JP2002543193A - Cyclocarbamate derivatives as progesterone receptor modulators - Google Patents

Abstract

(57) [Summary] The present invention relates to a compound of formula (I): Wherein R ¹ and R ² are a single substituent or can be fused to form a spirocyclic or heterospirocyclic ring; R ³ is H, OH, NH ₂ , C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl, C ₃ -C ₆ alkenyl, substituted C ₁ -C ₆ alkenyl, alkynyl or substituted alkynyl, be a COR ^C; R ^C is H, C ₁ -C ₃ alkyl, substituted C ₁ -C ₃ alkyl, aryl, substituted aryl, C ₁ -C ₃ alkoxy, substituted C ₁ -C ₃ alkoxy, C ₁ -C ₃ aminoalkyl or substituted and C ₁ -C be ₃ aminoalkyl; R ⁴ is H, _{halogen, CN, NO 2, C 1} ~C 6 alkyl, substituted C ₁ -C ₆ alkyl, alkynyl or substituted alkynyl, C ₁ ~ C ₆ alkoxy, C ₁ substituted -C ₆ alkoxy, amino, C ₁ -C ₆ aminoalkyl or substituted C ₁ Be a C ₆ aminoalkyl; and R ⁵ is tri-substituted benzene ring or O, S, SO, we have 1, 2 or 3 heteroatoms from the group comprising SO ₂ or NR ⁶ and H, halogen , CN, NO _2, amino, and C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ aminoalkyl, one or two independent substituents from the group comprising COR ^F or NR ^G COR ^F Or a pharmaceutically acceptable salt thereof, and pharmaceutical compositions and methods for using these compounds as antagonists of the progesterone receptor.

Description

DETAILED DESCRIPTION OF THE INVENTION

FIELD OF THE INVENTION The present invention relates to compounds that are progesterone receptor antagonists, their preparation and utility.

BACKGROUND intracellular receptors invention (IR) form a class of structurally related gene regulators known as "ligand dependent transcription factors" (RM Evans, Science, 2
40, 889, 1988). The steroid receptor family, including progesterone receptor (PR), estrogen receptor (ER), androgen receptor (AR), glucocorticoid receptor (GR) and mineralocorticoid receptor (MR), is a subgroup of the IR family It is.

[0003] The natural hormone or ligand for PR is steroid progesterone, but synthetic compounds such as medroxyprogesterone acetate or levonorgestrel have also been produced that also act as ligands. Once the ligand is present in the fluid surrounding the cell, it passes through the membrane by passive diffusion and binds to the IR resulting in a receptor / ligand complex. This complex binds to a specific gene promoter present in the DNA of the cell. Once bound to such DNA, the complex regulates the production of mRNA and protein encoded by that gene.

Compounds that bind to the IR and mimic the action of natural hormones are called agonists,
On the other hand, compounds that inhibit the action of hormones are antagonists.

[0005] PR antagonists can be used in contraception. In this context, they alone (Ulmann, et al, Ann. NY Acad. Sci., 261, 248, 1995) and in combination with PR agonists (Kekkonen, et al, Fertility and Sterility, 60, 610).
1993) or in combination with a partial ER antagonist such as tamoxifen (WO
96/19997 A1 July 4, 1996).

[0006] PR antagonists are also known as hormone-dependent breast cancers (Horwitz, et al, Horm. Canc.
ed., 283, pub: Birkhaeuser, Boston, Mass., ed. Vedeckis) and can also be useful in the treatment of uterine and ovarian cancer. PR antagonists are also known as fibroids (Murphy, et al, J. Clin. Endo.Metab., 76, 513, 1993) and endometriosis (
It can also be useful in the treatment of non-malignant chronic conditions such as Kettel, et al, Fertility and Sterility, 56, 402, 1991).

[0007] PR antagonists can also be useful in hormone replacement therapy in postmenopausal patients in combination with partial ER antagonists such as tamoxifen
(US 5719136).

[0008] PR antagonists, such as mifepristone and onapristone, have been shown to be effective in models of hormone-dependent prostate cancer, indicating their utility in treating this condition in humans (Michna, et al,
Ann, NY Acad. Sci., 761, 224, 1995).

The compounds of the present invention have been shown to act as antagonists of progesterone binding to PR and to act as antagonists in functional models and / or in vitro / in vivo. These compounds are used for the treatment of fibroids, endometriosis, breast, uterine, ovarian and prostate cancer for contraception,
As well as in postmenopausal hormone replacement therapy.

Prior art compounds are described by Jones, et al (US Pat. No. 5,688,688).
No. 810) is a PR antagonist dihydroquinoline 1.

[0011]

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[0012] Jones, et al have reported that enol ether 2 (US Pat. No. 5,693,646)
No.) was described.

[0013]

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[0014] Jones, et al described compound 3 (US Pat. No. 5,696,127) as a PR ligand.

[0015]

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[0016] Zhi, et al described lactones 4, 5 and 6 as PR antagonists (J. Med
Chem., 41, 291, 1998).

[0017]

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Zhi, et al described ether 7 as a PR antagonist (J. Med. Chem.,
41, 291, 1998).

[0019]

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Combs, et al disclosed amide 8 as a ligand for PR (J. Med. Chem., 38,
4880, 1995).

[0021]

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Perlman, et al described vitamin D analog 9 as a PR ligand (Tet. Lett.
ers, 35, 2295, 1994).

[0023]

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Hamann, et al described a PR antagonist 10 (Ann. NY Acad. Sci., 7
61, 383, 1995).

[0025]

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[0026] Chen, et al described PR antagonist 11 (Chen, et al, POI-37, 16 ^th
Int. Cong. Het. Chem., Montana, 1997).

[0027]

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Kurihari, et al described PR ligand 12 (J. Antibiotics, 50, 360, 199).
7).

[0029]

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[0030] Narr, et al. (German Patent, DE 3633861, CA 109: 22973) describes a cardiotonic agent (cardotoni
cs) claims imidazobenzoxazinones, such as A; benzoxazin-2-ones such as brofoxin (B), which are effective as anxiolytics, are described in Hartmann et al. (Pr.
oc. West. Pharmacol. Soc. 21, 51-55 (1978)); more recently, a number of patents (eg, Young et al. WO95 / 20389; Christ et al. WO98 / 14436).
Claimed quinazolin-2-ones and benzoxazin-2-ones, such as compounds C1 and C2, as inhibitors of HIV reverse transcriptase.

[0031]

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The compounds of the present invention contain a pendent aromatic substituent. These aromatic substituents have proven to be crucial for the resulting compounds to be effective as progesterone receptor modulators, and include aryl, substituted aryl,
It has a wide variety of structures that can consist of heteroaryl or substituted heteroaryl groups.

Description of the Invention The present invention provides a compound of formula (I):

[0034]

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Wherein R ¹ and R ² are H, C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, substituted C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, substituted C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, substituted C ₃ -C ₈ cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic wherein, COR ^a, or NR ^B COR a or is independent substituents selected from the group of ^a; or R ¹ and R ² are fused a) optionally spiro ring members 3-8 may be substituted A formula alkyl ring; b) an optionally substituted 3-8 membered spirocyclic alkenyl; or
c) forming an optionally substituted 3-8 membered heterocyclic ring containing 1-3 heteroatoms from the group comprising O, S and N; a), b) and c spirocyclic rings fluorine), C ₁ ~C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C _{6 thioalkyl, -CF 3, -OH, -CN,} NH 2, -NH (C 1 ~C R ^A is H, C ₁ -C ₃ alkyl, substituted, optionally substituted with 1-4 groups selected from ₆ alkyl) or -N (C ₁ -C ₆ alkyl) ₂ ; C ₁ -C ₃ alkyl, aryl, substituted aryl, C ₁ -C ₃ alkoxy, substituted C ₁ -C ₃ alkoxy, with C ₁ -C ₃ aminoalkyl or substituted C ₁ -C ₃ aminoalkyl R ^B is H, C ₁ -C ₃ alkyl or substituted C ₁ -C ₃ alkyl; R ³ is H, OH, NH ₂ , C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl, C ₃ -C ₆ alkenyl, substituted C ₁ -C ₆ alkenyl, alkynyl or substituted alkynyl, COR ^C ; R ^C is H, C ₁ -C ₃ alkyl, substituted C ₁ -C ₃ alkyl, aryl, substituted aryl, C ₁ R ⁴ is H, halogen, CN, NO ₂ , C ₁ -C ₃ alkoxy, substituted C ₁ -C ₃ alkoxy, C ₁ -C ₃ aminoalkyl or substituted C ₁ -C ₃ aminoalkyl; -C ₆ alkyl, substituted C ₁ -C ₆ alkyl, alkynyl or substituted alkynyl, C ₁ -C ₆ alkoxy, substituted C ₁ -C ₆ alkoxy, amino, C ₁ -C ₆ aminoalkyl or substituted has been located by C ₁ -C ₆ aminoalkyl; R ⁵ is selected from a) or b), a) R ⁵ is a substituent X as shown below, tri-substituted benzene ring containing the Y and Z Is:

[0036]

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Wherein: X is halogen, CN, C ₁ -C ₃ alkyl, substituted C ₁ -C ₃ alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, C ₁ -C ₃ alkoxy, substituted C ₁ -C ₃ alkoxy, C ₁ -C ₃ thioalkoxy, substituted C ₁ -C ₃ thioalkoxy, amino, C ₁ -C ₃ aminoalkyl, substituted C ₁ -C ₃ aminoalkyl, NO _2, C ₁ ~C ₃ perfluoroalkyl, 1-3 heterocyclic ring of 5 or 6 membered containing heteroatoms, COR ^D, is selected from the group comprising OCOR ^D or NR ^E COR ^D; R ^D It is H, C ₁ -C ₃ alkyl, substituted C ₁ -C ₃ alkyl, aryl, substituted aryl, C ₁ -C ₃ alkoxy, substituted C ₁ -C ₃ alkoxy, C ₁ -C ₃ amino an alkyl or substituted C ₁ -C ₃ aminoalkyl; R ^E is H, C ₁ ~C ₃ alkyl Properly is an C ₁ -C ₃ alkyl substituted; Y and Z are H, halogen, CN, NO _2, amino, aminoalkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkyl or C ₁ -C ₃ ) an independent substituent selected from the group comprising thioalkoxy; or b) R ⁵ has 1, 2 or 3 heteroatoms from the group comprising O, S, SO, SO ₂ or NR ⁶ and and H, halogen, CN, NO _2, amino, and C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ aminoalkyl, 1 or 2 from the group comprising COR ^F or NR ^G COR ^F It is a number of separate 5 or 6-membered ring containing substituents; R ^F is H, C ₁ -C ₃ alkyl, substituted C ₁ -C ₃ alkyl, aryl, substituted aryl, C ₁ -C R ^G is H, C ₃ alkoxy, substituted C ₁ -C ₃ alkoxy, C ₁ -C ₃ aminoalkyl or substituted C ₁ -C ₃ aminoalkyl; ₁ -C is ₃ alkyl or substituted C ₁ -C ₃ alkyl; R ⁶ is H or C ₁ -C ₃ alkyl is, to provide a compound or a pharmaceutically acceptable salt thereof.

Preferred compounds of the present invention include compounds of formula I

[0039]

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Wherein R ¹ is H, C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, substituted C ₃ -C ₈ cycloalkyl, aryl, substituted aryl, heterocyclic, heterocyclic substituted, be a COR ^A, or NR ^B COR ^A; R ² is H, C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl, C ₂ ~ C ₆ alkenyl, substituted C ₂ -C ₆ alkenyl, C ₃ -C ₈ cycloalkyl, substituted C ₃ -C ₈ cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic , COR ^a, or NR ^B be a COR ^a; or R ¹ and R ² are fused 3-8 membered spirocyclic spirocyclic alkyl as a ring, 3-8
Membered spirocyclic ring to form a substituted is constructed by condensing R ¹ and R ² spiro cyclic alkyl, so as to form a spiro cyclic ring of 3-8 members R ¹ and R spirocyclic alkenyl constructed by condensing ^2, 3-8 membered substituted spirocyclic alkenyl constructed by condensing R ¹ and R ² to form a spirocyclic ring, 3 and O is constructed by condensing R ¹ and R ² to form a 8-membered spirocyclic ring, spirocyclic alkyl containing 1-3 heteroatoms from the group comprising S and N A substituted, constructed by fusing R ¹ and R ² to form a 3-8 membered spirocyclic ring and containing 1-3 heteroatoms from the group comprising O, S and N; spirocyclic alkyl to form a; R ¹及R beauty of these produced ^{by 2} condensing spirocyclic ring Fluorine, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C _{6 thioalkyl, -CF 3, -OH, -CN,} NH 2, -NH (C 1 ~C 6 alkyl) or -N ( C ₁
-C ₆ alkyl) may be optionally substituted with 1-4 groups selected from _2; R ^A is H, C ₁ -C ₃ alkyl, substituted C ₁ -C ₃ alkyl, aryl, R ^B is H, C ₁ -substituted aryl, C ₁ -C ₃ alkoxy, substituted C ₁ -C ₃ alkoxy, C ₁ -C ₃ aminoalkyl or substituted C ₁ -C ₃ aminoalkyl; -C ₃ alkyl or be substituted C ₁ -C ₃ alkyl; R ³ is _{H, OH, NH 2, C} 1 ~C 6 alkyl, substituted C ₁ -C ₆ alkyl, C ₃ -C ₆ alkenyl , substituted C ₁ -C ₆ alkenyl, alkynyl or substituted alkynyl, be a COR ^C; R ^C is H, C ₁ -C ₄ alkyl, substituted C ₁ -C ₄ alkyl, aryl, substituted aryl, C ₁ -C ₄ alkoxy, substituted C ₁ -C ₄ alkoxy, C ₁ -C ₄ aminoalkyl or substituted C ₁ -C ₄ amino Is alkyl; R ⁴ is H, _{halogen, CN, NO 2, C 1} ~C 6 alkyl, substituted C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, substituted C ₁ -C ₆ alkoxy, Amino, C ₁ -C ₆ aminoalkyl or substituted C ₁ -C ₆ aminoalkyl; R ⁵ is a trisubstituted benzene ring containing substituents X, Y and Z as shown below:

[0041]

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X is halogen, CN, C ₁ -C ₃ alkyl, substituted C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, substituted C ₁ -C ₃ alkoxy, C ₁ -C ₃ thioalkoxy , Substituted C ₁ ~
C ₃ thioalkoxy, amino, C ₁ -C ₃ aminoalkyl, substituted C ₁ -C ₃ aminoalkyl, NO _2, C ₁ ~C ₃ perfluoroalkyl, 5-membered containing 1 to 3 heteroatoms heterocyclic ring, COR ^D, is selected from the group comprising OCOR ^D or NR ^E COR ^D; R ^D is H, C ₁ -C ₃ alkyl, substituted C ₁ -C ₃ alkyl, aryl, substituted aryl , C ₁ -C ₃ alkoxy, substituted C ₁ -C ₃ alkoxy, C ₁ -C ₃ aminoalkyl or substituted C ₁ -C ₃ aminoalkyl; ^RE is H, C ₁ -C ₃ alkyl or be substituted C ₁ -C ₃ alkyl; Y and Z are H, _{halogen, CN, NO 2, C 1} ~C 3 alkoxy, C ₁ -C ₃ alkyl or
R ⁵ is an independent substituent selected from the group comprising C ₁ -C ₃ thioalkoxy; or R ⁵ is 1, 2 or 3 heteroatoms from the group comprising O, S, SO, SO ₂ or NR ⁶ the a and H, halogen, CN, NO _2, amino, and C ₁ -C ₃ alkyl or C ₁ -C 5 or 6-membered ring containing one or two independent substituents from the group comprising ₃ alkoxy And R ⁶ is H or C ₁ -C ₃ alkyl; or a pharmaceutically acceptable salt thereof.

Another preferred compound is a compound of formula I

[0044]

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Wherein R ¹ = R ² and C ₁ -C ₃ alkyl, substituted C ₁ -C ₃ alkyl, R ¹ and R ² fused to form a 3 to 6 membered spirocyclic ring R ³ is H, OH, NH ₂ , C ₁ -C ₆ alkyl or substituted C ₁ -C ₆ alkyl, COR ^C ; R ³ is selected from the group comprising spirocyclic alkyls constructed by: ^C is H, C ₁ -C be ₄ alkyl or C ₁ -C ₄ alkoxy; R ⁴ is H, _{halogen, CN, NO 2, C 1} ~C 3 alkyl, substituted C ₁ -C ₃ alkyl, C R ⁵ is a di-substituted benzene ring containing substituents X and Y as shown below: _1- C ₃ alkoxy or substituted C ₁ -C ₃ alkoxy.

[0046]

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X is halogen, CN, C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkyl, NO ₂ , C ₁ -C ₃ perfluoroalkyl, 5 membered heterocyclic containing ₁ to ₃ heteroatoms Ring, selected from the group comprising C ₁ -C ₃ thioalkoxy; Y includes H, halogen, CN, NO ₂ , C ₁ -C ₃ alkoxy, C ₁ -C ₄ alkyl, C ₁ -C ₃ thioalkoxy Or a substituent from the group; or R ⁵ is a structure

[0048]

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A 5-membered ring having the formula: wherein U is O, S or NR ⁶ , R ⁶ is H or C ₁ -C ₃ alkyl or C ₁ -C ₄ CO ₂ alkyl; X ′ is halogen, From the group comprising CN, NO ₂ or C ₁ -C ₃ alkyl and C ₁ -C ₃ alkoxy, provided that when U is NR ⁶ , X ′ is not CN; Y ′ is H and C ₁ It is from the group including -C ₄ alkyl; or R ⁵ has the structure:

[0050]

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X ¹ is N or CX ² ; X ² is halogen, CN, alkoxy or NO ₂ ; or a pharmaceutically acceptable salt thereof.

Further preferred compounds are those of formula I

[0053]

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Wherein: R ¹ = R ² and CH ₃ and selected from the group comprising spirocyclic alkyl constructed by fusing R ¹ and R ² to form a 6-membered spirocyclic ring. ; R ³ is H, OH, NH _2, CH _3, substituted methyl, or be a -COR ^c; R ^c is H, be a C ₁ -C ₃ alkyl or C ₁ -C ₄ alkoxy; R ⁴ is H, halogen, NO _2, be a CN or C ₁ -C ₃ alkyl; R ⁵ is di-substituted benzene ring containing the substituents X and Y as shown below:

[0055]

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X is selected from the group comprising halogen, CN, methoxy, NO ₂ or 2-thiazole; Y is H or F; or R ⁵ has the structure:

[0057]

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A 5-membered ring having the formula: wherein U is O, S or NH; X ′ is halogen, CN or NO ₂ , provided that when U is NR ⁶ (NH)
'It is not the CN; Y' is H or C ₁ -C is ₄ alkyl; a thing and its pharmaceutically acceptable salts.

The compounds of the present invention may contain asymmetric carbon atoms, and some of the compounds of the present invention may contain one or more asymmetric centers, and thus include optical isomers and diastereomers. Stereomers can be generated. Although Formula I is shown without consideration of stereochemistry, the present invention is directed to such optical isomers and diastereomers; and racemic and resolved, enantiomerically pure R and S stereoisomers; And other mixtures of the S stereoisomer and pharmaceutically acceptable salts thereof. The term `` alkyl '' is used herein to refer to both straight and branched chain saturated aliphatic hydrocarbon groups having 1-8 carbon atoms, preferably 1-6 carbon atoms. "Alkenyl" refers to both straight and branched chain alkyl groups having at least one carbon-carbon double bond and 2-8 carbon atoms, preferably 2-6 carbon atoms. "Alkynyl" groups include straight and branched chain groups having at least one carbon-carbon triple bond and 2-8 carbon atoms, preferably 2-6 carbon atoms. It is intended that both alkyl groups be included.

The terms “substituted alkyl,” “substituted alkenyl,” and “substituted alkynyl” are halogen, CN, OH, NO ₂ , amino, aryl, heterocyclic,
Description having 1-3 substituents selected from the group comprising substituted aryl, substituted heterocyclic, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino, arylthio Alkyl, alkenyl and alkynyl as indicated. These substituents can be attached to any carbon of the alkyl, alkenyl or alkynyl group, provided that the attachment constitutes a stable chemical moiety.

The term “aryl” as used herein refers to an aromatic which can be a single ring or a polyaromatic ring fused or linked together such that at least a portion of the fused or linked rings form a conjugated aromatic system. Used to refer to a tribal system. Aryl groups include, but are not limited to, phenyl, naphthyl, biphenyl, anthryl, tetrohydronaphthyl, phenanthryl.

The term “substituted aryl” refers to halogen, CN, OH, NO ₂ , amino, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, Aryl as defined having 1-4 substituents from the group comprising alkylamino or arylthio.

The term “heterocyclic” as used herein refers to one to four saturated, partially unsaturated or unsaturated and selected from the group comprising carbon atoms and N, O and S atoms. Used to describe a stable 4-7 membered monocyclic or stable polycyclic heterocyclic ring consisting of heteroatoms. N and S atoms may be oxidized. Heterocyclic rings also include any polycyclic ring in which any of the above defined heterocyclic rings is fused to an aryl ring. Heterocyclic rings can be attached at any heteroatom or carbon atom provided the resulting structure is chemically stable. Such heterocyclic groups include, for example, tetrahydrofuran, piperidinyl, piperazinyl, 2-oxopiperidinyl, azepinyl, pyrrolidinyl, imidazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, morpholinyl, indolyl, quinolinyl, thienyl , Furyl, benzofuranyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide and isoquinolinyl.

The term “substituted heterocyclic” as used herein refers to halogen, CN, OH,
NO ₂ , amino, alkyl, substituted alkyl, cycloalkyl, alkenyl,
Heterocycle as defined having 1-4 substituents selected from the group comprising substituted alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino or arylthio. Used to describe an expression. The term "alkoxy" is used herein to refer to the OR group where R is alkyl or substituted alkyl. The term "aryloxy" is used herein to refer to an OR group where R is aryl or substituted aryl. The term "alkylcarbonyl" is used herein to refer to an RCO group where R is alkyl or substituted alkyl. The term “alkylcarboxy”
It is used herein to refer to a COOR group where R is alkyl or substituted alkyl. The term "aminoalkyl" refers to an alkyl containing 1 to 8 carbon atoms or a substituted alkyl group (to which can be the same or different) and a secondary where the point of attachment is on the nitrogen atom. And tertiary amines. The term "halogen" refers to Cl, Br, F or I.

The compounds of the present invention can be used in the form of salts obtained from pharmaceutically or physiologically acceptable acids or bases. These salts include, but are not limited to, salts with inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid and optionally with organic acids such as acetic acid, oxalic acid, succinic acid and maleic acid. Not something. Other salts include alkali metals such as sodium, potassium, calcium or magnesium in the form of esters, carbamates and other common "prodrugs" that convert to the active ingredient in vivo when administered in such form Or salts with alkaline earth metals are included.

The present invention includes a pharmaceutical composition comprising one or more compounds of the present invention and a pharmaceutically acceptable carrier or excipient. The invention also encompasses a method of treatment comprising administering to a mammal a pharmaceutically effective amount of one or more compounds as described above as an antagonist of the progesterone receptor.

The progesterone receptor antagonists of the present invention, used alone or in combination, can be used in methods of contraception and in the treatment and / or prevention of benign and malignant neoplastic diseases. Specific uses of the compounds and pharmaceutical compositions of the invention include myometrial fibroids, endometriosis, benign prostatic hyperplasia; endometrial, ovarian, breast, colon, prostate, pituitary and adenocarcinoma Treatment and / or prevention of meningioma and other hormone-dependent tumors. Further uses of the progesterone receptor antagonists of the present invention include synchronization of estrus in livestock.

When the compounds of the present invention are used in any of the above useful compounds, they can be combined with one or more pharmaceutically acceptable carriers or excipients, for example, solvents, diluents and the like. And tablets, capsules, dispersible powders, granules, or suspensions containing, for example, about 0.05 to 5% of suspending agents, such as syrups containing about 10 to 50% sugar, and for example, Orally, in the form of an elixir or the like containing 20-50% ethanol, or a sterile injectable solution or suspension containing about 0.05-5% suspending agent in an isotonic medium. It can be administered parenterally in the form. Such pharmaceutical preparations can be combined with a carrier, for example, from about 25 to about 90.
%, More usually between about 5 and 60% by weight of active ingredient.

The effective dose of the active ingredient employed may vary depending on the particular compound employed, the mode of administration and the severity of the condition being treated. In general, however, the compounds of the invention are administered in a daily dose of about 0.5 to about 500 mg / kg of animal body weight, preferably when given in divided doses 2 to 4 times per day or in a sustained release form Results are obtained. For most large mammals, the total daily dose is about 1-100 mg, preferably about 2-80 m
g. Dosage forms suitable for internal use comprise about 0.5 to 500 mg of the active compound in admixture with a solid or liquid pharmaceutically acceptable carrier. This regimen can be adjusted to give the optimal therapeutic response. For example, several divided doses may be administered daily or the dose may be correspondingly reduced as indicated by the exigencies of the therapeutic situation.

The active compounds can be administered orally as well as by intravenous, intramuscular or subcutaneous route. Solid carriers include starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin, as long as appropriate for the nature of the active ingredient and the particular form of administration desired. Sterile water, polyethylene glycol, nonionic surfactants and edible carriers such as corn oil, peanut oil, and sesame oil are included. Fragrances, colorants, preservatives and antioxidants, for example,
Additives commonly used in the manufacture of pharmaceutical compositions such as vitamin E, ascorbic acid, BHT and BHA can be conveniently included.

Preferred pharmaceutical compositions from the standpoint of ease of manufacture and administration are solid compositions, especially tablets and hard-filled or liquid-filled capsules. Oral administration of the compound is preferred.

These active compounds can also be administered parenterally or intraperitoneally.
Solutions or suspensions of these active compounds as free base or pharmacologically acceptable salts can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

Pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. You. In all cases, these forms must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. Carriers include, for example, water, ethanol (eg, glycerol, propylene glycol and liquid polyethylene glycol)
, A suitable mixture thereof and a solvent or dispersion medium containing vegetable oils.

The compounds of the present invention can be prepared according to the schemes illustrated below:

[0075]

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As shown in Scheme I, the compounds of the present invention are generally prepared by using a suitable coupling reaction as a final step. Appropriately substituted ortho-aminobenzoic acid or a derivative thereof such as an ethyl ester (X = Br, I, Cl, or a latent coupling such as an alkoxy group that can be converted to a suitable OTf group in a coupling reaction) Precursor) at -78 ° C to room temperature under an inert atmosphere such as argon or nitrogen in a suitable aprotic solvent including but not limited to THF or ether in a suitable aprotic solvent For example, treatment with a Grignard reagent produces ortho-aminocarbinol 2. Ring closure of carbinol 2 to form benzoxazin-2-one 3 generally involves carbonyldiimidazole, phosgene, dimethyl carbonate or dimethyl carbonate in a suitable aprotic solvent such as THF at a temperature ranging from room temperature to 65 ° C. Provided by a condensing agent such as diethyl carbonate. Arylation of benzoxazin-2-one 3 to produce 4 can be effected by various coupling reactions, including Suzuki and Stille reactions. These reactions generally involve transition metal catalysts, such as mostly phosphino ligands such as e.g.
The reaction is performed in the presence of a palladium or nickel complex with Ph ₃ P, 1,1′-bis (diphenylphosphino) ferrocene, 1,2-bis (diphenylphosphino) ethane or a palladium salt such as palladium acetate. Under this catalytic condition, an appropriately substituted nucleophile, such as an arylboronic acid, arylstannane or arylzinc compound, is coupled with benzoxazinone 3 to form 4. Where a base is required for the reaction, commonly used bases include, but are not limited to, sodium bicarbonate, sodium carbonate, potassium phosphate, barium carbonate, potassium acetate or cesium fluoride. . The most commonly used solvents for these reactions include benzene, DMF, isopropanol, toluene, ethanol, D
A mixture of ME, ether, acetone or any one of these solvents and water is included. The coupling reaction is generally performed under an inert atmosphere such as nitrogen or argon at a temperature ranging from room temperature to the boiling point of the solvent or solvent system or mixture.

Benzoxazinone 3 can be converted to a nucleophile such as a boronic acid,
This can be coupled to an appropriate electrophile, such as an aryl bromide or aryl iodide, using coupling reaction conditions as described above to produce 4. Conversion of 3 to 5 involves treating 3 with an organometallic reagent, e.g., n-BuLi, in an aprotic solvent such as THF or ether, and then treating the reaction solution under an inert atmosphere such as argon or nitrogen. It can be provided by quenching with a suitable electrophile such as trimethyl borate, triisopropyl borate, bishexaalkyltin reagent or zinc chloride at a temperature ranging from -78 ° C to reflux temperature.

[0078]

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Scheme Ia illustrates another method to provide benzoxazinone 3. Thus, allyloxycarbonyl, t-butoxycarbonyl, benzoxycarbonyl in a suitable solvent such as THF, acetonitrile in the presence or absence of a base, either as a catalyst or an acid scavenger, with the appropriate aniline 1 , Ethoxycarbonyl or methoxycarbonyl, but is not limited thereto by a suitable alkoxycarbonyl protecting group. The protected aniline is then
Treatment with a suitable organometallic reagent, such as an organolithium reagent or a Grignard reagent, to produce carbinol 6 in the same manner as preparing compound 2. 6 to room temperature ~
Suitable temperatures such as potassium t-butoxide, n-butyllithium, potassium hydroxide in a suitable solvent such as toluene, THF, alcohol under an inert atmosphere such as nitrogen or argon at a temperature in the range of the boiling point of the relevant solvent Benzoxazinone
Generate 3.

Scheme II describes a method for making benzoxazinones bearing two different substituents at the 4-position. Weinreb amide 8 can be obtained from an appropriately substituted isatoic anhydride 7 at reflux under an inert atmosphere such as argon or nitrogen in a protic solvent such as ethanol, isopropanol, N-, O-dimethylhydroxyl. -Can be prepared by treatment with amine hydrochloride. The coupling of an amide 8 with an aryl electrophile, such as an aryl boronic acid or aryl stannane, to produce 9 is similar to the Suzuki, Stille coupling method described for the preparation of benzoxazinone 4. It can be provided by using a typical coupling reaction. Weinreb amide 9 is treated with an organometallic compound, such as an alkyl lithium, alkynyl lithium, in an aprotic solvent such as THF or ether under an inert atmosphere such as argon or nitrogen at -78 ° C to room temperature.
Treatment with aryl lithium or their Grignard equivalents yields aminoketone 10
Is generated. Conversion of ketone 10 to carbinol 11 can be carried out at -78 ° C. to room temperature under an inert atmosphere such as argon or nitrogen in an aprotic solvent such as THF or ether, such as an alkyl, alkynyl or aryl Grignard compound. It can be provided by 10 treatments with organometallic reagents. The conversion of ketone 10 to carbinol 11 can also be achieved by lithium aluminum hydride, borohydride in a suitable solvent such as THF, ether or anhydrous alcohol under an inert atmosphere at a temperature ranging from 0 ° C. to the boiling point of the solvent. It can also result from the reduction of 10 ketone groups to 11 carbinol components using a suitable reducing reagent such as sodium. Ring closure of carbinol 11 to make compounds of the present invention can be carried out in a suitable aprotic solvent such as THF at a temperature ranging from room temperature to 65 ° C., such as carbonyldiimidazole, phosgene, dimethyl carbonate or diethyl carbonate. With a suitable condensing agent.

[0081]

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Alternatively, the ortho-aminoketone 10 can be substituted with -78 as illustrated in Scheme III.
Ortho-aminobenzonitrile with an organometallic compound such as an organolithium reagent or a Grignard reagent in a suitable solvent such as THF or ether under an inert atmosphere such as argon or nitrogen at a temperature ranging from C to room temperature. Can be produced. Benzonitrile 14 can be a suitably substituted benzonitrile such as bromobenzonitrile 13 using a suitable coupling reaction such as a Stille or Suzuki protocol performed as described for the preparation of Weinreb amide 9. Can be easily manufactured.

[0083]

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Scheme IV illustrates a method for making benzoxazinones having a lower perfluoroalkyl substituent at the 4-position, for example, where R ⁶ is a trifluoromethyl group. Appropriately substituted chloroaniline 15 is dissolved in a suitable solvent such as acetonitrile, acetone, THF, methylene chloride or methylene chloride and water under an inert atmosphere such as argon or nitrogen at a temperature ranging from 0 ° C to 70 ° C. Protected aniline 16 was formed by protecting with a suitable protecting reagent such as pivaloyl chloride or di-tert-butyl pyrocarbonate in a mixture of such solvents. If the reaction produces an acid such as the hydrochloride salt as a by-product, a suitable base such as sodium carbonate, sodium bicarbonate or potassium carbonate may be required. Treatment of 16 with a suitable alkyl lithium, such as n-butyllithium or s-butyllithium, followed by an aproton such as ether or THF under an inert atmosphere such as argon or nitrogen at -78 ° C to ambient Reaction with lower perfluorocarboxy derivatives such as trifluoroacetyl chloride, 1- (trifluoroacetyl) -imidazole or ethyl trifluoroacetate in an aprotic solvent produces the protected ortho-aminoketone. Subsequent removal of protecting groups can be carried out at 0 ° C. to the boiling point of the solvent in a suitable solvent such as methylene chloride or water with TFA,
This can be effected by reaction of the protected amino ketone with a suitable acid, such as aqueous 3N hydrochloride, to give the ortho-amino ketone 17. The preparation of 6-chlorobenzoxazinone 19 from 17 can be accomplished in a manner similar to that described for the synthesis of benzoxazinone 12 from ketone 10. Coupling of the aryl group with 19 to produce compound 12 of the present invention as shown in Scheme IV can be effected by a coupling reaction catalyzed by a nickel complex. The palladium catalyst was not found to be an efficient catalyst in this coupling step. The coupling reaction between the appropriate arylboronic acid and 19 is accomplished in the presence of a suitable base such as potassium phosphate and a catalyst of a nickel (0 or II) complex, for example a nickel complex of dppe, dppf or triphenylphosphine. be able to. The most commonly used solvents for the reaction include dioxane or THF. The coupling reaction is generally carried out at a temperature ranging from ambient temperature to 95 ° C under an inert atmosphere such as nitrogen or argon.

[0085]

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As illustrated in Scheme V, compound 6 or 12 can be further derivatized at position 1 by a number of methods to give 1-alkyl, 1-substituted alkyl, 1-carbonyl, 1-substituted carbonyl, A variety of novel cyclocarbamate derivatives can be provided, including 1-carboxy, substituted 1-carboxy derivatives. For example, an alkyl or substituted alkyl derivative 20 can be obtained by treating the carbamate 12 or 6 with a suitable base such as sodium hydride in a suitable solvent such as DMF under an inert atmosphere such as argon or nitrogen; Subsequent addition of a suitable electrophile such as an alkyl or substituted alkyl bromide, iodide or triflate can be used. Such a conversion of 12 or 6 at the 1 position can also be carried out using a biphasic catalyst such as tributylammonium bromide, where the alkylation is performed in a suitable solvent such as acetonitrile, as shown in Scheme V. It can also be provided using conditions. Another example of this type of modification includes, but is not limited to, those shown in Scheme V where 12 or 6 is heated with triethyl orthoformate to produce a 1-substituted derivative of compound 12 or 6. It is not something to be done.

[0087]

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The acylation or carboxylation of compound 12 or 6 at position 1 to form compound 21 can be accomplished by converting 12 or 6 in a suitable solvent such as acetonitrile under an inert atmosphere such as argon or nitrogen. Dimerization in the presence of a suitable basic catalyst such as DMAP
It can be readily provided by treatment with a suitable acylating or carboxylating reagent such as -t-butyl dicarbonate. Amination of the 1-position of compound 12 or 6 to produce 22 is by literature methods (Metlesics et al. J. Org. Chem. 30
, 1311 (1965)) in a suitable solvent such as THF or diethyl ether in the presence of a suitable base such as sodium hydride, using a suitable aminating reagent such as chloroamine.

Example 1 2- (2-amino-5-bromophenyl) propan-2-ol A solution of 2-amino-5-bromobenzoic acid (10 g, 46 mmol) in dry THF (200 mL) was added in ether. Treated with a solution of methylmagnesium bromide (3.0 M, 90 mL, 270 mmol) at -78 ° C under nitrogen. The reaction mixture was slowly warmed to ambient temperature and kept stirring under nitrogen for 48 hours, then poured into cold aqueous 0.5N hydrochloride (300 mL). The mixture was neutralized with a 1N aqueous sodium hydroxide solution, and ethyl acetate (300 mL) was added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3x100mL). The combined organic layers were washed with brine, dried (MgSO _4). After removal of the solvent in vacuo, the residue was purified by flash chromatography on silica gel (hexane: ethyl acetate / 3: 2) to give 2- (2-amino-5-bromophenyl) propan-2-ol with a yellowish tinge. Obtained as a white solid (6 g, 57%): m
p 62-63 ° C; ¹ H-NMR (CDCl ₃ ) δ 7.19 (d, 1H, J = 2.3 Hz), 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).

Example 2 6-Bromo-4,4-dimethyl-1,4-dihydro-benzo [d] [1,3] oxazin-2-one 2- (2-amino-) in dry THF (150 mL) 5-bromophenyl) propan-2-ol (18 g,
1,1′-carbonyldiimidazole (15.5 g, 94 mmol) was added to a solution of 78 mmol) under nitrogen. The reaction solution was heated at 50 ° C. overnight. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate (100mL). The solution was washed with a 1N aqueous solution of hydrochloride (2 × 40 mL), brine (20 mL) and dried over MgSO ₄ . After removing the solvent in vacuo, 6-bromo-4,4-dimethyl-1,4
-Dihydro-benzo [d] [1,3] oxazin-2-one was obtained as a white solid (20 g, 100%): mp 199-200 ° C .; ¹ H-NMR (DMSO-d ₆ ) δ10. 32 (s, 1H, D ₂ O interchangeable), 7.4
8 (d, 1H, J = 2.1Hz), 7.43 (dd, 1H, J = 8.5, 2.1Hz), 6.84 (d, 1H, J = 8.4Hz), 1.6
1 (s, 6H).

Example 3 6-Iodo-4,4-dimethyl-1,4-dihydro-benzo [d] [1,3] oxazin-2-one The product was prepared according to the method of Examples 1 and 2 Prepared from -amino-5-iodobenzoic acid as a white solid: mp 196-197 ° C .; ¹ H-NMR (DMSO-d ₆ ) δ 10.30 (s, 1H,
D ₂ O exchangeable), 7.58 (m, 2H) , 6.71 (d, 1H, J = 8.4Hz), 1.58 (s, 6H). MS (EI) m /
z 326 ([M + Na] ⁺ , 100%). Calcd _{C 10 H 10 INO 2: C} , 39.63, H, 3.33, N, 4.6
2. Found: C, 39.25, H, 3.24, N, 4.49.

Example 4 (1,4-Dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl) boron
A solution of 6-bromo-4,4-dimethyl-1,4-dihydro-benzo [d] [1,3] oxazin-2-one (2 g, 7.8 mmol) in anhydrous acid THF (60 mL) under nitrogen At −78 ° C. a solution of n-BuLi in hexane (10 M, 2.4 mL, 24 mmol) was added. After stirring at −78 ° C. for 30 minutes, a slurry was obtained, which was treated with triisopropyl borate (6.5 mL, 28 mmol). The reaction medium was slowly warmed to ambient temperature and quenched with 1N aqueous hydrochloric acid (60 mL). Ethyl acetate
(100 mL), the organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3 × 60 mL). The combined organic layers were washed with brine, dried over MgSO _4. The solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel (ethyl acetate: hexane / 2: 1) to give (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1 -Benzoxazine-6-
Yl) boronic acid was obtained as a white solid (1.4 g, 81%): mp 249-250 ° C .; ¹ H-NMR (DM
SO-d ₆ ) δ 10.21 (s, 1H, D ₂ O exchangeable), 7.90-7.95 (br s, 2H, D ₂ O exchangeable),
7.67 (m, 2H), 6.79 (d, 1H, J = 7.8Hz), 1.61 (s, 6H). MS (ESI) m / z 222 ([M + H] ⁺ , 87%).

Example 56- (3-chlorophenyl) -4,4-dimethyl-1,4-dihydrobenzo [d] [1,3] oxazine-2 -On (Method A) 6-Bromo-4,4-dimethyl-1,4-dihydro- in a mixture of DME and water (40 mL / 10 mL)
Benzo [d] [1,3] oxazin-2-one (1.5 g, 5.9 mmol), 3-chlorophenylboronic acid
(1.83 g, 11.7 mmol), tetrakis (triphenylphosphine) -palladium (0) (0.3
5 g, 0.3 mmol) and a mixture of sodium carbonate (2.48 g, 23.4 mmol) was degassed to remove oxygen.
Removed and then heated at 85 ° C. for 3 hours under a blanket of nitrogen. Bring the reaction mixture to ambient temperature
And quenched with saturated aqueous ammonium chloride (20 mL). Ethyl acetate
(50 mL) was added and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (3x15mL). Match
The organic layer was washed with brine and dried over MgSO_FourAnd dried. The solvent is removed in vacuo and the remaining
The distillate was subjected to silica gel flash chromatography (hexane: ethyl acetate / 2: 1).
Purify further to give 6- (3-chlorophenyl) -4,4-dimethyl-1,4-dihydrobenzo [d] [1,3]
Oxazin-2-one was obtained as a yellowish solid (1.4 g, 82%): mp 158-159 ° C; ¹ H-NMR (DMSO-d₆) δ 10.31 (s, 1H, D_TwoO exchangeable), 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). C₁₆H₁₄ClNO_Two・ 0.1H_TwoCalculated value for O: C, 66.37, H, 4.94, N, 4.8
Four. Found: C, 66.14, H, 4.61, N, 4.71.

[0094] Example 6 6- (3-methoxy - phenyl) -4,4-dimethyl-1,4-dihydro - benzo [d] [1,3] Okisaji emission-2-one according to the method A 6-bromo - Prepared from 4,4-dimethyl-1,4-dihydro-benzo [d] [1,3] oxazin-2-one and 3-methoxyphenylboronic acid. Yellow solid: mp 164-
165 ° C .; ¹ H-NMR (DMSO-d ₆ ) δ 10.3 (s, 1 H), 7.56 (m, 2 H), 7.36 (t, 1 H, J = 7.89 Hz
), 7.20 (m, 2H), 6.96 (d, 1H, H = 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%). Calcd _{C 17 H 17 NO 3: C} , 72.07, H, 6.05, N, 4.94. Found: C, 70.58, H, 5.73, N, 4.67.

Example 7 6- (2-Chloro-phenyl) -4,4-dimethyl-1,4-dihydro-benzo [d] [1,3] oxazin- 2-one 6-bromo-4 according to Method A Prepared from 1,4-dimethyl-1,4-dihydro-benzo [d] [1,3] oxazin-2-one and 2-chlorophenylboronic acid. White solid: mp 181-18
2 ° C; MS (ESI) m / z 288 ([M + H] ⁺ , 70%); Calculated value for C ₁₆ H ₁₄ ClNO ₂ : C, 66.79, H
, 4.90, N, 4.87. Found: C, 66.78, H, 4.82, N, 4.55.

Example 8 6- (4-Chloro-phenyl) -4,4-dimethyl-1,4-dihydro-benzo [d] [1,3] oxazin- 2-one 6-bromo-4 according to Method A Prepared from 1,4-dimethyl-1,4-dihydro-benzo [d] [1,3] oxazin-2-one and 4-chlorophenylboronic acid. White solid: mp 255-25
7 ° C .; ¹ H-NMR (DMSO-d ₆ ) δ 10.3 (s, 1 H), 7.7 (d, 2 H, J = 8.52 Hz), 7.55 (m, 2 H),
7.5 (d, 2H, H = 8.52Hz), 6.96 (d, 1H, J = 8.52Hz), 1.7 (s, 6H); MS (ESI) m / z 288
([M + H] ⁺ , 70%); calcd for C ₁₆ H ₁₄ ClNO ₂ : C, 66.79, H, 4.90, N, 4.87. Found: C, 66.34, H, 4.76, N, 4.75.

Example 96- (3-chloro-phenyl) -4-methyl-1,4-dihydro-benzo [d] [1,3] oxazine-2-
on 1- (4-amino-3'-chloro-biphenyl-3-yl) -ethanone (
See Example 35, 0.15 g, 0.61 mmol) in a solution of sodium borohydride (0.07 g, 1.03
mmol) was added at room temperature (rt) under nitrogen. After 15 minutes, the reaction mixture was treated with ice water. vinegar
Ethyl acid (30 mL) was added, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3x20 mL)
. The combined organic layers were washed with brine (10 mL) and MgSO_FourDry on top. Remove solvent
After that, the obtained residue was crystallized from toluene to give 1- (4-amino-3'-chloro-bi
Phenyl-3-yl) -ethanol was obtained as a white solid (0.087 g, 58%):¹H-NMR (
DMSO-d₆) δ7.55 (t, 1H, J = 1.4Hz), 7.50 (d, 1H, J = 7.8Hz), 7.44 (d, 1H, J = 2.1
Hz), 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 = 8.8 Hz); MS (EI) m / z 247 (M ⁺ ).

1- (4-Amino-3′-chloro-biphenyl-3-yl) -ethanol (0%) in dry THF (3 mL)
.03g, 0.13mmol) and triphosgene (0.01g, 0.04mmol) was stirred for 10 minutes under a blanket of nitrogen. 6- (3-Chloro-phenyl) -4-methyl-1,4-dihydro-benzo [d] [1,3] oxazin-2-one as a white solid (0.031 g, 91%) Obtained: mp 155-156 ° C .; ¹ H-NMR (DMSO-d ₆ ) δ 10.3 (s, 1 H), 7.72 (m, 1 H), 7.62 (m, 2
H), 7.56 (m, 1H), 7.47 (t, 1H, J = 8.00Hz), 7.39 (d, 1H, J = 8.0Hz), 6.98 (d, 1H
, H = 8.0Hz), 5.50 (q, 1H, J = 6.82Hz), 1.6 (d, 3H, J = 6.82Hz); MS (APCI) m / z 27
4 ([M + H] ⁺ , 100%).

Example 10 6- (3-Chloro-phenyl) -4-ethyl-1,4-dihydro-benzo [d] [1,3] oxazine-2-
According to the method of one Example 9 1- (4-amino-3'-chloro - biphenyl-3-yl) - were prepared from propanol and triphosgene. White solid: mp 146-148 ° C; ¹ H-NMR (DM
SO-d ₆ ) δ10.3 (s, 1H), 7.70 (m, 1H), 7.60 (m, 3H), 7.47 (t, 1H, J = 8.22Hz), 7
.39 (d, 1H, H = 8.28Hz), 6.97 (d, 1H, J = 8.22Hz), 5.4 (t, 1H, J = 10.9Hz), 1.9 (m
, 2H), 0.97 (t, 3H, J = 7.68 Hz); MS (ESI) m / z 286 ([MH] ^- , 100%).

Example 11 6- (3-Chloro-phenyl) -4-phenyl-1,4-dihydro-benzo [d] [1,3] oxazin-2 -one According to the method of Example 9, 1- (4 -Amino-3'-chloro-biphenyl-3-yl) -benzyl alcohol and triphosgene. Yellowish-white solid: mp 177
-178 ° C; ¹ H-NMR (DMSO-d ₆ ) δ 10.5 (s, 1 H), 7.68 (dd, 1 H, J = 8.7, 1.7 Hz), 7.62
(t, 1H, J = 1.74Hz), 7.54-7.5 (m, 1H), 7.48-7.34 (m, 8H), 7.04 (d, 1H, J = 8.7H
z), 6.6 (s, 1H); MS (ESI) m / z 336 ([M + H] ⁺ , 30%).

Example 12 3- (4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazin-6-yl ) -benzonitrile (Method B) DME And (1,4-dihydro-4,4-dimethyl-2-oxo-) in a mixture of water and water (70 mL / 15 mL).
2H-3,1-benzoxazin-6-yl) boronic acid (2.22 g, 10 mmol), 3-bromobenzonitrile (2.18 g, 12 mmol), tetrakis (triphenylphosphine) palladium (0) (0.
A mixture of 6 g, 0.52 mmol) and sodium carbonate (2.2 g, 21 mmol) was degassed to remove oxygen and then heated at 85 ° C. under a blanket of nitrogen for 3 hours. The reaction mixture was cooled to ambient temperature and quenched with saturated aqueous ammonium chloride (20 mL). Ethyl acetate (1
00 mL) and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (3x30mL). The combined organic layers were washed with brine, dried over MgSO _4. The solvent was removed in vacuo and the residue was purified by silica gel flash chromatography (hexane: ethyl acetate / 1: 1) to give 3- (4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo). [d] [1,3] oxazin-6-yl) -benzonitrile was obtained as an off-white solid (0.7 g, 25%): mp 236-237 ° C .; ¹ H-NMR (DMSO-d ₆ ) δ 10.34 (s, 1H, D ₂ O interchangeable), 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, H = 8.2Hz ), 1.71 (s, 6H); C 17 H 14 N 2 O 2 · 0.1H 2 O of Calcd: C, 72.89,
H, 5.11, N, 10.00. Found: C, 72.75, H, 5.05, N, 9.65.

Example 13 4,4-Dimethyl-6- (3-nitrophenyl) -1,4-dihydrobenzo [d] [1,3] oxazin-2 -one According to Method A, 6-iodo-4,4 Prepared from -dimethyl-1,4-dihydro-benzo [d] [1,3] oxazin-2-one and 3-nitrophenylboronic acid. Yellowish solid: mp
244-245 ° C; ¹ H-NMR (DMSO-d ₆ ) δ 10.38 (s, 1H, D ₂ O exchangeable), 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 ([MH] ^- , 100%). Calculated value for C ₁₆ H ₁₄ N ₂ O ₄ : C, 64.42, H, 4.73,
N, 9.39. Found: C, 63.93, H, 4.91, N, 8.71.

Example 14 6- (3-Bromo-5-fluorophenyl) -4,4-dimethyl-1,4-dihydrobenzo [d] [1,3]
Oxazin-2- one According to Method B (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazine
-6-yl) boronic acid and 1,3-dibromo-5-fluorobenzene. White solid: mp 182-183 ° C .; ¹ H-NMR (DMSO-d ₆ ) δ 10.36 (s, 1 H, D ₂ O exchangeable), 7.78 (
s, 1H), 7.58-7.65 (m, 3H), 7.49 (dd, 1H, J = 8.3, 1.8Hz), 6.96 (d, 1H, J = 8.5H
z), 1.69 (s, 6H); ¹⁹ F-NMR (DMSO-d ₆ ) δ-112.46 (m, 1F); MS (CI) m / z 352 ([M +
H] ⁺ , 78%), 350 ([M + H] ⁺ , 75%). C ₁₆ H ₁₃ BrFNO ₂ Analysis Calculated: C, 54.88, H, 3.7
4, N, 4.00. Found: C, 54.83, H, 3.82, N, 3.95.

Example 15 3- (4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazin-6-yl ) -5-fluorobenzonitrile dry DMF 6- (3-Bromo-5-fluorophenyl) -4,4-dimethyl-2H-benzo [d] [1,3] oxazin-2-one (1 g, 2.8 mmol) in (20 mL), zinc cyanide (0.2 g, 1.7 mmol) and a mixture of tetrakis (triphenylphosphine) -palladium (0) (0.2 g, 0.17 mmol) was degassed to remove oxygen, and then heated at 85 ° C for 6.5 hours under a blanket of nitrogen. did. The reaction solution was cooled to room temperature and poured onto a cold saturated aqueous solution of ammonium chloride (100 mL). A white precipitate formed which was collected on a filter. The white solid was washed with distilled water (3 × 20 mL) and dissolved in a mixture of ethyl acetate (10 ml) and methanol (10 ml). The solution was added onto a pad of silica gel and eluted with a mixture of ethyl acetate and hexane (1: 1). After evaporation, 3- (4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazin-6-yl) -5-fluorobenzonitrile was converted to a white solid ( 0.7g,
84%): mp 253-254 ° C .; ¹ H-NMR (DMSO-d ₆ ) δ 10.4 (s, 1 H, D ₂ O exchangeable), 8.13 (s, 1 H), 7.92 (m, 1H), 7.82 (m, 1H), 7.73 (m, 2H), 6.98 (d, 1H,
J = 8.2Hz), 1.68 (s, 6H); ¹⁹ F-NMR (DMSO-d ₆ ) δ-112.25 (m, 1F); MS (EI) m / z 2
96 (M ⁺ , 65%); calcd for C ₁₇ H ₁₃ FN ₂ O ₂ : C, 68.91, H, 4.42, N, 9.45. Found: C, 68.85, H, 4.58, N, 9.14.

Example 165- (4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazin-6-yl ) -Nicotinonitrile According to Method B (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazine
-6-yl) boronic acid and 3-bromo-5-cyanopyridine. Yellowish
White solid: mp 290-291 ° C;¹H-NMR (DMSO-d₆) δ 10.41 (s, 1H, D_TwoO replaceable),
 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 = 8.2 Hz), 1.70 (s, 6H); MS (ESI) m / z 278 (M-H, 96%); C ₁₆ H₁₃N_ThreeO_Two・ 0.2H_TwoCalculated value for O: C, 67.94, H, 4.77, N, 14.85. Measured value: C, 6
8.04, H, 4.70, N, 14.58.

Example 17 4- (4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazin-6-yl ) -thiophen-2-carbonitrile Method According to B (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazine
-6-yl) boronic acid and 4-bromo-2-thiophenecarbonitrile. Yellowish solid: mp 230-231 ° C (decomposed); ¹ H-NMR (CDCl ₃ ) δ 8.32 (s, 1H,
D ₂ O exchangeable), 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 (MH, 100%). Calculated value for C ₁₅ H ₁₂ N ₂ O ₂ S ・ 0.2H ₂ O: C, 62.57,
H, 4.34, N, 9.73. Found: C, 62.48, H, 4.31, N, 9.64.

Example 18 5-bromo-2-thiophenecarbonitrile 5-bromo-2-thiophenecarboxaldehyde (96.0 g, 500 mmol), hydroxylamine hydrochloride (111.9 g, 500 mmol), pyridine (500 mL) and ethanol (500 mL )) Was heated at reflux under nitrogen for 2 hours. The reaction mixture was cooled to ambient temperature and concentrated in vacuo to give an oil. The crude product was triturated twice with ice water and the resulting solid was collected on a filter. Part of the above solid in acetonitrile (1.4 L) (44.31 g, 215 mm
ol), copper (II) acetate monohydrate (4.2 g, 21 mmol) was heated at reflux for 3 hours. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate. The solution was 5% aqueous sulfuric acid (2X30 mL),
Washed with water (2 × 30 mL), brine (20 mL) and dried (MgSO ₄ ). The solvent was removed in vacuo and the residue was dissolved in a minimum amount of chloroform (1 L) and allowed to crystallize. The resulting crystals were collected on a filter, the filtrate was concentrated and purified by chromatography (silica gel, chloroform) to give the title compound as an off-white solid (31.5 g total).
, 58%). IR (film) cm- ¹ 2200. ¹ H-NMR (CDCl ₃ ) δ7.39-7.38 (d, 1
H, J = 4.1Hz), 7.10 (d, 1H, J = 4.0Hz); MS (EI) m / z 187 (M ⁺ , 98%) 189 (M ⁺ , 100
%).

Example 19 5-bromo-4-methyl-2-thiophenecarboxaldehyde To a solution of diethylamine (28 g, 0.383 mol) in anhydrous THF (400 mL) was added nB in hexane.
A solution of uLi (2.5 M, 153 mL, 0.383 mmol) was added. The solution is then placed under nitrogen at
Stirred for minutes, cooled to -78 ° C, and treated dropwise with a solution of 2-bromo-3-methylthiophene (45 g, 0.254 mol) in anhydrous THF (450 mL). The reaction solution was stirred at -78 ° C for 30 minutes and treated with anhydrous DMF (100 mL). Warm the mixture to ambient temperature and add 1N aqueous HCl
(1 L). The product was extracted with ethyl acetate (3x450mL). Extract with water,
Washed with brine and dried (MgSO ₄ ). After removing the solvent in vacuo, the title compound was obtained as a white solid (46 g, 88.3%). A sample of the product was crystallized from hexane: mp 63-65 ° C; IR (KBr) 1654 cm ^-1 . ¹ H-NMR (CDCl ₃ ) δ9.75 (S, 1H), 7.
45 (S, 1H), 2.26 (S, 3H); MS (EI) m / z 204/206 (M ⁺ ). Calculated value for C ₆ H ₅ BrOS: C
, 35.14; H, 2.46. Found: C, 35.00; H, 2.44.

Example 20 5-bromo-4-methyl-2-thiophenecarbonitrile Prepared from 5-bromo-4-methyl-2-thiophenecarboxaldehyde using the method of Example 18. White solid: mp 40-42 ° C; IR (KBr) 2200 cm ^-1 ; ¹ H-NMR (CDCl ₃ )
δ 7.29 (S, 1H), 2.21 (S, 3H). MS (EI) m / z 201/203 (M +, 98% / 100%); C 6 H 4 BrNS
Calculated for: C, 35.66; H, 1.99; N, 6.93. Found: C, 36.00; H, 2.14; N,
6.76.

Example 21 5- (4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazin-6-yl ) -thiophen-2-carbonitrile Method 5-bromo-2-thiophenecarbonitrile and (1,4-dihydro-4,4-
Prepared from dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl) boronic acid. Yellowish-white solid: mp 264-266 ° C. ¹ H-NMR (DMSO-d ₆ ) δ10.3 (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). M
S (APCI) m / z 285 (M + H) ⁺ , 302 (M + NH ₄ ) ⁺ . Calcd _{C 15 H 12 N 2 O 2} S: C, 63.36;
H, 4.25; N, 9.85. Found: C, 63.01; H, 4.36; N, 9.39.

Example 22 5- (4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazin-6-yl ) -4-methyl-thiophene-2 - according carbonitrile method B (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazine
-6-yl) boronic acid and 5-bromo-4-methyl-2-thiophenecarbonitrile. Yellowish-white solid: mp 195-200 ° C. ¹ H-NMR (DMSO-d ₆ ) δ10.2 (s, 1
H), 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] ⁺ . Calculated value for C ₁₆ H ₁₄ N ₂ O ₂ S: C, 64.41; H
, 4.75; N, 8.89. Found: C, 64.64; H, 4.62; N, 9.39.

Example 234- (4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazin-6-yl ) -Furan-2-carbonitrile According to Method B (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazine
-6-yl) boronic acid and 4-bromo-2-furancarbonitrile. Yellow
Pale solid: mp 255-256 ° C.¹H-NMR (DMSO-d₆) δ10.32 (s, 1H, D_TwoO exchange
Possible), 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 = 8.2 Hz), 1.65 (s, 6H); MS (ESI) m / z 269 (M + H, 72%). C_FifteenH₁₂N _Two O_ThreeCalculated for: C, 67.16; H, 4.51; N, 10.44. Found: C, 67.14; H, 4.59;
 N, 10.07.

Example 244,4-diethyl-6- (3-nitrophenyl) -1,4-dihydrobenzo [d] [1,3] oxazine-2 -on 4,4-Diethyl-6-iodo-1,4-dihydrobenzo [d] [1,3] oxazi according to Method A
Prepared from 1--2-one and 3-nitrophenylboronic acid. Yellowish-white solid
Body: mp 193-194 ° C.¹H-NMR (CDCl_Three) δ9.19 (s, 1H, D_TwoO exchangeable), 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%). C₁₈H₁₈N_TwoO _Four ・ 0.3H_TwoCalculated value for O: C, 65.17; H, 5.65; N, 8.44. Found: C, 65.31; H,
5.60; N, 8.10.

Example 25 6- (3-Chlorophenyl) -4,4-diethyl-1,4-dihydrobenzo [d] [1,3] oxazin-2 -one 4,4-diethyl-6-one according to Method A Prepared from iodo-1,4-dihydrobenzo [d] [1,3] oxazin-2-one and 3-chlorophenylboronic acid. White solid: mp 150-15
1 ° C. ¹ H-NMR (CDCl ₃ ) δ 8.52 (s, 1H, D ₂ O exchangeable), 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,
MS (EI) m / z 315 (M ⁺ , 53%). C ₁₈ H ₁₈ ClNO ₂ Analysis Calculated: C, 68.
46; H, 5.75; N, 4.44. Found: C, 68.16; H, 5.81; N, 4.32.

Example 26 1- (2-Amino-5-bromo-phenyl) cyclohexanol Prepared according to the method of Example 1 from Grignard reagent prepared from 2-amino-5-bromobenzoic acid and 1,5-dibromopentane did. Transparent oil: ¹ H-NMR (DMSO-d ₆ ) δ 7.07 (d, 1 H, J = 2.3 Hz), 7.03 (dd, 1 H, J = 8.4, 2.4 Hz), 6.55 (d, 1 H, J = 8.6H
z), 5.49 (s, 2H, D ₂ O can be exchanged), 5.00 (s, 1H, D ₂ O can be exchanged), 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%).

Example 27 6-Bromo-spiro [4H-3,1-benzoxazine-4,1′-cyclohexane-2- (1H) -one 1- (2-amino-5-bromo-phenyl) cyclohexanol and Prepared from carbonyldiimidazole according to the method of Example 2. Yellowish-white solid: mp 208-
210 ° C. ¹ H-NMR (DMSO-d ₆ ) δ 10.26 (s, 1 H), 7.45 (d, 1 H, J = 2.2 Hz), 7.39 (dd, 1
H, J = 8.2, 2.2Hz), 6.81 (d, 1H, J = 8.3Hz), 1.90-1.97 (m, 2H), 1.80-1.85 (m, 5
H), 1.25-1.35 (m, 1H); MS (APCI) m / z 296 ([M + H] ⁺ , 68%).

Example 28 6-Bromo-spiro [4H-3, spiro- (4,1′-cyclohexane-1,4-dihydro-2-oxo-2H-3,1-benzoxazin -6-yl) boronic acid Prepared according to the method of Example 4 from 1-benzoxazine-4,1′-cyclohexane-2- (1H) -one. Yellowish white solid: mp 223-225 ° C
. ¹ H-NMR (DMSO-d ₆ ) δ 10.17 (s, 1H, D ₂ O exchangeable), 7.92 (s, 2H, D ₂ O exchangeable), 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 26
2 (M + H) ⁺ .

Example 29 6- (3-Chlorophenyl) -spiro [4H-3,1-benzoxazine-4,1′-cyclohexane-2- (1H) -one 6-bromo-spiro [4H-3,1- Prepared according to Method A from benzoxazine-4,1′-cyclohexane-2 (1H) -one and 3-chlorophenylboronic acid. Yellowish white solid: mp 165-168 ° C. ¹ H-NMR (DMSO-d ₆ ) δ 10.25 (S, 1H), 7.74 (t, 1H, J = 1.9
Hz), 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%).

Example 30 6-Bromo-spiro [4H-3,1-benzoxazine-4,1′-cyclopentan-2- (1H) -one 2-amino-5-bromobenzoic acid and 1,4-dibromo It was prepared from Grignard reagent prepared from butane according to the methods of Examples 26 and 27. Yellowish-white solid:
mp 180-185 ° C. ¹ H-NMR (DMSO-d ₆ ) δ 10.29 (s, 1H, D ₂ O exchangeable), 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 ₁₂ H ₁₂ BrNO ₂ Analysis Calculated: C, 51.08; H, 4.29 ; N, 4.96. Found: C, 50.53; H, 4.21; N, 4.85.

Example 31 6- (3-Chlorophenyl) -spiro- [4H-3,1-benzoxazine-4,1′-cyclopentane] -2 (1H) -one 6-bromo -spiro- [4H-3 Prepared according to Method A from 1,1-benzoxazine-4,1′-cyclopentan-2- (1H) -one and 3-chlorophenylboronic acid. Yellowish-white solid: mp 140-145 ° C. ¹ H-NMR (DMSO-d ₆ ) δ 10.27 (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 _{1 8} H ₁₆ ClNO ₂ Analysis Calculated: C, 68.90; H, 5.14 ; N, 4.46. Found: C, 60.94; H,
4.94; N, 3.78.

Example 32 6- (3-Nitrophenyl) -spiro [4H-3,1-benzoxazine-4,1′-cyclohexane] -2 (1H) -one 6-bromo-spiro [4H-3,1 Prepared according to Method A from -benzoxazine-4,1'-cyclohexane] -2 (1H) -one and 3-nitrophenylboronic acid. Yellowish white solid: mp 245-246 ° C. ¹ H-NMR (CDCl ₃ ) δ8.39 (t, 1H, J = 1.9Hz), 8.20 (dd, 1H
, J = 8.2, 1.4Hz), 8.11 (s, 1H, D 2 O exchangeable), 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, 7.H), 1.31-1.42 (m, 1
H); MS (EI) m / z 337 ([MH] ^- , 100%). Calculated value for C ₁₉ H ₁₈ N ₂ O ₄・ 0.35H ₂ O: C, 6
6.21, H, 5.47; N, 8.13. Found: C, 66.22; H, 5.43; N, 7.86.

Example 33 2-Amino-5-bromo-N-methoxy-N-methylbenzamide N, O-dimethylhydroxylamine hydrochloride (9 in ethanol and water (100 mL / 10 mL)
To a mixture of .42 g, 96 mmol) and triethylamine (13.5 mL, 96 mmol) was added a solution of 5-bromoisatoic anhydride (20 g, 74 mmol) in ethanol and water (100 mL / 10 mL) under nitrogen at ambient temperature. The reaction mixture was heated at reflux for 3 hours. The solvent is removed in vacuo,
The residue was dissolved in ethyl acetate (100 mL), washed with 1N aqueous sodium hydroxide solution (2 × 20 mL), brine (30 mL) and dried over MgSO ₄ . After removing the solvent, the residue was purified by flash chromatography on silica gel (hexane: ethyl acetate / 3: 2).
2-Amino-5-bromo-N-methoxy-N-methylbenzamide was obtained as an off-white solid (13 g, 68%): mp 80-81 ° C .; ¹ H-NMR (CDCl ₃ ) δ7.49. (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); Calculated for C ₉ H ₁₁ BrN ₂ O ₂ : C, 41.72; H, 4.28; N, 10.
81. Found: C, 41.99; H, 4.16; N, 10.82.

Example 344-amino-3'-chloro-biphenyl-3-carbonitrile Method A from 2-amino-5-bromobenzonitrile and 3-chlorophenylboronic acid
Therefore manufactured. Yellowish-white solid: mp 118-119 ° C.¹H-NMR (DMSO-d₆)
δ7.80 (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); C₁₃H₉ClN _Two Calculated for: C, 68.28; H, 3.97; N, 12.25. Found: C, 67.68; H, 4.06; N
, 11.89.

Example 35 2-Amino-5-bromo-N-methoxy- in a mixture of 1- (4-amino-3′-chloro-biphenyl-3-yl) -ethanone DME and water (150 mL / 30 mL) N-methylbenzamide (7.78 g, 30 mmol), 3-chlorophenylboronic acid (5.63 g, 36 mmol)
A mixture of tetrakis (triphenylphosphine) palladium (0) (1.73 g, 1.5 mmol) and sodium carbonate (7.63 g, 72 mmol) was degassed to remove oxygen, and the mixture was cooled to 85 ° C under nitrogen at 85 ° C.
Heated for hours. The reaction mixture was cooled to room temperature, brine (30 mL) and ethyl acetate (1 mL).
00 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3x40mL). The combined organic layers were washed with brine, dried over MgSO _4. After removing the solvent, the residue was purified by flash chromatography (silica gel, hexane: ethyl acetate / 1: 1) to give 5- (3-chlorophenyl) -N-methoxy-N-methylbenzamide as a brown oil ( 5g, 57%). To a solution of this benzamide (5 g, 17.2 mmol) in anhydrous THF was added a solution of methyllithium in ether (1.4 M, 28.6 mL, 40 mL) at -78 ° C under nitrogen.
And added dropwise. After stirring for 30 minutes, the reaction mixture was treated with a saturated aqueous solution of ammonium chloride (50 mL) at -78 ° C. Ethyl acetate (100 mL) was added, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed (brine), dried (MgSO _4). After removing the solvent, the residue was purified by flash chromatography (silica gel, hexane: ethyl acetate / 2: 1) to give 1- (4-amino-3′-chloro-biphenyl-3-yl) -ethanone as a yellow Obtained as a solid (2 g, 47%): mp 89-90 ° C .; ¹ H
-NMR (CDCl ₃ ) δ7.89 (d, 1H, J = 2.0Hz), 7.51 (m, 2H), 7.25-7.40 (m, 3H), 6.73
(d, 1H, J = 8.6 Hz), 6.38 (br, 2H), 2.65 (s, 3H); MS (EI) m / z 268 ([M + Na] ⁺ , 60
%); C ₁₄ H ₁₂ ClNO Calcd: C, 68.44; H, 4.92 ; N, 5.70. Found: C, 68.40
H, 4.89; N, 5.61.

[0125] Example 36 4-allyl-6- (3-chlorophenyl) -4-methyl-1,4-dihydro - benzo [d] [1,3] oxazine-2-one (Method C) anhydrous THF ( 1- (4-Amino-3′-chloro-biphenyl-3-yl) -ethanone (0.10 mL).
Solution of allylmagnesium bromide in ether (1.0 M, 3 mL, 2 g, 0.82 mmol).
3 mmol) was added at 0 ° C. under nitrogen. The reaction solution was slowly warmed to ambient temperature and stirred for 1 hour under nitrogen. A saturated aqueous solution of ammonium chloride (10 mL) was added, followed by ethyl acetate (50 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3x10mL).
The combined organic layers were washed with brine, dried over MgSO _4. After removing the solvent, the residue was subjected to flash chromatography (silica gel, hexane: ethyl acetate / 3: 1).
To give the aminocarbinol intermediate, which was used without further purification.

To a solution of the above aminocarbinol in anhydrous THF was added CDI (0.38 g, 2.3 mmol) at ambient temperature under nitrogen. The reaction solution was heated at 55 ° C. for 12 hours, and then cooled to room temperature. The solvent was removed in vacuo and the residue was flash chromatographed (silica gel,
Hexane: ethyl acetate / 2: 1) to give 4-allyl-6- (3-chlorophenyl) -4-
Methyl-1,4-dihydro-benzo [d] [1,3] oxazin-2-one was obtained as a white solid (130 mg, 52% from two steps): mp 128-129 ° C .; ¹ H-NMR ( CDCl ₃ ) δ8.68 (s, 1H, D ₂ O
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 ₁₈ H ₁₆ ClNO ₂ Analysis Calculated: C, 68.90; H, 5.14 ; N, 4.46. Found: C, 68.90; H, 5.18; N, 4.4
3.

Example 37 6- (3-Chlorophenyl) -4-methyl-4-propyn-1-yl-1,4-dihydro-benzo [d] [1,3 ] oxazin-2-one According to Method C Prepared from 1- (4-amino-3′-chloro-biphenyl-3-yl) -ethanone and propynylmagnesium bromide, followed by treatment with CDI. White solid: m
p 184-185 ° C; ¹ H-NMR (CDCl ₃ ) δ 8.18 (s, 1 H, D ₂ O exchangeable), 7.53 (t, 1 H, 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 ([MH] -, 100%); C 18 H 14 ClNO 2 Analysis Calculated: C,
, 69.35; H, 4.53; N, 4.49. Found: C, 69.19; H, 4.37; N, 4.41.

[0128] Example 38 6- (3-chlorophenyl) -4-ethynyl-4-methyl-1,4-dihydro - according benzo [d] [1,3] Oki spoon-2-one method C, 1-( 4-amino-3'-chloro-biphenyl-3-yl) -ethanone (0.2 g
, 0.82 mmol) and ethynylmagnesium bromide, followed by treatment with CDI.
Yellowish-white solid: mp 185-186 ° C; ¹ H-NMR (CDCl ₃ ) δ 8.18 (s, 1 H, D ₂ O
Interchangeable), 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 ([MH] ^- , 100%);
C ₁₇ H ₁₂ ClNO ₂ Analysis Calculated: C, 68.58; H, 4.06 ; N, 4.70. Found: C, 68.24; H
, 3.94; N, 4.65.

[0129] Example 39 6- (3-chlorophenyl) -4-methyl-4-phenyl-1,4-dihydro - according benzo [d] [1,3] Oki spoon-2-one method C, 1-( 4-amino-3'-chloro-biphenyl-3-yl) -ethanone (0.2 g
, 0.82 mmol) and phenylmagnesium bromide, followed by treatment with CDI.
White solid: mp 179-180 ° C; ¹ H-NMR (CDCl ₃ ) δ 8.27 (s, 1 H, D ₂ O exchangeable), 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 ([MH] ^- , 100%); calcd for C ₂₁ H ₁₆ ClNO ₂ : C, 72.10; H, 4.61;
N, 4.00. Found: C, 71.72; H, 4.86; N, 3.91.

Example 40 4-benzyl-6- (3-chloro-phenyl) -4-methyl-1,4-dihydro-benzo [d] [1,3] o
1- (4-amino-3′-chloro-biphenyl-3-yl) -1- benzyl- in xazin-2-one dry THF (10 mL)
Ethanol (prepared according to Method C with 1- (4-amino-3′-chloro-biphenyl-3-yl) -ethanone and benzylmagnesium bromide, 0.14 g, 0.42 mmol) and triphosgene (0.04 g, 0.14 mmol )) Was stirred for 10 minutes under a blanket of nitrogen.
Upon completion of the reaction, THF was removed and the residue was purified by flash chromatography (silica gel, 35% ethyl acetate / hexane) to give 4-benzyl-6- (3-chloro-phenyl) -4-methyl-1,4 -Dihydro-benzo [d] [1,3] oxazin-2-one (0.045 g, 30%) was obtained as an off-white solid: mp 187-188 ° C; ¹ H-NMR (DMSO-d ₆ ) δ10.1 (
s, 1H), 7.70 (t, 1H, J = 2.3Hz), 7.6 (d, 1H, J = 8.0Hz), 7.58-7.53 (m, 2H), 7.4
6 (t, 1H, J = 8.0Hz), 7.38 (d, 1H, J = 8.0Hz), 7.22-7.17 (m, 3H), 7.06-7.0 (m, 2
H), 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%); Calculated value for C ₂₂ H ₁₈ ClNO ₂ : C
, 72.63; H, 4.99; N, 3.85. Found: C, 71.82; H, 5.09; N, 3.58.

Example 41 6- (3-Chloro-phenyl) -4-cyclopropyl-4-methyl-1,4-dihydro-benzo [d] [1,3 ] oxazin-2-one anhydrous THF at 52 ° C. To a solution of cyclopropylmagnesium bromide (prepared using cyclopropylbromide and magnesium metal, 70 mmol) in 4-amino-3'-chloro-
Biphenyl-3-carbonitrile (5.2 g, 22.7 mmol) was added under nitrogen. The reaction mixture was stirred at 52 ° C. for 1 hour, cooled to rt, and quenched with 1N aqueous HCl (100 mL). Ethyl acetate (100 mL) was added and the aqueous layer was extracted with ethyl acetate (3 × 40 mL). The combined organic layers were washed with brine, dried over MgSO _4. The solvent was removed and the residue was purified by a silica gel column (hexane: ethyl acetate / 20: 1) to give (4-amino-3′-chloro-biphenyl-3-yl) -cyclopropyl-methanone: ¹ H -NMR (hydrogen chloride
, DMSO-d ₆ ) δ8.30 (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 ⁺ ).

To a solution of (4-amino-3′-chloro-biphenyl-3-yl) -cyclopropyl-methanone (0.67 g, 2.5 mmol) in anhydrous THF (10 mL) at −78 ° C. was added methylmagnesium bromide. The solution (3.0 M in diethyl ether, 2.5 mL, 7.5 mmol) was added under nitrogen. The reaction mixture is slowly warmed to rt, stirred under nitrogen for 12 hours, and saturated aqueous ammonium chloride
(40 mL). Ethyl acetate (50 mL) was added, the organic layer was separated and dried
(MgSO ₄ ). After removing the solvent, the residue was purified by silica gel chromatography (hexane: ethyl acetate / 7: 1) to give 1- (4-amino-3′-chloro-biphenyl-3-yl).
) -1-Cyclopropyl-ethanol was obtained as a yellow oil: MS (EI) m / z 287/28
9 (M ⁺ ).

The title compound was prepared according to Method C by 1- (4-amino-3′-chloro-biphenyl-3-yl) -1-
Prepared from cyclopropyl-ethanol and 1,1'carbonyldiimidazole.
Yellowish-white solid: mp 158-159 ° C; ¹ H-NMR (DMSO-d ₆ ) δ 10.3 (s, 1 H), 7.
74 (t, 1H, J = 1.71Hz), 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%); Calculated for C ₁₈ H ₁₆ ClNO ₂ :
C, 68.9; H, 5.14; N, 4.46. Found: C, 68.13; H, 5.01; N, 4.36.

[0134] Example 42 6- (3-Chloro-phenyl) - 4-cyclopropyl-4-propyn-1-yl-1,4-dihydro - base down zone [d] [1,3] oxazin-2 On 1- (4-amino-3′-chloro-biphenyl-3-yl) -1-cyclopropyl-1-propynyl-methanol was converted to (4-amino-3′-chloro-biphenyl-3-yl) according to Example 41. )-
Prepared from cyclopropyl-methanone and propynylmagnesium bromide.

1- (4-Amino-3′-chloro-biphenyl-3-yl) -1-cyclopropyl-1-propynyl-methanol (0.02 g, 0.064 mmol) and 1,1 in dry THF (10 mL) A mixture of '-carbonyldiimidazole (0.016 g, 0.096 mmol) was stirred for 10 minutes under a blanket of nitrogen. Upon completion of the reaction, THF was removed and the residue was purified by flash chromatography (silica gel, 40% ethyl acetate / hexane) to give 6- (3-chlorophenyl) -4-cyclopropyl-4-prop-1-ynyl- 1,4-dihydro-benzo [d] [1,3] oxazine-2-
One (0.014 g, 56%) was obtained as a pale yellow solid: mp 178-179 ° C .; ¹ H-NMR (DMSO-d ₆ ) δ 10.6 (s, 1 H), 7.68 (m, 2 H), 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, 3
H), 1.66 (m, 1H), 0.82 (m, 1H), 0.66 (m, 3H); MS (ESI) m / z 336 ([MH] ^- , 100%
).

[0136] Example 43 6- (3-Chloro-phenyl) - 4,4-di-cyclopropyl-1,4-dihydro - benzo [d] [1,3] o Kisajin-2-one (4-amino - 3'-chloro-biphenyl-3-yl) -dicyclopropyl-methanol (mp
90-92 ° C; MS ((+) ESI) m / z 314 (M + H) ⁺ ) with (4-amino-3'-chloro-biphenyl-3-
Prepared according to Example 41 from yl) -cyclopropyl-methanone and cyclopropylmagnesium bromide.

The title compound was prepared according to Example 41 from (4-amino-3′-chloro-biphenyl-3-yl) -dicyclopropyl-methanol and 1,1′-carbonyldiimidazole. Yellow solid: mp 198-200 ° C; ¹ H-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 ₂₀ H ₁₈ ClNO ₂ Analysis Calculated: C, 70.69; H, 5.34 ; N, 4.12.
Found: C, 69.38; H, 5.07; N, 4.02.

[0138] Example 44 6- (3-chloro - phenyl) -4,4-Jipuropin-1-yl-1,4-dihydro-benzo [d] [1,3] o Kisajin-2-one Example 41 According to the method, (4-amino-3′-chloro-biphenyl-3-yl) -propynyl-methanone (mp 112-114 ° C .; MS ((+) ESI) m / z 270/272 (M + H) ⁺ ) Was treated with propynylmagnesium bromide to give (4-amino-3′-chloro-biphenyl-3-yl) -dipropynyl-methanol, which was reacted with 1,1′-carbonyldiimidazole to give the title compound. Was. Yellow solid: mp 151 ° C (decomposed); ¹ H-NMR (DMSO-d ₆ )
δ10.8 (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 = 8.2
3 Hz), 2.0 (s, 6H); MS (APCI) m / z 336 ([M + H] ⁺ , 20%).

Example 45 6- (3-Bromo-5-fluorophenyl) -1,4,4-trimethyl-1,4-dihydrobenzo [d] [1,3 ] oxazin-2-one dry DMF (10 mL Solution of 6- (3-bromo-5-fluorophenyl) -4,4-dimethyl-1,4-dihydrobenzo [d] [1,3] oxazin-2-one (0.34 g, 0.99 mmol) in To this was added sodium hydride (80 mg, 2.0 mmol) in one portion at room temperature under nitrogen. The mixture was stirred at ambient temperature for 30 minutes, treated with iodomethane (1 mL, excess) and stirred for 2 hours. A cooled saturated ammonium chloride solution (30 mL) was added to the reaction mixture, and the obtained white precipitate was collected on a filter and washed with distilled water to give the title compound as a white solid (0.31 g, 87%). : Mp 157-158 ° C; ¹ H-NMR (DMSO-d ₆ ) δ7.83 (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), 3.3
3 (s, 3H), 1.67 (s, 6H); ¹⁹ F-NMR (DMSO-d ₆ ) δ-111.01 (m, 1F); MS (APCI) m / z
364 ([M + H] ⁺ , 96%), 366 [M + H] ⁺ , 100%).

Example 46 1- (2-Amino-5-chloro-phenyl) -2,2,2-trifluoro-ethanone N- (4-chlorophenyl) in anhydrous THF (100 mL) at 0 ° C. under nitrogen Solution of n-BuLi in hexane (2.5 M, 30 mL, 70 mmo) in a solution of -2,2-dimethylpropanamide (6.7 g, 30 mmol)
l) was added dropwise. After the addition, the solution was kept stirring at 0 ° C. for 40 minutes, and anhydrous THF (1
(0 mL) was treated with a solution of 1- (trifluoroacetyl) imidazole (9 mL, 78 mmol). The reaction mixture was warmed to ambient temperature and maintained for 18 hours. To the reaction solution was added a saturated aqueous solution of ammonium chloride (50 mL), followed by ethyl acetate (100 mL). The organic layer was separated and the solvent was removed in vacuum. The resulting residue was suspended in a 3N aqueous solution of hydrochloride (50 mL) and heated at reflux overnight. The reaction solution was cooled to room temperature and treated to pH above 8 with cold ammonium hydroxide solution. The aqueous mixture was extracted with ethyl acetate (3 × 50 mL), the organic layer was washed with brine, dried (MgSO _4). After removing the solvent, the residue was purified by flash chromatography (silica gel, hexane: ethyl acetate / 4: 1) to give the title compound as a yellow solid (1 g, 15%): mp 93-94 ° C. ¹ H-NMR (CDC
l ₃ ) δ7.70 (m, 1H), 7.33 (dd, 1H, J = 9.0, 2.3Hz), 6.70 (d, 1H, J = 9.1Hz), 6.4
5 (bs, 2H); MS (ESI) m / z 222 (MH, 100%), 224 (MH, 33%).

[0141] Example 47 6-Chloro-4-methyl-4-trifluoromethyl-1,4-dihydro - according benzo [d] [1,3] method oxa-2-one Example 2, 1- From (2-amino-5-chloro-phenyl) -2,2,2-trifluoro-ethanone, addition of methylmagnesium bromide and subsequent treatment of the resulting carbinol with 1,1'-carbonyldiimidazole Manufactured by White solid: mp 216-216 ° C .; ¹ H-NMR (DMSO-d ₆ ) δ 10.91 (bs, 1 H, D ₂ O exchangeable), 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); ¹⁹ F-NMR (DMSO-d ₆ ) δ-82.0 (s, 1F); MS (EI) m / z 264 ([MH] ^- , 100%),
266 ([MH] ^- , 33%). C ₁₀ H ₇ ClF ₃ NO ₂ Analysis Calculated: C, 45.22; H, 2.66 ; N, 5.27
. Found: C, 45.32; H, 2.77; N, 4.83.

Example 48 6- (3-Methoxyphenyl) -4-methyl-4-trifluoromethyl-1,4-dihydro-benzo [d] [1,3] oxazin-2-one 6 in anhydrous dioxane -Chloro-4-methyl-4-trifluoromethyl-1,4-dihydro-
Benzo [d] [1,3] oxazin-2-one (0.2 g, 0.75 mmol), 3-methoxyphenylboronic acid (0.13 g, 0.9 mmol), potassium phosphate (0.23 g, 1.1 mmol) and nickel (II ) (Diphenylphosphino) ferrocenyl dichloride (52 mg, 0.076 mmol) was subjected to a blanket of nitrogen to remove oxygen and heated at 95 ° C under nitrogen for 48 hours. 3-Methoxyphenylboronic acid (0.13 g, 0.9 mmol) and nickel (II) (diphenylphosphino) ferrocenyl dichloride (52 mg, 0.076 mmol) were added again, and the reaction solution was added under nitrogen for 9 hours.
Heated at 5 ° C. for 48 hours. The reaction solution was cooled to room temperature. Saturated aqueous ammonium chloride (30 mL) and ethyl acetate (50 mL) were added. Separate the organic layer and the aqueous layer with ethyl acetate.
(3 × 20 mL). The combined organic layers were washed with brine, dried (MgSO ₄₎
. After removal of the solvent, the residue was purified by flash chromatography (silica gel, hexane: ethyl acetate / 4: 1) to give the title compound as a white solid (50 mg, 20%): mp 178-179 ° C .; ¹ H-NMR (DMSO-d ₆ ) δ 10.85 (bs, 1H, D ₂ O exchangeable),
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); ¹⁹ F-NMR (DMSO-d ₆ ) -81.88 (s, 1F); Calculated value for C ₁₇ H ₁₄ F ₃ NO ₃ : C,
60.54; H, 4.18; N, 4.15. Found: C, 60.58; H, 4.44; N, 4.19.

[0143] Example 49 7- (3-methoxy - phenyl) -4,4-dimethyl-1,4-dihydro - benzo [d] [1,3] 7 of Okisaji emission-2-one in dioxane (10 mL) -Chloro-4,4'-dimethylbenzoxazin-2-one (0.197
g, 0.93mmol), 3- methoxyphenylboronic acid (0.21g, 1.4mmol), Ni ( dppf) Cl 2 (0.
A mixture of 095 g, 0.14 mmol) and potassium phosphate (0.59 g, 2.79 mmol) was subjected to a nitrogen blanket at 50 ° C. for 15 minutes, then heated at 95 ° C. for 48 hours. The reaction mixture was cooled to room temperature, and ethyl acetate (100 mL) was added. The organic compound was treated with aqueous ammonium chloride (30 mL)
And twice with brine (30 mL) and dried over magnesium sulfate. The residue was purified by flash chromatography (silica gel, 40% ethyl acetate / hexane) to give 7- (3-methoxy-phenyl) -4,4-dimethyl-1,4-dihydro-benzo [d] [
[1,3] Oxazin-2-one (0.090 g, 35%) was obtained as a clear oil. The oil was triturated with ether (25 ml) to give a white solid: mp 167-168 ° C .; ¹ H-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%); Calcd _{C 17 H 17 NO 3: C} , 72.07, H, 6.05, N, 4.94. Found: C, 71.5
9, H, 6.08, N, 4.79.

[0144] Example 50 6- (3-acetyl-phenyl) - 4,4-dimethyl-1,4-dihydro - benzo [d] [1,3] Okisaji emission-2-one 3- (4,4 Dissolve dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazin-6-yl) benzonitrile (0.25 g, 0.9 mmol) in THF (10 mL) and bring to 0 ° C. Cool. To this solution was added methylmagnesium bromide (3.0 M in ether, 1.8 mL, 5.4 mmol) and the reaction mixture was heated to reflux under nitrogen. Upon completion of the reaction, the reaction mixture was cooled to rt before being quenched with 1N aqueous HCl. Extract the mixture with ethyl acetate (100 mL) and add M
Dried over gSO ₄ and concentrated. The resulting residue was purified by chromatography (silica gel, 50% ethyl acetate / hexane) to give 6- (3-acetyl-phenyl) -4,4-dimethyl-1,4-dihydro-benzo [d] [1 , 3] Oxazin-2-one as white solid (0.031 g,
12%): mp 178-179 ° C .; ¹ H-NMR (CDCl ₃ ) δ 8.15 (t, 1 H, J = 1.71 Hz), 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%).

[0145] Example 51 6- (3-benzoyl-phenyl) - 4,4-dimethyl-1,4-dihydro - benzo [d] [1,3] 3 according to the method of oxa-2-one Example 50 -(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo [
d] [1,3] oxazin-6-yl) benzonitrile and phenylmagnesium bromide. White solid: mp 156-157 ° C .; ¹ H-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%); Calculated value for C ₂₃ H ₁₉ NO ₃ : C, 77.29,
H, 5.36, N, 3.92. Found: C, 75.7, H, 5.28, N, 3.86.

Example 52 4,4-Dimethyl-6- [3- (1H-tetrazol-5-yl) -phenyl] -1,4-dihydrobenzo [ d] [1,3] oxazine-2- onedioxane 3- (4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] in (20 mL)
A mixture of [1,3] oxazin-6-yl) benzonitrile (0.77 g, 2.8 mmol), trimethylsilyl azide (0.68 g, 5.6 mmol) and dibutyltin oxide (0.071 g, 0.28 mmol) was refluxed under a blanket of nitrogen. And heated. When the reaction was completed, dioxane was removed and the organic compound was dissolved in ethyl acetate (100 mL) and washed with NaHCO ₃ (100 mL). Water layer
Acidified with 1N aqueous HCl and extracted with ethyl acetate (100 mL). The organic layer was dried over MgSO _4, and concentrated. Crystallized from ether (20 mL) to give 4,4-dimethyl-6- [3- (1H-tetrazol-5-yl) -phenyl] -1,4-dihydrobenzo [d] [1,3] -oxazine-2 The -one was obtained as a pale yellow solid (0.23 g, 26%): mp 238-240 ° C .; ¹ H-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 ([MH] ^- ,
_{100%); C 17 H 15} N 5 O 2 Analysis Calculated: C, 63.54, H, 4.71 , N, 21.79. Measured value: C, 6
2.16, H, 4.67, N, 21.31.

Example 53 4- (4,4-Dicyclopropyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxadi
-6-yl) -thiophen-2-carbonitrile (4,4-dicyclopropyl-1,4-dihydro-2-oxo-2H-3,1-benzoxazin-6-yl) boronic acid in Example 1 , 2 and 4 prepared from 2-amino-5-bromobenzoic acid. White solid: mp 240-242 ° C .; ¹ H-NMR (DMSO-d ₆ ) δ 10.13 (s, 1H), 8.01 (s, 2
H), 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).

The title compound was prepared according to Method B (4,4-dicyclopropyl-1,4-dihydro-2-oxo-2
H-3,1-benzoxazin-6-yl) boronic acid and 4-bromo-2-thiophenecarbonitrile. White solid: mp 244-245 ° C .; ¹ H-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, 6
H), 0.31-0.24 (m, 2H ); MS (ESI) m / z 335 ([MH] -, 100%); C 19 H 16 N 2 O 2 Calcd S: C, 67.84, H, 4.79, N, 8.33. Found: C, 64.92, H, 4.66, N, 7.71.

Example 54 6- (3-Bromo-5-fluoro-phenyl) -4,4-dicyclopropyl-1,4-dihydrobenzo- [d] [1,3] oxazin-2-one Method B From (4,4-dicyclopropyl-1,4-dihydro-2-oxo-2H-3,1-benzoxazin-6-yl) boronic acid and 1,3-dibromo-5-fluorobenzene. White solid: mp 228-229 ° C; ¹ H-NMR (DMSO-d ₆ ) δ 10.3 (s, 1 H), 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), 1.63-1.54 (m, 2H), 0.58-0.41 (m, 6H), 0.
MS (APCI) m / z 402/404 ([MH] ^- , 100%); Calculated value for C ₂₀ H ₁₇ BrFNO ₂ : C, 58.48, H, 4.17, N, 30-0.28 (m, 2H); 3.41. Found: C, 58.77, H, 4.23, N, 3.32.

Example 55 3- (4,4-Dicyclopropyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxadi
6- (3-Bromo-5-fluoro-phenyl) -4,4-dicyclopropyl-1, 6-yl) -5-fluorobenzonitrile in DMF (20 mL).
4-dihydro-benzo- [d] [1,3] oxazin-2-one (0.4 g, 1.0 mmol), Zn (CN) ₂ (0.71
g, 0.61 mmol) and tetrakis (triphenylphosphine) -palladium (0) (0.07 g,
0.06 mmol) was subjected to a nitrogen blanket at 50 ° C. for 15 minutes, then heated at 85 ° C. for 1 hour. After cooling to room temperature, the reaction mixture was poured into NH ₄ Cl (100 mL) and extracted with ethyl acetate (3 × 50 mL). The organic layer was washed with brine, dried over MgSO _4, and concentrated. The resulting clear oil was triturated with ether (30mL) to give a white solid.
The solid was recrystallized from ethyl acetate to give 3- (4,4-dicyclopropyl-2-oxo-1,4
-Dihydro-2H-benzo [d] [1,3] oxazin-6-yl) -5-fluoro-benzonitrile (
0.016 g, 4.6%): mp 250-252 ° C .; ¹ H-NMR (DMSO-d ₆ ) δ 10.3 (s, 1 H), 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 ([MH] ^- , 100%); Calculated for C ₂₁ H ₁₇ FN ₂ O ₂ : C, 72.4,
H, 4.92, N, 8.04. Found: C, 72.4, H, 4.74, N, 7.61.

Example 56 6- (3-Bromo-5-methyl-phenyl) -4,4-dimethyl-1,4-dihydrobenzo- [d] [1,3]
According oxazin-2-one Method B (4,4-dimethyl-1,4-dihydro-2-oxo-2H-3,1-benzoxazine
-6-yl) boronic acid and 3,5-dibromotoluene. White solid: mp 231
-233 ° C; ¹ H-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 ([MH] -, 100%); C 17 H 16 BrNO 2 Analysis Calculated: C, 58.98
, H, 4.66, N, 4.05. Found: C, 58.82, H, 4.62, N, 3.94.

[0152] Example 57 6- (3-bromo-5-trifluoromethoxy - phenyl) -4,4-dimethyl-1,4-Jihidorobe emission zone [d] [1,3] oxazin-2-one Method B According to (4,4-dimethyl-1,4-dihydro-2-oxo-2H-3,1-benzoxazine
-6-yl) boronic acid and 1,3-dibromo-5-trifluoromethoxybenzene. White solid: mp 214-216 ° C .; ¹ H-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 ([MH] -, 100%); C 17 H 13 Calcd _{BrF 3 NO 3: C, 49.06} , H,
3.15, N, 3.37. Found: C, 49.16, H, 3.05, N, 3.30.

Example 58 3- (4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazin-6-yl ) -5-methyl-benzonitrile procedure 6- (3-Bromo-5-methyl-phenyl) -4,4-dimethyl-1,4- according to the method of Example 55
Prepared from dihydrobenzo [d] [1,3] oxazin-2-one. White solid: mp 256-
258 ° C; ¹ H-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%); calcd for C ₁₈ H ₁₆ N ₂ O ₂ : C, 73.96, H, 5.52, N, 9.58
. Found: C, 73.26, H, 5.46, N, 9.24.

Example 59 3- (4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazin-6-yl ) -5-trifluoromethoxy-benzo Nitrile 6- (3-bromo-5-trifluoromethoxy-phenyl) -4,4 according to the method of Example 55.
-Dimethyl-1,4-dihydrobenzo [d] [1,3] oxazin-2-one. White solid: mp 227-228 ° C; ¹ H-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 18 H 13 F 3 N 2 Calcd O _3: C, 59.67, H
, 3.62, N, 7.73. Found: C, 59.63, H, 3.55, N, 7.58.

[0155] Example 60 6- (3,5-Difluoro-phenyl) - 4,4-dimethyl-1,4-dihydrobenzo - [d] [1,3] Oki spoon-2 according to one Method B (4 , 4-Dimethyl-1,4-dihydro-2-oxo-2H-3,1-benzoxazine
-6-yl) boronic acid and 1-bromo-3,5-difluorobenzene. White solid: mp 218-219 ° C; ¹ H-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 (
MS (APCI) m / z 290 ([M + H] ⁺ , 100%); Calculated for C ₁₆ H ₁₃ F ₂ NO ₂ : C, 66.
43, H, 4.53, N, 4.84. Found: C, 66.01, H, 4.46, N, 4.67.

[0156] Example 61 6- (3,5-dichloro - phenyl) -4,4-dimethyl-1,4-dihydrobenzo - [d] according to [1,3] oxazine-2-one Method A 6- Prepared from bromo-4,4-dimethyl-1,4-dihydro-benzo [d] [1,3] oxazin-2-one and 3,5-dichlorophenylboronic acid. White solid: mp 24
5-246 ° C; ¹ H-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 = 7.98 Hz), 1.7 (s, 6H); MS (EI) m / z 321 ([M + H] ⁺ , 40%); C ₁₆ H ₁₃ calcd _{Cl 2 NO 2: C, 59.32} , H, 4.11, N, 4.32. Observed value: C,
59.13, H, 4.29, N, 4.17.

Example 62 6- (3,5-Bis-trifluoromethyl-phenyl) -4,4-dimethyl-1,4-dihydrobenzo [d] [1,3] oxazin-2-one According to Method A Prepared from 6-bromo-4,4-dimethyl-1,4-dihydro-benzo [d] [1,3] oxazin-2-one and bis-trifluoromethylphenylboronic acid. White solid: mp 258-260 ° C; ¹ H-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%); calcd for C ₁₈ H ₁₃ F ₆ NO ₂ : C, 55.54, H, 3.37, N, 3.6.
Found: C, 55.5, H, 3.54, N, 3.47.

Example 63 3- (4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazin-6-yl ) -5-methoxy-benzonitrile DME (4,4-Dimethyl-1,4-dihydro-2-oxo-2H-3,1- (50 mL) and water (25 mL)
Benzoxazin-6-yl) boronic acid (4.2 g, 19.0 mmol), 3-cyano-5-methoxyphenyl triflate (5.1 g, 19.0 mmol), tetrakis (triphenylphosphine) -palladium (0) (1.1 g, 0.95 mmol) ), Sodium carbonate (4.0 g, 38.0 mmol) and lithium bromide (5 g, 57 mmol) were subjected to a gas blanket of nitrogen at 50 ° C. for 15 minutes, and then
For 1 hour. The reaction was cooled to room temperature and ethyl acetate (100 mL) was added. The organic layer was washed twice with aqueous ammonium chloride (100 mL) and once with brine (100 mL),
Dried over magnesium sulfate and concentrated. Chromatography (silica gel,
40% ethyl acetate / hexane) to give 3- (4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazin-6-yl) -5- Methoxy-benzonitrile was obtained as a white solid (0.69 g, 53%): mp 254-255 ° C .; ¹ H-NMR (DMSO-d ₆ ) δ 10.4 (s, 1
H), 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%); of C ₁₈ H ₁₆ N ₂ O ₃ Anal calculated values: C, 68.13, H, 5.40, N, 8.83. Found: C, 68.03, H, 5.
22, N, 8.46.

Example 64 6- (3-Fluoro-phenyl) -4,4-dimethyl-1,4-dihydro-benzo- [d] [1,3] oxa
Zin-2-one Prepared from 6-bromo-4,4-dimethyl-1,4-dihydro-benzo [d] [1,3] oxazin-2-one and 1-bromo-3-fluorobenzene according to Method A . Light yellow solid: mp 1
81-182 ° C; ¹ H-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 = 8.83Hz), 1.67 (s, 6H); MS (EI) m / z 271 ([M + H] ⁺ ,
_{40%); C 16 H 14} FNO 2 Analysis Calculated: C, 69.91, H, 5.3 , N, 5.1. Observed value: C, 70.0,
H, 5.32, N, 4.92.

Example 65 6- (3-Chloro-4-fluoro-phenyl) -4,4-dimethyl-1,4-dihydro-benzo- [d] [1,3 ] oxazin-2-one According to Method A Prepared from 6-bromo-4,4-dimethyl-1,4-dihydro-benzo [d] [1,3] oxazin-2-one and 1-bromo-3-chloro-4-fluorobenzene. White solid: mp 211-212 ° C .; ¹ H-NMR (DMSO-d ₆ ) δ 10.4 (s, 1 H), 7.92 (dd, 1 H, 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 ₁₆ H ₁₃ ClFN
Calcd _{O 2: C, 62.86, H} , 4.29 N, 4.58. Found: C, 62.52, H, 4.45, N,
4.42.

Example 66 3- (1-Diethoxymethyl-4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3 ] oxazin-6-yl) -5 -Fluoro -benzonitrile 3- (4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazin-6-yl) -5-fluoro-benzonitrile (0.25 g, 0.84 mmol) and triethyl orthoformate (5
(0 mL) was heated at 160 ° C. for 12 hours. The excess triethyl orthoformate is removed in vacuo and purified by chromatography (silica gel, 20% ethyl acetate / hexane) to give 3- (1-diethoxymethyl-4,4-dimethyl-2-oxo-1,4- Dihydro-2H-benzo
[d] [1,3] oxazin-6-yl) -5-fluoro-benzonitrile (0.116 g, 33%) was obtained as a white solid: mp 123-124 ° C .; ¹ H-NMR (DMSO-d ₆ ) δ7.97 (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), 3.88-3.7
8 (m, 2H), 3.73-3.61 (m, 2H), 1.77 (s, 6H), 1.27 (t, 6H, J = 7.05Hz); MS (ESI)
m / z 295 ([MH] -, 100%, lower MW ion than consistent with loss of diethyl acetal); Calcd _{C 22 H 23 FN 2 O 4} : C, 66.32, H, 5.82, N, 7.03 . Found: C, 65.
89, H, 5.92, N, 6.66.

Example 67 3-Fluoro-5- (1-methoxymethyl-4,4-dimethyl-2-oxo-1,4-dihydro-2H-be
3- (4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] in benzo [d] [1,3] oxazin-6-yl) -benzonitrile DMF (5 mL) A solution of [1,3] oxazin-6-yl) -5-fluorobenzonitrile (0.150 g, 0.51 mmol) was treated with sodium hydride (0.061 g, 1.53 mmol) at rt. The mixture was stirred for 30 minutes and treated with chloromethyl methyl ether (0.062g, 7.7mmol). Upon completion of the reaction, the reaction mixture was quenched with water (25 mL), extracted with ethyl acetate (3 × 30 mL), dried over MgSO ₄ and concentrated. The residue was chromatographed (silica gel, 25% ethyl acetate /
Hexane) to give 3-fluoro-5- (1-methoxymethyl-4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazin-6-yl ) -Benzonitrile was obtained as a white solid (0.11 g, 65%): mp 169-171 ° C .; ¹ H-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 = 8.4
9 (Hz), 5.33 (s, 2H), 3.35 (s, 3H), 1.7 (s, 6H); MS (APCI) m / z 341 ([M + H] ⁺ , 50%
); C ₁₉ H ₁₇ FN ₂ Calcd _{O 3: C, 65.32, H} , 5.19, N, 8.02. Found: C, 64.92
, H, 4.96, N, 7.73.

[0163] Example 68 phosphoric acid 6- (3-cyano-5-fluoro - phenyl) -4,4-dimethyl -4H- benzo [d] [1,3] o Kisajin 2-yl ester diethyl ether DMF ( 3- (4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazin-6-yl) -5-fluorobenzonitrile (0.25 g, 0.84 mmol) was added sodium hydride (60% in oil, 0.101 g, 2.53 mmol). After stirring for 30 minutes, the reaction mixture was treated with diethyl chlorophosphate (0.22 mL, 1.52 mmol). Upon completion of the reaction, the reaction solution was quenched with water (25 mL), and the product was extracted with ethyl acetate (2x50 mL) and extracted with Mg
Dried over SO ₄ and concentrated. The residue was purified by chromatography (silica gel, 25% ethyl acetate / hexane) to give 6- (3-cyano-5-fluoro-phenyl) phosphate
Dimethyl -4H- benzo [d] [1,3] oxazin-2-yl ester diethyl ether as a white solid (0.064g, 18%) was obtained as: mp 196-198 ℃; ¹ H- 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%); calcd for C ₂₁ H ₂₂ FN ₂ O ₅ P: C, 58.33, H, 5.13, N, 6.48. Found: C, 58.1, H, 5.11, N, 6.25.

Example 69 3- (4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazin-6-yl ) -4-fluoro-benzonitrile Method According to B (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxin-6
-Yl) boronic acid and 5-bromo-2-fluorobenzonitrile. White solid: mp 229-230 ° C .; ¹ H-NMR (DMSO-d ₆ ) δ 10.4 (s, 1 H), 8.15 (dd, 1 H, 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%); Calculated value for C ₁₇ H ₁₃ FN ₂ O ₂ : C, 68
.91, H, 4.42, N, 9.45. Found: C, 68.74, H, 4.83, N, 9.10.

Example 70 8-Fluoro-4,4-dimethyl-dihydro-benzo [d] [1,3] oxazin-2-one N- (tert-butoxycarbonylamino) -3-fluorobenzoic acid (Takagishi et al.S
ynlett 4, 360-2 (1992); mp 159-61 ° C) with deprotection using trifluoroacetic acid.
o-Aminobenzoic acid was obtained, which was treated with methylmagnesium bromide to obtain o-aminodimethylcarbinol. o-Aminodimethylcarbinol (2.23 g, 13.2 mmol) in T
Treated with 1,1′-carbonyldiimidazole (2.8 g, 17.2 mmol) in HF (20 mL) at 50 ° C. for 12 hours. Upon completion of the reaction, it was cooled to rt and ethyl acetate (100 mL) was added. The organic layer was washed with a 10% aqueous HCl solution (2 × 25 mL), dried over MgSO ₄ and concentrated.
The residue was purified by chromatography (silica gel, 10% ethyl acetate / hexane) to give 8-fluoro-4,4-dimethyl-dihydro-benzo [d] [1,3] oxazin-2-one as a white solid ( 1.3 g, 50%): mp 127-128 ° C .; ¹ H-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%); calcd for C ₁₀ H ₁₀ FNO ₂ : C, 61.53, H, 5.16, N, 7.18. Found: C, 61.27, H, 5.37, N, 7.02.

Example 71 6- (3-Chloro-4-fluoro-phenyl) -8-fluoro-4,4-dimethyl-1,4-dihydrobe
8-Fluoro-4,4-dimethyl-dihydro-benzo [d] [1,3] oxazine in benzo [d] [1,3] -oxazin- 2-oneacetic acid (5 mL)
To a solution of 2-one (0.15 g, 0.77 mmol) was added a solution of bromine (0.37 g, 2.31 mmol) in acetic acid (5 mL) dropwise at rt under nitrogen. After stirring for 10 minutes, the mixture was concentrated and the resulting residue was purified on a silica gel column (hexane: ethyl acetate / 4: 1) to give 6-bromo
-8-Fluoro-4,4-dimethyl-dihydro-benzo [d] [1,3] oxazin-2-one was obtained as an off-white solid (0.176 g, 84%), which was used without further purification. Was used in the next step.

6-Bromo-8-fluoro-4,4-dimethyl-dihydro-benzo [d] [1,3] oxazin-2-one (0.176 g, 0.64 mmol) in DME (10 mL) and water (5 mL) ), 4-fluoro-3-chlorophenylboronic acid (0.15 g, 0.84 mmol), a mixture of tetrakis (triphenylphosphine) -palladium (0) (0.04 g, 0.032 mmol) and sodium carbonate (0.20 g, 1.92 mmol). A nitrogen blanket was applied at 50 ° C. for 15 minutes, then heated at 85 ° C. for 1 hour. The reaction mixture was cooled to room temperature, and ethyl acetate (100 mL) was added. The organic layer was washed with aqueous ammonium chloride (
(100 mL) and once with brine (100 mL), dried over magnesium sulfate and concentrated. The residue was purified by chromatography (silica gel, 25% ethyl acetate / hexane) to give 6- (3-chloro-4-fluoro-phenyl) -8-fluoro-4,4-dimethyl-1,4-dihydrobenzo [ d] [1,3] oxazin-2-one as white solid (0.13 g, 66
%): Mp 246-248 ° C .; ¹ H-NMR (DMSO-d ₆ ) δ10.5 (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 ₁₆ H ₁₂ F ₂ NO ₂
0.5H ₂ O Analysis Calculated: C, 57.76, H, 3.94 , N, 4.21. Found: C, 57.49, H, 3.6
9, N, 4.03.

Example 72 6- (3-Bromo-phenyl) -4,4-dimethyl-1,4-dihydro-benzo- [d] [1,3] oxadi
Accordance emission-2-one method B (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-Benzokishin -6
-Yl) boronic acid and 1,3-dibromobenzene. White solid: mp 174-1
75 ° C .; ¹ H-NMR (DMSO-d ₆ ) δ 10.35 (s, 1H), 7.88 (bs, 1H), 7.68 (d, 1H, J = 7.5H
z), 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 16 H 14 BrNO 2 Analysis Calculated: C, 57.85, H, 4.25 , N, 4.22. Found: C, 57.7, H, 4.36, N, 4.09.

[0169] Example 73 4,4-dimethyl-6- (3-trimethylsilanylethynyl-phenyl) - 1,4-dihydro - Ben zo [d] [1,3] oxazin-2-one Triethylamine (20 mL) 6- (3-bromo-phenyl) -4,4-dimethyl-1,4-dihydro-benzo [d] [1,3] oxazin-2-one (0.8 g, 2.4 mmol), trimethylsilylacetylene (1 g , 10 mmol), tetrakis (triphenylphosphine) palladium (0) (0
.17 g, 0.24 mmol) and cuprous (I) iodide (0.05 g, .28 mmol) at 80 ° C. under nitrogen
For 3 hours. The reaction mixture was cooled to rt and the solvent was removed. The residue was dissolved in ethyl acetate (50 mL) and washed with 1N aqueous HCl (3 × 20 mL) and brine (20 mL). The organic layer was separated, dried (MgSO _4). After removal of the solvent, the residue was purified by silica gel chromatography (hexane: ethyl acetate / 3: 1) The title compound of white purified by solid (0.77 g, 92%) was obtained as: mp 240-242 ° C.; ¹ H-NMR (DMSO-d ₆ ) δ10.3 (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 = 7.98
Hz), 1.67 (s, 6H ), 0.25 (s, 9H); MS (EI) m / z 349 ([M +], 50%); C 21 H 23 NO 2 Si ·
Calculated value for 0.2 EtOAc: C, 71.32, H, 6.75, N, 3.82. Found: C, 71.08, H, 6
.64, N, 3.82.

Example 74 6- (3-Ethynyl-phenyl) -4,4-dimethyl-1,4-dihydro-benzo- [d] [1,3] oxa
Zin-2-one 4,4-Dimethyl-6- (3-trimethylsilanylethynyl-phenyl) -1,4-dihydro-benzo [d] [1,3] oxazin-2-one (0.7 g, 2 mmol) and potassium carbonate (2 g, excess) were stirred under nitrogen at rt for 4 h. Mixture with ice water (100 mL)
And extracted with ethyl acetate (2 × 80 mL). The organic layer is washed with brine and MgSO ₄
And dried. Excluding the solvent, the title compound was converted to a yellowish white solid (0.4 g, 72%).
Obtained as: mp 171-172 ° C .; ¹ H-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 18 H 15 NO 2 · 0.2
Calculated value for EtOAc: C, 76.56, H, 5.67, N, 4.75. Found: C, 76.34, H, 5.4,
N, 4.7.

Example 75 3- [3- (4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo- [d] [1,3] oxazin-6- yl) -phenyl]- propyne nitriles DMSO, acetonitrile and water (9 mL / 3 mL / 0.5 mL) cuprous cyanide to a stirred mixture of (
0.193 g, 2.2 mmol), sodium iodide (11 mg, 0.072 mmol) and 6- (3-ethynyl-phenyl) -4,4-dimethyl-1,4-dihydro-benzo [d] [1,3] oxazine- 2-one (0.2g,
0.72 mmol) was added at rt under nitrogen. Then chlorotrimethylsilane was added dropwise to the above mixture. After the addition, the mixture was heated at 50 ° C. for 72 hours. The reaction mixture was then cooled to rt and treated with cold 0.5N HCl aqueous solution (50 mL). The resulting precipitate was collected on a filter and washed with water. The solid was purified on a silica gel column (hexane: ethyl acetate / 2: 1) to give the title compound as an off-white solid (10 mg, 4.6%): mp 212-213 ° C .; ¹ H-NMR (CHCl ₃ -d ₆ ) δ7.96 (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, 1
H, 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%).

Example 76 6- (3-Fluoro-5-nitro-phenyl) -4,4-dimethyl-1,4-dihydro-benzo [d] [1,3 ] oxazin-2-one According to Method B ( 1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxin-6
-Yl) boronic acid and 1-bromo-3-fluoro-5-nitrobenzene. Yellow solid: mp 260-261 ° C .; ¹ H-NMR (DMSO-d ₆ ) δ 10.4 (s, 1H), 8.37 (bs, 1H), 8.1
4-8.05 (m, 2H), 7.77-7.74 (m, 2H), 7.01 (d, 1H, J = 7.94Hz), 1.7. (S, 6H); MS (
ESI) m / z 315 ([MH] ^- , 100%); calcd for C ₁₆ H ₁₃ FN ₂ O ₄ : C, 60.76, H, 4.14,
N, 8.86. Found: C, 60.34, H, 4.2, N, 8.61.

Example 77 6- (3-Chloro-5-fluoro-phenyl) -4,4-dimethyl-1,4-dihydro-benzo [d] [1,3 ] oxazin-2-one According to Method B ( 1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxin-6
-Yl) boronic acid and 1-bromo-3-chloro-5-fluorobenzene. White solid: mp 193-194 ° C .; ¹ H-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%); calcd for C ₁₆ H ₁₃ ClFNO ₂ : C, 62.86, H,
4.29, N, 4.58. Found: C, 62.98, H, 4.1, N, 4.6.

Example 78 3-Chloro-5- (4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxa
Zin-6-yl) -benzonitrile (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxin-6
-Yl) boronic acid and 1-bromo-3-chlorobenzonitrile. White solid: mp 256-257 ° C .; ¹ H-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 ([MH] -, 100%); C 17 H 13 ClN 2 O 2 Analysis Calculated: C, 65.29, H,
4.19, N, 8.96. Found: C, 65.25, H, 3.92, N, 8.71.

[0175] Example 79 6- (3,5-dinitro - phenyl) -4,4-dimethyl-1,4-dihydro - benzo [d] [1,3] according oxazine-2-one Method B (1 , 4-Dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxin-6
-Yl) boronic acid and 1-bromo-3,5-dinitrobenzene. Yellow solid: mp 297-298 ° C; ¹ H-NMR (DMSO-d ₆ ) δ 10.4 (s, 1 H), 8.88 (d, 2 H, J = 1.98 Hz),
8.78 (bs, 1H), 7.78-7.82 (m, 2H), 7.04 (d, 1H, J = 8.23Hz), 1.7 (s, 6H); MS (AP
CI) m / z 343 ([ MH] -, 100%); C 16 H 13 Calcd _{N 3 O 6: C, 55.98} , H, 3.82, N
, 12.24. Found: C, 55.65, H, 3.7, N, 11.92.

Example 80 5- (4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazin-6-yl ) -isophthalonitrile According to Method B ( 1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxin-6
-Yl) boronic acid and 5-bromoisophthalonitrile. White solid: mp
288-289 ° C; ¹ H-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%); calcd for C ₁₈ H ₁₃ N ₃ O ₂ · 1.65H ₂ O: C, 64.92, H, 4.93, N,
12.62. Found: C, 64.74, H, 4.69, N, 12.32.

Example 81 4,4-Dimethyl-6- (3-thiazol-2-yl-phenyl) -1,4-dihydro-benzo [d] [1,3 ] oxazin-2-one DMF (5 mL) 6- (3-bromo-phenyl) -4,4-dimethyl-1,4-dihydro-benzo [d] [
A mixture of 1,3] oxazin-2-one (0.25 g, 0.75 mmol), tri-n-butyl-thiazol-2-yltin (0.5 g, 1.3 mmol) was degassed to remove oxygen and then under nitrogen. Heated at 90 ° C. for 3 hours. The reaction mixture was cooled to rt and treated with ice water (70 mL). Ethyl acetate (1
200 mL) was added and the organic layer was separated, washed with brine, dried (MgSO _4). After removal of the solvent, the residue was purified by silica gel column (hexane: ethyl acetate / 1: 1) The title compound was purified by as a white solid (60mg, 23%): mp 223-224 ℃; 1 H- NMR (D
MSO-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 (AP
CI) m / z 337 ([ M + H] +, 100%); C 19 H 16 N 2 O 2 S · 0.25H 2 O for Calcd: C, 66.94,
H, 4.88, N, 8.22. Found: C, 66.57, H, 4.65, N, 7.92.

Example 826- (3-fluoro-5-methoxy-phenyl) -4,4-dimethyl-1,4-dihydro-benzo [d] [1 , 3] Oxazin-2-one According to Method B (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxin-6
-Yl) boronic acid and 3-bromo-5-fluoroanisole. White solid
: Mp 181-182 ° C;¹H-NMR (DMSO-d₆) 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%); C₁₇H₁₆FNO_Three・ 0.1H _Two Calculated value for O: C, 67.36, H, 5.39, N, 4.62. Found: C, 67.11, H, 5.44, N
, 4.48.

Example 83 6- (3-Fluoro-5-trifluoromethyl-phenyl) -4,4-dimethyl-1,4-dihydro-
Benzo [d] [1,3] oxazin-2-one According to Method B (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxin-6
-Yl) boronic acid and 1-bromo-3-fluoro-5-trifluoromethylbenzene. White solid: mp 207-208 ° C .; ¹ H-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 17 H 13 F 4 NO 2 Analysis Calculated: C, 6
0.18, H, 3.86, N, 4.13. Found: C, 59.9, H, 3.99, N, 4.06.

Example 846- (5-bromo-pyridin-3-yl) -4,4-dimethyl-1,4-dihydro-benzo [d] [1,3] o
Kisazin-2-one According to Method B (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxin-6
-Yl) boronic acid and 3,5-dibromopyridine. White solid: mp 211-2
12 ° C;¹H-NMR (DMSO-d₆) δ10.4 (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%); C_FifteenH ₁₃ BrN_TwoO_TwoAnalysis calculated for: C, 54.07, H, 3.93, N, 8.41. Found: C, 54.15, H, 3
.89, N, 8.31.

Example 85 6- (5-Bromo-1-oxy-pyridin-3-yl) -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-benzo [d] [1,3] oxazin-2-one in acetic acid (5 mL) (0.34 g, A mixture of 1 mmol) and hydrogen peroxide (30%, 5 mL) was heated at 60 ° C. for 3 hours. The reaction mixture was cooled to rt and neutralized by the addition of cold saturated sodium bicarbonate solution. The resulting white precipitate was collected on a filter, washed with distilled water and dried to give the title compound as a white solid (0.35g, 100%): mp 157-159 ° C; ¹ H-NMR ( DMSO-d ₆ ) δ 10.4 (s, 1H), 8.69 (s, 1H), 8.53 (s, 1
H), 7.99 (s, 1H), 7.73-7.69 (m, 2H), 6.97 (d, 1H, J = 8.18Hz), 1.7 (s, 6H); MS
(APCI) m / z 349 ([M + H] ⁺ , 100%), 351 ([M + H] ⁺ , 100%); C ₁₅ H ₁₃ BrN ₂ O ₃・ 2.5H ₂ O
Analysis calculated for: C, 45.70, H, 4.60, N, 7.11. Found: C, 45.34, H, 4.64, N,
7.

Example 86 tert-butyl 6- (3-cyano-5-fluoro-phenyl) -4,4-dimethyl-2-oxo-4H-benzo [d] [1,3] oxazine-1-carboxylate Ester 3- (4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [] in anhydrous acetonitrile
d] [1,3] oxazin-6-yl) -5-fluorobenzonitrile (0.3 g, 11 mmol), di-te
A mixture of rt-butyl dicarbonate (0.33 g, 1.5 mmol) and DMAP (50 mg) was treated under nitrogen with r
Stirred at t for 4 minutes. The reaction mixture was washed with 1N aqueous HCl, brine and dried (MgS
O ₄ ). After removing the solvent, the title compound was obtained as a white solid (0.25 g, 63%): m
p 139-140 ° C; ¹ H-NMR (CHCl ₃ -d ₆ ) δ7.66-7.63 (m, 2H), 7.53-7.48 (m, 2H), 7.3
8-7.35 (m, 2H), 1.79 (s, 6H), 1.62 (s, 9H); MS (APCI) m / z 289 ([MH] ^- , 100%)
; C ₂₂ H ₂₁ FN ₂ Calcd _{O 4: C, 66.66, H} , 5.34, N, 7.07. Found: C, 66.7,
H, 5.41, N, 7.

Example 87 5- (4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazin-6-yl ) -2-fluoro-benzonitrile Method According to B (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxin-6
-Yl) boronic acid and 1-bromo-2-fluorobenzonitrile. White solid: mp 255-256 ° C .; ¹ H-NMR (DMSO-d ₆ ) δ 10.4 (s, 1 H), 8.30 (dd, 1 H, 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%); Calculated value for C ₁₇ H ₁₃ FN ₂ O ₂ .0.1H ₂ O: C, 68.50, H , 4.46, N, 9.40. Found: C, 68.27, H, 4.81, N, 9.1.

[0184] Example 88 4- (8-fluoro-4,4-dimethyl-2-oxo-1,4-dihydro -2H- benzo [d] [1,3] oxazine-6-yl) - thiophene - 2-carbonitrile 8-fluoro- (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxin-6-
Il) boronic acid was prepared from 6-bromo-8-fluoro-4,4-dimethyl-dihydro-benzo [d] [1,3] oxazin-2-one using the method of Example 4.

The title compound was treated with 8-fluoro- (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxin-6-yl) boronic acid and 4-bromo-2 according to Method B. -Made from cyanothiophene. White solid: mp 250-251 ° C .; ¹ H-NMR (DMSO-d ₆ ) δ10.5 (s, 1H), 8
.54 (d, 1H, J = 1.42Hz), 8.43 (d, 1H, J = 1.35Hz), 7.69 (dd, 1H, J = 11.71, 1.54H
z), 7.58 (bs, 1H ), 1.7 (s, 6H); MS (EI) m / z 302 ([M +], 50%); C 15 H 11 FN 2 O 2 S ·
0.45H ₂ O Analysis Calculated: C, 58.04, H, 3.86 , N, 9.02. Measured value: C, 58.4, H, 3.8
9, N, 8.63.

Example 89 3-Fluoro-5- (8-fluoro-4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazin-6-yl) - benzonitrile method B 8- fluoro - (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-Benzokishin-6-yl) boronic acid and 5-bromo-3-fluoro-benzo Manufactured from nitrile. White solid: mp 256-257 ° C .; ¹ H-NMR (DMSO-d ₆ ) δ 10.5 (s, 1 H), 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, 1.81 Hz), 7.63 (s, 1H), 1.7 (s, 6H); MS (EI) m / z 314 ([M ⁺ ], 60%).

Example 90 5- (4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazin-6-yl ) -thiophen-3-carbonitrile Method According to B (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxin-6
-Yl) boronic acid and 2-bromo-4-thiophenecarbonitrile. Yellowish-white solid: mp 255-260 ° C; ¹ H-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 ([MH] ^- .

Example 91 2- (4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazin-6-yl ) -thiophen-3-carbonitrile Method According to B (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxin-6
-Yl) boronic acid and 2-bromo-3-thiophenecarbonitrile. Yellowish-white solid: mp 200-202 ° C; ¹ H-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
.1 Hz), 1.63 (s, 6H); MS (-ESI) m / z 283 (MH) ^- .

Example 92 6- (1,2,4-Thiadiazol-3-yl-phenyl) -4,4-dimethyl-1,4-dihydro-ben
5- [3-Bromo-phenyl]-[1,3,4] oxathiazole-2-in zo [d] [1,3] oxazin-2-one o-xylene (500 mL)
ON (21.25 g, 82.3 mmol), a mixture of ethyl cyanoformate (32.5 mL, 329 mmol) at 150 ° C.
For 60 hours. After removing the solvent from the reaction mixture, the product was recrystallized from ethanol to give ethyl 3- [3-bromo-phenyl]-[1,2,4] thiadiazole-5-carboxylate as white crystals (17.5 g). , 68%): mp 87-90 ° C; ¹ H-NMR (CDCl ₃ )
δ8.53 (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 = 7.1H)
z); MS ((+) APCI) [M + H] ⁺ @ m / z 313/315. C ₁₁ H ₉ BrN ₂ O ₂ Calcd S: C, 42.19
, H, 2.90, N, 8.94. Found: C, 41.81, H, 3.08, N, 8.78.

3- [3-bromo-phenyl]-[1,2,4] thiadiazole-5-carboxylic acid ethyl ester
(16.8 g, 53.5 mmol), a mixture of sodium hydroxide (2.4 g, 58.8 mmol), distilled water (120 mL) and ethanol (20 mL) was heated to 100 ° C. for 2 hours. The reaction mixture was cooled to room temperature. Concentrated hydrochloric acid (5.1 mL) was added and the reaction mixture was reheated to 100 ° C. for 3 hours. The solution was cooled to room temperature and extracted with diethyl ether (3x150mL). The combined organic layers are distilled water (
3 × 100 mL) and dried over MgSO ₄ . After removing the solvent, 3- [3-bromo-phenyl]-[1,2,4] thiadiazole was obtained as white needles (12.7 g, 99%): m
p 69-71 ° C; ¹ H-NMR (CDCl ₃ ) δ 9.89 (s, 1 H), 8.52 (t, 1 H, J = 1.8 Hz), 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 ₈ H ₅ BrN ₂ Calcd S: C, 39.85, H, 2.09,
N, 11.62. Found: C, 39.82, H, 2.43, N, 11.33.

According to Method B, (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl) boronic acid was converted to 3- [3-bromo-phenyl]-[ Coupling with 1,2,4] thiadiazole to give 6- (1,2,4-thiadiazol-3-yl-phenyl) -4,4-dimethyl-1,4-dihydro-benzo [d] [1,3 ] -Oxazin-2-one as a yellowish-white solid (0.5g, 35%)
Obtained as: mp 214-216 ° C .; ¹ H-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, 3
H), 7.02 (t, 1H, J = 4.4 Hz), 1.70 (s, 6H); MS ((+) APCI) [M + H] ⁺ @ m / z 338.

[0192] Example 93 6- (3-Fluoro-5-thiophen-3-yl-phenyl) - 4,4-dimethyl-1,4-dihydro - base down zone [d] [1,3] oxazin-2 - according to one method B 6- (3-bromo-5-fluoro - phenyl) -4,4-dimethyl-1,4-dihydro - benzo [d] [1,3] oxazin-2-one and 3-thiophene boronic Made from acid.
Brownish orange solid: mp 200-203 ° C; ¹ H-NMR (CDCl ₃ ) δ 8.62 (s, 1H), 7.5
3 (q, 1H, J = 1.4Hz), 7.50 (d, 1H, J = 1.5Hz), 7.49 (d, 1H, J = 2.0Hz), 7.45-7.40
(m, 1H), 7.35 (d, 1H, J = 1.8Hz), 7.27-7.24 (m, 2H), 7.15 (dt, 1H, J = 5.8, 2.0
Hz), 6.94 (d, 1H, J = 8.2 Hz), 1.80 (s, 6H); MS ((-) APCI) [MH] ^- @ m / z 352. _{C 2 0 H 16 FNO 2 S} · 0.50H 2 O for Calcd: C, 66.28, H, 4.73 , N, 3.87. Measured value: C, 6
6.54, H, 5.03, N, 3.52.

Example 942- (4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazin-6-yl ) -Pyrrole-1-carboxylic acid tert-butyl ester 6-Bromo-4,4-dimethyl-1,4-dihydro-benzo [d] [1,3] o-toluene (40 mL)
Xazin-2-one (0.87 g, 3.4 mmol) and tetrakis (triphenylphosphine)
A solution of radium (0) (96 mg, 0.08 mmol) was stirred under a stream of nitrogen for 25 minutes. In this solution
1-t-butoxycarbonylpyrrole-2-boronic acid (1.4 g,
 7.0 mmol) and potassium carbonate (0.94 g, 7.0 mmol) in water (10 mL) were added sequentially. mixture
The thing was heated at 80 ° C. for 16 hours and cooled to rt. The reaction mixture was saturated with sodium bicarbonate.
Poured into the aqueous solution (100 mL) and extracted with ethyl acetate (3 × 100 mL). Combine the organic layers,
Washed with water (100 mL) and brine (50 mL) and dried over magnesium sulfate. Dissolution
The solution is filtered, concentrated in vacuo and the residue is flash column chromatographed on silica gel.
Purify by chromatography (30% ethyl acetate / hexane) to give the title compound
Obtained as a pale white powder (0.7 g, 62%): mp 176 ° C.¹H NMR (CDCl_Three) δ1.40 (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, 3.3 Hz), 7.69 (bs, 1H). MS ((-) ESI) m / z 341 [M-H]^-. C ₁₉ H_{twenty two}N_TwoO_FourAnalysis calculated for: C, 66.65, H, 6.48, N, 8.18. Found: C, 65.46, H,
6.51, N, 7.74.

Example 95 2- (4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo- [d] [1,3] oxazin-6-i
-5-nitro-pyrrole-1-carboxylic acid tert-butyl ester 2- (4,4-dimethyl-2) in acetonitrile (25 mL) and dichloromethane (1 mL) at room temperature
-Oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazin-6-yl) -pyrrole-1-carboxylic acid tert-butyl ester (0.7 g, 2.0 mmol) in a solution of silver nitrate (0.37 g, 2.1 mmol). After 5 minutes acetyl chloride (0.15 mL, 2.0 mmol) in acetonitrile (3 mL) was added and the solution was allowed to stir for 2 hours. Pour the reaction mixture into water (50 mL) and add ethyl ether
(2 × 50 mL). The organic layers were combined, washed with brine (30 mL) and dried over magnesium sulfate. The solution was filtered, concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (30% ethyl acetate / hexane) to give a yellow oil, which was crystallized from 5% ethyl acetate / hexane. To give the title compound as a light yellow powder (350 mg, 45%): mp 125 ° C .; ¹ H NMR (CDCl ₃ ) δ 1.47 (s,
9H), 1.75 (s, 6H), 6.26 (d, 1H, J = 4.2Hz), 6.87 (d, 1H, J = 8.1Hz), 7.19 (d, 1
H, 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] ⁺ . Calcd _{C 19 H 21 N 3 O 6} : C, 58.91, H, 5.46,
N, 10.85. Found: C, 58.4, H, 5.55, N, 10.18.

Example 96 4,4-Dimethyl-6- (5-nitro-1H-pyrrol-2-yl) -1,4-dihydrobenzo [d] [1,3]
Stoppered with oxazin-2-one rubber septum, in a round-bottomed flask 25mL equipped with a needle to flow out with a nitrogen inlet and a gas 2- (4,4-dimethyl-2-oxo-1,4-dihydro -2H -Benzo- [d] [1,3] oxazin-6-yl) -5-nitro-pyrrole-1-carboxylic acid tert-butyl ester (0.7 g, 1.8 mm
ol). The flask was placed in an oil bath and heated to 180 ° C. to maintain a vigorous flow of nitrogen. After 10 minutes at this temperature, the flask was removed from the oil bath and allowed to cool to rt. The brown residue was washed in a larger flask with dichloromethane / ethyl acetate and adsorbed on a small amount of silica gel. Purification by flash column chromatography on silica gel (60% ethyl acetate / hexane) provided the title compound as a brown powder (200 mg, 40%): mp 265 ° C. (dec). _{^{1 H 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 [MH] ^- . Calcd _{C 14 H 13 N 3 O 4} : C, 58.53; H, 4.56; N, 1
4.63. Found: C, 58.25; H, 5.10; N, 12.57.

Example 97 4,4-Dimethyl-6- (1H-pyrrol-2-yl) -1,4-dihydro-benzo [d] [1,3] oxadi
Stoppered with emission-2-one rubber septum, in a round-bottomed flask 25mL equipped with a needle to flow out with a nitrogen inlet and a gas 2- (4,4-dimethyl-2-oxo-1,4-dihydro -2H -Benzo [d] [1,3] oxazin-6-yl) -pyrrole-1-carboxylic acid tert-butyl ester (3.5 g, 10 mmol) was placed. The flask was placed in an oil bath and heated to 180 ° C. to maintain a vigorous flow of nitrogen. After 10 minutes at this temperature, the flask was removed from the oil bath and allowed to cool. The brown residue was washed in a larger flask with dichloromethane / ethyl acetate and adsorbed on a small amount of silica gel. Flash column chromatography on silica gel (
Purification by 60% ethyl acetate / hexane) provided the title compound as a green solid (2g, 80%): mp 202 ° C (dec). _{^{1 H NMR (CDCl 3) δ1.75}} (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 ₁₄ H ₁₄ N ₂ O ₂ Analysis Calculated: C, 69.41, H, 5.82 , N, 11.56. Found: C, 69.20,
H, 5.96, N, 11.29.

Example 98 4,4-Dimethyl-6- (1-methyl-1H-pyrrol-2-yl) -1,4-dihydro-benzo [d] [1,3] oxazin-2-one at room temperature 4,4-Dimethyl-6- (1H-pyrrol-2-yl) in dimethylformamide (20 mL)
Iodide in a mixture of) -1,4-dihydro-benzo [d] [1,3] oxazin-2-one (1.5 g, 6.2 mmol) in potassium carbonate (4.28 g, 31 mmol) and dimethylformamide (5 mL) Methyl
(1.16 mL, 19 mmol) were added sequentially. After 1 hour, the reaction mixture was boiled. The reaction was cooled to room temperature, poured into water (50mL) and extracted with ethyl acetate (2x50mL). The organic layers were combined, washed with brine (30 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash column chromatography on silica gel (
(40% ethyl acetate / hexane) to give the title compound as a yellowish-white powder
(0.5 g, 31%): mp 230 ° C. ¹ H NMR (CDCl ₃ ) δ1.71 (s, 6H), 3.42 (s, 3
H), 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 / z 255 [MH] ^- . C ₁₅ H ₁₆ N ₂ O ₂ Analysis Calculated: C, 70.29, H, 6.29 , N,
10.93. Found: C, 68.59, H, 6.16, N, 10.49.

Example 99 4,4-Dimethyl-6- (1-methyl-5-nitro-1H-pyrrol-2-yl) -1,4-dihydro-ben
4,4-dimethyl-6- (1-methyl-1H-pyrrol-2-yl) -1 in azo [d] [1,3] oxazin-2- oneacetonitrile (20 mL)
Nitrate in a solution of 1,4-dihydro-benzo [d] [1,3] oxazin-2-one (0.3 g, 1.2 mmol)
(0.21 g, 1.26 mmol) was added. The solution was cooled to −78 ° C. and treated with a solution of acetyl chloride (0.08 mL, 1.2 mmol) in acetonitrile (1 mL). The reaction mixture was warmed to room temperature. After 1 hour, the reaction mixture was poured into water (50 mL) and extracted with ethyl ether (2 × 50 mL). The organic layers were combined, washed with brine (30 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification by flash column chromatography on silica gel (40% ethyl acetate / hexane) provided the title compound (5 mg, 1%) as a yellow solid: mp 180-185 ° C. ¹ H NMR (CDCl ₃ ) δ1.75 (s, 6H), 3.45 (s, 3
H), 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] ⁺ .

Example 100 5-bromo-4-ethylthiophen-2-carboxaldehyde Prepared in the same manner as in Example 19 from 2-bromo-3-ethylthiophene. ¹ H-NMR (D
_{MSO-d 6) δ9.82 (S} , 1H), 7.81 (S, 1H), 2.5 (q, 2H, J = 7.4Hz), 1.15 (t, 3H, J = 7
.5Hz).

Example 101 5-bromo-4-ethylthiophene-2-carbonitrile Prepared from 5-bromo-4-ethylthiophene-2-carboxaldehyde using a method similar to that in Example 18. ^{IR (KBr) 2221cm -1; 1} H-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 ⁺ ).

Example 102 5-bromo-4-n-propylthiophen-2-carboxaldehyde Prepared from 2-bromo-3-n-propylthiophene in the same manner as in Example 19. ¹ H-NM
R (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).

Example 103 5-bromo-4-n-propylthiophenecarbonitrile Prepared from 5-bromo-4-n-propylthiophene-2-carboxaldehyde using a method similar to that in Example 18. ¹ H-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 ⁺ ).

Example 104 5-bromo-4-n-butylthiophenecarboxaldehyde Prepared from 2-bromo-3-n-butylthiophene in the same manner as in Example 19. IR (KBr)
1660cm ^-1 . ¹ H-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 2
46 (M ⁺ ).

Example 105 5-bromo-4-n-butylthiophenecarbonitrile Prepared from 5-bromo-4-n-butylthiophenecarboxaldehyde using a method similar to that in Example 18. ¹ H-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 ⁺ ).

Example 106 3- (1,2-Dihydro-2-oxospiro [4H-3,1-benzoxazin-4,1-cyclohexane] -6-yl) -benzonitrile Spiro- (4,1 '-Cyclohexane-1,4-dihydro-2-oxo-2H-3,1
-Benzoxazin-6-yl) boronic acid and 3-bromobenzonitrile.
Tan powder: mp 245-247 ° C. ¹ H-NMR (DMSO-d ₆ ) δ 10.31 (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 (E
I) m / z 318 [M ⁺ ]. _{C 20 H 18 N 2 O 2} · 1 / 2H 2 O Analysis Calculated: C, 73.38, H, 5.85 , N, 8
.56. Found: C, 73.86, H, 5.81, N, 8.22.

Example 107 3- (1,2-Dihydro-2-oxospiro [4H-3,1-benzoxazin-4,1-cyclohexane] -6-yl) -5-fluorobenzonitrile Spiro- ( 4,1'-cyclohexane-1,4-dihydro-2-oxo-2H-3,1
-Benzoxazin-6-yl) boronic acid and 3-bromo-5-fluorobenzonitrile. White powder: mp 250-253 ° C. IR (KBr) 2220cm ^-1 . ¹ H-NMR (DMSO-d ₆ )
δ 10.34 (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 20 H 17 FN 2 O 2} H 2 O Analysis Calculated: C, 67.78, H, 5.40 ,
N, 7.90. Found: C, 67.9, H, 4.93, N, 7.67.

Example 108 4- (1,2-Dihydro-2-oxospiro [4H-3,1-benzoxazine-4,1-cyclohexane] -6-yl) -2-thiophenecarbonitrile Spiro- ( 4,1'-cyclohexane-1,4-dihydro-2-oxo-2H-3,1
-Benzoxazin-6-yl) boronic acid and 3-bromo-5-cyanothiophene. White crystals: mp 230-232 ° C. IR (KBr) 2200cm ^-1 . ¹ H-NMR (DMSO-d ₆ ) δ 10.29
(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 18 H 16 N 2 O 2} S 1 / 4H 2 O Analysis Calculated: C, 65.73, H, 5.06 , N, 8.
52. Found: C, 65.55, H, 5.06, N, 8.22.

Example 109 5- (1,2-Dihydro-2-oxospiro [4H-3,1-benzoxazine-4,1-cyclohexane] -6-yl) -2-thiophenecarbonitrile Spiro- ( 4,1'-cyclohexane-1,4-dihydro-2-oxo-2H-3,1
-Benzoxazin-6-yl) boronic acid and 2-bromo-5-cyanothiophene. Tan powder: mp 243-245 ° C. ¹ H-NMR (DMSO-d ₆ ) δ 10.41 (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 / z 324 (M ⁺ ). _{C 18 H 16 N 2 O 2} S 1 / 2H 2 O Analysis Calculated: C, 65.08, H, 5.04 , N, 8.18. Found: C, 64.8
4, H, 5.09, N, 8.40.

Example 110 5- (1,2-Dihydro-2-oxospiro [4H-3,1-benzoxazin-4,1-cyclohexane] -6-yl) -4-methyl-2-thiophenecarbonitrile Method B Spiro- (4,1'-cyclohexane-1,4-dihydro-2-oxo-2H-3,1
-Benzoxazin-6-yl) boronic acid and 2-bromo-3-methyl-5-cyanothiophene. White powder: mp 200-203 ° C. ¹ H-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 ^<+> ). Calcd _{C 19 H 18 N 2 O 2} S: C, 67.43, H, 5.36, N, 8.28. Found: C, 67.12, H, 5.45, N, 8.05.

Example 1115- (4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazin-6-yl ) -4-Ethyl-thiophene-2-carbonitrile Spiro- (4,1'-cyclohexane-1,4-dihydro-2-oxo-2H-3,1 according to Method B
-Benzoxazin-6-yl) boronic acid and 2-bromo-3-ethyl-5-cyanothiophene
Manufactured from. White crystals: mp 160-162 ° C.¹H-NMR (DMSO-d₆) 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 ₁₇ H₁₆N_TwoO_TwoS 1 / 4H_TwoCalculated value for O: C, 64.43, H, 5.25, N, 8.84. Measured value: C, 6
4.77, H, 5.23, N, 8.68.

Example 112 5- (4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazin-6-yl ) -4-n-propyl-thiophene Spiro- (4,1'-cyclohexane-1,4-dihydro-2-oxo-2H-3,1 according to 2-carbonitrile method B
-Benzoxazin-6-yl) boronic acid and 2-bromo-3-n-propyl-5-thiophenecarbonitrile. White crystals: mp 160-162 ° C. IR (KBr) 2220cm ^-1 . ¹ H
-NMR (DMSO-d ₆ ) δ 10.47 (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 [MH ] - 325. _{C 18 H 18 N 2 O 2} S · 3 / 4H 2 O Analysis Calculated: C, 63.60, H, 5.7
8, N, 8.24. Found: C, 63.48, H, 5.59, N, 8.04.

Example 113 5- (4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazin-6-yl ) -4-n-butyl-thiophene Spiro- (4,1'-cyclohexane-1,4-dihydro-2-oxo-2H-3,1 according to 2-carbonitrile method B
-Benzoxazin-6-yl) boronic acid and 2-bromo-3-n-butyl-5-thiophenecarbonitrile. White crystals: mp 167-168 ° C. ¹ H-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, 3
H, J = 7.4Hz). MS (-ESI) m / z [ MH] - 339. Calculated value for C ₁₉ H ₂₀ N ₂ O ₂ S ・ 1 / 4H ₂ O: C
, 66.16, H, 5.99, N, 8.12. Found: C, 66.33, H, 5.92, N, 7.85.

Example 114 6- (4-Cyano-3-fluoro) -4,4-dimethyl-1,4-dihydrobenzo [d] [1,3] oxadi
4-cyano-3-fluoro-bromobenzene (0.6 g, 3.0 mmol) and tetrakis (triphenylphosphine) palladium (2--2- one ethylene glycol dimethyl ether (20 mL)
0) (0.2 g) was stirred under N ₂ for 20 minutes. The mixture was then added to (1,4) in water (5 mL).
-Dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl) boronic acid (1.
0 g, 4.5 mmol) and sodium carbonate (1.1 g, 10.6 mmol). The solution was refluxed for 18 hours, then cooled to room temperature, poured into 2N NaOH and extracted with EtOAc (3x50mL). The combined extracts were washed with water, brine, dried (MgSO _4), and evaporated. The residue was purified by column chromatography (SiO ₂ , EtOAc: hexane = 1: 2) to give the title compound (0.05 g, 6%) as an off-white solid: mp 272-275 ° C .; ¹ H -NM
R (DMSO-d ₆ ) δ10.4 (s, 1H), 8.0 (t, 1H, J = 7.7Hz), 7.9 (dd, 1H, J = 10.3, 1.3H
z), 7.8 (dd, 1H, J = 6.8, 1.4Hz), 7.7 (m, 2H), 6.9 (d, 1H, H = 8.9Hz), 1.7 (s, 6
H); MS (EI) M ⁺ @ m / z 296.

[0214] Example 115 6- (4-fluoro - phenyl) -4,4-dimethyl-1,4-dihydro - benzo [d] [1,3] Okisaji emission-2 according to one Method B (l, 4 -Dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxin-6
-Yl) boronic acid and 1-bromo-4-fluorobenzene. Yellowish-white crystals: mp 232-233 ° C. ¹ H-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).

[0215] Example 116 6- (3,4-Difluoro-phenyl) - 4,4-dimethyl-1,4-dihydro - benzo [d] [1,3] according Oki spoon-2-one method B (1 , 4-Dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxin-6
-Yl) boronic acid and 1-bromo-3,4-difluorobenzene. Yellowish-white crystals: mp 207-208 ° C. ¹ H-NMR (DMSO-d ₆ ) δ 10.35 (s, 1H), 7.79 (m, 1
H), 7.40-7.63 (m, 4H), 6.95 (d, 1H, J = 8.9Hz), 1.62 (s, 6H).

Example 117 6- (2-Fluoro-phenyl) -4,4-dimethyl-1,4-dihydro-benzo [d] [1,3] -oxa
Zin-2-one Method B (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxin-6
-Yl) boronic acid and 1-bromo-2-fluorobenzene. Yellowish-white crystals: mp 164-165 ° C. ¹ H-NMR (DMSO-d ₆ ) δ 10.33 (s, 1H), 7.56 (m, 1H),
7.25-7.45 (m, 4H), 6.98 (d, 1H, J = 8.7Hz), 1.64 (s, 6H).

Example 118 3- (4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazin-6-yl ) phenylacetonitrile 3-bromophenylacetonitrile and (1,4-dihydro-4,4-dimethyl-2-oxo-
2H-3,1-6-yl) boronic acid. White solid: mp 188-190 ° C; ¹ H-NMR (DM
SO-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 (MH). _{C 18 H 16 N 2 O 2} · 0.3H 2 O of Calcd: C, 72.61, H, 5.62 , N,
9.41. Found: C, 73.00, H, 5.43, N, 8.81.

Example 119 5- (4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazin-6-yl ) -furan-2-carbonitrile The compound was treated according to Method B with 2-bromo-5-cyanofuran (1.0 g, 5.6 mmol) (J. Med
Chem. (1997), 40 (23), 3804-3819) and (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl) boronic acid (1.8 g, 8.18 mmol) to a white solid (0
.39 g, 1.45 mmol, 17%): mp 257-260 ° C .; ¹ H-NMR (DMSO-d ₆ ) δ10.
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) ⁺ .

Example 120 3- (4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazin-6-yl ) -2-fluoro-benzonitrile nitrogen Under dry methanol (5 mL) 3-bromo-2-fluorobenzoic acid (0.219 g, 1 mm
ol) with trimethyl orthoformate (0.22 mL, 2 mmol) and p-toluenesulfonic acid (
Catalytic amount) and then heated under reflux. The mixture was evaporated after 16 hours, the residue was partitioned between water and Et ₂ O, wash the organic layer saturated sodium hydrogen carbonate solution, water, brine, dried (MgSO _4), evaporated to 3-bromo Methyl 2-fluorobenzoate
(0.195 g, 0.84 mmol, 84%) obtained: ¹ H-NMR (CDCl ₃ ) δ7.90-7.85 (m, 1H), 7.71-7
.65 (m, 1H), 7.10 (dt, 1H, J = 8.0, 1.0 Hz), 3.94 (s, 3H): MS (EI) 232 (M ⁺ ).

The last listed compound (3.077 g, 13.2 mm) in dry toluene (80 mL) at −78 ° C. under nitrogen
ol) in di-iso-butylaluminum hydride in toluene (1 M, 15.7 mL, 15.7 mL).
mmol). After 1 hour at -78 ° C, the mixture was quenched with aqueous HCl (3M, 16mL).
The mixture was warmed to RT, partitioned between EtOAc / H ₂ O, the aqueous layer was re-extracted with EtOAc, the combined organic layers washed with water, dried (MgSO _4), evaporated 3-bromo-2 -Fluorobenzaldehyde (2.63 g, 12.9 mmol, 98%) was obtained, which was used without further purification: ¹ HN
MR (CDCl ₃ ) δ 10.35 (s, 1H), 7.82 (m, 2H), 7.18 (t, 7.8 Hz), last listed compound (2.63 g, 12.9 mmol), hydroxylamine hydrochloride (1.0 g, 14
mmol) and potassium acetate (1.37 g, 14 mmol) in ethanol / H ₂ O (60 mL, 8: 2)
And heated the mixture under reflux. After 30 minutes the mixture was cooled, evaporated and Et
Partitioned between OAc and water. The organic layer was washed with brine, dried (MgSO _4), evaporated to give 3-bromo-2-fluoro-benzaldoxime, was used without further characterization it.

A solution of the last listed compound (0.75 g, 3.43 mmol) and tetrakis (triphenylphosphine) palladium (0) (0.2 g) was stirred in dimethoxyethane (30 mL) at room temperature under nitrogen. After 15 minutes (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-
Benzoxazin-6-yl) boronic acid (1.1 g, 5.0 mmol) and sodium carbonate (1.35 g) were added and the mixture was heated under reflux. The mixture was cooled after 16 h, and partitioned between water and EtOAc, washed organic layer saturated sodium carbonate solution, brine, dried (MgSO _4), and evaporated. The residue was then dissolved in acetonitrile (50 mL) and copper acetate (0.2 g)
And heated under reflux. After 16 hours, the mixture was cooled and evaporated. The residue was partitioned between water and EtOAc, then the organic layer was washed with dilute sulfuric acid (1N), water, brine,
Dried (MgSO ₄ ) and evaporated. Then subjecting the residue to column chromatography (SiO _2, EtOAc / hexane, gradient elution), followed by the title compound was crystallized from EtOAc- hexane (0.176 g, 0.59 mmol, 17%) as a white solid: mp 192-198 ° C; ¹ H-
NMR (CDCl ₃ ) δ9.15 (s, 1H), 7.69-7.58 (m, 2H), 7.42-7.31 (m, 3H), 6.99 (d, 1
H, J = 8.2 Hz), 1.78 (s, 6H); MS ((+) ESI) 297 [M + H] ⁺ .

Example 121-Pharmacology Compounds of the invention are tested in related assays as described below, and their potency ranges from 0.01 nM to 5 μM in in vitro assays, and from 0.001 to 300 mg / kg in in vivo assays. It is.

[0223]

[Table 1]

[0224]

[Table 2]

ND, not determined; ** Percentage of inhibition at specified doses A. In vitro biology In vitro biology is based on (1) competitive radioligand binding: progesterone as a radioligand and human progesterone receptor A form Using (2) agonist EC
Cotransfection assay that gives functional activity expressed as IC50 and antagonist IC50 values; (3) T47D cell proliferation, a further functional assay that also provides agonist and antagonist data; and (4) also provides agonist and antagonist data As determined by a further functional assay, the T47D cell alkaline phosphatase assay.

1. hPR binding assay -This assay was performed according to the method of Pathirana, C .; Stein, RB; Berger,
TS; Fenical, W .; Ianiro, T .; Mais, DE; Torres, A .; Glodman, ME
, Nonsteroidal human progesterone receptor modulators from the marine al
Performed according to ga cymoplia barbata, J. Steroid Biochem. Mol. Biol., 1992, 41, 733-738.

2. PRE-Luciferase Assay in CV-1 Cells The purpose of this assay was to determine the progesterone or anti-progesterone potency of the compounds in human PR and PRE-luciferase reporter activity in CV-1 cells co-transfected with the PRE-luciferase plasmid. Is determined based on its effect on

A. Medium : Growth medium was as follows: 10% (v / v) fetal calf serum (heat inactivated), 0.1 mM MEM non-essential amino acids, 100 U / ml penicillin, 100 mg / ml DMEM (Bio Whittaker) containing streptomycin and 2 mM GlutaMax (GIBCO, BRL). The experimental medium was as follows: 10% (v / v) charcoal stripped fetal calf serum (heat inactivated), 0.1 mM MEM non-essential amino acids, 100 U / ml penicillin, 100 mg / ml streptomycin and 2 mM GlutaMax (GIBCO, BRL) containing DMEM (Bio Whittaker), not containing phenol red.

B. Cell Culture, Transfection, Treatment and Luciferase Assay Maintain stock CV-1 cells in growth medium. Cotransfection is 250m
1.2x10 ⁷ cells in l, 5 mg of pLEM plasmid hPR-B is inserted in the Sph1 and BamHI sites, ultrasound 50mg as pGL3 plasmid and carrier DNA of 10mg having two PRE upstream of the luciferase sequence Performed using the treated bovine thymus DNA. Electroporation is performed at 260 V and 1,000 mF on a Biorad Gene Pulser II. After electroporation, the cells are resuspended in growth medium and plated at 40,000 cells / well in 200 μl in 96-well plates. After overnight incubation, the medium is replaced with experimental medium. The cells are then treated with a reference or test compound in experimental medium. Compounds are tested for antiprogesterone activity in the presence of 3 nM progesterone. The medium is discarded 24 hours after the treatment, and the cells are washed three times with D-PBS (GIBCO, BRL). Add 50 μl of cell lysis buffer (Promega, Madison, WI) to each well and plate
Shake for 15 minutes on a Plate Shaker (Lab Line Instrument, Inc.). Luciferase activity is measured using a luciferase reagent from Promega.

C. Analysis of Results: Each treatment consists of at least four replicates. The log transformed data is used for analysis of variance in both agonist and antagonist modes and nonlinear dose response curve adjustment. Huber weighting is used to weight down the effects of outliers. EC ₅₀ or
The IC ₅₀ value is calculated from the reconverted value. JMP software (SAS Institute, Inc.) is used for both one-way analysis of variance and non-linear response analysis.

D. Reference compounds progesterone and trimegestone are reference progestins and RU486
Is a reference antiprogestin. All reference compounds are tested in a full dose response curve and EC ₅₀ or IC ₅₀ values are calculated.

[0232]

[Table 3]

[0233]

[Table 4]

Progesterone activity: Compounds that significantly (p <0.05) increase PRE-luciferase activity compared to vehicle controls are considered active.

Anti-progesterone activity: Compounds that significantly (p <0.05) reduce 3 nM progesterone-induced PRE-luciferase activity.

EC ₅₀ : concentration of compound that gives half the maximal increase in PRE-luciferase activity in SE (
(Default nM).

IC ₅₀ : concentration of compound that gives half the maximal decrease in PRE-luciferase activity induced by 3 nM progesterone in SE (default nM).

3. T47D Cell Proliferation Assay The purpose of this assay is to determine progesterone and anti-progesterone potency by using a cell proliferation assay on T47D cells. The effect of the compound on DNA synthesis in T47D cells is determined. Materials and methods used in this assay are as follows.

A. Growth medium : DM supplemented with 10% (v / v) fetal calf serum (not heat-inactivated), 100 U / ml penicillin, 100 mg / ml streptomycin and 2 mM GlutaMax (GIBCO, BRL).
EM: F12 (1: 1) (GIBCO, BRL).

B. Treatment medium : 0.5% charcoal stripped fetal calf serum, 100 U / ml penicillin, 200
Minimum essential medium (MEM) (# 51200-038GIBCO, BRL) supplemented with mg / ml streptomycin and 2 mM GlutaMax (GIBCO, BRL), without phenol red.

C. Cell Culture Stock T47D cells are maintained in growth medium. For BrdU incorporation assay,
Cells are plated in 96-well plates at 10,000 cells / well in growth medium (Falcon, Becton Dickinson
Labware). After overnight incubation, the medium is changed to treatment medium and the cells are cultured for an additional 24 hours before treatment. Stock compounds are dissolved in a suitable vehicle (100% ethanol or 50% ethanol / 50% DMSO), then diluted in treatment medium and added to the cells. Progestin and antiprogestin reference compounds are tested in the full dose response curve. The final concentration of excipient is 0.1%. In control wells, cells receive vehicle only. Antiprogestins are tested in the presence of 0.03 nM trimegestone, a reference progestin agonist. The medium was discarded 24 hours after treatment and cells were treated with 10 mM BrdU (Amersham Life Science, Arlington Heig) in treatment medium.
hts, IL) for 4 hours.

D. Cell Proliferation Assay At the end of BrdU labeling, the media was removed and a cell proliferation ELISA kit (# RPN250, Amersha
m Life Science) according to the manufacturer's instructions to measure BrdU incorporation. Briefly, cells are fixed in ethanol containing fixative for 30 minutes, followed by incubation in blocking buffer for 30 minutes to reduce background. Peroxidase labeled anti-BrdU antibody is added to the wells and incubated for 60 minutes. The cells are rinsed three times with PBS and incubated with 3,3 ', 5,5'-tetramethylbenzidine (TMB) substrate for 10-20 minutes depending on the potency of the test compound. Then 25 μl of 1 M sulfuric acid is added to each well to stop the color reaction and the optical density is read at 450 nm in a plate reader within 5 minutes.

E. Analysis of Results: Analysis of variance in both agonist and antagonist modes and use of square root transformed data for nonlinear dose response curve adjustment. Huber weighting is used to weight down the effects of outliers. The EC ₅₀ or IC ₅₀ values are calculated from the reconverted values. JMP software (SAS Institute, Inc.) is used for both one-way analysis of variance and non-linear dose response analysis in both single dose and dose response studies.

F. The reference compounds trimegestone and medroxyprogesterone acetate (MPA) are reference progestins, and RU486 is a reference antiprogestin. All reference compounds are tested in a full dose response curve and EC ₅₀ or IC ₅₀ values are calculated.

[0245]

[Table 5]

[0246]

[Table 6]

EC ₅₀ : concentration of compound that gives half the maximum increase in BrdU incorporation in SE; IC ₅₀ : 0.2 in SE.
1 Concentration of compound giving half the maximal decrease in BrdU incorporation induced by trimegestone.

4. T47D Cell Alkaline Phosphatase Assay The purpose of this assay is to identify progestins or antiprogestins by determining the effect of a compound on alkaline phosphatase activity in T47D cells. Materials and methods used in this assay are as follows.

A. Culture medium : 5% (v / v) charcoal stripped fetal calf serum (not heat inactivated)
), 100 U / ml penicillin, 100 μg / ml streptomycin and 2 mM GlutaMax (GIBCO,
DMEM: F12 (1: 1) supplemented with BRL) (GIBCO, BRL).

B. Alkaline phosphatase assay buffer : I. 0.1 M Tris-HCl, pH 9.8 containing 0.2% Triton X-100, 0.1 M Tris-HCl, containing 4 mM p-nitrophenyl phosphate (Sigma), pH 9.8 c. Cell culture and treatment: Frozen T47D cells were thawed in a 37 ° C. water bath and diluted to 280,000 cells / ml in culture medium. For each well in a 96-well plate (Falcon, Becton Dickinson Labware), add 180
μl of the diluted cell suspension was added. 20 μl of reference or test compound diluted in culture medium was then added to each well. When testing for progestin antagonist activity, a reference antiprogestin or test compound was added in the presence of 1 nM progesterone. Cells were incubated for 24 hours at 37 ° C. in a 5% CO ₂ / humidified atmosphere.

D. Alkaline phosphatase enzyme assay: At the end of the treatment, the media was removed from the plate and 50 μl of assay buffer I was added to each well. Plates were shaken on a titer plate shaker for 15 minutes. Then 15
0 μl of assay buffer II was added to each well. Optical density measurements were taken at a test wavelength of 405 nM at 5 minute intervals for 30 minutes.

E. Analysis of Results : Dose-response curves were plotted against dose (X-axis) versus rate of enzymatic response (D- Response data analysis criteria and test compound).
(Tilt) (Y axis). The square root transformed data is used for analysis of variance in both agonist and antagonist modes and nonlinear dose response curve adjustment. Huber weighting is used to weight down the effects of outliers. The EC ₅₀ or IC ₅₀ values are calculated from the reconverted values. JMP software (SAS Institute, Inc.) for both one-way analysis of variance and nonlinear dose-response analysis in both single-dose and dose-response studies
Is used.

F. Reference compounds; progesterone and trimegestone are reference progestins and RU486
Is a reference antiprogestin. All reference compounds are tested in a full dose response curve and EC ₅₀ or IC ₅₀ values are calculated.

[0254]

[Table 7]

[0255]

[Table 8]

B. In Vivo Biology The first in vivo assay is a rat shedding model that can be used to determine both agonist and antagonist progesterone effects. The second in vivo assay is a rat ovulation inhibition model, which is under development and therefore no protocol is available.

1. Rat Shedding Assay The purpose of this method is to evaluate the effect of progestins and antiprogestins on rat uterine shedding and to compare the relative efficacy of various test compounds. Materials and methods used in this assay are as follows.

A. Method : The test compound is dissolved in 100% ethanol and mixed with corn oil (excipient). A stock solution of the test compound in an oil (Mazola ^™ ) is then prepared by heating the mixture (〜80 ° C.) and evaporating the ethanol. The test compound is subsequently diluted with 100% corn oil or 10% ethanol in corn oil before treatment of the animals. No difference in decidualization reaction was observed when comparing the two excipients.

B. Animals (RACUC protocol # 5002) Ovariectomized adult female Sprague-Dawley rats (〜60 days and 230 g) are obtained from Taconic (Taconic Farms, NY) after surgery.
Ovariectomy is performed at least 10 days prior to treatment to reduce circulating sex steroids. Animals are housed under a 12-hour light-dark cycle and are fed standard rat chow and water ad libitum.

C. Treated rats are weighed and randomly assigned to groups of 4 or 5 prior to treatment. Test compounds in 0.2 ml of vehicle are administered by subcutaneous injection in the scruff or by gavage using 0.5 ml. Animals are treated once daily for 7 days. To test antiprogestin, animals receive test compound and an EC ₅₀ dose of progesterone (5.6 mg / kg) for the first three days of treatment. Following decidual stimulation, animals continue to receive progesterone until necropsy 4 days later.

[0261] d. Dosages are prepared based on mg / kg mean group body weight. All studies include a control group receiving vehicle. Determination of the dose-response curve is performed using doses that have a half log increase (eg, 0.1, 0.3, 1.0, 3.0 mg / kg ..).

E. About 24 hours after the third injection of decidual induction, a blunt 21G needle is used to prevent
rial) Induces shedding in one of the uterine horns by scratching the luminal epithelium. The opposite corner is not scratched and serves as an unstimulated control. Approximately 24 hours after the last treatment, the rats are killed by CO ₂ asphyxiation and weighed. Remove the uterus and remove fat. The shedding (D-horn) and control (C-horn) uterine horns are weighed separately.

F. Analysis of Results : The weight gain of sloughed uterine horns is calculated by the D-angle / C-angle and the log transformation is used to maximize the normality and homogeneity of the variance. The Huber M-estimator is used to down-weight transformation results outside of both the dose-response curve adjustment and the one-way analysis of variance. JMP software (SAS In) for both one-way ANOVA and nonlinear dose-response analysis
stitute, Inc.).

[0264] g. Reference compound All progestin reference compounds were tested in full dose response curves, and calculate the weight EC ₅₀ of wet uterus.

[0265]

[Table 9]

[0266]

[Table 10]

[0267]

[Table 11]

Concentration: concentration of compound in assay (default mg / kg body weight) Route of administration: route of administration of compound to animals Body weight: average total animal body weight (default kg) D-horn: wet weight of shed uterine horn (default) mg) C-horn: wet weight of control uterine horn (default mg) Decidual reaction: [(DC) / C] x 100% progesterone activity: significantly (p <0.05) induced shedding compared to vehicle control Are considered active.

Anti-progesterone activity: Significantly decreased EC ₅₀ progesterone-induced shedding (p
<0.05) Decreasing compounds.

EC _{50 of} Uterine Weight: The concentration of the compound that gives half the maximal increase in the decidual response (default mg / kg).

Uterine Weight IC ₅₀ : EC ₅₀ The concentration of the compound that gives half the maximal reduction of the decidual response induced by progesterone (default mg / kg).

Example 122 6- (3-Methoxyphenyl) spiro [4H-3,1-benzoxazine-4,1-cyclobutane] -2 ( 1H) -one Boc-protected 4-chloroaniline in anhydrous THF A solution of 1.15 g, 5 mmol) was treated with t-butyllithium (7.4 mL, 12.5 mmol) at -78 ° C under a blanket of nitrogen. The reaction solution was then slowly warmed to -20 ° C, kept stirring for 1.5 hours, and cyclobutanone (1
mL, 13.4 mmol). The mixture was warmed to rt, quenched with brine (30 mL), and 1N aqueous hydrogen chloride (10 mL) was added. Ethyl acetate was added, the organic layer was separated, dried (MgSO _4). After removing the solvent, the residue was purified by flash column chromatography (hexane: ethyl acetate / 3: 1) to give the alcohol, which was used for the next step without further purification.

To a solution of the above product in ethanol was added potassium hydroxide (2 g). The reaction mixture was stirred at rt for 18 h, followed by brine (20 mL) and cold 1 N aqueous hydrogen chloride (20 mL)
Was added. The precipitate is collected on a filter, washed with water and washed with 6-chlorospiro [4H-3,1-
Benzoxazine-4,1-cyclobutane] -2 (1H) -one was converted to a white solid (0.13 g, 12
%): Mp 183-184 ° C; MS (ESI) m / z 222 [MH] ^- .

6-chlorospiro [4H-3,1-benzoxazine-4,1-cyclobutane] -2 (1H) -one (0.1 g, 0.45 mmol) in dioxane (5 mL), 3-methoxyphenylboronic acid (0.1 g, 0.66mmo
l), [1,1′-bis (diphenylphosphino) ferrocene] dichloronickel (II) (50 m
g, 0.073 mmol) and potassium phosphate (0.35 g, 1.7 mmol) were degassed to remove oxygen and then heated at 85 ° C. for 72 hours under a blanket of nitrogen. The reaction mixture was allowed to cool to rt. Ethyl acetate (30 mL) and brine (20 mL) were added. The organic layer was separated, dried (MgSO _4). After removing the solvent, the residue was purified by column chromatography (hexane: ethyl acetate / 3: 1) to give 6- (3-methoxy-phenyl) spiro [4H-3,1-benzoxazine-4,1-cyclobutane ] -2 (1H) -one was obtained as a white solid (18 mg, 14%): mp 145-146 ° C; ¹ H-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), 2.45-2.62 (m, 4H), 1.81-2.12 (m, 2H); MS ((+) APCI) m / z 296 [M + H
] ⁺ .

Example 123 8-Bromo-6- (3-chloro-4-fluorophenyl) -4,4-dimethyl-1,4-dihydro-2H-3,1- benzoxazin-2-oneacetic acid (5 mL) 6- (3-chloro-4-fluorophenyl) -4,4-dimethyl-1,4-dihydro
-2H-3,1-benzoxazin-2-one (0.2 g, 0.65 mmol) and sodium acetate (0.1 g, 1.
To a mixture of (2 mmol) was added bromine (0.04 mL, 0.78 mmol) at rt under nitrogen. The reaction mixture
Stirred for 20 hours and poured into ice water (30 mL). Collect the precipitate on the filter and add water (3 x 5 mL
) To give 8-bromo-6- (3-chloro-4-fluorophenyl) -4,4-dimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one as a yellowish white Obtained as a solid (0.18, 72%): mp 194-195 ° C .; ¹ H-NMR (DMSO-d ₆ ) δ 9.77 (s, 1 H), 8.02 (dd, 1 H, 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 [MH] ^- .

Example 124 3- (8-Bromo-4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazine-6-
Yl) -5-fluorobenzonitrile 3- (4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl) -5-fluorobenzonitrile ( 0.5 g, 1.7 mmol) as an off-white solid (0.48 g, 75%): mp 216-217 ° C .; ¹ H-NMR (DMSO-d ₆ ) δ9
.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 [MH] ^- .

Example 125 5- (8-Bromo-4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazine-6-
Yl) -2-fluorobenzonitrile 5- (4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl) -2-fluorobenzonitrile ( Prepared from 0.2 g, 0.67 mmol) as an off-white solid (0.18 g, 72%): mp 235-236 ° C .; ¹ H-NMR (DMSO-d ₆ )
δ9.78 (s, 1H), 8.38 (dd, 1H, J = 6.1, 2.4Hz), 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 (E
SI) m / z 373, 375 [MH] ^- .

Example 126 6- (3-Bromophenyl) -1,4,4-trimethyl-1,4-dihydro-2H-3,1-benzoxadi
Down 2-one in anhydrous DMF 6- (3-bromophenyl) -4,4-dimethyl-1,4-hydro-2H-3,1-benzoxazin-2-one (1 g, 3.0 mmol) to a solution of Sodium hydride (60% in mineral oil, 0.24 g, 6
.0 mmol) was added at rt under a blanket of nitrogen. After stirring for 20 minutes, the reaction solution was treated with iodomethane and stirred for 1.5 hours. The mixture was added to a saturated aqueous solution of ammonium sulfate (
(40 mL) and ethyl acetate (40 mL) was added. Separate the organic layer and dry (MgSO ₄ )
Was evaporated to give 6- (3-bromophenyl) -1,4,4-trimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one as a yellowish white solid (0.75 g, 72 %) Obtained as: mp 14
2-143 ° C; ¹ H-NMR (DMSO-d ₆ ) δ7.93 (s, 1H), 7.71 (m, 1H), 7.65 (s, 1H), 7.55 (
d, 1H, J = 8.0Hz), 7.42 (t, 1H, 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] ^< +>.

Example 127 6- (3-Fluorophenyl) -4-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-o
Down 4-amino-3'-fluoro [1,1'-biphenyl] -3-carbonitrile was prepared from 3-fluorophenyl boronic acid and 2-amino-5-bromobenzonitrile according to Method A a. A solution of 4-amino-3′-fluoro [1,1′-biphenyl] -3-carbonitrile (6.65 g, 31.3 mmol) in anhydrous THF (100 mL) was treated with methyl magnesium bromide (3.0 M in ether,
(21 mL, 63 mmol) treated dropwise with rt under nitrogen. After the addition, the reaction mixture was heated at gentle reflux for 1.5 hours, cooled to rt, and treated with 3N aqueous hydrogen chloride (30 mL).
The mixture was heated at reflux for 3 hours, cooled to ambient temperature and adjusted to pH 5-6 by the addition of saturated aqueous sodium carbonate. Ethyl acetate (100 mL) was added, the organic layer was separated,
The aqueous layer was extracted with ethyl acetate (3x50mL). The combined organic layers were dried (MgSO _4), and evaporated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate / 3: 1) to give 1- (4-amino-3′-fluoro [1,1′-biphenyl] -3-yl).
Ethanone (3.1 g, 43%) was obtained: mp 156-157 ° C.

1- (4-Amino-3′-fluoro [1,1′-biphenyl] -3-in anhydrous methanol (60 mL)
Yl) ethanone (3 g, 13 mmol) in sodium borohydride under nitrogen at rt
It was processed one by one. After the addition, the reaction mixture was stirred for 4 hours,
The solution was treated with (50 mL) and ethyl acetate (100 mL). The organic layer was separated, dried (MgSO _Four ), Evaporated. The residue was subjected to silica gel column chromatography (hexane: vinegar)
Ethyl acid / 3: 1) to give 1- (4-amino-3'-fluoro [1,1'-biphenyl] -3-
Yl) Ethanol was obtained as a white solid (2 g, 67%): mp 136-137 ° C.

A mixture of the above alcohol (0.2 g, 0.87 mmol) and triphosgene in anhydrous THF (20 mL) was stirred at rt under nitrogen. After 15 minutes, the mixture was washed with saturated aqueous sodium bicarbonate (3.
0 mL) and ethyl acetate (40 mL). The organic layer was separated, dried (MgSO ₄ ) and evaporated to give 6- (3-fluorophenyl) -4-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one as a white solid (0.18 g, 81%): mp 160-161 ° C .; ¹ H-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), 1.6
3 (d, 3H, J = 6.6Hz). MS (ESI) m / z 256 [MH] ^- .

Example 128 3- (4,4-Dimethyl-8-methoxy-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6 -yl) -5-fluorobenzonitrile Anhydrous THF ( To a solution of 2-amino-3-methoxybenzoic acid (5 g, 30 mmol) in 100 mL) was added methyl magnesium bromide (3.0 M in THF, 50 mL, 150 mmol) at ambient temperature under a blanket of nitrogen. The reaction mixture was heated at 50 ° C. for 18 hours, cooled to rt, and treated with a saturated aqueous solution of ammonium chloride (50 mL). Ethyl acetate (100 mL) was added, the organic layer was separated,
Dried (MgSO ₄ ) and evaporated. The residue was dissolved in anhydrous THF (100 mL) and treated with 1,1'-carbonyldiimidazole (5.4 g, 33 mmol) under nitrogen at ambient temperature. After 24 hours, the mixture was quenched with 1N aqueous hydrogen chloride (30 mL). Ethyl acetate (100 mL) was added and the organic layer was separated, dried (MgSO _4), and evaporated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate / 3: 1) to give 8-methoxy-4,4.
-Dimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one as a white solid (3.5 g, 56
%): MS (ESI) m / z 208 [M + H] ^< +>.

8-Methoxy-4,4-dimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (2.1 g, 10.1 mmol) in acetic acid (30 mL), sodium acetate (1.5 g, To a mixture of (18 mmol) was added bromine (0.62 mL, 12 mmol) at ambient temperature. After 30 minutes, the solution is concentrated ammonium hydroxide solution
(50 mL). The precipitate was collected on a filter, washed with water (3x20 mL) and washed with 6-bromo-8-methoxy-4,4-dimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (2.7
g, 93%) as an off-white solid: MS (ESI) m / z 286, 288 [M + H] ⁺ .

6-Bromo-8-methoxy-4,4-dimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (1.6 g, 5.6 mmol) in DMF (30 mL), bis ( Pinacolato) diboron (1.6 g, 6.3 mmol
), Potassium acetate (1.5 g, 15.3 mmol) and [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) chloride (1: 1 complex with methylene chloride, 0.5 g, 0.6 mmol). Subject to a positive stream of nitrogen to remove oxygen, then 85 ° C under a nitrogen blanket
For 18 hours. The reaction mixture was allowed to cool to ambient temperature and 3-bromo in water (10 mL)
-5-fluoro-benzonitrile (1.2 g, 6 mmol), [1,1'-bis (diphenylphosphino) -ferrocene] palladium (II) chloride (1: 1 complex with methylene chloride, 0.5 g, 0.6
mmol) and sodium carbonate (2 g, 19 mmol). The resulting solution was heated at 85 ° C. for 3 hours under a blanket of nitrogen, cooled to rt, and treated with brine (50 mL). Ethyl acetate (100 mL) was added and the organic layer was separated, dried (MgSO _4), and evaporated. The residue was purified by flash silica gel column chromatography (THF: hexane / 2: 3) to give 3- (4,4-dimethyl-8-methoxy-2-oxo-1,4-dihydro-2H-3,1- Benzoxazin-6-yl) -5-fluorobenzonitrile was obtained as a white solid (0.6 g, 33%): mp 252-253 ° C .; ¹ H-NMR (DMSO-d ₆ ) δ 9.76 (s, 1H) ), 8.21 (s, 1H), 8.07 (d, 1
H, J = 10.6Hz), 7.82 (m, 1H), 7.39 (s, 1H), 7.36 (s, 1H), 3.93 (s, 3H), 1.66 (s
, 6H). MS (ESI) m / z 325 [MH] ^- .

Example 129 3- (4,4-Dimethyl-8-hydroxy-2-oxo-1,4-dihydro-2H-3,1-benzoxazin -6-yl) -5-fluorobenzonitrile 2,4 3- (4,4-Dimethyl-8-methoxy-2-oxo-1,4-dihydro-2H- in, 6-collidine
A mixture of 3,1-benzoxazin-6-yl) -5-fluorobenzonitrile (0.1 g, 0.31 mmol) and lithium iodide (0.3 g, 2.24 mmol) was heated at reflux under nitrogen for 5 hours. The solvent was removed in vacuo and the residue was dissolved in a mixture of brine (10mL) and ethyl acetate (30mL). The organic layer was separated, dried (MgSO _4), and evaporated. The residue obtained was purified on silica gel column chromatography (hexane: ethyl acetate / 1: 1) to give the title compound as a white plate (0.03 mg, 31%): mp 197-198 ° C .; ¹ H -NMR (DMS
Od ₆ ) δ10.16 (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 / z 311 [MH] ^- .

[0286] Example 130 6- (2,3-Difluoro-phenyl) - 4,4-dimethyl-1,4-dihydro - benzo [d] [1,3] according Oki spoon-2-one method B (1 , 4-Dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazine
-6-yl) boronic acid and 2,3-difluorobenzyl triflate. Yellow solid: mp 166-167 ° C .; ¹ H-NMR (DMSO-d ₆ ) δ 10.4 (s, 1 H), 7.5-7.2 (m, 5 H), 7
MS (EI) m / z 289 ([M + H] ⁺ ); calcd for C ₁₆ H ₁₃ F ₂ NO ₂ : .C, 66.43, .0 (m, 1H), 1.7 (s, 6H); H, 4.53, N, 4.84. Found: C, 66.15, H, 4.37, N, 4.64.

[0287] Example 131 3- (1-ethyl-4,4-dimethyl-2-oxo-1,4-dihydro -2H- benzo [d] [1,3] Okisaji down-6-yl) -5- Fluoro-benzonitrile 3- (4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo
Prepared from [d] [1,3] oxazin-6-yl) -5-fluoro-benzonitrile. White solid: mp 154-155 ° C .; ¹ H-NMR (DMSO-d ₆ ) δ 8.17 (s, 1H), 8.03 (d, 1H, J = 10.5H)
z), 7.84-7.77 (m, 3H), 7.27 (d, 1H, J = 8.54Hz), 3.97 (q, 2H, J = 6.89Hz), 1.67 (
s, 6H), 1.21 (t, 3H, J = 6.95 Hz); MS (EI) m / z 324 ([M + H] ⁺ ); Calculated value for C ₁₉ H ₁₇ FN ₂ O ₂ : C, 70.36. , H, 5.28, N, 8.64. Found: C, 70.33, H, 5.51, N, 8.48
.

[0288] Example 132 according to [6- (4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazine-6-yl) pyrimidin-2-yl] acetonitrile The method B ( 1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazine
-6-yl) boronic acid and (6-bromo-2-pyridyl) acetonitrile (J. Org. Chem. 19)
88, 53, 786-790). Yellowish-white solid: mp 210-212.5 ° C. ¹ H
NMR (DMSO-d ₆ ) δ 1.68 (s, 6H), 4.27 (s, 2H), 7.00 (d, 1H, J = 8.3 Hz), 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
) [MH] ^- = 292. Calcd _{C 17 H 15 N 3 O 2} : C, 69.61, H, 5.15, N, 14.33. Found: C, 68.49, H, 5.19, N, 13.74.

Example 133 3- (4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] -oxazin-6-i
3-bromo-5-fluorobenzaldehyde (22.25 g, 0.11 mol ) in methanol with 5-fluoro-phenylacetonitrile rt
)) Was added to NaBH ₄ (2.07 g, 0.055 mol), and the mixture was stirred at rt for 2 hours. The reaction was quenched with H ₂ O, and concentrated. The residue was diluted with diethyl ether, washed with 1N HCl, brine, dried over MgSO ₄ and concentrated. 3-Bromo-5-fluorobenzyl alcohol was collected as a colorless oil (14.6 g, 65%). ¹ H-NMR (DMSO-d ₆ ) δ4.50 (m, 2
H), 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 7 H 6 Br 2 FO Calcd: C, 41.01, H, 2.95 . Found: C, 41.30, H, 3.01.

[0290] CH_TwoCl_Two3-bromo-5-fluorobenzyl alcohol (2.3 g, 0.011 mol) in (15 mL)
12.4 mL of 1.0 M PBr in a solution of_Three(3.33g, 0.0123mol) (CH_TwoCl_TwoMedium) and stir for 3 hours
And diluted with ether (100 mL),_TwoWashed with O (50 ml, 3X), MgSO_FourDried on
Concentrated. 1: 9 column chromatography using ethyl acetate / hexane as eluent solvent system
Purified by chromatography. 3-bromo-5-fluorobenzyl bromide as white crystals
Obtained as quality, mp 41-43 ° C.¹H NMR (DMSO-d₆) δ4.69 (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; C₇H _Five Br_TwoCalculated value for F: C, 31.38, H, 1.88. Found: C, 31.75, H, 1.78.

To a solution of 3-bromo-5-fluorobenzyl bromide (3.2 g, 0.0112 mol) in 1,4-dioxane (20 mL) was added KCN (0.82 g) in H ₂ O (5 ml) and EtOH (5 mL). , 0.013 mol).
Refluxed for 2 hours. Extracted with ether, washed with brine, dried over MgSO _4,
Concentrated. Purified by column chromatography using hexane / ethyl acetate (19: 1). The obtained 3-bromo-5-fluorophenylacetonitrile was a colorless oil: ¹ H-NMR (DMSO-d ₆ ) δ 4.15 (s, 2 H), 7.29 (d, 1 H, J = 9.37 Hz) ), 7.4
7 (s, 1H), 7.55 (d, 1H, J = 8.45Hz); MS (EI): M + m / z 213; C 8 H 5 BrFN Calcd: C, 44.89, H, 2.35 , N , 6.54. Found: C, 44.88, H, 2.32, N, 6.46.

The title compound was prepared according to Method B using 3-bromo-5-fluorophenylacetonitrile and
Prepared from (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl) boronic acid. A white solid was obtained and recrystallized from ethanol / ether; mp 218-220. ¹ H-NMR (DMSO-d ₆ ) δ1.67 (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 18 H 15 FN 2 O 2 Analysis Calculated: C, 69.67, H, 4.87 , N, 9.03. Found: C, 69.78, H, 4.97, N, 8.36.

Example 134 3- (4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] -oxazine-6-i
) -4-Fluoro-phenylacetonitrile CCl ₄ (150 mL) in a solution of 5-bromo-2-fluorotoluene (15 g, 0.079 mol) in NBS (
14.2 g, 0.080 mol). The resulting reaction solution was heated under reflux and the starting material was completely consumed within 2 hours. CCl ₄ was removed under reduced pressure and the residue was diluted, dissolved in ether, washed with brine (3 ×), dried over MgSO ₄ and concentrated. Purification by chromatography / hexane provided 5-bromo-2-fluorobenzyl bromide.
The product was used immediately in the following reaction.

5-Bromo-2-fluorobenzyl bromide (8.0 g, 0.03 mol) in 1,4-dioxane (60 mL)
And added with H ₂ O (20 ml) and a solution of KCN (2.04 g, 0.031 mol) in ethanol (20 mL). The resulting mixture was heated under reflux for 5 hours. After cooling to rt, the product was extracted with ether (200 mL), washed with brine, dried over MgSO _4, and concentrated. Crystallization from ether / hexane gave 5-bromo-2-fluorophenylacetonitrile as white crystalline material (5.6 g, 88%): mp 55-58 ° C; ¹ H NMR (DMSO-d ₆ ) δ.
4.07 (s, 2H), 7.29 (t, 1H, J = 9.23Hz), 7.60-7.69 (m, 2H); MS (EI) M ⁺ m / z 213
; C ₈ H ₅ Br ₂ FN Calcd: C, 44.89, H, 2.35 , N, 6.54. Found: C, 44.90, H
, 2.24, N, 6.43.

The title compound was treated with 5-bromo-2-fluorophenylacetonitrile and (1,4-dihydro
Prepared from -4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl) boronic acid. White solid; mp 184-187 ° C .; ¹ H-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) (MH) - m / z 309; C 18 H 15 FN 2 O 2 Analysis Calculated: C, 69.67, H, 4.87 , N, 9.03. Found: C, 68.71, H, 4.80, N, 8.54.

Example 135 4- (4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] -oxazine-6-i
) -2-fluorophenylacetonitrile 4-bromo-2-fluorophenylacetonitrile (T.Alessi AHP
(US Pat. No. 4,895,862) and (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl) boronic acid. Gray solid; mp 253-256 ° C. ¹ HNM
R (DMSO-d ₆ ) δ 10.35 (s, 1H), 7.67-7.49 (m, 5H), 6.97 (d, 1H; J = 8.6 Hz), 4.09
(s, 2H), 1.67 ( s, 6H); MS [MH] - m / z 309. _{C 18 H 15 N 2 FO 2} · 0.15H 2 O for Calcd: C, 69.07, H, 4.93 , N, 8.95. Found: C, 69.27, H, 5.05, N, 8.50.

Example 136 2- (4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] -oxazine-6-i
Le) was prepared from 2-bromo-phenylacetonitrile and (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazine-6-yl) boronic acid according phenylacetonitrile method B. White solid; mp 176-179 ° C. ¹ H-NMR (DMSO-d ₆ ) δ 10.31 (s, 1H), 7.53 (m, 1H), 7.48 (m
, 2H), 7.22-7.32 (m, 3H), 6.98 (d, 1H; J = 8.0 Hz), 3.90 (s, 2H), 1.64 (s, 6H).
MS (+) APCI [M + H] ⁺ m / z = 293. C ₁₈ H ₁₆ N ₂ O ₂ Analysis Calculated: C, 73.95, H, 5.52 , N,
9.58. Found: C, 73.51, H, 5.70, N, 9.39.

Example 137 N- [4- (4,4-Dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl) -2 -fluoro-phenyl-acetamide Method B According to 4'-bromo-2'-fluoroacetanilide and (1,4-dihydro-4,
Prepared from 4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl) boronic acid.
Yellowish-white solid; mp 245-247 ° C. ¹ H-NMR (DMSO-d ₆ ) 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
/ z 329. Calcd _{C 18 H 17 N 2 FO 3} : C, 65.85, H, 5.22, N, 8.53. Observed value: C,
65.46, H, 5.24, N, 8.12.

Example 138 6- (3-Fluoro-4-methoxy-phenyl) 4,4-dimethyl-1,4-dihydro-benzo [d] [1,3 ] oxazin-2-one 4- Prepared from bromo-2-fluoroanisole and (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl) boronic acid. White solid; mp 210-211 ° C. ¹ H-NMR (DMSO-d ₆ ) δ 10.27 (s, 1H), 7.52-7.60 (m, 3H), 7.4
5 (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 [MH] - m / z} = 300. Calcd _{C 17 H 16 FNO 3: C} , 67.76, H, 5
.35, N, 4.65. Found: C, 67.88, H, 5.39, N, 4.70.

Example 139 3- (4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] -oxazine-6-i
Le) was prepared from 3-bromophenyl acetonitrile and (1,4-dihydro-4,4-dimethyl-2-oxo -2H-3,1-6- yl) boronic acid according phenylacetonitrile method B. White solid; mp 188-190
° C. ¹ H-NMR (DMSO-d ₆ ) δ 10.33 (s, 1H), 7.62 (m, 2H), 7.55 (m, 2H), 7.48 (d, 1
H, 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 (MH). _{C 18 H 16 N 2 O 2} ) 2.0.3H 2 O Analysis Calculated: C, 72.6
1, H, 5.62, N, 9.41. Found: C, 73.00, H, 5.43, N, 8.81.

Example 140 3- (4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] -oxazine-6-i
Le) was prepared from 3-bromo benzenesulfonamide and (1,4-dihydro-4,4-dimethyl-2-oxo -2H-3,1-6- yl) boronic acid benzenesulfonamide method B. White solid; mp 242-244
° C (dec). ¹ H-NMR (DMSO-d ₆ ) 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), 7.4
2 (s, wide 2H), 7.02 (d, 1H, J = 8.86Hz), 1.68 (s, 6H); MS m / z 331 (M + H). _{C 16 H 16 N 2 O 4} S) Calcd: C, 57.82, H, 4.85 , N, 8.43. Found: C, 57.49, H,
5.08, N, 8.05.

Example 141 5- (4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] -oxazine-6-i
Le) - 5-Bromo-thiophene-2-sulfonamide and according thiophene-2-sulfonamide method B (1,4-dihydro-4,4
Prepared from dimethyl-2-oxo-2H-3,1-6-yl) boronic acid. White solid; mp 258
-260 ° C, ¹ H-NMR (DMSO-d ₆ ) δ 10.41 (s, 1H), 7.71 (s, 2H), 7.58 (m, 2H), 7.52 (
d, 1H, J = 3.9Hz), 7.48 (d, 1H, J = 8.16Hz), 6.95 (d, 1H, J = 8.16Hz), 1.66 (s, 6
H); MS m / z 337 (MH). _{C 14 H 14 N 2 O 4} S 2) Calcd: C, 49.69, H, 4.17 , N, 8
.28. Found: C, 49.90, H, 4.28, N, 8.12.

[0303] Example 142 6- (6-amino - pyridin-3-yl) -4,4-dimethyl-1,4-dihydro - benzo [d] [1,3] - O Kisajin-2-one Method B According to 2-amino-5-bromopyridine and (1,4-dihydro-4,4-dimethyl-2
-Oxo-2H-3,1-6-yl) boronic acid. White crystals; mp 257-259 ° C. ¹ H
-NMR (DMSO-d ₆ ) δ 10.20 (S, 1H), 8.22 (d, 1H, J = 2.38 Hz), 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 269 M +. _{C 15 H 15 N 3 O 2} · 17H 2 O Analysis Calculated: C, 66.15, H, 5.68 , N, 15.43. Found: C, 66.10, H, 5.81, N, 15.02.

Example 143 6- (5-Diethoxymethyl-furan-3-yl) -4,4-dimethyl-1,4-dihydro-benzo [d] [1,3] oxazin-2-one Method B Prepared from 4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [3] [1,3] oxazine-6-boronic acid and 3-bromo-5-diethoxymethylfuran according to Brown gum; ¹ H NMR (DMSO-d ₆ ) δ 10.2 (s, 1 H), 8.12 (s, 1 H), 7.54-7.49 (m, 2 H),
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 [MH] -; C 19 H 23 NO 5 · 1 / 2H 2 O Analysis Calculated: C, 64.39,
H, 6.77, N, 3.95. Found: C, 64.90, H, 6.79, N, 3.78.

Example 144 4- (4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazin-6-yl ) -furan-2-carbaldehyde 6 -(5-Diethoxymethyl-furan-3-yl) -4,4-dimethyl-1,4-dihydro-benzo [
A solution of d] [1,3] oxazin-2-one (1.1 g, 3 mmol) was stirred in THF (20 mL) and 2N HCl (2 mL) for 1 hour. The crystalline product was filtered and dried (0.52 g, 69%): mp 262-263
° C; ¹ H NMR (DMSO-d ₆ ) δ 10.3 (s, 1 H), 9.65 (s, 1 H), 8.59 (s, 1 H), 8.04 (s, 1 H
), 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 [MH
] ^- .

[0306] Example 145 4- (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazine-6-yl) -2-off run carboxaldehyde oxime 4- (4, 4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazin-6-yl) -furan-2-carbaldehyde (2.7 g, 10 mmol), hydroxylamine hydrochloride (0.75
G, 10.6 mmol) and sodium acetate (0.87 g, 10.6 mmol) in 80% ethanol (2
(5 mL) at reflux for 2 hours. The title compound was crystallized from the cooled reaction mixture as tan crystals (1.5 g, 52.4%): mp 236-238 ° C. _{^{1 H NMR (DMSO-d 6}} ) δ11.9
7 (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] ^- . Calcd _{C 15 H 14 N 2 O 4} : C, 62.93, H, 4.93, N, 9.79. Found: C, 62.77, H, 5.00, N, 9.
79.

All publications cited herein are hereby incorporated by reference. Although the invention has been described with respect to particularly preferred embodiments, it will be understood that it can be modified without departing from the spirit of the invention. Such modifications fall within the scope of the appended claims.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 43/00 A61P 43/00 C07D 265/18 C07D 265/18 413/04 413/04 413/10 413 / 10 C07F 9/6533 C07F 9/6533 (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT , SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, TZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AG, AL, AM, AT, AU, AZ, B , BB, BG, BR, BY, CA, CH, CN, CR, CU, CZ, DE, DK, DM, DZ, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, NO , NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG, US, UZ, VN, YU, ZA, ZW ( 72) Inventor Telehuenco, Eugene A. 18951 Quakertown Live Oak Drive, Pennsylvania, United States 266 (72) Inventor Freccia, Horace, The Third, 1964 Potstown Shear Road, Pennsylvania, United States 2382 (72) Inventor Fuentham, Andriou 19087 Wayne Trefany Lane, Pennsylvania, United States 779 (72) Inventor Blobel, J.E. 7294 (72) Inventor, Georgia, Totdo Cay, California 92075 Solana Beach, Maverick Drive, Calif., United States 546 (72) Inventor, Tegri, Christopher M. 91,360 Thousand Oaks, California, USA Thunderhead Street 478 (72) Inventor Edwards, J. Ames P. 92129, San Diego Hesbycourt, Calif., USA 8723 F-term (reference) 4C056 AA02 AB01 AC02 AD03 AD08 AE01 AF01 AF05 DA03 D A05 DB04 DB07 DC01 DC02 DC03 DC08 4C063 AA01 BB01 BB06 CC54 CC75 CC92 DD04 DD12 DD47 DD54 EE01 4C086 AA01 AA02 AA03 BC72 GA02 GA03 GA07 GA08 MA01 MA04 NA14 ZA86 ZB26 ZC42 4H050 AA01 AB20

Claims (23)

[Claims] (1) Formula (I): Wherein R ¹ and R ² are H, C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, substituted C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, substituted C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, substituted C ₃ -C ₈ cycloalkyl, aryl, substituted aryl, heterocyclic, heterocyclic substituted, COR ^A or an independent substituent selected from the group of NR ^B COR ^A ; or R ¹ and R ² are fused to a) an optionally substituted 3- to 8-membered spirocyclic alkyl ring B) optionally substituted 3-8 membered spirocyclic alkenyl ring; or
c) forming an optionally substituted 3-8 membered heterocyclic ring containing 1-3 heteroatoms from the group comprising O, S and N; a), b) and c spirocyclic rings fluorine), C ₁ ~C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C _{6 thioalkyl, -CF 3, -OH, -CN,} NH 2, -NH (C 1 ~C R ^A is H, C ₁ -C ₃ alkyl, substituted, optionally substituted with 1-4 groups selected from ₆ alkyl) or -N (C ₁ -C ₆ alkyl) ₂ ; C ₁ -C ₃ alkyl, aryl, substituted aryl, C ₁ -C ₃ alkoxy, substituted C ₁ -C ₃ alkoxy, with C ₁ -C ₃ aminoalkyl or substituted C ₁ -C ₃ aminoalkyl R ^B is H, C ₁ -C ₃ alkyl or substituted C ₁ -C ₃ alkyl; R ³ is H, OH, NH ₂ , C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl, C ₃ -C ₆ alkenyl, substituted C ₁ -C ₆ alkenyl, alkynyl or substituted alkynyl, be a COR ^C; R ^C is H, C ₁ -C ₃ alkyl, substituted C ₁ -C ₃ alkyl, aryl, substituted aryl, C ₁ ~ R ⁴ is H, halogen, CN, NO ₂ , C ₁ -C ₃ alkoxy, substituted C ₁ -C ₃ alkoxy, C ₁ -C ₃ aminoalkyl or substituted C ₁ -C ₃ aminoalkyl; C ₆ alkyl, substituted C ₁ -C ₆ alkyl, alkynyl or substituted alkynyl, C ₁ -C ₆ alkoxy, substituted C ₁ -C ₆ alkoxy, amino, C ₁ -C ₆ aminoalkyl or substituted and be a C ₁ -C ₆ aminoalkyl; R ⁵ is selected from a) or b), a) R ⁵ is a trisubstituted benzene ring containing the substituents X, Y and Z as shown below Available: Wherein: X is halogen, CN, C ₁ -C ₃ alkyl, substituted C ₁ -C ₃ alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, C ₁ -C ₃ alkoxy, substituted C ₁ -C ₃ alkoxy, C ₁ -C ₃ thioalkoxy, substituted C ₁ -C ₃ thioalkoxy, amino, C ₁ -C ₃ aminoalkyl, substituted C ₁ -C ₃ aminoalkyl, NO _2, C ₁ -C ₃ perfluoroalkyl, 1-3 heterocyclic ring of 5 or 6 membered containing heteroatoms, COR ^D, is selected from the group comprising OCOR ^D or NR ^E COR ^D; R ^D is H, C ₁ -C ₃ alkyl, substituted C ₁ -C ₃ alkyl, aryl, substituted aryl, C ₁ -C ₃ alkoxy, substituted C ₁ -C ₃ alkoxy, C ₁ -C ₃ aminoalkyl or substituted in There C ₁ -C ₃ amino alkyl; R ^E is H, C ₁ ~C ₃ alkyl or is substituted It is a C ₁ -C ₃ alkyl; Y and Z are H, halogen, CN, NO _2, amino, aminoalkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkyl or C ₁ -C ₃ thioalkoxy Or b) R ⁵ has 1, 2 or 3 heteroatoms from the group comprising O, S, SO, SO ₂ or NR ⁶ and H , halogen, CN, NO _2, amino, and C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ aminoalkyl, one or two independent from the group comprising COR ^F or NR ^G COR ^F R ^F is H, C ₁ -C ₃ alkyl, substituted C ₁ -C ₃ alkyl, aryl, substituted aryl, C ₁ -C ₃ alkoxy, substituted C ₁ -C ₃ alkoxy, C ₁ -C ₃ aminoalkyl or substituted C ₁ -C ₃ aminoalkyl; R ^G is H, C ₁ -C ₃ alkyl Or be substituted C ₁ -C ₃ alkyl; acceptable salts of the compound or its pharmaceutically; R ⁶ is H or C ₁ -C ₃ alkyl. 2. Structure: embedded image Where: R ¹ is H, C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, substituted C ₃ -C ₈ cycloalkyl, aryl, substituted aryl , heterocyclic, heterocyclic substituted, COR is ^A or NR ^B COR ^A; R ² is H, C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl , substituted C ₂ -C ₆ alkenyl, C ₃ -C ₈ cycloalkyl, substituted C ₃ -C ₈ cycloalkyl, aryl, substituted aryl, heterocyclic, heterocyclic substituted, COR ^A or be NR ^B COR ^A; R ^A is H, C ₁ -C ₃ alkyl, substituted C ₁ -C ₃ alkyl, aryl, substituted aryl, C ₁ -C ₃ alkoxy, C ₁ ~ substituted C ₃ alkoxy, C ₁ -C ₃ aminoalkyl or substituted C ₁ -C ₃ aminoalkyl; R ^B is H, C ₁ -C ₃ alkyl or substituted R ³ is H, OH, NH ₂ , C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl, C ₃ -C ₆ alkenyl, substituted C ₁ -C ₃ alkyl; ₁ -C ₆ alkenyl, alkynyl or substituted alkynyl, be a COR ^C; R ^C is H, C ₁ -C ₄ alkyl, substituted C ₁ -C ₄ alkyl, aryl, substituted aryl, C ₁ ~ R ⁴ is H, halogen, CN, NO ₂ , C ₁ -C ₄ alkoxy, substituted C ₁ -C ₄ alkoxy, C ₁ -C ₄ aminoalkyl or substituted C ₁ -C ₄ aminoalkyl; C ₆ alkyl, substituted C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, substituted C ₁ -C ₆ alkoxy, amino, C ₁ -C ₆ aminoalkyl or substituted C ₁ -C ₆ amino R ⁵ is a component: In it, X is halogen, CN, C ₁ -C ₃ alkyl, substituted C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, substituted C ₁ -C ₃ alkoxy, C ₁ -C ₃ thioalkoxy , Substituted C ₁ ~
C ₃ thioalkoxy, amino, C ₁ -C ₃ aminoalkyl, substituted C ₁ -C ₃ aminoalkyl, NO _2, C ₁ ~C ₃ perfluoroalkyl, 5-membered containing 1 to 3 heteroatoms heterocyclic ring, COR ^D, is selected from the group comprising OCOR ^D or NR ^E COR ^D; R ^D is H, C ₁ -C ₃ alkyl, substituted C ₁ -C ₃ alkyl, aryl, substituted aryl , C ₁ -C ₃ alkoxy, substituted C ₁ -C ₃ alkoxy, C ₁ -C ₃ aminoalkyl or substituted C ₁ -C ₃ aminoalkyl; ^RE is H, C ₁ -C ₃ alkyl Or a substituted C ₁ -C ₃ alkyl; Y and Z are groups comprising H, halogen, CN, NO ₂ , C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkyl or C ₁ -C ₃ thioalkoxy It is independently a substituent selected from; or R ⁵ is O, S, SO, 1,2 or 3 f from the group comprising SO ₂ or NR ⁶ And H has a B atom, halogen, CN, NO _2, 5 or 6 containing one or two independent substituents from the group comprising amino and C ₁ -C ₃ alkyl or C ₁ -C ₃ alkoxy R ⁶ is H or C ₁ -C ₃ alkyl; or a pharmaceutically acceptable salt thereof. 3. Structure: embedded image Where: R¹Is H, C₁~ C₆Alkyl, substituted C₁~ C₆Alkyl, C_Three~ C₈Cycloalkyl
, Replaced C_Three~ C₈Cycloalkyl, aryl, substituted aryl, heterocyclic
, Substituted heterocyclic, COR^AOr NR^BCOR^AAnd R¹And R^TwoIs fused to a spirocyclic alkyl such as a 3-8 membered spirocyclic ring, 3-8
R to form a membered spirocyclic ring¹And R^TwoWhich is constructed by condensing
A substituted spirocyclic alkyl, R to form a 3-8 membered spirocyclic ring¹And R^Two Spirocyclic alkenyl, 3 to 8 membered spirocyclic ring constructed by condensing
To form R¹And R^TwoSpiro ring constructed by condensing
Formula alkenyl, R to form a 3- to 8-membered spirocyclic ring¹And R^TwoCondensing
And contains from 1 to 3 heteroatoms from the group comprising O, S and N.
Pyrocyclic alkyl; R to form a 3- to 8-membered spirocyclic ring¹And R^TwoCondensing
And contains 1-3 heteroatoms from the group comprising O, S and N
R to form a substituted spirocyclic alkyl;¹R^TwoProduced by condensation
These spirocyclic rings are fluorine, C₁~ C₆Alkyl, C₁~ C₆Alkoxy, C₁~
C₆Thioalkyl, -CF_Three, -OH, -CN, NH_Two, -NH (C₁~ C₆Alkyl) or -N (C₁~ C ₆ Alkyl)_TwoR may be optionally substituted with 1-4 groups selected from; ^A Is H, C₁~ C_ThreeAlkyl, substituted C₁~ C_ThreeAlkyl, aryl, substituted
Aryl, C₁~ C_ThreeAlkoxy, substituted C₁~ C_ThreeAlkoxy, C₁~ C_ThreeAminoal
Killed or replaced C₁~ C_ThreeAminoalkyl; R^BIs H, C₁~ C_ThreeAlkyl or substituted C₁~ C_ThreeR is alkyl;^ThreeIs H, OH, NH_Two, C₁~ C₆Alkyl, substituted C₁~ C₆Alkyl, C_Three~ C₆Arche
Nil, substituted C₁~ C₆Alkenyl, alkynyl or substituted alkynyl
, COR^CAnd R^CIs H, C₁~ C_FourAlkyl, substituted C₁~ C_FourAlkyl, aryl, substituted
Aryl, C₁~ C_FourAlkoxy, substituted C₁~ C_FourAlkoxy, C₁~ C_FourAminoal
Killed or replaced C₁~ C_FourAminoalkyl; R^FourIs H, halogen, CN, NO_Two, C₁~ C₆Alkyl, substituted C₁~ C₆Alkyl, C₁ ~ C₆Alkoxy, substituted C₁~ C₆Alkoxy, amino, C₁~ C₆Aminoalkyl
Or replaced C₁~ C₆Aminoalkyl; R^FiveIs a trisubstituted benzene containing substituents X, Y and Z as shown below
Is a ring: X is halogen, CN, C₁~ C_ThreeAlkyl, substituted C₁~ C_ThreeAlkyl, C₁~ C_ThreeAl
Coxy, substituted C₁~ C_ThreeAlkoxy, C₁~ C_ThreeThioalkoxy, substituted C₁~
C_ThreeThioalkoxy, amino, C₁~ C_ThreeAminoalkyl, substituted C₁~ C_ThreeAminoa
Lucil, NO_Two, C₁~ C_ThreePerfluoroalkyl, 5 members containing 1-3 heteroatoms
Heterocyclic ring, COR^D, OCOR^DOr NR^ECOR^DSelected from the group comprising: R^DIs H, C₁~ C_ThreeAlkyl, substituted C₁~ C_ThreeAlkyl, aryl, substituted
Aryl, C₁~ C_ThreeAlkoxy, substituted C₁~ C_ThreeAlkoxy, C₁~ C_ThreeAminoal
Killed or replaced C₁~ C_ThreeAminoalkyl; R^EIs H, C₁~ C_ThreeAlkyl or substituted C₁~ C_ThreeY and Z are H, halogen, CN, NO_Two, C₁~ C_ThreeAlkoxy, C₁~ C_ThreeAlkyl or
C₁~ C_ThreeAn independent substituent selected from the group comprising thioalkoxy; or R^FiveIs O, S, SO, SO_TwoOr NR⁶One, two or three heteroatoms from the group containing
And H, halogen, CN, NO_Two, Amino and C₁~ C_ThreeAlkyl or C₁~ C_ThreeA
5 or 6 members containing 1 or 2 independent substituents from the group comprising lucoxy
A ring; R⁶Is H or C₁~ C_Three2. The compound according to claim 1, which is alkyl;
A pharmaceutically acceptable salt. 4. A compound of the formula: Where: R¹= R^TwoAnd C₁~ C_ThreeAlkyl, substituted C₁~ C_ThreeAlkyl or 3- to 6-membered
Selected from pyrocyclic alkyl rings; R^ThreeIs H, OH, NH_Two, C₁~ C₆Alkyl or substituted C₁~ C₆Alkyl or
COR^CAnd R^CIs H, C₁~ C_FourAlkyl or C₁~ C_FourAlkoxy; R^FourIs H, halogen, CN, NO_Two, C₁~ C_ThreeAlkyl, substituted C₁~ C_ThreeAlkyl, C₁ ~ C_ThreeAlkoxy or substituted C₁~ C_ThreeAlkoxy; R^FiveIs selected from a), b) or c): a) R^FiveIs the component:X is halogen, CN, C₁~ C_ThreeAlkoxy, C₁~ C_ThreeAlkyl, NO_Two, C₁~ C_ThreePerful
Oloalkyl, a 5-membered heterocyclic ring containing 1-3 heteroatoms, or C₁~ C _Three Thioalkoxy; Y is H, halogen, CN, NO_Two, C₁~ C_ThreeAlkoxy, C₁~ C_FourAlkyl or C₁~ C _Three Or thioalkoxy; or b) R^FiveIs the structure:U is O, S or NR⁶X ′ is halogen, CN, NO_TwoOr C₁~ C_ThreeAlkyl and C₁~ C_ThreeIncluding alkoxy
From the group; Y 'is H and C₁~ C_FourFrom the group comprising alkyl; or c) R^FiveIs the structure:X is a 6-membered ring having¹Is N or CX^TwoAnd X^TwoIs halogen, CN, alkoxy or NO_TwoAnd R⁶Is H or C₁~ C_ThreeAlkyl or C₁~ C_Four CO_TwoIs alkyl; having
A compound according to claim 1 or a pharmaceutically acceptable salt thereof. 5. R ⁵ is: 5. The compound of claim 4, wherein the compound is selected from the group of 6. The formula: embedded image Wherein R ¹ and R ² are CH ₃ , or R ¹ and R ² are fused to form an alkyl 6-membered spirocyclic alkyl ring; R ³ is H, OH, NH ₂ , CH ₃ , Substituted methyl, or -COH, CO (C ₁ -C ₃ alkyl
), CO (C ₁ -C ₄ alkoxy); R ⁴ is H, halogen, NO ₂ , CN or C ₁ -C ₃ alkyl; R ⁵ is of the formula: X is selected from the group comprising halogen, CN, methoxy, NO ₂ or 2-thiazole; Y is H or F; or a pharmaceutically acceptable compound thereof. Salt. 7. A compound of the formula: Wherein R ¹ and R ² are CH ₃ , or R ¹ and R ² are fused to form an alkyl 6-membered spirocyclic alkyl ring; R ³ is H, OH, NH ₂ , CH ₃ , Substituted methyl, or -COH, CO (C ₁ -C ₃ alkyl
), CO (C ₁ -C ₄ alkoxy); R ⁴ is H, halogen, NO ₂ , CN or C ₁ -C ₃ alkyl; R ⁵ has the structure: U is O, S or NH, X ′ is halogen, CN or NO ₂ , provided that when U is NH, X ′ is not CN; and Y ′ is H or C ₁ -C ₄ compound or a pharmaceutically acceptable salt of claim 1 having an alkyl. 8. A) 6- (3-chlorophenyl) -4,4-dimethyl-1,4-dihydrobenzo [d] [1,3] oxazin-2-one; b) 6- (3-methoxy- Phenyl) -4,4-dimethyl-1,4-dihydro-benzo [d] [1,3] oxazin-2-one; c) 6- (2-chloro-phenyl) -4,4-dimethyl-1, 4-dihydro-benzo [d] [1,3] oxazin-2-one; d) 6- (4-chloro-phenyl) -4,4-dimethyl-1,4-dihydro-benzo [d] [1, 3] oxazin-2-one; e) 6- (3-chloro-phenyl) -4-methyl-1,4-dihydro-benzo [d] [1,3] oxazine-
2-one; f) 6- (3-chloro-phenyl) -4-ethyl-1,4-dihydro-benzo [d] [1,3] oxazine-
2-one; or g) 6- (3-chloro-phenyl) -4-phenyl-1,4-dihydro-benzo [d] [1,3] oxazin-2-one; 1 compound or a pharmaceutically acceptable salt thereof. 9. A) 3- (4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [
1,3] oxazin-6-yl) -benzonitrile; b) 4,4-dimethyl-6- (3-nitrophenyl) -1,4-dihydrobenzo [d] [1,3] oxazin-2-one C) 6- (3-bromo-5-fluorophenyl) -4,4-dimethyl-1,4-dihydrobenzo [d] [1,
3] oxazin-2-one; d) 3- (4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazine-6-
Yl) -5-fluorobenzonitrile; e) 5- (4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazine-6-
Yl) -nicotinonitrile; f) 4- (4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazine-6-
Yl) -thiophene-2-carbonitrile; g) 5- (4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazine-6-
Yl) -thiophene-2-carbonitrile; h) 5- (4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazine-6-
Yl) -4-methyl-thiophen-2-carbonitrile; i) 4- (4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazine-6-
Yl) -furan-2-carbonitrile; or j) 4,4-diethyl-6- (3-nitrophenyl) -1,4-dihydrobenzo [d] [1,3] oxazin-2-one; Or a pharmaceutically acceptable salt thereof. 10. A) 6- (3-chlorophenyl) -4,4-diethyl-1,4-dihydrobenzo [d] [1,3] oxazin-2-one; b) 6- (3-chlorophenyl) -Spiro [4H-3,, 1-benzoxazine-4,1'-cyclohexane] -2 (1H) -one; c) 6- (3-chlorophenyl) -spiro- [4H-3,, 1-benzoxazine-4 , 1'-cyclopentane] -2 (1H) -one; d) 6- (3-nitrophenyl) -spiro [4H-3,, 1-benzoxazine-4,1'-cyclohexane] -2 (1H)- E) 4-allyl-6- (3-chlorophenyl) -4-methyl-1,4-dihydro-benzo [d] [1,3] oxazin-2-one; f) 6- (3-chlorophenyl) -4-methyl-4-propyn-1-yl-1,4-dihydro-benzo [d
] [1,3] oxazin-2-one; or g) 6- (3-chlorophenyl) -4-ethynyl-4-methyl-1,4-dihydro-benzo [d] [1,3]
2. The compound of claim 1 selected from the group consisting of: oxazin-2-one; or a pharmaceutically acceptable salt thereof. 11. A) 6- (3-chlorophenyl) -4-methyl-4-phenyl-1,4-dihydro-benzo [d] [1,3] oxazin-2-one; b) 4-benzyl- 6- (3-chloro-phenyl) -4-methyl-1,4-dihydro-benzo [d] [1,3]
Oxazin-2-one; c) 6- (3-chloro-phenyl) -4-cyclopropyl-4-methyl-1,4-dihydro-benzo [d
] [1,3] oxazin-2-one; d) 6- (3-chloro-phenyl) -4-cyclopropyl-4-propyn-1-yl-1,4-dihydro
-Benzo [d] [1,3] oxazin-2-one; e) 6- (3-chloro-phenyl) -4,4-dicyclopropyl-1,4-dihydro-benzo [d] [1,3
] Oxazin-2-one; f) 6- (3-chloro-phenyl) -4,4-dipropyn-1-yl-1,4-dihydrobenzo [d] [1,3
] Oxazin-2-one; g) 6- (3-bromo-5-fluorophenyl) -1,4,4-trimethyl-1,4-dihydrobenzo [d
] [1,3] oxazin-2-one; h) 6-chloro-4-methyl-4-trifluoromethyl-1,4-dihydro-benzo [d] [1,3] oxazin-2-one; i ) 6- (3-methoxyphenyl) -4-methyl-4-trifluoromethyl-1,4-dihydro-benzo [d] [1,3] oxazin-2-one; or j) 7- (3-methoxy -Phenyl) -4,4-dimethyl-1,4-dihydro-benzo [d] [1,3] oxazin-2-one; or a pharmaceutically acceptable compound thereof. Salt. 12. A) 6- (3-acetyl-phenyl) -4,4-dityl-1,4-dihydro-
Benzo [d] [1,3] -oxazin-2-one; b) 6- (3-acetyl-phenyl) -4,4-dimethyl-1,4-dihydro-benzo [d] [1,3]- Oxazin-2-one; c) 6- (3-benzoyl-phenyl) -4,4-dimethyl-1,4-dihydro-benzo [d] [1,3] -oxazin-2-one; d) 4, 4-dimethyl-6- [3- (1H-tetrazol-5-yl) -phenyl] -1,4-dihydrobenzo [d] [1,3] oxazin-2-one; e) 4- (4,4 -Dicyclopropyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazin-6-yl) -thiophen-2-carbonitrile; f) 6- (3-bromo-5) -Fluoro-phenyl) -4,4-dicyclopropyl-1,4-dihydrobenzo- [d] [1,3] oxazin-2-one; g) 3- (4,4-dicyclopropyl-2- Oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazin-6-yl) -5-fluoro-benzonitrile; h) 6- (3-bromo-5-methyl-phenyl) -4 , 4-Dimethyl-1,4-dihydrobenzo- [d] [1,
3] oxazin-2-one; i) 6- (3-bromo-5-trifluoromethoxy-phenyl) -4,4-dimethyl-1,4-dihydrobenzo [d] [1,3] -oxazine-2 -One; j) 3- (4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazine-6-
2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: yl) -5-methyl-benzonitrile. (13) a) 3- (4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d
] [1,3] oxazin-6-yl) -5-trifluoromethoxy-benzonitrile; b) 6- (3,5-difluoro-phenyl) -4,4-dimethyl-1,4-dihydrobenzo [d ] [1,3] oxazin-2-one; c) 6- (3,5-dichloro-phenyl) -4,4-dimethyl-1,4-dihydrobenzo [d] [1,3] oxazin-2- On); d) 6- (3,5-bis-trifluoromethyl-phenyl) -4,4-dimethyl-1,4-dihydrobenzo [d] [1,3] oxazin-2-one; e) 3- (4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazine-6-
Yl) -5-methoxy-benzonitrile; f) 6- (3-fluoro-phenyl) -4,4-dimethyl-1,4-dihydro-benzo [d] [1,3] -oxazin-2-one; g) 6- (3-chloro-4-fluoro-phenyl) -4,4-dimethyl-1,4-dihydro-benzo [d] [
1,3] oxazin-2-one; h) 3- (1-diethoxymethyl-4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d]
[1,3] oxazin-6-yl) -5-fluoro-benzonitrile; i) 3-fluoro-5- (1-methoxymethyl-4,4-dimethyl-2-oxo-1,4-dihydro-2H -
Benzo [d] [1,3] oxazin-6-yl) -benzonitrile; j) 3-fluoro-5- (1-methoxymethyl-4,4-dimethyl-2-oxo-1,4-dihydro-2H -
The compound of Claim 1 selected from the group consisting of benzo [d] [1,3] oxazin-6-yl) -benzonitrile; or a pharmaceutically acceptable salt thereof. 14. a) 6- (3-cyano-5-fluoro-phenyl) -4,4-dimethyl-4H-benzo [d] [1,3] oxazin-2-yl ester diethyl ether phosphate; b. ) 3- (4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazine-6-
Yl) -4-fluoro-benzonitrile; c) 6- (3-chloro-4-fluoro-phenyl) -8-fluoro-4,4-dimethyl-1,4-dihydro
-Benzo [d] [1,3] -oxazin-2-one; d) 6- (3-bromo-phenyl) -4,4-dimethyl-1,4-dihydro-benzo [d] [1,3] -Oxazin-2-one; e) 4,4-dimethyl-6- (3-trimethylsilanylethynyl-phenyl) -1,4-dihydro-
Benzo [d] [1,3] oxazin-2-one; f) 6- (3-ethynyl-phenyl) -4,4-dimethyl-1,4-dihydro-benzo [d] [1,3] -oxazine 2-one; g) 3- [3- (4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazine-
6-yl) -phenyl] -propynenitrile; h) 6- (3-fluoro-5-nitro-phenyl) -4,4-dimethyl-1,4-dihydro-benzo [d] [
1,3] oxazin-2-one; i) 6- (3-chloro-5-fluoro-phenyl) -4,4-dimethyl-1,4-dihydro-benzo [d] [
The compound of Claim 1 selected from the group consisting of: 1,3] oxazin-2-one; or a pharmaceutically acceptable salt thereof. 15. A) 3-chloro-5- (4,4-dimethyl-2-oxo-1,4-dihydro-2H
-Benzo [d] [1,3] oxazin-6-yl) -benzonitrile; b) 6- (3,5-dinitro-phenyl) -4,4-dimethyl-1,4-dihydro-benzo [d] [1,3] oxazin-2-one; c) 5- (4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazin-6-yl) -iso Phthalonitrile; d) 4,4-dimethyl-6- (3-thiazol-2-yl-phenyl) -1,4-dihydro-benzo [d] [
1,3] oxazin-2-one; e) 6- (3-fluoro-5-methoxy-phenyl) -4,4-dimethyl-1,4-dihydro-benzo [d
] [1,3] oxazin-2-one; f) 6- (3-fluoro-5-trifluoromethyl-phenyl) -4,4-dimethyl-1,4-dihydro-benzo [d] [1,3 ] Oxazin-2-one; g) 6- (5-bromo-pyridin-3-yl) -4,4-dimethyl-1,4-dihydro-benzo [d] [1,3]
Oxazin-2-one; h) 6- (5-bromo-1-oxy-pyridin-3-yl) -4,4-dimethyl-1,4-dihydro-benzo [d] [1,3] oxazine-2 -One; i) 6- (3-cyano-5-fluoro-phenyl) -4,4-dimethyl-2-oxo-4H-benzo [d] [1
, 3] oxazine-1-carboxylic acid tert-butyl ester; j) 5- (4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazine-6-
2. The compound of Claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: yl) -2-fluoro-benzonitrile. 16. A) 4- (8-Fluoro-4,4-dimethyl-2-oxo-1,4-dihydro-
2H-benzo [d] [1,3] oxazin-6-yl) -thiophen-2-carbonitrile; b) 3-fluoro-5- (8-fluoro-4,4-dimethyl-2-oxo-1, 4-dihydro-2H-benzo
[d] [1,3] oxazin-6-yl) -benzonitrile; c) 5- (4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] Oxazin-6-yl) -thiophen-3-carbonitrile; d) 2- (4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazine-6-
Yl) -thiophen-3-carbonitrile; e) 6- (1,2,4-thiadiazol-3-yl-phenyl) -4,4-dimethyl-1,4-dihydro-benzo [d] [1,3 ] Oxazin-2-one; f) 6- (3-fluoro-5-thiophen-3-yl-phenyl) -4,4-dimethyl-1,4-dihydro
-Benzo [d] [1,3] oxazin-2-one; g) 2- (4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazine- 6-
Yl) -pyrrole-1-carboxylic acid tert-butyl ester; h) 2- (4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazine-6-
Yl) -5-nitro-pyrrole-1-carboxylic acid tert-butyl ester; i) 4,4-dimethyl-6- (5-nitro-1H-pyrrol-2-yl) -1,4-dihydrobenzo [d ] [1,
3] oxazin-2-one; j) 4,4-dimethyl-6- (1H-pyrrol-2-yl) -1,4-dihydro-benzo [d] [1,3] oxazin-2-one; A compound of Claim 1 selected from the group or a pharmaceutically acceptable salt thereof. 17. A) 4,4-dimethyl-6- (1-methyl-1H-pyrrol-2-yl) -1,4-
Dihydro-benzo [d] [1,3] oxazin-2-one; b) 4,4-dimethyl-6- (1-methyl-5-nitro-1H-pyrrol-2-yl) -1,4-dihydro -Benzo [d] [1,3] oxazin-2-one; c) 3- (1,2-dihydro-2-oxospiro [4H-3,1-benzoxazin-4,1-cyclohexane] -6-yl) -Benzonitrile; d) 3- (1,2-dihydro-2-oxospiro [4H-3,1-benzoxazin-4,1-cyclohexane] -6-yl) -5-fluorobenzonitrile; e) 4- ( 1,2-dihydro-2-oxospiro [4H-3,1-benzoxazine-4,1-cyclohexane] -6-yl) -2-thiophenecarbonitrile; f) 5- (1,2-dihydro-2-oxospiro) [4H-3,1-benzoxazine-4,1-cyclohexane] -6-yl) -2-thiophenecarbonitrile; g) 5- (1,2-dihydro-2-oxospiro [4H-3,1-benzoxazine- 4,1-cyclohexane] -6-yl) -4-methyl-2-thiophenecarbonitrile; h) 5- (4,4-dimethyl-2-oxo-1,4-dihydro-2H- Benzo [d] [1,3] oxazine-6-
Yl) -4-ethyl-thiophen-2-carbonitrile; i) 5- (4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazine-6-
2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: yl) -4-n-propyl-thiophen-2-carbonitrile. (18) a) 5- (4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d
] [1,3] oxazin-6-yl) -4-n-butyl-thiophen-2-carbonitrile; b) 6- (4-cyano-3-fluoro) -4,4-dimethyl-1,4- Dihydrobenzo [d] [1,3] -oxazin-2-one; c) 6- (4-fluoro-phenyl) -4,4-dimethyl-1,4-dihydro-benzo [d] [1,3] -Oxazin-2-one; d) 6- (3,4-difluoro-phenyl) -4,4-dimethyl-1,4-dihydro-benzo [d] [1,3]
Oxazin-2-one; e) 6- (2-fluoro-phenyl) -4,4-dimethyl-1,4-dihydro-benzo [d] [1,3] -oxazin-2-one; f) 3- (4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] -oxazine-6-
Yl) phenylacetonitrile; g) 5- (4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] -oxazine-6-
Yl) -furan-2-carbonitrile; h) 5- (4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazine-6-
Yl) -furan-2-carbonitrile; i) 3- (4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazine-6-
2. The compound of Claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: yl) -2-fluoro-benzonitrile. 19. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient. 20. A method of contraception in a mammal, comprising administering a pharmaceutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof to the mammal in need of induction of contraception. How to guide. 21. A hormone-dependent tumor in a mammal, comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof. A method for treating a sexual illness. 22. The hormone-dependent neoplastic disease is myometrial fibroid, endometriosis, benign prostatic hyperplasia; endometrial, ovarian, breast, colon, prostate, pituitary and adenocarcinoma, and meningioma. 22. The method of claim 21 selected from the group of: 23. An estrus in a mammal comprising administering a pharmaceutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof to the mammal in need of estrus synchronization. How to tune.