CN1953974A - Pyrimidine derivatives for the treatment of abnormal cell growth - Google Patents

Pyrimidine derivatives for the treatment of abnormal cell growth Download PDF

Info

Publication number
CN1953974A
CN1953974A CNA2005800155302A CN200580015530A CN1953974A CN 1953974 A CN1953974 A CN 1953974A CN A2005800155302 A CNA2005800155302 A CN A2005800155302A CN 200580015530 A CN200580015530 A CN 200580015530A CN 1953974 A CN1953974 A CN 1953974A
Authority
CN
China
Prior art keywords
amino
methyl
base
alkyl
pyrimidine
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CNA2005800155302A
Other languages
Chinese (zh)
Inventor
M·J·卢齐欧
J·C·卡斯
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pfizer Products Inc
Pfizer Inc
Original Assignee
Pfizer Products Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=34966230&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=CN1953974(A) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Pfizer Products Inc filed Critical Pfizer Products Inc
Publication of CN1953974A publication Critical patent/CN1953974A/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Abstract

The present invention relates to a compound of the formula (I) wherein R<1>-R<4> are as defined herein. Such novel pyrimidine derivatives are useful in the treatment of abnormal cell growth, such as cancer, in mammals. This invention also relates to a method of using such compounds in the treatment of abnormal cell growth in mammals, especially humans, and to pharmaceutical compositions containing such compounds.

Description

The pyrimidine derivatives of treatment abnormal cell growth
The cross reference of related application
No. the 60/500th, 742, U.S. Patent Application Serial (agent docket No.PC25937) with reference to U.S. Patent Application Serial of submitting on December 20th, 2002 the 60/435th, No. 670 (agent docket No.PC25339) and submission on September 5th, 2003.
Technical field
The present invention relates to can be used for treating the new pyrimidine derivatives of Mammals abnormal cell growth such as cancer.The invention still further relates to and use these compounds to be used for the treatment of the especially method of human abnormal cell growth of Mammals, and relate to the pharmaceutical composition that contains these compounds.
Background technology
Known cell can be transformed into oncogene (that is the gene that causes malignant cell to form) by its a part of DNA and become cancer cells when activating.Many oncogene encoded protein are the unusual Tyrosylprotein kinases that can cause cell transformation.Another situation is that the overexpression with Tyrosylprotein kinase of normal proto-oncogene also can cause proliferative disease, causes the malignant phenotype sometimes.
Receptor tyrosine kinase is the enzyme of cross-cell membrane, extracellular binding domains, membrane spaning domain and intracellular portion with somatomedin such as epithelical cell growth factor, the effect of this part is the kinases as specific tyrosine residues in the phosphorylated protein, therefore can cause cell proliferation.Other receptor tyrosine kinases comprise c-erbB-2, c-met, tie-2, PDGFr, FGFr and VEGFR.Known these kinases are frequent abnormal expression in common human cancer such as breast cancer, gastrointestinal cancer (as colon, rectum or cancer of the stomach), leukemia and ovarian cancer, bronchogenic carcinoma or carcinoma of the pancreas.Show that also the EGF-R ELISA (EGFR) with tyrosine kinase activity is sudden change and/or overexpression in many human cancers (as brain, lung, squamous cell, bladder, stomach, breast, incidence, oesophagus, gynaecology and thyroid tumor).
Therefore, have realized that receptor tyrosine kinase inhibitors can be used as the selective depressant of mammalian cancer cells growth.For example, tyrosine kinase inhibitor tabulation mycin (erbstatin) optionally suppresses the growth of the human breast carcinoma of the expression epidermal growth factor recipient tyrosine kinase (EGFR) transplanted in the nude mouse, but the growth of the another kind of cancer of not expressing the EGF acceptor is not had influence.Therefore, the selective depressant of some receptor tyrosine kinase can be used for treating mammiferous abnormal cell growth, especially cancer.Except that receptor tyrosine kinase, some nonreceptor tyrosine kinase such as FAK (focal adhesion kinase), Ick, src, abl or serine/threonine kinase are (for example, the kinases of cyclin dependent) selective depressant also can be used for treating mammiferous abnormal cell growth, especially cancer.FAK is also referred to as albumen-Tyrosylprotein kinase 2, PTK2.
Have definite evidence to show, tenuigenin nonreceptor tyrosine kinase FAK in the cell-matrix signal transduction pathway, play an important role (Clark and Brugge 1995, Science 268:233-239), that the metastatic potential of its abnormal activation and tumour increases is relevant (people such as Owens, 1995, Cancer Research 55:2752-2755).FAK is accredited as the albumen of 125 kDa of height tyrosine phosphorylation at first in by the v-Src cell transformed.Find that subsequently FAK is the Tyrosylprotein kinase that concentrates on the adhesion plaque, this adhesion plaque is the point of contact between culturing cell and its following substratum, is intensive tyrosine phosphorylation site.Therefore, phosphorylation takes place in response to extracellular matrix (ECM) with combining of integrin and is activated thus in FAK.Research recently is verified, and the aggressive that the increase of FAK mRNA level is accompanied by tumour transforms, reduce FAK express (by using antisense oligonucleotide) inducing apoptosis of tumour cell (people such as Xu, 1996, Cell Growth and Diff.7: 413-418).Except that in most of types of organizations, expressing, find in the especially level of the FAK rising in highly invasive metastasis of most of human cancers.
Chemical compound lot as styrene derivatives, has also shown to have the Tyrosylprotein kinase rejection characteristic.5 european patent applications, be EP 0 566 226 A1 (announcement on October 20th, 1993), EP 0 602 851 A1 (announcement on June 22nd, 1994), EP 0 635 507 A1 (announcement on January 25 nineteen ninety-five), EP 0 635 498 A1 (announcement on January 25 nineteen ninety-five) and EP 0,520 722 A1 (announcement on December 30th, 1992), relate to some bicyclic derivatives, especially quinazoline derivant, have anticancer property, these characteristics are from its Tyrosylprotein kinase rejection characteristic.
In addition, International Patent Application WO 92/20642 (announcement on November 26th, 1992) relates to some two-list and aryl bicyclic and heteroaryl compound as the tyrosine kinase inhibitor that is used to suppress abnormal cell proliferation.International Patent Application WO 96/16960 (announcement on June 6th, 1996), WO 96/09294 (announcement on March 6th, 1996), WO 97/30034 (announcement on August 21st, 1997), WO 98/02434 (announcement on January 22nd, 1998), WO 98/02437 (announcement on January 22nd, 1998) with WO 98/02438 (announcement on January 22nd, 1998) also mentioned the bicyclic heteroaromatic derivative that replaces as the tyrosine kinase inhibitor that is used for identical purpose.In addition, the following publication of enumerating relate to can be randomly as two-single and aryl bicyclic and heteroaryl compound: WO 03/030909, WO 03/032997, No. the 2003/0181474th, U.S. Patent application, No. the 2003/0162802nd, U.S. Patent application, the United States Patent (USP) the 5th of tyrosine kinase inhibitor, 863, No. 924, WO 03/078404, United States Patent (USP) the 4th, 507146, WO99/41253, WO 01/72744, WO 02/48133, U.S. Patent application the 2002/156087th, WO 02/102783 and WO 03/063794.
The 10/734th, No. 039 (agent docket No.PC25339A) coverage of U.S. Patent application of submitting on December 11st, 2003 be the new pyrimidine derivatives of a class of money very, and they are kinase inhibitor, more particularly, are the FAK inhibitor.And the U.S. Patent application of submitting on December 11st, 2003 the 10/733rd, No. 215 (agent docket No.PC25937A) relates more specifically to the subgroup of pyrimidine derivatives, the derivative that promptly has 5-hydroxy amino indoles, they are tyrosine kinase inhibitors, more specifically, are the FAK inhibitor.These compounds can be used for treating abnormal cell growth.
Therefore, need other selective depressants of some acceptor and nonreceptor tyrosine kinase, to be used for the treatment of mammiferous abnormal cell growth, as cancer.The invention provides new pyrimidine derivatives, they are inhibitor of kinase inhibitor and nonreceptor tyrosine kinase FAK, and can be used for treating abnormal cell growth.
Summary of the invention
Therefore, the invention provides the compound of structural formula 1, or the acceptable salt of its medicine, solvate, or its prodrug (prodrug):
Wherein n is 1 to 3 integer;
Each R 1Be the substituting group that is independently selected from following groups: hydrogen, hydroxyl ,-(C 1-C 6) alkyl ,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-O (C 1-C 6) alkyl ,-O (C 3-C 7) cycloalkyl ,-O (C 2-C 9) heterocyclic radical ,-NR 5R 6,-SR 7,-SOR 7,-SO 2R 7,-CO 2R 12,-CONR 5R 6,-SO 2NR 5R 6,-NHCOR 12,-NR 12CONR 5R 6, and-NR 12SO 2R 7Wherein said R 1Substituting group-(C 1-C 6) alkyl ,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-O (C 1-C 6) alkyl ,-O (C 3-C 7) cycloalkyl ,-O (C 2-C 9) heterocyclic radical ,-NR 5R 6,-SR 7,-SOR 7,-SO 2R 7,-CO 2R 12,-CONR 5R 6,-SO 2NR 5R 6,-NHCOR 12,-NR 12CONR 5R 6, and-NR 12SO 2R 7Randomly being independently selected from 1 to 3 of following groups part replaces: hydrogen, halogen, hydroxyl ,-CF 3,-CN ,-(C 1-C 6) alkyl ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6With-CONR 5R 8
Each R 2Be the substituting group that is independently selected from following groups: hydrogen ,-(C 1-C 6) alkyl ,-(C 2-C 6) thiazolinyl ,-(C 2-C 6) alkynyl ,-(C 3-C 7) cycloalkyl ,-(C 2-C 9Heterocyclic radical ,-CO 2R 12, and-CONR 5R 6Wherein said R 2Substituting group-(C 1-C 6) alkyl ,-(C 2-C 6) thiazolinyl ,-(C 2-C 6) alkynyl ,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12, and-CONR 5R 6Randomly being independently selected from 1 to 3 of following groups part replaces: hydrogen, halogen, hydroxyl ,-CF 3,-NO 2,-CN ,-(C 1-C 6) alkyl ,-(C 2-C 6) thiazolinyl ,-(C 2-C 6) alkynyl ,-C=N-OH ,-C=N-O ((C 1-C 6) alkyl) ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6,-CONR 5R 8,-SR 7,-SOR 7,-SO 2R 7,-SO 2NR 5R 6,-NHCOR 12,-NR 12CONR 5R 6, and-NR 12SO 2R 7, wherein said-(C 2-C 6) thiazolinyl and-(C 2-C 6) alkynyl R 2Part can be randomly by 1 to 3 R 12Group replaces;
R 1And R 2Can form with the atom that they connected cyclic group ,-(C 3-C 10) cycloalkyl or-(C 2-C 9) heterocyclic radical, optional 1 to 3 the part replacement that is selected from following groups of wherein said cyclic group: hydrogen, halogen, hydroxyl ,-CF 3,-NO 2,-CN ,-(C 1-C 6) alkyl ,-(C 2-C 6) thiazolinyl ,-(C 2-C 6) alkynyl ,-C=N-OH ,-C=N-O ((C 1-C 6) alkyl) ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6,-CONR 5R 8,-SR 7,-SOR 7,-SO 2R 7,-SO 2NR 5R 6,-NHCOR 12,-NR 12CONR 5R 6, and-NR 12SO 2R 7, the described-(C of wherein said cyclic group 2-C 6) thiazolinyl and-(C 2-C 6) the alkynyl part can be randomly by 1 to 3 R 12Group replaces, and 1 to 3 unit that described cyclic group randomly is selected from following groups interrupts :-(C=O) ,-SO 2,-S-,-O-,-N-,-NH-and-NR 12
R 3Be the substituting group that is selected from following groups:
(a) hydrogen;
(b)-(C 6-C 10) aryl or-(C 1-C 9) heterocyclic radical, it randomly is independently selected from 1 to 3 of following groups part and replaces: halogen, hydroxyl ,-(C 1-C 6) alkyl ,-(C 1-C 6) alkyl-P (O) (O (C 1-C 6) alkyl) 2,-(C 3-C 10) cycloalkyl, (C 6-C 10) aryl, (C 2-C 9) heterocyclic radical ,-(C 1-C 9) heteroaryl ,-NR 5R 6,-NHSO 2(C 1-C 6) alkyl ,-NHSO 2(C 3-C 6) cycloalkyl ,-N ((C 1-C 6) alkyl) (SO 2-C 1-C 6) alkyl) ,-N ((C 1-C 6) alkyl) (SO 2(C 3-C 6) cycloalkyl) ,-N ((C 3-C 6) cycloalkyl) (SO 2-C 1-C 6) alkyl) ,-N ((C 3-C 6) cycloalkyl) (SO 2(C 3-C 6) cycloalkyl) ,-O (C 1-C 6) alkyl ,-O-SO 2(C 1-C 6) alkyl ,-O-SO 2(C 3-C 6) cycloalkyl ,-(CO) (C 1-C 6) alkyl ,-(CO) CF 3(the C of ,-(CO) 3-C 10) cycloalkyl ,-(CO) (C 6-C 10) aryl ,-(CO) (C 2-C 9) heterocyclic radical ,-(CO) (C 1-C 9) heteroaryl ,-(CO) O (C 1-C 6) alkyl ,-(CO) O (C 3-C 10) cycloalkyl ,-(CO) O (C 6-C 10) aryl ,-(CO) O (C 2-C 9) heterocyclic radical ,-(CO) O (C 1-C 9) heteroaryl ,-(CO) (C 1-C 6) alkyl-O (C 1-C 6) alkyl ,-SO 2(C 1-C 6) alkyl ,-SO 2(C 3-C 6) cycloalkyl ,-SO 2CF 3,-SO 2NH 2,-SO 2NH (C 1-C 6) alkyl ,-SO 2NH (C 3-C 6) cycloalkyl ,-SO 2N ((C 1-C 6) alkyl) 2,-SO 2N ((C 1-C 6) alkyl) ((C 3-C 6) cycloalkyl) ,-SO 2N ((C 3-C 6) cycloalkyl) 2With-SO 2NR 5R 6, wherein said-(C 6-C 10) aryl or-(C 1-C 9) heteroaryl 1 to 3 unit randomly being selected from following groups interrupts :-S-,-O-,-N-,-NH-and-NR 12
(c)-(C 3-C 10) cycloalkyl ,-(C 2-C 9) heterocyclic radical and-(C 1-C 6) alkyl-(C 2-C 9) heterocyclic radical, it randomly is independently selected from 1 to 3 of following groups part and replaces: halogen, hydroxyl ,-(C 1-C 6) alkyl ,-(C 1-C 6) alkyl-P (O) (O (C 1-C 6) alkyl) 2 ,-(C 3-C 10) cycloalkyl ,-(C 6-C 10) aryl ,-(C 2-C 9) heterocyclic radical ,-(C 1-C 9) heteroaryl ,-NR 5R 6,-NSO 2(C 1-C 6) alkyl ,-NHSOx (C 3-C 6) cycloalkyl ,-N ((C 1-C 6) alkyl) (SO 2-C 1-C 6) alkyl) ,-N ((C 1-C 6) alkyl) (SO 2(C 3-C 6) cycloalkyl) ,-N ((C 3-C 6) cycloalkyl) (SO 2-C 1-C 6) alkyl) ,-N ((C 3-C 6) cycloalkyl) (SO 2(C 3-C 6) cycloalkyl) ,-O (C 1-C 6) alkyl ,-O-SO 2(C 1-C 6) alkyl ,-O-SO 2(C 1-C 6) alkyl ,-O-SO 2(C 3-C 6) cycloalkyl ,-(CO) (C 1-C 6) alkyl ,-(CO) CF 3(the C of ,-(CO) 3-C 10) cycloalkyl ,-(CO) (C 6-C 10) aryl ,-(CO) (C 2-C 9) heterocyclic radical ,-(CO) (C 1-C 9) heteroaryl ,-(CO) O (C 1-C 6) alkyl ,-(CO) O (C 3-C 10) cycloalkyl ,-(CO) O (C 6-C 10) aryl ,-(CO) O (C 2-C 9) heterocyclic radical ,-(CO) O (C 1-C 9) heteroaryl ,-(CO) (C 1-C 6) alkyl-O (C 1-C 6) alkyl ,-SO 2(C 1-C 6) alkyl ,-SO 2(C 3-C 6) cycloalkyl ,-SO 2CF 3,-SO 2NH 2,-SO 2NH (C 1-C 6) alkyl ,-SO 2NH (C 3-C 6) cycloalkyl ,-SO 2N ((C 1-C 6) alkyl) 2,-SO 2N ((C 1-C 6) alkyl) ((C 3-C 6) cycloalkyl) ,-SO 2N ((C 3-C 6) cycloalkyl) 2, and-SO 2NR 5R 6, wherein said-(C 3-C 10) cycloalkyl ,-(C 2-C 9) heterocyclic radical and-(C 1-C 6) alkyl-(C 2-C 9) heterocyclic radical 1 to 3 unit randomly being selected from following groups interrupts :-(C=O) ,-SO 2,-S-,-O-,-N-,-NH-and-NR 12
(d)-(C 1-C 6) alkyl randomly is selected from 1 to 3 of following groups part and replaced: halogen, hydroxyl ,-(C 1-C 6) alkyl ,-(C 1-C 6) alkyl-P (O) (O (C 1-C 6) alkyl) 2,-(C 3-C 10) cycloalkyl ,-(C 6-C 10) aryl ,-(C 2-C 9) heterocyclic radical ,-(C 1-C 9) heteroaryl ,-NR 5R 6,-NHSO 2(C 1-C 6) alkyl ,-NHSO 2(C 3-C 6) cycloalkyl ,-N ((C 1-C 6) alkyl) (SO 2-C 1-C 6) alkyl) ,-N ((C 1-C 6) alkyl) (SO 2(C 3-C 6) cycloalkyl) ,-N ((C 3-C 6) cycloalkyl) (SO 2-C 1-C 6) alkyl) ,-N ((C 3-C 6) cycloalkyl) (SO 2(C 3-C 6) cycloalkyl) ,-O (C 1-C 6) alkyl ,-O-SO 2(C 1-C 6) alkyl ,-O-SO 2(C 3-C 6) cycloalkyl ,-(CO) (C 1-C 6) alkyl ,-(CO) CF 3(the C of ,-(CO) 3-C 10) cycloalkyl ,-(CO) (C 6-C 10) aryl ,-(CO) (C 2-C 9) heterocyclic radical ,-(CO) (C 1-C 9) heteroaryl ,-(CO) O (C 1-C 6) alkyl ,-(CO) O (C 3-C 10) cycloalkyl ,-(CO) O (C 6-C 10) aryl ,-(CO) O (C 2-C 9) heterocyclic radical ,-(CO) O (C 1-C 9) heteroaryl ,-(CO) (C 1-C 6) alkyl-O (C 1-C 6) alkyl ,-SO 2(C 1-C 6) alkyl ,-SO 2(C 3-C 6) cycloalkyl ,-SO 2CF 3,-SO 2NH 2,-SO 2NH (C 1-C 6) alkyl ,-SO 2NH (C 3-C 6) cycloalkyl ,-SO 2N ((C 1-C 6) alkyl) 2,-SO 2N ((C 1-C 6) alkyl) ((C 3-C 6) cycloalkyl) ,-SO 2N ((C 3-C 6) cycloalkyl) 2, and-SO 2NR 5R 6, wherein said-(C 1-C 6) alkyl 1 to 3 unit randomly being selected from following groups interrupts :-(C=O) ,-SO 2,-S-,-O-,-N-,-NH-and-NR 12
And, wherein said each R 3(b)-(d) substituting group, part or unit 1 to 3 group randomly being independently selected from following groups replaces: hydrogen, halogen, hydroxyl ,-CF 3,-NO 2,-CN ,-(C 1-C 6) alkyl ,-(C 2-C 6) thiazolinyl ,-(C 2-C 6) alkynyl, (C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-(C 6-C 10) aryl ,-(C 1-C 9) heteroaryl ,-O (C 1-C 6) alkyl ,-O (C 3-C 7) cycloalkyl ,-O (C 2-C 9) heterocyclic radical ,-C=N-OH ,-C=N-O (C 1-C 6Alkyl) ,-NR 5R 6,-SR 7,-SOR 7,-SO 2R 7,-CO 2R 12,-CONR 5R 6,-SO 2NR 5R 6,-NHCOR 5,-NR 12CONR 5R 6, and-NR 12SO 2R 7
R 4Be the substituting group that is selected from following groups: hydrogen ,-(C 1-C 6) alkyl ,-(C 3-C 7) cycloalkyl and-(C 2-C 9) heterocyclic radical; Wherein said-(C 1-C 6) alkyl ,-(C 3-C 7) cycloalkyl and-(C 2-C 9) heterocyclic radical R 4Substituting group randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-(C 1-C 6) alkyl ,-CN ,-NR 5R 6,-OR 5,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-SO 2NR 5R 6,-NR 12SO 2R 7,-SO 2R 7With-CONR 5R 8Wherein said-CONR 5R 8The R of group 5And R 8Can form with the atom that they connected-(C 2-C 9) heterocyclic radical;
R 5And R 6Each all is the substituting group that is independently selected from following groups: hydrogen ,-(C 1-C 6) alkyl ,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-(C 6-C 10) aryl ,-(C 1-C 9) heteroaryl ,-COR 12With-SO 2R 12Wherein said-(C 1-C 6) alkyl ,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-(C 6-C 10) aryl ,-(C 1-C 9) heteroaryl ,-COR 12With-SO 2R 12R 5Or R 6Substituting group randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen ,-CF 3,-CN ,-(C 1-C 6) alkyl ,-NH (C 1-C 6) alkyl ,-NH (C 3-C 7) cycloalkyl ,-NH (C 2-C 9) heterocyclic radical ,-NH (C 6-C 10) aryl ,-NH (C 1-C 9) heteroaryl ,-N ((C 1-C 6) alkyl) 2.-N ((C 3-C 7) cycloalkyl) 2,-N ((C 2-C 9) heterocyclic radical) 2,-N ((C 6-C 10) aryl) 2,-N ((C 1-C 9) heteroaryl) 2,-O (C 1-C 6) alkyl ,-O (C 3-C 7) cycloalkyl ,-O (C 2-C 9) heterocyclic radical ,-O (C 6-C 10) aryl ,-O (C 1-C 9) heteroaryl ,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 7, SO 2NR 5R 6, NR 12SO 2R 7,-SO2R 7,-CONH 2,-CONHR 7, and-CONR 7R 8Wherein said-CONR 7R 8The R of group 7And R 8Can form with the nitrogen-atoms that they connected-(C 2-C 9) heterocyclic radical;
R 5And R 6Can form with the atom that they connected-(C 2-C 9) heterocyclic radical, wherein said-(C 2-C 9) heterocyclic radical randomly is selected from 1 to 3 of following groups part and replaced: hydrogen, halogen, hydroxyl ,-CF 3,-NO 2,-CN ,-(C 1-C 6) alkyl ,-(C 2-C 6) thiazolinyl ,-(C 2-C 6) alkynyl ,-C=N-OH ,-C=N-O ((C 1-C 6) alkyl) ,-NR 7R 8,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 7R 8,-CONR 5R 8,-SR 7,-SOR 7,-SO 2R 7,-SO 2NR 7R 8,-NHCOR 12,-NR 12CONR 7R 8, and-NR 12SO 2R 7, wherein said-(C 2-C 9) the described-(C of heterocyclic radical 2-C 6) thiazolinyl and-(C 2-C 6) the alkynyl part can be randomly by 1 to 3 R 7Group replaces, and is described-(C 2-C 9) heterocyclic radical 1 to 3 unit randomly being selected from following groups interrupts :-(C=O) ,-SO 2,-S-,-O-,-N-,-NH-and-NR 12
R 7Be the substituting group that is selected from following groups :-(C 1-C 6) alkyl ,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-(C 6-C 10) aryl and-(C 1-C 9) heteroaryl; Wherein said-(C 1-C 6) alkyl ,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-(C 6-C 10) aryl and-(C 1-C 9) heteroaryl R 7Substituting group randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-CN ,-(C 1-C 6) alkyl ,-NR 12 2, and-O (C 1-C 6) alkyl;
R 8Be the substituting group that is selected from following groups: hydrogen ,-(C 1-C 6) alkyl ,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-(C 6-C 10) aryl and-(C 1-C 9) heteroaryl; Wherein said-(C 1-C 6) alkyl ,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-(C 6-C 10) aryl and-(C 1-C 9) heteroaryl R 8Substituting group randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-CN ,-(C 1-C 6) alkyl ,-NH 2,-NHR 9,-NR 9 2, OR 9,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 10,-CONH 2,-CONHR 10, and-CONR 10R 11Wherein said-CONR 10R 11R 10And R 11Can form with the nitrogen-atoms that they connected-(C 2-C 9) heterocyclic radical;
R 9And R 10Be-(C 1-C 6) alkyl;
R 11Be hydrogen or-(C 1-C 6) alkyl; And
R 12Be the substituting group that is selected from following groups: hydrogen ,-(C 1-C 6) alkyl ,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-(C 6-C 10) aryl and-(C 1-C 9) heteroaryl; Wherein said-(C 1-C 6) alkyl ,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-(C 6-C 10) aryl and-(C 1-C 9) heteroaryl R 12Substituting group randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen ,-CF 3,-CN ,-(C 1-C 6) alkyl ,-NH (C 1-C 6) alkyl ,-NH (C 3-C 7) cycloalkyl ,-NH (C 2-C 9) heterocyclic radical ,-NH (C 6-C 10) aryl ,-NH (C 1-C 9) heteroaryl ,-N ((C 1-C 6) alkyl) 2,-N ((C 3-C 7) cycloalkyl) 2,-N ((C 2-C 9) heterocyclic radical) 2,-N ((C 6-C 10) aryl) 2,-N ((C 1-C 9) heteroaryl) 2,-O (C 1-C 6) alkyl ,-O (C 3-C 7) cycloalkyl ,-O (C 2-C 9) heterocyclic radical ,-O (C 6-C 10) aryl ,-O (C 1-C 9) heteroaryl ,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 7,-CONH 2,-CONHR 7, and-CONR 7R 8Wherein said-CONR 7R 8R 7And R 8Can form with the atom that they connected-(C 2-C 9) heterocyclic radical.
The present invention also comprises isotope-labeled compound, and it is identical with compound that structural formula 1 shows, but one or more atoms are different from nucleidic mass that nature finds usually by nucleidic mass or total mass number or the atom of total mass number replaces.Can be incorporated into the isotropic substance that isotopic example in the The compounds of this invention comprises hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, for example, respectively, 2H, 3H, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F and 36Cl.The drug acceptable salt that comprises other isotopic The compounds of this invention, its prodrug and the described compound or the described prodrug of above-mentioned isotropic substance and/or other atoms includes within the scope of the present invention.Some isotope-labeled compound of the present invention, for example wherein introduce radio isotope as 3H and 14The compound of C can be used in medicine and/or the substrate tissue distribution mensuration.Preferred especially tritium generation, promptly 3H and carbon-14, promptly 14The C isotropic substance is because they are easy to preparation and detect.In addition, with heavier isotropic substance such as deuterium, promptly 2H, thereby because the higher advantage that has in some treatments of metabolic stability, for example the transformation period is lower than length or dosage demand in the body, is preferred in some cases therefore.Isotope-labeled structural formula 1 compound of the present invention and prodrug thereof usually can by implement hereinafter synoptic diagram and/or example example and preparation in disclosed method, be prepared by nonisotopically labelled reagent being replaced with the isotope-labeled reagent that is easy to obtain.
The invention still further relates to the acceptable acid salt of medicine of structural formula 1 compound.The acid that is used to prepare the acceptable acid salt of medicine of basic cpd of the present invention mentioned above is such acid: form nontoxic acid salt, promptly contain medicine and can accept anionic salt, as muriate, bromide, iodide, nitrate, vitriol, hydrosulfate, phosphoric acid salt, superphosphate, acetate, lactic acid salt, Citrate trianion, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, mesylate, esilate, benzene sulfonate, tosilate and embonate are [promptly, 1,1 '-methylene radical-two-(2-hydroxyl-3-naphthoate)] salt.
The invention still further relates to the base addition salt of structural formula 1.The chemical bases that can accept the reagent that basic salt uses as the medicine that on the preparation property is tart structural formula 1 compound is the alkali with the nontoxic basic salt of these compound formation.This nontoxic basic salt includes but not limited to derive from these medicines can accept cationic salt, as alkali metal cation (for example, potassium and sodium) and alkaline earth metal cation (for example, calcium and magnesium), ammonium or water miscible amine additive salt such as N-methylglucosamine-(meglumine) and low-level chain triacontanol ammonium and other medicine can accept the basic salt of organic amine.
Phrase used herein " the acceptable salt of medicine " unless otherwise indicated, comprises the acidity that can exist or the salt of basic group in compound of the present invention.The The compounds of this invention that is alkalescence in nature can form the very wide salt of scope with multiple inorganic and organic acid.The acid that the medicine that can be used to prepare these basic cpds can be accepted acid salt is to form non-toxic acid addition hydrochloric acid, nontoxic additive salt promptly contains medicine can accept anionic salt, example hydrochloric acid salt, hydrobromate, hydriodate, nitrate, vitriol, hydrosulfate, phosphoric acid salt, superphosphate, Yi Yansuan salt, acetate, lactic acid salt, salicylate, Citrate trianion, acid citrate, tartrate, pantothenate, bitartrate, ascorbate salt, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutaminate, mesylate, esilate, benzene sulfonate, tosilate and embonate are [promptly, 1,1 '-methylene radical-two-(2-hydroxyl-3-naphthoate)] salt.Except above-mentioned acid, comprise that the The compounds of this invention of basic moiety such as amino can also form the acceptable salt of medicine with multiple amino acids.
The present invention also comprises the pharmaceutical composition of the prodrug that contains structural formula 1 compound.Structural formula 1 compound with free amine group, amide group, hydroxyl or carboxyl can be transformed into prodrug.Prodrug comprises that free amine group, hydroxyl or the carboxyl of the polypeptide chain of amino-acid residue wherein or two or more (for example, two, three or four) amino-acid residue and structural formula 1 compound are by the covalently bound compound of peptide bond.Amino-acid residue comprises 20 kinds of natural amino acids that three letter characters of common usefulness are represented, also comprises 4-Hydroxyproline, hydroxylysine, demosine, isodemosine, 3-Methyl histidine, norvaline, Beta-alanine, γ-An Jidingsuan, citrulline, homocysteine, homoserine, ornithine and methionine(Met) sulfone.Prodrug comprises that also wherein carbonic ether, carbamate, acid amides and alkyl ester are by the covalently bound compound of substituting group of carbonyl carbon prodrug side chain and said structure formula 1.
The present invention also comprises structural formula 1 compound that contains blocking group.Those skilled in the art will appreciate that compound of the present invention can also be prepared with some blocking group, and these blocking groups are used for purifying or storage, can be removed before giving the patient.The protection of functional group and deprotection are seen and are set forth in " Protective Groups in Organic Chemistry "; the J.W.F.McOmie chief editor; Plenum Press (1973) and " Protective Groups in OrganicSynthesis "; the third edition; T.W.Greene and P.G.M.Wuts, Wiley-Interscience (1999).
Compound of the present invention comprises all steric isomers (for example, cis and trans-isomer(ide)) and all optical isomers (for example, R and S enantiomer) of structural formula 1 compound, and the racemize of these isomer, diastereomer and other mixtures.
Compound of the present invention, salt and prodrug can several tautomeric forms exist, and comprise enol and imines form, ketone and enamine form, geometrical isomer and composition thereof.All these tautomeric forms include within the scope of the present invention.Tautomer exists as one group of tautomers mixture in solution.Under solid form, common a kind of tautomer is preponderated.Even described a kind of tautomer, but the present invention includes all tautomers of The compounds of this invention.
The present invention also comprises atropisomer of the present invention.Atropisomer is meant structural formula 1 compound that can be separated into the limited isomer of rotation.
Compound of the present invention can contain the two keys of chain alkene.When having this key, compound of the present invention exists with cis and transconfiguration and composition thereof.
" suitable substituents " is meant chemistry and the acceptable functional group of medicine,, can not offset the part of the biologic activity of The compounds of this invention that is.These suitable substituents can be selected by this area professional and technical personnel according to routine.The illustrative example of suitable substituents includes but not limited to: halogen; perfluoroalkyl; perfluoro alkoxy; alkyl; thiazolinyl; alkynyl; hydroxyl; oxo base (oxo group); sulfydryl; alkyl thio-base; alkoxyl group; aryl or heteroaryl; aryloxy or heteroaryloxy; aralkyl or heteroaralkyl; aralkoxy or assorted aralkoxy; HO-(C=O)-Ji; amino; alkyl-and dialkyl amido; formamyl; alkyl-carbonyl; alkoxy carbonyl; alkyl amino-carbonyl; dialkyl amino carbonyl; aryl carbonyl; aryloxycarbonyl; alkyl sulphonyl; aryl sulfonyl and similar substituting group.Those skilled in the art will appreciate that many substituting groups can be replaced by other substituting group.The further example of suitable substituent comprises the substituting group described in the definition of structural formula 1 compound, comprises R as defined above 1To R 12
Term " is interrupted " the unit replacement that the ring carbon atom that is meant in the compound is selected from following groups :-(C=O) ,-SO 2,-S-,-O-,-N-,-NH-and-NR 12For example, if substituting group be-(C 6-C 10) aryl, as
Figure A20058001553000321
This ring can be interrupted by nitrogen heteroatom or replace, and forms following ring:
Figure A20058001553000322
Make ring carbon atom be replaced by heteroatoms nitrogen.Compound of the present invention can be admitted nearly three such replacements or interruption.
As used herein, the moieties of term " alkyl " and other groups mentioned in this article (for example alkoxyl group) can be (as methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl) side chain or side chain; 1 to 3 suitable substituents that is randomly defined as mentioned replaces described substituting group such as fluorine, chlorine, trifluoromethyl, (C 1-C 6) alkoxyl group, (C 6-C 10) aryloxy, trifluoromethoxy, difluoro-methoxy or (C 1-C 6) alkyl.Term used herein " each described alkyl " is meant as any aforesaid moieties in the group of alkoxyl group, thiazolinyl or alkylamino.Preferred alkyl comprises (C 1-C 6) alkyl, more preferably (C 1-C 4) alkyl, most preferably be methyl and ethyl.
As used herein, term " cycloalkyl " is meant monocyclic, bicyclic or tricyclic ring-type carbocyclic ring (for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group, ring nonyl, cyclopentenyl, cyclohexenyl, two ring [2.2.1] heptyl, two ring [3.2.1] octyl groups and two ring [5.2.0] nonyls etc.); Randomly contain 1 or 2 two key, randomly replaced described substituting group such as fluorine, chlorine, trifluoromethyl, (C by 1 to 3 suitable substituents as indicated above 1-C 6) alkoxyl group, (C 6-C 10) aryloxy, trifluoromethoxy, difluoro-methoxy or (C 1-C 6) alkyl.
As used herein, term " halogen " comprises fluorine, chlorine, bromine or iodine or fluorochemical, muriate, bromide or iodide.
As used herein, " thiazolinyl " is meant the unsaturated group with 2 to 6 carbon atoms of straight or branched, includes but not limited to: vinyl, 1-propenyl, 2-propenyl (allyl group), pseudoallyl, 2-methyl isophthalic acid-propenyl, 1-butylene base, crotyl and similar group; 1 to 3 suitable substituents that is randomly defined as mentioned replaces described substituting group such as fluorine, chlorine, trifluoromethyl, (C 1-C 6) alkoxyl group, (C 6-C 10) aryloxy, trifluoromethoxy, difluoro-methoxy or (C 1-C 6) alkyl.
As used herein, term " alkynyl " is meant the hydrocarbon chain group with one three key of straight or branched, includes but not limited to: ethynyl, proyl, butynyl and analogue; The suitable substituents that is randomly defined as mentioned replaces, described substituting group such as fluorine, chlorine, trifluoromethyl, (C 1-C 6) alkoxyl group, (C 6-C 10) aryloxy, trifluoromethoxy, difluoro-methoxy or (C 1-C 6) alkyl.
As used herein, term " carbonyl " or " (C=O) " (for example use in phrase alkyl-carbonyl, alkyl-(C=O)-or alkoxy carbonyl) be meant＞the C=O part is connected with another part such as alkyl or amino (being amide group).(that is, alkoxyl group (C=O)-NH-) is meant the alkyl carbamate group to alkoxycarbonyl amino.Carbonyl is identical with (C=O) definition herein.Alkyl-carbonyl-amino is meant for example group of ethanamide.
As used herein, term " aryl " is meant aromatic group, for example phenyl, naphthyl, tetralyl, indanyl and analogue; 1 to 3 suitable substituents that is randomly defined as mentioned replaces.
As used herein, term " heteroaryl " is meant aromatic heterocycle, and it has a heteroatoms that is selected from O, S and N usually in ring.Except that described heteroatoms, aromatic base can randomly have 4 N atoms of as many as in ring.For example, heteroaryl (for example comprises pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, thienyl, furyl, imidazolyl, pyrryl, oxazolyl, 1,3-oxazolyl, 1,2-oxazolyl), thiazolyl (for example, 1,2-thiazolyl, 1,3-thiazoles base), pyrazolyl, tetrazyl, triazolyl (for example, 1,2,3-triazolyl, 1,2,4-triazolyl), oxadiazole base is (for example, 1,2,3-oxadiazole base), thiadiazolyl group (for example, 1,3,4-thiadiazolyl group), quinolyl, isoquinolyl, benzothienyl, indyl and analogue; Randomly by above defined 1 to 3 suitable substituents such as fluorine, chlorine, trifluoromethyl, (C 1-C 6) alkoxyl group, (C 6-C 10) aryloxy, trifluoromethoxy, difluoro-methoxy or (C 1-C 6) the alkyl replacement.
As used herein, term " heterocyclic radical " is meant that containing 1-9 carbon atom and 1 to 4 is selected from N, O, S (O) nOr the heteroatomic cyclic group of NR.The example of these rings comprises azelidinyl (azetidinyl), tetrahydrofuran base, imidazolidyl, pyrrolidyl, piperidyl, piperazinyl oxazolidinyl, thiazolidyl, pyrazolidyl, thio-morpholinyl, the tetrahydrochysene thiazinyl, tetrahydrochysene thiadiazine base, morpholinyl, oxa-cyclobutyl (oxetanyl), tetrahydrochysene diazine (tetrahydrodiazinyl) oxazinyl Evil thiazinyl (oxathiazinyl), indolinyl, iso-dihydro-indole-group, quinuclidinyl, chromanyl, isochroman base benzoxazinyl and analogue.Described monocyclic example saturated or the fractional saturation member ring systems has tetrahydrofuran (THF)-2-base, tetrahydrofuran (THF)-3-base, imidazolidine-1-base, imidazolidine-2-base, imidazolidine-4-base, tetramethyleneimine-1-base, tetramethyleneimine-2-base, tetramethyleneimine-3-base, piperidines-1-base, piperidines-2-base, piperidines-3-base, piperazine-1-base, piperazine-2-base, piperazine-3-base, 1,3-oxazolidine-3-base, the isothiazole alkyl, 1,3-thiazolidine-3-base, 1,2-pyrazolidine-2-base, 1,3-pyrazolidine-1-base, thio-morpholinyl, 1,2-tetrahydrochysene thiazine-2-base, 1,3-tetrahydrochysene thiazine-3-base, tetrahydrochysene thiadiazine base, morpholinyl, 1,2-tetrahydrochysene diazine-2-base, 1,3-tetrahydrochysene diazine-1-base, 1,4-oxazine-2-base, 1,2,5-Evil thiazine-4-base and analogue; Randomly contain 1 or 2 two key, randomly by suitable substituents defined above such as fluorine, chlorine, trifluoromethyl, (C 1-C 6) alkoxyl group, (C 6-C 10) aryloxy, trifluoromethoxy, difluoro-methoxy or (C 1-C 6) the alkyl replacement.
As used herein, nitrogen heteroatom be meant N=,＞N and-NH; Wherein-N=is meant the two keys of nitrogen;＞N is meant the nitrogen that is connected with two keys, and-N is meant the nitrogen that contains a key.
This paper employed " embodiment " is meant the group of concrete compound or is used for concrete subgroup.According to a specific substituting group such as concrete R 1Or R 3Group can be discerned these subgroups.Can discern other subgenus according to multiple substituent combination, as R wherein 2Be hydrogen, R 1Be (C 1-C 6) all compounds of alkyl.
Therefore, the invention provides structural formula 1Compound, R wherein 3Be hydrogen.
The present invention also provides structural formula 1Compound, R wherein 3Be selected from-(C 6-C 10) aryl and (C 1-C 9) heteroaryl, it randomly is independently selected from 1 to 3 of following groups part and replaces: halogen, hydroxyl ,-(C 1-C 6) alkyl ,-(C 1-C 6) alkyl-P (O) (O (C 1-C 6) alkyl) 2,-(C 3-C 10) cycloalkyl ,-(C 6-C 10) aryl ,-(C 2-C 9) heterocyclic radical ,-(C 1-C 9) heteroaryl ,-NR 5R 6,-NHSO 2(C 1-C 6) alkyl ,-NHSO 2(C 3-C 6) cycloalkyl ,-N ((C 1-C 6) alkyl) (SO 2-C 1-C 6) alkyl) ,-N ((C 1-C 6) alkyl) (SO 2(C 3-C 6) cycloalkyl) ,-N ((C 3-C 6) cycloalkyl) (SO 2-C 1-C 6) alkyl) ,-N ((C 3-C 6) cycloalkyl) (SO 2(C 3-C 6) cycloalkyl) ,-O (C 1-C 6) alkyl ,-O-SO 2(C 1-C 6) alkyl ,-O-SO 2(C 3-C 6) cycloalkyl ,-(CO) (C 1-C 6) alkyl ,-(CO) CF 3(the C of ,-(CO) 3-C 10) cycloalkyl ,-(CO) (C 6-C 10) aryl ,-(CO) (C 2-C 9) heterocyclic radical ,-(CO) (C 1-C 9) heteroaryl ,-(CO) O (C 1-C 6) alkyl ,-(CO) O (C 3-C 10) cycloalkyl ,-(CO) O (C 6-C 10) aryl ,-(CO) O (C 2-C 9) heterocyclic radical ,-(CO) O (C 1-C 9) heteroaryl ,-(CO) (C 1-C 6) alkyl-O (C 1-C 6) alkyl ,-SO 2(C 1-C 6) alkyl ,-SO 2(C 3-C 6) cycloalkyl ,-SO 2CF 3,-SO 2NH 2, SO 2NH (C 1-C 6) alkyl ,-SO 2NH (C 3-C 6) cycloalkyl ,-SO 2N ((C 1-C 6) alkyl) 2, SO 2N ((C 1-C 6) alkyl) ((C 3-C 6) cycloalkyl) ,-SO 2N ((C 3-C 6) cycloalkyl) 2With-SO 2NR 5R 6, wherein said-(C 6-C 10) aryl or-(C 1-C 9) optional 1 to 3 unit the interruption :-S-that is selected from following groups of heteroaryl ,-O-,-N-,-NH-and-NR 12
Another embodiment of the invention is a structural formula 1Compound, R wherein 3Be selected from down-(C 3-C 10) cycloalkyl and (C 2-C 9) heteroaryl and-(C 1-C 6) alkyl-(C 2-C 9) heterocyclic radical, it randomly is independently selected from 1 to 3 of following groups part and replaces: halogen, hydroxyl ,-(C 1-C 6) alkyl ,-(C 1-C 6) alkyl-P (O) (O (C 1-C 6) alkyl) 2,-(C 3-C 10) cycloalkyl ,-(C 6-C 10) aryl ,-(C 2-C 9) heterocyclic radical ,-(C 1-C 9) heteroaryl ,-NR 5R 6,-NSO 2(C 1-C 6) alkyl ,-NHSO 2(C 3-C 6) cycloalkyl ,-N ((C 1-C 6) alkyl) (SO 2-C 1-C 6) alkyl) ,-N ((C 1-C 6) alkyl) (SO 2(C 3-C 6) cycloalkyl) ,-N ((C 3-C 6) cycloalkyl) (SO 2-C 1-C 6) alkyl) ,-N ((C 3-C 6) cycloalkyl) (SO 2(C 3-C 6) cycloalkyl) ,-O (C 1-C 6) alkyl ,-O-SO 2(C 1-C 6) alkyl ,-O-SO 2(C 1-C 6) alkyl ,-O-SO 2(C 3-C 6) cycloalkyl ,-(CO) (C 1-C 6) alkyl ,-(CO) CF 3(the C of ,-(CO) 3-C 10) cycloalkyl ,-(CO) (C 6-C 10) aryl ,-(CO) (C 2-C 9) heterocyclic radical ,-(CO) (C 1-C 9) heteroaryl ,-(CO) O (C 1-C 6) alkyl ,-(CO) O (C 3-C 10) cycloalkyl ,-(CO) O (C 6-C 10) aryl ,-(CO) O (C 2-C 9) heterocyclic radical ,-(CO) O (C 1-C 9) heteroaryl ,-(CO) (C 1-C 6) alkyl-O (C 1-C 6) alkyl ,-SO 2(C 1-C 6) alkyl ,-SO 2(C 3-C 6) cycloalkyl ,-SO 2CF 3, SO 2NH 2, SO 2NH (C 1-C 6) alkyl ,-SO 2NH (C 3-C 6) cycloalkyl ,-SO 2N ((C 1-C 6) alkyl) 2,-SO 2N ((C 1-C 6) alkyl) ((C 3-C 6) cycloalkyl) ,-SO 2N ((C 3-C 6) cycloalkyl) 2With-SO 2NR 5R 6, wherein said-(C 3-C 10) cycloalkyl ,-(C 2-C 9) heterocyclic radical and-(C 1-C 6) alkyl-(C 2-C 9) heterocyclic radical 1 to 3 unit randomly being selected from following groups interrupts :-(C=O) ,-SO 2,-S-,-O-,-N-,-NH-and-NR 12
It is of the present invention that to advance an embodiment be structural formula 1Compound, R wherein 3Be that 1 to 3 part that randomly is selected from following groups replaces-(C 1-C 6) alkyl: halogen, hydroxyl ,-(C 1-C 6) alkyl ,-(C 1-C 6) alkyl-P (O) (O (C 1-C 6) alkyl) 2,-(C 3-C 10) cycloalkyl ,-(C 6-C 10) aryl ,-(C 2-C 9) heterocyclic radical ,-(C 1-C 9) heteroaryl ,-NR 5R 6,-NHSO 2(C 1-C 6) alkyl ,-NHSO 2(C 3-C 6) cycloalkyl ,-N ((C 1-C 6) alkyl) (SO 2-C 1-C 6) alkyl) ,-N ((C 1-C 6) alkyl) (SO 2(C 3-C 6) cycloalkyl) ,-N ((C 3-C 6) cycloalkyl) (SO 2-C 1-C 6) alkyl) ,-N ((C 3-C 6) cycloalkyl) (SO 2(C 3-C 6) cycloalkyl) ,-O (C 1-C 6) alkyl ,-O-SO 2(C 1-C 6) alkyl ,-O-SO 2(C 3-C 6) cycloalkyl ,-(CO) (C 1-C 6) alkyl ,-(CO) CF 3(the C of ,-(CO) 3-C 10) cycloalkyl ,-(CO) (C 6-C 10) aryl ,-(CO) (C 2-C 9) heterocyclic radical ,-(CO) (C 1-C 9) heteroaryl ,-(CO) O (C 1-C 6) alkyl ,-(CO) O (C 3-C 10) cycloalkyl ,-(CO) O (C 6-C 10) aryl ,-(CO) O (C 2-C 9) heterocyclic radical ,-(CO) O (C 1-C 9) heteroaryl ,-(CO) (C 1-C 6) alkyl-O (C 1-C 6) alkyl ,-SO 2(C 1-C 6) alkyl ,-SO 2(C 3-C 6) cycloalkyl, SO 2CF 3, SO 2NH 2, SO 2NH (C 1-C 6) alkyl ,-SO 2NH (C 3-C 6) cycloalkyl ,-SO 2N ((C 1-C 6) alkyl) 2,-SO 2N ((C 1-C 6) alkyl) ((C 3-C 6) cycloalkyl) ,-SO 2N ((C 3-C 6) cycloalkyl) 2With-SO 2NR 5R 6, wherein said-(C 1-C 6) alkyl 1 to 3 unit randomly being selected from following groups interrupts :-(C=O) ,-SO 2,-S-,-O-,-N-,-NH-and-NR 12
Further again, the invention provides structural formula 2Compound:
Figure A20058001553000361
Wherein A is selected from following groups:
Figure A20058001553000371
Wherein m is 0 to 3 integer, R 13Be the substituting group that is selected from following groups: hydrogen, halogen, hydroxyl, (C 1-C 6)-alkyl, (C 3-C 7)-cycloalkyl, (C 6-C 10)-aryl, (C 1-C 9) heteroaryl, (C 2-C 9)-heterocyclic radical, O-(C 1-C 6)-alkyl, O-(C 3-C 7)-cycloalkyl, SO 2-(C 1-C 6) alkyl, SO 2(C 3-C 7)-cycloalkyl, NHSO 2(C 1-C 6) alkyl, N ((C 1-C 6) alkyl) (SO 2(C 1-C 6-alkyl)) N ((C, 3-C 7) cycloalkyl) (SO 2(C 1-C 6-alkyl)) N (C, 1-C 6-alkyl) (SO 2(C 3-C 7) cycloalkyl), N ((C 3-C 7) cycloalkyl) (SO 2(C 3-C 7) cycloalkyl), OSO 2(C 1-C 6) alkyl, SO 2CF 3, SO 2NH 2, SO 2NH (C 1-C 6) alkyl, SO 2NH (C 3-C 7) cycloalkyl, SO 2NR 5R 6, SO 2N ((C 1-C 6) alkyl) 2, CF 3, CO-(C 1-C 6) alkyl, CO-(C 3-C 7) cycloalkyl, COCF 3, CO 2(C 1-C 6) alkyl,
Figure A20058001553000381
With
Figure A20058001553000382
Another embodiment of the invention is a structural formula 3Compound:
Figure A20058001553000383
Wherein B is selected from:
Figure A20058001553000384
The present invention also provides structural formula 4Compound:
Wherein said D is selected from:
Figure A20058001553000392
Wherein q is 1 to 2 integer.
It is of the present invention that to advance an embodiment be structural formula 5Compound:
Figure A20058001553000402
Wherein E is selected from:
Figure A20058001553000403
R wherein 14Be selected from: (C 1-C 6)-alkyl, (C 3-C 7)-cycloalkyl and (C 2-C 9)-heterocyclic radical, and R 15Be selected from hydrogen, (C 1-C 6)-alkyl, (C 3-C 7)-cycloalkyl and (C 2-C 9)-heterocyclic radical.
Therefore, the invention provides the compound of structural formula 1, wherein R 1Be selected from hydrogen, hydroxyl ,-(C 1-C 6) alkyl, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-CN ,-(C 1-C 6) alkyl ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6With-CONR 5R 8
The present invention further provides the compound of structural formula 1, wherein R 1Be-(C 1-C 6) alkyl, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-CN ,-(C 1-C 6) alkyl ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6With-CONR 5R 8
The present invention also provides the compound of structural formula 1, wherein R 1Be selected from-(C 3-C 7) cycloalkyl and-(C 2-C 9) heterocyclic radical, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-CN ,-(C 1-C 6) alkyl ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6With-CONR 5R 8
The present invention yet comprises the compound of structural formula 1, wherein R 1Be selected from-O (C 1-C 6) alkyl ,-O (C 3-C 7) cycloalkyl and-O (C 2-C 9) heterocyclic radical, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-CN ,-(C 1-C 6) alkyl ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6With-CONR 5R 8One preferred embodiment in, R 1Be-O (C 1-C 6) alkyl, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-CN ,-(C 1-C 6) alkyl ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6With-CONR 5R 8
An embodiment of the invention are the compound of structural formula 1, wherein R 1Be-NR 5R 6, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-CN ,-(C 1-C 6) alkyl ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6With-CONR 5R 8
The further embodiment of the present invention is the compound of structural formula 1, wherein R 1Be selected from-SR 7,-SOR 7,-SO 2R 7, and-SO 2NR 5R 6, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-CN ,-(C 1-C 6) alkyl ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6With-CONR 5R 8In preferred embodiment, R 1Be-SO 2NR 5R 6, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-CN ,-(C 1-C 6) alkyl ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6With-CONR 5R 8
The present invention also provides the compound of structural formula 1, wherein R 1Be-CO 2R 12,-CONR 5R 6,-NHCOR 12,-NR 12CONR 5R 6, or-NR 12SO 2R 7, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-CN ,-(C 1-C 6) alkyl ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6With-CONR 5R 8In preferred embodiment, R 1Be-NR 12SO 2R 7, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-CN ,-(C 1-C 6) alkyl ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6With-CONR 5R 8
The present invention also provides the compound of structural formula 1, wherein R 2Be hydrogen or-(C 1-C 6) alkyl, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-NO 2,-CN ,-(C 1-C 6) alkyl ,-(C 2-C 6) thiazolinyl ,-(C 2-C 6) alkynyl ,-C=N-OH ,-C=N-O ((C 1-C 6) alkyl) ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6,-CONR 5R 8,-SR 7,-SOR 7,-SO 2R 7,-SO 2NR 5R 6,-NHCOR 12,-NR 12CONR 5R 6, and-NR 12SO 2R 7, wherein said-(C 2-C 6) thiazolinyl and-(C 2-C 6) alkynyl R 2Part can be randomly by 1 to 3 R 12Group replaces.
The present invention further provides the compound of structural formula 1, wherein R 2Be-(C 3-C 7) cycloalkyl or-(C 2-C 9) heterocyclic radical, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-NO 2,-CN ,-(C 1-C 6) alkyl ,-(C 2-C 6) thiazolinyl ,-(C 2-C 6) alkynyl ,-C=N-OH ,-C=N-O ((C 1-C 6) alkyl) ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6,-CONR 5R 8,-SR 7,-SOR 7,-SO 2R 7,-SO 2NR 5R 6,-NHCOR 12,-NR 12CONR 5R 6, and-NR 12SO 2R 7, wherein said-(C 2-C 6) thiazolinyl and-(C 2-C 6) alkynyl R 2Part can be randomly by 1 to 3 R 12Group replaces.
Another embodiment of the invention is the compound of structural formula 1, wherein R 2Be-CO 2R 12With-CONR 5R 6, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-NO 2,-CN ,-(C 1-C 6) alkyl ,-(C 2-C 6) thiazolinyl ,-(C 2-C 6) alkynyl ,-C=N-OH ,-C=N-O ((C 1-C 6) alkyl) ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6,-CONR 5R 8,-SR 7,-SOR 7,-SO 2R 7,-SO 2NR 5R 6,-NHCOR 12,-NR 12CONR 5R 6, and-NR 12SO 2R 7, wherein said-(C 2-C 6) thiazolinyl and-(C 2-C 6) alkynyl R 2Part can be randomly by 1 to 3 R 12Group replaces.
The present invention also provides the compound of structural formula 1, wherein R 1Be selected from hydrogen, hydroxyl and-(C 1-C 6) alkyl, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-CN ,-(C 1-C 6) alkyl ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6,-CONR 5R 8R 2Be hydrogen or-(C 1-C 6) alkyl, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-NO 2,-CN ,-(C 1-C 6) alkyl ,-(C 2-C 6) thiazolinyl ,-(C 2-C 6) alkynyl ,-C=N-OH ,-C=N-O ((C 1-C 6) alkyl) ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6,-CONR 5R 8,-SR 7,-SOR 7,-SO 2R 7,-SO 2NR 5R 6,-NHCOR 12,-NR 12CONR 5R 6, and-NR 12SO 2R 7, wherein said-(C 2-C 6) thiazolinyl and-(C 2-C 6) alkynyl R 2Part can be randomly by 1 to 3 R 12Group replaces.
The present invention further provides the compound of structural formula 1, wherein R 1Be selected from hydrogen, hydroxyl and-(C 1-C 6) alkyl, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-CN ,-(C 1-C 6) alkyl ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6With-CONR 5R 8And R 2Be hydrogen.
The present invention further provides the compound of structural formula 1, wherein R 1Be-(C 1-C 6) alkyl, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-CN ,-(C 1-C 6) alkyl ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6With-CONR 5R 8And R 2Be hydrogen.
The present invention also provides the compound of structural formula 1, wherein R 1Be selected from-(C 3-C 7) cycloalkyl and-(C 2-C 9) heterocyclic radical, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-CN ,-(C 1-C 6) alkyl ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6With-CONR 5R 8And R 2Be hydrogen.
The present invention also comprises the compound of structural formula 1, wherein R 1Be selected from-O (C 1-C 6) alkyl ,-O (C 3-C 7) cycloalkyl and-O (C 2-C 9) heterocyclic radical, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-CN ,-(C 1-C 6) alkyl ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6With-CONR 5R 8And R 2Be hydrogen.
An embodiment of the invention are the compound of structural formula 1, wherein R 1Be-NR 5R 6, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-CN ,-(C 1-C 6) alkyl ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6With-CONR 5R 8And R 2Be hydrogen.
The further embodiment of the present invention is the compound of structural formula 1, wherein R 1Be selected from-SR 7,-SOR 7,-SO 2R 7, and-SO 2NR 5R 6, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-CN ,-(C 1-C 6) alkyl ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6With-CONR 5R 8And R 2Be hydrogen.
The present invention also provides the compound of structural formula 1, wherein R 1Be-CO 2R 12,-CONR 5R 6,-NHCOR 12,-NR 12CONR 5R 6, or-NR 12SO 2R 7, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-CN ,-(C 1-C 6) alkyl ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6With-CONR 5R 8And R 2Be hydrogen.
The present invention also provides the compound of structural formula 1, wherein R 2Be hydrogen or-(C 1-C 6) alkyl, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-NO 2,-CN ,-(C 1-C 6) alkyl ,-(C 2-C 6) thiazolinyl ,-(C 2-C 6) alkynyl ,-C=N-OH ,-C=N-O ((C 1-C 6) alkyl) ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6,-CONR 5R 8,-SR 7,-SOR 7,-SO 2R 7,-SO 2NR 5R 6,-NHCOR 12,-NR 12CONR 5R 6, and-NR 12SO 2R 7, wherein said-(C 2-C 6) thiazolinyl and-(C 2-C 6) alkynyl R 2Part can be randomly by 1 to 3 R 12Group replaces; And R 1Be hydrogen.
The present invention further provides the compound of structural formula 1, wherein R 2Be-(C 3-C 7) cycloalkyl or-(C 2-C 9) heterocyclic radical, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-NO 2,-CN ,-(C 1-C 6) alkyl ,-(C 2-C 6) thiazolinyl ,-(C 2-C 6) alkynyl ,-C=N-OH ,-C=N-O ((C 1-C 6) alkyl) ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6,-CONR 5R 8,-SR 7,-SOR 7,-SO 2R 7,-SO 2NR 5R 6,-NHCOR 12,-NR 12CONR 5R 6, and-NR 12SO 2R 7, wherein said-(C 2-C 6) thiazolinyl and-(C 2-C 6) alkynyl R 2Part can be randomly by 1 to 3 R 12Group replaces; And R 1Be hydrogen.
Another embodiment of the invention is the compound of structural formula 1, wherein R 2Be-CO 2R 12With-CONR 5R 6, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-NO 2,-CN ,-(C 1-C 6) alkyl ,-(C 2-C 6) thiazolinyl ,-(C 2-C 6) alkynyl ,-C=N-OH ,-C=N-O ((C 1-C 6) alkyl) ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6,-CONR 5R 8,-SR 7,-SOR 7,-SO 2R 7,-SO 2NR 5R 6,-NHCOR 12,-NR 12CONR 5R 6, and-NR 12SO 2R 7, wherein said-(C 2-C 6) thiazolinyl and-(C 2-C 6) alkynyl R 2Part can be randomly by 1 to 3 R 12Group replaces; And R 1Be hydrogen.
The present invention further provides the compound of structural formula 1, wherein R 1Be selected from hydrogen, hydroxyl and-(C 1-C 6) alkyl, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-CN ,-(C 1-C 6) alkyl ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6With-CONR 5R 8And R 2Be-(C 1-C 6) alkyl.
The present invention further provides the compound of structural formula 1, wherein R 1Be-(C 1-C 6) alkyl, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-CN ,-(C 1-C 6) alkyl ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6With-CONR 5R 8And R 2Be-(C 1-C 6) alkyl.
The present invention also provides the compound of structural formula 1, wherein R 1Be selected from-(C 3-C 7) cycloalkyl and-(C 2-C 9) heterocyclic radical, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-CN ,-(C 1-C 6) alkyl ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6With-CONR 5R 8And R 2Be-(C 1-C 6) alkyl.
The present invention also comprises the compound of structural formula 1, wherein R 1Be selected from-O (C 1-C 6) alkyl ,-O (C 3-C 7) cycloalkyl and-O (C 2-C 9) heterocyclic radical, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-CN ,-(C 1-C 6) alkyl ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6With-CONR 5R 8And R 2Be-(C 1-C 6) alkyl.
An embodiment of the invention are the compound of structural formula 1, wherein R 1Be-NR 5R 6, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-CN ,-(C 1-C 6) alkyl ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6With-CONR 5R 8And R 2Be-(C 1-C 6) alkyl.
The further embodiment of the present invention is the compound of structural formula 1, wherein R 1Be selected from-SR 7,-SOR 7,-SO 2R 7, and-SO 2NR 5R 6, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-CN ,-(C 1-C 6) alkyl ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6With-CONR 5R 8And R 2Be-(C 1-C 6) alkyl.
The present invention also provides the compound of structural formula 1, wherein R 1Be-CO 2R 12,-CONR 5R 6,-NHCOR 12,-NR 12CONR 5R 6, or-NR 12SO 2R 7, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-CN ,-(C 1-C 6) alkyl ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6With-CONR 5R 8And R 2Be-(C 1-C 6) alkyl.
The present invention also provides the compound of structural formula 1, wherein R 2Be hydrogen or-(C 1-C 6) alkyl, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-NO 2,-CN ,-(C 1-C 6) alkyl ,-(C 2-C 6) thiazolinyl ,-(C 2-C 6) alkynyl ,-C=N-OH ,-C=N-O ((C 1-C 6) alkyl) ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6,-CONR 5R 8,-SR 7,-SOR 7,-SO 2R 7,-SO 2NR 5R 6,-NHCOR 12,-NR 12CONR 5R 6, and-NR 12SO 2R 7, wherein said-(C 2-C 6) thiazolinyl and-(C 2-C 6) alkynyl R 2Part can be randomly by 1 to 3 R 12Group replaces; And R 1Be-(C 1-C 6) alkyl.
The present invention further provides the compound of structural formula 1, wherein R 2Be-(C 3-C 7) cycloalkyl or-(C 2-C 9) heterocyclic radical, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-NO 2,-CN ,-(C 1-C 6) alkyl ,-(C 2-C 6) thiazolinyl ,-(C 2-C 6) alkynyl ,-C=N-OH ,-C=N-O ((C 1-C 6) alkyl) ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6,-CONR 5R 8,-SR 7,-SOR 7,-SO 2R 7,-SO 2NR 5R 6,-NHCOR 12,-NR 12CONR 5R 6, and-NR 12SO 2R 7, wherein said-(C 2-C 6) thiazolinyl and-(C 2-C 6) alkynyl R 2Part can be randomly by 1 to 3 R 12Group replaces; And R 1Be-(C 1-C 6) alkyl.
Another embodiment of the invention is the compound of structural formula 1, wherein R 2Be-CO 2R 12With-CONR 5R 6, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-NO 2,-CN ,-(C 1-C 6) alkyl ,-(C 2-C 6) thiazolinyl ,-(C 2-C 6) alkynyl ,-C=N-OH ,-C=N-O ((C 1-C 6) alkyl) ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6,-CONR 5R 8,-SR 7,-SOR 7,-SO 2R 7,-SO 2NR 5R 6,-NHCOR 12,-NR 12CONR 5R 6, and-NR 12SO 2R 7, wherein said-(C 2-C 6) thiazolinyl and-(C 2-C 6) alkynyl R 2Part can be randomly by 1 to 3 R 12Group replaces; And R 1Be-(C 1-C 6) alkyl.
The present invention also provides the compound of structural formula 1, wherein R 1Be selected from hydrogen, hydroxyl and-(C 1-C 6) alkyl, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-CN ,-(C 1-C 6) alkyl ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6With-CONR 5R 8R 2Be hydrogen or-(C 1-C 6) alkyl, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-NO 2,-CN ,-(C 1-C 6) alkyl ,-(C 2-C 6) thiazolinyl ,-(C 2-C 6) alkynyl ,-C=N-OH ,-C=N-O ((C 1-C 6) alkyl) ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6,-CONR 5R 8,-SR 7,-SOR 7,-SO 2R 7,-SO 2NR 5R 6,-NHCOR 12,-NR 12CONR 5R 6, and-NR 12SO 2R 7, wherein said-(C 2-C 6) thiazolinyl and-(C 2-C 6) alkynyl R 2Part can be randomly by 1 to 3 R 12Group replaces; And n is 1.
The present invention further provides the compound of structural formula 1, wherein R 1Be selected from hydrogen, hydroxyl and-(C 1-C 6) alkyl, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-CN ,-(C 1-C 6) alkyl ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6With-CONR 5R 8R 2Be-(C 1-C 6) alkyl; And n is 1.
The present invention further provides the compound of structural formula 1, wherein R 1Be-(C 1-C 6) alkyl, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-CN ,-(C 1-C 6) alkyl ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6With-CONR 5R 8R 2Be-(C 1-C 6) alkyl; And n is 1.
The present invention also provides the compound of structural formula 1, wherein R 1Be selected from-(C 3-C 7) cycloalkyl and-(C 2-C 9) heterocyclic radical, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-CN ,-(C 1-C 6) alkyl ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6With-CONR 5R 8R 2Be-(C 1-C 6) alkyl; N is 1.
The present invention also provides the compound of structural formula 1, wherein R 1Be selected from-O (C 1-C 6) alkyl ,-O (C 3-C 7) cycloalkyl and-O (C 2-C 9) heterocyclic radical, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-CN ,-(C 1-C 6) alkyl ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6With-CONR 5R 8R 2Be-(C 1-C 6) alkyl; And n is 1.
An embodiment of the invention are the compound of structural formula 1, wherein R 1Be-NR 5R 6, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-CN ,-(C 1-C 6) alkyl ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6With-CONR 5R 8R 2Be-(C 1-C 6) alkyl; And n is 1.
The further embodiment of the present invention is the compound of structural formula 1, wherein R 1Be selected from-SR 7,-SOR 7,-SO 2R 7, and-SO 2NR 5R 6, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-CN ,-(C 1-C 6) alkyl ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6With-CONR 5R 8R 2Be-(C 1-C 6) alkyl; And n is 1.
The present invention also provides the compound of structural formula 1, wherein R 1Be-CO 2R 12,-CONR 5R 6,-NHCOR 12,-NR 12CONR 5R 6, or-NR 12SO 2R 7, optional 1 to 3 part that is independently selected from following groups replaces: hydrogen, halogen, hydroxyl ,-CN ,-(C 1-C 6) alkyl ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6With-CONR 5R 8R 2Be-(C 1-C 6) alkyl; And n is 1.
The present invention also provides the compound of structural formula 1, wherein R 2Be hydrogen or-(C 1-C 6) alkyl, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-NO 2,-CN ,-(C 1-C 6) alkyl ,-(C 2-C 6) thiazolinyl ,-(C 2-C 6) alkynyl ,-C=N-OH ,-C=N-O ((C 1-C 6) alkyl) ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6,-CONR 5R 8,-SR 7,-SOR 7,-SO 2R 7,-SO 2NR 5R 6,-NHCOR 12,-NR 12CONR 5R 6, and-NR 12SO 2R 7, wherein said-(C 2-C 6) thiazolinyl and-(C 2-C 6) alkynyl R 2Part can be randomly by 1 to 3 R 12Group replaces; R 1Be-(C 1-C 6) alkyl; And n is 1.
The present invention further provides the compound of structural formula 1, wherein R 2Be-(C 3-C 7) cycloalkyl or-(C 2-C 9) heterocyclic radical, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-NO 2,-CN ,-(C 1-C 6) alkyl ,-(C 2-C 6) thiazolinyl ,-(C 2-C 6) alkynyl ,-C=N-OH ,-C=N-O ((C 1-C 6) alkyl) ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6,-CONR 5R 8,-SR 7,-SOR 7,-SO 2R 7,-SO 2NR 5R 6,-NHCOR 12,-NR 12CONR 5R 6, and-NR 12SO 2R 7, wherein said-(C 2-C 6) thiazolinyl and-(C 2-C 6) alkynyl R 2Part can be randomly by 1 to 3 R 12Group replaces; R 1Be-(C 1-C 6) alkyl; And n is 1.
Another embodiment of the invention is the compound of structural formula 1, wherein R 2Be-CO 2R 12With-CONR 5R 6, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-NO 2,-CN ,-(C 1-C 6) alkyl ,-(C 2-C 6) thiazolinyl ,-(C 2-C 6) alkynyl ,-C=N-OH ,-C=N-O ((C 1-C 6) alkyl) ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6,-CONR 5R 8,-SR 7,-SOR 7,-SO 2R 7,-SO 2NR 5R 6,-NHCOR 12,-NR 12CONR 5R 6, and-NR 12SO 2R 7, wherein said-(C 2-C 6) thiazolinyl and-(C 2-C 6) alkynyl R 2Part can be randomly by 1 to 3 R 12Group replaces; R 1Be-(C 1-C 6) alkyl; And n is 1.
The present invention further provides the compound of structural formula 1, wherein R 1Be selected from hydrogen, hydroxyl and-(C 1-C 6) alkyl, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-CN ,-(C 1-C 6) alkyl ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6With-CONR 5R 8R 2Be-(C 1-C 6) alkyl; And n is 1.
The present invention further provides the compound of structural formula 1, wherein R 1Be-(C 1-C 6) alkyl, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-CN ,-(C 1-C 6) alkyl ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6With-CONR 5R 8R 2Be-(C 1-C 6) alkyl; And n is 1.
The present invention also provides the compound of structural formula 1, wherein R 1Be selected from-(C 3-C 7) cycloalkyl and-(C 2-C 9) heterocyclic radical, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-CN ,-(C 1-C 6) alkyl ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6With-CONR 5R 8R 2Be-(C 1-C 6) alkyl; And n is 1.
The present invention also comprises the compound of structural formula 1, wherein R 1Be selected from-O (C 1-C 6) alkyl ,-O (C 3-C 7) cycloalkyl and-O (C 2-C 9) heterocyclic radical, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-CN ,-(C 1-C 6) alkyl ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6With-CONR 5R 8R 2Be-(C 1-C 6) alkyl; And n is 1.
An embodiment of the invention are the compound of structural formula 1, wherein R 1Be-NR 5R 6, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-CN ,-(C 1-C 6) alkyl ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6With-CONR 5R 8R 2Be-(C 1-C 6) alkyl; And n is 1.
The further embodiment of the present invention is the compound of structural formula 1, wherein R 1Be selected from-SR 7,-SOR 7,-SO 2R 7, and-SO 2NR 5R 6, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-CN ,-(C 1-C 6) alkyl ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6With-CONR 5R 8R 2Be-(C 1-C 6) alkyl; And n is 1.
The present invention also provides the compound of structural formula 1, wherein R 1Be-CO 2R 12,-CONR 5R 6,-NHCOR 12,-NR 12CONR 5R 6, or-NR 12SO 2R 7, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-CN ,-(C 1-C 6) alkyl ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6With-CONR 5R 8R 2Be-(C 1-C 6) alkyl; And n is 1.
The present invention also provides the compound of structural formula 1, wherein R 2Be hydrogen or-(C 1-C 6) alkyl, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-NO 2,-CN ,-(C 1-C 6) alkyl ,-(C 2-C 6) thiazolinyl ,-(C 2-C 6) alkynyl ,-C=N-OH ,-C=N-O ((C 1-C 6) alkyl) ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6,-CONR 5R 8,-SR 7,-SOR 7,-SO 2R 7,-SO 2NR 5R 6,-NHCOR 12,-NR 12CONR 5R 6, and-NR 12SO 2R 7, wherein said-(C 2-C 6) thiazolinyl and-(C 2-C 6) alkynyl R 2Part can be randomly by 1 to 3 R 12Group replaces; R 1Be-(C 1-C 6) alkyl; And n is 1.
The present invention further provides the compound of structural formula 1, wherein R 2Be-(C 3-C 7) cycloalkyl or-(C 2-C 9) heterocyclic radical, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-NO 2,-CN ,-(C 1-C 6) alkyl ,-(C 2-C 6) thiazolinyl ,-(C 2-C 6) alkynyl ,-C=N-OH ,-C=N-O ((C 1-C 6) alkyl) ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6,-CONR 5R 8,-SR 7,-SOR 7,-SO 2R 7,-SO 2NR 5R 6,-NHCOR 12,-NR 12CONR 5R 6, and-NR 12SO 2R 7, wherein said-(C 2-C 6) thiazolinyl and-(C 2-C 6) alkynyl R 2Part can be randomly by 1 to 3 R 12Group replaces; R 1Be-(C 1-C 6) alkyl; And n is 1.
Another embodiment of the invention is the compound of structural formula 1, wherein R 2Be-CO 2R 12With-CONR 5R 6, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-NO 2,-CN ,-(C 1-C 6) alkyl ,-(C 2-C 6) thiazolinyl ,-(C 2-C 6) alkynyl ,-C=N-OH ,-C=N-O ((C 1-C 6) alkyl) ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6,-CONR 5R 8,-SR 7,-SOR 7,-SO 2R 7,-SO 2NR 5R 6,-NHCOR 12,-NR 12CONR 5R 6, and-NR 12SO 2R 7, wherein said-(C 2-C 6) thiazolinyl and-(C 2-C 6) alkynyl R 2Part can be randomly by 1 to 3 R 12Group replaces; R 1Be-(C 1-C 6) alkyl; And n is 1.
The present invention also provides the compound of structural formula 1, wherein R 1Be selected from hydrogen, hydroxyl and-(C 1-C 6) alkyl, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-CN ,-(C 1-C 6) alkyl ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6With-CONR 5R 8R 2Be hydrogen or-(C 1-C 6) alkyl, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-NO 2,-CN ,-(C 1-C 6) alkyl ,-(C 2-C 6) thiazolinyl ,-(C 2-C 6) alkynyl ,-C=N-OH ,-C=N-O ((C 1-C 6) alkyl) ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6,-CONR 5R 8,-SR 7,-SOR 7,-SO 2R 7,-SO 2NR 5R 6,-NHCOR 12,-NR 12CONR 5R 6, and-NR 12SO 2R 7, wherein said-(C 2-C 6) thiazolinyl and-(C 2-C 6) alkynyl R 2Part can be randomly by 1 to 3 R 12Group replaces; And n is 1.
The present invention further provides the compound of structural formula 1, wherein R 1Be selected from hydrogen, hydroxyl and-(C 1-C 6) alkyl, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-CN ,-(C 1-C 6) alkyl ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6With-CONR 5R 8R 2Be hydrogen; And n is 1.
The present invention further provides the compound of structural formula 1, wherein R 1Be-(C 1-C 6) alkyl, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-CN ,-(C 1-C 6) alkyl ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6With-CONR 5R 8R 2Be hydrogen; And n is 1.
The present invention also provides the compound of structural formula 1, wherein R 1Be selected from-(C 3-C 7) cycloalkyl and-(C 2-C 9) heterocyclic radical, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-CN ,-(C 1-C 6) alkyl ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6With-CONR 5R 8R 2Be hydrogen; N is 1.
The present invention also comprises the compound of structural formula 1, wherein R 1Be selected from-O (C 1-C 6) alkyl ,-O (C 3-C 7) cycloalkyl and-O (C 2-C 9) heterocyclic radical, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-CN ,-(C 1-C 6) alkyl ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6With-CONR 5R 8R 2Be hydrogen; And n is 1.
An embodiment of the invention are the compound of structural formula 1, wherein R 1Be-NR 5R 6, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-CN ,-(C 1-C 6) alkyl ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6With-CONR 5R 8R 2Be hydrogen; And n is 1.
The further embodiment of the present invention is the compound of structural formula 1, wherein R 1Be selected from-SR 7,-SOR 7,-SO 2R 7, and-SO 2NR 5R 6, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-CN ,-(C 1-C 6) alkyl ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6With-CONR 5R 8R 2Be hydrogen; And n is 1.
The present invention also provides the compound of structural formula 1, wherein R 1Be-CO 2R 12,-CONR 5R 6,-NHCOR 12,-NR 12CONR 5R 6, or-NR 12SO 2R 7, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-CN ,-(C 1-C 6) alkyl ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6With-CONR 5R 8R 2Be hydrogen; And n is 1.
The present invention also provides the compound of structural formula 1, wherein R 2Be hydrogen or-(C 1-C 6) alkyl, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-NO 2,-CN ,-(C 1-C 6) alkyl ,-(C 2-C 6) thiazolinyl ,-(C 2-C 6) alkynyl ,-C=N-OH ,-C=N-O ((C 1-C 6) alkyl) ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6,-CONR 5R 8,-SR 7,-SOR 7,-SO 2R 7,-SO 2NR 5R 6,-NHCOR 12,-NR 12CONR 5R 6, and-NR 12SO 2R 7, wherein said-(C 2-C 6) thiazolinyl and-(C 2-C 6) alkynyl R 2Part can be randomly by 1 to 3 R 12Group replaces; R 1Be hydrogen; And n is 1.
The present invention further provides the compound of structural formula 1, wherein R 2Be-(C 3-C 7) cycloalkyl or-(C 2-C 9) heterocyclic radical, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-NO 2,-CN ,-(C 1-C 6) alkyl ,-(C 2-C 6) thiazolinyl ,-(C 2-C 6) alkynyl ,-C=N-OH ,-C=N-O ((C 1-C 6) alkyl) ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6,-CONR 5R 8,-SR 7,-SOR 7,-SO 2R 7,-SO 2NR 5R 6,-NHCOR 12,-NR 12CONR 5R 6, and-NR 12SO 2R 7, wherein said-(C 2-C 6) thiazolinyl and-(C 2-C 6) alkynyl R 2Part can be randomly by 1 to 3 R 12Group replaces; R 1Be hydrogen; And n is 1.
Another embodiment of the invention is the compound of structural formula 1, wherein R 2Be-CO 2R 12With-CONR 5R 6, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-NO 2,-CN ,-(C 1-C 6) alkyl ,-(C 2-C 6) thiazolinyl ,-(C 2-C 6) alkynyl ,-C=N-OH ,-C=N-O ((C 1-C 6) alkyl) ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6,-CONR 5R 8,-SR 7,-SOR 7,-SO 2R 7,-SO 2NR 5R 6,-NHCOR 12,-NR 12CONR 5R 6, and-NR 12SO 2R 7, wherein said-(C 2-C 6) thiazolinyl and-(C 2-C 6) alkynyl R 2Part can be randomly by 1 to 3 R 12Group replaces; R 1Be hydrogen; And n is 1.
The present invention also provides the compound of structural formula 1, wherein R 1Be selected from hydrogen, hydroxyl and-(C 1-C 6) alkyl, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-CN ,-(C 1-C 6) alkyl ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6With-CONR 5R 8R 2Be hydrogen or-(C 1-C 6) alkyl, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-NO 2,-CN ,-(C 1-C 6) alkyl ,-(C 2-C 6) thiazolinyl ,-(C 2-C 6) alkynyl ,-C=N-OH ,-C=N-O ((C 1-C 6) alkyl) ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6,-CONR 5R 8,-SR 7,-SOR 7,-SO 2R 7,-SO 2NR 5R 6,-NHCOR 12,-NR 12CONR 5R 6, and-NR 12SO 2R 7, wherein said-(C 2-C 6) thiazolinyl and-(C 2-C 6) alkynyl R 2Part can be randomly by 1 to 3 R 12Group replaces; And n is 2.
The present invention further provides the compound of structural formula 1, wherein R 1Be selected from hydrogen, hydroxyl and-(C 1-C 6) alkyl, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-CN ,-(C 1-C 6) alkyl ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6With-CONR 5R 8R 2Be-(C 1-C 6) alkyl; And n is 2.
The present invention further provides the compound of structural formula 1, wherein R 1Be-(C 1-C 6) alkyl, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-CN ,-(C 1-C 6) alkyl ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6With-CONR 5R 8R 2Be-(C 1-C 6) alkyl; And n is 2.
The present invention also provides the compound of structural formula 1, wherein R 1Be selected from-(C 3-C 7) cycloalkyl and-(C 2-C 9) heterocyclic radical, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-CN ,-(C 1-C 6) alkyl ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6With-CONR 5R 8R 2Be-(C 1-C 6) alkyl; And n is 2.
The present invention also provides the compound of structural formula 1, wherein R 1Be selected from-O (C 1- 6) alkyl ,-O (C 3-C 7) cycloalkyl and-O (C 2-C 9) heterocyclic radical, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-CN ,-(C 1-C 6) alkyl ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6With-CONR 5R 8R 2Be-(C 1-C 6) alkyl; And n is 2.
An embodiment of the invention are the compound of structural formula 1, wherein R 1Be-NR 5R 6, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-CN ,-(C 1-C 6) alkyl ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6With-CONR 5R 8R 2Be-(C 1-C 6) alkyl; And n is 2.
The further embodiment of the present invention is the compound of structural formula 1, wherein R 1Be selected from-SR 7,-SOR 7,-SO 2R 7, and-SO 2NR 5R 6, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-CN ,-(C 1-C 6) alkyl ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6With-CONR 5R 8R 2Be-(C 1-C 6) alkyl; And n is 2.
The present invention also provides the compound of structural formula 1, wherein R 1Be-CO 2R 12,-CONR 5R 6,-NHCOR 12,-NR 12CONR 5R 6, or-NR 12SO 2R 7, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-CN ,-(C 1-C 6) alkyl ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6With-CONR 5R 8R 2Be-(C 1-C 6) alkyl; And n is 2.
The present invention also provides the compound of structural formula 1, wherein R 2Be hydrogen or-(C 1-C 6) alkyl, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-NO 2,-CN ,-(C 1-C 6) alkyl ,-(C 2-C 6) thiazolinyl ,-(C 2-C 6) alkynyl ,-C=N-OH ,-C=N-O ((C 1-C 6) alkyl) ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6,-CONR 5R 8,-SR 7,-SOR 7,-SO 2R 7,-SO 2NR 5R 6,-NHCOR 12,-NR 12CONR 5R 6, and-NR 12SO 2R 7, wherein said-(C 2-C 6) thiazolinyl and-(C 2-C 6) alkynyl R 2Part can be randomly by 1 to 3 R 12Group replaces; R 1Be-(C 1-C 6) alkyl; And n is 2.
The present invention further provides the compound of structural formula 1, wherein R 2Be-(C 3-C 7) cycloalkyl or-(C 2-C 9) heterocyclic radical, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-NO 2,-CN ,-(C 1-C 6) alkyl ,-(C 2-C 6) thiazolinyl ,-(C 2-C 6) alkynyl ,-C=N-OH ,-C=N-O ((C 1-C 6) alkyl) ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6,-CONR 5R 8,-SR 7,-SOR 7,-SO 2R 7,-SO 2NR 5R 6,-NHCOR 12,-NR 12CONR 5R 6, and-NR 12SO 2R 7, wherein said-(C 2-C 6) thiazolinyl and-(C 2-C 6) alkynyl R 2Part can be randomly by 1 to 3 R 12Group replaces; R 1Be-(C 1-C 6) alkyl; And n is 2.
Another embodiment of the invention is the compound of structural formula 1, wherein R 2Be-CO 2R 12With-CONR 5R 6, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-NO 2,-CN ,-(C 1-C 6) alkyl ,-(C 2-C 6) thiazolinyl ,-(C 2-C 6) alkynyl ,-C=N-OH ,-C=N-O ((C 1-C 6) alkyl) ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6,-CONR 5R 8,-SR 7,-SOR 7,-SO 2R 7,-SO 2NR 5R 6,-NHCOR 12,-NR 12CONR 5R 6, and-NR 12SO 2R 7, wherein said-(C 2-C 6) thiazolinyl and-(C 2-C 6) alkynyl R 2Part can be randomly by 1 to 3 R 12Group replaces; R 1Be-(C 1-C 6) alkyl; And n is 2.
The present invention further provides the compound of structural formula 1, wherein R 1Be selected from hydrogen, hydroxyl and-(C 1-C 6) alkyl, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-CN ,-(C 1-C 6) alkyl ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6With-CONR 5R 8R 2Be-(C 1-C 6) alkyl; And n is 2.
The present invention further provides the compound of structural formula 1, wherein R 1Be-(C 1-C 6) alkyl, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-CN ,-(C 1-C 6) alkyl ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6With-CONR 5R 8R 2Be-(C 1-C 6) alkyl; And n is 2.
The present invention also provides the compound of structural formula 1, wherein R 1Be selected from-(C 3-C 7) cycloalkyl and-(C 2-C 9) heterocyclic radical, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-CN ,-(C 1-C 6) alkyl ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6With-CONR 5R 8R 2Be-(C 1-C 6) alkyl; N is 2.
The present invention also comprises the compound of structural formula 1, wherein R 1Be selected from-O (C 1-C 6) alkyl ,-O (C 3-C 7) cycloalkyl and-O (C 2-C 9) heterocyclic radical, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-CN ,-(C 1-C 6) alkyl ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6With-CONR 5R 8R 2Be-(C 1-C 6) alkyl; And n is 2.
An embodiment of the invention are the compound of structural formula 1, wherein R 1Be-NR 5R 6, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-CN ,-(C 1-C 6) alkyl ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6With-CONR 5R 8R 2Be-(C 1-C 6) alkyl; And n is 2.
The further embodiment of the present invention is the compound of structural formula 1, wherein R 1Be selected from-SR 7,-SOR 7,-SO 2R 7, and-SO 2NR 5R 6, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-CN ,-(C 1-C 6) alkyl ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6With-CONR 5R 8R 2Be-(C 1-C 6) alkyl; And n is 2.
The present invention also provides the compound of structural formula 1, wherein R 1Be-CO 2R 12,-CONR 5R 6,-NHCOR 12,-NR 12CONR 5R 6, or-NR 12SO 2R 7, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-CN ,-(C 1-C 6) alkyl ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6With-CONR 5R 8R 2Be-(C 1-C 6) alkyl; And n is 2.
The present invention also provides the compound of structural formula 1, wherein R 2Be hydrogen or-(C 1-C 6) alkyl, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-NO 2,-CN ,-(C 1-C 6) alkyl ,-(C 2-C 6) thiazolinyl ,-(C 2-C 6) alkynyl ,-C=N-OH ,-C=N-O ((C 1-C 6) alkyl) ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6,-CONR 5R 8,-SR 7,-SOR 7,-SO 2R 7,-SO 2NR 5R 6,-NHCOR 12,-NR 12CONR 5R 6, and-NR 12SO 2R 7, wherein said-(C 2-C 6) thiazolinyl and-(C 2-C 6) alkynyl R 2Part can be randomly by 1 to 3 R 12Group replaces; R 1Be-(C 1-C 6) alkyl; And n is 2.
The present invention further provides the compound of structural formula 1, wherein R 2Be-(C 3-C 7) cycloalkyl or-(C 2-C 9) heterocyclic radical, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-NO 2,-CN ,-(C 1-C 6) alkyl ,-(C 2-C 6) thiazolinyl ,-(C 2-C 6) alkynyl ,-C=N-OH ,-C=N-O ((C 1-C 6) alkyl) ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6,-CONR 5R 8,-SR 7,-SOR 7,-SO 2R 7,-SO 2NR 5R 6,-NHCOR 12,-NR 12CONR 5R 6, and-NR 12SO 2R 7, wherein said-(C 2-C 6) thiazolinyl and-(C 2-C 6) alkynyl R 2Part can be randomly by 1 to 3 R 12Group replaces; R 1Be-(C 1-C 6) alkyl; And n is 2.
Another embodiment of the invention is the compound of structural formula 1, wherein R 2Be-CO 2R 12With-CONR 5R 6, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-NO 2,-CN ,-(C 1-C 6) alkyl ,-(C 2-C 6) thiazolinyl ,-(C 2-C 6) alkynyl ,-C=N-OH ,-C=N-O ((C 1-C 6) alkyl) ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6,-CONR 5R 8,-SR 7,-SOR 7,-SO 2R 7,-SO 2NR 5R 6,-NHCOR 12,-NR 12CONR 5R 6, and-NR 12SO 2R 7, wherein said-(C 2-C 6) thiazolinyl and-(C 2-C 6) alkynyl R 2Part can be randomly by 1 to 3 R 12Group replaces; R 1Be-(C 1-C 6) alkyl; And n is 2.
The present invention also provides the compound of structural formula 1, wherein R 1Be selected from hydrogen, hydroxyl and-(C 1-C 6) alkyl, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-CN ,-(C 1-C 6) alkyl ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6With-CONR 5R 8R 2Be hydrogen or-(C 1-C 6) alkyl, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-NO 2,-CN ,-(C 1-C 6) alkyl ,-(C 2-C 6) thiazolinyl ,-(C 2-C 6) alkynyl ,-C=N-OH ,-C=N-O ((C 1-C 6) alkyl) ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6,-CONR 5R 8,-SR 7,-SOR 7,-SO 2R 7,-SO 2NR 5R 6,-NHCOR 12,-NR 12CONR 5R 6, and-NR 12SO 2R 7, wherein said-(C 2-C 6) thiazolinyl and-(C 2-C 6) alkynyl R 2Part can be randomly by 1 to 3 R 12Group replaces; And n is 2.
The present invention further provides the compound of structural formula 1, wherein R 1Be selected from hydrogen, hydroxyl and-(C 1-C 6) alkyl, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-CN ,-(C 1-C 6) alkyl ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6With-CONR 5R 8R 2Be hydrogen; And n is 2.
The present invention further provides the compound of structural formula 1, wherein R 1Be-(C 1-C 6) alkyl, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-CN ,-(C 1-C 6) alkyl ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6With-CONR 5R 8R 2Be hydrogen; And n is 2.
The present invention also provides the compound of structural formula 1, wherein R 1Be selected from-(C 3-C 7) cycloalkyl and-(C 2-C 9) heterocyclic radical, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-CN ,-(C 1-C 6) alkyl ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6With-CONR 5R 8R 2Be hydrogen; And n is 2.
The present invention also comprises the compound of structural formula 1, wherein R 1Be selected from-O (C 1-C 6) alkyl ,-O (C 3-C 7) cycloalkyl and-O (C 2-C 9) heterocyclic radical, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-CN ,-(C 1-C 6) alkyl ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6With-CONR 5R 8R 2Be hydrogen; And n is 2.
An embodiment of the invention are the compound of structural formula 1, wherein R 1Be-NR 5R 6, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-CN ,-(C 1-C 6) alkyl ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6With-CONR 5R 8R 2Be hydrogen; And n is 2.
The further embodiment of the present invention is the compound of structural formula 1, wherein R 1Be selected from-SR 7,-SOR 7,-SO 2R 7, and-SO 2NR 5R 6, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-CN ,-(C 1-C 6) alkyl ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6With-CONR 5R 8R 2Be hydrogen; And n is 2.
The present invention also provides the compound of structural formula 1, wherein R 1Be-CO 2R 12,-CONR 5R 6,-NHCOR 12,-NR 12CONR 5R 6, or-NR 12SO 2R 7, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-CN ,-(C 1-C 6) alkyl ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6With-CONR 5R 8R 2Be hydrogen; And n is 2.
The present invention also provides the compound of structural formula 1, wherein R 2Be hydrogen or-(C 1-C 6) alkyl, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-NO 2,-CN ,-(C 1-C 6) alkyl ,-(C 2-C 6) thiazolinyl ,-(C 2-C 6) alkynyl ,-C=N-OH ,-C=N-O ((C 1-C 6) alkyl) ,-NR 5R 6,-OR 12,-(C 3- 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6,-CONR 5R 8,-SR 7,-SOR 7,-SO 2R 7,-SO 2NR 5R 6,-NHCOR 12,-NR 12CONR 5R 6, and-NR 12SO 2R 7, wherein said-(C 2-C 6) thiazolinyl and-(C 2-C 6) alkynyl R 2Part can be randomly by 1 to 3 R 12Group replaces; R 1Be hydrogen; And n is 2.
The present invention further provides the compound of structural formula 1, wherein R 2Be-(C 3-C 7) cycloalkyl or-(C 2-C 9) heterocyclic radical, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-NO 2,-CN ,-(C 1-C 6) alkyl ,-(C 2-C 6) thiazolinyl ,-(C 2-C 6) alkynyl ,-C=N-OH ,-C=N-O ((C 1-C 6) alkyl) ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6,-CONR 5R 8,-SR 7,-SOR 7,-SO 2R 7,-SO 2NR 5R 6,-NHCOR 12,-NR 12CONR 5R 6, and-NR 12SO 2R 7, wherein said-(C 2-C 6) thiazolinyl and-(C 2-C 6) alkynyl R 2Part can be randomly by 1 to 3 R 12Group replaces; R 1Be hydrogen; And n is 2.
Another embodiment of the invention is the compound of structural formula 1, wherein R 2Be-CO 2R 5With-CONR 5R 6, it randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-NO 2,-CN ,-(C 1-C 6) alkyl ,-(C 2-C 6) thiazolinyl ,-(C 2-C 6) alkynyl ,-C=N-OH ,-C=N-O ((C 1-C 6) alkyl) ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6,-CONR 5R 8,-SR 7,-SOR 7,-SO 2R 7,-SO 2NR 5R 6,-NHCOR 12,-NR 12CONR 5R 6, and-NR 12SO 2R 7, wherein said-(C 2-C 6) thiazolinyl and-(C 2-C 6) alkynyl R 2Part can be randomly by 1 to 3 R 12Group replaces; R 1Be hydrogen; And n is 2.
The present invention also provides the compound of structural formula 1, wherein R 1And R 2Form-(C with (a plurality of) atom that they connected 3-C 10) cycloalkyl, it randomly is selected from 1 to 3 of following groups part and is replaced: hydrogen, halogen, hydroxyl ,-NO 2,-CN ,-(C 1-C 6) alkyl ,-(C 2-C 6) thiazolinyl ,-(C 2-C 6) alkynyl ,-C=N-OH ,-C=N-O ((C 1-C 6) alkyl) ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6,-CONR 5R 8,-SR 7,-SOR 7,-SO 2R 7,-SO 2NR 5R 6,-NHCOR 12,-NR 12CONR 5R 6, and-NR 12SO 2R 7, the described-(C of wherein said cyclic group 2-C 6) thiazolinyl and-(C 2-C 6) the alkynyl part can be randomly by 1 to 3 R 12Group replaces.
The present invention further provides the compound of structural formula 1, wherein R 1And R 2Form-(C with (a plurality of) atom that they connected 2-C 9) heterocyclic radical, it randomly is selected from 1 to 3 of following groups part and is replaced: hydrogen, halogen, hydroxyl ,-NO 2,-CN ,-(C 1-C 6) alkyl ,-(C 2-C 6) thiazolinyl ,-(C 2-C 6) alkynyl ,-C=N-OH ,-C=N-O ((C 1-C 6) alkyl) ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6,-CONR 5R 8,-SR 7,-SOR 7,-SO 2R 7,-SO 2NR 5R 6,-NHCOR 12,-NR 12CONR 5R 6, and-NR 12SO 2R 7, the described-(C of wherein said cyclic group 2-C 6) thiazolinyl and-(C 2-C 6) the alkynyl part can be randomly by 1 to 3 R 12Group replaces.
The present invention also provides the compound of structural formula 1, wherein R 1And R 2Form-(C with (a plurality of) atom that they connected 3-C 10) cycloalkyl, it randomly is selected from 1 to 3 of following groups part and is replaced: hydrogen, halogen, hydroxyl ,-NO 2,-CN ,-(C 1-C 6) alkyl ,-(C 2-C 6) thiazolinyl ,-(C 2-C 6) alkynyl ,-C=N-OH ,-C=N-O ((C 1-C 6) alkyl) ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6,-CONR 5R 8,-SR 7,-SOR 7,-SO 2R 7,-SO 2NR 5R 6,-NHCOR 12,-NR 12CONR 5R4 6, and-NR 12SO 2R 7, the described-(C of wherein said cyclic group 2-C 6) thiazolinyl and-(C 2-C 6) the alkynyl part can be randomly by 1 to 3 R 12Group replaces; And n is 1.
The present invention further provides the compound of structural formula 1, wherein R 1And R 2Form-(C with (a plurality of) atom that they connected 2-C 9) heterocyclic radical, it randomly is selected from 1 to 3 of following groups part and is replaced: hydrogen, halogen, hydroxyl ,-NO 2,-CN ,-(C 1-C 6) alkyl ,-(C 2-C 6) thiazolinyl ,-(C 2-C 6) alkynyl ,-C=N-OH ,-C=N-O ((C 1-C 6) alkyl) ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6,-CONR 5R 8,-SR 7,-SOR 7,-SO 2R 7,-SO 2NR 5R 6,-NHCOR 12,-NR 12CONR 5R 6, and-NR 12SO 2R 7, the described-(C of wherein said cyclic group 2-C 6) thiazolinyl and-(C 2-C 6) the alkynyl part can be randomly by 1 to 3 R 12Group replaces; And n is 1.
One preferred embodiment in, R 4Be the substituting group that is selected from following groups: hydrogen ,-(C 1-C 6) alkyl ,-(C 3-C 7) cycloalkyl and-(C 2-C 9) heterocyclic radical; Wherein said-(C 1-C 6) alkyl ,-(C 3-C 7) cycloalkyl and-(C 2-C 9) heterocyclic radical R 4Substituting group randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-(C 1-C 6) alkyl ,-CN ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12With-CONR 5R 8Its condition is above-mentioned R 4Substituent heteroatoms can be not be incorporated into another heteroatomic sp 3The carbon atom combination; Wherein said-CONR 5R 8The R of group 5And R 8Can form with the atom that they connected-(C 3-C 10) cycloalkyl or-(C 2-C 9) heterocyclic radical.
In further preferred embodiment, R 4Be hydrogen.
The present invention further provides the compound of structural formula 1, wherein R 5And R 6Be separately be independently selected from hydrogen and-(C 1-C 6) substituting group of alkyl, its randomly as indicated above being substituted.
The specific embodiment of the present invention is to be selected from following compound:
(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for N-(1-methyl isophthalic acid-phenyl-ethyl)-3-{[2-]-methyl }-benzsulfamide;
(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 3-{[2-]-methyl }-benzsulfamide;
5-{4-[3-(three fluoro-methylsulfonyls)-benzylamino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
5-{4-[(piperidines-3-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
5-{4-[(1-methylsulfonyl-piperidines-3-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 3-{[2-]-methyl }-phenyl)-Toluidrin;
3-oxo-3-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 3-{[2-]-methyl }-piperidines-1-yl)-propionitrile;
5-{4-[3-(1,1-dioxo-1N 6-isothiazolidine-2-yl)-propyl group amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
5-[4-(2-methyl-butyl amino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one;
5-{4-[(1-methylsulfonyl-piperidines-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for N-{2-[2-]-ethyl }-Toluidrin;
(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for N-{4-[2-]-butyl }-Toluidrin;
5-{4-[(1-methylsulfonyl-piperidin-4-yl methyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for N-methyl-N-{2-[2-]-ethyl }-Toluidrin;
(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 3-{[2-]-methyl }-the phenyl methanesulfonamide acid esters;
(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for N-{3-[2-]-propyl group }-Toluidrin;
5-{4-[(4-methylsulfonyl-morpholine-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 4-fluoro-3-{[2-]-methyl }-phenyl)-Toluidrin;
5-{4-[(5-oxo-morpholine-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 4-methoxyl group-3-{[2-]-methyl }-phenyl)-Toluidrin;
N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 4-methyl-3-{[2-]-methyl }-phenyl)-Toluidrin;
5-[4-(3-methylsulfonyl methyl-benzylamino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one;
5-{4-[(4-trifluoroacetyl group-morpholine-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
5-{4-[(1-methylsulfonyl-azetidin-3-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 4-methyl-3-{[2-]-methyl }-phenyl }-Toluidrin;
5-{4-[(1-methylsulfonyl-tetramethyleneimine-3-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for N-methyl-N-{3-[2-]-propyl group }-Toluidrin;
5-{4-[2-(1-methylsulfonyl-piperidines-2-yl)-ethylamino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
5-{4-[(4-methylsulfonyl-pyridine-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
2, (2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 2-dimethyl-3-[2-]-propyl group }-t-butyl carbamate;
5-[4-(3-isopropoxy-propyl group amino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one;
5-{4-[(1-methyl-piperidines-3-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
5-{4-[(tetrahydrochysene-pyrans-4-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
5-[4-(2-ethyl-butyl amino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one;
5-{4-[(tetrahydrochysene-furans-2R-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
5-{4-[(tetrahydrochysene-furans-2S-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
5-{4-[(5-methyl-furans-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
5-{4-[(1-methylsulfonyl-tetramethyleneimine-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
5-{4-[(diamantane-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
5-{4-[(diamantane-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
5-[4-(2-methoxyl group-2-methyl-propyl group amino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one;
5-{44 (interior-two the ring [2.2.1] heptan-5-alkene-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino-1, the 3-dihydro-indol-2-one;
((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 3-{[2-]-methyl }-benzyl)-dimethyl phosphonate;
5-[4-(3-methyl-butyl amino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one;
5-{4-[(2-hydroxyl-cyclohexyl methyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 4-methoxyl group-3-{[2-]-methyl }-phenyl)-N-methyl-Toluidrin;
5-{4-[(4-ethylsulfonyl-morpholine-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
5-(4-{[4-(third-2-alkylsulfonyl)-morpholine-2-ylmethyl]-amino }-5-trifluoromethyl-pyrimidine-2--amino)-1, the 3-dihydro-indol-2-one;
5-{4-[(4-ethanoyl-morpholine-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
5-{4-[(4-propionyl-morpholine-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
5-(4-{[4-(2,2-dimethyl-propionyl)-morpholine-2-ylmethyl]-amino }-5-trifluoromethyl-pyrimidine-2--amino)-1, the 3-dihydro-indol-2-one;
(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 2-{[2-]-methyl }-morpholine-4-carboxylate methyl ester;
5-{4-[(4-methoxyl group ethanoyl-morpholine-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
5-[4-(3-ethylsulfonyl-benzylamino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one;
5-{4-[(4-methylsulfonyl-morpholine-2 R-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
5-{4-[(4-methylsulfonyl-morpholine-2 S-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
5-{4-[(pyrimidine-2-base methyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
5-{4-[(pyrazine-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 4-fluoro-3-{[2-]-methyl }-phenyl)-N-methyl-Toluidrin;
5-{4-[(1-methylsulfonyl-piperidines-3-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
5-{4-[(4-isobutyryl-morpholine-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
5-[4-(3,3-dimethyl-2-oxo-butyl amino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one;
5-[4-(1,2-dimethyl-propyl group amino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one;
5-[4-(2-methoxyl group-1-methyl-ethylamino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one;
5-{4-[(2-(1,1-dioxo-1D 6-isothiazolidine-2-yl)-ethylamino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
5-[4-(3-methylamino-propyl group amino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one;
5-{4-[(pyridin-3-yl methyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
5-{4-[(6-methylsulfonyl-pyridine-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
5-{4-[3-(1,1-dioxo-1,1,6-isothiazolidine-2-yl)-benzylamino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
5-[4-(1R-phenyl-ethylamino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one;
5-(4-sec.-propyl amino-5-trifluoromethyl-pyrimidine-2--amino)-1, the 3-dihydro-indol-2-one;
5-(4R-sec-butyl amino-5-trifluoromethyl-pyrimidine-2--amino)-1, the 3-dihydro-indol-2-one;
5-(4S-sec-butyl amino-5-trifluoromethyl-pyrimidine-2--amino)-1, the 3-dihydro-indol-2-one;
5-[4-(2-methylamino-ethylamino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one;
5-[4-(1S-phenyl-ethylamino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one;
5-{4-[(2-methylsulfonyl methyl-thiazole-4-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
5-(4-propyl group amino-5-trifluoromethyl-pyrimidine-2--amino)-1, the 3-dihydro-indol-2-one;
5-[4-(2-hydroxyl-1-methyl-ethylamino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one;
5-[4-(1-methylol-propyl group amino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one;
5-{4-[(5-methylsulfonyl-pyridin-3-yl methyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
5-{4-[(pyridin-4-yl methyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
5-[4-(1,3-dimethyl-butyl amino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one;
(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for N-sec.-propyl-N-{3-[2-]-propyl group }-Toluidrin;
5-[4-(1S-methylol-2-methyl-propyl group amino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one;
(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for N-cyclohexyl-N-{3-[2-]-propyl group }-Toluidrin;
5-[4-(1,2,3,4-tetrahydrochysene-naphthalene-1-base is amino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one;
5-{4-[(1-methylsulfonyl-tetramethyleneimine-2S-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
5-{4-[(3-methyl-thiophene-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
5-{4-[(1-methylsulfonyl-tetramethyleneimine-3R-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
5-[4-(2-hydroxyl-1S-phenyl-ethylamino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one;
5-[4-(2-hydroxyl-1S-methyl-ethylamino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one;
5-[4-(1R-methylol-propyl group amino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one;
5-[4-(1-pyrimidine-4-base-ethylamino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one;
5-[4-(1,1-dioxo-tetrahydrochysene-1-thiene-3-yl-amino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one;
5-{4-[(1H-imidazoles-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
5-[4-(2-piperidines-2-base-ethylamino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one;
5-[4-(isobutyl--methyl-amino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 3-{[2-]-methyl }-phenyl)-Toluidrin;
N-ethyl-N-((2-oxo-2,3-dihydro-1 H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 3-{[2-]-methyl }-phenyl)-Toluidrin;
5-[4-(2-methylsulfonyl-benzylamino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one;
N-sec.-propyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 3-{[2-]-methyl }-phenyl)-Toluidrin;
5-{4-[(3,4,5,6-tetrahydrochysene-2H-[1,2 '] dipyridyl-3-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
5-{4-[(1-pyrimidine-2-base-piperidines-3-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
5-{4-[(2R-(1-methylsulfonyl-piperidines-2-yl)-ethylamino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
5-{4-[(2S-(1-methylsulfonyl-piperidines-2-yl)-ethylamino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
5-{4-[(3-methyl sulfane base-propyl group amino]-5-trifluoromethyl-pyrimidine-2--amino }-1,3-dihydro-indol-2-one (the sulfane base is sulfanyl);
5-{4-[(1S-methylol-3-methyl sulfane base-propyl group amino)-and 5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
5-[4-(2-hydroxyl-1R-methyl-ethylamino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one;
5-[4-(1R-methylol-2-methyl-propyl group amino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one;
(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for N-ethyl-N-{3-[2-]-propyl group }-Toluidrin;
5-{4-[(1-methylsulfonyl-tetramethyleneimine-3R-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
5-[4-(1S-methylol-propyl group amino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one;
5-[4-(3,5-dinitrobenzene-benzylamino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one;
N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 2-{[2-]-methyl }-phenyl)-Toluidrin;
(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for N-sec.-propyl-N-{2-[2-]-ethyl }-Toluidrin;
5-[4-(2-hydroxyl-1-phenyl-ethylamino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one;
5-[4-(1R-methylol-3-methyl-butyl amino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one;
5-[4-(1S-methylol-3-methyl-butyl amino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one;
5-{4-[(1-methylsulfonyl-piperidines-2S-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
5-{4-[(1-methylsulfonyl-tetramethyleneimine-2R-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
5-[4-(methyl-pyridine-2-ylmethyl-amino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one;
5-{4-[(3-methylsulfonyl-benzyl)-methyl-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
N-methyl-N-((2-oxo-2,3-dihydro-1 H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 2-{[2-]-methyl }-phenyl)-Toluidrin;
5-[4-(methyl-pyridin-3-yl methyl-amino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one;
5-{4-[(1-methylsulfonyl-piperidines-3-ylmethyl)-methyl-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
5-[4-(methyl-pyridin-4-yl methyl-amino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one;
5-(4-cyclopentyl amino-5-trifluoromethyl-pyrimidine-2--amino)-1, the 3-dihydro-indol-2-one;
5-[4-(2,6-dimethoxy-benzylamino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one;
5-{4-[(1,5-dimethyl-1H-pyrazole-3-yl methyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one; H and
5-[4-(2-imidazoles-1-base-ethylamino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one;
Preferred implementations more of the present invention are to be selected from following compound:
5-{4-[(1-methylsulfonyl-piperidines-3-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for N-methyl-N-{2-[2-]-ethyl }-Toluidrin;
(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for N-methyl-N-{3-[2-]-propyl group }-Toluidrin;
5-{4-[2-(1-methylsulfonyl-piperidines-2-yl)-ethylamino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
5-{4-[(two ring [2.2.1] heptan-5-alkene-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
5-[4-(3-methyl-butyl amino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one;
5-{4-[(1-methylsulfonyl-piperidines-3-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for N-sec.-propyl-N-{3-[2-]-propyl group }-Toluidrin;
(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for N-cyclohexyl-N-{3-[2-]-propyl group }-Toluidrin;
5-{4-[2-(1-methylsulfonyl-piperidines-2-yl)-ethylamino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for N-sec.-propyl-N-{2-[2-]-ethyl }-Toluidrin;
5-{4-[(1-methylsulfonyl-tetramethyleneimine-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
5-(4-cyclopentyl amino-5-trifluoromethyl-pyrimidine-2--amino)-1, the 3-dihydro-indol-2-one;
Ethyl sulfonic acid-methyl-(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 3-[2-]-propyl group }-acid amides;
2,2, (2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 2-three fluoro-N-methyl-N-{3-[2-]-propyl group }-ethanamide;
(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for N-methyl-N-{2-[2-]-ethyl }-Toluidrin;
5-(4-cyclobutyl amino-5-trifluoromethyl-pyrimidine-2--amino)-1, the 3-dihydro-indol-2-one;
5-{4-[(2-hydroxyl-2-(1-methylsulfonyl-piperidines-2-yl)-ethylamino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
3-oxo-3-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 3-{[2-]-methyl }-piperidines-1-yl }-propionitrile;
5-{4-[(1-methylsulfonyl-piperidin-4-yl methyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
5-{4-[(4-methylsulfonyl-morpholine-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
5-{4-[(5-oxo-morpholine-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
5-{4-[(1-methylsulfonyl-tetramethyleneimine-3-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
5-[4-(3-sec.-propyl-propyl group amino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one;
5-{4-[(diamantane-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
N-{2, (2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 2-dimethyl-3-[2-]-propyl group }-Toluidrin;
5-{4-[(1-hydroxyl-cyclopentyl-methyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
5-{4-[(4-hydroxyl-tetrahydrochysene-pyrans-4-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
5-{4-[(2-hydroxyl-cyclohexyl methyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
5-[4-(3-methylsulfonyl-propyl group amino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one;
5-{4-[(1-pyrimidine-2-base-piperidines-3-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 3-[2-]-ethyl propionate;
5-{4-[(1-ethyl-5-oxo-tetramethyleneimine-3-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
2, (2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for N-dimethyl-N-{2-[2-]-ethyl }-Ding sulfanilamide (SN);
(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 2-methoxyl group-N-methyl-N-{3-[2-]-propyl group }-ethanamide;
5-{4-[(2-(1-ethanoyl-piperidines-2-yl)-ethylamino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
5-{4-[(1-methylsulfonyl-piperidines-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
5-{4-[(1-methylsulfonyl-tetramethyleneimine-3-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
5-{4-[(1-pyrimidine-2-base-piperidines-3-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 3-{[2-]-methyl }-benzsulfamide;
N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 3-{[2-]-methyl }-phenyl)-Toluidrin;
N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 4-methoxyl group-3-{[2-]-methyl }-phenyl)-Toluidrin;
5-[4-(3-methylsulfonyl methyl-benzylamino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 4-methyl-3-{[2-]-methyl }-phenyl)-Toluidrin;
5-{4-[(4-methylsulfonyl-pyridine-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
5-{4-[(5-methyl-furans-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 3-{[2-]-methyl }-benzyl)-dimethyl phosphonate;
5-{4-[(pyridine-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
5-[5-trifluoromethyl-4-(2-trifluoromethyl-benzylamino)-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one;
5-[4-(3-ethylsulfonyl-benzylamino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one;
5-{4-[(pyrimidine-2-base methyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
5-{4-[(pyrazine-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 4-fluoro-3-{[2-]-methyl }-phenyl)-N-methyl-Toluidrin;
5-{4-[(pyridin-3-yl methyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
5-{4-[(6-methylsulfonyl-pyridine-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
5-{4-[(2-methylsulfonyl methyl-thiazole-4-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
5-{4-[(5-methylsulfonyl-pyridin-3-yl methyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
5-{4-[(3-methyl-thiophene-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
5-{4-[(1H-imidazoles-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 3-{[2-]-methyl }-phenyl)-Toluidrin;
5-[4-(2-methylsulfonyl-benzylamino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one;
N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 2-{[2-]-methyl }-phenyl)-Toluidrin;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 2-{[2-]-methyl }-phenyl)-Toluidrin;
5-{4-[(1,5-dimethyl-1H-pyrazole-3-yl methyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
5-[4-(2-imidazoles-1-base-ethylamino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one;
N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 5-methyl-2-{[2-]-methyl }-phenyl)-Toluidrin;
5-{4-[(3-methyl-pyridine-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
5-[4-(3-methylsulfonyl-benzylamino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one;
5-{4-[(isochroman-1-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
5-{4-[2-(pyridin-3-yl oxygen base)-propyl group amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
5-{4-[2-(6-methyl-pyridine-2-yl)-ethylamino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
5-{4-[(2,3-dihydro-benzo [1,4] diox-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
5-{4-[2-(4-methyl isophthalic acid H-imidazoles-2-yl)-ethylamino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
5-{4-[2-(the 1H-benzimidazolyl-2 radicals-yl)-ethylamino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
5-{4-[(5-phenyl-4H-[1,1,4] triazole-3-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
5-{4-[(3-methyl-imidazo [2,1-b] thiazole-6-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 2-methyl-6-{[2-]-methyl }-phenyl)-Toluidrin;
N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 2-methyl-6-{[2-]-methyl }-phenyl)-Toluidrin;
N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 3-methylsulfonyl amino-5-{[2-]-methyl }-phenyl)-Toluidrin; With
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 3-{[2-]-methyl }-pyridine-2-yl)-Toluidrin.
Preferred implementation of the present invention is selected from:
5-[4-(3-methylsulfonyl-benzylamino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one;
Ethyl sulfonic acid-methyl-(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 3-[2-]-propyl group }-acid amides;
5-{4-[(isochroman-1-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
5-{4-[2-(pyridin-3-yl oxygen base)-propyl group amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 3-[[2-]-methyl }-benzsulfamide;
5-{4-[(1-methylsulfonyl-piperidines-3-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 3-{[2-]-methyl }-phenyl)-Toluidrin;
(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for N-methyl-N-{2-[2-]-ethyl }-Toluidrin;
5-{4-[(4-methylsulfonyl-morpholine-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
5-[4-(3-methylsulfonyl methyl-benzylamino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one;
5-{4-[(1-methylsulfonyl-tetramethyleneimine-3-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for N-methyl-N-{3-[2-]-propyl group }-Toluidrin;
5-{4-[(2-(1-methylsulfonyl-piperidines-2-yl)-ethylamino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
5-{4-[(4-methylsulfonyl-pyridine-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
5-[4-(3-isopropoxy-propyl group amino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one;
5-{4-[(5-methyl-furans-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
5-{4-[(two ring [2.2.1] heptan-5-alkene-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 4-fluoro-3-{[2-]-methyl }-phenyl)-N-methyl-Toluidrin;
5-{4-[(1-methylsulfonyl-piperidines-3-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
5-{4-[(6-methylsulfonyl-pyridine-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
5-{4-[(5-methylsulfonyl-pyridin-3-yl methyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
5-[4-(2-methylsulfonyl-benzylamino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one;
5-{4-[(1-pyrimidine-2-base-piperidines-3-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
5-{4-[(2-(1-methylsulfonyl-piperidines-2-yl)-ethylamino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
5-{4-[(2-(1-methylsulfonyl-piperidines-2-yl)-ethylamino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 2-{[2-]-methyl }-phenyl)-Toluidrin;
5-{4-[(1-methylsulfonyl-tetramethyleneimine-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 2-{[2-]-methyl }-phenyl)-Toluidrin;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 2-methyl-6-[[2-]-methyl }-phenyl)-Toluidrin;
5-[4-(2-hydroxyl-indane-1-base is amino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one;
5-{4-[(1-hydroxyl-cyclopentyl-methyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
5-{4-[2-hydroxyl-2-(1-methylsulfonyl-piperidines-2-yl)-ethylamino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one; With
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 3-{[2-]-methyl }-pyridine-2-yl)-Toluidrin.
Embodiments more of the present invention comprise following compounds:
N-methyl-N-{3-[({ methyl-[2-(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-yl]-amino })-methyl]-phenyl }-Toluidrin;
N-methyl-N-{4-methyl-3-[({ methyl-2-(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-yl]-amino })-methyl]-phenyl }-Toluidrin;
N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 5-methyl-2-{[2-]-methyl }-phenyl)-Toluidrin;
N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 3-methyl-2-{[2-]-methyl }-phenyl)-Toluidrin;
N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 4-methyl-2-{[2-]-methyl }-phenyl)-Toluidrin;
N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 2-methyl-6-{[2-]-methyl }-phenyl)-Toluidrin;
5-[4-(3-methylsulfonyl-propyl group amino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 5-methyl-2-{[2-]-methyl }-phenyl)-Toluidrin;
N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 3-methylsulfonyl amino-5-{[2-]-methyl }-phenyl)-Toluidrin;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 4-methyl-2-{[2-]-methyl }-phenyl)-Toluidrin;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 2-methyl-6-{[2-]-methyl }-phenyl)-Toluidrin;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 3-methyl-2-{[2-]-methyl }-phenyl)-Toluidrin;
5-{4-[((1S, 2R)-2-hydroxyl-cyclohexyl methyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
5-[4-((1R, 2S)-2-hydroxyl-indane-1-base is amino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one;
5-[4-((S)-1-methylol-2-phenyl-ethylamino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one;
N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 3-(methylsulfonyl-methyl-amino)-5-{[2-]-methyl }-phenyl)-N-methyl-Toluidrin;
5-{4-[(1-hydroxyl-cyclopentyl-methyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 3-[[2-]-methyl }-pyridine-2-yl)-Toluidrin;
N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 3-fluoro-2-[[2-]-methyl }-phenyl)-N-methyl-Toluidrin;
5-{4-[2-((S)-1-methylsulfonyl-tetramethyleneimine-2-yl)-ethylamino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
5-{4-[(1-hydroxyl-cyclobutylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
5-{4-[2-((R)-1-methylsulfonyl-tetramethyleneimine-2-yl)-ethylamino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 2-fluoro-6-{[2-]-methyl }-phenyl)-N-methyl-Toluidrin;
N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 4-fluoro-2-{[2-]-methyl }-phenyl)-N-methyl-Toluidrin;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 4-{[2-]-methyl }-pyridine-2-yl)-Toluidrin;
N-{2, (2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 2-dimethyl-3-[2-]-propyl group }-N-methyl-Toluidrin;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 6-{[2-]-methyl }-pyridine-2-yl)-Toluidrin;
N-(2, (2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 4-two fluoro-6-{[2-]-methyl }-phenyl)-N-methyl-Toluidrin;
5-[4-((R)-1-methylsulfonyl-piperidines-3-base is amino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 6-methyl-3-{[2-]-methyl }-pyridine-2-yl)-Toluidrin;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 5-{[2-]-methyl }-pyridin-3-yl)-Toluidrin;
5-[4-(1-methylsulfonyl-piperidin-4-yl amino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one;
5-{4-[methyl-((R)-1-phenyl-ethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
5-(4-benzylamino-5-trifluoromethyl-pyrimidine-2--amino)-1, the 3-dihydro-indol-2-one;
N-(4, (2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 6-dimethyl-3-{[2-]-methyl }-pyridine-2-yl)-N-methyl-Toluidrin;
5-(4-tertiary butyl amino-5-trifluoromethyl-pyrimidine-2--amino)-1, the 3-dihydro-indol-2-one;
5-[4-((1R, 5S, 6S)-3-methylsulfonyl-3-aza-bicyclo [3.1.0] oneself-6-base is amino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one;
(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for N-methyl-N-{3-methyl-3-[2-]-butyl }-Toluidrin;
N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 6-methyl-3-{[2-]-methyl }-pyridine-2-yl)-Toluidrin;
5-{4-[(2-methylsulfonyl-pyridin-4-yl methyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 2-[2-]-the ethyl sulfonic acid acid amides;
N-(3-{ methyl-[2-(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-yl]-amino }-propyl group)-Toluidrin;
N-(2-{ methyl-[2-(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-yl]-amino }-ethyl)-Toluidrin;
5-[4-(2-methylsulfonyl methyl-benzylamino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one;
(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 2-[2-]-the ethyl sulfonic acid diformamide;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 3-{[2-]-methyl }-pyrazine-2-yl)-Toluidrin;
Ethyl sulfonic acid-methyl-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 2-{[2-]-methyl }-phenyl)-acid amides;
Ethyl sulfonic acid-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 2-{[2-]-methyl }-phenyl)-acid amides;
N-ethyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 3-{[2-]-methyl }-pyridine-2-yl)-Toluidrin;
N-{1, (2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 1-dimethyl-3-[2-]-propyl group }-Toluidrin;
N-(5, (2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 6-dimethyl-3-{[2-]-methyl }-pyrazine-2-yl)-N-methyl-Toluidrin;
5-{4-[((R)-4-methylsulfonyl-morpholine-3-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
Propane-1-sulfonic acid-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 2-{[2-]-methyl }-phenyl)-acid amides;
5-{4-[2-((R)-4-methylsulfonyl-morpholine-3-yl)-ethylamino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
Ethyl sulfonic acid-methyl-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 3-{[2-]-methyl }-pyridine-2-yl)-acid amides;
(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for three fluoro-N-methyl-N-{3-[2-]-propyl group }-Toluidrin;
Ring propanesulfonic acid methyl-(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 3-[2-]-propyl group }-acid amides;
N-ethyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 2-{[2-]-methyl }-phenyl)-Toluidrin;
Ethyl sulfonic acid-methyl-(5-methyl-2-{[2-{2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino]-methyl }-phenyl)-acid amides;
Ethyl sulfonic acid-ethyl-(2-{[2-{2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino]-methyl }-phenyl)-acid amides;
Ethyl sulfonic acid-ethyl-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 5-methyl-2-{[2-]-methyl }-phenyl)-acid amides;
N-ethyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 5-methyl-2-{[2-]-methyl }-phenyl)-Toluidrin;
Ethyl sulfonic acid-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 5-methyl-2-{[2-]-methyl }-phenyl)-acid amides;
Ethyl sulfonic acid-(3-methyl-2-{[2-{2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino]-methyl }-phenyl)-acid amides;
Ethyl sulfonic acid-methyl-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 3-methyl-2-{[2-]-methyl }-phenyl)-acid amides;
(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 2-[2-]-the ethyl sulfonic acid methane amide;
Ethyl sulfonic acid-(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 3-[2-]-propyl group }-acid amides;
(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for C-methylsulfonyl-N-{3-[2-]-propyl group }-Toluidrin;
Ethyl sulfonic acid-(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 2-[2-]-ethyl }-acid amides;
(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for C-methylsulfonyl-N-{2-[2-]-ethyl }-Toluidrin;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 4-methyl-3-{[2-]-methyl }-pyridine-2-yl)-Toluidrin;
5-(4-{[1-(2,2,2-three fluoro-ethanoyl)-piperidines-3-ylmethyl]-amino }-5-trifluoromethyl-pyrimidine-2--amino)-1, the 3-dihydro-indol-2-one;
2,2,2-three fluoro-ethyl sulfonic acids-(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 3-[2-]-propyl group }-acid amides;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 4-{[2-]-methyl }-pyrimidine-2-base)-Toluidrin;
N-cyclopropyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 2-{[2-]-methyl }-phenyl)-Toluidrin;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 2-{[2-]-methyl }-pyrimidine-4-yl)-Toluidrin;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 6-{[2-]-methyl }-pyrazine-2-yl)-Toluidrin;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 2-{[2-]-methyl }-pyridin-3-yl)-Toluidrin;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 3-{[2-]-methyl }-pyridin-4-yl)-Toluidrin;
N-cyclopropyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 3-{[2-]-methyl }-pyridine-2-yl)-Toluidrin;
N-methyl-N-((2-oxo-2,3-dihydro-1 H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 6-methyl-3-{[2-]-methyl }-pyrazine-2-yl)-Toluidrin;
5-{4-[(2-methylsulfonyl methyl-pyridin-3-yl methyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 4-{[2-]-methyl }-pyridin-3-yl)-Toluidrin;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 3-methyl-6-{[2-]-methyl }-pyridine-2-yl)-Toluidrin;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 5-methyl-3-{[2-]-methyl }-pyridine-2-yl)-Toluidrin;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 4-methyl-6-{[2-]-methyl }-pyridine-2-yl)-Toluidrin;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 2-methyl-5-{[2-]-methyl }-pyridin-3-yl)-Toluidrin;
(5-methyl-6-{[2-{2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for N-methyl-N-]-methyl }-pyridine-2-yl)-Toluidrin;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 6-methyl-2-{[2-]-methyl }-pyridin-3-yl)-Toluidrin;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 5-methyl-2-{[2-]-methyl }-pyrimidine-4-yl)-Toluidrin;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 5-methyl-2-{[2-]-methyl }-pyridin-3-yl)-Toluidrin;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 4-methyl-2-{[2-]-methyl }-pyridin-3-yl)-Toluidrin;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 3-methyl-4-{[2-]-methyl }-pyridine-2-yl)-Toluidrin;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 5-methyl-4-{[2-]-methyl }-pyrimidine-2-base)-Toluidrin;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 6-methyl-5-{[2-]-methyl }-pyridin-3-yl)-Toluidrin;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 6-methyl-2-{[2-]-methyl }-pyrimidine-4-yl)-Toluidrin;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 5-methyl-4-{[2-]-methyl }-pyridine-2-yl)-Toluidrin;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 2-methyl-3-{[2-]-methyl }-pyridin-4-yl)-Toluidrin;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 6-methyl-4-{[2-]-methyl }-pyridine-2-yl)-Toluidrin;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 5-methyl-3-{[2-]-methyl }-pyridin-4-yl)-Toluidrin;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 5-methyl-6-{[2-]-methyl }-pyridin-4-yl)-Toluidrin;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 5-methyl-4-{[2-]-methyl }-pyridin-3-yl)-Toluidrin;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 6-{[2-]-methyl }-pyrimidine-4-yl)-Toluidrin;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 6-methyl-4-{[2-]-methyl }-pyrimidine-2-base)-Toluidrin;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 2-methyl-4-{[2-]-methyl }-pyridin-3-yl)-Toluidrin;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 5-{[2-]-methyl }-pyrimidine-4-yl)-Toluidrin;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 2-methyl-6-{[2-]-methyl }-pyrimidine-4-yl)-Toluidrin;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 6-methyl-4-{[2-]-methyl }-pyridin-3-yl)-Toluidrin;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 4-{[2-]-methyl }-pyrimidine-5-yl)-Toluidrin;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 2-methyl-5-{[2-]-methyl }-pyrimidine-4-yl)-Toluidrin;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 4-methyl-6-{[2-]-methyl }-pyrimidine-5-yl)-Toluidrin;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 5-methyl-6-{[2-]-methyl }-pyrazine-2-yl)-Toluidrin;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 5-methyl-3-{[2-]-methyl }-pyrazine-2-yl)-Toluidrin;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 2-methyl-6-{[2-]-methyl }-pyrimidine-5-yl)-Toluidrin;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 3-methyl-6-{[2-]-methyl }-pyrazine-2-yl)-Toluidrin; With
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 6-methyl-5-{[2-]-methyl }-pyrimidine-4-yl)-Toluidrin.
The invention still further relates to the method for treatment Mammals (comprising the mankind) abnormal cell growth, this method comprises that the compound of the structural formula 1 of definition as mentioned or the acceptable salt of its medicine, solvate or prodrug give described Mammals with the amount of effective treatment abnormal cell growth.In an embodiment of this method, abnormal cell growth is a cancer, and it includes but not limited to: lung cancer, osteocarcinoma, carcinoma of the pancreas, skin carcinoma, head or neck cancer, skin or intraocular melanoma, uterus carcinoma, ovarian cancer, the rectum cancer, the anal regions cancer, cancer of the stomach, colorectal carcinoma, breast cancer, uterus carcinoma, carcinoma of fallopian tube, carcinoma of endometrium, cervical cancer, carcinoma of vagina, carcinoma vulvae, He Jiejinshi (Hodgkin ' s) disease, esophagus cancer, carcinoma of small intestine, the endocrine system cancer, thyroid carcinoma, parathyroid carcinoma, renal adenocarcinoma, soft tissue sarcoma, urethral carcinoma, penile cancer, prostate cancer, chronic or acute leukemia, the lymphocyte lymphoma, bladder cancer, kidney or carcinoma of ureter, renal cell carcinoma, the renal plevis knurl, central nervous system (CNS) tumour, primary CNS lymphoma, tumor of spine, brain stem glioma, pituitary adenoma, or the combination of one or more above-mentioned cancers.In one embodiment, this method comprises structural formula 1Compound give Mammals with the amount of the described cancer noumenal tumour of effective treatment.In a preferred implementation, noumenal tumour is breast cancer, lung cancer, colorectal carcinoma, the cancer of the brain, prostate cancer, cancer of the stomach, carcinoma of the pancreas, ovarian cancer, skin carcinoma (melanoma), endocrine system cancer, uterus carcinoma, carcinoma of testis and bladder cancer.
In another embodiment of described method, described abnormal cell growth is optimum proliferative disease, and it includes but not limited to psoriasis, benign prostatauxe or restenosis.
The invention still further relates to the method for treatment Mammals abnormal cell growth, this method comprise with the compound of structural formula 1 or the acceptable salt of its medicine, solvate or prodrug with the amount of effective treatment abnormal cell growth be selected from mitotic inhibitor, alkylating agent, metabolic antagonist, embed microbiotic, growth factor receptor inhibitors, cell cycle inhibitor, enzyme, topoisomerase inhibitor, biological response modifier, antibody, the antitumor drug of cytotoxic agent, hormone antagonist and androgen antagonist is united and is given described Mammals.
The invention still further relates to the pharmaceutical composition that is used for the treatment of Mammals (comprising the mankind) abnormal cell growth, said composition comprises a certain amount of compound or the acceptable salt of its medicine, solvate or prodrug and the medicine acceptable carrier of the structural formula 1 of effective treatment abnormal cell growth of definition as mentioned.In an embodiment of described composition, described abnormal cell growth is a cancer, and it includes but not limited to: lung cancer, osteocarcinoma, carcinoma of the pancreas, skin carcinoma, head or neck cancer, skin or intraocular melanoma, uterus carcinoma, ovarian cancer, the rectum cancer, the anal regions cancer, cancer of the stomach, colorectal carcinoma, breast cancer, uterus carcinoma, carcinoma of fallopian tube, carcinoma of endometrium, cervical cancer, carcinoma of vagina, carcinoma vulvae, Hokdkin disease, esophagus cancer, carcinoma of small intestine, the endocrine system cancer, thyroid carcinoma, parathyroid carcinoma, renal adenocarcinoma, soft tissue sarcoma, urethral carcinoma, penile cancer, prostate cancer, chronic or acute leukemia, the lymphocyte lymphoma, bladder cancer, kidney or carcinoma of ureter, renal cell carcinoma, carcinoma of renal pelvis, central nervous system (CNS) tumour, primary CNS lymphoma, tumor of spine, brain stem glioma, pituitary adenoma, or the combination of one or more above-mentioned cancer.In another embodiment of described pharmaceutical composition, described abnormal cell growth is optimum proliferative disease, and it includes but not limited to psoriasis, benign prostatauxe or restenosis.
The invention still further relates to the method for treatment Mammals abnormal cell growth, this method comprises the compound of structural formula 1 or the acceptable salt of its medicine, solvate or prodrug united with the another kind of anti-tumor agents that is selected from mitotic inhibitor, alkylating agent, metabolic antagonist, embedding microbiotic, growth factor receptor inhibitors, cell cycle inhibitor, enzyme, topoisomerase inhibitor, biological response modifier, antibody, cytotoxic agent, hormone antagonist and androgen antagonist with the amount of effective treatment abnormal cell growth and gives described Mammals.The present invention also comprises the pharmaceutical composition that is used for the treatment of abnormal cell growth, wherein composition comprise a certain amount of effective smelting treat abnormal cell growth the structural formula 1 of definition as mentioned compound or the acceptable salt of its medicine, solvate or prodrug and be selected from the another kind of anti-tumor agents of mitotic inhibitor, alkylating agent, metabolic antagonist, embedding microbiotic, growth factor receptor inhibitors, cell cycle inhibitor, enzyme, topoisomerase inhibitor, biological response modifier, antibody, cytotoxic agent, hormone antagonist and androgen antagonist.
The invention still further relates to the treatment Mammals method with disease associated angiogenesis (comprising the mankind), this method comprises that the compound of the structural formula 1 of definition as mentioned or the acceptable salt of its medicine, solvate or prodrug are united with the amount of the described disease of effective treatment and one or more above listed anti-tumor agents and gives described Mammals.These diseases comprise cancerous tumour such as melanoma; The retina neovascularization that eye disease such as age-related macular degeneration, POHS and proliferative diabetic retinopathy cause; Rheumatoid arthritis; The osteoporosis that hypercalcinemia that osteoporosis disease such as osteoporosis, Pei Jiteshi (Paget ' s) disease, pernicious body fluid hypercalcinemia, metastases to bone cause and glucocorticoid treatment bring out; Coronary restenosis disease; And the certain micro-organisms infection, comprise those and the former relevant infection of microbiosis that is selected from adenovirus, Hantaan virus (hantavirus), Borrelia burgdoyferi bacterium (Borrelia burgdorferi), Yersinia (Yersinia spp.), bordetella pertussis (Bordetella pertussis) and A type suis (Streptococcus).
The invention still further relates to the method (and pharmaceutical composition) of treatment Mammals abnormal cell growth, this method comprises the compound of a certain amount of structural formula 1 or the acceptable salt of its medicine, solvate or prodrug and a certain amount of amount Combined Preparation that is selected from one or more materials of angiogenesis inhibitor medicament, signal conduction depressant drug and antiproliferative pharmaceutical agent with the described abnormal cell growth of effective treatment.
Can be used in combination with the compound of structural formula 1 as MMP-2 (matrix-metalloprotease 2) inhibitor, MMP-9 (matrix-metalloprotease 9) inhibitor and COX-II (cyclooxygenase II) inhibitor resisting neovascularity to generate medicament in method as herein described and the pharmaceutical composition.The example of useful COX-II inhibitor comprises CELEBREX TM(celecoxib), Bextra (valdecoxib), parecoxib (paracoxib), Vioxx (Luo Feikao former times) and Arcoxia (L-791456).The example of useful matrix metallo-proteinase inhibitor is seen and is set forth in WO96/33172 (announcement on October 24th, 1996), WO 96/27583 (announcement on March 7th, 1996), european patent application No. 97304971.1 (submission on July 8th, 1997), european patent application No. 99308617.2 (submission on October 29th, 1999), WO 98/07697 (announcement on February 26th, 1998), WO 98/03516 (announcement on January 29th, 1998), WO 98/34918 (announcement on August 13rd, 1998), WO 98/34915 (announcement on August 13rd, 1998), WO 98/33768 (announcement on August 6th, 1998), WO 98/30566 (announcement on July 16th, 1998), european patent application the 606th, No. 046 (announcement on July 13rd, 1994), european patent application the 931st, No. 788 (announcement on July 28th, 1999), WO 90/05719 (announcement on May 31 nineteen ninety), WO 99/52910 (announcement on October 21st, 1999), WO 99/52889 (announcement on October 21st, 1999), WO 99/29667 (announcement on June 17th, 1999), PCT International Application PCT/IB98/01113 (submission on July 21st, 1998), european patent application No. 99302232.1 (submission on March 25th, 1999), UK Patent Application the 9912961.1st (submission on June 3rd, 1999), U.S. Provisional Application the 60/148th, No. 464 (submission on August 12nd, 1999), United States Patent (USP) 5,863, No. 949 (mandate on January 26th, 1999), United States Patent (USP) 5,861,510 (mandates on January 19th, 1999), with european patent application 780,386 (announcements on June 25th, 1997), at this full content of incorporating all these documents into as a reference.Preferred L MP-2 and MMP-9 inhibitor are active minimum or do not have an activity to the inhibition of MMP-1.More preferably, these inhibitor optionally suppress MMP-2 and/or MMP-9 with respect to other matrix metalloproteinase (that is, MMP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12 and MMP-13).
Can AG-3340, RO 32-3555, RS 13-0830 and the following compound of enumerating be arranged with some object lessons that compound of the present invention is united the MMP inhibitor of use:
3-[[4-(4-fluoro-phenoxy group)-benzenesulfonyl]-(1-hydroxyl amino formyl radical-ring the eleventh of the twelve Earthly Branches base)-amino]-propionic acid;
Outside the 3--3-[4-(4-fluoro-phenoxy group)-benzenesulfonyl amino]-8-oxa--two ring [3.2.1] octane-3-carboxyl acid oxyamide;
(2R, 3R) 1-[4-(2-chloro-4-fluoro-benzyloxy)-benzenesulfonyl]-3-hydroxy-3-methyl-piperidines-2-carboxylic acid hydroxamides;
4-[4-(4-fluoro-phenoxy group)-benzenesulfonyl amino]-tetrahydrochysene-pyrans-4-carboxylic acid hydroxamides;
3-[[4-(4-fluoro-phenoxy group)-benzenesulfonyl]-(1-hydroxyl amino formyl radical-cyclobutyl)-amino]-propionic acid;
4-[4-(4-chloro-phenoxy group)-benzenesulfonyl amino]-tetrahydrochysene-pyrans-4-carboxylic acid hydroxamides;
3-[4-(4-chloro-phenoxy group)-benzenesulfonyl amino]-tetrahydrochysene-pyrans-3-carboxylic acid hydroxamides;
(2R, 3R) 1-[4-(4-fluoro-2-methyl-benzyloxy)-benzenesulfonyl]-3-hydroxy-3-methyl-piperidines-2-carboxylic acid hydroxamides;
3-[[4-(4-fluoro-phenoxy group)-benzenesulfonyl]-(1-hydroxyl amino formyl radical-1-methyl-ethyl)-amino]-propionic acid;
3-[[4-(4-fluoro-phenoxy group)-benzenesulfonyl]-(4-hydroxyl amino formyl radical-tetrahydrochysene-pyrans-4-yl)-amino]-propionic acid;
Outside the 3--3-[4-(4-chloro-phenoxy group)-benzenesulfonyl amino]-8-oxa--two ring [3.2.1] octane-3-carboxyl acid oxyamide;
In the 3--3-[4-(4-fluoro-phenoxy group)-benzenesulfonyl amino]-8-oxa--two ring [3.2.1] octane-3-carboxyl acid oxyamide; With
3-[4-(4-fluoro-phenoxy group)-benzenesulfonyl amino]-tetrahydrochysene-furans-3-carboxylic acid hydroxamides;
Drug acceptable salt class, solvate and prodrug with described compound.
The VEGF inhibitor, for example (Sugen Inc.ofSouth San Francisco, California USA) also can unite use with the compound of structural formula 1 for SU-11248, SU-5416 and SU-6668.The VEGF inhibitor is seen and is set forth in, for example, WO 99/24440 (May 20 in 1999 announced), PCT International Application PCT/IB99/00797 (submission on May 3rd, 1999), WO95/21613 (announcement on August 17 nineteen ninety-five), WO 99/61422 (announcement on December 2nd, 1999), United States Patent (USP) 5,834,504 (mandates on November 10th, 1998), WO 98/50356 (announcement on November 12nd, 1998), United States Patent (USP) 5,883,113 (mandates on March 16th, 1999), United States Patent (USP) 5,886,020 (mandate on March 23rd, 1999), United States Patent (USP) 5,792,783 (mandates on August 11st, 1998), United States Patent (USP) 6,653,308 (mandates on November 25th, 2003), WO 99/10349 (announcement on March 4th, 1999), WO 97/32856 (announcement on September 12nd, 1997), WO 97/22596 (announcement on June 26th, 1997), WO 98/54093 (announcement on December 3rd, 1998), WO 98/02438 (announcement on January 22nd, 1998), WO 99/16755 (announcement on April 8th, 1999) and WO 98/02437 (announcement on January 22nd, 1998), at this full content of incorporating all these documents into as a reference.Other examples of the VEGF inhibitor that some are concrete have IM862 (Cytran Inc.of Kirkland, Washington, USA); Avastin (Genentech, Inc.of South San Francisco, the anti-VEGF monoclonal antibody of California); And angiozyme (Ribozyme (Boulder, synthetic ribozyme Colorado)) and Chiron (Emeryville, California).
ErbB2 acceptor inhibitor such as GW-282974 (Glaxo Wellcome plc) and monoclonal antibody AR-209 (Aronex Pharmaceuticals, The woodiands, Texas, USA) and 2B-1 (Chiron) can unite use with structural formula 1 compound.These erbB2 inhibitor comprise Trastuzumab (Herceptin), 2C4 and pertuzumab.These erbB 2 inhibitor also comprise those inhibitor described in the following document: WO 98/02434 (announcement on January 22nd, 1998), WO 99/35146 (announcement on July 15th, 1999), WO 99/35132 (announcement on July 15th, 1999), WO 98/02437 (announcement on January 22nd, 1998), WO 97/13760 (announcement on April 17th, 1997), WO 95/19970 (announcement on July 27th, 1999), United States Patent (USP) 5,587,458 (mandates on December 24th, 1996), with United States Patent (USP) 5,877,305 (mandates on March 2nd, 1996), at this full content of incorporating each document into as a reference.Can be used for erbB2 acceptor inhibitor of the present invention and also see the U.S. Provisional Application the 60/117th that is set forth in submission on January 27th, 1999, the U.S. Provisional Application the 60/117th that No. 341 and on January 27th, 1999 submit to, No. 346, at this full content of incorporating two pieces of documents into as a reference.Other erbB2 acceptor inhibitor comprises TAK-165 (Takeda) and GW-572016 (Glaxo-Wellcome).
Multiple other compound such as styrene derivatives also shown to have the Tyrosylprotein kinase rejection characteristic, and some tyrosine kinase inhibitors have been accredited as the erbB2 acceptor inhibitor.Recently, 5 European patents are open, be EP 0 566 226 A1 (announcement on October 20th, 1993), EP 0 602 851 A1 (announcement on June 22nd, 1994), EP 0 635 507 A1 (announcement on January 25 nineteen ninety-five), EP 0 635 498 A1 (announcement on January 25 nineteen ninety-five) and EP 0 520722 A1 (announcement on December 30th, 1992), relate to some bicyclic derivatives, especially quinazoline derivant, it has the anticancer property from its Tyrosylprotein kinase rejection characteristic.In addition, International Patent Application WO 92/20642 (announcement on November 26th, 1992) also relates to some two-single and aryl bicyclic and heteroaryl compound, as the tyrosine kinase inhibitor that is used to suppress abnormal cell proliferation.International Patent Application WO 96/16960 (announcement on June 6th, 1996), WO 96/09294 (announcement on March 6th, 1996), WO 97/30034 (announcement on August 21st, 1997), WO 98/02434 (announcement on January 22nd, 1998), WO 98/02437 (announcement on January 22nd, 1998) and WO 98/02438 (announcement on January 22nd, 1998) also relate to the bicyclic heteroaromatic derivative of replacement, as the tyrosine kinase inhibitor that is used for identical purpose.Other patent application that relates to anticancer compound has International Patent Application WO 00/44728 (announcement on August 3rd, 2000), EP 1029853A1 (announcement on August 23rd, 2000) and WO01/98277 (announcement on December 12 calendar year 2001), at this full content of incorporating all these patent documentations into as a reference.
Other can comprise enzyme farnesyl (farnesyl) protein transferase inhibitor and receptor tyrosine kinase PDGFr inhibitor with the antiproliferative medicament that The compounds of this invention uses, and it comprises compound disclosed and claimed in the following U.S. Patent application: 09/221946 (submission on December 28th, 1998); 09/454058 (submission on December 2nd, 1999); 09/501163 (submission on February 9th, 2000); 09/539930 (submission on March 31st, 2000); 09/202796 (submission on May 22nd, 1997); 09/384339 (submission on August 26th, 1999); With 09/383755 (submission on August 26th, 1999); And disclosed and claimed compound in the following U.S. Provisional Patent Application: 60/168207 (submission on November 30th, 1999); 60/170119 (submission on December 10th, 1999); 60/177718 (submission on January 21st, 2000); 60/168217 (submission on November 30th, 1999) and 60/200834 (submission on May 1st, 2000).At this full content of incorporating above-mentioned each patent application and patent provisional application into as a reference.
The compound of structural formula 1 can also use with other medicament that is used for the treatment of abnormal cell growth or cancer, and these medicaments include but not limited to: can strengthen the medicine of anti tumor immune response such as CTLA4 (cellulotoxic lymphocyte antigen 4) antibody and other can block the medicine of CTLA4; And anti-proliferative drugs, as other farnesyl protein transferase inhibitor, for example the described farnesyl protein transferase inhibitor of reference quoted of " background technology " part sees above.The specific CTL A4 antibody that can be used among the present invention comprises the antibody described in the U.S. Provisional Patent Application 60/113,647 (submission on December 23rd, 1998), at this full content of incorporating the document into as a reference.(
Structural formula 1 compound can independently be used for the treatment of, and perhaps can have one or more other antitumorigenic substances to participate in, and for example is selected from following medicine: for example, and mitotic inhibitor (for example vinealeucoblastine(VLB)); Alkylating agent (for example cis-platinum (cis-platin), oxaliplatin (oxaliplatin), carboplatin (carboplatin) and endoxan); Metabolic antagonist (for example 5 FU 5 fluorouracil, capecitabine (capecitabine), cytosine(Cyt) cytosine arabinoside and hydroxyurea, perhaps such as one of disclosed preferred metabolic antagonist in No. the 239362nd, the european patent application, as N-(5-[ N-(3,4-dihydro-2-methyl-4-oxo quinazoline-6-ylmethyl)- N-methylamino]-the 2-Threonyl)-L-L-glutamic acid); Growth factor receptor inhibitors; Cell cycle inhibitor; Embed microbiotic (for example Zorubicin and bleomycin; Enzyme (for example Interferon, rabbit) and hormone antagonist (for example estrogen antagonist, as Nolvadex (tamoxifen)); Perhaps androgen antagonist for example is as Casodex (Casodex) (4 '-cyano group-3-(4-fluorophenyl alkylsulfonyl)-2-hydroxy-2-methyl-3 '-(trifluoromethyl) propionanilide)).
Compound of the present invention can use separately, and also anticancer agent that can be different with one or more or support medicament are united use.For example, compound of the present invention can use with the capable medicament of cell toxicant, for example, one or more are selected from following medicament: camptothecine (camptothecin), irinotecan hydrochloride (irinotecan) (Camptosar), edotecarin, SU-11248, pidorubicin (Epirubicin) (Ellence), Docetaxel (docetaxel) (Taxotere), taxol, Mabthera (rituximab) (Rituxan), rhuMAb-VEGF (bevacizumab) (Avastin), imatinib mesylate (imatinib mesylate) (Gleevac), Erbitux (Erbitux), Gefitinib (gefitinib) (Iressa) and the combination.The present invention also comprises the combined utilization of compound of the present invention and hormonotherapy, for example Exemestane (exemestane) (Aromasin), leuprorelin acetate (Lupron), anastrozole (anastrozole) (Arimidex), tamoxifen (tamoxifen) Citrate trianion (Nolvadex), Trelstar and combination thereof.In addition, the invention provides independent use The compounds of this invention, perhaps The compounds of this invention and one or more support medicine are united use, for example, these support medicines to have to be selected from filgrastim (filgrastim) (Neupogen), ondansetron (Ondansetron) (Zofran), the medicine of Fragmin (Fragmin), Epoetin Alfa (Procrit), A Lexi (Aloxi), Emend or its combination.These combination therapys can by every kind of composition simultaneously, successively or the mode of administration independently finish.
Compound of the present invention can use with anti-tumor agents, alkylating agent, metabolic antagonist, microbiotic, plant-derived antitumor drug, camptothecin derivative, tyrosine kinase inhibitor, antibody, Interferon, rabbit and/or biological response modifier.Thus, below be the non-limitative example of second kind of medicine that can use with compound of the present invention:
Alkylating agent, it includes but not limited to: mustargen N-oxide compound, endoxan, ifosfamide (ifosfamide), alkeran (melphalan), busulfan (busulfan), mitobronitol (mitobronitol), carboquone (carboquone), thiophene is for sending (thiotepa), ranomustine (ranimustine), nimustine (nimustine), Temozolomide (temozolomide), AMD-473, hexamethyl melamine (altretamine), AP-5280, apaziquone, brostallicin, bendamustine (bendamustine), carmustine (carmustine), estramustine (estramustine), fotemustine (fotemustine), glufosfamide (glufosfamide), ifosfamide, KW-2170, Mafosfamide (mafosfamide), and mitolactol (mitolactol); Platinum coordinate alkylated compound includes but not limited to: cis-platinum, carboplatin, eptaplatin (eptaplatin), Lip river platinum (lobaplatin), S 254 (nedaplatin), oxaliplatin or husky platinum (satraplatin);
Metabolic antagonist includes but not limited to: methotrexate, 6-MPR, purinethol, use separately or unite the 5 FU 5 fluorouracil (5-FU) of use with formyl tetrahydrofolic acid, Tegafur (tegafur), UFT, doxifluridine (doxifluridine), carmofur (carmofur), cytosine arabinoside (cytarabine), cytarabine ocfosfate, enocitabine (enocitabine), S-1, gemcitabine (gemcitabine), fludarabine (fludarabin), 5-azacitidine (5-azactidine), capecitabine (capecitabine), carat Qu Bin (cladribine), clofarabine (clofarabine), Decitabine (decitabine), eflornithine (eflornithine), the ethynyl cytidine, the cytosine(Cyt) cytosine arabinoside, hydroxyurea, TS-1, alkeran, Nelzarabine (nelarabine), Nolatrexed (nolatrexed), ocfosfate, train U.S. bent azoles disodium (disodiumpremetrexed), spray Si Tating (pentostatin), pelitrexol, thunder is for Qu Sai (raltitrexed), triapine, trimetrexate (trimetrexate), vidarabine (vidarabine), vincristine(VCR), vinorelbine (vinorelbine); Perhaps, a kind of in No. 239362 disclosed preferred metabolic antagonist of european patent application for example is as N-(5-[N-(3,4-dihydro-2-methyl-4-oxygen base quinazoline-6-ylmethyl)-N-methylamino]-2-Threonyl)-L-L-glutamic acid;
Microbiotic includes but not limited to: aclarubicin (aclarubicin), dactinomycin (actionmycin D), amrubicin (amrubicin), annamycin, bleomycin, daunorubicin (daunorubin), Zorubicin (doxorubicin), elsamitrucin (elsamitrucin), pidorubicin, galarubicin (galarubicin), idarubicin (idarubicin), ametycin, Nemorubicin (nemorubicin), neocarzinostatin (neocarzinostatin), Bleomycin (peplomycin), pirarubicin (pirarubicin), butterfly mycin (rebeccamycin), Zinostatin stimalamer (stimalamer), streptozotocin (streptozocin), valrubicin (valrubicin) or zinostatin (zinostatin);
The hormonotherapy medicament, for example Exemestane (exemestane) is (Aromasin), leuprorelin acetate (Lupron), anastrozole (Arimidex), degree ostelin (doxercalciferol), fadrozole (fadrozole), formestane (formestane), estrogen antagonist (as tamoxifen Citrate trianion (Nolvadex) and fulvestrant (fulvestrant)), Trelstar, toremifene (toremifene), Lei Luoxifen (raloxifene), Lasofoxifene (lasofoxifene), letrozole (letrozole) (Femara), or androgen antagonist is (as bicalutamide (bicalutamide), flutamide (flutamide), mifepristone (mifepristone), Nilutamide (nilutamide), Casodex  (4 '-cyano group-3-(4-fluorophenyl alkylsulfonyl)-2-hydroxy-2-methyl-3 '-(trifluoromethyl) propionanilide) and combination thereof;
Plant-derived antitumor drug comprises, for example, is selected from mitotic inhibitor, for example vinealeucoblastine(VLB), Docetaxel (Taxotere) and taxol;
Cytotoxicity topoisomerase inhibitor comprises one or more medicaments that are selected from following medicament: aclarubicin, amonafide (amonafide), belotecan, camptothecine, 10-hydroxycamptothecine, 9-aminocamptothecin, fluorine is for health (diflomotecan), irinotecan hydrochloride (Camptosar), edotecarin, pidorubicin (Ellence), etoposide (etoposide), exatecan (exatecan), gimatecan, lurtotecan (lurtotecan), mitoxantrone (mitoxantrone), pirarubicin, pixantrone, rubitecan (rubitecan), sobuzoxane (sobuzoxane), SN-38, tafluposide and topotecan (topotecan), and combination;
Immune drug comprises Interferon, rabbit and multiple other immunostimulant.Interferon, rabbit comprises interferon alpha, Intederon Alpha-2a, Interferon Alpha-2b, interferon beta, interferon-gamma-1a or interferon-gamma-n1.Other medicament comprises filgrastim (filgrastim), lentinan (lentinan), split wrinkle rhzomorph (sizofilan), TheraCys, ubenimex (ubenimex), WF-10, rIL-2 (aldesleukin), alemtuzumab (alemtuzumab), BAM-002, dacarbazine (dacarbazine), daclizumab (daclizumab), denileukin (denileukin), WAY-CMA 676 (gemtuzumab), ozogamicin (ozogamicin), ibritumomab tiuxetan (ibritumomab), Imiquimod (imiquimod), come the Nola to carry (lenograstim), lentinan, melanoma vaccines (Corixa), Sch-39300 (molgramostim), OncoVAX-CL, sargramostim (sargramostim), tasonermin (tasonermin), tecleukin, thymalasin, tositumomab (tositumomab), virulizin (virulizin), Z-100, epratuzumab (epratuzumab), mitumomab (mitumomab), oregovomab, pemtumomab, Provenge;
Biological response modifier makes them have anti-tumor activity for modifying the medicine of Living Organism or biological respinse defense mechanism (as histiocytic survival, growth or differentiation).These medicines comprise krestin (krestin), lentinan, Schizophyllan (sizofiran), molten chain bacterium (picibanil) or ubenimex (ubenimex);
Other cancer therapy drug comprises alitretinoin (alitretinoin), Polyinosinic-polycytidylic acid (ampliggen), atrasentan (atrasentan), bexarotene (bexarotene), ripple is for monoclonal antibody (bortezomib), bosentan (Bosentan), calcitriol (calcitriol), exisulind (exisulind), Fei Nasi carries (finasteride), fotemustine (fotemustine), according to class's phosphonic acids (ibandronic acid), miltefosine (miltefosine), mitoxantrone (mitoxantrone), the 1-asparaginase, Procarbazine (procarbazine), dacarbazine, hydroxyurea, Pegaspargase (pegaspargase), spray Si Tating (pentostatin), tazarotne, TLK-286, ten thousand jade-like stones (Velcade), it matches watt (Tarceva), vitamin A acid (tretinoin);
Other anti-angiogenic compounds comprises Acitretin (acitretin), fenretinide (fenretinide), thalidomide (thalidomide), Zoledronic acid (zoledronic acid), angiostatin (angiostatin), aplidine, cilengtide, combretastatin (combretastatin) A-4, blood vessel endothelium chalone (endostatin), Halofuginone (halofuginone), rebimastat, removab, Revlimid, squalamine (squalamine), ukrain and Vitaxin;
Iridium-platinum complex includes but not limited to cis-platinum, carboplatin, S 254 (nedaplatin) or oxaliplatin;
Camptothecin derivative includes but not limited to camptothecine, 10-hydroxycamptothecine, 9-aminocamptothecin, Rinotecan, SN-38, edotecarin and topotecan;
Tyrosine kinase inhibitor is Ai Nuosha (Iressa) or SU 5416;
Antibody comprises Trastuzumab (Herceptin), Erbitux (Erbitux), Avastin or Rituximab (Rituximab);
Interferon, rabbit comprises interferon alpha, Intederon Alpha-2a, Interferon Alpha-2b, interferon beta, interferon-gamma-1a or interferon-gamma-n1.
Biological response modifier makes them have the medicine of anti-tumor activity for modifying the defense mechanism (as histiocytic survival, growth or differentiation) of Living Organism or biological respinse.These medicines comprise krestin, lentinan, Schizophyllan (sizofiran), molten chain bacterium (picibanil) or ubenimex (ubenimex); With
Other antitumor drug comprises mitoxantrone, 1-asparaginase, Procarbazine, dacarbazine, hydroxyurea, spray Si Tating or vitamin A acid.
As used herein, except as otherwise noted, " abnormal cell growth " is meant the cell growth (for example forfeiture of contact inhibition) that does not rely on normal regulating mechanism.It comprises the misgrowth of following cell: the tumour cell (tumour) that breed by the Tyrosylprotein kinase or the overexpression receptor tyrosine kinase of expression sudden change (1); (2) the optimum and malignant cell of other proliferative disease of unusual Tyrosylprotein kinase activation wherein takes place; (4) any tumour of breeding by receptor tyrosine kinase; (5) any tumour of breeding by unusual serine/threonine kinase activation; (6) the optimum and malignant cell of unusual other proliferative disease of serine/threonine kinase activatory wherein takes place.
Compound of the present invention is effective inhibitor of FAK protein tyrosine kinase, thereby (for example all be suitable as the especially human anti-hyperplasia of Mammals, anticancer) medicament, antitumor (for example, effective to noumenal tumour) medicament, anti-new vessel form (for example, stop or prevent blood vessel hyperplasia) medicament.Compound of the present invention especially can be used for prevention and treats multiple human proliferative disease, as liver, kidney, bladder, breast, stomach, ovary, knot rectum, prostate gland, pancreas, lung, vulva, thyroid pernicious and innocent tumour, liver cancer, sarcoma, glioblastoma, tumor of head and neck, with the hyperplasia of prostate of other proliferative diseases such as skin (for example, psoriasis) and benign prostatic hyperplasia (for example, BPH).In addition, compound of the present invention is estimated and can antagonistic activity be arranged to the leukemia and the lymph malignant tumour of certain limit.
In a preferred embodiment of the present invention, cancer is selected from lung cancer, osteocarcinoma, carcinoma of the pancreas, cancer of the stomach, skin carcinoma, head or neck cancer, skin or intraocular melanoma, uterus carcinoma, ovarian cancer, gynecological tumor, the rectum cancer, the anal regions cancer, cancer of the stomach, colorectal carcinoma, breast cancer, uterus carcinoma, carcinoma of fallopian tube, carcinoma of endometrium, cervical cancer, carcinoma of vagina, carcinoma vulvae, Hokdkin disease, esophagus cancer, carcinoma of small intestine, the endocrine system cancer, thyroid carcinoma, parathyroid carcinoma, renal adenocarcinoma, soft tissue sarcoma, urethral carcinoma, penile cancer, squamous cell carcinoma, prostate cancer, chronic or acute leukemia, the lymphocyte lymphoma, bladder cancer, kidney or carcinoma of ureter, renal cell carcinoma, carcinoma of renal pelvis, central nervous system (CNS) tumour, primary CNS lymphoma, tumor of spine, the cancer of the brain, the combination of pituitary adenoma or one or more above-mentioned cancers.
In preferred embodiment, cancer is selected from noumenal tumour, for example, but be not limited to: breast cancer, lung cancer, colorectal carcinoma, the cancer of the brain, prostate cancer, cancer of the stomach, carcinoma of the pancreas, ovarian cancer, skin carcinoma (melanoma), internal secretion cancer, uterus carcinoma, carcinoma of testis and bladder cancer.
Compound of the present invention also can be used for treating other the ligand/receptor interaction relevant with multiple protein Tyrosylprotein kinase unconventionality expression or activation or signal conduction incident diseases associated.These diseases can comprise the disease of neurone, neurogliocyte, astroglia cell, hypothalamus and other body of gland, scavenger cell, epithelial cell, mesenchymal cell and the segmentation cavity cell relevant with function, expression, activation or the signal conduction abnormalities of erbB Tyrosylprotein kinase.In addition, compound of the present invention can be therein identified in the relevant inflammation of the unidentified Tyrosylprotein kinase of Buddhist monk, blood vessel originality and the immunological disease to have therapeutic action with compound of the present invention suppresses.
Concrete aspect of the present invention is the method that is used for the treatment of or prevents the low bone amount disease of Mammals (comprising the mankind), and this method comprises the compound of structural formula 1 of the Mammals therapeutic dose that needs the low bone amount of suffering from of this treatment disease or the drug acceptable salt of described compound.
The present invention relates to these methods particularly, and wherein low bone amount disease is that osteoporosis, sclerotin fragility, osteoporotic fracture, bony defect, the spontaneous osteoporosis of children, alveolus osteoporosis, mandibular bone osteoporosis, fracture, bone-culting operation, periodontitis or prosthese are grown into.
Concrete aspect of the present invention relates to the method for the osteoporosis that is used for the treatment of Mammals (comprising the mankind), and this method comprises needs to treat the Mammals of osteoporosis with the compound of the structural formula 1 of therapeutic dose or the drug acceptable salt of described compound.
Another aspect of the present invention relates to the method at treatment Mammals fracture or osteoporotic fracture, and this method comprises that the Mammals that needs treatment fracture or osteoporotic fracture is with the compound of the structural formula 1 of therapeutic dose or the drug acceptable salt of described compound.
Term " osteoporosis " comprises primary osteoporosis, as after senile, the menopause and teenager's osteoporosis, and secondary osteoporosis, as because osteoporosis, acromegaly, hypogonadism, anostosi and the hypophosphatemia that hyperthyroidism or Ke Xing Shi (Cushing) syndrome (owing to using reflunomide) cause.
As used herein, unless otherwise indicated, term " treatment (treating) " is meant reverse, alleviates, suppresses the progress of the applied disease of this term or the state of an illness or one or more symptoms of this disease or the state of an illness, perhaps prevents one or more symptoms of this disease or the state of an illness or this disease or the state of an illness.As used herein, unless otherwise indicated, term " is treated (treatment) ", is meant as defined above the treatment behavior of " treatment (treating) ".
The present invention also provides a kind of pharmaceutical composition, and it comprises compound or the acceptable salt of its medicine or the solvate of structural formula (1) as hereinbefore defined, and the acceptable adjuvant of medicine, diluent or carrier.
The present invention further provides preparation of drug combination method of the present invention, this method comprises mixes the compound of as hereinbefore defined structural formula (1) or the acceptable salt of its medicine or solvate with the acceptable adjuvant of medicine, diluent or carrier.
For therepic use referred to above, the dosage of administration will change according to used compound, administering mode, required treatment and specified disease certainly.The day dosage (activeconstituents) of structural formula (1) compound/salt/solvate can be 1mg to 1g, is preferably 1mg to 250mg, more preferably 10mg to 100mg.
The present invention also comprises the composition that continues release.
Embodiment
The compound of structural formula 1 can use the synthetic route described in synoptic diagram 1 to be prepared.Substituting group in the synoptic diagram 1 is identical with the substituting group definition in the structural formula 1.
Synoptic diagram 1
The compound of structural formula 1 can begin preparation from 5-amino-oxindole (6) and pyrimidine (7).In-15 to 45 ℃ temperature range, in inert solvent (or solvent mixture), mixed 10-60 minute with Louis silk acid 7, add 6 and suitable alkali then, obtain the intermediate product 4-chloropyrimide (8) of high yield after 1-24 hour.The example of inert solvent includes but not limited to THF, 1,4-diox, n-BuOH, i-PrOH, methylene dichloride and 1,2-ethylene dichloride.The example of employed suitable alkali includes but not limited to: (i) the organic bases of non-nucleophilicity, for example triethylamine or diisopropylethylamine; (ii) mineral alkali is as salt of wormwood or cesium carbonate; Or (iii) be combined in alkali on the resin, as the MP-carbonic ether.
The example of Louis silk acid includes but not limited to the halogen of magnesium, copper, zinc, tin or titanium.In next step reaction, the amine of intermediate product 8 and structural formula 9 at 0 to 150 ℃ temperature range internal reaction, obtains the compound of structural formula 1 directly or in the presence of inert solvent (or solvent mixture).This reaction can randomly be carried out in the presence of suitable alkali.The example of the solvent that this reaction is suitable includes but not limited to THF, 1,4-diox, DMF, N-methyl-pyrrolidone, EtOH, n-BuOH, i-PrOH, methylene dichloride, 1,2-ethylene dichloride, DMSO or acetonitrile.Suitable bases is listed as mentioned.
Compound of the present invention can be transformed into other compounds of the present invention by synthesizing according to this area professional and technical personnel's technique known.Only also unrestricted in order to describe to the greatest extent, these methods comprise:
A) by T.W.Greene and P.G.M.Wuts, " Protective Groups in OrganicSynthesis (blocking group in the organic synthesis) ", second edition, John Wiley and Sons, NewYork, generalized method removes blocking group in 1991; For example remove the BOG protecting group with acid source as HCl or trifluoroacetic acid.
B) use functional group to replace leavings group (halogenide, methanesulfonates, tosylate etc.), form secondary amine or tertiary amine, thioether or ether respectively such as but not limited to primary amine or secondary amine, mercaptan or alcohol.
C) handle phenyl carbamate (or the phenyl carbamate that replaces) with primary amine or secondary amine, form corresponding urea, as people such as Thavonekham.B, Synthesis (1997), 10, described in the p1189;
D) handle with two (2-methoxy ethoxy) sodium alanates (Red-AI), the primary amine of propargyl or high-propargyl (homopropargyl) alcohol or N-BOC protection is reduced into corresponding E-allyl group or E-high allyl (E-homoallylic) derivative, as Denmark, S.E.; Jones, T.K.J.Org.Chem. (1982) 47,4595-4597 or van Benthem.R.A.T.M.; Michels, J.J.; Speckamp is described in W.N.Synlett (1994) .368-370;
E) by hydrogen and Pd catalyst treatment, alkynes is reduced into corresponding Z-alkene derivatives, as Tomassy, people such as B., Synth.Commun. (1998), 28, described in the p1201;
F) handle primary amine and secondary amine with isocyanic ester, acyl group (or other activated carboxylic acid derivatives), chloroformic acid alkyl ester or SULPHURYL CHLORIDE, obtain corresponding urea, acid amides, carbamate or sulphonamide;
G) use aldehydes or ketones and appropriate reductant that primary amine or secondary amine are carried out reduction amination.
H) handle alcohol with isocyanic ester, acyl chlorides (or other activated carboxylic acid derivatives), chloroformic acid alkyl ester or SULPHURYL CHLORIDE, obtain corresponding carbamate, ester, carbonic ether or sulphonate.
The amine of structural formula 9 can directly be bought and use, and perhaps uses common chemical transformation to be prepared by this area professional and technical personnel alternatively in addition.For example, aromatic yl alkyl amine or heteroarylalkyl amine can use the catalyzer as Pd/C or raney (Raney) nickel to prepare by catalytic hydrogenation, perhaps prepare from its corresponding nitrile by lithium aluminium hydride reduction, (see Rylander, Catalytic Hydrogenation in Organic Synthesis, Academic Press, 1979).
Figure A20058001553000981
The nitrile starting raw material can be bought or from corresponding aryl/hetaryl bromine, iodine or trifluoromethanesulfonic acid and Zn (CN) 2Use the Pd coupling condition to be prepared, be found in Tschaen, people such as D.M., Synthetic Communications (1994), 24,6, pp 887-890.
Figure A20058001553000982
In addition alternatively, benzyl amine or heteroaryl methylamine can prepare by the following method: make suitable halo aralkyl or heteroarylalkyl and (BOC) 2The sylvite reaction of NH (object of reference) removes the BOC group with acid then.
Figure A20058001553000983
The precursor of the amine of the precursor of amine, the amine of the amine of structural formula 9, protection form and protection form can by will suitable alkynes or alkenylstannane, thiazolinyl borine, ene boric acid, boric acid ester and suitable aryl or heteroaryl bromine, iodine or trifluoromethanesulfonic acid use Pd coupling condition chemical combination be prepared, this method is found in Tsuji, J.; Palladium Reagents and Catalysis, JohnWiley and Sons 1999 and at this document of quoting.
Figure A20058001553000984
According to the known method of this area, this area professional and technical personnel, the amine of the structural formula 9 of due care can be transformed into the different amine of structural formula 9, these methods such as but not limited to:
(a) sulfide oxidation becomes sulfoxide or sulfone.
(b) use Brehme, R. " Synthesis ", (1976), the condition described in the pp 113-114 is finished the N-alkylation of sulfanilide under phase transition.
Figure A20058001553000992
The professional and technical personnel understands as this area, and the chemical conversion that aryl halide or trifluoromethanesulfonic acid or heteroaryl halogen or trifluoromethanesulfonic acid are transformed into aromatic amine or heteroaromatic amine can use in the following document generalized condition to carry out: referring to Hartwig, and J.F.; " Angew.Chem.Int.Ed. " (1998), 37.pp.2046-2067, Wolfe, J.P.; Wagaw, S.; Marcoux.J.F.; Buchwald, S.L.; " Acc.Chem.Res. ", (1998), 31, pp 805-818.Wolfe, J.P.; Buchwald.S.L.; " J.Org.Chem. ". (2000), 65, pp 1144-1157, Muci, A.R.; Buchwald, S.L; " Topics in Current Chemistry " (2002), pp 131-209 and at this reference of quoting.Further, the professional and technical personnel understands as this area, and these identical aryl or heteroaryl ammonification chemical conversion can be carried out on nitrile (or primary amide) precursor selectively, obtains the amine of structural formula 5 after nitrile (or acid amides) reduction.According to the method that this area professional and technical personnel is familiar with, the amine of the protection of structural formula 5 can further change into the different amine of structural formula 5.
Figure A20058001553000993
Structural formula 1The external activity of compound measure by following method.More specifically, following measuring method provides the mensuration structural formula 1Whether compound suppresses the method for the tyrosine kinase activity of catalytic construction FAK (410-689).This assay method is measured the restraining effect by FAK (410-689) poly-glu-tyr phosphorylation based on ELISA.
This measuring method has three parts:
I. purifying and the cutting of His-FAK (410-689)
II. FAK410-689 (a.k.a.FAKcd) activation
III. FAKcd kinases ELISA
Material:
-Ni-NTA agarose (Qiagen)
-XK-16 post (Amersham-Pharmacia)
-300mM imidazoles
-Superdex 200 HiLoad, 16/60 preparation scale posts (Amersham Biotech.)
-antibody: anti--the crosslinked Py20 (Transduction labs) of Tyrosine O-phosphate HRP-
-FAKcd: from Malaysia and China's purifying and activation (in house)
-TMB microtiter plate peroxidase substrate (Oncogene Research Products#CL07)
-BSA：Sigma#A3294
-Tween-20：Sigma#P1379
-DMSO：Sigma#D-5879
-D-PBS：Gibco#14190-037。
Purified reagent:
-buffer A: 50mM HEPES pH 7.0,
500mM NaCl，
0.1mM TCEP
CompleteTM proteinase inhibitor mixing tablet (Roche)
-buffer B: 25mM HEPES pH 7.0,
400mM NaCl
400mM NaCl
0.1mM TCEP
-damping fluid C:10mM HEPES pH 7.5,
200mM ammonium sulfate
0.1mM TCEP。
Activating reagent
-FAK (410-689): 3 pipe refrigerated equivalent reagent (150 μ l/ pipe), totally 450 μ l, 1.48mg/ml (660 μ g)
-His-Src (249-524): 10mM HEPES, 200mM (NH 4) 2SO 4In mother liquor ,～0.74mg/ml
-Src reaction buffer (Upstate Biotech):
100mM Tris-HCI pH 7.2，
125mM MgCl 2，
25mM MnCl 2，
2mM EDTA，
250μM Na 3VO 4，
2mM DTT
-Mn 2+/ ATP mixes (Upstate Biotech)
75mM MnCl 2
500μM ATP
20mM MOPS pH 7.2
1mM Na 3VO 4
25mM D-phosphoglyceride
5mM EGTA
1mM DTT
-ATP:150mM mother liquor
-MgCl 2: the 1M mother liquor
-DTT:1M mother liquor
FAKcd kinases ELISA reagent
-phosphorylation damping fluid:
50mM HEPES，pH 7.5，
125mM NaCl，
48mM MgCl 2
-dcq buffer liquid: TBS+0.1%Tween-20.
-sealing damping fluid:
The Tris buffer saline,
3％BSA，
0.05%Tween-20 filters.
-assay plate bag is cushioned liquid:
50mg/ml poly-Glu-Tyr (Sigma#P0275) is in the phosphate-buffered saline (DPBS).
-ATP:0.1M ATP H 2Among O or the HEPES, pH7.
Remarks: ATP measures damping fluid:
Consist of 75 μ M ATP/PBS among the PBS, make the final ATP concentration of 80 μ l=50 μ M in 120 μ l reaction volumes.
The purifying of I.His-FAKed (410-689)
1. the 130gbaculovirus cell mass (cell paste) that will contain the His-FAKcd410-689 recombinant protein of overexpression is suspended in 3 volumes (400ml) buffer A again,
2. dissolved cell is once on the fluidisation instrument.
On Sorval SLA-1500 whizzer under 40 ℃ with 14, centrifugal 35 minutes of 000rpm removes cell debris.
4. supernatant liquor is transferred in the clean test tube, adds 6.0ml Ni-NTA agarose (Qlagen).
5. hatched under 40 ℃ 1 hour, suspension gently vibrates simultaneously.
On the swing bucket rotor whizzer with the centrifugal suspension of 700 * g.
7. abandoning supernatant, and sepharose 4B is suspended in the 20.0ml buffer A again.
8. pearl is transferred on the XK-16 post (Amersham-Pharmacia) that is connected with FPLCTM.
9. wash sepharose 4B with the buffer A of 5 times of column volumes, and post is carried out wash-out with the damping fluid that contains the 300nM imidazoles of discontinuous gradient.
10. the buffer-exchanged with the cut of wash-out becomes buffer B.
11. after buffer-exchanged, cut is concentrated in together,, and, removes the His-mark (His-FAK410-698 → FAK410-689 (a.k.a.FAKcd)) of N-end 13 ℃ of following overnight incubation with the ratio adding zymoplasm of 1: 300 (w/w).
12. reaction mixture is added back to on the buffer A equilibrated Ni-NTA post, collects effluent.
13. effluent is concentrated into 1.7ml, it directly is encased in on the damping fluid C equilibrated Superdex 200 HiLoad 16/60 preparation scale post.Required albumen wash-out between 85-95ml.
14. with FAKcd albumen five equilibrium, and-80 ℃ of freezing preservations down.
The II.FAK activation
1. in the FAK (410-689) of 450 μ l 1.48mg/ml (660 μ g), add following reagent:
30μl 0.037mg/ml(1μM)His-Src(249-524)
30μl 7.5mM ATP
12μl 20mM MgCl 2
10 μ l Mn 2+/ ATP mixture (UpState Biotech.)
4μl 6.7mM DTT
60 μ l Src reaction buffers (UpState Biotech.)
2. under the room temperature reaction was hatched 3 hours at least
At t 0Constantly, nearly all FAK (410-689) coverlet phosphorylation all.Phosphorylation is very slow for the second time.At t 120(t=120 minute) adds 10 μ l 150mM ATP constantly.
T 0=(initially) 90% single phosphorylation FAK (410-689) (1 PO4)
T 43=(43min) 65% single phosphorylation (1 PO4), 35% bis phosphoric acidization (2 PO4)
T 90＝(90min)45％1 PO4，55％2 PO4
T 160＝15％1 PO4，85％2 PO4
T 210=＜10%1 PO4,＞90%2 PO4 desalination samples
3. in the NiNTA column spinner, add the desalination material of 180 μ l five equilibriums, and in column spinner, hatch.
4. with 10k rpm (microfuge) rotation 5 minutes, separate and collection effluent (activatory FAK (410-689)), remove His-Src (on post, capturing).
III.FAKcd kinases ELISA
1. wrap by 96-hole Nunc MaxiSorp assay plate with 10 μ g/ holes with poly-glu-tyr (pGT): prepare 10 μ g/ml pGT/PBS, and with 100 μ l hole five equilibriums.Assay plate 37 ℃ of following overnight incubation, is drawn supernatant liquor, wash assay plate 3 times, and pat, then 4 ℃ of storages down to dry with dcq buffer liquid.
2. the compound mother liquor that in 100%DMSO, prepares 2.5mM.Then mother liquor is diluted to ultimate density in 100%DMSO, and diluted with 1: 5 with the tyrosine phosphorylation damping fluid to 60X.
3. in the tyrosine phosphorylation damping fluid, prepare 75 μ M ATP working solutions.Add 80 μ l in every hole, making the ATP final concentration is 50 μ M.
4. the compound that 10 μ l have been diluted (0.5log serial dilution) is transferred in each hole of pGT assay plate, 3 holes of each compound determination on same assay plate.
5. after dilution on ice, FAKcd albumen joined in the tyrosine phosphorylation damping fluid with 1: 1000.Every hole adds 30 μ l.
6. note:, must pre-determine the linear lag and suitable extent of dilution for every batch of albumen.The enzyme concn of selecting should make the intensity of measured signal be approximately 0.8-1.0 at the OD450 place, and within the linearity range of speed of reaction.
7. prepare the contrast (background) of no ATP and the contrast (signal) of no compound:
8. (background) adds compound/DMSO, 80 μ l phosphorylation damping fluids (no ATP) and the 30 μ l FAKcd solution of 10 μ l dilution in 1: 5 in the hole of an emptying.
9. (signal) control wells adds DMSO (no compound)/tyrosine phosphorylation damping fluid, 80 μ l, 75 uM ATP and 1: 1000 FAKcd enzyme of 30 μ l of 10 μ l dilution in 1: 5.
10. at room temperature reaction is hatched 15 minutes vibration gently on plate vibrator simultaneously.
11. the sucking-off reaction mixture, termination reaction, and with dcq buffer liquid flushing 3 times.
12. (pY20HRP) antibody that phosphoric acid-tyrosine HRP-is crosslinked is diluted to 0.250 μ g/ml (1: 1000 mother liquor) in the sealing damping fluid.Every hole adds 100 μ l, and at room temperature hatches 30 minutes and jolting.
13. the absorption supernatant liquor washes assay plate 3 times with dcq buffer liquid.
14. the TMB solution that every hole adds under the 100 μ l room temperatures develops the color.Approximately 15-30 adds 100 μ l 0.09M H in every hole after second 2SO 4, color development stopping.
15., signal is carried out quantitatively by in BioRad automatic ration microplate reader or can be on the micro-microplate reader of OD450 place reading measure absorbancy at the 450nm place.
16. tyrosine kinase activity suppresses absorbance signal will be reduced.Signal typically is 0.8-1.0OD unit.Numerical value is reported as IC50s μ M concentration.
ELISA based on FAK inducibility cell: final plan
Material:
Reacti-Bind goat-anti rabbit 96 hole assay plate (Pierce Product#15135ZZ@115.00USD)
FAKpY397 rabbit polyclonal antibody (Biosource#44624@315.00 USD)
The ChromePure rabbit igg, full molecule (Jackson Laboratories#001-000-003@60/25mg USD)
UBI α FAK clones 2A7 mouse monoclonal antibody (Upstate#05-182@289.00USD)
The AffiniPure sheep anti-mouse igg (Jackson Labs#115-035-146@95/1.5mlUSD) that peroxidase is crosslinked
SuperBlock TBS(Pierce Product#37535ZZ@99 USD)
Bovine serum albumin (Sigma#A-9647@117.95/100g USD)
TMB peroxidase substrate (Oncogene Research Products#CL07-100ml@40.00 USD)
Na 3VO 4Sodium orthovanadate (Sigma#56508@43.95/50g USD)
MTT substrate (Sigma#M-2128@25.95/500mg USD)
Growth medium: DMEM+10%FBS, P/S, Glu, 750 μ g/ml Zeocin and 50 μ g/m Totomycin (hygromycin, Zeocin InVitrogen#R250-05@725 USD and Hygromycon InVitrogen#R220-05@150 USD)
Mifepristone (Mifepristone) InVitrogen#H110-01@125 USD
CompleteTM does not have EDTA-proteinase inhibitor tablet Boehringer Mannheim#1873580
Mensuration kinases dependency phosphoric acid FAKY397 Study on Selectivity scheme based on the FAK cell
Step:
Developed and a kind ofly screened chemical substance to identify the Tyrosylprotein kinase specific inhibitor based on the assay method of inducibility FAK cell with the ELISA form.Adopt the mechanism of GeneSwitchTM system (InVitrogen) based on the assay method of cell, controlled the expression and the phosphorylation in the kinases dependency autophosphorylation site at FAK and residue Y397 place exogenously.
Suppressing the dependent autophosphorylation of kinases at the Y397 place reduces the extinction signal of OD450.Signal typically is 0.9 to 1.5 OD450 unit, and the background scope is 0.08 to 0.1 OD450 unit.Numerical value is reported as IC 50sμ M concentration.
At the 1st day, A431FAKwt grew in the T175 culture dish.In the day before yesterday of carrying out the FAK raji cell assay Raji, with the A431FAKwt cell inoculation in the growth medium in culture plate at the bottom of the 96 hole U-shapeds.Cell is at 37 ℃/5%CO before FAK induces 2In left standstill 6 to 8 hours.The mifepristone mother liquor of preparation 10 μ M in 100% ethanol.Then mother liquor is diluted to the ultimate density of 10X in growth medium.10 these diluents of μ l (ultimate density is the 0.1nM mifepristone) are added in each hole.Cell is at 37 ℃, 5%CO 2Middle standing over night (12 to 16 hours).In addition, preparation does not have mifepristone to induce the control wells of FAK expression and phosphorylation.
At the 2nd day, will be with the 3.5 μ g/ml phosphoric acid specificity FAKpY397 polyclonal antibody bags that prepare in the SuperBlock TBS damping fluid by goat-anti rabbit assay plate, and assay plate at room temperature vibrated on the assay plate vibrator 2 hours.Control wells can randomly be used in the 3.5 μ g/ml contrast trapping antibody (full rabbit igg molecule) for preparing among the SuperBlock TBS and wrap quilt.With damping fluid flushing 3 times, the FAKpY397 antibody that flush away is excessive.On the assay plate vibrator, will resist the every hole of assay plate of FAKpY397 bag quilt at room temperature to seal 1 hour with 200 μ l 3%BSA/0.5%Tween sealing damping fluid.When the sealing assay plate, the compound mother liquor of preparation 5mM in 100%DMSO.Then with mother liquor in 100%DMSO serial dilution to the ultimate density of 100X.Use 100X solution in growth medium, to make 1: 10 diluent, and the diluted chemical compound liquid that 10 μ l are suitable is transferred to each and contain FAK inductive A431 cell or not in the hole of inductive contrast A431 cell, at 37 ℃, 5%CO 2The middle placement 30 minutes.Preparation RIPA dissolving damping fluid (contain 50mM Tris-HCl in every 50ml solution, pH7.4,1%NP-40,0.25% Sodium desoxycholate, 150mM NaCl, 1mM EDTA, 1mM Na3VO4,1mMNaF and 1 CompleteTM do not have EDTA proteinase inhibitor tablet).When compound treatment was finished in 30 minutes, use TBS-T dcq buffer liquid flushing 3 times, the flush away compound.Every hole adds 100 μ l RIPA damping fluid dissolved cells.
From the assay plate of bag quilt, remove the deblocking damping fluid, with TBS-T dcq buffer liquid flushing 3 times.Use 96-hole automatic micropipettor that the full cytolysis thing of 100 μ l (is added to from step 6) in the assay plate of goat-anti rabbit FAKpY397 bag quilt, to capture phosphoric acid FAKY397 albumen.Jolting at room temperature 2 hours.Use TBS-T dcq buffer liquid flushing 3 times, the unconjugated albumen of flush away.The UBI α FAK for preparing in 0.5 μ g/ml (dilution in 1: 2000) the 3%BSA/0.5%Tween sealing damping fluid detects antibody.In every hole, add 100 μ l UBI α FAK solution, and jolting at room temperature 30 minutes.Use TBS-T damping fluid flushing 3 times, the UBI α FAK antibody that flush away is excessive.Prepare 0.08 μ g/ml (1: 5000 dilution) anti-mouse peroxidase (anti--2MHRP) crosslinked two is anti-.Every hole adds 100 μ l anti--2MHRP solution, and jolting at room temperature 30 minutes.Use TBS-T damping fluid flushing 3 times, anti--2MHRP antibody that flush away is excessive.The tmb substrate solution that every hole adds 100 μ l room temperatures develops the color.Every hole adds TMB stop bath (0.09M H 2SO 4), stop the TMB reaction, and on the full-automatic microplate reader of BioRad, measure the absorbancy at 450nm place, signal is carried out quantitatively.
Incorporate Pfizer agent docket No.PC 11699 at this and be entitled as in " Inducible FocalAdhesion Kinase Cell Assay (inducibility focal adhesion kinase raji cell assay Raji) " other FAK raji cell assay Rajis as a reference.
One preferred embodiment in, measure the external activity that The compounds of this invention had by kinase assay, as described herein, less than 500nM.Preferably, the IC of compound in the kinase assays 50Less than 25nM, be more preferably less than 10nM.In further preferred embodiment, compound demonstrates IC in the mensuration based on the FAK cell 50, for example as described herein, less than 1 μ M, be more preferably less than 100nM, most preferably less than 25nM.
Further again, use the following ability that compound of the present invention suppresses osteoporosis mentioned above and/or low bone amount of estimating of measuring.
(1) testing compound is to not castration and ovariectomized female rats body weight, organization in old age Effect with bone density
This mensuration can be used for detecting in the female rats model of or spay (OVX) non-castrated in old age the effect of testing compound.
Research approach
The Sprague-Dawley female rats is carried out sham-operation or OVX when 18 monthly ages, one group of rat was put to death as baseline control at 0 day simultaneously.Performed the operation back 1 day, rat is handled with vehicle or testing compound.Twice of vehicle or testing compound subcutaneous injection administration weekly (s.c.) (Tuesday and Friday), the mean dose of testing compound administration are 10 milligrams of every kg body weight every day (10mg/kg/day).
(Sigma.St.Louis MO) carries out the fluorescence bone label to 2 and 12 days all rat skin lower injection 10mg/kg fluorexons before execution.Putting to death the same day, all rats are weighed under ketamine/xylazine anesthesia, and at the dual energy X-ray absorptiometry that the rat body scanning software is housed (DXA, QDR-4500/W.Hologic Inc., Waltham carries out fat-free and fatty body weight determination on MA).Rat is condemned to death, and dissects then, takes a blood sample by cardiac puncture.Every rat is analyzed distal femoral metaphysis and femoral shaft by peripheral bone quantitative computer layer scanning (pQCT), and measured cumulative volume bone, bone trabecula and cortex of bone mineral content and bone density.
Peripheral bone quantitative computer layer scanning (pQCT) is analyzed: (Fort Atkinson W1.) scans the pQCT X-line machine of the femur of excision by 5.40 version softwares are housed for Stratec XCT Research M, NorlandMedical Systems.In that the voxel with 0.1mm obtains metaphyseal 1 millimeter (mm) the thick square section of femur at 5.0mm (femur metaphysis near-end, main spongy bone position) and 13mm place (backbone, cortex bone position) from near-end from far-end.Selected cortex bone uses outline mode 2 and cortex pattern 4 to analyze.Outside threshold setting is 340mg/cm 3, in order to distinguish cortex bone shell and soft tissue, inboard threshold setting is 529mg/cm 3, in order to distinguish cortex bone along the cortex bone internal surface.Use separation mode 4 (peelmode 4) to measure bone trabecula, threshold value is 655mg/cm 3, to distinguish cortex (descending) bone and spongy bone.From selected spongy bone, additionally remove 1% with one heart, to guarantee from analyze, removing cortex (descending) bone.Bone trabecula and cortex bone are all measured volume, density and area (people such as Jamsa T., Bone 23:155-161,1998; Ke, people such as H.Z., Journal of Bone andMineral Research.16:765-773,2001).
Vagina tissue is learned: fixedly vagina tissue and embedding in paraffin.Downcut 5 microns sections, with alcian blue (Alcian Blule) dyeing.Vagina rose epithelial thickness and mucopolysaccharide (secretory cell) are carried out histological examination.
The experiment of experimental program is grouped as follows:
I group: baseline control
II group: sham-operation+vehicle
III group: OVX+ vehicle
IV group: OVX+10mg/kg/ days testing compound (in vehicle)
(2) union of fracture is measured
(a) behind the systemic administration to the mensuration of union of fracture effect
The fracture technology:3 monthly age Sprage-Dawley rats are used Patients Under Ketamine Anesthesia.The 1cm otch is made in preceding inboard at right side shin bone or femur proximal part.Hereinafter the shin bone surgical technic is described.The otch surface of bone that goes directly, at the tibial tuberosity near-end to far-end 4mm, inboard hole to 1 1mm of preceding ridge 2mm place brill.Stainless steel tube (maximum load 36.3N, maximum stiffness 61.8N/mm detect under the condition identical with bone) with 0.8mm carries out the intramedullary nail ligamentopexis.Not carrying out medullary space enlarges.Use specially designed adjustable jaws to cause the standard closure fracture by three-point bending 2mm on tibiofibula engages with blunt pawl.In order to reduce soft tissue injury as far as possible, note not making displacement fracture.With the closed skin of monofilament nylon suture.Operation is carried out under aseptic condition.After inserting intramedullary nail to all radiograpies immediately of fracturing, fracture outside the regulation backbone area or the rat of intramedullary nail displacement be excluded.Remaining animal be divided at random following several groups to detect the union of fracture situation, each has 10-12 animal in each grouping constantly.First group of every day raised vehicle with the buret of 1ml/ rat, and (water: 100% ethanol=95: 5), other group tube feed every day carried out 10,20,40 and 80 days with 0.01 to 100mg/kg/ day testing compound (1ml/ rat) always.
At the 10th, 20,40 and 80 day, every group a 10-12 rat was used Patients Under Ketamine Anesthesia, sacrificed by exsanguination.The both sides tibiofibula is removed in dissection, and peels off all soft tissues.The bone of every group of 5-6 rat is stored in and carries out histologic analysis in 70% ethanol, and the bone of every group of other 5-6 rat is stored in the buffering ringer's solution (+4 ℃, pH 7.4) and carries out radiograph, and carries out the biomechanics test.
Histologic analysis: the histologic analysis method of fractured bones was open by Mosekilde and Bak (The Effects of Growth Hormone on Fracture Healing in Rats:AHistological Description.Bone, 14:19-27,1993) in the past.In brief, astragalus broken line both sides 8mm is with under the fracture site saw, and undecalcified is embedded in the methyl methacrylate, is cut into the thick volume section (frontals section) of 8 μ m on Reichert-Jung Polycut slicing machine.In the painted volume of Ma Sensan look (masson-trichrome) section (comprising shin bone and fibula) be used for display process and when not handling to the cell and the tissue reaction of union of fracture.The painted section of Sirius red (siriusred) is used to prove the feature of poroma structure, and distinguishes woven bone and lamellar bone at fracture site.Carry out following measurement: (1) fracture face-measurement is as the shortest distance between the cortex bone end in the fracture, (2) poroma length and poroma diameter, (3) total bone volume in poroma zone, (4) osseous tissue of each tissue regions in the poroma zone, (5) cartilage area in the fibrous tissue in the poroma and (6) poroma.
Biomechanical analysis: the method for biomechanical analysis was open by Bak and Andreassen (The Effects of Aging on Fracture Healing in Rats.Calcif Tissue Int45:292-297,1989) in the past.In brief, before the biomechanics test, all fracture are carried out radiograph.The mechanical property of healing fracture is analyzed by destructiveness three or four-point bending method.Measure maximum load, rigidity, the energy of busy hour, the deflection and the maximum stress of busy hour.
(b) behind the topical to the mensuration of union of fracture effect
The fracture technology: the female or male beasle dog that in this research, uses about 2 ages of anesthesia.Cause cross-section property fracture of radius by the load that slowly continues with three-point bending, people's such as Lenehan article (Lenehan, T.M. seen in the description of this method; Balligand, M.; Nunamaker, D.M.; Wood, F.E.:Effects of EHDP on Fracture Healing in Dogs (EHDP is to the effect of dog union of fracture) .J Orthop Res 3:499-507; 1985).Wire is pulled through with the anatomical structure that guarantees bone destroyed fully from fracture site.Afterwards, carry by compound is slowly discharged in the part of fracture site prostaglandin agonists and to finish, the conveying of above-claimed cpd continued medication for 10,15 or 20 weeks by slow releasing tablet or with the dosage forms of compound such as pasty state gelating soln or suspension.
Histologic analysis: the histologic analysis method of fractured bones is in the past by people such as Peter (Peter, C.P.; Cook, W.O.; Nunamaker, D.M.; Provost, M.T.; Seedor, J.G; Rodan, G.A.Effects of alendronate on fracture healing and boneremodeling in dogs (diphosphonate is to the effect of dog union of fracture and remodeling) .J.Orthop.Res.14:74-70,1996) and Mosekilde and Bak (The Effects of GrowthHormone on Fracture Healing in Rats:A Histological Description (tethelin to the effect of fracture healing in rats: histology is described) .Bone.14:19-27,1993) open.In brief, after execution, saw fracture site down apart from every side seam broken line 3cm place, undecalcified is embedded in the methyl methacrylate, is cut into the thick volume section (frontals section) of 8 μ m on Reichert-Jung Polycut slicing machine.In the volume of the gloomy trichrome stain of horse section (comprising shin bone and fibula) be used for display process and when not handling to the cell and the tissue reaction of union of fracture.The section of Sirius red colouring is used for proving the feature of poroma structure, and distinguishes woven bone and lamellar bone at fracture site.Carry out following measurement: (1) fracture face-measurement is as the shortest distance between the cortex bone end in the fracture, (2) poroma length and poroma diameter, (3) total bone volume in poroma zone, (4) osseous tissue of each tissue regions in the poroma zone, (5) cartilage area in the fibrous tissue in the poroma and (6) poroma.
Biomechanical analysis: the method for biomechanical analysis is in the past by Bak and Andreassen (The Effects of Aging on Fracture Healing in Rats (old and feeble influence to fracture healing in rats) .Calcif Tissue Int 45:292-297,1989) and people (Peter, C.P. such as Peter; Cook, W.O.; Nunamaker, D.M.; Provost, M.T.; Seedor, J.G; Rodan, G.A.Effects of Alendronate On Fracture Healing And Bone Remodeling In Dogs (diphosphonate is to the effect of dog union of fracture and remodeling) .J.Orthop.Res.14:74-70,1996) open.In brief, before the biomechanics test, all fracture are carried out radiograph.The mechanical property of healing fracture is analyzed by destructiveness three or four-point bending method.Measure maximum load, rigidity, the energy of busy hour, the deflection and the maximum stress of busy hour.
The administration of The compounds of this invention (hereinafter being called " active compound ") can be undertaken by any method that can make compound be delivered to site of action.These methods comprise oral route, through intraduodenal route, parenteral injection (comprising in intravenously, subcutaneous, intramuscular, the blood vessel or infusion), part and rectal administration.
The dosage of active compound will depend on the seriousness of experimenter, disease or the state of an illness of being treated, the speed of administration, the processing of compound and prescription doctor's judgement.But effective dose is preferably about 1 to about 35mg/kg/ day, single or gradation administration in about 0.001 to about 100mg the scope of every kg body weight every day.For the people of 70kg, the scope of dosage can be about 0.05 to about 7g/ day, is preferably about 0.2 to about 2.5g/ day.In some cases, drug level under the lower bound of aforementioned range may be more suitable, simultaneously under other situation,, may use bigger and do not cause the dosage of any harmful side effect if these heavy dose ofly at first are divided into some low doses when natural gift administration several times.
Active compound can be used as single therapy and uses or have one or more other antitumorigenic substance to participate in, and for example is selected from following material: mitotic inhibitor, for example vinealeucoblastine(VLB); Alkylating agent, for example cis-platinum, carboplatin and endoxan; Metabolic antagonist, for example 5 FU 5 fluorouracil, cytosine(Cyt) cytosine arabinoside and hydroxyurea, perhaps, a kind of in the disclosed preferred metabolic antagonist in european patent application the 239362nd for example, as N-(5-[ N-(3,4-dihydro-2-methyl-4-oxo quinazoline-6-ylmethyl)-N-methylamino]-the 2-Threonyl)-L-L-glutamic acid; Growth factor receptor inhibitors; Cell cycle inhibitor; Embed microbiotic, for example Zorubicin and bleomycin; Enzyme, for example Interferon, rabbit; And hormone antagonist, for example estrogen antagonist such as Nolvadex (tamoxifen), or for example androgen antagonist such as Casodex (4 '-cyano group-3-(4-fluorophenyl alkylsulfonyl)-2-hydroxy-2-methyl-3 '-(trifluoromethyl) propionanilide).This combination therapy can by each component that will treat simultaneously, continuously or independently administration carry out.
Pharmaceutical composition can be, for example, be fit to oral administration formulation such as tablet, capsule, pill, powder, continue the formulation, solution, the suspension that discharge; The formulation such as sterile solution, suspension or the emulsion that are fit to the parenteral injection; The formulation such as ointment or the emulsifiable paste that are fit to topical; Or the form of suitable rectal administration such as suppository.Pharmaceutical composition can be to be fit to the unit dosage that single gives the accurate medication amount.Pharmaceutical composition comprise conventional pharmaceutical carrier or vehicle and as activeconstituents according to compound of the present invention.In addition, it can comprise other medical science or drug agents, carrier, adjuvant or the like.
The example of parenteral dosage forms comprises the solution or the suspension of the active compound in the aseptic aqueous solution (for example propylene glycol or D/W).If desired, these formulations can suitably cushion.
Suitable pharmaceutical carrier comprises inert diluent or weighting agent, water and multiple organic solvent.If desired, pharmaceutical composition can contain other composition, as seasonings, tackiness agent, vehicle and analogue.Therefore, for oral administration, contain multiple vehicle such as citric acid tablet can with multiple disintegrating agent such as starch, Lalgine and some composition silicate, use with tackiness agent such as sucrose, gelatin and gum arabic.In addition, lubricant is as being usually used in the tablet as Magnesium Stearate, Sodium Lauryl Sulphate BP/USP and talcum.The solids composition of similar type can also be used for soft hard filling type gelatine capsule.Its preferable material comprises lactose or toffee and high molecular weight polyethylene glycol.When oral administration needs aqueous suspension or elixir, active compound as herein described can rise with multiple sweeting agent or seasonings, tinting material or dyestuff amalgamation, if desired, can also with emulsifying agent or suspension agent, and thinner such as water, ethanol, propylene glycol, glycerine or its combination mix.
Various preparation of drug combination methods with specified quantitative active compound are that this area professional and technical personnel is known or conspicuous.For example, referring to Remington ' s Pharmaceutical Sciences.Mack Publishing Company, Easter, Pa., the 15th edition (1975).
Embodiment that below provides and preparation have further specified with illustration compound of the present invention, and the preparation method of these compounds.Should be understood that scope of the present invention is limited by the scope of the following example and preparation embodiment never in any form.In the following example, unless stated otherwise, the molecule with single chiral centre exists with the form of racemic mixture.Unless stated otherwise, the molecule with two or more chiral centres exists with the form of diastereomer racemic mixture.Single enantiomer/diastereomer can obtain by the known method of this area professional and technical personnel.
When mentioning the HPLC chromatogram among following preparation embodiment and the embodiment, unless stated otherwise, employed general conditions is as follows.The post that uses is the ZORBAX of distance 150mm, internal diameter 4.6mm TMRXC18 post (Hewlett Packard manufacturing).Sample moves in the HewlettPackard-1100 system.Use the gradient solvent method, running is 10 minutes from 100% ammonium acetate/acetate buffer (0.2M) to 100% acetonitrile.System uses 100% acetonitrile to proceed flush cycle 1.5 minutes then, then with 100% buffered soln operation 3 minutes.Constant flow rate during this period is 3mL/ minute.
Embodiment
Logical method:
Preparation 5-nitro-oxyindole:
In the solution of the 100mL vitriol oil, dropwise adding nitrosonitric acid (8.4mL) to oxyindole (26g) under-15 ℃.Attention remains on temperature of reaction-15 ℃.After adding finishes, will react and stir 30 minutes, pour in the frozen water then.Formed yellow mercury oxide,, obtained the 5-nitro oxyindole of 34g (98%) by filtering separation.
Preparation 5-oxygen base-oxyindole (2):
Add 10%Pd/C (0.5g) in 5-nitro-oxyindole (25g) in the Parr bottle/120mL dimethylamino acetyl amine aqueous solution.With mixture hydrogenation (40 psi H2) 16 hours.Filter and remove catalyzer, filtrate obtains 5-amino-oxyindole (10.5g with ether (2L) dilution; 50%).
Preparation 2,4-two chloro-5-trifluoromethyl pyrimidines (3):
With 5-trifluoromethyl uridylic (250g, 1.39mol) and Phosphorus Oxychloride (655mL, 6.94mol, 5 equivalents) put in the 3L 4 neck flasks that cantilever stirrer, reflux exchanger, dropping funnel and internal heat galvanic couple are housed.When being added in the slurry, content remains in the nitrogen in batches, produces appropriate heat release with strong phosphoric acid (85wt%, 9.5mL, 0.1 equivalent).Dropwise added diisopropylethylamine (245mL, 1.39mol, 1 equivalent) then in 15 minutes, in this speed, the internal temperature that adds reaction when finishing reaches 85-90 ℃.When adding the amine end, reaction mixture is the light orange solution of homogeneous.Begin heating, orange solution kept 20 hours at 100 ℃, and this moment, the HPLC analysis revealed starting raw material of reaction mixture was consumed.Remove indirect heating, make the content of flask be cooled to 40 ℃, in the refrigerative mixture, dropwise add 3N HCI (5L, 10 equivalents) and diethyl ether (2L) then, the temperature of the bottle that quenches is remained between 10 and 15 ℃.Separating mixture becomes multilayer, and the waterbearing stratum is extracted 1 time with ether (1L).Organic layer is merged, and the water flushing is neutral (5 * 1.5L flushing) until the flushing thing, uses MgSO 4Drying also concentrates, and obtains the pale yellow-orange oil (HPLC) of 288g (productive rate 95%) purity 96%.This material is further by distillation purifying (109 ℃ of bp/79mmHg).
Preparation 5-(4-chloro-5-trifluoromethyl-pyrimidine-2--amino)-1,3-dihydro-indol-2-one (4):
To 5-trifluoromethyl-2,4-dichloro pyrimidine (214.8g; 0.921mol) 1: 1M ethereal solution (1 equivalent that adds zinc chloride in the solution among the 1DCE/tBuOH (1.240L); 0.921L).0.5 after hour, add 5-amino-oxyindole (124g; 0.837mol), add triethylamine (129.4ml then; 0.921mol), temperature is remained on 25 ℃.Reaction is at room temperature stirred and is spent the night, and concentrates then, and the product that grinds out from methyl alcohol is yellow solid (224.3g; 82%). 1H NMR(DMSO-d 6，400MHz)，δ3.29(s，2H)，6.76(d，J＝7.9Hz，2H)，7.39(d，J＝8.3Hz)，7.51(br s，1H)，8.71(s，1H)，10.33(s，1H)，10.49(s，1H)。 13C NMR (DMSO-d 6, 100MHz), δ 177.0,161.3.158.7 (br) .140.7,132.8,126.9,123.7 (q, J=268Hz), 121.0,118.7,111.2 (q, J=32Hz), 109.6,36.7; HPLC retention time: 5.759min.LRMS(M +)329.1，331.1。
Embodiment 1
5-[4-(R-1-phenyl-ethylamino)-5-trifluoromethyl-pyrimidine-2--amino]-1.3-dihydro-indoles-2- Ketone
To 1: 1DCE/t-BuOH alcohol (ratio 1: 1,4mL) and 5-(4-chloro-5-trifluoromethyl-pyrimidine-2--amino)-1,3-dihydro-indol-2-one (0.15g; 0.456mmole) solution in add  (+) α phenylethylamine (0.071mL; 0.547mmole) and diisopropyl ethamine (0.081mL, 0.456mmole).The solution that obtains stirs under nitrogen, and be heated to 80 ℃ 16 hours.Reaction is cooled to room temperature, and 1: 1 mixture diluted with about 10mL methylene dichloride and methyl alcohol adds 0.5g MP-carbonic ether then.The mixture that obtains is stirred, filter, concentrate, by silica gel chromatography purifying (ratio of chloroform/methanol/dense ammonium hydroxide is 97: 2.8: 0.3).Obtain the required title compound (0.021g of white solid; 11%).HPLC retention time: 6.46min.LRMS(M +)413.4。
Following compounds of the present invention can prepare by as shown in Example 1 chloropyrimide (4) being heated with suitable amine.The amine that uses in a little reactions can be buied, and uses according to the using method of standard, and perhaps the common synthetic method of the amine of being understood by territory, this area professional and technical personnel alternatively in addition is prepared.Unless stated otherwise, the compound with chiral centre is made racemic mixture.
Table 1 passes through the compound of the method preparation of embodiment 1:
The compound title HPLC retention time (min) MS data (M+H)
(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for N-(1-methyl isophthalic acid-phenyl-ethyl)-3-{[2-]-methyl }-benzsulfamide 6.46 597.5
(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 3-{[2-]-methyl }-benzsulfamide 4.87 479.1
5-{4-[3-(three fluoro-methylsulfonyls)-benzylamino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one 6.35 532.1
5-{4-[(piperidines-3-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2-base is amino }-1, the 3-dihydro-indol-2-one 3.74 407.3
5-{4-[(1-methylsulfonyl-piperidines-3-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one 5.21 485.2
N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 3-[2-]-methyl }-phenyl)-Toluidrin 5.22 493.3
3-oxo-3-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 3-{[2-]-methyl }-piperidines-1-yl }-propionitrile 4.92 474.3
5-{4-[3-(1,1-dioxo-1N 6-isothiazolidine-2-yl)-propyl group amino]-5-trifluoromethyl-pyrimidine-2--amino }-1,3-dihydro-indoles-2-ketone 4.89 471.1
5-[4-(2-methyl-butyl amino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one 6.53 380.3
5-{4-[(1-methylsulfonyl-piperidines-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one 5.17 485.3
(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for N-{2-[2-]-ethyl }-Toluidrin 4.38 431.2
(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for N-{4-[2-]-butyl }-Toluidrin 4.78 459.3
5-{4-[(1-methylsulfonyl-piperidin-4-yl methyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one 5.22 485.3
(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for N-methyl-N-{2-[2-]-ethyl }-Toluidrin 4.81 445.1
(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for methylsulfonic acid 3-{[2-]-methyl }-phenyl ester 5.67 494.1
(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for N-{3-[2-]-propyl group }-Toluidrin 4.58 445.1
The compound title HPLC retention time (min) MS data (M+H)
5-{4-[(4-methylsulfonyl-morpholine-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one 4.87 487.2
N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 4-fluoro-3-{[2-]-methyl }-phenyl)-Toluidrin 5.29 511.1
5-{4-[(5-oxo-morpholine-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one 4.12 423.3
N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 4-methoxyl group-3-{[2-]-methyl }-phenyl)-Toluidrin 5.38 523.2
N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 4-methyl-3-{[2-]-methyl }-phenyl)-Toluidrin 5.30 507.2
5-[4-(3-methylsulfonyl methyl-benzylamino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one 5.14 492.2
5-{4-[(4-trifluoroacetyl group-morpholine-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one 5.64 505.1
5-{4-[(1-methylsulfonyl-azetidine-3-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1,3-dihydro-indoles-2- 4.76 457.2
Ketone
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 4-methyl-3-{[2-]-methyl }-phenyl }-Toluidrin 6.66 521.3
5-{4-[(1-methylsulfonyl-tetramethyleneimine-3-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one 4.97 471.2
N-methyl-N-{3-[2-(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-yl]-propyl group }-Toluidrin 5.02 459.2
5-{4-[2-(1-methylsulfonyl-piperidines-2-yl)-ethylamino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one 5.71 499.4
5-{4-[(4-methylsulfonyl-pyridine-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one 4.68 479.1
{ 2,2-dimethyl-3-[2-(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-yl]-propyl group }-t-butyl carbamate 7.01 495.0
5-[4-(3-isopropoxy-propyl group amino)-5-trifluoromethyl-pyrimidine-2-base is amino]-1, the 3-dihydro-indol-2-one 6.27 410.4
5-{4-[(1-methyl-piperidines-3-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one 3.71 421.0
5-{4-[(tetrahydrochysene-pyrans-4-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one 5.16 408.3
The compound title HPLC retention time (min) MS data (M+H)
5-[4-(2-ethyl-butyl amino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one 6.95 394.3
5-{4-[(tetrahydrochysene-furans-2R-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one 5.30 394.3
5-{4-[(tetrahydrochysene-furans-2S-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one 5.30 394.3
5-{4-[(5-methyl-furans-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one 5.98 404.2
5-{4-[(1-methylsulfonyl-tetramethyleneimine-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one 5.08 471.3
5-{4-[(diamantane-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one 7.89 458.3
5-{4-[(diamantane-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one 5.20 473.3
5-[4-(2-methoxyl group-2-methyl-propyl group amino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one 5.87 396.3
-two rings [2.2.1] heptan in the 5-{4-[(-5-alkene-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one 6.74 416.3
((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 3-{[2-]-methyl }-benzyl)-dimethyl phosphonate 5.03 522.2
5-[4-(3-methyl-butyl amino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one 6.87 380.2
5-{4-[(2-hydroxyl-cyclohexyl methyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one 6.66 422.2
N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 4-methoxyl group-3-{[2-]-methyl }-phenyl)-N-methyl-Toluidrin 5.69 537.2
5-{4-[(4-ethylsulfonyl-morpholine-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one 5.11 501.3
5-(4-{[4-(third-2-alkylsulfonyl)-morpholine-2-ylmethyl]-amino }-5-trifluoromethyl-pyrimidine-2--amino)-1, the 3-dihydro-indol-2-one 5.35 515.2
5-{4-[(4-ethanoyl-morpholine-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one 4.43 451.2
5-{4-[(4-propionyl-morpholine-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one 4.74 465.2
HPLC MS
The compound title Retention time (min) Data (M+H)
(4-{[(4-(2 for 5-; 2-dimethyl-propionyl)-morpholine-2-ylmethyl]-amino }-5-trifluoromethyl-pyrimidine-2--amino)-1,3-dihydro-indoles-2-ketone 5.43 493.2
(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 2-{[2-]-methyl }-morpholine-4-carboxylate methyl ester 5.04 467.2
5-{4-[(4-methoxy ethanoyl-morpholine-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one 4.44 481.2
5-[4-(3-ethylsulfonyl-benzylamino)-5-trifluoromethyl-pyrimidine-2-base is amino]-1, the 3-dihydro-indol-2-one 5.36 492.3
5-{4-[(4-methylsulfonyl-morpholine-2 R-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one 4.84 487.3
5-{4-[(4-methylsulfonyl-morpholine-2 S-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one 4.86 487.3
5-{4-[(pyrimidine-2-base methyl)-amino]-5-trifluoromethyl-pyrimidine-2-base is amino }-1, the 3-dihydro-indol-2-one 4.53 402.3
5-{4-[(pyrazine-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2-base is amino }-1, the 3-dihydro-indol-2-one 4.42 402.1
N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 4-fluoro-3-{[2-]-methyl }-phenyl)-N-methyl-Toluidrin 5.55 523.3
5-{4-[(1-methylsulfonyl-piperidines-3-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one 5.17 485.3
5-{4-[(4-isobutyryl-morpholine-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one 5.03 479.2
5-[4-(3,3-dimethyl-2-oxo-butyl amino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one 6.00 408.2
5-[4-(1,2-dimethyl-propyl group amino)-5-trifluoromethyl-pyrimidine-2-base is amino]-1, the 3-dihydro-indol-2-one 6.65 380.3
5-[4-(2-methoxyl group-1-methyl-ethylamino)-5-trifluoromethyl-phonetic 5.57 382.3
Pyridine-2-base is amino]-1, the 3-dihydro-indol-2-one
5-{4-[(2-(1,1-dioxo-1D 6-isothiazolidine-2-yl) ethylamino]-5-trifluoromethyl-pyrimidine-2--amino }-1,3-dihydro-indoles-2-ketone 4.59 457.3
5-[4-(3-methylamino-propyl group amino)-5-trifluoromethyl-pyrimidine-2-base is amino]-1, the 3-dihydro-indol-2-one 3.47 381.3
5-{4-[(pyridin-3-yl methyl)-amino]-5-trifluoromethyl-pyrimidine-2-base is amino }-1, the 3-dihydro-indol-2-one 4.62 401.3
The compound title HPLC retention time (min) MS data (M+H)
5-{4-[(6-methylsulfonyl-pyridine-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one 4.89 479.3
5-{4-[3-(1,1-dioxo-1,1,6-isothiazolidine-2-yl)-benzylamino]-5-trifluoromethyl-pyrimidine-2--amino }-1,3-dihydro-indoles-2-ketone 5.45 519.2
5-[4-(1R-phenyl-ethylamino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one 6.42 414.4
5-(4-sec.-propyl amino-5-trifluoromethyl-pyrimidine-2--amino)-1, the 3-dihydro-indol-2-one 5.84 352.2
5-(4R-sec-butyl amino-5-trifluoromethyl-pyrimidine-2--amino)-1, the 3-dihydro-indol-2-one 6.22， 366.2
5-(4S-sec-butyl amino-5-trifluoromethyl-pyrimidine-2--amino)-1, the 3-dihydro-indol-2-one 6.23 366.2
5-[4-(2-methylamino-ethylamino)-5-trifluoromethyl-pyrimidine-2-base is amino]-1, the 3-dihydro-indol-2-one 3.29 367.3
5-[4-(1S-phenyl-ethylamino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one 6.42 414.3
5-{4-[(2-methylsulfonyl-thiazole-4-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one 4.72 499.3
5-(4-propyl group amino-5-trifluoromethyl-pyrimidine-2--amino)-1,3-two 5.91 352.2
Hydrogen-indol-2-one
5-[4-(2-hydroxyl-1-methyl-ethylamino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one 4.49 368.2
5-[4-(1-methylol-propyl group amino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one 4.85 382.2
5-{4-[(5-methylsulfonyl-pyridin-3-yl methyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one 4.55 479.4
5-{4-[(pyridin-4-yl methyl)-amino]-5-trifluoromethyl-pyrimidine-2-base is amino }-1, the 3-dihydro-indol-2-one 4.49 401.2
5-[4-(1,3-dimethyl-butyl amino)-5-trifluoromethyl-pyrimidine-2-base is amino]-1, the 3-dihydro-indol-2-one 6.99 394.3
(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for N-sec.-propyl-N-{3-[2-]-propyl group }-Toluidrin 5.12 487.3
5-[4-(1S-methylol-2-methyl-propyl group amino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one 5.23 396.3
(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for N-cyclohexyl-N-{3-[2-]-propyl group }-Toluidrin 6.24 527.2
5-[4-(1,2,3,4-tetrahydrochysene-naphthalene-1-base is amino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one 440.4 7.17
The compound title HPLC retention time (min) MS data (M+H)
5-{4-[(1-methylsulfonyl-tetramethyleneimine-2S-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one 5.07 471.2
5-{4-[(3-methyl-thiophene-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one 6.18 420.4
5-{4-[(1-methylsulfonyl-tetramethyleneimine-3R-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one 4.95 471.2
5-[4-(2-hydroxyl-1S-phenyl-ethylamino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one 5.28 430.3
5-[4-(2-hydroxyl-1S-methyl-ethylamino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one 4.49 368.3
5-[4-(1R-methylol-propyl group amino)-5-trifluoromethyl-pyrimidine-2-base is amino]-1, the 3-dihydro-indol-2-one 4.85 382.2
5-[4-(1-pyrimidine-4-base-ethylamino)-5-trifluoromethyl-pyrimidine-2-base is amino]-1, the 3-dihydro-indol-2-one 4.84 416.3
5-[4-(1,1-dioxo-tetrahydrochysene-1-thiene-3-yl-amino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one 4.67 426.3
5-{4-[(1H-imidazoles-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one 3.27 390.3
5-[4-(2-piperidines-2-base-ethylamino)-5-trifluoromethyl-pyrimidine-2-base is amino]-1, the 3-dihydro-indol-2-one 3.79 421.4
5-[4-(isobutyl--methyl-amino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one 6.82 380.3
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 3-{[2-]-methyl }-phenyl)-Toluidrin 5.49 507.4
N-ethyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 3-{[2-]-methyl }-phenyl)-Toluidrin 5.67 521.3
5-[4-(2-methylsulfonyl-benzylamino)-5-trifluoromethyl-pyrimidine-2-base is amino]-1, the 3-dihydro-indol-2-one 5.47 478.2
N-sec.-propyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 3-{[2-]-methyl }-phenyl)-Toluidrin 5.81 535.3
5-{4-[(3,4,5,6-tetrahydrochysene-2H-[1,2 '] dipyridyl-3-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1,3-dihydro-indoles-2-ketone 5.79 484.3
5-{4-[(1-pyrimidine-2-base-piperidines-3-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one 6.17 485.3
The compound title HPLC retention time (min) MS data (M+H)
5-{4-[(2R-(1-methylsulfonyl-piperidines-2-yl)-ethylamino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one 5.70 499.4
5-{4-[(2S-(1-methylsulfonyl-piperidines-2-yl)-ethylamino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one 5.70 499.4
5-{4-[(3-methyl sulfane base-propyl group amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one 5.83 398.2
5-{4-[(1S-methylol-3-methyl sulfane base-propyl group amino)-and 5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one 5.02 428.2
5-[4-(2-hydroxyl-1R-methyl-ethylamino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one 4.49 368.3
5-[4-(1R-methylol-2-methyl-propyl group amino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one 5.23 396.4
(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for N-ethyl-N-{3-[2-]-propyl group }-Toluidrin 5.31 473.3
5-{4-[(1-methylsulfonyl-tetramethyleneimine-3R-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one 4.94 471.4
5-[4-(1S-methylol-propyl group amino)-5-trifluoromethyl-pyrimidine-2-base is amino]-1, the 3-dihydro-indol-2-one 4.86 382.3
5-[4-(3,5-dinitrobenzene-benzylamino)-5-trifluoromethyl-pyrimidine-2-base is amino]-1, the 3-dihydro-indol-2-one 6.04 490.1
N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 2-{[2-]-methyl }-phenyl)-Toluidrin 5.84 493.1
(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for N-sec.-propyl-N-{2-[2-]-ethyl }-Toluidrin 5.37 473.3
5-[4-(2-hydroxyl-1-phenyl-ethylamino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one 5.29 430.3
5-[4-(1R-methylol-3-methyl-butyl amino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one 5.59 410.4
5-[4-(1S-methylol-3-methyl-butyl amino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one 5.59 410.4
5-{4-[(1-methylsulfonyl-piperidines-2S-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one 5.16 485.3
5-{4-[(1-methylsulfonyl-tetramethyleneimine-2R-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one 5.08 471.3
The compound title HPLC retention time (min) MS data (M+H)
5-[4-(methyl-pyridine-2-ylmethyl-amino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one 5.37 415.3
5-{4-[(3-methylsulfonyl-benzyl)-methyl-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one 5.66 492.3
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 2-{[2-]-methyl }-phenyl)-Toluidrin 5.63 507.3
5-[4-(methyl-pyridin-3-yl methyl-amino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one 5.25 415.4
5-{4-[(1-methylsulfonyl-piperidines-3-ylmethyl)-methyl-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one 5.69 499.4
5-[4-(methyl-pyridin-4-yl methyl-amino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one 5.12 415.3
5-(4-cyclopentyl amino-5-trifluoromethyl-pyrimidine-2--amino)-1, the 3-dihydro-indol-2-one 6.47 378.3
5-[4-(2,6-dimethoxy-benzylamino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one 6.78 460.3
5-{4-[(1,5-dimethyl-1H-pyrazole-3-yl methyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one 4.99 418.3
5-[4-(2-imidazoles-1-base-ethylamino)-5-trifluoromethyl-pyrimidine-2-base is amino]-1, the 3-dihydro-indol-2-one 3.58 404.2
5-{4-[(pyridine-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2-base is amino }-1, the 3-dihydro-indol-2-one 4.95 401.4
5-[5-trifluoromethyl-4-(2-trifluoromethyl-benzylamino)-pyrimidine-2-base is amino]-1, the 3-dihydro-indol-2-one 6.57 468.2
5-{4-[(3-methyl-pyridine-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one 6.07 415.3
5-[4-(3-methylsulfonyl-benzylamino)-5-trifluoromethyl-pyrimidine-2-base is amino]-1, the 3-dihydro-indol-2-one 5.16 478.2
5-{4-[(2-(1-ethanoyl-piperidines-2-yl)-ethylamino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one 5.22 463.4
5-{4-[2-(1-propionyl-piperidines-2-yl)-ethylamino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one 5.65 477.4
5-{4-[2-(1-cyclopropane carbonyl-piperidines-2-yl)-ethylamino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one 5.86 489.4
The compound title HPLC retention time (min) MS data (M+H)
5-{4-[2-(1-isobutyryl-piperidines-2-yl)-ethylamino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one 6.07 491.3
5-{4-[2-(1-butyryl radicals-piperidines-2-yl)-ethylamino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one 5.99 491.4
5-{4-[2-(1-methoxyl group ethanoyl-piperidines-2-yl)-ethylamino]-5-trifluoromethyl-pyrimidine-2--amino }-1,3-dihydro-indoles-2-ketone 5.19 493.4
5-{4-[2-(1-tetramethylene carbonyl-piperidines-2-yl)-ethylamino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one 6.31 503.4
(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for N-methyl-N-{3-[2-]-propyl group }-ethanamide 4.47 423.3
(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for N-methyl-N-{3-[2-]-propyl group }-propionic acid amide 4.89 437.45
The cyclopropane carboxylic acid acid methyl-(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 3-[2-]-propyl group }-acid amides 5.07 449.3
(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for N-methyl-N-{3-[2-]-propyl group }-isobutyramide 5.24 451.3
(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for N-methyl-N-{3-[2-]-propyl group }-butyramide 5.25 451.4
(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine 4-base is amino for 2-methoxyl group-N-methyl-N-{3-[2-]-propyl group }-ethanamide 4.47 453.3
The cyclobutane-carboxylic acid methyl-(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 3-[2-]-propyl group }-acid amides 5.48 463.4
2,2, (2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for N-trimethylammonium-N-{3-[2-]-propyl group }-propionic acid amide 5.80 465.3
2, (2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for N-dimethyl-N-{3-[2-]-propyl group }-butyramide 5.55 465.3
(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for N-methyl-N-{3-[2-]-propyl group }-benzamide 5.38 485.3
Isoxazole-5-carboxylic acid methyl-(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 3-[2-]-propyl group }-acid amides 4.91 476.2
Morpholine-4-carboxylic acid methyl-(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 3-[2-]-propyl group }-acid amides 4.78 494.3
The ethyl sulfonic acid methyl-(2-oxo-2,3-dihydro-1 H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 3-[2-]-propyl group }-acid amides 5.29 473.3
The compound title HPLC retention time (min) MS data (M+H)
Propane-1-sulfonic acid methyl-(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 3-[2-]-propyl group }-acid amides 5.71 487.3
1,1, the 3-trimethylammonium-(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 3-[2-]-propyl group }-sulfonylurea 5.53 488.3
2,2, (2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 2-three fluoro-N-methyl-N-{3-[2-]-propyl group }-ethanamide 5.80 477.2
(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for N-methyl-N-{2-[2-]-ethyl }-ethanamide 4.23 409.2
(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for N-methyl-N-{2-[2-]-ethyl }-propionic acid amide 4.61 423.2
The cyclopropane carboxylic acid acid methyl-(2-oxo-2,3-dihydro-1 H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 2-[2-]-ethyl }-acid amides 4.77 435.2
(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for N-methyl-N-{2-[2-]-ethyl }-isobutyramide 4.94 437.2
(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for N-methyl-N-{2-[2-]-ethyl }-butyramide 4.95 437.2
(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 2-methoxyl group-N-methyl-N-{2-[2-]-second 4.21 439.2
Base }-ethanamide
The cyclobutane-carboxylic acid methyl-(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 2-[2-]-ethyl }-acid amides 5.17 449.3
2,2, (2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for N-trimethylammonium-N-{2-[2-]-ethyl }-propionic acid amide 5.57 451.4
2, (2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for N-dimethyl-N-{2-[2-]-ethyl }-butyramide 5.26 451.4
(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for N-methyl-N-{2-[2-]-ethyl }-benzamide 4.80 471.3
Isoxazole-5-carboxylic acid methyl-(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 2-[2-]-ethyl }-acid amides 4.51 462.3
Morpholine-4-carboxylic acid methyl-(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 2-[2-]-ethyl }-acid amides 4.41 480.3
(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for N-methyl-N-{2-[2-]-ethyl }-Toluidrin 4.77 445.1
The ethyl sulfonic acid methyl-(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 2-[2-]-ethyl }-acid amides 5.03 459.2
The compound title HPLC retention time (min) MS data (M+H)
Third-1-sulfonic acid methyl-(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 2-[2-]-ethyl }-acid amides 5.44 473.3
1,1,3-trimethylammonium-3-{2-[2-(2-oxo-2,3-dihydro-1H-indoles 5.49 474.2
-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino]-ethyl }-sulfonylurea
2,2, (2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 2-three fluoro-N-methyl-N-{2-[2-]-ethyl }-ethanamide 5.49 463.2
5-[4-(2-hydroxyl-ethylamino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one 4.05 354.3
5-(4-cyclopropyl amino-5-trifluoromethyl-pyrimidine-2--amino)-1, the 3-dihydro-indol-2-one 5.41 350.3
5-(4-cyclobutyl amino-5-trifluoromethyl-pyrimidine-2--amino)-1, the 3-dihydro-indol-2-one 6.01 364.3
5-[4-(1,4-dimethyl-amyl group amino)-5-trifluoromethyl-pyrimidine-2-base is amino]-1, the 3-dihydro-indol-2-one 7.45 408.4
5-[4-(3-imidazoles-1-base-propyl group amino)-5-trifluoromethyl-pyrimidine-2-base is amino]-1, the 3-dihydro-indol-2-one 3.77 418.3
5-[4-(2-phenoxy group-ethylamino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one 6.34 430.3
5-[4-(1-cyclohexyl-ethylamino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one 7.61 420.4
5-[4-(1-hydroxymethyl-2,2-dimethyl-propyl group amino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one 5.64 410.4
5-[4-(1-methoxymethyl-propyl group amino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one 5.96 396.3
5-[4-(indane-2-base is amino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one 6.78 426.4
5-[4-(1,2,3,4-tetrahydrochysene-naphthalene-1-base is amino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one 7.16 440.3
5-(4-suberyl amino-5-trifluoromethyl-pyrimidine-2--amino)-1, the 3-dihydro-indol-2-one 7.21 406.3
5-{4-[2-(2-oxo-imidazolidine-1-yl)-ethylamino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one 4.04 422.3
(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 4-[2-]-ethyl butyrate 5.65 424.2
5-[4-(2-hydroxyl-1-hydroxymethyl-ethylamino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one 3.72 384.2
5-[4-(3-hydroxyl-2,2-dimethyl-propyl group amino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one 5.09 396.3
The compound title HPLC retention time (min) MS data (M+H)
5-{4-[(isochroman base-1-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one 6.36 456.3
5-[4-(4-hydroxyl-1,1-dioxo-tetrahydrochysene-1﹠-thiene-3-yl-amino)-and 5-trifluoromethyl-pyrimidine-2--amino]-1,3-dihydro-indoles-2-ketone 4.42 442.2
5-[4-(2-methoxyl group-1-methyl-ethylamino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one 5.58 382.3
5-[4-(trans-4-methyl sulfane base-tetrahydrochysene-furans-3-base is amino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one 5.37 426.3
5-{4-[is trans-2-(pyrimidine-2-base sulfane base)-cyclopentyl amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one 6.32 488.3
5-[4-(indane-1-base is amino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one 6.86 426.3
5-{4-[2-(2-hydroxyl-ethyl sulfane base)-ethylamino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one 4.66 414.3
5-{4-[2-(pyridin-3-yl oxygen base)-propyl group amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one 5.20 445.3
5-{4-[2-(6-methyl-pyridine-2-yl)-ethylamino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one 5.00 429.3
5-{4-[(2,3-dihydro-benzo [1,4] dioxine-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1,3-dihydro-indoles-2-ketone 5.01 458.2
5-{4-[(1-methyl isophthalic acid H-pyrazoles-4-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one 4.60 404.3
5-{4-[(4,5,6,7-tetrahydrochysene-benzothiazole base-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1,3-dihydro-indoles-2-ketone 5.93 461.2
5-[4-(1-phenyl-3-[1,2,4] triazol-1-yl-propyl group amino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one 5.24 495.2
5-(4-isobutylamino-5-trifluoromethyl-pyrimidine-2--amino)-1, the 3-dihydro-indol-2-one 6.12 366.4
5-[4-(2-cyclohexyl-1-methylol-ethylamino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one 6.41 450.4
(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 2-[2-]-methyl propionate 5.26 396.3
5-(4-cyclohexyl amino-5-trifluoromethyl-pyrimidine-2--amino)-1, the 3-dihydro-indol-2-one 6.82 392.3
5-[4-(3-hydroxyl-propyl group amino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one 4.24 368.3
The compound title HPLC retention time (min) MS data (M+H)
5-{4-[(2-methyl isophthalic acid H-imidazoles-2-yl)-ethylamino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one 3.54 418.3
5-[4-(tetrahydrochysene-furans-3-base is amino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one 4.89 380.3
5-[4-(bicyclic methyl propyl-amino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one 6.59 404.3
5-{4-[2-(5-methyl-4H-[1,2,4] triazole-3-yl)-ethylamino]-5-trifluoromethyl-pyrimidine-2--amino }-1,3-dihydro-indoles-2-ketone 4.00 419.3
5-[4-(2-ethyl sulfane base-ethylamino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one 5.99 398.3
5-[4-(2-phenoxy group-propyl group amino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one 6.57 444.2
5-{4-[(1-ethyl-5-oxo-tetramethyleneimine-3-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one 4.57 435.2
5-(4-{[1-(2-methoxyl group-ethyl)-5-oxo-tetramethyleneimine-3-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1,3-dihydro-indol-2-one 4.44 465.2
5-[4-(diphenyl-methyl-amino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one 7.26 476.2
5-{4-[2-(1-methyl isophthalic acid H-pyrazoles-4-yl)-ethylamino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one 4.90 418.3
5-{4-[(4-methyl isophthalic acid H-imidazoles-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one 3.40 404.2
5-{4-[(5-cyclopropyl-1H-pyrazole-3-yl methyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one 5.00 430.2
5-{4-[2-(the 4-methyl-thiazole-5-yl)-ethylamino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one 5.18 435.2
5-{4-[2-(the 1H-benzimidazolyl-2 radicals-yl)-ethylamino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one 4.39 454.2
The 5-{4-[(5-methyl-[1,3,4] oxadiazole-2-ylmethyls)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one 4.25 406.3
5-{4-[(5-phenyl-4H-[1,2,4] triazole-3-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one 4.92 467.3
5-{4-[(1H-indoles-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one 6.10 439.3
The compound title HPLC retention time (min) MS data (M+H)
5-{4-[(1,5-dimethyl-1H-pyrazoles-4-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one 4.77 418.3
5-{4-[(benzothiazole-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one 5.77 457.2
5-{4-[(3-methyl-isoxazole-5-base methyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one 5.02 405.3
5-{4-[(4-methyl-thiazol-2-yl methyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one 5.12 421.2
5-{4-[1-(4-methyl-thiazol-2-yl)-ethylamino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one 5.62 435.2
5-{5-trifluoromethyl-4-[(1,3,5-trimethylammonium-1H-pyrazoles-4-ylmethyl)-amino]-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one 4.95 432.2
5-{4-[1-(2-methyl-thiazole-4-yl)-ethylamino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one 5.69 435.3
5-{4-[(3-methyl-imidazo [2,1-b] thiazole-6-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1,3-dihydro-indoles-2-ketone 5.03 460.3
5-{4-[1-(5-methyl-4H-[1,2,4] triazole-3-yl)-ethylamino]-5-trifluoromethyl-pyrimidine-2--amino }-1,3-dihydro-indoles-2-ketone 4.20 419.3
5-{4-[1-(3,5-dimethyl-1H-pyrazoles-4-yl)-ethylamino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one 5.02 432.3
5-{4-[2-(3,5-dimethyl-1H-pyrazoles-4-yl)-ethylamino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one 4.85 432.4
5-{4-[2-(4,6-dimethyl-pyrimidine-2-base)-ethylamino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one 5.17 444.4
5-{4-[2-(4-methyl-5,6,7,8-tetrahydrochysene-quinazoline-2-yl)-ethylamino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one 5.88 484.4
5-[4-(2-thiazole-4-base-ethylamino)-5-trifluoromethyl-pyrimidine-2-base is amino]-1, the 3-dihydro-indol-2-one 5.18 421.3
5-(4-dimethylamino-5-trifluoromethyl-pyrimidine-2--amino)-1, the 3-dihydro-indol-2-one 5.60 338.3
5-{4-[(1-pyrimidine-2-base-piperidines-3-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one 6.17 485.4
5-[4-(indane-1-base is amino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one 6.85 426.3
The compound title HPLC retention time (min) LRMS (MH+)
N-methyl-N-{3-[({ methyl-[2-(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-yl]-amino })-methyl]-phenyl }-Toluidrin 6.08 521.3
N-methyl-N-{4-methyl-3-[({ methyl-[2-(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-yl]-amino })-methyl]-phenyl }-Toluidrin 6.24 535.8
N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 5-methyl-2-{[2-]-methyl }-phenyl)-Toluidrin 6.23 507.2
N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 3-methyl-2-{[2-]-methyl }-phenyl)-Toluidrin 6.28 507.2
N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 4-methyl-2-{[2-]-methyl }-phenyl)-Toluidrin 6.12 507.3
N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 2-methyl-6-{[2-]-methyl }-phenyl)-Toluidrin 5.71 507.3
5-[4-(3-methylsulfonyl-propyl group amino)-5-trifluoromethyl-pyrimidine-2-base is amino]-1, the 3-dihydro-indol-2-one 4.42 430.4
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 5-methyl-2-{[2-]-methyl }-phenyl)-Toluidrin 5.95 521.2
N-(3-methylsulfonyl amino-5-{[2-(2-oxo-2,3-dihydro-1H- 4.85 586.2
Indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino]-methyl }-phenyl)-Toluidrin
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 4-methyl-2-{[2-]-methyl }-phenyl)-Toluidrin 5.87 521.3
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 2-methyl-6-{[2-]-methyl }-phenyl)-Toluidrin 5.86 521.3
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 3-methyl-2-{[2-]-methyl }-phenyl)-Toluidrin 5.97 521.3
5-{4-[((1S, 2R)-2-hydroxyl-cyclohexyl methyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one 5.56 422.3
5-[4-((1R, 2S)-2-hydroxyl-indane-1-base is amino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one 5.66 442.4
5-[4-((S)-1-methylol-2-phenyl-ethylamino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one 5.54 444.3
The compound title HPLC retention time (min) LRMS (MH+)
N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 3-(methylsulfonyl-methyl-amino)-5-{[2-]-methyl }-phenyl)-N-methyl-Toluidrin 5.36 614.2
5-{4-[(1-hydroxyl-cyclopentyl-methyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one 5.2 408.2
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 3-{[2-]-methyl }-pyridine-2-yl)-Toluidrin 5.26 508.2
N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 3-fluoro-2-{[2-]-methyl }-phenyl)-N- 5.86 525.2
Methyl-Toluidrin
5-{4-[2-((S)-1-methylsulfonyl-tetramethyleneimine-2-yl)-ethylamino]-5-trifluoromethyl-pyrimidine-2--amino }-1,3-dihydro-indoles-2-ketone 5.32 485.4
5-{4-[(1-hydroxyl-cyclobutylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one 4.91 394.3
5-{4-[2-((R)-1-methylsulfonyl-tetramethyleneimine-2-yl)-ethylamino]-5-trifluoromethyl-pyrimidine-2--amino }-1,3-dihydro-indoles-2-ketone 5.32 485.4
N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 2-fluoro-6-{[2-]-methyl }-phenyl)-N-methyl-Toluidrin 5.92 525.2
N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 4-fluoro-2-{[2-]-methyl }-phenyl)-N-methyl-Toluidrin 5.78 525.3
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 4-{[2-]-methyl }-pyridine-2-yl)-Toluidrin 5.17 508.1
N-{2, (2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 2-dimethyl-3-[2-]-propyl group }-N-methyl-Toluidrin 5.7 487.3
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 6-{[2-]-methyl }-pyridine-2-yl)-Toluidrin 5.61 508.2
N-{2, (2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 4-two fluoro-6-[2-]-methyl }-phenyl)-N-methyl-Toluidrin 5.98 543.2
5-[4-((R)-1-methylsulfonyl-piperidines-3-base is amino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one 5.24 471.3
N-methyl-N-(6-methyl-3-{[2-(2-oxo-2,3-dihydro-1H-Yin 5.58 522.2
Diindyl-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino]-methyl }-pyridine-2-yl)-Toluidrin
The compound title HPLC retention time (min) LRMS (MH+)
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 5-{[2-]-methyl }-pyridine-3-yl)-Toluidrin 4.79 508.2
5-[4-(1-methylsulfonyl-piperidin-4-yl amino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one 5.26 471.2
5-{4-[methyl-((R)-1-phenyl-ethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one 7.23 428.3
5-(4-benzylamino-5-trifluoromethyl-pyrimidine-2--amino)-1, the 3-dihydro-indol-2-one 6.05 400.3
N-(4, (2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 6-dimethyl-3-{[2-]-methyl }-pyridine-2-yl)-N-methyl-Toluidrin 6.1 536.3
5-(4-tertiary butyl amino-5-trifluoromethyl-pyrimidine-2--amino)-1, the 3-dihydro-indol-2-one 6.49 366.2
5-[4-((1R; 5S; 6S)-3-methylsulfonyl-3-aza-bicyclo [3.1.0] oneself-6-base is amino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one 4.99 469.3
(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for N-methyl-N-{3-methyl-3-[2-]-butyl }-Toluidrin 5.7 487.2
N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 6-methyl-3-{[2-]-methyl }-pyridine-2-yl)-Toluidrin 5.27 508.2
5-{4-[(2-methylsulfonyl-pyridin-4-yl methyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one 4.79 479
(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 2-[2-]-the ethyl sulfonic acid acid amides 4.19 417.1
N-(3-{ methyl-[2-(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-yl]-amino }-propyl group)-Toluidrin 5.07 459.3
N-(2-{ methyl-[2-(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-yl]-amino }-ethyl)-Toluidrin 4.89 445.3
5-[4-(2-sulfonyloxy methyl methyl-benzylamino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one 5.38 492.3
(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 2-[2-]-the ethyl sulfonic acid dimethylamine 5.09 445.2
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 3-{[2-]-methyl }-pyrazine-2-yl)-Toluidrin 5.49 509.2
The ethyl sulfonic acid methyl-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 2-{[2-]-methyl }-phenyl)-acid amides 5.96 521.3
The compound title HPLC retention time (min) LRMS (MH+)
Ethyl sulfonic acid ((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 2-{[2-]-methyl }-phenyl)-acid amides 6.23 507.2
N-ethyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 3-{[2-]-methyl }-pyridine-2-yl)-Toluidrin 5.54 522.2
N-{1, (2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 1-dimethyl-3-[2-]-propyl group }-Toluidrin 5.18. 473.1
N-(5, (2-oxo-2,3-dihydro-lH-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 6-dimethyl-3-{[2-]-methyl }-pyrazine-2-yl)-N-methyl-Toluidrin 6.31 537.1
5-{4-[((R)-4-methylsulfonyl-morpholine-3-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino)-1, the 3-dihydro-indol-2-one 4.62 487.2
Propane-1-sulfonic acid ((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 2-{[2-]-methyl }-phenyl)-acid amides 6.6 521.2
5-(4-[2-((R)-4-methylsulfonyl-morpholine-3-yl)-ethylamino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one 4.99 501.1
The ethyl sulfonic acid methyl-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 3-{[2-]-methyl }-pyridine-2-yl)-acid amides 5.64 522.2
(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for three fluoro-N-methyl-N-{3-[2-]-propyl group }-Toluidrin 6.42 513.3
Ring propanesulfonic acid methyl-(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 3-[2-]-propyl group }-acid amides 5.5 485.3
N-ethyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 2-{[2-]-methyl }-phenyl)-Toluidrin 5.94 521.2
The ethyl sulfonic acid methyl-(5-methyl-2-{[2-{2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino]-methyl }-phenyl)-acid amides
The ethyl sulfonic acid ethyl-(2-{[2-{2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino]-methyl }-phenyl)-acid amides 6.22 535
The ethyl sulfonic acid ethyl-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 5-methyl-2-{[2-]-methyl }-phenyl)-acid amides 6.55 549
N-ethyl-N-((2-oxo-2,3-dihydro-lH-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 5-methyl-2-{[2-]-methyl }- 6.27 535.1
Phenyl)-Toluidrin
Ethyl sulfonic acid ((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 5-methyl-2-{[2-]-methyl }-phenyl)-acid amides 6.59 521.1
The compound title HPLC retention time (min) LRMS (MH+)
(3-methyl-2-{[2-{2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for ethyl sulfonic acid]-methyl }-phenyl)-acid amides 6.7 521.3
The ethyl sulfonic acid methyl-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 3-methyl-2-{[2-]-methyl }-phenyl)-acid amides 6.33 535.2
(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 2-[2-]-the ethyl sulfonic acid methane amide 4.6 431.1
Ethyl sulfonic acid (2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 3-[2-]-propyl group }-acid amides 4.87 459.1
(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for C-methylsulfonyl-N-{3-[2-]-propyl group }-Toluidrin 4.84 523
Ethyl sulfonic acid (2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 2-[2-]-ethyl }-acid amides 4.65 445.2
(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for C-methylsulfonyl-N-{2-[2-]-ethyl }-Toluidrin 4.62 509
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 4-methyl-3-{[2-]-methyl }-pyridine-2-yl)-Toluidrin 5.63 522.1
5-(4-{[1-(2,2,2-three fluoro-ethanoyl)-piperidines-3-ylmethyl]-amino }-5-trifluoromethyl-pyrimidine-2--amino)-1,3-dihydro-indoles-2- 6.04 503.1
Ketone
2,2,2-three fluoro-ethyl sulfonic acids (2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 3-[2-]-propyl group }-acid amides 5.56 513.2
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 4-{[2-]-methyl }-pyrimidine-2-yl)-Toluidrin 5.21 509.3
N-cyclopropyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 2-{[2-]-methyl }-phenyl)-Toluidrin 6.01 533.3
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 2-{[2-]-methyl }-pyrimidine-4-yl)-Toluidrin 4.95 509.2
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 6-{[2-]-methyl }-pyrazine-2-yl)-Toluidrin 5.3 509.4
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 2-{[2-]-methyl }-pyridine-3-yl)-Toluidrin 5.54 508.3
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 3-{[2-]-methyl }-pyridine-4-yl)-Toluidrin 5.55 508.4
Title HPLC retention time (min) LRMS (MH+)
N-cyclopropyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 3-{[2-]-methyl }-pyridine-2-yl)-Toluidrin 5.6 534.1
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 6-methyl-3-{[2-]-methyl }- 5.93 523.4
Pyrazine-2-yl)-Toluidrin
5-{4-[(2-methylsulfonyl methyl-pyridin-3-yl methyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one 5.4 493.2
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 4-{[2-]-methyl }-pyridine-3-yl)-Toluidrin 4.77 508.2
The present invention is not limited to the scope of embodiment described herein.In fact, except that these embodiments as herein described, from above description and chart the present invention being made various modifications is conspicuous to this area professional and technical personnel.These modifications comprise within the scope of the appended claims.
At this full content of incorporating patent, patent application, publication, detection method, document and the other materials quoted to some extent into as a reference.

Claims (12)

1. the compound of a structural formula 1 or the acceptable salt of its medicine, solvate, hydrate or prodrug,
Wherein n is 1 to 3 integer;
Each R 1Be the substituting group that is independently selected from following groups: hydrogen, hydroxyl ,-(C 1-C 6) alkyl ,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-O (C 1-C 6) alkyl ,-O (C 3-C 7) cycloalkyl ,-O (C 2-C 9) heterocyclic radical ,-NR 5R 6,-SR 7,-SOR 7,-SO 2R 7,-CO 2R 12,-CONR 5R 6,-SO 2NR 5R 6,-NHCOR 12,-NR 12CONR 5R 6, and-NR 12SO 2R 7Wherein said R 1Substituting group-(C 1-C 6) alkyl ,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-O (C 1-C 6) alkyl ,-O (C 3-C 7) cycloalkyl ,-O (C 2-C 9) heterocyclic radical ,-NR 5R 6,-SR 7,-SOR 7,-SO 2R 7,-CO 2R 12,-CONR 5R 6,-SO 2NR 5R 6,-NHCOR 12,-NR 12CONR 5R 6, and-NR 12SO 2R 7Randomly being independently selected from 1 to 3 of following groups part replaces: hydrogen, halogen, hydroxyl ,-CF 3,-CN ,-(C 1-C 6) alkyl ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6With-CONR 5R 8
Each R 2Be the substituting group that is independently selected from following groups: hydrogen ,-(C 1-C 6) alkyl ,-(C 2-C 6) thiazolinyl ,-(C 2-C 6) alkynyl ,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12, and-CONR 5R 6Wherein said R 2Substituting group-(C 1-C 6) alkyl ,-(C 2-C 6) thiazolinyl ,-(C 2-C 6) alkynyl ,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12, and-CONR 5R 6Randomly being independently selected from one to three of following groups part replaces: hydrogen, halogen, hydroxyl ,-CF 3,-NO 2,-CN ,-(C 1-C 6) alkyl ,-(C 2-C 6) thiazolinyl ,-(C 2-C 6) alkynyl ,-C=N-OH ,-C=N-O ((C 1-C 6) alkyl) ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6,-CONR 5R 8,-SR 7,-SOR 7,-SO 2R 7,-SO 2NR 5R 6,-NHCOR 12,-NR 12CONR 5R 6, and-NR 12SO 2R 7, wherein said-(C 2-C 6) thiazolinyl and-(C 2-C 6) alkynyl R 2Part can be randomly by 1 to 3 R 12Group replaces;
R 1And R 2Can form cyclic group-(C with the atom that they connected 3-C 10) cycloalkyl or-(C 2-C 9) heterocyclic radical, wherein said cyclic group randomly is selected from 1 to 3 of following groups part and is replaced: hydrogen, halogen, hydroxyl ,-CF 3,-NO 2,-CN ,-(C 1-C 6) alkyl ,-(C 2-C 6) thiazolinyl ,-(C 2-C 6) alkynyl ,-C=N-OH ,-C=N-O ((C 1-C 6) alkyl) ,-NR 5R 6,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 5R 6,-CONR 5R 8,-SR 7,-SOR 7,-SO 2R 7,-SO 2NR 5R 6,-NHCOR 12,-NR 12CONR 5R 6, and-NR 12SO 2R 7, wherein said cyclic group-(C 2-C 6) thiazolinyl and-(C 2-C 6) the alkynyl part can be randomly by 1 to 3 R 12Group replaces, and 1 to 3 unit that described cyclic group randomly is selected from following groups interrupts :-(C=O) ,-SO 2,-S-,-O-,-N-,-NH-and-NR 12
R 3Be the substituting group that is selected from following groups:
(a) hydrogen;
(b)-(C 6-C 10) aryl or-(C 1-C 9) heterocyclic radical, it randomly is independently selected from 1 to 3 of following groups part and replaces: halogen, hydroxyl ,-(C 1-C 6) alkyl ,-(C 1-C 6) alkyl-P (O) (O (C 1-C 6) alkyl) 2,-(C 3-C 10) cycloalkyl, (C 6-C 10) aryl, (C 2-C 9) heterocyclic radical ,-(C 1-C 9) heteroaryl ,-NR 5R 6,-NHSO 2(C 1-C 6) alkyl ,-NHSO 2(C 3-C 6) cycloalkyl ,-N ((C 1-C 6) alkyl) (SO 2-C 1-C 6) alkyl) ,-N ((C 1-C 6) alkyl) (SO 2(C 3-C 6) cycloalkyl) ,-N ((C 3-C 6) cycloalkyl) (SO 2-C 1-C 6) alkyl) ,-N ((C 3-C 6) cycloalkyl) (SO 2(C 3-C 6) cycloalkyl) ,-O (C 1-C 6) alkyl ,-O-SO 2(C 1-C 6) alkyl ,-O-SO 2(C 3-C 6) cycloalkyl ,-(CO) (C 1-C 6) alkyl ,-(CO) CF 3(the C of ,-(CO) 3-C 10) cycloalkyl ,-(CO) (C 6-C 10) aryl ,-(CO) (C 2-C 9) heterocyclic radical ,-(CO) (C 1-C 9) heteroaryl ,-(CO) O (C 1-C 6) alkyl ,-(CO) O (C 3-C 10) cycloalkyl ,-(CO) O (C 6-C 10) aryl ,-(CO) O (C 2-C 9) heterocyclic radical ,-(CO) O (C 1-C 9) heteroaryl ,-(CO) (C 1-C 6) alkyl-O (C 1-C 6) alkyl ,-SO 2(C 1-C 6) alkyl ,-SO 2(C 3-C 6) cycloalkyl ,-SO 2CF 3,-SO 2NH 2,-SO 2NH (C 1-C 6) alkyl ,-SO 2NH (C 3-C 6) cycloalkyl ,-SO 2N ((C 1-C 6) alkyl) 2,-SO 2N ((C 1-C 6) alkyl) ((C 3-C 6) cycloalkyl) ,-SO 2N ((C 3-C 6) cycloalkyl) 2With-SO 2NR 5R 6, wherein said-(C 6-C 10) aryl or-(C 1-C 9) heteroaryl 1 to 3 unit randomly being selected from following groups interrupts :-S-,-O-,-N-,-NH-and-NR 12
(c)-(C 3-C 10) cycloalkyl ,-(C 2-C 9) heterocyclic radical and-(C 1-C 6) alkyl-(C 2-C 9) heterocyclic radical, its 1 to 3 part that randomly is independently selected from following groups replaces:
Halogen, hydroxyl ,-(C 1-C 6) alkyl ,-(C 1-C 6) alkyl-P (O) (O (C 1-C 6) alkyl) 2,-(C 3-C 10) cycloalkyl ,-(C 6-C 10) aryl ,-(C 2-C 9) heterocyclic radical ,-(C 1-C 9) heteroaryl ,-NR 5R 6,-NSO 2(C 1-C 6) alkyl ,-NHSO 2(C 3-C 6) cycloalkyl ,-N ((C 1-C 6) alkyl) (SO 2-C 1-C 6) alkyl) ,-N ((C 1-C 6) alkyl) (SO 2(C 3-C 6) cycloalkyl) ,-N ((C 3-C 6) cycloalkyl) (SO 2-C 1-C 6) alkyl) ,-N ((C 3-C 6) cycloalkyl) (SO 2(C 3-C 6) cycloalkyl) ,-O (C 1-C 6) alkyl ,-O-SO 2(C 1-C 6) alkyl ,-O-SO 2(C 1-C 6) alkyl ,-O-SO 2(C 3-C 6) cycloalkyl ,-(CO) (C 1-C 6) alkyl ,-(CO) CF 3(the C of ,-(CO) 3-C 10) cycloalkyl ,-(CO) (C 6-C 10) aryl ,-(CO) (C 2-C 9) heterocyclic radical ,-(CO) (C 1-C 9) heteroaryl ,-(CO) O (C 1-C 6) alkyl ,-(CO) O (C 3-C 10) cycloalkyl ,-(CO) O (C 6-C 10) aryl ,-(CO) O (C 2-C 9) heterocyclic radical ,-(CO) O (C 1-C 9) heteroaryl ,-(CO) (C 1-C 6) alkyl-O (C 1-C 6) alkyl ,-SO 2(C 1-C 6) alkyl ,-SO 2(C 3-C 6) cycloalkyl ,-SO 2CF 3,-SO 2NH 2,-SO 2NH (C 1-C 6) alkyl ,-SO 2NH (C 3-C 6) cycloalkyl ,-SO 2N ((C 1-C 6) alkyl) 2,-SO 2N ((C 1-C 6) alkyl) ((C 3-C 6) cycloalkyl) ,-SO 2N ((C 3-C 6) cycloalkyl) 2With-SO 2NR 5R 6, wherein said-(C 3-C 10) cycloalkyl ,-(C 2-C 9) heterocyclic radical and-(C 1-C 6) alkyl-(C 2-C 9) heterocyclic radical 1 to 3 unit randomly being selected from following groups interrupts :-(C=O) ,-SO 2,-S-,-O-,-N-,-NH-and-NR 12
(d) be selected from randomly that 1 to 3 of following groups part replaces-(C 1-C 6) alkyl: halogen, hydroxyl ,-(C 1-C 6) alkyl ,-(C 1-C 6) alkyl-P (O) (O (C 1-C 6) alkyl) 2,-(C 3-C 10) cycloalkyl ,-(C 6-C 10) aryl ,-(C 2-C 9) heterocyclic radical ,-(C 1-C 9) heteroaryl ,-NR 5R 6,-NHSO 2(C 1-C 6) alkyl ,-NHSO 2(C 3-C 6) cycloalkyl ,-N ((C 1-C 6) alkyl) (SO 2-C 1-C 6) alkyl) ,-N ((C 1-C 6) alkyl) (SO 2(C 3-C 6) cycloalkyl) ,-N ((C 3-C 6) cycloalkyl) (SO 2-C 1-C 6) alkyl) ,-N ((C 3-C 6) cycloalkyl) (SO 2(C 3-C 6) cycloalkyl) ,-O (C 1-C 6) alkyl ,-O-SO 2(C 1-C 6) alkyl ,-O-SO 2(C 3-C 6) cycloalkyl ,-(CO) (C 1-C 6) alkyl ,-(CO) CF 3(the C of ,-(CO) 3-C 10) cycloalkyl ,-(CO) (C 6-C 10) aryl ,-(CO) (C 2-C 9) heterocyclic radical ,-(CO) (C 1-C 9) heteroaryl ,-(CO) O (C 1-C 6) alkyl ,-(CO) O (C 3-C 10) cycloalkyl ,-(CO) O (C 6-C 10) aryl ,-(CO) O (C 2-C 9) heterocyclic radical ,-(CO) O (C 1-C 9) heteroaryl ,-(CO) (C 1-C 6) alkyl-O (C 1-C 6) alkyl ,-SO 2(C 1-C 6) alkyl ,-SO 2(C 3-C 6) cycloalkyl ,-SO 2CF 3,-SO 2NH 2,-SO 2NH (C 1-C 6) alkyl ,-SO 2NH (C 3-C 6) cycloalkyl ,-SO 2N ((C 1-C 6) alkyl) 2,-SO 2N ((C 1-C 6) alkyl) ((C 3-C 6) cycloalkyl) ,-SO 2N ((C 3-C 6) cycloalkyl) 2With-SO 2NR 5R 6, wherein said-(C 1-C 6) alkyl 1 to 3 unit randomly being selected from following groups interrupts :-(C=O) ,-SO 2,-S-,-O-,-N-,-NH-and-NR 12
And wherein said each R 3(b)-(d) substituting group, part or unit 1 to 3 group randomly being independently selected from following groups replaces: hydrogen, halogen, hydroxyl ,-CF 3,-NO 2,-CN ,-(C 1-C 6) alkyl ,-(C 2-C 6) thiazolinyl ,-(C 2-C 6) alkynyl, (C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-(C 6-C 10) aryl ,-(C 1-C 9) heteroaryl ,-O (C 1-C 6) alkyl ,-O (C 3-C 7) cycloalkyl ,-O (C 2-C 9) heterocyclic radical ,-C=N-OH ,-C=N-O (C 1-C 6Alkyl) ,-NR 5R 6,-SR 7,-SOR 7,-SO 2R 7,-CO 2R 12,-CONR 5R 6,-SO 2NR 5R 6,-NHCOR 5,-NR 12CONR 5R 6, and-NR 12SO 2R 7
R 4Be the substituting group that is selected from following groups: hydrogen ,-(C 1-C 6) alkyl ,-(C 3-C 7) cycloalkyl and-(C 2-C 9) heterocyclic radical; Wherein said R 4Substituting group-(C 1-C 6) alkyl ,-(C 3-C 7) cycloalkyl and-(C 2-C 9) heterocyclic radical randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-(C 1-C 6) alkyl ,-CN ,-NR 5R 6,-OR 5,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-SO 2NR 5R 6,-NR 12SO 2R 7,-SO 2R 7With-CONR 5R 8Wherein said-CONR 5R 8The R of group 5And R 8Can form with the atom that they connected-(C 2-C 9) heterocyclic radical;
R 5And R 6Be the substituting group that is independently selected from following groups: hydrogen ,-(C 1-C 6) alkyl ,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-(C 6-C 10) aryl ,-(C 1-C 9) heteroaryl ,-COR 12With-SO 2R 12Wherein said R 5Or R 6Substituting group-(C 1-C 6) alkyl ,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-(C 6-C 10) aryl ,-(C 1-C 9) heteroaryl ,-COR 12With-SO 2R 12Randomly being independently selected from 1 to 3 of following groups part replaces: hydrogen, halogen ,-CF 3,-CN ,-(C 1-C 6) alkyl ,-NH (C 1-C 6) alkyl ,-NH (C 3-C 7) cycloalkyl ,-NH (C 2-C 9) heterocyclic radical ,-NH (C 6-C 10) aryl ,-NH (C 1-C 9) heteroaryl ,-N ((C 1-C 6) alkyl) 2,-N ((C 3-C 7) cycloalkyl) 2,-N ((C 2-C 9) heterocyclic radical) 2,-N ((C 6-C 10) aryl) 2,-N ((C 1-C 9) heteroaryl) 2,-O (C 1-C 6) alkyl ,-O (C 3-C 7) cycloalkyl ,-O (C 2-C 9) heterocyclic radical ,-O (C 6-C 10) aryl ,-O (C 1-C 9) heteroaryl ,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 7, SO 2NR 5R 6, NR 12SO 2R 7,-SO 2R 7,-CONH 2,-CONHR 7, and-CONR 7R 8Wherein said-CONR 7R 8The R of group 7And R 8Can form with the nitrogen-atoms that they connected-(C 2-C 9) heterocyclic radical;
R 5And R 6Can form with the atom that they connected-(C 2-C 9) heterocyclic radical, wherein said-(C 2-C 9) optional 1 to 3 the part replacement that is selected from following groups of heterocyclic radical: hydrogen, halogen, hydroxyl ,-CF 3,-NO 2,-CN ,-(C 1-C 6) alkyl ,-(C 2-C 6) thiazolinyl ,-(C 2-C 6) alkynyl ,-C=N-OH ,-C=N-O ((C 1-C 6) alkyl) ,-NR 7R 8,-OR 12,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 12,-CONR 7R 8,-CONR 5R 8,-SR 7,-SOR 7,-SO 2R 7,-SO 2NR 7R 8,-NHCOR 12,-NR 12CONR 7R 8, and-NR 12SO 2R 7, wherein said-(C 2-C 9) the described-(C of heterocyclic radical 2-C 6) thiazolinyl and-(C 2-C 6) the alkynyl part can be randomly by 1 to 3 R 7Group replaces, and is described-(C 2-C 9) heterocyclic radical 1 to 3 unit randomly being selected from following groups interrupts :-(C=O) ,-SO 2,-S-,-O-,-N-,-NH-and-NR 12
R 7Be the substituting group that is selected from following groups :-(C 1-C 6) alkyl ,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-(C 6-C 10) aryl and-(C 1-C 9) heteroaryl; Wherein said R 7Substituting group-(C 1-C 6) alkyl ,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-(C 6-C 10) aryl and-(C 1-C 9) heteroaryl randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-CN ,-(C 1-C 6) alkyl ,-NR 12 2, and-O (C 1-C 6) alkyl;
R 8Be the substituting group that is selected from following groups: hydrogen ,-(C 1-C 6) alkyl ,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-(C 6-C 10) aryl and-(C 1-C 9) heteroaryl; Wherein said R 8Substituting group-(C 1-C 6) alkyl ,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-(C 6-C 10) aryl and-(C 1-C 9) heteroaryl randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen, hydroxyl ,-CN ,-(C 1-C 6) alkyl ,-NH 2,-NHR 9,-NR 9 2, OR 9,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 10,-CONH 2,-CONHR 10And-CONR 10R 11Wherein said-CONR 10R 11R 10And R 11Can form with the nitrogen-atoms that they connected-(C 2-C 9) heterocyclic radical;
R 9And R 10Be-(C 1-C 6) alkyl;
R 11Be hydrogen or-(C 1-C 6) alkyl; And
R 12Be the substituting group that is selected from following groups: hydrogen ,-(C 1-C 6) alkyl ,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-(C 6-C 10) aryl and-(C 1-C 9) heteroaryl; Wherein said R 12Substituting group-(C 1-C 6) alkyl ,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-(C 6-C 10) aryl and-(C 1-C 9) heteroaryl randomly is independently selected from 1 to 3 of following groups part and replaces: hydrogen, halogen ,-CF 3,-CN ,-(C 1-C 6) alkyl ,-NH (C 1-C 6) alkyl ,-NH (C 3-C 7) cycloalkyl ,-NH (C 2-C 9) heterocyclic radical ,-NH (C 6-C 10) aryl ,-NH (C 1-C 9) heteroaryl ,-N ((C 1-C 6) alkyl) 2,-N ((C 3-C 7) cycloalkyl) 2,-N ((C 2-C 9) heterocyclic radical) 2,-N ((C 6-C 10) aryl) 2,-N ((C 1-C 9) heteroaryl) 2,-O (C 1-C 6) alkyl ,-O (C 3-C 7) cycloalkyl ,-O (C 2-C 9) heterocyclic radical ,-O (C 6-C 10) aryl ,-O (C 1-C 9) heteroaryl ,-(C 3-C 7) cycloalkyl ,-(C 2-C 9) heterocyclic radical ,-CO 2R 7,-CONH 2,-CONHR 7, and-CONR 7R 8Wherein said-CONR 7R 8The R of group 7And R 8Can form with the atom that they connected-(C 2-C 9) heterocyclic radical.
2. according to the compound of claim 1, wherein said R 3Be hydrogen.
3. according to the compound of claim 1, wherein said R 3Be selected from-(C 6-C 10) aryl and-(C 1-C 9) heteroaryl, it randomly is independently selected from 1 to 3 of following groups part and replaces: halogen, hydroxyl ,-(C 1-C 6) alkyl ,-(C 1-C 6) alkyl-P (O) (O (C 1-C 6) alkyl) 2,-(C 3-C 10) cycloalkyl, (C 6-C 10) aryl, (C 2-C 9) heterocyclic radical ,-(C 1-C 9) heteroaryl ,-NR 5R 6,-NHSO 2(C 1-C 6) alkyl ,-NHSO 2(C 3-C 6) cycloalkyl ,-N ((C 1-C 6) alkyl) (SO 2-C 1-C 6) alkyl) ,-N ((C 1-C 6) alkyl) (SO 2(C 3-C 6) cycloalkyl) ,-N ((C 3-C 6) cycloalkyl) SO 2-C 1-C 6) alkyl) ,-N ((C 3-C 6) cycloalkyl) (SO 2(C 3-C 6) cycloalkyl) ,-O (C 1-C 6) alkyl ,-O-SO 2(C 1-C 6) alkyl ,-O-SO 2(C 3-C 6) cycloalkyl ,-(CO) (C 1-C 6) alkyl ,-(CO) CF 3(the C of ,-(CO) 3-C 10) cycloalkyl ,-(CO) (C 6-C 10) aryl ,-(CO) (C 2-C 9) heterocyclic radical ,-(CO) (C 1-C 9) heteroaryl ,-(CO) O (C 1-C 6) alkyl ,-(CO) O (C 3-C 10) cycloalkyl ,-(CO) O (C 6-C 10) aryl ,-(CO) O (C 2-C 9) heterocyclic radical ,-(CO) O (C 1-C 9) heteroaryl ,-(CO) (C 1-C 6) alkyl-O (C 1-C 6) alkyl ,-SO 2(C 1-C 6) alkyl ,-SO 2(C 3-C 6) cycloalkyl, SO 2CF 3, SO 2NH 2, SO 2NH (C 1-C 6) alkyl ,-SO 2NH (C 3-C 6) cycloalkyl ,-SO 2N ((C 1-C 6) alkyl) 2,-SO 2N ((C 1-C 6) alkyl) ((C 3-C 6) cycloalkyl) ,-SO 2N ((C 3-C 6) cycloalkyl) 2With-SO 2NR 5R 6, wherein said-(C 6-C 10) aryl or-(C 1-C 9) heteroaryl 1 to 3 unit randomly being selected from following groups interrupts :-S-,-O-,-N-,-NH-and-NR 12
4. according to the compound of claim 1, wherein said R 3Be selected from-(C 3-C 10) cycloalkyl ,-(C 2-C 9) heterocyclic radical and-(C 1-C 6) alkyl-(C 2-C 9) heterocyclic radical, it randomly is independently selected from 1 to 3 of following groups part and replaces: halogen, hydroxyl ,-(C 1-C 6) alkyl ,-(C 1-C 6) alkyl-P (O) (O (C 1-C 6) alkyl) 2,-(C 3-C 10) cycloalkyl, (C 6-C 10) aryl, (C 2-C 9) heterocyclic radical ,-(C 1-C 9) heteroaryl ,-NR 5R 6,-NSO 2(C 1-C 6) alkyl ,-NHSO 2(C 3-C 6) cycloalkyl ,-N ((C 1-C 6) alkyl) (SO 2-C 1-C 6) alkyl) ,-N ((C 1-C 6) alkyl) (SO 2(C 3-C 6) cycloalkyl) ,-N ((C 3-C 6) cycloalkyl) (SO 2-C 1-C 6) alkyl) ,-N ((C 3-C 6) cycloalkyl) (SO 2(C 3-C 6) cycloalkyl) ,-O (C 1-C 6) alkyl ,-O-SO 2(C 1-C 6) alkyl ,-O-SO 2(C 1-C 6) alkyl ,-O-SO 2(C 3-C 6) cycloalkyl ,-(CO) (C 1-C 6) alkyl ,-(CO) CF 3(the C of ,-(CO) 3-C 10) cycloalkyl ,-(CO) (C 6-C 10) aryl ,-(CO) (C 2-C 9) heterocyclic radical ,-(CO) (C 1-C 9) heteroaryl ,-(CO) O (C 1-C 6) alkyl ,-(CO) O (C 3-C 10) cycloalkyl ,-(CO) O (C 6-C 10) aryl ,-(CO) O (C 2-C 9) heterocyclic radical ,-(CO) O (C 1-C 9) heteroaryl ,-(CO) (C 1-C 6) alkyl-O (C 1-C 6) alkyl ,-SO 2(C 1-C 6) alkyl ,-SO 2(C 3-C 6) cycloalkyl, SO 2CF 3, SO 2NH 2, SO 2NH (C 1-C 6) alkyl ,-SO 2NH (C 3-C 6) cycloalkyl ,-SO 2N ((C 1-C 6) alkyl) 2,-SO 2N ((C 1-C 6) alkyl) ((C 3-C 6) cycloalkyl) ,-SO 2N ((C 3-C 6) cycloalkyl) 2With-SO 2NR 5R 6, wherein said-(C 3-C 10) cycloalkyl ,-(C 2-C 9) heterocyclic radical and-(C 1-C 6) alkyl-(C 2-C 9) heterocyclic radical 1 to 3 unit randomly being selected from following groups interrupts :-(C=O) ,-SO 2,-S-,-O-,-N-,-NH-and-NR 12
5. according to the compound of claim 1, wherein said R 3Be that 1 to 3 part that randomly is selected from following groups replaces-(C 1-C 6) alkyl: halogen, hydroxyl ,-(C 1-C 6) alkyl ,-(C 1-C 6) alkyl-P (O) (O (C 1-C 6) alkyl) 2,-(C 3-C 10) cycloalkyl, (C 6-C 10) aryl, (C 2-C 9) heterocyclic radical ,-(C 1-C 9) heteroaryl ,-NR 5R 6,-NHSO 2(C 1-C 6) alkyl ,-NHSO 2(C 3-C 6) cycloalkyl ,-N ((C 1-C 6) alkyl) (SO 2-C 1-C 6) alkyl) ,-N ((C 1-C 6) alkyl) (SO 2(C 3-C 6) cycloalkyl) ,-N ((C 3-C 6) cycloalkyl) (SO 2-C 1-C 6) alkyl) ,-N ((C 3-C 6) cycloalkyl) (SO 2(C 3-C 6) cycloalkyl) ,-O (C 1-C 6) alkyl ,-O-SO 2(C 1-C 6) alkyl ,-O-SO 2(C 3-C 6) cycloalkyl ,-(CO) (C 1-C 6) alkyl ,-(CO) CF 3(the C of ,-(CO) 3-C 10) cycloalkyl ,-(CO) (C 6-C 10) aryl ,-(CO) (C 2-C 9) heterocyclic radical ,-(CO) (C 1-C 9) heteroaryl ,-(CO) O (C 1-C 6) alkyl ,-(CO) O (C 3-C 10) cycloalkyl ,-(CO) O (C 6-C 10) aryl ,-(CO) O (C 2-C 9) heterocyclic radical ,-(CO) O (C 1-C 9) heteroaryl ,-(CO) (C 1-C 6) alkyl-O (C 1-C 6) alkyl ,-SO 2(C 1-C 6) alkyl ,-SO 2(C 3-C 6) cycloalkyl, SO 2CF 3, SO 2NH 2, SO 2NH (C 1-C 6) alkyl ,-SO 2NH (C 3-C 6) cycloalkyl ,-SO 2N ((C 1-C 6) alkyl) 2,-SO 2N ((C 1-C 6) alkyl) ((C 3-C 6) cycloalkyl) ,-SO 2N ((C 3-C 6) cycloalkyl) 2With-SO 2NR 5R 6, wherein said-(C 1-C 6) alkyl 1 to 3 unit randomly being selected from following groups interrupts :-(C=O) ,-SO 2,-S-,-O-,-N-,-NH-and-NR 12
6. according to compound any in the aforementioned claim, it has structural formula 2,
Wherein said A is selected from:
Wherein said m is 0 to 3 integer, and R 13Be the substituting group that is selected from following groups: hydrogen, halogen, hydroxyl, (C 1-C 6) alkyl, (C 3-C 7)-cycloalkyl, (C 6-C 10)-aryl, (C 1-C 9) heteroaryl, (C 2-C 9)-heterocyclic radical, O-(C 1-C 6)-alkyl, O-(C 3-C 7)-cycloalkyl, SO 2-(C 1-C 6) alkyl, SO 2(C 3-C 7)-cycloalkyl, NHSO 2(C 1-C 6) alkyl, N ((C 1-C 6) alkyl) (SO 2(C 1-C 6-alkyl)) N ((C, 3-C 7) cycloalkyl) (SO 2(C 1-C 6-alkyl)) N (C, 1-C 6-alkyl) (SO 2(C 3-C 7) cycloalkyl), N ((C 3-C 7) cycloalkyl) (SO 2(C 3-C 7) cycloalkyl), OSO 2(C 1-C 6) alkyl, SO 2CF 3, SO 2NH 2, SO 2NH (C 1-C 6) alkyl, SO 2NH (C 3-C 7) cycloalkyl, SO 2NR 5R 6, SO 2N ((C 1-C 6) alkyl) 2, CF 3, CO-(C 1-C 6) alkyl, CO-(C 3-C 7) cycloalkyl, COCF 3, CO 2(C 1-C 6) alkyl,
With
Figure A2005800155300010C2
7. according to compound any in the aforementioned claim, it has structural formula 3
Wherein said B is selected from:
Figure A2005800155300010C4
8. according to compound any in the aforementioned claim, it has structural formula 4:
Wherein said D is selected from:
Figure A2005800155300011C3
Figure A2005800155300012C1
Wherein said q is 1 to 2 integer.
9. according to compound any in the aforementioned claim, it has structural formula 5:
Figure A2005800155300013C1
Wherein said E is selected from:
Figure A2005800155300013C2
Wherein said R 14Be selected from: (C 1-C 6)-alkyl, (C 3-C 7)-cycloalkyl and (C 2-C 9)-heterocyclic radical, and R 15Be selected from hydrogen, (C 1-C 6)-alkyl, (C 3-C 7)-cycloalkyl and (C 2-C 9)-heterocyclic radical.
10. compound, it is selected from:
N-methyl-N-{3-[({ methyl-[2-(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-yl]-amino })-methyl]-phenyl }-Toluidrin;
N-methyl-N-{4-methyl-3-[({ methyl-2-(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-yl]-amino })-methyl]-phenyl }-Toluidrin;
N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 5-methyl-2-{[2-]-methyl }-phenyl)-Toluidrin;
N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 3-methyl-2-{[2-]-methyl }-phenyl)-Toluidrin;
N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 4-methyl-2-{[2-]-methyl }-phenyl)-Toluidrin;
N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 2-methyl-6-{[2-]-methyl)-phenyl)-Toluidrin;
5-[4-(3-methylsulfonyl-propyl group amino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 5-methyl-2-{[2-]-methyl }-phenyl)-Toluidrin;
N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 3-methylsulfonyl amino-5-{[2-]-methyl }-phenyl)-Toluidrin;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 4-methyl-2-{[2-]-methyl }-phenyl)-Toluidrin;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 2-methyl-6-{[2-]-methyl }-phenyl)-Toluidrin;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 3-methyl-2-{[2-]-methyl }-phenyl)-Toluidrin;
5-{4-[((1S, 2R)-2-hydroxyl-cyclohexyl methyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
5-[4-((1R, 2S)-2-hydroxyl-indane-1-base is amino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one;
5-[4-((S)-1-methylol-2-phenyl-ethylamino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one;
N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 3-(methylsulfonyl-methyl-amino)-5-{[2-]-methyl }-phenyl)-N-methyl-Toluidrin;
5-{4-[(1-hydroxyl-cyclopentyl-methyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 3-{[2-]-methyl }-pyridine-2-yl)-Toluidrin;
N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 3-fluoro-2-{[2-]-methyl }-phenyl)-N-methyl-Toluidrin;
5-{4-[2-((S)-1-methylsulfonyl-tetramethyleneimine-2-yl)-ethylamino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
5-{4-[(1-hydroxyl-cyclobutylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino)-1, the 3-dihydro-indol-2-one;
5-{4-[2-((R)-1-methylsulfonyl-tetramethyleneimine-2-yl)-ethylamino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 2-fluoro-6-{[2-]-methyl }-phenyl)-N-methyl-Toluidrin;
N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 4-fluoro-2-{[2-]-methyl }-phenyl)-N-methyl-Toluidrin;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 4-{[2-]-methyl }-pyridine-2-yl)-Toluidrin;
N-{2, (2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 2-dimethyl-3-[2-]-propyl group }-N-methyl-Toluidrin;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 6-{[2-]-methyl }-pyridine-2-yl)-Toluidrin;
N-(2, (2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 4-two fluoro-6-{[2-]-methyl }-phenyl)-N-methyl-Toluidrin;
5-[4-((R)-1-methylsulfonyl-piperidines-3-base is amino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 6-methyl-3-{[2-]-methyl }-pyridine-2-yl)-Toluidrin;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 5-{[2-]-methyl }-pyridin-3-yl)-Toluidrin;
5-[4-(1-methylsulfonyl-piperidin-4-yl amino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one;
5-{4-[methyl-((R)-1-phenyl-ethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
5-(4-benzylamino-5-trifluoromethyl-pyrimidine-2--amino)-1, the 3-dihydro-indol-2-one;
N-(4, (2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 6-dimethyl-3-{[2-]-methyl }-pyridine-2-yl)-N-methyl-Toluidrin;
5-(4-tertiary butyl amino-5-trifluoromethyl-pyrimidine-2--amino)-1, the 3-dihydro-indol-2-one;
5-[4-((1R, 5S, 6S)-3-methylsulfonyl-3-aza-bicyclo [3.1.0] oneself-6-base is amino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one;
(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for N-methyl-N-{3-methyl-3-[2-]-butyl }-Toluidrin;
N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 6-methyl-3-{[2-]-methyl }-pyridine-2-yl)-Toluidrin;
5-{4-[(2-methylsulfonyl-pyridin-4-yl methyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 2-[2-]-the ethyl sulfonic acid acid amides;
N-(3-{ methyl-[2-(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-yl]-amino }-propyl group)-Toluidrin;
N-(2-{ methyl-[2-(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-yl]-amino }-ethyl)-Toluidrin;
5-[4-(2-methylsulfonyl methyl-benzylamino)-5-trifluoromethyl-pyrimidine-2--amino]-1, the 3-dihydro-indol-2-one;
(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 2-[2-]-the ethyl sulfonic acid diformamide;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 3-{[2-]-methyl }-pyrazine-2-yl)-Toluidrin;
The ethyl sulfonic acid methyl-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 2-{[2-]-methyl }-phenyl)-acid amides;
Ethyl sulfonic acid ((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 2-{[2-]-methyl }-phenyl)-acid amides;
N-ethyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 3-{[2-]-methyl }-pyridine-2-yl)-Toluidrin;
N-{1, (2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 1-dimethyl-3-[2-]-propyl group }-Toluidrin;
N-(5, (2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 6-dimethyl-3-{[2-]-methyl }-pyrazine-2-yl)-N-methyl-Toluidrin;
5-{4-[((R)-4-methylsulfonyl-morpholine-3-ylmethyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
Propane-1-sulfonic acid ((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 2-{[2-]-methyl }-phenyl)-acid amides;
5-{4-[2-((R)-4-methylsulfonyl-morpholine-3-yl)-ethylamino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
The ethyl sulfonic acid methyl-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 3-{[2-]-methyl }-pyridine-2-yl)-acid amides;
(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for three fluoro-N-methyl-N-{3-[2-]-propyl group }-Toluidrin;
Ring propanesulfonic acid methyl-(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 3-[2-]-propyl group }-acid amides;
N-ethyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 2-{[2-]-methyl }-phenyl)-Toluidrin;
The ethyl sulfonic acid methyl-(5-methyl-2-{[2-{2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino]-methyl }-phenyl)-acid amides;
The ethyl sulfonic acid ethyl-(2-{[2-{2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino]-methyl }-phenyl)-acid amides;
The ethyl sulfonic acid ethyl-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 5-methyl-2-{[2-]-methyl }-phenyl)-acid amides;
N-ethyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 5-methyl-2-{[2-]-methyl }-phenyl)-Toluidrin;
Ethyl sulfonic acid ((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 5-methyl-2-{[2-]-methyl }-phenyl)-acid amides;
(3-methyl-2-{[2-{2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for ethyl sulfonic acid]-methyl }-phenyl)-acid amides;
The ethyl sulfonic acid methyl-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 3-methyl-2-{[2-]-methyl }-phenyl)-acid amides;
(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 2-[2-]-the ethyl sulfonic acid methane amide;
Ethyl sulfonic acid (2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 3-[2-]-propyl group }-acid amides;
(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for C-methylsulfonyl-N-{3-[2-]-propyl group }-Toluidrin;
(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for ethyl sulfonic acid 2-[2-]-ethyl }-acid amides;
(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for C-methylsulfonyl-N-{2-[2-]-ethyl }-Toluidrin;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 4-methyl-3-{[2-]-methyl }-pyridine-2-yl)-Toluidrin;
5-(4-{[1-(2,2,2-three fluoro-ethanoyl)-piperidines-3-ylmethyl]-amino }-5-trifluoromethyl-pyrimidine-2--amino)-1, the 3-dihydro-indol-2-one;
2,2,2-three fluoro-ethyl sulfonic acids-(2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 3-[2-]-propyl group }-acid amides;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 4-{[2-]-methyl }-pyrimidine-2-base)-Toluidrin;
N-cyclopropyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 2-{[2-]-methyl }-phenyl)-Toluidrin;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 2-{[2-]-methyl }-pyrimidine-4-yl)-Toluidrin;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 6-{[2-]-methyl }-pyrazine-2-yl)-Toluidrin;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 2-{[2-]-methyl }-pyridin-3-yl)-Toluidrin;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 3-{[2-]-methyl }-pyridin-4-yl)-Toluidrin;
N-cyclopropyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 3-{[2-]-methyl }-pyridine-2-yl)-Toluidrin;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 6-methyl-3-{[2-]-methyl }-pyrazine-2-yl)-Toluidrin;
5-{4-[(2-methylsulfonyl methyl-pyridin-3-yl methyl)-amino]-5-trifluoromethyl-pyrimidine-2--amino }-1, the 3-dihydro-indol-2-one;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 4-{[2-]-methyl }-pyridin-3-yl)-Toluidrin;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 3-methyl-6-{[2-]-methyl }-pyridine-2-yl)-Toluidrin;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 5-methyl-3-{[2-]-methyl }-pyridine-2-yl)-Toluidrin;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 4-methyl-6-{[2-]-methyl }-pyridine-2-yl)-Toluidrin;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 2-methyl-5-{[2-]-methyl }-pyridin-3-yl)-Toluidrin;
(5-methyl-6-{[2-{2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for N-methyl-N-]-methyl }-pyridine-2-yl)-Toluidrin;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 6-methyl-2-{[2-]-methyl }-pyridin-3-yl)-Toluidrin;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 5-methyl-2-{[2-]-methyl }-pyrimidine-4-yl)-Toluidrin;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 5-methyl-2-{[2-]-methyl }-pyridin-3-yl)-Toluidrin;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 4-methyl-2-{[2-]-methyl }-pyridin-3-yl)-Toluidrin;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 3-methyl-4-{[2-]-methyl }-pyridine-2-yl)-Toluidrin;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 5-methyl-4-{[2-]-methyl }-pyrimidine-2-base)-Toluidrin;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 6-methyl-5-{[2-]-methyl }-pyridin-3-yl)-Toluidrin;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 6-methyl-2-{[2-]-methyl }-pyrimidine-4-yl)-Toluidrin;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 5-methyl-4-{[2-]-methyl }-pyridine-2-yl)-Toluidrin;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 2-methyl-3-{[2-]-methyl }-pyridin-4-yl)-Toluidrin;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 6-methyl-4-{[2-]-methyl }-pyridine-2-yl)-Toluidrin;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 5-methyl-3-{[2-]-methyl }-pyridin-4-yl)-Toluidrin;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 5-methyl-6-{[2-]-methyl }-pyrimidine-4-yl)-Toluidrin;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 5-methyl-4-{[2-]-methyl }-pyridin-3-yl)-Toluidrin;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 6-{[2-]-methyl }-pyrimidine-4-yl)-Toluidrin;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 6-methyl-4-{[2-]-methyl }-pyrimidine-2-base)-Toluidrin;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 2-methyl-4-{[2-]-methyl }-pyridin-3-yl)-Toluidrin;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 5-{[2-]-methyl }-pyrimidine-4-yl)-Toluidrin;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 2-methyl-6-{[2-]-methyl }-pyrimidine-4-yl)-Toluidrin;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 6-methyl-4-{[2-]-methyl }-pyridin-3-yl)-Toluidrin;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 4-{[2-]-methyl }-pyrimidine-5-yl)-Toluidrin;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 2-methyl-5-{[2-]-methyl }-pyrimidine-4-yl)-Toluidrin;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 4-methyl-6-{[2-]-methyl }-pyrimidine-5-yl)-Toluidrin;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 5-methyl-6-{[2-]-methyl }-pyrazine-2-yl)-Toluidrin;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 5-methyl-3-{[2-]-methyl }-pyrazine-2-yl)-Toluidrin;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 2-methyl-6-{[2-]-methyl }-pyrimidine-5-yl)-Toluidrin;
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 3-methyl-6-{[2-]-methyl }-pyrazine-2-yl)-Toluidrin; With
N-methyl-N-((2-oxo-2,3-dihydro-1H-indoles-5-base is amino)-5-trifluoromethyl-pyrimidine-4-base is amino for 6-methyl-5-{[2-]-methyl }-pyrimidine-4-yl)-Toluidrin.
11. a method for the treatment of the Mammals abnormal cell growth, it comprises the compound according to claim 1 that gives described Mammals treatment abnormal cell growth significant quantity.
12. a pharmaceutical composition that is used for the treatment of the Mammals abnormal cell growth, it comprises the compound and the medicine acceptable carrier according to claim 1 of treatment abnormal cell growth significant quantity.
CNA2005800155302A 2004-05-14 2005-05-02 Pyrimidine derivatives for the treatment of abnormal cell growth Pending CN1953974A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US57131204P 2004-05-14 2004-05-14
US60/571,312 2004-05-14

Related Child Applications (1)

Application Number Title Priority Date Filing Date
CN2011100212904A Division CN102127058A (en) 2004-05-14 2005-05-02 Pyrimidine derivatives for the treatment of abnormal cell growth

Publications (1)

Publication Number Publication Date
CN1953974A true CN1953974A (en) 2007-04-25

Family

ID=34966230

Family Applications (2)

Application Number Title Priority Date Filing Date
CN2011100212904A Pending CN102127058A (en) 2004-05-14 2005-05-02 Pyrimidine derivatives for the treatment of abnormal cell growth
CNA2005800155302A Pending CN1953974A (en) 2004-05-14 2005-05-02 Pyrimidine derivatives for the treatment of abnormal cell growth

Family Applications Before (1)

Application Number Title Priority Date Filing Date
CN2011100212904A Pending CN102127058A (en) 2004-05-14 2005-05-02 Pyrimidine derivatives for the treatment of abnormal cell growth

Country Status (27)

Country Link
EP (1) EP1751143A1 (en)
JP (1) JP4099212B2 (en)
KR (1) KR100886990B1 (en)
CN (2) CN102127058A (en)
AP (1) AP2241A (en)
AR (1) AR049097A1 (en)
AU (2) AU2005243397A1 (en)
BR (1) BRPI0511138A (en)
CA (1) CA2566707A1 (en)
CR (1) CR8749A (en)
EA (1) EA200601796A1 (en)
EC (1) ECSP066997A (en)
GE (1) GEP20104875B (en)
GT (1) GT200500113A (en)
IL (1) IL178828A0 (en)
MA (1) MA28583B1 (en)
MX (1) MXPA06011890A (en)
NL (2) NL1029045C2 (en)
NO (1) NO20064576L (en)
NZ (1) NZ550448A (en)
PA (1) PA8632601A1 (en)
PE (1) PE20060240A1 (en)
TN (1) TNSN06370A1 (en)
TW (1) TWI303635B (en)
UY (1) UY28894A1 (en)
WO (1) WO2005111023A1 (en)
ZA (1) ZA200608394B (en)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102448943A (en) * 2009-05-29 2012-05-09 贝林格尔.英格海姆国际有限公司 2, 4 -diaminopyrimidines for the treatment of diseases characterised by excessive or abnormal cell proliferation
CN103951658A (en) * 2007-04-18 2014-07-30 辉瑞产品公司 Sulfonyl amide derivatives for the treatment of abnormal cell growth
CN109608444A (en) * 2018-11-27 2019-04-12 中国药科大学 ERK inhibitor containing isoindolinone and preparation method thereof and purposes
CN111732548A (en) * 2020-06-11 2020-10-02 浙江大学 N2-carbamyl aromatic ring-2-aminopyrimidine derivatives and medical application thereof

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2566531A1 (en) * 2004-05-18 2005-12-15 Rigel Pharmaceuticals, Inc. Cycloalkyl substituted pyrimidinediamine compounds and their uses
US20070032514A1 (en) * 2005-07-01 2007-02-08 Zahn Stephan K 2,4-diamino-pyrimidines as aurora inhibitors
EP1966207A2 (en) * 2005-12-21 2008-09-10 Pfizer Products Inc. Pyrimidine derivatives for the treatment of abnormal cell growth
WO2009012421A1 (en) * 2007-07-17 2009-01-22 Rigel Pharmaceuticals, Inc. Cyclic amine substituted pyrimidinediamines as pkc inhibitors
US8461147B2 (en) * 2007-12-03 2013-06-11 Boehringer Ingelheim International Gmbh Diaminopyridines for the treatment of diseases which are characterised by excessive or anomal cell proliferation
SI2300013T1 (en) * 2008-05-21 2018-03-30 Adriad Pharmacaceuticals, Inc. Phosphorous derivatives as kinase inhibitors
US8729265B2 (en) 2009-08-14 2014-05-20 Boehringer Ingelheim International Gmbh Regioselective preparation of 2-amino-5-trifluoromethylpyrimidine derivatives
US8933227B2 (en) 2009-08-14 2015-01-13 Boehringer Ingelheim International Gmbh Selective synthesis of functionalized pyrimidines
US20120244141A1 (en) 2010-09-28 2012-09-27 Boehringer Ingelheim International Gmbh Stratification of cancer patients for susceptibility to therapy with PTK2 inhibitors
WO2014174745A1 (en) * 2013-04-26 2014-10-30 国立大学法人京都大学 Eg5 INHIBITOR

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9721437D0 (en) * 1997-10-10 1997-12-10 Glaxo Group Ltd Heteroaromatic compounds and their use in medicine
AR042586A1 (en) 2001-02-15 2005-06-29 Sugen Inc 3- (4-AMIDOPIRROL-2-ILMETILIDEN) -2-INDOLINONE AS INHIBITORS OF PROTEIN KINASE; YOUR PHARMACEUTICAL COMPOSITIONS; A METHOD FOR THE MODULATION OF THE CATALYTIC ACTIVITY OF PROTEINQUINASE; A METHOD TO TREAT OR PREVENT AN AFFECTION RELATED TO PROTEINQUINASE
WO2003030909A1 (en) * 2001-09-25 2003-04-17 Bayer Pharmaceuticals Corporation 2- and 4-aminopyrimidines n-substtituded by a bicyclic ring for use as kinase inhibitors in the treatment of cancer
UA80767C2 (en) * 2002-12-20 2007-10-25 Pfizer Prod Inc Pyrimidine derivatives for the treatment of abnormal cell growth
PL379330A1 (en) * 2002-12-20 2006-08-21 Pfizer Products Inc. Pyrimidine derivatives for the treatment of abnormal cell growth

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103951658A (en) * 2007-04-18 2014-07-30 辉瑞产品公司 Sulfonyl amide derivatives for the treatment of abnormal cell growth
CN103951658B (en) * 2007-04-18 2017-10-13 辉瑞产品公司 Sulfamide derivative for treating abnormal cell growth
CN102448943A (en) * 2009-05-29 2012-05-09 贝林格尔.英格海姆国际有限公司 2, 4 -diaminopyrimidines for the treatment of diseases characterised by excessive or abnormal cell proliferation
CN109608444A (en) * 2018-11-27 2019-04-12 中国药科大学 ERK inhibitor containing isoindolinone and preparation method thereof and purposes
CN109608444B (en) * 2018-11-27 2022-02-11 中国药科大学 Isoindolinone-containing ERK inhibitor and preparation method and application thereof
CN111732548A (en) * 2020-06-11 2020-10-02 浙江大学 N2-carbamyl aromatic ring-2-aminopyrimidine derivatives and medical application thereof
CN111732548B (en) * 2020-06-11 2022-06-17 浙江大学 N2-carbamyl aromatic ring-2-aminopyrimidine derivatives and medical application thereof

Also Published As

Publication number Publication date
AP2241A (en) 2011-06-01
ECSP066997A (en) 2007-02-28
JP4099212B2 (en) 2008-06-11
GT200500113A (en) 2006-01-10
CN102127058A (en) 2011-07-20
AU2009238255A1 (en) 2009-12-03
CA2566707A1 (en) 2005-11-24
TNSN06370A1 (en) 2008-02-22
TW200539871A (en) 2005-12-16
PE20060240A1 (en) 2006-04-01
PA8632601A1 (en) 2006-06-02
NL1031845A1 (en) 2006-07-31
EA200601796A1 (en) 2007-04-27
JP2007537234A (en) 2007-12-20
UY28894A1 (en) 2005-12-30
AU2005243397A1 (en) 2005-11-24
TWI303635B (en) 2008-12-01
KR100886990B1 (en) 2009-03-04
NL1031845C2 (en) 2006-11-23
IL178828A0 (en) 2007-03-08
BRPI0511138A (en) 2007-11-27
AP2006003790A0 (en) 2006-10-31
ZA200608394B (en) 2008-05-28
NO20064576L (en) 2006-11-07
KR20070012477A (en) 2007-01-25
GEP20104875B (en) 2010-01-11
MA28583B1 (en) 2007-05-02
WO2005111023A1 (en) 2005-11-24
EP1751143A1 (en) 2007-02-14
NL1029045C2 (en) 2006-06-02
NL1029045A1 (en) 2005-11-15
MXPA06011890A (en) 2006-12-14
AR049097A1 (en) 2006-06-28
NZ550448A (en) 2010-11-26
CR8749A (en) 2006-12-05

Similar Documents

Publication Publication Date Title
CN1953974A (en) Pyrimidine derivatives for the treatment of abnormal cell growth
CN101346380B (en) Pyrimidine derivatives for the treatment of abnormal cell growth
US7109337B2 (en) Pyrimidine derivatives for the treatment of abnormal cell growth
JP5989664B2 (en) Therapeutic compounds and compositions
EP1625121B1 (en) Pyrimidine derivatives for the treatment of abnormal cell growth
US7145008B2 (en) Pyrimidine derivatives for the treatment of abnormal cell growth
JP2007537235A (en) Pyrimidine derivatives for the treatment of abnormal cell proliferation
TW202115024A (en) Imidazolyl pyrimidinylamine compounds as cdk2 inhibitors
CN101678215A (en) Sulfonyl amide derivatives for the treatment of abnormal cell growth
EP4021907A1 (en) Triazolopyrimidines as a2a / a2b inhibitors
US20060205945A1 (en) Pyrimidine derivatives for the treatment of abnormal cell growth

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
REG Reference to a national code

Ref country code: HK

Ref legal event code: DE

Ref document number: 1105203

Country of ref document: HK

C12 Rejection of a patent application after its publication
RJ01 Rejection of invention patent application after publication

Open date: 20070425

REG Reference to a national code

Ref country code: HK

Ref legal event code: WD

Ref document number: 1105203

Country of ref document: HK