatography (CH 2Cl 2) purifying, generate purified 1-cyclobutyl-6-oxyethyl group-2-(4-ethylamino-phenyl)-1H-indoles-3-nitrile (343mg, two the step yields be 53%) white solid.
Separate 1-cyclobutyl-2-(4-diethylamine-phenyl)-6-oxyethyl group-1H-indoles-3-nitrile (compound 1217,77mg, 11%), it is the by product of the described reaction of embodiment 1CO step B.
Embodiment 1CP:[4-(3-cyano group-1-cyclobutyl-6-oxyethyl group-1H-indoles-2-yl)-phenyl]-preparation of ethyl-carboxylamine ring pentyl ester (compound 1251).
Figure A20078000890205891
(35mg 0.10mmol) is dissolved in the pyridine (300 μ L) 1-cyclobutyl-6-oxyethyl group-2-(4-ethylamino-the phenyl)-1H-indoles-3-nitrile that will prepare according to embodiment 1CO step C.The adding chloroformate cyclopentyl ester (25 μ L, 0.17mmol).Reaction mixture at room temperature stirs 2.5h.(10 μ L 0.07mmol), drive reaction and finish to add more chloro-formic ester.After stirring 90min again, reaction mixture distributes with the HCl and the EtOAc aqueous solution.Dry and concentrated organic layer.Through the silica gel chromatography purifying, generate the white solid of [4-(3-cyano group-1-cyclobutyl-6-oxyethyl group-1H-indoles-2-yl)-phenyl]-ethyl-carboxylamine ring pentyl ester (41mg, 87%).
Use suitable chloro-formic ester to prepare compound 1252 in a similar manner.
Embodiment 1CQ:{4-[3-cyano group-1-cyclobutyl-6-(3-[1,2,4] triazol-1-yl-propoxy-)-1H-indoles-2-yl]-phenyl }-preparation of carbamic acid isopropyl ester (compound 1255).
Figure A20078000890205892
Steps A: toward [4-(3-cyano group-1-cyclobutyl-6-methoxyl group-1H-indoles-2-yl)-phenyl]-(950mg, DCM 2.35mmol) (10mL) solution added BBr to carbamic acid isopropyl ester in 20 minutes 3(556uL, 5.9mmol).Reaction mixture at room temperature stirs 1h again, adds water (1mL) then.Removal of solvent under reduced pressure.Resistates is dissolved among the MeOH, pours cold water then into.The collecting precipitation thing with hexane wash, after the vacuum-drying, generates [4-(3-cyano group-1-cyclobutyl-6-hydroxyl-1H-indoles-2-yl)-phenyl]-carbamic acid isopropyl ester (650mg, 71%) after filtration.
Step B: toward [4-(3-cyano group-1-cyclobutyl-6-hydroxyl-1H-indoles-2-yl)-phenyl]-(340mg adds K in DMF 0.87mmol) (2mL) solution to carbamic acid isopropyl ester 2CO 3(132mg, 0.96mmol) (172uL, 1.75mmol), reactant stirs 5h down at 60 ℃ with 3-bromo-n-propyl chloride.Pour reaction mixture into cold water then, the collecting precipitation thing with hexane wash, after the vacuum-drying, generates purpose product (370mg, 92%) after filtration.
Step C: to 4-[6-(3-chloro-propyl group)-3-cyano group-1-cyclobutyl-1H-indoles-2-yl]-phenyl }-carbamic acid isopropyl ester (37mg, CH 0.08mmol) 3CN (1mL) solution adding sodium iodide (71mg, 0.48mmol).The mixture that forms at room temperature refluxes to stir and spends the night.Evaporating solvent subsequently, resistates is with dry DMF (1mL) dilution, and then with 1,2, the sodium salt of 4-triazole (0.16mmol) is at room temperature handled and is spent the night.Removal of solvent under reduced pressure, resistates dilutes with ethyl acetate, subsequently with water washing.Concentrate organic layer, grind with hexane, collecting precipitation thing after filtration, with the hexane solution thorough washing of 50% ethyl acetate, after the vacuum-drying, generate { 4-[3-cyano group-1-cyclobutyl-6-(3-[1,2,4] triazol-1-yl-propoxy-)-1H-indoles-2-yl]-phenyl }-carbamic acid isopropyl ester (31mg, 78%), promptly compound 1255.
Adopt above-mentioned steps A-C to prepare following compounds in a similar manner: compound 1253,1254,1260,1261,1262,1427,1430.
Embodiment 1CR:{4-[3-cyano group-1-cyclobutyl-6-(2-[1,2,4] triazol-1-yl-oxyethyl group)-1H-indoles-2-yl]-phenyl }-preparation of carbamic acid isopropyl ester (compound 1276).
Figure A20078000890205901
Steps A: toward [4-(3-cyano group-1-cyclobutyl-6-hydroxyl-1H-indoles-2-yl)-phenyl]-carbamic acid isopropyl ester (390mg, CH 1.0mmol) 3Add K in CN (5mL) solution 2CO 3(414mg, 3.0mmol) (250uL, 3.0mmol), reactant stirs 18h down at 80 ℃ with 3-bromo-1-monochloroethane.Pour reaction mixture into cold water then, the collecting precipitation thing with hexane wash, after the vacuum-drying, generates purpose product (420mg, 93%) after filtration.
Step B: to 4-[6-(3-chloroethoxy)-3-cyano group-1-cyclobutyl-1H-indoles-2-yl]-phenyl }-carbamic acid isopropyl ester (42mg, CH 0.09mmol) 3CN (1mL) solution adding sodium iodide (56mg, 0.37mmol).The mixture that forms at room temperature refluxes to stir and spends the night.Evaporating solvent subsequently, resistates is with dry DMF (1mL) dilution, and then with 1,2, the sodium salt of 4-triazole (0.18mmol) is at room temperature handled and is spent the night.Removal of solvent under reduced pressure, resistates dilutes with ethyl acetate, subsequently with water washing.Concentrate organic layer, grind with hexane.Collecting precipitation thing after filtration is with the hexane solution thorough washing of 50% ethyl acetate, after the vacuum-drying, generate 4-[3-cyano group-1-cyclobutyl-6-(3-[1,2,4] triazol-1-yl-oxyethyl group)-1H-indoles-2-yl]-phenyl }-carbamic acid isopropyl ester (28mg, 64%) compound 1276, i.e..
Adopt above-mentioned steps A and B to prepare following compounds in a similar manner: compound 1269,1270,1271,1272,1273,1274,1275,1276,1277,1278,1434,1435.
Embodiment 1CS:{4-[3-cyano group-1-cyclobutyl-6-(2-[1,2,4] triazol-1-yl-oxyethyl group)-1H-indoles-2-yl]-phenyl }-preparation of carboxylamine 1-cyclopropyl ethyl ester (compound 1329).
Figure A20078000890205911
Steps A: (909mg adds 4-oil of mirbane chloro-formic ester (6mmol) in pyridine 3mmol) (5mL) solution, at room temperature stir 2h subsequently to 2-(4-aminophenyl)-1-cyclobutyl-6-hydroxyl-1H-indoles-3-nitrile under the room temperature.Add the cyclopropyl carbinol methine to reactant, stir 8h down at 80 ℃ then.Reaction mixture is with 1N HCl dilution, then with ethyl acetate extraction.Concentrate organic layer, resistates is dissolved among the EtOAc, grind with hexane.The collecting precipitation thing with hexane wash, after the vacuum-drying, generates [4-(3-cyano group-1-cyclobutyl-6-hydroxyl-1H-indoles-2-yl)-phenyl]-carboxylamine 1-cyclopropyl-ethyl ester (996mg, 80%) after filtration.
Step B: toward [4-(3-cyano group-1-cyclobutyl-6-hydroxyl-1H-indoles-2-yl)-phenyl]-carboxylamine 1-cyclopropyl-ethyl ester (1.5g, CH 3.61mmol) 3Add K in CN (8mL) solution 2CO 3(1.5g, 10.8mmol) (895uL, 10.8mmol), reactant stirs 18h down at 80 ℃ with 2-bromo-1-monochloroethane.Pour reaction mixture into cold water then, the collecting precipitation thing with hexane wash, after the vacuum-drying, generates purpose product (1.46g, 84%) after filtration.
Step C: to 4-[6-(2-chloroethoxy)-3-cyano group-1-cyclobutyl-1H-indoles-2-yl]-phenyl }-carboxylamine 1-cyclopentyl-ethyl ester (1.46g, CH 3.05mmol) 3CN (10mL) solution adding sodium iodide (1.84g, 12.22mmol).The mixture that forms at room temperature refluxes to stir and spends the night.Evaporating solvent, resistates be with dry DMF (20mL) dilution, need not to be further purified during follow-up use.Add 1,2 to the 1mL DMF solution that contains iodine ethyl intermediate (0.153mmol), the sodium salt of 4-triazole (0.31mmol), reactant is stirred overnight at room temperature.Reaction mixture is with 0.5mL DMF dilution, and the purpose product obtains { 4-[3-cyano group-1-cyclobutyl-6-(2-[1 through preparation scale LC purifying, 2,4] triazol-1-yl-oxyethyl group)-1H-indoles-2-yl]-phenyl }-carboxylamine 1-cyclopropyl ethyl ester (23mg, 29%), promptly compound 1329.
Adopt above-mentioned steps A-C to prepare following compounds in a similar manner: compound 1327,1328.
Embodiment 1CT:1-{4-[3-cyano group-1-cyclobutyl-6-(3-[1,2,4] triazol-1-yl-propoxy-)-1H-indoles-2-yl]-phenyl }-preparation of 3-sec.-propyl-urea (compound 1314).
Figure A20078000890205921
Steps A: under 0 ℃ to 1-[4-(3-cyano group-1-cyclobutyl-6-methoxyl group-1H-indoles-2-yl)-phenyl]-3-sec.-propyl-urea (2.21g, CH 5.49mmol) 2Cl 2(30mL) add 1M BBr in the solution 3CH 2Cl 2(16.5mL, 16.5mmol) solution.Make mixture be warming up to room temperature, keep 1h.Then reaction mixture is poured on ice, adds 1MNaHCO 3The aqueous solution is 7-8 until pH.Product is with 100mL ethyl acetate (3X) extraction, and organic phase is with the saturated NaCl washing of 100mL.Merge organic phase, with it with MgSO 4Dry.Remove and to desolvate, reclaim 1-[4-(3-cyano group-1-cyclobutyl-6-hydroxyl-1H-indoles-2-yl)-phenyl of 1.95g (92%)]-the brown solid of 3-sec.-propyl-urea.
Step B: to 1-[4-(3-cyano group-1-cyclobutyl-6-hydroxyl-1H-indoles-2-yl)-phenyl]-(750mg adds K in acetonitrile 1.93mmol) (10mL) solution to 3-sec.-propyl-urea 2CO 3(800mg, 5.79mmol) and 1-bromo-3-chloropropane (382 μ L, 3.86mmol).After 80 ℃ of following stirred overnight, reaction mixture is removed and is desolvated.Reactant is suspended in the ethyl acetate of 100mL again.Organic phase is with the H of 200mL 2O washing, water is with twice of the ethyl acetate extraction of 100mL.Merge organic phase, with MgSO 4Drying is removed and to be desolvated, and generates 1-{4-[6-(3-chlorine propoxy-)-3-cyano group-1-cyclobutyl-1H-indoles-2-yl of 769mg (86%)]-phenyl }-chocolate brown powder of 3-sec.-propyl-urea.
Step C: to 1-{4-[6-(3-chlorine propoxy-)-3-cyano group-1-cyclobutyl-1H-indoles-2-yl]-phenyl }-3-sec.-propyl-urea (400mg, and adding anhydrous Na I in acetonitrile/DMF 0.860mmol) (8mL, 4/1) solution (258mg, 1.72mmol).After 60 ℃ stirring is spent the night down, detect the demonstration reactant through LCMS-UV and be converted into product.Reaction mixture is removed and is desolvated, and reaction mixture is dissolved among the DMF again, and final volume is 14.0mL.
Step D: to above-mentioned 1mL DMF solution, 1-{4-[3-cyano group-1-cyclobutyl-6-(3-iodine propoxy-)-1H-indoles-2-yl]-phenyl-3-sec.-propyl-urea (34mg, add in 0.062mmol) anhydrous 1,2, the 4-triazole sodium salt (10.0mg, 0.110mmol).After ambient temperature overnight stirred, filter reaction mixture was used preparation scale LC/UV purification process purifying with it.Remove and to desolvate, obtain 1-{4-[3-cyano group-1-cyclobutyl-6-(3-[1,2,4] triazol-1-yl-propoxy-)-1H-indoles-2-yl of 12.3mg (40%)]-phenyl }-white powder of 3-sec.-propyl-urea (compound 1314).
According to the method for preparing following compounds: compound 1306,1307,1308,1309,1315,1316,1317,1318,1319,1320,1321,1323 and 1324.
Embodiment 1CU:1-ethyl-1 '-methylsulfonyl-6-methoxyl group-1H, 1 ' H-[2,5 '] preparation of two indoles-3-nitrile (compound 1330).
Figure A20078000890205931
The use methylsulfonyl chloride (0.034mL 0.44mmol) handles according to the prepared 1-ethyl-6-methoxyl group-1H of embodiment 1Gb, 1 ' H-[2,5 '] two indoles-3-nitrile (spend the night for 70mg, pyridine 0.22mmol) (2mL) solution by stirring.Use H then 2The O diluted reaction mixture, and extract with ethyl acetate (3X).Organic phase is with H 2O and saturated NaCl washing after dry the concentrating, uses EtOAc/ hexane (30-80%) through purified by flash chromatography, generate the 1-ethyl-1 of 70mg (81%) '-methylsulfonyl-6-methoxyl group-1H, 1 ' H-[2,5 '] the brown solid of two indoles-3-nitrile.
Use above-mentioned identical method and replace suitable ethyl sulfonyl chloride, generate following compounds: compound 1331.
Embodiment 1CV:3-cyano group-1-ethyl-2-[4-(propane-1-sulfoamido)-phenyl]-preparation of 1H-Indole-6-carboxylic acid diethylamide (compound 1360).
Figure A20078000890205941
Steps A: use 0.5N KOH (30mL, 15.2mmol) handle 3-cyano group-1-ethyl-2-[4-(propane-1-the sulfoamido)-phenyl for preparing from 2-(4-aminophenyl)-3-cyano group-1-ethyl-1H-indole-6-carboxylic methyl ester according to the described method of embodiment 1Y]-1H-indole-6-carboxylic methyl ester (1.25g, 3.04mmol), reflux 2.5h.After being cooled to room temperature, using 3N HCl is 2 with the pH acidifying.The throw out that filter to form, water (2X) washing is dried to constant weight, generates 3-cyano group-1-ethyl-2-[4-(propane-1-sulfoamido)-phenyl of 1.15g (96%)]-1H-Indole-6-carboxylic acid's white solid.
Step B: to PS-HOBt resin (2.84g, 1.02mmol/g load) sample adds the DCM (0.045M of DMAP successively, 39mL) solution and 3-cyano group-1-ethyl-2-[4-(propane-1-sulfoamido)-phenyl]-1H-Indole-6-carboxylic acid's DMF (0.38M, 7.5mL) solution.This mixture is stirred 15min, and (1.65M, 7.9mL) solution, reaction mixture at room temperature stir 18h to add the DCM of DIC subsequently.Filter resin, it with DMF (3X50mL), DCM (3X50mL) and THF (3X50mL) washing, behind the vacuum-drying 4h, is generated 4.1g active ester resin.CDCl with a small amount of active ester resin and benzylamine 3Solution directly mixes in the NMR pipe, the mixture that overnight shaking forms under the room temperature, and the proton with the unreacted benzylamine compares in conjunction with the proton with the acid amides that forms subsequently, thereby determines the load of this resin.
Step C: with above-mentioned active ester resin (400mg, 0.551mmol/g load), DIEA (0.036mL, 0.22mmol) and THF (3mL) mix, in this mixture, add diethylamine (0.03mL, 0.15mmol).The sealing test tube, the overnight shaking reaction mixture.Filter resin, wash with THF (2X5mL), DCM (2X5mL).Concentrate the organic constituent that merges.Crude product generates 3-cyano group-1-ethyl-2-[4-(propane-1-sulfoamido)-phenyl of 50mg (yield 71%) through preparation scale HPLC purifying]-1H-Indole-6-carboxylic acid diethylamide.
Use the replacement of aforesaid method and suitable amine to prepare following compounds: compound 1361,1362,1363,1364.
Embodiment 1CW: the preparation of isopropyl-methyl-carboxylamine 4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indoles-2-yl)-phenyl ester (compound 1349).
Figure A20078000890205951
Steps A: under-78 ℃ to 1-ethyl-6-methoxyl group-1H-indoles-3-nitrile (2.5g, THF 12.5mmol) (21mL) solution add LDA (23mL, 22.5mmol).Be warming up to 0 ℃, behind the stirring 10min, again mixture be cooled to-78 ℃, add B (O- iPr) 3(4.35mL, 18.8mmol).After the adding, make reactant return to room temperature, stir about 1h.Add the 4-iodophenol (2.89g, 13.1mmol), PdCl 2(dppf) (510mg, 0.625mmol), K 2CO 3(reaction mixture is stirred overnight at room temperature for 25mL, 50mmol) aqueous solution and DMF (42mL).The reduction vaporization organic solvent.Resistates is with water washing, filtering mixt.Concentrated filtrate generates thick solid, with EtOAc/ sherwood oil (1/5 to 2/1) as eluent on silica gel through this thick solid of column chromatography purifying, generate 1-ethyl-2-(4-hydroxy phenyl)-6-methoxyl group-1H-indoles-3-nitrile of 73%.
Step B: under the room temperature to 1-ethyl-2-(4-hydroxy phenyl)-6-methoxyl group-1H-indoles-3-nitrile (58mg, Et 0.2mmol) 3N and CH 2Cl 2(4mL, 1/1) solution adding p-nitrophenyl chloroformate (100mg, 0.5mmol).Behind the mixture stir about 1h, and adding N-sec.-propyl methylamine (0.062mL, 0.6mmol).Mixture stirs 3h, adds entry and ethyl acetate subsequently in reaction mixture.Separate organic layer, with HCl (1N) and salt water washing, with anhydrous Na 2SO 4Drying is filtered and is concentrated.Thick solid generates isopropyl-methyl-carboxylamine 4-(3-cyano group-1-ethyl-6-methoxyl group-1H-indoles-2-yl)-phenylester through preparation scale HPLC purifying.
Use aforesaid method to prepare following compounds: compound 1348,1350,1351,1385 with the replacement of suitable amine.
Embodiment 1CX:N-{4-[3-cyano group-6-difluoro-methoxy-1-(tetrahydrochysene-furans-2-ylmethyl)-1H-indoles-2-yl]-phenyl }-preparation of sulfonyloxy methyl amine (compound 1334).
Figure A20078000890205961
Steps A: utilize the described method of embodiment 1A (step B), replace iodoethane, generate 6-difluoro-methoxy-1-(tetrahydrofuran (THF)-2-ylmethyl)-1H-indoles-3-nitrile with 2-brooethyl tetrahydrofuran (THF).
Step B: with 6-difluoro-methoxy-1-ethyl-1H-indoles-3-nitrile (516.2mg, 1.77mmol) and the triisopropyl borate (532.7mg, THF 2.83mmol) (15mL) solution is cooled to-78 ℃, and (1.5M list-THF is dissolved in hexanaphthene with LDA, 1.43mL, 2.04mmol) handle.After the adding, acetone/the dry ice bath changes ice bath into, this solution is carried out 30min again stir.Solution is cooled to-78 ℃, adds 4-Iodoaniline (390.2mg, DMF 1.78mmol) (8mL) solution, K successively 2CO 3(2M, 2.7ml, 5.31mmol) and PdCl 2Dppf (67.4mg, 0.09mmol) solution.By continuous three vacuum exhaust/N 2Purging is removed the gas of mixture, stirs spend the night (ca.16h).Be poured into the water of 4 times of volumes subsequently, add the ethyl acetate of 4 times of volumes.Separate each phase, and use more ethyl acetate extraction water.Organic phase is with water and saturated NaCl washing, then with anhydrous MgSO 4Drying, filtration and evaporation.Residual substance with 5-15% ethyl acetate/hexane wash-out, generates the white solid of 2-(4-aminophenyl)-6-difluoro-methoxy-1-(tetrahydrofuran (THF)-2-ylmethyl)-1H-indoles-3-nitrile of 367.5mg (yield 55.0%) through the column chromatography purifying on silica gel.
Step C: use the described identical method of embodiment 1Y to obtain target compound N-{4-[3-cyano group-6-difluoro-methoxy-1-(tetrahydrochysene-furans-2-ylmethyl)-1H-indoles-2-yl]-phenyl }-Toluidrin (compound 1334).
Use essentially identical method and replace other SULPHURYL CHLORIDE, preparation following compounds: compound 1335,1336.
Embodiment 1CY:1-cyclobutyl-6-oxyethyl group-2-[4-(2-oxo-[1,3] oxazine-3-yl)-phenyl]-preparation of 1H-indoles-3-nitrile (compound 1346).
Figure A20078000890205971
Steps A: to 2-(4-aminophenyl)-1-cyclobutyl-6-oxyethyl group-1H-indoles-3-nitrile (50.0mg, 0.15mmol), K 2CO 3(2N, 0.45mL, 0.45mmol) and the suspension of ethyl acetate (5mL) add 3-chlorine third chloro-formic ester (35.6mg, 0.23mmol).The mixture that forms at room temperature stirs, and exhausts (measuring through TLC) fully until raw material.Separate each phase, organic phase is washed with saturated NaCl, with MgSO 4Drying concentrates.Through crystallization, generate the white solid of [4-(3-cyano group-1-cyclobutyl-6-oxyethyl group-1H-indoles-2-yl)-phenyl]-carboxylamine 3-chloro-propyl ester from the remaining oily matter of ether/hexane.
Step B: DMF (5mL) solution to [4-(3-cyano group-1-cyclobutyl-6-oxyethyl group-1H-indoles-2-yl)-phenyl]-carboxylamine 3-chloro-propyl ester adds anhydrous K 2CO 3The mixture that forms stirs under 80 ℃, exhausts (measuring through TLC) fully until raw material.After the cooling, in reaction mixture, add the water of 10mL, form solid sediment, collect this solid sediment after filtration, wash with ether subsequently.Obtain purpose product 1-cyclobutyl-6-oxyethyl group-2-[4-(2-oxo-[1,3] oxazine-3-yl)-phenyl]-white powder of 1H-indoles-3-nitrile (76.2mg, yield 91.8%).
Embodiment 1CZ:{4-[3-cyano group-1-cyclobutyl-6-(2-methoxyl group-oxyethyl group)-1H-indoles-2-yl]-phenyl }-preparation of urethanum (compound 1397).
Steps A: use the described same procedure of embodiment 1CW (step B) to obtain 2-(4-aminophenyl)-1-cyclobutyl-6-methoxyl group-1H-indoles-3-nitrile.
Step B: use the described method of embodiment 1B (steps A) to obtain 2-(4-aminophenyl)-1-cyclobutyl-6-hydroxyl-1H-indoles-3-nitrile.
Step C: to 2-(4-aminophenyl)-1-cyclobutyl-6-hydroxyl-1H-indoles-3-nitrile (519.2mg, 1.71mmol), K 2CO 3, 10mL methyl ethyl ketone and DMF (2mL) suspension add 2-bromotrifluoromethane methyl esters.The mixture that forms heats 8h down at 85 ℃.Enriched mixture, resistates distributes with ethyl acetate (20mL) and water (20mL).Use extra ethyl acetate (20mL) aqueous phase extracted.The organic phase that merges is washed with saturated NaCl, with MgSO 4Drying, concentrated solution with the ether washed product, obtains the yellow solid of 2-(4-aminophenyl)-1-cyclobutyl-6-(2-methoxyl group-oxyethyl group)-1H-indoles-3-nitrile of 505.0mg (yield 81.7%) subsequently.
Step D: use the white solid that obtains target compound { 4-[3-cyano group-1-cyclobutyl-6-(2-methoxyl group-oxyethyl group)-1H-indoles-2-yl]-phenyl }-urethanum (compound 1397) with the described identical method of embodiment 1AJ.
Prepare following compounds in a similar manner according to above-mentioned steps A to D: compound 1365,1366,1367,1368,1369,1370,1371,1372,1373,1398,1399,1400,1401,1402,1407,1431.
With similar approach the described method of embodiment 1BU is replaced with above-mentioned steps D, prepare following urea derivatives: compound 1403,1404,1405,1406,1412.
Embodiment 1DA:[4-(3-cyano group-1-cyclobutyl-6-(2-methoxyethoxy)-1H-indoles-2-yl)-phenyl]-preparation of carboxylamine 1-cyclopropyl-ethyl ester (compound 1423).
Figure A20078000890205991
To 2-(4-aminophenyl)-1-cyclobutyl-6-(2-methoxyl group-oxyethyl group)-1H-indoles-3-nitrile (76.0mg, 0.21mmol), pyridine (36.5mg, 0.46mmol) 1,1 ethylene dichloride (10mL) solution add 4-oil of mirbane chloro-formic ester (93.2mg, 0.46mmol).The mixture that forms at room temperature stirs 2h.Adding Alpha-Methyl cyclopropane methyl alcohol (54.3mg, 0.63mmol).Reaction mixture heats 5h down at 70 ℃.After the cooling, reaction mixture ethyl acetate (10mL) and saturated K 2CO 3(10mL) distribute.Organic phase is with extra saturated K 2CO 3(2 * 10mL), water and saturated NaCl wash.Colourless solution is with MgSO 4Drying is filtered and evaporation.Residual solid is washed with ether, generates the white solid of target compound [4-(3-cyano group-1-cyclobutyl-6-(2-methoxyethoxy)-1H-indoles-2-yl)-phenyl]-carboxylamine 1-cyclopropyl-ethyl ester (compound 1423).
Embodiment 1DB:4-[3-cyano group-2-(4-ethoxyl phenenyl)-1-ethylindole-6-yl] preparation of piperazine-1-carboxylic acid tert-butyl ester (compound 1337).
Figure A20078000890205992
Steps A: will use 6-bromo-2-(4-ethoxyl phenenyl)-1-ethyl-indoles-3-nitrile that the described method of embodiment 1Gb is prepared from from the 6-bromo indole (0.37g, 1.0mmol) and NaO T-Bu (0.13g, 1.4mmol), Pd 2(dba) 3(0.009g, 0.01mmol), BINAP (0.019g, 0.03mmol), the 1-Boc-piperazine (0.22g, 1.2mmol) and dry toluene (3.0mL) mix.This mixture heats 6h down in 80 ℃.After the cooling, be methylene dichloride with solvent replacing, chromatography (silica gel, DCM/EtOAc, 9.5/0.5) after, generate 4-[3-cyano group-2-(4-ethoxyl phenenyl)-1-ethylindole-6-yl] piperazine-1-carboxylic acid tert-butyl ester (0.41g, 86%).
Prepare compound 1338 in the same manner according to aforesaid method.
Embodiment 1DC:{N-{4-[3-cyano group-1-ethyl-6-(4-methylpiperazine-1-yl)-indoles-2-yl] phenyl } preparation of propionic acid amide (compound 1341).
Figure A20078000890206001
Steps A: will use 6-chloro-1-ethylindole-3-nitrile that the described method of embodiment 1A is prepared from from the 6-chloro-indole (1.02g, 5.0mmol) and K 3PO 4(1.48g, 7.0mmol), Pd 2(dba) 3(0.11g, 0.12mmol), phenylbenzene-2-base dicyclohexylphosphontetrafluoroborate (0.17g, 0.48mmol), 1-methylpiperazine (0.60g, 0.67mL 6.0mmol) and anhydrous DME (10.0mL) mix.This mixture is 100 ℃ of following heated overnight.After the cooling, be methylene dichloride, it is carried out chromatography (silica gel, DCM are followed successively by EtOAc and DCM/MeOH, 9/1), generate 1-ethyl-6-(4-methylpiperazine-1-yl) indoles-3-nitrile (0.96g, 72%) solvent replacing.
Step B: under-78 ℃ to 1-ethyl-6-(4-methylpiperazine-1-yl) indoles-3-nitrile (0.81g that above obtains, 3.0mmol) and triisopropyl borate (0.81g, 0.99mL, anhydrous THF (5mL) solution adding LDA (2.5mL 4.50mmol), 1.5M, 3.75mmol).After the adding, this mixture stirs 15min down at-78 ℃, makes it slowly return to room temperature then, and stirs 30min again.Make it be cooled to-78 ℃ subsequently, add the 4-Iodoaniline (0.78g, 3.6mmol), PdCl 2(dppf) (0.11g, 0.15mmol), DMF (10mL) and K 2CO 3(4.5mL, 2.0M, 9.0mmol).Make this mixture slowly return to room temperature, stirring is spent the night, and is poured into frozen water (200mL) then.The collecting precipitation thing washes with water, chromatography (silica gel, EtOAc/DCM/Et 3N, 6/4/0.02) after, generate 2-(4-aminophenyl)-1-ethyl-6-(4-methylpiperazine-1-yl) indoles-3-nitrile (0.90g, 83%).
Step C: to the resulting compound of step B (54mg, anhydrous pyridine 0.15mmol) (1.5mL) solution add propionyl chloride (26 μ L, 0.30mmol).Mixture is stirred overnight at room temperature, removes under the vacuum and desolvates.Resistates is dissolved in DCM (5mL), with water (2 * 4mL) washings, chromatography (silica gel, MeOH/DCM, 0.5/9.5) after, generate product { N-{4-[3-cyano group-1-ethyl-6-(4-methylpiperazine-1-yl) indoles-2-yl] phenyl } propionic acid amide (45mg, 73%).
Use ethyl chloroformate and cyclopropane carbonyl chloride through method for preparing compound 1339 and 1340.
Embodiment 1DD:{4-[3-cyano group-1-cyclopropyl-6-(2-methoxyethoxy) indoles-2-yl] phenyl } preparation of carboxylamine 1-cyclopropyl ethyl ester (compound 1436).
Figure A20078000890206011
Steps A: 2-(4-aminophenyl)-1-cyclopropyl-6-methoxyl group indoles-3-nitrile that embodiment 1CG step e is prepared under-30 ℃ (2.02g, anhydrous DCM (30mL) 6.7mmol) join boron tribromide (8.35g, 3.15mL, 33.3mmol).Mixture stirs 1.5h down at-30 ℃～-15 ℃, returns to envrionment temperature subsequently, stirs 15min.Pour mixture into saturated NaHCO 3In ice, stir 1h.Remove volatile matter on rotovap, the collecting precipitation thing washes with water after filtration, subsequently at N 2Dry under the atmosphere, 2-(4-the aminophenyl)-1-cyclopropyl-6-oxyindole-3-nitrile of generation quantitative yield.
Step B: the intermediate that will above obtain (0.29g, 1.0mmol) and Cs 2CO 3(0.98g, 3.0mmol), 2-methoxy ethyl bromide (0.21g, 0.14mL, 1.5mmol) and acetonitrile (5mL) mix, this mixture stirs down at 85 ℃ and spends the night.Remove under the vacuum and desolvate, resistates is handled with DCM, after the chromatography (silica gel, DCM/EtOAc, 9/1), generates 2-(4-aminophenyl)-1-cyclopropyl-6-(2-methoxyethoxy) indoles-3-nitrile (0.16g, 46%).
Step C: with 2-(4-aminophenyl)-1-cyclopropyl-6-(2-methoxyethoxy) indoles-3-nitrile (35mg, 0.1mmol), 4-oil of mirbane chloro-formic ester (50mg, 0.25mmol) the mixture of pyridine (2.0mL) solution stir down 2h at 35 ℃, add subsequently 1-cyclopropyl ethanol (98 μ L, 1.0mmol).This mixture stirs at 60 ℃ subsequently, dilutes with water (10mL) and DCM (5mL).Organic layer with water (3 * 5mL), HCl (2N, 3 * 5mL), saturated NaHCO 3(3 * 5mL) wash, chromatography (silica gel, EtOAc/DCM, 0.5/9.5) after, generate target compound { 4-[3-cyano group-1-cyclopropyl-6-(2-methoxyethoxy) indoles-2-yl] phenyl } carboxylamine 1-cyclopropyl ethyl ester (22mg, 48%).
Use above-mentioned chemical reaction to prepare compound 1437,1438 and 1439.
Embodiment 1DE:{4-[3-cyano group-1-cyclopropyl-6-(tetrahydrofuran (THF)-2-base oxygen base)-2-yl]-phenyl } preparation of carboxylamine 1-cyclopropyl ethyl ester (compound 1444).
Figure A20078000890206021
Steps A: the 2-that embodiment 1DD steps A is prepared (4-aminophenyl)-1-cyclopropyl-6-oxyindole-3-nitrile (0.29g, 1.0mmol) and K 2CO 3(0.35g, 2.5mmol), the toluene-4-sulfonic acid tetrahydrofuran (THF)-2-base ester (0.36g, 1.5mmol) and acetonitrile (5mL) mix, this mixture is 80 ℃ of following stirred overnight.Remove under the vacuum and desolvate, resistates is handled with DCM, after the chromatography (silica gel, DCM/EtOAc, 9/1), generates 2-(4-aminophenyl)-1-cyclopropyl-6-(tetrahydrofuran (THF)-2-base oxygen base) indoles-3-nitrile (0.27g, 75%).
Step B: with 2-(4-aminophenyl)-1-cyclopropyl-6-(tetrahydrofuran (THF)-2-base oxygen base) indoles-3-nitrile (36mg, 0.1mmol), 4-oil of mirbane chloro-formic ester (50mg, 0.25mmol) the mixture of pyridine (2.0mL) solution stir down 2h at 35 ℃, add subsequently 1-cyclopropyl ethanol (98 μ L, 1.0mmol).This mixture carries out stirred overnight at 60 ℃ subsequently, and dilutes with water (10mL) and DCM (5mL).Organic layer with water (3 * 5mL), HCl (2N, 3 * 5mL), saturated NaHCO 3(3 * 5mL) wash, chromatography (silica gel, EtOAc/DCM, 0.5/9.5) after, generate target compound { 4-[3-cyano group-1-cyclopropyl-6-(tetrahydrofuran (THF)-2-base oxygen base) indoles-2-yl] phenyl } carboxylamine 1-cyclopropyl ethyl ester (32mg, 68%).
Prepare following compounds in a similar manner according to aforesaid method: compound 1445,1446,1447,1448,1449,1453,1454,1455,1456,1457,1458,1459,1460,1461.
The preparation of embodiment 1DF:4-methyl-piperidines-1-carboxylic acid { 4-[3-cyano group-1-cyclobutyl-6-(2-methoxyl group-oxyethyl group)-1H-indoles-2-yl]-phenyl }-acid amides (compound 1377).
Figure A20078000890206031
Steps A: (530mg, EtOAc 1.58mmol) (10mL) solution adds 2M K in 5min to 2-(4-aminophenyl)-1-cyclobutyl-6-(2-methoxyethoxy)-1H-indoles-3-nitrile 2CO 3(556uL, 5.9mmol) aqueous solution and 4-anisole chloro-formic ester.This reaction mixture at room temperature further stirs 3h.This reaction mixture dilutes with EtOAc (20mL) subsequently, and extracts with water (5mL).Removal of solvent under reduced pressure is dissolved in EtOAc with resistates, grinds with hexane subsequently.Collecting precipitation thing after filtration, and with the 50%EtOAc/ hexane wash, after the vacuum-drying, generate 4-[3-cyano group-1-cyclobutyl-6-(2-methoxyl group-oxyethyl group)-1H-indoles-2-yl]-phenyl }-carboxylamine 4-methoxyl group-phenyl ester (761mg, 98%).
Step B: to 4-[3-cyano group-1-cyclobutyl-6-(2-methoxyl group-oxyethyl group)-1H-indoles-2-yl]-phenyl }-carboxylamine 4-methoxyl group-phenyl ester (40mg, 0.082mmol) DCM (4mL) solution add 4-methyl piperidine (0.16mmole), reactant is reflux 18h at room temperature.Removal of solvent under reduced pressure.Resistates is dissolved in EtOAc, grinds with hexane subsequently.Collecting precipitation thing after filtration, and with the 50%EtOAc/ hexane wash, after the vacuum-drying, generation 4-methyl-piperidines-1-carboxylamine 4-[3-cyano group-1-cyclobutyl-6-(2-methoxyethoxy)-1H-indoles-2-yl]-phenyl }-acid amides (26mg, 68%) compound 1377, i.e..
Adopt above-mentioned steps A and B to prepare following compounds in a similar manner: compound 1378,1379,1380,1381,1382,1383,1384.
Embodiment 1DG:{4-[3-cyano group-1-cyclobutyl-6-(2-hydroxyl-3-[1,2,4] triazol-1-yl-propoxy-)-1H-indoles-2-yl]-phenyl }-preparation of carbamic acid isopropyl ester (compound 1420).
Figure A20078000890206041
Steps A: (1.0g, DMF 2.57mmol) (10mL) solution adds K to [4-(3-cyano group-1-cyclobutyl-6-hydroxyl-1H-indoles-2-yl)-phenyl]-carbamic acid isopropyl ester 2CO 3(710mg, 5.13mmole) and epoxy bromopropane (436uL, 5.13mmole), reactant heats 42h at ambient temperature.Pour reaction mixture into cold water subsequently, collecting precipitation thing after filtration, and, after the vacuum-drying, generate purpose product (960mg, 84%) with hexane wash.
Step B: (40mg, DMF 0.09mmole) (1mL) solution adds 1,2, the sodium salt of 4-triazole (30mg) to [4-(3-cyano group-1-cyclobutyl-6-oxyethane methoxyl group-1H-indoles-2-yl)-phenyl]-carbamic acid isopropyl ester.This mixture is 60 ℃ of following stirred overnight.Removal of solvent under reduced pressure, resistates dilutes with ethyl acetate, and the back is with water washing.Concentrate organic layer, grind with hexane.Collecting precipitation thing after filtration, with 1/1 ethyl acetate/hexane solution thorough washing, after the vacuum-drying, generate { 4-[3-cyano group-1-cyclobutyl-6-(2-hydroxyl-3-[1,2,4] triazol-1-yl-propoxy-)-1H-indoles-2-yl]-phenyl }-carbamic acid isopropyl ester (29mg, 63%), promptly compound 1420.
Adopt above-mentioned steps A and B to prepare following compounds in a similar manner: compound 1418,1419.
Preparing urea derivatives in a similar manner according to above-mentioned chemical reaction is compound 1421.
Embodiment 1DH:{4-[3-cyano group-1-cyclobutyl-6-(3,4-dihydroxyl-butoxy)-1H-indoles-2-yl]-phenyl }-preparation of carbamic acid isopropyl ester (compound 1429).
Figure A20078000890206051
Steps A: (100mg, DMF 0.26mmol) (3mL) solution adds K to [4-(3-cyano group-1-cyclobutyl-6-hydroxyl-1H-indoles-2-yl)-phenyl]-carbamic acid isopropyl ester 2CO 3(43.2mg, 0.312mmole) (2,2-dimethyl-[1,3] dioxolane-4-yl)-(129mg, 0.39mmole), reactant heats 18h to ethyl ester at ambient temperature with 4-nitrobenzene-sulfonic acid 2-.Pour reaction mixture into cold water subsequently, collecting precipitation thing after filtration, use the EtOAc/ hexane wash, after the vacuum-drying, generate 96mg, and 84% purpose product (4-{3-cyano group-1-cyclobutyl-6-[2-(2,2-dimethyl-[1,3] dioxolane-4-yl)-oxyethyl group]-1H-indoles-2-yl }-phenyl)-carbamic acid isopropyl ester, promptly compound 1428.
Step B: to (4-{3-cyano group-1-cyclobutyl-6-[2-(2,2-dimethyl-[1,3] dioxolane-4-yl)-oxyethyl group]-1H-indoles-2-yl }-phenyl)-(70mg, DCM 0.135mmole) (2mL) solution adds TFA (10uL) to carbamic acid isopropyl ester.The mixture that forms stirs 2h at ambient temperature.Removal of solvent under reduced pressure, resistates dilutes with ethyl acetate, grind with hexane subsequently, collecting precipitation thing after filtration, and with the hexane solution thorough washing of 50% ethyl acetate, after the vacuum-drying, generate { 4-[3-cyano group-1-cyclobutyl-6-(3,4-dihydroxyl-butoxy)-1H-indoles-2-yl]-phenyl }-carbamic acid isopropyl ester (45mg, 70%), promptly compound 1429.
Embodiment 1DI:1-[4-(3-cyano group-1-cyclobutyl-6-oxyethyl group-1H-indoles-2-yl)-phenyl]-preparation of 3-(2-hydroxyl-ethyl)-urea (compound 1408).
Will according to prepared 2-(4-the aminophenyl)-1-cyclobutyl-6-oxyethyl group-1H-indoles-3-nitrile of embodiment 1CM step B (40mg, 0.12mmol) with 4-oil of mirbane chloro-formic ester (60mg, 0.30mmol), CH 2Cl 2(25 μ L 0.31mmol) mix for (400 μ L) and pyridine.This suspension was at room temperature stirred 1 hour.The adding thanomin (42 μ L, 0.70mmol).After stirring 30min again under the room temperature, reaction mixture is with CH 2Cl 2Dilution, and the NaOH solution washing to dilute are to remove xanchromatic nitrophenols by product.Dry and concentrated organic layer.Through silica gel chromatography (CH 2Cl 2/ acetone, 7/3) purifying generates 1-[4-(3-cyano group-1-cyclobutyl-6-oxyethyl group-1H-indoles-2-yl)-phenyl]-white solid of 3-(2-hydroxyl-ethyl)-urea (40mg, 80%).
Use suitable amine and aniline coupling auxiliary agent to prepare following compounds in a similar manner: compound 1375,1390,1391,1392,1396,1409,1440 and 1441.
Embodiment 1DJ:[4-(3-cyano group-1-cyclobutyl-6-oxyethyl group-1H-indoles-2-yl)-phenyl]-preparation of carboxylamine 2-(2-methoxyethoxy)-ethyl ester (compound 1424).
Figure A20078000890206062
Will be according to prepared 2-(4-the aminophenyl)-1-cyclobutyl-6-oxyethyl group-1H-indoles-3-nitrile (40mg of embodiment 1CM step B, 0.12mmol) and 4-oil of mirbane chloro-formic ester (60mg, 0.30mmol), (25 μ L 0.31mmol) mix for DCE (0.4mL) and pyridine.This suspension is at room temperature stirred 1h.Adding 2-(2-methoxyethoxy) ethanol (150 μ L, 1.25mmol).This mixture is in 80 ℃ of heated overnight.This reaction mixture is subsequently with CH 2Cl 2Dilution, and the NaOH solution washing to dilute are to remove xanchromatic nitrophenols by product.Dry and concentrated organic layer.Through silica gel chromatography (CH 2Cl 2) purifying generates the white solid of [4-(3-cyano group-1-cyclobutyl-6-oxyethyl group-1H-indoles-2-yl)-phenyl]-carboxylamine 2-(2-methoxyl group-oxyethyl group)-ethyl ester (51mg, 89%).
Use suitable alcohol to prepare following compounds in a similar manner: compound 1416,1426,1432.
Embodiment 1DK:1-[4-(3-cyano group-1-cyclobutyl-6-oxyethyl group-1H-indoles-2-yl)-phenyl]-preparation of 3-cyclopentyl-1-ethyl-urea (compound 1425).
(35mg 0.10mmol) is dissolved in the pyridine (300 μ L) 1-cyclobutyl-6-oxyethyl group-2-(4-ethamine the phenyl)-1H-indoles-3-nitrile that will prepare according to embodiment 1CO step C.Adding cyclopentyl isocyanic ester (130 μ L, 1.08mmol).Reaction mixture is heated 2h down at 110 ℃.Reaction mixture distributes with the HCl aqueous solution and EtOAc subsequently.Dry and concentrated organic layer.Need successively use hexane/EtOAc (6/4) and CH 2Cl 2/ EtOAc (95/5) carries out twice silica gel chromatography and carries out purifying, to remove two cyclopentyl urea impurity, thereby generate purified 1-[4-(3-cyano group-1-cyclobutyl-6-oxyethyl group-1H-indoles-2-yl)-phenyl]-the off-white color solid of 3-cyclopentyl-1-ethyl-urea (39mg, 82%).
Embodiment 1DL:1-cyclobutyl-6-oxyethyl group-2-[4-(2-pyridine-2-base-ethylamino-)-phenyl]-preparation of 1H-indoles-3-nitrile (compound 1433)
Will be according to prepared 2-(4-the aminophenyl)-1-cyclobutyl-6-oxyethyl group-1H-indoles-3-nitrile (40mg of embodiment 1CM step B, 0.12mmol) and 4-oil of mirbane chloro-formic ester (60mg, 0.30mmol), (25 μ L 0.31mmol) mix for DCE (0.4mL) and pyridine.This suspension is at room temperature stirred 1h.Adding 2-(2-methoxyethoxy) ethanol (150 μ L, 1.25mmol).This mixture is in 75 ℃ of heated overnight.This reaction mixture is subsequently with CH 2Cl 2Dilution, and the NaOH solution washing to dilute are to remove xanchromatic nitrophenols by product.Dry and concentrated organic layer.Through silica gel chromatography (CH 2Cl 2/ EtOAc, 4/1) purifying and hexane/acetone (2/1) are ground, and generate 1-cyclobutyl-6-oxyethyl group-2-[4-(2-pyridine-2-base-ethylamino-)-phenyl]-white solid of 1H-indoles-3-nitrile (23mg, 42%).
The preparation of embodiment 1DM:2-(2-diethylin benzothiazole-6-yl)-1-ethyl-6-methoxyl group-1H-indoles-3-nitrile (compound 1343).
Figure A20078000890206082
Steps A: will (2.50g 8.6mmol) is dissolved in anhydrous dimethyl oxygen base ethane (21.5mL) from 6-methoxyl group-1H-indoles-1-carboxylic acid tert-butyl ester of embodiment 1BO.To this solution add 2-chloro-6-iodobenzene and thiazole (2.42g, 8.2mmol), cesium fluoride (2.53g, 16.7mmol) and PdCl 2(PPh 3) 2(0.23g, 0.33mmol).This reaction mixture of reflux.Behind the 17h, reaction mixture is cooled to room temperature, water (100mL) dilutes, and (4 * 20mL) extract with ethyl acetate.Extract is with saturated NaHCO 3(20mL) washing is with MgSO 4Drying behind the vacuum concentration, generates the rigid foam thing of 2-(2-chloro benzothiazole-6-yl)-6-methoxyl group-indoles-1-carboxylic acid tert-butyl ester (2.95g, 83%).
Step B: (2.87g 6.9mmol) is dissolved in anhydrous CH with above-mentioned Boc indoles 2Cl 2(13mL).Under the room temperature to this solution add trifluoroacetic acid (3.0mL, 38.9mmol).This reaction mixture at room temperature stirs 17h.Add entry (20mL), this mixture is with CH 2Cl 2(3 * 10mL) extract.Extract is with water (1 * 15mL) and saturated NaHCO 3(20mL) solution washing is with MgSO 4Drying after rotatory evaporator concentrates, obtains crude product.Product obtains 2-chloro-6-(methoxyl group-1H-indoles-2-yl)-benzothiazole (0.40g, 18%) behind silica gel chromatography (1-50% ethyl acetate/hexane) purifying.
Step C: above-mentioned indoles is dissolved in dry DMF (3.0mL), the ice bath cooling.(0.12mL, 1.4mol), mixture stirs 2h in ice bath to add Sulfuryl chloride isocyanate.Add entry (15mL), this mixture at room temperature stirred 30 minutes.Filtering precipitate washes with water, obtains 2-(2-chloro benzothiazole-6-yl)-6-methoxyl group-1H-indoles-3-nitrile (0.39g, 95%) after the drying.
Step D: with above-mentioned indoles (373mg 1.1mmol) is dissolved in dry DMF (2.2mL), add iodoethane (0.20g, 1.3mmol) and salt of wormwood (0.31g 2.2mmol) stirs under room temperature.Mixture heats 22h down at 50 ℃.This mixture stirred 15 minutes under the room temperature with water (15mL) dilution.Cross filter solid, wash with water, obtain 2-(2-chloro benzothiazole-6-yl)-1-ethyl-6-methoxyl group-1H-indoles-3-nitrile (0.39g, 96%) after the drying.
Step e: (46mg 0.13mmol) is dissolved in 15% water/Virahol (1.5mL) with above-mentioned indoles.Add diethylamine (25mg, 0.34mmol), add subsequently sodium bicarbonate (43mg, 0.51mmol).With reaction mixture refluxed heating 21 hours.This mixture is cooled to room temperature, dilutes with water (5mL).Filtering precipitate washes with water, obtains 2-(2-diethylin benzothiazole-6-yl)-1-ethyl-6-methoxyl group-1H-indoles-3-nitrile (40mg, 79%) after the drying.
Embodiment 1DN: the preparation of ethyl sulfonic acid [4-(3-cyano group-6-diethylamino methyl-1-ethyl-1H-indoles-2-yl)-phenyl]-acid amides (compound 1352).
Figure A20078000890206101
Steps A: (4.11g, anhydrous THF (36mL) solution 18.0mmol) cools off in dry ice/ether is bathed 3-cyano group-1-ethyl-1H-indole-6-carboxylic methyl ester that embodiment 1A is prepared by the 1H indole-6-carboxylic methyl ester.The adding LDA (1.5M, 14.4mL, cyclohexane solution 21.6mmol), it adds speed makes temperature of reaction remain on below-60 ℃.After the adding, this reaction mixture stirred 30 minutes down at-60 ℃.(3.1mL 27.8mmol) joins in the reactant, and this mixture stirred 30 minutes down at-60 ℃ with the trimethyl-boron hydrochlorate.Make reaction mixture be warming up to room temperature, add DMF (60mL), 4-Iodoaniline (4.00g, 18.3mmol), PdCl 2(dppf) (735mg, 0.90mmol) and K 2CO 3(2M, 36mL) aqueous solution.This mixture heats 17h down in 40 ℃.Mixture is cooled to room temperature, removes THF through concentrating.Add water, make volume become 500mL, (3 * 50mL) extract this mixture with ethyl acetate.(3 * 50mL) washings are with MgSO with water for extract 4Drying obtains semi-solid product after concentrating.Product is separated out from the ethyl acetate crystallization, obtains 2-(4-aminophenyl)-3-cyano group-1-ethyl-1H-indole-6-carboxylic methyl ester's (2.53g, 44%) brown solid.
Step B: will (1.26g 3.95mmol) is dissolved in anhydrous pyridine (6mL) from above indoles product.To this solution add ethyl sulfonyl chloride (0.63g, 4.90mmol).Mixture heated 17 hours down at 50 ℃.Mixture is cooled to room temperature, adds entry (30mL).Mixture is with ethyl acetate (3 * 5mL) extractions.(2 * 10mL) washings are with MgSO with 10% aqueous hydrochloric acid (5mL) and water for extract 4Drying after rotatory evaporator concentrates, obtains 3-cyano group-2-(4-ethanesulfonamide group-phenyl)-1-ethyl-1H-indole-6-carboxylic methyl ester (1.47g, 90%).
Step C: will (0.72g 1.76mmol) is suspended in anhydrous THF (3.3mL) from above indoles product.Add lithium borohydride (2.6mL, 5.2mmol, THF solution 2M) under the room temperature.This mixture reflux 20h.Mixture is cooled to room temperature, adds entry (4mL).Add 10% aqueous hydrochloric acid, make pH regulator to 4.Mixture is with methylene dichloride (4 * 2mL) extractions.Extract is with water (2.2mL) washing, with MgSO 4Drying obtains the brown solid of ethyl sulfonic acid [4-(3-cyano group-1-ethyl-6-methylol-1H-indoles-2-yl)-phenyl]-acid amides (595mg, 88%) after concentrating.
Step D: will (471mg 1.23mmol) is suspended in methylene dichloride (6mL) from above indoles product.(0.135mL, 1.85mmol), this mixture at room temperature stirs 2h to add thionyl chloride.This mixture concentrates through rotatory evaporator, obtains ethyl sulfonic acid [4-(6-chloromethyl-3-cyano group-1-ethyl-1H-indoles-2-yl)-phenyl]-acid amides (493mg, 99%).
Step e: will (50mg 0.124mmol) is dissolved in anhydrous acetonitrile (1.0mL) from above indoles product.(28.1mg 0.38mmol), heats this mixture 17 hours down at 80 ℃ to add diethylamine.Mixture is cooled to room temperature, concentrates and through silica gel chromatography (0-10%MeOH/CH through rotatory evaporator 2Cl 2) behind the purifying, obtain ethyl sulfonic acid [4-(3-cyano group-6-diethylamino methyl-1-ethyl-1H-indoles-2-yl)-phenyl]-acid amides (33.6mg, 62%).
Embodiment 1DO:{4-[3-cyano group-1-cyclobutyl-6-(2-methylsulfonyl-oxyethyl group)-1H-indoles-2-yl]-phenyl }-preparation of carboxylamine 1-cyclopropyl-ethyl ester (compound 2695).
Figure A20078000890206111
Steps A: to 2-(4-aminophenyl)-1-cyclobutyl-6-hydroxyl-1H-indoles-3-nitrile (3.43g, CH 11.3mmol) 3CN (8mL) solution adds Cs 2CO 3(4.30g, 73.2mmol) (2.39mL, 13.2mmol), this reaction mixture stirs 18h down in 40 ℃ in sealed tube with 2-chloroethyl-p-tosylate.Carry out water treatment in 0.5M HCl (500mL), (2 * 500mL) extract this mixture with EtOAc.Merge organic layer, use MgSO 4Drying concentrates.Crude product is with 10%EtOAc/CH 2Cl 2Through the silicagel column purifying.Remove and desolvate, generate the white solid of 2-(4-amino-phenyl)-6-(2-chloro-oxyethyl group)-1-cyclobutyl-1H-indoles-3-nitrile of 4.06g (yield 98%).
Step B: (800mg, (2M, 10mL 5.00mmol), stir 2h in sealed tube under 80 ℃ 2.19mmol) to be dissolved in the toluene solution of phosgene with 2-(4-amino-phenyl)-6-(2-chloro-oxyethyl group)-1-cyclobutyl-1H-indoles-3-nitrile.Remove and desolvate, the white solid that obtains is suspended among the 1mL DCE.To this solution add (R)-1-cyclopropyl ethanol (400uL, 5.28mmol) and DMAP (268mg, 2.19mmol).Solution stirs 16h under room temperature in sealed tube.Carry out water treatment in 0.5M HCl (200mL), (2 * 100mL) extract with EtOAc.Merge organic layer, with MgSO 4Drying concentrates.Use ether abrasive solid product, generate the white solid of { 4-[6-(2-chloro-oxyethyl group)-3-cyano group-1-cyclobutyl-1H-indoles-2-yl]-phenyl }-carboxylamine 1-cyclopropyl-ethyl ester of 800mg (yield 77%).
Step C: to 4-[6-(2-chloro-oxyethyl group)-3-cyano group-1-cyclobutyl-1H-indoles-2-yl]-phenyl }-carboxylamine 1-cyclopropyl-ethyl ester (800mg, 1: 4 DMF/CH 1.67mmol) 3CN (8mL) solution adding sodium iodide (2.50g, 16.7mmol).The mixture overnight that forms refluxes.Carry out water treatment in 0.5M HCl (200mL), (2 * 100mL) extract with EtOAc.Merge organic layer, with MgSO 4Drying concentrates.Use ether abrasive solid product, it need not to be further purified when using.(113mg, 1.11mmol), reactant at room temperature stirs and spends the night to add methyl-sulfinic acid sodium (sodium methane sulfinate) to the 4mL DMF solution that contains iodine ethyl intermediate (0.56mmol).Carry out water treatment in 0.5M HCl (200mL), (2 * 100mL) extract with EtOAc.Merge organic layer, with MgSO 4Drying concentrates.Mixture is through silicagel column (CH 2Cl 2) purifying, generate the off-white color solid of { 4-[3-cyano group-1-cyclobutyl-6-(2-methylsulfonyl-oxyethyl group)-1H-indoles-2-yl]-phenyl }-carboxylamine 1-cyclopropyl ethyl ester of 100mg (yield 35%).
Embodiment 1DP:[4-(1-cyclopropyl methyl-6-oxyethyl group-3-iodo-1H-indoles-2-yl)-phenyl]-preparation of carbamic acid isopropyl ester (compound 2634).
Figure A20078000890206131
Steps A: to 6-oxyethyl group-1-H-indoles (5.0g, CH 31mmol) 3CN (31mL) solution add tert-Butyl dicarbonate (7.2g, 33mmol) and DMAP (480mg, 3.9mmol).This mixture at room temperature stirs and spends the night, and after concentrating, resistates is through silica gel chromatography (1: 1 CH 2Cl 2/ hexane), generate the brown oily matter of 6-oxyethyl group-indoles-1-carboxylic acid tert-butyl ester (7.67g, 95%).
Step B: with 6-oxyethyl group-indoles-1-carboxylic acid tert-butyl ester (8g, 30mmol) and B (OiPr) 3(12mL, THF 52mmol) (48mL) solution is cooled to 0 ℃, dropwise adds LDA (1.5M, 30mL, THF-cyclohexane solution 45mmol).Reaction mixture stirred 20 minutes down at 0 ℃, at room temperature stirred subsequently 30 minutes.(7.5mL 6M), is condensed into mixture the solution of about 30mL to add HCl.Concentrated solution is 1-2 with the HCl aqueous solution with the pH acidifying.Cross filter solid, use H 2O washing, and 50 ℃ of following drying under reduced pressure 30 minutes.Isolate white solid product 2-(6-oxyethyl group-indoles-uncle 1--butoxy-carbonyl-indoles)-boric acid trihydrate (10.32g, 96%).
Step C: to 2-(6-oxyethyl group-indoles-1-tert.-butoxy-carbonyl-indoles)-boric acid trihydrate (5.1g, 14.2mmol), 1-iodo-4-oil of mirbane (3.6g, 14.4mmol), Pd (dppf) Cl 2-CH 2Cl 2(205mg 0.25mmol) and in the mixture of DMF (45mL) adds K 2CO 3(2M, 20mL, the 40mmol) aqueous solution, this mixture at room temperature stirs 1h.Reaction mixture is with H 2O dilutes, and extracts with EtOAc.The EtOAc layer is successively with H 2O and salt water washing.Dry and concentrated organic layer is through silica gel chromatography (1: 1 CH 2Cl 2/ hexane) purifying and after 1: 1 hexane/ether grinds generates the yellow solid of 6-oxyethyl group-2-(4-nitro-phenyl)-indoles-1-carboxylic acid tert-butyl ester (3.63g, 67%).
Step D: to 6-oxyethyl group-2-(4-nitro-phenyl)-indoles-1-carboxylic acid tertiary butyl ester (8.1g, CH 21.2mmol) 2Cl 2(8mL) solution adds TFA (8mL).Mixture at room temperature stirred 2 hours, concentrated then.Resistates dilutes with EtOAc, and with saturated NaHCO 3Solution washing.Concentrate organic layer, through silica gel chromatography (successively with 7: 3CH 2Cl 2/ hexane and 100%CH 2Cl 2Wash-out) behind the purifying, generates the orange red solid of 6-oxyethyl group-2-(4-nitro-phenyl)-1H-indoles (4.5g, 68%).
Step e: with 6-oxyethyl group-2-(4-nitro-phenyl)-1H-indoles (4.5g, 16mmol), Cs 2CO 3(7.8g, 24mmol), (1.8mL 18mmol) stirred 16 hours down in 80 ℃ in sealed tube for DMF (23mL) and brooethyl cyclopropane.This reaction mixture is with H 2O dilutes, and extracts with EtOAc.Organic layer is with H 2Drying and concentrated is carried out in O and salt water washing subsequently.Through silica gel chromatography (1: 1CH 2Cl 2/ hexane) purifying generates the orange solids of 1-cyclopropyl methyl-6-oxyethyl group-2-(4-nitro-phenyl)-1H-indoles (4.73g, 88%).
Step F: (800mg, DMF 2.38mmol) (8.6mL) solution dropwise add N-iodo succimide (585mg, DMF 2.6mmol) (5.6mL) solution to 1-cyclopropyl methyl-6-oxyethyl group-2-(4-nitro-phenyl)-1H-indoles under the room temperature.Reaction mixture at room temperature stirs 2h, uses H 2O dilutes, and extracts with EtOAc.Organic layer is successively with H 2O and saturated NaHCO 3Solution washing carries out drying and concentrated subsequently.Use the hexane grinding residues, generate the orange solids of 1-cyclopropyl methyl-6-oxyethyl group-3-iodo-2-(4-nitro-phenyl)-1H-indoles (1.061g, 96%).
Step G: with 1-cyclopropyl methyl-6-oxyethyl group-3-iodo-2-(4-nitro-phenyl)-1H-indoles (990mg, 2.14mmol), iron powder (690mg, 11.8mmol), NH 4Cl (690mg, 12.9mmol), ethanol (22mL) and H 2The mixture of O (8mL) heated 90 minutes down at 80 ℃.This reaction mixture is with H 2The O dilution, and with CH 2Cl 2Extraction.Dry and concentrated organic layer, and through silica gel chromatography (CH 2Cl 2) be purified.The product that contains each component is directly used in subsequent reactions.(toluene solution 2.5mmol) is handled the CH of this compound for 1M, 2.5mL to use pyridine (15mL) and isopropyl chloroformate 2Cl 2(80mL) solution stirred 15 minutes under the room temperature.Reaction mixture extracts with the mixture of the EtOAc and the HCl aqueous solution after concentrating.Organic layer is with H 2O and salt water washing are carried out drying and concentrated, subsequently through silica gel chromatography (CH 2Cl 2/ hexane, 1: 1 to 3: 1) behind the purifying, generate the white solid of [4-(1-cyclopropyl methyl-6-oxyethyl group-3-iodo-1H-indoles-2-yl)-phenyl]-carbamic acid isopropyl ester (644mg, 58%).
Embodiment 1DQ:[4-(1-cyclopropyl methyl-6-oxyethyl group-3-fluoro-1H-indoles-2-yl)-phenyl]-preparation of carbamic acid isopropyl ester (compound 2640).
Figure A20078000890206151
Steps A: to 1-cyclopropyl methyl-6-oxyethyl group-2-(4-nitro-phenyl)-1H-indoles (600mg, CH 1.79mmol) 2Cl 2(4mL) solution add 1-fluoro-2 a tetrafluoro borate (418mg, 1.85mmol).Reaction mixture at room temperature stirred 3 days, subsequently with CH 2Cl 2Dilution, and with NaHCO 3Solution washing.Dry and concentrated organic layer is through silica gel chromatography (1: 1CH 2Cl 2/ hexane) purifying generates the orange solids of 1-cyclopropyl methyl-6-oxyethyl group-3-fluoro-2-(4-nitro-phenyl)-1H-indoles (161mg, 25%).
Step B: with 1-cyclopropyl methyl-6-oxyethyl group-3-fluoro-2-(4-nitro-phenyl)-1H-indoles (161mg, 0.45mmol), iron powder (170mg), NH 4Cl (170mg, 3.2mmol), ethanol (4mL) and H 2The mixture of O (1.5mL) heated 90 minutes down at 80 ℃.Reaction mixture is with H 2The O dilution, and with CH 2Cl 2Extraction.The organic layer drying and concentrate after, generate the white solid of 4-(1-cyclopropyl methyl-6-oxyethyl group-3-fluoro-1H-indoles-2-yl)-aniline (122mg, 83%).
Step C: with 4-(1-cyclopropyl methyl-6-oxyethyl group-3-fluoro-1H-indoles-2-yl)-aniline (30mg, 0.093mmol), pyridine (300 μ L) and isopropyl chloroformate (1M solution toluene, 110 μ L, mixture 0.11mmol) at room temperature stirred 90 minutes.Resistates extracts with the mixture of the EtOAc and the HCl aqueous solution.Organic layer is with H 2O and salt water washing, dry and concentrate after, through silica gel chromatography (CH 2Cl 2/ Hex, 1: 1) purifying, the white solid of generation [4-(1-cyclopropyl methyl-6-oxyethyl group-3-fluoro-1H-indoles-2-yl)-phenyl]-carbamic acid isopropyl ester (35mg, 92%).
Embodiment 1DR:[4-(3-cyclopropyl acethlene base-1-cyclopropyl methyl-6-oxyethyl group-1H-indoles-2-yl)-phenyl]-preparation of carbamic acid isopropyl ester (compound 2635).
Figure A20078000890206161
With [4-(1-cyclopropyl methyl-6-oxyethyl group-3-iodo-1H-indoles-2-yl)-phenyl]-carbamic acid isopropyl ester (100mg, 0.19mmol), cyclopropyl acethlene (50 μ L, 70%, toluene solution 0.4mmol), Pd (PPh 3) 2Cl 2(6.7mg, 0.0096mmol), CuI (5mg, 0.026mmol), triethylamine (600 μ L) and DMF (600 μ L) at room temperature stir 5h.Add extra Pd (PPh subsequently 3) 2Cl 2(5mg) and cyclopropyl acethlene (30 μ L), stirred overnight reaction mixture.Reaction mixture dilutes with EtOAc, and with H 2O and HCl solution washing.Dry and concentrated organic layer is through silica gel chromatography (3: 1CH 2Cl 2/ hexane) and for the second time chromatography (7: 3 hexane/ether) purifying organic layer generates the white solid of [4-(3-cyclopropyl acethlene base-1-cyclopropyl methyl-6-oxyethyl group-1H-indoles-2-yl)-phenyl]-carbamic acid isopropyl ester (21mg, 24%).
Embodiment 1DS:[4-(3-bromo-1-cyclopropyl methyl-6-oxyethyl group-1H-indoles-2-yl)-phenyl]-preparation of carbamic acid isopropyl ester (compound 2691).
Figure A20078000890206162
Steps A: (200mg, DMF 0.6mmol) (2.5mL) solution dropwise add N-iodo succimide (107mg, DMF 0.6mmol) (1.5mL) solution to 1-cyclopropyl methyl-6-oxyethyl group-2-(4-nitro-phenyl)-1H-indoles.This reaction mixture at room temperature stirred 90 minutes.This reaction mixture is with H 2O dilutes, and extracts with EtOAc.Organic layer is with H 2O and salt water washing are carried out drying and concentrated, subsequently through silica gel chromatography (1: 1CH 2Cl 2/ hexane) purifying generates the yellow solid of 3-bromo-1-cyclopropyl methyl-6-oxyethyl group-2-(4-nitro-phenyl)-1H-indoles (219mg, 88%).
Step B: according to the step B of embodiment 1DP, 3-bromo-1-cyclopropyl methyl-6-oxyethyl group-2-(4-nitro-phenyl)-1H-indoles (205mg, 0.5mmol) through reducing the faint yellow solid that generates 4-(3-bromo-1-cyclopropyl methyl-6-oxyethyl group-1H-indoles-2-yl)-aniline (164mg, 85%).
Step C: according to the step C of embodiment 1DP; 4-(3-bromo-1-cyclopropyl methyl-6-oxyethyl group-1H-indoles-2-yl)-aniline (30mg; 0.078mmol) generate the white solid of [4-(3-bromo-1-cyclopropyl methyl-6-oxyethyl group-1H-indoles-2-yl)-phenyl]-carbamic acid isopropyl ester (25mg, 68%) through carbamylation.
Embodiment 1DT:[4-(3-chloro-1-cyclopropyl methyl-6-methoxyl group-1H-indoles-2-yl)-phenyl]-preparation of carbamic acid isopropyl ester (compound 2804).
Figure A20078000890206171
Steps A: with 2-(6-methoxyl group-indoles-1-tert.-butoxy-carbonyl-indoles)-boric acid (14g, 48mmol) with N-(4-iodophenyl)-sec.-propyl carbamate (15.25g, 50mmol), Pd (dppf) Cl 2(678mg, 0.92mmol), K 2CO 3(132mmol) aqueous solution and DMF (150mL) mix for 2M, 66mL.Reaction mixture at room temperature stirs and spends the night, and uses H subsequently 2O dilutes, and extracts with EtOAc.Organic layer is with H 2O and salt water washing are carried out drying and concentrated, subsequently through silica gel chromatography (CH 2Cl 2) purifying and grind through 2: 1 hexanes/ether, generate the gray solid of 2-(4-isopropoxy carbonyl amino-phenyl)-6-methoxyl group-indoles-1-carboxylic acid tert-butyl ester (15.6g, 76%).
Step B: with 2-(4-isopropoxy carbonyl amino-phenyl)-6-methoxyl group-indoles-1-carboxylic acid tert-butyl ester (17.4g, 41mmol), CH 2Cl 2(50mL) and the mixture of TFA (50mL) at room temperature stir 1h.Concentrated reaction mixture is used CH 2Cl 2Dilution is subsequently with saturated NaHCO 3Solution washing.Dry and concentrated organic layer after ether grinds, generates the light gray solid of [4-(6-methoxyl group-1H-indoles-2-yl)-phenyl]-carbamic acid isopropyl ester (11.4g, 86%).
Step C: to [4-(6-methoxyl group-1H-indoles-2-yl)-phenyl]-carbamic acid isopropyl ester (11.3g, 34.9mmol) DMF (50mL) solution in 20 minutes, dropwise add N-chlorosuccinimide (5g, 37.4mmol), this mixture at room temperature stirs 1h subsequently.This reaction mixture is with H 2O dilutes, and extracts with EtOAc.Organic layer is with H 2O and salt water washing, dry and concentrate after, grind the brown solid that generates [4-(3-chloro-6-methoxyl group-1H-indoles-2-yl)-phenyl]-carbamic acid isopropyl ester (10.65g, 85%) through ether.
Step D: with [4-(3-chloro-6-methoxyl group-1H-indoles-2-yl)-phenyl]-carbamic acid isopropyl ester (50mg, 0.14mmol), Cs 2CO 3(95mg, 0.29mmol), the brooethyl cyclopropane (18 μ L, 0.18mmol) and the mixture of DMF (200 μ L) stir down 4h at 60 ℃.Reaction mixture at room temperature stirs 1h subsequently, uses H 2O dilutes, and extracts with EtOAc.Organic layer is with H 2O and salt water washing are carried out drying and concentrated, subsequently through silica gel chromatography (7: 3CH 2Cl 2/ hexane) purifying generates the white solid of [4-(3-chloro-1-cyclopropyl methyl-6-methoxyl group-1H-indoles-2-yl)-phenyl]-carbamic acid isopropyl ester (19mg, 33%).
Embodiment 1DU:(R)-preparation of [4-(3-cyano group-1-cyclobutyl-6-methylsulfonyl methoxyl group-1H-indoles-2-yl)-phenyl]-carboxylamine 1-cyclopropyl-ethyl ester (compound 2988).
Figure A20078000890206181
Steps A: with [4-(3-cyano group-1-cyclobutyl-6-hydroxyl-1H-indoles-2-yl)-phenyl]-t-butyl carbamate (1.6g, 4mmol) and Cs 2CO 3(2.6g, 8mmol), methyl chloride methyl thioether (410 μ L, 5mmol) and DMF (16mL) mix.Reaction mixture at room temperature stirs and spends the night, and uses H 2O dilutes, and extracts with EtOAc.Organic layer is with H 2O and salt water washing are carried out drying and concentrated, subsequently through silica gel chromatography (CH 2Cl 2) purifying generates the off-white color solid of [4-(3-cyano group-1-cyclobutyl-6-methylsulfonyl methoxyl group-1H-indoles-2-yl)-phenyl]-t-butyl carbamate (1.72g, 93%).
Step B: to [4-(3-cyano group-1-cyclobutyl-6-methylsulfonyl methoxyl group-1H-indoles-2-yl)-phenyl]-t-butyl carbamate (1.35g, CHCl 2.9mmol) 3(20mL) solution once add the 3-chloroperoxybenzoic acid (1.5g, 8.7mmol).After 10 minutes, reaction mixture is with the NaHCO of dilution 3Solution washing carries out drying and concentrated, subsequently through silica gel chromatography (95: 5CH 2Cl 2/ EtOAc) purifying generates the off-white color solid of [4-(3-cyano group-1-cyclobutyl-6-methylsulfonyl methoxyl group-1H-indoles-2-yl)-phenyl]-t-butyl carbamate (1.11g, 77%).
Step C: to [4-(3-cyano group-1-cyclobutyl-6-methylsulfonyl methoxyl group-1H-indoles-2-yl)-phenyl]-t-butyl carbamate (1.21g, CH 2.47mmol) 2Cl 2(6mL) solution adds TFA (2mL), stirs 1h under room temperature.Reaction mixture is with CH 2Cl 2Dilution is with NaHCO 3Solution washing, drying concentrates.Grind through acetone (5mL), generate the baby pink solid of 2-(4-amino-phenyl)-1-cyclobutyl-6-methylsulfonyl methoxyl group-1H-indoles-3-nitrile (891mg, 91%).
Step D: with 2-(4-amino-phenyl)-1-cyclobutyl-6-methylsulfonyl methoxyl group-1H-indoles-3-nitrile (100mg, 0.25mmol) and p-nitrophenyl chloro-formic ester (120mg, 0.6mmol), (60 μ L 0.75mmol) mix, and stir 1h under the room temperature for DCE (1mL) and pyridine.(90 μ L 0.92mmol), heat 2h down at 80 ℃ subsequently to add (R)-1-cyclopropyl ethanol to this mixture.Reaction mixture is with CH 2Cl 2Dilution, NaOH solution washing subsequently to dilute.Dry and concentrated organic layer is through silica gel chromatography (95: 5CH 2Cl 2/ EtOAc) purifying generates the white solid of (R)-[4-(3-cyano group-1-cyclobutyl-6-methylsulfonyl methoxyl group-1H-indoles-2-yl)-phenyl]-carboxylamine 1-cyclopropyl-ethyl ester (105mg, 83%).
Embodiment 1DV:[4-(3-cyano group-1-cyclobutyl-6-morpholine-4-base-1H-indoles-2-yl)-phenyl]-preparation of carbamic acid isopropyl ester (compound 2800).
Figure A20078000890206201
Steps A: under 0 ℃ to the 6-nitroindoline (16.2g, DMF 100mmol) (60mL) solution add Sulfuryl chloride isocyanate (10.9mL, 125.0mmol).Mixture at room temperature stirs subsequently and spends the night, and is poured into frozen water (1.0L), stirs 3h.Filtering precipitate washes with water, after the dry air, generates 3-cyano group-6-nitroindoline (17.63g, 94%).
Step B: with 3-cyano group-6-nitroindoline (3.74g, 20.0mmol), the cyclobutyl bromide (2.27mL, 24.0mmol), Cs 2CO 3(13.04g, the mixture of DMF 40.0mmol) (20mL) solution stirred 3 days down in 90 ℃ in sealed tube.After the cooling, pour mixture into frozen water (200mL), filtering precipitate washes with water, and it is transferred on the Paar hydrogenation instrument.The MeOH (50mL) of use 5%Pd/C (1.0g) and EtOAc (50mL) solution are at the H of 60psi 2Carry out the hydrogenation of 24h down.Mixture filters with Celite, with MeOH washing, is concentrated into driedly, generates 6-amino-1-cyclobutyl-3-cyanoindole (3.13g, 74%).
Step C: with 6-amino-1-cyclobutyl-3-cyanoindole (4.60g, 21.8mmol), bromine ether (6.07g, 26.16mmol), (10.79mL, the mixture of DMF 65.4mmol) (100mL) solution stir down at 90 ℃ and spend the night DIEA, are poured into frozen water (1.0L) subsequently.Filtering precipitate washes with water, through silica gel (CH 2Cl 2/ EtOAc, 9: 1) purifying, generate 1-cyclobutyl-6-morpholine-4-base-1H-indoles-3-nitrile (5.24g, 85%).
Step D: under-78C to 1-cyclobutyl-6-morpholine-4-base-1H-indoles-3-nitrile (1.20g, 4.27mmol), triisopropyl borate (1.28mL, 5.55mmol) THF (15mL) solution stirring add LDA (the single THF of 1.5M is dissolved in hexanaphthene, 3.27mL, 4.91mmol).This mixture stirred 10 minutes down at-78 ℃, at room temperature stirred 30min, add subsequently the 4-Iodoaniline (1.03g, 4.70mmol) and PdCl 2(dppf) (0.16g, 0.2mmol).Reaction system is cooled to-78 ℃,, adds DMF (30mL) and K subsequently with nitrogen wash 2CO 3(2.0M, 6.4mL, 12.8mmol) aqueous solution.Remove cryostat, mixture is stirred spend the night, pour frozen water (500mL) into.Filtering precipitate washes with water, air-dry after, through silica gel (CH 2Cl 2/ EtOAc, 9: 1) purifying, generate 2-(4-amino-phenyl)-1-cyclobutyl-6-morpholine-4-base-1H-indoles-3-nitrile (1.49g, 94%).
Step e: use isopropyl chloroformate (1.0M, 0.6mL, toluene solution 0.6mmol) handle 2-(4-amino-phenyl)-1-cyclobutyl-6-morpholine-4-base-1H-indoles-3-nitrile (0.112g, 0.3mmol), the CH of pyridine (1.0mL) 2Cl 2(2.0mL) solution.This mixture at room temperature stirs 5h, with CH 2Cl 2(5mL) dilution.Separate organic layer, with it with HCl (1.0N, 3 * 2mL), water (5mL * 2) and salt solution (5mL) washs, through silica gel (CH 2Cl 2/ EtOAc, 9: 1) purifying, generate [4-(3-cyano group-1-cyclobutyl-6-morpholine-4-base-1H-indoles-2-yl)-phenyl]-carbamic acid isopropyl ester (0.12g, 87%).
Embodiment 1DW:{4-[3-cyano group-1-cyclobutyl-6-(tetrahydrochysene-pyrans-4-base oxygen base)-1H-indoles-2-yl]-phenyl }-preparation of carbamic acid isopropyl ester (compound 2616).
Figure A20078000890206211
Steps A: with the 6-oxyindole (1.47g, 6.93mmol), toluene-4-sulfonic acid tetrahydrochysene-pyrans-4-base ester (2.65g, 10.42mmol), K 2CO 3(2.87g, 20.77mmol) and the mixture of DMF (15ml) stir down at 80 ℃ and spend the night.After the cooling, pour reaction mixture into frozen water (60ml), generate throw out, collecting precipitation thing after filtration, water and ether/hexane (1: 1) washing.The vacuum-drying solid obtains the brown solid of product (1.76g, 86%).
Step B: with 1-cyclobutyl-6-(tetrahydrochysene-pyrans-4-base oxygen base)-1H-indoles-3-nitrile (1.68g, 5.68mmol) and triisopropyl borate (1.39g, 7.38mmol) THF (15mL) solution be cooled to-78 ℃, dropwise add LDA (1.5M this moment, 4.73mL, THF-cyclohexane solution 7.10mmol).Make reaction mixture be warming up to room temperature, continue to stir 30 minutes.Reaction mixture is cooled to-78 ℃.Add 4-Iodoaniline (1.31g, DMF 5.96mmol) (10mL) solution, K successively 2CO 3(2M, 8.5mL, 17.0mmol) and PdCl 2Dppf (208mg, 0.29mmol).Remove the gas of mixture, use N 2Stir 3h under the filling, room temperature.Reaction mixture distributes with EtOAc (50mL) and water (50mL).Use EtOAc (40mL) washing water again.Water (2 * 30mL) and the organic phase that merges of salt water washing, it is used Mg 2SO 4Drying after concentrating, through silica gel (EtOAc/ hexane, 10% to 50%) purifying, generates brown solid product (1.81g, 83%).
Step C: to 2-(4-amino-phenyl)-1-cyclobutyl-6-(tetrahydrochysene-pyrans-4-base oxygen base)-1H-indoles-3-nitrile (897.8mg, 2.32mmol), K 2CO 3(7mL) and the mixture of ethyl acetate (7mL) add iPrOCOCl (6.9mL, 1M, toluene solution 6.96mmol).Reaction mixture at room temperature stirs and spends the night.Organic layer is with the salt water washing, with Mg 2SO 4Drying after concentrating, through silica gel (EtOAc/ hexane, 10% to 30%) purifying, generates white solid product (1.01g, 92%).
Embodiment 1DX:[4-(3-cyano group-1-cyclobutyl-6-ethylmercapto group-1H-indoles-2-yl)-phenyl }-preparation of carboxylamine 1-cyclopropyl-ethyl ester (compound 2720).
Figure A20078000890206221
Steps A: (30%wt. is dissolved in mineral oil, and 2.71g adds 6-bromo indole (3.98g, THF 20.3mmol) (10mL) solution 20.2mmol) and in the mixture of THF (30mL) to potassium hydride KH under 0 ℃.After 15 minutes, solution is cooled to-78 ℃, adds tert-butyl lithium (1.5M, 27.07mL, pentane solution 40.60mmol) with syringe.Mixture stirs 10min down at-78 ℃, adds diethyl two sulphur (4.97g, THF 40.6mmol) (10mL) solution subsequently.Make reaction mixture be warming up to room temperature, be poured into ice-saturated NH 4Cl (150mL) aqueous solution extracts with EtOAc (150mL) subsequently.Organic phase is with water (150mL) and salt solution (150mL) washing, with Mg 2SO 4Drying after concentrating, through silica gel (EtOAc/ hexane 5% to 15%) purifying, generates the clarified liq of 6-ethylmercapto group-1H-indoles (2.75g, 77%).
Step B: (2.75g, DMF 15.54mmol) (20mL) mixture dropwise adds Sulfuryl chloride isocyanate to 6-ethylmercapto group-1H-indoles under-30 ℃.After the adding temperature is increased to 0 ℃, stirred 30 minutes.This mixture distributes with EtOAc and water.Organic layer Yi Shui and salt water washing are with Mg 2SO 4Drying is after concentrating, through silica gel (CH 2Cl 2) purifying, the white solid of generation 6-ethylmercapto group-1H-indoles-3-nitrile (3.25g, 84%).
Step C: with 6-ethylmercapto group-1H-indoles-3-nitrile (2.13g, 10.5mmol), Cs 2CO 3(6.9g, 21mmol), (1.78g 13.2mmol) and the heating of spending the night under 85 ℃ of the mixture of DMF (20mL), after the cooling, distributes with ethyl acetate and water the cyclobutyl bromide.Organic layer Yi Shui and salt water washing are with Mg 2SO 4Drying after concentrating, through silica gel (EtOAc/ hexane 5% to 30%) purifying, generates the light yellow oil of 1-cyclobutyl-6-ethylmercapto group-1H-indoles-3-nitrile (2.58g, 96%).
Step D: to 1-cyclobutyl-6-ethylmercapto group-1H-indoles-3-nitrile (2.58g, 10.08mmol), triisopropyl borate (2.47g, 13.13mmol) THF (25mL) solution in slowly add LDA (1.5M, 9.41mL, THF-cyclohexane solution 14.1mmol).Make reaction mixture be warming up to room temperature, continue to stir 30 minutes.Reaction mixture is cooled to-78 ℃ subsequently, adds 4-Iodoaniline (2.42g, DMF 11.09mmol) (10mL) solution, K 2CO 3(15.5mL, 31.00mmol) and PdCl 2Dppf (368.0mg, 0.50mmol).Remove the gas of mixture, with N 2Stir 3h under the filling, room temperature, use EtOAc (40mL) subsequently and (40mL) distribute.Water is with more ethyl acetate (30mL) washing, the organic phase of merging with water (2 * 40mL) and the salt water washing, with Mg 2SO 4Drying concentrates subsequently.Collecting precipitation thing after filtration, water and ether washing generate the product of 1.45g.Concentrated filtrate through silica gel (EtOAc/ hexane 5% to 40) purifying, generates 2-(4-amino-phenyl)-1-cyclobutyl-6-ethylmercapto group-1H-indoles-3-nitrile (3.10g, 89%) solid of 1.65g again.
Step e: with 2-(4-amino-phenyl)-1-cyclobutyl-6-ethylmercapto group-1H-indoles-3-nitrile (230.0mg, 0.66mmol) and p-nitrophenyl chloro-formic ester (266mg, 1.32mmol), (104.7mg 1.32mmol) mixes, and stirs 2h under the room temperature for DCE (3.0mL) and pyridine.(115.0,1.34mmol), this mixture stirs 2h down at 80 ℃ to add (R)-1-cyclopropyl ethanol.Reaction mixture dilutes with EtOAc, and with saturated K 2CO 3(2 * 15mL) aqueous solution, water and salt water washing.Dry and concentrated organic layer through silica gel chromatography (EtOAc/ hexane 10%) purifying, generates the white solid of (R)-[4-(3-cyano group-1-cyclobutyl-6-ethylmercapto group-1H-indoles-2-yl)-phenyl]-carboxylamine 1-cyclopropyl-ethyl ester (209mg, 69%).
Embodiment 1DY:{4-[1-cyclobutyl-6-(pyrimidine-2-yloxy)-1H-indoles-2-yl]-phenyl }-carboxylamine 2,2, the preparation of 2-three fluoro-1-methyl-ethyl esters (compound 2888).
Figure A20078000890206241
Steps A: 0 ℃ down toward 6-methoxyl group indoles (18.32g, 124.0mmol) and tert-Butyl dicarbonate (35.3g, CH 162.2mmol) 2Cl 2(120mL) add in the solution DMAP (200mg, 1.64mmol).The mixture that forms at room temperature stirs 16h, after concentrating, distributes with EtOAc and water.Organic layer Yi Shui, salt water washing are carried out drying and concentrated to it, behind silica gel (EtOAc/ hexane 5%) purifying, generate 6-methoxyl group-indoles-1-carboxylic acid tert-butyl ester (30.4g, 99%) solid.
Step B: under-78 ℃ to 6-methoxyl group-indoles-1-carboxylic acid tert-butyl ester (14.33g, 57.90mmol), (15.25g, THF 81.06mmol) (80mL) solution slowly adds LDA to the triisopropyl borate.The mixture that forms at room temperature stirs 1h, and half that it is condensed into original volume poured frozen water (100mL) subsequently into, carries out acidifying with 1N HCl.The collecting precipitation thing with water and hexane wash, generates the brown solid of 6-methoxyl group-indoles-1-carboxylic acid tert-butyl ester (14.2g, yield 85%) after filtration.
Step C: (5.98g, 20.5mmol) (5.37g, DMF 21.6mmol) (60mL) solution dropwise adds K successively with 1-iodo-4-oil of mirbane to the indoles 2-boric acid from step B under 0 ℃ 2CO 3(2M, 30.8mL, 61.6mmol) aqueous solution and PdCl 2Dppf (375.4mg, 0.51mmol).Through continuous three vacuum exhaust/N 2The gas of mixture is removed in filling, and stirring at room 5h distributes with EtOAc and water subsequently.Organic layer is with H 2Drying and concentrated is carried out in O and salt water washing subsequently.Resistates is suspended in the hexane, collecting precipitation thing after filtration, and, generate red solid product (7.20g, 95%) with hexane wash.
Step D: under 0 ℃ to 6-methoxyl group-2-(4-nitro-phenyl)-indoles-1-carboxylic acid tert-butyl ester (7.20g, CH 19.55mmol) 2Cl 2(50mL) solution dropwise adds TFA (22mL).The mixture that forms at room temperature stirs 3h, is suspended in after concentrating and produces solid in the ether, and this solid is collected after filtration, with the ether washing, generates the red solid of 2.43g, promptly first batch of product.Concentrated filtrate, resistates generate 1.55g 6-methoxyl group-2-(4-nitro-phenyl)-1H-indoles red solid of (merging: 3.98g, productive rate 76%), i.e. second batch of product through silica gel (EtOAc/ hexane 5% to 20%) purifying.
Step e: with 6-methoxyl group-2-(4-nitro-phenyl)-1H-indoles (2.12g, 7.90mmol), Cs 2CO 3(5.15g, 15.80mmol), the cyclobutyl bromide (1.28g, 9.48mmol) and the mixture of DMF (20mL) 85 ℃ of down heating 2 days.After the cooling, reaction mixture distributes with EtOAc and water.Organic layer Yi Shui and salt water washing are carried out drying and concentrated to it, through silica gel (EtOAc/ hexane, 5% to 20%) purifying, generate yellow solid product (0.96g, 37%).
Step F: with 1-cyclobutyl-6-methoxyl group-2-(4-nitro-phenyl)-1H-indoles (0.83g, 2.60mmol), iron powder (0.84mg, 15.0mmol), ammonium chloride (0.96g, 18.0mmol) and the mixture of EtOH/ water (25mL/8mL) stir 1h down at 80 ℃, concentrate subsequently.Resistates is suspended in DMF (20mL) and MeOH/CH 2Cl 2(1: 1,20mL) in.Mixture flow is through the Celite pad, with MeOH/CH 2Cl 2(1: 1) washing adds water after concentrating, and generates throw out, and this throw out is collected after filtration, with water washing.Solid is dissolved in CH 2Cl 2, use MgSO 4Drying after concentrating, through silica gel (EtOAc/ hexane 20%) purifying, generates the white solid of 4-(1-cyclobutyl-6-methoxyl group-1H-indoles-2-yl)-aniline (0.57mg, 75%).
Step G: under-30 ℃ to 4-(1-cyclobutyl-6-methoxyl group-1H-indoles-2-yl)-aniline (518.5mg, CH 1.77mmol) 2Cl 2(15mL) solution add boron tribromide (1.33g, 5.31mmol).The mixture that forms stirs 2h down at 0 ℃, is poured into frozen water, with KHCO 3The aqueous solution neutralizes it, extracts with EtOAc subsequently.Water washs with more EtOAc, the organic phase Yi Shui of merging and salt water washing, dry and concentrate after, through silica gel (EtOAc/ hexane 20%) purifying, generate white solid product (480mg, 98%).
Step H: with 2-(4-amino-phenyl)-1-cyclobutyl-1H-indoles-6-alcohol (480mg, 1.72mmol), Cs 2CO 3(1.12g, 3.45mmol), the 2-chloropyridine (296mg, 2.60mmol) and the mixture of DMF (3mL) 50 ℃ of following stirred overnight.After the cooling, this mixture distributes with EtOAc and water.Water washs with more ethyl acetate, the organic phase Yi Shui of merging and salt water washing, dry and concentrate after, through silica gel (EtOAc/ hexane 25%) purifying, generate white solid product (567mg, 92%).
Step I: according to the step e preparation of embodiment 1DX.
Embodiment 1DZ:{4-[3-cyano group-1-cyclobutyl-6-(1,1-dioxo-six hydrogen-1 λ 6-thiapyran-4-base oxygen base)-1H-indoles-2-yl]-phenyl }-preparation of carbamic acid isopropyl ester (compound 3182).
Figure A20078000890206261
Steps A: under 0 ℃ to the CH of tetrahydric thiapyran-4-ketone 3CN (50mL) and H 2The gradation in 1 hour of O (35mL) solution add ozone (70.5g, 115mmol) and NaHCO 3(29.9g, mixture 356mmol).Reaction mixture at room temperature stirs 1h subsequently, uses CH 3CN (250mL) dilution, subsequent filtration.Filtrate concentrates the back and suspends with acetone, subsequent filtration.Obtain 1, the white solid of 1-dioxo-tetrahydric thiapyran-4-ketone (6.3g, quantitative yield).
Step B: to 1,1-dioxo-tetrahydric thiapyran-4-ketone (6.3g, H 36mmol) 2O (55mL) solution gradation adding sodium borohydride (720mg, 18.9mmol).Reaction mixture at room temperature stirred 30 minutes, was 4 with the HCl aqueous solution with pH regulator subsequently.After reaction mixture concentrates, suspend subsequent filtration with acetone.Concentrated filtrate after ether/hexane is ground, generates 1, the white solid of 1-dioxo-tetrahydric thiapyran-4-alcohol (5.63g, 90%).
Step C: with 1,1-dioxo-tetrahydric thiapyran-4-alcohol (1.0g, 6.6mmol), (1.6g 8.4mmol) mixes, at room temperature stirred overnight for pyridine (10mL) and toluene sulfonyl chloride.After reaction mixture concentrates, with the EtOAc dilution, and with the HCl aqueous solution and salt water washing.Dry and concentrated organic layer after hexane grinds, generates O-tosyl group-1, the white solid of 1-dioxo-tetrahydric thiapyran-4-alcohol (1.073g, 53%).
Step D: with [4-(3-cyano group-1-cyclobutyl-6-hydroxyl-1H-indoles-2-yl)-phenyl]-carbamic acid isopropyl ester (90mg, 0.23mmol) and Cs 2CO 3(156mg, 0.48mmol), DMF (0.9mL) and O-tosyl group-1, (96mg 0.32mmol) mixes 1-dioxo-tetrahydric thiapyran-4-alcohol.Reaction mixture stirs down at 80 ℃ and spends the night, and uses H 2O dilutes, and extracts with EtOAc.Organic layer is with H 2O and salt water washing are carried out drying and concentrated, subsequently through silica gel chromatography (95: 5CH 2Cl 2/ EtOAc) purifying generate 4-[3-cyano group-1-cyclobutyl-6-(1,1-dioxo-six hydrogen-1 λ 6-thiapyran-4-base oxygen base)-1H-indoles-2-yl]-phenyl }-white solid of carbamic acid isopropyl ester (66mg, 56%).
Embodiment 1EA:1-cyclobutyl-2-[4-(4-methyl-thiazol-2-yl amino)-phenyl]-preparation of 6-(pyrimidine-2-yloxy)-1H-indoles-3-nitrile (compound 3180)
Figure A20078000890206271
Steps A: according to the step H preparation of embodiment 1EA.
Step B:1. with the 6-pyrimidine-indole aniline of steps A preparation (2.25g, 5.90mmol), Fmoc-NCS (1.74g, 6.19mmol) and CH 2Cl 2(15mL) solution at room temperature stirs 2h, after concentrating, with the ethyl acetate washing, generates Fmoc-indoles-urea, and it need not to be further purified when using.Add CH to above-mentioned solid 2Cl 2(30mL) and piperidines (5mL).The mixture that forms at room temperature stirs 14h, concentrates the back with the ether washing, and drying generates light brown solid product (2.5g, 96%) with concentrating.
Step D: the indoles thiocarbamide that is obtained to step C (150mg, 0.34mmol), DIPEA (88mg, 0.68mmol), Virahol (3.5mL) and DMSO (2.0mL) add 1-chloro-third-2-ketone (92.5mg, 47.6mmol).The mixture that forms stirred 2 days down at 70 ℃.After the cooling, reaction mixture distributes with EtOAc and water, and organic layer Yi Shui and salt water washing are with MgSO 4After the drying,, generate brown solid product (102mg, yield 63%) through silica gel (EtOAc/ hexane 25%) purifying.
Embodiment 1EB:1-cyclobutyl-2-[4-(2,5-dimethyl-2H-pyrazole-3-yl amino)-phenyl]-preparation of 6-(pyrimidine-2-yloxy)-1H-indoles-3-nitrile (compound 3285)
Figure A20078000890206281
Steps A: with 2,5-dimethyl-2H-pyrazole-3-yl amine (2.53g, 22.8mmol), diacetyl oxide (2.67g, 26.2mmol) and the mixture of acetate (10mL) stir down 3h at 50 ℃.After the cooling, mixture is with saturated NaHCO 3The aqueous solution is handled, and forms throw out, and this throw out is collected after filtration, water and hexane wash, dry back generation white solid product (3.43g, quant.).
Step B: to N-(2,5-dimethyl-2H-pyrazole-3-yl)-ethanamide (2.01g, 13.1mmol), 1, the 4-diiodo-benzene (5.20g, 15.8mmol), K 3PO 4(5.57g, 26.2mmol), (125mg is 0.66mmol) with diox (50mL) adds N, N-dimethyl-hexanaphthene-1,2-diamines to CuI.Through continuous three vacuum exhaust/N 2Filling is removed the gas of mixture, subsequently reflux 14h.After the cooling, mixture distributes with EtOAc and water, organic layer Yi Shui and salt water washing, MgSO 4After the drying, through silica gel (EtOAc/CH 2Cl 220%) purifying generates white solid product (4.91g, 69%).
Step C. prepares N-[4-cyano group-1-cyclobutyl-6-hydroxyl-1H-indol-1-yl-according to the step D of embodiment 1EI)-phenyl]-N-(2,5-dimethyl-2H-pyrazole-3-yl)-ethanamide (2.12g, yield 86%).
Step D. is with N-[4-cyano group-1-cyclobutyl-6-hydroxyl-1H-indol-1-yl-)-phenyl]-N-(2,5-dimethyl-2H-pyrazole-3-yl)-ethanamide (1.54g, 3.50mmol) and HCl (6N, mixture 6mL) stirs down 15h at 80 ℃.After the cooling, reaction mixture distributes with EtOAc and water, and organic layer is with saturated NaHCO 3The aqueous solution, water and salt water washing are through MgSO 4After the drying, concentrate.Wash residual solid with ether, generate brown solid product (1.27g, yield 92%).
Step e: the step H according to embodiment 3 prepares 1-cyclobutyl-2-[4-(2,5-dimethyl-2H-pyrazole-3-yl amino)-phenyl]-preparation of 6-(pyrimidine-2-yloxy)-1H-indoles-3-nitrile (compound 3)
Embodiment 1EC{4-[3-cyano group-1-cyclobutyl-6-(2-sulfonyloxy methyl-vinyloxy group)-1H-indoles-2-yl]-phenyl }-preparation of t-butyl carbamate (compound 3301).
Figure A20078000890206291
To indole fluoroform sulfonic acid (1.07g, add in DMF 2.00mmol) (2mL) solution ethylene methacrylic sulfone (432mg, 3.99mmol), two (triphenylphosphine) Palladous chloride (II) (72mg, 0.103mmol) and Et 3N (0.84mL, 6.03mmol).Mixture is with nitrogen purging, and in 90 ℃ of heating 20h down.Add again subsequently the ethylene methacrylic sulfone (106mg, 1mmol) and two (triphenylphosphine) palladiums (72mg, 0.10mmol).Mixture heats 20h down at 90 ℃, is cooled to room temperature subsequently.Add entry (14mL), cross filter solid, with the water washing solid, drying is after silica gel (EtOAc/1: 1 CH 2Cl 2-hexane 0-10%) purifying obtains brown solid product (250mg, 26%).
Embodiment 1ED:(R)-{ 4-[3-cyano group-1-cyclopropyl-6-(pyrimidine-2-yloxy)-1H-indoles-2-yl]-phenyl }-preparation of carboxylamine 1-cyclopropyl ethyl ester (compound 3321).
Figure A20078000890206292
Steps A: under-78 ℃ to 1-cyclobutyl-6-hydroxyl-1H-indoles-3-nitrile (4.24g, THF 20mmol) (60.0mL) solution add LDA (30.7mL, 46.0mmol) and iodine (7.62g, 30.0mmol).Mixture stirs down 10min at-78 ℃, stirs 3h after being warming up to room temperature.Pour reaction mixture into frozen water (500mL), filtering precipitate is with its water and CH 2Cl 2Washing.Resulting thick iodide (3.99g) after the dry air are absorbed in DMF (25mL), add Cs to this solution subsequently 2CO 3(9.78g, 30.0mmol) and the 2-chloropyrimide (2.18g, 19.0mmol).This mixture is stirred 30min down at 70 ℃, be poured into frozen water (200mL), throw out is collected with filter, and with water washing, through silica gel (CH 2Cl 2/ EtOAc, 9.75: 0.25) behind the purifying, obtain 1-cyclobutyl-2-iodo-6-(pyrimidine-2-yloxy)-1H-indoles-3-nitrile (1.52g, 47%).
Step B: with the resulting iodide of steps A (0.83g, 2.0mmol), 5-(4,4,5,5-tetramethyl--[1,3,2] two oxa-s pentaborane-2-yl)-pyrimidine-2-base amine (0.48g, 2.2mmol), PdCl 2(dppf) (0.07g 0.1mmol) mixes with DMF (10.0mL), adds K subsequently 2CO 3(2.0M, 3.0mL, 6.0mmol) aqueous solution.This mixture stirs down at 80 ℃ and spends the night, and is poured into frozen water (100mL) then.Filtering precipitate washes with water, through silica gel (CH 2Cl 2/ EtOAc/MeOH, 5: 5: 0.2) purifying, generate 2-(6-amino-pyridine-3-yl)-1-cyclobutyl-6-(pyrimidine-2-yloxy)-1H-indoles-3-nitrile (0.61g, 80%).
Step C: with 2-(6-amino-pyridine-3-yl)-1-cyclobutyl-6-(pyrimidine-2-yloxy)-1H-indoles-3-nitrile (115mg, 0.3mmol), 4-chloroformate nitrophenyl ester (91mg, 0.45mmol) the mixture of pyridine (1.0mL) solution stir down 2h at 30 ℃, add subsequently (R)-1-cyclopropyl ethanol (150 μ L, 1.5mmol).This mixture stirs down at 80 ℃ and spends the night, with water (10mL) and CH 2Cl 2(5mL) dilute.Organic layer with water (3 * 5mL), HCl (2N, 3 * 5mL), saturated NaHCO 3(3 * 5mL) aqueous solution wash, through silica gel (CH 2Cl 2/ EtOAc, 1: 9) behind the purifying, generate (R)-4-[3-cyano group-1-cyclopropyl-6-(pyrimidine-2-yloxy)-1H-indoles-2-yl]-phenyl }-carboxylamine 1-cyclopropyl ethyl ester (25mg, 17%).
Embodiment 2: use based on the HCV IRES monocistron translation mensuration of cell and carry out the screening of low-molecular weight compound
The translation that the monocistron HCV-IRES based on cell of use through designing the natural HCV mRNA translation of close simulation regulates and control is measured and is screened the chemical storehouse, and the hit results based on library of compounds prepares the compound analogue subsequently, and it is screened.The DNA construction of preparation pHCVIRESmono by name, wherein HCV IRES sequence (HCV2b, Nucleotide 18-347) is inserted between promotor and Photinus pyralis LUC (Fluc) reporter gene.By pHCVIRESmono DNA transfection and selection hygromycin resistance, set up HepG 2 (hepatoblastoma) clone (HepGmono-4 by name) or the Huh7 clone (Huhmono 7 by name) or the Hela-clone (Helamono by name) of stable transfection.
Embodiment 3: use the translation analysis that adds cap based on cell and dependence that the selectivity of HCV translation that IRES regulates and control is carried out Measure
Owing to use translation to measure the inhibitor that screens HCV IRES, but that the translation that selected hit results specific action is driven in HCV IRES maybe can be regulated the total protein of mammalian cell is synthetic.Act on total protein synthetic compound and most possibly have overt toxicity.In order to inquire into this possibility, set up the various translations that add cap based on cell and dependence and measure, with the compound of further all selections of assessment.Structure contains the plasmid DNA of 130 Nucleotide of Fluc 5 end upstream carrier sequences.This construction is referred to herein as pLuc.Utilize 293T cell (human embryonic kidney cell line) in the translation that dependence adds cap is measured, to set up stable clone.Use compound that HepGmono-4 and pLuc were handled 20 hours, through quantitative Fluc signal measuring activity.5 times of selectivity that add between the cap translation between HCV IRES and dependence are considered to desirable.Use these to measure, identify its IC based on the translation that cell and dependence add cap 50Value in the translation that dependence adds cap is measured than big at least 5 times compound in HCV IRES translation is measured.
Use Western blotting to confirm that further compound selective has suppressed the translation that HCV IRES is driven.HepGmono-4 and pLuc cell were handled 20 hours with test-compound subsequently all with above-mentioned compound treatment, and collecting cell is to contain the ln damping fluid lysing cell of 0.5%SDS.Protein separates on 10%SDS-PAGE, is transferred to subsequently on the nitrocellulose filter, and the antibody that re-uses anti-Fluc (RDI) and anti-β-actin (Oncogene) detects.For example, compounds more of the present invention detect by this way.
Optimize the testing conditions that is used for these clones, through the quantitative Fluc mRNA of RT PCR in real time level, control mRNA level is to the influence of these compound activities.For example, compounds more of the present invention detect by this way.
Embodiment 4: use the translation of cell IRES-mediation to measure assessment drives translation to HCV IRES selectivity
Shown already that many people mRNA carried IRES element (18,19,39,44,45,91,126,130).Although the primary sequence of HCV IRES is different with cell IRES with secondary structure, one is used for optionally important test is to measure the compound of selecting whether the activity that suppresses cell IRES is arranged.VEGF IRES has poor initial activity in external test, but shows tangible activity (18,45) in measuring based on the translation of cell.For example, compounds more of the present invention have been tested.
Embodiment 5: the cytotoxicity assessment
The effect of on cell proliferation is the key issue of all medicament research and development work.Therefore, use eliminate the effects of the act any compound of mammalian cell growth of cell proliferation/cytotoxic assay.Go up the effect that detects selected hit results on cell proliferation at human cell line 293T and Huh7 (people's hepatoblastoma).Cell is grown in the DMEM substratum that is added with 10% foetal calf serum, L-glutaminate, penicillin and Streptomycin sulphate (Dulbecco ' s modified Eagle ' s medium).Use test-compound that the cell that is in logarithmic phase was handled three days, wherein 250 μ M are maximum concentrations of employed test-compound.Use CellTiter 96 AQueous One Solution Cell Proliferation Assay (Promega, Madison, WI) effect of the described compound on cell proliferation of mensuration.Its CC in HepGmono-4 50Value compares IC 50The compound that value is high at least 5 times is considered to have enough windows between activity and cytotoxicity, so be selected for further assessment.
Embodiment 6: the effectiveness of assessment compound in HCV replicon system
Can be used for cell cultures and the small animal model reliable and that easily obtain that HCV duplicates owing to lack, the exploitation of novel anti HCV medicament is restricted.Self-replacation subgene group HCV system is also referred to as the HCV replicon, obtains recently describing, and has been widely used in the effectiveness (8,70,104) of measuring anti-HCV inhibitor.It is reported that Interferon, rabbit (IFN) α and HCV proteolytic enzyme and AG14361 are activated (8,17,32,68,69,117) in HCV replicon system.
Identify the HCV replicon that comprises bicistronic mRNA and monocistron system, and set up the measuring method that is used to detect the HCVIRES inhibitor.In the bicistronic mRNA replicon, HCV IRES instructs the expression of selected marker thing (Neo and/or Fluc reporter gene), and EMCV IRES then mediates the expression of viral Nonstructural Protein.In the monocistron replicon, it is synthetic that HCV IRES directly mediates viral protein.In the bicistronic mRNA replicon, analyze HCV IRES inhibitor through quantitative Fluc report signal.Use compound of the present invention to the cell cultures that contains replicon 2 days or 3 days.Interferon, rabbit (IFN) α is as positive control.For example, compounds more of the present invention detect by this way.
In following table (Table 1A)
*=replicon or HCV-PV IC50＞2uM
*=replicon or HCV-PV IC50 are between 0.5uM and 2uM
* *=replicon or HCV-PV IC50＜0.5uM
The IC50 value of replicon is by the Photinus pyralis LUC signal deciding.
Reduce mensuration HCV-PV IC50 value through viral RNA.
Table 1A
Compound Fusing point (℃) Mass spectrum [M+H] Replicon IC 50μ M 2-days Replicon IC 50μ M 3-days 1H NMR data
Compound Fusing point (℃) Mass spectrum [M+H] Replicon IC 50μ M 2-days Replicon IC 50μ M 3-days 1H NMR data
1330 148-151 394.18 **
1331 157-160 408.20 **
1332 213-215 440.2 **
1333 160-164 482.2 **
1334 87-88 460.25 ** ***
1335 179-180 488.31 **
1336 173-176 488.31 (M-H+) **
1337 183-184 **
1338 186-187 389.4 **
1339 177-178 432.3 **
1340 249-250 428.3 ***
1341 170-171 416.3 **
1342 232-234 498.17 *** ***
1343 155-158 405.24 **
1344 294-296 398.15 *
1345 201-203 401.21 (M-H+) *** ***
1346 226-228 416.29 *
1347 Foam 437.10 **
1348 134.2- 139.5 392.1 ** (CDCl3，300MHz)，δ7.63(d， J＝8.7Hz，1H)，7.53(d，J＝8.7Hz，2H)， 7.32(d，J＝8.7Hz，2H)，6.96(dd，J＝2.1 Hz and 8.7Hz，1H)，6.87(d，J＝1.8Hz， 1H)，4.14(q，J＝6.9Hz，2H)，3.90(s， 3H)，3.49-3.40(m，4H)，1.36-1.21(m， 9H).
1349 111.3- 116.5 423.4 ** (CDCl3，300MHz)，δ7.63(d， J＝8.7Hz，1H)，7.52(d，J＝8.4Hz，2H)， 7.31(d，J＝7.8Hz，2H)，6.96(dd，J＝2.1 Hz and 8.7Hz，1H)，6.87(d，J＝1.8Hz， 1H)，4.61-4.43(m，1H)，4.14(q， J＝7.5Hz，2H)，3.90(s，3H)，2.97-2.90 (m，3H)，1.34(t，J＝7.2Hz，3H)，1.30- 1.16(m，6H).
1350 173.6- 435.5 ** (CDCl3，300MHz)，δ7.63(d，
Compound Fusing point (℃) Mass spectrum [M+H] Replicon IC 50μ M 2-days Replicon IC 50μ M 3-days 1H NMR data
182.1 J＝8.1Hz，1H)，7.52(d，J＝8.4Hz，2H)， 7.30(d，J＝8.4Hz，2H)，6.97(d， J＝7.5Hz，1H)，6.87(s，1H)，4.14(q， J＝6.6Hz，2H)，3.90(s，3H)，3.64-3.48 (m，4H)，1.72-1.62(m，6H)，1.34(t， J＝6.3Hz，3H).
1351 197.1- 205.3 421.5 ** (CDCl3，300MHz)，δ7.63(d， J＝8.7Hz，1H)，7.52(d，J＝8.7Hz，2H)， 7.33(d，J＝8.4Hz，2H)，6.96(dd，J＝1.8 Hz and 8.4Hz，1H)，6.88(s，1H)，4.14 (q，J＝7.2Hz，2H)，3.90(s，3H)，3.60(t， J＝6.6Hz，2H)，3.51(t，J＝6.6Hz，2H)， 2.04-1.91(m，4H)，1.34(t，J＝6.9Hz， 3H).
1352 Foam 439.25 **
1353 Foam 441.24 **
1354 110-115 488.3 **
1355 163-164 400.26 (M-H+) **
1356 251-252 550.4 ** ***
1357 278-280 554.3 ** **
1358 260-261 554.3 ***
1359 254-256 504.3 **
1360 163-165 453.22 *** **
1361 238-241 467.22 **
1362 236-238 542.27 **
1363 168-171 451.21 ** **
1364 128-131 451.21 **
1365 112-114 436.3 *** **
1366 168-169 336.3 **
1367 191-194 394.2 *** **
1368 175-177 408.2 *** ***
1369 154-156 422.2 *** ***
1370 145-148 436.2 *** ***
1371 166-168 426.2 *** ***
1372 107-109 470.2 *** ***
Compound Fusing point (℃) Mass spectrum [M+H] Replicon IC 50μ M 2-days Replicon IC 50μ M 3-days 1H NMR data
1373 148-151 442.1 **
1374 158-161 514.3 **
1375 108-120 418.2 **
1376 165-167 391.2 **
1377 161-163 417.2 **
1378 147-150 435.3 **
1379 152-155 461.4 **
1380 216-218 447.3 **
1381 151-154 433.3 **
1382 110-114 495.4 **
1383 196-198 524.4 **
1384 175-176 483.3 **
1385 122-127 408.0 ** (CDCl3，300MHz)，δ7.63(d， J＝8.7Hz，1H)，7.54-7.51(m，2H)， 7.34-7.29(m，2H)，6.96(dd，J＝2.4Hz and 8.7Hz，1H)，6.87(d，J＝2.1Hz， 1H)，4.13(q，J＝7.2Hz，2H)，3.90(s， 3H)，3.64-3.56(m，4H)，3.40(d， J＝1.8Hz，3H)，3.14(d，J＝29.7Hz，3H)， 1.34(t，J＝7.2Hz，3H).
1386 213-214 405.34 ** 1H NMR (300MHz，DMSO-d 6)：δ 8.44(1H，s)，7.72(2H，d，J＝8.8Hz)， 7.50(1H，d，J＝8.8Hz)，7.44(2H，d，J ＝8.8Hz)，7.24(1H，d，J＝2.0Hz)， 6.91(1H，dd，J＝8.8，2.0Hz)，4.15 (2H，t，J＝7.2Hz)，3.84(3H，s)，3.36 (4H，q，J＝7.0Hz)，1.56(2H，hx，J＝ 7.0Hz)，1.10(6H，t，J＝7.0Hz)，0.64 (3H，t，J＝7.2Hz).
1387 65-70 477.38 * 1H NMR(300MHz，DMSO-d 6)： δ8.54(1H，s)，7.40(2H，d，J＝8.8 Hz)，7.28(1H，d，J＝8.5Hz)，7.24 (2H，d，J＝8.8Hz)，6.89(1H，d，J＝ 2.0Hz)，6.62(1H，dd，J＝8.5，2.0 Hz)，6.06(1H，t，J＝5.7Hz)，3.98- 3.91(2H，m)，2.85(2H，q，J＝6.1Hz)， 1.30-1.20(2H，m)，0.76(9H，s)，0.67 (3H，t，J＝7.3Hz)，0.00(6H，s).
1388 161-164 429.25 **
Compound Fusing point (℃) Mass spectrum [M+H] Replicon IC 50μ M 2-days Replicon IC 50μ M 3-days 1H NMR data
1389 171-173 500.2 ***
1390 217-223 No ionizati on **
1391 195-200 433.25 **
1392 193-197 478.39 (ES-) ***
1393 193-197 478.39 (ES-) ***
1394 96.5-100.6 502.2 *** (MeOD，300MHz)，δ7.78(d， J＝8.4Hz，2H)，7.52-7.45(m，3H)，7.17 (s，1H)，7.02(dd，J＝1.8Hz and 8.4Hz. 1H)，4.40(t，J＝4.2Hz，2H)，4.19(q， J＝6.9Hz，2H)，3.89(t，J＝4.2Hz，4H)， 3.63-3.59(m，4H)，3.45(t，J＝6.3Hz， 2H)，3.29-3.23(m，4H)，1.85-1.77(m， 1H)，1.25(t，J＝7.2Hz，3H)，0.98-0.86 (m，4H).
1395 95.9-99 486.3 ** *** (MeOD，300MHz)，δ7.79(d， J＝8.4Hz，2H)，7.54-7.48(m，3H)，7.19 (s，1H)，7.02(d，J＝7.8Hz，1H)，4.46- 4.41(m，2H)，4.21(q，J＝6.9Hz，2H)， 3.84-3.79(m，4H)，3.66-3.61(m，4H)， 3.51(br，2H)，2.96(s，3H)，2.32(br， 2H)，1.81-1.79(m，1H)，1.26(t， J＝7.2Hz，3H)，0.97-0.87(m，4H).
1396 192-198 455.30 *** ***
1397 170-171 434.27 *** ***
1398 166-167 448.27 *** ***
1399 125-126 448.27 *** ***
1400 168-169 474.26 **
1401 182-183 516.25 *** ***
1402 144-145 494.20 (M-H+) *** ***
1403 168-171 483.1 ***
1404 174-176 407.2 ***
1405 182-185 421.3 *** ***
1406 141-144 422.3 *** ***
Compound Fusing point (℃) Mass spectrum [M+H] Replicon IC 50μ M 2-days Replicon IC 50μ M 3-days 1H NMR data
1407 137-140 448.3 **
1408 199-203 419.41 ***
1409 152-155 447.26 ***
1410 153-155 486.7 ***
1411 173-174 506.3 *** ***
1412 198-200 446.00 (M-H+) ** 1H NMR(300MHz，CDCl 3)：δ7.61 (1H，d，J＝8.8Hz)，7.50(2H，d，J＝ 8.6Hz)，7.36(2H，d，J＝8.6Hz)，7.29 (1H，d，J＝1.9Hz)，7.03(1H，s)，6.99 (1H，dd，J＝8.0，J＝2.2Hz)，4.95 (2H，m)，4.23(2H，t，J＝4.7Hz)，4.00 (1H，m)，2.81(2H，t，J＝4.7Hz)，3.49 (3H，s)，2.82(2H，m)，2.35(2H，m)， 1.80(2H，m)，1.20(6H，d，J＝6.3Hz).
1413 90.2-95.4 474.1 ** (CD3CN，300MHz)，δ9.04(s，1H)， 7.80(d，J＝8.7Hz，2H)，7.57 (d，J＝8.4Hz，1H)，7.50(d，J＝8.4Hz， 2H)，7.15(d，J＝1.5Hz，1H)，6.99(dd， J＝1.5Hz and 8.7Hz，1H)，4.44(t， J＝4.2Hz，2H)，4.15(q，J＝7.2Hz，2H)， 3.59-3.51(m，6H)，2.90(s，3H)，2.84 (s，6H)，1.78-1.72(m，1H)，1.25(t， J＝7.2Hz，3H)，0.93-0.82(m，4H).
1414 163.9- 168.8 516.5 ** (CD3CN，300MHz)，δ8.90(s，1H)， 7.79(d，J＝8.7Hz，2H)，7.56 (d，J＝8.7Hz，1H)，7.50(d，J＝8.7Hz， 2H)，7.11(d，J＝1.5Hz，1H)，6.96(dd， J＝1.8Hz and 8.7Hz，1H)，4.43(t， J＝4.2Hz，2H)，4.15(q，J＝7.2Hz，2H)， 3.71-3.68(m，8H)，3.70-3.67(m，2H)， 3.54(br，2H)，3.32-3.29(m，5H)， 1.95-1.92(m，1H)，1.24(t，J＝7.2Hz， 3H)，0.90-0.82(m，4H).
1415 220-222 474.22 *** 1H NMR(300MHz，DMSO-d 6)： δ8.75(1H，s)，7.62-7.39(7H，m)，6.98 (1H，d，J＝8.8Hz)，6.27(1H，t，J＝ 5.4Hz)，5.19(2H，s)，4.18(2H，q，J＝ 7.3Hz)，3.05(2H，q，J＝6.4Hz)，2.65 (3H，s)，1.44(2H，hx，J＝7.3Hz)， 1.18(3H，t，J＝7.0Hz)，0.87(3H，t，J ＝7.5Hz).
1416 115-121 489.35 **
Compound Fusing point (℃) Mass spectrum [M+H] Replicon IC 50μ M 2-days Replicon IC 50μ M 3-days 1H NMR data
1417 192-193 466.28 ***
1418 183-185 533.4 *** ***
1419 121-123 514.5 *** ***
1420 209-215 515.6 *** ***
1421 138-140 513.3 **
1422 201-203 516.6 *** ***
1423 192-193 474.36 *** **
1424 65-72 476.33 (ES-) **
1425 153-160 471.48 *** ***
1426 159-164 468.37 *** ***
1427 211-213 517.3 *** **
1428 141-145 518.4 ***
1429 132-134 478.4 ***
1430 122-125 487.3 ***
1431 136-138 432.3 (ES-) ***
1432 187-194 467.47 ***
1433 153-156 437.50 ***
1434 221-223 487.6 ***
1435 161-165 503.5 ***
1436 76-79 463.4 ***
1437 74-76 522.4 ***
1438 76-79 496.4 ***
1439 74-76 514.4 **
1440 232-236 459.43 ***
1441 192-196 447.40 **
1442 144-145 549.2 **
1443 199-201 360.1 ***
1444 189-191 472.4 ***
1445 112-115 508.4 ***
1446 207-208 474.4 ***
Compound Fusing point (℃) Mass spectrum [M+H] Replicon IC 50μ M 2-days Replicon IC 50μ M 3-days 1H NMR data
1447 220-222 488.4 ***
1448 182-184 525.4 ***
1449 180-181 446.3 ***
1450 162-163 468.41 **
1451 163-164 453.41 ***
1452 183-184 460.44 ***
1453 183-184 486.49 ***
1454 183-184 514.53 (M-H+) ***
1455 183-184 472.45 ***
1456 183-184 520.43 (M-H+) ***
1457 183-184 514.43 ***
1458 183-184 500.49 (M-H+) ***
1459 183-184 500.43 (M-H+) ***
1460 183-184 512.34 (M-H+) ***
1461 183-184 472.31 (M-H+) **
1462 183-184 459.43 **
1463 482.35 **
1464 496.41 ***
1465 418.31 ***
1466 223-224 434.3 ***
2600 200-202 446.3 ***
2601 191-193 432.3 ***
2602 202-204 458.3 ***
2603 167-169 480.3 ***
2604 256 (decomposition .) 562.5 **
2605 204-205 497.4 ***
2606 148-150 496.4 ***
Compound Fusing point (℃) Mass spectrum [M+H] Replicon IC 50μ M 2-days Replicon IC 50μ M 3-days 1H NMR data
2607 209-211 496.4 ***
2608 153-155 436.4 ***
2609 165-166 448.4 ***
2610 181-183 464.4 ***
2611 115-116 462 *** 1H NMR(300MHz，CDCl 3)：δ7.62 (1H，d，J＝8.8Hz)，7.55(2H，d，J＝ 8.8Hz)，7.42(2H，d，J＝8.8Hz)，7.27 (1H，d，J＝2.0Hz)，6.98(1H，dd，J＝ 8.8，2.0Hz)，6.73(1H，s)，5.05(1H， hp，J＝6.4Hz)，4.93(1H，p，J＝8.8 Hz)，4.25-4.21(2H，m)，3.87-3.83 (2H，m)，3.64(2H，q，J＝7.0Hz)， 2.91-2.78(2H，m)，2.40-2.28(2H，m)， 2.00-1.89(1H，m)，1.88-1.77(1H，m)， 1.32(6H，d，J＝6.4Hz)，1.28(3H，t，J ＝7.0Hz).
2612 148-150 461 *** 1H NMR(300MHz，CDCl 3)：δ7.62 (1H，d，J＝8.8Hz)，7.49(2H，d，J＝ 8.8Hz)，7.38(2H，d，J＝8.8Hz)，7.29 (1H，d，J＝2.3Hz)，6.99(1H，dd，J＝ 8.8，2.3Hz)，6.75(1H，s)，4.96(1H，p， J＝8.9Hz)，4.75(1H，d，J＝7.9Hz)， 4.25-4.21(2H，m)，4.02(1H，m，J＝ 7.3Hz)，3.90-3.86(2H，m)，3.64(2H， q，J＝7.0Hz)，2.90-2.78(2H，m)， 2.40-2.28(2H，m)，1.98-1.88(1H，m)， 1.87-1.77(1H，m)，1.28(3H，t，J＝7.0 Hz)，1.21(6H，d，J＝6.6Hz).
2613 141-142 488 *** 1H NMR(300MHz，CDCl 3)：δ7.62 (1H，d，J＝8.8Hz)，7.55(2H，d，J＝ 8.8Hz)，7.42(2H，d，J＝8.8Hz)，7.27 (1H，d，J＝2.0Hz)，6.97(1H，dd，J＝ 8.8，2.0Hz)，6.75(1H，s)，4.93(1H，p， J＝8.7Hz)，4.34(1H，dq，J＝8.4，6.4 Hz)，4.27-4.23(2H，m)，3.88-3.84 (2H，m)，3.64(2H，q，J＝7.0Hz)， 2.88-2.76(2H，m)，2.39-2.27(2H，m)， 2.01-1.91(1H，m)，1.90-1.80(1H，m)， 1.38(3H，d，J＝6.4Hz)，1.27(3H，t，J ＝7.0Hz)，1.08-0.98(1H，m)，0.62- 0.42(3H，m)，0.37-0.27(1H，m).
2614 181-182 464.4 **
2615 118-120 500.4 ***
Compound Fusing point (℃) Mass spectrum [M+H] Replicon IC 50μ M 2-days Replicon IC 50μ M 3-days 1H NMR data
2616 197-199 474.4 ***
2617 127-129 502.4 ***
2618 96-98 534.3 (M-1) ***
2619 102-103 534.3 (M-1) ***
2620 146-147 488.4 ***
2621 145-146 486.4 (M-1) ***
2622 198-200 527.8 (M-1) ***
2623 190-192 486.4 ***
2624 160-161 514.4 (M-1) ***
2625 187-189 473.4 ***
2626 130-132 485.4 ***
2627 523.1 **
2628 575.2 *
2629 194-195 483.4 ***
2630 182-184 390.2 ***
2631 185-188 482.4 ***
2632 155-161 427.1 ***
2633 170-175 426.3 ***
2634 135-140 519.2 ***
2635 175-180 457.3 ***
2636 122-124 516 *** 1H NMR(300MHz，CDCl 3)：δ7.63 (1H，d，J＝8.8Hz)，7.57(2H，d，J＝ 8.8Hz)，7.45(2H，d，J＝8.8Hz)，7.27 (1H，dd，J＝8.8，2.3Hz)，6.98(1H，d， J＝2.3Hz)，6.93(1H，br s)，5.35(1H， hp，J＝6.6Hz)，4.92(1H，p，J＝8.9 Hz)，4.23(2H，m)，3.86(2H，m)，3.64 (2H，q，J＝7.0Hz)，2.89-2.72(2H， m)，2.40-2.29(2H，m)，2.00-1.78(2H， m)，1.49(3H，d，J＝6.7Hz)，1.28(3H， t，J＝7.0Hz). 19F NMR(282MHz， CDCl 3)：δ-79.17(3F，d，J＝7.9Hz).
Compound Fusing point (℃) Mass spectrum [M+H] Replicon IC 50μ M 2-days Replicon IC 50μ M 3-days 1H NMR data
2637 485.4 ***
2638 196-197 458.3 (M-1) ***
2639 101-109 325.4 **
2640 178-184 411.3 ***
2641 191-197 410.3 ***
2642 93-95 592.5 ***
2643 168-169 567.3 ***
2644 108-110 593.5 ***
2645 118-120 629.2 ***
2646 187-189 530.3 ***
2647 130-133 486.4 ***
2648 203-205 502.3 ***
2649 207-209 514.4 ***
2650 540.4 ***
2651 590.4 ***
2652 576.4 ***
2653 189-192 539.4 ***
2654 100-104 453.3 ***
2655 121-122 554.3 (M-1) ***
2656 270-272 592.4 ***
2657 202-205 584.3 **
2658 471.4 ***
2659 102-105 489.4 ***
2660 487.4 ***
2661 195-202 464.3 * (CDCl 3，400MHz)，δ7.91(d， J＝8.4Hz，2H)，7.68-7.64(m，3H)，7.18 (d，J＝2.0Hz，1H)，7.00(dd，J＝8.8Hz and 1.6Hz，1H)，4.91-4.87(m，1H)， 4.14(q，J＝7.2Hz，2H)，3.09(t， J＝4.8Hz，4H)，2.78-2.70(m，2H)， 2.38-2.31(m，2H)，1.96-1.80(m，2H)， 1.69-1.65(m，4H)，1.51-1.48(m，5H).
2662 505.4 ***
Compound Fusing point (℃) Mass spectrum [M+H] Replicon IC 50μ M 2-days Replicon IC 50μ M 3-days 1H NMR data
2663 491.3 ***
2664 509.4 ***
2665 507.3 ***
2666 186-191 498.4 (M-1) ***
2667 184-190 517.4 (M+N H4) ***
2668 195-197 528.3 ***
2669 128-131 464.4 ***
2670 204-205 478.4 ***
2671 148-150 444.3 ***
2672 510.4 ***
2673 509.4 ***
2674 510.5 ***
2675 511.3 ***
2676 494.3 ***
2677 190-192 495.4 ***
2678 530.3 ***
2679 531.4 ***
2680 531.4 ***
2681 545.4 ***
2682 544.3 ***
2683 545.4 ***
2684 221-223 481.3 ***
2685 205-206 482.4 ***
2686 162-165 490.2 ***
2687 89-112 516.3 ***
2688 150-155 552.4 ***
2689 180-183 480.0 * (CDCl 3，300MHz)，δ8.01(d， J＝8.4Hz，2H)，7.69-7.65(m，3H)，7.17 (d，J＝2.1Hz，1H)，6.99(dd，J＝8.7Hz and 1.8Hz，1H)，4.92-4.83(m，1H)， 4.14(q，J＝7.2Hz，2H)，3.77-3.71(m，
Compound Fusing point (℃) Mass spectrum [M+H] Replicon IC 50μ M 2-days Replicon IC 50μ M 3-days 1H NMR data
3H)，3.77-3.69(m，1H)，3.58-3.51(m， 1H)，2.80-2.67(m，2H)，2.37-2.34(m， 2H)，2.00-1.79(m，5H)，1.70-1.61(m， 1H)，1.57(t，J＝7.2Hz，3H).
2690 170-172 480.0 *** (CDCl 3，400MHz)，δ8.01(d， J＝8.4Hz，2H)，7.68-7.65(m，3H)，7.18 (d，J＝2.0Hz，1H)，6.99(d，J＝8.8Hz and 2.0Hz，1H)，4.91-4.87(m，1H)， 4.14(q，J＝7.2Hz，2H)，3.77-3.70(m， 3H)，3.58-3.52(m，1H)，3.37-3.31(m， 1H)，2.76-2.71(m，2H)，2.36-2.34(m， 2H)，2.08-1.76(m，5H)，1.62-1.56(m， 1H)，1.47(t，J＝7.2Hz，3H).
2691 128-132 473.1 ***
2692 176-183 472.2 ***
2693 78-110 499.2 ***
2694 155-160 536.4 *** 1H-NMR(CDCl 3)δ7.63(d，1H)，7.55 (m，2H)，7.43(d，2H)，7.18(d，1H)， 6.91(dd，1H)，6.78(s，1H)，4.94(q， 1H)，4.34(m，1H)，4.21(t，2H)，3.32 (t，2H)，2.93(s，3H)，2.81(m，2H)， 2.41(m，4H)，1.93-1.40(m，4H)， 1.40(t，3H)，1.03(m，1H)，0.59-0.48 (m，3H)，0.32(m，1H).
2695 135-140 522.32 ***
2696 126-128 500.4 ***
2697 145-146 527.4 ** 1H NMR(300MHz，CDCl 3)：δ8.45 (1H，ddd，J＝5.0，1.9，1.0Hz)，7.63 (1H，d，J＝8.8Hz)，7.55(2H，d，J＝ 8.5Hz)，7.54-7.45(1H，m)，7.42(2H， d，J＝8.5Hz)，7.25-7.21(2H，m)， 7.05-7.00(2H，m)，6.70(1H，s)，5.05 (1H，hp，J＝6.3Hz)，4.93(1H，p，J＝ 8.9Hz)，4.35(2H，t，J＝6.7Hz)，3.64 (2H，t，J＝6.7Hz)，2.85-2.70(2H，m)， 2.37-2.27(2H，m)，1.97-1.86(1H，m)， 1.83-1.73(1H，m)，1.32(6H，d，J＝ 6.3Hz).
2698 69-72 528.4 *** 1H NMR(300MHz，CDCl 3)：δ8.54 (2H，d，J＝4.7Hz)，7.63(1H，d，J＝ 8.8Hz)，7.55(2H，d，J＝8.8Hz)，7.42 (2H，d，J＝8.8Hz)，7.24(1H，d，J＝
Compound Fusing point (℃) Mass spectrum [M+H] Replicon IC 50μ M 2-days Replicon IC 50μ M 3-days 1H NMR data
2.0Hz)，7.03(1H，dd，J＝8.8，2.0 Hz)，7.01(1H，t，J＝4.7Hz)，6.71 (1H，s)，5.05(1H，hp，J＝6.3Hz)， 4.93(1H，p，J＝8.7Hz)，4.37(1H，t，J ＝6.8Hz)，3.60(1H，t，J＝6.8Hz)， 2.89-2.70(2H，m)，2.40-2.29(2H，m)， 2.00-1.89(1H，m)，1.88-1.77(1H，m)， 1.32(6H，d，J＝6.3Hz).
2699 150-151 549.6 *** 1H NMR(300MHz，CDCl 3)：δ7.63 (1H，d，J＝8.8Hz)，7.55(2H，d，J＝ 8.8Hz)，7.42(2H，d，J＝8.8Hz)，7.23 (1H，d，J＝2.0Hz)，6.96(1H，dd，J＝ 8.8，2.0Hz)，6.71(1H，s)，5.05(1H， hp，J＝6.3Hz)，4.94(1H，p，J＝8.6 Hz)，4.46(2H，t，J＝6.2Hz)，3.76 (2H，t，J＝6.2Hz)，2.80-2.68(2H，m)， 2.74(3H，s)，2.40-2.29(2H，m)，2.00- 1.90(1H，m)，1.89-1.73(1H，m)，1.32 (6H，d，J＝6.3Hz).
2700 132-133 464.3 *** 1H NMR(300MHz，CDCl 3)：δ7.63 (1H，d，J＝8.8Hz)，7.55(2H，d，J＝ 8.5Hz)，7.42(2H，d，J＝8.5Hz)，7.22 (1H，d，J＝2.0Hz)，6.96(1H，dd，J＝ 8.8，2.0Hz)，6.71(1H，s)，5.05(1H， hp，J＝6.3Hz)，4.94(1H，p，J＝8.7 Hz)，4.26(2H，t，J＝6.8Hz)，2.95 (2H，t，J＝6.8Hz)，2.89-2.73(2H，m)， 2.40-2.30(2H，m)，2.25(3H，s)，2.00- 1.90(1H，m)，1.88-1.78(1H，m)，1.33 (6H，d，J＝6.3Hz).
2701 Foam 496.1 ***
2702 116-117 474.4 ***
2703 166-168 486.4 ***
2704 133-140 444.0 ***
2705 180-183 479.1 (M-1) ***
2706 180-183 481.2 ***
2707 211-213 522.3 ***
2708 200-202 548.4 ***
2709 246-248 584.4 ***
2710 240-242 547.4 ***
Compound Fusing point (℃) Mass spectrum [M+H] Replicon IC 50μ M 2-days Replicon IC 50μ M 3-days 1H NMR data
2711 157-159 459.4 ***
2712 149-151 486.4 ***
2713 150-152 432.4 (M-1) ***
2714 165-168 450.1 ***
2715 123-125 494.1 ***
2716 173-175 548.1 ***
2717 Foam 566.3 ***
2718 188-191 504.2 ***
2719 88-100 462.3 ***
2720 120-122 458.1 (M-1) ***
2721 126-128 476.2 ***
2722 179-181 522.3 ***
2723 182-184 524.3 ***
2724 178-180 536.3 ***
2725 188-190 538.3 ***
2726 229-231 544.3 ***
2727 232-234 495.3 **
2728 137-138 523.3 ***
2729 172-173 525.3 ***
2730 149-150 537.3 ***
2731 171-172 539.4 ***
2732 215-217 545.4 ***
2733 206-208 561.4 ***
2734 206-208 561.3 ***
2735 173-174 496.3 ***
2736 161-164 524.5 ***
2737 Vitreous state 530.2 ***
2738 Vitreous state 516.7 (M-1) ***
2739 179-183 498.5 ***
Compound Fusing point (℃) Mass spectrum [M+H] Replicon IC 50μ M 2-days Replicon IC 50μ M 3-days 1H NMR data
2740 Vitreous state 500.6 (M-1) ***
2741 208-210 488.3 ***
2742 189-192 474.3 ***
2743 151-153 474.3 ***
2744 195-197 524.3 ***
2745 207-209 480.6 ***
2746 185-187 494.2 ***
2747 202-204 492.5 ***
2748 211-213 494.5 ***
2749 224-226 492.5 ***
2750 221-225 497.5 ***
2751 Vitreous state 604.4 (M-1) ***
2752 136-138 446.3 ** (CDCl3，300MHz)，δ7.66(d， J＝8.7Hz，1H)，7.56-7.49(m，4H)，7.32 (d，J＝2.1Hz，1H)，7.01(dd，J＝8.7Hz and 2.4Hz，1H)，4.94-4.88(m.，1H)， 4.25-4.22(m，2H)，3.84-3.81(m，2H)， 3.58-3.55(m，2H)，3.50(s，3H)，3.43- 3.35(m，2H)，2.89-2.82(m，2H)，2.31 (q，J＝8.4Hz，2H)，1.97-1.79(m，2H)， 1.28-1.14(m，6H).
2753 202-204 432.2 ** (MeOD，300MHz)，δ7.98(d， J＝8.4Hz，2H)，7.64(d，J＝8.1Hz，2H)， 7.56(d，J＝8.7Hz，1H)，7.31(d， J＝2.1Hz，1H)，7.01(dd，J＝8.7Hz and 2.1Hz，1H)，5.07-4.98(m，1H)，4.29- 4.20(m，2H)，3.82-3.79(m，2H)，3.37 (s，3H)，2.68-2.58(m，2H)，2.42-2.34 (m，2H)，1.92-1.81(m，2H)，1.28(d， J＝6.6Hz，6H).
2754 148-150 460.2 ** (CDCl3，400MHz)，δ7.66(d， J＝8.8Hz，1H)，7.59-7.53(m，4H)，7.31 (s，1H)，7.01(dd，J＝8.4Hz and 2.0Hz， 1H)，4.92-4.88(m，1H)，4.24(t， J＝4.4Hz，2H)，3.84-3.49(m，13H)， 2.87-2.82(m，2H)，2.36-2.31(m，2H)， 1.97-1.80(m，2H).
Compound Fusing point (℃) Mass spectrum [M+H] Replicon IC 50μ M 2-days Replicon IC 50μ M 3-days 1H NMR data
2755 166-168 430.2 ** (CDCl3，400Hz)δ7.78(d，J＝8.0Hz， 2H)，7.65(d，8.8Hz，2H)，7.53(d， J＝8.0Hz，2H)，7.29(d，J＝2.0Hz，1H)， 7.01(d，J＝8.4Hz，1H)，4.92-4.88(m， 1H)，4.37-4.33(m，4H)，4.24(t， J＝4.4Hz，2H)，3.82(t，J＝4.8Hz，2H)， 3.50(s，3H)，2.83-2.77(m，2H)，2.44- 2.29(m，4H)，1.95-1.82(m，2H).
2756 162-164 444.2 ** (CDCl3，400MHz)，δ7.13-7.09(m， 3H)，6.97(d，J＝8.0Hz，2H)，6.76(s， 1H)，6.46(d，J＝8.8Hz，1H)，4.38-4.34 (m，1H)，3.71-3.68(m，2H)，3.27(t， J＝4.4Hz，2H)，3.14-3.11(m，2H)， 2.98-2.95(m，5H)，2.31-2.26(m，2H)， 1.78-1.76(m，2H)，1.44-1.25(m，6H).
2757 155-158 458.3 *** (CDCl3，400MHz)，δ7.66(d， J＝8.4Hz，1H)，7.59-7.50(m，4H)，7.32 (s，1H)，7.01(d，J＝8.8Hz，1H)，4.93- 4.86(m，1H)，4.25(t，J＝4.0Hz，2H)， 3.83(t，J＝4.4Hz，2H)，3.76(b， 2H)，.3.50(s，3H)，3.43(b，2H)，2.91- 2.81(m，2H)，2.32(q，J＝8.8Hz，2H)， 2.00-1.72(m，8H).
2758 194-196 456.2 ** (CDCl3，300MHz)，δ7.97(dd， J＝6.9Hz and 2.1Hz，2H)，7.63(dd， J＝6.9Hz and 2.1Hz，2H)，7.55(d， J＝8.7Hz，1H)，7.31(d，J＝1.8Hz，1H)， 7.02(dd，J＝9.0Hz and 2.4Hz，1H)， 5.07-5.01(m，1H)，4.38-4.33(m，1H)， 4.24-4.21(m，2H)，3.82-3.79(m，2H)， 3.52(s，3H)，2.68-2.58(m，2H)，2.43- 2.33(m，2H)，2.07-2.01(m，2H)， 1.92-1.76(m，8H).
2759 199-200 444.1 ** (MeOH，300MHz)，δ7.99(dd， J＝6.9Hz and 1.8Hz，2H)，7.64(dd， J＝6.6Hz and 2.1Hz，2H)，7.56(d， J＝8.7Hz，1H)，7.31(d，J＝2.1Hz，1H)， 7.02(dd，J＝8.7Hz and 2.1Hz，1H)， 5.07-5.01(m，1H)，4.57-4.51(m，1H)， 4.25-4.21(m，2H)，3.82-3.79(m，2H)， 3.46(s，3H)，2.68-2.61(m，2H)，2.43- 2.35(m，4H)，2.18-2.11(m，2H)， 1.91-1.80(m，4H).
2760 228-230 430.0 ** (CDCl3，400MHz)δ7.88(dd，
Compound Fusing point (℃) Mass spectrum [M+H] Replicon IC 50μ M 2-days Replicon IC 50μ M 3-days 1H NMR data
J＝8.0Hz，2H)，7.64(dd，J＝9.2Hz，1H)， 7.55(dd，J＝7.6Hz，2H)，7.01(dd， J＝8.8Hz，1H)，6.31(s，1H)，4.94-4.88 (m，1H)，4.23(t，J＝4.4Hz，2H)，3.82 (t，J＝4.4Hz，2H)，3.50(s，3H)，2.95(b， 1H)，2.82-2.72(m，2H)，2.32(q， J＝8.8Hz，2H)，1.97-1.76(m，2H)，0.92 (q，J＝6.0Hz，2H)，0.66(q，J＝6.0Hz， 2H).
2761 240-245 481.5 **
2762 264-269 501.9 **
2763 225-231 519.2 ***
2764 218-220 472.9 ***
2765 Vitreous state 504.4 ***
2766 195-196 449.4 ***
2767 Vitreous state 538.4 ***
2768 99-102 492.3 ***
2769 Vitreous state 606.5 ***
2770 Vitreous state 554.3 (M-1) ***
2771 Vitreous state 530.3 ***
2772 Vitreous state 488.3 ***
2773 Vitreous state 488.3 ***
2774 Vitreous state 518.3 **
2775 199-203 494.3 **
2776 183-184 494.4 (M-1) ***
2777 191 (decomposition .) 488.8 ***
2778 222-225 444.4 ***
2779 146-150 518.5 (M-1) **
2780 155-156 477.4 (M+N H 4) ***
Compound Fusing point (℃) Mass spectrum [M+H] Replicon IC 50μ M 2-days Replicon IC 50μ M 3-days 1H NMR data
2781 147-148 491.4 (M+N H 4) ***
2782 161-163 474.4 ***
2783 146-147 505.5 (M+N H 4) ***
2784 169-171 500.4 ***
2785 158-160 514.4 ***
2786 183-185 509.4 ***
2787 148-150 511.4 ***
2788 124-127 497.4 ***
2789 133-134 473.4 **
2790 188-189 519.4 (M+N H 4) *
2791 96-98 515.4 ***
2792 90-94 515.4 ***
2793 148-151 529.4 ***
2794 75-77 559.4 ***
2795 548.4 ***
2796 217-221 396.4 ***
2797 Vitreous state 496.3 ***
2798 Vitreous state 554.3 (M-1) ***
2799 162-169 530.2 ***
2800 206-208 458.8 *** 1H NMR(300MHz，CDCl 3)：δ1.33 (d，6H)，1.73-1.99(m，2H)，2.27-2.46 (m，2H)，2.68-2.88(m，2H)，3.16-3.29 (4H)，3.88-4.00(4H)，4.89-5.13(m， 2H)，6.69(s，br，1H)，7.01-7.04(dd， 1H)，7.15(d，1H)，7.39-7.46(m，2H)， 7.51-7.59(m，2H)，7.64(d，1H)
2801 220-220 479.3 ***
2802 222-224 476.8 ***
2803 203-204 479.4 ***
Compound Fusing point (℃) Mass spectrum [M+H] Replicon IC 50μ M 2-days Replicon IC 50μ M 3-days 1H NMR data
2804 171-177 413.9 ***
2805 174-175 591.8 ***
2806 175-176 589.9 (M-1) ***
2807 205-207 477.4 (M+N H 4) ***
2808 153-154 491.4 (M+N H 4) ***
2809 185-186 491.4 (M+N H 4) ***
2810 137-138 505.4 (M+N H 4) ***
2811 168-169 517.4 (M+N H 4) ***
2812 187-188 514.4 ***
2813 174-175 488.4 ***
2814 178-179 519.4 (M+N H 4) ***
2815 179-181 503.4 (M+N H 4) ***
2816 137-138 488.4 ***
2817 179-181 475.4 ***
2818 185-187 402.5 ***
2819 150 (decomposition .) 547.3 ***
2820 152 (decomposition .) 547.3 ***
2821 509.2 ***
2822 247-249 503.3 **
2823 209-211 489.3 ***
Compound Fusing point (℃) Mass spectrum [M+H] Replicon IC 50μ M 2-days Replicon IC 50μ M 3-days 1H NMR data
2824 201-203 507.3 ***
2825 125-128 505.3 **
2826 205-207 521.3 ***
2827 115-120 437.4 ***
2828 225-230 550 ***
2829 163-168 539.6 ***
2830 161-162 567.4 ***
2831 103-104 567.4 ***
2832 197-202 512.5 ***
2833 218-220 481.2 ***
2834 199-201 495.3 ***
2835 196-198 523.5 ***
2836 193-195 537.5 ***
2837 210-212 521.4 ***
2838 179-181 535.4 ***
2839 Vitreous state 505.3 (ES-) ***
2840 508.4 ***
2841 508.4 ***
2842 203-212 512.5 ***
2843 203-205 479.6 ***
2844 169-170 503.2 ** (CDCl3，8.8MHz)δ8.00(b，1H)，7.65 (d，J＝8.8Hz，1H)，7.58(d，J＝8.0Hz， 2H)，7.29(s，1H)，7.01(s，1H)，4.94- 4.90(m，1H)，4.24(t，J＝4.4Hz，2H)， 3.86-3.82(m，4H)，3.70-3.68(m，2H)， 3.50(s，3H)，2.84-2.69(m，6H)，2.33 (q，J＝8.0Hz，2H)，1.98-1.77(m，2H)， 1.68-1.48(m，4H).
2845 Vitreous state 536.4 (M-1) ***
2846 202-204 447.3 ***
2847 217-218 484.3 *
2848 206-207 486.3 **
2849 225-227 486.3 **
Compound Fusing point (℃) Mass spectrum [M+H] Replicon IC 50μ M 2-days Replicon IC 50μ M 3-days 1H NMR data
2850 161-163 498.3 **
2851 140-145 465.4 ***
2852 205-207 522.3 ***
2853 189-190 514.3 ***
2854 113-116 516.3 ***
2855 264 444.4 **
2856 220-227 445.4 ***
2857 176-179 471.5 ***
2858 230-232 456.4 ***
2859 200-201 502.2 (M-1) ***
2860 197-198 488.4 ***
2861 221-232 decomposes 516.2 (M-1) ***
2862 234-235 458.3 ***
2863 172 (decomposition .) 470.4 ***
2864 220-222 513.3 ***
2865 163-165 539.3 ***
2866 194-195 485.3 ***
2867 198-200 494.3 ***
2868 100-104 506.4 (M-1) ***
2869 108-111 538.4 (M-1) ***
2870 Vitreous state 554.2 (M-1) ***
2871 198-199 514.2 (M-1) ***
2872 215-216 488.4 ***
2873 170-180 495.4 ***
2874 Vitreous state 502.3 ***
2875 151-153 495.6 ***
2876 170-230 470.4 ***
Compound Fusing point (℃) Mass spectrum [M+H] Replicon IC 50μ M 2-days Replicon IC 50μ M 3-days 1H NMR data
2877 241-243 463.6 ***
2878 196-199 472.4 ***
2879 198-200 490.3 ***
2880 161-162 492.1 (M-1) **
2881 197-203 498.4 ***
2882 210-212 475.4 ***
2883 Vitreous state 554.5 (M-1) ***
2884 Vitreous state 530.4 ***
2885 189-190 530.4 ***
2886 179-780 492.6 ***
2887 165-166 580.7 ***
2888 99-101 497.5 ***
2889 129-130 488.6 ***
2890 186-189 479.6 ***
2891 170-180 459.6 ***
2892 145-148 457.5 ***
2893 Vitreous state 474.6 (M-1) ***
2894 208-210 476.6 ***
2895 185-187 494.7 ***
2896 217-219 508.7 ***
2897 247-249 **
2898 220-222 ***
2899 169-171 506 ***
2900 198-200 ***
2901 210-212 520 ***
2902 223-227 502.6 ***
2903 172-174 500.5 ***
2904 182-186 532.6 ***
2905 248-250 477.6 ***
Compound Fusing point (℃) Mass spectrum [M+H] Replicon IC 50μ M 2-days Replicon IC 50μ M 3-days 1H NMR data
2906 208-213 479.7 ***
2907 127-132 483.7 ***
2908 191-194 475.5 ***
2909 201-202 508.7 ***
2910 162-164 515.1 ***
2911 205-207 452.8 ***
2912 212-214 466.9 ***
2913 172-174 508.9 ***
2914 290-292 477.7 **
2915 269-271 451.7 **
2916 235-236 465.7 ***
2917 175-177 510.6 ***
2918 195-196 520.2 (M-1) ***
2919 200-204 508.5 ***
2920 196-198 496.4 ***
2921 241-245 477.5 **
2922 108-118 510.4 ***
2923 158-160 522.8 ***
2924 119-121 562.9 ***
2925 231-233 522.9 ***
2926 247-248 451.8 **
2927 260-265 463.6 **
2928 216-217 494.9 **
2929 221-223 496.6 ***
2930 227-229 522.8 ***
2931 227-230 502.9 ***
2932 224-225 489.7 **
2933 167-173 485.7 ***
2934 192-195 447.7 ***
2935 216-217 541.8 **
2936 209-210 507.6 ***
Compound Fusing point (℃) Mass spectrum [M+H] Replicon IC 50μ M 2-days Replicon IC 50μ M 3-days 1H NMR data
2937 183-184 508.6 ***
2938 191-193 488.8 ***
2939 239-241 488.7 ***
2940 222-227 466.8 **
2941 219-224 478.6 **
2942 191-193 473.7 ***
2943 215-217 508.0 ***
2944 234-239 488.8 *
2945 173-175 521.6 ***
2946 144-146 537.0 ***
2947 130 (decomposition .) 523.0 ***
2948 206-208 549.0 ***
2949 181-183 534.9 **
2950 224-226 435.1 ***
2951 196-197 443.1 ***
2952 148-150 501.1 ***
2953 231-234 527.3 ***
2954 241-244 443.2 ***
2955 229-234 463.6 ***
2956 198-200 490.8 ***
2957 203-204 528.0 *
2958 206-208 564.5 ***
2959 220-222 505.0 ***
2960 258-260 461.1 **
2961 246-249 497.3 ***
2962 244-250 449.4 **
2963 189-194 477.1 ***
2964 248-250 519.2 ***
2965 212-214 533.3 ***
2966 Vitreous state 487.0 **
2967 208-213 456 ***
Compound Fusing point (℃) Mass spectrum [M+H] Replicon IC 50μ M 2-days Replicon IC 50μ M 3-days 1H NMR data
2968 233-235 477.3 ***
2969 181-183 502.1 **
2970 183-185 508.4 ***
2971 208-210 511.4 ***
2972 235-237 504.9 ***
2973 220-229 493.9 (M-1) ***
2974 203-205 463.6 ***
2975 256-261 463.6 ***
2976 168-173 443.5 ***
2977 112-117 490.9 ***
2978 210-212 484.9 ***
2979 Vitreous state 569.3 ***
2980 167-170 515.9 **
2981 174-177 570.2 *
2982 198-202 491 ***
2983 232-238 475.6 ***
2984 229-233 449.5 **
2985 205-210 469 ***
2986 197-202 455.5 ***
2987 266-273 501.8 **
2988 218-223 508.0 ***
2989 234-238 500.0 **
2990 114-143 536.3 ***
2991 221-225 516.0 ***
2992 211-213 481.9 ***
2993 231-237 514.0 **
2994 84-94 539.1 ***
2995 206-208 493.8 ***
2996 200-202 493.9 ***
2997 90-98 544.7 ***
2998 490.9 ***
Compound Fusing point (℃) Mass spectrum [M+H] Replicon IC 50μ M 2-days Replicon IC 50μ M 3-days 1H NMR data
2999 226-228 491.0 ***
3000 208-210 511.0 ***
3001 111-122 511.0 ***
3002 88-102 491.0 ***
3003 223-225 552.7 ***
3004 188-190 440.8 **
3005 171-173 490.9 ***
3006 173-175 437.6 ***
3007 154-156 497.0 ***
3008 197-200 546.7 ***
3009 173-175 546.8 ***
3010 172-174 518.9 ***
3011 196-199 492.8 ***
3012 181-184 483.6 ***
3013 176-179 477.6 ***
3014 90-91 497.3 ***
3015 270 (decomposition .) 501.0 **
3016 499.6 ***
3017 120-125 561.8 ***
3018 155-157 545.9 ***
3019 227-229 542.8 ***
3020 118-124 607.7 ***
3021 195-196 535.7 ***
3022 165-168 524.8 ***
3023 158-160 515.9 **
3024 171-174 569.8 **
3025 214-220 493.7 (M-1) ***
3026 187-190 481.9 ***
3027 186-189 507.9 ***
3028 536.0 ***
Compound Fusing point (℃) Mass spectrum [M+H] Replicon IC 50μ M 2-days Replicon IC 50μ M 3-days 1H NMR data
3029 110-113 580.4 ***
3030 128-131 518.6 ***
3031 82-88 468.8 ***
3032 452.1 ***
3033 466.1 ***
3034 80-81 578.0 ***
3035 94-96 552.0 **
3036 144-154 503.8 ***
3037 529.9 ***
3038 236-243 502.9 ***
3039 150-155 469.8 (M-1) ***
3040 176-180 498.0 ***
3041 224-229 471.1 ***
3042 555.4 **
3043 505.6 (M-1) ***
3044 490.0 ***
3045 484.0 ***
3046 195-197 480.1 ***
3047 225 (decomposition .) 495.1 ***
3048 120 (decomposition .) 480.1 ***
3049 154-155 521.8 ***
3050 141-142 525.8 ***
3051 184-185 539.7 (M-1) ***
3052 166-187 467.8 ***
3053 203-208 493.8 ***
3054 190-196 521.9 ***
3055 72-73 496.8 ***
3056 85-94 533.5 ***
Compound Fusing point (C) Mass spectrum [M+H] Replicon IC 50μ M 2-days Replicon IC 50μ M 3-days 1H NMR data
3057 95-112 521.8 ***
3058 181-185 535.8 ***
3059 97-109 542.1 ***
3060 205-212 553.8 ***
3061 77-78 510.9 ***
3062 75-76 564.2 ***
3063 74-75 536.2 ***
3064 192-193 509.9 ***
3065 218-220 521.3 ***
3066 237-241 507.7 (M-1) ***
3067 265-271 496.0 ***
3068 218-224 521.9 ***
Compound Fusing point (℃) Mass spectrum [M+H] Replicon IC 50μ M 2-days Replicon IC 50μ M 3-days 1H NMR data
3069 207-211 559.5 ***
3070 237-242 551.5 ***
3071 236-241 563.5 ***
3072 211-215 501.5 **
3073 185-190 561.5 ***
3074 274 (decomposition .) 526.5 **
3075 513.4 *
3076 513.4 *
3077 109-110 448 *** 1H NMR(300MHz，CDCl 3)：δ7.60 (1H，d，J＝8.8Hz)，7.29(2H，d，J＝ 8.8Hz)，7.271H(d，J＝2.2Hz)，6.96 (1H，dd，J＝8.8，2.2Hz)，6.73(2H，d， J＝8.8Hz)，4.97(1H，p，J＝8.9Hz)， 4.36(1H，br)，4.24-4.21(2H，m)， 3.87-3.84(2H，m)，3.70-3.53(6H，m)， 3.37-3.34(2H，m)，2.92-2.81(2H，m)， 2.37-2.28(2H，m)，1.99-1.89(1H，m)， 1.88-1.77(1H，m)，1.28(3H.t，J＝7.0 Hz)，1.25(3H，t，J＝7.0Hz).
Compound Fusing point (℃) Mass spectrum [M+H] Replicon IC 50μ M 2-days Replicon IC 50μ M 3-days 1H NMR data
3078 180-182 516.2 * (CDCl 3，400MHz)，δ7.64(d，J＝8.4Hz， 2H)，7.56(d，J＝8.4Hz，2H)，7.40(d， J＝8.8Hz，1H)，7.19(d，J＝2.0Hz，1H)， 7.01(dd，J＝9.2Hz and 2.4Hz，1H)， 4.12(q，J＝6.8Hz，2H)，4.04(d， J＝6.4Hz，2H)，3.65(q，J＝7.2Hz，4H)， 1.68-1.46(m，9H)，1.07-0.98(m，1H)， 0.48(q，J＝9.6Hz，2H)，0.11-0.05(m， 2H).
3079 194-195 482 * 1H NMR(300MHz，DMSO-d 6)：δ 10.09(1H，s)，7.66(2H，d，J＝8.8 Hz)，7.51(1H，d，J＝8.8Hz)，7.48 (2H，d，J＝8.8Hz)，7.20(1H，d，J＝ 2.1Hz)，6.93(1H，dd，J＝8.8，2.1 Hz)，4.97(1H，p，J＝8.7Hz)，4.47 (2H，t，J＝5.7Hz)，4.11(2H，q，J＝ 7.0Hz)，3.55(2H，t，J＝5.7Hz)，3.08 (3H，s)，2.59-2.41(2H，m)，2.37-2.26 (2H，m)，1.83-1.65(2H，m)，1.36(3H， t，J＝7.0Hz).
3080 187-192 427.1 (M-1) ***
3081 500.4 ***
3082 520.4 **
3083 192-205 556.4 **
3084 156-162 516.1 **
3085 195-196 466.3 ** (CDCl 3，400MHz)，δ7.99(d， J＝8.0Hz，2H)，7.65-7.63(m，3H)，7.18 (s，1H)，6.99(d，J＝8.8Hz and 1.6Hz， 1H)，4.94-4.85(m，1H)，4.44(s，1H)， 4.13(q，J＝6.8Hz，2H)，3.50-3.46(m， 3H)，3.36(d，J＝11.2Hz，1H)，2.79- 2.71(m，2H)，2.41-2.30(m，2H)， 2.05-1.83(m，4H)，1.49(t，J＝6.8Hz， 3H).
3086 194-196 466.0 ** (CDCl 3，400MHz)，δ7.99(d， J＝8.4Hz，2H)，7.66-7.64(m，3H)，7.18 (d，J＝2.0Hz，1H)，6.99(d，J＝8.8Hz and 1.6Hz，1H)，4.92-4.87(m，1H)， 4.44-4.43(m，1H)，4.13(q，J＝6.8Hz， 2H)，3.50-3.46(m，3H)，3.36(d， J＝11.2Hz，1H)，2.77-2.72(m，2H)， 2.41-2.30(m，2H)，2.05-1.83(m， 4H)，1.49(t，J＝6.8Hz，3H).
Compound Fusing point (℃) Mass spectrum [M+H] Replicon IC 50μ M 2-days Replicon IC 50μ M 3-days 1H NMR data
3087 275 (decomposition .) 532.4 ***
3088 140 (decomposition .) 526.1 **
3089 172-177 540.6 ***
3090 196-201 514 **
3091 231-233 528.7 ***
3092 238-243 513.2 **
3093 112-119 481.0 (M-1) **
3094 236-237 465.2 ** (CDCl 3，400MHz)，δ7.81-7.77(m， 2H)，7.48-7.46(m，3H)，7.34(d， J＝8.4Hz，2H)，6.76(s，1H)，5.00-4.96 (m，1H)，3.23-3.13(m，8H)，2.83-2.76 (m，2H)，2.37(q，J＝8.0Hz，2H)，2.00- 1.82(m，4H)，1.09(t，J＝7.6Hz，3H).
3095 133-134 493.2 ** (CDCl 3，400MHz)，δ7.78-7.76(m， 2H)，7.46(d，J＝8.4Hz，2H)，7.39(d， J＝9.2Hz，1H)，7.33(d，J＝8.4Hz，2H)， 6.80(s，1H)，4.99-4.95(m，1H)，3.61 (b，2H)，3.36(b，2H)，3.20(t， J＝8.0Hz，2H)，2.84-2.78(m，2H)，2.38 (q，J＝9.6Hz，2H)，2.00-1.87(m，4H)， 1.27-1.18(m，6H)，1.09(t，J＝7.2Hz， 3H).
3096 138-139 479.2 ** (CDCl 3，400MHz)，δ7.80-7.77(m， 2H)，7.48-7.42(m，3H)，7.34(d， J＝8.4Hz，2H)，6.66(s，1H)，4.99-4.95 (m，1H)，3.62-3.32(m，2H)，3.23-3.19 (m，2H)，3.08-3.07(m，3H)，2.84-2.79 (m，2H)，2.42-2.35(m，2H)，2.00-1.85 (m，4H)，1.25-1.22(m，3H)，1.10(t， J＝7.6Hz，3H).
3097 200-202 491.2 *** (CDCl 3，400MHz)，δ7.93(s，1H)， 7.78-7.76(m，1H)，7.58-7.56(m，1H)， 7.51(s，1H)，7.45-7.43(m，2H)，7.38- 7.36(m，2H)，4.99-4.95(m，1H)，3.71 (s，2H)，3.55(s，2H)，3.21-3.17(m， 2H)，2.82-2.77(m，2H)，2.39-2.37(m， 2H)，1.99-1.84(m，7H)，1.07(t， J＝8.4Hz，3H).
3098 128-129 507.2 ** (CDCl 3，400MHz)，δ7.81-7.78(m， 2H)，7.48-7.43(m，3H)，7.35(d， J＝8.4Hz，2H)，6.75(s，1H)，5.00-4.96 (m，1H)，4.85-3.62(m，8H)，4.29(s， 2H)，3.23-3.19(m，2H)，2.83-2.75(m，
Compound Fusing point (℃) Mass spectrum [M+H] Replicon IC 50μ M 2-days Replicon IC 50μ M 3-days 1H NMR data
2H)，2.41-2.36(m，2H)，2.01-1.83(m， 4H)，1.10(t，J＝7.2Hz，3H).
3099 149-152 467.5 **
3100 201-203 633.9 *
3101 461.7 ***
3102 244 (decomposition .) 505.4 **
3103 187 (decomposition .) 531.6 *
3104 166-168 491.4 (M- C 5H 8O) ***
3105 187-189 489.4 (M+N H 4) ***
3106 104-106 526.4 ***
3107 156-158 513.4 ***
3108 150-153 525.4 ***
3109 152-153 488.5 *
3110 167-168 472.3 ***
3111 165-166 551.5 ***
3112 167-169 539.4 (M+N H 4) ***
3113 179-180 646.5 ***
3114 124-127 518.3 **
3115 175-178 551.5 ***
3116 214-217 537.3 ***
3117 208-210 551.6 ***
3118 105-108 506.3 ***
3119 157-159 520.3 **
3120 180-181 496.4 ***
Compound Fusing point (℃) Mass spectrum [M+H] Replicon IC 50μ M 2-days Replicon IC 50μ M 3-days 1H NMR data
3121 168-172 492.5 ***
3122 104-107 506.5 ***
3123 175-177 484.2 ***
3124 238-241 489.1 ***
3125 171-175 482.4 ***
3126 182-185 496.4 ***
3127 185-188 506.5 ***
3128 207-210 494.4 ***
3129 108-110 548.4 ***
3130 460.2 *** (CDCl 3，400MHz)，δ7.72-7.64(m， 3H)，7.53(d，J＝7.6Hz，2H)，7.31(s， 1H)，7.01(d，J＝9.2Hz，1H)，4.93-4.88 (m，1H)，4.64-4.51(m，1H)，4.24(t， J＝4.0Hz，2H)，3.89-3.79(m，4H)， 3.73-3.60(m，2H)，3.50(s，3H)，2.88- 2.78(m，2H)，2.34-2.32(m，2H)， 2.17-1.91(m，3H)，1.85-1.74(m，2H).
3131 149-152 494.0 ** (CDCl 3，400MHz)，δ7.91(d， J＝8.4Hz，2H)，7.64(d，J＝9.2Hz，1H)， 7.56(d，J＝8.0Hz，2H)，7.43-7.39(m， 4H)，7.32(d，J＝2.0Hz，1H)，7.00(d， J＝6.8Hz，1H)，5.40-5.34(m，1H)， 4.95-4.88(m，1H)，4.23(t，J＝4.4Hz， 2H)，3.82(t，J＝4.4Hz，2H)，3.49(s， 3H)，2.80-2.72(m，2H)，2.33(q， J＝8.8Hz，2H)，1.97-1.76(m，2H)，1.65 (d，J＝6.8Hz，3H).
3132 169-170 512.0 *** (CDCl 3，400MHz)，δ7.91(d， J＝8.0Hz，2H)，7.64(d，J＝8.8Hz，1H)， 7.56(dd，J＝8.4Hz，2H)，7.41-7.37(m， 2H)，7.09-7.04(m，2H)，7.01(dd， J＝8.8Hz and 1.2Hz，1H)，6.35(d， J＝8.4Hz，1H)，5.38-5.31(m，1H)， 4.93-4.88(m，1H)，4.23(t，J＝4.4Hz， 2H)，3.82(t，J＝4.4Hz，2H)，3.50(s， 3H)，2.82-2.72(m，2H)，2.33(q， J＝8.4Hz，2H)，1.94-1.76(m，2H)，1.62 (d，J＝6.8Hz，3H).
Compound Fusing point (℃) Mass spectrum [M+H] Replicon IC 50μ M 2-days Replicon IC 50μ M 3-days 1H NMR data
3133 156-157 524.8 *** (CDCl 3，400MHz)，δ7.91(d， J＝8.0Hz，2H)，7.64(d，J＝8.8Hz，1H)， 7.55(d，J＝8.0Hz，2H)，7.35(d， J＝8.8Hz，2H)，7.00(d，J＝7.2Hz，1H)， 6.91(d，J＝8.8Hz，2H)，6.32(d， J＝7.6Hz，1H)，5.36-5.29(m，1H)， 4.92-4.86(m，1H)，4.23(t，J＝4.4Hz， 2H)，3.83-3.82(m，5H)，3.50(s，3H)， 2.82-2.75(m，2H)，2.33(q，J＝8.8Hz， 2H)，1.96-1.76(m，2H)，1.63(d， J＝6.8Hz，3H).
3134 154-160 498.1 *** (CDCl 3，400MHz)，δ7.94(d， J＝8.0Hz，2H)，7.65(d，J＝8.8Hz，1H)， 7.57(d，J＝8.4Hz，2H)，7.38-7.33(m， 2H)，7.09-7.04(m，2H)，7.03(d， J＝8.8Hz，1H)，7.46(t，J＝6.8Hz，1H)， 4.95-4.86(m，1H)，4.66(d，J＝6.0Hz， 2H)，4.23(t，J＝4.4Hz，2H)，3.82(t， J＝4.4Hz，2H)，3.50(s，3H)，2.83-2.72 (m，2H)，2.32(q，J＝8.8Hz，2H)，1.97- 1.79(m，2H).
3135 216-218 493.9 * (CDCl 3，400MHz)，δ7.90(d，J＝8.0Hz， 2H)，7.64(d，J＝8.8Hz，1H)，7.55(d， J＝8.4Hz，2H)，7.35(d，J＝8.8Hz，2H)， 7.18(d，J＝1.6Hz，1H)，6.91((d， J＝8.4Hz，1H)，6.44(d，J＝7.6Hz， 1H)，5.34-5.30(m，1H)，4.93-4.88(m， 1H)，4.12(q，J＝2.8Hz，2H)，3.81(s， 3H)，2.81-2.71(m，2H)，2.35-2.30(m， 2H)，1.94-1.76(m，2H)，1.63(d， J＝6.8Hz，3H)，1.49(t，J＝6.8Hz，3H).
3136 250 (decomposition .) 472.3 ** (CDCl 3，400MHz)，δ7.76-7.72(m， 3H)，7.34(d，J＝8.0Hz，1H)，6.77-6.73 (m，4H)，4.84-4.80(m，1H)，4.00(t， J＝6.8Hz，1H)，3.65(b，2H)，3.46(b， 2H)，2.63-2.58(m，2H)，2.32-2.28(m， 2H)，1.90-1.75(m，2H)，1.36-1.23(m， 12H)
3137 477.2 ** (CDCl 3，400MHz)，δ7.99(s，1H)， 7.79-7.77(m，1H)，7.73-7.71(m，1H)， 7.48(d，J＝8.0Hz，2H)，7.36(d， J＝8.4Hz，2H)，6.71(s，1H)，4.96(m， 1H)，4.41(s，2H)，4.29(s，2H)，3.23- 3.19(m，2H)，2.84-2.76(m，2H)，2.40- 2.37(m，4H)，2.01-1.83(m，4H)，1.10 (t，J＝7.2Hz，3H).
Compound Fusing point (℃) Mass spectrum [M+H] Replicon IC 50μ M 2-days Replicon IC 50μ M 3-days 1H NMR data
3138 463.2 ** (CDCl 3，400MHz)，δ8.37(s，1H)， 8.15-8.13(m，1H)，7.80(d，J＝4.4Hz， 1H)，7.48(d，J＝8.4Hz，2H)，7.38(d， J＝8.4Hz，2H)，7.00(s，1H)，5.02-4.93 (m，1H)，4.63-4.59(m，2H)，4.20-4.16 (m，2H)，4.23-4.19(m，2H)，2.85-2.75 (m，2H)，2.40-2.36(m，2H)，2.18-1.84 (m，4H)，1.09(t，J＝6.8Hz，3H).
3139 458.2 *** (CDCl 3，400MHz)，δ7.76-7.73(m， 2H)，7.39-7.32(m，2H)，6.88-6.86(m， 4H)，4.91-4.82(m，1H)，4.05-3.97(m， 1H)，3.75-3.59(m，2H)，3.15(s，3H)， 2.66-2.56(m，2H)，2.35-2.29(m，2H)， 1.95-1.82(m，2H)，1.32-1.22(m，9H).
3140 470.2 *** (CDCl 3，400MHz)，δ7.87(s，1H)，7.76- 7.73(m，1H)，7.51-7.46(m，1H)， 7.34-7.32(m，1H)，7.00(s，4H)，4.91- 4.85(m，1H)，4.03-3.99(m，1H)， 3.80-3.72(m，2H)，3.62-3.59(m，2H)， 2.74-2.61(m，2H)，2.33-2.30(m，2H)， 2.10-1.94(m，6H)，1.24(d，J＝8.4Hz， 6H).
3141 496.1 ** (CDCl 3，400MHz)，δ7.78-7.75(m， 2H)，7.42-7.38(m，1H)，7.10(s，4H)， 5.24(s，1H)，4.94-4.88(m，1H)，4.03- 3.77(m，9H)，2.72-2.61(m，2H)，2.35- 2.29(m，2H)，1.94-1.81(m，2H)，1.22 (d，J＝7.6Hz，6H).
3142 444.2 ** (CDCl 3，400MHz)，δ7.78-7.75(m， 2H)，7.42-7.39(m，2H)，6.93-6.86(m， 4H)，5.62(s，1H)，4.88-4.82(m，1H)， 4.02-3.98(m，1H)，3.20-3.16(m，6H)， 2.67-2.60(m，2H)，2.35-2.26(m，2H)， 1.92-1.81(m，2H)，1.23(d，J＝8.8Hz， 6H).
3143 488.1 ** (CDCl 3，400MHz)，δ7.83-7.71(m， 2H)，7.48(s，1H)，7.41-7.38(m，1H)， 6.87(s，4H)，5.65(s，1H)，4.87-4.81 (m，1H)，3.80-3.74(m，2H)，3.64-3.55 (m，2H)，3.44-3.36(m，3H)，3.20(s， 3H)，2.66-2.59(m，2H)，2.34-2.25(m， 2H)，1.91-1.81(m，2H)，1.22(d， J＝8.8Hz，6H).
3144 500.1 ** (DMSO，400MHz)，δ8.65(s，1H)， 7.88(d，J＝7.6Hz，1H)，7.76(s，1H)， 7.59-7.57(m，2H)，7.44-7.42(m，2H)，
Compound Fusing point (℃) Mass spectrum [M+H] Replicon IC 50μ M 2-days Replicon IC 50μ M 3-days 1H NMR data
6.14(d，J＝8.0Hz，1H)，5.04-4.99(m， 1H)，4.18-4.16(m，1H)，3.78-3.74(m， 1H)，3.57-3.46(m，3H)，3.04-3.01(m， 1H)，2.60-2.55(m，2H)，2.32-2.30(m， 1H)，1.91-1.65(m，6H)，1.09(d， J＝6.8Hz，6H).
3145 225-226 473.3 *** (CDCl 3，400MHz)，δ7.76(dd， J＝7.6Hz and 1.6Hz，2H)，7.58(d， J＝8.4Hz，2H)，7.45(d，J＝8.4Hz，2H)， 7.37(d，J＝8.8Hz，1H)，6.76(s，1H)， 5.09-4.97(m，2H)，3.60-3.36(m，6H)， 2.87-2.76(m，2H)，2.38(q，J＝8.8Hz， 2H)，1.34-1.21(m，12H).
3146 136-138 445.2 ** (CDCl 3，400MHz)，δ7.81(d， J＝1.2Hz，1H)，7.77(d，J＝8.8Hz，1H)， 7.58(d，J＝8.4Hz，2H)，7.46-7.43(m， 3H)，6.74(s，1H)，5.09-4.98(m，2H)， 3.14-3.09(m，6H)，2.87-2.79(m，2H)， 2.38(q，J＝8.8Hz，2H)，2.01-1.82(m， 2H)，1.34(d，J＝6.4Hz，6H).
3147 459.2 *** (CDCl 3，400MHz)，δ7.79-7.75(m， 2H)，7.58(d，J＝8.4Hz，2H)，7.46-7.40 (m，3H)，6.76(s，1H)，5.09-4.98(m， 2H)，3.63-3.37(m，2H)，3.09(b，3H)， 2.86-2.76(m，2H)，2.38(q，J＝8.4Hz， 2H)，3.01-1.80(m，2H)，1.34-1.18(m， 9H).
3148 204-205 471.3 ** (CDCl 3，400MHz)，δ7.92(s，1H)， 7.76(d，J＝8.4Hz，1H)，7.59-7.55(m， 3H)，7.45(d，J＝8.8Hz，2H)，6.73(s， 1H)，5.07-5.00(m，2H)，3.70(t， J＝6.4Hz，2H)，3.54(t，J＝5.6Hz，2H)， 2.84-2.78(m，2H)，2.38(q，J＝10Hz， 2H)，2.01-1.89(m，6H)，1.33(d， J＝6.0Hz，6H).
3149 487.2 *** (CDCl 3，400MHz)，δ7.80-7.77(m， 2H)，7.59(d，J＝8.8Hz，2H)，7.46-7.41 (m，3H)，6.74(s，1H)，5.09-4.98(m， 2H)，3.73(b，8H)，2.85-2.77(m，2H)， 2.38(q，J＝8.8Hz，2H)，2.01-1.80(m， 2H)，1.34(d，J＝6.4Hz，6H).
3150 136-138 557.4 ***
3151 246-248 527.5 **
3152 215-217 485.5 ***
Compound Fusing point (℃) Mass spectrum [M+H] Replicon IC 50μ M 2-days Replicon IC 50μ M 3-days 1H NMR data
3153 269-271 565.5 ***
3154 182-185 556.5 ***
3155 164-166 506.2 ***
3156 168-169 550.4 ***
3157 137-138 515.4 ***
3158 129-130 489.3 ***
3159 195-201 508.4 ***
3160 125-128 498.3 ***
3161 174-179 512.4 ***
3162 148-152 506.4 ***
3163 211-212 465.3 ***
3164 225-227 466.4 ***
3165 210-212 463.4 (M-1) ***
3166 209-213 466.5 ***
3167 168-169 467.4 ***
3168 167-170 467.4 **
3169 147-149 466.4 **
3170 192-194 487.3 ***
3171 174-177 501.3 ***
3172 213-216 541.5 ***
3173 203-206 563.5 ***
3174 202-205 501.4 ***
3175 171-175 538.6 ***
3176 209-211 537.5 ***
Compound Fusing point (℃) Mass spectrum [M+H] Replicon IC 50μ M 2-days Replicon IC 50μ M 3-days 1H NMR data
3177 250-252 539.4 ***
3178 224-225 562.6 ***
3179 240-241 521.7 ***
3180 223-225 479.7 ***
3181 218-220 513.6 ***
3182 245-249 522.6 ***
3183 222-224 484.4 **
3184 259-264 528.5 **
3185 279-285 538.8 (M-1) ***
3186 226-231 548.7 ***
3187 243-249 577.1 ***
3188 137-138 547.6 *
3189 241-245 533.5 ***
3190 192-193 533.6 *
3191 227-229 519.7 ***
3192 201-203 512.6 *** 1H NMR(300MHz)δ，8.32(dd，1H，J ＝1.8，4.8Hz)，8.05(dd，1H，J＝1.8， 7.8Hz)，7.80(d，1H，J＝8.7Hz)，7.58 (d，1H，J＝1.8Hz)，7.10-7.49(m， 6H)，6.73(s，1H)，4.95(m，1H)，3.21 (t，2H，J＝7.8Hz)，2.74-2.82(m，2H)， 2.33-2.37(m，2H)，1.83-1.97(m，4H)， 1.10(t，3H，7.5Hz).
3193 189-191 475.7 **
3194 210-212 499.7 ***
3195 193-194 498.8 ***
3196 232-236 485.6 **
Compound Fusing point (℃) Mass spectrum [M+H] Replicon IC 50μ M 2-days Replicon IC 50μ M 3-days 1H NMR data
3197 215-217 512.6 ***
3198 279-282 477.8 ***
3199 205-210 535.1 ***
3200 208-212 487.0 ***
3201 181-184 555.7 ***
3202 240-242 501.3 ***
3203 241-242 474.3 **
3204 174-177 488.0 ***
3205 199-201 447.9 **
3206 234-236 527.1 ***
3207 116-118 501.1 ***
3208 243-245 485.9 ***
3209 219-221 528.2 *** 1H NMR(300MHz，CDCl 3)：δ1.21 (d，6H)，1.73-2.00(m，2H)，2.27-2.44 (m，2H)，2.66-2.86(m，2H)，3.57- 3.75(m，1H)，3.39(d，1H)，4.85-5.06 (m，1H)，6.62(d，br，1H)，7.12-7.15 (m，1H)，7.27-7.34(m，2H)，7.43- 7.50(m，2H)，7.58(d，1H)，7.82(d， 1H)，8.30(d，1H)，8.43(d，1H)
3210 269-271 511.8 *** 1H NMR(300MHz，CDCl3 )：δ1.21 (d，6H)，1.73-2.00(m，2H)，2.27-2.44 (m，2H)，2.66-2.86(m，2H)，3.57- 3.75(m，1H)，3.39(d，1H)，4.85-5.06 (m，1H)，6.62(d，br，1H)，7.12-7.15 (m，1H)，7.27-7.34(m，2H)，7.43- 7.50(m，2H)，7.58(d，1H)，7.82(d， 1H)，8.30(d，1H)，8.43(d，1H)
3211 189-191 525.9 ***
3212 224-226 435.1 ***
3213 195-197 434.1 ***
3214 262-268 491.3 **
Compound Fusing point (℃) Mass spectrum [M+H] Replicon IC 50μ M 2-days Replicon IC 50μ M 3-days 1H NMR data
3215 260-271 479.1 *
3216 251-256 486.2 **
3217 212-223 500.2 *
3218 180-187 506.4 **
3219 203-212 492.2 **
3220 187-196 500.3 *
3221 249-250 386.2 **
3222 233-235 464.0 **
3223 250-251 416.2 **
3224 178-180 513.3 ***
3225 194-197 527.3 ***
3226 193-194 535.4 ***
3227 148-150 373.5 **
3228 92-95 537.8 ***
3229 88-91 551.8 ***
3230 253-257 496.1 **
3231 189-196 522.2 **
3232 278-282 508.1 **
3233 193-198 548.5 ***
3234 243-247 522.1 **
3235 249-256 536.2 **
3236 173-190 510.1 *
3237 512.4 *
3238 205-208 539.2 ***
Compound Fusing point (℃) Mass spectrum [M+H] Replicon IC 50μ M 2-days Replicon IC 50μ M 3-days 1H NMR data
3239 193-196 511.1 ***
3240 121-124 468.4 ***
3241 169-173 446.0 ***
3242 242-245 512.2 ***
3243 183-185 502.3 ***
3244 223-225 495.9 **
3245 243-250 562.3 ***
3246 223-227 536.2 ***
3247 199-201 522.0 ***
3248 238-241 527.0 ***
3249 235-239 526.0 ***
3250 232-235 511.8 ***
3251 212-213 427.6 **
3252 223-224 409.5 *
3253 Vitreous state 516.8 (M-1) ***
3254 214-215 508.0 ***
3255 209-211 527.9 **
3256 217-218 517.9 **
3257 205-208 507.9 ***
3258 250-252 546.3 ***
3259 203-208 520.2 ***
3260 202-204 447.8 ***
3261 207-209 448.6 ***
3262 223 (decomposition .) 504.9 ***
Compound Fusing point (℃) Mass spectrum [M+H] Replicon IC 50μ M 2-days Replicon IC 50μ M 3-days 1H NMR data
3263 183-185 503.9 ***
3264 245-247 443.9 **
3265 172-174 469.8 **
3266 159-162 527.1 ***
3267 181-212 558.5 ***
3268 223-225 465.0 ***
3269 240-246 543.9 **
3270 193-195 481.9 ***
3271 80-83 541.1 ***
3272 79-81 556.1 *
3273 227-230 526.1 ***
3274 222-225 527.0 ***
3275 130 (decomposition .) 552.8 ***
3276 209-212 553.9 ***
3277 267-268.5 467.0 ***
3278 165-169 529.8 ***
3279 542.5 (M-1) ***
3280 543.9 ***
3281 211-213 529.7 ***
3282 181-182 468.8 ***
3283 145-147 494.9 ***
3284 99-101 522.9 ***
3285 236-238 476.9 ***
3286 233-235 501.9 **
3287 166-168 490.9 **
3288 215-217 526.7 ***
3289 177-178 540.6 ***
Compound Fusing point (℃) Mass spectrum [M+H] Replicon IC 50μ M 2-days Replicon 1C 50μ M 3-days 1H NMR data
3290 176-180 527.7 ***
3291 168-172 537.3 (M-1) ***
3292 159-161 432.0 ***
3293 232-250 513.6 ***
3294 187-192 527.3 (M-1) *
3295 236-238 524.8 ***
3296 215-216 548.8 *
3297 112-119 442.1 ***
3298 126-139 496.8 ***
3299 178-179 563.9 **
3300 215-216 470.8 **
3301 253 (decomposition .) 489.8 (M-1) ***
3302 175-179 545.8 ***
3303 138-142 525.8 ***
3304 222-226 512.4 ***
3305 225-228 513.4 ***
3306 218-220 546.0 ***
3307 243-246 547.0 ***
3308 138-142 559.1 **
3309 219-221 526.0 *
3310 272-274 561.9 **
3311 191-194 529.1 ***
3312 206-208 425.1 ***
3313 244-246 423.0 ***
3314 198-199 519.9 ***
3315 237-238 493.0 ***
3316 244-245 520.9 ***
3317 225 (decomposition .) 495.1 ***
3318 235 (decomposition .) 505.1 ***
3319 545.9 ***
Compound Fusing point (℃) Mass spectrum [M+H] Replicon IC 50μ M 2-days Replicon IC 50μ M 3-days 1H NMR data
3320 546.9 ***
3321 233 (decomposition .) 494.9 ***
3322 227-229 522.8 ***
3323 114-300 492.7 **
3324 117-300 518.8 ***
3325 173-181 491.8 ***
3326 98-99 460.9 ***
3327 213-215 426.0 ***
3328 227-229 424.0 ***
3329 237-238 438.0 ***
3330 230-231 452.0 ***
3331 217-218 466.0 ***
3332 140 (decomposition .) 483.2 ***
3333 108-115 ***
3334 108-116 531.6 ***
3335 227-230 540.0 ***
3336 257-259 541.0 ***
3338 280-281 507.0 ***
3337 227-230 560.0 ***
3339 284-285 481.0 ***
3340 290-291 515.4 ***
3341 265-266 535.0 ***
3342 266-267.5 480.0 ***
3343 109-110 466.0 ***
3344 227-230 541.9 ***
3345 167-169 561.8 ***
3346 113-116 529.9 ***
3347 160-162 549.9 ***
3348 229-231 436.9 ***
2150 170-172 402.4 ***
2186 189-191 473.4 ***
2194 493.4 ***
Compound Fusing point (℃) Mass spectrum [M+H] Replicon IC 50μ M 2-days Replicon IC 50μ M 3-days 1H NMR data
2249 155-156 487.3 ** 1H NMR(CDCl 3，400MHz)，δ7.65(d， J＝8.8Hz，1H)，7.58-7.52(m，4H)， 7.23(s，1H)，6.98(dd，J＝8.8Hz and 2.4Hz，1H)，4.93-4.88(m，1H)，4.14 (q，J＝7.2Hz，2H)，3.87(b，2H)，3.55 (b，4H)，3.37(s，3H)，2.87-2.82(m， 2H)，2.70-2.44(m，6H)，2.34-2.32(m， 2H)2.01-2.80(m，2H)，1.49(t， J＝6.8Hz，3H).
2250 194-195 465.2 ** 1H NMR(CDCl 3，400MHz)，δ8.61(d， J＝5.2Hz，1H)，7.96(d，J＝8.4Hz，2H)， 7.85(b，1H)，7.78-7.74(m，1H)，7.64 (d，J＝8.8Hz，1H)，7.55(d，J＝8.4Hz， 2H)，7.33-7.29(m，2H)，7.20(s，1H)， 6.97(d，J＝6.8Hz，1H)，4.94-4.90(m， 1H)，4.14(q，J＝7.2Hz，2H)，3.94(q， J＝5.4Hz，2H)，3.22(t，J＝6.0Hz，2H)， 2.83-2.72(m，2H)，2.37-2.31(m，2H)， 1.96-1.77(m，2H)，1.49(t，J＝6.8Hz， 3H).
2251 172-173 430.2 ** 1H NMR(CDCl 3，400MHz)，δ7.69- 7.64(m，3H)，7.53(d，J＝8.0Hz，2H)， 7.22(s，1H)，6.98(dd，J＝8.8Hz and 1.2Hz，1H)，4.93-4.89(m，1H)，4.63- 4.52(m，1H)，4.14(q，J＝6.8Hz，2H)， 3.83-3.49(m，4H)，2.85-2.80(m，2H)， 2.35-2.31(m，2H)，2.04-1.78(m，5H)， 1.49(t，J＝7.2Hz，3H).
2271 160-163 527.4 ***
2272 166-168 499.4 ***
2273 118-121 499.4 ***
2274 201-203 585.4 ***
2275 114-117 485.4 ***
2276 118-120 471.4 ***
2277 217-221 396.4 ***
2293 199-201 519.4 ***
2294 205-207 491.4 ***
2295 105-107 491.4 ***
2296 202-205 477.3 ***
2297 235-237 463.3 ***
Compound Fusing point (℃) Mass spectrum [M+H] Replicon IC 50μ M 2-days Replicon IC 50μ M 3-days 1H NMR data
2312 203-204 467.4 **
Embodiment 7: use HCV-poliomyelitis mosaic assessment compound activity
In HCV poliovirus (HCV-PV) mosaic, PV 5 ' UTR is replaced (140) by HCV5 ' UTR and part (preceding 123 amino acid) core encoder sequences (the Nucleotide 18-710 of HCV 1b).Therefore, the proteic expression of poliovirus is subjected to the regulation and control of HCV IRES.Poliovirus is a picornavirus, and wherein the protein translation startup is what to be mediated by an IRES element that is positioned at 5 ' UTR.At 5 ' end of HCV-PV chimeric gene group, there is the trifolium sample RNA structure of PV, it is essential cis acting reproducing signals, it is terminal to be the albumen VPg that genome is correlated with.The chimeric duplicating dynamics of HCV-PV meets the duplicating dynamics (Mahoney) of prototype poliovirus, can cause cytopathic effect (CPE) in cell cultures.Heptazyme is the ribozyme of target HCV IRES, and it has the activity (76,77) of the mosaic virus in the antagonism cell cultures.
In order to assess the activity of compound antagonism mosaic virus, inoculation HeLa cell, with it at 37 ℃ and 5%CO 2Following incubation 24 hours.Be that 0.1 HCV-PV pair cell carries out the infection of 30min with infection multiplicity (MOI) subsequently, handle 1 day (needing the optimization process time) with the compound pair cell subsequently.Generate the activity (for example referring to table 1A and 1B) of measuring compound by the pathogenic effect of cell, plaque assay and/or viral RNA.
Embodiment 8: assessment compound antagonism wild-type poliovirus (WT-PV) and poliovirus IRES The activity of (the single luc of WT-PV) is measured in translation
The DNA construction of preparation pPVIRESmono by name, wherein PV IRES sequence (Nucleotide 1-742) is inserted between promotor and Photinus pyralis LUC (Fluc) reporter gene.By using pPVIRESmono DNA transfection and selecting hygromycin resistance, set up the 293T clone of stable transfection.As mentioned above, use the compound pair cell to handle 20 hours, through quantitative Fluc signal measuring activity.In addition, in order to assess the activity of compound antagonism wild-type poliovirus, inoculation HeLa cell, with it at 37 ℃ and 5%CO 2Following incubation 24 hours.Be 0.1 wild-type poliovirus cells infected 30 minutes with MOI subsequently, handled 1 day with the compound pair cell subsequently.Variation, plaque assay and RT-PCR by the pathogenic effect of cell measure the activity of compound through using poliovirus IRES Yin thing and probe (for example referring to table 2).
In addition, if compound has the activity of antagonism poliovirus and other viral IRES, described compound then can be used for treating the caused virus infection of any virus by containing IRES.
Table 2
Compound number WT-PV CPE (100μM) * WT-PV CPE (10μM) * WT-PV CPE (1μM) * WTPV mono luc IC 50(μM)
4 3 2 1 0.8
5 3 2 1 9
9 3 2 2 ＞100
10 3 2 2 ＞100
19 3 2 1 15
24 3 2 2 1.5
Embodiment 9: external translation is measured
Can use external translation to measure and distinguish the compound that acts on HCV IRES RNA or cell translation factor.In exemplary mensuration, the mRNA that can instruct translation is the run-off transcription product from the t7 rna polymerase promotor of pHCVIRESmono plasmid DNA, and wherein the pHCVIRESmono plasmid DNA is with Ambion RNAMegaTranscript kit (Ambion, Inc., Austin TX) generates.Use the HeLa cell pyrolysis liquid to carry out external translation by those skilled in the art's currently known methods.PRELIMINARY RESULTS point out one or more compound of the present invention with the preincubation of HCVIRES rna transcription thing after, the translation activity of its antagonism HCV IRES regulation and control is significantly higher than itself and HeLa cell lysate at 37 ℃ of following preincubation 30min or the activity (data not shown) when not having preincubation.This points out this compound to interact in external translation is measured with HCV IRES RNA.Whether selectively acting is in HCV IRES in order to confirm described compound, unites and uses pLuc and cell IRES mRNA transcript as in vitro translated contrast.
The mode that any publication that this paper quoted and the equal nationality of patent application are quoted is included in, and each publication or patent application all are regarded as clear and definite independent land deeds way of reference and include in.
Although above described some embodiment in detail, those skilled in the art understand clearly might make many modifications to described embodiment, and does not depart from the instruction of described embodiment.All such modifications are intended to covered in the claim of the present invention.
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Claims (according to the modification of the 19th of treaty)
1. formula IIa compound
Figure A20078000890206941
Or the acceptable salt of its pharmacology, wherein:
X is:
-cyano group;
-nitro;
-formyl radical;
-COOH；
-COR x, R wherein xBe C 1To C 6Alkyl;
-CH=N-(C 1To C 6Alkoxyl group);
-CH=N-is (randomly by one or more C 1To C 6The amino that alkyl replaces);
-halogen;
-the alkyl that randomly replaced by one or more halogens;
-randomly by C 1To C 6The alkynyl that alkyl replaces, described alkyl are randomly replaced by one or more halogens of selecting independently or cyano group;
-oximido;
-SO 2R x；
-SO 2NH 2；
-SO 2NH(R x)；
-SO 2N(R x) 2；
-amino, it is randomly by one or more C 1To C 6Alkyl and/or-C (O)-C 1To C 6Alkyl replaces;
-amido, it is randomly by one or more C that select independently 1To C 6Alkyl replaces;
-five yuan or hexa-member heterocycle;
-five yuan or six membered heteroaryl, it is randomly by one or more C 1To C 6Alkyl replaces, and described alkyl is randomly replaced by one or more halogens; Or
-C 6To C 8Aryl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-C 1To C 6Alkyl, it is randomly replaced by one or more halogens;
-halogen; And
-cyano group;
Y is:
-the benzothiazolyl that randomly replaced by amino, described amino is randomly by one or more C 1To C 6Alkyl replaces;
-indyl, it is randomly at the quilt-SO of nitrogen-atoms place 2R xReplace;
-C 6To C 8Aryl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-halogen;
-C 1To C 6Alkyl;
-alkoxyl group, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-one or more halogens; And
-five yuan or hexa-member heterocycle;
-hydroxyl;
-amino, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-SO 2R x；
-C 1To C 6Alkyl, it is replaced by one or more five yuan or six membered heteroaryl randomly and independently; And
-PO 2R x；
-OC(O)NHR x；
-OC(O)N(R x) 2；
-OC(O)NH(OR x)；
-OC(O)NR x(OR x)；
-OC(O)N(OR x) 2；
-OC (O) R Ab, R wherein AbBe five yuan or hexa-member heterocycle;
-NR oCOR p, R wherein pBe:
-C 1To C 6Alkyl;
-randomly by one or more C 1To C 6The amino that alkyl replaces, described alkyl are randomly and independently by one or more C 6To C 8Aryl and/or alkoxyl group replace; Or
-five yuan or hexa-member heterocycle, it is randomly by one or more C 1To C 6Alkyl and/or C 6To C 8Aryl replaces;
And R wherein oBe:
-hydrogen; Or
-C 1To C 6Alkyl;
-NR qCONR qR r, R wherein qBe hydrogen;
And R wherein rBe:
-C 1To C 6Alkyl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-halogen;
-hydroxyl;
-alkoxyl group;
-five yuan or hexa-member heterocycle;
-five yuan or six membered heteroaryl, and
-the C that randomly replaced by one or more halogens 6To C 8Aryl;
-the C that randomly replaced by one or more halogens 2To C 6Thiazolinyl;
-C 1To C 6Alkoxyl group; Or
-five yuan or hexa-member heterocycle;
-SO 2R Aa, R wherein AaBe:
-five yuan or hexa-member heterocycle, it is randomly replaced by hydroxyl;
-C 1To C 6Alkoxyl group; Or
-C 1To C 6Alkyl;
-COR m, R wherein mBe:
-randomly by one or more C 1To C 6The amino that alkyl replaces, wherein this C 1To C 6Alkyl is randomly by five yuan or hexa-member heterocycle replacement; Or
-ternary is to seven membered heterocyclic, and it is randomly by C 1To C 6Alkyl replaces, and described alkyl is randomly replaced by dialkyl-7-amino;
-NR tCOOR u, R wherein tBe hydrogen, and R uBe:
-C 1To C 12Alkyl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-aryl, it is randomly replaced by one or more halogens and/or alkylhalide group;
-the alkoxyl group that randomly replaced by one or more alkoxyl groups;
-randomly by one or more C 1To C 6The amino that alkyl replaces;
-halogen;
-five yuan or six membered heteroaryl, and
-five yuan or hexa-member heterocycle;
-C 2To C 6Thiazolinyl; Or
-C 6To C 8Aryl, it is randomly replaced by halogen;
-NHR Bb, R wherein BbBe:
-C (=S) NH 2Or
-PO(OR x) 2；
-NR vSO 2R w, R wherein vBe hydrogen, and R wBe:
-C 1To C 6Alkyl; Or
-alkyl-amino or dialkyl-7-amino, it is randomly replaced by halogen;
Figure A20078000890206971
Z is:
-C 1To C 6Alkyl, it is randomly by five yuan or hexa-member heterocycle replacement; Or
-five yuan or hexa-member heterocycle;
R is a hydrogen;
R 1Be:
-hydrogen;
-five yuan or hexa-member heterocycle;
-C 1To C 6Alkyl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-randomly heterocyclically substituted amino;
-randomly by C 1To C 6The amido that alkyl replaces;
-five yuan or hexa-member heterocycle, it is randomly by C 1To C 6Alkyl replaces;
-five yuan or six membered heteroaryl, and
-C 6To C 8Aryl;
-C 1To C 6Alkoxyl group, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-randomly heterocyclically substituted amino;
-randomly by C 1To C 6The amido that alkyl replaces;
-five yuan or hexa-member heterocycle, it is randomly by C 1To C 6Alkyl replaces;
-five yuan or six membered heteroaryl, and
-C 6To C 8Aryl;
-(O)-five yuan or hexa-member heterocycle;
-(O)-five yuan or six membered heteroaryl;
-SO 2R x, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or hexa-member heterocycle;
-C 6To C 8Aryl; And
-five yuan or six membered heteroaryl; Or
-alkylthio, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or hexa-member heterocycle;
-C 6To C 8Aryl; And
-five yuan or six membered heteroaryl;
R 2Be:
-C 1To C 6Alkyl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or hexa-member heterocycle;
-five yuan or six membered heteroaryl;
-C 6To C 8Aryl;
-randomly by C 1To C 6The amido that alkyl replaces; And
-amino, it is randomly replaced by one or more substituting groups that are independently selected from heterocycle, alkoxyl group and alkyl, and described alkyl is randomly replaced by one or more alkoxyl groups;
-alkylthio, randomly by five yuan or six membered heteroaryl replacement, described heteroaryl is randomly replaced by alkyl for it;
-alkylthio, it is randomly by five yuan or hexa-member heterocycle replacement;
-alkylthio, it is randomly by C 6To C 8Aryl replaces;
-alkylthio, it is randomly by C 1To C 6Alkyl replaces;
-SO 2R x, randomly by five yuan or six membered heteroaryl replacement, described heteroaryl is randomly by one or more C for they 1To C 6Alkyl replaces;
-SO 2R x, it is randomly by five yuan or hexa-member heterocycle replacement;
-SO 2R x, it is randomly by C 6To C 8Aryl replaces;
-SO 2R x, it is randomly by C 1To C 6Alkyl replaces;
-S (O) R x, it is randomly by five yuan or six membered heteroaryl replacement;
-S (O) R x, it is randomly by five yuan or hexa-member heterocycle replacement;
-S (O) R x, it is randomly by C 6To C 8Aryl replaces;
-S (O) R x, it is randomly by C 1To C 6Alkyl replaces;
-alkoxyl group, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-halogen;
-hydroxyl;
-the alkoxyl group that replaces of alkoxy randomly;
-amino, it is randomly replaced by one or more substituting groups that are independently selected from five yuan or six membered heteroaryl, five yuan or hexa-member heterocycle and alkyl, and described alkyl is randomly replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or hexa-member heterocycle; And
-the amino that randomly replaced by one or more alkyl;
-randomly by C 1To C 6The amido that alkyl replaces;
Five yuan of-S-or hexa-member heterocycle;
Five yuan of-S-or six membered heteroaryl, it is randomly by C 1To C 6Alkyl replaces;
-S-C 1To C 6Alkyl;
-S-C 6To C 8Aryl;
-sulfinyl-five yuan or hexa-member heterocycle;
-sulfinyl-five yuan or six membered heteroaryl;
-sulfinyl-C 1To C 6Alkyl;
-sulfinyl-C 6To C 8Aryl;
-alkylsulfonyl-five yuan or hexa-member heterocycle;
-alkylsulfonyl-randomly by C 1To C 6Five yuan or six membered heteroaryl that alkyl replaces;
-alkylsulfonyl-C 1To C 6Alkyl;
-alkylsulfonyl-C 6To C 8Aryl;
-five yuan to seven membered heterocyclic, and it is randomly by one or more hydroxyl and C of being independently selected from 1To C 6The substituting group of alkyl replaces, and described alkyl is randomly by one or more C 1To C 6Alkoxyl group replaces;
-five yuan or six membered heteroaryl, it is randomly by one or more C 1To C 6Alkyl replaces; And
-C 6To C 8Aryl;
-C 6To C 8Aryl;
-(O)-five yuan or six membered heteroaryl, it is randomly by one or more C that select independently 1To C 6Alkyl replaces;
-C (O)-five yuan or hexa-member heterocycle, it is randomly by one or more C 6To C 8Aryl replaces;
-C (O)-C 6To C 8Aryl;
-five yuan or six membered heteroaryl, it is randomly replaced by one or more substituting groups that are independently selected from down group:
-C 1To C 6Alkyl; And
-five yuan or hexa-member heterocycle, it is randomly replaced by one or more substituting groups that are independently selected from down group:
-hydroxyl;
-C 1To C 6Alkyl;
-SO 2R x；
-C (O)-C 6To C 8Aryl; And
-C (O) OR xOr
-OR Kk, R wherein KkBe:
-C 6To C 8Aryl;
-five yuan or hexa-member heterocycle, it is randomly by C 1To C 6Alkyl replaces, and described alkyl is randomly by C 6To C 8Aryl replaces;
Five yuan or six membered heteroaryl, it is randomly by one or more halogen, C of being independently selected from 1To C 6Alkyl, C 1To C 6Alkoxyl group and C 1To C 6The substituting group of alkylhalide group replaces;
-SO 2R xOr
-Si (R x) 3And
R 3Be hydrogen;
Condition is X, Y, Z, R 1And R 2In have a following selection at least:
X is:
-COOH；
-CH=N-(C 1To C 6Alkoxyl group);
-CH=N-is (randomly by one or more C 1To C 6The amino that alkyl replaces);
-halogen;
-the alkyl that randomly replaced by one or more halogens;
-randomly by C 1To C 6The alkynyl that alkyl replaces, described alkyl are randomly replaced by one or more halogens and/or cyano group;
-oximido;
-SO 2R x；
-SO 2NH 2；
-SO 2NH(R x)；
-SO 2N(R x) 2；
-amino, it is randomly by one or more C 1To C 6Alkyl and/or-C (O)-C 1To C 6Alkyl replaces;
-amido, it is randomly by one or more C that select independently 1To C 6Alkyl replaces;
-five yuan or hexa-member heterocycle;
-five yuan or six membered heteroaryl, it is by one or more C 1To C 6Alkyl replaces, and described alkyl is replaced by one or more halogens; Or
-C 6To C 8Aryl, it is replaced by one or more substituting groups that are independently selected from following groups:
-C 1To C 6Alkyl, it is randomly replaced by one or more halogens;
-halogen; And
-cyano group;
Y is:
-by the amino benzothiazolyl that replaces, described amino is randomly by one or more C 1To C 6Alkyl replaces;
-indyl, it is at the quilt-SO of nitrogen-atoms place 2R xReplace; Or
-C 6To C 8Aryl, it is replaced by one or more substituting groups that are independently selected from following groups:
-amino, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-SO 2R x, and
-C 1To C 6Alkyl, it is by one or more five yuan or six membered heteroaryl replacements;
-OC(O)NHR x；
-OC(O)N(R x) 2；
-OC(O)NH(OR x)；
-OC(O)NR x(OR x)；
-OC(O)N(OR x) 2；
-OC (O) R Ab, R wherein AbBe five yuan or hexa-member heterocycle;
-NR oCOR p, R wherein pBe:
-randomly by one or more C 1To C 6The amino that alkyl replaces, described alkyl are randomly and independently by one or more C 6To C 8Aryl and/or alkoxyl group replace; Or
-five yuan or hexa-member heterocycle, it is by one or more C 1To C 6Alkyl and/or C 6To C 8Aryl replaces;
-NR qCONR qR r, R wherein rBe:
-C 1To C 6Alkyl, it is replaced by one or more substituting groups that are independently selected from following groups:
-hydroxyl;
-alkoxyl group;
-five yuan or hexa-member heterocycle;
-five yuan or six membered heteroaryl; And
-C 6To C 8Aryl, it is replaced by one or more halogens;
-C 2To C 6Thiazolinyl;
-C 1To C 6Alkoxyl group; Or
-five yuan or hexa-member heterocycle;
-NR tCOOR u, R wherein uBe:
Replaced by one or more substituting groups that are independently selected from following groups:
-the alkoxyl group that replaced by one or more alkoxyl groups;
-randomly by one or more C 1To C 6The amino that alkyl replaces; And
-five yuan or six membered heteroaryl; Or
-C 2To C 6Thiazolinyl; And
Figure A20078000890207031
R 1Be:
-C 1To C 6Alkyl, it is replaced by following groups:
-randomly by C 1To C 6The amido that alkyl replaces; And/or
-five yuan or six membered heteroaryl;
-C 1To C 6Alkoxyl group, it is replaced by following groups:
-randomly heterocyclically substituted amino;
-randomly by C 1To C 6The amido that alkyl replaces;
-five yuan or hexa-member heterocycle, it is randomly by C 1To C 6Alkyl replaces; And/or
-five yuan or six membered heteroaryl;
-(O)-five yuan or hexa-member heterocycle;
-(O)-five yuan or six membered heteroaryl;
-SO 2R x, it is randomly replaced by following groups:
-five yuan or hexa-member heterocycle;
-C 6To C 8Aryl; And/or
-five yuan or six membered heteroaryl; Or
-alkylthio, it is randomly replaced by following groups:
-five yuan or hexa-member heterocycle;
-C 6To C 8Aryl; And/or
-five yuan or six membered heteroaryl;
R 2Be:
-C 1To C 6Alkyl, it is replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or hexa-member heterocycle;
-five yuan or six membered heteroaryl;
-C 6To C 8Aryl;
-randomly by C 1To C 6The amido that alkyl replaces; And
-amino, it is randomly replaced by one or more substituting groups that are independently selected from heterocycle, alkoxyl group and alkyl, and described alkyl is randomly replaced by one or more alkoxyl groups;
-alkylthio, randomly by five yuan or six membered heteroaryl replacement, described heteroaryl is randomly replaced by alkyl for it;
-alkylthio, it is randomly by five yuan or hexa-member heterocycle replacement;
-alkylthio, it is randomly by C 6To C 8Aryl replaces;
-alkylthio, it is randomly by C 1To C 6Alkyl replaces;
-SO 2R x, randomly by five yuan or six membered heteroaryl replacement, described heteroaryl is randomly by one or more C for they 1To C 6Alkyl replaces;
-SO 2R x, it is randomly by five yuan or hexa-member heterocycle replacement;
-SO 2R x, it is randomly by C 6To C 8Aryl replaces;
-SO 2R x, it is randomly by C 1To C 6Alkyl replaces;
-S (O) R x, it is randomly by five yuan or six membered heteroaryl replacement;
-S (O) R x, it is randomly by five yuan or hexa-member heterocycle replacement;
-S (O) R x, it is randomly by C 6To C 8Aryl replaces;
-S (O) R x, it is randomly by C 1To C 6Alkyl replaces;
-alkoxyl group, it is replaced by following groups:
-alkoxyl group;
-amino, it is replaced by one or more substituting groups that are independently selected from five yuan or six membered heteroaryl, five yuan or hexa-member heterocycle and alkyl, and described alkyl is randomly replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or hexa-member heterocycle; And
-the amino that randomly replaced by one or more alkyl;
-randomly by C 1To C 6The amido that alkyl replaces;
Five yuan of-S-or hexa-member heterocycle;
Five yuan of-S-or six membered heteroaryl, it is randomly by C 1To C 6Alkyl replaces;
-S-C 1To C 6Alkyl;
-S-C 6To C 8Aryl;
-sulfinyl-five yuan or hexa-member heterocycle;
-sulfinyl-five yuan or six membered heteroaryl;
-sulfinyl-C 1To C 6Alkyl;
-sulfinyl-C 6To C 8Aryl;
-alkylsulfonyl-five yuan or hexa-member heterocycle;
-alkylsulfonyl-randomly by C 1To C 6Five yuan or six membered heteroaryl that alkyl replaces;
-alkylsulfonyl-C 1To C 6Alkyl;
-alkylsulfonyl-C 6To C 8Aryl;
-five yuan to seven membered heterocyclic, and it is by one or more hydroxyl and C of being independently selected from 1To C 6The substituting group of alkyl replaces, and described alkyl is by one or more C 1To C 6Alkoxyl group replaces;
-five yuan or six membered heteroaryl, it is by one or more C 1To C 6Alkyl replaces; Or
-C 6To C 8Aryl;
-C (O)-five yuan or hexa-member heterocycle, it is randomly by one or more C 6To C 8Aryl replaces;
-C (O)-C 6To C 8Aryl;
-five yuan or hexa-member heterocycle, it is replaced by one or more substituting groups that are independently selected from down group:
-hydroxyl;
-C 1To C 6Alkyl;
-SO 2R x；
-C (O)-C 6To C 8Aryl; And
-C(O)OR x；
-OR Kk, R wherein KkBe:
-C 6To C 8Aryl;
-five yuan or hexa-member heterocycle, it is randomly by C 1To C 6Alkyl and/or C 6To C 8Aryl replaces; Or
-Si(R x) 3；
-(O)-five yuan or hexa-member heterocycle, it is randomly by one or more C that select independently 1To C 6Alkyl replaces;
Or
-(O)-five yuan or six membered heteroaryl, it is randomly by one or more C that select independently 1To C 6Alkyl replaces.
2. compound as claimed in claim 1, wherein:
X is:
-COOH；
-CH=N-(C 1To C 6Alkoxyl group);
-CH=N-is (randomly by one or more C 1To C 6The amino that alkyl replaces);
-halogen;
-the alkyl that randomly replaced by one or more halogens;
-randomly by C 1To C 6The alkynyl that alkyl replaces, described alkyl are randomly replaced by one or more halogens and/or cyano group;
-oximido;
-SO 2R x；
-SO 2NH 2；
-SO 2NH(R x)；
-SO 2N(R x) 2；
-amino, it is randomly by one or more C 1To C 6Alkyl and/or-C (O)-C 1To C 6Alkyl replaces;
-amido, it is randomly by one or more C that select independently 1To C 6Alkyl replaces;
-five yuan or hexa-member heterocycle;
-five yuan or six membered heteroaryl, it is by one or more C 1To C 6Alkyl replaces, and described alkyl is replaced by one or more halogens; Or
-C 6To C 8Aryl, it is replaced by one or more substituting groups that are independently selected from following groups:
-C 1To C 6Alkyl, it is randomly replaced by one or more halogens;
-halogen; And
-cyano group.
3. compound as claimed in claim 2, wherein X is cyano group, halogen or the alkyl that replaced by one or more halogens.
4. compound as claimed in claim 3, wherein X is a cyano group.
5. compound as claimed in claim 3, wherein X is fluorine, bromine, chlorine or iodine.
6. compound as claimed in claim 3, wherein X is a trifluoromethyl.
7. the described compound of claim 1, wherein:
The C that Y is replaced by one or more following groups 6To C 8Aryl:
-amino, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-SO 2R xAnd
-C 1To C 6Alkyl, it is by one or more five yuan or six membered heteroaryl replacements;
-OC(O)NHR x；
-OC(O)N(R x) 2；
-OC(O)NH(OR x)；
-OC(O)NR x(OR x)；
-OC(O)N(OR x) 2；
-OC (O) R Ab, R wherein AbBe five yuan or hexa-member heterocycle;
-NR oCOR p, R wherein pBe:
-randomly by one or more C 1To C 6The amino that alkyl replaces, described alkyl are randomly and independently by one or more C 6To C 8Aryl and/or alkoxyl group replace; Or
-five yuan or hexa-member heterocycle, it is by one or more C 1To C 6Alkyl and/or C 6To C 8Aryl replaces ,-NR qCONR qR r, R wherein rBe:
-C 1To C 6Alkyl, it is replaced by one or more substituting groups that are independently selected from following groups:
-hydroxyl;
-alkoxyl group;
-five yuan or hexa-member heterocycle;
-five yuan or six membered heteroaryl; And
-C 6To C 8Aryl, it is randomly replaced by halogen,
-C 2To C 6Thiazolinyl;
-C 1To C 6Alkoxyl group; Or
-five yuan or hexa-member heterocycle;
-NR tCOOR u, R wherein uBe:
-C 1To C 12Alkyl, it is replaced by one or more substituting groups that are selected from following groups:
-the alkoxyl group that replaced by one or more alkoxyl groups;
-randomly by one or more C 1To C 6The amino that alkyl replaces; And
-five yuan or six membered heteroaryl;
8. compound as claimed in claim 7, wherein C 6To C 8Aryl is a phenyl.
9. compound as claimed in claim 8, wherein phenyl has at least one para-orienting group.
10. compound as claimed in claim 1, wherein Z is:
Cyclobutyl, cyclopropyl, cyclopropyl methyl or cyclopentyl.
11. compound as claimed in claim 1, wherein Z is C 1To C 6Alkyl.
12. compound as claimed in claim 11, wherein Z is cyclobutyl, cyclopropyl, cyclopropyl methyl, ethyl or cyclopentyl.
13. the described compound of claim 1, wherein:
R 1Be:
-C 1To C 6Alkyl, it is replaced by following groups:
-randomly by C 1To C 6The amido that alkyl replaces; And/or
-five yuan or six membered heteroaryl;
-C 1To C 6Alkoxyl group, it is replaced by following groups:
-randomly heterocyclically substituted amino;
-randomly by C 1To C 6The amido that alkyl replaces;
-five yuan or hexa-member heterocycle, it is randomly by C 1To C 6Alkyl replaces; And/or
-five yuan or six membered heteroaryl;
-(O)-five yuan or hexa-member heterocycle;
-(O)-five yuan or six membered heteroaryl;
-SO 2R x, it is randomly replaced by following groups:
-five yuan or hexa-member heterocycle;
-C 6To C 8Aryl; And/or
-five yuan or six membered heteroaryl; Or
-alkylthio, it is randomly replaced by following groups:
-five yuan or hexa-member heterocycle;
-C 6To C 8Aryl; And/or
-five yuan or six membered heteroaryl;
14. compound as claimed in claim 1, wherein:
R 2Be:
-C 1To C 6Alkyl, it is replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or hexa-member heterocycle;
-five yuan or six membered heteroaryl;
-C 6To C 8Aryl;
-randomly by C 1To C 6The amido that alkyl replaces; And
-amino, it is randomly replaced by one or more substituting groups that are independently selected from heterocycle, alkoxyl group and alkyl, and described alkyl is randomly replaced by one or more alkoxyl groups;
-alkylthio, randomly by five yuan or six membered heteroaryl replacement, described heteroaryl is randomly replaced by alkyl for it;
-alkylthio, it is randomly by five yuan or hexa-member heterocycle replacement;
-alkylthio, it is randomly by C 6To C 8Aryl replaces;
-alkylthio, it is randomly by C 1To C 6Alkyl replaces;
-SO 2R x, randomly by five yuan or six membered heteroaryl replacement, described heteroaryl is randomly by one or more C for they 1To C 6Alkyl replaces;
-SO 2R x, it is randomly by five yuan or hexa-member heterocycle replacement;
-SO 2R x, it is randomly by C 6To C 8Aryl replaces;
-SO 2R x, it is randomly by C 1To C 6Alkyl replaces;
-S (O) R x, it is randomly by five yuan or six membered heteroaryl replacement;
-S (O) R x, it is randomly by five yuan or hexa-member heterocycle replacement;
-S (O) R x, it is randomly by C 6To C 8Aryl replaces;
-S (O) R x, it is randomly by C 1To C 6Alkyl replaces;
-alkoxyl group, it is replaced by following groups:
-alkoxyl group;
-amino, it is replaced by one or more substituting groups that are independently selected from five yuan or six membered heteroaryl, five yuan or hexa-member heterocycle and alkyl, and described alkyl is randomly replaced by one or more substituting groups that are selected from following groups:
-five yuan or hexa-member heterocycle; And
-the amino that randomly replaced by one or more alkyl;
-randomly by C 1To C 6The amido that alkyl replaces;
Five yuan of-S-or hexa-member heterocycle;
Five yuan of-S-or six membered heteroaryl, it is randomly by C 1To C 6Alkyl replaces;
-S-C 1To C 6Alkyl;
-S-C 6To C 8Aryl;
-sulfinyl-five yuan or hexa-member heterocycle;
-sulfinyl-five yuan or six membered heteroaryl;
-sulfinyl-C 1To C 6Alkyl;
-sulfinyl-C 6To C 8Aryl;
-alkylsulfonyl-five yuan or hexa-member heterocycle;
-alkylsulfonyl-randomly by C 1To C 6Five yuan or six membered heteroaryl that alkyl replaces;
-alkylsulfonyl-C 1To C 6Alkyl;
-alkylsulfonyl-C 6To C 8Aryl;
-five yuan to seven membered heterocyclic, and it is by one or more hydroxyl and C of being independently selected from 1To C 6The substituting group of alkyl replaces, and described alkyl is by C 1To C 6Alkoxyl group replaces;
-five yuan or six membered heteroaryl, it is by one or more C 1To C 6Alkyl replaces; Or
-C 6To C 8Aryl;
-C (O)-five yuan or hexa-member heterocycle, it is randomly by one or more C 6To C 8Aryl replaces;
-C (O)-C 6To C 8Aryl;
-five yuan or hexa-member heterocycle, it is replaced by one or more substituting groups that are independently selected from down group:
-hydroxyl;
-C 1To C 6Alkyl;
-SO 2R x；
-C (O)-C 6To C 8Aryl; And
-C(O)OR x；
-OR Kk, R wherein KkBe:
-C 6To C 8Aryl;
-five yuan or hexa-member heterocycle, it is randomly by C 1To C 6Alkyl and/or C 6To C 8Aryl replaces; Or
-Si(R x) 3；
-(O)-five yuan or hexa-member heterocycle; Or
-(O)-five yuan or six membered heteroaryl, it is randomly by one or more C that select independently 1To C 6Alkyl replaces.
15. compound as claimed in claim 1, wherein:
X is:
-cyano group;
-halogen, or
-alkynyl, it is randomly by C 1To C 6Alkyl replaces;
Y is:
-C 6To C 8Aryl, it is replaced by one or more substituting groups that are independently selected from following groups:
-halogen;
-hydroxyl;
-alkoxyl group, it is randomly replaced by following groups:
-one or more halogens; Or
-five yuan or hexa-member heterocycle;
-C 1To C 6Alkyl;
-amino, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-SO 2R xAnd
-C 1To C 6Alkyl, it is replaced by one or more five yuan or six membered heteroaryl randomly and independently;
-OC(O)NHR x；
-NR oCOR p, R wherein pBe:
-C 1To C 6Alkyl; Or
-randomly by one or more C 1To C 6The amino that alkyl replaces;
And R wherein oBe hydrogen;
-NR qCONR qR r, R wherein qBe hydrogen, and R rBe:
-the C that randomly replaced by one or more halogens 1To C 6Alkyl; Or
-C 6To C 8Aryl, it is randomly replaced by halogen;
-SO 2R Aa, R wherein AaBe:
-five yuan or hexa-member heterocycle, it is randomly replaced by hydroxyl;
Or
-C 1To C 6Alkyl;
-COR m, R wherein mBe:
-randomly by one or more C 1To C 6The amino that alkyl replaces, wherein this C 1To C 6Alkyl is randomly by five yuan or hexa-member heterocycle replacement; Or
-ternary is to seven membered heterocyclic, and it is randomly by C 1To C 6Alkyl replaces, and described alkyl is randomly replaced by dialkyl-7-amino;
-NR tCOOR u, R wherein tBe hydrogen, and R uBe:
-C 1To C 12Alkyl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-C 6To C 8Aryl, it is randomly replaced by one or more halogens and/or alkylhalide group;
-halogen; And
-five yuan or six membered heteroaryl;
-C 6To C 8Aryl, it is randomly replaced by halogen; Or
-five yuan or hexa-member heterocycle;
-NHR Bb, R wherein BbBe:
-C (=S) NH 2Or
-PO(OR x) 2；
-NR vSO 2R w, R wherein vBe hydrogen, and R wBe:
-C 1To C 6Alkyl; Or
-alkyl-amino or dialkyl-7-amino, it is randomly replaced by halogen; Or
Figure A20078000890207121
Z is:
-C 1To C 6Alkyl;
R is a hydrogen;
R 1Be:
-hydrogen;
-C 1To C 6Alkoxyl group, it is replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or hexa-member heterocycle; And
-five yuan or six membered heteroaryl;
-(O)-five yuan or hexa-member heterocycle;
-(O)-five yuan or six membered heteroaryl; Or
-five yuan or hexa-member heterocycle;
R 2Be:
-alkoxyl group, it is replaced by one or more substituting groups that are independently selected from following groups:
-halogen;
-hydroxyl;
-the alkoxyl group that replaces of alkoxy randomly;
-amino, it is randomly replaced by one or more substituting groups that are independently selected from five yuan or six membered heteroaryl, five yuan or hexa-member heterocycle and alkyl, and described alkyl is randomly replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or hexa-member heterocycle; And
-the amino that randomly replaced by one or more alkyl;
-randomly by C 1To C 6The amido that alkyl replaces;
Five yuan of-S-or six membered heteroaryl, it is randomly by C 1To C 6Alkyl replaces;
-S-C 1To C 6Alkyl;
-sulfinyl-C 1To C 6Alkyl;
-alkylsulfonyl-C 1To C 6Alkyl;
-five yuan to seven membered heterocyclic, randomly by one or more hydroxyl and C of being independently selected from 1To C 6The substituting group of alkyl replaces, and described alkyl is randomly by one or more C that select independently 1To C 6Alkoxyl group replaces; And
-five yuan or six membered heteroaryl, it is randomly by one or more C 1To C 6Alkyl replaces;
-SO 2R x, it is randomly by C 1To C 6Alkyl replaces;
-S (O) R x, it is randomly by C 1To C 6Alkyl replaces;
-(O)-five yuan or six membered heteroaryl, it is randomly by one or more C that select independently 1To C 6Alkyl replaces;
-C (O)-five yuan or hexa-member heterocycle, it is randomly by one or more C 6To C 8Aryl replaces;
-C (O)-C 6To C 8Aryl;
Randomly replaced by one or more substituting groups that are independently selected from down group:
-C 1To C 6Alkyl; And
-five yuan or hexa-member heterocycle, it is randomly replaced by one or more substituting groups that are independently selected from down group:
-one or more halogens;
-C 1To C 6Alkyl; And
-SO 2R x；
-OR Kk, R wherein KkBe:
-five yuan or six membered heteroaryl, it is randomly by one or more halogen, C of being independently selected from 1To C 6Alkyl, C 1To C 6Alkoxyl group and C 1To C 6The substituting group of alkylhalide group replaces; Or
-five yuan or hexa-member heterocycle, it is randomly by C 1To C 6Alkyl replaces, and described alkyl is randomly by C 6To C 8Aryl replaces; And
R 3Be hydrogen.
16. compound as claimed in claim 15, wherein:
X is:
-cyano group; Or
-halogen;
Y is:
-phenyl, it is replaced by one or more substituting groups that are independently selected from following groups:
-halogen; And
-NR tCOOR u, R wherein tBe hydrogen, and R uBe:
-C 1To C 12Alkyl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-C 6To C 8Aryl, it is randomly replaced by one or more halogens;
-halogen; And
-five yuan or six membered heteroaryl;
-C 6To C 8Aryl, it is randomly replaced by halogen; Or
-five yuan or hexa-member heterocycle;
Z is C 1To C 6Alkyl;
R is a hydrogen;
R 1Be hydrogen;
R 2Be:
-alkoxyl group, it is replaced by one or more substituting groups that are independently selected from following groups:
-halogen; And
-the alkoxyl group that replaces of alkoxy randomly;
-(O)-five yuan or hexa-member heterocycle;
-amido, it is randomly by one or more C 1To C 6Alkyl replaces, and described alkyl is randomly by one or more C 1To C 6Alkoxyl group replaces;
-five yuan or hexa-member heterocycle, it is randomly replaced by one or more substituting groups that are independently selected from down group:
-one or more halogens;
-C 1To C 6Alkyl; And
-SO 2R xAnd
R 3Be hydrogen.
17. compound as claimed in claim 15, wherein:
X is a cyano group;
Y is C 6To C 8Aryl, it is by one or more NR that are independently selected from tCOOR uSubstituting group replace, wherein be hydrogen,
And R uBe randomly by one or more C 6To C 8The C that aryl replaces 1To C 12Alkyl;
Z is five yuan or hexa-member heterocycle;
R is a hydrogen;
R 1Be hydrogen;
R 2It is alkoxyl group; And
R 3Be hydrogen.
18. compound as claimed in claim 15, wherein:
X is a cyano group;
Y is C 6To C 8Aryl, it is replaced by one or more substituting groups that are independently selected from following groups:
-randomly by C 1To C 6The amino that alkyl replaces;
-NR qCONR qR r, R wherein qBe hydrogen, and R rBe C 1To C 6Alkyl:
-COR m, R wherein mBe:
-randomly by one or more C 1To C 6The amino that alkyl replaces, wherein said C 1To C 6Alkyl is randomly by five yuan or hexa-member heterocycle replacement; Or
-ternary is to seven membered heterocyclic; And
-NR tCOOR u, R wherein tBe hydrogen, and R uBe:
-C 1To C 12Alkyl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-C 6To C 8Aryl, it is randomly replaced by one or more alkylhalide groups; And
-halogen, or
-five yuan or hexa-member heterocycle;
Z is C 1To C 6Alkyl;
R is a hydrogen;
R 1Be hydrogen;
R 2It is the alkoxyl group that alkoxy replaces; And
R 3Be hydrogen.
19. compound as claimed in claim 15, wherein:
X is a cyano group;
Y is C 6To C 8Aryl, it is replaced by one or more substituting groups that are independently selected from following groups:
-NR tCOOR u, R wherein tBe hydrogen, and R uThe C that is replaced by one or more halogens 1To C 12Alkyl;
And
-NR vSO 2R w, R wherein vBe hydrogen, and R wBe C 1To C 6Alkyl;
Z is C 1To C 6Alkyl;
R is a hydrogen;
R 1Be hydrogen;
R 2Be amido, it is randomly by one or more C 1To C 6Alkyl replaces, and described alkyl is by one or more C 1To C 6Alkoxyl group replaces; And
R 3Be hydrogen.
20. compound as claimed in claim 15, wherein:
X is a cyano group;
Y is C 6To C 8Aryl, it is replaced by one or more substituting groups that are independently selected from following groups:
-randomly by one or more C 1To C 6The amino that alkyl replaces;
-NR tCOOR u, R wherein tBe hydrogen, and R uThe C that is replaced by one or more halogens 1To C 12Alkyl;
-NR vSO 2R w, R wherein vBe hydrogen, and R wBe C 1To C 6Alkyl; And
Figure A20078000890207161
Z is C 1To C 6Alkyl;
R is a hydrogen;
R 1Be hydrogen;
R 2By alkylsulfonyl-C 1To C 6The alkoxyl group that alkyl replaces; And
R 3Be hydrogen.
21. compound as claimed in claim 15, wherein Y is C 6To C 8Aryl, it is by one or more NR that are independently selected from tCOOR uSubstituting group replace R wherein tBe hydrogen, and R uThe C that is replaced by one or more halogens 1To C 12Alkyl.
22. compound as claimed in claim 15, wherein:
X is a cyano group;
Y is C 6To C 8Aryl, it is replaced by one or more substituting groups that are independently selected from following groups:
-C 1To C 6Alkyl;
-randomly by one or more C 1To C 6The amino that alkyl replaces;
-NR qCONR qR r, R wherein qBe hydrogen, and R rBe C 1To C 6Alkyl:
-NR tCOOR u, R wherein tBe hydrogen, and R uBe C 1To C 12Alkyl;
-NR vSO 2R w, R wherein vBe hydrogen, and R wBe:
-C 1To C 6Alkyl; Or
-alkyl-amino or dialkyl-7-amino;
Z is C 1To C 6Alkyl;
R is a hydrogen;
R 1Be hydrogen;
R 2Be OR Kk, R wherein KkBe five yuan or six membered heteroaryl, it is randomly by one or more halogen, C of being independently selected from 1To C 6Alkyl, C 1To C 6Alkoxyl group and C 1To C 6The substituting group of alkylhalide group replaces; And
R 3Be hydrogen.
23. compound as claimed in claim 22, wherein:
X is a cyano group;
Y is C 6To C 8Aryl, it is replaced by one or more substituting groups that are independently selected from following groups:
-NR tCOOR u, R wherein tBe hydrogen, and R uBe C 1To C 12Alkyl; And
-NR vSO 2R w, R wherein vBe hydrogen, and R wBe:
-C 1To C 6Alkyl; Or
-alkyl-amino or dialkyl-7-amino;
Z is C 1To C 6Alkyl;
R is a hydrogen;
R 1Be hydrogen;
R 2Be OR Kk, R wherein KkBe five yuan or six membered heteroaryl, it is randomly by one or more halogen, C of being independently selected from 1To C 6Alkyl, C 1To C 6Alkoxyl group and C 1To C 6The substituting group of alkylhalide group replaces; And R 3Be hydrogen.
24. compound as claimed in claim 22, wherein R 2Be OR Kk, R wherein KkBy one or more C 1To C 6Five yuan or six membered heteroaryl that alkylhalide group replaces.
25. compound as claimed in claim 22, wherein R 2Be OR Kk, R wherein KkBy one or more C 1To C 6Five yuan or six membered heteroaryl that alkyl replaces.
26. compound as claimed in claim 1, wherein:
X is a cyano group;
Y is C 6To C 8Aryl, it is replaced by one or more substituting groups that are independently selected from following groups:
-NR tCOOR u, R wherein tBe hydrogen, and R uBe C 1To C 12Alkyl; And
-NR vSO 2R w, R wherein vBe hydrogen, and R wBe C 1To C 6Alkyl;
Z is C 1To C 6Alkyl;
R is a hydrogen;
R 1Be hydrogen;
R 2Be C (O)-five yuan or hexa-member heterocycle; And
R 3Be hydrogen.
27. compound as claimed in claim 1, wherein:
X is a halogen;
Y is C 6To C 8Aryl, it is replaced by one or more substituting groups that are independently selected from following groups:
-amino;
-NR qCONR qR r, R wherein qBe hydrogen, and R rBe C 1To C 6Alkyl; And
-NR tCOOR u, R wherein tBe hydrogen, and R uBe C 1To C 12Alkyl;
Z is C 1To C 6Alkyl;
R is a hydrogen;
R 1Be hydrogen;
R 2It is alkoxyl group; And
R 3Be hydrogen.
28 compounds as claimed in claim 15, wherein:
X is a cyano group;
Y is C 6To C 8Aryl, it is replaced by one or more substituting groups that are independently selected from following groups:
-halogen;
-NR qCONR qR r, R wherein qBe hydrogen, and R rBe C 1To C 6Alkyl:
-NR tCOOR u, R wherein tBe hydrogen, and R uBe C 1To C 12Alkyl, this alkyl are randomly replaced by one or more substituting groups that are independently selected from following groups:
-C 6To C 8Aryl, it is randomly replaced by one or more halogens; And
-halogen;
-NR vSO 2R w, R wherein vBe hydrogen, and R wBe:
-C 1To C 6Alkyl; Or
-alkyl-amino or dialkyl-7-amino, it is randomly replaced by halogen; And
Figure A20078000890207191
Z is C 1To C 6Alkyl;
R is a hydrogen;
R 1Be hydrogen;
R 2Be five yuan or hexa-member heterocycle; And
R 3Be hydrogen.
29. compound as claimed in claim 28, wherein Y is by NR vSO 2R wThe C that replaces 6To C 8Aryl, wherein R vBe hydrogen, and R wBe C 1To C 6Alkyl.
30. compound as claimed in claim 28, the wherein C that replaced by following formula of Y 6To C 8Aryl:
Figure A20078000890207192
31. compound as claimed in claim 15, wherein:
X is a cyano group;
Y is C 6To C 8Aryl, it is replaced by one or more substituting groups that are independently selected from following groups:
-halogen;
-randomly by one or more C 1To C 6The amino that alkyl replaces;
-OC(O)NHR x；
-NR qCONR qR r, R wherein qBe hydrogen, and R rBe C 1To C 6Alkyl:
-NR tCOOR u, R wherein tBe hydrogen, and R uBe C 1To C 12Alkyl, this alkyl are randomly replaced by one or more substituting groups that are independently selected from following groups:
-C 6To C 8Aryl, it is randomly replaced by one or more halogens and/or alkylhalide group; And
-halogen;
-NHR Bb, R wherein BbBe-C (=S) NH 2
-NR vSO 2R w, R wherein vBe hydrogen, and R wBe:
-C 1To C 6Alkyl; Or
-alkyl-amino or dialkyl-7-amino, it is randomly replaced by halogen; And
Z is C 1To C 6Alkyl;
R is a hydrogen;
R 1Be hydrogen;
R 2Be (O)-five yuan or hexa-member heterocycle; And
R 3Be hydrogen.
32. compound as claimed in claim 31, wherein Y is by NR tCOOR uThe C that replaces 6To C 8Aryl, wherein R tBe hydrogen, and R uBe randomly to be independently selected from randomly by the C of one or more halogens and/or alkylhalide group replacement by one or more 6To C 8The C that the substituting group of aryl replaces 1To C 12Alkyl.
33. compound as claimed in claim 15, wherein:
X is a cyano group;
Y is C 6To C 8Aryl, it is by one or more NR that are independently selected from tCOOR uSubstituting group replace R wherein tBe hydrogen, and R uThe C that is replaced by one or more halogens 1To C 12Alkyl;
Z is C 1To C 6Alkyl;
R is a hydrogen;
R 1Be
-hydrogen;
-(O)-five yuan or hexa-member heterocycle; Or
-five yuan or hexa-member heterocycle;
R 2Be:
-alkoxyl group, it is replaced by one or more substituting groups that are independently selected from following groups:
-halogen;
-alkoxyl group;
-alkylsulfonyl-C 1To C 6Alkyl;
-five yuan to seven membered heterocyclic;
-five yuan or six membered heteroaryl;
-(O)-five yuan or hexa-member heterocycle;
-(O)-five yuan or six membered heteroaryl;
-five yuan or six membered heteroaryl;
-five yuan or hexa-member heterocycle; Or
-OR Kk, R wherein KkBe randomly by one or more C 1To C 6Five yuan or six membered heteroaryl that alkoxyl group replaces; And
R 3Be hydrogen.
34. compound as claimed in claim 33, wherein R 1Be hydrogen, and R 2The alkoxyl group that is replaced by one or more halogens.
35. compound as claimed in claim 33, wherein R 1Be hydrogen, and R 2The alkoxyl group that is replaced by one or more alkoxyl groups.
36. compound as claimed in claim 15, wherein:
X is a cyano group;
Y is C 6To C 8Aryl, it is replaced by one or more substituting groups that are independently selected from following groups:
-NR qCONR qR r, R wherein qBe hydrogen, and R rThe C that is replaced by halogen 6To C 8Aryl; And
-NR tCOOR u, R wherein tBe hydrogen, and R uBy C 6To C 8The C that aryl replaces 1To C 12Alkyl, described aryl is replaced by one or more halogens and/or alkylhalide group;
Z is C 1To C 6Alkyl;
R is a hydrogen;
R 1Be hydrogen;
R 2Be;
-alkoxyl group, it is replaced by one or more substituting groups that are independently selected from following groups:
-alkoxyl group; And
-five yuan or six membered heteroaryl;
-(O)-five yuan or hexa-member heterocycle; Or
-(O)-five yuan or six membered heteroaryl; And
R 3Be hydrogen.
37. compound as claimed in claim 36, wherein Y is by NR qCONR qR rThe C that replaces 6To C 8Aryl, wherein R qBe hydrogen, and R rThe C that is replaced by halogen 6To C 8Aryl.
38. compound as claimed in claim 36, wherein Y is by one or more NR that are independently selected from tCOOR uThe C that replaces of substituting group 6To C 8Aryl, wherein R tBe hydrogen, and R uBy C 6To C 8The C that aryl replaces 1To C 12Alkyl, described aryl is replaced by one or more halogens and/or alkylhalide group.
39. formula IIb compound
Figure A20078000890207221
Or the acceptable salt of its pharmacology, wherein:
X is a cyano group;
Y is C 6To C 8Aryl, it is replaced by one or more substituting groups that are independently selected from following groups:
-C 1To C 6Alkyl;
-by C 1To C 6The amino that alkyl replaces;
-NR tCOOR u, R wherein tBe hydrogen, and R uBe the C that is randomly replaced by one or more halogens 1To C 12Alkyl;
-NR vSO 2R w, R wherein vBe hydrogen, and R wBe C 1To C 6Alkyl;
Z is C 1To C 6Alkyl;
R is a hydrogen;
R 1Be hydrogen;
R 2Be:
-the alkoxyl group that replaced by one or more halogens;
-five yuan or hexa-member heterocycle;
-five yuan or six membered heteroaryl, it is randomly replaced by one or more substituting groups that are independently selected from down group:
-C 1To C 6Alkyl; And
-NO 2；
-C (O)-ternary to seven membered heterocyclic or-C (O)-five-membered ring; And
-OR Kk, R wherein KkBe:
-five yuan or six membered heteroaryl, it is randomly by one or more cyano group and C of being independently selected from 1To C 6The substituting group of alkyl replaces; Or
-five yuan or hexa-member heterocycle, it is randomly replaced by one or more=O; And
R 3Be hydrogen.
40. compound as claimed in claim 39, wherein:
X is a cyano group;
Y is C 6To C 8Aryl, it is by NR tCOOR uReplace, wherein R tBe hydrogen, and R uThe C that is replaced by one or more halogens 1To C 12Alkyl;
Z is C 1To C 6Alkyl;
R is a hydrogen;
R 1Be hydrogen;
R 2The alkoxyl group that is replaced by one or more halogens; And
R 3Be hydrogen.
41. compound as claimed in claim 40, wherein C 6To C 8Aryl is a phenyl.
42. compound as claimed in claim 41, wherein said phenyl is to be substituted in contraposition.
43. compound as claimed in claim 41, wherein R uThe C that is replaced by fluorine 1To C 12Alkyl.
44. compound as claimed in claim 39, wherein:
X is a cyano group;
Y is C 6To C 8Aryl, it is replaced by one or more substituting groups that are independently selected from following groups:
-C 1To C 6Alkyl;
-by C 1To C 6The amino that alkyl replaces; And
-NR vSO 2R w, R wherein vBe hydrogen, and R wBe C 1To C 6Alkyl;
Z is C 1To C 6Alkyl;
R is a hydrogen;
R 1Be hydrogen;
R 2Be OR Kk, R wherein KkFive yuan or six membered heteroaryl being replaced by cyano group; And
R 3Be hydrogen.
45. compound as claimed in claim 44, wherein Y is that contraposition is by NR vSO 2R wThe C that replaces 6To C 8Aryl, R wherein vBe hydrogen, R wBe C 1To C 6Alkyl.
46. compound as claimed in claim 44, wherein Y is that contraposition is by C 1To C 6Alkyl and NR vSO 2R wThe C that replaces 6To C 8Aryl, wherein R vBe hydrogen, and R wBe C 1To C 6Alkyl.
47. compound as claimed in claim 44, wherein Y is the C that contraposition is replaced by amino 6To C 8Aryl, this amino is by C 1To C 6Alkyl replaces.
48. compound as claimed in claim 44, wherein R 2Be OR Kk, R wherein KkBe five yuan or the six membered heteroaryl that the ortho position is replaced by cyano group.
49. compound as claimed in claim 39, wherein:
X is a cyano group;
Y is C 6To C 8Aryl, it is replaced by one or more substituting groups that are independently selected from following groups:
-NR tCOOR u, R wherein tBe hydrogen, and R uBe C 1To C 12Alkyl; And
-NR vSO 2R w, R wherein vBe hydrogen, and R wBe C 1To C 6Alkyl;
Z is C 1To C 6Alkyl;
R is a hydrogen;
R 1Be hydrogen;
R 2Be OR Kk, R wherein KkBy C 1To C 6Five yuan or six membered heteroaryl that alkyl replaces; And
R 3Be hydrogen.
50. compound as claimed in claim 49, wherein said C 6To C 8Aryl is a phenyl.
51. compound as claimed in claim 50, wherein Y is that contraposition is by NR vSO 2R wThe phenyl that replaces, wherein R vBe hydrogen, and R wBe C 1To C 6Alkyl.
52. compound as claimed in claim 50, wherein Y is that contraposition is by NR tCOOR uThe phenyl that replaces, wherein R tBe hydrogen, and R uBe C 1To C 12Alkyl.
53. compound as claimed in claim 39, wherein:
X is a cyano group;
Y is C 6To C 8Aryl, it is by NR tCOOR uReplace, wherein R tBe hydrogen, and R uThe C that is replaced by one or more halogens 1To C 12Alkyl;
Z is C 1To C 6Alkyl;
R is a hydrogen;
R 1Be hydrogen;
R 2Be OR Kk, R wherein KkBe five yuan or six membered heteroaryl; And
R 3Be hydrogen.
54. compound as claimed in claim 53, wherein said C 6To C 8Aryl is a phenyl.
55. compound as claimed in claim 54, wherein said phenyl is to be substituted in contraposition.
56. compound as claimed in claim 55, wherein R uThe C that is replaced by fluorine 1To C 12Alkyl.
57. compound as claimed in claim 39, wherein:
X is a cyano group;
Y is by NR tCOOR uThe C that replaces 6To C 8Aryl, wherein R tBe hydrogen, and R uBe the C that is randomly replaced by one or more halogens 1To C 12Alkyl;
Z is C 1To C 6Alkyl;
R is a hydrogen;
R 1Be hydrogen;
R 2Be five yuan or six membered heteroaryl, it is randomly by C 1To C 6Alkyl replaces; And
R 3Be hydrogen.
58. compound as claimed in claim 57, wherein said C 6To C 8Aryl is a phenyl.
59. compound as claimed in claim 58, wherein Y is that contraposition is by NR tCOOR uThe phenyl that replaces, wherein R tBe hydrogen, and R uBe C 1To C 12Alkyl.
60. compound as claimed in claim 58, wherein Y is that contraposition is by NR tCOOR uThe phenyl that replaces, wherein R tBe hydrogen, and R uThe C that is replaced by one or more halogens 1To C 12Alkyl.
61. compound as claimed in claim 60, wherein R uThe C that is replaced by fluorine 1To C 12Alkyl.
62. compound as claimed in claim 39, wherein:
X is a cyano group;
Y is by NR tCOOR uThe C that replaces 6To C 8Aryl, wherein R tBe hydrogen, and R uBe C 1To C 12Alkyl;
Z is C 1To C 6Alkyl;
R is a hydrogen;
R 1Be hydrogen;
R 2Be OR Kk, R wherein KkBe five yuan or hexa-member heterocycle; And
R 3Be hydrogen.
63. compound as claimed in claim 62, wherein said C 6To C 8Aryl is a phenyl.
64. as the described compound of claim 63, wherein said phenyl is to be substituted in contraposition.
65. compound as claimed in claim 39, wherein:
X is a cyano group;
Y is by NR tCOOR uThe C that replaces 6To C 8Aryl, wherein R tBe hydrogen, and R uBe C 1To C 12Alkyl;
Z is C 1To C 6Alkyl;
R is a hydrogen;
R 1Be hydrogen;
R 2Be five yuan or hexa-member heterocycle; And
R 3Be hydrogen.
66. as the described compound of claim 65, wherein said C 6To C 8Aryl is a phenyl.
67. as the described compound of claim 66, wherein said phenyl is to be substituted in contraposition.
68. compound as claimed in claim 39, wherein:
X is a cyano group;
Y is by NR tCOOR uThe C that replaces 6To C 8Aryl, wherein R tBe hydrogen, and R uBe C 1To C 12Alkyl;
Z is C 1To C 6Alkyl;
R is a hydrogen;
R 1Be hydrogen;
R 2By NO 2Five yuan or six membered heteroaryl replacing; And
R 3Be hydrogen.
69. as the described compound of claim 68, wherein said C 6To C 8Aryl is a phenyl.
70. as the described compound of claim 69, wherein said phenyl is to be substituted in contraposition.
71. compound as claimed in claim 39, wherein:
X is a cyano group;
Y is by NR tCOOR uThe C that replaces 6To C 8Aryl, wherein R tBe hydrogen, and R uBe C 1To C 12Alkyl;
Z is C 1To C 6Alkyl;
R is a hydrogen;
R 1Be hydrogen;
R 2Be-C (O)-ternary to seven membered heterocyclic or-C (O)-five-membered ring; And
R 3Be hydrogen.
72. as the described compound of claim 71, wherein said C 6To C 8Aryl is a phenyl.
73. as the described compound of claim 72, wherein said phenyl is to be substituted in contraposition.
74. compound as claimed in claim 39, wherein:
X is a cyano group;
Y is by NR tCOOR uThe C that replaces 6To C 8Aryl, wherein R tBe hydrogen, and R uBe C 1To C 12Alkyl;
Z is C 1To C 6Alkyl;
R is a hydrogen;
R 1Be hydrogen;
R 2Be OR Kk, R wherein KkBy five yuan or hexa-member heterocycle of one or more=O replacement; And
R 3Be hydrogen.
75. as the described compound of claim 74, wherein said C 6To C 8Aryl is a phenyl.
76. as the described compound of claim 75, wherein said phenyl is to be substituted in contraposition.
77. formula IIc compound
Figure A20078000890207281
Or the acceptable salt of its pharmacology, wherein:
X is a cyano group;
Y is C 6To C 8Aryl, it is replaced by one or more substituting groups that are independently selected from following groups:
-NR qCONR qR r, R wherein qBe hydrogen, and R rBe C 1To C 6Alkyl:
-NR tCOOR u, R wherein tBe hydrogen, and R uBe C 1To C 12Alkyl, this alkyl are randomly replaced by one or more substituting groups that are independently selected from following groups:
-C 6To C 8Aryl, it is randomly replaced by one or more halogens;
-halogen; And
-five yuan or six membered heteroaryl; And
-NR vSO 2R w, R wherein vBe hydrogen, and R wBe C 1To C 6Alkyl;
Z is:
-C 1To C 6Alkyl; Or
-five yuan or hexa-member heterocycle;
R is a hydrogen;
R 1Be:
-C 1To C 6Alkoxyl group, it is replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or hexa-member heterocycle; And
-five yuan or six membered heteroaryl;
-(O)-five yuan or hexa-member heterocycle;
-(O)-five yuan or six membered heteroaryl; Or
-five yuan or hexa-member heterocycle;
R 2Be hydrogen; And
R 3Be hydrogen;
Condition is to work as R 1The C that is replaced by five yuan or hexa-member heterocycle 1To C 6Alkoxyl group or R 1When being five yuan or hexa-member heterocycle, Y is by NR tCOOR uThe C that replaces 6To C 8Aryl, wherein R tBe hydrogen, and R uBe:
The C that is replaced by one or more halogens 1To C 12Alkyl; Or
The aryl that is replaced by one or more halogens.
78. as the described compound of claim 77, wherein:
Y is by NR tCOOR uThe C that replaces 6To C 8Aryl, wherein R tBe hydrogen, and R uBe C 1To C 12Alkyl;
Z is C 1To C 6Alkyl; And
R 1The C that is replaced by five yuan or six membered heteroaryl 1To C 6Alkoxyl group.
79. as the described compound of claim 77, wherein R 1The C that is replaced by five yuan or six membered heteroaryl 1To C 6Alkoxyl group.
80. as the described compound of claim 77, wherein R 1Be (O)-five yuan or hexa-member heterocycle.
81. as the described compound of claim 77, wherein R 1Be (O)-five yuan or six membered heteroaryl.
82. as the described compound of claim 77, wherein Z is cyclobutyl, cyclopropyl, cyclopropyl methyl, ethyl or cyclopentyl.
83. the compound of formula IId
Figure A20078000890207291
Or the acceptable salt of its pharmacology, wherein:
X is a hydrogen;
Y is C 6To C 8Aryl, it is replaced by one or more substituting groups that are independently selected from following groups:
-NR qCONR qR r, R wherein qBe hydrogen, and R rBe C 1To C 6Alkyl; And
-NR tCOOR u, R wherein tBe hydrogen, and R uThe C that is replaced by one or more halogens 1To C 12Alkyl;
Z is C 1To C 6Alkyl;
R is a hydrogen;
R 1Be hydrogen;
R 2Be OR Kk, R wherein KkBe:
-five yuan or six membered heteroaryl;
-five yuan or hexa-member heterocycle; Or
-five yuan or six membered heteroaryl, it is randomly replaced by one or more halogens of selecting independently; And R 3Be hydrogen.
84. as the described compound of claim 83, wherein:
X is a hydrogen;
Y is C 6To C 8Aryl, it is by NR tCOOR uReplace, wherein R tBe hydrogen, and R uThe C that is replaced by one or more halogens 1To C 12Alkyl;
Z is C 1To C 6Alkyl;
R is a hydrogen;
R 1Be hydrogen;
R 2Be OR Kk, R wherein KkBe five yuan or six membered heteroaryl; And
R 3Be hydrogen.
85. as the described compound of claim 84, wherein said C 6To C 8Aryl is a phenyl.
86. as the described compound of claim 84, wherein Y is that contraposition is by NR tCOOR uThe phenyl that replaces, wherein R tBe hydrogen, and R uThe C that is replaced by fluorine 1To C 12Alkyl.
87. as the described compound of claim 84, wherein Z is cyclobutyl, cyclopropyl, cyclopropyl methyl, ethyl or cyclopentyl.
88. as the described compound of claim 83, wherein R 2Be (O)-five yuan or hexa-member heterocycle.
89. the compound of formula IIe
Figure A20078000890207301
Or the acceptable salt of its pharmacology, wherein:
X is:
-hydrogen;
-cyano group;
-nitro;
-formyl radical;
-COOH；
-COR x, R wherein xBe C 1To C 6Alkyl;
-CH=N-(C 1To C 6Alkoxyl group);
-CH=N-is (randomly by one or more C 1To C 6The amino that alkyl replaces);
-halogen;
-the alkyl that randomly replaced by one or more halogens;
-optional by cyano or C 1To C 6The alkynyl that alkyl replaces, described alkyl is randomly replaced by one or more halogens;
-oximido;
-SO 2R x；
-SO 2NH 2；
-SO 2NH(R x)；
-SO 2N(R x) 2；
-amino, it is randomly by one or more C that select independently 1To C 6Alkyl and/or-C (O)-C 1To C 6Alkyl replaces;
-amido, it is randomly by one or more C that select independently 1To C 6Alkyl replaces;
-five yuan or hexa-member heterocycle;
-five yuan or six membered heteroaryl, it is randomly by one or more C 1To C 6Alkyl replaces, and described alkyl is randomly replaced by one or more halogens; Or
-C 6To C 8Aryl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-C 1To C 6Alkyl, it is randomly replaced by one or more halogens;
-halogen; And
-cyano group;
Y is:
-the benzothiazolyl that randomly replaced by amino, described amino is randomly by one or more C 1To C 6Alkyl replaces;
-indyl, it is randomly at the quilt-SO of nitrogen-atoms place 2R xReplace;
-C 6To C 8Aryl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-halogen;
-C 1To C 6Alkyl;
-alkoxyl group, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-halogen;
-five yuan or hexa-member heterocycle;
-C (O) NH 2, it is randomly by C 6To C 8Alkyl replaces;
-C (O) NH-(C 1To C 6)-alkyl;
-hydroxyl;
-alkylhalide group;
-cyano group;
-nitro;
-COOH；
-N＝CHN(R x) 2；
-amino, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-SO 2R x；
-hexa-atomic to eight yuan of aryl, it is randomly by one or more alkyl, halogen, alkylhalide group, cyano group, alkoxyl group, COR of being independently selected from xReplace with the substituting group of halogen alkoxyl group;
-five yuan or six membered heteroaryl, it is randomly by one or more alkyl, halogen, alkylhalide group, cyano group, alkoxyl group, halogen alkoxyl group and C of being independently selected from 6To C 8The substituting group of aryl replaces, wherein this C 6To C 8Aryl is randomly replaced by halogen;
-five yuan or hexa-member heterocycle, its randomly by one or more be independently selected from hydroxyl ,=substituting group of O, alkyl and alkylhalide group replaces;
-C 1To C 7Alkyl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or six membered heteroaryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, halogen and alkylhalide group;
-C 6To C 8Aryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, halogen and alkylhalide group;
-alkoxyl group; And
-halogen; And
-PO 2R x；
-OC (O) NHR x, R wherein xRandomly by vinyl substituted;
-OC (O) N (R u) 2, R wherein uBe alkyl or C 6To C 8Aryl, described alkyl or aryl is randomly replaced by dialkyl amido;
-OC (O) NH (OR Uu), R wherein UuBe the C that is randomly replaced by dialkyl amido 6To C 8Aryl;
-OC(O)NR x(OR x)；
-OC(O)N(OR x) 2；
-OC (O) R Ab, R wherein AbBe five yuan or the hexa-member heterocycle that is randomly replaced by heteroaryl, described heteroaryl is randomly replaced by alkyl or alkylhalide group;
-NR oC (O) R p, R wherein pBe:
-C 1To C 6Alkyl;
-randomly by one or more C 1To C 6The amino that alkyl replaces, described alkyl is randomly by one or more C that are independently selected from 6To C 8The substituting group of aryl and alkoxyl group replaces; Or
-five yuan or hexa-member heterocycle, it is randomly by one or more C that are independently selected from 1To C 6Alkyl and C 6To C 8The substituting group of aryl replaces;
And R wherein oBe:
-hydrogen; Or
-C 1To C 6Alkyl;
-NR qCONR qR r, R wherein qBe hydrogen, and R wherein rBe:
-C 1To C 6Alkyl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-halogen;
-hydroxyl;
-alkoxyl group;
-five yuan or hexa-member heterocycle;
-five yuan or six membered heteroaryl; And
-C 6To C 8Aryl, it is randomly replaced by halogen;
-the C that randomly replaced by one or more halogens 2To C 6Thiazolinyl;
-C 1To C 6Alkoxyl group;
-five yuan or hexa-member heterocycle; Or
-five yuan to six membered heteroaryl, and it is randomly replaced by alkyl;
-SO 2R Aa, R wherein AaBe:
-five yuan or hexa-member heterocycle, it is randomly replaced by one or more substituting groups that are independently selected from down group:
-hydroxyl;
-C 1To C 6Alkoxyl group; And
-C 1To C 6Alkyl;
-the amino that randomly replaced by alkyl, described alkyl are randomly replaced by one or more substituting groups that are independently selected from down group:
-alkoxyl group;
-hydroxyl;
-halogen;
-COR m, R wherein mBe:
-randomly by one or more C 1To C 6The amino that alkyl replaces, described alkyl is randomly by five yuan or hexa-member heterocycle or C 6To C 8Aryl replaces, and described heterocycle or aryl are randomly replaced by one or more substituting groups that are independently selected from halogen and alkoxyl group;
-the heterocycle that randomly replaced by hydroxyl;
-ternary is to seven membered heterocyclic, and it is randomly by C 1To C 6Alkyl replaces, and described alkyl is randomly replaced by dialkyl-7-amino;
-NR tCOOR u, R wherein tBe hydrogen, and R wherein uBe:
-C 1To C 12Alkyl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-C 6To C 8Aryl, it is randomly replaced by one or more halogens and/or alkylhalide group;
-the alkoxyl group that randomly replaced by one or more alkoxyl groups;
-randomly by one or more C 1To C 6The amino that alkyl replaces;
-halogen;
-SO 2R w；
-SO 2R x；
-five yuan or six membered heteroaryl; And
-five yuan or hexa-member heterocycle;
-C 2To C 6Thiazolinyl;
-C 6To C 8Aryl, it is randomly replaced by halogen;
-quaternary is to seven membered heterocyclic, and it is randomly replaced by one or more substituting groups that are independently selected from down group:
＝O；
-SO 2R w；
-COR pAnd
-(CO) O-(C 1To C 4Alkyl)-O-(C 1To C 4Alkyl);
-NHR Bb, R wherein BbBe:
-C(＝S)NH 2；
-C(＝S)NHR x；
-C(＝S)NR xR x；
-C (=N-CN) NHR xOr
-PO(OR x) 2；
-N(CONHR w) 2；
-NH(SOR w)；
-N(SO 2R w) 2；
-NR vSO 2R w, R wherein vBe hydrogen or the alkyl that randomly replaced by quaternary to seven membered heterocyclic;
And R wherein wBe:
-randomly by C 6To C 8The C that aryl replaces 1To C 6Alkyl, described aryl are randomly replaced by one or more substituting groups that are independently selected from alkylhalide group, halogen, alkoxyl group and alkyl;
-C 6To C 8Aryl;
-C 6To C 8Heteroaryl; Or
-randomly by the amino of heterocycle or alkyl replacement, described heterocycle or alkyl are randomly by one or more halogen, C of being independently selected from 1To C 6Alkoxyl group, carbalkoxy, (CO) O-(C 1To C 6) alkyl), the substituting group of hydroxyl, cyano group, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
Figure A20078000890207361
Figure A20078000890207371
-five yuan to six membered heteroaryl, and it is randomly replaced by one or more substituting groups that are independently selected from down group:
-halogen;
-C 1To C 6Alkyl;
-alkoxyl group, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-halogen;
-five yuan or hexa-member heterocycle; And
-C (O) NH 2, it is randomly by C 6To C 8Alkyl replaces;
-hydroxyl;
-alkylhalide group;
-cyano group;
-nitro;
-COOH；
-amino, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-SO 2R x；
-hexa-atomic to eight yuan of aryl, it is randomly by one or more alkyl, halogen, alkylhalide group, cyano group, alkoxyl group, COR of being independently selected from xReplace with the substituting group of halogen alkoxyl group;
-five yuan or six membered heteroaryl, it is randomly by one or more alkyl, halogen, alkylhalide group, cyano group, alkoxyl group, halogen alkoxyl group and C of being independently selected from 6To C 8The substituting group of aryl replaces, wherein this C 6To C 8Aryl is randomly replaced by halogen;
-C 5To C 6Heterocycle, it is randomly replaced by one or more substituting groups that are independently selected from hydroxyl, alkyl and alkylhalide group; And
-C 1To C 7Alkyl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or six membered heteroaryl, it is randomly replaced by one or more alkyl, halogen and/or alkylhalide group;
-C 6To C 8Aryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, halogen and alkylhalide group;
-alkoxyl group; And
-halogen;
-NR oCOR p, R wherein pBe:
-C 1To C 6Alkyl;
-randomly by one or more C 1To C 6The amino that alkyl replaces, described alkyl are randomly and independently by one or more C 6To C 8Aryl and/or alkoxyl group replace; Or
-five yuan or hexa-member heterocycle, it is by one or more C 1To C 6Alkyl and/or C 6To C 8Aryl replaces;
And R wherein oBe:
-hydrogen; Or
-C 1To C 6Alkyl;
-NR qCONR qR r, R wherein qBe hydrogen, and R wherein rBe:
-C 1To C 6Alkyl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-halogen;
-hydroxyl;
-alkoxyl group;
-five yuan or hexa-member heterocycle;
-five yuan or six membered heteroaryl; And
-C 6To C 8Aryl, it is randomly replaced by halogen;
-C 2To C 6Thiazolinyl, it is randomly replaced by one or more halogens;
-C 1To C 6Alkoxyl group;
-five yuan or hexa-member heterocycle; Or
-five yuan to six membered heteroaryl, and it is randomly replaced by alkyl;
-NR tCOOR u, R wherein tBe hydrogen, and R wherein uBe:
-C 1To C 12Alkyl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-C 6To C 8Aryl, it is randomly replaced by one or more halogens and/or alkylhalide group;
-the alkoxyl group that randomly replaced by one or more alkoxyl groups;
-randomly by one or more C 1To C 6The amino that alkyl replaces;
-halogen;
-SO 2R w；
-SO 2R x；
-five yuan or six membered heteroaryl; And
-five yuan or hexa-member heterocycle; And
-NR vSO 2R w, R wherein vBe hydrogen or the alkyl that randomly replaced by quaternary to seven membered heterocyclic;
And R wherein wBe:
-randomly by C 6To C 8The C that aryl replaces 1To C 6Alkyl, described aryl are randomly replaced by one or more substituting groups that are independently selected from alkylhalide group, halogen, alkoxyl group and alkyl;
-C 6To C 8Aryl;
-C 6To C 8Heteroaryl;
-randomly by the amino of heterocycle or alkyl replacement, described heterocycle or alkyl are randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, carbalkoxy, hydroxyl, cyano group, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
Figure A20078000890207391
Figure A20078000890207401
Z is:
-C 1To C 6Alkyl;
R is a hydrogen;
R 1Be:
-hydrogen;
-five yuan or hexa-member heterocycle, it is randomly replaced by one or more substituting groups that are independently selected from down group:
-hydroxyl;
-C 1To C 6Alkyl;
-SO 2R x；
-C (O)-C 6To C 8Aryl;
-COR pAnd
-C (O) OR xOr
-five yuan or six membered heteroaryl, it is randomly replaced by one or more substituting groups that are independently selected from down group:
-C 1To C 6Alkyl, it is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-alkoxyl group;
-halogen;
-alkylthio;
-alkylhalide group;
-cyano group;
-the amino that randomly replaced by alkyl, described alkyl is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, cyano group, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-heterocycle;
-nitro;
-hydroxyl;
-COOH；
-CO 2R x；
-COR x；
-randomly by one or more C 1To C 6C (O) NH that alkyl replaces 2, described alkyl is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-amido, it is randomly by one or more halogen, C of being independently selected from 1To C 6Alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle, five yuan or six membered heteroaryl and C 1To C 6The substituting group of alkyl replaces, and described alkyl is randomly by one or more C 1To C 6Alkoxyl group replaces;
-C 1To C 6Alkyl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-amino, it is randomly replaced by one or more substituting groups that are independently selected from heterocycle, alkoxyl group and alkyl, and described alkyl is randomly replaced by one or more alkoxyl groups;
-randomly by C 1To C 6The amido that alkyl replaces;
-five yuan or hexa-member heterocycle, it is randomly by C 1To C 6Alkyl replaces;
-five yuan or six membered heteroaryl; And
-C 6To C 8Aryl;
-SO 2R x；
-C 2To C 6Thiazolinyl, it is randomly by SO 2R xReplace;
-C 1To C 6Alkoxyl group, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-halogen;
-hydroxyl;
-cyano group;
-the alkoxyl group that replaces of alkoxy randomly;
-amino, it is randomly replaced by one or more substituting groups that are independently selected from five yuan or six membered heteroaryl, five yuan or hexa-member heterocycle and alkyl, and described alkyl is randomly replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or hexa-member heterocycle; And
-the amino that randomly replaced by one or more alkyl;
-randomly heterocyclically substituted amino;
-randomly by C 1To C 6The amido that alkyl replaces;
-five yuan to seven membered heterocyclic, and it is randomly by one or more hydroxyl and C of being independently selected from 1To C 6The substituting group of alkyl replaces, and described alkyl is randomly replaced by one or more substituting groups that randomly are selected from following groups;
-C 1To C 6Alkoxyl group; And
-C 6To C 8Alryl;
-five yuan or six membered heteroaryl, it is randomly replaced by one or more substituting groups that are independently selected from down group:
-C 1To C 6Alkyl; And
-quaternary is to seven membered heterocyclic;
-alkoxyl group; And
-C 6To C 8Aryl;
-(O)-five yuan or hexa-member heterocycle, it is randomly replaced by one or more substituting groups that are independently selected from down group:
-hydroxyl;
-C 1To C 6Alkyl;
-SO 2R x；
-C (O)-C 6To C 8Aryl;
-COR pAnd
-C (O) OR xOr
-(O)-five yuan or six membered heteroaryl, it is randomly replaced by one or more substituting groups that are independently selected from down group:
-C 1To C 6Alkyl, it is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-alkoxyl group;
-halogen;
-alkylthio;
-alkylhalide group;
-cyano group;
-the amino that randomly replaced by alkyl, described alkyl is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, cyano group, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-heterocycle;
-nitro;
-hydroxyl;
-COOH；
-CO 2R x；
-COR x；
-C (O) NH 2, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-C 1To C 6Alkyl, it is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces; And
-amido, it is randomly by one or more halogen, C of being independently selected from 1To C 6Alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle, five yuan or six membered heteroaryl and C 1To C 6The substituting group of alkyl replaces, and described alkyl is randomly by one or more C 1To C 6Alkoxyl group replaces;
-randomly by one or more C 1To C 6C (O) NH that alkyl replaces 2, described alkyl is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-C (O)-ternary is to seven membered heterocyclic, and it is randomly replaced by one or more substituting groups that are independently selected from down group:
-C 6To C 8Aryl;
-five yuan or six membered heteroaryl; And
-C 1To C 6Alkyl, it is randomly by one or more replacements that replaced by hydroxyl;
-SO 2R x, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or hexa-member heterocycle;
-C 6To C 8Aryl; And
-five yuan or six membered heteroaryl; Or
-alkylthio, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or hexa-member heterocycle;
-C 6To C 8Aryl; And
-five yuan or six membered heteroaryl;
-C 6To C 8Aryl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-C 1To C 6Alkyl, it is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-alkoxyl group;
-halogen;
-alkylthio;
-alkylhalide group;
-cyano group;
-the amino that randomly replaced by alkyl, described alkyl is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, cyano group, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-heterocycle:
-nitro;
-hydroxyl;
-COOH；
-CO 2R x；
-COR x；
-randomly by one or more C 1To C 6C (O) NH that alkyl replaces 2, described alkyl is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces; And
-amido, it is randomly by one or more halogen, C of being independently selected from 1To C 6Alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle, five yuan or six membered heteroaryl and C 1To C 6The substituting group of alkyl replaces, and described alkyl is randomly by one or more C 1To C 6Alkoxyl group replaces;
-C (O)-five yuan or six membered heteroaryl;
-C (O)-C 6To C 8Aryl;
-COOH; Or
-OR Kk, R wherein KkBe:
-C 6To C 8Aryl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-C 1To C 6Alkyl, it is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-alkoxyl group;
-halogen;
-alkylthio;
-alkylhalide group;
-cyano group;
-the amino that randomly replaced by alkyl, described alkyl is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, cyano group, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-heterocycle;
-nitro;
-hydroxyl;
-COOH；
-CO 2R x；
-COR x；
-randomly by one or more C 1To C 6C (O) NH that alkyl replaces 2, described alkyl is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces; And
-amido, it is randomly by one or more halogen, C of being independently selected from 1To C 6Alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle, five yuan or six membered heteroaryl and C 1To C 6The substituting group of alkyl replaces, and described alkyl is randomly by one or more C 1To C 6Alkoxyl group replaces;
R 2Be:
-C 1To C 6Alkyl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or hexa-member heterocycle;
-five yuan or six membered heteroaryl;
-C 6To C 8Aryl;
-randomly by C 1To C 6The amido that alkyl replaces; And
-amino, it is randomly replaced by one or more substituting groups that are independently selected from heterocycle, alkoxyl group and alkyl, and described alkyl is randomly replaced by one or more alkoxyl groups; And
-SO 2R x；
-C 2To C 6Thiazolinyl, it is randomly by SO 2R xReplace;
-alkylthio, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or six membered heteroaryl, it is randomly replaced by alkyl;
-five yuan or hexa-member heterocycle;
-C 6To C 8Aryl; And
-C 1To C 6Alkyl;
-SO 2R x, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or six membered heteroaryl, it is randomly by one or more C 1To C 6Alkyl replaces;
-five yuan or hexa-member heterocycle;
-C 6To C 8Aryl; And
-C 1To C 6Alkyl;
-S (O) R x, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or six membered heteroaryl;
-five yuan or hexa-member heterocycle;
-C 6To C 8Aryl; And
-C 1To C 6Alkyl;
-alkoxyl group, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-halogen;
-hydroxyl;
-cyano group;
-the alkoxyl group that replaces of alkoxy randomly;
-amino, it is randomly by one or more being independently selected from-SO 2-C 1To C 4The substituting group of alkyl, five yuan or six membered heteroaryl, five yuan or hexa-member heterocycle and alkyl replaces, and described alkyl is randomly replaced by one or more substituting groups that are selected from following groups:
-five yuan or hexa-member heterocycle; And
-the amino that randomly replaced by one or more alkyl;
-randomly by C 1To C 6The amido that alkyl replaces;
Five yuan of-S-or hexa-member heterocycle;
Five yuan of-S-or six membered heteroaryl, it is randomly by C 1To C 6Alkyl replaces;
-S-C 1To C 6Alkyl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-C 6To C 8Aryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, alkylhalide group and halogen; And
-C 5To C 6Heteroaryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, alkylhalide group and halogen;
-S-C 6To C 8Aryl;
-sulfinyl-five yuan or hexa-member heterocycle;
-sulfinyl-five yuan or six membered heteroaryl;
-sulfinyl-C 1To C 6Alkyl, this alkyl are randomly replaced by one or more substituting groups that are independently selected from following groups:
-C 6To C 8Aryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, alkylhalide group and halogen; And
-C 5To C 6Heteroaryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, alkylhalide group and halogen;
-sulfinyl-C 6To C 8Aryl;
-alkylsulfonyl-five yuan or hexa-member heterocycle;
-alkylsulfonyl-randomly by C 1To C 6Five yuan or six membered heteroaryl that alkyl replaces;
-alkylsulfonyl-C 1To C 6Alkyl, this alkyl are randomly replaced by one or more substituting groups that are independently selected from following groups:
-C 6To C 8Aryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, alkylhalide group and halogen; And
-C 5To C 6Heteroaryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, alkylhalide group and halogen;
-alkylsulfonyl-C 6To C 8Aryl;
-five yuan to seven membered heterocyclic, its randomly by one or more be independently selected from hydroxyl ,=O, heterocycle and C 1To C 6The substituting group of alkyl replaces, and described alkyl is randomly replaced by one or more substituting groups that are independently selected from following groups:
-C 1To C 6Alkoxyl group; And
-C 6To C 8Aryl;
-five yuan or six membered heteroaryl, it is randomly replaced by one or more substituting groups that are independently selected from down group:
-C 1To C 6Alkyl, it is randomly replaced by one or more alkoxyl groups;
-quaternary is to seven membered heterocyclic; And
-alkoxyl group; And
-C 6To C 8Aryl;
-C 6To C 8Aryl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-C 1To C 6Alkyl, it is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-alkoxyl group;
-halogen;
-alkylthio;
-alkylhalide group;
-cyano group;
-the amino that randomly replaced by alkyl, described alkyl is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, cyano group, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-heterocycle;
-nitro;
-hydroxyl;
-COOH；
-CO 2R x；
-COR x；
-randomly by one or more C 1To C 6C (O) NH that alkyl replaces 2, described alkyl is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces; And
-amido, it is randomly by one or more halogen, C of being independently selected from 1To C 6Alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle, five yuan or six membered heteroaryl and C 1To C 6The substituting group of alkyl replaces, and described alkyl is randomly by one or more C 1To C 6Alkoxyl group replaces;
-(O)-five yuan or hexa-member heterocycle, it is randomly replaced by one or more substituting groups that are independently selected from down group:
-hydroxyl;
＝O；
-C 1To C 6Alkyl;
-SO 2R x；
-C (O)-C 6To C 8Aryl;
-COR pAnd
-C (O) OR xOr
-(O)-five yuan or six membered heteroaryl, it is randomly replaced by one or more substituting groups that are independently selected from down group:
-C 1To C 6Alkyl, it is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-alkoxyl group;
-halogen;
-alkylthio;
-alkylhalide group;
-cyano group;
-the amino that randomly replaced by alkyl, described alkyl is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, cyano group, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-heterocycle;
-nitro;
-hydroxyl;
-COOH；
-CO 2R x；
-COR x；
-randomly by one or more C 1To C 6C (O) NH that alkyl replaces 2, described alkyl is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces; And
-amido, it is randomly by one or more halogen, C of being independently selected from 1To C 6Alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle, five yuan or six membered heteroaryl and C 1To C 6The substituting group of alkyl replaces, and described alkyl is randomly by one or more C 1To C 6Alkoxyl group replaces;
-C (O)-ternary is to seven membered heterocyclic, and it is randomly replaced by one or more substituting groups that are independently selected from down group:
-C 6To C 8Aryl;
-five yuan or six membered heteroaryl; And
-C 1To C 6Alkyl, it is randomly replaced by one or more hydroxyls;
-C (O)-five yuan or six membered heteroaryl;
-C (O)-C 6To C 8Aryl;
-amino, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-SO 2R x；
-hexa-atomic to eight yuan of aryl, it is randomly by one or more alkyl, halogen, alkylhalide group, cyano group, alkoxyl group, COR of being independently selected from xReplace with the substituting group of halogen alkoxyl group;
-five yuan or six membered heteroaryl, it is randomly by one or more alkyl, halogen, alkylhalide group, cyano group, alkoxyl group, halogen alkoxyl group and C of being independently selected from 6To C 8The substituting group of aryl replaces, wherein C 6To C 8Aryl randomly replaced by halogen;
-C 5To C 6Heterocycle, it is randomly replaced by one or more substituting groups that are independently selected from hydroxyl, alkyl and alkylhalide group;
-C 1To C 7Alkyl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or six membered heteroaryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, halogen and alkylhalide group;
-C 6To C 8Aryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, halogen and alkylhalide group;
-alkoxyl group; And
-halogen;
-five yuan or six membered heteroaryl, it is randomly replaced by one or more substituting groups that are independently selected from down group:
-C 1To C 6Alkyl, it is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-alkoxyl group;
-halogen;
-alkylthio;
-alkylhalide group;
-cyano group;
-the amino that randomly replaced by one or more alkyl, described alkyl is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, cyano group, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-heterocycle;
-nitro;
-hydroxyl;
-COOH；
-CO 2R x；
-COR x；
-randomly by one or more C 1To C 6C (O) NH that alkyl replaces 2, described alkyl is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-amido, it is randomly by one or more halogen, C of being independently selected from 1To C 6Alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle, five yuan or six membered heteroaryl and C 1To C 6The substituting group of alkyl replaces, and described alkyl is randomly by one or more C 1To C 6Alkoxyl group replaces;
-five yuan or hexa-member heterocycle, it is randomly replaced by one or more substituting groups that are independently selected from down group:
-hydroxyl;
＝O；
-C 1To C 6Alkyl;
-SO 2R x；
-C (O)-C 6To C 8Aryl;
-COR pAnd
-C(O)OR x；
-OR Kk, R wherein KkBe:
-C 6To C 8Aryl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-C 1To C 6Alkyl, it is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-alkoxyl group;
-halogen;
-alkylthio;
-alkylhalide group;
-cyano group;
-the amino that randomly replaced by alkyl, described alkyl is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, cyano group, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-heterocycle;
-nitro;
-hydroxyl;
-COOH；
-CO 2R x；
-COR x；
-randomly by one or more C 1To C 6C (O) NH that alkyl replaces 2, described alkyl is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces; And
-amido, it is randomly by one or more halogen, C of being independently selected from 1To C 6Alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle, five yuan or six membered heteroaryl and C 1To C 6The substituting group of alkyl replaces, and described alkyl is randomly by one or more C 1To C 6Alkoxyl group replaces;
-five yuan to hexa-member heterocycle, and it is randomly by C 1To C 6Alkyl replaces, and described alkyl is randomly by C 6To C 8Aryl replaces; Or
-five yuan to six membered heteroaryl, and it is randomly by one or more halogen, C of being independently selected from 1To C 6Alkyl, C 1To C 6Alkoxyl group and C 1To C 6The substituting group of alkylhalide group replaces;
-SO 2R xOr
-Si(Rx) 3；
-OC (O) NHR x, R wherein xRandomly by C 6To C 8Aryl replaces;
-OC (O) N (R x) 2Or
Figure A20078000890207531
R 3Be hydrogen; Or
-nitro;
Condition is X, Y, Z, R 1, R 2And R 3In have a following selection at least:
X is:
-CH=N-(C 1To C 6Alkoxyl group);
-CH=N-is (randomly by one or more C 1To C 6The amino that alkyl replaces);
-halogen;
-the alkyl that randomly replaced by one or more halogens;
-randomly by C 1To C 6The alkynyl that alkyl replaces, described alkyl are randomly replaced by one or more halogens and/or cyano group;
-oximido;
-SO 2R x；
-SO 2NH 2；
-SO 2NH(R x)；
-SO 2N(R x) 2；
-amino, it is randomly by one or more C that select independently 1To C 6Alkyl and/or C (O)-C 1To C 6Alkyl replaces;
-amido, it is randomly by one or more C that select independently 1To C 6Alkyl replaces;
-five yuan or hexa-member heterocycle;
-five yuan or six membered heteroaryl, it is by one or more C 1To C 6Alkyl replaces, and described alkyl is randomly replaced by one or more halogens; Or
-C 6To C 8Aryl, it is replaced by one or more substituting groups that are independently selected from following groups:
-C 1To C 6Alkyl, it is randomly replaced by one or more halogens;
-halogen; And
-cyano group;
Y is:
-by the amino benzothiazolyl that replaces, described amino is randomly by one or more C 1To C 6Alkyl replaces;
-indyl, it is at the quilt-SO of nitrogen-atoms place 2R xReplace;
-C 6To C 8Aryl, it is replaced by one or more substituting groups that are independently selected from following groups:
-alkoxyl group, it is replaced by one or more substituting groups that are independently selected from following groups:
-C (O) NH 2, it is randomly by C 6To C 8Alkyl replaces; And
-C (O) NH-(C 1To C 6)-alkyl;
-alkylhalide group;
-cyano group;
-COOH；
-N＝CHN(R x) 2；
-amino, it is replaced by one or more substituting groups that are independently selected from following groups:
-SO 2R x；
-hexa-atomic to eight yuan of aryl, it is randomly by one or more alkyl, halogen, alkylhalide group, cyano group, alkoxyl group, COR of being independently selected from xReplace with the substituting group of halogen alkoxyl group;
-five yuan or six membered heteroaryl, it is randomly by one or more alkyl, halogen, alkylhalide group, cyano group, alkoxyl group, halogen alkoxyl group and C of being independently selected from 6To C 8The substituting group of aryl replaces, wherein this C 6To C 8Aryl is randomly replaced by halogen;
-five yuan or hexa-member heterocycle, its randomly by one or more be independently selected from hydroxyl ,=substituting group of O, alkyl and alkylhalide group replaces;
-C 1To C 7Alkyl, it is replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or six membered heteroaryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, halogen and alkylhalide group;
-C 6To C 8Aryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, halogen and alkylhalide group;
-alkoxyl group; And
-halogen; And
-PO 2R x；
-OC (O) NHR x, R wherein xRandomly by vinyl substituted;
-OC (O) N (R u) 2, R wherein uBe alkyl or C 6To C 8Aryl, described alkyl or aryl is randomly replaced by dialkyl amido;
-OC (O) NH (OR Uu), R wherein UuBe the C that is randomly replaced by dialkyl amido 6To C 8Aryl;
-OC(O)NR x(OR x)；
-OC(O)N(OR x) 2；
-OC (O) R Ab, R wherein AbBe five yuan or the hexa-member heterocycle that is randomly replaced by heteroaryl, described heteroaryl is randomly replaced by alkyl or alkylhalide group;
-NR oC (O) R p, R wherein pBe:
-randomly by one or more C 1To C 6The amino that alkyl replaces, described alkyl is randomly by one or more C that are independently selected from 6To C 8The substituting group of aryl and alkoxyl group replaces; Or
-five yuan or hexa-member heterocycle, it is by one or more C that are independently selected from 1To C 6Alkyl and C 6To C 8The substituting group of aryl replaces;
-NR qCONR qR r, R wherein rBe:
-C 1To C 6Alkyl, it is replaced by one or more substituting groups that are independently selected from following groups:
-hydroxyl;
-alkoxyl group;
-five yuan or hexa-member heterocycle;
-five yuan or six membered heteroaryl; And
-the C that replaced by halogen 6To C 8Aryl,
-C 2To C 6Thiazolinyl, it is randomly replaced by one or more halogens;
-C 1To C 6Alkoxyl group;
-five yuan or hexa-member heterocycle; Or
-five yuan to six membered heteroaryl, and it is randomly replaced by alkyl;
-SO 2R Aa, R wherein AaBe:
-five yuan or hexa-member heterocycle, it is randomly replaced by one or more substituting groups that are independently selected from down group:
-hydroxyl;
-C 1To C 6Alkoxyl group; And
-C 1To C 6Alkyl;
-the amino that randomly replaced by alkyl, described alkyl are randomly replaced by one or more substituting groups that are independently selected from down group:
-alkoxyl group;
-hydroxyl;
-halogen;
-COR m, R wherein mBe:
-amino, it is by one or more C 1To C 6Alkyl replaces, and described alkyl is by five yuan or hexa-member heterocycle or C 6To C 8Aryl replaces, and described heterocycle is replaced by one or more halogens and/or alkoxyl group, and described aryl is randomly replaced by one or more halogens and/or alkoxyl group;
-the heterocycle that replaced by hydroxyl;
-NR tCOOR u, R wherein uBe:
-C 1To C 12Alkyl, it is replaced by one or more substituting groups that are independently selected from following groups:
-C 6To C 8Aryl, it is replaced by one or more halogens and/or alkylhalide group;
-the alkoxyl group that replaced by one or more alkoxyl groups;
-randomly by one or more C 1To C 6The amino that alkyl replaces;
-SO 2R w；
-SO 2R xAnd
-five yuan or six membered heteroaryl;
-C 2To C 6Thiazolinyl;
-quaternary is to seven membered heterocyclic, and it is replaced by one or more substituting groups that are independently selected from down group:
＝O；
-SO 2R w；
-COR pAnd
-(CO) O-(C 1To C 4Alkyl)-O-(C 1To C 4Alkyl);
-quaternary or seven membered heterocyclic, it is randomly replaced by one or more substituting groups that are independently selected from down group:
＝O；
-SO 2R w；
-COR pAnd
-(CO) O-(C 1To C 4Alkyl)-O-(C 1To C 4Alkyl);
-NHR Bb, R wherein BbBe:
-C(＝S)NHR x；
-C (=S) NR xR xOr
-C(＝N-CN)NHR x；
-N(CONHR w) 2；
-NH(SOR w)；
-N(SO 2R w) 2；
-NR vSO 2R w, R wherein vBy the alkyl of quaternary or seven membered heterocyclic replacement;
Or R wherein wBe:
-by C 6To C 8The C that aryl replaces 1To C 6Alkyl, described aryl is replaced by one or more substituting groups that are independently selected from alkylhalide group, halogen, alkoxyl group and alkyl;
-randomly by the amino of heterocycle or alkyl replacement, described heterocycle or alkyl are randomly by one or more halogen, C of being independently selected from 1To C 6Alkoxyl group, carbalkoxy, (CO) O-(C 1To C 6) alkyl), the substituting group of hydroxyl, cyano group, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
Figure A20078000890207571
Figure A20078000890207581
-five yuan to six membered heteroaryl, and it is randomly replaced by one or more substituting groups that are independently selected from down group:
-halogen;
-C 1To C 6Alkyl;
-alkoxyl group, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-halogen;
-five yuan or hexa-member heterocycle; And
-C (O) NH 2, it is randomly by C 6To C 8Alkyl replaces;
-hydroxyl;
-alkylhalide group;
-cyano group;
-nitro;
-COOH；
-amino, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-SO 2R x；
-hexa-atomic to eight yuan of aryl, it is randomly by one or more alkyl, halogen, alkylhalide group, cyano group, alkoxyl group, COR of being independently selected from xReplace with the substituting group of halogen alkoxyl group;
-five yuan or six membered heteroaryl, it is randomly by one or more alkyl, halogen, alkylhalide group, cyano group, alkoxyl group, halogen alkoxyl group and C of being independently selected from 6To C 8The substituting group of aryl replaces, wherein this C 6To C 8Aryl is randomly replaced by halogen;
-C 5To C 6Heterocycle, it is randomly replaced by one or more substituting groups that are independently selected from hydroxyl, alkyl and alkylhalide group; And
-C 1To C 7Alkyl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or six membered heteroaryl, it is randomly replaced by one or more alkyl, halogen and/or alkylhalide group;
-C 6To C 8Aryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, halogen and alkylhalide group;
-alkoxyl group; And
-halogen;
-NR oCOR p, R wherein pBe:
-randomly by one or more C 1To C 6The amino that alkyl replaces, described alkyl are randomly and independently by one or more C 6To C 8Aryl and/or alkoxyl group replace; Or
-five yuan or hexa-member heterocycle, it is randomly by one or more C 1To C 6Alkyl and/or C 6To C 8Aryl replaces;
-NR qCONR qR r, R wherein rBe:
-C 1To C 6Alkyl, it is replaced by one or more substituting groups that are independently selected from following groups:
-hydroxyl;
-alkoxyl group;
-five yuan or hexa-member heterocycle;
-five yuan or six membered heteroaryl; And
-the C that replaced by halogen 6To C 8Aryl,
-C 2To C 6Thiazolinyl, it is randomly replaced by one or more halogens;
-C 1To C 6Alkoxyl group;
-five yuan or hexa-member heterocycle; Or
-five yuan to six membered heteroaryl, and it is randomly replaced by alkyl;
-NR tCOOR u, R wherein uBe:
-C 1To C 12Alkyl, it is replaced by one or more substituting groups that are independently selected from following groups:
-C 6To C 8Aryl, it is replaced by one or more halogens and/or alkylhalide group;
-the alkoxyl group that replaced by one or more alkoxyl groups;
-randomly by one or more C 1To C 6The amino that alkyl replaces;
-SO 2R w；
-SO 2R xAnd
-five yuan or six membered heteroaryl;
-NR vSO 2R w, R wherein vBy the alkyl of quaternary to the seven membered heterocyclic replacement;
Or R wherein wBe:
-by C 6To C 8The C that aryl replaces 1To C 6Alkyl, described aryl is replaced by one or more substituting groups that are independently selected from alkylhalide group, halogen, alkoxyl group and alkyl;
-C 6To C 8Aryl;
-by the amino of heterocycle or alkyl replacement, described heterocycle is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, carbalkoxy, hydroxyl, cyano group, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces, and described alkyl is by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, carbalkoxy, hydroxyl, cyano group, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
Figure A20078000890207601
Figure A20078000890207611
Z is:
-C 1To C 6Alkyl;
R 1Be:
-five yuan or hexa-member heterocycle, it is replaced by one or more substituting groups that are independently selected from down group:
-hydroxyl;
-C 1To C 6Alkyl;
-SO 2R x；
-C (O)-C 6To C 8Aryl;
-COR pAnd
-C (O) OR xOr
-five yuan or six membered heteroaryl, it is replaced by one or more substituting groups that are independently selected from following groups:
-C 1To C 6Alkyl, it is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-alkoxyl group;
-halogen;
-alkylthio;
-alkylhalide group;
-cyano group;
-the amino that randomly replaced by alkyl, described alkyl is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, cyano group, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-heterocycle;
-nitro;
-hydroxyl;
-COOH；
-CO 2R x；
-COR x；
-randomly by one or more C 1To C 6C (O) NH that alkyl replaces 2, described alkyl is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-amido, it is randomly by one or more halogen, C of being independently selected from 1To C 6Alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle, five yuan or six membered heteroaryl and C 1To C 6The substituting group of alkyl replaces, and described alkyl is randomly by one or more C 1To C 6Alkoxyl group replaces;
-C 1To C 6Alkyl, it is replaced by one or more substituting groups that are independently selected from following groups:
-amino, it is randomly replaced by one or more substituting groups that are independently selected from heterocycle, alkoxyl group and alkyl, and described alkyl is replaced by one or more alkoxyl groups;
-randomly by C 1To C 6The amido that alkyl replaces;
-five yuan or hexa-member heterocycle, it is by C 1To C 6Alkyl replaces;
-five yuan or six membered heteroaryl,
-C 6To C 8Aryl;
-SO 2R x；
-C 2To C 6Thiazolinyl, it is randomly by SO 2R xReplace;
-C 1To C 6Alkoxyl group, it is replaced by one or more substituting groups that are independently selected from following groups:
-hydroxyl;
-cyano group;
-the alkoxyl group that replaces of alkoxy randomly;
-amino, it is randomly replaced by one or more substituting groups that are independently selected from five yuan or six membered heteroaryl, five yuan or hexa-member heterocycle and alkyl, and described alkyl is randomly replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or hexa-member heterocycle; And
-the amino that randomly replaced by one or more alkyl;
-randomly heterocyclically substituted amino;
-randomly by C 1To C 6The amido that alkyl replaces;
-five yuan to seven membered heterocyclic, and it is by one or more hydroxyl and C of being independently selected from 1To C 6The substituting group of alkyl replaces, and described alkyl is randomly replaced by one or more substituting groups that are independently selected from following groups;
-C 1To C 6Alkoxyl group; And
-C 6To C 8Alryl;
-five yuan or six membered heteroaryl, it is randomly replaced by one or more substituting groups that are independently selected from down group:
-C 1To C 6Alkyl; And
-quaternary is to seven membered heterocyclic; And
-alkoxyl group;
-(O)-five yuan or hexa-member heterocycle, it is randomly replaced by one or more substituting groups that are independently selected from down group:
-hydroxyl;
-C 1To C 6Alkyl;
-SO 2R x；
-C (O)-C 6To C 8Aryl;
-COR pAnd
-C (O) OR xOr
-(O)-five yuan or six membered heteroaryl, it is randomly replaced by one or more substituting groups that are independently selected from down group:
-C 1To C 6Alkyl, it is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-alkoxyl group;
-halogen;
-alkylthio;
-alkylhalide group;
-cyano group;
-the amino that randomly replaced by alkyl, described alkyl is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, cyano group, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-heterocycle;
-nitro;
-hydroxyl;
-COOH；
-CO 2R x；
-COR x；
-C (O) NH 2, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-C 1To C 6Alkyl, it is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces; And
-amido, it is randomly by one or more halogen, C of being independently selected from 1To C 6Alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle, five yuan or six membered heteroaryl and C 1To C 6The substituting group of alkyl replaces, and described alkyl is randomly by one or more C 1To C 6Alkoxyl group replaces;
-randomly by one or more C 1To C 6C (O) NH that alkyl replaces 2, described alkyl is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-C (O)-ternary is to seven membered heterocyclic, and it is randomly replaced by one or more substituting groups that are independently selected from down group:
-C 6To C 8Aryl;
-five yuan or six membered heteroaryl,
-C 1To C 6Alkyl, it is randomly by one or more replacements that replaced by hydroxyl;
-SO 2R x, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or hexa-member heterocycle;
-C 6To C 8Aryl; And
-five yuan or six membered heteroaryl; Or
-alkylthio, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or hexa-member heterocycle;
-C 6To C 8Aryl; And
-five yuan or six membered heteroaryl;
-C (O)-five yuan or six membered heteroaryl;
-C (O)-C 6To C 8Aryl;
-COOH；
-OR Kk, R wherein KkBe:
C 6To C 8Aryl, it is randomly by one or more halogen, C of being independently selected from 1To C 6Alkyl, C 1To C 6Alkoxyl group and C 1To C 6The substituting group of alkylhalide group replaces;
R 2Be:
-C 1To C 6Alkyl, it is replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or hexa-member heterocycle;
-five yuan or six membered heteroaryl;
-C 6To C 8Aryl;
-randomly by C 1To C 6The amido that alkyl replaces; And
-amino, it is randomly replaced by one or more substituting groups that are independently selected from heterocycle, alkoxyl group and alkyl, and described alkyl is randomly replaced by one or more alkoxyl groups;
-SO 2R x；
-C 2To C 6Thiazolinyl, it is randomly by SO 2R xReplace;
-alkylthio, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or six membered heteroaryl, it is randomly replaced by alkyl;
-five yuan or hexa-member heterocycle;
-C 6To C 8Aryl; And
-C 1To C 6Alkyl;
-SO 2R x, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or six membered heteroaryl, it is randomly by one or more C 1To C 6Alkyl replaces;
-five yuan or hexa-member heterocycle;
-C 6To C 8Aryl; And
-C 1To C 6Alkyl;
-S (O) R x, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or six membered heteroaryl;
-five yuan or hexa-member heterocycle;
-C 6To C 8Aryl; And
-C 1To C 6Alkyl;
-alkoxyl group, it is replaced by one or more substituting groups that are independently selected from following groups:
-halogen;
-hydroxyl;
-cyano group;
-the alkoxyl group that replaces of alkoxy randomly;
-amino, it is by one or more SO that are independently selected from 2-C 1To C 4The substituting group of alkyl and alkyl replaces, and described alkyl is replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or hexa-member heterocycle; And
-the amino that randomly replaced by one or more alkyl;
-by C 1To C 6The amido that alkyl replaces;
Five yuan of-S-or hexa-member heterocycle;
Five yuan of-S-or six membered heteroaryl, it is randomly by C 1To C 6Alkyl replaces;
-S-C 1To C 6Alkyl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-C 6To C 8Aryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, alkylhalide group and halogen; And
-C 5To C 6Heteroaryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, alkylhalide group and halogen;
-S-C 6To C 8Aryl;
-sulfinyl-five yuan or hexa-member heterocycle;
-sulfinyl-five yuan or six membered heteroaryl;
-sulfinyl-C 1To C 6Alkyl, this alkyl are randomly replaced by one or more substituting groups that are independently selected from following groups:
-C 6To C 8Aryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, alkylhalide group and halogen; And
-C 5To C 6Heteroaryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, alkylhalide group and halogen;
-sulfinyl-C 6To C 8Aryl;
-alkylsulfonyl-five yuan or hexa-member heterocycle;
-alkylsulfonyl-randomly by C 1To C 6Five yuan or six membered heteroaryl that alkyl replaces;
-alkylsulfonyl-C 1To C 6Alkyl, this alkyl are randomly replaced by one or more substituting groups that are independently selected from following groups:
-C 6To C 8Aryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, alkylhalide group and halogen; And
-C 5To C 6Heteroaryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, alkylhalide group and halogen;
-alkylsulfonyl-C 6To C 8Aryl;
-five yuan to seven membered heterocyclic, its randomly by one or more be independently selected from hydroxyl ,=O, heterocycle and C 1To C 6The substituting group of alkyl replaces, and described alkyl is randomly replaced by one or more substituting groups that are independently selected from following groups:
-C 1To C 6Alkoxyl group; And
-C 6To C 8Aryl;
-five yuan or six membered heteroaryl, it is randomly replaced by one or more substituting groups that are independently selected from down group:
-C 1To C 6Alkyl, it is randomly replaced by one or more alkoxyl groups;
-quaternary is to seven membered heterocyclic; And
-alkoxyl group; And
-C 6To C 8Aryl;
-C 6To C 8Aryl;
-(O)-five yuan or hexa-member heterocycle, it is replaced by one or more substituting groups that are independently selected from down group:
-hydroxyl;
＝O；
-C 1To C 6Alkyl;
-SO 2R x；
-C (O)-C 6To C 8Aryl;
-COR pAnd
-C (O) OR xOr
-(O)-five yuan or six membered heteroaryl, it is replaced by one or more substituting groups that are independently selected from down group:
-C 1To C 6Alkyl, it is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-alkoxyl group;
-halogen;
-alkylthio;
-alkylhalide group;
-cyano group;
-the amino that randomly replaced by alkyl, described alkyl is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, cyano group, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-heterocycle;
-nitro;
-hydroxyl;
-COOH；
-CO 2R x；
-COR x；
-randomly by one or more C 1To C 6C (O) NH that alkyl replaces 2, described alkyl is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-amido, it is randomly by one or more halogen, C of being independently selected from 1To C 6Alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle, five yuan or six membered heteroaryl and C 1To C 6The substituting group of alkyl replaces, and described alkyl is randomly by one or more C 1To C 6Alkoxyl group replaces;
-C (O)-ternary is to seven membered heterocyclic, and it is randomly replaced by one or more substituting groups that are independently selected from down group:
-C 6To C 8Aryl;
-five yuan or six membered heteroaryl; And
-C 1To C 6Alkyl, it is randomly replaced by one or more hydroxyls;
-C (O)-five yuan or six membered heteroaryl;
-C (O)-C 6To C 8Aryl;
-amino, it is replaced by one or more substituting groups that are independently selected from following groups:
-SO 2R x；
-hexa-atomic to eight yuan of aryl, it is randomly by one or more alkyl, halogen, alkylhalide group, cyano group, alkoxyl group, COR of being independently selected from xReplace with the substituting group of halogen alkoxyl group;
-five yuan or six membered heteroaryl, it is randomly by one or more alkyl, halogen, alkylhalide group, cyano group, alkoxyl group, halogen alkoxyl group and C of being independently selected from 6To C 8The substituting group of aryl replaces, wherein this C 6To C 8Aryl is randomly replaced by halogen;
-C 5To C 6Heterocycle, it is randomly replaced by one or more substituting groups that are independently selected from hydroxyl, alkyl and alkylhalide group;
-C 1To C 7Alkyl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or six membered heteroaryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, halogen and alkylhalide group;
-C 6To C 8Aryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, halogen and alkylhalide group;
-alkoxyl group; And
-halogen;
-five yuan or six membered heteroaryl, it is replaced by one or more substituting groups that are independently selected from down group:
-C 1To C 6Alkyl, it is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-alkoxyl group;
-halogen;
-alkylthio;
-alkylhalide group;
-cyano group;
-the amino that randomly replaced by one or more alkyl, described alkyl is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, cyano group, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-heterocycle;
-nitro;
-hydroxyl;
-COOH；
-CO 2R x；
-COR x；
-randomly by one or more C 1To C 6C (O) NH that alkyl replaces 2, described alkyl is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-amido, it is randomly by one or more halogen, C of being independently selected from 1To C 6Alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle, five yuan or six membered heteroaryl and C 1To C 6The substituting group of alkyl replaces, and described alkyl is randomly by one or more C 1To C 6Alkoxyl group replaces;
-five yuan or hexa-member heterocycle, it is randomly replaced by one or more substituting groups that are independently selected from down group:
-hydroxyl;
＝O；
-C 1To C 6Alkyl;
-SO 2R x；
-C (O)-C 6To C 8Aryl;
-COR pAnd
-C(O)OR x；
-OR Kk, R wherein KkBe:
C 6To C 8Aryl, it is randomly by one or more halogen, C of being independently selected from 1To C 6Alkyl, C 1To C 6Alkoxyl group and C 1To C 6The substituting group of alkylhalide group replaces;
-five yuan to hexa-member heterocycle, and it is randomly by C 1To C 6Alkyl replaces, and described alkyl is randomly by C 6To C 8Aryl replaces; Or
Five yuan to six membered heteroaryl, and it is by one or more halogen, C of being independently selected from 1To C 6Alkyl, C 1To C 6Alkoxyl group and C 1To C 6The substituting group of alkylhalide group replaces;
-SO 2R xOr
-Si(R x) 3；
-OC (O) NHR x, R wherein xRandomly by C 6To C 8Aryl replaces;
-OC (O) N (R x) 2Or
Figure A20078000890207711
R 3It is nitro.
90. as the described compound of claim 89, wherein:
X is;
-CH=N-(C 1To C 6Alkoxyl group);
-CH=N-is (randomly by one or more C 1To C 6The amino that alkyl replaces);
-halogen;
-the alkyl that randomly replaced by one or more halogens;
-randomly by C 1To C 6The alkynyl that alkyl replaces, described alkyl are randomly replaced by one or more halogens and/or cyano group;
-oximido;
-SO 2R x；
-SO 2NH 2；
-SO 2NH(R x)；
-SO 2N(R x) 2；
-amino, it is randomly by one or more C that select independently 1To C 6Alkyl and/or-C (O)-C 1To C 6Alkyl replaces;
-amido, it is randomly by one or more C that select independently 1To C 6Alkyl replaces;
-five yuan or hexa-member heterocycle;
-five yuan or six membered heteroaryl, it is by one or more C 1To C 6Alkyl replaces, and described alkyl is randomly replaced by one or more halogens; Or
-C 6To C 8Aryl, it is replaced by one or more substituting groups that are independently selected from following groups:
-C 1To C 6Alkyl, it is randomly replaced by one or more halogens;
-halogen; And
-cyano group.
91. as the described compound of claim 89, wherein:
Y is:
-by the amino benzothiazolyl that replaces, described amino is randomly by one or more C 1To C 6Alkyl replaces;
-indyl, it is at the quilt-SO of nitrogen-atoms place 2R xReplace; Or
-C 6To C 8Aryl, it is replaced by one or more substituting groups that are independently selected from following groups:
-alkoxyl group, it is replaced by one or more substituting groups that are independently selected from following groups:
-C (O) NH 2, it is randomly by C 6To C 8Alkyl replaces; And
-C (O) NH-(C 1To C 6)-alkyl;
-alkylhalide group;
-cyano group;
-COOH；
-N＝CHN(R x) 2；
-amino, it is replaced by one or more substituting groups that are independently selected from following groups:
-SO 2R x；
-hexa-atomic to eight yuan of aryl, it is randomly by one or more alkyl, halogen, alkylhalide group, cyano group, alkoxyl group, COR of being independently selected from xReplace with the substituting group of halogen alkoxyl group;
-five yuan or six membered heteroaryl, it is randomly by one or more alkyl, halogen, alkylhalide group, cyano group, alkoxyl group, halogen alkoxyl group and C of being independently selected from 6To C 8The substituting group of aryl replaces, wherein this C 6To C 8Aryl is randomly replaced by halogen;
-five yuan or hexa-member heterocycle, its randomly by one or more be independently selected from hydroxyl ,=substituting group of O, alkyl and alkylhalide group replaces;
-C 1To C 7Alkyl, it is replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or six membered heteroaryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, halogen and alkylhalide group;
-C 6To C 8Aryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, halogen and alkylhalide group;
-alkoxyl group; And
-halogen; And
-PO 2R x；
-OC (O) NHR x, R wherein xRandomly by vinyl substituted;
-OC (O) N (R u) 2, R wherein uBe alkyl or C 6To C 8Aryl, described alkyl or aryl is randomly replaced by dialkyl amido;
-OC (O) NH (OR Uu), R wherein UuBe the C that is randomly replaced by dialkyl amido 6To C 8Aryl;
-OC(O)NR x(OR x)；
-OC(O)N(OR x) 2；
-OC (O) R Ab, R wherein AbBe five yuan or the hexa-member heterocycle that is randomly replaced by heteroaryl, described heteroaryl is randomly replaced by alkyl or alkylhalide group;
-NR oC (O) R p, R wherein pBe:
-randomly by one or more C 1To C 6The amino that alkyl replaces, described alkyl is randomly by one or more C that are independently selected from 6To C 8The substituting group of aryl and alkoxyl group replaces; Or
-five yuan or hexa-member heterocycle, it is by one or more C that are independently selected from 1To C 6Alkyl and C 6To C 8Aryl replaces;
-NR qCONR qR r, R wherein rBe:
-C 1To C 6Alkyl, it is replaced by one or more substituting groups that are independently selected from following groups:
-hydroxyl;
-alkoxyl group;
-five yuan or hexa-member heterocycle;
-five yuan or six membered heteroaryl; And
-the C that replaced by halogen 6To C 8Aryl,
-C 2To C 6Thiazolinyl, it is randomly replaced by one or more halogens;
-C 1To C 6Alkoxyl group;
-five yuan or hexa-member heterocycle; Or
-five yuan to six membered heteroaryl, and it is randomly replaced by alkyl;
-SO 2R Aa, R wherein AaBe:
-five yuan or hexa-member heterocycle, it is replaced by one or more substituting groups that are independently selected from down group:
-hydroxyl;
-C 1To C 6Alkoxyl group; And
-C 1To C 6Alkyl;
-the amino that randomly replaced by alkyl, described alkyl are randomly replaced by one or more substituting groups that are independently selected from down group:
-alkoxyl group;
-hydroxyl;
-halogen;
-COR m, R wherein mBe:
-amino, it is by one or more C 1To C 6Alkyl replaces, and described alkyl is by five yuan or hexa-member heterocycle or C 6To C 8Aryl replaces, and described heterocycle is replaced by one or more halogens and/or alkoxyl group, and described aryl is randomly replaced by one or more halogens and/or alkoxyl group;
-the heterocycle that replaced by hydroxyl;
-NR tCOOR u, R wherein uBe:
-C 1To C 12Alkyl, it is replaced by one or more substituting groups that are independently selected from following groups:
-C 6To C 8Aryl, it is replaced by one or more halogens and/or alkylhalide group;
-the alkoxyl group that replaced by one or more alkoxyl groups;
-amino, it is randomly by one or more C 1To C 6Alkyl replaces;
-SO 2R w；
-SO 2R xAnd
-five yuan or six membered heteroaryl;
-C 2To C 6Thiazolinyl;
-quaternary is to seven membered heterocyclic, and it is replaced by one or more substituting groups that are independently selected from down group:
＝O；
-SO 2R w；
-COR pAnd
-(CO) O-(C 1To C 4Alkyl)-O-(C 1To C 4Alkyl);
-quaternary or seven membered heterocyclic, it is randomly replaced by one or more substituting groups that are independently selected from down group:
＝O；
-SO 2R w；
-COR pAnd
-(CO) O-(C 1To C 4Alkyl)-O-(C 1To C 4Alkyl);
-NHR Bb, R wherein BbBe:
-C(＝S)NHR x；
-C (=S) NR xR xOr
-C(＝N-CN)NHR x；
-N(CONHR w) 2；
-NH(SOR w)；
-N(SO 2R w) 2；
-NR vSO 2R w, R wherein vBy the alkyl of quaternary or seven membered heterocyclic replacement;
Or R wherein wBe:
-by C 6To C 8The C that aryl replaces 1To C 6Alkyl, described aryl is replaced by one or more substituting groups that are independently selected from alkylhalide group, halogen, alkoxyl group and alkyl;
-randomly by the amino of heterocycle or alkyl replacement, described heterocycle or alkyl are randomly by one or more halogen, C of being independently selected from 1To C 6Alkoxyl group, carbalkoxy, (CO) O-(C 1To C 6) alkyl), the substituting group of hydroxyl, cyano group, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
Figure A20078000890207751
Figure A20078000890207761
-five yuan to six membered heteroaryl, and it is randomly replaced by one or more substituting groups that are independently selected from down group:
-halogen;
-C 1To C 6Alkyl;
-alkoxyl group, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-halogen;
-five yuan or hexa-member heterocycle; And
-C (O) NH 2, it is randomly by C 6To C 8Alkyl replaces;
-hydroxyl;
-alkylhalide group;
-cyano group;
-nitro;
-COOH；
-amino, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-SO 2R x；
-hexa-atomic to eight yuan of aryl, it is randomly by one or more alkyl, halogen, alkylhalide group, cyano group, alkoxyl group, COR of being independently selected from xReplace with the substituting group of halogen alkoxyl group;
-five yuan or six membered heteroaryl, it is randomly by one or more alkyl, halogen, alkylhalide group, cyano group, alkoxyl group, halogen alkoxyl group and C of being independently selected from 6To C 8The substituting group of aryl replaces, wherein this C 6To C 8Aryl is randomly replaced by halogen;
-C 5To C 6Heterocycle, it is randomly replaced by one or more substituting groups that are independently selected from hydroxyl, alkyl and alkylhalide group; And
-C 1To C 7Alkyl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or six membered heteroaryl, it is randomly replaced by one or more alkyl, halogen and/or alkylhalide group;
-C 6To C 8Aryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, halogen and alkylhalide group;
-alkoxyl group; And
-halogen;
-NR oCOR p, R wherein pBe:
-randomly by one or more C 1To C 6The amino that alkyl replaces, described alkyl are randomly and independently by one or more C 6To C 8Aryl and/or alkoxyl group replace; Or
-five yuan or hexa-member heterocycle, it is randomly by one or more C 1To C 6Alkyl and/or C 6To C 8Aryl replaces;
-NR qCONR qR r, R wherein rBe:
-C 1To C 6Alkyl, it is replaced by one or more substituting groups that are independently selected from following groups:
-hydroxyl;
-alkoxyl group;
-five yuan or hexa-member heterocycle;
-five yuan or six membered heteroaryl; And
-the C that replaced by halogen 6To C 8Aryl,
-C 2To C 6Thiazolinyl, it is randomly replaced by one or more halogens;
-C 1To C 6Alkoxyl group;
-five yuan or hexa-member heterocycle; Or
-five yuan to six membered heteroaryl, and it is randomly replaced by alkyl;
-NR tCOOR u, R wherein uBe:
-C 1To C 12Alkyl, it is replaced by one or more substituting groups that are independently selected from following groups:
-C 6To C 8Aryl, it is replaced by one or more halogens and/or alkylhalide group;
-the alkoxyl group that replaced by one or more alkoxyl groups;
-amino, it is randomly by one or more C 1To C 6Alkyl replaces;
-SO 2R w；
-SO 2R xAnd
-five yuan or six membered heteroaryl; And
-NR vSO 2R w, R wherein vBy the alkyl of quaternary to the seven membered heterocyclic replacement;
Or R wherein wBe:
-by C 6To C 8The C that aryl replaces 1To C 6Alkyl, described aryl is replaced by one or more substituting groups that are independently selected from alkylhalide group, halogen, alkoxyl group and alkyl;
-C 6To C 8Aryl;
-by the amino of heterocycle or alkyl replacement, described heterocycle is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, carbalkoxy, hydroxyl, cyano group, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces, and described alkyl is by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, carbalkoxy, hydroxyl, cyano group, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
Figure A20078000890207781
Figure A20078000890207791
92. as the described compound of claim 89, wherein Z is:
-C 1To C 6Alkyl.
93. as the described compound of claim 89, wherein:
R 1Be:
-five yuan or hexa-member heterocycle, it is replaced by one or more substituting groups that are independently selected from down group:
-hydroxyl;
-C 1To C 6Alkyl;
-SO 2R x；
-C (O)-C 6To C 8Aryl;
-COR pAnd
-C (O) OR xOr
-five yuan or six membered heteroaryl, it is replaced by one or more substituting groups that are independently selected from following groups:
-C 1To C 6Alkyl, it is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-alkoxyl group;
-halogen;
-alkylthio;
-alkylhalide group;
-cyano group;
-the amino that randomly replaced by alkyl, described alkyl is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, cyano group, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-heterocycle;
-nitro;
-hydroxyl;
-COOH；
-CO 2R x；
-COR x；
-randomly by one or more C 1To C 6C (O) NH that alkyl replaces 2, described alkyl is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-amido, it is randomly by one or more halogen, C of being independently selected from 1To C 6Alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle, five yuan or six membered heteroaryl and C 1To C 6The substituting group of alkyl replaces, and described alkyl is randomly by one or more C 1To C 6Alkoxyl group replaces;
-C 1To C 6Alkyl, it is replaced by one or more substituting groups that are independently selected from following groups:
-amino, it is randomly replaced by one or more substituting groups that are independently selected from heterocycle, alkoxyl group and alkyl, and described alkyl is replaced by one or more alkoxyl groups;
-randomly by C 1To C 6The amido that alkyl replaces;
-five yuan or hexa-member heterocycle, it is by C 1To C 6Alkyl replaces;
-five yuan or six membered heteroaryl, and
-C 6To C 8Aryl;
-SO 2R x；
-C 2To C 6Thiazolinyl, it is randomly by SO 2R xReplace;
-C 1To C 6Alkoxyl group, it is replaced by one or more substituting groups that are independently selected from following groups:
-hydroxyl;
-cyano group;
-the alkoxyl group that replaces of alkoxy randomly;
-amino, it is randomly replaced by one or more substituting groups that are independently selected from five yuan or six membered heteroaryl, five yuan or hexa-member heterocycle and alkyl, and described alkyl is randomly replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or hexa-member heterocycle; And
-the amino that randomly replaced by one or more alkyl;
-randomly heterocyclically substituted amino;
-randomly by C 1To C 6The amido that alkyl replaces;
-five yuan to seven membered heterocyclic, and it is by one or more hydroxyl and C of being independently selected from 1To C 6The substituting group of alkyl replaces, and described alkyl is randomly replaced by one or more substituting groups that are independently selected from following groups;
-C 1To C 6Alkoxyl group; And
-C 6To C 8Alryl;
-five yuan or six membered heteroaryl, it is randomly replaced by one or more substituting groups that are independently selected from down group:
-C 1To C 6Alkyl; And
-quaternary is to seven membered heterocyclic; And
-alkoxyl group;
-(O)-five yuan or hexa-member heterocycle, it is randomly replaced by one or more substituting groups that are independently selected from down group:
-hydroxyl;
-C 1To C 6Alkyl;
-SO 2R x；
-C (O)-C 6To C 8Aryl;
-COR pAnd
-C (O) OR xOr
-(O)-five yuan or six membered heteroaryl, it is randomly replaced by one or more substituting groups that are independently selected from down group:
-C 1To C 6Alkyl, it is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-alkoxyl group;
-halogen;
-alkylthio;
-alkylhalide group;
-cyano group;
-the amino that randomly replaced by alkyl, described alkyl is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, cyano group, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-heterocycle;
-nitro;
-hydroxyl;
-COOH；
-CO 2R x；
-COR x；
-C (O) NH 2, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-C 1To C 6Alkyl, it is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces; And
-amido, it is randomly by one or more halogen, C of being independently selected from 1To C 6Alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle, five yuan or six membered heteroaryl and C 1To C 6The substituting group of alkyl replaces, and described alkyl is randomly by one or more C 1To C 6Alkoxyl group replaces;
-C (O)-ternary is to seven membered heterocyclic, and it is randomly replaced by one or more substituting groups that are independently selected from down group:
-C 6To C 8Aryl;
-five yuan or six membered heteroaryl,
-C 1To C 6Alkyl, it is randomly by one or more replacements that replaced by hydroxyl;
-SO 2R x, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or hexa-member heterocycle;
-C 6To C 8Aryl; And
-five yuan or six membered heteroaryl; Or
-alkylthio, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or hexa-member heterocycle;
-C 6To C 8Aryl; And
-five yuan or six membered heteroaryl;
-C (O)-five yuan or six membered heteroaryl;
-C (O)-C 6To C 8Aryl;
Or
-OR Kk, R wherein KkBe:
-C 6To C 8Aryl, it is randomly by one or more halogen, C of being independently selected from 1To C 6Alkyl, C 1To C 6Alkoxyl group and C 1To C 6The substituting group of alkylhalide group replaces.
94. as the described compound of claim 89, wherein:
R 2Be:
-C 1To C 6Alkyl, it is replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or hexa-member heterocycle;
-five yuan or six membered heteroaryl;
-C 6To C 8Aryl;
-randomly by C 1To C 6The amido that alkyl replaces; And
-amino, it is randomly replaced by one or more substituting groups that are independently selected from heterocycle, alkoxyl group and alkyl, and described alkyl is randomly replaced by one or more alkoxyl groups; And
-SO 2R x；
-C 2To C 6Thiazolinyl, it is randomly by SO 2R xReplace;
-alkylthio, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or six membered heteroaryl, it is randomly replaced by alkyl;
-five yuan or hexa-member heterocycle;
-C 6To C 8Aryl; And
-C 1To C 6Alkyl;
-SO 2R x, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or six membered heteroaryl, it is randomly by one or more C 1To C 6Alkyl replaces;
-five yuan or hexa-member heterocycle;
-C 6To C 8Aryl; And
-C 1To C 6Alkyl;
-S (O) R x, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or six membered heteroaryl;
-five yuan or hexa-member heterocycle;
-C 6To C 8Aryl; And
-C 1To C 6Alkyl;
-alkoxyl group, it is replaced by one or more substituting groups that are independently selected from following groups:
-halogen;
-hydroxyl;
-cyano group;
-the alkoxyl group that replaces of alkoxy randomly;
-amino, it is by one or more SO that are independently selected from 2-C 1To C 4The substituting group of alkyl and alkyl replaces, and described alkyl is replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or hexa-member heterocycle; And
-the amino that randomly replaced by one or more alkyl;
-by C 1To C 6The amido that alkyl replaces;
Five yuan of-S-or hexa-member heterocycle;
Five yuan of-S-or six membered heteroaryl, it is randomly by C 1To C 6Alkyl replaces;
-S-C 1To C 6Alkyl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-C 6To C 8Aryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, alkylhalide group and halogen; And
-C 5To C 6Heteroaryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, alkylhalide group and halogen;
-S-C 6To C 8Aryl;
-sulfinyl-five yuan or hexa-member heterocycle;
-sulfinyl-five yuan or six membered heteroaryl;
-sulfinyl-C 1To C 6Alkyl, this alkyl are randomly replaced by one or more substituting groups that are independently selected from following groups:
-C 6To C 8Aryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, alkylhalide group and halogen; And
-C 5To C 6Heteroaryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, alkylhalide group and halogen;
-sulfinyl-C 6To C 8Aryl;
-alkylsulfonyl-five yuan or hexa-member heterocycle;
-alkylsulfonyl-randomly by C 1To C 6Five yuan or six membered heteroaryl that alkyl replaces;
-alkylsulfonyl-C 1To C 6Alkyl, this alkyl are randomly replaced by one or more substituting groups that are independently selected from following groups:
-C 6To C 8Aryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, alkylhalide group and halogen; And
-C 5To C 6Heteroaryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, alkylhalide group and halogen;
-alkylsulfonyl-C 6To C 8Aryl;
-five yuan to seven membered heterocyclic, its randomly by one or more be independently selected from hydroxyl ,=O, heterocycle and C 1To C 6The substituting group of alkyl replaces, and described alkyl is randomly replaced by one or more substituting groups that are selected from following groups:
-C 1To C 6Alkoxyl group; And
-C 6To C 8Aryl;
-five yuan or six membered heteroaryl, it is randomly replaced by one or more substituting groups that are independently selected from down group:
-C 1To C 6Alkyl, it is randomly replaced by one or more alkoxyl groups;
-quaternary is to seven membered heterocyclic; And
-alkoxyl group; And
-C 6To C 8Aryl;
-C 6To C 8Aryl;
-(O)-five yuan or hexa-member heterocycle, it is replaced by one or more substituting groups that are independently selected from down group:
-hydroxyl;
＝O；
-C 1To C 6Alkyl;
-SO 2R x；
-C (O)-C 6To C 8Aryl;
-COR pAnd
-C (O) OR xOr
-(O)-five yuan or six membered heteroaryl, it is replaced by one or more substituting groups that are independently selected from down group:
-C 1To C 6Alkyl, it is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-alkoxyl group;
-halogen;
-alkylthio;
-alkylhalide group;
-cyano group;
-the amino that randomly replaced by alkyl, described alkyl is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, cyano group, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-heterocycle;
-nitro;
-hydroxyl;
-COOH；
-CO 2R x；
-COR x；
-randomly by one or more C 1To C 6C (O) NH that alkyl replaces 2, described alkyl is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-amido, it is randomly by one or more halogen, C of being independently selected from 1To C 6Alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle, five yuan or six membered heteroaryl and C 1To C 6The substituting group of alkyl replaces, and described alkyl is randomly by one or more C 1To C 6Alkoxyl group replaces;
-C (O)-ternary is to seven membered heterocyclic, and it is randomly replaced by one or more substituting groups that are independently selected from down group:
-C 6To C 8Aryl;
-five yuan or six membered heteroaryl; And
-C 1To C 6Alkyl, it is randomly replaced by one or more hydroxyls;
-C (O)-five yuan or six membered heteroaryl;
-C (O)-C 6To C 8Aryl;
-the amino that replaced by one or more substituting groups that are independently selected from following groups:
-SO 2R x；
-hexa-atomic to eight yuan of aryl, it is randomly by one or more alkyl, halogen, alkylhalide group, cyano group, alkoxyl group, COR of being independently selected from xReplace with the substituting group of halogen alkoxyl group;
-five yuan or six membered heteroaryl, it is randomly by one or more alkyl, halogen, alkylhalide group, cyano group, alkoxyl group, halogen alkoxyl group and C of being independently selected from 6To C 8The substituting group of aryl replaces, wherein this C 6To C 8Aryl is randomly replaced by halogen;
-C 5To C 6Heterocycle, it is randomly replaced by one or more substituting groups that are independently selected from hydroxyl, alkyl and alkylhalide group;
-C 1To C 7Alkyl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or six membered heteroaryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, halogen and alkylhalide group;
-C 6To C 8Aryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, halogen and alkylhalide group;
-alkoxyl group; And
-halogen;
-five yuan or six membered heteroaryl, it is replaced by one or more substituting groups that are independently selected from down group:
-C 1To C 6Alkyl, it is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-alkoxyl group;
-halogen;
-alkylthio;
-alkylhalide group;
-cyano group;
-the amino that randomly replaced by one or more alkyl, described alkyl is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, cyano group, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-heterocycle;
-nitro;
-hydroxyl;
-COOH；
-CO 2R x；
-COR x；
-randomly by one or more C 1To C 6C (O) NH that alkyl replaces 2, described alkyl is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-amido, it is randomly by one or more halogen, C of being independently selected from 1To C 6Alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle, five yuan or six membered heteroaryl and C 1To C 6The substituting group of alkyl replaces, and described alkyl is randomly by one or more C 1To C 6Alkoxyl group replaces;
-five yuan or hexa-member heterocycle, it is randomly replaced by one or more substituting groups that are independently selected from down group:
-hydroxyl;
＝O；
-C 1To C 6Alkyl;
-SO 2R x；
-C (O)-C 6To C 8Aryl;
-COR pAnd
-C(O)OR x；
-OR Kk, R wherein KkBe:
-C 6To C 8Aryl, it is randomly by one or more halogen, C of being independently selected from 1To C 6Alkyl, C 1To C 6Alkoxyl group and C 1To C 6The substituting group of alkylhalide group replaces;
-five yuan to hexa-member heterocycle, and it is randomly by C 1To C 6Alkyl replaces, and described alkyl is randomly by C 6To C 8Aryl replaces; Or
-five yuan to six membered heteroaryl, and it is by one or more halogen, C of being independently selected from 1To C 6Alkyl, C 1To C 6Alkoxyl group and C 1To C 6The substituting group of alkylhalide group replaces;
-SO 2R xOr
-Si (R x) 3Or
Figure A20078000890207881
95. as the described compound of claim 89, wherein R 3It is nitro.
96. as the described compound of claim 89, wherein:
X is cyano group or hydrogen;
Y is:
-C 6To C 8Aryl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-halogen;
-C 1To C 6Alkyl;
-amino, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-SO 2R x；
-five yuan or six membered heteroaryl, it is randomly replaced by one or more alkyl;
-C 1To C 7Alkyl;
-NR tCOOR u, R wherein tBe hydrogen, and R wherein uBe C 1To C 12Alkyl;
-NR vSO 2R w, R wherein vBe hydrogen, and R wherein wBe C 1To C 6Alkyl or the amino that is randomly replaced by alkyl;
Figure A20078000890207891
Z is C 1To C 6Alkyl;
R is a hydrogen;
R 1Be hydrogen;
R 2Replaced by cyano group-(O)-five yuan or six membered heteroaryl; And
R 3Be hydrogen.
97. as the described compound of claim 96, wherein said C 6To C 8Aryl is a phenyl.
98. as the described compound of claim 97, wherein:
X is a cyano group;
Y is contraposition quilt-NR vSO 2R wThe phenyl that replaces, wherein R vBe hydrogen, and R wBe C 1To C 6Alkyl; And R 2Be the ortho position replaced by cyano group-(O)-five yuan or six membered heteroaryl.
99. as the described compound of claim 97, wherein:
X is a cyano group;
Y is by C 1To C 6Alkyl and NR vSO 2R wThe phenyl that replaces, wherein R vBe hydrogen, and R wBe C 1To C 6Alkyl; And
R 2Replaced at the ortho position by cyano group-(O)-five yuan or six membered heteroaryl.
100. as the described compound of claim 97, wherein:
X is a cyano group;
Y is by halogen and NR vSO 2R wThe phenyl that replaces, wherein R vBe hydrogen, and R wBe C 1To C 6Alkyl; And
R 2Be the ortho position replaced by cyano group-(O)-five yuan or six membered heteroaryl.
101. as the described compound of claim 97, wherein:
X is a hydrogen;
Y is that contraposition is by NR tCOOR uThe phenyl that replaces, wherein R tBe hydrogen, and R uBe C 1To C 12Alkyl;
Z is cyclobutyl, cyclopropyl, cyclopropyl methyl, ethyl or cyclopentyl; And
R 2Be the ortho position replaced by cyano group-(O)-five yuan or six membered heteroaryl.
102. as the described compound of claim 89, wherein:
X is a cyano group;
Y is:
-C 6To C 8Aryl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-NR tCOOR u, R wherein tBe hydrogen, and R uBe the C that is randomly replaced by one or more halogens 1To C 12Alkyl; Or
-NR vSO 2R w, R wherein vBe hydrogen, and R wBe C 1To C 6Alkyl;
Z is C 1To C 6Alkyl;
R is a hydrogen;
R 1Be hydrogen;
R 2Replaced by one or more=O-(O)-five yuan or hexa-member heterocycle; And
R 3Be hydrogen.
103. be selected from the compound of compound 1330-2128 and 2600-3348.
104. as the described compound of claim 103, it is selected from:
Figure A20078000890207911
Figure A20078000890207921
105. composition that comprises described compound of claim 1 and the acceptable vehicle of one or more pharmacology.
106. composition that comprises described compound of claim 39 and the acceptable vehicle of one or more pharmacology.
107. composition that comprises described compound of claim 77 and the acceptable vehicle of one or more pharmacology.
108. composition that comprises described compound of claim 83 and the acceptable vehicle of one or more pharmacology.
109. composition that comprises described compound of claim 89 and the acceptable vehicle of one or more pharmacology.
110. a method that is used for the treatment of the infection with hepatitis C virus in the individuality, this method comprise to one or more compounds as claimed in claim 1 of the described individual effective dosage that these needs are arranged or comprise the pharmaceutical composition of one or more compounds as claimed in claim 1 of significant quantity.
111. a method that is used for the treatment of the infection with hepatitis C virus in the individuality, this method comprise to one or more compounds as claimed in claim 39 of the described individual effective dosage that these needs are arranged or comprise the pharmaceutical composition of one or more compounds as claimed in claim 39 of significant quantity.
112. a method that is used for the treatment of the infection with hepatitis C virus in the individuality, this method comprise to one or more of the described individual effective dosage that these needs are arranged as the described compound of claim 77 or comprise one or more pharmaceutical compositions as the described compound of claim 77 of significant quantity.
113. a method that is used for the treatment of the infection with hepatitis C virus in the individuality, this method comprise to one or more of the described individual effective dosage that these needs are arranged as the described compound of claim 83 or comprise one or more pharmaceutical compositions as the described compound of claim 83 of significant quantity.
114. a method that is used for the treatment of the infection with hepatitis C virus in the individuality, this method comprise to one or more of the described individual effective dosage that these needs are arranged as the described compound of claim 89 or comprise one or more pharmaceutical compositions as the described compound of claim 89 of significant quantity.
115. method that is used for the treatment of the virus infection in the individuality, wherein said virus comprises internal ribosome entry site, and this method comprises to one or more compounds as claimed in claim 1 of the described individual effective dosage that these needs are arranged or comprises the pharmaceutical composition of one or more compounds as claimed in claim 1 of significant quantity.
116. method that is used for the treatment of the virus infection in the individuality, wherein said virus comprises internal ribosome entry site, and this method comprises to one or more compounds as claimed in claim 39 of the described individual effective dosage that these needs are arranged or comprises the pharmaceutical composition of one or more compounds as claimed in claim 39 of significant quantity.
117. method that is used for the treatment of the virus infection in the individuality, wherein said virus comprises internal ribosome entry site, and this method comprises to one or more of the described individual effective dosage that these needs are arranged as the described compound of claim 77 or comprise one or more pharmaceutical compositions as the described compound of claim 77 of significant quantity.
118. method that is used for the treatment of the virus infection in the individuality, wherein said virus comprises internal ribosome entry site, and this method comprises to one or more of the described individual effective dosage that these needs are arranged as the described compound of claim 83 or comprise one or more pharmaceutical compositions as the described compound of claim 83 of significant quantity.
119. method that is used for the treatment of the virus infection in the individuality, wherein said virus comprises internal ribosome entry site, and this method comprises to one or more of the described individual effective dosage that these needs are arranged as the described compound of claim 89 or comprise one or more pharmaceutical compositions as the described compound of claim 89 of significant quantity.

Claims (119)

1. formula IIa compound
Figure A2007800089020002C1
Or the acceptable salt of its pharmacology, wherein:
X is:
-cyano group;
-nitro;
-formyl radical;
-COOH；
-COR x, R wherein xBe C 1To C 6Alkyl;
-CH=N-(C 1To C 6Alkoxyl group);
-CH=N-is (randomly by one or more C 1To C 6The amino that alkyl replaces);
-halogen;
-the alkyl that randomly replaced by one or more halogens;
-randomly by C 1To C 6The alkynyl that alkyl replaces, described alkyl are randomly replaced by one or more halogens of selecting independently or cyano group;
-oximido;
-SO 2R x；
-SO 2NH 2；
-SO 2NH(R x)；
-SO 2N(R x) 2；
-amino, it is randomly by one or more C 1To C 6Alkyl and/or-C (O)-C 1To C 6Alkyl replaces;
-amido, it is randomly by one or more C that select independently 1To C 6Alkyl replaces;
-five yuan or hexa-member heterocycle;
-five yuan or six membered heteroaryl, it is randomly by one or more C 1To C 6Alkyl replaces, and described alkyl is randomly replaced by one or more halogens; Or
-C 6To C 8Aryl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-C 1To C 6Alkyl, it is randomly replaced by one or more halogens;
-halogen; And
-cyano group;
Y is:
-the benzothiazolyl that randomly replaced by amino, described amino is randomly by one or more C 1To C 6Alkyl replaces;
-indyl, it is randomly at the quilt-SO of nitrogen-atoms place 2R xReplace;
-C 6To C 8Aryl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-halogen;
-C 1To C 6Alkyl;
-alkoxyl group, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-one or more halogens; And
-five yuan or hexa-member heterocycle;
-hydroxyl;
-amino, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-SO 2R x；
-C 1To C 6Alkyl, it is replaced by one or more five yuan or six membered heteroaryl randomly and independently; And
-PO 2R x；
-OC(O)NHR x；
-OC(O)N(R x) 2；
-OC(O)NH(OR x)；
-OC(O)NR x(OR x)；
-OC(O)N(OR x) 2；
-OC (O) R Ab, R wherein AbBe five yuan or hexa-member heterocycle;
-NR 0COR p, R wherein pBe:
-C 1To C 6Alkyl;
-randomly by one or more C 1To C 6The amino that alkyl replaces, described alkyl are randomly and independently by one or more C 6To C 8Aryl and/or alkoxyl group replace; Or
-five yuan or hexa-member heterocycle, it is randomly by one or more C 1To C 6Alkyl and/or C 6To C 8Aryl replaces;
And R wherein oBe:
-hydrogen; Or
-C 1To C 6Alkyl;
-NR qCONR qR r, R wherein qBe hydrogen;
And R wherein rBe:
-C 1To C 6Alkyl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-halogen;
-hydroxyl;
-alkoxyl group;
-five yuan or hexa-member heterocycle;
-five yuan or six membered heteroaryl, and
-the C that randomly replaced by one or more halogens 6To C 8Aryl;
-the C that randomly replaced by one or more halogens 2To C 6Thiazolinyl;
-C 1To C 6Alkoxyl group; Or
-five yuan or hexa-member heterocycle;
-SO 2R Aa, R wherein AaBe:
-five yuan or hexa-member heterocycle, it is randomly replaced by hydroxyl;
-C 1To C 6Alkoxyl group; Or
-C 1To C 6Alkyl;
-COR m, R wherein mBe:
-randomly by one or more C 1To C 6The amino that alkyl replaces, wherein this C 1To C 6Alkyl is randomly by five yuan or hexa-member heterocycle replacement; Or
-ternary is to seven membered heterocyclic, and it is randomly by C 1To C 6Alkyl replaces, and described alkyl is randomly replaced by dialkyl-7-amino;
-NR tCOOR u, R wherein tBe hydrogen, and R uBe:
-C 1To C 12Alkyl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-C 6To C 8Aryl, it is randomly replaced by one or more halogens and/or alkylhalide group;
-the alkoxyl group that randomly replaced by one or more alkoxyl groups;
-randomly by one or more C 1To C 6The amino that alkyl replaces;
-halogen;
-five yuan or six membered heteroaryl, and
-five yuan or hexa-member heterocycle;
-C 2To C 6Thiazolinyl; Or
-C 6To C 8Aryl, it is randomly replaced by halogen;
-NHR Bb, R wherein BbBe:
-C (=S) NH 2Or
-PO(OR x) 2；
-NR vSO 2R w, R wherein vBe hydrogen, and R wBe:
-C 1To C 6Alkyl; Or
-alkyl-amino or dialkyl-7-amino, it is randomly replaced by halogen;
Figure A2007800089020005C1
Z is:
-C 1To C 6Alkyl, it is randomly by five yuan or hexa-member heterocycle replacement; Or
-five yuan or hexa-member heterocycle;
R is a hydrogen;
R 1Be:
-hydrogen;
-five yuan or hexa-member heterocycle;
-C 1To C 6Alkyl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-randomly heterocyclically substituted amino;
-randomly by C 1To C 6The amido that alkyl replaces;
-five yuan or hexa-member heterocycle, it is randomly by C 1To C 6Alkyl replaces;
-five yuan or six membered heteroaryl, and
-C 6To C 8Aryl;
-C 1To C 6Alkoxyl group, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-randomly heterocyclically substituted amino;
-randomly by C 1To C 6The amido that alkyl replaces;
-five yuan or hexa-member heterocycle, it is randomly by C 1To C 6Alkyl replaces;
-five yuan or six membered heteroaryl, and
-C 6To C 8Aryl;
-(O)-five yuan or hexa-member heterocycle;
-(O)-five yuan or six membered heteroaryl;
-SO 2R x, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or hexa-member heterocycle;
-C 6To C 8Aryl; And
-five yuan or six membered heteroaryl; Or
-alkylthio, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or hexa-member heterocycle;
-C 6To C 8Aryl; And
-five yuan or six membered heteroaryl;
R 2Be:
-C 1To C 6Alkyl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or hexa-member heterocycle;
-five yuan or six membered heteroaryl;
-C 6To C 8Aryl;
-randomly by C 1To C 6The amido that alkyl replaces; And
-amino, it is randomly replaced by one or more substituting groups that are independently selected from heterocycle, alkoxyl group and alkyl, and described alkyl is randomly replaced by one or more alkoxyl groups;
-alkylthio, randomly by five yuan or six membered heteroaryl replacement, described heteroaryl is randomly replaced by alkyl for it;
-alkylthio, it is randomly by five yuan or hexa-member heterocycle replacement;
-alkylthio, it is randomly by C 6To C 8Aryl replaces;
-alkylthio, it is randomly by C 1To C 6Alkyl replaces;
-SO 2R x, randomly by five yuan or six membered heteroaryl replacement, described heteroaryl is randomly by one or more C for they 1To C 6Alkyl replaces;
-SO 2R x, it is randomly by five yuan or hexa-member heterocycle replacement;
-SO 2R x, it is randomly by C 6To C 8Aryl replaces;
-SO 2R x, it is randomly by C 1To C 6Alkyl replaces;
-S (O) R x, it is randomly by five yuan or six membered heteroaryl replacement;
-S (O) R x, it is randomly by five yuan or hexa-member heterocycle replacement;
-S (O) R x, it is randomly by C 6To C 8Aryl replaces;
-S (O) R x, it is randomly by C 1To C 6Alkyl replaces;
-alkoxyl group, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-halogen;
-hydroxyl;
-the alkoxyl group that replaces of alkoxy randomly;
-amino, it is randomly replaced by one or more substituting groups that are independently selected from five yuan or six membered heteroaryl, five yuan or hexa-member heterocycle and alkyl, and described alkyl is randomly replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or hexa-member heterocycle; And
-the amino that randomly replaced by one or more alkyl;
-randomly by C 1To C 6The amido that alkyl replaces;
Five yuan of-S-or hexa-member heterocycle;
Five yuan of-S-or six membered heteroaryl, it is randomly by C 1To C 6Alkyl replaces;
-S-C 1To C 6Alkyl;
-S-C 6To C 8Aryl;
-sulfinyl-five yuan or hexa-member heterocycle;
-sulfinyl-five yuan or six membered heteroaryl;
-sulfinyl-C 1To C 6Alkyl;
-sulfinyl-C 6To C 8Aryl;
-alkylsulfonyl-five yuan or hexa-member heterocycle;
-alkylsulfonyl-randomly by C 1To C 6Five yuan or six membered heteroaryl that alkyl replaces;
-alkylsulfonyl-C 1To C 6Alkyl;
-alkylsulfonyl-C 6To C 8Aryl;
-five yuan to seven membered heterocyclic, and it is randomly by one or more hydroxyl and C of being independently selected from 1To C 6The substituting group of alkyl replaces, and described alkyl is randomly by one or more C 1To C 6Alkoxyl group replaces;
-five yuan or six membered heteroaryl, it is randomly by one or more C 1To C 6Alkyl replaces; And
-C 6To C 8Aryl;
-C 6To C 8Aryl;
-(O)-five yuan or six membered heteroaryl, it is randomly by one or more C that select independently 1To C 6Alkyl replaces;
-C (O)-five yuan or hexa-member heterocycle, it is randomly by one or more C 6To C 8Aryl replaces;
-C (O)-C 6To C 8Aryl;
-COOH；
-C (O) NH 2, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-C 1To C 6Alkyl, it is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-amido, it is randomly by one or more C 1To C 6Alkyl replaces, and described alkyl is randomly by one or more C 1To C 6Alkoxyl group replaces;
-five yuan or six membered heteroaryl, it is randomly replaced by one or more substituting groups that are independently selected from down group:
-C 1To C 6Alkyl; And
-five yuan or hexa-member heterocycle, it is randomly replaced by one or more substituting groups that are independently selected from down group:
-hydroxyl;
-C 1To C 6Alkyl;
-SO 2R x；
-C (O)-C 6To C 8Aryl; And
-C (O) OR xOr
-OR Kk, R wherein KkBe:
-C 6To C 8Aryl;
-five yuan or hexa-member heterocycle, it is randomly by C 1To C 6Alkyl replaces, and described alkyl is randomly by C 6To C 8Aryl replaces;
Five yuan or six membered heteroaryl, it is randomly by one or more halogen, C of being independently selected from 1To C 6Alkyl, C 1To C 6Alkoxyl group and C 1To C 6The substituting group of alkylhalide group replaces;
-SO 2R xOr
-Si (R x) 3And
R 3Be hydrogen;
Condition is X, Y, Z, R 1And R 2In have a following selection at least:
X is:
-COOH；
-CH=N-(C 1To C 6Alkoxyl group);
-CH=N-is (randomly by one or more C 1To C 6The amino that alkyl replaces);
-halogen;
-the alkyl that randomly replaced by one or more halogens;
-randomly by C 1To C 6The alkynyl that alkyl replaces, described alkyl are randomly replaced by one or more halogens and/or cyano group;
-oximido;
-SO 2R x；
-SO 2NH 2；
-SO 2NH(R x)；
-SO 2N(R x) 2；
-amino, it is randomly by one or more C 1To C 6Alkyl and/or-C (O)-C 1To C 6Alkyl replaces;
-amido, it is randomly by one or more C that select independently 1To C 6Alkyl replaces;
-five yuan or hexa-member heterocycle;
-five yuan or six membered heteroaryl, it is by one or more C 1To C 6Alkyl replaces, and described alkyl is replaced by one or more halogens; Or
-C 6To C 8Aryl, it is replaced by one or more substituting groups that are independently selected from following groups:
-C 1To C 6Alkyl, it is randomly replaced by one or more halogens;
-halogen; And
-cyano group;
Y is:
-by the amino benzothiazolyl that replaces, described amino is randomly by one or more C 1To C 6Alkyl replaces;
-indyl, it is at the quilt-SO of nitrogen-atoms place 2R xReplace; Or
-C 6To C 8Aryl, it is replaced by one or more substituting groups that are independently selected from following groups:
-amino, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-SO 2R x, and
-C 1To C 6Alkyl, it is by one or more five yuan or six membered heteroaryl replacements;
-OC(O)NHR x；
-OC(O)N(R x) 2；
-OC(O)NH(OR x)；
-OC(O)NR x(OR x)；
-OC(O)N(OR x) 2；
-OC (O) R Ab, R wherein AbBe five yuan or hexa-member heterocycle;
-NR oCOR p, R wherein pBe:
-randomly by one or more C 1To C 6The amino that alkyl replaces, described alkyl are randomly and independently by one or more C 6To C 8Aryl and/or alkoxyl group replace; Or
-five yuan or hexa-member heterocycle, it is by one or more C 1To C 6Alkyl and/or C 6To C 8Aryl replaces;
-NR qCONR qR r, R wherein rBe:
-C 1To C 6Alkyl, it is replaced by one or more substituting groups that are independently selected from following groups:
-hydroxyl;
-alkoxyl group;
-five yuan or hexa-member heterocycle;
-five yuan or six membered heteroaryl; And
-C 6To C 8Aryl, it is replaced by one or more halogens;
-C 2To C 6Thiazolinyl;
-C 1To C 6Alkoxyl group; Or
-five yuan or hexa-member heterocycle;
-NR tCOOR u, R wherein uBe:
-C 1To C 12Alkyl, it is replaced by one or more substituting groups that are independently selected from following groups:
-the alkoxyl group that replaced by one or more alkoxyl groups;
-randomly by one or more C 1To C 6The amino that alkyl replaces; And
-five yuan or six membered heteroaryl; Or
-C 2To C 6Thiazolinyl; And
Figure A2007800089020011C1
Z is:
-C 1To C 6Alkyl, it is randomly by five yuan or hexa-member heterocycle replacement; Or
-five yuan or hexa-member heterocycle;
R 1Be:
-C 1To C 6Alkyl, it is replaced by following groups:
-randomly by C 1To C 6The amido that alkyl replaces; And/or
-five yuan or six membered heteroaryl;
-C 1To C 6Alkoxyl group, it is replaced by following groups:
-randomly heterocyclically substituted amino;
-randomly by C 1To C 6The amido that alkyl replaces;
-five yuan or hexa-member heterocycle, it is randomly by C 1To C 6Alkyl replaces; And/or
-five yuan or six membered heteroaryl;
-(O)-five yuan or hexa-member heterocycle;
-(O)-five yuan or six membered heteroaryl;
-SO 2R x, it is randomly replaced by following groups:
-five yuan or hexa-member heterocycle;
-C 6To C 8Aryl; And/or
-five yuan or six membered heteroaryl; Or
-alkylthio, it is randomly replaced by following groups:
-five yuan or hexa-member heterocycle;
-C 6To C 8Aryl; And/or
-five yuan or six membered heteroaryl;
R 2Be:
-C 1To C 6Alkyl, it is replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or hexa-member heterocycle;
-five yuan or six membered heteroaryl;
-C 6To C 8Aryl;
-randomly by C 1To C 6The amido that alkyl replaces; And
-amino, it is randomly replaced by one or more substituting groups that are independently selected from heterocycle, alkoxyl group and alkyl, and described alkyl is randomly replaced by one or more alkoxyl groups;
-alkylthio, randomly by five yuan or six membered heteroaryl replacement, described heteroaryl is randomly replaced by alkyl for it;
-alkylthio, it is randomly by five yuan or hexa-member heterocycle replacement;
-alkylthio, it is randomly by C 6To C 8Aryl replaces;
-alkylthio, it is randomly by C 1To C 6Alkyl replaces;
-SO 2R x, randomly by five yuan or six membered heteroaryl replacement, described heteroaryl is randomly by one or more C for they 1To C 6Alkyl replaces;
-SO 2R x, it is randomly by five yuan or hexa-member heterocycle replacement;
-SO 2R x, it is randomly by C 6To C 8Aryl replaces;
-SO 2R x, it is randomly by C 1To C 6Alkyl replaces;
-S (O) R x, it is randomly by five yuan or six membered heteroaryl replacement;
-S (O) R x, it is randomly by five yuan or hexa-member heterocycle replacement;
-S (O) R x, it is randomly by C 6To C 8Aryl replaces;
-S (O) R x, it is randomly by C 1To C 6Alkyl replaces;
-alkoxyl group, it is replaced by following groups:
-alkoxyl group;
-amino, it is replaced by one or more substituting groups that are independently selected from five yuan or six membered heteroaryl, five yuan or hexa-member heterocycle and alkyl, and described alkyl is randomly replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or hexa-member heterocycle; And
-the amino that randomly replaced by one or more alkyl;
-randomly by C 1To C 6The amido that alkyl replaces;
Five yuan of-S-or hexa-member heterocycle;
Five yuan of-S-or six membered heteroaryl, it is randomly by C 1To C 6Alkyl replaces;
-S-C 1To C 6Alkyl;
-S-C 6To C 8Aryl;
-sulfinyl-five yuan or hexa-member heterocycle;
-sulfinyl-five yuan or six membered heteroaryl;
-sulfinyl-C 1To C 6Alkyl;
-sulfinyl-C 6To C 8Aryl;
-alkylsulfonyl-five yuan or hexa-member heterocycle;
-alkylsulfonyl-randomly by C 1To C 6Five yuan or six membered heteroaryl that alkyl replaces;
-alkylsulfonyl-C 1To C 6Alkyl;
-alkylsulfonyl-C 6To C 8Aryl;
-five yuan to seven membered heterocyclic, and it is by one or more hydroxyl and C of being independently selected from 1To C 6The substituting group of alkyl replaces, and described alkyl is by one or more C 1To C 6Alkoxyl group replaces;
-five yuan or six membered heteroaryl, it is by one or more C 1To C 6Alkyl replaces; Or
-C 6To C 8Aryl;
-C (O)-five yuan or hexa-member heterocycle, it is randomly by one or more C 6To C 8Aryl replaces;
-C (O)-C 6To C 8Aryl;
-COOH；
-amido, it is by one or more C 1To C 6Alkyl replaces, wherein C 1To C 6Described alkyl is randomly by one or more C 1To C 6Alkoxyl group replace;
-five yuan or hexa-member heterocycle, it is replaced by one or more substituting groups that are independently selected from down group:
-hydroxyl;
-C 1To C 6Alkyl;
-SO 2R x；
-C (O)-C 6To C 8Aryl; And
-C(O)OR x；
-OR Kk, R wherein KkBe:
-C 6To C 8Aryl;
-five yuan or hexa-member heterocycle, it is randomly by C 1To C 6Alkyl and/or C 6To C 8Aryl replaces; Or
-Si(R x) 3；
-(O)-five yuan or hexa-member heterocycle, it is randomly by one or more C that select independently 1To C 6Alkyl replaces;
Or
-(O)-five yuan or six membered heteroaryl, it is randomly by one or more C that select independently 1To C 6Alkyl replaces.
2. compound as claimed in claim 1, wherein:
X is:
-COOH；
-CH=N-(C 1To C 6Alkoxyl group);
-CH=N-is (randomly by one or more C 1To C 6The amino that alkyl replaces);
-halogen;
-the alkyl that randomly replaced by one or more halogens;
-randomly by C 1To C 6The alkynyl that alkyl replaces, described alkyl are randomly replaced by one or more halogens and/or cyano group;
-oximido;
-SO 2R x；
-SO 2NH 2；
-SO 2NH(R x)；
-SO 2N(R x) 2；
-amino, it is randomly by one or more C 1To C 6Alkyl and/or-C (O)-C 1To C 6Alkyl replaces;
-amido, it is randomly by one or more C that select independently 1To C 6Alkyl replaces;
-five yuan or hexa-member heterocycle;
-five yuan or six membered heteroaryl, it is by one or more C 1To C 6Alkyl replaces, and described alkyl is replaced by one or more halogens; Or
-C 6To C 8Aryl, it is replaced by one or more substituting groups that are independently selected from following groups:
-C 1To C 6Alkyl, it is randomly replaced by one or more halogens;
-halogen; And
-cyano group.
3. compound as claimed in claim 2, wherein X is cyano group, halogen or the alkyl that replaced by one or more halogens.
4. compound as claimed in claim 3, wherein X is a cyano group.
5. compound as claimed in claim 3, wherein X is fluorine, bromine, chlorine or iodine.
6. compound as claimed in claim 3, wherein X is a trifluoromethyl.
7. the described compound of claim 1, wherein:
The C that Y is replaced by one or more following groups 6To C 8Aryl:
-amino, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-SO 2R xAnd
-C 1To C 6Alkyl, it is by one or more five yuan or six membered heteroaryl replacements;
-OC(O)NHR x；
-OC(O)N(R x) 2；
-OC(O)NH(OR x)；
-OC(O)NR x(OR x)；
-OC(O)N(OR x) 2；
-OC (O) R Ab, R wherein AbBe five yuan or hexa-member heterocycle;
-NR oCOR p, R wherein pBe:
-randomly by one or more C 1To C 6The amino that alkyl replaces, described alkyl are randomly and independently by one or more C 6To C 8Aryl and/or alkoxyl group replace; Or
-five yuan or hexa-member heterocycle, it is by one or more C 1To C 6Alkyl and/or C 6To C 8Aryl replaces,
-NR qCONR qR r, R wherein rBe:
-C 1To C 6Alkyl, it is replaced by one or more substituting groups that are independently selected from following groups:
-hydroxyl;
-alkoxyl group;
-five yuan or hexa-member heterocycle;
-five yuan or six membered heteroaryl; And
-C 6To C 8Aryl, it is randomly replaced by halogen,
-C 2To C 6Thiazolinyl;
-C 1To C 6Alkoxyl group; Or
-five yuan or hexa-member heterocycle;
-NR tCOOR u, R wherein uBe:
-C 1To C 12Alkyl, it is replaced by one or more substituting groups that are selected from following groups:
-the alkoxyl group that replaced by one or more alkoxyl groups;
-randomly by one or more C 1To C 6The amino that alkyl replaces; And
-five yuan or six membered heteroaryl;
-C 2To C 6Thiazolinyl, or
Figure A2007800089020016C1
8. compound as claimed in claim 7, wherein C 6To C 8Aryl is a phenyl.
9. compound as claimed in claim 8, wherein phenyl has at least one para-orienting group.
10. compound as claimed in claim 1, wherein Z is:
-C 1To C 6Alkyl, it is randomly by five yuan or hexa-member heterocycle replacement; Or
-five yuan or hexa-member heterocycle.
11. compound as claimed in claim 1, wherein Z is C 1To C 6Alkyl.
12. compound as claimed in claim 11, wherein Z is cyclobutyl, cyclopropyl, cyclopropyl methyl, ethyl or cyclopentyl.
13. the described compound of claim 1, wherein:
R 1Be:
-C 1To C 6Alkyl, it is replaced by following groups:
-randomly by C 1To C 6The amido that alkyl replaces; And/or
-five yuan or six membered heteroaryl;
-C 1To C 6Alkoxyl group, it is replaced by following groups:
-randomly heterocyclically substituted amino;
-randomly by C 1To C 6The amido that alkyl replaces;
-five yuan or hexa-member heterocycle, it is randomly by C 1To C 6Alkyl replaces; And/or
-five yuan or six membered heteroaryl;
-(O)-five yuan or hexa-member heterocycle;
-(O)-five yuan or six membered heteroaryl;
-SO 2R x, it is randomly replaced by following groups:
-five yuan or hexa-member heterocycle;
-C 6To C 8Aryl; And/or
-five yuan or six membered heteroaryl; Or
-alkylthio, it is randomly replaced by following groups:
-five yuan or hexa-member heterocycle;
-C 6To C 8Aryl; And/or
-five yuan or six membered heteroaryl;
14. compound as claimed in claim 1, wherein:
R 2Be:
-C 1To C 6Alkyl, it is replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or hexa-member heterocycle;
-five yuan or six membered heteroaryl;
-C 6To C 8Aryl;
-randomly by C 1To C 6The amido that alkyl replaces; And
-amino, it is randomly replaced by one or more substituting groups that are independently selected from heterocycle, alkoxyl group and alkyl, and described alkyl is randomly replaced by one or more alkoxyl groups;
-alkylthio, randomly by five yuan or six membered heteroaryl replacement, described heteroaryl is randomly replaced by alkyl for it;
-alkylthio, it is randomly by five yuan or hexa-member heterocycle replacement;
-alkylthio, it is randomly by C 6To C 8Aryl replaces;
-alkylthio, it is randomly by C 1To C 6Alkyl replaces;
-SO 2R x, randomly by five yuan or six membered heteroaryl replacement, described heteroaryl is randomly by one or more C for they 1To C 6Alkyl replaces;
-SO 2R x, it is randomly by five yuan or hexa-member heterocycle replacement;
-SO 2R x, it is randomly by C 6To C 8Aryl replaces;
-SO 2R x, it is randomly by C 1To C 6Alkyl replaces;
-S (O) R x, it is randomly by five yuan or six membered heteroaryl replacement;
-S (O) R x, it is randomly by five yuan or hexa-member heterocycle replacement;
-S (O) R x, it is randomly by C 6To C 8Aryl replaces;
-S (O) R x, it is randomly by C 1To C 6Alkyl replaces;
-alkoxyl group, it is replaced by following groups:
-alkoxyl group;
-amino, it is replaced by one or more substituting groups that are independently selected from five yuan or six membered heteroaryl, five yuan or hexa-member heterocycle and alkyl, and described alkyl is randomly replaced by one or more substituting groups that are selected from following groups:
-five yuan or hexa-member heterocycle; And
-the amino that randomly replaced by one or more alkyl;
-randomly by C 1To C 6The amido that alkyl replaces;
Five yuan of-S-or hexa-member heterocycle;
Five yuan of-S-or six membered heteroaryl, it is randomly by C 1To C 6Alkyl replaces;
-S-C 1To C 6Alkyl;
-S-C 6To C 8Aryl;
-sulfinyl-five yuan or hexa-member heterocycle;
-sulfinyl-five yuan or six membered heteroaryl;
-sulfinyl-C 1To C 6Alkyl;
-sulfinyl-C 6To C 8Aryl;
-alkylsulfonyl-five yuan or hexa-member heterocycle;
-alkylsulfonyl-randomly by C 1To C 6Five yuan or six membered heteroaryl that alkyl replaces;
-alkylsulfonyl-C 1To C 6Alkyl;
-alkylsulfonyl-C 6To C 8Aryl;
-five yuan to seven membered heterocyclic, and it is by one or more hydroxyl and C of being independently selected from 1To C 6The substituting group of alkyl replaces, and described alkyl is by C 1To C 6Alkoxyl group replaces;
-five yuan or six membered heteroaryl, it is by one or more C 1To C 6Alkyl replaces; Or
-C 6To C 8Aryl;
-C (O)-five yuan or hexa-member heterocycle, it is randomly by one or more C 6To C 8Aryl replaces;
-C (O)-C 6To C 8Aryl;
-COOH；
-amido, it is by one or more C 1To C 6Alkyl replaces, wherein C 1To C 6Described alkyl is randomly by one or more C 1To C 6Alkoxyl group replace;
-five yuan or hexa-member heterocycle, it is replaced by one or more substituting groups that are independently selected from down group:
-hydroxyl;
-C 1To C 6Alkyl;
-SO 2R x；
-C (O)-C 6To C 8Aryl; And
-C(O)OR x；
-OR Kk, R wherein KkBe:
-C 6To C 8Aryl;
-five yuan or hexa-member heterocycle, it is randomly by C 1To C 6Alkyl and/or C 6To C 8Aryl replaces; Or
-Si(R x) 3；
-(O)-five yuan or hexa-member heterocycle; Or
-(O)-five yuan or six membered heteroaryl, it is randomly by one or more C that select independently 1To C 6Alkyl replaces.
15. compound as claimed in claim 1, wherein:
X is:
-cyano group;
-halogen, or
-alkynyl, it is randomly by C 1To C 6Alkyl replaces;
Y is:
-C 6To C 8Aryl, it is replaced by one or more substituting groups that are independently selected from following groups:
-halogen;
-hydroxyl;
-alkoxyl group, it is randomly replaced by following groups:
-one or more halogens; Or
-five yuan or hexa-member heterocycle;
-C 1To C 6Alkyl;
-amino, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-SO 2R xAnd
-C 1To C 6Alkyl, it is replaced by one or more five yuan or six membered heteroaryl randomly and independently;
-OC(O)NHR x；
-NR oCOR p, R wherein pBe:
-C 1To C 6Alkyl; Or
-randomly by one or more C 1To C 6The amino that alkyl replaces;
And R wherein oBe hydrogen;
-NR qCONR qR r, R wherein qBe hydrogen, and R rBe:
-the C that randomly replaced by one or more halogens 1To C 6Alkyl; Or
-C 6To C 8Aryl, it is randomly replaced by halogen;
-SO 2R Aa, R wherein AaBe:
-five yuan or hexa-member heterocycle, it is randomly replaced by hydroxyl;
-C 1To C 6Alkoxyl group; Or
-C 1To C 6Alkyl;
-COR m, R wherein mBe:
-randomly by one or more C 1To C 6The amino that alkyl replaces, wherein this C 1To C 6Alkyl is randomly by five yuan or hexa-member heterocycle replacement; Or
-ternary is to seven membered heterocyclic, and it is randomly by C 1To C 6Alkyl replaces, and described alkyl is randomly replaced by dialkyl-7-amino;
-NR tCOOR u, R wherein tBe hydrogen, and R uBe:
-C 1To C 12Alkyl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-C 6To C 8Aryl, it is randomly replaced by one or more halogens and/or alkylhalide group;
-halogen; And
-five yuan or six membered heteroaryl;
-C 6To C 8Aryl, it is randomly replaced by halogen; Or
-five yuan or hexa-member heterocycle;
-NHR Bb, R wherein BbBe:
-C (=S) NH 2Or
-PO(OR x) 2；
-NR vSO 2R w, R wherein vBe hydrogen, and R wBe:
-C 1To C 6Alkyl; Or
-alkyl-amino or dialkyl-7-amino, it is randomly replaced by halogen; Or
Z is:
-C 1To C 6Alkyl; Or
-five yuan or hexa-member heterocycle;
R is a hydrogen;
R 1Be:
-hydrogen;
-C 1To C 6Alkoxyl group, it is replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or hexa-member heterocycle; And
-five yuan or six membered heteroaryl;
-(O)-five yuan or hexa-member heterocycle;
-(O)-five yuan or six membered heteroaryl; Or
-five yuan or hexa-member heterocycle;
R 2Be:
-alkoxyl group, it is replaced by one or more substituting groups that are independently selected from following groups:
-halogen;
-hydroxyl;
-the alkoxyl group that replaces of alkoxy randomly;
-amino, it is randomly replaced by one or more substituting groups that are independently selected from five yuan or six membered heteroaryl, five yuan or hexa-member heterocycle and alkyl, and described alkyl is randomly replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or hexa-member heterocycle; And
-the amino that randomly replaced by one or more alkyl;
-randomly by C 1To C 6The amido that alkyl replaces;
Five yuan of-S-or six membered heteroaryl, it is randomly by C 1To C 6Alkyl replaces;
-S-C 1To C 6Alkyl;
-sulfinyl-C 1To C 6Alkyl;
-alkylsulfonyl-C 1To C 6Alkyl;
-five yuan to seven membered heterocyclic, randomly by one or more hydroxyl and C of being independently selected from 1To C 6The substituting group of alkyl replaces, and described alkyl is randomly by one or more C that select independently 1To C 6Alkoxyl group replaces; And
-five yuan or six membered heteroaryl, it is randomly by one or more C 1To C 6Alkyl replaces;
-SO 2R x, it is randomly by C 1To C 6Alkyl replaces;
-S (O) R x, it is randomly by C 1To C 6Alkyl replaces;
-(O)-five yuan or six membered heteroaryl, it is randomly by one or more C that select independently 1To C 6Alkyl replaces;
-C (O)-five yuan or hexa-member heterocycle, it is randomly by one or more C 6To C 8Aryl replaces;
-C (O)-C 6To C 8Aryl;
-COOH；
-C (O) NH 2, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-C 1To C 6Alkyl, it is randomly by one or more halogen, C of being independently selected from 1To C 6Alkoxyl group, hydroxyl, five yuan or the substituting group of hexa-member heterocycle and five yuan or six membered heteroaryl replace;
-five yuan or six membered heteroaryl, it is randomly replaced by one or more substituting groups that are independently selected from down group:
-C 1To C 6Alkyl; And
-five yuan or hexa-member heterocycle, it is randomly replaced by one or more substituting groups that are independently selected from down group:
-one or more halogens;
-C 1To C 6Alkyl; And
-SO 2R x；
-amido, it is randomly by one or more C 1To C 6Alkyl replaces, and described alkyl is randomly by one or more C 1To C 6Alkoxyl group replace; Or
-OR Kk, R wherein KkBe:
-five yuan or six membered heteroaryl, it is randomly by one or more halogen, C of being independently selected from 1To C 6Alkyl, C 1To C 6Alkoxyl group and C 1To C 6The substituting group of alkylhalide group replaces; Or
-five yuan or hexa-member heterocycle, it is randomly by C 1To C 6Alkyl replaces, and described alkyl is randomly by C 6To C 8Aryl replaces; And
R 3Be hydrogen.
16. compound as claimed in claim 15, wherein:
X is:
-cyano group; Or
-halogen;
Y is:
-phenyl, it is replaced by one or more substituting groups that are independently selected from following groups:
-halogen; And
-NR tCOOR u, R wherein tBe hydrogen, and R uBe:
-C 1To C 12Alkyl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-C 6To C 8Aryl, it is randomly replaced by one or more halogens;
-halogen; And
-five yuan or six membered heteroaryl;
-C 6To C 8Aryl, it is randomly replaced by halogen; Or
-five yuan or hexa-member heterocycle;
Z is C 1To C 6Alkyl;
R is a hydrogen;
R 1Be hydrogen;
R 2Be:
-alkoxyl group, it is replaced by one or more substituting groups that are independently selected from following groups:
-halogen; And
-the alkoxyl group that replaces of alkoxy randomly;
-(O)-five yuan or hexa-member heterocycle;
-amido, it is randomly by one or more C 1To C 6Alkyl replaces, and described alkyl is randomly by one or more C 1To C 6Alkoxyl group replaces;
-five yuan or hexa-member heterocycle, it is randomly replaced by one or more substituting groups that are independently selected from down group:
-one or more halogens;
-C 1To C 6Alkyl; And
-SO 2R xAnd
R 3Be hydrogen.
17. compound as claimed in claim 15, wherein:
X is a cyano group;
Y is C 6To C 8Aryl, it is by one or more NR that are independently selected from tCOOR uSubstituting group replace, wherein be hydrogen, and R uBe randomly by one or more C 6To C 8The C that aryl replaces 1To C 12Alkyl;
Z is five yuan or hexa-member heterocycle;
R is a hydrogen;
R 1Be hydrogen;
R 2It is alkoxyl group; And
R 3Be hydrogen.
18. compound as claimed in claim 15, wherein:
X is a cyano group;
Y is C 6To C 8Aryl, it is replaced by one or more substituting groups that are independently selected from following groups:
-randomly by C 1To C 6The amino that alkyl replaces;
-NR qCONR qR r, R wherein qBe hydrogen, and R rBe C 1To C 6Alkyl:
-COR m, R wherein mBe:
-randomly by one or more C 1To C 6The amino that alkyl replaces, wherein said C 1To C 6Alkyl is randomly by five yuan or hexa-member heterocycle replacement; Or
-ternary is to seven membered heterocyclic; And
-NR tCOOR u, R wherein tBe hydrogen, and R uBe:
-C 1To C 12Alkyl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-C 6To C 8Aryl, it is randomly replaced by one or more alkylhalide groups; And
-halogen, or
-five yuan or hexa-member heterocycle;
Z is C 1To C 6Alkyl;
R is a hydrogen;
R 1Be hydrogen;
R 2It is the alkoxyl group that alkoxy replaces; And
R 3Be hydrogen.
19. compound as claimed in claim 15, wherein:
X is a cyano group;
Y is C 6To C 8Aryl, it is replaced by one or more substituting groups that are independently selected from following groups:
-NR tCOOR u, R wherein tBe hydrogen, and R uThe C that is replaced by one or more halogens 1To C 12Alkyl;
And
-NR vSO 2R w, R wherein vBe hydrogen, and R wBe C 1To C 6Alkyl;
Z is C 1To C 6Alkyl;
R is a hydrogen;
R 1Be hydrogen;
R 2Be amido, it is randomly by one or more C 1To C 6Alkyl replaces, and described alkyl is by one or more C 1To C 6Alkoxyl group replaces; And
R 3Be hydrogen.
20. compound as claimed in claim 15, wherein:
X is a cyano group;
Y is C 6To C 8Aryl, it is replaced by one or more substituting groups that are independently selected from following groups:
-randomly by one or more C 1To C 6The amino that alkyl replaces;
-NR tCOOR u, R wherein tBe hydrogen, and R uThe C that is replaced by one or more halogens 1To C 12Alkyl;
-NR vSO 2R w, R wherein vBe hydrogen, and R wBe C 1To C 6Alkyl; And
Figure A2007800089020025C1
Z is C 1To C 6Alkyl;
R is a hydrogen;
R 1Be hydrogen;
R 2By alkylsulfonyl-C 1To C 6The alkoxyl group that alkyl replaces; And
R 3Be hydrogen.
21. compound as claimed in claim 15, wherein Y is C 6To C 8Aryl, it is by one or more NR that are independently selected from tCOOR uSubstituting group replace R wherein tBe hydrogen, and R uThe C that is replaced by one or more halogens 1To C 12Alkyl.
22. compound as claimed in claim 15, wherein:
X is a cyano group;
Y is C 6To C 8Aryl, it is replaced by one or more substituting groups that are independently selected from following groups:
-C 1To C 6Alkyl;
-randomly by one or more C 1To C 6The amino that alkyl replaces;
-NR qCONR qR r, R wherein qBe hydrogen, and R rBe C 1To C 6Alkyl:
-NR tCOOR u, R wherein tBe hydrogen, and R uBe C 1To C 12Alkyl;
-NR vSO 2R w, R wherein vBe hydrogen, and R wBe:
-C 1To C 6Alkyl; Or
-alkyl-amino or dialkyl-7-amino;
Z is C 1To C 6Alkyl;
R is a hydrogen;
R 1Be hydrogen;
R 2Be OR Kk, R wherein KkBe five yuan or six membered heteroaryl, it is randomly by one or more halogen, C of being independently selected from 1To C 6Alkyl, C 1To C 6Alkoxyl group and C 1To C 6The substituting group of alkylhalide group replaces; And
R 3Be hydrogen.
23. compound as claimed in claim 22, wherein:
X is a cyano group;
Y is C 6To C 8Aryl, it is replaced by one or more substituting groups that are independently selected from following groups:
-NR tCOOR u, R wherein tBe hydrogen, and R uBe C 1To C 12Alkyl; And
-NR vSO 2R w, R wherein vBe hydrogen, and R wBe:
-C 1To C 6Alkyl; Or
-alkyl-amino or dialkyl-7-amino;
Z is C 1To C 6Alkyl;
R is a hydrogen;
R 1Be hydrogen;
R 2Be OR Kk, R wherein KkBe five yuan or six membered heteroaryl, it is randomly by one or more halogen, C of being independently selected from 1To C 6Alkyl, C 1To C 6Alkoxyl group and C 1To C 6The substituting group of alkylhalide group replaces; And
R 3Be hydrogen.
24. compound as claimed in claim 22, wherein R 2Be OR Kk, R wherein KkBy one or more C 1To C 6Five yuan or six membered heteroaryl that alkylhalide group replaces.
25. compound as claimed in claim 22, wherein R 2Be OR Kk, R wherein KkBy one or more C 1To C 6Five yuan or six membered heteroaryl that alkyl replaces.
26. compound as claimed in claim 1, wherein:
X is a cyano group;
Y is C 6To C 8Aryl, it is replaced by one or more substituting groups that are independently selected from following groups:
-NR tCOOR u, R wherein 1Be hydrogen, and R uBe C 1To C 12Alkyl; And
-NR vSO 2R w, R wherein vBe hydrogen, and R wBe C 1To C 6Alkyl;
Z is C 1To C 6Alkyl;
R is a hydrogen;
R 1Be hydrogen;
R 2Be C (O)-five yuan or hexa-member heterocycle; And
R 3Be hydrogen.
27. compound as claimed in claim 1, wherein:
X is a halogen;
Y is C 6To C 8Aryl, it is replaced by one or more substituting groups that are independently selected from following groups:
-amino;
-NR qCONR qR r, R wherein qBe hydrogen, and R rBe C 1To C 6Alkyl; And
-NR tCOOR u, R wherein tBe hydrogen, and R uBe C 1To C 12Alkyl;
Z is C 1To C 6Alkyl;
R is a hydrogen;
R 1Be hydrogen;
R 2It is alkoxyl group; And
R 3Be hydrogen.
28 compounds as claimed in claim 15, wherein:
X is a cyano group;
Y is C 6To C 8Aryl, it is replaced by one or more substituting groups that are independently selected from following groups:
-halogen;
-NR qCONR qR r, R wherein qBe hydrogen, and R rBe C 1To C 6Alkyl:
-NR tCOOR u, R wherein tBe hydrogen, and R uBe C 1To C 12Alkyl, this alkyl are randomly replaced by one or more substituting groups that are independently selected from following groups:
-C 6To C 8Aryl, it is randomly replaced by one or more halogens; And
-halogen;
-NR vSO 2R w, R wherein vBe hydrogen, and R wBe:
-C 1To C 6Alkyl; Or
-alkyl-amino or dialkyl-7-amino, it is randomly replaced by halogen; And
Figure A2007800089020028C1
Z is C 1To C 6Alkyl;
R is a hydrogen;
R 1Be hydrogen;
R 2Be five yuan or hexa-member heterocycle; And
R 3Be hydrogen.
29. compound as claimed in claim 28, wherein Y is by NR vSO 2R wThe C that replaces 6To C 8Aryl, wherein R vBe hydrogen, and R wBe C 1To C 6Alkyl.
30. compound as claimed in claim 28, the wherein C that replaced by following formula of Y 6To C 8Aryl:
Figure A2007800089020028C2
31. compound as claimed in claim 15, wherein:
X is a cyano group;
Y is C 6To C 8Aryl, it is replaced by one or more substituting groups that are independently selected from following groups:
-halogen;
-randomly by one or more C 1To C 6The amino that alkyl replaces;
-OC(O)NHR x；
-NR qCONR qR r, R wherein qBe hydrogen, and R rBe C 1To C 6Alkyl:
-NR tCOOR u, R wherein tBe hydrogen, and R uBe C 1To C 12Alkyl, this alkyl are randomly replaced by one or more substituting groups that are independently selected from following groups:
-C 6To C 8Aryl, it is randomly replaced by one or more halogens and/or alkylhalide group; And
-halogen;
-NHR Bb, R wherein BbBe-C (=S) NH 2
-NR vSO 2R w, R wherein vBe hydrogen, and R wBe:
-C 1To C 6Alkyl; Or
-alkyl-amino or dialkyl-7-amino, it is randomly replaced by halogen; And
Figure A2007800089020029C1
Z is C 1To C 6Alkyl;
R is a hydrogen;
R 1Be hydrogen;
R 2Be (O)-five yuan or hexa-member heterocycle; And
R 3Be hydrogen.
32. compound as claimed in claim 31, wherein Y is by NR tCOOR uThe C that replaces 6To C 8Aryl, wherein R tBe hydrogen, and R uBe randomly to be independently selected from randomly by the C of one or more halogens and/or alkylhalide group replacement by one or more 6To C 8The C that the substituting group of aryl replaces 1To C 12Alkyl.
33. compound as claimed in claim 15, wherein:
X is a cyano group;
Y is C 6To C 8Aryl, it is by one or more NR that are independently selected from tCOOR uSubstituting group replace R wherein tBe hydrogen, and R uThe C that is replaced by one or more halogens 1To C 12Alkyl;
Z is C 1To C 6Alkyl;
R is a hydrogen;
R 1Be
-hydrogen;
-(O)-five yuan or hexa-member heterocycle; Or
-five yuan or hexa-member heterocycle;
R 2Be:
-alkoxyl group, it is replaced by one or more substituting groups that are independently selected from following groups:
-halogen;
-alkoxyl group;
-alkylsulfonyl-C 1To C 6Alkyl;
-five yuan to seven membered heterocyclic;
-five yuan or six membered heteroaryl;
-(O)-five yuan or hexa-member heterocycle;
-(O)-five yuan or six membered heteroaryl;
-five yuan or six membered heteroaryl;
-five yuan or hexa-member heterocycle; Or
-OR Kk, R wherein KkBe randomly by one or more C 1To C 6Five yuan or six membered heteroaryl that alkoxyl group replaces; And
R 3Be hydrogen.
34. compound as claimed in claim 33, wherein R 1Be hydrogen, and R 2The alkoxyl group that is replaced by one or more halogens.
35. compound as claimed in claim 33, wherein R 1Be hydrogen, and R 2The alkoxyl group that is replaced by one or more alkoxyl groups.
36. compound as claimed in claim 15, wherein:
X is a cyano group;
Y is C 6To C 8Aryl, it is replaced by one or more substituting groups that are independently selected from following groups:
-NR qCONR qR r, R wherein qBe hydrogen, and R rThe C that is replaced by halogen 6To C 8Aryl; And
-NR tCOOR u, R wherein tBe hydrogen, and R uBy C 6To C 8The C that aryl replaces 1To C 12Alkyl, described aryl is replaced by one or more halogens and/or alkylhalide group;
Z is C 1To C 6Alkyl;
R is a hydrogen;
R 1Be hydrogen;
R 2Be:
-alkoxyl group, it is replaced by one or more substituting groups that are independently selected from following groups:
-alkoxyl group; And
-five yuan or six membered heteroaryl;
-(O)-five yuan or hexa-member heterocycle; Or
-(O)-five yuan or six membered heteroaryl; And
R 3Be hydrogen.
37. compound as claimed in claim 36, wherein Y is by NR qCONR qR rThe C that replaces 6To C 8Aryl, wherein R qBe hydrogen, and R rThe C that is replaced by halogen 6To C 8Aryl.
38. compound as claimed in claim 36, wherein Y is by one or more NR that are independently selected from tCOOR uThe C that replaces of substituting group 6To C 8Aryl, wherein R tBe hydrogen, and R uBy C 6To C 8The C that aryl replaces 1To C 12Alkyl, described aryl is replaced by one or more halogens and/or alkylhalide group.
39. formula IIb compound
Figure A2007800089020031C1
Or the acceptable salt of its pharmacology, wherein:
X is a cyano group;
Y is C 6To C 8Aryl, it is replaced by one or more substituting groups that are independently selected from following groups:
-C 1To C 6Alkyl;
-by C 1To C 6The amino that alkyl replaces;
-NR tCOOR u, R wherein tBe hydrogen, and R uBe the C that is randomly replaced by one or more halogens 1To C 12Alkyl;
-NR vSO 2R w, R wherein vBe hydrogen, and R wBe C 1To C 6Alkyl;
Z is C 1To C 6Alkyl;
R is a hydrogen;
R 1Be hydrogen;
R 2Be:
-the alkoxyl group that replaced by one or more halogens;
-five yuan or hexa-member heterocycle;
-five yuan or six membered heteroaryl, it is randomly replaced by one or more substituting groups that are independently selected from down group:
-C 1To C 6Alkyl; And
-NO 2；
-C (O)-ternary to seven membered heterocyclic or-C (O)-five-membered ring; And
-OR Kk, R wherein KkBe:
-five yuan or six membered heteroaryl, it is randomly by one or more cyano group and C of being independently selected from 1To C 6The substituting group of alkyl replaces; Or
-five yuan or hexa-member heterocycle, it is randomly replaced by one or more=O; And
R 3Be hydrogen.
40. compound as claimed in claim 39, wherein:
X is a cyano group;
Y is C 6To C 8Aryl, it is by NR tCOOR uReplace, wherein R tBe hydrogen, and R uThe C that is replaced by one or more halogens 1To C 12Alkyl;
Z is C 1To C 6Alkyl;
R is a hydrogen;
R 1Be hydrogen;
R 2The alkoxyl group that is replaced by one or more halogens; And
R 3Be hydrogen.
41. compound as claimed in claim 40, wherein C 6To C 8Aryl is a phenyl.
42. compound as claimed in claim 41, wherein said phenyl is to be substituted in contraposition.
43. compound as claimed in claim 41, wherein R uThe C that is replaced by fluorine 1To C 12Alkyl.
44. compound as claimed in claim 39, wherein:
X is a cyano group;
Y is C 6To C 8Aryl, it is replaced by one or more substituting groups that are independently selected from following groups:
-C 1To C 6Alkyl;
-by C 1To C 6The amino that alkyl replaces; And
-NR vSO 2R w, R wherein vBe hydrogen, and R wBe C 1To C 6Alkyl;
Z is C 1To C 6Alkyl;
R is a hydrogen;
R 1Be hydrogen;
R 2Be OR Kk, R wherein KkFive yuan or six membered heteroaryl being replaced by cyano group; And
R 3Be hydrogen.
45. compound as claimed in claim 44, wherein Y is that contraposition is by NR vSO 2R wThe C that replaces 6To C 8Aryl, R wherein vBe hydrogen, R wBe C 1To C 6Alkyl.
46. compound as claimed in claim 44, wherein Y is that contraposition is by C 1To C 6Alkyl and NR vSO 2R wThe C that replaces 6To C 8Aryl, wherein R vBe hydrogen, and R wBe C 1To C 6Alkyl.
47. compound as claimed in claim 44, wherein Y is the C that contraposition is replaced by amino 6To C 8Aryl, this amino is by C 1To C 6Alkyl replaces.
48. compound as claimed in claim 44, wherein R 2Be OR Kk, R wherein KkBe five yuan or the six membered heteroaryl that the ortho position is replaced by cyano group.
49. compound as claimed in claim 39, wherein:
X is a cyano group;
Y is C 6To C 8Aryl, it is replaced by one or more substituting groups that are independently selected from following groups:
-NR tCOOR u, R wherein tBe hydrogen, and R uBe C 1To C 12Alkyl; And
-NR vSO 2R w, R wherein vBe hydrogen, and R wBe C 1To C 6Alkyl;
Z is C 1To C 6Alkyl;
R is a hydrogen;
R 1Be hydrogen;
R 2Be OR Kk, R wherein KkBy C 1To C 6Five yuan or six membered heteroaryl that alkyl replaces; And
R 3Be hydrogen.
50. compound as claimed in claim 49, wherein said C 6To C 8Aryl is a phenyl.
51. compound as claimed in claim 50, wherein Y is that contraposition is by NR vSO 2R wThe phenyl that replaces, wherein R vBe hydrogen, and R wBe C 1To C 6Alkyl.
52. compound as claimed in claim 50, wherein Y is that contraposition is by NR tCOOR uThe phenyl that replaces, wherein R tBe hydrogen, and R uBe C 1To C 12Alkyl.
53. compound as claimed in claim 39, wherein:
X is a cyano group;
Y is C 6To C 8Aryl, it is by NR tCOOR uReplace, wherein R tBe hydrogen, and R uThe C that is replaced by one or more halogens 1To C 12Alkyl;
Z is C 1To C 6Alkyl;
R is a hydrogen;
R 1Be hydrogen;
R 2Be OR Kk, R wherein KkBe five yuan or six membered heteroaryl; And
R 3Be hydrogen.
54. compound as claimed in claim 53, wherein said C 6To C 8Aryl is a phenyl.
55. compound as claimed in claim 54, wherein said phenyl is to be substituted in contraposition.
56. compound as claimed in claim 55, wherein R uThe C that is replaced by fluorine 1To C 12Alkyl.
57. compound as claimed in claim 39, wherein:
X is a cyano group;
Y is by NR tCOOR uThe C that replaces 6To C 8Aryl, wherein R tBe hydrogen, and R uBe the C that is randomly replaced by one or more halogens 1To C 12Alkyl;
Z is C 1To C 6Alkyl;
R is a hydrogen;
R 1Be hydrogen;
R 2Be five yuan or six membered heteroaryl, it is randomly by C 1To C 6Alkyl replaces; And
R 3Be hydrogen.
58. compound as claimed in claim 57, wherein said C 6To C 8Aryl is a phenyl.
59. compound as claimed in claim 58, wherein Y is that contraposition is by NR tCOOR uThe phenyl that replaces, wherein R tBe hydrogen, and R uBe C 1To C 12Alkyl.
60. compound as claimed in claim 58, wherein Y is that contraposition is by NR tCOOR uThe phenyl that replaces, wherein R tBe hydrogen, and R uThe C that is replaced by one or more halogens 1To C 12Alkyl.
61. compound as claimed in claim 60, wherein R uThe C that is replaced by fluorine 1To C 12Alkyl.
62. compound as claimed in claim 39, wherein:
X is a cyano group;
Y is by NR tCOOR uThe C that replaces 6To C 8Aryl, wherein R tBe hydrogen, and R uBe C 1To C 12Alkyl;
Z is C 1To C 6Alkyl;
R is a hydrogen;
R 1Be hydrogen;
R 2Be OR Kk, R wherein KkBe five yuan or hexa-member heterocycle; And
R 3Be hydrogen.
63. compound as claimed in claim 62, wherein said C 6To C 8Aryl is a phenyl.
64. as the described compound of claim 63, wherein said phenyl is to be substituted in contraposition.
65. compound as claimed in claim 39, wherein:
X is a cyano group;
Y is by NR tCOOR uThe C that replaces 6To C 8Aryl, wherein R tBe hydrogen, and R uBe C 1To C 12Alkyl;
Z is C 1To C 6Alkyl;
R is a hydrogen;
R 1Be hydrogen;
R 2Be five yuan or hexa-member heterocycle; And
R 3Be hydrogen.
66. as the described compound of claim 65, wherein said C 6To C 8Aryl is a phenyl.
67. as the described compound of claim 66, wherein said phenyl is to be substituted in contraposition.
68. compound as claimed in claim 39, wherein:
X is a cyano group;
Y is by NR tCOOR uThe C that replaces 6To C 8Aryl, wherein R tBe hydrogen, and R uBe C 1To C 12Alkyl;
Z is C 1To C 6Alkyl;
R is a hydrogen;
R 1Be hydrogen;
R 2By NO 2Five yuan or six membered heteroaryl replacing; And
R 3Be hydrogen.
69. as the described compound of claim 68, wherein said C 6To C 8Aryl is a phenyl.
70. as the described compound of claim 69, wherein said phenyl is to be substituted in contraposition.
71. compound as claimed in claim 39, wherein:
X is a cyano group;
Y is by NR tCOOR uThe C that replaces 6To C 8Aryl, wherein R tBe hydrogen, and R uBe C 1To C 12Alkyl;
Z is C 1To C 6Alkyl;
R is a hydrogen;
R 1Be hydrogen;
R 2Be-C (O)-ternary to seven membered heterocyclic or-C (O)-five-membered ring; And
R 3Be hydrogen.
72. as the described compound of claim 71, wherein said C 6To C 8Aryl is a phenyl.
73. as the described compound of claim 72, wherein said phenyl is to be substituted in contraposition.
74. compound as claimed in claim 39, wherein:
X is a cyano group;
Y is by NR tCOOR uThe C that replaces 6To C 8Aryl, wherein R tBe hydrogen, and R uBe C 1To C 12Alkyl;
Z is C 1To C 6Alkyl;
R is a hydrogen;
R 1Be hydrogen;
R 2Be OR Kk, R wherein KkBy five yuan or hexa-member heterocycle of one or more=O replacement; And
R 3Be hydrogen.
75. as the described compound of claim 74, wherein said C 6To C 8Aryl is a phenyl.
76. as the described compound of claim 75, wherein said phenyl is to be substituted in contraposition.
77. formula IIc compound
Figure A2007800089020037C1
Or the acceptable salt of its pharmacology, wherein:
X is a cyano group;
Y is C 6To C 8Aryl, it is replaced by one or more substituting groups that are independently selected from following groups:
-NR qCONR qR r, R wherein qBe hydrogen, and R rBe C 1To C 6Alkyl:
-NR tCOOR u, R wherein tBe hydrogen, and R uBe C 1To C 12Alkyl, this alkyl are randomly replaced by one or more substituting groups that are independently selected from following groups:
-C 6To C 8Aryl, it is randomly replaced by one or more halogens;
-halogen; And
-five yuan or six membered heteroaryl; And
-NR vSO 2R w, R wherein vBe hydrogen, and R wBe C 1To C 6Alkyl;
Z is;
-C 1To C 6Alkyl; Or
-five yuan or hexa-member heterocycle;
R is a hydrogen;
R 1Be:
-C 1To C 6Alkoxyl group, it is replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or hexa-member heterocycle; And
-five yuan or six membered heteroaryl;
-(O)-five yuan or hexa-member heterocycle;
-(O)-five yuan or six membered heteroaryl; Or
-five yuan or hexa-member heterocycle;
R 2Be hydrogen; And
R 3Be hydrogen;
Condition is to work as R 1The C that is replaced by five yuan or hexa-member heterocycle 1To C 6Alkoxyl group or R 1When being five yuan or hexa-member heterocycle, Y is by NR tCOOR uThe C that replaces 6To C 8Aryl, wherein R tBe hydrogen, and R uBe:
The C that is replaced by one or more halogens 1To C 12Alkyl; Or
The aryl that is replaced by one or more halogens.
78. as the described compound of claim 77, wherein:
Y is by NR tCOOR uThe C that replaces 6To C 8Aryl, wherein R tBe hydrogen, and R uBe C 1To C 12Alkyl;
Z is C 1To C 6Alkyl; And
R 1The C that is replaced by five yuan or six membered heteroaryl 1To C 6Alkoxyl group.
79. as the described compound of claim 77, wherein R 1The C that is replaced by five yuan or six membered heteroaryl 1To C 6Alkoxyl group.
80. as the described compound of claim 77, wherein R 1Be (O)-five yuan or hexa-member heterocycle.
81. as the described compound of claim 77, wherein R 1Be (O)-five yuan or six membered heteroaryl.
82. as the described compound of claim 77, wherein Z is cyclobutyl, cyclopropyl, cyclopropyl methyl, ethyl or cyclopentyl.
83. the compound of formula IId
Figure A2007800089020038C1
Or the acceptable salt of its pharmacology, wherein:
X is a hydrogen;
Y is C 6To C 8Aryl, it is replaced by one or more substituting groups that are independently selected from following groups:
-NR qCONR qR r, R wherein qBe hydrogen, and R rBe C 1To C 6Alkyl; And
-NR tCOOR u, R wherein tBe hydrogen, and R uThe C that is replaced by one or more halogens 1To C 12Alkyl;
Z is C 1To C 6Alkyl;
R is a hydrogen;
R 1Be hydrogen;
R 2Be OR Kk, R wherein KkBe:
-five yuan or six membered heteroaryl;
-five yuan or hexa-member heterocycle; Or
-five yuan or six membered heteroaryl, it is randomly replaced by one or more halogens of selecting independently; And
R 3Be hydrogen.
84. as the described compound of claim 83, wherein:
X is a hydrogen;
Y is C 6To C 8Aryl, it is by NR tCOOR uReplace, wherein R tBe hydrogen, and R uThe C that is replaced by one or more halogens 1To C 12Alkyl;
Z is C 1To C 6Alkyl;
R is a hydrogen;
R 1Be hydrogen;
R 2Be OR Kk, R wherein KkBe five yuan or six membered heteroaryl; And
R 3Be hydrogen.
85. as the described compound of claim 84, wherein said C 6To C 8Aryl is a phenyl.
86. as the described compound of claim 84, wherein Y is that contraposition is by NR tCOOR uThe phenyl that replaces, wherein R tBe hydrogen, and R uThe C that is replaced by fluorine 1To C 12Alkyl.
87. as the described compound of claim 84, wherein Z is cyclobutyl, cyclopropyl, cyclopropyl methyl, ethyl or cyclopentyl.
88. as the described compound of claim 83, wherein R 2Be (O)-five yuan or hexa-member heterocycle.
89. the compound of formula IIe
Figure A2007800089020039C1
Or the acceptable salt of its pharmacology, wherein:
X is:
-hydrogen;
-cyano group;
-nitro;
-formyl radical;
-COOH；
-COR x, R wherein xBe C 1To C 6Alkyl;
-CH=N-(C 1To C 6Alkoxyl group);
-CH=N-is (randomly by one or more C 1To C 6The amino that alkyl replaces);
-halogen;
-the alkyl that randomly replaced by one or more halogens;
-optional by cyano or C 1To C 6The alkynyl that alkyl replaces, described alkyl is randomly replaced by one or more halogens;
-oximido;
-SO 2R x；
-SO 2NH 2；
-SO 2NH(R x)；
-SO 2N(R x) 2；
-amino, it is randomly by one or more C that select independently 1To C 6Alkyl and/or-C (O)-C 1To C 6Alkyl replaces;
-amido, it is randomly by one or more C that select independently 1To C 6Alkyl replaces;
-five yuan or hexa-member heterocycle;
-five yuan or six membered heteroaryl, it is randomly by one or more C 1To C 6Alkyl replaces, and described alkyl is randomly replaced by one or more halogens; Or
-C 6To C 8Aryl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-C 1To C 6Alkyl, it is randomly replaced by one or more halogens;
-halogen; And
-cyano group;
Y is:
-the benzothiazolyl that randomly replaced by amino, described amino is randomly by one or more C 1To C 6Alkyl replaces;
-indyl, it is randomly at the quilt-SO of nitrogen-atoms place 2R xReplace;
-C 6To C 8Aryl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-halogen;
-C 1To C 6Alkyl;
-alkoxyl group, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-halogen;
-five yuan or hexa-member heterocycle;
-C (O) NH 2, it is randomly by C 6To C 8Alkyl replaces;
-C (O) NH-(C 1To C 6)-alkyl;
-hydroxyl;
-alkylhalide group;
-cyano group;
-nitro;
-COOH；
-N＝CHN(R x) 2；
-amino, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-SO 2R x；
-hexa-atomic to eight yuan of aryl, it is randomly by one or more alkyl, halogen, alkylhalide group, cyano group, alkoxyl group, COR of being independently selected from xReplace with the substituting group of halogen alkoxyl group;
-five yuan or six membered heteroaryl, it is randomly by one or more alkyl, halogen, alkylhalide group, cyano group, alkoxyl group, halogen alkoxyl group and C of being independently selected from 6To C 8The substituting group of aryl replaces, wherein this C 6To C 8Aryl is randomly replaced by halogen;
-five yuan or hexa-member heterocycle, its randomly by one or more be independently selected from hydroxyl ,=substituting group of O, alkyl and alkylhalide group replaces;
-C 1To C 7Alkyl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or six membered heteroaryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, halogen and alkylhalide group;
-C 6To C 8Aryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, halogen and alkylhalide group;
-alkoxyl group; And
-halogen; And
-PO 2R x；
-OC (O) NHR x, R wherein xRandomly by vinyl substituted;
-OC (O) N (R u) 2, R wherein uBe alkyl or C 6To C 8Aryl, described alkyl or aryl is randomly replaced by dialkyl amido;
-OC (O) NH (OR Uu), R wherein UuBe the C that is randomly replaced by dialkyl amido 6To C 8Aryl;
-OC(O)NR x(OR x)；
-OC(O)N(OR x) 2；
-OC (O) R Ab, R wherein AbBe five yuan or the hexa-member heterocycle that is randomly replaced by heteroaryl, described heteroaryl is randomly replaced by alkyl or alkylhalide group;
-NR oC (O) R p, R wherein pBe:
-C 1To C 6Alkyl;
-randomly by one or more C 1To C 6The amino that alkyl replaces, described alkyl is randomly by one or more C that are independently selected from 6To C 8The substituting group of aryl and alkoxyl group replaces; Or
-five yuan or hexa-member heterocycle, it is randomly by one or more C that are independently selected from 1To C 6Alkyl and C 6To C 8The substituting group of aryl replaces;
And R wherein oBe:
-hydrogen; Or
-C 1To C 6Alkyl;
-NR qCONR qR r, R wherein qBe hydrogen, and R wherein rBe:
-C 1To C 6Alkyl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-halogen;
-hydroxyl;
-alkoxyl group;
-five yuan or hexa-member heterocycle;
-five yuan or six membered heteroaryl; And
-C 6To C 8Aryl, it is randomly replaced by halogen;
-the C that randomly replaced by one or more halogens 2To C 6Thiazolinyl;
-C 1To C 6Alkoxyl group;
-five yuan or hexa-member heterocycle; Or
-five yuan to six membered heteroaryl, and it is randomly replaced by alkyl;
-SO 2R Aa, R wherein AaBe:
-five yuan or hexa-member heterocycle, it is randomly replaced by one or more substituting groups that are independently selected from down group:
-hydroxyl;
-C 1To C 6Alkoxyl group; And
-C 1To C 6Alkyl;
-the amino that randomly replaced by alkyl, described alkyl are randomly replaced by one or more substituting groups that are independently selected from down group:
-alkoxyl group;
-hydroxyl;
-halogen;
-COR m, R wherein mBe:
-randomly by one or more C 1To C 6The amino that alkyl replaces, described alkyl is randomly by five yuan or hexa-member heterocycle or C 6To C 8Aryl replaces, and described heterocycle or aryl are randomly replaced by one or more substituting groups that are independently selected from halogen and alkoxyl group;
-the heterocycle that randomly replaced by hydroxyl;
-ternary is to seven membered heterocyclic, and it is randomly by C 1To C 6Alkyl replaces, and described alkyl is randomly replaced by dialkyl-7-amino;
-NR tCOOR u, R wherein tBe hydrogen, and R wherein uBe:
-C 1To C 12Alkyl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-C 6To C 8Aryl, it is randomly replaced by one or more halogens and/or alkylhalide group;
-the alkoxyl group that randomly replaced by one or more alkoxyl groups;
-randomly by one or more C 1To C 6The amino that alkyl replaces;
-halogen;
-SO 2R w；
-SO 2R x；
-five yuan or six membered heteroaryl; And
-five yuan or hexa-member heterocycle;
-C 2To C 6Thiazolinyl;
-C 6To C 8Aryl, it is randomly replaced by halogen;
-quaternary is to seven membered heterocyclic, and it is randomly replaced by one or more substituting groups that are independently selected from down group:
＝O；
-SO 2R w；
-COR pAnd
-(CO) O-(C 1To C 4Alkyl)-O-(C 1To C 4Alkyl);
-NHR Bb, R wherein BbBe:
-C(＝S)NH 2；
-C(＝S)NHR x；
-C(＝S)NR xR x；
-C (=N-CN) NHR xOr
-PO(OR x) 2；
-N(CONHR w) 2；
-NH(SOR w)；
-N(SO 2R w) 2；
-NR vSO 2R w, R wherein vBe hydrogen or the alkyl that randomly replaced by quaternary to seven membered heterocyclic;
And R wherein wBe:
-randomly by C 6To C 8The C that aryl replaces 1To C 6Alkyl, described aryl are randomly replaced by one or more substituting groups that are independently selected from alkylhalide group, halogen, alkoxyl group and alkyl;
-C 6To C 8Aryl;
-C 6To C 8Heteroaryl; Or
-randomly by the amino of heterocycle or alkyl replacement, described heterocycle or alkyl are randomly by one or more halogen, C of being independently selected from 1To C 6Alkoxyl group, carbalkoxy, (CO) O-(C 1To C 6) alkyl), the substituting group of hydroxyl, cyano group, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
Figure A2007800089020045C1
Figure A2007800089020046C1
-five yuan to six membered heteroaryl, and it is randomly replaced by one or more substituting groups that are independently selected from down group:
-halogen;
-C 1To C 6Alkyl;
-alkoxyl group, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-halogen;
-five yuan or hexa-member heterocycle; And
-C (O) NH 2, it is randomly by C 6To C 8Alkyl replaces;
-hydroxyl;
-alkylhalide group;
-cyano group;
-nitro;
-COOH；
-amino, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-SO 2R x；
-hexa-atomic to eight yuan of aryl, it is randomly by one or more alkyl, halogen, alkylhalide group, cyano group, alkoxyl group, COR of being independently selected from xReplace with the substituting group of halogen alkoxyl group;
-five yuan or six membered heteroaryl, it is randomly by one or more alkyl, halogen, alkylhalide group, cyano group, alkoxyl group, halogen alkoxyl group and C of being independently selected from 6To C 8The substituting group of aryl replaces, wherein this C 6To C 8Aryl is randomly replaced by halogen;
-C 5To C 6Heterocycle, it is randomly replaced by one or more substituting groups that are independently selected from hydroxyl, alkyl and alkylhalide group; And
-C 1To C 7Alkyl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or six membered heteroaryl, it is randomly replaced by one or more alkyl, halogen and/or alkylhalide group;
-C 6To C 8Aryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, halogen and alkylhalide group;
-alkoxyl group; And
-halogen;
-NR oCOR p, R wherein pBe:
-C 1To C 6Alkyl;
-randomly by one or more C 1To C 6The amino that alkyl replaces, described alkyl are randomly and independently by one or more C 6To C 8Aryl and/or alkoxyl group replace; Or
-five yuan or hexa-member heterocycle, it is by one or more C 1To C 6Alkyl and/or C 6To C 8Aryl replaces;
And R wherein oBe:
-hydrogen; Or
-C 1To C 6Alkyl;
-NR qCONR qR r, R wherein qBe hydrogen, and R wherein rBe:
-C 1To C 6Alkyl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-halogen;
-hydroxyl;
-alkoxyl group;
-five yuan or hexa-member heterocycle;
-five yuan or six membered heteroaryl; And
-C 6To C 8Aryl, it is randomly replaced by halogen;
-C 2To C 6Thiazolinyl, it is randomly replaced by one or more halogens;
-C 1To C 6Alkoxyl group;
-five yuan or hexa-member heterocycle; Or
-five yuan to six membered heteroaryl, and it is randomly replaced by alkyl;
-NR tCOOR u, R wherein tBe hydrogen, and R wherein uBe:
-C 1To C 12Alkyl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-C 6To C 8Aryl, it is randomly replaced by one or more halogens and/or alkylhalide group;
-the alkoxyl group that randomly replaced by one or more alkoxyl groups;
-randomly by one or more C 1To C 6The amino that alkyl replaces;
-halogen;
-SO 2R w；
-SO 2R x；
-five yuan or six membered heteroaryl; And
-five yuan or hexa-member heterocycle; And
-NR vSO 2R w, R wherein vBe hydrogen or the alkyl that randomly replaced by quaternary to seven membered heterocyclic;
And R wherein wBe:
-randomly by C 6To C 8The C that aryl replaces 1To C 6Alkyl, described aryl are randomly replaced by one or more substituting groups that are independently selected from alkylhalide group, halogen, alkoxyl group and alkyl;
-C 6To C 8Aryl;
-C 6To C 8Heteroaryl;
-randomly by the amino of heterocycle or alkyl replacement, described heterocycle or alkyl are randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, carbalkoxy, hydroxyl, cyano group, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
Figure A2007800089020049C1
Z is:
-C 1To C 6Alkyl, it is randomly by five yuan or hexa-member heterocycle replacement; Or
-five yuan or hexa-member heterocycle;
R is a hydrogen;
R 1Be:
-hydrogen;
-five yuan or hexa-member heterocycle, it is randomly replaced by one or more substituting groups that are independently selected from down group:
-hydroxyl;
-C 1To C 6Alkyl;
-SO 2R x；
-C (O)-C 6To C 8Aryl;
-COR pAnd
-C (O) OR xOr
-five yuan or six membered heteroaryl, it is randomly replaced by one or more substituting groups that are independently selected from down group:
-C 1To C 6Alkyl, it is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-alkoxyl group;
-halogen;
-alkylthio;
-alkylhalide group;
-cyano group;
-the amino that randomly replaced by alkyl, described alkyl is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, cyano group, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-heterocycle;
-nitro;
-hydroxyl;
-COOH；
-CO 2R x；
-COR x；
-randomly by one or more C 1To C 6C (O) NH that alkyl replaces 2, described alkyl is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-amido, it is randomly by one or more halogen, C of being independently selected from 1To C 6Alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle, five yuan or six membered heteroaryl and C 1To C 6The substituting group of alkyl replaces, and described alkyl is randomly by one or more C 1To C 6Alkoxyl group replaces;
-C 1To C 6Alkyl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-amino, it is randomly replaced by one or more substituting groups that are independently selected from heterocycle, alkoxyl group and alkyl, and described alkyl is randomly replaced by one or more alkoxyl groups;
-randomly by C 1To C 6The amido that alkyl replaces;
-five yuan or hexa-member heterocycle, it is randomly by C 1To C 6Alkyl replaces;
-five yuan or six membered heteroaryl; And
-C 6To C 8Aryl;
-SO 2R x；
-C 2To C 6Thiazolinyl, it is randomly by SO 2R xReplace;
-C 1To C 6Alkoxyl group, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-halogen;
-hydroxyl;
-cyano group;
-the alkoxyl group that replaces of alkoxy randomly;
-amino, it is randomly replaced by one or more substituting groups that are independently selected from five yuan or six membered heteroaryl, five yuan or hexa-member heterocycle and alkyl, and described alkyl is randomly replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or hexa-member heterocycle; And
-the amino that randomly replaced by one or more alkyl;
-randomly heterocyclically substituted amino;
-randomly by C 1To C 6The amido that alkyl replaces;
-five yuan to seven membered heterocyclic, and it is randomly by one or more hydroxyl and C of being independently selected from 1To C 6The substituting group of alkyl replaces, and described alkyl is randomly replaced by one or more substituting groups that randomly are selected from following groups;
-C 1To C 6Alkoxyl group; And
-C 6To C 8Alryl;
-five yuan or six membered heteroaryl, it is randomly replaced by one or more substituting groups that are independently selected from down group:
-C 1To C 6Alkyl; And
-quaternary is to seven membered heterocyclic;
-alkoxyl group; And
-C 6To C 8Aryl;
-(O)-five yuan or hexa-member heterocycle, it is randomly replaced by one or more substituting groups that are independently selected from down group:
-hydroxyl;
-C 1To C 6Alkyl;
-SO 2R x；
-C (O)-C 6To C 8Aryl;
-COR pAnd
-C (O) OR xOr
-(O)-five yuan or six membered heteroaryl, it is randomly replaced by one or more substituting groups that are independently selected from down group:
-C 1To C 6Alkyl, it is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-alkoxyl group;
-halogen;
-alkylthio;
-alkylhalide group;
-cyano group;
-the amino that randomly replaced by alkyl, described alkyl is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, cyano group, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-heterocycle;
-nitro;
-hydroxyl;
-COOH；
-CO 2R x；
-COR x；
-C (O) NH 2, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-C 1To C 6Alkyl, it is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces; And
-amido, it is randomly by one or more halogen, C of being independently selected from 1To C 6Alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle, five yuan or six membered heteroaryl and C 1To C 6The substituting group of alkyl replaces, and described alkyl is randomly by one or more C 1To C 6Alkoxyl group replaces;
-randomly by one or more C 1To C 6C (O) NH that alkyl replaces 2, described alkyl is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-C (O)-ternary is to seven membered heterocyclic, and it is randomly replaced by one or more substituting groups that are independently selected from down group:
-C 6To C 8Aryl;
-five yuan or six membered heteroaryl; And
-C 1To C 6Alkyl, it is randomly by one or more replacements that replaced by hydroxyl;
-SO 2R x, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or hexa-member heterocycle;
-C 6To C 8Aryl; And
-five yuan or six membered heteroaryl; Or
-alkylthio, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or hexa-member heterocycle;
-C 6To C 8Aryl; And
-five yuan or six membered heteroaryl;
-C 6To C 8Aryl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-C 1To C 6Alkyl, it is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-alkoxyl group;
-halogen;
-alkylthio;
-alkylhalide group;
-cyano group;
-the amino that randomly replaced by alkyl, described alkyl is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, cyano group, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-heterocycle;
-nitro;
-hydroxyl;
-COOH；
-CO 2R x；
-COR x；
-randomly by one or more C 1To C 6C (O) NH that alkyl replaces 2, described alkyl is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces; And
-amido, it is randomly by one or more halogen, C of being independently selected from 1To C 6Alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle, five yuan or six membered heteroaryl and C 1To C 6The substituting group of alkyl replaces, and described alkyl is randomly by one or more C 1To C 6Alkoxyl group replaces;
-C (O)-five yuan or six membered heteroaryl;
-C (O)-C 6To C 8Aryl;
-COOH; Or
-OR Kk, R wherein KkBe:
-C 6To C 8Aryl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-C 1To C 6Alkyl, it is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-alkoxyl group;
-halogen;
-alkylthio;
-alkylhalide group;
-cyano group;
-the amino that randomly replaced by alkyl, described alkyl is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, cyano group, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-heterocycle;
-nitro;
-hydroxyl;
-COOH；
-CO 2R x；
-COR x；
-randomly by one or more C 1To C 6C (O) NH that alkyl replaces 2, described alkyl is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces; And
-amido, it is randomly by one or more halogen, C of being independently selected from 1To C 6Alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle, five yuan or six membered heteroaryl and C 1To C 6The substituting group of alkyl replaces, and described alkyl is randomly by one or more C 1To C 6Alkoxyl group replaces;
R 2Be:
-C 1To C 6Alkyl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or hexa-member heterocycle;
-five yuan or six membered heteroaryl;
-C 6To C 8Aryl;
-randomly by C 1To C 6The amido that alkyl replaces; And
-amino, it is randomly replaced by one or more substituting groups that are independently selected from heterocycle, alkoxyl group and alkyl, and described alkyl is randomly replaced by one or more alkoxyl groups; And
-SO 2R x；
-C 2To C 6Thiazolinyl, it is randomly by SO 2R xReplace;
-alkylthio, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or six membered heteroaryl, it is randomly replaced by alkyl;
-five yuan or hexa-member heterocycle;
-C 6To C 8Aryl; And
-C 1To C 6Alkyl;
-SO 2R x, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or six membered heteroaryl, it is randomly by one or more C 1To C 6Alkyl replaces;
-five yuan or hexa-member heterocycle;
-C 6To C 8Aryl; And
-C 1To C 6Alkyl;
-S (O) R x, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or six membered heteroaryl;
-five yuan or hexa-member heterocycle;
-C 6To C 8Aryl; And
-C 1To C 6Alkyl;
-alkoxyl group, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-halogen;
-hydroxyl;
-cyano group;
-the alkoxyl group that replaces of alkoxy randomly;
-amino, it is randomly by one or more being independently selected from-SO 2-C 1To C 4The substituting group of alkyl, five yuan or six membered heteroaryl, five yuan or hexa-member heterocycle and alkyl replaces, and described alkyl is randomly replaced by one or more substituting groups that are selected from following groups:
-five yuan or hexa-member heterocycle; And
-the amino that randomly replaced by one or more alkyl;
-randomly by C 1To C 6The amido that alkyl replaces;
Five yuan of-S-or hexa-member heterocycle;
Five yuan of-S-or six membered heteroaryl, it is randomly by C 1To C 6Alkyl replaces;
-S-C 1To C 6Alkyl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-C 6To C 8Aryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, alkylhalide group and halogen; And
-C 5To C 6Heteroaryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, alkylhalide group and halogen;
-S-C 6To C 8Aryl;
-sulfinyl-five yuan or hexa-member heterocycle;
-sulfinyl-five yuan or six membered heteroaryl;
-sulfinyl-C 1To C 6Alkyl, this alkyl are randomly replaced by one or more substituting groups that are independently selected from following groups:
-C 6To C 8Aryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, alkylhalide group and halogen; And
-C 5To C 6Heteroaryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, alkylhalide group and halogen;
-sulfinyl-C 6To C 8Aryl;
-alkylsulfonyl-five yuan or hexa-member heterocycle;
-alkylsulfonyl-randomly by C 1To C 6Five yuan or six membered heteroaryl that alkyl replaces;
-alkylsulfonyl-C 1To C 6Alkyl, this alkyl are randomly replaced by one or more substituting groups that are independently selected from following groups:
-C 6To C 8Aryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, alkylhalide group and halogen; And
-C 5To C 6Heteroaryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, alkylhalide group and halogen;
-alkylsulfonyl-C 6To C 8Aryl;
-five yuan to seven membered heterocyclic, its randomly by one or more be independently selected from hydroxyl ,=O, heterocycle and C 1To C 6The substituting group of alkyl replaces, and described alkyl is randomly replaced by one or more substituting groups that are independently selected from following groups:
-C 1To C 6Alkoxyl group; And
-C 6To C 8Aryl;
-five yuan or six membered heteroaryl, it is randomly replaced by one or more substituting groups that are independently selected from down group:
-C 1To C 6Alkyl, it is randomly replaced by one or more alkoxyl groups;
-quaternary is to seven membered heterocyclic; And
-alkoxyl group; And
-C 6To C 8Aryl;
-C 6To C 8Aryl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-C 1To C 6Alkyl, it is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-alkoxyl group;
-halogen;
-alkylthio;
-alkylhalide group;
-cyano group;
-the amino that randomly replaced by alkyl, described alkyl is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, cyano group, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-heterocycle;
-nitro;
-hydroxyl;
-COOH；
-CO 2R x；
-COR x；
-randomly by one or more C 1To C 6C (O) NH that alkyl replaces 2, described alkyl is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces; And
-amido, it is randomly by one or more halogen, C of being independently selected from 1To C 6Alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle, five yuan or six membered heteroaryl and C 1To C 6The substituting group of alkyl replaces, and described alkyl is randomly by one or more C 1To C 6Alkoxyl group replaces;
-(O)-five yuan or hexa-member heterocycle, it is randomly replaced by one or more substituting groups that are independently selected from down group:
-hydroxyl;
＝O；
-C 1To C 6Alkyl;
-SO 2R x；
-C (O)-C 6To C 8Aryl;
-COR pAnd
-C (O) OR xOr
-(O)-five yuan or six membered heteroaryl, it is randomly replaced by one or more substituting groups that are independently selected from down group:
-C 1To C 6Alkyl, it is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-alkoxyl group;
-halogen;
-alkylthio;
-alkylhalide group;
-cyano group;
-the amino that randomly replaced by alkyl, described alkyl is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, cyano group, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-heterocycle;
-nitro;
-hydroxyl;
-COOH；
-CO 2R x；
-COR x；
-randomly by one or more C 1To C 6C (O) NH that alkyl replaces 2, described alkyl is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces; And
-amido, it is randomly by one or more halogen, C of being independently selected from 1To C 6Alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle, five yuan or six membered heteroaryl and C 1To C 6The substituting group of alkyl replaces, and described alkyl is randomly by one or more C 1To C 6Alkoxyl group replaces;
-C (O)-ternary is to seven membered heterocyclic, and it is randomly replaced by one or more substituting groups that are independently selected from down group:
-C 6To C 8Aryl;
-five yuan or six membered heteroaryl; And
-C 1To C 6Alkyl, it is randomly replaced by one or more hydroxyls;
-C (O)-five yuan or six membered heteroaryl;
-C (O)-C 6To C 8Aryl;
-COOH；
-randomly by one or more C 1To C 6C (O) NH that alkyl replaces 2, described alkyl is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-amido, it is randomly by one or more C 1To C 6Alkyl replaces, and described alkyl is randomly by one or more C 1To C 6Alkoxyl group replaces;
-amino, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-SO 2R x；
-hexa-atomic to eight yuan of aryl, it is randomly by one or more alkyl, halogen, alkylhalide group, cyano group, alkoxyl group, COR of being independently selected from xReplace with the substituting group of halogen alkoxyl group;
-five yuan or six membered heteroaryl, it is randomly by one or more alkyl, halogen, alkylhalide group, cyano group, alkoxyl group, halogen alkoxyl group and C of being independently selected from 6To C 8The substituting group of aryl replaces, wherein C 6To C 8Aryl randomly replaced by halogen;
-C 5To C 6Heterocycle, it is randomly replaced by one or more substituting groups that are independently selected from hydroxyl, alkyl and alkylhalide group;
-C 1To C 7Alkyl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or six membered heteroaryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, halogen and alkylhalide group;
-C 6To C 8Aryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, halogen and alkylhalide group;
-alkoxyl group; And
-halogen;
-five yuan or six membered heteroaryl, it is randomly replaced by one or more substituting groups that are independently selected from down group:
-C 1To C 6Alkyl, it is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-alkoxyl group;
-halogen;
-alkylthio;
-alkylhalide group;
-cyano group;
-the amino that randomly replaced by one or more alkyl, described alkyl is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, cyano group, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-heterocycle;
-nitro;
-hydroxyl;
-COOH；
-CO 2R x；
-COR x；
-randomly by one or more C 1To C 6C (O) NH that alkyl replaces 2, described alkyl is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-amido, it is randomly by one or more halogen, C of being independently selected from 1To C 6Alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle, five yuan or six membered heteroaryl and C 1To C 6The substituting group of alkyl replaces, and described alkyl is randomly by one or more C 1To C 6Alkoxyl group replaces;
-five yuan or hexa-member heterocycle, it is randomly replaced by one or more substituting groups that are independently selected from down group:
-hydroxyl;
＝O；
-C 1To C 6Alkyl;
-SO 2R x；
-C (O)-C 6To C 8Aryl;
-COR pAnd
-C(O)OR x；
-OR Kk, R wherein KkBe:
-C 6To C 8Aryl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-C 1To C 6Alkyl, it is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-alkoxyl group;
-halogen;
-alkylthio;
-alkylhalide group;
-cyano group;
-the amino that randomly replaced by alkyl, described alkyl is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, cyano group, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-heterocycle;
-nitro;
-hydroxyl;
-COOH；
-CO 2R x；
-COR x；
-randomly by one or more C 1To C 6C (O) NH that alkyl replaces 2, described alkyl is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces; And
-amido, it is randomly by one or more halogen, C of being independently selected from 1To C 6Alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle, five yuan or six membered heteroaryl and C 1To C 6The substituting group of alkyl replaces, and described alkyl is randomly by one or more C 1To C 6Alkoxyl group replaces;
-five yuan to hexa-member heterocycle, and it is randomly by C 1To C 6Alkyl replaces, and described alkyl is randomly by C 6To C 8Aryl replaces; Or
-five yuan to six membered heteroaryl, and it is randomly by one or more halogen, C of being independently selected from 1To C 6Alkyl, C 1To C 6Alkoxyl group and C 1To C 6The substituting group of alkylhalide group replaces;
-SO 2R xOr
-Si(Rx) 3；
-OC (O) NHR x, R wherein xRandomly by C 6To C 8Aryl replaces;
-OC (O) N (R x) 2Or
Figure A2007800089020062C1
And
R 3Be hydrogen; Or
-nitro;
Condition is X, Y, Z, R 1, R 2And R 3In have a following selection at least:
X is:
-CH=N-(C 1To C 6Alkoxyl group);
-CH=N-is (randomly by one or more C 1To C 6The amino that alkyl replaces);
-halogen;
-the alkyl that randomly replaced by one or more halogens;
-randomly by C 1To C 6The alkynyl that alkyl replaces, described alkyl are randomly replaced by one or more halogens and/or cyano group;
-oximido;
-SO 2R x；
-SO 2NH 2；
-SO 2NH(R x)；
-SO 2N(R x) 2；
-amino, it is randomly by one or more C that select independently 1To C 6Alkyl and/or C (O)-C 1To C 6Alkyl replaces;
-amido, it is randomly by one or more C that select independently 1To C 6Alkyl replaces;
-five yuan or hexa-member heterocycle;
-five yuan or six membered heteroaryl, it is by one or more C 1To C 6Alkyl replaces, and described alkyl is randomly replaced by one or more halogens; Or
-C 6To C 8Aryl, it is replaced by one or more substituting groups that are independently selected from following groups:
-C 1To C 6Alkyl, it is randomly replaced by one or more halogens;
-halogen; And
-cyano group;
Y is:
-by the amino benzothiazolyl that replaces, described amino is randomly by one or more C 1To C 6Alkyl replaces;
-indyl, it is at the quilt-SO of nitrogen-atoms place 2R xReplace;
-C 6To C 8Aryl, it is replaced by one or more substituting groups that are independently selected from following groups:
-alkoxyl group, it is replaced by one or more substituting groups that are independently selected from following groups:
-C (O) NH 2, it is randomly by C 6To C 8Alkyl replaces; And
-C (O) NH-(C 1To C 6)-alkyl;
-alkylhalide group;
-cyano group;
-COOH；
-N＝CHN(R x) 2；
-amino, it is replaced by one or more substituting groups that are independently selected from following groups:
-SO 2R x；
-hexa-atomic to eight yuan of aryl, it is randomly by one or more alkyl, halogen, alkylhalide group, cyano group, alkoxyl group, COR of being independently selected from xReplace with the substituting group of halogen alkoxyl group;
-five yuan or six membered heteroaryl, it is randomly by one or more alkyl, halogen, alkylhalide group, cyano group, alkoxyl group, halogen alkoxyl group and C of being independently selected from 6To C 8The substituting group of aryl replaces, wherein this C 6To C 8Aryl is randomly replaced by halogen;
-five yuan or hexa-member heterocycle, its randomly by one or more be independently selected from hydroxyl ,=substituting group of O, alkyl and alkylhalide group replaces;
-C 1To C 7Alkyl, it is replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or six membered heteroaryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, halogen and alkylhalide group;
-C 6To C 8Aryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, halogen and alkylhalide group;
-alkoxyl group; And
-halogen; And
-PO 2R x；
-OC (O) NHR x, R wherein xRandomly by vinyl substituted;
-OC (O) N (R u) 2, R wherein uBe alkyl or C 6To C 8Aryl, described alkyl or aryl is randomly replaced by dialkyl amido;
-OC (O) NH (OR Uu), R wherein UuBe the C that is randomly replaced by dialkyl amido 6To C 8Aryl;
-OC(O)NR x(OR x)；
-OC(O)N(OR x) 2；
-OC (O) R Ab, R wherein AbBe five yuan or the hexa-member heterocycle that is randomly replaced by heteroaryl, described heteroaryl is randomly replaced by alkyl or alkylhalide group;
-NR oC (O) R p, R wherein pBe:
-randomly by one or more C 1To C 6The amino that alkyl replaces, described alkyl is randomly by one or more C that are independently selected from 6To C 8The substituting group of aryl and alkoxyl group replaces; Or
-five yuan or hexa-member heterocycle, it is by one or more C that are independently selected from 1To C 6Alkyl and C 6To C 8The substituting group of aryl replaces;
-NR qCONR qR r, R wherein rBe:
-C 1To C 6Alkyl, it is replaced by one or more substituting groups that are independently selected from following groups:
-hydroxyl;
-alkoxyl group;
-five yuan or hexa-member heterocycle;
-five yuan or six membered heteroaryl; And
-the C that replaced by halogen 6To C 8Aryl,
-C 2To C 6Thiazolinyl, it is randomly replaced by one or more halogens;
-C 1To C 6Alkoxyl group;
-five yuan or hexa-member heterocycle; Or
-five yuan to six membered heteroaryl, and it is randomly replaced by alkyl;
-SO 2R Aa, R wherein AaBe:
-five yuan or hexa-member heterocycle, it is randomly replaced by one or more substituting groups that are independently selected from down group:
-hydroxyl;
-C 1To C 6Alkoxyl group; And
-C 1To C 6Alkyl;
-the amino that randomly replaced by alkyl, described alkyl are randomly replaced by one or more substituting groups that are independently selected from down group:
-alkoxyl group;
-hydroxyl;
-halogen;
-COR m, R wherein mBe:
-amino, it is by one or more C 1To C 6Alkyl replaces, and described alkyl is by five yuan or hexa-member heterocycle or C 6To C 8Aryl replaces, and described heterocycle is replaced by one or more halogens and/or alkoxyl group, and described aryl is randomly replaced by one or more halogens and/or alkoxyl group;
-the heterocycle that replaced by hydroxyl;
-NR tCOOR u, R wherein uBe:
-C 1To C 12Alkyl, it is replaced by one or more substituting groups that are independently selected from following groups:
-C 6To C 8Aryl, it is replaced by one or more halogens and/or alkylhalide group;
-the alkoxyl group that replaced by one or more alkoxyl groups;
-randomly by one or more C 1To C 6The amino that alkyl replaces;
-SO 2R w；
-SO 2R xAnd
-five yuan or six membered heteroaryl;
-C 2To C 6Thiazolinyl;
-quaternary is to seven membered heterocyclic, and it is replaced by one or more substituting groups that are independently selected from down group:
＝O；
-SO 2R w；
-COR pAnd
-(CO) O-(C 1To C 4Alkyl)-O-(C 1To C 4Alkyl);
-quaternary or seven membered heterocyclic, it is randomly replaced by one or more substituting groups that are independently selected from down group:
＝O；
-SO 2R w；
-COR pAnd
-(CO) O-(C 1To C 4Alkyl)-O-(C 1To C 4Alkyl);
-NHR Bb, R wherein BbBe:
-C(＝S)NHR x；
-C (=S) NR xR xOr
-C(＝N-CN)NHR x；
-N(CONHR w) 2；
-NH(SOR w)；
-N(SO 2R w) 2；
-NR vSO 2R w, R wherein vBy the alkyl of quaternary or seven membered heterocyclic replacement;
Or R wherein wBe:
-by C 6To C 8The C that aryl replaces 1To C 6Alkyl, described aryl is replaced by one or more substituting groups that are independently selected from alkylhalide group, halogen, alkoxyl group and alkyl;
-randomly by the amino of heterocycle or alkyl replacement, described heterocycle or alkyl are randomly by one or more halogen, C of being independently selected from 1To C 6Alkoxyl group, carbalkoxy, (CO) O-(C 1To C 6) alkyl), the substituting group of hydroxyl, cyano group, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
Figure A2007800089020067C1
-five yuan to six membered heteroaryl, and it is randomly replaced by one or more substituting groups that are independently selected from down group:
-halogen;
-C 1To C 6Alkyl;
-alkoxyl group, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-halogen;
-five yuan or hexa-member heterocycle; And
-C (O) NH 2, it is randomly by C 6To C 8Alkyl replaces;
-hydroxyl;
-alkylhalide group;
-cyano group;
-nitro;
-COOH；
-amino, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-SO 2R x；
-hexa-atomic to eight yuan of aryl, it is randomly by one or more alkyl, halogen, alkylhalide group, cyano group, alkoxyl group, COR of being independently selected from xReplace with the substituting group of halogen alkoxyl group;
-five yuan or six membered heteroaryl, it is randomly by one or more alkyl, halogen, alkylhalide group, cyano group, alkoxyl group, halogen alkoxyl group and C of being independently selected from 6To C 8The substituting group of aryl replaces, wherein this C 6To C 8Aryl is randomly replaced by halogen;
-C 5To C 6Heterocycle, it is randomly replaced by one or more substituting groups that are independently selected from hydroxyl, alkyl and alkylhalide group; And
-C 1To C 7Alkyl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or six membered heteroaryl, it is randomly replaced by one or more alkyl, halogen and/or alkylhalide group;
-C 6To C 8Aryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, halogen and alkylhalide group;
-alkoxyl group; And
-halogen;
-NR oCOR p, R wherein pBe:
-randomly by one or more C 1To C 6The amino that alkyl replaces, described alkyl are randomly and independently by one or more C 6To C 8Aryl and/or alkoxyl group replace; Or
-five yuan or hexa-member heterocycle, it is randomly by one or more C 1To C 6Alkyl and/or C 6To C 8Aryl replaces;
-NR qCONR qR r, R wherein rBe:
-C 1To C 6Alkyl, it is replaced by one or more substituting groups that are independently selected from following groups:
-hydroxyl;
-alkoxyl group;
-five yuan or hexa-member heterocycle;
-five yuan or six membered heteroaryl; And
-the C that replaced by halogen 6To C 8Aryl,
-C 2To C 6Thiazolinyl, it is randomly replaced by one or more halogens;
-C 1To C 6Alkoxyl group;
-five yuan or hexa-member heterocycle; Or
-five yuan to six membered heteroaryl, and it is randomly replaced by alkyl;
-NR tCOOR u, R wherein uBe:
-C 1To C 12Alkyl, it is replaced by one or more substituting groups that are independently selected from following groups:
-C 6To C 8Aryl, it is replaced by one or more halogens and/or alkylhalide group;
-the alkoxyl group that replaced by one or more alkoxyl groups;
-randomly by one or more C 1To C 6The amino that alkyl replaces;
-SO 2R w；
-SO 2R xAnd
-five yuan or six membered heteroaryl;
-NR vSO 2R w, R wherein vBy the alkyl of quaternary to the seven membered heterocyclic replacement;
Or R wherein wBe:
-by C 6To C 8The C that aryl replaces 1To C 6Alkyl, described aryl is replaced by one or more substituting groups that are independently selected from alkylhalide group, halogen, alkoxyl group and alkyl;
-C 6To C 8Aryl;
-by the amino of heterocycle or alkyl replacement, described heterocycle is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, carbalkoxy, hydroxyl, cyano group, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces, and described alkyl is by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, carbalkoxy, hydroxyl, cyano group, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
Z is:
-the C that replaced by five yuan or hexa-member heterocycle 1To C 6Alkyl; Or
-five yuan or hexa-member heterocycle;
R 1Be:
-five yuan or hexa-member heterocycle, it is replaced by one or more substituting groups that are independently selected from down group:
-hydroxyl;
-C 1To C 6Alkyl;
-SO 2R x；
-C (O)-C 6To C 8Aryl;
-COR pAnd
-C (O) OR xOr
-five yuan or six membered heteroaryl, it is replaced by one or more substituting groups that are independently selected from following groups:
-C 1To C 6Alkyl, it is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-alkoxyl group;
-halogen;
-alkylthio;
-alkylhalide group;
-cyano group;
-the amino that randomly replaced by alkyl, described alkyl is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, cyano group, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-heterocycle;
-nitro;
-hydroxyl;
-COOH；
-CO 2 R x；
-COR x；
-randomly by one or more C 1To C 6C (O) NH that alkyl replaces 2, described alkyl is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-amido, it is randomly by one or more halogen, C of being independently selected from 1To C 6Alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle, five yuan or six membered heteroaryl and C 1To C 6The substituting group of alkyl replaces, and described alkyl is randomly by one or more C 1To C 6Alkoxyl group replaces;
-C 1To C 6Alkyl, it is replaced by one or more substituting groups that are independently selected from following groups:
-amino, it is randomly replaced by one or more substituting groups that are independently selected from heterocycle, alkoxyl group and alkyl, and described alkyl is replaced by one or more alkoxyl groups;
-randomly by C 1To C 6The amido that alkyl replaces;
-five yuan or hexa-member heterocycle, it is by C 1To C 6Alkyl replaces;
-five yuan or six membered heteroaryl,
-C 6To C 8Aryl;
-SO 2 R x；
-C 2To C 6Thiazolinyl, it is randomly by SO 2R xReplace;
-C 1To C 6Alkoxyl group, it is replaced by one or more substituting groups that are independently selected from following groups:
-hydroxyl;
-cyano group;
-the alkoxyl group that replaces of alkoxy randomly;
-amino, it is randomly replaced by one or more substituting groups that are independently selected from five yuan or six membered heteroaryl, five yuan or hexa-member heterocycle and alkyl, and described alkyl is randomly replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or hexa-member heterocycle; And
-the amino that randomly replaced by one or more alkyl;
-randomly heterocyclically substituted amino;
-randomly by C 1To C 6The amido that alkyl replaces;
-five yuan to seven membered heterocyclic, and it is by one or more hydroxyl and C of being independently selected from 1To C 6The substituting group of alkyl replaces, and described alkyl is randomly replaced by one or more substituting groups that are independently selected from following groups;
-C 1To C 6Alkoxyl group; And
-C 6To C 8Alryl;
-five yuan or six membered heteroaryl, it is randomly replaced by one or more substituting groups that are independently selected from down group:
-C 1To C 6Alkyl; And
-quaternary is to seven membered heterocyclic; And
-alkoxyl group;
-(O)-five yuan or hexa-member heterocycle, it is randomly replaced by one or more substituting groups that are independently selected from down group:
-hydroxyl;
-C 1To C 6Alkyl;
-SO 2R x；
-C (O)-C 6To C 8Aryl;
-COR pAnd
-C (O) OR xOr
-(O)-five yuan or six membered heteroaryl, it is randomly replaced by one or more substituting groups that are independently selected from down group:
-C 1To C 6Alkyl, it is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-alkoxyl group;
-halogen;
-alkylthio;
-alkylhalide group;
-cyano group;
-the amino that randomly replaced by alkyl, described alkyl is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, cyano group, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-heterocycle;
-nitro;
-hydroxyl;
-COOH；
-CO 2R x；
-COR x；
-C (O) NH 2, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-C 1To C 6Alkyl, it is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces; And
-amido, it is randomly by one or more halogen, C of being independently selected from 1To C 6Alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle, five yuan or six membered heteroaryl and C 1To C 6The substituting group of alkyl replaces, and described alkyl is randomly by one or more C 1To C 6Alkoxyl group replaces;
-randomly by one or more C 1To C 6C (O) NH that alkyl replaces 2, described alkyl is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-C (O)-ternary is to seven membered heterocyclic, and it is randomly replaced by one or more substituting groups that are independently selected from down group:
-C 6To C 8Aryl;
-five yuan or six membered heteroaryl,
-C 1To C 6Alkyl, it is randomly by one or more replacements that replaced by hydroxyl;
-SO 2R x, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or hexa-member heterocycle;
-C 6To C 8Aryl; And
-five yuan or six membered heteroaryl; Or
-alkylthio, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or hexa-member heterocycle;
-C 6To C 8Aryl; And
-five yuan or six membered heteroaryl;
-C (O)-five yuan or six membered heteroaryl;
-C (O)-C 6To C 8Aryl;
-COOH；
-OR Kk, R wherein KkBe:
C 6To C 8Aryl, it is randomly by one or more halogen, C of being independently selected from 1To C 6Alkyl, C 1To C 6Alkoxyl group and C 1To C 6The substituting group of alkylhalide group replaces;
R 2Be:
-C 1To C 6Alkyl, it is replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or hexa-member heterocycle;
-five yuan or six membered heteroaryl;
-C 6To C 8Aryl;
-randomly by C 1To C 6The amido that alkyl replaces; And
-amino, it is randomly replaced by one or more substituting groups that are independently selected from heterocycle, alkoxyl group and alkyl, and described alkyl is randomly replaced by one or more alkoxyl groups;
-SO 2R x；
-C 2To C 6Thiazolinyl, it is randomly by SO 2R xReplace;
-alkylthio, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or six membered heteroaryl, it is randomly replaced by alkyl;
-five yuan or hexa-member heterocycle;
-C 6To C 8Aryl; And
-C 1To C 6Alkyl;
-SO 2R x, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or six membered heteroaryl, it is randomly by one or more C 1To C 6Alkyl replaces;
-five yuan or hexa-member heterocycle;
-C 6To C 8Aryl; And
-C 1To C 6Alkyl;
-S (O) R x, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or six membered heteroaryl;
-five yuan or hexa-member heterocycle;
-C 6To C 8Aryl; And
-C 1To C 6Alkyl;
-alkoxyl group, it is replaced by one or more substituting groups that are independently selected from following groups:
-halogen;
-hydroxyl;
-cyano group;
-the alkoxyl group that replaces of alkoxy randomly;
-amino, it is by one or more SO that are independently selected from 2-C 1To C 4The substituting group of alkyl and alkyl replaces, and described alkyl is replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or hexa-member heterocycle; And
-the amino that randomly replaced by one or more alkyl;
-by C 1To C 6The amido that alkyl replaces;
Five yuan of-S-or hexa-member heterocycle;
Five yuan of-S-or six membered heteroaryl, it is randomly by C 1To C 6Alkyl replaces;
-S-C 1To C 6Alkyl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-C 6To C 8Aryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, alkylhalide group and halogen; And
-C 5To C 6Heteroaryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, alkylhalide group and halogen;
-S-C 6To C 8Aryl;
-sulfinyl-five yuan or hexa-member heterocycle;
-sulfinyl-five yuan or six membered heteroaryl;
-sulfinyl-C 1To C 6Alkyl, this alkyl are randomly replaced by one or more substituting groups that are independently selected from following groups:
-C 6To C 8Aryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, alkylhalide group and halogen; And
-C 5To C 6Heteroaryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, alkylhalide group and halogen;
-sulfinyl-C 6To C 8Aryl;
-alkylsulfonyl-five yuan or hexa-member heterocycle;
-alkylsulfonyl-randomly by C 1To C 6Five yuan or six membered heteroaryl that alkyl replaces;
-alkylsulfonyl-C 1To C 6Alkyl, this alkyl are randomly replaced by one or more substituting groups that are independently selected from following groups:
-C 6To C 8Aryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, alkylhalide group and halogen; And
-C 5To C 6Heteroaryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, alkylhalide group and halogen;
-alkylsulfonyl-C 6To C 8Aryl;
-five yuan to seven membered heterocyclic, its randomly by one or more be independently selected from hydroxyl ,=O, heterocycle and C 1To C 6The substituting group of alkyl replaces, and described alkyl is randomly replaced by one or more substituting groups that are independently selected from following groups:
-C 1To C 6Alkoxyl group; And
-C 6To C 8Aryl;
-five yuan or six membered heteroaryl, it is randomly replaced by one or more substituting groups that are independently selected from down group:
-C 1To C 6Alkyl, it is randomly replaced by one or more alkoxyl groups;
-quaternary is to seven membered heterocyclic; And
-alkoxyl group; And
-C 6To C 8Aryl;
-C 6To C 8Aryl;
-(O)-five yuan or hexa-member heterocycle, it is replaced by one or more substituting groups that are independently selected from down group:
-hydroxyl;
＝O；
-C 1To C 6Alkyl;
-SO 2R x；
-C (O)-C 6To C 8Aryl;
-COR pAnd
-C (O) OR xOr
-(O)-five yuan or six membered heteroaryl, it is replaced by one or more substituting groups that are independently selected from down group:
-C 1To C 6Alkyl, it is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-alkoxyl group;
-halogen;
-alkylthio;
-alkylhalide group;
-cyano group;
-the amino that randomly replaced by alkyl, described alkyl is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, cyano group, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-heterocycle;
-nitro;
-hydroxyl;
-COOH；
-CO 2R x；
-COR x；
-randomly by one or more C 1To C 6C (O) NH that alkyl replaces 2, described alkyl is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-amido, it is randomly by one or more halogen, C of being independently selected from 1To C 6Alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle, five yuan or six membered heteroaryl and C 1To C 6The substituting group of alkyl replaces, and described alkyl is randomly by one or more C 1To C 6Alkoxyl group replaces;
-C (O)-ternary is to seven membered heterocyclic, and it is randomly replaced by one or more substituting groups that are independently selected from down group:
-C 6To C 8Aryl;
-five yuan or six membered heteroaryl; And
-C 1To C 6Alkyl, it is randomly replaced by one or more hydroxyls;
-C (O)-five yuan or six membered heteroaryl;
-C (O)-C 6To C 8Aryl;
-COOH；
-randomly by one or more C 1To C 6C (O) NH that alkyl replaces 2, described alkyl is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-amido, it is by one or more C 1To C 6Alkyl replaces, and described alkyl is randomly by one or more C 1To C 6Alkoxyl group replaces;
-amino, it is replaced by one or more substituting groups that are independently selected from following groups:
-SO 2R x；
-hexa-atomic to eight yuan of aryl, it is randomly by one or more alkyl, halogen, alkylhalide group, cyano group, alkoxyl group, COR of being independently selected from xReplace with the substituting group of halogen alkoxyl group;
-five yuan or six membered heteroaryl, it is randomly by one or more alkyl, halogen, alkylhalide group, cyano group, alkoxyl group, halogen alkoxyl group and C of being independently selected from 6To C 8The substituting group of aryl replaces, wherein this C 6To C 8Aryl is randomly replaced by halogen;
-C 5To C 6Heterocycle, it is randomly replaced by one or more substituting groups that are independently selected from hydroxyl, alkyl and alkylhalide group;
-C 1To C 7Alkyl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or six membered heteroaryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, halogen and alkylhalide group;
-C 6To C 8Aryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, halogen and alkylhalide group;
-alkoxyl group; And
-halogen;
-five yuan or six membered heteroaryl, it is replaced by one or more substituting groups that are independently selected from down group:
-C 1To C 6Alkyl, it is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-alkoxyl group;
-halogen;
-alkylthio;
-alkylhalide group;
-cyano group;
-the amino that randomly replaced by one or more alkyl, described alkyl is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, cyano group, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-heterocycle;
-nitro;
-hydroxyl;
-COOH；
-CO 2R x；
-COR x；
-randomly by one or more C 1To C 6C (O) NH that alkyl replaces 2, described alkyl is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-amido, it is randomly by one or more halogen, C of being independently selected from 1To C 6Alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle, five yuan or six membered heteroaryl and C 1To C 6The substituting group of alkyl replaces, and described alkyl is randomly by one or more C 1To C 6Alkoxyl group replaces;
-five yuan or hexa-member heterocycle, it is randomly replaced by one or more substituting groups that are independently selected from down group:
-hydroxyl;
＝O；
-C 1To C 6Alkyl;
-SO 2R x；
-C (O)-C 6To C 8Aryl;
-COR pAnd
-C(O)OR x；
-OR Kk, R wherein KkBe:
C 6To C 8Aryl, it is randomly by one or more halogen, C of being independently selected from 1To C 6Alkyl, C 1To C 6Alkoxyl group and C 1To C 6The substituting group of alkylhalide group replaces;
-five yuan to hexa-member heterocycle, and it is randomly by C 1To C 6Alkyl replaces, and described alkyl is randomly by C 6To C 8Aryl replaces; Or
Five yuan to six membered heteroaryl, and it is by one or more halogen, C of being independently selected from 1To C 6Alkyl, C 1To C 6Alkoxyl group and C 1To C 6The substituting group of alkylhalide group replaces;
-SO 2R xOr
-Si(R x) 3；
-OC (O) NHR x, R wherein xRandomly by C 6To C 8Aryl replaces;
-OC (O) N (R x) 2Or
Figure A2007800089020080C1
And
R 3It is nitro.
90. as the described compound of claim 89, wherein:
X is:
-CH=N-(C 1To C 6Alkoxyl group);
-CH=N-is (randomly by one or more C 1To C 6The amino that alkyl replaces);
-halogen;
-the alkyl that randomly replaced by one or more halogens;
-randomly by C 1To C 6The alkynyl that alkyl replaces, described alkyl are randomly replaced by one or more halogens and/or cyano group;
-oximido;
-SO 2R x；
-SO 2NH 2；
-SO 2NH(R x)；
-SO 2N(R x) 2；
-amino, it is randomly by one or more C that select independently 1To C 6Alkyl and/or-C (O)-C 1To C 6Alkyl replaces;
-amido, it is randomly by one or more C that select independently 1To C 6Alkyl replaces;
-five yuan or hexa-member heterocycle;
-five yuan or six membered heteroaryl, it is by one or more C 1To C 6Alkyl replaces, and described alkyl is randomly replaced by one or more halogens; Or
-C 6To C 8Aryl, it is replaced by one or more substituting groups that are independently selected from following groups:
-C 1To C 6Alkyl, it is randomly replaced by one or more halogens;
-halogen; And
-cyano group.
91. as the described compound of claim 89, wherein:
Y is:
-by the amino benzothiazolyl that replaces, described amino is randomly by one or more C 1To C 6Alkyl replaces;
-indyl, it is at the quilt-SO of nitrogen-atoms place 2R xReplace; Or
-C 6To C 8Aryl, it is replaced by one or more substituting groups that are independently selected from following groups:
-alkoxyl group, it is replaced by one or more substituting groups that are independently selected from following groups:
-C (O) NH 2, it is randomly by C 6To C 8Alkyl replaces; And
-C (O) NH-(C 1To C 6)-alkyl;
-alkylhalide group;
-cyano group;
-COOH；
-N＝CHN(R x) 2；
-amino, it is replaced by one or more substituting groups that are independently selected from following groups:
-SO 2R x；
-hexa-atomic to eight yuan of aryl, it is randomly by one or more alkyl, halogen, alkylhalide group, cyano group, alkoxyl group, COR of being independently selected from xReplace with the substituting group of halogen alkoxyl group;
-five yuan or six membered heteroaryl, it is randomly by one or more alkyl, halogen, alkylhalide group, cyano group, alkoxyl group, halogen alkoxyl group and C of being independently selected from 6To C 8The substituting group of aryl replaces, wherein this C 6To C 8Aryl is randomly replaced by halogen;
-five yuan or hexa-member heterocycle, its randomly by one or more be independently selected from hydroxyl ,=substituting group of O, alkyl and alkylhalide group replaces;
-C 1To C 7Alkyl, it is replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or six membered heteroaryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, halogen and alkylhalide group;
-C 6To C 8Aryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, halogen and alkylhalide group;
-alkoxyl group; And
-halogen; And
-PO 2R x；
-OC (O) NHR x, R wherein xRandomly by vinyl substituted;
-OC (O) N (R u) 2, R wherein uBe alkyl or C 6To C 8Aryl, described alkyl or aryl is randomly replaced by dialkyl amido;
-OC (O) NH (OR Uu), R wherein UuBe the C that is randomly replaced by dialkyl amido 6To C 8Aryl;
-OC(O)NR x(OR x)；
-OC(O)N(OR x) 2；
-OC (O) R Ab, R wherein AbBe five yuan or the hexa-member heterocycle that is randomly replaced by heteroaryl, described heteroaryl is randomly replaced by alkyl or alkylhalide group;
-NR oC (O) R p, R wherein pBe:
-randomly by one or more C 1To C 6The amino that alkyl replaces, described alkyl is randomly by one or more C that are independently selected from 6To C 8The substituting group of aryl and alkoxyl group replaces; Or
-five yuan or hexa-member heterocycle, it is by one or more C that are independently selected from 1To C 6Alkyl and C 6To C 8Aryl replaces;
-NR qCONR qR r, R wherein rBe:
-C 1To C 6Alkyl, it is replaced by one or more substituting groups that are independently selected from following groups:
-hydroxyl;
-alkoxyl group;
-five yuan or hexa-member heterocycle;
-five yuan or six membered heteroaryl; And
-the C that replaced by halogen 6To C 8Aryl,
-C 2To C 6Thiazolinyl, it is randomly replaced by one or more halogens;
-C 1To C 6Alkoxyl group;
-five yuan or hexa-member heterocycle; Or
-five yuan to six membered heteroaryl, and it is randomly replaced by alkyl;
-SO 2R Aa, R wherein AaBe:
-five yuan or hexa-member heterocycle, it is replaced by one or more substituting groups that are independently selected from down group:
-hydroxyl;
-C 1To C 6Alkoxyl group; And
-C 1To C 6Alkyl;
-the amino that randomly replaced by alkyl, described alkyl are randomly replaced by one or more substituting groups that are independently selected from down group:
-alkoxyl group;
-hydroxyl;
-halogen;
-COR m, R wherein mBe:
-amino, it is by one or more C 1To C 6Alkyl replaces, and described alkyl is by five yuan or hexa-member heterocycle or C 6To C 8Aryl replaces, and described heterocycle is replaced by one or more halogens and/or alkoxyl group, and described aryl is randomly replaced by one or more halogens and/or alkoxyl group;
-the heterocycle that replaced by hydroxyl;
-NR tCOOR u, R wherein uBe:
-C 1To C 12Alkyl, it is replaced by one or more substituting groups that are independently selected from following groups:
-C 6To C 8Aryl, it is replaced by one or more halogens and/or alkylhalide group;
-the alkoxyl group that replaced by one or more alkoxyl groups;
-amino, it is randomly by one or more C 1To C 6Alkyl replaces;
-SO 2R w；
-SO 2R xAnd
-five yuan or six membered heteroaryl;
-C 2To C 6Thiazolinyl;
-quaternary is to seven membered heterocyclic, and it is replaced by one or more substituting groups that are independently selected from down group:
＝O；
-SO 2R w；
-COR pAnd
-(CO) O-(C 1To C 4Alkyl)-O-(C 1To C 4Alkyl);
-quaternary or seven membered heterocyclic, it is randomly replaced by one or more substituting groups that are independently selected from down group:
＝O；
-SO 2R w；
-COR pAnd
-(CO) O-(C 1To C 4Alkyl)-O-(C 1To C 4Alkyl);
-NHR Bb, R wherein BbBe:
-C(＝S)NHR x；
-C (=S) NR xR xOr
-C(＝N-CN)NHR x；
-N(CONHR w) 2；
-NH(SOR w)；
-N(SO 2R w) 2；
-NR vSO 2R w, R wherein vBy the alkyl of quaternary or seven membered heterocyclic replacement;
Or R wherein wBe:
-by C 6To C 8The C that aryl replaces 1To C 6Alkyl, described aryl is replaced by one or more substituting groups that are independently selected from alkylhalide group, halogen, alkoxyl group and alkyl;
-randomly by the amino of heterocycle or alkyl replacement, described heterocycle or alkyl are randomly by one or more halogen, C of being independently selected from 1To C 6Alkoxyl group, carbalkoxy, (CO) O-(C 1To C 6) alkyl), the substituting group of hydroxyl, cyano group, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
Figure A2007800089020085C1
-five yuan to six membered heteroaryl, and it is randomly replaced by one or more substituting groups that are independently selected from down group:
-halogen;
-C 1To C 6Alkyl;
-alkoxyl group, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-halogen;
-five yuan or hexa-member heterocycle; And
-C (O) NH 2, it is randomly by C 6To C 8Alkyl replaces;
-hydroxyl;
-alkylhalide group;
-cyano group;
-nitro;
-COOH；
-amino, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-SO 2R x；
-hexa-atomic to eight yuan of aryl, it is randomly by one or more alkyl, halogen, alkylhalide group, cyano group, alkoxyl group, COR of being independently selected from xReplace with the substituting group of halogen alkoxyl group;
-five yuan or six membered heteroaryl, it is randomly by one or more alkyl, halogen, alkylhalide group, cyano group, alkoxyl group, halogen alkoxyl group and C of being independently selected from 6To C 8The substituting group of aryl replaces, wherein this C 6To C 8Aryl is randomly replaced by halogen;
-C 5To C 6Heterocycle, it is randomly replaced by one or more substituting groups that are independently selected from hydroxyl, alkyl and alkylhalide group; And
-C 1To C 7Alkyl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or six membered heteroaryl, it is randomly replaced by one or more alkyl, halogen and/or alkylhalide group;
-C 6To C 8Aryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, halogen and alkylhalide group;
-alkoxyl group; And
-halogen;
-NR oCOR p, R wherein pBe:
-randomly by one or more C 1To C 6The amino that alkyl replaces, described alkyl are randomly and independently by one or more C 6To C 8Aryl and/or alkoxyl group replace; Or
-five yuan or hexa-member heterocycle, it is randomly by one or more C 1To C 6Alkyl and/or C 6To C 8Aryl replaces;
-NR qCONR qR r, R wherein rBe:
-C 1To C 6Alkyl, it is replaced by one or more substituting groups that are independently selected from following groups:
-hydroxyl;
-alkoxyl group;
-five yuan or hexa-member heterocycle;
-five yuan or six membered heteroaryl; And
-the C that replaced by halogen 6To C 8Aryl,
-C 2To C 6Thiazolinyl, it is randomly replaced by one or more halogens;
-C 1To C 6Alkoxyl group;
-five yuan or hexa-member heterocycle; Or
-five yuan to six membered heteroaryl, and it is randomly replaced by alkyl;
-NR tCOOR u, R wherein uBe:
-C 1To C 12Alkyl, it is replaced by one or more substituting groups that are independently selected from following groups:
-C 6To C 8Aryl, it is replaced by one or more halogens and/or alkylhalide group;
-the alkoxyl group that replaced by one or more alkoxyl groups;
-amino, it is randomly by one or more C 1To C 6Alkyl replaces;
-SO 2R w；
-SO 2R xAnd
-five yuan or six membered heteroaryl; And
-NR vSO 2R w, R wherein vBy the alkyl of quaternary to the seven membered heterocyclic replacement;
Or R wherein wBe:
-by C 6To C 8The C that aryl replaces 1To C 6Alkyl, described aryl is replaced by one or more substituting groups that are independently selected from alkylhalide group, halogen, alkoxyl group and alkyl;
-C 6To C 8Aryl;
-by the amino of heterocycle or alkyl replacement, described heterocycle is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, carbalkoxy, hydroxyl, cyano group, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces, and described alkyl is by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, carbalkoxy, hydroxyl, cyano group, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
Figure A2007800089020088C1
92. as the described compound of claim 89, wherein Z is:
-the C that replaced by five yuan or hexa-member heterocycle 1To C 6Alkyl; Or
-five yuan or hexa-member heterocycle.
93. as the described compound of claim 89, wherein:
R 1Be:
-five yuan or hexa-member heterocycle, it is replaced by one or more substituting groups that are independently selected from down group:
-hydroxyl;
-C 1To C 6Alkyl;
-SO 2R x；
-C (O)-C 6To C 8Aryl;
-COR pAnd
-C (O) OR xOr
-five yuan or six membered heteroaryl, it is replaced by one or more substituting groups that are independently selected from following groups:
-C 1To C 6Alkyl, it is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-alkoxyl group;
-halogen;
-alkylthio;
-alkylhalide group;
-cyano group;
-the amino that randomly replaced by alkyl, described alkyl is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, cyano group, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-heterocycle;
-nitro;
-hydroxyl;
-COOH；
-CO 2R x；
-COR x；
-randomly by one or more C 1To C 6C (O) NH that alkyl replaces 2, described alkyl is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-amido, it is randomly by one or more halogen, C of being independently selected from 1To C 6Alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle, five yuan or six membered heteroaryl and C 1To C 6The substituting group of alkyl replaces, and described alkyl is randomly by one or more C 1To C 6Alkoxyl group replaces;
-C 1To C 6Alkyl, it is replaced by one or more substituting groups that are independently selected from following groups:
-amino, it is randomly replaced by one or more substituting groups that are independently selected from heterocycle, alkoxyl group and alkyl, and described alkyl is replaced by one or more alkoxyl groups;
-randomly by C 1To C 6The amido that alkyl replaces;
-five yuan or hexa-member heterocycle, it is by C 1To C 6Alkyl replaces;
-five yuan or six membered heteroaryl, and
-C 6To C 8Aryl;
-SO 2R x；
-C 2To C 6Thiazolinyl, it is randomly by SO 2R xReplace;
-C 1To C 6Alkoxyl group, it is replaced by one or more substituting groups that are independently selected from following groups:
-hydroxyl;
-cyano group;
-the alkoxyl group that replaces of alkoxy randomly;
-amino, it is randomly replaced by one or more substituting groups that are independently selected from five yuan or six membered heteroaryl, five yuan or hexa-member heterocycle and alkyl, and described alkyl is randomly replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or hexa-member heterocycle; And
-the amino that randomly replaced by one or more alkyl;
-randomly heterocyclically substituted amino;
-randomly by C 1To C 6The amido that alkyl replaces;
-five yuan to seven membered heterocyclic, and it is by one or more hydroxyl and C of being independently selected from 1To C 6The substituting group of alkyl replaces, and described alkyl is randomly replaced by one or more substituting groups that are independently selected from following groups;
-C 1To C 6Alkoxyl group; And
-C 6To C 8Alryl;
-five yuan or six membered heteroaryl, it is randomly replaced by one or more substituting groups that are independently selected from down group:
-C 1To C 6Alkyl; And
-quaternary is to seven membered heterocyclic; And
-alkoxyl group;
-(O)-five yuan or hexa-member heterocycle, it is randomly replaced by one or more substituting groups that are independently selected from down group :-hydroxyl;
-C 1To C 6Alkyl;
-SO 2R x；
-C (O)-C 6To C 8Aryl;
-COR pAnd
-C (O) OR xOr
-(O)-five yuan or six membered heteroaryl, it is randomly replaced by one or more substituting groups that are independently selected from down group:
-C 1To C 6Alkyl, it is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-alkoxyl group;
-halogen;
-alkylthio;
-alkylhalide group;
-cyano group;
-the amino that randomly replaced by alkyl, described alkyl is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, cyano group, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-heterocycle;
-nitro;
-hydroxyl;
-COOH；
-CO 2R x；
-COR x；
-C (O) NH 2, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-C 1To C 6Alkyl, it is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces; And
-amido, it is randomly by one or more halogen, C of being independently selected from 1To C 6Alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle, five yuan or six membered heteroaryl and C 1To C 6The substituting group of alkyl replaces, and described alkyl is randomly by one or more C 1To C 6Alkoxyl group replaces;
-randomly by one or more C 1To C 6C (O) NH that alkyl replaces 2, described alkyl is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-C (O)-ternary is to seven membered heterocyclic, and it is randomly replaced by one or more substituting groups that are independently selected from down group:
-C 6To C 8Aryl;
-five yuan or six membered heteroaryl,
-C 1To C 6Alkyl, it is randomly by one or more replacements that replaced by hydroxyl;
-SO 2R x, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or hexa-member heterocycle;
-C 6To C 8Aryl; And
-five yuan or six membered heteroaryl; Or
-alkylthio, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or hexa-member heterocycle;
-C 6To C 8Aryl; And
-five yuan or six membered heteroaryl;
-C (O)-five yuan or six membered heteroaryl;
-C (O)-C 6To C 8Aryl;
-COOH; Or
-OR Kk, R wherein KkBe:
-C 6To C 8Aryl, it is randomly by one or more halogen, C of being independently selected from 1To C 6Alkyl, C 1To C 6Alkoxyl group and C 1To C 6The substituting group of alkylhalide group replaces.
94. as the described compound of claim 89, wherein:
R 2Be:
-C 1To C 6Alkyl, it is replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or hexa-member heterocycle;
-five yuan or six membered heteroaryl;
-C 6To C 8Aryl;
-randomly by C 1To C 6The amido that alkyl replaces; And
-amino, it is randomly replaced by one or more substituting groups that are independently selected from heterocycle, alkoxyl group and alkyl, and described alkyl is randomly replaced by one or more alkoxyl groups; And
-SO 2R x；
-C 2To C 6Thiazolinyl, it is randomly by SO 2R xReplace;
-alkylthio, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or six membered heteroaryl, it is randomly replaced by alkyl;
-five yuan or hexa-member heterocycle;
-C 6To C 8Aryl; And
-C 1To C 6Alkyl;
-SO 2R x, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or six membered heteroaryl, it is randomly by one or more C 1To C 6Alkyl replaces;
-five yuan or hexa-member heterocycle;
-C 6To C 8Aryl; And
-C 1To C 6Alkyl;
-S (O) R x, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or six membered heteroaryl;
-five yuan or hexa-member heterocycle;
-C 6To C 8Aryl; And
-C 1To C 6Alkyl;
-alkoxyl group, it is replaced by one or more substituting groups that are independently selected from following groups:
-halogen;
-hydroxyl;
-cyano group;
-the alkoxyl group that replaces of alkoxy randomly;
-amino, it is by one or more SO that are independently selected from 2-C 1To C 4The substituting group of alkyl and alkyl replaces, and described alkyl is replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or hexa-member heterocycle; And
-the amino that randomly replaced by one or more alkyl;
-by C 1To C 6The amido that alkyl replaces;
Five yuan of-S-or hexa-member heterocycle;
Five yuan of-S-or six membered heteroaryl, it is randomly by C 1To C 6Alkyl replaces;
-S-C 1To C 6Alkyl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-C 6To C 8Aryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, alkylhalide group and halogen; And
-C 5To C 6Heteroaryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, alkylhalide group and halogen;
-S-C 6To C 8Aryl;
-sulfinyl-five yuan or hexa-member heterocycle;
-sulfinyl-five yuan or six membered heteroaryl;
-sulfinyl-C 1To C 6Alkyl, this alkyl are randomly replaced by one or more substituting groups that are independently selected from following groups:
-C 6To C 8Aryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, alkylhalide group and halogen; And
-C 5To C 6Heteroaryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, alkylhalide group and halogen;
-sulfinyl-C 6To C 8Aryl;
-alkylsulfonyl-five yuan or hexa-member heterocycle;
-alkylsulfonyl-randomly by C 1To C 6Five yuan or six membered heteroaryl that alkyl replaces;
-alkylsulfonyl-C 1To C 6Alkyl, this alkyl are randomly replaced by one or more substituting groups that are independently selected from following groups:
-C 6To C 8Aryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, alkylhalide group and halogen; And
-C 5To C 6Heteroaryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, alkylhalide group and halogen;
-alkylsulfonyl-C 6To C 8Aryl;
-five yuan to seven membered heterocyclic, its randomly by one or more be independently selected from hydroxyl ,=O, heterocycle and C 1To C 6The substituting group of alkyl replaces, and described alkyl is randomly replaced by one or more substituting groups that are selected from following groups:
-C 1To C 6Alkoxyl group; And
-C 6To C 8Aryl;
-five yuan or six membered heteroaryl, it is randomly replaced by one or more substituting groups that are independently selected from down group:
-C 1To C 6Alkyl, it is randomly replaced by one or more alkoxyl groups;
-quaternary is to seven membered heterocyclic; And
-alkoxyl group; And
-C 6To C 8Aryl;
-C 6To C 8Aryl;
-(O)-five yuan or hexa-member heterocycle, it is replaced by one or more substituting groups that are independently selected from down group:
-hydroxyl;
＝O；
-C 1To C 6Alkyl;
-SO 2R x；
-C (O)-C 6To C 8Aryl;
-COR pAnd
-C (O) OR xOr
-(O)-five yuan or six membered heteroaryl, it is replaced by one or more substituting groups that are independently selected from down group:
-C 1To C 6Alkyl, it is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-alkoxyl group;
-halogen;
-alkylthio;
-alkylhalide group;
-cyano group;
-the amino that randomly replaced by alkyl, described alkyl is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, cyano group, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-heterocycle;
-nitro;
-hydroxyl;
-COOH；
-CO 2R x；
-COR x；
-randomly by one or more C 1To C 6C (O) NH that alkyl replaces 2, described alkyl is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-amido, it is randomly by one or more halogen, C of being independently selected from 1To C 6Alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle, five yuan or six membered heteroaryl and C 1To C 6The substituting group of alkyl replaces, and described alkyl is randomly by one or more C 1To C 6Alkoxyl group replaces;
-C (O)-ternary is to seven membered heterocyclic, and it is randomly replaced by one or more substituting groups that are independently selected from down group:
-C 6To C 8Aryl;
-five yuan or six membered heteroaryl; And
-C 1To C 6Alkyl, it is randomly replaced by one or more hydroxyls;
-C (O)-five yuan or six membered heteroaryl;
-C (O)-C 6To C 8Aryl;
-COOH；
-randomly by one or more C 1To C 6C (O) NH that alkyl replaces 2, described alkyl is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-amido, it is by one or more C 1To C 6Alkyl replaces, and described alkyl is randomly by one or more C 1To C 6Alkoxyl group replaces;
-the amino that replaced by one or more substituting groups that are independently selected from following groups:
-SO 2R x；
-hexa-atomic to eight yuan of aryl, it is randomly by one or more alkyl, halogen, alkylhalide group, cyano group, alkoxyl group, COR of being independently selected from xReplace with the substituting group of halogen alkoxyl group;
-five yuan or six membered heteroaryl, it is randomly by one or more alkyl, halogen, alkylhalide group, cyano group, alkoxyl group, halogen alkoxyl group and C of being independently selected from 6To C 8The substituting group of aryl replaces, wherein this C 6To C 8Aryl is randomly replaced by halogen;
-C 5To C 6Heterocycle, it is randomly replaced by one or more substituting groups that are independently selected from hydroxyl, alkyl and alkylhalide group;
-C 1To C 7Alkyl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-five yuan or six membered heteroaryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, halogen and alkylhalide group;
-C 6To C 8Aryl, it is randomly replaced by one or more substituting groups that are independently selected from alkyl, halogen and alkylhalide group;
-alkoxyl group; And
-halogen;
-five yuan or six membered heteroaryl, it is replaced by one or more substituting groups that are independently selected from down group:
-C 1To C 6Alkyl, it is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-alkoxyl group;
-halogen;
-alkylthio;
-alkylhalide group;
-cyano group;
-the amino that randomly replaced by one or more alkyl, described alkyl is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, cyano group, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-heterocycle;
-nitro;
-hydroxyl;
-COOH；
-CO 2R x；
-COR x；
-randomly by one or more C 1To C 6C (O) NH that alkyl replaces 2, described alkyl is randomly by one or more halogen, C of being independently selected from 1To C 6The substituting group of alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle and five yuan or six membered heteroaryl replaces;
-amido, it is randomly by one or more halogen, C of being independently selected from 1To C 6Alkoxyl group, hydroxyl, five yuan or hexa-member heterocycle, five yuan or six membered heteroaryl and C 1To C 6The substituting group of alkyl replaces, and described alkyl is randomly by one or more C 1To C 6Alkoxyl group replaces;
-five yuan or hexa-member heterocycle, it is randomly replaced by one or more substituting groups that are independently selected from down group:
-hydroxyl;
＝O；
-C 1To C 6Alkyl;
-SO 2R x；
-C (O)-C 6To C 8Aryl;
-COR pAnd
-C(O)OR x；
-OR Kk, R wherein KkBe:
-C 6To C 8Aryl, it is randomly by one or more halogen, C of being independently selected from 1To C 6Alkyl, C 1To C 6Alkoxyl group and C 1To C 6The substituting group of alkylhalide group replaces;
-five yuan to hexa-member heterocycle, and it is randomly by C 1To C 6Alkyl replaces, and described alkyl is randomly by C 6To C 8Aryl replaces; Or
-five yuan to six membered heteroaryl, and it is by one or more halogen, C of being independently selected from 1To C 6Alkyl, C 1To C 6Alkoxyl group and C 1To C 6The substituting group of alkylhalide group replaces;
-SO 2R xOr
-Si(R x) 3；
-OC (O) NHR x, R wherein xRandomly by C 6To C 8Aryl replace;
-OC (O) N (R x) 2Or
Figure A2007800089020098C1
95. as the described compound of claim 89, wherein R 3It is nitro.
96. as the described compound of claim 89, wherein:
X is cyano group or hydrogen;
Y is:
-C 6To C 8Aryl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-halogen;
-C 1To C 6Alkyl;
-amino, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-SO 2R x；
-five yuan or six membered heteroaryl, it is randomly replaced by one or more alkyl;
-C 1To C 7Alkyl;
-NR tCOOR u, R wherein tBe hydrogen, and R wherein uBe C 1To C 12Alkyl;
-NR vSO 2R w, R wherein vBe hydrogen, and R wherein wBe C 1To C 6Alkyl or the amino that is randomly replaced by alkyl;
Figure A2007800089020099C1
Z is C 1To C 6Alkyl;
R is a hydrogen;
R 1Be hydrogen;
R 2Replaced by cyano group-(O)-five yuan or six membered heteroaryl; And
R 3Be hydrogen.
97. as the described compound of claim 96, wherein said C 6To C 8Aryl is a phenyl.
98. as the described compound of claim 97, wherein:
X is a cyano group;
Y is contraposition quilt-NR vSO 2R wThe phenyl that replaces, wherein R vBe hydrogen, and R wBe C 1To C 6Alkyl; And
R 2Be the ortho position replaced by cyano group-(O)-five yuan or six membered heteroaryl.
99. as the described compound of claim 97, wherein:
X is a cyano group;
Y is by C 1To C 6Alkyl and NR vSO 2R wThe phenyl that replaces, wherein R vBe hydrogen, and R wBe C 1To C 6Alkyl; And
R 2Replaced at the ortho position by cyano group-(O)-five yuan or six membered heteroaryl.
100. as the described compound of claim 97, wherein:
X is a cyano group;
Y is by halogen and NR vSO 2R wThe phenyl that replaces, wherein R vBe hydrogen, and R wBe C 1To C 6Alkyl; And
R 2Be the ortho position replaced by cyano group-(O)-five yuan or six membered heteroaryl.
101. as the described compound of claim 97, wherein:
X is a hydrogen;
Y is that contraposition is by NR tCOOR uThe phenyl that replaces, wherein R tBe hydrogen, and R uBe C 1To C 12Alkyl;
Z is cyclobutyl, cyclopropyl, cyclopropyl methyl, ethyl or cyclopentyl; And
R 2Be the ortho position replaced by cyano group-(O)-five yuan or six membered heteroaryl.
102. as the described compound of claim 89, wherein:
X is a cyano group;
Y is:
-C 6To C 8Aryl, it is randomly replaced by one or more substituting groups that are independently selected from following groups:
-NR tCOOR u, R wherein tBe hydrogen, and R uBe the C that is randomly replaced by one or more halogens 1To C 12Alkyl; Or
-NR vSO 2R w, R wherein vBe hydrogen, and R wBe C 1To C 6Alkyl;
Z is C 1To C 6Alkyl;
R is a hydrogen;
R 1Be hydrogen;
R 2Replaced by one or more=O-(O)-five yuan or hexa-member heterocycle; And
R 3Be hydrogen.
103. be selected from the compound of compound 1330-2128 and 2600-3348.
104. as the described compound of claim 103, it is selected from:
Figure A2007800089020100C1
Figure A2007800089020101C1
Figure A2007800089020102C1
105. composition that comprises described compound of claim 1 and the acceptable vehicle of one or more pharmacology.
106. composition that comprises described compound of claim 39 and the acceptable vehicle of one or more pharmacology.
107. composition that comprises described compound of claim 77 and the acceptable vehicle of one or more pharmacology.
108. composition that comprises described compound of claim 83 and the acceptable vehicle of one or more pharmacology.
109. composition that comprises described compound of claim 89 and the acceptable vehicle of one or more pharmacology.
110. a method that is used for the treatment of the infection with hepatitis C virus in the individuality, this method comprise to one or more compounds as claimed in claim 1 of the described individual effective dosage that these needs are arranged or comprise the pharmaceutical composition of one or more compounds as claimed in claim 1 of significant quantity.
111. a method that is used for the treatment of the infection with hepatitis C virus in the individuality, this method comprise to one or more compounds as claimed in claim 39 of the described individual effective dosage that these needs are arranged or comprise the pharmaceutical composition of one or more compounds as claimed in claim 39 of significant quantity.
112. a method that is used for the treatment of the infection with hepatitis C virus in the individuality, this method comprise to one or more of the described individual effective dosage that these needs are arranged as the described compound of claim 77 or comprise one or more pharmaceutical compositions as the described compound of claim 77 of significant quantity.
113. a method that is used for the treatment of the infection with hepatitis C virus in the individuality, this method comprise to one or more of the described individual effective dosage that these needs are arranged as the described compound of claim 83 or comprise one or more pharmaceutical compositions as the described compound of claim 83 of significant quantity.
114. a method that is used for the treatment of the infection with hepatitis C virus in the individuality, this method comprise to one or more of the described individual effective dosage that these needs are arranged as the described compound of claim 89 or comprise one or more pharmaceutical compositions as the described compound of claim 89 of significant quantity.
115. method that is used for the treatment of the virus infection in the individuality, wherein said virus comprises internal ribosome entry site, and this method comprises to one or more compounds as claimed in claim 1 of the described individual effective dosage that these needs are arranged or comprises the pharmaceutical composition of one or more compounds as claimed in claim 1 of significant quantity.
116. method that is used for the treatment of the virus infection in the individuality, wherein said virus comprises internal ribosome entry site, and this method comprises to one or more compounds as claimed in claim 39 of the described individual effective dosage that these needs are arranged or comprises the pharmaceutical composition of one or more compounds as claimed in claim 39 of significant quantity.
117. method that is used for the treatment of the virus infection in the individuality, wherein said virus comprises internal ribosome entry site, and this method comprises to one or more of the described individual effective dosage that these needs are arranged as the described compound of claim 77 or comprise one or more pharmaceutical compositions as the described compound of claim 77 of significant quantity.
118. method that is used for the treatment of the virus infection in the individuality, wherein said virus comprises internal ribosome entry site, and this method comprises to one or more of the described individual effective dosage that these needs are arranged as the described compound of claim 83 or comprise one or more pharmaceutical compositions as the described compound of claim 83 of significant quantity.
119. method that is used for the treatment of the virus infection in the individuality, wherein said virus comprises internal ribosome entry site, and this method comprises to one or more of the described individual effective dosage that these needs are arranged as the described compound of claim 89 or comprise one or more pharmaceutical compositions as the described compound of claim 89 of significant quantity.
CNA2007800089028A 2007-01-13 2007-01-16 The method of treatment hepatitis C Pending CN101605758A (en)

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