CN1145618C - Cyclocarbamate derivatives as progesterone receptor modulators - Google Patents

Cyclocarbamate derivatives as progesterone receptor modulators Download PDF

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CN1145618C
CN1145618C CNB008071004A CN00807100A CN1145618C CN 1145618 C CN1145618 C CN 1145618C CN B008071004 A CNB008071004 A CN B008071004A CN 00807100 A CN00807100 A CN 00807100A CN 1145618 C CN1145618 C CN 1145618C
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dihydro
benzo
dimethyl
oxazin
phenyl
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CN1349517A (en
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张普文
�ȶ��Ҹ�
E·A·捷烈弗柯
H·弗莱彻三世
A·芬森
J·E·弗罗贝尔
智林
��ظ�
T·K·琼斯
»
C·M·特格利
J·P·爱德华兹
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Hui Shi
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Ligand Pharmaceuticals Inc
American Home Products Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/04—1,3-Oxazines; Hydrogenated 1,3-oxazines
    • C07D265/12—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems
    • C07D265/14—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D265/18—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with hetero atoms directly attached in position 2
    • 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
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic 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
    • C07D417/04—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 directly linked by a ring-member-to-ring-member bond

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  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
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Abstract

This invention provides compounds of Formula (I): wherein R1 and R2 may be single substituents or fused to form spirocyclic or hetero-spirocyclic rings; R3 is H, OH, NH2, C1 to C6 alkyl, substituted C1 to C6 alkyl, C3 to C6 alkenyl, substituted C1 to C6 alkenyl, alkynyl, or substituted alkynyl, CORC; RC is H, C1 to C3 alkyl, substituted C1 to C3 alkyl, aryl, substituted aryl, C1 to C3 alkoxy, substituted C1 to C3 alkoxy, C1 to C3 aminoalkyl, or substituted C1 to C3 aminoalkyl; R4 is H, halogen, CN, NO2, C1 to C6 alkyl, substituted C1 to C6 alkyl, alkynyl, or substituted alkynyl, C1 to C6 alkoxy, substituted C1 to C6 alkoxy, amino, C1 to C6 aminoalkyl, or substituted C1 to C6 aminoalkyl; and R5 is selected from a trisubstituted benzene ring of a five or six membered ring with 1, 2, or 3 heteroatoms from the group including O, S, SO, SO2 or NR6 and containing one or two independent substituents from the group including H, halogen, CN, NO2, amino, and C1 to C3 alky, C1 to C3 alkoxy, C1 to C3 aminoalkyl, CORF, or NRGCORF; or pharmaceutically acceptable salt thereof, as well as pharmaceutical compositions and methods using the compounds as antagonists of the progesterone receptor.

Description

Cyclic carbramates derivative as progesterone receptor modulator
Invention field
The present invention relates to the antagonist of progesterone receptor, their preparation and purposes.
Background of invention
Intracellular receptor (IR) forms the relevant generegulation agent of a class formation, is called " ligand dependent transcription factor " (R.M.Evans, Science, 240,889,1988).Steroid receptor family is a subclass of IR family, comprises progesterone receptor (PR), estrogen receptor (ER), androgen receptor (AR), glucocorticoid receptor (GR) and mineralcorticoid receptor (MR).
For PR natural hormone or part is the steroid Progesterone, but has also synthesized compound such as medroxyprogesterone acetate or Levonorgestrel as part.In case have part in the pericellular liquid, part is just by the passive film that diffuses through, and combines with IR and to produce the receptor/ligand mixture.The specific gene promoter that exists in this mixture and the cell DNA combines.In case be incorporated into DNA, this mixture is with regard to the proteinic generation of regulating mRNA and this genes encoding.
The compound that is incorporated into IR and the effect of simulation natural hormone is called agonist, and the compound of inhibitory hormone effect is called antagonist.
The PR antagonist can be used for contraception.They can give (people such as Ulmann separately in this case, Ann.N.Y.Acad.Sci., 261,248,1995), also can with PR agonist coupling (people such as Kekkonen, Fertilityand Sterility, 60,610,1993) or with part ER antagonist (as Tamoxifen Citrate) coupling (WO96/19997 A1 on July 4th, 1996).
The PR antagonist can be used for the treatment of hormonal dependent mammary cancer (283, publisher: Birkhaeuser, Boston, Mass writes Vedeckis for people such as Horwitz, Horm.Cancer) and uterus and ovarian cancer.The PR antagonist also can be used for treating non-pernicious chronic disease such as fibroma (people such as Murphy, J.Clin.Endo.Metab., 76,513,1993) and endometriosis (people such as Kettel, Fertility andSterility, 56,402,1991).
The PR antagonist also can be used for hormone replacement therapy, treats postclimacteric patient (US5719136) with part ER antagonist (as Tamoxifen Citrate) coupling.
Be presented in the hormonal dependent prostate cancer model, PR antagonist (as mifepristone and onapristone) is effectively, shows that they can be used for treating this class disease of male sex people such as (, Ann.N.Y.Acad.Sci., 761,224,1995) Michna.
Compound of the present invention has shown the competitive inhibitor that can be used as the Progesterone that is incorporated into PR, and all works as antagonist in the functional model in vitro and in vivo.These compounds can be used in contraception and fibroma, endometriosis, mammary cancer, uterus carcinoma, ovarian cancer and the treatment of prostate cancer, and also can be used for after climacteric in the hormone replacement therapy.
The compound that people (U.S. Patent No. 5,688,810) such as Jones describes in the prior art is a PR antagonist dihydroquinoline 1.
People such as Jones (U.S. Patent No. 5,693,646) have described the enol ether 2 as the PR part.
People such as Jones (U.S. Patent No. 5,696,127) have described the compound 3 as the PR part.
Figure C0080710000113
People such as Zhi (J.Med.Chem., 41,291,1998). the lactone 4,5 and 6 as the PR antagonist has been described.
Figure C0080710000121
People such as Zhi have described the ether 7 (J.Med.Chem., 41,291,1998) as the PR antagonist.
Figure C0080710000122
People such as Combs disclose the acid amides 8 (J.Med.Chem., 38,4880,1995) as the PR part.
People such as Perlman have described the novel vitamin D analogues 9 (Tet.Letters, 35,2295,1994) as the PR part.
Figure C0080710000124
People such as Hamann have described PR antagonist 10 (Ann.N.Y.Acad.Sci., 761,383,1995).
People such as Chen have described PR antagonist 11 (people POI-37 such as Chen, 16 ThInt.Cong.Het.Chem., Montana, 1997).
Figure C0080710000132
People such as Kurihari have described PR ligand 12 (J.Antibiotics, 50,360,1997).
Figure C0080710000133
People such as Narr (German patent DE 3633861, CA 109:22973) disclose the imidazo benzoxazinone, and A for example is as cardiotonic drug (Cardotonics); Benzoxazine-2-ketone such as brofoxine (B) have the activity of the anxiolytic of people such as Hartmann (Proc.West.Pharmacol.Soc.21,51-55 (1978)) report; Some patents are (as people WO95/20389 such as Young recently; People WO98/14436 such as Christ) quinazoline-2-ketone and benzoxazine-2-ketone such as Compound C 1 and C2 are disclosed, as the inhibitor of hiv reverse transcriptase.
Figure C0080710000134
Compound of the present invention contains aromatics and replaces side group.This aromatic substituent has proved that the activity that has a progesterone receptor modulator for formed compound is critical and very wide structural changes is arranged, and can comprise the heteroaryl groups of aryl, heteroaryl or the replacement of aryl, replacement.
Detailed Description Of The Invention
The invention provides the compound of formula (I), or its pharmacy acceptable salt:
Figure C0080710000141
Wherein:
R 1And R 2Respectively be to be selected from following substituting group: H, C 1-C 6The C of alkyl, replacement 1-C 6Alkyl, C 2-C 6The C of alkenyl, replacement 2-C 6Alkenyl, C 2-C 6The C of alkynyl, replacement 2-C 6Alkynyl, C 3-C 8The C of cycloalkyl, replacement 3-C 8The heterocycle of the aryl of cycloalkyl, aryl, replacement, heterocycle, replacement, COR AOr NR BCOR A
Or R 1And R 2Condense formation:
A) the optional 3-8 unit spirocyclane basic ring that replaces;
B) the optional 3-8 unit volution alkenyl that replaces; Or
C) the optional 3-8 unit heterocycle that replaces contains 1-3 heteroatoms that is selected from O, S and N; A), b) and volution c) can randomly be selected from following 1-4 group and be replaced: fluorine, C 1-C 6Alkyl, C 1-C 6Alkoxyl group, C 1-C 6Alkylthio ,-CF 3,-OH ,-CN, NH 2,-NH (C 1-C 6Alkyl) or-N (C 1-C 6Alkyl) 2
R ABe H, C 1-C 3The C of alkyl, replacement 1-C 3The aryl of alkyl, aryl, replacement, C 1-C 3The C of alkoxyl group, replacement 1-C 3Alkoxyl group, C 1-C 3Aminoalkyl or the C that replaces 1-C 3Aminoalkyl;
R BBe H, C 1-C 3Alkyl or the C that replaces 1-C 3Alkyl;
R 3Be H, OH, NH 2, C 1-C 6The C of alkyl, replacement 1-C 6Alkyl, C 3-C 6The C of alkenyl, replacement 1-C 6Alkenyl, alkynyl or the alkynyl, the COR that replace C
R CBe H, C 1-C 3The C of alkyl, replacement 1-C 3The aryl of alkyl, aryl, replacement, C 1-C 3The C of alkoxyl group, replacement 1-C 3Alkoxyl group, C 1-C 3Aminoalkyl or the C that replaces 1-C 3Aminoalkyl;
R 4Be H, halogen, CN, NO 2, C 1-C 6The C of alkyl, replacement 1-C 6Alkyl, alkynyl or the alkynyl, the C that replace 1-C 6The C of alkoxyl group, replacement 1-C 6Alkoxyl group, amino, C 1-C 6Aminoalkyl or the C that replaces 1-C 6Aminoalkyl;
R 5Be selected from a) or b)
A) R 5Be the trisubstituted benzene ring that contains substituent X, Y and Z as follows:
Wherein:
X is selected from halogen, CN, C 1-C 3The C of alkyl, replacement 1-C 3The alkynyl of the alkenyl of alkyl, alkenyl, replacement, alkynyl, replacement, C 1-C 3The C of alkoxyl group, replacement 1-C 3Alkoxyl group, C 1-C 3The C of thio alkoxy, replacement 1-C 3Thio alkoxy, amino, C 1-C 3The C of aminoalkyl, replacement 1-C 3Aminoalkyl, NO 2, C 1-C 3Perfluoroalkyl, contain 1-3 heteroatomic 5 or 6 yuan of heterocycles, COR D, OCOR D, or NR FCOR D
R DBe H, C 1-C 3The C of alkyl, replacement 1-C 3The aryl of alkyl, aryl, replacement, C 1-C 3The C of alkoxyl group, replacement 1-C 3Alkoxyl group, C 1-C 3Aminoalkyl or the C that replaces 1-C 3Aminoalkyl;
R EBe H, C 1-C 3Alkyl or the C that replaces 1-C 3Alkyl;
Y and Z are selected from following substituting group: H, halogen, CN, NO 2, amino, aminoalkyl, C 1-C 3Alkoxyl group, C 1-C 3Alkyl or C 1-C 3Thio alkoxy; Or
B) R 5Be 5 or 6 yuan of rings, contain 1,2 or 3 and be selected from following heteroatoms O, S, SO, SO 2Or NR 6, and contain individual following substituting group: H, halogen, CN, the NO of respectively being selected from of 1-2 2, amino and C 1-C 3Alkyl, C 1-C 3Alkoxyl group, C 1-C 3Aminoalkyl, COR F, or NR GCOR F
R FBe H, C 1-C 3The C of alkyl, replacement 1-C 3The aryl of alkyl, aryl, replacement, C 1-C 3The C of alkoxyl group, replacement 1-C 3Alkoxyl group, C 1-C 3Aminoalkyl or the C that replaces 1-C 3Aminoalkyl;
R GBe H, C 1-C 3Alkyl or the C that replaces 1-C 3Alkyl;
R 6Be H or C 1-C 3Alkyl.
Preferred compound of the present invention comprises the compound of those formulas I, or its pharmacy acceptable salt
Wherein:
R 1Be H, C 1-C 6The C of alkyl, replacement 1-C 6Alkyl, C 3-C 8The C of cycloalkyl, replacement 3-C 8The heterocycle of the aryl of cycloalkyl, aryl, replacement, heterocycle, replacement, COR A, or NR BCOR A
R 2Be H, C 1-C 6The C of alkyl, replacement 1-C 6Alkyl, C 2-C 6The C of alkenyl, replacement 2-C 6Alkenyl, C 3-C 8The C of cycloalkyl, replacement 3-C 8The heterocycle of the aryl of cycloalkyl, aryl, replacement, heterocycle, replacement, COR A, or NR BCOR A
Or
R 1And R 2Condense and form spiro cycloalkyl group such as 3-8 unit volution, by R 1And R 2Condense the replacement spiro cycloalkyl group that forms 3-8 unit spirane structure, by R 1And R 2Condense the volution alkenyl that forms 3-8 unit spirane structure, by R 1And R 2Condense the volution alkenyl of the replacement that forms 3-8 unit spirane structure, by R 1And R 2Condense the spiro cycloalkyl group that forms 3-8 unit spirane structure and contain 1-3 and be selected from following heteroatoms: O, S and N; By R 1And R 2Condense the spiro cycloalkyl group of the replacement that forms 3-8 unit spirane structure and contain 1-3 and be selected from following heteroatoms: O, S and N; By R 1And R 2The volution that condenses formation can randomly be selected from following 1-4 group and be replaced: fluorine, C 1-C 6Alkyl, C 1-C 6Alkoxyl group, C 1-C 6Alkylthio ,-CF 3,-OH ,-CN, NH 2,-NH (C 1-C 6Alkyl) or-N (C 1-C 6Alkyl) 2
R ABe H, C 1-C 3The C of alkyl, replacement 1-C 3The aryl of alkyl, aryl, replacement, C 1-C 3The C of alkoxyl group, replacement 1-C 3Alkoxyl group, C 1-C 3Aminoalkyl or the C that replaces 1-C 3Aminoalkyl;
R BBe H, C 1-C 3Alkyl or the C that replaces 1-C 3Alkyl;
R 3Be H, OH, NH 2, C 1-C 6The C of alkyl, replacement 1-C 6Alkyl, C 3-C 6The C of alkenyl, replacement 1-C 6Alkenyl, alkynyl or the alkynyl, the COR that replace C
R CBe H, C 1-C 4The C of alkyl, replacement 1-C 4The aryl of alkyl, aryl, replacement, C 1-C 4The C of alkoxyl group, replacement 1-C 4Alkoxyl group, C 1-C 4Aminoalkyl or the C that replaces 1-C 4Aminoalkyl;
R 4Be H, halogen, CN, NO 2, C 1-C 6The C of alkyl, replacement 1-C 6Alkyl, C 1-C 6The C of alkoxyl group, replacement 1-C 6Alkoxyl group, amino, C 1-C 6Aminoalkyl or the C that replaces 1-C 6Aminoalkyl;
R 5Be the trisubstituted benzene ring that contains substituent X, Y and Z as follows:
Figure C0080710000161
X is selected from: halogen, CN, C 1-C 3The C of alkyl, replacement 1-C 3Alkyl, C 1-C 3The C of alkoxyl group, replacement 1-C 3Alkoxyl group, C 1-C 3The C of thio alkoxy, replacement 1-C 3Thio alkoxy, amino, C 1-C 3The C of aminoalkyl, replacement 1-C 3Aminoalkyl, NO 2, C 1-C 3Perfluoroalkyl, contain 1-3 heteroatomic 5 yuan of heterocycles, COR D, OCOR D, or NR ECOR D
R DBe H, C 1-C 3The C of alkyl, replacement 1-C 3The aryl of alkyl, aryl, replacement, C 1-C 3The C of alkoxyl group, replacement 1-C 3Alkoxyl group, C 1-C 3Aminoalkyl or the C that replaces 1-C 3Aminoalkyl;
R EBe H, C 1-C 3Alkyl or the C that replaces 1-C 3Alkyl;
Y and respectively be to be selected from following substituting group to comprise: H, halogen, CN, NO 2, C 1-C 3Alkoxyl group, C 1-C 3Alkyl or C 1-C 3Thio alkoxy;
Or
R 5Be 5 or 6 yuan of rings, contain 1,2 or 3 and be selected from O, S, SO, SO 2Or NR 6Heteroatoms, and contain 1 or 2 and respectively be selected from following substituting group, comprising: H, halogen, CN, NO 2, amino and C 1-C 3Alkyl or C 1-C 3Alkoxyl group;
R 6Be H or C 1-C 3Alkyl.
Other preferred compounds are compound and their pharmacy acceptable salts of those formulas I:
Wherein:
R 1=R 2And be selected from: C 1-C 3The C of alkyl, replacement 1-C 3Alkyl, by R 1And R 2Condense the spiro cycloalkyl group of the 3-6 unit spirane structure of formation;
R 3Be H, OH, NH 2, C 1-C 6Alkyl or the C that replaces 1-C 6Alkyl, COR C
R CBe H, C 1-C 4Alkyl or C 1-C 4Alkoxyl group;
R 4Be H, halogen, CN, NO 2, C 1-C 3The C of alkyl, replacement 1-C 3Alkyl, C 1-C 3Alkoxyl group or the C that replaces 1-C 3Alkoxyl group;
R 5Be the disubstituted benzenes ring that contains substituent X and Y as follows:
X is selected from following group, comprising: halogen, CN, C 1-C 3Alkoxyl group, C 1-C 3Alkyl, NO 2, C 1-C 3Perfluoroalkyl, contain 1-3 heteroatomic 5 yuan of heterocycles, C 1-C 3Thio alkoxy;
Y is selected from following substituting group, comprising: H, halogen, CN, NO 2, C 1-C 3Alkoxyl group, C 1-C 4Alkyl, C 1-C 3Thio alkoxy;
Or
R 5Be 5 yuan of rings of following structure
Figure C0080710000181
U is O, S or NR 6,
R 6Be H or C 1-C 3Alkyl or C 1-C 4CO 2Alkyl;
X ' is selected from following group: halogen, CN, NO 2, or C 1-C 3Alkyl and C 1-C 3Alkoxyl group, condition be when U be NR 6The time X ' be not CN;
Y ' is selected from following group: H and C 1-C 4Alkyl;
Or
R 5Be 6 yuan of rings of following structure:
X 1Be N or CX 2
X 2Be halogen, CN, alkoxyl group or NO 2
Other preferred compounds are those compounds shown in the formula I and their pharmacy acceptable salts:
Figure C0080710000183
Wherein:
R 1=R 2And be to be selected from following group: CH 3With by R 1And R 2Condense the spiro cycloalkyl group of 6 yuan of spirane structures of formation
R 3Be H, OH, NH 2, CH 3, the methyl or the COR that replace C
R CBe H, C 1-C 3Alkyl or C 1-C 4Alkoxyl group;
R 4Be H, halogen, NO 2, CN or C 1-C 3Alkyl;
R 5Be the disubstituted benzenes ring that contains substituent X and Y as follows:
Figure C0080710000191
X is selected from: halogen, CN, methoxyl group, NO 2, or 2-thiazole;
Y is H or F;
Or
R 5Be 5 yuan of rings of following structure:
Figure C0080710000192
U be O, S or NH,
X ' is halogen, CN or NO 2, condition be when U be NR 6The time X ' be not CN;
Y ' is H or C 1-C 4Alkyl.
Compound of the present invention can contain asymmetric carbon, and compounds more of the present invention can contain one or more asymmetric centers, and therefore optical isomer and diastereomer can be arranged.Though formula I does not show with stereochemistry, the present invention includes this type of optical isomer and diastereomer; And racemic and enantiomer-pure R and S steric isomer that disassemble; And other mixtures of R and S steric isomer and their pharmacy acceptable salts.
Term used herein " alkyl " refers to the aliphatic hydrocarbon group that contains 1-8 carbon atom that straight or branched is saturated, is preferably to contain 1-6 carbon atom; " alkenyl " comprises straight chain and the branched hydrocarbyl that contains at least one carbon-carbon double bond and 2-8 carbon atom, preferably contains 2-6 carbon atom; " alkynyl " comprises straight chain and the branched hydrocarbyl that contains at least one carbon carbon triple bond and 2-8 carbon atom, preferably contains 2-6 carbon atom.
Term " alkyl of replacement ", " alkenyl of replacement " and " alkynyl of replacement " refer to be selected from abovementioned alkyl, alkenyl and the alkynyl that following substituting group replaces by 1-3 at least: halogen, CN, OH, NO 2, amino, aryl, heterocycle, the aryl of replacement, the heterocycle of replacement, alkoxyl group, aryloxy, the alkoxyl group of replacement, alkyl-carbonyl, alkyl carboxyl, alkylamino, arylthio.These substituting groups can be connected on any carbon atom of alkyl, alkenyl or alkynyl group, but condition is this stable chemical part that connects and composes.
The term of this paper " aryl " refers to aromatic systems, can be monocycle or condensed or the list that links together or many aromatic rings, thereby condenses or at least one part of shack forms conjugated virtue system.Aromatic yl group can comprise (but being not restricted to): phenyl, naphthyl, xenyl, anthryl, tetralyl, phenanthryl.
Term " aryl of replacement " refers to be selected from the above-mentioned aryl that following group replaces by 1-4: halogen, CN, OH, NO 2, amino, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxyl group, aryloxy, replacement alkoxyl group, alkyl-carbonyl, alkyl carboxyl, alkylamino or arylthio.
Term used herein " heterocycle " refers to stable 4-to 7-unit monocycle or stable many rings heterocycle, can be saturated, part is undersaturated or undersaturated, and by carbon atom be selected from a following 1-4 heteroatoms and constitute: N, O and S atom.N and S atom can be oxidized.Heterocycle also can comprise any many rings, and wherein arbitrary above-mentioned heterocycle can condense in aromatic ring.This heterocycle can be connected in any heteroatoms or carbon atom, but the structure that is generated must be chemically stable.These heterocycles comprise as tetrahydrofuran (THF), piperidyl, piperazinyl, 2-oxo-piperidine base, azepines base, pyrrolidyl, imidazolyl, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, oxazolyl, isoxazolyl, morpholinyl, indyl, quinolyl, thienyl, furyl, benzofuryl, benzothienyl, thio-morpholinyl, thio-morpholinyl sulfoxide and isoquinolyl.
Term used herein " heterocycle of replacement " refers to by following 1-4 the above-mentioned heterocycle of substituting group that replaces: halogen, CN, OH, NO 2, amino, alkyl, replacement alkenyl, alkynyl, alkoxyl group, aryloxy, alkoxyl group, alkyl-carbonyl, alkyl carboxyl, alkylamino or the aryl sulphur of replacement of alkyl, cycloalkyl, alkenyl, replacement.Term used herein " alkoxyl group " refers to the OR group, and wherein R is the alkyl of alkyl or replacement.The term of this paper " aryloxy " refers to the OR group, and wherein R is the aryl of aryl or replacement.The term of this paper " alkyl-carbonyl " refers to the RCO group, and wherein R is the alkyl of alkyl or replacement.The term of this paper " alkyl carboxyl " refers to the COOR group, and wherein R is the alkyl of alkyl or replacement.Term " aminoalkyl " refers to secondary amine or tertiary amine, and wherein the alkyl of alkyl or replacement contains 1-8 carbon atom, can be identical or different, and tie point is on nitrogen-atoms.Term " halogen " refers to Cl, Br, F or I.
Compound of the present invention can by pharmaceutically or the acceptable acid of physiology or alkali deutero-salt form use.These salt comprise the salt that (but being not restricted to) and following mineral acid form: example hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, organic acid then refer to acetate, oxalic acid, Succinic Acid and maleic acid.Other salt comprise the salt with basic metal or alkaline-earth metal, as sodium, potassium, calcium or magnesium, with the form (when giving this form, can change into active part in vivo) of " prodrug " of ester, carbamate or other routines.
The present invention also comprises the pharmaceutical composition that contains one or more The compounds of this invention and pharmaceutically acceptable carrier or vehicle.The present invention also comprises methods of treatment, and this method comprises one or more above-mentioned compounds as the progesterone receptor antagonist that give the Mammals pharmacy effective dose.
Single using or coupling progesterone receptor antagonist of the present invention can be used for practising contraception and treating and/or preventing in the method for optimum and malignant tumour.The special purposes of compound of the present invention and composition comprises and treats and/or prevents myometrium fibroma, endometriosis, benign prostatauxe; The cancer of uterine mucosa, ovary, mammary gland, colon, prostate gland, hypophysis and gland cancer, meningioma and other hormone-dependent tumors.Other purposes of progesterone receptor antagonist of the present invention comprise the synchronization that domestic animal oestruses.
When compound of the present invention is used for such use; they can with one or more pharmaceutically acceptable carrier or mixed with excipients; as solvent, thinner etc.; and can following form oral administration: tablet, capsule, dispersible powder, particle or suspension (containing 0.05-5% suspension agent according to appointment), syrup (containing sugar) and elixir (containing the 20-50% ethanol of having an appointment) etc. just like 10-50%, or with sterile injectable solution or form of suspension (containing the 0.05-5% suspension agent of having an appointment in the medium waiting to ooze) administered parenterally.These pharmaceutical preparations can contain just like with the about 25-90% activeconstituents of carrier blended, more generally be about between 5%-60% (weight).
The effective dose of used activeconstituents can be by the severity of the pattern of used compound, administration and disease to be treated and is different.But when compound of the present invention every day gives with the dosage of about 0.5-500mg/kg the weight of animals, can obtain gratifying effect usually, preferably give with the dosage that separates for 2-4 time every day, or with the slowly-releasing form administration.For most of large mammal, the total dose of every day is about 1-100mg, preferably is about 2-80mg.Be applicable to that dosage form for oral administration comprises the active compound of about 0.5-500mg, with solid-state or liquid meticulous mixing of pharmaceutically acceptable carrier.Can regulate this dosage replys to obtain optimal treatment.For example, but give the dosage that several times separate every day, or dosage is reduced pari passu by the needs of treatment situation.
Can give these active compounds by oral and intravenously, intramuscular or subcutaneous route.Solid-state carrier comprises: starch, lactose, secondary calcium phosphate, Microcrystalline Cellulose, sucrose and white bole, and liquid carrier comprises: sterilized water, polyoxyethylene glycol, nonionic surface active agent and edible oil (as Semen Maydis oil, peanut oil and sesame oil), as long as be adapted to the characteristic of activeconstituents and required form of medication.Can be included in advantageously that normally used adjuvant comprises as seasonings, pigment, sanitas and antioxidant such as vitamin-E, vitamins C, BHT and BHA in the pharmaceutical compositions.
From being easy to preparation and administration, preferred pharmaceutical composition is a solid-state composition, especially tablet and hard capsule that fill or topping up.The oral administration of compound is preferred.
But these active compounds are parenteral or intraperitoneal administration also.The solution or the suspension that also can in the water that suitably is mixed with tensio-active agent (as hydroxypropylcellulose), prepare these active compounds (free alkali or pharmacy acceptable salt).Also can in glycerine, liquid macrogol and their mixtures in oil, prepare dispersion liquid.Under common storage and working conditions, contain sanitas in these preparations to prevent microorganism growth.
The medicament forms that is adapted to inject comprises aseptic aqueous solution or dispersion liquid and aseptic powder (being used for temporarily preparing aseptic injectable solution or dispersion liquid).In all situations, these forms must be aseptic and must be that fluid is to be easy to the use of syringe.Under manufacturing and condition of storage must be stable, and must be able to resist the pollution effect of microorganism (as bacterium and fungi).Carrier can be solvent or dispersion medium, contains just like water, ethanol (as glycerine, propylene glycol and liquid polyethylene glycol), their suitable mixture and vegetables oil.
Can be by following flow preparation compound of the present invention:
Shown in flow process I, common compound of the present invention can prepare as last step with suitable linked reaction.(comprise at suitable non-proton property (nonprotic) solvent, but be not restricted to: THF or ether), (as argon gas or nitrogen)-78 ℃ arrives room temperature in the inert atmosphere, with neighbour-benzaminic acid or derivatives thereof such as ethyl ester (X=Br, I, Cl or potential coupling precursor such as the alkoxyl group that suitably replaces, can in linked reaction, change into the OTf group), organometallic reagent (as Grignard reagent) reaction with suitable obtains adjacent amino methanol 2.In suitable non-protonic solvent (as THF), temperature range is a room temperature to 65 ℃, uses condensing agent such as carbonyl dimidazoles, phosgene, methylcarbonate or diethyl carbonate usually, and methyl alcohol 2 rings are closed, obtains benzoxazine-2-ketone 3.Comprise Suzuki, Stille reaction with various linked reactions, benzoxazine-2-ketone 3 arylations can be obtained 4.Normally there is transition-metal catalyst in these reactions, as palladium or nickel usually and the phosphino-part (as Ph 3P, 1,1 '-two (diphenylphosphino) ferrocene, 1,2-two (diphenylphosphino) ethane) mixture or palladium salt (as acid chloride) carry out when existing.Under this catalytic condition, suitably nucleophilic reagent (as aryl boric acid, aryl stannane or aryl zn cpds) that replaces and benzoxazinone 3 couplings generate 4.If reaction needed alkali, normally used alkali comprise (but being not restricted to) sodium bicarbonate, yellow soda ash, potassiumphosphate, barium carbonate, Potassium ethanoate or cesium fluoride.The most frequently used solvent comprises the mixture of benzene, DMF, Virahol, toluene, ethanol, DME, ether, acetone or arbitrary above-mentioned solvent and water in these reactions.Usually in inert atmosphere (as nitrogen or argon gas), temperature range is carried out linked reaction from the room temperature to the solvent or the boiling point of solvent systems or mixture.
Benzoxazinone 3 can be changed into nucleophile such as boric acid, it can with suitable electrophile (as aryl bromide or aryl iodide) coupling, use above-mentioned linked reaction condition to generate 4.In non-protonic solvent such as THF or ether, available organometallic reagent such as n-BuLi handle 3, then-78 ℃ of temperature ranges to reflux temperature, under inert atmosphere (as argon gas or nitrogen), with suitable electrophilic reagent such as trimethyl borate, triisopropyl borate ester, two six alkyl (bishexalkyl) tin reagent or zinc chloride cancellation reaction soln, thereby change into 5 with 3.
Flow process Ia
Figure C0080710000231
Flow process Ia has illustrated the method for another kind of generation benzoxazinone 3.In the solvent (as THF, acetonitrile) that is fit to; exist or when not having alkali (as catalyzer or acid scavenger); (comprise with suitable alkoxy carbonyl blocking group; but be not restricted to allyl group carbonyl, uncle-butoxy carbonyl, phenyloxycarbonyl, ethoxy carbonyl or methoxycarbonyl) the suitable aniline 1 of protection.Use suitable organometallic reagent (as organic lithium reagent or Grignard reagent) then, use the method identical to handle this protected aniline, generation methyl alcohol 6 with preparing compound 2.Under inert atmosphere (as nitrogen or argon gas), in the temperature range of room temperature to the related solvents boiling point, in suitable solvent (as toluene, THF, ethanol), handle 6 with suitable alkali (as potassium tert.-butoxide, n-Butyl Lithium, potassium hydroxide), generate benzoxazinone 3.
Flow process II has shown that preparation has the method for the benzoxazinone of two different substituents at 4 bit strips.Under inert atmosphere (as argon gas or nitrogen), in protic solvent (ethanol, Virahol), reflux, handle the isatoic anhydride 7 that suitably replaces with N-, O-dimethyl hydroxyl-amine hydrochlorate, can generate Weinreb acid amides 8.By with typical linked reaction such as Suzuki, Stille linked reaction, with the similar mode of preparation benzoxazinone 4, acid amides 8 and aryl electrophilic reagent (as aryl boric acid or aryl stannane) coupling can be generated 9.Under inert atmosphere (as argon gas or nitrogen),-78 ℃ of temperature ranges to room temperature, in non-protonic solvent (as THF or ether), handle Weinreb acid amides 9, generate keto-amine 10 with organometallic compound (as lithium alkylide, alkynyl lithium, lithium aryl or their Grignard counterpart).Under inert atmosphere (as argon gas or nitrogen) ,-78 ℃ of temperature ranges to room temperature handle 10 with organometallic reagent (as alkyl, alkynyl or aryl Grignard compound) in non-protonic solvent (as THF or ether), ketone 10 can be changed into methyl alcohol 11.Also can be under inert atmosphere, 0 ℃ of temperature range to solvent boiling point, in suitable solvent (as THF, ether or dehydrated alcohol), be reduced into 11 methyl alcohol part with the ketone groups of suitable reductive agent (as lithium aluminum hydride, sodium borohydride), thereby ketone 10 is changed into methyl alcohol 11 10.In room temperature to 65 ℃ temperature range, with condensing agent (as carbonyl dimidazoles, phosgene, methylcarbonate or diethyl carbonate) that methyl alcohol 11 rings are closed in suitable non-protonic solvent (as THF), can generate compound of the present invention.
Figure C0080710000251
In addition, shown in flow process III, also can be under inert atmosphere (as argon gas or nitrogen),-78 ℃ of temperature ranges to room temperature, be used in the suitable solvent (THF or ether), handle neighbour-aminobenzonitrile 14 with organometallic compound (as organic lithium reagent or Gringard reagent), can prepare neighbour-keto-amine 10 easily.With suitable linked reaction (as Stille or Suzuki flow process),, can prepare benzonitrile 14 from the benzonitrile (as bromination benzonitrile 13) of suitable replacement in the mode similar to preparation Weinreb acid amides 9.
Flow process III
Flow process IV has shown that preparation has the substituent benzoxazinone of rudimentary perfluoroalkyl (as R at 4 6Be trifluoromethyl group) method.Under inert atmosphere (as argon gas or nitrogen); in 0 ℃ of-70 ℃ of temperature range; in the solvent (as the mixture of acetonitrile, acetone, THF, methylene dichloride or solvent such as the mixture of methylene dichloride and water) that is fit to; with the chloroaniline 15 that suitable protection reagent (as pivalyl chloride or Di-tert butyl pyrocarbonate) protection suitably replaces, the aniline 16 that is protected.When reaction produces by-product acids (example hydrochloric acid), may need to add suitable alkali such as yellow soda ash, Sodium Hydrogen Carbonate or salt of wormwood.Under inert atmosphere (as argon gas or nitrogen);-78 ℃ to room temperature; with 16 with suitable lithium alkylide (as just-butyllithium or the second month in a season-butyllithium) reaction; then in non-protonic solvent (as ether or THF); with rudimentary perfluor carboxy derivatives (as trifluoroacetyl chloride, 1-(trifluoroacetyl group)-imidazoles or Trifluoroacetic Acid Ethyl Ester) reaction, the adjacent keto-amine that is protected.Then, 0 ℃ of temperature range to solvent boiling point in suitable solvent (as methylene dichloride or water), with the keto-amine reaction of suitable acid (as TFA, 2N aqueous hydrochloric acid) with protection, to remove blocking group, obtains neighbour-keto-amine 17.With preparing 6-Lv benzoxazinone 19 from 17 from ketone 10 synthetic benzoxazinone 12 identical modes.Shown in flow process IV,, can obtain compound 12 of the present invention with the aryl coupling with 19 by the catalytic linked reaction of nickel composite.Proved that palladium catalyst is not effective catalyzer in this linked reaction.When having suitable alkali (as potassiumphosphate) and nickel (0 or II) complex catalyst (as the mixture of nickel and dppe, dppf or triphenylphosphine), can carry out 19 with the linked reaction of suitable aryl boric acid.The most frequently used reagent comprises diox or THF in this reaction.Usually this linked reaction is carried out in the temperature range of room temperature to 95 ℃ down at inert atmosphere (nitrogen or argon gas).
Shown in flow process V, can further derive at 1 by several different methods compound 6 or 12, generate various new cyclic carbramates derivatives, comprise the 1-carboxy derivatives of carbonyl that alkyl, 1-carbonyl, 1-that 1-alkyl, 1-replace replace, 1-carboxyl, replacement.For example, under inert atmosphere (as argon gas or nitrogen), by being used in the appropriate solvent (as DMF), handle carbamate 12 or 6 with suitable alkali (as sodium hydride), add suitable electrophilic reagent (as alkyl bromide, iodide or the triflate (triflate) of alkyl or replacement) then, can make the alkyl derivative 20 of alkyl or replacement.Two-phase condition shown in the also available flow process V is carried out 12 or 6 conversion at 1, for example in appropriate solvent (as acetonitrile), carries out alkylation with two-phase catalyzer (as the tributyl brometo de amonio).Such another example comprises (but being not restricted to): heat 12 or 6 with triethyl orthoformate shown in flow process V, the derivative that the 1-of generation 12 or 6 replaces.
Flow process V
Figure C0080710000281
Under inert atmosphere (as argon gas or nitrogen); in appropriate solvent (as acetonitrile), when having suitable basic catalyst (as DMAP), handle 12 or 6 with suitable acylating agent or carboxylating agent (as Di-tert butyl pyrocarbonate); easily, generate compound 21 in 1-position acidylate or compound carboxylation 12 or 6.In The suitable solvent (as THF or diethyl ether), in the presence of suitable alkali such as sodium hydride, with the 1-2 position amination of suitable aminating agent (as chloramines) with compound 12 or 6, generate compound 22, as (people .J.Org.Chem.30 such as Metlesics, 1311 (1965)) as described in the flow process of reference.
Embodiment 1
2-(2-amino-5-bromophenyl) propan-2-ol
Under-78 ℃ of nitrogen, with ether (3.0M, 90ml, 270mmol) solution-treated 2-amino-5-bromo-benzoic acid (10g, dried THF (200ml) solution 46mmol) of methyl-magnesium-bromide.This reaction mixture slowly is warming up to room temperature, and nitrogen stirred 48 hours down, poured into then in the cold 0.5N aqueous hydrochloric acid (300ml).With 1N aqueous sodium hydroxide solution this mixture that neutralizes, add ethyl acetate (300ml).Separately organic layer is used ethyl acetate (3 * 100ml) extraction water layers.Organic layer and dry (MgSO with salt water washing merging 4).After the solvent removed in vacuo, (the hexane: ethyl acetate/3: 2), obtain being 2-(2-amino-5-bromophenyl) propan-2-ol (6g, 57%) of pale solid: mp 62-63 ℃ of flash chromatography residue on silica gel; 1H-NMR (CDCl 3) δ 7.19 (d, 1H, J=2.3Hz), 7.12 (dd, 1H, J=8.4,2.3Hz), 6.51 (d, 1H, J=8.4Hz), 4.70 (s, 2H), 1.82 (s, 1H), 1.65 (s, 6H).
Embodiment 2
6-bromo-4,4-dimethyl-1,4-dihydro-benzo [d] [1,3] oxazine-2-ketone
In dried THF (150ml) solution of 2-(2-amino-5-bromophenyl) propan-2-ol, add 1 under the nitrogen, and 1 '-carbonyl dimidazoles (15.5g, 94mmol).50 ℃ of these reaction solns of heating spend the night.Solvent removed in vacuo is dissolved in residue in the ethyl acetate (100ml).With the 1N aqueous hydrochloric acid (2 * 40ml), salt solution (20ml) washs this solution, and uses MgSO 4Dry.After the solvent removed in vacuo, the solid 6-bromo-4 that obtains being white in color, 4-dimethyl-1,4-dihydro-benzo [d] [1,3] oxazine-2-ketone (20g, 100%): mp 199-200 ℃; 1H-NMR (DMSO-d 6) δ 10.32 (s, 1H, D 2O is tradable), 7.48 (d, 1H, J=2.1Hz), 7.43 (dd, 1H, J=8.5,2.1Hz), 6.84 (d, 1H, J=8.4Hz), 1.61 (s, 6H).
Embodiment 3
6-iodo-4,4-dimethyl-1,4-dihydro-benzo [d] [1,3] oxazine-2-ketone
With the flow process of embodiment 1 and 2, prepare this product from 2-amino-5-iodo-benzoic acid, solid is white in color: mp 196-197 ℃; 1H-NMR (DMSO-d 6) δ 10.30 (s, 1H, D 2O is tradable), 7.58 (m, 2H), 6.71 (d, 1H, J=8.4Hz), 1.58 (s, 6H) .MS (EI) m/z 326 ([M+Na] +, 100%).C 10H 10INO 2Analytical value: C, 39.63, H, 3.33, N, 4.62, measured value: C, 39.25, H, 3.24, N, 4.49.
Embodiment 4
(1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazine-6-yl) boric acid
Under-78 ℃ of nitrogen, at 6-bromo-4,4-dimethyl-1,4-dihydro-benzo [d] [1,3] oxazine-2-ketone (2g, and the hexane solution of adding n-BuLi in the solution of anhydrous THF (60ml) 7.8mmol) (10M, 2.4ml, 24mmol).-78 ℃ were stirred 30 minutes, obtained slurries, and (6.5ml 28mmol) handles with triisopropyl borate ester.This reactant slowly is heated to room temperature, with the 1N salt solution aqueous solution (60ml) cancellation.Add ethyl acetate (100ml), separately organic layer is used ethyl acetate (3 * 60ml) extraction water layers.With the organic layer of salt water washing merging, and use MgSO 4Dry.Solvent removed in vacuo, (ethyl acetate: hexane/2: 1), solid (1 obtains being white in color with this residue of flash chromatography on silica gel purifying, 4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazine-6-yl) boric acid (1.4g, 81%): mp 249-250 ℃; 1H-NMR (DMSO-d 6) δ 10.21 (s, 1H, D 2O is tradable), 7.90-7.95 (br s, 2H, D 2O is tradable), 7.67 (m, 2H), 6.79 (d, 1H, J=7.8Hz), 1.61 (s, 6H); MS (ESI) m/z 222 ([M+H] +, 87%).
Embodiment 5
6-(3-chloro-phenyl-)-4,4-dimethyl-1,4-dihydrobenzo [d] [1,3] oxazine-2-ketone (flow process A)
With the 6-bromo-4 in DME and the water (40ml/10ml), 4-dimethyl-1,4-dihydro-benzo [d] [1,3] oxazine-2-ketone (1.5g, 5.9mmol), the 3-chlorophenylboronic acid (1.83g, 11.7mmol), four (triphenylphosphines) close-palladium (0) (0.35g, 0.3mmol) and yellow soda ash (2.48g, 23.4mmol) the mixture degassing to remove oxygen, heating 3 hours in 85 ℃ of nitrogen then.Reaction mixture is cooled to room temperature, with saturated aqueous ammonium chloride (20ml) cancellation.Add ethyl acetate (50ml), separately organic layer.(3 * 15ml) extract water layer with ethyl acetate.With the organic layer that the salt water washing merges, MgSO 4Dry.Solvent removed in vacuo, (the hexane: ethyl acetate/2: 1), obtain being the 6-(3-chloro-phenyl-)-4 of light yellow solid of flash chromatography purifying residue on the silica gel, 4-dimethyl-1,4-dihydrobenzo [d] [1,3] oxazine-2-ketone (1.4g, 82%): mp 158-159 ℃; 1H-NMR (DMSO-d 6) δ 10.31 (s, 1H, D 2O is tradable), 7.75 (s, 1H), 7.61 (m, 3H), 7.46 (t, 1H, J=7.9Hz), 7.39 (dd, 1H, J=7.0,1.1Hz), 6.96 (d, 1H, J=8.6Hz), 1.68 (s, 6H); C 16H 14CINO 20.1 H 2The analytical value of O: C, 66.37, H, 4.94, N, 4.84.Measured value: C, 66.14, H, 4.61, N, 4.71.
Embodiment 6
6-(3-methoxyl group-phenyl)-4,4-dimethyl-1,4-dihydro-benzo [d] [1,3]-oxazines-2-ketone
Use flow process A, from 6-bromo-4,4-dimethyl-1,4-dihydro-benzo [d] [1,3] oxazine-2-ketone and the preparation of 3-anisole ylboronic acid.Yellow solid: mp 164-165 ℃; 1H-NMR (DMSO-d 6) δ 10.3 (s, 1H), 7.56 (m, 2H), 7.36 (t, 1H, J=7.89Hz), 7.20 (m, 2H), 6.96 (d, 1H, J=8.88Hz), 6.91 (dd, 1H, J=8.13,2.35Hz), 3.8 (s, 3H), 1.7 (s, 6H); MS (ESI) m/z 284 ([M+H] +, 30%); C 17H 17NO 3Analytical value: C, 72.07, H, 6.05, N, 4.94.Measured value: C, 70.58, H, 5.73, N, 4.67.
Embodiment 7
6-(2-chloro-phenyl)-4,4-dimethyl-1,4-dihydro-benzo [d] [1,3] oxazine-2-ketone
Use flow process A, from 6-bromo-4,4-dimethyl-1,4-dihydro-benzo [d] [1,3] oxazine-2-ketone and the preparation of 2-chlorophenylboronic acid.White solid: mp 181-182 ℃; MS (ESI) m/z 288 ([M+H] +70%); C 16H 14ClNO 2Analytical value: C, 66.79, H, 4.90, N, 4.87.Measured value C, 66.78, H, 4.82, N, 4.55.
Embodiment 8
6-(4-chloro-phenyl)-4,4-dimethyl-1,4-dihydro-benzo [d] [1,3]-oxazines-2-ketone
Use flow process A, from 6-bromo-4,4-dimethyl-1,4-dihydro-benzo [d] [1,3] oxazine-2-ketone and the preparation of 4-chlorophenylboronic acid.255-257 ℃ of white solid mp; 1H-NMR (DMSO-d 6) δ 10.3 (s, 1H), 7.7 (d, 2H, J=8.52Hz), 7.55 (m, 2H), 7.5 (d, 2H, J=8.52Hz), 6.96 (d, 1H, J=8.52Hz), 1.7 (s, 6H); MS (ESI) m/z 288 ([M+H] +, 70%); C 16H 14ClNO 2Analytical value C, 66.79, H, 4.90, N, 4.87.Measured value: C, 66.34, H, 4.76, N, 4.75.
Embodiment 9
6-(3-chloro-phenyl)-4-methyl isophthalic acid, 4-dihydro-benzo [d] [1,3] oxazine-2-ketone
Under the room temperature nitrogen, 1-(4-amino-3 '-chloro-xenyl-3-yl)-ethyl ketone (see embodiment 35,0.15g, add in absolute methanol solution 0.61mmol) sodium borohydride (0.07g, 1.03mmol).After 15 minutes, handle this reaction mixture with frozen water.Add ethyl acetate (30ml) then, separately organic layer is used ethyl acetate (3 * 20ml) extraction water layers.With the organic layer that salt solution (10ml) washing merges, MgSO 4Dry.Except that after desolvating, the residue from the toluene crystallization obtains obtains to be white in color solid 1-(4-amino-3 '-chloro-xenyl-3-yl)-ethanol (0.087g, 58%): 1H-NMR (DMSO-d 6) δ 7.55 (t, 1H, J=1.4Hz), 7.50 (d, 1H, J=7.8Hz), 7.44 (d, 1H, J=2.1Hz), 7.39 (t, 1H, J=8.2Hz), 7.31-7.21 (m, 2H), 6.68 (d, 1H, J=8.1Hz), 5.25 (s, 2H), 5.20 (m, 1H), 4.83 (m, 1H), 1.35 (d, 3H, J=8.8Hz); MS (EI) m/z 247 (M +).
Under the nitrogen, be stirred in 1-(4-amino-3 '-chloro-xenyl-3-yl)-ethanol of doing among the THF (3ml) (0.03g, 0.13mmol) and triphosgene (0.01g, mixture 0.04mmol) 10 minutes.Removing desolvates obtains being white in color solid 6-(3-chloro-phenyl)-4-methyl isophthalic acid, 4-dihydro-benzo [d] [1,3] oxazine-2-ketone (0.031g, 91%): mp 155-156 ℃; 1H-NMR (DMSO-d 6) δ 10.3 (s, 1H), 7.72 (m, 1H), 7.62 (m, 2H), 7.56 (m, 1H), 7.47 (t, 1H, J=8.00Hz), 7.39 (d, 1H, J=8.0Hz), 6.98 (d, 1H, J=8.0Hz), 5.50 (q, 1H, J=6.82Hz), 1.6 (d, 3H, J=6.82Hz); MS (APCI) m/z 274 ([M+H] +, 100%).
Embodiment 10
6-(3-chloro-phenyl)-4-ethyl-1,4-dihydro-benzo [d] [1,3] oxazine-2-ketone
Press the flow process of embodiment 9, with 1-(4-amino-3 '-chloro-xenyl-3-yl)-propyl alcohol and triphosgene preparation.White solid: mp 146-148 ℃; 1H-NMR (DMSO-d 6) δ 10.3 (s, 1H), 7.70 (m, 1H), 7.60 (m, 3H), 7.47 (t, 1H, J=8.22Hz), 7.39 (d, 1H, J=8.28Hz), 6.97 (d, 1H, J=8.22Hz), 5.4 (t, 1H, J=10.9 Hz), 1.9 (m, 2H), 0.97 (t, 3H, J=7.68 Hz); MS (ESI) m/z286 ([M-H] -, 100%).
Embodiment 11
6-(3-chloro-phenyl)-4-phenyl-1,4-dihydro-benzo [d] [1,3] oxazine-2-ketone
Press the flow process of embodiment 9, with 1-(4-amino-3 '-chloro-xenyl-3-yl)-phenylcarbinol and triphosgene preparation.Pale solid: mp 177-178 ℃; 1H-NMR (DMSO-d 6) δ 10.5 (s, 1H), 7.68 (dd, 1H, J=8.7,1.7Hz), 7.62 (t, 1H, J=1.74Hz), 7.54-7.5 (m, 1H), 7.48-7.34 (m, 8H), 7.04 (d, 1H, J=8.7Hz), 6.6 (s, 1H); MS (ESI) m/z 336 ([M+H] +, 30%).
Embodiment 12
3-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazine-6-yl) benzonitrile (flow process B)
With (1 in DME and the water (70ml/15ml), 4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazine-6-yl) boric acid (2.22g, 10mmol), 3-bromobenzyl nitrile (2.18,12mmol), four (triphenylphosphines) close palladium (0) (0.6g, 0.52mmol) and yellow soda ash (2.2g, the degassing of 21mmol) mixture, to remove oxygen, 85 ℃ of heating 3 hours under nitrogen then.This reaction mixture is cooled to room temperature, with saturated aqueous ammonium chloride (20ml) cancellation.Add ethyl acetate, separately organic layer.(3 * 30ml) extract water layer with ethyl acetate.With the organic layer that the salt water washing merges, MgSO 4Dry.Solvent removed in vacuo is with flash chromatography on silica gel purifying residue (hexane: ethyl acetate/1: 1), obtain being the 3-(4 of pale solid, 4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazine-6-yl)-benzonitrile (0.7g, 25%): mp 236-237 ℃; 1H-NMR (DMSO-d 6) δ 10.34 (s, 1H, D 2O is tradable), 8.21 (s, 1H), 8.02 (d, 1H, J=8.1Hz), 7.79 (d, 1H, J=7.7Hz), 7.60-7.70 (m, 3H), 6.98 (d, 1H, J=8.2Hz), 1.71 (s, 6H); C 17H 14N 2O 20.1 H 2The analytical value of O: C, 72.89, H, 5.11, N, 10.00.Measured value: C, 72.75, H, 5.05, N, 9.65.
Embodiment 13
4,4-dimethyl-6-(3-nitrophenyl)-1,4-dihydrobenzo [d] [1,3] oxazine-2-ketone
Use flow process A, from 6-iodo-4,4-dimethyl-1,4-dihydro-benzo [d] [1,3] oxazine-2-ketone and the preparation of 3-nitrophenyl boric acid.Light yellow solid: mp 244-245 ℃; 1H-NMR (DMSO-d 6) δ 10.38 (s, 1H, D 2O is tradable), 8.47 (s, 1H), 8.14-8.20 (m, 2H), 7.70-7.76 (m, 3H), 7.01 (d, 1H, J=8.1Hz), 1.68 (s, 6H); MS (EI) m/z 297 ([M-H] -, 100%).C 16H 14N 2O 4Analytical value: C, 64.42, H, 4.73, N, 9.39.Measured value: C, 63.93, H, 4.91, N, 8.71.
Embodiment 14
6-(3-bromo-5-fluorophenyl)-4,4-dimethyl-1,4-dihydrobenzo [d] [1,3] oxazine-2-ketone
Use flow process B, from (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazine-6-yl) boric acid and 1,3-two bromo-5-fluoridize the benzene preparation.White solid: mp 182-183 ℃; 1H-NMR (DMSO-d 6) δ 10.36 (s, 1H, D 2O is tradable), 7.78 (s, 1H), 7.58-7.65 (m, 3H), 7.49 (dd, 1H, J=8.3,1.8Hz), 6.96 (d, 1H, J=8.5Hz), 1.69 (s, 6H); 19F-NMR (DMSO-d 6) δ-112.46 (m, 1F); MS (CI) m/z 352 ([M+H] +, 78%), 350 ([M+H] +, 75%).C 16H 13BrFNO 2Analytical value: C, 54.88, H, 3.74, N, 4.00.Measured value: C, 54.83, H, 3.82, N, 3.95.
Embodiment 15
3-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazine-6-yl)-5-fluorine benzonitrile
To do the 6-(3-bromo-5-fluorophenyl)-4 among the DME (20ml), 4-dimethyl-2H-benzo [d] [1,3] oxazine-2-ketone (1g, 2.8mmol), zinc cyanide (0.2g, 1.7mmol) and four (triphenylphosphines) close-palladium (0) (0.2g, 0.17mmol) the mixture degassing, to remove oxygen, heating 6.5 hours under 85 ℃ of nitrogen then.This reaction mixture is cooled to room temperature, pours in the cold saturated aqueous ammonium chloride (100ml).White precipitate occurs, filter and collect.(3 * 20ml) wash this white precipitate, are dissolved in the mixture of ethyl acetate (10ml) and methyl alcohol (10ml) with distilled water.This solution is added on the silicagel column, with the mixture wash-out of ethyl acetate and hexane (1: 1).After the evaporation, the solid 3-that obtains being white in color (4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazine-6-yl)-5-fluorine benzonitrile (0.7g, 84%): mp 253-254 ℃; 1H-NMR (DMSO-d 6) δ 10.4 (s, 1H, D 2O is tradable), 8.13 (s, 1H), 7.92 (m, 1H), 7.82 (m, 1H), 7.73 (m, 2H), 6.98 (d, 1H, J=8.2Hz), 1.68 (s, 6H); 19F-NMR (DMSO-d 6) δ-112.25 (m, 1F); MS (EI) m/z 296 (M +, 65%); C 17H 13FN 2O 2Analytical value: C, 68.91, H, 4.42, N, 9.45.Measured value: C, 68.85, H, 4.58, N, 9.14.
Embodiment 16
5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazine-6-yl)-cigarette formonitrile HCN (nicotinonitrile)
Use flow process B, from (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazine-6-yl) boric acid and the preparation of 3-bromo-5-cyanopyridine.Pale solid: mp 290-291 ℃; 1H-NMR (DMSO-d 6) δ 10.41 (s, 1H, D 2O is tradable), 9.21 (d, 1H, J=2.2Hz), 8.97 (d, 1H, J=1.7Hz), 8.68 (t, 1H, J=2.1Hz), 7.76 (m, 2H), 7.01 (d, 1H, J=8.2Hz), 1.70 (s, 6H); MS (ESI) m/z 278 (M-H, 96%).C 16H 13N 3O 20.2H 2The analytical value of O: C, 67.94, H, 4.77, N, 14.85.Measured value: C, 68.04, H, 4.70, N, 14.58.
Embodiment 17
4-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazine-6-yl)-thiophene-2-formonitrile HCN
Use flow process B, from (1,4-dihydro-4,4-dimethyl-2-oxo-3,1-benzoxazine-6-yl) boric acid and the preparation of 4-bromo-2-thiophene formonitrile HCN.Light yellow solid: mp 230-231 ℃ (decomposition); 1H-NMR (CDCl 3) δ 8.32 (s, 1H, D 2O is tradable), 7.83 (d, 1H, J=1.5Hz), 7.61 (d, 1H, J=1.4Hz), 7.43 (dd, 1H, J=8.2,1.9Hz), 7.29 (d, 1H, J=1.8Hz), 6.85 (d, 1H, J=8.2Hz), 1.78 (s, 6H); MS (EI) m/z 283 (M-H, 100%).C 15H 12N 2O 2S0.2 H 2The analytical value of O: C, 62.57, H, 4.34, N, 9.73.Measured value: C, 62.48, H, 4.31, N, 9.64.
Embodiment 18
5-bromo-2-thiophene formonitrile HCN (carbonitrile)
Reflux 5-bromo-2 thiophene carboxaldehyde under nitrogen (96.0g, 500mmol), oxammonium hydrochloride (111.9g, 500mmol), the mixture of pyridine (500ml) and ethanol (500ml) 2 hours.Reaction mixture is cooled to room temperature, and vacuum concentration obtains oil.Grind this raw product 2 times with frozen water, filter and collect the solid that obtains.With the above-mentioned solid of part (44.31g, 215mmoL), (4.2g, 21mmol) mixture heating up in acetonitrile (1.4L) refluxed 3 hours venus crystals four monohydrates.Solvent removed in vacuo is dissolved in residue in the ethyl acetate.With 5% sulfuric acid (2 * 30ml), water (2 * 30ml), salt solution (20ml) washs this solution, MgSO 4Dry.Solvent removed in vacuo is dissolved in residue in the chloroform (1L) of minimum, makes its crystallization.Filter and collect the crystal that obtains, concentrated filtrate, chromatography (silica gel, chloroform) purifying obtain being the title compound (31.5g merges, 58%) of pale solid.IR (film) cm -12200. 1H-NMR(CDCl 3)δ7.39-7.38(d，1H，J＝4.1Hz)，7.10(d，1H，J＝4.0Hz)；MS(EI)m/z 187(M +，98％)189(M +，100％)。
Embodiment 19
5-bromo-4-methyl-2 thiophene carboxaldehyde
(28g adds n-BuLi (2.5M, 153ml, hexane solution 0.383mol) in dried THF (400ml) solution 0.383mol) at diethylamine.-40 ℃ of nitrogen stirred this solution 30 minutes down, were cooled to-78 ℃, dropwise used 2-bromo-3 methyl thiophene (45g, anhydrous THF (450ml) solution-treated 0.254mol).-78 ℃ were stirred this reaction soln 30 minutes, handled with dry DMF (100ml).Allow this mixture be warming up to room temperature, with 1N aqueous hydrochloric acid (1L) cancellation.(3 * 450ml) extract product with ethyl acetate.Water, salt water washing extract, dry (MgSO 4).After the solvent removed in vacuo, the solid title compound that obtains being white in color (46g, 88.3%).Produce matter sample from the hexane crystallization: mp 63-65 ℃; IR (KBr) 1654cm -1 1H-NMR(CDCl 3)δ9.75(S，1H)，7.45(S，1H)，2.26(S，3H)；MS(EI)m/z 204/206(M +)。C 6H 5The analytical value of BrOS: C, 35.14; H, 2.46.Measured value: C, 35.00; H, 2.44.
Embodiment 20
5-bromo-4-methyl-2-thiophene formonitrile HCN
With the flow process of embodiment 18, from 5-bromo-4-methyl-2 thiophene carboxaldehyde preparation.White solid: mp 40-42 ℃; IR (KBr) 2200cm -1 1H-NMR (CDCl 3) δ 7.29 (S, 1H), 2.21 (S, 3H).MS (EI) m/z 201/203 (M +, 98%/100%); C 6H 4The analytical value of BrNS: C, 35.66; H, 1.99; N, 6.93.Measured value: C, 36.00; H, 2.14; N, 6.76.
Embodiment 21
5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazine-6-yl)-thiophene-2-formonitrile HCN
Use flow process B, from 5-bromo-2-thiophene formonitrile HCN and the preparation of (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazine-6-yl) boric acid.Pale solid: mp264-266 ℃. 1H-NMR (DMSO-d 6) δ 10.3 (s, 1H), 7.97 (d, 1H, J=7.9Hz), 7.60-7.66 (m, 3H).6.96(d，1H，J＝8.1Hz)，1.65(S，6H)。MS(APCI)m/z 285(M+H) +，302(M+NH 4) +。C 12H 12N 2O 2The analytical value of S: C, 63.36; H, 4.25; N, 9.85.Measured value: C, 63.01; H, 4.36; N, 9.39.
Embodiment 22
5-(4,4-dimethyl-2-oxo-1,4-dihydro-benzo [d] [1,3] oxazine-6-yl)-4-methyl-thiophene-2-formonitrile HCN
By flow process B, from (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazine-6-yl) boric acid and 5-bromo-4-methyl-2-thiophene formonitrile HCN preparation.Pale solid: mp 195-200 ℃. 1H-NMR (DMSO-d 6) δ 10.2 (s, 1H), 8.32 (s, 1H), 7.41-7.44 (m, 2H), 7.01 (d, 1H, J=8.8Hz), 2.28 (S, 3H), 1.64 (S, 6H); MS (APCI) m/z 299[M+H] +C 16H 14N 2O 2The analytical value of S; C, 64.41; H, 4.75; N, 8.89.Measured value: C, 64.64; H, 4.62; N, 9.39.
Embodiment 23
4-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazine-6-yl)-furans-2-formonitrile HCN
Use flow process B, from (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazine-6-yl) boric acid and the preparation of 4-bromo-2-furans formonitrile HCN.Pale solid: mp 255-256 ℃. 1H-NMR (DMSO-d 6) δ 10.32 (s, 1H, D 2O is tradable), 8.57 (s, 1H), 8.15 (s, 1H), 7.61 (s, 1H), 7.55 (dd, 1H, J=8.3,1.5Hz), 6.92 (d, 1H, J=8.2Hz), 1.65 (s, 6H); MS (ESI) m/z 269 (M+H, 72%).C 15H 12N 2O 3Analytical value: C, 67.16, H, 4.51, N, 10.44.Measured value: C, 67.14, H, 4.59, N, 10.07.
Embodiment 24
4,4-diethyl-6-(3-nitrophenyl)-1,4-dihydrobenzo [d] [1,3] oxazine-2-ketone
Use flow process A, from 4,4-diethyl-6-iodo-1,4-dihydrobenzo [d] [1,3] oxazine-2-ketone and the preparation of 3-nitrophenyl boric acid.Pale solid: mp193-194 ℃. 1H-NMR (CDCl 3) δ 9.19 (s, 1H, D 2O is tradable), 8.38 (t, 1H, J=1.9Hz), 8.20 (m, 1H), 7.83 (m, 1H), 7.61 (t, 1H, J=8.0Hz), 7.50 (dd, 1H, J=8.2,2.0Hz), 7.23 (d, 1H, J=1.7Hz), 6.99 (d, 1H, J=8.3Hz), 2.09 (q, 4H, J=7.4Hz), 0.96 (t, 6H, J=8.3Hz); MS (EI) m/z 325 ([M-H] -, 100%).C 18H 18N 2O 40.3 H 2The analytical value of O: C, 65.17, H, 5.65, N, 8.44.Measured value: C, 65.31, H, 5.60, N, 8.10.
Embodiment 25
6-(3-chloro-phenyl-)-4,4-diethyl-1,4-dihydrobenzo [d] [1,3] oxazine-2-ketone
By flow process A, from 4,4-diethyl-6-iodo-1,4-dihydrobenzo [d] [1,3] oxazine-2-ketone and the preparation of 3-chlorophenylboronic acid.White solid: mp 150-151 ℃. 1H-NMR (CDCl 3) δ 8.52 (s, 1H, D 2O is tradable), 7.50 (s, 1H), 7.31-7.44 (m, 4H), 7.16 (d, 1H, J=1.5Hz), 6.89 (d, 1H, J=8.2Hz), 2.03 (m, 4H), 0.94 (t, 6H, J=7.4Hz); MS (EI) m/z 315 (M +, 53%).C 18H 18ClNO 2Analytical value: C, 68.46, H, 5.75, N, 4.44.Measured value: C, 68.16, H, 5.81, N, 4.32.
Embodiment 26
1-(2-amino-5-bromo-phenyl) hexalin
With the flow process of embodiment 1, prepare by pentamethylene bromide from 2-amino-5-bromo-benzoic acid and Grignard reagent.Clarifying oil body: 1H-NMR (DMSO-d 6) δ 7.07 (d, 1H, J=2.3Hz), 7.03 (dd, 1H, J=8.4,2.4Hz), 6.55 (d, 1H, J=8.6Hz), 5.49 (s, 2H, D 2O is tradable), 5.00 (s, 1H, D 2O is tradable), 2.01 (d, 2H, J=1.8Hz), 1.66-1.77 (m, 2H), 1.44-1.61 (m, 4H), 1.16-1.34 (m, 2H).MS(ESI)m/z 270/272([M+H] +，98％/100％)。
Embodiment 27
6-bromo-spiral shell [4H-3,1-benzoxazine-4,1 '-hexanaphthene]-2-(1H)-ketone
With the flow process of embodiment 2, from 1-(2-amino-5-bromo-phenyl) hexalin and carbonyl dimidazoles preparation.Pale solid: mp 208-210 ℃. 1H-NMR(DMSO-d 6)δ10.26(s，1H)，7.45(d，1H，J＝2.2Hz)，7.39(dd，1H，J＝8.2，2.2Hz)，6.81(d，1H，J＝8.3Hz)，1.90-1.97(m，2H)，1.80-1.85(m，5H)，1.25-1.35(m，1H)；MS(APCl)m/z 296([M+H] +，68％)。
Embodiment 28
Spiral shell-(4,1 '-hexanaphthene-1,4-dihydro-2-oxo--2H-3,1-benzoxazine-6-yl) boric acid
With the flow process of embodiment 4, from 6-bromo-spiral shell [4H-3,1-benzoxazine-4,1 '-hexanaphthene]-2-(1H)-ketone preparation.Pale solid: mp 223-225 ℃. 1H-NMR (DMSO-d 6) δ 10.17 (s, 1H, D 2O is tradable), 7.92 (s, 2H, D 2O is tradable), 7.67 (S, 1H), 7.63 (dd, 1H, J=8.0,1.1Hz), 6.81 (d, 1H, J=7.9Hz), 1.96 (s, 1H), 1.93 (s, 1H), 1.57-1.88 (m, 7H), 1.24-1.34 (m, 1H); MS (ESI) m/z 262 (M+H) +
Embodiment 29
6-(3-chloro-phenyl-)-spiral shell [4H-3,1-benzoxazine-4,1 '-hexanaphthene]-2-(1H)-ketone
Use flow process A, from 6-bromo-spiral shell [4H-3,1-benzoxazine-4,1 '-hexanaphthene]-2 (1H)-ketone and the preparation of 3-chlorophenylboronic acid.Pale solid: mp 165-168 ℃. 1H-NMR(DMSO-d 6)δ10.25(S，1H)，7.74(t，1H，J＝1.9Hz)，7.50-7.67(m，3H)，7.42-7.49(m，1H)，7.35-7.38(m 1H)，6.93-6.95(d，1H，J＝4.2Hz)，1.91-1.98(m，4H)，1.64-1.76(m，3H)，1.60(m，2H)，1.29-1.39(m，1H)；MS(APCI)m/z 328([M+H] +，80％)。
Embodiment 30
6-bromo-spiral shell-[4H-3,1-benzoxazine-4,1 '-pentamethylene]-2-(1H)-ketone
With the flow process of embodiment 26 and 27, from 2-amino-5-bromo-benzoic acid and Grignard reagent by 1, the preparation of 4-dibromobutane.Pale solid: mp 180-185 ℃. 1H-NMR (DMSO-d 6) δ 10.29 (s, 1H, D 2O is tradable), 7.45 (d, 1H, J=2.2Hz), 7.41 (dd, 1H, J=8.1,2.1Hz), 6.82 (d, 1H, J=8.0Hz), 1.96-2.09 (m, 4H), 1.76-1.87 (m, 4H); MS (EI) m/z 281 (M +, 98%).C 12H 12BrNO 2Analytical value: C51.08; H, 4.29; N, 4.96.Measured value: C, 50.53; H, 4.21; N, 4.85.
Embodiment 31
6-(3-chloro-phenyl-)-spiral shell-[4H-3,1 benzoxazine-4,1 '-pentamethylene]-2 (1H)-ketone
Use flow process A, from 6-bromo-spiral shell-[4H-3,1-benzoxazine-4,1 '-pentamethylene]-2-(1H)-ketone and the preparation of 3-chlorophenylboronic acid.Pale solid: mp 140-145 ℃. 1H-NMR(DMSO-d 6)δ10.27(s，1H)，7.75(t，1H，J＝1.8Hz)，7.53-7.63(m，3H)，7.44(t，1H，J＝7.9Hz)，7.36(m，1H)，6.95(d，1H，J＝8.6Hz)，2.09-2.15(m，4H)，1.81-1.89(m，4H)。MS(ESI)m/z 314[M+H] +。C 18H 16ClNO 2Analytical value: C, 68.90; H, 5.14; N, 4.46.Measured value: C, 60.94; H, 4.94; N, 3.78.
Embodiment 32
6-(3-nitrophenyl)-spiral shell [4H-3,1-benzoxazine-4,1 '-hexanaphthene]-2 (1H)-ketone
Use flow process A, from 6-bromo-spiral shell [4H-3,1-benzoxazine-4,1 '-hexanaphthene]-2 (1H)-ketone and the preparation of 3-nitrophenyl boric acid.Pale solid: mp 245-246 ℃. 1H-NMR (CDCl 3) δ 8.39 (t, 1H, J=1.9Hz), 8.20 (dd, 1H, J=8.2,1.4Hz), 8.11 (s, 1H, D 2O is tradable), 7.86 (d, 1H, J=8.0Hz), 7.62 (t, 1H, J=8.1Hz), 7.50 (dd, 1H, J=8.2,1.9Hz), 7.39 (d, 1H, J=1.8Hz), 6.93 (d, 1H, J=8.2Hz), 2.25 (d, 2H, J=12.7Hz), 1.60-1.99 (m, 7H), 1.31-1.42 (m, 1H); MS (EI) m/z 337 ([M-H] -, 100%).C 19H 18N 2O 40.35H 2The analytical value of O: C, 66.21, H, 5.47, N, 8.13.Measured value: C, 66.22, H, 5.43, N, 7.86.
Embodiment 33
2-amino-5-bromo-N-methoxyl group-N-methylbenzene acid amides
Under the room temperature nitrogen, N in second alcohol and water (100ml/10ml), and O-dimethyl hydroxylamine hydrochloric acid (9.42g, 96mmol) and triethylamine (13.5ml, add 5-bromine isatoic acid acid anhydride (20g, solution 74mmol) that second alcohol and water (100ml/10ml) is joined in mixture 96mmol).This reaction mixture of reflux 3 hours.Solvent removed in vacuo is dissolved in residue in the ethyl acetate (100ml), with the 1N NaOH aqueous solution (2 * 20ml), salt solution (30ml) washing, MgSO 4Dry.Except that after desolvating, by flash chromatography on silica gel purifying residue (hexane: ethyl acetate/3: 2), obtain being the 2-amino-5-bromo-N-methoxyl group-N-methylbenzene acid amides (13g, 68%) of pale solid: mp 80-81 ℃; 1H-NMR (CDCl 3) δ 7.49 (d, 1H, J=2.1Hz), 7.26 (dd, 1H, J=8.3,2.0Hz), 6.59 (d, 1H, J=8.4Hz), 4.69 (br, 2H), 3.58 (s, 3H), 3.34 (s, 3H); C 9H 11BrN 2O 2Analytical value: C, 41.72, H, 4.28, N, 10.81.Measured value: C, 41.99, H, 4.16, N, 10.82.
Embodiment 34
4-amino-3 '-chloro-xenyl-3-formonitrile HCN
Use flow process A, from 2-amino-5-bromobenzyl nitrile and the preparation of 3-chlorophenylboronic acid.Pale solid: mp118-119 ℃; 1H-NMR (DMSO-d 6) δ 7.80 (d, 1H, J=2.3Hz), 7.65-7.72 (m, 2H), 7.57 (d, 1H, J=8.0Hz), 7.42 (t, 1H, J=7.9Hz), 7.31 (m, 1H), 6.87 (d, 1H, J=8.7Hz), 6.29 (br, 2H); C 13H 9ClN 2Analytical value: C, 68.28, H, 3.97, N, 12.25.Measured value: C, 67.68, H, 4.06, N, 11.89.
Embodiment 35
1-(4-amino-3 '-chloro-xenyl-3-yl)-ethyl ketone
Will be at the 2-amino in DME and the water (150ml/30ml)-5-bromo-N-methoxyl group-N-methylbenzene acid amides (7.78g, 30mmol), 3-chlorophenylboronic acid (5.63g, 36mmol), four (triphenylphosphines) close palladium (0) (1.73g, 1.5mmol) and yellow soda ash (7.63g, mixture degassing 72mmol) is to remove oxygen, and heating is 3 hours under 85 ℃ of nitrogen.Reaction mixture is cooled to room temperature, handles with salt solution (30ml) and ethyl acetate (100ml).Separately organic layer is used ethyl acetate (3 * 40ml) extraction water layers.With the organic layer that the salt water washing merges, MgSO 4Dry.Except that after desolvating, (silica gel, hexane: ethyl acetate/1: 1) purifying residue obtains being brown butyrous 5-(3-chloro-phenyl-)-N-methoxyl group-N-methylbenzene acid amides to flash chromatography.Under-78 ℃ of nitrogen, (5g dropwise adds ether (1.4M, 28.6ml, 40ml) solution of lithium methide in anhydrous THF solution 17.2mmol) at this benzamide.Stir after 30 minutes, reaction mixture is handled with saturated aqueous ammonium chloride (50ml) at-78 ℃.Add ethyl acetate (100ml), separately organic layer is used ethyl acetate (3 * 20ml) extraction water layers.The organic layer that washing (salt solution) merges, dry (MgSO 4).Remove desolvate after, flash chromatography (silica gel, hexane: ethyl acetate/2: 1) residue obtains being 1-(4-amino-3 '-chloro-xenyl-3-yl)-ethyl ketone (2g, 47%) of yellow solid: mp 89-90 ℃; 1H-NMR (CDCl 3) δ 7.89 (d, 1H, J=2.0Hz), 7.51 (m, 2H), 7.25-7.40 (m, 3H), 6.73 (d, 1H, J=8.6Hz), 6.38 (br, 2H), 2.65 (s, 3H); MS (EI) m/z 268 ([M+Na] +, 60%); C 14H 12The analytical value of ClNO: C, 68.44, H, 4.92, N, 5.70.Measured value: C, 68.40, H, 4.89, N, 5.61.
Embodiment 36
4-allyl group-6-(3-chloro-phenyl-)-4-methyl isophthalic acid, 4-dihydro-benzo [d] [1,3] oxazine-2-ketone (flow process C)
Under 0 ℃ of nitrogen, (0.2g adds allyl group bromination magnesium (1.0M, 3ml, diethyl ether solution 3mmol) in anhydrous THF (10ml) solution 0.82mmol) at 1-(4-amino-3 '-chloro-xenyl-3-yl)-ethyl ketone.This reaction soln slowly is heated to room temperature, under nitrogen, stirred 1 hour.Add saturated aqueous ammonium chloride solution (10ml), and then add ethyl acetate (50ml).Separately organic layer is used ethyl acetate (3 * 10ml) extraction water layers.With the organic layer of saline water extraction merging, and use MgSO 4Dry.Except that after desolvating, and flash chromatography (silica gel, hexane: ethyl acetate 3/1) purifying residue, obtain the amino methanol intermediate, it need not to be further purified and can directly use.
Under the room temperature nitrogen, in the anhydrous THF solution of above-mentioned amino methanol, add CDI (0.38g, 2.3mmol).Heat these reaction solns 12 hours at 55 ℃, be cooled to room temperature then.Solvent removed in vacuo, flash chromatography (silica gel, hexane: ethyl acetate/2: 1) purifying residue, solid 4-allyl group-6-(3-chloro-phenyl-)-4-methyl isophthalic acid obtains being white in color, 4-dihydro-benzo [d] [1,3] oxazine-2-ketone (two go on foot 130mg, 52%): mp 128-129 ℃; 1H-NMR (CDCl 3) δ 8.68 (s, 1H, D 2O is tradable), 7.50 (s, 1H), 7.44 (dd, 1H, J=8.2,1.9Hz), 7.31-7.40 (m, 3H), 7.25 (d, 1H, J=1.6Hz), 6.92 (d, 1H, J=8.2Hz), 5.70-5.85 (m, 1H), 5.17 (m, 2H), 2.76 (m, 2H), 1.79 (s, 3H); MS (ESI) m/z 314 ([M+H] +, 40%); C 18H 16ClNO 2Analytical value: C, 68.90, H, 5.14, N, 4.46.Measured value: C, 68.90, H, 5.18, N, 4.43.
Embodiment 37
6-(3-chloro-phenyl-)-4-methyl-4-propine-1-base-1,4-dihydro-benzo [d] [1,3] oxazine-2-ketone
Use flow process C, handle with CDI then from 1-(4-amino-3 '-chloro-xenyl-3-yl)-ethyl ketone and the preparation of proyl magnesium bromide.White solid: mp 184-185 ℃; 1H-NMR (CDCL 3) δ 8.18 (s, 1H, D 2O is tradable), 7.53 (t, 1H, J=1.7Hz), 7.49 (s, 1H), 7.31-7.48 (m, 4H), 6.92 (d, 1H, J=8.1Hz), 2.02 (s, 3H), 1.87 (s, 3H); MS (ESI) m/z 304 ([M-H] -, 100%); C 18H 14ClNO 2Analytical value: C, 69.35, H, 4.53, N, 4.49.Measured value: C, 69.19, H, 4.37, N, 4.41.
Embodiment 38
6-(3-chloro-phenyl-)-4-ethynyl-4-methyl isophthalic acid, 4-dihydro-benzo [d] [1,3] oxazine-2-ketone
Use flow process C, (0.2g 0.82mmol) with the preparation of ethynyl bromination magnesium, handles with CDI then from 1-(4-amino-3 '-chloro-xenyl-3-yl)-ethyl ketone.Pale solid: mp 185-186 ℃; 1H-NMR (CDCl 3) δ 8.18 (s, 1H, D 2O is tradable), 7.53 (t, 1H, J=1.7Hz), 7.49 (s, 1H), 7.31-7.48 (m, 4H), 6.92 (d, 1H, J=8.1Hz), 2.81 (s, 1H), 1.87 (s, 3H); MS (ESI) m/z 304 ([M-H] -, 100%); C 17H 12ClNO 2Analytical value: C, 68.58, H, 4.06, N, 4.70.Measured value: C, 68.24, H, 3.94, N, 4.65.
Embodiment 39
6-(3-chloro-phenyl-)-4-methyl-4-phenyl-1,4-dihydro-benzo [d] [1,3] oxazine-2-ketone
Use flow process C, (0.2g 0.82mmol) with the phenyl-magnesium-bromide preparation, handles with CDI then from 1-(4-amino-3 '-chloro-xenyl-3-yl)-ethyl ketone.White solid: mp179-180 ℃; 1H-NMR (CDCl 3) δ 8.27 (s, 1H, D 2O is tradable), 7.51-7.57 (m, 2H), 7.28-7.45 (m, 9H), 6.92 (d, 1H, J=8.4Hz), 2.12 (s, 3H); MS (ESI) m/z 348 ([M-H] -, 100%); C 21H 16ClNO 2Analytical value: C, 72.10, H, 4.61, N, 4.00.Measured value: C, 71.72, H, 4.86, N, 3.91.
Embodiment 40
4-benzyl-6-(3-chloro-phenyl)-4-methyl isophthalic acid, 4-dihydro-benzo [d] [1,3] oxazine-2-ketone
Being stirred in 1-(4-amino-3 '-chloro-xenyl-3-yl)-1-benzyl-ethanol of doing among the THF (10ml) under the nitrogen (prepares by flow process C with 1-(4-amino-3 '-chloro-xenyl-3-yl)-ethyl ketone and benzyl magnesium bromide, 0.14g, 0.42mmol) and triphosgene (0.04g, mixture 0.14mmol) 10 minutes.Reaction is removed THF after finishing, with flash chromatography (silica gel, 35% ethyl acetate/hexane) the purifying residue obtains being 4-benzyl-6-(3-chloro-the phenyl)-4-methyl isophthalic acid of pale solid, 4-dihydro-benzo [d] [1,3] oxazine-2-ketone (0.045g, 30%): mp187-188 ℃; 1H-NMR (DMSO-d 6) δ 10.1 (s, 1H), 7.70 (t, 1H, J=2.3Hz), 7.6 (d, 1H, J=8.0Hz), 7.58-7.53 (m, 2H), 7.46 (t, 1H, J=8.0Hz), 7.38 (d, 1H, J=8.0Hz), 7.22-7.17 (m, 3H), 7.06-7.0 (m, 2H), 6.84 (d, 1H, J=9.14Hz), 3.24 (d, 1H, J=14.3Hz), 3.06 (d, 1H, J=14.3Hz), 1.68 (s, 3H); MS (ESI) m/z 364 ([M+H] +, 100%); C 22H 18ClNO 2Analytical value: C, 72.63; H, 4.99; N, 3.85.Measured value: C, 71.82; H, 5.09; N, 3.58.
Embodiment 41
6-(3-chloro-phenyl)-4-cyclopropyl-4-methyl isophthalic acid, 4-dihydro-benzo [d] [1,3] oxazine-2-ketone
Under 52 ℃ of nitrogen, the anhydrous THF solution of cyclopropyl bromination magnesium (with Cyclopropyl Bromide and MAGNESIUM METAL preparation, add in 70mmol) 4-amino-3 '-chloro-xenyl-3-formonitrile HCN (5.2g, 22.7mmol).52 ℃ are stirred this reaction mixture cooling 1 hour, are cooled to room temperature, with 1N aqueous hydrochloric acid (100ml) cancellation.Add ethyl acetate (100ml), (3 * 40ml) extract water layer with ethyl acetate.With the organic layer that the salt water washing merges, MgSO 4Dry.Remove and to desolvate, by silicagel column purifying residue (hexane: ethyl acetate/20: 1), obtain (4-amino-3 '-chloro-xenyl-3-yl)-cyclopropyl-ketone (methanone): 1H-NMR (hydrochloride, DMSO-d 6) δ 8.30 (d, 1H, J=2.1Hz), 7.76 (t, 1H, J=1.7Hz), 7.68-7.63 (m, 2H), 7.43 (t, 1H, J=7.9Hz), 7.32 (m, 1H), 6.88 (d, 1H, J=8.7Hz), 4.50 (bs, 3H), 3.07 (m, 1H), 0.98 (m, 4H); (MS ((+) ESI) m/z 272/274 (M +).
Under-78 ℃ of nitrogen, (0.67g adds methyl-magnesium-bromide (3.0M diethyl ether solution, 2.5ml, solution 7.5mmol) in anhydrous THF (10ml) solution 2.5mmol) at (4-amino-3 '-chloro-xenyl-3-yl)-cyclopropyl-ketone.The reaction mixture cooling slowly is heated to room temperature, under nitrogen, stirred 12 hours, with saturated aqueous ammonium chloride (40ml) cancellation.Add ethyl acetate, separate organic layer, dry (MgSO 4).Remove and desolvate, (hexane: ethyl acetate/7: 1) purifying residue obtains being yellow butyrous 1-(4-amino-3 '-chloro-xenyl-3-yl)-1-cyclopropyl-ethanol: MS (EI) m/z 287/289 (M by silica gel column chromatography +).
Use flow process C, from 1-(4-amino-3 '-chloro-xenyl-3-yl)-1-chloropropyl-ethanol and 1,1 '-carbonyl dimidazoles prepares title compound.Pale solid: mp 158-159 ℃; 1H-NMR (DMSO-d6) δ 10.3 (s, 1H), 7.74 (t, 1H, J=1.71Hz), and 7.67-7.57 (m, 3H), 7.47 (t, 1H, J=7.88Hz), 7.39 (d, 1H, J=8.1Hz), 6.95 (d, 1H, J=8.12Hz), 1.7 (s, 3H), 1.45 (m, 1H), 0.48 (m, 2H), 0.28 (m, 2H); MS (APCI) m/z 314 ([M+H] +, 100%); C 18H 16ClNO 2Analytical value: C, 68.9; H, 5.14; N, 4.46.Measured value: C, 68.13; H, 5.01; N, 4.36.
Embodiment 42
6-(3-chloro-phenyl)-4-cyclopropyl-4-propine-1-base-1,4-dihydro-benzo [d] [1,3] oxazine-2-ketone
With the flow process of embodiment 41, prepare 1-(4-amino-3 '-chloro-xenyl-3-yl)-1-cyclopropyl-1-proyl-methyl alcohol with (4-amino-3 '-chloro-xenyl-3-yl)-cyclopropyl-ketone and proyl magnesium bromide.
Be stirred under the nitrogen 1-(4-amino-3 '-chloro-xenyl-3-yl)-1-cyclopropyl-1-proyl-methylene ketone of doing THF (10ml) (0.02g, 0.064mmol) and 1,1 '-carbonyl dimidazoles (0.016g, mixture 0.096mmol) 10 minutes.After reaction is finished, remove THF, by flash chromatography (silica gel, 40% ethyl acetate/hexane) purifying residue, obtain being 6-(3-chloro-phenyl-)-4-cyclopropyl-4-third-1-alkynyl-1 of light yellow solid, 4-dihydro-benzo [d] [1,3]-oxazines-2-ketone (0.014g, 56%): mp 178-179 ℃; 1H-NMR (DMSO-d 6) δ 10.6 (s, 1H), 7.68 (m, 2H), 7.64 (bs, 1H), 7.59 (d, 1H, J=7.72Hz), 7.49 (t, 1H, J=7.82Hz), 7.42 (d, 1H, J=7.95Hz), 7.02 (d, 1H, J=8.0Hz), 1.86 (s, 3H), 1.66 (m, 1H), 0.82 (m, 1H), 0.66 (m, 3H); MS (ESI) m/z 336 ([M-H] -, 100%).
Embodiment 43
6-(3-chloro-phenyl)-4,4-two or two cyclopropyl-1,4-dihydro-benzo [d] [1,3] oxazine-2-ketone
Press embodiment 41 flow processs, prepare (mp 90-92 ℃ of (4-amino-3 '-chloro-xenyl-3-yl)-two cyclopropyl-methyl alcohol with (4-amino-3 '-chloro-xenyl-3-yl)-cyclopropyl-ketone and cyclopropyl bromination magnesium; MS ((+) ESI) m/z 314 (M+H) +).
With the flow process of embodiment 41, with (4-amino-3 '-chloro-xenyl-3-yl)-two cyclopropyl-methyl alcohol and 1,1 ,-carbonyl dimidazoles prepares title compound.Yellow solid: mp 198-200 ℃; 1H-NMR (DMSO-d 6) δ 10.3 (s, 1H), 7.72 (bs, 1H), 7.67 (bs, 1H), 7.62 (m, 2H), 7.48 (t, 1H, J=7.88Hz), 7.40 (d, 1H, J=8.04Hz), 6.94 (d, 1H, J=8.27Hz), 1.55 (m, 2H), 0.5 (m, 6H), 0.28 (m, 2H); MS (EI) m/z 339 (M +, 40%); C 20H 18ClNO 2: C, 70.69; H, 5.34 N, 4.12.Measured value: C, 69.38; H, 5.07; N, 4.02.
Embodiment 44
6-(3-chloro-phenyl)-4,4-two proyls-1-base-1,4-diynyl benzo [d] [1,3] oxazine-2-ketone
Press the flow process of embodiment 41, handle (mp 112-114 ℃ of (4-amino-3 '-chloro-xenyl-3-yl)-proyl-ketone with the proyl magnesium bromide; MS ((+) ESI) m/z 270/272 (M+H) +), obtain (4-amino-3 '-chloro-xenyl-3-yl)-two proyls-methyl alcohol, then with itself and 1,1 '-carbonyl dimidazoles reaction obtains title compound.151 ℃ of yellow solid: mp (decomposition); 1H-NMR (DMSO-d 6) δ 10.8 (s, 1H), 7.71 (dd, 1H, J=8.52,1.94Hz), 7.69 (m, 2H), 7.61 (d, 1H, J=7.64Hz), 7.50 (t, 1H, J=7.85Hz), 7.43 (d, 1H, J=7.99Hz), 7.06 (d, 1H, J=8.23Hz), 2.0 (s, 6H); MS (APCl) m/z 336 ([M+H] +, 20%).
Embodiment 45
6-(3-bromo-5-fluorophenyl)-1,4,4-trimethylammonium-1,4-dihydrobenzo [d] [1,3] oxazine-2-ketone
Under the room temperature nitrogen, at 6-(3-bromo-5-fluorophenyl)-4,4-dimethyl-1,4-dihydrobenzo [d] [1,3] oxazine-2-ketone (0.34g, and disposable adding sodium hydride in dried DMF (10ml) solution 0.99mmol) (80mg, 2.0mmol).This mixture of stirring at room 30 minutes is handled with methyl iodide (1ml, excessive), stirs 2 hours.In this reaction mixture cooling, add cold saturated ammonium chloride (30ml) solution, filter and collect the white precipitate that forms, with obtaining the solid title compound (0.31g, 87%) that is white in color behind the distilled water wash: mp 157-158 ℃; 1H-NMR (DMSO-d 6) δ 7.83 (s, 1H), 7.76 (dd, 1H, J=8.5,2.0Hz), 7.67 (m, 2H), 7.53 (dt, 1H, J=8.3,1.9Hz), 7.18 (d, 1H, J=8.5Hz), 3.33 (s, 3H), 1.67 (s, 6H); 19F-NMR (DMSO-d6) δ-111.01 (m, 1F); MS (APCI) m/z 364 ([M+H] +, 96%), 366 ([M+H] +, 100%).
Embodiment 46
1-(2-amino-5-chloro-phenyl)-2,2,2-three fluoro-ethyl ketones
Under 0 ℃ of nitrogen, at N-(4-chloro-phenyl-)-2, (6.7g dropwise adds n-BuLi (2.5M, 30ml, hexane solution 70mmol) in anhydrous THF (100ml) solution 30mmol) to 2-dimethyl propylene acid amides.After interpolation finished, 0 ℃ was stirred this solution 40 minutes, with 1-(trifluoroacetyl group) imidazoles (9ml, anhydrous THF (10ml) solution-treated 78mmol).The reaction mixture cooling is warming up to room temperature, and kept 18 hours.In this reaction soln, add saturated aqueous ammonium chloride (50ml), and then add ethyl acetate (100ml).Separate organic layer, solvent removed in vacuo.The residue that obtains is suspended in the 3N aqueous hydrochloric acid (50ml), and reflux is spent the night.This reaction soln is cooled to room temperature, with cold ammonium hydroxide aqueous solution handle to pH more than 8.(3 * 50ml) extract this mixed aqueous solution, use salt water washing organic layer, dry (MgSO with ethyl acetate 4).Remove desolvate after, flash chromatography (silica gel, hexane: ethyl acetate/4: 1) purifying residue obtains being the title compound (1g, 15%) of yellow solid: mp93-94 ℃; 1H-NMR (CDCl 3) δ 7.70 (m, 1H), 7.33 (dd, 1H, J=9.0,2.3Hz), 6.70 (d, 1H, J=9.1Hz), 6.45 (bs, 2H); MS (ESI) m/z222 (M-H, 100%), 224 (M-H, 33%).
Embodiment 47
6-chloro-4-methyl-4-Trifluoromethyl-1,4-dihydro-benzo [d] [1,3] oxazine-2-ketone
Press the flow process of embodiment 2, by at 1-(2-amino-5-chloro-phenyl)-2,2, add methyl-magnesium-bromide in the 2-three fluoro-ethyl ketones, use 1 then, 1 '-carbonyl dimidazoles is handled the methyl alcohol that obtains and is prepared.White solid: mp 216-216 ℃; 1H-NMR (DMSO-d 6) δ 10.91 (bs, 1H, D 2O is tradable), 7.64 (d, 1H, J=1.6Hz), 7.49 (dd, 1H, J=8.6,2.3Hz), 6.95 (d, 1H, J=8.6Hz), 1.91 (s, 3H); 19F-NMR (DMSO-d6) δ-82.0 (s, 1F); MS (EI) m/z 264 ([M-H] -, 100%), 266 ([M-H] -, 33%).C 10H 7ClF 3NO 2Analytical value: C, 45.22, H, 2.66, N, 5.27.Measured value: C, 45.32, H, 2.77, N, 4.83.
Embodiment 48
6-(3-p-methoxy-phenyl)-4-methyl-4-Trifluoromethyl-1,4-dihydro-benzo [d] [1,3] oxazine-2-ketone
In nitrogen with the 6-chloro-4-methyl-4-Trifluoromethyl-1 in no Shui diox, 4-dihydro-benzo [d] [1,3]-oxazines-2-ketone (0.2g, 0.75mmol), 3-anisole ylboronic acid (0.13g, 0.9mmol), potassiumphosphate (0.23g, 1.1mmol) and dichloride (diphenylphosphino) ferrocenyl nickel (II) (52mg, mixture 0.076mmol) is removed oxygen with nitrogen, under the nitrogen 95 ℃ the heating 48 hours.Add again 3-anisole ylboronic acid (0.13g, 0.9mmol) and dichloride (diphenylphosphino) ferrocenyl nickel (II) (52mg 0.076mmol), heats this reaction soln 48 hours under 95 ℃ of nitrogen.Reaction soln is cooled to room temperature.Add saturated ammonium chloride (30ml) aqueous solution and ethyl acetate (50ml).Separately organic layer is used ethyl acetate (3 * 20ml) extraction water layers.With the organic layer of salt water washing merging, and dry (MgSO 4).Except that after desolvating, flash chromatography (silica gel, hexane: ethyl acetate/4: 1) purifying residue, the solid title compound that obtains being white in color (50mg, 20%): mp 178-179 ℃; 1H-NMR (DMSO-d 6) δ 10.85 (bs, 1H, D 2O is tradable), 7.73 (m, 2H), 7.38 (t, 1H, J=7.9Hz), 7.23 (d, 1H, J=7.7Hz), 7.19 (d, 1H, J=1.9Hz), 7.02 (d, 1H, J=8.2Hz), 6.94 (dd, 1H, J=8.2,2.4Hz), 3.88 (s, 3H), 1.98 (s, 3H); 19F-NMR (DMSO-d 6) δ-81.88 (s, 1F); C 17H 14F 3NO 3Analytical value: C, 60.54, H, 4.18, N, 4.15.Measured value: C, 60.58, H, 4.44, N, 4.19.
Embodiment 49
7-(3-methoxyl group-phenyl)-4,4-dimethyl-1,4-dihydro-benzo [d] [1,3]-oxazines-2-ketone
50 ℃ with the 7-chloro-4 in the diox (10ml), 4 '-dimethyl benzo oxazine-2-ketone (0.197g, 0.93mmol), 3-anisole ylboronic acid (0.21g, 1.4mmol), Ni (dppf) Cl 2(0.095g, 0.14mmol) and potassiumphosphate (0.59g, mixture 2.79mmol) placed nitrogen blanket 15 minutes, then 95 ℃ the heating 48 hours.This reaction mixture is cooled to room temperature, adds ethyl acetate (100ml).This organic layer washs 2 times with aqueous ammonium chloride solution (30ml), and salt solution (30ml) washs once, dried over mgso.Flash chromatography (silica gel, 40% ethyl acetate/hexane) purifying residue obtains being clarification butyrous 7-(3-methoxyl group-phenyl)-4,4-dimethyl-1,4-dihydro-benzo [d] [1,3] oxazine-2-ketone (0.090g, 35%).(25ml) grinds this oil body with ether, obtains white solid: mp 167-168 ℃; 1H-NMR (DMSO-d 6) δ 10.3 (s, 1H), 7.42-7.28 (m, 3H), 7.14 (d, 1H, J=8.11Hz), 7.11 (bs, 2H), 6.96 (dd, 1H, J=8.11Hz), 3.56 (s, 3H), 1.52 (s, 6H); MS (EI) m/z 283 ([M+H] +, 90%); C 17H 17NO 3Analytical value: C, 72.07, H, 6.05, N, 4.94.Measured value: C, 71.59, H, 6.08, N, 4.79.
Embodiment 50
6-(3-ethanoyl-phenyl)-4,4-dimethyl-1,4-dihydro-benzo [d] [1,3]-oxazines-2-ketone
With 3-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazine-6-yl) (0.25g 0.9mmol) is dissolved among the THF (10ml) benzonitrile, is cooled to 0 ℃.In this solution, add methyl-magnesium-bromide (3.0M, in ether, 1.8ml, 5.4mmol), this reaction mixture of reflux under the nitrogen.After reaction finishes,, be cooled to room temperature then with this reaction mixture of 1N HCl aqueous solution cancellation.(100ml) extracts this mixture, MgSO with ethyl acetate 4Dry and concentrated.By chromatography (silica gel, 50% ethyl acetate/hexane) this residue of purifying solid 6-(3-ethanoyl-phenyl)-4 that obtains being white in color, 4-dimethyl-1,4-dihydro-benzo [d] [1,3] oxazine-2-ketone (0.031g, 12%): mp178-179 ℃; 1H-NMR (CDCl 3) δ 8.15 (t, 1H, J=1.71Hz), 8.04 (s, 1H), 7.95 (dt, 1H, J=8.85,1.13Hz), 7.76 (dt, 1H, J=7.90,1.43Hz), 7.57 (t, 1H, J=7.72Hz), 7.52 (dd, 1H, J=8.28,2.11Hz), 7.39 (d, 1H, J=1.81Hz), 6.93 (d, 1H, J=8.19Hz), 2.69 (s, 3H), 1.81 (s, 6H); MS (EI) m/z 295 ([M+H] +, 40%).
Embodiment 51
6-(3-benzoyl-phenyl)-4,4-dimethyl-1,4-dihydro-benzo [d] [1,3]-oxazines-2-ketone
With the flow process of embodiment 50, from 3-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazine-6-yl) preparation of benzonitrile and phenyl-magnesium-bromide.White solid: mp 156-157 ℃; 1H-NMR (DMSO-d 6) δ 10.33 (s, 1H), 8.0-7.96 (m, 2H), 7.80 (m, 2H), 7.73-7.56 (m, 7H), 6.99 (d, 1H, J=8.06Hz), 1.67 (s, 6H); MS (EI) m/z 357 ([M+H] +, 40%); C 23H 19NO 3Analytical value: C, 77.29, H, 5.36, N, 3.92.Measured value: C, 75.7, H, 5.28, N, 3.86.
Embodiment 52
4,4-dimethyl-6-[3-(1H-tetrazolium-5-yl)-phenyl]-1,4-dihydrobenzo [d] [1,3] oxazine-2-ketone
3-(4 under the nitrogen in the reflux Zai diox (20ml), 4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazine-6-yl) benzonitrile (0.77g, 2.8mmol), trimethyl silyl trinitride (0.68g, 5.6mmol) and Dibutyltin oxide (0.071g, mixture 0.28mmol).After reaction finishes, remove diox, extract organic layer, NaHCO with ethyl acetate (100ml) 3(100ml) washing.With 1N HCl acidified aqueous solution water layer, extract with ethyl acetate (100ml).MgSO 4Dry organic layer, and concentrate.After ether (20ml) crystallization, obtain being 4 of light yellow solid, 4-dimethyl-6-[3-(1H-tetrazolium-5-yl)-phenyl]-1,4-dihydrobenzo [d] [1,3]-oxazines-2-ketone (0.23g, 26%): mp238-240 ℃; 1H-NMR (DMSO-d 6) δ 10.4 (s, 1H), 8.3 (bs, 1H), 8.02 (d, 1H, J=7.66Hz), 7.9 (d, 1H, J=7.91Hz), 7.72-7.65 (m, 3H), 7.03 (d, 1H, J=8.75Hz), 1.70 (s, 6H); MS (ESI) m/z 320 ([M-H] -, 100%); C 17H 15N 5O 2Analytical value: C, 63.54, H, 4.71, N, 21.79.Measured value: C, 62.16, H, 4.67, N, 21.31.
Embodiment 53
4-(4,4-two cyclopropyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazine-6-yl)-thiophene-2-formonitrile HCN
With the flow process of embodiment 1,2 and 4, with 2-amino-5-bromo-benzoic acid preparation (4,4-two cyclopropyl-1,4-dihydro-2-oxo--2H-3,1-benzoxazine-6-yl) boric acid.White solid: mp 240-242 ℃; 1H-NMR (DMSO-d 6) δ 10.13 (s, 1H), 8.01 (s, 2H), 7.85 (s, 1H), 7.64 (d, 1H, J=7.9Hz), 6.77 (d, 1H, J=7.9Hz), 1.38 (m, 2H), 0.52 (m, 2H), 0.39 (m, 4H), 0.22 (m, 2H).
By flow process B, prepare title compound with (4,4-two cyclopropyl-1,4-dihydro-2-oxo--2H-3,1-benzoxazine-6-yl) boric acid and 4-bromo-2-thiophene formonitrile HCN.White solid: mp 244-245 ℃; 1H-NMR (DMSO-d 6) δ 10.25 (s, 1H), 8.49 (d, 1H, J=0.87Hz), 8.33 (s, 1H), 7.74 (d, 1H, J=1.44Hz), 7.67 (dd, 1H, J=8.28,1.54Hz), 6.90 (d, 1H, J=8.28Hz), 1.53 (m, 2H), 0.59-0.41 (m, 6H), 0.31-0.24 (m, 2H); MS (ESI) m/z 335 ([M-H] -, 100%); C 19H 16N 2O 2The analytical value of S: C, 67.84, H, 4.79, N, 8.33.Measured value: C, 64.92, H, 4.66, N, 7.71.
Embodiment 54
6-(3-bromo-5-fluoro-phenyl)-4,4-two cyclopropyl-1,4-two dihydrobenzos-[d] [1,3] oxazine-2-ketone
By flow process B, with (4,4-two cyclopropyl-1,4-dihydro-2-oxo--2H-3,1-benzoxazine-6-yl) boric acid and 1,3-two bromo-5-fluoridize the benzene preparation.White solid: mp 228-229 ℃; 1H-NMR (DMSO-d 6) δ 10.3 (s, 1H), 7.76-7.72 (m, 2H), 7.65 (dd, 1H, J=8.32,1.74Hz), 7.60 (d, 1H, J=10.36Hz), 7.51 (d, 1H, J=8.3Hz), 6.93 (d, 1H, J=8.31Hz), and 1.63-1.54 (m, 2H), 0.58-0.41 (m, 6H), 0.30-0.28 (m, 2H); MS (APCI) m/z 402/404 ([M-H] -, 100%); C 20H 17BrFNO 2Analytical value: C, 58.48, H, 4.17, N, 3.41.Measured value: C, 58.77, H, 4.23, N, 3.32.
Embodiment 55
3-(4,4-two cyclopropyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] dihydro-6-yl)-5-fluoro-benzonitrile
50 ℃ with the 6-among the DMF (20ml) (3-bromo-5-fluoro-phenyl)-4,4-two cyclopropyl-1,4-dihydro-benzo [d] [1,3] oxazine-2-ketone (0.4g, 1.0mmol), Zn (CN) 2(0.71g, 0.61mmol) and four (triphenylphosphines) close-palladium (0) (0.07g, mixture 0.06mmol) placed nitrogen blanket 15 minutes, then 85 ℃ the heating 1 hour.After being cooled to room temperature, reaction mixture is poured into NH 4Among the Cl (100ml), (3 * 50ml) extract with ethyl acetate.With salt water washing organic layer, MgSO 4Dry and concentrated.Grind the limpid oil body that obtains with ether, obtain white solid.From re-crystallizing in ethyl acetate obtain 3-(4,4-two cyclopropyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazine-6-yl)-5-fluoro-benzonitrile (0.016g, 4.6%): mp 250-252 ℃; 1H-NMR (DMSO-d 6) δ 10.3 (s, 1H), 8.12 (s, 1H), 7.97 (d, 1H, J=10.54Hz), 7.81-7.79 (m, 2H), 7.73 (dd, 1H, J=8.3,1.59Hz), 6.94 (d, 1H, J=8.34Hz), 1.59 (m, 2H), 0.58-0.42 (m, 6H), 0.30-0.28 (m, 2H); MS (ESI) m/z 347 ([M-H] -, 100%); C 21H 17FN 2O 2Analytical value: C, 72.4, H, 4.92, N, 8.04.Measured value: C, 72.4, H, 4.74, N, 7.61.
Embodiment 56
6-(3-bromo-5-methyl-phenyl)-4,4-dimethyl-1,4-dihydrobenzo [d] [1,3] oxazine-2-ketone
By flow process B, with (4,4-dimethyl-1,4-dihydro-2-oxo--2H-3,1-benzoxazine-6-yl) boric acid and 3, the preparation of 5-dibromomethylbenzene.White solid: mp 231-233 ℃; 1H-NMR (DMSO-d 6) δ 10.4 (s, 1H), 7.66 (s, 1H), 7.58-7.56 (m, 2H), 7.50 (s, 1H), 7.37 (s, 1H), 6.95 (d, 1H, J=8.67Hz), 2.37 (s, 3H), 1.67 (s, 6H); MS (ESI) m/z 344/346 ([M-H] -, 100%); C 17H 16BrNO 2Analytical value: C, 58.98, H, 4.66, N, 4.05.Measured value: C, 58.82, H, 4.62, N, 3.94.
Embodiment 57
6-(3-bromo-5-trifluoromethoxy-phenyl)-4,4-dimethyl-1,4-dihydrobenzo [d] [1,3] oxazine-2-ketone
By flow process B, with (4,4-dimethyl-1,4-dihydro-2-oxo--2H-3,1-benzoxazine-6-yl) boric acid and 1, the preparation of 3-two bromo-5-Trifluoromethyl phenyl ethers.White solid: mp 214-216 ℃; 1H-NMR (DMSO-d 6) δ 10.4 (s, 1H), 7.99 (s, 1H), 7.73 (s, 1H), 7.68-7.62 (m, 3H), 6.97 (d, 1H, J=8.0Hz), 1.68 (s, 6H); MS (ESI) m/z 414 ([M-H] -, 100%); C 17H 13BrF 3NO 3Analytical value: C, 49.06, H, 3.15, N, 3.37.Measured value: C, 49.16, H, 3.05, N, 3.30.
Embodiment 58
3-(4,4-dimethyl-2-oxo-1,4-dihydro-benzo [d] [1,3] oxazine-6-yl)-5-methyl-benzonitrile
Press the flow process of embodiment 55, with 6-(3-bromo-5-methyl-phenyl)-4,4-dimethyl-1,4-dihydrobenzo [d] [1,3] oxazine-2-ketone preparation.White solid: mp 256-258 ℃; 1H-NMR (DMSO-d 6) δ 10.4 (s, 1H), 7.99 (s, 1H), 7.86 (s, 1H), 7.67-7.62 (m, 3H), 6.97 (d, 1H, J=8.11Hz), 2.42 (s, 3H), 1.68 (s, 6H); MS (APCI) m/z 293 ([M+H] +, 100%); C 18H 16N 2O 2Analytical value: C, 73.96, H, 5.52, N, 9.58 measured values: C, 73.26, H, 5.46, N, 9.24.
Embodiment 59
3-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazine-6-yl)-5-trifluoromethoxy-benzonitrile
Press the flow process of embodiment 55, with 6-(3-bromo-5-trifluoromethoxy-phenyl)-4,4-dimethyl-1,4-dihydrobenzo [d] [1,3] oxazine-2-ketone preparation.White solid: mp 227-228 ℃; 1H-NMR (DMSO-d 6) δ 10.4 (s, 1H), 8.32 (s, 1H), 8.09 (s, 1H), 7.97 (s, 1H), 7.75-7.72 (m, 3H), 6.99 (d, 1H, J=8.11Hz), 1.7 (s, 6H); MS (APCI) m/z 363 ([M+H] +, 80%); C 18H 13F 3N 2O 3Analytical value: C, 59.67, H, 3.62, N, 7.73.Measured value: C, 59.63, H, 3.55, N, 7.58.
Embodiment 60
6-(3,5-two fluoro-phenyl)-4,4-dimethyl-1,4-dihydrobenzo-[d] [1,3] oxazine-2-ketone
By flow process B, with (4,4-dimethyl-1,4-dihydro-2-oxo--2H-3,1-benzoxazine-6-yl) boric acid and 1-bromo-3, the preparation of 5-two fluorobenzene.White solid: mp 218-219 ℃; 1H-NMR (DMSO-d 6) δ 10.4 (s, 1H), 7.67-7.65 (m, 2H), 7.49 (d, 2H, J=7.73Hz), 7.19 (t, 1H, J=9.29Hz), 6.96 (d, 1H, J=8.88Hz), 1.7 (s, 6H); MS (APCI) m/z 290 ([M+H] +, 100%); C 16H 13F 2NO 2Analytical value: C, 66.43, H, 4.53, N, 4.84.Measured value: C, 66.01, H, 4.46, N, 4.67.
Embodiment 61
6-(3,5-two chloro-phenyl)-4,4-dimethyl-1,4-dihydrobenzo [d] [1,3] oxazine-2-ketone
By flow process A, with 6-bromo-4,4-dimethyl-1,4-dihydro-benzo [d] [1,3] oxazine-2-ketone and 3, the preparation of 5-dichlorophenyl boric acid.White solid: mp 245-246 ℃; 1H-NMR (DMSO-d 6) δ 10.4 (s, 1H), 7.77 (m, 2H), 7.67-7.64 (m, 2H), 7.56 (bs, 1H), 6.96 (d, 1H, J=7.98Hz), 1.7 (s, 6H); MS (EI) m/z 321 ([M+H] +, 40%); C 16H 13Cl 2NO 2Analytical value: C, 59.32, H, 4.11, N, 4.32.Measured value: C, 59.13, H, 4.29, N, 4.17.
Embodiment 62
6-(3,5-di-trifluoromethyl-phenyl)-4,4-dimethyl-1,4-dihydrobenzo [d] [1,3] oxazine-2-ketone
By flow process A, with 6-bromo-4,4-dimethyl-1,4-dihydro-benzo [d] [1,3] oxazine-2-ketone and the preparation of di-trifluoromethyl phenyl-boron dihydroxide.White solid: mp 258-260 ℃; 1H-NMR (DMSO-d 6) δ 10.4 (s, 1H), 8.35 (s, 2H), 8.05 (s, 1H), 7.79-7.76 (m, 2H), 7.01 (d, 1H, J=8.01Hz), 1.7 (s, 6H); MS (ESI) m/z 390 ([M+H] +, 20%); C 18H 13F 6NO 2Analytical value: C, 55.54, H, 3.37, N, 3.6.Measured value: C, 55.5, H, 3.54, N, 3.47.
Embodiment 63
3-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazine-6-yl)-5-methoxyl group-benzonitrile
50 ℃, will be in DME (50ml) and water (25ml) (4,4-dimethyl-1,4-dihydro-2-oxo--2H-3,1-benzoxazine-6-yl) boric acid (4.2g, 19.0mmol), 3-cyano group-5-p-methoxy-phenyl trifluoromethayl sulfonic acid ester (triflate) (5.1g, 19.0mmol), four (triphenylphosphines) close-palladium (0) (1.1g, 0.95mmol), yellow soda ash (4.0g, 38.0mmol) and lithiumbromide (5g, 57mmol) mixture places nitrogen blanket last 15 minute, then 85 ℃ of heating 1 hour.This reactant is cooled to room temperature, adds ethyl acetate (100ml).With ammonium chloride (100ml) solution washing organic layer 2 times,, and concentrate with salt solution (100ml) washing 1 time, dried over mgso.By chromatography (silica gel, 40% ethyl acetate/hexane) purifying obtain being white in color solid 3-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazine-6-yl)-5-methyl-benzonitrile (0.69g, 53%): mp 254-255 ℃; 1H-NMR (DMSO-d 6) δ 10.4 (s, 1H), 7.84 (s, 1H), 7.67-7.61 (m, 2H), 7.55 (bs, 1H), 7.4 (bs 1H) 6.99 (d, 1H, J=7.94Hz), 3.88 (s, 3H), 1.67 (s, 6H); MS (EI) m/z 308 ([M+H] +, 30%); C 18H 16N 2O 3Analytical value: C, 68.13, H, 5.40, N, 8.83.Measured value: C, 68.03, H, 5.22, N, 8.46.
Embodiment 64
6-(3-fluoro-phenyl)-4,4-dimethyl-1,4-dihydro-benzo [d] [1,3]-oxazines-2-ketone
By flow process A, with 6-bromo-4,4-dimethyl-1, [1,3] oxazine-2-ketone and 1-bromo-3-fluoridize the benzene preparation to 4-dihydro-benzo [d].Light yellow solid: mp 181-182 ℃; 1H-NMR (DMSO-d 6) δ 10.4 (s, 1H), 7.62-7.44 (m, 5H), 7.16 (t, 1H, J=2.22Hz), 6.97 (d, 1H, J=8.83), 1.67 (s, 6H); MS (EI) m/z 271 ([M+H] +, 40%); C 16H 14FNO 2Analytical value: C, 69.91, H, 5.3, N, 5.1.Measured value: C, 70.0, H, 5.32, N, 4.92.
Embodiment 65
6-(3-chloro-4-fluoro-phenyl)-4,4-dimethyl-1,4-dihydro-benzo [d] [1,3] oxazine-2-ketone
By flow process A, with 6-bromo-4,4-dimethyl-1,4-dihydro-benzo [d] [1,3] oxazine-2-ketone and the preparation of 1-bromo-3-chloro-4-fluorobenzene.White solid: mp 211-212 ℃; 1H-NMR (DMSO-d 6) δ 10.4 (s, 1H), 7.92 (dd, 1H, J=7.13,2.19Hz), 7.71-7.66 (m, 1H), 7.60-7.57 (m, 2H), 7.49 (t, 1H, J=8.95Hz), 6.96 (d, 1H, J=8.01Hz), 1.67 (s, 6H); MS (EI) m/z 305 ([M+H] +, 20%); C 16H 13ClFNO 2Analytical value: C, 62.86, H, 4.29, N, 4.58.Measured value: C, 62.52, H, 4.45, N, 4.42.
Embodiment 66
3-(1-diethoxymethyl-4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazine-6-yl)-5-fluoro-benzonitrile
160 ℃ of heating 3-(4,4-two dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazine-6-yl)-5-fluoro-benzonitrile (0.25g, 0.84mmol) and triethyl orthoformate (50ml) 12 hours.Vacuum is removed excessive triethyl orthoformate, chromatography (silica gel, 20% ethyl acetate/hexane) purifying, solid 3-(1-diethoxymethyl-4 obtains being white in color, 4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazine-6-yl)-5-fluoro-benzonitrile (0.116g, 33%): mp 123-124 ℃; 1H-NMR (DMSO-d 6) δ 7.97 (d, 1H, J=8.68Hz), 7.66 (bs, 1H), 7.53-7.44 (m, 2H), 7.35-7.32 (m, 2H), 6.65 (s, 1H), 3.88-3.78 (m, 2H), 3.73-3.61 (m, 2H), 1.77 (s, 6H), 1.27 (t, 6H, J=7.05Hz); MS (ESI) m/z 295 ([M-H] -, 100%, lower MW ion, and to lose diethyl acetal consistent); C 22H 23FN 2O 4Analytical value: C, 66.32, H, 5.82, N, 7.03.Measured value: C, 65.89, H, 5.92, N, 6.66.
Embodiment 67
3-fluoro-5-(1-methoxymethyl-4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazine-6-yl)-benzonitrile
Room temperature with sodium hydride (0.061g, 1.53mmol) handle 3-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazine-6-yl)-5-fluorine benzonitrile (0.150g, DMF 0.51mmol) (5ml) solution.Stirred this mixture 30 minutes, (0.062g 7.7mmol) handles with the chloromethyl methyl ether.After reaction finishes, water (25ml) cancellation reaction mixture, (3 * 30ml) extract MgSO with ethyl acetate 4Drying, and concentrate.Chromatography (silica gel, 25% ethyl acetate/hexane) purifying residue, solid 3-fluoro-5-(1-methoxymethyl-4 obtains being white in color, 4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazine-6-yl)-benzonitrile (0.11g, 65%): mp169-171 ℃; 1H-NMR (DMSO-d 6) δ 8.17 (bs, 1H), 8.03 (dt, 1H, J=10.4,2.13Hz), 7.85-7.77 (m, 3H), 7.31 (d, 1H, J=8.49Hz), 5.33 (s, 2H), 3.35 (s, 3H), 1.7 (s, 6H); MS (APCI) m/z 341 ([M+H] +, 50%); C 19H 17FN 2O 3Analytical value: C, 65.32, H, 5.19, N, 8.02.Measured value: C, 64.92, H, 4.96, N, 7.73.
Embodiment 68
Phosphoric acid 6-(3-cyano group-5-fluoro-phenyl)-4,4-dimethyl-4H-benzo [d] [1,3] oxazine-2-base ester Anaesthetie Ether
3-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazine-6-yl)-5-fluorine benzonitrile (0.25g, add in DMF 0.84mmol) (5ml) solution sodium hydride (60%, in oil, 0.101g, 2.53mmol).Stir after 30 minutes, with chloro diethyl phosphoric acid (0.22ml, 1.52mmol) reaction mixture.After reaction finishes, water (25ml) cancellation reaction soln, (2 * 50ml) extract product, MgSO with ethyl acetate 4Dry and concentrated.By chromatography (silica gel, 25% ethyl acetate/hexane) purifying residue, the solid phosphoric acid 6-that obtains being white in color (3-cyano group-5-fluoro-phenyl)-4,4-dimethyl-4H-benzo [d] [1,3] oxazine-2-base ester Anaesthetie Ether (0.064g, 18%): mp 196-198 ℃; 1H-NMR (DMSO-d 6) δ 8.19 (bs, 1H), 8.05 (d, 1H, J=10.4Hz), 7.9-7.8 (m, 3H), 7.51 (d, 1H, J=8.41Hz), 4.33-4.41 (m, 4H), 1.76 (s, 6H), 1.27 (t, 6H, J=7.05Hz); MS (APCI) m/z 433 ([M+H] +, 80%); C 21H 22FN 2O 5The analytical value of P: C, 58.33, H, 5.13, N, 6.48.Measured value: C, 58.1, H, 5.11, N, 6.25.
Embodiment 69
3-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazine-6-yl)-4-fluoro-benzonitrile
By flow process B, with (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazine-6-yl) boric acid and the preparation of 5-bromo-2-fluorine benzonitrile.White solid: mp 229-230 ℃; 1H-NMR (DMSO-d 6) δ 10.4 (s, 1H), 8.15 (dd, 1H, J=7.39,2.12Hz), 7.95-7.89 (m, 1H), 7.59-7.48 (m, 3H), 6.99 (d, 1H, J=8.1Hz), 1.7 (s, 6H); MS (APCI) m/z 297 ([M+H] +, 100%); C 17H 13FN 2O 2Analytical value: C, 68.91, H, 4.42, N, 9.45.Measured value: C, 68.74, H, 4.83, N, 9.10.
Embodiment 70
8-fluoro-4,4-dimethyl-dihydro-benzo [d] [1,3] oxazine-2-ketone
With trifluoroacetic acid with N-(uncle-butoxy carbonyl amino)-3-fluorobenzoic acid (people .Synlett 4 such as Takagishi, 360-2 (1992); Mp 159-161 ℃) go protection to obtain anthranilic acid, handle the neighbour-benzaminic acid that obtains with methyl-magnesium-bromide, generate neighbour-amino dimethylcarbinol.50 ℃ with 1,1 '-carbonyl dimidazoles (2.8g, this neighbour of THF 17.2mmol) (20ml) solution-treated-amino dimethylcarbinol (2.23g, 13.2mmol) 12 hours.After reaction finishes, it is cooled to room temperature, adds ethyl acetate (100ml).With the 10%HCl aqueous solution (2 * 25ml) washing organic layers, MgSO 4Drying, and concentrate.Chromatography (silica gel, 10% ethyl acetate/hexane) purifying residue, the solid 8-fluoro-4 that obtains being white in color, 4-dimethyl-dihydro-benzo [d] [1,3] oxazine-2-ketone (1.3g, 50%): mp 127-128 ℃; 1H-NMR (DMSO-d 6) δ 10.4 (s, 1H), 7.22-7.12 (m, 2H), 7.07-7.00 (m, 2H), 1.6 (s, 6H); MS (APCI) m/z 196 ([M+H] +, 100%); C 10H 10FNO 2Analytical value: C, 61.53, H, 5.16, N, 7.18.Measured value: C, 61.27, H, 5.37, N, 7.02.
Embodiment 71
6-(3-chloro-4-fluoro-phenyl)-8-fluoro-4,4-dimethyl-1,4-dihydrobenzo [d] [1,3]-oxazines-2-ketone
Under the room temperature nitrogen, at 8-fluoro-4, [(0.15g dropwise adds bromine (0.37g, acetate 2.31mmol) (5ml) solution to 1,3] oxazine-2-ketone to 4-dimethyl-dihydro-benzo [d] in acetate 0.77mmol) (5ml) solution.Stir after 10 minutes, concentrate this mixture, the residue that the silicagel column purifying obtains (hexane: ethyl acetate/4: 1), acquisition is the 6-bromo-8-fluoro-4 of pale solid, 4-dimethyl-dihydro-benzo [d] [1,3] oxazine-2-ketone (0.176g, 84%) need not to be further purified and can be directly used in next step.
50 ℃, with the 6-bromo-8-fluoro-4 in DME (10ml) and the water (5ml), 4-dimethyl-dihydro-benzo [d] [1,3] oxazine-2-ketone (0.176g, 0.64mmol), 4-fluoro-3-chlorophenylboronic acid (0.15g, 0.84mmol), four (triphenylphosphines) close palladium (0) (0.04g, 0.032mmol) and yellow soda ash (0.20g, 1.92mmol) mixture placed nitrogen blanket 15 minutes, then 85 ℃ the heating 1 hour.This reaction mixture is cooled to room temperature, adds ethyl acetate (100ml).Organic layer, with salt solution (100ml) washing 1 time, dried over mgso and concentrates with aqueous ammonium chloride solution (100ml) washing 2 times.Chromatography (silica gel, 25% ethyl acetate/hexane) purifying residue, the solid 6-that obtains being white in color (3-chloro-4-fluoro-phenyl)-8-fluoro-4,4-dimethyl-1,4-dihydrobenzo [d] [1,3]-oxazines-2-ketone (0.13g, 66%): mp 246-248 ℃; 1H-NMR (DMSO-d 6) δ 10.5 (s, 1H), 8.00 (dd, 1H, J=7.09,2.32Hz), 7.78-7.73 (m, 1H), 7.62 (dd, 1H, J=11.86,1.77Hz), 7.7 (t, 2H, J=9Hz), 1.7 (s, 6H); MS (APCI) m/z 324 ([M+H] +, 100%); C 16H 12F 2NO 20.5 H 2The analytical value of O: C, 57.76, H, 3.94, N, 4.21.Measured value: C, 57.49, H, 3.69, N, 4.03.
Embodiment 72
6-(3-bromo-phenyl)-4,4-dimethyl-1,4-dihydro-benzo [d] [1,3]-oxazines-2-ketone
By flow process B, with (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazine-6-yl) boric acid and 1, the preparation of 3-dibromobenzene.White solid: mp 174-175 ℃; 1H-NMR (DMSO-d 6) δ 10.35 (s, 1H), 7.88 (bs, 1H), 7.68 (d, 1H, J=7.5Hz), 7.6-7.51 (m, 3H), 7.4 (t, 1H, J=7.5Hz), 6.97 (d, 1H, J=8.57Hz), 1.64 (s, 6H); MS (EI) m/z 331 ([M +], 60%), 333 ([M +], 60%); C 16H 14BrNO 2Analytical value: C, 57.85, H, 4.25, N, 4.22.Measured value: C, 57.7, H, 4.36, N, 4.09.
Embodiment 73
4,4-dimethyl-6-(3-trimethyl silyl ethynyl-phenyl)-1,4-dihydro-benzo [d] [1,3] oxazine-2-ketone
The 6-(3-bromo-phenyl)-4 of heating in triethylamine (20ml) under 80 ℃ of nitrogen, 4-dimethyl-1,4-dihydro-benzo [d] [1,3] oxazine-2-ketone (0.8g, 2.4mmol), trimethyl silyl acetylene (1g, 10mmol), four (triphenylphosphines) close palladium (0) (0.17g, 0.24mmol) and cuprous iodide (I) (0.05g, mixture 28mmol) 3 hours.This reaction mixture is cooled to room temperature, removes and desolvate.Extract residue with ethyl acetate (50ml), with 1NHCl (3 * 20ml) and salt solution (20ml) wash.Separate organic layer, dry (MgSO 4).Except that after desolvating, by silica gel column chromatography (hexane: ethyl acetate/3: 1) purifying residue, the solid title compound that obtains being white in color (0.77g, 92%): mp 240-242 ℃; 1H-NMR (DMSO-d 6) δ 10.3 (s, 1H), 7.74-7.69 (m, 2H), 7.61-7.58 (m, 2H), 7.48-7.40 (m, 2H), 6.96 (d, 1H, J=7.98Hz), 1.67 (s, 6H), 0.25 (s, 9H); MS (EI) m/z 349 ([M +], 50%); C 21H 23NO 2The analytical value of Si0.2 EtOAc: C, 71.32, H, 6.75, N, 3.82.Measured value: C, 71.08, H, 6.64, N, 3.82.
Embodiment 74
6-(3-ethynyl-phenyl)-4,4-dimethyl-1,4-dihydro-benzo [d] [1,3]-oxazines-2-ketone
Under the room temperature nitrogen, be stirred in 4 in the anhydrous methanol, 4-dimethyl-6-(3-trimethyl silyl ethynyl-phenyl)-1,4-dihydro-benzo [d] [1,3] oxazine-2-ketone (0.7g, 2mmol) and the mixture of salt of wormwood (2g, excessive) 4 hours.(100ml) handles this mixture with frozen water, and (2 * 80ml) extract with ethyl acetate.With salt water washing organic layer, use MgSO 4Dry.Remove and desolvate, obtain being the title compound (0.4g, 72%) of pale solid: mp 171-172 ℃; 1H-NMR (DMSO-d 6) δ 10.3, (s, 1H), 7.78 (bs, 1H), 7.72-7.69 (m, 1H), 7.6-7.57 (m, 2H), 7.49-7.43 (m, 2H), 6.97 (d, 1H, J=7.98Hz), 4.25 (s, 1H), 1.67 (s, 6H); MS (EI) m/z 277 ([M +], 100%); C 18H 15NO 20.2 the analytical value of EtOAc: C, 76.56, H, 5.67, N, 4.75.Measured value: C, 76.34, H, 5.4, N, 4.7.
Embodiment 75
3-[3-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazine-6-yl)-phenyl]-cyanoacetylene
Under the room temperature nitrogen, in the stirring the mixture of DMSO, acetonitrile and water (9ml/3ml/0.5ml), add cuprous cyanide (0.193g, 2.2mmol), sodium iodide (11mg, 0.072mmol) and 6-(3-ethynyl-phenyl)-4,4-dimethyl-1,4-dihydro-benzo [d] [1,3] oxazine-2-ketone (0.2g, 0.72mmol).In said mixture, dropwise add the chloro trimethyl silyl then.After interpolation finishes, heated these mixtures 72 hours at 50 ℃.Then reaction mixture is cooled to room temperature, handles with 0.5N HCl cold water solution (50ml).Filter and collect the precipitation that obtains, wash with water.(hexane: ethyl acetate/2: 1) this solid obtains being the title compound (10mg, 4.6%) of pale solid: mp 212-213 ℃ to purifying on silicagel column; 1H-NMR (CHCl 3-d 6) δ 7.96 (s, 1H), 7.77 (s, 1H), 7.65 (d, 1H, J=7.8Hz), 7.60 (d, 1H, J=7.69Hz), 7.51 (d, 1H, J=7.77Hz), 7.45 (dd, 1H, J=8.67,2.21Hz), 7.31 (d, 1H, J=1.55Hz), 6.91 (d, 1H, J=8.19Hz), 1.8 (s, 6H); MS (EI) m/z 302 ([M +], 30%).
Embodiment 76
6-(3-fluoro-5-nitro-phenyl)-4,4-dimethyl-1,4-dihydro-benzo [d] [1,3] oxazine-2-ketone
By flow process B, with (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazine-6-yl) boric acid and the preparation of 1-bromo-3-fluoro-5-oil of mirbane.White solid: mp 260-261 ℃; 1H-NMR (DMSO-d 6) δ 10.4 (s, 1H), 8.37 (bs, 1H), 8.14-8.05 (m, 2H), 7.77-7.74 (m, 2H), 7.01 (d, 1H, J=7.94Hz), 1.7 (s, 6H); MS (ESI) m/z 315 ([M-H] -, 100%); C 16H 13FN 2O 4Analytical value: C, 60.76, H, 4.14, N, 8.86.Measured value: C, 60.34, H, 4.2, N, 8.61.
Embodiment 77
6-(3-chloro-5-fluoro-phenyl)-4,4-dimethyl-1,4-dihydro-benzo [d] [1,3] oxazine-2-ketone
By flow process B, with (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazine-6-yl) boric acid and the preparation of 1-bromo-3-chloro-5-fluorobenzene.White solid: mp 193-194 ℃; 1H-NMR (DMSO-d 6) δ 10.4 (s, 1H), 7.67-7.64 (m, 3H), 7.61-7.57 (m, 1H), 7.41-7.37 (m, 1H), 6.96 (d, 1H, J=8.72Hz), 1.7 (s, 6H); MS (APCI) m/z 306 ([M+H] +, 100%); C 16H 13ClFNO 2Analytical value: C, 62.86, H, 4.29, N, 4.58.Measured value: C, 62.98, H, 4.1, N, 4.6.
Embodiment 78
3-chloro-5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazine-6-yl)-benzonitrile
By flow process B, with (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazine-6-yl) boric acid and the preparation of 1-bromo-3-benzyl chloride nitrile.White solid: mp 256-257 ℃; 1H-NMR (DMSO-d 6) δ 10.4 (s, 1H), 8.22 (bs, 1H), 8.15 (bs, 1H), 7.98 (bs, 1H), 7.74-7.71 (m, 2H), 6.97 (d, 1H, J=8.09Hz), 1.7 (s, 6H); MS (ESI) m/z 311 ([M-H] -, 100%); C 17H 13ClN 2O 2Analytical value: C, 65.29, H, 4.19, N, 8.96.Measured value: C, 65.25, H, 3.92, N, 8.71.
Embodiment 79
6-(3,5-dinitrobenzene-phenyl)-4,4-dimethyl-1,4-dihydro-benzo [d] [1,3] oxazine-2-ketone
By flow process B, with (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazine-6-yl) boric acid and 1-bromo-3, the preparation of 5-dinitrobenzene.Yellow solid: mp 297-298 ℃; 1H-NMR (DMSO-d 6) δ 10.4 (s, 1H), 8.88 (d, 2H, J=1.98Hz), 8.78 (bs, 1H), 7.78-7.82 (m, 2H), 7.04 (d, 1H, J=8.23Hz), 1.7 (s, 6H); MS (APCI) m/z 343 ([M-H] -, 100%); C 16H 13N 3O 6Analytical value: C, 55.98, H, 3.82, N, 12.24.Measured value: C, 55.65, H, 3.7, N, 11.92.
Embodiment 80
5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [e] [1,3] oxazine-6-yl)-the isophthalonitrile preparation.White solid: mp 288-289 ℃; 1H-NMR (DMSO-d 6) δ 10.4 (s, 1H), 8.58 (s, 2H), 8.40 (d, 1H, J=0.77Hz), 7.80-7.75 (m, 2H), 6.99 (d, 1H, J=8.2Hz), 1.7 (s, 6H); MS (EI) m/z 303 ([M +], 20%); C 18H 13N 3O 21.65 H 2The analytical value of O: C, 64.92, H, 4.93, N, 12.62.Measured value: C, 64.74, H, 4.69, N, 12.32.
Embodiment 81
4,4-dimethyl-6-(3-thiazol-2-yl-phenyl)-1,4-dihydro-benzo [d] [1,3] oxazine-2-ketone
With the 6-among the DMF (5ml) (3-bromo-phenyl)-4,4-dimethyl-1,4-dihydro-benzo [d] [1,3] oxazine-2-ketone (0.25g, 0.75mmol), (0.5g, the degassing of 1.3mmol) mixture to be to remove oxygen, 90 ℃ of heating 3 hours under nitrogen then for three-just-butyl-thiazol-2-yl tin.Reaction mixture is cooled to room temperature, handles with frozen water (70ml).Add ethyl acetate, separately organic layer is used salt water washing and dry (MgSO 4).Remove and desolvate, and purifying residue on silicagel column (hexane: ethyl acetate/1: 1), the solid title compound that obtains being white in color (60mg, 23%): mp 223-224 ℃; 1H-NMR (DMSO-d 6) δ 10.4 (s, 1H), 9.13 (s, 1H), 8.45 (s, 1H), 7.94 (bs, 1H), 7.67-7.61 (m, 4H), 7.53 (t, 1H, J=7.68Hz), 7.00 (d, 1H, J=8.81Hz), 1.7 (s, 6H); MS (APCI) m/z 337 ([M+H] +, 100%); C 19H 16N 2O 2S0.25 H 2The analytical value of O: C, 66.94, H, 4.88, N, 8.22.Measured value: C, 66.57, H, 4.65, N, 7.92.
Embodiment 82
6-(3-fluoro-5-methoxyl group-phenyl)-4,4-dimethyl-1,4-dihydro-benzo [d] [1,3] oxazine-2-ketone
By flow process B, from (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazine-6-yl) boric acid and the preparation of 3-bromo-5-fluoroanisole.White solid: mp 181-182 ℃; 1H-NMR (DMSO-d 6) δ 10.4 (s, 1H), 7.62-7.59 (m, 2H), 7.13-7.06 (m, 2H), 6.97-6.94 (d, 1H, J=8.89Hz), 6.80 (dt, 1H, J=10.95,2.12Hz), 3.8 (s, 3H), 1.7 (s, 6H); MS (ESI) m/z 302 ([M+H] +, 100%); C 17H 16FNO 30.1 H 2The analytical value of O: C, 67.36, H, 5.39, N, 4.62.Measured value: C, 67.11, H, 5.44, N, 4.48.
Embodiment 83
6-(3-fluoro-5-trifluoromethyl-phenyl)-4,4-dimethyl-1,4-dihydro-benzo [d] [1,3] oxazine-2-ketone
By flow process B, from (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazine-6-yl) boric acid and the preparation of 1-bromo-3-fluoro-5-trifluoromethylbenzene.White solid: mp 207-208 ℃; 1H-NMR (DMSO-d 6) δ 10.4 (s, 1H), 7.94-7.9 (m, 2H), 7.73-7.7 (m, 2H), 7.63 (d, 1H, J=8.58Hz), 6.99 (d, 1H, J=8.68Hz), 1.7 (s, 6H); MS (EI) m/z 339 ([M +], 60%); C 17H 13F 4NO 2Analytical value: C, 60.18, H, 3.86, N, 4.13.Measured value: C, 59.9, H, 3.99, N, 4.06.
Embodiment 84
6-(5-bromo-pyridin-3-yl)-4,4-dimethyl-1,4-dihydro-benzo [d] [1,3] oxazine-2-ketone
By flow process B, from (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazine-6-yl) boric acid and 3, the preparation of 5-dibromo pyridine.White solid: mp 211-212 ℃; 1H-NMR (DMSO-d 6) δ 10.4 (s, 1H), 8.92 (d, 1H, J=1.9Hz), 8.66 (d, 1H, J=2.09Hz), 8.40 (t, 1H, J=2.02Hz), 7.72-7.68 (m, 2H), 6.99 (d, 1H, J=8.1Hz), 1.7 (s, 6H); MS (APCI) m/z 333 ([M+H] +, 100%), 335 ([M+H] +, 100%); Analytical value: C 15H 13BrN 2O 2: C, 54.07, H, 3.93, N, 8.41.Measured value: C, 54.15, H, 3.89, N, 8.31.
Embodiment 85
6-(5-bromo-1-oxo-pyridin-3-yl)-4,4-dimethyl-1,4-dihydro-benzo [d] [1,3] oxazine-2-ketone
With the 6-in the acetate (5ml) (5-bromo-pyridin-3-yl)-4,4-dimethyl-1,4-dihydro-benzo [d] [1,3] oxazine-2-ketone (0.34g, 1mmol), hydrogen peroxide (30%, mixture 5ml) 60 ℃ the heating 3 hours.This reaction mixture is cooled to room temperature, adds cold saturated Sodium Hydrogen Carbonate solution neutralization.The white precipitate that filter to collect forms is used distilled water wash, the drying solid title compound (0.35g, 100%) that obtains being white in color: mp 157-159 ℃; 1H-NMR (DMSO-d 6) δ 10.4 (s, 1H), 8.69 (s, 1H), 8.53 (s, 1H), 7.99 (s, 1H), 7.73-7.69 (m, 2H), 6.97 (d, 1H, J=8.18Hz), 1.7 (s, 6H); MS (APCI) m/z349 ([M+H] +, 100%), 351 ([M+H] +, 100%); C 15H 13BrN 2O 32.5 H 2The analytical value of O: C, 45.70, H, 4.60, N, 7.11.Measured value: C, 45.34, H, 4.64, N, 7.
Embodiment 86
6-(3-cyano group-5-fluoro-phenyl)-4,4-dimethyl-2-oxo-4H-benzo [d] [1,3] oxazine-1-carboxylic acid tert-butyl ester
Under the room temperature nitrogen, be stirred in 3-in the anhydrous acetonitrile (4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazine-6-yl)-5-fluorine benzonitrile (0.3g ,～1mmol), Di-tert butyl pyrocarbonate (0.33g, 1.5mmol) and the mixture of DMAP (50mg) 4 minutes.With the 1N HCl aqueous solution, salt solution washing reaction mixture, dry (MgSO 4).Except that after desolvating, the solid title compound that obtains being white in color (0.25g, 63%): mp 139-140 ℃; 1H-NMR (CDCl3-d 6) δ 7.66-7.63 (m, 2H), 7.53-7.48 (m, 2H), 7.38-7.35 (m, 2H), 1.79 (s, 6H), 1.62 (s, 9H); MS (APCI) m/z 289 ([M-H] -, 100%); C 22H 21FN 2O 4Analytical value: C, 66.66, H, 5.34, N, 7.07.Measured value: C, 66.7, H, 5.41, N.7.
Embodiment 87
5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazine-6-yl)-2-fluoro-benzonitrile
By flow process B, from (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazine-6-yl) boric acid and the preparation of 1-bromo-2-fluorine benzonitrile.White solid: mp 255-256 ℃; 1H-NMR (DMSO-d 6) δ 10.4 (s, 1H), 8.30 (dd, 1H, J=6.15,2.41Hz), 8.12-8.07 (m, 1H), 7.76-7.58 (m, 3H), 6.97 (d, 1H, J=8.22Hz), 1.7 (s, 6H); MS (APCI) m/z 297 ([M+H] +, 100%); C 17H 13FN 2O 20.1 H 2The analytical value of O: C, 68.50, H, 4.46, N, 9.40.Measured value: C, 68.27, H, 4.81, N, 9.1.
Embodiment 88
4-(8-fluoro-4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazine-6-yl)-thiophene-2-formonitrile HCN
With the flow process of embodiment 4, with 6-bromo-8-fluoro-4, [1,3] oxazine-2-ketone prepares 8-fluoro-(1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazine-6-yl) boric acid to 4-dimethyl-dihydro-benzo [d].
By flow process B, prepare title compound with 8-fluoro-(1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazine-6-yl) boric acid and 4-bromo-2-cyano thiophene.White solid: mp 250-251 ℃; 1H-NMR (DMSO-d 6) δ 10.5 (s, 1H), 8.54 (d, 1H, J=1.42Hz), 8.43 (d, 1H, J=1.35Hz), 7.69 (dd, 1H, J=11.71,1.54Hz), 7.58 (bs, 1H), 1.7 (s, 6H); MS (EI) m/z 302 ([M +], 50%); C 15H 11FN 2O 2S0.45 H 2The analytical value of O: C, 58.04, H, 3.86, N, 9.02.Measured value: C, 58.4, H, 3.89, N, 8.63.
Embodiment 89
3-fluoro-5-(8-fluoro-4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazine-6-yl) benzonitrile
By flow process B, and usefulness 8-fluoro-(1,4-dihydro-4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazine-6 base) boric acid and the preparation of 5-bromo-3-fluorine benzonitrile.White solid: mp 256-257 ℃; 1H-NMR (DMSO-d 6) δ 10.5 (s, 1H), 8.20 (bs, 1H), 8.06 (dt, 1H, J=10.48,2.16Hz), 7.85-7.82 (m, 1H), 7.77 (dd, 1H, J=11.89,1.81Hz), 7.63 (s, 1H), 1.7 (s, 6H); MS (EI) m/z 314 ([M +], 60%).
Embodiment 90
5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazine-6-yl)-thiophene-3-formonitrile HCN
By flow process B, with (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazine-6-yl) boric acid and the preparation of 2-bromo-4-thiophene formonitrile HCN.Pale solid: mp 255-260 ℃; 1H-NMR (DMSO-d 6) δ 10.36 (s, 1H), 8.48 (d, 1H, J=1.1Hz), 7.88-7.87 (d, 1H J=1.3Hz), 7.63 (d, 1H J=1.9Hz), 7.56-7.54 (dd, 1H, J=8.0,2.0Hz), 6.93 (d, 1H, J=8.1Hz), 1.64 (s, 6H) .MS (ESI) m/z 283 (M-H) -
Embodiment 91
2-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazine-6-yl)-thiophene-3-formonitrile HCN
By flow process B, from (1,4-dihydro-4-dimethyl-2-oxo-2H-3,1-benzoxazine-6-yl) boric acid and the preparation of 2-bromo-3-thiophene formonitrile HCN.Pale solid: mp 200-202 ℃; 1H-NMR (DMSO-d 6) δ 10.49 (s, 1H), 7.75 (m, 1H), 7.63 (d, 1H, J=2.2Hz), 7.59 (m, 1H), 7.50 (m, 1H), 7.02 (d, 1H, J=8.1Hz), 1.63 (s, 6H); MS (ESI) m/z 283 (M-H) -
Embodiment 92
6-(1,2,4-thiadiazoles (thiadiazol)-3-base-phenyl)-4,4-dimethyl-1,4-dihydro-benzo [d] [1,3] oxazine-2-ketone
Will be at the 5-[3-bromo-phenyl in the o-Xylol (500ml)]-[1,3,4] oxa-thiazole-2-ketone (21.25g, 82.3mmol), (32.5ml, mixture 329mmol) was 150 ℃ of heating 60 hours for ethyl cyanoformate.From reaction mixture, remove desolvate after, from the ethyl alcohol recrystallization product crystalline 3-[3-bromo-phenyl that obtains being white in color]-[1,2,4] thiadiazoles-5-carboxylic acid, ethyl ester (17.5g, 68%): mp 87-90 ℃; 1H-NMR (CDCl 3) δ 8.53 (t, 1H, J=1.76Hz), 8.28 (dt, 1H, J=5.4,1.2Hz), 7.62 (dq, 1H, J=5.1,1.0Hz), 7.36 (t, 1H, J=7.9Hz), 4.55 (q, 2H, J=7.1Hz), 1.48 (t, 3H, J=7.1Hz); MS ((+) APCI) [M+H] +@m/z 313/315.C 11H 9BrN 2O 2The analytical value of S: C, 42.19, H, 2.90, N, 8.94.Measured value: C, 41.81, H, 3.08, N, 8.78.
With 3-[3-bromo-phenyl]-[1,2,4] thiadiazoles-5-carboxylic acid, ethyl ester (16.8g, 53.5mmol), sodium hydroxide (2.4g, 58.8mmol), the mixture heating up to 100 of distilled water (120ml) and ethanol (20ml) ℃ 2 hours.This reaction mixture is cooled to room temperature.Heating concentrated hydrochloric acid (5.1ml) was with this reaction mixture reheat to 100 ℃ 3 hours.This solution is cooled to room temperature, and (3 * 150ml) extract with ether.With distilled water (organic layer that 3 * 100ml) washings merge, MgSO 4Dry.Remove desolvate after, the 3-[3-bromo-phenyl of the spicule that obtains being white in color]-[1,2,4] thiadiazoles (12.7g, 99%): mp 69-71 ℃; 1H-NMR (CDCl 3) δ 9.89 (s, 1H), 8.52 (t, 1H, J=1.8Hz), 8.28 (dt, 1H, J=5.2,1.3Hz), 7.61 (dq, 1H, J=4.9,1.1Hz), 7.35 (t, 1H, J=7.9Hz); MS ((+) APCI) [M+H] +@m/z 241/243.C 8H 5BrN 2The analytical value of S: C, 39.85, H, 2.09, N, 11.62.Measured value: C, 39.82, H, 2.43, N, 11.33.
By flow process B, will (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazine-6-yl) boric acid is coupled to 3-[3-bromo-phenyl]-[1,2,4] thiadiazoles, obtain being the 6-(1,2,4-thiadiazoles-3-base-phenyl)-4 of pale solid, 4-dimethyl-1,4-dihydro-benzo [d] [1,3]-oxazines-2-ketone (0.5g, 35%): mp214-216 ℃; 1H-NMR (DMSO-d 6) δ 10.40 (s, 1H), 10.36 (s, 1H), 8.49 (s, 1H), 8.23 (d, 1H, J=7.7Hz), 7.83 (d, 1H, J=7.9Hz), 7.66-7.61 (m, 3H), 7.02 (t, 1H, J=4.4Hz), 1.70 (s, 6H); MS ((+) APCI) [M+H] +@m/z 338.
Embodiment 93
6-(3-fluoro-5-thiene-3-yl--phenyl)-4,4-dimethyl-1,4-dihydro-benzo [d] [1,3] oxazine-2-ketone
By flow process B, from 6-(3-bromo-5-fluoro-phenyl)-4,4-dimethyl-1,4-dihydro-benzo [d] [1,3] oxazine-2-ketone and 3 thienylboronic acid preparation.Brown-orange solids: mp 200-203 ℃; 1H-NMR (CDCl 3) δ 8.62 (s, 1H), 7.53 (q, 1H, J=1.4Hz), 7.50 (d, 1H, J=1.5Hz), 7.49 (d, 1H, J=2.0Hz), and 7.45-7.40 (m, 1H), 7.35 (d, 1H, J=1.8Hz), and 7.27-7.24 (m, 2H), 7.15 (dt, 1H, J=5.8,2.0Hz), 6.94 (d, 1H, J=8.2Hz), 1.80 (s, 6H); MS ((-) APCI) [M-H] -@m/z352.C 20H 16FNO 2S0.50 H 2The analytical value of O: C, 66.28, H, 4.73, N, 3.87.Measured value: C, 66.54, H, 5.03, N, 3.52.
Embodiment 94
2-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazine-6-yl)-pyrroles-1-carboxylic acid tert-butyl ester
Under nitrogen gas stream, be stirred in the 6-bromo-4 in the toluene (40ml), 4-dimethyl-1, [(0.87g 3.4mmol) closes palladium (0) (96mg, solution 0.08mmol) 25 minutes with four (triphenylphosphines) to 1,3] oxazine-2-ketone to 4-dihydro-benzo [d].Order adds dehydrated alcohol (10ml) solution and salt of wormwood (0.94g, aqueous solution 7.0mmol) (10ml) of uncle 1--butoxy carbonyl pyrroles-2-boric acid (1.4g.7.0mmol) in this solution.Heat these mixtures 16 hours at 80 ℃, be cooled to room temperature then.This reaction mixture is poured in the saturated Sodium Hydrogen Carbonate aqueous solution (100ml), and (3 * 100ml) extract with ethyl acetate.Merge organic layer, water (100ml) and salt solution (50ml) washing, dried over mgso.This solution is overanxious, and flash chromatography purifying residue (30% ethyl acetate/hexane) on silica gel obtains being the title compound (0.7g, 62%) of pale powder: 176 ℃ of mp. 1HNMR (CDCl 3) δ 1.40 (s, 9H), 1.73 (s, 6H), 6.17 (dd, 1H, J=1.8,3.3Hz), 6.22 (dd, 1H, J=3.3,3.3Hz), 6.77 (d, 1H, J=8.1Hz), 7.13 (d, 1H, J=1.8Hz), 7.23 (dd, 1H, J=1.8,8.1Hz), 7.33 (dd, 1H, J=1.8,3.3Hz), 7.69 (bs, 1H) .MS ((-) ESI) m/z 341[M-H] -C 19H 22N 2O 4Analytical value: C, 66.65; H, 6.48; N, 8.18.Measured value: C, 65.46; H, 6.51; N, 7.74.
Embodiment 95
2-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazine-6-yl) 5-nitro-pyrroles-1-carboxylic acid tert-butyl ester
Room temperature, 2-(4,4-dimethyl-2-oxo-1,4-dihydro-benzo [d] [1,3] oxazine-6-yl)-(0.7g adds Silver Nitrate (0.37g.2.1mmol) in acetonitrile 2.0mmol) (25ml) and methylene dichloride (1ml) solution to pyrroles-1-carboxylic acid tert-butyl ester.After 5 minutes, (0.15ml 2.0mmol), stirred this solution 2 hours to the Acetyl Chloride 98Min. that adding acetonitrile (3ml) is joined.This reaction mixture is toppled in the entry (50ml), and (2 * 50ml) extract with ethyl acetate.Merge organic layer, with salt solution (30ml) washing, dried over mgso.Solution is filtered, vacuum concentration, and make flash chromatography residue (30% ethyl acetate/hexane) at silica gel, with the yellow oil body recrystallization in 5% ethyl acetate/hexane that obtains, acquisition is glassy yellow powdered title compound (350mg, 45%): 125 ℃ of mp. 1H NMR(CDCl 3)δ1.47(s，9H)，1.75(s，6H)，6.26(d，1H，J＝4.2Hz)，6.87(d，1H，J＝8.1Hz)，7.19(d，1H，J＝4.2Hz)，7.34(d，1H，J＝2Hz)，7.4(dd，1H，J＝1.8，8.1Hz)，8.17(bs，1H).MS((+)APCI)m/z 388[M+H] +。C 19H 21N 3O 6Analytical value: C, 58.91; H, 5.46; N, 10.85.Measured value: C, 58.4; H, 5.55; N, 10.18.
Embodiment 96
4,4-dimethyl-6-(5-nitro-1H-pyrroles-2-yl)-1,4-dihydrobenzo [d] [1,3] oxazine-2-ketone
With 2-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazine-6-yl)-5-nitro-pyrroles-1-carboxylic acid tert-butyl ester (0.7g, 1.8mmol) place 25ml round-bottomed flask, this flask to clog with rubber membrane and have nitrogen inlet and allow the effusive nozzle needle of gas.When flask is placed oil bath, keep violent nitrogen gas stream, and be heated to 180 ℃., after 10 minutes this flask is shifted out from oil bath in this temperature, be cooled to room temperature.With dichloromethane/ethyl acetate the brown residue is washed in the bigger flask, absorb on a spot of silica gel.Flash chromatography purifying on silica gel (60% ethyl acetate/hexane) obtains being the title compound (200mg, 40%) of brown powder: 265 ℃ of mp (dec). 1H NMR(DMSO-d 6)δ1.65(s，6H)，6.81(d，1H，J＝4.4Hz)，6.90(d，1H，J＝8.6Hz)，7.25(d，1H，J＝4.2Hz)，7.79(dd，1H，J＝2，8.3Hz)，7.91(d，1H，J＝2Hz)，10.37(s，1H)，13.17(bs，1H).MS((-)ESI)m/z 286[M-H] -。C 14H 13N 3O 4Analytical value: C, 58.53; H, 4.56; N, 14.63.Measured value: C, 58.25; H, 5.10; N, 12.57.
Embodiment 97
4,4-dimethyl-6-(1H-pyrroles-2-yl)-1,4-dihydro-benzo [d] [1,3]-oxazines-2-ketone
With 2-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazine-6-yl)-pyrroles-1-carboxylic acid tert-butyl ester (3.5g, 10mmol) place the 25ml round-bottomed flask, this flask clogs with rubber membrane and has nitrogen inlet and allow the effusive nozzle needle of gas.When flask is placed oil bath, keep violent nitrogen gas stream, and be heated to 180 ℃.After 10 minutes, this flask is shifted out cooling from oil bath in this temperature.With dichloromethane/ethyl acetate the brown residue is washed in the bigger flask, absorb on a spot of silica gel.Flash chromatography purifying on silica gel (60% ethyl acetate/hexane) obtains being the title compound (2g, 80%) of green solid: 202 ℃ of mp (dec). 1H NMR (CDCl 3) δ 1.75 (s, 6H), 6.30 (m, 1H), 6.45 (m, 1H), 6.85 (d, 1H, J=8.5Hz), 6.86 (m, 1H), 7.24 (d, 1H, J=2Hz), 7.33 (dd, 1H, J=2,8.4Hz), 8.44 (bs, 1H), 8.66 (s, 1H) .MS ((+) APCI) m/z 243[M+H] +C 14H 14N 2O 2Analytical value: C, 69.41; H, 5.82; N, 11.56.Measured value: C, 69.20; H, 5.96; N, 11.29.
Embodiment 98
4,4-dimethyl-6-(1-methyl isophthalic acid H-pyrroles-2-yl)-1,4-dihydro-benzo [d] [1,3] oxazine-2-ketone
Room temperature in dimethyl formamide (20ml) 4,4-dimethyl-6-(1H-pyrroles-2-yl)-1,4-dihydro-benzo [d] [1,3] oxazine-2-ketone (1.5g, 6.2mmol) mixture in order add salt of wormwood (4.28g, 31mmol) and liquor kalii iodide (1.16ml, 19mmoD (in dimethyl formamide (5ml)).After 1 hour, with this reaction mixture boiling.Reactant is cooled to room temperature, topples in the entry (50ml), (2 * 50ml) extract with ethyl acetate.Merge organic layer, with salt solution (30ml) washing, dried over mgso is filtered and vacuum concentration.On silica gel, begin column chromatography purification (40% ethyl acetate/hexane), obtain being 230 ℃ of title compound (0.5g, the 31%) mp of pale powder. 1H NMR(CDCl 3)δ1.71(s，6H)，3.42(s，3H)，6.31(dd，1H，J＝2.9，5.9Hz)，6.47(m，1H)，6.88(m，1H)，6.94(d，1H，J＝8.6Hz)，7.26(d，1H，J＝2.2Hz)，7.41(dd，1H，J＝2.2，8.6Hz)，8.43(bs，1H).MS((-)ESI)m/z255[M-H] -。C 15H 16N 2O 2Analytical value: C, 70.29; H, 6.29; N, 10.93.Measured value: C, 68.59; H, 6.16; N, 10.49.
Embodiment 99
4,4-dimethyl-6-(1-methyl-5-nitro-1H-pyrroles-2-yl)-1,4-dihydro-benzo [d] [1,3] oxazine-2-ketone
4,4-dimethyl-6-(1-methyl isophthalic acid H-pyrroles-2-yl)-1,4-dihydro-benzo [d] [1,3] oxazine-2-ketone (0.3g, add in acetonitrile 1.2mmol) (20ml) solution Silver Nitrate (0.21g, 1.26mmol).This solution is cooled to-78 ℃, with Acetyl Chloride 98Min. (0.08ml, acetonitrile 1.2mmol) (1m) solution-treated.This reaction mixture is warming up to room temperature.After 1 hour, reaction mixture is toppled in the entry (50ml), (2 * 50ml) extract with ethyl acetate.Merge organic layer, with salt solution (30ml) washing, dried over mgso is filtered and vacuum concentration.Rapid column chromatography purifying on silica gel (40% ethyl acetate/hexane) obtains being the title compound (5mg, 1%) of yellow solid, mp 180-185 ℃. 1H NMR(CDCl 3)δ1.75(s，6H)，3.45(s，3H)，6.57(dd，1H，J＝2.9，4.3Hz)，7.04(d，1H，J＝8.5Hz)，7.22(dd，1H，J＝2.5，4.3Hz)，7.36(d，1H，J＝2.1Hz)，7.56(dd，1H，J＝2.1，8.5Hz)，9.67(bs，1H)。MS((+)APCI)m/z 302[M+H] +。
Embodiment 100
5-bromo-4-ethylthiophene-2-formaldehyde
By method similar to Example 19, with the preparation of 2-bromo-3-ethylthiophene. 1H-NMR(DMSO-d 6)δ9.82(S，1H)，7.81(S，1H)，2.5(q，2H，J＝7.4Hz)，1.15(t，3H，J＝7.5Hz)。
Embodiment 101
5-bromo-4-ethylthiophene-2-formonitrile HCN
By flow process similar to Example 18, with 5-bromo-4-ethylthiophene-2-prepared formaldehyde.IR(KBr)2221cm -1； 1H-NMR(DMSO-d 6)δ7.87(S，1H)，2.55(q，2H，J＝7.3Hz)，1.18(t，3H，J＝7.6Hz).MS(EI)m/z 215/217(M +)。
Embodiment 102
5-bromo-4-just-the propyl group thiophene-2-formaldehyde
By method similar to Example 19, with 2-bromo-3-just-preparation of propyl group thiophene. 1H-NMR(DMSO-d 6)δ9.82(S，1H)，2.6-2.5(m，2H)，1.65-1.51(m，2H)，1.0(t，3H，J＝4.7Hz)。
Embodiment 103
5-bromo-4-n-propyl thiophene formonitrile HCN
By with the similar method of embodiment 18, with 5-bromo-4-just-preparation of propyl group thiophene-2-formaldehyde. 1H-NMR(DMSO-d 6)δ7.87(S，1H)，2.5(t，2H，J＝5.2Hz)，1.64-1.5(m，2H)，1.91(t，3H，J＝5.1Hz).MS(EI)m/z 229-231(M +)。
Embodiment 104
5-bromo-4-normal-butyl thiophenecarboxaldehyde
By with the similar method of embodiment 19, with 2-bromo-3-just-the butyl thiophene preparation.IR(KBr)1660cm -1。 1H-NMR(DMSO-d 6)δ9.78(S，1H)，7.85(S，1H)，2.57-2.53(m，2H)，1.57-1.53(m，2H)，1.32-1.25(m，2H)，0.88(t，3H，J＝5.2Hz).MS(EI)m/z 246(M +)。
Embodiment 105
5-bromo-4-just-the butyl thiophene formonitrile HCN
By with the similar method of embodiment 18, with 5-bromo-4-just-the butyl thiophene prepared formaldehyde. 1H-NMR(DMSO-d 6)δ7.87(S，1H)，2.58-2.44(m，2H)，1.65-1.48(m，2H)，1.38-1.23(m，2H)，0.89(t，3H，J＝5.3Hz)。MS(EI)m/z 243(M +)。
Embodiment 106
3-(1,2-dihydro-2-oxo-spiral shell [4H-3,1-benzoxazine-4,1-hexanaphthene]-6-yl)-benzonitrile
By flow process B, with spiral shell-(4,1 '-hexanaphthene-1,4-dihydro-2-oxo--2H-3,1-benzoxazine-6-yl) boric acid and the preparation of 3-bromobenzyl nitrile.Brown powder: mp 245-247 ℃. 1H-NMR(DMSO-d 6)δ10.31(S，1H)，8.21(S，1H)，8.02(d，1H，J＝8.0Hz)，7.78(d，1H，J＝7.7Hz)，7.68-7.61(m，3H)，6.97(d，1H，J＝8.2Hz)，1.98-1.96(m，4H)，1.75-1.64(m，5H)，1.40-1.32(m，1H).MS(EI)m/z 318[M +]。C 20H 18N 2O 21/2 H 2The analytical value of O: C 73.38; H, 5.85; N, 8.56.Measured value: C, 73.86; H, 5.81; N, 8.22.
Embodiment 107
3-(1,2-dihydro-2-oxo-spiral shell [4H-3,1-benzoxazine-4,1-hexanaphthene]-6-yl)-5-fluorine benzonitrile
By flow process B, with spiral shell-(4,1 '-hexanaphthene-1,4-dihydro-2-oxo--2H-3,1-benzoxazine-6-yl) boric acid and the preparation of 3-bromo-5-fluorine benzonitrile.White powder: mp 250-253 ℃.IR(KBr)2220cm -1。 1H-NMR(DMSO-d 6)δ10.34(S，1H)，8.13(S，1H)，8.0(d，1H，J＝10.6Hz)，7.80-7.7(m，3H)，6.98-6.95(d，1H，J＝8.1Hz)，1.99-1.97(m，4H)，1.76-1.65(m，6H)，1.37-1.33(m.1H)。MS(EI)m/z 336(M +)。C 20H 17FN 2O 2H 2The analytical value of O: C, 67.78; H, 5.40; N, 7.90.Measured value: C, 67.9; H, 4.93; N, 7.67.
Embodiment 108
4-(1,2-dihydro-2-oxo-spiral shell [4H-3,1-benzoxazine-4,1-hexanaphthene]-6-yl)-2-thiophene formonitrile HCN
By flow process B, with spiral shell-(4,1 '-hexanaphthene-1,4-dihydro-2-oxo--2H-3,1-benzoxazine-6-yl) boric acid and the preparation of 3-bromo-5-cyano thiophene.White crystal: mp 230-232 ℃ .IR (KBr) 2200cm -1 1H-NMR(DMSO-d 6)δ10.29(S，1H)，8.49(S，1H)，8.33(S，1H)，7.69-7.63(m，2H)，6.93-6.91(d，1H，J＝8.2Hz)，1.99-1.87(m，4H)，1.73-1.64(m，5H)，1.38-1.31(m，1H).MS(+)APCI m/z 325(M+H) +。C 18H 16N 2O 2S1/4H 2The analytical value of O: C, 65.73; H, 5.06; N, 8.52.Measured value: C, 65.55; H, 5.06; N, 8.22.
Embodiment 109
5-(1,2-dihydro-2-oxo-spiral shell [4H-3,1-benzoxazine-4,1-hexanaphthene]-6-yl)-2-thiophene formonitrile HCN
By flow process B, with spiral shell-(4,1 '-hexanaphthene-1,4-dihydro-2-oxo--2H-3,1-benzoxazine-6-yl) boric acid and the preparation of 2-bromo-5-cyano thiophene.Brown powder: mp 243-245 ℃. 1H-NMR(DMSO-d 6)δ10.41(s，1H)，7.98-7.97(d，1H，J＝3.9Hz)，7.67-7.60(m，3H)，6.97-6.94(d，1H，J＝8.3Hz)，1.98-1.92(m，4H)，1.74-1.64(m，5H)，1.45-1.21(m，1H)。MS(EI)m/z324(M +)。C 18H 16N 2O 2S 1/2 H 2The analytical value of O: C, 65.08; H, 5.04; N, 8.18.Measured value: C, 64.84; H, 5.09; N, 8.40.
Embodiment 110
5-(1,2-dihydro-2-oxo-spiral shell [4H-3,1-benzoxazine-4,1-hexanaphthene]-6-yl)-4-methyl-2-thiophene formonitrile HCN
By flow process B, with spiral shell-(4,1 '-hexanaphthene-1,4-dihydro-2-oxo--2H-3,1-benzoxazine-6-yl) boric acid and 2-bromo-3-methyl-5-cyano thiophene preparation.White powder: mp 200-203 ℃. 1H-NMR(DMSO-d 6)δ10.4(s，1H)，7.85(s，1H)，7.43-7.40(m，2H)，7.0(d，1H，J＝8.8Hz)，2.27(s，3H)，2.00-1.62(m，9H)，1.42-1.23(m，1H)。MS(EI)m/z 338(M +)。C 19H 18N 2O 2The analytical value of S: C, 67.43; H, 5.36, N, 8.28.Measured value: C, 67.12; H, 5.45; N, 8.05.
Embodiment 111
5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazine-6-yl)-4-ethyl-thiophene-2-formonitrile HCN
By flow process B, with spiral shell-(4,1 '-hexanaphthene-1,4-dihydro-2-oxo--2H-3,1-benzoxazine-6-yl) boric acid and 2-bromo-3-ethyl-5-cyano thiophene preparation.White crystal: mp 160-162 ℃.1H-NMR(DMSO-d 6)δ10.46(s，1H)，7.96(s，1H)，7.40-7.38(m，2H)，7.02-6.99(d，1H，J＝8.8Hz)，2.61(q，2H，J＝7.5Hz)，1.64(s，6H)，1.16(t，3H，J＝7.6Hz)。MS(+)APCI m/z[M+H] +313。C 17H 16N 2O 2S1/4 H 2The analytical value of O: C, 64.43; H, 5.25; N, 8.84.Measured value: C, 64.77; H, 5.23; N, 8.68.
Embodiment 112
5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazine-6-yl)-4-just-propyl group-thiophene-2-formonitrile HCN
By flow process B, with spiral shell-(4,1 '-cycloalkyl-1,4-dihydro-2-oxo--2H-3,1-benzoxazine-6-yl) boric acid and 2-bromo-3-just-propyl group-5-thiophene formonitrile HCN preparation.White crystal: mp 160-162 ℃.IR(KBr)2220cm -1。 1H-NMR(DMSO-d 6)δ10.47(s，1H)，7.93(s，1H)，7.38-7.36(m，2H)，7.01(d，1H，J＝8.7Hz)，2.59-2.48(m，2H)，1.64-1.51(m，2H)，0.85(t，3H，J＝7.3Hz).MS(-ESI)m/z[M-H] -325。C 18H 18N 2O 2S3/4H 2The analytical value of O: C, 63.60; H, 5.78, N, 8.24.Measured value: C, 63.48; H, 5.59; N, 8.04.
Embodiment 113
5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazine-6-yl)-4-just-butyl-thiophene-2-formonitrile HCN
By flow process B, with spiral shell-(4,1 '-hexanaphthene-1,4-dihydro-2-oxo--2H-3,1-benzoxazine-6-yl) boric acid and 2-bromo-3-just-butyl-5-thiophene formonitrile HCN preparation.White crystal: mp 167-168 ℃. 1H-NMR(DMSO-d 6)δ10.46(s，1H)，7.93(s，1H)，7.38-7.36(m，2H)，7.01(d，1H，J＝8.7Hz)，2.59(t，2H，J＝8.1Hz)，1.63(s，6H)，1.58-1.51(m，2H)，1.48-1.17(m，2H)，0.82(t，3H，J＝7.4Hz).MS(-ESI)m/z[M-H] -339。C 19H 20N 2O 2S1/4 H 2The analytical value of O: C, 66.16; H, 5.99; N, 8.12.Measured value: C, 66.33; H, 5.92; N, 7.85.
Embodiment 114
6-(4-cyano group-3-fluorophenyl)-4,4-dimethyl-1,4-dihydrobenzo [d] [1,3]-oxazines-2-ketone
Under the nitrogen, (0.6g 3.0mmol) closed palladium (O) glycol dimethyl ether (20ml) solution (0.2g) 20 minutes with four (triphenylphosphines) to stir 4-cyano group-3-fluoro-bromination benzene.In this mixture, add (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazine-6-yl) boric acid (1.0g, 4.5mmol) and yellow soda ash (1.1g, 10.6mmol) (in 5ml water).Allow this solution reflux 18 hours, be cooled to room temperature then, pour among the 2N NaOH, (3 * 50ml) extract with EtOAc.The extract that water, salt water washing merge, dry (MgSO 4) and evaporation.Column chromatography purification residue (SiO 2, EtOAc: hexane=1: 2) obtain being the title compound (0.05g, 6%) of pale solid: mp:272-275 ℃; 1H-NMR (DMSO-d 6) δ 10.4 (s, 1H), 8.0 (t, 1H, J=7.7Hz), 7.9 (dd, 1H, J=10.3,1.3Hz), 7.8 (dd, 1H, J=6.8,1.4Hz), 7.7 (m, 2H), 6.9 (d, 1H, J=8.9Hz), 1.7 (s, 6H); MS (EI) M +@m/z 296.
Embodiment 115
6-(4-fluoro-phenyl)-4,4-dimethyl-1,4-dihydro-benzo [d] [1,3]-oxazines-2-ketone
By flow process B, with (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazine-6-yl) boric acid and the preparation of 1-bromo-4-fluorobenzene.Canescence crystal: mp 232-233 ℃. 1H-NMR (DMSO-d 6) δ 10.3 (s, 1H), 7.74 (m, 2H), 7.53 (m, 2H), 7.28 (m, 2H), 6.96 (d, 1H, J=8.9Hz), 1.63 (s, 6H).
Embodiment 116
6-(3,4-two fluoro-phenyl)-4,4-dimethyl-1,4-dihydro-benzo [d] [1,3] oxazine-2-ketone
By flow process B, with (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazine-6-yl) boric acid and 1-bromo-3, the preparation of 4-two fluorobenzene.Canescence crystal: mp 207-208 ℃. 1H-NMR(DMSO-d 6)δ10.35(s，1H)，7.79(m，1H)，7.40-7.63(m，4H)，6.95(d，1H，J＝8.9Hz)，1.62(s，6H)。
Embodiment 117
6-(2-fluoro-phenyl)-4,4-dimethyl-1,4-dihydro-benzo [d] [1,3]-oxazines-2-ketone
By flow process B, with (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazine-6-yl) boric acid and the preparation of 1-bromo-2-fluorobenzene.Canescence crystal: mp 164-165 ℃. 1H-NMR(DMSO-d 6)δ10.33(s，1H)，7.56(m，1H)，7.25-7.45(m，4H)，6.98(d，1H，J＝8.7Hz)，1.64(s，6H)。
Embodiment 118
3-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3]-oxazines-6-yl) phenylacetonitrile
With 3-bromophenyl acetonitrile and the preparation of (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazine-6-yl) boric acid.White solid: mp 188-190 ℃; 1H-NMR (DMSO-d 6) δ 10.33 (s, 1H), 7.62 (m, 2H), 7.55 (m, 2H), 7.48 (d, 1H, J=8.00Hz), 7.33 (d, 1H, J=7.57Hz), 6.99 (d, 1H, J=8.81Hz), 4.09 (s, 2H), 1.67 (s, 6H); MS m/z 291 (M-H).C 18H 16N 2O 20.3 H 2O analytical value: C, 72.61, H, 5.62, N, 9.41.Measured value: C, 73.00, H, 5.43, N, 8.81.
Embodiment 119
5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazine-6-yl) furans-2-formonitrile HCN
By flow process B, with 2-bromo-5-cyano group furans (1.0g, 5.6mmol) (J.Med.Chem. (1997), 40 (23), 3804-3819) with (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazine-6-yl) boric acid (1.8g, 8.18mmol) the preparation title compound, white solid (0.39g, 1.45mmol, 17%): mp.257-260C; 1H-NMR (DMSO-d 6) 10.48 (s, 1H), 7.73-7.70 (m, 3H), 7.19 (d, 1H, J=3.8Hz), 6.98 (d, 1H, J=8.9Hz), 1.66 (s, 6H); MS ((+)-APCI) m/z=269 (M+H) +
Embodiment 120
3-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazine-6-yl)-2-fluoro-benzonitrile
Under the nitrogen, with trimethyl orthoformate (0.22ml, 2mmol) and tosic acid (catalytic amount) handle 3-bromo-2-fluorobenzoic acid in the dried methyl alcohol (5ml) (0.219g, 1mmol), reflux then.After 16 hours, evaporate this mixture, residue is at water and Et 2Layering between O.With saturated sodium bicarbonate solution, water, salt water washing organic layer, dry (MgSO 4) and evaporation, obtain 3-bromo-2-fluorophenyl carbamate (0.195g, 0.84mmol, 84%): 1H-NMR (CDCl 3) δ 7.90-7.85 (m, 1H), 7.71-7.65 (m, 1H), 7.10 (dt, 1H, J=8.0,1.0Hz), 3.94 (s, 3H): MS (EI) 232 (M +).
Under-78 ℃ of nitrogen, will (3.077g, solution 13.2mmol) are used in two in the toluene-different-butyl aluminum hydride, and (1M, 15.7ml 15.7mmol) handle at the above-claimed cpd in the dried toluene (80ml).At-78 ℃ after 1 hour, with the HCl aqueous solution (3M, 16ml) cancellation mixture.This mixture is warming up to room temperature, at EtOAc/H 2Layering between O is extracted water layer with EtOAc, washes the organic layer of merging with water, dry (MgSO 4) and the evaporation obtain 3-bromo-2-fluorobenzaldehyde (2.63g, 12.9mmol, 98%), it need not to be further purified and can be directly used in next step: 1H-NMR (CDCl 3) δ 10.35 (s, 1H), 7.82 (m, 2H), 7.18 (t, 7.8Hz).
With above-claimed cpd (2.63g, 12.9mmol), oxammonium hydrochloride (1.0g, 14mmol) and potassium acetate (1.37g, mixture 14mmol) places ethanol/H 2Among the O (60ml, 8: 2), this mixture of reflux.After 30 minutes, cool off this mixture, evaporation, layering between EtOAc and water.With salt water washing organic layer, dry (MgSO 4), evaporation obtains 3-bromo-2-fluorobenzaldehyde oxime, and it need not further evaluation can be directly used in next step.
Under the room temperature nitrogen, (0.75g 3.43mmol) closes (0.2g) solution in glycol dimethyl ether (30ml) of palladium (0) with four (triphenylphosphines) to stir above-claimed cpd.After 15 minutes, add (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazine-6-yl) boric acid (1.1g, 5.0mmol) and the aqueous solution (10ml) of yellow soda ash (1.35g), this mixture of reflux.After 16 hours, cool off this mixture, it distributes between water and EtOAc, with saturated sodium carbonate solution, salt water washing organic layer, and dry (MgSO 4) and evaporation.Then residue is dissolved in the acetonitrile (50), handles reflux with crystal aerugo (0.2g).After 16 hours, with mixture cooling and evaporation.Residue distributes between water and EtOAc, uses dilute sulphuric acid (1N), water, salt water washing organic layer then, dry (MgSO 4) and evaporation.Residue is carried out column chromatography (SiO 2, EtOAc/ hexane, gradient elution), then from EtOAc-hexane recrystallization, the solid title compound that obtains being white in color (0.176g, 0.59mmol): mp.192-198 ℃; 1H-NMR (CDCl 3) δ 9.15 (s, 1H), 7.69-7.58 (m, 2H), 7.42-7.31 (m, 3H), 6.99 (d, 1H, J=8.2Hz), 1.78 (s, 6H); MS ((+) ESI) 297[M+H] +
Embodiment 121
Pharmacology
Compound of the present invention is tested with correlation test as described below, in vitro tests their scope of validity be 0.01nM to 5 μ M, be 0.001 to 300mg/kg in the in vivo test.
Table 1
Selected cyclic carbramates derivative is as the effectiveness of PR antagonist in following external and body inner model:
HPR decidua CV-1
Compound R 1R 2R 3IC 50(nM) IC 50(mg/kg)
1 3-cyano group-4-fluorophenyl Me Me 55 80%@1 *
2 3-fluoro-5-trifluoromethyls-phenyl Me Me 54 50%@1
3 3-fluorophenyl Me Me, 6 80%@3
43,5-two chloro-phenyl Me Me 134 60%@1
5 5-cyano group-2-fluorophenyl Me Me 68 60%@1
6 3-fluoro-5-nitrophenyl Me Me, 11.5 50%@1
7 4-(2-cyano group-furyl) Me Me, 30 75%@3
8 3-bromo-5-fluorophenyl Me Me, 11 50%@3
9 3-cyano group-4-fluorophenyl Me Me 13 6.96 ± 0.84
10 5-(2-cyano group-4-spirocyclohexyl 2.7 50%@10
The methylthio group phenyl)
11 5-(2-cyano group sulfo--phenyl) spirocyclohexyl 12 50%@10
12 5-(2-cyano group sulfo--phenyl) Me Me, 19 3.34 scholars 0.22
13 3-bromophenyl Me Me 11.5 3
14 3-chloro-5-fluoro-phenyl Me Me, 22 50%@3
15 3-cyano group-5-fluoro-phenycyclopropyl cyclopropyl 22 3
16 5-(3-bromo-pyridyl) Me Me 26 50%@3
17 4-(2-cyano group sulfo--phenyl) Me Me 12.7 2.3 ± 0.46
18 5-(2-cyano group-4-Me Me 5.23 1.5
Methylthio group is for phenyl)
19 3-cyano group-5-fluoro-phenyl Me Me 13.8 0.35
20 3-chloro-4-fluoro-phenyl Me Me 37 1
ND, undetermined; *Inhibition per-cent at deciding dosage
A. extracorporeal biology
Measure extracorporeal biology by the following method: (1) competitive radioligand combination: with having the A type people progesterone receptor of Progesterone as radioligand; (2) cotransfection test can provide with agonist EC 50With antagonist IC 50The functional vigor that value is expressed; (3) T47D cell proliferation, this provides the another kind of functional trial of agonist and antagonist data; (4) T47D cell alkaline phosphatase test, this also is a kind of functional trial that agonist and antagonist data are provided.
1.hPR in conjunction with testing: with reference to Pathirana, C.; Stein, R.B.; Berger, T.S.; Fenical, W.; Ianiro, T.; Mais, D.E.; Torres, A.; Glodman, M.E., " from the non-steroid class people progesterone receptor modulators of marine alga cymoplia barbata ", and J.Steroid Biochem.Mol.Biol., 1992,41,733-738 carries out.
2.CV-1 the test of the PRE-luciferase in the cell
The purpose of this test is based on compound influence to PRE-luciferase reporter activity in the CV-1 cell of personnel selection PR and PRE-luciferase plasmids cotransfection, determines the progestogenic or the anti-pregnant effect of compound.Material used in this test is as follows:
A. substratum: growth medium is as follows: contain 10% (v/v) foetal calf serum (hot deactivation), 0.1mM MEM non-essential amino acid, 100U/ml penicillin, 100mg/ml Streptomycin sulphate and 2mM GlutaMax (GIBCO, DMEM BRL) (BioWhittaker).Test medium is as follows: foetal calf serum (hot deactivation), 0.1mM MEM non-essential amino acid, 100U/ml penicillin, 100mg/ml Streptomycin sulphate and the 2mM GlutaMax (GIBCO, the no phenol red DMEM (BioWhittaker) BRL) that contain the desorb of 10% (v/v) activated carbon.
B. the cultivation of cell, transfection, processing and luciferase test
CV-1 cell stoste is maintained in the growth medium.With 1.2 * 10 7The calf thymus DNA that individual cell, 5mg pLEM plasmid (inserting hPR-B at Sph1 and BamH1 site), 10mg pGL3 plasmid (two PRE are arranged in the luciferase sequence upstream) and 50mg supersound process are crossed carries out cotransfection as carrier DNA (250ml).
In 260V and 1,000mF carries out electroporation with Biorad Gene Pulser II.Behind the electroporation, cell is resuspended to growth medium, and on 96 orifice plates, inoculates with 40,000 cells/well (200 μ l).After the overnight incubation, change substratum into test medium.In test medium, handle these cells then with contrast or test compounds.In the presence of the 3nM Progesterone, measure the contraception activity of compound.Handle after 24 hours, discard substratum, (GIBCO BRL) washs these cells 3 times with D-PBS.Each hole adds 50 μ l cell lysis buffer solution, and (WI), dull and stereotyped (Lab LineInstrument Inc) goes up vibration 15 minutes at the titration oscillator plate for Promega, Madison.Measure the activity of luciferase with the luciferase reagent of Promega.
C. interpretation of result
Various processing repeat 4 times at least.Be matched with the variance and the non-linear dose response curve of agonist and antagonist pattern with the data analysis of logarithm conversion.Reduce the influence of outlier (outlier) with the Huber weighted method.With the numerical evaluation EC that converts again 50Or IC 50In two one-way analysises of variance and non-linear response analysis, and use JMP software (SAS Institute, Inc.).
D. control compound
Progesterone and trimegestone (trimegestone) be progestogen in contrast, and RU486 is antiprogestin in contrast.All control compounds are all tested in full dose response curve, and calculate EC 50Or IC 50Value.
The expectation EC of contrast progestogen in three independent studies of table 2. 50, standard deviation (SE) and 95% fiducial interval (CI)
EC50 95％CI
Compound Experiment (nM) SE Lower limit The upper limit
Progesterone 1 0.616 0.026 0.509 0.746
2 0.402 0.019 0.323 0.501
3 0.486 0.028 0.371 0.637
Trimegestone 1 0.0075 0.0002 0.0066 0.0085
2 0.008 10.0003 0.0070 0.0094
3 0.0067 0.0003 0.0055 0.0082
The expectation IC of antiprogestin RU486 in three independent studies of table 3. 50, standard deviation (SE) and 95% fiducial interval (CI)
IC 50 95％CI
Compound experiment (nM) SE lower limit upper limit
RU486 1 0.028 0.002 0.01 90.042
2 0.037 0.002 0.029 0.048
3 0.019 0.001 0.013 0.027
Progestogenic activity: compare with control vector, the compound that makes the PRE-uciferase activity significantly increase (p＜0.05) is thought activated.
Anti-pregnant activity: the compound that significantly reduces the activity (p＜0.05) of 3nM Progesterone inductive PRE-luciferase.
EC 50: in the time of increasing the peaked semiactive of PRE-uciferase activity, compound concentrations (being defaulted as " nM ") and standard deviation.
IC 50: in the time of reducing the peaked semiactive of 3nM Progesterone inductive PRE-uciferase activity, compound concentrations (being defaulted as " nM ") and standard deviation.
3.T47D the proliferation experiment of cell
The purpose of this experiment is to measure progestogenic and anti-pregnant effectiveness with the cell proliferation experiment of T47D cell.Measure compound to DNA synthetic effect in the T47D cell.Below be this experiment used material and method:
A. growth medium: be supplemented with 10% (v/v) foetal calf serum (not heat inactivation), 100U/ml penicillin, 100mg/ml Streptomycin sulphate and 2mM GlutaMax (GIBCO, DEME BRL): F12 (1: 1) (GIBCO, BRL).
B. handle substratum: be supplemented with 0.5% activated carbon desorb foetal calf serum, 100U/ml penicillin, 200mg/ml Streptomycin sulphate and 2mM GlutaMax (GIBCO, no phenol red minimum essential medium (MEM) BRL) (#51200-038 GIBCO, BRL).
C. cell cultures
T47D cell stoste is maintained in the growth medium.BrdU is mixed experiment, the amount (in growth medium) of cell with 10,000 cells/well placed cell in 96 orifice plates (Falcon, BectonDickinson Labware).After the overnight incubation, change substratum into the processing substratum, before processing, cultivated these cells again 24 hours.Compound stoste is dissolved in appropriate carriers (in 100% ethanol or 50% ethanol/50%DMSO), with handling the substratum dilution, adds to cell then.Progestogen and antiprogestin control compound are all tested in full dose-response curve mode.The final concentration of carrier is 0.1%.In control wells, cell is only accepted carrier.In the presence of 0.03nM trimegestone (contrast progestogen agonist), measure antiprogestin.Handle after 24 hours, discard substratum, with 10mM BrdU (Amersham Life Science, Arlington Heights, IL) labeled cell 4 hours in handling substratum.
D. cell proliferation experiment
When the BrdU mark finishes, discard substratum, by supplier's explanation, measure mixing of BrdU with cell proliferation ELISA test kit (#RPN 250, Amersham Life Science).In brief, cell is fixed 30 minutes in containing the ethanol of fixing agent, in the damping fluid of blockading, cultivate 30 minutes then to reduce background.The anti-BrdU antibody of peroxidase labelling is added in the hole, cultivated 60 minutes.With PBS rinsing cell 3 times, with 3,3 ', 5,5 '-tetramethyl benzidine (TMB) substrate cultivation 10-20 minute (effectiveness that depends on the compound of being tested).Add 25 μ l 1M sulfuric acid then and react with color development stopping in each hole, inherent 450nm place read optical density(OD) with plate reader in 5 minutes.
E. interpretation of result
The data that square root converts are used to analyze the variance and the non-linear dose response curve that are matched with agonist and antagonist pattern.Reduce the influence of outlier with the Huber weighted method.By the numerical evaluation EC that converts again 50Or IC 50In the single dose and dose response analysis of variance and the analysis of non-linear dose response, and use JMP software (SAS Institute, Inc.).
F. control compound
Trimegestone and medroxyprogesterone acetate (MPA) be progestogen in contrast, and RU486 is antiprogestin in contrast.All control compounds are tested in full dose response curve mode, and calculate EC 50Or IC 50Value.
Expectation EC in each research of table 4. 50, standard deviation (SE) and 95% fiducial interval (CI)
EC 50 95％CI
The compound experiment (nM)The SE lower limit upper limit
Trimegestone 1 0.017 0.003 0.007 0.040
2 0.014 0.001 0.011 0.017
3 0.019 0.001 0.016 0.024
MPA 1 0.019 0.001 0.013 0.027
2 0.017 0.001 0.011 0.024
The expectation IC of table 5. antiprogestin RU486 50, standard deviation (SE) and 95% fiducial interval (CI)
IC50 95％CI
Compound experiment (nM) SE lower limit upper limit
RU486 1 0.011 0.001 0.008 0.014
2 0.016 0.00l 0.014 0.020
3 0.018 0.001 0.014 0.022
EC 50: can increase BrdU incorporation maximum value one half compound concentrations and standard deviation;
IC 50: can make 0.1 trimegestone inductive BrdU incorporation reduce maximum value one half compound concentrations and standard deviation.
4.T47D cell alkaline phosphatase experiment
The purpose of this experiment is by measuring the effect of compound to T47D cell neutral and alkali Phosphoric acid esterase enzymic activity, identifying progestogen or antiprogestin.Below be this experiment used material and method.
A. substratum: be supplemented with the desorb of 5% (v/v) activated carbon foetal calf serum (not heat inactivation), 100U/ml penicillin, 100 μ g/ml Streptomycin sulphates and 2mM GlutaMax (GIBCO, DMEM BRL): F12 (1: 1) (GIBCO, BRL).
B. alkaline phosphatase is tested damping fluid:
I.0.1M Tris-HCl, pH9.8 contains 0.2%Triton X-100
II.0.1M Tris-HCl, pH9.8, contain 4mM phosphoric acid right-nitro phenyl ester (Sigma)
C. cell cultures and processing:
Refrigerated T47D cell is thawed in 37 ℃ of water-baths, and be diluted to 280,000 cell/ml with substratum.The cell suspending liquid that in each hole of 96 orifice plates (Falcon, Becton Dickinson Labware), adds 180 μ l dilution.In each hole, add contrast or the test compounds of 20pl then with the substratum dilution.When the test progesterone antagonist is active, in the presence of the 1nM Progesterone, add contrast antiprogestin or test compounds.At 37 ℃, 5%CO 2Cultivated these cells 24 hours in the/moistening atmosphere.
D. alkaline phosphatase enzyme experiment
When processing finishes, discard the substratum in the flat board, in each hole, add 50 μ l experiment damping fluid I.These flat boards were vibrated 15 minutes on the titer plate vibrator.Then 150 μ l experiment damping fluid II is added in each hole.At 405nM test wavelength, be measuring space optical density(OD) totally 30 minutes with 5 minutes.
E. interpretation of result: analyze the dosage reply data
To reference and test compounds, the speed (slope) (Y-axle) of enzyme reaction is drawn dose response curve with dosage (X-axle).The data that square root converts are used to analyze the variance and the non-linear dose response curve that are matched with agonist and antagonist pattern.Reduce the influence of outlier with the Huber weighted method.By the numerical evaluation EC that converts again 50Or IC 50In the single dose and dose response analysis of variance and non-linear response analysis, and use JMP software (SAS Institute, Inc.).
F. control compound
Progesterone and trimegestone be progestogen in contrast, and RU486 is antiprogestin in contrast.All control compounds are all tested in full dose response curve mode, and calculate EC 50Or IC 50Value.
The expectation EC of contrast progestogen in three independent experiments of table 6. 50, standard deviation (SE) and 95% puts the letter district
Between (CI)
EC50 95％CI
Compound experiment (nM) SE lower limit upper limit
Progesterone 1 0.839 0.030 0.706 0.996
2 0.639 0.006 0.611 0.669
3 1.286 0.029 1.158 1.429
Trimegestone 1 0.084 0.002 0.076 0.091
2 0.076 0.001 0.072 0.080
3 0.160 0.004 0.141 0.181
The expectation IC of contrast antiprogestin RU486 in three independent experiments of table 7. 50, standard deviation (SE) and 95%
Fiducial interval (CI)
IC 50 95％CI
Compound experiment (nM) SE lower limit upper limit
RU486 1 0.103 0.002 0.092 0.115
2 0.120 0.001 0.115 0.126
3 0.094 0.007 0.066 0.134
B. biology in the body
Carry out testing in the initial body with rat decidua model, it can be used for measuring the gestagenic action of agonist and antagonist.Experiment is to suppress model with the rat ovulation in the secondary body, therefore fails to obtain flow process because this model still also is in the development phase.
1. rat decidua experiment: the purpose of this flow process is the effect to the rat uterus deciduaization of assessment progestogen and antiprogestin, and the relative effectivenes of various test compounds is compared.Below be used material and method:
A. method: test compounds is dissolved in 100% ethanol, and mixes with Semen Maydis oil (carrier).Then by heating (～80 ℃) this mixture evaporating ethanol, thereby preparation is at oil (Mazola TM) in test compounds stoste.Subsequently before handling animal, with 100% Semen Maydis oil or 10% ethanol (in Semen Maydis oil) dilution test compounds.When these two kinds of carriers are compared, do not find the difference of decidua between replying.
B. animal (RACUC flow process #5002)
After operation, (Taconic Farms NY) obtains the ovariectomized female Sprague-Dawley rat (～60 day age and 230g) that grows up from Taconic.Before processing, carried out oophorectomize to reduce the sex steroid in the recycle system at least 10 days.These animals passes are supported in the room of 12 hours light/dark cycle, and feed with standard rat feed and feedwater arbitrarily.
C. handle
Before processing, rat is weighed and random packet 4 or 5 every group.With the nape of the 0.2ml carrier subcutaneous injection rat that contains test compounds, or carry out with the 0.5ml carrier with gavage.Handle these animals every day 1 time, totally 7 days.In test during antiprogestin, at preceding 3 days animals received test compounds handling and EC 50The Progesterone of dosage (5.6mg/kg).After decidua stimulated, animal was still accepted Progesterone and dissected corpse after 4 day.
D. dosage
By preparing dosage based on mg/kg average group body weight.In all researchs, comprise the control group of only accepting carrier.Determine dose response curve (as 0.1,0.3,1.0,3.0mg/kg) with the semilog increased value.
E. decidua is brought out
Injected for the third time about 24 hours, and, thereby brought out decidua at an angle in uterus by anti-uterine veil (antimesometrial) the chamber endothelium of swiping with the 21G pin.Thereby do not swipe as unprovoked contrast in the diagonal angle.After about 24 hours, pass through CO in final processing 2Suffocate and put to death rat, measure body weight.Take out the uterus, clean out fat.Weigh respectively decidua (D-angle) and the contrast (C-angle) horn of uterus.
F. interpretation of result
Calculate the increase of decidua horn of uterus weight by D-angle/C-angle, and use normality and the homogeneity maximization that number conversion is made variance.Reduce the influence of viewed improper conversion value in dose response curve match and the variance one-way analysis with Huber M-estimated value.In unidirectional ANOVA and non-linear response analysis, and use JMP software (SAS Institute, Inc.).
G. control compound
All progestogen control compounds are all tested in full dose response curve mode, and calculating is for the EC of uterus weight in wet base 50Value.
The expectation EC of each experiment of table 8. 50, standard deviation (SE) and 95% fiducial interval (CI)
EC50 95％CI
Compound experiment (mg/kg, s.c.) the SE lower limit upper limit
Progesterone 1 5.50 0.77 4.21 7.20
2 6.21 1.12 4.41 8.76
3-ketone desogestrel 1 0.11 0.02 0.07 0.16
2 0.10 0.05 0.11 0.25
3 0.06 0.03 0.03 0.14
Levonorgestrel 1 0.08 0.03 0.04 0.16
2 0.12 0.02 0.09 0.17
3 0.09 0.02 0.06 0.13
4 0.09 0.02 0.06 0.14
MPA 1 0.42 0.03 0.29 0.60
2 0.39 0.05 0.22 0.67
3 0.39 0.04 0.25 0.61
Estimated average EC in the dose response curve of three kinds of control compounds of table 9. 50, standard deviation and 95%
Fiducial interval
EC50 95％CI
Compound (mg/kg, s.c.) the SE lower limit upper limit
Progesterone 5.62 0.62 4.55 7.00
(3-0.10 0.02 0.07 0.14 for 3-ketone desogestrel
Ketodesogestrel)
Levonorgestrel 0.10 0.01 0.08 0.12
The expectation IC of table 10. antiprogestin RU486 50, standard deviation and 95% fiducial interval
IC50 95％CI
Compound experiment (mg/kg, p.o.) the SE lower limit upper limit
RU 486 1 0.21 0.07 0.05 0.96
2 0.14 0.02 0.08 0.27
Concentration: compound concentrations in the experiment (is defaulted as: the mg/kg body weight)
Administration path: the path that gives the animalizing compound.
Body weight: the average overall of animal is heavy (to be defaulted as: kg).
The D-angle: the weight in wet base of decidua horn of uterus (is defaulted as: mg).
The C-angle: the weight in wet base of contrast horn of uterus (is defaulted as: mg).
Decidua is replied: [(D-C)/C] * 100%
Progestogenic activity: compare with control vector, the compound that energy remarkable (p＜0.05) brings out the decidua effect is considered to activated.
Anti-pregnant activity: significantly reduce EC 50The compound of the decidua effect that Progesterone brought out (p＜0.05).
The EC of uterus weight 50: make decidua reply the compound concentration (being defaulted as mg/kg) that maximum value increases by a half.
The IC of uterus weight 50: make EC 50The compound concentration (being defaulted as mg/kg) that maximum value reduces a half is replied in the decidua that Progesterone brings out.
Embodiment 122
6-(3-p-methoxy-phenyl) spiral shell [4H-3,1-benzoxazine-4,1-tetramethylene]-2 (1H)-ketone
Under-78 ℃ of nitrogen, with tert-butyl lithium (7.4ml, 12.5mmol) handle the Boc protection in anhydrous THF the 4-chloroaniline (1.15g, 5mmol).This solution slowly is warming up to-20 ℃ then, stirred 1.5 hours, (1ml 13.4mmol) handles with cyclobutanone.Mixture is warming up to room temperature,, adds 1N aqueous hydrochloric acid (10ml) with salt solution (30ml) cancellation.Add ethyl acetate, separately organic layer, and drying (MgSO4).Except that after desolvating, (hexane: ethyl acetate/3: 1) purifying residue, the alcohol that obtains need not to be further purified and can be directly used in next step rapid column chromatography.
Add potassium hydroxide (2g) in the solution of the above-mentioned product in ethanol.This reaction mixture of stirring at room 18 hours adds the cold aqueous hydrochloric acid (20ml) of salt solution (20ml) and 1N then.Filter collecting precipitation, with the water washing, mp 183-184 ℃ of the solid 6-chlorine spiral shell that obtains being white in color [1-encircles fourth for 4H-3,1-benzoxazine-4]-2 (1H)-ketone (0.13g, 12%, two step); MS (ESI) m/z 222[M-H] -
6-chlorine spiral shell [4H-3 in diox (5ml), 1-benzoxazine-4,1-encircles fourth]-2 (1H)-ketone (0.1g, 0.45mmol), 3-anisole ylboronic acid (0.1g, 0.66mmol), [1,1 '-two (diphenylphosphino) ferrocene] dichloro closes nickel (II) (50mg, 0.073mmol), potassiumphosphate (0.35g, 1.7mmol) the mixture degassing, removing oxygen, 85 ℃ of heating are 72 hours under nitrogen.Allow this reaction mixture be cooled to room temperature.Add ethyl acetate (30ml) and salt solution (20ml).Separate organic layer and dry (MgSO4).Remove desolvate after, column chromatography purification residue (hexane: ethyl acetate/3: 1) solid 6-(3-methoxyl group-phenyl) spiral shell [1-encircles fourth for 4H-3,1-benzoxazine-4]-2 (the 1H)-ketone (18mg, 14%) that obtain being white in color: mp 145-146 ℃; 1H-NMR (DMSO-d 6) δ 8.04 (s, 1H), 7.69 (d, 1H, J=1.6Hz), 7.59 (dd, 1H, J=8.2,1.5Hz), 7.36 (d, 1H, J=7.9Hz), 7.27 (d, 1H, J=7.7Hz), 7.22 (d, 1H, J=2.2Hz), 6.99 (d, 1H, J=8.2Hz), 6.92 (dd, 1H, J=8.0,2.4Hz), 3.83 (s, 3H), and 2.45-2.62 (m, 4H), 1.81-2.12 (m, 2H)); MS ((+) APCI) m/z 296[M+H] +
Embodiment 123
8-bromo-6-(3-chloro-4-fluorophenyl)-4,4-dimethyl-1,4-dihydro-2H-3,1-benzoxazine-2-ketone
Under the room temperature nitrogen, the 6-in acetate (5ml) (3-chloro-4-fluorophenyl)-4,4-dimethyl-1,4-dihydro-2H-3, and 1-benzoxazine-2-ketone (0.2g, 0.65mmol) and sodium acetate (0.1g, 1.2mmol) mixture in add bromine (0.04ml, 0.78mmol).Stirred this reaction mixture 20 hours, and poured in the frozen water (30ml).Filter collecting precipitation, (3 * 5ml) wash water, obtain being the 8-bromo-6-(3-chloro-4-fluorophenyl)-4 of pale solid, 4-dimethyl-1,4-dihydro-2H-3,1-benzoxazine-2-ketone (0.18,72%): mp 194-195 ℃; 1H-NMR (DMSO-d 6) δ 9.77 (s, 1H), 8.02 (dd, 1H, J=7.10,1.81Hz), 7.92 (s, 1H), 7.77 (m, 1H), 7.66 (s, 1H), 7.47-7.53 (m, 1H), 1.71 (s, 6H) .MS (ESI) m/z 384,386[M-H] -
Embodiment 124
3-(8-bromo-4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazine-6-yl)-5-fluorine benzonitrile
Use above-mentioned flow process, (0.5g 1.7mmol) prepares, and obtains pale solid (0.48g, 5%): mp 216-217 ℃ from 3-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazine-6-yl)-5-fluorine benzonitrile; 1H-NMR (DMSO-d 6) δ 9.78 (s, 1H), 8.18 (t, 1H, J=1.6Hz), 8.02-8.08 (m, 2H), 7.81 (m, 1H), 7.75 (d, 1H, J=1.8Hz), 1.66 (s, 6H).MS(ESI)m/z 373，375[M-H] -。
Embodiment 125
5-(8-bromo-4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazine-6-yl)-2-fluorine benzonitrile
By above-mentioned flow process, (0.2g 0.67mmol) is prepared into pale solid (0.18g, 72%): mp 235-236 ℃ with 5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazine-6-yl)-2-fluorine benzonitrile; 1H-NMR (DMSO-d 6) δ 9.78 (s, 1H), 8.38 (dd, 1H, J=6.1,2.4z), 8.14-8.20 (m, 1H), 7.98 (d, 1H, J=1.9Hz), 7.71 (d, 1H, J=1.8Hz), 7.62 (t, 1H, J=9.1Hz), 1.69 (s, 6H).MS(ESI)m/z 373，375[M-H] -。
Embodiment 126
6-(3-bromophenyl)-1,4,4-trimethylammonium-1,4-dihydro-2H-3,1-benzoxazine-2-ketone
Under the room temperature nitrogen, the 6-in dry DMF (3-bromophenyl)-4,4-dimethyl-1,4-dihydro-2H-3,1-benzoxazine-2-ketone (1g, add in solution 3.0mmol) sodium hydride (60% in mineral oil, 0.24g, 6.0mmol).Stir after 20 minutes,, stirred 1.5 hours with methyl iodide processing reaction solution.This mixture is poured in the saturated ammonium sulfate solution (40ml), add ethyl acetate (40ml).Separate organic layer, dry (MgSO 4), obtain being the 6-(3-bromophenyl)-1,4 of pale solid, 4-trimethylammonium-1,4-dihydro-2H-3,1-benzoxazine-2-ketone (0.75g, 72%): mp 142-143 ℃ after the evaporation; 1H-NMR (DMSO-d 6) δ 7.93 (s, 1H), 7.71 (m, 1H), 7.65 (s, 1H), 7.55 (d, 1H, J=8.0Hz), 7.42 (t1H, J=7.7Hz), 7.18 (d, 1H, J=8.4Hz), 3.35 (s, 3H), 1.67 (s, 6H) .MS (ESI) m/z 368,370[M+Na] +
Embodiment 127
6-(3-fluorophenyl)-4-methyl isophthalic acid, 4-dihydro-2H-3,1-benzoxazine-2-ketone
By flow process A, prepare 4-amino-3 '-fluorine [1,1 '-xenyl]-3-formonitrile HCN with 3-fluorophenyl boric acid and 2-amino-5-bromobenzyl nitrile.Under the room temperature nitrogen 4-amino-3 '-fluorine [1,1 '-xenyl]-3-formonitrile HCN (6.65g, dropwise add in anhydrous THF (100ml) solution 31.3mmol) methyl-magnesium-bromide (3.0M in ether, 21ml, 63mmol).After interpolation finishes, this reaction mixture heating was slowly refluxed 1.5 hours, be cooled to room temperature, with 3N aqueous hydrochloric acid (30ml) processing.This mixture of reflux 3 hours is cooled to room temperature, add saturated aqueous sodium carbonate with pH regulator to 5-6.Add ethyl acetate (100ml), separately organic layer is used ethyl acetate (3 * 50ml) extraction water layers.Dry organic layer (MgSO4) that merges and evaporation.Purification by silica gel column chromatography residue (hexane: ethyl acetate/3: 1) obtain 1-(4-amino-3 '-fluorine [1,1 '-xenyl]-3-yl) ethyl ketone (3.1g, 43%): mp 156-157 ℃.
Under the room temperature nitrogen, with sodium borohydride (gradation addings) processing in anhydrous methanol (60ml) 1-(4-amino-3 '-fluorine [1,1 '-xenyl-3-yl] ethyl ketone (and 3g, 13mmol).After interpolation finishes, stirred this reaction mixture 4 hours, handle with the saturated ammonium sulphate aqueous solution (50ml) and ethyl acetate (100ml).Separately organic layer, drying (MgSO4) and evaporation.(the hexane: ethyl acetate/3: 1) solid 1-(4-amino-3 '-fluorine [1,1 '-xenyl]-3-yl) ethanol (2g, 67%) that obtains being white in color: mp 136-137 ℃ of column chromatography purification residue on silica gel.
Be stirred under the room temperature nitrogen above-mentioned alcohol among the anhydrous THF (20ml) (0.2g, 0.87mmol) and the mixture of triphosgene.After 15 minutes, handle this mixture with the saturated Sodium Hydrogen Carbonate aqueous solution (30ml) and ethyl acetate (40ml).Separate organic layer, dry (MgSO4), and evaporate solid 6-(3-the fluorophenyl)-4-methyl isophthalic acid that obtains being white in color, 4-dihydro-2H-3,1-benzoxazine-2-ketone (0.18g, 81%): mp 160-161 ℃; 1H-NMR (DMSO-d 6) δ 10.31 (s, 1H), 7.62 (dd, 1H, J=8.2,1.9Hz), 7.57 (s, 1H), 7.44-7.53 (m, 3H), 7.13-7.20 (m 1H), 6.97 (d, 1H, J=8.2Hz), 5.57 (q, 1H, J=6.6Hz), 1.63 (d, 3H, J=6.6Hz) .MS (ESI) m/z 256[M-H] -
Embodiment 128
3-(4,4-dimethyl-8-methoxyl group-2-oxo-1,4-dihydro-2H-3,1-benzoxazine-6-yl)-5-fluorine benzonitrile
Under the room temperature nitrogen, the 2-amino-3-methoxybenzoic acid in anhydrous THF (100ml) (5g, add in solution 30mmol) methyl-magnesium-bromide (3.0M in THF, 50ml, 150mmol).Heated these reaction mixtures 18 hours at 50 ℃, be cooled to room temperature, handle with saturated aqueous ammonium chloride (50ml).Add ethyl acetate (100ml), separately organic layer, drying (MgSO4) and evaporation.Residue is dissolved among the anhydrous THF (100ml), and (4.5g 33mmol) handles room temperature nitrogen with 1,1 '-carbonyl dimidazoles down.After 24 hours, with 1N aqueous hydrochloric acid (30ml) cancellation mixture.Add ethyl acetate (100ml), separately organic layer, drying (MgSO4) and evaporation.The purification by silica gel column chromatography residue (hexane: ethyl acetate/3: 1) the solid 8-methoxyl group-4 that obtains being white in color, 4-dimethyl-1,4-dihydro-2H-3,1-benzoxazine-2-ketone (3.5g, 56%): MS (ESI) m/z 208[M+H] +
The 8-methoxyl group-4 of room temperature in acetate (30ml), 4-dimethyl-1,4-dihydro-2H-3,1-benzoxazine-2-ketone (2.1g, 10.1mmol), sodium acetate (1.5g, add in mixture 18mmol) bromine (0.62ml, 12mmol).After 30 minutes, (50ml) handles this solution with ammonium hydroxide solution,stronger.Filter collecting precipitation, water (3 * 20ml) washings obtain being the 6-bromo-8-methoxyl group-4 of pale solid, 4-dimethyl-1,4-dihydro-2H-3,1-benzoxazine-2-ketone (2.7g, 93%): MS (ESI) m/z 286,288[M+H] +
With the 6-bromo-8-methoxyl group-4 among the DMF (30ml), 4-dimethyl-1,4-dihydro-2H-3,1-benzoxazine-2-ketone (1.6g, 5.6mmol), two (Knit-the-brows any pure root close (pinacolato)), two boron (1.6g, 6.3mmol), potassium acetate (1.5g, 15.3mmol) and chlorination [1,1 '-two (diphenylphosphino) ferrocene] close palladium (II) (1: 1 mixture with methylene dichloride, 0.5g, 0.6mmol) mixture feed positive nitrogen gas stream, to remove oxygen, then under nitrogen 85 ℃ the heating 18 hours.Allow this reaction mixture be cooled to room temperature, be used in 3-bromo-5-fluoro-benzonitrile in the water (1.2g, 6mmol), chlorination [1,1 '-two (diphenylphosphine)-ferrocene] close palladium (II) (1: 1 mixture with methylene dichloride, 0.5g, 0.6mmol) and yellow soda ash (2g 19mmol) handles.Under the nitrogen solution that obtains was heated 3 hours at 85 ℃, be cooled to room temperature, handle with salt solution (50ml).Add ethyl acetate (100ml), separately organic layer, drying (MgSO4) and evaporation.Purification by silica gel column chromatography residue (THF: solid 3-(4,4-dimethyl-8-methoxyl group-2-oxo-1,4-dihydro-2H-3,1-benzoxazine-6-the yl)-5-fluorine benzonitrile (0.6g, 33%) that obtains being white in color hexane/2: 3): mp 252-253 ℃; 1H-NMR (DMSO-d 6) δ 9.76 (s, 1H), 8.21 (s, 1H), 8.07 (d, 1H, J=10.6Hz), 7.82 (m, 1H), 7.39 (s1H), 7.36 (s, 1H), 3.93 (s, 3H), 1.66 (s, 6H).MS(ESI)m/z 325[M-H] -。
Embodiment 129
3-(4,4-dimethyl-8-hydroxyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazine-6-yl)-5-fluorine benzonitrile nitrile
Reflux is 2,4 under the nitrogen, and the 3-in the 6-collidine (4,4-dimethyl-8-methoxyl group-2-oxo-1,4-dihydro-2H-3,1-benzoxazine-6-yl)-5-fluorine benzonitrile (0.1g, 0.31mmol), lithium iodide (0.3g, mixture 2.24mmol) 5 hours.Solvent removed in vacuo absorbs residue in the mixture of salt solution (10ml) and ethyl acetate (30ml).Separately organic layer, drying (MgSO4) and evaporation.Purification by silica gel column chromatography residue (hexane: ethyl acetate/1: 1) the flaky title compound (0.03mg, 31%) that obtains being white in color: mp 197-198 ℃; 1H-NMR (DMSO-d 6) δ 10.16 (s, 1H), 9.55 (s, 1H), 8.01 (s, 1H), 7.79-7.87 (m, 2H), 7.20 (s, 1H), 7.08 (d, 1H, J=1.0Hz), 1.65 (s, 6H).MS(ESI)m/z311[M-H] -。
Embodiment 130
6-(2,3-two fluoro-phenyl)-4,4-dimethyl-1,4-dihydro-benzo [d] [1,3] oxazine-2-ketone
By flow process B, with (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazine-6-yl) boric acid and 2, the preparation of 3-difluorobenzyl trifluoromethayl sulfonic acid ester.Yellow solid: mp 166-167 ℃; 1H-NMR (DMSO-d 6) δ 10.4 (s, 1H), 7.5-7.2 (m, 5H), 7.0 (m, 1H), 1.7 (s, 6H); MS (EI) m/z289 ([M+H] +); C 16H 13F 2NO 2Analytical value: C, 66.43, H, 4.53, N, 4.84.Measured value: C, 66.15, H, 4.37, N, 4.64.
Embodiment 131
3-(1-ethyl-4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazine-6-yl)-5-fluoro-benzonitrile
Press the flow process of embodiment 125, usefulness 3-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazine-6-yl)-preparation of 5-fluoro-benzonitrile.White solid: mp 154-155 ℃; 1H-NMR (DMSO-d 6) δ 8.17 (s, 1H), 8.03 (d, 1H, J=10.5Hz), 7.84-7.77 (m, 3H), 7.27 (d, 1H, J=8.54Hz), 3.97 (q, 2H, J=6.89Hz), 1.67 (s, and 6H) 1.21 (t, 3H, J=6.95Hz); MS (EI) m/z 324 ([M+H] +); C 19H 17FN 2O 2Analytical value: C, 70.36, H, 5.28, N, 8.64.Measured value: C, 70.33, H, 5.51, N, 8.48.
Embodiment 132
[6-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazine-6-yl) pyridine-2-yl] acetonitrile
By flow process B, with (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazine-6-yl) boric acid and (6-bromo-2-pyrrole is than pyridine base) acetonitrile (J.Org.Chem.1988,53,786-790) preparation.Pale solid: mp210-212.5 ℃. 1H NMR(DMSO-d 6)δ1.68(s，6H)，4.27(s，2H)，7.00(d，1H，J＝8.3Hz)，7.34(d，1H，J＝7.1Hz)，7.89-7.96(m，2H)，8.00-8.05(m，2H)，10.42(s，1H).MS(ESI)[M-H] -＝292。C 17H 15N 3O 2Analytical value: C, 69.61; H, 5.15; N, 14.33.Measured value: C, 68.49; H, 5.19; N, 13.74
Embodiment 133
3-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3]-oxazines-6-yl)-5-fluoro-phenylacetonitrile
(22.25g adds NaBH in solution 0.11mol) to the 3-bromo-5-fluorobenzaldehyde of room temperature in methyl alcohol 4(2.07,0.055mol), stirring at room 2 hours.Use H 2O cancellation reactant, and concentrate.Dilute residue with ether, with 1N HCl, salt water washing, MgSO 4Drying concentrates.Collection is the 3-bromo-5-fluorophenyl methanol (14.6g, 65%) of colourless oil body. 1H NMR (DMSO-d 6) 4.50 (m, 2H), 5.44 (t, 3H, J=5.93Hz), 7.16 (dd, 1H, J=1.09,8.79Hz), 7.36 (s, 1H), 7.38 (dd, 1H, J=2.99,6.15Hz); C 7H 6Br 2The analytical value of FO: C, 41.01, H, 2.95.Measured value: C, 41.30, H, 3.01.
At CH 2Cl 2(2.3g adds 12.4ml0.1M PBr to 3-bromo-5-fluorophenyl methanol (15ml) in solution 0.011mol) 3(3.33g, 0.0123mol) (CH 2Cl 2In) solution, stirred 3 hours, with ether (100ml) dilution, use H 2O (50ml, 3X) washing, MgSO 4Drying concentrates.Carry out column chromatography purification with 1: 9 ethyl acetate/hexane as the eluting solvent wash-out.Obtain being the 3-bromo-5-fluoro benzyl bromide of crystalline substance, mp 41-43 ℃. 1H NMR (DMSO-d 6) δ 4.69 (s, 2H), 7.52 (d, 1H, J=1.76Hz) 7.54 (d, 1H, J=1.91Hz), 7.56 (s, 1H); MS (EI): M+.m/z 266; C 7H 5Br 2The analytical value of F: C, 31.38, H, 1.88.Measured value: C, 31.75, H, 1.78.
1, (3.2g adds H in solution 0.0112mol) to the 3-bromo-5-fluoro benzyl bromide in the 4-diox (20ml) 2(0.82g, solution 0.013mol) refluxed 2 hours KCN among O (5ml) and the EtOH (5ml).Use ether extraction, use the salt water washing, the MgSO4 drying concentrates.Carry out column chromatography with hexane/ethyl acetate (19: 1).Obtain the 3-bromo-5-fluorophenyl acetonitrile of colorless oil: 1H NMR (DMSO-d 6) d 4.15 (s, 2H), 7.29 (d, 1H, J=9.37Hz), 7.47 (s, 1H), 7.55 (d, 1H, J=8.45Hz); MS (EI) M+m/z213; C 8H 5The analytical value of BrFN: C, 44.89, H, 2.35, N, 6.54.Measured value: C, 44.88, H, 2.32, N, 6.46.
By flow process B, prepare title compound with 3-bromo-5-fluorophenyl acetonitrile and (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazine-6-yl) boric acid.Obtain white solid behind ethanol/ether recrystallization: mp 218-220. 1H NMR (DMSO-d 6) δ 1.67 (s, 6H), 4.11 (s, 2H), 6.98 (d, 1H, J=8.92Hz), 7.18 (d, 1H, J=9.26), 7.52-7.62 (m, 3H), 10.37 (s, 1H); MS (EI) (M-H) -M/z 309; C 18H 15FN 2O 2Analytical value: C, 69.67, H, 4.87, N, 9.03.Measured value: C, 69.78, H, 4.9/, N, 8.36.
Embodiment 134
3-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3]-oxazines-6-yl)-4-fluoro-phenylacetonitrile
At CCl 45-bromo-2-toluene fluoride (150ml) (15g, add in solution 0.079mol) NBS (14.2g, 0.080mol).This solution of reflux, initiator react completely needs 2 hours.Remove CCl under the decompression 4, the residue dilution is dissolved in the ether, with salt solution (3X) washing, MgSO 4Drying concentrates.Chromatography/hexane obtains 5-bromo-2-fluorine cylite.This product can be directly used in following reaction.
(8.0g 0.03mol) is dissolved in 1, and 4-diox (60ml) joins KCN (2.04g, 0.031mol) solution in water (20ml) and the ethanol (20ml) with 5-bromo-2-fluorine cylite.The mixture that reflux obtains (5 hours).Be cooled to room temperature, extract product, use the salt water washing, the MgSO4 drying with ether (200ml).From the ether/hexane crystallization crystalline 5-bromo-2-fluorophenyl acetonitrile (5.6g, 88%) that obtains being white in color: mp 55-58 ℃; 1H NMR (DMSO-d 6) 4.07 (s, 2H), 7.29 (t, 1H, J=9.23Hz), 7.60-7.69 (m, 2H); MS (EI) M+.m/z 213; C 8H 5Br 2The analytical value of FN: C, 44.89, H, 2.35, N, 6.54.Measured value: C, 44.90, H, 2.24, N, 6.43.
Prepare title compound with 5-bromo-2-fluorophenyl acetonitrile and (1,4-dihydro-4,4-two dimethyl-2-oxo-2H-3,1-benzoxazine-6-yl) boric acid.White solid: mp 184-187 ℃; 1H NMR (DMSO-d 6) δ 1.67 (s, 6H), 4.11 (s, 2H), 6.98 (d, 1H, J=8.92Hz), 7.36 (t, 1H, J=9.13Hz) 7.54 (d, 2H, J=7.91Hz), 7.67-7.75 (m, 2H), 10.37 (s, 1H); MS (EI) (M-H) -M/z309; C 18H 15FN 2O 2Analytical value: C, 69.67, H, 4.87, N, 9.03.Measured value: C, 68.71, H, 4.80, N.8.54.
Embodiment 135
4-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazine-6-yl)-2-fluorophenyl acetonitrile
By flow process B, with 4-bromo-2-fluorophenyl acetonitrile (T.Alessi A.H.P. US Patent No: 4895862) and (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazine-6-yl) boric acid prepare.Gray solid: mp 253-256 ° C 1HNMR (DMSO-d6) δ 10.35 (s, 1H) 7.67-7.49 (m, 5H), 6.97 (d, 1H; J=8.6Hz) 4.09 (s, and 2H) 1.67 (s, 6H); MS[M-H] -M/z309.C 18H 15N 2FO 2.0.15H20 analytical value: C, 69.07, H, 4.93, N, 8.95.Measured value: C, 69.27, H 5.05, N, 8.50.
Embodiment 136
2-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3]-oxazines-6-yl) phenylacetonitrile
By flow process B, with 2-bromophenyl acetonitrile and the preparation of (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazine-6-yl) boric acid.White solid: mp 176-179 ℃; 1H-NMR (DMSO-d6), δ 10.31 (s, 1H), 7.53 (m, 1H), 7.48 (m, 2H), 7.22-7.32 (m, 3H), 6.98 (d, 1H; J=8.0Hz), 3.90 (s, 2H), 1.64 (s, 6H) .MS (+) APCI[M+H] +M/z=293.C 18H 16N 2O 2Analytical value: C, 73.95, H, 5.52, N, 9.58.Measured value: C, 73.51, H, 5.70, N, 9.39.
Embodiment 137
N-[4-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazine-6-yl)-2-fluoro-phenyl]-ethanamide
By flow process B, with 4 '-bromo-2 '-fluoroacetanilide and the preparation of (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazine-6-yl) boric acid.Pale solid: mp 245-247 ℃. 1H-NMR(DMSO-d6)δ10.3(s，1H)，9.79(s，1H)，7.95(t，1H；J＝8.4Hz)，7.56-7.63(m，3H)，7.47(dd，1H J＝1.64，8.47Hz)，6.95(d，1H；J＝8.9Hz)，2.1(s，3H)，1.67(s，6H)；MS+APCI[M+H] +m/z329。C 18H 17N 2FO 3Analytical value: C, 65.85, H, 5.22, N, 8.53.Measured value: C, 65.46, H, 5.24, N, 8.12.
Embodiment 138
6-(3-fluoro-4-methoxyl group-phenyl)-4,4-dimethyl-1,4-dihydro-benzo [d] [1,3] oxazine-2-ketone
By flow process B, with 4-bromo-2-fluoroanisole and the preparation of (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazine-6-yl) boric acid.White solid: mp 210-211 ℃ 1H-NMR (DMSO-d6), δ 10.27 (s, 1H), 7.52-7.60 (m, 3H), 7.45 (d, 1H, J=8.6Hz), 7.22 (t, 1H; J=8.9Hz), 6.94 (d, 1H, J=8.8Hz), 3.87 (s, 3H), 1.66 (s, 6H).MS[M-H] -m/z＝300。C 17H 16FNO 3Analytical value: C, 67.76, H, 5.35, N, 4.65.Measured value: C, 67.88, H, 5.39, N, 4.70.
Embodiment 139
3-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3]-oxazines-6-yl) phenylacetonitrile
By flow process B, with 3-bromophenyl acetonitrile and the preparation of (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazine-6-yl) boric acid.White solid: mp 188-190 ℃. 1H-NMR(DMSO-d6)δ10.33(s，1H)，7.62(m，2H)，7.55(m，2H)，7.48(d，1H J＝8.00Hz)，7.33(d，1H，J＝7.57Hz)，6.99(d，1H，J＝8.81Hz)4.09(s，2H)，1.67(s，6H)；MS m/z291(M-H)。C 18H 16N 2O 2) 2.0.3 H 2The analytical value of O: C, 72.61, H, 5.62, N, 9.41.Measured value: C, 73.00, H, 5.43, N, 8.81.
Embodiment 140
3-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3]-oxazines-6-yl) benzene sulfanilamide (SN)
By flow process B, with 3-bromobenzene sulfanilamide (SN) and the preparation of (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazine-6-yl) boric acid.White solid: mp 242-244 ℃ (dec) 1H-NMR (DMSO-d6) δ 10.28 (s, wide 1H), 8.07 (s, 1H), 7.9 (d, 1H, J=7.80Hz), 7.78 (d, 1H J=7.86Hz), 7.64 (t, 1H, J=7.79Hz), 7,59 (m, 2H), (7.42 s, wide 2H), 7.02 (d, 1H, J=8.86Hz), 1.68 (s, 6H); MS m/z 331 (M+H).C 16H 16N 2O 4S) analytical value: C, 57.82, H, 4.85, N, 8.43.Measured value: C, 57.49, H, 5.08, N, 8.05.
Embodiment 141
5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3]-oxazines-6-yl)-thiophene-2-sulfanilamide (SN)
By flow process B, with 5-bromothiophene-2-sulfanilamide (SN) and the preparation of (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazine-6-yl) boric acid.White solid: mp 258-260 ℃, 1H-NMR (DMSO-d6) δ 10.41 (s, 1H), 7.71 (s, 2H), 7.58 (m, 2H), 7.52 (d, 1H, J=3.9Hz), and 7.48 (d, 1H J=8.16Hz), 6.95 (d, 1H J=8.16), 1.66 (s, 6H); MS m/z 337 (M-H).C 14H 14N 2O 4S 2) analytical value: C, 49.69, H, 4.17, N, 8.28.Measured value: C, 49.90, H, 4.28, N, 8.12.
Embodiment 142
6-(6-amino-pyridine-3-yl)-4,4-dimethyl-1,4-dihydro-benzo [d] [1,3]-oxazines-2-ketone
By flow process B, with 2-amino-5-bromopyridine and the preparation of (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazine-6-yl) boric acid.White crystal: mp 257-259 ℃. 1H-NMR(DMSO-d6)δ10.20(S，1H)，8.22(d，1H，J＝2.38Hz)7.69，7.66(dd，1H，J＝2.5，2.5Hz)，7.42(m，2H)，6.89(d，1H，J＝8.8Hz)，6.49(d，1H，J＝8.64Hz)，6.02(s，2H)，1.64(s，6H)；MS m/z 269M+。C 15H 15N 3O 2.17 H 2The analytical value of O: C, 66.15, H, 5.68, N, 15.43.Measured value: C, 66.10, H, 5.81, N, 15.02.
Embodiment 143
6-(5-diethoxymethyl-furans-3-yl)-4,4-dimethyl-1,4-dihydro-benzo [d] [1,3] oxazine-2-ketone
By flow process B, with 4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazine-6-boric acid and the preparation of 3-bromo-5-diethoxymethyl furans.The brown jelly: 1H NMR (DMSO-d 6) δ 10.2 (s, 1H), 8.12 (s, 1H), 7.54-7.49 (m, 2H), 6.93-6.88 (m, 2H), 5.56 (s, 1H), 3.60-3.38 (m, 4H), 1.67 (s, 6H), 1.2-1.14 (m, 6H).MS(ESI)m/z 344[M-H] -。C 19H 23NO 51/2 H 2The analytical value of O: C, 64.39; H, 6.77; N, 3.95.Measured value: C, 64.90; H, 6.79; N, 3.78.
Embodiment 144
4-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazine-6-yl)-furans-2-formaldehyde
In THF (20ml) and 2N HCl (2ml), stir 6-(5-diethoxymethyl-furans-3-yl)-4,4-dimethyl-1,4-dihydro-benzo [d] [1,3] oxazine-2-ketone (1.1g, 3mmol) 1 hour.Filter crystalline product, and dry (0.52g, 69%): mp 262-263 ℃; 1H NMR (DMSO-d 6) δ 10.3 (s, 1H), 9.65 (s, 1H), 8.59 (s, 1H), 8.04 (s, 1H), 7.65-7.64 (d, 1H, J=1.5Hz), 7.61-7.60 (d, 1H, J=1.8Hz), 7.59-7.58 (d, 1H, J=1.8Hz), 6.94-6.91 (d, 1H, J=8.2Hz), 1.65 (s, 6H).MS(ESI)m/z 270[M-H] -。
Embodiment 145
4-(1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazine-6-yl)-2 furan carboxyaldehyde oxime
Reflux 4-in 80% ethanol (25ml) (4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazine-6-yl)-furans-2-formaldehyde (2.7g, 10mmol), oxammonium hydrochloride (0.75g, 10.6mmol) and sodium acetate (0.87g, mixture 10.6mmol) 2 hours.Go out to be brown crystalline title compound (1.5g, 52.4%) from the crystallization of refrigerative reaction mixture: mp 236-238 ℃. 1H NMR(DMSO-d 6)δ11.97(s，1H)，10.26(s，1H)，8.2(s，1H)，7.63(s，1H)，7.56-7.52(m，3H)，6.91-6.88(d，1H，J＝8.1Hz)，1.66(s，6H)。MS ESI m/z 285[MH] -。C 15H 14N 2O 4.：C，62.93；H，4.93；N，9.79。Measured value: C, 62.77; H, 5.00; N, 9.79.
This paper includes the publication of all references as a reference in.Though the present invention is described with preferred embodiment, be appreciated that not breaking away from spirit of the present invention can also do some improvement.These improvement are in the appended claim scope of the present invention.

Claims (18)

1. the compound of a following structure or its pharmacy acceptable salt:
Figure C0080710000021
It is characterized in that, wherein:
R 1And R 2Respectively be to be selected from following substituting group: H, C 1-C 6Alkyl, the C that is replaced by halogen 1-C 6Alkyl, C 2-C 6Alkenyl, by C 1-C 6The C that alkyl replaces 2-C 6Alkenyl, C 2-C 6Base, C 3-C 8Cycloalkyl, phenyl and benzyl;
Or R 1And R 2Condense the 3-8 unit saturated volution of formation based on carbon;
R 3Be H, C 1-C 6Alkyl, by C 1-C 6The C that alkoxyl group replaces 1-C 6Alkyl or COR C
R CBe C 1-C 4Alkoxyl group;
R 4Be H, halogen, OH or C 1-C 6Alkoxyl group;
R 5Be selected from a) or b):
A) phenyl ring that contains substituent X, Y and Z as follows:
Figure C0080710000022
Wherein:
X is selected from halogen, CN, C 1-C 3Alkyl, the C that is replaced by halogen or CN 1-C 3Alkyl, C 2-C 6Alkynyl, the C that is replaced by CN or TMS 2-C 6Alkynyl, C 1-C 3Alkoxyl group, the C that is replaced by halogen 1-C 3Alkoxyl group, NO 2, thiazole, thiophene, thiadiazoles, tetrazolium, SO 2NH 2, COR D, and NR ECOR D
R DBe C 1-C 3Alkyl, C 1-C 3Aminoalkyl, perhaps phenyl;
R EBe H;
Y and Z are selected from following substituting group: H, halogen, CN, NO 2, C 1-C 3Alkyl, trifluoromethoxy and trifluoromethyl; Or
B) be selected from 5 or 6 yuan of rings of thiophene, furans, pyrroles or pyridine, and contain individual following substituting group: H, halogen, CN, the NO of respectively being selected from of 1-2 2, amino and C 1-C 4Alkyl, acetonitrile, diethoxymethyl, SO 2NH 2, and COR FWherein, on the N atom of described pyrroles and pyridine ring by R 6Replace R 6Be selected from H or C 1-C 3Alkyl;
Condition is to work as R 5Be that a NR is arranged on the main chain 6Heteroatomic pyrrole ring, and R 5Be when 2 of described ring, do not have the CN substituting group on 5 of described ring;
R FBe H;
Condition is to work as R 5The phenyl ring that is replaced by 1 or 2 substituting groups a) or 5 or 6 yuan of ring b), and R 1When alkenyl that is alkenyl, is replaced by alkyl or alkynyl, R 2The alkyl that is not alkyl, is replaced by halogen, cycloalkyl, alkenyl, the alkenyl or the alkynyl that are replaced by alkyl; Or work as R 2The alkenyl or the alkynyl that are alkenyl, are replaced by alkyl, R 1The alkyl that is not alkyl, is replaced by halogen, cycloalkyl, alkenyl, the alkenyl or the alkynyl that are replaced by alkyl;
Condition is to work as R 5The phenyl ring that is replaced by 1 or 2 substituting groups a) or 5 or 6 yuan of ring b), and R 1When being alkyl or the alkyl that replaced by halogen, R 2It or not cycloalkyl; Or work as R 2When being alkyl or the alkyl that replaced by halogen, R 1It or not cycloalkyl.
2. compound as claimed in claim 1 or its pharmacy acceptable salt is characterized in that, wherein:
R 1Be H, C 1-C 6Alkyl, the C that is replaced by halogen 1-C 6Alkyl, C 3-C 8Cycloalkyl, phenyl or benzyl;
R 5Be 5 or 6 yuan of rings that are selected from thiophene, furans, pyrroles or pyridine, wherein said one or two substituting groups are selected from: H, halogen, CN, NO 2, amino or C 1-C 3Alkyl.
3. compound as claimed in claim 1 or its pharmacy acceptable salt is characterized in that, wherein:
R 1=R 2And be selected from C 1-C 3Alkyl and the C that is replaced by halogen 1-C 3Alkyl, or R 1And R 2Condense the 3-6 unit saturated volution of formation based on carbon;
R 5Be selected from a), b) and c):
A) phenyl ring of as shown in the formula replacement:
Figure C0080710000031
Wherein:
X is halogen, CN, C 1-C 3Alkoxyl group, C 1-C 3Alkyl, NO 2, thiazole, thiophene or thiadiazoles; With
Y is H, halogen, CN or NO 2
B) 5 of following structure yuan of rings:
Wherein:
U is O, S or NR 6,
X ' is selected from following group: halogen, CN, NO 2, C 1-C 3Alkyl and C 1-C 3Alkoxyl group;
Y ' is selected from following group: H and C 1-C 3Alkyl; With
R 6Be H or C 1-C 3Alkyl; With
C) 6 of following structure yuan of rings:
Wherein:
X 1Be CX 2
X 2Be halogen, CN or NO 2
4. compound as claimed in claim 1 or its pharmacy acceptable salt is characterized in that, wherein:
R 1=R 2And be CH 3, or R 1And R 2Condense the 6 yuan saturated volutions of formation based on carbon;
R 3Be H, C 1Alkyl, by C 1-C 6The C that alkoxyl group replaces 1Alkyl or COR C
R 4Be H;
R 5The phenyl ring of formula replacement a):
Wherein:
X is selected from: halogen, CN, C 1Alkoxyl group, NO 2, or 2-thiazole;
Y is H or halogen.
5. compound as claimed in claim 1 or its pharmacy acceptable salt is characterized in that, wherein:
R 1=R 2And be CH 3, or R 1And R 2Condense the 6 yuan saturated volutions of formation based on carbon;
R 3Be H, C 1Alkyl, by C 1-C 6The C that alkoxyl group replaces 1Alkyl or COR C
R 4Be H;
R 5Be 5 yuan of ring b of following structure):
Wherein:
U is O, S or NH;
X ' is halogen, CN or NO 2, condition is when U is NH, X ' is not CN;
Y ' is H or C 1-C 3Alkyl.
6. compound as claimed in claim 1 is characterized in that, described R 5Be selected from:
Figure C0080710000053
With
Figure C0080710000054
As claimed in claim 1, wherein a compound, wherein said compound is selected from: 6 - (3 - Chlorophenyl) -4,4 - dimethyl -1,4 - dihydro-benzo [d] [1,3] oxazin-2 - one; 6 - (3 - methoxy - phenyl)-4 4 - dimethyl -1 ,4 - dihydro - benzo [d] [1,3] - oxazin-2 - one; 6 - (2 - chloro - phenyl) -4,4 - dimethyl -1,4 - dihydro - benzo [D] [1,3] oxazin-2 - one; 6 - (4 - chloro - phenyl) -4,4 - dimethyl -1,4 - dihydro - benzo [d] [1,3 ] - oxazin-2 - one; 6 - (3 - chloro - phenyl)-4 - methyl-1 ,4 - dihydro - benzo [d] [1,3] oxazin-2 - one; 6 - (3 - chloro - phenyl) -4 - ethyl-1 ,4 - two H - benzo [d] [1,3] oxazin-2 - one; 6 - (3 - chloro - phenyl)-4 - phenyl-1 ,4 - dihydro - benzo [d] [1, 3] oxazin-2 - One; 3 - (4,4 - dimethyl-2 - oxo-1 ,4 - dihydro-2H-benzo [d] [1,3] oxazin-6 - yl) - benzonitrile; 4, 4 - dimethyl - 6 - (3 - nitrophenyl) -1,4 - dihydro-benzo [d] [1,3] oxazin-2 - one; 6 - (3 - bromo-5 - fluorophenyl) -4, 4 - dimethyl - 1,4 - dihydro-benzo [d] [1,3] oxazin-2 - one; 3 - (4,4 - dimethyl-2 - oxo-1 ,4 - dihydro-2H-benzo [d] [1,3] Oxazin-6 - yl) -5 - fluoro-benzonitrile; 5 - (4,4 - dimethyl-2 - oxo-1 ,4 - dihydro-2H-benzo [d] [1,3] evil triazine -6 - yl) - Smoke carbonitrile; 4 - (4,4 - dimethyl-2 - oxo-1 ,4 - dihydro-2H-benzo [d] [1,3] oxazin-6 - yl) - thiophene-2- - A Nitrile; 5 - (4,4 - dimethyl-2 - oxo-1 ,4 - dihydro-2H-benzo [d] [1,3] oxazin-6 - yl) - thiophene-2 ​​- methyl nitrile; 5 - (4, 4 - dimethyl-2 - oxo-1 ,4 - dihydro-2H-benzo [d] [1,3] oxazin-6 - yl) -4 - methyl - thiophene-2 ​​- carbonitrile; 4 - (4,4 - dimethyl-2 - oxo-1 ,4 - dihydro-2H-benzo [d] [1,3] oxazin-6 - yl) - furan-2 - carbonitrile; 4, 4 - diethyl -6 - (3 - nitrophenyl) -1,4 - dihydro-benzo [d] [1,3] oxazin-2 - one; 6 - (3 - chlorophenyl) -4,4 - diethyl-1 ,4 - Dihydro-benzo [d] [1,3] oxazin-2 - one; 6 - (3 - chlorophenyl) - spiro [4H-3, 1 - benzoxazine-4, 1 '- cyclohexane ] -2 - (1H) - one; 6 - (3 - chlorophenyl) - spiro - [4H-3, 1 - benzoxazine-4, 1 '- cyclopentane] -2 (1H) - one; 6 - ( 3 - nitrophenyl Yl) - spiro [4H-3, 1 - benzoxazine-4, 1 '- cyclohexane] -2 (1H) - one; 4 - allyl-6 - (3 - chlorophenyl) -4 - methyl - 1,4 - dihydro - benzo [d] [1,3] oxazin-2 - one; 6 - (3 - chlorophenyl)-4 - methyl - 4 - phenyl-1 ,4 - dihydro- - benzo [D] [1,3] oxazin-2 - one; 4 - benzyl-6 - (3 - chloro - phenyl)-4 - methyl-1 ,4 - dihydro - benzo [d] [1 , 3] oxazin-2 - Ketone; 6 - (3 - chloro - phenyl) -4 - cyclopropyl-4 - methyl-1 ,4 - dihydro - benzo [d] [1,3] oxazin-2 - one; 6 - (3 - chloro - benzene Yl) -4,4 - bicyclo propyl-1 ,4 - dihydro - benzo [d] [1,3] oxazin-2 - one; 6 - (3 - bromo-5 - fluorophenyl) - 1,4,4 - trimethyl -1,4 - Dihydro-benzo [d] [1,3] oxazin-2 - one; 6 - (3 - methoxyphenyl) -4 - methyl-4 - trifluoromethyl-1 , 4 - H - benzo [d] [1,3] oxazin-2 - one; 6 - (3 - acetyl - phenyl) -4,4 - dimethyl -1,4 - dihydro - benzo [d ] [1,3] - Oxazin-2 - one; 6 - (3 - benzoyl - phenyl) -4,4 - dimethyl -1,4 - dihydro - benzo [d] [1,3] - oxazin-2 - ketone; 4,4 - Dimethyl -6 - [3 - (1H-tetrazol-5 - yl) - phenyl] -1,4 - dihydro-benzo [d] [1,3] oxazin-2 - one; 4 - ( 4,4 - cyclopropylmethyl -2 - oxo-1 ,4 - dihydro-2H-benzo [d] [1,3] oxazin-6 - yl) - thiophene-2 ​​- carbonitrile; 6 - (3 - bromo-5 - Fluoride - phenyl) - 4,4 - bicyclo propyl-1 ,4 - dihydro-benzo - [d] [1,3] oxazin-2 - one; 3 - (4,4 - bicyclo-propyl-2 - oxo - 1,4 - dihydro- -2H-benzo [d] [1,3] oxazin-6 - yl) -5 - fluoro - benzonitrile; 6 - (3 - bromo-5 - methyl - phenyl) -4,4 - dimethyl -1,4 - two Hydrogen benzo - [d] [1,3] oxazin-2 - one; 6 - (3 - bromo-5 - trifluoromethoxy - phenyl) -4,4 - dimethyl -1,4 - dihydro-benzo [D] [1,3] - oxazin-2 - one; 3 - (4,4 - dimethyl-2 - oxo-1 ,4 - dihydro-2H-benzo [d] [1,3 ] oxazin-6 - yl) -5 - Methyl - benzonitrile; 3 - (4,4 - dimethyl-2 - oxo-1 ,4 - dihydro-2H-benzo [d] [1,3] oxazin-6 - yl) -5 - trifluoromethanesulfonic Group - benzonitrile; 6 - (3,5 - difluoro - phenyl) -4,4 - dimethyl -1,4 - dihydro-benzo - [d] [1,3] oxazin-2 - ketone; 6 - (3,5 - Dichloro - phenyl) -4,4 - dimethyl -1,4 - dihydro-benzo - [d] [1,3] oxazin-2 - one; 6 - (3,5 - II - trifluoro- methyl - benzene Yl) -4,4 - dimethyl -1,4 - dihydro-benzo [d] [1,3] oxazin-2 - one; 3 - (4,4 - dimethyl-2 - oxo - 1,4 - dihydro - 2H-benzo [d] [1,3] oxazin-6 - yl) -5 - methoxy - benzonitrile; 6 - (3 - fluoro - phenyl) -4,4 - dimethyl-1, 4 - dihydro - benzene And [d] [1,3] - oxazin-2 - one; 6 - (3 - chloro-4 - fluoro - phenyl) -4,4 - dimethyl -1,4 - dihydro - benzo [ d] [1,3] oxazin - 2 - one; 3 - (1 - diethoxy-4 ,4 - dimethyl-2 - oxo-1 ,4 - dihydro-2H-benzo [d] [1,3] oxazine -6 - Yl) -5 - fluoro - benzonitrile; 3 - fluoro-5 - (1 - methoxymethyl-4 - dimethyl-2 - oxo-1 ,4 - dihydro-2H-benzo [D] [1,3] oxazin-6 - yl) - benzonitrile; 6 - (3 - cyano-5 - fluoro - phenyl) -4,4 - twenty-two methyl-4H-benzo [d ] [1,3] oxazin - 2 - group diethyl ether phosphate; 3 - (4,4 - dimethyl-2 - oxo-1 ,4 - two dihydro-2H-benzo [d] [1,3] oxazin-6 - yl) - 4 - fluoro - benzonitrile; 6 - (3 - chloro-4 - fluoro - phenyl) -8 - fluoro -4,4 - dimethyl -1,4 - dihydro-benzo [d] [1,3] - oxazin-2 - Ketone; 6 - (3 - bromo - phenyl) -4,4 - dimethyl -1,4 - dihydro - benzo [d] [1,3] - oxazin-2 - one; 4,4 - dimethyl-6 - (3 - Trimethylsilyl ethynyl - phenyl) -1,4 - dihydro - benzo [d] [1,3] oxazin-2 - one; 6 - (3 - ethynyl - benzene Yl) -4,4 - dimethyl -1,4 - dihydro - benzo [d] [1,3] - oxazin-2 - one; 3 - [3 - (4,4 - dimethyl - 2 - oxo-1 ,4 - two H-2H-benzo [d] [1,3] oxazin-6 - yl) - phenyl] - propiolonitrile; 6 - (3 - fluoro-5 - nitro - phenyl) -4,4 - dimethyl - 1,4 - dihydro - benzo [d] [1,3] oxazin-2 - one; 6 - (3 - chloro-5 - fluoro - phenyl) -4,4 - dimethyl-1 ,4 - dihydro - benzo [D] [1,3] oxazin-2 - one; 3 - chloro-5 - (4,4 - dimethyl-2 - oxo-1 ,4 - dihydro-2H-benzo [d] [ 1,3] oxazin-6 - Yl) - benzonitrile; 6 - (3,5 - dinitro - phenyl) -4,4 - dimethyl -1,4 - dihydro - benzo [d] [1,3] oxazin-2 - ketone; 5 - (4,4 - dimethyl-2 - oxo-1 ,4 - dihydro-2H-benzo [d] [1,3] oxazin-6 - yl) - isophthalonitrile; 4,4 - dimethyl - 6 - (3 - thiazol-2 - yl - phenyl) -1,4 - dihydro - benzo [d] [1,3] oxazin-2 - one; 6 - (3 - fluoro-5 - methoxy- Base - phenyl) - 4,4 - dimethyl -1,4 - dihydro - benzo [d] [1,3] oxazin-2 - one; 6 - (3 - fluoro-5 - (trifluoromethyl) - phenyl) - 4,4 - dimethyl -1 ,4 - dihydro - benzo [d] [1,3] oxazin-2 - one; 6 - (5 - bromo - pyridin-3 - yl) -4,4 - dimethyl-1, 4 - dihydro - benzene And [d] [1,3] oxazin-2 - one; 6 - (5 - bromo-1 - oxo - pyridin-3 - yl) -4,4 - dimethyl -1,4 - dihydro - benzo [d] [1,3] Oxazin-2 - one; 5 - (4,4 - dimethyl-2 - oxo-1 ,4 - dihydro-2H-benzo [d] [1,3] oxazin-6 - yl) - 2 - fluoro - benzyl Nitrile; 4 - (8 - fluoro-4 - dimethyl-2 - oxo-1 ,4 - dihydro-2H-benzo [d] [1,3] oxazin-6 - yl) - thiophene -2 - A Nitrile; 3 - fluoro-5 - (2 - fluoro-4 - dimethyl-2 - oxo-1 ,4 - dihydro-2H-benzo [d] [1,3] oxazin-6 - yl) - benzonitrile; 5 - (4,4 - dimethyl-2 - oxo-1 ,4 - dihydro-2H-benzo [d] [1,3] oxazin-6 - yl) - thiophene-3 - carbonitrile China; - (4,4 - Methyl-2 - oxo-1 ,4 - dihydro-2H-benzo [d] [1,3] oxazin-6 - yl) - thiophene-3 - carbonitrile; 6 - (1,2,4 - thiadiazol - ³ - - phenyl) -4,4 - dimethyl -1,4 - dihydro - benzo [d] [1,3] oxazin-2 - one; 6 - (3 - fluoro-5 - thiophene -3 - yl - benzene Yl) -4,4 - dimethyl -1,4 - dihydro - benzo [d] [1,3] oxazin-2 - one; 4,4 - dimethyl-6 - (5 - nitro - -1H-pyrrole - ₂ -) -1,4 - dihydro-benzo [d] [1,3] oxazin-2 - one; 4,4 - dimethyl -6 - (1H-pyrrol-2 - yl) -1, 4 - dihydro - benzene And [d] [1,3] - oxazin-2 - one; 4,4 - dimethyl-6 - (1 - methyl-1H-pyrrol-2 - yl) -1,4 - dihydro - benzene and [D] [1,3] oxazin-2 - one; 4,4 - dimethyl-6 - (1 - methyl-5 - nitro-1H-pyrrol-2 - yl) -1,4 - two Hydrogen - benzo [D] [1,3] oxazin-2 - one; 3 - (1,2 - dihydro-2 - oxo-spiro [4H-3, 1 - benzoxazin-4,1 - cyclohexane] -6 - yl) - benzyl Nitrile; 3 - (1,2 - dihydro-2 - oxo-spiro [4H-3, 1 - benzoxazin 4,1 - cyclohexane] -6 - yl) -5 - fluorobenzonitrile; 4 - (1,2 - Dihydro-2 - oxo-spiro [4H-3, 1 - benzoxazin-4,1 - cyclohexane]-6 - yl) - 2 - thiophene carbonitrile; 5 - (1,2 - dihydro - 2 - -Oxo-spiro [4H-3, 1 - benzoxazin 4,1 - cyclohexane]-6 - yl) - 2 - thiophene carbonitrile; 5 - (1,2 - dihydro-2 - oxo-spiro [4H-3, 1 - benzoxazin-4,1 - cyclohexane] -6 - yl) -4 - methyl-2 - thiophene carbonitrile; 5 - (4,4 - dimethyl-2 - oxo - 1,4 - dihydro-2H-benzo [d] [1,3] oxazin-6 - yl) -4 - ethyl - thiophene-2 ​​- carbonitrile; 5 - (4,4 - dimethyl - 2 - oxo - 1,4 - dihydro-2H-benzo [d] [1,3] oxazin-6 - yl) -4 - n-propyl - thiophene-2 ​​- carbonitrile; 6 - (4 - cyano-3 - Fluoride - benzene Yl) -4,4 - dimethyl -1,4 - dihydro-benzo [d] [1,3] - oxazin-2 - one; 6 - (4 - fluoro - phenyl) -4,4 - dimethyl-1 - two H - benzo [d] [1,3] - oxazin-2 - one; 6 - (3,4 - difluoro - phenyl) -4,4 - dimethyl -1,4 - dihydro - benzene and [d] [1,3] Oxazin-2 - one; 6 - (2 - fluoro - phenyl) -4,4 - dimethyl -1,4 - dihydro - benzo [d] [1,3] - oxazin-2 - one ; 3 - (4,4 - Methyl-2 - oxo-1 ,4 - dihydro-2H-benzo [d] [1,3] - oxazin-6 - yl)-phenyl-acetonitrile; 5 - (4,4 - dimethyl - 2 - Oxygen 1 ,4 - dihydro-2H-benzo [d] [1,3] oxazin-6 - yl) - furan-2 - carbonitrile; 3 - (4,4 - dimethyl-2 - O 1 ,4 - Dihydro-2H-benzo [d] [1,3] oxazin-6 - yl) -2 - fluoro - benzonitrile; and 6 - (3 - cyano-5 - fluoro - phenyl) -4,4 - dimethyl -2 - oxo-4H-benzo [d] [1,3] oxazin-1 - carboxylic acid tert-butyl ester; or a pharmaceutically acceptable salt thereof. ...
8. compound as claimed in claim 1 is characterized in that, described compound be 2-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazine-6-yl)-pyrroles-1-carboxylic acid tert-butyl ester; 2-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazine-6-yl)-5-nitro-pyrroles-1-carboxylic acid tert-butyl ester; 5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazine-6-yl)-4-normal-butyl-thiophene-2-formonitrile HCN; Or its pharmacy acceptable salt.
9. a pharmaceutical composition is characterized in that, contains compound as claimed in claim 1 or its pharmacy acceptable salt and pharmaceutically acceptable carrier or vehicle.
10. the purposes of the described compound of claim 1 or its pharmacy acceptable salt is characterized in that, can be used for preparing the medicine that gives mammalian object, and wherein the described compound of significant quantity can cause the contraception of described mammalian object.
11. the purposes of the described compound of claim 1 or its pharmacy acceptable salt is characterized in that, can be used for preparing the medicine that gives mammalian object, wherein said compound can be treated the hormone-dependent tumor disease of described mammalian object.
12. purposes as claimed in claim 11 is characterized in that, described hormone-dependent tumor disease is selected from: the myometrium fibroma; Endometriosis; Benign prostatauxe; The gland cancer of uterine mucosa, ovary, mammary gland, colon, prostate gland, hypophysis and malignant adenoma; And meningioma.
13. the purposes of the described compound of claim 1 or its pharmacy acceptable salt is characterized in that, can be used for preparing the medicine that gives mammalian object, wherein said compound makes described mammalian object synchronization of estrus.
14. be selected from: 6-(3-chloro-phenyl-)-4-methyl-4-propine-1-base-1,4-dihydro-benzo [d] [1,3] oxazine-2-ketone; 6-(3-chloro-phenyl-)-4-ethynyl-4-methyl isophthalic acid, 4-dihydro-benzo [d] [1,3] oxazine-2-ketone; 6-(3-chloro-phenyl-)-4-cyclopropyl-4-propine-1-base-1,4-dihydro-benzo [d] [1,3] oxazine-2-ketone and 6-(3-chloro-phenyl)-4,4-two propine-1-base-1, [compound of 1,3] oxazine-2-ketone or the purposes of their pharmacy acceptable salts is characterized in that 4-two dihydrobenzos [d], can be used for preparing the medicine that gives mammalian object, wherein the described compound of significant quantity can cause the contraception of described mammalian object.
15. be selected from: 6-(3-chloro-phenyl-)-4-methyl-4-propine-1-base-1,4-dihydro-benzo [d] [1,3] oxazine-2-ketone; 6-(3-chloro-phenyl-)-4-ethynyl-4-methyl isophthalic acid, 4-dihydro-benzo [d] [1,3] oxazine-2-ketone; 6-(3-chloro-phenyl-)-4-cyclopropyl-4-propine-1-base-1,4-two dihydros-benzo [d] [1,3] oxazine-2-ketone and 6-(3-chloro-phenyl)-4,4-two propine-1-base-1, [compound of 1,3] oxazine-2-ketone or the purposes of their pharmacy acceptable salts is characterized in that 4-dihydrobenzo [d], can be used for preparing the medicine that gives mammalian object, wherein said compound can be treated the hormone-dependent tumor disease of described mammalian object.
16. purposes as claimed in claim 15 is characterized in that, described hormone-dependent tumor disease is selected from: the myometrium fibroma; Endometriosis; Benign prostatauxe; The gland cancer of uterine mucosa, ovary, mammary gland, colon, prostate gland, hypophysis and malignant adenoma; And meningioma.
17. be selected from: 6-(3-chloro-phenyl-)-4-methyl-4-propine-1-base-1,4-dihydro-benzo [d] [1,3] oxazine-2-ketone; 6-(3-chloro-phenyl-)-4-ethynyl-4-methyl isophthalic acid, 4-dihydro-benzo [d] [1,3] oxazine-2-ketone; 6-(3-chloro-phenyl-)-4-cyclopropyl-4-propine-1-base-1,4-dihydro-benzo [d] [1,3] oxazine-2-ketone and 6-(3-chloro-phenyl-)-4,4-two propine-1-base-1, [compound of 1,3] oxazine-2-ketone or the purposes of their pharmacy acceptable salts is characterized in that 4-dihydrobenzo [d], can be used for preparing the medicine that gives mammalian object, wherein said compound makes described mammalian object synchronization of estrus.
18. the purposes of the described compound of claim 1 or its pharmacy acceptable salt is characterized in that, is used to prepare the medicine that the mammalian object hormone replacement therapy is used, wherein said compound is regulated the generation of Progesterone hormone.
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